- An improved and economical process for the manufacture of the key intermediate of aliskiren, a new potent renin inhibitor
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An improved, practical, economical and efficient process for the production of (2S,4S)-2-amino-4-(4-methoxy-3-(3-methoxypropoxy)benzyl)-5-methylhexanoic acid, a key intermediate of the new potent renin inhibitor of aliskiren, in a total yield over 30% is described. This process avoids expensive reagents and chromatographic purifications, and is easily scaled up in industry.
- Wang, Fan,Xu, Xiao-Ying,Wang, Fei-Ying,Peng, Lin,Zhang, Yong,Tian, Fang,Wang, Li-Xin
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Read Online
- JAK INHIBITORS
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Described herein are Janus kinase (JAK) inhibitors and methods of utilizing JAK inhibitors in the treatment of diseases, disorders or conditions. Also described herein are pharmaceutical compositions containing such compounds.
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Paragraph 00166
(2021/04/02)
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- JAK INHIBITORS
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Described herein are Janus kinase (JAK) inhibitors and methods of utilizing JAK inhibitors in the treatment of diseases, disorders or conditions. Also described herein are pharmaceutical compositions containing such compounds.
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Paragraph 00165
(2021/02/12)
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- Structure-based drug design of novel and highly potent pyruvate dehydrogenase kinase inhibitors
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Pyruvate dehydrogenase kinases (PDHKs) are fascinating drug targets for numerous diseases, including diabetes and cancers. In this report, we describe the result of our structure-based drug design from tricyclic lead compounds that led to the discovery of highly potent PDHK2 and PDHK4 dual inhibitors in enzymatic assay. The C3-position of the tricyclic core was explored, and the PDHK2 X-ray structure with a representative compound revealed a novel ATP lid conformation in which the phenyl ring of Phe326 mediated the interaction of the Arg258 sidechain and the compound. Compounds with amide linkers were designed to release the ATP lid by forming an intramolecular pi-pi interaction, and these compounds showed single-digit nM IC50 values in an enzymatic assay. We also explored the C4-position of the tricyclic core to reproduce the interaction observed with the C3-position substitution, and the pyrrolidine compound showed the same level of IC50 values. By optimizing an interaction with the Asn255 sidechain through a docking simulation, compounds with 2-carboxy pyrrole moiety also showed single-digit nM IC50 values without having a cation-pi interaction with the Arg258 sidechain.
- Bessho, Yuki,Akaki, Tatsuo,Hara, Yoshinori,Yamakawa, Maki,Obika, Shingo,Mori, Genki,Ubukata, Minoru,Yasue, Katsutaka,Nakane, Yoshitomi,Terasako, Yasuo,Orita, Takuya,Doi, Satoki,Iwanaga, Tomoko,Fujishima, Ayumi,Adachi, Tsuyoshi,Ueno, Hiroshi,Motomura, Takahisa
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- JAK INHIBITORS
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Described herein are Janus kinase (JAK) inhibitors and methods of utilizing JAK inhibitors in the treatment of diseases, disorders or conditions. Also described herein are pharmaceutical compositions containing such compounds.
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Paragraph 00223
(2020/11/22)
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- A Highly Selective Hydantoin Inhibitor of Aggrecanase-1 and Aggrecanase-2 with a Low Projected Human Dose
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Aggrecanase-1 and -2 (ADAMTS-4 and ADAMTS-5) are zinc metalloproteases involved in the degradation of aggrecan in cartilage. Inhibitors could provide a means of altering the progression of osteoarthritis. We report the identification of 7 which had good oral pharmacokinetics in rats and showed efficacy in a rat chemical model of osteoarthritis. The projected human dose required to achieve sustained plasma levels ≥10 times the hADAMTS-5 IC50 is 5 mg q.d.
- Durham, Timothy B.,Marimuthu, Jothirajah,Toth, James L.,Liu, Chin,Adams, Lisa,Mudra, Daniel R.,Swearingen, Craig,Lin, Chaohua,Chambers, Mark G.,Thirunavukkarasu, Kannan,Wiley, Michael R.
