- Method for preparing high-purity 4,4'-oxybisbenzensulfonyl chloride
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The invention discloses a method for preparing high-purity 4,4'-oxybisbenzensulfonyl chloride. The method includes the following steps that (1) concentrated sulfuric acid is dropwise added into diphenyl ether at the temperature of 60 DEG C and the negative pressure, the mixture is fully reacted at the temperature of 130 DEG C to 140 DEG C after the concentrated sulfuric acid is dropwise added, the reaction is completed, and a sulfonic acid mixture is prepared; (2) an organic solvent is added into the sulfonic acid mixture at the temperature of 0 DEG C to 30 DEG C, the pH value of a system is adjusted to be 7 to 9 with alkali, solid-liquid separation is carried out, and diphenyl ether disulfonate is obtained; (3) the diphenyl ether disulfonate is added into acid, the mixture is fully reacted, water is removed after reacting, and a mixed product is obtained; (4) phosphorus oxychloride is dropwise added into the mixed product at the temperature of 80 DEG C or above, the mixture is fully reacted after the temperature of 100 DEG C to 105 DEG C after the phosphorus oxychloride is dropwise added, a reaction product is obtained after reacting, the reaction product is washed, and the 4,4'-oxybisbenzensulfonyl chloride is obtained. OBSC prepared with the method is narrow in melting range, high in purity and whiteness degree and capable of allowing a downstream product foaming agent OBSH to have the advantages of being high in gas-forming amount, narrow in gas-forming temperature range and high in purity and whiteness degree.
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Paragraph 0018-0023
(2017/08/28)
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- Fragment-Based Design, Synthesis, and Biological Evaluation of 1-Substituted-indole-2-carboxylic Acids as Selective Mcl-1 Inhibitors
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Based on a known selective Mcl-1 inhibitor, 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylic acid, we applied a fragment-based approach to obtain new molecules that extended into the p1 pocket of the BH3 groove and then exhibited binding selectivity for the Mcl-1 over the Bcl-2 protein. After we deconstructed the 1H-indole-2-carboxylic acid from the parental molecule, a benzenesulfonyl was substituted at the 1-position to adopt a geometry preferred for accessing the p1 pocket according to the binding mode of the parental molecule identified by X-ray crystallography. A linear relationship between the free energy of ligand binding (ΔG) and the count of non-hydrogen heavy atoms (HAC) was maintained during the molecular growing to occupy the p1 pocket. Finally, we not only obtained compound 12 with a 7.5-fold selectivity to Mcl-1 (Ki = 0.48 μM by fluorescence polarization) over Bcl-2 (Ki = 3.6 μM), but also provided evidence that additional occupation of the p1 pocket is more favorable for Mcl-1 than for Bcl-2 binding, and contributes more to Mcl-1 inhibition than occupation of the p2 pocket. Compound 12 exhibited a selective killing ability on Mcl-1-dependent cancer cells.
- Wang, Ziqian,Xu, Wenjie,Song, Ting,Guo, Zongwei,Liu, Lu,Fan, Yudan,Wang, Anhui,Zhang, Zhichao
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- Design, synthesis and molecular modeling study of iminodiacetyl monohydroxamic acid derivatives as MMP inhibitors
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As the matrix metalloproteinases (MMPs) can be massively up-regulated in degenerative tissues and degrade the extracellular matrix, these key enzymes are promising targets for the therapy of cancer and other degenerative diseases. Here, we are presenting a series of new non-peptidic hydroxamate-based matrix metalloproteinase inhibitors, MMPIs, incorporating the iminodiacetic (IDA) hydroxamic acid scaffold, as mimics of truncated peptidic MMPIs. A series of alkylaryl and sulfonylaryl groups, on the IDA basic scaffold, was investigated with the aim of improving potency and selectivity against MMPs involved in degenerative diseases. The sulfonamide based IDA derivatives studied (compounds B1-B3) showed to be potent (nM range) against deep S1′ pocket MMPs enzymes (i.e., MMP-2).
- Amelia Santos,Marques, Sergio M.,Tuccinardi, Tiziano,Carelli, Paolo,Panelli, Laura,Rossello, Armando
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p. 7539 - 7550
(2008/02/09)
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- Synthesis and biological activity of various derivatives of a novel class of potent, selective, and orally active prostaglandin D2 receptor antagonists. 1. Bicyclo[2.2.1]heptane derivatives
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Novel prostaglandin D2 (PGD2) receptor antagonists were synthesized as a potential new class of antiallergic agents having a bicyclo[2.2.1] heptane ring system with sulfonamide groups. Some of them exhibit extremely potent antagonism of the PGD2 receptor in radioligand binding and cAMP formation assays with IC50 values below 50 nM and much less antagonism of TXA2 and PGI2 receptors. These potent PGD2 receptor antagonists, when given orally, dramatically suppress various allergic inflammatory responses such as increased vascular permeability in allergic rhinitis, conjunctivitis, and asthma models. The excellent pharmacological profiles of PGD2 receptor antagonists, originally synthesized in our laboratories, are of potentially great clinical significance. This study also provides experimental evidence suggesting that PGD2 plays an important role in the pathogenesis of allergic diseases.
