- A scalable synthesis of a 1,7-naphthyridine derivative, a PDE-4 inhibitor
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A six-step synthesis of a 4-[8-(3-fluorophenyl)[1,7]naphthyridin-6-yl]- trans-cyclohexanecarboxylic acid with an overall yield of 27% starting from 2-cyano-3-methylpyridine, cyclohexane-1,4-dicarboxylic acid dimethyl ester, and 3-fluorophenylboronic acid is described. The trans stereochemistry in the cyclohexane moiety was achieved through a series of equilibration steps at different stages of the synthesis.
- Jiang, Xinglong,Lee, George T.,Villhauer, Edwin B.,Prasad, Kapa,Prashad, Mahavir
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- HETEROARYLDIHYDROPYRIMIDINE DERIVATIVES AND METHODS OF TREATING HEPATITIS B INFECTIONS
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Provided herein are compounds useful for the treatment of HBV infection in a subject in need thereof, pharmaceutical compositions thereof, and methods of inhibiting, suppressing, or preventing HBV infection in the subject.
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Page/Page column 106
(2019/01/17)
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- Design, Synthesis, and Biological Evaluation of First-in-Class Dual Acting Histone Deacetylases (HDACs) and Phosphodiesterase 5 (PDE5) Inhibitors for the Treatment of Alzheimer's Disease
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Simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylases (HDAC) has recently been validated as a potentially novel therapeutic approach for Alzheimer's disease (AD). To further extend this concept, we designed and synthesized the first chemical series of dual acting PDE5 and HDAC inhibitors, and we validated this systems therapeutics approach. Following the implementation of structure- and knowledge-based approaches, initial hits were designed and were shown to validate our hypothesis of dual in vitro inhibition. Then, an optimization strategy was pursued to obtain a proper tool compound for in vivo testing in AD models. Initial hits were translated into molecules with adequate cellular functional responses (histone acetylation and cAMP/cGMP response element-binding (CREB) phosphorylation in the nanomolar range), an acceptable therapeutic window (>1 log unit), and the ability to cross the blood-brain barrier, leading to the identification of 7 as a candidate for in vivo proof-of-concept testing (Cuadrado-Tejedor, M.; Garcia-Barroso, C.; Sánchez-Arias, J. A.; Rabal, O.; Mederos, S.; Ugarte, A.; Franco, R.; Segura, V.; Perea, G.; Oyarzabal, J.; Garcia-Osta, A. Neuropsychopharmacology 2016, in press, doi: 10.1038/npp.2016.163).
- Rabal, Obdulia,Sánchez-Arias, Juan A.,Cuadrado-Tejedor, Mar,De Miguel, Irene,Pérez-González, Marta,García-Barroso, Carolina,Ugarte, Ana,Estella-Hermoso De Mendoza, Ander,Sáez, Elena,Espelosin, Maria,Ursua, Susana,Haizhong, Tan,Wei, Wu,Musheng, Xu,Garcia-Osta, Ana,Oyarzabal, Julen
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supporting information
p. 8967 - 9004
(2016/10/22)
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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 71
(2014/09/16)
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- A biocatalytic/reductive etherification approach to substituted piperidinyl ethers
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A synthetically useful protocol has been developed for the preparation of highly functionalized piperidinyl ethers. Biocatalytic reduction of cyclhexanones 7, 10, and 14 allows for the preparation of both cis- and trans diastereomers with an extremely high degree of stereochemical control. Reductive etherification of the corresponding trimethylsilylethers with 1-(benzyloxycarbonyl)-4-piperidinone 17 in the presence of triethylsilane and catalytic TMSO-Tf provides the desired piperidinyl ethers in good to excellent yields. Finally hygrogenolysis of the nitrogen protecting group leads to piperidinyl ethers in near quantitative yields. Application of the methodology to a range of piperidinyl ethers, including the core scaffolds of diphenylpyraline and ebastine, is also described.
