JPS58183652A - (n-substituted cyclohexyloxyphenyl)-alpha-amino acid compound and lipid reducing agent containing said compound - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R<1> is methyl, ethyl, n- or isopropyl or n-butyl; R<2> is H or 1-6C alkyl; R<3> is R<2> or -(CH2)n- (A is phenyl, cyclopentyl or cyclohexyl; n is an integer 0-2); R<4> and R<5> are H or lower alkyl] and a salt thereof. EXAMPLE:2-[4-( 1- Methyl-cis-4-tert- butylcyclohexyloxy ) anilino ] -n-valeric acid. USE:A lipid reducing agent capable of exhibiting remarkable increasing action on high-density lipoprotein without side effects. PROCESS:A 1,4-disubstituted cyclohexanol of formula II is reacted with p-fluronitrobenzene in the presence of a strong base to give a compound of formula III. The nitro group in the resultant compound of formula III is reduced, e.g. catalytically reduced, to afford a compound of formula IV, which is then reacted with an alpha-halogeno-alpha-substituted acetic acid of formula V in the presence of a deacidifying agent to give the aimed compound of formula I .

Description

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

[In the formula, R1 is a methyl group, an ethyl group, a n-propyl group,
R2 is a hydrogen atom or a linear or branched argyl group having 1 to 6 carbon atoms R9 is a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, or -(OH2). -A (in the formula, AH phenyl group, cyclopentyl group or hankurohegysyl group 'f
c and n represent 0.1.2. ), R4
and R5 optionally represents a hydrogen atom or a lower argyl group. ] In the general formula [I], the linear or branched alkyl group having 1 to 6 carbon atoms in 12 and R3 is a methyl group.

Ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n
-amyl group, isoamyl group, tert-amyl group,
n-hexyl group, 1,1-dimethylbutyl group, etc.

The group represented by -(c■12)n-A in R8 is a phenyl group, benzyl group, 2-phenylethyl group, cyclopentyl group, cyclopentylmethyl group, 2-cyclopentylethyl group, cyclohexyl group, cyclohexylmethyl group. etc. The lower argyl group of R4 and R5 is a methyl group,
Examples include ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, and tert-butyl group.

The compound of the present invention of the general formula [I] has an acid salt such as hydrochloric acid or sulfuric acid,
In addition, when R6 is a hydrogen atom, thorium, potassium,
Metal salts such as calcium and aluminum can all be formed.

Since the substituent R2 at the 4-position and the C--O bond at the 1-position of the cyclohexane ring in the general formula [I] have a total cis or trans coordination, each stereoisomer exists. Also.

When R8 and R4 are different substituents, there are optical isomers in the form of crystal or L form.

Arteriosclerosis, which has become a problem as an adult disease today, is known to be closely related to hyperlipidemia caused by an increase in lipids such as cholesterol and triglycerides in the blood. Also in recent years.

Lipids have been studied at the riboprotein level, and it is known that increasing high-density riboprotein (I (D r, )) is effective in treating and preventing arteriosclerosis.

Conventionally, clofibrate (clof) has been used as a lipid-lowering agent.
j 1) rate) is widely used, but it causes liver dysfunction.

It was not satisfactory as it caused side effects such as loss of appetite and muscle pain. We reduced cholesterol and triglycerides in the blood.

As a result of research to develop a drug that increases I-ID L and has fewer side effects, two compounds of the present invention [
[2]] was found to exhibit excellent effects, particularly a remarkable HDL increasing effect.

Next, the lipid-lowering effect, acute toxicity, and
and the effect of increasing the measured weight will be explained.

Representative compounds are shown in the table below.

(Left below) -/- Male SD rats immediately after weaning were treated with 1% cholesterol and 0
Hypercholesterolemia was induced by feeding on a high-cholesterol diet containing 5% cholic acid for 7 days, and during the latter 4 days of feeding on a high-cholesterol diet, the test drug was suspended in an aqueous solution of 5% gum arabic, and the voltage was adjusted to 25 mV', g/ It was orally administered at a rate of 1 day. Heart blood was collected 18 hours after the final administration, and serum total cholesterol and high-density lipoprotein (HDL) were measured.
Cholesterol was measured. POD (: 583 (1970)) was used to measure total cholesterol.

As a result, the serum total cholesterol reduction rate and HDL-cholesterol increase rate relative to the control are shown in Table 1-1.

Lipid lowering effect in normal rats A group of 8 male Wi, 5tar rats with a body weight of around 2002 were used and were given normal feed ad libitum during the experimental period.

