JPS61106564A - Unsaturated fatty acid amide derivative and inhibitor of blood platelet aggregation containing same - Google Patents

Abstract

NEW MATERIAL:An unsaturated fatty acid amide derivative shown by the formula I [R<1> is H, or methyl; R<2> is H, or methyl, and when R<1> is H, R<2> is also H; m is number of double bonds in trans configuration, 1 or 2; Y is group shown by the formula II (n is 2, 4, or 4; X is acyl derived from either triene higher fatty acid or pentaene higher fatty acid), or group shown by the formula III]. E X A M P L E : 1 - [ N - [ 3 - ( 3 - Methoxy-4-hydroxy)phenyl]-2-propenoyl]-beta-aminoethyl]-4-(5,8,11,14,1 7-eicosapentaenoyl)piperazine. USE:An inhibitor of blood platelet aggregation. PREPARATION:For example, a carboxylic acid derivative shown by the formula IV (R<1> is methyl, or methoxyethoxymethyl; R<2> is R<1>) or a reactive derivative shown by the formula V is subjected to a condensation reaction and a protecting group removing reaction, to give a compound shown by the formula I.

Description

Detailed Description of the Invention 10. Background Technical Field of the Invention The present invention relates to a novel unsaturated fatty acid amide derivative and a platelet aggregation inhibitor containing the same. The unsaturated fatty acid amide derivative provided by the present invention is a new compound and has a strong platelet aggregation inhibiting effect. Therefore, it is effective in preventing diseases caused by platelet aggregation, such as thrombosis. Furthermore, it is known that platelet aggregation is also involved in cancer metastasis, and the compounds of the present invention also have a preventive effect on cancer metastasis.

Prior art α-linolenic acid, which is a triene higher fatty acid, is an essential fatty acid, and r-17 phosphoric acid is an essential fatty acid.
It is known that it is converted in vivo to dihomo-γ-linolenic acid, which is a precursor of 1), and each is an important compound.

For pentaene higher fatty acids, 5, 8, 11, 14
．． It has been reported that 17-eicosapentaenoic acid is contained in large amounts in fish oil and has the effect of lowering low-density lipoprotein (LDL). Thrombosis such as myocardial infarction and cerebral hemorrhagic stroke has recently come to occupy a large proportion of adult diseases, and there is a strong desire for a drug to effectively prevent this.

■0 Purpose of the Invention The present inventors synthesized various unsaturated fatty acid amide derivatives,
As a result of intensive research into their pharmacological activities, it was discovered that the unsaturated fatty acid amide derivative according to the present invention has an excellent platelet aggregation inhibiting effect, leading to the completion of the present invention.

An object of the present invention is to provide a novel unsaturated fatty acid amide derivative and a platelet aggregation inhibitor containing the same. The unsaturated fatty acid amide derivative according to the present invention has a strong platelet aggregation inhibiting effect and is useful as a preventive agent for diseases caused by platelet aggregation, such as thrombosis and cancer metastasis.

The object of the present invention is achieved by the configuration shown below. That is, the present invention relates to the general formula (I) [wherein R1 is a hydrogen atom or a methyl group, and R2
represents a hydrogen atom or a methyl group. However, when R1 is a hydrogen atom, R2 is also a hydrogen atom. m represents the number of double bonds in the trans configuration, and is an integer of 1 or 2. Y is a group represented by the general formula (If) (where n is 2, 3 or 4, and x represents an acyl group derived from either a triene higher fatty acid or a pentaene higher fatty acid) and a general formula (
III)::, (EI=t=・8°1゛'"71A
Wk lll l1iFF @ > j: U 4 y
/indicates an acyl group derived from any of the di-higher fatty acids)) represents an unsaturated fatty acid amide derivative represented by the following. The present invention also provides compounds of the general formula (I) [wherein R1 represents a hydrogen atom or a methyl group, and R2
represents a hydrogen atom or methyl. However, when R1 is a hydrogen atom, R2 is also a hydrogen atom. m represents the number of double bonds in the trans configuration, and is an integer of 1 or 2. Y is a group represented by the general formula (II) (wherein n is 2, 3 or 4, and X represents an acyl group derived from either a triene higher fatty acid or a pentaene higher fatty acid) and a general Contains an unsaturated fatty acid amide derivative represented by the formula (III) (wherein X represents an acyl group derived from either a triene higher fatty acid or a pentaene higher fatty acid) It is a platelet aggregation inhibitor.

