JPS6048503B2 - Novel 1-phenyl-2-aminoethanol derivative - Google Patents

Description

[Detailed description of the invention] OHR1CH3 j1.1 , --CH-1-CH-1-NH-1-C-1-C
H2-(X)m-1 In the above formula, X is a hydrogen atom, a hydroxyl group,
The present invention relates to a hydroxymethyl group, a halogen atom or a methylsulfamoyl group, m is a number of 1 or 2, and R1, R2 and R5 are the same but different.The present invention relates to a novel 1-phenyl-2-aminoethanol derivative.

The compound of the present invention is represented by the following formula. R3R.

-Ho-CH--C--CH3(I), each a hydrogen atom or a methyl group, JR.

is a hydrogen atom, R. represents a hydrogen atom or a hydroxyl group, or R. and R. may be taken together to represent a double bond.
Since the compounds of the present invention have at least one asymmetric carbon atom, the present invention also includes optically active forms and racemic forms thereof. The compound of the present invention may be prepared by, for example, the general formula (wherein -COCH2Hal or -COCHO, where R1 has the above-mentioned meaning, and Hal shows a chlorine atom or a bromine atom). It can be easily produced by reacting a compound represented by (having a meaning).

As for the reaction conditions, when Y is a group in compound ①,
The objective compound 1 is obtained by heating Compound (1) and Compound (2) in a solvent in a sealed tube at 80 to 100°C for 1 to 30 hours.

When Y is a group -C(1)CH2HaI, the target compound I can be obtained by stirring compound (1) and compound (2) in a solvent at 0 to 10'C for 1 to 3 hours and reducing the resulting compound. can get. When Y is a group -COCHO, the target compound 1 can be obtained by adding a reducing agent to Compound (1) and Compound (2) in a solvent with ice-cooling and stirring for several hours.
As the solvent, for example, methanol, ethanol, acetonitrile, etc. are used.

As the reducing agent, for example, a catalytic reduction catalyst such as palladium or palladium oxide, or a complex metal hydride compound such as lithium aluminum hydride or sodium borohydride can be appropriately selected and used. In a reaction involving a reduction step, it is preferable to protect the compound (1) having a hydroxyl group or hydroxyalkyl group as a substituent with an appropriate protecting group such as a benzyl group or an acyl group.

The protecting group of the protected hydroxyl group or hydroxyalkyl group is removed by, for example, hydrolysis, hydrogenolysis, or the like. R3
A compound of formula 1 in which R4 and R4 together form a double bond can be produced by the same reaction as described above, starting from the corresponding compound (2) having a double bond. Compound 1 in which R3 is a hydrogen atom and R4 is a hydrogen atom or a hydroxyl group can also be produced by cleaving this double bond by a conventional method. The position of the substituent X in the phenyl group is not particularly limited, whether it is one or two. The compound of the present invention has β-receptor stimulating action and is useful as a therapeutic agent for asthma, and is usually used in the form of a salt. Preferred salts include, for example, hydrochloride, sulfate, maleate, tartrate, citrate, oxalate, and the like. The β-receptor stimulating action stimulates β-adrenergic receptors in the trachea, relaxes bronchial smooth muscles, suppresses asthma attacks, and stimulates β-adrenergic receptors in the heart.
It is known that they act on the circulatory system, and the former is classified as a β2-receptor and the latter as a β1-receptor.

In the field of asthma treatment, β1 receptors are weak and β2 receptors are weak.
A drug that strongly acts on one receptor is desirable. The results of testing the selectivity of the compounds of the present invention for β1-receptors and β2-receptors are explained below. (1) Tracheal muscle relaxation effect on isolated guinea pigs After killing male guinea pigs (body weight 400-600y), tracheal sections were prepared according to the method of Takagi et al. , suspended in a Magnus apparatus filled with Tyrode's solution kept at 37±1°C, and air was vented.

