Substituted benzhydryl 2-hydroxypropyl piperazine derivatives and methods of synthesis of the derivatives are described. The substituted benzhydryl 2-hydroxypropyl piperazine derivatives are useful as cardiotonic agents.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention relates to compounds of the formula: 
##STR1## 
as further defined herein. The compounds are useful as cardiovascular 
agents. The compounds possess positive ionotropic activity and are 
especially useful as cardiotonic agents for improving cardiac ejection, 
particularly in the setting of acute or chronic congestive heart failure 
2. Description of the Prior Art 
British Patent Application No. GB2186573 and German Patent Application No. 
DE3703633 relate to purine derivatives possessing cardiotonic and 
antiarrhythmic activity and having the following formula: 
##STR2## 
wherein R is an optionally substituted diphenylalkyl group. The side chain 
in the above formula is bonded to a ring nitrogen atom. 
U.S. Pat. No. 4,460,586 relates to 3-aminopropoxyaryl derivatives of the 
formula: 
##STR3## 
These compounds are useful as cardiotonic, antiarrhythmic and .alpha.- and 
.beta.-adrenoceptor blocking agents. This United States patent is one of a 
series of patents that have issued claiming various 4-substituted indole 
derivatives. 
U.S. Pat. No. 4,885,300 relates to 4-substituted pyrazolo pyrimidine 
derivatives of the formula: 
##STR4## 
These compounds are useful as cardiotonic and antiarrhythmic agents. 
U.S. Pat. No. 4,876,257 relates to 6-substituted purinyl piperazine 
derivatives of the formula: 
##STR5## 
These compounds are also useful as cardiotonic and antiarrhythmic agents. 
SUMMARY OF THE INVENTION 
The present invention is directed to substituted-benzhydryl-2-hydroxypropyl 
piperazine derivatives of the general formula: 
##STR6## 
wherein R is hydrogen or acetyl; 
Ar.sub.1 and Ar.sub.2 are independently phenyl or substituted phenyl 
wherein the substituent on the phenyl ring is C.sub.1 -C.sub.4 alkyl, 
C.sub.1 -C.sub.4 alkoxy, trifluoromethyl or halogen; and 
X is selected from the group consisting of 
##STR7## 
wherein Y is a mono or disubstituent selected from hydrogen, halogen, 
amino, C.sub.1 -C.sub.4 alkylamino, C.sub.2 -C.sub.4 alkanoylamino or 
C.sub.1 -C.sub.4 alkoxy wherein the substituents are the same or 
different; and 
R.sub.1 is hydrogen, methyl or benzyl. 
Also included are optically active isomers of the substituted benzhydryl 
2-hydroxypropyl piperazine derivatives. 
The compounds of the general formula are useful as cardiovascular agents, 
and in particular as cardiotonic agents.

DETAILED DESCRIPTION OF THE INVENTION 
The invention in its broadest aspects relates to substituted benzhydryl 
2-hydroxypropyl piperazine derivatives which exhibit positive ionotropic 
activity. 
The compounds of the present invention can be prepared as outlined in 
Scheme 1, below. 
##STR8## 
In this case, the appropriately substituted starting compound 1 is treated 
with a base such as an amine (for example, triethylamine), a metal 
hydroxide (for example, sodium or potassium hydroxide), a metal hydride 
(for example, sodium hydride) in an inert solvent such as 
dimethylformamide (DMF), dimethylsulfoxide (DMSO) or tetrahydrofuran 
(THF). The anion so formed is reacted with appropriately substituted 
alkylating agents such as the chloride 2 or the epoxide 3 and the 
reactants are allowed to react for about 2 to 200 hours at a temperature 
of about 0.degree. to about 100.degree. C. to form the compounds of the 
invention 4. The chlorides 2 and epoxides 3 used as the alkylating agents 
are either commercially available or they can be prepared by procedures 
found in the chemical literature and available to those skilled in the 
art. 
The compounds of the present invention can also be prepared as described in 
Scheme 2. 
##STR9## 
In Scheme 2, an appropriately substituted alcohol 5 is reacted with acetic 
anhydride in a suitable solvent such as THF or methylene chloride, for 
example, to form the ester derivative 6. 
