DE3001016A1 - PHARMACEUTICAL PREPARATIONS CONTAINING BENZO SQUARE CLAMP ON SQUARE CLAMP ON SQUARE CLAMP ON 1.6 SQUARE CLAMP ON NAPHTYRIDINE - Google Patents

Description

·. C, - Cm

100-5155

PHARMACEUTICAL PREPARATIONS CONTAINING BENZO [C] [1,6] NAPHTYRIDINE

The invention relates to new pharmaceutical preparations which are described in US patents No. 3,899,494 and No. 3,862,153 and a P-adrenoceptor blocker.

The invention relates to new pharmaceutical preparations that

A) a compound of the formula I,

wherein either

i) R is hydrogen, alky " ¹ with 1 to 3 carbon atoms, alkoxy with 1-3 carbon atoms, alkylthio with 1-3 carbon atoms, fluorine, bromine, chlorine, nitro, trifluoromethyl, amino or -NHCOR, in which

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-COR alkanoyl with 1-18 carbon atoms, benzoyl, substituted by a radical X and a radical Y Benzoyl, where X is alkyl with 1-4 carbon atoms, alkoxy with 1-4 Carbon atoms, fluorine, chlorine or bromine

and Y is hydrogen, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms or chlorine is Cinnair.oyl, phenylalkanoyl, in which the alkylene part is 1-3 Contains carbon atoms in the phenyl ring

cinnamoyl or phenylalkanoyl substituted by one radical X and one radical Y, wherein the alkylene part contains 1-3 carbon atoms, where X and Y have the above meaning own, or -COA, where A is thienyl,

Furyl, pyrrolyl or pyridyl means

R _{2 represents} hydrogen, chlorine, alkyl with 1-3 carbon atoms or alkoxy with 1-3 carbon atoms and

either R, and R, both hydrogen or both

• mean methoxy

or R, and R.. together for methylenedioxy -> 4th

stand,.

or

ii) R _{1 is} -NHCOR ¹ , where R ^{1 is} dichloromethyl, cycloalkyl with 3-6 carbon atoms or alkenyl with 2-5 carbon atoms,

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R is hydrogen and

R and R both stand for methoxy,

in particular the compound cis-6- (4-acetamidophenyl) -l, 2,3,4,4a, lOb-hexahydro-8, 9-dimethoxy-2-methylbenzo [c] [l, 6] naphtyridine (hereinafter referred to as "compound X") and

B) contain a ß-adrenoceptor blocker.

Suitable ß-adrenoceptor blockers are e.g.

bonds that have a chain -OCH_CHCH ₃ N ^,

0-

those directly through the oxygen atom in the 1-position

is bound to an aryl radical, or which have a chain N ^, which is immediately followed by the

Carbon atom in the 1-position is bonded to an aryl radical.

The aryl radical can for example contain up to 10 carbon atoms, for example it is phenyl or naphthyl, e.g. 1-naphthyl, and may contain 1 or 2 heteroatoms, e.g. a nitrogen atom as in 4-indolyl, or a nitrogen atom and a sulfur atom such as a thiazolyl. The aryl radical can optionally also be 1 or have 2 substituents, e.g. acetyl, allyl, allyloxy, aminocarbonylmethyl, cyano, methyl, chlorine, Methoxy, methoxyethyl, amido, hydroxy, nitro, propinyloxy, alkanoylamino with 1-4 carbon atoms,

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Methylsulfamoyl, morpholine), methylthio and / or tetrahydrofurylmethyloxy. The aryl radical can also carry an alkylene chain bonded to two adjacent carbon atoms , a saturated ring being formed. For example, the aryl radical can represent a tetraion or tetralin ring.

The amino radical of -OCH ₂ CHCH ₂ N ^ or -CHCH ₂ N <^

0- 0-

chain expediently bears a branched alkyl substituent with 3-7 carbon atoms, e.g. isopropyl or tert-butyl.

