Note: Descriptions are shown in the official language in which they were submitted.
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3-Amiaoalkylamino-2H-1,4-benzoxazinas and
3-Amiaoalkylamino-2Ii-1.4-benzothiazinas:
Dopamine Receptor Subtype Specific Ligaada
BACKGROUND OF THE INVENTION
F;P» of the Invention
This invention relates to certain 3-aminoalkylamino-2H-
1,4-benzoxazines and 3-aminoalkylamino-2H-1,4-benzothiazines
and pharmaceutical compositions 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.
nescriTlt,'_on 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 the brain.
The dopamine D4 receptor subtype has recently been identified
(Nature, 47: 146, Sokoloff et al., 1990; Nature, ~0: 610, Van
Tol et al., 1991). Its unique localization in limbic brain
areas and its differential recognition of various
antipsychotics indicates that the D4 receptor plays a major
role in the etiology of schizophrenia. Selective D4
antagonists are considered effective antipsychotics free from
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the neurological side effects displayed by conventional
neuroleptics.
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~~Y OF THE LION
This invention provides novel compounds which interact
with dopamine subtypes. Accordingly, in a broad aspect, the
invention provides compounds of Formula I:
R' X
N N~A~N
~ ~W~Ar
I
or the pharmaceutically acceptable acid addition salts thereof,
wherein:
Ar represents aryl or heteroaryl of the formula
Ra
Z ~~~
i
J R3
io Y
where Y and Z independently represent CH or nitrogen;
R1. R2. R3 and R4 are the same or different and represent
hydrogen, halogen, C1-C6 alkyl, Cl-C4 alkoxy, cycloalkoxy,
alkylthio, hydroxy, amino, mono- or dialkylamino where
each alkyl is C1-C6 alkyl, cyano, nitro, trifluoromethyl
or trifluoromethoxy; or
R, and R, together represent a Cl-CZ alkylene dioxy group or a
C1-C, alkylene oxy group;
R5 is hydrogen or Cl-C6 alkyl;
W represents CH or nitrogen;
X is oxygen or sulfur; and
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A represents an alkylene group of 2 to 5 carbon atoms, each of
which carbon atoms is optionally substituted with one or
two alkyl groups having from 1 to 4 carbon atoms.
Dopamine D4 receptors are concentrated in the limbic
system (Science, 265: 1034 (Taubes, 1994)) which controls
cognition and emotion. Therefore, compounds that 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. Other
disorders include those involving memory impairment or
attention deficit disorders.
Compounds of the present invention demonstrate high
affinity and selectivity in binding to the D4 receptor subtype.
These compounds are therefore useful in treatment of a variety
of neurospychological disorders, such as, for example,
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 treatment and/or prevention of neuropsychochological or
affective disorders including, for example, schizophrenia,
mania, dementia, depression, anxiety, compulsive behavior,
substance abuse, memory impairment, cognitive deficits,
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Parkinson-like motor disorders, e.g., Parkinsonism and
dystonia, and motion disorders related to the use of
neuroleptic agents. In addition, the compounds of the
invention are useful in treatment of memory-impairment or
Alzheimer's disease by modulation of D4 receptors which
selectively exist in limbic area known to control emotion and
cognitive functions. Further, the compounds of the present
invention are useful for the treatment of other disorders that
respond to dopaminergic blockade, e.g., substance abuse and
obsessive compulsive disorder. These compounds are also useful
in treating the extrapyramidal side effects associated with the
use of conventional neuroleptic agents.
In yet another aspect, the invention provides
pharmaceutical compositions comprising compounds of Formula I.
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DETAILED DESCRIPTION OF THE INVENTION
The compounds of Formula I can be used in in the
treatment of affective disorders such as schizophrenia,
depression, Alzheimer's disease and certain movement disorders
such as Parkinsonism and dystonia. Furthermore compounds of
this invention can be used in 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.
As mentioned above, the invention encompasses 3-
aminoalkylamino-2H-1,4-benzoxazines and 3-aminoalkylamino-2H-
1,4-benzothiazines of Formula I. Preferred compounds of
Formula I are those where R1 and Rz are hydrogen, and A is
alkylene of from 2-4 carbon atoms.