Alternately, the compounds of the present invention can be prepared as 
outlined in Scheme 3 where an appropriately substituted racemic or 
optically active glycidyl derivative 7 is treated with an appropriately 
substituted benzhydryl piperazine 8 either neat or in the presence of a 
solvent at a temperature of about 15.degree.-50.degree. C. for from about 
several hours to several weeks. The resulting product is the piperazine 
derivative 9 in the racemic or optically active form. Suitable solvents 
that can be employed in the reaction include methanol, ethanol, DMF and 
DMSO. The benzhydryl piperazine compounds 8 are available commercially or 
they can be prepared according to literature procedures known to those 
skilled in the art. 
##STR10## 
Pharmaceutical compositions containing a compound of the present invention 
as the active ingredient in intimate admixture with a pharmaceutical 
carrier can be prepared according to conventional pharmaceutical 
compounding techniques. The carrier may take a wide variety of forms 
depending on the form of preparation desired for administration, e.g., 
intravenous, oral or parenteral. The composition may also be administered 
by means of an aerosol. In preparing the compositions in oral dosage form, 
any of the usual pharmaceutical media may be employed, such as, for 
example, water, glycol, oils, alcohols, flavoring agents, preservatives, 
coloring agents and the like in the case of oral liquid preparations (such 
as, for example, suspensions, elixirs and solutions); or carriers such as 
starches, sugars, diluents, granulating agents, lubricants, binders, 
disintegrating agents and the like in the case of oral solid preparations 
(such as, for example, powders, capsules and tablets). Because of their 
ease in administration, tablets and capsules represent the most 
advantageous oral dosage unit form, in which case solid pharmaceutical 
carriers are obviously employed. If desired, tablets may be sugar-coated 
or enteric-coated by standard techniques. For parenterals, the carrier 
will usually comprise sterile water, though other ingredients, for 
example, to aid solubility or for preservative purposes, may be included; 
injectable suspensions may also be prepared, in which case appropriate 
liquid carriers, suspending agents and the like may be employed. The 
pharmaceutical compositions will generally contain a dosage unit, e.g., 
tablet, capsule, powder, injection, teaspoonful and the like, from about 
0.01 to about 50 mg/kg, and preferably from about 0.1 to about 10 mg/kg of 
the active ingredient. 
The following examples describe the invention in greater particularity and 
are intended to be a way of illustrating but not limiting the invention. 
Some of the compounds in the examples were obtained as the hydrate. The 
water can be removed from the hydrates by drying at temperatures below the 
melting point of the compound. 
EXAMPLE 1 
5-Acetamido-4-amino-6-[1-[1-[bis(4-fluorophenyl)methyl]-piperazin-4-yl]-2-a 
cetoxy -3-propanylthio]pyrimidine Hydrate 
To 
4,5-diamino-6-[1-[1-[bis(4-fluorophenyl-)methyl]piperazin-4-yl]2-hydroxy-3 
-propanylthio]pyrimidine (1.0 g, 2.0 mmol) was added an excess of acetic 
acid (11 mL). The mixture was heated to 80.degree. C. for 3 days and then 
heated to reflux for 4 days. The acetic acid was removed in vacuo and the 
residue purified through silica gel (10% methanol:methylene chloride) to 
give the pure product (320 mg, 31.4%) as a brown solid; mp. 
79.degree.-81.degree. C. (dec.); DCI/MS (M+1)=571. (300 MHz) .sup.1 H NMR 
(CDCl.sub.3).delta.: 8.2 (s,1H); 7.3 (m,4H); 6.9 (m,4H); 5.2 (m, 1H); 4.2 
(s,1H); 3.2-3.75 (q of q,2H); 2.5 (m,10H); 2.2 (s,3H); 2.0 (s,3H). 
Calc for C.sub.28 H.sub.32 F.sub.2 N.sub.6 O.sub.3 S.multidot.H.sub.2 O: 
C,58.02; H,5.74; N 14.50. 
Found: C,58.02; H,5.55; N,14.67. 
