- Discovery of Novel Tacrine-Pyrimidone Hybrids as Potent Dual AChE/GSK-3 Inhibitors for the Treatment of Alzheimer's Disease
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Based on a multitarget strategy, a series of novel tacrine-pyrimidone hybrids were identified for the potential treatment of Alzheimer's disease (AD). Biological evaluation results demonstrated that these hybrids exhibited significant inhibitory activities toward acetylcholinesterase (AChE) and glycogen synthase kinase 3 (GSK-3). The optimal compound 27g possessed excellent dual AChE/GSK-3 inhibition both in terms of potency and equilibrium (AChE: IC50 = 51.1 nM; GSK-3β: IC50 = 89.3 nM) and displayed significant amelioration on cognitive deficits in scopolamine-induced amnesia mice and efficient reduction against phosphorylation of tau protein on Ser-199 and Ser-396 sites in glyceraldehyde (GA)-stimulated differentiated SH-SY5Y cells. Furthermore, compound 27g exhibited eligible pharmacokinetic properties, good kinase selectivity, and moderate neuroprotection against GA-induced reduction in cell viability and neurite damage in SH-SY5Y-derived neurons. The multifunctional profiles of compound 27g suggest that it deserves further investigation as a promising lead for the prospective treatment of AD.
- Yao, Hong,Uras, Giuseppe,Zhang, Pengfei,Xu, Shengtao,Yin, Ying,Liu, Jie,Qin, Shuai,Li, Xinuo,Allen, Stephanie,Bai, Renren,Gong, Qi,Zhang, Haiyan,Zhu, Zheying,Xu, Jinyi
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p. 7483 - 7506
(2021/06/28)
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- Development of a Novel Chemoenzymatic Process for (S)-1-(Pyridin-4-yl)-1,3-propanediol
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We first developed a novel and efficient chemoenzymatic process to prepare (S)-1-(pyridin-4-yl)-1,3-propanediol, a vital HepDirect prodrug intermediate, from inexpensive and commercially available isonicotinic acid. Through this process, we provide a creative way to obtain the key chiral intermediate, β-hydroxyester, with ketoreductase (KRED) EA. After optimization of the process, we performed the reaction on a 100 g scale with a substrate concentration of up to 150 g/L, a yield of 93%, and an ee value of up to 99.9%. Additionally, we used a simple and effective NaBH4/MgCl2 reduction system to obtain (S)-1-(pyridin-4-yl)-1,3-propanediol with >99.9% ee and an 80% yield. This novel chemoenzymatic process has the potential to be a cost-effective and environmentally friendly process suitable for industrial use.
- Chen, Shao-Xin,Peng, Peng,Tang, Jia-Wei,Wang, Hong-Yi,Yan, Hai-Jun,Zhang, Fu-Li
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p. 2890 - 2897
(2020/12/22)
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- Cu-Mediated Expeditious Annulation of Alkyl 3-Aminoacrylates with Aryldiazonium Salts: Access to Alkyl N2-Aryl 1,2,3-Triazole-carboxylates for Druglike Molecular Synthesis
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Alkyl N-aryl 1,2,3-triazole-carboxylates are important molecules or intermediates in medicinal chemistry, but the synthesis of N2-aryl counterparts remains elusive. Herein, we describe a Cu-mediated annulation reaction of alkyl 3-aminoacrylates with aryldiazonium salts, both of which are readily available substrates. Furthermore, alkyl 2-aminoacrylates are also viable substrates. Diverse alkyl N2-aryl 1,2,3-triazole-carboxylates and their analogues can be rapidly prepared under mild conditions. Especially, this protocol allows one to access several druglike variants of carbonic anhydrase inhibitors and celecoxib.
- Liu, Hao-Nan,Cao, Hao-Qiang,Cheung, Chi Wai,Ma, Jun-An
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supporting information
p. 1396 - 1401
(2020/02/22)
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- Preparation method of 4-ethylpyridine
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The invention relates to the technical field of organic synthesis, in particular to a preparation method of 4-ethylpyridine. The preparation method of the 4-ethylpyridine comprises the following stepsof: mixing ethyl 4-picolinate with sodium ethoxide, heating to 90 to 110 DEG C, then dropwise adding ethyl acetate, and carrying out claisen condensation reaction, thus obtaining ethyl 3-oxo-3-(4-pyridyl) propionate; mixing the ethyl 3-oxo-3-(4-pyridyl) propionate, dimethyl sulfoxide and water, and carrying out heating treatment, thus obtaining 4-acetylpyridine; cooling after mixing glycol with potassium hydroxide, adding hydrazine hydrate, rising the temperature to 60 to 80 DEG C, then mixing with the 4-acetylpyridine, and carrying out reduction reaction, thus obtaining the 4-ethylpyridine.The 4-ethylpyridine prepared through the preparation method provided by the invention is higher in yield and purity.
