JPS6214545B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the formula [In the formula, R ¹ and R ¹ ' are the same or different and represent hydrogen or an alkyl or alkoxy group having 1 to 4 carbon atoms, an allyl group, a halogen atom or a nitro group, R ² is each formula

[Formula] and Beauty

【formula】 (R in the formula^Fiveis hydrogen, C₁~C_FiveAlkyl group, substituted
or lower alkyl or lower alkyl
Aryl or aryl substituted by alkoxy
Ryl represents a lower alkyl group, R⁶represents hydrogen
Wasabi or Al having 1 to 8 carbon atoms
represents a kill group and R⁷is hydrogen, lower alkyl
or aryl lower alkyl group)
acrylic acid group or acrylic acid nitrile group
Representation, R³and R^Fouris combined with nitrogen atom
C in some cases₁~C_Four5 substituted by alkyl
-membered to 7-membered heterocycle (carbon atoms in this ring are acid
by an elementary atom, a sulfur atom, or even another nitrogen atom.
) and the latter may be replaced by
Alkyl, alkyl each having 1 to 5 carbon atoms
koxy, oxyalkyl, acyl or carboa
Residues of lukoxy, pyridyl or phenyl groups
(itself has one or more hydroxyl groups, halogen groups)
or alkyl having 1 to 4 carbon atoms
or may be substituted by an alkoxy group)
May be substituted by R³is hydrogen
and R^Fouris a linear or branched chain 1
alkyl or oxy having ~8 carbon atoms
Alkyl group, linear or branched 2 to 6
unsaturated aliphatic hydrocarbon group having carbon atoms, 3-
Cycloaliphatic hydrocarbon group having 6 carbon atoms
Ruiha formula (In the formula, n is a number from 1 to 3, and R⁸and R⁹teeth
are the same or different, and these are hydrogen, 1 to
Alkoxy group with 3 carbon atoms or ben
Represents a zyloxy group or R⁸and R⁹are together
(represents bismethylene-dioxy group)
phenyl-alkylene or phenyl represented
-represents an alkylidene group]
Base-substituted phenol ethers and also these
Physiologically acceptable acid addition salts of. The present invention provides a racemic mixture represented by the formula and
Both individual optically active isomers are included. Moreover, the present invention (a) Eq. (R in the formula¹,R¹′ and R²is the definition in the expression
) has the formula (R in the formula³and R^Fourhas a definition in Eq.
) or react with an amine represented by
Taha (b) Eq. (R in the formula¹,R¹′ and R²is the definition in the expression
and X is a halogen atom, a sulfate group, or
(representing a sulfonic acid group)
React with an amine represented by the general formula, or
or (c) Eq. (R in the formula¹,R¹′ and R²is the definition in the expression
) has the formula X-R^Four (R in the formula^Fourhas a definition in the expression and
X has the definition in the formula)
react with a compound, or (d) Equation (R in the formula¹,R¹′ and R²is the definition in the expression
The phenol represented by the formula (R in the formula³and R^Fourhas a definition in Eq.
and X has the definition in the formula)
react with the compound to be mixed in the presence of an acid binder.
or (e) expression or expression; (R in the formula¹,R¹′ and R²is the definition in the expression
) with a suitable ketone
and then reduce the condensation product
or (f) Formula X (R in the formula¹,R¹′, R²and R^Fouris in Eq.
reduce the compound represented by
or (g) Formula XI (R in the formula¹,R¹′, R²and R^Fouris in Eq.
and Z is a carbonyl group or
phenyl group or one or two lower
represents a methylene group substituted by a class alkyl group.
Hydrolyze the compound represented by
or (h) Formula XII (R in the formula¹,R¹′, R²and R³is in Eq.
has the definition R^Tenis hydrogen, lower acyl group or
represents a benzyl group and R¹¹is hydrogen or
represents a ndyl group, but R^Tenand R¹¹is both and
cannot represent hydrogen at the same time).
The presence of noble metals in the benzyl group in the compound
split by catalytic hydrogenation and/or
or hydrolyze the acyl group, Then, obtained according to methods (a) to (h)
Addition of compounds to physiologically acceptable acids
convert to salted A method for producing a compound represented by the formula characterized by
Regarding. Among the above-mentioned substituents, the following are more preferable:
stomach. R^Four(R³= H) is as follows.
be. an alkyl group having 1 to 5 carbon atoms,
Alkoxy or oxyalkyl groups, especially
such as isopropyl group or tertiary butyl group
branched groups, also having 2 to 4 carbon atoms
unbranched unsaturated aliphatic hydrocarbons, especially
lyl group, cyclic with 4 or 5 carbon atoms
Aliphatic hydrocarbon groups, especially cyclopentyl groups and
dialkoxyphenylethylidene group, especially 5′,
4′-dimethoxyphenylethylidene group or 1-
Methyl-2-3',4'-dimethoxyphenylethyl
Den group. R³and R^Fouris combined with nitrogen atom to form a heterocycle
In this case, the ring system is a 5-membered ring or a 6-membered ring.
For example pyrrolidine, piperidine and morphol
Preferably, these include one or two lower
Substituted by alkyl group or by pyridyl group
It may be Particularly preferred is the piperazine ring.
, which means that there are 1 to 4 atoms in the second nitrogen atom.
Alkyl, alkoxy, oxy with carbon atoms
Alkyl or acyl group, 1 to 5 carbon atoms
carbalkoxy group, pyridyl group or
substituted with a phenyl group substituted by
I can be there. R^FiveThe details are as follows. Hydrogen, 1~
unbranched alkyl with 4 carbon atoms
groups, especially methyl, ethyl, and phenyl groups. R⁶The details are as follows. Hydrogen, 1~
Alkyl group with 4 carbon atoms. R⁷The details are as follows. 1 to 4
Alkyl groups having carbon atoms, especially methyl, ethyl
and tertiary butyl groups and also benzyl groups.
Base. R¹and R¹′ is as follows. water
an alkyl group having 1 to 3 carbon atoms or
is an alkoxy group, fluorine, chlorine and also nitro
Base. For the reaction according to method (a) and (b) above, the formula
The following amines are represented by
It can be done. 1 Primary amines such as methylamine, ethyl
Amine, Isopropylamine, Isobutylamine
, secondary butylamine, tertiary butylamine
1-methylpropylamine, 2-aminoethane
Tanol, 2-methoxy-ethylamine, 1-
Methyl-3-hydroxy-propylamine, a
Rylamine, 3-dimethylamino-propyla
amine, phenylethylamine, 3-phenyl-
Propylamine, 1-phenyl-ethylamine
1-methyl-2-phenyl-ethylamine
1-methyl-2-(4-methoxy)-phene
Nylethylamine, 1-methyl-2-(3,4
-dimethoxy)-phenylethylamine, 3,
4-dimethoxyphenylethylamine, 3-methoxy
Toxy-4-ethoxy-phenylethylamide
3-methoxy-4-hydroxy-phenyl
Ethylamine, 3-methoxy-4-benzyl
xyphenylethylamine, 3-benzyloxy
C-4-methoxy-phenylethylamine,
3,4-methylenedioxy-phenylethyl a
Min, 2,5-dimethoxyphenylethylamine
2,4-dimethoxyphenylethylamine
2,3-dimethoxyphenylethylamine
3,4,5-trimethoxy-phenylethyl
Ruamine, 2-methoxyphenylethylamine
3-methoxyphenylethylamine, 4-
Methoxyphenylethylamine, 3,4-dimethylamine
Toxyphenylmethylamine, 2-hydroxy
-2-phenylethylamine, 1-methyl-2
-Hydroxy-2-phenylethylamine,
3,4-dimethylphenylethylamine, 4-
Chlorophenylethylamine, 3,4-dichloro
Lofenylethylamine, 4-hydroxyphene
Nylethylamine, heptaminol
(heptaminol), cyclopropylamine, cyclopropylamine
Lopentylamine, cyclohexylamine, 2
-Adamantylamine. Isopropylamine
and tertiary butylamine and also homoverate
It is said to be particularly advantageous to use lylamine.
It was found that 2 5- to 6-membered cyclic secondary amine, e.g.
Phenylpiperazine, N-2'-methylphenyl
Piperazine, N-3'-methylphenylpiperazie
N-, N-4′-methylphenylpiperazine, N-
2'-methoxyphenylpiperazine, N-3'-meth
Toxyphenylpiperazine, N-4'-methoxy
Phenylpiperazine, N-2'-chlorophenyl
Piperazine, N-3'-chlorophenylpiperazi
N-, N-4'-chlorophenylpiperazine, N-
2′-pyridylpiperazine, N-3′-pyridylpiperazine
Perazine, N-4'-pyridylpiperazine, N-
2'-Hydroxyphenylpiperazine, N-3'
-Hydroxyphenylpiperazine, N-4'-H
Droxyphenylpiperazine, N-oxyethyl
Lupiperazine, N-methylpiperazine, N-ethylpiperazine
Chilpiperazine, N-carbomethoxypiperazine
N-carboethoxypiperazine, N-cal
Bo-(2-hydroxy-2-methyl)-propo
xypiperazine, 2-methylpiperazine, 2,
6-dimethylpiperazine, 2,6-dimethylpiperazine
Peridine, 3-β-pyridylpiperidine, Pipe
Lysine, morpholine and also pyrrolidine. The introduction of amine groups by method (a) above may optionally be
Organic solvents such as methanol, ethanol, iso
Alcohols like propanol, e.g.
aromatic solvents like zene, toluene or
agents such as dioxane, tetrahydrofuran, etc.
ester or carboxylic acid amide especially dimethylform
By reacting the two components in the presence of an amide
It is done. In a more preferred variant, alco
The two components dissolved in the melt are mixed at an elevated temperature.
You may also react in different ways. Is the reaction temperature room temperature?
The temperature can be varied from the temperature to the boiling point of the solvent. The formula used as starting material in method (a)
The glycidyl ether produced by the inventors in Germany
Obtained according to patent application no. P2623313.6. In method (b), α-halogen-β expressed by the formula
-Hydroxy-propyl ether as the starting material
used. Halogen atom preference at α-position
Preferably the corresponding sulfuric acid instead of chlorine or bromine
using esters of or esters of sulfonic acids.
It's okay. The starting material is an epoxide represented by the formula
Split with hydrohalic acid, sulfuric acid or sulfonic acid
It can also be obtained by letting in the ceremony
The reaction with the represented amine can be carried out using a suitable organic solvent.
For example, methanol, ethanol, isopropanol
Alcohols such as benzene, toluene
Aromatic solvents such as dioxane, tetra
Ethers or carvone such as hydrofuran
Also in the presence of acid amides, especially dimethylformamide
is carried out in your absence. This reaction starts at room temperature
is carried out at temperatures up to the boiling point of
It is preferable to carry out the test at a degree. liberated acid analogy
In order to combine halogen hydrides,
For example, tertiary amines such as triethylamine
Mine, pyridine or alkali metal or alkali
Potassium earth metal hydroxides, carbonates or bicarbonates
It can be carried out in the presence of an acid binder such as. use
The amine to be reacted is reacted in excess, e.g. twice the molar amount.
It is advantageous to use it for. For method (c), phenoxy expressed by the formula
-2-hydroxy-1-aminopropane derivative
used. The latter can also exist in salt form. Expression
The reaction with reactive esters is described in method (b).
The reaction is carried out under the following reaction conditions. used as starting material
For example, an amine represented by the formula
React the expressed epoxide with ammonia
It can be obtained by This is also a halogen compound
It can also be obtained by reaction with ammonia from
Ru. In addition, the method for producing the product of the method of the present invention is as described in (d).
It is also carried out in accordance with the law, where it is expressed as a formula.
The phenols mentioned above are used. Also this frame
Enol is its alkali metal salt such as natri
Also used in the form of um salt or potassium salt
Ru. The reaction component represented by the formula is 1-halo
Geno-2-hydroxy-3-alkylaminopro
Bread is used. Also, 1,2-dihydroxy-
3-Alkylaminopropane sulfate ester or
It is also possible to start from a sulfonic acid ester.
be. This reaction occurs when an acid binder such as an alkali metal
It is advantageous to carry out in the presence of hydroxide. a
1-halogeno-2-hydride used in alkali medium
Roxy-3-alkylaminopropane is intermediate
This replaces the corresponding 1,2-epoxypropane.
reacts with phenol. The reaction is carried out at normal temperature or
or at elevated temperatures up to the boiling point of the solvent used.
For example, methanol, ethanol, isopropanol
Alcohols such as benzene or tortoise
Aromatic solvents like luene or e.g.
Ethers such as xane and tetrahydrofuran
or carboxylic acid amide, especially dimethylformamide.
in the presence or absence of a solvent such as
It can be implemented. In the formula used as starting material
For example, the represented compound has the formula
React the represented amine with epichlorohydrin.
It can be obtained by In method (e), the amine represented by the formula
R in the presence of active hydrogen on the medium^Fourroughly corresponds to the meaning of
hydrogenated with a ketone. As a ketone
For example, acetone, methyl ethyl ketone, cyclopro
Panone and cyclohexanone may be mentioned. touch
As a medium, for example, Raney nickel, platinum or
Palladium is used. Generally the operation is for example
methanol, ethanol or isopropanol
It is carried out in the presence of an inert solvent such as. Also
First, the amine represented by the formula is condensed with the ketone.
obtained without combining and optionally isolating it.
The Schiff base can also be reduced as described above.
