Propionic Acid Derivatives Research Articles

Structure of naproxen, C14H14O3

An effective inhibitor of cyclo-oxygenase. Mr=230.25 , monoclinic, P21, a= 13.3150(10), b = 5.7765 (4), c= 7.8732 (4)A, fl= 93.88 (1) °, V= 604.2 (1)A 3, Z= 2, Din= 1.25 (2) (flotation), D~= 1.265 Mg m -3, 2(Mo Ka 1) = 0.70926/~, #(Mo Ka) = 0.095 mm -1, F(000) = 244, T= 296 K, final R(F) = 0.061 for 1037 observed reflections. The rotation of the carboxyl group with respect to the benezene ring, which seems to be connected with anti-inflammatory potential, is similar to the other two substituted propionic acids already reported. The benzene rings in the naphthyl group are inclined at an angle of 5.2 (2) °. Introduction. The title compound, an effective inhibitor of the cyclo-oxygenase responsible for biosynthesis of prostaglandins, was obtained from Dr Natarajan, Institute of Basic Medical Sciences, Madras. It exhibits anti-inflammatory, analgesic and antipyretic activity in man (Goodman & Gilman, 1980). The analysis of its structure was undertaken to help to establish the structure-activity relationship in propionic acid derivatives.

Synthesis of 3-aromatic ring substituted 2-(4-chlorobenzoylamino)propionic acid derivatives and their antiulcer activities

Synthesis of 3-aromatic ring substituted 2-(4-chlorobenzoylamino)propionic acid derivatives and their antiulcer activities

Antirheumatic medication during lactation.

All nonsteroidal anti-inflammatory drugs (NSAIDs) and antirheumatic drugs are likely to be distributed into human milk to some extent; whether they are detected is a function of the assay sensitivity. For minimal infant exposure, the ideal drug for lactating women is one which has a short half-life, is found in minimal quantities in human milk and has inactive metabolites which also are present only in small amounts. In order to reduce the quantity of drug presented to the child, the drug should be taken by the mother at the time of breast-feeding with the next feed occurring after a time period equivalent to one half-life of the drug. Using the above-mentioned criteria, the choice of NSAIDs would be between a short half-life propionic acid derivative, with little biotransformation, such as ibuprofen or flurbiprofen. Diclofenac is also suitable. Gold salts and corticosteroids would seem safe to prescribe. However, the infant should be closely monitored if antimalarials are being used by lactating women.

Study of the interactions between sulfamethizole and three anti-inflammatory propionic acid derivatives at the renal level in rats.

The effects of three anti-inflammatory propionic acid derivatives (ketoprofen, fenbufen and flurbiprofen) on renal excretion of sulfamethizole were investigated in rats, in order to clarify the mechanisms involved. The clearance ratio of sulfamethizole was markedly decreased after ketoprofen or fenbufen infusion, while flurbiprofen had no effect on sulfamethizole excretion. From these results, it is speculated that the decrease of renal excretion of sulfamethizole caused by ketoprofen or fenbufen is mainly due to competitive interaction between sulfamethizole and ketoprofen or fenbufen at the renal secretory level.

Synthesis and biological activity of β-(3-methyl-7-xanthinyl)propionic acid derivatives

Synthesis and biological activity of β-(3-methyl-7-xanthinyl)propionic acid derivatives

High-performance liquid chromatographic determination of citalopram and four of its metabolites in plasma and urine samples from psychiatric patients

A high-performance liquid chromatographic method is used for the determination of citalopram [1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-5-phthalancarbonitrile] and four of its metabolites (the methylamino, amino, propionic acid and N-oxide derivatives) in plasma and urine. The plasma samples were extracted with diethyl ether at pH 10 and pH 4. Filtered urine samples could be injected directly on to the column. Steady-state drug and metabolite levels were investigated in fifteen psychiatric patients. In urine, 12 ± 5% (mean ± S.D.) of a given dose of citalopram was excreted in unchanged from. The propionic acid derivative was further conjugated, possibly to glucuronic acid. Mean steady-state plasma levels and metabolites in 24-h urine are given as percentages of the dose.

