JPS61183264A - Pyrrolidonylbutylbenzene derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R is phenyl, thienyl, furyl pyrrolidinyl or formula II (Y is 1-3C alkyl) or formula III (Z is H, alkyl or arylalkyl)]. EXAMPLE:4, 4-Diphenyl-1-pyrrolidonylbutane. USE:An ameliorant and remedy for symptoms caused by intracephalic organic disorder and pathergasia. PREPARATION:gamma-Phenyl-gamma-butyrolactone is reacted with thiophene, furan or benzene in the presence of an acid to give a compound expressed by formula IV (R<1> is thienyl, furyl or phenyl), which is then reduced and treated with methanesulfonyl chloride, etc., to form a mesylate. The resultant mesylate is then condensed with pyrrolidone in the presence of sodium hydride, etc., to afford the aimed substance.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention is based on the general formula [wherein R is a phenyl group, a chenyl group, a furyl group, a pyrrolidinyl group, or a group (where Y is an alkyl group having 1 to 3 carbon atoms] or a group (where Y represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or an allyl alkyl group)] Regarding derivatives.

More specifically, the present invention relates to a pyrrolidonyl butylbenzene derivative represented by the general formula (1), which is effective for improving and treating symptoms caused by organic disorders and mental dysfunctions in the brain.

Here, "organic disorders in the brain" are symptoms derived from cerebral ischemic disorders such as aftereffects of cerebral infarction, aftereffects of cerebral hemorrhage, aftereffects of cerebral arteriosclerosis, as well as senile dementia, presenile dementia, amnesia, aftereffects of head trauma, Refers to various organic disorders resulting from after-effects of brain surgery. Furthermore, ``Mental dysfunction-1'' refers to chronic illness, depression, neurosis, Pargin's disease, schizophrenia, schizophrenia-like disorder, chorea, and psychosexual dysfunction derived from drugs and alcohol.

[Prior art]

Brain cells maintain an intracellular environment that is completely different from the surrounding environment (extracellular fluid), and live by maintaining this difference.

For this reason, it is necessary to constantly produce and supply energy.

Most of this energy is supported by oxygen and 1g of gas, which is hardly stored in the brain and is constantly supplied from the blood.

If a brain disorder occurs and the supply of oxygen and glucose is cut off, the energy metabolism disorder generally progresses in stages, with cells losing function over time and eventually organically collapsing. and become unable to perform its functions normally. For this reason, the brain blood vessels themselves have a well-developed mechanism to adjust the cerebral blood flow in order to stably supply an energy source to the brain's S and I tissues and to maintain a constant external environment for brain neurons.

By the way, many drugs have been developed to medically treat organic disorders and mental dysfunctions in the brain. For example, 2-(4-methylaminobutoxy)diphenylmethane (see JP-A No. 59-55829) and compounds having a butylamine skeleton (see JP-A No. 1-24276 and JP-A-52-19672) ), and these compounds have been proposed as central nervous system drugs.

However, regarding senile dementia, which has become a serious social problem in recent years, there are 111 unresolved problems due to its various mental function symptoms.

[Problem that the invention seeks to solve]

Therefore, the present inventors aimed to find a compound that is effective in improving and treating symptoms caused by various disorders in the brain caused by iAS, and according to the present invention, this problem can be solved by the general The pyrrolidonyl butylbenzene derivative represented by formula (1) is thought to be closely involved in the improvement and treatment of symptoms caused by the various disorders mentioned above, and has been shown to have an effect on lipid peroxidation and on various brain nerve cells. We succeeded in achieving this goal by discovering that it is extremely effective against oxygen deficient conditions (cerebral anoxia).

[Means for solving problems]

The pyrrolidonyl butylbenzene derivative according to the present invention is represented by the general formula (1), and this pyrrolidonyl butylbenzene derivative has activity against various experimental model animals of cerebral anoxia at low doses, and therefore This compound is a completely new compound that is useful for the oxygen-deficient state of Φ, and also has a lipid peroxidation effect.

The pyrrolidonyl butylbenzene derivative represented by formula (I) above can be synthesized, for example, by the following method.

