Note: Descriptions are shown in the official language in which they were submitted.
~15~45Z
The present invention relates to benzaminoethylphenoxy-
cyclohexylacetic acid derivati~es, to the preparation of such
derivatives and to antihyperlipidemic agents comprising such
compounds as the active in~redients.
It is known clinically to use Bezafibrate, Clofibrate and
analogous compounds; nicotinic acid derivatives; hormones, such
as protein assimilation steroids; unsaturated aliphatic acids,
such as linoleic acid; cholestylamine and ~-sitosterols as anti-
0 hyperlipidemic agents.
; It has now been found that certain oxyacetic acid de-
rivatives have desired antihyperlipidemic properties.
The present invention thus provides benzaminoethylphenoxy-
cyclohexylacetic acid derivatives which are effective against
hyperlipidemia.
The present invention also provides a process for pro-
ducing the benzaminoethylphenoxycyclohexylacetic acid derivatives.
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Accoxding to the present invention there is provided
benzaminoethylphenoxycyclohexylacetic acid derivatives having the
formula
~ ~ CONHCH2CH2 ~ O ~ COOR
wherein Rl represents hydrogen atom, a halogen atom, hydroxyl
group, a lower alkyl group or a lower alkoxy group; n is 1 or
2; and R represents hydrogen atom, a lower alkyl group which
may be substituted by a phenyl group, a lower alkoxycarbonyl
group; the 3,3,5-trimethylcyclohexyloxycarbonyl group or a hetero-
cycli.c group, the hexadecyl group; a phenyl group which may be
substituted by a lower alkyl group, a lower alkoxy group, a
: 15 lower alkoxycarbonyl group or a halogen atom; a cyclohexyl group
:~ or ~-[4-~4-chlorobenzaminoethyl)phenoxy]-a-cyclohexylacetoxy
cyclohexyl group which derivatives have excellent antihyperlipi-
demic activity.
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115445Z
In the formula (I) as R and R , the halogen atom may
be a fluorine, chlorine, bromine or iodine atom; the lower alkyl
group and the lower alkoxy group may have a straight or branched
alkyl group, and the lower alkyl group may be a methyl, ethyl,
propyl or butyl group; the lower alkoxy group may be a methoxy,
ethoxy, propoxy or butoxy group; the lower alkoxycarbonyl group
may be a methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or
butoxycarbonyl group; the heterocyclic group may be a furyl,
thienyl, morphorino, benzothiazole, pyridyl or 3,4-methylene-
dioxyphenyl group.
The benzaminoethylphenoxycyclohexlacetic acid derivativeshaving the formula
~ -CONHCH2CH2 ~ O ~ COOR (I)
wherein R , R and n are defined above may be produced by react-
ing a benzaminoethylphenol compound having the formula (II)
20
1 ~ -CONHCH2CH2 ~ - OH (II)
wherein R and n are defined above with ~-halocyclohexylacetic
acid compound having the formula ( II)
X-CHCOOR (III)
, ~
, 30 wherein X represents a halogen atom and R represents the groups
R as defined above; if necessary, followed by hydrolyzing the
product or interesterifying the product.
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` The compounds havin~ the formula (IIX) wherein X is
-I, -Br, or -Cl are preferably used. In the reaction, an equi-
molar amount of the ~-halocyclohexylacetate (III) is usually
reacted with the compound (II). However, it :is possible to use
an excess of either the compound (II) or the compound (III).
The solvents are organic solvents which are inert under the
reaction conditions, such as dimethyl formamide and acetone. A
mixed solvent may be used for the reaction. The reaction may be
accelerated by adding a base such as potassium carbonate, sodium
carbonate, sodium methylate or sodium ethylate. It is possible
to separate the reaction product obtained by reacting the base
with the compound (II) from the reaction system and then, to
react the compound (III) with the separated reaction product.
The reaction conditions such as temperature, time and pressure
may be chosen depending upon the starting materials, the solvent
and the base. The reaction is ussually completed, at room tem-
perature, in 1 to 2 days or at 100 to 180C for 5 to 20 hours.