The specimens were contracted by administering 10-5 M of acetylcholine, and after the contraction reached a maximum and stabilized, the test substance was cumulatively administered to examine the relaxing effect. All specimen contractions are F
Recording was performed isometrically using a D pickup (manufactured by Nihon Kohden, SB-1T type), and the static tension was set to 0.6y. The results are shown in Table 1. The effect of the test substance is expressed as a relaxation rate of 100% when the contraction caused by acetylcholine is completely relaxed. Note that the test substance is a compound obtained in an example described later, and its number corresponds to the example number. (2)
Inotropic and chronotropic effects on isolated guinea pig atrium specimens Killing of male guinea pigs (body weight 500-1000y) 2
．． Thereafter, the heart was immediately exsanguinated, the heart was removed, and an atrial specimen was prepared in oxygen-saturated Krebs-Henseleit solution.

The left atrium was cut into strips along the path of the muscle, and electrically stimulated (0.5 Hz) for 0.7 msec to examine the inotropic effect.
The contractions induced by 2 to 5 V) were measured. The surrounding connective tissue of the right atrium was removed as much as possible without damaging the pacemaker site, and the rate of automatic contractions was measured to examine the chronotropic effect. The contractile force was recorded isometrically using a FD Vicky Niup (manufactured by Nihon Kohden, model SB-IT) with a resting tension of 0.75 da, and the heart rate was recorded using a tachometer (manufactured by Nihon Kohden, model RT-2). ) was recorded continuously.

A Krebs-Henseleit solution kept at 37±1°C was used as the nutrient solution, and a mixed gas (95% oxygen, 5% carbon dioxide) was constantly aerated. The test substance was dissolved in 0.1 ml of saline and administered cumulatively into the 507711 bath. The test results are shown in Table 2 (inotropic effect) and Table 3 (chronotropic effect).

The effect of the test substance is expressed in each case with the effect of isoproterenol 10-5M as 100%. (3
) Effect of suppressing airway resistance in cats Cats (body weight 2.5 to 4.0 k9), regardless of sex, were used to perform the Konzetsuto Ressler method (Arch, exp. pa.
th. pharmak. Volume 195, pages 71-74, 19
The experiment was carried out according to the method described in 1940).

The animal is urethane-chloralose (500m9/K914
After anesthesia with 0 mg/K9 (intraperitoneal administration), the animal was fixed in the dorsal position, the throat was incised, a tracheal cannula was inserted, and the animal was connected to a positive pressure ventilation machine.

Air was delivered from the artificial respirator at a rate of 45 mι at a time and 25 times per minute, and changes in airway pressure were recorded as changes in water pressure via a low-pressure transducer (manufactured by Nihon Kohden, model Lpu-0.1). Histamine 1 μg/K9 was administered into the femoral vein every m minutes, and after the change in airway pressure became constant, the test substance was administered intravenously. K9 was administered, and the increase in airway pressure was observed until it returned to the value before test substance administration. The test results are shown in Table 4.

The effect of the test substance is to determine the amount of histamine 1 in the river before administration of the test substance.
The increase in airway pressure due to pg/K9 is set as 100, and is expressed as the suppression rate (%). Note that blood pressure and heart rate were recorded from the femoral artery. Based on the above test results, the effects of the compound of the present invention are compared with those of isoproterenol as follows.

Regarding the relaxing effect on bronchial smooth muscle, compound 11
and 1 are stronger than isoproterenol, compound 2 is comparable, compounds 5, 7 and 13 are about 80% stronger, and the others are weaker. The inotropic and chronotropic effects on the atrial muscle are shown in descending order of maximum response. The action is compound 11, isoproterenol, 5, 23,
13. The order is 7, 3, 2, 1. That is, compound 11
Both effects are stronger than isoproterenol, and the others are weaker. Regarding the airway resistance suppressing effect, Compounds 2, 3, and 11 are almost on the same level as isoproterenol, and the present compound is superior in terms of duration of action. Compounds 1 and 13 showed about 80% of the effect of isoproterenol,
Compounds 7 and 23 were found to have approximately the same effect at 10 times the amount. Therefore, the compounds of the present invention are useful as drugs having P-1 receptor stimulating action.

Example 1 1-(3'-Hydroxymethyl-4'-hydroxyphenyl)-2-(1,5-dimethylhexylamino)monoethyl.

The preparation method and properties of this compound are shown below.

6-epoxyethyl-2-phenyl-1,3-benzodioxane 3 da, 1,5-dimethylhexylamine 8 da and methanol 1.5 m. 1 mixture in a sealed tube at 100%
Heat at °C for 23 hours.

