Note: Descriptions are shown in the official language in which they were submitted.
~4 ~ ~ 3~
1 Thls invention relates to novel ~-naphthylmethyl
piperazinyl derivatives having valuable pharmacodynamic
activity. More specifically, the compounds of this invention
possess anti-Parkinsonism activity.
Parkinson's disease is a neurological disorder
characterized by hypokinesia~ akinesia, tremor and rigidity
of the limbs. Parkinsonism is believed to be brought about
by imbalance in the biochemical systems in the brain between
the dopaminergic and cholinergic neural pathways. In
patients suffering from Parkinsonism, a depletion of dopamine ~
in the brain is observed which is the result of progressive ; -
degeneration of nigro-striatal dopaminergic neurons.
Prior to the present invention, there has been a
great need for compounds and compositions which produce
anti-Parkinsonism activity without having limiting side
effects. It is well known that L-dopa, a potential source ~-
of brain dopamine, has clinical utility in treating Parkin- -
sonism. The L-dopa is a precursor of dopamine and is
decarboxylated in the brain to form dopamine, thereby
raising the levels of dopamine in patients who are deficient
in it. However, L-dopa does not qualify as an ideal com-
pound in the treatment of Parkinsonism due in part to its
limiting sicle effects, such as, for example, nausea, emesis
and anorexia. -
It is therefore the object of the present invention ;~ ;
to provide dopaminergic-like compounds for the treatment of
Parkinson's disease which do not possess the limiting side
effects of L-dopa.
The compounds of this invention have been
demonstrated as having anti-Parkinsonism activity without lhe
-2- ~
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1 corresponding side effects by employing a modified standard
animal pharmacolo~ical test p]^ocedure reported by Un~erstedt
et al., in Brain Research 24, 1970, 485-493. This test dis-
closes a drug induced rotation of rats having extensive
unilateral lesions of the substantia nigra. Briefly, the
test comprises the quantitative recording of rotational
behavior in rats after 6~hydroxydopamine lesions of the
nigrostriatal dopamine system. A unilateral brain lesion in
the left substantia nigra causes the dopamine receptor in the
left caudate to become hypersensitive subsequent to the
resulting degeneration of the nigral cell bodies. These
lesions destroy the source of the neurotransmitter dopamine
in the caudate but leave the caudate cell bodies and their
dopamine receptors intact. Activation of these receptors by
drugs which produce contralateral rotation~ with respect to
the lesioned side of the brain, i~ used as a measure of
central dopaminergic activlty of the drug.
Compounds which are known to be clinically
effective in controlling Parkinsonism, such as,for example,
L-dopa and apomorphine, are also effective in the rat turning
model. These compounds directly activate the dopamine
receptors and cause contralateral rotation of the lesioned
rat.
Rotational activity is defined as the ability of a
compound to produce 500 contralateral rotations during a
two-hour period after administration, usually intraperitone-
ally. The dose corresponding to 500 contralateral rotations
per two hours is obtained and assigned as the RD500.
A preferred compound of this invention is 1~
naphthylmethyl)-4-(2-pyridyl) piperazine which produced
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an RD500 of mg.~kg. as compared to 22.6 mg./kg. for L-dopa
when tested in t~e a~ov~ modi~ed Ungerstedt test.
The compounds of this in~rention are represented by
the following general structural fc)rmula:
Formulcl 1
1 ~ \
1 0
in w~i~h
R represents phenyl, C-pyridyl or C-pyrimidinyl;
Rl represents hydrogen, lower alkyl of 1-5 carbon
atoms, straight or branched chain, hydroxy, lower alkoxy of
1-5 carbon atoms, or halogen.
The pharmacodynamically active compounds of this
invention have the basic structure of Formula 1. However, it ~
is apparent to one skilled in the art that well known nuclear ~ -
substituents may be incorporated on the phenyl, pyridyl or
pyrimidinyl rings. Such substituents may be, for example,
lower alkyl, lower alkoxy, hydroxy or halogen. These sub- ~
stituted compounds are used as are the parent compounds. ~ ~ -
Advantageous compounds of this invention are repre-
sented by the above structural formula when R represents -
C-pyridyl or C-pyrimidinyl and Rl represents hydrogen.