That is, by treating the known compound γ-phenyl-γ-butyrolactone with thiophene, furan or Hensen in the presence of an acid, a compound represented by the general formula (Ha) (wherein R1 represents a chenyl group, a furyl group or a phenyl group) is obtained. 4-phenylbutyric acid is obtained. As the acid used in the reaction, aluminum chloride, polyphosphoric acid, phosphorus pentoxide, phosphorus oxychloride, or sulfuric acid can be suitably used.

Alternatively, a γ-phenyl-γ-butyI'lactone can be treated with a phenol derivative (Trl) of the formula %formula%) (where Y is as defined above) in the presence of a base. n
b) A 4-phenylbutyric acid derivative represented by (It b) (wherein Y is as defined in "-") is obtained.

Examples of the base used here include sodium alkoxide, potassium alkoxide, thorium hydroxide,
Potassium hydroxide, sulfur hydride, lithium hydride, metallic sodium, etc. can be mentioned.

Furthermore, the phenol derivative (III) and γ-phenyl-γ-butyrolactone were added in the presence of the above-mentioned acid (in the formula, Y
benzoxebine m (as defined above)
1 liter is obtained.

The compounds (na), (Ilb) and (Hc) are reduced to form (■a) and (IVb) (IVa), respectively.
) (rVb) (wherein R1 and Y are as defined above) As the reducing agent used in the above reaction (J general lithium aluminum hydride, sodium borohydride, etc. are suitable.

The 4-phenylbutanol derivative (lVa) and (I
Vb) is methanesulfonyl chloride or l1l as usual
-) treatment with luenesulponyl chloride, respectively;
After binding mesylate or tosylate 1-, it is condensed with pyrrolidone in the presence of sodium hydride, metallic sodium, sodium alkoxide, potassium alkoxide, etc. to obtain the compound of the present invention, which is the compound of the general formula (I a).
and (Ib) (wherein R1 is as defined above) (wherein yti is as defined above) can be obtained.

This condensation reaction is preferably carried out in the presence of dimethyl sulfoxide, dioxane, tetrabi-1'lofuran, dimethoxymethane, dimethylformamide, etc. as a solvent, and the reaction is preferably carried out by heating to, for example, room temperature to 150°C. .

Furthermore, the above-mentioned γ-phenyl-γ-butyrolactone (lc)
is first treated with an alcohol represented by the general formula] (in which R2 represents a lower alkyl group) under acidic conditions to obtain the general formula (V) (in which Y and R2 represent a lower alkyl group).
is defined above). At this time, it is preferable to use hydrogen chloride gas as the acid.

Next, the phenolic hydroxyl group of the compound of formula (V) is treated with a halide represented by the general formula (R3 represents an allyl alkyl group and X represents a halogen atom) in the presence of a base, for example, to obtain a compound of the general formula (V
l) (Vl) (wherein Y, R2 and R3 are as defined in "-"), and this compound (Vl) is reduced with a reducing agent such as lithium aluminum hydride to give the corresponding alcohol, and then the above-mentioned The compound of the present invention, general formula (Ic) (in the formula Y and R3 can be obtained (as defined in section 2).

In the condensation reaction, it is preferable to use dioxane, tetrahydrofuran, dimethoxymethane, dimethylformamide, dimethylsulfate, etc. as a solvent, and the reaction is preferably carried out by heating at room temperature to 150°C.

In the above formula, when R3 is a benzyl group, it is then catalytically reduced in the presence of a catalyst such as palladium carbon, palladium black, platinum, etc. to obtain the compound of general formula (I d) (in the formula , Y is as defined in Section 2). This compound (
I d) can be prepared by treatment with an acylating agent such as acetic anhydride, probionyl chloride, acetyl chloride, butyl chloride or propionic anhydride to form compounds of the general formula (I e) (wherein Y is as defined in 2). , A has 2 or more carbon atoms
(representing an acyl group of 4).

Furthermore, the compound of the present invention represented by the general formula (I f) can be produced, for example, by the following method.

