JPH0130820B2 - - Google Patents

Description

[Detailed description of the invention]

This invention provides the first in a group of anti-obesity properties.
Secondary amine derivative, its production method and its pharmaceutical composition
pharmaceutical compositions, especially for anti-obesity and anti-polysaccharidosis
relating to things. Formula (I): (In the formula, R₁are hydrogen atoms, fluorine atoms, chlorine atoms,
hydroxy, hydroxymethyl, methyl, methoxy
ci, amino, formamide, acetamide, methane
rusulfonylamide, nitro, benzyloxy,
Methylsulfonylmethyl, ureido, trifluoro
lomethyl or p-methoxybenzylamino group;
R₂is a hydrogen atom, a fluorine atom, a chlorine atom, or a hydrogen atom.
Roxy group; R₃is a hydrogen atom, a chlorine atom, or a hydrogen atom
Roxy group; and Q is isopropyl or t-butyl
chill group) Certain compounds contained in β-adrenoseb
β-adrenoceptor agonist
It is known to have activity (e.g.
T. Collins et al., J.Med.Chem., 1970,
13674). Q is a phenylaminoethyl group.
When certain compounds of formula () are β-
Adrenoceptor Steimlant (β-
It is said to have adrenoceptor stimulant (adrenoceptor stimulant) activity.
This is disclosed in Belgian patent no. 851232.
Ru. Belgian patent no. 809831 states that Q is specifically substituted
Certain species of formula (I) which are phenylethyl groups
Compounds are useful as medicines for treating skin diseases.
It is disclosed that it is for use. US Patent No. 3818101
The issue is to encourage meat-producing animals to eat more.
The formula used, especially where Q is an aralkyl group
Discloses certain compounds included in (I).
Q is hydroxybenzyl or alkoxybenzyl
Certain compounds of formula (I) which are β-
Adrenalistic stimulant and bloat
South African Patent No. 67/
Disclosed in No. 5591. Prior publications include the formula
The compounds of (I) have anti-fertilizing activity as well as anti-polysaccharidosis activity.
have anti-obesity activity or only anti-obesity activity.
There is no mention of having one. We are anti-obesity
and compounds of formula (I) having antipolysaccharidotic properties.
We have found a group of somewhat related compounds. Hidden
Therefore, such compounds may cause obesity or polysaccharidosis.
Can be used to treat and often treat obesity
Maturity onset when polysaccharidosis occurs
Diabetes (maturity onset diabetes)
Expected to be particularly important in cases of symptoms such as
has been done. This invention is based on the formula (): [In the formula, R₁are hydrogen atoms, fluorine atoms, chlorine atoms,
hydroxy, hydroxymethyl, methyl, methoxy
cy, amino, acetamide, methylsulfonyla
mido, nitro, benzyloxy, methylsulfony
methyl or ureido group; R₂is a hydrogen atom,
elementary atom, chlorine atom, benzyloxy or hydro
xy group; R₃is a hydrogen atom or a chlorine atom; R_FourHaka
Rubonic acid group, its salt, C_1-4Alkyloxycarbo
Nyl group or C_1-4Alkylcarbamoyl group; R_Five
is hydrogen atom, chlorine atom, fluorine atom or methyl,
Methoxy or hydroxy group or carbon
Acid groups, their salts, C_1-4Alkyloxycarbonyl group
or C_1-4Alkylcarbamoyl group; R₆is hydrogen
atom, methyl, ethyl or propyl group; R₇teeth
Hydrogen atom, methyl, ethyl or propyl group;
is an oxygen atom or one bond; and Y is carbon
Alkylene group with up to 6 atoms or one bond
hand] Compounds represented by or their pharmaceutical acceptance
It provides salt of the highest quality. Appropriate X in compounds of formula () is an oxygen atom
However, in the compounds of formula (), further
A suitable X is a bond. If desired, the Y molecule may include one or more Y molecules, for example.
has two methyl groups.
It's okay. However, it is better not to branch Y.
It is very convenient. Thus, the preferred group Y is n
is 0 or an integer from 1 to 6 - (CH₂)n-
It is a group represented by Particularly suitable R₂is a hydrogen atom. preferred R₃is a hydrogen atom. Particularly suitable groups R₁R₂R₃C₆H₂- is 3-urei
Do-4-hydroxyphenyl, 3-methylsulfo
Nylamino-4-hydroxyphenyl, 3,5-
Dihydroxyphenyl, 3,4-dihydroxyphenyl
enyl, 3-methylsulfonylmethyl-4-hydro
Roxiphenyl, 3,5-dichloro-4-amino
Phenyl, 2-chlorophenyl, and 3-hydro
Contains roxymethyl-4-hydroxyphenyl group
It will be done. Preferred group R₁R₂R₃C₆H₂- is a phenyl group
Ru. Other preferred groups R₁R₂R₃C₆H₂- is 3,5-jiku
It is rolo-4-aminophenyl group. Even better
Shii group R₁R₂R₃C₆H₂- is 3-hydroxymethylene
is a -4-hydroxyphenyl group. preferred R₆is a hydrogen atom. even more preferable
IR₆is a methyl group. preferred R₇is a hydrogen atom
It is. More preferable R₇is a methyl group.
The most preferable C(R₆) R₇is CH₂,
CHCH₃or C(CH₃)₂It is the basis of C(R₆)
R₇is CH₂or C(CH₃)₂This development, which is the basis of
The light compounds are C(R₆) R₇is CH(CH₃)of
as an anti-obesity agent than the compounds of this invention which are
The efficacy of the former compounds tends to be low;
has one less irregular center, so it can be synthesized a little easier.
It shows the advantage of being able to C(R₆) R₇but
CH(CH₃) compounds are used as anti-obesity agents.
have greater potency and have shown significant benefits.
Ru. Y is the group - (CH₂) n-
Compounds in which n is 0 or 6 in
has low efficacy as an anti-obesity agent, so n is 1 to 1.
An integer of 5 is most appropriate. Particularly suitable n are 1, 2, 3 and 4;
1, 2 and 3 are preferred. in general,
R_Fiveis an electron-accepting group such as a fluorine atom
The compounds obtained in this case are R_Fiveis a hydrogen atom or
A corresponding group that donates electrons such as a methoxy group
It is less potent than other compounds. Therefore, suitable
NaR_Fiveis a methoxy group, preferably R_Fiveis a hydrogen atom
That's what happens. base R_FourThe bonding position is the phenyl group of the molecule.
Meta position or
The para position is preferred. Maximize the anti-obesity effects of the compounds of this invention
To use it, R_FourThe phenyl group is the molecule
at the para position with respect to the position where it joins with the remaining part of
It is desirable that One group of preferred compounds of this invention has the formula
(): (In the formula, R₁₅is a hydrogen atom or a methyl group; R₁₆teeth
Hydrogen atom or methyl group; and m is 1, 2 or
is the compound represented by 3), which is accepted as a medicine.
salt or ester. The most appropriate R₁₅is a hydrogen atom. Motsuto
Also suitable R₁₆is a methyl group. Preferably m is 1
It is. Preferably m is 2. Esters of the compound of formula () are C_1-4Archi
It is luester. Another preferred group of compounds of this invention has the formula
(): (In the formula, R₁₇is a hydrogen atom or a methyl group; R₁₈teeth
Hydrogen atom or methyl group; and p is 1, 2 or
3) Compounds represented by and their pharmaceutically acceptable salts
or an ester. The most appropriate R₁₇is a hydrogen atom. Motsuto
Also suitable R₁₈is a methyl group. Preferably p is 1
It is. Preferably p is 2. Esters of compounds of formula () are C_1-4Archi
It is luester. A particularly preferred group of compounds of formula () are
(): [In the formula, R_Fourand R₆is the same as the definition for expression ()] These are compounds represented by Another particularly preferred group of compounds of formula ()
is the expression (): [In the formula, R_Fourand R₆is the same as the definition for expression ()] These are compounds represented by One of the most appropriate expressions for expressions () and ()
R₆is a methyl group. This product deserves special mention for its anti-obesity activity.
Certain compounds of the invention include Examples 1, 7,
10, 12, 13, 14, 16, 17, 21 (high melting point), 22, 23,
Contains compounds 24, 26, 30, 35, 37 and 44.
Ru. These compounds are free bases or pharmaceuticals.
and can be provided as acceptable salts. This compound deserves special mention for its antipolysaccharidosis activity.
Certain compounds of the invention include Examples 1, 7,
12, 17, 19, 21 (high melting point), 22, 25, 30, 31, 33,
Includes 36 and 39 compounds. These compounds
Free bases or pharmaceutically acceptable salts
It can be provided as a similar product. Preferred compounds of this invention include N-[2-
(4-carbomethoxyphenyl)-1-methylethyl
]-2-hydroxy-2-(4-hydroxy
-3-hydroxymethylphenyl)ethanamine
and N-[2-(4-carboethoxyphenyl
)-1-methylethyl]-2-hydroxy-2
-(4-hydroxy-3-hydroxymethylphene
(nil) ethanamines and pharmaceuticals of these compounds
Includes acid addition salts that are acceptable as Other preferred compounds of this invention include N-
[3-(4-carbomethoxyphenyl)-1-meth
tylpropyl]-2-hydroxy-2-(4-hydroxy)
Droxy-3-hydroxymethylphenyl)etha
amine and N-[3-(4-carboethoxy)
phenyl)-1-methylpropyl]-2-hydro
xy-2-(4-hydroxy-3-hydroxymeth)
Tylphenyl) ethanamine and these drugs
Includes acid addition salts that are acceptable as Other preferred compounds of this invention include
is N-[2-(4-carboxyphenyl)-1
-Methylethyl]-2-hydroxy-2-(4-
Hydroxy-3-hydroxymethylphenyl)
Tanamine and N-[3-(4-carboxif)
enyl)-1-methylpropyl]-2-hydroxy
C-2-(4-hydroxy-3-hydroxymethylene)
Contains (ruphenyl) ethanamine. More preferred compounds of this invention include:
N-[2-(4-carboxyphenyl)-1-mer
ethylethyl]-2-hydroxy-2-phenylethyl
Tanamine and N-[3-(4-carboxif)
enyl)-1-methylpropyl]-2-hydroxy
Contains ci-2-phenylethanamine. Even more preferred compounds of this invention include
is N-[2-(4-carbomethoxyphenyl)
-1-methylethyl]-2-hydroxy-2-ph
enylethanamine; N-[3-(4-carbome
toxyphenyl)-1-methylpropyl]-2-
Hydroxy-2-phenylethanamine; N-
[2-(4-carboethoxyphenyl)-1-meth
ethylethyl]-2-hydroxy-2-phenylethyl
Tanamine and N-[3-(4-carboethoxylate)
Cyphenyls)-1-methylpropyl]-2-hydro
Roxy-2-phenylethanamine and these
Included are pharmaceutically acceptable acid addition salts of the compounds. In addition, the preferred methyl and ethyl esters
n-propyl and isopropyl corresponding to
Esters are highly preferred compounds of this invention.
It is. R_Fouris other than a carboxylate salt
Compounds can be provided as salt addition salts.
Wear. Such salts are salts of organic or inorganic acids.
salts of acids that are normally pharmaceutically acceptable;
It is. Suitable acid addition salts include hydrochloric acid and hydrogen bromide.
acids, orthophosphoric acid, sulfuric acid, methanesulfonic acid, tolu
Ensulfonic acid, acetic acid, propionic acid, lactic acid,
Enoic acid, fumaric acid, malic acid, succinic acid, salic acid
Formed with acids such as cylic acid, acetylsalicylic acid, etc.
Contains salt. Compounds of formula () are of formula (a): [In the formula, R₁~R₇, Y and X in formula ()
Same as the definition In , the position of the carbon atom marked with a single asterisk is
It has an irregular center. R₆is R₇Unlike R₁~
R₇, Y and X are the same as the definition for formula ()
In the case of formula (a), the compounds of formula () are
and place another carbon atom in the position marked with two stars.
It has two irregular centers. This invention includes individual structures of compounds of formula ().
Isomers and mixtures thereof are included. two
Preferred compounds of formula () having an asymmetric center
Stereoisomers are separated diastereoisomers
It is provided in the form of such isolated gia
Stereo isomers are, of course, mirror images of each other.
Contains a pair of compounds. N-[2-(4-carbomethoxy) with higher melting point
Cyphenyls)-1-methylethyl]-2-hydro
xy-2-(4-hydroxy-3-hydroxymeth)
tylphenyl)-ethanamine diastereoisomer
The isomer is a more potent diastereoisomer.
It was found that somar and therefore this dias
Teleisomers are particularly preferred. R in the formula₆is R₇Other transformations of expression () that are not the same as
Structurally equivalent diastereoisomers of compounds
classes (compounds with the same stereochemistry) are the same.
very preferable. Thus, for example, N-[2-(4-carbometh
xyphenyl)-1-methylethyl]-2-hydro
Roxy-2-phenylethanamine (above and structure
diastereoisomers) have low melting points.
The lower diastereoisomer is more potent.
is a large diastereoisomer and therefore especially
This is preferable. To measure absolute stereochemistry and investigate correlations,
X-ray analysis can be used. Compounds of Examples 1, 22, 28, 29, 30 and 32
Methyl on the carbon atom at the α-position to the nitrogen atom, as shown in
Compounds with group¹³In CNMR, active
The diastereoisomer with higher
d₆The methyl group in the DMSO solution is exposed to a higher magnetic field.
(If expressed in ppm, it will be a lower number)
It was observed that Paired resonance is 20ppm
slightly higher than 20ppm (lower activity)
slightly lower (higher activity, tetramethyl
(lower magnetic field than silane). other
Paired resonances bond directly to the nitrogen atom.
Nitrogen atoms with carbon atoms and hydroxy groups
This can occur for the carbon atom in the β position relative to the child. this
In this case, the most active of the compounds studied
Diastereoisomers pair up at higher magnetic fields
Shows summer resonance. This invention also provides for the use of the compound of this invention as a pharmaceutical.
and an acceptable carrier, especially for anti-obesity.
The present invention provides a composition for use. The compositions of this invention are suitable for parenteral administration, e.g.
Although compositions formulated for injection are expected,
Usually formulated for oral administration. Particularly suitable oral dosage forms are tablets or capsules.
In unit dosage form. Also during the sashiei
Other fixed unit dosage forms such as powdered
Can be used. According to normal pharmaceutical practice, diluents,
Binders, fillers, disintegrants, wetting agents, lubricants, pigments,
A carrier consisting of perfume or the like is used. Therefore, typical carriers include microcrystalline cellulose
starch, starch, sodium starch glycolate, poly
vinylpyrrolidone, polyvinylpolypyrrolidone,
Magnesium stearate, sodium lauryl sulfate
It consists of umum, sucrose, etc. However, suitable compositions are provided in unit dosage form.
It will be done. Its unit dose is usually 0.01-100mg,
more usually 0.2 to 50 mg and preferably 0.5 to 20 mg
It is. Also, per day for an adult weighing 70 kg.
The total dosage is generally about 0.1 to 100 mg, more usually about
2 to 80 mg 1 to 6 times per day
can be given. Preferably the one with higher potency
Compounds generally range from 0.1 to 10 mg, more commonly from 0.25 to
A unit dose containing 5 mg. these days
The dosage is generally about 0.5-20mg, more commonly
is 1 to 10 mg, for example 2 to 5 mg. The compositions of this invention can be used as human medicine.
In addition to treating obesity in domestic animals such as dogs.
It can be used to Generally used for livestock.
Administration is done orally, usually 1 to 2 times per day, approximately
0.025mg/Kg~2.5mg/Kg, e.g. 0.1mg/Kg~2
mg/Kg. This invention also uses the formula (): [In the formula, Z is -N=CR₆-or-NH-C
(OH)R₆--;R₁,R₂,R₃,R_Four,R_Five,R₆,Yo
and X are the same as the definition for formula ()] reduce the compound represented by
The oxidative addition of the initially generated compound of formula ()
of the compounds of this invention consisting of forming salts.
It provides a manufacturing method. Reduction of compounds of formula () is usually done by catalytic hydrogenation
Achieved by reaction. Suitable catalysts include para
Dium, e.g. palladium on charcoal, platinum, e.g.
Includes noble metal catalysts such as platinum oxide. para
When nickel is the catalyst, medium or high pressure hydrogen gas is used.
pressure is used, but generally elevated pressure, e.g.
50-100p.s.i. (3.5-7.0Kg/cm²) using hydrogen
is preferable. When platinum is used as a catalyst,
Hydrogen at atmospheric pressure can be used. reaction is extreme
It can be done at any normal temperature, but generally
is 30-100℃, for example, from room temperature like 40-80℃
It is most appropriate to use a slightly higher temperature.