Synthesis of [3](1,1′)[3](3,3′)- and [4](1,1′)[4](3,3′)Ruthenocenophanes

Abstract [3](1,1′)[3](3,3′)- and [4](1,1′)[4](3,3′)Ruthenocenophanes were synthesized via cyclization of the propionic acid derivatives of [3](1,1′)- and [4](1,1′)ruthenocenophanes with polyphosphoric acid or trifluoroacetic anhydride, respectively. The 1H NMR, IR, and electronic spectra of these dibridged ruthenocenes were measured and compared with those of monobridged ruthenocenes.

The metabolism of loxtidine in rat and dog

Loxtidine hemisuccinate is a potent, long-acting H,-receptor antagonist under investigation as an anti-ulcer drug (Brittain & Jack, 1983). We have studied the metabolism of loxtidine hemisuccinate labelled with either 3H or I4C (Fig. I). Rats and dogs were given single oral doses of 1-50mg of I I4C lloxtidine base/kg body wt. In both species the compound was well absorbed with peak concentrations of loxtidine in plasma occurring within 1 h of dosing. Urinary excretion of radioactivity accounted for 5 6 7 5 % of the dose, most of which was excreted in 24 h. The balance of the radioactive dose was recovered in faeces. The urinary metabolites of radiolabelled loxtidine were examined by t.1.c. [silica-gel 60 F254, 0.2mm thick, developed in either ethyl acetate/propan-2-ol/water/ ammonia solution (sp. gr. 0.88) (25 : I5 : 8: 2 , by vol.) or ethyl acetate/ethanol/ammonia solution (sp. gr. 0.88) (10: 2 : 1, by vol.)]. Authentic samples of synthetic loxtidine metabolites I, 111, IV and V (Fig. l), used as reference standards, were detected on t.1.c. plates under U.V. light (254 nm). Radioactive metabolites were quantified by the use of a Berthold LB 2832 automatic t.1.c. linear analyser with an LB 3500 data system. In rat the extent of loxtidine metabolism was dose-dependent. At doses of 2 and 50mg of IJ4CIloxtidine/kg body wt. the unchanged compound represented 20 and 75% respectively of the radioactivity excreted in 0-24 h urine. The major metabolite was the propionic acid derivative (IV; Fig. I ) , which represented 55% of the urinary radioactivity after 2mg of 114CJloxtidine/kg body wt., but only 15%) after 50mg of II4CIloxtidine/kg body wt. Confirmation of the N-dealkylation of loxtidine in rat was obtained by the recovery of a radiolabelled hydroxymethyltriazole metabolite (111) in urine after administration of [ 3H lloxtidine hemisuccinate. For a given dose level the proportions of metabolites 111 and IV were equivalent.

Indoprofen - another NSAID

Indoprofen (Flosint - Farmitalia) is a non-steroidal anti-inflammatory analgesic (NSAID) recently introduced in the UK. The manufacturer claims that it ‘possesses both the powerful anti-inflammatory properties of indomethacin and the potent analgesic effects of the propionic acid derivatives ... without an unacceptable level of adverse effects’.

Hydrophilic polymers containing chiral nucleic acid base pendants as polynucleotide analogs

A survey of our recent work on synthetic polynucleotide analogs is given. Propionic acid and 3-methyl butyric acid derivatives substituted in the 2-position with nucleic acid bases have been used as chiral pendants for attachment to hydrophilic polyamine backbones. Hindered rotation about the amide bonds formed promotes a base-stacked structure as shown by ultraviolet hypochromic effects versus model compounds. If the pendant has been resolved, an optically active polymer results which may be studied by circular dichroism (CD). Thus, poly(ethylenimine) containing the (−)-2-(thymin-1-yl)-propionyl group as the grafted pendant showed exciton coupling of the B2u transition of the base chromophores in the CD, as observed in polynucleotides. This implies at least a local helical order in the stacking. The biological activity of such structures is briefly discussed.

