JPS58194873A - 1-(3,4,5-trimethoxycinnamoyl)-4-aminocarbonylmethyl- substituted piperazine derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R is 4-6C straight chain or branched chain alkyl or 5-7C cycloalkyl) and an acid addition salt thereof. USE:A vasodilator. PROCESS:A 1-aminocarbonylmethyl-substituted piperazine derivative of formula IIis reacted with a 3,4,5-trimethoxycinnamyl halide of formula III in an anhydrous inert organic solvent, e.g. acetone or benzene, at room temperature to give the compound of formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel 1-0, 4.
5-)rimethoxycinnamoyl)-4-aminocarbonylmethyl-substituted piperazine derivatives and pharmacologically acceptable acid addition salts thereof.

(In the formula, R represents a linear or branched alkyl group having 4 to 6 carbon atoms, or a cycloalkyl group having 5 to 7 carbon atoms.) Trimethoxycinnamoyl-4-aminocarbonylmethyl-substituted piperazine derivatives and their pharmacologically acceptable acid addition salts.

Many vasodilators have been developed and researched, but
There still remained various problems to be improved in terms of drug efficacy, side effects, etc. As a result of intensive research to find a drug with excellent vasodilatory effect, the inventors of the present application discovered a novel 1-(i4.5-trime-1-xinnnnamoyl>4-aminocarbonylmethyl substituted drug represented by general formula (1) in d11). It has been discovered that piperazine derivatives and their pharmacologically acceptable acid addition salts have excellent vasodilatory effects in the brain, periphery, and coronary vessels, and are extremely advantageous as pharmaceuticals, and the present invention has been achieved. 1. I did.

In the general formula (]) of the present invention, the linear or branched alkyl group having 4 to 6 carbon atoms represented by R is butyl, isobutyl, SθC-butyl, tert-butyl, pentyl, impentyl. .

Neopentyl, tert-pentyl, hexyl, isohexyl groups, etc., and cycloalkyl groups having 5 to 7 carbon atoms include cyclopentyl, cyclohexyl, and cycloheptyl groups.

The compound represented by the general formula (1) of the present invention has a desired t
Accordingly, it can be converted into a pharmacologically acceptable acid addition salt, or the base can be liberated from the acid addition salt formed.

Examples of pharmacologically acceptable acid addition salts of the compound represented by the general formula (1) of the present invention include hydrochloric acid,
Mineral acid salts such as nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, or acetic acid.

Maleic acid, fumaric acid, citric acid, shiulic acid.

Organic acid salts such as tartaric acid may be mentioned, and particularly preferred acid addition salts include maleic acid and fumarate salts.

The novel 1-(3,
,! I',5-1-rimethquincinnamoyl)-4-aminocarbonylmethyl-substituted piperazine derivative can be produced as follows.

That is, the compound represented by the general formula (+) according to the present invention is 1- represented by the following general formula (11) (wherein R represents the same meaning as above).
Produced by reacting with a 3,4,5-)rimethoxycinnamic acid halide represented by aminocarbonylmethyl-substituted pi (wherein, I can do it.

In a particularly preferred embodiment of the method of the present invention, the 1-aminocarbonylmethyl-substituted piperazine derivative represented by the general formula (11) is added to 1 equivalent of the general formula (Ill
3,4.5-)rimethoxycinnamic acid halide represented by the following formula is reacted in an anhydrous inert organic solvent using at least 1 equivalent or more, preferably 12 to 1.3 equivalents.

Any inert organic solvent may be used in the method of the present invention as long as it does not inhibit the reaction, such as acetone and ether.

Tetrahydrofuran, dioxane, benzene.

Sarel uses toluene, chloroform, etc.

Further, the reaction is carried out at room temperature while heating and refluxing the organic solvent used, and is particularly preferably carried out at room temperature.

All of the 1-ami7carbonylmethyl-converted piperazine derivatives represented by the general formula (11), which are the starting materials in the production method of the present invention, are new substances with the exception of some, and their production is described in reference examples. Described in .

In addition, 3,4+ 5- represented by the general formula (Ill)
Trimethoxycinnamic acid halide is produced by converting 3,4°5-trimethoxycinnamic acid into an acid halide according to a conventional method before use.

The structure of the compound of the present invention represented by the above general formula (1) has been determined from a nuclear magnetic resonance (NMR) spectrum and an infrared absorption (R) spectrum. NMR spectra were performed using a JEOL FX-90Q spectrometer with tetramethylsilane (TMS) as an internal standard.
The measurement was carried out at room temperature. The engineering R spectrum was measured using JASCO RA-202. In the Examples below, the data will be shown using the following abbreviations. 8 double single line.

d: double line, t: triple '1! + BeX: Sextet 1
m = multiplet, br nibroad, R: infrared absorption.

