Derived 1,4-benzodiazepin

 

(57) Abstract:

The invention provides compounds with KD (kinetic cell death) inhibitory effects of myocardial unaccompanied side cardiodepressant effect, more specifically, the invention discloses a derivative of 1,4-benzothiazepine, represented by the following formula (1):

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where each Deputy is defined as follows:

R represents H or C1-C3the lower alkoxygroup, X represents O or H2n represents 1 or 2, R1is H, phenyl group, substituted by OH or C1-C3lowest alkoxygroup, a group of the formula

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C1-C3the lower alkoxygroup or a group of the formula

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where R2represents C1-C3acyl group, and ph represents a phenyl group, or their pharmaceutically acceptable salts. table 1.

The invention relates to new derivatives of 1,4-benzothiazepine, in particular the new derivatives of 1,4-benzothiazepine, having the effect of inhibiting sverhsekretnye the heart muscle and the surge of the heart muscle and protective effect against necrosis of the heart muscle with no side effect suppression of cardiac activity is,4-benzodiazepine as an effective ingredient, which affect the circulatory system, in particular to derivatives of 1,4-benzothiazepine containing new derivatives of 1,4-benzothiazepine, as effective ingredients, which have an inhibitory influence on sverhsekretnye heart muscle and stress to the heart muscle and protective effect against necrosis of the heart muscle with no side effect suppression of cardiac activity.

Modern increase the life expectancy of the population accompanied by an increase in circulatory diseases such as hypertension, angina and myocardial infarction. In particular, there were many unexpected manifestations of myocardial infarction with a high level of deaths. First cause of myocardial infarction was attributed to blockage, blood clot, or coronary spasm coronary artery, which provides power for the heart. Recently, however, Kaneko with TCS. proposed a new mechanism of inhibition of myocardial infarction, according to which the infarction myocardial infarction patient finds two forms of necrosis, static cell death (hereinafter referred to as MD) and kinetic cell death (hereinafter referred to as KD) KD, which is the main cause of myocardial infarction (Journal of Tokyo Women's Medical College 52, 1443, a KD, and the use of calcium antagonists for inhibition of symptoms of myocardial infarction (see Japanese patent N Sho 61-40651). In addition, recently the authors have succeeded in creating a model of myocardial infarction induced CD in the Langendorff systems in vitro, using isolated from the body the heart of rats, and using this model they found that some calcium antagonists have a KD-inhibiting effect, similar to that found in systems in vivo. However, some calcium antagonists have a strong effect suppression activities and, therefore, desirable to find compounds with weak side effect of suppression of cardiac activity and a strong KD-inhibiting effect.

The purpose of the invention to provide compounds with CD-inhibiting effect without side effect of suppression of cardiac activity and new derivatives of 1,4-benzothiazepine, in particular new derivatives of 1,4-benzothiazepine containing specific substituents and their pharmaceutically acceptable salts.

In addition, another objective of the invention is the provision of medication to prevent necrosis of the heart muscle and the treatment of acute myocardial infarction, in which the above-mentioned new proizvoditsa as effective ingredients.

The purpose of the invention is achieved derivatives of 1,4-benzothiazepine and their pharmaceutically acceptable salts.

It is the compounds of this invention are derivatives of 1,4-benzodiazepine, which are represented by the following formula (1)

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where each Deputy is defined as follows: R represents H or C1-C3the lower alkoxygroup, X represents O or H2n represents 1 or 2, R1is H, phenyl group substituted by the group, OH or C1-C3-lower alkoxygroup, a group of the formula

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C1-C3the lower alkoxygroup or a group of the formula:

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where R2represents C1-C3acyl group, and pH represents a phenyl group, or their pharmaceutically acceptable salts.

The ability to cause severe KD-inhibiting effect without side suppression of cardiac activity is a new property open to this invention the new compounds 1,4-benzothiazepine.

The compound represented by formula (1) contains a basic nitrogen atom and is thus contributed to the formation of acid salt additive on this nitrogen atom. Acid, which is used for the formation of acid additive salt compounds, shown in the formula (1), also included in the scope of the compounds according to the invention. Salt may include, for example, inorganic salts such as hydrochloride, sulfate and the like, or organic acid salts such as citrate, maleate, fumarate, benzoate, succinate, acetate, tartrate, ester of malic acid and the like.

Drugs according to the invention to prevent necrosis of the heart muscle and for the prevention and treatment of acute myocardial infarction contain as an effective ingredient one or more derivatives of 1,4-benzothiazepine represented by the formula (1) or their pharmaceutically acceptable salts.

