JPS58194861A - Novel piperidine derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:A piperidine derivative of formula I (R1 is H, alkoxy; R2 is group having double bonds) and its acid adduct. EXAMPLE:4'-Allyl-2'-methoxyphenyl 1-amidino-4-piperidinepropionate hydrochloride. USE:Since it has an effect of inhibiting blood platelet coagulation, it is suitable for use as a remedy for a variety of thromboses. PREPARATION:The reaction of 1-amidino-4-piperidinepropionic acid of formula IIor this reactive derivative with a phenol of formula III gives the compound of formula I . The above reaction between the reactive derivative of formula IIand the compound of formula III is carried out in a solvent such as dimethylformamide at -10 deg.C to room temperature and the reaction using the compound of formula II is preferably using a carbodiimide as a condensation reagent at room temperature in a solvent such as dimethylformamide.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention describes the following general formula (1) (wherein R
1 represents a hydrogen atom or an alkoxy group, R2 represents a group having a double bond), an acid addition salt thereof, and a method for producing the same.

The present inventors synthesized a number of piperidine-based compounds and investigated their pharmacological effects, and found that a new compound represented by the above general formula (I) has an excellent platelet aggregation inhibiting effect and is useful as a medicine. They discovered something and completed the present invention.

Therefore, an object of the present invention is to provide a novel compound represented by general formula (1) that is useful as a medicine.

Another object is to provide an alternative method for producing the compound represented by general formula (I).

Examples of R1 in the novel piperidine derivative of general formula (1) include a toxoxy group, an ethyloxy group, a propoxy group, and a butoxy group. Examples of the group represented by R2 include a vinyl group, an allyl group, a butenyl group, a phenylvinyl group, a benzoylvinyl group, a cinnamoyl group, a carboxyvinyl group, a benzyloxycarbonylvinyl group, and a diphenylmethyloxycarbonylvinyl group. .

Examples of acid addition salts of the compound of the present invention of general formula (1) include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, citric acid, methanesulfone Wl,
Examples include acid addition salts with p-)luenesulfonic acid and the like.

The novel piperidine derivatives of general formula (1) and acid addition salts thereof of the present invention are produced as follows (wherein R1 and R2 are the same as above), that is, the formula (
By reacting 1-amidino-4-piperidinepropionic acid represented by n) or a reactive derivative thereof with a phenol represented by general formula (I),
) A new piperidine derivative is produced.

However, if the target compound is a compound containing a carboxyl group in R2 in general formula (1), the dicarboxyl group may be removed by diphenylmethyl group, etc. After the protected compound is reacted with a compound of formula (It) to obtain a compound of general formula (I) with a protected carboxyl group, the protecting group is removed with formic acid or trifluoroacetic acid. Manufactured by separating.

Examples of reactive derivatives of the compound of formula (II) include acid halides such as acid chloride and acid bromide, mixed acid anhydrides and active esters such as ethyl chlorocarbonate and butyl chlorocarbonate. The reaction between these reactive derivatives and the phenols of the general formula (to) is -1
Stirring is carried out for 15 to 5 hours at 0°C to room temperature. Examples of the reaction solvent include dimethylformamide, dichloromethane, dichloroethane, chloroform, and acetonitrile, and the reaction is preferably carried out in the presence of a tertiary amine such as triethylamine and dimethylaniline.

The reaction between the compound of formula (Il) or a salt thereof and the compound of general formula (-) is preferably carried out using a carbodiimide such as dicyclohexylcarbodiimide as a condensing agent and stirring at room temperature for 5 hours to 5 days. Preferred reaction solvents include dimethylpolamide, dimethylacetamide, pyridine, toluene, xylene, -dimethylsulfoxide, and mixtures thereof.

In addition, the elimination reaction of the diphenylmethyl group, which is a protective group for the carboxyl group of the compound of the general formula (Natsu) obtained by the above condensation reaction, is carried out at 0 to 1°C in the presence of formic acid or trifluoroacetic acid. This is easily accomplished by stirring at room temperature for several hours.

In order to obtain the acid addition salt of the novel piperidine derivative of general formula (1), it is preferable to use the compound of formula (It) as a starting material in the form of an acid addition salt and to obtain the target product in the form of the salt.

Note that the raw material 1-amidino-4-piperidinepropionic acid of formula (II) can be obtained by reacting 4-piperidinepropionic acid with 0-methylisourea or S-methylisothiourea at room temperature for 5 to 20 hours). easily obtained.

The compound of the present invention represented by the general formula (1) obtained as described above has a platelet aggregation inhibiting effect and is useful as a therapeutic agent for various thrombotic diseases.

