cas 39613-92-8, D-Alanine Isopropyl Ester HCl

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Evaluation of chiral amino acid discrimination by a permethylated cyclic tetrasaccharide, cyclo-{→6)-α-D-Glcp-(1→3)-α-D-Glcp- (1→6)-α-D-Glcp-(1→3)-α-D-Glcp-(1→}, using FAB mass spectrometry
The novel cyclic oligosaccharide, permethylated tetrasaecharide (CTS), determinates the enantiomers of chiral amino acid isopropyl ester hydrochlorides. Copyright
Shizuma, Motohiro,Kiso, Taro,Terauchi, Hisashi,Takai, Yoshio,Yamada, Hitoshi,Nishimoto, Tomoyuki,Ono, Daisuke,Shimomura, Osarnu,Nomura, Ryoki,Miwa, Yoshikatsu,Nakamura, Masaki,Nakano, Hirofumi
p. 1054 - 1055
(2008)
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4'-HALOGEN CONTAINING NUCLEOTIDE AND NUCLEOSIDE THERAPEUTIC COMPOSITIONS AND USES RELATED THERETO
Disclosed are halogen containing nucleotide and nucleoside therapeutic compositions and uses related thereto. In certain embodiments, the disclosure relates to the treatment or prophylaxis of viral infections. Such viral infections can include tongaviridae, bunyaviridae, arenaviridae, coronaviridae, flaviviridae, picornaviridae, Eastern, Western, and Venezuelan Equine Encephalitis (EEE, WEE and VEE, respectively), Chikungunya fever (CHIK), Ebola, Influenza, RSV, and Zika virus infections.
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Page/Page column 317

(2021/07/10)

Re-Engineering Organocatalysts for Asymmetric Friedel-Crafts Alkylation of Indoles through Computational Studies
The discovery of efficient organocatalysts is generally carried out by thorough experimental screening of different candidates. We recently reported an efficient organocatalyst for iminium-ion-based asymmetric Diels-Alder reactions following a rational design approach. This result encouraged us to test this optimal catalyst in the mechanistically related Friedel-Crafts alkylation of indoles, but to our surprise, almost null enantioselectivity was observed. The results did not significantly improve with structurally related catalysts, and a totally unexpected facial selectivity inversion was also noticed. Using DFT calculations by modeling the competing transition structures with ONIOM, we could unravel the origins of those findings, further employed to predict the most efficient catalyst for this new transformation. The computational results were validated experimentally (up to 92:8 er), providing another successful example of a general strategy to accelerate catalyst development which still remains underexplored.
Gerosa, Gabriela G.,Marcarino, Maribel O.,Spanevello, Rolando A.,Suárez, Alejandra G.,Sarotti, Ariel M.
p. 9969 - 9978
(2020/09/03)

4'-HALOGEN CONTAINING NUCLEOTIDE AND NUCLEOSIDE THERAPEUTIC COMPOSITIONS AND USES RELATED THERETO
Disclosed are halogen containing nucleotide and nucleoside therapeutic compositions and uses related thereto. In certain embodiments, the disclosure relates to the treatment or prophylaxis of viral infections. Such viral infections can include tongaviridae, bunyaviridae, arenaviridae, coronaviridae, flaviviridae, picornaviridae, Eastern, Western, and Venezuelan Equine Encephalitis (EEE, WEE and VEE, respectively), Chikungunya fever (CHIK), Ebola, Influenza, RSV, and Zika virus infections.
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Page/Page column 297

(2019/10/01)

