DE8718021U1 - Condensed bis-(3,4-dihydro-1-pyridiny1)methanes, processes for their preparation and pharmaceutical compositions containing these compounds - Google Patents

Description

The invention relates to novel condensed bis-(3,4-dihydro-1-pyridinyl)methanes, processes for their preparation and pharmaceuticals containing these compounds.

The new compounds have the general formula I

lim

A and B independently represent a benzo or thieno radical;

R ₁ hydrogen, (C -C,_)alkyl, phenyl, phenyl =

1 1 1U

(C -C )alkyl, (C -C )alkoxy or -NHCOX (wherein X is (C -C )alkyl);

R is hydrogen, (C -C )alkyl or hydroxymethyl;

R ₀ , R_, R _£ and R independently

Δ i b I

hydrogen or (C -C )alkyl or R with R and/or R with R and the respective

3 6 7

Carbon atom to which they are attached represents a 5- or 6-membered carbocycle;

R and R independently of one another are (C -C )alkyl, halogen (F, Cl, Br, I), hydroxy, (C -C )alkoxy, amino, thiomethyl, methanesulfonyloxy or methanesulfonamido or two adjacent substituents R or R together are -O-CH -O- or -O-CH -CH-O-;

m and η independently of one another are O, 1, 2 or 3 if A or B is a benzo radical and are O, 1 or 2 if A or B is a thieno radical;

and their pharmaceutically acceptable salts with inorganic and organic acids;

except for the compound of formula 1, wherein R ,

R_, R_, R ₁ -. R and R, are hydrogen and A 2 3 5 6 /

and B the rest

_CH3O .

_CH3O

mean.

Compounds of formula I in which R is hydrogen form tautomers of formulas Ia and Ib,

(R ₁₉ ) 12 &eegr;

where R is also hydrogen. The definition of formula I also includes the tautomers mentioned.

A compound of the above general formula I was described by Kobar, Jeno in Szegedi Tonarkepzo Foiskala Ind. Kozl. 1985 , pages 145-153 (cf. Chem. Abstr. �Egr;&Ggr;7; 134980Z), wherein R ₁ , R_, R., R, R, and R„

1 Z ϳ b ϳ /

hydrogen and A and B represent the rest

This publication does not contain any information on physiological effects of this compound.

It was surprisingly found that the new bis-(3,4-dihydro-1-pyridinyl)-methanes of the general formula I have valuable therapeutic properties both as bases and in the form of their salts.

Of the compounds of formula I, the following can be highlighted as particularly interesting:

-) Compounds (I) wherein R is hydrogen, (C -C )alkyl, phenylKC -C )alkyl or -NHCOX (wherein X is (C -C )alkyl);

R and R independently of one another are (C -C )alkyl, hydroxy, (CC ₄ )alkOXy, methanesulfonyloxy or methanesulfonamido, or two adjacent substituents R or R together are -O-CH -O- or

-O-CH -CH -O-;
2 2

-) Compounds (I) wherein R is hydrogen, (C -C )alkyl or -NHCOX (wherein X is (C -C )alkyl);

R-. ^R -, - ^R r ^{and R} -7 independently of each other 2 3 6 7

hydrogen or R with R and/or R

2 3 6

with R and the respective carbon atom to which they are attached represent a 5- or 6-membered carbocycle;

R and R independently of one another are hydroxy, (C -C )alkoxy, methanesulfonyloxy or methanesulfonamido, or two adjacent substituents R or R together are -O-CH -O- or -O-CH -CH -O-;

Ct L·, C*

-) in particular compounds in which R is hydrogen,

(C -C )alkyl, or -NHCOCH and/or 16 3

R is hydrogen, methyl or hydroethyl and/or

^R o' ^R -> - ^R /r ^{and R} -7 independently

2 3 6 7
hydrogen or R with R and/or R with R and the respective carbon atom to which they are attached, represent a 5-membered carbocycle and/or

R and R independently of one another are hydroxy, methoxy, methanesulfonyloxy or methanesulfonamido, or two adjacent substituents R or R together are -O-CH -O-.

Preference is given to compounds (I) in which m and/or η is 2, in particular those in which A and/or B is a benzo radical, with the two substituents R and/or R preferably being in meta- or para-position to the fusion points of the radicals A and B respectively.