Hereinafter, the present invention will be explained by examples.

Reference Example 1 1-(Ptylaminol) Piperazine 120ml/suspension of 12.02g of piperazine in benzene, 14.12g of triethylamine and N-butyl-2
-10°45g of chloroacetamide in 50ml of benzene
Add the solution and heat to reflux for 3 hours. The solvent was distilled off, and a mixture of potassium carbonate aqueous solution and chloroform was added to the residue and shaken. Separate the chloroform layer and dehydrate. The solvent was removed and the resulting residue was distilled to a boiling point of 147-149° (5
8.64 g of a colorless liquid of rtan Hgl is obtained.

Engineering R spectrum v (filmJ cyn 1
: Example 1 1-(3,4,5-trimethoxycinnamoyl)-4
8.49 g of 1-(butylaminoluponylmethylpiperazine obtained in Reference Example 1) and 5.5 g of triethylamine.
To a solution of 18 g of benzene in 200 ml, add 3
,4.5-)IJ methoxycinnamic acid chloride (3,4,5
-) A solution of J in 100 ml of benzene prepared from 12.20 g of rimethoxycinnamic acid and 50.49 g of thionyl chloride is added and stirred at room temperature for 6 hours. After the reaction, extract with 10% aqueous hydrochloric acid solution. The aqueous layer was made alkaline with potassium carbonate and extracted with ethyl acetate. The acetic acid ethyl ester layer was washed with water and dehydrated. The solvent was distilled off to obtain an orange-yellow liquid.

A small amount of ethyl acetate is added and the precipitated crystals are collected to give 11.47 g of pale yellow crystals. Recrystallization from ethyl acetate gives pale yellow prismatic crystals with a melting point of 148-149°.

Engineering R spectrum v (KBr) Cm-1:34
10(,;NH), 1670.1650(-0ONg) Elemental analysis value 022H33N305 Theoretical value 0.62.99 iH,7,93;N, 10
．． 02 experimental value 0.62.75iH, 7,92iN,
10.09 Reference Example 2 1-(Inbutylamine 7Carponylmethylnopiperazine 14.96 g of biperazine in 150 m/suspension of benzene, 17.57 g of triethylamine and 15.00 g of N-isobutyl-2-chloroacetamide in benzene 60
ml solution and heat to reflux for 5 hours. Hereinafter, the same treatment as in Reference Example 1 was carried out, and the boiling point was 146 to 151° (5 mm
11.49 g of a colorless liquid of Hgl is obtained.

Engineering R spectrum y (filmJ Cm 1:
Example 2 l-(3,4,5-)rimethoxycinnamoyl)-4-
(Isobutylaminocarbonylmethylph) Piperazine 1-(Imbutylaminocarbonylmethylph) obtained in Reference Example 2 1-(Imbutylaminocarbonylmethylph) Piperazine 11.24 g and triethylamine 685 g were added to a solution of 100 m/benzene under water-cooling and stirring.
,4.5-)IJ methoxycinnamic acid chloride (3,4,5
-) Add 100 m/solution of benzene prepared from 16.13 g of rimethoxycinnamic acid and 40.34 g of thionyl chloride and stir at room temperature for 6 hours. After the reaction, extract with 10% aqueous hydrochloric acid solution. The aqueous layer is extracted with chloroform, and the chloroform layer is shaken with an aqueous potassium carbonate solution. Separate the chloroform layer, wash with water, and dehydrate.

The solvent was distilled off to obtain 23.17 g of an orange-yellow viscous liquid. Add a small amount of ethyl acetate, take one portion of the precipitated crystals,
10.81 g of white crystals are obtained. Recrystallized from ethyl acetate to give pale yellow scaly crystals 6, melting point 155-156°.
．． Obtain 44 g.

Engineering R spectrum v (KBr'J cm l:
5420 C, NH)', 1660 (-0ON\J
Elemental analysis value 0g2H33N305 Theoretical value 0.62.99iH,7,931,10,02
Experimental value 0.62.9! l + H, 8,09; N,
9.93 Reference Example 5 1 (sea-butylaminocarbonyl methinolipiperazine) 14.97 g of triethylamine and N-(8θC-
Butyl no 2-chloroacetamide 11.08g benzene 50 shoulders? Add the solution and heat to reflux for 3 hours. below,
Treated in the same manner as in Reference Example 1, the boiling point was 146-145° (7
849 g of a colorless liquid of mmHgJ are obtained.

