Note: Descriptions are shown in the official language in which they were submitted.
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1 This invention re~ tes to novel hypolipidemic compo-
sitions containing an active in~redient which lower plasma
lipi~ concentrations and to a method of producing hypolipi-
demic activity by administering nontoxic effective quantities
of said ingredient to hyperlipidemic subjects. More specifi- -
cally, the active ingredient used in the compositions and
- methods of this invention is 4-(2-thenoyl)-2,3-dichloro-
phenoxyacetic acid which has the following formula:
2CO~H
F0RMULA I
or an alkali metal salt of said acid, for example the sodium
or potassium salt, or a pharmaceutically acceptable addition
nontoxic salt of said acid formed with a base, for example
the piperazine or (trihydroxymethyl)methylamine salt.
This acid and its preparation is described in U.S.
Patent No. 3 J 758,506. Generally, 2,3-dichloroanisole is
condensed wLth thiophene-2-carboxylic acid chloride in the ~-
presence of aluminum chloride, the re~ulting ketone is
demethylated and ~he hydroxyketone i9 reacted with an ester
of chloroacetic acid to give the product after hydrolysis
of the ester. The compound iq dLsclosed as having diuretic
activity.
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In accordance with the present teachings, a
pharmaceutical composition is provided which comprises
4-(2-thenaly~-2, 3-dichlorophenoxyacetic acid, or a
pharmaceutically acceptable salt thereof, in a dosage unit
range of from about 100 mg. to 500 mg., in combination
with a second active medicinal ingredient used to treat
a disease in which hyperlipidemia is a significant component
or with a second hypolipidemic agent, the second active
medicinal ingredient is selected from the group wherein
guanethidine, alpha methyldopa, phentolamine, yohimbine,
phenoxybenzamine, reserpine, propranolol, hydralazine,
diazoxide, tolbutamide, chlorpropamide, phenformin, allopurinol,
probenacid, sulfimpyrazine, cholestyramine, nicotinamide, para-
aminosalicylic acid, norethynodrel, norethindrone, norethin-
drone acetate, medroxyprogesterone acetate, ethynodiol
diacetate, mestranol, ethinyl estradiol, spironolactone,
triamterene or chlorothalidone and a nontoxic pharmaceutical
carrier.
Abnormal plasma lipid concentrations are a part of
coronary heart disease and therefore the reduction of ele-
vated plasma lipids is a desirable goal in the long term
management of such disease. The hypolipidemic activity
o~ 4-(2-thenoyl)-2,3-dichlorophenoxyacetic acid or its
f
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1 salts is readily demonstrated in rats by oral administra-
tion of the compound at a dose of 300 mg/kg/day for 14 days.
On the morning of the fifteenth day, animals are given
150 mg/kg of compound 30 minutes prior to sacrifice. The
animals are anesthetized and bled by cardiac puncture.
Livers are removed, blotted, weighed and homogenized.
Kidneys are excised, decapsulated and weighed. Plasma free
- fatty acid is analyzed, and plasma and hepatic triflycerides
and cholesterol are determined by standard methods.
The results of testing 4-(2-thenoyl)-2,3-dichloro-
phenoxyacetic acid as described above are summarized in
Table I. Compared to controls, the test compound showed a
significant decrease in body weight gain, kidney weight
was unaffected and liver weight was increased. Pla~ma tri-
glycerides were significantly reduced but plasma cholesterol
concentrations were not significantlg affected, nor was
there a significant effect on free fatty acids. Hepatic
- lipid concentrations are expressed as mg/g liver wet weight
and~as mg/liver. The test compound did not have a signifi-
cant effect~on hepatic cholesterol when expressed as mg/g
liver, however total hepatic chole~terol was increased.
Hepatic triglyceride concentration was significantly reduced
but total hepatic triglyceride was not affected.
