DD297640A5 - METHOD FOR PRODUCING ANELLULATED TETRAHYDROPYRIDINEIGSAEUREDERIVATE - Google Patents

Abstract

The invention relates to a process for the preparation of fused Tetrahydropyridinessigsaeurederivate for cardioprotection. According to the invention, compounds of the general formula (I) are prepared in which A, R, R4, R5, R6 and m have the meaning given in the claims and in the description. Formula (I) {new fused tetrahydropyridine acetic acid derivatives; cardioprotective effect; Drug}

Description

Field of application of the invention

The invention relates to a process for the preparation of novel fused Tetrahydropyridinessigsäurederivate, pharmaceutical preparations containing these new or structurally related known compounds and the use of the novel compounds or structurally related known compounds for cardioprotection. Furthermore, the invention relates to novel intermediates for the preparation of the abovementioned compounds.

Characteristics of known prior art

Some of the compounds covered by the general definition of formula I in which A is a benzo or indolo radical are known, some of which have been described as tranquillizers:

Eur. J. Med. Chem. - Chim. Ther, 14 (1), 77-89; Heterocycles, 3 (2), 179-182; Synthesis (5), 474-477

J. Med. Pharm. Chem. 3,505-517 (1961) -EP-PS 21857, US-PS 302-331, US-PS 3081306.

Object of the invention

The aim of the invention is the provision of new fused tetrahydropyridine acetic acid derivatives with valuable pharmacological properties, in particular with cardioprotective action.

Explanation of the essence of the invention

The invention has for its object to find new fused Tetrahydropyridinessigsäurederivate with the desired properties.

According to the invention, novel compounds of the formula I

or their pharmaceutically acceptable salts with an inorganic or organic acid, wherein A, R, m, R ⁴ , R ⁶ and R ^e wio are defined above except a) compounds of the formula Ic

(Ic)

R is hydrogen, hydroxy or methoxy,

m is 1,2 or 3,

R ⁴ and R ^{e are} hydrogen and

R ^{e is} hydroxy or ethoxy;

and compounds in which

2 is and

Methoxy in positions 6 and 7, and hydrogen, R ^{5 is} etheyl and R ^{6 is} methoxy, or methyl, H ^{6 is} hydrogen and R ^{6 is} hydroxy or ethoxy

Hydrogen, R ^{5 is} methyl and R ^{6 is} ethoxy;

and compounds of the formula Id, K

wherein

R is hydrogen or methoxy, R ^{4 is} methyl, R ^{G is} hydrogen or phenyl and R ^{6 is} ethoxy;

(Id)

b) compounds of the formula Ie,

(Ie)

wherein

R is hydrogen, (C, -C ₄ ) alkyl, hydroxy or (C ₁ -C ₄ ) alkoxy, or the two adjacent substituents R together

-O-CH ₂ -O-,

H ^{s is} hydrogen, alkenyl, alkyl which may be substituted by hydroxy, methoxy, dimethylamine or phenyl; means;

c) compounds of the formula If

(If)

wherein R is hydrogen, (C, -C ₄ ) alkyl, halogen or (C ₁ -C ₄ ) alkoxy, R ^{4 is} hydrogen or (C ₁ -C ₄ ) AlkYl; R ⁸ (C ₁ -C ₄ ) alkoxy-NHR ^{8 group} means where

R ^{8 is} hydrogen or (C ₁ -C ₄ ) Alkyl, where the alkyl may be substituted by phenyl.

The general formula I also includes the respective isomeric forms of the compounds. The compounds of the general formula I

A represents a benzo, thieno or indolo radical; R is hydrogen, (C 1 -C ₄ ) alkyl, halogen (F, Cl, Br, J), hydroxy, (C 1 -C ₄ ) alkoxy, amino, methylthio, methanesulfonyloxy or Methanesulfonamido, or two adjacent substituents R together are -O-CHj-O-OdBr-O-CH ₂ -CH ₂ -O-;

Is 1,2 or 3, when A is a benzo or indolo radical and 1 or 2 when A is a thifino radical;

Is hydrogen or (C, -O,) alkyl; Hydrogen, (C ₁ -C ₁₀ ) alkyl, phenyl, phenyl (C ₁ -C ₆ ) alkyl, (C 1 -C ₄ ) alkoxy or -NHCOX [wherein X is (C ₁ -C ₆ ) alkyl];

Hydroxy, (C) -C ₄ ) alkoxy or a -NR ⁷ R ⁸ group, wherein R ⁷ and R ^{8 are} independently

(a) hydrogen,

(b) branched or unbranched alkenyl having 3 to 6 carbon atoms,

(c) branched or unbranched alkynyl having 3 to 6 carbon atoms, or

(d) branched or unbranched alkyl having 1-12 carbon atoms, wherein the alkyl may be substituted by hydroxy, (C) -C ₄ ) alkoxy, di (C] -C ₄ ) alkylamino, furyl, pyridyl, pyrrolidinyl, morpholine » , Indolyl, nitrilo, thienyl, phenyl or phenyl, which is monosubstituted or polysubstituted by hydroxy, methoxy or fluorine;

or R ^{7 is} hydrogen and R ^{8 is} phenyl, fluorophenyl, pyridyl or N-benzylpiperidyl; or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached represent pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl, where the piperazinyl ring is optionally substituted by methyl, unsubstituted phenyl, mono- or di (C 1 -C ₄ ) alkoxyphenyl , pyrimidinyl or phenyl (C) -C ₄₎ alkyl may be N-substituted;

or its pharmaceutically acceptable salt with an inorganic or organic acid for cardioprotection. Furthermore, the invention relates to a pharmaceutical preparation containing a compound of formula I, which is as defined above, or their pharmaceutically acceptable salts with inorganic or organic acids, except

a) compounds of the formula Ig

(Ig)

ir> _fc W) - ir

R ⁴ is H, R ^{6 is} H and

R ^{6 is} NH (CH ₂ I ₃ OH, NH (CH ₂ J ₂ OH or NH (CH ₂ I ₃ OCH ₃ ;

b) compounds of the formula I, wherein A is an indolo radical;

