- The shortest strategy for generating phosphonate prodrugs by olefin cross-metathesis - Application to acyclonucleoside phosphonates
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A short synthetic route to phosphonate prodrugs by olefin cross-metathesis, which uses either (acyloxymethyl) or (hexadecyloxypropyl) allylphosphonate building blocks is described. A study of eight ruthenium catalysts including the Ru-indenylidene catalyst, which bears the N-heterocyclic carbene 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene, was undertaken. This method was applied to the synthesis of acyclonucleoside phosphonate prodrugs. This strategy is appealing for further uses in pharmaceutical and medicinal research. A short synthetic route to phosphonate prodrugs by olefin cross-metathesis, which uses either (acyloxymethyl)- or (hexadecyloxypropyl) allylphosphonate building blocks, is described. A study of eight Ru catalysts including the Ru-indenylidene catalyst, which bears an N-heterocycliccarbene, was undertaken. This method was applied to the synthesis of acyclonucleoside phosphonate prodrugs. Copyright
- Pradere, Ugo,Clavier, Herve,Roy, Vincent,Nolan, Steven P.,Agrofoglio, Luigi A.
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Read Online
- Halogenated imidazole compound as well as preparation method and application thereof
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The invention discloses alogenated imidazole compounds as well as a preparation method and application thereof. The structure of the halogenated imidazole compounds is disclosed in the invention, wherein, C * in the formula is R-type chiral carbon, and R1 and R2 can be independently selected from H and C1-6 alkyl; R3 is a substituted or unsubstituted C1-18 saturated or unsaturated aliphatic hydrocarbon, the aliphatic hydrocarbon comprises linear, branched or cyclic aliphatic hydrocarbon groups; X is H or a halogen atom; Y is H or a halogen atom; and X and Y cannot be H at the same time. The compounds or pharmaceutically acceptable salts or solvates thereof almost have no corticoid inhibition effect, can generate a rapid reversible anesthetic effect, can be rapidly metabolized into inactivecarboxylic acid metabolites, and have good revival quality after drug withdrawal; the corticoid function of the body can be rapidly recovered after single administration or continuous administration,the occurrence rate of muscular tremor after administration is low, and the body is rapidly awakened after drug withdrawal. The compounds or the salt compounds thereof can be used for preparing central inhibitory drugs which have sedative-hypnotic and/or anesthetic effects on humans or animals.
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Paragraph 0025-0031
(2020/01/25)
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- Benzodiazepine compound as well as preparation method and medical action thereof (by machine translation)
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The invention provides a benzodiazepine compound as well as a preparation method and a medicine effect thereof, and belongs to the field of chemical medicine. The benzodiazepine compound is a compound shown in formula I. Or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a eutectic thereof, or a composition thereof. The anesthetic effect of the compound of the invention is good, and the anesthetic effect of the compound is equivalent to that of Ramozolam, and even better than that of repirzolam, and particularly shows that the effective dosage is obviously reduced, and the duration and the recovery time are remarkably reduced. At the same time, in the rat tail vein anesthesia model, the compound of the present invention is remarkably improved in comparison with the quality of the Ramozolam wake-up. The compound has the advantages of high effectiveness, short duration, fast resuscitation and good tolerance, can be used for anesthesia induction, anesthesia maintenance and inter-day operation anesthesia, and has a good application prospect. (by machine translation)
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Paragraph 0204-0206; 0310; 0311; 0313
(2021/01/11)
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- INHIBITORS OF INDOLEAMINE 2,3-DIOXYGENASE AND METHODS OF THEIR USE
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The present invention provides a compound of formula (II): an inhibitor of indoleamine 2,3-dioxygenase (IDO), which may be used as medicaments for the treatment of proliferative disorders, such as cancer, viral infections and/or autoimmune diseases. Its prodrugs are disclosed.