Ru. The hydrogenation reaction is performed using lower alkanols, e.g.
in common hydrogenation reaction solvents such as ethanol.
It will be done. The desired compound can be obtained by evaporating the filtrated solution.
can be separated from the reaction mixture. got first
The resulting product can be processed using conventional methods, e.g. chromatography.
It can be purified by efficiencies, crystallization, etc. Also, the reduction reaction of the compound of formula () is with boron hydride.
This can be achieved using complex hydrides such as sodium.
Ru. This reduction reaction is generally carried out in lower alkanol solutions.
medium, e.g., methane if a methyl ester is desired.
This is done during the course. Almost normal temperature, for example 20~30℃
used. The desired compound is extracted by evaporating the reaction mixture and adding ethyl acetate.
obtained by extraction with a suitable solvent such as
Ru. The initial product obtained was prepared as outlined above.
It can be purified by A compound of formula () is a compound of formula (): [In the formula, R₁,R₂and R₃is a constant regarding the expression ()
same as righteousness] A compound represented by formula (X): [In the formula, R_Four,R_Five,R₆, Y and X are in the formula ()
Same as the related definition] It can be produced by reaction with the compound represented by
Wear. This coupling reaction involves lower alkanols,
For example, it is carried out in a common solvent such as ethanol.
Ru. This reaction is generally carried out at elevated temperatures, e.g.
Performed at flow temperature. The compound of formula () is prepared and then isolated.
It is convenient to use it as is without
There are many. In this case, the reaction is between the compound of formula () and the formula
A mixture with the compound (X) [wherein, R₁,
R₂,R₃,R_Four,R_Five,R₆, X and Y are in the formula ()
The hydrogenation reaction is the same as the definition for Such a hydrogenation reaction involves the addition of water to the compound of formula ().
The addition reaction should be carried out under the conditions described.
I can do it. Compounds of formula () can be prepared by conventional methods, e.g.
I.T.Collins, J.Med.Chem.1970,
It can be manufactured by the method described in 13674. In addition, the compounds of the formula () defined above are of the formula
(XI): [In the formula, R₁,R₂and R₃is a constant regarding the expression ()
same as righteousness] Compound represented by formula (XII): [In the formula, R_Four,R_Five,R₆,R₇, X and Y are the formula
Same as the definition for compounds in ()] It can be produced by reaction with the compound represented by
Wear. This reaction involves methylene chloride, chloroform,
It can be carried out in a solvent such as benzene. Other methods for producing compounds of formula () include
(X): [In the formula, R₁,R₂,R₃,R_Four,R_Five,R₆,R₇, X and
and Y are the same as the definitions for formula ()] It consists of a reduction reaction of a compound represented by The reduction reaction of the compound of formula (X) is the reduction reaction of the compound of formula (V)
In the same way as described for the reduction reaction of the compound
This can be done using hydrides or hydrogen. The compound of formula (X) is the compound of formula (X): [In the formula, R₁,R₂and R₃is a constant regarding the expression ()
same as righteousness] Compounds represented by or their hydrides or
Hemi-acetal of alkanol and formula (X
): [In the formula, R_Four,R_Five,R₆,R₇, X and Y are the formula
Same as the definition for ()] It can be produced by reaction with the compound represented by
Wear. The above reaction generally requires that the water produced during the reaction be removed.
It is carried out under conditions in which it is removed. Therefore, Dean
Reflux the benzene solution and add water using Stark's apparatus.
Azeotropic removal is convenient. The compound of formula (X) is dissolved from the reaction mixture.
Obtained by evaporating the medium and optionally subjected to chromatography.
It can be purified by subjecting it to a feed. Another method for producing compounds of formula ()
is the formula (XV): [In the formula, R₁,R₂,R₃,R_Four,R_Five,R₆,R₇, X and
and Y are the same as the definitions for formula ()] It consists of a hydrogenation reaction of a compound represented by The hydrogenation reaction of the compound of formula (XV) is the hydrogenation reaction of the compound of formula (V
) described the hydrogenation reaction of the compound
It can be done similarly. The compound of formula (XV) is the compound of formula (X): [In the formula, R₁,R₂and R₃is a constant regarding the expression ()
same as righteousness] N- of the compound represented by and the compound of formula (X)
It can be produced by reaction with benzyl derivatives. This reaction is similar to acetonitrile or butanone.
when carried out in a solvent at elevated temperatures, e.g. under reflux.
I can. While this reaction is taking place, the general
An acid acceptor is present in, for example, a compound of formula (X)
The number of moles of the tertiary compound is larger than that of the N-benzyl derivative of
Amines are used. After the reaction is complete, the reaction mixture is diluted with ether,
The liquid was evaporated through filtration. base R₁,R₂,R₃and especially R_FourIf necessary,
After the condensation reaction, changes can be made. For example,
ndyloxy group can be converted into hydrocarbon by hydrogenation reaction.
can be converted to xyl group, and the ester can be hydrolyzed.
The benzyl ester can be made into an acid by adding water to the benzyl ester.
An acid can be obtained by subjecting it to an elementary addition reaction. acidic
Salts are reactive chlorides, bromides or tosylates
It can be esterified by reaction with.
The acid is reacted with the hydroxy compound under dehydrating conditions.
can be esterified. Amides are converted to acid chlorides
It can be prepared from acids or by similar reactions.
Ru. Compounds of formula () with only one asymmetric center
can be divided using known methods. example
For example, an optically active acid is used as the resolving agent. 2
Compounds of formula () with two asymmetric centers are suitable
It can be obtained by fractional crystallization from suitable solvents such as ethyl acetate.
They can be separated into their diastereoisomers. mosquito
After separation of the individual diastereoisomers as
The components can be separated using known methods, e.g. as a resolving agent.
Obtained by resolution using a chemically active acid. Suitable optically active acids for use in the resolution method
Stereochemistry (Volume 6, Wiley
Interscience, 1971, Alingier
N.L. and Iraial D.A.L.)
are listed in the topics. Also, in order to obtain specific enantiomers,
Body-specific synthetic methods are used. Thus, the analogy
A single enantiomer of a compound of formula () is
Before reduction with borohydride or catalytic reduction, the formula
Used in the reaction with compound (X). Similarly, the expression
A single enantiomer of a compound of (XI) is of formula (XII)
It is used in reactions with compounds of Similarly, formula (XII)
A single enantiomer of the compound (where R₆but
R₇) is reduced by boron hydride
reaction with a compound of formula (XI) or (X) before
used for. Specific enantiomers produced by these methods
are then removed from a suitable solvent such as ethyl acetate.
It can be separated by conventional means such as fractional crystallization. In addition, preparative high-pressure liquid chromatography is
For example, N-[2-(4-carbomethoxyphenyl)
-1-methylethyl]-2-hydroxy-2-ph
Diastema of compounds such as enylethanamine
Rheomers, e.g. 98:2 dichloromethane:
Used for separation on silica using methanol.
I can stay. Next, the present invention will be explained with reference to Examples.
It is not limited to. Also, please refer to the following reference example.
Next, a method for producing a useful intermediate will be explained. Example 1 N-[2-(4-carbomethoxyphenyl-1
-methylethyl]-2-hydroxy-2-(4
-Hydroxy-3-hydroxymethylpheni
) Ethanamine 1-(4-carbomethoxyphenyl)propane
-2-on (7.0g) 2-hydroxy-2-(4-hydroxy-3-
Hydroxymethylphenyl)ethaneamine
(6.67g) added to ethanol (200ml) containing
and the solution was refluxed for 4 hours. Bring the solution to room temperature.
Cool to a temperature, add 10% palladium on charcoal (2 g),
75~85psi (5.3~6.0Kg/cm²), water at 50-60℃ for 12 hours
Added element. The solution is filtered and evaporated to leave a residue.
It was poured into ethyl acetate and filtered again. evaporate the liquid
Crystallize and then recrystallize from benzene to obtain the following
7.3 g of the title compound having physical properties was obtained. Melting point: 88~91℃ NMR: τ(d₆DMSO) 9.1 (3H, d, J=6
Hz), 6.9-7.8 (5H, m), 6.2 (3H, S), 5.51
(2H, S+1H, t, J=6Hz), 3.7-5.9 (4H,
Broad)D₂), 3.34 (2H, d, J = 8
Hz), 2.5−3.18 (3H, m) and 2.14 (2H, d,
J=8Hz) ¹³C NMR and glc
Lee and G. Munro's Perkin-Elmer Minutes
Analysis News Vol. 13 method) is diastereoiso
showed a 1:1 mixture of mer.¹³C NMR:
(d₆DMSO) ppm20.01, 19.78, 53.96, 53・71;
55.11, 54.84; 71.87, 71.66. Example 2 N-[2-(3-carbomethoxyphenyl)-
1-methylethyl]-2-hydroxy-2-
(4-hydroxy-3-hydroxymethylphene
nil) ethanamine In the method of Example 1, 1-(4-carbomethane)
1 instead of propan-2-one (toxyphenyl)
-(3-carbomethoxyphenyl)propane-2
-on to obtain the title compound (melting) with the following physical properties.
point: 60-70°C, recrystallized from benzene). NMR: τ(d₆DMSO) 9.05 (3H, d, J=6
Hz), 6.8−7.8 (5H, m), 6.1 (3H, s), 5.42
(2H, s + 1H, t), 4.1-5.7 (4H, broad,
D₂) and 2.0−3.3 (7H, m). Example 3 N-[2-(4carbomethoxy-3-hydroxy
Cyphenyls)-1-methylethyl]-2-hydro
Roxy-2-(4-hydroxy-3-hydroxy
dimethylphenyl)ethaneamine In the method of Example 1, 1-(4-carbomethane)
1 instead of propan-2-one (toxyphenyl)
-(4-carbomethoxy-3-hydroxypheni
) Using propan-2-one, it has the following physical properties.
The title compound (melting point: 81-83°C, from benzene)
Recrystallization) was obtained. NMR; τ(d₆DMSO) 9.0 (3H, d, J=6
Hz), 6.9−7.6 (5H, m), 6.1 (3H, s), 5.5 (2H,
s + 1H, t, ), 3.5-5.2 (5H, broad, D₂At O
disappearance) 2.5−3.35 (5H, m) and 2.25 (1H, d,
J=8Hz) ¹³C NMR shows approximately diastereoisomers.
A 1:1 mixture was shown. Example 4 N-[2-(3-carbomethoxy-4-hydro
xyphenyl]-1-methylethyl]2-hydro
Roxy-2-(4-hydroxy-3-hydroxy
dimethylphenylethanamine In the method of Example 1, 1-(4-carbomethane)
1 instead of propan-2-one (toxyphenyl)
-(3-carbomethoxy-4-hydroxypheni
) It has the following physical properties using prop-2-one.
The title compound (melting point: 65-69°C, reconstituted from benzene)
crystals) were obtained. NMR: τ(d₆DMSO) 9.05 (3H, d, J=6
Hz), 7.0−7.6 (5H, m), 6.2 (3H, s), 5.5 (2H,
s+1H, t), 3.4−5.2((5H, broad, D₂In O
disappearance) and 2.3−3.4 (6H, m). Example 5 N-[2-(3-carbomethoxy-4-methoxy)
Cyphenyls)-1-methylethyl]-2-hydro
Roxy-2-(4-hydroxy-3-hydroxy
dimethylphenyl)ethaneamine In the method of Example 1, 1-(4-carbomethane)
xyphenyl) propane-2-one instead of 1-
(3-carbomethoxy-4-methoxyphenyl)
Using propan-2-one, it has the following physical properties.
The title compound (melting point: 69-73°C, reconstituted from benzene)
crystals) were obtained. NMR: τ(d₆DMSO), 9.05 (3H, d, J=6
Hz), 7.0−7.7 (5H, m), 6.2 (3H, s+3H, s),
5.5 (2H, s + 1H, t,) 4.0-5.8 (4H, broad,
D₂) and 2.4−3.4 (6H, m) Example 6 N-[2-(4-carbomethoxyphenyl)-
1-ethylethyl]-2-hydroxy-2-
(4-hydroxy-3-hydroxymethylphene
nil) ethanamine In the method of Example 1, 1-(4-carbomethane)
1 instead of propan-2-one (toxyphenyl)
-(4-carbomethoxyphenyl)butane-2-
The title compound with the following physical properties is prepared using
Obtained as a 1:1 mixture of diastereoisomers
Ta. Melting point: 64-67℃ (recrystallized from benzene) NMR: τ(d₆DMSO) 9.14 (3H, t, J=6
Hz), 8.9-8.4 (2H, m), 7.6-7.0 (5H, m),
6.18 (3H, s), 5.5 (2H, S+1H, t,), 4.3−
5.9 (4H, broad) D_2O) and 2.05−3.4
(7H, m). Example 7 N-[3-(4-carbomethoxyphenyl)-
1-methylpropyl]-2-hydroxy-2-
(4-hydroxy-3-hydroxymethylphene
nil) ethanamine In the method of Example 1, 1-(4-carbomethane)
1 instead of propan-2-one (toxyphenyl)
-(4-carbomethoxyphenyl)butane-3-
diasteride the title compound with the physical properties below using
Obtained as a 2:3 mixture of rheoisomers. Melting point: 84.5-87℃ (recrystallized from benzene) NMR: τ(d₆DMSO) 8.95 (3H, d,), 8.7−
8.1 (2H, m), 7.7-7.0 (5H, m), 6.17 (3H,
s), 5.49 (2H, s+1H, t,), 4.5-5.7 (4H, block
Road, D₂) and 2.05−3.33 (7H,
m). Example 8 N-[2-(4-carbomethoxyphenoxy)
-1-methylethyl]-2-hydroxy-2-
(4-hydroxy-3-hydroxymethylphene
nil) ethanamine In the method of Example 1, 1-(4-carbomethane)
1 instead of propan-2-one (toxyphenyl)
-(4-Carbomethoxyphenoxy)propane-
Using 2-one, further add 10% palladium on charcoal.
Instead, platinum oxide (ptO₂) has the following physical properties.
and the title contains 1/2 mole of benzene in the crystal.
compound in a 2:3 mixture of diastereoisomers.
Obtained as a compound. Melting point: 60-68℃ (recrystallized from benzene) NMR: τ(d₆DMSO) 8.95 (3H, d,), 7.3
(2H, d), 7.0 (1H, dq), 6.25 (3H, s), 6.15
(2H, d), 5.52 (2H,, s+1H, t), 4.0−5.4
(4H, Broad, D₂) and 2.18−3.4
(7H, m). Example 9 N-[2-(4-carbomethoxy-2-fluoro
Lofenyl)-1-methylethyl]-2-hydro
Roxy-2-(4-hydroxy-3-hydroxy
dimethylphenyl)ethaneamine In the method of Example 1, 1-(4-carbomethane)
1 instead of propan-2-one (toxyphenyl)
-(4-carbomethoxy-2-fluorophene
) Using propan-2-one, it has the following physical properties.
