- Methyl acetate reaction with OH and Cl: Reaction rates and products for a biodiesel analogue
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Relative rate experiments performed in a photochemical reactor at 293 ± 0.5 K and a total air pressure of 980 mbar were used to determine k(CH3C(O)OCH3 + Cl) = (1.93 ± 0.27) × 10-12 cm3 molecule-1 ss
- Andersen, Vibeke F.,Nilsson, Elna J.K.,J?rgensen, Solvejg,Nielsen, Ole John,Johnson, Matthew S.
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Read Online
- PYRAZOLE DERIVATIVE
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A pyrazole derivative having the following formula stru-1: The pyrazole derivative is used for prevention and control of pests.
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Paragraph 0100; 0106; 0112-0113
(2020/11/30)
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- Erufosine (ErPC3) Cationic Prodrugs as Dual Gene Delivery Reagents for Combined Antitumor Therapy
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Sixteen cationic prodrugs of the antitumor alkylphospholipid (APL) erufosine were rationally synthesized to provide original gene delivery reagents with improved cytotoxicity profile. The DNA complexation properties of these cationic lipids were determined and associated transfection rates were measured. Furthermore, the self-assembly properties of the pro-erufosine compounds were investigated and their critical aggregation concentration was determined. Their hydrolytic stability under pH conditions mimicking the extracellular environment and the late endosome milieu was measured. Hemolytic activity and cytotoxicity of the compounds were investigated. The results obtained in various cell lines demonstrate that the prodrugs of erufosine display antineoplastic activity similar to that of the parent antitumor drug but are not associated with hemolytic toxicity, which is a dose-limiting side effect of APLs and a major obstacle to their use in anticancer therapeutic regimen. Furthermore, by using lipoplexes prepared from a prodrug of erufosine and a plasmid DNA encoding a pro-apoptotic protein (TRAIL), evidence was provided for selective cytotoxicity towards tumor cells while nontumor cells were resistant. This study demonstrates that the combination approach involving well tolerated erufosine cationic prodrugs and cancer gene therapy holds significant promise in tumor therapy.
- Gaillard, Boris,Seguin, Cendrine,Remy, Jean-Serge,Pons, Fran?oise,Lebeau, Luc
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p. 15662 - 15679
(2019/11/14)
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- COMPOUNDS WITH HIV MATURATION INHIBITORY ACTIVITY
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The present invention relates to compound of Formula I or a pharmaceutically acceptable salt thereof (Formula I) wherein R1 is Formula (AA) or Formula (BB) where the squiggly line indicates the point of attachment to the rest of the molecule; R2 is F or Formula (CC) where the squiggly line indicates the point of attachment to the rest of the molecule; R3 is H or CH3; Z is O or is absent; and R4 is -OC1-3alkyl, C1-30alkyl, or -N(CH3)2.
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Page/Page column 12
(2019/11/12)
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- A class of pyrazole derivatives, preparation method and application thereof (by machine translation)
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The invention discloses a following formula stru - 1 indicated by the pyrazole derivatives, The definition of each substituent in the specification. This invention relates to pyrazole derivatives suitable for use in the pest. (by machine translation)
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Paragraph 0203; 0219; 0222; 0223; 0224
(2018/10/11)
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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 0375; 0377; 0378
(2018/11/03)
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- Prodrugs of NH-acidic compounds
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The invention provides a method of sustained delivery of a lactam, imide, amide, sulfonamide, carbamate or urea containing parent drug by administering to a patient an effective amount of a prodrug compound of the invention wherein upon administration to the patient, release of the parent drug from the prodrug is sustained release. Prodrug compounds suitable for use in the methods of the invention are labile conjugates of parent drugs that are derivatized through carbonyl linked prodrug moieties. The prodrug compounds of the invention can be used to treat any condition for which the lactam, imide, amide, sulfonamide, carbamate or urea containing parent drug is useful as a treatment.
