JPS5852261A - 2-benzoylamino-substituted benzylamine derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:2-(4-Hydroxy-3-methoxybenzoylamino)-3,5-dibromo-N-cyclohexyl- N-methylbenzylamine shown by the formulaIand its acid addition salt. USE:An agent for removing sputum. An improved agent for removing sputum having a secretion promoting action on the cell of glandulae tracheales and a decomposing action on acidic mucopolysaccharide of acinus of glandulae tracheales. PROCESS:An ester compound shown by the formula II (R is lower alkyl or lower alkoxy) is hydrolyzed in an aqueous medium (e.g., mixture of water and methanol, etc.) containing sodium hydroxide or potassium hydroxide, to give a compound shown by the formulaI.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a zoylamino-substituted penzylamine derivative, a pharmacologically acceptable thallic acid addition salt thereof, and a method for producing the same.

More specifically, the present invention relates to a novel cobesizoylamino-substituted benzylamine derivative represented by formula (1), a pharmacologically acceptable thallic acid addition salt thereof, and a method for producing the same.

BACKGROUND OF THE INVENTION As a conventional compound having an expectorant action, the general name promhexisi represented by the following formula (1) is well known and has been widely used clinically. Recently, an acyl derivative of bromide has been synthesized (Japanese Unexamined Patent Publication No. 166410/1983), and from among the compounds, the generic name propanexy, represented by the following formula (Rin), has been found to have an expectorant effect.

As a result of intensive research to find a compound with superior expectorant action, the present inventors discovered that the compound of the present invention represented by the above formula (1) has extremely low toxicity and strong expectorant action. invention or completion, r6. Craftsmanship, pot.

Examples of pharmacologically acceptable phosphoric acid addition salts of the compound represented by formula (1) include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc., or acetic acid. , Murray > III 7 Mar #.

Examples include Illic acids #1 such as citric acid, sialic acid, and Ws tarnic acid.

According to the method of the present invention, the novel cobesizoylamino-substituted pedylamine derivative represented by the formula (1) of the present invention is produced as follows.

That is, it can be produced by hydrolyzing an ester compound represented by the general formula (fV) (wherein R represents a lower alkyl group or a lower alkoxy group) in an aqueous medium.

A particularly preferred embodiment of the method of the present invention is the general formula (
This is carried out by hydrolyzing the ester compound represented by IV) in an aqueous medium containing sodium hydroxide or potassium hydroxide. The aqueous medium used in this case may be water or a mixture of water and methanol or water and ethanol, particularly preferably a mixture of water and methanol. Further, the reaction is carried out under heating from room temperature, and is particularly preferably carried out at room temperature.

In addition, in the production method of the present invention, among the starting materials represented by the general formula (fV), the following general formula (V) in which R is a lower alkoxy group (wherein, Ro represents a lower alkyl group) is used. The compound shown is a new substance and its preparation is described in the Examples. Further, in the general formula (IV), compounds in which R is a lower alkyl group are, for example,
It is a known substance already disclosed in No. 440.

The novel 1-1-besizoylamino-substituted bezylaminodermic derivative represented by the formula (1) produced in this way and its pharmacologically acceptable acid addition salt have excellent expectorant action. It is extremely useful as a medicine.

The excellent expectorant action of the compound represented by the formula (1) of the present invention is shown below in Table 1 and! ! An example is shown in 2. As for the expectorant effect, secretion promoting effect on tracheal gland cells and acidic mucopolysaccharide degrading effect in tracheal acini were investigated.

Further, as a control drug, one type of compound having a structure similar to the compound of the present invention was used.

[Test compound]

A: Compound 11 of the present invention (4t-human Roxy 3-methoxybesizoylamino)-3,! -dibromo H-cyclohexyl-y-
Methylbesidylamine>・Salt #broken0H3-1(4t-acetoxy-3nimethoxyben1silylamino)-3,3-dibromo-N-cyclohexyl-N-methylbesidylamide>・#1fl! Salt O: Control drug Jl (*il! bromhexy) co-amino-3,5-dibromo-N-cyclohexyl-N-
Methylbesidyl-R-C hydrochloride [Test method] Method of Yanagura et al. (Japan Pharmacological Journal, 77.33ri ~ 56g
'PK/) ) lc follow 7 lines 7Th.

A male mongrel dog with a weight of 10~/cm was penned under rubital sodium (JOq/#, intravenous injection) anesthesia with a length of approximately 10 e.
Remove the 1M trachea and immediately add HJInkI solution (RIJ%).
OB-j% 002. j 7 + / 0)
tjp "Q, The connective tissue of the suspect was peeled off and cut into approximately 21 tracheal pieces.The tracheal pieces were brain-baked for 30 minutes in H-d solution, then the test drug was added, and
I bet for a minute. Thereafter, the trachea piece was fixed in 10% isotonic formalin, dehydrated in an alcohol series, embedded in a conventional manner, and finely sectioned in μ using a thin Yug type microtome. 7-2 section is 1eimn blue@
(pHJ,j)-psrlodia *oid 8
ohiff(A B (pHJ, j) / PAS
) dyed, l! i#1 was used to investigate the secretion-promoting effect on tracheal gland cysts and the acid mucolytic decomposition effect on tracheal gland cells.

l Secretagogue effect on tracheal gland cells Thickness of the fixed layer from the basement membrane to the cartilage layer vn + ll
: W) and the inner diameter (1") of the tracheal acinus were measured, and the amount occupied by the tracheal tissue of the tracheal gland acinus (AX WR)
It was expressed as Incidentally, the larger the Axvn value, the greater the amount of secretion present in the tracheal gland acini, and the greater the airway secretion promoting effect.

