JPH0832698B2 - Piperazine derivative - Google Patents

Description

The present invention relates to piperazine derivatives, and more specifically,
The following general formula (I) (In the formula, R ¹ represents an alkyl group or an aralkyl group, and R ² represents And n represents an integer of 0 to 3. ) Relating to the piperazine derivative.

The present inventors previously described the following formula (II) It has been found that the compound represented by and a derivative thereof are useful as a preventive or therapeutic agent for myocardial infarction, and has applied for a patent. (Masaki et al., JP-A-57-169478, 58-12687
9) Hara et al. (Biomedical Research 4 (1) 121-124, 1983) show that the piperazine derivative represented by the above formula (II) is a proteolytic enzyme whose thiol group is involved in expression of activity. It has been confirmed that it has inhibitory activity against papain calcium ion-activated neutral protease (CANP).

By the way, in the case of oral administration, the piperazine derivative represented by the above formula (II) needs to be used at a high dose in order to obtain an effective blood concentration for manifesting a drug effect. However, when a high dose is used, side effects may occur when used for a long period of time, and there has been a demand for a substance that produces an effective blood concentration at a low dose to exert a drug effect. The present inventors have conducted extensive studies in view of the above circumstances, and as a result, the piperazine derivative represented by the general formula (I) inhibits the activity of a protease whose thiol group participates in the expression of the activity even in oral administration. As a result, they have completed the present invention.

 The present invention will be described in detail below.

The object of the present invention is to formula The object is to provide a piperazine derivative represented by

In the general formula (I), the alkyl group represented by R ¹ includes a methyl group, an ethyl group, a propyl group, a butyl group, and the like, and the aralkyl group includes a benzyl group, a phenylethyl group, a benzhydryl group, and the like. These may have halogen or the like as a substituent.

The oxirane in the general formula (I) is preferably a trans isomer, that is, a (2S, 3S) or (2R, 3R) coordinated one.

Also included in the present invention are acid addition salts of compounds of general formula (I), that is, salts of hydrochloric acid, hydrobromic acid, formic acid, sulfuric acid, fumaric acid, maleic acid, tartaric acid and the like.

The piperazine derivative represented by the general formula (I) can be obtained, for example, by the method shown below.

The condensation reaction of each of the above (A), (B), and (C) can be carried out by a conventional acid chloride method, mixed acid anhydride method, active ester method, or a known condensing agent such as 1-methyl-2-.
1-alkyl-2-, such as chloropyridinium silate
Halopyridinium acid, or N, N-dicyclohexylcarbodiimide or N-hydroxysuccinimide in combination with an organic solvent such as methylene chloride ethylene chloride, chloroform or tetrahydrofuran in the presence or absence of a base such as triethylamine. , -10 to 40 ℃
And preferably at -5 to 30 ° C.

Usefulness of the compound of the present invention as a therapeutic and preventive agent for myocardial infarction is confirmed by the method described in JP-A-58-126879.

On the other hand, inhibition of activity against papain is confirmed by the method described in Biomedical Research 4 (1) 121-124, 1983, etc. That is, the compound of the present invention (2R, 3R) -2-benzylcarbamoyl-3-[(S)
The IC ₅₀ of the inhibitory activity of papain using 3-methyl-1- {4- (2,3,4-trimethoxyphenylmethyl) piperazin-1-ylcarbonyl} butylcarbamoyl] oxirane 1/2 sulfate is 5.5. It was × 10 ^-8 M.

Further, the fact that the ethyl ester form represented by the above formula (II) is difficult to be used for oral administration has a residual rate of 52% in an experimental system in which the compound is placed in rabbit serum for 5 minutes. Again, the compounds of the present invention showed a significant survival rate in the same experiment. This indicates that the compound of the present invention has strong resistance to degrading enzymes, has improved stability in the digestive tract, and is effective even in oral administration.

Clinical uses of the compound of the present invention include prophylactic and therapeutic agents for myocardial infarction, therapeutic agents for inflammation, muscular dystrophi, and renal hypertension, which are diseases involving thiol protease.

The dose of the compound of the general formula (I) and the salt thereof according to the present invention varies depending on the kind of the compound and the degree of symptoms, but in the case of oral administration, about 10 mg to 1 g per day may be usually administered to a patient.

The compound represented by formula (I) and a salt thereof are usually in the form of a pharmaceutical composition together with a pharmaceutical carrier. As the carrier, diluents or excipients such as a bulking agent, a binder, a disintegrating agent, a lubricant and the like which are usually used for preparing a drug depending on the usage form are used.

The dosage form may be any of injections, powders, capsules, granules, tablets and the like.