Effects of two nonsteroidal anti-inflammatory drugs, indomethacin and oxaprozin, on the kidney.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been found to cause sodium retention and to decrease glomerular filtration rate (GFR). We studied the effects of two such drugs, indomethacin and oxaprozin, a new propionic acid derivative, on renal function of awake, normal human subjects during sustained water diuresis. Although neither drug had a long-term effect on GFR or sodium clearance (CNa), indomethacin (six subjects) but not oxaprozin (seven subjects) transiently reduced GFR and CNa. Given over the short term, oxaprozin caused a reduction in GFR from 113.7 +/- 5.7 to 99.8 +/- 4.7 ml/min (p < 0.01) and CNa from 0.84 +/- 0.07 to 0.61 +/- 0.08 ml/min (p < 0.005). The results were much the same when an additional dose of indomethacin was given to subjects who had been receiving the drug for a week. Inference from clearance data at a time when urinary osmolality (Uosm) remained constant but urine flow per GFR (V/GFR) fell suggests that both drugs stimulated proximal tubular sodium and fluid resorption. Both suppressed renin and aldosterone levels comparably and reduced potassium excretion transiently, but only indomethacin caused a sustained change in serum potassium concentration; serum potassium rose from 4.32 +/- 0.10 to 4.56 +/- 0.11 mEq/l (p < 0.05) after 1 wk. These disparate findings suggest that prostaglandin synthesis inhibition may not be the sole mechanism of action of NSAIDs.

Recently Approved Alternatives to Aspirin

Antiinflammatory analgesics recently approved by the FDA for use in the United States are evaluated and compared with aspirin and other older agents. The drugs discussed are propionic acid derivatives, tolmetin, and sulindac. Indications, dosages, efficacy, side effects, cost, precautions, and interactions are discussed. The propionic acid derivatives and tolmetin are structurally different from older drugs and provide new alternatives in the treatment of inflammatory disease and pain. Of these new agents, naproxen appears to be first choice. Sulindac is the result of efforts to improve indomethacin. It possesses a longer duration of action, and it appears to cause fewer side effects.

Electroluminescence, photoluminescence and electroabsorption of a lightly substituted anthracene langmuir film

Optical data are presented for a novel thin film structure based on anthracene. Thin films of the 9-butyl–10-anthryl propionic acid derivative were prepared using the Langmuir-Blodgett technique. By applying electric fields in excess of 10 6 V cm −1 both electroabsorption and electroluminescence results have been obtained. The electroluminescence spectrum exhibits a shoulder at the wavelength where the maximum in the fluorescence spectrum occurs.

Retinopathic effects of 2-aminooxy propionic acid derivatives in the rat

Administration of methyl 2-(ureidooxy) propionate caused retinal lesions in male rats after 21 days of feeding at 2500 ppm (160 mg/kg/day). Retinal lesions were also apparent after 28 days of feeding at 1500 ppm (125 mg/kg/day), after 91 days of feeding at 1000 or 500 ppm (75 or 40 mg/kg/day), and after 10 intragastric intubations of 1000 mg/kg body wt/day. Single oral doses as high as 4000 mg/kg had no effect on the retina. Of three similar compounds tested in 20-day feeding studies for retinopathic activity, p-nitrophenyl 2-(aminooxy) propionate (2500 ppm, 230 mg/kg/day) was inactive. Methyl 2-(cinnamidooxy) propionate and methyl 2-(acetamidooxy) propionate at the same dose and duration produced lesions similar to those with methyl 2-(ureidooxy) propionate but differing in magnitude. With light microscopy, the lesions produced were characterized by focal migrations of the outer nuclear cells into outer photoreceptor segments. This migration appeared to be a result of displacement due to loss of the outer photoreceptor segments, since under electron microscopy, the primary target sites appeared to be the lamellar disks of the outer photoreceptor segments and the inner segments were less damaged. With electron microscopy, photoreceptor nuclei migrated into the area of destroyed outer segments and apposed to the pigment cells. Some photoreceptor nuclei showed pycnosis and karyorrhexis. Retinal pigment cells exhibited disruption of cytoplasmic processes, cytoplasmic vacuolation, and numerous phagosomes which contained the degraded outer photoreceptor segments.

