- Synthesis and evaluation of prodrugs of corticotropin-releasing factor-1 (CRF1) receptor antagonist BMS-665053 leading to improved oral bioavailability
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A series of phosphate and ester-based prodrugs of anilinopyrazinone 1 (BMS-665053) containing either a methylene or an (acyloxy)alkoxy linker was prepared and evaluated in rat pharmacokinetic studies with the goal of improving the oral bioavailability of the parent (1). The prodrugs, in general, had improved aqueous solubility and oral bioavailability compared to 1. Prodrug 12, which contains an (acyloxy)alkoxy linker, showed the greatest improvement in the oral bioavailability relative to the parent (1), with a seven-fold increase (from 5% to 36%) in rat pharmacokinetic studies.
- Hartz, Richard A.,Vrudhula, Vivekananda M.,Ahuja, Vijay T.,Grace, James E.,Lodge, Nicholas J.,Bronson, Joanne J.,Macor, John E.
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Read Online
- Novel triclabendazole prodrug: A highly water soluble alternative for the treatment of fasciolosis
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In this work we present the synthesis, aqueous solubility and stability, hydrolysis by alkaline phosphatase, and in vivo fasciolicidal activity in sheep of a highly water soluble phosphate salt prodrug of triclabendazole (MFR-5). The aqueous solubility of MFR-5 at pH 7 was 88,000-fold that of triclabendazole. MFR-5 showed excellent aqueous stability (>95% after 26?h) at pH 7, making it ideal for developing pharmaceutical compositions in the form of solutions that can easily be hydrolyzed by the enzyme alkaline phosphatase (t?=?13.6?s) to liberate the precursor compound. An aqueous solution of MFR-5 administered intramuscularly to sheep at concentrations of 4, 6 and 8?mg/kg presented a fasciolicidal efficiency of 96.5%, 98.4% and 99.2%, respectively. In the in vivo experiments, MFR-5 reduced 100% the excretion of eggs in all of the above concentrations.
- Flores-Ramos, Miguel,Ibarra-Velarde, Froylán,Jung-Cook, Helgi,Hernández-Campos, Alicia,Vera-Montenegro, Yolanda,Castillo, Rafael
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Read Online
- A novel synthetic route for the preparation of alkyl and benzyl chloromethyl phosphates
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An efficient and simple synthesis is described for the production of various chloromethyl phosphates as useful reagents for the preparation of phosphonooxymethyl prodrugs.
- M?ntyl?, Antti,Veps?l?inen, Jouko,J?rvinen, Tomi,Nevalainen, Tapio
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Read Online
- A highly water soluble benzimidazole derivative useful for the treatment of fasciolosis
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This study describes the synthesis of compound (7), a highly hydrosoluble phosphonooxymethyl prodrug of compound alpha (4). Compound (7) improved the aqueous solubility of its precursor compound (4) by 50,000 times and it is stable at neutral pH. The prodrug showed faciolicidal activity when evaluated in vitro against excysted Fasciola hepatica metacercariae. The in vivo evaluation of (7) was carried out via oral, intramuscular and subcutaneous administration in sheep artificially infected with F. hepatica metacercariae. At an intramuscular dose of 4 mg/kg, the activity of (7) was similar to that of compound alpha (4) at an oral dose of 15 mg/kg.
- Flores-Ramos, Miguel,Ibarra-Velarde, Froyln,Hernndez-Campos, Alicia,Vera-Montenegro, Yolanda,Jung-Cook, Helgi,Cant-Alarcn, Germinal J.,Del Rivero, Lauro Misael,Castillo, Rafael
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Read Online
- PRODRUGS IN THE MODULATION OF INTERLEUKIN
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There are disclosed prodrugs of the compounds of the formula. The prodrugs are useful in the modulation of IL-12, IL-23 and/or IFNα, by acting on Tyk-2 to cause signal transduction inhibition.
