N-substituted alpha-arylazacycloalkylmethanamines and their use as cardiovascular agents

Novel compounds of the formula below wherein W is azetidine, pyrrolidine or piperidine, Q is a straight chain hydrocarbon radical of 1-4 carbons and may contain a double bond, and ##STR1## Ar is phenyl, pyridinyl or pyrimidinyl, a process for their preparation, and novel intermediates are disclosed. The novel compounds and the pharmaceutical compositions of this invention are useful in the treatment of hypertension, arrhythmias and angina.

BACKGROUND OF THE INVENTION 
1. Field of Invention 
Novel N-substituted-.alpha.-arylazacycloalkylmethanamines compounds useful 
in treating certain cardiovascular disorders, novel intermediates thereto, 
and a novel process for the preparation of these compounds are herein 
disclosed. 
2. Information Disclosure Statement 
Four compounds similar to the compounds of the present invention have been 
reported. Compounds 1 and 2 are reported in Khim.-Farm. Zh., 1979, 13(1), 
47-51 (CA 90:16841x) as having neurotropic activity. 
##STR2## 
Compound 3 has a Chemical Abstracts registry number (101997-50-6) but no 
additional information is available. 
##STR3## 
1-Benzhydryl-N-benzyl-.alpha.-phenyl-2-azetidmemethanamine 4 is disclosed 
in the British patent 1,517,934 (and German patent 2,548,053) as being a 
preferred compound useful in the treatment of mammalian obesity. 
##STR4## 
Compounds related to those of the present invention having the formula 
##STR5## 
where R is aryl, cycloalkyl or loweralkyl; p is 0 or 1; R.sup.1 and 
R.sup.2 are selected independently from H, loweralkyl, phenyl or 
phenylloweralkyl; B is 
##STR6## 
and D is aryl which are useful in treating cardiac disturbances and are 
also antihistamines and antisecretory agents are the subject of our U.S. 
application Ser. No. 154,390 filed on Feb. 2, 1988. 
SUMMARY OF THE INVENTION 
The novel N-substituted-.alpha.-phenylazacycloalkylmethanamines of the 
present invention where the azacycloalkyl group is azetidine, pyrrolidine, 
or piperidine have the formula 
##STR7## 
wherein 
R is selected from H, loweralkyl, R.sup.2 C(O)--, R.sup.2 NHC(O), 
(R.sup.2).sub.2 NC(O)-- or R.sub.2 OC(O)--; 
Q is a straight chain hydrocarbon radical of 1-4 carbons and may contain a 
double bond; 
n=0 or 1; 
W is 
1-R.sup.1 -2(or 3) azetidinyl 
1-R.sup.1 -2(or 3) pyrrolidinyl, or 
1-R.sup.1 -2(or 3 or 4) piperidinyl; 
Ar is 
##STR8## 
or, when n is 0, can be pyridinyl or 2-pyrimidinyl; 
m is 0-2; 
X and X.sup.1 are independently selected from halogen, loweralkyl, 
trifluoromethyl, or --OR.sup.2 ; 
R.sup.1 is selected from hydrogen, loweralkyl, loweralkylene, 
cycloloweralkyl, loweralkylcycloloweralkyl, CF.sub.3 CH.sub.2 --, or 
-(alk).sub.p --Y where p is 0 or 1, Y is --C(O)NHR.sup.2, 
--C(.dbd.NH)NH.sub.2, phenyl, naphthyl, 2-quinolinyl, 2-pyrimidinyl, 
2,4-(1H, 3H)quinazolinedione-3-yl, hydroxy, loweralkoxy, 
--O-loweralkylene, --O-aryl (where aryl is phenyl, naphthyl, 
2-methoxy-4-acetylphenyl, 4-loweralkylcarbonylphenyl, or 
4-loweralkoxycarbonylphenyl), 4-loweralkoxycarbonylphenyl), benzoyl, 
4-phenylpiperazine, 3H or 3-loweralkyl-2-oxoimidazolidin-1-yl, 3H or 
3-loweralkyl or benzoyl-2-oxobenimidazolidin-1-yl, phthalimide, amino, 
NHR.sup.3 (R.sup.3 is --C(.dbd.NH)--NH.sub.2, --C(O)NH-loweralkyl or 
