JPH02138161A - Substituted cinnamamide derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula l [X and Y are H, halogen, CF3 or 1-5C alkyl or alkoxy; a, b and m are 1-3; Z is (substituted) 2-4C alkylene; R<1> is H, 1-8C alkyl or benzyl; R<2> is 1-8C alkyl, benzyl or R<1> is joined with Z to form cyclic diamino expressed by formula III or formula IV and also R<2> is joined with Z to form cyclic diamino expressed by formula V or formula VI] or salt of said compound. EXAMPLE:N-(3,4-dimethoxyphenethyl)-N-methyl-N'-(3-trifluoromethylcinna moyl) propylene-1,3-diamine. USE:Used as a medicine. Useful for remedy of circulatory system such as anti- arhythmia drug, anti-stenocardia drug or antihypertension drug. PREPARATION:For instance, substituted cinnamic acid derivative expressed by formula II (R<3> is OH, halogen or 1-5C alkoxy, etc.) is reacted with diamine expressed by formula VII in the presence of condensing agent, and in the coexistence of deoxidizer as necessary, to afford the compound expressed by formula I.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to novel substituted cinnamic acid amide derivatives having antitachycardia and vasodilatory effects and useful as medicines for the circulatory system, or their pharmaceutical properties. Concerning acid addition salts acceptable to.

[Problems to be solved by the prior art and the invention] JP-A-37-/3gAA discloses that 2-(N-methyl=N
It has been described that -(3,tx-dimethoxyphenethyl)aminopropyl) -S,t,-dimethoxyphthalimidin-/-one (AQA-, 7q) exhibits a bradycardic effect.

OR' Tokukai Akira again! ;3-, 3/1, 7th publication, JP-A-Sho&?
AQA-, 7? It has been described that a compound having a structure similar to that, that is, a cyclic amide fused to an N-alkyl-substituted benzene ring, exhibits bradycardic effects.

Additionally, West German Published Patent No. 32112.3'l'l
is a trifluoromethyl group represented by the following formula, alkyl having carbon number/~S, Z represents an optionally substituted alkylene group having 2 to 2 carbon atoms, R+ is a hydrogen atom, and carbon number/~S is an optionally substituted alkylene group; It represents an alkyl group or a benzyl group, and R2 represents an alkyl group or a benzyl group having carbon number/~g. It is also stated that when R1 and Z are connected to each other, the following formula shows a bradycardia effect.

Therefore, in order to find a new compound that is useful as a medicine for the circulatory system, the present invention was achieved as a result of intensive studies.

[Failure to solve the problem]

That is, the gist of the present invention is that R2 may represent a cyclic diamino group represented by the following general formula (I) (with the same meaning as above).
R2 and Z may be connected to each other to represent a cyclic diamino group represented by the following formula (R+ has the same meaning as above). ] or their pharmaceutically acceptable acid addition salts.

Hereinafter, the present invention will be explained in detail with reference to specific examples.

In the formula (1), the alkyl group having carbon number/~S expressed in the definition of , impentyl group, and n-pentyl group.

Examples of the alkoxy group having 7 to S carbon atoms represented in the definitions of X and Y include methoxy group, ethoxy group, n
-propoxy group, inpropoxy group, n-butoxy group,
An n-pentoxy group is mentioned. Examples of the halogen atom represented in the definitions of X and Y include fluorine atom, chlorine atom, bromine atom, and iodine atom.

Examples of the alkyl group having carbon number/~g expressed in the definition of R1 and R2 include methyl group, ethyl group, n-
Propyl group, n-butyl group, 5ec-butyl group, cyclopropylmethyl group, n-pentyl group, n-hexyl group,
cyclopentylmethyl group, cyclohexylmethyl group, n
-octyl group.

X and Y may be mono-substituted, di-substituted, or tri-substituted, respectively; when X or Y is di-substituted or tri-substituted, the substituents may be the same or different from each other.

The configuration of the double bond in the substituted cinnamic acid may be trans configuration or cis configuration, but trans configuration is preferable from the viewpoint of stability.

