U.S. patent number 4,954,526 [Application Number 07/316,958] was granted by the patent office on 1990-09-04 for stabilized nitric oxide - primary amine complexes useful as cardiovascular agents.
This patent grant is currently assigned to The United States of America as represented by the Department of Health. Invention is credited to Larry K. Keefer.
United States Patent |
4,954,526 |
Keefer |
September 4, 1990 |
**Please see images for:
( Certificate of Correction ) ** |
Stabilized nitric oxide - primary amine complexes useful as
cardiovascular agents
Abstract
A method of treating cardiovascular disorders in a mammal, by
administering to said mammal an effective amount of a compound of
the formula: wherein R is loweralkyl, aryl, arylalkyl, or
cycloalkyl, any of which R groups may be optionally substituted by
one to three substituents selected from the group consisting of:
halo, hydroxyl, alkoxy, amino, amido, formyl, carboxyl, or nitro;
and wherein X is a pharmaceutically acceptable cation, a
pharmaceutically acceptable metal center, or a pharmaceutically
acceptable organic group selected from loweralkyl, acyl or amido,
and Y is 1 to 3 consistent with the valence of X. Pharmaceutical
compositions containing the compounds are also provided.
Inventors: |
Keefer; Larry K. (Bethesda,
MD) |
Assignee: |
The United States of America as
represented by the Department of Health (Washington,
DC)
|
Family
ID: |
23231459 |
Appl.
No.: |
07/316,958 |
Filed: |
February 28, 1989 |
Current U.S.
Class: |
514/611; 514/149;
514/563; 514/610; 564/113; 514/558; 514/564; 564/112 |
Current CPC
Class: |
A61P
9/10 (20180101); A61P 9/08 (20180101); A61K
31/655 (20130101); A61K 31/14 (20130101); A61K
47/54 (20170801); A61P 9/12 (20180101); A61K
31/135 (20130101); A61K 31/13 (20130101) |
Current International
Class: |
A61K
31/655 (20060101); A61K 31/13 (20060101); A61K
31/135 (20060101); A61K 47/48 (20060101); A61K
31/14 (20060101); A61K 031/13 (); A61K 031/20 ();
A61K 031/195 (); A61K 031/655 () |
Field of
Search: |
;514/645,610,615,824,611,149,558,563,564 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Other References
Drago & Karstetter, The Reaction of NO with Various Primary
& Secondary Amines, Aug. 4, 1960, p. 1819, JACS. .
Palmer et al., Nitric Oxide Release Accounts for the Biological
Activity of Endothelium-Derived Relaxing Factor, Nature, pp.
524-526. .
CA 108:68610c, Red Blood Cells Generate Nitric Oxide from Directly
Acting, Nitrogenous Vasodilators, Kruzyna et al. .
Palmer et al., Nature, 317, 524-526, 1987. .
Kruszyna et al., Toxicol. and Applied Pharmacol., 91, 429-438,
1987. .
Ignarro, The FASEB Journal, 3, 31-36, 1989. .
Ignarro et al., J. Pharmacol. and Exper. Theraput., 218(2),
739-749, 1981. .
Atston et al., The Journal of Biological Chemistry, 260(7),
4069-4074 and 9948, 1985. .
Kubrina et al., Izvestiia Akademii Nauk SSSR.Seriia Biologicheska
6, 844-850, 1988 & Abstract. .
Drago, "Free Radicals in Inorganic Chemistry", No. 36, Advances in
Chemistry Series, American Chemical Society, Washington, DC, 1962,
pp. 143-149. .
Weirsdorff et al., Chemical Abstracts, 77: 48034f, 1972. .
Fujitsuka et al., Chemical Abstracts, 82: 31108p, 1975. .
DeLuca et al., Parenteral Drug Delivery Systems, pp. 238-250 of
"Pharmaceutics and Pharmacy Practice", J. B. Lippincott Co.,
Philadelphia, 1987. .
