- Efficient, Protecting Group Free Kilogram-Scale Synthesis of the JAK1 Inhibitor GDC-4379
-
The development of an improved kilogram-scale synthesis of the JAK1 inhibitorGDC-4379for the treatment of asthma is described. The new process is highlighted by a step-economical construction of a 3-substituted-4-aminopyrazole employing a telescoped oximation and hydrazine condensation of a 1,3-dielectrophile to generate nitrosopyrazole and a novel copper-catalyzed NaBH4reduction of the nitroso group. The endgame process features an amidation of aminopyrazole with acid chloride under Schotten-Baumann conditions to provide access to the penultimate intermediate. A selective N-1 alkylation of the pyrazole moiety was accomplished under phase-transfer conditions, which deliveredGDC-4379with a defined particle-size distribution suitable for micronization after recrystallization and wet milling.
- Angelaud, Remy,Burkhard, Johannes,Gosselin, Francis,Lao, David,Marx, Andreas,Ochsenbein, Miriam,Ranjan, Rohit,Stumpf, Andreas,Xu, Di
-
p. 2537 - 2550
(2021/11/24)
-
- MACROCYCLIC SULFONYLAMIDE DERIVATIVES USEFUL AS NLRP3 INHIBITORS
-
The present invention relates to macrocyclic compounds, such as macrocyclic sulfonyl amides. The present invention further relates to associated salts, solvates, prodrugs and pharmaceutical compositions, and to the use of such compounds in the treatment and prevention of medical disorders and diseases, most especially by NLRP3 inhibition.
- -
-
Page/Page column 164
(2021/02/26)
-
- Discovery and structure ? activity relationship exploration of pyrazolo[1,5-a]pyrimidine derivatives as potent FLT3-ITD inhibitors
-
Internal tandem duplications of FLT3 (FLT3-ITD) occur in approximately 25% of all acute myeloid leukemia (AML) cases and confer a poor prognosis. Optimization of the screening hit 1 from our in-house compound library led to the discovery of a series of pyrazolo[1,5-a]pyrimidine derivatives as potent and selective FLT3-ITD inhibitors. Compounds 17 and 19 displayed potent FLT3-ITD activities both with IC50 values of 0.4 nM and excellent antiproliferative activities against AML cell lines. Especially, compounds 17 and 19 inhibited the quizartinib resistance- conferring mutations, FLT3D835Y, both with IC50 values of 0.3 nM. Moreover, western blot analysis indicated that compounds 17 and 19 potently inhibited the phosphorylation of FLT3 and attenuated downstream signaling in AML cells. These results indicated that pyrazolo[1,5-a]pyrimidine derivatives could be promising FLT3-ITD inhibitors for the treatment AML.
- Chen, Yun,Bai, Gang,Li, Yan,Ning, Yi,Cao, Sufen,Zhou, Jinpei,Ding, Jian,Zhang, Huibin,Xie, Hua,Duan, Wenhu
-
-
- A class of FLT3 kinase inhibitors, preparation and application thereof
-
The invention relates to a class of FLT3 kinase inhibitors, preparation and application thereof, wherein specifically the compound has a structure represented by a formula (I), and all groups and substituents are defined in the specification. The invention also discloses a preparation method of the compound, and application of the compound in inhibition of FLT3.
- -
-
Paragraph 0158; 0161-0164
(2020/06/20)
-
- Design and synthesis of Imidazo[1,2-b]pyridazine IRAK4 inhibitors for the treatment of mutant MYD88 L265P diffuse large B-cell lymphoma
-
Harboring MYD88 L265P mutation triggers tumors growth through the activation of NF-κB by interleukin-1 receptor associated kinase 4 (IRAK4) in diffuse large B-cell lymphoma (DLBCL), highlighting IRAK4 as a therapeutic target for tumors driven by aberrant MYD88 signaling. Herein, we report the design, synthesis, and structure?activity relationships of imidazo[1,2-b]pyridazines as potent IRAK4 inhibitors. The representative compound 5 exhibited excellent IRAK4 potency (IRAK4 IC50 = 1.3 nM) and favorable kinase selectivity profile. It demonstrated cellular selectivity for activated B cell–like (ABC) subtype DLBCL with MYD88 L265P mutation in cytotoxicity assay. The kinase inhibitory efficiency of compound 5 was further validated by Western blot analysis of phosphorylation of IRAK4 and downstream signaling in OCI-LY10 and TMD8 cells. Besides, combination of compound 5 and BTK inhibitor ibrutinib synergistically reduced the viability of TMD8 cells. These results indicated that compound 5 could be a promising IRAK4 inhibitor for the treatment of mutant MYD88 DLBCL.
