JPS59141543A - N-(substituted cyclohexyloxyphenyl)-alpha-amino acid compound and antilipemic agent containing said compound - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R<1> is lower alkyl, lower alkoxyl, halogen, etc.; R<2> is H or lower alkyl which may have a substituent group; n is 0, 1 or 2; m is 1 or 2) and a salt thereof. EXAMPLE:2-[4-( 1-Methyl-cis-4-tert-butylcyclohexyloxy )anilino]-3-( 4-methoxyphenyl)propionic acid. USE:Having the increasing action on high-density lipoprotein (HDL) cholesterol, and useful for treatment and prevention of arteriosclerosis. PREPARATION:A compound expressed by formula II is reacted with a compound expressed by formula III in the presence of a strong base, e.g. metallic sodium, to give a compound expressed by formula IV, and the nitro group of the resultant compound expressed by formula IV is reduced to form a compound expressed by formula V. The resultant compound expressed by formula V is then reacted with an alpha-halogeno-alpha-substituted acetic acid derivative expressed by formula VI in the presence of a deacidifying agent, e.g. pyridine, to afford the aimed compound expressed by formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a lipid-lowering agent containing an N-(substituted cyclohexyloxyphenyl)-α-amino acid compound represented by the general formula CI), a salt thereof, and a series of compounds thereof as active ingredients. be.

(In the formula, R1 represents a lower alkyl group, a lower alkoxy group, a halodane atom, a nitro group, or an amino group, R2 represents a water atom or a lower alkyl group which may have a substituent, and n represents 0, 1 or 2. , m means l or 2) In the general formula CI), the lower alkyl group of R1 and R2 is a methyl group, ethyl group, n-globyl group, isobutyl group, n-butyl group, isobutyl group or tert-butyl group. In the group p, the lower alkyl group of R2 may be substituted with a pyridyl group or a phenyl group, and the lower alkoxy group of R1 includes a methoxy group, ethoxy group, n-propoxy group, n-butoxy group, imbutoxy group. or tert-
An ethoxy group and a nologon atom include chlorine, bromine, fluorine, or iodine.

The compound [l] of the present invention can be used with acid salts such as hydrochloric acid and sulfuric acid, and with R2
When is a water atom, metal salts such as sodium, potassium, calcium, and aluminum can be formed.

tert − at the 4-position of the cyclohexane ring of general formula [l]
Since the butyl group and the C-0 bond at the 1st position are in cis or trans coordination, the compound of the present invention exists in the cis or trans form. Moreover, since the compound CI of the present invention has three asymmetric carbon atoms, various optical isomers exist.

Today, arteriosclerosis is closely related to hyperlipidemia due to an increase in lipids such as cholesterol and triglycerides in the blood, and an increase in high-density lipoprotein (HDL) cholesterol is a treatment for arteriosclerosis. It is known to be effective for prevention. Clofibrate, which has been widely used as a lipid-lowering agent, has been unsatisfactory because it exhibits side effects such as liver dysfunction, anorexia, and muscle pain. The present inventors reduced cholesterol and triglycerides in the blood, and
As a result of research to develop a drug that increases DL cholesterol and has fewer side effects, the compound of the present invention [
[2]] was found to exhibit excellent effects, particularly a remarkable effect of increasing HDL cholesterol.

Next, the lipid-lowering effect, acute toxicity, and liver weight-increasing effect of representative compounds of the present invention will be explained. Representative compounds are as follows.

(Left below) Lipid-lowering effect in hyperlipidemic rats Immediately after weaning, male SD rats were treated with 1% cholesterol and 0.
．． Hypercholesterolemia was induced by feeding the mice on a high-cholesterol diet containing 5% cholic acid for 7 days, and during the latter 4 days of feeding on the high-cholesterol diet, the test drug was suspended in a 5% gum arabic aqueous solution. It was orally administered at a rate of kg/day. 18 hours after the final administration, blood was collected from the heart to determine serum total cholesterol and high-density lipoprotein (HDL).
- Cholesterol was measured. To measure total cholesterol, 4-
Aminoantipyrine color method [A11ain, C, C,
et al, : C11n, Chem, r-kei: 4
70 (1974))], and Burstein modified CBurstein+ for HDL-cholesterol measurement.
M, et al: J, Lipid, Res, .
11:583 (1970)] was used.