Of particular interest are compounds in which R and R are methoxy.

Examples of specific compounds according to the invention are given in Tables 1 to 3, with particular emphasis being given to 1-(3,4-dihydroxy-6,7-dimethoxy-isoquinolin-l-yl)-l-(3,4-dihydro-6,7-dimethoxy-isoquinolin-l-ylidene)-ethane or its physiologically acceptable salt.

The compounds according to the invention can be prepared in a manner known per se.

In the presence of a condensing agent, an amide of the general formula 11,

II

where A, R , R , R , R , R , R ₁₁ , R.. and m 1 L 3 6 7 11 12

as defined above, Ar is phenyl or thienyl and n' is O, 1, 2 or 3 when Ar is phenyl, and O, 1 or 2 when Ar is thienyl, and R is hydrogen or (C -C )alkyl, to a

1 4

corresponding compound (I) can be cyclized.

Strong Lewis acids are suitable as condensing agents, such as phosphorus oxychloride, 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 of condensing agents such as a mixture of phosphorus oxychloride and phosphorus pentachloride, or a mixture of phosphorus pentoxide and (C-C) alkylsulfonic acid e.g. with a P O content of approx. 10 percent by weight.

If a compound II, in which R is hydrogen, is cyclized in the presence of the mixture of phosphorus pentoxide and (C -C )alkylsulfonic acid, one obtains in addition to the corresponding compound I, in which R

5 is hydrogen, also the analogous compound I in which R is (C -C )alkyl. Preferably, this process variant is carried out with methanesulfonic acid.

The cyclization can 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 a sufficiently high boiling point, for example benzene, alkylbenzenes (e.g. toluene, xylene), chlorobenzenes, chloroform, acetonitrile, decalin. A preferred variant of the process consists in using the condensation agent, for example phosphorus oxychloride or a (C-C)alkylsulfonic acid/phosphorus pentoxide mixture, without the addition of solvent.

The cyclization is preferably carried out with phosphorus oxychloride or, in difficult cases, with a mixture of phosphorus pentoxide and (C -C )alkylsulfonic acid (preferably methanesulfonic acid).

The reaction can be carried out within a wide temperature range, preferably by warming or heating to B0 ⁰ C up to about the boiling point of the reaction mixture.

The required reaction time is between several days and several hours, depending on the starting compound II.

The compounds of the general formula II defined above are new compounds. They can be prepared by cyclizing the corresponding malonic acid diamide of the general formula III

?2 fl
C-CH ₂ -NHCO-CH-CO-NH-CH ₂ -C-(Ar

are manufactured in which R , R , R , R., R ,

L Z γ b /

R and R are as defined above, Ar is phenyl or thienyl and m' and n' independently of one another are O, 1, 2 or 3 when Ar is phenyl and O, 1 or when Ar is thienyl.

The reaction is carried out as described above for the cyclization of compound II to compound I. If the reaction is carried out with the mixture of phosphorus pentoxide and (C -C )alkylsulfonic acid, in addition to the corresponding compound II, in which R is hydrogen, the analogous compound II, in which R is (C -C )alkyl, is obtained.

The reaction starting from compound III can be carried out in situ without isolating the intermediate II to produce compound I. Since in some compounds the isoquinoline or thienopyridine ring closes only with great difficulty,

if necessary or desired, isolate the intermediate compound of general formula II or its tautomer formed during the cyclization reaction, release the base and subject it to the second cyclization reaction. In this case, the first step is preferably carried out with phosphorus oxychloride with gentle heating. In the second step, the ring is closed with phosphorus pentachloride, a mixture of phosphorus oxychloride and phosphorus pentachloride or with a methanesulfonic acid-VPO mixture.

The compounds of general formula III are essentially known compounds and can be prepared by processes known per se.

Compounds of formula 1 in which R is hydrogen are optionally N-alkylated. In principle, all known alkylating agents are suitable for N-alkylation, provided they have sufficient reactivity, e.g. active alkyl esters such as dialkyl sulfate, toluenesulfonic acid = alkyl ester or fluoromethanesulfonic acid alkyl ester. The reaction takes place at temperatures up to the boiling point of the reaction mixture (alkyl here stands for (C -C) alkyl).