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Page/Page column 33-34
(2021/02/12)
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- POMALIDOMIDE DERIVATIVE AND PREPARATION METHOD THEREFOR
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Disclosed in the present invention are a Pomalidomide derivative and a preparation method therefor. Specifically, the present invention relates to the Pomalidomide derivative and a stereoisomer thereof, or a pharmaceutically acceptable salt, and applications thereof in the preparation of drugs for treating cancers.
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Paragraph 0120-0121
(2020/07/14)
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- POMALIDOMIDE DERIVATIVES AND THE PREPARING METHOD THEREOF
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The invention relates to pomalidomide derivatives and their stereoisomers or pharmaceutically acceptable salts, and their use in preparing medicaments for treating cancers.
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Paragraph 0111-0113
(2019/08/01)
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- TRIAZOLE ANTIMICROBIAL DERIVATIVE, PHARMACEUTICAL COMPOSITION AND USE THEREOF
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The present disclosure provides a triazole antibacterial derivative and a pharmaceutical composition thereof and a use thereof and in particular relates to a compound represented by the following formula (I), and a racemate, a stereoisomer, a tautomer, an oxynitride or a pharmaceutically acceptable salt thereof: The compound of the present disclosure has a desirable water solubility and can be formulated into an injection for use without adding a cosolvent having a potential safety risk (such as hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, and the like), facilitating drug administration for patients, and greatly improving clinical safety. The drug can be used even by patients with moderate or severe renal impairment, thereby expanding the application scope of the drug.
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- Posaconazole derivative, pharmaceutical composition and use thereof
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The present disclosure provides a posaconazole derivative, a pharmaceutical composition and use thereof, which specifically include a compound represented by the following formula (I), a racemate, stereoisomer, tautomer, oxynitride, or a pharmaceutically acceptable salt thereof: The compounds of the present disclosure have strong antifungal activity, high safety, and good water solubility, without the need for the addition of a cosolvent (such as hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and the like) with potential safety risks. Furthermore, the formulation process of the compound could have less difficulty and less cost, and therefore can be used to prepare improved antifungal drugs.
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- PHENYL-HETEROCYCLE-PHENYL DERIVATIVES FOR USE IN THE TREATMENT OR PREVENTION OF MELANOMA
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The present invention relates to a compound represented by the formula (E) which is useful for treating or preventing melanoma.
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Page/Page column 34; 35; 36
(2018/12/02)
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- GLUCOKINASE ACTIVATORS AND METHODS OF USING SAME
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A compound, enantiomer, prodrug, diastereomer, or salt is provided which is an activator of the enzyme glucokinase and thus is believed to be useful in treating diabetes and related diseases, which compound has the structure (I). A method for treating diabetes and related disease employing the compound, enantiomer, prodrug, diastereomer, or salt is also provided.
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Page/Page column 44
(2018/02/28)
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- ALVOCIDIB PRODRUGS AND THEIR USE AS PROTEIN KINASE INHIBITORS
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Compounds having the following structure (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R1, R2 and R3 are as defined herein, and wherein at least one of R1, R2 and R3 is not H, are provided. Pharmaceutical compositions comprising the compounds and methods for use of the compounds for treating diseases associated with overexpression of a cyclin-dependent kinase (CDK) are also provided.
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Page/Page column 70
(2018/06/06)
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- Discovery of the Human Immunodeficiency Virus Type 1 (HIV-1) Attachment Inhibitor Temsavir and Its Phosphonooxymethyl Prodrug Fostemsavir
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The optimization of the 4-methoxy-6-azaindole series of HIV-1 attachment inhibitors (AIs) that originated with 1 to deliver temsavir (3, BMS-626529) is described. The most beneficial increases in potency and pharmacokinetic (PK) properties were attained by incorporating N-linked, sp2-hybridized heteroaryl rings at the 7-position of the heterocyclic nucleus. Compounds that adhered to a coplanarity model afforded targeted antiviral potency, leading to the identification of 3 with characteristics that provided for targeted exposure and PK properties in three preclinical species. However, the physical properties of 3 limited plasma exposure at higher doses, both in preclinical studies and in clinical trials as the result of dissolution- and/or solubility-limited absorption, a deficiency addressed by the preparation of the phosphonooxymethyl prodrug 4 (BMS-663068, fostemsavir). An extended-release formulation of 4 is currently in phase III clinical trials where it has shown promise as part of a drug combination therapy in highly treatment-experienced HIV-1 infected patients.