That is, commercially available 4-chlorobutyrophenone was mixed with a catalytic amount of acid (
For example, the ketone is protected with a protecting group such as ethylene glycol in the presence of p-)luenesulfonic acid, boron trifluoride, sulfuric acid, camphorsulfonic acid, and then condensed with a metal salt of pyrrolidone, followed by conventional methods. Deprotection using acid yields 4-pyrrolidonylbutyrophenone represented by formula (■) (■).

Next, this compound (■) and pyrrolidine can be subjected to a reductive amination reaction to obtain the compound (If) of the present invention.

As the reducing agent, it is preferable to use sodium borohydride or 1-lium cyanoborohydride.

〔Example〕

The present invention will be explained below according to examples, but it goes without saying that the technical scope of the present invention is not limited to these examples.

8. Synthesis of 4.4-diphenyl-1-pyrroli-1'nylbutane 4. Add 1.5 equivalents of triethylamine methanesulfonyl chloride to the methylene chloride volume of 4-diphenylbutanol and stir at room temperature for 2 hours. did. Wash the reaction solution with water and dry the methylene chloride layer? Agriculture was reduced.

The resulting residue was purified by silica gel column chromatography to obtain 4,4-diphenylbutanol mesylate in a yield of 98%.

On the other hand, pyrrolidone to dioxane? After dissolving and adding 1.1 equivalents of hydrogenated Triu-J, and heating under reflux for 1 hour,
The mixture was cooled to room temperature to obtain the thorium salt of pylori-one.

Add 4 of -1- to this pyrrolidone paste monotrium salt solution,
Mesylate of 4-diphenylbutanol to dimethylsulleboxy F? The dissolved solution was strained and heated under reflux for 1 hour.

After filtering off insoluble materials, the filtrate was concentrated, water was added to the residue, and the mixture was extracted with ether. After washing the ether layer with water, it was concentrated and purified using silica gel column chromatography Goo 7F.
The title compound was obtained in 70% yield.

The properties of the obtained compound were as follows.

Properties: Colorless oil IR spectrum (film, cm-'): ]
6'7 ONMR spectrum (Cl]Cff 3.δI
、． ,lll):1, 38-1. 5 8
(m, 211).

1, 84-2. 1 1 (m, 4 IIL2,
2 5 ~2. 4 5 (t, 211, J=7.
611z).

3, 1 2-3.4 0 (m, 4tl).

3, 9 0 (t, l It, J= 8. Of
iz).

7, 0 6 ~1. 40 (m, 10il)
.

High-resolution mass spectrum: Calculated value as C201123NO: 293.1180 Actual value: 2 9 3. 1 7 8 5 Synthesis of 4-(,l'-methoxy)phenyloxy-4-phenyl-1-pyrrolidonylbutane 4-<4'-methoxy)phenyloxy-4-phenyl-1-butanol The mesylate form of i(4'-methoxy)phenyloxy-4-phenyl-1-butanol was prepared in the same manner as in Example 1.

The obtained mesylate was reacted with the 1-lium salt of pyridone in the same manner as in Example 1 to obtain the title compound in a yield of 92%.

Properties of the obtained compound! It was as follows.

Properties: Colorless, fade-like substance IR spectrum (film, cm-'): I
675 NMR spectrum (CDC 7!, δppm
)'1, 55-1. 8 7 (m, 211).

1, 87-2. 0 5 (m, 4 II).

2, 28-2. 4 4 (t, 2 lL.I=
8. 4 112).

3, 20-3. 4 3 (m. 4 II), 3
．． 6 9 (s, 311).

5, 0 4 (cld, 1 11, J・4.0.
8. Ollz).

6, 66-6. 8 4 (m. 4 II).

7, 17-7. 3 9 (m. 5 If) High resolution mass spectrum: Calculated value as C 2 1 II□, N03: 3 3 9. Synthesis of 4-phenyl-4-thiophen-2-yl-1-pyrroli-1-nylbutane 4-phenyl-4-thiophene- Using 2-yl-butanol, the mesylate was prepared in the same manner as in Example 1, and then reacted with the ditrium salt of pyrroline to obtain the title compound in a yield of 82%.

