58-55-9 Usage
Chemical Description
Different sources of media describe the Chemical Description of 58-55-9 differently. You can refer to the following data:
1. Theophylline is a xanthine derivative used in the treatment of respiratory diseases.
2. Theophylline, thymine, and uracil are nucleic acid bases, while 1-chloro-2,3-epoxypropane and methacryloyl chloride are used in the preparation of 2-propanol derivatives.
Description
Theophylline is a methylxanthine that acts as a weak bronchodilator. It is useful for chronic therapy and is not helpful in acute exacerbations.Theophylline is a methylxanthine alkaloid that is a competitive inhibitor of phosphodiesterase (PDE; Ki = 100 μM). It is also a non-selective antagonist of adenosine A receptors (Ki = 14 μM for A1 and A2). Theophylline induces relaxation of feline bronchiole smooth muscle precontracted with acetylcholine (EC40 = 117 μM; EC80 = 208 μM). Formulations containing theophylline have been used in the treatment of asthma and chronic obstructive pulmonary disease (COPD).
Chemical Properties
white to light yellow crystal powder
Physical properties
Appearance: white, crystalline powder, odorless, with a bitter taste. Solubility:
freely soluble in solutions of alkali hydroxides and in ammonia; sparingly soluble
in alcohol, in chloroform, and in ether; slightly soluble in water. Water solubility,
7.36?g/L (20?°C); density, 1.62?g/cm3
; melting point, 270–274?°C; boiling point,
390.1?°C (760? mmHg); flash point, 189.7?°C; vapor pressure, 2.72E-06? mmHg
(25?°C).
History
Theophylline was firstly extracted from tea leaves and chemically identified by the
German biologist Albrecht Kossel. A cup of tea contains about 1?mg/mL theophylline. In 1895, a chemical synthesis of theophylline starting with 1,3-dimethyluric
acid was described by Emil Fischer and Lorenz Ach. Theophylline was synthesized by Wilhelm Traube in 1900. Aminophylline, a derivative of theophylline ethylenediamine, is widely used due to its greater aqueous solubility.Theophylline was firstly used clinically as a diuretic in 1902. Twenty years later
it was firstly reported by D.I.?Macht and G.C.?Ting for asthma treatment in pig bronchial smooth muscle. The first successful clinical use of theophylline in bronchial
asthma was reported in 1922 by S.? Hirsch, who described that four patients
responded well to the rectal administration of a mixture of 66.7% theophylline and
33.3% theobromine. He also tested the combination of theophylline with theobromine on bovine bronchial smooth muscle strips and noted smooth muscle relaxation. Thus he concluded that dimethylxanthines act by producing relaxation of
bronchial smooth muscle. In 1937, two concurrent but independent clinical trials
reported that methylxanthines were efficacious in asthma. The Food and Drug
Administration approved the use of theophylline for asthma in the USA in 1940.There are more than 300 derivatives of theophylline. The main derivatives
include aminophylline, dihydroxypropyl theophylline, and oxtriphylline.2. Doxofylline: 7-(1,3-dioxalan-2-ylmethyl) theophylline. It has antitussive and
bronchodilator effects. In animal and human studies, it has shown similar
efficacy to theophylline but with fewer side effects. Related research has
showed that the effect of doxofylline on airway relaxation is 10–15 times that of
aminophylline.3. Diprophylline: 7-(2,3-dihydroxypropyl)-1,3-dimethyl-3,7-dihydro-1H-purine-
2,6-dione. Diprophylline is the neutral preparation of theophylline. It causes less
of nausea and gastric irritation.4. Oxtriphylline: choline theophyllinate; administered orally. Oxtriphylline is five
times more soluble than aminophylline.
Uses
theophylline is tonic and skin conditioning. Its cosmetic activity is not clearly or definitively established. It is most often found in anti-cellulite products. Theophylline is in the same family of bio chemicals as caffeine. It is naturally occurring in tea.
Definition
ChEBI: Theophylline is a dimethylxanthine having the two methyl groups located at positions 1 and 3. It is structurally similar to caffeine and is found in green and black tea. It has a role as a vasodilator agent, a bronchodilator agent, a muscle relaxant, an EC 3.1.4.* (phosphoric diester hydrolase) inhibitor, an anti-asthmatic drug, an anti-inflammatory agent, an immunomodulator, an adenosine receptor antagonist, a drug metabolite, a fungal metabolite and a human blood serum metabolite.
