- FERROPORTIN INHIBITORS AND METHODS OF USE
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The subject matter described herein is directed to Ferroportin inhibitor compounds of Formula I and pharmaceutical salts thereof, methods of preparing the compounds, pharmaceutical compositions comprising the compounds and methods of administering the compounds for prophylaxis and/or treatment of diseases caused by a lack of hepcidin or iron metabolism disorders, particularly iron overload states, such as thalassemia, sickle cell disease and hemochromatosis.
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Paragraph 0199; 0200
(2020/07/07)
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- A hydrochloric acid of the medicinal Starlite degradation impurity synthetic method
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The invention belongs to the technical field of pharmaceutical chemistry, and in particular relates to a hydrochloric acid of the medicinal Starlite degradation impurity synthetic method. The synthetic method, in order to N - Cbz - beta - alanine as raw m
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Paragraph 0043-0045; 0064-0066
(2019/07/10)
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- Formamide catalyzed activation of carboxylic acids-versatile and cost-efficient amidation and esterification
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A novel, broadly applicable method for amide C-N and ester C-O bond formation is presented based on formylpyrrolidine (FPyr) as a Lewis base catalyst. Herein, trichlorotriazine (TCT), which is the most cost-efficient reagent for OH-group activation, was employed in amounts of ≤40 mol% with respect to the starting material (100 mol%). The new approach is distinguished by excellent cost-efficiency, waste-balance (E-factor down to 3) and scalability (up to >80 g). Moreover, high levels of functional group compatibility, which includes acid-labile acetals and silyl ethers, are demonstrated and even peptide C-N bonds can be formed. In comparison to reported amidation procedures using TCT, yields are considerably improved (for instance from 26 to 91%) and esterification is facilitated for the first time in synthetically useful yields. These significant enhancements are rationalized by activation by means of acid chlorides instead of less electrophilic acid anhydride intermediates.
- Huy, Peter H.,Mbouhom, Christelle
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p. 7399 - 7406
(2019/08/20)
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- METHOD FOR PRODUCING L-CARNOSINE DERIVATIVE AND L-CARNOSINE
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PROBLEM TO BE SOLVED: To provide a convenient method for producing a high-purity N-protected L-carnosine derivative and L-carnosine. SOLUTION: A production method includes reacting an acid halide (1) with an L-histidine derivative (2). (R1 and R2 are H or a protection group of an amino group; X is a halogen atom). (A TMS group is a trimethylsilyl group). SELECTED DRAWING: None COPYRIGHT: (C)2020,JPOandINPIT
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Paragraph 0093
(2019/12/05)
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- IMMUNOMODULATOR COMPOUNDS
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Compounds are provided that are useful as immunomodulators. The compounds have the following Formula (II): including stereoisomers and pharmaceutically acceptable salts thereof, wherein R1, R2a, R2b, R2c, R3, R4, R5, R6a, R6b, m and n are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
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Paragraph 0221; 0222
(2018/02/28)
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- NEAR-INFRARED FLUORESCENT CONTRAST BIOIMAGING AGENTS AND METHODS OF USE THEREOF
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The instant invention provides near-infrared fluorescent biological contrast agents and methods of using them.
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Page/Page column 116; 117
(2015/05/19)
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- The Synthesis of Structurally Diverse Macrocycles by Successive Ring Expansion
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Structurally diverse macrocycles and medium-sized rings (9-24 membered scaffolds, 22 examples) can be generated through a telescoped acylation/ring-expansion sequence, leading to the insertion of linear fragments into cyclic β-ketoesters without performin
- Kitsiou, Christiana,Hindes, Jordan J.,I'Anson, Phillip,Jackson, Paula,Wilson, Thomas C.,Daly, Eleanor K.,Felstead, Hannah R.,Hearnshaw, Peter,Unsworth, William P.
