- Diastereoselective Synthesis of a cis-1,3-Disubstituted Cyclobutane Carboxylic Acid Scaffold for TAK-828F, a Potent Retinoic Acid Receptor-Related Orphan Receptor (ROR)-γt Inverse Agonist
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A scalable synthesis of the cis-1,3-disubstituted cyclobutane carboxylic acid scaffold of TAK-828F (1) has been developed, featuring the diastereoselective reduction of a cyclobutylidene Meldrum's acid derivative with NaBH4. Controlling acidic impurities was crucial for improving the diastereomeric ratio by recrystallization. Furthermore, reaction optimization and the streamlining of several steps established a scalable synthetic method free from column chromatography purification with an overall yield improved from 23 to 39%.
- Majima, Keisuke,Yamano, Mitsuhisa
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p. 11464 - 11471
(2021/09/02)
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- Two Scalable Syntheses of 3-(Trifluoromethyl)cyclobutane-1-carboxylic Acid
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Two efficient synthetic methods for preparation of 3-(trifluoromethyl)cyclobutane-1-carboxylic acid are reported starting from readily available 4-oxocyclobutane precursors. These cyclobutanones can be converted to their CF3 carbinols upon treatment with TMSCF3 and a fluoride source. The bis-carboxylate system 9 was deoxygenated by treatment of Bu3SnH and provided desired compound 1 upon decarboxylation. In the monocarboxylate system 15, the triflate could be efficiently eliminated; subsequent hydrogenation afforded cis-1.
- Song, Zhiguo J.,Qi, Ji,Emmert, Marion H.,Wang, Jinxing,Yang, Xuezhi,Xiao, Dong
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- PYRAZOLO[1,5-D][1,2,4]TRIAZINE-5(4H)-ACETAMIDES AS INHIBITORS OF THE NLRP3 INFLAMMASOME PATHWAY
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The invention relates to novel compounds for use as inhibitors of NLRP3 inflammasone production, wherein such compounds are as defined by compounds of formula (I) and wherein the integers R1, R2 and R3 are defined in the description, and where the compounds may be useful as medicaments, for instance for use in the treatment of a disease or disorder that is associated with NLRP3 inflammasome activity.
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Page/Page column 93
(2021/10/22)
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- COMPOUNDS
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The invention relates to novel compounds for use as inhibitors of NLRP3 inflammasone production, wherein such compounds are as defined by compounds of formula (I) and wherein the integers R1, R2 and R3 are defined in the description, and where the compounds may be useful as medicaments, for instance for use in the treatment of a disease or disorder that is associated with NLRP3 inflammasome activity.
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Page/Page column 52; 73
(2021/12/08)
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- METHOD FOR PRODUCING HETEROCYCLIC COMPOUND
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PROBLEM TO BE SOLVED: To provide a production method suitable for industrial production of a compound (A). SOLUTION: A compound (A) or a salt thereof is produced in an increased total yield and at low cost, with a reduced number of steps, and without requiring cryogenic reaction conditions or complex operation such as column purification or chiral column purification [where each symbol is as described in the specifications]. SELECTED DRAWING: None COPYRIGHT: (C)2020,JPO&INPIT
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Paragraph 0124-0126
(2020/10/16)
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- Bicyclobutane carboxylic amide as a cysteine-directed strained electrophile for selective targeting of proteins
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Expanding the repertoire of electrophiles with unique reactivity features would facilitate the development of covalent inhibitors with desirable reactivity profiles. We herein introduce bicyclo[1.1.0]butane (BCB) carboxylic amide as a new class of thiol-reactive electrophiles for selective and irreversible inhibition of targeted proteins. We first streamlined the synthetic routes to generate a variety of BCB amides. The strain-driven nucleophilic addition to BCB amides proceeded chemoselectively with cysteine thiols under neutral aqueous conditions, the rate of which was significantly slower than that of acrylamide. This reactivity profile of BCB amide was successfully exploited to develop covalent ligands targeting Bruton's tyrosine kinase (BTK). By tuning BCB amide reactivity and optimizing its disposition on the ligand, we obtained a selective covalent inhibitor of BTK. The in-gel activitybased protein profiling and mass spectrometry-based chemical proteomics revealed that the selected BCB amide had a higher target selectivity for BTK in human cells than did a Michael acceptor probe. Further chemical proteomic study revealed that BTK probes bearing different classes of electrophiles exhibited distinct off-target profiles. This result suggests that incorporation of BCB amide as a cysteine-directed electrophile could expand the capability to develop covalent inhibitors with the desired proteome reactivity profile.
