Note: Descriptions are shown in the official language in which they were submitted.
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1-(Isoquinolin-1-yl)-4-(1-phenylmethyl)piperazines;
Dopamine Receptor Subtype Specific Ligands.
BACKGROUND OF THE INVENTION
~ 5 Field of the Invention
This invention relates to 1-(isoquinolin-1-yl)-4-(1-phenylmethyl)piperazines
and
pharmaceutical compositions and preparations containing such compounds. It
also relates to
the use of such compounds in the treatment or prevention of psychotic
disorders such as
schizophrenia and other central nervous system diseases.
Description of the Related Art
The therapeutic effect of conventional antipsychotics, known as neuroleptics,
is
generally believed to be exerted through blockade of dopamine receptors.
However,
neuroleptics are frequently responsible for undesirable extrapyramidal side
effects (EPS) and
tardive dyskinesias, which are attributed to blockade of D2 receptors in the
striatal region of
1 S the brain. The dopamine D4 receptor subtype has recently been identified
(Sokoloff, P. et al.,
Nature, 1990, 347, 146). Its unique localization in limbic brain areas and its
differential
recognition of various antipsychotics suggest that the D4 receptor may play a
major role in the
etiology of schizophrenia. Selective D4 antagonists are considered effective
antipsychotics
free from the neurological side effects displayed by conventional
neuroleptics.
European Patent Application EP 512755 A2 discloses piperazine derivatives
said to be 5-HT 1 a antagonists.
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SUMMARY OF THE INVENTION
This invention provides novel compounds of Formula I which interact with
dopamine
receptor subtypes. A broad aspect of the invention is directed to compounds of
Formula I:
R5
Ar~NUN
ry
Rz~~\R~
wherein:
Ar represents an optionally substituted heteroaryl group or an optionally
substituted aryl
group;
R~ and R~ independently represent hydrogen, haiogen, C~-C6 alkyl, C~-C4
alkoxy, C,-C4
alkylthio, hydroxy, amino, mono- or di(C,-C6)alkyl amino, cyano or
trifluoromethyl;
and
RS represents hydrogen or C~-C6 alkyl.
In this aspect, when Ar is phenyl, it is not an unsubstituted phenyl group. In
other
words, where Ar is phenyl, the phenyl is substituted with at least one non-
hydrogen group.
In yet another aspect, the invention provides pharmaceutical compositions
comprising
compounds of Formula I.
Since dopamine D4 receptors are concentrated in the limbic system (Taubes,
Science
265: 1034, 1994) which controls cognition and emotion, compounds which
interact with these
receptors are useful in the treatment of cognitive disorders. Such disorders
include cognitive
deficits which are a significant component of the negative symptoms (social
withdrawal and
unresponsiveness) of schizophrenia. In addition, disorders involving memory
impairment or
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attention deficit disorders can be treated with the compounds of this
invention. These
compounds interact specifically with the dopamine D4 receptor subtype.
The compounds of the invention demonstrate high affinity and selectivity in
binding to
the D4 receptor subtype. The use of the compounds of this invention in methods
of treating
neuropsychological disorders is predicated on the ability of the compounds to
bind selectively
to a dopamine receptor subtype, the D, receptor. The compounds of the
invention can
therefore be used in the treatment of schizophrenia, psychotic depression and
mania. Other
dopamine-mediated diseases such as Parkinsonism and tardive dyskinesias can
also be treated
directly or indirectly by modulation of D4 receptors.
Thus, in another aspect, the invention provides methods for treating and/or
preventing
neuropsychological disorders including, for example, schizophrenia, mania,
dementia,
depression, anxiety, compulsive behavior, substance abuse, memory impairment,
cognitive
deficits, Parkinson-like motor disorders and motion disorders related to the
use of neuroleptic
agents. It also provides methods of treating affective disorders such as
Alzheimer's disease
1 S and certain movement disorders such as Parkinsonism and dystonia.
The invention further provides methods for treating the extrapyramidal side
effects
associated with the use of conventional neuroleptic agents. The compounds of
the present
Invention are also useful for the treatment of other disorders which respond
to dopaminergic
blockade such as substance abuse and obsessive compulsive disorder.
