Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
257839
Thi!q i a divisional application of copending application
490,241, filed September 9, 1985.
BACKGROUND OF THE INVENTION
Various aminoalkoxybenzopyranones have been
described in the literature. Compounds of the formula:
O ~o ~ (C~2)nN 3 R3
wherein R2 is lower alkyl have been described in
US Patent 3,~10,898 as having antioedematous activity
and the ability to reduce increased capillary
permeability.
The pres-nt benzopyranones have been found to have
valuable neuroleptic properties and as such are useful
as antipsychotic agents.
SUMMARY OF THE INVENTION
Accordingly, the present invention relates to a
compound of the formula:
0 ~ ~ -O~CH~)n Rl
wherein n is an integer from 2-5; R is hydrogen,
lower alkyl, trifluoromethyl, or lower alkoxy; Rl is
a radical of the formulae:
- ~ N-Ar , -N N -Het , or -N 3 Ar ,
DIU-7
~ -2- ~2S7~39
in which --- represents a single or double bond, Ar is
phenyl or phenyl substituted by lower alkyl, lower
alkoxy, lower thioalkoxy, halogen, or trifluoromethyl,
and Het is 2-, 3- or 4-pyridinyl or 2-, 3- or
4-pyridinyl substituted by lower alkyl, lower alkoxy, or
halogen; 2-, 4-, or 5-pyrimidinyl or 2-, 4-, or
- 5-pyrimidinyl substituted by lower alkyl, lower alkoxy,
or halogen; 2-pyrazinyl or 2-pyrazinyl substituted by
lower alkyl, lower alkoxy, or halogen; 2- or 3-thienyl
or 2- or 3-thienyl substituted by lower alkyl or
halogen; 2- or 3-furanyl or 2- or 3-furanyl substituted
by lower alkyl or halogen, or 2- or 5-thiazolyl or 2- or
5-thiazolyl substituted by lower alkyl or halogen, or a
pharmaceutically acceptable acid addition salt thereof,
with the exclusion of the compound wherein n is 3, R is
methyl, and Rl is a radical of the formula
-N ~ N-Ar
in which Ar is phenyl.
The present invention also relates to a pharmaceu-
tical composition comprising an antipsychotic effective
amount of a compound of formula I as a pharmaceutically
acc~ptable acid addition salt thereof with a
pharmaceutically acceptable carrier.
The present invention further relates to a method of
treating psychoses, e.g., schizophrenia, in a subject
suffering therefrom comprising administering to said
subject an effective amount of a compound of the
formula I, wherein n is an integer from 2-5; R is
hydrogen, lower alkyl, lower al~oxy, or trifluoromethyl;
~1 is a radical of the formulae
-N N-Ar , -N ~ N-~et , or -~Ar
v l u
-3- ~.257~339
in which = represents a single or double bond, Ar is
phenyl or phenyl substituted by lower alkyl, lower
alkoxy, lower thioalkoxy, halogen, or trifl~oromethyl,
and Het is 2-, 3-, or 4-pyridinyl or 2-, 3-, or
4-pyridinyl substituted by lower alkyl, lower alkoxy, or
halogen, 2-, 4-, or 5-pyrimidinyl, or 2-, 4-, or
5-pyrimidinyl substituted by lower alkyl, lower alkoxy,
or halogen; 2-pyrazinyl or 2-pyrazinyl substituted by
lower alkyl, lower alkoxy, or halogen; 2- or 3-thienyl,
lû or 2- or 3- thienyl substituted by lower alkyl or
halogen, 2- or 3-furanyl or 2- or 3-furanyl substituted
by lower alkyl or halogen, or 2- or 5-thiazolyl or 2- or
5-thiazolyl substituted by lower alkyl or halogen, or a
pharmaceutically acceptable acid addition salt thereof
in unit dosage form.
DETAIL~:D DESCRIPTION
In the compounds of the formula I, the term "lower
alkyl" is meant to include a straight or branched alkyl
group having from one to six carbon atoms such as, for
example, methyl, ethyl, propyl, isopropyl, butyl, sec-
butyl, isobutyl, tert-butyl, amyl, isoamyl, neopentyl,
hexyl, and the like.
