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Патент USA US3092644

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United States Patent ()??ce
Patented June 4, 1963
on the skin alone, serious side reactions, such as profound
lowering of the flood pressure, as well as direct action on
the heart muscle, require that these drugs be used very
cautiously. Severe headache is also common for the
patient who takes nitrates in larger dosages, and this limits
Alfred Halpern, Great Neck, N.Y., assignor to Synergis
tics, Inc, New York, N.Y., a corporation of New York
No Drawing. Filed Aug. 24, E59, Ser. No. 335,406
the amount of the drug which may be administered, con
sequently may prevent a patient from receiving the opti
5 Claims.
(Ql. zen-295.5)
mal therapeutic dosage. Furthermore, the duration of
The present invention relates to novel nitric acid ester
derivatives of nicotinic acid and their method of prepara 10 the pharmaocologic effects of a nitrate compound is run
predictable, with certain nitrates causing a short and fleet
tion. In particular, it describes the bis-nitric acid ester
ing e?ect (as for example, nitroglycerin), while others,
of nicotinic acid-‘bis—i(beta -hydroxyethyl) - amide, which
derived from closely relating materials, cause a rather
may also be referred to as nicotinic acid-bis-(beta-nitro
effect (such as erythritol tetran-itrate). A
ethyl)~amide; its acid addition salts as well as the salt, the
tolerance to nitrate drugs is known to develop and this
nitric acid ester of bis-(beta-hydroxyethyl)amine nicotin 15 requires
increasing dosage to sustain its effect.
ate, which may also be referred to as, bis-(beta-nitro
ethyl)amine nicotinate and the chemical processes for
In contrast to these problems associated with the use of
the older vasodilating drugs, the products or“ the present
their synthesis.
invention exert a uniform vasodilating effect on the blood
An object of this invention is the provision of new and
vessels situated both in [the skin and in the deep muscles.
improved therapeutic agents which may be used to relax 20 The
compounds are non-toxic and highly effective as
blood vessels, thereby causing a vasodilatation, with con
drugs capable of causing a rapid onset of
sequent lowering of the systemic blood pressure as well
action, which extends over a su?-lcient period of time to
as improving the circulation of blood through the tissues.
permit a continuous therapeutic action by proper spacing
The role of vIasodi'la-tation in modern medical practice is
of dosage administration. These agents may be com
becoming increasingly more important since it has been
determined that many serious diseases are caused by cir
culatory de?ciencies. These de?ciencies may arise from a
spasm (or a blockade) of conducting blood vessels, which
25 pounded into tablets or liquid preparations suitable for use
reduces the volume of blood coursing through the tissues
which these vessels supply. While the immediate e?ect
of a reduction of the blood supply to an area may be evi
denced through pain and cyanosis, this state, if allowed
to persist, will result in gangrene and loss of a limb.
Should this reduced blood supply occur in a vital area,
such as the blood supply of the heart muscle ‘or ‘the blood
supply of the brain, 'the immediate elfects may be total
incapacitation and very often death.
The method of treatment of such circulatory disturb
ances involves the institution of appropriate vasodil-ating
measures, either by pharmacologic means or through sur 40
gery. Because of the ‘general widespread nature of oc
clusive artertial disease, the surgical approach is of limited
value and has been found useful in relatively ‘few types of
these pathologic entities. In addition, the inherent risks
of surgery to a patient with an already deteriorating vas
in both veterinary and human medicine.
The bis-nitric acid ester of nicotinic acid-‘bis-(beta-hy
droxyethyl)amide is obtained as a result of the inter
reaction between nicotinyl acid chloride and the bis-nitric
acid ester of diethanolamine, carried out under anhydrous
conditions in the presence of a hydrogen chloride acceptor,
for example, triethyl amine. The reaction may be pos
tulated to proceed as fol-lows:
0001 onou
Bis-nitric acid ester of nicotinic acid-b-is-(beta-hydroxy
ethyl)amide is a crystalline compound, melting at 147°
cular system further detracts trom this manner of therapy.
to 149 ° C., which is di?icultly soluble in isoprop'anol, but
Conservative medical management remains the method of
is soluble in methanol. This compound, obtained in
choice for approaching problems of diminished blood
the monohydrate form, has an empirical ‘formula of
circulation resulting :trom occlusive vascular disease.