Indications
Twenty years ago theophylline (Theo-Dur, Slo-bid,
Uniphyl, Theo-24) and its more soluble ethylenediamine
salt, aminophylline, were the bronchodilators of
choice in the United States. Although the β2-adrenoceptor
agonists now fill this primary role, theophylline
continues to have an important place in the therapy of
asthma because it appears to have antiinflammatory as
well as bronchodilator activity.
General Description
Odorless white crystalline powder. Odorless. Bitter taste.
Air & Water Reactions
Slightly soluble in water.
Reactivity Profile
Theophylline neutralizes acids in exothermic reactions to form salts plus water. May be incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides. Flammable gaseous hydrogen may be generated in combination with strong reducing agents, such as hydrides.
Hazard
Questionable carcinogen.
Fire Hazard
Flash point data for Theophylline are not available, however Theophylline is probably combustible.
Biological Activity
Bronchodilator, anti-inflammatory and immunomodulator. Antagonizes adenosine receptors and is a weak non-selective inhibitor of phosphodiesterases (PDEs).
Biochem/physiol Actions
Phosphodiesterase inhibitor; diuretic; cardiac stimulant; muscle relaxant; asthma medication.
Mechanism of action
In spite of a great deal of investigation, just how theophylline causes bronchodilation is not clearly understood. Inhibition of the enzyme PDE, which is responsible for the hydrolysis of cAMP and cyclic guanosine monophosphate (cGMP), generally is put forth as the mechanism of action; however, theophylline also is an adenosine antagonist and has been implicated in stimulation of the release of catecholamines. It has been clearly shown that theophylline does inhibit PDEs in vitro, and x-ray crystallographic studies have identified the binding residues that interact with the methylxanthines. Theophylline binds to a subpocket of the active site and appears to be sandwiched between a phenylalanine and a valine via hydrophobic bonds. Its binding affinity is reinforced by hydrogenbonding between a tyrosine and N-7 and a glutamine and O-6 of the xanthine ring system. There are more than 11 families of PDEs, and studies have shown that theophylline binds in a similar manner to both the PDE4 and PDE5 family isoforms.
Pharmacology
Different sources of media describe the Pharmacology of 58-55-9 differently. You can refer to the following data:
1. Smooth muscle relaxation, central nervous system
(CNS) excitation, and cardiac stimulation are the principal
pharmacological effects observed in patients
treated with theophylline.The action of theophylline on
the respiratory system is easily seen in the asthmatic by
the resolution of obstruction and improvement in pulmonary
function. Other mechanisms that may contribute
to the action of theophylline in asthma include
antagonism of adenosine, inhibition of mediator release,
increased sympathetic activity, alteration in immune
cell function, and reduction in respiratory muscle
fatigue. Theophylline also may exert an antiinflammatory
effect through its ability to modulate inflammatory
mediator release and immune cell function.
Inhibition of cyclic nucleotide phosphodiesterases is
widely accepted as the predominant mechanism by
which theophylline produces bronchodilation. Phosphodiesterases
are enzymes that inactivate cAMP and
cyclic guanosine monophosphate (GMP), second messengers
that mediate bronchial smooth muscle relaxation.
2. Theophylline can reduce the tension of smooth muscle and dilate respiratory tract; It can promote the release of endogenous epinephrine and norepinephrine and relax airway smooth muscle; Inhibit the release of calcium ions from the endoplasmic reticulum of smooth muscle, reduce the concentration of intracellular calcium ions and produce respiratory tract dilation. Theophylline has a strong relaxation effect on smooth muscle, but it is not as good as β Receptor agonists. On October 27, 2017, the list of carcinogens published by the international agency for research on cancer of the World Health Organization was preliminarily sorted out for reference. Theophylline was included in the list of Category 3 carcinogens.
Clinical Use
The principal use of theophylline is in the management
of asthma. It is also used to treat the reversible component
of airway obstruction associated with chronic obstructive
pulmonary disease and to relieve dyspnea associated
with pulmonary edema that develops from
congestive heart failure.
Side effects
Theophylline has a narrow therapeutic index and produces
side effects that can be severe, even life threatening.
