Note: Descriptions are shown in the official language in which they were submitted.
ll~S6~9 MERZ-4-CANADA
The invention relates to new pharmaceutically effective
compounds and their pharmaceutically applicable salts formed
with organic acids as well as to a process for the manufacture
of these compounds.
It is known that atherosclerosis is caused by the accumula-
tion of lipids in the aorta and the coronary, cerebral and peri-
pheral arteries. This results in an increased risk of throm-
boses or artery obstruction. Dependent on the nature of the
increased plasma protein level, either the elevated cholesterol
or triglyceride level is of importance. In this connection even
cholesterol levels exceeding 200-300 mg/100 ml serum and tri-
glyceride levels of 45-66 mg/100 ml serum are considered to be
extremely elevated.
The two most widely known classes of active substances used
in the treatment of hyperlipidemias comprise the ethyl ester of
2-(p-chlorophenoxy)-isobutyric acid - known as clofibrate - and
its salts as well as nicotinic acid which influence the serum
lipids by different modes of action. While in test animals
doses of 30-500 mg/kg body weight mainly effect a lowering of
the cholesterol level in addition to a slight reduction of the
free fatty acids, 3-pyridyl carbinol, nicotinic acid and its
salts bring about a great reduction of the free fatty acids
already at a low dosage between 0.5 and 30 mg/kg body weight.
None of the substances has, however, a significant reducing
influence on triglycerides~ 8esides that, due to its unpleasant
and known side effects (flush, headache, nausea, vomiting)
nicotinic acid can only be conditionally used so that thereapy
often has to be discontinued prematurely.
.~ ~
MERZ-4-CANADA
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Additionally, it is known that clofibrate, in fact, effects
a fall of the initial values of triglycerides (TG) and pre-B-
lipoproteins by up to 50%, this degree of lowering not being
achieved in the case of cholesterol. In about 20% of the cases
the cholesterol (CH) in the B- and ~-lipoproteins is even
further increased. Nicotinic acid and its derivatives, on the
contrary, act predominantly on elevated cholesterol values and
free fatty acids, whereas the decrease of the endogenous re-
synthesis of the triglycerides via inhibition of tissue lipoly-
sis is only a secondary effect (cf. Verhandlungen der Deutschen
Gesellschaft f~r innere Medizin, 82. Kongress, gehalten zu
Weisbaden vom 25. bis 29.4.1976, Teil I, J.F. Bergmann Verlag
M~nchen).
Moreover, FR-PS 6975 mentions the 3-pyridyl carbinol ester
of clofibric acid as effective lipid- and cholesterol-lowering
component. This compound, although being predominantly used in
the form of nicotinate, can only be administered in low dosage
due to the high portion of its pyridine component and the thus
resulting side effects. It is, therefore, of only little thera-
peutic benefit.
All the aforementioned substances effect a significant
reduction of only one of the lipid components, e.g., the tri-
glycerides, while the other lipid components are therapeutic-
ally not or only slightly influenced. This therapeutic effect
can only be achieved by a dose increase.
Therefore, the objective was to find other compounds having
a lowering effect on several lipid components but without dose
increase.
Unexpectedly, this requirement is met by the claimed new
compounds having the general formula explained in claim 1. The
~13Sfi~ M~RZ-4-CANADA
compounds according to the invention exhibit a strong effect on
both increased serum triglyceride and cholesterol values.
In comparison with nicotinic acid and the ethyl ester of 2-(p-
chlorophenoxy)-isobutyric acid the dosages are incomparably
lower so that possible side effects are reduced to minimum.
The new compounds are solid substances.
