- Efficient synthesis of 7-substituted or 3,7-disubstituted 1H-indazoles
-
This work reports on the synthesis of the novel indazole scaffolds 7-OTf-1H-indazole (trifluoromethanesulfonic acid 1H-indazol-7-yl ester), 7-iodo-1H-indazole and 3-bromo-7-iodo-1H-indazole. These new compounds are potent building blocks in divergent syntheses of indazoles via palladium cross-coupling reactions. Georg Thieme Verlag Stuttgart.
- Cottyn, Betty,Vichard, Dominique,Terrier, Fran?ois,Nioche, Pierre,Raman
-
-
Read Online
- Synthesis and biological evaluation of indazole-4,7-dione derivatives as novel BRD4 inhibitors
-
Bromodomain-containing protein 4 (BRD4) is known to regulate the expression of c-Myc to control the proliferation of cancer cells. Therefore, development of small-molecule inhibitors targeting the bromodomain has been widely studied. However, some clinical trials on BRD4 inhibitors have shown its drawbacks such as toxicity including the loss of organ weight. Here, we report the development of the novel and promising scaffold, 1H-indazol-4,7-dione, as a bromodomain inhibitor and synthesized derivatives for the inhibition of binding of bromodomain to acetylated histone peptide. Through this effort, we obtained 6-chloro-5-((2,6-difluorophenyl)amino)-1H-indazole-4,7-dione (5i), which showed a highly potent activity with a half-maximal inhibitory concentration (IC50) of 60?nM. The in vivo xenograft assay confirmed that the 1H-indazol-4,7-dione compound reduced the tumor size significantly. These results show that the 1H-indazol-4,7-dione scaffold is highly potent against bromodomain.
- Yoo, Minjin,Yoo, Miyoun,Kim, Ji Eun,Lee, Heung Kyoung,Lee, Chong Ock,Park, Chi Hoon,Jung, Kwan-Young
-
-
Read Online
- Synthesis of new α-amino-1H indazolyl-phosphonate derivatives: Crystal structure, Hirshfeld surface analysis and DFT studies
-
A new α-amino-1H Indazolyl-phosphonates derivative 3a–e were synthesized and subjected to solid state characterization by single-crystal X-ray diffraction analysis, and to study their NMR and Hirshfeld surface analysis. The P atom exhibits tetrahedral geometry involving two O-ethyl groups, a C atom and a double-bonded O atom. The P–C bond has an approximately staggered conformation, with the aniline and substituted groups in gauche positions with respect to the P[dbnd]O double bond. The molecules are arranged as centrosymmetric or pseudocentrosymmetric dimers connected by two N–H?O[dbnd]P hydrogen bonds and also by C–H … π interaction in the case of structures 3a–e, which are responsible for the formation and stability of the molecular assemblies. Hirshfeld surface analysis (dnorm surface and two-dimensional (2D) fingerprint plots) revealed the nature of intermolecular contacts. The most important contributions for the crystal packing are from H?H, H?C/C?H, O?H/H?O, and H?N/N?H interactions. In addition, frontier molecular orbitals and Molecular Electrostatic Potential map of the compounds was produced by using the optimized structures.
- Ihammi, Aziz,Chigr, Mohammed,Ketatni, El Mostafa,Saadi, Mohamed,El Ammari, Lahcen,Rakib, El Mostapha
-
-
Read Online
- N'-hydroxyindazolecarboximidamide derivatives, optical isomer thereof, or pharmaceutically acceptable salts thereof, and, a anticancer composition containing the same as an active ingredient
-
A Nandprime;-hydroxyindazolecarboxyimidamide derivative compound, which is a pharmaceutical composition for anticancer medicine according to the present invention, an optical isomer thereof or a pharmaceutically acceptable salt thereof have excellent effect of inhibiting indoleamine 2,3-dioxygenase-1, and thus can be usefully used as an anticancer pharmaceutical composition.COPYRIGHT KIPO 2019
- -
-
Paragraph 0070; 0073; 0074
(2019/02/16)
-
- Synthesis and molecular modeling studies of N-Hydroxyindazolecarboximidamides as novel indoleamine 2,3-Dioxygenase 1 (IDO1) inhibitors
-
Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive enzyme that is highly overexpressed in various cancer cells and antigen-presenting cells. It has emerged as an attractive therapeutic target for cancer immunotherapy, which has prompted high interest in the development of small-molecule inhibitors. To discover novel IDO1 inhibitors, we designed and synthesized a series of N-hydroxyindazolecarboximidamides. Among the compounds synthesized, compound 8a inhibited both tryptophan depletion and kynurenine production through the IDO1 enzyme. Molecular docking studies revealed that 8a binds to IDO1 with the same binding mode as the analog, epacadostat (INCB24360). Here, we report the synthesis and biological evaluation of these hydroxyindazolecarboximidamides and present the molecular docking study of 8a with IDO1.