In a human clinic~l study, ~-(2-thenoyl)- ~
2,3-dichlorophenoxyacetic acid has been found to decrease ~ -
serum triglycexide levels at an oral daily dose of 1000 mg.
after six weeks administration.
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TABL~ 1
EFFECT OF 4~ THENOYL)-2,3-DICHLOROPHENOXYACETIC ACID ON
BODY WEIGHT GAIN, LIVER W~IGHT, KIDN~Y WEIGHT, AND PLASMA
AND HEPATIC LIPID CONCENTRATIONS
ENDPOINT CONTROL COMPOUND
0.5% Gum 150 mg/kg
Tragacanth b.i.d.
. .
INITIAL BODY WEIGHT (g) 196 + 7 193 ~ 6
_
FINAL BODY WEIGHT (g) 286 _ 13 268 ~ 10**
- BODY WEIGHT GAIN (g) 90 + 11 74 + 6***-
1 0 ~ V/ )
LIVER WEIGHT (g) 11.8 + 1.1 13.8 + 1.2**
(+17V/
.
. KIDNEY WEIGHT 2.1 + 0.2 - 2.1 + 0.1 NS
,: _
PLASMA LIPIDS
Cholesterol mg/100 ml 64 + 13 61 + 5 NS
(-5~
Triglyceride mg/100 ml 77 + 33 35 + 15**
(-54/0)
Free Fatty Acid~ ~Eq/liter 338 ~ 106 287 i 116 NS
: (-33%)
HEPATIC LIPIDS
Cholesterol mg/g liver 2.9 + 0.1 2.8 + 0.4 NS
( _3V/o~
Cholesterol mg/liver 33.8 _ 3.2 38.1 + 5.4*
(+13V/o~
Triglyceride mg/g liver 5.0 + 0.7 3.9 + 0.5***.
~ (-22~
Triglyceride mg/liver 58.8 + 11.0 53 8 + 9.0 NS
. ~ .
NS = Not significant
*p~ 0.05; **P ~ 0.01; ***P~ 0.001 compared to control group.
Values are ~ + S.D. Values in parentheses are percent
change from control.
10 animals per group.
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1 The hypolipidemic compositions of this invention
are prepared in conventional dosage unit forms by incorpora-
ting 4-(2-thenoyl)-2,3-dichlorophenoxyacetic acid or a
pharmaceutically acceptable salt thereof, in a nontoxic
amount sufficient to produce hypolipidemic activity in the
designated subject, with a nontoxic pharmaceutical carrier
according to accepted procedures. Preferably the composi-
tions will contain the active ingredient in an active but
nontoxic amount selected from about 100 mg. to about 500
mg. of active ingredient per dosage unit.
The pharmaceutical carrier employed may be, for
example, either a solid or liquid. Exemplary of solid
carriers are lactose, terra alba, sucrose, talc, gelatin, -
agar, pectin, acacia, magnesium stearate, stearic acid and
the like. Exemplary of liquid carriers are syrup, peanut
oil, olive oil, water and the like. Similarly the carrier
or diluent include any time delay material well known to
the art, such as glyceryl monostearate or glyceryl di- -
stearate alone or with a wax.
A wide yariety of pharmaceutical forms can be
employed. Thus, if a solid carrier is used the preparation
can be tableted, placed in a hard gelatin capsule in powder
or pellet form or in the form ~f a troche or lozenge. The
amount of solid carrier will v2ry widely but preferably - -
will be from about 25 mg. to about 1 g. If a liquid car-
rier is u8ed, the preparation will be in the form of a
syrup, emulsion, soft gelatin capsule, sterile injectable
liquid such as an ampule or an aqueous or nonaqueous
liquid suspension.
