JPS58121274A - N-pyridyl-amide of 1-phenyl-cyclopentane carboxylic acid, manufacture and medicine - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an N-pyridylamide of carboxylic acid, a method for producing the same, and a medicine containing the same as an active ingredient.

More specifically, 1 represented by general formula (I): (wherein, pyridine is a substituted or unsubstituted pyridine ring, and if substituted, it is substituted with one or more methyl groups or chlorine atoms) The present invention relates to N- and -Iλ diruamide of -phenyl-Schifta pentanecarboxylic acid, a method for producing the same, and a pharmaceutical having anti-inflammatory and antitussive effects containing the same as an active ingredient.

It has been found that the compound represented by general formula (I) has pharmacologically interesting properties, namely anti-inflammatory and antitussive effects.

The reaction in the method for producing the compound represented by general formula (I) of the present invention is carried out according to the following reaction formula.

(I[) [) That is, 1 represented by the general formula (I) (wherein, - Reaction of an activated derivative of phenyl-Schifta pentanecarboxylic acid with an aminopyridine represented by the general formula @ (wherein R and R1 are the same or different and are a hydrogen atom, a methyl group or a chlorine atom) The compound represented by general formula (I) can be produced by doing this.

The reaction is preferably carried out using approximately equimolar amounts of the compound represented by the general formula ([and general formula (2)), and can be carried out in the absence of a solvent, but preferably in a solvent, such as ether, dioxane, chloroform,
It is carried out in benzene or toluene at m degrees between 0°0 and the boiling point of the solvent.

When X in the general formula () is a helogen atom, it is preferable to use an excess amount of aminopyridine represented by the general formula (2) as a acceptor for hydrohalic acid, and an alkali metal or alkaline earth It may be a metal carbon #I salt or hydrogen carbonate, or a hexavalent base.

Next, the manufacturing method of the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these Examples.

Example 1 (Production of 6-((1-phenyl)-cyclobenthylcarbonylcouaminopyridine) 6-amitubiridine 60 mmol 11 anhydrous benzene 50 m
1 and 5 Qmmol of anhydrous sodium carbonate in a stirring device,
It was placed in a three-necked flask with a reflux condenser and addition funnel. Then add thionyl chloride and the corresponding alcohol to J.
A solution containing 5 Q mmol of 1-phenyl-cyclopentanecarboxylic acid chloride prepared by reaction in benzene somt according to the method of Org, Ohem, 4.619 (1959) was added dropwise little by little with stirring. After the addition was complete, the reaction mixture was stirred for an additional hour and then refluxed for 6 hours. After heating, benzene was removed under reduced pressure, and the residue was recrystallized from ethanol to obtain the desired compound. m11 (in ethanol): 122
~126°0 Example 2 (Production of 2-((1-phenyl)-cyclobenthylcarbonylcouaminopyridine) 2-aminopyridine was substituted for 3-aminopyridine,
The reaction was carried out in the same manner as in Example 1 except that triethylamine was used instead of anhydrous sodium carbonate to obtain the desired compound. mp (in methanol): 86-87 In Examples 3 to 7 shown below, 1-phenyl-cyclopentanecarboxylic acid and ethyl chlorocarbonate were substituted for the chloride of 1-phenyl-Schifftetrapentanecarboxylic acid. The corresponding mixed anhydride obtained by reacting in the presence of a hexavalent base, 1-phenyl-1-chlorocarbonylcyclopentane, was used, and the corresponding aminopyridine was used instead of 3-aminopyridine. Example 3 Production of 2-((1-'phenyl)-cyclopentyl-carbonyl]-amino-6-methylpyridine Example 4 2-((1 -Phenyl)-cyclopentyl-carbonylquaamino-4-methylpyridine Production Example 5 2-((1-phenyl)-cyclopentyl-carbonyltuamino-6-methylpyridine Production Example 6 2-((1-phenyl) )-Cyclopentyl-carbonyltuamino-4,6-dimethylpyridine Production Example 7 Production of 2-((1-phenyl)-cyclopentyl-carbonyl]-amino/-5-chloropyridine Next, Examples 1 to 2) Table 1 shows the characteristic values of each compound obtained in Step 7.

Moreover, the compounds found in Examples 1 to 7 had the following common characteristic values.

Engineering R spectrum analysis (ν・am) 5600-5400 (liH), 1650-1700
(oo) HMR spectrum analysis (J value: ppm
) 1.40-1.90 (!11. Hydrogen atom of cycloalkyl), 6860-8.20 (!!l, benzene,
(Hydrogen atom of pyridine) Next, the results of examining the toxicity and pharmacological activity of the compounds of the present invention are shown.

[Acute toxicity]

2-((1-phenyl)-cyclopentyl-carbonylcyamino-6-methylpyridine (hereinafter referred to as MR549) was administered orally or intraperitoneally to mice or rats to examine its acute toxicity. (Li-cut hfisl+1-Wilcaxon
) (J, Pharm, lrp, Therap,,
LD according to the method of 96.99 (1949)
The so value was determined. The results are shown in Table 2.

From the results in Table 2, Table 11!2, it was found that the acute toxicity of MR549 was very low under the experimental conditions used.

