- Preparation method of topiroxostat crystal form I
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The invention relates to a preparation method of a topiroxostat crystal form I and belongs to the technical field of medicine. The invention provides the topiroxostat crystal form I suitable for preparing preparation and provides a preparation method of the topiroxostat crystal form I with environmental friendliness and suitability for industrial operation. According to the technical scheme of thepreparation method disclosed by the invention, 4-methyl formate pyridine is utilized as a starting material, and the topiroxostat crystal form I is prepared by the steps of introducing acylamino, dehydrating, performing nucleophilic substitution, performing nucleophilic addition, condensation salifying and the like. According to the technical scheme of the preparation method disclosed by the invention, a telescoping technology is utilized, so that solvent use and energy consumption are reduced; meanwhile, reasonable salifying can prevent genotoxic impurities from being generated.
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Paragraph 0055-0064
(2018/03/26)
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- POLYSUBUNIT OPIOID PRODRUGS RESISTANT TO OVERDOSE AND ABUSE
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The invention provides compositions and methods for the treatment or prevention of pain. Compositions provided are resistant to overdose and abuse. Compositions provided comprise two or more different molecules, where each molecule comprises at least one GI enzyme-labile opioid agonist releasing subunit comprising an opioid agonist that is covalently linked to at least one GI enzyme inhibitor subunit.
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Paragraph 248
(2018/10/19)
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- A combination of flow and batch mode processes for the efficient preparation of mGlu2/3 receptor negative allosteric modulators (NAMs)
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Benzodiazepinones are privileged scaffolds with activity against multiple therapeutically relevant biological targets. In support of our ongoing studies around allosteric modulators of metabotropic glutamate receptors (mGlus) we required the multigram synthesis of a β-ketoester key intermediate. We report the continuous flow synthesis of tert-butyl 3-(2-cyanopyridin-4-yl)-3-oxopropanoate and its transformation to potent mGlu2/3 negative allosteric modulators (NAMs) in batch mode.
- Dhanya, Raveendra Panickar,Herath, Ananda,Sheffler, Douglas J.,Cosford, Nicholas D.P.
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p. 3165 - 3170
(2018/04/16)
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- C?H Cyanation of 6-Ring N-Containing Heteroaromatics
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Heteroaromatic nitriles are important compounds in drug discovery, both for their prevalence in the clinic and due to the diverse range of transformations they can undergo. As such, efficient and reliable methods to access them have the potential for far-reaching impact across synthetic chemistry and the biomedical sciences. Herein, we report an approach to heteroaromatic C?H cyanation through triflic anhydride activation, nucleophilic addition of cyanide, followed by elimination of trifluoromethanesulfinate to regenerate the cyanated heteroaromatic ring. This one-pot protocol is simple to perform, is applicable to a broad range of decorated 6-ring N-containing heterocycles, and has been shown to be suitable for late-stage functionalization of complex drug-like architectures.
- Elbert, Bryony L.,Farley, Alistair J. M.,Gorman, Timothy W.,Johnson, Tarn C.,Genicot, Christophe,Lallemand, Bénédicte,Pasau, Patrick,Flasz, Jakub,Castro, José L.,MacCoss, Malcolm,Paton, Robert S.,Schofield, Christopher J.,Smith, Martin D.,Willis, Michael C.,Dixon, Darren J.
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supporting information
p. 14733 - 14737
(2017/10/07)
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- POLYSUBUNIT OPIOID PRODRUGS RESISTANT TO OVERDOSE AND ABUSE
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The invention provides compositions and methods for the treatment or prevention of pain. The invention provides constructs whereby hydrolysis of the construct by a specified gastrointestinal enzyme directly, or indirectly, releases an opioid when taken orally as prescribed. The gastrointestinal enzyme mediated release of opioid from constructs of the invention is designed to be attenuated in vivo via a saturation or inhibition mechanism when overdoses are ingested. The invention further provides constructs that are highly resistant to oral overdose, chemical tampering, and abuse via non-oral routes of administration.
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Paragraph 1104
(2017/05/02)
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- Synthesis and structural studies of new asymmetric pyridyl-tetrazole ligands for supramolecular chemistry
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The synthesis of asymmetric diester derivatives of pyridyl-tetrazole ligands was successfully undertaken. Five crystal structures are reported including three asymmetric diesters (one of which is a mixed methyl ethyl ester derivative), a dicarboxylic acid and a monosodium (dicarboxylic acid)(monoacid-carboxylate) dihydrate intermediate. The dicarboxylic acid assembles by an unusual and unexpected route with the primary assembly based on carboxylic…pyridine (COOH?N) synthons that form an unusual cyclic hydrogen bonded ring with the R22(17) motif. Assembly in hydrogen bonding motifs using ‘odd’ numbers of atoms is the exception rather than the rule.
