DK149626B - Azepino(1,2-a)pyrimidine derivatives or pharmaceutically acceptable acid addition salts thereof and pharmaceutical preparation comprising them - Google Patents

Description

o in U9626

The present invention relates to novel azepino [1,2-a] pyrimidine derivatives of the general formula 5 Υ Υ \ J J J J H2 H2 mo mo mo mo in which p is 1 or 2, or pharmaceutically acceptable acid addition salts thereof and a pharmaceutical composition. containing these derivatives or salts.

GB-PS No. 2,003,870 discloses compounds of the general formula R 3 R 4 r 2 20 r 1 - n (CH ~) (VI), 2 m 25, wherein R means hydrogen, halogen, alkyl of 1-4 carbon atoms, hydroxy, nitro, amino, carboxy or a carboxylic acid-12 4 derivative group, R, R and R are hydrogen or alkyl 35 with 1-4 carbon atoms, R, R and R are hydrogen, or 30 3 4 5 6 R and R and / or R and R together form an additional chemical bond, m means 1, 2, 3 or 4, n means 0, 1, 2 or 3, and the dotted line indicates any additional bond present.

The compounds 35 described in the above patent exhibit CNS activity, especially analgesic activity.

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It has now been found that the novel compounds of the present invention, not specifically described in the aforementioned GB-PS No. 2,003,870, exhibit excellent bronchodilatory activity without having CNS activity.

It is also known that 6,7,8,9,10,12-hexahydro-azepino [2,1-b] quinazolin-12-one of the formula

10 _ N

/ Y HC1 (VII)

WJ

o 15 exhibits bronchodilatory activity (Drugs of the Future 1981, 6, 352).

It has been found that the bronchodilatory activity of the present compounds of general formula (I) significantly outweighs the bronchodilatory activity of the known compound of formula (VII) and of the commercially available theophylline anisate having similar efficacy.

The effect of the compounds of this invention has been investigated by means of Konzett experiments (H. Konzett and R.

Rossier, Arch. Exp. Path. Pharm., 1940, 195, '71) using guinea pigs. Activity is determined on the basis of inhibition of spasm induced by three endogenous spasmogenic agents (5-hydroxy-tryptamine, histamine, acetylcholine). The results 30 are given in Table I.

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Table I

5 Experimental compound inhibition of plasma induced by 5-hydroxytryptamine histamine acetylcholine / 3.01 3.11 7.81

VIII

15 / \ yN · HCl \ 15.7 5.4 6.3 0

IX

/ Λ / ΝγΛ (I \ 13.8 6.5 3.7 \ _ ^ \ isy

25 Y

X

C. N '/ V HCl in I 36.0 6.2 26.3 N Z O VII (known) theophylline 14.0 14.0 22.0 35 anisate (known) long-lasting action 4

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As a further example, the activity of the compound of formula (IX) is illustrated by means of a human bronchus experiment. Surgically obtained human bronchus is dipped in an oxygenated physiological solution at a temperature of 37 ° C.

5 The contraction is induced by 1 jamol of Carbacol.

The amount of active ingredient needed for 50% inhibition is determined. The results are given in Table II.

Table II

10 Determination of bronchodilatory activity on the human bronchus

Dose Spasm Reduction Icso

Compound _mol / liter _% _ mol / liter 15 10 ~ 6'0 3 10 "5.5 23

Ix 10 "5.0 48 5.4 x 10" 6 10 "4'5 113 20 10-4 184 10-4'5 5 theophylline 10 410 150.0 x 10 ^ 25 anise 10_4'0 28 10-3 '75 64

The compounds of the general formula 30 / γγ \ \ _ ^ • '^ jsv / (CH2, p (I> 35 lf

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Wherein p is 1 or 2, and acid addition salts thereof can be prepared by a) reacting a compound of formula cr "with a compound of general formula two (CH2) p (111) 15 7 wherein p is as defined above, and R is alkoxycarbonyl having 2-5 carbon atoms or carboxamido, or b) reacting a compound of the general formula / vor8 (I

Q

wherein R is alkyl of 1-4 carbon atoms, with a compound of the general formula H9N / \ 30 Δ 7 I <CH2> p IV) wherein R is as defined above and, if desired, converts the compound obtained with the general formula in to an acid addition salt or release it from the salt thereof.

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The reaction of the compound of formula (II) with the compound of general formula (III) wherein p is as defined above and R is alkoxycarbonyl of 2-5 carbon atoms or carboxamido, or the reaction of the compound with

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Preferably, the general formula (IV) wherein R is alkyl of 1-4 carbon atoms with a compound of the general formula (V) wherein R 7 is as defined above is preferably carried out in an inert solvent under heating. Alcohols, preferably methanol or ethanol, may be used as inert solvents, aromatic hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as chloroform, dichloromethane, chlorobenzene or carbon tetrachloride, ketones, preferably acetone or methyl ethyl ketone or esters, preferably ethyl acetate or esters.