After the reaction is complete, excess amine is distilled off, the residue is dissolved in ether, washed with water, dried, and the ether is distilled off.
4.7f1 of brown candy-like substance is obtained. Dissolve this in 4 ml of ethanol, add 540 m9 of oxalic acid, dissolve it, add 80 ml of ether, and leave it in a cold place overnight to obtain 6-[2°-(1",5-) with a melting point of 168-174°C. dimethylhexylamino)-1゛-hydroxyethyl]-
2-phenyl-1,3-benzodioxane oxalate 3.4
4 g (67.8% yield) are obtained as colorless powdery crystals. 3.44 g of the obtained oxalate was added to 80 ml of chloroform.
of sodium hydroxide in 100 ml of water.
Add the solution and stir.

The chloroform layer is separated, washed with water, dried, and then the chloroform is distilled off to obtain 3.07 Da of 1,3-dioxane compound in the form of a free base as a brown oil. This free base was added to 0. IN Hydrochloric acid 160ml and methanol 70ml
mL of the mixture and stirred at room temperature for 2. Stir for an hour to dissolve.

Methanol was distilled off, water was added to the residue to make it 500 resistant, and this was adsorbed on 45 ml of Dowex 50W-X4 (H+ type ion exchange resin manufactured by Dow Chemical Company), and after sequentially washing with methanol and water, Elute with aqueous ammonia and then methanol. When the solvent is distilled off from the eluate, a candy-like substance 2.17y is obtained. Dissolve this in 4 ml of ethanol, add 330 ml of oxalic acid, dissolve, add ether 6, and leave in a cool place. When the precipitated crystals are collected and recrystallized from ethanol, the melting point is 134-1.
370C of 1-(3゜-hydroxymethyl-4゛-hydroxyphenyl)-2-(1〃,5〃-dimethylhexylamino) monoethanol oxalate 1.27 das (yield 31.
8%) is obtained as colorless prismatic crystals. Elemental analysis value:
C,,H3ONC). Calculated value (%) 63.508
．． 884.11 Actual value (%) 63.248.783.9
2NMR value: 8 fraud?ゝ7.4be 6.80 (3H, -N once) 4.73 (2FI..s..H0-C exclusive-Ar-)UV
Spectnoreni Sergeant 90Hmp (E) 227.0 (17
616), 278.5 (4826) Example 21-(3′-hydroxymethyl-4′-hydroxyphenyl)-2
-(1,5-dimethyl-4-hexenylamino)
One ethanol.

The preparation method and properties of this compound are shown below.

A mixture of 4.8 g of 6-epoxyethyl-2-phenyl-1,3-benzodioxane, 12.1 y of 1,5-dimethyl-4-hexenylamine and 2 ml of methanol was heated in a sealed tube at 100° C. for 2 (inversion). Heat.

After the reaction is complete, excess amine is distilled off, 10 ml of n-hexane is added to the residue, and the mixture is left overnight to precipitate crystals. When the obtained crystals are recrystallized from ether, the melting point is 109~
6-[2゜-(1゜゛,5''-dimethyl-4゜゜-hexenylamino)-1゛-hydroxyethyl]-2-phenyl-1,3-benzodioxane at 112°C 2.24
y (yield 31.1%) is obtained as colorless prism crystals. The obtained benzylidene compound (1.86 da) was mixed with 0. IN hydrochloric acid 9
Add to a mixture of 0ml and 70nL of methanol, and stir and dissolve at room temperature for 3.5 hours.

After the reaction was completed, water was added to the reaction solution to dilute it three times, insoluble matter was removed, and the resulting solution was adsorbed onto 30 ml of Dowex 50W-X4, washed with methanol and water, and then diluted with 2N aqueous ammonia and then methanol. When the solvent is distilled off from the eluate, 1.4y of brown oil is obtained. This stuff solidifies if left alone. When this is recrystallized from ether, 1-(3゛-hydroxymethyl-4゛-hydroxyphenyl)-2-(1〃,
0.88 y of 5-dimethyl-4-hexenylamino)-ethanol (yield 63.3%) was obtained as colorless prism crystals.

