JPH01190658A - Phenylacetonitrile derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I (R1 is H, lower alkyl or lower alkoxy lower alkyl; R2 is H, lower alkyl or benzyl; R3 is H, lower alkyl, lower alkoxy or halogen) and an acid addition salt thereof. EXAMPLE:alpha-[3-[2-(5-Fluoro-2-trimethoxyphenoxy)ethylamino]propyl]-a lpha- isopropyl-3,4,5-trimethoxyphenylacetonitrile.fumarate. USE:A hypotensor a remedy for urination difficulty. PREPARATION:An aldehyde derivative shown by formula II is reacted with an amine derivative shown by formula III in a solvent such as methanol, ethanol or THF and then treated with a reducing agent such as NaBH4 to give a compound shown by formula I.

Description

Detailed Description of the Invention - No. 1 The present invention provides a phenylacetonitrile derivative that has excellent sympathetic α-receptor blocking action and is useful as an antihypertensive agent and a therapeutic agent for dysuria, and a pharmacologically acceptable phenylacetonitrile derivative thereof. This invention relates to acid addition salts.

Yoshiyoshi Masayoshi: ``Drugs that block sympathetic α-receptors are being actively researched both domestically and internationally, and have already been shown to be effective against 1-(4-amino-6.
7-Simethoxy2-quinazolinyl)-4-(2-furanylcarbonyl)piperazine [generic name: prazo/n: The Merck Index, 10th edition, 7610 and other drugs have been used clinically as antihypertensive agents. It is provided.

In recent years, it has also been discovered that this type of compound is effective as a therapeutic agent for dysuria.

u(J, yo)! However, it cannot be said that this type of drug is necessarily a perfect drug in terms of efficacy and safety. development is desired.

As a result of intensive research in view of the above circumstances, the present inventors discovered that the phenylacetonitrile derivative according to the present invention has an excellent sympathetic α-receptor blocking effect, and the present invention completed.

That is, the present invention relates to the general formula (1) (wherein R represents a hydrogen atom, a linear or branched lower alkyl group, or a lower alkoxy lower alkyl group, and R2
represents a hydrogen atom, a lower alkyl group or a benol group,
R3 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom. ) and its pharmacologically acceptable thallic acid addition salts.

In the general formula (1) of the present invention, the lower alkoxy lower alkyl group represented by R is, for example, 2-methynethyl, 2-ethoxyethyl, 2-n-propoxyethyl, 3-methoxypropyl.

4-methquinbutyl, 3-ethoxypropyl group, etc. are %R
, R2 and R3 include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and 5ec-butyl.

Examples of the lower alkoxy group represented by R3 include tert-butyl group, methoxy, nidoxy, n-propoxy,
Examples of the halogen atom include impropoxy and n-butoxy groups, and examples of the halogen atom include fluorine, chlorine, bromine, and iodine atoms.

Examples of the pharmacologically acceptable acid addition salts of the compound represented by the general formula (I) of the present invention include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid. salt,
Or acetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, malic acid.

Examples include organic acid salts such as tartaric acid.

The novel phenylacetonitrile derivative represented by the general formula (I) of the present invention can be produced by various methods.

According to the first mode of the method for producing a compound according to the present invention, the compound represented by the general formula (I) is produced by the following general formula (
If) an aldehyde derivative represented by (wherein R represents the same meaning as above) and the following general formula (III) (wherein R and R3 represent the same meaning as above) It can be produced by reacting an amine derivative with an amine derivative in a solvent and then treating with a reducing agent.

Any solvent may be used in the method of the present invention as long as it does not inhibit the reaction, such as methanol, ethanol, and n-butanol.

Examples include ether and tetrahydrofuran.

Examples of reducing agents used in this reaction include:
Examples include sodium borohydride and lithium aluminum hydride.

Further, the reaction is carried out in a range from room temperature to the reflux temperature of the solvent used.

In addition, +1i, which was the starting material in the production method of the present invention
Some of the aldehyde derivatives represented by the general formula (II) described in j are disclosed in JP-A-53-25539 and JP-A-62-1261.
The compound is known from No. 60, and other novel compounds are also produced as shown in the figure below.

(In the formula, R1 represents the same meaning as above, R4 represents a lower alkyl group, and X and Y represent a halogen atom.) According to the second mode of the method for producing a compound according to the present invention, the general formula Among the compounds represented by (I), a compound in which R2 is a hydrogen atom can be produced by hydrogenating a compound in which R2 is a benzyl group in the general formula (I) in the presence of a metal catalyst. .

Examples of the metal catalyst used in this reaction include Raney nickel, platinum oxide, palladium on carbon, and the like.

Further, examples of the solvent used in this reaction include hydrochloric acid, acetic acid, methanol, and ethanol.