Halogen includes particularly fluorine, chlorine,
or bromine.
Lower alkoxy and thioalkoxy are 0-alkyl or S-alkyl
of from one to six carbon atoms as defined above for
n lower alkyl. n
A preferred embodiment of the present invention is
a compound of the formula II
0 ~ 0 ~ 0(CL2)n 1
L~ l U ~
~4- 1257~339
wherein n, R, and Rl are as defined above, or a
pharmaceutically acceptable acid addition salt thereof.
Another preferred embodiment of the present
invention is a compound of the formula II, wherein n is
an integer of 2-5; R is hydrogen, and Rl is as defined
previously, or a pharmaceutically acceptable acid
addition salt thereof.
Another preferred embodiment is a compound of the
formula II, wherein n is 2-5; R is hydrogen, and Rl is
a radical of the formulae
-N ~ -Ar , - ~ -Het or -N 3 Ar
in which --- is a single or double bond; Ar is phenyl
or phenyl substituted by methyl, methoxy, thiomethoxy,
or chloro, and Het is 2-, 3-, or 4-pyridinyl; 2-, 3-,
or 4-pyridinyl substituted by methyl, chloro, or bromo;
2-, 4- or 5-pyrimidinyl; 2-pyrazinyl, or 2-thiazolyl.
Still another preferred embodiment is a compound of
the formula II, wherein n is 2-5, but more preferably 3
or 4; R is hydrogen, and Rl is a radical of the formulae
-N ~ ~ , -N ~ N-Het or -N ~
.
in which Het is 2-, 3-, or 4-pyridinyl; 2-, 4-, or
5-pyrimidinyl; 2-pyrazinyl or 2-thiazolyl.
.
-- ~2 S~3~
Particularly preferred embodiments of the present
invention are; 7-[3-(4-phenyl-l-piperazinyl)propoxy]-2H-
l-benzopyran-2-one, 7-[3-(l,2,3,6-tetrahydro-4-phenyl-l-
pyridinyl)propoxy]-2H -l-benzopyran-2-one, 7-13-~4-
(~-pyrimidinyl)-l-piperazinyl~propoxy]-2~-l-benzopyran- , -
2-one, and 7-~4-phenyl-l-piperazinyl)butoxy]-2H-l-
benzopyran-2-one, or a pharmaceutically acceptable acid
addition salt thereof.
In addition to the previous preferred compounds, a
particular preferred embodiment of the method for
treating psychoses aspec~ o~ the invention comprises
treating a host with an effective amount of
7-13-(4-phenyl-l~piperazinyl)-propoxy~-4-methyl-2H-l-
benzopyran-2-one in unit dosage form.
The compounds of the invention form pharmaceu-
tically acceptable acid addition salts with organic and
inorganic acids. Examples of suitable acids for salt
formulation are hydrochloric, sulfuric, phosphoric,
acetic, citric, oxalic, malonic, salicylic, malic,
fumaric, succinic, ascorbic, maleic, methanesulfonic,
and the li~e. The salts are prepared by contacting the
free base form with a sufficient amount of the desired
acid in the conventional manner. The free base forms
may be regenerated by treating the salt form with a
base. For example, dilute aqueous base solutions may
be utilized. Dilute aqueous sodium hydroxide, potassium
carbonate, ammonia, and sodium bicarbonate solutions
are suitable for this purpose. The free base forms
differ from their respective salt forms somewhat in
certain physical properties such as solubility in polar
solvents, but the salts are otherwise equivalent to
their respective free base forms for purposes of the
invention.
The compounds of the invention can exist in unsol-
vated as well as solvated forms, including hydrated
forms. In general, the solvated forms, with pharmaceu-
tically acceptable solvents such as water, ethanol, and
IJlU--I
-6 -~.257839
the like are equivalent to the unsolvated forms for
purposes of the-invention.