- Chen, Yun,Bai, Gang,Ning, Yi,Cai, Shi,Zhang, Tao,Song, Peiran,Zhou, Jinpei,Duan, Wenhu,Ding, Jian,Xie, Hua,Zhang, Huibin
-
supporting information
(2020/02/04)
-
- Design, Synthesis, and Evaluation of the Anticancer Properties of a Novel Series of α-(Benzoylamino)-β-substituted Acrylic Amide Derivatives of Pyrazolo[1,5-a]pyrimidine
-
A novel series of α-(benzoylamino)-β-substituted acrylic amide derivatives of pyrazolo[1,5-a]pyrimidine has been synthesized using a convergent multistep synthesis. The synthesized compounds were characterized by 1H NMR, 13C NMR, ESI-MS, and IR analyses. Those new compounds were screened for their in vitro antiproliferative activity using an MTT assay analysis. Out of nine derivatives synthesized in the current study, compounds 13g, 13d, 13h, and 13i exhibited the greatest anticancer activities in HeLa and HepG2 cell lines. The in vitro anticancer activity of compound 13g against HeLa, HepG2, and MCF-7 cell lines is superior to the marketed drugs paclitaxel and SAHA.
- Sasikumar,Mohanasrinivasan,Ajeesh Kumar,Krishnaswamy
-
p. 214 - 225
(2018/01/26)
-
- Synthetic method of pesticide intermediate pyrazole-4-ethyl formate
-
The invention discloses a synthetic method of pesticide intermediate pyrazole-4-ethyl formate. The method comprises the following steps: 1) ethyl cyanoacetate and triethyl orthoformate are placed in a flask, acetic anhydride is added for a reaction, an oil pump is used for performing underpressure distillation to obtain efhylene efhoxymethylene cyanoncetata; 2) efhylene efhoxymethylene cyanoncetata is dissolved in ethanol, hydrazine hydrate is added drop by drop, a solvent is used for underpressure distillation to obtain 3-amino-pyrazoles-4-ethyl formate; and 3) adding pyrazoles-4-ethyl formate and glacial acetic acid are added in a reaction bottle, hydrochloric acid is added drop by drop, a sodium nitrite solution is added drop by drop, after the reaction, ethanol is added for backflow and vacuum concentration, dichloromethane and water are added for stirring and layering, and an organic layer is re-crystallized to obtain the finished product. By employing ester condensation, cyclization and deamination reactions, the preparation technology is simple, and the product is easily purified, production cost is low, and the method is suitable for large-scale industrial production.
- -
-
Paragraph 0009
(2017/06/02)
-
- Synthesis and antiviral activity of sulfonohydrazide and 1,3,4-oxadiazole derivatives of 6,6-dimethyl-9-oxo-4,5,6,7,8,9-hexahydropyrazolo[5,1-b] quinazoline
-
A series of new 6,6-dimethyl-9-oxo-4,5,6,7,8,9-hexahydropyrazolo[5,1-b]quinazoline substituted benzenesulfonohydrazide and 1,3,4-oxadiazole derivatives has been synthesised and characterised using spectral techniques. The antiviral activity of these compounds against an avian paramyxovirus (APMV-1) has been screened and the results show that some of the compounds possess good antiviral activity.
- Selvakumar, Balaraman,Vaidyanathan, Saraswathy P.,Madhuri, Subbiah,Elango, Kuppanagounder P.
-
p. 221 - 224
(2017/06/20)
-
- Design, synthesis and anti-cancer evaluation of a novel series of pyrazolo [1, 5-a] pyrimidine substituted diamide derivatives
-
A novel series of pyrazolo [1, 5-a] pyrimidine substituted diamides has been designed and synthesized using a linear mode multistep synthesis. The synthesized compounds were characterized by 1H NMR, 13C NMR, ESI-MS and IR analyses. These new compounds were screened for their in vitro antiproliferative activity using an MTT assay. Out of 23 derivatives synthesized in the current study, compounds 10q, 10u and 10w showed good anticancer activity against HeLa cell line. Furthermore, these derivatives gave IC50 values of less than 10 μM against HeLa cell and were therefore more potent than the marketed anticancer drug cis-platin (17.83 μM).