Ru. In addition, the reduction of azomethine is sodium borana
lithium aluminate or other complex metal hydrogen
compound and also with aluminum amalgam
It can also be carried out in a conventional manner. By method (e), the group R in the formula^Fouris the second carbon
Only compounds that are bonded to the nitrogen atom by an atom
can get. In addition, method (e) uses the aminoketone represented by the formula
It can also be implemented by using The reaction is the formula
Same as for aminopropanol represented by
carried out in a method. This is because at one reaction stage
or azomethine and optionally
for any reduction after isolating it.
The keto group is simultaneously reduced together with the azomethine double bond.
This is because it will be restored. used as starting material
For example, the production of aminoketone is expressed by the formula
carried out by mild oxidation of aminopropanol
sell. Also, the method described in (f), that is, expressed by formula
The reduction of aminoketones has already been described with respect to (e).
This method can be carried out by catalytic hydrogenation.
Ru. In addition, the reduction of keto groups can be done using lithium aluminate or
or other complex metal hydrides?
Alternatively, use aluminum isopropylate
Performed by the Matebein-Pondorf method
Ru. For example, the production of a ketone of formula
True 1-halogen-2-oxo-3-(Fenoki
c) - Reacting propane with the amine represented by the formula
This can be implemented by Yet another variant of the invention is in formula XI according to method (g).
Oxazolidone or oxazolidine expressed
is the hydrolysis of Such oxazolidones
For example, the corresponding 1-amino-2-hydroxy-3
-(Phenoxy)-propane, for example, diethyl
carbonate, methyl chlorocarbonate or
React with reactive derivatives of carbonic acid such as phosgene
or in some cases suitable in the 3-position.
and hydrohalic acid ester, sulfur
in the form of acid esters or sulfonic esters.
5-Hydroxymethyl-oxazolidone-2
by reacting with a suitable alkyl phenolate.
You can get more. Suitable oxazolidines
For example, the corresponding 1-amino represented by the formula
-2-hydroxy-3-phenoxy-propane
By reacting with aldehydes or ketones
can be manufactured. Oxygen atoms not substituted with nitrogen atoms
Sazolidone or oxazolidine is described in method (c)
Alkylated with a compound represented by the formula
It can be done. These oxazolidone derivatives or
Hydrolysis of sazolidine derivatives can be carried out in acid media or in alkaline media.
In potash medium such as dilute hydrochloric acid, dilute sulfuric acid, dilute sodium hydroxide.
using a solution of thorium or dilute potassium hydroxide solution.
It can be implemented by To promote hydrolysis
Heating is advantageous. Also, hydrolysis is water-soluble
It may also be carried out in a solvent such as a lower alcohol.
stomach. The products of the invention also have a hydroxyl group or
and/or the secondary amino group is the group R^TenMa
Or group R¹¹This from compounds protected by
It can also be obtained by splitting the protective groups of
Wear. Protecting groups include, for example, acyl or base groups.
Examples include the ndyl group. What is the splitting of benzyl group?
Presence of precious metals such as palladium or platinum
This is carried out by catalytic hydrogenation. Acyl compound
For example, the acyl group may be
Lower fats such as cetyl or propionyl
Group acyl groups are preferred and the cleavage is carried out by acid or alkali groups.
by hydrolysis in any aqueous medium of potash.
will be implemented. The corresponding benzene represented by formula XII
The production of acyl compounds or acyl compounds is as described above.
carried out by one of the methods, in which case the corresponding acylation
starting material or benzylated starting material is used.
Ru. In formula XII, R²starting material in which represents an acyl group
For example, when trying to manufacture quality,
Acylation of the compound to be treated and then the corresponding acyl
- compound represented by formula XII is reacted according to method (b).
It is possible to produce a compound that is This is the formula
Medium R^Tenis also compatible with compounds in which is a benzyl group.
where the corresponding hydroxylation
The compound is benzylated instead of acylated. Formula XII
In R¹¹is derived from a compound representing a benzyl group.
Can be used in place of primary amines if you want to emit
N-benzyl compound (a), (b), (c), (f) or (d)
It can be used according to the method. Asil
group and benzyl group are R^Tenand R¹¹parallel as
If present in
It can be divided one after another. Methods (a), (b), (d) or (h) often result in direct output.
The production of the emitting substance can be further combined with the next reaction.
and that the starting materials are not isolated separately.
It can be advantageous. The product of the invention is in base form or in its salt form.
and if necessary these are usually
methods such as recrystallization or in some cases
Converting to the free base followed by treatment with a suitable acid
It is purified by The products of the invention may optionally be
to physiologically acceptable salts of organic or inorganic acids.
can be converted. Examples of organic acids include acetic acid, malonic acid, and
Pionic acid, lactic acid, succinic acid, tartaric acid, maleic acid
Acid, fumaric acid, citric acid, malic acid, benzoic acid
acid, salicylic acid, oxyethanesulfonic acid, acetic acid
Tuluric acid, ethylenediaminetetraacetic acid, Embom
Acids and also synthetic resins containing acid groups can be mentioned.
Wear. Inorganic acids such as hydrochloric acid or hydrobromic acid
Hydrohalic acids such as sulfuric acid, phosphoric acid and
Amido-sulfonic acid can be mentioned. Racemic base-substituted phenol represented by the formula
The optically active isomer of the ether is the optically active acid
can be obtained by decomposing them into their components in
can. As an acid for the production of optically active salts according to the invention
For example, (+)- and (-)-tartaric acid,
(+)- and (-)-dibenzoyltartaric acid,
(+)- and (-)-ditolyltartaric acid, (+)
- and (-)-mandelic acid, (+)- and
(-)-camphoric acid, (+)-camphor-β-sulfonic acid,
(+)-α-bromocamphor-α-sulfonic acid and
N-(para-nitrobenzoyl)-(+)-glue
I can give you tamic acid. Production of optically active salts
The preparation is carried out in water or in an aqueous or anhydrous organic solvent.
It can be implemented. Alcohols or organic carvone
It has been found that it is advantageous to use acid esters.
There used to be. Racemic forms of bases to produce optically active compounds
an optically active acid in a solvent preferably in molar proportions.
The optics of the compound expressed by the formula after reacting with
The active salt is isolated. In some cases, racemic
Simply to remove one of the optically active enantiomers from
It is also possible to use a half-equivalent amount of optically active acid.
Moreover, excess amounts of optically active acid may also be used. Due to the properties of optically active acids, the desired enantiomer can be directly obtained.
Alternatively, it can be obtained from the mother liquor of the initial crystallization.
Ru. This optically active base is then converted into a salt using the usual method.
This optically active base is then liberated from
a salt of one of the chemically acceptable organic or inorganic acids;
can be converted into The compound represented by the formula and its physiological
Acceptable acid addition salts have been tested in animal studies on dogs.
Valuable therapeutic properties, especially β-adrenergic,
β₁-Adrenergic and/or antihypertensive
and/or found to have antiarrhythmic properties
Therefore, they are useful in human medicine, for example.
treatment or prevention of coronary vasculopathy, cardiac arrhythmia
It can be used therapeutically and for the treatment of hypertension. In particular, the following may be emphasized: therapeutically favorable
β₁Receptor blocking action and β₂Receptor blocking effect
split between (then β₂receptors are blocked
) is R in Eq.³If is H then R^Fouris Hue
Indicated by a compound representing a nyl-alkylene group
Ru. For example, the product according to Example 15 is the known 1-
[(3,4-dimethoxyphenethyl)-amino-3
-Aryloxy-2-propanols e.g.
1-[(3,4-dimethoxyphenethyl)-ami
No-3-(meth-tolyloxy)-2-propano
Hydrochloride (J.Med.Chem.Vol. 18 (1975), No. 148
(see page) than (β₂- Absence of sympatholytic effect
) substantially strong β₁-Sympathetic nerve blockade
Indicates purpose. The product of the process of the invention is a free base or a salt thereof.
optionally in the form of a conventional pharmaceutical carrier.
Tablets mixed together with quality and/or stabilizers
or orally in the form of dragees or ampoules
It can be administered parenterally in solution form. for tablets
Examples of carrier substances include lactose, starch,
Tragacan and/or Magne Stearate
Possibly Sium. For injection, the dosage is about 2-20 mg and for oral use.
A dosage of about 6 to 150 mg is possible. 1 piece
Tablets or dragees contain approximately 5-50 mg of active substance
I can do it. Shows only a small amount of β-receptor blocking effect
or not at all therapeutically desirable
The formula shows a significant blood pressure lowering effect with a long-lasting effect.
R³is R^Fourand N- together with the atom complex
Rings such as unsubstituted or second N-
Piperazino group substituted with an atom, piperidino
or a compound representing a morpholino group.
It can be done. In the formula R³is H and R^Fouris a branched chain
aliphatic hydrocarbon group or cycloaliphatic hydrocarbon group
Compounds that express generally have very strong β-receptors.
Characterized by blocking action. Next, the present invention will be explained by examples. Example 1 [D,L]-3-[2-(3-tertiary butyl acetate)
mino-2-hydroxypropoxy)-phenylene
]--Crotonic acid nitrile hydrochloride 7.0g of [D,L]-3-[2-(2,3-O)
Oxide-propoxy)-phenyl]-crotonic acid
Nitrile with 80 ml of ethanol (98% concentration) and
In a mixture with 15 ml of tertiary butylamine
Heat at boiling reflux for 11/4 hours. Then in a vacuum Concentrate to dryness and evaporate several times in vacuo with toluene.
let 50 ml of oily distillation residue (free base)
Dissolve in ethanol and add dropwise the mixture to concentrated hydrochloric acid.
Adjust the pH value to 4 and evaporate to dryness in a vacuum.
Ru. By evaporating with toluene several times in vacuo
Dry the distillation residue and add a small amount of ethanol and
and ether and again recrystallized from ethanol.
let 7.1g of [D,L]-3 melting at 155-156℃
-[2-(3-tertiary butylamino-2-hydro
xypropoxy)-phenyl]-crotonate nito
Riru hydrochloride was obtained. Example 1a [D,L]-3-[2-(3-tertiary butyl acetate)
Minnow-2-hydroxy-propoxy)-4-ph
[Luolophenyl] Crotonic acid nitrile hydrochloride 50ml ethanol and 100ml tert-butyl
14.0g of [D,L]-3- in amine
[2,3-oxide-propoxy)-4-fluoro
(lofenil)-Crotonitrile is refluxed for 2 hours.
Heat on a steam bath to the bottom. As described in Example 1
melts at 158-159℃ by post-treatment to
8.6g of [D,L]-3-[2-(3-tertiary block)
thylamino-2-hydroxy-propoxy)-4
-Fluorophenyl]-Crotonic acid nitrile hydrochloric acid
Salt was obtained. Example 1b [D, L]-3-[2-(3-3^*,4^*- Ji
Methoxy-phenethyl-amino-2-hydroxy
C-propoxy)-4-fluoro-phenyl]
-Crotonic acid nitrile hydrochloride 14.0 g of [D,
L]-3-[2-(2,3-oxide-propoxy)
C)-4-fluorophenyl]-crotonate nitrate
Under reflux with 20.0 g of homoveratrylamine
Heat on a steam bath for 2 hours and as described in Example 6.
After post-processing the sea urchin, the hydrochloride is dissolved in isopropanol/
Recrystallize from ether. Melts at 153-155℃
[D,L]-3-[2-(3-3
^*,4^*-dimethoxy-phenethylamino-2-
Hydroxy-propoxy)-4-fluorophene
]-Crotonic acid nitrile hydrochloride is obtained. Example 1c [D, L]-3-[2-(3-3^*,4^*- Ji
Methoxy-phenethyl-amino-2-hydroxy
C-propoxy)-5-fluorophenyl]-
Crotonic acid nitrile hydrochloride 12.0g [D,L]-3- in 15ml ethanol
[2-(2,3-oxide-propoxy)-5-
Fluorophenyl]-Crotonitrile carried out
12.0 g of homoveratrylua as described in Example 16e
React with Min. Initially obtained melting point 105-107
10.6 g of free base at ℃ in a conventional manner (same as Example 1)
8.8g of melts at 145-147℃ [D, L] -3-
[2-(3-3^*,4^*-dimethoxy-fuenechi
Ruamino-2-hydroxy-propoxy)-5-
Fluorophenyl]-crotonitrile hydrochloride
Convert to Example 1a [D,L]-3-[2-(3-tertiary butyl acetate)
Minnow-2-hydroxy-propoxy)-5-ph
fluorophenyl]-crotonic acid nitrile hydrochloride 12.0 g of [D,
L]-3-[2-(2,3 oxide-propoxy
C)-5-fluorophenyl]-crotonate nitrate
Rilu hydrochloride with 100ml of tertiary butylamine
Heat to boil under reflux for 2 hours. Normal post-processing
(Example 1). Crude hydrochloride is converted into isopro
Panol/ether and again isopropanol
Recrystallize from. Yield melting at 134-135℃
9.7g of [D,L]-3-[2-(3-tertiary block)
thylamino-2-hydroxypropoxy)-5-
Fluorophenyl]-crotonitrile hydrochloride
is obtained. Example 2 [D,L]-3-[2-(3-morpholino-2
-Hydroxy-propoxy)-phenyl]-
Rotonate nitrile hydrochloride A mixture of 90 ml of ethanol and 6.1 g of morpholine
15g of [D,L]-3-[2-
(2,3 oxide-propoxy)-phenyl]-
Crotonic acid nitrile is heated to boiling under reflux for 21/4 hours. do. Post-treatment was then carried out as described in Example 1.
and convert the product into the hydrochloride salt. 12.9g of [D,L] melting at 184.5-185℃
3-[2-(3-morpholino-2-hydroxy-
Propoxy)-phenyl]-crotonitrile
The hydrochloride was obtained. Example 3 [D,L]-3-[2-(3-N-phenyl-
piperazino-2-hydroxy-propoxy)-
Phenyl]-crotonic acid nitrile hydrochloride 15g [D,L] in 90ml ethanol
-3- [2-(2,3-oxide-propoxy)
-Phenyl]-Crotonitrile and 11.4 g of N
- Boil phenylpiperazine under reflux for 1 1/2 hours. Ru. Work-up and hydrochloride as described in Example 1
Perform the conversion to 14.0g of [D,L]-3 melts at 177-178℃
-[2-(3-N-phenyl-piperazino-2-
Hydroxy-propoxy)-phenyl]-chloro
nitrile hydrochloride was obtained. Example 4 [D,L]-3-[2-(3-isopropyla
mino-2-hydroxy-propoxy)-phenylene
]--Crotonic acid nitrile hydrochloride 270ml ethanol and 60ml isopropylamine
27g of [D,L]-3- in a mixture with
[2-(2,3-oxide-propoxy)-fe
] - Boil crotonitrile under reflux for 1 hour.