- Wang, Tao,Ueda, Yasu,Zhang, Zhongxing,Yin, Zhiwei,Matiskella, John,Pearce, Bradley C.,Yang, Zheng,Zheng, Ming,Parker, Dawn D.,Yamanaka, Gregory A.,Gong, Yi-Fei,Ho, Hsu-Tso,Colonno, Richard J.,Langley, David R.,Lin, Pin-Fang,Meanwell, Nicholas A.,Kadow, John F.
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p. 6308 - 6327
(2018/06/27)
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- WATER-SOLUBLE DERIVATIVES OF 3,5-DIPHENYL-DIAZOLE COMPOUNDS
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The present invention is concerned with derivatives of 3,5-diphenyl-diazole derivatives, which are effective therapeutic agents for use in treating diseases linked to protein aggregation and/or neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD). and Transmissible spongi form encephalopathies (TSEs) such as Creutzfeldt- Jakob disease CJD). Formula :(I) The therapeutic effect is caused by the inhibition of the protein aggregation in the affected tissue, such as the brain, 3,5-Diphenyl-diazole derivatives have been shown to be effective in inhibiting aggregation of proteins but arc also characterized by their poor solubility in aqueous solutions. The prodrugs of the invention are modified 3,5-diphenyl-diazole derivatives, which are characterized by their improved solubility in aqueous solutions, and by their increased bioavailability.
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Page/Page column 15
(2017/07/14)
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- Preparation of the HIV Attachment Inhibitor BMS-663068. Part 1. Evolution of Enabling Strategies
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The development of two enabling routes that led to the production of >1000 kg of BMS-663068 (3) is described. The route identified for the initial 100 kg delivery to support development activities and initial clinical trials involved the conversion of 2-amino-4-picoline to the parent active pharmaceutical ingredient (API), followed by pro-drug installation and deprotection. To eliminate the problematic isolation of the parent API and synthesis of di-t-butyl(chloromethyl)phosphate, a second-generation pro-drug installation route was developed which involved the conversion of a late-stage common intermediate to an N(1)-thioether derivative followed by chloromethylation, displacement with di-t-butylpotassium phosphate, and deprotection. This second strategy resulted in the multikilogram scale preparation of the API in 14 linear steps and ~7% overall yield.
- Fox, Richard J.,Tripp, Jonathan C.,Schultz, Mitchell J.,Payack, Joseph F.,Fanfair, Dayne D.,Mudryk, Boguslaw M.,Murugesan, Saravanababu,Chen, Chung-Pin H.,La Cruz, Thomas E.,Ivy, Sabrina E.,Broxer, Sévrine,Cullen, Ryan,Erdemir, Deniz,Geng, Peng,Xu, Zhongmin,Fritz, Alan,Doubleday, Wendel W.,Conlon, David A.
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p. 1095 - 1109
(2017/08/23)
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- NITRIC OXIDE DONORS
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The present invention provides, in part a novel class of nonoate compounds which exhibit nitric oxide releasing activity and their pharmaceutically acceptable salts, esters and prodrugs. The compounds release nitric oxide upon activation by contact with plasma. The present invention also relates to the use of the disclosed compounds to deliver nitric oxide to treat disorders arising from nitric oxide dysregulation.
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Page/Page column 35-36
(2018/04/11)
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- NOVEL HYDROSOLUBLE COMPOUNDS DERIVED FROM BENZIMIDAZOLE USED IN TREATING FASCIOLOSIS
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The present invention relates to hydrosoluble compounds derived from benzimidazole represented by general formula I: wherein: Y1 e Y2 are independently O or S, and at least one of Y1 and Y2 is O; R1 and R2 are independently hydrogen or a cation, both are hydrogen or both are cations; R3 is a C1-4 alkyl; R4 and R5 are independently halogen or a —OR6 alkoxide; R6 is C6-C10 aryl linked in 5- or 6-position of benzimidazole nucleus.
