- Synthesis and biological evaluation of some new tricyclic pyrrolo[3,2-e]tetrazolo[1,5-c]pyrimidine derivatives as potential antitubercular agents
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A series of new tricyclic pyrrolo[3,2-e]tetrazolo[1,5-c]pyrimidines 8a–l were synthesized and characterized by IR, NMR (1H and 13C), and mass spectral analysis. The newly synthesized compounds 8a–l were inspected for their in vitro antitubercular activity against Mycobacterium tuberculosis (MTB) H37Ra using an established XTT reduction menadione assay (XRMA). The title compounds exhibited minimum inhibitory concentrations (MIC90) ranging from 0.09 to >30 μg/mL. Five compounds (8c, 8i–l) were further confirmed for their dose-dependent effect against MTB. These compounds were evaluated in the THP-1 infection model, where 8i (MIC90 = 0.35 μg/mL), 8j (MIC90 = 1.17 μg/mL), 8k (MIC90 = 2.38 μg/mL), and 8l (MIC90 = 1.17 μg/mL) demonstrated significant antitubercular activity. All the ex vivo active compounds showed insignificant cytotoxicity against the human cancer cell lines, HeLa, MCF-7, and THP-1. Inactivity of all these compounds against Gram positive and Gram negative bacteria indicates their specificity. Molecular docking studies in the active site of the sterol 14alpha-demethylase (CYP51) enzyme revealed a similar binding mode to the native ligand in the crystal structure, thereby helping to understand the ligand–protein interactions and to establish a structural basis for inhibition of MTB. The results suggest novel pharmacophores as selective and specific inhibitors against MTB that can be explored further to synthesize lead compounds against tuberculosis. In summary, the results clearly indicate the identification of some novel, selective, and specific inhibitors against MTB that can be explored further for potential antitubercular drugs.
- Patil, Yogesh,Shingare, Ramesh,Choudhari, Amit,Borkute, Rachana,Sarkar, Dhiman,Madje, Balaji R.
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- Production process 4 -chloropyrrolo [2, 3 - d] pyrimidine
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The production process of 4 - chloropyrrolo [2, 3 - d] pyrimidine comprises the following steps: S1, adding the compound I and the compound II to the mixed solvent I, carrying out temperature rise reaction under the catalysis of the base I to obtain the compound III. S2, sodium alkoxide I was added to alcoholic solvent II, compound IV and compound III were added to raise the temperature, and organic solvent III, organic solvent IV and compound V were added to raise the temperature to give 4 - chloropyrrolo [2, 3 - d] pyrimidine crude product. Among them, compound I is. . Compound II was obtained. . Compound III was obtained. . The compound IV is formamidine. Compound V was POCl. 3 To the method, bromoacetaldehyde dimethyl acetal and cyanoethyl acetate are subjected to reflux reaction, and 2 - cyano -4, 4 - methoxybutyric acid ethyl ester and formamidine acetate are subjected to one-pot chlorofluorination reaction, so that the reaction period is greatly shortened.
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Paragraph 0037-0038; 0040-0041; 0043; 0046-0049; 0051-0052
(2021/10/27)
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- Production system of medical intermediate 4-chloropyrrolopyrimidine
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The invention discloses a production system of medical intermediate 4-chloropyrrolopyrimidine. The production system is used for a novel production process of 4-chloropyrrolopyrimidine by taking pyrrolo[2,3-d]pyrimidin-4-ol as a reaction substrate, and comprises a high-temperature and high-pressure stirring reaction kettle for preparing 4-chloropyrrolopyrimidine by taking pyrrolo[2,3-d]pyrimidin-4-ol as a substrate; the top of the high-temperature and high-pressure stirring reaction kettle is connected with an alkali liquor pool for absorbing tail gas through a pipeline with a valve; the bottom of the high-temperature and high-pressure stirring reaction kettle is connected with a distillation tower used for evaporating a solvent through a pipeline; the distillation tower is connected witha condenser used for condensing solvent steam and a washing kettle used for washing an obtained product; the condenser is connected with a solvent recovery tank used for recovering the solvent; and the washing kettle is connected with a suction filtration barrel used for separating a solid product. Because a large amount of POCl3 does not need to be used in a new production method, the quenching process is safe, the whole set of device is closed, little toxic gas is discharged, and the purpose of green production can be achieved.
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Paragraph 0019; 0021-0025; 0029-0040
(2020/03/06)
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- Synthetic method of medical intermediate 4-chloropyrrolopyrimidine
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The invention discloses a synthetic method of a medical intermediate, i.e., 4-chloropyrrolopyrimidine. The synthetic method comprises the following steps: with 4-hydroxypyrrolo[2, 3-d]pyrimidine as areaction substrate and a mixed solution of NMP/methylbenzene as a solvent; adding 2.0 to 4.0 equivalents of 1,2,3-trichloropropane into a reaction kettle, carrying out a refluxing and stirring reaction for 4-5 h at 100-120 DEG C in a chlorine environment, carrying out vucummizing at 160-180 DEG C to evaporate excessive solvent so as to obtain an oily substance, starting stirring, adding a sodium hydroxide solution with a concentration of 0.5-1mol/L into the oily substance, and performing filtering and drying to obtain the 4-chloropyrrolopyrimidine product. POCl3 is replaced by using the novelmethod, so the problems of quenching danger and low working efficiency of conventional synthesis methods are solved.
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Paragraph 0020; 0027-0028; 0030-0033; 0035
(2020/02/14)
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- Method for preparing 4-chloro-7H-pyrrolo[2,3-d]pyrimidine by adopting non-phosphorus chlorination reagent
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The invention discloses a method for preparing 4-chloro-7H-pyrrolo[2,3-d]pyrimidine from a non-phosphorus chlorination reagent, which is technically characterized by comprising the following steps: 1)preparing a Vilsmeier reagent from a non-phosphorus reagent and N,N-dimethylformamide (DMF) in an aprotic solvent; and 2) adding 4-hydroxy-7H-pyrrolo[2,3-d]pyrimidine into the prepared Vilsmeier reagent, and carrying out a chlorination reaction to generate the 4-chloro-7H-pyrrolo[2,3-d]pyrimidine. The objective of the invention is to provide the method for preparing the 4-chloro-7H-pyrrolo[2,3-d]pyrimidine by using the non-phosphorus chlorination reagent. A large amount of phosphorus-containing waste liquid in the production process can be avoided.