Naproxen up to Date

Naproxen is a propionic acid derivative with analgesic and anti-inflammatory activity which has been widely used in the treatment of rheumatic diseases. Naproxen has been well studied in rheumatoid arthritis and is as effective as aspirin but better tolerated, thus enabling more patients to continue with treatment. For this reason some clinicians now prefer to try propionic acid derivatives, such as naproxen, before aspirin in arthritic patients. In comparative studies with other non-steroidal anti-inflammatory drugs, such as indomethacin, ibuprofen, fenoprofen and others, all drugs were usually of similar overall efficacy although naproxen was sometimes preferred: but as with other non-steroidal anti-inflammatory agents, not all patients will respond to naproxen and in such cases other agents should also be tried until the most satisfactory drug is found for each patient. Naproxen is also effective in degenerative joint diseases of the hip and knee, although further well designed studies are needed to more clearly define its relative place compared with newer drugs such as diclofenac or diflunisal. Results of other comparative studies have shown that naproxen is a suitable alternative to phenylbutazone or indomethacin in ankylosing spondylitis and to aspirin in juvenile rheumatoid arthritis. Naproxen appears to be effective in reducing pain and swelling in acute gout and is an effective analgesic in patients with pain following surgery or trauma and in pain of dysmenorrhoea. Naproxen has generally been better tolerated than aspirin or indomethacin at the dosages used. Because of its relatively long plasma half-life, naproxen can with convenieice be given twice daily, and there is some evidence that once daily dosage is as effective in rheumatoid arthritis.

Naproxen

Naproxen, a propionic acid derivative, is a nonsteroidal anti-inflammatory, antipyretic and analgesic agent which has been widely used in the treatment of rheumatoid arthritis, degenerative joint disease, ankylosing spondylitis, acute gout, and periarticular diseases such as bursitis, tendinitis and tenosynovitis since 1973. It has also proved effective in the treatment of patients with painful states and with dysmenorrhoea. Pharmacology. Its activity in animal models of inflammation is presumed to be mediated through its demonstrated ability to inhibit prostaglandin synthesis although other actions of the drug may play a role. Its administration effectively blocks the erosion of cartilage and bone occurring in the adjuvant arthritis syndrome in the rat. It interferes with platelet aggregation both in animals and man. It blocks yeast-induced hyperpyrexia in the rodent and suppresses fever in man. Pharmacokinetics. The pharmacokinetics of naproxen in man are relatively simple. It is essentially completely absorbed after oral or rectal administration and reaches peak plasma concentrations in about two hours. The sodium salt is absorbed more rapidly than naproxen acid. Naproxen is extensively bound to plasma proteins. Its metabolic half-life averages 13 hours, justifying a loading dose regimen when acute effects are desired, and twice-daily administration for maintenance. Naproxen is excreted almost entirely in the urine as the native molecule, its oxidative 6-desmethyl metabolite and their respective conjugates. Its kinetics are dose dependent. As the dose is increased above one gram a day, plasma level increments are less than proportional to dose. Therapeutic trials. Naproxen, in doses of 500–700 mg daily, has been evaluated in comparative trials with aspirin and indomethacin in rheumatoid arthritis and degenerative joint disease. Its therapeutic efficacy has been similar to and sometimes superior to these agents; in most cases naproxen was better tolerated. In more limited trials it has also compared favourably to the newer NSAIs: ibuprofen, fenoprofen and ketoprofen. Initial results in patients with ankylosing spondylitis and gout showed efficacy comparable to phenylbutazone. Comparative trials against a wide variety of control agents have shown naproxen to be an effective analgesic in patients with moderate pain resulting from orthopaedic, dental, and other surgical procedures; it has been particularly useful in pain associated with uterine contractions. Side effects. Naproxen has been well tolerated in short and long term studies. Adverse effects necessitated the discontinuance of less than six per cent of a large cohort of rheumatoid arthritis patients in one year of treatment. Gastrointestinal side effects such as heartburn, nausea and dyspepsia have been most frequently reported; these occur significantly less frequently than when therapeutically equivalent doses of aspirin are administered. Potentially serious events such as gastrointestinal bleeding have been uncommon but a few fatalities have been reported. Other rare reactions reported include angioneurotic oedema, thrombocytopenia, agranulocytosis, and jaundice. Dosage. The usual adult dose in the treatment of rheumatic conditions is 500–750 mg daily, usually in two divided doses. Dosage may be adjusted according to individual requirements and response. Increasing the dose to one gram daily may provide a greater therapeutic effect without loss of tolerance. Doses over one gram a day have been used primarily in the treatment of acute gout and for the control of pain.

