JPS634827B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to new derivatives of 3,4,5-trimethoxycinnamoylpiperazine, processes for their preparation and their use in therapy. These new compounds more precisely have the general formula [In the formula, R is (a) formula

2-methylthioethoxy group of [Formula], (b) an ester group of formula COOR ₁ (wherein R ₁ represents a 2-ethyl-n-butyl group, a phenyl group or a 3-methyl-n-butyl group, the latter (c) a carbamate group of formula NH-COOR ₂ (wherein,
R ₂ is a group selected from the group consisting of a methyl group, a linear or branched alkyl group having 3 to 5 carbon atoms, a cycloalkyl group having 5 or 6 carbon atoms, or a benzyl group. This corresponds to [representation]. Additionally, the present invention refers to pharmaceutically acceptable salts of compounds of formula (), ie, salts of non-toxic organic and inorganic acids, especially salts of hydrochloric, oxalic, maleic and the like. Compounds of formula () in which R represents a 2-methylthioethoxy group, and special formulas To prepare compounds of formula () except for compounds of formula () corresponding to 3,4,5-trimethoxycinnamoylpiperazine having the formula (b), (c) or (
d) (In each formula, R' ₁ is a 2-ethyl-n-butyl group or a phenyl group, and R ₂ ' is a methyl group, 3
to an epoxide having a linear or branched alkyl group having 5 carbon atoms or a cycloalkyl group having 5 to 6 carbon atoms. The compounds of formula (b) and (c) are new;
With epichlorohydrin or epibromohydrin in acetonitrile (or acetone) in the presence of potassium carbonate, the formula (wherein R ₁ ' and R ₂ ' have the same meanings as in formulas (b) and (c)) are subjected to reflux condensation. The novel compound of formula (d) is prepared by combining epichlorohydrin with epichlorohydrin in benzyl alcohol in the presence of potassium carbonate. It can be obtained by condensing the compound. Compounds of formula (b), (c) and formula (d) are novel in which the benzyl group of compounds of formula (b) and (c, d) is converted to hydrogen in the presence of palladium-carbon (5%) in ethanol medium. Obtained by addition decomposition. (However, in the above formula, R′ ₁ has the same meaning as in formula (b), and R ₂ ″ is a methyl group, a straight or branched chain alkyl group having 3 to 5 carbon atoms,
(represents a cycloalkyl group or phenyl nucleus having 5 to 6 carbon atoms). The novel compound of formula (b) has been awarded Belgian patent no.
Formula listed in 865990 A compound having the formula () R′ ₁ OH () (where R′ ₁ has the same meaning as in formula (b)) is then treated with thionyl chloride.
It is obtained in a two-step operation by treatment with alcohol. Novel compounds of formula (c, d) in which R″ ₂ is a methyl group, isopropyl group, n-butyl group, isobutyl group, or phenyl group can be prepared by:
Chlorformiate having the formula () Cl-CO-OR ₃ () (wherein R ₃ represents a methyl group, isopropyl group, n-butyl group, isobutyl group or phenyl group) and Belgian patent no. The formula given in .865990 It is obtained by reacting with the compound of R ₂ ″ is n-propyl group, 3-methylbutyl group,
New compounds of formula (c, d) representing a cyclopentyl group or a cyclohexyl group are those of the formula () R ₄ OH () (wherein R ₄ is an n-propyl group, 3-methylbutyl group, cyclopentyl group or cyclohexyl group). ) and an alcohol having the formula (XI) isocyanate having the following. The novel compound of formula (XI) can be obtained by reacting a compound of formula () with phosgene. To prepare compounds of formula () in which R represents a 2-methylthioethoxy group, 1-chloro-2-methylthioethane and the formula described in Belgian patent no. is condensed with a compound having In the process of the invention for preparing compounds of formula (a), in an acetone or acetonitrile medium in the presence of potassium carbonate, a compound of formula () and a compound of formula () condensate with the compound. To obtain a compound of formula (), use formula () The compound is reacted with para-toluenesulfonyl chloride. Furthermore, to obtain a compound of formula (), the formula () The compound of is hydrolyzed in acetone medium. The compound of formula () itself has the formula () tosylate (J.Org.Chem. 42.1006 , (1977))
and the compound (b) in which R' ₁ represents a 3-methyl-n-butyl group. Next, the present invention will be explained using examples. Example 1 3,4,5-trimethoxycinnamoylpiperazine () and formula (b), (c) or (d)
A solution containing the compound in ethanol was brought to reflux. The solvent was evaporated, the residue was dissolved in acetone, oxalic acid in acetone was added and the precipitate was removed to give the desired product. This method gave the compounds of formula () shown in the following table with code numbers 10-19 and 71.