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Paragraph 0062-0071
(2020/08/25)
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- Preparation method for catalyzing pyrimidine cyclic hydroxyl chlorination by tetraethylammonium chloride
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The invention discloses a preparation method for catalyzing pyrimidine cyclic hydroxyl chlorination by tetraethylammonium chloride, which comprises the following steps: (1) adding phosphorus oxychloride into a container, adding tetraethylammonium chloride as a catalyst, adding a pyrimidine cyclic hydroxyl compound, and heating to react; (2) preparing an alkali liquor, cooling to 0 DEG C, and slowly dropwise adding an obtained reaction liquid into the alkali liquor for quenching to obtain a target product. The method has the advantages that the provided pyrimidine cyclic hydroxyl chlorination catalysis method is small in environmental pollution, the obtained product is light in color, the catalysis efficiency is high, and the phosphorus oxychloride recovery pressure is small.
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Paragraph 0020-0022
(2020/04/17)
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- Preparation method of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine
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The invention discloses a preparation method of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine, wherein the preparation method comprises the steps: carrying out alpha-alkylation reaction on ethyl cyanoacetate and 2-chloromethyl-1,3-dioxolane under the actions of a catalyst and alkali to generate 2-cyano-3-(1,3-dioxolyl)ethyl propionate; carrying out a ring closing reaction on 2-cyano-3-(1,3-dioxolyl)ethyl propionate and formamidine acetate under the action of alkali, and then carrying out hydrolysis ring closing by virtue of hydrochloric acid, so as to obtain 4-hydroxy-7H-pyrrolo[2,3-d]pyrimidine; carrying out a reaction of 4-hydroxy-7H-pyrrolo[2,3-d]pyrimidine under the action of a chlorination reagent, and generating 4-chloro-7H-pyrrolo[2,3-d]pyrimidine. The raw materials adopted in the method arecheap and easy to obtain, and the synthesis method is simple to operate, mild in reaction condition, low in equipment requirement and suitable for industrial large-scale production.
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Paragraph 0052-0054; 0059-0062; 0063-0064; 0069-0072; 0073-
(2020/07/15)
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- Method for synthesizing 4 -chloropyrropyrimidine compound (by machine translation)
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The invention relates to a synthesis method of 4 -lopyrrolopyrimidine compound, which comprises the following steps: mixing 4 -hydroxypyrrolopyrimidine, phosphorus oxychloride and organic base in a temperature range &at;timetimewise and removing excess ethanol to obtain 3 - 7-amino-4 -iodopyrrolopyrimidine; thirdly, dissolving the product 4 -amino-4 -methyl pyrrolopyrimidine in DMF at room temperature and then drying and concentrating 4 -aminopyrrolopyridine. 4 -aminopyrimidine is dissolved in dichloromethane and then subjected to a heat preservation reaction to get -5 -aminopyrrolopyrimidine; and the mixture is dried to remove the solid insoluble matter and is dried and concentrated to yield 12 hours-aminopyrroyrimidine after the heat preservation reaction is carried out; and the solvent is evaporated to remove the solid insoluble matter and is dried and concentrated to remove the solid insoluble matter 4 -5 -7. (by machine translation)
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Paragraph 0025; 0030
(2020/08/09)
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- Preparation method of 4-chlorin-7H-pyrrolo[2,3-d]pyrimidine
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The invention provides a preparation method of 4-chlorin-7H-pyrrolo[2,3-d]pyrimidine. The preparation method comprises the following steps that in a solvent A, under the action of a catalyst, a compound of a formula II and a compound of a formula III of a methylene reagent are subjected to condensation reaction to obtain a compound of a formula IV; in a solvent B, under the action of alkali, the compound of the formula IV and a formamidine salt are subjected to addition condensation cyclization reaction, elimination reaction to obtain the 4-chlorin-7H-pyrrolo[2,3-d]pyrimidine (I). The preparation method of the 4-chlorin-7H-pyrrolo[2,3-d]pyrimidine is cheap and easy in raw material obtaining, simple in preparation method, easy to operate, small in the amount of waste water acid, safe and environmentally friendly and low in cost; and meanwhile, the preparation method is high in yield and high in selectivity, and less in side reactions.
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Paragraph 0063-0066
(2019/11/13)
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- Method for preparing 4-chloro-7H-pyrrolo[2,3-d] pyrimidine
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The invention provides a method for preparing 4-chloro-7H-pyrrolo[2,3-d] pyrimidine. The method comprises the following steps: (1) enabling a compound of a formula (I) shown in the specification to react with ammonium hydroxide in a dichloromethane solvent so as to be converted into a compound of a formula (II) shown in the specification; (2) enabling the compound of the formula (II) to react under catalysis of sodium periodate and a transition metal ruthenium so as to obtain a compound of formula (III) shown in the specification; and (3) under an acid condition, performing a ring-closure reaction on the compound of the formula (III) self so as to generate a target product, namely the 4-chloro-7H-pyrrolo[2,3-d] pyrimidine. Initial raw materials for preparing the 4-chloro-7H-pyrrolo[2,3-d]pyrimidine by using the method are easy to obtain, waste liquids are easy to treat in the reaction process, reaction conditions at different steps are gentle, purification is easy to implement, the operation is simple and feasible, and the yield is high.
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Paragraph 0016; 0020-0021
(2019/10/29)
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- PROCESSES AND INTERMEDIATES FOR MAKING A JAK INHIBITOR
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This invention relates to processes and intermediates for making {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, useful in the treatment of diseases related to the activity of Janus kinases (JAK) including inflammatory disorders, autoimmune disorders, cancer, and other diseases.