- Sheridan, Ursula,Gallagher, John F.,McGinley, John
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p. 8470 - 8478
(2016/12/06)
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- 4 - [5 - (pyridin-4-yl) - 1H-[ 1, 2, 4] triazol-3-yl] pyridine-2-carbonitrile method for the preparation of (by machine translation)
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The invention relates to a preparation of 4-[5-(pyridine-4-yl)-1H-[1,2,4]triazole-3-yl]pyridine-2-formonitrile. The method includes following steps: preparing a compound methyl 2-cyanoisonicotinate represented as the formula (4) with a compound methylisonicotinic-N-oxide (5) being a starting raw material in the presence of a copper catalyst (CuX), a metal cyanide and dimethylcarbamyl chloride; performing hydrazinolysis to the methyl 2-cyanoisonicotinate to obtain a compound 2-cyanoisoniazide represented as the formula (3); and finally performing condensation with a compound 4-cyanopyridine represented as the formula (2) to obtain a compound topiroxostat represented as the formula (1). The method only comprises three steps and is simple in operation and post-treatment. By means of the copper catalyst, a usage amount of the metal cyanide is greatly reduced so that reaction conditions are milder. The method is high in purity of the prepared product and is suitable for industrial production.
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Paragraph 0041; 0042
(2017/02/02)
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- Active agent prodrugs with heterocyclic linkers
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The embodiments provide prodrug compounds of Formulae I-XVII. The present disclosure also provides compositions, and their methods of use, where the compositions comprise a prodrug compound of Formulae I-XVII that provides controlled release of an active agent. Such compositions can optionally provide a trypsin inhibitor that interacts with the enzyme that mediates the controlled release of an active agent from the prodrug so as to attenuate enzymatic cleavage of the prodrug.
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Page/Page column 153; 154; 159
(2015/10/28)
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- COMPOUNDS AND METHODS for the inhibition of HDAC
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Disclosed are compounds having the formula: wherein X1, X2, X3, R1, R2, R3, R4, Y, A, Z, L and n are as defined herein, and methods of making and using the same.
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Paragraph 0425-0426
(2015/11/24)
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- AMIDO-BENZYL SULFONE AND SULFONAMIDE DERIVATIVES
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Disclosed are certain amido-benzyl sulfone and sulfonamide compounds, pharmaceutical compositions comprising such compounds, land methods of treatment using such compounds.
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- Discovery of tetrasubstituted imidazolines as potent and selective neuropeptide Y Y5 receptor antagonists: Reduced human ether-a-go-go related gene potassium channel binding affinity and potent antiobesity effect
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A series of novel imidazoline derivatives was synthesized and evaluated as neuropeptide Y (NPY) Y5 receptor antagonists. Optimization of previously reported imidazoline leads, 1a and 1b, was attempted by introduction of substituents at the 5-position on the imidazoline ring and modification of the bis(4-fluorphenyl) moiety. A number of potent derivatives without human ether-a-go-go related gene potassium channel (hERG) activity were identified. Selected compounds, including 2a, were shown to have excellent brain and CSF permeability. Compound 2a displayed a suitable pharmacokinetic profile for chronic in vivo studies and potently inhibited D-Trp34NPY-induced acute food intake in rats. Oral administration of 2a resulted in a potent reduction of body weight in a diet-induced obese mouse model.
- Sato, Nagaaki,Ando, Makoto,Ishikawa, Shiho,Jitsuoka, Makoto,Nagai, Keita,Takahashi, Hirobumi,Sakuraba, Aya,Tsuge, Hiroyasu,Kitazawa, Hidefumi,Iwaasa, Hisashi,Mashiko, Satoshi,Gomori, Akira,Moriya, Ryuichi,Fujino, Naoko,Ohe, Tomoyuki,Ishihara, Akane,Kanatani, Akio,Fukami, Takehiro
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supporting information; experimental part
p. 3385 - 3396
(2010/03/24)
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- NOVEL 1,2,4-TRIAZOLE COMPOUND
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A novel 1,2,4-triazole compound which is useful as a therapeutic agent for hyperuricemia and gout due to hyperuricemia is provided. A compound is represented by the following general formula (1): wherein R2 represents an unsubstituted or substituted pyridyl group, R1 represents a similar pyridyl group, a pyridine-N-oxide group corresponding to these pyridyl groups, or a phenyl group, and R3 represents hydrogen or a lower alkyl group substituted with pivaloyloxy group and R3 bonds to a nitrogen atom in the ring. A process for production of a compound by reacting a nitrile and a hydrazide, and a therapeutic agent, particularly a xanthine oxidase inhibitor are also provided.
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