DE3919246A1 - Fused benzene- or (benzo)-thiophene or-pyrrole tetra:hydro-indolizine - useful in pharmaceutical preparations having cardio:protective effect - Google Patents

Abstract

New derivatives are of general formula (I). A = H, CH3, CH20H, 1-5C alkyl-0CH2, 1-4C alkyl-0C0CH2, CH2NH2, 1-5C alkyl-0C(R)NCH2 or CH2NHR; R, R3, R4 = H; or (un)substitd (2-12C)1-12C branched or linear hydrocarbon (II) 3-6C cyclic hydrocarbon; or unsubsttd or up to 5 times substd phenyl, where (II) can be substd once or pref twice -0H, 0CH3, -NH2, 1-5C alkyl-NH2, di-(1-5C alkyl-NH2), 3-6C cycloalkyl, phenyl or 5-6 membered unsubstd heterocycle. B = (i)-(v); X = S or NH, NCH3, N-Bensyl; Y = S, 0 or NH, NCH3, N-Benzyl; R1, R2 = H, 1-4C alkoxy, mercapto, methylmercapto, amino, or 0-(CH2)n-0; n = 1-2; R8 = H, 1-3C alkyl, 3-6C cycloalkyl or -SCH3; or opt R3 and R4 can form a 5-6 membered ring with N, in which this ring opt contains N, 0 or S. (I) can either be administered enterally or parenterally in an amt of 2-20 mg/kg, pref 5-10 mg/kg 1-3 times a day. USE/ADVANTAGE - (I) is useful in pharmaceutical prepns exhibiting a cardio-protective effect

Description

The present invention relates to new ones fused tetrahydroindolizine derivatives, process for their manufacture and pharmaceutical preparations, that contain the new connections.

Tetrahydroindolizine derivatives of the general formula

are from German patent application No. 36 03 194 known. D stands for -CHO and -CH = NR⁷ (where R⁷ (i) hydrogen, or (ii) a saturated one (C₁-C₁₂) or unsaturated (C₂-C₁₂), straight-chain or branched or cyclic (C₃-C₆) hydrocarbon residue, which if appropriate one or more times by hydroxy, methoxy, amino, (C₁-C₅) alkylamino, di- (C₁-C₅) alkylamino, Phenyl (optionally one or more times Hydroxy, methoxy or halogen substituted), or by a 5- or 6-membered saturated or unsaturated heterocycle (one or two N, S or O contains heteroatoms, and by (C₁-C₃) alkyl may be substituted) is substituted means). These compounds are called cardioprotective described.  

The DOS 36 03 194 are for those claimed as new Compounds Ia, Ib and Ic given wrong formulas been. In the following compilation the in DOS 36 03 194 specified formulas of the compounds Ia, Ib and Ic compared the correct formulas.

The present invention relates to new ones Compounds of the general formula I

or their acid addition salt, wherein
A is H, CH₃, CH₂OH, CH₂O (C₁-C₅) alkyl, CH₂OCO (C₁-C₄) alkyl, CH₂NH₂, CH₂N (R) CO (C₁-C₅) alkyl or CH₂NHR;
R (i) is hydrogen or (ii) is a saturated (C₁-C₁₂) or unsaturated (C₂-C₁₂), straight-chain or branched hydrocarbon radical or cyclic (C₃-C₆) hydrocarbon radical, the hydrocarbon radical being one or more, preferably one or twice by hydroxy, methoxy, amino, (C₁-C₅) alkylamino, di- (C₁-C₅) alkylamino, (C₃-C₆) cycloalkyl, phenyl (the phenyl can be up to five times, preferably one or two times by hydroxy , Methoxy or halogen substituted), or by a 5- or 6-membered saturated or unsaturated heterocycle (the heterocycle contains one or two heteroatoms of the groups N, S and O and can be substituted by (C₁-C₃) alkyl); or (iii) is unsubstituted phenyl or up to 5-fold (preferably mono- or disubstituted) substituted phenyl, the substituent (s) being (are) hydroxyl, methoxy or halogen, preferably fluorine;
B together with the two vicinal C atoms is an aromatic system

