- 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
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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.
- 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
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p. 8303 - 8332
(2021/06/30)
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- CDK9 Kinase inhibitors
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The present application relates to CDK9 kinase inhibitors which provide a compound of formula (I) or a stereoisomer thereof. A solvate, a metabolite, a pharmaceutically acceptable salt or prodrug, and a pharmaceutical composition comprising the same. Also provided are the use of compounds and pharmaceutical compositions in the manufacture of a medicament for the treatment of cancer.
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Paragraph 0174-0176
(2021/11/21)
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- ?-LACTAMASE INHIBITOR AND USE THEREOF
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Provided are a β-lactamase inhibitor of formula (I), or an ester, a stereoisomer or a pharmaceutically acceptable salt thereof, and a method of preparing the same. Further provided is a pharmaceutical composition comprising the β-lactamase inhibitor of formula (I), or the ester, the stereoisomer or pharmaceutically acceptable salt thereof. In addition, the present invention relates to a method for treating diseases caused by bacterial infection, which comprises administering the β-lactamase inhibitor of formula (I), or the ester, the stereoisomer or the pharmaceutically acceptable salt thereof to a patient or a subject in need.
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Paragraph 0206; 0208; 0217; 0219
(2020/12/10)
-
- Production methods of nitrogen heterocyclic carboxylic acid intermediate and 3-azetidine carboxylic acid
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The invention discloses production methods of a nitrogen heterocyclic carboxylic acid intermediate and 3-azetidine carboxylic acid, and relates to the technical field of pharmaceutical and chemical industry. The production method of the nitrogen heterocyclic carboxylic acid intermediate used for producing the 3-azetidine carboxylic acid comprises the steps of mixing a nitrogen heterocyclic compound and a Wittig reaction agent, carrying out a Wittig reaction, and conducting separation to obtain a nitrogen heterocyclic formaldehyde intermediate; and subjecting the nitrogen heterocyclic formaldehyde intermediate to an oxidation reaction, and conducting separation to obtain the nitrogen heterocyclic carboxylic acid intermediate, wherein the nitrogen heterocyclic compound is selected from at least one of 1-benzhydrylazetidin-3-one, 1-benzylazetidin-3-one, 1-Boc-3-azetidinone and 1-acetylazetidin-3-one. According to the production method of the 3-azetidine carboxylic acid, the nitrogen heterocyclic carboxylic acid intermediate is subjected to hydrogenolysis, a production cycle is short, a production process is safe and reliable, the production cost is low, the purity is higher than 98%,and the yield can reach 82.8%.
- -
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Paragraph 0098-0100
(2019/11/20)
-
- Facile synthesis of 2-azaspiro[3.4]octane
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Our annulation strategy utilized for the synthesis of 2-azaspiro[3.4]octane is explained. Three successful routes for the synthesis were developed. One of the approaches involved annulation of the cyclopentane ring and the remaining two approaches involved annulation of the four membered ring. All three approaches employ readily available starting materials with conventional chemical transformations and minimal chromatographic purifications to afford the title compound. The merits and limitations of the three approaches are also discussed.
- Ramesh, Subbiah,Balakumar, Ramadas,Rizzo, John R.,Zhang, Tony Y.
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p. 3056 - 3065
(2019/03/21)
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- TARGETING COMPOUNDS
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The disclosure provides, at least in part, liver, intestine and/or kidney-targeting compounds and their use in treating liver, intestine and/or kidney disorders, such as non-alcoholic steatohepatitis, alcoholic steatohepatitis, hepatocellular carcinoma, liver cirrhosis, and hepatitis B; and/or chronic kidney disease, glomerular disease such as IGA nephropathy, lupus nephritis, or polycystic kidney disease. The compounds are contemplated to have activity against methionyl aminopeptidase 2.
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Paragraph 0140; 0355
(2019/07/19)
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- MCL-1 INHIBITORS
-
The present disclosure generally relates to compounds and pharmaceutical compositions that may be used in methods of treating cancer.