In addition to compounds of general Formula I_ described
above, the invention encompasses compounds of Formula _I~:
X
C'
N N.A.N
4
Y
R3
IA
wherein:
Y and Z independently represent CH or nitrogen;
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R1, R2, R3 and Rg are the same or different and represent
hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, alkylthio,
hydroxy, amino, mono- or dialkylamino where each alkyl is
C1-C6 alkyl, cyano, vitro, trifluoromethyl or
trifluoromethoxy;
R5 is hydrogen or C1-C6 alkyl;
W represents CH or nitrogen;
X is oxygen or sulfur; and
A represents an alkylene group of 2 to 5 carbon atoms each of
which carbon atoms is optionally substituted with one or
two alkyl groups having from 1 to 4 carbon atoms.
Preferred compounds of Formula IA are those where Z and Y
are both nitrogen. More preferably, W, Y and Z are all
nitrogen. Other preferred compounds of Formula IA are those
where R1 and RZ are hydrogen and RS is hydrogen, methyl, or
ethyl.
The present invention also provides compounds of Formula
IB:
R' S
_ C',
R2 ~ N N'A'N
4
Y
R3
IB
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wherein:
Y and Z independently represent CH or nitrogen;
R1, R2, R3 and R4 are the same or different and represent
hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, alkylthio,
hydroxy, amino, mono- or dialkylamino where each alkyl is
C1-C6 alkyl, cyano, nitro, trifluoromethyl or
trifluoromethoxy;
R5 is hydrogen or C1-C6 alkyl;
W represents CH or nitrogen;
l0 X is oxygen or sulfur; and
A represents an alkylene group of 2 to S carbon atoms each of
which carbon atoms is optionally substituted with one or
two alkyl groups having from 1 to 4 carbon atoms.
Preferred compounds of Formula IB are those where Z and Y
are both nitrogen. More preferred compounds of Formula IB are
where W, Y and Z are nitrogen and RS is hydrogen, methyl, or
ethyl. Particularly preferred compounds of Formula IH are
where W, Y and Z are nitrogen, RS is hydrogen, methyl, or
ethyl, and R1 and RZ are both hydrogen.
The invention further provides compounds of Formula IC.
_g_
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R~ O
C'
R2 N N-A.N
R5 ~W Z~ 4
Y~~R
3
IC
wherein:
Y and Z independently represent CH or nitrogen;
R1, R2, R3 and R4 are the same or different and represent
hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, alkylthio,
hydroxy, amino, mono- or dialkylamino where each alkyl is
Cl-C6 alkyl, cyano, nitro, trifluoromethyl or
trifluoromethoxy;
R5 is hydrogen or C1-C6 alkyl;
W represents CH or nitrogen;
X is oxygen or sulfur; and
A represents an alkylene group of 2 to 5 carbon atoms each of
which carbon atoms is optionally substituted with one or
two alkyl groups having from 1 to 4 carbon atoms.
Preferred compounds of Formula IC are those where Z and Y
are both nitrogen. More preferred compounds of Formula IC are
where W, Y and Z are nitrogen and RS is hydrogen, methyl, or
ethyl. Particularly preferred compounds of Formula IC are
where W, Y and Z are nitrogen, RS is hydrogen, methyl, or
ethyl, and R, and RZ are both hydrogen.
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The invention further encompasses compounds of Formula II:
R' S
C'
R2. N N.A.N
R5
YWR
3
II
wherein:
Y and Z independently represent CH or nitrogen;
R1, R2, R3 and R4 are the same or different and represent
hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, alkylthio,
hydroxy, amino, mono- or dialkylamino where each alkyl is
l0 Cl-C6 alkyl, cyano, vitro, trifluoromethyl or
trifluoromethoxy;
R5 is hydrogen or C1-C6 alkyl;
W represents CH or nitrogen;
X is oxygen or sulfur; and
A represents an alkylene group of 2 to 5 carbon atoms each of
which carbon atoms is optionally substituted with one or
two alkyl groups having from 1 to 4 carbon atoms.
