- Design, synthesis and biological evaluation of novel FXIa inhibitors with 2-phenyl-1H-imidazole-5-carboxamide moiety as P1 fragment
-
Factor XIa, as a blood coagulation enzyme, amplifies the generation of the last enzyme thrombin in the blood coagulation cascade. It was proved that direct inhibition of factor XIa could reduce pathologic thrombus formation without an enhanced risk of bleeding. WSJ-557, a nonpurine imidazole-based xanthine oxidase inhibitor in our previous reports, could delay blood coagulation during its animal experiments, which prompted us to investigate its action mechanism. Subsequently, during the exploration of the action mechanism, it was found that WSJ-557 exhibited weak in vitro factor XIa binding affinity. Under the guide of molecular modeling, we adopted molecular hybridization strategy to develop novel factor XIa inhibitors with WSJ-557 as an initial compound. This led to the identification of the most potent compound 44g with a Ki value of 0.009 μM, which was close to that of BMS-724296 (Ki = 0.0015 μM). Additionally, serine protease selectivity study indicated that compound 44g display a desired selectivity, more 400-fold than those of thrombin, factor VIIa and factor Xa in coagulation cascade. Moreover, enzyme kinetics studies suggested that the representative compound 44g acted as a competitive-type inhibitor for FXIa, and molecular modeling revealed that it could tightly bind to the S1, S1′ and S2′ pockets of factor XIa. Furthermore, in vivo efficacy in the rabbit arteriovenous shunt model suggested that compound 44g demonstrated dose-dependent antithrombotic efficacy. Therefore, these results supported that compound 44g could be a potential and efficacious agent for the treatment of thrombotic diseases.
- Lei, Yu,Zhang, Bing,Zhang, Yan,Dai, Xiwen,Duan, Yulin,Mao, Qing,Gao, Jun,Yang, Yuwei,Bao, Ziyang,Fu, Xuefeng,Ping, Kunqi,Yan, Chengda,Mou, Yanhua,Wang, Shaojie
-
-
- Synthesis, SAR study, and bioactivity evaluation of a series of Quinoline-Indole-Schiff base derivatives: Compound 10E as a new Nur77 exporter and autophagic death inducer
-
We previously reported 5-((8-methoxy-2-methylquinolin-4-yl)amino)-1H-indole- 2-carbohydrazide derivatives as new Nur77 modulators. In this study, we explored whether the 8-methoxy-2-methylquinoline moiety and bicyclic aromatic rings at the N’-methylene position were critical for their antitumor activity against hepatocellular carcinoma (HCC). For this purpose, a small library of 5-substituted 1H-indole-2-carbohydrazide derivatives was designed and synthesized. We found that the 8-methoxy-2-methylquinoline moiety was a fundamental structure for its biological function, while the introduction of the bicyclic aromatic ring into the N’-methylene greatly improved its anti-tumor effect. We found that the representative compound 10E had a high affinity to Nur77. The KD values were in the low micromolar (2.25–4.10 μM), which were coincident with its IC50 values against the tumor cell lines (IC50 3.78 μM). Compound 10E could induce autophagic cell death of liver cancer cells by targeting Nur77 to mitochondria while knocking down Nur77 greatly impaired anti-tumor effect. These findings provide an insight into the structure–activity relation of Quinoline-Indole-Schiff base derivatives and further demonstrate that antitumor agents targeting Nur77 may be considered as a promising strategy for HCC therapy.
- Chen, Jingwei,Chen, Kun,Fang, Meijuan,He, Fengming,Huang, Jiangang,Li, Baicun,Lin, Zongxin,Liu, Jie,Liu, Shunzhi,Wang, Wang,Wu, Tong,Yao, Jie,Zeng, Jin-Zhang
-
-
- INHIBITORS OF HSP70 PROTEINS
-
Provided are compounds useful for selectively inhibiting HSP70 isoforms. Also provided are methods of inhibiting HSP70 proteins and methods of treating a disease characterized by overexpression of a HSP70, such as cancer. In particular embodiments, the disclosed compounds may be used as potent inhibitors for HSPA5 and may display greater than 20-fold selectivity over other HSP70 isoforms.
