U.S. patent number 3,922,261 [Application Number 05/371,779] was granted by the patent office on 1975-11-25 for adenosine derivative.
This patent grant is currently assigned to Merck Patent Gesellschaft mit beschrankter Haftung. Invention is credited to Karl-Heinz Becker, Werner Mehrhof, Herbert Nowak, Rolf Pohlke, Hans-Jochen Schliep, Zdenek Simane.
United States Patent |
3,922,261 |
Pohlke , et al. |
November 25, 1975 |
Adenosine derivative
Abstract
N.sup.6 -(1,2,3,4-tetrahydronaphthyl-2)-adenosine has valuable
pharmaceutical properties, and is useful in reducing the serum
concentration of free fatty acids and triglycerides and selectively
improving coronary blood circulation.
Inventors: |
Pohlke; Rolf (Darmstadt,
DT), Mehrhof; Werner (Darmstadt, DT),
Becker; Karl-Heinz (Darmstadt, DT), Schliep;
Hans-Jochen (Darmstadt, DT), Nowak; Herbert
(Darmstadt, DT), Simane; Zdenek (Darmstadt,
DT) |
Assignee: |
Merck Patent Gesellschaft mit
beschrankter Haftung (Darmstadt, DT)
|
Family
ID: |
5848279 |
Appl.
No.: |
05/371,779 |
Filed: |
June 20, 1973 |
Foreign Application Priority Data
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|
|
|
|
Jun 21, 1972 [DT] |
|
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2230160 |
|
Current U.S.
Class: |
536/27.62 |
Current CPC
Class: |
C07H
19/16 (20130101) |
Current International
Class: |
C07H
19/16 (20060101); C07H 19/00 (20060101); C07H
019/16 () |
Field of
Search: |
;260/211.5R |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Jahn " Chem. Abst." Vol. 71, 1969 p. 89799d..
|
Primary Examiner: Brown; Johnnie R.
Attorney, Agent or Firm: Millen, Raptes & White
Claims
What is claimed is:
1. A member of the group consisting of N.sup.6
-(1,2,3,4-tetrahydronaphthyl-2-)-adenosine, the optical isomer
thereof having a melting point of 164.degree.-166.degree. C. and
the optical isomer thereof having a melting point of
175.degree.-176.degree. C.
2. A compound of claim 1, the optical isomer of N.sup.6
-(1,2,3,4-tetrahydronaphthyl-2-)-adenosine having a melting point
of 164.degree.-166.degree. C.
Description
BACKGROUND OF THE INVENTION
This invention relates to N.sup.6
-(1,2,3,4-tetrahydronaphthyl-2)-adenosine and to novel
pharmaceutical compositions useful in the treatment of
hyperlipoproteinemia, particularly hypertriglyceridemia, as well as
in lowering free fatty acid levels in blood and which exhibit
advantageous properties as compared to conventional
preparations.
The N.sup.6 -substituted adenosines are of great significance due
to their advantageous biological properties, e.g., their cardiac
circulatory effects.
Many efforst are also being directed to investigating agents for
the treatment of hyperlipoproteinemia. However, many of the known
agents effective in reducing serum triglyceride and free fatty acid
levels exhibit undesirable circulatory side effects at the dosages
required for best therapeutic results.
OBJECTS OF THE INVENTION
Accordingly, it is a general object of this invention to provide a
new adenosine derivative.
Another object of this invention is to provide a pharmaceutical
composition suitable for the treatment of hyperlipoproteinemia,
particularly hyperlipidemia.
A further object of this invention is to provide a pharmaceutical
composition useful in lowering serum free fatty acid and
triglyceride levels, particularly in animals afflicted with
hyperlipidemia, especially in humans.
An additional object of this invention is to provide a process for
treating hyperlipidemia in animals, particularly humans.
Yet another object of this invention is to provide a process for
selectively increasing coronary circulation without adversely
affecting the systemic blood pressure or heart rate.
Other objects and advantages of this invention will become apparent
to those skilled in the art upon further study of the specification
and appended claims.
SUMMARY OF THE INVENTION
Briefly the above and other objects are attained in one aspect of
the present invention by providing N.sup.6
-(1,2,3,4-tetrahydronaphthyl-2)-adenosine and pharmaceutical
compositions containing this compound as an active ingredient and
methods for their use.
DETAILED DISCUSSION
It has been found that this compound possesses valuable
pharmacological properties. This compound reduces the lipoprotein
level in the blood and, independently thereof, has favorable
selective effects on the heart circulation. In particular, the
compound of this invention effects a strong reduction in the serum
concentration of free fatty acids and triglycerides, which has been
demonstrated in rat serum. In animal tests on narcotized dogs, the
substance produces even in low doses a strong and prolonged
increase in coronary circulation while the values for arterial
blood pressure and the heart rate remain approximately the same.
Furthermore, the compound also inhibits thrombocyte aggregation in
the serum of rabbits and humans.