When used in the form of tablets, as a carrier, for example, lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, crystalline cellulose, excipients such as silicic acid, water, ethanol, propanol, glucose solution, starch solution, gelatin. Solution, carboxymethyl cellulose, methyl cellulose, binder such as potassium phosphate, dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, stearic acid monoglyceride, starch, disintegrating agent such as lactose, stearate salt, boric acid powder Lubricants such as solid polyethylene glycol, which are widely used in this field, can be used. If necessary, sugar-coated tablets, gelatin-coated tablets,
It may be a film-coated tablet or the like.

When prepared as an injection, examples of the diluent include water, ethyl alcohol, propylene glycol, polyoxyethylene sorbit, sorbitan ester and the like. At this time, sodium chloride, glucose, or glycerin may be contained in an amount sufficient to prepare an isotonic solution, and a usual solubilizing agent, buffer, soothing agent, preservative, etc. may be added as necessary. May be included.

Next, the present invention will be specifically described with reference to Examples and Reference Examples.

Reference Example 1 (2R, 3R) -3-[(S) -3-methyl-1- {4-
(2,3,4-Trimethoxyphenylmethyl) piperazine-
1-ylcarbonyl} butylcarbamoyl] oxirane-2-carboxylic acid sodium salt (2R, 3R) -3-[(s) -3-methyl-1- {4-
(2,3,4-Trimethoxyphenylmethyl) piperazine-
Ethyl 1-ylcarbonyl} butylcarbamoyl] oxirane-2-carboxylate (14.0g) (100m
l) To the solution was added 0.48N-sodium hydroxide-ethanol solution (55.9 ml) under ice cooling, and the mixture was stirred at room temperature for 2.5 hours. Ethanol is distilled off under reduced pressure, water is added to separate insoluble components,
The liquid was concentrated to dryness under reduced pressure, and (2R, 3R) -3-[(s)
13.5 g of sodium 3--3-methyl-1- {4- (2,3,4-trimethoxyphenylmethyl) piperazin-1-ylcarbonyl} butylcarbamoyl] oxirane-2-carboxylate as a pale yellow powder (yield 98%) obtained.

Reference Example 2 (2R, 3R) -3-[(S) -3-methyl-1- {4-
(3-Phenyl-2-propenyl) piperazin-1-ylcarbonyl} butylcarbamoyl] oxirane-2-
Carboxylic acid sodium salt (2R, 3R) -3-[(S) -3-methyl-1- {4-
(3-Phenyl-2-propenyl) piperazin-1-ylcarbonyl} butylcarbamoyl] oxirane-2-
The title compound is obtained in the same manner as in Reference Example 1 using ethyl carboxylate.

¹ H NMR (CDCl ₃ ) δ: 0.7 to 1.8 (9H, m), 2.0 to 2.7 (4H, m),
2.7 to 3.9 (8H, m), 4.8 to 5.2 (1H, m), 5.9 to 6.6 (2H,
m), 7.1 to 7.5 (5H, m) ▲ [α] ²² _D ▼ = -53.9 ° (c = 1.05, methanol) Example 1 (1) (2R, 3R) -2-ethylcarbamoyl-3-
[(S) -3-Methyl-1- {4- (2,3,4-trimethoxyphenylmethyl) piperazin-1-ylcarbonyl} butylcarbamoyl] oxirane 10.0 g (19 mmol) of the sodium salt obtained in Reference Example 1 ) Is dissolved in 40 ml of methylene chloride, 1-methyl-2-chloropyridinium tosylate (7.0 g, 22.8 mmol) is added at 0 ° C, and the mixture is stirred at 0 ° C, 30 minutes, and room temperature for 60 minutes. To this, a suspension of ethylamine hydrochloride (1.6 g, 22.8 mmol) and triethylamine (4.7 g, 45.6 mmol) in methylene chloride is slowly added. After stirring for 1.5 hours at room temperature, the solvent is distilled off and the mixture is extracted with ethyl acetate. The extract is washed with water and saturated brine, dried over anhydrous sodium sulfate, the solvent is evaporated, and the residue is purified by silica gel chromatography to obtain 3.7 g of the title compound as a white solid.

¹ HNMR (CDCl ₃ ) δ: 0.9 (6H, d × 2, J = 6Hz), 1.1 (3H, t, J =
6Hz), 1.3 to 1.7 (3H, m), 2.3 to 2.6 (4H, m), 3.1 to 3.5
(2H, m), 3.3 ~ 3.8 (8H, m), 3.8 ~ 3.9 (9H, s x 3), 4.8
~ 5.1 (1H, m), 6.1 (1H, t, J = 5Hz), 6.6 (1H, d, J = 8H
z), 6.9 (2H, d × 2, J = 8Hz) ▲ [α] ²² _D ▼ ＝ -44.0 ° (c = 1.005, methanol) (2) (2R, 3R) -2-ethylcarbamoyl-3-
[(S) -3-Methyl-1- {4-2,3,4-trimethoxyphenylmethyl) piperazin-1-ylcarbonyl}
Butylcarbamoyl] oxirane 1/2 sulfate 3.4 g (6.4 mmol) of the amide obtained above was added to 30 ml of acetone.
, 1NH ₂ SO ₄ / acetone (6.1 ml) is added, and the solvent is distilled off under reduced pressure. The residue is dissolved by heating in acetone and stirred at room temperature overnight. The precipitated crystals are collected by filtration and dried under reduced pressure to give the title compound (1.1 g) as a white powder.