- -
-
Paragraph 00113; 00146
(2021/09/17)
-
- Design, synthesis and biological evaluation of methylenehydrazine-1-carboxamide derivatives with (5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1H-indole scaffold: Novel potential CDK9 inhibitors
-
In continuation of our previous work on the investigation of CDK9 inhibitors bearing indole moiety for the discovery of novel anticancer agents, novel methylenehydrazine-1-carboxamide derivatives with (5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1H-indole scaffold were designed, synthesized, and evaluated for the CDK9 inhibitory activity and anticancer activity. Biological activity results demonstrated that most of these derivatives possessed good inhibitory on the kinase activity of CDK9 such as blocking its phosphorylation function and inhibiting HIV-1 transcription. Compound 12i was found to be the most potent CDK9 inhibitor and exhibited excellent anticancer activity against HepG2, A375, MCF-7, and A549, but low toxic on normal cells including HaCaT and MCF-10A. Further studies revealed that as a result of CDK9 inhibition and subsequent inhibition of phosphorylation at Serine 2 of the RNAPII CTD, the representative compound 12i dose-dependently increased cleaved PARP level, exerting its antiproliferative effect through induction of apoptosis in cancer cells. Finally, the molecular docking analysis implied that 12i had a good binding affinity with CDK9. In summary, 12i is a potent CDK9 inhibitor and can be considered as a good lead-candidate for developing potential anticancer drugs.
- Ao, Mingtao,Cui, Zhenzhen,Fang, Meijuan,Hu, Hongyu,Li, Boqun,Wang, Lijuan,Wu, Jun,Wu, Tong,Wu, Zhen,Xue, Yuhua,Zhou, Xiaoping
-
-
- Design, synthesis, and biological evaluation of 5-((8-methoxy-2-methylquinolin-4-yl)amino)-1H-indole-2-carbohydrazide derivatives as novel Nur77 modulators
-
Nur77 is a potential target for the treatment of cancer such as HCC. Herein, we detailed the discovery of a novel series of 5-((8-methoxy-2-methylquinolin-4-yl)amino)-1H-indole-2-carbohydrazide derivatives as potential Nur77 modulators. The studies of antiproliferative activity and Nur77-binding affinity of target compounds resulted in the discovery of a lead candidate (10g), which was a good Nur77 binder (KD = 3.58 ± 0.16 μM) with a broad-spectrum antiproliferative activity against all tested hepatoma cells (IC50 2.0 μM) and was low toxic to normal LO2 cells. 10g could up-regulate Nur77 expression and mediate sub-cellular localization of Nur77 to induce apoptosis in hepatocellular carcinoma cell lines, which relied on 10g inducing Nur77-dependent autophagy and endoplasmic reticulum stress as the upstream of apoptosis. Moreover, the in vivo assays verified that 10g significantly inhibited xenograft tumor growth. These results indicate that 10g has the potential to be developed as a novel Nur77-targeting anti-hepatoma drug.
- Li, Baicun,Yao, Jie,Guo, Kaiqiang,He, Fengming,Chen, Kun,Lin, Zongxin,Liu, Shunzhi,Huang, Jiangang,Wu, Qiaoqiong,Fang, Meijuan,Zeng, Jinzhang,Wu, Zhen
-
-
- Pyrimidine indole Nur77 receptor regulating agent, preparation method and application thereof
-
The invention provides a pyrimidine indole Nur77 receptor regulating agent, a preparation method and an application thereof and relates to pyrimidine indole derivatives. The invention provides a pyrimidine indole derivative with a novel structure, a pharm
- -
-
Paragraph 0064; 0066; 0069
(2019/05/22)
-
- An optimised series of substituted N-phenylpyrrolamides as DNA gyrase B inhibitors
-
ATP competitive inhibitors of DNA gyrase and topoisomerase IV have great therapeutic potential, but none of the described synthetic compounds has so far reached the market. To optimise the activities and physicochemical properties of our previously reported N-phenylpyrrolamide inhibitors, we have synthesized an improved, chemically variegated selection of compounds and evaluated them against DNA gyrase and topoisomerase IV enzymes, and against selected Gram-positive and Gram-negative bacteria. The most potent compound displayed IC50 values of 6.9 nM against Escherichia coli DNA gyrase and 960 nM against Staphylococcus aureus topoisomerase IV. Several compounds displayed minimum inhibitory concentrations (MICs) against Gram-positive strains in the 1–50 μM range, one of which inhibited the growth of Enterococcus faecalis, Enterococcus faecium, S. aureus and Streptococcus pyogenes with MIC values of 1.56 μM, 1.56 μM, 0.78 μM and 0.72 μM, respectively. This compound has been investigated further on methicillin-resistant S. aureus (MRSA) and on ciprofloxacin non-susceptible and extremely drug resistant strain of S. aureus (MRSA VISA). It exhibited the MIC value of 2.5 μM on both strains, and MIC value of 32 μM against MRSA in the presence of inactivated human blood serum. Further studies are needed to confirm its mode of action.