The corresponding carboxylic acids can be obtained by
hydrolyzing the benzaminoethylphenoxycyclohexylacetic acid ester
(I). The hydrolysis can be carried out by using conventional
processes. It is preferable to carry out the hydrolysis under
alkaline conditions with an aqueous solution of sodium hydroxide
or an alcoholic solution of potassium hydroxide. The resulting
benzaminoethylphenoxycyclohexylacetic acid or ester thereof can
be converted into the corresponding ester by reacting it with a
chlorinating agent such as thionyl chloride and phosphorus
trichloride to form the corresponding carboxylic acid chloride
and further reacting the produce with a compound having the for-
; 30 mula 2
R -OH
wherein R is defined above, in the presence of a base, such as
pyridine or triethylamine; or by reacting it with a compound
having the formula
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R2 X
wherein R2 and X are defined ahove; or by reacting it with a
compound having the formula
R2_oH
in the presence of an esterifying agent such as tosyl acid and
tosyl chloride.
The reaction products (I) can be separated and purified
by conventional separating methods such as concentration, parti-
cularly concentration under reduced pressure; distillation; par-
ticularly distillation under a reduced pressure; fractional
distillation; the adjustment of alkalinity or acidity; solvent
extraction; crystallization; recrystallization; inversion and
chromatography.
The benzaminoethylphenoxycyclohexylacetic acid deriva-
tives (I) have excellent antihyperlipidemic activity and are ef-
fective in practice as an antihyperlipidemic agent for the treat-
ment of hyperlipidemia. The benzaminoethylphenoxycyclohexylacetic
acid derivatives (I) have low toxicity and do not cause hepatitis
which is found in the administration of ethyl-~-(p-chlorophenoxy)-
isobutyrate (Clofibrate) or [2-{4-12-(4-chlorobenzamine)-ethyl]-
phenoxy}-2-methylpropionic acid](Bezafibrate).
The antihyperlipidemic agents of the present invention
comprising the benzaminoethylphenoxycyclohexylacetic acid deri-
vatives (I) can be administered orally in the form of tablets,
` capsules, powders or granules; and they can also be administered
i~ 30 parenterally in the form of injectable solutions, suppositories
or pellets. The benzaminoethylphenoxycyclohexylacetic acid
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derivative (I~ can be combined with other antihyperlipidemic
a~ents, ,a, hypotensive agent or an ~nticoagulant agent. The dose
of the benzaminoethylphenoxycyclohexylacetic acid derivative (I)
is usually in a range of 25 to 2500 mg., preferably 100 to 1000
S mg. per day per adult inoral dose.
The invention will be further illustrated by the follow-
ing examples.
EXAMPLE 1:
Ethyl-~-[4-(4-chlorobenzaminoethyl)phenoxy]-
~-cyclohexylacetate: (Compound No. l)
; 15 Into 50 ml. of dimethylformamide containing 3.2 g.(0.0479 mol) of sodium ethylate, ll g. (0.04 mol) of N-(4-chloro-
benzoyl)-tyramine was added and further 39.8 g. (0.16 mol) of
ethyl ~-bromocyclohexylacetate was added and the mixture was
stirred at 170C for 10 hours. After the reaction, dimethyl-
formamide was distilled off under a reduced pressure and ice water
was added and the reactionproductwas extracted with benzene.
The extracted benzene layer was washed with 2% NaOH aq.sol. and
' then with water and was dehydrated over sodium sulfate and the,
benzene was distilled off under a reduced pressure. The residue
was recrystallized from a mixed solvent of ethanol and n-hexane
' to obtain 5.7 g. of ethyl ~-[4-(4-chlorobenzaminoethyl)phenoxy]-
~; ~-cyclohexylacetate (yield: 35.2%).