C1OH12O7N4l-I2O and the molecular weight of 318.2. It
Vasodilating drugs have been widely employed for this
analyzes for carbon, hydrogen, and nitrogen in good
purpose although with varying success.
agreement with the theoretical values which are calculated
Among the ‘drugs utilized for vasodilatation are included
as 37.74 percent carbon, 4.43 percent hydrogen, and 17.61
nicotinic acid; its derivatives, and the inorganic and or
percent nitrogen. The analysis of the product obtained
ganic nitrates. Both of these classes of compounds have
by the method described shows that it contains carbon,
many speci?c advantages, as well as limitations (in the
38.37%; hydrogen, 4.43%; and nitrogen, 17.94%. The
scope of their application to vascular medicine). Thus,
structural formula of the base may be postulated as:
it is found that the action of nicotinic acid is ?eeting and,
since short transient vasodilatation is of little value in
the over-all management of these disease entities, con
tinued administration of nicotinic acid therapy becomes a
necessity. This is both impractical and uneconomic for
the patient. Another limitation of the use of nicotinic
The nicotinic acid salt ‘of the bis-nitric acid ester of di
acid is its predominant action on the vessels of the skin,
ethanolamine although having the same empiric formula
resulting in both a ‘feeling of discomfort and an onset Of a
disturbing reddening of the skin which has been noted as a 65 (C10H14O3N4) as the “amide” monohydr-ate exhibits dif
‘ “blush.”
Furthermore, uasodilatation of the surface ves
sels is only of ancillary importance to the over-all thera
peutic program.
The nitrates exert a direct vasodilating action on the
muscle of the arteries. While the action of the nitrates
is exerted on the deeper vessels of the muscles rather than
ferent chemical and pharmacologic properties. The
major and signi?cant ‘difference between the two resides
in the manner and site of action of these drugs.
The salt, which is a polar compound, is dissociated at
the pH of physiologic ?uid so that rapid tissue availabil
ity of the nicotinic acid moiety results, when the com
pound reaches the physiologic pH range of the blood
ice water, and the solvent evaporated under diminished
stream. This earlier availability of nicotinic acid permits
pressure. The residue is dried in vacuo over phosphorus
pentoxide and consists of a dark-red oil which readily
the vasodilatation of the vessels of the skin to precede that
of the deeper vessels which results from the nitric acid
ester of diethanolamine portion of the molecule. Thus,
the more ?eeting vasodilatation of the nicotinic acid is
dissolves in methanol and ethanol although after standing
(for approximately 12 hours) the ethanol solubility is
greatly diminished. The “oil” is boiled with isopropanol
and a large insoluble fraction remains which is slightly
soluble in methanol. The isopropanol extract is ?ltered
supported and sustained by the onset of secondary action
of the nitrates. This synergism of physiologic etfects is
extremely important since it permits a more etfective dual
and the ?ltrate set aside to crystallize.
approach to the problem of obtaining an increased blood
The crystalline precipitate which develops in the iso
supply to surface areas and consequently is important to 10
propanol extract melts between 135° and 139° C. This
the treatment of cold induced vaso-constrictive disorders
crystalline material is only slightly soluble in boiling iso
of the skin, such as Raynaud’s disease, acrocyanosis,
propanol but can be readily recrystallized from methanol,
chilbains and the like. Since the nicotinic amide is much
more resistant to cleavage than is the polar bond of the
after which, it melts at 147° to 149° C. The pure, crystal
line material is the bis-nitric acid ester of nicotinic acid
salt, the “amide" compound begins its principal actions
bis-(beta-hydroxyethyl)-arnide (monohydrate) with an
through the nitrate moiety on the deeper vessels. In
the course of its metabolic degradation, however, the
empirical formula of C101'I140g1‘14 and a molecular weight
of 318.2. It analyzes for carbon, hydrogen and nitrogen
as 38.3% carbon; 4.43% hydrogen; and 17.94% nitrogen.