New derivatives of 1,4-benzothiazepine and their pharmaceutically acceptable salts possess strong inhibitory effect necrosis of the heart muscle with no side effect suppression of cardiac activity and can be used as an excellent medicine to prevent necrosis of the heart muscle and an excellent remedy for the prevention and treatment of acute myocardial infarction. Therefore, this invention can provide an excellent medicine for the prevention of necrosis of the heart muscle and an excellent remedy for the prevention and treatment of astrogeology can be obtained according to different methods, for example, the following reaction scheme the following steps from A) to E), provided that R, R1, X, n and ph in the reaction formulas represent values as defined in the formula (1).

Let A). This path usually proceeds in the following sequence.

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The compound (1) reacts with akriloilkhlorida in the presence of a base triethylamine, di-isopropylaniline or similar in aprotonin solvent methylene chloride, chloroform, tetrahydrofuran (THF) or the like, preferably at 0-25oC with the formation of amide compounds (2). Amide compound (2) interacts with 4-benzylpiperidine in the solvent methylene chloride, chloroform, methanol, THF or the like at room temperature with the formation of compound (3) of this invention. The product is isolated and cleaned in the usual way.

Let (B). This path usually proceeds in the following sequence.

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The compound (1) reacts with bromoacetylation in the presence of a base triethylamine or similar in aprotonin solvent methylene chloride, chloroform, THF or the like, preferably at 0-25oC with the formation of amide compounds (4). Amide coupling (4) Naga is sodium carbonate, potassium hydroxide, sodium hydroxide and the like in the solvent acetonitrile, methyl ethyl ketone, acetone and the like to the formation of compound (5). The product is isolated and cleaned in the usual way.

Path). This path usually proceeds in the following sequence

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where R3represents the same meanings as defined above for R1except for H.

This path includes three stages of the reaction. In the first stage, the original connection (2) chlorinated in position 2. Amide compound (2) is heated by boiling under reflux in the presence of imide N-chlorochromate (NCS) in a suitable aprotonin solvent, preferably toluene, or spend interaction with sulfurylchloride in aprotonin solvent methylene chloride, chloroform or the like at 0-25oC, preferably at 0oC with the formation of klostergasse connection (6). Then the compound (6) interacts with the Lewis acid chloride tin, chloride zinc, aluminium chloride and the like in the presence of a derivative of indole, substituted derivative of benzene, alcohol or similar in aprotonin solvent methylene chloride, acetonitrile or the like, preferably in the m the same way as in the above (A) with the formation of compound (8), the product is isolated and cleaned in the usual way.

Path D).This path usually proceeds in the following sequence.

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This path has three stages of the reaction in the same sequence as in the above path). In the first stage, the chlorinated compound (4). Amide coupling (4) is heated by boiling under reflux in the presence of imide N-glocalnet (NCS) in a suitable aprotonin solvent, preferably toluene, or through interaction with sulfurylchloride in aprotonin solvent methylene chloride, chloroform and the like at room temperature with the formation of chlorinated compounds (9). Connection (9) communicates with the Lewis acid chloride of tin, zinc chloride or aluminium chloride and the like in the presence of a derivative of indole, substituted derivative of benzene, alcohol, and the like in aprotonin solvent methylene chloride, acetonitrile or the like, preferably at 0-25oC with the formation of compound (10). This compound interacts with 4-benzylpiperidine in the presence of a base, potassium carbonate, sodium carbonate or the like in the same manner as in the above) with the formation of compound (11). is outermost.

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In this reaction, the amide compound (12) reacts in the presence of an appropriate reducing agent selected from, for example, sociallyengaged, methoxyisobutylisonitrile and DIBORANE in aprotonin solvent, preferably THF, preferably at 0-25oC or heated to boiling under reflux with the formation of the amide compound (13). The product is isolated and cleaned in the usual way.

Compounds of the invention, which can be obtained as mentioned above can be converted into acid salt accession specified in the usual way.

Practical use of the compounds of this invention.

Derivatives of 1,4-benzothiazepine formula (1) of the invention and their pharmaceutically acceptable salts, having a KD-inhibiting effect, as can be seen from the results of pharmacological tests, as mentioned below can be used as medicaments in the treatment of circulatory diseases.

Specifically derivatives are used as drugs for the treatment of myocardial infarction, in particular drugs for the prevention or treatment of acute myocardial infarction or inhibitor of necrosis of the heart muscle.