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Page/Page column 426
(2015/11/16)
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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 0289-0290
(2014/03/24)
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- Synthesis of acyloxyalkyl esters of thiocarbonic and dithiocarbamic acids
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Reactions of acyloxyalkyl chloride with alkaline salts of alkylxanthic, butyltrithiocarbonic, and diethyldithiocarbamic acids afforded a series of acyloxyalkyl esters of various nature and positions of the acyl groups in the molecule.
- Mustafaev,Kulieva,Mustafaev,Kulibekova,Kakhramanova,Safarova,Novotorzhina
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p. 198 - 203
(2013/07/25)
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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 93-94
(2012/10/18)
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- PRODRUGS OF FUSED HETEROCYCLIC INHIBITORS OF D-AMINO ACID OXIDASE
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The invention relates to prodrugs of fused heterocyclic inhibitors of D-amino oxidase (DAAO) and methods of treating diseases and conditions, wherein modulation of D-amino acid oxidase activity, D-serine levels, D-serine oxidative products and NMDA receptor activity in the nervous system of a mammalian subject is effective.
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Page/Page column 81; 82; 94
(2011/02/26)
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- PRODRUGS OF FUSED HETEROCYCLIC INHIBITORS OF D-AMINO ACID OXIDASE
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The invention relates to prodrugs of fused heterocyclic inhibitors of D-amino oxidase (DAAO) and methods of treating diseases and conditions, wherein modulation of D- amino acid oxidase activity, D-serine levels, D-serine oxidative products and NMDA receptor activity in the nervous system of a mammalian subject is effective.
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Page/Page column 117
(2010/04/03)
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- Synthesis and In Vivo acute anti hyperglycemic evaluation of novel isosteviol derivatives
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Isosteviol is a beyerane tetracyclic diterpenoid with a large variety of biological activities. In this article, a series of novel isosteviol derivatives containing the modification of C-18 carboxyl group (5-12), C-16 carbonyl group (14-16) and heteroatom-containing frameworks fused with isosteviol structure (18-19) were synthesized and evaluated for their in vivo acute antihyperglycemeric effects. Among them, compound 8 exhibited the most potent antihyperglycemeric effects. Furthermore, primarily, structure-activity relationship (SAR) was also analyzed. The structures of all the newly synthesized compounds were determined by 1H, 13CNMR, MS, IR and elementary analysis.
- Chen, Junqing,Zha, Xiaoming,Sun, Min,Cai, Jin,Zhou, Wen,Ji, Min
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experimental part
p. 686 - 693
(2011/12/01)
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- Huperzine a prodrugs and uses thereof
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Disclosed are huperzine A prodrugs and method of synthesis thereof. The invention further relates to methods of treating, preventing or reversing neurodegenerative diseases, such as, Alzheimer's Disease and neuronal dysfunctions, such as, memory impairment using a pharmaceutical composition comprising a huperzine A prodrug as disclosed herein.
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Page/Page column 12
(2008/06/13)
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- SITE AND RATE SELECTIVE PRODRUG FORMULATIONS OF D609 WITH ANTIOXIDANT AND ANTICANCER ACTIVITY
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Compounds that are heteroatom substituted alkyl derivatives of tricyclodecan-9-yl-xanthogenate, and pharmaceutical compositions of these compounds, are disclosed. Methods of treating a disease or disorder in a subject and methods of protecting normal tissues in a subject from toxicity associated ionizing radiation or chemotherapy using compositions comprising these novel compounds are also disclosed. The invention also concerns methods of treating a disease or disorder in a subject using compositions that include these novel compounds while concurrently or consecutively treating the subject with ionizing radiation or a chemotherapeutic agent.