The reaction is preferably carried out at the boiling point of the inert solvent. The residue obtained after evaporation of the reaction mixture is crystallized from a suitable solvent or solvent mixture.

Acid addition salts may be formed from the compounds of general formula (I) by methods known per se using pharmaceutically acceptable inorganic or organic acids. Hydrogen halides such as hydrobromide, hydrochloride, hydroiodide, and salts of sulfuric acid, phosphoric acid, perchloric acid, formic acid, acetic acid, citric acid, maleic acid, or fumaric acid can be prepared.

The compounds of formulas (II), (III), (IV) and (V) used as starting materials are commercially available compounds or can be prepared from commercially available derivatives thereof by methods known per se (J. Am. Chem. Soc. 1948, 70, 21115, Zsur. Prikl. Him. 1965, 38, 1097, J. Pharm. Sci. 1964, 53, 1427, FR-PS No. 1,367,799).

The compounds of general formula (I) and pharmaceutically acceptable salts thereof can be used as active bronchodilators. The toxicity of the compounds of general formula (I) is low, LD 1 is above 500 mg / kg when administered per os in rats and mice.

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The compounds of general formula (I) are used as active ingredients of pharmaceutical compositions mixed with inert solid or liquid organic or inorganic carriers. The compositions are prepared by methods known per se.

The compositions are prepared in a form suitable for administration per os, parenterally or by inhalation, such as tablets, dragons, capsules, lozenges, powder mixtures, aerosol atomizers, aqueous solutions or suspensions or injectable solutions or syrups.

The compositions may contain solid carriers or diluents, sterile aqueous solvents or non-toxic organic solvents. Sweeteners or flavors may be added to the orally administered preparations.

The orally used tablets may contain as carrier materials lactose, sodium citrate, calcium carbonate as well as disintegrants, e.g. starch, alginic acid, lubricants such as talc, sodium lauryl sulfate or magnesium stearate. Capsules may contain lactose or polyethylene glycol 20 as carrier. The aqueous suspension may contain emulsifiers or suspending agents. As the diluent for organic suspensions, ethanol, glycerol or chloroform may preferably be used.

For parenteral use and inhalation, the active ingredient can be dissolved or suspended in a suitable medium such as peanut oil, sesame oil, polypropylene glycol or water. The injection preparations may be administered intravenously or subcutaneously. Preferably, the injectable solutions can be prepared in an aqueous medium and the pH is adjusted to an appropriate value. The solutions may, if desired, be prepared in saline or glucose solution.

The active ingredient content of the pharmaceutical compositions may be varied within wide limits and may range from 0.005 to 90%.

The daily dose of active ingredient can be varied within wide limits and depends on the severity of the patient's condition, his age, weight and on the formulation of the medicine and the effect of the active ingredient. For oral use, the daily dose is usually in the range of 0.05 to 1 mg / kg, for inhalation or intravenous administration, the dose is in the range of 0.0001 to 5 mg / kg in a single or 5 divided dose. On the basis of the doctor's instructions, doses outside this area are also possible.

The preparation of the subject compounds and compositions containing them is set forth in the Examples below.

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Example 1 148 g (1 mole) of 2-amino-4,5,6,7-tetrahydro-3H-azepine hydrochloride are dissolved in 600 ml of ethanol and a sodium ethoxide solution prepared from 23 g of sodium metal and 600 ml of ethanol is added dropwise. The solution is stirred for one hour and the precipitated sodium chloride is filtered off. To the solution is added 170 g (1 mole) of 2-ethoxy-carbonyl-eyclohexanone and the reaction mixture is heated for 5 hours on a hot water bath. The ethanol is then distilled off at reduced pressure. The remaining solid is suspended in acetone, filtered and washed with some acetone.

179 g (82%) of 2,3-tetramethylene-4-oxo-4,6,7,8,9,10-hexahydro-azepino [1,2-a] pyrimidine is obtained. Mp: 152-153 ° C.

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Analysis for the formula ci3HigN2®:

Calculated: C 71,571? H 8.32%? N, 12.84%.

Found: C, 71.52%? H 8.30%? N, 12.88%.

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Example 2 20 g of 2,3-tetramethylene-4-oxo-4,6,7,8,9,10-hexahydro-azepino [1,2-a] pyrimidine are dissolved in 200 ml of ethyl acetate and the solution is saturated with dry hydrogen chloride gas. under cooling with water. The precipitated white solid is distilled off and washed with ethyl acetate. 2,3-Tetramethylene-4-oxo-4,6,7,8,9,10-hexahydro-azepino [1,2-a] pyrimidine hydrochloride yields: 20.8 g (89% ), mp: 218 ° C.

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Analysis for Formula C13H19N2OC1:

Calculated: C, 61.28%; Η 7.51%: N 10.99%; Cl, 13.91%.

Found: C, 61.31%; H, 7.49%; N, 10.95%; Cl, 13.87%.