Boil. Then post-treatment and treatment as described in Example 1
and conversion to hydrochloride. 21.5g of [D,L]-3 melts at 145-146℃
-[2-(3-isopropylamino-2-hydro
xy-propoxy)-phenyl]-crotonic acid di
Tolyl hydrochloride was obtained. Example 5 [D, L]-3-[2-(3-2^*,6^*- Ji
Methylpiperidino-2-hydroxy-propoxy
c)-Phenyl]-crotonic acid nitrile hydrochloride 90ml of ethanol and 8.0g of 2,6 dimethylpi
15 g of [D,L] in a mixture with peridine
-3- [2-(2,3-oxide-propoxy)
-Phenyl]-Crotonitrile refluxed for 13 hours
Boil under water and work up as described in Example 1.
and conversion to the hydrochloride salt. 12.4g of [D,L]-3 melting at 157-158℃
-[2-(3-2^*,6^*- Dimelpiperidino -
2-Hydroxy-propoxy)-phenyl]-k
Rotonic acid nitrile hydrochloride was obtained. Example 6 [D, L]-3-[2-(3-3^*,4^*- Ji
Methoxyphenethylamino-2-hydroxy-
Propoxy)-phenyl]-crotonic acid nitric acid
le hydrochloride 100ml ethanol and 12.7g homoveratryl
19 g of [D,L] in a mixture with amine
3-[2-(2,3-oxide-propoxy)-
Phenyl]-Crotonitrile under reflux for 5 hours
Boil it. Post-treatment and treatment as described in Example 1.
and conversion to hydrochloride. 10.8g of [D,L]-3 melting at 164-165℃
-[2-(3-3^*,4^*-Dimethoxyfuenethi
Ruamino-2-hydroxy-propoxy)-feu
]-crotonic acid nitrile hydrochloride was obtained. The free base can be prepared in the usual way (alkaline, toluent).
The mother liquor is extracted with ene and concentrated to dryness in vacuo.
and then toluene/diisopropyl ether
1.2 g of crystallized from a glass melt at 88-89℃
The desired product was obtained. Example 6a [D, L]-3-[2-(3-3^*,4^*- Ji
Methoxy-phenethylamino-2-hydroxy
-propoxy)-4-methoxy-phenyl]-
Crotonic acid nitrile hydrochloride 7.0g homoveratrylamine and 7.0ml ethano
7.0 g of [D,L] in a mixture with
3-[2-(2,3-oxide-propoxy)-
4-Methoxyphenyl]-crotonitrile
Heat on a steam bath (at reflux) for 1 hour. anti
Carefully adjust the reaction mixture to a pH of 3.5 with concentrated hydrochloric acid.
Stir in water of step 1 and add toluene/acetic acid ethyl chloride.
Extract 3 times with chill. The aqueous phase is then diluted with bicarbonate.
Adjust the PH value to 8-8.5 with thorium and retard.
Extract with luene. Dry the base extract and spin
and salt the crude base as described in Example 1.
Convert to acid salt. 9.4g of [D,L]-3 melting at 169-170℃
-[2-(3-3^*,4^*-dimethoxy-phene
thylamino-2-hydroxy-propoxy)-4
-methoxy-phenyl]-crotonic acid nitrile salt
An acid salt was obtained. Example 7 [D, L]-3-[2-(3-N-[2^*〕―
Pyridino-piperazino-2-hydroxy-pro
poxy)-phenyl]-crotonic acid nitrile
Rihydrochloride 70 ml of ethanol and 6 g of N-(2-pyridine)
) - 7 g in a mixture with piperazine
[D,L]-3-[2-(2,3-oxide dope)
Ropoxy)-phenyl]-crotonitrile
Boil under reflux for 3 hours. As described in Example 1
and then converted to the trihydrochloride. 5.1g of [D,L]-3-[2] melts at 121℃
-(3-N-[2^*]-Pyridino-Piperazino-
2-Hydroxy-propoxy)-phenyl]-k
Rotonic acid nitrile trihydrochloride is obtained. Example 8 [D, L]-3-[2-(3-N-[4-ace
tylphenyl]-piperazino-2-hydroxy
-propoxy)-phenyl]-crotonate nitrate
Rildihydrochloride 6.8 g of N-(4
- piperazino) - 7 g in a solution of acetophenone
[D,L]-3-[2-(2,3-oxide-
Propoxy)-phenyl]-crotonitrile
Boil under reflux for 3 hours. Then evaporate in vacuum
Let dry. An oily distillation residue crystallizes after several hours.
let Grind with a small amount of ether and suction.
Ru. Remove filter residue in sufficient amount of chloroform
and add a saturated solution of hydrochloric acid/chloroform to this
Little by little while stirring until the reactants become acidic.
Add. After a while, dissolve the dihydrochloride into a clear solution.
Separate from Aspirate and add a small amount of chloroform/ascent.
9 g, washed and dried and melted at 151°C.
[D,L]-3-[2-(3-N-[4-acetate)
[rufenyl]-piperazino-2-hydroxy-p
Ropoxy)-phenyl]-crotonic acid nitrile di
The hydrochloride is obtained. Example 9 [D,L]-3-[2-(3-N-[2-meth
xyphenyl]-piperazino-2-hydroxy
-propoxy)-phenyl]-crotonate nitrate
Rildihydrochloride 5.5 g of N-(2
-methoxyphenyl)-6 in a solution of piperazine
g [D,L]-3-[2-(2,3-oxide
-propoxy)-phenyl]-crotonic acid nitri
The mixture is boiled under reflux for 3 hours. Then put it in a vacuum
Concentrate to dryness and dissolve the residue in chloroform.
and acidify the solution with hydrochloric acid/chloroform.
Ru. Then spin dry in vacuo and dry a little.
Crystallize by trituration with a large amount of ether.
at 171°C by suction filtering and drying.
Melt 10.5g of [D,L]-3-[2-(3-
N-[2-methoxyphenyl]-piperazino-2
-Hydroxy-propoxy)-phenyl]-chloro
Tonic acid nitrile dihydrochloride is obtained. Example 10 [D, L]-3-[2-(3-N-[2-Methi
[rufenyl]-piperazino-2-hydroxy-
Propoxy)-phenyl]-crotonic acid nitric acid
Rudihydrochloride 6.5 g N-(ortho-tolyl)-piperazine
7 g of [D,
L]-3-[2-(2,3-oxide-propoxy)
Examples of C)-Phenyl]-Crotonitrile
9, followed by work-up. 10g of [D,L]-3-[2] melts at 138℃
-(3-N-[2-methylphenyl]-piperazi
No-2-hydroxy-propoxy)-phenyl]
- Crotonic acid nitrile dihydrochloride is obtained. Example 11 [D,L]-3-[2-(3-N-[methylpi
Pelagino]-2-hydroxy-propoxy)-
Phenyl]-crotonic acid nitrile dihydrochloride 7 g of [D,L]-3 as described in Example 9
--[2-(2,3-oxide-propoxy)-]
Enyl] - 60ml of anhydrous ethyl nitrile crotonate
3 g of N-methylpiperazine in alcohol and
React and post-process. 50ml of crude dihydrochloride
Dissolve in water and filter over 3 g of activated carbon.
Finally, the liquid is concentrated to dryness under high vacuum. Generate
Grind the foam with ether and suck it up.
Dry with. 4.9g of highly hygroscopic [D,L]-3-[2
-(3-N-[methylpiperazino]-2-hydro
xy-propoxy)-phenyl]-crotonic acid di
Tolyl dihydrochloride is obtained. This compound is 2203cm in IR^-1, 1590cm^-1,
1435cm^-1, 1235cm^-1and 745cm^-1Features of
Indicates a band with a . Example 12 [D,L]-3-[2-(3-N-[2-hydro
[loxyethyl]-piperazino-2-hydroxy
-propoxy)-phenyl]-crotonate nitrate
Rildihydrochloride 7 g of [D,L]-3 as described in Example 9
--[2-(2,3-oxide-propoxy)-]
Enyl] - 70ml of anhydrous ethyl nitrile crotonate
4.7 g of N-(2-hydroxy
ethyl)--reacted with piperazine and then worked up.
Ru. 8.5g of [D,L]-3-[2] melts at 146℃
-(3-N-[2-hydroxyethyl]-pipera
Dino-2-hydroxy-propoxy)-pheni
]-crotonic acid nitrile dihydrochloride is obtained. Example 12a [D,L]-3-[4-(3-tertiary butyl acetate)
mino-2-hydroxy-propoxy)-phenylene
]--Crotonic acid nitrile hydrochloride in 40 ml of ethanol as described in Example 1.
6.0g of [D,L]-3-[4-(2,3
-Oxide-Propoxy)-Phenyl]-Klotho
Reacting acid nitrile with 40ml of tertiary butylamine
Then post-process. Yield 6.0g [D, L] melting at 186-187℃
-3-[4-(3-tertiary butylamino-2-h)
Droxypropoxy)-phenyl]-crotonic acid
Nitrile hydrochloride is obtained. Example 12b [D,L]-3-[2-methoxy-4-(3-
Tertiary butylamino-2-hydroxy-propo
xy)-phenyl]-crotonic acid nitrile hydrochloric acid
salt 3.4 g of [D,L]-- as described in Example 1
3-[2-methoxy-4-(2,3-oxide-
Propoxy)-phenyl]-crotonitrile
of 20 ml of ethanol and 40 ml of tertiary butyl alcohol.
Boil under reflux for 21/2 hours with min and work up. do. Yield 4.0g [D, L] melting at 145-146℃
-3-[2-methoxy-4-(3-tertiary butyl
amino-2-hydroxy-propoxy)-phenylene
]-Crotonic acid nitrile hydrochloride is obtained. Example 12a [D,L]-3-[2-(3-tertiary butyl acetate)
mino-2-hydroxy-propoxy)-4-meth
Toxy-phenyl]-crotonic acid nitrile hydrochloric acid
salt 5.0 g [D,
L]-3-[2-(2,3-oxide-propoxy)
C)-4-methoxyphenyl]-crotonate nitrate
3 hours after addition of 50 ml of tertiary butylamine
Heat to boiling under reflux and then as described in Example 1.
Post-process. Yield 4.3g [D,L] melting at 144-145℃
-3-[2-(3-tertiary butylamino-2-h)
Droxy-propoxy)-4-methoxy-phenylene
]-Crotonic acid nitrile hydrochloride is obtained. Example 13 [D,L]-3-[4-(3-N-phenylpi
perazino-2-hydroxy-propoxy)-fu
[enyl]crotonic acid nitrile hydrochloride 8.1g phenyl in 60ml ethanol
10.75 g of [D,L]-3 in a solution of piperazine
-[4-(2,3-oxide-propoxy)-F
Enyl]-Crotonitrile under reflux for 3 hours
Boil. The reaction mixture was then cooled with ice and
After a short period of time, the crystals that separate are aspirated and then
Recrystallize from ethanol. 12.9 g of free base melting at 133-134°C was obtained.
It can be done. This base was dissolved in approximately sufficient amount of acetone at room temperature.
After dissolving in concentrated hydrochloric acid, the pH value is 4.5 while stirring.
Add dropwise until Hydrochloride precipitates after a while
do. This is suctioned and then dried. 158
13.9 g of crude hydrochloride was obtained, melting at ~160 °C.
Ru. Recrystallized once from a large amount of ethanol
13.3g of [D,L] which melts at 160-161℃.
3-[4-(3-N-phenylpiperazino-2-
Hydroxy-propoxy)-phenyl]-chloro
nitrile hydrochloride is obtained. Example 14 [D,L]-3-[4-(3-morpholino-2
-Hydroxy-propoxy)-phenyl]-
Rotonate nitrile hydrochloride 6.1 g of morpholin in 100 ml of ethanol
15.0g of [D,L]-3-[4-
(2,3-oxide-propoxy)-phenyl]
- Heat crotonitrile at 80°C for 4 1/2 hours. Ru. The mixture is left at room temperature for a further 12 hours. unintentionally
The mixture was concentrated to dryness in vacuo and dissolved in toluene.
Evaporate three times. Add a small amount of toluene to the distillation residue.
Addition of diisopropyl ester after dissolving in
Crystallize by 79 due to over-suction and drying
18.0 g of free base is obtained which melts at ~80°C.
Conversion to the hydrochloride salt was then carried out as described in Example 1.
Let's do it. 16.4g of [D,L]-3 melting at 121-122℃
- [4-(3-morpholino-2-hydroxy-p
Ropoxy)-phenyl]-crotonic acid nitrile salt
An acid salt is obtained. Example 15 [D, L]-3-[4-(3-2^*,6^*- Ji
Methylpiperidino-2-hydroxy-propoxy
c)-Phenyl]-crotonic acid nitrile hydrochloride 8.0 g of 2,6- in 100 ml of ethanol
15 g of [D,L] in a solution of dimethylpiperidine
-3-[4-(2,3-oxide-propoxy)
-Phenyl]-Crotonitrile is reduced for 61/2 hours. Boil under running water. The mixture was then evaporated to dryness in vacuo.