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Paragraph 0060; 0064-0065; 0070; 0074-0075; 0080; 0084-0085
(2019/04/10)
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- Pyrazole alcohol compound, pharmaceutical composition thereof and application thereof to drugs
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The invention discloses a 1-(3,5,6-trimethyl pyrazine-2-yl)-5-pyrazole alcohol compound, a tautomer thereof, a pharmaceutical composition thereof and application thereof to drugs. The 1-(3,5,6-trimethyl pyrazine-2-yl)-5-pyrazole alcohol compound has double effects of resisting platelet aggregation and protecting nerve cells, and comprises a compound as shown in the formula (I), a tautomer (Ia) thereof, or a stereoisomer, a geometrical isomer, a hydrate or a solvate thereof, or a pharmaceutically acceptable salt or prodrug as shown in the description. The 1-(3,5,6-trimethyl pyrazine-2-yl)-5-pyrazole alcohol compound and the pharmaceutical composition thereof provided by the invention can be used for preparing drugs for prevention and/or treatment and/or auxiliary treatment of cerebral apoplexy, cardiovascular and cerebrovascular diseases, senile dementia and complications thereof caused by thrombosis and excessive free radicals.
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Paragraph 0128; 0146
(2018/10/19)
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- Synthesis method of ceftaroline fosamil intermediate 4-(4'-pyridyl)-1,3-thiazolyl-2-thiol
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The invention discloses a synthesis method of an important antibiotic ceftaroline fosamil intermediate 4-(4'-pyridyl)-1,3-thiazolyl-2-thiol. The method comprises the following steps: carrying out Claisen condensation reaction on ethyl isonicotinate and ethyl acetate under alkaline conditions, carrying out acidic hydrolysis for decarboxylation, carrying out bromination reaction on the hydrolysis product and bromine, carrying out cyclization on the bromination product and ammonium dithiocarbamate, and finally, refluxing the cyclization product in glacial acetic acid to obtain the corresponding 4-(4'-pyridyl)-1,3-thiazolyl-2-thiol. The method has the advantages of fewer synthesis steps, low cost, cheap and accessible materials and low pollution, and is beneficial to industrial production.
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Paragraph 0008; 0009
(2016/11/24)
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- A copper-mediated oxidative coupling route to 3H- and 1H-indoles from N-aryl-enamines
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A facile copper(II)-mediated C-H bond oxidation and C-C bond formation procedure has been applied to the synthesis of indole derivatives. Intramolecular oxidative coupling of 3,3-disubstituted enamines proceeded using a non-expensive and air-stable copper
- Drouhin, Pauline,Taylor, Richard J. K.
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supporting information
p. 2333 - 2336
(2015/04/22)
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- 2-(2-Phenylmorpholin-4-yl)pyrimidin-4(3H)-ones; A new class of potent, selective and orally active glycogen synthase kinase-3β inhibitors
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A series of 2-(2-phenylmorpholin-4-yl)pyrimidin-4(3H)-ones was synthesized and examined for their inhibitory activity against glycogen synthase kinase-3β (GSK-3β). We found 21, 29 and 30 to possess potent in vitro GSK-3β inhibitory activity with good in vitro PK profiles. 21 demonstrated significant decrease of tau phosphorylation after oral administration in mice and excellent PK profiles.
- Fukunaga, Kenji,Uehara, Fumiaki,Aritomo, Keiichi,Shoda, Aya,Hiki, Shinsuke,Okuyama, Masahiro,Usui, Yoshihiro,Watanabe, Kazutoshi,Yamakoshi, Koichi,Kohara, Toshiyuki,Hanano, Tokushi,Tanaka, Hiroshi,Tsuchiya, Susumu,Sunada, Shinji,Saito, Ken-Ichi,Eguchi, Jun-Ichi,Yuki, Satoshi,Asano, Shoichi,Tanaka, Shinji,Mori, Akiko,Yamagami, Keiji,Baba, Hiroshi,Horikawa, Takashi,Fujimura, Masatake
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p. 6933 - 6937
(2014/01/06)
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- COMPOUNDS
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The present invention features compounds of formula (I): and salts thereof, pharmaceutical compositions comprising said compounds, and uses of such compounds in treating or preventing viral infections, such as HCV infections, and diseases associated with such infections.
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- Simple, fast and efficient synthesis of β-keto esters from the esters of heteroaryl compounds, its antimicrobial study and cytotoxicity towards various cancer cell lines
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A series of β-keto esters were synthesized from heteroaryl esters and ethyl acetate using LiHMDS as base at -50 to -30 °C. The increase in yields of cross condensed product were observed and the percentage of self condensed product was reduced drastically by applying the suitable base (LiHMDS), solvent and the minimum amount of ethyl acetate. All these β-keto esters were characterized using 1H NMR, 13C NMR and mass spectral data. A plausible mechanism is also depicted to prove the formation of trans-esterified products. All the synthesized compounds were subjected to test for their cytotoxicity towards various cancer cell lines and also tested for their antimicrobial activity towards various bacterial and fungal strains and some of them were found to have promising activity.