EXAMPLE 2 
2-[1-[1-[Bis(4-fluorophenyl)methyl]piperazin-4-yl]-2-hydroxy-3-propanylthio 
]pyridine Hemihydrate 
To NaH (10 mmol, 0.48 g, pentane washed) in DMF (10 mL) was added 
2-mercaptopyridine (10 mmol, 1.11 g) at 0.degree. C. After stirring for 2 
hours at 0.degree. C., 1-(1-chloro-2-hydroxy-3-propanyl)-4-(4, 
4'-difluorobenzhydryl)piperazine (5 mmol, 1.91 g) in DMF (20 mL) was added 
dropwise under nitrogen over 10 minutes. The mixture was stirred 15 
minutes at 0.degree. C. and 5 days at room temperature. The mixture was 
then filtered and the filtrate concentrated in vacuo (1 mmHg, 70.degree. 
C.). The concentrated mixture was purified on a silica gel column using 5% 
methanol:methylene chloride. Crude material thus obtained was 
rechromatographed on silica gel using 10% acetone:methylene chloride and 
then 10% methanol:methylene chloride. After drying in a vacuum dessicator 
overnight, the pure product was an amber glass (0.87 g, 38.1%); DCI MS 
(M+1)=456; (300 MHz) .sup.1 H NMR (CDCl.sub.3).delta.:8.4 (d,1H) and 7.5 
(m,1H), 7.3 (m,4H), 7.25 (m,1H), 7.0 (m,5H), 4.0 (m, 1H), 3.2-3.6 (m,4H), 
2.5 (m,10H). 
Calc for C.sub.25 H.sub.27 F.sub.2 N.sub.3 OS.multidot.1/2H.sub.2 O: 
C,64.63; H,6.07; N 9.04. 
Found: C,64.70; H,5.98; N, 8.50. 
EXAMPLE 3 
4-[1-[1-[Bis(4-fluorophenyl)methyl]piperazin-4-yl]-2-acetoxy-3-propanylthio 
]pyridine 
To 4-mercaptopyridine (0.555 g, 5 mmol) in DMF Hemihydrate 
To 4-mercaptopyridine (0.555 g, 5 mmol) in DMF (5 mL) with triethylamine 
(0.7 mL, 5 mmol) was added 1-(1-chloro-2-hydroxy-3-propanyl)-4-(4, 
4'-difluorobenzhydryl) piperazine (1.91 g, 5 mmol) in DMF (15 mL) dropwise 
over 15 minutes under nitrogen. After 8 days, the reaction mixture was 
heated to 60.degree. C. and stirred for 3 days. The DMF was removed in 
vacuo (1 mmHg, 60.degree. C.) and to this crude material was added 
methylene chloride (5 mL), acetic anhydride (5 mmol, 0.47 mL) and 
triethylamine (5 mmol, 0.7 mL), and the mixture was stirred overnight. 
Silica gel flash chromatography using 10% methanol:methylene chloride gave 
an amber oil which was dissolved in methylene chloride (10 mL) and 
extracted with saturated sodium bicarbonate (2.times.20 mL), water 
(1.times.20 mL), saturated brine (1.times.20 mL) and dried over sodium 
sulfate. The solvent was removed in vacuo to give pure product (0.38 g, 
15.3%); DCI/MS (M+1)= 498; 300 MHz .sup.1 H NMR (CDCl.sub.3).delta.: 
8.4(d,2H,J=1.25 Hz), 7.3 (m,4H), 7.2 (d,2H,J=1.4 Hz), 6.95 (m, 4H), 5.1 
(m, 1H), 4.2 (s, 1H), 3.3 and 3.2 (d of d and d of d, 2H), 2.6 (d, 
2H,J=6.1 Hz), 2.35 (m, 8H), 2.0 (s,3H). 
Calc for C.sub.27 H.sub.29 F.sub.2 N.sub.3 O.sub.2 S.multidot.1/2 H.sub.2 
O: C, 64.01; H, 5.97; N, 8.29. 
Found: C, 63.95; H, 5.77; N, 7.80 
EXAMPLE 4 
2-[1-[1-[Bis(4-fluorophenyl)methyl]-piperazin-4-yl]-2-hydroxy-3-propanylthi 
o] -benzothiazole Monomalonate Dihydrate 
To ethanol (10 mL) was added 2-mercaptobenzothiazole (5 mmol, 836 mg), 
triethylamine (5 mmol, 0.7 mL) and then 
1-(1-chloro-2-hydroxy-3-propanyl)-4-(4,4'-difluorobenzhydryl)piperazine 
(5mmol, 1.9 g) in ethanol (40 mL) dropwise over 40 minutes under nitrogen. 
