cas 314268-40-1, METHYL 4-[(4-METHYLPIPERAZIN-1-YL)METHYL]BENZOATE

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Amination of functionally substituted benzaldehydes in the presence of sodium tetrahydroborate: New preparation method for benzylamines
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Ignatovich,Gusak,Kozlov,Koroleva
p. 1573 - 1574
(2007)
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Discovery and Structural Optimization of 4-(Aminomethyl)benzamides as Potent Entry Inhibitors of Ebola and Marburg Virus Infections
The recent Ebola epidemics in West Africa underscore the great need for effective and practical therapies for future Ebola virus outbreaks. We have discovered a new series of remarkably potent small molecule inhibitors of Ebola virus entry. These 4-(aminomethyl)benzamide-based inhibitors are also effective against Marburg virus. Synthetic routes to these compounds allowed for the preparation of a wide variety of structures, including a conformationally restrained subset of indolines (compounds 41-50). Compounds 20, 23, 32, 33, and 35 are superior inhibitors of Ebola (Mayinga) and Marburg (Angola) infectious viruses. Representative compounds (20, 32, and 35) have shown good metabolic stability in plasma and liver microsomes (rat and human), and 32 did not inhibit CYP3A4 nor CYP2C9. These 4-(aminomethyl)benzamides are suitable for further optimization as inhibitors of filovirus entry, with the potential to be developed as therapeutic agents for the treatment and control of Ebola virus infections.
Gaisina, Irina N.,Peet, Norton P.,Wong, Letitia,Schafer, Adam M.,Cheng, Han,Anantpadma, Manu,Davey, Robert A.,Thatcher, Gregory R. J.,Rong, Lijun
p. 7211 - 7225
(2020/09/11)

Synthesis of imatinib, a tyrosine kinase inhibitor, labeled with carbon-14
Imatinib (Gleevec) is a multiple tyrosine kinase inhibitor that decreases the activity of the fusion oncogene called BCR-ABL (breakpoint cluster region protein-Abelson murine leukemia viral oncogene homolog) and is clinically used for the treatment of chronic myelogenous leukemia and acute lymphocytic leukemia. Small molecule drugs, such as imatinib, can bind to several cellular proteins including the target proteins in the cells, inducing undesirable effects along with the effects against the disease. In this study, we report the synthetic optimization for 14C-labeling and radiosynthesis of [14C]imatinib to analyze binding with cellular proteins using accelerator mass spectroscopy. 14C-labeling of imatinib was performed by the synthesis of 14C-labeld 2-aminopyrimidine intermediate using [14C]guanidine·HCl, which includes an in situ reduction of an inseparable byproduct for easy purification by HPLC, followed by a cross-coupling reaction with aryl bromide precursor. The radiosynthesis of [14C]imatinib (specific activity, 631 MBq/mmol; radiochemical purity, 99.6%) was achieved in six steps with a total chemical yield of 29.2%.
Kang, Julie,Lee, Jun Young,Park, Jeong-Hoon,Chang, Dong-Jo
p. 174 - 182
(2020/02/13)

C-3 NOVEL TRITERPENONE WITH C-17 REVERSE AMIDE DERIVATIVES AS HIV INHIBITORS
The present invention relates to C-3 novel triterpenone with C-17 reverse amide compounds of Formula (I); and pharmaceutically acceptable salts thereof, wherein ring Formula (II), R1, R2, R3, R4, R5, R6, R7, 'n' and 'm' are as defined in Formula (I). The invention also relates to C-3 novel triterpenone with C-17 reverse amide derivatives, related compounds, and pharmaceutical compositions useful for the therapeutic treatment of viral diseases and particularly HIV mediated diseases.
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Page/Page column 48; 49

(2018/03/06)

N-phenyl-2-pyrimidine-amine derivatives
The present invention relates to novel amides and a process for preparing these amides.
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Page/Page column 11

(2017/03/14)

With xanthine oxidase inhibitory activity of the compound and use thereof
The invention discloses a compound with xanthine oxidase inhibition activity, and a use thereof. The compound has better blood uric acid content reducing ability than febuxostat, and can be used for treating hyperuricemia and relevant diseases caused by hyperuricemia.
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Paragraph 0060; 0061

(2017/06/19)

COMPOSITIONS AND METHODS FOR INHIBITING KINASES
The present invention provides compounds for the prevention or treatment of cancer or a bacterial or viral infection. Additionally, the present invention provides compositions and methods for using these compounds and compositions in the prevention or treatment of cancer or a bacterial or viral infection in a subject.
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Page/Page column 33; 35

(2016/11/14)