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DETAILED DESCRIPTION OF THE INVENTION
In addition to compounds of Formula I, the invention provides compounds of
Formula
IA:
R5 ~ N \
Ar~NUN
R2/~\ R
IA
wherein:
Ar represents aryl or heteroaryl, each of which is optionally substituted with
R, and/or R4,
provided that Ar is not unsubstituted phenyl;
R~ and R~ independently represent hydrogen, halogen, C~-C6 alkyl, C~-C4
alkoxy, C,-C4
alkylthio, hydroxy, amino, mono- or di(C,-C6)alkyl amino, cyano or
trifluoromethyl;
and
RS represents hydrogen or C~-C6 alkyl.
Preferred compounds of Formula IA are those where R3 and R4 independently
represent hydrogen, halogen, hydroxy, C1-C6 alkyl, trifluoromethyl,
trifluoromethoxy or
S02NH2, with the proviso provided that not both R3 and R4 are hydrogen
simultaneously; or
R3 and R4 together represent an alkylene, alkenylene, alkyleneoxy, or
alkylenedioxy chain
that together with the atoms to which they are attached form a ring having 5-7
ring atoms.
In compound IA, R3 is preferably in a position para to the point of attachment
of the
aryl or heteroaryl group to the methylene group.
Thus, in the compounds of the invention, Ar is not unsubstituted phenyl since
a
substituent on the phenyl group is required for activity at the D~ receptor.
Le., phenyl must
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contain at least one non-hydrogen substituent. Suitable non-hydrogen
substituents are the
non-hydrogen R3 and R4 substituents defined above.
Preferred Ar groups of Formulas I and IA are
F
C~ \ I F \ I \ I O i i i H3C i
~ ~ I ~ ~ I or
F O ~~
F
5
In addition to compounds of Formula I above, the invention provides compounds
of
Formula II:
%v
R2 ~ R1
II
wherein:
R~ and R2 independently represent hydrogen, halogen, Ci-C6 alkyl, C~-C4
alkoxy, C,-C4
alkylthio, hydroxy, amino, mono- or di(C,-C6)alkyl amino, cyano or
trifluoromethyl;
R3 and R4 independently represent hydrogen, halogen, hydroxy, C~-C6 alkyl,
trifluoromethyl,
1 S trifluoromethoxy or S02NH2, with the proviso provided that not both R; and
R4 are
hydrogen simultaneously; and
RS represents hydrogen or C I -C6 alkyl.
In preferred compounds of Formula II, at least one of R, and R4 is C,-C6 alkyl
or
halogen. In more preferred compounds of Formula II, RS is hydrogen, and R, and
R, are
independently hydrogen or C,-C6 alkyl. In still other more preferred compounds
of Formula
II, RS is hydrogen, and R, and R4 are hydrogen and halogen, respectively, or
are both halogen.
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In still other preferred compounds of Formula II, the phenyl group (Ar) is
substituted
with methyl or mono- or disubstituted with halogen, and RS is hydrogen.
The most preferred compounds of Formula II are those where R, and R, are both
hydrogen.
Particularly preferred compounds of Formula II are those where R, and R= are
hydrogen and the phenyl group (Ar) is monosubstituted in the 4 position with
methyl or
chioro (4-methylphenyl or 4-chlorophenyl) or the phenyl group is disubstituted
with fluoro in
both the 3 and 4-positions (3,4-difluorophenyl).
