cas 145013-05-4, N,N'-BIS-TERT-BUTOXYCARBONYLTHIOUREA

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Preparation of N,N'-bis-tert-butoxycarbonylthiourea
The preparation of N,N'-bis-tert-butoxycarbonylthiourea from thiourea and di-tert-butyl dicarbonate in tetrahydrofuran is described.
Iwanowicz,Poss,Lin
p. 1443 - 1445
(1993)
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Preparation of N-tert-butoxycarbonylthiourea opens the way to protected 2-aminothiazoles
The preparation of N-tert-butoxycarbonylthiourea from thiourea and di-tert-butyldicarbonate in tetrahydrofuran is described. It has been successfully used for the preparation of 2-aminothiazole intermediates.
Schiavi, Bruno,Ahond, Alain,Poupat, Christiane,Potier, Pierre
p. 1671 - 1674
(2002)
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Di-aryl guanidinium derivatives: Towards improved α2-Adrenergic affinity and antagonist activity
Compounds with excellent receptor engagement displaying α2-AR antagonist activity are useful not only for therapeutic purposes (e.g. antidepressants), but also to help in the crystallization of this particular GPCR. Therefore, based on our broad experience in the topic, we have prepared eighteen di-aryl (phenyl and/or pyridin-2-yl) mono- or di-substituted guanidines and 2-aminoimidazolines. The in vitro α2-AR binding affinity experiments in human brain tissue showed the advantage of a 2-aminoimidazolinium cation, a di-arylmethylene core, a conformationally locked pyridin-2-yl-guanidine and a di-substituted guanidinium to achieve good α2-AR engagement. After different in vitro [35S]GTPγS binding experiments in human prefrontal cortex tissue, it was possible to identify that compounds 7a, 7b and 7c were α2-AR partial agonist, whereas 8h was a potent α2-AR antagonist. Docking and MD studies with a model of α2A-AR and two crystal structures suggest that antagonism is achieved by compounds carrying a di-substituted guanidine which substituent occupy a pocket adjacent to TM5 without engaging S2005.42 or S2045.46, and a mono-substituted cationic group, which favorably interacts with E942.65.
McMullan, Michela,Kelly, Brendan,Mihigo, Helene B.,Keogh, Aaron P.,Rodriguez, Fernando,Brocos-Mosquera, Iria,García-Bea, Aintzane,Miranda-Azpiazu, Patricia,Callado, Luis F.,Rozas, Isabel
supporting information

(2020/11/05)

ANTI-INFLAMMATORY DRUG AND USES THEREOF
An anti-inflammatory drug containing a G0/G1 switch 2 (G0S2) inhibitor as an active ingredient is useful as a novel anti-inflammatory drug.
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Paragraph 0202; 0203

(2018/05/24)

α-Amino Acid-Isosteric α-Amino Tetrazoles
The synthesis of all 20 common natural proteinogenic and 4 otherα-amino acid-isosteric α-amino tetrazoles has been accomplished, whereby the carboxyl group is replaced by the isosteric 5-tetrazolyl group. The short process involves the use of the key Ugi tetrazole reaction followed by deprotection chemistries. The tetrazole group is bioisosteric to the carboxylic acid and is widely used in medicinal chemistry and drug design. Surprisingly, several of the common α-amino acid-isosteric α-amino tetrazoles are unknown up to now. Therefore a rapid synthetic access to this compound class and non-natural derivatives is of high interest to advance the field.
Zhao, Ting,Kurpiewska, Katarzyna,Kalinowska-T?us?cik, Justyna,Herdtweck, Eberhardt,D?mling, Alexander
supporting information
p. 3009 - 3018
(2016/03/26)

Neuraminic acid inhibitor prodrug composition and use thereof
Provided are a compound as represented by formula Ia, or pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof. As a neuraminidase inhibitor prodrug, the compound can improve the half-life in vivo of the neuraminidase inhibitor. Also provided are a preparation method of the compound, pharmaceutical composition containing the compound, and uses of the compound and the pharmaceutical composition in the preparation of neuraminidase inhibitor drugs for treating related diseases.
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Paragraph 0054; 0057-0059