Stereoselective Synthesis of Sofosbuvir through Nucleoside Phosphorylation Controlled by Kinetic Resolution
The preparation of Sofosbuvir, the potent key component of recent Hepatitis C (HCV) infection therapies, is reported. The process is based on the dynamic kinetic resolution of the stereochemically unstable isopropyl-2-{[chloro(phenoxy)phosphoryl]-amino}propanoate (8). A high stereoselectivity was obtained when the right protective group for 3′-OH was chosen. Ester and carbonate-based protective groups gave lower stereoselectivities, but benzyl protection allowed the phosphorylation to occur with a 92:8 ratio in favour of the product with the right configuration at the P-stereogenic centre. Starting from the γ-lactone of 2-deoxy-2-fluoro-2-methylpentonic acid, the synthesis was accomplished in eight steps in 40 % overall yield using commercially available reagents, and without any enzymatic or chemical resolution technique.
Cini, Elena,Barreca, Giuseppe,Carcone, Luca,Manetti, Fabrizio,Rasparini, Marcello,Taddei, Maurizio
p. 2622 - 2628
(2018/04/30)

Novel preparation method of L-alanine isopropyl ester hydrochloride
The invention provides a novel preparation method of L-alanine isopropyl ester hydrochloride, and relates to a preparation method of an intermediate of a new drug sofosbuvir for treating chronic hepatitis. The method sequentially comprises the following steps that L-alanine is adopted as a raw material to react with triphosgene for ring closure, after ring opening is conducted through isopropanol under the acidic condition, salt formation is conducted, and the product L-alanine isopropyl ester hydrochloride is obtained. According to the novel preparation method, a brand-new synthetic route is provided, the adopted raw material is wide and sufficient in source, the cost is low, the reaction conditions are mild, the processes are simple, all the reactions are conventionally operated, the condition that a large quantity of high-irritation raw materials such as thionyl chloride are used is avoided, and a good industrial prospect is achieved.
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Paragraph 0007; 0013

(2017/05/20)

NUCLEOTIDE AND NUCLEOSIDE THERAPEUTIC COMPOSITIONS AND USES RELATED THERETO
This disclosure relates to nucleotide and nucleoside therapeutic compositions and uses in treating infectious diseases, viral infections, and cancer, where the base of the nucleotide or nucleoside contains at least one thiol, thione or thioether.
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Page/Page column 77

(2017/07/14)

NUCLEOTIDE AND NUCLEOSIDE THERAPEUTIC COMPOSITIONS AND USES RELATED THERETO
This disclosure relates to nucleotide and nucleoside therapeutic compositions and uses in treating infectious diseases, viral infections, and cancer, where the base of the nucleotide or nucleoside contains at least one thiol, thione or thioether.
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Page/Page column 152

(2017/09/27)

Nucleotide phosphoramidate formulation
Compound 1 with the formula I is an HCV antiviral protide, which is surprisingly soluble in ethanol, thereby facilitating the preparation of pharmaceutical formulations, such as adsorbed mesoporous carriers or SEDDS of Pouton Types III or IV.
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Paragraph 0210; 0211; 0212

(2017/12/27)

ALKYNE CONTAINING NUCLEOTIDE AND NUCLEOSIDE THERAPEUTIC COMPOSITIONS AND USES RELATED THERETO
This disclosure relates to nucleotide and nucleoside therapeutic compositions and uses in treating infectious diseases, viral infections, and cancer, where the base of the nucleotide or nucleoside contains at least one thiol, thione or thioether.
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Page/Page column 316

(2017/12/09)

ANTIVIRAL PHOSPHODIAMIDE PRODRUGS OF TENOFOVIR
Compounds of Formula I and pharmaceutically acceptable salts and co-crystals thereof are useful for the inhibition of HIV reverse transcriptase. The compounds may also be useful for the prophylaxis or treatment of infection by HIV and in the prophylaxis, delay in the onset or progression, and treatment of AIDS. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antiviral agents, immunomodulators, antibiotics or vaccines.
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Page/Page column 27; 30

(2017/07/06)

PROCESS FOR MAKING CHLORO-SUBSTITUTED NUCLEOSIDE PHOSPHORAMIDATE COMPOUNDS
The present invention is directed to a process for making Chloro-Substituted Nucleoside Phosphoramidate Compounds of formula (I): which are useful for the treatment and prophylaxis of HCV infection. The present invention is also directed to compounds that are useful as synthetic intermediates for making the compounds of formula (I).
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Paragraph 0246; 0247

(2017/09/02)