- Tiz, Davide Benedetto,Skok, ?iga,Durcik, Martina,Toma?i?, Tihomir,Ma?i?, Lucija Peterlin,Ila?, Janez,Zega, Anamarija,Draskovits, Gábor,Révész, Tamás,Nyerges, ákos,Pál, Csaba,Cruz, Cristina D.,Tammela, P?ivi,?igon, Du?an,Kikelj, Danijel,Zidar, Nace
-
p. 269 - 290
(2019/02/20)
-
- Synthesis method of indole-2-carboxylic acid and derivative thereof
-
The invention relates to a synthesis method of indole-2-carboxylic acid and a derivative thereof, belonging to the field of organic synthesis. In the synthesis method, the indole-2-carboxylic acid isprepared through two steps of reaction with phenylhydrazine hydrochloride and ethyl pyruvate as raw materials and sulfuric acid as a catalyst. The synthesis method has a short process and uses fewer raw materials, the total yield of indole-2-carboxylic acid reaches 70% or above. The method can synthesize both indole-2-carboxylic acid and the derivative thereof, thereby being suitable for industrial production.
- -
-
Paragraph 0065-0071
(2019/02/21)
-
- N-substituted-5-((4-substituted pyrimidine-2-yl)amino)indole derivative as well as preparation method and purpose thereof
-
The invention discloses an N-substituted-5-((4-substituted pyrimidine-2-yl)amino)indole derivative as well as a preparation method and a purpose thereof, and relates to malignant tumor drugs. A structure of the N-substituted-5-((4-substituted pyrimidine-2
- -
-
Paragraph 0036; 0037; 0038; 0041
(2018/04/03)
-
- 1 H - indole -2 - hydrazine derivative and its preparation and use
-
The invention provides a 1H-indol-2-carbohydrazide derivative as well as a preparation method and the use of the derivative. The preparation method comprises the following steps: 1) synthesizing an intermediate ethyl pyruvate p-nitrobenzene hydrazine; 2) preparing an intermediate 5-nitroindole-2-ethyl carboxylate; 3) preparing an intermediate 5-amino-1H-indol-2-ethyl carboxylate; 4) preparing 5-(4-(pyridyl-3)pyrimidyl-2-amino)-1H-indol-2-ethyl carboxylate; 5) preparing 5-(4-(pyridyl-3)pyrimidyl-2)amino)-1H-indol-2-carbohydrazide; 6) preparing the N'-substituted methylene-5-((4-(pyridyl-3)pyrimidyl-2)amino)-1H-indol-2-carbohydrazide derivative. The 1H-indol-2-carbohydrazide derivative can be applied to preparation of medicines for preventing or treating related CDK9 receptor related diseases.
- -
-
Paragraph 0040; 0041
(2018/07/30)
-
- 5 - (Substituted carbonylamino-) - 1H - indole -2 - hydrazine derivative and its preparation method and application
-
The invention provides 5-(substituted carbonylamino)-1H-indole-2-carbohydrazide derivatives as well as a preparation method and an application thereof. The preparation method comprises steps as follows: 1), preparing an intermediate ethyl pyruvate p-nitrobenzoylhydrazone; 2), preparing an intermediate 5-nitroindole-2-carboxylic ethyl ester; 3), preparing an intermediate 5-amino-1H-indole-2-carboxylic ethyl ester; 4), preparing an intermediate 5-(substituted carbonylamino)-1H-indole-2-carboxylic ethyl ester; 5), preparing an intermediate 5-(substituted carbonylamino)-1H-indole-2-carbohydrazide; 6), preparing N'-substituted methylene-5-(substituted carbonylamino)-1H-indole-2-carbohydrazide derivatives. The N'-substituted methylene-5-(substituted carbonylamino)-1H-indole-2-carbohydrazide derivatives can be applied to preparation of drugs for preventing or treating CDK9 (cyclin-dependent kinase 9) receptor related diseases. The reaction cost is low, the yield is high, the reaction process is simple and easy to control, and the derivatives have antitumor activity.