Toissel, ASHP, "Handbook on Injectable Drugs", 4th ed., pp.
622-630, 1986..
|
Primary Examiner: Robinson; Allen J.
Attorney, Agent or Firm: Birch, Stewart, Kolasch &
Birch
Claims
What is claimed is:
1. A method of treating hypertension, wherein said method comprises
administering to a mammal, in need thereof, a therapeutically
effective amount of a compound of the formula:
wherein:
R is C.sub.3-8 lower alkyl, phenyl, benzyl, or C.sub.3-8
cycoloalkyl, any of which R groups may be substituted by one to
three substituents, same or different, selected from the group
consisting of halo, hydroxy, C.sub.1-8 alkoxy, --NH.sub.2,
--C(O)NH.sub.2, --CH(O), --C(O)OH and --NO.sub.2 :
X is a pharmaceutically acceptable cation,
a pharmaceutically acceptable metal center, or
a pharmaceutically acceptable organic group selected from the group
consisting of C.sub.1-8 lower alkyl, --C(O)CH.sub.3 and
--C(O)NH.sub.2 ; and
Y is one to three, consistent with the valence of X.
2. The method of claim 1, wherein R is branched chain lower alkyl
group of 3-6 carbon length, optionally substituted by one to three
substituents, same or different, selected from the group consisting
of halo, --NH.sub.2, hydroxy, --CH(O) and --C(O)OH.
3. The method of claim 1, wherein R is C.sub.3-8 cycloalkyl,
optionally substituted by one to three substituents, same or
different, selected from the group consisting of halo, --NH.sub.2,
hydroxy, --CH(CO) and --C(O)OH.
4. The method of claim 1, wherein R is isopropyl.
5. The method of claim 1, wherein said compound is administered by
intravenous injection.
6. The method of claim 1, wherein R is isopropyl; and wherein said
compound is administered by intravenous injection.
7. The method of claim 1, wherein X is a pharmaceutically
acceptable cation.
8. The method of claim 7, wherein R is branched chain lower alkyl
group of 3-6 carbon length, optionally substituted by one to three
substituents, same or different, selected from the group consisting
of halo, --NH.sub.2, hydroxy, --CH(O) and --C(O)OH.
9. The method of claim 7, wherein R is isopropyl.
10. The method of claim 7, wherein R is isopropyl; and wherein said
compound is administered by intravenous injection.
11. A pharmaceutical composition comprising:
(I) a therapeutically effective hypertension treating amount of a
compound of the formula:
wherein:
R is C.sub.3-8 lower alkyl, phenyl, benzyl, or C.sub.3-8
cycloalkyl, any of which R groups may be substituted by one to
three substituents, same or different, selected from the group
consisting of halo, hydroxy, C.sub.1-8 alkoxy, --NH.sub.2,
--C(O)NH.sub.2, --CH(O), --C(O)OH and --NO.sub.2 :
X is a pharmaceutically acceptable cation, a pharmaceutically
acceptable metal center, or a pharmaceutically acceptable organic
group, selected from the group consisting of C.sub.1-8 lower alkyl,
--C(O)CH.sub.3 and --C(O)NH.sub.2 ;
Y is one to three, consistent with the valence of X; and
(II) a pharmaceutically acceptable carrier therefor.
12. The composition of claim 11, wherein R is a branched chain
lower alkyl group having 3-6 carbon length, optionally substituted
by one to three substituents, same or different, selected from the
group consisting of halo, hydroxyl, --NH.sub.2, --CH(O) and
--C(O)OH.
13. The composition of claim 11, wherein R is C.sub.3-8 cycolalkyl,
optionally substituted by one to three substituents, same or
different, selected from the group consisting of halo, --NH.sub.2,
hydroxy, --CH(O), and --C(O)OH.
14. The composition of claim 11, wherein R is isopropyl.
15. The composition of claim 11, wherein said composition is
suitable for intravenous injection.