The properties of the obtained compound were as follows.

Properties: Colorless oily substance R spectrum (film, cm-'): 167
ONMR spec (/l/(CDCe 3. δppm
): 1,35-1.70 (m, 211).

1,85-2.20 (m, 411).

2.28-2.46 (t,, 21f,, I=8.
711z).

3, 18-3.40 (m, 411).

4, + 4 (t, I II, J=8.411z
).

6.78-7.00 (m, 211).

7.10-7.40 (m, 6 II).

Mass spectrum (m/z)': 299 (M'),
Synthesis of 4-phenyl-1-pylicin-1-ylbukun 3 equivalents of ethylene glycol and a catalytic amount in a Hensen's solution of 4-chlorobutyrophenone of p-toluenesulfonic acid, Dean
The mixture was heated to reflux for 3 hours in an azeotropic dehydrator in a reactor equipped with a stark lamp. After cooling the reaction solution, it was washed with water, further washed with an aqueous sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate. After filtering and concentrating the -.concentration layer, the compound 4-chlorobutyrophenone-ethylene acecool was obtained in a yield of 97%.

On the other hand, 700 ■ pyrrolidone (8.2 mmol) in tetrahydrofuran? 1.1 feet per day (9.3 mmol)
After adding thorium hydride and refluxing for 1 hour, the mixture was cooled to room temperature to obtain a thorium salt of pyrrolidone.

Is this pyrrolidone nozuthorium? Yong? 1.24g at night (
A mixed solution of 4-chlorobutyrophenone/ethylene acecool (1:1) of tetrahydrofuran/dimethylsulfoxyl (5.5 mmol) was added, and the mixture was heated under reflux for 3 hours. The reaction solution was poured into ice water, extracted with ether, and condensed to give 1.43 g (yield 95%) of 4- (]-
Pipyrrolidonylbutyrophenone ethylene acetal was obtained.

6.38 g (23,'2 mmol) of this 4-(1-pyrrolidonyl)butyrophenone ethylene acecool was added to 100 ml! 00 m7! of 5% hydrochloric acid dissolved in lofuran and cooled with water was added and stirred at room temperature for 5 hours. The reaction solution was diluted with water and extracted with ethyl acetate.

The extract was washed with water, dried over anhydrous magnesium sulfate, and the resulting residue was subjected to silica gel column chromatography to obtain 4.03 g of 4-4-pyrrolidonyl)butyrophenone.
(yield 75%).

Next, 1.4 g (19.7 mmol) of pyrrolidine]
Omj! to methanol? It was dissolved, and a 4N hydrogen chloride/methanol solution of 164 mβ was added. This mixture? Yong? 10 m7 of 760 nv (3.3 mmol) of 4-pyrrolido'nylbuty cophenone at night! of sodium cyanoborohydride dissolved in methanol were added. After stirring at room temperature for 2 days, the reaction solution was poured into a cooled 5% aqueous solution of sodium hydroxide, and extracted with ether.

The ether layer was dried over anhydrous magnesium sulfate, concentrated,
The resulting residue was purified by silica gel column chromatography to obtain the title compound 520.mu. (yield 55%).

The properties of the obtained compound were as follows.

Properties: Colorless oil JR spectrum (film, CI-'): 16
7ONMR spectrum (CIIICA 3.δp,
. ): 1.10-1.40 (m, 2 II)'.

1.60-2. ] O(m, 6 II).

2, 20-2.70 (m, 611).

3.0-3.40 (m, '511).

7.15-7.50 (m, 5 It).

Mass spectrum (m/z): 286 (M”
)Synthesis of 4-(2'-benzyloxy-5'-methoxy)phenyl-4-phenyl-1-pyrroli-1-nylbutane], 5 equivalents of pyrroly] to di;1-zan? Dissolve and add 1.5 parts of 11 parts hydrogenated 15.
Heat it for 1 hour and let it flow. Add 4-(2-hensyloxy-5-methoxy)phenyl-4-phenyl-1- to this solution.
Dimenal sulfoxy of methane sulfur and methane! Add the solution and leave for 3 hours? I ran AriW.

