DOXOFYLLINE SPECTRAL DATA

DOXOFYLLINE

69975-86-6  CAS NO

7-(1,3-dioxolan-2-ylmethyl)-1,3-dimethylpurine-2,6-dione

Formula	C11H14N4O4
Mol. mass	266.25 g/mol

Doxofylline (INN), (also known as doxophylline) is a xanthine derivative drug used in the treatment of asthma.^[1]

It has antitussive and bronchodilator^[2] effects, and acts as aphosphodiesterase inhibitor.^[3]

In animal and human studies, it has shown similar efficacy to theophylline but with significantly fewer side effects.^[4]

Unlike other xanthines, doxofylline lacks any significant affinity for adenosine receptorsand does not produce stimulant effects. This suggests that its antiasthmatic effects are mediated by another mechanism, perhaps its actions on phosphodiesterase.^[1]

Doxofylline, [7-(1, 3-dioxolan-2-ylmethyl)-3, 7-dihydro-1, 3-dimethyl-1H-purine-2, 6-dione] is a new bronchodilator xanthine based drug which differs from theophylline by the presence of dioxalane group at position 7. It is used in the treatment of bronchial asthma, chronic obstructive pulmonary disease (COPD), and chronic bronchitis . The mechanism of action is similar to that of theophylline in that it inhibits phosphodiesterase (PDE-IV), thereby preventing breakdown of cyclic adenosine monophosphate (cAMP). Increase in cAMP inhibits activation of inflammatory cells resulting in bronchodilating effect [52]. In contrast to theophylline, doxofylline has very low affinity towards adenosine A1 and A2 receptors which explain its better safety profile

Doxofylline (7-(l,3-dioxalan-2-ylmethyl)-theophylline) is a drug derived from theophylline which is used in therapy as a bronchodilator, with anti-inflammatory action, in reversible airway obstruction. It is commonly administered in doses ranging from 800 to 1200 mg per day, orally, according to a dosage which provides for the intake of two to three dosage units per day in order to maintain therapeutically effective haematic levels. The doxofylline tablets commercially available generally contain 400 mg of active ingredient and release almost all the drug within one hour from intake. The half- life of the drug is around 6-7 hours and for this reason several administrations are required during the 24-hour period.

Obviously a drop in haematic concentration of the drug in an asthmatic patient or patient suffering from COPD (chronic obstructive pulmonary disease) can result in serious consequences, in which case the patient must have recourse to rescue medication, such as salbutamol inhalers.

Pharmaceutical techniques for obtaining the modified release of drugs have been known for some time, but no modified release formulation of doxofylline is known. In fact the present inventors have observed that there are significant difficulties in the production of a doxofylline formula that can be administered only once a day and in particular have encountered problems correlated with bioequivalence.

Various attempts to formulate doxofylline in modified release systems, with different known polymers, have not provided the desired results, i.e. a composition that can be administered once a day, bio equivalent to the plasmatic concentration obtained with the traditional compositions currently on sale. In fact currently, dosage units containing 400 mg of active ingredient are currently administered two/three times a day for a daily average of approximately 1000 mg of active ingredient, a dosage considered necessary to maintain the therapeutic haematic levels of doxofylline.

Such a dosage unit is currently marketed by Dr. Reddy's Laboratories Ltd as DOXOBID and has the following quali-quantitative composition: doxofylline (400 mg), colloidal silicon dioxide (13 mg), corn starch (63 mg), mannitol (40 mg), povidone (7 mg), microcrystalline cellulose (64 mg), talc (30 mg), magnesium stearate (3 mg) and water (0.08 ml).