After 10 days the ethanol was removed in vacuo to give a brown oil. Silica 
gel flash column chromography gave pure product as an amber oil (1.81 g, 
70.7%). To this oil (1.5 g, 2.93 mmol) in methanol (5 mL), was added 
malonic acid (305 mg, 2.93 mmol) in methanol. After 4 hours, the methanol 
was removed in vacuo to give pure product (1.68 g, 93.1%); mp 
58.degree.-61.degree. C.; DCI/MS (M+1)=512; (400 MHz .sup.1 H NMR 
(CDCl.sub.3).delta.: 8.0 (m, 1H), 7.85 (d of d, 1H), 7.45 (m, 2H), 7.4 (m, 
4H), 7.1 (m, 4H), 4.1 (m, 1H), 3.6 and 3.7 (q of q, 2H), 3.05 (s, 2H), 2.6 
(m, 10H). 
Calc for C.sub.27 H.sub.27 F.sub.2 N.sub.3 O.multidot.C.sub.3 H.sub.4 
O.sub.4 .multidot.2 H.sub.2 O: 
C, 55.30; H, 5.41; N, 6.44. 
Found: C, 55.34; H, 5.34; N, 6.09. 
When in the above procedure, 6-ethoxy-2-mercaptobenzothiazole is used as 
the starting material in place of 2-mercaptobenzothiazole, 
6-ethoxy-2-[1-[1-[bis(4-fluorophenyl) 
methyl]piperazin-4-yl]-2-hydroxy-3-propanylthio]benzothiazole monomalonate 
dihydrate is obtained. 
Furthermore, when 5-chloro-2-mercaptobenzothiazole is used as the starting 
material in the above procedure, 
5-chloro-2-[1-[1-[bis(4-fluorophenyl)methyl]piperazin-4-yl]-2-hydroxy-3-pr 
opanylthio ]benzothiazole monomalonate dihydrate is obtained. 
EXAMPLE 5 
4,5-Diamino-6-[1-[1-[bis(4-fluorophenyl)-methyl]piperazin-4-yl]-2-hydroxy-3 
-propanylthio]pyrimidine.multidot.1/4Hydrate 
To 4,5-diamino-6-mercaptopyrimidine (25 mmol, 3.55 g) in DMF (30 mL) with 
triethylamine (25 mmol, 3.5 mL) was added 
1-(1-chloro-2-hydroxy-3-propanyl)-4-(4,4'-difluorobenzhydryl)piperazine 
(25 mmol, 9.55 g) in DMF (45 mL) dropwise over 15 minutes under nitrogen. 
The mixture was heated at 60.degree. C. for 24 hours and the DMF was 
removed in vacuo (1 mmHg, 70.degree. C.). The crude product was eluted 
through silica gel using 10% methanol:methylene chloride. The material 
thus obtained was dissolved in methylene chloride (50 mL) and washed with 
water (2.times.50 mL) and saturated brine (1.times.50 mL), and dried over 
sodium sulfate. Concentration in vacuo gave pure product (4.40 g, 36.1%); 
mp 104.degree.-106.degree. C.; DCI/MS (M+1)= 487; (300 MHz) .sup.1 H NMR 
(CDCl.sub.3).delta.: 8.0 (s, 1H), 7.3 (m, 4H), 7.0 (m, 4H), 4.2 (s, 1H), 
4.15 (m, 1H), 3.2 and 3.4 (q of q, 2H), 2.9 (m, 4H), 2.8 (m, 2H), 2.5 (m, 
4H). 
Calc for C.sub.24 H.sub.28 N.sub.6 F.sub.2 OS.multidot.1/4 H.sub.2 O: C, 
58.69; H, 5.85; N, 17.11. 
Found: C, 58.44; H, 5.64; N, 16.54. 