The compounds of Formula 1 are prepared according
to the following synthetic procedure:
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434
~CH2Cl ~\ DMF/Na2CO
Rl ~ + H ~ /N-R - 3
Rl ~ CH2 ~ -R
in which R and Rl are as defined above.
The method is carried out using readlly available
starting materials and gives excellent yields of the end
product. ~here certain compounds desired for use as starting
materials are not available, they can be prepared by methods
described in the literature and well known to the art for pre-
paring analogous compounds as described in the examples. Thus
as shown above, a substituted chloromethylnaphthalene is
reacted with the appropriate piperazinyl derivative in the
presence of an organic solvent, such as, for example, dimethyl-
formamide and an acid binding agent such as sodium or potassium
carbonate, and heated to yield the desired compound~ Alterna- -
tively the unsubstituted piperazine can be reacted with ~ ~ -
?0 ~-chloromethylnaphthalene to form ~ (naphthylmethyl)piperazine - -
which in turn can be reacted with the appropriately reactive
R moiety.
The invention also includes nontoxic pharmaceutically
acceptable addition salts of the abo-ve-defined bases formed
wlth organic and inorganic acids. Such salts are easily
prepared by methods known to the art. The base is reacted
with either the stoichiometric amount of organic or inorganic
acid in aqueous miscible solvent~ such as acetone or ethanol~
with isolation of the salt by concentration and cooling or an
excess of the acid in aqueous immiscible solvent~ such as
ethyl ether or chloroform, with the desired salt separating
directly. Exemplary of such organic salts are those with
maleic, fumaric, benzoic, ascorbic, pamoic, succinic,
-5-
.. . . ..
104~4~4
1 bismethylenesalicylic, methanesulfonic, ethanedisulfonic,acetic, propionic, tartaric, salicylic, citric, gluconic,
lactic, malic, mandelic, cinnamic, citraconic, aspartic,
stearic, palmitic, itaconlc, glycolic, p-aminobenzoic,
glutamic, benzenesulfonic and theophylline acet~c acids as
well as with the 8-halotheophyllines, for example3 8-chloro~ ;
theophylline and 8-bromotheophylline. Exemplary of such
inorganic salts are those with hydrochloric, hydrobromic~ -;
sulfuric, phosphoric and nitric acids. These salts may also
be prepared by the classical method of double decomposition
of appropriate salts which is well known to the art.
The novel compounds of this in~-ention may be
administered orally or parenterally in conventional dosage
unit forms such as tablets, capsules, injectables or the like
by incorporating the appropriate dose of a compound of
Formula 1 with carriers according to the accepted pharma-
ceutical practices. The substituted ~-naphthylmethyl
plperazinyl derivatives will be present in an amount to
produce anti-Parkinsonism activity. Preferably the dosage
unit forms will contain the compounds of Formula 1 in an
amount of from about 10 mg. to about 100 mg., advant~geously
from about 25 mg. to about 50 mg. Most advantageously equal -~
daily doses are administered one to four times daily to pro~
vide a daily dosage regimen of from about 10 mg. to about
400 mg.
The pharmaceutical carrier employed may be, for
example, either a solid or liquid. Exemplary of solid
carriers are lactose, terra alba, talc, sucrose, gelatin3
agar, pectin, acacia, magnesium stearate, ste~ric acid~ and
the like. Exemplary of liquid carriers are syrup, peanut oil
--6--
~34~2434
1 ollve oil, water and the like. Similarly, the carrier as
diluent can include any time delay materl~l well known to the
art such as glyceryl monostearate or ~lyceryl distearate
alone or with a wax.
S A wide variety of pharmaceutical forms can be
employed. Thus if a solld carrier is used the preparation
can be tableted, placed in a hard gelatin capsule in powder
or pellet form or in the form of a troche or lozenge. The
amount of solid carrier will vary widely but preferably will
be about 25 mg. to about 1 g. If a liquid carrier is used9
the preparation will be in the form of a syrup, emulsion,
soft gelatin capsule, sterile in~ectable liquid such as an
ampule, or an aqueous liquid suspension.
The followin~ examples illustrate the preparation
of specific compounds having anti-Parkinsonism activity.
