N-substituted-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine and related compounds as analgesic and hypotensive agents

There are disclosed compounds having the formula ##STR1## wherein R.sub.1 is hydrogen or loweralkyl; R.sub.2 is loweralkyl, arylloweralkyl, diarylloweralkyl or --CH.sub.2 CHOHCH.sub.2 OR.sub.5, R.sub.5 being aryl, or alternatively --NR.sub.1 R.sub.2 taken together is ##STR2## or ##STR3## R.sub.6 being aryl, arylloweralkyl, diarylloweralkyl, ##STR4## or ##STR5## and R.sub.3 and R.sub.4 are each independently methoxy or hydroxy, which compounds are useful as analgesic and hypotensive agents.

This invention relates to compounds having formula I below 
##STR6## 
where R.sub.1 is hydrogen or loweralkyl; R.sub.2 is loweralkyl, 
arylloweralkyl, diarylloweralkyl or --CH.sub.2 CHOHCH.sub.2 OR.sub.5, 
R.sub.5 being aryl, or alternatively --NR.sub.1 R.sub.2 taken together is 
##STR7## 
or 
##STR8## 
R.sub.6 being aryl, aryllowrealkyl, diarylloweralkyl, 
##STR9## 
##STR10## 
and R.sub.3 and R.sub.4 are each independently methoxy or hydroxy, which 
compounds are useful as analgesic and hypotensive agents; to 
pharmaceutical compositions comprising an effective amount of such a 
compound; to a method of alleviating pain which comprises administration 
of an effective amount of such a compound and to a method of reducing 
blood pressure which comprises administration of an effective amount of 
such a compound. 
Throughout the specification and the appended claims, a given chemical 
formula or name shall encompass all stereo, optical and geometrical 
isomers thereof where such isomers exist, as well as pharmaceutically 
acceptable acid addition salts thereof and solvates thereof such as for 
instance hydrates. 
The following general rules of terminology shall apply throughout the 
specification and the appended claims. 
Unless otherwise stated or indicated the term loweralkyl denotes a straight 
or branched alkyl group having from 1 to 6 carbon atoms. Examples of said 
loweralkoxy include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, 
iso-butoxy, sec-butoxy, t-butoxy and straight- and branched-chain pentoxy 
and hexoxy. 
Unless otherwise stated or indicated, the term loweralkoxy denotes a 
straight or branched alkoxy group having from 1 to 6 carbon atoms. 
Examples of said loweralkoxy include methoxy, ethoxy, n-propoxy, 
iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy an d straight- and 
branched-chain pentoxy and hexoxy. 
Unless otherwise stated or indicated, the term halogen shall means 
fluorine, chlorine, bromine or iodine. 
Unless otherwise stated or indicated, the term aryl shall mean a phenyl 
group having 0, 1, 2 or 3 substituents each of which being independently 
hydroxy, nitro, loweralkyl, loweralkoxy, halogen or CF.sub.3. 
The compounds of formula I are prepared by utilizing one or more of the 
reaction steps described below. Throughout the description of the 
synthetic steps, the definitions of R.sub.1 through R.sub.6 are as given 
above unless otherwise stated or indicated. 
STEP A 
The chloro compound of formula II is reacted with an amine of the formula 
III to obtain a compound of formula Ia. 
##STR11## 
This reaction is typically conducted in the presence of milled K.sub.2 
CO.sub.3 (acid scavenger) and KI (catalyst) as well as a suitable solvent 
(including polar solvent) such as anhydrous dimethylforamide and stirring 
the reaction mixture at a temperature of about 50 to 100.degree. C. 
Where the group R.sub.1 is loweralkyl in the above reaction step, the amine 
of formula III is prepared from the secondary amine R.sub.2 --NH.sub.2 and 
loweralkyl chloride R.sub.1 --Cl in a routine manner known to the art. 
STEP B 
A compound of formula I where one or both of R.sub.3 and R.sub.4 are 
hydroxy is prepared by reacting compound Ia with pyridine hydrochloride in 
a routine manner known to the art. 
##STR12## 
STEP C 
For introducing a substituent --CH.sub.2 CHOHCH.sub.2 OR.sub.5 onto the 
amino nitrogen, the following scheme is used. 
First, compound II is coverted to the compound of formula IV in a routine 
manner known to the art (Gabriel synthesis). 
##STR13## 
Secondly, compound IV is reacted with an epoxy compound of formula V in a 
routine manner known to the art to afford a compound of formula VI. 
##STR14## 
Alternatively to the above, compound IV may be reacted with 
chloromethyloxirane in a routine manner known to the art to obtain the 
compound of formula VII and the latter reacted with an aryloxy anion of 
formula VIII in a routine manner known to the art to obtain compound VI. 
##STR15## 
STEP D 
The secondary amine hydrogen of compound VI can be replaced with a 
loweralkyl group R.sub.1 in a routine manner known to the art to afford a 
compound of formula IX. 
##STR16## 
STEP E 
One or both of the methoxy groups in compound IX can be converted to 
hydroxy groups in substantially the same manner as described in STEP B. 
##STR17## 
(where R.sub.3 or R.sub.4 or both are hydroxy). 
STEP F 
Where the group --NR.sub.1 Rhd 2 has the formula, 
##STR18## 
it is convenient to react piperazine with compound II at 1:2 
stoichiometric ratio to obtain a compound of formula X. 
##STR19## 
Compounds of this invention having formula I are useful as analgesic agents 
due to their ability to alleviate pain in mammals. The activity of the 
compounds is demonstrated in the 2-phenyl-1,4-benzoquinone-induced 
writhing test in mice, a standard assay for analgesia [Proc. Soc. Exptl. 
Biol. Med. 15, 729 (1957)]. Table 1 shows test results for some of the 
compounds of this invention. 
TABLE 1 
______________________________________ 
Analgesic Activity 
(Phenylquinone Writhing) 
Compound ED.sub.50 mg/kg, s.c. 