R is hydrogen, (C) -C ₄ ) alkyl, halogen or (C, -C ₄ ) alkoxy; full

Is hydrogen or (C _t -C ₄ ) alkyl; R ^{5 is} hydrogen;

R ^{6 is} (C ₁ -C ₄ ) alkoxy or a NHR ⁸ group in which

R ^{8 is} hydrogen or alkyl of 1 to 4 carbon atoms (which may be substituted by phenyl); or containing a compound of general formula I h,

(Ih)

wherein R ^{$ is} ethoxy or -NHCH ₂ CH (CH ₃ I ₂ .

It is novel and surprising that the compounds of formula I show cardioprotective activity. The compounds of the general formula I can be prepared by processes known per se. A compound of the formula I in which A, R, m, R ⁴ , R ⁵ and R ^{6 are} as defined above can be prepared by the

corresponding compound of the general formula II

is reduced. In the compound of formula II, A, R, m, R ⁴ , R ⁵ and R "are as defined in the desired compound of formula I.

This process is preferably applied to compounds of the formula II in which R ^{4 is} hydrogen.

Red.

Ha

Ia

For the preparation of a compound of the formula I in which R ^{4 is} (C 1 -C 8) alkyl, one of the following variants can be used:

a) a compound of formula Ia is N-alkylated;

b) a compound of the formula Ha is converted into its quaternary ammonium salt: (for example by reaction with (C 1 -C 3) alkyl iodide) and then to the compound of the formula I (in which R _{4 is} (C 1 -C ₄ ) alkyl) reduced.

Complex metal hydrides (such as, for example, sodium borohydride, sodium cyanoborohydride, if appropriate in combination with a noble metal catalyst) or catalytically activated hydrogen are suitable for the reduction of the compounds of the formula II or IIa.

The reduction is preferably carried out in a solvent such as methanol or ethanol at room temperature or optionally at elevated temperature up to the reflux temperature of the reaction mixture.

A part of the compounds of general formula I (shown below as formula I b) can be prepared by reduction of a corresponding compound of general formula V,

reduction

ib

A represents a benzo, thieno or indolo radical;

R is hydrogen, (C, -C ₄ ) alkyl, halo (F, Cl, Br, J), hydroxy, (C ₁ -C ₄ ) alkoxy, amino, methylthio, methanesulfonyloxy or

Methanesulfonamido, or two adjacent substituents R together are -O-CHz-O- or -O-CHj-CHj-O-; m is 1,2 or 3 when A is a benzo or indolo radical and 1 or 2 when A is a thieno radical; R ^{9 is} hydrogen or (Ci-C ₃ ) alkyl;

R ^{s is} hydrogen, (C 1 -C ₁₀ ) alkyl, phenyl, phenyl (C ₁ -C ₆ ) alkyl, (C 1 -C ₄ ) alkoxy or -NHCOX (wherein X is (C ₁ -C ₆ ) alkyl); R ^{8 is} (a) hydrogen,

(b) branched or unbranched alkenyl having 3 to 6 carbon atoms,

(c) branched or unbranched alkynyl having 3 to 6 carbon atoms, or

(d) branched or unbranched alkyl having 1-12 carbon atoms, wherein the alkyl may be substituted by

hydroxy,

(C, -C ₄ ) A! Koxy,

Di (C ₁ -C ₄ ) alkylamino,

Fury I,

pyridyl,

pyrrolidinyl,

morpholines

indolyl,

nitrilo,

thienyl,

Phenyl or phenyl which is monosubstituted or polysubstituted by hydroxy, methoxy or fluorine;

(e) phenyl, fluorophenyl, pyridyl or N-benzylpiperidyl; means.

The reduction is carried out with NaBH ₄ in glacial acetic acid, possibly with addition of a solvent (based on C. Dierassi, HJ Monteiro, A. Walser, LH Durham J. Am. Chem. Soc., 88, (1966) 1792) dissolving a compound of the general formula V in glacial acetic acid and adding an excess of sodium borohydride in portions while cooling and stirring The reaction time is very largely determined by the length of the radical R ⁶ and is between 1 and 15 hours at room temperature sequence

R ⁶ = H <CH ₃ <C ₂ H ₆ <C ₄ H ₈ <CjH ₁ ,

to. They are not or only insignificantly influenced by R ⁸ .

The reaction temperature is largely uncritical and may be between ö ° C and the boiling point of the reaction mixture. For safety reasons, the reaction is carried out under ice-cooling in a temperature range between 5 ° C and room temperature.

Suitable solvents besides glacial acetic acid, which simultaneously occurs as a reactant, are mixtures of glacial acetic acid and a suitable inert solvent, for example THF, dioxane, ethanol, etc. The reaction is preferably carried out in glacial acetic acid.

Preferred embodiment of the reduction:

The starting compounds (V) are dissolved in glacial acetic acid. With stirring and cooling to 5 ⁰ C, the finely pulverized NaBH ₄ (4-10facher excess) is added in portions. After completion of the reaction, carefully mixed with water, made alkaline with dilute NaOH, extracted with CH ₂ Cl ₂ . The organic phase is washed with water, dried over Na ₂ SO ₄ and concentrated. The residue is, if appropriate after purification, brought to crystallization over a silica gel column (eluant: CH ₂ Cl ₂ / MeOH 100: 10).