- -
-
Paragraph 0035-0036
(2018/07/30)
-
- Synthesis, structure–activity relationship studies and biological evaluation of novel 2,5-disubstituted indole derivatives as anticancer agents
-
Three novel series of 2,5-disubstituted indole derivatives were synthesized and evaluated in vitro for their antiproliferative activity against human cancer cells and HIV-1 inhibition activity used as a readout of cellular activity. Most compounds were found to have potent anticancer activity. In particular, 2c and 3b which showed effectively to repress HIV-1 transcription had a pan antiproliferative activity in cervical cancer cells (HeLa), breast cancer cells (MCF-7), liver cancer cells (HepG2), and lung cancer cells (H460 and A549). While 3b exhibited high sensitivity to A549 cells with the IC50 value 0.48?±?0.15?μm, 2c showed high selectivity toward HepG2 cells with the IC50 value 13.21?±?0.30?μm. With respect to the cellular mechanism of action, HepG2 cells treated with 2c and A549 cells treated with 3b for 24?h were studied by annexin V/PI staining and Western blot analysis, and results revealed that 2c and 3b may induce cancer cells apoptosis through inhibiting the phosphorylation at Ser2 of RNAPII CTD which can be phosphorylated by cyclin-dependent kinase 9. These studies indicated that 2c and 3b may develop as potent lead compounds in the therapy of cancer. However, determining their roles in preventing HIV-1 still requires further intensive study.
- Hu, Hongyu,Wu, Jun,Ao, Mingtao,Wang, Huiru,Zhou, Tongtong,Xue, Yuhua,Qiu, Yingkun,Fang, Meijuan,Wu, Zhen
-
p. 766 - 778
(2016/11/04)
-
- SACCHARIDE DERIVATIVE OF A TOXIC PAYLOAD AND ANTIBODY CONJUGATES THEREOF
-
A molecule comprising a saccharide bound via an O- glycosidic bond to a hydroxyl group of a toxic payload molecule is disclosed. An antibody-drug conjugate comprising an antibody covalently bound to a toxic payload molecule, optionally via a linker group,
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-
Page/Page column 138
(2016/01/25)
-
- Oligomer modified diaromatic substituted compounds
-
Disclosed are compounds comprising diaromatic substituted compound residues, namely the anti-viral (anti-HIV) drug delavirdine, covalently attached via a linkage to water-soluble, non-peptidic oligomers, specifically to poly(ethylene glycol) (PEG) oligome
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-
Page/Page column 43
(2016/01/30)
-
- 2,4-Pyrimidinediamine Compounds and Their Uses
-
The present invention provides 2,4-pyrimidinediamine compounds that inhibit the IgE and/or IgG receptor signaling cascades that lead to the release of chemical mediators, intermediates and methods of synthesizing the compounds and methods of using the compounds in a variety of contexts, including in the treatment and prevention of diseases characterized by, caused by or associated with the release of chemical mediators via degranulation and other processes effected by activation of the IgE and/or IgG receptor signaling cascades.
- -
-
Paragraph 0485; 0506
(2015/11/10)
-
- 1-(CYCLOALKYL-CARBONYL)PROLINE DERIVATIVE
-
A compound represented by formula (1) (in the formula: ring-D represents a three- to eight-membered hydrocarbon ring; Ra represents an optionally substituted amino C1-6 alkyl group or the like; Rb1 and Rb2 each independently represent a hydrogen atom, a halogen atom, or the like; Rc represents an optionally substituted C6-10 aryl group or the like; Rd represents a hydrogen atom or the like; and ring-Q represents a (hetero)aryl group or the like which may be substituted with a carboxyl group or the like) or a pharmaceutically acceptable salt thereof exhibits an excellent FXIa inhibitory activity, and is useful as a therapeutic agent against thrombosis or the like.