Moreover, the pharmaceutically acceptable acid addition salt means an acid addition salt that does not substantially increase the toxicity of the basic compound. These are, for example, mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, or acetic acid, malonic acid, fumaric acid, maleic acid, succinic acid,
Examples include salts of organic acids such as tartaric acid, methanesulfonic acid, and halatoluenesulfonic acid. Such acid addition salts can be obtained by dissolving the compound of the present invention in a suitable solvent and adding the acid as it is or dissolved in a suitable solvent. Suitable solvents include, for example, ether, ethanol, and the like.

The compounds of the invention are administered orally or parenterally to humans in a conventional manner. When used orally, 7 times 0. /~100
Preferably H7 is administered 787 to 3 times, 0.787/day if administered intravenously. It is preferable to administer θ/~iomg 787 to 5 times, and in the case of rectal administration, /times θ, /
Preferably, ~100 μ is administered 787 ~3 times. In this case, the compound (1) of the present invention or a salt thereof is generally used in a composition containing commonly used pharmaceutical carriers, excipients, and other additives. Pharmaceutical carriers may be solid or liquid; examples of solid carriers include lactose, china clay, sucrose, crystalline cellulose, cornstarch, Merck, agar,
Examples include hectin, acacia, stearic acid, magnesium stearate, lecithin, and sodium chloride. Examples of liquid carriers include syrup, glycerin, peanut oil, polyvinylpyrrolidone 1, tlJ-propylene oil, ethanol, benzyl alcohol, propylene glycol, water, and the like.

Pharmaceuticals containing the compound of the present invention can take various dosage forms, and when a solid carrier is used, tablets, powders, granules,
It can be presented as a powder or granules in hard gelatin capsules, suppositories, or troches.

The amount of solid carrier can vary widely, but is preferably about 1/2 to 1/9. When a liquid carrier is used, it can be a syrup, emulsion, soft gelatin capsule, sterile injectable preparation such as an ampoule, or an aqueous or non-aqueous suspension.

Furthermore, the compound (1) of the present invention or a salt thereof can be used by incorporating it into a cyclodextrin conjugate compound or into a liposome. Next, a method for producing the compound of the present invention will be described. The compound of the present invention represented by Formation (1) above can be produced, for example, according to the following synthetic routes A to E.

<Synthetic route A> (wherein, , represents an alkylcarbonyloxy group with carbon number/~.) This route is a production method for obtaining the compound (I) of the present invention by condensing a substituted cinnamic acid derivative (U) and a diamine (■). Various methods can be used to form an amide bond from the above compound (n) and the above compound (■) and lead to compound (1). For example, (1) substituted cinnamic acid (n; R3 is a hydroxyl group). ) and diamine (■) using a condensing agent such as dicyclohexylcarbodiimide (DCC), diphenylphosphoric azide (DPPA),
), etc. (2) Reactive derivatives of substituted cinnamic acids, such as acid...light''(If; R3 is a halogen atom), mixed acid anhydrides (n
;R3 is an alkylcarbonyloxy group), ester (l
Compound (I) is obtained by a method such as a method of condensing l:R" is an alkoxy group) and a diamine (■).

In the production method (1) above, the substituted cinnamic acid (n) is added at 0.00% relative to the compound (■). ! ; -2 equivalents are used. The condensing agent is 0.5-. 2 equivalents, preferably o,
g to 8-equivalents are used. The reaction solvent is not particularly limited as long as it does not participate in the reaction, and examples thereof include halogenated hydrocarbons such as dichloroethane and chloroform; and ethers such as diethyl ether and tetrahydrofuran. The reaction temperature was -da0~daθ℃, and the reaction time was θ,! ;-eg time.

In the synthesis method (2) above, the reactive derivative of substituted cinnamic acid is used in an amount of 0.3 to 2 equivalents based on compound (■).

The reaction proceeds smoothly by using a deoxidizing agent if necessary. The deoxidizing agent is not particularly limited as long as it does not react with compound (II), but examples include organic bases such as triethylamine and pyridine, alkali metal salts such as potassium carbonate and sodium acetate, sodium hydroxide, potassium hydroxide, etc. Examples include inorganic bases. The solvent is not particularly limited as long as it does not participate in the reaction, and examples thereof include ketones such as acetone and methyl ethyl ketone; ethers such as tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene and toluene; and water. The reaction temperature is 0° C. to /θ0° C., and the reaction temperature is O, S to tIg time.