1.  Cirillo R, Barone D, Franzone JS (1988). "Doxofylline, an antiasthmatic drug lacking affinity for adenosine receptors". Arch Int Pharmacodyn Ther 295: 221–37.PMID 3245738.
2. Poggi R, Brandolese R, Bernasconi M, Manzin E, Rossi A (October 1989). "Doxofylline and respiratory mechanics. Short-term effects in mechanically ventilated patients with airflow obstruction and respiratory failure". Chest 96 (4): 772–8.doi:10.1378/chest.96.4.772. PMID 2791671.
3.  Dini FL, Cogo R (2001). "Doxofylline: a new generation xanthine bronchodilator devoid of major cardiovascular adverse effects". Curr Med Res Opin 16 (4): 258–68.doi:10.1185/030079901750120196. PMID 11268710.
4. Sankar J, Lodha R, Kabra SK (March 2008). "Doxofylline: The next generation methylxanthine". Indian J Pediatr 75 (3): 251–4. doi:10.1007/s12098-008-0054-1.PMID 18376093.

• Dali Shukla, Subhashis Chakraborty, Sanjay Singh & Brahmeshwar Mishra. Doxofylline: a promising methylxanthine derivative for the treatment of asthma and chronic obstructive pulmonary disease. Expert Opinion on Pharmacotherapy. 2009; 10(14): 2343-2356, DOI 10.1517/14656560903200667, PMID 19678793

At present, domestic synthetic Doxofylline composed of two main methods: one is by the condensation of theophylline prepared from acetaldehyde and ethylene glycol, but this method is more complex synthesis of acetaldehyde theophylline, require high periodate oxidation operation. Another is a halogenated acetaldehyde theophylline and ethylene glycol is prepared by reaction of an organic solvent, the method were carried out in an organic solvent, whereby the product Theophylline caused some pollution, conducive to patients taking.

current domestic Doxofylline synthetic methods reported in the literature are: 1, CN Application No. 94113971.9, the name "synthetic drugs Doxofyllinemethod" patents, the patent is determined by theophylline with a 2 - (halomethyl) -1,3 - dimethoxy-dioxolane in a polar solvent, with a base made acid absorbent,Doxofylline reaction step. 2,  CN Application No. 97100911.2, entitled "Synthesis of Theophylline," the patent, the patent is obtained from 7 - (2,2 - dialkoxy-ethyl) theophylline with ethylene glycol in N, N-dimethylformamide solvent with an alkali metal carbonate to make the condensing agent, p-toluenesulfonic acid catalyst in the condensation Doxofylline.

Doxofylline of xanthine asthma drugs, and its scientific name is 7 - (1,3 - dioxolan - ethyl methyl) -3,7 - dihydro-1,3 - dimethyl-1H - purine-2 ,6 - dione. The drug developed by the Italian Roberts & Co. in 1988, listed its tablet tradename Ansimar. This product is compared with similar asthma drugs, high efficacy, low toxicity, oral LD50 in mice is 1.5 times aminophylline, non-addictive. Adenosine and its non-blocking agents, it does not produce bronchial pulmonary side effects, no aminophylline like central and cardiovascular system. U.S. patent (US4187308) reported the synthesis of doxofylline, theophylline and acetaldehyde from ethylene glycol p-toluenesulfonic acid catalyst in the reaction of benzene as a solvent Doxofylline. Theophylline acetaldehyde by the method dyphylline derived reaction with a peroxy periodate or 7 - (2,2 - dialkoxy-ethyl) ammonium chloride aqueous solution in the decomposition of theophylline converted to acetaldehyde theophylline . Former method is relatively complex, and the high cost of using periodic acid peroxide, low yield after France. And theophylline acetaldehyde and ethylene glycol solvent used in the reaction of benzene toxicity, harm to health, and the yield is low, with an average around 70%, not suitable for industrial production.

Theophylline-7-acetaldehyde (I) could react with ethylene glycol (II) in the presence of p-toluenesulfonic acid in refluxing benzene to produce Doxofylline.

.........................