NUCLEOSIDE PHOSPHORAMIDATES USEFUL FOR THE TREATMENT OF VIRAL INFECTIONS AND PREPARATION THEREOF
The present invention relates to an industrially applicable process for the preparation of phosphoramidates useful for the treatment of viral infections, such as sofosbuvir, and to intermediates useful for the preparation thereof. Formula (I):
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Page/Page column 19

(2016/10/11)

Discovery of 2'-α-C-Methyl-2'-β-C-fluorouridine Phosphoramidate Prodrugs as Inhibitors of Hepatitis C Virus
2′-α-C-Methyl-2′-β-C-fluorouridine and its phosphoramidate prodrugs were synthesized and evaluated for their inhibitory activity against HCV. The structure?activity relationship analysis of the phosphoramidate moiety found that 17m, 17q, and 17r exhibit potent activities against HCV, with EC50 values of 1.82 ± 0.19, 0.88 ± 0.12, and 2.24 ± 0.22 μM, respectively. The docking study revealed that the recognition of the 2′-β-F by Arg158, 3′-OH by N291, and the Watson?Crick pairing with the template allowed 23 to form the in-line conformation necessary for its incorporation into the viral RNA chain.
Zeng, Debin,Zhang, Rui,Nie, Quandeng,Cao, Lin,Shang, Luqing,Yin, Zheng
supporting information
p. 1197 - 1201
(2016/12/18)

NUCLEOTIDE AND NUCLEOSIDE THERAPEUTICS COMPOSITIONS AND USES RELATED THERETO
This disclosure relates to nucleotide and nucleoside therapeutic compositions and uses in treating infectious diseases, viral infections, and cancer, where the base of the nucleotide or nucleoside contains at least one thiol, thione or thioether.
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Page/Page column 287

(2016/09/26)

DIOXOLANE ANALOGUES OF URIDINE FOR THE TREATMENT OF CANCER
The invention provides compounds of formula (I), wherein: R1 is OR11, or NR5R5'; R2 is H or F; R5 is H, C1-C6alkyl, OH, C(=O)R6, O(C=O)R6 or O(C=O)OR6; R5′ is H or C1-C6alkyl; R6 is C1-C6alkyl or C3-C7cycloalkyl; R13 is H, phenyl, pyridyl, benzyl, indolyl or naphthyl wherein the phenyl, pyridyl, benzyl, indolyl and naphthyl is optionally substituted with 1, 2 or 3 R22; and the other variables are as defined in the claims, which are of use in the treatment of cancer, and related aspects.
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Page/Page column 50

(2016/03/22)

Acyclic nucleoside phosphamide D-amino-acid ester derivative, preparation method of derivative salt and application of derivative to antiviral effect
The invention belongs to the field of medical chemical antiviral effects, and relates to an acyclic nucleoside phosphamide D-amino-acid ester derivative, a preparation method of derivative salt and an application of the derivative to the antiviral effects. The invention further provides a compound comprising the derivative, a stereoisomer of the derivative, pharmaceutically acceptable salt, a hydrate, a solvate or crystal and drug combination and an application of the compound or combination to treatment and/or prevention of Aids and hepatitis B virus infection. The in vivo activity of the compound is remarkably superior to that of a pro-drug of acyclic nucleoside phosphamide L-amino-acid ester, and the compound has obvious clinical application values.
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Paragraph 0065; 0066; 0073; 0074; 0075

(2017/03/22)

NUCLEOTIDE AND NUCLEOSIDE COMPOSITIONS AND USES RELATED THERETO
This disclosure relates to nucleotide and nucleoside therapeutic compositions and uses in treating infectious diseases, viral infections, and cancer, where the base of the nucleotide or nucleoside contains at least one thiol, thione or thioether.
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Page/Page column 237; 238

(2015/03/28)

PURIFICATION OF TENOFOVIR ALAFENAMIDE AND ITS INTERMEDIATES
The present disclosure provides process for the purification of 9-{(R)-2-[((R,S)-{[(S)-l- (isopropoxycarbonyl)ethyl]amino} phenoxyphosphinyl) methoxy] propyl}adenine using acids to give enantiomerically pure tenofovir alafenamide.
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Page/Page column 7

