JPH08807B2 - Novel homoveratryl amine derivative and method for producing the same - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel homoveratrylamine derivative and a method for producing the same.

[Conventional technology]

It is well known that many homoveratryl amine compounds exhibit useful physiological actions, and that these compounds are used as pharmaceuticals. For example, verapamil is known to have a strong calcium antagonism and thereby exhibit a blood pressure lowering action (Sin-El-Protto and Peter, "Drax", Vol. 15, 1978, 169-197).
See page). As other homoveratryl amine compounds, N-methyl-N-bis (3,4-dimethoxyphenethyl) useful as a therapeutic agent for cardiovascular diseases and cerebral circulation disorders
Amine derivative (see JP-A-59-62553), substitution 1,5
-Diaminopentane derivatives (see JP-A-58-88343), ω-cyano-1, ω-diphenylazaalkane derivatives (see JP-A-57-181050) and the like have been reported.

[Problems to be solved by the invention]

The present inventors have synthesized novel homoveratryl amines in which pentanenitrile groups having various heterocycles are introduced as substituents on the nitrogen atom of homoveratryl amine, and these compounds show strong calcium antagonistic activity. It has been found to be useful as a therapeutic drug for cardiovascular disease.

[Structure and Description of the Present Invention]

The present invention has the general formula (In the formula, Het represents an optionally substituted pyridyl group, pyrrolyl group, furyl group, benzofuranyl group, benzoxazolyl group, benzothienyl group, benzimidazolyl group)
A novel homoveratryl amine derivative represented by and an acid addition salt thereof.

INDUSTRIAL APPLICABILITY The homoveratrylamine derivative (I) and its acid addition salt of the present invention are compounds having an excellent antihypertensive action based on calcium antagonistic action and useful as a medicine.

The pyridyl group, pyrrolyl group, furyl group, benzofuranyl group, benzoxazolyl group, benzothienyl group, bezothiazolyl group or benzimidazolyl group for the substituent Het of the compound of formula I may have the following atoms or groups . Halogen atom such as chlorine atom, bromine atom, etc., lower alkyl group such as methyl group, ethyl group, propyl group, butyl group, etc., lower alkoxy group such as methoxy group, ethoxy group, propoxy group, butoxy group, etc., nitro group, amino group, An alkylamino group, an aminoalkyl group or an alkylaminoalkyl group.

Examples of compounds of formula I include:

2-isopropyl-2- (2-pyridyl) -5-[(3,
4-dimethoxyphenethyl) methylamino] pentanenitrile (Ia), 2-isopropyl-2- (3-pyridyl) -5-[(3,
4-dimethoxyphenethyl) methylamino] pentanitrile (1b), 2-isopropyl-2- (4-pyryl) -5-[(3,
4-dimethoxyphenethyl) methylamino] pentanenitrile (1c), 2- (1-methyl-2-pyrrolyl) -2-isopropyl-5-[(3,4-mizetoxyphenethyl) methylamino] pentane Nitrile (1d), 2- (2-furyl) -2-isopropyl-5-[(3,4
-Dimethoxyphenethyl) methylamino] pentanenitrile (Ie), 2- (2-benzofuranyl) -2-isopropyl-5-
[(3,4-Dimethoxyphenethyl) methylamino] pentanenitrile (If), 2- (2-benzoxazolyl) -2-isopropyl-5
-[(3,4-Dimethoxyphenethyl) methylamino] pentanenitrile (Ig), 2- (2-benzothienyl) -2-isopropyl-5
[(3,4-Dimethoxyphenyl) methylamino] pentanenitrile (Ih), 2- (2-benzothiazolyl) -2-isopropyl-5
-[(3,4-Dimethoxyphenethyl) methylamino] pentanenitrile (Ii), 2- (1-methyl-2-benzimidazolyl) -2-isopropyl-5-[(3,4-dimethoxyphenethyl) ) Methylamino] pentanenitrile (Ij), 2- (6-methoxy-2-benzothiazolyl) -2-isopropyl-5-[(3,4-dimethoxyphenethyl) methylamino] pentanenitrile (Ik).