______________________________________ 
N-methyl-N-(2-phenylethyl)-5,6-dimethoxy- 
13.6 
1,2-benzisoxazole-3-propanamine 
N-[2-(4-fluorophenyl)ethyl]-5 6-dimethoxy- 
3.8 
1,2-benzisoxazole-3-propanamine 
3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]- 
1.7 
propyl]-5,6-dimethoxy-1,2-benzisoxazole 
pentazocine (reference compound) 
1.3 
______________________________________ 
Compounds of the present invention are also useful as antihypertensive 
agents due to their ability to depress blood pressure in mammals. 
Antihypertensive activity is measured in the spontaneous hypertensive rate 
by the indirect tail cuff method described in "Methods in Pharmacology", 
A. Schwartz, Ed., Vol. I, Appleton-Century Crofts, New York, N.Y., 1971, 
p. 135. In this procedure a group of five animals are treated orally for 
three days with the test compound in relation to a control group of the 
same number. The drop in blood pressure is measured on the third day 
following administration. The antihypertensive activities of some of the 
compounds, expressed as a decrease in mean arterial blood pressure (in mm 
Hg), are given in Table 2. 
TABLE 2 
______________________________________ 
Antihypertensive Activity 
Pressure Drop 
(mmHg) 
Compound at 50 mg/kg, p.o. 
______________________________________ 
N-(2-phenylethyl)-5,6-dimethoxy-1,2- 
32 
benzisoxazole-3-propanamine 
3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]- 
68 
propyl]-5,6-dimethoxy-1,2-benzisoxazole 
Diltiazem (reference compound) 
39 
______________________________________ 
Antihypertensive activities of the compounds of this invention can also be 
ascertained with reference to .alpha..sub.1 -adrenergic receptor 
antagonist activity as determined according to the method of Peroutka, et 
al., Neuropharmacology, 16, 549 (1977) The procedure used in this 
invention is described below. 
[.sup.3 H]-WB4101: .alpha..sub.1 -ADRENERGIC RECEPTOR BINDING IN RAT BRAIN 
This in vitro [.sup.3 H-WB4101 receptor binding assay quantitates the 
primary blood pressure lowering effects through .alpha..sub.1 -receptor 
blockage. WB-4101 
(2-(2,6-dimethoxyphenoxyethyl)aminoethyl-1,4-benzodioxane) is a specific 
and potent antagonist of the .alpha..sub.1 -adrenoceptor characterized in 
vitro in rat brain, heart, vascular smooth muscle and gastrointestinal 
smooth muscle. Peroutka et al. (1977) demonstrated a good correlation 
between the inhibition of .sup.3 H-WB4101 binding in brain membrane 
preparations and the blockage of peripheral vascular effects of 
norepinephrine. WB4101 labels an antagonist binding site on the 
.alpha..sub.1 -adrenoceptor, since it is preferentially displaced by 
antagonists while .alpha.-noradrenergic agonists preferentially displace 
the .sup.3 H-agonists. 
Procedure 
This Assay method is adapted from the Peroutka article mentioned above. 
A. Reagents 
1. 0.5 M Tris Buffer, pH 7.7 
a. 57.2 Tris HCl 16.2 g Tris base q.s. to 1 liter. (0.5 M Tris buffer, pH 
7.7 at 25.degree. C.). 
b. Make a 1:10 dilution is distilled H.sub.2 O (0.05 M Tris Buffer, pH 7.7) 
2. [Phenoxy-3-.sup.3 H(N)]-WB4101, 
(2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane, (20-25 
Ci/mmol) is obtained from New England Nuclear. 
For IC.sub.650 determination: .sup.3 H-WB4101 is made up to a concentration 
of 20 nM and 50 micro liter is added to each tube (yields a final 
concentration of 0.5 nM in the 2 ml assay volume). 
3. L-norepinephrine bitartrate is obtained from Sigma Chemical Co. 
A 10 mM stock solution of norepinephrine is made up in 0.01 N HCl and 20 
micro liter added to three tubes to determine nonspecific binding. This 
yields a final concentration of 100 micro liter in the assay. 
4. Test Compounds 
For most assays, a 1 mM stock solution is made up in a suitable solvent and 
serially diluted, such that the final concentration in the assay ranges 
from 10.sup.-5 to 10.sup.-8 M. Seven concentrations are usually used for 
each assay. Higher or lower concentrations may be used, depending on the 
potency of the drug. 
B. Tissue Preparation 
Male Wistar rats (100-150 g) are killed by decapitation and their brains 
rapidly removed. Whole brains minus cerebella are homogenized in 50 
volumes of ice-cooled 50 mM Tris buffer (pH 7.7 at 25.degree. C.) using a 
Tekmar homogenizer. The homogenate is centrifuged at 40,000 g, the 
supernatant discarded and the pellet resuspended in fresh 50 mM Tris 
buffer and recentrifuged at 40,000 g. The final pellet is resuspended in 
the original volume of fresh 50 mM Tris buffer, pH 7.7. The final tissue 
concentration in the assay is 10 mg/ml. Specific binding is approximately 
9% of the total added ligand and approximately 80% of the total bound 
ligand. 
C. Assay 
______________________________________ 
100 micro liter 
0.05 M Tris buffer, pH 7.7 
830 micro liter 
H.sub.2 O 
20 micro liter 
Vehicle (for total binding) or 10 mM 
L-NE (for nonspecific binding) or 
appropriate drug concentrations 
50 micro liter 
.sup.3 H-WB4101 stock solution 
1000 micro liter 
Tissue suspension 
______________________________________ 
Sample tubes are kept on ice for additions, then vortexed and incubated for 
15 minutes at 15.degree. C. The binding is terminated by rapid vacuum 
filtration through Whatman GF/B filters, followed by three 5 ml washes the 
ice-cold 0.05 M Tris buffer. The filters are counted in 10 ml of liquid 
scintillation cocktail. Specific WB 4101 binding is defined as the 
difference between the total binding and that bound in the presence of 100 
micro molar NE. IC.sub.50 calculations are performed using computer 
derived log-probit analysis. 
Test results for some of the compounds of this invention are presented in 
TAble 3. 