The test drug was suspended in a 5% gum arabic aqueous solution and
The drug was orally administered for 7 days at a rate of 9/day. Blood was taken from the heart 18 hours after the final administration, and serum total cholesterol was measured. The measurement method is POD (PerOxi-d,
4-aminoantipyrine coloring method (A
11ain, C, O, at a'1. :01in, Oh
Em, 20: 470 (1974)) was used.

Results: The rate of decrease in a-cholesterol compared to the control is shown in Table 'A-2.

(Left below) Toxicity test 1) Acute toxicity Litchfield-Wilkott method
ield and Wilcoxon method
), a test was conducted by oral administration using 10 OR male mice.

North horse weight was not recognized in mvIcy horse throwing weight, so T-1
1) The 5g value was 3000 rnyAcy or more. The LD5o value of clofibrate was 1650 ml/kg.

2) Measurement of weight increase Male SL CT O)' (mice (5 weeks old), 1 group of 8 mice were suspended in a 2% gum arabic aqueous solution containing 300 mV'Ic9'e of the test drug, O,Lml/10?
Oral administration was performed for 11 consecutive days. On the day after the final administration, the animals were sacrificed by bleeding from the carotid artery, and the liver was removed and its weight was measured.

Results: The ratio of the liver weight of each group to the total weight of the control group is shown in Table 3.

(Margins below) As shown in Table 3, Compound A-1i'Id had a significantly superior lipid-lowering effect on hypercholesterolemic rats compared to clofibrate. Acute toxicity and weight increase effect were significantly reduced. moreover.

The lipid-lowering effect on normal rats was similar to that of clofibrate. Therefore, the compound 9 of the present invention is considered to be a promising compound as a drug having a lipid-lowering effect.

The lipid-lowering agent of the present invention has a dosage of 0.052 mg/day as an active ingredient.
-37 is preferably administered in several doses, and can be adjusted as appropriate depending on the age and condition of the patient.33 When the lipid-lowering agent of the present invention is administered orally.

For example, tablets, powders, capsules, granules, oil suspensions,
They can be made into syrups, etc., which may optionally contain conventional excipients such as calcium carbonate, calcium phosphate, cellulose, powder a, glucose, lactose, calcium carboxymethyl cellulose, talc, magnesium stearate, etc. Good too. Furthermore, when the compound of the present invention is made into a metal salt, it is soluble in water, so it can also be prepared as an injection.

Example 10 Tablet Compound A 100mJ Crystalline Cellulose 40m, V Potato Starch
30 Akebono Carboxymethyl Cellulose Calcium 28 Akebono Magnesium Stearate
Total of 2 200q Example 2 Capsule Compound C120111! Potato starch 18m! lactose
40ml Magnesium stearate 2■ Total 180nvj Example 3 Injection compound rinothorium salt 20ml Physiological saline
10m1 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 and 9% Application No. 56-189092). Also, JP-A-57-213
No. 53 describes an 11-substituted phenyl-α-amino acid compound in which the N-substituted phenyl group is 2-[4-(Nsu 1)
-71ntane-8-1luoquin)phenyl] group. However, one compound of the present invention is clearly different from these described compounds.

(IV) (In the formula, R1, R2, R9, R4 and R6J, J- have the same meaning as above, and X represents a halogen atom.)■,
4-Disubstituted cyclohexanol [li:: is reacted with p-fluoronitrobenzene in the presence of a strong base such as sodium metal, thorium hydride, potassium metal, etc. at a temperature range from room temperature to the boiling point of the solvent used for 1 to 10 hours. 4.
-[1,4-disubstituted cyclohexyloxy]nitrobenzene [1113? obtain. This compound [[formerly used 21. Reduction method 2 for example by catalytic reduction 4- (:
1,4-disubstituted cyclohexyloxy)aniline [
IVE is obtained in high yield. The obtained compound [1v'3 is α
- Lognow α-substituted acetic acid [■] and a deoxidizing agent such as thorium carbonate, sodium hydrogen carbonate, potassium carbonate, nonorium hydrogen carbonate.