16. The composition of claim 11, wherein R is isopropyl, and said
composition is suitable for intravenous injection.
17. The composition of claim 11, wherein X is a pharmaceutically
acceptable cation.
18. The composition of claim 17, wherein R is a branched chain
lower alkyl group having 3-6 carbon length, optionally substituted
by one to three substituents, same or different, selected from the
group consisting of halo, hydroxyl, --NH.sub.2, --CH(O) and
--(O)OH.
19. The composition of claim 17, wherein R is isopropyl.
20. The composition of claim 17, wherein said composition is
suitable for intravenous injection.
Description
BACKGROUND OF THE INVENTION
Numerous nitric oxide nucleophile complexes have been described,
e.g. R.S. Drago, ACS Adv. Chem. Ser., Vol. 36, p. 143-149 (1962).
Some of these complexes are known to evolve nitric oxide on heating
or hydrolysis, e.g., T.J. Hansen, et al., IARC SCI. PUBL., Vol. 41,
p. 21-29 (1982); and nitric oxide has been postulated to be
identical to endothelium-derived relaxing factor (EDRF) which
mediates the action of some vasodilators, R.M.J. Palmer, et al.,
Nature, Vol. 327, p. 524-526 (1987), as well as certain types of
intercellular communication in the brain, J. Garthwaite, et al.,
Nature, Vol. 336, p. 385-388 (1988). The use of nitric
oxide-primary amine complexes as biologically active agents has not
been previously disclosed.
SUMMARY OF THE INVENTION
One object of the present invention is to provide potent
cardiovascular agents useful in treating cardiovascular disorders.
The cardiovascular agents provided in the present invention are
complexes formed from nitric oxide and primary amines, and esters,
ethers, or other derivatives thereof. These nitric oxide-primary
amine complexes and esters, ethers or other derivatives regenerate,
i.e., release, nitric oxide in vivo, and it is this release of
nitric oxide in vivo which accounts for their potent biological
activity. Furthermore, since the release rate of nitric oxide from
nitric oxide-nucleophile complexes and their esters may vary from
almost instantaneous to very slow depending on pH, and other
factors such as temperature, a second object of the present
invention is to provide stabilized complexes of nitric oxide which
release nitric oxide in vivo in an acceptable fashion (as
determined by pharmacological testing). A third object of the
present invention is to provide pharmaceutical compositions for
administering the cardiovascular agents disclosed herein to
mammals.
Accordingly, and in consideration of the above objects, the present
invention provides a method of treating cardiovascular disorders,
wherein said method comprises administering to a mammal, in need
thereof, an effective amount of a compound of the formula:
[R-N(H)N(NO)O--].sub.y X
wherein R is loweralkyl, aryl, arylalkyl, or cycloalkyl, any of
which R groups may be substituted by one to three substituents,
same or different, selected from halo, hydroxy, alkoxy, amino,
amido, formyl, carboxy or nitro; and
X is a pharmaceutically acceptable cation,
a pharmaceutically acceptable metal center, or
a pharmaceutically acceptable organic group selected from
loweralkyl acyl or amido; and
Y is one to three, consistent with the valence of X.
Furthermore, the present invention provides a pharmaceutical
composition, comprising:
(I) an effective cardiovascular disorder treating amount of a
compound of the formula:
[R-N(H)N(NO)O--].sub.y X
wherein:
R is loweralkyl, aryl, arylalkyl, or cycloalkyl, any of which R
groups may be substituted by one to three substituents, same or
different, selected from halo, hydroxy, alkoxy, amino, amido,
formyl, carboxy or nitro;
X is pharmaceutically acceptable cation,
a pharmaceutically acceptable metal center, or
a pharmaceutically acceptable organic group selected from
loweralkyl, acyl or amido;
Y is one, two or three, consistent with the valence of X; and
(II) a pharmaceutically acceptable carrier therefor.