Results: Table 1 shows the decrease rate of serum total cholesterol and increase rate of human HDL-cholesterol compared to the control.

(Left below) Table 1 (1) Acute toxicity Litchfield-Wilcocknon method (Litchfield-Wilcocknon method)
1eld and Wilcoxon method
), the test was conducted by oral administration using 10 ICR male mice.

Results: No deaths were observed at the 3,000-μm dose for any of Compounds A-D, so the LD5o value was 300.
0mV'kg or more"?'I> fc.

The LD5o value of clofibrate was 1650 μm.

(2) Measurement of increase in liver weight Male 5LCICR mice (5 weeks old), 1 group of 8 mice, were tested at 3001ψ/1? was suspended in a 2% aqueous gum arabic solution and orally administered at a rate of 0.1 m/IQ g for 11 consecutive days. On the day after the final administration, the animals were sacrificed by bleeding from the carotid artery, the liver was removed, and its weight was measured.

Results: The ratio of the liver weight of each group to that of the control group is shown in Table 2.

As shown in Table 2 and above, Compounds A-D had a significantly superior lipid-lowering effect on hypercholesterolemic rats compared to clofibrate, and significantly reduced P1 acute toxicity and weight increase effect. Therefore, the compound of the present invention can be said to be a promising compound as a drug having a lipid-lowering effect.

When the compound of the present invention is used as a lipid-lowering agent, the active ingredient is the daily allowance! l) O, (15 to 3 g is preferably administered in several divided doses, and the use can be adjusted as appropriate depending on the patient's condition and age.

When the lipid-lowering agent of the present invention is administered orally, it can be made into tablets, powders, capsules, granules, oil suspensions, syrups, etc., and when it is administered parenterally, it can be made into injections. These formulations can optionally contain conventional excipients such as calcium carbonate.

Calcium phosphate, cellulose, starch, glucose.

Lactose, carboxymethylcellulose calcium.

It may also contain talc, magnesium stearate, etc.

Example 1 Tablet Compound A 100Tn9 Crystalline Cellulose 40! ng potato starch
30mg carboxymethylcellulose calcium 28■Magnesium stearate
2In9 total 200Tn9 Example 2 Capsule Compound C120 Potato starch 18Tn9 Lactose 40〃l Magnesium stearate 2Tn9 Total 180m9 Example 3 Injection Compound D 20m9 Physiological saline
1om1 The present applicant previously filed a patent application for an N-substituted phenyl-α-amino acid compound having a lipid-lowering effect (Japanese Patent Application No. 56-122477,
No. 6-189092, No. 57-66372, No. 57-
No. 206139).

Furthermore, JP-A No. 57-21353 describes a case where the N-substituted phenyl group is a 4-(cis-p-menthan-8-yloxy) phenyl group as an N-substituted phenyl-α-amino acid compound. . However, the compounds of the present invention are different from these described compounds.

Next, a method for producing the compound of the present invention will be explained.

(In the formula, R1, R2, n and m have the same meanings as above,
X represents a no-logon atom. )1-methyl-4-te
rt-butylcyclohexanol [J, Chem, S
oc, ((ri, P, 1106-1109.1968
] p-fluoronitrobenzene metal sodium.

Hydrogenation) 4-(1-Methyl-4-tart-butylcyclohexyloxy)nitrobenzene is reacted in the presence of a strong base such as IJium or metallic potassium at a temperature ranging from room temperature to the boiling point of the solvent used for 1 to 10 hours. obtain. This compound is subjected to a conventional nitro group reduction method, such as catalytic reduction, to obtain 4-(1-methyl-4-tert-butylcyclohexyloxy)aniline in a high yield. This aniline compound itself also had a strong hypolipidemic effect. Then, the aniline compound was converted into an α-no-logno-α-substituted acetic acid derivative [
(2)] in the presence of a deoxidizing agent such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, silver carbonate, triethylamine, pyridine, etc. at room temperature to the boiling point of the solvent used to obtain the compound of the present invention [ 1) is obtained. The nologon atom of X in compound [■] is preferably bromine. Solvents that can be used in each reaction are water, methanol, ethanol, n-7'lonogol, isoglopanol in-butanol, jet-butanol rsec-butanol.