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[Table] Example 2 1-[4-(2-methylthioethoxy)-2・3
-ethylenedioxy)phenoxy]-3-[4-
(3,4,5-trimethoxycinnamoyl)piperazin-1-yl]-2-propanol hydrochloride hydrate () Code No.: 2 13.3g of 1-(4-hydroxy-2,3-ethylenedioxy) ) Phenoxy-3-[4-(3・4・
5-trimethoxycinnamoyl)piperazine-1
-yl]-2-propanol (XII) and 3.5 ml of 1
-Chloro-2-methylthioethane and 10.3 g of potassium carbonate were refluxed in 150 ml of ethanol for 18 hours. The solution was evaporated and the residue was taken up in chloroform and washed with water. The solvent phase was dried over sodium sulphate, the solvent was evaporated and the residue was chromatographed on silica gel. Chloroform and chloroform (99%)-methanol (1%)
After elution with a mixture of 13 g of pure product were obtained. This was dissolved in acetone, 4.5 ml of about 6.5 N hydrochloric acid ethanol was added, the precipitate was collected, dissolved in as little alcohol as possible, and diluted with acetone to obtain 9.35 g of product. Melting point: 175℃ Molecular formula: C ₃₀ H ₄₁ ClN ₂ O ₉ S + 7/6H ₂ O Elemental analysis value: C H N Calculated value (%) 54.41 6.60 4.23 Experimental value (%) 54.31 6.37 4.07 Example 3 Production of compound (b) First step: Preparation of compound (b) Thionyl chloride was added to the toluene solution of (5-benzyloxy-1,4-benzodioxane)-8-ylcarboxylic acid and the mixture was heated to 70-80°C for 2 hours. The solvent was evaporated and the residue was taken up in tetrahydrofuran and the alcohol compound () and triethylamine were added. Mixture at 60℃
The mixture was heated for an hour to remove the formed precipitate. The liquid was evaporated and the residue was chromatographed on silica gel, eluting with methylene chloride. This product was used as a raw material for the synthesis of the compound of formula (b). Using the same method but using the corresponding reagents, the compounds designated by codes No. 27 and 78 in Table 2 below were obtained. 2nd step: Production of compound (b) A solution containing the compound of formula (b) obtained in the previous step in 200 ml of ethanol was added to 2 g of palladium-
Hydrogenolysis was carried out in the presence of carbon (5%) under pressure and at room temperature. The desired product was then obtained by filtration and evaporation of the solvent. This compound was used as a raw material for the synthesis of the compound of formula (b). Using the same method but using the corresponding reagents, the compounds of formula (b) shown as codes No. 35 and 84 in Table 2 below were obtained. Third step: Preparation of compound (b) A mixture containing the compound of formula (b) obtained in the previous step, epibromohydrin and potassium carbonate in acetonitrile was refluxed for 4 hours. The solution was evaporated, the residue was taken up in methylene chloride, washed with water, and washed with 1N NaOH solution.
Dry over sodium sulfate and evaporate the solvent. The residue was recrystallized from ethyl acetate to obtain the desired product. Using the same method but using the corresponding reagents, the compounds of formula (b) shown as codes No. 43 and 90 in Table 2 below were obtained.

