- New crystal forms of dihydropyrazolone compound and preparation method of new crystal form
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The invention relates to new crystal forms of a dihydropyrazolone compound and a preparation method of the new crystal form. Specifically, the invention relates to a crystal form A and a crystal formB of 1-(6-(2-oxa-8-azaspiro [4.5] decane-8-yl) pyrimidine-4-yl)-4-(1H-1, 2, 3-triazole-1-yl)-1, 2-dihydro-1H-pyrazole-3-sodium phenolate. The preparation method comprises the following steps: preparing 2-(6-(2-oxa-8-azaspiro [4.5] decane-8-yl) pyrimidine-4-yl)-4-(1H-1, 2, 3-triazole-1-yl)-1, 2-dihydro-3H-pyrazole-3-one into a sodium salt in an organic solvent, and crystallizing, thereby obtainingthe product. The new crystal forms of the dihydropyrazolone compound can be used to prevent and/or treat diseases associated with PHD activity.
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Paragraph 0082-0084; 0085; 0086
(2020/11/05)
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- New crystal forms of PHD inhibitor and preparation method thereof
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The invention relates to new crystal forms of a PHD inhibitor and a preparation method of the new crystal forms. Specifically, the invention relates to a crystal form A and a crystal form B of 1-(6-(7-oxa-2-azaspiro [3.5] non-2-yl) pyrimidine-4-yl)-4-(1H-1, 2, 3-triazole-1-yl)-1, 2-dihydro-3H-pyrazole-3-sodium phenolate. The preparation method comprises the following steps: preparing 2-(6-(7-oxa-2-azaspiro [3.5] non-2-yl) pyrimidine-4-yl)-4-(1H-1, 2, 3-triazole-1-yl)-1, 2-dihydro-3H-pyrazole-3-one into a sodium salt in an organic solvent, and crystallizing, thereby obtaining the product. It can be used to prevent and/or treat diseases associated with PHD activity.
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Paragraph 0077-0079; 0080; 0081
(2020/11/05)
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- Dihydropyrazolone compound as well as preparation method and medical application thereof
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The invention relates to a dihydropyrazolone compound as well as a preparation method and medical application thereof, in particularly relates to a general formula (I) compound shown in the specification, as well as a preparation method thereof, a pharmaceutical composition containing the compound, and application of the compound as a proline hydroxylase (PHD) inhibitor, the compound and the pharmaceutical composition containing the compound can be used in treating and/or preventing of PHD -activity- related diseases such as cardiovascular diseases, chronic kidney disease, anemia, wounds, cancer, autoimmune diseases and the like. In the general formula (I), the definition of each substituent in the formula is the same as that in the specification.
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Paragraph 0170; 0173-0176
(2019/05/15)
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- Discovery of Molidustat (BAY 85-3934): A Small-Molecule Oral HIF-Prolyl Hydroxylase (HIF-PH) Inhibitor for the Treatment of Renal Anemia
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Small-molecule inhibitors of hypoxia-inducible factor prolyl hydroxylases (HIF-PHs) are currently under clinical development as novel treatment options for chronic kidney disease (CKD) associated anemia. Inhibition of HIF-PH mimics hypoxia and leads to increased erythropoietin (EPO) expression and subsequently increased erythropoiesis. Herein we describe the discovery, synthesis, structure–activity relationship (SAR), and proposed binding mode of novel 2,4-diheteroaryl-1,2-dihydro-3H-pyrazol-3-ones as orally bioavailable HIF-PH inhibitors for the treatment of anemia. High-throughput screening of our corporate compound library identified BAY-908 as a promising hit. The lead optimization program then resulted in the identification of molidustat (BAY 85-3934), a novel small-molecule oral HIF-PH inhibitor. Molidustat is currently being investigated in clinical phase III trials as molidustat sodium for the treatment of anemia in patients with CKD.