Trogo myocardial infarction, dose of them varies depending on the extent of the disease, weight of patient, mode of application and is not limited to them. Typically, the compounds can be applied orally or parenterale (e.g., intravenously) approximately once a day in amounts of from 10 mg to 1000 mg/day for adults (the average weight of 60 kg). The form may include, for example, powder, parvule, granules, tablets, capsules, injections and the like. In addition, drugs can be manufactured using conventional carriers or diluents according to conventional methods.

Compounds according to the invention possess a strong inhibitory effect against necrosis of the heart muscle without side cardiodepressant effect. As a result, you may receive excellent medicine for the prevention or treatment of acute myocardial infarction without side cardiodepressant effect. As a result, it is possible to provide an excellent medicine for the prevention or treatment of acute necrosis of the heart muscle. It should be noted the fact that the above-mentioned effect was unexpected for compounds of the invention in the specified application.

The invention is not limited experimental is of the compounds of the invention and their chemical and physical properties are presented in the following images. NMR measurements are performed using tetramethylsilane as internal standard and the results are presented in M. D. "Parts" shown in the examples of volume.

Example 1 (experimental).

2,3,4,5-tetrahydro-1,4-benzothiazepine (11 g) and triethylamine (13.5 g) was dissolved in THF (300 ml) and the solution added dropwise to akriloilkhlorida (9.5 g) with ice cooling and stirred at room temperature for 30 minutes To the solution was added 10% aqueous solution of potassium hydroxide, stirred at room temperature and the Ambassador of this extracted with chloroform. Chloroformate phase was washed with saturated saline solution, dried over sodium sulfate and remove the solvent under reduced pressure. The residue is cleaned chromatography on a column of silica gel (Wako Gel C-200, 200 g) and elute mixed solvent of n-hexane (60 hours) + ethyl acetate (40 hours) with the formation of 4-acryloyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (12.5 g), pl. 108. 110.0oC.

These IR spectraKVmAto(cm-1):1635, 1590

1H-NMR (CDCI3, 100 MHz), 2.76-2.97 (2H, m), 3.99-4.23 (2H, m), 4.72-4.86 (2H, m), 5.57-5.79 (1H, m), 6.13-6.91 (2H, m), 7.12-7.68 (4H, m).

Data FD-MS: (m/z: 219(M+).

Example 2 (experimental).

oC

IRCVGpoppy(cm-1)1635, 1595.

1H-NMR (CDCI3, 100 MHz) 2.69-2.90 (2H, m), 3.80 (3H, s), 3.97-4.24 (2H, m), 4.67-4,82 (2H, m), 5.56-5.82 (1H, m), 6.10-7.53 (5H, m).

Data FD-249 MS(M+).

Example 3 (experimental).

2,3,4,5-tetrahydro-1,4-benzothiazepin (4.8 g), triethylamine (5.9 g) and bromocatechol (5.5 g) interact in the same way as in experimental example 1 with the formation of 4-bromoacetyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (3.5 g).

IR 1640

1H-NMR(CDCI3, 100 MHz) 2.80-3.00 (2H, m), 3.78-4.18 (4H, m), 4.70-4.84 (2H, m), 4.70-4.84 (2H, m), 7.15-7.65 (4H, m).

Example 4 (experimental).

7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepin (3.0 g), triethylamine (3.1 g) and bromocatechol (3.2 g) interact in the same manner as in experimental example 1 with the formation of 4-bromoacetyl-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (2.5 g).

IR 1640

1H-NMR (CDCI3, 100 MHz) 2.75-2.94 (2H, m), 3.68-4.18 (4H, m), 3.80 (3H, s), 4.66-4.81 (2H, m), 6.65-7.58 (3H, m).

Example 5 (experimental).

4-acryloyl-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepin (4.0 g), and 4-benzylpiperidine (3.7 g) dissolved in chloroform (15 ml) and left at room temperature for 2 days. Rectile chloroform (98 hours) + methanol (2 hours) with the formation of 4-/3-/1-(4-benzyl)-piperidinyl/propionyl/-7-methoxy-2,3,4,5 - tetrahydro-1,4-benzothiazepine (6.8 g) (compound (a)). This compound (1.0 g) dissolved in methanol (10 ml) and the solution for acidification add a methanol solution of hydrogen chloride (10% (weight/weight), 2 ml). The solvent is then distilled off and the residue is washed with ether to obtain the hydrochloride (0.95 g) in powder form.

IR CVGpoppy(cm-1) 3400, 2920, 1635, 1590 (hydrochloride)

1H-NMR (CDCI3, 100 MHz) 1.11-2.95 (17H, m), 3.78 (3H, s), 3.86-4.16 (2H, m), 4.65 (2H, s), 6.63-7.54 (8H, m)

FD-MS (m/z 424 (M+).