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Page/Page column 65; 66
(2019/07/20)
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- N-substituted imidazole carboxylate compound, preparation method and use thereof
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A N-substituted imidazole carboxylate compound shown as a formula (I), a preparation method and use thereof are disclosed. In the formula (I), C * is a R type chiral carbon atom, R 1 and R 2 are independently selected from the group consisting of H, methyl, ethyl, cyclopropyl, cyclobutyl or isopropyl or a C2-5 ene-group formed by R1 and R2; and R3 is substituted or unsubstituted C1-18 saturated orunsaturated aliphatic hydrocarbon or aromatic hydrocarbon, wherein the aliphatic hydrocarbon includes a linear, branched or cyclic aliphatic hydrocarbon group. The N-substituted imidazole carboxylatecompound or pharmaceutically acceptable salts thereof can be used to prepare central inhibitory drugs that exert sedative, hypnotic and/or anesthetic effects on humans or animals, can produce rapid and reversible anesthetic effects, and rapidly metabolises into inactive etomidate acid, and after drug withdrawal, recovery quality is good; body's corticosteroid function can be quickly recovered after single administration or continuous administration, the incidence of muscle tremor is low after the administration, and after the drug withdrawal, the recovery is quick.
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Paragraph 0025
(2018/03/26)
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- A chloromethyl isopropylacrylamides carbon ester preparation method
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The present invention belongs to the field of antiviral chemical drugs, and particularly relates to a chloromethyl isopropyl carbonate preparation method. According to the present invention, a novel catalyst is used so as to completely carry out the reaction, and the reaction conditions are mild and the catalyst can be reused so as to reduce the production cost and easily achieve industrial production; the wastewater, the waste material and the waste gas are less after completing the preparation, and characteristics of high yield, cleaning process, economy and environmental protection are provided; and isopropyl chloroformate and paraformaldehyde react to prepare the chloromethyl isopropyl carbonate, and the synthesis process has characteristics of simple operation, low cost, high yield, high product purity, cleaning, and environmental protection, and is suitable for industrial production.
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Paragraph 0021-0028
(2020/02/07)
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- Substituted aza indole compounds and salts thereof, composition and use thereof
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The invention provides a substituted azaindole compound having a structure as represented by a formula (I) and a pharmaceutically acceptable salt and a medicinal preparation thereof. The compound is used for adjusting activity of protein kinase and adjusting intercellular or intracellular signal response. The invention further relates to a pharmaceutical composition including the compound and a method of applying the pharmaceutical composition to treatment of highly proliferative diseases of mammals, especially of mankind.
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Paragraph 0586; 0587; 0593; 0595; 0596
(2018/11/03)
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- NUCLEOTIDE ANALOGS
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PROBLEM TO BE SOLVED: To provide, e.g., intermediates for phosphonomethoxy nucleotide analogs, in particular, intermediates suitable for use in efficient oral delivery of such analogs. SOLUTION: Novel compounds are provided that comprise esters of antiviral phosphonomethoxy nucleotide analogs with carbonates and/or carbamates having the structure -OC(R2)2OC(O)X(R)a, The compounds are useful as intermediates for the preparation of antiviral compounds or oligonucleotides, or are useful for administration directly to patients for antiviral therapy or prophylaxis (R2 is as described in the specifications ). COPYRIGHT: (C)2015,JPOandINPIT
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Paragraph 0195
(2018/11/22)
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- 4-((R)-2-{[6-((S)-3-Methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carbonyl]amino}-3-phosphonopropionyl)piperazine-1-carboxylic Acid Butyl Ester (ACT-246475) and Its Prodrug (ACT-281959), a Novel P2Y12 Receptor Antagonist with a Wider Therapeutic Window in the Rat Than Clopidogrel
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Recent post hoc analyses of several clinical trials with P2Y12 antagonists showed the need for new molecules being fully efficacious as antiplatelet agents and having a reduced propensity to cause major bleeding. We have previously reported the discovery of the 2-phenylpyrimidine-4-carboxamide analogs as P2Y12 antagonists with nanomolar potency in the disease-relevant platelet aggregation assay in human plasma. Herein we present the optimization steps that led to the discovery of clinical candidate ACT-246475 (30d). The key step was the replacement of the carboxylic acid functionality by a phosphonic acid group which delivered the most potent molecules of the program. In addition, low in vivo clearance in rat and dog was achieved for the first time. Since the bioavailability of 30d was low in rat and dog, we developed the bis((isopropoxycarbonyl)oxy)methyl ester prodrug (ACT-281959, 45). Compound 30d showed efficacy in the rat ferric chloride thrombosis model when administered intravenously as parent or orally as its prodrug 45. Moreover, 30d displays a wider therapeutic window as compared to clopidogrel in the rat surgical blood loss model.