Table 1 Secretion-promoting effect on tracheal knee cells I A-WR = - Significant difference from control ◇The strength of this action is approximately 70 times stronger than that of control drugs 1 and 2 in terms of dosage.

-Acidic mucopolysaccharide decomposition effect in tracheal gland acini The acidic mucopolysaccharide decomposition effect of tracheal mars was investigated as an airway mucus decomposition effect.

In double staining of AB (pH Yuj)/pAs, tracheal gland acini containing a large amount of acidic mucopolysaccharide react with AB and exhibit a blue color, but f! ! When the mucopolysaccharide is degraded and acidic groups are lost, the positive AB staining weakens and becomes positive Pjl staining, and as a result, the color tone of the tracheal gland acini changes from blue to red. The acidic mucopolysaccharide decomposition effect was determined by calculating the ratio of the number of blue-colored tracheal gland acini to the total number of tracheal gland acini, and determining from the decrease in this ratio ◇ Significant difference from control ※※ p < o, oi Compound of the present invention was found to exhibit a strong expectorant effect due to its gradual decomposition of acidic mucopolysaccharide, which is considered to be one of the viscous components of airway mucus. The strength of this effect is more than 10 times stronger than that of control drugs 1 and 2 in terms of dosage.

[Acute toxicity test]

The test was carried out using d4Y male mice weighing -0S-5g. Oral and intraperitoneal routes of administration, respectively.
Group 10 animals were used for the experiment to LD50Litohfi.
The e14- value was calculated from the number of deaths 7 days after administration, WilCOXO! Calculated using method 1.

Table 3 Acute toxicity in mice Hereinafter, the present invention will be explained by examples.

Example 1. 2-(4t-hyrroquine-3-methoxybesizoylamino)-3,! ;-1 bromo N-cyclohexyl-N
-Methylbenzylamino, 2-(Q-acetoxy-3-methoxybesizoylamino)-3,3-dibromo-N-cyclohexyl-N-methylbenzylamino salt fll salt tt og in methanol 30 ml suspension , -〇zSodium hydroxide aqueous solution/
Add Od and stir at room temperature for an hour. After the reaction, methanol is distilled off under reduced pressure, and 4 tons of chloroform and 100 ml of chloroform are added to the resulting residue. The mixture was then made weakly acidic with a 20% aqueous hydrochloric acid solution, further made weakly alkaline with 20% potassium carbonate, and extracted with chloroform. The chloroform layer is washed with water and dehydrated. The solvent was distilled off, and the resulting residue was recrystallized from methanol to give a colorless prism group with a melting point of 99 to -00°.
, obtain 2Kg.

Elemental analysis value 022H26Br2N203 theoretical value
a, to, ko/, H, ri, ri, r'I N, ! , 3 experimental values o, so, ozahōH, solid 1. j, 3 Prepare the hydrochloride according to the conventional method. Recrystallization from ethanol gives colorless needle-like crystals with a melting point of 4tJ° (decomposition).

Elemental analysis value a221126Br2v2o3 @M
ol theoretical value o, sg, ri61H, J, za4111
, 4t, experimental value 0.4, 7ri, H, 4t,
7 answer W, 4t, 74 as Example λ 2-(couethoxycarbonioxy-3-methoxybesizoylamino)-3,3-dibromo-1-cyclohexyl-N-methylbenzylamicy-amino-31S-
A solution of 6.410 g of dibromo-N-cyclohexyl-N-methylbesidylamine in 30-chloroform was added with 4t-ethoxycarbonyloxy-3-methoxybesizoyl chloride (4t-ethoxycarbonyloxy-3-methoxybenzoic acid). 10 ml of chloroform (prepared from lOg and thionyl chloride according to a conventional method) was added dropwise under heating under reflux. After the addition, the mixture was heated under reflux for 7 hours. From now on, it will be made alkaline with an aqueous potassium carbonate solution and extracted with chromium alum. The aroform layer (washed with water and dehydrated. The solvent was distilled off, and the resulting residue was recrystallized from ethanol to give a melting point of /4
tlr~/! 7 g of colorless needle crystals of θ° are obtained.