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Paragraph 1287-1288
(2019/12/01)
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- AZOLE-SUBSTITUTED PYRIDINE COMPOUND
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The present invention provides a compound represented by formula [I'| shown below or a pharmaceutically acceptable salt thereof that has an inhibitory effect on 20-HETE producing enzyme, wherein the structure represented by formula [III] shown below represents any of the structures represented by formula group [IV] shown below, wherein R1 represents a hydrogen atom, a fluorine atom, methyl, etc.; R2, R3, and R4 each independently represent a hydrogen atom, a fluorine atom, or methyl; W represents a single bond, C1-3alkanediyl, or the formula -O-CH2CH2-; and ring A represents (a) substituted C4-6cycloalkyl, (b) substituted 4- to 6-membered saturated nitrogen-containing heterocyclyl, (c) substituted phenyl, (d) substituted pyridyl, (e) substituted 2,3-dihydrobenzofuran, (f) 4- to 6-membered saturated oxygen-containing heterocyclyl, etc.
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Paragraph 0656; 0657; 0690
(2019/01/08)
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- CYCLOBUTANE- AND AZETIDINE-CONTAINING MONO AND SPIROCYCLIC COMPOUNDS AS ALPHA V INTEGRIN INHIBITORS
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The present invention provides compounds of Formula (I): or stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates thereof, wherein all the variables are as defined herein. These compounds are antagonists to αv- containing integrins. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating a disease, disorder, or condition associated with dysregulation of av-containing integrins, such as pathological fibrosis, transplant rejection, cancer, osteoporosis, and inflammatory disorders, by using the compounds and pharmaceutical compositions.
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Page/Page column 102-104
(2018/05/27)
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- Polysubstituted-indazole compounds and application of same as IDO inhibitors
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The invention discloses polysubstituted-indazole compounds as shown in a formula (I) which is described in the specification, a preparation method for the compounds, and application of the compounds as IDO inhibitors. The compounds provided by the invention can be used for preventing and/or treating a plurality of diseases, such as Alzheimer's disease, cataract, infections related to cellular immune activation, autoimmune diseases, AIDS, cancers, depression, the metabolic disorder of tryptophan or the like.
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Paragraph 0116; 0121; 0122
(2018/11/04)
-
- COMPOUNDS, COMPOSITIONS AND METHODS OF INCREASING CFTR ACTIVITY
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The present disclosure features compounds such as those having the Formulae (I) and (II), which can increase cystic fibrosis transmembrane conductance regulator (CFTR) activity as measured in human bronchial epithelial (hBE) cells. The present disclosure also features methods of treating a condition associated with decreased CFTR activity or a condition associated with a dysfunction of proteostasis comprising administering to a subject an effective amount of a disclosed compound, such as a compound of Formula (I) or (II).
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Paragraph 0192
(2017/02/24)
-
- METHODS OF TREATING PULMONARY DISEASES AND DISORDERS
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The present disclosure features disclosed method of treating disorders such as COPD, bronchitis and/or asthma using disclosed compounds, optionally together with one or more additional active agents. Contemplated methods include administrating orally or by inhalation to a patient one or more disclosed compounds.
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Paragraph 0192
(2017/07/14)
-
- Benzimidazole-2-piperazine compound, its pharmaceutical composition and its preparation and use
-
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.
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Paragraph 0209; 0406; 0409; 0410
(2016/10/20)
-
- A base promoted multigram synthesis of aminoisoxazoles: Valuable building blocks for drug discovery and peptidomimetics
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A practical multigram metal free synthesis of isoxazole-containing building blocks from commercially available amino acids was elaborated. The key reaction was a regioselective [3 + 2]-cycloaddition of in situ generated nitrile oxides with alkynes/enamines. The obtained building blocks were used in the preparation of bioactive compounds and peptidomimetics.
- Chalyk, Bohdan A.,Kandaurova, Inna Y.,Hrebeniuk, Kateryna V.,Manoilenko, Olga V.,Kulik, Irene B.,Iminov, Rustam T.,Kubyshkin, Vladimir,Tverdokhlebov, Anton V.,Ablialimov, Osman K.,Mykhailiuk, Pavel K.