- Shindo, Naoya,Ojida, Akio,Tokunaga, Keisuke,Sato, Mami,Kuwata, Keiko,Miura, Chizuru,Fuchida, Hirokazu,Matsunaga, Naoya,Koyanagi, Satoru,Ohdo, Shigehiro
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supporting information
p. 18522 - 18531
(2020/11/02)
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- JAK INHIBITORS
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Disclosed is a series of JAK inhibitors, which specifically relates to a compound shown in formula (I) or pharmaceutically acceptable salts thereof.
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Paragraph 0178; 0179
(2018/05/03)
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- COMBINATIONS OF HEPATITIS C VIRUS INHIBITORS
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The present disclosure is generally directed to antiviral compounds, and more specifically directed to combinations of compounds which can inhibit the function of the NS5A protein encoded by Hepatitis C virus (HCV), compositions comprising such combinations, and methods for inhibiting the function of the NS5A protein.
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Page/Page column 613; 614
(2015/02/02)
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- Lactonization reactions through hydrolase-catalyzed peracid formation. Use of lipases for chemoenzymatic Baeyer-Villiger oxidations of cyclobutanones
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A one-pot chemoenzymatic method has been described for the synthesis of γ-butyrolactones starting from the corresponding ketones through a Baeyer-Villiger reaction. The approach is based on a lipase-catalyzed perhydrolysis for the formation of peracetic acid, which is the responsible for the ketone oxidation. Optimization studies have been performed in the oxidation of cyclobutanone, finding Candida antarctica lipase type B, ethyl acetate and urea-hydrogen peroxide complex as the best system. The relative ratio of these reagents has also been analyzed in depth. This synthetic approach has been successfully extended to a family of 3-substituted cyclobutanones in high substrate concentration, yielding the corresponding lactones with excellent isolated yields and purities, under mild reaction conditions and after a simple extraction protocol.
- González-Martínez, Daniel,Rodríguez-Mata, María,Méndez-Sánchez, Daniel,Gotor, Vicente,Gotor-Fernández, Vicente
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- THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE
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Provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1/2 comprising administering to a subject in need thereof a compound described here.
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Page/Page column
(2015/03/31)
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- Synthesis and Physicochemical Properties of 3-Fluorocyclobutylamines
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Hitherto unknown cis- and trans-3-alkyl- and 3-aryl-3-fluorocycobutylamines have been synthesised selectively from 3-oxocyclobutane carboxylic acid in six or seven steps. Comparison of their pKa and logD values with those of the fluorine-free p
- Chernykh, Anton V.,Radchenko, Dmytro S.,Chernykh, Alla V.,Kondratov, Ivan S.,Tolmachova, Nataliya A.,Datsenko, Olexandr P.,Kurkunov, Maxim A.,Zozulya, Sergey X.,Kheylik, Yuri P.,Bartels, Katharina,Daniliuc, Constantin G.,Haufe, Günter
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supporting information
p. 6466 - 6471
(2015/10/19)
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- THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE
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Provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1/2 comprising administering to a subject in need thereof a compound described here.
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Page/Page column
(2015/02/19)
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- THERAPEUTICALLY ACTIVE COMPOUNDS AND USE THEREOF
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Provided are therapeutically active compounds and the use in manufacture of medicaments for treating a cancer characterized by the presence of a mutant allele of IDH1.
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Page/Page column 62
(2015/02/19)
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- THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE
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Provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1/2 comprising administering to a subject in need thereof a compound described here.
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Page/Page column 61
(2015/02/19)
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- N-Acyl-N'-(pyridin-2-yl) Ureas and Analogs Exhibiting Anti-Cancer and Anti-Proliferative Activities
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Described are compounds of Formula I which find utility in the treatment of cancer, autoimmune diseases and metabolic bone disorders through inhibition of c-FMS (CSF-1R), c-KIT, and/or PDGFR kinases. These compounds also find utility in the treatment of other mammalian diseases mediated by c-FMS, c-KIT, or PDGFR kinases.
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Paragraph 0407
(2014/09/30)
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- Conformationally restricted glutamic acid analogues: Stereoisomers of 1-aminospiro[3.3]heptane-1,6-dicarboxylic acid
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All four stereoisomers of the title compound (1a-d) were prepared, starting from a common precursor, 3-oxocyclobutanecarboxylic acid. Lewis acid-catalyzed rearrangement of a 8-oxadispiro[2.0.3.1]octane-6-carboxylic acid derivative was used as the key synthetic step to construct the suitably functionalized spiro[3.3]heptane skeleton. A stabilized oxaphosphetane intermediate of the Wittig reaction was detected along the synthetic route. Separation of the diastereomeric intermediates allowed each target compound to be obtained as a single stereoisomer. The target compounds are all analogues of the glutamic acid; they mimic glutamate in a large array of restricted conformations, which might be used in mechanistic studies or in a systematic search for biologically active compounds.
