JPS6045179B2 - Novel cyclic amino alcohols and their production method - Google Patents

Description

Detailed Description of the Invention The present invention relates to novel cyclic amino alcohols, more specifically, the following general formula (1), (wherein R1 is a phenoxy group, a phenylalkyl group, a phenyl group, a cyclohexyl group, a lower alkyl group, R2 represents a hydrogen atom, a lower alkyl group, a halogen atom, or R1 and R2 together form an alkyl ring consisting of 3 or 4 carbon atoms)
The present invention relates to cyclic amino alcohols and their salts represented by the following formulas, and their production methods.

The compound represented by the general formula (1) of the present invention has a coronary vasodilatory effect and a myocardial contractility suppressing effect, and is important as a preventive or therapeutic agent for heart diseases, especially angina pectoris, and is an excellent drug. It is useful as an intermediate for the synthesis of compounds with anti-anginal effects.

Examples of the phenoxy group represented by R1 in general formula (1) include phenoxy and substituted phenoxy groups; examples of the phenylalkyl group include benzyl, substituted benzyl, phenethyl, and substituted phenethyl groups; examples of the phenyl group include phenyl or a substituted phenyl group; Examples of lower alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, S
Examples include eC-butyl and tert-butyl groups.
Examples of the above substituents include methyl, ethyl, n-
Propyl, isopropyl, n-butyl, isobutyl, S
Lower alkyl groups such as ec-butyl or tert-butyl; lower alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butyloxy or isobutyloxy; or chlorine, bromine, iodine, fluorine, etc. These halogen atoms may be substituted with 1 to 3 of the same or different substituents. Further, the lower alkyl group represented by R2 in the general formula (1) is the same as that listed for R1, and the halogen atom includes chlorine, bromine, iodine, and fluorine.

Furthermore, examples of the alkyl ring consisting of 3 or 4 carbon atoms formed by R1 and R2 together in general formula (1) include 1(CH2)n- (n represents 3 or 4). .

According to the present invention, the cyclic aminophenyl of the present invention of formula (1) is produced by any of the following methods.

1 Method 1: Hydroxyiminoketones (■) are reduced to produce cyclic amino alcohols (1).

(In the formula, R1 and R2 are the same as above) Raw material for this method (■)
For example, γ-monosubstituted butyric acid represented by the general formula can be prepared by a known method [Organic ● Synthesis, Collective ● Volume 3, 798~
[page 800] to form a ketone represented by the general formula, which is then reacted with an alkyl nitrate (for example, butyl nitrate) in the presence of a potassium alcoholate.

To carry out this method, reduction is carried out in water or an organic solvent such as methanol, ethanol, ether, dioxane, benzene, xylene, or a mixed solvent thereof, preferably methanol or ethanol in an alcoholic solvent.

Reduction methods include catalytic reduction using palladium, platinum oxide, Raney nickel, etc. as catalysts; reduction with metal hydride compounds such as lithium aluminum hydride and sodium borohydride; reduction with metal sodium and alcohols:
Alternatively, a reduction product of a metal such as iron or zinc and an acid such as hydrochloric acid or acetic acid may be employed, but catalytic reduction using platinum oxide as a catalyst is particularly preferred. The reduction reaction proceeds under ice cooling or at 130°C, but is usually carried out at a temperature of 25 to 50°C under normal pressure.
2 Method 2 Aminoketones (■) are reduced to produce cyclic amino alcohols (1).

(In the formula, R1 and R2 are the same as above) The raw material (■) of this method is obtained by reducing the hydroxyiminoketones (■) or reducing the hydroxyiminoketones (■) in acetic anhydride monoacetic acid. It is produced by hydrolyzing acetamidoketones represented by the general formula obtained.

To carry out this method, reduction is carried out in water or an organic solvent such as methanol, ethanol, ether, dioxane, tetrahydrofuran, benzene, xylene, or a mixed solvent thereof, preferably methanol or ethanol in an alcoholic solvent.