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Paragraph 0061; 0064
(2017/12/15)
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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 0460; 0461; 0566; 0568; 0569
(2018/11/03)
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- METHODS OF BLADDER CANCER TREATMENT WITH CICLOPIROX, CICLOPIROX OLAMINE, OR A CICLOPIROX PRODRUG
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A method of treating bladder cancer is provided. The method of treating bladder cancer can include: providing a pharmaceutical composition having ciclopirox or ciclopirox olamine or a ciclopirox-POM prodrug having a structure of one of the formulae provided herein or derivative thereof or stereoisomer thereof or pharmaceutically acceptable salt thereof; and administering the pharmaceutical composition to a subject having the bladder cancer. The ciclopirox or ciclopirox olamine or a ciclopirox-POM prodrug can be administered in a therapeutically effective amount.
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- 4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)pyridin-2-yl)-1-methyl-1-((phosphonooxy)methyl)piperazin-1-ium as a neurokinin receptor modulator
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Compounds and methods for the prevention and/or treatment of diseases which are pathophysiologically mediated by the neurokinin (NK1) receptor, based on 4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)3yridine-2-yl)-1-methyl-1-((phosphonooxy)methyl)piperazin-1-ium and pharmaceutically acceptable salts thereof.
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- Pharmaceutical Process and Intermediates
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The present disclosure provides for processes and intermediates in the large-scale manufacture of the compound of formula (I) or hydrates thereof.
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Paragraph 0168; 0169
(2015/07/02)
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- METHOD OF TREATMENT WITH PRODRUGS OF 6-CYCLOHEXYL-1-HYDROXY-4-METHYLPYRIDIN IN-2-1H-ONE AND DERIVATIVES THEREOF
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A prodrug can have a structure of Formula 10 or derivative thereof or stereoisomer thereof or pharmaceutically acceptable salt thereof. The prodrug can be included in a pharmaceutical composition for use in treatment of fungus, cancer, dermatitis, superficial mycoses; inflammation, tinea pedis, tinea cruris, and tinea corporis, Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, and Microsporum canis, candidiasis (moniliasis), Candida albicans, tinea (pityriasis) vesicolor, Malassezia furfur, acute myeloid leukemia, acute lymphoid leukemia, chronic myelogenous leukemia, lymphoma or multiple myeloma.
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- SUBSTITUTED 4-PHENYL-PYRIDINES FOR TREATMENT OF NK-1 RECEPTOR RELATED DISEASES
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PROBLEM TO BE SOLVED: To provide new derivatives of 4-phenyl-pyridine compounds that are effective NK1 receptor antagonists, with enhanced physicochemical and/or biological properties, and methods for producing the 4-phenyl-pyridine compounds. SOLUTION: Disclosed are compounds, compositions and methods for the prevention and/or treatment of diseases which are pathophysiologically mediated by the neurokinin (NKj) receptor. The compounds have the general formula (I). COPYRIGHT: (C)2015,JPOandINPIT
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- HEPATITIS C VIRUS INHIBITORS
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Provided herein are hepatitis C virus inhibitor compounds, for example, of any of Formulae I to XIV, Ilia to XlVa, Illb to XlVb, IIIc to XIVc, Hid to XlVd, Ille to XlVe, IA to IAe, IIA to IIAe, IB, IIB to IIBd, IIIB to IIIBd, IC to ICc, ID to IDd, and IE to lEc.pharmaceutical compositions comprising the compounds, and processes of preparation thereof. Also provided are methods of their use for treating an HCV infection.
