JPS60197642A - Ethanolamine derivative and inhibitor of blood platelet aggregation containing it as active ingredient - Google Patents

Abstract

NEW MATERIAL:An ethanolamine shown by the formula I (R<1> and R<2> are H, or acyl derived from nicotinic acid, triene higher fatty acid, or pentaenoic acid). EXAMPLE:N-5,8,11,14,17-Eicosapentaenoyl-2-aminoethanol. USE:An inhibitor of blood platelet aggregation. Having strong inhibitory action on blood platelet aggregation, useful as a preventive for thrombosis such as especially myocardial infarction, cerebral infarct, etc. and also as a preventive for cancer metastasis. PREPARATION:For example, nicotinic acid, a triene higher fatty acid, or a pentaene higher fatty acid or its reactive derivative is condensed with ethanolamine in a solvent such as tetrahydrofuran, etc. in an argon atmosphere in the presence of a condensation agent such as ethyl chloroformate, etc. to give a compound shown by the formula I .

Description

[Detailed description of the invention]! BACKGROUND OF THE INVENTION TECHNICAL FIELD The present invention relates to a novel ethanolamine derivative and a platelet aggregation inhibitor containing the same as an active ingredient. The ethanolamine 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 It is known that α-lylunic acid, a triene higher fatty acid, is an essential fatty acid, and that r-lylunic acid is converted in vivo to dihomo-r-lylunic acid, which is a precursor of glosstaglandin Es. Each of these is an important compound. For pentaene higher fatty acids, 5, 8.11, 14.17
- It has been reported that nicosabentaenoic acid is contained in large amounts in fish oil and has the effect of lowering low-density riboprotein (LDL). Thrombosis, such as myocardial infarction and cerebral thrombosis, has recently come to account for a large proportion of adult diseases, and there is a strong desire for a drug to effectively prevent this.

As a result of synthesizing various ethanolamine derivatives and intensively researching their pharmacological activities, the present inventors discovered that they have an excellent platelet aggregation inhibiting effect, leading to the completion of the present invention. 〇 ■ Purpose of the Invention The present invention An object of the present invention is to provide a novel ethanolamine derivative and a platelet aggregation inhibitor containing the same as an active ingredient. That is, it is useful as a preventive agent for thrombosis, cancer metastasis, etc. The object of the present invention is achieved by the configuration shown below. That is, the present invention is based on the general formula (1) % formula % (1) (wherein R1 represents a hydrogen atom or R1 represents an acyl group derived from either nicotinic acid, triene higher fatty acid, or pentaene higher fatty acid Hs represents a hydrogen atom, or R2 represents an acyl group derived from either nicotinic acid, triene higher fatty acid or pentaene higher fatty acid). The present invention also relates to the general formula (1) % formula % (1) (wherein R1 represents a hydrogen atom or R1 represents an acyl group derived from either nicotinic acid, triene higher fatty acid, or pentaene higher fatty acid. , R2 represents a hydrogen atom, or R3 represents an acyl group derived from either nicotinic acid, triene higher fatty acid, or pentaene higher fatty acid). It is a drug.

The triene higher fatty acids include 9.12.15-octadecatriene rlCa-lylunic acid) or ti, 6,
9,12-octadecatrienoic acid (r-lylunic acid) is preferable, and the pentaene higher fatty acids include 5, 8.
11,14.17-Elicosapentaenoic acid is preferred.

Incidentally, in this publication 1jl, the term "platelet aggregation inhibitor" means a preparation that has the effect of inhibiting platelet aggregation.

Group Detailed Description of the Invention The ethanolamine derivative of the present invention is obtained by condensing nicotinic acid, triene higher fatty acid, pentaene higher fatty acid, or a reactive derivative thereof with ethanolamine. As the agent, for example, ethyl chlorbate is preferably used. The ethanolamine derivative of the present invention, which can be used as a reactive derivative, may be a carboxylated thiazolidine thioneamide derivative. It can also be obtained by condensation reaction of pentaene higher fatty acids. Examples of the condensing agent used in the condensation reaction include N,N'-dicyclohexylcarbodiimide, 2-chloro-1-methylpyridinium P-)luenesulfonate, and the like.