The invention also provides compounds of Formula III:
R5
N N
O
s
O R6 R2 ~--' R~
III
wherein:
I 5 R i and R2 independently represent hydrogen, halogen, C ~ -C6 alkyl, C ~ -
C4 alkoxy, C,-C,
alkylthio, hydroxy, amino, mono- or di(C,-C~)alkyl amino, cyano or
trifluoromethyl;
R6 represents hydrogen, halogen, hydroxy, C~-C6 alkyl, trifluoromethyl,
trifluoromethoxy or
S02NH2; and
RS represents hydrogen or C ~ -C6 alkyl.
In preferred compounds of Formula III, R6 is hydrogen, C,-C6 alkyl, or
halogen. In
more preferred compounds of Formula IV, RS is hydrogen and R6 is hydrogen, C,-
C6 alkyl, or
halogen. In still other preferred compounds of Formula III, R, and R, are
halogen, C~-C~,
alkyl, or hydroxy, RS is hydrogen and R~ is hydrogen, C,-C6 alkyl, or halogen.
The most preferred compounds of Formula III are those where R, and R, are both
hydrogen, and RS and R6 are hydrogen.
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The invention also provides compounds of Formula IV:
~ R5 N N N \
U
_1~ ~s
R6 RZ ~ R~
IV
wherein:
R~ and R2 independently represent hydrogen, halogen, C~-C6 alkyl, C~-C4
alkoxy, C,-C4
alkylthio, hydroxy, amino, mono- or di(C,-C6)alkyl amino, cyano or
trifluoromethyl;
R6 represents hydrogen, halogen, hydroxy, C~-C6 alkyl, trifluoromethyl,
trifluoromethoxy or
SO2NH2; arid
RS represents hydrogen or C ~ -C6 alkyl.
In preferred compounds of Formula IV, R6 is hydrogen, C,-C6 alkyl, or halogen.
In
more preferred compounds of Formula IV, RS is hydrogen and R6 is hydrogen, C,-
C5 alkyl, or
halogen. In still other preferred compounds of Formula IV, R, and R, are
halogen, Ci-C6
alkyl, or hydroxy, RS is hydrogen and R6 is hydrogen, C,-C6 alkyl, or halogen.
The most preferred compounds of Formula IV are those where R, and R, are both
hydrogen, and RS and R6 are hydrogen.
In certain situation, compounds of Formula I may contain one or more
asymmetric
carbon atoms, so that the compounds can exist in different stereoisomeric
forms. These
compounds can be, for example, racemates or optically active forms. For
example, where RS
in Formula I is a methyl group, the resulting compound can be present as (R)
and (S)
stereoisomers. In these situations, the single enantiomers, i.e., optically
active forms, can be
obtained by asymmetric synthesis or by resolution of the racemates. Resolution
of the
racemates can be accomplished, for example, by conventional methods such as
crystallization
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in the presence of a resolving agent, or chromatography, using, for example a
chiral HPLC
column.
Representative compounds of the present invention, which are encompassed by
Formula I, include, but are not limited to the compounds in Table I and their
pharmaceutically
acceptable salts. If the compound of the invention is obtained as an acid
addition salt, the free
base can be obtained by basifying a solution of the acid salt. Conversely, if
the product is a
free base, an addition salt, particularly a pharmaceutically acceptable
addition salt, may be
produced by dissolving the free base in a suitable organic solvent and
treating the solution
with an acid, in accordance with conventional procedures for preparing acid
addition salts
from base compounds.
Non-toxic pharmaceutically acceptable salts include salts of acids such as
hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,
toluenesulfonic,
methanesulfonic, nitric, benzoic, citric, tartaric, malefic, hydroiodic,
alkanoic such as, for
example, acetic, HOOC-(CH2)n-COOH where n is 0-4, such as, for example, oxalic
(n=0),
and the like. Those skilled in the art will recognize a wide variety of non-
toxic
pharmaceutically acceptable addition salts.
The present invention also encompasses the acylated prodrugs of the compounds
of
Formula I. Those skilled in the art will recognize various synthetic
methodologies which may
be employed to prepare non-toxic pharmaceutically acceptable addition salts
and acylated
prodrugs of the compounds encompassed by Formula I.