pharmacologic activity is transferred to the nicotinic acid
portion and the vessels of the skin. Thus, virtually op
The theoretical content of these atoms are carbon,
posite pathways of pharmacologic activity are obtained
through the administration of these separate compounds,
37.74%; hydrogen, 4.43%; and nitrogen, 17.61%. This
compound is the monohydrate corresponding to the fol
lowing structural formula:
although a similar end-result of an increased blood supply
to the tissues is obtained. It is just these differences in
the mechanism of therapeutic action that bestow special
signi?cance to each of these compounds in therapy. Each 25
compound has an important and valuable place in supply
ing a special pharmacologic effect ‘for a particular patient
The nicotinic acid salt of the bis-nitric acid ester of
Example 2
diethanolamine is obtained by reacting stoichiometric 30
To 3.5 grams ‘of the bis-nitric acid ester of diethanol
equivalents ‘of nicotinic acid and bis-nitroethanolamine
amine dissolved in 75 cc. of absolute ether and contained
in an alcoholic solvent. The desired compound, obtained
in a glass vessel ?tted with a delivery funnel, a moisture
by precipitation with ether, is a crystalline, yellow colored
trap, and a stirring device, and cooled to a temperature
solid melting at 130° to 131° C. The compound is ob
tained as a monohydrate corresponding to the formula
C10H14O8N4-I-12O, with a molecular weight of 336.26 and
has a theoretical nitrogen content of 16.66% (Found per
of less than 5° C., is added 2.5 grams of nicotinyl chloride
dissolved in 25 cc. of absolute ether. A light yellow
precipitate forms immediately which after 15 minutes of
stirring is vacuum ?ltered at room temperature and
cent nitrogen, 16.50%). The following structure may be
washed with dry ether. The dried precipitate is ground
postulated for the salt:
40 with 30 cc. of methanol and the mixture heated to boil
ing and allowed to crystallize by cooling. The crystal
line material obtained in this manner melts at 153°-155°
C. and is the hydrochloride of the bis-nitric acid ester of
nicotinic acid-bis- (beta-hydroxyethyl ) -amide.
The base material may be obtained by neutralization
When it is desired to utlize these novel nitric acid alkyl 45 with sodium carbonate solution, although this is not neces
ester derivatives of nicotinic acid in clinical practice, they
may be compounded into tablets, capsules and solutions
both for oral and parenteral administration. These
pharmaceutical preparations are prepared so that each
sary since the hydrochloride salt of the amide may be
utilized in therapy.
Should it be desired to utilize other pharmacologieally
acceptable acid addition salts than the hydrochloride salt
unit will supply a dose of from 25 to 50 mg. of the active 50 of the “base,” then these may be formed from the base
compound and may be administered several times daily
in accordance with the individual patient’s needs.
The following examples describe the products of my in
vention and the processes for obtaining them:
Example 1
To 3.5 grams of nicotinyl chloride hydrochloride dis
solved in 25 cc. of dry chloroform, is added 2.0 grams
compound by treatment with the appropriate acid in either
aqueous or alcoholic media. Thus, through the utilization
of either hydrogen bromide, sulfuric acid or dilute nitric
acid, the respective acid salts of the base would be ob
tained. Other pharmacologically ‘acceptable acid addition
salts may be similarly formed. Such salts may also be
obtained by metathesis between the hydrochloride and
a salt of the desired acid.
However, other than from
of triethylamine in the cold. This mixture is slowly added,
the viewpoint of different solubility characteristics and
35:117 (1935)) and 4.0 grams of triethylarnine in 50 cc.
of dry chloroform, contained in a ?ask ?tted with a mois
Example 3
with constant stirring, to a mixture of 5.0 grams of nitric 60 physical properties, these acid salts impart no new thera
acid ester of diethanolamine nitrate (Mem. Poudres.
peutic properties.
ture trap, a delivery tube and a stirring device. The tem
A mixture of 1.5 grams of the bis-nitric acid ester of
perature of the reacting mixture is maintained below 65 diethanolamine and 0.95 gram of nicotinic acid in 10 cc.
0° C., and the reaction allowed to proceed until no further
of methanol are heated for 15 to 30 minutes to dissolve
evolution of hydrogen chloride occurs. The stirring is
the components. The solution is allowed to cool slowly
continued while the reaction mixture is allowed to warm
to room temperature and set aside to stand overnight.
to room temperature and then maintained ‘at room tem
The dark-red solution is then mixed with su?icient ether
perature for an additional two hours. The ‘resultant pre 70 to just initiate precipitation and the mixture cooled. The
cipitate is ?ltered and consists of the hydrochloride acid
precipitate is ?ltered; dried and is found to melt (with
salt of the bis~nitric acid ester of diethanolamine (melt
decomposition) ‘over a range of from 110° to 160° C.
ing point 145° C. and may be identi?ed by mixed melt
This dried impure salt is recrystallized several times from
ing point techniques as well as chloride analysis).