However, this should not be construed as a limitation of the
invention since other variations will be obvious to those
skilled in the art.
EXAMPLE 1
~0 To a mixture containing 5.0 g. of ~chloromethyl~
naphthalene, 3.0 g. of sodium carbonate and 30 ml. of
dimethylformamide is added 4.6 g. of pyrimidinylpiperazine~
The mixture is stirred and heated on a steam bath for
approximately two hours. The mixture is then cooled,
filtered and the filtrate is concentrated to a small volume
in vacuo. The residue is washed with water and crystallized
from ethanol to yield l-(~-napthylmethyl)-4-(2-pyrimidinyl)~
piperazine having a melting point of 109-110 C.
An ethereal solution of the free base is treated
with hydrogen chloride to yield the hydrochloride salt
:~.0~2434
1 EXAMPLE 2
A mixture containing 7.0 g. of ~-chloromethyl-
naphthalene, 6.56 g. of 2-pyridylpiperazlne and 4.4 g. of
so~ium carbonate in 40 ml. of dimethylformamide is stirred on
a steambath for 90 minutes. The reaction mixture is
filtered and the filtrate stirred with ice water. The
precipitate was filtered and recrystallized from isobutyl
alcohol to yield l-(~-napthylmethyl)-4-(2-pyridyl)piperazine
having a melting point of 124-126 C.
An acetone solution of the free base is reacted with
succinic acid to yield the succinate salt.
EXAMPLE 3
A mixture of 10.0 g. of ~-chloromethylnapthalene,
6.0 g. of sodium carbonate and 9.0 g. of phenylpiperazine in
60 ml. of dimethylformamide is stirred under nitrogen on a
steambath for five hours. The reaction mixture is then
cooled and filtered. The filtrate is concentrated and stirred
with ice water. The formed precipitate is filtered off~
dissolved in isobutyl alcohol and treated with ethereal
hydrogen chloride to yield the hydrochloride salt of 1~
napthylmethyl)-4-(phenyl)piperazine having a melting point of ;
226-228 C.
- EXAMPLE 4
Employing the procedure outlined above and using
10.9 g. of 1-~4-methoxyphenyl)piperazine as a starting
material in place of phenylpiperazine yielded l-(~naphthyl~
methyl)-4-(4-methoxyphenyl)piperazine having a melting point
of 117-118 C.
EXAMPLE 5 ~ -
Similarly using the above procedures, 9,8 gO of
i~34~4~4
1 1-(3-chlorophenyl)piperazine used as a starting material
yielded l-(~-naphthylmethyl)-4 (m-chlorophenyl)piperazine
having a melting point of 114-L15 C.
EXAMPLE 6
A solution of 2.0 g. of 1-(~-naphthylmethyl)~4-
(4-methoxyphenyl)piperazine as prepared in Example 4 in
100 ml. of hot 48% hydrogen bromide is refluxed for two hours.
The solution is then cooled and filtered. The collected
precipitate is then recrystallized from isobutyl alcohol to
yield the dihydrobromide salt of 1-(~-naphthylmethyl)-4-
(4-hydroxyphenyl)piperazine having a melting point of
225-227 C.
EXAMPLE 7
A solution of 20.0 g. of ~-chloromethylnaphthalene,
17.9 g. of piperazine dihydrochloride and 22.0 g. of
piperazine hexahydrate in 55 ml. of methanol is refluxed for
two hours. The solution is then cooled and filtered and the -
filtrate concentrated. The resulting solid is taken up in
water and treated with 10% sodium hydroxide. The basic
solution is extracted with chloroform and the fractions are
combined, washed w~lth water and dried. The oily material
is distilled to give ~-(napthylmethyl)piperazine.
A mixture of 4.5 g. of ~-(naphthylmethyl)piperazine9
2.6 g. of 2-chloro-3-hydroxypyridine and 2.~ g. of sodium
carbonate in 50 ml. of dimethylformamide is stirred on a steam-
bath for four hours. The mixture is cooled and filtered. The ~ ;
filtrate is stirred with ice water and the formed precipitate
is filtered, clissolved in isobutyl alcohol and treated with
ethereal hydrogen chloride to form the hydrochloride salt of
1-(~-naphthylmethyl)-4-(3-hydroxy-2-pyridyl)piperazine.