The compounds of the present invention and of the
formula I may be prepared by first reacting a
hydroxy-2H-l~benzopyran-2-one of the formula:
0~\0~
III
wherein R is as defined previously, with a compound of
the formula:
X-(cH2)n~Y
IIIa
wherein n is an integer of 2-5; X and Y are the same or
different and are a leaving group such as halogen or a
sulfonyloxy group, for example, methanesulfonyloxy or
p-toluenesulfonyloxy; and secondly, reacting the
resulting product of the formula IY
~O(CH2)n-X(Y)
IV
DIU-7. . -
~7~ 1257~39
with an amine selected from the formulae
~ r~ r~ .
H~ - Ar , HN ~- Het or H~Ar
wherein Ar and Het are as defined previously, and, if
desired, converting the resulting free base by known
met~Jods to a pharmaceutically acceptable acid addition
salt.
The reaction of the benzopyran-2-one of formula III
with a compound of formula IIIa is carried out in an
inert solvent, preferably a polar solvent such as a
ketone, for example, acetone or methyl isobutyl ketone,
in the presence of an acid scavenger, such as, for
example, sodium or preferably, potassium carbonate in
anhydrous form, at the reflux temperature of the
solvent.
The intermediate product of formula IV is then
reacted with the appropriate amine in a polar aprotic
solvent such as, for example, dimethylformamide and in
the- presence of a neutralizing agent such as, for
example, sodium bicarbonate. The reaction is carried
out at elevated temperatures, e.g., from about
50 to 150C.
An alternate method for the preparation of a
compound of formula I is to first prepare a compound of
the formula:
X(C~2)nRl
V
- z -
- 1257~339
wherein Rl and X are as defined above, according to a
method described in Ind. J. Chem. 435 (1982), and react
said compound of formula V directly with a benzopyran-2-
one of formula III. This reaction is also best carried
out at elevated temperatures, e.g., 50-150C, in a
solvent such as dimethylformamide and in the presence
of an acid neutralizing agent such as sodium
bicarbonate.
The appropriate hydroxy-coumarin derivatives,
compounds of formula III, and amine derivatives are
available commercially or may be prepared by well-known
methods. For example, 4-substituted-7-~ydroxy-coumarins
are prepared by slight variations on the method
described in Organic Synthesis, Coll Vol 3, p 282, for
preparing 4-methyl-7-hydroxy-coumarin.
The compounds of the present invention are new
chemical substances which are useful as pharmaceutical
agents for the treatment of psychoses such as, for
example, schizophrenia. The antipsychotic activity of
representative compounds of the invention was estab-
lished b~ the Mouse Activity and Screen Test Procedure
(MAST) described below:
A~IMALS: Nine unfasted Swiss-Webster male mice
(Buckberg Labs) weighing 20-30 g are equally divided
into three groups for each drug dose to be tested. m at
is, data for each dose level was generated by three
separate groups of three mice each.
DRUGS: A minimum of three dose levels (10, 30,
and 100 mg/kg) are tested or each drug. Treatments
are administered intraperitoneally one hour prior to
testing. All dosages are calculated as parent compound
and given in volumes of 10 mg/kg. Compounds are
dissolved or suspended in 0.2% Methocel. Control
animals are injected with Methocel.
DIU-7
-9- ~LZ57839
TESTING: A two-part testing procedure is started
one hour postinjection. ~irst, the screen test is per-
formed ~see Pharmac Biochem Behav 6, 351-353, 1977).
Briefly, this test consists of placing mice on indivi-
dual wire screens which are then rotated 180 degrees at
the start of a 60-second observation period. m e number
of mice falling off the inverted screen is recorded.
Immediately following the screen test, the final
phase of testing is initiated by placing each group of
three mice in one actophotometer (Life Sciences, 22,
1067-1076, 1978). T&e actophotometer consists o~ a
cylindrical chamber whose center is occupied by another
cylinder which contains the illumination for six photo-
cells located on the perimeter of the chamber. Six
light-beam interruptions equal one count Locomotor
activity is recorded by computer at ten-minute
intervals for 60 minutes.
DATA: The data obtained from the screen test are
expressed as percent of mice falling off the screen.
Data derived from locomotor ac~ivity of drug-treated
mice are compared to the activity of vehicle-treated
animals and are expressed as percent inhibition of
spontaneous locomotion. All percentages reported for
inhibition of locomotion are based upon data accumulated
for one hour. Both phases of testing are graded:
A = 60-100%; C = 31-59%; and N = 0-30%. An overall dose
rating is obtained by the following criteria.