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Paragraph 0125; 0129
(2019/08/22)
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- Synthetic method of 4-chloropyrrolopyrimidine
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The invention relates to a synthetic method of 4-chloropyrrolopyrimidine. The synthetic method takes ethyl cyanoacetate, bromoacetaldehyde diethyl acetal, thiourea, sodium ethoxide and hydrogen peroxide as raw materials and takes DMF, ethanol, water and phosphorous oxychloride as solvents to obtain the target product 4-chloropyrrolopyrimidine through four steps of reactions. The method improves amethod of removing a mercapto group in a third step. The mercapto group is first oxidized to sulfinic acid by using the hydrogen peroxide and then is removed under acidic conditions. The method is mild in reaction conditions, safe in operation and high in yield, is environmentally friendly, and is suitable for industrial production.
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- METHOD OF MANUFACTURING 4-CHLORO-7H-PYRROLO[2,3-d]PYRIMIDINE
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The present invention discloses a method of manufacturing 4-chloro-7H-pyrrolo[2,3-d]pyrimidine comprising the steps: a) Preparing ethyl 2-cyano-4,4-dimethoxybutanoate by coupling ethyl 2- cyanoacetate and 2-bromo-1,1-dimethoxyethane; b) Preparing 6-amino-5-(2,2- dimethoxyethyl)pyrimidin-4-ol by adding formamidine to ethyl 2-cyano-4,4-dimethoxybutanoate; c) Converting 6-amino-5-(2,2-dimethoxyethyl)pyrimidin-4-ol to 7H-pyrrolo[2,3-d]pyrimidin-4-ol; and d) Converting the 7H-pyrrolo[2,3-d]pyrimidin-4-ol to 4-chloro-7H-pyrrolo[2,3-d]pyrimidine. The method offers increased yield, less by-products and a decrease in waste compared to methods known as being state of the art.
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- An improved synthesis of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine
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[Figure not available: see fulltext.] An improved seven-step synthesis of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine from dimethyl malonate with 31% overall yield is described. The procedure is operationally simple and practical for the synthesis of the 4-chloro-7H-pyrrolo[2,3-d]pyrimidine building block.
- Zhang, Yu-Liu,Xu, Cheng-Tao,Liu, Ting,Zhu, Yong,Luo, Yu
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p. 638 - 642
(2018/08/17)
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- 4-chloro-7H-pyrrolo[2,3-d]pyrimidine synthetic method
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The invention discloses a 4-chloro-7H-pyrrolo[2,3-d]pyrimidine synthetic method. A compound is an important intermediate for synthesizing ruxolitinib and tofacitinib as a JAK inhibitor for treating rheumatoid arthritis. The 4-chloro-7H-pyrrolo[2,3-d]pyrimidine synthetic method comprises the following steps of by taking a compound I (4,6-dichloro-5-allyl pyrimidine) as a starting material, performing oxidation reaction on the compound I and ozone to produce a compound II; then performing nucleophilic substitution reaction on the compound II and triethyl orthoformate to produce a compound III; then performing nucleophilic substitution reaction on the compound III and ammonia gas to produce a compound IV; and finally, performing ring closing on the compound IV self in an acid environment to produce a compound V, i.e., 4-chloro-7H-pyrrolo[2,3-d]pyrimidine, wherein a synthetic route is shown as the following formula (described in the description). The synthetic method disclosed by the invention is cheap and available in raw materials, simple and short in synthetic route, low in cost, high in yield and easy in industrial production.
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- A 4 - chloro - 7 H - pyrrolo [2, 3 - d] pyrimidine of the preparation method (by machine translation)
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The invention discloses a 4 - chloro - 7 H - pyrrolo [2, 3 - d] pyrimidine of the preparation method, comprises the following steps: in the non-polar organic solvent, under the catalysis of organic base, so that the 4 - hydroxy - 7 H - pyrrolo [2, 3 - d] pyrimidine with double-(trichloromethyl) carbon esters in the chlorination reaction, the temperature of the reaction solution to adjust pH value 8 - 9, heat preservation mixing, filtering, washing, vacuum drying, to obtain 4 - chloro - 7 H - pyrrolo [2, 3 - d] pyrimidine. The preparation method adopts a double-(trichloromethyl) carbonate (BTC) to replace the phosphorus oxychloride, reaction finishes does not need to vacuum distillation phosphorus oxychloride, also will not produce a large amount of phosphorus-containing waste water; organic alkali as a catalyst, reducing the reaction temperature, to avoid double-molecule formation of impurities. The method has simple operation, green environmental protection and easy industrial production and the like. (by machine translation)
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Paragraph 0050 0058; 0064; 0066; 0067; 0068
(2018/05/16)
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- Synthesis and photophysical evaluation of new fluorescent 7-arylethynyl-7-deazaadenosine analogs
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Three new fluorescent 7-deaza-2′-deoxyadenosine analogs were synthesized via the Sonogashira cross-coupling reaction of 7-iodo-7-deaza-2′-deoxyadenosine with 1-ethynylpyrene, 2-ethynyl-6-methoxynaphthalene, and 9-ethynylphenanthrene. The spectral properties of these analogs were evaluated in dioxane, EtOH, and H2O to determine their potential for use as environmentally sensitive fluorescent probes. All three analogs displayed large solvatofluorochromicity in H2O, relative to their emission wavelengths in dioxane or EtOH. Moreover, all three analogs exhibited microenvironmental sensitivity of their fluorescence emission intensity, being moderate to high quantum yields in dioxane and EtOH and significantly lower in H2O. Various attempts to perform domino cross-coupling and annuation reactions on 7-deaza-7-alkynyladenine derivatives to form a new fused tricyclic adenine analog were unsuccessful.
- Matarazzo, Augusto,Brow, Justin,Hudson, Robert H.E.