The ethanolamine derivative of the present invention can be used as a platelet aggregation inhibitor, and is effective in treating diseases caused by platelet aggregation, but it is particularly used as an antithrombotic agent or cancer metastasis preventive agent, and the dosage is generally for adults. Daily amount: about 100~
It is recommended to take 1,500 doses in 1 to 3 doses, if necessary. The method of administration can take any form suitable for administration, with oral administration being particularly preferred, although 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, talc, magnesium stearate, and the like. In addition to the above-mentioned solid formulations, the compounds of the present invention can also be formulated into liquid formulations such as oily suspensions and syrups.

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

Next, the present invention will be explained in more detail by showing examples and test examples, but the present invention is not limited to these in any way. Example 1 Under argon atmosphere, 5, 8.11, 14.17 -Nicosabentaenoic acid thiazolidine thioneamide 500”j
A tetrahydrofuran (1,51d) solution in which 2-aminoethanol 8411P (1,38 mmot) was dissolved was added at room temperature to a tetrahydrofuran (IC)+d) solution in which 2-aminoethanol 8411P (1,38 mmot) was dissolved. 20 at room temperature
After reacting for minutes, IN-sodium hydroxide aqueous solution 101
The extracted organic layer was washed with water and extracted with anhydrous sulfuric acid) After drying with IJum, the solvent was distilled off under reduced pressure to obtain an extraction residue of 4371 ml.The residue was subjected to silica gel column chromatography and extracted with chloroform. - Methanol 95:5 elution fraction N-5, 8, 11, 14,
The physicochemical data of Okono, which obtained 3561 kl (1,03 mmot) of 17-eicosapentaenoyl-2-amine ethanol, are shown below.

IRvMWi (cya-li: 3530, 3340
, 1655, 1595, 1530' H-NMR
(CDCAs) δ: 0.97 (3Ht, J=7
．． 5Hz).

1.53-2.33 (8H), 2.67-2.93 (8H)
H), 3.39 (2Hz, J=5Hz), 3.70(
2Ht, J=5Hz), 5.39(IOHbt
, J=5.5Hz) mass(m/e):
345 (molecular ion peak'), 327 (dehydration peak), 276 Example 2 Nicotinic acid 600 my (4,8
7 mmot) was suspended in tetrahydrofuran (15 m), and 0.68 d of triethylamine was added thereto at room temperature.
(4.88 mmot) was added, and then a tetrahydrofuran (1-) solution in which 556 mg (5.12 mmot) of ethyl chlorocarbonate was dissolved was added at -10°C. -10℃
After reacting for 13 minutes at 0°C, a solution of 2-aminoethanol 313'19 (5,12 mmol) dissolved in a mixed solvent of tetrahydrofuran (2-) and water (2-) was added, followed by triethylamine 0. .72 d (5
, 17 mmot) was added. After reacting at 0° C. for 1 hour and 20 minutes, 20% of water was added and extracted three times with n-butanol. The extracted organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain an extraction residue of 949q. -Nicotinoyl-2-aminoethanol 608 M? (3,65m
mot) was obtained.

Under an argon atmosphere, 5,8,11,14,17-eicosapentaenoic acid 431 cape (1,43 mmot) was dissolved in 1,2-dichloroethane (8d) solution at room temperature.
-dimethylaminopyridine 18q (0,15mmot)
.

N,N'-dicyclohexylcarbodiimide 324 w
e (1,57mm0L), followed by N-nicotinoyl-
2-aminoethanol 237 q (1,43 mmot)
A solution of N,N-dimethylformamide (4-) in which was dissolved was added. After reacting at room temperature for 20 hours, the resulting precipitate was filtered off and washed with benzene. Water was added to the mother liquor and extracted three times with dichloromethane. Wash the extracted organic layer with water and dilute with anhydrous sulfuric acid)
After drying with IJum, the solvent was distilled off under reduced pressure and the extraction residue 665
111P was obtained. The residue was subjected to silica gel column chromatography, and the eluate fraction was purified with chloroform/methanol 99:1, N-nicotinoyl-2-7minoethyl,
5,8.11.14,17-nicosapentaenoate 4181q (0.93 mmot) was obtained.