Examples of suitable β-adrenergic blockers are Acebutolol, Alprenolol, Atenolol, Bufetolol, Bunitrolol, Bunolol, Bupranolol, 'Lab'stalol, Metoprolol, Nadoxolol, Oxprenolol, Pargolol, Practolol, Procinolol, Propranolol (Compound I), Talinolol, Timolol, Tiprenolol, Tolamolol, Toliprolol and Trimepranol.

Particularly interesting ß-adrenoceptor blockers are 4- (2-hydroxy-3-isopropylaminopropoxy) indole (pindolol, compound II), 4- (2-benzoyloxy-3-tert-butylaminopropoxy) -2-methylindole and 4- (2-hydroxy-3-isopropylaminopropoxy) -2-methylindole (Mepindolol).

Preferred ß-adrenoceptor blockers are those that reduce myocardial contractility and cardiac

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Little influence on frequency, e.g. connections with intrinsic sympathomimetic activity.

The active ingredients A) and B) can be in free form or in salt form, e.g. in acid addition salt form.

The new preparations can be made by using a ß-adrenoceptor blocker with a cis-l, 2,3,4,4a, 10b-hexahydro-6-phenylbenzo [c] [l, 6] naphtyridine as defined above into a dosage form suitable for therapeutic purposes, e.g. with each other and optionally with auxiliary or Mixed carriers.

ß-adrenoceptor blockers are suitable for the treatment of coronary heart disease. However, you are at Presence of manifest or latent kerf failure contraindicated.

It has now been found that the combination of a compound of the formula I and a ß-adrenoceptor blocker for the treatment of coronary artery disease, e.g. angina pectoris, and myocardial infarction in particular suitable is.

The effectiveness of the combination results from the following effects:

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a) in vitro: an increase in myocardial contractility indicative of a positive inotropic Effect of the compounds of the formula I can be concluded ',

b) in the clinic: a randomized _/ double-blind, placebo-controlled study on patients with left ventricular heart failure, which also suggests a positive inotropic effect of the compounds of the formula I;

c) in vivo: the changes in cardiac hemodynamic parameters caused by administration of the compounds of the formula I were caused only insignificantly by Pretreatment with a ß-adrenoceptor blocker, especially if it is intrinsic sympathomimetic Activity.

Effect a) was measured as follows:

Cats were anesthetized with chlorolose urethane (43 or 430 mg / kg), the left atrium was cut off from the heart and small, approximately 2 mm wide strips were poured into a modified Tyrod solution (NaCl 8g, KCl 0.2 g, CaCl ₂ .2H ₂ O 0.265 g, NaH ₂ PO ₄ OH ₃ O 0.05 g, MgCl ₃ .6H ₃ O 0.1 g, NaHCO ₃ 0.4 g, glucose 1 g per

Liters). Oscillated during an equalization time of 5.0 minutes and during the experiment the atrium at 60 pulse beats / min., the duration of the

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to

The pulse rate was 10 msec. The contractions of the organ were measured isometrically and with a Beckmann recorder registered. Dose-response curves were obtained with cumulative doses of the test compounds (1 + 3 + 10 + 30 yuM).

At bath concentrations of 1 to 50 / uM was based on the compound X measured a dose-dependent increase in the contraction force from 20 to 50%. No change the heart rate was found.

Effect b) was measured as follows:

6 patients with overt left insufficiency were given 300 mg of compound 1 hour after a light meal X administered orally. Another 300 mg was administered orally 30 minutes later. 6 patients one Control group was given a placebo. A day later the experiment was repeated, with an exchange of test and control patients. The study was consistently double-blind and randomized carried out. A statistically significant percentage increase in mean circumferential Fiber shortening rate of 23% was measured by echocardiography, while the ventricular diameter, the pulse rate and systolic blood pressure were not significantly changed. From this it can be concluded that the effect is due to a direct positive-inotropic effect of the compound X is due. No side effects occurred.

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This observation was made in another study of 5 patients with left ventricular insufficiency confirmed who did not respond to normal therapy with digitalis and / or diuretics Orally administered 200 mg of Compound X three times a day for 15 days. A significant increase of approx. 0.1 circ./sec. the mean circumferential fiber shortening rate was determined by echocardiography measured.