The compounds of the formula I thus obtained may be subjected to one or more of the following post-treatments:

a) A compound of the general formula I in which R ^{e is} hydroxy or (C _t -C ₄ ) alkoxy can be converted into the corresponding amide in which R ^{6 is} the group NR ⁷ R ⁸ . In this case, the starting compound, (optionally after previous protection of the basic ring nitrogen and / or activation of the carboxy or ester group) is reacted with the corresponding amine NHR ⁷ R ⁸ (III).

Acid halides, acid azides or mixed acid anhydrides (for example with an aromatic or aliphatic carboxylic acid, alkyl carbonic acid or dialkylphosphoric acid, etc.), furthermore acid amides (for example with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole, etc., may be mentioned as reactive carboxylic acid derivatives or active esters (such as cyanomethyl, methoxymethyl, vinyl, propargyl or p-nitrophenyl esters, etc.) or esters with dimethylhydroxylamine, 1-hydroxysuccinimide, dicyclohexylurea, etc., the active imidazolides are preferred. The amide formation is generally carried out in an inert solvent such as dioxane, acetonitrile, dimethylformamide or a mixture of one or more of these solvents, optionally in the presence of an organic or inorganic base as acid scavenger. But it is also possible to carry out the reaction without solvent with the amine in excess.

Depending on the starting materials used, the reaction temperature can vary within wide limits and can be between about 0 ° C. and the boiling point of the reaction mixture.

b) A compound of the general formula I in which R ^{4 is} hydrogen can be converted by N-alkylation into the corresponding compound of the formula I in which R ^{4 is} (C 1 -C ₄ ) alkyl.

For the N-alkylation are in principle all known alkylating agents, provided they have a sufficient reactivity, for. As active alkyl esters, such as dialkyl sulfate, Toluolsulfonsäurealkylester or Fluorsulfonsäurealkylester or alkyl halides, such as alkyl bromides or alkyl iodides. The reaction takes place at temperatures up to the boiling point of the reaction mixture. Alkyl here stands for (C, -C ₄ ) alkyl.

The aminoalkylation can also be carried out according to Leuckart-Wallach (Bersch. Chem. Ges. 18, [1985], 2341) or Eschweiler-Clarke (Teilheimer 2, [1948] No. 352; 4 [1950] No. 378) , In general, the substance is treated with an approximately 30% aldehyde solution, preferably formalin solution in the presence of formic acid at reflux temperature. The duration varies between 3 and 18 hours. This reaction is particularly suitable for compounds (I) in which R ^{6 is} not NH ₂ or NHR ⁸ .

c) A compound of the formula I in which R ^{6 is} hydroxy can be converted into the corresponding ester (R ⁶ = (C 1 -C ₄ ) alkoxy).

d) A compound of formula I in which R ^{e is} (C, -C ₄ ) alkoxy or NR ⁷ R ⁸ can be hydrolyzed to the corresponding free acid.

β) The diastereomer separation succeeds partly spontaneously by crystallization or by applying the usual methods of racemate separation, for. B. column chromatography.

f) The conversion of the free base of the general formula I into their acid addition salts is carried out in a manner known per se. Suitable acids for salt formation are for example hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, acetic, propionic, butyric, oxalic, malonic, succinic, maleic, fumaric, lactic, tartaric, citric, malic, benzoic, cinnamic, ascorbic or methanesulfonic.

The compounds of the formula II can be prepared by processes known per se, preferably by the method described in the German patent application P 3718570.5.

In the presence of a condensing agent, a malonic acid of the general formula IV,

NHCO-C CO R

in which R, m, R ^s and R ^{6 are} as defined above and Ar is phenyl, 2- or 3-indolyl or 2- or 3-thienyl, to the corresponding compounds II and II ', be cyclized.

(R)

II

Here, A, m, R, R ⁵ and R ^{e are} as defined above for the compounds IV, R ⁴ is hydrogen or (C _t -C ₄ ) alkyl.

The implementation of the method will be discussed in more detail below. Will Jie reaction z. Example, with a mixture of phosphorus pentoxide and (Ci-C ₄ ) alkyl sulfonic acid, it is obtained in addition to the corresponding compounds II and II, wherein R ^{4 is} hydrogen, and the analogous compounds II and II ', wherein R ⁴ (Ci-C ₄ ) is alkyl.

Suitable condensing agents for this process are strong Lewis acids, such as B. Phosphoro.xychlorid, phosphorus pentachloride, phosphorus trichloride, phosphorus pentoxide, titanium tetrachloride, boron trifluoride, tin tetrachloride, but also inorganic acids, such as polyphosphoric acid, sulfuric acid, fluorosulfonic acid and hydrofluoric acid, or mixtures condensation agents, e.g. a mixture of phosphorus oxychloride and phosphorus pentachloride, or a mixture of phosphorus pentoxide and (C 1 -C ₄ ) alkylsulfonic acid, e.g. with a P ₂ O ₆ content of about 10% by weight.

If a compound IV is cyclized in the presence of the mixture of phosphorus pentoxide and (C 1 -C 4 -alkylsulfonic acid, then, as has been mentioned above, the analogous compounds II and II are obtained in addition to the corresponding compounds II and II 'in which R ^{4 is} hydrogen In which R ^{4 is} (C 1 -C ₄ ) alkyl, this process variant is preferably carried out with methanesulfonic acid.

The cyclization may be carried out in the presence or absence of a solvent. All inert solvents are suitable, provided they have sufficient solubility for the reactants and have a sufficiently high boiling point, for example benzene, alkylbenzenes (eg toluene, xylene), chlorobenzenes, chloroform, acetonitrile, decalin.

A preferred variant of the process consists in using the condensing agent, for example phosphorus oxychloride or a (C 1 -C 4) alkylsulfonic acid / phosphorus pentoxide mixture, without addition of solvent.