Synthetic route B> (wherein, . ) This route produces compound (1) through the reaction of a substituted cinnamic acid amide derivative (1) with a phenylalkane derivative (VllD).
This is a manufacturing method that obtains Compound (formerly compound (III)
0.2 to 5 equivalents are used. Reaction solvents are not particularly limited as long as they are not involved in the reaction; examples include aromatic hydrocarbons such as benzene, toluene, and xylene; alcohols such as methanol, ethanol, and ingropanol; tetrahydrofuran, dioxane, and ethylene glycol diethyl. Ethers such as ether; ketones such as acetone and methyl ethyl ketone; dimethyl formamide, ethyl acetate, dimethyl sulfoquinide, and the like. The reaction temperature is 0
-200°C, preferably SO to /SO°C, and reaction time is O,S to qg hours, preferably 7 to 29 hours.

During the reaction, the presence of an excess of the above compound (■) as a deoxidizing agent, an organic base such as triethylamine, pyridine, or diazabicycloundecene, or an inorganic base such as sodium hydroxide, potassium hydroxide, potassium carbonate, etc. may inhibit the reaction. It is preferable to proceed smoothly.

<Synthesis route C> (However, in the formula, X, Y, Z, R', R2, R', a,
b and m are as defined above. ) This route produces the compound (
This is a production method for obtaining I). Compound (IX) is compound (I
5 equivalents of O, S of V) are used. Conditions such as reaction solvent, reaction time, reaction temperature, deoxidizing agent, etc. are the same as in synthetic route B.

Synthetic route D> (wherein, X, Y, Z, R', R'', R', a, b
and m are as defined above. ) This route is a production method in which compound (1) is obtained by reacting a substituted cinnamic acid amide derivative (V) with a non-rogenated alkyl or alkyl sulfonate (X).

Compound (X) is used in an O, S -S equivalent amount relative to compound (V). The reaction solvent, reaction temperature, reaction time, and deoxidizing agent are the same as in synthetic route B.

<Synthetic route E> (Vl) (wherein, This is a method for producing compound (I) by reaction with alkyl halide (or alkyl sulfonate) (XI).
i'l), 0.2 to 5 equivalents are used. The reaction solvent is not particularly limited as long as it does not participate in the reaction, but includes, for example, aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as tetrahydrofuran, dioxane, and ethylene glycol diethyl ether; ketones such as acetone and methyl ethyl ketone; and ethyl acetate. , dimethylformamide,
Examples include dimethylacetamide, dimethylsulfoxide, and the like. The reaction temperature was o-ao.

℃, preferably 30-750℃, reaction time o, s
-ug hours, preferably 7 to 29 hours. During the reaction, the reaction proceeds smoothly if a base such as sodium metal, sodium hydride, sodium amide, potassium t-butoxide, etc. is present.

Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited in any way by these Examples.

Example/ (Compound/) N-cinnamoyl-N'-cyclopropylmethyl-N'
Synthesis of -(3,11-dimethoxyphenethyl)propylene-3-diamine cinnamic acid 2,y g vq (/, b/mmol)
and triethylamine/A,? my (7,4/
mmol) in methylene chloride, and to the resulting solution was added ethyl chlorocarbonate/? p ray (/,b/
mmol) was cooled with ice, and then stirred at room temperature for several hours. Add this solution to N-cyclopropylmethyl-N-(3,I
A methylene chloride solution of q, gmt of f-dimethoxyphenethyl)propylene-/,3-diamine'+<7/rn9 (ha/mmol) was poured under ice-cooling. After further stirring at room temperature for S hours, the reaction solution was washed with water, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: methylene chloride-methanol; ro/l) to obtain the above-mentioned target product having the following physical properties.