TABLE 3 
______________________________________ 
.alpha..sub.1 -adrenergic receptor antagonist activity (IC.sub.50) 
[.sup.3 H]-WB4101: .alpha..sub.1 -Adren- 
ergic Receptor (IC.sub.50) 
Compound Antagonist Activity 
______________________________________ 
N-(2-phenylethyl)-5,6-dimethoxy-1,2- 
8.3 .times. 10.sup.-8 M 
benzisoxazole-3-propanamine 
N-methyl-N-(2-phenylethyl)-5,6- 
6.7 .times. 10.sup.-8 M 
dimethoxy-1,2-benzisoxazole-3- 
propanamine 
phenoxybenzamine (reference 
1.2 .times. 10.sup.-8 M 
compound) 
Prazocin (reference compound) 
8.0 .times. 10.sup.-10 M 
______________________________________ 
Effective quantities of the compounds of the invention may be administered 
to a patient by any of the various methods, for example, orally as in 
capsules or tablets, parenterally in the form of sterile solutions or 
suspensions, and in some cases intravenously in the form of sterile 
solutions. The free base final products, while effective themselves, may 
be formulated and administered in the form of their pharmaceutically 
acceptable acid addition salts for purposes of stability, convenience of 
crystallization, increased solubility and the like. 
Acids useful for preparing the pharmaceutically acceptable acid addition 
salts of the invention include inorganic acids such as hydrochloric, 
hydrobromic, sulfuric, nitric, phosphoric and perchloric acids, as well as 
organic acids such as tartaric, citric, acetic, succinic, maleic, fumaric 
and oxalic acids. 
The active compounds of the present invention may be orally administered, 
for example, with an inert diluent or with an edible carrier, or they may 
be enclosed in gelatin capsules, or they may be compressed into tablets. 
For the purpose of oral therapeutic administration, the active compounds 
of the invention may be incorporated with excipients and used in the form 
of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, 
chewing gum and the like. These preparations should contain at least 0.5% 
of active compound, but may be varied depending upon the particular form 
and may conveniently be between 4% to about 70% of the weight of the unit. 
The amount of active compound in such compositions is such that a suitable 
dosage will be obtained. Preferred compositions and preparations according 
to the present invention are prepared so that an oral dosage unit form 
contains between 1.0-300 milligrams of active compound. 
The tablets, pills, capsules, troches and the like may also contain the 
following ingredients: a binder such as micro-crystalline cellulose, gum 
tragacanth or gelatin; an excipient such as starch or lactose, a 
disintegrating agent such as alginic acid, Primogel, cornstarch and the 
like; a lubricant such as magnesium stearate or Sterotex; a glidant such 
as colloidal silicon dioxide; and a sweetening agent such as sucrose or 
saccharin may be added or a flavoring agent such as peppermint, methyl 
salicylate, or orange flavoring. When the dosage unit form is a capsule, 
it may contain, in addition to materials of the above type, a liquid 
carrier such as a fatty oil. Other dosage unit forms may contain other 
various materials which modify the physical form of the dosage unit, for 
example, as coatings. Thus tablets or pills may be coated with sugar, 
shellac, or other enteric coating agents. A syrup may contain, in addition 
to the active compounds, sucrose as a sweetening agent and certain 
preservatives, dyes, coloring and flavors. Materials used in preparing 
these various compositions should be pharmaceutically pure and non-toxic 
in the amounts used. 
For the purpose of parenteral therapeutic administration, the active 
compounds of the invention may be incorporated into a solution or 
suspension. These preparations should contain at least 0.1% of active 
compound, but may be varied between 0.5 and about 30% of the weight 
thereof. The amount of active compound in such compositions is such that a 
suitable dosage will be obtained. Preferred compositions and preparations 
according to the present invention are prepared so that a parenteral 
dosage unit contains between 0.5 to 100 milligrams of active compound. 
The solutions or suspensions may also include the following components: a 
sterile diluent such as water for injection, saline solution, fixed oils, 
polyethylene glycols, glycerine, propylene glycol or other synthetic 
solvents; antibacterial agents such as benzyl alcohol or methyl parabens; 
antioxidants such as ascorbic acid or sodium bisulfite; chelating agents 
such as ethylenediaminetetraacetic acid; buffers such as acetates, 
citrates or phosphates and agents for the adjustment of tonicity such as 
sodium chloride or dextrose. The parenteral preparations can be enclosed 
indisposable syringes or multiple dose vials made of glass or plastic. 
Examples of the compounds of this invention include: 
N-(phenylmethyl)-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine; 
N-[(2,4-dimethoxy)phenylmethyl]-5,6-dimethoxy-1,2-benzisoxazole-3-propanami 
ne; 
N-methyl-N-(phenylmethyl)-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine; 
N-(2-phenylethyl)-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine; 
N-[2-(4-fluorophenyl)ethyl]-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine; 
N-[2-(4-nitrophenyl)ethyl]-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine; 
N-[2-(3,4-dimethoxyphenyl)ethyl]-5,6-dimethoxy-1,2-benzisoxazole-3-propanam 
ine; 
N-methyl-N-(2-phenylethyl)-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine; 
N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methyl-5,6-dimethoxy-1,2-benzisoxazole-3 
-propanamine; 
N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methyl-6-hydroxy-5-methoxy-1,2-benzisoxa 
zole-3-propanamine; 
N-[3-(diphenyl)propyl]-N-methyl-5,6-dimethoxy-1,2-benzisoxazole-3-propanami 
ne; 
N-[(2-hydroxy-3-phenoxy)propyl]-5,6-dimethoxy-1,2-benzisoxazole-3-propanami 
ne; 
3-[3-[4-[2-oxobenzimidazol-l-yl]-1-piperidinyl]propyl]-5,6-dimethoxy-1,2-be 
nzisoxazol e; 
3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-5,6-dimethoxy-1,2-benzisoxa 
zole; 
3-[3-(4-diphenylmethyl-1-piperazinyl)propyl]5,6-dimethoxy-1,2-benzisoxazole 
3-[3-[4-(2,3,4-trimethoxyphenyl)-1-piperazinyl]propyl]-5,6-dimethoxy-1,2-be 
nzisoxazole; 
3-[3-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]propyl]-5,6-dimethoxy-1,2 
-benzisoxa zole; 
3-[3-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]propyl-5,6-dimethoxy-1 
,2-benzisoxa zole; 
3-[3-[4-[4-[bis(4-fluorophenyl)butyl]]-1-piperazinyl]propyl]-5,6-dimethoxy- 
1,2 -benzisoxazole; 
3-[3-[4-[3-[6-fluoro-1,2-benzisoxazol-3-yl]propyl]-1-piperazinyl]propyl] 
-5,6-dimethoxy-1,2-benzisoxazole; and 
3-[3-[4-[3-[5,6-dimethoxy-1,2-benzisoxazol-3-yl]propyl]-1-piperazinyl] 
propyl]-5,6-dimethoxy-1,2-benzisoxazole. 
