- Prodrug compound and application ofprodrug compound in treatment of cancer
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The present invention provides a compound indicated by a formula (I), pharmaceutically acceptable salts or esters thereof, a pharmaceutical composition of the compound, and application of the compoundand the pharmaceutical composition in the inhibition or regulation of the activity of tyrosine kinase and treating disease symptoms or symptoms including cancer mediated by tyrosine kinase.
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Paragraph 0164-0165
(2021/03/06)
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- PRODRUGS OF THE TYROSINE KINASE INHIBITOR FOR TREATING CANCER
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There are provided compounds of Formula (I), and pharmaceutically acceptable salts and esters thereof, and pharmaceutical compositions thereof, useful for inhibition or modulation of the activity of tyrosine kinases and treatment of disease states or conditions mediated by tyrosine kinases, including cancers. (I)
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Paragraph 00125-00126
(2021/03/05)
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- Discovery of a dual tubulin polymerization and cell division cycle 20 homologue inhibitor via structural modification on apcin
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Apcin is one of the few compounds that have been previously reported as a Cdc20 specific inhibitor, although Cdc20 is a very promising drug target. We reported here the design, synthesis, and biological evaluations of 2,2,2-trichloro-1-aryl carbamate derivatives as Cdc20 inhibitors. Among these derivatives, compound 9f was much more efficient than the positive compound apcin in inhibiting cancer cell growth, but it had approximately the same binding affinity with apcin in SPR assays. It is possible that another mechanism of action might exist. Further evidence demonstrated that compound 9f also inhibited tubulin polymerization, disorganized the microtubule network, and blocked the cell cycle at the M phase with changes in the expression of cyclins. Thus, it induced apoptosis through the activation of caspase-3 and PARP. In addition, compound 9f inhibited cell migration and invasion in a concentration-dependent manner. These results provide guidance for developing the current series as potential new anticancer therapeutics.
- Huang, Pan,Le, Xiangyang,Huang, Fei,Yang, Jie,Yang, Haofeng,Ma, Junlong,Hu, Gaoyun,Li, Qianbin,Chen, Zhuo
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p. 4685 - 4700
(2020/06/08)
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- External-Radiation-Induced Local Hydroxylation Enables Remote Release of Functional Molecules in Tumors
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Radiation-induced cleavage for controlled release in vivo is yet to be established. We demonstrate the use of 3,5-dihydroxybenzyl carbamate (DHBC) as a masking group that is selectively and efficiently removed by external radiation in vitro and in vivo. D
- Duan, Dongban,Fu, Qunfeng,Li, Hongyu,Liu, Zhibo,Ma, Huimin,Shen, Siyong,Wang, Changlun
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supporting information
p. 21546 - 21552
(2020/09/07)
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- PRODRUGS OF KALLIKREIN INHIBITORS
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Disclosed are compounds of formula I, II, and III, and pharmaceutically acceptable salts thereof, which are inhibitors of kallikrein. Also provided are pharmaceutical compositions comprising such a compound, and methods involving use of the compounds and compositions in the treatment and prevention of acquired or hereditary angioedema, or other diseases and conditions characterized by aberrant kallikrein activity. (I) (II) (III)
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Page/Page column 112; 119
(2018/05/24)
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- Alkyl and aryl 4,5-dichloro-6-oxopyridazin-1(6 H)-carboxylates: A practical alternative to chloroformates for the synthesis of symmetric and asymmetric carbonates
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Symmetric and asymmetric carbonates were synthesized by using alkyl or aryl 4,5-dichloro-6-oxopyridazin-1(6H)-carboxylates. Five aryl 4,5-dichloro-6-oxopyridazin-1(6H)-carboxylates were converted into the corresponding diaryl carbonates in good to excellent yields by treatment with potassium carbonate in refluxing THF. When the 4,5-dichloro-6-oxopyridazin-1(6H)-carboxylates were treated with aliphatic or aromatic alcohols in the presence of potassium tert-butoxide in toluene at room temperature, they gave the corresponding symmetric or asymmetric carbonates in moderate to excellent yields. Alkyl and aryl 4,5-dichloro-6-oxopyridazin-1(6H)-carboxylates are therefore efficient, stable, and ecofriendly alternatives to chloroformates.