The compound [1] of the present invention is obtained by reacting in the presence of silver carbonate, 1-IJ ethylamine, pyridine, etc. at a temperature ranging from room temperature to the boiling point of the solvent used. Bromine is preferred as the halogen in compound [V]. The solvents that can be used for each reaction are water, methanol, and ethanol.

propanol, impropanol, n-butanol,
Tert-butanol, 5ec-butanol, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, dimethylformamide, hexamethylphosphoric triamide, pyridine, triethylamine, benzene, toluene, pysylene, dimethylsulfoquine, etc., and in each reaction They can be selected appropriately and used alone or in combination. In the obtained target compound [], when B6 is a lower alkyl group, a compound in which R5 is a hydrogen atom can be obtained by a conventional hydrolysis method. If each cis or trans isomer is used as the starting material [1st item], the isomer of the target compound (I) that reacts with each can be obtained.

[TD Nsu> [■] Sisu> [■] Sisu> [Trans [■] Trans → (In:)) Lance → [■] Trans → [■] Trans again. When using a cis-trans mixture as the starting material [n], column chromatography is performed at the compound [■] stage.・Separate into cis or trans by graphography or fractional crystallization before proceeding to the next reaction.

[I■] trans-lance mixture->CIII:] cis-trans mixture->[trans-1'-) (r]] l-lance The method for producing the compound CI of the present invention] will be explained with Examples. The silica gel for column chromatography used was Wako Gel 0-200 (manufactured by Wako Tsumugi Pharmaceutical Co., Ltd.).

Example 1 (Il 4-(1-Methyl-cis-4-t-butylcyclohexyloxy)nido-benzene 1-methyl-cis-4-t-butylcyclohexanol 22. Of? k benzene 300 m/, dimethyl It was dissolved in a mixed solvent of 150 ml of formamide, and 5.655"i of thorium hydride (55% in mineral oil) was added thereto.
The mixture was heated to reflux for 0 minutes. This reaction bath liquid was cooled (Lp-fluoronitrobenzene 18.29) The whole process was heated under reflux for 6 hours. After cooling, this reaction *-1 was washed with water and saturated brine,
It was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure,
The resulting residue was subjected to silica gel column chromatography and bathed with a mixed solvent of benzene and n-hegizan (1:4).

Both fractions containing the target product were collected and the solvent was distilled off to obtain 32.87 (87%) of 4-(1-methyl-cis-4-t-butylcyclohexyloxy)nitrobenzene as a white powder.

Melting point 84-86C (recrystallized from petroleum ether) NMR (
CDC13) δppm: o, 85 (9H+s) 1.39 (3H, s) 6.91, 8. o 1 (4n + A2B2Q)
Elemental analysis value 0.7T12. C'i-114 as No. 3 Theoretical value 70,07 8.65 4.81 Experimental value
70,21 8,63 4.90) 4-(1-
methyl-cis-4-t-butylcyclohexyloxy)
Aniline 4-(1-methyl-cis-4-t-butylcyclohexyloxy)nitrobenzene obtained in (4) above 30,09
was dissolved in 200 ml of ethyl acetate, 3.07 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.

The P solution was distilled off under reduced pressure to obtain a white powder of 4-(1-methyl-
cis-4-t-butylcyclohexyloxy)aniline25. (i!/(95 cycles) was obtained.

Melting point 56-58C (1 crystal recrystallized from petroleum ether) NMR
(CDCl,) δppm: 0.88 (91(,s) 1.11(3H,s) 3.33 (2H, broad) 6.42, 6.68 (4H, A2B,,q) Elemental analysis value C !,,H,,□CHN as No. Theoretical value 1 78.11 10.41 5.36 Experimental value%
78.09 10.32 5.33 (c) 2-(4
-(1-Methyl-cis-4-t-butylcyclohexyloxy)anilino)-n-valeric acid ethyl ester 4-(1-methyl-cis-4-butylcyclohexyloxy)aniline obtained in (b) above 5.0? .

2-bromo-n.-valeric acid ethyl ester 4.09 and storium bicarbonate 1.6? f ethanol 50ml
and the suspension was heated under reflux for 21 hours.

After cooling, the insoluble matter was removed, and the P solution was concentrated under reduced pressure.

The resulting residue was subjected to silica gel column chromatography and eluted with chloroform. Both fractions containing all of the target compound were collected, and the solvent was distilled off under reduced pressure to obtain 2-[4-(1-methyl-cis-4-t-butylcyclohexyloxy)anilino]-n-valeric acid ethyl ester 6, tr. (s1%) was obtained as an oil.