The following examples are presented in order to illustrate this invention.

EXAMPLE 1 
N-(phenylmethyl)-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine 
hydrochloride 
To 75 ml of dry dimethylformamide (DMF) were added 
3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (5.0 g), benzylamine 
(4.5 ml), milled potassium carbonate (10 g) and potassium iodide (0.01 g). 
After five hours of stirring at 80.degree. C., the mixture was poured into 
500 ml of water, stirred for five minutes and then extracted with ethyl 
acetate. The organic layer was washed with water (2X) and thereafter dried 
(saturated sodium chloride, anhydrous magnesium sulfate). 
After filtration, the solvent was evaporated, leaving about 10 g of oil 
which was eluted on a silica gel column with 5% methanol/dichloromethane 
(DCM) via high performance liquid chromatography (HPLC). The desired 
fractions were combined and concentrated to about 4 g of oil. 
This oil was dissolved in ether, the pH adjusted to 1 with etheral-HCl, and 
the resultant precipitate collected and dried, 3.2 g, d @ 240.degree. C. 
This material was recrystallized from isopropanol/ether (1:10) to yield 
2.3 g of crystals, d @ 240.degree. C. 
ANALYSIS 
Calculated for C.sub.19 H.sub.22 N.sub.2 O.multidot.HCl: 62.89%C; 6.39%H; 
7.72%N; 
Found: 62.75%C; 6.36%H; 7.63%N. 
EXAMPLE 2 
N-[(2,4-dimethoxy)phenylmethyl]-5,6-dimethoxy-1,2-benzisoxazole-3-propanami 
ne hydrochloride 
To 90 ml of dry DMF were added 
3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (5.1 g), 
2,4-dimethoxybenzylamine hydrochloride (8.1 g), milled potassium carbonate 
(20 g) and potassium iodide (0.01 g). 
After six hours of stirring at 90.degree. C., the mixture was poured into 
500 ml of water, stirred for five minutes and then extracted with ethyl 
acetate/ether. The organic layer was washed with water (2.times.100 ml) 
and saturated sodium chloride solution (1.times.100 ml), and then dried 
over anhydrous magnesium sulfate. 
After filtration, the solvents were evaporated, leaving about 10 g of oil 
which was eluted on a silica gel column with 5% methanol/DCM via HPLC. The 
desired fractions were combined, concentrated to 4 g of oil, dissolved in 
ether and then acidified to pH 1 with ethereal-HCl. The resultant 
precipitate was collected and dried to yield 3.0 g, d @ 210.degree. C. 
This material was recrystallized from methanol/ether (1:5) to yield 2.5 g 
of solid, d @ 214.degree. C. 
Analysis: 
Calculated for C.sub.21 H.sub.26 N.sub.2 O.sub.5 .multidot.HCl: 59.46%C; 
6.44%H; 6.63%N; 
Found: 59.53%C; 6.37%H; 6.54%N. 
EXAMPLE 3 
N-methyl-N-(phenylmethyl)-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine 
oxalate 
To 75 ml of dry DMF were added 
3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (5.1 g), 
N-benzylemethylamine (2.4 ml), milled K.sub.2 CO.sub.3 (10 g) and KI (0.01 
g). 
After seven hours of stirring at 90.degree. C., the mixture was poured into 
200 ml of water, stirred for five minutes and then extracted with 
ether/ethyl acetate. The organic layer was washed with water (2X) and 
saturated NaCl, and then dried over anhydrous magnesium sulfate. 
After filtration, the solvents were evaporated, leaving about 10 g of oil, 
which was eluted on a silica gel column with 5% methanol/DCM via HPLC. The 
desired fraction was collected, concentrated to about 5 g of oil, 
dissolved in ether, and then acidified to pH 1 with ethereal oxalic acid. 
The resultant precipitate was collected and dried to yield 2.6 g of solid, 
d @ 110.degree. C. This material was recrystallized from isopropanol to 
yield 2.3 g of crystals, d @ 132.degree. C. 
ANALYSIS 
Calculated for C.sub.20 H.sub.24 N.sub.2 O.sub.3 .multidot.C.sub.2 H.sub.2 
O.sub.4 : 61.38%C; 6.09%H; 6.51%N; 
Found: 61.49%C; 6.18%H; 6.47%N. 
EXAMPLE 4 
N-(2-phenylethyl)-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine 
hydrochloride 
To 100 ml of dry DMF were added 
3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (6.4 g), 
2-(phenyl)ethylamine (6.05 g), milled K.sub.2 CO.sub.3 (20 g) and KI (0.01 
g) 
After six hours of stirring at 90.degree. C., the mixture was poured into 
500 ml of water, stirred for five minutes and then extracted with 
ether/ethyl acetate. The organic layer was washed with water (2.times.200 
ml) and saturated NaCl (1.times.100 ml), and then dried over anyhydrous 
MgSO.sub.4. 
After filtration, the solvents were evaporated, leaving about 12 g of oil 
which was eluted on a silica gel column with 5% methanol/DCM via HPLC. The 
desired fractions were combined and concentrated to 4.3 g of oil. 
This oil was dissolved in ether, the pH of the solution adjusted to 1 with 
ethereal-HCl, and the resultant precipitate collected and dried to yield 
3.4 g, d @ 220.degree. C. This material was recrystallized from 
methanol/ether (1:1) to yield 3.0 g of crystals, d @ 227.degree. C. 
ANALYSIS 
Calcualted for C.sub.20 H.sub.24 N.sub.2 O.sub.3 .multidot.HCl: 63.73%C; 
6.69%H; 7.43%H; 
Found: 63.55%C; 6.70%H; 7.34%N. 