Synthesis and Biopharmaceutical Evaluation of Imatinib Analogues Featuring Unusual Structural Motifs
A convenient synthesis of imatinib, a potent inhibitor of ABL1 kinase and widely prescribed drug for the treatment of a variety of leukemias, was devised and applied to the construction of a series of novel imatinib analogues featuring a number of non-aromatic structural motifs in place of the parent molecule's phenyl moiety. These analogues were subsequently evaluated for their biopharmaceutical properties (e.g., ABL1 kinase inhibitory activity, cytotoxicity). The bicyclo[1.1.1]pentane- and cubane-containing analogues were found to possess higher themodynamic solubility, whereas cubane- and cyclohexyl-containing analogues exhibited the highest inhibitory activity against ABL1 kinase and the most potent cytotoxicity values against cancer cell lines K562 and SUP-B15. Molecular modeling was employed to rationalize the weak activity of the compounds against ABL1 kinase, and it is likely that the observed cytotoxicity of these agents arises through off-target effects.
Nicolaou, Kyriacos C.,Vourloumis, Dionisios,Totokotsopoulos, Sotirios,Papakyriakou, Athanasios,Karsunky, Holger,Fernando, Hanan,Gavrilyuk, Julia,Webb, Damien,Stepan, Antonia F.
supporting information
p. 31 - 37
(2016/01/15)

Combination of 4-anilinoquinazoline, arylurea and tertiary amine moiety to discover novel anticancer agents
In present study, 4-anilinoquinazolines scaffold, arylurea and tertiary amine moiety were combined to design, synthesize gefitinib analogs and discover novel anticancer agents. A series of 4-anilinoquinazoline derivatives (1, 2, 3 and 4) bearing arylurea and tertiary amine moiety at its 6-position were synthesized. Their antiproliferative activities in vitro were evaluated via MTT assay against A431 cell and A549 cell. The SAR of the title compounds was discussed. The compounds 2d, 2i and 2j with potent antiproliferative activities were evaluated their inhibitory activity against EGFR-TK. Compound 2j displayed potent inhibitory activity against EGFR-TK. In addition, compound 2j, at 50 mg/kg, can completely inhibit cancer growth in established nude mouse A549 xenograft model in vivo. These results suggest that the 4-anilinoquinazoline derivatives bearing diarylurea and tertiary amino moiety at its 6-position can serve as anticancer agents and EGFR inhibitors.
Zuo, Sai-Jie,Zhang, Sai,Mao, Shuai,Xie, Xiao-Xiao,Xiao, Xue,Xin, Min-Hnag,Xuan, Wei,He, Yuan-Yuan,Cao, Yong-Xiao,Zhang, San-Qi
p. 179 - 190
(2015/12/31)

3,4-Dihydro-1,3,5-triazin-2(1H)-ones as the First Dual BACE-1/GSK-3β Fragment Hits against Alzheimer's Disease
One of the main obstacles toward the discovery of effective anti-Alzheimer drugs is the multifactorial nature of its etiopathology. Therefore, the use of multitarget-directed ligands has emerged as particularly suitable. Such ligands, able to modulate different neurodegenerative pathways, for example, amyloid and tau cascades, as well as cognitive and neurogenic functions, are fostered to come. In this respect, we report herein on the first class of BACE-1/GSK-3β dual inhibitors based on a 3,4-dihydro-1,3,5-triazin-2(1H)-one skeleton, whose hit compound 1 showed interesting properties in a preliminary investigation. Notably, compound 2, endowed with well-balanced potencies against the two isolated enzymes (IC50 of 16 and 7 μM against BACE-1 and GSK-3β, respectively), displayed effective neuroprotective and neurogenic activities and no neurotoxicity in cell-based assays. It also showed good brain permeability in a pharmacokinetic assessment in mice. Overall, triazinone derivatives, thanks to the simultaneous modulation of multiple points of the diseased network, might emerge as suitable candidates to be tested in in vivo Alzheimer's disease models.
Prati, Federica,De Simone, Angela,Armirotti, Andrea,Summa, Maria,Pizzirani, Daniela,Scarpelli, Rita,Bertozzi, Sine Mandrup,Perez, Daniel I.,Andrisano, Vincenza,Perez-Castillo, Ana,Monti, Barbara,Massenzio, Francesca,Polito, Letizia,Racchi, Marco,Sabatino, Piera,Bottegoni, Giovanni,Martinez, Ana,Cavalli, Andrea,Bolognesi, Maria L.
p. 1665 - 1682
(2015/11/09)