Melting point: 103 - 104C
IR Spectrum (KBr):
~(cm ): 3325 (NH), 1740 (C=0), 1640 (C-NH)
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1154452
In accordallce with the s(lme process, the products shown
in T~ble 1 were produced by using the corresponding starting materi-
als. The physical properties of the products are also shown in Table
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_~ble 1
(R )n
~ CONHCH2CH2~O-C~lCOO~
Comp. (R ) ¦ R I :I\,Ielting _ C-0 _
2 ¦2 5 89 - 90 1760, 1655
_ _
3 3-Cl C2 5 106 - 107 1755, 1630
4 . 2-F ¦C2H5 85 - 86 1745, 1650
s S 3-F . ~ 104 - 105 1750, 1640
l _
6 4-F ¦ ' j 111 - 112 1755, 1640
7 2-CH3 ~ 86 - 87 1755, 1630
8 3-CH3 ¦i~ 80 - 81 1740, 1630
'.~ l
~. . 4-CH3 l ' 88- 89 Oil
2-OCH3 l Oil ~/C o 1740,1645
11 3_oCH3 1 ~ 78-79 ! 1740,1640
:~
'' 12 4-OCH3 _ 120 - 121 1755, 1640
13 H " ¦ 95.5 - 97 1755, 1640
¦ 14 ~ 4- C3H7 =
:t.: 16 4 -t- C4Hg 125 126 1750
: j __
~ I 17 4-Cl n-C4Hg 92 - 93 1750, 1645
;~ 18 4-Cl n C16 33109 - 110 1740, i645
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51 2-OH C2H5 oil 1750, 16~0
.. .
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1154452
XA MPLE 2:
S~-[ 4-(4-chlorobenzaminoethyl)phenoxy~-
c~-cyclohexylacetatic acid: (Com~ound No, 19)
Into 70 ml. of 70% ethanol containing 2 g. of sodium
:
hydroxide, 5. 7 g. (O. 0128 mol ) of the ester obtained in Example 1
was dissolved and the mixture was refluxed for 30 minutes and then,
the solvent was distilled off under a reduced pressure and then water
was added and the mixture was acidified with 5~oHCl and the reaction
product was extracted with benzene. The extracted benzene layer
was washed with water and dehydrated over sodium sulfate and
benzene was distilled off and the residue was recrystallized fromethanol to obtain 3.8 g. of o~-(4-(4-chlorobenzaminoethyl)phen
O;- cy cl ohexylacetic aci d (yield: 71.7~o).
Melting point: 187 - 188C
lS IR Spectrum (KBr):
-1
~(cm ): 3320(NH); 1735(C=0); 1640 (CONH)
In accordance with the same process, the products shown in
Table 2 were produced by using the corresponding starting materials.
The physical properties of the products are also shown in Table 2.
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1159~52
Tab1e 2
(Rl)n
\~ CONHCH2CH2~0- CHcc)oR2
Comp . I ( ~1 )n ¦ R2 point( C ) L~R ~ C o ( cm
_
20 2-C1 126 127 1740, 1650
21 1 3-C1 __ 165- 166 1730, 1640
-22 l2-F I !153-154 1740,1650
23 l3-F I I !175-176T1740,1620
24 ¦ 4-F I , ¦ 186 187 ¦ 1740, 1620
25 ¦ 2-CH3 ¦ 138 139 1 1740, 1620
26 ¦ 3-CH3 1 181 182 1 1730, 1620
27 14-CH3 1 !195-1961 1740,1620
28 ¦ 2-OCH3 1 ¦ 124 125 1 1750, 1630
29 ¦ 3-OCH3 1 ¦ 205 206 1 1730, 1720
30 4-OCH3 1 " 1 213~ 1730
31 H I I _ 2
32 ! 4~i~C3H7 ¦ ¦ 1 55 1 56 1 1740, 1640
33 ! 4 n-C4 9 ¦ 1 154 155 1 1740, 1650
34 ¦ 4~t~C4H9 ¦ " ¦ 1 65 166 ~0, 1640
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_XA MP l.E 3
Cyclohexyl o~-(4-(4-chlorobenzaminoethyl)phcllox
_
~)(-cyclohexylacetate:(Compound No, 35)
Into 6 ml. of pyridine, 1. 65 g. (0. 004 mol ) of ~ (4-
chlorobenæaminoethyl)phenoxy)-~(-cyclohexylacetic acid w<-s dissolved,
and then, 0. 40 g. (0. 004 mol ) of cyclohexanol was added and then,
0. 95 g, (0. 005 mol ) of tosyl chloride was added and the mixture was
heated at 80 - 90C for 2 hours to react them, The reaction mixture
was poured into ice water and the precipitate was separated by a
filtration and washed withwater and the reaction product was recrys-
tallized from a mixed solvent of ethanol and water to obtain 1. 7 g. of
the object compound (yield: 86. l~o).