Elemental analysis value: CHN as Cl7H, 7NO3 Calculated value (%) 69.579.284.77 Actual value (%)
69.319.254.64 NMR value: 8 fraud S 7.37-6.74 (3H..m,.Ar-N.)4.
70 (2H..s..H0-C-Ar) 1.09 (3
H,,ds. J=6.5, ″>CHCW) UV spectrum 90 Hmp (E) 227.0 (24251)
, 278.5 (6880) Example 31-(3゛-hydroxymethyl-4゛-hydroxyphenyl)-2-(1〃
, 5-dimethyl-5-hydroxyhexylamino)
One ethanol.

The preparation method and properties of this compound are shown below.

A mixture of 11.4 ml of 1,5-dimethyl-5-hydroxyhexylamine and 2 ml of methanol is heated in a sealed tube at 100 DEG C. for 2 hours.

When treated in the same manner as in Example 1, the melting point was 120 to 160.
6-[2'-(1'',5''-dimethyl-5''-hydroxyhexylamino)-1'-hydroxyethyl] at °C
-2-Phenyl-1,3-benzodioxane oxalate4.
6y (yield 66.0%) is obtained as colorless powdery crystals. The obtained oxalate salt is added to a mixed solution of an aqueous sodium hydroxide solution and ether, and dissolved with stirring. Separate the ether layer, wash with water, dry, and remove the ether. After evaporation, the target compound 3.95y is obtained in the form of the free base. Add 170 mι of 0.2N hydrochloric acid to this, and 1. Stir for an hour. After the reaction, add water to dilute 3 times, remove insoluble matter, adsorb the solution on 60ml of Dowex 50W-X4, wash twice with methanol and water, and elute with 2N aqueous ammonia and then methanol. When the solvent was distilled off from the eluate, 2.96y of a yellow oil was obtained. This oil was treated in the same manner as in Example 1 to obtain oxalate, and when recrystallized from ethanol, the melting point was 168.5-169.5°C.
(Decomposition) of 13-(3'-hydroxymethyl-4'-
1.5 Da (yield 42.6%) of monoethanol oxalate (hydroxyphenyl)-2-(1'',5'-dimethyl-5'-hydroxyhexylamino) is obtained as colorless prismatic crystals. 3- Elemental analysis Value: C, 8H3OO6N ■Svector Ni λΓHmμ(E) 227.0 (18076), 2790 (12.320)
(B) 6-[2'-(1'', 5''-) obtained in Example 2
0.89% of dimethynole-4''-hexenylinoleamino)-dihydroxyethyl]-2-phenyl-1,3-benzodioxane was suspended in 0.2N hydrochloric acid, and the mixture was heated and stirred at 100°C for 6 hours.

After the reaction is completed, the mixture is treated in a conventional manner to obtain 600 mg of a brown syrupy substance. This was treated in the same manner as in Example 1 to obtain oxalate salt, and recrystallized from an ethanol mixed solvent to obtain 322m9 of colorless powdery crystals. When this crystal is further recrystallized from ethanol, the melting point is 164.0-1.
1-(3'-Hydroxymethyl-4'-hydroxyphenyl)-2-(1'',5''-dimethyl-5''-hydroxyhexylamino) monoethanol oxalate at 66.5°C (decomposed) in the form of a colorless powder. This compound was obtained as a crystal.The elemental analysis, infrared absorption spectrum, ultraviolet absorption spectrum, and gas chromatography of this compound completely matched the compound obtained in (2).

Example 4 1-Phenynole-2-(di,5'-dimethynolehexylamino)-ethanol.

CH,. The following is a list of the shocking rifts and assignments that occurred during this time.

A mixture of 3 g of stynone oxide, 15 y of 1,5-dimethylhexylamine and 2 ml of methanol is heated in a sealed tube at 100° C. for 2-3 hours. After completion of the reaction, excess amine is distilled off, the residue is dissolved in ether, washed with water and dried, the ether is distilled off, and the hydrochloride is prepared by a conventional method. When the obtained hydrochloride was recrystallized from a methanol-ether mixed melt, 2.66 da crystals of 1-phenyl-2-(',5'-dimethylhexylamino)-ethanol hydrochloride with a melting point of 125-12TC were obtained. rate 36.5%)
can get.

Elemental analysis value: Example 5 as C, 6H2, NO-HCI
1-(3゛,5゛-dihydroxyphenyl)-2-(1
〃,5〃-dimethyl-5゜゛-hydroxyhexylamino)-ethanol.