Yield: 34g (yield: 5q%) Melting point: Oily substance infrared absorption spectrum (pure + Cn1-'): 32
gθ, /A! ;! ;, /A/3. /! ; /θ, /θ3θ
Mass spectrum (m/z); Hiroshi 22. λ/ (Reference peak) Example 2 (Compound A2) N-(u,5-dimethoxyphenethyl)-N-methyl-N'-(3-methylcinnamoyl)propylene-/,
J-cyamino synthesis The above-mentioned target product with the following physical properties was obtained.

Melting point; Oily substance infrared absorption spectrum (pure + Crn-'); 32
70, //,! 0. /1.20,1500 mass spectrum (m/z); , 797. sg (Reference peak) Example 3 (Compound 4.7) / -(3,ta-dimethoxycinnamoyl)-ri-(
Synthesis Example of #-(,?,Q-dimethoxyphenethyl)methylamino)piperidine/3-methylcinnamic acid and N
-(2,!;-dimethoxyphenethyl)-N-methylglobylene-3-diaminecara CH.

β-(3,Hiro-dimethoxyphenethyl)methylamine/
Ag (0, g Ammol) and triethylamine/901rli (0,7 mmol) were dissolved in toluene, and 3. Tadimethoxycinnamoyl-tartosyloxypiperazine J4'6■ (0,7
Add a toluene solution 2- of ffmmol) for 10 hours.
The mixture was stirred under reflux. After cooling to room temperature, the mixture was washed with water and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (developing solvent: methylene chloride/methanol = 20/1) to obtain the above-mentioned target product having the following physical properties.

Yield: 20θ■ (yield free%) Melting point: Infrared absorption spectrum of oily substance (pure+l1M?!-');/
63! ; , /390, /! ;0! , 102θ mass spectrum (m/z): 'II, 9,377, /9/, gda (reference peak) Example 1I (compound waste) N-(3,y-dimethoxyphenethyl)-Nmethyl-N
Synthesis of N-(34-dimethoxyphenethyl)-N-methylpropylene-/,3-diamine 337■ (7,3/mmol
) 2~! of dioxane.

Add potassium carbonate/Ogmf<0.79mmo to this solution.
Add 335 ml of 3-trifluoromethylcinnamoyl chloride (H'
A solution of I 3 mmol) in dioxane was added dropwise. After stirring at room temperature for S hours, water was added and extracted with methylene chloride. After drying the organic layer over sodium sulfate, the solvent was distilled off under reduced pressure to obtain a crude product. This was purified by silica gel column chromatography (developing solution: methylene chloride/methanol: to/1) to obtain the above-mentioned target product having the following physical properties.

Yield: 376■ (yield: 6%) Melting point: Infrared absorption spectrum of oily substance (pure + (:tn-');
32KO, /44θ, /6koo, 1sio, io3° mass spectrum (m/z″) )-N'-(
Synthesis of 3,Gudimethoxy7enethyl) -N,N'-dimethylpropylene-/,3-diamine e 30181
(/, 9 mmol) as a starting material, the above-mentioned target product having the following physical properties was obtained.

Yield: λ g 6 (yield q 0%)
Point; Oily substance infrared absorption spectrum (pure, crn-');/A'
IO, /! ;9! ;Mass spectrum (M"/Z); Geta b, 30!;, 242./9/ (Reference ion peak) Examples 6~+x (Compounds -, 6~! in Tables 7 and 8) In the same manner, various substituted cinnamic acid amide derivatives were synthesized using the corresponding substituted cinnamic acid chlorides and amines as starting materials. and mass spectrum measurement results are shown in Tables 1 and 3.

By the same method as in Example Tei, N-(3,9dimethoxyphenethyl)-N,N'-dimethylgropylene-ha 3
-Diaminetei 03■ (i, 6 mmol) and 3. Tadimethoxycinnamoyl chloride Hereinafter, pharmacological tests on the antitachycardia effect and vasodilator effect, which are the characteristics of the compound of the present invention as a pharmaceutical, will be described.

Example 4t7 A pharmacological test was conducted on the antitachycardia effect of the compound of the present invention using guinea pigs. The method and results are shown below.

Hartlay male guinea pigs weighing approximately Sθop were used. After hitting him in the back of the head and dislocating his neck, his heart was separated and removed. In Krebs-Henslide solution (KH solution)? Under j%02-j%CO□ gas ventilation, ventricular muscle, blood vessels, and surrounding connective tissue were peeled off, and the left and right atria were separated.