The cyclization preferably takes place with phosphorus oxychloride or, in difficult cases, with a mixture of phosphorus pentoxide and (C 1 -C 6 -alkylsulfonic acid (preferably methanesulfonic acid).) The reaction can be carried out within a wide temperature range, preferably with heating or heating to 50 ^° C. to about the boiling point of the reaction mixture become.

The required reaction time is depending on the starting compound IV between 2 and 15 hours.

The tautomers of general formulas II and II, wherein R ^{4 is} hydrogen, can be separated by known methods, such as. B. by column chromatography.

The compounds of general formula II or ΙΓ in which A is an indolo radical, R, m, R ⁴ , R ⁵ and R ⁸ as defined above for the compounds of general formula I are novel compounds, except those in which m is one is

R is hydrogen, (C, -C ₄ ) alkyl, halogen or (C, -C ₄ ) alkoxy,

R ^{4 is} hydrogen or (C) -C ₄ ) alkyl,

R ^{5 is} hydrogen,

R ^{6 is} (C, -C ₄ ) alkoxy-a-NHR ⁸ group,

R ^{8 is} hydrogen or (C 1 -C 4) alkyl, where the alkyl may be substituted by phenyl.

The invention further relates to novel compounds of general formula V,

wherein,

A represents a benzo, thieno or indolo radical;

R is hydrogen, (C 1 -C ₄ ) alkyl, halogen (F, Cl, Br, J), hydroxy, (C 1 -C ₄ ) alkoxy, amino, methylthio, methanesulfonyloxy or

Methanesulfonamido, or two adjacent substituents R together are -O-CHr-O- or -O-C-CHj-O-; m is 1,2 or 3 when A is a benzo or indolo radical and 1 or 2 when A is a thieno radical; R ^{9 is} hydrogen or (C, -C ₃ ) alkyl;

R ^{5 is} hydrogen, (C ₁ -C 10) alkyl, phenyl, phenyl (C) -C ₆ ) alkyl, (C ₁ -C ₄ ) alkoxy or -NHCOX (wherein X is (C, -C ₅ ) alkyl); R ^{8 is} (a) hydrogen,

(b) branched or unbranched alkenyl having 3 to 6 carbon atoms,

(c) branched or unbranched alkynyl having 3 to 6 carbon atoms, or

(d) branched or unbranched alkyl having 1-12 carbon atoms, wherein the alkyl may be substituted by

Hydroxy, (C ₁ -C ₄₎ -alkoxy, di (C | -C ₄₎ alkylamino, furyl, pyridyl, pyrrolidinyl, morpholino, indolyl, nitrilo, thienyl,

Phenyl or phenyl which is monosubstituted or polysubstituted by hydroxy, methoxy or fluorine; (o) phenyl, fluorophenyl, pyridyl or N-benzylpiperidyl; means

and their salts with an inorganic or organic acid. These compounds are starting compounds for the

corresponding compounds of the general formula I in which R ^{4 is} the group -CR ⁹ Hj and R ^{e is} the group -NHR ⁸ . These compounds also show cardioprotective action.

The invention further relates to a pharmaceutical preparation comprising a compound of the formula V, which is as defined above, or its pharmaceutically acceptable salt with an inorganic or organic acid.

The compounds of general formula V can be prepared by reacting a corresponding compound of

general formula I, wherein R ^{4 is} hydrogen and R ^{6 is} the group -NHR ⁸ and R, m, R ⁶ and R ^{8 are} as defined in the desired compound of formula V (this compound corresponds to the general formula I '), with an aldehyde of

general formula R ⁹ CHO (Vl) is reacted:

I · V

R ⁹ is hydrogen or (Ci-C ₃ ) alkyl. The reaction is conveniently carried out with a 30% aldehyde solution at elevated temperature. Preferably, the reaction is carried out with formalin solution in the presence of formic acid at reflux temperature. The compounds described by the general formulas I and V have, as mentioned above, valuable therapeutic properties both as bases and in the form of their salts. In particular, these substances have a marked cardioprotective effect, which was determined as follows:

It is known that the myocardial Ca ² content is a measure of the cardiac damage caused by hypoxia or toxic catecholamine doses (Higgins et al., Mol Cell, Cardial, 10, 427-438, 1984, Nakanishi et al., Am J. Physiol, 242, 437-449 Fleckenstein, A. Lectures of the Erlangen Physiol Conference 1970, Edit Keidel, Springer Verlag Berlin, Heidelberg, New York, 1971). Conversely, inhibition of hypoxic or isoprenaline-induced myocardial calcium uptake is a measure of the cardioprotective efficacy of calcium antagonists (Fleckenstein, supra), calmodulin inhibitors (higgins) and other drugs, e.g. B. beta-adrenergic agents (Arndts, Arzneimittelforschung 25, 1279-1284, 1975). The cardioprotective effect was on

Rats were detected after subcutaneous or peroral drug administration by the method described by Arndts (see above) and the potency of the test substances indicated as H _M value. This value corresponds to the dose that inhibits 50% of the myocardial radiocalcus intake caused by the administration of 30 mg / kg sc isoprenaline.

Here, the compounds investigated prove to be up to five times more effective than the known commercial product propranolol.

In vitro studies on the smooth muscle (aortic strip) have shown that it is the calcium antagonist with a novel mechanism of action in the compounds of the invention:

Calcium antagonists inhibit the transmembrane calcium ion influx into the cell. This inhibition affects the voltage-dependent (slow) calcium channel in the cell membrane. The determination of transmembrane calcium ion currents on tissue strips under potassium depolarization according to the method described by van Breemen clearly detects calcium antagonists (van Breemen et al., Chest., 78, 157, p.165, 1980, van Breemen et al., Am., J. Cardiol, 49, 507 Casteels et al., Pflügers Arch. 392, 139-145, 1981; Deth and van Breemen, J. Membrane Biol. 30, 363-380, 1977).