The N-hydroxymethylation is carried out under the conditions of aminoalkylation according to Leuckart-Wallach (Ber. dtsch. Chem. Ges. IJi^ (1885) 2341) or Eschweiler-Clarke (Teilheimer 2, (1948) No. 352; i (1950) No. 378). In general, the substance is treated with a 30% formalin solution in the presence of formic acid at room temperature.

The conversion of the free base of general formula I into its acid addition salts takes place in a manner known per se.

Acids suitable for salt formation include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, butyric acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, malic acid, benzoic acid, cinnamic acid, ascorbic acid, methanesulfonic acid.

As mentioned at the beginning, the new bis-(3,4-dihydro-l-pyridinyl)-methanes of the general formula I have valuable therapeutic properties both as bases and in the form of their salts. In particular, these substances have a significant 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 by toxic doses of catecholamines (Higgins et al., Mol. Cell. Cardiol. IjD, 427-438, 1984; Nakanishi et al., Am. J. Physiol. 242 , 437-449, 1982; Fleckenstein, A. Proceedings of the Erlanger Physiol. Conference 1970, Edit. Keidel, Springer Verlag Berlin, Heidelberg, New York, 1971). Conversely, the inhibition of hypoxic or isoprenaline-induced myocardial calcium uptake is a measure of the cardioprotective effectiveness of calcium antagonists (Fleckenstein, see above), of calmodulin inhibitors (Higgins) and other drugs, e.g. beta-adrenolytics (Arndts, Arzneimittelforschung 2S_, 1279-1284, 1975). The cardioprotective effect was determined in conscious rats after subcutaneous or oral administration of the active substance using the method described by Arndts (see above) and the potency of the test substances was given as the H value. This value corresponds to the dose that inhibits by 50% the myocardial radiocalcium uptake caused by an administration of 30 mg/kg sc isoprenaline.

Here, the new compounds investigated proved to be up to five times more effective than the well-known commercial product propranolol.

In vitro studies on smooth muscle (aortic strip) have shown that the compounds according to the invention are calcium antagonists with a new mechanism of action:

Calcium antagonists inhibit the transmembrane influx of calcium ions 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. 7_8, 157 p. - 165 p., 1980; van Breemen et al., Am J. Cardiol. 4_9, 507 - 510, 1982; Casteels et al. Pflügers Arch. 392 , 139 - 145, 1981; Deth. and van Breemen, J. Membrane Biol. 3JD> 363 - 380, 1977).

Based on these findings, the compounds of general formula I or their acid addition salts are suitable as active ingredients for drugs for the treatment of coronary heart disease and acute myocardial infarction.

The invention also relates to medicaments which contain the substances of general formula I and their salts with inorganic or organic acids. The medicaments are suitable for oral or parenteral administration. The drug forms used are mainly tablets, dragees, ampoules and juice preparations. The individual dose for these drug forms is between 1.0 and 200 mg, preferably 20 and 50 mg per 75 kg of body weight. Depending on the severity of the case, 1 to 2 individual doses are generally administered daily.

The following examples are intended to illustrate the invention in more detail:

example 1

l-(3,4-dihydro-6,7-dimethoxy-isoquinolin-l-yl)-l-(l,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolin-l-ylidene)-pentane and

1-(3,4-Dihydro-6,7-dimethoxy-isoquinolin-l-yl)-1-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-N-methyl-isoquinolin-l-ylidene)-pentane

4.9 g of n-butylmalonic acid di-N-[2-(3,4-dimethoxy-phenyl)-ethyl]-amide are heated in 20 ml of a methanesulfonic acid-P O mixture (10 percent by weight PO content) at 100 ^° C for 1-2 hours. After the reaction is complete (thin layer chromatography control), the reaction mixture is poured onto ice, made alkaline with saturated sodium carbonate solution and extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulfate, evaporated in vacuo and the residue is separated on silica gel (eluent: methylene chloride: methanol = 100:5, V:V). The N-�EEgr; compound is eluted first.

N-H compound: mp = 158-159°C (hydrochloride)

N-CH compound: mp = 136-137°C (hydrochloride)

Example 2

l-(3,4-dihydro-6,7-dimethoxy-isoquinolin-l-yl)-l-(3,4-dihydro-6,7-dimethoxy-2-N-methyl-isoquinolin-l-ylidene)-pentane hydrochloride

1 g of the product prepared according to Example 1
1-(3,4-Dihydro-6,7-dimethoxy-isoquinolin-l-yl)-l-(1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolin-l-ylidene)-pentane is heated to boiling in 2 ml of freshly distilled dimethyl sulfate for 6 hours. After the usual
After work-up, the residue is chromatographed on silica gel (eluent: CHCl:MeOH = 100:5, V:V), the hydrochloride is formed and crystallized from ethanol/ether.