After concentrating the reaction solution, water was added and extracted with ether.

This ether layer was dried over anhydrous sulfuric acid, filtered, and concentrated. The residue was chromatographed on silica gel column 1 to obtain the title compound in a yield of 97%.

The properties of the obtained compound were as shown below.

Properties: Colorless oil NMR spectrum (CDCβ3.δppIl): 1
．． 40-1.57 (kawa, 2+1).

1.83-2.06 (m, 4 II).

2.25-2.4:3 (m, 2 It).

3.13-3.38 (m, 411), 3.79
(s, 311).

4, 39 (t, I 11.J=7.211z)
.

4, 9 4 (q, 21f,,I-] 0.81
1z).

6.66 (dd, III, J-jO, 0,3,511
z).

6.75~6.88 (m, 211L7, 07~7
．． 4 8 (m, 10ff) IR spectrum 1-(
Film, cm-1): 30 ] 0°29
20, 1675, 1495. 1280°1205,
1040. 730. Synthesis of phenyl-4-phenyl-1-pyrrolidonylbutane 4-(obtained in Example 5) 2-hensyloxy-5-methoxy)phenyl-4-phenyl-1-pyrroli-1-ylbutane and palladium black at a weight ratio of 1/10 were used as a catalyst for catalytic reduction under a hydrogen stream for 3 hours. After separation of 71ε, the residue was subjected to column chromatography on silica gel to obtain the title compound with a yield of 95%.

The properties of the obtained compound were as follows.

Properties: Colorless crystal Melting point = 189-190°C (recrystallization solvent: ethanol)'
N M R schek l-Jl/ (CrlCff 3.δ
ppm)'1, 40 = 1.7 (1(m, 2 I
f).

1.82-2. ] 5 (m, 4 It).

230-2.45 (m, 211).

3.08=3.58 (m, jll), 3.6
9 (s, 311).

4, 42 (t, ] I+,, 1・9.011z).

6.48 (br, s, 1tl).

6,59 (dd, ] ] II,, I-10.8
, 311z).

6, 66　(d,　I　If,,b　3　fiz).

6,75 (d, ] ILJ= I 0.8 ll
z,).

7, 09-7.42 (m, 511).

IR spectrum (KBr, Cm-'): 318
0°2930.1660.1595.1500°145
0,]430.1260,1215°1190.104
0,865,835°800.700 4.4-Diphenylbutylmesylate-1 - The physical properties of 4,4-diphenylbutanol mesylate, which is the intermediate compound of Example 1, are as follows. there were.

Properties: Oily substance IR spectrum (fill J, -, cm-'):
+350,117ONMR spectrum (CDCII 3
．． δpp□): 1,64~1.80 (m, 211)
.

2.1 (1-2, 23 (m, 211), 2.95
(s, 311) 3, 91 (c, 11L, I= 7
．． 51lz).

4, 2] (t, 211., l= 6.411z
).

7.13-7.97 (m, ) (l II).

Mass spectrum (m/z): 304 (M”)
.

20 B (M ” Cll3SO3+1) Connected 4-(4'--methoxy)phenyl-4-phenyl-1
-Synthesis of Butanol 4-(4'-Methoxy)phenyl-4-phenylbutyric acid was dissolved in Te1-Rahi1kawa coflan, excess lithium aluminum hydride was added, and the mixture was stirred at room temperature for 2 hours. The obtained reaction solution was decomposed with a 2N hydroxide solution, and -
The clear liquid No. 12 was dried over anhydrous magnesium sulfate. After concentration,
The resulting residue was subjected to silica gel gel chromatography to obtain the title compound in a yield of 69%.

The 12th J of the obtained compound, j of 1 or less! It was ηri.

Properties: Colorless oil IR spectrum (fill 1.cm-'): 33
5ONlv4R spectrum (CDCff 3.δppm
)'1.54~2. ] 0 (m, 4 II).

3, 62 (t, 211., I-6, 211z),
3.66 (s, 3tl).

5,00 (dr], ] II,, I=8.0,
5.311z).

