Indomethacin, properties

In the early clinical trials of Pravadoline (248), the Sterling-Winthrop Research group observed CNS side effects. In an effort to circumvent these issues, indenes were explored as an alternative core [197]. The rationale behind this approach came from the observation that sulindac (308), an indene analogue of indomethacin (309), had anti-inflammatory properties comparable to (309) but without the CNS-associated side effects. 

Indomethacin (3.2.51) Synthesis and properties of indomethacin are described in Chapter 3. 

Naproxen (Naprosyn) also has pharmacological properties and clinical uses similar to those of ibuprofen. It exhibits approximately equal selectivity for COX-1 and COX-2 and is better tolerated than certain NSAIDs, such as indomethacin. Adverse reactions related to the GI tract occur in about 14% of all patients, and severe GI bleeding has been reported. CNS complaints (headache, dizziness, drowsiness), dermatological effects (pruritus, skin eruptions, echinoses), tinnitus, edema, and dyspnea also occur. 

ML-3000 ((2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl)-acetic acid) is a nonantioxidant dual inhibitor of both cyclooxygenase and 5-lipoxygenase. ML-3000 has been compared to indomethacin in a number of experimental models of inflammation. The analgesic effects of ML-3000 have also been assessed in a number of animal models. Phase II studies have shown a wide range of activities, including anti-inflammatory, analgesic, antiplatelet and antiasthmatic properties (Laufer et al., 1994 Chin and Wallace, 1999). 

Among five triterpenoids isolated from Calendula officinalis flowers, P-amyrin (119), faradiol (232), i /-taraxasterol (238), taraxasterol (239), and lupeol (238), the diol 232 was the most active. It showed a dose-dependent effect with a potency that equals that of indomethacin (5) in the topical anti-inflammatory assay with croton oil [33]. Esterification at C-3 of 232 with a fatty acid reduced the activity by more than 50% [33] consistent with our observation in the TPA-induced assay described above. The anti-inflammatory properties, as determined by croton oil-induced edema of mouse ear, of faradiol-3-O-myristate (233) and its 3-O-palmitate (234), the main components of lipophilic extracts of C. officinalis flowers, were shown to be contribute significantly to the pronounced antiphlogistic activity of the lipophilic extracts of C. officinalis flowers [34]. 

Chokshi, R. J., H. K. Sandhu, R. M. Iyer, N. H. Shah, A. W. Malick, and H. Zia. 2005. Characterization of physico-mechanical properties of indomethacin and polymers to assess their suitability for hot-melt extrusion process as a means to manufacture solid dispersion/soJUflbarm ScB4 2463-2474. 

Imai T, Shiraishi S, Saito H et al (1991) Interaction of indomethacin with low molecular weight chitosan, and improvements of some pharmacuetical properties of indomethacin by low molecular weight chitosans. Int J Pharm 67 11-20... 

Among these, saponins isolated from the rhizome of Panax japonicus and the fruit of Kochia scoparia (that contain approximately 20% of saponins) have been demonstrated to possess gastroprotective properties. Some oleanolic acid oligoglycosides, extracted from P. japonicus and K. scoparia, showed protective effects on ethanol- and indomethacin-induced gastric damage. Moreover, a methanol extract of P. japonicus rhizome was demonstrated to possess protective activity also on stress- or HCl-induced ulcers. The protective activities of all these active saponins are not due to inhibition of gastric acid secretion but probably due to activation of mucous membrane protective factors. 

Given the insolubility of indomethacin, a number of formulation approaches have been taken to improve the physical properties of this nonsteroidal anti-inflammatory drug substance. A 1 1 cocrystal was successfully prepared with saccharin using both solid-state dry grinding and... 

Indomethacin is a non-steroidal, anti-inflammatory agent with anti-pyretic and analgesic properties discovered and developed by the Merck Sharp and Dohme Research Laboratories(1). 

Allessandro and co-workers using silica gel G were able to separate indomethacin from drugs of similar pharmacological properties(40). Likewise Thompson and Johnson reported values for a variety of analgesics, antipyretics and anti-inflammatory drugs which were separable from indomethacin(48). Polyamide gels were also used by Hsiu et al. to resolve a series of antipyretics including indomethacin(49). 

Wang CY, Ye SQ, Dai L et al (2007) Enhanced resistance of polyelectrolyte multilayer microcapsules to pepsin erosion and release properties of encapsulated indomethacin. Biomacromolecules 8 1739-1744... 

Because tetrazoles have similar acidities to those of carboxylic acids, they have been used in drugs as replacements for the CO2H unit when the carboxylic acid has unsatisfactory properties for human medicine. A simple example is the anti-arthritis drug indomethacin whose carboxylic acid group maybe replaced by a tetrazole with no loss of activity. 

There are two major groups of synthetic compounds which have cannabin-oid activity, but which differ chemically from the tricyclic THC-like canna-binoids the bicyclic cannabinoids, exemplified by compound CP55940 (23), and the (aminoalkyl)indoles exemplified by pravadoline (24a). A detailed SAR analysis of these groups of compounds is beyond the scope of this review. The bicyclic cannabinoids and derivatives have been reviewed previously [105] recent publications deal mainly with related tricyclic non-classical cannabinoids [106] and with the (aminoalkyl)indoles [92, 107]. It is of interest to note that while the bicyclic cannabinoids were originally prepared as simplified cannabinoids, the cannabinoid-type activity of the (ami-noalkyl)indoles was discovered by serendipity. These compounds were synthesized in a project aimed at the discovery of novel nonsteroidal anti-inflammatory agents presumably based on the indomethacin structure. However, while they did not possess anti-inflammatory properties, they were found to be antinociceptive, and to inhibit the electrically evoked contractions in a mouse vas deferens muscle preparation. This led to binding experi-... 

Andronis, V. and Zografi, G. (2000). Crystal nucleation and growth of indomethacin polymorphs from the amorphous state. J. Noncryst. Solids, 271, 236 8. [252] Anex, B. G. (1966). Optical properties of highly absorbing crystals. Mol. Cryst., 1, 1-36. [226]... 

The mixed-crystal system formed by indomethacin and saccharin (l,2-benzisothiazol-3(2H)-one-l,1-dioxide) has been used to evaluate the feasibility of using supercritical fluids as media for the design and preparation of new cocrystals [44]. In this work, the relative merits of supercritical fluid processes (i.e., cocrystallization with a supercritical solvent, supercritical fluid as anti-solvent, and the atomization and anti-solvent technique) were evaluated, as well as the influence of processing parameters on product formation and particle properties of the yields. It was reported that while the anti-solvent and atomization procedures yielded pure cocrystal products, only partial to no cocrystal formation took place when using the crystallization process. 

Matsuda Y, Kouzuki K, Tanaka M, Tanigaki J. Photostability of gelatin capsules effect of ultraviolet irradiation on the vapor transmission properties and dissolution rates of indomethacin. Yakugaku Zassi 1979 99(9) 907-913. 

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... 

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