phenyl, 2-pyrimidinyl, phenyl, loweralkylcarbonylphenyl or 
benzenesulfonyl), benzenesulfonyl, benzenesulfinyl, benzenesulfenyl, 
--CH(OH)CH.sub.2 OC.sub.6 H.sub.5, or phenylaminocarbonyl or 
loweralkylaminocarbonyl; R.sup.2 is H, loweralkyl, phenyl or phenyl 
substituted by halogen, loweralkyl, loweralkoxy, trifluoromethyl, 
loweralkylcarbonyl or diloweralkylaminoloweralkyl; with a proviso that 
when --(Q).sub.n Ar is --CH.sub.2 C.sub.6 H.sub.5 or --CH.sub.2 
CH.dbd.CHC.sub.6 H.sub.5, X cannot be H and W cannot be 
1-methyl-4-piperidinyl; the stereoisomers thereof and pharmaceutically 
acceptable acid addition salts. 
The term loweralkyl means straight, cyclic and branched chain hydrocarbon 
radicals of from one to eight carbons including, but not limited to 
methyl, ethyl propyl, cyclopropyl, isopropyl, butyl, isobutyl, t-butyl, 
pentyl isopentyl, neopentyl, hexyl, cyclohexyl, heptyl, octyl, isooctyl, 
and the like. 
The term loweralkylene means straight and branched chain hydrocarbon 
radicals of from 2-6 carbons having one or more double bonds including, 
but not limited to propylene, butylene; isobutylene and the like. 
Loweralkylcycloloweralkyl includes, but is not limited to 
cyclopropylmethyl, cyclohexylmethyl and the like. 
The term halogen means fluorine, chlorine, bromine, and iodine radicals. 
The term substituted phenyl refers to a phenyl radical substituted by a 
radical or radicals such as those under the definitions of X, X.sup.1 and 
Z. 
The term "alk" refers to a hydrocarbon radical, straight or branched, of 
from one to 6 carbons and may include one or more double bonds. 
Loweralkoxy refers to an oxygen radical to which a loweralkyl group is 
attached. 
The term stereoisomers includes optical isomers, diasterisomers, and 
geometric isomers. 
The term "pharmaceutically acceptable acid addition salts" includes acid 
addition salts, solvates, and quaternary salts which are physiologically 
compatible in warm blooded animals. Acid addition salts may be formed from 
the pharmaceutically acceptable acids, including but not limited to, 
hydrochloric hydrobromic, sulfuric, phosphoric, methanesulfonic, fumaric, 
maleic, succinic, oxalic, citric, hexamic and the like. 
The term cardiovascular disorders refers to hypertension, arrhythmias, and 
angina. 
It is an object of this invention to provide novel compounds of Formula I. 
It is another object to provide a novel process for the preparation of 
some of the Formula I compounds from which other compounds of Formula I 
can be prepared. 
It is a further object of this invention to provide a method of treating 
warm blooded animals for hypertension, arrththmias, and angina with 
compounds of Formula I and a further object to provide a pharmaceutical 
composition useful in treating hypertension, arrhythmias, and angina. A 
still further object is to provide novel intermediates to compounds of 
Formula I. 
Formula I compounds of this invention are evaluated for antihypertensive 
activity in the spontaneously hypertensive rat, for calcium channel 
blockade in the isolated rabbit aorta preparation, and for angina by 
measuring changes in coronary arterial blood flow. Compounds which have 
calcium channel blocking activity, such as the known drug verapamil, would 
be expected to be useful in treating hypertension and cardiac arrhythmias.