Compounds of formula I have the general formula (Wherein Het has the above meaning), an acetonitrile derivative represented by the general formula It can be produced by reacting with a compound represented by the formula (X represents a halogen atom).

This reaction is carried out in a solvent in the presence of sodium hydrogen, sodium amide and the like. As the solvent, for example, benzene,
Toluene, xylene, dimethylformamide, dimethylsulfoxide and the like and mixtures thereof are used.

The reaction temperature is preferably 60 ° C. to the boiling point of the solvent, and the reaction is completed in 4 to 8 hours.

Compounds of formula II may, for example, the general formula Het-CH ₂ CN IV (wherein Het is as defined above) is obtained by reacting isopropyl bromide acetonitrile derivative represented by the.

This reaction is carried out in a solvent in the presence of caustic, caustic-triethylamine, sodium hydride, sodium amide and the like. As the solvent, for example, benzene, toluene, xylene, dimethyl sulfoxide, etc., and a mixture thereof are used.

The reaction temperature is room temperature to the boiling point of the solvent, preferably 60 to
100 ° C. When the reaction is carried out at a relatively low temperature, it is preferable to stir the reaction mixture. The reaction is usually completed in 1 to 3 hours.

In the compound of formula II, α-isopropyl-3-pyridylacetonitrile, α-isopropyl-1-methyl-2-pyrrolylacetonitrile, α-isopropyl-2-furylacetonitrile, α-isopropyl-2-benzoxazolylacetonitrile, α-isopropyl-2-benzothienylacetonitrile, α-isopropyl-2-benzothiazolylacetonitrile, α-isopropyl-1-methyl-2-benzimidazolylacetonitrile and α-isopropyl-6-methoxy-2-benzothiazolylacetonitrile Is a novel compound.

The compound of formula I has the general formula It can also be obtained by reacting an acetonitrile derivative represented by the formula (wherein Het and X have the above meanings) with N-methylhomoveratrylamine.

This reaction is carried out without solvent or in a solvent which does not participate in the reaction, for example, alcohol, and a base such as triethylamine,
It is preferable to carry out in the presence of pyridine and the like.

The reaction temperature is preferably 60 to 120 ° C, and the reaction is usually 4 to 8
Complete in time.

The compound of formula V is obtained by converting the acetonitrile derivative of formula II into α, γ
It can be prepared by reacting with dihalogenopropane under the conditions of normal alkylation. This product (V)
Can be used without isolation and purification.

The reaction product (I) can be isolated and purified by a conventional method, for example, by appropriately combining extraction, column chromatography, recrystallization and the like.

The compounds of formula I can optionally be acid addition salts. As the acid therefor, physiologically acceptable acids such as hydrochloric acid, fumaric acid, maleic acid, and citric acid are preferable.

Test Example A production test was conducted using the following test compounds. 2-
(2-Benzofuranyl) -2-isopropyl-5-
[(3,4-Dimethoxyphenethyl) methylamino] pentanenitrile (If compound), 2- (2-benzoxazolyl) -2-isopropyl-5-[(3,4-dimethoxyphenethyl) methylamino] Pentanenitrile (compound of Ig) and 2- (2-benzothiazolyl) -2-isopropyl-5
-[(3,4-Dimethoxyphenethyl) methylamino] pentanenitrile (compound of Ii).

1. Calcium Antagonism Test Using male and female rabbits having a body weight of 2 to 3 kg, anesthesia was performed by intravenous administration of pentobarbital sodium, and then the femoral artery was exsanguinated to death, and the thoracic aorta was immediately removed. The excised blood vessel was used as a spiral sample. Aerated with a mixed gas of 95% oxygen and 5% carbon dioxide, kept at 37 ° C, and 10 ml.
Nutrient solution (NaCl147.2, KCl5.4, CaCl ₂ 2.2, MgCl ₂ 1.0, N
The excised blood vessel sample was suspended in a Magnesian tube containing aHCO ₃ 14.9 and glucose 5.6 mM) under a tension of 1.5 g. KC as a control
10 to 20 mM (0.1 ml of KCl1M solution) was cumulatively administered, and the blood vessels were gradually contracted to obtain a dose-response line. Then, 10 minutes after the administration of the test drug (using 3 doses), the dose of KCl was again measured-
Obtain the response line and calculate the contraction height obtained by administration of 40 mM KCl as 1
The concentration of the test drug that suppresses the contraction height of the control by 50% was determined as the ED ₅₀ value. The results are shown in Table 1.