- Moon, Hyun Kyung,Sung, Gi Hyeon,Yoon, Yong-Jin,Yoon, Hyo Jae
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supporting information
p. 1577 - 1581
(2016/06/14)
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- Synthesis of organic carbonates with alkyl/aryl 4,5-dichloro-6-oxopyridazine-1(6H)-carboxylates and ROH/AlCl3under ambient condition
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We demonstrated the synthesis of organic carbonates using alkyl/aryl 4,5-dichloro-6-oxopyridazine-1(6H)-carboxylates and alcohol in the presence of aluminum chloride. Alkyl/aryl 4,5-dichloro-6-oxopyridazine-1(6H)-carboxylates were reacted with alcohol in the presence of AlCl3 in toluene at room temperature to afford the corresponding unsymmetric and symmetric organic carbonates in good to excellent yields. These are efficient and convenient processes. Alkyl/aryl 4,5-dichloro-6-oxopyridazine-1(6H)-carboxylates are solid, stable and non-toxic CO2/CO2R(Ar) source. It is noteworthy that the reaction is carry out under an ambient and acidic conditions, the easy-to prepare and readily available starting materials and the quantitative isolation of reusable 4,5-dichloropyridazin-3(2H)-one.
- Sung, Gi Hyeon,Bo, Ram Kim,Ryu, Ki Eun,Kim, Jeum-Jong,Yoon, Yong-Jin
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p. 2758 - 2764
(2015/04/22)
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- NEW ACETYL COENZYME A CARBOXYLASE (ACC) INHIBITORS AND USES IN TREATMENTS OF OBESITY AND DIABETES MELLITUS - 087
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The present invention relates to Acetyl Coenzyme A Carboxylase (ACC) inhibitors according to formula (I), or an enantiomer thereof, or a pharmaceutically acceptable salt thereof, where R1, R2, R3, R4, R5, E, L, Z and n are as defined herein, to processes for preparing such compounds, to pharmaceutical compositions containing them, to the use of such inhibitors and to methods for th eir therapeutic use, particularly in the treatments of obesity and diabetes mellitus.
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Page/Page column 238
(2009/07/25)
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- Acyl transfer from carboxylate, carbonate, and thiocarbonate esters to enzymatic and nonenzymatic thiolates
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Transglutaminases (EC 2.3.2.13) (TGases) catalyze calcium-dependent acyl transfer reactions between peptide-bound glutamine residues as acyl donors and peptide-bound lysine residues as acyl acceptors, resulting in the formation of intermolecular ε-(γ-glutamyl)lysine crosslinks. The mechanistic details of its "ping-pong" transamidation reaction remain unknown. In particular, few studies have been published probing the nucleophilicity of TGase using acyl-donor substrates of varied electrophilicity. Herein we report the synthesis of activated esters of carbonates, carbamates, and thiocarbonates and their reactions with simple thiols, as a nonenzymatic point of reference, and with the catalytic cysteine residue of guinea pig liver TGase. Our kinetic results show that the simple substitution of a side chain methylene unit by oxygen or sulphur had a surprising effect on both substrate affinity and acylation reactivity. Furthermore, they provide unexpected insight into the importance of a side chain heteroatom for conferring affinity for tissue TGase as well as revealing an interesting class of irreversible inhibitors.
- Gravel, Christian,Lapierre, Danielle,Labelle, Judith,Keillor, Jeffrey W.
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p. 164 - 174
(2008/02/13)
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- A new, mild, general and efficient route to aryl ethyl carbonates in solvent-free conditions promoted by magnesium perchlorate
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A new, general and mild method for the direct synthesis of aryl and alkyl ethyl carbonates promoted by a Lewis acid is reported. The reaction proceeds smoothly with diethyl dicarbonate in the presence of Mg(ClO4) 2, a specific activator of 1,3-dicarbonyl compounds, and shows general applicability. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.
- Bartoli, Giuseppe,Bosco, Marcella,Carlone, Armando,Locatelli, Manuela,Marcantoni, Enrico,Melchiorre, Paolo,Palazzi, Paolo,Sambri, Letizia
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p. 4429 - 4434
(2007/10/03)
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- Synthesis and CB1 receptor activities of novel arachidonyl alcohol derivatives
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Novel derivatives of arachidonyl alcohol were synthesized and evaluated for their CB1 receptor activity by [35S]GTPγS assay using rat cerebellar membranes.
