- A compression ammonia urea apperception compound of preparation method and in biological and medical application
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The present invention provides a semicarbazone compound preparation method and application in biomedicine. The compound is a compound of formula (I) or an enantiomer, a diastereomer, a raceme, a pharmaceutically acceptable salt, a crystalline hydrate or a solvate thereof. The compound has the formula shown in the description, wherein X is sulfur or oxygen; R1 and R2 are separately and independently hydrogen and alkyl containing 1-3 carbon atoms or N=CHR 5, wherein R5 is optionally substituted aryl or optionally substituted alkyl; R3 and R4 are separately and independently hydrogen or alkyl containing 1-3 carbon atoms or substituents selected from formulas III, III, IV, and V shown in the description, wherein X1 is sulfur or oxygen. Y, Y1 and Y2 are separately and independently at least one of hydrogen, alkyl containing 1-3 carbon atoms, halogen, hydroxy, methoxy, amino, sulfonic acid group, nitro, carboxyl, thiol, methylamino, ethylamino, dimethylamino or diethylamino; and Z1 is hydrogen, alkyl containing 1-3 carbon atoms, halogen, hydroxy, amino, methylamino, ethylamino, dimethylamino or diethylamino. The semicarbazone compound is applicable to related diseases caused by copper metabolic dysfunction.
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Paragraph 0179; 0184; 0187
(2017/08/24)
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- Diazine indole acetic acids as potent, selective, and orally bioavailable antagonists of chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2) for the treatment of allergic inflammatory diseases
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New classes of CRTH2 antagonists, the pyridazine linker containing indole acetic acids, are described. The initial hit 1 had good potency but poor permeability, metabolic stability, and PK. Initial optimization led to compounds of type 2 with low oxidative metabolism but poor oral bioavailability. Poor permeability was identified as a liability for these compounds. Addition of a linker between the indole and diazine moieties afforded a series with good potency, low rates of metabolism, moderate permeability, and good oral bioavailability in rodents. 32 was identified as the development track candidate. It was potent in cell based, binding, and whole blood assays and exhibited good PK profile. It was efficacious in mouse models of contact hypersensitivity (1 mg/kg b.i.d.) and house dust (20 mg/kg q.d.) when dosed orally. In sheep asthma, administration at 1 mg/kg iv completely blocked the LAR and AHR and attenuated the EAR phase.
- Kaila, Neelu,Huang, Adrian,Moretto, Alessandro,Follows, Bruce,Janz, Kristin,Lowe, Michael,Thomason, Jennifer,Mansour, Tarek S.,Hubeau, Cedric,Page, Karen,Morgan, Paul,Fish, Susan,Xu, Xin,Williams, Cara,Saiah, Eddine
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experimental part
p. 5088 - 5109
(2012/08/28)
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- Synthesis, tautomeric forms, specific intermolecular interactions, and lipophilicity of methylated 6-hydroxypyridazine-3-carboxylic acid and its 4,5-dihydro analogs
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Effects of methylation for intermolecular interactions and lipophilicity have been studied for a series of methylated 4,5-dihydro-6-hydroxypyridazine-3- carboxylic and 6-hydroxypyridazine-3-carboxylic acids (1 and 2). In solution they exist in equilibrium of the lactam and lactim tautomers, with the reverse preferences for analogs 1 and 2, which affect the syntheses of their methylated derivatives. Carboxylic acid 2 preferably crystallizes as a hydrate, built of carboxylate anions and hydronium cations 2-·H 3O+, hydrogen bonded into catemeric patterns involving both ions. In methyl 4,5-dihydro-6-oxopyridazine-3-carboxylate (4A) the molecules are NH?O hydrogen bonded into chains. In both structures 2 -·H3O+ and 4A, there are relatively strong CH?O hydrogen bonds, arranging the molecules into sheets. The increased lipophilicity of the methylated derivatives has been correlated with the formation of CH?O bonds.