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Paragraph 00442
(2015/04/15)
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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 0345-0347; 0422-0424
(2014/03/24)
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- Development of efficient processes for the preparation of Di-tert-butyl potassium phosphate and Di-tert-butyl (Chloromethyl) phosphate
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A new and efficient process to prepare di-tert-butyl (chloromethyl) phosphate, a key compound in the formation of many phosphon-oxymethyl pro-drugs, from chloromethyl chlorosulfate (CMCS) and di-tert-butyl potassium phosphate (DTBPP) is described. To develop a process to this important compound with overall efficiency, an improved synthesis of DTBPP was required. The two-step process to DTBPP starts from PCl3 and leverages a H2O 2/catalytic KI mediated oxidation of di-tert-butyl phosphite to provide DTBPP in 81% yield and high purity. In the development of the new process to di-tert-butyl (chloromethyl) phosphate, a comparison to the corresponding tosylate derivative was made. A rational selection of base, phase-transfer catalyst (PTC), and stabilizing additive minimized CMCS decomposition and led to an optimized yield (90% solution yield), improved product purity, and identification of a technique to enable the long-term storage of di-tert-butyl (chloromethyl) phosphate.
- Zheng, Bin,Fox, Richard J.,Sugiyama, Masano,Fritz, Alan,Eastgate, Martin D.
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p. 636 - 642
(2014/06/09)
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- SUBSTITUTED PYRROLIDINE-2-CARBOXAMIDES
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There are provided compounds of the formula wherein X, Y, Z, R1, R2, R3 and R4 are as described herein and enantiomers and pharmaceutically acceptable salts and esters thereof. The compounds are useful as anticancer agents.
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Paragraph 0106; 0107
(2013/09/26)
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- PHOSPHATE PRODRUGS
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Phosphate and phosphonate prodrug derivatives, for example of Formula IV; where p, A, LA, and R1, R3-R6 are as defined herein, are useful for treating various disorders, including diarrhea.
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Paragraph 0229
(2013/03/26)
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- PURINE COMPOUNDS AS PRODRUGS OF A2B ADENOSINE RECEPTOR ANTAGONISTS, THEIR PROCESS AND MEDICINAL APPLICATIONS
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The present disclosure relates to purine compounds of formula (I) or formula (II) or its tautomers, polymorphs, stereoisomers, solvates or a pharmaceutically acceptable salts, or pharmaceutical compositions containing them and methods of treating conditions and diseases that are mediated by thereof as A2B adenosine receptor antagonists. The compounds of the present disclosure are useful in the treatment, prevention or suppression of diseases and disorders that may be susceptible to improvement by the mediation of adenosine A2B receptor. Such conditions include, but are not limited to, asthma, chronic obstructive pulmonary disorder, angiogenesis, pulmonary fibrosis, emphysema, allergic diseases, inflammation, reperfusion injury, myocardial ischemia, atherosclerosis, hypertension, congestive heart failure, retinopathy, diabetes mellitus, obesity, inflammatory gastrointestinal tract disorders including inflammatory bowel disease, sickle cell disease, and/or autoimmune diseases, and to their use in treating mammals for various disease states, such as gastrointestinal disorders, immunological disorders, hypersensitivity disorders, neurological disorders, and cardiovascular diseases due to both cellular hyperproliferation and apoptosis, and the like. The present disclosure also relates to methods for the preparation of such compounds, and to pharmaceutical compositions containing them.
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Paragraph 0296
(2013/07/19)
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- Substituted 4-phenyl pyridines having anti-emetic effect
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Disclosed are compounds, compositions and methods for the prevention and/or treatment of diseases which are pathophysiologically mediated by the neurokinin (NK1) receptor. The compounds have the general formula (I):
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- PYRAZOLE COMPOUNDS ACTING AGAINST ALLERGIC, INFLAMMATORY AND IMMUNE DISORDERS
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The present invention relates to pyrazole amide derivatives pharmaceutical compositions containing these compounds and to their use in therapy.
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Page/Page column 44-45
(2012/05/05)
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- PYRAZOLE COMPOUNDS ACTING AGAINST ALLERGIC, IMMUNE AND INFLAMMATORY CONDITIONS
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The present invention relates to a pyrazole amide derivative, pharmaceutical compositions containing this compound and to its use in therapy.