means what
X is S or NR⁵ (where R⁵ is H, methyl or benzyl);
Y is S, O or NR⁶ (where R⁶ is H, methyl or benzyl);
R¹ and R² independently of one another hydrogen, (C₁-C₄) alkoxy, mercapto, methylmercapto or amino or together the group

where n is 1 or 2;
R³ and R⁴ independently of one another denote (i) hydrogen or (ii) a saturated (C₁-C₁₂) or unsaturated (C₂-C₁₂), straight-chain or branched hydrocarbon radical or cyclic (C₃-C₆) hydrocarbon radical, the hydrocarbon radical being one or more, preferably one or two times by hydroxy, methoxy, amino, (C₁-C₅) alkylamino, di- (C₁-C₅) alkylamino, (C₃-C₆) cycloalkyl, phenyl (the phenyl can be up to five times, preferably mono- or substituted twice by hydroxy, methoxy or halogen), or by a 5- or 6-membered saturated or unsaturated heterocycle (the heterocycle contains one or two heteroatoms of the group N, S and O and can be substituted by (C₁-C₃) alkyl) can be; or (iii) unsubstituted phenyl or up to 5-fold (preferably mono- or disubstituted) substituted phenyl, the substituent (s) being (are) hydroxyl, methoxy or halogen, preferably fluorine; or
R³ and R⁴ together with the nitrogen atom form a 5- or 6-membered ring which optionally contains a further N, O or S heteroatom. and
R⁸ is H, (C₁-C₃) alkyl, (C₃-C₆) cycloalkyl or SCH₃.

The new compounds are pharmaceutically valuable Compounds, their cardioprotective activity is to emphasize.

Compounds are preferred in which B together with the vicinal carbon atoms the group

means, especially where B together with the vicinal C atoms the group

means;
R⁸ represents hydrogen;
A is H, CH₃, CH₂OH, CH₂O (C₁-C₂) alkyl, CH₂OCO (CH₃), CH₂NH₂ or CH₂N (R) COCH₃; and R is as defined above (of the compounds in which A is CH₂N (R) COCH₃, those are to be emphasized in which R is a saturated (C₁-C₁₂) hydrocarbon radical, the hydrocarbon radical being one or more times, preferably one or two times, by hydroxyl, Methoxy, phenyl may be substituted);
R³ and R⁴ independently of one another mean: (i) hydrogen or (ii) a saturated (C₁-C₁₂) hydrocarbon radical, the hydrocarbon radical one or more times, preferably one or two times, by hydroxyl, methoxy or phenyl (the phenyl can be obtained simply by Hydroxy, methoxy or halogen may be substituted), or by a 5- or 6-membered saturated or unsaturated heterocycle (the heterocycle contains one or two heteroatoms of the group N, S and O and can be substituted by (C₁-C₃) alkyl) ; or (iii) unsubstituted phenyl or up to 5-fold (preferably mono- or disubstituted) substituted phenyl, the substituent (s) being (are) hydroxyl, methoxy or halogen, preferably fluorine; or
R³ and R⁴ together with the nitrogen atom form a 5- or 6-membered ring which optionally contains a further N, O or S heteroatom.

The preparation of the compounds of the general formula I and its pharmaceutically acceptable salts can be after known methods are carried out.

A manufacturing process is as follows Reaction scheme summarized:

The starting compounds are from the German Patent application P 36 03 194 known. The production of the new compounds of general formula I according to known methods.

The preparation of the alcohols shown above general formula Ia is carried out by reducing the corresponding formyl compounds.

Complex metal hydrides are suitable as reducing agents (such as sodium boranate or Sodium cyanoborohydride, optionally in combination with a precious metal catalyst) or catalytic activated hydrogen.

The reduction is preferably in an organic Solvents such as methanol or ethanol executed, at room temperature or, if necessary elevated temperature to the reflux temperature of the Reaction mixture.

The reduction of the ship bases IIb can be done in analogy to Reduction of the formyl compounds Ia take place.

