73365-02-3Relevant articles and documents
X-ray Structure-Guided Discovery of a Potent, Orally Bioavailable, Dual Human Indoleamine/Tryptophan 2,3-Dioxygenase (hIDO/hTDO) Inhibitor That Shows Activity in a Mouse Model of Parkinson’s Disease
Ning, Xiang-Li,Li, Yu-Zhi,Huo, Cui,Deng, Ji,Gao, Cheng,Zhu, Kai-Rong,Wang, Miao,Wu, Yu-Xiang,Yu, Jun-Lin,Ren, Ya-Li,Luo, Zong-Yuan,Li, Gen,Chen, Yang,Wang, Si-Yao,Peng, Cheng,Yang, Ling-Ling,Wang, Zhou-Yu,Wu, Yong,Qian, Shan,Li, Guo-Bo
, p. 8303 - 8332 (2021/06/30)
Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan 2,3-dioxygenase (hTDO) have been closely linked to the pathogenesis of Parkinson’s disease (PD); nevertheless, development of dual hIDO1 and hTDO inhibitors to evaluate their potential efficacy against PD is still lacking. Here, we report biochemical, biophysical, and computational analyses revealing that 1H-indazole-4-amines inhibit both hIDO1 and hTDO by a mechanism involving direct coordination with the heme ferrous and ferric states. Crystal structure-guided optimization led to23, which manifested IC50values of 0.64 and 0.04 μM to hIDO1 and hTDO, respectively, and had good pharmacokinetic properties and brain penetration in mice.23showed efficacy against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse motor coordination deficits, comparable to Madopar, an anti-PD medicine. Further studies revealed that different from Madopar,23likely has specific anti-PD mechanisms involving lowering IDO1 expression, alleviating dopaminergic neurodegeneration, reducing inflammatory cytokines and quinolinic acid in mouse brain, and increasing kynurenic acid in mouse blood.
Process Development and GMP Production of a Conjugate Warhead: Auristatin F-HPA-Ala/TFA (XMT-1864/TFA)
Conlon, Patrick R.,Gurijala, Venu Reddy,Kaufman, Michael,Li, Dachang,Li, Jiuyuan,Li, Yuanyuan,Reddy, Bollu Satyanarayan,Wagler, Thomas,Wang, Zedong,Xu, Zhongmin,Yin, Mao,Yurkovetskiy, Aleksandr V.,Zhu, Lei
, (2022/03/01)
An efficient, large-scale manufacturing process is described for XMT-1864/TFA (1-TFA), an auristatin F derivative, used as a novel, highly potent, cytotoxic warhead in Mersana's oncology antibody-drug conjugate platforms. The process achieves high diastereomeric purity and controls the impurities with all intermediates readily isolated by crystallization or precipitation in high yield and purity. Protecting groups were selected to ensure tolerability, scalability, and stability of the intermediates under various solution-phase peptide coupling conditions. Crystallization of the final product was developed to remove specified impurities and provide a high-purity active warhead molecule for use in the bioconjugation processing. The convergent synthesis involving six non-GMP steps and five GMP steps has been carried out in multiple cGMP productions on 1-kg scale to produce 1-TFA in >98% chemical purity and 1% total diastereomeric contamination with ~50% overall yield for the GMP steps.
NOVEL POTASSIUM CHANNEL INHIBITORS
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Page/Page column 56; 72, (2020/10/20)
The present invention relates to novel compounds, pharmaceutical compositions comprising such compounds and their use for treating, alleviating or preventing diseases or disorders relating to the activity of potassium channels.
Preparation Method for Tyrosine Kinase Inhibitor and Intermediate Thereof
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Paragraph 0094, (2020/08/19)
Provided is a preparation method for a tyrosine kinase inhibitor and an intermediate thereof. Specifically, a preparation method for a cyanoquinoline compound is provided. The method has a high yield, good product purity, and mild reaction conditions.
Compound, preparation method thereof, pharmaceutical composition and application of compound
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, (2020/01/03)
The invention discloses a compound, a preparation method thereof, a pharmaceutical composition and application of the compound. The compound I, and a stereoisomer or a pharmacologically acceptable salt thereof can serve as a CDK7 kinase inhibitor, are high in inhibition activity, and can be used for treatment of various malignant tumors.