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p. 25713 - 25723
(2016/03/25)
-
- Preparation method of 2-(1-(tertbutyloxycarbonyl)azacyclobutyl-3-yl)cyclopropanecarboxylic acid
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The invention relates to a preparation method of 2-(1-(tertbutyloxycarbonyl)azacyclobutyl-3-yl)cyclopropanecarboxylic acid. The preparation method solves the problem that the existing appropriate 2-(1-(tertbutyloxycarbonyl)azacyclobutyl-3-yl)cyclopropanecarboxylic acid industrial synthesis method does not exist. The preparation method comprises that 1, a compound 1 and iodomethane undergo a reaction under alkaline conditions to produce a compound 2, 2, the compound 2 is treated by sodium borohydride to form a compound 3, 3, the compound 3 is oxidized by Dess-Martin periodinane to form a compound 4, 4, the compound 4 and a compound 5 undergo a reaction to produce a compound 6, 5, the compound 6 and trimethylsulfoxonium iodide undergo a reaction to produce a compound 7, and 6, the compound 7 is hydrolyzed under alkaline conditions to form an end product compound 8. The reaction equation is shown in the following description. The 2-(1-(tertbutyloxycarbonyl)azacyclobutyl-3-yl)cyclopropanecarboxylic acid is a useful intermediate or product for synthesis of many drugs.
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-
-
- COMPOUNDS, COMPOSITIONS, AND METHODS FOR INCREASING CFTR ACTIVITY
-
The present disclosure is directed to disclosed compounds that increase cystic fibrosis transmembrane conductance regulator (CFTR) activity as measured in human bronchial epithelial (hBE) cells.
- -
-
Paragraph 0218
(2016/07/27)
-
- Novel spiroketal pyrrolidine GSK2336805 potently inhibits key hepatitis C virus genotype 1b mutants: From lead to clinical compound
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Rapid clinical progress of hepatitis C virus (HCV) replication inhibitors, including these selecting for resistance in the NS5A region (NS5A inhibitors), promises to revolutionize HCV treatment. Herein, we describe our explorations of diverse spiropyrrolidine motifs in novel NS5A inhibitors and a proposed interaction model. We discovered that the 1,4-dioxa-7-azaspiro[4.4]nonane motif in inhibitor 41H (GSK2236805) supported high potency against genotypes 1a and 1b as well as in genotype 1b L31V and Y93H mutants. Consistent with this, 41H potently suppressed HCV RNA in the 20-day RNA reduction assay. Pharmacokinetic and safety data supported further progression of 41H to the clinic.
- Kazmierski, Wieslaw M.,Maynard, Andrew,Duan, Maosheng,Baskaran, Sam,Botyanszki, Janos,Crosby, Renae,Dickerson, Scott,Tallant, Matthew,Grimes, Rick,Hamatake, Robert,Leivers, Martin,Roberts, Christopher D.,Walker, Jill
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p. 2058 - 2073
(2014/04/03)
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- AZETIDINE DERIVATIVE AND ANTIDEPRESSANT COMPOSITION INCLUDING THE SAME
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The present invention relates to an azetidine derivative or a pharmaceutically acceptable salt thereof, and an antidepressant agent or a composition for the prevention or treatment of psychiatric disorders including the same. The azetidine derivative is useful as a triple reuptake inhibitor capable of inhibiting reuptake of the neurotransmitters, dopamine, serotonin, and norepinephrine at the same time.
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- AZETIDINE DERIVATIVE AND ANTIDEPRESSANT COMPOSITION CONTAINING SAME
-
The present invention relates to an azetidine derivative or a pharmaceutically acceptable salt thereof, and an antidepressant agent or a composition for the prevention or treatment of psychiatric disorders including the same. The azetidine derivative is useful as a triple reuptake inhibitor capable of inhibiting reuptake of the neurotransmitters, dopamine, serotonin, and norepinephrine at the same time.
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-
- ANTIBACTERIAL AGENTS
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Antibacterial compounds of formula (I) are provided, as well as stereoisomers and pharmaceutically acceptable salts and esters thereof; pharmaceutical compositions comprising such compounds; methods of treating bacterial infections by the administration of such compounds; and processes for the preparation of such compounds.