Reduction methods include catalytic reduction using palladium, platinum oxide, Raney nickel, etc. as a catalyst; reduction using metal hydride compounds such as lithium aluminum hydride, lithium borohydride, and sodium borohydride; or Meyer Wein-Dollhuber using aluminum isopropoxide, etc. Examples include ray reduction. Particularly for producing trans isomers of cyclic amino alcohols, reduction with sodium borohydride is preferred. The reduction reaction proceeds under ice cooling or at a temperature of 130°C under normal pressure or increased pressure, but
It is usually carried out at room temperature and pressure. 3 Method 3 Amide alcohols (■) are hydrolyzed to produce cyclic amino alcohols (1).

(In the formula, R3 is a lower alkyl group, a phenylalkyl group,
Represents a phenyl group or a cyclohexyl group, R1, R2
is the same as above) The raw material (V) of the present method is, for example, by reducing the acetamidoketones (■) or converting the aminoketones (■) by the general formula R3COX (where X represents a halogen atom and R3 is It is produced by reacting with an acid halide (same as above) and reducing an amide ketone represented by the general formula.

To carry out this method, hydrochloric acid, sulfuric acid, acetic acid, etc. are used in water or an organic solvent such as methanol, ethanol, dioxane, or a mixed solvent thereof, preferably in water or a mixed solvent of water and an alcohol such as methanol or ethanol. Hydrolysis is carried out with acid.

The reaction is carried out at room temperature or under reflux. In particular, when producing cis isomers of cyclic amino alcohols, 0.1 to
It is preferable to use 1.0% hydrochloric acid or 5-10% acetic acid. The cyclic amino alcohols (1) of the present invention and their salts obtained by the above methods 1 to 3 can be obtained by, for example, concentration, filtration,
It can be isolated from the reaction mixture by general separation and purification methods such as washing, recrystallization, and column chromatography.

In addition to cis and trans isomers, cyclic amino alcohols (1) and their salts include optical isomers based on asymmetric carbon atoms, and are usually obtained as racemates, but if necessary, The optically active substance can also be separated using a conventional method, for example, a method in which diastereomers are formed with an optically active acid and optically resolved.

The cyclic amino alcohol (1) can be treated with an acid according to a conventional method to form, for example, a mineral acid salt such as hydrochloric acid, sulfuric acid, or hydrobromic acid, or an organic acid salt such as acetic acid, oxalic acid, or tartaric acid. can.

Next, the pharmacological effects of the compounds of the present invention will be shown.

Test method: After killing a guinea pig weighing 200 to 250 y, the heart was immediately removed, a camille was inserted retrogradely through the aorta according to the Langendorff method, and the animal was incubated at 36.5°C saturated with 95% oxygen gas and 5% carbon dioxide gas. Klebsufuensrite solution was perfused at a constant pressure of 70 Hg.

Coronary blood flow was measured using an electromagnetic flow meter [manufactured by Nihon Kohden Co., Ltd., E-4], and myocardial contractile force and heart rate were measured using a force displacement transducer (manufactured by Tamoto Kohden Co., Ltd., SB-1). The measurements were recorded on a written oscillograph (Sanei Sokki). The test compound was added at 5 x 10-7 mol/Heart into the perfusate at the aortic cannula insertion site. The degree of increase in coronary vascular flow caused by the test compound is expressed as a percentage (increase rate) of the coronary vascular flow before excision, and the degree of suppression of myocardial contractile force and heart rate is determined by the extent of the increase in coronary vascular flow before excision. It was expressed as a percentage of the contraction force (before use) and heart rate (inhibition rate).

Test results: The effects of each test compound on coronary vascular flow, myocardial contractile force, and heart rate are shown in the following table.