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p. 1093 - 1100
(2018/11/25)
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- Synthetic method of 4-chloro-7H-pyrrolo[2,3-d] pyrimidine
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The invention discloses a synthetic method of 4-chloro-7H-pyrrolo[2,3-d] pyrimidine. The compound is an important intermediate for synthesizing rheumatoid arthritis JAK inhibitors: ruxolitinib and tofacitinib. The synthetic method comprises the following steps: by taking a compound I (4,6-dichloro-5-allyl pyrimidine) as an initial raw material, performing a nucleophilic substitution reaction with ammonia water to generate a compound II; then performing a reaction on the compound II and ozone and performing a reduction reaction to generate a compound III; and finally, performing self ring-closing reaction in an acidic environment to generate a compound IV, that is, the 4-chloro-7H-pyrrolo[2,3-d] pyrimidine. The synthetic route is as shown in the formula in the description. According to the synthetic process provided by the invention, the raw material is cheap and easily available, the synthetic route is simple, the cost is low, the yield is high, and the synthetic method is easy for industrial production.
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Paragraph 0023; 0064; 0065; 0068; 0069; 0072; 0073; 0076
(2017/08/31)
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- 6-methyl 7-position-denitrified purine nucleoside compounds and application thereof
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The invention discloses6-methyl 7-position-denitrified purine nucleoside compounds and an application thereof and belongs to the field of medicinal chemistry. The 6-methyl 7-position-denitrified purine nucleoside compounds or pharmaceutically acceptable salts of the compounds having characteristics of a structure shown as formula I are a kind of novel-structured compounds designed and synthesized according to protein structure characteristics of RNA virus polymerase, and the compounds can inhibit RNA viruses, thereby being capable of serving as potential drugs for preventing and treating infection of RNA viruses such as HCV (hepatitis c virus), influenza virus, HRV (rhinovirus), RSV, Ebola virus, DENV (Dengue virus), enterovirus and the like.
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Paragraph 0091; 0105; 0106; 0107
(2017/09/02)
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- Groove modification of siRNA duplexes to elucidate siRNA-protein interactions using 7-bromo-7-deazaadenosine and 3-bromo-3-deazaadenosine as chemical probes
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Elucidation of dynamic interactions between RNA and proteins is essential for understanding the biological processes regulated by RNA, such as RNA interference (RNAi). In this study, the logical chemical probes, comprising 7-bromo-7-deazaadenosine (Br7C7A) and 3-bromo-3-deazaadenosine (Br3C3A), to investigate small interfering RNA (siRNA)-RNAi related protein interactions, were developed. The bromo substituents of Br7C7A and Br3C3A are expected to be located in the major and the minor grooves, respectively, and to act as a steric hindrance in each groove when these chemical probes are incorporated into siRNAs. A comprehensive investigation using siRNAs containing these chemical probes revealed that (i) Br3C3A(s) at the 5′-end of the passenger strand enhanced their RNAi activity, and (ii) the direction of RISC assembly is determined by the interaction between Argonaute2, which is the main component of RISC, and siRNA in the minor groove near the 5′-end of the passenger strand. Utilization of these chemical probes enables the investigation of the dynamic interactions between RNA and proteins.
- Saito-Tarashima, Noriko,Kira, Hirotaka,Wada, Tomoya,Miki, Kazuya,Ide, Shiho,Yamazaki, Naoshi,Matsuda, Akira,Minakawa, Noriaki
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p. 11096 - 11105
(2016/12/07)
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- COMBINATION THERAPIES FOR TREATMENT OF CANCER
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Combination therapies for treatment of cancers associated with mutations in the KRAS gene are provided. Compositions comprising therapeutic agents for treatment of cancers associated with mutations in the KRAS gene are also provided.
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Page/Page column 257
(2016/04/09)
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- Preparation method of 4-chloropyrrolo[2,3-d]pyrimidine
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The invention relates to a preparation method of 4-chloropyrrolo[2,3-d]pyrimidine.The method includes the following steps of obtaining 2-cyano-3-(1,3-dioxolan)ethyl propionate after 2-bromomethyl-1,3-dioxolane and ethyl cyanoacetate which are used as the raw materials react with alkaline matter as the catalyst; conducting cyclization on obtained 2-cyano-3-(1,3-dioxolan)ethyl propionate and formamidine acetate with alkaline matter as the catalyst, and adding hydrochloric acid for hydrolysis cyclization to obtain pyrrolo[2,3-d]pyrimidin-4-ol; making obtained pyrrolo[2,3-d]pyrimidin-4-ol react with phosphorus oxychloride to obtain 4-chloropyrrolo[2,3-d]pyrimidine.The method for preparing 4-chloropyrrolo[2,3-d]pyrimidine is simple in technological process, the requirement for production conditions is low, the product is easy to purify and high in yield, and the production efficiency and product quality of 4-chloropyrrolo[2,3-d]pyrimidine are remarkably improved.
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Paragraph 0053; 0054; 0055
(2016/12/01)
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- Synthesis of responsive fluorescent nucleobases 7-(benzofuran-2-yl)-7-deazahypoxanthine and 7-(benzofuran-2-yl)-7-deazaguanine using cross-coupling reaction
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In order to develop fluorescent guanine analogs having substitutions at the 7-positions, 7-(benzofuran-2-yl)-7-deaza-hypoxanthine (1a) and 7-(benzofuran-2-yl)-7-deazaguanine (1b), were synthesized from 7-deaza-7-iodohypoxanthine and 7-deaza-7-iodo-2-N-pivaloylguanine via a Suzuki-Miyaura cross-coupling, respectively. Compound 1b showed strong fluorescence, with higher fluorescent quantum yields in less polar solvents; meanwhile, 1a showed higher activity in more polar solvents. It is expected that the guanine analogs can be incorporated into nucleosides to develop new fluorescent oligonucleotides.
- Tokugawa, Munefumi,Kaneko, Kazuhei,Saito, Masanori,Masaki, Yoshiaki,Ohkubo, Akihiro,Sekine, Mitsuo,Seio, Kohji,Kanamori, Takashi
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- INHIBITORS OF KRAS G12C
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Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I): or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein R1, R2a, R3a, R3b, R4a, R4b, G1, G2, L1, L2, m1, m2, A, B, W, X, Y, Z and E are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided.
