- Predictable site-selective functionalization: Promoter group assistedpara-halogenation ofN-substituted(hetero)aromatics under metal-free condition
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Herein, regioselectivepara-C-H halogenation ofN-pyrimidyl (hetero)aromatics through SEAr (electrophilic aromatic substitution) type reaction is disclosed. SEAr type reaction has been utilized for the C5-bromination of indolines (para-selective) withN-bromosuccinimide under metal and additive-free conditions in good to excellent yields. The developed methodology is also applicable for iodination and challenging chlorination. The pyrimidyl group is identified as a reactivity tuner that also controls the regioselectivity. The present method is also applicable for selective halogenation of aniline, pyridine, indole, oxindole, pyrazole, tetrahydroquinoline, isoquinoline, and carbazole. DFT studies such as Fukui nucleophilicity and natural charge maps also support the observedp-selectivity. Post-functionalization of the title compound into the corresponding arylated, olefinated, and dihalogenated products is achieved in a one-pot, two-step fashion. Late-stage C-H bromination was also executed on drug/natural molecules (harmine, etoricoxib, clonidine, and chlorzoxazone) to demonstrate the applicability of the developed protocol.
- Gupta, Shiv Shankar,Manisha,Kumar, Rakesh,Dhiman, Ankit Kumar,Sharma, Upendra
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p. 9675 - 9687
(2021/12/01)
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- Efficient synthesis process of medical intermediate 5-bromoindole
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The invention discloses an efficient synthesis process of a medical intermediate 5-bromoindole, comprising the following steps of: using an indole compound as a raw material, carrying out low-pressureliquid-phase hydrogenation to destroy five-membered ring conjugation of indole to obtain an indoline compound; enabling the indoline compound to react with an acylation reagent, and protecting nitrogen, so as to obtain an N-acyl indoline compound; carrying out bromination on the N-acyl indoline compound to obtain a 5-bromo-N-acyl indoline compound; carrying out deacylation protection on the 5-bromo-N-acyl indoline compound to obtain a 5-bromoindoline compound; and carrying out oxidative dehydrogenation on the 5-bromoindoline compound by using oxygen or air under the action of a cuprous catalyst and nitric oxide to obtain the target compound 5-bromoindole. The steps involved in the process are convenient to operate, the conditions are mild, and environmental pollution is reduced; finally,the prepared product is high in yield, high in purity and low in energy consumption.
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- COMPOUND HAVING ERK KINASE INHIBITORY ACTIVITY AND USE THEREOF
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The invention relates to a compound of formula (I): wherein variables are as defined in the specification. The compound is an inhibitor of an ERK kinase, e.g. ERK1 and/or ERK2 kinase. The invention also relates to the use of the compound and a method for preparing the compound, and a pharmaceutical composition containing the compound.
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Paragraph 0309-0310
(2020/08/20)
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- The Relation Between Position and Chemical Composition of Bis-Indole Substituents Determines Their Interactions with G-Quadruplex DNA
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G-quadruplex (G4) DNA structures are linked to fundamental biological processes and human diseases, which has triggered the development of compounds that affect these DNA structures. However, more knowledge is needed about how small molecules interact with G4 DNA structures. This study describes the development of a new class of bis-indoles (3,3-diindolyl-methyl derivatives) and detailed studies of how they interact with G4 DNA using orthogonal assays, biophysical techniques, and computational studies. This revealed compounds that strongly bind and stabilize G4 DNA structures, and detailed binding interactions which for example, show that charge variance can play a key role in G4 DNA binding. Furthermore, the structure–activity relationships generated opened the possibilities to replace or introduce new substituents on the core structure, which is of key importance to optimize compound properties or introduce probes to further expand the possibilities of these compounds as tailored research tools to study G4 biology.
- Prasad, Bagineni,Das, Rabindra Nath,Jamroskovic, Jan,Kumar, Rajendra,Hedenstr?m, Mattias,Sabouri, Nasim,Chorell, Erik
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p. 9561 - 9572
(2020/07/09)
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- Indoline‐6‐sulfonamide inhibitors of the bacterial enzyme dape
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Inhibitors of the bacterial enzyme dapE‐encoded N‐succinyl‐L,L‐diaminopimelic acid desuccinylase (DapE; EC 3.5.1.18) hold promise as antibiotics with a new mechanism of action. Herein we describe the discovery of a new series of indoline sulfonamide DapE inhibitors from a high‐throughput screen and the synthesis of a series of analogs. Inhibitory potency was measured by a ninhydrin‐based DapE assay recently developed by our group. Molecular docking experiments suggest active site binding with the sulfonamide acting as a zinc‐binding group (ZBG).
- Reidl, Cory T.,Heath, Tahirah K.,Darwish, Iman,Torrez, Rachel M.,Moore, Maxwell,Gild, Elliot,Nocek, Boguslaw P.,Starus, Anna,Holz, Richard C.,Becker, Daniel P.
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- Cooperativity within the catalyst: alkoxyamide as a catalyst for bromocyclization and bromination of (hetero)aromatics
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Alkoxyamide has been reported as a catalyst for the activation ofN-bromosuccinimide to perform bromocyclization and bromination of a wide range of substrates in a lipophilic solvent, where adequate suppression of the background reactions was observed. The key feature of the active site is the alkoxy group attached to the sulfonamide moiety, which facilitates the acceptance as well as the delivery of bromonium species from the bromine source to the substrates.
- Mondal, Haripriyo,Sk, Md Raja,Maji, Modhu Sudan
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supporting information
p. 11501 - 11504
(2020/10/12)
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- Identifying new lead structures to enhance tolerance towards drought stress via high-throughput screening giving crops a quantum of solace
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Novel synthetic lead structures interacting with RCAR/(PYR/PYL) receptor proteins were identified based on the results of a high-throughput screening campaign of a large compound library followed by focused SAR studies of the three most promising hit clusters. Whilst indolinylmethyl sulfonamides 8y,z and phenylsulfonyl ethylenediamines 9y,z showed strong affinities for RCAR/ (PYR/PYL) receptor proteins in wheat, thiotriazolyl acetamides 7f,s exhibited promising efficacy against drought stress in vivo (wheat, corn and canola) combined with confirmed target interaction in wheat and arabidopsis thaliana. Remarkably, binding affinities of several representatives of 8 and 9 were on the same level or even better than the essential plant hormone abscisic acid (ABA).
- Frackenpohl, Jens,Schneider, Linn,Decker, Luka J.B.,Dittgen, Jan,Fenkl, Franz,Fischer, Christian,Franke, Jana,Freigang, Joerg,Getachew, Rahel,Gonzalez Fernandez-Nino, Susana M.,Helmke, Hendrik,Hills, Martin J.,Hohmann, Sabine,Kleemann, Jochen,Kurowski, Karoline,Lange, Gudrun,Luemmen, Peter,Meyering, Nicole,Poree, Fabien,Schmutzler, Dirk,Wrede, Sebastian
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- N-{[2-(PIPERIDIN-1-YL)PHENYL](PHENYL)METHYL}-2-(3-OXO-3,4-DIHYDRO-2H-1,4-BENZOXA ZIN-7-YL)ACETAMIDE DERIVATIVES AND RELATED COMPOUNDS AS ROR-GAMMA MODULATORS FOR TREATING AUTOIMMUNE DISEASES
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The present invention provides e.g. N-{[2-(piperidin-1-yl)phenyl] (phenyl)methyl}-2-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)acetamide derivatives and related compounds as ROR-gamma modulators for treating e.g. autoimmune diseases, autoimmune-related diseases, inflammatory diseases, metabolic diseases, fibrotic diseases or cholestatic diseases, such as e.g. arthitis and asthma.
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Page/Page column 68; 112; 113
(2018/08/20)
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- Using weak interactions to control C-H mono-nitration of indolines
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An unprecedented C-H mononitration of indolines either at the -C5 or -C7 positions under mild condition is reported here. The roles of multiple weak interactions and factors such as steric factors, electronic effects, cation-π interactions, and solvent polarity were established, and we achieved a 100% regioselective electrophilic aromatic (EArS) nitration using Cu(NO3)2 or AgNO3.
- Bose, Anima,Mal, Prasenjit
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p. 11368 - 11371
(2017/10/19)
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- Environment-friendly synthesis method for medicine intermediate 5-bromoindole
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The invention relates to an environment-friendly synthesis method for a medicine intermediate 5-bromoindole. The method comprises the following steps: (1) subjecting indole to low-temperature low-pressure liquid-phase hydrogenation in the presence of a metal catalyst, so as to obtain indoline; (2) subjecting indoline to an action with an acetylation reagent, so as to produce N-acetylindoline; (3) subjecting N-acetylindoline to a clean bromination reaction, so as to produce N-acetyl-5-bromoindoline; (4) subjecting N-acetyl-5-bromoindoline to deacetylation under acidic conditions, so as to obtain 5-bromoindoline; and (5) subjecting 5-bromoindoline to oxidative dehydrogenation, thereby preparing the key medicine intermediate 5-bromoindole. Compared with the prior art, the method has the beneficial effects that a new environment-friendly synthesis process is developed, compared with the original process, bromo isomers of the 5-bromoindole product are effectively controlled, and the safety of medicine products can be higher; compared with the original acetic anhydride and bromine bromination process, the reaction conditions are mild, the environmental pollution is light, and the cost is low; and the equipment investment is small, the process is simple, the operation is easy, the equipment corrosion is low, and the process is more applicable to industrial production.
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- Preparation method of drug intermediate 5-bromoindole
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The invention relates to a preparation method of a drug intermediate 5-bromoindole. The preparation method uses an N-acyl indoline compound 3 as a raw material, a 5-bro-N-acyl indoline compound 4 is obtained through bromization, then a 5-bromoindole compound 5 is obtained through diacylation protection, and a target compound 6, namely 5-bromoindole, is obtained through oxidative dehydrogenation. The preparation method is suitable for large-scale production, the production cost is relatively lower, colors can be thoroughly removed through pure recrystallization, and the preparation method has the positive significance on application of the 5-bromoindole and quality control of relevant drugs.
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Paragraph 0021
(2017/08/29)
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- INDOLINE SULFONAMIDE INHIBITORS OF DAPE AND NDM-1 AND USE OF THE SAME
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Indoline sulfonamide compounds that can inhibit DapE and/or bacterial metallo-β- lactamases (MBLs), such as NDM-1, are disclosed. Also disclosed are methods of treating an individual suffering from a bacterial infection using the indoline sulfonamide compounds disclosed herein.
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- A rapid and clean synthetic approach to cyclic peptides: Via micro-flow peptide chain elongation and photochemical cyclization: Synthesis of a cyclic RGD peptide
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A cyclic RGD peptide was efficiently synthesized based on micro-flow, triphosgene-mediated peptide chain elongation and micro-flow photochemical macrolactamization. Our approach enabled a rapid (amidation for peptide chain elongation 5 s, macrolactamization 5 min) and clean (only one column chromatographic separation) synthesis of a cyclic peptide.
- Mifune, Yuto,Nakamura, Hiroyuki,Fuse, Shinichiro
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p. 11244 - 11249
(2016/12/09)
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- Rhodium-catalyzed direct C7 alkynylation of indolines
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An efficient rhodium(III)-catalyzed direct C7 alkynylation of indoline C-H bonds with the alkynylated hypervalent iodine reagents has been developed. This reaction proceeds smoothly under mild conditions over a wide structural scope with high site-selectivity and excellent functional-group tolerance. N-Acetyl as well as other N-acyls served as effective directing groups (DG). This procedure allows for the synthesis of a variety of 7-alkynyl-substituted indolines in good to excellent yield. More significantly, C7-alkynylated indoles through further transformations have been successfully accessed.