6.64-6.80 (m, 4 IIL7.15-7
．． 38 (m, 5 It) mass spectrum (m/z)
: 207 (M') Reference-in 1: L Synthesis of 4-(4'-methoxy)phenyl-4-phenylbutyl mesylate I. 4-(4'-methoxy) was synthesized in the same manner as in Example 1. ) The title compound was synthesized from phenyl-4-phenyl-1-butanol and methanesulfonyl chloride.

The properties of the obtained compound were as follows.

Properties: Colorless oily substance IR spectrum (film, (:m''):
1520.122ONMR spectrum (CDCN,
, δppm): 1.83-2.12 (m, 411
), 2.97 (s, 3tl).

3.70 (s, 311), 4.18-4.40
(m, 211).

5, 04 (dd, 111., I-7, 5, 3, 51
1z).

6.66~6.84 (m, 411L7.21~7
．． 41 (m, 511) mass spectrum (m/z)
: 350 (M") 254 (M'-CI
hSO, 11) Preparation [1 Synthesis of 4-phenyl-4-(2-chenyl)-butanol 4-phenyl-4-chenyl acetic acid was reduced in the same manner as in Reference Example 2 to obtain the title compound in a yield of 63%. Obtained.

The properties of the obtained compound were as follows.

Properties: Colorless oil IR spectrum (film, cm-'): 3
35ONMR spectrum (CIIC13, δ114.

): 1.40-1.6 4 (m, 2 II).

1.96-2.24 (m, 211).

3, 57-3.70 (m, 211).

4, 1 4 (t, ] It, J= 7.711z
L6.8 0-1.3 6 (m, 811).

Mass spec I le (m/z): 232 (M')
214 (M+ -○H).

Codfish - Example - 4-phenyl-4-(2-chenyl)-butylmesylem
4-phenyl-4-(2-chenyl) in the same manner as in Synthesis Example 1 of 1.
The title compound was synthesized from butanol and methanesulfonyl chloride 1-' in a yield of 93%.

The properties of the obtained compound were as follows.

Properties: Oily substance IR spectrum (film, cm-'): 136
0.118ON MR spectrum (CDCff 3.
δppm): 1,62~1.85 (m, 211
).

2.01-2.30 (m, 211), 2.96
(s, 311L4, ] 4 (t, 111.
, r-7,711zL6, 80-7.42 (m,
811L mass vector (m/z): 3 ] 0
(M”)2] 4 (M”-C1h
SO, 11) 1 [4-chlorobutylphenone ethylene acetal The title compound was obtained as an intermediate in Example 4, and its physical properties were as follows.

Properties: Oily substance NMR spectrum (CDC7!s, 611111111
): 1,85-1.95 (m, 211).

1.95-2.15 (m, 211).

3.45-3.65 (m, 211).

3.65-3.90 (m, 211).

3,95-4.10 (m, 211).

7.25-7.65 (m, 5 II) Reference λ flame ↑ 4-(1-pyrrolidonyl)butyrophenone/ethylene acecool The title compound is a compound obtained as an intermediate in Example 4, and its physical properties are as follows: It was ri.

Properties of oily substance NMR spectrum (CDC#, δppm): 1
, 45-1.75 (m, 211).

1.8-2.1 (m, 411), 2.2-2.
5 (m, 211).

3.2-3.4 (m, 411), 3.6-3.
9 (m, 211).

3.9-4.2 (m, 211), 7.2-7.6
(m, 511)l□t? Li-fi-4-(1-pyl, 1-ridonyl)butyrophenone The title compound was an intermediate compound obtained in Example 4 in a yield of 75%, and its physical properties were as in J below.

Properties Two oily substances IR spectrum (film, cm-'): 16
81NMR spectrum 1-(CDC7!3.δppm):
1,90-2.15 (m, 411).

2.36 (i, 2 + 1., summer - 7,4 tlz).

3, 01 (t, 211.J=6.911z).

3.30-3.50 (m, 4 If).