Melting point: 104 - 105C
Spectrum:
~ C-O 1760, 1750, 1650 cm~
EXAMPLE 4
~ .
2 -Ethoxycarbonvlphenylo( - ~4 - (4 -chlorobenz -
aminoethyl)phenoxy~ -cyclohexylacetate: (Compound No. 36)
; In 15 ml. of dichloroethane, 1. 65 g. (0. 004 mol ) of
C~- ~4-(4-chlorobenzaminoethyl)phenoxy~ -cyclohexylacetic acid
obtained in E~ample 2 was suspended and then, 2 ml. of thionyl
chloride was added. The mixture was refluxed for 1 hour to react
them. The solvent was distilled off under a reduced pressure and
10 ml. of dichloroethane was added to the residue and the solvent
^ 25 was distilled off under a reduced pressure. The residue was
adn~ixed with 1 ml. of pyridine and 0, 73 g. (0. 0044 mol ) of ethyl
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salicylate dissolved in 0. 5 ml. of pyridirle was added to react them
for 30 minutes. The reaction mixture was cooled and added into
5%HC1 aqueous solution. The reaction product was extractcd with
benzene and the benzene layer was washed with water, with 5~/~ONaOH
aq. sol. and then with water and the benzene laycr W.-IS clchyclr.lted
over sodium sulfate. ~enzene was distilled off and the residue was
recrystallized from ethanol to obtain 1. 6 g. of the object compound
(yield: 71. 5 ~0) .
Melting point: 12 5 - 12 6C
IR Spectrum:
y cBo : 1770, 1740, 1640 cm~1
In accordance with the process of Example 3 or 4, the
products shown in Table 3 were produced by using the corresponding
starting materials. The physical properties of the products are
also shown in Table 3.
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llS~452
T.lbl e 3
(Rl)n
~- CoNI'lcH2cH2~-o-cHcooR
No. ( Rl )n _ __ Mc 1 ~in g _ __ C _0____
37 ~-C1 _ ~ 148 - 1~9 1775, 1650
38 _ - CH ~ Oil C = 0 1650
39 " ~O2C-~H-O~ 1755, 1740,
-CH2-CH2NHCO 82 83 1650
ll -CH2~ 88 - 89 1765, 1650
_
41 ~Cl 152 - 153 1775, 1650
42 ~CH3 131 - 13Z 1775, 1650
43 ~______ -C~2~ 122 - 123 1750, 1660 .
44 ~ -CH2~ 133 - 134 1745, 1650
., Et 1 Z 4 - 1 Z 5 1750, 1660,
46 2 2 ~_~ Oil ~Oil 1750
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rCol-np- ¦ (R1)n R polnt 5~ \/'C=0 (
_ l_ (o
48 I. 3-Cl ~Oil ~Oil 1750 1650
~ ~coo~ ~ I~c ( I~-o
50 ~ 4-Cl -ÇHCO;?~ 59 - 60 1760, 1655
Preparation 1:
A 400 g. of ethyld~4-(4-chlorobenzaminoethyl)phenoxy3-~-
cyclohexylacetate, 400 g. of fine powdery silicondioxide and 185 g.
of corn starch were uniformly mixed and charged in a kneader and
1000 ml. of 3% aqueous solution of hydroxypropyl cellulose was
added and the mixture was kneaded. The mixture was granulated by
passing it through the 16 mesh screen to form uniform granules
which comprises an antihyperlipidemic agent.
Preparation 2:
A 400 g. of ~-~4-(4-chlorobenzaminoethyl)phenoxy~
cyclohexylacetic acid, 400 g~ of lactose and 175 g. of potato starch were
uniformly mixed and charged in a kneader and 3% aqueous solution of
hydroxypropyl cellulose was added and the mixture was kneaded and
granulated by passing through a 16 mesh screen and 0. 3~0 of mag-
nesium stearate was added and the mixture was compressed to form
tablcts which comprise an antihyperlipidemic agent.