- -
-
Paragraph 0285; 0286
(2015/06/03)
-
- 1-(HETEROARYL CARBONYL) PROLINE DERIVATIVE
-
PROBLEM TO BE SOLVED: To provide a 3-substituted proline derivative having excellent FXIa inhibitory activity and useful as a therapeutic agent for thrombosis or the like, and its pharmaceutically acceptable salt. SOLUTION: This invention relates to a com
- -
-
Paragraph 0165-0166
(2016/10/10)
-
- AMINO-INDOLYL-SUBSTITUTED IMIDAZOLYL-PYRIMIDINES AND THEIR USE AS MEDICAMENTS
-
The invention relates to new amino-indole-substituted imidazolyl-pyrimidines of formula (1), wherein R1, R2, R3, R4 and R5 are defined as in claim 1 and pharmaceutically acceptable salts thereof and the use of these compounds for the preparation of a medicament for treating a disease selected from asthma, COPD, rheumatoid arthritis, specific lymphomas and specific diseases of the nervous system
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-
Page/Page column 56
(2013/11/05)
-
- Amino-Indolyl-Substituted Imidazolyl-Pyrimidines and Their Use as Medicaments
-
The invention relates to new amino-indole-substituted imidazolyl-pyrimidines of formula 1 wherein R1, R2, R3, R4 and R5 are defined as in claim 1 and pharmaceutically acceptable salts thereof and the use of these compounds for the preparation of a medicament for treating a disease selected from asthma, COPD, rheumatoid arthritis, specific lymphomas and specific diseases of the nervous system.
- -
-
Paragraph 0310; 0311; 0292
(2013/11/05)
-
- Synthesis and biological evaluation of antibody conjugates of phosphate prodrugs of cytotoxic DNA alkylators for the targeted treatment of cancer
-
The synthesis and biological evaluation of phosphate prodrugs of analogues of 1 (CC-1065) and their conjugates with antibodies are described. The phosphate group on the 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) portion of the compounds conf
- Zhao, Robert Yongxin,Erickson, Hans K.,Leece, Barbara A.,Reid, Emily E.,Goldmacher, Victor S.,Lambert, John M.,Chari, Ravi V. J.
-
experimental part
p. 766 - 782
(2012/03/11)
-
- INHIBITORS OF DIACYLGLYCEROL ACYLTRANSFERASE
-
The present invention relates to novel heterocyclic compounds as diacylglycerol acyltransferase (“DGAT”) inhibitors, pharmaceutical compositions comprising the heterocyclic compounds and the use of the compounds for treating or preventing a cardiovascular disease, a metabolic disorder, obesity or an obesity-related disorder, diabetes, dyslipidemia, a diabetic complication, impaired glucose tolerance or impaired fasting glucose. An illustrative compound of the invention is shown below: formula (I).
- -
-
-
- CHEMICAL LINKERS AND CLEAVABLE SUBSTRATES AND CONJUGATES THEREOF
-
The present disclosure provides drug-ligand conjugates and drug-cleavable substrate conjugates that are potent cytotoxins. The disclosure is also directed to compositions containing the drug-ligand conjugates, and to methods of treatment using them.
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-
Page/Page column 62; 64
(2010/06/19)
-
- Synthesis and evaluation of a series of C5′-substituted duocarmycin SA analogs
-
The synthesis and evaluation of a key series of analogs of duocarmycin SA, bearing a single substituent at the C5′ position of the DNA binding subunit, are described.
- Robertson, William M.,Kastrinsky, David B.,Hwang, Inkyu,Boger, Dale L.
-
scheme or table
p. 2722 - 2725
(2011/07/06)
-
- SUBSTITUTED ARYLSULFONYLAMINOMETHYLPHOSPHONIC ACID DERIVATIVES, THEIR PREPARATION AND THEIR USE IN THE TREATMENT OF TYPE I AND II DIABETES MELLITUS
-
The present invention relates to substituted arylsulphonylaminomethylphosphonic acid derivatives of general formula (I) wherein R, X, Y and Z are defined as in claim 1, the tautomers, enantiomers, diastereomers, mixtures thereof and salts thereof which ha
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Page/Page column 54-55
(2009/03/07)
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- 5-Hydroxyindole-2-carboxylic acid amides: Novel histamine-3 receptor inverse agonists for the treatment of obesity
-
Obesity is a major risk factor in the development of conditions such as hypertension, hyperglycemia, dyslipidemia, coronary artery disease, and cancer. Several pieces of evidence across different species, including primates, underscore the implication of the histamine 3 receptor (H3R) in the regulation of food intake and body weight and the potential therapeutic effect of H3R inverse agonists. A pharmacophore model, based on public information and validated by previous investigations, was used to design several potential scaffolds. Out of these scaffolds, the 5-hydroxyindole-2-carboxylic acid amide appeared to be of great potential as a novel series of H3R inverse agonist. Extensive structure-activity relationships revealed the interconnectivity of microsomal clearance and hERG (human ether-a-go-go-related gene) affinity with lipophilicity, artificial membrane permeation, and basicity. This effort led to the identification of compounds reversing the (R)-R-methylhistamine-induced water intake increase in Wistar rats and, further, reducing food intake in diet-induced obese Sprague-Dawley rats. Of these, the biochemical, pharmacokinetic, and pharmacodynamic characteristics of (4,4-difluoropiperidin- 1-yl)[1-isopropyl-5-(1-isopropylpiperidin-4-yloxy)-1H-indol-2-yl]-methanone 36 are detailed.