2. Antihypertensive test Male SHR weighing 280-350g (systolic blood pressure 180-230mmHg)
After fasting for about 15 hours, the test drug was orally administered, and changes in systolic blood pressure were measured over time using a noninvasive blood pressure measuring device (NARCO, PE-300). Table 2 shows the results.
The systolic blood pressure in the table shows the maximum change in each dose of the test drug.

As is clear from the above results, the compound of the present invention was known to have a calcium antagonistic action and a hypotensive action based thereon.

Reference Example 1 Production of α-isopropyl-3-pyridylacetonitrile Isopropyl bromide 20.9 g (0.169 mol), sodium hydroxide 13.5 g (0.338 mol) and triethylamine 0.94
2-pyridylacetonitrile 10 g (0.085 mol) was added to g (0.9 x 10 ^-3 mol) while heating at 60 ° C in a nitrogen stream,
Heat and stir at 80-90 ° C for 3 hours. After cooling, ice water is added and the mixture is extracted with ether. The ether layer is washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The resulting black-brown oily substance is distilled under reduced pressure to obtain 9.9 g (73.0%) of α-isopropyl-3-pyridylacetonitrile as a yellowish oily substance having a boiling point of 77 ° C / 0.2 mmHg.

Elemental analysis value: C H N theoretical value (%) as C ₁₀ H ₁₂ N ₂ 74.97 7.55 17.48 Experimental value (%) 74.94 7.56 17.46 Similarly, α-isopropyl-2- which is a known compound.
Pyridylacetonitrile, α-isopropyl-4-pyridylacetonitrile and α-isopyropyr-2-benzofuranylacetonitrile were obtained.

Reference Example 2 Production of α-isoproyl-2-benzothiazolylacetonitrile 10 ml of anhydrous toluene was added to 1.25 g (2.6 × 10 ^-2 mol) of 50% atrium hydride, and anhydrous toluene-dimethylsulfoxide (2: 1 was added under stirring at room temperature. ) 2. Benzothiazolyl acetonitrile 3.48 g (2 x 10 ^-2
Mol) and stirred in a nitrogen stream for 2 hours. Then add 3.69 g (3 × 10 ^-2 mol) of isopropyl bromide, and add 90
Heat and stir at ~ 100 ° C for 2 hours. After cooling, ice water is added to the reaction mixture and the mixture is extracted with ether. The ether layer is washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained yellow-red oily substance was subjected to silica gel column chromatography to obtain ethyl acetate-n.
-A yellow crystalline residue is obtained from the eluate of hexane (1: 7). When recrystallized from n-hexane, the melting point is 56-57.
1.66 g (47.7%) of α-isopropyl-2-benzothiazolylacetonitrile are obtained as yellowish needle crystals at ℃.

Elemental analysis value: C H N theoretical value (%) 66.63 5.59 12.95 experimental value (%) 66.89 5.62 13.06 as C ₁₂ H ₁₂ N ₂ S The following compounds are obtained in the same manner.