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-
- Exploration of novel 3-substituted azetidine derivatives as triple reuptake inhibitors
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Novel azetidines based on the 3-aryl-3-oxypropylamine scaffold were designed, synthesized, and evaluated as TRIs. Reduction of 1 followed by Swern oxidation and then Grignard reaction gave 3. The alkylation of 3 provided the corresponding azetidine derivatives 6, of which the two most promising, 6bd and 6be, were selected from 86 prepared analogues based on their biological profiles. Compound 6be showed activity in vivo in FST at 10 mg/kg IV or 20-40 mg/kg PO.
- Han, Younghue,Han, Minsoo,Shin, Dongyun,Song, Chiman,Hahn, Hoh-Gyu
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p. 8188 - 8192
(2012/11/07)
-
- ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS
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Compounds having antibacterial activity are disclosed. The compounds have the following structure (I): (Formula (I)), including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein Q1, Q2, R1, R2, R3, Z1 and Z2 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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Page/Page column 89
(2011/04/26)
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- ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS
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Compounds having antibacterial activity are disclosed. The compounds have one of the following structures (I) or (II): including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein Q1, Q2, R1, R2, R3 and Z1 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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Page/Page column 114
(2011/04/26)
-
- Enantioselective hydroformylation of N-vinyl carboxamides, allyl carbamates, and allyl ethers using chiral diazaphospholane ligands
-
Rhodium complexes of diazaphospholane ligands catalyze the asymmetric hydroformylation of N-vinyl carboxamides, allyl ethers, and allyl carbamates; products include 1,2- and 1,3-aminoaldehydes and 1,3-alkoxyaldehydes. Using glass pressure bottles, short reaction times (generally less than 6 h), and low catalyst loading (commonly 0.5 mol %), 20 substrates are successfully converted to chiral aldehydes with useful regioselectivity and high enantioselectivity (up to 99% ee). Chiral Roche aldehyde is obtained with 97% ee from the hydroformylation of allyl silyl ethers. Commonly difficult substrates such as 1,1- and 1,2-disubstituted alkenes undergo effective hydroformylation with 89-97% ee and complete conversion for six examples. Palladium-catalyzed aerobic oxidative amination of allyl benzyl ether followed by enantioselective hydroformylation yields the β3-aminoaldehyde with 74% ee.
- McDonald, Richard I.,Wong, Gene W.,Neupane, Ram P.,Stahl, Shannon S.,Landis, Clark R.
-
supporting information; experimental part
p. 14027 - 14029
(2011/01/04)
-
- ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS
-
Compounds having antibacterial activity are disclosed. The compounds have the following structure (I): (I) including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein Ql, Q2, Rl, R2 and R3 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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Page/Page column 75
(2010/04/28)
-
- 8-Substituted isoquinoline derivative and the use thereof
-
The present invention relates to a compound represented by the following formula (1): wherein D1, A1, D2, R1, D3, and R2 each have the same meaning as defined in the present specification or a salt thereof. The compound represented by the formula (1) or a salt thereof has an IKKβ inhibiting activity and the like and is useful for the prevention and/or treatment of IKKβ-associated diseases or symptoms and the like.
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Page/Page column 145
(2010/11/03)
-
- ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS
-
Compounds having antibacterial activity are disclosed. The compounds have the following structure (I): (I) including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein Q1, Q2, R1, R2 and R3 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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Page/Page column 75
(2010/04/28)
-
- TREATMENT OF URINARY TRACT INFECTIONS WITH ANTIBACTERIAL AMINOGLYCOSIDE COMPOUNDS
-
A method for treating a urinary tract infection in a mammal in need thereof is disclosed, the method comprising administering to the mammal an effective amount of an antibacterial aminoglycoside compound.