2-ACYLAMINOTHIAZOLES FOR THE TREATMENT OF CANCER
The present invention relates to inhibitors of the oncogenic protein kinase ALK of formula (I) as herein described and pharmaceutical compositions thereof. The compounds of formula (I) are useful in the preparation of a medicament, in particular for the treatment of cancer.
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Page/Page column 68

(2015/01/16)

DIARYLALKYLAMINE REV-ERB ANTAGONISTS AND THEIR USE AS MEDICAMENTS
The present invention relates to compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof : It further discloses a pharmaceutical composition comprising the compounds of Formula (I) and their uses as anti-proliferative and pro-apoptotic agents for cancer therapy.
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Page/Page column 44; 45; 66; 67; 79

(2015/04/28)

Synthesis and in Vitro Anticancer Activity of the First Class of Dual Inhibitors of REV-ERBβ and Autophagy
Autophagy inhibition is emerging as a promising anticancer strategy. We recently reported that the circadian nuclear receptor REV-ERBβ plays an unexpected role in sustaining cancer cell survival when the autophagy flux is compromised. We also identified 4-[[[1-(2-fluorophenyl)cyclopentyl]amino]methyl]-2-[(4-methylpiperazin-1-yl)methyl]phenol, 1 (ARN5187), as a novel dual inhibitor of REV-ERBβ and autophagy. 1 had improved cytotoxicity against BT-474 breast cancer cells compared to chloroquine, a clinically relevant autophagy inhibitor. Here, we present the results of structure-activity studies, based around 1, that disclose the first class of dual inhibitors of REV-ERBβ and autophagy. This study led to identification of 18 and 28, which were more effective REV-ERBβ antagonists than 1 and were more cytotoxic to BT-474. The combination of optimal chemical and structural moieties of these analogs generated 30, which elicited 15-fold greater REV-ERBβ inhibitory and cytotoxic activities compared to 1. Furthermore, 30 induced death in a panel of tumor cell lines at doses 5-50 times lower than an equitoxic amount of chloroquine but did not affect the viability of normal mammary epithelial cells.
Torrente, Esther,Parodi, Chiara,Ercolani, Luisa,De Mei, Claudia,Ferrari, Alessio,Scarpelli, Rita,Grimaldi, Benedetto
supporting information
p. 5900 - 5915
(2015/08/24)

PROTEIN KINASE INHIBITORS
The present invention relates to compounds of the following formula (I) and/or the pharmaceutically acceptable addition salts, solvates, enantiomers, diastereoisomers thereof, as well as mixtures thereof. The subject matter of the present invention thus also includes the preparation of compounds of formula (I), their uses, in particular in the inhibition of protein kinases which are implicated for example in numerous diseases such as cancers or immune system disorders.
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Page/Page column 43

(2014/07/21)

AZAINDOLE DERIVATIVES AS MULTI KINASE INHIBITORS
The present invention relates to compounds of the following formula (I) and/or the pharmaceutically acceptable addition salts, solvates, enantiomers, diastereoisomers thereof, as well as mixtures thereof. The subject matter of the present invention thus also includes the preparation of compounds of formula (I), their uses, in particular in the inhibition of protein kinases which are implicated for example in numerous diseases such as cancers or immune system disorders.
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Page/Page column 48

(2014/07/21)

Preparative synthesis of heterocyclic and aromatic N-benzyl amines
A simple and highly efficient procedure has been proposed for the synthesis of heterocyclic and aromatic N-benzyl amines via reductive amination of substituted aromatic aldehydes in the presence of sodium tetrahydridoborate- acetic acid system generating reactive sodium triacetoxyhydridoborate.
Koroleva,Gusak,Ermolinskaya,Ignatovich
p. 563 - 567
(2013/06/26)

A practical synthesis of 4-[(4-methylpiperazin-1-yl)methyl]benzoic acid - The key precursor toward imatinib
A simple and efficient in situ synthesis of 4-[(4-methylpiperazin-1-yl) methyl]benzoic acid through direct reductive alkylation of 1-methylpiperazine in the presence of triacetoxy sodium borohydride in 95-99% yields is elaborated. The process is easy to scale-up for the large-scale synthesis of 4-[(4-methylpiperazin-1-yl)methyl]benzoic acid as the key synthetic intermediate of imatinib. This method was used for the synthesis of benzyl derivatives of heterocyclic amines in 87-90% yields.
Koroleva, Elena V.,Kadutskii, Aleksey P.,Farina, Alexander V.,Ignatovich, Janna V.,Ermolinskaya, Anastasiya L.,Gusak, Klaudiya N.,Kalinichenko, Elena N.
experimental part
p. 5056 - 5058
(2012/09/25)