The diastereoisomer of the title compound
Obtained as a 1:1 mixture. Melting point: 97-100℃ (recrystallized from benzene) NMR: τ(d₆DMSO) 9.1 (3H, d, J=6
Hz), 6.9−7.7 (5H, m), 6.2 (3H, s), 5.45
(2H, s + 1H, t), 4.5-5.9 (4H, broad,
D₂) and 2.2−3.4 (6H, m). Example 10 N-[2-(4-carbomethoxy-3-methoxy)
Cyphenyls)-1-methylethyl]-2-hydro
Roxy-2-(4-hydroxy-3-hydroxy
dimethylphenyl)ethaneamine In the method of Example 1, 1-(4-carbomethane)
1 instead of propan-2-one (toxyphenyl)
-(4-carbomethoxy-3-methoxypheni
) Using propan-2-one, it has the following physical properties.
diastereoisomers of the title compound
Obtained as a 42:58 mixture. Melting point: 64-71℃ (recrystallized from benzene) NMR: τ(d₆DMSO) 9.1 (3H, d, J=6
Hz), 7.0−7.5 (5H, m), 6.3 (3H, s+3H, s),
5.55 (2H, s + 1H, t), 4.7-5.8 (4H, blow
D, D₂) and 2.3−3.45 (6H, m) Example 11 N-[2-4-N'-methylcarboxamide
enyl)-1-methylethyl]-2-hydro
xy-(4-hydroxy-3-hydroxymethy)
(ruphenyl) ethanamine In the method of Example 1, 1-(4-carbomethane)
1 instead of propan-2-one (toxyphenyl)
-(4-N-methylcarboxamidophenyl)
Using ropan-2-one, foam with the following physical properties
Diasteride the title compound (acetonitrile)
Obtained as an 11:9 mixture of rheoisomers. NMR: τ(d₆DMSO) 9.05 (3H, d, J=6
Hz), 7.2 (3H, d, J = 4Hz, D₂O becomes a single line
), 7.0−7.5 (5H, m), 5.5 (2H, s + 1H, t),
4.0−5.5 (4H, Broad, D₂Disappears at O, 3.3 (1H,
d, J=8Hz), 3.0 (1H, d, J=8Hz), 2.8
(2H, d, J=9Hz), 2.7 (1H, s), 2.25 (2H,
d, J = 9Hz) and 1.7 (1H, q, J = 4Hz,
D₂disappears with O) Example 12 N-[2-(4-carbomethoxy-2-methoxy)
Cyphenyls)-1-methylethyl]-2-hydro
Roxy-2-(4-hydroxy-3-hydroxy
dimethylphenyl)ethaneamine In the method of Example 1, 1-(4-carbomethane)
1 instead of propan-2-one (toxyphenyl)
-(4-carbomethoxy-2-methoxypheni
) Using propan-2-one, it has the following physical properties.
diastereoisomers of the title compound
Obtained as a 3:2 mixture. Melting point: 96-105℃ (recrystallized from benzene) NMR: τ(d₆DMSO) 9.1 (3H, d, J=6
Hz), 7.0−7.5 (5H, m), 6.2 (3H, s+3H, s),
5.55 (2H, s + 1H, t,) 4.5-5.5 (4H, blow
D, D₂) 3.35 (1H, d, J = 8Hz) and
and 3.1−2.4 (5H, m). Example 13 N-[2-(4-carboisopropoxyphenyl)
)-1-methylethyl]-2-hydroxy-
2-(4-hydroxy-3-hydroxymethyl
Phenyl) ethanamine In the method of Example 1, 1-(4-carbomethane)
1 instead of propan-2-one (toxyphenyl)
-(4-carboisopoxyphenyl)propane-
Using 2-one, the title of the compound has the following physical properties.
compound with a 1:1 mixture of diastereoisomers
I got it. Melting point: 68-76℃ (recrystallized from benzene) NMR: τ(d₆DMSO) 9.05 (3H, d, J=6
Hz), 8.75 (6H, d, J=6Hz), 7.0−7.5 (5H,
m), 5.55 (2H, s + 1H, t), 4.95 (1H, h, J
= 6Hz), 4.0-5.5 (4H, broad, D₂disappears with O),
3.35 (1H, d, J = 8Hz), 3.05 (1H, d, J = 8
Hz), 3.8 (1H, 3), 3.75 (2H, d, J=8Hz) and
and 3.2 (2H, d, J = 8Hz). Example 14 N-[2-(4-carbomethoxy-3-methyl
phenyl)-1-methylethyl]-2-hydro
xy-2-(4-hydroxy-3-hydroxy
methylphenyl)ethaneamine In the method of Example 1, 1-(4-carbomethane)
1 instead of propan-2-one (toxyphenyl)
-(4-carbomethoxy-3-methylphenyl)
Using propan-2-one, it has the following physical properties.
The title compound was divided into 1:1 diastereoisomers.
Obtained as a mixture. Melting point: 82-85℃ (recrystallized from benzene) NMR: τ(d₆DMSO) 9.05 (3H, d, J=6
Hz), 7.55 (3H, s). 7.2−7.6 (5H, m), 6.25
(3H, s), 5.55 (2H, s+1H, t), 4.55 (4H,
Broad, D.₂), 3.35 (1H, d, J = 8
Hz), 3.05 (1H, d, J=8Hz), 2.9 (1H, s+
1H, s), 2.7 (1H, d, J=8Hz) and 2.25
(1H, d, J = 8Hz). Example 15 N-[2-(4-pivaloyloxymethyloxy)
cyclocarbonylphenyl)-1-methylethyl]
-2-hydroxy-2-(4-hydroxy-3
-Hydroxymethylphenyl)ethaneamine In the method of Example 1, 1-(4-carbomethane)
1 instead of propan-2-one (toxyphenyl)
-(4-pivaloyloxymethyloxycarboni
The following properties were obtained by using propane-2-
diastereoisomers of the title compound with
Obtained as a 1:1 mixture. Melting point: 55-57℃ (recrystallized from benzene) NMR: τ(d₆DMSO) 9.1 (3H, d, J=6
Hz), 8.9 (9H, s), 7.0-7.5 (5H, m), 5.55
(2H, s + 1H, t), 4.5-5.4 (4H, broad,
D₂Disappeared in O) 4.1 (2H, s) 3.35 (1H, d, J = 9
Hz), 3.0 (1H, d, J=9Hz), 2.75 (1H, s),
2.7 (2H, d, J = 8Hz) and 2.15 (2H, d, J
=8Hz). Example 16 N-[2-(4-carboethoxyphenyl)-
1-methylethyl]-2-hydroxy-2-
(4-hydroxy-3-hydroxymethylphene
nil) ethanamine In the method of Example 1, 1-(4-carbomethane)
1 instead of propan-2-one (toxyphenyl)
-(4-carbomethoxyphenyl)propane-2
-on, the title compound having the following physical properties
as a 1:1 mixture of diastereoisomers
Obtained. Melting point: 92-96℃ (recrystallized from benzene) NMR: τ(d₆DMSO) 9.1 (3H, d, J=6
Hz), 8.7 (3H, t, J = 7Hz) 6.85-7.65 (5H,
m), 5.75 (2H, q, J=0Hz), 5.55 (2H, s+
1H, t) 4.0−6.0 (4H, broad, D₂disappears with O),
3.35 (1H.d, J=8Hz), 3.0 (1H.d, J=8Hz)
Hz), 2.8 (1H, s) 2.75 (2H, d, J = 9Hz) and
and 2.2 (2H, d, J = 9Hz). Example 17 N-[4-(4-carbomethoxyphenyl)-
1-methylbutyl]-2-hydroxy-2-
(4-hydroxy-3-hydroxymethylphene
nil) ethanamine In the method of Example 1, 1-(4-carbomethane)
1 instead of propan-2-one (toxyphenyl)
-(4-carbomethoxyphenyl)pentane-4
-on, the title compound with the following physical properties:
as a 1:1 mixture of diastereoisomers
I got it. Melting point: 73-75℃ (recrystallized from benzene) NMR: τ(d₆DMSO) 9.05 (3H, d, J=6
Hz), 8.0-8.8 (4H, m), 7.1-7.5 (5H, m), 6.2
(3H, s), 5.5 (2H, s+1H, t), 4.2−5.4
(4H, Broad, D₂) 3.35 (1H, d, J
= 8Hz), 3.0 (1H, d, J = 8Hz), 2.75 (1H,
s), 2.7 (2H, d, J=9Hz) and 2.15 (2H,
d, J=9Hz). Example 18 N-[1-(4-carbomethoxyphenyl)-
1-methylmethyl]-2-hydroxy-2-
(4-hydroxy-3-hydroxymethylphene
nil) ethanamine 4-Carbomethoxy-α-methylbenzylamide
(0.66g) and 4-benzyloxy-3-hydro
Oxymethylphenylglyoxal, (1.0g)
The mixture of Dean and Stark in benzene
The mixture was refluxed for 2 hours under these conditions. Remove solvent under reduced pressure
Then, the residue was taken up in methanol and diluted with sodium borohydride.
Lium (1.0g) was added. Evaporate the solvent and
Ter and water were added and both layers were separated. ether
The layer was dried with magnesium sulfate and the solvent removed.
O-benzyl derivative (1.62g) of the title compound
Obtained as an oil. Dissolve this in ethanol,
Hydrogenated with 10% palladium on carbon at room temperature and atmospheric pressure
diastereoisomer of the title compound with the following physical properties.
A 96:4 mixture of isomers was obtained. Melting point: 102-105℃ (recrystallized from benzene) NMR: τ(d₆DMSO) 8.82 (3H, d, J=6
Hz), 7.3−7.8 (3H, m), 6.18 (3H, s), 5.52
(2H, s+1H, t), 4.0-7.0 (4H, broad),
3.34 (1H, d, J=8Hz), 2.97 (1H, dd, J=8
Hz, J=2Hz), 2.73 (1H, d, J=2Hz), 2.5
(2H, d, J = 8Hz) and 2.07 (2H, d, J =
8Hz). Example 19 N-[2-(4-carbomethoxyphenyl)-
1-methylethyl]-2-(3,4-dihydro
xyphenyl)-2-hydroxyethanamine In the method of Example 1, 2-hydroxy-2
-(4-hydroxy-3-hydroxymethylphene
2-(3,4-dihydryl) instead of
Droxifel)-2-hydroxyethanamine
The title compound with the following properties was prepared using
Obtained as an 8:92 mixture of stereoisomers.
Ta. Melting point: 169℃ (recrystallized from ethyl acetate) NMR: τ(d₆DMSO) 8.94 (3H, d, J=6
Hz), 6.90−7.50 (7H, m), 6.03 (3H, s), 5.44
(1H, m) 4.50 (2H, b), 3.10−3.40 (3H, m),
2.54 (2H, d, J=8Hz) and 2.00 (2H, d,
J=8Hz). Example 20 N-[2-(4-carboxyphenyl)-1-
methylethyl]-2-hydroxy-2-(4-
hydroxy-3-hydroxymethylphenyl)
Ethanamine 2-hydroxy-2-(4-hydroxy-3-
Hydroxymethylphenyl)ethaneamine
(1.09g) and 1-(4-carbobenzyloxyphene)
2-propane (1.6g) and water
Dean Stark's device until stoichiometry is collected
The mixture was refluxed using xylene in the tank. remove the solvent
Add ethanol and bring the mixture to 70psi (4.9Kg/cm²),
Using 10% palladium on charcoal as a catalyst for 3 hours at 50℃
It was subjected to a hydrogenation reaction. Pass through the catalyst and evaporate the solvent.
to obtain a foamy title compound with the following properties:
Ta. NMR: τ(d₆DMSO) 8.95 (3H, d, J=7
Hz), 6.8-7.4 (5H, m), 5.5 (2H, s+1H, t),
3.65 (5H, broad), 2.3−3.3 (5H, m) and
2.0 (2H, d, J = 8Hz). Example 21 N-[2-(4-carbomethoxyphenyl)-
1-methylethyl]-2-hydroxy-2-
(4-hydroxy-3-hydroxymethylphene
diastereoisomers of ethanamine
separation of Diastereoisomer 1 obtained in Example 1:
1 mixture (4g) was reconstituted from ethyl acetate (200ml).
crystallization, content of one diastereoisomer
Product with increased (1.53g, melting point 140.5-143.5℃)
I got it. The obtained substance was mixed with ethyl acetate (100ml) or
crystallized again to form a diastereomer with a higher melting point.
Isomer (isomer purity: 97%, melting point 145.5 ~
147.5°C) (0.8g) was obtained. Furthermore, by recrystallizing
A product with the following physical properties was obtained. Isomer purity: 99.5% Melting point 145.5-147.5℃ ¹³C NMR:ppm(d₆DMSO) 19.80, 42.78,
51.78, 53.55, 54.81, 58.55, 71.57, 114.11,
124.93, 125.19, 127.28, 127.82, 128.93,
129.17, 129.48, 134.45, 145.54, 153.21,
166.19. Oil obtained by evaporating ethyl acetate from the original mother liquor
crystallize by putting it in benzene and scratching it.
The solid product (1.81g) (melting point 92.5-94.5℃) was
Obtained. Reconstitute this material from ethyl acetate (100ml).
Crystallized to obtain a solid (0.2g) (melting point 137.5-140.5℃),
This was discarded. Evaporate the ethyl acetate,
Ether (20ml) was added to the residue. This is 0℃
Leave it for 3 days, then let it cool.¹³C NMR
As shown, the diastereoisomers
Solid (0.64g) made up of a 23:77 mixture (melting point 97
~100℃) was obtained. Add this to ethyl acetate (50ml)
The material obtained by recrystallization (0.44 g) was discarded.
Ta. The oil obtained by evaporating the mother liquor (0.2 g) is
It was recrystallized from 10 ml of 100 ml of sulfuric acid and had the following physical properties.
Diasteel with isomer purity of 78% and low melting point
Obtained rheoisomer (0.14g) (melting point 70-73℃)
Ta. ¹³C NMR:ppm(d₆DMSO) 20.10, 42.81,
51.84, 53.83, 55.14, 58.50, 71.82, 114.07,
124.88, 125.17, 127.37, 127.86, 129.00,
129.21, 129.53, 134.54, 145.59, 153.16,
166.19. Example 22 N-[2-(4-carbomethoxyphenyl)-
1-methylethyl]-2-hydroxy-2-ph
enylethanamine 2-Hydroxy-2-phenylethanamine
(2.15g) and 1-(4-carbomethoxyphenyl)
Propane-2-one (3.0g) at Dean Star
the theoretical amount in refluxing benzene (100 ml) under
water was collected. methanol solvent
The mixture is stirred and cooled with water.
Add sodium boron chloride (3.0g) little by little.
Ta. The mixture was stirred for 2 hours, the solvent was evaporated,
The residue was partitioned between water and chloroform. organic extract
The extract was dried, evaporated and recrystallized from hexane.
45 of the diastereoisomers with a melting point of 82-84 °C:
55 mixture was obtained and also recrystallized from benzene/hexane.
When crystallized, it has a melting point of 121-122℃ and is a diastereoisomer.
An 80:20 mixture of mer was obtained. NMR: τ(CDCI₃)8.97 (3H, d, J=6Hz),
6.85−7.60 (7H, m), 6.15 (3H, s), 5.33 (1H,
m), 2.81 (2H, d, J=8Hz), 2.70 (5H, m)
and 2.04 (2H, d, J=8Hz). ¹³C NMR: (d₆DMSO) ppm.20.15, 19.90;
53.82, 53.64; 55.03, 54.86; 71.91, 71.73. Example 23 N-[2-(4-carbomethoxy-2-chloro
phenyl)-1-methylethyl]-2-hydro
xy-2-phenylethanamine In Example 22, 1-(4-carbomethoxy
phenyl) propane-2-one instead of 1-(4
-carbomethoxy-2-chlorophenyl)propa
Using ion-2-one, the title compound with the following physical properties
hydrochloride as a mixture of diastereoisomers
I got it. Melting point: 145-147°C (reproduced from benzene-hexane)
crystal) NMR: τ(CDCI₃)8.70 (3H, d, J=6Hz),
6.00−7.10 (5H, m), 6.17 (3H, s), 4.50 (1H,
m) and 1.60−3.20 (11H, m). Example 24 N-[2-(4-carbomethoxy-2-methoxy)
Cyphenyls]-1-methylethyl)-2-hydro
Roxy-2-phenylethanamine In the method of Example 22, 1-(4-carbomethane)
1 instead of toxyphenyl) propan-2-one
-(4-carbomethoxy-2-methoxypheni
) Using propan-2-one, the following physical properties were measured.
The hemifumarate of the title compound is diastereoisolated.
Obtained as a mixture of sommers. Melting point: 102-104℃ (recrystallized from ethyl acetate) NMR: τ(d₆DMSO) 8.92 (3H, d, J=6
Hz), 6.50−7.60 (7H, m), 6.19 (6H, s), 5.05
(1H, m), 3.45 (2H, s), 2.30−2.80 (6H, m)
and 1.60−2.00 (4H, m) Example 25 N-[2-(4-carbomethoxyphenyl)eth
Chil]-2-hydroxy-2-phenylethane
amine Phenylglyoxal (0.8g) and 2-(4-
Carbomethoxyphenyl)ethanamine (1.1g)
The theoretical amount of water is collected in the Dean-Stark apparatus.
Heat in refluxing benzene (100 ml) until concentrated.
Ta. Replace the solvent with methanol and cool with ice.
Add sodium borohydride (2.0g) little by little.
did. The mixture was stirred for 2 hours and the solvent was evaporated.
and the residue was partitioned between water and ethyl acetate. organic extraction
Dry the extract and crystallize from benzene/hexane.