Elemental analysis value 02sH3oBrtzM20s theoretical value
a, SQ, /Y+H,3,0! ;%w, 4IAI
Experimental value 0. jO, /4 + H, 41, beg r + M
, Yu, Ri 3 Example 3 2-(4t-hyVroxy3-methoxybesizoylamino)-,? ,,5-dibromo■-cyclohexyl-
-Methylbenzylamine hydrochloride Example (4-monoethoxycarbonyloxy-3-methoxybenzylamine)-3,5-dibromo-N-cyclohexyl-■-methylbenzylamine 3. Add 20% hydroxide to a suspension of 00 g of methanol in 30 ml of IJum aqueous solution 3. Add Od and stir for /vf at room temperature. After neutralizing the reaction solution with concentrated hydrochloric acid while cooling, the solvent was distilled off. Chloroform/3- is added to the obtained residue, made weakly alkaline with an aqueous sodium bicarbonate solution, and extracted with chloroform. The chloroform layer was washed with water and dehydrated. The solvent is distilled off, a 10% aqueous hydrochloric acid solution is added to the resulting residue, and the precipitated crystals are separated. The material for analysis was recrystallized from ethanol and had a melting point of 24t2.
~2413° (decomposed) colorless needles 41. ? lr
get g.

The crystal was identified by the material obtained in Example/R.

Patent applicant Kita I! @Pharmaceutical Stock Exchange Procedures Amendment (Voluntary) October 1981. 1-day Commissioner of the Japan Patent Office Shima 1) Spring 4!1 Mr. 1 Indication of the case 1982 Patent Application No. 147746 2 Title of the invention 2-benzoylamino-substituted benzylamine derivative and its manufacturing method 3 Comparison with the case of the person making the amendment Related Patent Application Person Address: 1-6-144 Giyocho, Katsuyama City, Fukui Prefecture Date of Amendment Order Voluntary 5 Number of Inventions Increased by Amendment Su Shiloh
7111 Correct contents of "Claims" in the I-correct subject specification 2-benzoylamino-substituted benzylamine derivatives shown in the claims as attached, and pharmacologically acceptable phosphoric acid additions thereof salt.

In the method for producing a 2-benzoylamino-substituted benzylamine derivative represented by the formula 2 and a pharmacologically acceptable truncated acid addition salt thereof, the following -(wherein R represents a lower alkyl group or a lower alkoxy group). ) Patent procedure correction document characterized by hydrolyzing an ester compound represented by in an aqueous medium (spontaneous) 1981, 2nd, Commissioner of the Japan Patent Office, Shima 1) Haruki Tono 1 Display of the case, 1980 1956 Patent Application No. 147746
No. 3 Relationship with the case of the person making the amendment Patent 1) Appointment Office 1-3-14411 Mameyo-cho, Katsuyama City, Gakai Prefecture
1. Date of official order 5. Number of inventions increased by amendment 2. Shiloh I
711 Correct contents of "Detailed explanation of the invention" in the specification to be corrected (1) Page 115 of the specification, bottom line 15 and the same page 5, page 4
Insert the following σ] sentence between the lines.

"The novel 2-benzoylamino-substituted benzylamine derivative represented by the above formula (1) of the present invention can also be produced as follows.

That is, it can be produced by reacting the 2-amino-substituted benzylamine derivative represented by the above formula (11) with vanillic acid represented by the following formula () in the presence of a condensing agent.

The reaction is carried out in an organic solvent, and examples of the organic solvent used include acetone, dioxane, acetonitrile, chloroform, methylene chloride, and tetrahydrofuran.

As a condensing agent, N,M'-dicyclohexyl carmediimide, N-cyclohexyl-N"-morpholinoethyl carme diimide.

N-V chlorohexyl-r-(4-diethylaminone chlorohexyl)calmediimide and the like are used. J (2) Specification page 115 1: Add the following Example 4 between line 7 and applicant's name.

[Example 4 2-(4-Hydroxy V 3-methoxybenzoylamino)-3,5-dibromo-N-cuclohexyl N-methylbenzylamine hydrochloride 2-amino-3,5-dibromo-M-V Chlohexyl −
0.75 g of N-methylbenzylamine and vanillin!
0.50g of chloroform 10g/1%! ! IHI! Add 0.49 g of dichlorohexylcal diimide to
Stir in room m for 20 minutes. After the reaction, the precipitate is removed from the oven. After washing with sodium hydrogen carbonate, the F solution is concentrated under reduced pressure. Add dilute hydrochloric acid to the residual liquid to make it machinable, and remove the precipitate by F.
Ru. Recrystallize the first sample from ethanol to obtain a melting point of 242 ~
0.37 g of colorless needles of 243° (decomposition) are obtained.

The main island was identified by the substance obtained in Example 1 and by Engineering R. ”

Claims (1)

[Scope of Claims] A novel -~be〉zoylaceno-substituted be〉dylami〉It conductor represented by formula 7, and a pharmacologically acceptable acid addition salt thereof. In the method for producing a novel cobesizoylamino-substituted benzylamine derivative represented by Formula 2 and its pharmacologically acceptable acid addition salt, the following general formula (wherein B is a lower alkyl group or a lower A method characterized by hydrolyzing an ester compound represented by (representing an alkoxy group) in an aqueous medium.