Aminomethylation via cyclopalladated-ferrocenylimine-complexes-catalyzed Suzuki-Miyaura coupling of aryl halides with potassium N, N - dialkylaminomethyltrifluoroborates
Using cyclopalladated ferrocenylimine complexes (1-3 mol%) as catalysts, the Suzuki-Miyaura coupling of potassium N,N-dialkylaminomethyltrifluoroborates with aryl and heteroaryl halides were carried out in a 10:1 THF-H2O mixture at 80° in the presence of Cs2CO3 (3.0 equiv) as base, giving the desired cross-coupling products in 14-87% yields. A variety of potassium alkyltrifluoroborates were also examined. Georg Thieme Verlag Stuttgart New York.
Zou, Dapeng,Cui, Hongmeng,Qin, Lijin,Li, Jingya,Wu, Yangjie,Wu, Yusheng
scheme or table
p. 349 - 356
(2011/03/23)

FLUORO-SUBSTITUTED COMPOUNDS AS KINASE INHIBITORS AND METHODS OF USE THEREOF
The present invention provides for novel compounds of Formula I and pharmaceutically acceptable salts and solvates thereof which have kinase inhibitor activity. The present invention further provides for pharmaceutical compositions comprising the same as well as methods of treating and preventing a Bcr-Abl, c-Kit or PDGF-R mediated disorder for which one or more kinase inhibitor is indicated, including neoplasia such as chronic myelogenous leukemia or gastrointestinal stromal tumors. The present invention also provides for processes of making the compounds of Formula I, including salts and solvates thereof, and pharmaceutical compositions comprising the same.
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Page/Page column 24-25

(2011/02/24)

Tricyclononene carboxamide derivatives as novel anti-HIV-1 agents
By modifying the chemical structure of anti-orthopoxvirus compound ST-246, we designed and synthesized a series of tricyclononene carboxamide derivatives and tested their anti-HIV-1 activity and cytotoxicity. We found that benzoimidazol-containing compound 7g was highly effective in inhibiting HIV-1 R5 infection with an IC50 value of 0.41 μM and a selectivity index of 292, but it exhibited no significant inhibitory activity on HIV-1 reverse transcriptase, integrase and protease. CoMFA was used to analyze structure-activity relationships with good predictive power (r2 = 0.921; q2 = 0.582). Moreover, the CoMFA model showed that the length of the molecule, the amide, and the amine moieties all played crucial roles in anti-HIV activity. These results suggest that 7g may serve as a lead for the development of novel anti-HIV-1 therapies. A series of tricyclononene carboxamide derivatives based on anti-orthopoxvirus compound ST-246 were synthesized and characterized as novel anti-HIV-1 agents.
Dong, Ming-Xin,Zhang, Jian,Peng, Xu-Qing,Lu, Hong,Yun, Liu-Hong,Jiang, Shibo,Dai, Qiu-Yun
experimental part
p. 4096 - 4103
(2010/10/02)

Synthesis of imatinib: A convergent approach revisited
A classical convergent approach for the synthesis of the anticancer drug imatinib has been substantially improved. Imatinib was assembled by coupling the amine and carboxylic acid precursors by using N,N′-carbonyldiimidazole (CDI) as a condensing agent. Both intermediates have been synthesized by novel efficient methods.
Ivanov, Andrey S.,Shishkov, Sergey V.
experimental part
p. 619 - 623
(2010/05/02)

Hydrazinopyrimidines as cysteine protease inhibitors
Substituted heteroaryl nitrile derivatives of Formula I, processes for their preparation, pharmaceutical compositions comprising such compounds and use of the compounds as cysteine protease inhibitors are provided.
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Page/Page column 36

(2008/12/04)

PURINES AS CYSTEINE PROTEASE INHIBITORS
Substituted heteroaryl nitrile derivatives of Formula I, processes for their preparation, pharmaceutical compositions comprising such compounds and use of the compounds as cysteine protease inhibitors are provided.
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Page/Page column 47; 48

(2008/12/07)

NOVEL COMPOUNDS
There is provided a compound of formula (I): or a pharmaceutically acceptable salt thereof. There are also provided processes for the manufacture of a compound of Formula 1, and the use of a compound of Formula 1 as a medicament and in the treatment of cancer.
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Page/Page column 121

(2008/12/06)

Interaction of secondary amines with aromatic aldehydes-efficient method for synthesis of the functionalized heterocyclic amines
A method is proposed for the benzylation of secondary heterocyclic amines with functionalized derivatives of benzaldehyde in the presence of formic acid under conditions close to amination according to the Leuckart-Wallach reaction.
Ignatovich,Gusak,Chernikhova,Kozlov,Koroleva
p. 1540 - 1543
(2008/09/20)