Examination on isolated rat heart

If an isolated heart maintained under ischemic conditions for a long time is perfused normally again, no immediate normalization of cardiac function occurs. Rather, there is a transient period characterized by contracture and arrhythmias. This arrhythmia phase is due to changes in the function and structure of the myocardial cell with intracellular calcium overload (Hoss and Manson, J. Mol. Cell. Cardiol., 16,969,1984). Cardioprotective compounds such as verapamil and dilitiazem reduce calcium overload and improve contraction behavior upon reperfusion (Watts et al., Am J. Physiol 238, H 909, 1980; Meno et al., Am J. Physiol 247, H 380, 1984 ). The cardioprotective effect is studied on isolated rat hearts under ischemia and subsequent reperfusion.

Methodology I

Isolated hearts are exposed to a pronounced lack of oxygen due to extensive reduction of coronary flow (more than 95%). As a result of disturbances in the metabolism of the heart, there is a rapid arrest of cardiac activity, after the end of the coronary flow reduction. The heart activity is delayed and irregular, and regular action is observed after 10-15 minutes.

Cardioprotective compounds added to the perfusion medium during the period of flux reduction shorten the period of irregular cardiac activity.

connection conc. [Μ / ml] Shortening the Arrhythmiephase 10-15minauf A 13.2 to 26.6 6.2 to 10 B 6.6 to 13.3 4.0-4.8 C 6.6 2.3 alinidine 13.3 to 33.3 3.25 to 4.15 propranolol 6.6 2,6 min F 6.6 3.75 min

Methodology Il

If the coronary flow of isolated hearts is throttled by 75%, the heart initially reacts with a decrease of the contraction amplitude, a cardiac arrest occurs within one hour. Cardioprotective agents, added to the perfusion medium during the period of flux reduction, prevent the decrease in contraction amplitude.

connection

Required concentrations

Comparison: Compounds A to E:

D E alinidine

3.0pg / ml, 1.0mg / ml, 8.3mg / ml.

C ₁ -H, -CH-CO-NH-CH ₉ -CH, 5 11 ?

NH H CH-CO-NH-CH ₂ -CH = CH ₂

N-H

CH-CONH-CH ₂ -CH ₂ -

N-H

.HCl

^S CH,

On the basis of these findings, the compounds of the general formula I or their acid salts can be used as active ingredients for medicaments for coronary heart disease. Another object of the invention are pharmaceutical compositions containing the substances of general formulas I and V and their salts with inorganic or organic acids. The medicines are suitable for oral or parenteral administration. The main forms of medication are tablets, dragees, ampoules and juice preparations. The single dose of these dosage forms is between 1.0 and 200 mg, preferably 20 and 50 mg per 75 kg body weight. Depending on the severity of the case, 1 to 3 single doses should generally be administered daily.

embodiment

The invention is explained in more detail below with reference to some examples.

example 1

2- (1,2,3,4-tetrahydro-6-methylmercapto-1-isoquinolinyl) -N- (1-pentyl) -hexanamide 2.5 g of 2- (3,4-dihydro-6-methylmer! 1-isoquinolinyl) -N- (1-pentyl) -hexanamide are added in portions to 0.5 g of NaBH ₄ in 100 ml of methanol and stirred at room temperature for 3 hours After completion of the reaction, excess NaBH _{4 is} added, the solvent is stripped off in vacuo, and the residue partitioned between CH ₂ Cl ₂ and water and dried after drying the organic phase over anhydrous sodium sulfate vJrci and the residue is crystallized from ethyl acetate / petroleum ether.

Example 2

Ethyl 2- {1,2,3,4-tetrahydro-6-methylmercapto-1-isoquinolinyl) -hexanoate hydrochloride 20g of ethyl 2- (3,4-dihydro-6-methylmercapto-1-isoquinolinyl) -hexanoate are dissolved in 200 ml of boiling ethanol added byprogram with 5.2 g of solid NaBH ₄ and stirred for 2 hours at boiling temperature. After working up the reaction mixture, the hydrochloride is formed and crystallized from ethanol / ether.

Example 3

2- (1,2,3,4-Tetrahydro-8,7-dimethoxy-1-isoquinolinyl) -hexanoic acid ethyl ester-hyd'-chloride 60g of 2- (3,4-dihydro-6,7-dimethoxy-1-isoquinolinyl) Ethylhexanoate are catalytically hydrogenated in 600 ml of ethanol with the addition of 17 g of concentrated HCl in the presence of 6 g of PtO ₂ at 20 ° C. and 5 bar with hydrogen. After removing the catalyst, the reaction solution is concentrated and the product is crystallized by the addition of ether.

Mp 141-145 ⁰ C

Example 4

2- (1,2,3,4-Tetrahydro-6,7-dimethoxy-2-N-methyl-1-isoquino! Inyl) -hexanoic acid, ethyl ester hydrochloride A mixture of 12 g of 2- (1,2,3,4- Tetrahydro-6,7-dimethoxy-1-isoquinolinyl) -hexanoic acid ethylester, 33 g formalin (30%) and 16 g formic acid (98%) are heated to boiling for 1 hour. The evaporation of the reaction mixture is made alkaline with semisaturated sodium carbonate solution, extracted with CH ₂ Cl ₂ , the organic phase washed with water, dried over Na ₂ SO ₄ and evaporated in vacuo. The reaction product is purified on AI ₂ O ₃ activity level III (eluons CCI ₄ ) and converted into the hydrochloride.

Mp 156-157 ° C (ethanol / ether)

Example 5

2- (1,2,3,4-Tetrahydro-6,7-dimethoxy-2-N-methyl-1-isoquinolinyl) hexanoic acid hydrochloride 15.5 g of 2- (1,2,3,4-tetrahydro-6 , 7-dimethoxy-1-isoquinolinyl) -hexanoic acid ethyl ester are concentrated in 100 ml. Hydrochloric acid heated to boiling for 1.5 hours. After completion of the reaction is largely concentrated in vacuo and a diastereomer by the addition of acetone to crystallize (mp. 180-183 ⁰ C), the second diastereomer remains in the mother liquor.