- Chernykh, Anton V.,Radchenko, Dmytro S.,Grygorenko, Oleksandr O.,Volochnyuk, Dmitriy M.,Shishkina, Svitlana V.,Shishkin, Oleg V.,Komarov, Igor V.
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p. 10894 - 10902
(2014/03/21)
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- C5-Alkyl-2-methylurea-substituted pyridines as a new class of glucokinase activators
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Glucokinase (GK) activators represent a class of type 2 diabetes therapeutics actively pursued due to the central role that GK plays in regulating glucose homeostasis. Herein we report a novel C5-alkyl-2-methylurea-substituted pyridine series of GK activators derived from our previously reported thiazolylamino pyridine series. Our efforts in optimizing potency, enzyme kinetic properties, and metabolic stability led to the identification of compound 26 (AM-9514). This analogue showed a favorable combination of in vitro potency, enzyme kinetic properties, acceptable pharmacokinetic profiles in preclinical species, and robust efficacy in a rodent PD model.
- Du, Xiaohui,Hinklin, Ronald J.,Xiong, Yumei,Dransfield, Paul,Park, Jaehyeon,Kohn, Todd J.,Pattaropong, Vatee,Lai, Sujen,Fu, Zice,Jiao, Xianyun,Chow, David,Jin, Lixia,Davda, Jasmine,Veniant, Murielle M.,Anderson, Deborah A.,Baer, Brian R.,Bencsik, Josef R.,Boyd, Steven A.,Chicarelli, Mark Joseph,Mohr, Peter J.,Wang, Bin,Condroski, Kevin R.,Dewolf, Walter E.,Conn, Marion,Tran, Thanhvien,Yang, Jerry,Aicher, Thomas D.,Medina, Julio C.,Coward, Peter,Houze, Jonathan B.
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supporting information
p. 1284 - 1289
(2015/02/02)
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- NOVEL COMPOUNDS AS DUAL INHIBITORS OF PHOSPHODIESTERASES AND HISTONE DEACETYLASES
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It relates to certain compounds having a polycyclic structure and a hydroxamic acid moiety, wherein the polycyclic structure comprises at least three ring systems, wherein one ring system is a polycyclic ring system comprising from 2 to 4 rings; at least one ring is an aromatic ring; and wherein the structure comprises at least 3 nitrogen atoms and 1 oxygen atom. It also relates to a process for their preparation, as well as to pharmaceutical compositions containing them, and to their use in medicine, in particular in the treatment and/or prevention of neurological disorders coursing with a cognition deficit or impairment, or neurodegenerative diseases. wherein B1 is a radical selected from the group consisting of formula (A"), formula (B"), formula (C"), and formula (D"):
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Page/Page column 67
(2014/09/16)
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- SUBSTITUTED SPIROPYRIDO[1,2-a]PYRAZINE DERIVATIVE AND PHARMACEUTICAL USE OF SAME AS HIV INTEGRASE INHIBITOR
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Provided is a substituted spiropyrido[1,2-a]pyrazine derivative or a pharmaceutically acceptable salt thereof, which is useful as an anti-HIV agent. The present invention relates to a compound represented by the following formula [I] or [II] or a pharmace
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Paragraph 1409; 1410; 1411
(2014/08/19)
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- RAF INHIBITOR COMPOUNDS
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This invention provides compounds of Formula (I) or a pharmaceutically acceptable salt thereof; pharmaceutical compositions comprising a compound of Formula (I); and use of a compound of Formula (I) for treating specified cancers.
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Page/Page column 78
(2013/09/26)
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- IMIDAZOLE DERIVATIVES
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Disclosed herein are novel imidazole derivative compounds i.e., benzimidazole and aza-benzimidazole derivatives that act as DGAT1 inhibitors and can be useful in preventing, treating or acting as a remedial agent for hyperiipidemia, diabetes mellitus and obesity. Further disclosed are methods of treating various DGAT1 -related diseases, and the use of such imidazole compounds as described herein in the manufacture of a medicament for such treatment.
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Page/Page column 52
(2013/06/05)
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- THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE
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Provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1/2 comprising administering to a subject in need thereof a compound described here.
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Page/Page column 42
(2013/07/31)
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- THERAPEUTICALLY ACTIVE COMPOSITIONS AND THEIR METHODS OF USE
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Provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1/2 comprising administering to a subject in need thereof a compound described here.
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Page/Page column
(2013/07/31)
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- THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE
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Provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1/2 comprising administering to a subject in need thereof a compound described here.
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Page/Page column 61
(2013/07/31)
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- TRIAZINE-OXADIAZOLES
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The invention relates to new derivatives of formula (I), wherein the substituents are as defined in the specification; to processes for the preparation of such derivatives; pharmaceutical compositions comprising such derivatives; such derivatives as a medicament; such derivatives for the treatment of chronic pain.