The triene higher fatty acids include 9, 12, 15-
Octadecatrienoic acid (α-linolenic WIL) or 6.9.12-octadecatrienoic acid (γ-linolenic acid) is preferable, and the pentaene higher fatty acid is 5
．． 8.11.14,17-eicosapentaenoic acid is preferred.

In the present invention, the term "platelet aggregation inhibitor" means a preparation that has the effect of inhibiting platelet aggregation.

(6) Detailed Description of the Invention The unsaturated fatty acid amide derivative of the present invention is, for example, a caldic acid derivative represented by the following formula (F/) as shown in the following examples.

(In the formula, 11 represents a methyl group or a methoxyethoxymethyl group, and R2 represents a methyl group or a methoxyethoxymethyl group. However, when R1 is a methoxyethoxymethyl group, R is also a methoxyethoxymethyl group. m is trans represents the number of double bonds in the configuration and is an integer of 1 or 2) or, for example, its reactive derivative (V) (wherein the definitions of R', R2, m are the same as the definitions of formula (■) It can be obtained by carrying out a condensation reaction and a deprotection reaction on

The unsaturated fatty acid amide derivative of the present invention can be used as an active ingredient or one of the active ingredients of a platelet aggregation inhibitor,
It works effectively for diseases caused by platelet aggregation, but
It is especially used as an anti-hematopoietic agent or an agent for preventing cancer metastasis.
The dosage varies depending on the symptoms, but in general, the daily dose for adults is about 50~
It is 1,500 Da, and should be administered in 1 to 3 doses if necessary.

The method of administration can take any form suitable for administration;
Oral administration is particularly desirable, but intravenous injection is also possible.

The compound of the present invention may be formulated into tablets, powders, capsules, or granules either alone or mixed with pharmaceutical carriers or excipients in a conventional manner. Examples of carriers or excipients include calcium carbonate, calcium phosphate, starch, sucrose, lactose, Merck, magnesium stearate, and the like. In addition to the above-mentioned solid formulations, the compounds of the present invention can also be used in oily suspensions,
Shiro.

It can also be made into a liquid formulation such as a liquid.

The compound of the present invention can also be stabilized by inclusion with cyclodextrin.

EXAMPLES Next, the present invention will be explained in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.

Example 1 1-(N-7thalyl-β-aminoethyl)-4-ethoxycar-nylpiperazine 4.45N under argon atmosphere
was dissolved in ethanol 5Qd, 1.68 g of 80 thihydrazine hydrate aqueous solution was added, and the mixture was heated under reflux for 3.5 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and dry N,N-dimethylformamide 2011/ was added to the obtained residue. Add N-[3-[3-methoxy-4-(β-
methoxyethoxymethoxy)phenyl]furopenoyl]
Thiazolidine-2-thione 5.36. Drying of pN,N-
Add dimethylformamide solution (201t) and add 4.5
The reaction was carried out at 90°C for a period of time. The reaction solution was concentrated under reduced pressure, and a 0.7N aqueous solution of IJ (hydroxide) was added to the resulting residue, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue 6.
, Oll was subjected to silica gel column chromatography, and the fraction eluted with chloroform/methanol (SO:1) was extracted with 1-(N-(3-(3-methoxy-4-(β-methoxyethoxymethoxy)phenyl)furopenoyl). ]−β−
Aminoethyl]-4-ethoxycar-nylpiperazine 4
．． I got 4011.

Under an argon atmosphere, the amide compound 4.40.9 was mixed with methanol/water (2:1) 45114! 10.58.9% of potassium hydroxide was added, and the mixture was heated under reflux for 22 hours.

Water was added to the reaction solution, and methanol/chloroform (1:9
) Extraction was performed with a mixed solvent. The organic layer is treated with anhydrous sulfuric acid)
After drying with IJum, it was concentrated under reduced pressure to give 1-(N-['3-
2.90 g of [3-methoxy-4-(β-methoxyethoxymethoxy)phenyl]-2-propenoyl]-β-aminoethyltwopiperazine was obtained.

Under an argon atmosphere, the piperazine compound 1.50.5+
in dry tetrahydrofuran (15 m) was added N-(5
A solution of 1.54 g of thiazolidine-2-thione (8,11,14,17-nicosapentaenoyl) in dry tetrahydrofuran (15 m) was added, and the mixture was reacted for 2 hours.