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supporting information
p. 15794 - 15798
(2016/01/29)
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- Macrocyclic pyridyl polyoxazoles: Structure-activity studies of the aminoalkyl side-chain on G-quadruplex stabilization and cytotoxic activity
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Pyridyl polyoxazoles are 24-membered macrocyclic lactams comprised of a pyridine, four oxazoles and a phenyl ring. A derivative having a 2-(dimethylamino)ethyl chain attached to the 5-position of the phenyl ring was recently identified as a selective G-quadruplex stabilizer with excellent cytotoxic activity, and good in vivo anticancer activity against a human breast cancer xenograft in mice. Here we detail the synthesis of eight new dimethylamino-substituted pyridyl polyoxazoles in which the point of attachment to the macrocycle, as well as the distance between the amine and the macrocycle are varied. Each compound was evaluated for selective G-quadruplex stabilization and cytotoxic activity. The more active analogs have the amine either directly attached to, or separated from the phenyl ring by two methylene groups. There is a correlation between those macrocycles that are effective ligands for the stabilization of G-quadruplex DNA (ΔTtran 15.5-24.6 °C) and cytotoxicity as observed in the human tumor cell lines, RPMI 8402 (IC 50 0.06-0.50 μM) and KB3-1 (IC50 0.03-0.07 μM). These are highly selective G-quadruplex stabilizers, which should prove especially useful for evaluating both in vitro and in vivo mechanism(s) of biological activity associated with G-quaqdruplex ligands.
- Blankson, Gifty,Rzuczek, Suzanne G.,Bishop, Cody,Pilch, Daniel S.,Liu, Angela,Liu, Leroy,LaVoie, Edmond J.,Rice, Joseph E.
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p. 11938 - 11963
(2013/11/06)
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- Design, Synthesis, ADME Properties, and Pharmacological Activities of β-Alanyl-D-histidine (D-Carnosine) Prodrugs with Improved Bioavailability
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β-Alanyl-D-histidine (D-CAR, the enantiomer of the natural dipeptide carnosine) is a selective and potent sequestering agent of reactive carbonyl species (RCS) that is stable against carnosinase, but is poorly absorbed in the gastrointestinal tract. Herein we report a drug discovery approach aimed at increasing the oral bioavailability of D-CAR. In our study we designed, synthesized, and evaluated a series of novel lipophilic D-CAR prodrugs. The considered prodrugs can be divided into two categories: 1)derivatives with both terminal groups modified, in which the carboxyl terminus is always esterified while the amino terminus is protected by an amidic (N-acetyl derivatives) or a carbamate (ethyloxy or benzyloxy derivatives) function; 2)derivatives with only one terminus modified, which can be alkyl esters as well as amidic or carbamate derivatives. The prodrugs were designed considering their expected lipophilicity and their hydrolysis predicted by docking simulations on the most important human carboxylesterase (hCES1). The stability and metabolic profile of the prodrugs were studied by incubating them with rat and human serum and liver fractions. The octyl ester of D-CAR (compound 13) was chosen as a candidate for further pharmacological studies due to its rapid hydrolysis to the bioactive metabolite invitro. Pharmacokinetic studies in rats confirmed the invitro data and demonstrated that the oral bioavailability of D-CAR is increased 2.6-fold if given as an octyl ester relative to D-CAR. Compound 13 was then found to dose-dependently (at daily doses of 3 and 30mgkg-1 equivalent of D-CAR) decrease the development of hypertension and dyslipidemia, to restore renal functions of Zucker fa/fa obese rats, and to inhibit the carbonylation process (AGEs and pentosidine) as well as oxidative stress (urinary 8-epi-prostaglandin F2α and nitrotyrosine). A plausible mechanism underlying the protective effects of 13 is RCS sequestration, as evidenced by the significant increase in the level of adduct between CAR and 4-hydroxy-trans-2-nonenal (HNE, the main RCS generated by lipid oxidation) in the urine of treated animals. The modest oral absorption of D-carnosine (D-CAR), a bioactive compound able to detoxify reactive carbonyl species, prompted us to design, synthesize, and evaluate new lipophilic D-CAR prodrugs. Among these, D-CAR with an octyl ester has greater oral bioavailability than D-CAR, as demonstrated by pharmacokinetic studies. The new compound reduces the development of hypertension and dyslipidemia, and restores renal function in Zucker fa/fa obese rats.
- Orioli, Marica,Vistoli, Giulio,Regazzoni, Luca,Pedretti, Alessandro,Lapolla, Annunziata,Rossoni, Giuseppe,Canevotti, Renato,Gamberoni, Luca,Previtali, Massimo,Carini, Marina,Aldini, Giancarlo
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experimental part
p. 1269 - 1282
(2012/05/20)
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- VIGABATRIN BIOISOTERES AND RELATED METHODS OF USE
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Compounds bioisoteric to vigabatrin and related methods of use.