Preferred compounds of Formula II are those where Z and Y
are both nitrogen. More preferred compounds of Formula II are
where Y and Z are nitrogen and RS is hydrogen, methyl, or
ethyl. Particularly preferred compounds of Formula II are
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where Y and Z are nitrogen, R5 is hydrogen, methyl, or ethyl,
R, , RZ and R, are hydrogen .
In addition, the invention provides compounds of Formula
IIA:
R~. S
N N'A~N
R2 4
R5 Z
~I l
Y .v
v Rs
IIA
wherein:
Y and Z independently represent CH or nitrogen;
R1, R2, R3 and R4 are the same or different and represent
hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, alkylthio,
hydroxy, amino, mono- or dialkylamino where each alkyl is
C1-C6 alkyl, cyano, nitro, trifluoromethyl or
trifluoromethoxy;
R5 is hydrogen or C1-C6 alkyl;
W represents CH or nitrogen;
X is oxygen or sulfur; and
A represents an alkylene group of 2 to 5 carbon atoms each of
which carbon atoms is optionally substituted with one or
2o two alkyl groups having from 1 to 4 carbon atoms.
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Preferred compounds of Formula IIA are those where Z and Y
are both nitrogen. More preferred compounds of Formula IIA are
where Y and Z are nitrogen and RS is hydrogen, methyl, or
ethyl. Particularly preferred compounds of Formula IIA are
where Y and Z are nitrogen, RS is hydrogen, methyl, or ethyl,
R1, RZ and R4 are hydrogen .
Further, the present invention encompasses compounds of
Formula III:
O
y.
N.A.N
Z~ a
~I
Yy
io Rs
III
wherein:
Y and Z independently represent CH or nitrogen;
R1. R2. R3 and R4 are the same or different and represent
hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, alkylthio,
hydroxy, amino, mono- or dialkylamino where each alkyl is
C1-C6 alkyl, cyano, nitro, trifluoromethyl or
trifluoromethoxy;
R5 is hydrogen or C1-C6 alkyl;
W represents CH or nitrogen;
X is oxygen or sulfur; and
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A represents an alkylene group of 2 to 5 carbon atoms each of
which carbon atoms is optionally substituted with one or
two alkyl groups having from 1 to 4 carbon atoms.
Preferred compounds of Formula III are those where Z and Y
are both nitrogen. More preferred compounds of Formula III are
where Y and Z are nitrogen and RS is hydrogen, methyl, or
ethyl. Particularly preferred compounds of Formula III are
where Y and Z are nitrogen, RS is hydrogen, methyl, or ethyl,
R1, RZ and R4 are hydrogen .
The invention further provides compounds of Formula IIIA:
R' O
C'
N N'A~N
R2 ' a
R5 Z
Y
R3
IIIA
wherein:
Y and Z independently represent CH or nitrogen;
R1, R2, R3 and R4 are the same or different and represent
hydrogen,. halogen, C1-C6 alkyl, C1-C4 alkoxy, alkylthio,
hydroxy, amino, mono- or dialkylamino where each alkyl is
C1-C6 alkyl, cyano, nitro, trifluoromethyl or
trifluoromethoxy;
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R5 is hydrogen or C1-C6 alkyl;
W represents CH or nitrogen;
X is oxygen or sulfur; and
A represents an alkylene group of 2 to 5 carbon atoms each of
which carbon atoms is optionally substituted with one or
two alkyl groups having from 1 to 4 carbon atoms.
Preferred compounds of Formula IIIA are those where Z and
Y are both nitrogen. More preferred compounds of Formula IIIA
are where Y and Z are nitrogen and RS is hydrogen, methyl, or
ethyl. Particularly preferred compounds of Formula IIIA are
where Y and Z are nitrogen, RS is hydrogen, methyl, or ethyl,
R1, R2 and R4 are hydrogen .
Representative Ar groups of Formula I above include the
following:
N ~ N~N N ~ N~N
w I Re '~.\J w i Re ~.\J Rb ~.\ I U
Ra Ra Ra
In the above Ar groups, the following definitions apply:
Ra is halogen, alkyl, hydroxy, or alkoxy; and
Rb represents hydrogen or alkyl.
