- 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 80; 81
(2019/07/20)
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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 13-14
(2019/11/12)
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- NMDA ANTAGONIST PRODRUGS
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Prodrugs of an NMDA antagonist, (S)-1-phenyl-2-(pyridin-2-yl)ethanamine, useful for the treatment of depression (particularly major depressive disorder) or pain; compositions comprising them, and methods of making them.
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Paragraph 0081-0083
(2018/04/17)
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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 0377; 0378; 0384; 0386; 0387
(2018/11/03)
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- NMDA ANTAGONIST PRODRUGS
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Prodrugs of an NMDA antagonist, (S)-1-phenyl-2-(pyridin-2-yl)ethanamine, useful for the treatment of depression (particularly major depressive disorder) or pain; compositions comprising them, and methods of making them.
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Paragraph 00072; 00073; 00074
(2015/05/26)
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- NOVEL COMPOUNDS, THEIR PREPARATION AND THEIR USES
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Novel compounds and their synthesis are described. Methods for using these compounds in the prevention or treatment of cancer, a bacterial infection or a viral infection in a subject are also described.
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Page/Page column
(2014/04/18)
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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; 0294-0296
(2014/03/24)
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- COMPOUNDS AND THERAPEUTIC USES THEREOF
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The invention relates to compounds, pharmaceutical compositions and methods useful for treating cancer, systemic or chronic inflammation, rheumatoid arthritis, diabetes, obesity, T-cell mediated autoimmune disease, ischemia, and other complications associated with these diseases and disorders.
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Paragraph 00310-00311; 00322
(2014/01/17)
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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 88
(2012/10/18)
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- 4-SUBSTITUTED-3-PHENYLSULFANYLMETHYL-BICYCLO[3.1.0]HEXANE COMPOUNDS AS mGluR 2/3 ANTAGONISTS
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A mGlu2/3 receptor antagonist of the formula: its uses, and methods for its preparation are described.
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Page/Page column 12
(2012/06/01)
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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 97; 98
(2011/02/26)
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- Water-soluble prodrugs of an Aurora kinase inhibitor
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Compound 1 (SNS-314) is a potent and selective Aurora kinase inhibitor that is currently in clinical trials in patients with advanced solid tumors. This communication describes the synthesis of prodrug derivatives of 1 with improved aqueous solubility profiles. In particular, phosphonooxymethyl-derived prodrug 2g has significantly enhanced solubility and is converted to the biologically active parent (1) following iv as well as po administration to rodents.
- Oslob, Johan D.,Heumann, Stacey A.,Yu, Chul H.,Allen, Darin A.,Baskaran, Subramanian,Bui, Minna,Delarosa, Erlie,Fung, Amy D.,Hashash, Ahmad,Hau, Jonathan,Ivy, Sheryl,Jacobs, Jeffrey W.,Lew, Willard,Maung, Jack,McDowell, Robert S.,Ritchie, Sean,Romanowski, Michael J.,Silverman, Jeffrey A.,Yang, Wenjin,Zhong, Min,Fuchs-Knotts, Tarra
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scheme or table
p. 1409 - 1412
(2009/10/15)
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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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- Pivalase catalytic antibodies: Towards abzymatic activation of prodrugs
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Screening of monoclonal-an-tibody libraries generated against the tert-butyl phosphonate hapten 2 and the chloromethyl phosphonate hapten 3 with pivaloyloxymethyl-umbelliferone 1 as a fluorogenic substrate led to the isolation of eleven catalytic antibodies with rate accelerations around kcat/kuncat=103. The antibodies are not inhibited by the product and accept different acyloxymethyl derivatives of acidic phenols as substrates. The highest activity was found for the bulky, chemically less-reactive pivaloyloxymethyl group; there is no activity with acetoxymethyl or acetyl esters. This difference might reflect the preference of the immune system for hydrophobic interactions in binding and catalysis. Pivalase catalytic antibodies might be useful for activating orally available pivaloyloxymethyl prodrugs.
- Bensel, Nicolas,Reymond, Martine T.,Reymond, Jean-Louis
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p. 4604 - 4612
(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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- Process for preparing β-lactam derivative and synthetic intermediate thereof
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Disclosed is a process for preparing a β-lactam compound represented by the formula: STR1 wherein R1 represents a hydroxy-substituted lower alkyl group or an amino group each of which may be protected; R2 represents hydrogen atom or an ester residue; X represents a methylene group which may be substituted by a lower alkyl group, sulfur atom or a group represented by the formula: --A--CH2 -- where A represents sulfur atom, oxygen atom or methylene group; and W represents an active ester residue of hydroxyl group, or a salt thereof, which comprises the steps of treating a 1-aza-3-thia-bicycloalkane compound represented by the formula: STR2 wherein R1, R2 and X have the same meanings as defined above, or a salt thereof with a base in the presence of a desulfurizing agent and then reacting the resulting compound with an active esterifying agent of hydroxyl group.
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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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- 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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- A process for producing haloalkyl alkanoates
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A haloalkyl alkanoate (III) is useful as a reagent for preparing some oral antibacterials. The compound is now found to be preparable economically and safely by treating alkanoic acid salt (I) with 10 equivalents or more of dihaloalkane (II) in 2 to 5 parts by weight of alkanoic acid dialkylamide. (wherein R and R1 each is hydrogen or optionally substituted alkyl, M is a salt forming atom or group, and X and Hal each is halogen)
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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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- Cephalosporin antibiotics
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The invention provides novel antibiotic cefuroxime esters of the formula STR1 (wherein R is a primary or secondary alkyl group containing 1 to 4 carbon atoms). These compounds are useful as orally administrable broad spectrum antibiotics.
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- Antifibrinolytically active derivatives of tranexamic acid
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Novel antifibrinolytically active compounds of the formula STR1 and therapeutically acceptable salt thereof, wherein R1 is selected from the group consisting of (a) alkyl groups containing 1-4 carbon atoms, (b) alkoxy groups containing 1-4 carbon atoms, STR2 R2 is selected from the group consisting of (a) H, (b) alkyl groups containing 1-4 carbon atoms, (c) --COOR3, wherein R3 is an alkyl group containing 1-4 carbon atoms, (d) --CONR4 R5, wherein R4 and R5 are the same or different alkyl groups containing 1-3 carbon atoms; or wherein R1 and R2 represent together the radical STR3
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