NMR (CDC13) δppm: 0.86 (9H, θ) 1.15 (3H, t) 3.77 (l H, broad) 4.05 (2H, q) 6.35, 6.6.6 (4H , A2B, q) Elemental analysis value 0. ．． 41 (OHN as Bg NOs Theoretical value % 73.99 10.09 3.60 Experimental value % 73.9G 10,12 3.53 Example 2 2-[4-(1-methyl-cis-4-t-butylcyclo hexyloxy)anilino]-n-valeric acid 2-I obtained in Example 1: 4-(1-methyl-cis-4-
t-Butylcyclohexyloxy)anilino]-n-valeric acid ethyl ester 6.02 and potassium hydroxide 3.59
't Dissolved in 50 ml of 9% aqueous ethanol (v/v) and stirred at room temperature for 6 hours. The reaction solution was then concentrated under reduced pressure, and the resulting residue was dissolved in 200 ml of water, and the pH was adjusted to 5 with dilute hydrochloric acid under water cooling, and the mixture was thoroughly stirred to precipitate crystals. The precipitated crystals are collected.

After washing with water and drying under reduced pressure at room temperature, 2-(4-
(1-Methyl-cis-4-t-butylcyclohexyloxy)anilino]-n-kiyoshi14i acid 5.3ii' (95
%) was obtained as white crystals.

Melting point 154-156C (recrystallized from ethanol) NMI
((DMSO-dfl)δppm: 0.85 (9H,
s) 1.04 (3H, e) 3.71 (III, t) 6.33, 6.58 (41 (, A, B,, q) 8
．． 68 (2H, broad) ■R (KBr) cm”; 3450.2.950,1600,1510゜Elemental analysis value C22HB5 OT-IN as N03 Theoretical value % 73,09 9.76 3.87 Experimental value
72,93 9,69 3.78 Example 3 (a) 4-(1-methyl-trans-4,-t-butylcyclohexyloxy)nitrobenzene 1-1 thyl-1
-Rance-4-t-bufcyclohexanol20.
Or, benzene 300mg, dimethylformamide 15
Dissolve in 0ml of mixed solvent.

Add to this sodium hydride (55% in mineral oil) 5.1
After adding r, the mixture was heated under reflux for 30 minutes. After cooling the reaction solution.

16.5 gk of p-fluoronitrobenzene was added and the mixture was heated under reflux for 6 hours. Thereafter, the same operation as in the section (a) of Example 1 was carried out to obtain 4-(1-methyl-trans-4-t-).
Dimethylcyclohexyloxy)nitrobenzene 30.5
S' (89%) was obtained.

Melting point 54-55C (recrystallized from petroleum ether) NMR (
CDC18) δppm: 0.87 (9H, s) 1.41 (3H, s) 6.92, 8.00 (4H, A2B2q) Elemental analysis value 01□H,, CHN as No3 Theoretical value coefficient 70,07 8 .65 4.81 Experimental value section
69,93 8,55 4.76 (mouth l 4-(1-
Methyl-trans-4-t-butylcyclohegycyl)aniline 4-(1-methyl-trans-4-t) obtained in (a) above
-7”Tylcyclohexyloxy)nitrobenzene 3
0.0? 'fr 200ml of ethyl acetate was dissolved in 1K, and the same operation as in Example 1 (b) was carried out to obtain the desired 4-(
25.8r (96%) of 1-methyl-trans-4-t-butylcyclohexyloxy)aniline was obtained.

Melting point 111-113C (recrystallized from petroleum ether) +vyrt (CI) C18) δ ppm: 0
．． 85 (9H, s) 1.23 (3H, s ) 3, 42 (21 (, broad, ) 6, 41 +
6.69 (4II + A213□q) Elemental analysis value C
, 71127No as CHN Theoretical value 78.11 10.41 5.36 Experimental value 78.16 10.47 5.29←l 2-(4
-(1-Methyl-trans-4- to -butylcyclohexyloxy)anilinocyne n-valeric acid ethyl ester 4-(1-methyl-trans-4-t) obtained in (b) above
-butylcyclohexyloxy)aniline 5.07.2
-Bromo-n-valeric acid ethyl ester (4.07 g) and potassium hydrogen carbonate (20 g) were sequentially added to 60 ml of methanol, and the suspension was heated under reflux for 23 hours.

Among them, the same operation as in section (c) of Example 1 was performed to obtain 2-(4-(1-methyl-trans-4-t-butylcyclohexyloxy)anilinosy n-valeric acid ethyl ester 649 (ss%)ffi Obtained as oil fall product.

