JPS6023100B2 - Process for producing 1-aryloxy-4-amino-2-butanol - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to processes for the preparation of di-substituted-2-butanols, particularly 1-aryloxy-4-amino-2-butanols and intermediates thereof.

The invention particularly relates to the formula: AJO-CH2-CHOH-CH2-CH2-NRIR
2 (1) [wherein ~ is a 1-naphthyl group, 2-naphthyl group, inden-5-yl group, or 5-chloro-2-pyridyl group, or is unsubstituted or a halogen atom, a lower alkoxy group, a lower alkyl group, A phenyl group mono- or di-substituted with a substituent selected from the group consisting of a trihalomethyl group, a lower acyl group, a phenyl group, and an acetylamino group; RI
is lower alkyl group, phenylalkyl group, 2-hydroxymethyl-2-p.

is a pyru group, an adamantyl group or a lower cycloalkyl group; R2 is H or a lower alkyl group; RI and R2 together with the adjacent nitrogen atom represent a 1,2,3,4-tetrahydroisoquinoline ring, phenyl Piverazine ring, phthalimide ring, morpholine ring, di(lower alkyl)morpholine residue, piveridine ring, phenylpiveridine ring, 4-phenyl-1.
A heterocyclic ring selected from the group consisting of a 2,3,6-phenylpiveridine ring and a 1-decahydroquinoline ring may be formed.

] and its pharmaceutically acceptable acid addition salts.

- The compounds of the invention of formula 1 above exhibit important and significant pharmacological activity as a general characteristic, which indicates that they can be used in the treatment of certain physiological abnormalities in animals.

These compounds are local anesthetics, Q-adrenergic flocs, 6-adrenergic flocs, and antiarrhythmic agents.
Prior literature discloses various 1-aryloxy-3-amino-2-propanols that are said to have 8-adrenergic floc activity, anti-dusting activity, sedative activity, and tranquilizer activity.

The US patent disclosing the 1,3-disubstituted-2-propanols and their pharmacological activities is Patent No. 333762.
8:3415873:3432545:3520919
No. etc. In particular, in US Patent No. 3,337,628,
1-isopropylamide/1-3-(1-naphthyloxy)-12-propanol, a potent 8-adrenergic blocking agent, is disclosed. When the pharmacological activity of the novel 1-aryloxy-4-amino-2-butanol of the present invention was measured, it was found to have antiarrhythmic effects against large cardiac arrhythmias induced experimentally. A prior art analog, 1,3-disubstituted-2-propanol, also has antiarrhythmic activity. However, the novel 2-butanol of the present invention, in contrast to the prior art 2-propanol, has a very low 8-adrenergic floc activity and is therefore at risk of cardiac dysfunction and dyspnea (as opposed to the conventional 2-butanol, which has a strong 8-adrenergic floc activity). It can be used to control moderate to severe arrhythmias without the 1,3-substituted-2-propanols associated with the use of cardiac arrhythmias. In formula 1, Ar
is a 1-naphthyl group, and -NRIR2 is a lower alkylamino group, a lower cycloalkylamino group (lower cycloalkyl has 5 to 7 carbon atoms), a phenylalkylamino group, a 2-hydroxymethyl-2- Compounds having a propylamino group or a phenylamino group are preferred from the viewpoint of antiarrhythmic activity. In formula 1, Ar is a 0-lower alkoxy (especially methoxy, ethoxy) phenoxy group, and -NRIR2 is a lower alkylamino group, a lower cycloalkylamino group (lower cycloalkyl has 5 to 7 carbon atoms), phenyl Compounds which are alkylamino, 2-hydroxymethyl-2-propylamino or phenylamino groups are also of particular interest because of their antiarrhythmic activity.

It is therefore a principal object of the present invention to provide a process for the preparation of new 1-aryloxy-4-amino-2-butanols and intermediates thereof, which are pharmacologically useful because of the above-mentioned type of activity.