Inhibition of Screen Test Dose
Locomotion rating with Failure Rating = Rating
A - N or C = A
A - A = C
C - N or C = C
All other combinations = N
DIV-7
- -1 - 1257~33~3
Compo~nds which exhibit an overall dose rating of A
at a dose of 100 milligrams/kilogram or less are con-
sidered active. Utilizing this procedure, an overall
dose rating of A was obtained for the noted compounds at
the indicated dose as reported in Table 1.
TABLE 1
O ~ O(CH7)nRl
I I Dose
R I n I Rl ¦ mg/kg
H ¦ 3 ¦ - ~ N ~ ¦ 3.0
CH3 ¦ 3 ¦ ~ ~ ¦ 1.0
H 3 ~ ~ N ~ 3.0
H 3 -N/ ~ . ¦ 1.0
Thioridazine ¦ ~ ¦ 10.0
DIU-7
2 S~9~9
The antipsychotic activity of representative com-
po~nds of the invention was also established by the
~3H] haloperidol binding assay method (HRBA) which is
described in Mol. Pharmacol. 1~, 800 (1976) and reports
excellent correlation between the amount of binding and
clinical potency.
[3H] Haloperidol Binding Assay. The relative
affinities of compounds for dopamine receptors were
evaluated on the basis of their ability to displace
[3H] haloperidol from striatal membranes prepared from
Long-Evans hooded rats. Rats were decapitated; the
- brains were removed, and the corpus striata were
dissected. The corpus striata were homogenized in
40 volumes of 50 nM Tris buffer (p~ 7.6) and centri-
fuged. Pellets were rehomogenized in 50 volumes of the
same buffer and used for the binding assay. Incubations
were carried out in 10 ml of 50 nM Tris-HCl buffer
(pH 7.6) containing 2 mg/ml of original wet tissue
weight of homogenate, 100 ~1 o test agent or solvent,
and 0.6 nM of [3H] haloperidol. Nonspecific binding
was determined in the presence of 0.1 ~M (+)-butaclamol.
Szmples were incubated in reciprocating water bath at
25C for 40 minutes. Incubation was terminated by rapid
filtration under reduced pressure through glass fiber
filters (Whatman~GF/B). The filters were rinsed three
times with 10 ml of Tris-HCl buffer. The filters were
placed in 10 ml of scintillation coctail (Bechman
Ready-Solv HP) and shaken for one hour. Radioactivity
retained on the filter was determined by liquid
scintillation spectrophotometry. Compounds were
initially evaluated at 10 nM. ICsos when determined
wére calculated from a nonlinear computer curve, fit on
the data from four or more concentrations, each done in
triplicate.
ICsos for representative compounds of the present
invention are reported in Ta~le 2.
DIU-7
-1 2- ~L2~7839
TABLE 2
- HRBA Assay
R
~ (CH2) nRl
.
R¦ n I Rl IIC50
H1 3 1 3 ~ ,1 5 x 10--8
CH3¦ 3 --N N~> ~ 5. x 10--8
H 3 ~ 93 x 10--8
H 3 ~ 1. 6 x 10--8
Thioridazine ¦ I 1. 9 x 10-9
I
. .
DIU-7
-13- ~2S~93~9
The compounds o~ the present invention can be
prepared and administered in a wide variety of oral and
parenteral dosage forms. It will be obvious to those
skilled in the art that the following dosage forms may
comprise as the active component, either a compound of
formula I, a corresponding pharmaceutically acceptable
salt of a compound of formula I, or a mixture of such
compounds and/or salts.