- Ajeesh Kumar,Bodke, Yadav D.,Lakra, Peter Serjious,Sambasivam, Ganesh,Bhat, Kishore G.
-
p. 714 - 744
(2017/03/06)
-
- Design, Synthesis, and Evaluation of the Anticancer Properties of a Novel Series of Imidazolone Fused Pyrazolo[1,5-a]pyrimidine Derivatives
-
A novel series of imidazolone fused pyrazolo[1,5-a]pyrimidine derivatives has been designed and synthesized using a convergent approach, and the structures of these compounds were confirmed by 1H NMR, 13C NMR, ESI-MS, and IR analyses. These new compounds were tested for their in vitro antiproliferative activity using an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Out of the 20 derivatives prepared in the current study, compounds 8h, 8n, and 8r exhibited good anticancer activities tested against HeLa cells and HepG2 cells. However, the in vitro anticancer activity of compound 8r against HeLa, HepG2, and MCF-7 cell lines is superior to the marketed drugs Paclitaxel and SAHA.
- Ajeesh Kumar,Bodke, Yadav D.,Gowda, Ashwath N.,Sambasivam, Ganesh,Bhat, Kishore G.
-
p. 1904 - 1924
(2017/05/29)
-
- Substituted heteroaryl compounds and compositions and uses thereof
-
The invention discloses a substituted ceteroary compound as well as a composition and an application thereof. The compound is a compound shown in a formula (I) or a stereisomer, a tautomer, a nitric oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or prodrug of the compound shown in the formula (I). The invention further discloses a pharmaceutical composition including the compound. The compound and the pharmaceutical composition are capable of adjusting the activity of the AK kinase and can be used for preventing, processing, treating and relieving the JAK-mediated disease or disorder.
- -
-
-
- Synthesis method of 5-(4-fluorophenyl)-N-(3-(dimethylamino) propyl)-7-trifluoromethyl pyrazol[1, 5-a] pyrimidine-3-amide
-
The invention discloses a synthesis method of 5-(4-fluorophenyl)-N-(3-(dimethylamino) propyl)-7-trifluoromethyl pyrazol[1, 5-a] pyrimidine-3-amide. The synthesis method includes: using arone which is low in cost and easy to obtain as a starting raw material; synthesizing arone and para-trifluoromethyl ethyl acetate into an intermediate-aryl butanedione, adding glacial acetic acid and aminopyrazol, and heating for backflow to generate a target intermediate; hydrolyzing to obtain 5-aryl-7-substitutent pyrazol[1, 5-a] pyrimidine acid, and obtaining a target product through condensation reaction. Through continuous reaction of condensation and cyclization, 5-(4-fluorophenyl)-N-(3-(dimethylamino) propyl)-7-trifluoromethyl pyrazol[1, 5-a] pyrimidine-3-amide is synthesized with high yield. The synthesis method is simple and convenient to operate and high in yield, and the product is easy to purify.
- -
-
Paragraph 0048-0053
(2017/05/27)
-
- Synthesis method of 2-(5-(4-fluorophenyl)-7-trifluoromethylpyrazolo[1,5-a]pyrimidine-3-amide)diethyl glutarate
-
The invention discloses a synthesis method of 2-(5-(4-fluorophenyl)-7-trifluoromethylpyrazolo[1,5-a]pyrimidine-3-amide)diethyl glutarate. The method takes aryl ketone which is cheap and easy to obtain as a starting raw material, and a synthesis route comprises the following steps: synthesizing an intermediate aryl butanedione by aryl ketone and p-trifluoromethyl ethyl acetate; adding glacial acetic acid and amino-pyrazole, and heating and reflowing to generate a target intermediate; hydrolyzing to obtain 5-aryl-7-substituent pyrazolo[1,5-a]pyrimidine acid; and finally, carrying out a condensation reaction to obtain a target product. By carrying out condensation and closed-ring two-step continuous reaction, 2-(5-(4-fluorophenyl)-7-trifluoromethylpyrazolo[1,5-a]pyrimidine-3-amide)diethyl glutarate is synthesized at a relatively high yield. The method is simple and convenient to operate, the yield is relatively high, and the product is easy to purify.