Methyl acetate, ethyl acetate, acetic acid, tetrahydrofuran,
Dioxane, trimethylformamide, hexamethylphosphoric triamide, pyridine, triethylamine, benzene, toluene, xylene.

Dimethyl sulfoxide and the like can be selected as appropriate in each reaction and used alone or in combination.

If each cis or trans isomer is used in the starting material 1-methyl-4-tert-butylcyclohexanol, the corresponding isomer of the target compound CI) can be obtained. If the above starting material is a cis-trans mixture, it can be separated into the cis- or trans-isomer by column chromatography or fractional crystallization in the next 4-(1-methyl-4-tert-butylcyclohexyloxy)nitrobenzene step. After that, the reaction proceeds to the next step to obtain the corresponding isomers of the target compound [1). When R in the compound [I] of the present invention is a lower alkyl group, the compound [I] in which R2 is a hydrogen atom can be obtained by subjecting it to a conventional hydrolysis method.

The method for producing the compound [1] of the present invention will be explained below with reference to Examples. In addition, a production example of 4,-(1-methyl-cis or hatrans-4-tert-butylcyclohexyloxy)aniline, which is an intermediate raw material, will be described as a reference example.

The silica gel for column chromatography used in the examples and reference examples was Wakodal C-200 [Wako Tsumugi Pharmaceutical ■]
It is.

Reference Example 1 (() 4-(1-Methyl-cis-4-tart-butylcyclohexyloxy)nitrobenzene 1-meflucis-4-tert-7” tylcyclohexanol 22.
OF was dissolved in a mixed solvent of 300M' of benzene and 60D of hexamethylphosphoric triamide, and 5.65 g of sodium hydride (containing 55% in mineral oil) was added thereto.
The mixture was heated under reflux for 1 hour.

Next, 1 p-fluoronitrobenzene was added to this reaction solution.
8.2 g was added and heated under reflux for 2 hours. After cooling, the reaction solution was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the resulting residue was subjected to silica gel column chromatography, and benzene:n
Elution was carried out with a mixed solvent of -hexane (1:4). Fractions containing the target product were collected and the solvent was distilled off to obtain a white powder of 4-
(1-Methyl-cis-4-tert-butylcyclohexyloxy)nitrobenzene 32.8g (87%)li
'c.

Melting point 84-86°C. (Recrystallized from petroleum ether.) NM
R(CDCl2)δppm: 0.85 (9H, s).

1.39 (3H, s).

6.91.8.01 (4H, A2B2q) elemental analysis value (
As C17H25N05) CHN Theoretical value Chi 70.07 8.65 4.81 Experimental value%
70.26 8.68 4.86 (b) 4-(1
-Methyl-cis-4-tert-butylcyclohexyloxy)aniline 4-(1-methyl-cis-4-tert obtained in (a) above)
t-Butylcyclohexyloxy)nitrobenzene 30
．． 0.9 was dissolved in 200 g of ethyl acetate, 3.0 g of 10% palladium on carbon was added, and the mixture was stirred in a hydrogen stream until the theoretical amount of hydrogen was absorbed. After removing the catalyst from F, the furnace liquid was distilled off under reduced pressure to obtain 4-(1-methyl-cis-4-
tert-butylcyclohexyloxy)aniline 25
．． 6. ! i' (95%) was obtained. Melting point 56-58°C. (
Recrystallized from petroleum ether. ) NMR (CDC13) δppm: 0.88 (9H, s
).

1.11 (3H, s).