(2015/12/30)

D-AMINO ACID PHOSPHORAMIDATE PRONUCLEOTIDES OF HALOGENO PYRIMIDINE COMPOUNDS FOR LIVER DISEASE
Provided herein are compounds, compositions, and methods for the treatment of viral infections, for example, Flaviviridae infections, including HCV infections. In certain embodiments, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-viral agents. In certain embodiments, the compounds are D-amino acid phosphoramidate halogeno pyrimidine nucleoside analog compounds which display remarkable efficacy and bioavailability for the treatment of, for example, HCV infection in a human. In certain embodiments, the compounds are of Formula I: or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein: PD, X, R1, R2, RA, and RB are as described herein.
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Paragraph 0298; 0310; 0311

(2015/02/19)

NUCLEOTIDES FOR THE TREATMENT OF LIVER CANCER
Provided herein are compounds, compositions and methods for the treatment of liver cancer such as hepatocellular carcinoma, cholangiocarcinoma, or biliary tract cancer. In certain embodiments, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-cancer agents. In certain embodiments, the compounds are nucleoside analogs of Formula I: (I); or a pharmaceutically acceptable salt thereof, wherein Base, Z1, Z2, Z3, Z4, V, W, X, Ar, R1 and R2 are as described herein.
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Paragraph 00249

(2015/06/11)

2'-DICHLORO AND 2'-FLUORO-2'-CHLORO NUCLEOSIDE ANALOGUES FOR HCV INFECTION
Provided herein are compounds, compositions and methods for the treatment of Flaviviridae infections, including HCV infections. In certain embodiments, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-viral agents. In certain embodiments, the compounds are 2'-dichloro or 2'-fluoro-2'-chloro nucleoside analogue compounds which display remarkable efficacy and bioavailability for the treatment of, for example, HCV infection in a human. In certain embodiments, the compounds are of Formula (I):or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form or polymorphic form thereof; wherein each of RA and RB is independently Cl or F, wherein at least one of RA and RB is C1; and Base, PD and Z are as described herein.
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Paragraph 00317

(2015/06/11)

Chiral recognition of carboxylates by a static library of thiourea receptors with amino acid arms
Chiral recognition is based on a large network of very subtle interactions whose outcome is difficult to predict. A combinatorial approach is therefore the most suitable to search for the most efficient receptor and obtain a structure-enantioselectivity correlation. We synthesized a set of 12 receptors constructed with 1,9-diaminoantracene and α-amino acid esters, linked via thiourea groups. The association constants and enantioselectivities for the complexes with mandelate and N-acetylphenylalanine were determined by competitive NMR titrations. Association constants quite regularly depend on the substituents in the receptor structure, but the distribution of enantioselectivities across the library could not easily be rationalized.
Ulatowski, Filip,Jurczak, Janusz
p. 4235 - 4243
(2015/05/13)

HETEROAROMATIC DERIVATIVES AND PHARMACEUTICAL APPLICATIONS THEREOF
Provided herein are novel heteroaromatic derivatives, or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a prodrug, a pharmaceutically acceptable salt or a prodrug thereof, and pharmaceutical compositions containing such compounds. Also provided herein are uses of such compounds or pharmaceutical compositions thereof in the manufacture of a medicament for treating respiratory diseases, especially chronic obstructive pulmonary disease (COPD).
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Paragraph 00512

(2015/11/10)

THIOPHOSPHATE NUCLEOSIDES FOR THE TREATMENT OF HCV
Provided herein are compounds, compositions and methods for the treatment of Flaviviridae infections, including HCV infections. In certain embodiments, the compounds are according to Formula 2001: where PD, Base, RA and RB are as provided herein. In certain embodiments, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-viral agents.
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Paragraph 0361; 0366

(2014/09/16)