NMR (CDcll) δppm: 0.85 (9H, s) 1.19 (3H, t) 1.22 (3H, s) 3.80 (I n , broad) 4.07 (2
n, q) 6.34, 6.66 (4H, A2B,, q) Elemental analysis value 0. ,,, ]+,, No8CII
N Theoretical value section? 3.99 10.09 3.60 Experimental value 73.86 10.20 3.73 Example 4 2-C4-Cl-methyl-trans-4-t-butylcyclohexyloxy)anilino]-n-valeric acid implementation 2-[4-(1-methyl-trans-4) obtained in Example 3
-t-butylcyclohexyloxy)anilino]-〇-
Valeric acid ethyl ester 6.02 and potassium hydroxide 3.5
9'i 9% aqueous ethanol (v/v) 5Cml
and stirred at room temperature for 6 hours. below.

The same operation as in Example 2 was carried out to obtain 2-L:4-(1-methyl-trans-4-t-butylcyclohexyloxy)anilino]-n-valeric acid s, 4r (c+6).

White crystal. Melting point 132-135C (recrystallized from ethanol) NMR (DM8046) δppm: 0.83 (9TI, s) 1.15 (311, s) 3.73 (II-1, t) 6.36, 6.61 ( 4H,A,,13.,Q)
6.67 (2H, broad) Ding R (K, Br)z-”: 3400.
2950, 1580.1510 Elemental analysis value C22H35
1qO8 CHN Theoretical value% 73.09 9.76 3.87 Experimental value%
73,22 9,65 3.81 Example 5 (Il 4-(1-methyl-7-4-t-butylcyclohexyloxy)nitrobenzene 1-methyl-4-t-butylcyclohexanol (cis-trans8 material) 30 f/f: Benzene 400
ml, dissolved in a mixed solvent of 200 ml of dimethylformamide and added sodium hydride (55% in mineral oil)7.
79 k and heated under reflux for 30 minutes. reaction solution ti
fl, p-fluoronitrobenzene 2487 was added, and the mixture was heated under reflux for 6 hours. After cooling, the reaction solution was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was applied to a silica gel column/10 column and subjected to thin layer chromatography [Wakogel B5-FM, Benzene: n-hexane (
The product-containing fractions corresponding to f-values of 0.54 and 0.43 were eluted, respectively.
．． Both fractions corresponding to 54 were collected and the solvent was distilled off under reduced pressure to obtain 4-
(1-Methyl-cis-4-t-butylcyclohexyloxy)nitrobenzene 2o,oy (a9%) was obtained.

Melting point 84-86C (recrystallized from petroleum ether) Elemental analysis value CT as C1□H and No3 l 4-(1
-Methyl-cis-4,-t-butylcyclohexyloxy)aniline The 4-(1-methyl-cis-4-butylcyclohexyloxy)nitrobenzene 1507 obtained in (a) above was added to (b) of Example 1. 4-(1-
methyl-cis-4-t-butylcyclohexyloxy)
Aniline 126r (9a%) was obtained.

Melting point 56-58C (recrystallized from petroleum ether) (c)
2-[4-(1-Methyl-cis-4-t-butylcyclohexyloxy)anilino]-〇-valeric acid ethyl ester 4-(1-methyl-cis-4-t-butylcyclo) obtained in (b) above hexyloxy)aniline 10.0? f Perform the reaction treatment in the same manner as in section (c) of Example 1 to obtain 2-(4,
-(1-Methyl-cis-4-t-butylcyclohexyl)anilino)-n4 grass acid ethyl ester 12.7f(8
5%) was obtained as an oil.

Elemental analysis value C24Hllll OHN as NO3 Theoretical value 73.99 10.09 3.60 Experimental value Chi 74.00 10.11 3.56 Example 6 2-(4-(1-methyl-trans-4-t- Butyl/
Chlorhexyloxy)anilinosyvaleric acid 34 Both fractions corresponding to the Rf value of 0.43 obtained in the section (a) of Example 5 were collected and the solvent was distilled off under reduced pressure to give 4-(1-methyl-trans- 4-1,-Butylcyclohexyloxy)nitrobenzene 1s,oy (35%) f:m.

Next, reduction was carried out in the same manner as in Section (b) of Example 5, and the reduction product was subjected to reaction treatment in the same manner as in Section (c) of Example 5 to obtain 2-[
4-(1-Methyl-trans-4-t-butyl/chlorohexyloxy)anilino)-n-4 grass acid ethyl ester 1857 was obtained as an oil.

This compound was then reacted in the same manner as in Example 4 to obtain 2-
[4-(1-Methyl-trans-4-71butylcyclohexyloxy)anilino)-n-valeric acid 14.8ge
Obtained as white crystals.