3.33 (2H+ broad) j6.42,
6.68 (4H, A2B2q) elemental analysis value (C17H2
yNQ) CHN Theoretical value % 78.11 10.41 5.36 Experimental value CH 78.21 10.43 5.37 Reference example 2 4-(1-methyl-trans-4-tert-butylcyclohexyloxy)aniline reference 1-methyl-cis-4-ter in item (a) of Example 1
1-methyl- in place of t-butylcyclohexanol
4-(1-methyl-
Trans-4-tert-butylcyclohexyloxy)nitrobenzene was obtained, and this compound was then subjected to the same reaction and treatment operations as described in section (b) on the same side to give 4-(1-
Methyl-trans-4-tert-butylcyclohexyloxy)aniline was obtained. Melting point 111-113°C. (
Recrystallized from petroleum ether. ) NMR (CDCl2) δppm: 0.85 (9H, s
), 1.23 (3H, s).

3.42 (2H, broad).

6.41.6.69 (A2B2q) Elemental analysis value (as C1, H27No) CHN Theoretical value % 78.11 10.41 5.36 Experimental value % 78.16 10.47 5□29 Using the above two compounds as raw materials The compound of the present invention was produced as follows. This is shown in the examples below.

Example 1 2-(4-(1-Methyl-cis-4-tert-butylcyclohexyloxy)anilino)-3-(4-methoxyphenyl)propionic acid 4-(1-methyl-cis-4
-tert-butylcyclohexyloxy)aniline 5
．． 7.4 g of 2-promo-3-(4-meth)xyphenyl)propionic acid and 5.19 g of sodium carbonate were sequentially added to a methanol solution, and the suspension was heated under reflux for 4 hours.

After cooling, the reaction solution was dissolved in 200 rL of water, and diluted with dilute hydrochloric acid.
It was set as H4. The precipitated crystals were collected in a furnace, then washed with petroleum ether, and then recrystallized from methanol to obtain 2-
6.4 g (76%) of (:4-(1-methyl-cis-4-tert-butylcyclohexyloxy)anilino]-3-(4-methoxyphenyl)propionic acid was obtained. Melting point 115.5-117. 5℃.

IR(KBr)crn, 3290,2960,295
0.1710,1610°50O NMR (DMSO-d6) δppm: 0.6-2.1
(9H, m), 0.85 (9H.

@), 1.02 (3H, s), 2.86 (2H.

d), 3.62 (3H, s), 3.93 (IH.

t), 6. s46.58 (4H, A2B2(1).

6.68, 7.05 (4H, AzB2g) Elemental analysis value (as C27H37NO4) CHN Theoretical value Chi 73,77 8,48 3.19 Experimental value% 73.81 8.36 3.10 Example 2 2-[ 4-(1-Methyl-cis-4-tert-butylcyclohexyloxy)anilino)-3-(4-methylphenyl)f lobionic acid ethyl ester 4-(1-methyl-cis-4-tert-butylcyclohexyloxy) Aniline 5.0g, 2-g.

Mo3-(4-methylphenyl)! 7.8 g of ethyl ropionate and 2.4 g of aqueous sodium carbonate were sequentially added to 50 rL of ethanol, and the suspension was heated under reflux for 30 hours. After cooling, insoluble matter was removed, and the p solution was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted with chloroform. Fractions containing the target product were collected, and the solvent was distilled off to give 2-(4-(1-methyl-cis-4-tert-7''f-lycyclohexyloxy)anilino]-3-(4-methylphenyl). 6.5 g (75%) of f-ropionic acid ether ester were obtained as an oil.

NMR (cvct, )δppm: 0.6-2.2
(9H, m'), 0.89 (9H, s).

1.10. (3H, s), 1.12 (3H, t).

2.27 (3H, s), 3.01 (2H, d).

3.6:3-4.32 (2H, m), 4.03 (2H
.

q), 6.39.6.72(4) (, A2B2q).