A glossary of certain terms utilized herein is also provided
herewith, in order to remove any vagueness, which may exist as to
the meanings of those terms.
The term "loweralkyl" as used herein means branched and straight
chain radicals of three to eight carbons inclusive, and is
exemplified by such groups as propyl, isopropyl, butyl, 2-butyl,
tert. butyl, amyl, isoamyl, hexyl, heptyl, octyl, and the like.
The term "aryl" as used herein means phenyl, naphthyl, pyrrolyl,
pyridinyl, quinolinyl, isoquinolinyl, and the like.
The term "arylalkyl" as used herein means an aryl group, as defined
herein, substituted by a straight or branched carbon chain radical
of one to three carbon atoms inclusive.
The term "cycloalkyl" as used herein means cyclopropyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
The term "halo" or "halogen" as used herein means a halogen atom
selected from fluorine, chlorine, bromine, and iodine.
The term "hydroxy" or "hydroxyl" as used herein means --OH.
The term "amino" as used herein means --NH.sub.2.
The term "amido"[as used herein means --C(0)NH.sub.2.
The term "formyl" as used herein means --CH(0).
The term "carboxy" as used herein means --C(O)OH.
The term "nitro" as used herein means -NO.sub.2.
The term "pharmaceutically acceptable cation" as used herein means
any cation biologically compatible in a mammal, and includes
alkylammonium cations, e.g. isopropyl ammonium cation and the like;
alkali metals, e.g., sodium, potassium, lithium and the like; and
alkaline earth metals, e.g., calcium, barium, magnesium and the
like. The only essential characteristic of the cation chosen is
that it not be biologically incompatible in a mammal.
The term "pharmaceutically acceptable metal center" as used herein
means a central metal ion, having a valence of 1 to 3, attached by
coordinate links to one or more nonmetal atoms of each of the Y
organic groups of Formula I [i.e., R--N(H)N(NO)O--]. Exemplary of
such a metal center would be Fe.sup.+2, or the like, coordinately
linked to two oxygen atoms, or at least one oxygen atom and another
nonmetalic atom, of each of the Y organic groups of Formula I.
The term "central metal ion" as used herein includes biologically
acceptable metal ions selected from: alkali metals such as sodium,
potassium, lithium and the like; alkaline earth metals such as
calcium, magnesium, barium and the like; transition metals,
including iron, copper, nickel, zinc and the like; Group III metals
including aluminum and the like; and lanthanide series metals. The
only principal requirement, for the central metal ion chosen is
biological compatibility, in a mammal.
The term "pharmaceutically acceptable organic group" as used herein
refers to those biologically acceptable organic groups which
covalently bond to the organic grouping of Formula I [i.e.,
R--N(H)N(NO)O--] to form ethers, esters and other derivatives
thereof [e.g., R--N(H)N(NO)O--X; wherein X is a biologically
acceptable organic group]. Exemplary of such acceptable organic
groups are loweralkyl, acyl, amido and the like.
The term "acyl" as used herein means an organic acid group in which
the --OH of a carboxyl group is replaced by some other substituent.
Exemplary of such acyl groups are --C(O)CH.sub.3, --C(O)C.sub.6
H.sub.5 and the like.
The term "alkoxy" as used herein means --O--CH.sub.3, --O--CH.sub.2
H.sub.5 --O--loweralkyl.
The term "pharmaceutically acceptable carrier" as used herein means
those excipients and carriers known in the pharmaceutical
manufacturing art to be acceptable when one wishes to administer a
pharmaceutical composition by an intravenous or oral route.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of Formula I are stable nitric oxide-primary amine
complexes and their esters, both of which generally release nitric
oxide in vivo in a controlled fashion. This controlled release of
nitric oxide makes the compounds valuable as pharmaceutical agents;
and the same compounds are fully contemplated herein as useful in
the treatment of such cardiovascular disorders as hypertension,
arteriosclerosis, cerebral vasospasm, and coronary vasospasm.