- Lee, Dong-Ho,Lee, Joo-Youn,Jeong, Jieun,Kim, Miok,Lee, Kyung Won,Jang, Eunseo,Ahn, Sunjoo,Lee, Chang Hoon,Hwang, Jong Yeon
-
-
- Synthesis, antiproliferative and apoptotic activities of N-(6(4)-indazolyl)-benzenesulfonamide derivatives as potential anticancer agents
-
Recently, it has been reported that compounds bearing a sulfonamide moiety possess many types of biological activities, including anticancer activity. The present work reports the synthesis and antiproliferative evaluation of some N-(6(4)-indazolyl)benzenesulfonamides and 7-ethoxy-N-(6(4)-indazolyl) benzenesulfonamides. All compounds were evaluated for their in vitro antiproliferative activity against three tumor cell lines: A2780 (human ovarian carcinoma) A549 (human lung adenocarcinoma) and P388 (murine leukemia). The results indicated that sulfonamides 2c, 3c, 6d, 8, 13, 3b and 16 were endowed with a pharmacologically interesting antiproliferative activity with compounds 2c and 3c showing the lower IC50 (from 0.50 ± 0.09 to 1.83 ± 0.52 μM and from 0.58 ± 0.17 to 5.83 ± 1.83 μM, respectively). Moreover, these indazoles were able to trigger apoptosis through the upregulation of the typical apoptosis markers p53 and bax. As regard to the hypothetic targets of these compounds, a preliminary docking analysis showed that all compounds seemed to interact with β-tubulin, in particular compound 3b that showed the lower Ki. The cytofluorimetric analysis of the cell cycle phases indicates that all compounds, when administered at their IC 75, caused a block in the G2/M phase of the cell cycle with the generation of subpopulations of cells with a number of chromosome >4n. When the IC50s were applied we observed a prevalent block in the G0/G1 phase except for compounds 16 and 8 where a partial G2/M block was present with a concomitant decrease of cells in the G0/G1 and S phases of the cell cycle. Altogether these results suggest a possible, but not exclusive, interaction with microtubules.
- Abbassi, Najat,Chicha, Hakima,Rakib, El Mostapha,Hannioui, Abdellah,Alaoui, Mdaghri,Hajjaji, Abdelouahed,Geffken, Detlef,Aiello, Cinzia,Gangemi, Rosaria,Rosano, Camillo,Viale, Maurizio
-
p. 240 - 249
(2013/01/15)
-
- SUBSTITUTED AROMATIC CARBOXAMIDE AND UREA DERIVATIVES AS VANILLOID RECEPTOR LIGANDS
-
The invention relates to substituted aromatic carboxamide and urea derivatives, to processes for the preparation thereof, to pharmaceutical compositions containing these compounds and also to the use of these compounds for preparing pharmaceutical compositions (formula (I)).
- -
-
Page/Page column 124; 125
(2010/11/18)
-
- Anti-cancer agents and uses thereof
-
The present invention is in the area of novel compounds and salts thereof, their syntheses, and their use as anti-cancer agents. The compounds include compounds of Formula I: and solvates, hydrates and pharmaceutically-acceptable salts thereof, wherein A1 is N or CR1; A3 is N or CR3; A5 is N or CR5; R1, R3-R6 and L are defined in the specification; n is 0 or 1; and X is an optionally-substituted aryl group having 6-10 carbons in the ring portion, an optionally-substituted 6-membered heteroaryl group having 1-3 nitrogen atoms in the ring portion, an optionally-substituted 5-membered heteroaryl group having 0-4 nitrogen atoms in the ring portion and optionally having 1 sulfur atom or 1 oxygen atom in the ring portion, or an optionally-substituted heteroaryl group in which a 6-membered ring is fused either to a 5-membered ring or to a 6-membered ring, wherein in each case 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from nitrogen, oxygen and sulfur. They are effective against a broad range of cancers, especially leukemia, prostate, non-small cell lung and colon. They are additionally useful in the treatment of proliferative retinopathies such as diabetic neuropathy and macular degeneration.