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Example 3 14.8 g (0.1 mole) of 2-amino-4,5,6,7-tetrahydro-3H-azepine hydrochloride are dissolved in 50 ml of ethanol and a sodium ethoxide solution prepared from 2.3 g. sodium metal in 50 ml of ethanol is added dropwise. After one hour, the precipitated sodium chloride is filtered off. To the solution is added 15.6 g (0.1 mole) of 2-ethoxy-carbonyl-cyclopentanone. The reaction mixture is heated for 7 hours on a hot water bath. The ethanol is then distilled off at reduced pressure. The remaining 15 oily product is taken up in 80 ml of a 5% w / v aqueous hydrochloric acid solution and the aqueous layer is shaken twice with 10 ml of ether. The aqueous layer is then neutralized with sodium bicarbonate solution and extracted four times with 20 ml of chloroform. The combined chloroform layers are dried over anhydrous sodium sulfate and evaporated. The remaining oily product slowly crystallizes upon standing.

There is obtained 4-oxo-2,3-trimethylene-4,6,7,8,9,10-hexahydro-azepino [1,2-a] pyrimidine, yield: 12.7 g, (62%) which after recrystallization from methyl ethyl ketone melts at 96-98 ° C.

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Analysis for the formula ^ 12 ^ 16 ^ 2 ^ 5

Calculated: C, 70.55%; H, 7.89%; N, 13.71%.

Found: C, 70.59%; H, 7.85%; N, 13.66%.

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Example 4 10 g of 2,3-trimethylene-4-oxo-4,6,7,8,9,10-hexahydro-azepino [1,2-a] pyrimidine are dissolved in 50 ml of ethyl acetate and added to the solution hydrogen chloride gas. The ethyl acetate solution 35 is evaporated. The remaining partially solid product is digested with a mixture of ethyl acetate and ether, thus obtaining white crystals. The crystals are filtered off and washed with diethyl ether.

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Obtain 2,3-trimethylene-4-oxo-4,6,7,8,9,10-hexahydro-azepino [1,2-a] pyrimidine hydrochloride, yield 8.5 g (72%), snip .s 180-182 ° C.

Analysis for Formula C12H17N2OC1:

Calculated: C, 59.87%; H 7.12% *, N 11.64%; Cl, 14.72%.

Found: C, 60.07%; H, 7.08%; N, 11.39%; Cl, 14.85%.

Example 5 10 g of 2,3-trimethylene-4-oxo-4,6,7,8,9,10-hexahydro-azepino [1,2-a] pyrimidine are dissolved in 20 ml of ethanol and added to the solution. 70% w / v perchloric acid.

The elevated temperature solution is cooled to 0 ° C and the precipitated crystals are filtered off and washed with ethanol.

There is obtained 2,3-trimethylene-4-oxo-4,6,7,8,9,10-hexahydro-azepino [1,2-a] pyrimidine perchlorate, yield: 12 g (80.5%), which after recrystallization from ethanol melts at 206-208 ° C.

Analysis for the formula ci2Hi7N2O5Cl:

Calculated: C, 47.30%; H, 5.62%; N, 9.19%.

Found: C, 47.51%; H, 5.54%; N, 9.20%.

Example 6

Preparation of 75 mg tablets 375 g of 2,3-tetramethylene-4-oxo-4,6,7,8,9,10-hexa-hydro-azepino [1,2-a] pyrimidine hydrochloride are homogenized with 525 g of crystalline cellulose and 70 g of amylopectin.

The mixture is then granulated with 75 g of Eudragit varnish solution, dried at 40 ° C, regranulated and homogenized with a powder mixture of 10 g of talc and 10 g of magnesium stearate, and tablets are prepared by a method known per se with a 200 mg of adjustment.

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Example 7

Preparation of 150 mg retarded 1500 g of 2,3-tetramethylene-4-oxo-4,6,7,8,9,10-hexa-5-hydro-azepino [1,2-a] pyrimidine hydrochloride, 1500 g of crystalline cellulose and 250 g of polyvinylpyrrolidone powder are homogenized. The mixture is then granulated with a solution of 45 g of Eudragit varnish for approx. 350 ml of propanol. The granulate is dried at 50 ° C, re-granulated and homogenized with a powder mixture of 65 g of talc and 45 g of magnesium stearate, and tablets prepared with a 345 mg adjustment using a convex convex tool. The tablet dredge core is coated with a foil or sugar layer by a method known per se.

Example 8

Preparation of 50 mg capsules

A powder mixture of 500 g of 2,3-trimethylene-4-oxo - 4,6,7,8,9,10-hexahydro-azepino [1,2-a] pyrimidine hydrochloride, 230 g of potato starch is moistened with 10 g gelatin, 60 g distilled water and 10 g 2N hydrochloric acid and 120 g 90% w / v ethanol solution in a suitable kneading machine and dried at 40 ° C after granulation on a 0.3 mm sieve. The thus obtained granulate is again granulated on a 0.15 mm sieve and mixed with a powder mixture of 50 g potato starch, 50 g talc and 10 g stearin. Hard gelatin capsules are obtained in a suitable filling apparatus by a 0.115 g adjustment. The finished capsules are packed as usual.