For preparing pharmaceutical compositions from the
compounds described by this invention, inert, pharmaceu-
tically acceptable carriers can be either solid or
liquid. Solid form preparations incluae powders,
tablets, dispersable granules, capsules, cachets, and
suppositories. A solid carrier can be one or more
substances which may also act as diluents, flavoring
agents, solubilizers, lubricants, suspending agents,
binders, or tablet disintegrating agents; it can also be
an encapsulating material. In powders, the carrier is a
finely divided solid which is in admixture with the
finely divided active compound. In the tablet the
active compound is mixed with carrier having the
necessary binding properties in suitable proportions
and compacted in the shape and size desired. m e
powders and tablets preferably contain from 5 or 10 to
about 70 percent of the active ingredient. Suitable
solid carriers are magnesium carbonate, magnesium
sterate, talc, sugar, lactose, pectin, dextrin, starch,
gelatin, tragacanth, methyl cellulose, sodium carboxy-
methyl cellulose, a low-melting wax, cocoa butter, and
the like. The term "preparation" is intended to include
the formulation of the active compound with encapsu-
lating material as carrier providing a capsule in which
the active component (with or without other carriers) is
surrounded by carrier, which is thus in association with
it. Similarly, cachets are included. Tablets, powders,
~IU-7 -
-14-
~257~39
cachets, and capsules can be used as solid dosage forms
suitable for oral administration.
Liquid form preparations include solutions, suspen-
sions, and emulsions. As an e~ample may be mentioned
water or water-propylene glycol solutions for parenteral
injection. Liquid preparations can also be formulated
in solution in aqueous polyethylene glycol solution.
Aqueous solutions suitable for oral use can be prepared
~ by dissolving the active component in water and adding
suitable colorants, flavors, stabilizing, and
thickening agents as desired. Aqueous suspensions
suitable for oral use can be maae by dispersing the
finely divided active component in water with viscous
material, i.e., natural or synthetic gums, resins,
methyl cellulose, sodium carboxymethyl cellulose, and
other well-known suspending agents.
Preferably, the pharmaceutical preparation is in
unit dosage form. In such form, the preparation is
subdivided into unit doses containing appropriate
quantities of the active component. Ihe unit dosage
form can be a packaged preparation, the package con-
taining discrete quantities of preparation, for example,
packeted tablets, capsules, and powders in vials or
ampoules. The unit dosage form can also be a capsule,
cachet, or tablet itself or it can be the appropriate
number of any of these packaged forms
The quantity of active compound in a unit dose af
preparation may be varied or adjusted from 1 mg to
100 mg according to the particular application and the
potency of the active ingredient.
In therapeutic use as antipsychotic agents, the
compounds utilized in the pharmaceutical method of this
invention are administered at the initial dosage of
about 0.1 mg to about 100 mg per kilogram daily. A
DIU-7
-l5- ~257839
daily dose range of about l.0 mg to about 50 mg per
kilogram is preferred. The dosages, however, may be
varied depending upon the requirements of the patient,
the severity of the condition being treated, and the
compound being employed. Determination of the proper
dosage for a particular situation is within the skill
of the art. Generally, treatment is initiated with
smaller dosages which are less than the opti~um dose of
the compound. Thereafter, the dosage is increased by
small increments until the optimum effect under the
circumstances is reached. For convenience, the total
daily dosage may be divided and administered in
portions during the day if desired.
The following nonlimiting examples illustrate the
inventor's preferred methods for preparing the compounds
of the invention.
EXAMPLE 1
7-[3-(4-Phenyl-l-piperazinyl)propoxy]-2H-l-benzopyran-2-
one.
7-(3-halopropyloxy~-2~ benzopyran-2-one.
A mixture of 32 g (0.3 mol) of 7-hydroxy-2H-l-
benzopyran-2-one, 43 g (0.3 mol) anhydrous potassium
carbonate, and 48 g (0.3 mol) of l-bromo-3-chloropropane
in 350 ml of acetone is stirred under reflux for 18 hours.
The mixture is filtered, and the filtrate is evaporated
in vacuo. The residue is dissolved in dichloromethane
and washed with water. The organic phase is dried over
anhydrous magnesium sulfate and evaporated in vacuo.
The remaining crude product is recrystallized from ethyl
acetate - petroleum ether. m ere is obtained 32 g (68%1
of solid, mp. 92-98C, which is a mixture of
7-(3-chloropropoxy)- and 7-l3-bromopropoxy)-2H-l-
benzopyran-2-one.
L~l U--I
-16- 3L2~i7~
- - 7-l3-(4-phenyl-l-piperazinyl) propoxY~ -2H-l-benzopyran-2-
one.