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In those formulas where more than one of the same
substituent appears, e.g., alkyl, those substituents are the
same or different.
Preferred Ar groups of formula I above include the
following:
N ~ N~N N ~ N~N
,~ ~ ~ ~ ~ I ~ ~ ~ I
F OCH3 OH OCH3 OCH3
CH3 N ~ N~N N ~ N~N
wl wl wl wl wI U
CH3
OH F F OH
Particularly preferred Ar groups of formula I above
include 5-fluoropyrimidin-2-yl and pyrimidin-2-yl.
In certain situations, the compounds of this invention 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. 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
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as crystallization 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
acid addition salts. In addition, 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,
l0 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 pharmaceutical salts include salts of acids such
as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic,
formic, toluenesulfonic, methanesulfonic, nitric, benzoic,
citric, tartaric, malefic, hydroiodic, alkanoic such as acetic,
HOOC-(CHZ)n-ACOOH where n is 0-4, 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
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addition salts and acylated prodrugs of the compounds
encompassed by Formula I.
By "aryl" and "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 can optionally be unsubstituted or
substituted with e.g., halogen, lower alkyl, lower alkoxy,
lower alkylthio, trifluoromethyl, lower acyloxy, aryl,
heteroaryl, and hydroxy.
By "heteroaryl" in the present invention is meant one or
more aromatic ring systems of 5-, 6-, or 7-membered rings
containing at least one and up to four hetero atoms selected
from nitrogen, oxygen, or sulfur. Such heteroaryl groups
include, for example, thienyl, furanyl, thiazolyl, imidazolyl,
(is)oxazolyl, pyridyl, pyrimidinyl, (iso)quinolinyl,
naphthyridinyl, benzimidazolyl, and benzoxazolyl.
By "alkyl" or "lower alkyl" in the present invention is
meant C1-C6 alkyl, i.e., straight or branched chain alkyl
groups having 1-6 carbon atoms, such as, for example, methyl,
ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl,
pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-
hexyl, and 3-methylpentyl.
By "alkoxy" or "lower alkoxy" in the present invention is
meant C1-C6 alkoxy, i.e.,straight or branched chain alkoxy
groups having 1-6 carbon atoms, such as, for example, methoxy,
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ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy,
pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-
hexoxy, and 3-methylpentoxy.
By "cycloalkoxy" in the present invention is meant
cycloalkylalkoxy groups having 3-7 carbon atoms where
cycloalkyl is defined above.
Hy "C1-Cz alkylene dioxy group" is meant a group of the
formula:
'~-O-(CH2)~ O-~_
where n is 1 or 2.
By "C1-C, alkylene ~oxy group" is meant a group of the
formula:
y-O-(CH2)~ ~.
where n is 1, 2 or 3.
By halogen in the present invention is meant fluorine,
bromine, chlorine, and iodine.
Representative free bases of compounds of the invention
are shown below in Table 1.
O _ O
I ~ N I y--v N_
N N ~ ~ N N
W
N N ~/ ~ N N ~J N
N Me
Compound l Compound 2
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O ~ S
N
N H N~ ~ / N H N~ ~~
N
Compound 3 Compund 4
O ~ O
N- ~ N
N N I ~ ~ ~N N ~ F
N N~ U ~ / N N U
H H
Compound 5 Compound 6
The compounds of the invention are useful in the treatment
of neuropsychological disorders; the pharmaceutical utility of
compounds of this invention is indicated by the assays for
dopamine receptor subtype affinity described below in the
Examples. The interaction of the compounds of the invention
with dopamine receptor subtypes results in the pharmacological
activities of these compounds.
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
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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 carriers 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, 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 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
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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 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 hexitol
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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.