The representation of the compounds of the general formula Ic (A = H) can be obtained by decarbonylation of the analog Formyl compounds Ia are made by this briefly treated with boiling concentrated HCl or at room temperature with aqueous 48% Hydrobromic acid. Decarbonylation can, however also with the help of a noble metal catalyst such. B. Ph₃PRhCl₃ in an inert solvent such as. B. Toluene can be carried out.  

The compounds of the formulas Ia and Ib thus obtained, can be subjected to the following post-treatments will:

• a) A compound of general formula Ia is converted into the corresponding alkyl ether (A: CH₂O (C₁-C₅) alkyl.
  For this purpose, a compound of the general formula Ia is etherified with the corresponding aliphatic alcohol, preferably methanol or ethanol, with acid catalysis.
  The reaction can be carried out in an inert solvent such as CH₂Cl₂, THF, dioxane, acetonitrile, CHCl₃ and others or a mixture of one or more of these solvents. A reaction variant in which the reaction component simultaneously serves as a solvent is preferred.
  Suitable catalysts are non-aqueous inorganic acids such as. B. HClgas, conc. H₂SO₄, HBF₄, H₃PO₄, organic acids such as methanesulfonic acid or p-toluenesulfonic acid, but also Lewis acids, such as. B. TiCl₄, BF₃ etherate, SnCl₄, AlCl₃.
  Gaseous HCl in ethereal or alcoholic solution is preferred. The etherification usually ends in a few hours (1-18 hours) at room temperature.
• b) A compound of general formula Ia can be converted into a carboxylic acid ester of formula I in which A is CH₂OCO (C₁-C₄) alkyl.
  The esterification of an alcohol of the general formula I, in which R¹ = CH₂OH, can be carried out by the customary methods known from the literature, in which it is reacted with an active carboxylic acid derivative.
  As active carboxylic acid derivatives, carboxylic anhydrides, chlorides, azides or mixed carboxylic anhydrides can be used, furthermore acid amides (for example with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole, etc.). Carboxylic anhydrides are preferred.
  The esterification is generally carried out in an inert solvent such as dioxane, acetonitrile, DMF or in a mixture of one or more of these solvents, optionally in the presence of an organic or inorganic base as an acid scavenger and optionally a catalyst.
  Depending on the reactivity of the acyl component used, the reaction temperature can vary within wide limits and can be between 0 ° C. and the boiling temperature of the reaction mixture.
• c) A compound of general formula Ia can be converted into the corresponding methyl compound (A: CH₃).
  To prepare the methyl compounds, the corresponding alcohol of the formula Ia is reduced in the presence of an acid or Lewis acid.
  Complex metal hydrides (such as sodium boranate) are suitable as reducing agents, optionally in combination with a noble metal catalyst. The reduction is carried out in a suitable solvent, at room temperature or optionally at an elevated temperature. Preferred solvents are organic acids such as acetic acid, optionally in a mixture with an inert solvent such as CH₂Cl₂, tetrahydrofuran, dioxane or acetonitrile.
  In a preferred process variant, the corresponding formyl compounds of the formula IIa are used as starting compounds and as described by C. Djerassi, HJ Manteiro, A. Walser and LJ Durham; J. Am. Chem. Soc. 88 (1966), 1792, with NaBH₄ / glacial acetic acid. Under these reduction conditions, the intermediately formed hydroxymethyl compounds of the general formula Ia are converted into the methyl analogs in situ.
• d) The compounds of the formula Ib can be converted into the corresponding amide using an active carboxylic acid derivative by methods known from the literature.
  Examples of suitable reactive carboxylic acid derivatives are: acid anhydrides, acid halides, acid azides, mixed acid anhydrides (e.g. with an aromatic or aliphatic carboxylic acid, alkyl carbonic acid or dialkyl phosphoric acid etc.), and also acid amides (for example with imidazole, 4-substituted imidazole, triazole, triazole etc.) or active esters (e.g. cyanomethyl, methoxymethyl, vinyl, propargyl or p-nitrophenyl) or esters with dimethylhydroxylamine, 1-hydroxysuccinimide, dicyclohexylurea, etc.).
  The amide formation is usually in an inert solvent such as dioxane, CH₂Cl₂, acetonitrile, dimethylformamide etc. or a mixture of one or more of these solvents, optionally in the presence of an inorganic or organic base as an acid scavenger and optionally in the presence of an acylation catalyst, such as. B. 4-Dimethylaminopyridine performed. It is also possible to carry out the reaction in excess in a carboxylic anhydride without solvent. The reaction with a carboxylic anhydride in the presence of pyridine as an acid scavenger and 4-dimethylaminopyridine as a catalyst in CH₂Cl₂ is preferred.

