- Indoline ureas as potential anti-hepatocellular carcinoma agents targeting VEGFR-2: Synthesis, in vitro biological evaluation and molecular docking
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In our effort to develop potent and effective agents with anti-proliferative activity towards HepG2 hepatocellular carcinoma cells with potential inhibitory activity against VEGFR-2, a novel series of 1-(4-((2-oxoindolin-3-ylidene)amino)phenyl)-3-arylurea
- Eldehna, Wagdy M.,Fares, Mohamed,Ibrahim, Hany S.,Aly, Mohamed H.,Zada, Suher,Ali, Mamdouh M.,Abou-Seri, Sahar M.,Abdel-Aziz, Hatem A.,Abou El Ella, Dalal A.
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- Synthesis and biological evaluation of diaryl urea derivatives designed as potential anticarcinoma agents using de novo structure-based lead optimization approach
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To develop inhibitors blocking VEGFR2 and the Raf/MEK/ERK mitogen-activated protein kinase signaling pathway new compounds based on sorafenib were designed, synthesized and biologically evaluated. Using de novo design method, a library of new ligands was
- Azimian, Fereshteh,Dastmalchi, Siavoush,Hamzeh-Mivehroud, Maryam,Hemmati, Salar,Shahbazi Mojarrad, Javid
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- Bis amide-aromatic-ureas - Highly effective hydro- and organogelator systems
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A series of hydro- and organo-supergelators have been synthesised via coupling of simple bis aromatic-ureas via alkyl amide linkages. These bis amide-aromatic-ureas exhibited reduced critical gelator concentrations, improved gelator stability, mechanical
- Baker,Acton,Stevens,Hayes
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- Probing 2H-Indazoles as Templates for SGK1, Tie2, and SRC Kinase Inhibitors
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The broader and systematic application of a novel scaffold is often hampered by the unavailability of a short and reliable synthetic access. We investigated a new strategy for the design and synthesis of an array of N2-substituted aza-2H-indazole derivatives as potential kinase inhibitors. Guided by a rational ligand alignment approach to qualify the so-far underrepresented aza-2H-indazole scaffold, indazoles were connected at the N2 position with a phenyl spacer and an arylsulfonamide or amide linkage. Initial profiling against a panel of 30 kinases confirmed the in silico predicted selectivity bias. A synthesized focused library of 52 different aza-2H-indazole derivatives showed good initial selective inhibition against SGK1, Tie2, and SRC kinases, with the best representatives having IC50 values in the range of 500 nm. In a comparative computational study, these data were analyzed and rationalized in light of docking studies.
- Schoene, Jens,Gazzi, Thais,Lindemann, Peter,Christmann, Mathias,Volkamer, Andrea,Nazaré, Marc
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- One-pot synthesis and transmembrane chloride transport properties of C3-symmetric benzoxazine urea
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One-pot synthesis of a C3-symmetric benzoxazine-based tris-urea compound is discussed. 1H NMR titrations indicate a stronger Cl- binding compared that of Br- and I- by the receptor. Effective Cl- transport across liposomal membranes via a Cl-/X- antiport mechanism is confirmed. Theoretical calculation suggests that a few water molecules with N-H, C=O, and the aromatic ring of the receptor create a H-bonded polar cavity where a Cl- is recognized by O-H···Cl- interactions from five bridged water molecules.
- Roy, Arundhati,Saha, Debasis,Mukherjee, Arnab,Talukdar, Pinaki
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- Molecular design, synthesis and in vitro biological evaluation of thienopyrimidine–hydroxamic acids as chimeric kinase HDAC inhibitors: a challenging approach to combat cancer
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A series of thieno[2,3-d]pyrimidine-based hydroxamic acid hybrids was designed and synthesised as multitarget anti-cancer agents, through incorporating the pharmacophore of EGFR, VEGFR2 into the inhibitory functionality of HDAC6. Three compounds (12c, 15b and 20b) were promising hits, whereas (12c) exhibited potent VEGFR2 inhibition (IC50=185 nM), potent EGFR inhibition (IC50=1.14 μM), and mild HDAC6 inhibition (23% inhibition). Moreover, compound (15c) was the most potent dual inhibitor among all the synthesised compounds, as it exhibited potent EGFR and VEGFR2 inhibition (IC50=19 nM) and (IC50=5.58 μM), respectively. While compounds (20d) and (7c) displayed nanomolar selective kinase inhibition with EGFR IC50= 68 nM and VEGFR2 IC50= 191 nM, respectively. All of the synthesised compounds were screened in vitro for their cytotoxic effect on 60 human NCI tumour cell lines. Additionally, molecular docking studies and ADMET studies were carried out to gain further insight into their binding mode and predict the pharmacokinetic properties of all the synthesised inhibitors.
