JPS62289560A - Novel homoveratrylamine derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A homoveratrylamine derivative of formula I [Het is (substituted) pyridyl, pyrrolyl, furanyl, benzofuranyl, benzoxazolyl, benzothienyl, benzothiazolyl or benzoimidazolyl] and its acid addition salt. EXAMPLE:2-Isopropyl-2-(2-furanyl)-5-[(3,4-dimethoxyphenetyl)methylamin o]penta nenitrile. USE:It has strong calcium antagonistic action and is useful as a remedy for circulatory diseases. Characteristic feature of the compound is the use of pentanenitrile group having various heterocyclic group as a substituent group introduced to the nitrogen atom of homoveratrylamine. PREPARATION:The compound of formula I can be produced either by reacting the compound of formula II with the compound of formula III (X is halogen) or by reacting the compound of formula IV with N-methylhomoveratrylamine.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel homoveratrylamine derivative and a method for producing the same.

[Conventional technology]

It is well known that many homoveratrylamine compounds exhibit useful physiological effects, and these compounds are used as pharmaceuticals. For example, verapamil has a strong calcium antagonistic effect, and is known to have a hypotensive effect (Seinerplot and Peter, "Drugs", Vol. 15, 1978, p. 16).
(See pages 9-197). Other homoveratrylamine compounds include N-methyl-N-bis(3,4-dimethoxyphenethyl)amine derivatives (see JP-A-59-62553), which are useful as therapeutic agents for cardiovascular diseases and cerebral circulation disorders. ), substituted 1,5-diaminopentane derivatives (see JP-A-58-88343), ω-cyano-1,
ω-Diphenylazaalkane derivatives (JP-A-57-18
(see Publication No. 1050) have been reported.

[Problem that the invention seeks to solve]

The present inventors synthesized novel homoveratrylamines in which he/tanenitrile groups having various heterocycles were introduced as substituents on the nitrogen atom of homoveratrylamines, and demonstrated that these compounds have strong calcium antagonistic properties. It has been found that the compound has active effects and is useful as a therapeutic agent for circulatory system diseases.

[Structure of the present invention and its explanation]

The present invention relates to a novel homozygous compound represented by the general formula (wherein Het represents an optionally substituted pyridyl group, pyrrolyl group, furanyl group, benzofuranyl group, benzoxacylyl group, benzothenyl group, benzothiazolyl group or benzimidazolyl group). Veratrylamine derivatives and acid addition salts thereof.

The homoveratrylamine derivative (I) of the present invention and its acid addition salt are compounds useful as pharmaceuticals, having an excellent antihypertensive effect based on calcium antagonism.

The pyridyl, pyrrolyl, furanyl, benzofuranyl, benzoxacylyl, benzothenyl, benzothiazolyl or benzimidazolyl group of the substituent He1t of the compound of formula I may have the following atoms or groups: Halogen atoms such as chlorine and bromine; lower alkyl groups such as methyl, ethyl, propyl and butyl; lower alkoxy groups such as methoxy, ethoxy, propoxy and butoxy; nitro and amino groups; Alkylamino group, aminoalkyl group or alkylaminoalkyl group.

Examples of compounds of formula I include the following:

2-isopropyl-2-(2-pyridyl)-5-C(3
,4-dimethoxyphenethyl)methylaminocopentanenitrile (Ia), 2-inpropyl-2-(6-pyridyl)-5-C(3
,4-dimethoxyphenethyl)methylaminecupentanenitrile (Ib), 2-isopropyl-2-(4-pyridyl)-5-I:
(3,4-dimethoxyphenethyl)methylaminocupentanenitrile (Ic), 2-(1-methyl-2-pyrrolyl)-2-inpropyl-5-((S,a-dimethoxyphenethyl)methylaminocopentanenitrile (Ia) ), 2-(2-furanyl)
-2-inpropyl-5-((3,4-dimethoxyphenethyl)methylaminecupentanenitrile (Is), 2 (2-benzofuranyl)-2-inpcobyl-5
-((3,4-dimethoxyphenethyl)methylaminocopeatanenitrile (If), 2-(2-benzoxasilyl)-2-isopropyl-5-1: (3,4-dimethoxyphenethyl)methylaminecupentane Nitrile (I
g), 2-(2-benzochenyl)-2-i:/7' lobi-5-((5,4-dimethoxyphenethyl)methylamine cupentanenitrile (Ih), 2-(2-benzothiazolyl)-2-isopropyl -5-((3,4-dimethoxyphenethyl)methylaminocopentanenitrile (Ii), 2-(1-methyl-2-penzimitazoryl)-2-isopropyl-5-C(3,4-dimethoxy phenethyl) methylaminocopentanenitrile (Ij), 2-(6-medoxy-2-benzothiazolyl)-2-isopropyl-5-((3,4-dimethoxyphenethyl)
Methylamine Cupitanitrile (Ik).