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l The method in accordance with this invention com-
prises administering internally to an animal subject in need
of hypolipidemic activity, i.e. a hyperlipidemic subject,
the compound 4-(2-thenoyl)-2,3-dichlorophenoxyacetic acid or
a salt thereof, usually combined with a pharmaceutical car-
rier, in a nontoxic amount sufficient to produce hypolipi-
demic activity. The àctive ingredient will be administered
preferably in a dosage unit, in an active, nontoxic quanti-
ty selected from about lO0 mg. to about 500 mg. of the
parent chemical of Formula I. The route of administration
may be orally or parenterally, the oral route being pre-
ferred. Advantageou.sly equal doses will be administered
two to four times daily with the daily dosage regimen being -
from about 200 mg. to about 2000 mg. When the method
described above is carried out hypolipidemic activity is
produced with a minimum of side effects.
The pharmaceutical preparations are made following
the conventional techniques of the pharmaceutical chemist
involving mixing, granulating and compressing when necessary,
or variously mixing and dissolving the ingredients as
appropriate to the desired end product;
Also included within the scope of this invention r-
are pharmaceutical compositions comprising 4-(2-thenoyl)-
2,3-dichlorophenoxyacetic acid or a salt thereof as
described above in combination either with a second active
medicinal ingredient used to treat a disease in which
hyperlipidemia is a significant component but which agent
- u8ed to treat the disease or abnormal condition does not
reduce the plasma lipid levels of the subject, or with a
second hypo1ipidemic agene. Such disease8 and ingredients
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1 useful in the combination with the active ingredient of
this invention are as follows:
1. Hypertension with associated hyperlipidemia
a) drugs acting on the afferent sympathetic
nervous system
(1) ganglionic blocking agents such as
guanethidine
(2) centrally active drugs such as alpha
. methyldopa, phentolamine or yohimbine and alpha adrenergic
blocking agents such as phenoxybenzamine
(3) peripherally and centrally active
drugs such as re~erpine and beta adrenergic blocking agents 8uch as propranolol
: . b) drugs acting on arteriola smooth muæcle
8uch as hydralazine or diazoxide -
2. Diabetes with associated hyperlipidemia
. hypoglycemic agents such as tolbutamide,
` ~ chlorpropamide or phenformin
;.i 3. Hyperuricemia with associated hyperlipidemia
agents such as allopurinol, probenacid or
- 8ulfimpyrazine
4. Hyperlipidemia
agents such as cholestyramine, nicotinamide
or para-aminocalicylic acid
25. 5. Hyperlipidemia induced by oral contraceptives
agents such as norethynodrel, norethindrone
and acetate, medroxyprogesterone acetate, ethynodiol
diacetate, mestranol or ethinyl estradiol
6. Edema treated with potas8ium sparing diuretics
such as spironolactone or triamterene, or hypertension
.. . .
treated with a diuretic such as chlorthalidone.
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These combination compositions will contain per
dosage unit the same amount of 4-(2-thenoyl)-2,3-dichloro-
phenoxyacetic acid or a salt thereof as indicated above,
namely within the dosage unit range of from about 100 mg.
to 500 mg. The amount of the second active ingredient will
be the same dosage set forth for the ingredient in the
"Physicians' Desk Reference", 28th Edition, 1974. Specific
examples of combination compositions are as follows:
4-(2-Thenoyl)-2,3-dichloro- Second Active
Phenoxyacetic acid Ingredient In~ication
100 mg. to 500m.mg. allopurinol hyperuricemia
100 mg, to with hyper-
300 mg. lipidemia
100 mg. to 500 mg,cholestyramine hyperlipidemia
4 g,
100 mg, to 500 mg,alpha methyldo- hypertension
pa 250 mg. with hyper-
lipidemia
100 mg. to 500 mg.chlorthalido- hypertension
ne 50 mg. to with hyper-
100 mg. lipidemia
100 mg, to 500 mg, reserpine hypertension
0.1 mg. to with hyper- -
1 mg. lipidemia
100 mg, to 500 mg, triamterene edema with
25 mg, to hyp~rlipi-
100 mg. demia
The following examples illustrate the preparation
of the hypolipidemic and combination compositions of this
invention,
Ingredients Mg./Table~
4-(2-Thenoyl)-2,3-dichloro 250
phenoxyacetic acid
Corn starch 30
Polyvinyl pyrrolidone 12
Corn starch 16
30 Magnesium stearate 3
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The first two ingredients are thoroughly mixed and granulated
with a 20~ w/v solution of polyvinyl pyrrolidone in water.
