DE1807165B - oJ-Dimethoxy ^ H-l ^ -benzothiazin-4-ones - Google Patents

Description

The invention relates to 6,7-dimethoxy-4H-1,3-benzothiazin-4-ones the general formula

in which R ₁ and R _{2 are} identical and denote hydrogen atoms or methyl or n-propyl groups, and their pharmacologically suitable salts. The compounds according to the invention are of pharmacological importance and are, in particular, bronchodilators.

The treatment of bronchial constrictions that are either functional or caused by or by allergies Asthma can be caused, requires that the therapeutic agent used an effective bronchodilator at doses that do not cause undesirable side effects. the Compounds according to the invention meet this requirement and are therefore suitable for symptomatic Treatment of asthma and other respiratory diseases, such as chronic bronchitis and emphysema. The compounds according to the invention also inhibit the effectiveness of the cyclic 3 ', 5' nucleotide phosphodiesterase.

The unsubstituted 2-amino-4H-1,3-benzothiazin-4-one is known and in J. Org. Chem., Vol. 29, p. 761 and 762 (1964), on its chemotherapeutic However, nothing was known about its effects, and in fact it has no bronchodilator activity.

On the basis of comparative experiments it was found that the compounds according to the invention are superior to the well-known theophylline in their bronchodilating effect. On female Guinea pigs that were not fed for 12 hours became the compounds to be tested administered orally at a dose of 60 mg / kg. The control animals received saline without Active ingredient addition. One hour after the administration, each animal was treated with a histamine aerosol.

This treatment consisted of spraying a 0.4% aqueous histamine solution under a pressure of 0.35 kg / cm ^{2 for} 1 minute into a 20 × 20 × 30 cm plastic container. Immediately thereafter, the animals were placed in the container. After one minute, the breathing was checked for bronchial constriction. The evaluation was carried out in the following stages:

normal breathing = 0,

heavy breathing = 2,

(slightly deepened breathing = 1), very heavy breathing and ataxia = 3 and Unconsciousness = 4.

Each group of animals consisted of 8 to 10 individual animals, as did the control groups. The reviews for the control groups and the treated groups were compared and the protective effect in relation expressed on the action of theophylline.

R ₁ H R ₂ H Protective effect
in relation to
Theophylline LD ₅₀ , mg / kg CH ₃ CH ₃ 2.6 > 1000 nC ₃ H ₇ nC ₃ H ₇ 1.5 300 to 1000 Theophylline 1.7 100 to 300 1 100 to 300

The compounds according to the invention can be prepared by using a method known per se Way an ester of 3,4-dimethoxy-thiosalicylic acid of the formula

with a cyanide of the general formula

NC

reacted, in which R ₁ and R _{2 have} the meaning given above, and optionally treated the free base obtained with a pharmacologically suitable acid.

When R ₁ and R ₂ in the cyanamide used as a reactant are hydrogen atoms, the condensation is carried out with heating in an inert organic solvent such as dimethylformamide and so on. Neither the reaction time nor the temperature are critical. The reaction can be carried out at the reflux temperature of the solvent or at lower temperatures, the lower temperatures requiring longer reaction times. Warming up on a steam bath for about 1 hour has proven sufficient in many cases. Preferably, approximately equimolar amounts of the two reactants are used, although an excess of one of the reactants can optionally be used. The product can be isolated and purified in any manner, e.g. B. by precipitation and recrystallization from a suitable solvent.

Ethyl acetate, methanol, chloroform, diethyl ether, etc. are suitable for this purpose.

If the desired product is to contain a substituted amino group in the 2-position, the must

3 4

Reaction mixture to catalyze the condensate- For parenteral administration and for insation, a base can be added. Substituted halations, solutions or suspensions of the cyanamides cannot condense spontaneously with the new compounds in sesame oil or peanut oil 3,4-dimethoxy-thiosalicylic acid ester. Basic sub- or punches used in aqueous propylene glycol solutions, such as amines, are suitable for this purpose. 5 are, furthermore, sterile solutions of the acid accumulation - it is advisable to use at least the equi-salts in water. Inhalation preparations containing the equivalent amount of base. It can be advantageous to contain active ingredients in 1% solution, if a lot of base is to be used that this is preferably used several times a day as a solvent,
acts and in this way the use of additional The active ingredient content in the therapeutic pre-solvent is saved. For example, io should not be less than 0.01%. The reaction can be carried out successfully in an excess of 10, 50, 75, 95 or even more percent by weight of triethylamine. be.