The objects of the present invention will be apparent to those skilled in the art from the description herein. As used herein, a "lower alkyl group" is a straight or branched chain group having up to 8 carbon atoms, methyl,
Examples include groups such as ethyl, propyl, isopropyl, tert-butyl, amyl, isoamyl, hexyl, heptyl, octyl, and the like.

The "lower alkoxy group" has the formula: -0-lower alkyl.The "halogen" preferably has an atomic weight of 18 or more and 80 or less, but is not necessarily limited thereto.

A "phenylalkyl group" is a group such as penzyl, phenethyl, methylbenzyl, phenpropyl, etc.

A "lower cycloalkyl group" is a cyclic group having up to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclobentyl, cyclohexyl, cyclohebutyl, cyclooctyl, and the like.

"Phenyl group" is an unsubstituted phenyl group, a monosubstituted phenyl group, or a disubstituted phenyl group.

Suitable mono-, di-substituted phenyl groups are groups that are not reactive, ie, do not interfere with the reaction under the reaction conditions for preparing the desired compound, such as lower alkyl, lower alkoxy, trifluoromethyl, acetyl, acetylamino, halo, trifluoromethyl, It is substituted with one or more of the following, such as phenyl. The substituted phenyl group preferably has one or two of the above-mentioned substituents, and can be attached to various positions on the phenyl nucleus, and when two or more substituents are present, they may be the same or different. and various combinations of relative positions. The substituents lower alkyl and lower alkoxy each preferably have 1 to 4 carbon atoms, and can be arranged in either a straight chain or a branched chain. The preferred maximum value is that the total number of carbon atoms in the ring substituent is 9, and the total number of carbon atoms including the ring is 19. The compounds of this invention are most conveniently employed in the form of pharmaceutically acceptable acid addition salts.

Such salts are more water soluble than their free bases. Suitable acid addition salts are those derived from mineral acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric acids, and organic acids such as acetic, citric, lactic, maleic, hakama, fumaric, and tartaric acids. be. A preferred acid addition salt is the hydrochloride. These acid addition salts are conventionally prepared by reaction of a basic compound with the selected acid (either or both can be in the form of an ether, alcohol or acetone solution). The present invention also includes new 1-aryloxy-4-chloro-2-butanols of Formula W that serve as intermediates in the preparation of the final amine products of Formula 1, which can be prepared by the methods illustrated in Table 1.

In the table, all symbols are as defined above. Table 1 1-aryloxy-4-chloro-2-but/ol (W
) is generally produced by treating a basic aqueous solution or basic water/alcoholic solution of a phenol, substituted phenol or other aryl compound of formula 0 with an acidic hydroxy group with 1,4-dichloro-2-butanol of formula m. Ru.

Addition takes about 3 to 8 hours at 70 pm or less.
Preferably it is carried out at about 30-65°C. Following this addition, the reaction mixture is heated to about 50 DEG-75 DEG C., preferably 60 DEG-70 DEG C., for about 6 to 4 hours, usually 12 to 1 hour. The 1-aryloxy-4-chloro-2-butanol is isolated from the reaction mixture by extraction with a suitable organic solvent (eg ether, isopropyl ether or chloroform), drying followed by evaporation of the solvent, distillation and crystallization.

Alternatively, 1-aryloxy-4-chloro-2-butanol can be prepared by adding an aqueous base solution to a mixture of a substituted or unsubstituted phenol or an aryl compound with an acidic hydroxy group and 1,4-dichloro-2-butanol.
H about 9.0-10. It can also be produced by adding at a rate such that the concentration is preferably maintained between 9.5 and 10.0. The product is isolated as described above. The following Preparation Examples are intended to be illustrative and in no way limiting.

Production example 1 4-chloro-1-phenoxy-2-butanol 282 parts (3 mol) of phenylene, 1 part of water, 50 parts of 300 parts
Nawa Azusa in a mixture consisting of % NaOH, 443 at 60 qo
．． 36 ml (3.1 mol) of 1,4-dichlorobutanol was slowly added.

I continued Roku Azusa for 1 hour at 6000. Extracted twice with one portion of ether, the combined ether extracts were neutralized by washing with water, and dried over sodium sulfate overnight.