The wetted mass is passed through a ~4 mesh screen directly
onto drying trays. The granules are dried at 50C. and
mixed with the remaining corn starch and magnesium stearate,
and compressed into tablets. The tablets are administered
to a hyperlipidemic subject 3 times daily.
Ingredients Mg./Capsule
4-t2-Thenoyl)-2,3-dichloro- 500
phenoxyacetic acid
Magnes~nm stearate 2
10 Lactose 50
The above ingredients are screened through a #40 mesh
screenn, mixed and filled into #0 hard gelatin capsules.
; The capsules are administered to a hyperlipidemic subject
twice daily.
Ingredients Mg./Tablet
4-(2-Thenoyl)-2,3-dichloro- 250
phenoxyacetic acid
Starch 30
Povidone 12
20 Triamterene 25
Starch 16
Primojel R 12.5
Magnesium stearate 3
The ~irst two ingredients are thoroughly mixed and
granulated with a 25% w/v solution of Povidone in
water. The wetted mass is passed through a ~4 mesh
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screen and placed onto trays. The granulated material
is dried at 500C. and passed through a ~10 mesh screen.
The triamterene, Primojel, magnesium stearate and
remaining starch, after passing through a #40 mesh screen,
are mixed with the granulated material and compressed
into tablets.
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In accordance with the teachings of the principal
disclosure, a hypolipidemic composition is disclosed which
contains 4-(2-thenoyl)-2,3-dichlorophenoxyacetic acid or a
pharmaceutically acceptable salt thereof and a nontoxic
pharmaceutical carrier. The pharmaceutical composition may
comprise in addition to the active ingredient 4-(2-thenoyl)-2,
3-dichlorophenoxyacetic acid a second active medicinal ingredient
used to treat a disease in which hyperlipidemia is a significant
component or with a second hypolipidemic agent together with a
nontoxic pharmaceutical carrier. The preferred second active
medicinal ingredient is triamterene and may be present in a
dosage unit range of from 25 mg. to 100 mg. with the active
ingredient the 4-(2-thenoyl)-2,3-dichlorophenoxyacetic acid in
a dosage unit range of from about 100 mg. to 500 mg.
Now, and in accordance with the teachings of the
supplementary disclosure, it has been found that the composition
comprising 4-(2-thenoyl)-2,3-dichlorophenoxyacetic acid or a
pharmaceutically acceptable salt thereof and triamterene with
a nontoxic pharmaceutical carrier has been found useful as a
diuretic and has further been found to have hypotensive
properties. Thus, the new teachinqs now include a diuretic or
hypotensive pharmaceutical composition in dosage unit form
comprising per dosage unit 4-(2-thenoyl)-2,3-dichlorophenoxy-
acetic acid, and an alkali metal salt of said acid or a
- pharmaceutically acceptable addition salt of the acid formed
with a base, in a nontoxic amount selected from about 100 mg.
to about 500 mg. and from about 25 mg. to about 100 mg. of
triamterene, and a nontoxic pharmaceutical carrier.
A particularly useful diuretic combination
composition of this invention contains per dosage unit
4-(2-thenoyl)-2,3-dichlorophenoxyacetic acid or a pharmaceutic-
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ally acceptable salt thereof in an active but nontoxic amountselected from about 100 mg. to about 500 mg. and from about
25 mg. to about 100 mg. of triamterene. This combination is
also useful as a hypotensive composition. Preferably the
combination composition will contain a ratio of said phenoxy-
acetic acid ingredient to triamterene of 10:1. Such combination
compositions have a synergistic effect on sodium excretion
thereby increasing the amount of sodium excreted above the
responses achieved by the single ingredients at comparable
doses. The synergistic effect is demonstrated in the Na
deficient rat test which measures saluretic and kaliuretic
effects in rats which have been on a Na deficient diet for
4 days, fasted overnight and then given-a water load and sodium
chloride providing 10 mg. Na per rat. Urine is collected for
6 hours and analyzed-for Na AND K . Results of 2 separate
experiments are set forth in Table II.