- -
-
Paragraph 0048; 0049; 0050; 0051; 0052; 0053
(2017/10/14)
-
- Synthesis method of 5-(4-fluorophenyl)-N-morpholinyl-7-trifluoromethylpyrazolo[1,5-a]pyrimidyl-3-amide
-
The invention discloses a synthesis method of 5-(4-fluorophenyl)-N-morpholinyl-7-trifluoromethylpyrazolo[1,5-a]pyrimidyl-3-amide. By using the cheap accessible arone as the initial raw material, the synthesis route comprises the following steps: synthesizing an intermediate aryl butanedione from aryl ketone and ethyl p-trifluoromethylacetate, adding glacial acetic acid and amino pyrazole, and heating under reflux to generate a target intermediate; hydrolyzing to obtain 5-aryl-7-substituted-pyrazolo[1,5-a]pyrimidine acid; and finally, carrying out condensation reaction to obtain the target product. By using the condensation-cyclization two-step continuous reaction, the 5-(4-fluorophenyl)-N-morpholinyl-7-trifluoromethylpyrazolo[1,5-a]pyrimidyl-3-amide is synthesized at higher yield. The method is simple to operate and higher in yield, and can easily purify the product.
- -
-
Paragraph 0048; 0049; 0050; 0051; 0052; 0053
(2017/10/21)
-
- Synthesis method of 5-(4-fluorophenyl)-N, N-dimethyl-7-trifluoromethylpyrazol[1, 5-a] pyrimidine-3-amide
-
The invention discloses a synthesis method of 5-(4-fluorophenyl)-N, N-dimethyl-7-trifluoromethylpyrazol[1, 5-a] pyrimidine-3-amide. The synthesis method includes: using arone which is low in cost and easy to obtain as a starting raw material; synthesizing arone and para-trifluoromethyl ethyl acetate into an intermediate-aryl butanedione, adding glacial acetic acid and aminopyrazol, and heating for backflow to generate a target intermediate; hydrolyzing to obtain 5-aryl-7-substitutent pyrazol[1, 5-a] pyrimidine acid, and obtaining a target product through condensation reaction. Through continuous reaction of condensation and cyclization, 5-(4-fluorophenyl)-N, N-dimethyl-7-trifluoromethylpyrazol[1, 5-a] pyrimidine-3-amide is synthesized with high yield. The synthesis method is simple and convenient to operate and high in yield, and the product is easy to purify.
- -
-
Paragraph 0047-0052
(2018/02/04)
-
- Method for synthesizing 5-arylpyrazole [1, 5-alpha] pyrimindine derivatives
-
The invention discloses a method for synthesizing 5-arylpyrazole [1, 5-alpha] pyrimindine derivatives. Inexpensive and easily available arone is used as a starting material. The method includes synthetic paths of synthesizing aryl ketone and phenyl acetic acid ethyl acetate to obtain aryl diacetyl which is an intermediate, adding glacial acetic acid and aminopyrazole into the aryl diacetyl and carrying out heating reflux to generate a target intermediate; hydrolyzing the target intermediate to obtain 5-aryl-7-substituent pyrazole [1, 5-alpha] pyrimindine acid; ultimately carrying out condensation reaction to obtain target products. The method has the advantages that a series of 5-aryl-substituted pyrazole [1, 5-alpha] pyrimindine compounds with high yields can be synthesized via condensation and ring closing two-step continuous reaction; the method is easy and convenient to implement and high in yield, and the products are easy to purify.