Example 6 (experimental).

4-bromoacetyl-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepin (1.3 g) and 4-benzylpiperidine (0.9 g) dissolved in acetonitrile (50 ml) and to the solution add carbonate potassium (1.1 g) and the mixture heated to boiling under reflux for 3 hours After cooling, add water to the mixture and extracted with chloroform. Chloroformate phase was washed with saturated saline solution and dried over sodium sulfate and the solvent is distilled off under reduced pressure. The residue is cleaned chromatography on a column of silica gel (Wako Gel C-200, 60 g) and elute mixed solvent by chloform (98 hours) + methanol (2 hours) with the formation of 4-/1-(4-benzyl)piperidinyl/-acetyl-7-methoxy-2,3,4,5-tetrahydro - 1,4-benzothiazepine (1.7 g).

IR 1640

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Example 7 (experimental).

4-acryloyl-2,3,4,5-tetrahydro-1,4-benzothiazepin (10 g), dissolved in methylene chloride (150 ml) and to the solution add sulfurylchloride (9.3 g) under ice cooling and stirring at 0oC for 1 h To the reaction mixture are added water and extracted with chloroform. Chloroformate phase was washed with saturated saline solution and dried over sodium sulfate and then the solvent is distilled off under reduced pressure. The residue is cleaned chromatography on a column of silica gel (Wako Gel C-200, 200 g) and elute mixed solvent of n-hexane (70 hours) + ethyl acetate (30 hours) with the formation of compound 4-acryloyl-2-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (10.5 g). so pl. 66.0-68.0oC

IRCVGpoppy(cm-1) 1640

1H-NMR (CDCI3, 100 MHz), 4.05-4.15 (2H, m), 4.45-5.00 (2H, m), 5.01-5.22 (1H, m), 5.55-5.85 (1H, m), 6.15-6.85 (2H, m), 7.20-7.70 (4H, m).

Example 8(experimental).

4-acryloyl-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepin (4.0 g) and sulfurylchloride (2.3 g) interact in the same way as in experimental example 7 with the formation of 4-acryloyl-2-chloro-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (2.4 g). so pl. 97.5-99.5oC

IRCVGpoppy(cm-1) 1640

Ntally).

The above 4-acryloyl-2-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepin (2.9 g) and 5-acetamidino (2.5 g) dissolved in acetonitrile (80 ml) and to the solution was added zinc chloride (4.8 g) at room temperature and stirred at this temperature for 4 hours To the reaction mixture are added water and extracted with chloroform. Chloroformate phase was washed with saturated saline solution and dried over sodium sulfate and then the solvent is distilled off under reduced pressure. The residue is cleaned chromatography on a column of silica gel (Wako Gel C-200, 100 g) and elute mixed solvent of chloroform (98 hours) + methanol (2 hours) with the formation of 4-acryloyl-2-/(5-ndimethylacetamide)-indol - 3-yl/-1,4-benzothiazepine (3.0 g).

IRCVGpoppy(cm-1) 3250, 1640

1H-NMR (CDCI3, 100 MHz) 2.08, 2.12 (each 1.5 H, each s) 3.50-5.80 (5H, m), 6.10-8.05 (M, m), 9.08 (1H, br.C).

FD-MS (m/z 391(+).

Example 10 (experimental).

The above 4-acryloyl-2-/(5-ndimethylacetamide)indol-3-yl/-1,4-benzothiazepin (3.0 g) and 4-benzylpiperidine (1.7 g) dissolved in chloroform (30 ml) and methanol (5 ml) and the mixture is left at room temperature for 24 hours the Solvent is distilled off under reduced pressure and then the residue chromatographic clean on the cation 2-/(5-ndimethylacetamide)indole-2,3,4,5-tetrahydro-1,4-3-yl/-4-/3-/1-/4-benzyl /piperidinyl/propionyl/-2,3,4,5-tetrahydro-1,4-benzothiazepine (4,0) connection (b). This compound (1.0 g) is treated in the same manner as in experimental example 5 to obtain hydrochloride (1.0 g) in powder form.

IRCVGpoppy(cm-1) 3400, 3250, 1635 (hydrochloride)

1H-NMR (CDCI3, 100 MHz) 1.00-3.00 (13H, m), 2.07-2.13 (each 1.5 H, each s), 3.40-5.20 (7H, m), 6.65-8.10 (14H, m), 9.35 (1H, br,s).