The compound of formula (1) is a compound represented by the general formula (wherein X represents a halogen atom), which is an acetonitrile derivative represented by the general formula Het CHI [CH(CH,)2 (wherein Het has the above-mentioned meaning). It can be produced by reacting with

This reaction is carried out in a solvent with sodium hydride, sodium amide,
It is carried out in the presence of de, etc. Examples of solvents used include benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide, and mixtures thereof.

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

The compound of formula (1) is, for example, a compound of the general formula Hs t -CH2CN (wherein Het
is obtained by reacting an acetonitrile derivative represented by (has the above-mentioned meaning) with isopropylbromide.

This reaction is carried out in a solvent in the presence of caustic alkali, caustic alkali-triethylamine, sodium hydride, sodium amide, etc. Examples of solvents that can be used include alcohol, toluene, xylene, dimethyl sulfoxide, and mixtures thereof.

The reaction temperature is room temperature to the boiling point temperature of the solvent, preferably 60 to
The temperature is 100°C. When reacting at a relatively low temperature, it is preferable to stir the reaction mixture. The reaction is usually completed in 1 to 6 hours.

Among the compounds of 2), α-isopropyl-6-pyridylacetonitrile, α-inpropyl-1-methyl-2-pyrrorylacetonitrile, α-ingrobyl-2-furanylacetonitrile, α-ingrobyl-2-benzooxacylylacetonitrile, α -isopropyl-2-benzochenylacetonitrile, α-inpropyl-2-benzothiazolyl acetonitrile, α-isopropyl-1-
Methyl-2-benzimidazolylacetonitrile and α
-Isopropyl-6-medoxy 2-benzothiazolyl acetonitrile is a new compound.

Compounds of formula I have the general formula CN He t-C-CH2Cd2CH2X VCH
It is obtained by reacting an acetonitrile derivative of the formula (CH3)2 (Het and/or having the meanings given above) with N-methylmoveratrylamine.

This reaction is carried out without a solvent or in a solvent that does not participate in the reaction, such as alcohol, and is preferably carried out in the presence of a base such as triethylamine, pyridine, etc.

The reaction temperature is preferably 60 to 120°C, and the reaction is usually carried out at 4 to 120°C.
Complete in 8 hours.

The compound of formula V is an acetonitrile derivative of formula
It can be produced by reacting with dihalogenopropane under conventional alkylation conditions. This product (Vl) can be used without isolation and purification.

The reaction product (I) can be isolated and purified by conventional methods, for example, by appropriately combining extraction, column chromatography, recrystallization, etc.

The compound of formula (1) can be made into an acid addition salt if desired. The preferred acid is a physiologically acceptable acid such as hydrochloric acid, fumaric acid, maleic acid or oxalic acid.

test, inspection Biological tests were conducted using the following test compounds.

2-(2-Benzofuranyl')-2-isopropyl-5
-CC6,4-dimethoxyphenethyl)methylaminocopenta/nitrile (compound of If), 2-(2-benzoxasilyl)-2-isopropyl-5-C(3,4-
dimethoxyphenethyl)methylaminocopentanenitrile (Ig compound) and 2-(2-benzothiazolyl)-2-inopropyl-5
-[(3,4-dimethoxyphenethyl)methylaminecupentanenitrile (compound 11).

1. Calcium antagonism test Male and female rabbits weighing 2-Skg were anesthetized by intravenous administration of bendoparbital sodium, then sacrificed by femoral artery exsanguination, and the thoracic aorta was removed at maturity. The extracted blood vessels were made into spiral specimens. Aerate a mixed gas of 95% oxygen and 5% carbon dioxide and maintain at 67°C.
10ml of nutrient solution (NaC1147.2, KCI 5.
4, CaCL□2.2, Lig C12,1,01Na
The excised blood vessel specimen was suspended under a tension of 1.5 g in a Magnes tube containing 14.9 mM HCO and 5.6 mM glucose. KCl 10-20mM (KCI
A dose-response curve was obtained by cumulatively administering 0.1 rnl of 1M solution to gradually constrict blood vessels. Then, 10 minutes after administration of the test drug (using the S dose), the dose-response curve of KCI was obtained again, and the contraction height obtained by administering 40 mM of KCl was taken as 100%, and the test subject suppressed the contraction height of the control by 50%. The drug concentration was determined based on the ED5° value. The results are shown in Table 1.