It was concentrated to dryness under reduced pressure. The retentate was distilled to yield a product of 435 mm (135 to 1 mm, collected at 010.05 mm).

The product was solidified and petroleum ether (60oo~11000
) to form a white crystalline solid (mp52~54o
o) was obtained. Analysis calculation value (C, rainbow, 3CI02) = C, 59.86: day,
6.53 Measured value = C, 59.72; Sun, 6.37 Production example "2 4-chlorophenol (2-chlorophenoxy)-2-butanol 129 (1 mol) of 2-chlorophenol, 6
1.3 mol (185.9 mol) of 1,4-dichloro-2-butanol was added to a mixture of 0.0 mol of KOH, 100 ml of water, and 400 mol of isopropanol at 5000 ml.

It was heated overnight at 65q0 in a vapor grade and extracted with 300 g of isopropyl ether. The ether extract was diluted with INNaOH.
It was then washed with water and dried over sodium sulfate. concentrate,
The oily residue was distilled under reduced pressure to obtain an oily substance (bp 13
0 to 1310010.01 side) was obtained. Analysis calculation value (C
, Sawa, 5CI02) = C, 51.08: day, 5.15 Measured value = C, 51.13; day, 5.14 Production example 3 4-chloro-1-(3,5-dimethylphenoxy) -2
-Butanol 2.5 mol of 1,4-dichlorobutanol was added to a mixture of 245 mol (2 mol) of 3,5-dimethylphenol and 2 mol of NaOH, and the mixture was incubated at 65°C overnight.

The solid precipitate separated by cooling was collected in the oven and washed with water to make it neutral. 375 recrystallized with isopropyl ether
A white crystalline solid (mp 74-76°C) was obtained. Analysis calculation value (C, 2 days, 7CI02) = C, 62.02: days, 7.49 Measured value = C, 63.96: days, 7.66 Production example 4 4-chloro-1-(4-chlor -3-methylphenoxy)-2-butanol 286 units (2 mol) of 3-methyl-
4-chlorophenol, 700 units' tert-butanol,
Add N to a mixture consisting of 700 ml of water and 3.0 mol of 1,4-dichloro-2-butanol at 4000 ml of N.
aOH (2.9 mol, 230 ml dissolved in 700 ml of water) was added to maintain the pH between 9.5 and 10.0.

The addition took 1 feeding hour and the reaction mixture was incubated at 4000 ml for 4 morning hours. Extracted with 2500 chloroform/NaOH.

The extract was dried with sodium sulfate. Concentrate and vacuum distillate Sunwan to obtain 135-14 yolo. 110 with 007 ribs.
A product of 9 min was obtained. The mp after recrystallization with isoprobanol and petroleum ether (30-60qC) was 87-8pi0. Analysis calculation value (C,.day, 4CI202) = C, 5
3.03: day, 5.66 measurement value = C, 53.11: day,
5.61 Production Example 5 4-chloro-1-(4-chloro-2-methylphenoxy)-12-butanol 105 units (0.74 mol) of 2-methyl-4-chlorophenol, 171.5 units (1.2 mol) 84 days (45.5%) using the method of Production Example 4 using 1,4-dichloro-2-butanol of ), 50.3 hours of NaOH, 300 hours of water and 300 minutes of tert-butanol.
A product (distilled at 135 pm, 10.01 pm) was produced.

Analysis calculation value (C,.day, 402CI2) = C, 53.03;
Day, 5.66 Measured value = C, 53.41; Day, 5.70 Production example 6 4-chloro-1-(1-naphthyloxy)-2-butanol 1 mole (147 days) of 1-naphthol, 350 of [of water, 1 mol (143 mol) of 1,4-dichloro-2- was added at 54°C to a mixture consisting of 2 mol (112 mol) of KOH.
Butanol was added.

During this addition, the temperature of the reaction mixture was kept below 6000°C. Heat at 6500 for 12 hours, add 500 ml of water and 350 ml of water.
Mixed with M chloroform.