α-isopropyl-1-methyl-2-pyrrolylacetonitrile Yield: 32.6% Colorless oil, ▲ n ²⁴ _D ▼: 1.4973 Elemental analysis: C ₁₀ H ₁₄ N ₂ · 1 / 10H ₂ O CHN theory Value (%) 73.22 8.73 17.07 Experimental value (%) 73.28 8.86 16.98 α-Isopropyl-2-furylacetonitrile Yield: 31.3% Yellowish oil, boiling point: 95 ° C / 20mmHg ▲ n ²⁴ _D ▼: 1.4622 Elemental analysis: As C ₉ H ₁₁ NO ・ 1 / 10H ₂ O CH N theoretical value (%) 71.73 7.94 9.30 experimental value (%) 71.59 7.45 9.20 α-isopropyl-2-benzoxazolylacetonitrile yield: 56.9% yellowish candy Substance, ▲ n ²⁴ _D ▼: 1.5335 Elemental analysis value: C ₁₂ H ₁₂ N ₂ O CH N theoretical value (%) 71.98 6.04 13.99 Experimental value (%) 71.78 6.09 13.97 α-isopropyl-2-benzothienylacetonitrile yield: 49.0% colorless fine needle crystals, mp: 69-71 ° C. elemental analysis: C ₁₃ H ₁₃ NS as C H N Logical value (%) 72.52 6.09 6.51 Found (%) 72.34 6.10 6.43 alpha-isopropyl-1-methyl-2-benzimidazolyl acetonitrile. Yield: 56.7% colorless needles, mp 105-106 ° C. Elemental analysis: C ₁₃ CH ₃ as H ₁₅ N ₃ theoretical value (%) 73.21 7.09 19.70 experimental value (%) 73.40 7.22 19.81 α-isopropyl-6-methoxy-2-benzothiazolylacetonitrile yield: 53.3% yellowish oil, ▲ n ²⁴ _D ▼: 1.5811 Elemental analysis value: C ₁₃ H ₁₄ N ₂ OS C H N theoretical value (%) 63.39 5.73 11.37 Experimental value (%) 63.13 5.73 11.30 Example 1 2-isopropyl-2- (2-furyl) ) -5-[(3,4
Preparation of -dimethoxyphenethyl) methylamino] pentanenitrile α-isopropyl-2-furylacetonitrile 600 mg
(4 × 10 ⁻³ mol), N- (3-chloropropyl) -N-
To 11 g (4 × 10 ⁻³ mol) of methyl homoveratrylamine and 362 mg (9.3 × 10 ⁻³ mol) of sodium amide were added 15 ml of anhydrous toluene, and the mixture was heated under reflux for 4 hours in a nitrogen stream.

After cooling, ice water is added to the reaction mixture and the mixture is extracted with ether.
The ether layer is washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained reddish brown oily matter was subjected to silica gel column chromatography to obtain 458 mg of a yellowish oily matter from the elution part of chloroform-methanol (98: 2). When this oily substance was recrystallized from ethanol-ether by forming a oxalate salt in ethanol, 2-isopropyl-2- (2-furyl) -5-[(3,4) was obtained as a colorless powder having a melting point of 139-140 ° C. 508 mg (26.8%) of dimethoxyphenethyl) methylamino] pentanenitrile (oxalate) are obtained.

Elemental analysis value: C ₂₃ H ₃₂ N ₂ O ₃ · (CO ₂ H) ₂ C H N theoretical value (%) 63.28 7.22 5.90 Experimental value (%) 63.32 7.21 5.87 The following compounds are obtained in the same manner.