The title compound with the following physical properties was obtained. Melting point: 105-106℃ NMR: τ(CDCI₃) 6.80−7.60 (8H, m), 6.18
(3H, s), 5.34 (1H, m), 2.94 (2H, d, J=
8Hz), 2.77 (5H, m) and 2.09 (2H, d, J=
8Hz). Example 26 N-[2-(4-carbomethoxyphenyl)-
1,1-dimethylethyl]-2-hydroxy-
2-Phenylethanamine In the method of Example 25, 2-(4-carbomethane)
2-(4) instead of toxyphenyl)ethanamine
-Carbomethoxyphenyl)-1,1-dimethyl
Using ethanamine to prepare the title compound with the following physical properties:
Obtained. Melting point: 125℃ (recrystallized from benzene) NMR: τ(CDCI₃) 8.98 (6H, s), 6.90−7.60
(6H, m), 6.18 (3H, s), 5.38 (1H, m), 2.87
(2H, d, J=8Hz), 2.72 (5H, m) and 2.12
(2H, d, J=8Hz). Example 27 N-[2-(4-carbomethoxyphenyl)eth
Chil]-2-(2-chlorophenyl)-2-hy
Droxyethanamine In the method of Example 25, phenylglyoxa
2-chlorophenylglyoxal instead of alcohol
Using this, the title compound with the following physical properties was obtained. Melting point: 94-95℃ (recrystallized from benzene) NMR: τ(CDCl₃) 6.78−7.54 (8H, m), 6.18
(3H, s), 4.89 (1H, m), 2.28−3.03 (6H, m),
2.11 (2H, d, J = 8Hz). Example 28 N-[2-(4-carbomethoxyphenyl)-
1-Methylethyl]-2-(2-chlorophenylene
)-2-hydroxyethanamine In the method of Example 25, phenylglyoxa
2-chlorophenylglyoxal instead of alcohol
, 2-(4-carbomethoxyphenyl)ethane
2-(4-carbomethoxyphenylene instead of amine)
diasulfate using 1-methylethanamine)
24:76 mixture of teleoitsummer [melting point: 109~
110℃ (hexane)] and pure high melting point isomer
Titled as body [melting point: 115-117℃ (benzene)]
The compound was obtained. NMR: τ(CDCl₃)8.97 (3H, d, J=6Hz),
6.75−7.72 (7H, m), 6.17 (3H, s), 5.01 (1H,
m), 2.34−3.09 (6H, m), 2.11 (2H, d, J=
8Hz). ¹³C NMR(d₆DMSO) ppm.20.24, 19.84;
68.81, 68.43. Example 29 N-[2-(4-carbomethoxyphenyl)-
1-methylethyl]-2-(4-chlorophenylene)
)-2-hydroxyethanamine In the method of Example 25, phenylglyoxa
4-chlorophenylglyoxal instead of alcohol
, 2-(4-carbomethoxyphenyl)ethane
2-(4-carbomethoxyphenylene instead of amine)
The following physical properties were obtained using (l)-1-methylethanamine.
A 1:1 mixture of diastereoisomers of the compound
I got it as a thing. Melting point: 134-135℃ (recrystallized from benzene) NMR: τ(CDCI₃/d₆DMSO) 8.97 (3H, d,
J = 6Hz), 6.81-7.54 (7H, m), 6.16 (3H,
s), 5.40 (1H, m), 2.30−2.92 (6H, m) and
and 2.07 (2H, d, J=8Hz). ¹³C NMR: (d₆DMSO) ppm20.14, 19.91;
71.28, 71.14. Example 30 N-[2-(4-carbomethoxyphenyl)-
1-methylethyl]-2-(4-amino-3,
5-dichlorophenyl)-2-hydroxyetha
Namine In the method of Example 25, phenylglyoxa
4-amino-3,5 dichlorophenylene instead of
Luglioxal, 2-(4-carbomethoxy)
2-(4-cal instead of phenyl)ethanamine
bomethoxyphenyl)-1-methylethanamine
The title compound with the following physical properties is diastereotically
Obtained as a 10:90 mixture of isomers. Melting point: 131-135℃ (reproduced from benzene 1 hexane)
crystal) NMR: τ(d₆DMSO-CDCI₃) 8.95 (3H, d,
J=6Hz), 6.90-7.05 (6H, m), 6.10 (3H,
s), 5.45 (1H, m), 5.45 (2H, b), 2.90 (2H,
s), 2.80 (2H, d, J=8Hz) and 2.10 (2H,
d, J=8Hz). ¹³C NMR: (d₆DMSO) ppm20.17, 19.97. Example 31 N-[2-(4-carbomethoxyphenyl)-
1,1-dimethylethyl)-2-hydroxy-
2-(4-hydroxy-3-hydroxymethyl
Phenyl) ethanamine In the method of Example 33 described later, N-[2-(4
-carbomethoxyphenyl)-1-methylethyl
)-2-(4-benzyloxy-2-chloroph)
enyl)-2-hydroxyethanamine instead of
N-[2-(4-carbomethoxyphenyl)-
1,1-dimethylethyl)-2-(4-benzyl
oxy-3hydroxymethylphenyl)-2-hy
Using droxyethanamine, the following physical properties are shown.
The hydrochloride of the compound was obtained. Melting point: 103-106℃ (recrystallized from ethyl acetate) NMR: τ(d₆DMSO) 8.74 (6H, s), 6.60−
7.10 (6H, m), 6.14 (3H, s), 5.45 (2H, s),
5.00 (1H, m) 3.16 (2H, d, J=8Hz), 2.40−
3.00 (3H, m) and 2.04 (2H, d, J=8Hz). Example 32 N-[2-(4-carbomethoxyphenyl)-
1-methylethyl]-2-hydroxy-2-
(4-methoxyphenyl)ethanamine In the method of Example 25, phenylglyoxa
4-methoxyphenyl glyoxer instead of alcohol
2-(4-carbomethoxyphenyl)ethyl
2-(4-carbomethoxyphene) instead of amine
Using Nyl)-1-methylethanamine, the following
The diastereoisomer mixture of the title compound with
Obtained as a compound. Melting point: 87-89℃ (recrystallized from ether) NMR: τ(CDCl₃)8.98 (3H, d, J=6Hz),
6.80−7.70 (7H, m), 6.28 (3H, s), 6.16 (3H,
s), 5.42 (1H, m) 3.18 (2H, d, J = 8Hz),
2.60−2.98 (4H, m) and 2.08 (2H, d, J=
8Hz). ¹³C NMR(d₆DMSO) ppm.20.06, 19.84;
71.37, 71.29. Example 33 N-[2-(4-carbomethoxyphenyl)-
1-methylethyl]-2-(2-chloro-4-
Hydroxyphenyl)-2-hydroxyethane
amine N-[2-(4-carbomethoxyphenyl)-
1-methylethyl]-2-(4-benzyloxy
-2-chlorophenyl)-2-hydroxyethane
The amine was prepared at 5% para in ethanol at atmospheric pressure and room temperature.
Hydrogenation was carried out in the presence of dium-carbon. remove catalyst
The product was recrystallized from ethyl acetate and had the following physical properties.
diastereoisomer of the hydrochloride salt of the title compound
It was obtained as a 28:72 mixture of mer. Melting point: 194-195℃ NMR: τ(d₆DMSO) 8.79 (3H, d, J=6
Hz), 6.20−7.50 (6H, m), 6.16 (3H, s), 4.67
(1H, m), 2.30−3.30 (5H, m), 2.07 (2H, d,
J=8Hz) and 0.67 (1H, br). Example 34 N-[2-(4-carbomethoxyphenyl)-
1-methylethyl]-2-(3-amino-4-
Hydroxyphenyl-2-hydroxyethanea
min In the method of Example 33, N-[2-(4-ka
Rubomethoxyphenyl)-1-methylethyl]-
2-(4-benzyloxy-2-chlorophenylene)
)-N- instead of -2-hydroxyethanamine
[2-(4-carbomethoxyphenyl)-1-meth
ethyl]-2(4-benzyloxy-3-di
trophenyl)-2-hydroxyethanamine
dihydroc of the title compound with the following physical properties using
lorido as a mixture of diastereoisomers
Obtained. Melting point: 169-171℃ (recrystallized from ethanol) NMR: τ(d₆DMSO) 8.81 (3H, d, J=6
Hz), 6.2-7.3 (7H, m), 5.87 (1H, m), 6.18
(3H, s), 2.2−3.0 (5H, m), 2.08 (2H, d, J
= 8Hz) and 0.32 (2H, br). Example 35 N-[1-(R)-2-(4-carbomethoxy
phenyl)-1-methylethyl]-2-hydro
xy-2-(4-hydroxy-3-hydroxy
methylphenyl)ethaneamine In the method of Example 33, N-[2-(4-ka
Rubomethoxyphenyl)-1-methylethyl]-
2-(4-benzyloxy-2-chlorophenylene)
)-2-hydroxyethaneamine instead of N-
[1-(R)-2-(4-carbomethoxypheni
)-1-methylethyl]-2-hydroxy-2
-(4-benzyloxy-3-hydroxymethy
) Characterization of the following physical properties using phenylethanamine
The title compound was prepared in a 1:1 mixture of diastereoisomers.
Obtained as a compound. Melting point: 86.5-88℃ (recrystallized from benzene) NMR: τ (DMSO), same as the compound of Example 1
one. Example 36 N-[1-(S)-2-(4-carbomethoxy
phenyl)-1-methylethyl]-2-hydro
xy-2-(4-hydroxy-3-hydroxy
methylphenyl)ethaneamine In the method of Example 35, the 1-(R) isomer
Instead, using the 1-(S) isomer, the following physical properties can be measured.
The title compound is a 1:1 mixture of diastereoisomers.
I got it as a thing. Melting point: 88-89° (recrystallized from benzene) NMR: τ (DMSO), same as the compound of Example 1
one. Example 37 N-[2-(4-carbomethoxyphenyl)-
1-methylethyl]-2-(4-hydroxy-
3-Methanesulfonamidophenyl)-2-H
Droxyethanamine In the method of Example 33, N-[2-(4-ka
Rubomethoxyphenyl)-1-methylethyl]-
2-(4-benzyloxy-2-chlorophenylene)
)-N- instead of -2-hydroxyethanamine
[2-(4-carbomethoxyphenyl)-1-meth
ethyl]-2(4-benzyloxy-3-methyl
Tansulfonamidophenyl)-2-hydroxy
Using ethanamine, the title compound with the following physical properties
as a 35:65 mixture of diastereoisomers
Obtained. Melting point: 133-140℃ (recrystallized from ethyl acetate) NMR: τ(d₆DMSO) 9.10 (3H, d, J=6
Hz), 7.00−7.50 (5H, m), 7.08 (3H, s), 6.18
(3H, s), 5.50 (1H, m), 4.16 (4H, b), 2.50
−3.20 (5H, m) and 2.10 (2H, d, J=8
Hz). Example 38 N-[2-(4-carbomethoxyphenyl)-
1-methylethyl]-2-(3-acetamide
-4-hydroxyphenyl)-2-hydroxy
Ethanamine In the method of Example 33, N-[2-(4-ka
Rubomethoxyphenyl)-1-methylethyl)-
2-(4-benzyloxy-2-chlorophenylene)
)-N- instead of -2-hydroxyethanamine
[2-(4-carbomethoxyphenyl)-1-meth
ethyl)-2-(3-acetamido-4-beta)
(2-hydroxyphenyl)-2-hydroxy-etha
The title compound with the following physical properties is prepared using
33:67 diastereoisomers of hydrochloride
Obtained as a mixture. Melting point: 154-156℃ (recrystallized from ethyl acetate) NMR: τ(d₆DMSO) 8.90 (3H, d, J=6
Hz), 7.92 (3H, s), 6.30-7.20 (6H, m), 6.19
(3H, s), 5.10 (1H, m) 3.95 (1H, m), 2.00−
3.20 (7H, m), 1.10 (1H, b), 0.55 (1H, s)
and 0.10 (1H, s). Example 39 N-[2-(4-carbomethoxyphenyl)-
1-methylethyl]-2-(4-hydroxy-
3-methylsulfonylmethylphenyl)-2-
hydroxyethanamine N-[2-(4-carbomethoxyphenyl)-
1-methylethyl]-2-(4-benzyloxy
-3-methylsulfonylmethylphenyl)-2-
Convert hydroxyethanamine (2.3g) to hydrochloride
and ethanol in a Parr hydrogenator.
(200ml), 50psi (3.5Kg/cm²), 2 hours at 25℃
hydrogen in the presence of 10% palladium on charcoal (0.5 g)
Added. The product, excluding the catalyst, has the following physical properties:
mixture of diastereoisomers of the title compound
It was separated as a substance. Melting point: 145-148℃ (from methanol:ether
recrystallization) NMR: τ(d₆DMSO) 8.90 (3H, d, J=6
Hz), 7.2 (3H, s), 6.20−7.10 (6H, m), 6.20
(3H, s), 5.70 (2H.s), 5.00 (1H, m), 3.90
(1H, b), 2.40−3.10 (5H, m), 2.08 (2H, d,
J=8Hz), 0.70 (1H, br), -0.10 (1H, br). Example 40 N-[2-(4-carbomethoxyphenyl)-
1-methylethyl]-2-(4-hydroxy-
3-ureidophenyl)-2-hydroxyetha
Namine In Example 39, N-[2-(4-carbomethane)
toxyphenyl)-1-methylethyl-2-(4
-benzyloxy-3-methylsulfonylmethyl
Substitute for phenyl)-2-hydroxyethanamine
N-benzyl-N-[2-(4-carbomethoxy)
Cyphenyls)-1-methylethyl]-2-(4-
Benzyloxy-3-ureidophenyl)-2-
Using oxoethaneamine, it has the following physical properties.
Diastereoisomers of the hydrochloride salt of the title compound
A mixture was obtained. NMR: τ(CDCI₃)9.00 (3H, d, J=6Hz),
6.70−7.60 (6H, m), 6.30 (3H, s), 5.45 (1H,
m), 4.20−5.00 (2H, b), 3.75 (2H, b), 3.25
(2H, s), 2.65 (2H, d, J=8Hz), 2.00−
2.30 (3H, m) and 1.75 (1H, b). Example 41 N-[2-(4-carbomethoxyphenyl)-
1-methylethyl]-2-hydroxy-2-
(4-hydroxy-3-methylphenyl)etha
Namine N-[2-(4-carbomethoxyphenyl)-
1-methylethyl]-2-hydroxy-2-(4
-Hydroxy-3-hydroxymethylphenyl)
Ethanamine (3.0g), ethanol (200ml)
and chloroform (20 ml), 5% para
In the presence of dium-charcoal (150 mg) at 1 atm and room temperature,
Hydrogenation was continued until hydrogen absorption was completed. catalyst
The product was recrystallized from ethyl acetate and converted to hydrochloride.
32.5:67.5 mixture of diastereoisomers
The title compound (2.0g) was obtained. The physical properties are as below.
Ori. Melting point: 103~107℃ NMR: τ(d₆DMSO) 8.88 (3H, d, J=6
Hz), 7.90 (3H, s), 6.10−7.20 (7H, m), 6.20
(3H, s), 5.20 (1H, m), 2.70−3.30 (3H, m),
2.62 (2H, d, J=8Hz), 2.10 (2H, d, J=8
Hz) and 0.62 (1H, br). Example 42 N-[1-(S)-2-(4-carbomethoxy
phenyl)-1-methylethyl]-2-hydro
xy-2-(4-hydroxy-3-methylphene)
nil) ethanamine In the method of Example 41, N-[2-(4-ka
Rubomethoxyphenyl)-1-methylethyl]-
2-Hydroxy-2-(4-hydroxy-3-H)
instead of droxymethylphenyl)ethanamine
N-[1-(S)-2-(4-carbomethoxif
using the enyl)-1-methylethyl) isomer,
The diastereoisomer of the hydrochloride salt of the title compound
It was obtained as a 1:1 mixture of The physical properties are as follows. Melting point: 110-113℃ (recrystallized from ethyl acetate) NMR: τ(d₆DMSO) is the compound of Example 41
Same. Example 43 N-[2-(4-carbomethoxyphenyl)-
1,1-dimethylethyl]-2-hydroxy-
2-(4-benzyloxy-3-hydroxymeth)
Tylphenyl) ethanamine In the method of Example 25, phenylglyoxa
4-benzyloxy-3-hydroxy instead of
Dimethylphenylglyoxal, 2-(4-
instead of carbomethoxyphenyl) ethanamine
2-(4-carbomethoxyphenyl)-1,1-
Using dimethylethanamine, the following physical properties are
The compound was obtained. NMR: τ(d₆DMSO) 9.06 (6H, s), 7.10−
7.60 (5H, m), 6.20 (3H, s), 5.39 (2H, s),
5.00 (1H, m), 4.88 (2H, s), 3.04 (2H, d, J
= 8Hz), 2.40−3.00 (10H, m) and 2.12 (2H,
d, J=8Hz). Example 44 N-[2-(4-carboxyphenyl)-1-
methylethyl]-2-hydroxy-2-phenylene
Ruethanamine 2-Hydroxy-2-phenylethanamine
(0.68g) and 1-(4-carbobenzyloxyphene)
dipropan-2-one (1.34g)
Benzene (50 ml) for 2 hours in a Horn-Stark apparatus.
Reflux occurred inside. Remove the solvent and add tetrahydrofura
(50ml), benzene (10ml) and water (3ml)
and then sodium borohydride (0.9g)
added. The reaction mixture was left at room temperature overnight to reduce
The solvent was removed under pressure and the residue was separated between water and ether.
Arranged. Separate both layers and add the organic layer to magnesium sulfate.
to remove the solvent and extract the title compound with benzene.