CN102936248A

https://www.google.co.in/patents/CN102936248A?cl=en&dq=doxofylline&hl=en&sa=X&ei=prmeUp_yKMqClQXlj4DYDw&ved=0CIABEOgBMAg

the reaction is:

a, anhydrous theophylline and bromoacetaldehyde ethylene glycol as the basic raw material, purified water as a solvent with anhydrous sodium carbonate as acid-binding agent;

NMR

UV (95% C2H5OH, nm) λmax273 (ε9230); λmin244 (ε2190)

IR (KBr, cm-1) 1134 (CO); 1233 (CN) ; 1547 (C = N); 1656 (C = C); 1700 (C = O); 2993 (CH)

1H-NMR [CDCl3, δ (ppm)] 3.399 (s, 3H, N-CH3); 3.586 (S, 3H, N-CH3); 3.815-3.885 (m, 4H, OCH2 × 2); 4.581 (d, 2H, CH2); 5.211 (t, 1H, CH ); 7.652 (S, 1H, CH = N)

13C-NMR [CDCL3, δ (ppm)] 27.88 (CH3); 29.69 (CH3); 47.87 (CH2); 65.37 ( OCH2); 100.76 (CH); 107.26 (C = C); 142.16 (CH = N); 148.22 (C = C); 151.59 (C = O); 155.25 ( C

.........................

Spectral data of doxofylline
The ESI mass spectrum exhibited a protonated molecular ion peak at m/z 267 in positive ion mode indicating the molecular weight of 266. The tandem mass spectrum showed the fragment ions m/z 223, 181.2, 166.2, 138.1, 124.1 and 87.1.

The FT-IR spectrum, two strong peaks at 1697cm-1 and 1658cm-1 indicated presence of two carbonyl groups. A strong peak at frequency 1546cm-1 indicated presence of C=N stretch. A medium peak at 1232cm-1 was due to C-O stretch

FT IR

1H and 13C-NMR spectra of doxofylline and its degradation products were recorded by using Bruker NMR 300MHz instrument with a dual broad band probe and z-axis gradients. Spectra were recorded using DMSO-d6 as a solvent and tetramethylsilane as an internal standard.

1H NMR

13 C NMR

COMPARISONS

Zafirlukast

 

 

read at http://newdrugapprovals.org/2013/12/03/drug-spotlight-zafirlukast/

 

An Improved and Scalable Process for Zafirlukast: An Asthma Drug

Gilla Goverdhan ,^{ET AL}

Research and Development, Integrated Product Development, Dr. Reddy’s Laboratories Ltd., Survey No.’s 42, 45, 46, and 54, Bachupally, Qutubullapur, Ranga Reddy District - 500 072, Andhra Pradesh, India, Institute of Science and Technology, Center for Environmental Science, J.N.T. University, Kukatpally, Hyderabad - 500 072, Andhra Pradesh, India, and Research and Development, Inogent Laboratories Private Limited (A GVK BIO Company), 28A, IDA, Nacharam, Hyderabad - 500 076, India

Org. Process Res. Dev., 2009, 13 (1), pp 67–72

DOI: 10.1021/op800137b

 http://pubs.acs.org/doi/abs/10.1021/op800137b

 Melting range: 142−145 °C; MS (m/z): 576 (M⁺ + H); IR (KBr, cm⁻¹): 3326 (NH), 1679 (−C═O), ¹H NMR (CDCl₃) δ 7.0−8.0 (m, 11H), 3.7 (s, 3H), 4.0 (s, 2H), 3.9 (s, 3H), 2.6 (s, 3H), 1.45−1.8 (s, 9H).

..........................................................................

 US 20040186300 A1

 http://www.google.com/patents/US20040186300

 zafirlukast ethanolate as white powder with mp 132-133° C. (dec.) and 99.8% purity by HPLC. ¹H NMR (CDCl₃, δ, ppm): 1.22 (t, J 7.05 Hz, 3H), 1.45-1.87 (m, 8H), 2.66 (s, 3H), 3.67 (s, 3H), 3.73 (q, J 7.05 Hz, 4H), 3.79 (s, 3H), 3.98 (s, 2H), 5.08-5.23 (m, 1H), 6.58 (s, 1H), 6.73 (s, 1H), 7.01-7.51 (m, 9H), 8.23 (d, J 7.52 Hz, 1H), 9.67 (s, 1H).