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Page/Page column 204
(2015/04/28)
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- 4-AMINO-6-ARYL[2,3-D]PYRIMIDINES FOR THE INHIBITION OF EGFR TYROSINE KINASE
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This invention relates to certain new pyrrolo-, thieno-, and furo-[2,3- d]pyrimidine compounds, such as of general formula (I) These compounds are epidermal growth factor receptor tyrosine kinase inhibitors and therefore offer potential in the treatment of cancer.
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Page/Page column 61
(2015/01/16)
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- PROCESSES AND INTERMEDIATES FOR MAKING A JAK INHIBITOR
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This invention relates to processes and intermediates for making {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, useful in the treatment of diseases related to the activity of Janus kinases (JAK) including inflammatory disorders, autoimmune disorders, cancer, and other diseases.
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Paragraph 0171
(2014/09/29)
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- Identification of new 4-N-substituted 6-aryl-7H-pyrrolo[2,3-d]pyrimidine-4- amines as highly potent EGFR-TK inhibitors with Src-family activity
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The epidermal growth factor receptor is an important target in molecular cancer therapy. Herein, the enzymatic inhibition potential of a series of chiral and non chiral pyrrolopyrimidine based derivatives have been investigated and optimised. Overall, seven new compounds were identified having enzymatic IC 50 values comparable to or better than the commercial drug Erlotinib. High activity was also confirmed towards the epidermal growth factor receptor L858R and L861Q mutants. Based on calculated druglike properties, eight compounds were further evaluated towards a panel of 52 other kinases revealing interesting Src-family kinase and colony stimulating factor 1 receptor kinase inhibitory activity. Cell proliferation studies with the cell lines A431, C-33A, AU-565, K-562 and genetically engineered Ba/F3-EGFRL858R cells also showed several molecules to be more active than Erlotinib, and thus confirming these pyrrolopyrimidines as attractive drug candidates or lead structures.
- Kaspersen, Svein Jacob,Han, Jin,N?rsett, Kristin G.,Ryds?, Line,Kj?bli, Eli,Bugge, Steffen,Bj?rk?y, Geir,Sundby, Eirik,Hoff, B?rd Helge
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- Discovery of a 4-aryloxy-1H-pyrrolo[3,2-c]pyridine and a 1-aryloxyisoquinoline series of TRPA1 antagonists
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A series of TRPA1 antagonists is described having a 4-aryloxy-1H-pyrrolo[3,2-c]pyridine or a 1-aryloxyisoquinoline scaffold. These compounds have high ligand efficiency and favorable physical properties and may thus serve as scaffolds for further optimization.
- Hu, Yun-Jin,St.-Onge, Miguel,Laliberté, Sébastien,Vallée, Frédéric,Jin, Shujuan,Bedard, Leanne,Labrecque, Jean,Albert, Jeffrey S.
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supporting information
p. 3199 - 3203
(2015/02/19)
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- First total synthesis of a naturally occurring iodinated 5′-deoxyxylofuranosyl marine nucleoside
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4-Amino-7-(5′-deoxy-β-D-xylofuranosyl)-5-iodo-pyrrolo[2,3-d] pyrimidine 1, an unusual naturally occurring marine nucleoside isolated from an ascidan, Diplosoma sp., was synthesized from D-xylose in seven steps with 28% overall yield on 10 g scale. The key step was Vorbrueggen glycosylation of 5-iodo-pyrrolo[2,3-d]pyrimidine with 5-deoxy-1, 2-O-diacetyl-3-O-benzoyl-D- xylofuranose. Its absolute configuration was confirmed.
- Sun, Jianyun,Dou, Yanhui,Ding, Haixin,Yang, Ruchun,Sun, Qi,Xiao, Qiang
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scheme or table
p. 881 - 889
(2012/07/14)
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- Pre-steady state kinetic analysis of cyclobutyl derivatives of 2′-deoxyadenosine 5′-triphosphate as inhibitors of HIV-1 reverse transcriptase
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Pre-steady state kinetic analysis was utilized for biochemical evaluation of a series of cyclobutyl adenosine nucleotide analogs with HIV-1 RT WT. The phosphonyl-diphosphate form of the cyclobutyl nucleotide, 5, was the most efficiently incorporated of the series. Nucleotide 5 was fourfold more efficiently incorporated than the FDA approved TFV-DP by RTWT. The kinetics of incorporation for 5 using the drug resistant mutant enzyme K65R was also determined. Compound 5 was threefold more efficiently incorporated compared to TFV-DP with RTK65R. These results demonstrate cyclobutyl adenosine analogs can act as substrates for incorporation by HIV-1 RT and be a potential scaffold for HIV inhibitors.
- Kim, Jiae,Wang, Ligong,Li, Yongfeng,Becnel, Kimberlynne D.,Frey, Kathleen M.,Garforth, Scott J.,Prasad, Vinayaka R.,Schinazi, Raymond F.,Liotta, Dennis C.,Anderson, Karen S.
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supporting information; experimental part
p. 4064 - 4067
(2012/07/14)
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- Targeting conserved water molecules: Design of 4-aryl-5-cyanopyrrolo[2,3-d] pyrimidine Hsp90 inhibitors using fragment-based screening and structure-based optimization
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Inhibitors of the Hsp90 molecular chaperone are showing promise as anti-cancer agents. Here we describe a series of 4-aryl-5-cyanopyrrolo[2,3-d] pyrimidine ATP competitive Hsp90 inhibitors that were identified following structure-driven optimization of purine hits revealed by NMR based screening of a proprietary fragment library. Ligand-Hsp90 X-ray structures combined with molecular modeling led to the rational displacement of a conserved water molecule leading to enhanced affinity for Hsp90 as measured by fluorescence polarization, isothermal titration calorimetry and surface plasmon resonance assays. This displacement was achieved with a nitrile group, presenting an example of efficient gain in binding affinity with minimal increase in molecular weight. Some compounds in this chemical series inhibit the proliferation of human cancer cell lines in vitro and cause depletion of oncogenic Hsp90 client proteins and concomitant elevation of the co-chaperone Hsp70. In addition, one compound was demonstrated to be orally bioavailable in the mouse. This work demonstrates the power of structure-based design for the rapid evolution of potent Hsp90 inhibitors and the importance of considering conserved water molecules in drug design.