The product is the same as that prepared according to Example 1.
identical.

Example 3:

l-(3,4-Dihydro-6 ^-dimethoxy-isoquinolin-l-yD-l-OM-dihydro-6,7-dimethoxy-1-N-hydroxymethyl-isoquinolin-1-ylidene)-ethane hydrochloride

12 g of 1-(3,4-dihydro-6,7-dimethoxy-isoquinolin-1-yl)-�IΩ,4-dihydro-6,7-dimethoxy-isoquinolin-l-ylidene)-ethane are dissolved in a mixture consisting of 20 ml of 30 %
Formalin solution and 10 ml formic acid (98 %) for 20 hours at room temperature.
Water jet vacuum evaporated to dryness, the
Reaction product taken up in CH Cl, with
diluted soda solution and then with water
washed, the organic phase over Na SO
dried, the solvent removed in vacuo, the residue in just sufficient amount of ethanol
and precipitated as hydrochloride with the addition of ethereal hydrochloric acid. Mp = 155°C

Example 4

α-(3,4-dihydro-6,7-dimethoxy-isoquinolin-l-yl)-l,2,3,4-tetrahydro-6,7-dimethoxy-l-benzylidene-isoquinoline

4.9 g of 1,2,3,4-tetrahydro-6,7-dimethoxy-la-[2-(3,4-di-methoxyphenyl)-ethyl]-aminocarbonylj-benzyl-isoquinoline are heated to boiling in 20 ml of freshly distilled phosphorus oxychloride for 4 hours. After the reaction is complete (thin layer chromatography check), excess POCl is distilled off, the residue is partitioned between CH Cl and dilute sodium carbonate solution, the organic phase is washed with water, dried over Na SO and concentrated. The residue is chromatographed on silica gel (eluent: CH Cl :MeOH = 100:10, V:V). The rapidly migrating yellow fraction yields α-(3,4-dihydro-6,7-dimethoxy-isoquinolin-l-yl)-l,2,3,4-tetrahydro-6,7-dimethoxy-1-benzylidene-2-N-phosphono-isoquinoline (m.p. > 270 ⁰ C (hydrochloride)), the subsequent red zone the NH compound (m.p. = 95-100 ⁰ C) which is indicated in the title.

Example 5

(4,5-Dihydro-thieno[2,3-c]pyridin-1-yl)-4,5,6,7-tetrahydrol-methylidene-thieno[2,3-c]pyridin

19 g of malonic acid di-N-[2-(3-thieno-)ethyl]amide are heated to boiling in 25 ml of phosphorus oxychloride for 3 hours. As soon as no more starting material can be detected, the reaction product is processed as usual, the reaction product is purified on Al O neutral, activity level III (Woelm) (eluent CH Cl ) and the hydrochloride is formed. (Mp. = 233-235°C)

Examples of compounds according to the invention are summarized in the following Tables 1-3.

Table 1

Ri

Fp°C/Salt

_{CH3SO2NH ​}

-0- _CH3O

-0 _CH2 -

_CH2 -

_CH3O

_CH3O

_CH3O

_CH3O

_CH3O

_CH3O

_CH3O

_CH3O

_CH3SO ,

_CH3O

_CH3O

_CH3O

_CH3O

_CH3O

_CH3O

_CH3O

_CH3O

-0- _CH3O

-0-

H
H

_CH3

CHs

_CH3

n-CsHn

_{C2H5 ​}

CeHs

CHs

C ₂ Hs

C ₂ Hs

CH ₃ COCH

CeHs

- ( _CH2 )4-

H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H

H H H H H H H H H H H H H H H H H H H

_CH3

_CH3

_CH3

_CH3

_CH2OH

_CH3

_CH3

_CH3O

_CH3O

_CH3O

_CH3O

CHsO

_CH3O

_{CH3SO2O ​}

_CH3O

HO

_CH3O

_CH3O

_CH3O

_CH3O

-0 _CH2 -

-0 _CH2 -

_CH3O

-0 _CH2 -

-0 _CH2 -

_CH3O

_{CH3SO2NH ​}

_CH3O

_CH3O

_CH3O

_CH3O

HO

_CH3O

_CH3O

_CH3O

_CH3O

_CH3O

_CH3O
-0-
-0-

_CH3O
-0—

CH:

