- Iron-promoted sulfur sequestration for the substituent-dependent regioselective synthesis of tetrazoles and guanidines
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We have established a facile and versatile synthetic methodology for the construction of tetrazoles and guanidines in the presence of an eco-friendly, inexpensive, easily available iron reagent. Aromatic thioureas with electron-donating substituents produced their respective target products in quantitative yield. In contrast, when electron-withdrawing substituted aromatic thioureas were used, the expected products were obtained in reduced yield. However, the desired products were obtained in good yield at moderate temperature. In addition, mechanistic studies revealed that the synthetic route involved iron-based subsequent reactions of addition and removal of sulfur.
- Pendem, Venkata Bhavanarushi,Tamminana, Ramana,Nannapaneni, Madhavi
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p. 499 - 509
(2021/04/09)
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- The utilization of ball milling in synthesis of aryl guanidines through guanidinylation and N-Boc-deprotection sequence
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Solid state ball milling was used in guanidinylation reactions of aromatic amines with N,N′-Di-Boc-1H-pyrazole-1-carboxamidine reagent. Reaction conditions are advantageous, and in general reactions proceed in significantly shorter reaction times and in higher yields than under the conventional solution conditions. Mechanochemical conditions were also successfully applied to the cleavage of N-Boc protecting group.
- ?ud, Mateja,Glasovac, Zoran,Margeti?, Davor
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p. 109 - 115
(2018/11/30)
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- One-Pot Evolution of Ageladine A through a Bio-Inspired Cascade towards Selective Modulators of Neuronal Differentiation
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A bio-inspired cascade reaction has been developed for the construction of the marine natural product ageladine A and a de novo array of its N1-substituted derivatives. This cascade features a 2-aminoimidazole formation that is modeled after an arginine post-translational modification and an aza-electrocyclization. It can be effectively carried out in a one-pot procedure from simple anilines or guanidines, leading to structural analogues of ageladine A that had been otherwise synthetically inaccessible. We found that some compounds out of this structurally novel library show a significant activity in modulating the neural differentiation. Namely, these compounds selectively activate or inhibit the differentiation of neural stem cells to neurons, while being negligible in the differentiation to astrocytes. This study represents a successful case in which the native biofunction of a natural product could be altered by structural modifications.
- Iwata, Takayuki,Otsuka, Satoshi,Tsubokura, Kazuki,Kurbangalieva, Almira,Arai, Daisuke,Fukase, Koichi,Nakao, Yoichi,Tanaka, Katsunori
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supporting information
p. 14707 - 14716
(2016/10/03)
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- Direct guanylation of amino groups by cyanamide in water: Catalytic generation and activation of unsubstituted carbodiimide by scandium(iii) triflate
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Guanylation proceeded efficiently upon treatment of the various amines with cyanamide in the presence of catalytic amounts of scandium(III) triflate under mild conditions. The method did not require the guanylation reagents to be preactivated, and the reaction proceeded efficiently in water. The method, therefore, has practical utility for substrates that dissolve only in aqueous solutions, for example, peptides or pharmacologically important compounds. Georg Thieme Verlag Stuttgart New York.
- Tsubokura, Kazuki,Iwata, Takayuki,Taichi, Misako,Kurbangalieva, Almira,Fukase, Koichi,Nakao, Yoichi,Tanaka, Katsunori
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p. 1302 - 1306
(2014/06/10)
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- Reaction of quinones and guanidine derivatives: Simple access to bis-2-aminobenzimidazole moiety of benzosceptrin and other benzazole motifs
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A new strategy for the synthesis of 2-aminobenzimidazol-6-ols via a reaction of quinones with guanidine derivatives is reported. Sequential application of this methodology provided a simple access to the first benzosceptrin analogue bearing a bis-2-aminoimidazole moiety. A concomitant addition of two guanidines to the naphtho[1′,2′:4,5]imidazo[1,2-a] pyrimidine-5,6-dione, which includes the redox neutral debenzylation and guanidine-assisted cleavage of the 2-aminopyrimidine part resulted in the synthesis of the free challenging contiguous bis-2-aminoimidazole moiety of benzosceprins in one step.