- -
-
Page/Page column 6; 7; 23
(2018/02/04)
-
- 5 - (4-fluoro phenyl)-N - (4-chloro-ethyl) - 7-trifluoromethyl-pyrazolo [1,5-a] pyrimidine-3-carboxamide synthesis method (by machine translation)
-
The present invention discloses the 5 [...] (the 4 [...] phenyl)-N - (the 4 [...] paradichlorbenzene ethyl) - 7 the [...] trifluoromethyl-pyrazolo [1,5 the ??a] pyrimidine -3 the method for synthesizing amide of [...], the method uses the cheap and easily obtained arone as the starting material, the synthesis route to ketones with the trifluoromethyl ethyl acetate synthetic intermediate aryl diacetyls, by adding glacial acetic acid and Aminopyrazole, heating to reflux to generate the target intermediate. After hydrolysis of the 5 [...] aryl -7 the substituted pyrazoles and [...] [1, the 5 ??a] pyrimidine acid, the final condensation reaction to obtain the target product. This invention, through condensation, ring two-step continuous reaction, at a high yield of the synthesis of the 5 [...] (the 4 [...] phenyl)-N - (the 4 [...] paradichlorbenzene ethyl) - 7 the [...] trifluoromethyl-pyrazolo [1,5 the ??a] pyrimidine -3 the amide [...]. The method is simple and convenient to operate, the yield is high, the product can be easily purified. (by machine translation)
- -
-
Paragraph 0048-0053
(2018/02/04)
-
- 5 - (4-fluoro phenyl) - 7-trifluoromethyl-pyrazolo [1,5-a] pyrimidine-3-carboxylic acid ethyl ester synthesis method (by machine translation)
-
The present invention discloses the 5 [...] (the 4 [...] phenyl) - 7 the [...] trifluoromethyl-pyrazolo [1,5 the ??a] pyrimidine -3 the method for synthesizing [...] carboxylic acid ethyl ester, the method uses the cheap and easily obtained arone as the starting material, synthetic intermediates first 5 the amino- [...] the 1H [...] pyrazole -4 the and the intermediate carboxylic acid ethyl ester [...] the 1 [...] P-phenyl -4, 4, 4, -trifluoro diacetyls; then the synthesis intermediate for synthesis of the 5 [...] (the 4 [...] phenyl) - 7 the [...] trifluoromethyl-pyrazolo [1,5 the ??a] pyrimidine -3 the [...] carboxylic acid ethyl ester. This invention, in order to synthesize a high yield the 5 [...] (the 4 [...] phenyl) - 7 the [...] trifluoromethyl-pyrazolo [1,5 the ??a] pyrimidine -3 the [...] carboxylic acid ethyl ester. The method is simple and convenient to operate, the yield is high, the product can be easily purified. (by machine translation)
- -
-
Paragraph 0031; 0035
(2016/12/01)
-
- Design, synthesis, and evaluation of the anticancer properties of a novel series of carboxamides, sulfonamides, ureas, and thioureas derived from 1,2,4-oxadiazol-3-ylmethyl-piperazin-1-yl substituted with pyrazolo[1,5-a]pyrimidine derivatives
-
Abstract: A series of novel carboxamides, sulfonamides, ureas, and thioureas derived from 1,2,4-oxadiazol-3-ylmethyl-piperazin-1-yl substituted with pyrazolo[1,5-a]pyrimidine analog were designed and synthesized. The newly synthesized compounds were characterized by 1H NMR, 13C NMR, ESI–MS, and IR and were tested for their in vitro antiproliferative activity by MTT assay. Out of these twenty derivatives, five compounds showed good anticancer activity against HeLa cell line. These are superior with less than 10?μg/cm3 of IC50 when compared to the marketed anticancer drug paclitaxel with 30?μg/cm3 of IC50 against Hela cell line. Graphical abstract: [Figure not available: see fulltext.]
- Ajeesh Kumar,Nair, Kanya B.,Bodke, Yadav D.,Sambasivam, Ganesh,Bhat, Kishore G.
-
p. 2221 - 2234
(2016/11/17)
-
- Synthesis method of 5-(4-fluorophenyl)-N-1-(3-hydroxyadamantyl)-7-trifluoromethylpyrazolo[1,5-a]pyrimidyl-3-amide
-
The invention discloses a synthesis method of 5-(4-fluorophenyl)-N-1-(3-hydroxyadamantyl)-7-trifluoromethylpyrazolo[1,5-a]pyrimidyl-3-amide. By using the cheap accessible arone as the initial raw material, the synthesis route comprises the following steps: synthesizing an intermediate aryl butanedione from aryl ketone and ethyl p-trifluoromethylacetate, adding glacial acetic acid and amino pyrazole, and heating under reflux to generate a target intermediate; hydrolyzing to obtain 5-aryl-7-substituted-pyrazolo[1,5-a]pyrimidine acid; and finally, carrying out condensation reaction to obtain the target product. By using the condensation-cyclization two-step continuous reaction, the 5-(4-fluorophenyl)-N-1-(3-hydroxyadamantyl)-7-trifluoromethylpyrazolo[1,5-a]pyrimidyl-3-amide is synthesized at higher yield. The method is simple to operate and higher in yield, and can easily purify the product.