- Kuethe, Jeffrey T.,Janey, Jacob M.,Truppo, Matthew,Arredondo, Juan,Li, Tao,Yong, Kelvin,He, Shuwen
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p. 4563 - 4570
(2014/06/10)
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- IMIDAZOLE DERIVATIVES
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Described herein are compounds of formula (I), The compounds of formula I act as DGAT1 inhibitors and can be useful in preventing, treating or acting as a remedial agent for hyperlipidemia, diabetes mellitus and obesity.
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Page/Page column 60
(2013/02/27)
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- 2,4-DIAMINOQUINAZOLINES FOR SPINAL MUSCULAR ATROPHY
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2,4-Diaminoquinazolines of formula (I) are provided herein and are useful for treating spinal muscular atrophy (SMA).
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Page/Page column 75
(2008/06/13)
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- 4-CYCLOALKYLAMINOPYRAZOLO PYRIMIDINE NMDA/NR2B ANTAGONISTS
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Compounds represented by Formula (I): or pharmaceutically acceptable salts thereof, are effective as NMDA/NR2B antagonists useful for treating neurological conditions such as, for example, pain, Parkinson's disease, Alzheimer's disease, epilepsy, depression, anxiety, ischemic brain injury including stroke, and other conditions.
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(2010/02/11)
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- THERAPEUTIC AMIDE DERIVATIVES
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The present invention relates to compounds of the formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein: A and B independently represent CH2 or O, with the proviso that A and B are not simultaneously O; Cy represents one of the following Formula (II) optionally substituted by one to three groups selected from hydroxy, halogen, C1-6alkyl, C1-6alkoxy, C1-6 haloalkyl, C1-6alkylamino and amino; R1 and R2 are independently selected from hydroxy, halogen, C1-6alkyl, C1-6alkoxy, C1-6 haloalkyl and C3-8 cycloalkyl; n represents an integer from 0-4; X is hydrogen, hydroxy, halogen or C1-6alkoxy; Y is oxy, thio, a 1-4 membered alkylene, a 2-4 membered alkylene ether, 2-4 membered alkylene thioether or an oxyethyleneoxy group, optionally substituted by 1 to 4 groups independently selected from hydroxy, halogen, C1-6alkyl, C1-6alkoxy and C1-6 haloalkyl; Z is CH or N; and p represents an integer from 0-5 when Z is CH or 0-4 when Z is N; when p represents 2 or more, two of R2s may be taken together with the carbon atoms to which they are attached to form a 5-8 membered cycloalkyl ring to processes for the preparation of, intermediates used in the preparation of, compositions containing such compounds and the uses of such compounds as antagonists of the NMDA NR2B receptor.
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Page/Page column 150
(2010/02/13)
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- Selective reductions with stable indium trihydride reagents
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The carbene and tertiary phosphine adducts of indane, [InH3{CN(Mes)C2H2N(Mes)}] and [InH3{P(C6H11)3}] (Mes = 2,4,6-trimethylphenyl), have been used to reduce unsaturated organic functionalities. The success and selectivity of these reductions relative to those carried out with lighter group 13 hydride complexes is discussed. (C) 2000 Elsevier Science Ltd.
- Abernethy,Cole,Davies,Jones
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p. 7567 - 7570
(2007/10/03)
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- BENZAMIDINE DERIVATIVES SUBSTITUTED BY CYCLIC AMINO ACID AND CYCLIC HYDROXY ACID DERIVATIVES AND THEIR USE AS ANTI-COAGULANTS
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This invention is directed to benzamidine derivatives substituted by cyclic amino acid and cyclic hydroxy acid derivatives which are useful as anti-coagulants. This invention is also directed to pharmaceutical compositions containing the compounds of the invention, and methods of using the compounds to treat disease-states characterized by thrombotic activity.
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- Catalytic enantioselective synthesis of a spriofused azetidinone
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A process for producing a compound of the formula STR1 comprises the following sequence of steps: STR2 wherein the various radicals are as defined in the specification.