The platelet aggregation inhibitory effect was tested using rabbit platelets as follows. Specifically, blood was collected from the carotid artery of a rabbit using a conventional method, and platelet rich plasma (P
RP) and Platelet poorplas
ma (P P P ) was obtained. PRP was diluted with PPP to obtain a platelet suspension having a platelet count of 20 to 30 x 104/cumm. The test compound was added to 45011t of this platelet suspension, and after stirring for 1 minute at 37°C, collagen or arachidonic acid was added for 25 minutes, and the progress of platelet aggregation was recorded as a change in permeability using an abbrevometer.
The aggregation rate was determined by the method of Emmons et al. (:c+ancet
.

1-77). The results are shown in Table 1.

Table 1: No effect +: 25-50 inhibition: 51-75% inhibition F: 76-100 inhibition Arachidonic acid concentration: 6mM Collagen concentration = 10μ A: 1-amidino-4-piperidine propion Acid 41-
Aryl-2+-methoxyphenyl ester [flm B: Aspirin As shown in Table 1, the compounds of the present invention strongly inhibit platelet aggregation induced by arachidonic acid or collagen, and are useful as therapeutic agents for thrombotic diseases.

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

Example 1 1-amidino-4-piperidinepropionic acid 41-allyl-2'-methoxyphenyl ester hydrochloride: 1-amidino-4-piperidinepropionic acid hydrochloride'!
h, Osl+ and eugenol 2.12 in anhydrous Pyri 9
2.6f of dicyclohexylcarbodiimide was added thereto, and after stirring for 2 nights, 4f of dicyclohexylcarbodiimide was further added, followed by stirring overnight at room temperature. The precipitated crystals were separated in a furnace, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, and the mixture was left in a cold place for 2 days, and the precipitated crystals were collected. After washing with total ethyl acetate and ether, air dry. Add 50% of water to this, stir at room temperature for 1 hour, remove insoluble matter, wash with ether,
Air-dried to give 41-allyl-2' 1-amidino-4-viveridineprobionic acid as colorless crystals with a melting point of 83-86°C.
-Methoxyphenyl ester hydrochloride 1.4 t (yield: 29 cm) was obtained.
)&80(5H,8,Ph-0-0dan3)4.92~5
．． 24 (2H, m, =OO205,72~6.16
(IH, m, -Cdan=)1,. 64-7.04 (5H
, m, aromatic hydrogen) Example 2 1-amidino-4-piperidinepropionic acid 21- (
β-phenylcarbonylethynyl) phenyl ester t
Jl salt: 1-amidino-4-biveridineprobion Wl salt tl [
[5y, A mixture of 4.82 t of 2-hydroxychalcone, 4.4 t of dicyclohexylcarbodiimide and 30 t of anhydrous pyridine was stirred at room temperature for 46 hours. After removing insoluble matter, the solvent was distilled off under reduced pressure, and the resulting orange oil was washed with ethyl acetate to give a gum-like product. This was dissolved in water, then water and ether were added to the precipitated solid, stirred, and left in a cool place overnight.

The resulting solid was washed several times with water and ether and
1-amidino-4-piperidinepropionic acid 21-(β-phenylcarbonylethynyl)phenyl ester hydrochloride 32 as yellow needles with a melting point of about 85°C (yield 32.
s %) was obtained.

&5~aO(11H,m, -0H=OR-.

Aromatic hydrogen) Example 3 1-amidino-4-piperidinepropionic acid 2'-cinnamoylphenyl ester hydrochloride: 1-amidino-4-piperidinepropionic acid hydrochloride 59
v2'-hydroxychalcone 4.811 dicyclohexylcarbodiimide 4.4f and anhydrous pyridine 30-
The mixture was stirred at room temperature for 46 hours. After separating the insoluble matter by F,
The solvent was distilled off under reduced pressure at 11°C, and the resulting yellow oil was washed with ethyl acetate. The resulting gum was dissolved in water, water and ether were added to the precipitated solid, stirred, and left in a cool place overnight. The resulting solid was washed several times with water and ether to give a white powder with a melting point of 103-105° C. 1-amidino-4-piperidinepropion l122'-cinnamoyl phenyl ester! acid! 1.82 (yield 194%) was obtained.

6.6-7.6 (11H, m, -0H=OH-.