In the following the manufacture of the new compounds is
described:
Example 1: Preparation of p-cyclohexylphenyl nicotinate
17.6 g l100 mmol) of cyclohexylphenol and 19 g (106 mmol) of
nicotinic acid chloride hydrochloride was mixed with 250 ml
of dry pyridine and kept at 40C for 4 hours. Subsequently,
the mixture was cooled in the ice bath, and water added in
portions. After addition of 10 ml of water a clear solution
was obtained. Water (50 ml) was admixed until strong turbidity
appeared. After stirring the mixture for a longer period of
time the product crystallized in the ice bath. The precipitate
was sucked off, freed from pyridine by washing with water and
dried. A second fraction was obtained from the filtrate by
further addiing water (60 ml).
Yield: 70% of the theoretical value. Fp.: 103~C
Analysis
calculated found
C76.86 76.83
H6.76 6.76
N4.98 5.05
Example ~: Preparation of p-(t-adamantylphenyl)-nicotinate
11.4 g (S0 mmol) of p-1-adamantylphenol and 10 g (56 mmol) of
--3--
MERZ-4-CANADA
113~g
nicotinic acid chloride hydrochloride was mixed with 150 ml of
dry pyridine and kept at 45~C for 4 hours. By adding 40 ml of
water and stirring in the ice bath the product formed a pre-
cipitate which was sucked off, washed with water and dried.
Yield: 78% of the theoretical value. Fp.: 199~C
Analysis
calculatedfound
C79.27 78.01
H6.90 6.82
N4.20 4.50
Example 3: Preparation or 2-(p-chlorophenoxy)-isobutyric
acid-p-(1-adamantylacetyl)-phenyl ester
6.75 9 (25 mmol) of p-(1-adamantylacetyl)-phenol and 6 9 (25.7
mmol) of 2-(p-chlorophenoxy)-isobutyric acid chloride was mixed
with 60 ml of dry pyridine and kept at 40C for 4 hours. After
addition of 40 ml of water a crystalline product was obtained
which was sucked off, washed with water and dried.
Yield: 77% of the theoretical value. Fp.: 114C
Analysis
calculated found
C 72.03 72.12
H 6.64 6.61
Example 4: Preparation of p-cyclododecylphenyl nicotinat~
8 9 (30.8 mmol) of p-cyclododecylphenol and 5.9 q (33.2 mmol) of
nicotinic acid chloride hydrochloride was mixed with 140 ml of
dry pyridine and kept at 30C for 15 hours. Subsequently, 42 ml
of water was added slowly drop by drop, and the mixture cooled
to 0C. The crystallized precipitate was sucked off, freed from
~'
3S~Ei9 MF,RZ-4-CANADA
pyridine by washing with water and dried.
Yield: 85% of the theoretical value. Fp.: 98UC
Analysis
calculated found
C 79.91 79.01
H 8.50 8.54
Example 5: Preparation of p-(cyclohexylacetyl)-phenyl nicotinate
11 g (50 mmol) of p-cyclohexylacectylphenol and 9.6 g (54 mmol)
of nicotinic acid chloride hydrochloride was mixed with 160 ml
of dry pyridine and stirred for 8 hours at 40~C. Subsequently,
water (66 ml) was added drop by drop until the solution was
turbid. The solution was placed in the ice bath, the precipi-
tate sucked off, freed from pyridine by washing with water and
dried.
Yield: 55% of the theoretical value. Fp.~ 103~C
Analysis
calculated found
C 74.30 74.07
H 6.50 6.51
Example 6: Preparation of o-cyclohexylphenyl nicotinate
hydrochloride
15 g (85 mmol) of o-cyclohexylphenol and 16.5 g (93 mmol) of
nicotinic acid chloride hydrochloride was mixed with 200 ml
of dry pyridine and stirred for 24 hours at 30~C. After cooling
precipitated pyridine hydrochloride was sucked off and 300 ml
of water added. The precipitated raw prod~ct was washed with
200 ml portions of water, dissolved in alcohol and reduced by
means of a rotary evaporator. The remaining viscous oil was
MERZ-4-CANADA
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dissolved in 500 ml of dry ether and hydrochlorinated with HCl
gas. Subsequently, the mixture was filtered, washed with ether
and dried.