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Suitable emulsifying agents may be naturally-occurring gums,
for example gum acacia or gum tragacanth, naturally-occurring
phosphatides, for example soy bean, lecithin, and esters or
partial esters derived from fatty acids and hexitol,
anhydrides, for example sorbitan monooleate, and condensation
products of the said partial esters with ethylene oxide, for
example polyoxyethylene sorbitan monooleate. 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
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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-irritating 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 of the order of from about O.lmg to about
140mg per kilogram of body weight per day are useful in the
treatment of the above-indicated conditions (about 0.5mg to
about 7g per patient per day). The amount of active ingredient
that may be combined with the carrier 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 lmg to about 500mg of
an active ingredient.
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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
S of administration, route of administration, and rate of
excretion, drug combination and the severity of the particular
disease undergoing therapy.
Representative illustrations of methods suitable for the
preparation of compounds of the present invention are shown in
the following Schemes. 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. For example, in certain situations,
protection of reactive moieties such as amino groups, will be
required:
Preparation Of 3-Aminoalkylamino-2H-1,4-Benzoxazines And 3-
Aminoalkylamino-2H-1,4-Benzothiazines
A compound of Formula I, or a pharmaceutically acceptable
acid addition salt thereof may be prepared according to the
reactions described generally in Scheme 1.
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Scheme 1
R~ X
+ H N W -Ar
C. . I , R ~ N~A/
R2 N L 5
IV V
R~ X
C.,. I
R ~~ N N A~N~ -Ar
2 R
I
wherein R1, R2, R3, R4, R5, A, W, X, Y and Z are as defined
5 above for Formula I.
As shown, a 2H-1,4-benzoxazine or 2H-1,4-benzothiazine of
general structure IV, possessing an appropriate leaving group
at the 3 position, may be reacted with a primary or secondary
amine of general structure V in the presence of a base to
afford a compound of Formula I as the desired product.
Where they are not commercially available, the compounds
of general structure IV may be prepared by procedures
analogous to those described in literature. Representative
procedures are set forth in the examples below. The compounds
of general structure V are either known or capable of being
prepared by the methods known in the art. Those having skill
in the art will recognize that the starting material may be
varied and additional steps employed to produce compounds
encompassed by the present invention.
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Example 1 demonstrates the preparation of a 1-aryl-4-
aminoalkylpiperazine. Example 2 provides an example of the
preparation of a 2H-1,4-benzoxazine. For similar procedures
can be used to synthesize 2H-1,4-benzothiazines. Example 3
demonstrates the preparation of a 3-aminoalkylamino-2H-1,4-
benzoxazine. Example 4 is an example of the preparation of 3-
aminoalkylamino-2H-1,4-benzothiazine.
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 inventions, as
demonstrated by the following examples. In some cases,
protection of certain reactive functionalities may be necessary
to achieve some of the above transformations. In general, the
need for such protecting groups will be apparent to those
skilled in the art of organic synthesis as well as the
conditions necessary to attach and remove such groups.
The disclosures in this application of all articles and
references, including patents, are incorporated herein by
reference.
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
described in them.
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Example 1
Preparation of 1-(Pyrimidin-2-yl)-4-(4-aminobutvl)piperazine
N-
H N'w N~/N---~~
2 N
A mixture of N-(2-bromobutyl)phthalimide (18.2 g, 0.065
mole), 1-(pyrimidin-2-yl)piperazine (10.58 g, 0Ø65 mole) and
potassium carbonate (17.84 g, 0.13 mole) in dimethyl formamide
(150 mL) is heated at 80 °C for 16 hours under a nitrogen
atmosphere. After cooling, the reaction mixture is poured into
water (0.5 L) and ether (0.5 L) and the aqueous layer is then
further extracted with ether (2 X 100 mL). The combined
organic layers are dried (Na2S04) and concentrated to provide a
white solid {23.5 g, 96 %, m.p. °C).