- Parkkari, Teija,Savinainen, Juha R.,Rauhala, Anu L.,Tolonen, Tiina L.,Nevalainen, Tapio,Laitinen, Jarmo T.,Gynther, Jukka,Jaervinen, Tomi
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p. 3231 - 3234
(2007/10/03)
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- PEPTIDIC THROMBIN INHIBITOR COMPOUND
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The present invention relates to a novel thrombin inhibitor compound which has a good inhibitory effect against thrombosis and can be orally administered, a process for preparing the same, and to a composition for the therapeutic and/or prophylactic treatment of various diseases associated with thrombin inhibition mechanism, which comprises the same as an active ingredient.
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- BENZAMIDINE DERIVATIVE
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Compounds of general formula (1) and pharmacologically acceptable salts thereof: ???[wherein ??????R1 represents a hydrogen atom, a halogen atom, an alkyl group or a hydroxyl group; ??????R2 represents a hydrogen atom or a halogen atom; ??????R3 represents a hydrogen atom, an alkyl group which may be substituted, an aralkyl group, an alkylcarbonyl group which may be substituted, an alkylsulfonyl group which may be substituted or the like; ??????each of R4 and R5 represents a hydrogen atom, a halogen atom, an alkyl group which may be substituted, a carbamoyl group or the like; ??????R6 represents a heterocycle or the like; ??????each of R7 and R8 represents a hydrogen atom, an alkyl group or the like; ??????n represents 0, 1 or 2] ???exhibit excellent activated blood coagulation factor X inhibitory activity and are useful for the prevention or treatment of blood coagulation-related diseases.
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- Novel prodrugs for antimicrobial amidines
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A methods of treating an infection comprises administering a therapeutically effective amount of a compound described by the Formula (I): wherein: X may be O, S, or NR′ wherein R′ is H or loweralkyl; R1 and R2 may be independently selected from the group consisting of H, loweralkyl, oxyalkyl, alkoxyalkyl, cycloalkyl, aryl, hydroxyalkyl, aminoalkyl, and alkylaminoalkyl; R3 and R4 are each independently selected from the group consisting of H, loweralkyl, halogen, oxyalkyl, oxyaryl, and oxyarylalkyl; R5 is represented by a formula selected from the group consisting of: ?wherein: X1, X2, and X3 are independently selected from O and S; and R6 and R7 are independently selected from the group consisting of loweralkyl, aryl, alkylaryl, oxyaryl, an ester-containing substituent, and oxyalkyl; or a pharmaceutically acceptable salt thereof.
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- Prodrugs for amidines: Synthesis and anti-Pneumocystis carinii activity of carbamates of 2,5-bis(4-amidinophenyl)furan
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Syntheses of several carbamate analogues of 2,5-bis(4- amidinophenyl)furan (1) under mild conditions and their evaluation as prodrugs against Pneumocystis carinii pneumonia (PCP) in an immunosuppressed rat model are described. Thus, nine new bis-carbamates: methoxycarbonyl (2), 2,2,2-trichloroethoxycarbonyl (3), ethylthiocarbonyl (4), benzyloxycarbonyl (5), (4-methyl-2-oxo-1,3-dioxol-4-en-5-yl)methoxycarbonyl (6), phenoxycarbonyl (7), 4-fluorophenoxycarbonyl (8), 4-methoxyphenoxycarbonyl (9), and (1-acetoxy)ethoxycarbonyl (10) and a biscarbonate ethoxycarbonyloxy (1) of the bis-amidine 1 have been synthesized and evaluated. The in vivo results show that the 4-fluorophenyl carbamate 8 and the 4-methoxyphenyl carbamate 9 in this series had the best anti-PCP activity by both intravenous and oral administration at a dosage level of 22 mol and 33 μmol/kg/day, respectively. Compounds 3-7 were also more active than the parent drug (1) on oral administration. The acute toxicity usually exhibited by the parent amidine 1 at a dosage level of 22 μmol/kg/day on intravenous administration has been significantly reduced by the prodrug modifications, with the exception of compound 10 which exhibited some toxicity. This report also describes the synthesis of several aryl-alkyl and aryl-aryl carbonates (12- 14, 16-23) as efficient reagents for the preparation of carbamate derivatives from bis-arylamidines.
- Rahmathullah, Syed M.,Hall, James Edwin,Bender, Brendan C.,McCurdy, Donald R.,Tidwell, Richard R.,Boykin, David W.