Let solidify and dissolve the distillation residue in 80 ml of toluene.
Understand. Shake the mixture well after adding 300 ml of water.
Adjust the pH value to 4 with concentrated hydrochloric acid. 80ml for the aqueous phase
of fresh toluene followed by sodium hydroxide
Adjust the pH value to 10 while shaking the solution. that
Extraction was carried out twice with 50 ml of toluene each and
Combine the extracts, wash with water, and dilute with sodium sulfate.
dried over a vacuum and concentrated to dryness in vacuo.
Ru. produced by grinding with diisopropyl ether
By suctioning the crystals and drying them97
15.0 g of free base is obtained which melts at ~98°C. From the latter, it was heated to 168-169℃ using the method described in Example 1.
14.5g of [D,L]-3-[4-(3
-2^*,6^*-dimethylpiperidino-2-hydro
xy-propoxy)-phenyl]-crotonic acid di
Tolyl hydrochloride is obtained. Example 16 [D, L]-3-[4-(3-3^*,4^*- Ji
Methoxyphenethylamino-2-hydroxy-
Propoxy)-phenyl]-crotonic acid nitric acid
le hydrochloride 15.0g of homobete in 100ml of ethanol
17.5 g of [D,L] in a solution of latrylamine
3-[4-(2,3-oxide-propoxy)-
Phenyl]-Crotonitrile under reflux for 5 hours
Heat to boil. Normal post-processing (see Example 1)
After that, the free crude base was dissolved in ethanol/diisopropyl ether.
ether and again from ethanol. 16.1 g of free base melting at 141.5-142°C was obtained.
It will be done. From the latter, 148
13.6g of [D,L]-3- melting at ~149℃
[4-(3-3^*,4^*-dimethoxyphenethyl
amino-2-hydroxy-propoxy)-phenylene
]-Crotonic acid nitrile hydrochloride is obtained. Example 16a [D,L]-3-[2-methoxy-4-(3-
3^*,4^*-dimethoxy-dimethoxyfuenethi
Ruamino-2-hydroxy-propoxy)-fluoride
[enyl]-crotonic acid nitrile hydrochloride in 7 ml of ethanol as described in Example 16.
6.7g of [D,L]-3-[2-methoxy
-4-(2,3-oxide-propoxy)-hue
] - 7.0g of crotonic acid nitrile
boiled under reflux for 1 hour with tolylamine and
Make it react. Yield 6.6g [D,L] melting at 131-132℃
-3-[2-methoxy-4-(3-3^*,4^*―
Dimethoxyphenethylamino-2-hydroxy-
Propoxy)-phenyl]-crotonitrile
The hydrochloride is obtained. Example 16b [D, L]-3-[3-(3-chloro-4-
(3-3^*,4^*-dimethoxyphenethylamide
(2-Hydroxy-propoxy)-Phenyl
]--Crotonic acid nitrile hydrochloride 5.0g of [D,L]-3-[3-chloro-4-
(2,3-oxide-propoxy)-phenyl]
-Crotonitrile in 15 ml of ethanol and
Under reflux for 4 hours with 5g of homoveratrylamine
Boil it. Then add 50g of ethanol and
Adjust the mixture to a pH value of 3.5 with concentrated hydrochloric acid and add the reaction mixture.
Pour the mixture into the water from Step 5. Neutral fraction in vinegar
The aqueous phase was extracted with ethyl chloride/toluene (2:1).
Make it slightly alkaline with sodium bicarbonate. Toluet
Extraction was carried out with chlorine/ethyl acetate (2:1) and
The organic phase is dried and then rotated. toluene/
117-119 by crystallization with diisopropyl ether
5.1 g of free base is obtained, melting at °C. this
was converted to the hydrochloride salt as described in Example 1.
Ru. Yield 4.7g [D,L] melting at 146-148℃
-3-[3-chloro-4-(3-3^*,4^*- Ji
Methoxyphenethylamino-2-hydroxyp
Ropoxy)-phenyl]-crotonic acid nitrile salt
An acid salt is obtained. Example 16c [D,L]-3-[3-chloro-4-(3-th
Tertiary butylamino-2-hydroxy-propoxy
c)-Phenyl]-crotonic acid nitrile hydrochloride in 15 ml of ethanol as described in Example 6a.
4.5g of [D,L]-3-[3-chloro-
4-(2,3-oxide-propoxy)-pheni
] - 50 ml of tertiary butyl crotonate nitrile
amine for 3 hours and then as described in Example 1.
Post-process by method. Yield 6.0g [D, L] melting at 188-189℃
-3-[3-chloro-4-(3-tertiary butyl acetate)
mino-2-hydroxy-propoxy)-phenylene
]-Crotonic acid nitrile hydrochloride is obtained. Example 16a [D,L]-3-[3-fluoro-4-(3-
Tertiary butylamino-2-hydroxy-propo
xy)-phenyl]-crotonic acid nitrile hydrochloric acid
salt in 15 ml of ethanol as described in Example 1.
5.0g of [D,L]-3-[3-fluoro
-4-(2,3-oxide-propoxy)-hue
] - 50 ml of tertiary nitrile crotonate
After boiling under reflux for 3 1/2 hours with the Process. Yield 6.9g [D,L] melting at 190-191℃
-3-[3-fluoro-4-(3-tertiary butyl
amino-2-hydroxy-propoxy)-phenylene
]-Crotonic acid nitrile hydrochloride is obtained. Example 16e [D,L]-3-[3-fluoro-4-(3-
3^*,4^*-dimethoxyphenethylamino-2
-Hydroxy-propoxy)-phenyl]-
Rotonate nitrile hydrochloride 10g [D,L] in 20ml ethanol
-3-[3-(Fluoro-4-(2,3-oxy)
Do-propoxy)-phenyl]-crotonate nitrate
Lil and 10.0g of homoveratrylamine for 31/2 hours. Heat under reflux on a steam bath. Then Example 16b
Post-process as follows. 111-112 obtained in this way
7.9 g of free base melting at °C as described in Example 1
7.3g converted to melt at 163-164℃
[D,L]-3-[3-fluoro-4-(3-
3^*,4^*-dimethoxyphenethylamino-2-
Hydroxy-propoxy)-phenyl]-chloro
nitrile hydrochloride. Example 16f [D,L]-3-[3-methoxy-4-(3-
3^*,4^*-dimethoxyphenethylamino-2
-Hydroxy-propoxy)-phenyl]-
Rotonate nitrile hydrochloride 9.8g of [D,L]-3-[3-methoxy-4
-(2,3-oxide-propoxy)-pheni
]-Crotonitrile was heated on a steam bath under reflux for 2 hours.
Heat for an hour. The mixture was then diluted with approximately 50 ml of ethanol,
Adjust the pH value to 1 with concentrated hydrochloric acid and reduce the reaction mixture to 5.
pour into the water. Neutral component toluene/ethyl acetate
Extract with Weakly salt the aqueous phase with sodium bicarbonate.
Make basic, extract with toluene and basic extract
was dried by rotation and toluene/ether.
It is then recrystallized from ethanol. Yield 7.6 g of free base melting at 115-116°C.
can get. This is done in the usual way (see Example 1).
) is converted into hydrochloride and this hydrochloride is
Reconsolidation from ethanol/ether and ethanol
crystallize Yield 6.4g [D,L] melting at 110-112℃
-3-[3-methoxy-4-(3-3^*,4^*―
Dimethoxyphenethylamino-2-hydroxy-
Propoxy)-phenyl]-crotonitrile
The hydrochloride is obtained. Example 16g [D,L]-3-[3-methoxy-4-(3-
Tertiary butylamino-2-hydroxy-propo
xy)-phenyl]-crotonic acid nitrile hydrochloric acid
salt 28ml ethanol and 70ml tertiary butylamine
7.0g of [D,L]-3- in a mixture with
[3-Methoxy-4-(2,3-oxide-pro
1 poxy)-phenyl]-crotonitrile
Heat to boiling under reflux for an hour. Next, described in Example 1.
Post-process as shown. Yield 7.1g [D,L] melting at 157-158℃
-3-[3-methoxy-4-(3-tertiary butyl
amino-2-hydroxy-propoxy)-phenylene
]-Crotonic acid nitrile hydrochloride is obtained. Example 17 [D, L]-3-[4-(3-N-2^*- Piri
Zyl-piperazino-2-hydroxy-propoxy
c)-Phenyl]-crotonic acid nitrile dihydrochloride
salt Pyridyl-piperazine 8.2 in 60ml ethanol
10.75 g of [D,L]-3-[4-
(2,3-oxide-propoxy)-phenyl]
-Crotonitrile is boiled under reflux for 3 hours.
Ru. The mixture was then cooled with ice and the precipitated crystals
Collect the crystals and then dry them. Melts at 131-132℃
17.1 g of the free base produced by
15.1g of [D,L]-3- melts at 259-260℃
[4-(3-N-2^*-Pyridyl-Piperazino-
2-Hydroxy-propoxy)-phenyl]-k
Convert to rotonate nitrile dihydrochloride. Example 18 [D, L]-3-[4-(3-N-4^*-Ace
Thyl-phenyl-piperazino-2-hydroxy
-propoxy)-phenyl]-crotonate nitrate
ril hydrochloride 10.75g of [D,L]-3-[4-(2,3-
oxide-propoxy)-phenyl]-croton
acid nitrile for 4 hours 10.2g parapiperazinoa
Boil the cetophenone solution under reflux. Cool this
Cool, crystallize, suction, and dry.
Base obtained by (20.1 g, melted at 160-161℃)
) with 100 ml of absolute ethanol and 30 ml of
PH value 5 with concentrated hydrochloric acid in dimethylformamide
Adjust to. Collect the crystallized hydrochloride and boil it hot.
Immediately recrystallize from ethanol/water. 17.7g of [D,L]-3 melting at 221-222℃
-[4-(3-N-acetylphenylpiperazino
-2-hydroxy-propoxy)-phenyl]-
Crotonic acid nitrile hydrochloride is obtained. Example 19 [D, L]-3-[4-(3-N-2^*-Metho
Xyphenylpiperazino-2-hydroxyp
Ropoxy)-phenyl]-crotonic acid nitrile
hydrochloride 10.75g of [D,L]-3-[4-(2,3-
oxide-propoxy)-phenyl]-croton
Add 14.0 ml of triethylamine and 60 ml of acid nitrile.
10.3 g of N in a mixture with ethanol
(2-methoxyphenyl)-piperazine dihydrochloride
Boil under reflux for 5 hours in a solution of Then vacuum
Concentrate to dryness in a medium and add the crude base to ethanol.
Make it more crystallized. Aspirate this and ethanol
and by washing with water and drying.
15.0 g of free base melting at 102-103°C was obtained.
It can be done. This is then carried out in the usual manner (see Example 1).
Convert to hydrochloride. Recrystallized twice from ethanol
13.3g of melting at 198-199℃ by letting
[D, L]-3-[4-(3-N-2^*-Metoki
C-phenylpiperazino-2-hydroxy-pro
poxy)-phenyl]-crotonic acid nitrile hydrochloric acid
Salt is obtained. Example 20 [D, L]-3-[4-(3-N-2^*-Methi
Le-phenyl-piperazino-2-hydroxy-
Propoxy)-phenyl]-crotonic acid nitric acid
le hydrochloride 10.95g of [D,L]-3-[4-(2,3-
oxide-propoxy)-phenyl]-croton
Add 8.8 g of acid nitrile to ortho-tolyl-piperazide.
Boil under reflux for 3 hours in a solution of water. After cooling
16.5 g of free base crystallizes, melting at 104-105°C.
Ru. This was converted to the hydrochloride salt as described in Example 1.
do. Finally, recrystallize twice from ethanol.
10.0 g of [D,
L]-3-[4-(3-N-2^*-Methylpheni
lu-piperazino-2-hydroxy-propoxy)
-Phenyl]-Crotonitrile hydrochloride is obtained.
It can be done. Example 21 [D, L]-3-[4-(3-N-3^*-Methi
Le-phenyl-piperazino-2-hydroxy-
Propoxy)-phenyl]-crotonic acid nitric acid
le hydrochloride 10.75 g of [D,L] as described in Example 19
-3-[4-(2,3-oxide-propoxy)
- Phenyl] - 8.8 g of crotonitrile
React with tertrile-piperazine. at 108-109℃ by post-treatment in the same way.
Melting at 151-152°C from 16.4g free base
14.6g of [D,L]-3-[4-(3-N-
3^*-Methyl-phenyl-piperazino-2-hydro
Roxy-propoxy)-phenyl]-crotonic acid
Nitrile hydrochloride is obtained. Example 22 [D,L]-3-[4-(3-N-methyl-pi
perazino-2-hydroxy-propoxy)-fu
[enyl]-crotonic acid nitrile dihydrochloride 10.75 g of [D,L] as described in Example 19
-3-[4-(2,3-oxide-propoxy-
Phenyl] - Crotonic acid nitrile with 60 ml of ethano
react with 5.0 g of N-methylpiperazine in a
then post-treated as described in Example 1 and
Convert to dihydrochloride. 11.8g of [D,L]-3 melting at 217-218℃
-[4-(3-N-methyl-piperazino-2-hyphenyl)
Droxy-propoxy)-phenyl]-croton
Acid nitrile dihydrochloride is obtained. Example 23 [D, L]-3-[4-(3-N-2^*-Oki
ethyl-piperazino-2-hydroxy-pro
poxy)-phenyl]-crotonic acid nitrile di
hydrochloride 5.0g of [D,L]-3-[4-(2,3-O)
Oxide-propoxy)-phenyl]-crotonic acid
3.5g of nitrile in 50ml of ethanol
In a solution of hydroxyethyl-piperazine
Boil under reflux for 2 hours. Evaporate to dryness in vacuum
After that, crystallization from toluene is performed. at 101-102℃
The resulting free base, 5.7 g, was melted as described in Example 1.