The physicochemical data of this product are shown below.

IR & Ia Takashi (crn: 3305, 1745
, 1655, 1595, 1540'' H-NMR (
CDCts) δ: 0.94 (3Ht, J=7.
5Hz).

1.58-2.43 (8H), 2.67-2.93 (8H)
H), 3.72 (2Hz, J=5.5Hz), 4.
30 (2Ht, J=5.51(z).

5.37 (IOHbt, J=5.5Hz), 7.37 (
IHdd.

J=8Hz, 5Hz), 8.10(IHdt
, J=8Hz.

2Hz), 8.72(IHdd, J=5Hz, 2
Hz).

8.99 (IHbd, J=2Hz) mass(
m/e): 450 (molecular ion peak).

381, 149, 106, 78 Example 3 α-Lilunic acid 4G2q (1,44m
1,2-dichloroethane (8wt) in which mot) was dissolved
Add 4-dimethylaminopyridine to the solution at room temperature.
, 15 mmot), N, N'-dicyclohexylcarbodiimide 328q (1,59 mmot), followed by N-nicotinoyl-2-aminoethanol 240q
A solution of (1,44 mmot) in N,N-dimethylformamide (4-) was added. After reacting at room temperature for 14 hours, the resulting precipitate was separated by filtration and washed with benzene. Water was added to the mother liquor and extracted three times with dichloromethane.

After washing the extracted organic layer with water and anhydrous sulfuric acid, and drying with IJum,
The solvent was distilled off under reduced pressure to obtain an extraction residue of 684. The residue was subjected to silica gel column chromatography, and the eluted fraction of chloroform/methanol 99:1 was extracted with N-nicotinoyl-2-aminoethyl 9,12.15 -Octadecatrienoate 407 ”f (0,95 mmot) was obtained.The physicochemical data of this are given below.
5.1595.1545” HNMR (CDCAs)
δ: o, 97 (aat, J=7Hz).

1.13-2.50 (16H), 2.78 (2Hb
t, J=5.5Hz).

, 3.73 (2Hz, J=5.5Hz), 4.32 (2
Ht, J=5.5Hz), 5.33(6Hbt, J=5
．． 5Hz), 7.33 (IHdd, J=8Hz, 5Hz
), 8.10 (IHdt, J=8Hz.

2Hz), 8.70(IJ(dd, J=5Hz
, 2Hz), 8.97 (IHbd, J=2H
z) mass (m/e): 426 (molecular ion peak)
, 357°149. 106. 78 Example 1 Example 4 (-N-nicotinoyl-2
-Aminoethyl 6.9.12-Octadecatrienoate 280 ml was obtained.The physicochemical data of this product are shown below.

IRuu'F'j (Confucian-"): 1740 e
1680,. 1590, 1520mass (m/e)
: 426 (molecular ion peak).

149, 106 Example 5 Nicotinic acid 77119 (0,63
mmot) in a mixed solvent of tetrahydrofuran (2m) and 1,2-dichloroethane (2-).
4-dimethylaminopyridine 7q (0,06 mmo
A) e N # N'-dicyclohexylcarbodiimide 129q (0,63 mmol), N-5, 8,
A solution of 1,2-dichloroethane (1,5d) in which 11,14,17-eicosapentaenoyl-2-aminoethano-k 196q (0.57 mmot) was dissolved was sequentially added. After reacting overnight at room temperature, the resulting precipitate was filtered off and washed with benzene. Water was added to the mother liquor and extracted three times with dichloromethane. The extracted organic layer was washed with water, dried over anhydrous sulfuric acid, and then the solvent was distilled off under reduced pressure to obtain extracted residue 311q.

The residue is subjected to silica gel column chromatography,
Chloroform-methanol 98:2 elution fraction, N-
5,8,11,14,17-Nicosaventaenoyl 2-7 Minoethyl Nicotinate 246119 (0,55
mmot) was obtained. The physicochemical data of this product are shown below: 3425, 17
25, 1665, 1580.