- Caroff, Eva,Hubler, Francis,Meyer, Emmanuel,Renneberg, Dorte,Gnerre, Carmela,Treiber, Alexander,Rey, Markus,Hess, Patrick,Steiner, Beat,Hilpert, Kurt,Riederer, Markus A.
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p. 9133 - 9153
(2015/12/23)
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- SUBSTITUTED AZAINDOLE COMPOUNDS, SALTS, PHARMACEUTICAL COMPOSITIONS THEREOF AND METHODS OF USE
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The present invention provides substituted azaindole prodrugs, methods of making said prodrugs, pharmaceutical compositions of said prodrugs and methods of using said prodrugs and pharmaceutical compositions thereof to treat or prevent diseases or disorders such as cancer.
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Paragraph 0435-0436; 0441-0442
(2014/03/24)
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- SUBSTITUTED METHYLFORMYL REAGENTS AND METHOD OF USING SAME TO MODIFY PHYSICOCHEMICAL AND/OR PHARMACOKINETIC PROPERTIES OF COMPOUNDS
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The present invention relates to the synthesis and application of novel chiral/ achiral substituted methyl formyl reagents to modify pharmaceutical agents and/or biologically active substances to modify the physicochemical, biological and/or pharmacokinetic properties of the resulting compounds from the unmodified original agent.
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Page/Page column 93; 100
(2012/10/18)
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- Expeditious convergent procedure for the preparation of bis(POC) prodrugs of new (E)-4-phosphono-but-2-en-1-yl nucleosides
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A series of unsaturated acyclonucleoside bis(POC) prodrugs of E configuration were synthesized through an expeditious, highly efficient and stereoselective one-step procedure from corresponding bis(POC)allylphosphonate through Ru catalyzed cross-coupling metathesis reaction. The [RuCl 2(PCy3)(SIPr)(Indenylidene)] and [RuCl 2(PCy3)(IMes)(benzylidene)] catalysts were employed; the unsaturated ANP were used bore C5-halovinyl uracil, C5-dihalovinyluracil or furanopyrimidine motifs. The chemical cleavage of biolabile (POC) group is a useful pathway to acid phosphonate derivatives.
- Montagu, Aurélien,Pradére, Ugo,Roy, Vincent,Nolan, Steven P.,Agrofoglio, Luigi A.
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scheme or table
p. 5319 - 5328
(2011/08/06)
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- Prodrugs of perzinfotel with improved oral bioavailability
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Previous studies with perzinfotel (1), a potent, selective, competitive NMDA receptor antagonist, showed it to be efficacious in inflammatory and neuropathic pain models. To increase the low oral bioavailability of 1 (3-5%), prodrug derivatives (3a-h) were synthesized and evaluated. The oxymethylene-spaced diphenyl analogue 3a demonstrated good stability at acidic and neutral pH, as well as in simulated gastric fluid. In rat plasma, 3a was rapidly converted to 1 via 2a. Pharmacokinetic studies indicated that the amount of systemic exposure of 1 produced by a 10 mg/kg oral dose of 3a was 2.5-fold greater than that produced by a 30 mg/kg oral dose of 1. Consistent with these results, 3a was significantly more potent and had a longer duration of activity than 1 following oral administration in a rodent model of inflammatory pain. Taken together, these results demonstrate that an oxymethylene-spaced prodrug approach increased the bioavailability of 1.