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1 EXAMPLE 8
To a mixture of 4.50 g. of l~ napthylmethyl)-
piperazine(as prepared ~n Example 7), 2.5 g. of 2-chloro~5
hydroxypyrimidine in 30 ml. of dimethylformamide is added
2.0 g. of sodium bicarbonate and the mixture is refluxed for
six hours. The mixture is cooled and filtered and the
filtrate concentrated to ~ small volume in vacuo. The con~
centrate is diluted with 100 ml. of water and the insoluble
material is washed with water and hexane to yield 1~0 napthylmethyl)-4-(5-hydroxy-2-pyrimidinyl)piperazine.
EXA~PLE 9
To a suspension of 2.7 g. of lithium aluminum
hydride in 75 ml. of dry ether i8 added dropwise a solution
containing 5.5 g. of 6~methyl-2~naphthoic acid in 7S ml. of
dry ether. The mixture i8 refluxed for three hoursJ cooled,
and treated with 10% ~odium hydroxide solution. The mixture
is then iltered snd dried to yield 6-methyl-2-naphthalene-
methanol,
20.3 g. of 6-methyl-2~naphthslenemethanol is
dissol~ed in lOO ml. of dry benzene and to this solution ls
added 30 ml. of thionyl chlorida. The solution i8 stirred
for about one hour and concentrated to yi~lt 2~chloromethyl=
6-methylnaphthalene.
A mixture of 11.0 ~. o~ 2-chloromathyl~6~methyl~
naphthalene, 7~0 g. o~ ~o~ium csrbonat~ And 10~0 g. of
2-pyrldylpiperaz~ne in 75 ml. of dimethylformamide 1~ stirred
for 9iX hour~, The r~actlon mixt~re i~ coolQd~ 11~ered and
the ~iltrate i9 concentr~t~. The p~ecipl~at~ i~ th~n w~hed
with water snd crystallized ~ra~ ~hanol ~o yi~ld l~ mQ~hyl~
~-naphthylmethyl)~4~(2~pyridyl)p~per~8in~.
, - - ..
~4Z43~
EXAMPLE 10
In like manner using the procedure of Example 9,
5-methoxy-2-naphthoic acid and 7-chloro-2-naphtholc acid were
employed as starting materials in place of 6-methyl~2
naphthoic acid to yield respectively 10(5 methoxy~
naphthylmethyl)-4-(2-pyridyl)piperazine, (7~chloro~naphthyl~
methyl)-4-(2-pyridyl)piperazine.
EXAMPLE 11
A solution of 3.4 g, of 1-(5-methoxy-~-naphthyl~
methyl)-4-(2-pyridyl)piperazine in lOO ml. of 48% hydrogen
bromide is refluxed for three hours. The mixture is cooled~
concentrated and treated with sodium carbonate~ The mixture
is extracted with chloroform and the chloroform extractions
are dried to yield 1-(5-hydroxy-~-naphthylmethyl)~4-(2
15 pyridyl)piperazine.
EX~MPLE 12
Ingredients Mgo /Tablet
~ naphthylmethyl)-4-(2-pyridyl)piperazine 25 mg~
Calcium sulfate dihydrate 100 mg.
20 Sucrose 25 mg~
Starch 15 mg~
Talc 5 mg
Stearic acid 3 mgO
The sucrose, calcium sulfate and l~ naphthyl~
methyl)-4-(2-pyridyljpiperazine are thoroughly mixed and
granulated with hot 10% gelatin solutionO The wetted mass
is passed through a #16 U. S. standard mesh screen directly
onto drying trays. The granules are dried at 120 F. and
passed through a #20 U. S. standard mesh screenO These
granules are then mixed with starch, talc and stearic acid7
.. . .
i~4;~43~
l passed through a #60 U. S. standard mesh screen and
compressed into tablets.
One tablet is administered four times a dayO
EXAMPLE 13
In~redients M~/Capsule
~ naphthylmethyl)-4-(2-pyrimidinyl)piperazine 50 mg~
Lactose 200 mg~
The above ingredients are thoroughly mixed and
filled into a #2 hard gelatin capsuleO
l() One capsule is administered twic Q a dayO ;
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