Effect c) was measured as follows;

Cats were anesthetized with urethane Chlorolose (43 and 4, 30 mg / kg) and ventilated with a Loosco MK II fan with positive endexpi ^r atoric pressure. Catheters were inserted into the femoral artery and vein. The thorax was opened, the aorta exposed and fitted with an electromagnetic current probe (Nycotron). The electromagnetic current velocity signal and the resulting blood acceleration in the aorta were recorded on a black polygraph. The mean aortic blood pressure, the heart rate and the mean aortic current were recorded with a Texas polygraph and the percentage changes for these three parameters were calculated. The test compound was infused IV over a period of about 10 minutes.

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At a dose of 0.1 to 10 mg / kg of compounds of the formula I, for example 1 mg / kg of compound X, the values measured for output and heart rate did not differ significantly from those for the control group , but during and after After the infusion, a dose-dependent increase in the peak velocity and the peak acceleration of the blood in the aorta was found.

These results indicate an increase in left ventricular ejection; the latter is a sign of increased myocardial contractility (GC van den Bos et al., Cardiovascular Res . ] _ [1973] 834).

The experiment was then repeated, but the animals were infused with 50 to 1000 jag / kg iv

a β-adrenoceptor blocker, e.g. 100 μg / kg of compound II or 500 μg / kg of the Connection I, over a period of 5-10 minutes and only 45-60 minutes later after a new one Base value had been reached, a compound of the formula I, as listed above, for example 1 mg / kg of the Compound X administered. Again a can-off dependent increase in the peak velocity and peak acceleration of the blood in the aorta, only slightly less than after administration of the compounds of formula I alone.

Because of their positive-inotropic effect, the preparations can be used as cardiotonics, i.e. for treatment

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heart failure, especially left ventricular heart failure, e.g. for the treatment of chronic or acute congestive heart failure, especially chronic heart failure, especially heart failure associated with hypertension or coronary artery disease and myocardial infarction.

It was also found that the preparations lead to results that are particularly favorable in the Comparison with the results obtained with the sole administration of a ß-adrenoceptor blocker for treatment coronary artery disease, e.g. angina pectoris and myocardial infarction, e.g. to a better tolerance.

For use as cardiotonics, the ones to be used vary Doses, of course, depending on the compound, route of administration and the condition to be treated. in the however, in general, satisfactory results will be obtained with a daily dose of about 200 mg to about 1200 mg of the compounds of formula I achieved. This dose can be divided into 2 to 4 parts or even if necessary be administered as a sustained release form. Suitable dosage forms for e.g. oral administration contain generally about 50 to about 600 mg in addition to solid or liquid carriers or diluents.

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The preparations contain the active ingredients A) and B) preferably in a weight ratio from about 500: 1 to about 1: 1, preferably about 200: 1 to about 2: 1 based on the compound in free form as a base. For the compounds X and II, a preferred quantitative ratio is about 200: 1 up to about 20: 1, in particular about 60: 1, and for the compounds X and I about 20: 1 to about 2: 1, in particular about 6: 1.

The active ingredients A) and B) are expediently administered in the form of pharmaceutical preparations which a compound of the formula I in free form or in pharmacologically acceptable acid addition salt form and a ß-adrenoceptor blocker in free form or in pharmacologically acceptable salt form together with pharmaceutically indifferent excipients or carriers contain. Such preparations, e.g. a tablet or a solution, can be prepared according to known methods getting produced. Salt forms have a pharmacological Activity that is in the same order of magnitude as that of the active ingredients in free form.

The active ingredients can be combined in one dosage form or side by side, e.g. in the form of a double pack, be used.

The following examples illustrate the invention.