FD-MS (m/z 566 (M+).

Example 11 (experimental)11.

The above 4-acryloyl-2-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepin (1.0 g), geraniol (0.9 g) and zinc chloride (0.8 g) interact in the same manner as in experimental example 9 with the formation of 4-acryloyl-2-geranyloxy-2,3,4,5-tetrahydro-1,4-benzodiazepine (1.0 g ).

IR 16401H-NMR (CDCI3MHz) 1.60 (3H, s), 1.65 (6H, s), 2.00 (4H, br. s), 3.75-5.20 (9H, m), 5.40-5.80 (1H, m), 6.10-6.75 (2H, m), 7.10-7.35 (2H, m),7.40-7.60 (2H, m).

FD-MS (m/z 371(M+).

Example 12 (experimental).

The above 4-acryloyl-2-geranyloxy-2,3,4,5-tetrahydro - 1,4-benzothiazepin (1.0 g) and 4-benzyl/piperidine (0,62 g) interact in the same manner as in experimental example 10 with the formation of 4-/3-/1-(4-benzyl)piperidinyl/propionyl/-2-geranyloxy-2,3,4,5-tetrahydro - 1,4-benzothiazepine (1.3 g) (connect ()). This compound (1.1 g process that the tx2">

IR 1640 (hydrochloride)

1H-NMR (CDCI3, 100 MHz) 0.80-1.70 (5H, m), 1.58, 1.62, 1.68 (each H, each s), 1.80-2.10 (4H, br, s), 2.30-3.00 (8H, m), 3.70-5.30 (11H, m), 7.05-7.35 (7H, m), 7.40-7.60 (2H, m).

FD-MS (m/z 546 (M+)

Example 13 (experimental).

The above 4-acryloyl-2-chloro-7-methoxy-2,3,4,5-tragida-1,4-benzothiazepine (2.3 g) and anisole (1.1 g) dissolved in methylene chloride (50 ml) and a solution of tin chloride (2.8 g) and stirred at room temperature for 2 hours To the reaction mixture are added water and extracted with chloroform. Chloroformate phase was washed with saturated saline solution and dried over sodium sulfate and then the solvent is distilled off under reduced pressure. The residue is cleaned chromatography on a column of silica gel (Wako Gel c-200, 50 g) and elute mixed solvent of n-hexane (70 hours) + ethyl acetate (30 hours ) with the formation of 4-acryloyl-2-(4-methoxyphenyl)-7-methoxy,3,4,5-tetrahydro-1,4-benzothiazepine (1.7 g).

IR 1640

1H-NMR (CDCI3, 100 MHz), 3.81 (3H, s), 3.83 (3H, s), 3.60-5.45 (5H, m), 5.50-7.60 (10H, m).

FD-MS (m/z 355 (M+).

Example 14 (experimental).

The above 4-acryloyl-2-(4-methoxyphenyl)-7-methoxy - 2,3,4,5-tetrahydro-1,4-benzothiazepin (1.2 g) and 4-benzylpiperidine (0.95 g is opional/-2-(4-methoxyphenyl)7-methoxy - 2,3,4,5-tetrahydro-1,4-benzothiazepine (1,75 g) (compound (d)). This compound (1.2 g) is treated in the same manner as in experimental example 5 to obtain hydrochloride (1.2 g) in powder form.

IRCVGpoppy(cm-1) 3430, 1640 (hydrochloride)

1H-NMR (CDCI3, 500 MHz) 1.10-3.00 (15 NM, m), 3.80 (3H, s), 3.81 (3H, s), 3.71-5.21 (5H, m), 6,62-7.65 (12H, m).

FD-MS (m/z 530 (M+)

Example 15 (experimental).

The above 4-bromacetyl-2,3,4,5-tetrahydro-1,4-benzothiazepin (2.5 g) and sulfurylchloride (1.5 g) interact in the same way as in experimental example 7 with the formation of 4-bromoacetyl-2-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.4 g). This compound (0,30 g), geraniol (0,30) and zinc chloride (0.26 g) interact in the same way as in experimental example 9 with the formation of 4-bromoacetyl-2-geranyl-hydroxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (0.21 g). Then this compound (0.21 g), 4-benzylpiperidine (0.11 g) and potassium carbonate (0,13 g) interact in the same way as in experimental example 6 with the formation of 4-/1-(4-benzyl)piperidinyl/-acetyl-2-geranyloxy-2,3,4,5-tetrahydro - 1,4-benzothiazepine (0.26 g).