Obtained as ester (1.67g). Etano this
75psi (5.3Kg/cm²), 4 hours at 50℃
Hydrogenated. After evaporating the solvent, the following
The title compound was obtained. Melting point: 180-190℃ (ethyl acetate-methanol)
recrystallization) NMR: τ(TFA-d)8.5 (3H, d, J=7
Hz), 5.85-7.45 (5H, m), 4.72 (1H, blow
), 2.6 (7H, m) and 1.8 (2H, d, J = 8
Hz); τ(d₆DMSO＋D₂O + NaOD) 9.05 (3H,
d, J=7Hz), 6.9-7.7 (5H, m), 2.85 (2H,
d, J=8Hz), 2.7 (5H, s) and 2.17 (2H,
d, J=8Hz). Example 45 N-[2-(4-carbomethoxyphenyl)-
1-Methylethyl]-2-(4-benzyloxy
C-2-chlorophenyl)-2-hydroxye
Tanamine In the method of Example 25, phenylglyoxa
4-benzyloxy-2-chloro instead of
Enylglyoxal was converted into 2-(4-carbometh
2-(4-
Carbomethoxyphenyl)-1-methylethanea
The diastereoisomer of the title compound using
obtained as a mixture of mer. The physical properties are as follows. NMR: τ(CDCI₃)8.92 (3H, d, J=6Hz),
6.72−7.71 (7H, m), 6.13 (3H, s), 5.00 (2H,
s), 2.33−3.23 (12H, m), 2.03 (2H, d, J=
8Hz). Example 46 N-[2-(4-carbomethoxyphenyl)-
1-methylethyl)-2-(4-benzyloxy)
C-3-nitrophenyl)-2-hydroxye
Tanamine In Example 25, phenylglyoxal
4-benzyloxy-3-nitrophenyl instead
Glyoxal, 2-(4-carbomethoxif)
2-(4-carbo instead of enyl) ethanamine
methoxyphenyl)-1-methylethanamine
diastereoisomers of the title compound using
It was obtained as a mixture of. NMR: τ(CDCI₃)8.93 (3H, d, J=6Hz),
6.70−7.80 (7H, m), 6.14 (3H, s), 5.40 (1H,
m), 4.81 (2H, s), 2.30-3.10 (10H, m) and
and 2.02 (2H, d, J=8Hz). Example 47 N-[1-(R)-2-(4-carbomethoxy
phenyl)-1-methylethyl)-2-hydro
xy-2-(4-benzyloxy-3-hydro
oxymethylphenyl)ethaneamine In the method of Example 25, phenylglyoxa
4-benzyloxy-3-hydroxy instead of
Dimethylphenylglyoxal, 2-(4-
instead of carbomethoxyphenyl) ethanamine
1-(R)-2-(4-carbomethoxypheni
)-1-methylethanamine, the title
Compound as a mixture of diastereoisomers
Obtained. NMR: τ(CDCI₃)8.98 (3H, d, J=6Hz),
6.70−7.50 (7H, m), 6.17 (3H, s), 5.43 (1H,
m), 5.31 (2H, s), 4.96 (2H, s), 7.16 (2H,
d, J=8Hz), 2.45−3.00 (10H, m) and
2.07 (2H, d, J = 8Hz). Example 48 N-[1-(S)-2-(4-carbomethoxy
phenyl)-1-methylethyl)-2-hydro
xy-2-(4-benzyloxy-3-hydro
oxymethylphenyl)ethaneamine In the method of Example 47, the 1-(R) isomer
Alternatively, the 1-(S) isomer can be used to prepare the title compound.
Obtained. NMR: τ(CDCl₃) is the same as the compound of Example 47.
one. Example 49 N-[2-(4-carbomethoxyphenyl)-
1-Methylethyl]-2-(4-benzyloxy
C-3-methylsulfonylmethylphenyl)-
2-hydroxyethanamine In the method of Example 25, phenylglyoxa
4-benzyloxy-3-methyls instead of
sulfonylmethylphenylglyoxal, 2-
(4-carbomethoxyphenyl)ethanamine
2-(4-carbomethoxyphenyl)-1 instead
-Distillation of the title compound using methylethanamine
Obtained as a mixture of astereoisomers. NMR: τ(CDCI₃)8.96 (3H, d, J=6Hz),
7.40 (3H, s), 6.90−7.60 (5H, m), 6.52 (2H,
br), 6.20 (3H, s), 5.69 (2H, s), 5.35 (1H,
m), 4.59 (2H, s), 2.40−3.20 (10H, m) and
and 2.07 (2H, d, J = 8Hz). Example 50 N-[2-(4-carbomethoxyphenyl)-
1-Methylethyl]-2-(4-benzyloxy
C-3-methanesulfonamidophenyl)-2
-Hydroxyethanamine In the method of Example 25, phenylglyoxa
4-benzyloxy-3-methane instead of
sulfonamidophenylglyoxal, 2-
(4-carbomethoxyphenyl)ethanamine
2-(4-carbomethoxyphenyl)-1 instead
-Prepare the title compound using methylethanamine
Obtained as a mixture of diastereoisomers. NMR: τ(CDCI₃)8.98 (3H, d, J=6Hz),
7.20 (3H, s), 6.90-7.50 (5H, m), 6.20 (3H,
s), 6.00 (2H, b), 5.4 (1H, m), 4.96 (2H,
s), 2.50−3.10 (10H, m) and 2.15 (2H, d,
J=8Hz). Example 51 N-[2-(4-carbomethoxyphenyl)-
1-methylethyl]-2-(3-acetamide
-4-benzyloxyphenyl)-2-hydro
xyethaneamine In the method of Example 25, phenylglyoxa
3-acetamido-4-benzyl instead of
Xyphenylglyoxal, 2-(4-cal)
2- instead of bomethoxyphenyl) ethanamine
(4-carbomethoxyphenyl)-1-methylethyl
The title compound was diasterinized using tanamine.
Obtained as a mixture of oisomers. NMR: τ(CDCl₃)8.98 (3H, d, J=6Hz),
7.94 (3H, s), 7.20 (6H, m), 6.20 (3H, s),
5.40 (1H, m), 4.95 (2H, s), 2.00−2.75 (11H,
m) and 1.70 (1H, b). Example 52 N-[2-(4-carbomethoxyphenyl)-
1-Methylethyl]-2-(3,5-dibendi
(2-hydroxyphenyl)-2-hydroxyethanea
min In the method of Example 25, phenylglyoxa
3,5 dibenzyloxyphenyl group instead of
Lioxal was converted into 2-(4-carbomethoxyphene).
2-(4-carbome instead of nil) ethanamine
using toxyphenyl)-1-methylethanamine
and labeled as a mixture of diastereoisomers.
The title compound was obtained. NMR: τ(CDCl₃)8.95 (3H, d, J=6Hz),
6.90−7.60 (6H, m), 6.18 (3H, s), 5.02 (4H,
s), 3.20−3.60 (3H, m), 2.71 (2H, d, J=
8Hz), 2.40-2.70 (10H, m) and 2.02 (2H,
d, J=8Hz). Example 53 N-[2-(4-carbomethoxyphenyl)-
1-methylethyl]-2-(3,5-dihydro
xyphenyl)-2-hydroxyethanamine In the method of Example 41, N-[2-(4-ka
Rubomethoxyphenyl)-1-methylethyl]-
2-Hydroxy-2-(4-hydroxy-3-H)
instead of droxymethylphenyl)ethanamine
N-[2-(4-carbomethoxyphenyl)-1
-Methylethyl]-2-(3,5-dibenzyl)
xyphenyl)-2-hydroxyethanamine
Using a 33:67 mixture of diastereoisomers
The hydrochloride salt of the title compound was obtained. The physical properties are as follows
Street. Melting point: 118-120℃ (recrystallized from ethyl acetate) NMR: τ(d₆DMSO) 8.90 (3H, d, J=6
Hz), 6.80−7.70 (7H, m), 6.16 (3H, s), 5.48
(1H, m), 3.60−3.90 (3H, m), 2.62 (2H, d,
J=8Hz) and 2.04 (2H, d, J=8Hz). Example 54 N-[2-(3,4-dicarbomethoxyphenyl)
)-1-methylethyl]-2-hydroxy-
2-(4-hydroxy-3-hydroxymethyl
Phenyl) ethanamine In the method of Example 1, 1-(4-carbomethane)
1 instead of propan-2-one (toxyphenyl)
-(3,4-dicarbomethoxyphenyl)propyl
The title compound was diasterinized using ion-2-one.
Obtained as a 37:63 mixture of rheoisomers. Melting point: 124-129℃ (recrystallized from benzene) NMR: τ(d₆DMSO) 9.1 (3H, d, J=7
Hz), 7.0−7.7 (5H, m), 6.3 (6H, s), 5.5 (2H,
s+1H, t), 4.5-5.8 (4H, /broad) and
and 2.2-3.5 (6H, m). Example 55 N-[2-(4-carbomethoxyphenyl)-
1-methylethyl]-2-hydroxy-2-
(4-hydroxy-3-hydroxymethylphene
nil) ethanamine 1-(4-carbomethoxyphenyl)propane
-2-one (70g) and 2-hydroxy-2-(4
-Hydroxy-3-hydroxymethylphenyl)
Ethanol containing ethanamine (66.7g)
(1750cm³) The solution was stirred at reflux for 4 hours.
Cool the solution and add 10% palladium on charcoal.
87L) (20g) of ethanol (50
cm³) and the resulting mixture
90psi (6.3Kg/cm³), hydrogenated at 50-55℃ for 18 hours.
Ta. The mixture is called Claraid bed.
, and remove the residue with ethanol (approximately 500cm³) and wash with
The liquid was evaporated under reduced pressure to obtain a viscous gum. child
of hot ethyl acetate (100cm²) dissolved in
Then decant to remove a small amount of brown oily residue.
Ta. When this is left still, a white solid crystallizes, and this
Separately, add diethyl ether (approx. 100cm³) wash with
Dry to give 56.3 g (43%) of the title compound (melting point: 139~
141℃,¹³C NMR shows that this compound
It shows that it is a 7:3 mixture of isomers.
obtained). Further, the liquid is allowed to stand and crystallizes twice.
A total yield of 84.9g (64.7%) was obtained. Repeat this experiment and extend the reaction time to 24 hours.
However, there was no significant change in yield. one more
In the follow-up test, the product was obtained three times as follows, and the product was small.
The reaction yield was 72g (55%). That is, the first
Time: 44g (34%), melting point 139-141℃; 2nd time: 16g
(12%), melting point 118-120℃; 3rd time: 12g (9%),
The melting point was 88-90°C. In some experiments,
600~700cm of liquid³2nd by concentrating up to
and/or a third product was obtained. that gum
When ethyl acetate is added to the product, the product crystallizes.
Ta. In a follow-up test, the initially obtained gum-like substance was
diethyl ether before recrystallization from ethyl acetate
It was tritiated with. Example 56 N-[2-(4-carbomethoxyphenyl)-
1-methylethyl]-2-hydroxy-2-
(4-hydroxy-3-hydroxymethylphene
diastereoisomers with high melting points of
isomer Sample of the title compound produced by the method of Example 55
(36g, melting point: 133-144℃)
Mix and boil ethyl acetate (1400cm³) dissolved in charcoal
(1 g) and heated. The liquid at 45-50℃
While stirring, extract the pure diastereoisomer.
(ratio: 95:5, 2g) and then
Stirring was continued for 3 hours, during which time a white solid crystallized.
Ta. Collect the solid and diethyl ether (approximately 100cm³)
Wash and dry to obtain 26g of the title compound (including seeds).
A recovery rate of 72%, melting point: 148°C) was obtained. glc cyril
Chemical analysis reveals that the product is a diastereoisomer.
It was found to be a 98:2 mixture of mer. Example 57 N-[2-(4-carbomethoxyphenyl)-
1-methylethyl]-2-hydroxy-2-ph
enylethanamine 2-Hydroxy-2-phenylethanamine
(3.6g) and 1-(4-carbomethoxyphenyl)
- Etha containing propane-2-one (5.0g)
Nord (200ml) was heated under reflux for 1 hour. So
solution in the presence of 10% palladium on charcoal (2.0 g)
Below, in the Pal hydrogenator, 60psi (4.2Kg/cm²)Water of
Hydrogenation was carried out at 60° C. for 6 hours at bare pressure. Remove the catalyst and dissolve
The solvent was evaporated and the title compound was diastereoisomerized.
Obtained as a 1:1 mixture of somers (7.5 g). Example 58 N-[2-(4-carbomethoxyphenyl)-
1-methylethyl]-2-hydroxy-2-ph
Separation of diastereomers of enylethanamine The oil of Example 57 was dissolved in methanol (7.5 ml).
It was taken and left to stand at 4°C for 16 hours. collected crystals
(2.0g, melting point 124-124.5℃) is¹³By C NMR
It is composed of an 8:92 mixture of diastereoisomers.
I found out that it was done. Furthermore, ether is added to the mother liquor for a second production.
A product (1.5 g, melting point: 115-120°C) was obtained. ¹³C NMRppm(d₆DMSO): 20.12, 42.85,
51.85, 53.81, 55.03, 71.90, 125.87, 126.67,
127.83, 129.00, 129.54, 144.56, 145.60, 166.21. Evaporate the mother liquor to obtain an oil, add hexane (75 ml) or
Colorless crystals (0.25 g, melting point: 83-84
°C) was obtained. This crystal is¹³By C NMR
From an 86.5:13.5 mixture of diastereoisomers
was shown to be configured. ¹³C NMRppm(d₆DMSO): 19.90, 42.87,
51.84, 53.64, 54.86, 71.73, 125.86, 126.69,
127.82, 129.00, 129.53, 144.54, 145.59, 166.20. Example 59 Composition (a) Two-part hard gelatinka mixed with the following ingredients:
I was able to fill the container. Active ingredient 20mg Lactose 200mg This formulation is suitable for oral administration to humans.
Ru. (b) Mix the following ingredients and place in a hard gelatin capsule.
I was able to fill it. Compound of Example 21 (High melting point) 20mg Lactose 200mg This formulation is suitable for oral administration to humans.
Ru. Reference example 1 1-(4-carbomethoxyphenyl)propane
-2-on Sodium metabisulfite
water (300ml) containing (131g)
, 1-(4-carbomethoxyphenyl) propane
Meth containing 2-one oxime (37.5g)
(200 ml) and the mixture was kept for 6 hours.
It refluxed. Cool the reaction mixture and add concentrated hydrochloric acid (100ml)
was added and the mixture was extracted with chloroform.
The form extracts were combined and washed with water, then hydrogen carbonate.
Washed with sodium solution. chloroform layer with sulfuric acid
Dry with magnesium and evaporate to give the title compound as an oil.
(boiling point 126-129℃/0.7mm) was obtained, and this was left to stand.
crystallized. (Melting point 40-47℃) NMR: τ(CDCl₃) 7.88 (3H, s), 6.28 (2H,
s), 6.14 (3H, s), 2.77 (2H, d, J=8Hz),
2.04 (2H, d, J=8Hz). Reference example 2 1-(3-carbomethoxyphenyl)propane
-2-on 1-(4-carbomethoxyphenyl)-2-di
Tropropylene (32.94g) and iron powder
(32.94g) suspension in methanol containing
Add concentrated hydrochloric acid (207 ml) to this suspension while refluxing.
was added dropwise over 1 hour. Add the solution for another hour
Reflux for a while, cool, add water (500ml) and add methanol.
was evaporated. Extract the residue with ether (3 times)
The combined ether layers were washed with water (3 times) and then soaked with charcoal.
Washed three times with sodium hydroxide solution. ether layer
was dried over magnesium sulfate and evaporated to form the title compound.
19.1 g of a compound (boiling point 130-140°C/2mm) was obtained. NMR: τ(CDCl₃) 7.85 (3H, s), 6.28 (2H,
s), 6.15 (3H, s), 2.7 (2H, m), 1.9−2.3
(2H, m). Reference example 3 1-(4-carbomethoxy-3-hydroxyph)
enyl)propan-2-one 1-(4-carbomethoxy-3-hydroxyph)
using enyl)-2-nitroprop-1-ene
The title compound was prepared in the same manner as described in Reference Example 2.
I got something. NMR: τ(CDCl₃) 7.85 (3H, s), 6.35 (2H,
s), 6.09 (3H, s), 3.28 (1H, dd, J=9Hz,
J = 2Hz), 3.20 (1H, d, J = 2Hz), 2.23 (1H,
d, J = 9Hz) and −0.71 (1H, s, D₂Turn off with O
loss) Reference example 4 1-(3-carbomethoxy-4-hydroxyph)
enyl)propan-2-one 1-(3-carbomethoxy-4-hydroxyph)
using enyl)-2-nitroprop-1-ene
The title compound was prepared in the same manner as described in Reference Example 2.