METHOD FOR PREPARING TYROSINE KINASE INHIBITOR AND DERIVATIVE THEREOF
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Paragraph 0061-0063, (2019/05/15)
The present invention relates to a method for preparing a tyrosine kinase inhibitor and a derivative thereof. The present method has a short synthesis route, low costs, easy operation, and is suitable for large-scale production.
MACROCYCLIC COMPOUNDS AS TRK KINASE INHIBITORS AND USES THEREOF
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Paragraph 173, (2019/05/30)
The present disclosure describes novel TRK kinase inhibitors and methods for preparing them. The pharmaceutical compositions comprising such TRK kinase inhibitors and methods of using them for treating cancer, infectious diseases, and other disorders are also described.
COMPOUNDS, COMPOSITIONS AND METHODS FOR SYNTHESIS
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Paragraph 001705; 001706; 001707; 001708, (2019/01/10)
The present disclosure, among other things, provides technologies for synthesis, including reagents and methods for stereoselective synthesis. In some embodiments, the present disclosure provides compounds useful as chiral auxiliaries. In some embodiments, the present disclosure provides reagents and methods for oligonucleotide synthesis. In some embodiments, the present disclosure provides reagents and methods for chirally controlled preparation of oligonucleotides. In some embodiments, technologies of the present disclosure are particularly useful for constructing challenging internucleotidic linkages, providing high yields and stereoselectivity.
Compound (E)-3-(1-methylpyrrolidine-2-yl)-acrylic hydrochloride and synthetic method
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Paragraph 0069; 0070; 0071, (2018/08/03)
The invention discloses a compound (E)-3-(1-methylpyrrolidine-2-yl)-acrylic hydrochloride and a synthetic method. The compound is structurally as shown in a formula (I). The synthetic method of the compound comprises the following steps: using BOC-L-prolinol (or BOC-D-prolinol) as an initial material, and by oxidization, forming aldehyde; removing a BOC protective agent; then reacting with haloalkane; then by a Wittig reaction, synthesizing (S,E)-3-(1-methylpyrrolidine-2-yl)-ethyl acrylate; after hydrolysis, salifying to obtain (S,E)-3-(1-methylpyrrolidine-2-yl)-acrylic hydrochloride [or (R,E)-3-(1-methylpyrrolidine-2-yl)-acrylic hydrochloride]. The compound, as a medical intermediate, can be used for preparing quinazoline or quinolines medicine derivatives. The formula is shown in the description.
Benzimidazole-2-piperazine compound, its pharmaceutical composition and its preparation and use
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Paragraph 0209; 0246; 0249; 0250, (2016/10/20)
The invention relates to a benzimidazole-2-piperazine derivative and a preparing method and application of the benzimidazole-2-piperazine derivative in medicine, in particular to a novel benzimidazole-2-piperazine derivative shown in the general formula (I), a preparing method of the derivative, a pharmaceutical composition containing the derivative and application of the derivative serving as a therapeutic agent, especially serving as a poly (ADP-ribose) polymerase (PARP) inhibitor. In the general formula (I), R refers to hydrogen or halogen, G refers to carbonyl or methylene, m is 1-2, n is 1-3, and Q refers to hydrogen or C1-C4 alkyl. When X is methylene and Y is NR1 or methylene, X is NR1; R1 refers to hydrogen, C1-C6 alkyl, benzyl, COR2 or SO2R2; R2 refers to the following groups which are not substituted or groups substituted by 1-3 substituent groups, including C1-C6 alkyl, C3-C8 naphthenic base, phenyl, benzyl, naphthyl and C5-C10 aromatic heterocycle base, heterocycle in the C5-C10 aromatic heterocycle base comprises 1-3 heteroatoms selected from N, O and S, and the substituent groups are selected from the following atoms or groups of C1-C6 alkyl, C1-C6 alkoxy, halogen, amidogen, nitryl, sulfydryl, hydroxyl, cyanogroup and trifluoromethyl. The general formula (I) is shown in the specification.