Examples

2- (1,2,3,4-Tetrahydro-6-methylmercapto-1-isoquinolinyl) -N- (1-pentoxy-hexanamide 3g2- (1,2,3,4-tetrahydro-6-methylmercapto-1-isoquinolinyl After completion of the reaction (TLC check), excess amine is removed in vacuo, the residue is taken up in CH ₂ Cl ₂ , shaken out a number of times with water, the organic phase is dried over anhydrous Na ₂ SO ₄ dried, evaporated and the residue on silica gel (eluent CH ₂ Cl ₂ / Me0H = 100: 3).

Example 7

2- (1,2,3,4-Tetrahydro-6,7-dimethoxy-2-N-methyl-1-isoquinolinyl) -hexane-N- [2- (2,4-dimethoxyphenyl) -ethyl] -amide 2 58 g of 2- (1,2,3,4-tetrahydro-6,7-dimethoxy-2-N-methyl-1-isoquinolinyl) hexanoic acid are dissolved in 50 ml of anhydrous DMF with 3.2 g of N, N'-carbonyldiimidazole 4 Stirred hours at room temperature. Thereafter, it is mixed with 3 ml of 3,4-dimethoxyphenylethylamine and worked up after standing at room temperature for 15 hours. This implementation runs without structural change. If an isomer is used as the starting material, the corresponding isomer of the end compound is obtained.

Diastereomer 1: m.p. 94-96 ⁰ C (Essigester / ligroin).

Diastereomer 2: m.p. 75-78 ⁰ C (Essigester / ligroin).

Example 8 2- (1,2,3,4-Tetrahydro-6 _L 7-dimethoxy-1-isoquinolinyl) -hexane-N- (2-phenylethyl) -amide hydrochloride

a) 2- [1,2,3,4-Tetrahydro-6,7-dimethoxy-2-N- (9-fluorenylmethyloxycarbonyl) -1-isoquinolinyl] -hexanoic acid

In a mixture of 10.8 g of 2- (1,2,3,4-tetrrahydro-6,7-dimethoxy-1-isoquinolinyl) hexanoic acid, 70 ml of aqueous sodium carbonate solution (10%) and 35 ml of dioxane at ^{0 0} C in the course a solution of 9.1 g of 9-Fluorenylmethyloxycarbonykhlorid in 55 ml of dioxane was added dropwise from 30min. After Istündigem stirring at ^{0 0} C is allowed to stand for 15 hours at room temperature, poured onto 1000 ml of ice water and extracted 3 times with 100 ml of ether. The aqueous phase is brought to pH = 2, the solid white precipitate is filtered off with suction and crystallized after dissolving in CHCl ₃ / MeOH (1: 1) by addition of petroleum ether. Fp.169-172 ° C

b) 2- [1,2,3,4-Tetrahydro-6,7-dimethoxy-2-N- (9-fluorenylmethyloxycarbonyl) -1-isoquinolinyl) -hexane-N- (2-phenylethyl) -amod2 65 g of 2- (1,2,3,4-tetrahydro-6,7-dimethoxy-2-N- (9-fluorenylmethyloxycarbonyl) -1-isoquinolinyl] -hexanoic acid are dissolved in 15 ml of anhydrous DMF with 1 g of Ν, Ν'- carbonyldiimidazole is reacted after 1 hour with an equivalent

Amount of 2-phenyl ethylamine added; After a further 15 hours at room temperature, the mixture is worked up, purified on silica gel (eluant CHCl ₂ / MeOH = 100: 2) and crystallized from ethyl acetate / petroleum ether. Mp 168-170 ⁰ C

c) 1,5 g 2 - [1,2,3,4-tetrahydro-6,7-dimethoxy-2-N- (9-fluorenylmethyloxycarbonyl) -1-isoquinolinyl] -hexane-N- (2-phenylethyl) -amide in 30 ml of a mixture of trifluoroacetic acid and anisole (1%) for 15 hours at room temperature. After removal of the solvent, the residue is partitioned between CH ₂ Cl ₂ and a 10% sodium carbonate solution, the organic phase washed with water, dried over Na ₂ SO ₄ , concentrated, the hydrochloric acid) and crystallized from ethanol / ether

 Mp. 154-156 "C

Examples 2- (1,2,3,4-Tetrahydro-6,7-dimethoxy-2-methyl-1-isoquinolinyl-butyric acid, ethyl ester hydrochloride

a) 2- (3,4-dihydro-6,7-dimethoxy-1-isoquinolinyl) -butyric acid ethyl ester methoiodide

0.35 g 2- (3,4-dihydro-6,7-dimethoxy-1-isochinolmyl) -butyric acid ethyl ester and 1 mL of methyl iodide in 10 ml of an ethanol / nitromethane mixture (1: 1) heated to 60 ⁰ C for 1.5 h , After complete reaction (TLC control) is evaporated in vacuo and the residue crystallized from ethanol / petroleum ether

Mp 183-185 ⁰ C

b) 0.5 g of 2- (3,4-dihydro-6,7-dimethoxy-1-isoquinolinyl) -butyric acid ethyl ester methoiodide are stirred in 5 ml of ethanol at room temperature with 0.1 g of NaBH _{4 for} 3 hours. After completion of the reaction (TLC control) is worked up as usual and the hydrochloride is formed.