Table 1 Inhibitory effect on contraction by KCI Z Blood pressure lowering effect test Male sgR weighing 280-350 g (systolic blood pressure 180
~250mrttHg) after fasting for about 15 hours,
The test drug was orally administered, and a non-volatile blood pressure measuring device (MARC) was used.
Changes in systolic blood pressure were measured over time using PE-300). The results are shown in Table 2. The systolic blood pressure in the table indicates the maximum change in the dose of the test drug.

Table 2 As is clear from the above results, the compounds of the present invention were known to have a calcium antagonistic effect and a dish pressure lowering effect based on the calcium antagonistic effect.

Reference Example 1 Production of α-Inglovir-6-pyridylacetonitrile Inpropylbromide 20.99 (0,169 mol)
, sodium hydroxide 13.5.9 (0,358 mol) and triethylamine 0.94 g (0,9X 10-
2-pyridylacetonitrile 10 & (0,085 mol) was added to the solution (0,085 mol) while heating to 60°C in a nitrogen stream, and the mixture was heated and stirred at 80 to 90°C for 3 hours. Next, add ice water and extract with ether.

The ether layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. When the resulting dark brown oil was distilled under reduced pressure, it had a boiling point of 77°C/0.
9.9 g of α-isopropyl-6-pyridylacetonitrile (75,
0%) is obtained.

Elemental analysis value: CHN as C+oHt□N2 Theoretical value (%) 74.97 7.55 17.
48 Experimental value (%) 74.94 7.56 1
7.46 Similarly, the known compounds α-ingrobyl-2-pyridylacetonitrile and α-isopropyl-4
-pyridylacetonitrile and α-ingrovir-2-
Benzofuranylacetonitrile was obtained.

Reference Example 2 Production of α-isopropyl-2-benzothiazolyl acetonitrile 1.25 g of 50% sodium hydride (2,6×10
-2 mol), add 10 ml of anhydrous toluene, and
Anhydrous toluene-dimethyl sulfoxide (2:
2-Benzothiazolylacetonitrile (3.46.1x2-X 10-2 mol) dissolved in 6Qml of the mixed solvent of 1) was added dropwise and stirred for 2 hours in a nitrogen stream. Then, 3.69 p (3X 10-2 mol) of inpropylbromide is added, and the mixture is heated and stirred at 90-100'C for 2 hours. from now on,
Add ice water to the reaction mixture and extract with ether. The ether layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting yellow-red oil was subjected to silica gel column chromatography, and a yellow crystalline residue was obtained from the eluate of ethyl acetate-n-hexane (1N). When this is recrystallized from n-hexane, α-ingloby-2-benzothiazolyl acetonitrile 1°66
, ¥ (47.7%).

Elemental analysis value: CHN as Cl2H1□N2S Theoretical value (%) 66.63 5.59 12.
95 experiments (direct (%) 66.89 5.62
13.06 The following compounds are obtained in the same manner.

α-inopropyl-1-methyl-2-pyrrorylacetonitrile Yield: 32.6% Colorless oil, sweetness: 1.4973 Elemental analysis: CloH1JT2・1/'IOH
C3N as 2O Theory f direct (%) 73,22 8.71
17.07 experimental value f%) 75.28 8.
86 16.98α-isopropyl-2-7 ranylacetonitrile Yield: 51.3% Yellowish oil, boiling point = 95°C/20mmHg hood: 1.4
622 Elemental analysis value: CQHIINO・1710 CHN as H2O Theoretical value (%) 71.73 7.94 9.3
0 experimental value (%+ 71.59 7.45 9.
20α-inpropyl-2-benzoxasilylacetonitrile Yield: 561% Yellowish candy, n”p: 1.5365 Elemental analysis value CHN as 201□H,2N20 Theoretical value (%) 71.98 6. 04 13.
99 Experimental value (%) 71.78 6.09 1
3.97α-isopropyl-2-benzochenylacetonitrile Yield: 49.0% Colorless fine needles, melting point: 69-71°C Elemental analysis value 2C
13H13N C'HN as S Theoretical value (%) 72-52 6.09 6.5
1 Experimental value (%) 72.64 6.10 6.
46α-isopropyl-1-methyl-2-penzimidazolylacetonitrile Yield: 56.7N6 Colorless needle crystals, melting point 105-106°C Elemental analysis value CHN as C15Ht5N3 Theoretical value (%) 73.21 7.09 19 ．．
70 Experimental value (%) 73.40 7.22 1
9.81 α-isopropyl-6-methoxy-2-benzothiazolyl acetonitrile Yield: 56.3% Yellowish oil, continued: 1.5811 Elemental analysis: CHN theoretical value as C13H,4NtO3 (%l 66. 69 5.7611.37
Experimental value (%) 63.13 5.73 1ti
Example 1 2-inpropyl-2-(2-furanyl)-5-((3
, 4-dimethoxyphenethyl) methylaminocopentanenitrile production α-isopropyl-2-furanylacetonitrile 600
■(4x1o-'mol), N-(5-chloropropyl)
-N-methyl homoveratrylamine 1.1.9 (4X
10-3 mol) and sodium amide 662rn9 (
15 g of anhydrous toluene was added to 9.3×10 −3 mol) and heated under reflux in a nitrogen stream for 4 hours.