- -
-
Paragraph 0048; 0049; 0050; 0051; 0052; 0053
(2016/10/17)
-
- An efficient synthesis of pyrazolo[1,5-a]pyrimidines and evaluation of their antimicrobial activity
-
A series of new pyrazolo[1,5-a]pyrimidine derivatives has been synthesized by using 7-hydrazinyl- 5-methylpyrazolo[1,5-a]pyrimidine-3-carbonitrile 1 and 7-amino-5-methylpyrazolo[1,5-a]pyrimidine-3-carbonitrile 2 as precursors. The pyrazolo[3,4-d] pyrimidines 3a–b have been synthesized by a three-step reaction starting with 1. Compound 1 was utilized for the synthesis of dioxopyrrolidindolinylamio-pyrazolo-pyrimidines 4a–b, and dioxoisoindolin-pyrazolo-pyrimidines 4c–d. Also, compounds 4a-dwere synthesized using deep eutectic solvents (DES). This method using DES provides several advantages such as benign environment, high yield, scalable and simple work-up procedure. Similarly, the cyclocondensation of 2 with α-acetyl- γ-butyrolactone afforded pyrazolo-pyrido-pyrimidine 5 and dihydrofuro-pyrido-pyrazolo-pyrimidine 6. All synthesized compounds were screened for antimicrobial activity. [Figure not available: see fulltext.]
- Deshmukh, Someshwar,Dingore, Kunal,Gaikwad, Vishwas,Jachak, Madhukar
-
p. 1459 - 1468
(2016/09/19)
-
- THERAPEUTIC COMPOUNDS AND USES THEREOF
-
The present invention relates to compounds formula (I): and to salts thereof, wherein R1-R4 and A have any of the values defined in the specification, and compositions and uses thereof. The compounds are useful as inhibitors of histone demethylases, such as KDM5. Also included are pharmaceutically acceptable compositions comprising the compounds of the present invention and methods of using said compositions in the treatment of various disorders.
- -
-
Paragraph 0429; 0430
(2015/03/16)
-
- SUBSTITUTED HETEROARYL COMPOUNDS AND METHODS OF USE
-
The present invention provides novel heterocyclic compounds, pharmaceutical acceptable salts and formulations thereof useful in preventing, treating or lessening the severity of a JAK-mediated disease. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of JAK-mediated disease.
- -
-
-
- Facile synthesis of 1H-imidazo[1,2-b]pyrazoles via a sequential one-pot synthetic approach
-
5-Aminopyrazole-4-carbonitrile and ethyl 5-aminopyrazole-4-carboxylate, as potential trifunctional building blocks are introduced in a facile, chemo- and regioselective multicomponent assembly of imidazo[1,2-b]pyrazoles via the Groebke-Blackburn-Bienaym reaction (GBB reaction). Besides the synthetic elaboration of a green-compatible isocyanide-based access in three-component mode, we describe an operationally simple, one-pot two-step GBB protocol for the rapid construction of a 46 membered imidazo[1,2- b ] pyrazole library with yields up to 83%.
- Demjn, Andrs,Gyuris, Mri,W?lfling, Jnos,Pusks, Lszl G.,Kanizsai, Ivn
-
supporting information
p. 2338 - 2344
(2014/12/12)
-
- HETEROCYCLIC COMPOUNDS FOR THE INHIBITION OF PASK
-
Disclosed herein are new heterocyclic compounds and compositions and their application as pharmaceuticals for the treatment of disease. Methods of inhibiting PAS Kinase (PASK) activity in a human or animal subject are also provided for the treatment of diseases such as diabetes mellitus.
- -
-
-
- Fused 3-hydroxy-3-trifluoromethylpyrazoles inhibit mutant huntingtin toxicity
-
Here, we describe the selection and optimization of a chemical series active in both a full-length and a fragment-based Huntington's disease (HD) assay. Twenty-four thousand small molecules were screened in a phenotypic HD assay, identifying a series of compounds bearing a 3-hydroxy-3- trifluoromethylpyrazole moiety as able to revert the toxicity induced by full-length mutant Htt by up to 50%. A chemical exploration around the series led to the identification of compound 4f, which demonstrated to be active in a Htt171-82Q rat primary striatal neuron assay and a PC12-Exon-1 based assay. This compound was selected for testing in R6/2 mice, in which it was well-tolerated and showed a positive effect on body weight and a positive trend in preventing ventricular volume enlargment. These studies provide strong rationale for further testing the potential benefits of 3-hydroxy-3-trifluoromethylpyrazoles in treating HD.