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Te~st 1.
The antihyperlipidemic activity in rats with dictary
hyperlipidemia,
In the tests, Wister type m~ale rats (weigllt: 1~0 ~:~.) were
used in groups of 5 each.
A feed containing 2% of cholesterol, 1% of sodium cholate
and 5% of coconut oil was given for ~ days to cause hyperlipiclemia
Each active ingredient was suspended in a l% aqueous
solution of Tween 80 ( (~) polyoxyethylene sorbitane monoa]kylate)
and the suspension was orally administered in a dose of lO0 mg. /kg.
once daily for 4 days starting with the supply of the cholesterol
supplemented diet,
After 24 hours from the administration, blood was sarnpled
and the concentration of total cholesterols in blood-plasma was
measured by the method described in Clinical chemistry Vol. 22
page 393 (1968) and the concentration of triglyceride (neutral fat)
was measured by Fletcher method (Clinica Chimica Acta)Vol. 10
page 451 (1964).
Percent liver weight was given by extracting liver and
measuring each weight of liver and calculating a ratio of the liver
weight to a total weight.
As the active ingredients, the compounds of the invention
shown in Table and ethyl-~-(p-chlorophenoxy)-isobutylate having
the formula
CH
Cl4~3O ~-COOC2H5 (Clofibrate)
CH3
,
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- 1 6
llS9~4SZ
and 2-~4-~2- (4- chloroben~aln;de)ethyl)pllenoxy~2-methylpropionic
acid
Cl~CONHCH2cl~2~30-c-coo~l (Bc/afibrF,tc)
The test results are shown in Table 4.
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Table 4
(p,o, 100 mg/kg)
_ Ant.;hyperlip;deln;c activity(%) Percent weioilt
Compoulld No _ _ _ __ inc l e ~lse of
_ _ Cholesterol I Triglycerlde ¦liver _ _"lo)
1 44 62 8.8
_ _ ~ . , ,~
2 77 66 0
___,_____ ... __
3 33 21 0.9
_ _ ___
4 45 45 0
_
53 69 0
6 54 45 0
7 42 63 2.1
8 23 42 0
9 14 0 0.5
0
_ .
11 31 56 0
12 28 0 0
_ __
13 14 72 4.5
14 18 23 0
_
~ 15 16 20 0
.
16 11 18 0
17 53 48 12.8
: 18 47 42 10.3
: 19 46 68 4.5
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: 20 1 65 89 1.6
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1~5445Z
(p o, 100 mg/kg)
Antihyperlipidernic activity % percent weight
Compound No. -- I increase of
Cholesterol Triglyceride ]iver (~0)
21 57 99 6,2
_ ___ _
22 41 35 O.9
_ ~_
23 51 O 9.7
24 65 25 9.6
62 89 10. 2
26 25 64 7,3
27 4. 2 41.1 6.4
28 3Z 43 O
_
29 61 53 O
54 10.7
31 49 90 9.7
32 21 27 O
33 19 25 O
34 16 23 O
37 42 2.8
36 42 47 3.0
37 39 42 3.9
38 46 50 4.2
39 43 48 3.8
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48 49 4,0
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115445Z
(p, o, 1 OOmg/kg)
C om p o U nd N o C h ol e s t e ro l ~m i c a cti lt~ ~ e ~: ei
41 ____ __________ 1 5.2
42 40 36 3, 8
43 33 37 2, 6
44 . 47 52 4.2
38 41 3. 9
46 41 ^ 42 4. 3
47 32 39 2.9
48 45 50 1 4.2
. 49 42 48 3. 9
40 . 51 0. 9
51 41 34 0
Clofibrate 38 39 24. 2
Bezafibrate 36 32. 8
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1154452
Test 2:
In the acute toxicity tests, male mice (weight: 22 to 25 g. )
were used in groups of 10 each.
Each active ingredient was dissolved in olive oil and the
solution was orally administrated in a volume corresponding to the
body weight.
LD50 was calculated by the area method from the mortal
percent after 72 hours from the administration,
' The LD50 of the Compound No. 1, 2, 5, 6 and 19 were
respectively greater than 4, 000 mg. /kg.
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