NOVEL CYSTEINE PROTEASE INHIBITORS
Substituted heteroaryl nitrile derivatives of Formula (I), processes for their preparation, pharmaceutical compositions comprising such compounds and use of the compounds as cysteine protease inhibitors are provided.
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Page/Page column 47-48

(2010/11/26)

2,4-SUBSTITUTED PYRIMIDINES AS CYSTEINE PROTEASE INHIBITORS
Substituted heteroaryl nitrile derivatives of Formula (I) processes for their preparation, pharmaceutical compositions comprising such compounds and use of the compounds as cysteine protease inhibitors are provided.
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Page/Page column 55-56

(2010/10/20)

USE OF C-KIT INHIBITORS FOR TREATING TYPE II DIABETES
The present invention relates to a method for treating type II diabetes, comprising administering a compound capable of depleting mast cells to a human in need of such treatment. Such compounds can be chosen from non-toxic, selective and potent c-kit inhibitors.
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Page/Page column 83

(2008/06/13)

PYRIDINE DERIVATIVES USEFUL FOR INHIBITING SODIUM/CALCIUM EXCHANGE SYSTEM
Therapeutically active compounds of formula (I) or (II) wherein X is -O-, -CH2- or -C(O)-; Z is -CHR12- or a valence bond; Y is -CH2-, -C(O)-, CH(OR13)-, -O-, -S-; provided that in case Z is a valence bond, Y is not C(O); the dashed line representing an optional double bond in which case Z is -CR12- -and Y is -CH2-, -C(O)- or -CH(OR10)- (in formula II) or -CH- (in formula I); R2 and R3 are independently H, lower alkyl, lower alkoxy, -NO2, halogen, -CF3, -OH, benzyloxy or a group of formula (IIIa). R1 is H, CN, halogen, -CONH2, -COOR15, CH2NR15R18, NHC(O)R5, NHCH2R5, NHR20, NR21R22, NHC(NH)NHCH3 or, in case the compound is of formula (II) wherein the optional double bond exists or in case R2 or R3 is benzyloxy or a group of formula (IIIa) or in case the pyridine ring of formula (I) or (II) is attached to the oxygen atom in 3-, 4- or 5-position, R1 can also be -NO2 or NR16R17; R4 is H, -NO2, CN, halogen, -CONH2, -COOR15, -CH2NR15R18, -NR16R17, NHC(O)R5 or -NHC(NH)NHCH3; R5 is alkyl substituted with 1-3 substituents selected from the group consisting of halogen, amino and hydroxy, or carboxyalkyl, in which the alkyl portion is optionally substituted with 1-3 substituents selected from the group consisting of halogen, amino and hydroxyl, -CHR6NR,R8 or one of the following groups: formula (IVa), (IVb), (IVc), (IVd), (IVe), and pharmaceutically acceptable salts and esters thereof. The compounds are potent inhibitors of Na+/Ca2+ exchange mechanism.
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Page 8; 74

(2008/06/13)

2-(3-AMINOARYL) AMINO-4-ARYL-THIAZOLES AND THEIR USE AS C-KIT INHIBITORS
The present invention relates to the use of masitinib or a pharmaceutically acceptable salt thereof, and in particular of masitinib mesylate, for the preparation of a medicament for the treatment of GIST, to the use of this therapy for the treatment of GIST, and a method of treating mammals, including humans, suffering from GIST by administering to said mammal in need of such treatment an effective dose of masitinib, and in particular masitinib mesylate
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Page 79-80

(2010/11/30)

PIPERAZINE BENZOTHIAZOLES AS AGENTS FOR THE TREATMENT OF CEREBRAL ISCHEMIC DISORDERS OR CNS DISORDERS
The present invention is related to piperazine benzothiazole derivatives, notably for use in the treatment and/or prophylaxis of cerebral ischemic disorders or CNS disorders. The present invention is furthermore related to methods of their preparation.
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Page/Page column 21-22

(2010/02/07)

The ester and amide derivatives of 4-(4-methyl piperazinomethyl) benzoic acid
Synthesis of 4-(4-methyl piperazinomethyl) benzoic acid (1) from a commercially available and inexpensive starting material with enhanced yields. This acid (1) is then further used for the synthesis of the ester and amide.
Sairam,Puranik, Ramachandra,Kelkar, Avijit S.,Sasikiran,Veerender,Parvathi
p. 3597 - 3605
(2007/10/03)

Non-Steroidal Analogues of Veratridine: Model-Based Design, Synthesis and Insecticidal Activity
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Ujvary, Istvan,Polgar, Laszlo,Darvas, Bela,Casida, John E.
p. 96 - 102
(2007/10/03)