(2016/10/20)

INHIBITORS OF BETA-SECRETASE
The present invention relates to spirocyclic acylguanidines and their use as inhibitors of the β-secretase enzyme (BACE1) activity, pharmaceutical compositions containing the same, and methods of using the same as therapeutic agents in the treatment of neurodegenerative disorders, disorders characterized by cognitive decline, cognitive impairment, dementia and diseases characterized by production of β-amyloid aggregates.
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Paragraph 0182; 0183

(2014/03/24)

Copper(II) chloride promoted transformation of amines into guanidines and asymmetrical N,N'-disubstituted guanidines
We present a concise, less-toxic and broadly applicable method for coupling weakly nucleophilic amines with N,N'-di-(tert-butoxycarbonyl)thiourea, N-(tert-butxoycarbonyl), N'-alkyl/arylsubstituted-thioureas and N,N'-di-(tert-butoxycarbonyl)imidazolidine-2-thione in the presence of copper(II) chloride. Subsequent removal of Boc protecting groups affords guanidines, di-substituted guanidines and 2-aminoimidazolines in modest to excellent overall yields.
Kelly, Brendan,Rozas, Isabel
supporting information
p. 3982 - 3984
(2013/07/25)

Proline editing: A general and practical approach to the synthesis of functionally and structurally diverse peptides. Analysis of steric versus stereoelectronic effects of 4-substituted prolines on conformation within peptides
Functionalized proline residues have diverse applications. Herein we describe a practical approach, proline editing, for the synthesis of peptides with stereospecifically modified proline residues. Peptides are synthesized by standard solid-phase peptide synthesis to incorporate Fmoc-hydroxyproline (4R-Hyp). In an automated manner, the Hyp hydroxyl is protected and the remainder of the peptide synthesized. After peptide synthesis, the Hyp protecting group is orthogonally removed and Hyp selectively modified to generate substituted proline amino acids, with the peptide main chain functioning to "protect" the proline amino and carboxyl groups. In a model tetrapeptide (Ac-TYPN-NH2), 4R-Hyp was stereospecifically converted to 122 different 4-substituted prolyl amino acids, with 4R or 4S stereochemistry, via Mitsunobu, oxidation, reduction, acylation, and substitution reactions. 4-Substituted prolines synthesized via proline editing include incorporated structured amino acid mimetics (Cys, Asp/Glu, Phe, Lys, Arg, pSer/pThr), recognition motifs (biotin, RGD), electron-withdrawing groups to induce stereoelectronic effects (fluoro, nitrobenzoate), handles for heteronuclear NMR (19F:fluoro; pentafluorophenyl or perfluoro-tert-butyl ether; 4,4-difluoro; 77SePh) and other spectroscopies (fluorescence, IR: cyanophenyl ether), leaving groups (sulfonate, halide, NHS, bromoacetate), and other reactive handles (amine, thiol, thioester, ketone, hydroxylamine, maleimide, acrylate, azide, alkene, alkyne, aryl halide, tetrazine, 1,2-aminothiol). Proline editing provides access to these proline derivatives with no solution-phase synthesis. All peptides were analyzed by NMR to identify stereoelectronic and steric effects on conformation. Proline derivatives were synthesized to permit bioorthogonal conjugation reactions, including azide-alkyne, tetrazine-trans-cyclooctene, oxime, reductive amination, native chemical ligation, Suzuki, Sonogashira, cross-metathesis, and Diels-Alder reactions. These proline derivatives allowed three parallel bioorthogonal reactions to be conducted in one solution.
Pandey, Anil K.,Naduthambi, Devan,Thomas, Krista M.,Zondlo, Neal J.
supporting information
p. 4333 - 4363
(2013/05/08)