Yield: 52% of the theoretical value. Fp.: 151-2C
Analysis
calculated found
C68.03 68.11
H6.29 6.30
Cl11.18 11~20
Example 7: Preparation of 5,6,7,8-tetrahydro-1-naphthyl
nicotinate
7 g (47 mmol) of 5,6,7,8-tetrahydro-1-naphthol and 9 g (50 mmol)
of nicotinic acid chloride hydrochloride was mixed with 130 ml
of dry pyridine and stirred for 24 hours at 30 degrees centi-
grade. After cooling precipitated pyridine hydrochloride was
sucked off, and the filtrate mixed with 300 ml of water. The
precipitated raw product was washed with 200 ml portions of
water and recrystallized from methanol.
Yield: 65% of the theoretical value
Melting point: 86 degrees centigrade
Analysis
calculated found
C75.88 75.81
H5.93 6.07
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1135~ MERZ-4-CANADA
Toxicity tests:
Table 1
No. of LDso Human merap.
~ound R1 R2 R3 Mouse daily dose Index
(mg~kg) (mg)
_
2 I Cyclohexyl ~ ridinoyl-(3) ZZ00 300 0,13
1 1-Adamantyl H Pyridinoy1-(3) 3200 300 0,093
= ===___ = ____ ~ -- =_= = = =====
2-0-Chlorophenoxy isobutyric acid
ethyl ester (standard) 1500 1500 1,0
Nicotinic acid (standard) 4000 3000 0,75
Table 1 shows that the toxicity values are in a comparable range thus
resulting in excellent values for the therapeutic index~
Evidence of effectiveness:
Additionally, experiments on female Wistar rats were
carried out. For a period of 3 weeks the animals received a
special diet with a very high fat content. Starting from the
second week, half the rats were treated with a dosage of
100 mg/kg body weight. After the third week blood samples were
taken 18 hours after administration of the last dose. Trigly-
ceride and cholesterol concentrations were compared with that
of the untreated animals. Cholesterol and triglycerides were
determined with the aid of the Boehringer enzymatic test. As
summarized in Table 2, highly significant reductions of both
parameters were achieved. Table 2 also show that the separate
administration of clofibrate and nicotinic acid was by far less
effective.
MERZ-4-CANADA
~3S6~'3
Table 2
Red. ofRed. of triglycer-
~ f R1 R2 R3 choles-ides in %
compound terol in %
1l-Adamantyl H Pyridincyl-(3) 28 47
_
2 Cyclohexyl H Pyridinoyl-(3) 45
4 Cumyl H Pyridinoyl-(3) 24
7 p-Chloro- H Pyridinoyl-(3) 29
benzoyl
8 1-Adamantyl- H 2-Methyl-2-(p- 27 35
acetyl chlorcphenoxy)
propionyl
_ _
Nicotinic
acid (100 mg/kg) 7
2-(p-Chloro-
phenoxy iso- (100 mg/kg) _ 8
butyric acid
ethyl ester
Subject matter of the invention are therefore new compounds of the general
20formula:
R
R~ 0 - R3
/CH--(CH2)-- C 11 ;
Wherein Rl = a) (CH )
H where n = 3 - 12
2 m = 0 - 1
z = O -- 1
b) ~ 2 m ( ~ where m - 0 - 1
MERZ-4-CANADA
~356~
c) Cumyl
d) p-Chlorobenzoyl
e) 1-Piperidinyl
f) 2-Pyrimidinyl
g) Hydrogen, when R2 equals cycloalkyl or cyclo-
alkylene (~CH2~)n'
and R~ = a) (-CH2-)n, where n = 0 or 4
b) Halogen
C ) C1 -C6-Alkyl
d) Methoxy
e) Ethoxy
f) Trifluoromethyl
g) Nitro
O
and R3 = a) - C - ~
b) 2-Methyl-~-(p-chlorophenoxy)-propionyl
and their pharmaceutically applicable salts formed with organic
or inorganic acids.
