GB2096606A

GB2096606A - 7-Substituted theophylline derivatives

Info

Publication number: GB2096606A
Application number: GB8209165A
Authority: GB
Original assignee: CROSARA FARMA BILOG LAB
Current assignee: CROSARA FARMA BILOG LAB
Priority date: 1981-04-15
Filing date: 1982-03-29
Publication date: 1982-10-20
Also published as: BE892869A; FR2509309A1; IT8121198A0; IT8121198A1; NL8201438A; IT1195778B; DE3213081A1

Abstract

Novel compounds of formula <IMAGE> or a salt thereof with a pharmacologically acceptable acid in which Q represents the radical of a pharmacologically acceptable primary, secondary or cyclic amine, have analeptic activity.

Description

SPECIFICATION 7-Substituted theophylline derivatives The present invention concerns 7-substituted theophylline derivatives.

More particularly, the present invention concerns derivatives of 7(w-amino-P-hydroxy)propyl- theophylline having pharmacological activity.

It is known to those skilled in the art that three purine bases have analeptic activity. It is also known that among these three purine bases, theophylline prevails over the other two, with respect to diuretic, coronary dilating and cardiostimulating action.

It is also well known that theophylline and, more particularly, the water-soluble derivatives thereof, represent the active base of many commercial compositions for the treatment of chronic asthma and bronchial asthma (bronchospasmolytics).

It has now been found that theophylline derivatives of formula:

in which Q represents the radical of a pharmacologically acceptable primary or secondary amine such as, for example, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, dipropylamine, butylamine, dibutylamine, isobutylamine, sec- and tert-butylamine, N-methylhexylamine, benzylamine, dibenzylamine, ethanolamine, diethanolamine, aminobutanol and other hydrophilic derivatives of this type; a cyclic amine, such as, for example, ethyleneimine, trimethyleneimine, cyclopentyleneimine, piperidine, morpholine, pyrolidine, piperazine, homopiperazine, wherein the cyclic amines, particular those with a 5 or more atom ring, may, in turn, be variously substituted, preferably by alkyl (01-C4), oxyalkyl (C,-C4), carbonylalkyl (C,-C4) groups, and wherein, for piperzine and homopiperazine, also the symmetric bis-theophylline Nderivatives may be obtained, present an improved solubility in water.

The 7-substituted theophylline derivatives of the present invention are obtainable by processes of a general kind well known to those skilled in the art. Particularly, they may be obtained by condensing a 7-(3-halogen-2-hydroxy)-propyl-theophylline with any of the primary, secondary or cyclic amines as previously mentioned. More particularly, 7-(3-chloro-2-hydroxy)-propyltheophyl- line is condensed with any of the above referred amines, in an alcoholic or hydroalcoholic medium, according to DE-Patent 1.102.750 and Korbonits, Acta Pharm.Hung., 38, 98 (1968).

The compounds of this invention may be easily converted to pharmaceutically acceptable salts by treatment with an equivalent of the pharmaceutically acceptable acid, in the same medium in which condensation of 7-(3-chloro-2-hydroxy)-propyltheophylline and amine is carried out.

Examples of pharmaceutically acceptable acids are: hydrochloric, hydrobromic, sulphuric, citric, fumaric, tartaric, malic, maleic, methanesulphonic, ethanesulphanic, nicotinic, succinic acid.

The pharmacologically acceptable salts of the compounds of the present invention are particularly useful for preparing aqueous solutions of the 7-substituted theophylline derivatives according to this invention.

The following examples will better illustrate the present invention.

EXAMPLE 1 7-[3-(N-methylpiperazinylJ-2-hydroxy]-2-propyltheophylline nicotinate 27.3 g (0.1M) of 7-(3-chloro-2-hydroxy)-propyltheophylline and 10 g of N-methylpiperazine are hot (about 80"C) dissolved in 200 ml of isopropanol. Then, to this solution a suspension of 4 g (0.1 M) of NaOH in isopropanol is added and the mixture is refluxed for one hour. It is allowed to cool to 50"C, 12.3 g (0.1M) of nicotinic acid are added and it is further refluxed for 30 minutes (80"C). It is filtered by hot suction, allowed to crystallize and the solid phase is separated and recrystallized from ethanol.