In Experiment #73075, the rats on 15 and 30 mg/kg p.o.
of triamterene excreted approximately the same amount of sodium
(3.31 and 3.04 mg., average pe~ group of 8). With 150~and 300
mg!kg p.o. of 4-(2-thenoyl)-2,3-dichlorophenoxyacetic acid
("phenoxyacetic acid"), the quantity of sodium excreted was less
than with triamterene (0.61 and 1.71 mg.). When both compounds
were combined at the low and high doses, a synergistic effect
on sodium excretion was observed. After the combination of
15 mg/kg of triamterene and 150 mg/kg of phenoxyacetic acid,
sodium excretion was 5.14 mg. At the higher doses, 30 mg/kg of
triamterene and 300 mg/kg of phenoxyacetic acid, sodium excretion
rose to 10.18 mg. This value greatly exceeds the response of the
o .
- individual effects at these doses. The combination doses were
also effective in lowering potassium excretion a~d elevating
the ~ajK ratio. Wlth either triamterene or phenoxyacetic acid
~ 12
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alone the Na/K ratio did not rise above 1.93. After low and
high doses of the combination these values were elevated to
3.41 and 9.03 respectively.
In Experiment $92475, 15 and 20 mg/kg p.o. of
triamterene produced a dose response effect on sodium excretion
(2.91 and 4.88 mg.). The responses to 150 and 300 mg/kg p.o. of
phenoxyacetic acid were 0.78 and 1.18 mg. The combination of
15 mg/kg of triamterene and 150 mg/kg of phenoxyacetic acid
resulted in a sodium excretion of 5.79 mg. At the higher doses
(30 mg/kg of triamterene and 300~mg/kg of phenoxyacetic acid)
of the combination the output of sodium was 7.47 mg. Again, the
combined effect was much more pronounced than the natriuretic -
response seen with each compound alone. Potassium excretion was
also less with the combination.
With either compound alone the highest Na/K ratios
were observed with triamterene (2.32 and 3.48). Values for the
low and high doses of the combination rose to 5.32 and 6.22.
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TABLE II
Sodium Deficient Rat Test
4-(2-Thenoyl)~2,3-Dichlorophenoxyacetic acid + Triamterene
Sodium Potassium
Dose Excreted Excreted Na/K
Drug mg/kg p.o. (m~)* (mg)* Ratio
Experiment #73075
Control ---_ 0.13 3.99 0.6
Triamterene 15 3.31** 2.88 1.93
3.04** 4.18 1.23
Phenoxyacetic150 0.61 3.07 0.34
acid
300 1.71 8.88 0.32
Triamterene15 ) 5.14** 2.59 3.41
+
Phenoxyacetic150 )
acid
Triamterene30 ) 10.18** 1.91 9.03
+
Phenoxyacetic300 )
acid
Experiment #92475
Control --- 0.25 2.37 0.18
Triamterene 15 2.91** 2.13 2.32
4.88** 2.35 3.48**
Phenoxyacetic150 0.78 2.17 0.64
acid
300 1.18 5.17 0.39
Triamterene15 ) 5.79** 1.82 5.32**
Phenoxyacetic150 )
acid
Triamterene30 ) 7.47** 2.06 6.22**
Phenoxyacetic300 )
acid
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* Average per group
** Significant p= < 0.05
8 ar,imal~ per group
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The invention has been described in detail with
particular reference to preferred embodiments thereof, but it
will be understood that variations and modifications can be
effected within the spirit and scope of the invention.
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