The following examples illustrate the present invention, but without its scope to restrict.

example 1 2-aminomethylidene-5,6-dihydro-1-hydroxymethyl-8,9- dimethoxy-pyrrolo [2,1-a] isoquinolin-3 (2H) -one

2.7 g (1.11 mmol) of 2-aminomethylidene-1-formyl-5,6-dihydro-8,9-dimethoxypyrrolo [2,1-a] isoquinolin-3 (2H) -one are dissolved in 80 ml of ethanol and at the boiling point with 0.5 g NaBH₄. The reaction is complete after about 30 minutes. It is concentrated in vacuo, mixed with ice water, extracted with CH₂Cl₂, the organic phase dried over Na₂SO₄, and the solvent removed in vacuo. The residue is crystallized from ethyl acetate.
Yellow crystals; Melting point: 197-203 ° C.

Example 2 5,6-dihydro-1-hydroxymethyl-2 - [(3-methylbutyl) amino] - methylidene-8,9-dimethoxypyrrolo [2,1-a] isoquinoline 3 (2H) -on

In a solution of 3.5 g (9.5 mmol) of 1-formyl-5,6-dihydro-8,9-dimethoxy-2 [(3-methylbutyl) amino] methylidene pyrrolo [2,1-a] isoquinoline 3 (2H) -one in 200 ml of methanol, a solution of 0.7 g (20 mmol) of NaBH₄ in 100 ml of methanol is added dropwise with stirring at room temperature. The mixture is stirred for about 2 hours, concentrated in vacuo, the reaction mixture is poured onto water and extracted with CH₂Cl₂. After drying the organic phase over Na₂SO₄, the solvent is removed, and the residue crystallized from ethyl acetate.
Yellow crystals; Melting point: 151-152 ° C.

Example 3 5,6-dihydro-8,9-dimethoxy-2 - [(3-methylbutyl) amino] - methylidene-1-methylpyrrolo [2,1-a] isoquinolin-3 (2H) -one

In a solution of 5.0 g (13.5 mmol) of 1-formyl-5,6-dihydro-8,9-dimethoxy-2 - [(3-methylbutyl) amino] - methylidene pyrrolo [2,1-a] isoquinoline -3 (2H) -on in 20 ml glacial acetic acid are added in portions with cooling 1.6 g NaBH₄. When the reaction is complete after about 15 minutes, it is diluted with ice water, neutralized with sodium carbonate solution and extracted with CH₂Cl₂. The organic phase is dried over Na₂SO₄, evaporated in vacuo, and the residue, if necessary, purified over Al₂O₃ neutral (eluent: CH₂Cl₂) and crystallized from ethyl acetate / petroleum ether.
Yellow crystals; Melting point: 136-140 ° C.

Example 4 5,6-dihydro-8,9-dimethoxy-1-methyl-2- [2- (2-thienylethyl) - amino] methylidene pyrrolo [2,1-a] isoquinolin-3 (2H) -one

3.8 g (9.3 mmol) of 1-formyl-5,6-dihydro-8,9-dimethoxy-2- [2- (2-thienylethyl) amino] methylidene pyrrolo [2,1-a] isoquinoline-3 (2H) -on are implemented analogously to Example 3.
Yellow crystals; Melting point: 161-164 ° C.