6.96 (4H, s) Elemental analysis value (as C29H41NO6) Experimental value%
77.09 9.23 3.18 Example 3 2-(4-(1-Methyl-cis-4-tert-butylcyclohexyloxy)anilino)-3-(4-methylphenyl)globionic acid obtained in Example 2 2-(4-(1-methyl-cis-4-t)
art-butylcyclohexyloxy)anilino)-'
5.0 g of ethyl 3-(4-methylphenyl)gropionate and 1.8 g of sodium hydroxide were dissolved in 50 M of 10% aqueous ethanol and stirred at room temperature for 6 hours. The reaction solution was then concentrated under reduced pressure, and the resulting residue was mixed with 300 IL of water.
When the solution was dissolved in 1 liter of water, brought to -5 with dilute hydrochloric acid, and stirred thoroughly, crystals were precipitated. The precipitated crystals were separated, washed sequentially with water, methanol, and water, and then dried under reduced pressure.
(1-Methyl-cis-4-tert-butylcyclohexyloxy)anilino,]-3-(4-methylphenyl)globionic acid 4.1.9 (87%) was obtained. melting point 12
1.5-122.5°C. (Recrystallized from methanol.)I
R(KBr)crn, 3290, 2960, 2950
．． 2860, 1710, 150ONMR (DMSO-d
6) δppm: 0.6 to 2.1 (9H, m), 0.
87 (9H, s).

1.05 (3H, s), 2.25 (3H, s).

2.97 (2H, d), 4.03 (IH, t).

s, C6,6,71 (4H, A2n2q), 6.92
~7.35 (4H, m) Elemental analysis value (as 27H57NO3°) Example 4 2-[4-(1-methyl-cis-4-tert-fk
cyclohexyloxy)anili/ ) -2-(4-nitrophenyl)acetic acid ethyl ester 4-(1-methyl-
cis-4-tert-butylcyclohexyloxy)aniline5. 6.6 g of OII, 2-promo 2-(4-nitrophenyl)acetic acid ethyl ester and 2.4 g of sodium carbonate were sequentially added to 30 rrLl of ethanol, and the suspension was heated under reflux for 2 hours. After cooling, insoluble matter in the reaction solution was removed, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography using methylene chloride.

Elution was performed with a mixed solution of hexane=1=1. Fractions containing the target product were collected and the solvent was distilled off to obtain 2-[4-(1-methyl-cis-4-tert-butylcyclohexyloxy)anilino]-2-(4-nitrophenyl)acetic acid ethyl ester. 7,3,P (>81%) was obtained as an oil.

NMR (CDC7ρδppm: 0.6-2.1 (9H
, m), 0.88 (9H,s).

1.08 (3H, s), 1.18 (3H, t).

4.10(2)I, q), 4.73-5. 'l 5 (
2H.

rn), 626, 6.62 (4H2A2B2'l).

7.41.7.95 (4H, A2B2q) elemental analysis value (
(as C27H36N205) CHN Theoretical value % 69.21 7.74 5.98 Experimental value CH 69.30 7.69 5.81 Example 5 2-[j-(1-methyl-cis-4-tert-butylcyclohexyloxy )anilino]-2-(4-aminophenyl)acetic acid ethyl ester 2-('
4-(1-Methyl-cis-4-tert-butylcyclohexyloxy)anilino)-2-(4-nitrophenyl)acetic acid ethyl ester 5.0.9 to ethyl acetate 50
0.59 of 10T Yaradium carbon was added, and the mixture was stirred until the theoretical amount of hydrogen was absorbed in the leaf air stream. After removing the catalyst, liquid F was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography and eluted with chloroform. Fractions containing the target product were collected and the solvent was distilled off to give 2-(4-(1-methyl-cis-4-tert-
butylcyclohexyloxy)anilino]-2-(4-
aminophenyl) acetic acid ethyl ester 3.4F (72%
) was obtained as an oil.

NMR (CDCL, ) δppm: 0.7-2.
1 (9H, m), 0.85 (9H, s).

1.04 (3H, s), 1.13 (3H, t).

3.61 (2H, broad), 4.00 (2
H, q).