The following compounds were used as test compounds. Known compound A: cis-2-amino-1-tetralol hydrochloride Compound A of the present invention: cis-2-amino-7-phenoxy-1-
Tetrale hydrochloride Compound B: trans-2-amino-7-phenoxy-1-tetralole hydrochloride Compound C: cis-2-amino-7-benzyl-1-tetralole hydrochloride Compound D: trans-2-amino 7-benzyl-1-tetralole hydrochloride Compound E: cis-2-amino-7-phenyl-1-tetralole hydrochloride Compound F: cis-2-amino-6,7
-Dimethyl-1-tetralol hydrochloride acid As is clear from the above results, the compound of the present invention has stronger effects on increasing coronary vascular flow and suppressing myocardial contractile force than known compounds without increasing heart rate. , can be used as a therapeutic or prophylactic agent for heart diseases, especially angina pectoris.

In addition to the above-mentioned effects, the cyclic amino alcohol (1) of the compound of the present invention serves as an intermediate for the synthesis of compounds useful as pharmaceuticals. , R5 represents a hydrogen atom, a lower alkyl group, a phenylalkyl group, a phenyl group, or a phenylalkenyl group). This can lead to a compound represented by the general formula (wherein R1, R2, R4, and R5 are the same as above) that has an excellent antianginal effect.

Next, reference examples and examples will be given and explained.

Reference example 1 4.95y of metallic potassium and 33y of absolute ethanol
Potassium alcoholate ether 400 prepared from m1
mt solution, 26y of 7-benzyl-1-tetralone and 12.1y of butyl nitrate were added in 200ml of anhydrous ether.
A mixed solution of 1 and 1 was added dropwise in three portions while stirring on ice.

After leaving in a cool place overnight, add water or dilute KOH aqueous solution and shake well. The aqueous layer is further washed with ether, then acidified with acetic acid, and the precipitate is collected and washed with water and benzene.
Recrystallization from benzene gives 2-hydroxyimino-7-benzyl-1-tetralone having a melting point of 156-15 (decomposition). Elemental analysis value: Calculated value as Cl7H, 5O2N: Cl76.96; Hl5.7O; Nl5.28
Actual value: Cl76.99: Hl5.73; Nl5.22
Reference Examples 2 to 11 Hydroxyiminoketones shown in Table 1 were obtained in the same manner as in Reference Example 1.

Reference Example 12 2-Hydroxyimino-7-phenoxy-1-tetralone 11f is dissolved in a solution of 70 mt of acetic acid and 60 ml of acetic anhydride, and a 5% palladium-barium sulfate catalyst 6y is added to the mixture to form a compound of the present invention at room temperature and pressure.

Once the theoretical amount of hydrogen has been absorbed, the reaction is stopped and the catalyst is centrifuged. The supernatant liquid is dried under reduced pressure, and the residue is washed with water and ether and recrystallized from ethanol to obtain 2-acetamido-7-phenooxy-1-tetralone having a melting point of 133-135°C. Calculated value as elemental analysis value Cl8Hl7O3N: Cl73.2O: Hl5.8O; Nl4.74
Actual value: Cl73.43; Hl5.88; Nl4.82
Reference Examples 13 to 22 The acetamidoketones shown in Table 2 were obtained as each reference example.

Reference Example 23 2-acetamido-7-phenooxy-1-tetralone 3y is added to 50 ml of a 7N aqueous hydrochloric acid solution and reacted under reflux for 8 hours.

The reaction solution is treated with activated carbon and filtered. The citrus liquid was dried under reduced pressure,
The residue was washed with ether and then recrystallized from isopropanol to obtain 2-amino-7-phenoxy-1-tetralone hydrochloride having a melting point of 189-191°C. Elemental analysis value: Cl6
Calculated value as Hl5O2N-HCl: Cl66.32;
Hl5.57; Nl4.83 actual value: Cl66.27:
Hl5.59; Nl4.8O Reference Example 24 - Feather Reference Example 23
In the same manner as above, the hydrochloride salts of aminoketones shown in Table 3 are obtained.

Reference Example 34 1.0y of 2-hydroxyimino-7-phenoxy-1-tetralone is dissolved in 20TfL1 of methanol, an equivalent amount of 1N hydrochloric acid and 30m9 of platinum oxide are added, and catalytic reduction is carried out at room temperature and pressure.