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Page/Page column 226
(2010/12/17)
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- SEROTONIN 5-HT2B RECEPTOR INHIBITORS
-
Disclosed are Serotonin 5-HT2B receptor inhibitors of the formula I. Also disclosed are methods of making and methods of using these compounds
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Page/Page column 45-46
(2010/08/04)
-
- 6,7,8,9-TETRAHYDRO-5H-1,4,7,10A-TETRAAZA-CYCLOHEPT[F]INDENE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS CONTAINING THESE COMPOUNDS, THEIR USE AND PROCESSES FOR PREPARING THEM
-
The present invention relates to compounds defined by formula (I), wherein the groups X, Y, W and R 1 to R 4 are defined as in claim 1, possessing valuable pharmacological activity. Particularly the compounds are agonists of the 5-HT2C receptor, and thus are suitable for treatment and prevention of diseases which can be influenced by inhibition of this receptor, such as metabolic and CNS-related disorders
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Page/Page column 98
(2010/06/17)
-
- ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS
-
Compounds of structure (I): having antibacterial activity are disclosed, including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein Q1, Q2, Q3, R8 and R9 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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Page/Page column 217
(2009/06/27)
-
- Azetidine, pyrrolidine and piperidine derivatives as 5-HT receptor agonists
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PCT No. PCT/GB97/01137 Sec. 371 Date Oct. 14, 1998 Sec. 102(e) Date Oct. 14, 1998 PCT Filed Apr. 24, 1997 PCT Pub. No. WO97/42189 PCT Pub. Date Nov. 13, 1997A class of compounds of formula (I) wherein Z, E, Q, T, U, V, W, M, R1, R7 and R8 are as defined herein; are selective agonists of 5-HT1-like receptors, being potent agonists of the human 5-HT1D alpha receptor subtype whilst possessing at least a 10-fold selective affinity for the 5-HT1D alpha receptor subtype relative to the 5-HT1D beta subtype; they are therefore useful in the treatment and/or prevention of clinical conditions, in particular migraine and associated disorders, for which a subtype-selective agonist of 5-HT1D receptors is indicated, whilst eliciting fewer side-effects, notably adverse cardiovascular events, than those associated with non-subtype-selective 5-HT1D receptor agonists.
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-
-
- Compounds with growth hormone releasing properties
-
Compounds of peptide mimetic nature having the general formula I STR1 wherein a and b are independently 1 or 2, R1 and R2 are independently H or C1-6 alkyl, G and J are independently, inter alia, aromats, and D and E are independently several different groups are growth hormone secretagogous with improved bioavailability.
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-
- Synthesis and in vitro characterization of new growth hormone secretagogues derived from ipamorelin with dipeptidomimetic N-terminals
-
The structural requirements for N-terminal features for the minimal structure of growth hormone secretagogues derived from ipamorelin are investigated. It is found, that incorporation of nonpolar peptidomimetic amino acids at the N-terminal can replace the Aib-His moiety and lead to compounds with high in vitro potency with respect to their growth hormone secretagogue properties. New unnatural amino acids with double bonds, ether- linkages, and 1,3-phenylene-moieties in the backbone proved to be valuable dipeptidomimetics. Using them, growth hormone secretagogues with high potencies were obtained.
- Peschke, Bernd,Ankersen, Michael,Sehested Hansen, Birgit,Kruse Hansen, Thomas,Langeland Johansen, Nils,Lau, Jesper,Madsen, Kjeld,Petersen, Hans,Thogersen, Henning,Watson, Brett
-
p. 363 - 380
(2007/10/03)
-
- Azetidine, pyrrolidine and piperidine derivatives
-
A class of substituted azetidine, pyrrolidine and piperidine derivatives are selective agonists of 5-HT1 -like receptors, being potent agonists of the human 5-HT1Dα receptor subtype whilst possessing at least a 10-fold selective affinity for the 5-HT1Dα receptor subtype relative to the 5-HT1Dβ subtype; they are therefore useful in the treatment and/or prevention of clinical conditions, in particular migraine and associated disorders, for which a subtype-selective agonist of 5-HT1D receptors is indicated, whilst eliciting fewer side-effects, notably adverse cardiovascular events, than those associated with non-subtype-selective 5-HT1D receptor agonists.
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-