EXAMPLE 5 
N-[2(4-fluorophenyl)ethyl]-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine 
hydrochloride 
To 100 ml of dry DMF were added 2-(4-fluorophenyl)-ethylamine hydrochloride 
(10 g) and milled K.sub.2 CO.sub.3 (20 g). After five minutes of stirring, 
3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (6.4 g) and KI (0.01 g) 
were added. 
After fourteen hours of stirring at 90.degree. C., the mixture was filtered 
and the filtrate was concentrated to a dark oil, stirred with water and 
then extracted with ether. The ether solution was washed with water (2X) 
and then dried (saturated NaCl, anhydrous MgSO.sub.4). 
After filtration, the solvent was evaporated, leaving about 11 g of oil, 
which was eluted on a silica gel column with 5% methanol/DCM. The desired 
fractions were combined and concentrated to 3.8 of oil which was dissolved 
in ether, the pH was adjusted to 1 with etheral-HCl, and the resultant 
precipitate collected and dried to give 3.5 g, d @ 210.degree. C. This 
material was recrystallized twice from methanol/ether (1:2) to give 2.3 g 
of crystals, d @ 228.degree. C. 
ANALYSIS 
Calculated for C.sub.20 H.sub.23 FN.sub.2 O.sub.3 .multidot.HCl: 60.83%C; 
6.13%H; 7.10%N; 
Found: 60.79%C; 6.44%H; 7.00%N 
EXAMPLE 6 
N-[2-(4-nitrophenyl)ethyl]-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine 
hydrochloride 
To 100 ml of dry DMF were added 
3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (6.4 g), 
(4-nitrophenyl)ethylamine hydrochloride (10 g), milled K.sub.2 DO.sub.3 
(20 g) and KI (0.01 g). 
After twelve hours of stirring at 90.degree. C., the mixture was poured 
into 500 ml of water and then extracted with ethyl acetate. The organic 
layer was washed with water (2S) and then dried (saturated NaCl, anhydrous 
MgSO.sub.4). 
After filtration, the solvent was evaporated, leaving about 16 g of oil, 
which was eluted on a silica gel column with 4% methanol/DCM via HPLC. The 
desired fractions were combined and concentrated to 3.0 g of oil, which 
solidified on standing, m..p. 96.degree. C. 
This material was dissolved in ether, pH adjusted to 1 with etheral-HCl, 
and the resultant precipitate collected and dried to yield 2.5 g, d @ 
175.degree. C. This was recrystallized from methanol/ether (1:2) to give 
2.0 g of solid, d @ 188.degree. C. 
ANALYSIS 
Calcualted for C.sub.20 H.sub.23 N.sub.3 O.sub.5 .multidot.HCl: 56.94%C; 
5.73%H; 9.96%N; 
Found: 56.90%C; 5.61%H; 10.01%N 
EXAMPLE 7 
N-[2-(3,4-dimethoxyphenyl)ethyl]-5,6-dimethoxy-1,2-benzisoxazole-3-propanam 
ine oxalate 
To 100 ml of dry DMF were added 
3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (5.1 g), 
2-(3,4-dimethoxyphenyl)-ethylamine (7.2 g), milled K.sub.2 CO.sub.3 (20 g) 
and KI (0.01 g). 
After six hours of stirring at 80.degree. C., the mixture was poured into 
500 ml of water, stirred for five minutes and then extracted with ethyl 
acetate/ether. The organic layer was washed with water (2.times.100 ml) 
and saturated NaCl (1.times.100 ml), and then dried over anhydrous 
MgSO.sub.4. 
After filtration, the solvents were evaporated, leaving 8 g of oil which 
was eluted on a silica gel column with 8% methanol/DCM via HPLC. The 
desired fractions were combined and concentrated to 3 g of foil, which was 
dissolved in ether/ethyl acetate and acidified to pH 1 with ethereal 
oxalic acid. The resultant precipitate was collected and dried to yield 
3.0 g, d @ 192.degree. C. This material was recrystallized from methanol 
to yield 2.8 g, d @ 196-7.degree. C. 
ANALYSIS 
Calculated for C.sub.22 H.sub.28 N.sub.2 O.sub.5 .multidot.C.sub.2 H.sub.2 
O.sub.4 : 58.76%C; 6.17%H; 5.71%N; 
Found: 58.77%C; 6.18%H; 5.63%N. 
EXAMPLE 8 
N-methyl-N-(2-henylethyl)-5,6-dimethoxy-1,2benzisoxazole-3-propanamine 
oxalate 
To 75 ml of DMF were added 
3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (4.0 g), 
N-methylphenylethylamine (2.0 g), milled K.sub.2 DO.sub.3 (5.0 g) and KI 
(0.01 g). 
After six hours of stirring at 90.degree. C. and twenty hours at ambient 
temperature, the mixture was poured into 300 ml of water, stirred for five 
minutes, and then extracted with ethyl acetate/ether. The organic layer 
was washed with water (2X), and then dried (saturated NaCl, anhydrous 
MgSO.sub.4). 
After filtration, the solvents were evaporated, leaving about 5 g of oil, 
which was eluted on a silica gel column with ethyl acetate via HPLC. The 
desired fraction was collected and concentrated to 2.6 g of oil. This oil 
was dissolved in ether and acidified to pH 1 with ethereal-oxalic acid. 
The resultant precipitate was collected and dried to yield 2.8 g, d @ 
157.degree. C. This material was recrystallized from isopropanol/ether 
(1:10) to yield 2.2 g of solid, d @157 C. 
ANALYSIS 
Calcualted for C.sub.21 H.sub.26 N.sub.2 O.sub.3 .multidot.(CO.sub.2 
H).sub.2 : 62.15%C; 6.35%H; 6.30%N; 
Found: 62.40%C; 6.40%H; 6.32%N. 
EXAMPLE 9 
N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methyl-5,6-dimethoxy-1,2-benzisoxazole-3 
-propanamine oxalate 
To 50 ml of DMF were added 3-(3-chloro-5,6-dimethoxy-1,2-benzisoxazole (5.0 
g), N-[2-(3,4-dimethoxyphenethyl)]-N-methylamine (3.4 g), milled K.sub.2 
CO.sub.3 (4.0 g) and KI (0.01 g). 