By the terms (C,-C6)alkyl and lower alkyl is meant straight and branched chain
alkyl
groups having from 1-6 carbon atoms as well as cyclic alkyl groups such as,
for example,
cyclopropyl, cyclobutyl, or cyclohexyl. Specific examples of such alkyl groups
are methyl,
ethyl, propyl, isopropyl, n-butyl, isobutyl, tent-butyl, sec-butyl, neopentyl
and n-pentyl.
Preferred C,-C~ alkyl groups are methyl, ethyl, propyl, butyl or
cyclopropylmethyl.
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By the terms (C,-C6)alkoxy and lower aikoxy is meant straight and branched
chain
alkoxy groups having from 1-6 carbon atoms.
By hydroxy C,-C6 alkyl is meant a C,-C6 alkyl group carrying a terminal
hydroxy
moiety.
' S By the term piperonyl as used herein is meant a group of the Formula:
1
By halogen, halo; or halide is meant fluorine, chlorine, bromine and iodine
substituents.
By aryl or "Ar" is meant an aromatic carbocyclic group having a single ring
(e.g.,
phenyl), multiple rings (e.g., biphenyl), or multiple condensed rings in which
at least one is
aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or
phenanthryl), which is
optionally mono-, di-, or trisubstituted with, e.g., halogen, lower alkyl,
lower alkoxy, lower
alkylthio, trifluoromethyl, lower acyloxy, aryl, heteroaryl, and hydroxy.
By aryl or "Ar" is also meant heteroaryl groups where heteroaryl is defined as
5, 6, or
7 membered aromatic ring systems having at least one hetero atom selected from
the group
consisting of nitrogen, oxygen and sulfur. Examples of heteroaryl groups are
pyridyl,
pyrimidinyl, pyrrolyl, pyrazolyl, pyrazinyl, pyridazinyl, oxazolyl, furanyl,
quinolinyl,
isoquinolinyl, thiazolyl, and thienyl, which can optionally be substituted
with, e.g., halogen,
lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy,
aryl, heteroaryl,
and hydroxy.
As noted above, R3 and R4 may be connected together to form another ring with
the
atoms to which they are attached on the parent aryl or heteroaryl group. Thus,
R, and R~
may represent an alkylene, alkenylene, alkyleneoxy, or aikylenedioxy chain
that together
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with the atoms to which they are attached form a ring having 5-7 atoms. For
example, Ar
may be an optionally substituted naphthyl group or a bicyclic oxygen-
containing group of
the formula
-o
Rs
5 wherein the heterocyclic oxygen containing ring has a total of from 5 to 7
ring members, the
heterocyclic ring being saturated or unsaturated, and optionally substituted.
.R6 is as defined
above for Formula III.
Preferred examples of bicyclic oxygen-containing groups are:
O ~ ~ ~ ~ ~ ~ O
CO ~s O ~6 O ~s
'~ O
O I-_~ O ~ \ I ~R
R R R ~ s
10 s s s O
Representative examples of isoquinolinylpiperazines according to the invention
are
shown in Table 1 below.
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Tab 1
i i I I i N~ i
C~ I ~ F ' ~N
I
N~ F N
1 2
F
N'~ ~ \ N ~l ~ I
i ~N I w I O ( i ~N w
F NJ ~O N
3 4
N i
I I ~ i N
w
I I H3C I w
N~ N i
6
The number in Table 1 below each structure is its compound number.
As noted above, the invention also pertains to the use of compounds of general
Formula I in the treatment of various neuropsychological disorders.