Consequently, this compound can be employed as a medicine and also
as an intermediate for the preparation of other drugs, e.g., by
methylation or acylation to the respective trimethyl ethers or
triacylates.
The compound of this invention may occur in several isomers which
are included in this invention. Two of these isomers described in
the Examples 2 and 3 are especially interesting because they show
particularly outstanding triglyceride- and free-fatty-acid-lowering
properties.
N.sup.6 -(1,2,3,4-tetrahydronaphthyl-2)-adenosine can be prepared
by reacting 6-chloro-9-(.beta.-D-ribofuranosyl)-purine with
(1,2,3,4-tetrahydronaphthyl-2)-amine. The starting compounds for
this process are conventional and can be obtained commercially.
N.sup.6 -(1,2,3,4-tetrahydronaphthyl-2)-adenosine can also be
prepared according to the methods described in Coll. Czech. Chem.
Commun., 30: 1880 (1965).
The reaction can be conducted in the presence of an inert organic
solvent, e.g., dimethylformamide, dioxane, tetrahydrofuran,
methanol, ethanol, propanol, n-butanol, isobutanol, tert.-butanol,
and the higher alcohols; especially preferred as the solvent is
isopropanol. Mixtures of these solvents can likewise be employed,
for example, a mixture of dimethylformamide and isopropanol, 1:1.
The reaction is suitably carried out with the addition of an
inorganic or organic base, e.g. pyridine or preferably
triethylamine. It is also possible to utilize an excess of
1,2,3,4-tetrahydronaphthyl-(2)-amine. The reaction is generally
conducted at temperatures of between 0.degree. and 180.degree. C.,
preferably under reflux at the boiling point of the solvent used.
The reaction times are generally between about 3 and 30 hours,
preferably between 6 and 12 hours. When operating at lower
temperature, e.g., room temperature, the reaction times can become
longer, e.g., up to 4 days. Pressures are generally not critical
beyond a minimum required to maintain the reaction mixture in a
liquid phase, and ambient pressures are conveniently used.
Due to its serum lipid lowering activity, the compound of this
invention is particularly useful as a lipid lowering agent in human
and veterinary medicine, and is suitable for the treatment of
primary and secondary hyperlipidemias, e.g. hypertriglyceridemia
and hyperlipidacidemia.
The compound of this invention can be employed in mixture with
conventional excipients, i.e., pharmaceutically acceptable organic
or inorganic carrier substances suitable for therapeutic
application which do not deleteriously react with the active
compound. Suitable pharmaceutically acceptable carriers include but
are not limited to water, salt solutions, alcohols, vegetable oils,
polyethylene glycols, gelatin, lactose, amylose, magnesium
stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty
acid monoglycerides and diglycerides, pentaerythritol fatty acid
esters, hydroxy methylcellulose, polyvinyl pyrrolidone, etc. The
pharmaceutical preparations can be sterilized and if desired mixed
with auxiliary agents, e.g., lubricants, preservatives,
stabilizers, wetting agents, emulsifiers, salts for influencing
osmotic pressure, buffers, coloring, flavoring and/or aromatic
substances and the like which do not deleteriously react with the
active compound.
For parenteral application, particularly suitable are solutions,
preferably oily or aqueous solutions, as well as suspensions,
emulsions, or implants, including suppositories. Ampoules are
convenient unit dosages.
For enteral application, particularly suitable are tablets, dragees
or capsules having talc and/or a carbohydrate carrier or binder or
the like, the carrier preferably being lactose and/or corn starch
and/or potato starch. A syrup, elixir or the like can be used
wherein a sweetened vehicle is employed. Sustained release
compositions can be formulated including those wherein the active
compound is protected with differentially degradable coatings,
e.g., by mimcroencapsulation, multiple coatings, etc.
Generally, the compound of this invention is dispensed in forms
comprising 10-5,000 mg. of a pharmaceutical carrier per each unit
dosage, and the amount per unit dosage for men is about 1 -- 300
mg. of the active compound. For animals, higher amounts of the
active compound per unit dosage may be used.
The compound of this invention is generally administered to
animals, including but not limited to mammals, e.g., humans,
livestock, household pets and poultry. A lipid-lowering effective
daily dosage of the active compound as administered orally to
humans generally comprises about 0.1 to 10, preferably 0.5 to 5.
mg/kg., together with 0.5 (capsule) - 600 mg (syrup) per kg. of
body weight of pharmaceutically acceptable carrier. The dose can be
administered singly or as divided dosages throughout the day. For
lowering the lipoprotein level it is possible to extend the time of
administration up to 6 months.
The usefulness of the compound of this invention as a serum
lipid-lowering agent has been established in laboratory test
animals. Oral administration is preferred, the compound of this
invention being particularly valuable in the treatment of humans
afflicted with primary and secondary hyperlipidemias. In this
regard, it can be employed in substantially the same manner as the
known compound clofibrate.