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Page/Page column 6; 11-12
(2010/11/26)
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- Syntheses of phosphonic esters of alendronate, pamidronate and neridronate
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Several synthetic pathways for obtaining phosphonic esters of the amino bisphosphonic acids (NBPs) pamidronate, alendronate and neridronate were investigated. The general guideline was to react N-protected amino acids activated as phthalimide esters or as acyl chlorides. Succinimide esters were found less reactive and quickly abandoned. γ-Lactam formation arises when starting from Boc- or Cbz-protected amino acids. The phthalimide N-protecting group allowed access to alkyl or aryl mono-, di- (symmetric or not) and triesters of these three NBPs in high yields. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.
- Guenin, Erwann,Monteil, Maelle,Bouchemal, Nadia,Prange, Thierry,Lecouvey, Marc
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p. 3380 - 3391
(2008/02/10)
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- New substrates and inhibitors of γ-aminobutyric acid aminotransferase containing bioisosteres of the carboxylic acid group: Design, synthesis, and biological activity
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A series of potential substrates of γ-aminobutyric acid aminotransferase (GABA-AT) with lipophilic bioisosteres of the carboxylic acid group (2-7) were synthesized and tested. Most of the synthesized compounds showed substrate activities with GABA-AT; 1H-tetrazole-5-propanamine (6) was the best of those tested. The potential time-dependent inhibitor of GABA-AT, 1H-tetrazole-5-(α-vinyl-propanamine) (8), was designed based on the structures of 6 and the antiepilepsy drug vigabatrin (4-aminohex-5-enoic acid, 1). The synthesized compound 8 showed time-dependent inhibition of GABA-AT, but its potency is lower than that of vigabatrin. Methylation of the tetrazole group in 8 resulted in loss of time-dependent activity, suggesting that the tetrazole ring, the carboxylate bioisostere, exists in its deprotonated form in the enzyme active site.
- Yuan, Hai,Silverman, Richard B.
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p. 1331 - 1338
(2007/10/03)
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- Hexahydropyridazine-3-carboxylic acid hydrazide and hydrazone derivatives, combinatorial libraries containing same, pharmaceutical compositions containing same and methods of preparation
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The present invention discloses and claims hexahydropyridazine-3-carboxylic acid hydrazides and hydrazones of formula (I) as inhibitors of proteases and kinases, and methods of using said compounds of formula (I) for the prevention or treatment of certain
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Page/Page column 7
(2008/06/13)
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- Hexahydropyridazine-3-carboxylic acid derivatives, pharmaceutical compositions containing same and methods of preparation
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The present invention discloses and claims compounds of formula (I) as inhibitors of proteases and kinases, method using said compounds of formula (I) for the prevention or treatment of certain cardiovascular, central nervous system, inflammatory, and bon
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Page/Page column 9
(2010/02/13)
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- Chemical transformations of 3-amino-2-quinolones
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In order to find new antimalarial drugs, an exploration about the chemical properties of the starting compounds 3-amino-6-chloro-4-phenyl-1H-quinolin-2-one (1) and 3-amino-4-methyl-1H-quinolin-2-one (2) was developed. Acylation with acyl chloride, sulfony
- Asis, Silvia E.,Bruno, Ana M.,Dominici, Diego A.,Bollini, Mariela,Gaozza, Carlos H.
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p. 107 - 112
(2007/10/03)
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- Enantioselective synthesis of β-amino acids. Part 11: Diastereoselective alkylation of chiral derivatives of β-aminopropionic acid containing the α-phenethyl group
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Several novel, chiral derivatives of β-aminopropionic acid were studied as potentially useful precursors of enantiopure α-substituted-β-amino acids. In particular, the diastereoselectivity of alkylation of (R,R)-2-Li enolate showed substantial stereoinduction by the bis[α-phenylethyl]amide auxiliary, leading to 80% ds in the methylation reaction. No appreciable effect upon diastereoselectivity was observed by the presence of additives (LiCl, HMPA, DMPU) in the reaction. On the other hand, stereoinduction by the α-phenylethylamino group in the methylation of ester enolate (S)-3-Li was lower (65% ds) under standard conditions (THF, -78°C) but improved to 81% ds in the presence of 3 equiv. of HMPA as cosolvent. 'Matched' and 'mismatched' derivatives, (R,R,S)-11 and (R,R,R)-11, respectively, were methylated via their corresponding lithium enolates. Observed diastereoselectivities generally followed the anticipated tendencies based on double stereoinduction. Thus diastereoselectivity reached 89% ds in the methylation of the matched isomer, (R,R,S)-11-Li.
- Gutiérrez-García, Víctor Manuel,López-Ruiz, Heraclio,Reyes-Rangel, Gloria,Juaristi, Eusebio
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p. 6487 - 6496
(2007/10/03)
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