- La Rosa, Salvatore,Benicchi, Tiziana,Bettinetti, Laura,Ceccarelli, Ilaria,Diodato, Enrica,Federico, Cesare,Fiengo, Pasquale,Franceschini, Davide,Gokce, Ozgun,Heitz, Freddy,Lazzeroni, Giulia,Luthi-Carter, Ruth,Magnoni, Letizia,Miragliotta, Vincenzo,Scali, Carla,Valacchi, Michela
-
supporting information
p. 979 - 984
(2013/10/22)
-
- Discovery of tetrahydropyrazolopyrimidine carboxamide derivatives as potent and orally active antitubercular agents
-
Tetrahydropyrazolo[1,5-a]pyrimidine scaffold was identified as a hit series from a Mycobacterium tuberculosis (Mtb) whole cell high through-put screening (HTS) campaign. A series of derivatives of this class were synthesized to evaluate their structure-activity relationship (SAR) and structure-property relationship (SPR). Compound 9 had a promising in vivo DMPK profile in mouse and exhibited potent in vivo activity in a mouse efficacy model, achieving a reduction of 3.5 log CFU of Mtb after oral administration to infected mice once a day at 100 mg/kg for 28 days. Thus, compound 9 is a potential candidate for inclusion in combination therapies for both drug-sensitive and drug-resistant TB.
- Yokokawa, Fumiaki,Wang, Gang,Chan, Wai Ling,Ang, Shi Hua,Wong, Josephine,Ma, Ida,Rao, Srinivasa P. S.,Manjunatha, Ujjini,Lakshminarayana, Suresh B.,Herve, Maxime,Kounde, Cyrille,Tan, Bee Huat,Thayalan, Pamela,Ng, Seow Hwee,Nanjundappa, Mahesh,Ravindran, Sindhu,Gee, Peck,Tan, Maria,Wei, Liu,Goh, Anne,Chen, Pei-Yu,Lee, Kok Sin,Zhong, Chen,Wagner, Trixie,Dix, Ina,Chatterjee, Arnab K.,Pethe, Kevin,Kuhen, Kelli,Glynne, Richard,Smith, Paul,Bifani, Pablo,Jiricek, Jan
-
supporting information
p. 451 - 455
(2013/07/11)
-
- HETEROCYCLIC COMPOUNDS FOR THE INHIBITION OF PASK
-
Disclosed herein are new heterocyclic compounds and compositions and their application as pharmaceuticals for the treatment of disease. Methods of inhibiting PAS Kinase (PASK) activity in a human or animal subject are also provided for the treatment of diseases such as diabetes mellitus.
- -
-
Page/Page column 18
(2012/11/08)
-
- Application of Ullmann and Ullmann-Finkelstein reactions for the synthesis of N-aryl-N-(1H-pyrazol-3-yl) acetamide or N-(1-aryl-1H-pyrazol-3-yl) acetamide derivatives and pharmacological evaluation
-
Ullmann-type reactions are becoming a major tool in medicinal chemistry. In this article, we describe the use of these Copper-catalyzed reactions with various precursors, acyl-heteroarylamines or pyrazoles of interest for pharmacomodulation. To the medicinal chemist they offer new, usually untapped disconnection approaches to compounds of interest. They thus open the way to new original analogues of bioactive compounds possibly not patented, from common building-blocks. They also allow C to N bioisosteric replacements, which sometimes are synthetically challenging. We report for the first time the critical effect of acetylamino substituents on the regioselective arylation of unsymmetrical pyrazoles that are useful for medicinal chemists. Finally, we have applied this strategy to the design of novel AT1 receptor antagonists. Though this family has been extensively investigated in the past 30 years, N-arylation and C to N replacement made possible by Ullmann chemistry, can produce original antagonists.