- Davies, Nicholas G.M.,Browne, Helen,Davis, Ben,Drysdale, Martin J.,Foloppe, Nicolas,Geoffrey, Stephanie,Gibbons, Ben,Hart, Terance,Hubbard, Roderick,Jensen, Michael Rugaard,Mansell, Howard,Massey, Andrew,Matassova, Natalia,Moore, Jonathan D.,Murray, James,Pratt, Robert,Ray, Stuart,Robertson, Alan,Roughley, Stephen D.,Schoepfer, Joseph,Scriven, Kirsten,Simmonite, Heather,Stokes, Stephen,Surgenor, Allan,Webb, Paul,Wood, Mike,Wright, Lisa,Brough, Paul
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supporting information
p. 6770 - 6789
(2013/01/15)
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- PROCESSES FOR PREPARING JAK INHIBITORS AND RELATED INTERMEDIATE COMPOUNDS
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The present invention is related to processes for preparing chiral substituted pyrazolyl pyrrolo[2,3-d]pyrimidines of Formula III, and related synthetic intermediate compounds. The chiral substituted pyrazolyl pyrrolo[2,3-d]pyrimidines are useful as inhibitors of the Janus Kinase family of protein tyrosine kinases (JAKs) for treatment of inflammatory diseases, myeloproliferative disorders, and other diseases.
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Page/Page column 101-102
(2010/08/07)
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- NOVEL CYCLOBUTYL COMPOUNDS AS KINASE INHIBITORS
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The invention relates to compounds of the formula I, to the preparation and use thereof for the preparation of a medicament for the treatment of diseases, in particular tumours and/or diseases in the formation or course of which protein kinases are involved.
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Page/Page column 33
(2010/07/04)
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- THERAPEUTIC AGENTS
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The invention provides a compound of formula (I): wherein R1, and W have any of the values defined in the application; or a salt thereof. The compounds and salts thereof have beneficial therapeutic properties (e.g. immunosuppressant properties).
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Page/Page column 61
(2010/04/03)
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- Synthesis and anti-HCV activity of a new 2′-deoxy-2′-fluoro- 2′-C-methyl nucleoside analogue
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2′-Deoxy-2′-fluoro-2′-C-methyl nucleoside analogue 4 was designed and synthesized. Initial biological studies indicated that this compound showed promising activity against HCV replication.
- Hu, Weidong,Wang, Ping'An,Song, Chuanjun,Pan, Zhenliang,Wang, Qiang,Guo, Xiaohe,Yu, Xuejun,Shen, Zhenhua,Wang, Shuyang,Chang, Junbiao
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scheme or table
p. 7297 - 7298
(2011/02/21)
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- SUBSTITUTED PIPERIDINES HAVING PROTEIN KINASE INHIBITING ACTIVITY
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The invention provides PKA and PKB kinase-inhibiting compounds of the formula (I); or salts, solvates, tautomers or N-oxides thereof, wherein E is a five membered heteroaryl ring containing 1, 2, 3 or 4 heteroatoms selected from O, N and S provided that no more than 1 heteroatom may be other than N; q and r are each is 0 or 1; provided that q+r is 1 or 2; T is N or a group CR5; J1-J2 is N=C(R6), (R7)C=N, (R8)N- C(O), (R8)2C-C(O), N=N or (R7)C=C(R6); Q3 is a bond or a saturated C1-3 hydrocarbon linker group optionally substituted by fluorine and hydroxy; G is NR2R3, CN or OH; m and n are each 0 or 1, provided that m+n is 1 or 2, and provided also that m or n are each 0 when the adjacent ring member of ring E is S or O; R1a and R1b are the same or different and each is hydrogen or a substituent R10; or R1a and R1b together with the carbon atoms or heteroatoms to which they are attached form a 5 or 6-membered aryl or heteroaryl ring, wherein the aryl or heteroaryl rings are optionally substituted by one or more substituents R10; and R2, R3, R4, R5, R7, R6, R8, and R10 are as defined in the claims.
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Page/Page column 113
(2008/12/06)
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- Xanthine oxidase-activated prodrugs of thymidine phosphorylase inhibitors
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Thymidine phosphorylase (TP) is over-expressed in various tumour types and plays an important role in tumour angiogenesis, growth, invasion and metastasis. The enzymatic activity of TP is required for the angiogenic effect of TP, therefore, inhibitors of TP are of significant interest in cancer chemotherapy. A series of xanthine oxidase (XO) activated prodrugs of known inhibitors of TP have been designed and synthesized with the ultimate intent of improving tumour selectivity and pharmacokinetic characteristics. These prodrugs were not inhibitors of TP, but were selectively oxidized by XO at C-2 and/or C-4 of the uracil ring moiety to generate the desired TP inhibitor. Molecular modelling of both the TP inhibitors and XO-activated prodrugs rationalized their binding in the active site of the human TP crystal structure.