Melting point 132-135 tr (recrystallized from ethanol, crystal) Elemental analysis value C22I■35NO3 as CHN Theoretical value % 73,09 9.76 3.87 Experimental value %
73,19 9,72 3.86 Example 7 2-44-(1-methyl-cis-4-ethylcycloheginyloxy)anilino]-〇-valeric acid ethyl ester 4-(1-methyl-cis-4-ethylcyclo Gysyloxy)aniline 5. Of, 2-bromo-n-valeric acid ethyl ester (4.02 kg) and sodium bicarbonate (1.62 kg) were sequentially added to 5 Qml of ethanol, and the suspension was heated under reflux for 25 hours. After cooling, the insoluble matter was removed, and the P solution was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography.

It was eluted with chlorporum. Both fractions containing the target product were collected and the bath medium was distilled off under reduced pressure to obtain 2-[:4-(1-methyl-cis-4-ethylcyclohegycyloxy)anilinosynyl n-
6.5 ji' (84%) of valeric acid ethyl ester was obtained as an oil.

NMR (C!]) C13) δppm: 065-222
(21■19m) 1.10 (3n, θ) t18(3n, t) 3.89 (ITi, broad) 4.10(
2H, (]) 6, 39, 6.71 (4H+ A213□q) Elemental analysis value 02. , H as 03 OHN Theoretical value % 73,09 9.76 3.87 Actual value %
73,12 9,66 3.83 Example 8 2-[4-(1-Methyl-trans-4-ethylcyclohexyloxy)anilinocy n-valeric acid ethyl ester 4-(1-methyl-trans-4 to ethylcyclo Gysyloxy)aniline 5. Of, 2-bromo-n-valeric acid ethyl ester 402 and sulfur and lithium carbonate 1,647
The suspension was heated under reflux for 25 hours.The same procedure as in Example 7 was then carried out to obtain 2-(4-(1-methyl-trans-
6.79 (87%) of 4-ethylcyclohexyloxy)anilinocyne n-valeric acid ethyl ester was obtained as an oil.

NMn (CDC1,,) δ ppm: 05
2-2.02 (21Hm) 1.17 (3H, t) 1.19 (3H, s) 3.80 (IH, broad) 4.06 (2H, q) 6.36.6.69 (4H, A2B2q) Elemental analysis value 022H8, CHN as NO3 Theoretical value section 73,09 9.76 3.87 Experimental value section
73,20 9,77 3.76 Example 9 2-(4,-(1-methyl-cis-4-t-butylcycloheginyl)anilino]-2-methylpropionic acid ethyl ester'1 of Example 1 ) 4-(1-methyl-cis-
4-t-Butylcyclohegycyloxy)aniline 5.0
2. α-Bromisobutyric acid ethyl ester 372 and thorium hydrogen carbonate 1.6 W f: n-propatool 3
The suspension was heated under reflux for 20 hours. After cooling, insoluble materials were removed, and the P solution was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography and washed out with chloroform. Both fractions containing the target product were collected and the solvent was distilled off under reduced pressure to obtain 5.2 g of 2-[4-(1-methyl-cis-4-t-butylcyclohexyloxy)anilinocu 2-methylpropionic acid ethyl ester.
(72%) was obtained as an oil.

NMn (cr+c]3) δppm 0.89 (9H, s) 1.14 (3H, s) 1.20 (3I (, t ) 1.51 (6H, S) 3.70 (I H, broad ) 4 .18 (2n, q) 6.42, 6.70 (4H, A, B2q) Elemental analysis value C23H3□HN as No3 Theoretical value % 73,56 9,93 3.73 Experimental value
73,52 9,91 3.62 Example 10 2-[4-(1-methyl-/no-4-t-butylcyclohexyloxy)anilino]-2-methylpropionic acid 2-(4 ,-(1-methyl-cis-4
-t-butylcyclohexyloxy)anilinocu2-
Methyl propionate ethyl ester 5.07 and sodium hydroxide 2.1? 'e 9% aqueous ethanol (V/
V) Dissolved in 50 ml K and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in 200 ml of 50% aqueous ethanol, adjusted to pH 5 with dilute hydrochloric acid, and then cooled with water to precipitate crystals. The precipitated crystals were separated, recrystallized from ethanol, and then dried under reduced pressure at room temperature. .ay (94 t) was obtained. White crystals. Melting point 184.
~187NMT ((DMso-a6)δppm: 0.
86 (9H, s) 1.05 (3H, s) 1.40 (6H, s) 6.34, 6.62 (4Ht A2B2'l,)
8.35 (2H, broacl) I R (KBr) (?7F+-1; 2960.2950,2930,2870.16001
580.1500 Elemental analysis value C2□H33No3 as OHN Theoretical value% 72,58 9,57 4.03 Experimental value%
72,64 9,46 3.98 Examples 11 to 48 The above Examples were applied accordingly. Table 1'4 shows the synthesized compounds, their melting points, and elemental analysis values.

