Indole acetic acid derivatives

Q89 Indometacin is an indole acetic acid derivative that has a lov/er frequency of gastrointestinal side-effects compared v/ith naproxen. Indometacin may cause headache and dizziness as side-effects. 

Indometacin is an indole acetic acid derivative, while naproxen is a propionic acid derivative. Both are non-steroidal anti-inflammatory drugs (NSAIDs). Indometacin is associated with a higher incidence of side-effects, particularly gastrointestinal as well as headache and dizziness. 

Brand Name(s) Indocin, Indocin IV, Indocin SR, Indo-Lemmon Chemical Class Indole acetic acid derivative... 

It is indole acetic acid derivative possessing potent antiinflammatory property and having a good analgesic and antipyretic action also. Mechanism of action is same as other NSAIDs. 

Indole-acetic acid derivatives with NSAID action include etodolac, indomethacin and sulindac. The first produced was indomethacin which, though very powerful as an antirheumatic and antiosteoarthritic agent, has serious toxic GI effects. The more recently introduced members seem better and show promise. 

Coupling reactions of indole-3-acetic acid derivatives have also p ovided convenient routes to indolo[2,3-a]carbazoles (Scheme 5). An iodine-p-omoted coupling... 

Eventually, indole acetic acid 2 was prepared from iodoaniline 28 and propargyl alcohol derivative 61 via the newly developed coupling reaction followed by a cyanide displacement-hydrolysis sequence, as shown in Scheme 4.16. 

Auxins Derivative of tryptophan - e.g. indole acetic acid. Controls H+/K+ balance and growth... 

Acetic acid derivatives (including INDOLE derivatives) diclofenac potassium diclofenac sodium etodolac indomethacin ketorolac tromethamine sulindac tolmetin sodium... 

Bergman, J. Koch, E. Pelcman, B. Reactions of Indole-3-acetic Acid Derivatives in Trifluoroacetic Acid, Tetrahedron Lett. 1995,36,3945-3948. 

The radiolabel was introduced by displacement of a quaternary amine with potassium 14C-cyanide to give a nitrile. The nitrile was readily converted to indole-3-acetic acid by hydrolysis with 20% aqueous potassium hydroxide. Reduction of the indole-3-acetic acid derivative with lithium aluminum hydride in tetrahydrofuran gave a typtophol with 95% yield. 

Several new routes involve formation of one carbon-carbon bond in pre-formed substrates. Palladium-catalyzed cyclization of /3-hydroxyenamine derivatives has been employed in a route to substituted pyrroles and 4,5,6,7-tetrahy-droindoles with multiple substituents by formation of the C-3-C-4 bond as the key feature, as illustrated by construction of the molecule 534 (Equation 146) <2006T8533>. Zinc perchlorate-catalyzed addition of alcohols to the nitrile functionality of a-cyanomethyl-/3-ketoesters, followed by annulation gave access to a series of substituted ethyl 5-alkoxypyrrole-3-carboxylates <2007T461>. Similar chemistry has also been used for synthesis of a related set of pyrrole-3-phosphonates <2007T4156>. A study on preparation of 3,5,7-functionalized indoles by Heck cyclization of suitable A-allyl substituted 2-haloanilines has also appeared <2006S3467>. In addition, indole-3-acetic acid derivatives have been prepared by base induced annulation of 2-aminocinnamic acid esters (available for instance from 2-iodoani-lines) <2006OL4473>. 

In an approach employing oxidative radical alkylation, the pyrrole 61 was converted to the corresponding pyrrol-2-acetic acid derivative 62 by treatment with the xanthate 63 in the presence of dilauroyl peroxide (DLP). This procedure was also useful for the alkylation of other heterocyclic systems (e,g, indole) producing ethyl indole-2-acetate <03CC2316>. Alternatively, pyrrole-2-acetic acids have been obtained by treatment of pyrrole with various substituted iodoacetic acids and Na2S203/n-Bu4NI with propylene oxide as the Hl-trap in... 