Importantly, the plasma concentration of theophylline
cannot be predicted reliably from the dose. In
one study, the oral dosage of theophylline required to
produce therapeutic plasma levels (i.e., between 10 and
20 μg/mL) varied between 400 and 3,200 mg/day.
Heterogeneity among individuals in the rate at which
they metabolize theophylline appears to be the principal
factor responsible for the variability in plasma levels.
Such conditions as heart failure, liver disease, and severe
respiratory obstruction will slow the metabolism of
theophylline.
Safety Profile
Human poison by
ingestion, parenteral, intravenous, and rectal
routes. Experimental poison by multiple
routes. An experimental teratogen. Human
systemic effects: coma, convulsions or effect
on seizure threshold, cyanosis, EKG
changes, fever and other metabolic effects,
heart arrhythmias, heart rate change,
hyperglycemia, metabolic acidosis, nausea or
vomiting, potassium-level changes,
respiratory stimulation, salivary gland
changes, somnolence, tremor. Experimental
reproductive effects. Human mutation data
reported. Used as a dturetic, cardtac
stimulant, smooth muscle relaxant, and to
treat asthma. When heated to
decomposition it emits toxic fumes of NOx.
Synthesis
Theophylline, 1,3-dimethylxanthine (23.3.5), is present in small quantities
in tea leaves. It is synthesized synthetically by the Traube method, a general method suggested
for making purine bases. In the given example, reacting N,N-dimethylurea with
cyanoacetic ether in the presence of acetic anhydride gives cyanoacetylmethylurea (23.3.1),
which cyclizes into 6-amino-1,3-dimethyluracil (23.3.2). The resulting compound transforms
into 5-nitroso-6-amino-1,3-dimethyluracil (23.3.3) upon reaction with nitric acid.
Reduction of the nitroso group gives 5,6-diamino-1,3-dimethyluracil (23.3.4), the subsequent
reaction of which with formamide gives the desired theophylline (23.3.5).
Drug interactions
Potentially hazardous interactions with other drugs Antibacterials: increased concentration with azithromycin, clarithromycin, erythromycin, ciprofloxacin, norfloxacin and isoniazid; decreased plasma levels of erythromycin if erythromycin taken orally; increased risk of convulsions if given with quinolones; rifampicin accelerates metabolism of theophylline. Antidepressants: concentration increased by fluvoxamine - avoid or halve theophylline dose and monitor levels; concentration reduced by St John’s wort - avoid. Antiepileptics: metabolism increased by carbamazepine, phenobarbital and primidone; concentration of both drugs increased with fosphenytoin and phenytoin. Antifungals: concentration increased by fluconazole and ketoconazole. Antivirals: metabolism of theophylline increased by ritonavir; concentration possibly increased by aciclovir. Calcium-channel blockers: concentration increased by diltiazem and verapamil and possibly other calcium-channel blockers. Deferasirox: concentration of theophylline increased. Febuxostat: use with caution. Interferons: reduced metabolism of theophylline. Tacrolimus: may increase tacrolimus levels. Ulcer-healing drugs: metabolism inhibited by cimetidine; absorption possibly reduced by sucralfate.
Environmental Fate
Theophylline is readily broken down in the environment.
It may undergo photolytic degradation in the air or when
exposed to light. In moist soil, or aqueous environments, it
undergoes rapid biodegradation.
Metabolism
Chemically, theophylline is 1,3-dimethylxanthine and contains both an acidic and a basic nitrogen
(N-7 and N-9, respectively). Physiologically, it behaves as an acid (pKa = 8.6), and its poor
aqueous solubility can be enhanced by salt formation with organic bases. Theophylline is
metabolized by a combination of C-8 oxidation and N-demethylation to yield methyluric acid
metabolites. The major urinary metabolite is 1,3-dimethyl uric acid, which is the
product of the action of xanthine oxidase. Because none of the metabolites is uric acid itself, theophylline can be safely given to patients who suffer from gout.
Purification Methods
It crystallises from H2O as the monohydrate which becomes anhydrous above 100o. It is freely soluble in hot H2O, but its solubility at 15o is 0.44%. It complexes with heavy metals. It is a diuretic, vasodilator and a cardiac stimulant. [Lister Purines Part II, Fused Pyrimidines Brown Ed, Wiley-Interscience pp253-254 1971, ISBN 0-471-38205-1, Beilstein 26 H 455, 26 I 134, 26 II 263, 26 III/IV 2331.]