- Reigan, Philip,Gbaj, Abdul,Stratford, Ian J.,Bryce, Richard A.,Freeman, Sally
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p. 1248 - 1260
(2008/09/21)
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- PYRROLOPYRIMIDINE DERIVATIVES USED AS HSP90 INHIBITORS
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Compounds of formula (I) have HSP90 inhibitory activity and are therefore useful in the treatment of, inter alia, cancer: Formula (I) wherein Ri is hydrogen, fluoro, chloro, bromo, or a radical of formula -X-Alk1-(Z)m-(Alk2)n-Q wherein X is -O-, -S- -S(O)-, -SO2-, or -NH-, Z is -O-, -S-, -(C=O)-, -(C=S)-, -S(O)-, -SO2-, -NRA-, or, in either orientation -C(=O)O-, -C(=O)NRA- , -C(=S)NRA-, -SO2NRA-, -NRAC(=O)-, or -NRASO2- wherein RA is hydrogen or C1-C6 alkyl AIk1 and AIk2 are optionally substituted divalent C1-C3 alkylene or C2-C3 alkenylene radicals, m, n and p are independently 0 or 1 , and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical; R2 is a radical of formula -(Ar1)p-(Alk1)q-(Z)r-(Alk2)s-Q wherein Ar1 is an optionally substituted aryl or heteroaryl radical, Alk1, Alk2, Z, and Q are as defined above, and p, q, r and s are independently 0 or 1 ; and R3 is cyano (-CN), fluoro, chloro, bromo, methyl in which in which one or more hydrogen atoms are optionally replaced by fluorine atoms, ethyl in which in which one or more hydrogen atoms are optionally replaced by fluorine atoms, cyclopropyl, -OH, -CH2OH, -C(O)NH2, -C(O)CH3, Or -NH2.
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Page/Page column 44
(2008/06/13)
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- PHARMACEUTICAL COMPOUNDS
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The invention provides a compound of the formula (I) or salts, solvates, tautomers or N-oxides thereof, wherein T is N or CR5; J1-J2 is N=C(R6), (R7)C=N, (R8)N-C(O), (R8)2C-C(O), N=N or (R7)C=C(R6); E is a monocyclic carbocyclic or heterocyclic group of 5 or 6 ring members, the heterocyclic group containing up to 3 heteroatoms selected from O, N and S; Q1 is a bond or a saturated C1-3 hydrocarbon linker group, one of the carbon atoms in the linker group being optionally be replaced by an oxygen or nitrogen atom, or an adjacent pair of carbon atoms may be replaced by CONRq or NRqCO where Rq is hydrogen or methyl, or Rq is a C1-4 alkylene chain linked to R1 or a carbon atom of Q1 to form a cyclic moiety; and wherein the carbon atoms of the linker group Q1 may optionally bear one or more substituents selected from fluorine and hydroxy; Q2 is a bond or a saturated hydrocarbon linker group containing from 1 to 3 carbon atoms, wherein one of the carbon atoms in the linker group may optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group may optionally bear one or more substituents selected from fluorine and hydroxy, provided that the hydroxy group when present is not located at a carbon atom α with respect to the G group; and provided that when E is aryl or heteroaryl, then Q2 is other than a bond; G is hydrogen, NR2R3, OH or SH provided that when E is aryl or heteroaryl and Q2 is a bond, then G is hydrogen; R1 is hydrogen or an aryl or heteroaryl group, with the proviso that when R1 is hydrogen and G is NR2R3, then Q2 is a bond; and R2, R3, R4, R6 and R8 are as defined in the claims, wherein the compound is for use in: (a) the treatment or prophylaxis of a disease or condition in which the modulation (e.g. inhibition) of ROCK kinase or protein kinase P70S6K is indicated; and/or (b) the treatment of a subject or patient population in which the modulation (e.g. inhibition) of ROCK kinase or protein kinase P70S6K is indicated.
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Page/Page column 117
(2008/06/13)
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- PHARMACEUTICAL COMPOUNDS
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The invention provides a compound having the formula (I): or salts, solvates, tautomers or N-oxides thereof, wherein T is N or CR5; J1-J2 is N=C(R6), (R7)C=N, (R8)N-C(O), (R8)2C-C(O), N=N or (R7)C=C(R6); A is an optionally substituted saturated C1-7 hydrocarbon linker group having a maximum chain length of 5 atoms extending between R1 and NR2R3 and a maximum chain length of 4 atoms extending between E and NR2R3, one of the carbon atoms in the linker group being optionally replaced by oxygen or nitrogen; E is a monocyclic or bicyclic carbocyclic or heterocyclic group or an acyclic group X-G wherein X is CH2, O, S or NH and G is a C1-4 alkylene chain wherein one of the carbon atoms is optionally replaced by O, S or NH; R1 is hydrogen or an aryl or heteroaryl group; R2 and R3 are each hydrogen, optionally substituted C1-4 hydrocarbyl or optionally substituted C1-4 acyl; or NR2R3 forms an imidazole group or a saturated monocyclic heterocyclic group having 4-7 ring members; or NR2R3 and A together form a saturated monocyclic heterocyclic group having 4-7 ring members which is optionally substituted by C1-4 alkyl; or NR2R3 and the adjacent carbon atom of linker group A together form a cyano group; or R1, A and NR2R3 together form a cyano group; and R4, R5, R6, R7 and R8 are each independently selected from hydrogen and various substituents as defined in the claims, wherein the compound is for use in: (a) the treatment or prophylaxis of a disease or condition in which the modulation (e.g. inhibition) of ROCK kinase or protein kinase p70S6K is indicated; and/or (b) the treatment of a subject or patient population in which the modulation (e.g. inhibition) of ROCK kinase or protein kinase p70S6K is indicated.
