JPS5944367A - Bronchial secretion promotive, mucus fluidization active and antitussive novel compound, manufacture and pharmaceutical composition - 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 provides useful pharmacodynamic properties with respect to absorption, bioavailability, and composition level, and is a significant bronchial secretagogue. A) Novel compounds with air, bronchial, and mucus fluidizing activity and cough suppressant activity.

The compound according to the present invention is guaiacol N-acedel-4-thiazolidine-lupogysylate represented by the following general formula (1).

Another object of the present invention is to provide a method for preparing compound (1) of C.

Finally, another object of the present invention is to provide 11. Or it has bronchial secretagogue activity, mucolytic activity and cough suppressant activity as an active ingredient! +1. ! ! Pharmaceutical composition gold is to be provided.

According to the present invention, compound (I) (hereinafter referred to as -1., 5 to Jij)
(abbreviated as A734) is 4-thiazolidinetwocarboxylic acid as all starting materials, and that? The presence of base 1 is acetylated by reacting with acetyl chloride, and then the obtained i′
1. r, HIN-acetyl-4-thiazolidine-carboxylic acid prepared by esterification from guaiacol (2-methquine-phenol) K in a neutral solvent of total anhydridett 60 The compound thus obtained ( 1)
Compared to other drugs already used in therapy, such as tJ, Calphox/Methyl/Stin, α-Merkaftono1 Copionylglycine, Guaiacol and Codin.
It was found to have excellent toxicity, bronchial secretagogue activity, cough suppressant activity, and mucus a!U-forming activity.

Compound SA 734μ was well absorbed after oral administration.
Compared to this case, the original form and the lung's 1/bel are clearly more 1111 and longer songs, thiazolidine-carvone! From this perspective, 5A734 has a +itI bioavailability and a +VII J-'J,' 711 (!tlU property:
It can be seen that (a1'-ta).

The following Examples V, J, the invention remains +, ll]-f 11 or Ijllfi'J are limited to small inventions (the above).

Example a) Ilg (0.11 mol)
Tsum and 8.5m13 (0,10mo/L, ) Tour L + #chloride/acetone 4 of 20ITII3
Stir for about 1 () minute from f and c? By lowering the suspension, 13.3 g (0.1 mol) of 4-thiandylysine-carboxylic acid/10 (l m, 13 attenuated VC) was added and stirred at room temperature for 12 hours. 8 things in all mouths, eyes 7, 7t obtained sediment sound R Hidon to purify it).

Next, the 41st layer was concentrated under a total vacuum (7,127 g of f1 was produced, and then mixed with acetone/diethyl ether).
Crystallized in Kunshuan, 6g of IN--7'cetyl-4-
Thiazolidine-carboxylic acid (1 mouth, P==t:U()-
] 38 ℃ n i'c・i (f kuji).

b) 5.5 g of 6.5 g of carbonyl imidazole
(0,0314 mol) of N-acetyl-4-thiylsilidine-carboxylic acid, plus 5 g of guaiacol/1. (l me chitrahydrofuran and o, i g 1 VleoIN
a Full power 11 increase.

Temperature 3 () minutes 1! Incubate the mixture at room temperature for 12 hours until the temperature rises to 1°C. Finally, evaporate the bath medium under reduced pressure and dissolve the residue with water. Afterwards, extract with diether ether.

After drying the 41-layer layer with anhydrous 1' Ja2SO, the solution was evaporated under pressure to obtain 8 g of crude product.

By 5 in 2 chromatography, the eluent and petroleum ether/ethyl ether (5:1) were added (with ~, this crude bM? + After complete purification, 6 g of the product (magenta mucilage) was purified. 1 (do.

This monster had the following characteristics.

) Jibow analysis: ni 13H,, N(J, S (Numerator JSt = 281
, I:4) VC vs. (7 shifts, 1 shift (%) C = 55.4!J; H = 5.33
N=-4,98 fresh value (%) C-55,32; H=5.44;
l'J -5,112 infrared spectrum (liquid 1i (
film)::31 (1(1cm-' (C-H aromaticity); 2970-295cm-I (c-t-+aliphatic t'J=): I 785c+
++ −' (ni = Q); 167 (Jcm-1 (C=O-y mido); l I(iocm-' (C
=C)): 86ocm-'< c-H aromaticity), H NMR spectrum (measured in CDCe, internal standard [MS): 2.2 ti (S, 3H, COCH2-n;
3.3-3.7 δ (rn, 2H.