The compounds of general Formula I may be administered orally, topically,
parenterally, by inhalation or spray or rectally in dosage unit formulations
containing
conventional non-toxic pharmaceutically acceptable carriers, adjuvants and
vehicles. The
term parenteral as used herein includes subcutaneous injections, intravenous,
intramuscular,
intrasternal injection or infusion techniques. In addition, there is provided
a pharmaceutical
formulation comprising a compound of general Formula I and a pharmaceutically
acceptable
carrier. One or more compounds of general Formula I may be present in
association with one
or more non-toxic pharmaceutically acceptable Garners and/or diluents and/or
adjuvants and if
desired other active ingredients. The pharmaceutical compositions containing
compounds of
general Formula I may be in a form suitable for oral use, for example, as
tablets, troches,
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lozenges, aqueous or oily suspensions, dispersible powders or granules,
emulsion, hard or soft
capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any method
known
to the art for the manufacture of pharmaceutical compositions and such
compositions may
S contain one or more agents selected from the group consisting of sweetening
agents, flavoring
agents, coloring agents and preserving agents in order to provide
pharmaceutically elegant and
palatable preparations. Tablets contain the active ingredient in admixture
with non-toxic
pharmaceutically acceptable excipients which are suitable for the manufacture
of tablets.
These excipients may be for example, inert diluents, such as calcium
carbonate, sodium
carbonate, lactose, calcium phosphate or sodium phosphate; granulating and
disintegrating
agents, for example, corn starch, or alginic acid; binding agents, for example
starch, gelatin or
acacia, and lubricating agents, for example magnesium stearate, stearic acid
or talc. The
tablets may be uncoated or they may be coated by known techniques to delay
disintegration
and absorption in the gastrointestinal tract and thereby provide a sustained
action over a
longer period. For example, a time delay material such as glyceryl
monostearate or glyceryl
distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules
wherein the
active ingredient is mixed with an inert solid diluent, for example, calcium
carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient
is mixed with
water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients
suitable
for the manufacture of aqueous suspensions. Such excipients are suspending
agents, for
example sodium carboxymethylcellulose, methylcellulose,
hydropropylmethylcellulose,
sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;
dispersing or wetting
agents may be a naturally-occurring phosphatide, for example, lecithin, or
condensation
products of an alkylene oxide with fatty acids, for example polyoxyethylene
stearate, or
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condensation products of ethylene oxide with long chain aliphatic alcohols,
for example
heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with
partial esters
derived from fatty acids and a hexitol such as polyoxyethylene sorbitol
monooleate, or
condensation products of ethylene oxide with partial esters derived from fatty
acids and
' S hexitol anhydrides, for example polyethylene sorbitan monooleate. The
aqueous suspensions
may also contain one or more preservatives, for example ethyl, or n-propyl p-
hydroxybenzoate, one or more coloring agents, one or more flavoring agents,
and one or more
sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredients in a
vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil,
or in a mineral oil
such as liquid paraffin. The oily suspensions may contain a thickening agent,
for example
beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set
forth above, and
flavoring agents may be added to provide palatable oral preparations. These
compositions
may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous
suspension by
the addition of water provide the active ingredient in admixture with a
dispersing or wetting
agent, suspending agent and one or more preservatives. Suitable dispersing or
wetting agents
and suspending agents are exemplified by those already mentioned above.
Additional
excipients, for example sweetening, flavoring and coloring agents, may also be
present.
Pharmaceutical compositions of the invention may also be in the form of oil-in-
water
emulsions. The oily phase may be a vegetable oil, for example olive oil or
arachis oil, or a
mineral oil, for example liquid paraffin or mixtures of these. Suitable
emulsifying agents may
be naturally-occurring gums, for example gum acacia or gum tragacanth,
naturally-occurnng
phosphatides, for example soy bean, lecithin, and esters or partial esters
derived from fatty
acids and hexitol, anhydrides, for example sorbitan monoleate, and
condensation products of
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the said partial esters with ethylene oxide, for example polyoxyethylene
sorbitan monoleate.