- Abdel-Atty, Mona M.,Farag, Nahla A.,Serya, Rabah A. T.,Abouzid, Khaled A. M.,Mowafy, Samar
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p. 1290 - 1312
(2021/07/09)
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- NOVEL HYDROGELATOR
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A novel hydrogelator that contains a monourea compound having a sugar structure, which can be produced by a simple method, includes a compound of the following Formula [1]: (wherein Sg is a sugar group, A is a divalent linking group, and R is a
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- Phenyl and Diaryl Ureas with Thiazolo[5,4-d]pyrimidine Scaffold as Angiogenesis Inhibitors: Design, Synthesis and Biological Evaluation
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Angiogenesis is crucial for tumor growth and inhibition of angiogenesis has been regarded as a promising approach for cancer therapy. Vascular endothelial growth factor receptor-2 (VEGFR-2) is an important factor in angiogenesis. In this work, a novel series of thiazolo[5,4-d]pyrimidine derivatives inhibiting angiogenesis were rationally designed and synthesized. Their inhibitory activities against human umbilical vein endothelial cells (HUVEC) were investigated in vitro. 1-(4-Fluorophenyl)-3-{4-[(5-methyl-2-phenyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl)amino]phenyl}urea (19b) and 1-(3-Fluorophenyl)-3-{4-[(5-methyl-2-phenyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl)amino]phenyl}urea (19g) exhibited the most potent inhibitory effect on HUVEC proliferation (IC50=12.8 and 5.3 μm, respectively). Compound 19g could inhibit the migration of human umbilical vein endothelial cells. These results support the further investigation of these compounds as potent anticancer agents.
- Xue, Wen-Jun,Deng, Ya-Hui,Yan, Zhong-Hui,Liu, Ji-Ping,Liu, Yu,Sun, Li-Ping
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- Design, synthesis and molecular modeling study of certain VEGFR-2 inhibitors based on thienopyrimidne scaffold as cancer targeting agents
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Different series of novel thieno [2,3-d]pyrimidine derivative (9a-d,10a-f,l,m and 15a-m) were designed, synthesized and evaluated for their ability to in vitro inhibit VEGFR-2 enzyme. Also, the cytotoxicity of the final compounds was tested against a panel of 60 different human cancer cell lines by NCI. The VEGFR-2 enzyme inhibitory results revealed that compounds 10d, 15d and 15 g are among the most active inhibitors with IC50 values of 2.5, 5.48 and 2.27 μM respectively, while compound 10a remarkably showed the highest cell growth inhibition with mean growth inhibition (GI) percent of 31.57%. It exhibited broad spectrum anti-proliferative activity against several NCI cell lines specifically on human breast cancer (T7-47D) and renal cancer (A498) cell lines of 85.5% and 77.65% inhibition respectively. To investigate the mechanistic aspects underlying the activity, further biological studies like flow cytometry cell cycle together with caspase-3 colorimetric assays were carried on compound 10a. Flow cytometric analysis on both MCV-7 and PC-3 cancer cells revealed that it induced cell-cycle arrest in the G0-G1phase and reinforced apoptosis via activation of caspase-3. Furthermore, molecular modeling studies have been carried out to gain further understanding of the binding mode in the active site of VEGFR-2 enzyme and predict pharmacokinetic properties of all the synthesized inhibitors.
- Ghith, Amna,Youssef, Khairia M.,Ismail, Nasser S.M.,Abouzid, Khaled A.M.