6.7 g of [D,
L]-3-[4-(3-N-2^*-Oxyethyl
-Piperazino-2-hydroxy-propoxy)-
phenyl]-converted to crotonic acid nitrile dihydrochloride
be done. Example 24 [D, L]-3-[4-(3-7^*,5^*- Ji
Methyl-5^*-Hydroxy-hexylamino-
2-Hydroxy-propoxy)-phenyl]-
Crotonic acid nitrile oxalate 8.5 [D,L]-3-[4-(2,3-Oki)
Sid-propoxy)-phenyl]-crotonic acid di
Trill in 1.6g water in 50ml ethanol
Sodium oxide and 7.2g of 7^*,5^*-dimethyl
-5^*-Hydroxy-hexylamine hydrochloride
Boil the solution under reflux for 2 hours. Then
Concentrate the mixture in vacuo and dissolve the distillation residue in 85 ml of water.
and adjust the pH value to 7 with hydrochloric acid. That's it
Washed twice with toluene and ethyl acetate and then
The aqueous phase is alkalised with sodium hydroxide solution to a pH value of 10.
make it more natural. Then ethyl acetate/toluene (1:
1) Extract, dry the organic extract and vacuum
Evaporate to dryness in a medium. Put the crude base in ethanol
The mixture was diluted with concentrated oxalic acid in ethanol.
Adjust the pH value to 4 with a solution. I can't absorb this too much
7.7 g melting at 155°C by drying at
[D, L]-3-[4-(3-7^*,5^*-Jime
Chill-5^*-Hydroxy-hexylamino-2-
Hydroxy-propoxy)-phenyl]-chloro
A nitrile oxalate salt is obtained. Example 25 [D,L]-3-[2-(3-tertiary butyl acetate)
mino-2-hydroxy-propoxy)-phenylene
]--acrylic acid nitrile hydrochloride 15 ml of tertiary butyl chloride in 80 ml of absolute ethanol
7.0 g of [D,L]-3- in a solution of
[2-(2,3-oxide-propoxy)-fe
- Boil acrylic acid nitrile under reflux for 1 hour.
Boil. Work-up and salt as described in Example 1
Conversion to acid salt takes place. 5.3g melting at 155℃
[D,L]-3-[2-(3-tertiary butyl amine
No-2-hydroxy-propoxy)-phenyl]
- Acrylic acid nitrile hydrochloride is obtained. Example 26 [D,L]-3-[2-(3-tertiary butyl acetate)
mino-2-hydroxy-propoxy)-phenylene
]-acrylic acid tertiary butyl ester hydrochloride 30.0g of [D,L]-3-[2-(2,3-O)
Oxide-propoxy)-phenyl]-acrylic acid
Add 30 ml of tertiary butyl ester to tertiary butyl amide.
3 in a mixture of water and 150 ml of ethanol.
Boil under reflux for an hour. Usual method (see Example 1)
Dissolve the crude hydrochloride in water and add the
The aqueous solution was extracted twice with toluene and the aqueous
Add to the phase a concentrated aqueous solution of sodium chloride. This way
[D, L]-3-[2-(3-tertiary block)
thylamino-2-hydroxy-propoxy)-fu
Enyl]-acrylic acid tertiary butyl ester hydrochloric acid
Salt crystallizes. Aspirate the product and dry in vacuo.
Dry and reconstitute twice with isopropanol.
crystallize 13.8 g of [D,
L]-3-[2-(3-tertiary butylamino-2
-Hydroxy-propoxy)-phenyl]-ac
Rilic acid tertiary butyl ester hydrochloride is obtained. Example 27 [D, L]-3-[2-(3-3^*,4^*- Ji
Methoxy-phenethylamino-2-hydroxy
-propoxy)-phenyl]-acrylic acid tertiary
butyl ester hydrochloride 20.0g homovera in 60ml ethanol
30.0 g of [D,L]-3 in a solution of tolylamine
--[2-(2,3-oxide-propoxy)-]
Enyl]-Acrylic acid tertiary butyl ester is 2
Heat to boiling under reflux for an hour. Usual method (Example
After post-treatment (see 1), melt at 167-168℃.
15.9g of [D,L]-3-[2-(3-3^*,4
^*-dimethoxy-phenethylamino-2-hydro
xy-propoxy)-phenyl]-acrylic acid No.
Tertiary butyl ester hydrochloride is obtained. Example 28 [D, L]-3-[2-(3-N-2^*-Oki
ethyl-piperazino-2-hydroxy-pro
poxy)-phenyl]-acrylic acid tertiary butylene
ester dihydrochloride 55 g of N-hydroxyethyl-piperazine and 60
11.0 g of [D,
L]-3-[2-(2,3-oxide propoxy
c)-Phenyl]-tertiary butyl acrylate
The solution is boiled under reflux for 2 hours. Next, Example 14
Post-processing is performed as shown below, but in this case the PH value is 4.
It is 3 instead. 6.4g melts at 168℃ (decomposition)
[D,L]-3-[2-(3-N-2^*-Oki
ethyl-piperazino-2-hydroxy-propo
xy)-phenyl]-tertiary butyl acrylate
Sterdihydrochloride is obtained. Example 29 [D,L]-3-[2-(3-N-phenylpi
perazino-2-hydroxy-propoxy)-fu
Enyl]-acrylic acid tertiary butyl ester salt
acid salt 11.0g of [D,L]-3-[2-(2,3-O)
Oxidopropoxy)-phenyl]-acrylic acid No.
tertiary butyl ester to 6.5g phenylpiperazi
Reflux for 1 hour in a mixture of water and 50 ml of ethanol.
Boil under water and work up as described in Example 1.
Do this. In this case, the hydrochloride is finally ethanol
Recrystallize twice from Melting at 200-201℃ (decomposition)
6.2g of [D,L]-3-[2-(3-N
-Phenylpiperazino-2-hydroxy-propo
xy)-phenyl]-tertiary butyl acrylate
Stell hydrochloride is obtained Example 30 [D,L]-3-[4-(3-tertiary butyl acetate)
mino-2-hydroxy-propoxy)-phenylene
]-acrylic acid tertiary butyl ester hydrochloride 15.0g of [D,L]-3-[4-(2,3-O)
Oxidopropoxy)-phenyl]-acrylic acid No.
Add tertiary butyl ester to 25ml of tertiary butyl amine.
in a mixture of and 100 ml ethanol (98% strength)
Boil under reflux for 2 hours. Then vacuum the mixture
The distillation residue was concentrated (in vacuo) to dryness.
evaporated twice with ene and finally with diisopropyl
Crystallize with ether. Melts at 107-108℃
16.7 g of free base are obtained. Example 28 from now on
Melt at 192-193°C (decomposition) as described in
12.3g of [D, L]-3-[4-(3-tertiary grade
Butylamino-2-hydroxy-propoxy)-
phenyl]-acrylic acid tertiary butyl ester salt
An acid salt is obtained. Example 31 [D, L]-3-[4-(3-3^*,4^*- Ji
Methoxyphenethylamino-2-hydroxy-
Propoxy)-phenyl]-acrylic acid tertiary
Butyl ester hydrochloride 15.0g of [D,L]-3-[4-(2,3-O)
Oxidopropoxy)-phenyl]-acrylic acid No.
Add 10.5g of tertiary butyl ester to homoveratrylua.
Boil under reflux for 8 hours in a solution of min.
After treatment in the usual way, the crude hydrochloride was added to water in step 6.
Dissolve, extract several times with toluene, and remove the aqueous phase with water.
Adjust the pH value to 9 with sodium oxide solution. Then
The mixture is extracted with toluene and ethyl acetate.
Combine the organic extracts and evaporate this to dryness in vacuo.
and then crystallized with diisopropyl ether.
Ru. 6.95 g of free base melting at 100-101°C was obtained.
It can be done. From now on, as described in Example 1, 176
7.4 g of [D,L]-3-[4] melting at ~177°C
-(3-3^*,4^*-dimethoxyphenethylamide
No-2-hydroxy-propoxy)-phenyl]
-Acrylic acid tertiary butyl ester hydrochloride obtained
This was finally recrystallized twice from ethanol.
let Example 32 [D,L]-3-phenyl-3-[2-(3-
Tertiary butylamino-2-hydroxy-propo
xy)-phenyl]-acrylic acid nitrile hydrochloric acid
salt 5.4g of [D,L]-3-phenyl-3-[2
-(2,3-oxidepropoxy)-phenyl]
- Add 15 ml of acrylic acid nitrile to tertiary butyl amide
The mixture is boiled under reflux for 2 hours. One
The mixture was evaporated to dryness in vacuo and
Evaporate twice with toluene. Toluene the distillation residue
crystallized by immersion in petroleum ether
let 6.4 g of free base melting at 92-93°C was obtained.
It will be done. Now proceed as described in Example 1.
5.5g of [D,L]-3- melts at 171-172℃
Phenyl-3-[2-(3-tertiary butylamino
-2-hydroxy-propoxy)-phenyl]-
Acrylic acid nitrile hydrochloride is obtained. Example 33 [D,L]-3-phenyl-3-[2-(3-
3^*,4^*-dimethoxyphenethylamino-2
-Hydroxy-propoxy)-phenyl]ac
Lyric acid nitrile hemi-oxalate 5.4g of [D,L]-3-phenyl-3-[2
-(2,3-oxidepropoxy)-phenyl]
- Soak acrylic acid nitrile in 50ml of ethanol.
in a solution of 3.7 g of homoveratrylamine.
Boil under reflux for 3 hours. Next, to Example 30
Perform post-processing as described. Next, this oily
The free base was prepared as described in Example 23 to form oxalic acid.
converts to salt, but in this case it is oxalic acid
By adding , the pH value is adjusted to 6.5. Rough again
The sulfate salt was recrystallized twice from ethanol and
4.1g of [D,L]-3- melting at 172-173℃
Phenyl-3-[2-(3-3^*,4^*- Dimeth
Xyphenethylamino-2-hydroxy-propo
xy)-phenyl]-acrylic acid nitrile half-boiled
This yields borate. Example 34 [D,L]-3-phenyl-3-[2-(3-
N-phenylpiperazino-2-hydroxyp
Ropoxy)-phenyl]-acrylic acid nitrile
hydrochloride 6.0g of [D,L]-3-phenyl-3-[2
-(2,3-oxidepropoxy)-phenyl]
- Soak acrylic acid nitrile in 50ml of ethanol.
in a solution of 3.5 g of phenyl-piperazine.
Boil under reflux for 2 hours. Next, to Example 1
Work-up and conversion to hydrochloride salt as described.
cormorant. For further purification as described in Example 30
Manipulate. Free base is toluene/diisopropyl
Purified by crystallization in ether. 102~103℃
4.1 g is obtained. Again this free base
was converted to the hydrochloride salt as described in Example 1.
Ru. 4.4g with dual melting point 85℃/184℃ was obtained.
Ru. Example 35 [D,L]-3-phenyl-3-[4-(3-
Tertiary butylamino-2-hydroxy-propo
xy)-phenyl]-acrylic acid nitrile hydrochloric acid
salt 10.0g of [D,L]-3-phenyl-3-[4
-(2,3-oxide-propoxy)-pheni
] - 20ml of tertiary butyl acrylic acid nitrile
In a mixture of amine and 50 ml of ethanol
Heat to boil under reflux for 2 hours. Next, to Example 1
Perform work-up and conversion to hydrochloride salt as described.
do. Finally, the crude hydrochloride was washed twice again from ethanol.
recrystallize. 4.6g melting at 233-234℃
[D,L]-3-phenyl-3-[4-(3-th
Tertiary butylamino-2-hydroxy-propoxy
c)-Phenyl]-acrylic acid nitrile hydrochloride
can get. Ethanolic mother liquor from second recrystallization
was concentrated to dryness in vacuo and then treated in the same manner as in Example 30.
Convert to the free base by Diisopropyl crude base
112 ~ after crystallization by grinding with ether
1.1 g of free base is obtained, melting at 114°C. Example 36 [D,L]-3-phenyl-3-[4-(3-
3^*,4^*-Dimethoxy-phenethylamino-
2-Hydroxy-propoxy)-phenyl]-
Acrylic acid nitrile oxalate 10.0g of [D,L]-3-phenyl-3-[4
-(2,3-oxide-propoxy)-pheni
] - Homoverate 6.5 ml of acrylic acid nitrile.
into a mixture of lylamine and 50 ml of ethanol.