When in the above procedure, 4,6-diamino-2-mercaptopyrimidine is used as 
the starting material in place of 
4,5-diamino-6-mercaptopyrimidine,4,6-diamino-2-[1-[1-[bis(4-fluorophenyl)m 
ethyl] piperazin-4-yl]-2-hydroxy-3-propanylthio]pyrimidine.multidot.1/4 
hydrate is obtained. 
EXAMPLE 6 
1-[1-[1-(Bis(4-fluorophenyl)methyl]-piperazin-4-yl]-2-hydroxy-3-propanyl]-2 
,3, 6,7-tetrahydro-3,7-dimethyl-2,6-dioxo-1H-purine 
To sodium hydride (0.3 g, 6.25 mmol of 50% with oil, prewashed with 
pentane) was added dry dimethyl sulfoxide (12 mL) and theobromine (0.9 g, 
5 mmol). A fine suspension was formed to which was added 
1-(1-chloro-2-hydroxy-3-propanyl)-4-(4, 4'-difluorobenzhydryl)piperazine 
(1.9 g, 5 mmol) dissolved in dry DMSO (10 mL) over 5 minutes. The mixture 
was stirred at room temperature under nitrogen for 24 hours and then 
heated to 70.degree. C. for 20 hours. The DMSO was evaporated in vacuo (1 
mmHg) at 75.degree. C. and the residue was triturated in methylene 
chloride and filtered through Celite.RTM.. The filtrate was evaporated in 
vacuo to give a tacky solid (2.62 g) which was purified by flash 
chromatography over silica gel using 10% methanol/methylene chloride to 
give the desired product which was further purified with ether. The ether 
insoluble material was pure product (0.6 g, 25%), mp 138.degree. 
-140.degree. C.; DCI/MS: 525; 100 MHz .sup.1 H NMR (CDCl.sub.3).delta.: 
7.85 (s, 1H), 7.32 (m, 4H), 6.95 (m, 4H), 4.2 (s, IH), 4.1-4.22 (m, 3H), 
3.97 (s, 3H), 3.57 (s, 3H), 2.3-2.5 (m, 10H). 
Calc for C.sub.27 H.sub.30 F.sub.2 N.sub.6 O.sub.3 : C, 61.82; H, 5.76; N, 
16.02. 
Found: C, 61.71; H, 5.81; N, 15.85. 
EXAMPLE 7 
2-[1-[1-[Bis (4-fluorophenyl)-methyl] 
piperazin-4-yl]-2-hydroxy-3-propanylthio]pyrimidine 
To NaH (240 mg, 5 mmol, 50% in oil, prewashed with pentane) in DMF (5 mL) 
was added 2-mercaptopyrimidine (5 mmol, 560 mg) in portions over 5 minutes 
at 0.degree. C. After 30 minutes, 
1-(1-chloro-2-hydroxy-3-propanyl)-4-(4,4'-diflurobenzhydryl)piperazine 
(1.9 g, 5 mmol) in DMF (15 mL) was added over 10 minutes under nitrogen. 
After 12 days, the sodium chloride was removed by filtration and the DMF 
was removed in vacuo (.about.0.5 mm Hg, .about.50.degree. C.) to give the 
crude (1.82 g). Flash column chromatography over silica gel using 2% 
methanol:methylene chloride (2.times.) and subsequent washings of the 
product with pentane gave the pure product (380 mg, 16.7%) as a white 
solid, mp 75.degree.-76.degree. C.; DCI/MS (M+1)=456; (400 MHz) .sup.1 H 
NMR (CDCl.sub.3).delta.: 8.55 (s, 1H), 8.50 (s, 1H), 7.35 (m, 4H), 7.0 
(m, 4H), 4.2 (s, 1H) , 4.0 (m, 1H), 3.3 (m, 2H), 2.65 (m, 2H), 2.4 (m, 
8H). 
Calc for C.sub.24 H.sub.26 F.sub.2 N.sub.4 OS: C, 63.26; H, 5.75; N, 12.29. 
Found: C, 62.97; H, 5.87; N, 11.91. 
