US 3624215 A
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United States Patent [7 2] Inventors Herman Hal Stein Skokie; Elizabeth Goodsell, Waukegan, both of III.  Appl. No. 49,921  Filed June 25, 1970  Patented Nov. 30, 1971 [7 3 1 Assignee Abbott Laboratories North Chicago, Ill.
 S-SUBSTITUTED THEOPHYLLINES AS ANTI- ANXIETY AGENTS 4 Claims, No Drawings s21 u.s.c| 424/253 OTHER REFERENCES Quevauviller, Actualitis PharmacoL, 8: 106- 52 1955).
Primary ExaminerStanley .l. Freidman Attorney-Robert L. Niblack ABSTRACT: A method of alleviating anxiety in mammals exhibiting such symptoms by administering from I to 50 mg./kg. daily of an 8-substituted theophylline.
S-SUBSTITUTED TI-IEOPHYLLINES AS ANTI-ANXIETY AGENTS DETAILED DESCRIPTION OF THE INVENTION This invention relates to a method of relieving anxiety in patients in order to restore such patients to a more normal and thus contribute to their physical and mental well being.
Patients suffering from depression manifest one or more of a variety of symptoms. Generally speaking, depressed patients feel incapable of dealing with their responsibilities; they lose interest in their jobs, families and hobbies. The predominant symptoms of depression are hypochondria, anorexia, insomnia, anergia, anhedonia and pessimism. However, some patients suffering from depression are also anxious and nervous. In treating such patients, it is desirable to have a therapeutic agent which has tranquilizing or sedative overtones. The present invention provides a method of treating anxious or depressed patients employing compounds which exhibit antidepressant and sedative properties. Accordingly, for the purpose of this disclosure, the ii-substituted theophyllines used herein shall he referred to as nntianxiety agents.
Theophyllinc and a number of its derivatives have been reported to possess activity as central nervous system stimulants and as diuretics. (Quevauviller, Actualitis Pharmacol. 8: 106-52 (I955). We have'unexpectedly found that certain 8- substituted theophyllines possess activity as sedative antidepressants. Thus, the compounds are generally useful in treating patients who are suffering from anxiety or manifesting other symptoms of depression.
The compounds useful in the practice of this invention are 8-substituted theophyllines represented by the formula wherein R is C C alkyl or C -C cycloalkyl.
The term alkyl, as used herein, refers to both straight and branched chain alkyl such as methyl, ethyl, n-propyl, isopropyl, nbutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl and the like.
The antidepressant activity of the above compounds was established using the modified DOPA test described by Everett et al., Fed. Proc., 23, 198(1964).
In the practice of this invention, the compounds are administered to patients exhibiting the symptoms of depression, including anxiety, particularly in patients in need of sedation, in dosages of from 1 to 50 mg./kg. of body weight daily, either in single or divided doses. While the compounds exhibit both oral and parenteral activity, the preferred route of administration is the oral route.
The compounds of the present invention for use as antidepressant or antianxiety agents can be incorporated in to various pharmaceutically acceptable dosage forms such as tablets, capsules, pills, suspensions and the like, for immediate or sustained release, by combining them with suitable carriers or diluents according to methods well known in the art. In addition to active agent and the carrier or diluent, the dosage forms may include various excipients, binders, fillers, flavoring and sweetening agents, and the like, necessary in the formulation of the desired pharmaceutical preparation. However, in the case of filled capsules, for example, the antianxiety agent can be the sole ingredient.
Illustrative compounds useful in the practice of this invention are:
B-n-Pentyl-theophylline S-Cyclopentyl-theophylline 8-n-Hexyl-theophylline 8 n-Butyl-theophylline 8-iso-Butyl-theophylline ll-Cyclopropyl-theophyllinc 8-n-Heptyl-theophylline The B-substituted theophyllines employed in the practice of 5 this invention were prepared according to the methods described by Hager et al., J.Am. Pharm. Assoc., 43, I52 (I954) and by first et al., J. Chem Ber., 93, 99 (I960). Generally speaking, the active agents can be prepared by reacting 5,6-diamino-l,B-dimethyluracil (commercially available from Aldrich Chemical Company, Milwaukee, Wis.)
O l with an acid of the formula wherein R is C C, alkyl or C -C cycloalkyl. The synthesis is represented by the following reaction sequence.
HgC-N N A The following example further illustrates the present invention.
EXAMPLE 1 marked activity. The results are summarized in table I.
TABLE I Compound Dosage (mg/kg.) Modified DOPA Test Response Elavil 30 2+ il-n-Propyl theophylline 30 3+ B-Cyclopropyl theophylline 30 4+ 8-Cyclopentyl theophylline 30 3+ wherein R is C C, alkyl, or C -C cycloalkyl. cyciogr opyl theophylline. 2. The method of claim 1 wherein the compound is 8-n- 4. The method of claim 1 wherein the compound is 8- propyl theophylline. cxciopentyl theophylline.
3. The method of claim 1 wherein the compound is 8-