A mixture of 6.3 g (0.025 mol) of 7-(3-halopropoxy)-
2H-l-benzopyran-2-one, 10 g (0.12 mol) sodium bicarbo-
nate, and 4.1 g (0.025 mol) of l-phenylpiperazine in
100 ml of dimethylformamide is stirred and heated at
80C for 16 hours. I~ne mixture is filtered, and the
filtrate is evaporated in vacuo. The residue is
dissolved in dichloromethane and extracted with water.
The organic phase is dried over anhydrous magnesium
sulfate and evaporated in vacuo. Il~e residue is
crystallized from ethyl acetate to give 5.9 g (61%) of
title compound, mp. 117-118C.
EXAMPLE 2
7-~3-[4-(2,3-Dimethylphenyl~-l-piperazinyl] propoxy]-2H-l-
benzopyran-2-one.
By the same procedure as in Example 1 but using
4.8 9 (0.025 mol) of 1-(2,3-dimethylphenyl)piperazine
in place of l-phenylpiperazine, there is obtained 3.7 g
(37%) o title compound, mp. 89C, from ethyl acetate.
The corresponding hydrochloride salt was obtained by
dissolving the free base in 1096 isopropanolic hydrogen
chloride and dilution with ethyl acetate, mp. 247-250C.
EXAMPLE 3
In an analagous manner as in Example 1, the following
compounds were prepared:
7-13-(4-phenyl-1-piperazinyl)-propoxy]-4-methyl-2H-l-
benzopyran-2-one, m.p. 127-130C, its hydrochloride,
m.p. 253C;
7-[3-14-~2,3-dimethylphenyl)-1-piperazinyl]propoxy]-
4-methyl-2H-l-benzopyran-2-one hydrochloride,
m.p. 253-255C;
7-[3-[4-~2-methylphenyl~-1-piperazinyl] propoxy]-2H-
benzopyran-2-one, m.p. 123-125C;
-17~
7-[4-(4-phenyl-1-piperazinyl)butoxy~-2H-l-benzopyran-2-
one, m.p. 145-147C;
7-[3 (4-phenyl-1-piperazinyl)propoxy]-4-trifluoromethyl-
2H-l-benzopyran-2-one, dihydrochloride, m.p. 190C;
7-[3-[4-(3-methylphenyl-1-piperazinyl]propoxy~-2H-l-
benzopyran-2-one hydrochloride, m.p. 217-220C;
7-[3-[4-(4-methylphenyll-1-piperazinyl]propoxy]-2H-l-
benzopyran-2-one, m.p. 140-142C;
7-[3-[4-(3-chlorophenyl)-1-piperazinyl~propoxy]-2H-l-
benzopyran-2-one hydrochloride, m.p. 228C;
7-13-[4-(4-chlorophenyl)-1-piperazinyl]propoxy~-2H-l-
benzopyran-2-one, m.p. 129-131C;
7-[3-[4-(2,3-dichlorophenyl)-1-piperazinyl]-proxy]-2H-l-
benzopyran-2-one hydrochloride, m.p. 215C.
7-~3-14-(3,4-dimethylphenyl)-1-piperazinyl]propoxy]-2H-
l-~enzopyran-2-one, m.p. 132C, its hydrochloride, m.p.