The chloroform layer was separated, washed with water, dried over sodium sulfate, concentrated, and the residual oil was distilled under reduced pressure to give 162-
165q0lo. A crystalline solid of 128 mm was obtained on 01 legs.
The mp after recrystallization with ether or petroleum ether (30-60o) was 75-770. Analysis calculation value (C, 4 days, 502 CI) = C, 67.07; day, 6.03 Measured value = C, 67.19: day, 6.19 Production example 7 4-chloro-(4-biphenylyloxy) -2-Butanol 1 mole (158 m) of 4-phenylphenol and 100 molar of NaOH are dissolved in 500 molar water and 40 molar
1.4 of 1 mole (143.02 evening) while worshiping the bride at qo
-Dichloro-2-butanol was added.

It was heated in a steam bath for 6 hours at 10°C, cooled and extracted with 300 g of chloroform. The chloroform extract was washed with water to make it neutral, dried over sodium sulfate, and concentrated to dryness. The solid residue was recrystallized from isopropanol to give a white crystalline solid (mp 123-124 qo). Analysis calculation value (C, 6 days, 7CI02) = C, 69.44; day, 6.19 Measured value = C, 69.79; day, 6.22 Production example 8 4-chloro-1-(3-trifluoro (methylphenoxy) mono-2-butanol 0.5 mol (75 mol) of m-trifluoromethylphenol, 1 mol (56 mol) of KOH,
To a mixture consisting of 100 ml of water and 400 ml of isopropanol was added 0.6 mol (84 ml) of 1,4-dichloro-2-butanol at a temperature below 55°C.

Heat the bait at 65°C for 2 hours, mix with water for 2 hours, and mix with 400' of water.

Extracted with lopyether. This ether extract was added to 0.
NaOH, then washed with water, dried with sodium sulfate,
Distilled under reduced pressure. The distillate collected at 120-1240010.01 was solidified at room temperature (mp 50-52°C).

Analysis calculation value (C,.day, 2CIF302) = C, 49.18
: Day, 4.50 Measured value = C, 49.35: Day, 4.47
Production example 94-chlororu-1-(4-chlorophenoxy)
1-2-Butanol Production Example 7
4-dichloro-2-butanol, 85 min (36.1 mol) from 40 min (1.0 mol) NaOH and 400 ml water
%) product was obtained (after recrystallization from isopropanol)
p62-6400).

Analysis calculation value (C, rainbow, 5CI02) = C, 51.09: day,
5.14 Measured value = C, 51.76; Sun, 5.12 Production example 10 2-methoxy of 4-chloro-1-(2-methoxyphenoxy)-2-butanol 2 moles (248.26 m) Phenol, 4 moles (160 molar) NaOH, 250 molar water 1 molar.

2.2 mol (31
1,4-dichloro-2-butanol (4.64 pm) was added. It refluxed quietly overnight. The extract was extracted with 1 portion of isopropanol ether, dried over sodium sulfate, and distilled under reduced pressure.

136-138qo/0.015 skin-collected distillate (3
96.8 evening) solidified into a white crystalline solid (mp48-5
0o○).

Analytical calculated value (C,.day, 403 CI) = C, 57.52; day, 6.14 Measured value = C, 57.49: day, 6.54 using the method disclosed in Preparation Examples 1 to 10. , appropriate phenol (D) and 1,4-dichloro-2-butanol (m)
starting material and various other 1-aryloxy-4-4
-Chloro-2-butanol (N) was produced.

Manufacturing example 11 2-methyl-5-k.

4-chloro-1-(2-methyl-5-chlorophenoxy)-2-butanol (bp 135-8°C/0.05 skin) was produced from luphenol and 1,4-dichloro-2-butanol. Production example 12 4-k from 2-naphthol and 1,4-dichloro-2-butanol.

1-(2-naphthyloxy)-2-butanol (m
plol~10 was 0) was produced. Production example 13 4-acetylaminophenol and 1,4-dichloro-2
-butanol and 4-chloro-1-(4-acetylaminophenoxy)-12-butanol (mp125-12
8q0) was produced.