NMR (CDCl ₃ ) δ: 0.8 to 1.0 (6H, m), 1.1 (3H, t, J = 7Hz),
1.3 to 1.7 (3H, m), 2.6 to 3.7 (6H, m), 3.6 (1H, s), 3.7
(1H, s), 3.7 ~ 4.2 (9H, s x 2), 3.7 ~ 4.2 (4H, m), 4.1
~ 4.2 (2H, s), 4.6 ~ 5.0 (1H ~ m), 6.7 (1H, d, J = 9H
z), 6.9 (1H, d, J = 9Hz), 7.3 (1H, d, J = 9Hz), 7.2 to 7.6
(1H, broad S) ▲ [α] ²² _D ▼ = −39.5 ° (c = 0.950, methanol) Example 2 (1) (2R, 3R) -2-benzylcarbamoyl-3-
[(S) -3-Methyl-1- {4- (2,3,4-trimethoxyphenylmethyl) piperazin-1-ylcarbonyl} butylcarbamoyl] oxirane 10.0 g (19 mmol) of the sodium salt obtained in Reference Example 1 ), Benzylamine (2.5 g, 22.8 mmol), 1-methyl-2
-Chloropyridinium tosylate (7.0g, 22.8mmol),
Triethylamine (2.4g, 22.8mmol), methylene chloride 80m
was used in the same manner as in Example 1- (1) to give the title compound 4.7
g is obtained as a white solid.

NMR (CDCl ₃ ) δ: 0.9 (6H, d × 2, J = 6Hz), 1.3 to 1.8 (3H,
m), 3.3 to 3.7 (4H, m), 3.5 (2H, s), 3.5 (1H, d, J = 2H
z), 3.6 (1H, d, J = 2Hz), 3.9 (9H, s × 3), 4.4 to (2H,
d, J = 6Hz), 4.7 to 5.1 (1H, m), 6.6 (1H, d, J = 9Hz), 6.6
(1H, t, J = 6Hz), 6.9 (2H, d × 2, J = 9Hz), 7.2 to 7.3 (5
H, broad S) ▲ [α] ²² _D ▼ = −40.0 ° (c = 1.016, methanol) (2) (2R, 3R) -2-benzylcarbamoyl-3-
[(S) -3-Methyl-1- {4- (2,3,4-trimethoxyphenylmethyl) piperazin-1-ylcarbonyl} butylcarbamoyl] oxirane 1/2 sulphate Amide derivative 4.3 1 NH ₂ SO for g (7.4 mmol)
Example 4 using ₄ / acetone (7.1 ml) and 40 ml of acetone
-In the same manner as in (2), 3.1 g of the title compound is obtained as a white powder.

NMR (CDCl ₃ ) δ: 0.8 to 1.0 (6H, m), 1.3 to 1.7 (3H, m), 2.5
~ 4.3 (4H, m), 3.6 (1H, d, J = 2Hz), 3.7 (1H, d, J = 2H
z), 3.8 to 3.9 (9H, s × 3), 4.1 (2H, s), 4.4 (2H, d, J =
6Hz), 4.6 to 5.0 (1H, m), 6.6 (1H, d, J = 9Hz), 6.9 (1H,
d, J = 9 Hz), 7.2 (6H, m), 7.9 (1H, m) ▲ [α] ²² _D ▼ = −36.6 ° (c = 0.942, methanol) Example 3 (1) (2R, 3R) − 2-ethylcarbamoyl-3-
[(S) -3-Methyl-1- {4- (3-phenyl-2
-Propenyl) piperazin-1-ylcarbonyl} butylcarbamoyl] oxirane 2.258 g (5 mmol) of the sodium salt obtained in Reference Example 2 was dissolved in dichloromethane (12 ml) and cooled. 2-chloro-1-methylpyridinium tosylate (1.789 g (6 mmo)
l) was added, and the mixture was stirred under ice-cooling for 45 minutes and at room temperature for 1 hour. Then, ethylamine hydrochloride 0.489 g (6 mmol) and triethylamine 1.214 g (12 mmol) in 8 ml of dichloromethane were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to give the title compound (1.06 g) as a slightly yellow solid.