- -
-
Page/Page column 26
(2008/12/08)
-
- ANTI-CANCER AGENTS ANS USES THEREOF
-
The present invention is in the area of novel compounds and salts thereof, their syntheses, and their use as anti-cancer agents. The compounds include compounds of Formula (I): and solvates, hydrates and pharmaceutically-acceptable salts thereof, wherein A1 is N or CR1; A3 is N or CR3; A5 is N or CR5; R1, R3 R6 and L are defined in the specification; n is 0 or 1; and X is an optionally-substituted aryl group having 6- 10 carbons in the ring portion, an optionally-substituted 6- membered heteroaryl group having 1- 3 nitrogen atoms in the ring portion, an optionally-substituted 5- membered heteroaryl group having 0- 4 nitrogen atoms in the ring portion and optionally having 1 sulfur atom or 1 oxygen atom in the ring portion, or an optionally-substituted heteroaryl group in which a 6- membered ring is fused either to a 5- membered ring or to a 6- membered ring, wherein in each case 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from nitrogen, oxygen and sulfur. They are effective against a broad range of cancers, especially leukemia, prostate, non-small cell lung and colon. They are additionally useful in the treatment of proliferative retinopathies such as diabetic neuropathy and macular degeneration.
- -
-
Page/Page column 65
(2010/11/29)
-
- Inhibitory effects of a series of 7-substituted-indazoles toward nitric oxide synthases: Particular potency of 1H-indazole-7-carbonitrile
-
A series of new 7-monosubstituted and 3,7-disubstituted indazoles have been prepared and evaluated as inhibitors of nitric oxide synthases (NOS). 1H-Indazole-7-carbonitrile (6) was found equipotent to 7-nitro-1H-indazole (1) and demonstrated preference for constitutive NOS over inducible NOS. By contrast, 1H-indazole-7-carboxamide (8) was slightly less potent but demonstrated a surprising selectivity for the neuronal NOS. Further substitution of 6 by a Br-atom at carbon-3 of the heterocycle enhanced 10-fold the inhibitory effects. Inhibition of NO formation by 6 appeared to be competitive versus both substrate and the cofactor (6R)-5,6,7,8-tetrahydro-l-biopterin (H4B). In close analogies with 1, compound 6 strongly inhibited the NADPH oxidase activity of nNOS and induced a spin state transition of the heme-FeIII. Our results are explained with the help of the X-ray structures that identified key-features for binding of 1 at the active site of NOS.
- Cottyn, Betty,Acher, Francine,Ramassamy, Booma,Alvey, Luke,Lepoivre, Michel,Frapart, Yves,Stuehr, Dennis,Mansuy, Daniel,Boucher, Jean-Luc,Vichard, Dominique
-
p. 5962 - 5973
(2008/12/23)
-
- Anti-cancer agents and uses thereof
-
The present invention is in the area of novel compounds and salts thereof, their syntheses, and their use as anti-cancer agents. The compounds include compounds of Formula I: and solvates, hydrates and pharmaceutically-acceptable salts thereof, wherein A1 is N or CR1; A3 is N or CR3; A5 is N or CR5; R1, R3—R6 and L are defined in the specification; n is 0 or 1; and X is an optionally-substituted aryl group having 6-10 carbons in the ring portion, an optionally-substituted 6-membered heteroaryl group having 1-3 nitrogen atoms in the ring portion, an optionally-substituted 5-membered heteroaryl group having 0-4 nitrogen atoms in the ring portion and optionally having 1 sulfur atom or 1 oxygen atom in the ring portion, or an optionally-substituted heteroaryl group in which a 6-membered ring is fused either to a 5-membered ring or to a 6-membered ring, wherein in each case 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from nitrogen, oxygen and sulfur. They are effective against a broad range of cancers, especially leukemia, non-small cell lung and colon.