I got something. NMR: τ(CDCl₃) 7.85 (3H, s), 6.4 (2H,
s), 6.1 (3H, s), 3.1 (1H, d, J=8Hz),
2.7 (1H, dd, J=8Hz, J=2Hz), 2.37 (1H,
d.J=2Hz) and −0.75(1H, s, D₂disappears with O) Reference example 5 1-(4-carbomethoxyphenyl)butane-
2-on 1-(4-carbomethoxyphenyl)-2-di
Those described in Reference Example 2 using trobuta-1-ene
The title compound was obtained in the same manner as described above. NMR: τ(CDCl₃)9.0 (3H, t, J=7Hz),
7.53 (2H, q, J=7Hz), 6.3 (2H, s), 6.15
(3H, s), 3.24 (2H, d, J=8Hz), 2.05 (2H,
d, J=8Hz). Reference example 6 1-(4-carbomethoxy-3-methylphenylene)
) Propane-2-one 1-(4-carbomethoxy-3-methylphenylene)
Reference example using -2-nitroprop-1-ene
The title compound was obtained by the same method as described in 2.
Ta. Boiling point: 130℃/0.2mm NMR: τ(CDCl₃) 7.85 (3H, s), 7.42 (3H,
s), 6.3 (2H, s), 6.15 (3H, s), 2.9 (2H, m)
and 2.05 (1H, d, J=8Hz). Reference example 7 1-(4-carbomethoxy-2-methoxyphene)
propan-2-one 1-(4-carbomethoxy-2-methoxyphene)
Reference using propan-2-one oxime
The title compound was prepared in the same manner as described in Example 1.
(boiling point 156-158°C/0.7mm) was obtained. NMR: τ(CDCl₃) 7.85 (3H, s), 6.25 (2H,
s), 6.13 (3H, s), 6.07 (3H, s), 2.77 (1H,
d, J=8Hz), 2.37 (1H, s) and 2.30 (1H,
d, J=8Hz). Reference example 8 1-(4-carbomethoxy-3-methoxyphene)
propan-2-one 1-(4-carbomethoxy-3-methoxyphene)
Reference using propan-2-one oxime
The title compound was prepared in the same manner as described in Example 1.
(boiling point 160°C/1mm) was obtained. NMR: τ(CDCl₃) 7.88 (3H, s), 6.33 (2H,
s), 6.17 (3H, s+3H, s), 3,20 (1H, dd,
J=8Hz, J=2Hz), 3.20 (1H, d, J=2Hz)
and 2.25 (1H, d, J=8Hz). Reference example 9 1-(3-carbomethoxy-4-methoxyphene)
propan-2-one 1-(3-carbomethoxy-4-hydrophenyl
) Propan-2-one (3.0g), iodomethane
(5.0) g and potassium carbonate (7.0) g.
in acetone, TLC (thin layer chromatogram)
The solution was refluxed until it showed that the emitting substance was gone (~
6 hours). The mixture is cooled and evaporated,
The residue was partitioned between ether and water and the layers were separated. A
The tel layer was dried with magnesium sulfate and evaporated to give the standard
The title compound (3.2g) was obtained. NMR: τ(CDCl₃) 7.84 (3H, s), 6.35 (2H,
s), 6.1 (3H, s), 3.05 (1H, d, J=8Hz),
2.68 (1H, dd, J=8Hz, J=2Hz) and 2.36
(1H, d, J=2Hz). Reference example 10 1-(4-carbomethoxyphenoxy)propa
N-2-ON Methyl 4-hydroxybenzoate (30.4g)
Chloroacetone (18.5g), potassium carbonate (54g)
and potassium iodo (33.3g).
The mixture was refluxed for 4 hours in a ton of water. Cool the reaction mixture;
The solids were filtered and the solvent was evaporated. Remove the residue with water.
After separating both layers, the organic layer is separated into sulfuric acid.
Dried with gnesium. Title compound without solvent
(36g) was obtained. NMR: τ(CDCl₃) 7.75 (3H, s), 6.11 (3H,
s), 5.39 (2H, s), 3.09 (2H, d, J=9Hz)
and 2.0 (2H, d, J=9Hz). Reference example 11 4-acetonylbenzoic acid 1-(4-carboxyphenyl)-2-nitro
Propy-1-ene (61.17g) and iron powder (61.17g)
Reflux dioxane (500 ml) containing a mixture of
Meanwhile, concentrated hydrochloric acid (367 ml) was added dropwise to this solution.
Heating was continued for 1 hour until the addition of the solution
Cool, add water, evaporate the dioxane and remove the residue.
Extract with chloroform and dry with magnesium sulfate
Ta. The solvent was removed to obtain a solid, which was diluted with ethyl acetate.
Recrystallization was performed to obtain 26 g of the title compound. NMR: τ(d₆DMSO) 7.83 (3H, s), 6.14
(2H, s), 2.69 (2H, d, J=9Hz) and 2.05
(2H, d, J=9Hz) Reference example 12 4-acetonylbenzoyl chloride Ben containing 4-acetonylbenzoic acid (3.65g)
Add thionyl chloride (1.45ml) to the
The mixture was refluxed for 1 hour. Benzene evaporates to yellow
The title compound as a colored oil (2.61 g, boiling point 135-140
°C/0.5mm) was obtained. NMR: τ(CDCl₃) 7.78 (3H, s), 6.17 (2H,
s), 2.63 (2H, d, J=9Hz), 1.88 (2H, d,
J=9Hz). Reference example 13 1-(4-carboethoxyphenyl)propane
-2-on 1-(4-carboethoxyphenyl)-2-di
Troprop-1-ene was used, and the solvent was ethanol.
Instead, the labeling method is the same as described in Reference Example 2.
The title compound was obtained. NMR: τ(CDCl₃)8.62 (3H, t, J=7Hz),
7.87 (3H, s), 6.29 (2H, s), 5.64 (2H, q, J
= 7Hz), 2.76 (2H, d, J = 9Hz), 2.0 (2H,
d, J=9Hz). Reference example 14 1-(4-carboisopropoxyphenyl)
Ropan-2-on Isopropanol (30ml) was added to 4-acetonyl bene.
of chloride (2.61g) and the solution
It was left at room temperature for 3 days. Remove the solvent and leave an oily title
The compound was obtained. NMR: τ(CDCl₃)8.66 (3H, d, J=7Hz),
7.88 (3H, s), 6.28 (2H, s), 4.78 (1H, h, J
= 7Hz), 2.80 (2H, d, J = 9Hz) 2.04 (2H,
d, J=9Hz). Reference example 15 1-(4-N-methylcarboxamide phenylene)
) Propane-2-one 4-acetonylbenzoyl chloride (4.05g)
Monomethylamine was passed through the ether solution. melt
The medium was evaporated and the residue was dissolved in chloroform and hydrochloric acid (2N
(determined). Separate both layers and dry the organic layer.
Ta. The solvent was removed to give the title compound (3.51g). NMR: τ(d₆DMSO/CDCl₃) 7.86 (3H, s),
7.15+7.06 (3H, s, s), 6.28 (2H, s), 2.80
(2H, d, J=9Hz), 2.18 (2H, d, J=9Hz)
and 2.83 (1H, broad) Reference example 16 1-(4-pivaloyloxymethyloxycal)
(bonylphenyl)propan-2-one Contains 4-acetonylbenzoic acid (3.56g)
Sodium hydride (0.48g) in acetonitrile
and the solution was refluxed for approximately 30 minutes. Then
Add lolomethylpavalate (3.02g) and mix.
The mixture was refluxed for 22 hours. remove acetonitrile
Partition the residue between ether and water and separate the organic layer.
and washed twice with sodium bicarbonate solution. this
The ether layer was dried with magnesium sulfate and evaporated.
and recrystallized from hexane to obtain the title
The compound was obtained. NMR: τ(CDCl₃) 8.77 (9H, s), 7.82 (3H,
s), 6.25 (2H, s), 4.02 (2H, s), 2.73 (2H,
d, J=9Hz), 1.96 (2H, d, J=9Hz). Reference example 17 1-(4-carbomethoxyphenyl)butane-
3-on Tetra containing ethyl acetoacetate (5.2g)
Add sodium hydride (0.95g) to hydrofuran
Then, the solution was heated for 30 minutes. Methyl 4-bro
Tetrahyde containing momethylbenzoate (9.36g)
Dorofuran was added and the solution was refluxed for 20 hours.
The solvent was removed and the residue was partitioned between ether and water.
The organic layer was dried over magnesium sulfate, evaporated and filtered.
of the intermediate as a mixture of toenol tautomers
β-ketoester (9.4g) was obtained. In addition to this, 5%
Add sodium hydroxide solution (120ml) and at room temperature
Stirred for 4 hours. Extract the aqueous layer with ether to make it acidic
The mixture was refluxed for 1 hour. The solution was cooled to room temperature,
During this time, 1-(4-carboxyphenyl)butane
-3-one crystals were precipitated. This contains sulfuric acid.
The title compound was refluxed with methanol for 15 hours.
(3.26g, boiling point 126-132°C/0.4mm) was obtained. NMR: τ(CDCl₃) 7.9 (3H, s), 6.85-7.45
(4H, m), 6.15 (3H, s), 2.85 (2H, d, J=
9Hz) and 2.1 (2H, d, J=9Hz). Reference example 18 1-(4-carbomethoxyphenyl)pentane
-4-on Methyl 4-(2-promoethyl)benzoate
(E.L. Forman and S.M. Matsuke
Rubine, Journal of American Chemistry
Cal Society, 1940, Vol. 62, p. 1435.
Reference example using a method similar to that described)
The title compound (boiling point:
148-151°C/0.8mm). NMR: τ(CDCl₃)
8.0−8.2 (2H, m), 7.86 (3H, s), 7.1−7.7 (4H,
m), 6.1 (3H, s), 2.7 (2H, d, J=9Hz) and
and 1.95 (2H, d, J=9Hz). Reference example 19 1-(4-carbomethoxy-2-fluorophe
propan-2-one 1-(4-carbomethoxy-2-fluorophe
nitropropylene)-2-nitroprop-1-ene.
The title compound was prepared in the same manner as described in Example 2.
(boiling point 122-128°C/1 mm) was obtained. NMR: τ(CDCl₃) 7.78 (3H, s), 6.2 (2H,
s), 6.1 (3H, s), 2.72 (1H, dd, J=8Hz, J
= 2Hz) and 2.1−2.4 (2H, m). Reference example 20 1-(4-carbomethoxy-2-chloropheni
) Propane-2-one 1-(4-carbomethoxy)propane-2-o
The same method as described in Reference Example 1 was carried out using
The title compound was obtained. NMR: τ(CDCl₃) 7.82 (3H, s), 6.15 (3H,
s+2H, s) and 1.85-2.85 (3H, m) Reference example 21 1-(4-carbomethoxyphenyl)octane
-7-on heptane-1-yn-7-one ethylene-digit
n-butyl-lithium in an ether solution of (5.0 g)
(1 eq.) dropwise at ice-salt temperature under a nitrogen atmosphere.
When it was lowered, it turned dark red. This solution at this temperature
Stir for 40 minutes, then add 4-carbomethoxyben.
added to a solution of dualdehyde (5.3 g) at the same temperature.
A gray precipitate was obtained. Warm this mixture to room temperature
Leave to stand until then add water, separate the layers and evaporate.
The ether layer was dried with magnesium sulfate. solvent
The oil was removed and chromatographed on silica (300g).
Attached to graphie. Elute with ether to obtain 1-
(4-carbomethoxyphenyl)-1-hydroxy
Thioctane-2-yn-7-one ethylene keter
was obtained as a clear oil (5g). NMR: τ(CDCl₃) 8.77 (3H, s), 8.35 (4H,
m), 7.75 (2H, t, J = 7Hz), 6.85 (1H, block
), 6.16 (3H, S+4H, s), 4.52 (1H, s),
2.45 (2H, d, J = 8Hz), 2.0 (2H, d, J = 8
Hz). The above oil was dissolved in ethanol and heated to room temperature and atmospheric pressure.
Below, using 10% peradium on carbon, the theoretical amount of hydrogen
Hydrogenated until absorbed. Passage and steam the mixture.
The residue was diluted with methanol/5N hydrochloric acid at room temperature.
After treatment for 1 hour, the title compound was obtained. NMR: τ(CDCl₃)8.05−9.05 (8H, m), 7.92
(3H, s), 7.61 (2H, t, J=7Hz), 7.36 (2H,
t, J = 7Hz), 6.16 (3H, s), 2.8 (2H, d, J
= 8Hz) and 2.05 (2H, d, J = 8Hz). Reference example 22 1-(4-carbobenzyloxyphenyl)
Ropan-2-on 4-acetonylbenzoyl chloride (3.92g)
and benzyl alcohol (2.16g) in benzene.
The mixture was refluxed for 4 hours and then left at room temperature for 48 hours.
Removal of the solvent gave the title compound. NMR: τ(CDCl₃) 7.9 (3H, s), 6.32 (2H,
s), 4.69 (2H, s), 2.78 (2H, d, J=8Hz),
2.70 (5H, m) and 1.99 (2H, d, J=8Hz). Reference example 23 1-(4-carbomethoxyphenyl)propane
-2-one oxime 1-(4-carbomethoxyphenyl)-2-di
Tet containing troprop-1-ene (31.0g)
Radhydrofuran (900ml), aluminum
(13.5g) and mercuric chloride (6.9g) using a conventional method.
The mixture was stirred with aluminum amalgam. So
Cool the mixture in ice and stir until the reaction is complete.
Continued stirring. Pass the resulting slurry through Celite.
and evaporate the liquid to obtain a cream-colored solid (17.0g).
Obtained. NMR: τ(CDCl₃) 8.27 (3H, s), 6.22 (2H,
s), 6.13 (3H, s), 2.63 (2H, d, J=8Hz)
and 1.95 (2H, d, J=8Hz). Reference example 24 1-(4-carbomethoxy-2-methoxyphene)
propan-2-one oxime 1-(4-carbomethoxy-2-methoxyphene)
Reference using (Ni)-2-nitroprop-1-ene
The title compound was prepared in the same manner as described in Example 23.
Obtained. NMR: τ(CDCl₃) 8.27 (3H, s), 6.22 (2H,
s), 6.11 (3H, s+3H, s), 2.77 (1H, d, J
= 8Hz) 2.45 (1H, s) and 2.37 (1H, d, J
=8Hz). Reference example 25 1-(4-carbomethoxy-3-methoxyphene)
propan-2-one oxime 1-(4-carbomethoxy-3-methoxyphene)
Reference using (Ni)-2-nitroprop-1-ene
The title compound was prepared in the same manner as described in Example 23.
Obtained. NMR: τ(CDCl₃) 8.2 (3H, s) 6.29 (2H,
s), 6.17 (3H, s+3H, s), 3.30 (1H, d, J
= 8Hz), 3.15 (1H, s), 2.29 (1H, d, J = 8
Hz) and 2.29−3.5 (1H, broad). Reference example 26 1-(4-carbomethoxy-2-chloropheni
) Propane-2-one oxime 1-(4-carbomethoxy-2-chloropheni
Reference example using -2-nitroprop-1-ene
The title compound was obtained in the same manner as described in 23.
Ta. NMR: τ(d₆DMSO/CDCl₃) 8.22 (3H, s),
6.10 (3H, s + 2H, s), 1.8−2.8 (3H, m) and
and 0.2−1.2 (1H, broad). Reference example 27 1-(4-carbomethoxyphenyl)-2-di
Tropropylene 4-Carbomethoxybenzaldehyde
(101.8g) and n-butylamine (80.7ml),
Dean Star until the theoretical amount of water has been collected.
The mixture was heated in refluxing benzene (500ml) in a refrigerator.
The benzene was evaporated and the residual oil was dissolved in glacial acetic acid (300
ml) and add nitroethane (108.5ml).
and heat the mixture at 95-105℃ for 1 hour while stirring.
heated for an hour. The product crystallized on cooling.
(87.9g). NMR: τ(CDCl₃) 7.58 (3H, s), 6.11 (3H,
s), 2.55 (2H, d, 8Hz), 1.94 (2H, d, 8Hz)
and 1.97 (1H, s). Reference example 28 1-(3-carbomethoxyphenyl)-2-di
Tropropylene Using 3-carbomethoxybenzaldehyde
The title compound was prepared in the same manner as described in Reference Example 27.