The compound represented by the general formula (1) of the present invention can be formulated into tablets, capsules, powders, granules, injections, suppositories, etc. by a conventional method using formulation additives commonly used for pharmaceuticals. It can be done.

The dosage for treatment of liquid medicine for patients with both cardiovascular and urinary system diseases is usually 1 to 1 dose per day for adults.
00gg.

The present invention will now be explained by way of example, but the invention is not limited to the specific details of this example.

Example 1 α-[3-[2-(5-fluoro-2-methquinphenoxy/)ethylaminocopropyl-α-isopropyl-
3,4,5-trimethoxyphenylacetonitrile fumarate 4-cyano-4-isopropyl-4-(3,4°5-trimethoxyphenyl)butyroaldehyde 1.27 g, 2
A solution of 0.70 g of -(5-fluoro-2-methoxyphenoxy)ethylamine in 251 methanol is heated under reflux for 2 hours. After cooling, add sodium borohydride O to the mixture.
, leg and stirred at room temperature for 1 hour. After the reaction, the solvent is distilled off, and the resulting residue is made acidic by adding 10% hydrochloric acid, washed with ether, and then extracted with chloroform. After washing the chloroform layer with an aqueous potassium carbonate solution, it is washed with water and dehydrated. After evaporating the solvent, the residue was converted into a fumarate salt in a conventional manner and recrystallized from Improper Tool to obtain 1.93 g of a colorless prism product having a melting point of 141-142''.

Elemental analysis value C26H35F N 20s・C4H40
4 Theoretical values C, G1.01; H, G, GG; N,
4.74 Experimental value C, GO, 88; H, G, 71
; N, 4.89 According to the method of Example 1, the compounds of Examples 2 to 12 are obtained.

Example 2 α-[3-[2-(2,3-dimethoxyphenoxy/)ethylaminocopropyl]-α-isopropyl-3,4,
5-trimethoxyphenylacetonitrile hydrochloride Properties Colorless needle crystals (EtOll-Et20) Melting point 15
1 to 153 @ Elemental analysis value C27H3BN 2 o6 ・HCI theoretical value C, G2.00; H, 7,52; N, 5.
3B experimental value C, G1.79; H, 7, EiO;
N, 5.29 Example 3 α-isopropyl-α-[3-[2-(2-propoxyphenoxy/)ethylaminocobropylco-3,4,5-
Trimethoxyphenylacetonitrile fumarate Properties Colorless needle crystals (EtOH-Et20) Melting point 16
2.5-164° Elemental analysis value C28H4oN205/C4H404 theoretical value C, G3.98; H, 7,38; N, 4.
6G experimental value C, G3.99; H, 7,69; N
, 4゜56 Example 4 α-[3-[2-(2-Butquinphenoxy)ethylaminocobropyl-α-inpropyl-3,4,5-trimethoxyphenylacetonitrile I/2 oxalate・L/2 hydrate Properties Colorless needle crystals (EtOH-1so-Pr20) Melting point 128.5-130° Elemental analysis C29H42N2o5・+/2C2H20
4・l/2H20 theoretical value C, G5.20; H, 8
,02; N, 5.07 experimental value C, 1li4.94
; H, 7,90; N, 4.88 Example 5 α-[3-[2-(2,4-dimethoxyphenoxy/)ethylamino]propyl-α-isopropyl-3,4,
5-) Rimethoxyphenylacetonitrile fumarate Properties Colorless needle crystals (EtOH-Et20) Melting point 133
~134° Elemental analysis value C27H38N206 ・C4H404 theoretical value C, G1.78; H, 7,02; N, 4
．． 1li5 experimental value C, G1.39; H, 7,08
; N, 4.43 Example 6 α-[3-[2-(2,5-dimethoxyphenox7)ethylamino]propyl]-α-isopropyl-3,4,
5-)' Rimethoxyphenylacetonitrile fumarate Properties Colorless scale crystals (EtOH) Melting point 142-145" Elemental analysis C27H3BN206", C4H4o
4 Theoretical value C, lEl, 78; H, 7,02; N
, 4.65 experimental value C, 1li1.75; H, 7
, 14; N, 4.60 Example 7 α-inpropyl-α-[3-[2-(2-methoxy-
5-methylphenoxy)ethylamino]propylco 3
．． 4.5-Trimethoxyphenylacetonitrile Properties Pale yellow liquid IR spectrum ν (liq) cta-': 22
3G (CN) NMR spectrum δ (CDC13)
I) pll '0.81 (30, d, J=6.5Hz
), 1.21 (31(, d, J: [i, 5 Hz).

1.96 (IH, s), 2.27 (3H, s), 2.9
3 (2H, t, J=5Hz).