The identification of ibuprofen and analogues in urine by pyrolysis gas chromatography mass spectrometry.

The pyrolysis gas chromatography mass spectrometry of Ibuprofen, Fenoprofen, Naproxen and Ketoprofen, a series of anti-inflammatory propionic acid derivatives, is shown to proceed via decarboxylation and elimination to yield characteristic ethyl and vinyl fragments. The pyrogram enables the identification of the drug to be achieved as the pure compound, in a formulated dosage form or excreted in urine. The presence of metabolites derived from Ibuprofen causes four new fragments to be observed in the urine pyrogram. The identification of 16 components of the control urine pyrogram is presented.

ChemInform Abstract: THE SYNTHESIS AND PRELIMINARY BIOLOGICAL TESTING OF SOME BICYCLIC GUANIDINE DERIVATIVES

AbstractDie Kondensation des Imidazolins (I) mit den ogß‐ungesättigten Estern (II) gibt bei Raumtemp.‐ mit (IId) beim Erhitzen ‐ die Imidazopyrimidinone (III).

Fenbufen compared with indomethacin in osteoarthrosis

A double-blind, crossover clinical trial was carried out with a new propionic acid derivative, fenbufen, versus indomethacin and placebo in 20 patients with osteoarthrosis. Active drug dosages of 75 mg indomethacin daily and 600 mg fenbufen daily were used. Fenbufen scored significantly better than placebo with respect to two and indomethacin better than placebo with respect to five of the assessment indices used. Indomethacin was significantly better than fenbufen with respect to two indices and, overall, appeared more effective in the dosages tested. Biochemical abnormalities of liver function (serum alkaline phosphatase and/or SGOT) were noted in 5 patients after fenbufen therapy (in 3 patients after 4-weeks' treatment and in 2 after 6 weeks) but in none after indomethacin therapy. The significance of these findings is discussed. It is concluded that fenbufen should be withdrawn from further clinical use until the true incidence and significance of hepatotoxicity has been evaluated.

The synthesis and preliminary biological testing of some bicyclic guanidine derivatives

Condensation of 2-amino-2-imidazoline with α,β-unsaturated esters yields an imidazo[1,2-a]pyrimidin-7-one system whereas reaction with an acetylenic ester or β-keto esters gives the corresponding unsaturated imidazo[1,2-a]pyrimidin-5-one product. In some cases a non-cyclized product is obtained under milder reaction conditions. Cyclization of ω- (imidazolin-2-ylamino) acids yields fused bicyclic products for the acetic and propionic acid derivatives whereas the butyric acid analogue cyclizes to yield an N-substituted pyrrolidone. Representative examples of all these compounds do not show mutagenic properties in a modified Ames test and are mainly inactive when tested for central nervous system activity.