I got something. NMR: τ(CDCl₃) 8.05 (3H, s), 6.08 (3H,
s), 2.25−2.5 (2H, m) and 1.7−2.0 (3H,
s). Reference example 29 1-(3-carbomethoxy-4-hydroxyph)
enyl)-2-nitroprop-1-ene 3-Carbomethoxy-4-hydroxybenza
Same method as described in Reference Example 27 using aldehyde
The title compound was obtained. NMR: τ(d₆DMSO) 7.59 (3H, s), 6.08
(3H, s), 2.94 (1H, d, J=8Hz), 2.29 (1H,
dd, J=8Hz, J=2Hz), 2.09(1H, d, J=
2Hz), 2.0 (1H, s) and 0.8 (1H, broad). Reference example 30 1-(4-carbomethoxy-3-hydroxyph)
enyl)-2-nitroprop-1-ene 4-Carbomethoxy-3-hydroxybenza
Same method as described in Reference Example 27 using aldehyde
The title compound was obtained by method. NMR: τ(CDCl₃) 7.59 (3H, s), 6.02 (3H,
s), 3.07 (1H, d, J=9Hz), 3.00 (1H, s),
2.1 (1H, d, J=9Hz), 2.04 (1H, s) and
-0.02 (1H, s). Reference example 31 1-(4-carbomethoxy-3-methylphenylene)
)-2-nitropropyl-1-ene 4-Carbomethoxy-3-methylbenzalde
Using the same method as described in Reference Example 27 using
The title compound was obtained. NMR: τ(CDCl₃) 7.6 (3H, s), 7.46 (3H,
s), 6.16 (3H, s), 2.5 (1H, d, J=8Hz),
2.46 (1H, s), 2.08 (1H, d, J=8Hz), 1.94
(1H, s). Reference example 32 1-(4-carbomethoxy-2-methoxyphene)
nitropropylene)-2-nitroprop-1-ene 4-Carbomethoxy-2-methoxybenzal
Same method as described in Reference Example 27 using dehyde
The title compound was obtained. NMR: τ(CDCl₃) 7.66 (3H, s), 6.08 (3H,
s), 2.68 (1H, d, J=8Hz), 2.38 (1H, s)
2.29 (1H, d, J=8Hz) and 1.8 (1H, s). Reference example 33 1-(4-carbomethoxy-3-methoxyphene)
nitropropylene)-2-nitroprop-1-ene 4-Carbomethoxy-3-methoxybenzal
Same method as described in Reference Example 27 using dehyde
The title compound was obtained. NMR: τ(CDCl₃) 7.59 (3H, s), 6.2 (3H,
s), 6.14 (3H, s) 2.77 (1H, d, J=8Hz),
2.68 (1H, s), 2.24 (1H, d, J=8Hz) and
1.9 (1H, s). Reference example 34 1-(4-carboethoxyphenyl)-2-di
Tropropylene Reference using 4-carboethoxybenzaldehyde
The title compound was prepared in the same manner as described in Example 27.
I got it. NMR: τ(d₆DMSO) 8.68 (3H, t, J=7
Hz), 7.62 (3H, s), 5.64 (2H, q, J=7Hz),
2.3 (2H, d, J = 9Hz), 1.94 (2H, d, J =
Hz), 1.86 (1H, s). Reference example 35 1-(4-carbomethoxyphenyl)-2-di
trobuta-1-en 4-carbomethoxybenzaldehyde and 1-di
Same method as described in Reference Example 27 using tropropane.
The title compound was obtained by one method. NMR: τ(d₆DMSO) 8.8 (3H, t, J=7
Hz), 8.08 (3H, s), 7.19 (2H, q, J=7Hz),
6.12 (3H, s), 2.38 (2H, d, J=8Hz), 1.97
(2H, d, J=8Hz), 1.97 (1H, s). Reference example 36 1-(4-carboxyphenyl)-2-nitro
but-1-ene 4-carboxybenzaldehyde and 2 equivalents of n
-The method described in Reference Example 27 using butylamine
The title compound was obtained in the same manner. NMR: τ(d₆DMSO) 7.61 (3H, s), 2.42
(2H, d, J=8Hz), 2.02 (2H, d, J=8Hz)
and 1.95 (1H, s). Reference example 37 1-(4-carbomethoxy-2-fluorophe
nitropropylene)-2-nitroprop-1-ene 4-Carbomethoxy-2-fluorobenzal
Same method as described in Reference Example 27 using dehyde
The title compound was obtained. NMR: τ(CDCl₃) 7.61 (3H, s), 6.02 (3H,
s), 2.48 (1H, dd, J=8Hz, J=8Hz), 1.95
−2.2 (2H, m) and 1.85 (1H, s). Reference example 38 1-(4-carbomethoxy-2-chloropheni
)-2-nitroprop-1-ene 4-Carbomethoxy-2-chlorobenzalde
Using the same method as described in Reference Example 27 using
The title compound (melting point: 74-77°C) was obtained. NMR: τ(CDCl₃) 7.65 (3H, s), 6.05 (3H,
s), 1.6-2.7 (4H, m). Reference example 39 4-Carbomethoxy-3-methoxybenzal
dehyde Sodium methoxide (0.24g sodium or
(prepared from ) in methanol (30 ml) containing 2-ni
Add tropropane (1.0g) and let the solution stand for 30 minutes.
It refluxed. 4-Carbomethoxy-3-methoxybe
Methanol containing ndilbromide (2.67g)
was added and the solution was refluxed for 1 hour. methanol
evaporated and the residue was dissolved with 2N sodium hydroxide.
It was divided into loloform. yellow color is no longer extracted
The chloroform layer is further diluted with sodium hydroxide until
Shake with water. It is then dried and evaporated to form the title.
A compound (1.66 g) was obtained. NMR: τ(CDCl₃) 6.1 (3H, s), 6.05 (3H,
s), 2.4−2.6 (2H, m), 2.07 (1H, d, J=8
Hz), -0.05 (1H, s). Reference example 40 4-Carbomethoxy-2-methoxybenzal
dehyde 4-Carbomethoxy-2-methoxybenzilb
Same method as described in Reference Example 39 using Lomid
The title compound was obtained. NMR: τ(CDCl₃) 6.1 (3H, s), 6.04 (3H,
s), 2.0−2.5 (3H, m) and −0.55 (1H, s) Reference example 41 4-Carbomethoxy-2-methylbenzalde
Hido 4-Carbomethoxy-3-methylbenzylpro
using the same method as described in Reference Example 39 using
The title compound was obtained. NMR: τ(CDCl₃) 7.31 (3H, s), 6.04 (3H,
s), 2.15 (1H, d, J=8Hz), 2.15 (1H, s),
1.89 (1H, d, J = 8Hz) and -0.09 (1H,
s). Reference example 42 4-Carbomethoxy-2-fluorobenzal
dehyde Methyl-2-fluoro-4-methylbenzoate
F. Irabele et al., J.Biol.Chem.1961
The same method as described in 2007, Volume 236, Page 1093
The title compound was obtained by method. NMR: τ(CDCl₃) 6.1 (3H, s), 2.0−2.45
(3H, m) and −0.45 (1H, s) Reference example 43 4-Carbomethoxy-2-chlorobenzalde
Hido 4-Carbomethoxy-2-chlorobenzylpro
using the same method as described in Reference Example 39 using
The title compound was obtained. NMR: τ(CDCl₃) 6.06 (3H, s), 1.80−2.15
(3H, m) and −0.50 (1H, s). Reference example 44 4-Carbomethoxy-3-methoxybenzilb
Romid Tetrachloride with traces of dibenzoyl peroxide
Methyl 2-methoxy-4-methane in carbon (approx. 1)
Tilbenzoate (45.8g), N-bromosque
Cinimide (45.3g) was added. This suspension
Heat under reflux until the microwave color disappears, then
Cool, filter and evaporate the liquid to give the title compound (boiling
136-144°C/7mm) was obtained. NMR: τ(CDCl₃) 6.17 (3H, s), 6.13 (3H,
s), 5.59 (2H, s), 2.9−3.15 (2H, m) and
2.3 (1H, d, J=8Hz). Reference example 45 4-Carbomethoxy-2-methoxybenzylp
Romid Methyl-methoxy-4-methylbenzoade
Using the same method as described in Reference Example 44,
The compound was obtained. NMR: τ(CDCl₃) 6.1 (3H, s), 6.06 (3H,
s), 5.45 (2H, s), 2.2-2.8 (3H, m). Reference example 46 4-Carbomethoxy-3-methylbenzylbro
Mido Methyl 2,4-dimethylbenzoate
(41.36g) with traces of dibenzoyl peroxide.
In a solution of carbon tetrachloride containing oxide,
Mosuccinimide (44.9g) was added. The mixture
Heat under reflux until the orange color of the mixture disappears.
Then cool, filter, and evaporate the liquid.
An oil was obtained. Distill this and get about 16g of distillate
[Boiling point: 98-140℃/0.8-5mm, (starting material)]
Obtained. Then, methylbromide is generated from the residue.
Heat at normal pressure until it disappears, and add the title compound and 4.
- A mixture with methylphthalide was obtained. thermal oil a
The phthalide was removed by adding filtrate and evaporated to the standard.
The title compound was obtained. NMR: τ(CDCl₃) 7.43 (3H, s), 6.21 (3H,
s), 5.65 (2H, s), 2.6−2.93 (2H, m) and
2.18 (1H, d, J=8Hz). Reference example 47 4-Carbomethoxy-α-methylbenzylamide
hydrochloride Methyl 4-acetylbenzoate oxime
(10g) with ethanol (150ml) and chloroform
Oxidized white as a catalyst dissolved in a mixture with (25ml)
Using gold, 75psi (5.3Kg/cm²), hydrogen at 60℃ for 24 hours
Added. Strain the reaction mixture and evaporate the liquid
The residue was recrystallized from ethyl acetate-methanol.
3g of the title compound (yield from the first recrystallization)
I got it. NMR: τ(d₆DMSO) 8.45 (3H, d, J=7
Hz), 6.18 (3H, s) 5.54 (1H, q, J = 7Hz),
2.34 (2H, d, J = 7Hz), 2.05 (2H, d, J = 7
Hz) and 1.18 (3H, s, D₂disappears with O) Reference example 48 1-(s)-(+)-2-(4-carbomethoxy
Cyphenyls)-1-methylethanamine F.F. Blitzke on ethyl esters
and D. M. Lilienfield, Ji.
YEARNAL OF AMERICAN CHEMICAL SOCIETY
Manufactured by the method of Tei, 1943, Vol. 65, p. 2377.
1-(s)-(+)-2-phenyl-1-methy
The title compound was obtained from ruethaneamine. the salt
Recrystallization of the acid salt produces colorless needle-like crystals [Melting point: 210
~212℃, α²⁰ _D+8.9° (5% methanol)] was obtained. Reference example 49 1-(R)-(-)-2-(4-carbomethoxy
Cyphenyls)-1-methylethanamine In the method of Reference Example 48, 1-(S)-(+)
Using 1-(R)-(-) isomer instead of isomer
The title compound with the following physical properties was obtained. Melting point: 210-211℃ (methanol-ethyl acetate)
recrystallization) Specific rotation: α²⁰ _D-8.7° (5% methanol) Reference example 50 2-(4-carbomethoxyphenyl)-1-meth
Tylethanamine Alcohol-free (300ml) and chloroform (25ml)
1-(4-carbomethoxyphenylene) in a mixture with
) propane-2-one-oxime (10.0g),
50psi (3.5Kg/cm²), oxidized at 50℃
No longer absorbs hydrogen in the presence of platinum (250 mg)
Hydrogenated to Removal of catalyst, residue with methanol
Recrystallized as the hydrochloride salt from ethyl acetate/ethyl acetate
(8.5g, melting point: 206-210℃) NMR: τ(d₆DMSO) 8.84 (3H, d, 6Hz),
6.2−7.5 (3H, m), 6.17 (3H, s), 2.59 (2H,
d, J=8Hz), 2.09 (2H, d, J=8Hz) and
and 1.50 (2H, br). Reference example 51 2-(4-carbomethoxyphenyl)ethanea
min In the method of Reference Example 48, 1-(S)-(+)
- instead of 2-phenyl-1-methylethanamine
using 2-phenylethanamine as a hydrochloride.
The title compound was obtained. Melting point: 225-228℃ (recrystallized from methanol) NMR: τ(d₆DMSO) 6.65−7.15 (4H, m),
6.17 (3H, s), 2.65 (2H, d, J=8Hz), 2.13
(2H, d, J=8Hz) and 1.63 (2H, br). Reference example 52 2-(4-carbomethoxyphenyl)-1,1
-dimethylethanamine In the method of Reference Example 48, 1-(S)-(+)
- instead of 2-phenyl-1-methylethanamine
1,1-dimethyl-2-phenylethanamine
The title compound was obtained as a hydrochloride salt. Melting point: 196-198℃ (methanol-ethyl acetate)
recrystallization) NMR: τ(d₆DMSO) 8.74 (6H, s), 6.93
(2H, s), 6.15 (3H, s), 2.56 (2H, d, J=
8Hz), 2.05 (2H, d, J=8Hz), 1.54 (2H,
br）． Reference example 53 N-benzyl-2-(4-carbomethoxyphene)
)-1-methylethanamine 1-(4-carbomethoxyphenyl)propane
-2-one (8.2g) and benzylamine (4.5g)
The water is completely removed using the Dean Stark device.
Heat in refluxing benzene (150 ml) until evaporated.
Ta. Replace the solvent with methanol, then cool.
While stirring, add a small amount of sodium borohydride (5.0g).
Added little by little. The mixture was stirred for 2 hours and evaporated.
and the residue was partitioned between water and ether. dry
Evaporate the organic extract to obtain a yellow oil, which is salted.
Acid salt (melting point: 189-192℃ (methanol-ethyl acetate)
(recrystallized) NMR: τ(CDCl₃)8.90 (3H, d, J=6Hz),
6.90−7.50 (4H, m), 6.25 (2H, s), 6.19 (3H,
s), 2.50−3.00 (7H, m) and 2.15 (2H, d,
J=8Hz). Reference example 54 4-benzyloxy-3-hydroxymethylphenate
enylglyoxal containing selenium dioxide (5.5 g) while stirring at 60°C.
Mixture of water (0.9ml) and dioxane (100ml)
1-(4-benzyloxy-3
-Hydroxymethylphenyl)ethanone (10.4g)
was added little by little. The mixture was refluxed for 4 hours.
The mixture was stirred, strained while still hot, and cooled. solid
The dimer was collected and recrystallized from dioxane (melting point:
180-181°C, 7.7g). NMR: τ(d₆DMSO) 5.13 (1H, s), 4.94
(1H, s), 4.72 (2H, s), 3.42 (1H, d, J=
10Hz), 3.24 (1H, d, J = 10Hz), 2.72 (1H,
m), 2.54 (5H, m), 2.04 (1H, m) and 1.46
(1H, m). Reference example 55 4-benzyloxy-3-methanesulfonamide
dophenylglyoxal In Reference Example 54, 1-(4-benzyloxy
-3-hydroxymethylphenyl)ethanone
1-(4-benzyloxy-3-methanesulfate)
Using honamidophenyl) ethanone, the title
The compound is converted into ethanol hemiacetal (melting point: 125
-128℃, obtained as (recrystallized from ethanol-water)
Ta. NMR: τ(CDCl₃)8.75 (3H, t, J=6Hz),
7.05 (3H, s), 5.90−6.40 (2H, m), 4.90 (1H,
b), 4.80 (2H, s), 4.46 (1H, s), 2.90 (1H,
d, J=8Hz), 2.60 (5H, s), 2.20 (1H, s),
2.09 (1H, dd, J=8Hz, 2Hz) and 1.80 (1H,
d, J=2Hz). Reference example 56 3-acetamido-4-benzyloxypheni
Lugliokizal In the method of Reference Example 54, 1-(4-benzyl
oxy-3-hydroxymethylphenyl)ethano
1-(3-acetamido-4-benzi instead of
The title compound is
hydrate (melting point: 123-128℃, dioxane-ether)
(recrystallized from ether). NMR: τ(d₆DMSO) 7.74 (3H, s), 6.66
(2H, s), 7.88 (2H, s), 1.80−3.10 (7H, m),
1.45 (1H, m) and 1.05 (1H, d, J=2Hz). Reference example 57 4-benzyloxy-3-nitrophenylgly
Oxal 1-(4-benzyloxy-3-nitropheni
)-2-bromoethanone (12.6g) in dimethyl
Dissolve in sulfoxide (40ml) and let stand at room temperature for 3 days.
I placed it. Pour this solution into ice to hydrate the product.