IN aqueous lithium hydroxide solution was added to the reaction solution, and extraction was performed with chloroform. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the resulting residue 2.3I was subjected to silica gel column chromatography, and the fraction eluted with chloroform/methanol (50:1) was purified. 3-
(3-Methoxy-4-(β-methoxyethoxymethoxy)phenyl2-ptetrapenoyl]-°β-aminoethyl)-4-(5,8,11,14,17-nicosabentaenoyl)piperazine 1.98g was obtained.

Under an argon atmosphere, 111 da of p-)luenesulfonic acid aqueous was added to a solution of 199 da of the amide compound in methanol (IQ-) and heated under reflux for 2 hours. The reaction solution was adjusted to -10 with a saturated aqueous solution of carbonic acid, and then extracted with chloroform.

The organic layer was dried over anhydrous sulfuric acid (IJ) and concentrated under reduced pressure. The resulting residue (141cm) was subjected to Sephadex column chromatography, and the methanol eluted fraction was separated into 1-(
N-(3-(3-methoxy-4-hydroxy)phenyl)-2-fropenoyl]-β-aminoethyl)-4
-(5,8,11,14,17-eicosapentaenoyl)piperazine 107 ml was obtained. However, spectroscopic data support the structure of formula (M) below.

IRj/””yn-’: 3300, 1625 s
1520llX'H-NMR (deuterated chloroform) δ: 0.93
(3H, t, J = 7Hz).

22m 3.78 (3H, s), 5.00-5.63 (IOH)
, 6.20 (IH.

d, J = 16 Hz), 7.45 (IH, d, J = 16
Hz) Example 2 Under an argon atmosphere, N-3-(3-methoxy-4-(β□(f
-i) Yatse, guy 2. 78=Yap. A solution of inoylthiazolidine-2-thione z, ool dissolved in 20 m of tetrahydro7ran was added dropwise at room temperature over 30 minutes. After reacting for an additional 40 minutes at room temperature, the reaction mixture was acidified with 2N hydrochloric acid and washed three times with a mixed solvent of ethyl ether and dichloromethane (3:1). The aqueous layer was diluted to about 11 with a 2N hydroxide solution, extracted with chloroform three times, and washed with water. After drying the extracted organic layer with anhydrous sulfuric acid (+7 um), the solvent was distilled off under reduced pressure and the extraction residue 2.
090 Ii was obtained. The residue was subjected to silica column chromatography, and the fraction eluted with chloroform/methanol (95:5) was purified to give 1-[:3-[3-methoxy-4-(
1.683 g of β-methoxyethoxymethoxy)phenylflopenoylpiperazine was obtained.

N-(9,1
2,15-octadecatrienoyl)thiazolidine-2
A solution of -thione 2'12 da dissolved in tetrahydro 7:7 4- was added and reacted overnight at room temperature. To the reaction mixture was added a 7 um aqueous solution of 1N hydroxide, extracted three times with dichloromethane, and washed with water.

The extracted organic layer was dried over 13 ml of anhydrous sulfuric acid, and the solvent was distilled off under reduced pressure to obtain an extracted residue of 391 ml. The residue was subjected to silica gel column chromatography, and the fraction eluted with chloroform/methanol (98:2) was filtered.
Methoxy-4-(β-methoxyethoxymethoxy)phenyl]penoyl]-4-(9,12,15-octadecatrienoyl)piperazine 264η was obtained.

Under an argon atmosphere, 2441 ng of the compound and 15 ml of paratoluenesulfonic acid hydrate were dissolved in 5 d of methanol and reacted under heating under reflux for 2 hours and 30 minutes.

After cooling, saturated aqueous sodium hydrogen carbonate solution was added, extracted three times with chloroform, and washed with water. The extracted organic layer is treated with anhydrous sulfuric acid)
After drying with IJum, the solvent was distilled off under reduced pressure and the extraction residue 212
mg was obtained. The residue was subjected to silica gel column chromatography, and the fraction eluted with chloroform/methanol (97:3) was eluted with 1-(3-(3-methoxy-4-human tetraxyphenyl)furopenoyl)-4-(9 ,12,15
-octadecatrienoyl)piperazine 191 das were obtained. Spectroscopic data of this product support the structure of the following formula (■).

