JPS63275575A - Piperazine derivative - Google Patents

Abstract

NEW MATERIAL:A piperazine derivative expressed by formula I (R<1> is alkyl or aralkyl; R<2> is expressed by formula II, V or VI; n is an integer of 0-3). EXAMPLE:( 2R,3R )-2-Ethylcarbamoyl-3-[( S )-3-methyl-1-{ 4-( 2,3,4- trimethoxyphenylmethyl )piperazin-1-ylcarbonyl }butylcarbamoyl ]oxirane. USE:A preventive and treating agent for cardiac infraction effective even by oral administration and remedy for inflammations, myodystrophia and renal hypertension participated with thiol protease. PREPARATION:A compound expressed by formula III is reacted with a compound expressed by formula IV or reactive derivative thereof by a conventional acid chloride, mixed acid anhydride, active esterification methods, etc., to afford the aimed compound expressed by formula I. Furthermore, since the above- mentioned compound has high resistance to decomposing enzymes and high stability in digestive tracts, it is effective even by oral administration.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to piperazine derivatives, more specifically, the following general formula (I) (wherein R1 represents an alkyl group or an aralkyl group,
n represents an integer from 0 to 3. ) is related to a piperazine derivative represented by

The present inventors have previously discovered that the compound represented by the following formula (II) and its derivatives are useful as preventive or therapeutic agents for myocardial infarction, and have filed a patent application. (Masaki et al., JP-A-57-169478.
58-126879) Hara et al. (Biomedical Research 4(1) pp. 121-124, 1983) found that the piperazine derivative represented by the above formula (II) is a proteolytic enzyme in which a thiol group is involved in the expression of activity. A papain calcium ion-activated neutral protease (
It has been confirmed that it has inhibitory activity against substances such as CANP).

By the way, when the piperazine derivative represented by the above formula (II) is orally administered, it is necessary to use a high dose in order to obtain an effective blood concentration for exerting the drug effect. However, when high doses are used, long-term use may cause side effects, and there has been a need for substances that can achieve effective blood concentrations and exhibit medicinal efficacy at low doses. In view of the above circumstances, the present inventors conducted intensive research and found that the piperazine derivative represented by the above general formula (I) inhibits the activity of protease in which the thiol group is involved in the expression of activity even when administered orally. The present invention was completed based on this discovery.

The present invention will be explained in detail below.

(In the formula, R+ and R1 are the same as above) An object of the present invention is to provide a piperazine derivative represented by:

Examples include an alkyl group, a phenylethyl group, and a benzhydree group represented by R+ in the above general formula (1), and these may have a halogen or the like as a substituent.

The oxirane in formula (I) is trans isomer, that is, (
2S, 3S) or (2R, 3R) coordination is preferred.

Salts of maleic acid, tartaric acid, etc. are also included in the present invention.

The piperazine derivative represented by general formula (1) is, for example,
It can be obtained by the method shown below.

or a reactive derivative thereof (III) (IV) (V)
(Vl) or a reactive derivative thereof (■) (■) Known condensing agents, e.g. 1-alkyl-2-halopyridinium salts such as 1-methyl-2-chloropyridinium tosylate, or N,N-dicyclohexyl In combination with carbodiimide or N-hydroxysuccinimide, etc., in the presence or absence of a base such as triethylamine, in an organic solvent such as methylene chloride, chloroform, or tetrahydrofuran, at -10 to 40 °C, preferably, It is carried out at -5 to 30°C.

The usefulness of the compounds of the present invention as therapeutic and preventive agents for myocardial infarction is confirmed by the method described in JP-A-58-126879 and the like.

On the other hand, regarding inhibition of papain activity, see Biomedical Research 4(1), pages 121-124.

Confirmed by the method described in 1983 etc. That is, the compound of the present invention (2R,3R)-2-benzylcarbamoyl-3-[(S)-3-methyl-1-[4-(
ICg of inhibitory activity of papain using 2,3,4-trimethoxyphenylmethyl)piperazin-1-ylcarbonyl)butylcarbamoylcooxirane 1/2 sulfate
o was 5.5XIOM.

In addition, the ethyl ester represented by the formula (II') is difficult to be used for oral administration because in an experimental system in which the compound was injected into rabbit serum for 5 minutes, it had a survival rate of only 52%. As can be seen from the above, clinical uses of the compounds of the present invention include agents for preventing and treating myocardial infarction, and agents for treating inflammation, muscular dystrophy, and renal hypertension, which are diseases involving thiol proteases.