Mp 164-166 ⁰ C

Example 10 2- (1H-1,2,3,4-Tetrahydropyrido [3,4-b] indol-1-yl) -N- (2-morpholinoethyl) acetamide hydrochloride

a) 2 (1H-3,4-dihydropyrido [3,4-b] indol-1-yl) -N- (2-morpholinoethyl) acetamide

15 g of 2- (3-indolyl) ethylaminocarbonylacetic acid N- (2-morpholinoethyl) amide and 45 ml of POCl ₃ are heated to 40-45 ° C. in 250 ml of an acetonitrile-benzene mixture (1: 1) for 5 hours. After removal of the solvent and excess POCl ₃ , the residue is partitioned between ice-water and chloroform, purified over Al ₂ O ₃ (eluent: CH ₂ Cl ₂ / MeOH = 100: 3) and extracted from ethyl acetate / ether with addition of Ligroin 55- 75 ° C crystallized.

b) The product thus obtained is reduced analogously to Example 1, the product is isolated and converted into the hydrochloride (title compound).

Mp 262-265 ⁰ C

By way of example, the compounds summarized in the following tables can also be prepared by the processes described or the above examples.

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Table 2:

No.

^R 4 ^R 5 salt form

170

171-172

HCl

171

172 173

174 175

CH ₀

H H H

C ₄ -H ₁ . if

^C 6 ^H 5

NH (CH _O

NH (CH ₀ J ₀ -N 0 * < s /

N

C ₁ -H ₁ - (CH ₀ ), N (C ₀ H _1. )

"6 5 * 2

C ^ H ₁ - (CHJ ₀ N whether Ci \ /

101-105

191-193

BS

128 BS

(Dec.) 210-215 HCl

HCl

145 HCl

(Dec.)

Table 3:

176 HC ₄ -H ₁ .

ο b

177 H

178 H

NH- (CH ₀ J ₀ -N 0 c. C \ /

175 (Zers.)

195 (Zers.)

90 (Zers.)

HCl HCl HCl

Table 4:

No. R ₄ R ₅

salt form

179 HC ₆ H ₅

NH 197-200 HCl

180 H H

NH (CH

0 262-265 HCl

181 H H

182 H H

NH-CH ₂ CH (CH ₃ J ₂ 165-168 BS

OC ₂ H ₅

120-130 BS

table

No.

R "

Fp ( ⁰ C)

salt form

183 CH ₃ -CH ₂ -CH ₂ - 184 CH ₃ - 185 CH ₂ = CH-CH ₂ - 186 CH ₃ O-CH ₂ -CH ₂ 187 CH ₃ - (CH ₂ J ₄ - 188 CH ₃ - (CH ₂ J ₃ - 189 (CH), N- (CH 3 2 2 190 (CH ₃ J ₂ CH-CH ₂ 191 (CH ₃ J ₂ CH- 192 CH ₃ O- (CH ₂ J ₃ - 193 CH ₃ -CH ₂ -CH ₂ - 194 Q-CH ₂ -CH ₂ - 195 ^CH 3 ^{(CH 2)} 4-

196 197 198

H 95-96 BS H 96-100. BS H 87-91 BS H OIL H 87-90 BS H 74-75 BS H , 170-190 HCl (ZersetzungJ H 84-90 BS H 144-145 BS H 71-75 BS CH ₃ 119-124 BS CH ₃ 96-102 BS ^C 2 ^H 5 93-95 BS ^C 2 ^H 5 86-89 BS ^C 2 ^H 5 110-112 BS ^C 5 ^H 11 123-125 BS

table

ChLCO

NO

No.

R "

Mp ( ⁰ C) salt form

199 200 201 202 203 204 205 206 207 208 209 210 211

CH ₂ -CH ₂ -CH ₃

-CH ₂ -CH = CH ₂ -CH ₂ -CH ₂ -OCH ₃ -CH ₂ -CH ₂ -N (CH ₃ ) ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₃ -CH ₂ -CH ₂ -CH ₂ -CH ₃ -CH ₂ -CH ₂ -CH ₂ -N (CH ₃ ) ₂ -CH-CH: -CH ₂ -CH (CH ₃ ) -CH (CH ₃ J ₂

-CH ₂ -CH ₂ -CH ₂ -OCH ₃

H 226-228 HCl H 183-186 HCl H 198-203 HCl H 173-176 HCl H 177-179 HCl H 189-191 HCl H 168-172 HCl H 218-222 HCl H 189-194 HCl H 209-211 HCl H 182-185 HCl H 206-208 HCl H HCl

212

213

-CH ₂ CH ₂ CH ₃

OCH,

CH.

CH,

181-184

HCl

HCl

214

-CH ₂ -CH (CH ₃ ) ₂ CH.

194-195

HCl

215 CH.

170-172

HCl

216 -CH CH OCH

217 -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃

CH

 CH.

173-175 168-170

HCl HCl

218

-CH CH

CH.

190-194

HCl

-CH ₂ CH ₂

197-200

HCl

No.

R "

-29- 297 m.p. ( ⁰ C) salt form

OCH,

220

221 -CH CH CH CH CH

JL ι * £ / * «3

222 CH CH

223 - / "V- F

^C 2 ^H 5 159-164 ^C 2 ^H 5 124-133 ^C 2 ^H 5 192-202 ^C 2 ^H 5 157-162

HCl

HCl

HCl

HCl

224 CH CH OCH 171-175 HCL

225 -CH (CH ₃ JCH ₂ CH ₂ CH ₂ CH (CH ₃

^C 2 ^H 5

151-159 HCl

226 ·

227 ^C 2 ^H 5

^C 2 ^H 5

178-184 HCl

192-193 HCl

228 229 230 231

232

-CH ₂ CH (CH ₃ -CH CH = CH

-CH ₂ CH ₂ OCH ₃ ^C 2 ^K 5 ⁿ " ^C 4 ^H 9 ^{n -C} 4 ^H 9 ^{n -C} 4 ^H 9

ⁿ " ^C 4 ^H 9

164-167 HCl

76-78 (A) HCl

181 HCl

47-62 (A) HCl

111-118 HCl

233 234 235 236 237 238 239 240

-CH ₀ CH ₀ CH (CH ₀ ) 4. 2 ^ Vv. 3

-CH -Q ⁿ - ^C 4 ^H 9 HC ₄ H ₉

ⁿ " ^C 4 ^H 9 -C ₄ H ₉

ⁿ - ^C 4 ^H 9 ⁿ - ^C 4 ^H 9 ⁿ - ^C 5 ^H ll ^{n "C} 5 ^H II

95-96 (A) HCl

68-73 (A) HCl

54-57 (A) HCl

90-92 (A) HCl

197-198 HCl

150-152 HCl

134-138 BS

107-109 BS

R "

