Title: Method for synthesizing certain selected pro-drug forms of theophylline

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1. A method for preparing a pro-drug form of theophylline having the formula: ##STR7## or ##STR8## wherein R represents a member selected from the group consisting of straight or branched C.sub.4 -C.sub.20 alkyl, straight or branched C.sub.4 -C.sub.20 alkenyl, substituted phenyl or a substituted or unsubstituted naphthyl whose substituents are selected from the group consisting of hydroxy, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, acyloxy derived from an alkanoic acid of up to 4 carbon atoms, chlorine, bromine, and iodine, 2,3,4 pyridyl or quinoline, and wherein A represents a member selected from the group consisting of --CO--, --CO--(CH.sub.2).sub.n --CO-- wherein n represents an integer of from 1-16, --CO--CH=CH--CO--(cis or trans), ##STR9##

which comprises: 1. Reacting stoichiometric amounts of theophylline with a member selected from the group consisting of the corresponding R-mono-carboxylic acid or anhydride or A-dicarboxylic acid or anhydride, wherein R and A are defined as above, in the presence of:

a. a solvent selected from the group consisting of a halogenated hydrocarbon solvent and a mixture of said halogenated hydrocarbon solvent with hydrocarbon solvent and/or dimethylformamide,

b. an excess of a member selected from the group consisting of COCl.sub.2 and SOCl.sub.2 to yield the desired pro-theophylline compound, said member being present in an amount of from 1.0 to 1.5 equivalents per carboxylic acid group and 1.0 to 2.0 equivalents per anhydride molecule,

c. about 2 moles of dimethylformamide for each mole of COCl.sub.2 or SOCl.sub.2,

d. an inert gas as a carrier or an organic tertiary or aromatic amine base as a scavenger for removing HCl formed during the reaction,

2.

2. Separating the thus obtained pro-theophylline compound from the reaction mixture,

said reaction being carried out in an anhydrous environment at a temperature ranging from 0.degree. to 120.degree. C, standard pressure and

for a period ranging from 1 to 72 hours. 2. The method of claim 1, wherein said halogenated hydrocarbon solvent is a member selected from the group consisting of dichloromethane, dichloroethane, and chloroform.

3. The method of claim 1, wherein said hydrocarbon solvent is a member selected from the group consisting of benzene, toluene, and xylene.

4. The method of claim 1, wherein said solvent is a mixture of dimethylformamide with a halogenated hydrocarbon solvent.

5. The method of claim 1, wherein said organic tertiary or aromatic amine base is a member selected from the group consisting of trimethylamine, triethylamine, pyridine, methylimidazole, quinoline, quinuclidine, and 2,2-diazabicyclo [2.2.2] octane.

6. The method of claim 1, wherein said reaction is carried out at the boiling point of the solvent or solvent mixture employed.

7. The method of claim 1, wherein the reaction is carried out at a period of time ranging from 20 to 48 hours.

8. The method of claim 1, further comprising the step of purifying the pro-drug theophylline compound by trituration with a hot halogenated hydrocarbon solvent.

9. The method of claim 1, wherein said inert gas is a member selected from the group consisting of nitrogen, helium and purified methane.

Other info:

Inventors: Bodor, Nicolae S. (Lawrence, KS, US)
Sloan, Kenneth B. (Lawrence, KS, US)
Kuo, Yu-Neng (Lawrence, KS, US)

Application Number: 526219
Filing Date: 1974-11-22
Publication_date: 1976-12-28
Assignee: Interx Research Corporation (Lawrence, KS)
Primary Class(es): 544/271 544/269
Other Classes:
US Patent Ref:

2729643

Jan, 1956

Stoll et al.

260/256.

Other Refs:
Primary Examiner: Coughlan, Jr., Paul M.
Assistant Examiner:
Attorney: McDonnell; John J.