- Pierson, Pascale David,Fettes, Alec,Freichel, Christian,Gatti-McArthur, Silvia,Hertel, Cornelia,Huwyler, J?rg,Mohr, Peter,Nakagawa, Toshito,Nettekoven, Matthias,Plancher, Jean-Marc,Raab, Susanne,Richter, Hans,Roche, Olivier,Sarmiento, Rosa María Rodríguez,Schmitt, Monique,Schuler, Franz,Takahashi, Tadakatsu,Taylor, Sven,Ullmer, Christoph,Wiegand, Ruby
-
supporting information; experimental part
p. 3855 - 3868
(2010/02/28)
-
- NEW SUBSTITUTED ARYLSULPHONYLGLYCINES, THE PREPARATION THEREOF AND THE USE THEREOF AS PHARMACEUTICAL COMPOSITIONS
-
The present invention relates to substituted arylsulphonylglycines of general formula (I) wherein R, X, Y and Z are defined as in claim 1, the tautomers, enantiomers, diastereomers, mixtures thereof and salts thereof, which have valuable pharmacological properties, particularly the suppression of the interaction of glycogen phosphorylase a with the GL subunit of glycogen-associated protein phosphatase 1 (PP1 ), and their use as pharmaceutical compositions.
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Page/Page column 95
(2008/12/07)
-
- CHEMICAL LINKERS WITH SINGLE AMINO ACIDS AND CONJUGATES THEREOF
-
The present disclosure provides drug-ligand conjugates that are potent cytotoxins and include a linker between the drug and ligand where the linker has a single amino acid. The disclosure is also directed to compositions containing the drug-ligand conjugates, and to methods of treatment using them.
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Page/Page column 85
(2008/12/08)
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- CHEMICAL COMPOUNDS
-
The present invention relates to compounds that are a non-nucleoside reverse transcriptase inhibitors, and to processes for the preparation and use of the same. Specifically, the present invention includes methods of using such compounds in the treatment of human immunodeficiency virus infection.
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Page/Page column 122
(2009/01/24)
-
- Inhibitors of soluble adenylate cyclase
-
The invention relates to compounds of general formula I as well as the production and use thereof as a medication.
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Page/Page column 9
(2008/06/13)
-
- Inhibitors of soluble adenylate cyclase
-
The invention relates to compounds of general formula I as well as the production and use thereof as a medication.
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Page/Page column 9
(2008/06/13)
-
- WATER-SOLUBLE CC-1065 ANALOGS AND THEIR CONJUGATES
-
This invention relates to novel analogs of the DNA-binding alkylating agent CC-1065 and to their conjugates. Furthermore this invention concerns intermediates for the preparation of said agents and their conjugates. The conjugates are designed to release their (multiple) payload after one or more activation steps and/or at a rate and time span controlled by the conjugate in order to selectively deliver and/or controllably release one or more of said DNA alkylating agents. The agents, conjugates, and intermediates can be used to treat an illness that is characterized by undesired (cell) proliferation. As an example, the agents and the conjugates of this invention may be used to treat a tumor.
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Page/Page column 102
(2010/11/28)
-
- INDOL DERIVATIVES AS INHIBITORS OF SOLUBLE ADENYLYL CYCLASE
-
The invention relates to compounds of general formula (I), to the production thereof, and to the use of the same as medicaments.
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Page/Page column 66-67
(2008/06/13)
-
- 5-Aminoindole derivatives as H3 inverse agonists
-
The present invention relates to compounds of formula I wherein R1, R2, R3, R4 and m are as defined in the description and claims, and pharmaceutically acceptable salts thereof as well as to pharmaceutical compositions comprising these compounds and to methods for their preparation. The compounds are useful for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors.
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Page/Page column 12-13
(2008/06/13)
-
- Synthesis of new water-soluble DNA-binding subunits for analogues of the cytotoxic antibiotic CC-1065 and their prodrugs
-
Novel water-soluble indole-2-carboxylic acid derivatives (7, 13, 21 and 25) bearing a substituent with a tertiary amino functionality at C-5 have been prepared. These new DNA-binding subunits can be used for the synthesis of new analogues of the cytotoxic antibiotic CC-1065 and their corresponding prodrugs for antibody-directed enzyme prodrug therapy (ADEPT) within a selective treatment of cancer. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.