- Tran, Minh Quan,Ermolenko, Ludmila,Retailleau, Pascal,Nguyen, Thanh Binh,Al-Mourabit, Ali
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supporting information
p. 920 - 923
(2014/03/21)
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- Discovery of 5-(2-(phenylamino)pyrimidin-4-yl)thiazol-2(3H)-one derivatives as potent Mnk2 inhibitors: Synthesis, SAR analysis and biological evaluation
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Phosphorylation of eIF4E by human mitogen-activated protein kinase (MAPK)-interacting kinases (Mnks) is crucial for human tumourigenesis and development. Targeting Mnks may provide a novel anticancer therapeutic strategy. However, the lack of selective Mnk inhibitors has so far hampered pharmacological target validation and clinical drug development. Herein, we report, for the first time, the discovery of a series of 5-(2-(phenylamino) pyrimidin-4-yl)thiazole-2(3H)-one derivatives as Mnk inhibitors. Several derivatives demonstrate very potent Mnk2 inhibitory activity. The most active and selective compounds were tested against a panel of cancer cell lines, and the results confirm the cell-type-specific effect of these Mnk inhibitors. Detailed cellular mechanistic studies reveal that Mnk inhibitors are capable of reducing the expression level of anti-apoptotic protein Mcl-1, and of promoting apoptosis in MV4-11 acute myeloid leukaemia cells. Highly active Mnk2 inhibitors: Mnk-related cancer biology is an area of intensive research, but its inhibitor discovery has lagged behind due to a lack of understanding of the protein structure. Herein we report the discovery of Mnk2 inhibitors (e.g. 8 e). These potent and selective inhibitors are extremely valuable for target validation and drug discovery.
- Diab, Sarah,Teo, Theodosia,Kumarasiri, Malika,Li, Peng,Yu, Mingfeng,Lam, Frankie,Basnet, Sunita K. C.,Sykes, Matthew J.,Albrecht, Hugo,Milne, Robert,Wang, Shudong
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p. 962 - 972
(2014/05/20)
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- Synthesis of a 2,4,6-trisubstituted 5-cyano-pyrimidine library and evaluation of its immunosuppressive activity in a Mixed Lymphocyte Reaction assay
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A series of novel pyrimidine analogues were synthesized and evaluated for immunosuppressive activity in the Mixed Lymphocyte Reaction assay, which is well-known as the in vitro model for in vivo rejection after organ transplantation. Systematic variation of the substituents at positions 2, 4 and 6 of the pyrimidine scaffold led to the discovery of 2-benzylthio-5-cyano-6-(4- methoxyphenyl)-4-morpholinopyrimidine with an IC50 value of 1.6 μM in the MLR assay.
- Stella, Alessandro,Van Belle, Kristien,De Jonghe, Steven,Louat, Thierry,Herman, Jean,Rozenski, Jef,Waer, Mark,Herdewijn, Piet
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supporting information
p. 1209 - 1218
(2013/03/28)
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- Identification of pyrimidine derivatives as hSMG-1 inhibitors
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hSMG-1 kinase plays a dual role in a highly conserved RNA surveillance pathway termed nonsense-mediated RNA decay (NMD) and in cellular genotoxic stress response. Since deregulation of cellular responses to stress contributes to tumor growth and resistance to chemotherapy, hSMG-1 is a potential target for cancer treatment. From our screening efforts, we have identified pyrimidine derivatives as hSMG-1 kinase inhibitors. We report structure-based optimization of this pan-kinase scaffold to improve its biochemical profile and overall kinome selectivity, including mTOR and CDK, to generate the first reported selective hSMG-1 tool compound.
- Gopalsamy, Ariamala,Shi, Mengxiao,Bennett, Eric M.,Bard, Joel,Zhang, Wei-Guo,Yu, Ker
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p. 6636 - 6641,6
(2012/12/12)
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- Palladium-catalyzed C-H functionalization using guanidine as a directing group: Ortho arylation and olefination of arylguanidines
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Palladium-catalyzed C-H functionalization using guanidine as the directing group was achieved under mild reaction conditions. Various guanidine derivatives were produced in moderate to good yields by using simple unactivated arenes or ethyl acrylate as the source of arylation or olefination, respectively.