While all compounds encompassed by Formula I are considered of
value in treating cardiovascular disorders and effective in the
method of the present invention, generally, it is thought that
compounds of Formula I having an R group which is a branched
loweralkyl of 3-6 carbons inclusive, substituted or unsubstituted,
are most preferred in the present invention; but other Formula I
compounds wherein the R groups cycloalkyl or cycloalkylloweralkyl
appear, substituted or unsubstituted, are also preferred. Moreover,
if one of the above preferred R groups is substituted, it is
thought that the most preferable substituents would include one to
three, same or different, of the following: halo, hydroxy, amino,
formyl or carboxyl groups.
It is also thought that compounds having X as loweralkylammonium
cation, alkali metal cation or alkaline earth metal cation are the
most preferable to use in the method of the present invention.
It should be understood that Formula I compounds useful in the
method of the present invention can be most probably prepared by a
variety of chemical synthesis methods known to those skilled in the
art, and that the following methods are only exemplary of methods
which may be used to prepare Formula I compounds, and that as such
they should not be construed to limit the scope of the present
invention in any manner.
Nitric oxide-primary amine complexes useful in the method of the
present invention may be prepared if desired by the method of R.S.
Drago et al, J. Am. Chem. Soc., Vol. 83, p. 1819-1822 (1961). The
following is a scheme of the reaction taught by Drago. In the
reaction (BNO) is a transition state or intermediate formed in the
reaction.
The above Drago reaction may be carried out by bubbling nitric
oxide into a cold (-78.degree. C.) ether solution of the
appropriate amine. Pure solid product should precipitate, Drago
teaches, and these precipitated products may, if desired, be
reprecipitated from chloroform solution with ether. Additionally,
high pressure techniques taught by R.S. Drago et al in J. Am. Chem.
Soc., Vol. 83, p. 1819-1822 (1961) may be utilized in the above
reaction to produce a product in a yield of about 70-80% of
theoretical.
When one utilizes the above reaction the X grouping of the complex
initially formed is necessarily an ammonium cation, i.e., RNH.sub.3
.sup.+. In order to change the complexes, cation to an alkali metal
or alkaline earth metal cation, the following reaction scheme may
be utilized. In the reaction M+ is either an alkali metal or
alkaline earth metal cation.
The desired salt thus obtained may be recrystallized from
appropriate organic solvents known to those skilled in the art, or
simply washed with appropriate solvents, in order to obtain
purified product.
Once obtained, the above salts can be converted to covalent metal
complex, ether or ester encompassed by Formula I by reaction with
an appropriate metal center, alkylating, acylating or
carbamoylating agent. Suitable derivatization methods and
procedures for preparing the same are generally known to those
skilled in the art and the use of such in preparing compounds of
Formula I wherein the X group is a biologically acceptable metal
center or a biologically acceptable organic group, as defined
herein, are fully contemplated.
When the above Drago reaction mechanisms are utilized, certain of
the primary amines to be reacted with nitric oxide may contain
additional nitrogen, oxygen or other heteroatoms substituted by
hydrogen, which one does not desire to react with nitric oxide. In
such cases, these hydrogen substituted heteroatoms should be
blocked with an appropriate blocking group before reaction with
nitric oxide. The blocked heteroatoms may then be unblocked
subsequent to the Drago reaction of the primary amine with nitric
oxide. Appropriate blocking agents and deblocking agents and
methods of using the same are generally known to those skilled in
the art, and the use of such in preparing compounds of Formula I
wherein an R group is substituted by and/or contains at least one
heteroatom substituted by at least one hydrogen atom, is fully
contemplated herein.
The following Preparations serve as further illustration of the
methods, described herein, which may be utilized to prepare Formula
I compounds, and should not be construed to limit the scope of the
present invention.
