- 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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- 2,4-Pyrimidinediamine Compounds and Their Uses
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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.
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Paragraph 0485; 0495
(2015/11/10)
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- PROCESS FOR PREPARING VILAZODONE HYDROCHLORIDE
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The present invention relates, in a first aspect, to a process preparing vilazodone hydrochloride that comprises the reaction of 3-(4-chloro-1-hydroxy-butyl)-1H-indol-5-carbonitrile with 5-piperazin-1-yl-benzofuran-2-carboxylate methyl hydrochloride with the formation of a 1,4-piperazine, with subsequent dehydration, hydrogenation and treatment with ammonia, to obtain vilazodone in free base form that is then converted into the hydrochloride thereof.
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Paragraph 0071; 0072
(2013/09/12)
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- Process for preparing vilazodone hydrochloride
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The present invention relates, in a first aspect, to a process preparing vilazodone hydrochloride that comprises the reaction of 3-(4-chloro-1-hydroxy-butyl)-1H-indol-5-carbonitrile with 5-piperazin-1-yl-benzofuran-2-carboxylate methyl hydrochloride with the formation of a 1,4 -piperazine, with subsequent dehydration, hydrogenation and treatment with ammonia, to obtain vilazodone in free base form that is then converted into the hydrochloride thereof.
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Paragraph 0049; 0050; 0051
(2013/10/22)
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- PHENYL CARBOXAMIDE AND SULFONAMIDE DERIVATIVES FOR USE AS 11-BETA-HYDROXYSTEROID DEHYDROGENASE
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There is provided a compound having Formula (I) R1-Z-R2 Formula (I) wherein R1 is an optionally substituted phenyl ring; R2 is or comprises an optionally substituted aromatic ring; and Z is -X-Y-L- or -Y-X-L- wherein either X is selected from -S(=O)(=O)- and -C(=O)-, and Y is -NR3-; or X is selected from -S(=O)(=O)- and -S-, and Y is -C(R4)(R5)-; L is an optional linker; and R3, R4 and R5 are each independently selected from H and hydrocarbyl; and wherein when R2 comprises the following structural moiety, Formula (II) wherein Q is an atom selected from the group consisting of S, O, N and C; the compound is selected from compounds of the formulae R1-C(=O)-NR3-L-R2; R1-S(=O)(=O)-C(R4)(R5)-L-R2; R1-S-C(R4)(R5)-L-R2; R1-NR3-S(=O)(=O)-L-R2; R1-NR3-C(=O)-L-R2; R1-C(R4)(R5)-S(=O)(=O)-L-R2; and R1-C(R4)(R5)-S-L-R2. These compounds are useful as 11β-hydroxysteriod dehydrogenase inhibitors in the treatment of i.a. diabetes.
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Page/Page column 60
(2010/02/11)
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- INHIBITORS OF HISTONE DEACETYLASE
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The invention relates to a series of compounds useful for inhibiting histone deacetylase (HDAC) enzymatic activity. The invention also provides a method for inhibiting histone descetylase in a cell using said compounds as well as a method for treating cell proliferative diseases and conditions using said HDAC inhibitors. Further, the invention provides pharmaceutical compositions comprising the HDAC inhibiting compounds and a pharmaceutically acceptable carrier.
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Page/Page column 97
(2010/02/14)
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- Triamide-substituted heterobicyclic compounds
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The invention relates to triamide MTP/ApoB inhibitors of the formula 1 wherein R1-R8 are as defined in the specification, as well as pharmaceutical compositions and uses thereof, and processes for preparing the compounds. The compounds of the invention are useful for the treatment of obesity and lipid disorders.
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- Total synthesis of distamycin A and 2640 analogues: A solution-phase combinatorial approach to the discovery of new, bioactive DNA binding agents and development of a rapid, high-throughput screen for determining relative DNA binding affinity or DNA binding sequence selectivity
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The development of a solution-phase synthesis of distamycin A and its extension to the preparation of 2640 analogues are described. Thus, solution-phase synthesis techniques with reaction workup and purification employing acid/base liquid - liquid extractions were used in the multistep preparation of distamycin A (8 steps, 40% overall yield) and a prototypical library of 2640 analogues providing intermediates and final products that are ≥95% pure on conventional reaction scales. The complementary development of a simple, rapid, and high-throughput screen for DNA binding affinity based on the loss of fluorescence derived from displacement of prebound ethidium bromide is disclosed which is applicable for assessing relative or absolute binding affinity to DNA homopolymers or specific sequences (hairpin oligonucleotides). Using hairpin oligonucleotides, this method permits the screening of a library of compounds against a single predefined sequence to identify high affinity binders, or the screening of a single compound against a full library of individual hairpin oligionucleotides to define its sequence selectivity. The combination permits the establishment of the complete DNA binding profile of each member of a library of compounds. Screening the prototypical library provided compounds that are 1000 times more potent than distamycin A in cytotoxic assays (67, IC50 = 29 nM, L1210), that bind to poly[dA]-poly[dT] with comparable affinity, and that exhibit an altered DNA binding sequence selectivity. Several candidates were identified which bound the five-base-pair AT-rich site of the PSA-ARE-3 sequence, and one (128, K = 3.2 x 106 M-1) maintained the high affinity binding (K = 4.5 x 106 M-1) to the ARE-consensus sequence containing a GC base-pair interrupted five-base-pair AT-rich site suitable for inhibition of gene transcription initiated by hormone insensitive androgen receptor dimerization and DNA binding characteristic of therapeutic resistant prostate cancer.
- Boger, Dale L.,Fink, Brian E.,Hedrick, Michael P.
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p. 6382 - 6394
(2007/10/03)
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