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[Table] Example 4 5-(2,3-epoxypropoxy)-8-methoxycarbonylamino-1,4-benzodioxane (c) Code No.: 62 1st step: 5-benzyloxy-8-methoxycarbonylamino -1,4-Benzodioxane (c, d) Code No.: 44 25g of 5-amino-8-benzyloxy-1.
A solution containing 4-benzodioxane () in 250 ml of tetrahydrofuran and 17.6 ml of triethylamine was cooled to 0°C, 1 ml of methyl chloroformate was added slowly and then stirred for 7 hours. The solution was washed with dilute hydrochloric acid solution, water, sodium bicarbonate solution, and water. The solvent was evaporated and the residue was recrystallized from ethyl acetate. 17.8 g of product was obtained. Yield: 58% Melting point: 100°C Molecular formula: C ₁₇ H ₁₇ NO ₅ NMR spectrum (CDCl ₃ ): δppm=7.4, d;
6.5, d and 4.3, s (6 benzene protons) = 6.82, s (NH-CO-) = 7.4, m and 5.18, s

[Formula] = 3.76s (COOCH ₃ ) IR spectrum (KBr): Carbamate absorption bands at 3420 and 1715 cm ^-1 Compounds of formula (c, d) were obtained in the same manner, but from the corresponding reagents. These are Table 3
shown as codes No. 46, 47, 48 and 52. Second step: 5-hydroxy-8-methoxycarbonylamino-1,4-benzodioxane (
c) Code No.: 53 Compound of formula (c, d) obtained in the above step, code
A solution containing 17.8 g of No. 44 in 400 ml of ethanol was hydrolyzed under pressure at room temperature in the presence of 2 g of palladium-charcoal powder (5%). passed,
Evaporation of the liquid gave 11.5 g of product. This was used in the next step. Yield: 90% Melting point: 150℃ NMR spectrum (CDCl ₃ ): δppm=7.95, s
(OH) = 7.30, d; 6.50, d and 4.3, s (6 benzene protons) = 7, S (NH-) = 3.78, s (COO- _CH3 ) IR spectrum (KBr): carbamate absorption band,
3410 and 1710 cm ^-1 . By the same method, but with the corresponding reagent, the code
Compounds of formula (c) from No. 54 to 60 and Table 3
A compound of formula (d) represented by code No. 61 was obtained. Third step: 5-(2,3-epoxypropoxy)-
8-Methoxycarbonylamino-1,4-benzodioxane (c) Code No.: 62 11 g of the compound of formula (c) with code No. 53 obtained in the above step, 23 ml of epibromohydrin, and potassium carbonate. A suspension containing 17 g of
Evaporate the liquid and take up the residue in chloroform.
It was washed with water and the solvent was evaporated. The product (13g) is
It was used to synthesize the compound of formula () with code No. 11 in Table 1. Melting point: 134°C NMR spectrum (CDCl ₃ ): δppm=7.5, d;
6.6, d and 4.35, s (6 benzodioxane protons) = 6.90, s (-NH-) = 4.20, m; 3.4, m and 2.80, m (5 protons

[Formula]) IR spectrum (KBr): Carbamate absorption bands at 3415 and 1710 cm ^-1 . The same method, but with the corresponding reagent,
Table 3 shows codes 63 to 69 (
The compound c) was obtained. Example 5 5-benzyloxy-8-cyclopentyloxycarbonylamino-1,4-benzodioxane (c, d) Code No.: 50 1st step: (5-benzyloxy-1,4-benzodioxane)-8- isocyanate (XI) 77 g of 8-benzyloxy-5-amino-1.
A solution of 4-benzodioxane () in 500 ml of toluene was adsorbed with 100 g of phosgene.
The mixture was allowed to return to room temperature, the solvent was evaporated, and the residue was crystallized from hexane. 62 g of product was obtained.
This was used as the raw material for the next step. 2nd step: 5-benzyloxy-8-cyclopentyloxycarbonylamino-1,4-benzodioxane (c, d) Code No.: 50 9 g of the product obtained in the previous step (compound of formula (XI)) , 200ml tetrahydrofuran and 10ml
5.3 g of cyclopentanol was added to the solution containing triethylamine and refluxed for 48 hours. The solvent was evaporated and the residue was taken up in chloroform, washed with water, dried over sodium sulfate, the solvent was evaporated and the residue was crystallized from hexane to give 9 g of product. This was used to synthesize the compound of formula (c) shown as code No. 59 in Table 3. Yield: 78% NMR spectrum (CDCl ₃ ): δppm=7.4, d;
6.5, d and 4.3, s (6 benzodioxane protons) = 7.4, m and 5.05, s (5 protons