Production Example 14 4-Chlor-1-(4-methoxyphenoxy)-2-butanol (mp61-6yo
) was manufactured.

Production Example 15 4-chloro-1-(3-chloro-2-pyridyloxy)-2-butanol (mp56) from 3-chloro-2-hydroxypyridine and 1,4-dichloro-2-butanol
~ mottled °C) were produced.

Production example 165-chloro-2-hydroxypyridine and 1
・4-dichloro-2-butanol and 4-chlor-1
-(5-chloro-2-pyridyloxy)-12-butanol was produced.

Production Example 17 4-Chloro-1-(inden-5-yloxy)-2-butanol (mp 56 to 0.degree. C.) was produced from 6-hydroxyindene and 1,4-dichloro-2-butanol.

Production example 18 4-chloro-11 (3-chlorophenoxy) from 3-chlorophenol and 1,4-dichloro-2-butanol
1-2-Butanol (mp 60-62°C) was produced.

Production example 19 4-chloro-1-(2-ethoxyphenoxy)-2-butanol (bp130-13○/0.0
1 side) was manufactured.

Production Example 20 4-chloro-11(4-acetylphenoxy)-2-butanol (mp125-12800) was produced from 4-acetylphenol and 1,4-dichloro-2-butanol.

Production Example 21 4-chloro-1-(0-phenylphenoxy)-2-butanol (bp156-16000/0.
25 ribs) were produced.

The production of the novel 1-aryloxy-4-ami/-2-butanol (1) of the present invention is shown by the following formula.

Table 2 (All symbols in the formula are as defined above) In the above reaction formula, 1-aryloxy-4-chloro-2-butanol (N) is reacted with amine (V) to create a new 1-aryloxy-4-amino-2- Butanol (1) is obtained.

This reaction consists of: ■ A mixture of a chlorine compound (W) and an amine (V) is heated with a solvent in a steel container, and a mixture of a 'B' chloride compound (N) and an amine (V) is heated in a steel container without a solvent. A mixture of a chloro compound (W), an amine (V) and a solvent is refluxed at atmospheric pressure, or a mixture of a chloro compound (W) and an amine (V) is refluxed at atmospheric pressure and a solvent at an appropriate temperature. It can be carried out by heating without heating. The method chosen will depend somewhat on the nature of the amine reactant.
For example, when the amine is a low molecular weight volatile amine, Methods A or B are preferred and the contents of the container are heated for about 12 to 2 hours.
Heat at about 100-150 qo. Methods C or D are preferred when the amine is a high molecular weight non-volatile amine or a low volatility amine, in which the reaction mixture is heated to reflux at the boiling point of the solvent used, i.e. about 100-150°C. Reaction times vary and are somewhat shorter when the chlorine compound and amine are reacted in the absence of a solvent and when high reaction temperatures are used. In each case, the reaction product is isolated by conventional acid-base extraction techniques and, if desired, the free base is converted into a pharmaceutically acceptable acid addition salt;
Purification by crystallization from a suitable solvent or solvent system. 1-aryloxy-4-amino-2 which does not form the above salts
-Butanol can be purified by vacuum distillation. Examples 1-6 are illustrative of the preparation of the novel 1-aryloxy-4-amino-2-butanols of the present invention by one of the four methods described above. Table 3 shows physical data and compliant manufacturing methods for other compounds of formula 1. Table 4 provides analytical data for the compounds listed in Table 3.

Example 1 4-isopropylamino-1-(1-naphthyloxy)
-2-butanol hydrochloride 27.1 parts (0.1 mol)
A mixture of -(1-naphthyloxy)-2-hydroxybutyl chloride and 100 g of isopropylamine was heated in a steel vessel for 2 hours at 120 pm.

The mixture was mixed with 300' of Iso HCI and extracted with ether at room temperature.