Chemical insight into the emergence of influenza virus strains that are resistant to Relenza
A reagent panel containing ten 4-substituted 4-nitrophenyl α-d-sialosides and a second panel of the corresponding sialic acid glycals were synthesized and used to probe the inhibition mechanism for two neuraminidases, the N2 enzyme from influenza type A virus and the enzyme from Micromonospora viridifaciens. For the viral enzyme the logarithm of the inhibition constant (Ki) correlated with neither the logarithm of the catalytic efficiency (kcat/Km) nor catalytic proficiency (kcat/Kmkun). These linear free energy relationship data support the notion that these inhibitors, which include the therapeutic agent Relenza, are not transition state mimics for the enzyme-catalyzed hydrolysis reaction. Moreover, for the influenza enzyme, a correlation (slope, 0.80 ± 0.08) is observed between the logarithms of the inhibition (Ki) and Michaelis (Km) constants. We conclude that the free energy for Relenza binding to the influenza enzyme mimics the enzyme-substrate interactions at the Michaelis complex. Thus, an influenza mutational response to a 4-substituted sialic acid glycal inhibitor can weaken the interactions between the inhibitor and the viral neuraminidase without a concomitant decrease in free energy of binding for the substrate at the enzyme-catalyzed hydrolysis transition state. The current findings make it clear that new structural motifs and/or substitution patterns need to be developed in the search for a bona fide influenza viral neuraminidase transition state analogue inhibitor.
Shidmoossavee, Fahimeh S.,Watson, Jacqueline N.,Bennet, Andrew J.
supporting information
p. 13254 - 13257
(2013/09/24)

Synthesis of novel 3,4-diaryl-5-aminopyrazoles as potential kinase inhibitors
Synthesis of a diverse series of novel 3,4-diaryl-5-aminopyrazoles as candidates in the development of new protein kinase inhibitors is reported for the first time. In the course of a wider study into bisindolylmaleimide (BIM) derivatives, we examined a novel 5-aminopyrazole heterocyclic moiety as a structural analogue of the highly potent VEGF-R2/3 inhibitor pyrrole-2-one (8). The versatile nature of this pharmacophore allows considerable scope for derivatisation and hence exploration of structure activity relationships. Consequently, a variety of structural modifications were used in order to diversify the aminopyrazole ring substituents. Bicyclic derivatives of the parent aminopyrazoles (11, 12) were also synthesised as a means of probing the kinase active site, leading to formation of complex planar pyrimidine moieties. This work provides the framework for new explorations into kinase inhibition and critical investigations into selectivity of inhibitory activity.
Pierce, Larry T.,Cahill, Michael M.,McCarthy, Florence O.
experimental part
p. 4601 - 4611
(2011/07/08)

Self-association of an indole based guanidinium-carboxylate-zwitterion: Formation of stable dimers in solution and the solid state
The indole based zwitterion 2 forms stable dimers held together by H-bond assisted ion pairs. Dimerisation was confirmed in the solid state and studied in solution using dilution NMR experiments. Even though zwitterion 2 forms very stable dimers even in D
Rether, Carolin,Sicking, Wilhelm,Schmuck, Carsten,Boese, Roland
experimental part

(2010/07/18)

ANTIBACTERIAL HETEROCYCLIC UREAS
The present invention provides novel heterocyclic urea compounds having useful antibacterial activity, pharmaceutical compositions comprising one or more of these compounds, methods of making the same, and methods of using the same.
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Page/Page column 38

(2010/11/29)

ALKYNYL CONTAINING HYDROXAMIC ACID DERIVATIVES, THEIR PREPARATION AND THEIR USE AS MATRIX METALLOPROTEINASE (MMP) INHIBITORS / TNF-ALPHA CONVERTING ENZYME (TACE) INHIBITORS
Compounds of the formula:useful in the treatment of arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, diabetes (insulin resistance) and HIV infection.
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Page/Page column 47

(2010/02/14)