4.75 (IH, s), 6.16-7.26 (8H.

m) Elemental analysis value (as 27H58N205) CHN Theoretical value% 73.94 8.73 6.39 Experimental value%
73.87 8.66 6.40 Example 6 Sodium 2-[4-(1-methyl-cis-4-tert-butylcyclohexyloxy)anilino]-2-(4-aminophenyl)acetate obtained in Example 5 2-(4-(
1-Methyl-cis-4-tert-butylcyclohexyloxy)anilino-2-(4-aminophenyl)acetic acid ethyl ester 2.011 and sodium hydroxide 0.7
ge50 was dissolved in 40ml of an aqueous timeethanol solution and stirred at 50°C for 6 hours. The methanol was then removed under reduced pressure,
Upon cooling, crystals precipitated. The precipitated crystals were recrystallized from a mixed solvent of water:methanol (7:3) and 2-(4
13 g (65%) of sodium -(1-methyl-cis-4-tert-7" tylcyclohexyloxy]anilino]-2-(4-aminophenyl) acetate was obtained. Melting point 15
2-154℃.

IR (KBr) cm-': 2970.2950.
2870.1600, 1500, 138ONMR(
CD50D) δpp, m: 0.6 to 2.1 (9H, m
), 0.87 (9H, s).

1.03 (3H, s), 4.53 (IH, a).

6.35.6.58 (4H, A2B2q).

6.49.7.12C4H, A2B2q) Elemental analysis value (
As C25H55N2Nao5) CHN Theoretical value % 69.42 7.69 6.48 Experimental value CH 69.41 7.55 6.59 Example 7 2-(4-(1-Methyl-cis-4-tert-glutylcyclohexyloxy ) anilino) -2-(4-rio
o phenyl)acetic acid ethyl ester 4-(1-methyl-
cis-4-tert-butylcyclohexyl)aniline 5.0 &, 2-bromo-2-(4-chlorophenyl)acetate ys, oI! and 2.4 g of leaf sodium carbonate were sequentially added to 50 d of ethanol, and the same operation as in Example 2 was performed to obtain 2-(4-(1-methyl-cis-4-te).
rt-butylcyclohexyloxy)anilino, l-2
-(4-chlorophenyl)acetic acid ethyl ester 7.4F
(84%) I got it. Melting point 86-87°C. (Recrystallized from petroleum ether.) I R (KBr) cm-': 3
340.2960.2940.2920.2850,
1730, 150ONMR (cDctρδppm:
0.7-22 (9H, m), 0.87 (9H, s)
.

1.07 (3H, s), 1.13 (3H, t).

4.10 (2H2 (1), 4.70 (IH, broad
).

4.87 (IH, broad), 6.30, 6.7
0 (4H.

A2B2q), 7.13, 7.33 (4H,
A2B2q) Elemental analysis value (as C27H36C bar 03) CH' N Theoretical value Chi 70.80 7.92 3-06 Experimental value%
70.89 7.87 2.98 Example 8 2-(4-(1-methyl-cis-4-tert-butylcyclohexyloxy)anilino]-2-(4-chlorophenyl)acetic acid 2 obtained in Example 7 -(4-(1-methyl-cis-4-t
ert-butylcyclohexyloxy)anilino':l
-2-(4-chlorophenyl)acetic acid ethyl ester5.
0g was treated in the same manner as in Example 3 to obtain 4.2% of 2-[4-(1-methyl-cis-4-tart-butylcyclohexyloxy)anilino)-2-(4-chlorophenyl)acetic acid.
i (s 9%) is i.

Melting point 173-174°C. (Recrystallized from methanol.)I
R(KBr)m-': 2970 2950, 2870,
1580.150ONMR (DMSO-d6+CDC4
3) δ1) pm: 0.7 22 (9I(, m), 0.8
7 (9H.

s), 1.07 (3H, s), 4.90 (IH, s),
6.40°6.63 (4H, A2B2q), 7.20,
7.43 (4HJA2B-Elemental analysis value (C25H52C
(as tNO3) CHN Theoretical value % 69.83 7.50 3.26 Experimental value % 70.00 7.42 3.19 Example 9 2-[4-(1-Methyl-cis-4-tert-butylcyclohexyloxy) )anilino']-2-(4-chlorophenyl)acetic acid 3-pyridylmethyl ester 2-(4-(1-methyl-cis-4-t) obtained in Example 8
ert-butylcyclohexyloxy)anilino)-2
-(4-chlorophenyl)acetic acid 4.0.9゜3-picolyl chloride Hydrochloric acid group 2.41 and triethylamine 4 hemp were sequentially added to dimethylformamide 40I/Ll, and the mixture was heated and stirred at 95℃ for 1.5 hours. did. After cooling, the reaction solution was poured into a mixed solution of 5 Qm of benzene and 60 rr*l of water, and the benzene layer was separated, washed with water, and dried over anhydrous sodium sulfate. Benzene was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography and eluted with a mixed solvent of chloroform:methanol (30:1).