- Beck, Hartmut,Jeske, Mario,Thede, Kai,Stoll, Friederike,Flamme, Ingo,Akbaba, Metin,Ergüden, Jens-Kerim,Karig, Gunter,Keldenich, J?rg,Oehme, Felix,Militzer, Hans-Christian,Hartung, Ingo V.,Thuss, Uwe
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p. 988 - 1003
(2018/04/19)
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- 7-OXO -6-(SULFOOXY)- 1,6-DIAZABICYCLO [3.2.1] OCTANE CONTAINING COMPOUNDS AND THEIR USE IN TREATMENT OF BACTERIAL INFECTIONS
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Compounds of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, their preparation, and use in treating a bacterial infection are disclosed.
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Page/Page column 26
(2017/06/19)
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- Potent and selective triazole-based inhibitors of the hypoxia-inducible factor prolyl-hydroxylases with activity in the murine brain
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As part of the cellular adaptation to limiting oxygen availability in animals, the expression of a large set of genes is activated by the upregulation of the hypoxia-inducible transcription factors (HIFs). Therapeutic activation of the natural human hypoxic response can be achieved by the inhibition of the hypoxia sensors for the HIF system, i.e. the HIF prolylhydroxylases (PHDs). Here, we report studies on tricyclic triazole-containing compounds as potent and selective PHD inhibitors which compete with the 2-oxoglutarate co-substrate. One compound (IOX4) induces HIFα in cells and in wildtype mice with marked induction in the brain tissue, revealing that it is useful for studies aimed at validating the upregulation of HIF for treatment of cerebral diseases including stroke.
- Chan, Mun Chiang,Atasoylu, Onur,Hodson, Emma,Tumber, Anthony,Leung, Ivanhoe K.H.,Chowdhury, Rasheduzzaman,Gómez-Pérez, Verónica,Demetriades, Marina,Rydzik, Anna M.,Holt-Martyn, James,Tian, Ya-Min,Bishop, Tammie,Claridge, Timothy D.W.,Kawamura, Akane,Pugh, Christopher W.,Ratcliffe, Peter J.,Schofield, Christopher J.
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- METHOD FOR THE PREPARATION OF TRIAZOLE COMPOUNDS
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The present invention relates to a process for preparing 1-[6-(morpholin-4-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1H-pyrazol-5-ol (I—enol form) or 2-[6-(morpholin-4-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1,2-dihydro-3H-pyrazol-3-one (I—keto form) and sodium 1-[6-(morpholin-4-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1H-pyrazol-5-olate (II) from 1,2,3-triazole (III), methyl bromoacetate (IV-Me-Br) or ethyl bromoacetate (IV-Et-Br), 4,6-dichloropyrimidine (VIII), morpholine (IX) and hydrazine (XII).
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Paragraph 0138
(2015/03/31)
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- Water-soluble NHC-Cu catalysts: Applications in click chemistry, bioconjugation and mechanistic analysis
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Copper(i)-catalyzed 1,3-dipolar cycloaddition of azides and terminal alkynes (CuAAC), better known as "click" reaction, has triggered the use of 1,2,3-triazoles in bioconjugation, drug discovery, materials science and combinatorial chemistry. Here we report a new series of water-soluble catalysts based on N-heterocyclic carbene (NHC)-Cu complexes which are additionally functionalized with a sulfonate group. The complexes show superior activity towards CuAAC reactions and display a high versatility, enabling the production of triazoles with different substitution patterns. Additionally, successful application of these complexes in bioconjugation using unprotected peptides acting as DNA binding domains was achieved for the first time. Mechanistic insight into the reaction mechanism is obtained by means of state-of-the-art first principles calculations.
- Daz Velzquez, Heriberto,Ruiz Garca, Yara,Vandichel, Matthias,Madder, Annemieke,Verpoort, Francis
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supporting information
p. 9350 - 9356
(2014/12/11)
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- SUBSTITUTED DIHYDROPYRAZOLONES FOR TREATING CARDIOVASCULAR AND HEMATOLOGICAL DISEASES
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The invention relates to dihydropyrazolon-derivatives of formula (I), to methods for their production, to their use for treating and/or for preventing diseases and their use for producing medicaments for treating and/or for preventing diseases, in particular cardiovascular and haematological diseases, kidney diseases and for promoting the healing of wounds.