IR 1640

1H-NMR (CDCI3, 500 MHz) 1.28-2.15 (11N, m), 2.48-3.40 (6N, m), 1.57 (3H, s), 1.64 (3H, s), 1.68 (3H, s), 3.80-5.30 (7H, m), 7.10-7.56 (M, m).

FD-MS (m/z 532 (M4-benzothiazepin (0.50 g), 5-(ndimethylacetamide)indole (1.0 g) and zinc chloride (0,78 g) interact in the same way as in experimental example 9 with the formation of 4-bromoacetyl-2-/(5-ndimethylacetamide)indol-3-yl/-1,4-benzothiazepine (0,67 g). This compound (0,67 g), 4-benzylpiperidine (0.33 g) and potassium carbonate (0.40 g) interact in the same way as in experimental example 6 with the formation of 2-/(5-ndimethylacetamide)indol-3-yl/-4-/1-(4-benzyl)piperidinyl/acetyl - 2,3,4,5-tetrahydro-1,4-benzothiazepine (0.66 g).

IR 3470, 1670, 1630

1H-NMR (CDCI3, 500 MHz) 1.10-5.35 (M, m), 2.13, 2.15 (each 1.5 H, each s), 6.80-7.95 (13H, m), 8.65 (1H, br, s), 8.80 (1H, s).

FD-MS (m/z 552 (M+)

Example 17 (experimental).

The above 4-bromoacetyl-2-chloro-7-methoxy-2,3,4,5-tetrahydro-1,4 benzodiazepin (0.19 g) anisole (0.07 g) and tin chloride (0.17 g) vzaimodeistvuet in the same manner as in experimental example 13 with the formation of 4-bromoacetyl-7-methoxy-2-(4-methoxyphenyl)-2,3,4,5-tetrahydro - 1,4-benzothiazepine (0.17 g). This compound (0.17 g) 4-benzyl piperidine (0.09 g) and potassium carbonate (0.11 g) interact in the same way as in experimental example 6 with the formation of 4-/1-(4-benzyl)piperidinyl/acetyl-7-methoxy-2-(4-methoxyphenyl)- 2,3,4,5-tetrahydro-1,4-benzothiazepine (0.20 g).

IR 1640

1
Example 18 (experimental).

The above 4-/3-/1-(4-benzyl)piperidinyl/propionyl/-7-methoxy-2,3,4,5-tetrahydro - 1,4-benzothiazepin (0,90 g) dissolved in THF (50 ml) and to the solution add sociallyengaged (0.24 g) at 0oC under stirring at 0oC for 2 h and Then the excess sociallyengaged decompose sodium sulfate. 10 hydrate, filtered with telicom. After the final concentration of the filtrate under reduced pressure, the concentrate is cleaned khromatograficheskii on a column of silica gel (Wako Gel C-200, 20 g) and elute mixed solvent of chloroform (98 hours) + methanol (2 hours) with the formation of 4-/3-/1-(4-benzyl)piperidinyl/propyl/-7-methoxy-2,3,4,5-tetrahydro - 1,4-benzothiazepine (0.71 g).

IR 1595, 1480

1H-NMR (CDCI3, 500 MHz) 1.24-2.92 (M, m), 3.30-3.35 (2H, m), 3.78 (3H, s), 4.11 (2H, s), 6.65-7.45 (8H, m).

FD-MS (m/z 410 (M+)

Example 19 (experimental).

The above 4-/3-/1-(4-benzyl)piperidinyl/propionyl/-2-(methoxyphenyl)-7-methoxy - 2,3,4,5-tetrahydro-1,4-benzothiazepin (1.0 g) and sociallyengaged (0,22 g) interact in the same way as in experimental example 18 with the formation of 4-/3-/1-(4-benzyl)piperidinyl/propyl/-2-(4-methoxyphenyl)-7-methoxy - 2,3,4,5-tetrahydro-1,4-benzothiazepine (0,46 g).

FD-MS (m/z 516 (M+)

Example 20 (experimental).

The above 4-acryloyl-2-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepin (0.20 g), methanol (0.1 ml) and tin chloride (0.31 g) interact in the same way as in experimental example 13 with the formation of 4-acryloyl-2-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (0,19 g). This compound (0.18 g) and 4-benzylpiperidine (0,19 g) interact in the same way as in experimental example 5, with the formation of 4-/3-/1-(4-benzyl)piperidinyl/propionyl/-2-methoxy-2,3,4,5-tetrahydro - 1,4-benzothiazepine (0.25 g).