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p. 5933 - 5939
(2017/07/22)
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- Rational Design of Thermodynamic and Kinetic Binding Profiles by Optimizing Surface Water Networks Coating Protein-Bound Ligands
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A previously studied congeneric series of thermolysin inhibitors addressing the solvent-accessible S2′ pocket with different hydrophobic substituents showed modulations of the surface water layers coating the protein-bound inhibitors. Increasing stabilization of water molecules resulted in an enthalpically more favorable binding signature, overall enhancing affinity. Based on this observation, we optimized the series by designing tailored P2′ substituents to improve and further stabilize the surface water network. MD simulations were applied to predict the putative water pattern around the bound ligands. Subsequently, the inhibitors were synthesized and characterized by high-resolution crystallography, microcalorimetry, and surface plasmon resonance. One of the designed inhibitors established the most pronounced water network of all inhibitors tested so far, composed of several fused water polygons, and showed 50-fold affinity enhancement with respect to the original methylated parent ligand. Notably, the inhibitor forming the most perfect water network also showed significantly prolonged residence time compared to the other tested inhibitors.
- Krimmer, Stefan G.,Cramer, Jonathan,Betz, Michael,Fridh, Veronica,Karlsson, Robert,Heine, Andreas,Klebe, Gerhard
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p. 10530 - 10548
(2016/12/16)
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- A preparation N-substituted oxazole alkone chiral method of ligand
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The invention relates to the technical field of a method for preparing an N-substituted oxazolone chiral ligand. The method for preparing the N-substituted oxazolone chiral ligand provided by the invention comprises the following steps of: reacting a compound A shown as the following formula (described in the specification) with R1-COC1 under the action of alkaline reagent potassium tert-butoxide, sodium methyoxide or NaNH2 to obtain a target product (I), wherein R1 is an alkyl with the number of carbon atoms of being less than or equal to 7, and R2 is phenyl, benzyl or isopropyl. In the invention, potassium tert-butoxide is used for substituting butyl lithium and lithium bis(trimethylsilyl)amide which are frequently used in the prior art, reaction can be carried out at normal temperature, reaction time is shortened, reaction is completed after batch charging is completed, then aftertreatment operation can be carried out, and dynamic cost is saved; less gas is released in the aftertreatment process, and safety is high; and yield of the obtained target compound is high, and purity is high, thus the method provided by the invention is applicable to industrial production.
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Paragraph 0030; 0031
(2017/02/09)
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- Convergent Synthesis of the Renin Inhibitor Aliskiren Based on C5-C6 Disconnection and CO2H-NH2 Equivalence
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A novel synthesis of the renin inhibitor aliskiren based on an unprecedented disconnection between C5 and C6 was developed, in which the C5 carbon acts as a nucleophile and the amino group is introduced by a Curtius rearrangement, which follows a simultaneous stereocontrolled generation of the C4 and C5 stereogenic centers by an asymmetric hydrogenation. Operational simplicity, step economy, and a good overall yield makes this synthesis amenable to manufacture on scale.
- Cini, Elena,Banfi, Luca,Barreca, Giuseppe,Carcone, Luca,Malpezzi, Luciana,Manetti, Fabrizio,Marras, Giovanni,Rasparini, Marcello,Riva, Renata,Roseblade, Stephen,Russo, Adele,Taddei, Maurizio,Vitale, Romina,Zanotti-Gerosa, Antonio
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p. 270 - 283
(2016/03/04)
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- A Facile, Six-Step Process for the Synthesis of (3 S,5 S)-3-Isopropyl-5-((2 S,4 S)-4-isopropyl-5-oxo-tetrahydrofuran-2-yl)-2-oxopyrrolidine-1-carboxylic Acid tert -Butyl Ester, the Key Synthetic Intermediate of Aliskiren
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A facile, six-step process for the synthesis of (3S,5S)-3-isopropyl-5-((2S,4S)-4-isopropyl-5-oxotetrahydro- furan-2-yl)-2-oxopyrrolidine-1-carboxylic acid tert-butyl ester from (S)-4-benzyloxazolidin-2-one 2 in an overall 50% yield is reported. The key transformations include: a highly efficient diastereoselective epoxidation, Lewis acid-catalyzed ring-opening with bromide, an SN2 reaction using NaN3, and a tandem reduction-cyclization reaction.