The dosage of the compound of general formula (I) and its salt in the present invention varies depending on the type of compound and the severity of symptoms, but
In the case of oral administration, usually about 10 mg to 1 g per day may be administered to the patient.

The compound represented by general formula (I) and its salt are usually formulated into a pharmaceutical composition together with a pharmaceutical carrier. As the carrier, diluents or excipients such as fillers, binders, disintegrants, lubricants, etc., which are commonly used to prepare drugs according to the usage form, are used.

The dosage form may be any form such as injection, powder, capsule, granule, or tablet.

When used in tablet form, carriers include binders such as lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, crystalline cell-local boxyl methylcellulose, methylcellulose, potassium phosphate, dry starch, sodium alginate, agar powder, etc. , disintegrants such as sodium bicarbonate, calcium carbonate, stearic acid monoglyceride, starch, and lactose, and lubricants such as stearate, boric acid powder, and solid polyethylene glycol, which are widely used in this field. be able to. Furthermore, if necessary, it can be made into sugar-coated tablets, gelatin-encapsulated tablets, film-coated tablets, etc.

When prepared as an injection, examples of diluents include water, ethyl alcohol, brobylene guacol, polyoxyethylene sorbitol, and nrubitan ester. At this time, a sufficient amount of salt, glucose, or glycerin may be included to prepare an isotonic solution, and usual solubilizing agents, buffering agents, soothing agents, preservatives, etc. may be added as necessary. It may also be included.

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

Reference example 1 (2R,3R)-3-[(S)-3-methyl-1-(4
-(2,3,4-trimethoxyphenylmethyl)piperazin-1-ylcarbonyl)butylcarbamoyl]oxirane-2-carboxylic acid sodium salt (2R,3R) -3-((s) -3-methyl-1-
(4-(2,3,4-)rimethoxyphenylmethyl)pyradin-1-ylcarbonyl)butylcarbamoyl]
To a solution of ethyl oxirane-2-carboxylate (14.0 g) in ethanol (100 il) was added 0.48N-sodium hydroxide-ethanol i'1 (55.9 rnl) under water cooling.
was added and stirred at room temperature for 2.5 hours. Ethanol was distilled off under reduced pressure, water was added to separate insoluble components, and the solution was concentrated to dryness under reduced pressure to obtain (2R,3R) -3-C(s')-3
-Methyl-1-(4-(2,3,4-trimethoxyphenylmethyl)pi is radin-1-ylcarbonyl)butylcarbamoyl] Sodium oxirane-2-carboxylate as pale yellow powder 13.5! (yield: 98 cm).

I R (KBr) cm-': 1 (520,90O
NMR(DMso-d,)δ: 0.90 (6)(,m,(CH,),CH-
) Te1.30~1.70 (3g9m, -C3CH-)4
．． 70 ('IH,m, -NHCH-CO-
)6.64 (iH, d, J: 8) (z, aromatic proton) 6.88 (IH, d, J=
8Hz, aromatic proton) 8.08 (1)
1. d, -NHCO-) [α) o = -43,8° (C:
I H2O) Reference Example 2 (2R,3R)-3-[(S) -3-methyl-1-(
4-(3-phenyl-2-propenyl)piperazine-1
-ylcarbonyl)butylcarbamoyl1oxirane-
2-carboxylic acid sodium salt (2R,3R) -3-((S)-3-methyl-1-(
4-(3-phenyl-2-propenyl)piperazine-1
-ylcarbonyl)butylcarbamoyl]oxirane-
2-carboxylic acid ÷ horn), the title compound is obtained in the same manner as in Reference Example 1.

IRv"cry-': 2955.1630,145
0.1385.1235°1145.1000.970
,900,740,895'HN M R (CDCh
) δ: 0.7-1.8 (9E(,m), 2.0-
2.7 (4H, m), 2.7-3.9 (8H, m), 4
．． 8-5.2 (IH.

m), 5.9-8.6 (2H, m), 7.1-7.5 (
5H, m) [α]. =-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 Sodium salt obtained in Reference Example 1 10.0 g (19 mmol)
) was dissolved in 40 ml of methylene chloride, and 1-methyl-2-chloropyridinium tosylate (7.0 g,
22.8 mmol) and stirred for 08C930 minutes and at room temperature for 60 minutes. To this, ethylamine hydrochloride (1,6
g.