IR 1640

1H-NMR (CDCI3, 100 MHz) 1.10-2.10 (7H, m), 2.40-2.95 (6N, m), 3.35 (3H, s), 3.65-5.10 (7H, m), 7.00-7.30 (7H, m), 7.35-7.55 (2H, m).

FD-MS (m/z 424 (M+). (Obtaining input connections, 7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine).

Example 1 (preparation).

2,5-dihydroxybenzoic acid (50.0 g) was dissolved in acetonitrile (400 ml) and to the solution add dimethylsulfate (67,5 ml) and potassium carbonate (98,1 g) and the mixture heated to boiling under reflux for 3 hours To the reaction mixture are added water and extracted with chloroform. Chloroformate phase was washed with saturated saline, then dried over sodium sulfate and ko Gel C-200, 200 g) and elute mixed solvent of n-hexane (95 hours) + ethyl acetate (5 o'clock) with the formation of methyl 2-hydroxy-5-methoxybenzoate (47,1 g).

IR 3250, 1680, 1620

1H-NMR (CDCI3, 100 MHz), 3.77 (3H, s), 3.94 (3H, s), 6.89 (1H, d, J=8.5 Hz), 7.06 (1H, DD, J=2.9 Hz, 8.5 Hz), 7.27 (1H, d, J=1.9 Hz), 10.27 (1H, s)

Example 2 (preparation).

The above methyl-2-hydroxy-5-methoxybenzoate (47,4 g) dissolved in dimethylformamide (400 ml) and to the solution was added 1,4-diazabicyclo/2,2/octane (43,8 g) and dimethylthiocarbamate (48,00 g) and stirred at room temperature for 20 hours, the Reaction mixture was poured into 10% hydrochloric acid (300 ml) and extracted with ethyl acetate. An ethyl acetate phase was washed with saturated saline solution, dried over sodium sulfate and the solvent is distilled off under reduced pressure. Thus obtained residue was washed with a mixed solvent of n-hexane (2 hours) + ethyl acetate (1 h) with the formation of methyl-2-/(dimethylamino)toocomplex/-5-methoxy-benzoate (55,0 g). so pl. 99.5-100.5oC

IR 1710, 1490

1H-NMR (CDCI3, 100 MHz) 3.37 (3H, s), 3.45 (3H, s),3.83 (6N, s), 7.02-7.09 (2H, m), 7.45-7.51 (1H, m).

Example 3 (preparation).

The aforementioned methyl-2-/(dimethylamino)thiooxamate/-5-methoxybenzo the Xia, the reaction mixture is cleaned chromatography on a column of silica gel (Wako Gel C-200, 200 g) and elute mixed solvent of n-hexane (65 hours) + ethyl acetate (35 hours) with the formation of methyl-2-dimethylcarbamoyl-5 - methoxybenzoate (16.4 g). so pl. 64.0-65.0oC.

IR 1720, 1650, 1590

1H-NMR (CDCI3, 100 MHz) 3.04 (6N, (, 3.83 (3H, s), 3.87 (3H, s), 7.00 (1H, DD, J=2.9 Hz), 7.39 (1H, d, J=2.9 Hz), 7.42 (1H, d, J=8.5 Hz).

Example 4 (preparation).

The above methyl-2-dimethylcarbamoyl-5-methoxybenzoate (20,0 g) dissolved in methanol (200 ml) and to the solution add sodium methoxide (8.0 g) and heated to boiling under reflux for 20 hours, the Reaction mixture is poured into a solution of 10% hydrochloric acid (300ml) and extracted with ethyl acetate. An ethyl acetate phase was washed with saturated saline, then dried over sodium sulfate and the solvent is distilled off under reduced pressure. Thus obtained residue is cleaned chromatography on a column of silica gel (Wako Gel C-200, 200 g) and elute mixed solvent of n-hexane (90 hours) + ethyl acetate (10 o'clock) with the formation of methyl-2-mercapto-5-methoxybenzoate (11,0 g).