Additionally, the invention relates to a process for the
manufacture of the compounds according to claim 1, characterized
in that known esterification methods are used such as, e.g.,
the reaction of 1 mol of nicotinic acid chloride with 1 mol of
starting phenol in the presence of at ieast 1 mol of an acid-
binding substance, e.g., pyridine. The preparations according
to the invention consist of compounds according to claim 1 and
usual pharmaceutical adjuvants.
The compounds according to the invention may be processed
into pharmaceutical agents containing a carrier or a diluent in
addition to the active substance. They can be administered by`
` MERZ-4-C~NAD~
1~3S6~3
the oral and the parenteral route.
Solid preparations for oral administration are capsules,
tablets, pills, powders, granulates. In such solid prepara-
tions the active substance is mixed with at least one inert
diluent such as cane sugar, lactose or starch. Additional sub-
stances may be added such as lubricants or buffers. The tablets
or pills may be subject to enteric-coating.
Liquids for oral application are emulsions, solutions,
suspensions containing the commonly used inert diluents such as
water. Additionally, such liquid agents may contain wetting~
emulsifying and dispersing agents as well as sweetening, flavor-
ing and odorous substances.
Preparations for parenteral application are, among others,
sterile, aqueous or non-aqueous solutions, suspensions or emul-
sions. Substances known for this form of presentation are used
as carrier material.
Dependent on mode of application and d~ration of treatment,
the dosage of the active substances in the preparationS may vary.
'.
~3s~g ( ME~Z-4 CANADA
SUPPLEMENTARY DISCLOSURE
-
FURTHER EXAMPLES
Example 8: 2-t-butyl-4-eyelohexylphenyl nieotinate
12 g (52 mmol) of 2-t-butyl-4-eyelohexylphenol and 10 g (56 mmol)
of nieotinie aeid chloride hydrochloride was mixed with 150 ml
of dry pyridine and stirred for 48 hours at 35C. After cooling
preeipitated pyridine hydrochloride was sucked off and the
filtrate mixed with 75 ml of water. The precipitated raw pro-
duct was freed from pyridine by washing with water and re-
erystallized from alcohol.
Yield: 73% of the theoretieal value. m.p.: 115C.
Analysis
calculated found
C 78.33 78.03
H 8.01 7.88
N 4.15 4.07
The eompound had an LD50 in the rat in mg/kg of 1700, an ED50
in the rat in mg/kg of 30 and a therapeutie index of 56. At
a dosage of 25 mg/kg, the percentage cholesterol reduction
- with this compound was 9% and the reduction in triglycerides
was 8~ in the rat.
Example g: p-cumylphenyl nicotinate
42.4 g (200 mmol) of p-cumylphenol and 40 g (220 mmol) nicotinie
acid ehloride hydroehloride was mixed with 600 ml dry pyridine
and stirred for 24 hours at 40C. After eooling preeipitated
pyridine hydrochloride was sucked off and the filtrate mixed
with 150 ml of water. The precipitated raw product was washed
with two 100 ml portions of water and recrystallized from methanol.
Yield: 70% of the theoretical value. m.p.: 56C.
Analysis
calculated found
C79.49 79.59
B5.99 6.06
, ~ /o
( ~RZ-4 CANADA
11356~9
At a dosage of 100 mg/kg of this compound, the cholesterol
reduction was 24% and the triglycerides reduction was 1% in the rat.
Example 10: p-chlorobenzoylphenyl nicotinate
15 g (64.5 mmol) of p-chlorobenzoylphenol and 12 g (68 mmol)
of nicotinic acid chloride hydrochloride was mixed with 200
ml dry pyridine and stirred for 24 hours at 40C. After
cooling 200 ml water were added and the precipitated pro-
duct washed twice with 80 ml of water and recrystallized
from methanol,
Yield: 80% of the theoretical value. m.p.: 172C.