- Baudy, Reinhardt B.,Butera, John A.,Abou-Gharbia, Magid A.,Chen, Hong,Harrison, Boyd,Jain, Uday,Magolda, Ronald,Sze, Jean Y.,Brandt, Michael R.,Cummons, Terri A.,Kowal, Diane,Pangalos, Menelas N.,Zupan, Bojana,Hoffmann, Matthew,May, Michael,Mugford, Cheryl,Kennedy, Jeffrey,Childers Jr., Wayne E.
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experimental part
p. 771 - 778
(2009/12/27)
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- Imidazole-5-Carboxylic Acid Derivatives, The Preparation Method Therefor and The Uses Thereof
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The invention discloses imidazole-5-carboxylic acid derivatives, and their preparation methods. The derivatives of the invention are Angiotensin II receptor antagonists with angiotensin II antagonistic activity and antihypertensive activity, and thereby can be used as a therapeutical agent to treat hypertension.
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Page/Page column 13-14
(2009/04/24)
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- NOVEL NUCLEOTIDE ANALOGUES AS PERCURSOR MOLECULES FOR ANTIVIRALS
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This invention relates to a purine or pyrimidine phosphonate compound of formula (I) or pharmaceutically acceptable salt thereof; wherein B, X, and R1-R3 are as defined in classes and subclasses herein. These compounds may be used as antiviral precursors. The invention also relates to therapeutic compositions of these compounds and their use for the preparation of a medication for treating and/or preventing a viral infection in a patient. The invention also provides methods for making these compounds. In particular, the invention provides an H- phosphinate precursor intermediate of formula (II) wherein B is a purine or pyrimidine base as defined herein and R1 is selected from the group comprising a hydrogen atom, and a methyl, ethyl, hydroxymethyl, hydroxyethyl and C1-6haloalkyl group.
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Page/Page column 92; 93
(2008/12/05)
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- IMIDAZOL-5-CARBOXYLIC ACID DERIVATIVES, PREPARATION METHODS AND USE THERROF
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The invention discloses imidazole-5-carboxylic acid derivatives, and their preparation methods. The derivatives of the invention are Angiotensin II receptor antagonists with angiotensin II antagonistic activity and antihypertensive activity, and thereby can be used as a therapeutical agent to treat hypertension.
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Page/Page column 16
(2008/12/08)
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- Overcoming steric effects in the coupling reaction of alkyloxycarbonyloxymethyl (AOCOM) halides with phenols: an efficient synthesis of AOCOM phenolic prodrugs
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Steric hindrance is a key factor in the coupling reaction of AOCOM halides with phenols. Sterically unhindered alkoxy groups favor the formation of acylated phenol. Under phase-transfer conditions, alkylated phenol is favored regardless of steric hindrance.
- Thomas, Joshua D.,Sloan, Kenneth B.
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p. 109 - 112
(2007/10/03)
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- 3', 5' - CYCLIC NUCLEOSIDE ANALOGUES FOR TREATMENT OF HCV
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This invention provides compounds according to formula (I) where B is a 6-membered monocyclic nitrogen-containing heteroaryl group or a 5 + 6 fused bicyclic nitrogen-containing heteroaryl group, and A is selected from Groups (1), (2), (3), and (4) where Groups (1), (2), (3), and (4), are defined herein. These compounds are useful in the treatment of Hepatitis C infection.
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Page/Page column 21
(2010/11/26)
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- Second-generation cycloSal-d4TMP pronucleotides bearing esterase-cleavable sites - The "trapping" concept
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An extension of the cycloSal-pronucleotide approach is presented. Attachment of an enzyme-cleavable ester/acylal group to the cycloSal-d4TMP triesters should allow these compounds to be trapped intracellularly after cleavage. The ester/acylal groups were introduced in the 3- or 5-position of the cycloSal ring system, and surprising differences were observed in hydrolysis studies in CEM cell extracts with respect to the ester/acylal moiety. While acetyl and levulinyl esters were readily cleaved, alkyl esters of cycloSal-d4TMP acids proved to be resistant to enzymatic cleavage. In contrast, AM-, POM- and POC-acylals were rapidly cleaved in the extracts, leading to cycloSal-d4TMP acids. The antiviral activity of the compounds against HIV is also presented. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.