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Page/Page column 32-33
(2012/05/05)
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- PURINE COMPOUNDS AS PRODRUGS OF A2B ADENOSINE RECEPTOR ANTAGONISTS, THEIR PROCESS AND MEDICINAL APPLICATIONS
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The present disclosure relates to purine compounds of formula (I) or formula (II) or its tautomers, polymorphs, stereoisomers, solvates or a pharmaceutically acceptable salts, or pharmaceutical compositions containing them and methods of treating conditions and diseases that are mediated by thereof as A2B adenosine receptor antagonists. {Formulas should be inserted here} The compounds of the present disclosure are useful in the treatment, prevention or suppression of diseases and disorders that may be susceptible to improvement by the mediation of adenosine A2B receptor. Such conditions include, but are not limited to, asthma, chronic obstructive pulmonary disorder, angiogenesis, pulmonary fibrosis, emphysema, allergic diseases, inflammation, reperfusion injury, myocardial ischemia, atherosclerosis, hypertension, congestive heart failure, retinopathy, diabetes mellitus, obesity, inflammatory gastrointestinal tract disorders including inflammatory bowel disease, sickle cell disease, and/or autoimmune diseases. and to their use in treating mammals for various disease states, such as gastrointestinal disorders, immunological disorders, hypersensitivity disorders, neurological disorders, and cardiovascular diseases due to both cellular hyperproliferation and apoptosis, and the like. The present disclosure also relates to methods for the preparation of such compounds, and to pharmaceutical compositions containing them.
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Page/Page column 39
(2012/04/04)
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- 2-AMINO-4-ARYLTHIAZOLE COMPOUNDS AS TRPAI ANTAGONISTS
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The present invention is related to 2-amino-4-arylthiazole derivatives as TRPA (Transient Receptor Potential subfamily A) modulators. In particular, compounds described herein are useful for treating or preventing diseases, conditions and/or disorders modulated by TRPA1 (Transient Receptor Potential subfamily A, member 1). Also provided herein are processes for preparing compounds described herein, intermediates used in their synthesis, pharmaceutical compositions thereof, and methods for treating or preventing diseases, conditions and/or disorders modulated by TRPA1.
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Page/Page column 27
(2012/06/30)
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- Use of A2B Adenosine Receptor Antagonists for Treating Pulmonary Hypertension
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This disclosure relates generally to treating patients having pulmonary hypertension, or symptoms associated therewith, by administering a therapeutically effective amount of an A2B receptor antagonist to the patient.
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- Inhibitors of human immunodeficiency virus type 1 (HIV-1) attachment 6. Preclinical and human pharmacokinetic profiling of BMS-663749, a phosphonooxymethyl prodrug of the HIV-1 attachment inhibitor 2-(4-benzoyl-1-piperazinyl)-1-(4,7-dimethoxy-1 H -pyrrolo[2,3- c ]pyridin-3-yl)-2-oxoethanone (BMS-488043)
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BMS-663749, a phosphonooxymethyl prodrug 4 of the HIV-1 attachment inhibitor 2-(4-benzoyl-1-piperazinyl)-1-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin- 3-yl)-2-oxoethanone (BMS-488043) (2) was prepared and profiled in a variety of preclinical in vitro and in vivo models designed to assess its ability to deliver parent drug following oral administration. The data showed that prodrug 4 had excellent potential to significantly reduce dissolution rate-limited absorption following oral dosing in humans. Clinical studies in normal healthy subjects confirmed the potential of 4, revealing that the prodrug significantly increased both the AUC and Cmax of 2 compared to a solid capsule formulation containing the parent drug upon dose escalation. These data provided guidance for further efforts to obtain an effective HIV-1 attachment inhibitor.
- Kadow, John F.,Ueda, Yasutsugu,Meanwell, Nicholas A.,Connolly, Timothy P.,Wang, Tao,Chen, Chung-Pin,Yeung, Kap-Sun,Zhu, Juliang,Bender, John A.,Yang, Zhong,Parker, Dawn,Lin, Pin-Fang,Colonno, Richard J.,Mathew, Marina,Morgan, Daniel,Zheng, Ming,Chien, Caly,Grasela, Dennis
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experimental part
p. 2048 - 2056
(2012/05/20)
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- Synthesis of 2,4-Pyrimidinediamines
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Disclosed herein are methods for synthesizing 2,4-pyrimidinediamines as well as intermediates used therein.