The acidic aqueous solution was made basic, extracted with isopropyl ether, dried over sodium sulfate, and then concentrated to dryness. Dissolve the residue in isopropanol and add ethyl HCI.
mixed with. The white crystalline precipitate was recrystallized from isopropanol and isopropyl ether to give the title hydrochloride (mp1
26-128oo) were obtained. Analysis calculation value (C, 7 days C
IN02) = C, 65.90: Sun, 7.81: N, 4.
52 measurement value = C, 65.67; day, 7.91: N, 4.
34 Example 24-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1-(1-naphthyloxy)
-2-Butanol hydrochloride 12.5 mol (0.05 mol) of 1-(1-naphthyloxy)-12-hydroxybutyl chloride, 9.97 mol (0.075 mol) of 1.2.3.
A mixture consisting of 4-tetrahydroisoquinoline, 300 g of isopropanol was refluxed for one period.

A crystalline precipitate formed upon standing at room temperature. The mixture was heated in a furnace, and the furnace liquid was concentrated and dried under reduced pressure. The crystallized semi-solid residue was recrystallized from acetone. A crystalline solid of 12.2 hours was obtained (169-17100).

Analysis calculation value (C23 CIN02) = C, 71.96: day, 6.83: N, 3.65 Measured value = C, 71.69: day, 6.76: N, 3.60 Example 31 -(1 naphthyloxy)-4-phenethylamine-2-butanol hydrochloride 12.5 units (0.05 mol) of 1-(1 naphthyloxy)-2-hydroxybutyl chloride and 14.5 units (0.1 mol) of -(1 naphthyloxy)-4-phenethylamine-2-butanol hydrochloride ) with phenethylamine was heated on a heating ramp for 20 minutes at 120 qo.

250 ml of acetone, heated to boiling, then filtered at room temperature.

The stagnant solution was treated with 50% ethereal HCI. The resulting white precipitate was filtered out. 11. Recrystallize from acetone.
The title hydrochloride was obtained after 8 hours. (mp163-16500)
. Analysis calculation value (C retention date 26N02CI) = C, 71.05: day, 7.05; N, 3.77 Measured value = C, 70.99: day, 6. Spots: N, 3.61 Example 41-(2-chlorophenoxy)-4-(1,2,3,4-tetrahydroisoquinolyl)-2-butanol hydrochloride hydrate 11.8 (0.05 mole) of 1-(2-chlorophenoxy)-2
-hydroxybutyl chloride, 13.3 mol (0.1 mol) of 1,2,3,4-tetrahydroisoquinoline, 10
A mixture consisting of 0M n-butanol was heated in a steel vessel for 2 hours at 120 qo.

Heat the oven at room temperature, mix the oven solution with 200 g of HCI, and add 1
Extracted twice with 0.00g isopropyl ether. The aqueous acid solution was made basic, extracted with isopropyl ether, and treated with ethereal HCI. Recrystallization from isopropanol gave the title hydrochloride hydrate (mpl 18-1).
20℃). Analysis. Calculated value (C, 9 days 25CI2N03) = C, 59.07
: day, 6.52: N, 3.63 measurement value = C, 59.08
: Day, 6.51; N, 3.55 Example 54-(isopropylamino)-1-(0-methoxyphenoxy)-2
-butanol hydrochloride 11.6 mol (0.05 mol)
A mixture of (2-methoxyphenoxy)-2-hydroxybutyl chloride, 50' of isopropylamine, and 100' of n-butanol is placed in a steel container;
It was heated at 120 pm for 2 hours.

After filtration, the filtrate was concentrated to dryness, mixed with 200' HCI, extracted with ether, and the aqueous layer was made basic. The base-insoluble oil was transferred to isopropyl ether, dried over sodium sulfate, and concentrated to dryness. The retentate was dissolved in isopropanol and mixed with 20' of ethereal HCI.
The gummy precipitate was recrystallized using isopropyl ether and isopropanol. Yield 8.3 evenings; mp83-85
oo. Analysis calculation value (C, 4 days treatment CIN03) = C, 58
．． 02: Sun, 8.35; N, 4.83 Measured value = C, 57
．． 44: Sun, 8.31: N, 4.72 Example 61-(
0-chlorophenoxy)-4-(4-phenyl-1-piverazinyl)-12-butanol 35.1 moles (0.15 mol) of 1-(0-chlorophenoxy)-12-hydroxybutyl chloride, 32.6 moles (0.15 mole) A mixture consisting of 2 mol) of N-phenylpiverazine and 400 M of isopropanol was refluxed for 4 hours.