- Meier, Chris,Ducho, Christian,Jessen, Henning,Vukadinovic-Tenter, Dalibor,Balzarini, Jan
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p. 197 - 206
(2007/10/03)
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- Heterocyclic Anti-Viral Compounds Comprising Metabolizable Moieties And Their Uses
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The present invention relates to prodrugs and compositions thereof useful for treating or preventing Hepatitis C virus (HCV) infections. In particular, the present invention relates to prodrugs of substituted diphenyl-, diheteroaryl- and mixed phenyl heteroaryl substituted five-membered heterocycle compounds, compositions comprising the compounds and the use of such compounds and compositions to inhibit HCV replication and/or proliferation as a therapeutic approach towards the treatment and/or prevention of HCV infections in humans and animals.
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Page/Page column 43
(2008/06/13)
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- DERIVATIVES OF 2-(8,9-DIOXO-2,6-DIAZABICYCLO(5.2.0)NON-1(7)-EN-2-YL)ALKYL PHOSPHONIC ACID AND THEIR USE AS N-METHYL-D-ASPARTATE (NMDA) RECETOR ANTAGONISTS
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Compounds of formula (I) or pharmaceutically acceptable salts thereof are provided where at least one of R2 or R3 is not hydrogen. The compounds of the present invention are N-methyl-D-aspartate (NMDA) receptor antagonists and are useful in treating a variety of conditions present in a mammal that benefit from inhibiting the NMDA receptor.
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- THIOPHENEDERIVATIVES FOR THE TREATMENT OF FLAVIVIRUS INFECTIONS
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The present invention provides novel compounds represented by formula ( I): or pharmaceutically acceptable salts thereof useful for treating flaviviridae viral infection.
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- BETA-LACTAMASE INHIBITOR PRODRUG
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Prodrugs of 6-?-hydroxymethylpenicillanic acid sulfone having the structure wherein R is H or methyl, and solvates thereof, are disclosed. Also disclosed are pharmaceutical compositions comprising a prodrug of the present invention, or a solvate thereof, an optional beta-lactam antibiotic and at least one pharmaceutically acceptable carrier. Further disclosed is a method for increasing the therapeutic effectiveness of a beta-lactam antibiotic in a mammal by administering an effective amount of a betalactam antibiotic and an effectiveness-increasing amount of a prodrug of the present invention, or a solvate thereof. Additionally disclosed is a method for treating a bacterial infection in a mammal by administering a therapeutically effective amount of a pharmaceutical composition of the present invention to a mammal in need thereof.
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- BETA-LACTAMASE INHIBITOR PRODRUG
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Prodrugs of 6-β-hydroxymethylpenicillanic acid sulfone having the structure wherein R is H or methyl, each X is methylene, and Y is 0, or wherein R is H, each X is 0 and Y is methylene, and solvates thereof are disclosed. Also disclosed are pharmaceutical compositions comprising a prodrug of the present invention, or a solvate thereof, an optional beta-lactam antibiotic and at least one pharmaceutically acceptable carrier. Further disclosed is a method for increasing the therapeutic effectiveness of a beta-lactam antibiotic in 20 a mammal by administering an effective amount of a beta-lactam antibiotic and an effectiveness-increasing amount of a prodrug of the present invention, or a solvate thereof. Additionally disclosed is a method for treating a bacterial infection in a mammal by administering a therapeutically effective amount of a pharmaceutical composition of the present invention to a mammal in need thereof.
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- α-Haloalkyl Haloformates and Related Compounds 1. A Convenient Synthesis of Carbamates via Chloromethyl Carbamates
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The preparation of carbamates under mild conditions utilizing a new class of activated carbonates (containing chloromethyl function) is described.
- Patonay, Tamas,Patonay-Peli, Erzsebet,Mogyorodi, Ferenc
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p. 2865 - 2885
(2007/10/02)
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