In a systematic search for novel analogues of the anti-inflammatory indole-3-acetic acid derivative indomethacin (216), scientists at the Pierrel Laboratories in Milan reasoned that substitution of an azido group for the 4-chloro substituent on the A-benzoyl ring might represent an effective bioisosteric replacement, and thus confer interesting biological properties to the molecule [266]. l-(4-Azidobenzoyl)-5-methoxy-2-methyl-l/f-indole-3-acetic acid (zidometacin) (217) was synthesized and evaluated for its... 

The scope of this initiation reaction may be widened by using an arylamino-acetic acid derivative as the electron donor, with the same sensitisers, and of these indol-3yl-acetic acid (IAA) is experimentally convenient. In these cases it is thought that the initiating radicals arise via decarboxylation following the normal photoinduced electron transfer. Quantum yields for initiation by the combination FL/DME, FL/IAA and NMA/IAA lie in the range 0.1—0.2 and it is clear that this technique affords a new versatile range of initiating systems for radical polymerization. 

The ability to accommodate altered levels of intermediates depends on the type of compounds involved. In A. thaliana, tryptophan-derived oximes are key intermediates in the formation of the phytohormone indole acetic acid as well as in the synthesis of glucosinolates. CYP83A1 and CYP83B1 are the enzymes responsible for converting oximes into glucosinolates. Overexpression... 

Acetic acid derivatives Indomethacin (methylated indole)... 

Biological effects of oxidation of indole-3-acetic acid derivatives... 

A sequence of bromination of a 3-indolyl acyl group followed by azide displacement and reduction, provides an effective route to 3-(a-aminoacyl)indoles <88JHC469>. Indoles react readily with oxalyl chloride at C-3 and the products have been used in combination with aryl acetic acid derivatives to generate indolyl-substituted maleic anhydrides and imides, as precursors for indolocarbazole antibiotics <90TL2353,93TL5623>. 

Circumstantial evidence for rigid control of the tryptophan synthesis is found in the relatively small pool sizes (1-10 /iim) of free tryptophan in all plant sources examined, an observation which is especially noteworthy in view of the accepted role of tryptophan as a precursor of indole acetic acid and other indole derivatives. Since repression of synthesis of key pathway enzymes apparently does not occur in the presence of high levels of tryptophan in tobacco, rice, carrot, and tomato cell cultures (Widholm, 1972b Chu and Widholm, 1972) control would most likely occur by end product feedback inhibition. 

Various intermediate products derived from tryptophane have been reported as occasional urinary constituents. These include indole aldehyde, indole acetic acid, scatoxyl, and indole carboxylic acid. Indole and scatole, themselves, are improbable urinary constituents. 

One of the virtues of the Fischer indole synthesis is that it can frequently be used to prepare indoles having functionalized substituents. This versatility extends beyond the range of very stable substituents such as alkoxy and halogens and includes esters, amides and hydroxy substituents. Table 7.3 gives some examples. These include cases of introduction of 3-acetic acid, 3-acetamide, 3-(2-aminoethyl)- and 3-(2-hydroxyethyl)- side-chains, all of which are of special importance in the preparation of biologically active indole derivatives. Entry 11 is an efficient synthesis of the non-steroidal anti-inflammatory drug indomethacin. A noteworthy feature of the reaction is the... 

Naturally Occurring Compounds. Many derivatives of iadole are found ia plants and animals where they are derived from the amino acid tryptophan. Several of these have important biological function or activity. Serotonin [50-67-9] (12) functions as a neurotransmitter and vasoconstrictor (35). Melatonin [73-31-4] (13) production is controlled daily by the circadian cycle and its physiological level iafluences, and seasonal rhythms ia humans and other species (36). Indole-3-acetic acid [87-51-4] (14) is a plant growth stimulant used ia several horticultural appHcations (37). 

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