It was left in the refrigerator overnight and then filtered. Convert the furnace liquid to ethereal HC
I and the salts were precipitated by addition of ether. The white crystalline solid that formed was dissolved in 0.1 molar HCI and then neutralized with NaOH to produce a crystalline precipitate. Recrystallized from isopropanol to give the title free base (mp
101.5°C) was obtained. Analysis calculation value (25N202CI of C2) = C, 66.56;
Day, 6.98:N, 7.76 measurement value = C, 66.49:
7.03:N, 7.86 Representative 1-aryloxy-4-amino-2-butanols prepared from 1-aryloxy-4-chloro-2-butanol and the appropriate amine by Methods A, B, C, D The physical constants of are shown in Tables 3 and 4.

Table 3 Examples 7 to 72 Examples a. Morpholino b. 3,5-dimethylmorpholinyl c. Beveridi/d.4-phenylbiverasono e. 4-phenyl biverazino f. 1, 2, 3
,4-tetrahydroisoquinolyl g,4-phenyl-1,2,3,6-tetrahydro-1-pyridino
h.4ben(2-pyridyl)piverazino-i. Cyclobentylamino i.1-Atamantylamino
k-isoden-5-yl-5-chloro-2-pyridyl m. 1-decahydroquinoline n・1-(2,6
-Somethyl)morpholino Table 4 Analytical data for the products of Examples 7 to 72 Examples Example 73 1-(2-Methoxyphenoxy)-4-phthalimide-
2-butanol 24.6 units (0.1 mol) of 1-(2-methoxyphenoxy)-4-chloro-2-butanol,
18.5 (0.1 mol) of potassium phthalimide, 1
A mixture of 50% dimethylformamide and 150% toluene was refluxed for 8 hours.

After cooling, the toluene layer was separated and washed with water until the washings were neutral. The product, isolated as a crystalline solid, was recrystallized from acetone. mp
108-110°C. Analysis calculation value (C, 9th, 9N05) = C, 66.85: day,
5.61; N, 4.10 measurement value = C, 66.94: day,
5.74:N, 4.15 Example 741-(2-ethoxyphenoxy)-4-phthalimide 2-butanol 3
0 (0.12 mol) of 1-(2-ethoxyphenoxy)-4-chloro-2-butanol and 18.5 (0.1 mol) of 1-(2-ethoxyphenoxy)-4-chloro-2-butanol.
0 mol) of potassium phthalimide,
Heat slowly over 10 minutes to 130oo,
Heated at 0oC for 1 hour.

Extracted with 250' hot toluene.

The toluene extract was cooled to room temperature and the crystalline solid was separated. This solid was recrystallized from toluene. mp93~
95 qo. Analysis calculation value (C spotted milk N05) = C, 67.59; day, 5.
96; N, 3.94 measurement value = C, 67.78: day, 6.
03:N, 4.06 The invention further provides pharmaceutical compositions for administration to animals, comprising at least one compound of the invention as an active ingredient, together with a pharmaceutical carrier or excipient.

Therefore, the compounds of the present invention can be administered orally, rectally, parenterally, i.e. by injection (
provided in a form suitable for intracardial) administration. Thus, for example, orally administered compositions are preferably solid and may take the form of capsules, tablets, double tablets containing carriers conveniently used in the pharmaceutical art. Suitable tablet excipients are lactose, potato starch, maize starch, talc, gelatin, stearic acid, silicic acid, magnesium stearate, polyvinylpyridosol, and the like. For parenteral administration, the carrier or excipient can be included in the ampoule as a sterile parenterally acceptable liquid, such as sterile water, or a parenterally acceptable oil, such as peanut oil.