IR 1700, 1590, 1470

1H-NMR (CDCI3, 100 MHz) 3.80 (3H, s), 2.92 (3H, s), 4.47 (1H, s), 6.88 (1H, DD, J=3.0 Hz), 7.22 the vet-5-methoxy-benzoate (6.5 g), and 2-cluetrain hydrochloride (4.6 g) was dissolved in dimethylformamide (100 ml) and to the solution add sodium methoxide (4.7 g) with ice cooling and then stirred at room temperature for 12 hours, the Reaction mixture is poured into a solution of 10% hydrochloric acid (100 ml) and extracted with chloroform. Chloroformate phase was washed with saturated saline solution, dried over sodium sulfate and then the solvent is removed under reduced pressure to obtain crude crystals. The crystals are washed with a mixed solvent of ethyl acetate (50 hours ) + n-hexane (50 hours) with the formation of 7-methoxy-5-oxo-2,3,4,5-tetrahydro-1,4-benzothiazepine (3.2 g). so pl. 164.0-166.0oC

IR 3350, 1645, 1450

1H-NMR (CDCI3, 100 MHz) 2.93-3.14 (2H, m), 3.24-3.48 (2H, m), 6.92 (1H, DD, J=2.9 Hz, 8.5 Hz), 7.17 (1H, br, s), 7.23 (1H, d, J=2.9 Hz), 7.41 (1H, d, J=8.5 Hz).

FD-MS (m/z 209 (M+)

Example 6 (preparation).

Sociallyengaged (2.73 g) and the above-mentioned 7-methoxy-5-oxo-2,3,4,5-tetrahydro-1,4-benzothiazepin (5.0 g) is added to tetrahydrofuran (150 ml) under ice cooling and heated at the boil under reflux for 3 hours Then add an excess of sodium sulfate. 10 hydrate and filtered with telicom. The final filtrate is concentrated to education is) 2.62-2.88 (2H, m), 3.27-3.58 (2H, m), 3.79 (3H, s), 4.09 (2H,s), 6.59-7.00 (2H, m), 7.46 (1H, d, J=8,5 Hz).

FD-MS (m/z 195 (M+)

Pharmacological tests

Method 1. Heart of male rats weighing 300-380 g is isolated and pour water under a pressure of 80 cm according to the Langendorff method. Solution of bicarbonate Krebs-Henseleit (37oC, pH 7.4) containing 11 mg of glucose, saturated with oxygen gas mixture of 95% O2+ 5% CO2. In addition, heart compulsive stimulate stimulation at a frequency of 330 beats/min After stabilization for 10 minutes perform washing with a solution of Krebs-Henseleit for 10 min, containing 5.5 mmol of calcium as calcium standard, which is dissolved test the connection. After that, 0.5 ml of an aqueous solution, soderzhaschego,1 mg of adrenaline poured into the perfusion solution as starting medication (trigger drug) and after 1 min, 1 ml of an aqueous solution containing 10 mg caffeine add to the solution. Additionally, after 2 min, the heart is removed and placed in a solution of formaldehyde. Heart fixed in formaldehyde solution and then cut into horizontal strips with an interval of 3 mm Each cut piece dehydrate, degreased and placed in paraffin in the proper shape and then cut into thick slices 3-4 MK. Cut samples podkrasit assessment on a five-point system (-, , +, ++, +++) on the basis of necrosis of the heart muscle. Where the ratio of necrosis of the heart muscle to the area of the slice of the left ventricle of the heart was not more than 5% i.e. ( - ) and () and was defined as the inhibitory effect of necrosis of the heart muscle.

Method 2. Heart of male rats weighing 300-380 g produce and implement a water perfusion pressure of 80 cm according to the method Zangenorff in the same conditions as in test method 1. The balloon catheter is introduced into the left ventricle and is used to measure pressure in the left ventricle and the speed of the heartbeat. In this test, if cardiac function is stable, perform perfusion for 10 min, using a perfusion solution containing the test compound, and record changes of cardiac function. The speed of heart beat (NR) x pressure in the left ventricle (LVP) is estimated as the indicator function of the heart.

The results are given in the table.

As can be seen from the above test (1), all the compounds (a)-(d) have great potential inhibitory effect of necrosis of the myocardium, dictionarydownload (brand HERBESSER). In addition, as can be seen from the test (2), compounds (a)-(d) even in doses large enough for the inhibition of necrosis neocaridina infarction, which inhibit necrosis of the myocardium, are effective compounds able to achieve a pharmacological effect without inhibiting the function of the heart among drugs for the prevention of acute myocardial infarction or prevent its recurrence.

Derived 1,4-benzodiazepin General formula

< / BR>
where R is hydrogen or C1WITH3-lower alkoxygroup;

X is oxygen or H2;

n is 1 or 2;

R1hydrogen, a substituted phenyl group, where the Deputy is the group HE or1WITH3-lower alkoxygroup, and a group of the formula

< / BR>
WITH1WITH3-lower alkoxygroup or a group of the General formula

< / BR>
where R2WITH1WITH3-acyl group;

Ph phenyl group

or their pharmaceutically acceptable salts.

 

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