【formula】) =5.10, m and 1.75, m9 protons

[Formula]) IR spectrum (KBr): Carbamate absorption bands at 3415 and 1710 cm ^-1 Using the same method, the formula (c,
Compounds of d) (codes No. 45, 49 and 51 in Table 3)
I got it. Example 6 8-benzyloxycarbonylamino-5-
(2,3-Epoxypropoxy)-1,4-benzodioxane (d) Code No.: 70 10 g of the compound of formula (d) (Code No. 61) obtained by the method of Step 2 of Example 4; A suspension containing 20 ml of epibromohydrin, 10 g of benzyl alcohol and 15 g of potassium carbonate in 200 ml of acetonitrile was refluxed for 6 hours. It was then filtered, the liquid was evaporated and the residue was taken up in chloroform, washed with water, dried over sodium sulfate and the solvent was evaporated. The residue was recrystallized from ethyl acetate. Yield: 75% Melting point: 110℃ Molecular formula: C ₁₉ H ₁₉ NO ₆ elemental analysis value: C H N Calculated value (%) 63.86 5.36 3.92 Experimental value (%) 63.27 5.26 3.80

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[Table] Example 7 3-[8-(3-Methyl-n-butyloxycarbonyl)-1,4-benzodioxan-5-yl]oxy-1-[4-(3,4,5-trimethoxycinnamate) moyl)piperazin-1-yl]-
2-propanol [S(-)] chlorohydrate (
a), Code No.: 72 1st step 4-[8-(3-methyl-n-butyloxycarbonyl)-1,4-benzodioxan-5-yl]
Oxymethyl-1,3-dioxolane [S] (
) 14.5 g of the compound of formula (b), where R′ ₁ =3−
methyl-n-butyl; code No. 32), 17.5 g of the compound of formula () and 38 g of potassium carbonate.
The suspension contained in 300 ml of dimethylformamide was refluxed for 12 hours. The solution was evaporated and the residue was chromatographed on a silica column. Elution with ethyl acetate (5-20%)/hexane (95-80%) gave 8 g of the desired product. Yield: 30% Melting point: 85°C Molecular formula: C ₂₉ H ₂₈ O ₇ [α] ²⁰ _D ] = minus 13.2° (C = 1, ethanol) NMR spectrum: δppm = 7.4, d; 6.5, d, and 4.35, s (6 benzodioxane protons) = 4.25, t (-COO-CH ₂ -) = 4.12, m

[Formula] = 1.65, m(-CH ₂ -CH) = 1.4, d

【formula】 =0.95,d

[Formula] Second stage 3-[8-(3-methyl)-n-butyloxycarbonyl-1,4-benzodioxan-5-yl]oxy-1,2-propanediol [s]
() A solution containing 7 g of the compound of formula () in 100 ml of acetone and 36 ml of 1N hydrochloric acid was refluxed for 3 hours. Then evaporate the acetone,
The residue was taken up in methylene chloride, neutralized with sodium bicarbonate, the organic phase was washed with diaphragm, water and washed with water.
It was dried over magnesium sulfate, filtered, the solvent was evaporated and the residue was recrystallized from ethyl acetate. Yield: 92% Melting point: 100℃ Molecular formula: C ₂₆ H ₂₄ O ₇ [α] ²⁰ _D ] = plus 4.8° (C = 4, methanol) NMR spectrum (DMSO): δppm = 7.35, d;
6.6, d and 4.22, (6 benzodioxane protons) = 4.10, t(-COO- _CH2- ) = 4.9, d and 4.6, t