Boil under reflux for 2 hours. Next, to Example 30
Perform post-processing as described. Then oily release
Converting the base to the oxalate salt as described in Example 23
do. 4.9g [D,L] melting at 124-125℃
-3-phenyl-3-[4-(3-3^*,4^*―
Dimethoxy-phenethylamino-2-hydroxy
-propoxy)-phenyl]-acrylic acid nitric acid
The result is sulfuric acid salt. Example 37 [D,L]-3-phenyl-3-[4-(3-
N-phenylpiperazino-2-hydroxyp
Ropoxy)-phenyl]-acrylic acid nitrile
dihydrochloride 10.0g of [D,L]-3-phenyl-3-[4
-(2,3-oxide-propoxy)-pheni
] - Acrylic acid nitrile in 50ml of ethanol
in a solution of 5.9 g of phenyl-piperazine in
Boil under reflux for 2 hours. Same as Example 1
Melts at 189-190℃ by post-processing
6.8g of [D,L]-3-phenyl-3-
[4-(3-N-phenylpiperazino-2-hydro
Roxy-propoxy)-phenyl]-acrylic acid
Nitrile dihydrochloride is obtained. Example 38 [D,L]-3-phenyl-3-[4-(3-
N-[2-hydroxyethyl]-piperazino-
2-Hydroxy-propoxy)-phenyl]-
Acrylic acid nitrile dihydrochloride 10.0g of [D,L]-3 in the same manner as Example 36
-Phenyl-3-[4-(2,3 oxide-pro
poxy)-phenyl]-acrylic acid nitrile
4.7g N-hydroxyethylpiperazine and 50ml
reaction in ethanol followed by post-treatment.
Ru. 9.8g of [D,L] melting at 164-165℃
3-phenyl-3-[4-(3-N-[2-hydro
[roxyethyl]-piperazino-2-hydroxy-
propoxy)-phenyl]-acrylic acid nitrile
The dihydrochloride is obtained. Example 39 [D, L]-3-[4-(3-3^*,4^*- Ji
Methoxyphenethylamino-2-hydroxy-
propoxy)-phenyl]-methyl acrylate
ester hydrochloride 6g of [D,L]-3-[4-(2,3-ok)
Sid-propoxy)-phenyl]-acrylic acid
The methyl ester in 60 ml of absolute ethanol
21/2 hours in a solution of 4.7 g homoveratrylamine Boil under reflux and then as described in Example 1.
Post-process. 6.2g [D,L] melts at 162℃
-3-[4-(3-3^*,4^*-dimethoxyphene
Netylamino-2-hydroxy-propoxy)-
phenyl]-acrylic acid methyl ester hydrochloride
can get. Example 40 [D,L]-3-[4-(3-1,5-dimethylene)
-5-hydroxy]-hexylamino-2-
Hydroxy-propoxy)-phenyl]-ac
Rilic acid methyl ester hydrochloride 5.5g of [D,L]-3-[4-(2,3-O)
Oxide-propoxy)-phenyl]-acrylic acid
Place the methyl ester in 70 ml of absolute ethanol.
4.6 g of 6-amino-2-methyl-2-hepta
Nor hydrochloride (heptaminol hydrochloride) and
Reflux for 4 hours in a solution of 1.02g sodium hydroxide
Bring to a boil below. Then as described in Example 1.
Process. Recrystallization of free base and hydrochloride
Ether is used for recrystallization. Melts at 110℃
1.2g of [D,L]-3-[4-(3-
[1,5-dimethyl-5-hydroxy]-hexy
Ruamino-2-hydroxy-propoxy)-feu
]-acrylic acid methyl ester hydrochloride was obtained.
It can be done. Example 40a [D, L]-3-[4-(3-N-2^*-Metho
Xyphenyl-piperazino-2-hydroxy-
Propoxy)-phenyl]-methyl crotonate
ester 15.0g of [D,L]-3-[4-(2,3-O)
Oxide-propoxy)-phenyl]-crotonic acid
The methyl ester was dissolved in 50 ml of ethanol and 10 g of
Evaporation in 2-methoxy-phenylpiperazine
Heat on an air bath for 1 hour. Then described in Example 1
Perform post-processing as follows. Melts at 183-184℃
6.2g of [D,L]-3-[4-(3-N-2^*
-Methoxyphenylpiperazino-2-hydroxy
-propoxy)-phenyl]-methyl crotonate
An ester is obtained. Example 41 [D, L]-3-[4-(3-N-2^*-Metho
Xyphenyl-piperazino-2-hydroxy-
propoxy)-phenyl]-methyl acrylate
Ester dihydrochloride 4.5g of [D,L]-3-[4-(2,3-O)
Oxide-propoxy)-phenyl]-acrylic acid
Place the methyl ester in 60 ml of absolute ethanol.
4.0 g of N-(2-methoxy-phenyl)-pi
Boil under reflux for 3 hours in a solution of perazine.
Ru. 204℃ with normal post-treatment (see Example 39)
6.05g of [D,L]-3-[4-(3
-N-2^*-Methoxyphenyl-piperazino-2
-Hydroxy-propoxy)-phenyl]-ac
Rilic acid methyl ester dihydrochloride is obtained. Example 42 [D, L]-3-[2-(3-3^*,4^*- Ji
Methoxy-phenethylamino-2-hydroxy
-propoxy)-phenyl]-methyacrylate
ester hydrochloride 10.0g of [D,L]-3-[2-(2,3-O)
Oxide-propoxy)-phenyl]-acrylic acid
Ethyl ester in 60ml ethanol
4 hours in a solution of 7.3 g homoveratrylamine
Boil under reflux. The mixture is then placed under vacuum.
Concentrate to dryness. Oily by soaking in hexane
The distillation residue of is crystallized. After filtration and drying
9.8 g of free base melting at 80-82 °C was obtained.
Ru. From this, the hydrochloride salt was prepared as described in Example 1.
is produced, which is again mixed with ethanol/water and then finally
It is then recrystallized from isopropanol. 161〜
8.1g of [D,L]-3-2- melts at 162℃
(3-3^*,4^*-dimethoxy-phenethylamide
No-2-hydroxy-propoxy)-phenyl]
-Acrylic acid ethyl ester hydrochloride is obtained. Example 43 [D,L]-3-[2-(3-N-phenylpi
perazino-2-hydroxy-propoxy)-fu
Enyl]-acrylic acid ethyl ester hydrochloride 10.0g of [D,L]-3-[2-(2,3-O)
Oxide-propoxy)-phenyl]-acrylic acid
Ethyl ester in 60ml ethanol
4 in a solution of 6.54 g N-phenyl-piperazine.
Boil for 1/2 hour. Then as described in Example 1 Work up and convert to hydrochloride. thus
Finally, the obtained hydrochloride is converted into isopropanol again.
It is then recrystallized from ethanol/water. 186～
10.2g of [D,L]-3-[2] melts at 187℃
-(3-N-phenylpiperazino-2-hydroxy
(propoxy)-phenyl]-ethyl acrylate
ester hydrochloride is obtained. Example 44 [D,L]-3-[2-(3-tertiary butyl acetate)
mino-2-hydroxy-propoxy)-phenylene
]-Acrylic acid ethyl ester hydrochloride 10.0g of [D,L]-3-[2-(2,3-O)
Oxide-propoxy)-phenyl]-acrylic acid
Ethyl ester with 4.25ml of tertiary butylamine
Boil for 5 1/2 hours in a mixture with 60 ml of ethanol. Ru. Post-treatment was then carried out as described in Example 1.
Then precipitate from ethanol/hydrochloric acid in the usual manner.
Crude hydrochloric acid obtained by drying and evaporating with toluene
Reconstitute salt from ethanol/diisopropyl ether
crystallize. Then hydrochloric acid as described in Example 30
The salt is purified again with the free base. In this case hydroxy acid
into approximately 100 ml of water by adding sodium solution.
A suspension of the hydrochloride salt in water is sufficient. isopropa
Melts at 133-134℃ upon recrystallization from nol
5.8g of [D,L]-3-[2-(3-tertiary block)
thylamino-2-hydroxy-propoxy)-fu
Enyl]-acrylic acid ethyl ester hydrochloride is obtained.
It will be done. Example 45 [D,L]-3-[4-(3-tertiary butyl acetate)
mino-2-hydroxy-propoxy)-phenylene
]-3-ethyl-acrylic acid nitrile hydrochloride 10.0g of [D,L]-3-[4-(2,3-O)
oxide-propoxy)-phenyl]-3-ethyl
- Add 15 ml of acrylic acid nitrile to tertiary butyl amide
Reflux for 2 hours in a mixture of water and 50 ml of ethanol.
Bring to a boil below. Then as described in Example 1.
Process. The crude free base obtained initially was
Recrystallize from ene/hexane. Melt at 73-75℃
Example 1 7.0 g of the product thus obtained was
Convert to the hydrochloride salt as described in . At 170-171℃
Melt 3.4g of [D,L]-3-[4-(3-
Tertiary butylamino-2-hydroxy-propoxy
c)-phenyl]-3-ethyl-acrylic acid nitrate
Riru hydrochloride is obtained. Example 46 [D, L]-3-[4-(3-3^*,4^*- Ji
Methoxy-phenethylamino-2-hydroxy
-propoxy)-phenyl]-3-ethyl-a
Acrylic acid nitrile hydrochloride 15.0g of [D,L]-3-[4-(2,3-O)
oxide-propoxy)-phenyl]-3-ethyl
- Acrylic acid nitrile in 100ml of ethanol
in a solution of 12.0 g of homoveratrylamine in
Boil for 2 hours and then boil as described in Example 30.
Process. 10.3 first melting at 103-104℃
g of free base is obtained. This will now be described in Example 1.
7.5g of melting at 120-121℃ as described above.
[D, L]-3-[4-(3-3^*,4^*-Jime
Toxi-phenethylamino-2-hydroxyp
Ropoxy)-phenyl]-3-ethyl-acrylic
Acid nitrile hydrochloride is obtained. Example 47 [D, L]-3-[4-(3-N-phenyl-
piperazino-2-hydroxy-propoxy)-
phenyl]-3-ethyl-acrylic acid nitrile
dihydrochloride 10.0g of [D,L]-3-[4-(2,3-O)
oxide-propoxy)-phenyl]-3-ethyl
- Soak acrylic acid nitrile in 50ml of ethanol.
in a solution of 11.0 g of phenylpiperazine for 2 hours.
Boil under reflux for a while. Then the reaction mixture
Cool to 5° C. and crystallize the free base.
8.2 g of free base melting at 110-115°C was obtained.
From now on, using 4.19 ml of 10N hydrochloric acid, Example 1
8.1 g melting at 202-204°C as described in
[D,L]-3-[4-(3-N-phenyl-
Piperazino-2-hydroxy-propoxy)-F
Enyl]-3-ethyl-acrylic acid nitrile di-salt
An acid salt is obtained. Example 48 [D,L]-3-[4-(3-N-[2-hydro
[loxyethyl]-piperazino-2-hydroxy
-propoxy)-phenyl]-3-ethyl-a
Acrylic acid nitrile dihydrochloride 6.0g of N-hydroxyethyl-piperazine
10.0g of [D,L]-3-[4-] in solution
(2,3-oxide-propoxy)-phenyl]
-3-Ethyl acrylic acid nitrile was added to Example 45.
or as in 30 (2.0 water).
Post-process. 6.4 First melt at 80-81℃
g of free base was obtained, from which 3.57 ml of 10N salt was obtained.
7.2 g of [D,
L]-3-[4-(3-N-[2-hydroxye
Chil]-piperazino-2-hydroxy-propoxy
c)-phenyl]-3-ethyl-acrylic acid nitrate
Rildihydrochloride is obtained. Example 49 [D, L]-3-[2-(3-3^*,4^*- Ji
Methoxy-phenethylamino-2-hydroxy
-propoxy)-phenyl]-3-ethyl-a
Acrylic acid methyl ester hydrochloride 8g of [D,L]-3-[2-(2,3-ok)
cydopropoxy)-phenyl]-3-ethyl-a
Acrylic acid methyl ester hydrochloride in 80 ml of anhydrous ether
5.7g homoveratrylamine in nol
Boil under reflux for 3 hours in a solution of unintentionally
Workup is carried out as described in Example 45. 4.3
g [D, L]-3-[2-(3-3^*,4^*―
Dimethoxy-phenethylamino-2-hydroxy
-propoxy)-phenyl]-3-ethyl-ac
Lyric acid methyl ester hydrochloride is obtained. free salt
Base is 2920cm^-1, 1710cm^-1, 1630cm^-1, 1585cm^-1,
1505cm^-1, 1437cm^-1, 1225cm^-1, 1145cm^-1, 1015
cm^-1, 798cm^-1, and 748cm^-1characteristic of
Shows IR absorption. Example 50 [D, L]-3-[2-(3-N-2^*-Metho
xy-phenyl-piperazino-2-hydroxy
-propoxy)-phenyl]-3-ethyl-a
Acrylic acid methyl ester dihydrochloride 8 g of [D,L] as described in Example 41
-3-[2-(2,3 oxide-propoxy)-
Phenyl]-3-ethyl-methyl acrylate
6.8 g of tel in 80 ml of absolute ethanol
Dissolution of N-(2-methoxyphenyl)-piperazine
React with liquid. 4.4g melting at 120-122℃
[D, L]-3-[2-(3-N-2^*-Metoki
Siphenyli-piperazino-2-hydroxy-pro
poxy)-phenyl]-3-ethyl-acrylic acid
Methyl ester dihydrochloride is obtained. Example 51 [D,L]-3-[2-(3-tertiary butyl acetate)
mino-2-hydroxy-propoxy)-phenylene
]-Crotonic acid ethyl ester hydrochloride 10.5g of [D,L]-3-[2-(2,3-O)
Oxide-propoxy)-phenyl]-crotonic acid
Ethyl ester with 20 ml of tertiary butylamine and 50
ml of ethanol at 20-25 °C.