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Page/Page column 43-44
(2008/06/13)
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- Bioreversible quaternary N-acyloxymethyl derivatives of the tertiary amines bupivacaine and lidocaine - Synthesis, aqueous solubility and stability in buffer, human plasma and simulated intestinal fluid
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Design of water-soluble prodrugs may constitute a means to improve the oral bioavailability of drugs suffering from dissolution rate-limited absorption. The model drug bupivacaine containing a tertiary amine function has been converted into bioreversible quaternary N-acyloxymethyl derivatives. The pH-independent solubility of the N-butanoyloxymethyl derivate exceeded 1000 mg ml-1 corresponding approximately to a 10,000-fold increase in water solubility compared to that of bupivacaine base. The kinetics of hydrolysis of the prodrugs was studied in the pH range 0.1-9.8 (37°C). Decomposition was found to follow first-order kinetics and U-shaped pH-rate profiles were constructed. The observed differences between the hydrolytic lability of the derivatives might most likely be ascribed to steric effects. In most cases, the prodrugs were quantitatively converted into bupivacaine. However, for the hydrolysis of the N-butanoyloxymethyl derivative at neutral to slightly alkaline pH parallel formation of bupivacaine (～80%) and an unknown compound X (～20%) was observed. LC-MS analysis of the latter compound suggests that an aromatic imide structure has been formed from an intramolecular acyl transfer reaction involving a nucleophilic attack of the amide nitrogen atom on the ester carbonyl carbon atom. Whereas the derivatives were poor substrates for plasma enzymes; they were hydrolyzed rapidly to parent bupivacaine in the presence of pancreatic enzymes (simulated intestinal fluid) at 37°C. The data indicate that such prodrugs possess sufficient stability in the acidic environment of the stomach to reach the small intestine in intact form where they can be cleaved efficiently by action of pancreatic enzymes prior to drug absorption. Thus, the N-acyloxymethyl approach might be of potential utility to enhance oral bioavailability of tertiary amines exhibiting pKa values below approximately 6 and intrinsic solubilities in the low μM range.
- Nielsen, Anders Bach,Buur, Anders,Larsen, Claus
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p. 433 - 440
(2007/10/03)
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- Prodrugs of CL316243: A selective β3-adrenergic receptor agonist for treating obesity and diabetes
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CL316243 is a highly selective and potent β3-adrenergic receptor agonist, and has been shown in rodent models to be an effective agent for treating obesity and Type II diabetes. To improve the oral absorption and pharmacokinetic profiles of CL316243, a number of prodrugs have been synthesized and evaluated. Several ester-type prodrugs show significant improvements in oral bioavailability in both rodent and primate models.
- Sum,Gilbert,Venkatesan,Lim,Wong,O'Dell,Francisco,Chen,Grosu,Baker,Ellingboe,Malamas,Gunawan,Primeau,Largis,Steiner
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p. 1921 - 1926
(2007/10/03)
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- Synthesis of iodoalkylacylates and their use in the preparation of S-alkyl phosphorothiolates
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Synthesis of iodoalkylacylates 3a-f and use of 3c in the preparation of an oligonucleoside phosphorothiate prodrug analog 5 is described.
- Iyer,Yu,Ho,Agrawal
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p. 2739 - 2749
(2007/10/02)
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- PRODRUGS OF IMIDAZOLE CARBOXYLIC ACIDS AS ANGIOTENSIN II RECEPTOR ANTAGONISTS
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Prodrugs of imidazole carboxylic acids which are AII antagonists useful in treating hypertension, pharmaceutical compositions thereof and a method of treating hypertension using such prodrugs are disclosed.
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- Synthesis, hydrolytic behavior, and anti-HIV activity of selected acyloxyalkyl esters of trisodium phosphonoformate (foscarnet sodium)
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The synthesis and anti-HIV activity of selected (acyloxy)-alkyl esters of trisodium phosphonoformate (foscarnet sodium) are described. The conversion of bis(trimethylsilyl) (alkoxycarbonyl)phosphonates 11a-d to the corresponding disilver salts 12a-d and their subsequent reaction with iodoalkyl acrylates 4a-c gave the desired bis(acyloxyalkyl) phosphonates 6- 9(a-c). Of the analogs tested, only the dichlorophenyl analog 9a showed a dose-dependent inhibition of HIV activity in H9 cells. Using 31P-NMR, bioreversibility has been investigated in an attempt to rationalize these results.