Task-specific, biodegradable amino acid ionic liquid surfactants
VersatAAIL Surfactants: Biodegradable, chiral amino acid ionic liquid surfactants (AAILSs) with a very high surface activity are synthesized and characterized. The AAILS can be applied as task-specific ionic liquids; two examples given are the mitigation of harmful algal blooms from sea water and the shape- and size-specific synthesis of nanomaterials. Copyright
Trivedi, Tushar J.,Rao, K. Srinivasa,Singh, Tejwant,Mandal, Subir Kumar,Sutradhar, Narottom,Panda, Asit Baran,Kumar, Arvind
scheme or table
p. 604 - 608
(2012/03/22)

Serine side chain-linked peptidomimetic conjugates of cyclic HPMPC and HPMPA: Synthesis and interaction with hPEPT1
Cidofovir (HPMPC), a broad spectrum antiviral agent, cannot be administered orally due to ionization of its phosphonic acid group at physiological pH. One prodrug approach involves conversion to the cyclic form (cHPMPC, 1) and esterification by the side chain hydroxyl group of a peptidomimetic serine. Transport studies in a rat model have shown enhanced levels of total cidofovir species in the plasma after oral dosing with l-Val-l-Ser-OMe cHPMPC, 2a. To explore the possibility that 2a and its three l/d stereoisomers 2b-d undergo active transport mediated by the peptide-specific intestinal transporter PEPT1, we performed radiotracer uptake and electrophysiology experiments applying the two-electrode voltage clamp technique in Xenopus laevis oocytes overexpressing human PEPT1 (hPEPT1, SLC15A1). 2a-d did not induce inward currents, indicating that they are not transported, but the stereoisomers with an l-configuration at the N-terminal valine (2a and 2b) potently inhibited transport of the hPEPT1 substrate glycylsarcosine (Gly-Sar). A "reversed" dipeptide conjugate, l-Ser-l-Ala-OiPr cHPMPC (4), also did not exhibit detectable transport, but completely abolished the Gly-Sar signal, suggesting that affinity of the transporter for these prodrugs is not impaired by a proximate linkage to the drug in the N-terminal amino acid of the dipeptide. Single amino acid conjugates of cHPMPC (3a and 3b) or cHPMPA (5, 6a and 6b) were not transported and only weakly inhibited Gly-Sar transport. The known hPEPT1 prodrug substrate valacyclovir (7) and its l-Val-l-Val dipeptide analogue (8) were used to verify coupled transport by the oocyte model. The results indicate that the previously observed enhanced oral bioavailability of 2a relative to the parent drug is unlikely to be due to active transport by hPEPT1. Syntheses of the novel compounds 2b-d and 3-6 are described, including a convenient solid-phase method to prepare 5, 6a and 6b.
Peterson, Larryn W.,Sala-Rabanal, Monica,Krylov, Ivan S.,Serpi, Michaela,Kashemirov, Boris A.,McKenna, Charles E.
experimental part
p. 2349 - 2361
(2011/10/09)

Antiviral phosphoramidates
The invention provides novel nucleoside compounds of formula I wherein R1, R2a, R2b, R3, R4, R5, R6, R8a, R9 and R10 are as defined herein which are useful for the treatment of Hepatitis C Virus (HCV) mediated diseases. The invention further provides methods for treatment or prophylaxis of HCV mediated diseases with compounds of formula I and pharmaceutical compositions comprising these compounds,
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Page/Page column 35

(2008/06/13)

Practical synthesis, separation, and stereochemical assignment of the PMPA pro-drug GS-7340
The practical synthesis of a mixed phenoxy-amidate derivative of PMPA with high oral bioavailability and favorable pharmacokinetics is described. The non-stereoselective synthetic route produces a 1:1 mixture of two diastereomers at phosphorous. Simulated moving bed chromatography using Chiralpak AS enabled kilo-scale isolation of the more potent diastereomer (GS-7340). The GS-7340 phosphorous chiral center was found to be (S) by X-ray crystallography.
Chapman,Kernan,Prisbe,Rohloff,Sparacino,Terhorst,Yu
p. 621 - 628
(2007/10/03)