ABX system] AB part); 3.85 a (S,
: 1t-1, Q - to H3) ; 5.4δ (double d
, IH, X portion of ABX yarn); 6.85-7.
3δ (m, 4H aromaticity), Hanokanezu (Swiss) and i, i6 (v
Acute 41J characteristics against Litch
fieffld J, Ding and W i-1? COX
OI'l U) method (J, )'ilarm, EX
p, Tieler, 96,991.13 (1949))
Ni yo vOt! I have a lot of power. I issue
Ra noshi 1ko A' old (Y3<-f in the seven gold table 1, or SAD from this table; 14 is very small I barrel Sumitomo Metal M-t I)
It turns out that it is no more than .

Table 1 Acute bronchial secretagogue activity of 734 to S
734i In comparison with carboxymethylcysteine and α-mercaptoglobionylpuricine, mapp
ri method (IVlawata'ri I7 1ゝKagoshima human science medicine hi, J=# -27,561 (1 (17+;
)) was administered orally to Lv4L rats ε (((
11 [Usanoshi fko. The fruit is shown in Table 2)J': -
f.

Table 2 Bronchial secretion-promoting activity (sodium fluorescein k mjτ removal in the qi and L'1 auxiliaries of Kizumi) Based on the obtained values, SAγ34 is twice as effective as the drug compared to 11.
It is clear that the bronchial secretagogue activity is extremely low compared to the case of administration.

In order to compare SA 734 with guaiacol, it was administered orally at the same dose. The rice polishing was determined by the political viscosity d1 as shown in Table 3. !The συ-forming activity seems to be much higher than that of the guaiacol that was previously administered to the adopted child.

Table 3: 1t In vivo "fluidization activity cough suppressant activity" The cough suppressant activity of SA 734 was determined by intraperitoneal injection of male and female male and female with 200 to 350 g of Ij'E. After the setup, the method of Bourer et al. (Pr.
og, tJr i t, Pharrnac, soc
, April, 197(1) (/Ken; The force of coughing with an aerosol was tested last month and the control standard was 12.5 mg/ kg of 4'i'
In j-jt'k, treated with coteine, one of the tl1 groups was used.

Table 4 SA7 in rabbits by citrate aerosol test
: From the results obtained from the 4th and 11th occupancies, it was found that SA 734 was uniformly significant when compared with the control, and had a certain codin-like effect. ), (compared to quasi-1 bite 1. It can be seen that the percentage of cases is very [[4J (and low (4[ cough medicine 1 antiquity)].

Mulberry dynamic characteristics Mulberry dynamic test? , SA 7:44, and he gave 1 '1' and administered thiazolidine-carboxylic acid, etc.
It turns out that if you move '1, of course: ] l, te (-r, SA 734 will be absorbed as such 'J1.;4). It appears that the concentration has existed for a long time and that living organisms have four sexes. In particular, both treatments showed a very distinct pattern due to the loss of SA 734 in the protoplasmic levels of thiazolidine carboxylic acids.

Moreover, when using 5A734, vcit, ll1I
ll of thiazolidinecarboxylic acid at i level:! J
ek e v:r, probably attracted attention due to the strong 111J characteristic of this vessel's eyes, γko.

In addition, the present invention V, the use of 5A734 in human treatment. ] A) Regarding the opening - C I, Ryo - J' rut, T, = D' - T /N of the present invention 7' B + 'J
lc point f: t,, SA 734 k θ in advance l-
) ;ti, 7j Iij,! 1 piece C1, tl (
1 to 25f) mg K';

Claims (1)

[Scope of Claims] (1) Guayaco-ru N-aceti# having the general formula of the small 71-lr order
-4-1-Asolysinocarbogizolate compound (7) A method for producing all the compounds represented by the general formula V by esterifying with N-7cetyl-4-thiaolysinocarboxylate carbon M and dayacol. (3) The method according to item 2 in box +U of the claims, characterized in that the reaction is carried out in an anhydrous neutral solution. (4 carponyl diimita sole or γJ is also supported
It was. + 1u7 hydrated gold can be produced by other known test chestnuts such that the reaction is complete.
3. The method according to claim 2 or 3, wherein the method is a ``ry sign''. (5) A pharmaceutical composition having bronchial secretion promoting activity, tracheobronchial mucus fluidizing activity, and cough suppressant activity, all of which are characterized by the general formula % thiasilicinocarboxylate as an active ingredient. (6) 2 encapsulated tablets, syrup - loan of doses. In the form of small bottles, suppositories, etc. Knee 4' Rokotoke Jr, J sign and 1
- patent, i [“Sought range #Tg W to item 5”!
Accumulated product.