Preparation I
Isooroovlamine - nitric oxide isooroovlammonium salt complex
1:11
(CH.sub.3).sub.2 CHNH.sub.3.sup.+
O--N(NO)N(H)(--CH(CH.sub.3).sub.2)
Utilizing the high pressure reaction method of R.S. Drago, et al.,
J. Am. Chem. Soc., Vol. 83, p. 1819-1822 (196), the above nitric
oxide complex was obtained by reacting a solution of isopropylamine
and ether with nitric oxide at a temperature of -78.degree. C. for
a period of about 24 hr. The reaction took place under high
pressure in a high pressure reaction vessel, and nitric oxide was
incorporated into the reaction mixture via a high pressure
reservoir. The title compound was obtained in satisfactory
yield.
Preparation II
Isooroovlamine-nitric oxide sodium salt complex [1:1]
Na.sup.+- O--N(NO)N(H)(--CH(CH.sub.3).sub.2)
Utilizing the method of R.S. Drago, et al., J. Am. Chem. Soc. Vol.
83, p. 1819-1822 (1961) the title compound is obtained by reacting
a slightly greater than stoichiometric amount of the compound of
Preparation I (slurried in ethyl alcohol) with sodium ethoxide.
Upon stirring for about 5 minutes, ether is added to the reaction
mixture to precipitate the title compound, which may be
additionally washed with ether and ethyl alcohol to remove
impurities.
Preparation III
Utilizing the procedure of Preparation I, and reacting nitric oxide
with solutions of the following loweralkylamines in ethyl
ether:
isobutylamine,
n-butylamine, and
2-butylamine,
the following loweralkylamine-nitric oxide ammonium salt complexes
are obtained:
Preparation V
Utilizing the procedure of Preparation I, and reacting each of the
following primary amines (in a solution of ethyl ether):
benzylamine,
cyclohexylmethylamine,
cyclohexylamine,
p-methoxyaniline, and
m-bromoaniline,
with nitric oxide, at -78.degree. C for 24 hr under high pressure,
there are obtained the following primary amine-nitric oxide
ammonium salt complexes:
Preparation VI
Utilizing the procedure of Preparation II, and reacting each of the
primary amine-nitric oxide ammonium salts obtained in preparation
V, with sodium ethoxide in a slurry of ethyl alcohol, the following
compounds are obtained, by precipitation, after addition of ethyl
ether:
Pharmacological Testing
Certain compounds encompassed by the present invention were tested
in pharmacological models to determine their activity as
cardiovascular agents. Inasmuch as the compounds, pharmacological
activity, disclosed herein, is related principally to their ability
to release nitric oxide in vivo, the following Examples should not
be considered limiting to the number of compounds, disclosed
herein, which are useful in the methods of the present invention,
since all Formula I compounds are capable of regenerating nitric
oxide in vivo. The following examples can and should, however, be
assumed to illustrate the general ability of all the Formula I
compounds disclosed herein to effectively treat certain
cardiovascular disorders such as hypertension, arteriosclerosis,
cerebral vasospasm and coronary vasospasm, by way of a controlled
release of nitric oxide in vivo .
EXAMPLE 1
A 0.05 M solution of the compound of Preparation I, i.e.,
(CH.sub.3).sub.2 CHNH.sub.3.sup.+-
O--N(NO)N(H)(CH(CH.sub.3).sub.2), in normal saline was prepared.
Injection of 0.04 ml of this solution over a 30 sec. period into an
anesthetized rat (350g) via a catheter in the femoral vein resulted
in an immediate drop in blood pressure from 80 to 30 mm Hg, and a
compensatory increase in heart rate from 320 to 340/min. The
reduced blood pressure remained steady for 10 min. at 30 mm Hg
before a perceptible increase could be seen. Full recovery to
baseline values had occurred by 30 min after the injection. Later,
smaller bolus doses of the compound of Preparation I were also
given to the same anesthetized rat and these smaller doses elicited
responses similar to those seen with the larger dose. Later still,
a 0.0014 M solution of the compound of Preparation I was
administered by continuous infusion to the same anesthetized rat at
a rate of 1.4 ml/min. Baseline blood pressure was lowered over 10
min. from 105/73 to 83/65 mm Hg. It was also determined during
continuous infusion (at the above rate) that the compound of
Preparation I had no effect on the action of a 0.5 nmole dose of
angiotensin II given to the rat, but that the continuous infusion
of the compound of Preparation I (at the above rate) did completely
abolish the vasoconstrictor activity of a 0.5 nmole bolus dose of
endothelin given to the rat. In view of the above results, it is
concluded that the compound of Preparation I is an active
cardiovascular agent, and that its actions are predictable and
reversible.