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Page/Page column 91-92
(2012/04/04)
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- SPIRO-OXINDOLE MDM2 ANTAGONISTS
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Provided herein are compounds, compositions, and methods in the field of medicinal chemistry. The compounds and compositions provided herein relate to spiro-oxindoles which function as antagonists of the interaction between p53 and MDM2, and their use as
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Page/Page column 86
(2012/05/21)
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- RADIOLABELLING METHOD USING CYCLOALKYL GROUPS
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This invention relates to novel cyclo alkyl compounds suitable for labeling by 18F, methods of preparing such a compound, compositions comprising such compounds, kits comprising such compounds or compositions and uses of such compounds, compositions or kits for diagnostic imaging by positron emission tomography (PET).
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Page/Page column 38
(2011/02/24)
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- SPIRO-OXINDOLE MDM2 ANTAGONISTS
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Provided herein are compounds, compositions, and methods in the field of medicinal chemistry. The compounds and compositions provided herein relate to spiro-oxindoles which function as antagonists of the interaction between p53 and MDM2, and their use as
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Page/Page column 148
(2011/05/16)
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- Triazole derivatives which are SMO antagonists
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The present invention provides a method for the treatment or prevention of conditions which can be ameliorated by Smo antagonism, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula I or a com
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Page/Page column 12
(2008/12/04)
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- TRIAZOLE DERIVATIVES AS INHIBITORS OF 11-BETA-HYDROXYSTEROID DEHYDROGENASE-1
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Triazole derivatives of structural formula I are selective inhibitors of the 11β-hydroxysteroid dehydrogenase-1. The compounds are useful for the treatment of diabetes, such as noninsulin-dependent diabetes (NIDDM), hyperglycemia, obesity, insulin resista
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Page/Page column 23
(2008/06/13)
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- DIAMINE DERIVATIVES
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A compound represented by formula (1):Q1-Q2-To-N(R1) -Q3-N(R2)-T1-Q4 [wherein R1 and R2 are hydrogen atoms or the like; Q1 is a saturated or unsaturated, 5- or 6- membered cyclic hydrocarbon group which may be substituted, or the like; Q2 is a single bond or the like; Q3 represents the following group: (wherein Q5 is an alkylene group having 1 to 8 carbon atoms, or the like); and T0 and T1 are carbonyl groups or the like], a salt thereof, a solvate thereof, or an N-oxide thereof. The compound is useful as an agent for preventing and/or treating cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, Buerger's disease, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after artificial valve or joint replacement, thrombus formation and reocclusion after angioplasty, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), thrombus formation during extracorporeal circulation, or blood clotting upon blood drawing.
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Page/Page column 144-145
(2008/06/13)
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- Diamine derivatives
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A compound represented by the general formula (1): Q1-Q2-T0-N(R1)-Q3-N(R2)-T1-Q4??(1) wherein R1 and R2 are hydrogen atoms or the like; Q1 is a saturated or unsaturated, 5- or 6-membered cyclic hydrocarbon group which may be substituted, or the like; Q2 is a single bond or the like; Q3 is a group in which Q5 is an alkylene group having 1 to 8 carbon atoms, or the like; and T0 and T1 are carbonyl groups or the like; a salt thereof, a solvate thereof, or an N-oxide thereof. The compound is useful as an agent for preventing and/or treating cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, Buerger's disease, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after valve or joint replacement, thrombus formation and reocclusion after angioplasty, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), thrombus formation during extracorporeal circulation, or blood clotting upon blood drawing.
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- AMINO CYCLOBUTYLAMIDE MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY
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The present invention is directed to compounds of the formulas I and II : wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R15, R16, R17, R18, R19, R25, R26, Y, Z, l, m, n and the broken lines are as defined herein which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptor CCR-2.
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- DIAMINE DERIVATIVES
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A compound represented by the general formula (1):Q1-Q2-T0-N(R1)-Q3-N(R2)-T1-Q4 wherein R1 and R2 are hydrogen atoms or the like; Q1 is a saturated or unsaturated, 5- or 6- membered cyclic hydrocarbon group which may be substituted, or the like; Q2 is a single bond or the like; Q3 is a group in which Q5 is an alkylene group having 1 to 8 carbon atoms, or the like; and T0 and T1 are carbonyl groups or the like; a salt thereof, a solvate thereof, or an N-oxide thereof. The compound is useful as an agent for preventing and/or treating cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, Buerger's disease, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after valve or joint replacement, thrombus formation and reocclusion after angioplasty, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), thrombus formation during extracorporeal circulation, or blood clotting upon blood drawing.
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