Apply a self-in to the right atrial appendage, ligate the other side, apply the thread to the big amplifier, and q! ;%0□-5% In a nutrient tank filled with KHH2O2 at 37°C under CO2 gas aeration, approximately 0.0% was placed.
．． It was fixed with a tension of 111. Thirty minutes after the start of incubation, the KH solution was replaced, and the mixture was left to stand for an additional 30 minutes. After the movement of the atrium became stable, ingroterenol/θ-8M was added.

After about 7 S minutes, after the heart rate stabilized, the compound of the present invention was added cumulatively, and the drug concentration (EC3o) that reduced the heart rate by 30% before addition of the compound was determined. The results are shown in the table below.

Table q * For comparison, nee (N-methyl-N(3, cudimethoxyphenethyl) aminopropyl l -s, 6-cymethoxyphthalimidine-l-off (AQA-J?) (JP-A-Sho!; l -//3gl, l, see publication.] was also subjected to a similar test.

Example g Regarding the relaxing effect of the compound of the present invention on the contraction induced by norepinephrine (NE) in isolated rat blood vessels,
Pharmacological tests were conducted. The method and results are shown below. Male Wistar rats were used. Hit the back of the head,
After exsanguination, the thoracic aorta was removed. Adipose tissue was removed in Krebs-Henslid solution (KH solution), and the width was approximately 3p.
A ring-shaped piece was prepared by cutting into m, and the section was further incised in the long sleeve direction.
The animal was suspended and fixed in a nutrient tank filled with H2O2 along the course of the orbicularis muscle, and incubation was performed while replacing the KH solution every 30 minutes. (Tension o, sg) approx./hour Norepinephrine (NE) #7-7M was added and contracted, then washed with KH solution. This was repeated every hour, and after the third contraction, the present invention was applied to the specimen. compound was added. After relaxing for -0 minutes, add 3 x 10-5 M of bapaperine hydrochloride and
Contractile force was measured until maximum relaxation was reached in minutes.

The relaxation rate of the compound was expressed as a percentage of the maximum relaxation by bapaverine. The results are shown in Table 5 below.

Table S It was shown to.

Table 6 *A similar test was conducted as comparative data.

Examples Acute toxicity test Acute toxicity tests of the compounds of the present invention were conducted using mice, and the methods and results are shown below.

<Method> The compound of the present invention suspended in a 7% aqueous tragacanth solution was orally administered to male JCI:ICR mice (SPF) (6 stations) by forced administration using a metal stomach tube for mice.
After a two-day observation period, Litchfield-Wi
Acute toxicity value (LD5o) was calculated by lcoxon method. The results are shown in Table 6 below. [Effects of the Invention] The compounds of the present invention have pharmacological effects such as antitachycardia and vasodilatory effects, and are effective against circulatory system effects such as antiarrhythmic drugs, antianginal drugs, and antihypertensive drugs. It is useful as a medicine.

applicant

Claims (1)

[Claims] (1) The following general formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, X and Y are each independently a hydrogen atom, a halogen atom, a trifluoromethyl group, or a carbon number of 1 to 5 represents an alkyl group or an alkoxy group having 1 to 5 carbon atoms, and a
, b and m each independently represent an integer of 1 to 3,
Z represents an optionally substituted alkylene group having 2 to 4 carbon atoms, R^1 represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or a benzyl group, and R^2 represents an optionally substituted alkylene group having 1 to 8 carbon atoms; Represents an alkyl group or a benzyl group. Also R^1 and Z
are connected to each other to form a cyclic diamino group represented by the following formula ▲ There is a mathematical formula, chemical formula, table, etc. ▼ or the following formula ▲ There is a mathematical formula, chemical formula, table, etc. ▼ (wherein R^2 has the same meaning as above) R^2 and Z may be connected to each other to form the following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or the following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1
may represent a cyclic diamino group represented by (same meaning as above). ] Substituted cinnamic acid amide derivatives or pharmaceutically acceptable acid addition salts thereof.