2-isopropyl-2- (4-pyridyl) -5-[(3,
4-dimethoxyphenethyl) methylamino] pentanenitrile (silic acid salt) Yield: 19.0% colorless granular crystals, melting point: 154-155 ° C (ethanol-ethyl acetate) Elemental analysis value: C ₂₄ H ₃₃ N ₃ O ₂・ (CO ₂ H) ₂ CH N theoretical value (%) 64.31 7.26 8.65 experimental value (%) 64.05 7.23 8.59 2- (1-methyl-2-benzimidazolyl) -2-isopropyl-5 [(3 , 4-Dimethoxyphenethyl) methylamino] pentanenitrile (silic acid salt) Yield: 49.5% Colorless fine needle crystals, melting point: 134-135 ° C (methanol-ether) Elemental analysis value: C ₂₇ H ₃₆ N ₄ O ₂ · (CO ₂ H) ₂ · H ₂ O CHN theoretical value (%) 62.57 7.24 10.06 Experimental value (%) 62.54 7.08 10.05 Example 2 2-isopropyl-2- (2-benzothiazolyl) -5
Preparation of-[(3,4-dimethoxyphenethyl) methylamino] pentanenitrile 10 ml of a mixed solvent of 0.42 g (10.8 x 10 ^-3 mol) of sodium amide and anhydrous toluene-dimethyl sulfoxide (1: 1)
And α-isopropyl-2-benzothiazolylacetonitrile 1.44 g (8.3 × 10 ^-3 mol) were added with stirring at room temperature,
Heat and stir at 50-60 ° C for 1 hour. Then, 2.6 g (16.5 × 10 ⁻³ mol) of 1-bromo-3-chloropropane was added at the same temperature, and the mixture was stirred for 1 hour. After cooling, it is poured into ice water and extracted with ether. After washing the ether layer with water and saturated saline,
After drying over anhydrous magnesium sulfate, the solvent and excess 1-bromo-3-chloropropane were distilled off under reduced pressure to give a crude oily α- (3-chloropropyl) -α-isopropyl-2-benzothiazolylacetonitrile. 2.1 g are obtained. The crude product is purified by silica gel column chromatography [ethyl acetate-n-hexane (1: 7)] to give a yellowish oil of (n ²⁴ _D) 1.5702.

To 1.75 g of the obtained crude α- (3-chloropropyl) -α-isopropyl-2-benzothiazolylacetonitrile, 2.33 g (12 × 10 ⁻³ mol) of N-methylhomoveratrylamine and 4 ml of triethylamine were added, Heat at reflux for 8 hours. After cooling, add ice water and extract with ether. The ether layer is washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The resulting yellow oil is subjected to silica gel column chromatography, and 2.35 g of a yellowish oil is obtained from the elution part of chloroform-methanol (98: 2). The oil was formed into oxalate salt in methanol and recrystallized from ethanol to give a melting point of 17
As colorless needles at 4-175 ° C, 2-isopropyl-2-
(2-Benzothiazolyl) -5-[(3,4-dimethoxyphenethyl) amino] pentanenitrile (silic acid salt)
2.25 g (60.4%) are obtained.

Elemental analysis value: C ₂₆ H ₃₃ N ₂ O ₂ S · (CO ₂ H) ₂ C H N theoretical value (%) 62.09 6.51 7.76 Experimental value (%) 61.92 6.65 7.68 Similarly, the compounds shown in Table 3 were obtained. can get. The upper column of the elemental analysis value column in the table is the theoretical value, and the lower column is the experimental value.

Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI Technical display area C07D 307/54 307/79 333/60 // A61K 31/34 31/38 31/40 ABN 31/415 31 / 42 31/425 31/44 ADD (72) Inventor Senichi Narita 6-14-7 Ryoke, Urawa-shi, Saitama (56) Reference JP-A 61-289090 (JP, A) JP-A 61-106578 (JP, A) Japanese Patent Publication Sho 49-46629 (JP, B1)

Claims (3)

[Claims] 1. A general formula (Wherein Het represents an optionally substituted pyridyl group, a pyrrolyl group, a furyl group, a benzofuranyl group, a benzoxazolyl group, a benzothienyl group or a benzimidazolyl group), and a novel homoveratryl amine derivative and an acid addition salt thereof. . 2. General formula (Wherein Het represents an optionally substituted pyridyl group, pyrrolyl group, furyl group, benzofuranyl group, benzoxazolyl group, benzothienyl group or benzimidazolyl group), a compound represented by the general formula A general formula characterized by reacting with a compound represented by the formula (wherein X represents a halogen atom) A process for producing a novel homoveratryl amine derivative represented by the formula (wherein X has the above meaning). 3. General formula (Wherein Het represents an optionally substituted pyridyl group, pyrrolyl group, furyl group, benzofuranyl group, benzoxazolyl group, benzothienyl group or benzimidazolyl group, X
Represents a halogen atom) and is reacted with N-methyl homoveratryl amine. A process for producing a novel homoveratryl amine derivative represented by the formula (wherein X has the above meaning).