The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example
glycerol,
propylene glycol, sorbitol or sucrose. Such formulations may also contain a
demulcent, a
preservative and flavoring and coloring agents. The pharmaceutical
compositions may be in
the form of a sterile injectable aqueous or oleaginous suspension. This
suspension may be
formulated according to the known art using those suitable dispersing or
wetting agents and
suspending agents which have been mentioned above. The sterile injectable
preparation may
also be sterile injectable solution or suspension in a non-toxic parentally
acceptable diluent or
solvent, for example as a solution in 1,3-butanediol. Among the acceptable
vehicles and
solvents that may be employed are water, Ringer's solution and isotonic sodium
chloride
solution. In addition, sterile, fixed oils are conventionally employed as a
solvent or
suspending medium. For this purpose any bland fixed oil may be employed
including
synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid
find use in the
preparation of injectables.
The compounds of general Formula I may also be administered in the form of
suppositories for rectal administration of the drug. These compositions can be
prepared by
mixing the drug with a suitable non-irntating excipient which is solid at
ordinary temperatures
but liquid at the rectal temperature and will therefore melt in the rectum to
release the drug.
Such materials are cocoa butter and polyethylene glycols.
Compounds of general Formula I may be administered parenterally in a sterile
medium. The drug, depending on the vehicle and concentration used, can either
be suspended
or dissolved in the vehicle. Advantageously, adjuvants such as local
anesthetics, preservatives
and buffering agents can be dissolved in the vehicle.
Dosage levels on the order of from about 0.1 mg to about 140 mg per kilogram
of
body weight per day are useful in the treatment of the above-indicated
conditions (about
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0.5 mg to about 7 g per patient per day). The amount of active ingredient that
may be
combined with the Garner materials to produce a single dosage form will vary
depending upon
the host treated and the particular mode of administration. Dosage unit forms
will generally
contain between from about 1 mg to about 500 mg of an active ingredient.
' S It will be understood, however, that the specific dose level for any
particular patient
will depend upon a variety of factors including the activity of the specific
compound
employed, the age, body weight, general health, sex, diet, time of
administration, route of
administration, and rate of excretion, drug combination and the severity of
the particular
disease undergoing therapy.
10 Representative illustrations of methods suitable for the preparation of
compounds of
the present invention are shown in Schemes I and II. Those having skill in the
art will
recognize that the starting materials may be varied and additional steps
employed to produce
compounds encompassed by the present invention.
Scheme I
N
CI ~ ~ N
H ~N H + .,. H N N ~
V
RZ~u R~ /
R2~~-=-~~ R,
V
H
A~~O
VII ~ NON
--~' Ar I
1 S NaBH3CN R ~u~. R
z
wherein Ar, R~ and R~ are as defined above for Formula I.
VI
' As depicted in Scheme I, a suitably substituted I-chloroisoquinoIine of
Formula V is
condensed with piperazine to provide a 1-isoquinolin-I-ylpiperazine of Formula
VI. The
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compound of Formula VI is typically reductively alkylated with an arylaldehyde
of Formula
VII with a reducing agent such as, for example, sodium cyanoborohydride to
yield the desired
1-(1-isoquinolin-1-yl)-4-(1-phenylmethyl)piperazine of Formula 1. In certain
situations,
protection of reactive moieties such as nitrogen and hydroxy groups will be
necessary to allow
S a conversion to be achieved without adversely affecting the reactive moiety.
Those having
skill in the art will recognize suitable protecting groups and methods for
facilitating removal
of the protecting groups. The protecting groups can be added and removed using
methods
taught in the literature or analogous methods.
Alternatively, compounds of Formula I may be prepared according to Scheme II
Scheme II
N Ar ~ X ~--~ N
H NON ~ ~ ~ ~ NON
Ar
R2~~i R~ R2~~i R,
VI I
wherein Ar, R i and R2 are as defined above for Formula I.