Stir for 16 hours. Then as described in Example 1
Perform post-processing. Hydrochloride in this case is isopropano
Recrystallized twice from alcohol/ether. 118～119
5.4 g of [D,L]-3-[2-
(3-tertiary butylamino-2-hydroxy-p
Ropoxy)-phenyl]-crotonate ethyl ester
Teru hydrochloride is obtained. Example 52 [D, L]-3-[2-(3-3^*,4^*- Ji
Methoxy-phenethylamino-2-hydroxy
-propoxy)-phenyl]-ethyl crotonate
ester oxalate 12.0g of [D,L]-3-[2-(2,3-O)
Oxide-propoxy)-phenyl]-crotonic acid
Ethyl ester in 100ml of ethanol
20-25 in a solution of 7.2 g homoveratrylamine
℃ for 16 hours and then stirred as described in Example 24.
Post-process as follows. Melts at 115-117℃ (decomposition)
4.5g of [D,L]-3-[2-(3-3^*，
4^*-dimethoxy-phenethylamino-2-hydro
Roxy-propoxy)-phenyl]-crotonic acid
Ethyl ester oxalate is obtained. Example 53 [D, L]-3-[2-(3-N-2^*-Metho
xy-phenylpiperazino-2-hydroxy-
propoxy)-phenyl]-ethyl crotonate
Ester dihydrochloride 7.9g of [D,L]-3-[2-(2,3-O)
Oxide-propoxy)-phenyl]-crotonic acid
Ethyl ester in 100ml of ethanol
5.8g N-2-methoxy-phenylpiperazine
Stir in the solution for 48 hours at room temperature. Then
The crude base was post-treated as described in Example 1.
Let's do it. Dissolve this in a small amount of ethyl acetate and
240 g of silica gel (Silica Gel 60, Merck & Co.)
Chromatography is carried out on a column manufactured by M. Co., Ltd.).
Finally, 4.4 g of oil was obtained by elution with ethyl acetate.
A purified base in the form was obtained. Then this
is melted at 134-136°C in the usual manner (see Example 1).
2.9g of [D,L]-3-[2-(3-N
-2^*-Methoxy-phenylpiperazine-2-H
Droxy-propoxy)-phenyl]-croton
Converted to acid ethyl ester dihydrochloride. Example 54 [D,L]-3-[3-(3-tertiary butyl acetate)
mino-2-hydroxy-propoxy)-phenylene
]--acrylic acid nitrile hydrochloride 15g of [D, L]-3-[3-(3-2,3-
Oxide-propoxy)-phenyl]-acrylic
Add the acid nitrile to 40 ml of tertiary butylamine and
1 hour in a mixture with 200ml ethanol
Boil under reflux. 8.3g after normal post-processing
Very hygroscopic [D,L]-3-[3-(3-th
Tertiary butylamino-2-hydroxy-propoxy
c)-Phenyl]acrylic acid nitrile hydrochloride is obtained.
It will be done. Free base is 3300cm^-1, 2950cm^-1, 2208cm
^-1, 1608cm^-1(Shoulder part), 1590cm^-1(shoulder part),
1570cm^-1, 1473cm^-1, 1435cm^-1, 1372cm^-1and
743cm^-1This shows the characteristic IR absorption band in . Example 55 [D, L]-3-[3-(3-N-2^*-Metho
xy-phenyl-piperazino-2-hydroxy
-propoxy)-phenyl]-acrylic acid nitrate
Rildihydrochloride 12.0g of [D,L]-3-[3-(2,3-O)
Oxide-propoxy)-phenyl]-acrylic acid
11.5g of nitrile in 50ml of ethanol
In a solution of N-2-methoxy-phenylpiperazine
Boil under reflux for 1 hour. Same as Example 31
(However, in this case NaCl
(4 l of soda water solution is used instead). casual play
The free base is oily and is prepared as described in Example 1.
15.7g of sea urchin melts at 210℃ (decomposition) [D,
L]-3-[3-(3-N-2^*-Methoxyfue
Nyl-piperazino-2-hydroxy-propoxy
c)-Phenyl]-acrylic acid nitrile dihydrochloride
is converted to Example 56 [D,L]-3-[3-(3-N-[2-hydro
[loxyethyl]-piperazino-2-hydroxy
-propoxy)-phenyl]-acrylic acid nitrate
Rildihydrochloride 12.0 g of [D,L]-- as described in Example 55.
3-[3-(2,3-oxide-propoxy)-
Phenyl] - Acrylic acid nitrile with 50 ml of ethano
20.0g of N-2-hydroxyethyl
React with tilpiperazine and work up.
13.5g of [D,L]-3- melts at 180-182℃
[3-(3-N-[2-hydroxyethyl]-pi
perazino-2-hydroxy-propoxy)-hue
]-acrylic acid nitrile dihydrochloride was obtained.
Ru. Example 57 [D, L]-3-[3-(3-3^*,4^*- Ji
Methoxyphenethylamino-2-hydroxy-
propoxy)-phenyl]-acrylic acid nitric acid
le hydrochloride 12.0 g of [D, L]-3- as in Example 55
[3-2,3-oxide-propoxy)-pheni
] - Acrylic acid nitrile in 50ml of ethanol
20.0g of N-2-hydroxyethyl-piperazi
After reacting with water and post-processing, melt at 180-182℃.
13.5g of [D, L]-3-[3-(3-3
^*,4^*-dimethoxyphenethylamino-2-hyde
Droxy-propoxy)-phenyl]-acrylic
Acid nitrile hydrochloride is obtained. Example 58 [D,L]-3-[3-(3-tertiary butyl acetate)
mino-2-hydroxy-propoxy)-phenylene
]--Crotonic acid nitrile hydrochloride 15 g of [D,L]-3 as described in Example 55
―[3-(2,3-oxide-propoxy)-fu
Enyl] - 200ml of ethyl nitrile
react with 40 ml of tertiary butylamine in a
Post-process. 3320cm^-1, 2960cm^-1, 2205cm
^-1, 1668cm^-1, 1570cm^-1, 1473cm^-1, 1430cm^-1,
1370cm^-1and 772cm^-1Characteristic IR absorption in
13.8g [D,L]-3-[3-(3
-Tertiary butylamino-2-hydroxy-propo
xy)-phenyl]-crotonic acid nitrile hydrochloride
is obtained. Example 59 [D, L]-3-[3-(3-3^*,4^*- Ji
Methoxy-phenethylamino-2-hydroxy
-propoxy)-phenyl]-ethyl acrylate
ester hydrochloride 6.0g of [D,L]-3-[3-(2,3-O)
Oxide-propoxy)-phenyl]-acrylic acid
Ethyl ester in 30ml ethanol
in a solution of 3.6 g homoveratrylamine at room temperature.
Leave to stir for 16 hours and then stir as described in Example 24.
The crude base is then post-treated. Example of this
React as described in 1 and melt at 128-129℃.
3.6g of [D,L]-3-[3-(3-3^*，
4^*-dimethoxy-phenethylamino-2-hydro
Roxy-propoxy)-phenyl]-acrylic acid
Obtain ethyl ester. Example 60 [D, L]-3-[3-(3-N-2^*-Metho
Xyphenyl-piperazino-2-hydroxy-
propoxy)-phenyl]-ethyl acrylate
Ester dihydrochloride 6.0g of [D,L]-3-[3-(2,3-O)
Oxide-propoxy)-phenyl]-acrylic acid
ethyl ester to 3.9 g of N-2-methoxyf
48 hours at room temperature in a solution of enylpiperazine
Stir. Post-processing in the same manner as in Example 1
3.4g of [D,L] melts at 164-165℃
-3-[3-(3-N-2^*-Methoxyphenyl
Piperazino-2-hydroxy-propoxy)-F
enyl]-acrylic acid ethyl ester dihydrochloride
can get. Example 61 [D,L]-3-[3-(3-N-[2-hydro
[loxyethyl]-piperazino-2-hydroxy
-propoxy)-phenyl]-ethyl acrylate
ester dihydrochloride 12.0g of [D,L]-3-[3-(2,3-O)
Oxide-propoxy)-phenyl]-acrylic acid
Ethyl ester in 60 ml of ethanol
- In a solution of 2-hydroxyethyl-piperazine
Stir at 20-24°C for 48 hours. Same as Example 59
Melts at 189-190℃ by post-processing
9.3g of [D,L]-3-[3-(3-N-
[2-Hydroxyethyl]-piperazin-2-H
Droxy-propoxy)-phenyl]-acrylic
Acid ethyl ester dihydrochloride is obtained. Example 62 [D,L]-3-[Phenyl-3-[4-(3
-N-2^*-Methoxyphenyl-piperazino-
2-Hydroxy-propoxy)-phenyl]-
Acrylic acid methyl ester dihydrochloride 15.0g of [D,L]-2-phenyl-3-[4
-(2,3-oxide-propoxy)-pheni
] - 150 ml of acrylic acid methyl ester
9.3 g of N-2-methoxyphene in alcohol
16 at 20-24°C in a solution of Nyl-piperazine.
Stir for an hour. As described in Example 31 for the free base
Perform post-processing as follows. obtained as an oil
The purified base was prepared as a hydrochloride salt as described in Example 1.
is converted to methanol/ether and last
168~ by recrystallizing from methanol to
13.8g of [D,L] melts at 170℃ (decomposition)
2-phenyl-3-[4-(3-N-2^*-Metho
Xyphenylpiperazino-2-hydroxy-pro
poxy)-phenyl]-methyl acrylate ester
rudihydrochloride is obtained. Example 63 [D,L]-3-phenyl-3-[4-(3-
N-[2-hydroxyethyl]-piperazino-
2-Hydroxy-propoxy)-phenyl]-
Acrylic acid methyl ester dihydrochloride 15.0 g of [D,L]-- as described in Example 62.
2-phenyl-3-[4-(2,3-oxide-
propoxy)-phenyl]-methyl acrylate
6.3g of N-2- in 150ml of methanol
After reacting with hydroxyethyl-piperazine
Post-process. 16.4g melting at 218-220℃
[D,L]-2-phenyl-3-[4-(3-N
-[2-Hydroxyethyl]-piperazino-2-
Hydroxy-propoxy)-phenyl]-acrylic
methyl ester dihydrochloride is obtained. Example 64 [D,L]-3-phenyl-3-[4-(3-
3^*,4^*-dimethoxyphenethylamino-2
-hydroxy-propoxy)-phenyl]-a
Acrylic acid methyl ester 15g of [D,L]-2-phenyl-3-[4-
(2,3-oxide-propoxy)-phenyl]
-8.22g of acrylic acid methyl ester
Stir in solution of tolylamine for 24 hours at room temperature
do. Same as Example 1 except adjusting the PH value to 6
The crude hydrochloride obtained by
/ diisopropyl ether and finally toluene
Recrystallize from methylene chloride/methylene chloride. 145
4.1 g of [D,L]-2-phene melting at ~147°C
Nil-3-[4-(3-3^*,4^*-dimethoxy
Phenethyl amino-2-hydroxy-propoxy
c)-phenyl]-acrylic acid methyl ester
can get. Example 65 [D, L]-3-[3-(3-3^*,4^*- Ji
Methoxyphenethylamino-2-hydroxy-
Propoxy)-phenyl]-crotonic acid nitric acid
le hydrochloride 15g of [D,L]-3-[3-(2,3-ok)
Cyd-propoxy)-phenyl]crotonate nitrate
12.62 g of phosphorus in 150 ml of ethanol
in a solution of moberatrylamine for 2 1/2 hours under reflux. Boil and post-treat as described in Example 31.
Understand. The oily free base thus purified is
It was then melted at 135-138°C as described in Example 1.
6.5g of pure [D,L]-3-[3-
(3-3^*,4^*-dimethoxyphenethylamino
-2-hydroxy-propoxy)-phenyl]-
Converted to crotonitrile hydrochloride. Example 66 [D, L]-3-[3-(3-N-2^*-Metho
Xyphenyl-piperazino-2-hydroxy-
Propoxy)-phenyl]-crotonic acid nitric acid
le hydrochloride 15g of [D,L]-3-[3-(2,3-ok)
Sid-propoxy)-phenyl]-crotonic acid di
Tolyl 3.9g N in 150ml ethanol
- In a solution of 2-methoxy-phenylpiperazine
Boil under reflux for 11/2 hours. Same as Example 1 Melts at 160-162℃ by post-processing
17.1g of [D,L]-3-[3-(3-N-
2^*-Methoxyphenyl-piperazino-2-hydro
Roxy-propoxy)-phenyl]-crotonic acid
Nitrile hydrochloride is obtained. Example 67 [-]-3-[4-(3-3^*,4^*- Dimeth
Xyphenethylamino-2-hydroxy-pro
poxy)-phenyl]-crotonic acid nitrile salt
Acid acid and [+]-3-[4-(3-3^*,4
^*-dimethoxyphenethylamino-2-hydro
xy-propoxy)-phenyl]-crotonic acid
Nitrile hydrochloride 50 g of [D,
L]-3-[4-(3-3^*,4^*-dimethoxy
Phenethyl amino-2-hydroxy-propoxy
C)-Phenyl]-Crotonitrile solution
19.2g of D- in 150ml of ethanol
(−)—mix with a solution of mandelic acid. Shiba
After allowing it to stand for a while, the crystals that separate are filtered off with suction. Small
Wash with a large amount of ethanol and dry in vacuum.
Almost insoluble in ethanol due to
32.8g of [-]-3-[4 melting at 114-116℃
-(3-3^*,4^*-dimethoxyphenethylamide
No-2-hydroxy-propoxy)-phenyl]
-Crotonitrile-D-9-mandelate
isolated. [α]^D=-35.4゜(c=0.6, methano
). Recrystallize from 200ml of hot ethanol.
It melts at 118-119℃ and [α]^D=-
It has an optical rotation value of 38.2° (c=0.6, methanol)
28.9 g of pure mandelate are obtained. yield
83.5%. 23g of the above levorotatory mandolate, 230ml of water
and 100 ml of chloroform and stir rapidly.