- Katrusiak, Anna,Piechowiak, Pawe?,Katrusiak, Andrzej
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experimental part
p. 84 - 90
(2011/09/16)
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- ALPHA-KETO HETEROCYCLES AS FAAH INHIBITORS
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The invention provides a series of -alpha ketoheterocyclic compounds, for example, compounds of formula (I). The compounds can inhibit fatty acid amide hydrolase and can be useful for treatment of malconditions modulated by fatty acid amide hydrolase. The invention further provides methods of making compounds of formula (I), useful intermediates for the preparation of compounds of formula (I), and methods of using compounds of formula (I) and compositions thereof.
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Page/Page column 84-85
(2010/04/03)
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- Optimization of the central heterocycle of α-ketoheterocycle inhibitors of fatty acid amide hydrolase
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The synthesis and evaluation of a refined series of α- ketoheterocycles based on the oxazole 2 (OL-135) incorporating systematic changes in the central heterocycle bearing a key set of added substituents are described. The nature of the central heterocycle, even within the systematic and minor perturbations explored herein, significantly influenced the inhibitor activity. 1,3,4-oxadiazoles and 1,2,4-oxadiazoles 9 > tetrazoles, the isomeric 1,2,4-oxadiazoles 10, 1,3,4-thiadiazoles > oxazoles including 2 > 1,2-diazines > thiazoles > 1,3,4-triazoles. Most evident in these trends is the observation that introduction of an additional heteroatom at position 4 (oxazole numbering, N > O > CH) substantially increases activity that may be attributed to a reduced destabilizing steric interaction at the FAAH active site. Added heterocycle substituents displaying well-defined trends may be utilized to enhance the inhibitor potency and, more significantly, to enhance the inhibitor selectivity. These trends, exemplified herein, emerge from both enhancements in the FAAH activity and simultaneous disruption of binding affinity for competitive off-target enzymes.
- Garfunkle, Joie,Ezzili, Cyrine,Rayl, Thomas J.,Hochstatter, Dustin G.,Hwang, Inkyu,Boger, Dale L.
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supporting information; experimental part
p. 4392 - 4403
(2009/06/17)
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- Synthesis and evaluation of a conformationally constrained pyridazinone PNA-monomer for recognition of thymine in triple-helix structures
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A novel conformationally constrained pyridazinone Eag-base PNA-monomer 2 capable of binding thymine in a triplex motif was designed and synthesised. A bis-PNA with the Eag-base incorporated in the Hoogsteen strand was hybridised with a complementary DNA. Thermal stability studies revealed an increase in Tm (4.3°C per mod.) compared to a no-base unit, but showed no improvement over a previously described unconstrained analogue (E, 1). Surprisingly, no significant difference was found in the thermodynamic parameters (ΔH°, ΔS° and ΔG°) for PNA-DNA triplex formation involving 2 or the unconstrained analogue 1.
- Olsen, Anne Goldbech,Dahl, Otto,Nielsen, Peter E.
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p. 1551 - 1554
(2007/10/03)
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- A novel PNA-monomer for recognition of thymine in triple-helix structures
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To expand the triplex recognition repertoire of Nucleic Acids, novel nucleobases that recognize thymine in a T-A base pair are still required. A novel conformationally constrained PNA-monomer (II) capable of binding T in a triplex motif was designed and s
- Olsen, Anne Goldbech,Dahl, Otto,Nielsen, Peter E.
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p. 1331 - 1333
(2007/10/03)
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- Endothelin receptor antagonists
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This invention relates to pyridizinone derivatives of formula I STR1 wherein the various substituents are defined in the specification, and salts thereof, which have useful pharmacological properties, in particular endothelin receptor-antagonistic properties. The compounds are thus useful for the treatment of illnesses associated with endothelin activities, such as hypertension, cardiac insufficiency, coronary heart disease, renal, cerebral and myocardial ischaemia, renal insufficiency, cerebral infarct, subarachnoid haemorrhage, arteriosclerosis pulmonary high blood pressure, inflammations, asthma, prostate hyperplasia, endotoxic shock and in complications after the administration of immunosuppressants which produce renal vasoconstriction.
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