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Page/Page column 25
(2010/12/29)
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- SUBSTITUTED DIHYDROPYRAZOLONES AND THEIR USE
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The present application relates to novel substituted dihydropyrazolone derivatives, processes for their preparation, their use for treatment and/or prophylaxis of diseases and their use for the preparation of medicaments for treatment and/or prophylaxis of diseases, in particular cardiovascular and haematological diseases and kidney diseases, and for promoting wound healing.
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- TRIAZOLE DERIVATIVES AS VASOPRESSIN ANTAGONISTS
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Compounds of formula (I), or pharmaceutically acceptable derivatives thereof, wherein: R1 represents a group selected from H, CF3, and C1-6 alkyl (optionally substituted by C1-6 alkyloxy or triazolyl); R2/
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Page/Page column 50
(2010/11/24)
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- 1, 2, 4 -TRIAZOLE DERIVATIVES AS VASOPRESSIN ANTAGONISTS
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Compounds of formula (I), or a pharmaceutically acceptable salt, solvate, ester or amide thereof, wherein R1 represents [CH2]n-R2; R2 represents H, C1-6 alkyloxy or Het; n represents a numb
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Page/Page column 34
(2010/11/25)
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- Compounds useful in therapy
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Compounds of formula (I), or pharmaceutically acceptable derivatives thereof, wherein: X represents —[CH2]a—R or —[CH2]a—O—[CH2]b—R; a represents a number selected from 0 to 6; b represents a number selected from 0 to 6; R represents H, CF3 or Het; Het represents an optionally substituted 5- or 6-membered saturated, partially saturated or aromatic heterocyclic ring; Y represents one or more substituents independently selected from —[O]c—[CH2]d—R1, which may be the same or different at each occurrence; c at each occurrence independently represents a number selected from 0 or 1; d at each occurrence independently represents a number selected from 0 to 6; R1 at each occurrence independently represents H, halo, CF3, CN or Het1; Het1 at each occurrence independently represents a 5- or 6-membered unsaturated heterocyclic ring; V represents a direct link or —O—; Ring A represents an optionally substituted 5- to 7-membered saturated heterocyclic ring, or a phenylene group; Q represents a direct link or —N(R2)—; R2 represents hydrogen or C1-6 alkyl; Z represents —[O]e—[CH2]f—R3, a phenyl ring (optionally fused to a benzene ring or Het2, and the group as a whole being optionally substituted), or Het3 (optionally fused to an benzene ring or Het4, and the group as a whole being optionally substituted); R3 represents C1-6 alkyl (optionally substituted), C3-6 cycloalkyl, C3-6 cycloalkenyl, phenyl (optionally substituted), Het5 or NR4R5; e represents a number selected from 0 or 1; f represents a number selected from 0 to 6; Het2 and Het5 independently represent optionally substituted 5- or 6-membered saturated, partially saturated or aromatic heterocyclic rings; Het3 represents an optionally substituted 4 to 6-membered saturated, partially saturated or aromatic heterocyclic ring; Het4 represents an optionally substituted 6-membered aromatic heterocyclic ring; R4 and R5 independently represent optionally substituted C1-6 alkyl, C1-6 alkyloxy, C3-8 cycloalkyl (optionally fused to C3-8 cycloalkyl), Het6, or hydrogen; Het6 represents an optionally substituted 5- or 6-membered saturated, partially saturated or aromatic heterocyclic ring; are useful for treating a disorder for which a V1a antagonist is indicated.
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Page/Page column 26
(2010/02/12)
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- 1,3-DIPOLAR CYCLOADDITIONS TO 2,3-DIMETHOXYCARBONYL-7-OXABICYCLO-2,5-HEPTADIENE, 1,4-EPOXY-1,4-DIHYDRONAPHTHALENE, AND exo-endo-1,6-DIMETHOXYCARBONYL-11,12-DIOXATETRACYCLO2,5,17,10>-3,8-DODECADIENE
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The paper deals with site-selectivity of l,3-dipolar cycloadditions of ethyl azidoformate, azidoacetate, and diazo acetate to 2,3-dimethoxycarbonyl-7-oxabicyclo-2,5-heptadiene.The exo-endo stereoselectivity has been studied of the reactions of 1,4-
- Fisera, L'ubor,Pavlovic, Dusan
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p. 1990 - 2000
(2007/10/02)
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