_CH3O
—0-—0-

_CH3O
— 0-

H H H H H H H H H H H H H H H H H H H

H H H H H H H H H H H H H H H H H H H

119/BS

233-238 (Z)/BS 136-137/C1

180/C1

177/BS

]82-186/BS

138-140/BS

222-225/BS

155/C1

75-79(amorphous)/BS

80 (amorphous)/BS

95-100/BS

156-158/C1

148-155/C1

177-179/C1

251 253/C1

251-253(Z)/C1

171-172/C1

191-195/BS

BS = Base
Cl = chloride
Z = decomposition

Table 2

Sa 1 &zgr;f&ogr; rm

Fp( ⁰ C)

218-222

239-235

Table 3

Sa 1 2 f&ogr; rm

Fp( ⁰ C)

162-172

237-239

250-253

Pharmaceutical application examples

a) Coated tablets

1 tablet core contains:

Active ingredient of general formula I 30.0 mg

Lactose 100.0 mg

Corn starch 75.0 mg

Gelatin 3.0 mg

Magnesium stearate 2.0 mg

210.0mg

Manufacturing

The mixture of the active substance with lactose and
Corn starch is mixed with a 10% aqueous
Gelatin solution is granulated through a sieve with a mesh size of 1 mm, dried at 40 ⁰ C and rubbed through a sieve again. The granulate thus obtained is mixed with
Magnesium stearate and pressed. The cores thus obtained are coated in the usual way with a shell, which is applied using an aqueous suspension of sugar, titanium dioxide, talcum and gum arabic. The finished dragees are polished with beeswax.

-2D-

b) Tablets

Active ingredient of general formula I 30.0 mg

Lactose 100.0 mg

Corn starch 70.0 mg

soluble starch 7.0 mg

Magnesium stearate 3.0 mg

210.0 mg Production

The active ingredient and magnesium stearate are granulated with an aqueous solution of the soluble starch, the granules are dried and thoroughly mixed with lactose and corn starch. The mixture is then pressed into tablets weighing 210 mg.

c) Capsules

Active ingredient according to claim 1 20.0 mg

Lactose 230.0 mg

Corn starch 40.0 mg

Talc 10.0 mg

300.0mg

Manufacturing

The active ingredient, lactose and corn starch are first mixed in a mixer and then in a shredding machine. The mixture is put back into the mixer, thoroughly mixed with the talc and machine-filled into hard gelatin capsules.

In these examples, the active ingredient can be e.g.

l-(3,4-Dihydroxy-6,7-dimethoxyisoquinolin-l-yl)-l-(3,4-dihydro-6,7-dimethoxyisoquinolin-l-ylidene)-ethane can be used.

Claims (17)