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p. 3994 - 4000
(2007/10/03)
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- Synthesis and evaluation of 2-amino-9-(3-acyloxymethyl-4-alkoxycarbonyloxybut-1-yl)purines and 2-Amino-9-(3-alkoxycarbonyloxymethyl-4-alkoxycarbonyloxybut-1-yl)purines as potential prodrugs of penciclovir
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A series of 2-amino-9-(3-acyloxymethyl-4-alkoxycarbonyloxybut-1-yl)purines (1-8) and 2-amino-9-(3-alkoxycarbonyl- oxymethyl-4-alkoxycarbonyloxybut-1-yl)purines (9-12) were synthesized as potential prodrugs of penciclovir. Treatment of 6- deoxypenciclovir
- Kim, Dae-Kee,Lee, Namkyu,Ryu, Do Hyun,Kim, Young-Woo,Kim, Jae-Sun,Chang, Kieyoung,Im, Guang-Jin,Choi, Won-Son,Cho, Yong-Baik,Kim, Key H.,Colledge, Danni,Locarnini, Stephen
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p. 1715 - 1725
(2007/10/03)
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- Kinetics and mechanism of the aminolysis of ethyl aryl carbonates in acetonitrile
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The aminolysis reactions of ethyl aryl carbonates with benzylamines in acetonitrile at 25.0°C are investigated. The base-catalyzed path, k2, disappears when strong nucleophiles (X = p-CH3O and p-CH3) react with a substrate activated by a strong nucleofuge (Z = p-NO2). The large magnitude of ρ(x) (-1.7 to -2.5), ρ(z) (3.4 to 4.3), and ρ(xz) (1.4) values, and relatively large k(H)/k(D) (1.6 to 1.8) found for the uncatalyzed path (k1) can be accounted for in terms of a stepwise mechanism with rate-limiting expulsion of the phenoxide leaving group. The catalyzed process (k2) is characterized by the much smaller magnitude of ρ(x) (-1.0 to -1.7), ρ(z) (0.4 to 0.7), and ρ(xz) (0.2), the larger k(H)/k(D) (2.1 to 2.5) values, and the lower ΔH(+) values (1.8-1.9 kcal mol-1) than those of the uncatalyzed process (k1) with large negative ΔS(+) values (-65 to -67 cal K-1 mol- 1). These results are consistent with four- and six-centered transition states for the two processes, k1 and k2, respectively.
- Koh, Han Joong,Lee, Ji-Won,Lee, Hai Whang,Lee, Ikchoon
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p. 710 - 716
(2007/10/03)
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- Water-Soluble Acylating Agents: Preparation of 2-Acylthio-1-alkylpyridinium Salts and Acylation of Phenols, Acids, and/or Amines with These Salts in an Aqueous Phase
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Reaction of phenols, amines, and acids with 2-benzoylthio-1-methylpyridinium chloride prepared in situ from benzoyl chloride and 1-methyl-2(1H)-pyridinethione, afforded the corresponding benzoyl derivatives in good yields.In the reaction of p-nitrophenol, even catalytic amount of 1-methyl-2(1H)-pyridinethione proved to be effective.Similar reactions of p-nitrophenol with isobutyryl chloride and acetyl chloride in the presence of 1-methyl-2(1H)-pyridinethione afforded p-nitrophenyl isobutyrate and p-nitrophenyl acetate in 63 and 44percent yields, respectively. 2-Benzoylthio-, 2-acetylthio-, and 2-isobutyrylthio-1-ethylpyridinium tetrafluorobora tes were prepared by treatment of the corresponding 2-acylthiopyridines with triethyloxonium tetrafluoroborate.These pyridinium salts also acted as acylating agents in an aqueous phase. some competitive reactions of 2-aminoethanol and phenols with 2-benzoylthio-1-methylpyridinium chloride were also investigated.
- Sakakibara, Tohru,Watabe, Yukie,Yamada, Masahide,Sudoh, Rokuro
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p. 247 - 254
(2007/10/02)
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- Kinetics of the Aminolysis of Ethyl p-Nitrophenyl Carbonate in the Presence of Dodecylammonium Diethylarsinate Aggregates in Chloroform. Complex Effects of Solubilized Water
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The kinetics of the aminolysis of ethyl p-nitrophenyl carbonate (ENPC) by dodecylamine (DA), dodecylammonium diethylarsinate (DADEA; dry aggregates and in the presence of solubilized water), and DA plus dry DADEA in chloroform were studied spectrophotomet
- Seoud, Monica I. El,Seoud, Omar A. El
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p. 2686 - 2690
(2007/10/02)
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