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Page/Page column 9
(2011/01/12)
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- PRODRUGS OF AN HIV REVERSE TRANSCRIPTASE INHIBITOR
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Compounds of Formula I are described: (I), wherein RP and RQ are defined herein. The compounds of Formula I are useful in the inhibition of HIV reverse transcriptase, the prophylaxis and treatment of infection by HIV, and the prophylaxis, delay in the onset or progression, and treatment of AIDS. The compounds can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines.
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Page/Page column 23; 24
(2011/10/31)
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- Diaryldiazepine Prodrugs for the Treatment of Neurological and Psychological Disorders
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The present invention provides prodrug compounds of diaryldiazepine drug compounds.
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Page/Page column 71
(2011/07/29)
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- N-PYRAZOLYL CARBOXAMIDES AS CRAC CHANNEL INHIBITORS
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The present invention relates to amide compounds, processes for their preparation, pharmaceutical compositions containing these compounds and to their use in the treatment of disorders, conditions or disorders such as allergic disorders, inflammatory disorders and disorders of the immune system.
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Page/Page column 78
(2010/11/05)
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- RAF INHIBITORS AND THEIR USES
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The present invention provides imidazooxazole and imidazothiazole compounds and their syntheses. The compounds of the present invention are capable of inhibiting the activity of RAF kinase, such as B-RAF V600E. The compounds are useful for the treatment of cell proliferative disorders such as cancer.
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Page/Page column 39
(2010/06/20)
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- COMPOSITION CONTAINING CHLOROMETHYL PHOSPHATE DERIVATIVE WITH IMPROVED STABILITY AND METHOD FOR PRODUCING THE SAME
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The present invention provides a process or the like which is employed for producing chloromethyl phosphate derivatives that are useful for producing water-soluble prodrugs, and which are excellent from the points of view of workability, operativity and energy saving. According to the present invention, there is provided a process for producing a composition containing a compound represented by the following formula (I) and a tertiary amine, (wherein R1 and R2 are identical or different from each other, and represent a C1-C6 alkyl group, a C2-C6 alkenyl group or a C6-C14 aryl C1-C6 alkyl group which may have a substituent, and R1 and R2 may together form a ring), the proces comprising the step of adding the tertiary amine having a boiling point at 1 atmosphere of 150°C or higher to the compound represented by formula (I).
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Page/Page column 12
(2009/12/27)
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- ALDH-2 INHIBITORS IN THE TREATMENT OF ADDICTION
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Disclosed are novel isoflavone derivatives having the structure of Formula I which are useful as ALDH-2 inhibitors for treating mammals for dependence upon drugs of addiction, for example addiction to dopamine-producing agent such as cocaine, morphine, amphetamines, nicotine, and alcohol.
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Page/Page column 100
(2009/09/05)
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- ALDH-2 INHIBITORS IN THE TREATMENT OF PSYCHIATRIC DISORDERS
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Disclosed are isoflavone derivatives having the structure of Formula I which are useful as ALDH-2 inhibitors for use treating in mammals suffering from psychiatric disorders such as, for example, depression, generalized anxiety, social phobia, panic disorder, and sleep disorders.
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- Highly water-soluble prodrugs of anthelmintic benzimidazole carbamates: Synthesis, pharmacodynamics, and pharmacokinetics
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Highly water-soluble prodrugs 1a-g of anthelmintic benzimidazole carbamates 2a-g were synthesized. These prodrugs combine high aqueous solubility and stability with high lability in the presence of alkaline phosphatases. The veterinary utility of 1a was shown by a pharmacodynamic and pharmacokinetic study performed in swine. Comparable anthelmintic efficacy was observed with prodrug 1a or the parent fenbendazole 2a. The pharmacokinetic results showed that 2a is better absorbed when derived from 1a than when applied as such.