Once the theoretical amount of hydrogen has been absorbed, the reaction is stopped and the catalyst is removed. ■Concentrate the liquid to dryness. The residue was washed with ether and acetone and then recrystallized from isopropanol to give a melting point of 189-1.
2-amino-7-phenoxy-1-tetralonic acid hydrochloride at 91°C is obtained. This product matched that obtained in Reference Example 23 in the blending test. Reference example 35 2-amino-7-benzyl-1-tetralone hydrochloride 2.
7y is dissolved in 50 ml of a mixture of benzene and water, 1.8 g of potassium carbonate is added, and a solution of 0.95y of acetyl chloride dissolved in benzene 5TrLt is added dropwise while stirring under ice cooling.

Thereafter, the mixture is stirred and reacted at room temperature for 2 hours, then at 40 t to 45°C, and the precipitated crystals are collected. The crystals were washed with a small amount of benzene and then recrystallized from ethanol to give a melting point of 127-129.
C. 2-acetamido-7-benzyl-1-tetralone is obtained. This product was in agreement with 2-acetamido-7-benzyl-1-tetralone obtained in Reference Example 23 in a blending test. Reference Example 36 2.5 y of 2-acetamido-6-chloro-7-methyl-1-tetralone is dissolved in 20 mt of ethanol, and 0.3 y of sodium borohydride is added under ice-cooling and stirring.

The reaction solution was heated for 1 hour at room temperature, then heated to complete the reduction, and the reaction solution was cooled and the excess sodium borohydride was decomposed with dilute hydrochloric acid. Then, the mixture is made alkaline with an aqueous ammonia solution and extracted with chloroform. The extract is washed with water, dried, and the solvent is distilled off. The residue is washed with ether and then recrystallized from ethanol to obtain trans-2-acetamido-6-chloro-7-methyl-1-tetraleol having a melting point of 201-204°C.
Elemental analysis value: Calculated value as Cl3Hl6O2NCl: C
l6l. 54; Hl6.36; Nl5.52 Actual value: C
l6l. 55: Hl6.34; Nl5.57 Reference example 37
~46 Amide alcohols shown in Table 4 are obtained in the same manner as in Reference Example 36. Example 1 3.0y of 2-acetamido-7-phenooxy-1-tetralole is added to 100Tnt of 0.1% hydrochloric acid and refluxed for 12 hours.

Is the reaction solution treated with activated carbon? Dry the liquid under reduced pressure. The residue was washed with ether and then recrystallized from isopropanol to obtain cis-21-amino-7-phenoxy-1-tetralol hydrochloride having a melting point of 227-228°C. NMR spectrum (DMSO-↓-D2O) δ: 4.68 (IH, .d.
．． J=4Hz) Elemental analysis value: Cl6Hl7O2N-HC
Calculated value as I: Cl65.86; Hl6.22; Nl
4.8O actual value: Cl65.97; Hl6.33; Nl
4.6l Examples 2 to 11 Hydrochlorides of cis-2-amino-1-alcohols shown in Table 5 are obtained in the same manner as in Example 1.

Example 12 Trans-2-acetamide 6●7-dimethyl-1-tetralol 3y in 700ml of 5% aqueous acetic acid solution
1 and reflux for 12fI1.

The reaction solution is treated with activated carbon, and the Oki solution is concentrated under reduced pressure. The residue is dissolved in water, neutralized with sodium carbonate and extracted with chloroform. The chloroform extract is washed with water and then concentrated. The residue is dissolved in ethanol and diluted hydrochloric acid is added to make the hydrochloride. Next, the solvent was concentrated, and the residue was washed with ether and acetone.
Recrystallized from isopropanol to give cis-2-amino-6
● Obtain 7-dimethyl-1-tetralol hydrochloride. Even when this product was mixed with the product obtained in Example 5, it did not show a drop in melting point, and 1. R also agreed. Example 13 2.8y of 2-amino-7-cyclohexyl-1-tetralone hydrochloride was dissolved in 15mL of ethanol, 0.3y of sodium borohydride was added under stirring under ice cooling, and the mixture was heated for 1 hour at room temperature and then heated for 1 hour. Make a confusing reaction.