In rectal administration compositions, the suppository base may be comprised of a suppository base, such as cocoa butter or a glyceride.

Advantageously, the compositions of the invention can be administered in dosage units to provide a fixed amount of the active ingredient.

Tablets, coated tablets, capsules, ampoules and suppositories are examples of preferred dosage units of the invention. Oral dosage units may conveniently contain from 10 to 40 m/cc of active ingredient, and intracardial or intravenous dosage units may contain from 1 to 2 p/cc of active ingredient. while for an intramuscular dosage unit, 5 to 10 wc'c
It is convenient to include the active ingredient c. Examples of preferred compositions are as follows.

Powerful.

cell method 1 Blend ingredients 1, 2, and 3.

2. Grind and reblend this blend.

3 Then fill into #1 hard gelatin couple.

tablet Method 1 Blend ingredients 1, 2, 3, and 4.

2 Add the charged amount of water a little at a time to this blend, carefully following each addition.

This addition of water and rubbing continues until the mass has a hardness that allows it to be converted into wet grains. 3. Pass through a vibrating granulator and convert the wet mass into granules using an 8-mesh screen.

4 Then dry in the oven at 1400F.

5. The dried grains are then passed through a vibrating neck mill.

10 - Use mesh screen.

6. Lubricate the dry forehead grains with 0.5% magnesium stearate.

7. Compress the lubricant granules with a suitable tablet press.

static liquid Method 1 Dissolve the active ingredient in the buffer.

2 Pass through a sterile oven.

3 Aseptically fill into sterile ampoules.

4 Seal the ampoule under aseptic conditions.

Intramuscular injection Method 1 Dissolve the active ingredient in the buffer.

2 Pass through a sterile oven.

3 Fill aseptically into sterile ampoules.

4 Seal the ampoule under aseptic conditions.

suppository Method 1 Melt ingredients 2 and 3 and stir until homogeneous.

2. Dissolve component 1 into the molten mass and stir until homogeneous.

3 Pour into suppository mold and cool.

4 Remove the suppository from the mold and package it.

As is clear from the above, the compound of Formula 1 or its pharmaceutically acceptable amount has a cardiac arrhythmia-blocking activity and a very low 8-adrenergic blocking activity, and is present in a dosage unit and a pharmaceutical carrier and a cardiac arrhythmia-blocking amount. Pharmaceutical compositions containing acid addition salts are one of the objects of the present invention. spirit of the invention,
It will be obvious to those skilled in the art that various modifications, equivalents, and substitutions of equivalent means can be made to the invention without departing from its scope.

Claims (1)

[Claims] 1 Formula: ArO-CH_2-CHOH-CH_2-CH_2-C
l [In the formula, Ar is a 1-naphthyl group, 2-naphthyl group, inden-5-yl group, or 5-chloro-2-pyridyl group, or is unsubstituted or a halogen atom, lower alkoxy group, lower alkyl group, trihalo Methyl group, lower acyl group,
A phenyl group mono- or di-substituted with a substituent selected from the group consisting of a phenyl group and an acetylamino group] and 1-aryloxy-4-chloro-2-butanol of the formula: NHR^1R^2 ( In the formula, R^1 is a lower alkyl group, a phenyl alkyl group,
is a 2-hydroxymethyl-2-propyl group, an adamantyl group or a lower cycloalkyl group; R^2 is H or a lower alkyl group; R^1 and R^2 together with the adjacent nitrogen atom, 1, 2, 3, 4-tetrahydroisoquinoline ring, piperazine ring substituted with phenyl group or 2-pyridyl group, phthalimide ring, morpholine ring, di-(lower alkyl)morpholine ring, piperazine ring,
Phenylpiperidine ring, 4-phenyl-1, 2, 3, 6
- may form a heterocycle selected from the group consisting of a tetrahydropyridine ring and a 1-decahydroquinoline ring)
The formula: ArO-
CH_2-CHOH-CH_2-CH_2-NR^1R
A method for producing 1-aryloxy-4-amino-2-butanol of ^2 (wherein Ar, R^1, and R^2 are as defined above).