IRj/"aL (m-'): 1650,1595ax 'H-NMR (deuterated chloroform) δ (ppm):
0.93 (3H,t, J=7.5Hz), 3.87 (
3H, s), 5.17-5.43 (61).

6.60 (IH, d, J = 14Hz), 7.57 (IH
, d, J=14Hz) Example 3 Under an argon atmosphere, 1-(3-(3-methoxy-4-(
To a solution of 350 d of β-methoxyethoxymethoxy)phenyl]propenoyl]piperazine dissolved in 7 d of tetrahydro, 371 μ of N-(6,9,12-octadecatrienoyl)thiazolidine-2-thione was added 5 d of tetrahydro 72 A solution dissolved in rnl was added and reacted at room temperature for 1 hour and 30 minutes.

A 1N aqueous sodium hydroxide solution was added to the reaction mixture, extracted with dichloromethane three times, and washed with water. After drying the extracted organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 666 cm of extracted residue. The residue was subjected to silica gel column chromatography, and the fraction eluted with chloroform/methanol (98:2) was extracted with 1-C3-C3-methoxy-4-(β-methoxyethoxymethoxy)phenyl]propenoyl)-4-(6
,9,12-octadecatrienoyl)piperazine 39
I got 1 da.

Under an argon atmosphere, the compound 361 was beaten and paratofitZ
Aqueous solution of sulfonic acid 19rn9 was dissolved in 8d of methanol and reacted under heating under reflux for 1 hour and 20 minutes.

After drying over sodium sulfate, the solvent was distilled off under reduced pressure to obtain an extraction residue 3111n9. The residue was subjected to silica dull column chromatography, and chloroform/methanol (97%
3) 1-(3-(3-methoxy-4-hydroxyphenyl)propenoyl)-
4-(6,9,12 octadecatrienoyl) Vihera'
)7259# was obtained. Spectroscopic data of this product support the structure of the following formula (■).

IRy""(z-'): 1645, 1590ax 'H-NMR (deuterochloroform) δ (ppm):
3.92 (3H, fi), 5.23-5.50
(6H), 6.63(IH, d, J=14I(z), 7
．． 63 (IH, d, J = 14 Hz) Example 4 Under argon atmosphere, 1-(3-[3-methoyasi-4-(
β-methoxyethoxymethoxy)phenyl]propenoyl]piperazine 1941n9 in tetrahydro7ran 5d
N-(5,8,11゜14,1
A solution of 225 das of 7-nicosapentaenoyl)thiazolidine-2-thione dissolved in 5 d of tetrahydro7ran was added and reacted at room temperature for 40 minutes. Add 1N lithium hydroxide aqueous solution to the reaction mixture.

The extract was extracted three times with dichloromethane and washed with water. After drying the extracted organic layer over anhydrous sulfuric acid (IJ), the solvent was distilled off under reduced pressure to obtain an extracted residue of 396 ml. The residue was subjected to silica gel column chromatography using chloroform/methanol (98%
2) Elution fraction, 9l-(3-[3-methoxy-4-
(β-methoxyethoxymethoxy)phenyl]propenoyl)-4-(5,8°11.14.17-nicosapentaenoyl)piperazine 27911t9 was obtained.

Under an argon atmosphere, the compound 245■ and para-toluenesulfonic acid hydrate x41n9 were extracted three times with methanol 5d loloform and washed with water. The extracted organic layer was diluted with anhydrous sulfuric acid)
After drying over Jumbo, the solvent was distilled off under reduced pressure to obtain 225 cm of extraction residue. The residue was subjected to silica gel column chromatography, and the fraction eluted with chloroform/methanol (97:3) was purified to 1-[:3-, (3-methoxy-4-hydroxyphenyl)propenoyl] -4-(5,8 ,11,1
4,17-di; sapentaenoyl) piperazine 200
I got 1R9. The spectroscopic data of this substance is expressed by the following formula (■
) supports the structure.

, jRν""(a+s-'): 1640.1585
ax'H-NMR (deuterochloroform) δ (ppm): 0
．． 95 (3H, t, J=7Hz), 3.87 (3
H,s), 5.13-5.50 (IOH).

