Theophyllines 7-substitution

In the USA, LTRAs have largely replaced theophylline as the incremental drug for the treatment of moderate and severe asthma, where LABA plus ICS alone do not provide adequate control. For patients with mild persistent asthma, LTRAs have been designated as a suitable substitute for low dose ICS by the National Asthma Education Panel Program (NAEPP) of the National Heart and Lung Institute (National Institutes of Health). However, inhaled ICS are more efficacious. 

Alkylation of substituted theophylline 237 with 1,2-dibromoethane furnished oxazinopurine 238 in good yield (Equation 28) <2000EJ03489>. 

Purines A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric add is the metabolic end product of purine metabolism. [NIH]... 

Complexation with caffeine and theophylline-7-acetate depresses the rate of alkaline hydrolysis of substituted phenyl benzoates and is consistent with the formation of molecular complexes with 1 1 stoichiometry between the hosts and esters stacking of the xanthines is excluded as an explanation in the range of concentrations studied. Inhibition of hydrolysis is attributed to repulsion of the hydroxide ion from the host-ester complex by the extra hydrophobicity engendered by the xanthine host, as well as by the weaker binding of the transition state to the host compared with that in the host-ester complex. ... 

Smoking cessation, with or without nicotine substitutes, may alter response to concomitant medication in ex-smokers. Smoking may affect alcohol, benzodiazepines, beta-adrenergic blockers, caffeine, clozapine, fluvoxamine, olanzapine, tacrine, theophylline, clorazepate, lidocaine (oral), estradiol, flecanide, imipramine, heparin, insulin, mexiletine, opioids, propranolol, catecholamines, and cortisol. 

A structure determination of CdL(H20)5 3H20 (L = guanosine-5 -phosphate) reveals a cadmium ion octahedrally coordinated by live water molecules and the N-7 of the purine ring system (Cd—N = 2.37 A Cd—O = 2.24-2.34 A).568 Similarly, a structure determination of CdL2(H20)4 (L = 8-azahypoxanthinato) reveals octahedral cadmium bonded to N-7 of the purine anions and to four water molecules.569 Theophylline (83) is frequently used as a substitute for guanine (84) in model systems, and the complexes [CdI (RNH2)2(H20)2] (L = 83) have been described.570... 

For the relief of pain arising from spasm of smooth muscle, as in renal or biliary colic, morphine is frequently employed. Other measures including antispasmodics such as atropine, atropine substitutes, theophylline, nitrites, and heat may be employed first however, if they are ineffective, meperidine, methadone, or opiates must be used. Morphine relieves pain only by a central action and may aggravate the condition producing the pain by exaggerating the smooth muscle spasm. Morphine may also be indispensable for the relief of pain due to acute vascular occlusion, whether this be peripheral, pulmonary, or coronary in origin. In painful acute pericarditis, pleurisy, and spontaneous pneumothorax, morphine is likewise indicated. Carefully chosen and properly spaced doses of codeine or morphine may occasionally be necessary in pneumonia to control pain, dyspnea, and restlessness. Traumatic pain arising from fractures, bums, etc., frequently requires morphine. In shock, whether due to trauma, poisons, or other causes, morphine may be required to relieve severe pain. 

Furafylline, a structural analogue of theophylline, was produced as a long-acting substitute for theophylline. Early clinical studies showed that the compound... 

An unusual ring contraction proceeded on treatment of 6-alkyl-7-methoxy-l, 3-dimethyllumazines (413) with activated aluminum in methanolic ammonia to give 8-substituted theophyllines (416)... 

The principal IR absorptions of 3,20,23 5, and 913,18 (which compounds have been recommended for the identification of alcohols24 25 and primary or secondary amines18) and of 2-substituted saccharins (10)20,23 recorded under identical conditions appear as sets of relatively constant frequencies. For structures with an acidic hydrogen, e.g., compounds (l)16 (2), (9), self-association and complex formation is expected, but the dipolar 3-dialkylamino derivatives (5b) also tend to associate in various solvents.14 Saccharin (1) has been reported to form 1 1 complexes with purines, e.g., theophylline and caffeine, and with amides and... 

The naturally occurring purines fall into 4 main groups. (1) Simple substituted derivatives of purine (1) such as adenine (2) and various 6-AT-substituted derivatives. (2) Monoxo-dihydropurines such as hypoxanthine (3), guanine (4), and isoguanine (5). f3) Dioxotetra-hydropurines such as xanthine (6) and methylated derivatives including the 3,7-dimethyl derivative theobromine (7), 1,3-dimethylxanthine or theophylline f8), and 1,3,7-trimethylxanthine or caffeine (9). (4) Trioxohexahydropurines such as uric acid (10). 

Alkylation of the thioxopurines may lead to both S- and A-alkylation but in many examples the 5-alkyl derivative is probably first formed under mild conditions and then rearranges to the A-substituted derivative under more fordng conditions. An exception appears to be 6-thioxo-l,6-dihydropurine (123) which with dimethyl sulfate in alkaline solution produces the relatively stable 6-methylthiopurine (124) (22LA(426)306). Similar methylation of 6-thiotheobromine in alkali with methyl iodide at room temperature furnishes the methylthio derivative (125) whereas, in contrast, the 6-thiocaffeine derivative (126) is produced with dimethyl sulfate and alkali at 40 °C (62JCS1863) and corresponding 5- and A-methyl derivatives are produced from the 6-thio analogue of theophylline. 

Purines have also been obtained by transformations of appropriate pteridines (75CPB2678,73CB3203). Also the 6-azapteridine (363) on reduction produced 8-substituted theophylline (Scheme 154) (69MI40900). Similarly the 7-azapteridine (364) with hot formamide afforded 8-phenyltheophylline (Scheme 154) (76H(4)749), and the diazepinone (365) with alkoxide also produced the 9-(2-propenyl)purine (366) by what is ultimately a Traube synthesis (Scheme 155) (70JHC1029). 

This type of precursor has been widely used for the synthesis of different 8-substituted theophyllines.Thus, treatment of 5-(aryldiazenyl)-l,3-dimethyluracil-6-amines with ethyl propiolate gives the corresponding Michael-type adducts, 5-(aryldiazenyl)-l, 3-dimethyl-6-[(2-cthoxycarbonylvinyl)amiiio]uiacils, which on treatment with a mixture of hydrochloric and acetic acid result in acid-catalyzed rearrangement to give the 8-(anilinomethyl)theophylline derivatives, c.g. the sequence 8 9 10. 

Pnrines, substituted (direct injection, LLE, SPE) Racemethorphan, racemorphan (optical isomers) Theophylline metabolites (SPE)... 

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