The preparation method and properties of this compound are shown below.

3,5-dibenzyloxystyrene oxide 6.4 da, 1,5-dimethyl-5-hydroxyhexylamine 1
A mixture of 5.0 f and 20 m/-l was heated to 10 ml in a sealed tube.
Heat at 0°C for 21 hours.

After the reaction is completed, excess amine is distilled off, the residue is dissolved in chloroform, washed with water, dried, and the solvent is distilled off to obtain an oily substance. When this oil is dissolved in ether and left at room temperature, crystals will precipitate. When the obtained crystals are recrystallized from anhydrous ether, 1-
(3゛,5゛-dibenzyloxyphenyl)-2-(``
1.3 da.,5-dimethyl-5-hydroxyhexylamino)-ethanol (yield: 14.0%) is obtained as colorless powdery crystals. Elemental analysis value: C3. )FI39
NMR value as O, N: 8 7.25 (IOH, s-0-CI (2-C6) 7.45-6.25 (3FI
．． ．． Ar-U) 1.0 da of the obtained dibenzyl compound was dissolved in 20 mL of methanol, and 10% palladium carbon 400
Add m9 and perform catalytic reduction at room temperature.

After the reaction is complete, the catalyst is removed and the solvent is distilled off, resulting in 1-(3
゛,5゛-dihydroxyphenyl)-2-(1〃,5〃
650 m9 of -dimethyl-5-hydroxyhexylamino)-ethanol are obtained as a white powder. Example 6 1-(3'-methanesulfonamide 4'-hydroxyphenyl)-2-(1,5-dimethylhexylamino)monoethanol.

The preparation method and properties of this compound are shown below.

2-Benzyloxy-2-(2'-bromoacetyl)-
Methanesulfonanilide 25f to acetonitrile 170
A solution of 27.5 da of 2-benzylamino-6-methylheptane in 40 h of acetonitrile is added dropwise to this, keeping the temperature at 0 to 10 °C.

After completion of the dropwise addition, the mixture was stirred at the same temperature for 2.5 hours. After the reaction, the acetonitrile was distilled off at below room temperature, the residue was dissolved in chloroform, washed with an aqueous sodium bicarbonate solution and water, dried, and the chloroform was distilled off at below 30°C, leaving an oily substance of 47.4 d. is obtained. This is purified by silica gel column chromatography eluting with chloroform. When chloroform is distilled off from the eluate, 2
-benzyloxy-5-[2゛1 (N-benzyloxy-1〃
, 5-dimethylhexylamino)-acetyl]-methanesulfonanilide 19.0y (yield 60.0%) is obtained as a syrupy substance. The obtained N-benzyl compound is dissolved in 240 ml of ethanol, 3.5 y of 5% palladium on carbon is added thereto, and catalytic reduction is carried out at room temperature.

After the reaction is completed, the catalyst is removed and the solvent is distilled off to obtain a crude product 12.4y. This is purified by silica gel column chromatography eluting with a chloroform-methanol mixed solvent (10:1). After distilling off the solvent from the eluate, 6.7 da of amorphous material is obtained. This was treated in the same manner as in Example 1 to obtain oxalate using 84.1 m9 of oxalic acid, and recrystallized from a methanol-ethanol mixed solvent.
3゛-Methanesulfonamide 4゛-hydroxyphenyl)゜-2- (1〃,5〃-dimethylhexylamino) monoethanol oxalate 2.6y (yield 17.1%) as colorless powder crystals can get. Elemental analysis value: C, 8H3
Example 7 1-(2''-chlorophenyl)-2-(1,5-dimethylhexylamino)monoethanol as IN,O6S.

The preparation method and properties of this compound are shown below.