【formula】 =3.95,m and 3.45,m

[Formula] =1.52, m(-CH ₂ -CH) =0.95, d

[Formula] Third step 3-[8-(3-methyl-n-butyloxycarbonyl)-1,4-benzodioxan-5-yl]
Oxy-1-[4-(3,4,5-trimethoxycinnamoyl)piperazin-1-yl]-2-propanol[S(-)]hydrochloride hydrate (a) code
No.: 72 5.7 g of the diol of formula () obtained above
A solution containing in 10 ml of pyridine and 100 ml of benzene was cooled to 0°C, and 2.4 g of tosyl chloride was slowly added. The mixture was left at room temperature for 45 hours, diluted with benzene and ether, washed with 1N hydrochloric acid, water, filtered, and the solvent was evaporated. 7.3 g (95%) of tosylate of formula () was obtained. Dissolved in 50 ml of acetonitrile, 3.67 g of the compound of formula () and 5 g of potassium carbonate were dissolved in 50 ml of acetonitrile.
ml of acetonitrile. It was refluxed in a nitrogen bath for 15 hours, filtered, the liquid was evaporated and the residue was taken up in methylene chloride. Washed with water, dried over magnesium sulphate, filtered and evaporated. 8g (98%) of desired product
I got it. Dissolved in 100ml of methyl ethyl ketone.
Hydrochloric acid gas was passed through the mixture to collect the formed precipitate. 3g. Yield: 37% Melting point: 162℃ Molecular formula: C ₃₃ H ₄₅ ClN ₂ O ₁₀ +4/5H ₂ O [α] ²⁰ _D = minus 7.8° (C = 2, methanol) Elemental analysis value C H N Calculated value (%) ) 57.63 6.96 4.07 Experimental value (%) 57.71 6.95 3.92 The compound of formula () showed anti-cardiac ischemic activity in tests using experimental animals. Anti-cardiac ischemic activity was demonstrated in anesthetized (sodium pentobarbital 30 mg/Kg/iv) dogs. Oxygen consumption in the left ventricle was estimated by the product of the coronary venous flow rate multiplied by the difference (%) between the arterial and venous oxygen content of the coronary vessels. Coronary venous flow velocity was measured at the coronary venous sac using a modified Morawitz cannula introduced under radioscopic control. Arterial and venous oxygen content was measured with a blood gas analyzer (IL Meter213). Cardiac activity was measured using the KATZ index, which is the average blood pressure multiplied by the number of strokes. The heart rate was measured from the electrocardiogram recorded in lead _D2 . Systemic blood pressure was measured in the aorta using a pressure sensor (SANBORN267-BC). The compound of formula () and the reference compound are
Table 4 shows the results of LIDOFLAZINE and AMIODARONE injections. Test compounds were administered intravenously by slow perfusion.

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[Table] From the above, the difference between the therapeutically effective dose and the toxic dose is sufficiently wide, and the compound of formula () can be used as an anti-cardiac ischemic agent in the treatment of cardiovascular system failure. I understand. It is administered intravenously as an ampule for injection containing 60 to 120 mg of active ingredient, or in the form of a tablet, pill or capsule containing 20 to 200 mg of active ingredient, 1 to 3 times a day.

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Claims (1)

[Claims] 1 formula [In the formula, R is (a) [Formula] (b) -COOR ₁ (In the formula, R ₁ is a 2-ethylbutyl group,
phenyl group or 3-methylbutyl group, the latter compound being the levorotatory enantiomer of the S structure) and (c) -NH-COOR ₂ (wherein R ₂ is a methyl group, 3-
and pharmaceutically acceptable salts thereof. 2 formulas [In the formula, R is (a) [Formula] (b) -COOR ₁ (In the formula, R ₁ is a 2-ethylbutyl group,
phenyl group or 3-methylbutyl group, the latter compound being the levorotatory enantiomer of the S structure) and (c) -NH-COOR ₂ (wherein R ₂ is a methyl group, 3-
alkyl group of 5 carbon atoms, cycloalkyl group of 5 or 6 carbon atoms, or benzyl group] and pharmaceutically acceptable salts thereof. A pharmaceutical composition for treating diseases of the cardiovascular system in combination with a pharmaceutical carrier. 3 formulas A compound with the formula or (wherein R' ₁ is a 2-ethylbutyl group or a phenyl group, and R' ₂ is a methyl group, an alkyl group having 3 to 5 carbon atoms, or a cycloalkyl group having 5 or 6 carbon atoms) with the epoxide of
characterized by condensation in an alcoholic medium, the formula [In the formula, R is -COOR ₁ (in the formula, R ₁ is a 2-ethylbutyl group or a phenyl group), and -NHCOOR ₂ (in the formula, R ₂ is a methyl group, an alkyl group having 3 to 5 carbon atoms) , a cycloalkyl group having 5 or 6 carbon atoms, or a benzyl group]. 4 1-chloro-2-methylthioethane and the formula in the presence of potassium carbonate in an ethanolic medium, with the formula A method for producing a compound having 5 formula A compound with the formula in the presence of potassium carbonate, with the formula A method for producing a compound having