6.60 (IH, d, J=14Hz), 7.60 (IH
, d, J=14Hz) Example 5 In an argane atmosphere, 1-(N-7thalyl-β-aminoethyl)-4-ethoxyca/L/? Nilpiperazine 623
130 ml of an aqueous solution of 80 thihydrazine hydrate was added to the ethanol solution (15, d) of 1, and the mixture was heated under reflux for 3 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and 6d of dry N,N-dimethylformamide was added to the resulting residue. To this solution was added a dry N,N-dimethylformamide solution (6d) of N-[:3-[3,4-di(β-methoxyethoxymethoxy)7enyl]propenoyl-thiazolidine-2-thione 865Tv; The reaction was allowed to proceed for 15 hours. The reaction solution was concentrated under reduced pressure, and IN aqueous sodium hydroxide solution was added to the resulting residue, followed by extraction with chloroform.

The organic layer was dried with anhydrous sulfuric acid) and concentrated under reduced pressure. The resulting residue 1.29.9 was subjected to silica dull column chromatography, and the 2% methanol-chloroform elution fraction was separated into 1-CN. -C3-C3,4-di(β-methoxyethoxymethoxy)phenyl]deo he/(ru)-β-aminoethyl-4-ethoxymethanol solution 1
1.7 g of potassium hydroxide in methanol/water (2:
1) Added 20 g of solution and heated under reflux for 50 hours. Water was added to the reaction solution, and extraction was performed with a 1:9 mixed solvent of methanol and chloroform. The organic layer was dried with anhydrous sulfuric acid), concentrated under reduced pressure, and the resulting residue 6081n9 was subjected to Sephadex column chromatography.
Methanol solution' 1lie! , D, 1-CN-(3-
(:3.4-,- (/-j )-+7ethoxymethoxy)phenyl]furopenoyl]-β-7minoethyl]-
460 m9 of piperazine were obtained.

Under an argon atmosphere, N-(5,8,1
A dry tetrahydrofuran solution (411 liters) of 1,14,17-nicosapentaenoyl)thiazolidine-2-thione 4231R9 was added and reacted for 48 hours. To the reaction solution was added an aqueous solution of N lithium hydroxide.

1.05 g of the residue was subjected to silica dull column chromatography, and the fraction eluted with methanol/chloroform (2:98) was purified to obtain 1-CN-(3-[:3,4-di(β-methoxyethoxymethoxy)phenyl]). Propenoyl]-
β-aminoethyl) -4-(5,8,11,14゜1
600 μl of 7-nicosapentaenoyl)piperazine were obtained.

Under an argon atmosphere, □Cough amide compound 444■ Methanol 11? [Add 119 μl of p-)luenesulfonic acid hydrate to (81ff7) and heat under reflux for 2.5 hours.
I got it. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and extraction was performed with chloroform. The organic layer was dried over 17 km of anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was subjected to silica dull column chromatography.
Chloroform (5:95)! The output fraction is 1-(N
-[a-(3,4-dihydroxyphenyl)flopenoyl]-β-7minoethyl]-4-(5,8,11,14
, 17-A; sapentaenoyl) piperazine 2501
I got 19. The spectroscopic data of this is the following formula (X)
supports the structure of

IRνKBr, m-': 3240.1650.160
0ax'H-NMR [deuterated chloroform/deuterated methanol (9:1
)) δppm 20, 97 (31'1.t, J=7Hz
), 5.05-5.70 (IOH).

6.23 (1) i, a, J = 16 Hz), 7.42 (1
1, a, J = $6 Hz) Example 6 Under an argon atmosphere, piperazine 1.3251 was dissolved in water 15-
N-5-[3-methoxy-4-(β-methoxyethoxymethoxy)phenyl)-2,4-pentagenoylthiazolidine-2-thione 7001R9 was dissolved in a mixed solvent of 151 liters of tetrahydrofuran. A solution dissolved in 1Qil was added dropwise at room temperature over 15 minutes. After reacting for an additional 20 minutes at room temperature, the reaction mixture was acidified with 2N hydrochloric acid and washed three times with a mixed solvent of ethyl ether and dichloromethane (3:1) f1. An aqueous layer was obtained with 2N hydroxide. # The residue was subjected to silica glu column chromatography, and the fraction eluted with chloroform/methanol (9m)
(β-methoxyethoxymethoxy)phenyl) 2.4
-Pentagenoylcopiperazine 564rv was obtained.