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- Potentiating effects of β-eudesmol-related cyclohexylidene derivatives on succinylcholine-induced neuromuscular block in isolated phrenic nerve-diaphragm muscles of normal and alloxan-diabetic mice
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β-Eudesmol, a sesquiterpenoid alcohol contained in Atractylodes lancea, potentiates succinylcholine (SuCh)-induced neuromuscular blockade. The potentiating effect is greater in diabetic muscles than in normal ones. As a ligand for affinity chromatography to study the potentiating mechanism, we designed and synthesized newly β-eudesmol-related cyclohexylidene derivatives (2-(3-hydroxy-3-methylbutyl)cyclohexylidene KTE-13, 2-(3-hydroxy-3-methylbutyl)-4-cyclohexyl carboxylic acid; KTE-32 and 4-tert-butoxycarbonyl-2- (3-hydroxy-3-methylbutyl) cyclohexylidene; KTE-33). We examined the potentiating effects of those compounds in phrenic nerve-diaphragm muscle preparations of normal and alloxan-diabetic mice. KTE-33 (100 μM) potentiated more greatly SuCh-induced neuromuscular blockade in diabetic muscles than in normal ones (the potentiating ratios in normal and diabetic muscles were 6.7 and 10.6, respectively), while KTE-13 (100 μM) and -32 (200 μM) potentiated weakly. These results suggest that the ester group in KTE-33 rather than a carboxyl group in KTE-32 is important in inducing the potentiation of SuCh-induced neuromuscular blockade in diabetic state.
- Kimura,Diwan,Yanagi,Kon-No,Nojima,Kimura
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p. 407 - 410
(2007/10/03)
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- Functional Group Reductions with Lewis Base Adducts of Gallane
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Tertiary amine and tertiary phosphine adducts of gallane, L*GaH3 (L=Me3N, quinuclidine, (C6H11)3P) reduce a variety of unsaturated functional groups with a selectivity different to that observed for similar alane adducts.
- Raston, Colin L.,Siu, Anna F. H.,Tranter, Carolyn J.,Young, David J.
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p. 5915 - 5918
(2007/10/02)
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- Synthesis of Bridgehead-Substituted Bicycloheptanes by Radical Cyclization
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A kinetic investigation shows that the rate of cyclization (kC) of the (4-methylenecyclohexyl)methyl radical 3 at 25 deg C is 4.4 x 102 s-1, which is considerably slower than that (2.3 x 105 s-1) of the parent 5-hexenyl radical.The energy of activation for the process 3 -> 4 is 12.8 kcal mol-1, which is in excellent agreement with theoretical values derived from force-field calculations.Ring-closure of appropriately substituted (4-methylenecyclohexyl)methyl radical precursors allows the synthesis of bicycloheptyl systems with useful functionality at the bridgehead to be achieved readily and in high yield.An interesting example is given of the application of an iodine-atom-transfer cyclization to the synthesis of a bicycloheptane functionalized at C7 and C1.
- Della, Ernest W.,Knill, Andrew M.,Pigou, Paul E.
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p. 2110 - 2114
(2007/10/02)
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- 8-(OXO-SUBSTITUTED CYCLOALKYL)XANTHINES
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1,3-Substituted-8-(oxo-substituted cycloalkyl)xanthines and pharmaceutically acceptable salts of such compounds are disclosed. Preferred compounds include the cis and trans isomers of 1,3-dipropyl-8-(3-hydroxycyclopentyl) xanthine and the cis and trans isomers of 1,3-dipropyl-8-(4-hydroxycyclohexyl) xanthine. The compounds are potent and selective bronchodilators and/or cardiotonic agents.
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- Synthesis of aminoiderivatives of 4,5,6,7-tetrahydro-benzothiazole. II. 4, 5 and 6-aminomethyl derivatives with cardiovascular activity
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The ethyl esters of 4,5,6,7-tetrahdyro-benzothiazolyl-4 carboxylic acids were synthesized from corresponding ethyl 1-oxo-2 bromo-cyclohexane-carboxylates. Their reduction to alcohols, which were then transformed into tosylates, leads to the aminomethyl derivatives. These derivatives are practically devoid of antihistaminic H2 and dopaminergic activities but have interesting cardiovascular properties.
- Maillard,Delaunay,Langlois,et al.
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p. 457 - 460
(2007/10/02)
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