The reaction solution is cooled, excess sodium borohydride is decomposed with dilute hydrochloric acid, and the solvent is concentrated. The residue is dissolved in water, made alkaline with ammonia aqueous solution, and extracted with chloroform.
After the extract is washed with water and dried, the solvent is distilled off. The residue is dissolved in ethanol and treated with hydrochloric acid to give a hydrochloric acid. Next, the solvent was distilled off, the residue was washed with ether and acetone, and then recrystallized from ethanol to obtain trans-2 with a melting point of 223-225°C.
-Amino-7-cyclohexyl-1-tetralol hydrochloride is obtained. Elemental analysis value: Calculated value as Cl6H23ON-HCl: C. ．． 68. l9; Hl8.58; Nl4.
97 Actual value: C,, 68. O3; Hl8.54; Nl4
．． 9O Examples 14 to 23 In the same manner as Example 13, the sixth
Hydrochloride salts of trans-cyclic amino alcohols shown in the table are obtained.

Example 23 Using 2-amino-7-phenooxy-1-tetralone, the same reaction treatment as in Example 13 is carried out to obtain trans-2-amino-7-phenooxy-1-tetralol hydrochloride.

NMR spectrum (DMSO-D6, -D2O) δ: 4
．． 44 (1H,.d,,J=8Hz) Elemental analysis value: Cl
Calculated value as 6Hl7O2N-HCl: Cl65.86
; Hl6.22: Nl4.8O actual value: Cl65.7O
; Hl 6.2O; Nl 4.68 Example 24 2.9y of 2-amino-7-phenooxy-1-tetralone hydrochloride is dissolved in 25ml of ethanol, and 0.3y of sodium borohydride is gradually added while stirring under ice cooling.

Next, one powder is reacted at room temperature for 2 hours while heating. The reaction solution is cooled, excess sodium borohydride is decomposed with dilute hydrochloric acid, and the solvent is concentrated under reduced pressure. The residue is dissolved in water, neutralized with aqueous ammonia, and extracted with chloroform. After the chloroform extract is washed with water and dried, the solvent is distilled off. The residue is recrystallized from benzene to obtain trans-2-amino-7-phenooxy-1-tetralol having a melting point of 123-125°C. Elemental analysis value: Calculated value as Cl6Hl7O2N:
Cl75.27; Hl6.7l; Nl5.49 Actual value:
Cl75. l3; Hl6.77; Nl5.34 Example 2
Dissolve 2f of 52-hydroxyimino-7-phenoxy-1-tetralone in 50ml of ethanol, and dissolve 50ml of platinum oxide.
m9 is added and catalytic reduction is carried out at 40 to 50°C under normal pressure.

Once the theoretical amount of hydrogen has been absorbed, the reaction is stopped and the catalyst is removed. Add dilute hydrochloric acid to the licorice and concentrate to dryness. The residue was washed with ether and acetone to obtain 2-amino-7-phenoxy-1-tetralol hydrochloride. In the NMR spectrum (DMSO''-↓, -D2O) of this product, the absorption of C1 proton in the following formula is 4.44 PPM (Dl
j=8Hz) and 4.68PPM (D...J=4Hz).