Fractions containing the target product were collected, and the solvent was distilled off under reduced pressure.
-(:4-(1-methyl-cis-4-tert-butylcyclohexyloxy)anilino]-2-(4-chlorophenyl)acetic acidff3-pyridylmethyl ester 3.79
(77%) was obtained as an oil.

NMR (CDCl2) δppm: 0.6-2-2(9
H,m), 0.88 (9H,s).

1.07 (3H, s), 4.64 (LH, d).

4.93 (IH, d), 5.04 (2H,'s).

6.27, 6.64 (4H, A2B2q), 6.93-
7.46 (6H, m), 8.25-8.49 (
2H, m) Elemental analysis value (as C31H57CtN203) CHN Theoretical value % 71.45 7.16 5.38 Experimental value % 71.52 7.23 5.3] Example 10 2-(4-(1-methyl- ethyl ethyl 4-(1-methyl-cis-4-tart-butylcyclohexyloxy)aniline 5.09,2-bromo -2-
(3,4-dimethoxyphenyl)acetic acid ethyl ester 8
．． 7g and 2.4g of sodium hydrogen carbonate in ethanol 5
4-tert-
butylcyclohexyloxy)anilino) -2-(3
,4-dimethoxyphenyl)acetic acid ethyl ester 6.9
# (75%) was obtained as an oil.

NMR (CDC/-3) δppm: 0.6-2.1 (9
H, m), 0.89 (9H, a).

1.05 (3H, s), 1.19 (3H, t).

3.74 (6H, g), 4.11 (2H, q).

4.4CL-4,93(2H,m), 6.20-7.
27 (7H, m) Elemental analysis value (as C2, H41NO5) CHN Theoretical value % 72.02 8.55 2.90 Actual value % 72,13 8.622.81 Example 11 2-[4-(1 -Methylcis-4-tert-butylcyclohexyloxy)aniso/)-2-(3,4-dimethoxyphenyl)acetic acid 2-(4-(1-methyl-cis-4-
tert-butylcyclohexyloxy)anilino)
-2-(3,4-dimethoxyphenyl)acetic acid ethyl ester5. OI was manipulated in the same manner as in Example 3 to prepare 2-[4-(
4.3 g (91 g) of 1-methyl-cis-4-tert-butylcyclohexyloxy)anilino]acetic acid was obtained.

Melting point 114-117°C.

IR: (KBr)z-1: 3260.2960,29
30,2860,2830°1710.150O NMR (DMSO-d6) δppm: 0.6-2.
1 (9H, m), 0.88 (9H, s).

1.03 (3H, s), 3.72 (6H, I!I).

4.88 (IH, s), 6.37-7.17 (7H.

m) Elemental analysis value (as C27H37NO5) CHN Theoretical value % 71.18 8.19 3.07 Experimental value % 71.07 8.20 3.11 Example 1
2-26 The compounds shown in Table 3 were produced by applying the above examples as appropriate. The physicochemical values are also listed.

(Margin below)

Claims (1)

[Claims] (In the formula, R1 represents a lower alkyl group, a lower alkoxy group, a halodane atom, a nitro group, or an amino group, R2 represents a hydrogen atom or a lower alkyl group that may have a substituent, and n is 0 .1 or 2, and m means 1 or 2) N-(substituted cyclohexyloxyphenyl)-α-amino acid compound and its salt. (2) General formula (in the formula, R1 represents a lower alkyl group, lower alkoxy group, halokene atom, nitro group, or amino group, R represents a hydrogen atom or a lower alkyl group that may have a substituent, and n is 0 , 1 or 2, m means 1 or 2) or a physiologically acceptable salt thereof as an active ingredient. .