- Pan, Xianhua,Xu, Siyao,Huang, Rui,Yu, Wansheng,Liu, Feng
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p. 611 - 617
(2015/06/30)
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- Process for Producing Aliskiren
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A new route of synthesis of the compound Aliskiren of formula (I), used in the treatment of hypertension, is described.
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Paragraph 0124-0127
(2013/03/28)
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- Efficient diastereoselective synthesis of (2R,3R,4R)-2-amino-3-hydroxy-4,5- dimethylhexanoic acid, the lactone linkage unit of homophymine A
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For the total synthesis of novel cyclodepsipeptide homophymine A, (2R,3R,4R)-2-amino-3-hydroxy-4,5- dimethylhexanoic acid was successfully synthesized by Evans' asymmetric alkylation and the anti-selective asymmetric hydrogenation of a chiral α-amino-β-keto ester as the key steps.
- Ohtaka, Junpei,Hamajima, Akinari,Nemoto, Tetsuhiro,Hamada, Yasumasa
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p. 245 - 250
(2013/03/28)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF ALISKIREN
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The present invention relates to an improved process for the preparation of renin inhibitor Aliskiren intermediates of Formula-II and further conversion into Aliskiren and its pharmaceutically acceptable salts.
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Page/Page column 7; 12
(2013/12/03)
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- A total synthesis of aliskiren
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A total synthesis of aliskiren (20) was accomplished. A key in our synthesis was to use the symmetric trans-cisoid-trans-bis-lactone 1 as a precursor. It was expediently prepared by three different routes (Scheme 2). Appending the end groups and functional group transformations completed the synthesis (Scheme 3). Copyright
- Nam, Gyeok,Ko, Soo Y.
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p. 1937 - 1945,9
(2012/12/12)
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- Structure-activity relationship studies of S1P agonists with a dihydronaphthalene scaffold
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Structure-activity relationship (SAR) of sphingosine-1-phosphate receptor agonists with a dihydronaphthalene scaffold was investigated. Compound 1 was modified to improve S1P1 agonistic activity and in vivo peripheral lymphocyte lowering (PLL) activity without impairing selectivity over S1P 3 agonistic activity. A detailed SAR study of the terminal lipophilic part revealed that the introduction of substituents on the propylene linker and the terminal benzene ring influences in vitro and PLL activities. Compound 6n bearing a (S)-methyl group at the 2-position on the propylene linker and chlorine at the para-position on the terminal benzene ring showed potent hS1P1 agonistic activity with excellent selectivity over hS1P 3 and in vivo PLL activity in mice.
- Kurata, Haruto,Kusumi, Kensuke,Otsuki, Kazuhiro,Suzuki, Ryo,Kurono, Masakuni,Tokuda, Natsuko,Takada, Yuka,Shioya, Hiroki,Mizuno, Hirotaka,Komiya, Takaki,Ono, Takeji,Hagiya, Hiroshi,Minami, Masashi,Nakade, Shinji,Habashita, Hiromu
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scheme or table
p. 144 - 148
(2012/02/16)
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- PROCESS FOR PRODUCING ALISKIREN
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A new route of synthesis of the compound Aliskiren of formula (I), used in the treatment of hypertension, is described.