It will be appreciated that the actual preferred amounts of the
active compound used will vary according to the particular
compositions formulated, the mode of application, the severity of
the disease being treated, and the particular organism being
treated. Optimal application rates for a given set of conditions
can be ascertained by those skilled in the art using conventional
dosage determination tests in view of the above guidelines.
Without further elaboration, it is believed that one skilled in the
art can, using the preceding description, utilize the present
invention to its fullest extent. The following preferred specific
embodiments are, therefore, to be construed as merely illustrative,
and not limitative of the remainder of the disclosure in any way
whatsoever. In the following examples, the temperatures are set
forth uncorrected in degrees Celsius; unless otherwise indicated,
all parts and percentages are by weight.
EXAMPLE 1
2.9 g. of 6-chloro-9-(.beta.-D-ribofuranosyl)-purine and 1.5 g. of
2-amino-1,2,3,4-tetrahydronaphthalene are refluxed in 200 ml. of
isopropanol with 5 ml. of triethylamine for 10 hours. The solvent
is eliminated by evaporation, and the residue is treated with
chloroform and water. The chloroform extract is dried and
concentrated by evaporation, yielding N.sup.6
-(1,2,3,4-tetrahydronaphthyl-2)-adenosine; m.p.
118.degree.-120.degree. C. (from methanol.)
EXAMPLE 2
In analogy to Example 1, from
6-chloro-9-(.beta.-D-ribofuranosyl)-purine and
(+)-2-amino-1,2,3,4-tetrahydronaphthalene (described in J. Chem.
Soc., 79: 74 (1901)) an isomer of N.sup.6
-(1,2,3,4-tetrahydronaphthyl-2)-adenosine, melting at 164.degree. -
166.degree.C and having an optical rotation [.alpha.].sub.D.sup.20
= 39.1.degree. (methanol) is prepared.
EXAMPLE 3
In analogy to Example 1 from
6-chloro-9-.beta.-D-ribofuranosyl)-purine and
(-)-2-amino-1,2,3,4-tetrahydronaphthalene (described in J. Chem.
Soc., 79: 74 (1901)) an isomer of N.sup.6
-(1,2,3,4-tetrahydronaphthyl-2)-adenosine, melting at 175.degree. -
176.degree.C and having an optical rotation [.alpha.].sub.D.sup.20
= 72.3.degree. (methanol) is prepared.
The following Examples include pharmaceutical compositions of the
novel compounds:
EXAMPLE A:
Tablets
Each tablet contains N.sup.6
-(1,2,3,4-tetrahydronaphthyl-2)-adenosine 2 mg. lactose 70 mg. corn
starch 26 mg. magnesium stearate 2 mg.
EXAMPLE B:
Coated Tablets
Each tablet contains
N.sup.6 -(1,2,3,4-tetrahydronaphthyl-2-)-adenosine 3 mg. lactose 80
mg. potato starch 15 mg. talc 2 mg.
The coating (150 mg) is a conventional mixture of corn starch,
sugar, talc, and tragacanth.
EXAMPLE C:
Syrup
A mixture of
N.sup.6 -(1,2,3,4-tetrahydronaphthyl-2-)-adenosine 0.01 kg.
glycerol (twice distilled) 7.5 kg. cane sugar 56.0 kg. methyl
p-hydroxybenzoate 0.07 kg. n-propyl p-hydroxybenzoate 0.03 kg.
ethanol 10.0 kg. fruit flavorings as desired
is prepared and mixed with distilled water in such a manner that
the volume of the entire preparation is 100 l. A dosage unit (5
ml.) contains 10 mg of active substance.
Instead of N.sup.6 -(1,2,3,4-tetrahydronaphthyl-2)-adenosine (free
base) physiologically compatible acid addition salts can be
incorporated into similar compositions.
The pharmacological properties of the compound of this invention
were tested according to methods which are described in the
literature. Thus, the triglyceride-lowering properties were tested
according to the method of Noble and Campbell described in Clinical
Chemistry, 16: 166 (1970), and the fatty-acid-lowering properties
were tested according to the method of Dalton and Kowalski
described in Clinical Chemistry, 13: 744 (1967).
In a comparison test with clofibrate, the compound of the invention
shows markedly better triglyceride-lowering and fatty-acid-lowering
effects.
The properties of the (-)-isomer of the inventive compound having
the optical rotation [.alpha.].sub.D.sup.20 =-39.1.degree.
(methanol) are especially advantageous. A dose of 0.3 mg of said
isomer gives better triglyceride- and free fatty-acid-lowering
effects than 300 mg of clofibrate.
The preceding examples can be repeated with similar success by
substituting the generically or specifically described reactants
and/or operating conditions of this invention for those used in the
preceding examples.
From the foregoing description, one skilled in the art can easily
ascertain the essential characteristics of this invention, and
without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions.
* * * * *