Afterwards, ice water is added to the reaction mixture and extracted with ether. The ether layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting reddish-brown oil was subjected to silica gel column chromatography, and a yellowish oil 45819 was obtained from the chloroform-methanol (98:2) eluate. This oil is recrystallized from ethanol-ether by forming the oxalate salt in ethanol to give 2-isopropyl-2-(2-furanyl)-5-((
3,4-dimethoxy7enethyl)methylaminecupentanenitrile (oxalate) 508 m9 (26,8%
) is obtained.

Elemental analysis value: c23a,,N,C3・(C○2H)2
CHN Theoretical value (%) 63.28 7.22 5.9
0 Experimental value (%) 63.32 7.21 5.
The following compound is obtained in the same manner as 87.

2-isopropyl-2-(4-pyridyl)-5-C(3
,4-Dimethoxyphenethyl)methylamine cupentanenitrile (silicate) Yield: 19.0% Colorless granular crystals, melting point: 154-155°C (ethanol ethyl acetate) Elemental analysis: C24H33N302・(C02H)z
CHN Theoretical value (%) 64.31 7.26 &65
Experimental value (%) 64.05 7.23 8.592-(1
-Methyl-2-benzimidazolyl)-2-inpropyl-5-[(3,4-dimethoxyphenethyl)methylaminocopentanenitrile (oxalate) Yield: 495% Colorless fine needles, melting point: 134~ 165°C (methanol-ether) Elemental analysis value: CttHs6NaOt (C02H)2
CHN theoretical value (%) as ΦH20 62.57 7.24 10.
06 Experimental value (%) 62.54 7.08 1
0.05 Example 2 2-isopropyl-2-(2-benzothiazolyl)-5
-1: Production of (5,4-dimethoxyphenethyl)methylaminocopentanenitrile Sodium amide 0.42g
(10,8X 10-3 mol) was added with 10 ml of a mixed solvent of anhydrous toluene-dimethylsulfoxide (1:1), and while stirring at room temperature, α-isopropyl-2-benzothiazolyl acetonitrile t44.9 (8,3X 10- 3 mol) and stirred while heating at 50 to 60°C for 1 hour. Next, at the same temperature, 2.6 g of 1-promo-3-chloropropane (16
, 5X 10-3 mol) and stirred for 1 hour. From now on, I'll put it in ice water and extract it with ether. The ether layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent and excess 1-promo-3-chloropropane were distilled off under reduced pressure to form a yellow oil with the gas composition α-(3-chloropropyl). 2.1 g of )-α-ingrobyl-2-benzothiazolyl acetonitrile are obtained. This crude product was purified by silica gel column chromatography [ethyl acetate-n
-hexane (1nia)], n241.
5702 becomes a yellowish oily substance.

Obtained crude α-(6-chloropropyl)-α-isopropyl-2-benzothiazolyl acetonitrile 1.75
2.33 g of N-methyl homoperatolylamine (12
x 10-3 mol) and triethylamine 4 mol),
Heat to reflux for 8 hours.

Next, add ice water and extract with ether. The ether layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting yellow oil was subjected to silica gel column chromatography to obtain 2.35 g of a yellowish oil from the chloroform-methanol (98:2) eluate. Formation of the oxalate salt of this oil in methanol and recrystallization from ethanol gives 2-improvil-2-(2-pentthiazolyl)-5-(( 3,4
-dimethoxyphenethyl)amine]pentanenitrile (
2.25 g (60.4%) of oxalate) are obtained.

Elemental analysis value: C26H33N202S” (C02
CHN as H)2 Theoretical value (%) 62.09 6.51 7.7
6 Experimental value (%) 61.92 6.65 7.
Compounds shown in Table 6 were obtained in the same manner as No. 68.

The upper row of the elemental analysis value column in the table is the theoretical value, and the lower row is the experimental value.

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. A novel homoveratrylamine derivative represented by a thienyl group, a benzothiazolyl group or a benzimidazolyl group, and an acid addition salt thereof. 2. General formulas ▲ Numerical formulas, chemical formulas, tables, etc. (representing a benzimidazolyl group),
General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, X represents a halogen atom) There are general formulas ▲mathematical formulas, chemical formulas, tables, etc., characterized by reacting a compound represented by A method for producing the novel homoveratrylamine derivative.