IR spectrum y (film J cm l:
Example 1-(3,4,5-)rimethoxycinnamoyl)4-
(see-butylaminocarbonylmethyl) PiperazineTo a solution of 8.47 g of 1-(6θC-butylamino7carponylmethyl nopiperazine obtained in Reference Example 3 and 5.16 g of triethylamine in 180 ml of benzene, under water-cooling and stirring,
3. 4. 5-1- IJ methoxycinnamic acid chloride (
Benzene 10 of J prepared from 12.17 g of 3,4,5-trimethoxycinnamic acid and 30.42 g of thionyl chloride
Add 0 ml solution and stir at room temperature for 8 hours. After reaction 1
Extract with 0% aqueous hydrochloric acid solution. The aqueous layer is made alkaline with potassium carbonate and extracted with chloroform. The chloroform layer was washed with water and dehydrated. The solvent was distilled off and the resulting residue (9,
10 g J was treated with column chromatography (silica gel, chloroform layer) to obtain 481 g of a yellow solid. Recrystallized from ethyl acetate, melting point 157-158°.
Obtain pale yellow scaly crystals.

Engineering R spectrum νCKBr)cm 1°3360
(, NH), 1 680. 1 645 (-
aoN,) Elemental analysis value 022'33N305 Theoretical value 0,62.9νiH,7,93i N, 10
．． 02 experimental value 0.62.67; H, 8,04; N,
9.92 Reference Example 4 l-(tert-butylaminocarbonylmethylpiperazine Suspension of 21.88 g of piperazine in 250 ml of benzene G
This, 25.70 g of triethylamine and N-(tar
A solution of 99 g of t-butyl-2-chloroacetamide 18 in 100 ml of benzene is added, and the mixture is heated under reflux for 6 hours.

Hereinafter, the same treatment as in Reference Example 1 was carried out, and the boiling point was 119 to 122°.
15.26 g of a colorless liquid (5 g Hg) was obtained.

Engineering R spectrum ν (film) cm 1: Example 4 1-(3,4.5-)rimethoxycinnamoyl)
-4- (tert-butylaminocarbonylmethylpiperazine) To a solution of 13.26 g of 1 (tert-butylaminocarponylmethyl)piperazine obtained in Reference Example 4 and 8.07 g of triethylamine in 25 i'l ml of benzene was added 3. 4.5-) IJ methoxycinnamic acid chloride (3,4.5-1 rimethoxycinnamic acid 19.03g
and thionyl chloride (prepared from 47.55 g of thionyl chloride) in 100 ml of benzene, and stirred at room temperature for 2 hours. Take one precipitated crystal and dissolve it in chloroform. The chloroform layer is shaken with an aqueous potassium carbonate solution. Separate the chloroform layer, wash with water, and dehydrate. The solvent was distilled off and pale yellow solid 2
D. Obtain 60 g. Recrystallization from ethyl acetate gives a colorless scale product with a melting point of 185-186°.

Engineering R Spectrum” (KBr J Cfi-],
.

5590 (, NHJ. 1660. 1650 (
-〇〇N\]/ Elemental analysis value 0 22I133N305 Theoretical value C, 6
2,99; H, 7.93; N, 1 0.02 experimental value 0, 62.80iH. 7.9QiN, 10
．． 02 Reference Example 5 1-(Pentylaminocarbonylmethyl nobiperazine To 10.55 g of benzene 100 years old,
12°36 g of triethylamine and N-pentyl-2
-10.00 g of chloroacetamide and 10 scraps of benzene
Add the solution and heat to reflux for 6 hours. Thereafter, the same treatment as in Reference Example 1 was carried out to obtain 4.95 g of a pale yellow liquid with a boiling point of 169 to 141° (6 HgJ).

Engineering R spectrum v (filmJCml: Example 5 1-(3,4,5-)rimethoxycinnamoyl)-4
-(bentylaminoruponylmethylnopiperazine) 1-(pentylaminoluponylmethylnopiperazine 4' obtained in Reference Example 5) was added to a solution of 90 g of 100 liters of chloroform under stirring under water cooling for 3,4.5 hours. -trimethoxycinnamic acid chloride (3,4,5-')rimethoxycinnamic acid 657
g and thionyl chloride 16.42 g of chloroform 50*i! Add the solution and stir at room temperature for 2 hours. The solvent was removed, and benzene and an aqueous hydrochloric acid solution were added to the residue, which was then shaken. The aqueous layer and insoluble body are separated, made alkaline with potassium carbonate, and extracted with chloroborum.

The chloroform layer was washed with water and dehydrated. The solvent is distilled off to obtain a yellow viscous liquid. Add a small amount of ethyl acetate and separate the precipitated crystals to obtain 7.92 g of pale yellow crystals. Recrystallization from ethyl acetate gives pale yellow prismatic crystals with a melting point of 168-139°.