220C;
7-[3-[4-t3,4-dichlorophenyl)-1-piperazinyl]propoxy]-2H-
1-benzopyran-2-one, m.p. 135-136C;
8-[3-(4-phenyl-1-piperazinyl)propoxy]-2H-l-benzopyran-2-
cne, m.p. 95-97C;
7-¦3-[4-(2-pyrimidinyl)-1-piperazinyl]propoxy]-2H-l-
benzopyran-2-one, m.p. 135-137C;
7-[3-[4-(3-chloro-2-pyridinyl)-1-piperazinyl~propoxy]-
2H-l-benzopyran-2-one hydrochloride, m.p. 235-238C;
7-l3-[4-(3-pyridinyl)-1-piperazinyl]propoxy]-2H-l-
benzopyran-2-one, m.p. 122-12SC;
7-13-[4-(6-fluoro-2-pyridinyl)-1-piperazinyl]propoxy]-
2H-l-benzopyran-2-one hydrochloride, m.p. 241-243C;
7-13-[4-(6-bromo-2-pyridinyl1-1-piperazinyl]propoxy
-2H-l-benzopyran-2-one, m.p. 95-97C;
7-13-[4-(5-methyl-2-pyridinyl)-1-piperazinyl]propoxy]-
2H-lbenzopyran-2-one, m.p. 120-122C;
7-[3-~4-(3-methyl-2-pyridinyl1-1-piperazinyl]propoxy]-
2H-l-benzopyran-2-one hydrochloride, m.p. 210-215C;
L~ ~ u~
-18- 12~7~39
7-~3-~4-(4-methyl-2-pyridinyl)-1-piperazinyl]propoxy~-
2H-l-benzopyran-2-one, m.p. 113-115C;
7-~3-~4-(6-methyl-2-pyridinyl)-1-piperazinyl]propoxy]-
2H-l-benzopyran-2-one, m.p. 105-107C;
7-~3-(1,2,3,6-tetrahydro-4-phenyl-1-pyridinyl)propoxy]
-2H-l-benzopyran-2-one, m.p. 127C;
7-12-(1.2,3,6-tetrahydro-4-phenyl-1-pyridinyl)ethoxy]-
2H-l-benzopyran-2-one, m.p. 120-125C;
7-[4-(1,2,3,6-tetrahydro-4-phenyl-1-pyridinyl)butoxy]-
2H-l-benzopyran-2-one hydrochloride, m.p. 195C; and
_ 7-[3-(1,2,3,6-tetrahydro-4-phenyl-1-pyridinyl)propoxy~-
4-methyl-2H-l-benzopyran-2-one hydrochloride,
m.p. 215-221C;
7-~3-[4-(2-methylthiophenyl)-1-piperazinyl]propoxy~-2H-
benzopyran-2-one hydrochloride, m.p. 228-232C;
7-L3-[4-(2-methoxyphenyl)-1-piperazinyl]propoxy]-2H-
benzopyran-2-one hydrochloride, m.p. 228-231C;
7-[3-(1,2,3,4,5,6-hexahydro-~-phenyl-1-pyridinyl]propoxy]
-2H-l-benzopyran-2-one hydrochloride, m.p. 218-221C;
7-[3-[4-(2-pyrazinyl)-1-piperazinyl]propoxy~-2H-l-
benzopyran-2-one, m.p. 176-179C; and
7-[3-14-(2-thiazolyl)-1-piperazinyl]propoxy]-2H-l-
benzopyran-2-one hydrochloride, m.p. 167-170C.
EXAMPLE 4
7-[3-(4-Phenyl-l-piperazinyl)propoxy]-4-propyl-2H-l-
benzopyran-2-one.
Nl-(3-chloropropoxy)N4-phenylpiperazine was
prepared as described in Ind. J. Chem. 435 (1982) by
adding dropwise 87 g (0.55 mole) of 1-bromo-3-chloro-
propane to a stirred solution of 81 g (0.5 mole) of
N-phenylpiperazine in 100 ml acetone and 75 ml of 25
aqueous sodium hydroxide. The organic layer was
separated, concentrated, slurried with ethyl acetate,
washed, dried over magnesium sulfate, and concentrated
. .
DIU-?
19- ~2S7~3~9
to an oil weighing 85 g and analyzed by thin layer
chromatography and mass spectrometry to be the title
compound.
The above compound as an oil, 4.6 g (0.02 mole~,
was reacted with 4.4 g (0.02 mole) of 7-hydroxy-4-propyl
coumarin in 100 ml of dimethylformamide and 4 g of
anhydrous potassium carbonate. m e reaction mixture was
stirred at 85-95C for 16 hours. The mixture was
filtered, concentrated, and the oil taken up in methylene
chloride which solution was washed with sodium bicarbo-
nate, dried over anhydrous magnesium sulfate, and
concentrated. The oil solidified on standing and was
recrystallized from ethyl acetate to afford 5 g o~
7-[3-~4-phenyl-1-piperazinyl~propoxy]-4-
propyl-2H-l-benzopyran-2-one, m.p. 114-116C.