- Deprez-Poulain, Rebecca,Cousaert, Nicolas,Toto, Patrick,Willand, Nicolas,Deprez, Benoit
-
experimental part
p. 3867 - 3876
(2011/11/12)
-
- PROCESS FOR THE PREPARATION OF A PYRAZOLE DERIVATIVE
-
Disclosed here is a process for the preparation of 3 - amino pyrazole derivative of Formula (I) where R1 = H, C1 - C4 alkyl group or benzyl group or phenyl group; R2 = C1 - C6 alkyl group or benzyl group; comprising a step of reacting the compound of Formula (Ill) with hydrazine hydrate.
- -
-
Page/Page column 7-8
(2011/06/23)
-
- Synthesis of pyrazolo[5,1-d][1,2,3,5]tetrazine-4(3H)-ones
-
A solid-phase synthesis of 5-aminopyrazole has been developed and applied to the preparation of pyrazolo[5,1-d]-[1,2,3,5]tetrazine-4(3H)-ones. In this strategy, a one-pot reaction from 5-aminopyrazoles to the pyrazolo[5,1-d]-[1,2, 3,5]tetrazine-4(3H)-ones which provided the compounds in good yields was demonstrated. Using this synthetic strategy, we prepared a representative set of 16 pyrazolo[5,1-d][l,2,3,5]tetrazine-4(3H)-ones.
- Gao, Yaojun,Lam, Yulin
-
experimental part
p. 69 - 74
(2010/10/04)
-
- Synthesis of 3-substituted-1-methyl-1H-thieno[2,3-c]pyrazoles
-
We report a simple and practical six-step synthesis of new 1-methyl-1H-thieno[2,3-c]pyrazoles from 3-amino-1H-pyrazole-4-carboxylic acid ethyl ester. Copyright Taylor & Francis Group, LLC.
- Toto, Patrick,Chenault, Jacques,Hakmaoui, Ahmed El,Akssira, Mohamed,Guillaumet, Gerald
-
p. 674 - 683
(2008/09/16)
-
- Rapid hit to lead evaluation of pyrazolo[3,4-d]pyrimidin-4-one as selective and orally bioavailable mGluR1 antagonists
-
Our HTS effort yielded a preferential mGluR1 pyrimidinone antagonist 1 with lead-like characteristics. Rapid hit to lead (HTL) study identified compounds with improved functional activity and selectivity such as 1b with little improvements in ADME properties. Addition of an aminosulfonyl group on the N-1 aromatic ring led to 2f, a compound with similar in vitro biochemical profiles as those of 1b but drastically improved in vitro ADME properties. These improvements were paralleled by rat PK study characterized by low clearance and quantitative bioavailability. Compound 2f represented a true lead-like molecule that is amenable for further lead optimization (LO) evaluation.
- Wang, Xueqing,Kolasa, Teodozyi,El Kouhen, Odile F.,Chovan, Linda E.,Black-Shaefer, Candace L.,Wagenaar, Frank L.,Garton, Jennifer A.,Moreland, Robert B.,Honore, Prisca,Lau, Yau Yi,Dandliker, Peter J.,Brioni, Jorge D.,Stewart, Andrew O.
-
p. 4303 - 4307
(2008/03/14)
-
- Design, synthesis, and structure - Activity relationship studies of ATP analogues as DNA gyrase inhibitors
-
We report herein the design and synthesis of ATP-analogues, namely 4-amino-pyrazolo[3,4-d]pyrimidines and 4-amino-pyrazolo[1,5-a][1,3,5]triazines, with DNA gyrase inhibitory activity. Among these series, some compounds exhibited promising antibacterial activity. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Luebbers, Thomas,Angehrn, Peter,Gmuender, Hans,Herzig, Silvia,Kulhanek, Josef
-
p. 821 - 826
(2007/10/03)
-
- Pyrazole derivatives and their pharmaceutical use
-
The present invention relates to a pyrazole derivative represented by formula (I) or (II) STR1 wherein R1 is hydrogen C2-C6 alkyl benzyl or phenyl; each of R2 and R3 is hydrogen, C1-C6 alkyl or benzyl; each of R4 and R5 is hydrogen, C1-C6 alkyl, C3-C6 alkenyl, C3-C8 cycloalkyl, benzyl or phenyl; X is oxygen or sulfur; R5 is hydrogen, C2-C6 alkyl, C3-C6 alkenyl, C3-C8 cycloalkyl or benzyl when R1 is benzyl, R2 is ethyl, R3 is hydrogen, and R4 is hydrogen, and its pharmaceutical use.
- -
-
-