(8.7g). NMR: τ(d₆DMSO) 4.58 (2H, s), 4.33
(1H, s), 2.25−2.65 (6H, m), 2.07 (2H, br)
and 1.30−1.87 (2H, m). Reference example 58 4-Amino-3,5-dichlorophenylglio
Kizar In the method of Reference Example 57, 1-(4-benzyl
Oxy-3-nitrophenyl)-2-bromoeta
1-(4-amino-3,5-dichloro) instead of non-
Lofenyl)-2-bromoethanone was used, and the title
compound of its ethanol hemiacetal (molten
Point: 51-54℃, recrystallized from ethanol-water)
I got it. NMR: τ(d₆DMSO) 8.85 (3H, t, J=6
Hz), 6.00−6.50 (2H, m), 4.62 (1H, d, J=
8Hz), 3.56 (2H, b), 3.05 (1H, d, J = 8Hz)
and 2.12 (2H, s). Reference example 59 3,5-dibenzyloxyphenylglyoxa
rule In the method of Reference Example 54, 1-(4-benzyl
oxy-3-hydroxymethylphenyl)ethano
1-(3,5-dibenzyloxyphene) instead of
the title compound as a hydrate using
I got it. NMR: τ(CDCl₃) 6.40 (2H, s) 5.00 (4H,
s) and 2.40-3.50 (14H, m). Reference example 60 1-(3,4-dicarbomethoxyphenyl)
Ropan-2-on 1-(3,4-dicarbomethoxyphenyl)
Described in Reference Example 1 using Ropan-2-one oxime
The title compound was obtained in the same manner as in . NMR: τ(CDCl₃) 7.84 (3H, s), 6.24 (2H,
s), 6.14 (6H, s), 2.2-2.8 (3H, m). Reference example 61 1-(3,4-dicarbomethoxyphenyl)
Ropan-2-one oxime 1-(3,4-dicarbomethoxyphenyl)-
As described in Reference Example 23 using 2-nitroprop-1-ene.
The title compound was obtained in the same manner as described above. NMR: τ(CDCl₃) 8.22 (3H, s), 6.23 (2H,
s), 6.12 (6H, s), 2.1−2.9 (3H, m) and
0.5−1.5 (1H, broad). Reference example 62 1-(3,4-dicarbomethoxyphenyl)-
2-nitroprop-1-ene 3,4-dicarbomethoxybenzaldehyde
Using the same method as described in Reference Example 27,
The compound was obtained. NMR: τ(CDCl₃) 7.6 (3H, s), 4.1 (6H,
s), 1.5-2.8 (4H, m). Reference example 63 3,4-dicarbomethoxybenzaldehyde 3,4-dicarbomethoxybenzyl bromide
Using the same method as described in Reference Example 39,
The compound was obtained. NMR: τ(CDCl₃) 6.10 (3H, s), 1.7−2.5
(3H, m)-1.1 (1H, s). Reference example 64 3,4-dicarbomethoxybenzyl bromide Reference example using dimethyl-4-methyl phthalate
The title compound was obtained in the same manner as described in 44.
Ta. NMR: τ(CDCl₃) 6.12 (6H, s) 5.53 (2H,
s), 2.1-2.8 (3H, m). Reference example 65 N-benzyl-N-[2-(4-carbomethoxy)
Cyphenyl)-1-methylethyl]-2-(4
-Benzyloxy-3-ureidophenyl)-
2-oxoethaneamine 1-(4-benzyloxy-3-ureidofe
)-2-bromoethanone (3.1g) and N-ben
Zyl-[2-(4-carbomethoxyphenyl)-
1-Methyl]ethanamine (4.85 g) in a refluxing aqueous solution.
Heat in setonitrile (50ml) for 2 hours. this
Dilute the solution with the same volume of ether and filter.
was further diluted with ether (200ml). solution
Wash with water, dry and evaporate to give the title compound.
Ta. Melting point: 140-145℃ (recrystallized from ethyl acetate) NMR: τ(CDCl₃)9.00 (3H, d, J=6Hz),
6.70−7.60 (3H, m), 6.0−6.4 (4H, m), 6.20
(3H, s), 4.90 (2H, s), 6.32 (2H, b), 2.1−
3.3 (17H, m), 1.20 (1H, d, J = 2Hz). Test results (a) Efficacy of compounds (i) Compounds of the present invention and comparative compounds
(salbutamol) with water or potassium.
into a ruboxymethyl cellulose suspension,
This was administered orally to genetically obese mice.
Administered daily for 28 days by oral gavage
did. At the end of that period, the cadaver of the tested mouse
The composition of The results are as follows
It is.

【table】

Table (ii) Hypoglycemic activity Female CFLP mice weighing approximately 25 g were fasted for 24 hours before conducting the test. The compounds under test were administered orally (20 mg and 5 mg/Kg) to each of 8 mice. Blood samples (20 ml) were taken from the tail after 30 minutes to measure blood glucose. Immediately after taking this blood sample, each mouse was given a glucose load (1 g/Kg body weight, subcutaneous administration) and then blood samples were taken from each mouse at 30 minute intervals for 120 minutes. Compounds that significantly (P<0.05) reduced blood glucose compared to water-fed control mice were found to be active at both times. The area under the blood glucose curve over 2 hours after glucose loading was calculated for each compound and compared to the value for control mice. If blood glucose levels were maintained at similar concentrations to fasted, untreated mice, the compound would have resulted in a 100% reduction in the area under the blood glucose curve. A decrease in the glucose curve of more than 100% indicates that the compound maintained blood glucose levels below those found in control fasted mice despite the glucose load. It shows. The results were as follows.

【table】

[Table] (b) Acute toxicity It was found that the single lethal dose of the compound of Example 1 in CFLP mice was 900 mg/Kg, or more than the oral dose. Other compounds of this invention had similarly low toxicity. (c) Bronchodilatory activity The in vivo bronchodilatory efficacy of the compound of Example 1 and salbutamol was compared in anesthetized and artificially respired guinea pigs (Konzetorosler preparation). It was found that the amount of the compound of Example 1 required to prevent the bronchial stenosis caused by 5-hydroxytryptamine was only 1/12 of salbutamol.

Claims (1)

[Claims] 1 Formula (): (In the formula, R ₁ is a hydrogen atom, a fluorine atom, a chlorine atom,
Hydroxy, hydroxymethyl, methyl, methoxy, amino, acetamido, methylsulfonylamide, nitro, benzyloxy, methylsulfonylmethyl or ureido group; R ₂ is hydrogen atom, fluorine atom, chlorine atom, benzyloxy or hydroxy group; R ₃ is hydrogen atom, fluorine atom, chlorine atom, benzyloxy or hydroxy group; Hydrogen or chlorine atom; R ₄ is a carboxylic acid group, its salt, C _1-4 alkyloxycarbonyl group or C _1-4 alkylcarbamoyl group; R ₅
is hydrogen atom, chlorine atom, fluorine atom or methyl,
Methoxy or hydroxy group or carboxylic acid group, salt thereof, C _1-4 alkyloxycarbonyl group or C _1-4 alkyl carbamoyl group; R ₆ is a hydrogen atom, methyl, ethyl or propyl group; R ₇ is a hydrogen atom, methyl , ethyl or propyl group;
is an oxygen atom or one bond; and Y is an alkylene group having up to 6 carbon atoms or one bond) or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, wherein the R ₁ R ₂ R ₃ C ₆ H ₂ group is a phenyl group. 3 R ₁ R ₂ R ₃ C ₆ H ₂ - group is 3,5-dichloro-4-
The compound according to claim 1, which is an aminophenyl group. 4 R ₁ R ₂ R ₃ C ₆ H ₂ -The group is 3-hydroxymethyl-
The compound according to claim 1, which is a 4-hydroxyphenyl group. 5. The compound according to any one of claims 1 to 4, wherein 5C( _R6 ) _R7 is a _CH2 or C( _CH3 ) ₂ group. 5. The compound according to any one of claims 1 to 4, wherein 6C( _R6 ) _R7 is a _CHCH3 group. 7 Y is a group -( _CH2 )n- (wherein, n is 1, 2,
3 or 4) according to any one of claims 1 to 6. 8 Claims 1 to 8 in which R ₅ is a hydrogen atom
A compound according to any one of Item 7. 9. The compound according to any one of claims 1 to 7, wherein _R4 is a methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, or butyloxycarbonyl group. 10. A compound according to any of claims 1 to 9, wherein _R4 is in the para position to the position where the phenyl group is attached to the remainder of the molecule. 11 Formula (): (wherein R ₁₅ is a hydrogen atom or a methyl group; R ₁₆ is a hydrogen atom or a methyl group; and m is 1, 2, or 3), and a pharmaceutically acceptable salt or ester thereof. 1st to 1st
A compound according to any one of Item 0. 12 Formula (): (wherein, R ₁₇ is a hydrogen atom or a methyl group; R ₁₈ is a hydrogen atom or a methyl group; and p is 1, 2, or 3); and a pharmaceutically acceptable salt or ester thereof. A compound according to any one of Items 1 to 11. 13 Formula () or (): Claims 1 to 11 which are a compound represented by the formula [wherein R ₆ is the same as the definition for formula () in claim 1; R ₄ is the same as the above definition] or a pharmaceutically acceptable salt thereof A compound according to any of the paragraphs. 14. The compound according to claim 13, wherein R ₄ is a C _1-4 alkyloxycarbonyl group. 12. The compound according to claim 11, wherein 15C( _R15 ) _R16 is CH( _CH3 ). 13. The compound according to claim 12, wherein 16C( _R17 ) _R18 is CH( _CH3 ). 17. The compound according to claim 13 or 14, wherein 17 CH(R ₆ ) is CH(CH ₃ ). 18 N-[2-(4-carbomethoxyphenyl)-1-methylethyl]-2-hydroxy-2
-(4-hydroxy-3-hydroxymethylphenyl)ethanamine and N-[2-(4-carboethoxyphenyl)-1-methylethyl]-2
-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethanamine and pharmaceutically acceptable acid addition salts of these compounds; N-[3
-(4-carbomethoxyphenyl)-1-methylpropyl]-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethanamine and N-[3-(4-carboethoxyphenyl)- 1-methylpropyl]-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethanamine and pharmaceutically acceptable acid addition salts thereof; -methylethyl]-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethanamine and N-[3-(4
-carboxyphenyl)-1-methylpropyl]
-2-hydroxy-2-(4-hydroxy-3-
Hydroxymethylphenyl)ethanamine; N-
[2-(4-carboxyphenyl)-1-methylethyl]-2-hydroxy-2-phenylethanamine and N-[3-(4-carboxyphenyl)-1-methylpropyl]-2-hydroxy ―
2-Phenylethanamine; N-[2-(4-carbomethoxyphenyl)-1-methylethyl]-
2-Hydroxy-2-phenylethanamine; N
-[3-(4-carbomethoxyphenyl)-1-
methylpropyl]-2-hydroxy-2-phenylethanamine; N-[2-(4-carboethoxyphenyl)-1-methylethyl)-2-hydroxy-2-phenylethanamine and N-[3
-(4-carboethoxyphenyl)-1-methylpropyl]-2-hydroxy-2-phenylethanamine and pharmaceutically acceptable acid addition salts of these compounds. Compounds described in Section. 19 Formula (): (wherein R ₁₅ is a hydrogen atom; R ₁₆ is a hydrogen atom or a methyl group; and m is 1), a pharmaceutically acceptable salt or ester thereof; Compound. 20 N-[2-(4-carboxyphenyl)-
20. The compound according to claim 19, which is 1-methylethyl]-2-hydroxy-2-phenylethanamine, a pharmaceutically acceptable salt or ester thereof. 21. The compound according to claim 19 or 20, wherein the ester is a lower alkyl ester. 22. The compound according to any one of claims 19 to 21, wherein the ester is a methyl ester. 23 N-[2-(4-carbomethoxyphenyl)-1-methylethyl]-2-hydroxy-2
- Phenylethanamine or a pharmaceutically acceptable acid addition salt thereof Claims 19 to 22
A compound according to any of the paragraphs. 24. The compound according to any one of claims 1 to 23, wherein the salt is a hemifumarate. 25. A compound according to claim 1 in the form of a single stereoisomer. 26. A compound according to claim 1, which is in the form of a mixture of stereoisomers. 27. The compound according to claim 1, which is provided as one diastereoisomer having two asymmetric centers and containing no other diastereoisomer. 28 N-[2-(4-carbomethoxyphenyl)-1-methylethyl]-2-hydroxy-2
2. A compound according to claim 1 in the form of a diastereoisomer having the same stereochemistry as the higher melting diastereoisomer of -(4-hydroxy-3-hydroxymethylphenyl)ethanamine. 29 N-[2-(4-carbomethoxyphenyl)-1-methylethyl]-2-hydroxy-2
-(4-Hydroxy-3-hydroxymethylphenyl)ethanamine, the higher melting diastereoisomer or a single stereoisomer derived from this compound, or a pharmaceutically acceptable salt thereof; Compounds described. 30 N-[2-(4-carbomethoxyphenyl)-1-methylethyl]-2-hydroxy-2
- The compound according to claim 1, which is the lower melting point diastereoisomer of phenylethanamine or a single stereoisomer derived from this compound or a pharmaceutically acceptable salt thereof. 31 Formula (): (In the formula, R ₁ is a hydrogen atom, a fluorine atom, a chlorine atom,
Hydroxy, hydroxymethyl, methyl, methoxy, amino, acetamido, methylsulfonylamide, nitro, benzyloxy, methylsulfonylmethyl or ureido group; R ₂ is hydrogen atom, fluorine atom, chlorine atom, benzyloxy or hydroxy group; R ₃ is hydrogen atom, fluorine atom, chlorine atom, benzyloxy or hydroxy group; Hydrogen or chlorine atom; R ₄ is a carboxylic acid group, its salt, C _1-4 alkyloxycarbonyl group or C _1-4 alkylcarbamoyl group; R ₅
is hydrogen atom, chlorine atom, fluorine atom or methyl,
Methoxy or hydroxy group or carboxylic acid group, salt thereof, C _1-4 alkyloxycarbonyl group or C _1-4 alkyl carbamoyl group; R ₆ is a hydrogen atom, methyl, ethyl or propyl group; R ₇ is a hydrogen atom, methyl , ethyl or propyl group;
is an oxygen atom or one bond; and Y is an alkylene group having up to 6 carbon atoms or one bond) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Composition for use. 32 (a) Formula (): [In the formula, Z is a group -N=CR ₆ - or -NH-C
(OH)R ₆ -, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ ,
Y and X are the same as defined for the following formula ()] A compound represented by the following formula () is subjected to a reduction reaction, and then, if desired, an acid addition salt of the compound of the following formula () is formed.Formula (): (In the formula, R ₁ is a hydrogen atom, a fluorine atom, a chlorine atom,
Hydroxy, hydroxymethyl, methyl, methoxy, amino, acetamido, methylsulfonylamide, nitro, benzyloxy, methylsulfonylmethyl or ureido group; R ₂ is hydrogen atom, fluorine atom, chlorine atom, benzyloxy or hydroxy group; R ₃ is hydrogen atom, fluorine atom, chlorine atom, benzyloxy or hydroxy group; Hydrogen or chlorine atom; R ₄ is a carboxylic acid group, its salt, C _1-4 alkyloxycarbonyl group or C _1-4 alkylcarbamoyl group; R ₅
is hydrogen atom, chlorine atom, fluorine atom or methyl,
Methoxy or hydroxy group or carboxylic acid group, salt thereof, C _1-4 alkyloxycarbonyl group or C _1-4 alkyl carbamoyl group; R ₆ is a hydrogen atom, methyl, ethyl or propyl group; R ₇ is a hydrogen atom, methyl , ethyl or propyl group;
is an oxygen atom or one bond; and Y is an alkylene group having up to 6 carbon atoms or one bond) or a method for producing a pharmaceutically acceptable salt thereof. 33 Formula (X): A compound represented by [wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , X and Y are the same as the definitions for the following formula ()] is subjected to a reduction reaction. , then optionally forming an acid addition salt of a compound of formula (): (In the formula, R ₁ is a hydrogen atom, a fluorine atom, a chlorine atom,
Hydroxy, hydroxymethyl, methyl, methoxy, amino, acetamido, methylsulfonylamide, nitro, benzyloxy, methylsulfonylmethyl or ureido group; R ₂ is hydrogen atom, fluorine atom, chlorine atom, benzyloxy or hydroxy group; R ₃ is Hydrogen or chlorine atom; R ₄ is a carboxylic acid group, its salt, C _1-4 alkyloxycarbonyl group or C _1-4 alkylcarbamoyl group; R ₅
is hydrogen atom, chlorine atom, fluorine atom or methyl,
Methoxy or hydroxy group or carboxylic acid group, salt thereof, C _1-4 alkyloxycarbonyl group or C _1-4 alkylcarbamoyl group; R ₆ is a hydrogen atom, methyl, ethyl or propyl group; R ₇ is a hydrogen atom, methyl , ethyl or propyl group;
is an oxygen atom or one bond; and Y is an alkylene group having up to 6 carbon atoms or one bond) or a method for producing a pharmaceutically acceptable salt thereof.