DETAILED DESCRIPTION OF THE INVENTION 
The compounds of Formula I are prepared from intermediates having the 
structure of Formula II. 
##STR9## 
Some Formula II compounds and their precursors where W is pyrrolidine or 
piperidine and X is 4-F, 3-CF.sub.3 or 4-OCH.sub.3 are disclosed in the 
commonly owned U.S. Pat. Nos. 3,479,370 and 3,489,769 and 3,576,810 and 
the related publications in J. Med. Chem. 11, 472-475 (1968), J. Med. 
Chem. 12, 1098-1100 (1969), J. Med. Chem. 13, 1-6 (1970) and J. Med. Chem. 
32, 105-118 (1989) which are hereby incorporated by reference. The 
following methods are illustrative of the preparation of Formula I 
compounds from Formula II intermediates. In these methods, the 
azacycloalkyl group W is represented by the 4-piperidinyl group. The group 
W also includes 2- and 3-azetidinyl, 2- and 3-pyrrolidinyl, and 2- and 
3-piperidinyl. 
##STR10## 
The intermediate II is first alkylated with the desired group R'X, where X 
is halogen to give the intermediate IIa. Reaction of IIa with the 
appropriate amine or aniline gives the imine IIb which is reduced under 
standard conditions with lithium aluminum hydride and the like to obtain 
the Formula I compound. 
##STR11## 
In Method B, pt. A, the intermediate of Formula II is first protected with 
a benzene (or toluene) sulfonyl group to give the intermediate IIc which 
is reacted with the appropriate amine or aniline to obtain the imine IId. 
Reduction as in Method A gives the compound of Formula I where R' is the 
benzene or toluene sulfonyl group. 
##STR12## 
Method B, pt. B discloses removal of the protecting benzene (or toluene) 
sulfonyl group, preferably in refluxing 48% hydrobromic acid and phenol. 
Alkylation of the deprotected Formula I compound under the usual 
conditions gives additional Formula I compounds. 
##STR13## 
Method C comprises a novel process for preparing compounds of Formula I 
where R' is H and n is O which avoids the isolation of the intermediate 
IId. Acid catalysis of the imine formation is provided by employing the 
hydrogen halide salt, preferably the hydrogen chloride salt, of the 
intermediate Formula II compound. Water formed in the reaction is removed, 
preferably by azeotropic distillation. Once the imine is formed, a 
reducing agent such as lithium aluminum hydride, sodium bis 
(2-methoxyethoxy) aluminum hydride solution in toluene, sodium 
borohydride, or sodium cyanoborohydride and the like is introduced into 
the reaction vessel, along with a solubilizing solvent if needed, 
accomplishing the reduction of the imine to the Formula I compound (R'=H)) 
without isolation of the intermediate imine. This provides a Formula I 
compound to which desired R' groups can be readily attached. 
Advantageously this method allows fluoroanilines to be used in imine 
formation without the occurrence of fluorine displacement which can occur 
if the hydrogen halide salt of the formula II compound is not employed. 
##STR14## 
Method D provides an alternative procedure that can be used when 
sufficiently activated arylhalides are available. The oxime is prepared 
and reduced, preferably with hydrogen and Raney nickel, using standard 
laboratory procedures. The aromatic substitution reaction would be carried 
out under standard conditions to obtain the Formula I compound. 
##STR15## 
The benzoylazacycloalkanes II are reduced using known chemical procedures 
to the intermediate alcohol III. Bubbling gaseous hydrogen bromide through 
a solution of III gives the bromide compound IV which can be reacted with 
the appropriate amine to obtain a Formula I compound. 
##STR16## 
Ureas and amides of Formula I compounds where R.sup.2 is as defined 
previously can be prepared from the appropriate acid halide, carbamoyl 
chloride or isocyanate by techniques known to those skilled in the art. It 
would be obvious to one skilled in the art to reduce an amide prepared by 
this method to the corresponding alkyl or arylalkyl Formula I compound. 