EXAMPLE 8 
2-(3-Indolyl)-2-[1-[1-bis(4-fluorophenyl)-methyl]-piperazin-4-yl]-2-hydroxy 
-3 -propyl]acetonitrile 3/4hydrate 
To sodium hydride (300 mg, 50% in mineral oil prewashed with pentane, 6.25 
mmol) was added pentane (10 mL). After stirring under nitrogen for 5 
minutes, the pentane was decanted, dry DMF (12 mL) was added and the 
mixture was cooled in an ice bath to 0.degree. C. 3-Indolyl acetonitrile 
(780 mg, 5 mmol) was then added in DMF (7.5 mL) over a period of 15 
minutes. After stirring for an additional 1 hour at 0.degree. C., 
1-(1-chloro-2-hydroxy-3-propanyl)-4-[bis(4-fluorophenyl) methyl]piperazine 
(1.9 g, 5 mmol) dissolved in DMF (7.5 mL) was added under nitrogen over a 
period of 10 minutes. The mixture was allowed to come to room temperature 
and was stirred under nitrogen at room temperature for 7 days. The solvent 
was evaporated in vacuo (1 mm Hg, 50.degree. C.); the residue was 
dispersed in methylene chloride, filtered through Celite.RTM., and the 
filtrate was evaporated vacuo to give the crude reaction product (2.5 g). 
Purification by flash column chromatography using silica gel (140 g) and 
methylene chloride eluent gave 1.1 g in the slowest fractions which was 
rechromatographed over silica gel (60 g) using 5% methanol-methylene 
chloride eluent to give the title compound (230 mg), mp 
79.degree.-81.degree. C. (dec), as a light beige powder; 300 MH.sub.z 
.sup.1 H-NMR (CDCl.sub.3).delta.: 7.58 (d, 1H), 7.2-7.4 (m, 8H), 6.95 (m, 
4H), 4.2 (s, 1H), 4.15 (m, 1H), 3.8 (m, 3H), 2.3-2.6 (m, 10H); IR (KBr) 
2240 cm.sup.-1 ; DCI-MS M+1=501. 
Calc for C.sub.30 H.sub.30 F.sub.2 N.sub.4 O.multidot.3/4H.sub.2 O: C, 
70.09, H, 6.18, N, 10.89. 
Found: C, 70.10; H, 6.19; N, 10.68. 
EXAMPLE 9 
1-[1-[1[Bis(4-fluorophenyl)methyl]-piperazin-4-yl]-2-hydroxy-3-propanylthio 
]naphthalene.multidot.1/3H.sub.2 O 
To sodium hydride (500 mg, 50% in mineral oil prewashed with pentane, 10 
mmol) was added pentane (30 mL). After stirring under nitrogen for 5 
minutes, the pentane was decanted, and dry DMF (12 mL) was added. It was 
cooled in an ice bath to 0.degree. C., and naphthalene-1-thiol (1.4 mL, 
1.6 g, 10 mmol) was added in DMF (10 mL) over a period of 15 minutes. To 
the resulting greenish-yellow fine suspension was added 
1-(1-chloro-2-hydroxy-3-propanyl)-4-[bis(4-fluorophenyl) methyl]piperazine 
(3.8 g, 10 mmol) dissolved in DMF (20 mL) under nitrogen over a period of 
10 minutes at 0.degree. C. The mixture was allowed to come to room 
temperature and stirred under nitrogen for 5 days, and the solvent was 
evaporated in vacuo (1 mm Hg, 50.degree. C.). The resulting oil (4.8 g) 
was purified by flash column chromatography over silica gel using 
methylene chloride eluent. The first eluate gave a solid (1.0 g) which was 
identified as bis(1-naphthyl)disulfide. The second eluate (using 10% 
methanol-methylene chloride) gave the title compound (2.0 g), mp 
50.degree.-52.degree. C., as a light-beige powder; 300 MH.sub.z .sup.1 
H-NMR (CDCl.sub.3).delta.: 8.41 (d, J=8Hz, 1H), 7.37-7.85 (m, 6H), 
6.93-7.37 (m, 8H), 4.19 (s, 1H), 3.82 (m, 1H), 3.81 (m, 2H), 2.3-2.8 (m, 
10H); DCI-MS (M+1)=505. 