- Venkat Ragavan,Vijayakumar,Rajesh,Palakshi Reddy,Karthikeyan,Suchetha Kumari
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supporting information; experimental part
p. 4193 - 4197
(2012/07/14)
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- INDOLE DERIVATIVES AS CRAC MODULATORS
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Compounds of the formula I: or pharmaceutically acceptable salts thereof, wherein R1, R2, R3 and R4 are as defined herein. Also disclosed are methods of making the compounds and using the compounds for treatment of diseases associated with calcium release-activated calcium channels (CRAC).
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Page/Page column 27
(2012/01/30)
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- HETEROARYLOXY-SUBSTITUTED PHENYLAMINOPYRIMIDINES AS RHO-KINASE INHIBITORS
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The invention relates to heteroaryloxy-substituted phenylaminopyrimidines, to methods for the production thereof, and to the use of the same for producing medicaments for the treatment and/or prophylaxis of diseases, especially cardiovascular diseases. The inventive compounds inhibit Rho-kinase.
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Page/Page column 73-74
(2010/02/06)
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- PHENYLAMINOPYRIMIDINES AND THEIR USE AS RHO-KINASE INHIBITORS
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The invention relates to the phenylaminopyrimidines of formula (I), wherein A, D, R1, R2, R3 and R4 are defined as in the description. The invention also relates to methods for producing said phenylaminopyrimidines and to their use for producing drugs for the treatment and/or the prophylaxis of diseases, especially cardiovascular diseases.
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Page column 39,40
(2010/02/06)
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- 2-Amino-3-(alkyl)-pyrimidone derivatives as gsk3β inhibitors
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A pyrimidone derivative represented by formula (I) or a salt thereof: Wherein: R1 represents a hydrogen atom or a C1-6 alkyl group which may be substituted by a C6,10 aryl group; R2 represents a C1-10 alkyl group which may
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- MEDICINAL COMPOSITION
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The present invention is composed of a pharmaceutical composition for the therapy of nephritis which comprises an amide derivative represented by the following formula [1] or pharmaceutically acceptable salt thereof, as an active ingredient: ???wherein R1 and R2 may be the same or different and each is hydrogen, alkyl which may be substituted, acyl, aryl which may be substituted, or an aromatic heterocyclic group which may be substituted; R3, R4, R5 and R6 may be the same or different and each is hydrogen, halogen, hydroxy, amino which may be substituted, alkyl which may be substituted, alkoxy or nitro and the like; and R7 represents cyclic amino which may be substituted or azabicycloalkylamino which may be substituted. The pharmaceutical composition of the invention is useful for the therapy of nephritis.
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- AMIDE DERIVATIVES AND DRUG COMPOSITIONS
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The present invention is composed of an amide derivative represented by the following formula [1] or pharmaceutically acceptable salt thereof: ???wherein R1 and R2 may be the same or different and each is hydrogen, alkyl which may be substituted, acyl, aryl which may be substituted, or an aromatic heterocyclic group which may be substituted; R3, R4, R5, and R6 may be the same or different and each is hydrogen, halogen, hydroxy, amino which may be substituted, alkyl which may be substituted, alkoxy, or nitro and the like; and R7 represents cyclic amino which may be substituted or azabicycloalkylamino which may be substituted, and a pharmaceutical composition which comprises it as an active ingredient. The compound of the invention is useful as an inhibitor of TGF-β production or an antagonist of TGF-β.
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- 2-(Indolylalkylamino)pyrimidone derivatives as GSK3beta inhibitors
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A pyrimidone derivative represented by formula (I) or a salt thereof: wherein:R1 represents a hydrogen atom or a C1-6 alkyl group;R2 represents a hydrogen atom or a C 1-6 alkyl group;R3 represents a 2, 3 or 4-pyridyl group optionally
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- 2-[Piperazinyl]pyrimidone derivatives
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A pyrimidone derivative represented by formula (I) or a salt thereof: wherein R1 representsa C6,10 aryl group,a heterocyclic ring having 1-4 hetero atoms selected from oxygen atom, sulfur atom, and nitrogen atom, and having total ring-constitut
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- Substituted pyridyl pyrroles, compositions containing such compounds and methods of use
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The present invention addresses substituted pyridyl pyrroles, as well as compositions containing such compounds and methods of treatment. The compounds in the present invention are glucagon antagonists and inhibitors of the biosynthesis and action of TNF-
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- 3-(Pyridinyl)-2-cyclohexen-1-ones
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3-(4 OR 3-Pyridinyl)-2-cyclohexen-1-ones (I) and their oxime derivatives are useful in preparing (3-aminophenyl)-pyridines, in turn, useful in preparing known antibacterial agents. Also shown is the preparation of I by starting with the reaction of methyl vinyl ketone with either 1-(pyridinyl)-1-(lower-tertiary-amino)-ethylene (II) or lower-alkyl 3-(pyridinyl)-3-oxopropanoate. Also shown is the process of converting I to its oxime, acylating the oxime and heating the acylated oxime under acidic conditions to produce N-(lower-acyl)-3-(pyridinyl)-aniline (VII), and hydrolyzing VII under aqueous alkaline conditions to produce the corresponding 3-(pyridinyl)aniline.
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