To the pharmaceutically acceptable salts of the doctor determines the appropriate dose, which according to

compounds according to the invention, d. H. the salts, age, weight and the respective tolerance

the no significantly greater toxicity than the free 15 as well as the nature and extent of the symptoms

Compound belong to the acid deposition fluctuations. In general, they start out small

salts with mineral acids, such as hydrochloric acid, bromine water doses administered and then increased until the

chemical acid, hydriodic acid, phosphoric acid, meta- optimal amount is reached. Generally effect

phosphoric acid, nitric acid and sulfuric acid, amounts from about 0.02 to about 200 mg of active ingredient

as well as the salts with organic acids, such as wine, 20 per kilogram of body weight, in a single or

Vinegar, milk, lemon, maleic, benzoin, glycol, multiple doses administered, sufficient linden

Gluconic, gulonic, succinic, aryl sulfonic acids, e.g. B. tion of bronchial constriction. Of course it can

p-Toluenesulfonic acid and the like give individual cases in which higher or lower

The pharmaceutically incompatible salts are doses are desirable.

although not suitable for therapy, they can, as already mentioned, inhibit the substances according to the invention for the separation and purification of the new compounds also the effectiveness of the cyclic compounds bindings are used. Of these salts 3 ', 5'-nucleotide phosphodiesterase, which belong to the the salts with hydrogen fluoride and perchloride conversion of adenosine 3 ', 5'-monophosphate (cyacid. The hydrofluorides can be used to produce clisches 3 ', 5'-AMP) in adenosine - monophosphate pharmaceutically acceptable salts used and 30 (5'-AMP) catalyzed. You can therefore with great this z. B. be dissolved in hydrochloric acid. The hydro advantage in systems containing phosphodiesterase Chlorides are then used from this solution, in which a high content of crystallized out. cyclic 3 ', 5'-AMP is desired. You inhibit

For use as bronchodilators, the enzyme activity so strong that already concentrator, compounds of the invention alone 35 concentrations from 10 ^-4 molar or less effective or, preferably, together with pharmaceutically. This property of the suitable carriers of the invention can be administered. You can bind is of great importance because z. B. with inert carriers to tablets, capsules, many tissues Cyclo-S '^' - nucleotide phosphodiesterase pills, lozenges, candies, powders, sprays, effectiveness and the cyclic mononucleous aqueous suspensions or solutions, injectable 40 tid 3 ', 5'- AMP is an important regulator for numerous solutions, elixirs, syrups and the like. Cell and tissue operations, e.g. B. in relaxation These carriers include solid extenders or smooth muscle in which fat splitting and fillers, sterile aqueous media and various substances in the splitting of sugars. The non-toxic organic solvents of the invention. The oral compounds inhibit the effectiveness of the enzyme. Pharmaceutical preparations can be sweetened and tissue-specific, ie only in certain tissues, but not in others with the flavoring substances customary for this purpose. That is why the application should be provided. of the compounds according to the invention then particularly

The selection of the respective carrier and advantageous if an increase in the content of

Amount ratio of active ingredient to carrier are cyclic 3 ', 5'-AMP in only one type of tissue.

by solubility and chemical nature 50 is desired.

of the therapeutic compound, by the nature of the The following examples illustrate the preparation

Administration and by the usual pharmaceutical of the compounds of the invention.
Practice determined. For example, if the

Compounds Administered Orally in Tablet Form Example 1

extenders such as lactose, sodium 55 2-amino-6,7-dimethoxy-4H-1,3-benzothiazin-4-one

citrate, calcium carbonate and dicalcium phosphate, a mixture of 5.0 g (0.022 mol) 3,4-dimethoxy-

as well as disintegrants such as starch, methyl thiosalicylate and 0.92 g (0.022 mol)

Alginic acid and certain complex silicates, as well as cyanamide in 30 ml of triethylamine was 1 hour

Lubricants such as magnesium stearate, sodium auryl- stirred at reflux temperature. After 5 minutes

sulfate and talc. In the case of capsules for oral use, the material was completely dissolved, and after 10 minutes

Delivery includes lactose as well as high molecular weight grooves dropped the desired product. The mixture

Polyethylene glycols are the preferred carriers. For was cooled and then filtered. 5.3 g were obtained

Aqueous orally administered suspensions can contain (100%) product which is recrystallized from methanol

the compounds according to the invention with emulsification was. Yield 2.7 g (52%) of pure compound from

or suspending agents are combined. Also 65 melting point 329 to 331 ° C (decomposition).

Diluents such as ethanol, propylene glycol, GIy- The hydrochloride of l-amino-6,7-dimethoxy-

cerin and combinations of these agents can be 4H-1,3-benzothiazin-4-ons obtained by that

be set. one an alcoholic solution of the free base with

diluted hydrochloric acid mixed and the solution evaporated to dryness; M.p. = 299 to 305 ° C (decomposition).

Example 2

2-Dimethylamino-6,7-dimethoxy-4H-1,3-benzothiazin-4-one

The procedure of Example 1 was repeated using the equivalent amount of dimethylcyanamide in place of cyanamide. The obtained compound was recrystallized from methanol / chloroform; Mp = 267-268 ⁰ C. The hydrochloride of this compound melts at 253-259 ° C.

B e i s ρ i e 1 3

Following the procedure of Example 1 was further 2-di (n-propyl) amino-6,7-dimethoxy-4H-l, 3-benzothiazin-4-one of melting point 104 to 106 ⁰ C. The hydrochloride of this compound melts at 182-183 ° C.

Claims (2)

Patent claims: 1. 6,7-Dimethoxy-4H-1,3-benzothiazin-4-ones of the general formula CH ₃ O CH ₃ O in which R ₁ and R _{2 are} identical and denote hydrogen atoms or methyl or n-propyl groups, and their pharmacologically suitable salts. 2. 2-Amino-6,7-dimethoxy-4 H -1,3-benzothiazin-4-one.