NMR (CDCl ₃ ) δ: 0.92 (3H, d, J = 6Hz), 0.98 (3H, d, J = 6H)
z), 1.14 (3H, t, J = 7Hz), 1.3 to 1.8 (3H, m), 2.3 to 2.6
(4H, m), 3.17 (2H, d, J = 6Hz), 3.37 (2H, q, J = 7Hz),
3.47 (1H, d, J = 2Hz), 3.54 (1H, d, J = 2Hz), 3.3 to 3.7
(4H, m), 4.7 to 5.1 (1H, m), 5.9 to 6.1 (1H, m), 6.1 to 6.
7 (2H, m), 6.7 to 6.9 (1H, m), 7.1 to 7.4 (5H, m) (2) (2R, 3R) -2-ethylcarbamoyl-3-
[(S) -3-Methyl-1- {4- (3-phenyl-2
-Propenyl) piperazin-1-ylcarbonyl} butylcarbamoyl] oxirane 1/2 sulfate 1.05 g (2.30 mmol) of the amide obtained above was added to acetone 10 m.
It was dissolved in 1 l, 2.18 ml of 1 NH ₂ SO ₄ / acetone was added, and the solvent was distilled off under reduced pressure. This was recrystallized from 5 ml of acetone and dried under reduced pressure at room temperature overnight to obtain 0.66 g of the title compound as white crystals.

NMR (CDCl ₃ ) δ: 0.7 to 1.0 (6H, m), 1,11 (3H, t, J = 7Hz),
1.3 to 1.7 (3H, m), 2.6 to 4.2 (14H, m), 4.6 to 5.0 (1H,
m), 6.1 to 6.8 (2H, m), 7.0 to 7.6 (7H, m), 8.0 to 8.8 (1
H, broad s) ▲ [α] ²² _D ▼ = −38.5 ° (c = 1.07, methanol) Example 4 (1) (2R, 3R) -2-benzylcarbamoyl-3-
[(S) -3-Methyl-1- {4- (3-phenyl-2
-Propenyl) piperazin-1-ylcarbonyl} butylcarbamoyl] oxirane 3.386 g (7.5 mmol) of the sodium salt obtained in Reference Example 2 was dissolved in 15 ml of dichloromethane and cooled with ice. 2.698 g of 2-chloro-1-methylpyridinium tosylate (9 mmo
l) was added, and the mixture was stirred under ice-cooling for 40 minutes and at room temperature for 1 hour. Then, 15 ml of a dichloromethane solution containing 0.804 g (7.5 mmol) of benzylamine and 0.911 g (9 mmol) of triethylamine was added, and stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (2.09 g) as a slightly yellow solid.

NMR (CDCl ₃ ) δ: 0.91 (3H, d, J = 6Hz), 0.98 (3H, d, J = 6H
z), 1.3 to 1.8 (3H, m), 2.3 to 2.6 (4H, m), 3.17 (2H, d, J
= 6Hz), 3.3 to 3.7 (4H, m), 3.50 (1H, d, J = 2Hz), 3.61
(1H, d, J = 2Hz), 4.43 (2H, d, J = 6Hz), 4.7 to 5.1 (1H,
m), 6.0 to 6.9 (4H, m), 7.1 to 7.4 (10H, m) (2) (2R, 3R) -2-benzylcarbamoyl-3-
[(S) -3-Methyl-1- {4- (3-phenyl-2
-Propenyl) piperazin-1-ylcarbonyl} butylcarbamoyl] oxirane 1/2 sulphate 2.39 g (4.61 mmol) of the amide obtained above was added to 20 m of acetone.
The mixture was dissolved in 1 l, 1NH ₂ SO ₄ / acetone (4.38 ml) was added, and the mixture was concentrated to dryness under reduced pressure. To this, 40 ml of ether was added and stirred at room temperature. Then, it was filtered, washed with ether, and dried under reduced pressure at room temperature overnight to obtain 2.17 g of the title compound as a slightly yellow solid.

NMR (CDCl ₃ ) δ: 0.7 to 1.0 (6H, m), 1.3 to 1.7 (3H, m), 2.5
~ 3.2 (4H, m), 3.3 ~ 4.1 (8H, m), 4.3 ~ 4.5 (2H, m), 4.
6 to 5.0 (1H, m), 6.0 to 6.8 (2H, m), 7.0 to 7.9 (12H, m),
9.2 to 9.5 (1H, broad s) ▲ [α] ²² _D ▼ ＝ -37.4 ° (c = 1.04, methanol)

Claims (1)

[Claims] 1. A general formula (In the formula, R ¹ represents an alkyl group or an aralkyl group, and R ² represents And n represents an integer of 0 to 3. ) A piperazine derivative represented by: