Indolinone derivatives

Methylidenyl-2-indolinone derivatives, (I), effective as modulators of protein kinase effective in the treatment of protein kinase-related cellular disorders including cancer, were previously prepared by Tang (1) and used in treating cellular disorders such as cancer. 

Ma, Y. et al., Indolinone derivatives inhibit constitutively activated KIT mutants and kill neoplastic mast cells, J. Invest. Dermatol, 114, 392, 2000. 

Fig. 2 Biologically active iodolinones and di-indolinones derived from CMF...

Pyrrolo[3,2-c]pyridine-4-one-2-indolinone derivatives as tyrosine kinase inhibitors... 

Receptor tyrosine kinases (RTKs) have been implicated as therapeutic targets for the treatment of human diseases including cancers, inflammatory diseases. A series of Pyrrolo [3,2-c] pyridine-4-one 2-indolinone derivatives as tyrosine kinase inhibitors were designed and synthesized. They were found to inhibit the tyrosine kinase activity associated with vascular endothelial growth factor receptor 2(VEGF-R2). Their biological evaluation results and structure-activity relationship will be discussed. 

Friedel-Crafts acylation of 3,3-dimethyl-2-indolinone by succinic anhydride gives 3,3-dimethyl-5-(3-catboxyptopionyl)-2-indoline, which is used as an intermediate in the preparation of inotropic agents for treatment of heart failure (94). Antibacterial phlotophenone derivatives have been prepared by Friedel-Crafts acylation with ptopanoyl chlotide (95). 

Substituted imidazo[2,l-3]thiazoles with a lactam ring derived from 2-iminothiazolidine-4-one 482 and from pyr-imidine-2,4,6-trione 483 and 6-substituted-2,3-dihydro-imidazo[2,l-3]thiazole with a bicyclic 2-indolinone system 125 were discovered as new cardotonic agents and showed a positive inotropic activity <1996EJM383, 1997EJM919>. 

Laser irradiation of isatin (70) gave 71 as a result of bimolecular condensation (78TL3007). The diazine ring of 73 was formed during the cyclocondensation of anthranilic acids with the imidate esters derived from indolinone (72) (81AP271). 

The base-catalyzed reaction at the activated methylene positions of the pyrrolinones and indolinones with aromatic aldehydes is a general reaction producing the benzylidene derivatives. Products of the Ehrlich reaction with pyrrolinones are generally yellow-orange... 

The C-2 and C-3 hydroxy derivatives of pyrrole are special in the sense that the tautomeric equilibria favor the pyrrolinone structures (see Section 3.04.6.2). Furthermore, the general synthetic methods are not usually applicable so that we will call attention in this section not only to the methods of directly introducing these substituents, which are rare, but also to those ring construction processes which specifically give the pyrrolinones and indolinones. The indole derivatives have widely used trivial names, oxindole (5) for indolin-2-one and indoxyl (6) for indolin-3-one, Carbocyclic hydroxy substituents in indole and carbazole, on the other hand, for the most part act as normal aromatic phenolic groups. These compounds are usually prepared by application of the standard ring syntheses. 

Interaction of substituted dienediamines with ethylenediamine yields im-idazo[3,2-n]pyridine derivatives (95JHC477). 3-Arylaminoindoles, with distinct enamine properties, are the starting materials for the synthesis of indolo[3,2-b]quinoline derivatives [96KFZ(7)42]. a-Carboline derivatives can be obtained from enamine-based 3-dimethylamino-2-indolinones [96KFZ(9)35, 96KFZ(10)32], The synthesis and transformation of enamines based on the pyrido[l,2-n]pyrazine ring system into imidazo[l,2-n]pyridine and imidazo[l,2-a]pyrimidine derivatives have been reported... 

Doyle et al.344 and Wee and Liu345 have reported the ring-closing transformation of a-diazoacetamides 108 and 109 to yield 2(3//)-indolinones over Nafion-H [Eq. (5.136)]. In the transformation of compounds 109 the electrophilic intramolecular substitution is followed by decarboxylation.345 Small amounts of 2-azetidinone derivatives (4—10%) formed through a carbene intermediate were also detected. The yield of products from compounds 108 are even higher than observed in the presence of Rh(OAc)2 often applied in the decomposition of diazo compounds.344... 

The reaction of isatin 49a and its 1-acetyl derivative 49b with diphenylchlorophosphine leads to the phosphorylated 2-indolinones 50a,b [44] ... 

In [62] the synthesis of phosphorus-containing derivatives of 2-indolinone was reported. Thus, in 5-bromoisatin one phosphorus-containing fragment was introduced by the Abramov reaction with the formation of compound 66 [233], and a second was then introduced by the Arbuzov reaction (compound 67) ... 

The same paper describes the reaction of trialkyl phosphites with isatin arylazomethines in the presence of nickel or copper monohalides, leading to the previously unknown phosphorus-containing derivatives of 2-indolinone 68 ... 

The extension of the use of lactams to include indolin-2-ones provides a Vilsmeier-type methodology for the construction of biindolyl systems, which are of considerable current interest.37,39-43 In this situation, the initially formed imines are indolenines, which readily isomerize to the related 2-indolyl derivatives.43 In view of our general interest in activated indoles, as well as a specific interest in continuing to synthesize structures containing indoles directly linked to each other, we investigated not only reactions with indolinone itself but also with substituted derivatives. These were variously methoxy-substituted at C-4 and C-6, and in some cases substituted also at C-3 with methyl, phenyl, or dithiolan groups. 

The reaction of arylsulfur radicals with a range of indolinonic and quinolinic aminoxyls has been reported and results indicated that the main products were deoxygenated derivatives formed by initial attack of the sulfur radical on the NO group followed by decomposition to aminyl and arylsulfinyl radicals. ... 

Piperidines and Reiated Heterocycles.—Linking with the preceding section on pyrrolidine derivatives, an intriguing combination of reactions is worthy of closer examination. Condensation of p-hydroxy-phenyl acetic acid with the carbodi-imides (300) afforded the spiro-fused indolinones (301) in yields of about 60%. 

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