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Page/Page column 122
(2008/06/13)
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- ORTHO- CONDENSED PYRIDINE AND PYRIMIDINE DERIVATIVES (E. G. PURINES) AS PROTEIN KINASES INHIBITORS
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The invention provides a compound for use in the prophylaxis or treatment of a disease state or condition mediated by protein kinase B, the compound having the formula (I): or salts, solvates, tautomers or N-oxides thereof, wherein T is N or CR5; J1-J2 is N=C(R6), (R7)C=N, (R8)N-C(O), (R8)2C-C(O), N=N or (R7)C=C(R6); A is an optionally substituted saturated C1-7 hydrocarbon linker group having a maximum chain length of 5 atoms extending between R1 and NR2R3 and a maximum chain length of 4 atoms extending between E and NR2R3, one of the carbon atoms in the linker group being optionally replaced by oxygen or nitrogen; E is a monocyclic or bicyclic carbocyclic or heterocyclic group or an acyclic group X-G wherein X is CH2, O, S or NH and G is a C1-4 alkylene chain wherein one of the carbon atoms is optionally replaced by O, S or NH; R1 is hydrogen or an aryl or heteroaryl group; R2 and R3 are each hydrogen, optionally substituted C1-4 hydrocarbyl or optionally substituted C1-4 acyl; or NR2R3 forms an imidazole group or a saturated monocyclic heterocyclic group having 4-7 ring members; or NR2R3 and A together form a saturated monocyclic heterocyclic group having 4-7 ring members which is optionally substituted by C1-4alkyl; or NR2R3 and the adjacent carbon atom of linker group A together form a cyano group; or R1, A and NR2R3 together form a cyano group; and R4, R5, R6, R7 and R8 are each independently selected from hydrogen and various substituents as defined in the claims.
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Page/Page column 123-124
(2008/06/13)
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- Synthesis and enzymatic evaluation of xanthine oxidase-activated prodrugs based on inhibitors of thymidine phosphorylase
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A series of xanthine oxidase-activated prodrugs of known inhibitors of thymidine phosphorylase are described. These prodrugs were oxidised by xanthine oxidase at C-2 and/or C-4 of the uracil ring to generate the desired TP inhibitor. The scheme shows the prodrug of TPI. A series of xanthine oxidase-activated prodrugs of known inhibitors of thymidine phosphorylase has been designed and synthesised to introduce tumour selectivity. These prodrugs were oxidised by xanthine oxidase at C-2 and/or C-4 of the uracil ring to generate the desired TP inhibitor.
- Reigan, Philip,Gbaj, Abdul,Chinje, Edwin,Stratford, Ian J.,Douglas, Kenneth T.,Freeman, Sally
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p. 5247 - 5250
(2007/10/03)
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- Monocyclic-7H-pyrrolo[2,3-d]pyrimidine compounds, compositions, and methods of use
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Novel pyrrolo[2,3-d]pyrimidine compounds useful as inhibitors of the enzyme protein tyrosine kinases such as Janus Kinase 3 as well as immunosuppressive agents for organ transplants, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, Leukemia and other autoimmune diseases are described.
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Page/Page column 17
(2008/06/13)
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- 4-substituted 7-aza-indolin-2-ones and their use as protein kinase inhibitors
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This invention relates to 4-substituted 7-aza-indolin-2-ones and their use as protein kinase inhibitors. Particular 4-substituted 7-aza-indolin-2-ones disclosed herein are of Formula 1 and pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof, wherein R1, R2, R3, R4, X, Y, and Z are defined herein. The invention fuirther relates to pharmaceutical compositions and dosage forms comprising compounds of Formula 1 and to methods of their use for the treatment and/or prevention of diseases such as, but not limited to, cancer.
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- Rational design of 4,5-disubstituted-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-ones as a novel class of inhibitors of epidermal growth factor receptor (EGF-R) and Her2(p185(erbB)) tyrosine kinases.
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A novel class of 4,5-disubstituted-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-ones has been discovered as potent and selective inhibitors of the EGF-R tyrosine kinase family. These compounds selectively inhibit EGF-R kinase activity at low nanomolar concentration and tyrosine autophosphorylation in cells expressing EGF-R or Her2 (p185(erbB)). Structure-activity relationships (SARs) for this class of compounds are presented.
- Sun,Cui, Jean,Liang, Congxin,Zhou, Yong,Nematalla, Asaad,Wang, Xueyan,Chen, Hui,Tang, Cho,Wei, James
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p. 2153 - 2157
(2007/10/03)
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- β-Homoalanyl-PNA: A Special Case of β-Peptides with β-Sheet-Like Backbone Conformation; Organization in Higher Ordered Structures
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Although β-homoalanyl peptide nucleic acid oligomers possess a β-peptide backbone, they contain nucleobases in their side chains and are thus an interesting special case of β-peptides. These nucleobases are mainly responsible for the formation of secondary structures through base pairing and stacking. We have investigated the pairing properties of β-homoalanyl-PNA oligomers using adenine and 7-carbaadenine. Simple model studies indicate the existence of Watson-Crick and Hoogsteen pairing planes as an intrinsic structural feature of purinyl β-PNA. As a consequence, the adeninyl-β-PNA hexamer and pentamer form higher ordered structures and the 7-carbaadenine-β-PNA hexamer, which lacks a Hoogsteen pairing site, pairs as a double strand. The synthesis of adeninyl and carbaadeninyl β-nucleoamino acids and their oligomerization is described. Pairing mode and strand orientation were investigated through experiment and simple model studies. In the context of β-peptides the β-PNA oligomers for the most part tend to exist as double strands and prefer the extended β-sheet-like backbone conformation which provides an interesting structure motif in addition to the 31-helix observed for β-peptides.
- Diederichsen, Ulf,Schmitt, Harald W.
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p. 827 - 835
(2007/10/03)
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- Acyclic Nucleoside Analogs. II. Acyclic Analogs of Guanosine, 7-Deazaguanosine, and 7-Deazaadenosine with a cis-Hydroxypentene Fragment
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Condensations of 5-acetoxy-1-bromo-2-pentene with 2-amino-6-chloropurine, 4-chloropyrrolopyrimidine, and 2-amino-4-chloropyrrolopyrimidine sodium salts gave acyclic analogs of guanosine, 7-deazaguanosine, and 7-deazaadenosine.The subsequent deprotection with 0.1 N NaOH or methanol saturated with ammonium yielded the desired nucleoside analogs containing a cis-hydroxypentene fragment and either natural or modified heterocycle. - Keywords: nucleosides; acyclic analogs; pyrrolopyrimidines.
- Tsytovich, A. V.,Shamshin, D. V.,Burkovskii, V. B.,Shvets, V. I.
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p. 756 - 761
(2007/10/03)
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