a mixture of ethanol and ether until a light-yellow, crys
The chloroform solution is extracted several times with
talline ?ake is obtained which melts sharply at 130° to
131° C. This compound is the m‘onohydrate of nicotinic
acid salt of the bis-nitric acid ester of diethanolamine
simple solution of the active material in the desired ve
hicle which may consist of from 10 to 30 percent of alco
i101 and water. It is desirable to maintain the concen
tration of active material per unit dose (teaspoonful) of
drum 25 to 50 mg. of active material whether the aqueous
syrup solutions are used or the hydroalcoholic vehicles are
and has a molecular weight of C10H16O9N4 corresponding
to the ‘following structural formula:
Example 7
Solutions for injection may also be prepared by dissolv
ing the appropriate quantity of the active material in
The compound analyzes for nitrogen, as follows: Calcu
sterile water for injection, maintaining an aseptic tech
lated percent nitrogen, 16.66%; found percent nitrogen,
nique throughout. The solution may be sterilized
through the process of bacteriol-ogic ?ltration and ?lled
Example 4
‘In place of the nicotinyl chloride, described in Example
2, may be substituted nicotinyl bromide, in stoichiometri
into sterile glass ampules so that each cc. contains from
25 to 50 mg. of active material. The solution may be
administered by either intravenous ‘or intramuscular injec
c-ally equivalent amounts and the remainder of the process
carried out as described in Example 2. The resultant
tion, in accordance with the patient’s needs, utilizing the
able cations may be substituted for the chlorine atom
When it is desired to take advantage of the different
well-known precautions common to this method of admin
product is the hydrobromide salt, in place of the hydrogen 20 istration.
chloride salt. Similarly, other pharmacologically accept
and other pharmacologically acceptable acid salts secured
Example 8
times of action of the “amide” base and/ or its acid addi
directly as the reaction product. ‘In each case the base
tion salts, on the one hand and the “salt” on the other,
may be obtained by neutralization of the salt.
25 the two may be combined in a tablet or any of the other
dosage forms mentioned above in unit dosages so that the
Example 5
combined active material equals 25 to 50 mg. Ordinarily
When it is desired to utilize ‘for therapy the bis-nitric
50 percent of each group is preferred, but if the action
acid ester of nicotinic acid-lbis-(beta-hydroxyethyl) amide,
desired calls for more emphasis on the quicker action of
or its acid salts, or the salt, bis~(beta-nitroethyl)amine 30 one or the other the percentage mixture may be varied.
nicotinate, as a tablet or a capsule, the ‘concentration of
What is claimed is:
active material per unit dose is adjusted so that it con
tains from 25 to 50 mg. of active material and is admin
1. A compound selected from the group consisting of
the nitric acid ester of bis-(beta-hydroxyethyl)-amine
nieotinate, bis-nitric acid ester of nicotinic acid-bis~(beta—
istered according to the patient’s needs.
Tablets may be prepared by granulating the active ma
terials with a diluent, as for example, milk sugar, in ratio
hydroXyethyD-amide and the pharmacologically accept
able acid addition salts of the last mentioned compound.
of at least one part active material to 9 parts of diluent.
2. The nitric acid ester of ibis-(beta~hydroxyethyl)
The use of the well-known binders or lubricants which
amine nicotinate.
are essential to good tablet manufacture also may be
3. Bis-nitric acid ester of nicotinic acid~bis~(beta-hy
added in appropriate concentrations as is well known to 40 droxyethyl) amide.
the art, in accordance with the particular tablet require
4. Bis-nitric acid ester of nicotinic acid-bis-(betaby
ments. After the granulation step, in the preparation of
droxyethyD-amide hydrogen chloride.
tablets, the mixture is compressed into tablets each con
5. The bis-nitric acid ester of nicotinic acid-bis-(beta
taining from 25 to 50 mg. of active material. These tab
hydroxyethyl) -amide hydrogen bromide.
lets are then administered to the patient in accordance 45
with his own needs dependent upon the age of the patient
References Cited in the ?le of this patent
and the severity of the disease.
The granulating mixture which is obtained prior to
Hein et al. ____________ __ Sept. 7, 1954
compressing of tablets may be ?lled into gelatin capsules,
O?e et al. ____________ __ Oct. 16, 1956
utilizing the same unit range of dosage (viz. 25 to 50 mg.
N-ishizawa _____________ __ Jan. 8, 1957
of active material per capsule). These capsules are ad
Mueller ______________ __ May 13, 1958
ministered to the patient in the same order of frequency
as would be the tablets.
Example 6
Should a solution be preferred as a dosage form for
therapeutic administration then both aqueous and hydro
alcohol-ic solutions may be prepared. The preparation of
an aqueous solution is accomplished by dissolving the
appropriate amount of the active material in simple syrup 60
and adding ?avoring and coloring agents, if desired. The
preparation of hydroalcoholic solutions is achieved by
Sahyun ______________ __ June 16, 1959
Tien ________________ __ Aug. 18, 1959
Ferguson _____________ __ Aug. 2, 1960
Germany ____________ __ Feb. 18, 1954
Karrer: “Org. Chemistry,” page 131 (1950).
Drefahl et al.: Chem. Ber, volume 87, pages 1628-31
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