Example 5 1- (N-acetylbenzylamino) methyl-2- (benzylamino) methylidene 5,6-dihydro-8,9-dimethoxypyrrolo [2,1-a] isoquinoline-3 (2H) - on

3.5 g (7.3 mmol) of 1-benzyliminomethyl-2- (benzylamino) methylidene, 5,6-dihydro-8,9-dimethoxypyrrolo [2,1-a] isoquinolin-3 (2H) - one, as described in Example 1, reduced in methanol with NaBH₄. After working up, acetylation is carried out with pyridine / acetic anhydride and working up as usual.
Greenish yellow crystals; Melting point: 181-184 ° C.

Example 6 1-ethoxymethyl-5,6-dihydro-8,9-dimethoxy-2 - [(3-methylbutyl) amino] metylidenepyrrolo [2,1-a] isoquinoline- 3 (2H) -on

600 mg of 5,6-dihydro-1 prepared according to Example 2 hydroxymethyl-2 - [(3-methylbutyl) amino] methylidene-8,9- dimethoxypyrrolo [2,1-a] isoquinolin-3 (2H) -one are in 20 ml of ethanol dissolved and with a drop added ethanolic hydrochloric acid. After about 1 minute is between aqueous soda solution and CH₂Cl₂ distributed. The organic phase is with water washed, dried over Na₂SO₄ and over Al₂O₃ (activity level III, neutral) cleaned. The Reaction product failed to crystallize to be brought.  

Example 7 5,6-dihydro-8,9-dimethoxy-2 [(3-methylbutyl] amino] - methylidene pyrrolo [2,1-a] isoquinolin-3 (2H) -one

3.7 g (10 mmol) of 1-formyl-5,6-dihydro-8,9-dimethoxy-2- [(3-methylbutyl) amino] methylidene pyrrolo [2,1-a] - isoquinoline-3 (2H) - are heated in 150 ml of semi-concentrated hydrochloric acid at 150 ° C for 3 minutes. After cooling, it is made basic with aqueous sodium carbonate solution, extracted with CH₂Cl₂, the organic phase is dried over Na₂SO₄, evaporated and neutralized on Al₂O₃ (activity level III, eluent CH₂Cl₂ / MeOH = 100: 1).
Yellow crystals; Melting point: 164-167 ° C.

Example 8 1-acetoxymethyl-5,6-dihydro-8,9-dimethoxy-2 [(3-methylbutyl) amino] metylidenepyrrolo [2,1-a] isoquinoline 3 (2H) -on

1.0 g (2.7 mmol) 1-formyl-5,6-dihydro-8,9-dimethoxy-2- [(3-methylbutyl) amino] methylidene pyrrolo [2,1-a] - isoquinolin-3- (2H) -one and 100 mg anhydrous Sodium acetate in 10 ml of acetic anhydride for 18 hours stirred at room temperature. Then it is in a vacuum concentrated between CH₂Cl₂ and dilute Soda solution distributed and neutral over Al₂O₃ (Activity III, eluent CH₂Cl₂) cleaned. The The reaction product could not be crystallized to be brought.  

Following the procedures described above e.g. B. receive the following compounds of the invention will:

table

The compounds of formula I according to the invention are Bases and can in the usual way with inorganic or organic acids converted into acid addition salts be, with acid addition salts also by salting out other acid addition salts can be prepared.

Acids suitable for salt formation are, for example Hydrochloric acid, hydrobromic acid, hydroiodic acid, Hydrofluoric acid, sulfuric acid, phosphoric acid, Nitric acid, acetic acid, propionic acid, butyric acid, Caproic acid, valeric acid, oxalic acid, malonic acid, Succinic acid, maleic acid, fumaric acid, lactic acid, Tartaric acid, citric acid, malic acid, benzoic acid, p-hydroxybenzoic acid, p-aminobenzoic acid, phthalic acid, Cinnamic acid, salicylic acid, ascorbic acid, methanesulfonic acid and the same.

The compounds of general formula I and their Acid addition salts have valuable effects in animal experiments therapeutic properties.