Toxicity evaluation
In acute overdoses, theophylline often causes severe emesis (75% in acute vs 30% in chronic). The emesis is often difficult to control with antiemetics. It is thought that theophylline causes increased gastric acid secretion and smooth muscle relaxation. Theophylline causes a release of endogenous catecholamines, and therefore is a cardiac stimulant. There is a positive inotropic and dose-dependent chronotropic response. Tachydysrhythmias, especially supraventricular tachycardia, are common due to adenosine receptor antagonism. Ventricular tachydysrhythmias can occur as well in acute overdose; however, they are rare at therapeutic concentrations. Rapid administration of aminophylline has resulted in sudden cardiac death. Hypokalemia, hypercalcemia, and hyperglycemia may contribute to arrhythmias as well. In cases of chronic toxicity, dysrhythmias occur at lower serum concentrations (40–80 mg ml-1) compared to acute overdose. Theophylline will stimulate the CNS respiratory center causing increased respiratory rate and can lead to respiratory alkalosis. Theophylline will cause CNS stimulation and vasoconstriction, similar to caffeine, and may lead to headache, anxiety, agitation, insomnia, tremor, irritability, hallucinations, and seizures. Methylxanthines exhibit weak diuretic effects by increasing cardiac output and renal vasodilation. Theophylline has a narrow therapeutic index, with 12–25% of overdose patients developing serious or life-threatening symptoms including arrhythmias and seizure. Toxicity can develop at lower serum concentrations for those treated chronically or older patients. Age greater than 60 years and chronic use are risk factors for increased morbidity and mortality.
Precautions
Theophylline should be used with caution in patientswith myocardial disease, liver disease, and acutemyocardial infarction. The half-life of theophylline isprolonged in patients with congestive heart failure.Because of its narrow margin of safety, extreme cautionis warranted when coadministering drugs, such as cimetidineor zileuton, that may interfere with the metabolismof theophylline. Indeed, coadministration of zileutonwith theophylline is contraindicated. It is alsoprudent to be careful when using theophylline in patientswith a history of seizures.
References
Fischer., Ber., 30, 553 (1897) Schwabe., Arch. Pharm., 245, 312 (1907)Biltz, Strufe.,Annalen, 404, 137, 170(1914)Yoshitomi., Chem. Abstr., 19,2303 (1925) Mossini., Boll. chim. farm., 75, 557 (1936)Deichmeister., Farm. Zhur., 13, 18 (1940) Deichmeister., Chem. Zentr., 1, 1280 (1942) Deniges., Bull. trav. soc. ph arm. Bordeaux, 79, 141 (1941)Lesser., Drug & Cosmetic Ind., 66, 276,340 (1950)
Check Digit Verification of cas no
The CAS Registry Mumber 58-55-9 includes 5 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 2 digits, 5 and 8 respectively; the second part has 2 digits, 5 and 5 respectively.
Calculate Digit Verification of CAS Registry Number 58-55:
(4*5)+(3*8)+(2*5)+(1*5)=59
59 % 10 = 9
So 58-55-9 is a valid CAS Registry Number.
InChI:InChI=1/C7H10N4O2/c1-10-5-4(8-3-9-5)6(12)11(2)7(10)13/h3-5H,1-2H3,(H,8,9)
58-55-9Relevant articles and documents
Coordination polymers as potential solid forms of drugs: Three zinc(ii) coordination polymers of theophylline with biocompatible organic acids
Lou, Benyong,He, Fengdan
, p. 309 - 316 (2013)
The biocompatible organic acids such as acetic acid (Hac), benzoic acid (Hbz) and nicotinic acid (Hnit), have been employed as second ligands to assemble biocompatible coordination polymers of theophylline (Hthp), respectively. As a result, three coordination polymers [Zn2(thp) 2(ac)(OH)]n (1), [Zn2(thp)2(bz)(OH)] n (2) and [Zn(thp)(nit)]∞ (3) have been synthesized through hydrothermal and mechanochemical reactions. Theophylline could be released rapidly in simulated gastroenteric fluid (phosphate-buffered solution, PBS) and slow release of theophylline could be achieved from the three polymers in pure water at 37 °C with continuous stirring.
-
Kostareva et al.