3.79 (31, s), 3.85 (3H, s), 3.8
G (61,s), 4.0G (2H,t, J:5Hz)
t6.58 (2H, S), G, C8-Ei, 74
(3H4) High resolution mass spectrum” C27H3B
N 205 theoretical value ts/z: 470.2781 experimental value -/z: 470.27711i Example 8 α-[3-[2-(2-benzyloxyphenoxy/)ethylamino]propylco α-isopropyl-3, 4,
5-) Rimethoxyphenylacetonitrile 1/2 oxalate 1/2 hydrate Properties Colorless needle crystals (MeOH) Melting point 164-185° Elemental analysis C32H40N205-1/2 C2H2
04-1/2820 theoretical value C, 67, 56; H, 7
,22;N, 4.77Experimental value C,67,7G;
H,7,34;N, 4.78 Example 9 α-[3-[2-(2-ethoxyphenoxy)ethylaminocopropyl]-α-ethyl-3,4°5-trimethoxyphenylacetonitrile Properties Light Yellow liquid IR spectrum ν (llq) czen-1: 223
B(CN) NMR spectrum δ (CDC13) p
pm: 0.94 (3H, t, J=7.5112), 1
．． 40 (3■+t+C7Hz).

1.93 (IH, brs), 2.94 (28, t, J
:5Hz), 3.85 (3H.

s), 3.86(6)1. s>, 4.05 (2B, q,
J Near Hz), 4.09 (2H.

t, J: 5Hz), 11i, 59 (2H, s), 6.8
9(4H,s) high resolution mass spectrum: C26G3
6 N 20s theoretical value ta/z: 4511i, 2
624 Experimental value IIIHz: 45G, 2B25 Example 1O α-[3-[2-(2-methquinphenoxy)ethylamino]propylco 3.4.5-Trimethquine phenylacetonitrile hydrochloride hydrate Properties colorless Needle crystals (E
tOH-Et20) Melting point 112-114° Elemental analysis value C23H3oN205・HCl11H20
Theoretical value C, 58,91; H, 7,09; N, 5.
97 experimental value C, 58, 50; H, 7, 1G; N,
5.87 Example 11 α-(2-methoxyethyl)-α-[3-[2-(2-
methoxyphenoquine) ethylaminocopropyl]-3,
4,5-Trimethquine phenylacetonitrile oxalate Properties Colorless crystals (Neon-Et20) Melting point 175~
176゜Elemental analysis value CHN O11C2H204 theoretical value C,
59,78; H, 6,81; N, 4.98 Experimental value C, 59,85; H, G, 97; N, 4.89
Example 12 α-(2-ethoxy7ethyl)-α-[3-[2-(2-
methoxyphenoxy)ethylaminocopropyl]-3,
4,5-) Rimethquine phenylacetonitrile oxalate Properties Colorless crystals (MeOH) Melting point 160-161° Elemental analysis CHN O11C2H204 Theoretical value C,
GO, 40; H, G, 99; N, 4.8G experimental value C, GO, 17; H, F, 14; N, 4.82
Example 13 α-[3-[2-(2-hydroxyphenoxy)ethylaminocobropylco α-isopropyl-3,4,5-
Trimethquine phenylacetonitrile fumarate α-[3-[2-(2-pennoquinphenoquine)ethylaminocopropyl coα-isopropyl-3,4,
5-) 2.80 g of rimethoxyphenylacetonitrile,
A methanol 601 solution containing 0.28 g of platinum oxide is hydrogenated at room temperature and pressure.

The catalyst is filtered off, and the filtrate is evaporated to remove the solvent. The residue was treated with column chromatography (silica gel, eluted with a chloroform-methanol mixture) to obtain 1.40 g of a colorless liquid.
get. This is converted into a fumarate salt according to a conventional method and recrystallized from methanol to obtain a colorless plate having a melting point of 190.5 to 192.5°.

Elemental analysis value C25H34N205/C4H404 theoretical value C, 62,35; H, 6,8G; N, 5. Old experimental values C, G2.18; H, G, 70; N,
4.951 The novel phenylacetonitrile derivatives and conductors represented by the general formula (I) and their pharmacologically acceptable acid addition salts produced in this way have excellent sympathetic nerve α - It has a receptor blocking effect and is extremely useful as a therapeutic agent for various types of hypertension and dysuria.

Claims (1)

[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ (In the formula, R_1 represents a hydrogen atom, a linear or branched lower alkyl group, or a lower alkoxy lower alkyl group,
R_2 represents a hydrogen atom, a lower alkyl group, or a benzyl group, and R_3 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a halogen atom. ) A phenylacetonitrile derivative represented by: and a pharmacologically acceptable acid addition salt thereof.