- Mitsumori, Susumu,Honma, Tsunetoshi,Tsuri, Tatsuo,Hiramatsu, Yoshiharu,Okada, Toshihiko,Hashizume, Hiroshi,Inagaki, Masanao,Arimura, Akinori,Yasui, Kiyoshi,Asanuma, Fujio,Kishino, Junji,Ohtani, Mitsuaki
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p. 2436 - 2445
(2007/10/03)
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- Metalloproteinase inhibitors-compositions, uses preparation and intermediates thereof
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The invention relates to compounds of the formula 1: wherein: Z is O or S; V is a divalent radical which together with C* and N forms a ring having six ring atoms, where each of said ring atoms other than C* and N independently is unsubstituted or substituted by a suitable substituent, and at least one of said other ring atoms is a heteroatom selected from O, N and S, and the remainder are carbon atoms; and Ar is an aryl or heteroaryl group; and pharmaceutically acceptable prodrugs, salts and solvates thereof. The invention further relates to pharmaceutically acceptable prodrugs, salts and solvates of these compounds. The invention also relates to methods of inhibiting the activity of metalloproteinases by administering a compound of the formula I or a prodrug, salt of solvate thereof. The invention further relates to pharmaceutical compositions comprising an effective amount of these compounds, prodrugs, salts, and solvates. The invention still further relates to methods and intermediates useful for preparing these compounds, prodrugs, salts, and solvates.
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- Metalloproteinase inhibitors and intermediates useful for their preparation
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PCT No. PCT/US96/19328 Sec. 371 Date Jun. 29, 1998 Sec. 102(e) Date Jun. 29, 1998 PCT Filed Dec. 5, 1996 PCT Pub. No. WO97/20824 PCT Pub. Date Jun. 12, 1997The invention relates to compounds of formula (1) wherein: Z is O or S; V is a divalent radical which together with C* and N forms a ring having six ring atoms, where each of said ring atoms other than C* and N independently is unsubstituted or substituted by a suitable substituent, and at least one of said other ring atoms is a heteroatom selected from O, N and S, and the remainder is carbon atoms; and Ar is an aryl or heteroaryl group; and pharmaceutically acceptable prodrugs, salts and solvates thereof. The invention further relates to pharmaceutically acceptable prodrugs, salts and solvates of these compounds. The invention also relates to methods of inhibiting the activity of metalloproteinases by administering a compound of formula (1) or a prodrug, salt or solvate thereof. The invention further relates to pharmaceutical compositions comprising an effective amount of these compounds, prodrugs, salts, and solvates. The invention still further relates to methods and intermediates useful for preparing these compounds, prodrugs, salts, and solvates.
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- Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses
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The invention relates to compounds of the formula I STR1 in which Q is a divalent radical having four ring atoms which together with C* and N form a six-membered ring, each of these four ring atoms being unsubstituted or substituted by a suitable substituent and at least one being a heteroatom selected from O, N and S, with the remainder being carbon atoms; and Ar is an aryl or heteroaryl group. The invention further relates to pharmaceutically acceptable prodrugs and pharmaceutically acceptable salts of these compounds. The invention also relates to methods of inhibiting the activity of metalloproteinases, especially MMPs or TNF-α, by administering a compound of the formula I or a salt or prodrug thereof. The invention further relates to pharmaceutical compositions comprising an effective amount of these compounds, salts, and prodrugs.
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- SULFUR TRIOXIDE SULFONATION OF DIPHENYL ETHER, DIPHENYL SULFIDE, DIBENZODIOXIN, AND XANTHENE
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The sulfur trioxide sulfonation of diphenyl ether (1), diphenyl sulfide (2), and the related tricyclic dibenzodioxin (3) and xanthene (4) has been studied.The substrates 1 and 2 both yield initially the 4-sulfonic acid derivative (4-S) and subse
- Cerfontain, Hans,Koeberg-Telder, Ankie,Lindert, Helen C. A. Van,Bakker, Bert H.,Wit, Peter De
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p. 239 - 244
(2007/10/02)
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