Furthermore the R group can be lower alkyl and synthesized by alkylation 
with a loweralkylhalide or sulfate where the R' group would not interfere 
with the reaction. 
The intermediate benzoylazacycloalkanes of Formula II are prepared by known 
procedures illustrated in the following schemes where the azacycloalkyl 
group W is represented by the 4-piperidinyl group. The group W also 
includes 2- and 3-azetidinyl, 2- and 3-pyrrolidinyl, and 2- and 
3-piperidinyl. 
##STR17## 
R' is a removable protecting group such as benzyl or a non-interfering 
group under the definition of R'. M represents the Grignard reagent or the 
lithium compound which reacts with the nitrile to form an intermediate 
imine which gives the intermediate of Formula II upon hydrolysis. The 
reactions are carried out in anhydrous ether or tetrahydrofuran using 
conventional laboratory techniques. 
##STR18## 
N-Acylazacycloalkylcarbonyl chlorides and substituted benzenes are reacted 
together under conventional Freidel-Crafts reaction conditions. The acyl 
group such as acetyl, benzoyl, carbobenzyloxy, carboethoxy and the like, 
can be readily removed using standard laboratory procedures to obtain the 
unsubstituted benzoylazacycloalkanes which provides the intermediates to 
Formula I compounds. Synthesis of Formula II compounds by Scheme II is 
discussed in J. Med. Chem. 13, 1-6 (1970) and elsewhere. 
##STR19## 
Synthesis by Scheme III is discussed in J. Med. Chem. 13,1-6 (1970). 
Other synthetic methods by which Formula II intermediates can be prepared 
are known in the literature and should be apparent to one skilled in the 
art. 
The foregoing methods of preparation of compounds of Formula I and Formula 
II are broadly described and the reactions may not be applicable as 
described to each compound included within the scope of this invention. 
Where this occurs will be easily recognized by those skilled in the art 
and such reactions can be carried out by modifications known to those 
skilled in the art. Exact conditions may vary with substrates, solvents, 
reagents, temperature, and the like. 
Without further elaboration, it is believed that one skilled in the art 
will be able to carry out this invention without undue experimentation. 
The following preferred specific embodiments are therefore to be construed 
as illustrative and not limiting to this disclosure in any way. 
The various reagents used in the following preparations and examples are 
either commercially available or readily synthesized by procedures given 
in the chemical and patent literature. 
PREATION 1 
4-(p-Fluorobenzoil)-piperidine hydrochloride 
A solution of 70.6 g (0.27 mole) of 1-acetyl-4-(p-fluorobenzoyl)piperidine 
(U.S. Pat. No. 3,576,810, J. Med. Chem. 13(1), 1-5, 1970) in 200 mL of 6N 
HCl was refluxed for 2 hours. The cooled solution was extracted twice with 
ether. The aqueous solution was made basic and extracted with benzene. The 
benzene extracts were dried over anhydrous sodium sulfate and 
concentrated. The oily residue weighed 38.5 g (69%). The hydrochloride 
salt was made in the usual manner. Recrystallization of the hydrochloride 
from isopropanol gave a crystalline solid melting at 
222.degree.-224.degree. C. 
Analysis calculated for: C.sub.12 H.sub.15 ClFNO: C, 59.14; H, 6.20; N, 
5.75. Found: C, 59.40; H, 6.20; N, 5.73. 
PREATION 2 
(4-Fluorophenyl)[1-(phenylsulfonyl)-4-piperidinyl]methanone 
A mixture of 4-(4-fluorobenzoyl)piperidine hydrochloride (53.30 g, 0.219 
mol) and benzenesulfonyl chloride (44 g, 0.25 mol) in 500 mL of pyridine 
was stirred at room temperature overnight. The solvent was removed in 
vacuo, and the residue was partitioned between CH.sub.2 Cl.sub.2 and 
dilute NaOH. The CH.sub.2 Cl.sub.2 solution was extracted with dilute 
H.sub.2 SO.sub.4 and then dried (MgSO.sub.4). The volume was reduced to 
400 mL, hexane was added, and 39.20 g (50.6%) of the title compound was 
collected as a white crystalline solid, mp 156.5.degree.-158.degree. C. 