- Jin, Ning,Pan, Changduo,Zhang, Honglin,Xu, Pan,Cheng, Yixiang,Zhu, Chengjian
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supporting information
p. 1149 - 1153
(2015/04/22)
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- Compositions for Treatment of Cystic Fibrosis and Other Chronic Diseases
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The present invention relates to pharmaceutical compositions comprising an inhibitor of epithelial sodium channel activity in combination with at least one ABC Transporter modulator compound of Formula A, Formula B, Formula C, or Formula D. The invention also relates to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis using the pharmaceutical combination compositions.
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- Ruthenium-catalyzed C7 amidation of indoline C-H bonds with sulfonyl azides
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A ruthenium-catalyzed direct C7 amidation of indoline C-H bonds with sulfonyl azides was developed. This procedure allows the synthesis of a variety of 7-amino-substituted indolines, which are useful in pharmaceutical. The good functional tolerances, as well as the mild conditions, are prominent feature of this method.
- Pan, Changduo,Abdukader, Ablimit,Han, Jie,Cheng, Yixiang,Zhu, Chengjian
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supporting information
p. 3606 - 3609
(2014/04/03)
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- Iridium(I)-catalyzed direct C-H bond alkylation of the C-7 position of indolines with alkenes
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A cationic iridium-catalyzed C-7 alkylation of N-substituted indoline derivatives with various alkenes has been developed. A variety of 7-alkylindolines were obtained in moderate to high yields. This protocol relies on the use of the carbonyl group on the nitrogen atom of indoline as a directing group and it is potentially applicable to the large-scale synthesis of 7-alkylindoles.
- Pan, Shiguang,Ryu, Naoto,Shibata, Takanori
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supporting information
p. 929 - 933
(2014/04/03)
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- Novel pyridyl- or isoquinolinyl-substituted indolines and indoles as potent and selective aldosterone synthase inhibitors
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Pathologically, high levels of aldosterone are associated with severe cardiovascular diseases such as congestive heart failure, hypertension, and myocardial fibrosis. The inhibition of aldosterone synthase (CYP11B2) to reduce aldosterone levels has been proposed as a promising treatment for diseases related to CYP11B2 because it is the crucial enzyme in the biosynthesis of aldosterone. A series of novel pyridyl- or isoquinolinyl-substituted indolines and indoles was designed via a ligand-based approach. The synthesized compounds were tested and found to be strong CYP11B2 inhibitors. The most potent ones showed IC50 values of less than 3 nM, being similarly potent as fadrozole and LCI699. Among them, compounds 14 and 23 showed good selectivity over the highly homologous CYP11B1, with selectivity factors (SF = IC 50 CYP11B1/IC50 CYP11B2) around 170; thus, they are superior to fadrozole and LCI699 (SFs 50 > 50 μM) of a panel of hepatic CYP enzymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 and the crucial steroidogenic enzymes, CYP17 and CYP19. Because of these advantageous profiles, compounds 14 and 23 are considered to be candidates for further in vivo evaluation.
- Yin, Lina,Hu, Qingzhong,Emmerich, Juliette,Lo, Michael Man-Chu,Metzger, Edward,Ali, Amjad,Hartmann, Rolf W.
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supporting information
p. 5179 - 5189
(2014/07/08)
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- MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS
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The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator, compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.
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- One-pot synthesis of triazolothiadiazepine 1,1-dioxide derivatives via copper-catalyzed tandem [3+2] cycloaddition/N-arylation
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A practical and efficient synthesis of triazolothiadiazepine-1,1-dioxide derivatives via copper-catalyzed [3+2]cycloaddition, followed by N-arylation is described. The method is also applicable to the synthesis of indoline- and thiophene-fused triazolothiadiazepine 1,1-dioxide derivatives.