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Example 1: capsule

A preparation suitable for oral administration 2 to 6 times a day is one according to known ones Methods produced capsule, has the following composition and for the treatment of the coronary Heart disease and myocardial infarction can apply:

Ingredient Total capsule
(mg) Compound X (in bishydrogen
maleinatform
Compound II (in free form
as base) 318.0 (= 200 mg
Base)
5.0 lactose 46.0 Cornstarch 18.0 Magnesium stearate 6.0 Colloidal silica 2.0 395.0

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Example 2 :. Oral liquid suspension

The following preparation can be made by known methods. It is for 4 to 12 times more every day Can be administered for the treatment of coronary artery disease and myocardial infarction?

Ingredient Oral liquid
Suspension (mg) Compound X (in bishydrogen
maleinatform) 159.0 (= 100 mg
Base) Compound II (in free form
as base) 2.5 Sodium carboxymethyl cellulose
USP 12.5 Magnesium aluminum silicate 47.5 Dyes q.s. Methyl paraben U.S.P. 4.5 Propyl Paraben U.S.P. 1.5 Polysorbate 80 (e.g. Tween 80)
USP 5 Sorbitol solution 70% U. S ^ P. 2500 Buffering agent for pH stabilizer
lization q.s. water q.s. ad 5 ml

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Example 3 : tablet

The following preparation can be made by known methods. It is for 2 to 6 times every day Administration suitable for the treatment of coronary artery disease and myocardial infarction.

Ingredient Total tablet
(mg) Compound X (in bishydrogen
maleinatform) 318.0 (= 200 mg
Base) Compound II (in free form
as base) 5.0 Polyvinyl pyrrolidone 15.0 lactose 203.0 Cornstarch 30.0 Talk 20.0 Colloidal silica 6.0 Magnesium stearate 9.0 600.0

Example 4:

The compound X in the preparations of Examples 1 to 3 and 5 can be replaced by the compound cis-1,2,3,4,4a, lOb-Hexahydro-8,9-dimethoxy-2-methyl-6-phenylbenzo [c] [1,6] naphthyridine to be replaced. Preparations suitable for similar purposes are obtained.

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Example 5:

The compound II in the preparations of Examples to 4 can be replaced by the compound I, in a 10-fold amount to der.der compound II. Preparations suitable for similar purposes are obtained.

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Summary;

100-5155

PHARMACEUTICAL PREPARATIONS CONTAINING BENZO [C] [1,6 3NAPHTYRIDINe

The new pharmaceutical preparations that act as active ingredients

wherein either

i) R ₁ denotes hydrogen, alkyl with 1 to 3 carbon atoms, alkoxy with 1-3 carbon atoms, alkylthio with 1-3 carbon atoms, fluorine, bromine, chlorine, nitro, trifluoromethyl, amino or -NHCOR, in which

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-COR alkanoyl with 1 -18 carbon atoms, benzoyl, benzoyl substituted by a radical X and a radical Y, in which X is alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, fluorine, chlorine or bromine

and Y is hydrogen, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms or is chlorine, cinnamoyl, phenylalkanoyl, in which the alkylene part is 1-3 Contains carbon atoms in the phenyl ring

cinnamoyl or phenylalkanoyl substituted by one radical X and one radical Y, wherein the alkylene part contains 1-3 carbon atoms, where X and Y have the above meaning own, or -COA, where A is thienyl,

Furyl, pyrrolyl or pyridyl means

R for hydrogen, chlorine, alkyl with 1-3 carbon atoms or alkoxy with 1-3 carbon atoms and

either R, and R. both hydrogen or both

Mean methoxy

or R_ and R. together for methylenedioxy

stand,

or

ii) R is -NHCOR ¹ , in which R is dichloromethyl, cycloalkyl with 3-6 carbon atoms or alkenyl with 2-5 carbon atoms.