Analysis
calculated found
C - 67.55 67.41
H 3.56 3.64
At a dosage of 100 mg/kg of this compound, the cholesterol
reduction was 29% in the rat.
Example 11: 2-chloro-4-cyclohexylphenylnicotinate
6.4 g (28 mmol) 2-chloro-4-cyclohexylphenol and 5.9 g (33 mmol)
nicotinic acid chloride hydrochloride was mixed with 100 ml
dry pyridine and kept at 40C for 48 hours. By adding 200 ml
of water and stirring in an ice bath, the product formed a
precipitate which was sucked off, washed with water and dried.
Yield: 72% of the theoretical value. m.p. 68C.
Analysis
calculated found
C 68.46 68.66
H 5.71 5.73
Cholesterol reduction is 29%, triglycerides reduction is 2
at a dosage of 100 mg/kg in the rat.
ME~Z-4 CANADA
1135~39
Example 12: 2-nitro-4-cyclohexylphenylnicotinate
8 g (36 ~mol) 2-nitro-4-cyclohexylphenol and 6.9 g (39 mmol)
nicotinic acid chloride hydrochloride was mixed with 100 ml
dry pyridine and kept at 40C for 24 hours. By adding 30 ml
of water and stirring in an ice bath, the product formed a
precipitate which was sucked off, washed with water and
dried. The product was recrystallized from 75 ml methanol.
Yield: 77% of the theoretical value. m.p.: 113C.
Analysis
calculated found
C66.25 66.27
H5.52 5.63
N8.59 8.69
Example 13: 2-chloro-4-(1-adamantyl)phenylnicotinate
13 g (49.5 mmol) 2-chloro-4-(1-adamantylphenyl) and 9.7 g
(54.5 mmol) nicotinic acid chloride hydrochloride was
mixed with 100 ml dry pyridine and kept at 75C for 72
hours. By adding 150 ml of water and stirring in an ice
bath, the produce formed a precipitate which was sucked
off, washed with water and dried. The product was re-
crystallized from 100 ml ethanol.
Yield: 84.5% of the theoretical value. m.p.: 185C.
Analysis
calculated found
C71.83 71.89
H6.03 5.98
N3.81 3.83
Cholesterol reduction is 22%, triglycerides reduction is
14% at a dosage of 100 mgtkg in the rat.
1~
1~3S6~9
EXAMPLE 14, 4-(1-PIPERIDINO)-PHENYLNICOTINATE
Eight (8) grams (45 MMOL) of 4-(1-piperidino)-phenol and
8,5 G (48 ~OL) of nicotinic acid chloride hydrochloride were
mixed with 150 ML dry pyridine and maintained at 40 degrees
centigrade for 24 hours. Then 80 ML of water was added slowly
and, after further addition of 60 ML water, the mixture was cooled
in an icebath. The precipitate was removed by suction filtration,
freed from pyridine by washing with water, and dried.
YIELD: 60% of the theoretical. MP: 126C
ANALYSIS
CALCULATED FOUND
CARXON: 72,34 72,24
H 6,38 6,40
N 9,90 9,92
EXAMPLE 15, 2-(P-CHLOROPHENOXY)-ISOBUTYRIC ACID-4-CYCLOHEXYL-
PHENYLESTER
Seven (7) grams (40 ~OL) of 4-cyclohexylphenol and 10 G (43 MMOL)
of p-chlorophenoxyisobutyric acid chloride were mixed in 70 ML of dry
pyridine and maintained at 40C for 24 hours. Then 20 ML of water
was added slowly and the reaction mixture cooled in an icebath. The
precipitate was removed by suction filtration, freed from pyridine
by washing with water and dried.
YIELD: 81% of the theoretical. MP: 100C
A~ALYSIS
CALCULATED FOUND
CARBON:70,8771,02
H 6,71 6,83
-13~-