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Page/Page column 24
(2011/12/14)
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- β N-O turns and helices induced by β2-aminoxy peptides: Synthesis and conformational studies
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Herein, we report an efficient route for the asymmetric synthesis of β2-aminoxy acids as well as experimental and theoretical studies of conformations of peptides composed of β2-aminoxy acids. The nine-membered-ring intramolecular hydrogen bonds, namely, β N-O turns, are generated between adjacent residues in those peptides, in accordance with our computational results. The presence of two consecutive homochiral β N-O turns leads to the formation of β N-O helical structures in solution, although both helical (composed of two β N-O turns of the same handedness) and reverse-turn (composed of two β N-O turns with opposite handedness) structures are of similar stability, as suggested by theoretical studies. Nevertheless, two slightly different conformations, with the same handedness, of β2-aminoxy monomers have been observed in the solid state and in solution according to our X-ray and 2D NOESY studies.
- Jiao, Zhi-Gang,Chang, Xiao-Wei,Ding, Wei,Liu, Guo-Jun,Song, Ke-Sheng,Zhu, Nian-Yong,Zhang, Dan-Wei,Yang, Dan
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supporting information; experimental part
p. 1791 - 1799
(2012/02/02)
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- Total synthesis of "Aliskiren": The first renin inhibitor in clinical practice for hypertension
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We report a "macrocycle route" toward aliskiren, a drug presently marketed for the treatment of hypertension, using a highly stereocontrolled approach starting from a common "isopropyl chiron". Highlights of the synthesis include a challenging RCM reaction to produce a nine-membered unsaturated lactone, a highly stereoselective catalytic Du Bois aziridination, and a regio- and diastereoselective aziridine ring-opening to a vicinal amino alcohol.
- Hanessian, Stephen,Guesne, Sebastien,Chenard, Etienne
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supporting information; scheme or table
p. 1816 - 1819
(2010/09/16)
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- Process and intermediates for the preparation of aliskiren
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The present invention relates to a process and intermediates for the manufacture of aliskiren or pharmaceutically acceptable salts thereof.
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Page/Page column 22; 23
(2010/06/15)
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- Functional analysis of an aspartate-based epoxidation catalyst with amide-to-alkene peptidomimetic catalyst analogues
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Subtle exchange: Replacement of an amide function with alkene or fluoroalkene groups provides a new class of epoxidation catalysts (see scheme). The structure-dependent catalytic behavior of these isosteric peptides provides mechanistic insights in their mode of action. (Chemical Equation Presented).
- Jakobsche, Charles E.,Peris, Gorka,Miller, Scott J.
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supporting information; experimental part
p. 6707 - 6711
(2009/03/12)
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- 1-HETEROCYCLYLAMINO-2-HYDROXY-3-AMINO-ω-ARYLALKANES
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1-Heterocyclylamino-2-hydroxy-3-amino-?-arylalkanes of formula (I) and the salts thereof have renin-inhibiting properties and can be used as antihypertensive, medicinally active ingredients.
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- 1-ACYLAMINO-2-HYDROXY-3-AMINO-W-ARYLALKANES AS RENIN INHIBITORS
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1-Acylamino-2-hydroxy-3-amino-ω-arylalkanes of formula I. and the salts thereof, have renin-inhibiting properties and can be used as antihypertensive, medicinally active ingredients.
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Page/Page column 73-75
(2008/06/13)
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- Quinolizinone compound and use thereof as HIV integrase inhibitor
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A pharmaceutical agent having an anti-HIV action, particularly, a pharmaceutical agent having an integrase inhibitory action, is provided. The present invention relates to a quinolizinone compound represented by the following formula [I] wherein each symbol is as defined in the specification, a pharmaceutically acceptable salt thereof, and an anti-HIV agent containing same as an active ingredient. The compound of the present invention has an HIV integrase inhibitory action and is useful as an anti-HIV agent for the prophylaxis or therapy of AIDS. Moreover, by a combined use with other anti-HIV agents such as protease inhibitors, reverse transcriptase inhibitors and the like, the compounds can become a more effective anti-HIV agent. Since the compound has a high inhibitory activity specific for integrases, the compound can provide a safe pharmaceutical agent for human with a fewer side effects.