Engineering R spectrum v (KBrJcm 1:341
0(,NH), 1670.1650 (-0ON
Nini: Nino elemental analysis value 023H35N305 Theoretical value 0.65.72 i H,8,14; N,
9.69 Experimental value 0.63.70 i H, 7,85i
N, 9.54 Reference Example 6 1-(hexylamine 7carbonylmethylph) Piperazine To 9.79 g of piperazine, 1150 g of triethylamine
and N-hexyl-2-chloroacetamide 10.1
Add 0g of benzene 7Dwrtl'4 fl and heat to reflux for 15 hours. Hereafter, the same treatment as in Reference Example 1 was carried out, and the boiling point was 1.
6.70 g of pale yellow liquid with a temperature of 72-178° (6 Hg) is obtained.

Engineering R spectrum v (film) Cm ]-: Example 6 1-(,3,4,5-1-rimethoxycinnamoyl)-
4-(Hexylaminocarbonylmethyl)piperazine 6.60 g of 1-(hexylaminocarbonylmethyl)piperazine obtained in Reference Example 6 chloroform h9omlRJ
11.20 g of 3,4.5-)Plum 1-xycinnamic acid chloride was added to the liquid 1 while stirring under water cooling, and the mixture was stirred at room temperature for 30 minutes. After the reaction, the mixture is made alkaline with an aqueous sodium hydroxide solution and extracted with chloroform. The chloroform layer was washed with water and dehydrated.

The solvent was distilled off, and a small amount of isopropyl ether was added to the resulting residue to obtain 789 g of precipitated crystals.

Recrystallized from ethyl acetate, melting point 115-11
Colorless scaly crystals of 7° are obtained.

IR spectrum ν(KEr) cm ]: \3400(NH), 1660(-0ON")/
＼ Elemental analysis value 024H37N305 Theoretical value 0.64.41, H, 8,33iN, 9.
39 Experimental value a, 64.25; H, 8,45;
N, 9.32 Reference Example 7 1-(cyclohexylamine 7carponylmethyl)piperazine Piperazine 9.62 g K, triethylamine 11
30g and N-cyclohexyl-2-chloroace1-
Add a solution of 982 g of amide in 70 ygl of benzene, 1.
Heat to reflux for 5 hours. Hereafter, the same process as in Reference Example 1 was carried out,
5.30 g of pale brown crystals are obtained.

Recrystallized from ethyl acetate, melting point 110-11
Light brown needles of 1° are obtained.

Engineering R spectrum 11 (KBr) cm l :3
350.3230 (NH), 1/+40 (-aoN')
/ \Example 7 l-(3,4,5-)rimetquin cinnamoyl)-4-
(Cyclohexylaminocarbonylmethyl)piperazine 3.37 g of 1-(cyclohexylaminocarbonylmethyl)piperazine obtained in Reference Example 7 in 60 ml of chloroform
4.62 g of 6,4°5-trimethoxycinnamic acid chloride was added to the solution while stirring under water cooling, and the mixture was stirred at room temperature for 10 minutes. After the reaction, the mixture is made alkaline with an aqueous solution of sodium hydroxide and extracted with chloroform. The chloroform layer was washed with water and dehydrated. The solvent was distilled off, and a small amount of a mixed solution of ethanol and ether was added to the resulting residue to obtain 510 g of precipitated crystals. Recrystallized from ethyl acetate, melting point 141-142
386 g of colorless scaly crystals are obtained.

IR spectrum v (KBr) cyrr-]: 3
400(≧NI(), 1660.1650(-0ON'
)\ Elemental analysis value 024H35N305 Theory ti C964,70; N+7.92; N+9.
43 experiments ti a, 64.65:H, 7, 9B, N,
9.40 The nuclear magnetic resonance spectrum data of the compounds obtained in Reference Examples 1 to 7 are shown in Table 1, and the nuclear magnetic resonance spectrum data of the compounds obtained in Examples 1 to 7 are shown in Table 1.
Original document (method) September 2, 1980 Director-General of the Patent Office Kazuo Wakasugi 1 Indication of case 1981 Patent Application No. 77569 2
Title of the invention 1-(3,4,5-) IJ methoxycinnamoyl-aminocarbonylmethyl-substituted bi<lacine derivative 6 Relationship with the amended party case Patent Applicant

Claims (1)

[Scope of Claims] 1 represented by the general formula (wherein R represents a linear or branched alkyl group having 4 to 6 carbon atoms, or a cycloalkyl group having 5 to 7 carbon atoms) -1,4,5-trimethoxycinnamoyl)-4-aminocarbonylmethyl-substituted piperazine derivatives, and pharmacologically acceptable tric acid addition salts thereof.