EXAMPLE 2 When the compound of Preparation II, i.e., Na.sup.+-
O--N(NO)N(H)(--CH(CH.sub.3).sub.2) is administered to an
anesthetized rat via a catheter as was the compound of Preparation
I in Example 1, a similar predictable and reversible reduction in
blood pressure is expectable.
EXAMPLE 3 When any of the following Formula I compounds:
are administered, either separately or in combination, to an
anesthetized rat via a catheter as was the compound of Preparation
I in Example 1, a similarly predictable and reversible reduction in
blood pressure is expectable.
EXAMPLE 4
When any of the compounds encompassed by Formula I, herein, is
administered to an anesthetized rat by the methods provided herein
in Example 1, it is predictable that a similar reduction in blood
pressure will occur, due to in vivo release of nitric oxide by the
Formula I compounds utilized.
Pharmaceutical Compositions
Due to their chemical structures, the compounds of the present
invention wherein X is a pharmaceutically acceptable cation are
most preferably administered by intravenous injection, those
compounds of Formula I wherein X is a pharmaceutically acceptable
metal center or an organic group are preferably administered either
intravenously or orally. Preferably, the compounds of the present
invention are made into pharmaceutical injectable or oral
compositions by combination with appropriate pharmaceutically
acceptable carriers or diluents. Furthermore, while Formula I
compounds provided herein may be formulated into injectable
preparations and oral preparations in ways usual for these routes
of administration, and the following methods and excipients are
exemplary of usual and acceptable means, they should not be
considered to limit the scope of the present invention with respect
to pharmaceutical compositions.
The compounds of the present invention may be formulated into
preparations for injections by dissolving, suspending, or
emulsifying them in an aqueous or non-aqueous solvent, such as
vegetable oil, synthetic aliphatic acid glycerides, esters of
higher aliphatic acids or propylene glycol; and if desired, with
conventional additives such as solubilizers, isotonic agents,
suspending agents, emulsifying agents, stabilizers and
preservatives. Parenteral administration of the compounds of the
present invention may also be had by a pharmaceutically acceptable
carrier such as dextrose, sterile water for injection, USP, or by
normal saline.
In the case of oral preparations, the compounds may be used alone
or in combination with appropriate additives to make tablets,
powders, granules or capsules, e.g., with conventional additives
such as lactose, mannitol, corn starch or potato starch; with
binders such as crystalline cellulose, cellulose derivatives,
acacia, corn starch or gelatins; with disintegrators such as corn
starch, potato starch or sodium carboxymethylcellulose; with
lubricants such as talc or magnesium stearate; and if desired, with
diluents, buffering agents, moistening agents, preservatives and
flavoring agents.
The amount of the compounds of the present invention to be used as
cardiovascular agents of course varies according to the type of
cardiovascular disorder encountered and the route of administration
chosen. A suitable dosage is thought to be about 0.01 to 10.0
mg/kg/day body weight where one is treating hypertension,
arteriosclerosis, cerebral vasospasm or coronary vasospasm and the
route of administration is intravenous. The preferred dosage is of
course that amount just sufficient to treat a particular
cardiovascular disorder and would preferably be an amount from
about 0.05 to 5.0 mg/kg/day.
It should be understood that the scope of the present invention is
only limited by the appended claims.
* * * * *