-30- 297 p. ( ⁰ C) salt form

241 -CH-CH -Nb

151

-OCH

155

HCl

-OCH

127-128

BS

-CH ₂ CH ₂ -N (CH ₃ ) ₂

(A): amorphous isomer mixture

HCl

Com. isomer 30.0 mg 229 50:50 100.0 mg 231 70:30 75.0 mg 233 40:60 3.0 mg 234 90:10 2.0 mg 235 60:40 236 70:30 Pharmaceutical applications a) Dragoes 1 dragoekern contains Active ingredient of the general formula I or V lactose corn starch gelatin magnesium stearate

210,0mg

manufacturing

The mixture of the active substance with lactose and corn starch is granulated with a 10% aqueous gelatin solution through a sieve with 1 mm mesh size, dried at 40 ^c C and again driven through a sieve. The resulting granules are mixed with magnesium stearate and pressed. The cores thus obtained are coated in a conventional manner with a shell which is applied with the aid of an aqueous suspension of sugar, Tiandioxyd, talc and gum arabic. The finished Dragoes are polished with beeswax.

b) tablets 30.0 mg Active ingredient of the general formula I or V 100.0 mg lactose 70.0 mg corn starch 7.0 mg soluble starch 3.0 mg magnesium stearate

210,0mg

manufacturing

Active ingredient and magnesium stearate are granulated with an aqueous solution of the soluble starch, the granules dried and intimately mixed with lactose and corn starch. The mixture is then compressed into tablets of 210 mg weight.

c) capsules 20.0 mg Active ingredient of the general formula I or V 230.0 mg lactose 40.0 mg corn starch / .10.0 mg talc

300.0 mg

manufacturing

Active ingredient, lactose and corn starch are first mixed in a mixer and then in a crusher.

The mixture is again added to the mixer, mixed thoroughly with the talc and mechanically into hard gelatin capsules

bottled.

Claims (8)

1. A process for the preparation of a compound of formula II orthe salt thereof with an inorganic or organic acid, wherein A is an indole residue, R, m, R ⁴ , R ⁵ and R ⁶ are defined as follows
R is hydrogen, (C ₁ -C ₄ ) alkyl, halogen (F, Cl, Br, I), hydroxy, (C ₁ -C ₄ ) alkoxy, amino, methylthio, Methanesulfonyloxy or methanesulfonamido, or two adjacent substituents R together are -O-CH ₂ -O-OdOr-O-CH ₂ -CH ₂ -O;
m is 1,2 or 3 when A is benzo or indole and 1 or 2 when A is a Thienorestist; R ^{4 is} hydrogen or (C ₁ -C ₄ ) AlkYl;
R ^{5 is} hydrogen (C ₁ -C ₁₀ ) alkyl, phenyl, phenyl (C ₁ -C ₅ ) alkyl, (C ₁ -C ₄ ) alkoxy or -NHCOX [wherein X (C ₁ -C ₅ ) Al kyl is]; R ^{6 represents} hydroxy, (C ₁ -C ₄ ) alkoxy, a -NR ⁷ R ⁸ group,
except compounds in which
m is one, R is hydrogen, (C ₁ -C ₄₎ -alkyl, halogen or (C ₁ -C ₄ -alkoxy-J,
R ⁴ denotes hydrogen oror (C ₁ -C ₄ ) alkyl group,
R ^{5 is} hydrogen, R ⁶ (C ₁ -C ₄ ) alkoxy-NHR ^{8 group} means
wherein R ^{8 is} hydrogen or (C 1 -C ₄ ) -alkyl, where the alkyl may be substituted by phenyl.
characterized in that a malonic acid diamide of the general formula IV, (IV) - NHCO - C CO-R in which R, m, R ⁵ and R ^{6 are} as defined in the desired compound of formula II and Ar is 2- or 3-indolyl is cyclized to the corresponding compound II. 2. A method according to claim 1, characterized in that a compound of formula II is prepared in which A is a benzene radical. A method according to claim 1, characterized in that a compound of the formula II is prepared in which R is hydroxy, methoxy or methylthio. A process according to claim 1, characterized in that a compound of formula II is prepared in which R is methoxy and m is 2 and the substituents R are in positions 6 and 7. 5. The method according to claim 1, characterized in that a compound of formula II is prepared, in which R _{5 is} (C ₁ -C ₅ ) alkyl, phenyl, phenyKC ^ CsJalkyl or (C ₁ -C ₄ ) alkoxy. Process according to claim ₁ , characterized in that a compound of the formula II is prepared in which R _{6 is} (C ₁ -C ₅ ) alkyl, phenyl, phenethyl or methoxy, preferably C ₄ or C ₅ alkyl or phenethyl. A process according to claim 1, characterized in that a compound of the formula II is prepared in which R ^{6 is} hydroxy. Process according to Claim 1, characterized in that a compound of the formula II is prepared in which R ^{7 is} hydrogen and R ^{8 is} alkyl of 5-8 carbon atoms.