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R_ means hydrogen and R- and R. both stand for methoxy, and

B) contain a ß-adrenoceptor blocker are suitable for the treatment of coronary artery disease "

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Claims (11)

SANDOZ-PATENT-GMBH 7850 Lörrach Case 100-5155 PHARMACEUTICAL PREPARATIONS, CONTAINING BENZO [c] [1,6] NAPHTYRIDINE Patent claims r 1. Pharmaceutical preparations, characterized in that that they act as active ingredients A) a compound of the formula I, wherein either i) R ₁ denotes hydrogen, alkyl with 1 to 3 carbon atoms / alkoxy with 1-3 carbon atoms, alkylthlo with 1-3 carbon atoms, fluorine, bromine, chlorine, nitro, trifluoromethyl, amino or -NHCOR, in which 030031/06 2 - 100-5155 -COR alkanoyl with 1 -18 carbon atoms, benzoyl, substituted by a radical X and a radical Y Benzoyl, where X is alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, fluorine, chlorine or bromine and Y is hydrogen, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms or is chlorine, cinnamoyl, phenylalkanoyl, in which the alkylene part is 1-3 Contains carbon atoms in the phenyl ring cinnamoyl or phenylalkanoyl substituted by one radical X and one radical Y, wherein the alkylene part contains 1-3 carbon atoms, where X and Y have the above meaning own, or -COA, where A is thienyl, Furyl, pyrrolyl or pyridyl means R for hydrogen, chlorine, alkyl with 1-3 carbon atoms or alkoxy with 1-3 carbon atoms and either R 1 and R _{f are} both hydrogen or both .Methoxy or R 1 and R ₄ together represent methylenedioxy stand, or ii) R is -NHCOR ¹ , where R ^{1 is} dichloromethyl, cycloalkyl with 3-6 carbon atoms or alkenyl 'with 2-5 carbon atoms, 030031/0658 - 3 - ■■ "'1 (00-5155 R is hydrogen and R_ and R. both stand for methoxy, and B) contain a ß-adrenoceptor blocker in free form or in salt form. 2. Pharmaceutical preparations according to claim 1, characterized in that they are used as active ingredient A) the cis 6- (4-acetamidophenyl) -1,2,3,4,4a, lOb -hexahydro-8,9-dimethoxy-2-methyl-benzo [c] [1,6] naphthyridine contain. 3. Pharmaceutical preparations according to claim 1, characterized in that they are used as active ingredient B) the 4- (2-Hydroxy-3-isopropylaminopropoxy) indole. 4. Pharmaceutical preparations according to claim 1, characterized in that they are used as active ingredient B) the 4- (2-Benzoyloxy-3-tert-butylaminopropoxy) -2-methylindole contain. 5. Pharmaceutical preparations according to the claims 1 and 2, characterized in that they contain as active ingredient B) a compound that has a Chain -OCH CHCH N ^- C ^ which has immediately through the oxygen atom in position 1 to an aryl radical is bound. 030031/0658 BATH ORIGINAL -4 "" - 1OÖ-5155 6. Pharmaceutical preparations according to the claims 1 and 2, characterized in that they contain as active ingredient B) a compound that has a Chain -CHCH-N ^, which is immediately followed by the ·. 5 carbon atom in 1-position attached to an aryl radical is. 7. Pharmaceutical preparations according to claims 1, 2, 5 and 6, characterized in that as active ingredient B) they contain a compound which has an intrinsic sympathomxmetic effect. 8. Pharmaceutical preparations according to claims 1 to 7, characterized in that the Active ingredients A) and B) are present in a weight ratio of about 500: 1 to about 1: 1. 9. Pharmaceutical preparations according to claims 1 to 7, characterized in that the Active ingredients A) and B) are present in a weight ratio of about 200: 1 to about 2: 1. 10. A process for the production of pharmaceutical preparations which are defined in claim 1 Active ingredients A) 'and B), characterized in that the active ingredients A) and B) mixed with one another and optionally with carriers. 030031/0658 BAD ORIGfNAL ΪΟΟ-5155 <r 11. A process for the production of pharmaceutical preparations which are defined in claim 1 Active ingredients A) and B), characterized in that the active ingredients A) and B) into a dosage form suitable for therapeutic purposes. • 12. Use of the pharmaceutical preparations according to claim 1 for the treatment of the coronary Heart disease. 03 0 0 31/0658