Calc for C.sub.30 H.sub.30 F.sub.2 N.sub.2 OS.multidot.1/3H.sub.2 O: C, 
70.56, H, 6.05; N, 5.49. 
Found: C, 70.49; H, 5.98; H 5.95. 
EXAMPLE 10 
1-Benzyl-5-[4-[bis(4-fluorophenyl)methyl]-piperazin-1-yl]-2-hydroxy..3-prop 
anyl]-1 H-pyrrolo[3,2-c1pyridino-4(5H)-one 
Sodium hydroxide (0.088 g, 2.2 mmol) was added to a solution of 
1-benzyl-4,5-dihydro-4-oxo-5-azaindole (0.5 g, 2.2 mmol) in DMF (20 mL). 
After the mixture was stirred for 15 minutes, 
1-(1-chloro-2-hydroxy-3-propanyl)-4-[bis(4-fluorophenyl)methyl]piperazine 
(0.844 g, 2.2 mmol) was added and the mixture was stirred at room 
temperature for 18 hours. The solvent was removed in vacuo, the residue 
was dissolved in methylene chloride and the solution washed with water and 
saturated brine and dried over sodium sulfate. The solid thus obtained 
(0.32 g, 26%) was purified on silica gel using 5% methanol in methylene 
chloride to give the title compound as a beige solid, mp 
86.degree.-88.degree. C.; MS (DCI) 569 M+H; IR (KBr) 2937, 1637, 1562, 
1512, 1450, 1394, 1225 cm.sup.-1 ; 400 MH.sub.z .sup.1 H NMR 
(CDCl.sub.3).delta.: 7.34-6.88 (m, 16H), 6.25 (d, 1H), 4.37 (d, 1H), 4.18 
(s, 1H), 4.05 (brs, 1H), 3.88-3.10 (m, 1H), 2.65-2.6 (m, 13H). 
Calc for C.sub.34 H.sub.34 F.sub.2 N.sub.4 O.sub.2 : C, 71.81; H, 6.02; N, 
9.85. 
Found: C, 71.58; H, 5.96; N, 9.83. 
EXAMPLE 11 
8-[3-[4-(Diphenylmethyl)piperazin-1-yl]-2-hydroxypropoxy]-3,4-dihydro-2H, 
1-benzothiopyran 
A mixture of 8-(2,3-epoxypropoxy)-3,4-dihydro-4H-benzothiopyran (0.45 g, 
2.024 mmol) and 1-diphenyl)methylpiperazine (0.612 g, 2.43 mmol) in 
methanol (15 mL) was heated to reflux under nitrogen for hours. The 
solvent was removed in vacuo and the residue dissolved in methylene 
chloride which was reevaporated. The residue was purified using silica gel 
flash chromatography with 3% methanol in methylene chloride to give the 
title compound as a colorless foam, 0.96 g (100%), mp 
68.degree.-70.degree. C.; IR (KBr) 3400, 1569, 1447, 1256 cm.sup.-1 ; 300 
MH.sub.z .sup.1 H NMR (CDCl.sub.3).delta.: 2.07 (m, 2H), 2.2-3.08 (m, 
12H), 3.9-4.2 (m, 5H), 4.22 (s, 1H), 6.6-7.6 (m, 13H); MS (DCI) 475 (MH)+. 
Calc for C.sub.29 H.sub.34 N.sub.2 O.sub.2 S: C, 73.38; H, 7.22; N, 5.90. 
Found: C, 73.29; H, 7.15; N, 5.90. 
EXAMPLE 12 
8-[3-[4-(Diphenylmethyl)piperazin-1-yl]-2-hydroxypropoxy]-2,3-dihydro-4H-be 
nz5,6]oxazin-3-one.multidot.1/4 Hydrate 
A mixture of 8-(2,3-epoxy)-2,3-dihydro-4H-benz[5,6]oxazin-3-one (0.442 g, 2 
mmol) and 1-(diphenyl)methylpiperazine (0.505 g, 2 mmol) in methanol (5 
mL) was heated to reflux for 2 hours under nitrogen. The solvent was 
removed in vacuo and the residue was purified using flash chromatography 
on silica gel using 5% methanol in methylene chloride to give the title 
compound as a colorless foam, 0.86 g (90%). Recrystallization from 
methanol/ether gave the analytical product, mp 160.degree.-162.degree.-C.; 
IR (KBr) 1690 cm.sup.-1 ; 300 Mc .sup.1 H NMR (CDCl.sub.3).delta.: 2.0-2.8 
(m, 6H), 4.02 (s, 1H), 4.22 (s, 1H), 4.62 (s, 2H), 6.45 (d, 1H), 6.66 (d, 
1H), 6.86 (d, 1H), 7.1-7.5 (m, 10H), 8.45 (br s, 1H); MS (DCI) 474 (MH)+. 