- Shao, Jiaan,Chen, Wenteng,Giulianotti, Marc A.,Houghten, Richard A.,Yu, Yongping
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supporting information
p. 5452 - 5455
(2013/01/15)
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- CURABLE COMPOSITION
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The present invention has its object to provide a curable composition which comprises a guanidine compound as a non-organotin type catalyst, is less discolored, has good surface curability, depth curability, strength rise and adhesiveness, and can retain the curability even after storage; the above object can be achieved by a curable composition which comprises: (A) an organic polymer containing a silyl group capable of crosslinking under siloxane bond formation, the silyl group being a group represented by the general formula (1): -SiX 3 (1) (wherein X represents a hydroxyl group or a hydrolyzable group and the three X groups may be mutually the same or different), (B) a guanidine compound (B-1) as a silanol condensation catalyst, and (C) a plasticizer, wherein the content of the component (B-1) is not lower than 0.1 part by weight but lower than 8 parts by weight per 100 parts by weight of the component (A), and a non-phthalate ester plasticizer accounts for 80 to 100% by weight of the (C) component plasticizer.
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- One-pot two-step solvent-free rapid and clean synthesis of 2-(substituted amino)pyrimidines by microwave irradiation
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abs A series of diversely 2-(substituted amino)pyrimidines (along with ring substitution) has been synthesized under solvent- and catalyst-free microwave conditions from substituted guanidines and β-diketones. The substituted guanidines are synthesized from (S)-methylisothiourea sulfate and different amines (various alkyl, aryl, or heterocyclic and also chiral amines) under microwave irradiation. These two-step reactions are performed in one-pot without isolating any intermediate. This protocol has been successfully applied for the synthesis of bisaminopyrimidines and 2-substituted aminopyrimidines containing chiral moiety where chirality remains undisturbed.
- Goswami, Shyamaprosad,Hazra, Anita,Jana, Subrata
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experimental part
p. 1175 - 1181
(2009/12/25)
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- Novel heterocycle-substituted pyrimidines as inhibitors of NF-κB transcription regulation related to TNF-α cytokine release
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Novel heterocyclic ring-substituted pyrimidines have been designed as inhibitors of glycogen synthase kinase-3β (GSK-3β) from the modification of known inhibitors. Several potent inhibitors exhibiting nanomolar activities were discovered against GSK-3β kinase as well as in an NF-κB reporter gene assay. Based on the results from in vitro TNF-α release inhibition and in vivo endotoxima, these inhibitors are expected to be useful candidates for treatment of inflammation-related diseases.
- Ha, Hyung-Ho,Kim, Jee Seon,Kim, B. Moon
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p. 653 - 656
(2008/12/23)
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- Solvent-free synthesis of azole carboximidamides
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A one-pot procedure is described for the preparation of azole carboximidamides 2, 3 and guanidinylation of amines with 3. The X-ray crystal structure of 3b, has been determined. A one-pot procedure is described for the preparation of 1H-pyrazole-carboximidamides 2, 1H-benzotriazole-carboximidamides 3 and guanidinylation of amines with 3. The X-ray crystal structure of N,N-dimethyl-1H-benzotriazole-1-carboximidamide 3b, has been determined.
- Zahariev, Sotir,Guarnaccia, Corrado,Lamba, Doriano,?ema?ar, Ma?a,Pongor, Sándor
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p. 9423 - 9426
(2007/10/03)
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- COMPOUNDS USEFUL AS INHIBITORS OF JAK AND OTHER PROTEIN KINASES
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The present invention provides a compound of formula I: or a pharmaceutically acceptable salt thereof. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of utilizing those compounds and compositions in the treatment of various protein kinase mediated disorders.
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- Solid-phase synthesis of N-aryl-N′-carboalkoxy guanidines by the mitsunobu reaction of Fmoc-guanidines
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A new method for the solid-phase synthesis of N-aryl-N′-carboalkoxy guanidines is described. Aromatic amines were reacted with Fmoc-isothiocyanate to provide Fmoc-thioureas, which were coupled with Rink amide resin to provide the corresponding resin-bound Fmoc-guanidines. Subsequent Mitsunobu alkylation with a variety of alcohols delivered N-aryl-N′ carboalkoxy guanidines in good to high purity after resin cleavage.