I S As shown in Scheme II, a 1-isoquinolin-1-ylpiperazine of Formula VI
(prepared as
shown above in Scheme I) may be alkylated using an arylmethylhalide compound
of Formula
VIII to provide the desired 1-(isoquinolin-1-yl)-4-(1-arylmethyl)piperazine of
Formula 1.
Again, when necessary reactive groups may be protected according to literature
methods or
modified literature methods.
The disclosures in this application of all articles and references, including
patents, are
incorporated herein by reference.
Those having skill in the art will recognize that the starting materials may
be varied
and additional steps employed to produce compounds encompassed by the present
invention.
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The invention is illustrated further by the following examples which are not
to be
construed as limiting the invention in scope or spirit to the specific
procedures and
compounds described in them.
Example 1
1. 1-(Isoauinolin~l-yl~piperazine
A solution of 2-chloroisoquinoline (5 g) in 20 mL of toluene is added dropwise
to a
refluxing solution of piperazine (20 g) in 150 mL of toluene. The solution is
heated for an
additional 48 h. After cooling to 0 °C for 0.5 h, the solution is
filtered. The filtrate is then
extracted with 10 % acetic acid. The aqueous extracts are washed with ether,
basified and
subsequently extracted with dichloromethane. The dichloromethane layer is
finally washed
with water, dried and concentrated. The material is placed under vacuum
overnight to yield
the title compound (6.8 g, m.p. 54-56 °C). ~H NMR (CDC13) 8.14 (d, J =
5.5 Hz, 1H), 8.10
(d, J = 8.5 Hz, 1 H}, 7.74 (d, J = 8.5 Hz, 1 H), 7.60 (t, J = 7.2 Hz, 1 H),
7.50 (t, J = 7.6 Hz, 1 H),
7.24 (d, J = 5.5 Hz, 1H), 3.39 (t, J = S.0 Hz, 4H), 3.16 (t, J = 5.0 Hz, 4H).
2_. 1-lIso4uinolin-1-vll-4-(1-fpiperonvllmethvllninP~a~;ne hydrochloride
O
/ \
Co ~HC~
A solution of 1-(isoquinolin -1-yl)piperazine (215 mg, 1.0 mmol) and piperonal
(160
mg) in methanol (10 mL) is prepared and adjusted to pH 4 using acetic acid.
Sodium
cyanoborohydride (500 mg) is then added and the reaction mixture allowed to
stir at room
temperature overnight. The solvent is evaporated and the residual oil
partitioned between
dichloromethane and 5% aqueous ammonia. The organic layer is then subjected to
preparative TLC (10:2 hexane:ethylacetate) which yields the free base of the
title compound
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as a colorless oil (300 mg}. The hydrochloride salt is then obtained from an
ethylacetate
solution after treatment with hydrochloric acid (m.p.250-251 °C). ~H
NMR (CDCl3) 8.15 (d,
J = 5 . S Hz, 1 H}, 8.06 (d, J = 8.5 Hz, 1 H), 7.75 (d, J = 8.0 Hz, 1 H), 7.65
(t, J = 7.0 Hz, 1 H),
7.48 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 6.1 Hz, 1H), 6.91 (s, 1H), 6.80 (m,
2H), 3.55 (s, 2H), 3.43
(s br, 4H), 2.71 (s br, 4H).
Examele 2
1-(Isoquinolin-1- 1~1-j4-chloropheny~methvll p~erazine oxalate
N
i ~N i
CI
I
'H02CC02H N i
A solution of 1-(isoquinolin-1-yl)piperazine (215 mg, 1.0 mmol) and 4-
chlorobenzyl
chloride (180 mg) in acetonitrile (10 mL) containing potassium carbonate (500
mg) is stirred
and heated at 60°C for 4h. After cooling, the reaction mixture is
partitioned between ether
and water. The organic layer was extracted with 1 N HCI. The acidic extract is
then basified
and extracted with chloroform. The resulting organic layer is dried and
concentrated to
provide the free base of the title compound as a white solid ( 300 mg, 88%).