A and B independently of each other a benzo or thieno residue; R ₁ is hydrogen, (C -C )alkyl, phenyl, phenyl = (C -C )alkyl, (C -C )alkoxy or -NHCOX (wherein X is (C -C )alkyl); R is hydrogen, (C -C )alkyl or hydroxymethyl; 2' R. R and R independently 6 7 hydrogen or (C -C )alkyl or R with R and/or R with R and the respective 3 6 7 Carbon atom to which they are attached represents a 5- or 6-membered carbocycle; R and R independently of one another are (C -C )alkyl, halogen (F, Cl, Br, I), hydroxy, (C -C )alkoxy, amino, thiomethyl, methanesulfonyloxy or methanesulfonamido, or two adjacent substituents R or R -0-CH ₂ -CH ₂ -O-; together -O-CH -O- or m and η independently of one another are O, 1, 2 or 3 when A or B is a benzo radical, and are O, 1 or 2 when A or B is a thieno radical; and their pharmaceutically acceptable salts with inorganic and organic acids; except the compound of formula I wherein R , ^R ->· ^R t ' ^R _c ' ^{R and K} -7 hydrogen mean 2 3 5 6 7 and A and B the rest CH ₇ O. 2) A compound according to claim 1, wherein R is hydrogen, (C -C )alkyl, phenylKC -C )alkyl or -NHCOX (wherein X is (C -C )alkyl); R and R independently of one another are (C -C )alkyl, hydroxy, (C -C )alkoxy, methanesulfonyloxy or methanesulfonamido, or two adjacent substituents R or R together are -O-CH -O- or -O-CH -CH -O-. 3) A compound according to claim 1 or 2, wherein R is hydrogen, (C -C )alkyl or -NHCOX (wherein X is (C -C )alkyl); R_» R ₀ t R, and R independently 2 3 6 7 hydrogen or R with R and/or R with 2 3 6 R and the respective carbon atom to which they are attached represent a 5- or 6-membered carbocycle; R and R independently of one another are hydroxy, (C -C )alkoxy, methanesulfonyloxy or methanesulfonamido, or two adjacent substituents R or R together -O-CH -O- or -O-CH -CH -O-. 2 2 2 4) A compound according to any one of claims 1 to 3, wherein R is hydrogen, (C-C)alkyl, or -NHCOCH. 5) A compound according to any one of claims 1 to 4, wherein R is hydrogen, methyl or hydroxymethyl. 6) A compound according to any one of claims 1 to 5, wherein R ₀ , R-, R, and R“ independently of one another are hydrogen or R with R and/or R with 2 3 6 R and the respective carbon atom to which they are bonded form a 5-membered carbocycle. 7) A compound according to any one of claims 1 to 6, wherein R and R independently of one another are hydroxy, methoxy, methanesulfonyloxy or methanesulfonamido, or two adjacent substituents R and R together are -O-CH -O-. 8) A compound according to any one of claims 1 to 7, wherein A and/or B is a benzo radical. 9) A compound according to any one of claims 1 to 7, wherein A and/or B is a thieno residue. 10) A compound according to any one of claims 1 to 9, wherein m and/or η is 2. 11) A compound according to claim 10, wherein, when A and/or B is a benzo radical, the two substituents R and/or
R in meta- or para-position to the
Fusion points of the remainder A or B. 12) A compound according to any one of claims 1 to 11, wherein R and R are methoxy. JL i* 13) A compound according to claim 1, namely 1-(3,4-dihydroxy-6,7-dimethoxyisoquinolin-l-yl)-l-(3,4-dihydro-6,7-dimethoxyisoquinolin-l-ylidene)-ethane or its physiologically
harmless salt. 14) Process for the preparation of a compound according to one of claims 1 to 13, characterized in that
a compound (II), II ^(R 12>n' where A, R , R , R , R , R , R ₁₁ , R ₁₀ and m 1 / JO / 11 LL as defined in any one of claims 1 to 13, Ar is phenyl or thienyl and η', O, 1, 2 or if Ar is phenyl, and O, 1 or 2 if Ar is thienyl, and R is hydrogen or (C -C )alkyl means,
1 4 condensed in the presence of a condensing agent and that, if necessary, one or more of the following post-treatments are carried out: Alkylating a compound (I) in which R is hydrogen, to a compound (I) in which R is (C -C )alkyl; Hydroxyethylating a compound (I) in which R is hydrogen to give a compound (I) in which R is hydroxymethylene; Isolating the free compound (I) from its salt; Converting a compound (I) into its pharmaceutically acceptable salt. 15) Process according to claim 14, characterized in that for the preparation of the compound (I), a compound (III), fe Ti ^(R ll\i—TAr )-C-CH ₂ -NHCO-CH-CO-NH-CH ₂ -CJAr &Lgr;—(R^)^ &Pgr; I R, _R7 in which R , R , R , R,, R”, R.. and R as 1 2 3 6 / 11 12 are defined in any one of claims 1 to 13, Ar is phenyl or thienyl and m' and n ¹ independently represent 0, 1, 2 or 3 when Ar is phenyl and 0, 1 or 2 when Ar is thienyl; condensed in the presence of a condensing agent without isolating the intermediate of the general formula (II). 16) Pharmaceutical preparation containing as active ingredient one or more compounds of the general formula I or their salt(s) according to one of claims 1 to 13. 17) Use of a compound of general formula I or a salt thereof according to any one of claims 1 to 13 in the treatment of coronary heart disease and acute myocardial infarction.