Derivatives of pyrimido[6.1-a]isoquinolin-4-one
The invention provides compounds or salts thereof of the general formula (I): wherein each of R1 and RX independently represents a C1-6 alkyl or C2-7 acyl group; X represents OCH2 or a group CR3R
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(2008/06/13)

Total synthesis and absolute configuration of minalemine A, a guanidine peptide from the marine tunicate Didemnum rodriguesi
The total synthesis of the 3S,2S and 3R,2S diastereomers (1a and 1b) of minalemine A and the identification of the natural compound as the 3R,2S isomer is described. The key step in the synthesis is the preparation of the two enantiomers of the β-amino diacid 3-(N-carboxymethyl)-aminodecanoic acid (Ncma), which were obtained by stereoselective alkylation with allyl bromide of two nonanoic acid imides bearing chiral oxazolidinones as chiral auxiliaries. Natural minalemine A shows identical 1H NMR and very similar 13C NMR spectra compared to the two synthetic diastereomers. Sufficient differences in their chromatographic behavior to allow conclusive identification were not found. However, the corresponding N-2-naphthoyl amides presented quite distinct circular dichroism spectra (CD), and these confirmed the 3R,2S configuration for the natural minalemines and the R configuration for the constituent β-amino diacid, Ncma.
Exposito,Fernandez-Suarez,Iglesias,Munoz,Riguera
p. 4206 - 4213
(2007/10/03)

New aromatic iminoimidazolidine derivatives as α1-adrenoceptor antagonists: A novel synthetic approach and pharmacological activity
The design, synthesis and α1-adrenoceptor antagonism of a series of bis-imidazoline (1a, 2a, 3a and 4a)Figure 2New families of compounds prepared in this work: (a) bis-2-iminoimidazolidinium derivatives, and (b) bis-guanidinium derivatives.Scheme 1 and bis-guanidine (1b, 2b, 3b and 4b) diphenyl derivatives are reported. All of these compounds fulfil the conditions of the most recent pharmacophore proposed for α1-adrenoceptors and found in the literature. Besides, a novel synthetic approach to the preparation of 2-(arylimino)imidazolidine derivatives is described. All the tested compounds, except the bis-guanidinium derivative 3b, inhibit the contractile responses induced by noradrenaline in aortic rings of rat and rabbit in a dose-dependent manner. Our results indicate that, even though some discrepancies are observed in terms of the α1 subtype targeted by this new family of compounds, they show an interesting profile as antagonists of α1-adrenoceptors and a new prototype, compound 1a, has been found deserving further development. Copyright (C) 2000 Elsevier Science Ltd.
Dardonville, Christophe,Goya, Pilar,Rozas, Isabel,Alsasua, Angela,Martin, M Isabel,Borrego, M Jose
p. 1567 - 1577
(2007/10/03)

A Constrained Diketopiperazine as a New Scaffold for the Synthesis of Peptidomimetics
As a new scaffold for peptidomimetic synthesis, a highly constrained bifunctional diketopiperazine, 4, has been prepared by smooth N-alkylation with tert-butyl bromoacetate. As a first application, we describe herein the synthesis of new peptidomimetics of the Arg-Gly-Asp (RGD) sequence. The product 30, which shows a selective platelet-aggregation inhibiting activity, can be used as a lead for the preparation of more potent products.
Pons, Jean-Francois,Fauchere, Jean-Luc,Lamaty, Frederic,Molla, Annie,Lazaro, Rene
p. 853 - 859
(2007/10/03)

A Mild and Efficient Method for the Preparation of Guanidines
A mild and efficient method for the preparation of guanidines by reaction of an acylated thiourea with an amine followed by removal of the acyl groups(s) from the intermediate acylguanidine is reported.Key Words: acylguanidine, acylthiourea, guanidine, water soluble carbodiimide
Poss, Michael A.,Iwanowicz, Edwin,Reid, Joyce A.,Lin, James,Gu, Zhengxiang
p. 5933 - 5936
(2007/10/02)