This solid is subsequently refluxed under nitrogen in
hydrazine hydrate (100 mL) for 2 h., and after cooling, the
solution is poured into 30% potassium carbonate solution (50
mL) and extracted with methylene chloride. The organic
extracts are dried (Na2S04) and concentrated to give colorless
crystals (18 g). This material is dissolved in methanol (50
mL) and combined with a methanolic solution {10 mL) of fumaric
acid (17.8 g). Isopropanol is added (150 mL) and the mixture
concentrated on a hot plate to a volume of 50 mL. Upon
cooling, crystals of the fumarate salt are collected (33.1 g,
%, m.p. 166-167 °C)
Example 2
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2-Keto-5 6-benzomor~holine (4-azachroman-3-one)
N O
H
A mixture of 2-nitrophenol (47.92 g, 0.34 mol), ethyl
bromoacetate (50.1 g, 0.3 mol) and potassium carbonate (96 g,
0.7 mol) in dimethyl formamide (200 mL) is heated at 80 °C for
22 h., cooled, poured into water (500 mL), and extracted with
ether (2 X 250 mL) . The combined organic extracts are washed
once with water, dried and concentrated to give an orange oil
which crystallizes upon standing.
A portion of the crystals (15 g) is dissolved in ethanol
(120 mL) and hydrogenated over 10 ~ Pd/C at 40 PSI H2 for 6 h.
The resulting heterogeneous mixture is filtered through celite
and concentrated to give 9.49 g of grey crystals (m.p. 163-164
oC) .
Example 3
3-(1-[4-{(4-Pyrimidin-2-yl)piperazin-1-yl}]butyl)
amino-2H-1 4-benzoxazine difumarate (Compound 1)
A solution of 2-keto-5,6-benzomorpholine (4-azachroman-3-
one, 521 mg) and trimethyloxonium tetrafluoroborate (590 mg) in
50 mL of dry pentene stabilized chloroform is stirred at room
temperature overnight. To this mixture is added a solution of
1-(pyrimidin-2-yl)-4-(4-aminobutyl)piperazine (822 mg) and
triethylamine (5 mL) and the resultant solution refluxed
overnight under nitrogen. After cooling, the solution is
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concentrated and partitioned between water and ethyl acetate
and the organic layer is dried and concentrated to give a brown
oil. Purification using preparative thin layer chromatography
on silica eluting with 10% CH30H, 89 % CHC13, 1% NH40H provides
the product as a colorless oil (340 mg, Rf - 0.52). This
material is combined with 215 mg of fumaric acid in 5 mL of
methanol. Isopropanol (20 mL) is added and the solution volume
reduced to approximately 5 mL on a hot plate. Upon cooling,
the product (alternatively named 4-azachroman-3-yl(4-(4
pyrimidin-2-ylpiperazinyl)butyl)amine, 305 mg, m.p. 169-171 °C)
is collected by filtration.
Exam 1~ a 4
3-(1-[3-{(4-Pyrimidin-2-yl)piperazin-1-yl}]
ropyl)amino-2H-1,4-benzothiazine (ComBound 4)
A solution of commercially available 2-keto-5,6-
benzothiomorpholine (1,3,4-trihydro-4-thiaquinolin-2-one, 500
mg, 3 mmol) and trimethyloxonium tetrafluoroborate (480 mg, 3.3
mmol) in 50 mL of dry pentene stabilized chloroform is stirred
at room temperature overnight. To this is then added 1-
(pyrimidin-2-yl)-4-(3-aminopropyl)piperazine (1.36 g) and
triethylamine (5 mL) and the resultant solution refluxed
overnight under nitrogen. After cooling, the solution is
concentrated and partitioned between water and ethyl acetate.
The organic layer is dried and concentrated to give a brown oil
which is purified using preparative thin layer chromatography
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on silica eluting with 10~ CH30H, 89 ~S CHC13, 1~ NH40H to
provide the product as a yellow oil (500 mg, Rf - 0.31). This
material is combined with 315 mg of fumaric acid in 5 mL of
methanol. Isopropanol (20 mL) is added and the solution
reduced to a volume of approximately 5 mL on a hot plate. Upon
cooling, the product (alternatively named, ((3-(4-pyrimidin-2-
ylpiperazinyl)propyl)-2-1,2,3,4-tetrahydro-4-thiaquinolylamine,
480 mg, m.p. 212-213°C) is collected by filtration.
Example 5
The following compounds are prepared essentially according
to the procedures set forth above in Examples 1-4.