7.40~7.65 (m, 311L7, 90~8
．． l O (m, 211) way 1 (inverted 7-medoxy 5-phenyl-2-oxo-2,3,4
Synthesis of ,5-tetrahydro-1-henzuoxibin
The mixture was stirred at room temperature for 5 hours. The reaction solution was poured into ice water, extracted with ether, and the ether layer was washed with a 2N aqueous sodium hydroxide solution and then with water.

After drying and concentrating the ether layer, the title compound was obtained in a yield of 30%.

The obtained crystals could be purified by recrystallization from ethanol. The properties of the obtained compound were as follows.

Melting point: 65.0-67.0°C IR spectrum (Kllr, cm-'): 176
0 High-resolution mass spectrum: Calculation Direct: 26B, 1096 Actual loss II (Direct: 268.] 090 Hiko 11 example above Q- 4-(2'--Hydroxy-5'-methoxy)phenyl-4-phenyl-butyric acid 2.68 g (10 mmol) of 7-medoxy-5-phenyl-2-oxo-2,3,4,5-tetrahydro-1-benzoxepine obtained in Reference Example of Synthesis of Methyl Ester was dissolved in 100 ml of methanol, and chlorinated. 2 at room temperature while blowing hydrogen gas.
Stir for hours. The residue was recrystallized from ethanol to obtain 2.94 g (yield 98%) of the title compound.

The properties of the obtained compound were as follows.

Melting point = 110-113°C NMR spectrum (CrlC7!, δp□): 2.2
1-2.45 (m, 411), 3.67 (s,
311L3.70 (s, 311), 4.29
(m, III).

5, 82 (hr, s, 111L 6.57-6.
79 (m, 311).

7.14-7.45 (m, 5 II) 11L rho, 1-(2'-hensyloxy-5'-methoxy) phenyl-4-phenyl acetic acid methyl ester synthesis 4-(2'-hy)S rhoxy- 5'-Me1hexy)phenyl-4-phenyl acetic acid methyl ester was dissolved in acetone, 1.5 equivalents of Henzylbromi F and 2 equivalents of potassium carbonate were added, and the mixture was heated and stirred overnight.

After filtering the reaction solution, it was concentrated, and the residue was purified by silica gel column chromatography to obtain the standard.
“The above compound was obtained in a yield of 90%.

The properties of the obtained compound were as follows.

Properties: Colorless oil IR spectrum (film, c+++-'): 3020
゜2940.1730, 1590.1580゜1490
．． 1445.1210,1040°725.69O NMR spectrum (CIIC123,6p□); 2.2
0-2.45 (m, 4 It).

3,59 (s, 311L 3.74 (s,
311).

4, 40 (t, III, J=7.01lz).

4, 93 (q, 21LJ = 11.711z).

6.66 (dd, IILJ=] 0.6. 3.
011z).

6.80 (d, ] II, J= 1 0.611
z).

6, 8 4 (d, l II, J=3.0111)
.

7, 1 0 to 7.4 6 (m, ] 011).

1. Synthesis of (2'-hensyloxy-5'-methoxy)phenyl-4-phenyl-1-butanol 4-(2'-benzyloxy-5'-methoxy)phenyl-4-phenylbutyric acid Methyl ester was dissolved in ether, excess lithium aluminum hydride was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was decomposed with a 3N aqueous sodium hydroxide solution. The ether layer was dried over anhydrous magnesium sulfate, concentrated, and the residue was purified by silica gel column chromatography to obtain the title compound in a yield of 95%.

The properties of the obtained compound were as follows.

Properties: Colorless oil IR spectrum (film, Cm-'): 3350°3020.2940.1592, 1495°1450.
1040,725.690 NMR Spec I Le (CDC7!, δp,,): 1,
4 7~], 6 5 (m, 211).

1, 99-2. ], 8 (m, 2 II).

3.56-3.70 (m, 211).

4, 4 3 (t, I It, J= 7.Ol1
z).

4, 96 (q, 211, J= ] 21
1z).

6.67(dd, ]1LJ=IO,2,3,511
z).

6,82 (d, ] II,, I=I O,2f
iz).

6, 84 (d, Ill, J=3.511z).