Then, add 3.15ml of concentrated ammonia solution and 30ml of
The mixture with water is added dropwise while cooling with ice. organic
Separate the phases and wash with some water and sodium sulfate
Dry on top and concentrate to dryness in vacuo. Generate (-)-3-[4-(3-3^*,4^*
-dimethoxyphenethylamino-2-hydroxy
-propoxy)-phenyl]-crotonic acid nitri
The hydrochloride salt described in Example 1 was obtained from
at 166-167℃ after recrystallization from ethanol/ether
Melt and [α]^D=-12.8゜(c=0.5, meta
The final yield was 17.5 g (96
%). Ethanolic mother liquor of the above racemate being decomposed
By evaporating [+]-3-[4-(3
-3^*,4^*-dimethoxyphenethylamino-2
-Hydroxy-propoxy)-phenyl]-chloro
Tonitrile-D-(-)-mandelate is obtained.
It dissolves very easily in ethanol.
Ru. From now on [+]-3-[4-(3-3^*,4
^*-dimethoxyphenethylamino-2-hydroxy
C-propoxy)-phenyl]-crotonate nitrate
A rill may be manufactured as described above. Toluet
132-135℃ by recrystallization from petroleum ether
25.4 g of nitrile are obtained, melting at . this is
As in the case of the (−)-enantiomer above, dextrorotatory hydrochloric acid
converted to salt. Regeneration from ethanol/ether
It melts at 162-164℃ due to crystallization, [α]^D=+9.7゜
If it has an optical rotation value of (c=0.6, methanol)
Not perfect, but optically pure [+]-3
-[4-(3-3^*,4^*-Dimethoxyfuenethi
Ruamino-2-hydroxy-propoxy)-feu
] - Crotonic acid nitrile hydrochloride 25.5g (93
%) is obtained. The pharmacological effects of the compounds of the present invention are described below.
I will post it. Introduction Pindolol, a β-receptor blocker
(1-(indol-4-yloxy)-3-
(isopropylamino)-2-propanol)
shows the superiority of the compound of the present invention over The following compounds were investigated. :<D,L>-3-<2-(3-3^*,4^*―
Dimethoxyphenylethylamino-2-hydro
xy-propoxy)-phenyl>-crotonic acid
Nitrile hydrochloride (Example 6) :<->-3-<4-(3-3^*,4^*-Jime
Toxiphenylethylamino-2-hydroxy
-propoxy)-phenyl>-crotonate nitrate
Rilu hydrochloride (Example 67) :<D,L>-3-<4-(3-3^*,4^*―
Dimethoxyphenylethylamino-2-hydro
xypropoxy)-phenyl>-acrylic acid-
Tertiary butyl ester hydrochloride (Example 31) :<D,L>-3-<3-(3-3^*,4^*―
Dimethoxyphenylethylamino-2-hydro
xypropoxy)-phenyl>-acrylate
Tyl ester hydrochloride (Example 59) V: Pindolol as a comparative compound A β in guinea pigs₁- Sympathoblocking effect
test of Effects on contraction of isolated guinea pig hearts
Antagonistic inhibition of soproterenol action by each compound
I checked the system. Method: Isolated, perfused guinea pig heart
to Langendorff's method
Isoproterenol 0.05 μg per heart
Inject one dose of Ringer's solution into the heart through the cannula.
was injected into. isoprotere at intervals of several minutes.
By administering Nord several times, the contraction magnitude and
After confirming its effect on the
Inject cannula with various doses of each compound.
injection in the hospital and then again immediately afterward.
Injection of lotenol at a dose of 0.05μg/heart
did. The effect of iso on the magnitude of contraction and cardiac frequency
The reduction in proterenol action was measured. β-shield
Varying the amount of abstinence and 5 hearts per dose
ED by investigating the internal organs₅₀is the calculation
came. Results: The results are summarized in Table A below.

Table: Compounds and were not investigated in this study. B β ₂ - Test for sympathoblocking effect The effect on isolated guinea pig trachea was examined. Method: Cut out the guinea pig's trachea and de Beer
and chopped into rings by Castillo's method. The individual rings were adhered to each other using tissue adhesive (Histo-acryl).
Muscle fragments were contracted by adding carbachol to a 50 ml bath volume. Relaxation was achieved by administering isoproterenol before and after compound addition. Results: The results are summarized in Table B.

Table: Compounds were not investigated in this study. C. Test method for β ₁ -sympatholytic effects in dogs: The inhibition of isoproterenol effects in dogs anesthetized intraperitoneally with pentobarbital was tested after intravenous administration of the compound. Peripheral blood pressure and left ventricular pressure were measured. The rate of blood pressure rise in the left ventricle (dp/dt) was measured electronically. On top of each pressure amplitude interval of left ventricular pressure, cardiac frequency was also measured. Parameters were recorded on a Brush260 6-tube recorder. Antagonism to isoproterenol was tested at a single intravenous dose of 0.1 μg/Kg isoproterenol. Results: The results are summarized in Table C.

[Table] D. Test for effects on circulation The effects (iv) on blood pressure in anesthetized dogs were examined. Methods: Arterial peripheral blood pressure was measured in dogs (both male and female) weighing 7.5-20.5 kg under pentobarbital anesthesia. This measurement is performed using PVC-catheters and
Tests were performed on brachial artery blood using a Statham blood pressure recorder model P23Gb. Blood pressure amplitudes were recorded continuously on a Brush-Mark 260 recorder. Compounds were injected intravenously in 0.05-2% aqueous solution. Results: Measurements (average values for all dogs) are summarized in Table D below.

【table】

[Table] E Test for acute toxicity LD ₅₀ was determined by intravenous administration to mice.

[Table] F Summary The compound shows a pronounced reduction in blood pressure, especially at low doses. This substance already has a β-blocking effect in small amounts. The relationship of β-blockade to blood pressure lowering is
This is considerably more advantageous than in pindolol, which produces only a moderate reduction in blood pressure in its strong β-blocking action. The compounds are exclusively β ₁ -blockers and β ₁
-Causes a strong hypotensive effect relative to blockade. On the other hand, pindolol has strong β ₁ and β
₂ -blockers and cause only a relatively moderate hypotensive effect on β ₁ -blockers. The compound shows a pronounced hypotensive effect and only a slight β ₁ -blocking effect. This drug is suitable as a hypotensive agent without β ₁ -blocking action. The compounds exhibit neither β ₁ -blocking nor β ₂ -blocking effects. A significant, immediate onset and longer lasting blood pressure reduction with pindolol was observed. The compound of Example 16 will now be compared with a compound marketed by ICI, known as atenolol. Compound 1: [D,L]-3-[4-(3-3 ^* ,
4 ^* -dimethoxyphenylethylamino-2-
Compound 2: 1-p-carbamoylmethylphenoxy-3-isopropyl-amino-2-propanol (common name: atenolol) ) The test was conducted as follows. 1 Isoproterenol 0.05μg per heart
The ED ₅₀ for isolated guinea pig hearts required to inhibit the increase in cardiac contractility induced by (β ₁ -blockade) was 5.25 μg per heart for Compound 1 and 1.16 for Compound 2.
It is μg. The ED ₅₀ for isolated guinea pig trachea required to control the muscle relaxation induced by 0.05 μg/ml isoproterenol is 1.9 μg/ml for compound 2, while 40 μg/ml for compound 1.
Even at μg/ml, muscle relaxation cannot be suppressed. From the above test results, compound 2 has β ₁ - and β ₂
- exhibits a clear blocking effect on the β ₁ - and β ₂ -receptors with little dissociation between -blocking, but compound 1 shows a somewhat weaker β ₁ -blocking effect and no β ₂ -blocking effect. It is concluded that this is not the case. Therefore, β ₁ − of the compound
The difference between blockade and β ₂ -blockade is very important. 2 Increased dp/dt (rate of pressure increase in the left heart) (β ₁ ) and increased peripheral blood flow (β
₂ ) The effect of Compound 1 on the following was measured in dogs anesthetized with pentobarbital. When 50μg/Kg of compound 1 is administered intravenously
dp/dt increase by 32.5%, whereas compound 1
100 μg/Kgi.v. showed 64% inhibition (mean value for each of 3 dogs). On the other hand, compound 1 is 300
However, 7 μg/Kg did not reduce the increase in peripheral blood flow induced by isoproterenol.
Enhanced blood flow by 6-93% in dogs. 1
A 6% reduction was observed only in one dog. This test also shows that the compounds have a clear difference between β ₁ -blocking and β ₂ -blocking. 3 48 hours and 24 hours before blood pressure and heart rate measurements
Rats that had previously received 0.5 mg/Kg of reserpine each and no longer had any endogenous catecholamines were used to test the β ₁ -sympathomimetic effect. Compound 1 (rats 5
(4 rats) and Compound 2 (4 rats). 5-sec-butyl-5-ethyl-2
-Thiobarbituric acid (Inactin) 125mg/
Patients were anesthetized intraperitoneally with Kg and blood pressure and heart rate were recorded. Cumulative doses of Compound 1 and Compound 2, each totaling 4.1 mg/Kgi.v., had no effect on increasing cardiac frequency (β-sympathomimetic effect). In contrast to this, more in compound 1 than in compound 2 as can be seen in Tables 1 and 2.
A much more pronounced decrease in heart rate was observed.

【table】

【table】

Claims (1)

[Claims] 1 formula [In the formula, R ¹ and R ¹ ' are the same or different, and represent hydrogen or 1 to
represents an alkoxy group, an allyl group or a halogen atom having 4 carbon atoms, and R ₂ is of the formula (wherein R ⁵ represents hydrogen, a C ₁ -C ₅ alkyl group or a phenyl group that is unsubstituted or substituted by lower alkyl or lower alkoxy, and R ⁶ represents hydrogen) R ³ and R ⁴ together with the nitrogen atom represent a 6-membered heterocycle optionally substituted by C ₁ -C ₄ alkyl, in which one of the carbon atoms in this ring is an oxygen atom. or may be replaced by another nitrogen atom, and said another nitrogen atom is an alkyl, alkoxy, oxyalkyl or acyl group, each having 1 to 5 carbon atoms, a pyridyl group or a phenyl group (which is itself optionally substituted by one or more alkyl or alkoxy groups having 1 to 4 carbon atoms, or if R ³ represents hydrogen and R ⁴ is chain or branched chain 1-8
an alkyl or oxyalkyl group or formula having 4 carbon atoms (In the formula, n is a number from 1 to 3, R ⁸ and R ⁹ are the same or different, and these are hydrogen or 1
phenyl-alkylene group or phenyl-alkylidene group), which represents an alkoxy group having ~3 carbon atoms, and physiologically acceptable acid addition salts thereof. 2 formulas (wherein R ¹ , R ¹ ′ and R ² have the definitions in the formula) (wherein R ³ and R ⁴ have the definitions in the formula) and the resulting compound is optionally converted into a physiologically acceptable acid addition salt thereof. [In the formula, R ¹ and R ¹ ' are the same or different, and represent hydrogen or 1 to
represents an alkoxy group, an allyl group or a halogen atom having 4 carbon atoms, and R ² is of the formula (wherein R ⁵ represents hydrogen, a C ₁ -C ₅ alkyl group or a phenyl group that is unsubstituted or substituted by lower alkyl or lower alkoxy, and R ⁶ represents hydrogen) R ³ and R ⁴ together with the nitrogen atom represent a 6-membered heterocycle optionally substituted by C ₁ -C ₄ alkyl, in which one of the carbon atoms in this ring is an oxygen atom. or may be replaced by another nitrogen atom, and said another nitrogen atom is an alkyl, alkoxy, oxyalkyl or acyl group, each having 1 to 5 carbon atoms, a pyridyl group or a phenyl group (which is itself optionally substituted by one or more alkyl or alkoxy groups having 1 to 4 carbon atoms, or if R ³ represents hydrogen and R ⁴ is chain or branched chain 1-8
an alkyl or oxyalkyl group having carbon atoms, or of the formula (In the formula, n is a number from 1 to 3, R ⁸ and R ⁹ are the same or different, and these are hydrogen or 1
phenyl-alkylene group or phenyl-alkylidene group] represented by phenyl-alkylene group or phenyl-alkylidene group] and physiologically acceptable acid addition salts thereof. 3 formulas [In the formula, R ¹ and R ¹ ' are the same or different, and represent hydrogen or 1 to
represents an alkoxy group, an allyl group or a halogen atom having 4 carbon atoms, and R ² is of the formula (wherein R ⁵ represents hydrogen, a C ₁ -C ₅ alkyl group or a phenyl group that is unsubstituted or substituted by lower alkyl or lower alkoxy, and R ⁶ represents hydrogen) R ³ and R ⁴ together with the nitrogen atom represent a 6-membered heterocycle optionally substituted by C ₁ -C ₄ alkyl, in which one of the carbon atoms in this ring is an oxygen atom. or may be replaced by another nitrogen atom, and said another nitrogen atom is an alkyl, alkoxy, oxyalkyl or acyl group each having 1 to 5 carbon atoms, a pyridyl group or a phenyl group (which itself is , optionally substituted by one or more alkyl or alkoxy groups having 1 to 4 carbon atoms), or R ³ represents hydrogen and R ⁴ is a linear alkyl or oxyalkyl radicals having 1 to 8 carbon atoms in a straight or branched chain, or of the formula (In the formula, n is a number from 1 to 3, R ⁸ and R ⁹ are the same or different, and these are hydrogen or 1
phenyl-alkylene group or phenyl-alkylidene group) (representing an alkoxy group having ~3 carbon atoms), and also physiologically acceptable acid addition salts thereof. Pharmaceutical drugs for the treatment of coronary diseases.