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Page/Page column 47
(2010/10/20)
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- P3 cap modified Phe*-Ala series BACE inhibitors
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With the aim of reducing molecular weight and adjusting log D value of BACE inhibitors to more favorable range for BBB penetration and better bioavailability, we synthesized and evaluated several series of P3 cap modified BACE inhibitors obtained via replacement of the P3 NHBoc moiety as seen in 3 with other polar functional groups such as amino, hydroxyl and fluorine. Several promising inhibitors emerging from this P3 cap SAR study (e.g., 15 and 19) demonstrated good enzyme inhibitory potencies (BACE-1 IC50 50 ～1 μM).
- Chen, Shu-Hui,Lamar, Jason,Guo, Deqi,Kohn, Todd,Yang, Hsiu-Chiung,McGee, James,Timm, David,Erickson, Jon,Yip, Yvonne,May, Patrick,McCarthy, James
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p. 245 - 250
(2007/10/03)
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- HYDROXAMATE SULFONAMIDES AS CD23 SHEDDING INHIBITORS
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A class of piperidine and related heterocyclic derivatives, C-substituted by a substituted aryl or heteroaryl moiety, and N-substituted by an ethylsulfonyl group which in turn is substituted at the 2-position by a hydroxamic acid moiety and also by a range of alternative substituents, being potent inhibitors of CD23 shedding, are useful in the treatment and/or prevention of allergic, inflammatory and neoplastic diseases.
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- HYDROXAMATE SULFONAMIDES AS CD23 SHEDDING INHIBITORS
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A class of piperazine and related heterocyclic derivatives, substituted at the 4-position by a substituted aryl or heteroaryl moiety, and at the 1-position by an ethylsulfonyl group which in turn is substituted at the 2-position by a hydroxamic acid moiety and also by a range of alternative substituents, being potent inhibitors of CD23 shedding, are useful in the treatment and/or prevention of allergic, inflammatory and neoplastic diseases.
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- Asymmetric total synthesis of ent-(-)-roseophilin: Assignment of absolute configuration
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An asymmetric total synthesis of ent-(-)-roseophilin (1), the unnatural enantiomer of a novel naturally occurring antitumor antibiotic, is described. The approach enlists a room temperature heterocyclic azadiene inverse electron demand Diels-Alder reaction of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (7) with the optically active enol ether 6 bearing the C23 chiral center followed by a reductive ring contraction reaction for formation of an appropriately functionalized pyrrole ring in a key 1,2,4,5-tetrazine → 1,2-diazine → pyrrole reaction sequence. A Grubbs' ring closing metathesis reaction was utilized to close the unusual 13-membered macrocycle prior to a subsequent 5-exo-trig acyl radical-alkene cyclization that was used to introduce the fused cyclopentanone and complete the preparation of the tricylic ansa-bridged azafulvene core 32. Condensation of 32 with 33 under the modified conditions of Tius and Harrington followed by final deprotection provided (22S,23S)-1. Comparison of synthetic (22S,23S)-1 ([α]25D, CD) with natural 1 established that they were enantiomers and enabled the assignment of the absolute stereochemistry of the natural product as 22R,23R. Surprisingly, ent-(-)-1 was found to be 2-10-fold more potent than natural (+)-1 in cytotoxic assays, providing ah unusually rewarding culmination to synthetic efforts that provided the unnatural enantiomer.
- Boger,Hong
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p. 8515 - 8519
(2007/10/03)
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- The synthesis of novel matrix metalloproteinase inhibitors employing the Ireland-Claisen rearrangement
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Matrix metalloproteinase inhibitors of general formula (1) were synthesised by a route involving an Ireland-Claisen rearrangement which enables systematic modification of the substituent alpha to the hydroxamic acid. An analogue (12c) possessing an α-cyclopentyl group is a potent broad spectrum inhibitor that displays high and sustained blood levels following oral dosing in both the rat and marmoset ex-vivo bioassays. This compound and analogues are also potent inhibitors of TNFα release.