- Robinson, Dale E.,Seth, Punit P.,Jefferson, Elizabeth A.
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p. 2743 - 2749
(2007/10/03)
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- Reaction of thiourea dioxides with amines
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The reaction mechanism of thiourea dioxides with ammonia and primary aliphatic amines involves direct nucleophile (ammonia or amine) reactions with thiourea dioxides, followed by dissociation of the resulting adduct to form the sulfoxylate ion. 2004 MAIK "Nauka/Interperiodica".
- Makarov,Kudrik,Terskaya,Davydov
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p. 1383 - 1385
(2007/10/03)
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- Inhibitors of c-Jun N-terminal kinases (JNK) and other protein kinases
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The present invention provide a compound of formula I or II: or a pharmaceutically acceptable derivative thereof, wherein R1, R2, R3, and R4 are as described in the specification. These compounds are inhibitors of protein kinase, particularly inhibitors of JNK, a mammalian protein kinase involved cell proliferation, cell death and response to extracellular stimuli; and Src-family kinases, especially Src and Lck kinases. These compounds are also inhibitors of GSK3 and CDK2 kinases. The invention also relates to methods for producing these inhibitors. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of utilizing those compositions in the treatment and prevention of various disorders.
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- A novel, facile methodology for the synthesis of N,N′-bis(tert-butoxycarbonyl)-protected guanidines using polymer-supported carbodiimide
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A novel methodology for the synthesis of guanidines from amines has been developed using polymer assisted synthesis, potentially allowing the preparation of series of compounds in a high throughput manner. The methodology comprises the use of polymer-supported carbodiimide as the activating agent for N,N′-bis(tert-butoxycarbonyl) thiourea with polymer-supported trisamine as a scavenger, followed by deprotection with trifluoroacetic acid. For the first time, polymer-supported carbodiimide has been utilized as an activating agent to synthesize guanidines.
- Guisado, Olga,Martínez, Sonia,Pastor, Joaquín
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p. 7105 - 7109
(2007/10/03)
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- Novel linker for the solid-phase synthesis of guanidines
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A novel linker for the generation of alkyl-, acyl- and arylguanidines as an attachment point in solid phase synthesis has been developed. Introduction of a suitably functionalized thiourea to Wang resin via a carbamate linkage, followed by displacement of sulfur with a 1°or 2°amine affords resin bound guanidines suitably protected for further manipulation. Activation of the thiourea with Mukaiyama's reagent allows for the generation of arylguanidines. Mild acid treatment effects deprotection and liberation from the resin to afford guanidines in good yield and high purity.
- Josey, John A.,Tarlton, Catherine A.,Payne, Courtney E.
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p. 5899 - 5902
(2007/10/03)
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- Substituted benzene derivatives useful as neuraminidase inhibitors
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A compound of the Formula (I): STR1 or pharmaceutically-suitable salts or prodrug forms thereof, wherein: n is 0-1; m is 0; p is 0-1; R1 is --CO2 H; R2 is selected from the group consisting of H, --OH, and --NH2 ; R3 is H; R4 is --C(O)NHR8 ; R5 is --NHC(R6)NH2 R6 is selected from the group consisting of =NH, =NOH, =NCN, =O, and =S; and R8 is selected from the group consisting of C1 -C4 linear or branched alkyl substituted with 0-3 halogens on each carbon.
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- Urethane protected derivatives of 1-guanylpyrazole for the mild and efficient preparation of guanidines
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Bis-urethane protected derivatives of 1-guanylpyrazole were prepared and found to readily react with relatively amines at room temperature to produce bis-protected guanidines in good yields. Simultaneous removal of both protecting groups from these products efficiently produced monosubstituted guanadines.
- Bernatowicz, Michael S.,Wu, Youling,Matsueda, Gary R.