They have a clear cardioprotective effect, e.g. B. by examinations on the isolated Langendorff heart according to O. Langendorff, Pflügers Arch. 61, 291 (1895) can be determined with minor modifications:
Isolated rat heart, retrograde perfusion over the aorta. Electrical stimulation (300 pulses / min, pulse duration 1 msec). Measurement of the left ventricular pressure with a liquid-filled latex balloon. After 20 min equilibration, an oxygen deficiency with a 100-fold reduced flow is triggered by throttling the perfusion flow for 60 min, return to normal flow causes a strong increase in the basic tension, under control conditions the cardiac activity returns irregularly after 6-7 min, after 15-18 min rapid transition to regular contractions. Cardioprotective compounds reduce the time until regular contractions begin. Infusion of the test substance (dissolved in ungased perfusion medium) into the perfusion system close to the heart during the O₂ deficiency state.

The active compounds tested give one significant reduction in time to onset regular contractions.

In vitro examinations on smooth muscles (Aortic strips) according to the method of C. Van Breemen, P. Aaranson, R. Loutzenheiser and K. Meisheri (Chest 78: 1575-1655 [1980]) and by R. Casteels and C. Droogman (J. Physiol. 317: 263-279 [1981]) have shown that it the compounds of the invention Calcium antagonists with a new mechanism of action acts.

Based on these findings, the connections of the general formula I or their Acid addition salts as active ingredients for drugs against coronary artery disease, e.g. B. angina pectoris, Heart attack and fibrillation, find use. They also improve blood circulation and tissue Tissue oxygenation especially in the central Nervous system.  

When checking the viability of animals in a closed chamber (hypoxia tolerance test), which with a gas mixture consisting of 96.5% nitrogen and 3.5% oxygen, was flowed through, that with the animals pretreated new substances statistically highly significantly greater survivability than Control animals or with diltiazem, verapamil or Animals treated with nifedipine. The one with this method tested brain-protective effect of the substances was even at a dose of 5 mg / kg p. pronounced. This makes the new connections both in terms of effective dose and that of animal experiments Performance improvement of the known substances mentioned clearly superior.

Based on these findings, the connections of the general formula I or their acid addition salts as Active substances for drugs against the organic brain Psychosyndrome as well as post-traumatic and alcoholic Find brain damage.

The compounds can be both enteral and administered parenterally. As a dose for oral Use 2 to 20 mg / kg, preferably 5 to 10 mg / kg of active ingredient suggested 1 to 3 times a day.

Suitable forms of use are, for example, tablets, Capsules, suppositories, solutions, juices, emulsions, aerosols or dispersible powder.

Appropriate preparations can, for example, by Mixing the active ingredient (s) with known ones Auxiliary substances are obtained.

Claims (9)