- Tietze, Lutz F.,Major, Felix
-
p. 2314 - 2321
(2007/10/03)
-
- NOVEL INDOLE DERIVATIVE FOR ALKYLATING SPECIFIC BASE SEQUENCE OF DNA AND ALKYLATING AGENT AND DRUG EACH COMPRISING THE SAME
-
There is provided a novel pyrrole-imidazole polyamide compound for alkylating the specific base sequence of DNA, the polyamide compound being capable of being synthesized through fewer reaction steps than known hybrid molecules and having a combination of a high reactivity in DNA alkylation and the ability to recognize a sequence. Furthermore, there is provided an alkylating agent and a molecule serving as a drug, the alkylating agent and the molecule containing the polyamide compound. An indole derivative is represented by general formula (1): wherein R 1 represents a functional group for alkylating DNA; R 2 represents a hydrogen atom, an alkyl group, or an acyl group; and X represents a divalent group having one constitutional unit or having two or more constitutional units which may be the same or different, the constitutional unit being represented by the following formula: (wherein m is an integer of 0 to 10), wherein among the constitutional units, a terminal constitutional unit adjacent to R 2 may be a constitutional unit represented by the following formula: (wherein k is an integer of 0 to 10).
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Page/Page column 10; 13
(2008/06/13)
-
- EP2 RECEPTOR AGONISTS
-
A compound of Formula (I) or a salt, solvate and chemically protected form thereof, wherein: R5 is an optionally substituted C5-20 aryl or C4-20 alkyl group; A is selected from the group consisting of Formulae (Ai), (Aii), (Aiii) D is selected from Formulae (Di), (Dii), (Diii), (Div), (Dv) B is selected from the group consisting of Formulae (Bi), (Bii), (Biii), (Biv) (Bv).
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Page/Page column 67-68; 113-114
(2008/06/13)
-
- CBI analogues of the duocarmycins and CC-1065
-
An extensive series of CBI analogues of the duocarmycins and CC-1065 exploring substituent effects within the first indole DNA binding subunit is detailed. In general, substitution at the indole C5 position led to cytotoxic potency enhancements that can be ≧1000-fold providing simplified analogues containing a single DNA binding subunit that are more potent (IC50=2-3 pM) than CBI-TMI, duocarmycin SA, or CC-1065. The increases in cytotoxicity correlate well with accompanying increases in the rate and efficiency of DNA alkylation. This effect is more pronounced with the CBI versus DSA or CPI based analogues. Moreover, this effect is largely insensitive to the electronic character of the C5 substituent but is sensitive to the size, rigid length, and shape (sp, sp2, sp3 hybridization) of this substituent consistent with expectation that the impact is due simply to its presence.
- -
-
-
- CYSTEINE PROTEASE INHIBITORS
-
A compound of the formula (II) wherein one of R1 and R2 is halo and the other is H or halo; R3 is C1-C4 straight or branched chain, optionally fluorinated, alkyl; R4 is H; or R3 together with R4 and the adjoining backbone carbon defines: a spiro-C5-C7 cycloalkyl, optionally substituted with 1 to 3 substituents selected from halo, hydroxyl, C1-C4 alkyl or C1-C4 haloalkyl; or optionally bridged with a methylene group; or a C4-C6 saturated heterocycle having a hetero atom selected from O, NRa, S, S(=O)2 ; where Ra is H, C1-C4 alkyl or CH3C(=O); R5 is independently selected from H or methyl; E is -C(=O)-, -S(=O)m-, -NR5S(=O)m-, -NR5C(=O)-, -OC(=O)-, R6 is a stable, optionally substituted, monocyclic or bicyclic, carbocycle or hetorocycle; m is independently 0,1 or 2; are inhibitors of cathepsin K and useful in the treatment or prophylaxis of osteoporosis.