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p. 3389 - 3392
(2007/10/02)
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- N-PHENYL-N,N"-GUANIDINEDICARBOXYLIC ACID ESTERS. SYNTHESIS, ANTHELMINTIC AND PESTICIDAL EFFECTS
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Substituted phenylammonium chlorides react with cyanamide to give the corresponding phenylguanidines which on treatment with chloroformate esters give N-subst.phenyl-N,N''-guanidinedicarboxylic acid esters.All substances prepared have been tested for their anthelmintic activity against the model helminths Nippostrongylus brasiliensis and Hymenolepis nana var. fraterna.The most significant activity has been found with diethyl N-(4-nitrophenyl)-N,N''-guanidinedicarboxylate.In pesticidal screening the compounds have shown fungicidal activity and particularly ovicidal activity against Tetranychus urticae which activity is increased with the compounds having a nitro group in the benzene ring.
- Palat, Karel,Celadnik, Milan,Danek, Jaroslav,Varkonda, Stefan
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p. 1127 - 1133
(2007/10/02)
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- MONOSUBSTITUTED GUANIDINES FROM PRIMARY AMINES AND AMINOIMINOMETHANESULFONIC ACID
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Aminoiminomethanesulfonic acid, H2N-C(=NH)SO3H, converts primary amines to the corresponding guanidine derivatives at 20 deg C.This crystalline reagent is readily prepared by the peracetic acid oxidation of formamidinesulfinic acid, H2N-C(=NH)SO2H.The synthesis is illustrated by a representative group of simple monosubstituted guanidines shown in Table I.
- Kim, Keekyung,Lin, Yi-Tsong,Mosher, Harry S.
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p. 3183 - 3186
(2007/10/02)
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- N1- and N2-Substituted 2-Amino-5,6-dihydro-4(1H)-pyrimidinones (Heterocyclic Compounds, 79)
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The reactions of the monosubstituted guanidines 2b-h with methyl acrylate in dimethylformamide or ethanol as solvent preferentially afford 1-substituted 2-amino-5,6-dihydro-4(1H)-pyrimidinones 6b-h.The structures of 1-hexyl- and 1-benzyl-4-pyrimidinones 6c, e and of the picrate of 1-phenylpyrimidinone 6g were proved by comparison with authentic samples, which were prepared from N-substituted ethyl 3-amino-propionates 14c, e and g and cyanamide.Accordingly, 6g is not identical with authentic 2-phenylaminopyrimidinone 7g (prepared from 2-methylthio-4-pyrimidinone 10 and 2-thioxo-4-pyrimidinone 12 respectively, compare.N,N-Disubstituted guanidines 2i-m react with methyl acrylate in dimethylformamide as solvent to afford N2,N2-disubstituted 2-amino-5,6-dihydro-4-(1H)-pyrimidinones 7i-m.Action of morpholine-4-carboxamidine (2l) on methyl acrylate in ethanol yields 2-morpholinopyrimidinone 7l as byproduct and 3-ethoxy-N-propionamide (9l) as mainproduct.Keywords: Acrylic acid methylester, reactions; Guanidines, mono- and N,N-disubstituted; Propionamide, 3-ethoxy-N-; 4(1H)-Pyrimidinones, 2-amino; Pyrimidine-1-propionic acid ethylester, hexahydro-4-oxo-2-thioxo
- Wendelin, Winfried,Riedl, Renate
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p. 237 - 252
(2007/10/02)
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- Bicyclic amidines
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New amidine/isocyanate adducts are particularly useful as catalysts for hardening epoxy resins, in particular pulverulent coating compositions based on epoxy resins. New bicyclic amidines are excellent starting materials for manufacturing these amidine/isocyanate adducts.
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- Oxidation of Mixtures of Thioureas: Part VIII - Formation of 3-Amino-4-aryl-5-benzylimino-4,5-dihydro-1,2,4-thiadiazoles
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Oxidation of binary mixtures of 1-aryl-3-benzylthioureas and thiourea in acidic ethanol affords 3-amino-4-aryl-5-benzylimino-4,5-dihydro-1,2,4-thiadiazoles (3). 1-Aryl-3-benzylthioureas used are: 1-phenyl-3-benzyl-, 1-p-tolyl-3-benzyl-, 1-benzyl-3-p-chlorophenyl-, 1-p-anisyl-3-benzyl- and 1-benzyl-3-p-nitrophenyl-thioureas.
- Indukumari, P. V.,Joshua, C. P.
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p. 672 - 675
(2007/10/02)
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