- -
-
Page/Page column 25
(2008/06/13)
-
- Synthesis and biological evaluation of N-(7-indazolyl)benzenesulfonamide derivatives as potent cell cycle inhibitors
-
We herein describe a new synthesis of N-(7-indazolyl)benzenesulfonamide derivatives. These compounds were evaluated for their antiproliferative activities toward L1210 murine leukemia cells. One of them, 4-methoxy-N-(3- chloro-7-indazolyl)benzenesulfonamide, was identified as the most potent with an IC50 of 0.44 μM.
- Bouissane,El Kazzouli,Leonce,Pfeiffer,Rakib,Khouili,Guillaumet
-
p. 1078 - 1088
(2007/10/03)
-
- THIADIAZOLEDIOXIDES AND THIADIAZOLEOXIDES AS CXC- AND CC-CHEMOKINE RECEPTOR LIGANDS
-
Disclosed are novel compounds of the formula (IA) and the pharmaceutically acceptable salts and solvates thereof. Examples of groups comprising Substituent A include heteroaryl, aryl, heterocycloalkyl, cycloalkyl, aryl, alkynyl, alkenyl, aminoalkyl, alkyl or amino. Examples of groups comprising Substituent B include aryl and heteroaryl. Also disclosed is a method of treating a chemokine mediated diseases, such as, cancer, angiogenisis, angiogenic ocular diseases, pulmonary diseases, multiple sclerosis, rheumatoid arthritis, osteoarthritis, stroke and cardiac reperfusion injury, acute pain, acute and chronic inflammatory pain, and neuropathic pain using a compound of formula (IA).
- -
-
-
- 3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands
-
There are disclosed compounds of the formula or a pharmaceutically acceptable salt or solvate thereof which are useful for the treatment of chemokine-mediated diseases such as acute and chronic inflammatory disorders and cancer.
- -
-
-
- 3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands
-
There are disclosed compounds of the formula or a pharmaceutically acceptable salt or solvate thereof which are useful for the treatment of chemokine-mediated diseases such as acute and chronic inflammatory disorders and cancer.
- -
-
-
- Structure-activity relationships for pyrido-, imidazo-, pyrazolo-, pyrazino-, and pyrrolophenazinecarboxamides as topoisomerase-targeted anticancer agents
-
Heterocyclic phenazinecarboxamides were prepared by condensation of aminoheterocycles and 2-halo-3-nitrobenzoic acids, followed by reductive ring closure and amidation. They showed similar inhibition of paired cell lines that underexpressed topo II or overexpressed P-glycoprotein, indicating a non topo II mechanism of cytotoxicity and indifference to P-glycoprotein mediated multidrug resistance. Compounds with a fused five-membered heterocyclic ring were generally less potent than the pyrido[4,3-a]phenazines. A 4-methoxypyrido[4,3-a]phenazine (IC50s 2.5-26 nM) gave modest (ca. 5 day) growth delays in H69/P xenografts with oral dosing.
- Gamage, Swarna A.,Spicer, Julie A.,Rewcastle, Gordon W.,Milton, John,Sohal, Sukhjit,Dangerfield, Wendy,Mistry, Prakash,Vicker, Nigel,Charlton, Peter A.,Denny, William A.
-
p. 740 - 743
(2007/10/03)
-
- Reactivity of 7-aminoindazole as a bidendate nucleophile
-
A simple route for the preparation of two new classes of heterocyclic systems: halopyrazolo[4,5-h]quinolines and halopyrazolo[1,5,4-ef][1,5]benzodiazepines, is presented. The effect of the solvent and the reactivity of pyrazolo-1,5-benzodiazepine were studied.
- Rakib, El Mostapha,Benchidmi, Mohammed,Essassi, El Mokhtar,Bouadili, Abdelaziz El,Khouili, Mostafa,Visseaux, Mark,Pujol, M.Dolors
-
p. 2617 - 2627
(2007/10/03)
-
- SYNTHESE DE NOUVEAUX SYSTEMES HETEROCYCLIQUES : LES PYRAZOLOTRIAZOLOBENZODIAZEPINES
-
The synthesis of new pyrazolotriazolobenzodiazepines have been described.Hydrazinolysis of pyrazolobenzodiazepinethiones leads to 7-pyrazolylamino indazole.
- Benchidmi, M.,Essassi, E. M.,Ibnmansour, A.
-
p. 995 - 1000
(2007/10/02)
-