The oxalate salt is prepared from isopropanol (m.p.207-208 °C). ~H NMR
(DMSO)
8.09 (d, J = 5.5 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H),
7.69 (t, J = 7.0 Hz,
1H), 7.58 (t, J = 7.6 Hz, 1H), 7.46 (s br, 4H), 7.40 (d, J = 6.1 Hz, 1H), 3.93
(s br, 2H), 3.40 (s
br, 4H), 2.95 (s br, 4H).
Example 3
The following compounds are prepared essentially according to the procedures
set
forth above in Examples 1 and 2.
CA 02283256 1999-09-02
WO 98/39301 PCT/US98/04051
19
1-(isoquinolin-1-yl)-4-(1-[3,4-difluorophenyl)methyl)piperazine oxalate (m.p.
212-213
°C).
1-(isoquinolin-1-yl)-4-(1-[3,5-difluorophenyl]methyl)piperazine oxalate (m.p.
223-224
°C).
S 1-(isoquinolin-1-yl)-4-(1-[2-naphthyl]methyl)piperazine hydrochloride (m.p.
265-268
°C).
1-(isoquinolin-1-yl)-4-{1-[4-methylphenyl]methyl)piperazine oxalate (m.p. 192-
194
°C).
1-(isoquinolin-1-yl)-4-( 1-[3-chlorophenyl]methyl)piperazine.
Example 4
The pharmaceutical utility of compounds of this invention is indicated by the
following assays for dopamine receptor subtype affinity.
1. Assay For D2 And D4 Receptor Binding Activity
1 S Pellets of COS cells containing recombinantly produced D2 or D4 receptors
from
African Green monkey are used for the assays. The sample is homogenized in 100
volumes
(w/vol) of 0.05 M Tris HCl buffer at 4°C and pH 7.4. The sample is then
centrifuged at
30,000 x g and resuspended and rehomogenized. The sample is again centrifuged
as
described above and the final tissue sample is frozen until use. The tissue is
resuspended 1:20
(wt/vol) in 0.05 M Tris HCl buffer containing 100 mM NaCI.
Incubations are carried out at 48°C and contain 0.4 ml of tissue
sample, 0.5 nM 3H-
YM 091 S 1-2 and the compound of interest in a total incubation of 1.0 ml.
Nonspecific
binding is defined as that binding found in the presence of 1 mM spiperone;
without further
additions, nonspecific binding is less than 20% of total binding. Binding
characteristics for
representative examples of this invention for the D2 and D4 receptor subtypes
are shown in
CA 02283256 1999-09-02
WO 98/39301 PCT/US98/04051
Table 2 below for rat striatal homogenates. The binding characteristics of
compounds of
Formula I for the D4 receptor, expressed in nM, generally range from about 0.5
nanomolar
(nM) to about 25 nanomolar (nM). These compounds typically have binding
constants for the
D, receptor of from about 200 nM to more than 1000 nM. Thus, the compounds of
the
5 invention are generally at least about 10 time more selective for the Da
receptor than the D,
receptor. More preferably, these compounds are at least 20, and more
preferably at least 25-
50, times more selective for the Da receptor than the D, receptor.
TABLE 2
10 Binding characteristics of 1-(isoquinolin-1-yl)-4-
ll-phenvlmeth~rl~piperazines to D4 and D~ receptors
Compound Number' D4 K; (nM) Dz K; (nM)
1 5 556
2 13 1003
4 19 ND
6 9 220
1 Compound numbers relate to compounds shown in Table 1.
The invention and the manner and process of making and using it, are now
described
in such full, clear, concise and exact terms as to enable any person skilled
in the art to which it
pertains, to make and use the same. It is to be understood that the foregoing
describes
preferred embodiments of the present invention and that modifications may be
made therein
without departing from the spirit or scope of the present invention as set
forth in the claims.
To particularly point out and distinctly claim the subject matter regarded as
invention, the
following claims conclude this specification.