22g of white of crystalline substance, i.e. of the nicotinate of the compound of formula (I,D) are obtained.

EXAMPLE 2 7-(3-methylcyclohexylamino-2-hydroxyJ-propyltheophylline succinate 18.02 g (0.1 M) of anhydrous theophylline in 200 ml of boiling isopropanol is treated under stirring with 1 6.9 g (0.1 M) of 1 -methyl-cyclohexylamino-2,2-epoxypropane. The mixture is taken slowly to boiling and kept so for one hour. Then 11.8 g (0.1 M) of succinic acid are added, the resulting mixture is hot filtered with decolorizing carbon and is allowed to crystallize to give the title compound of formula (I, B) which, when recrystallized from ethanol, shows conforming IR spectrophotometry.

EXAMPLES 3-8 By proceeding as described in the preceding examples, the other compounds referred to in the Table are obtained.

Q PERCENT ANALYSIS EMPIRICAL FORMULA MOLECLLAR WEIGHT C H N A # Calc. 51.62 6.14 25.08 C12H17N5O3 279.21 Found 51.5 6.2 25.3 B # Calc. 58.44 7.79 20.04 C17H27N5O3 349.45 Found 57.9 7.81 20.5 C # Calc. 51.24 6.13 25.07 C24H34N10O6 558.61 Found 50.95 6.15 24.9 D # Calc. 53.59 7.19 24.98 C15H24N6O3 336.41 Found 53.0 7.24 25.2 E # Calc. 50.25 6.85 21.98 C16H26N6O5 382.44 Found 49.6 6.8 22.0

../continuation

Q PERCENT ANALYSIS EMPIRICAL FORMULA MOLECLLAR WEIGHT C H N F # Calc. 50.52 6.36 22.09 C16H24N6O5 380.42 Found 51.0 6.3 21.6 G # Calc. 52.45 6.34 24.45 C25H36N10O6 572.56 Found 53.1 6.4 23.85 H # Calc. 54.84 7.48 23.99 C6H26N6O3 350.44 Found 55.3 7.6 23.6

Claims

1. A compound of formula

or a salt thereof with a pharmacologically acceptable acid in which Q represents the radical of a pharmacologically acceptable primary, secondary or cyclic amine.

2. 7-[3-(N-methylpiperazinyl)-2-hydroxy]-propyl-theophylline nicotinate.

3. 7-(3-methylcyclohexylamino-2-hydroxy)-propyl-theophilline succinate.

4. A compound of the formula I substantially as hereinbefore described in any one of Examples 1 to 8.

5. A process for preparing compounds of formula I as defined in claim 1, comprising reacting for about one hour, at boiling temperature, 7-(3-halogen-2-hydroxy)-propyltheophylline with the corresponding pharmacologically acceptable primary, secondary or cyclic amine, in an alcoholic or hydroalcoholic medium, and optionally adding one equivalent of a pharmaacologi cally acceptable acid in order to obtain the corresponding salt.

6. A process as claimed in claim 5 substantially as hereinbefore described in Example 1 or Example 2, or either of these Examples modified by substantially the materials required in any one of Examples 3 to 8.

7. A compound of formula I produced by a process as claimed in claim 5 or claim 6.

8. A pharmaceutical or veterinary formulation comprising a compound as claimed in any one of claims 1 to 4 or claim 7 formulated for pharmaceutical or veterinary use.

9. A pharmaceutical or veterinary composition comprising a compound as claimed in any one of claims 1 to 4 or claim 7 and a pharmaceutically or veterinarily acceptable carrier or excipient.

1 0. A compound as defined in claim 1 for use as a method of treatment of the human or animal body by therapy.