After five hours of stirring at 80.degree. C., the mixture was poured into 
500 ml of water, stirred for five minutes and then extracted with ethyl 
acetate. The organic layer was collected, washed with water (2X) and dried 
(saturated NaCl, anhydrous MgSO.sub.4). 
After filtration, the solvent was evaporated, leaving 8 g of oil, which was 
purified via HPLC on silica gel using 3% methanol/DCM as the eluting 
solvent. The desired fraction was collected and concentrated to 5 g of 
oil. This oil was dissolved in ether, the pH adjusted to 1 with 
ethereal-oxalic acid, and the resultant precipitate collected and dried to 
yield 4.0 g, d @ 146.degree. C. This material was recrystallized from 
dichloromethane/ether (1:1) to yield crystals, d @ 146.degree. C. 
ANALYSIS 
Calculated for C.sub.23 H.sub.30 N.sub.2 O.sub.5 .multidot.(CO.sub.2 
H).sub.2 : 59.51%C; 6.39%H; 5.55%N; 
Found: 59.33%C; 6.28%H; 5.55%N. 
EXAMPLE 10 
N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methyl-6-hydroxy-5-methoxy-1,2-benzisoxa 
zole-3-propanamine 
To 70 ml of dry DMF were added 
3-(3-chloropropyl)-6-hydroxy-5-methoxy-1,2-benzisoxazole (4.4 g), 
N-[2-(3,4-dimethoxyphenethyl)]-methylamine (3.0 g), NaHCO.sub.3 (10 g) and 
KI (0.01 g). 
After four hours of stirring at 90.degree. C., the mixture was poured into 
200 ml of water, stirred for five minutes and then extracted with ethyl 
acetate. The ethyl acetate layer was washed with water (2.times.200 ml) 
and saturated NaCl (1.times.100 ml), and then dried over anhydrous 
MgSO.sub.4. 
After filtration, the solvent was evaporated, leaving about 8 g of oil, 
which was eluted on a silica gel column with 10% methanol/DCM via HPLC. 
The desired fraction was concentrated to a brown oil, which solidified to 
4 g of solid, m.p. 98-100.degree. C. This material was recrystallized 
twice from isopropyl ether/methanol (10:1) to yield 2.5 g of solid, m.p. 
112-3.degree. C. 
ANALYSIS 
Calculated for C.sub.22 H.sub.28 N.sub.2 O.sub.5 : 65.98%C; 7.05%H; 7.00%N; 
Found: 65.56%C; 7.06%H; 6.86%N. 
EXAMPLE 11 
N-[3-(diphenyl)propyl]-N-methayl-5,6-dimethoxy-1,2-benzisoxazole-3-propanam 
ine oxalate 
To 100 ml of dry DMF were added 
3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (6.0 g), 
N-methyl-3,3-diphenylpropylamine (5.6 g), milled K.sub.2 CO.sub.3 (10 g), 
and KI (0.01 g). 
After seven hours of stirring at 90.degree. C., the mixture was poured into 
500 ml of water, stirred for five minutes and then extracted with 
ether/ethyl acetate. The organic layer was washed with water (2X) and 
dried (saturated NaCl, anhydrous MgSO.sub.4). 
After filtration, the solvents were evaporated, leaving about 11 g of oil, 
which was eluted on a silica gel column with ethyl acetate via HPLC. The 
desired fraction was concentrated to about 4 g of oil, which was dissolved 
in ether, and acidified to pH 1 with ethereal-oxalic acid. The resultant 
precipitate was collected, washed with ether, and then dried to yield 3.8 
g, d @ 65.degree. C. This material was recrystallized from 
isopropanol/ether (1:5) to give 3.0 g of crystals, d @ 137.degree. C. 
ANALYSIS 
Calcualted for C.sub.28 H.sub.32 N.sub.2 O.sub.3 .multidot.C.sub.2 H.sub.2 
O.sub.4 : 65.86%C; 6.71%H; 5.49%N; 
Found: 65.97%C; 6.59%H; 5.02%N. 
EXAMPLE 12 
N-[(2-hydroxy-3-phenoxy)propyl]-5,6-dimethoxy-1,2-benzisoxazole-3-propanami 
ne oxalate 
To 75 ml of dry DMF were added 
3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (3.8 g), 
2-hydroxy-3-phenoxypropylamine (5.0 g), milled K.sub.2 CO.sub.3 (10 g) and 
KI (0.01 g). 
After seven hours of stirring at 90.degree. C., the mixture was poured into 
200 ml of water, stirred for five minutes and then extracted with ethyl 
acetate. The organic layer was washed with water (2X) and saturated NaCl, 
and then dried over anhydrous MgSO.sub.4. 
After filtration, the solvent was evaporated, leaving about 7 g of oil, 
which was eluted on a silica gel column with 8% methanol/DCM via HPLC. The 
desired fractions were combined and concentrated to about 3 g of oil, 
which was dissolved in ether and then acidified to pH 1 with 
ethereal-oxalic acid. The resultant precipitate was collected and dried to 
yield 3.0 g (d @ 135.degree. C.). This material was recrystallized twice 
from isopropanol/methanol (1:1) to yield 2.3 g of solid, d @ 180.degree. 
C. 
ANALYSIS 
Calculated for C.sub.21 H.sub.26 N.sub.2 O.sub.5 .multidot.C.sub.2 H.sub.2 
O.sub.4 : 57.97%C; 5.92%H; 5.88%N; 
Found: 58.35%C; 5.93%H; 6.00%N. 
EXAMPLE 13 
3-[3-[4-[2-oxobenzimidazol-3-yl]-1-piperidinyl]propyl]-5,6-dimethoxy-1,2-be 
nziso xazole hydrochloride 
To 80 ml of dry DMF were added 
3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (5.0 g), 
4-(2-oxo-1-benzimidazol-1-yl)piperidine (4.3 g), milled K.sub.2 CO.sub.3 
(10 g) and KI (0.01 g). 