(Leaving space below) Procedural Amendment (Method) August 26, 1981 Kazuo Wakasugi, Commissioner of the Patent Office 1. Patent Application No. 1983-66.372 2. Name of the Invention N-(Substituted Cyclohexyl) Oxyphenyl)-4 Agent 1-1-12 Toranomon, Minato-ku, Tokyo. Toranomon Pill No. 505 (
6217) Hisataka Masanobu (foreign name) 5, Date of amendment order July 27, 1982 6, Subject of amendment Full text of application and specification 7, Contents of amendment Engrave of application and specification as attached (
(No changes to the contents).

Procedure Amendment Written July 6, 1981 Kazuo Wakasugi, Commissioner of the Patent Office1, Patent Application No. 1983-66.3722 Name of Invention N-(ft-substituted cyclohexylogysyphenyl)-α - Amino acid compound and lipid-lowering agent containing the compound 3, Relationship with the amended person's case Temporary applicant: Tokyo Tanabe Pharmaceutical Co., Ltd. 4, Attorney: 5 Detailed description of the invention in the specification to be amended Application No. 57-66.372 1 Procedural Amendment (1) The following words and phrases in the specification (engraved copy dated August 26, 1980; the same shall apply hereinafter) have not been amended.

(2) Insert the words in each of the following places in the statement.

(3) In Table 1 on page 9 of the specification, "Serum total cholesterol reduction rate ('I"-Ch) J is 1" Serum total cholesterol (T-Ch) reduction rate" and "Serum HDL-cholesterol increase Rate (III) L-Ch) J [: Serum H
I) L-cholesterol (III I) L-Ch
) "increase rate" and corrected for each.

(4) After Table 4 (continued) on page 45 of the specification.

Change the page and insert the following example.

c) "Example 49 2-(4-(1-methyl-cis-4-tert-butylcyclohexyloxy)anilino]-n-valeric acid 4-(1-methyl-cis-4-tert-butylcyclo Hegisyloxy) Ani!J 75.0?, 2-
7” rom-n-valeric acid 5.22 and sodium carbonate 5
．． 17 was sequentially added to 10 ml of n-gropanol, and the suspension was heated under reflux for 15 hours. After cooling, add 15 ml of water to the 2 reaction solutions.
Add 0ml of ethyl ether and dilute this water bath with 150ml of ethyl ether.
150 ml of methanol was added to the aqueous layer, and the pH was adjusted to 4 with dilute hydrochloric acid while cooling with water. Count the precipitated crystals,
Recrystallized from a mixed solvent of methanol and benzene to obtain 2-(
4-(1-Methyl-cis-4-t+3rt-butylcyclohexyloxy)anilino]-n-valeric acid 6.2?
(90 chi) was obtained. Melting point 154-1.56iC8 Example 50 2-(4-(1-Methyl-cis-4-tert-butylcyclohexyloxy)anilinotiso-valerate 4-(1-methyl-cis-4-tert-butylcyclohexyloxy) Aniline 5.07, 2-bromo-iso-valeric acid 5.22 and sodium carbonate 5.17 were sequentially added to 101 nl of ethanol, and this suspension was heated under reflux for 7 hours.Hereinafter, the same purification procedure as in Example 49 was carried out. Do 2
-(4-(1-Methyl-cis-4-tert-butylcyclohexyloxy)anilinotiso-valeric acid 4.9
? (71%).

Melting point 148-150C8 I n (KBr) crn-': 3280.29
80,2950,1720,150ONMl't (1
) MSO-(16)δppm: 0.6 to 2.2 (
16H,m) 0,85 (9H,s) 1,. 04 (314,5) a53 (1, a) 6.43, e, a5 (4+I, A2B2q) Elemental analysis value (as C221185NO3) CHN Theoretical value % 73,09 9,76 3.87 Experimental value CH
73,01 9.733.77 Example 51 2-(4-(1-methyl-cis-4-tert-butylcyclohexyloxy)anilino)-4-methyl-n-
4-(1-Methyl-cis-4-tert-butylcyclohexyloxy)aniline pentanoate5. ot, 2-'.