To a solution of 7y of o-chlorophenylglyoxal in 70ml of methanol was added dropwise 5.9y of 1,5-dimethylhexylamine under ice-cooling and stirring, and then 1.75y of sodium borohydride was added in small portions between the three powders. , stir under ice cooling for 3 hours. After the reaction is complete, the solvent is distilled off under reduced pressure, and the residue is made acidic with dilute hydrochloric acid and extracted with ether. The ether layer is separated, washed with water, dried, and the solvent is distilled off to obtain a colorless oil. The aqueous layer is made alkaline with potassium carbonate, extracted with ether, the ether layer is made acidic with dilute hydrochloric acid, and then treated in the same manner as above to obtain an oily substance. The resulting oils were combined and recrystallized from a mixed solvent of ether and isopropyl ether, giving a melting point of 84 to 87.
6.1y (yield: 45.9%) of 1-(2'-chlorophenyl)-2-(1',5-dimethylhexylamino)monoethanol hydrochloride at 20°C is obtained as needle crystals.

The following compound with elemental analysis value: Q6H26NOCl.HCI is also produced in the same manner as above.

Example 81-Phenyl-2-(',5''-dimethyl-5
(Hydroxyhexylamino) monoethanol.

NMR value: 8 Milk Example 9 1-(4'-Hydroxyphenyl)-2-(1″, 5″
-dimethyl-5''-hydroxyhexylamino)monoethanol.

NMR value: δIg'D Ca^Λ-Ii) Example 10 1-(3',4'-dihydroxyphenyl)-2-(
1″,5″-dimethyl-5′-hydroxyhexylamino)-ethanol.

NMR value: δine D Example 11 1-(4'-hydroxyphenyl)-2-(1″, 5″
-dimethylhexylamino)-ethanol.

NMR value: δ life
,5'-dimethylhexylamino) monoethyl.

NMR value: δ; minor 0D Example 13 1-(2'-hydroxyphenyl)-2-(l″5″-
dimethylhexylamino) monoethanol.

NMR value: δ well [D Example 14 1-(2'-hydroxyphenyl)-2-(1″, 5″
-dimethyl-5″-hydroxyhexylamino)-ethanol.

Example 15 1-(3'-hydroxyphenyl)-2-(1",5"
-dimethylhexylamino)-ethanol.

NMR value: δ; Example 16 1-(2',4'-dihydroxyphenyl)-2-5(
1",5'-dimethylhexylamino) monoethanol NMR value: δI ID - - - - ^l ^- ▼1, Example 17 1-(2',4'-dihydroxyphenyl)-2- 5(
1″,5″-dimethyl-5″-hydroxyhexylamino)-ethanol.

NMR value: δKane D Example 18 1-(3'-hydroxyphenyl)-2-(1″, 5″
-dimethyl-5″-hydroxyhexylamino)-ethanol.

NMR value: δ? Fragment 00 Example 19 1-(2″,5″-dihydroxyphenyl)-2-(1
″″, 5″″-dimethyl-derhydroxyhexylamino)-ethanol.

NMR value: δz Hatake 00 Example 20 1-(2″,5″-dihydroxyphenyl)-2-(1
″″, 5″″-dimethylhexylamino)-ethanol.

NMR value: δZFrD Example 21 1-(2″-chlorophenyl)-2-(1″″,5″-dimethyl-5″-hydroxyhexylamino)monoethanol.

NMR value: δzθ=13 Example 22 1-(3″,5-dihydroxyphenyl)-2-(1″
, 5″″-dimethylhexylamino)-ethanol.

NMR value: δEBfD Example 23 1-(3″-hydroxymethyl-4″-hydroxyphenyl)-2-(11,1″-dimethyl-derhydroxyhexylamino)monoethanol.

NMR value: δz? 0D -\▼,. Example 24 1-(3″-Hydroxymethyl-4″-hydroxy7phenyl)-2-(11,5″-dimethyl-5″-hydroxyhexylamino)-propanol.

NMR value: δz? 0 Example 25 1-(3''-hydroxymethyl-4''-hydroxy7phenyl)-2-(',5''-dimethylhexylamino)-propanol.

NMR value: δ:? 0 Example 26 1-(3''-hydroxymethyl-4-hydroxyphenyl)-2-(17,1''-dimethyl-5''-hydroxyhexylamino)-propanol.

NMR value: δCp■r

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula,
, R_1, R_2 and R_5 may be the same or different, and each represents a hydrogen atom or a methyl group, R_3 represents a hydrogen atom, R_4 represents a hydrogen atom or a hydroxyl group, or R_
A 1-phenyl-2-aminoethanol derivative represented by (3 and R_4 may be taken together to represent a double bond).