(a) 3-(1-[2-{(4-Pyrimidin-2-yl)piperazin-1-
yl}]ethyl)amino-2H-1,4-benzoxazine fumarate (m.p. 169-171°C,
Compound 7)
(b) 3-(1-[3-{(4-Pyrimidin-2-yl)piperazin-1-
yl}]propyl)amino-2H-1,4-benzoxazine fumarate (m.p. 179-181°C,
Compound 8)
(c) 3-(1-[4-{(4-Pyrimidin-2-yl)piperazin-1-
yl}]butyl)amino-2H-1,4-benzoxazine fumarate (m.p. 180-181°C,
Compound 9)
-
(d) 3-(1-[3-{(4-Pyridin-2-yi)piperazin-1-
yl}]propyl)amino-2H-1,4-benzoxazine fumarate (Compound 10)
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(e) 3-(1-[3-{4-Phenylpiperazin-1-yl}]propyl)amino-2H-1,4-
benzoxazine fumarate (Compound 3)
(f) 3-(1-[2-{(4-[5-Fluoropyrimidin-2-yl])piperazin-1-
yl}]ethyl)amino-2H-1,4-benzoxazine fumarate (m.p. 163-164°C,
Compound 6)
(g) 3-(1-[3-{(4-[5-Fluoropyrimidin-2-yl])piperazin-1-
yl}]propyl)amino-2H-1,4-benzoxazine fumarate (m.p. 179-180°C,
Compound 11)
(h) 3-(1-[4-{(4-[5-Fluoropyrimidin-2-yl])piperazin-1-
yl}]butyl)amino-2H-1,4-benzoxazine fumarate (m.p. 144-154°C,
Compound 12)
(i) 3- (1- [4-{ (4- [5-Methylpyrimidin-2-yl] )piperazin-1-
yl}]butyl)amino-2H-1,4-benzoxazine hydrobromide (m. p. 278-
279°C, Compound 13)
(j) 3-(1-[2-{(4-Pyrimidin-2-yl)piperazin-1-
yl}]ethyl)amino-2H-1,4-benzothiazine fumarate (m.p. 169-171°C,
Compound 14)
(k) 3- (1- [4-{ (4-Pyrimidin-2-yl)piperazin-1-
yl}]butyl)amino-2H-1,4-benzothiazine (m. p. 182-183°C, Compound
15)
(1) Benzo[b]morpholin-3-ylmethyl[4-(4-pyrimidin-2-
ylpiperazinyl)butyl]amine (Compound 2; alternate name: 3-(N-[4-
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{(4-Pyrimidin-2-yl)piperazin-1-yl}]butyl)-N-methylamino-2H-1,4-
benzoxazine)
(m) Benzo [b] morpholin-3-yl [2- (4- (2-
pyridyl)piperazinyl)ethyl]amine (Compound 5; alternate name: 3
(1-[2-{(4-[Pyrid-2-yl])piperazin-1-yl}]ethyl)-amino-2H-1,4
benzoxazine)
Example 6
Assay for D2 an D4 Receptor Binding Activity
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 HC1 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 HC1 buffer containing
100 mM NaCl.
Incubations are carried out at 48°C and contain 0.4 ml of
tissue sample, 0.5 nM 3H-YM 09151-2 (Nemonapride, cis-5-Chloro-
2-methoxy-4-Cmethylamino)-N-(2-methyl-2-(phenylmethyl)-3-
pyrrolidinyl)benzamide)and the test compound in a total
incubation of 1.0 ml. Nonspecific binding is defined as that
binding found in the presence of 1 mM spiperone; without
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further additions, nonspecific binding is less than 20% of
total binding. Binding characteristics of examples of the
invention for the D2 and D4 receptor subtypes are shown in
Table 2 for rat striatal homogenates.
TABLE 2
Compound Numberl D4 Ki (nM) D2 Ki (~)
1 4 >1000
4 10 >100
182 >100
The above compound numbers relate to compounds shown in
Table 1. The compounds tested are the compounds described in
l0 the above examples. In all cases, test compounds are acid
addition salts.
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.
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