Zafirlukast, cyclopentyl 3 - [2-methoxy-4- [(o-tolylsulfonyl)carbamoyl]- benzyl]-l-methyIindole-5-carbamate, having the formula:

is a first anti-asthmatic leukotriene antagonist (Matassa, V.G. et al, J. Med. Chem., v. 33, 1781 ^'(1990); U. S. Patent No. 4,859,692 and The Merck Index, 12th Edition, 10241). Methods for the preparation of Zafirlukast are described in J. Med. Chem., v. 33, 1781 (1990), U. S. Patent 4,859,692 and U.S. Patent 5,993,859 starting from methyl 3-methoxy-4-(l-methyl-5-nitroindol-3-ylmethyl)benzoate [la]

Alkyl (l-alkylindol-3-ylmethyl)benzoates of formula [lb] are useful as chemical intermediates in the pharmaceutical industry.

These compounds may be obtained by a process described in J. Med. Chem., v. 33, 1781 (1990) and U. S. Patent 4,859,692. This process comprises the steps of:

(a) reacting an alkyl (halomethyl)benzoate of formula [2] with an equivalent amount of an indole of formula [3]

in the presence of an equivalent quantity of silver(I) oxide,

(b) isolating the alkyl (indol-3-ylmethyl)benzoates of formula [4] from the reaction mixture obtained in step (a) above,

(c) reacting the compound [4] with an alkylating agent of formula [6],

The above process has serious disadvantages in the isolation of the product [4] in step (b) which is due to the fact that alkylation of indole, that is unsubstituted at positions 1-, 2- and 3-, at the 3-position, is accompanied by the undesired process of poly alkylation, to form polysubstituted indoles of formula [7] and/or formula [8] :

while at the same time some quantity of the starting unreacted indole remains in the reaction mixture. Most common methods for the separation of alkyl (indol-3-ylmethyl)benzoate of formula [4] from by-products of polyalkylation and starting unreacted indole, which are all covalent compounds with similar physical properties, include column chromatography that is an unpractical method for industrial scale applications.

updated info

PRODUCT PATENT ROUTE

Allylic bromination of methyl ester 54 using bromine in presence
of CCl4 resulted bromo compound 55, which was reacted with 5-nitro
indole 124 using silver oxide as catalyst to obtain condensed compound
125. N-methylation of 125 utilizing methyl iodide in presence of NaH
afforded N-methyl indole derivative 57. Thus obtained 57 was subjected
to reduction using palladium carbon (Pd/C) in methanol followed by
reacted with cyclopentyl chloroformate to obtain compound 59.
Hydrolysis of 59 using LiOH.H2O subsequently reaction with o-toluene
sulfonamide (OTSA) in presence of 1-[3-(dimethylamino)propyl]-3-ethyl
carbodiimide hydrochloride (DMAPEC) and DMAP furnished zafirlukast
4. Matassa et al3 also reported similar procedure for the synthesis of
Zafirlukast 4.

zafirlukast…….{3-[2-Methoxy-4-(toluene-2-sulfonylaminocarbonyl)
benzyl]-1-methyl-1H-indol-5-yl} acetic acid cyclopentyl ester……………………………….Arie, G.; Genndy, N.; Igor, Z.; Victor, P.; Maxim, S. WO 02/46153

A2, 2002.

Share this:

Drug spotlight, Celecoxib from G. D. Searle Company « New Drug Approvals

Drug spotlight, Celecoxib from G. D. Searle Company « New Drug Approvals:

'via Blog this'

GET SPECTRAL DATA FROM THIS POST





Addis ababa ethiopia

.


 

 

 

 


 
 :Lion of Judah, Addis Ababa, Ethiopia.JPG
 



 


 




 

 St Matthew's, Addis Ababa



 Founder Mariam Kinkladze & The Children of Addis Ababa, Ethiopia


 

 
 
 




////////////