, (1976)
-
Isolation and characterization of 1,3-dimethylisoguanine from the Bermudian sponge Amphimedon viridis
Mitchell,Whitehill,Trapido-Rosenthal,Ireland
, p. 727 - 728 (1997)
The new compound 1,3-dimethylisoguanine has been isolated and characterized from the Bermudian sponge Amphimedon viridis. Chemical conversion of the natural product to theophylline and 2D NMR methods were used to determine the position of the methyl groups on the purine ring. Analysis of the mass spectral fragmentation pattern allowed assignment of the purine ring as isoguanine.
SERS multiplexing of methylxanthine drug isomersviahost-guest size matching and machine learning
Chio, Weng-I Katherine,Dinish, U. S.,Jones, Tabitha,Lee, Tung-Chun,Liu, Jia,Olivo, Malini,Parkin, Ivan P.,Perumal, Jayakumar
supporting information, p. 12624 - 12632 (2021/10/06)
Multiplexed detection and quantification of structurally similar drug molecules, methylxanthine MeX, incl. theobromine TBR, theophylline TPH and caffeine CAF, have been demonstratedviasolution-based surface-enhanced Raman spectroscopy (SERS), achieving highly reproducible SERS signals with detection limits down to ～50 nM for TBR and TPH, and ～1 μM for CAF. Our SERS substrates are formed by aqueous self-assembly of gold nanoparticles (Au NPs) and supramolecular host molecules, cucurbit[n]urils (CBn,n= 7, 8). We demonstrate that the binding constants can be significantly increased using a host-guest size matching approach, which enables effective enrichment of analyte molecules in close proximity to the plasmonic hotspots. The dynamic range and the robustness of the sensing scheme can be extended using machine learning algorithms, which shows promise for potential applications in therapeutic drug monitoring, food processing, forensics and veterinary science.
Synthesis of a new class of bisheterocycles via the Heck reaction of eudesmane type methylene lactones with 8-bromoxanthines
Patrushev, Sergey S.,Rybalova, Tatyana V.,Ivanov, Igor D.,Vavilin, Valentin A.,Shults, Elvira E.
, p. 2717 - 2726 (2017/04/14)
The eudesmane-type methylene lactones (isoalantolactone, alantolactone, 4,15-epoxyisoalantolactone, 2′,2′-dichloro-4H-spiro[cyclopropane-1′,4-eudesma-11(13)-en-8β,12-olide], and alantolactone) react with 8-bromoxanthines (8-bromocaffeine, 8-bromotheobromine, 8-bromo-3-butyltheobromine, 8-bromotheophylline, 8-bromo-9-butyltheophylline) under Heck reaction conditions to produce the target (E)-13-(2,6-dioxo-2,3-dihydro-1H-purin-8-yl)eudesma-4(15),11(13)-dien-8β,12-olides and the subsequent endocyclic isomers - 11-(2,6-dioxo-2,3-dihydro-1H-purin-8-yl)-13-normethyleudecma-4(15)-7(11)-dien-8α,12-olides. It was revealed that the yield and product ratio depends on the reaction conditions and the structure of methylene lactone. The effectiveness of Pd(OAc)2–caffeine catalytic system has been demonstrated in this reaction. The electric eel acetylcholinesterase inhibitory activity of the eudecmanolide-xanthine hybrids was evaluated. Among the new type bisheterocycles compound 27 with butyl and 2-oxodecahydronaphtho[2,3-b]furan-3(2H)-ylidene)methyl substituents at C-7 and C-8 of the xanthine core showed moderate activity with IC50 value of 40?μM.
A method of synthesis of theophylline
-
Paragraph 0027; 0028; 0032, (2016/10/08)
The invention discloses a method for synthesizing theophylline. The method comprises the following steps: performing a methylation reaction on dimethyl sulfate, 6-aminouracil and a sodium hydroxide solution; adding formic acid for a carboxylation reaction; adding a mixed acid solution formed by mixing fuming nitric acid and concentrated sulfuric acid at a volume ratio of (0.8-1.1):(0.9-1.2), and performing heating reflux for a nitrosylation reaction; and finally, adding iron powder and anhydrous acetic acid for a cyclization reaction to obtain theophylline. According to the method disclosed by the invention, the yield is greatly higher than that of the prior art, the operation process is simple, and the reaction conditions are simple.