[Drug layer test]

(Antitussive action) Boura wsA 0o11. (Frog, Br
1t, Ph&r! atw, Sac, % apr.

1970) using rabbits according to the method of MR5.
The antitussive effect of 49 was investigated. That is, citric acid was administered as an aerosol to the test animals to induce coughing, and immediately prior to this, MR549 was administered intraperitoneally. Note that Tubuin was used as a comparative example. The cough attacks (@trok) of each test animal were counted during 10 minutes after the aerosol treatment, and the average value for each group was calculated to calculate the cough suppression rate. The results are shown in Table 3.

From the results in Table 6, MR549 has a remarkable antitussive effect, is statistically superior to the control group, and is almost comparable to the comparative example Tubuin. .

(Analgesic effect) Siegmund et al.
(Proo, 5oc.

Mxp, Biol, Mal, , 95% 729
(1957)), phenylquinone was administered to mice to induce torsion.
The analgesic effect of No. 9 was investigated. That is, 60 minutes before phenylquinone administration, MR549 was orally administered at a weight of 50 kg. As a comparative example, a7tylsalicylic acid having an analgesic effect was used at 100 servings/last weight. The results are shown in Table 4.

11141! From the results, MR549 is
It was found to have a strong analgesic effect comparable to that of thylic acid.

(Anti-inflammatory effect) Winter et al. (Wint@r @t &l) (Pro
a, goo, Rxp.

! l1o1. MI &, ■, 544 (1962)
) The anti-inflammatory effect of MR549 was investigated using carrageenan edema in rats. That is, Wt54
9 was orally administered, and 30 minutes later, carrageen was injected into the sole of the foot, and the volume of edema was examined 3 hours later. Note that indomethacin was used as a comparative example. The results are shown in Table 5.

Table 5 From the results shown in Table 5, it was found that MFI549 had an excellent anti-inflammatory effect, although it was slightly inferior to indomethacin.

(Gastro-resistant) Pisanti-Volte
rra) (IFarmaao Di, pr, Vo
MR according to the method of I, 25 (2), 105)
The effect of 549 on the gastric mucosa was investigated.

That is, male 8-D rats weighing 180 to 200 g were fasted for 48 hours with only water available ad libitum. Then, MR549 was administered intraperitoneally at a single dose of 1 Q Q mp/kp body weight from the start of fasting to 24 days after the start of fasting.
and 31 hours later, and in the case of oral administration, doses of 1 @ 15011q ~ body weight were administered at 9.24 and 51 hours after the start of fasting. In addition, phenylbutacin was used as a comparative example, and only a solvent (1% carboxymethyl cellulose) was administered to a control group.

The results are shown in Table 6.

Table 6 (Effect on motor activity) The effect of MR549 on motor activity was investigated using Swiss mice. That is, the test animals were divided into two groups and subjected to spontaneous movement.
ity) in a box with a measuring device, and the first group contains MR549.
was administered intraperitoneally at a dose of 50 μm to 50 μg, and the second group (control group) was administered only the vehicle, and the movement per minute was measured for 2 hours after administration. The results are shown in Table 7.

Table 7 From the results in Table 7, it was found that MR549 did not change the locomotor effect under the experimental conditions used.

From the above results, it was found that -99 of the present invention can be used as a useful medicine for the treatment of cough and inflammation. The drug is used in the following dosage form.

(a) Capsules, pills or tablets containing MR649 from 100 to 5001!19.

(b) A syrup containing 300 to 1500 μ of Mu 549 per day, administered in two or more divided doses.

(c) Suppositories containing 200-1000 mp of MR549.

Claims (1)

[Claims] 1 General formula (I): (wherein each is a substituted or unsubstituted pyridine ring, and if substituted, it is substituted with one or more methyl groups or chlorine atoms) N-pyridyl-amide of 1-phenyl-cyclopentane-carboxylic acid represented by: 2 The compound according to claim 1, which is 2-((1-phenyl)-cyclobentyl-carbonyl-aminopyridine. 3 B-((1-7-el)-cyclopentyl-carbonyl)-anobiridine. A compound according to claim 1, which is 4 2-((1-phenyl)-cyclopentyl-carbonyltuamino-4-methylpyridine. 5 2-(( The compound according to claim 1, which is 1-phenyl)-cyclopentyl-carbonyltoamino-6-methylpyridine. 6 2-((1-phenyl)-cyclopentyl-carbonyltoamino-6-methylpyridine) The compound according to claim 1. 7 The compound according to claim 1, which is 2-((1-phenyl)-cyclopentyl-carbonylcyamino-4,6-dimethylpyridine. 82-( The compound according to claim 11, which is (1-phenyl)-cyclobenticarbonylcouamino-5-chloropyridine. 9 General formula (■): (wherein, X is a halogen atom, an alkoxy group, or a 1- activated derivatives of 1-phenyl-cyclopentanecarboxylic acid represented by the general formula (2); R1 is the same or black, hydrogen atom, methyl group or chlorine atom). 10 General formula (■): (In the formula, the light is substituted or substituted with one or more methyl groups or chlorine atoms). A medicament having anti-inflammatory and antitussive effects containing as an active ingredient a compound represented by an unsubstituted pyridine ring (if substituted, it is substituted with one or more methyl groups or chlorine atoms).