- Iyer,Boal,Phillips,Thakker,Egan
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p. 1269 - 1273
(2007/10/02)
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- Synthesis of α-Haloalkyl Esters from α-Arylthioalkyl Esters
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α-Monohaloalkyl esters have been prepared under mild conditions in high yields by selective cleavage of the carbon-sulfur bond in α-phenylthioalkyl esters using sulfuryl chloride or bromine.The intermediate α-phenylthioalkyl esters have been prepared by alkylation of the corresponding carboxylic acids with readily accessible α-haloalkyl phenyl sulphides.
- Benneche, Tore,Strande, Per,Wiggen, Unni
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- Synthesis of acyloxyalkyl acylphosphonates as potential prodrugs of the antiviral, trisodium phosphonoformate (foscarnet sodium)
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Bis(trimethylsilyl) acylphosphonates via their silver salts couple with iodoalkyl esters to provided an efficient synthesis of the corresponding acyloxyalkyl esters as potential prodrugs of the antiviral agent, trisodium phophonoformate. These compounds were tested as inhibitors of HIV-1 in chronically infected H9 cells.
- Iyer,Phillips,Biddle,Thakker,Egan
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p. 7141 - 7144
(2007/10/02)
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- Structural Studies on Bioactive Compounds. Part 7. The Design and Synthesis of &α-Substituted Serines as Prospective Inhibitors of Serine Hydroxymethyltransferase
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A short series of α-substituted analogues of serine, designed as enzyme-activated, irreversible inhibitors of serine hydroxymethyltransferase, has been prepared. (+/-)-α-Allyl- and (+/-)-α-prop-2-ynyl-serine were synthesised by appropriate alkylation of the anion derived from ethyl acetamidocyanoacetate, followed by selecttive reduction of the ester function and hydrolysis of protecting groups.Acetoxymethylation of the anion derived from methyl 2-(benzylideneamino)but-2-enoate gave (+/-)-α-vinylserine after deprotection.These novel analogues of serine were largely inactive as inhibitors of the enzyme, except that (+/-)-α-vinylserine showed weak competitive inhibition.
- Tendler, Saul J. B.,Threadgill, Michael D.,Tisdale, Michael J.
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p. 2617 - 2624
(2007/10/02)
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- Effects of vehicles and prodrug properties and their interactions on the delivery of 6-mercaptopurine through skin: Bisacyloxymethyl-6-mercaptopurine prodrugs
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A series of S6,9-bisacyloxymethyl-6-mercaptopurine (6,9-bis-6-MP) prodrug derivatives was synthesized and characterized. The solubilities of the derivatives in solvents (vehicles), which exhibited a wide range of polarities from water to oleic acid, were measured. The abilities of the prodrugs to deliver 6-mercaptopurine (6-MP) from the vehicles have also been determined, and experimental fluxes and permeability coefficients (K(p)) have been calculated for a large number of prodrug:vehicle combinations. Generally the best prodrugs of the series in terms of delivering 6-MP, regardless of the vehicle, were the first two members -the bisacetyl- and the bispropionyloxymethyl-6-mercaptopurine prodrugs. This result has been attributed mainly to the increased water solubility of these two prodrugs compared with that of 6-MP and the other prodrugs, since all of the prodrugs are much more lipid soluble than 6-MP. For three vehicles -isopropyl myristate, propylene glycol, and water- there was a good correlation between log experimental K(p) for the delivery of 6-MP by the prodrugs from those vehicles and the theoretical solubility parameters of the prodrugs. The stabilities of the bisacetyl-(2), bispropionyl-(3), and bisbutyryloxymethyl-6-mercaptopurine (4) derivatives were determined in buffer and in buffer containing enzymes leached from the dermis. Prodrug 2 was more stable than 3 or 4 in the buffer containing the enzymes, while 4 was more stable than 2 or 3 in the plain buffer.
- Waranis,Sloan
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p. 587 - 595
(2007/10/02)
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