Under an argon atmosphere, N-(5,8,
11,14,17-nicosape/taenoyl)thiacyridin-2-thione 275tn9 in tetrahydrofuran 3
A solution of water was added to the mixture, and the mixture was allowed to react overnight at room temperature. A 1N aqueous lithium hydroxide solution was added to the reaction mixture, extracted three times with dichloromethane, and washed with water.

The extracted organic layer was dried over anhydrous sulfuric acid (IJ) and the solvent was distilled off under reduced pressure to obtain an extracted residue of 464 cm. The residue was subjected to silica gel column coomadography, and the eluted fraction was chloroform/methanol/I/(98:2).
5,8,11,14,17-Nicosapentaenoi,-
) Piperazine 3659 was obtained.

Under an argon atmosphere, the compound 330cm and paratoluenesulfonic acid hydrate 19cm were dissolved in methanol 6d and reacted under heating under reflux for 2 hours and 50 minutes.

After cooling, add saturated hydrogen carbonate) +3 um aqueous solution,
, extracted with chloroform three times and washed with water. The extracted organic layer was dried over +7 um of anhydrous sulfuric acid, and the solvent was distilled off under reduced pressure to obtain an extraction residue of 311 cm.The residue was subjected to silica dull column chromatography and chloroform/methanol (97:3). The elution fraction is 1-[5-(3-
methoxy-4-hydroxyphenyl)-2,4-pentagenoyl)-4-(5,8,11,14,17-
Niicosapentaenoyl)piperazine 239■ was obtained.

Spectroscopic data of this product support the structure of formula (XI) below.

IRy""(m-'):1640s1585ax' H=NMR (heavy/a o phor A) a (p
pm): 0.95 (3H*t, J==
7Hz), 3.88 (3H, @), 5.18~
5.50 (IOH).

6.32 (IH, d, J-14Hz) Example 7 1-(N-7thalyl-δ-aminobutyl)-4-dithocycargonylbipe2 under argon atmosphere.

diy650rn9(1)xfi/-le solution (15m)
Add 130 da of 80 thihydrazine hydrate aqueous solution to
The mixture was heated under reflux for 3 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and 6" ynt of dry N,N-dimethylformamide was added to the resulting residue. To this solution was added N-[5-[3-methoxy-4-(β-methoxy) ethoxymethoxy)phenyl)-2,4-pentagenoylcorchiazolidine-2
A dry solution of -thione 7574 in N,N-dimethylformamide (51I7) was added and reacted for 15 hours. The reaction solution was concentrated under reduced pressure, and an aqueous solution of IN hydroxide was added to the resulting residue, and chlorine 1,5! i was subjected to silica gel column chromatography, and the fraction eluted with methanol/chloroform (2:98) was extracted with 1-(N-(5-(3-methoxy-4-(β-methoxyethoxymethoxy)phenyl))-2 , 4-Hentadienoyl]-δ-aminobutyl-4-ethoxyl was obtained as Nilpiperazine 652rn9.

Under an argon atmosphere, 20 mJ of a methanol/water (2:1) solution of potassium hydroxide 1.7.9 was added to a methanol solution 101 of the amide compound 635, and the mixture was heated under reflux for 5°. Water was added to the reaction solution, and extraction was performed with 10-thimethanol/couloform. The organic layer is treated with anhydrous sulfuric acid) +7
The resulting residue (572 cm) was subjected to Sephadex column chromatography, and from the methanol elution fraction, 1-CM-C5-C3-methoxy-
4-(β-methoxyethoxymethoxy)phenyl]-2
,4-pentazoenoyl]-δ-aminobutyl]-piperazine 4361! Ig was obtained.

Under an argon atmosphere, the piperazine compound 430-2-
Thione 38011v dry tetrahydrofuran solution (4
d) was added and reacted for 48 hours. IN aqueous lithium hydroxide solution was added to the reaction solution, and extraction was performed with chloroform. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the resulting residue (898 cm) was subjected to silica gel column chromatography and mixed with methanol/chloroform (2:9B
) elution fraction, 1-(N-(5-(3-methoxy-4
-(β-methoxyethoxymethoxy)phenyltwo2.
4-Pentadienoyl]-δ-aminobutyl]-4-(
564 ml of 9,12,15-octadecatrienoyl)piperazine was obtained.