- Pratt, Lisa M.,Beckett, R. Paul,Bellamy, Claire L.,Corkill, Dominic J.,Cossins, Judy,Courtney, Paul F.,Davies, Stephen J.,Davidson, Alan H.,Drummond, Alan H.,Helfrich, Karen,Lewis, Christopher N.,Mangan, Matthew,Martin, Fionna M.,Miller, Karen,Nayee, Prakash,Rickerts, Michelle L.,Thomas, Wayne,Todd, Richard S.,Whittaker, Mark
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p. 1359 - 1364
(2007/10/03)
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- Dipeptide mimetics can substitute for the receptor activation domain resulting in highly potent analogues of hPTH(1-36) fragment
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A series of hPTH(1-36) analogues were prepared to study the role of the first peptide bond between residues Ser1-Val2. Some of these analogues were found to show high affinity binding in intact opossum kidney (OK-1) cells and were very active in their ability to stimulate adenylate cyclase production in intact OK-1 cells, rat UMR106-06 osteosarcoma cells, and SaOS-2 human osteosarcoma cells.
- Waelchli, Rudolf,Gamse, Rainer,Bauer, Wilfried,Meigel, Harald,Lier, Edouard,Feyen, Jean H.M.
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p. 1151 - 1156
(2007/10/03)
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- Stereoselective Conjugate Addition of Organoaluminum Chlorides to α,β-Unsaturated Carboxylic Acid Derivatives
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Organoaluminum chlorides react smoothly with α,β-unsaturated N-acyloxazolidinones providing chiral β-branched carboxylic acid derivatives.An unexpected contrast between the mode of reaction of dimethylaluminum chloride and that of the higher homologues is observed.While diethylaluminum chloride and its higher homologues react with the acceptors at low temperature via a polar pathway, dimethylaluminum chloride requires activation by UV-light or radical initiation under otherwise identical conditions.With bicyclic oxazolidinones derived from galactosamine a high stereoselection is accomplished in the formation of the branched carboxylic acid derivative.
- Rueck, Karola,Kunz, Horst
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p. 1018 - 1028
(2007/10/02)
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- The Asymmetric Synthesis of α-Amino and α-Hydrazino Acid Derivatives via The Stereoselective Amination of Chiral Enolates with Azodicarboxylate Esters.
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The utility of azodicarboxylate esters as (+)NH2 and (+)NH-NH2 synthons in highly diastereoselective reactions with chiral carboximide-derived enolates has been demonstrated.The lithium enolates derived from 4-substituted N-acyl 2-oxazolidinones were found to react with di-tert-butyl azodicarboxylate (DBAD) to afford the derived 2-hydrazido carboxylic acid derivetives in yields in excess of 90 percent.The diastereoselectivities of these reactions ranged from 97percent to greater than 99percent.The subsequent transformation of these adducts to both α-hydrazino and α-amino acids in enantiomeric purities in excess of 99percent is described.
- Evans, David A.,Britton, Thomas C.,Dorow, Roberta L.,Dellaria, Joseph F.
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p. 5525 - 5540
(2007/10/02)
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- ASYMMETRIC HALOGENATION OF CHIRAL IMIDE ENOLATES. A GENERAL APPROACH TO THE SYNTHESIS OF ENANTIOMERICALLY PURE α-AMINO ACIDS.
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The chiral N-acyl oxazolidones 2, as the derived dibutyl boron enolates, have been demonstrated to undergo diastereoselective bromination and subsequent azide displacement to give the α-azido carboximides 4a (5 cases).These adducts may be hydrolyzed under mild conditions to the enantiomerically pure α-azido carboxylic acids 5a.
- Evans, David A.,Ellman, Jon A.,Dorow, Roberta L.
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p. 1123 - 1126
(2007/10/02)
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