Aromatic hydrogen) Example 4 1-amidino-4-piperidine propion II 4'
-(β-diphenylmethyloxycarbonyl)ethynyl phenyl ester! Acid [: p-hydroxycinnamic acid diphenyl methyl ester prepared from p-hydroxycinnamic acid and diphenyldiazomethane 9.9f'llkHilJ1
2-Dissolved in Zine 70-, 1-amidino-4-piperidine propionic hydrochloride &42 and 5.6 t of dicyclohexylcarbodiimide were added thereto, and after stirring at room temperature for 6 days, the temperature was raised to 45°C and stirred overnight. Then, 1.42 g of dicyclohexylcarbodiimide was added, and the mixture was further stirred at 45°C overnight. After cooling, the precipitated crystals were separated, washed several times with cold pyridine, then washed with ethyl acetate and ether, and air-dried. The obtained crystals were stirred in 100% dichloromethane, insoluble matter was filtered out, the solvent was distilled off under reduced pressure, and ether was added. The precipitated crystals were collected, washed with ethyl acetate and ether, and air-dried to give 1-amidino-4-piperidinepropionic acid 41 as colorless crystals with a melting point of 135-138°C.
- (β-diphenylmethyloxycarbonyl)ethenyl phenyl esteta hydrochloride Lat (yield: 43 cm) was obtained.

6.46(IH, (1,16H2,=Odan-co) &9
6 (IH, s -0-0 dan 2) 6.80-7.70 (14H, m, aromatic hydrogen → 7.
67 (1H, d, 16Hz, -0 temps =) Example 5 1-amicino 4-biperidineprobionic acid 4'-(β
-Carboxy)ethynyl phenyl ester hydrochloride: 1-amidino-4-piperidinepropionic acid 4'-(β
-diphenylmethyloxycarbonyl)ethynyl phenyl ester tJ [[2,6] was dissolved in formic acid 50-,
The mixture was stirred at 0°C for 2 hours. The solvent was distilled off under reduced pressure, ether was added to the residue, and the precipitated crystals tF were collected and washed several times with ether to give 1-amidino-4-piperidinepropionic acid 41 as colorless crystals with a melting point of 249-250°C. (
β-carboxy)ethynyl phenyl ester tJ[ff
11.7f (yield 9.i%) was obtained.

&45(I H,a, , r = 16Hz, =aH
Oo) 7.68 (IH, (1, J=16H2, -0 degrees=)7,0-4~7.a2 (4n, m, aromatic hydrogen) Example 6 1-amidino-4-piperidine propion Acid 2'-methoxy-41-(β-diphenylmethyloxycarbonyl)ethynylphenyl ester hydrochloride: 1-amidino-4-piperidinepropionate hydrochloride 6f
14-Hydroxy-3-methoxycinnamic acid diphenylmethyl ester 1 of dicyclohexylcarbodiimide5.
A mixture of 6f and anhydrous dimethylformamide 5o- was stirred at room temperature for 66 hours. The mixture was further stirred at 1/C60'C for 1 hour, and after the insoluble matter was filtered out, the solvent was distilled off, and the resulting pale yellow oil was treated with ethyl acetate and ether to obtain a solid. This was dissolved in water, and the precipitated powder was washed with acetone and ether. Further crystallization with methanol-ether gives 1 as a white powder with a melting point of 118-120'C.
-amidino-4-piperidinepropionic acid 2'-methoxy-, sl -(β-diphenylmethyloxycarbonyl)ethynyl phenyl ester hydrochloride 2.8? (yield 1
9.4%) was obtained. ) 6.94-7.50 (13H, m, aromatic hydrogen) 7.5
4(IH, (1,J=27Hz, -0Fl=ri) Example 7 1-amidino-4-piperidinepropionic acid 21-methoxy-41-(β-carboxy)ethynyl phenyl ester [acid [: 1-amidino-4 A solution of 16 t of -piperidinepropionic acid 2'-methoxy-41-(β-diphenylmethyloxycarbonyl)ethynyl phenyl hydrochloride 16- salt and 30- of formic acid was stirred at 50°C for 1 hour.The reaction solution was concentrated and Add amount of ether, −
I left it in a cool place at night. The precipitated crystals were washed with ether and air-dried to form a white powder with a melting point of 198-200°C.
1.12 of amidino-4-piperidinepropionic acid 21-methoxy-41-(β-carboxy)ethynyl phenyl ester hydrochloride was obtained.

381 (5H, s, -00dan3) 6.47 (1H,a, J=16nz, =QdanC0)7.
78 (IH, d,, T=16Hz, -0dan=) a15
~a50 (5H, m, aromatic hydrogen) or more

Claims (2)

[Claims] (1) A novel piperidine derivative represented by the general formula C (in which R1 represents a hydrogen atom or an alkoxy group and R2 represents a group having a double bond) and an acid addition salt thereof. (2) Adding phenols represented by the general formula (wherein R1 represents a hydrogen atom or an alkoxy group, and R2 represents a group having a double bond) to 1-amidino-4-piperidinepropionic acid or its reactive derivative. A method for producing a novel piperidine derivative represented by the general formula (wherein R1 and R2 are the same as above) or an acid addition salt thereof, which is characterized by causing a reaction.