- Chassaing,Berger,Heckeroth,Ilg,Jaeger,Kern,Schmid,Uphoff
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p. 1111 - 1114
(2008/09/20)
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- ALDH-2 INHIBITORS IN THE TREATMENT OF DRUG ADDICTION
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Disclosed are novel isoflavone derivatives having the structure of Formula I which are useful as ALDH-2 inhibitors for treating mammals for dependence upon drugs of addiction, for example addiction to dopamine-producing agent such as cocaine, morphine, amphetamines, nicotine, and alcohol.
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Page/Page column 36
(2008/06/13)
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- PRODRUGS AND METHODS OF MAKING AND USING THE SAME
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Prodrugs of parent drugs and methods of making and using the same are described. The prodrugs comprise an amine-containing parent drug moiety and a prodrug moiety, such as methoxyphosphonic acid or ethoxyphosphonic acid. The prodrugs may be employed in therapy for the treatment of various indications, such as pain, and in methods of decreasing the abuse potential of abuse-prone drugs and/or delaying the onset of parent drug activity and/or prolonging parent drug activity as compared to administration of a parent drug.
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Page/Page column 63-64
(2008/12/06)
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- QUINOLINE DERIVATIVES
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The invention relates to new quinoline derivatives which are active CLK-1 inhibitors. More specifically, the CLK-1 inhibitors of the invention are compounds of formula (A). The invention also relates to pharmaceutical compositions comprising such compounds and to methods for the prophylaxis and/or treatment of disorders or their associated symptoms for which the inhibition of CLK-1 is beneficial.
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Page/Page column 59
(2008/06/13)
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- NOVEL BENZIMIDAZOLE (THIO) CARBAMATES WITH ANTIPARASITIC ACTIVITY AND THE SYNTHESIS THEREOF
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The present invention is concerned with novel benzimidazole (thio)carbamates with antiparasitic activity. The present invention provides compounds of the following general formula (I) wherein X1 and X2 are O or S, wherein at least one of X1 and X2 is O, Y1 and Y2 are O or S, wherein at least one of Y1 and Y2 is O, R1 is alkyl of 1-4 carbon atoms, R2, R3 and R4 are independently of each other hydrogen, or a cation, R5 and R6 may both independently be hydrogen or halogen or alkyl having from 1-8 carbon atoms, or -OR7, wherein R7 is alkyl having from 1-8 carbon atoms, or -SR8, wherein R8 may be alkyl having from 1-8 carbon atoms, or aryl, or -CO-R9, wherein R9 is alkyl having from 1-8 carbon atoms, cycloalkyl having from 3-6 carbon atoms, or R9 is aryl, or -OSO2-Ar, wherein Ar is aryl, or -S(O)R10, wherein R10 is alkyl having from 1-8 carbon atoms, or wherein R10 is aryl. The compounds of the invention are highly soluble and stable in water. Moreover, it has been found that the compounds according to the invention are stable for over 8 hours at pH 5 and at pH 9, which are the lower and upper pH limits at which compounds should be stable for over 8 hours in order to be suitable for drinking water application. The compounds of the present invention have excellent antiparasitic, and especially anthelmintic activity in vivo, which is comparable to the state of the art, water insoluble, benzimidazole carbamates such as albendazole and fenbendazole.
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Page/Page column 9-10
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- Process for preparing chloromethyl di-tert-butylphosphate
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A process is provided for preparing chloromethyl di-tert-butylphosphate (an intermediate for use in preparing water-soluble azole antifungal compounds), wherein potassium di-tert-butylphosphate is reacted with chloromethyl chlorosulfate under mild conditions (15 to 25° C.) in the presence of a base such as sodium carbonate or potassium carbonate, catalyst such as tetrabutylammonium sulfate or tetrabutylammonium chloride and an organic solvent such as dichloromethane or tetrahydrofuran. A process for preparing an azole antifungal agent employing the chloromethyl di-tert-butylphosphate (prepared in accordance with the present invention) is also provided.
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Page/Page column 3-4
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- Prodrugs of A2B adenosine receptor antagonists
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Disclosed are prodrugs of A2B adenosine receptor antagonists, and their use in treating mammals for various disease states.
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Page/Page column 13
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