7.10 to 7.50 (Canada, 1011) Expansion λ Example: Main 4-C2'-hensyloxy-5'-methoxy)phenyl-4-phenyl-1-butanol methanesulfone
1. Synthesis of 4-(2'--hensyloxy-5'-methoxy)phenyl-4-phenyl-1-butanol in methylene chloride? 2 equivalents of triethylamine and 1.2 equivalents of methanesulfonyl chloride were dissolved and stirred at room temperature for 2 hours. After filtration and concentration, the title compound was obtained in a yield of 85%.

The properties of the obtained compound were as follows.

Properties: Colorless oily substance TR spectrum (film, Cm-') = 304
0.

2950, 1590, 1500, 1360.

1215, 11B0, 1050.980.

94'0.750,735,70O NMR spectrum (CIIC Ra.δp-): 1,
63~], 77 (m, 2tl).

2, 0 3 ~ 2. 19 (m, 211).

2, 90 (s. 311), 3.7 5
(s, 311).

4, 1 8 (t. 2+1,, I=6.0112
).

4, 4 2 (t, III, J= 7.211z
).

4, 9 6 (q, 211, J= 1 0.
811zL6, 6 7 (dd, ] III, J
=9. 0, 3.5) 1z).

6, 79-6. 8 8 (m, 2 If).

7, 10-7. 4 3 (m, 1 0il) 41
The toxicity (50% lethal dose, LDSO) of the compound of the present invention is dd
Up and doii for Y-series-STF mice
Determined by n method.

The results showed that L of 110-5 (lomg or more) was administered intraperitoneally.
Ds. The value was shown.

? - Mineral damage m Ifll (1 horse ischemia 6ζ vs. t'a
A group of 6 male ddY mice weighing 22 to 30 g were prepared using H'r 4"p. The test drug was administered intraperitoneally, and the mice turned their heads 30 minutes after administration. Panting appeared after turning their heads. Gasping Time
were measured and compared with a control group given only liquid medium.

Among the test compounds, the compound of Example 1 showed a significant shortening effect at 50 mg/kg.

3. Anti-ha (common ±21-made) LN waves, 1 group of ddY xii mice weighing 22-30 g against Jnu 1 under the decoy.
Ten animals were used. Place the mouse in a desiccator (volume: approximately 1β)
inside the desiccator, suction with a vacuum pump, and vacuum the inside of the desiccator.
It was adjusted to 80mm 1g. The test drug was administered intraperitoneally, and the pressure was reduced 30 minutes after administration. The survival time was defined as the time from the start of decompression to the stop of breathing, and if the animal remained alive even after 15 minutes of Noivoxia challenge, it was calculated as 15 minutes and compared with the vehicle-administered group.

In the test compound, the compounds of Examples 1 and 6 were added at 50 mg/
kg showed a tendency to prolong life.

4-1-hole j4 fill p i B! l+, 7-'1-1y111
Groups of 5 to 9 ddY j# mice weighing 24 to 27 g
I used two. After fasting mice for 16-17 hours, 85 mg
/kg of alloxan was injected into the tail vein. After alloxan administration, mice were given free access to river water-1 Part 24.
After an hour, the test drug was administered intrathecally.

Furthermore, 24 hours later, the mouse was anesthetized with ether, and blood was collected from the abdominal aorta and vena cava.

The amount of lipid peroxide in serum was determined by the method of Yagi et al. (KJagi).

Biochem, Med, + vol. 15, p. 212, 197
6 years ago) and compared with the vehicle-administered group.

Among the test compounds, the compound of Example 1 was 50 mg/kg,
Moreover, the compounds of Examples 2 and 6 are I Omf! /kg suppressed lipid peroxidation.

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) [In the formula, R is a phenyl group, thienyl group, furyl group, pyrrolidinyl group, group ▲ Numerical formula, chemical formula, table, etc. ▼ (Here, Y represents an alkyl group having 1 to 3 carbon atoms) or a group ▲ Numerical formula, chemical formula, table, etc. ▼ (Here, Y is as defined above, Z is a hydrogen atom,
(representing an alkyl group or allyl alkyl group having 1 to 3 carbon atoms).