22.8+u+ol), ) ethylamine (4.7g
, 45.6+uaol) suspended in methylene chloride is slowly added. After stirring at room temperature for 1.5 hours, the solvent was distilled off and the mixture was extracted with ethyl acetate. After washing with water and saturated brine, it is dried over anhydrous sodium sulfate, the solvent is distilled off, and the residue is purified by silica gel chromatography to obtain 3.7 g of the title compound as a white solid.

I Rv"crs-' =3300.2950.16
50.1530.1495°1460.1280,10
90,1050.1000,900.800'HN M
R(CDCb)δ: 0.9(6H, dX2.J
=6Hz).

1.1 (3H, t, J = 8Hz), 1.3-1.7
(3H, m).

2.3-2.6 (4H, m), 3.1-3.5 (2H,
m), 3.3-3.8 (8H, m), 3.8-3.9 (
9H, s X3), 4.8-5.1 (IH.

m), 6.1 (IH,t, J = 5Hz), 6.6 (
IH, d, J = 8 Hz), 6.9 (2H, d
．． , J = 8Hz) [α]H = -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 1
Oxirane 1/2 sulfate amide compound obtained above 3.4g
(6,4@mol) in 30ml of acetone, I
NHλS04/acetone (6.1 ml) was added and the solvent was distilled off under reduced pressure. The residue is heated and dissolved in acetone and stirred at room temperature overnight. The precipitated crystals are collected by filtration and dried under reduced pressure to obtain 1.1 g of the title compound as a white powder.

I Rvk8'am-': 3280.2950,
1660, 1540, 1470°1280.1230.
1100.1040.960,900,810,610
．． 46ONMR(CDCI,) δ: 0.8-1.0(
6H, m), 1.1 (3H.

t, J = 7Hz), 1.3-1.7 (3H, m),
2.6-3.7 (6H.

m), 3.6 (IH, s), 3.7 (IH, s), 3.
7-4.2 (9H.

s X2), 3.7-4.2 (4H, m), 4.1-
4.2 (2H, s).

4, (5-5,0(IH, m), 6.7(IH, d,
J = 9Hz), 6.9 (IH, d, J = 9H
z), 7.3 (IH, d, J = 9 Hz).

7.2-7.6 (I H, broad S) 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
) to benzylamine (2.5 g, 22.8 mmo
l), 1-methyl-2-chloropyridinium tosylate (7.0g, 22.8+aa+ol), triethylamine (2.4g, 22.8m+++ol), and methylene chloride 80ml, in the same manner as in Example 1-(1). 4.7 g of the title compound is obtained as a white solid.

I Ry""cm-': 3300,2950.1
6G0,1530.1490゜Wμ× 1460.1280.1090,1040.1000.
900,800.70ON MR(CDC1B)δ
: 0.9 (6H, dX2.J = 6Hz).

1.3-1.8 (3H, m), 3.3-3.7 (4H,
m), 3.5 (2H.

s), 3.5 (IH, d, J = 2Hz), 3.6
(IH, d, J = 2Hz), 3.9 (9H, s
X3), 4.4 (2H, d, J = 6Hz).

4.7-5-1 (IH+m), 6-6<IH9d,
J = 9Hz), 6.6 (IH,t, J = 6Hz
), 6.9 (2H, d X2. J = 9Hz).

7.2-7.3 (5H, broad S) [α]D=-
40,0° (C=1.010.methanol) (2) (2
R,3R) -2-benzylcarbamoyl-3-[(S
)-3-methyl-1-(4-(2,3,4-trimethoxyphenylmethyl)piperazin-1-ylcarbonyl)
Butylcarbamoyl]oxirane 1/2 sulfate For 4.3g (7,4+amol) of the amide compound obtained above, I
N HzSO4/7 setone (7,1m1) s 7
Using Setone 40@1, 3.1 g of the title compound is obtained as a white powder in the same manner as in Example 1-(2).

I Rv"'cm"-1: 3280, 2950, 16
80,1630,1540°1470.1280.12
40.1100,960,900,700,600.4
6ONMR (also CDCI) δ: 0.8. -1.
0 (6H, m), 1.3-1.7 (3H, m), 2.5
−4.3 (4H, m), 3.6 (IH, d, J −
2Hz), 3.7 (IH, d, J = 2Hz), 3
．． 8-3.9 (9H.

s X3), 4.1 (2H, s ), 4.4 (2H, d
, J = 6Hz).

4.6-5.0 (IH, m), 6.6 (IH, d,
J -9Hz), 6.9 (IH, d, J=9Hz), 7
．． 2 (6H, m), 7.9 (IH, m) [α row = -3
6,6° (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+al) and cooled.