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc.
R_2 represents a hydrogen atom, a lower alkyl group, a halogen atom, or R_1 and R_2 together represent 3 carbon atoms.
or forming an alkyl ring consisting of four alkyl rings) and salts thereof. 2. The cyclic amino alcohol and its salt according to claim 1, wherein R_1 is a phenoxy group and R_2 is a hydrogen atom. 3. The cyclic amino alcohol and its salt according to claim 1, wherein R_1 is a phenylalkyl group and R_2 is a hydrogen atom. 4. Cyclic amino alcohols and salts thereof according to claim 1, wherein R_1 is a phenyl group and R_2 is a hydrogen atom. 5. Cyclic amino alcohols and salts thereof according to claim 1, represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (in the formula, n represents 3 or 4). 6. Cyclic amino alcohols and salts thereof according to claim 1, wherein R_1 is a cyclohexyl group and R_2 is a hydrogen atom. 7. Cyclic amino alcohols and salts thereof according to claim 1, wherein R_1 is a lower alkyl group and R_2 is a halogen atom. 8. Cyclic amino alcohols and salts thereof according to claim 1, wherein R_1 is a lower alkyl group and R_2 is a hydrogen atom. 9. The cyclic amino alcohol and its salt according to claim 1, wherein both R_1 and R_2 are lower alkyl groups. 10. Cyclic amino alcohols and salts thereof according to claim 3, which are 2-amino-7-benzyl-1-tetrolol in which the phenylalkyl group is a benzyl group. 11 2-amino-1, 2, 3, 4, 5, 6, 7 represented by the formula where n is 4 ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
- The cyclic amino alcohol and its salt according to claim 5, which is 8-octahydro-1-anthrol. 12 2-Amino-6,7-cyclopentano-1 represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼ where n is 3
- Cyclic amino alcohol and its salt according to claim 5, which is tetralol. 13 2-amino-6-chloro-7-methyl-1 where the lower alkyl group is a methyl group and the halogen atom is a chlorine atom
- Cyclic amino alcohol and its salt according to claim 7, which is tetralol. 14 2-amino-7 whose lower alkyl group is a methyl group
-Methyl-1-tetrolol Claim 8
Cyclic amino alcohols and salts thereof as described in . 15 2-amino-7 whose lower alkyl group is a methyl group
-ethyl-1-tetraleol Claim 8
Cyclic amino alcohols and salts thereof as described in . 16. Cyclic amino alcohols and salts thereof according to claim 8, which are 2-amino-7-isopropyl-1-tetralol in which the lower alkyl group is an isopropyl group. 17. The cyclic amino alcohol and its salt according to claim 9, which is 2-amino-6,7-dimethyl-1-tetrale in which both of the lower alkyl groups are methyl groups. 18. A cyclic amino alcohol and a salt thereof according to any one of claims 1 to 17, wherein the cyclic amino alcohol is a trans isomer. 19. The cyclic amino alcohol and its salt according to any one of claims 1 to 17, wherein the cyclic amino alcohol is a cis isomer. 20. Cyclic amino alcohols and salts thereof according to any one of claims 1 to 17, wherein the cyclic amino alcohols are a mixture of trans and cis isomers. 21 General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R_1 is a phenoxy group, a phenylalkyl group, a phenyl group, a cyclohexyl group, a lower alkyl group,
R_2 represents a hydrogen atom, a lower alkyl group, a halogen atom, or R_1 and R_2 together represent 3 carbon atoms.
There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. that are characterized by reducing hydroxyiminoketones represented by A method for producing a cyclic amino alcohol represented by and a salt thereof. 22 General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R_1 is a phenoxy group, a phenylalkyl group, a phenyl group, a cyclohexyl group, a lower alkyl group,
R_2 represents a hydrogen atom, a lower alkyl group, a halogen atom, or R_1 and R_2 together represent 3 carbon atoms.
or forming an alkyl ring consisting of four alkyl rings).
There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1 and R_2 are the same as above) A method for producing cyclic amino alcohols and their salts. 23 General formulas ▲ Numerical formulas, chemical formulas, tables, etc. ▼
R_2 represents a hydrogen atom, a lower alkyl group, a halogen atom, or R_1 and R_2 together represent 3 carbon atoms.
▲Mathematical formula, chemical formula , tables, etc. ▼ (In the formula, R_1 and R_2 are the same as above) A method for producing cyclic amino alcohols and their salts.