Mu4-methyl-n-pentanoic acid 5.67 and potassium hydroxide 27? were sequentially added to 10 ml of ethanol.

This suspension was heated to reflux for 1.5 hours. Below, Example 4
Perform the same purification operation as in 9 to obtain the above target product 6, 4 r
(89chi) was obtained. Melting point: 158-160 h.

IR, (KBr)cm-': 3250.2980,2950,1700,151ON
MR (DM80-a6) δppm: 0.6-1! ,1
．． (48II, m) 0.87 (91-1, s) l, 05 (3H+ s) 3+4 (ui, t) 6.38, 6.64 (4H, A2B2'l) Elemental analysis value (C, H8□ No, as) CI (N Theoretical value section ・7B, 56 9.93 3.73 Experimental value%
7B, 52 9.89 3.61 Example 52 2-[4-(1-methyl-cis-4-tert-butylcyclohexyloxy)anilino]-2-74-(1-
Methyl-cis-4-10rt-butylcyclohexyloxy)aniline5. OS', α-bromphenylacetic acid 627 and potassium carbonate 66? 30ml of ethanol
and the suspension was heated under reflux for 3.5 hours. J
2) The same purification operation as in Example 49 was carried out to obtain the desired product 6.3r (83%). Melting point 191-193C
8 J R (KBr) cm-': 2980.2950, 1590, 1570, 150ON
MIL (1) Mso-C6) δppm: 0.6-2
．． 1 (9H, m) 0.85 (9H, +3) 1.02 (3I], s) 5.86 (11-1, s) 6.38, 6.56 (411, A2B, q) 703~7
50 (51 (, m) Elemental analysis value (as C25I]33NO3) CHN Theoretical value 75.91 841 3.54 Experimental value 7
5.88 &53 3.66 Example 53 2-(4-(1-Methyl-cis-4-tert -butylcyclohexyloxy)anilino)-3-cyclopentylpropionic acid 4-(l-methyl-cis-4-tert -Butylcyclohexyloxy) Ayurif 5.0? , 2-bromo-3-
1316.49 ml of cyclopentylpropion and 6.62 ml of potassium carbonate were sequentially added to 30 ml of methanol, and the suspension was heated under reflux for 3 hours. After cooling.

Add 170 ml of methanol and 170 ml of water to the reaction solution.

It was made into P1]4 with dilute hydrochloric acid while cooling with water. The precipitated crystals were collected from F and recrystallized from methanol to give 2-[:4-(1-methyl-cis-4-tert-butylcyclohexyloxy)
Anilino-3-cyclopentylpropionic acid 6.3
r (82 chi) was obtained. Melting point 165-1670 TR, (KBr) c an-: 3380.2970, 2950, 2870, 1700°50O NMR, (DMSG-C6) δppm: 0.6-2.
1 (20H, m) o, s5 (9H, s) 1.04 (3H, s) 3.69 (IH, t) 6.36, 6.61 (4H, A2B2q) Elemental analysis value (C2I, 113. as NO8) C1,I
N Theoretical value % 74.77 i), 79 3.49 Experimental value Chi 7a, 699.73 3.52 J- or more
”21

Claims (2)

[Claims] (1) General formula [wherein R' is a methyl group, ethyl group, n-propyl group,
R11 is a hydrogen atom or a straight chain or branched alkyl group having 1 to 6 carbon atoms, RB is a hydrogen atom or a straight chain or branched alkyl group having 1 to 6 carbon atoms. group or -(OH,,)n' (wherein A
l'i represents a phenyl group, a cyclopentyl group or a hacyclohexyl group, and n represents 0.1.2. ) +
R' and R5 optionally represent a hydrogen atom or a lower alkyl group. ] An N-(substituted cyclohexyloxyphenyl)-α-amino acid compound and a physiologically acceptable salt thereof. (2) General formula [wherein R1 is a methyl group, ethyl group, n-propyl group,
R2 is a hydrogen atom or a straight chain or branched alkyl group having 1 to 6 carbon atoms; RB is a hydrogen atom or a straight chain or branched alkyl group having 1 to 6 carbon atoms; or -(c H-system-A (wherein, AIi
phenyl group, cyclopentyl group or hacyclohexyl group; n represents O, I, or 2; ), the group shown by ■(
- and R6 optionally represent a hydrogen atom or a lower alkyl group. ] A hypolipidemic agent containing an N-(substituted cyclohexyloxyphenyl)-α-amino acid compound or a physiologically acceptable salt thereof as an active ingredient.