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Page/Page column 83-84
(2010/02/12)
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- USE OF SUBSTITUTED 2,5-DIAMIDOINDOLES FOR THE TREATMENT OF UROLOGICAL DISEASES
-
The present invention relates to the use of 2,5-diamidoindole derivatives for the preparation of medicaments for treating urological disorders in humans and/or animals.RCK 41-Foreign Countries
- -
-
-
- Novel aromatic compounds possessing antifungal or antibacterial activity
-
The present invention provides novel compounds possessing antibacterial, antifungal, antiviral, anticancer, and/or antiparasitic activities. Pharmaceutical compositions containing these compounds, methods of making and methods for using these compounds ar
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Page/Page column 33; 48
(2010/02/06)
-
- CC-1065 analog synthesis
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Improved synthesis of seco(?)CBI (5-hydroxy-3-amino-1-[S]-(chloromethyl)-1,2 -dihydro-3H-benz(e)indole): and improved syntheses therefrom of a wide variety of CC-1065 analogs that comprise a cyclopropabenzidole (CBI) alkylating moiety, and which are collectively DC1and its derivatives, for the synthesis of cell-targeted therapeutic agents.
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- Benzoxazepinones and their use as squalene synthase inhibitors
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There is disclosed a compound represented by the formula [I]: wherein R1 is optionally substituted 1-carboxyethyl group, optionally substituted alkyl-sulfonyl group, optionally substituted (carboxy-cycloalkyl)-alkyl group, -X1-X2-Ar-X3-X4-COOH (wherein X1 and X4 are a bond or alkylene group, X2 and X3 are a bond, -O-, -S-, Ar is divalent aromatic group etc.), R2 is alkyl group optionally substituted with alkanoyloxy group and/or hydroxy group, R3 is alkyl group, and W is halogen atom, etc., or a salt thereof. The compound has the cholesterol lowering activity and the triglyceride lowering activity and is useful for preventing and/or treating hyperlipidemia.
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- Synthesis and preliminary cytotoxicity study of glucuronide derivatives of CC-1065 analogues
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Glucuronide derivatives of CBI-bearing CC-1065 analogues have been synthesized, and their cytotoxicities tested against U937 leukemia cells. The new compounds show potent antitumor activity in vitro. Compounds 1 and 2, and their corresponding glucuronides
- Wang, Yuqiang,Yuan, Huiling,Wright, Susan C.,Wang, Hong,Larrick, James W.
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p. 1569 - 1575
(2007/10/03)
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- Vanilloid receptor ligands and their use in treatments
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Compounds having the general structure and compositions containing them, for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders.
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- Bicyclic oxazolidinones as antibacterial agents
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The present invention provides compounds of formula I useful as antimicrobial agents wherein W, X, Y, R1, R2 and n are as defined in thereof.
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- Synthesis and preliminary biological evaluations of CC-1065 analogues: Effects of different linkers and terminal amides on biological activity
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CC-1065 analogues possessing a biologically active CBI functional group and amide-substituted indole and benzofuran were synthesized. The IC50 values of compounds 26, bearing two indoles, and 25, bearing only one indole, are 0.4 and 3 nM, respectively, against U937 leukemia cells in vitro. The IC50 values of compounds 28, bearing a butyramino group, and 27, bearing an acetamino group, are 0.008 and 0.4 nM, respectively, against U937 leukemia cells in vitro. Compound 29, bearing a double-bond linker, is about 4-fold more potent than 25, bearing no double-bond linker. Compound 26 is highly potent against all cell lines tested in the NCI in vitro screening with IC50 values in the 0.1-5 nM range for most cell lines. Compounds 26 and 30 are highly active against L1210 leukemia in mice. Compound 26 is also active against B16BL6 melanoma in mice. Most importantly, 26 and 30 are not myelosuppressive at therapeutically effective doses. The mechanism of tumor cell death is through induction of apoptosis, and is accompanied by DNA fragmentation.
- Wang, Yuqiang,Yuan, Huiling,Ye, Wenqing,Wright, Susan C.,Wang, Hong,Larrick, James W.
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p. 1541 - 1549
(2007/10/03)
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- Alkyl substituted piperadinyl and piperazinyl anti-AIDS compounds
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Anti-AIDS compounds of formula (I) STR1 wherein R1, R2, R3, R4, R5, R6, and R7 are as defined in the specification and R8 is alkyl of substituted alkyl.
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- Total Synthesis of U-71,184, A Potent New Antitumor Agent Modeled on CC-1065
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The synthesis of U-71,184 (2), a highly potent analog of the novel antitumor antibiotic CC-1065, is described, the penultimate step of which involves the unmasking of a p-hydroxy phenethyl mesylate, which undergoes facile intramolecular elimination to aff
- Warpehoski, M.A.
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p. 4103 - 4106
(2007/10/02)
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