Calc for C.sub.28 H.sub.31 N.sub.3 O.sub.4 .multidot.1/4 H.sub.2 O: C, 
70.34; H, 6.64; N, 8.77. 
Found: C, 70.33; H, 6.66; N, 8.81. 
EXAMPLE 13 
Cardiotonic Activity 
Adult mongrel dogs were anesthetized with sodium pentobarbital (45 mg/kg, 
i.p.) and artificially respired by the method of Alousi, A. A. et al. 
(Circl. Res., 1979, 45, 666). Mean arterial pressure (MAP) was recorded 
from a cannulated femoral artery and drugs were infused into a cannulated 
femoral vein. The arterial pressure pulse was used to trigger a 
cardiotachometer for determination of heart rate (HR). Left ventricular 
pressure was measured with a Millar catheter and dP/dt.sub.max was 
derived. A right thoracotomy was performed and myocardial contractile 
force (CF) was measured with a Walton Brodie strain gauge sutured to the 
right ventricle. The ventricular muscle was stretched to produce a 
baseline tension of 100 g. A catheter was inserted 2 cm distal to the 
pyloric valve via a flank incision for intraduodenal (i.d.) drug 
administration. A standard dose of dopamine (10-15 .mu.g/kg/minute for 3 
minutes) was administered to determine myocardial responsiveness to 
inotropic stimulation. 
Example compounds were solubilized in a small volume of DMF diluted to a 
final concentration of 10% in physiological saline. Alternatively, where 
possible, a soluble hydrochloride salt was prepared by addition of 0.1N 
HCl diluted in physiological saline. Vehicles were tested in appropriate 
volumes and found to exert less than a 5% effect on contractile fore. For 
i.v. studies, compounds were administered by infusion pump (one drug per 
animal) at rates of 0.58-2.2 mL/minute in three to four stepwise 
increasing doses. Each dose was infused over 5 minutes immediately after 
the effect of the previous dose peaked. For i.d. studies, compounds were 
injected into the duodenum through an indwelling catheter in a 10 mL 
bolus. MAP, HR, dP/dt.sub.max and CF responses were continuously monitored 
on a Beckman or Gould recorder and expressed as a percent change from 
pre-drug control values vs. the cumulative dose of drug administered. For 
these studies, n of 1 to 5 test animals were used. 
Quantitation of the inotropic potency was obtained by calculation of the 
contractile force (CF) ED.sub.50. This was defined as the dose of compound 
that produced a 50% increase above baseline in myocardial contractile 
force. The value was obtained from three to four point dose-response 
curves using either graphical estimation (n&lt;3) or linear regression 
analysis (n.gtoreq.3). Data from this evaluation are shown in Table 1 
below. Numbers in parentheses are the number of animals screened. 
TABLE 1 
______________________________________ 
Biological Data For Substituted- 
Benzhydryl 2-Hydroxypropyl 
Piperazine Derivatives 
Compound 
of 
Example DOSE (i.v.) 
MAP HR dP/dt CF 
______________________________________ 
1 1.875 (1) -1 12 75 92 
2 1.875 (1) -6 -2 8 28 
3 1.875 (1) 0 7 31 40 
4 1.875 (1) -1 9 45 29 
5 1.875 (1) 4 16 78 55 
6 1.875 (1) 1 4 28 32 
7 1.875 (2) -10 -10 65 112 
8 1.875 (1) -4 -1 45 51 
9 1.875 (1) -1 6 16 26 
10 1.875 (1) -8 8 66 78 
11 1.875 (2) 0 8 36 58 
12 1.938 (2) -7 6 44 48 
______________________________________