Under an argon atmosphere, 145 µm of p-)luenesulfonic acid hydrate was added to 546 µm of the amide compound (8!111) in methanol, and the mixture was heated under reflux for 2.5 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, and extraction was performed with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was subjected to silica column chromatography. -Methoxy-
・4-hydroxyphenyl)-2,4-pentagenoyl-δ-aminobutyl] -4+-(9,12,15
-Octadecatrie, Noyl) Piperazine 3351
I got n9. Spectroscopic data of this product support the structure of the following formula (X[[).

Engineering R, KBr cm-': 1645, 1590a
x (XI[) Example 8 A solution of piperazine 1.32.9' in water and te2-thione 80011v in tetohydride a7 run solution (1
0 m) was added dropwise over 45 minutes and reacted for 17 hours. IN aqueous sodium hydroxide solution was added to the reaction solution, and extraction was performed with chloroform. The organic layer was dried with anhydrous sulfuric acid, and concentrated under reduced pressure. The resulting residue (900 μm) was subjected to silica gel column chromatography, and the fractions eluted with methanol and chloroform (4:96 to 1:9) were separated. 1-C
3(3,4-di(β-methoxyethoxymethoxy)phenyl)-2,4-hentadienoyl]-piperazine 4671f - was obtained.

Under an argon atmosphere, a solution of the amide compound 404■ in dry tetrahydrofuran 41111 was added with N-(6,9,12
-Octadecatrienoyl) thiazolidine-2-thione 341# dry tetrahydro 7 run solution 3- is added, 1
The reaction was allowed to proceed for 3 hours. IN aqueous sodium hydroxide solution was added to the reaction solution, and extraction was performed with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue 820# was subjected to silica gel column chromatography to obtain 1thimephenyl]-2,4-pentagenoyl) -
630 μ of 4-(6°9.12-octadecatrienoyl)piperazine was obtained.

Under an argon atmosphere, 630 da of the amide compound dissolved in methanol (161,111 JCp-) 37 da of luenesulfone water was added, and the mixture was heated under reflux for 6.5 hours.

A saturated aqueous solution of hydrogen carbonate (IJ) was added to the reaction solution, and extraction was performed with chloroform. The organic layer is treated with anhydrous sulfuric acid)
After drying in a U ram, the residue obtained by concentration under reduced pressure was 5511v.
was subjected to silica gel column chromatography, and the fractions extracted from methanol/chloroform (2:98) were separated.
(5-(3,4-dihydroxyphenyl)-2,4-pentagenoyl)-4-(6,9,12-octadecatrienoyl)piperazine 360W was obtained.

Spectroscopic data of this product support the structure of the following formula (XI[[).

KBr-1゜IRI/an, 3230.1630.162
0ax 'H-NMR (heavy methanol) δ' 0.70-1
．． 06 (311), 3.40~ppm" 3.90 (8H= br, s) t 5°00~
5.68 (6H), 6.43 (IH, d, J=
15Hz) Example 9 Under an argon atmosphere, 450 da of 1-[5-C3,4-di(β-methoxyethoxymethoxy)7el)-2,4-pentadienoylbiperanone was mixed with tetrahydro7 ly
l Q d ) f Knee-dissolved Shita solution K N -(5,8
, 11,14゜l7-nicosapentaenoyl)thiazolidine-2-thione 405■ in tetrahydro7 run 10
A solution of water was added to the mixture, and the mixture was allowed to react at room temperature for 2 hours and 30 minutes. A 1N aqueous lithium hydroxide solution was added to the reaction mixture, extracted three times with dichloromethane, and washed with water. After drying the extracted organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain an extracted residue of 750 cm. The residue was subjected to silica gel column chromatography to obtain 692WIg of chloro(5,8,11,14,17-nicosapentaenoyl)piperazine.

Under a blouson atmosphere, the compound 5101! Ig and paratoluenesulfonic acid hydrate 25119 in methanol 15,
ml and reacted under heating and reflux for 2 hours and 50 minutes.

;: After cooling, a saturated aqueous sodium bicarbonate solution was added, extracted three times with chloroform, and washed with water. After drying the extracted organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain an extraction residue 4.
I got 51■. The residue was subjected to silica gel column chromatography using chloroform/methanol (97:3).
The eluted fraction was 1-C3-(3,4-dihydroquiphenyl)-2,4-pentagenoyl)-4-(5,8,
11,14,17-nicosapentaenoyl)piperazine 40111Ig was obtained. Spectroscopic data of this product support the structure of formula (XIV) below.

eat IRv(3-'): 1630, 1590ax Experimental example Platelet aggregation inhibitory effect Nine volumes of blood were collected from the rabbit carotid artery using a syringe containing 3.8% sodium citrate solution (1 volume). The blood is centrifuged to obtain platelet-rich blood.