495” BNMR (CDCAs) δ: 0.93 (3Ht
, J=7.5Hz).

1.50-2.33 (8H), 2.67-2.93 (8H)
H).

3.67 (2Hq, J=5.5Hz), 4.43 (2H
t, J=5.5Hz), 5.36(lOHbt, J=5
．． 5Hz) s7.36 (IHd<1.J=8Hz, 5H
z), 8.28 (IHdt, J=8Hz, 2Hz), 8
．． 77 (IHdd, J=5Hz.

2Hz), 9.18 (IHbd, J=2Hz) mass
(m/e): 450 (molecular ion beak).

381. 106. 78 Test Example Platelet Aggregation Inhibition Effect Nine volumes of blood are 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 plasma (PRP: 5
x 10fi pieces/μt).

250 μt of the PRP was placed in a cuvette, heated for 2 minutes in a 37°C constant temperature bath, and 20 μt of a solution of the ethanolamine derivative to be tested (7×10 −8 M ethanol solution diluted with Tris-buffered isotonic saline solution) was added and incubated for 3 minutes. Platelet aggregation is stimulated by adding arachidonic acid solution or collagen solution, which are aggregation-inducing agents (13orn
) of nephelometry [e.g., Journal Op.), Igeology (J, physiot,) Vol. 168, No. 178
Page, published in 1968].

Arachidonic acid (100 μM), collagen (20 μg/
Table 1 shows the 50% inhibitory concentration against platelet aggregation induced by 0.0 aspirin as a comparative example.As a result of the test, we found a significant anti-platelet aggregation activity as shown in Table IK below as a representative example. Furthermore, it was confirmed that ethanolamine derivatives according to the present invention not shown in Table 1 also have similar anti-platelet aggregation activity. In addition, 5 in the table
0% inhibitory concentration means that when the platelet aggregation ability without introducing the ethanolamine derivative according to the present invention is 100%, the platelet aggregation ability is suppressed to 50% by introducing the ethanolamine derivative. It means the concentration of ethanolamine derivative solution required for

Table 1 Anti-platelet aggregation activity Acute toxicity An acute toxicity test was conducted by oral administration using ICR male mice (5 weeks old). The LDso values of the compounds of the present invention were all 4f/Icf or higher, confirming their high safety.

(2) Effects of the Invention According to the present invention, a novel ethanolamine derivative and a platelet aggregation inhibitor containing the same as an active ingredient are provided.

The above-mentioned compound of the present invention significantly suppresses the platelet aggregation effect induced by arachidonic acid or collagen, and therefore is used as a preventive agent for diseases caused by platelet aggregation, particularly thrombosis involving platelet aggregation such as myocardial infarction and cerebral infarction. can do. 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.

Patent applicant Terumo Corporation

Claims (6)

[Claims] (1) General formula 0) % Formula % (1) (In the formula, R1 represents a hydrogen atom or represents an acyl group derived from either nicotinic acid, triene higher fatty acid or pentaene higher fatty acid, and R2 represents An ethanolamine derivative represented by a hydrogen atom or an acyl group derived from either nicotinic acid, triene higher fatty acid, or pentaene higher fatty acid. (2)) Ethanolamine derivative according to claim 1, wherein the acyl group derived from IJ ene higher fatty acid is an acyl group derived from α-lylunic acid or r-lylunic acid. (3) Acyl fi derived from pentaene higher fatty acids
The ethanolamine derivative according to claim 1, which is an acyl group derived from caeicosapentaenoic acid. (4) General formula (1) % Formula % (1) (In the formula, R1 represents a hydrogen atom or R1 represents an acyl group derived from either nicotinic acid, triene higher fatty acid, or pentaene higher fatty acid; Hg is A platelet aggregation inhibitor containing as an active ingredient an ethanolamine derivative represented by a hydrogen atom or an acyl group derived from either nicotinic acid, triene higher fatty acid, or pentaene higher fatty acid. (5)) The platelet aggregation inhibitor according to claim 4, wherein the acyl group derived from the IJene higher fatty acid is an acyl group derived from α-lyllunic acid or r-lyllunic 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 l:=+sapentaenoic acid.