After four hours of stirring at 85.degree. C., the mixture was poured into 
200 ml of water, stirred for five minutes and then extracted with ethyl 
acetate. The organic layer was washed with water (2X) and dried (saturated 
NaCl, anhydrous MgSO.sub.4). 
After filtration, the solvents were evaporated, leaving 10 g of solid which 
was eluted on a silica gel column with 5% methanol/DCM via HPLC. The 
desired fractions were combined and concentrated to 5 g of solid, which 
was dissolved in warm isopropanol and acidified to pH 1 with etheral-HC1. 
The mixture was cooled and diluted with ether, whereupon a solid 
precipitated, which was collected and dried to give 6.0 g, m.p. 
.about.255.degree. C. 
ANALYSIS 
Calculated for C.sub.24 H.sub.28 N.sub.4 O.sub.4 .multidot.HCl: 60.94%C; 
6.18%H; 11.85%N; 
Found: 60.61%C; 6.21%H; 11.74%N. 
EXAMPLE 14 
3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-5,6-dimethoxy-1,2-benzisoxa 
zole 
To 80 ml of dry DMF were added 
3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (6.4 g), 
4-(2-methoxyphenyl)-piperazine (3.8 g), milled K.sub.2 CO.sub.3 (10 g) and 
KI (0.1 g). 
After three hours of stirring at 85.degree. C., the mixture was poured into 
200 ml of water and extracted with ethyl acetate. The organic layer was 
washed with water (2X) and dried (saturated NaCl, anhydrous MgSO.sub.4). 
After filtration, the solvent was evaporated, leaving about 8 g of oil, 
which was eluted on a silica gel column with 3% methanol/DCM via HPLC. The 
desired fractions were combined and concentrated to an oil, which was 
dissolved in ether, the pH adjusted to 1 with ethereal-HCl, and the 
resultant precipitate collected and dried to give 2.7 g, d @ 220.degree. 
C. 
ANALYSIS 
Calculated for C.sub.23 H.sub.29 N.sub.3 O.sub.4 .multidot.HCl: 61.67%C: 
6.75%H; 9.38%N; 
Found: 61.49%C; 6.61%H; 9.24%N. 
EXAMPLE 15 
3-[3-(4-diphenylmethyl-1-piperazinyl)propyl)-5,6-dimethoxy-1,2-benzisoxazol 
e oxalate 
To 75 ml of dry DMF were added 
3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (3.5 g), 
1-(diphenylmethyl)-piperazine (3.5 g), milled K.sub.2 CO.sub.3 (10 g) and 
KI (0.01 g). 
After six hours of stirring at 90.degree. C., the mixture was poured into 
500 ml water, stirred for five minutes and then extracted with ethyl 
acetate. The ethyl acetate layer was washed with water (2X) and dried 
(saturated NaCl, anhydrous MgSPO.sub.4). 
After filtration, the solvent was evaporated, leaving about 7 g of oil 
which was eluted on a silica gel column with ethyl acetate via HPLC. The 
desired fraction was concentrated to about 4 g of oil which was dissolved 
in ethyl ether and the pH adjusted to 1 with ethereal oxalic acid. The 
resultant precipitate was collected and dried to yield 4.0 g, d @ 
115.degree. C. This material was recrystallized twice from 
isopropanol/methanol (1:1) to yield 2.7 g, d @ 228.degree. C. 
ANALYSIS 
Calculated for C.sub.29 H.sub.33 N.sub.3 O.sub.3 .multidot.C.sub.2 H.sub.2 
O.sub.4 : 66.29%C 6.28%H 7.48%N 
Found: 66.13%C 6.43%H 7.40%N 
EXAMPLE 16 
3-[3-[4-(2,3,4-trimethoxyphenyl)-1-piperazinyl]propyl]-5,6-dimethoxy-1,2-be 
nzisoxazole oxalate 
To 75 ml of dry DMF were added 
3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (3.5 g), 
N-(2,3,4-trimethoxybenzyl)-piperazine (3.5 g), milled K.sub.2 CO.sub.3 (10 
g) and KI (0.01 g). 
After seven hours of stirring at 90.degree. C., the mixture was poured into 
300 ml of water, stirred for five minutes and then extracted with ethyl 
acetate. The ethyl acetate layer was washed with water (2X) and dried 
(saturated NaCl, anhydrous MgSO.sub.4). 
After filtration, the solvent was evaporated, leaving about 6.5 g of oil 
which was eluted on a silica gel column with 1% methanol/ethyl acetate via 
HPLC. The desired fraction was concentrated to 5.0 g of oil which was 
dissolved in ethyl ether and the solution acidified to pH 1 with ethereal 
oxalic acid. The resultant precipitate was collected and dried to yield 
5.1 g, d @ 237.degree. C. This material was recrystallized twice from 
isopropanol/methanol (1:1) to yield 3.5 g of crystals, d @ 237.degree. C. 
ANALYSIS 
Calculated for C.sub.26 H.sub.35 N.sub.3 O.sub.6 .multidot.2C.sub.2 H.sub.2 
O.sub.4 : 54.13%C; 5.91%H; 6.31%N; 
Found: 53.85%C; 6.12%H; 6.21%N. 
EXAMPLE 17 
3-[3-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]propyl]-5,6-dimethoxy-1,2 
-benzisoxazole 
To 75 ml of dry DMF were added 
3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (4.1 g), 
1-[bis(4-fluorophenyl)-methyl]piperazine (4.3 g), milled K.sub.2 CO.sub.3 
(10 g) and KI (0.01 g). 
After six hours of stirring at 90.degree. C., the mixture was poured into 
300 ml of water, stirred for five minutes and then extracted with 
ether/ethyl acetate. The organic layer was washed with water (2X) and 
dried (saturated NaCl, anhydrous MgSO.sub.4). 
After filtration, the solvents were evaporated, leaving about 9 g of oil 
which was eluted on a silica gel column with ethyl acetate via HPLC. The 
desired fraction was concentrated to 2.8 g of solid, m.p. 163-8.degree. C. 
This material was recrystallized twice from isopropyl ether/methanol (3:1) 
to yield 2.1 g, m.p. 173-5.degree. C. 