1. Compound of the general formula I or their acid addition salt, wherein
A is H, CH₃, CH₂OH, CH₂O (C₁-C₅) alkyl, CH₂OCO (C₁-C₄) alkyl, CH₂NH₂, CH₂N (R) CO (C₁-C₅) alkyl or CH₂NHR;
R (i) is hydrogen or (ii) is a saturated (C₁-C₁₂) or unsaturated (C₂-C₁₂), straight-chain or branched hydrocarbon radical or cyclic (C₃-C₆) hydrocarbon radical, the hydrocarbon radical being one or more, preferably one or twice by hydroxy, methoxy, amino, (C₁-C₅) alkylamino, di- (C₁-C₅) alkylamino, (C₃-C₆) cycloalkyl, phenyl (the phenyl can be up to five times, preferably one or two times by hydroxy , Methoxy or halogen substituted), or by a 5- or 6-membered saturated or unsaturated heterocycle (the heterocycle contains one or two heteroatoms of the groups N, S and O and can be substituted by (C₁-C₃) alkyl); or (iii) is unsubstituted phenyl or up to 5-fold (preferably mono- or disubstituted) substituted phenyl, the substituent (s) being (are) hydroxyl, methoxy or halogen, preferably fluorine;
B together with the two vicinal C atoms is an aromatic system means what
X is S or NR⁵ (where R⁵ is H, methyl or benzyl);
Y is S, O or NR⁶ (where R⁶ is H, methyl or benzyl);
R¹ and R² independently of one another hydrogen, (C₁-C₄) alkoxy, mercapto, methylmercapto or amino or together the group where n is 1 or 2;
R³ and R⁴ independently of one another mean: (i) hydrogen or (ii) a saturated (C₁-C₁₂) or unsaturated (C₂-C₁₂), straight-chain or branched hydrocarbon radical or cyclic (C₃-C₆) hydrocarbon radical, the hydrocarbon radical being one or more times , preferably one or two times by hydroxy, methoxy, amino, (C₁-C₅) alkylamino, di- (C₁-C₅) alkylamino, (C₃-C₆) cycloalkyl, phenyl (the phenyl can be up to five times, preferably one or be substituted twice by hydroxy, methoxy or halogen), or by a 5- or 6-membered saturated or unsaturated heterocycle (the heterocycle contains one or two heteroatoms of the group N, S and O and can be substituted by (C₁-C₃) alkyl) can be substituted; or (iii) unsubstituted phenyl or up to 5-fold (preferably mono- or disubstituted) substituted phenyl, the substituent (s) being (are) hydroxyl, methoxy or halogen, preferably fluorine; or
R³ and R⁴ together with the nitrogen atom form a 5- or 6-membered ring which optionally contains a further N, O or S heteroatom. and
R⁸ is H, (C₁-C₃) alkyl, (C₃-C₆) cycloalkyl or SCH₃. 2. A compound of general formula I according to claim 1, wherein
A is H, CH₃, CH₂OH, CH₂O (C₁-C₂) alkyl, CH₂OCOCH₃, CH₂NH₂ or CH₂N (R) COCH₃; and R is as defined in claim 1. 3. A compound according to claim 2, wherein A CH₂N (R) COCH₃ is where R is a saturated (C₁-C₁₂) Hydrocarbon residue means, the Hydrocarbon residue one or more times, preferably one or two times by hydroxy, Methoxy, phenyl can be substituted. 4. A compound according to any one of claims 1 to 3, wherein B together with the two vicinal C atoms is an aromatic system means what
R¹ and R² are as defined in claim 1, preferably methoxy. 5. A compound according to any one of claims 1 to 4, wherein R³ and R⁴ independently represent: (i) hydrogen or (ii) a saturated (C₁-C₁₂) hydrocarbon radical, the hydrocarbon radical one or more times, preferably one or two times Hydroxy, methoxy, phenyl (the phenyl can be simply substituted by hydroxy, methoxy or halogen), or by a 5- or 6-membered saturated or unsaturated heterocycle (the heterocycle contains one or two heteroatoms of the group N, S and O and can be replaced by ( C₁-C₃) alkyl substituted) may be substituted; or (iii) unsubstituted phenyl or up to 5-fold (preferably mono- or disubstituted) substituted phenyl, the substituent (s) being (are) hydroxyl, methoxy or halogen, preferably fluorine; or
R³ and R⁴ together with the nitrogen atom form a 5- or 6-membered ring which optionally contains a further N, O or S heteroatom. 6. A compound according to any one of claims 1 to 5, wherein R⁸ H means. 7. A process for the preparation of a compound of general formula I according to claim 1, characterized in that a compound of general formula II where D means -CHO or -CHNR,
R, R³, R⁴, R⁸ and B are as defined in claim 1, to the corresponding compound of general formula I decarbonylated (in which AH) or reduced, in which A is -CH₂OH or -CH₂NHR and the compound thus obtained, if desired, to form a compound I implement in the
A is H, CH₃, CH₂O (C₁-C₅) alkyl, CH₂OCO (C₁-C₄) alkyl or CH₂NH₂ or CH₂N (R) CO (C₁-C₅) alkyl and, if desired, the compound thus obtained is converted into its pharmaceutically acceptable salt. 8. Pharmaceutical preparation containing one Compound of the general formula I or its pharmaceutically acceptable salt defined in one of claims 1 to 6. 9. Use of a compound of the general formula I according to one of claims 1 to 6 Cardioprotection.