Obtain plasma (PRP: 5 x 10' cells/μl).

250 μj of the PRP was placed in a medium 2 bed, heated for 2 minutes in a 37°C constant temperature bath, 20 μj of an aqueous solution containing tS ethanol of the unsaturated fatty acid amide derivative to be tested was added, and incubated for 3 minutes, followed by a solution of arachidonic acid, which is an aggregation inducing agent. Alternatively, add Kotugun solution to check platelet aggregation (B
orn) turbidimetry [for example, Journal Otsu Physiol (J, Physiol, Vol. 168, No. 17]
8, published in 1968)]. Arachidonic acid (70μM), = Rahn (10μμ)
We found a significant anti-platelet aggregation activity in preventing platelet aggregation caused by. Furthermore, it was confirmed that unsaturated fatty acid amide derivatives according to the present invention not shown in Table 1 also have similar anti-platelet aggregation activity. In addition, the 50% inhibitory concentration in the table refers to the aggregation of platelets due to the introduction of the unsaturated fatty acid amide derivative according to the present invention, assuming that the platelet aggregation ability without introducing the unsaturated fatty acid amide derivative according to the present invention is 100. It means the concentration of unsaturated fatty acid amide derivative solution required to suppress the activity by 50%.

Acute Toxicity An acute toxicity test was conducted by oral administration using ICR male mice (5 weeks old). All of the compounds of the present invention have a LD5o value of 300 m9A9 or higher, providing a high LD5o value and a platelet aggregation inhibitor containing the same.

The above-mentioned compounds of the present invention significantly inhibit platelet aggregation induced by arachidonic rim or collagen, and therefore are associated with diseases caused by platelet aggregation, particularly myocardial infarction, ischemic attack after cerebral hemorrhage, cerebral infarction, etc. It can be used as a prophylactic agent for thrombosis. Furthermore, since platelet aggregation is involved in cancer metastasis, the above compounds of the present invention can also be used as agents for preventing cancer metastasis.

Claims (6)

[Claims] (1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R^1 represents a hydrogen atom or a methyl group, and R
^2 represents a hydrogen atom or a methyl group. However, when R^1 is a hydrogen atom, R^2 is also a hydrogen atom. m represents the number of double bonds in the trans configuration, and is an integer of 1 or 2. Y is general formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) (In the formula, n is 2, 3 or 4, and X is derived from either triene higher fatty acid or pentaene higher fatty acid acyl group) and general formula (III) ▲Mathematical formulas, chemical formulas, tables, etc.▼(III) (wherein, X is an acyl group derived from either triene higher fatty acid or pentaene higher fatty acid An unsaturated fatty acid amide derivative represented by a group selected from the groups represented by (2) The acyl group derived from triene higher fatty acid is α
- The unsaturated fatty acid amide derivative according to claim 1, which is an acyl group derived from linolenic acid or γ-linolenic acid. (3) The unsaturated fatty acid amide derivative according to claim 1, wherein the acyl group derived from pentaene higher fatty acid is an acyl group derived from eicosapentaenoic acid. (4) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R^1 represents a hydrogen atom or a methyl group, and R
^2 represents a hydrogen atom or a methyl group. However, when R^1 is a hydrogen atom, R^2 is also a hydrogen atom. m represents the number of double bonds in the trans configuration, and is an integer of 1 or 2. Y is general formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) (In the formula, n is 2, 3 or 4, and X is derived from either triene higher fatty acid or pentaene higher fatty acid acyl group) and general formula (III) ▲Mathematical formulas, chemical formulas, tables, etc.▼(III) (wherein, X is an acyl group derived from either triene higher fatty acid or pentaene higher fatty acid A platelet aggregation inhibitor containing an unsaturated fatty acid amide derivative represented by: (5) The acyl group derived from triene higher fatty acid is α
- The platelet aggregation inhibitor according to claim 4, which is an acyl group derived from linolenic acid or γ-linolenic acid. (6) The platelet aggregation inhibitor according to claim 4, wherein the acyl group derived from pentaene higher fatty acid is an acyl group derived from eicosapentaenoic acid.