- Barange, Deepak Kumar,Tu, Yu-Chen,Kavala, Veerababurao,Kuo, Chun-Wei,Yao, Ching-Fa
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- COMPOSITIONS FOR TREATMENT OF CYSTIC FIBROSIS AND OTHER CHRONIC DISEASES
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The present invention relates to pharmaceutical compositions comprising an inhibitor of epithelial sodium channel activity in combination with at least one ABC Transporter modulator compound of Formula A, Formula B, Formula C, or Formula D. The invention also relates to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis using the pharmaceutical combination compositions.
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- Solvent-free aromatic C-H functionalisation/halogenation reactions
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The solvent-free, palladium-catalysed reaction of anilides with CuCl 2 in the presence or absence of copper acetate yields ortho-chlorinated anilides in good to excellent yields, even on a large scale (100 mmol). By contrast, the equivalent reactions with copper bromide, either solvent free or in 1,2-dichloroethane, in the presence or absence of palladium, under air or inert conditions, gave the products of simple electrophilic bromination. Mechanistic studies highlighted the involvement of palladacyclic intermediates, one of which was characterised crystallographically, which undergo subsequent reaction with copper(ii) chloride to yield the chlorinated anilide products.
- Bedford, Robin B.,Engelhart, Jens U.,Haddow, Mairi F.,Mitchell, Charlotte J.,Webster, Ruth L.
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supporting information; experimental part
p. 10464 - 10472
(2011/01/05)
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- Bioavailable acyl-CoA : Cholesterol acyltransferase inhibitor with anti- peroxidative activity: Synthesis and biological activity of novel indolinyl amide and urea derivatives
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We synthesized a series of indoline derivatives with an amide or urea moiety and examined their inhibitory effects on acyl-CoA : cholesterol acyltransferase (ACAT) activity, lipid-peroxidation and serum cholesterol levels in experimental animals. Among the derivatives synthesized, a series of N-(1-alkyl-4,6- dimethylindolin-7-yl)-2,2-dimethylpropanamides potently inhibited rabbit intestinal ACAT activity and lipid-peroxidation of rat brain homogenate. The effect on ACAT activity was related to the length of the alkyl chain at the 1-position of indoline. N-(4,b-Dimethyl-1-octylindolin-7- yl)-2,2-dimethylpropanamide hydrochloride (55) showed inhibitory effects on intestinal and hepatic ACAT activity slightly weaker than those of YM-750, and an inhibitory effect on low density lipoprotein (LDL)-peroxidation similar to that of probucol. Compound 55 also reduced serum cholesterol at 10 mg/kg/d in hyperlipidemic rats and 20 mg/kg/d in normolipidemic hamsters. The plasma concentration of 55 reached 716 ng/ml in dogs (10 mg/kg, p.o.), which is an effective concentration against hepatic ACAT activity and LDL- peroxidation. In conclusion, compound 55 is a novel bioavailable ACAT inhibitor with anti-peroxidative activity and is thus a promising anti- atherosclerotic and anti-hyperlipidemic drug. Indoline proved to be a useful pharmacophore for molecular design of new anti-peroxidative drugs.
- Kamiya, Shoji,Shirahase, Hiroaki,Yoshimi, Akihisa,Nakamura, Shohei,Kanda, Mamoru,Matsui, Hiroshi,Kasai, Masayasu,Takahashi, Kenji,Kurahashi, Kazuyoshi
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p. 817 - 827
(2007/10/03)
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- Color transfer photographic processes and products with indole phthalein filter dyes
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This invention relates to diffusion transfer photographic processes adapted to be performed in the presence of ambient light and to diffusion transfer products useful in such processes wherein enhanced opacification particularly, in the green region of the visible spectrum is achieved by employing a 7-sulfonamido/5- or 6-sulfamoyl indole phthalein as the light-absorbing, pH-sensitive optical filter agent for the shorter wavelength region of the visible spectrum.
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