To this, 1.789 g (6 mmol) of 2-chloro-1-methylpyridinium tosylate was added, and after stirring for 45 minutes under water cooling and for 1 hour at room temperature, 0.48 g of ethylamine hydrochloride was added.
9g (6mmol) and triethylamine 1.214
g (12 mmol) of dichloromethane solution 81 was added,
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 distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain 1.06 g of the title compound as a slightly yellow solid.

I Rv"'cm-1: 3280, 2960, 169
0,1670,1630°1530.1445.123
0,995,970,890,740,69ON M
R (CDC1B) δ: 0.92 (3H, d
, J = 6Hz).

0.98 (3H, d, J = (5Hz), 1.14 (
3H, t, J = 7Hz), 1.3-1.8 (3H,
m), 2.3-2.6 ('4H, m).

3.17 (2H, d, J = 6Hz), 3.37 (2
H, q , J = 7Hz), 3.47 (IH, d , J
=2Hz), 3.54(IH,d.

J = 2Hz), 3.3-3.7 (4H, mL4.7-
5.1 (LH.

m), 5.9-6.1 (IH, m), 6.1-6.7 (
2H, m).

0.7-6.9 (IH, m), 7.1-7.4 (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 of the amide compound obtained above (2,30ma+ol
) in 10 ml of acetone, IN)I,SO+/
2.18@1 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.

I Rv'::cm-': 3280.2960.1
655+1530.1450°1220, 1150.1
125.1050.9 (50,895,750,690
,620°8O NMR (CDC13) δ: 0.7-1.0 (68
, m), 1.11 (3H,t, J = 7Hz), 1
．． 3-1.7 (3H, m), 2.6-4.2 (14H,
m), 4.6-5.0 (I H, m), 6.1-6.8
(2H, m), 7.0-7. ! 5 (7H, m), 8.0
-8.8 (IH.

broad s) [C3” = -38,5° (cm107.methanol)
Example 4 (1) (2R,3R)-2-penzylrubamo1'-3-[(S)-3-methyl-1-(4-(3-phenyl-2-propenyl)piperazin-1-yl) carbonyl)butylcarbamoyl]oxirane Sodium salt 3 obtained in Reference Example 2, 386 g (7,5
mmo 1) was dissolved in 15 ml of dichloromethane and cooled on ice. To this, 2.698 g (9 mmol) of 2-chloro-1-methylpyridinium tosylate was added, and the mixture was cooled with water.
After stirring for 1 hour at room temperature for 0 minutes, benzylamine 0.8
04 g (7,5+++ mol) and triethylamine 0.911 g (9 mmol) in dichloromethane solution 15
ml 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 distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 2.09 g of the title compound as a slightly yellow solid.

c in I Rv (': 3290, 1690, 1670
, 1630, 1525 ° consideration 1450, 1230.995, 970, 895, 740
,89ONMR(CDC13)δ: 0.91(3H,
d, J = 6Hz).

0.98 (3H, d, J = 6Hz), 1.3-
1.8 (3H, m).

2.3-2.6 (4H, m), 3.17 (2H, d,
J = 6Hz).

3.3-3.7 (4H, m), 3.50 (IH, d,
J = 2Hz).

3.01 (IH, d, J = 2Hz), 4-43 (2
H, d, J = 6Hz), 4.7-5.1 (I
H, m), 6.0-6.9 (4H, m), 7.1-7.
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 sulfate 2.39 g (4,61 mmol) of the amide compound obtained above was dissolved in acetone 20111, and IN 82 SO4/
4.38 ml of acetone was added, and the mixture was concentrated to dryness under reduced pressure. 40 ml of ether was added to this, and the mixture was stirred at room temperature. The residue was filtered, washed with ether, and dried under reduced pressure at room temperature overnight to obtain 2.1'/g of the tF title compound as a slightly yellow solid.

I Rv"'cm-I: 3280.1650.152
0,1450,1120°1025.960,745.
Q95. (515N M R (CDCh) δ:
0.7-1.0 (6H, m), 1.3-1.7 (3H,
m), 2.5-3.2 (4H, m), 3.3-4.1 (
8H, m).

4.3-4.5 (2H, m), 4.6-5.0 (IH,
m), 6.0-E5.8 (2H, m), 7.0-7.9
(12H, m), 9.2-9.5 (IH.

broads)

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 represents an alkyl group or an aralkyl group, and R
^2 indicates ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and n indicates an integer from 0 to 3. ) A piperazine derivative represented by