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p. 111 - 128
(2018/10/24)
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- 3D-QSAR pharmacophore modelling, virtual screening and docking studies for lead discovery of a novel scaffold for VEGFR 2 inhibitors: Design, synthesis and biological evaluation
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A series of novel 6,7-dihydro-5H-cyclopenta[d]pyrimidine derivatives was successfully designed, synthesized and evaluated as a new chemical scaffold with vascular endothelial growth factor receptor (VEGFR 2) inhibitory activity. Compounds 6c and 6b showed enzyme inhibition of 97% and 87% at 10 μM, respectively, and exhibited potent dose-related VEGFR 2 inhibition with IC50 values of 0.85 μM and 2.26 μM, respectively. The design of the 6,7-dihydro-5H-cyclopenta[d]pyrimidine scaffold was implemented via consecutive molecular modelling protocols prior to the synthesis and biological evaluation of the derivatives. First, sorafenib was docked in the binding site of VEGFR 2 to study its binding orientation and affinity, followed by the generation of a valid 3D QSAR pharmacophore model for use in the virtual screening of different 3D databases. Structures with promising pharmacophore-based virtual screening results were refined using molecular docking studies in the binding site of VEGFR 2. A novel scaffold was designed by incorporating the results of the pharmacophore model generation and molecular docking studies. The new scaffold showed hydrophobic interactions with the kinase front pocket that may be attributed to increasing residence time in VEGFR 2, which is a key success factor for ligand optimization in drug discovery. Different derivatives of the novel scaffold were validated using docking studies and pharmacophore mapping, where they exhibited promising results as VEGFR 2 inhibitors to be synthesized and biologically evaluated. 6,7-dihydro-5H-cyclopenta[d]pyrimidine is a new scaffold that can be further optimized for the synthesis of promising VEGFR 2 inhibitors.
- Sobhy, Mahitab K.,Mowafy, Samar,Lasheen, Deena S.,Farag, Nahla A.,Abouzid, Khaled A.M.
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- Inducing hardening and healability in poly(ethylene-co-acrylic acid) via blending with complementary low molecular weight additives
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The design and synthesis of low molecular weight additives based on self-assembling nitroarylurea units, and their compatibility with poly(ethylene-co-acrylic acid) copolymers are reported. The self-assembly properties of the low molecular weight additive
- Baker, Benjamin C.,German,Stevens, Gary C.,Colquhoun, Howard M.,Hayes, Wayne
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p. 41445 - 41453
(2019/01/03)
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- Design and discovery of 4-anilinoquinazoline-urea derivatives as dual TK inhibitors of EGFR and VEGFR-2
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EGFR and VEGFR-2 are involved in pathological disorders and the progression of different kinds of tumors, the combined blockade of EGFR and VEGFR signaling pathways appears to be an attractive approach to cancer therapy. In this work, a series of 4-anilinoquinazoline derivatives containing substituted diaryl urea or glycine methyl ester moiety were designed and identified as EGFR and VEGFR-2 dual inhibitors. Compounds 19i, 19j and 19l exhibited the most potent inhibitory activities against EGFR (IC50?=?1?nM, 78?nM and 51?nM, respectively) and VEGFR-2 (IC50?=?79?nM, 14?nM and 14?nM, respectively), they showed good antiproliferative activities as well. Molecular docking established the interaction of 19i with the DFG-out conformation of VEGFR-2, suggesting that they might be type II kinase inhibitors.
- Zhang, Hai-Qi,Gong, Fei-Hu,Ye, Ji-Qing,Zhang, Chi,Yue, Xiao-Hong,Li, Chuan-Gui,Xu, Yun-Gen,Sun, Li-Ping
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p. 245 - 254
(2016/10/03)
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- Aza-acridine compound and preparation method and application thereof
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The invention discloses a method for efficiently preparing an aza-acridine compound. The structural formula of the aza-acridine compound is shown as a formula I; the preparation method comprises the following steps: adding a 2-aminoquinoline-3-methanamide compound and a solvent under an air condition, and heating to reaction temperature; after the reaction is ended, separating and purifying to obtain multisubstituted acridine derivatives shown as the following formula, wherein the reaction temperature is 100 to 200DEG C, and the reaction time is 1 to 24 hours. A synthetic method of the aza-acridine compound, disclosed by the invention, has the advantages of scientificity, reasonability, simple and easily-operated synthesis process and high synthetic yield; a product is easy to purify. The invention also relates to the aza-acridine compound which can be used for inhibiting EGFR (Epidermal Growth Factor Receptor) and SrC, a preparation method of the aza-acridine compound, activity of a drug containing the aza-acridine compound and the application of the drug. The compound is shown in a formula II and can be used for preparing an EGFR and SrC activity inhibitor and a disease treatment medicine activated and mediated by the EGFR and the SrC.
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- Design, synthesis and evaluation of acridine derivatives as multi-target Src and MEK kinase inhibitors for anti-tumor treatment
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Clinical studies have shown enhanced anticancer effects of combined inhibition of Src and MEK kinases. Development of multi-target drugs against Src and MEK is of potential therapeutic advantage against cancers. As a follow-up of our previous studies, and by using molecular docking method, we designed and synthesized a new series of 9-anilinoacridines containing phenyl-urea moieties as potential novel dual Src and MEK inhibitors. The anti-proliferative assays against K562 and HepG-2 tumor cells showed that most of the derivatives displayed good cytotoxicity in vitro. In particular, kinase inhibition assays showed that compound 8m inhibited Src (59.67%) and MEK (43.23%) at 10 μM, and displayed moderate inhibitory activity against ERK and AKT, the downstream effectors of both Src and MEK. Moreover, compound 8m was found to induce K562 cells apoptosis. Structure-activity relationships of these derivatives were analyzed. Our study suggested that acridine scaffold, particularly compound 8m, is of potential interest for developing novel multi-target Src and MEK kinase inhibitors.
- Cui, Zhishan,Li, Xi,Li, Lulu,Zhang, Bin,Gao, Chunmei,Chen, Yuzong,Tan, Chunyan,Liu, Hongxia,Xie, Weiyi,Yang, Ti,Jiang, Yuyang
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p. 261 - 269
(2015/12/31)
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- Increasing the binding affinity of VEGFR-2 inhibitors by extending their hydrophobic interaction with the active site: Design, synthesis and biological evaluation of 1-substituted-4-(4-methoxybenzyl)phthalazine derivatives
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A series of anilinophthalazine derivatives 4a-j was initially synthesized and tested for its VEGFR-2 inhibitory activity where it showed promising activity (IC50 = 0.636-5.76 μM). Molecular docking studies guidance was used to improve the binding affinity for series 4a-j towards VEGFR-2 active site. This improvement was achieved by increasing the hydrophobic interaction with the hydrophobic back pocket of the VEGFR-2 active site lined with the hydrophobic side chains of Ile888, Leu889, Ile892, Val898, Val899, Leu1019 and Ile1044. Increasing the hydrophobic interaction was accomplished by extending the anilinophthalazine scaffold with a substituted phenyl moiety through an uriedo linker which should give this extension the flexibility required to accommodate itself deeply into the hydrophobic back pocket. As planned, the designed uriedo-anilinophthalazines 7a-i showed superior binding affinity than their anilinophthalazine parents (IC50 = 0.083-0.473 μM). In particular, compounds 7g-i showed IC50 of 0.086, 0.083 and 0.086 μM, respectively, which are better than that of the reference drug sorafenib (IC50 = 0.09 μM).
- Eldehna, Wagdy M.,Abou-Seri, Sahar M.,El Kerdawy, Ahmed M.,Ayyad, Rezk R.,Hamdy, Abdallah M.,Ghabbour, Hazem A.,Ali, Mamdouh M.,Abou El Ella, Dalal A.
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- Synthesis and cytotoxic activity of biphenylurea derivatives containing indolin-2-one moieties
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In our endeavor towards the development of potent anticancer agents, two different sets of biphenylurea-indolinone conjugates, 5a-s and 8a,b were synthesized. The in vitro cytotoxicity of the synthesized compounds was examined in two human cancer cell lin
- Eldehna, Wagdy M.,Fares, Mohamed,Ibrahim, Hany S.,Alsherbiny, Muhammad A.,Aly, Mohamed H.,Ghabbour, Hazem A.,Abdel-Aziz, Hatem A.
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- Diarylureas and Diarylamides with Oxazolo[5,4-d]pyrimidine Scaffold as Angiogenesis Inhibitors
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A series of oxazolopyrimidine-based ureas and amides were designed, synthesized, and biologically evaluated for their antiproliferative and antiangiogenic activities. These compounds were identified to exhibit inhibitory activities against human umbilical vein endothelial cells (HUVEC) in vitro. Among these compounds, compound 22 effectively inhibited the migration and capillary-like tube formation of human umbilical vein endothelial cells. It also exhibited a concentration-dependent inhibition on capillary sprouting from the rat aorta rings. Preliminary mechanistic studies revealed that compound 22 suppressed protein kinases activation, by decreasing PI3K and ERK 1/2 phosphorylation. These results support the further investigation of this class of compounds as potential anticancer agents.
- Deng, Ya-Hui,Liu, Ji-Ping,Cheng, Yi-Juan,Liu, Yu,Sun, Li-Ping
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p. 1230 - 1239
(2016/09/28)
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- 4-substituted anilinoquinazoline derivatives, and preparation method and application thereof
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The invention discloses novel 4-substituted anilinoquinazoline derivatives or pharmaceutically acceptable salts thereof, or polymorphic substances, solvates or stereomers of the 4-substituted anilinoquinazoline derivatives, and a preparation method and application thereof. The 4-substituted anilinoquinazoline compounds have favorable inhibition activities for EGFR and VEGFR-2 in a biological test and have obvious effects in an in-vitro anti-human tumor cell proliferation activity test.
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Paragraph 0032; 0033
(2017/01/31)
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- RECORDING MATERIAL PRODUCED USING NON-PHENOL COMPOUND
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An object of the present invention is to provide a recording material or a recording sheet using, as a color-developing agent, a non-phenol compound that is a safe compound in no danger of corresponding to an endocrine disruptor and is good in color devel
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Paragraph 0142
(2015/10/28)
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- Design, synthesis and biological evaluation of type-II VEGFR-2 inhibitors based on quinoxaline scaffold
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In an effort to develop ATP-competitive VEGFR-2 selective inhibitors, a series of new quinoxaline-based derivatives was designed and synthesized. The target compounds were biologically evaluated for their inhibitory activity against VEGFR-2. The design of the target compounds was accomplished after a profound study of the structure activity relationship (SAR) of type-II VEGFR-2 inhibitors. Among the synthesized compounds, 1-(2-((4-methoxyphenyl)amino)-3- oxo-3,4 dihydroquinoxalin-6-yl)-3-phenylurea (VIIa) displayed the highest inhibitory activity against VEGFR-2. Molecular modeling study involving molecular docking and field alignment was implemented to interpret the variable inhibitory activity of the newly synthesized compounds.
- Shahin, Mai I.,Abou El Ella, Dalal A.,Ismail, Nasser S.M.,Abouzid, Khaled A.M.
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- Synthesis and structure-activity relationships of (aryloxy)quinazoline ureas as novel, potent, and selective vascular endothelial growth factor receptor-2 inhibitors
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In our continuing search for medicinal agents to treat proliferative diseases, quinazoline derivatives were synthesized and evaluated pharmacologically as epithelial growth factor receptor and vascular endothelial growth factor receptor 2 (VEGFR-2) tyrosine kinase inhibitors. A quantitative structure-activity relationship analysis was conducted to rationalize the structure-activity relationship and to predict how similar the inhibitor-binding profiles of two protein kinases are likely to be on the basis of the docking of lead coumpounds into the ATP-binding site. This model was used to direct the synthesis of new compounds. A series of N-(aromatic)-N′-{4-[(6,7- dimethoxyquinazolin-4-yl)oxy]phenyl}urea were identified as potent and selective inhibitors of the tyrosine kinase activity of VEGFR-2 (fetal liver kinase 1, kinase insert domain-containing receptor). An efficient route was developed that enabled the synthesis of a wide variety of analogues with substitution on several positions of the template. Substitution of diarylurea, competitive with ATP, afforded several analogues with low nanomolar inhibition of enzymatic activity of VEGFR-2. In this paper, we describe the synthesis, structure-activity relationships, and pharmacological characterization of the series.
- Garofalo, Antonio,Farce, Amaury,Ravez, Séverine,Lemoine, Amélie,Six, Perrine,Chavatte, Philippe,Goossens, Laurence,Depreux, Patrick
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scheme or table
p. 1189 - 1204
(2012/03/27)
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- Discovery of potent and selective thienopyrimidine inhibitors of Aurora kinases
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In an effort to discover Aurora kinase inhibitors, an HTS hit revealed an amide containing pyrrolopyrimidine compound. Replacement of the pyrrolopyrimidine residue with a thienopyrimidine moiety led to a series of potent and selective Aurora inhibitors.
- McClellan, William J.,Dai, Yujia,Abad-Zapatero, Cele,Albert, Daniel H.,Bouska, Jennifer J.,Glaser, Keith B.,Magoc, Terry J.,Marcotte, Patrick A.,Osterling, Donald J.,Stewart, Kent D.,Davidsen, Steven K.,Michaelides, Michael R.
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p. 5620 - 5624
(2011/10/12)
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- UREA SUBSTITUTED SULPHONAMIDE DERIVATIVES
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The present invention relates to sulphonamide derivatives, whith a urea moiety. The invention also relates to the use of the derivatives as inhibitors of collagen receptor integrins, especially α2β1 integrin inhibitors e.g. in connection with diseases and
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Page/Page column 48-49
(2010/12/31)
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- 1-[4-(N-Benzylamino)phenyl]-3-phenylurea derivatives as a new class of hypoxia-inducible factor-1α inhibitors
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A series of 1-[4-(N-benzylamino)phenyl]-3-phenylurea derivatives 2a-r were synthesized as HIF-1α inhibitors. Among the compounds synthesized, compound 2k was found to be a potent inhibitor against HIF-1α accumulation under hypoxic condition and inhibited the hypoxia-induced HIF-1 transcriptional activity in HEK293 cells (IC50 = 7.2 μM). Furthermore, compound 2k suppressed the hypoxia-induced secretion of VEGF in HeLa cells (IC50 = 15 μM).
- Uno, Masaharu,Ban, Hyun Seung,Nakamura, Hiroyuki
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p. 3166 - 3169
(2010/03/03)
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- De novo Design and synthesis of N-benzylanilines as new candidates for VEGFR tyrosine kinase inhibitors
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N-Benzylanilines were designed and synthesized as vascular endothelial growth factor (VEGF)-2 inhibitors using de novo drug design systems based on the X-ray structure of VEGFR-2 kinase domain. Among compounds synthesized, compound 3 showed the most potent inhibitory activity toward VEGFR-2 (KDR) tyrosine kinase and its IC50 value was 0.57 μM.
- Uno, Masaharu,Ban, Hyun Seung,Nabeyama, Wataru,Nakamura, Hiroyuki
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scheme or table
p. 979 - 981
(2009/02/05)
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- New bis(2-aminoimidazoline) and bisguanidine DNA minor groove binders with potent in vivo antitrypanosomal and antiplasmodial activity
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A series of 75 guanidine and 2-aminoimidazoline analogue molecules were assayed in vitro against Trypanosoma brucei rhodesiense STIB900 and Plasmodium falciparum K1. The dicationic diphenyl compounds exhibited the best activities with IC50 values against T. b. rhodesiense and P. falciparum in the nanomolar range. Five compounds (7b, 9a, 9b, 10b, and 14b) cured 100% of treated mice upon ip administration at 20 mg/kg in the difficult to cure T. b. rhodesiense STIB900 mouse model. Overall, the compounds that bear the 2-aminoimidazoline cations benefit from better safety profiles than the guanidine counterparts. The observation of a correlation between DNA binding affinity at AT sites and trypanocidal activity for three series of compounds supported the view of a mechanism of antitrypanosomal action due in part to the formation of a DNA complex. No correlation between antiplasmodial activity and in vitro inhibition of ferriprotoporphyrin IX biomineralisation was observed, suggesting that additional mechanism of action is likely to be involved.
- Rodríguez, Fernando,Rozas, Isabel,Kaiser, Marcel,Brun, Reto,Nguyen, Binh,Wilson, W. David,García, Rory Nelson,Dardonville, Christophe
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p. 909 - 923
(2008/12/22)
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- QUINOLINE DERIVATIVE, USE AND PRODUCTION THEREOF, AND DRUG CONTAINING THE SAME
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The invention relates to a quinoline derivative of general formula (A), wherein R1, R2, R3, X, Y, Z and A are defined as in the description and the claims. The invention also relates to the use of the compounds of general
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Page/Page column 42
(2008/06/13)
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