ANALYSIS 
Calcualted for C.sub.29 H.sub.31 F.sub.2 N.sub.3 O.sub.3 : 68.26%C; 6.16%H; 
8.28%N; 
Found: 68.95%C: 6.13%H; 8.33%N. 
EXAMPLE 18 
3-[3-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]propyl]-5,6-dimethoxy- 
1,2-benzis oxazole oxalate 
To 75 ml of dry DMF were added 
3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (5.12 g), 
1-[(4-chlorophenyl)-phenylmethyl]-piperazine (5.0 g), milled K.sub.2 
CO.sub.3 (10 g) and KI (0.01 g). 
After six hours or stirring at 90.degree. c., the mixture was poured into 
500 ml of water, stirred for five minutes and then extracted with ethyl 
acetate. The ethyl acetate layer was washed with water (2X) and dried 
(saturated NaCl, anhydrous MgSO.sub.4). 
After filtration, the solvent was evaporated, leaving about 8 g of oil 
which was eluted on a silica gel column with ethyl acetate via HPLC. The 
desired fraction was collected, concentrated to 4.5 g of oil, then 
dissolved in ether, the pH of the solution adjusted to 1 with etheral 
oxalic acid, and the resultant precipitate collected and dried to yield 
4.3 g, d @ 115.degree. C. 
ANALYSIS 
Calculated for C.sub.29 H.sub.32 ClN.sub.3 O.sub.2 .multidot.C.sub.2 
H.sub.2 O: 62.46%C; 5.75%H; 7.05%N; 
Found: 62.35%C; 5.78%H; 7.13%N. 
EXAMPLE 19 
3-[3-[4-[4-[bis(4-fluorophenyl)butyl]]-1-piperazinyl]propyl]-5,6-dimethoxy- 
1,2 -benzisoxazole dioxalate 
To 75 ml of dry DMF were added 
3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (4.1 g), 
1-[4,4-bis-(4-fluorophenyl)-butyl]piperazine (4.0 g), milled K.sub.2 
CO.sub.3 (10 g) and KI (0.01 g). 
After four hours of stirring at 90.degree. C., the mixture was poured into 
300 ml of water, stirred for five minutes and then extracted with ethyl 
acetate (3.times.100 ml). The organic layer was washed with water 
(2.times.100 ml) and saturated Nacl solution (1.times. 100 ml) and then 
dried over anhydrous MgSO.sub.4. 
After filtration, the solvent was evaporated, leaving about 9 g of oil 
which was eluted on a silica gel column with ethyl acetate via HPLC. The 
desired fractions were combined and concentrated to about 3.8 g of oil 
which was dissolved in ether and then acidified to pH 1 with 
etheral-oxalic acid. The resultant precipitate was collected and dried to 
yield 3.7 g, d @ 225.degree. C. This material was recrystallized from 
methanol/water/ether (50:1:5), to yield 3.0 g of crystals, d @ 228.degree. 
C. 
ANALYSIS 
Calculated for C.sub.32 H.sub.37 F.sub.2 N.sub.3 O.sub.3 .multidot.2C.sub.2 
H.sub.2 O.sub.4 : 59.25%C; 5.66%H; 5.76 %N; 
Found: 59.13%C; 5.72%H; 5.69%N. 
EXAMPLE 20 
3-[3-[4-[3-[6-fluoro-1,2-benzisoxazol-3-yl]propyl]-1-piperazinyl] 
propyl]-5,6-dimethoxy-1,2-benzisoxazole dioxalate 
To 100 ml of dry DMF were added 
3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (6.4 g), 
6-fluoro-3-[3-(1-piperazinyl)propyl] -1,2-benzisoxazole (5.5 g), milled 
K.sub.2 CO.sub.3 (10 g) and KI (0.01 g). 
After two hours of stirring at 90.degree. C., the mixture was poured into 
300 ml of water, stirred for five minutes and then extracted with 
ether/ethyl acetate (2.times.150 ml). The organic layer was washed with 
water (2.times.100 ml) and saturated NaCl (1.times.100 ml) and then dried 
over anhydrous MgSO.sub.4. 
After filtration, the solvents were evaporated, leaving about 12 g of oil 
which was eluted on a silica gel column with 5% methanol/DCM. The desired 
fractions were combined and concentrated to 3 g of solid, which was 
redissolved in ether, the pH adjusted to 1 with ethereal-oxalic acid and 
the resultant precipitate collected and dried to yield 2.5 g, d @ 
214.degree. C. This material was recrystallized from methanol/water/ether 
(50:1:5) to yield 2.1 g of solid, d @ 221.degree. C. 
ANALYSIS 
Calculated for C.sub.26 H.sub.31 FN.sub.4 O.sub.4 .multidot.2C.sub.2 
H.sub.2 O.sub.4 : 54.38%C; 5.32%H; 8.46%N; 
Found: 54.92%C; 5.37%H; 8.51%N. 
EXAMPLE 21 
3-[3-[4-[3-[5,6-dimethoxy-1,2-benzisoxazol-3-yl]propyl]-1-piperazinyl] 
propyl]-5,6-dimethoxy-1,2-benzisoxazole 
To 80 ml of dry DMF were added 
3-(3-chloroproyl)-5,6-dimethoxy-1,2-benzisoxazole (8.9 g), piperazine (1.3 
g), milled K.sub.2 CO.sub.3 (10.0 g) and KI (0.01 g). 
After seven hours of stirring at 95.degree. C., the mixture was poured into 
500 ml of water, stirred for five minutes and then extracted with ethyl 
acetate. The organic layer was washed with water (2X) and saturated NaCl 
solution and then dried over anhydrous MgSO.sub.4. 
After filtration, the solvent was evaporated, leaving about 10 g of oil 
which was purified by elution on a silica gel column with 5% methanol/DCM 
via HPLC. The desired fractions were collected, combined and concentrated 
to 4.7 g of solid, m.p. 164-165.degree. C. This material was 
recrystallized form isopropyl ether/methanol (1:1) to yield 3.0 g of 
solid, m.p. 166-7.degree. C. 
ANALYSIS 
Calculated for C.sub.28 H.sub.36 N.sub.4 O.sub.6 : 64.10%C; 6.92%H; 
10.68%N; 
Found: 64.54%C; 7.00%H; 10.75%N.