Analysis calculated for: C.sub.18 H.sub.18 NO.sub.3 SF: C, 62.23; H, 5.22; 
N, 4.03. Found: C, 62.13; H, 5.20; N, 4.13. 
PREATION 3 
.alpha.-(4-Fluorophenyl)-N-(2-phenylethyl)-1-(phenylsulfonyl)-4-piperidinem 
ethanimine 
A mixture of 15.56 g (0.045 mol) of 
N-benzenesulfonyl-4-(p-fluorobenzoyl)-piperidine, 8.50 g (0.0702 mol) of 
phenethylamine and 0.20 g (0.0013 mol) of benzenesulfonic acid in 400 mL 
of toluene was heated at reflux for 111 hr. Water was removed from the 
reaction mixture with a Dean-Stark trap. The solvent was removed in vacuo, 
and the residue was partitioned between CH.sub.2 Cl.sub.2 and dilute 
Na.sub.2 CO.sub.3. The CH.sub.2 Cl.sub.2 solution was dried (MgSO.sub.4), 
and the solvent was removed in vacuo. The residue was recrystallized from 
ether to give 18.32 g (90.5%) of title compound as a light tan solid, mp 
123.degree.-126.degree. C. 
Analysis calculated for: C.sub.26 H.sub.27 N.sub.2 O.sub.2 SF: C, 69.31; H, 
6.04; N, 6.22. Found: C, 68.97; H, 6.04; N, 6.17. 
PREATION 4 
.alpha.-(4-Fluorophenyl)-N-(2-phenylethyl)-1-(phenylsulfonyl)-4-piperidinem 
ethanamine 
A mixture of 10.0 g (0.022 mol) of 
.alpha.-(4-fluorophenyl)-N-(2-phenylethyl)-1-(phenylsulfonyl)-4-piperidine 
methanimine and 1.0 g (0.025 mol) of LiAlH.sub.4 in 200 mL of dry THF was 
stirred at room temperature for 8.5 hr. A 10 mL solution of 10% NaOH was 
slowly added followed by 100 mL of water. The mixture was extracted with 
CH.sub.2 Cl.sub.2, and the solution was dried (MgSO.sub.4). The solvent 
was removed in vacuo to give an oil. This was crystallized from 200 ml of 
methanol to give 7.32 g (72.9%) of a white crystalline solid, mp 
115.degree.-117.degree. C. 
Analysis calculated for: C.sub.26 H.sub.29 N.sub.2 O.sub.2 SF: C, 69.00; H, 
6.46; N, 6.17. Found: C, 69.18; H, 6.45; N, 6.23. 
PREATION 5 
N,.alpha.-bis(4-fluorophenyl)-1-(phenylsulfonyl)-4-piperidinemethanimine 
A mixture of 13.0 g (0.037 mol) of 
(4-fluorophenyl)[1-(phenylsulfonyl)-4-piperidinyl]methanone, 24.4 g (0.22 
mol) of 4-fluoroaniline, and 0.7 g (0.004 mol) of benzenesulfonic acid in 
500 mL of xylene was heated at reflux for 7 days. Water was removed with a 
Dean-Stark trap. The solvent was removed in vacuo, and the residue was 
partitioned between CH.sub.2 Cl.sub.2 and dilute NaOH. The CH.sub.2 
Cl.sub.2 phase was dried (Na.sub.2 SO.sub.4), and the solvent was removed 
in vacuo. The residue was recrystallized from CH.sub.2 Cl.sub.2 /hexane to 
give 11.24 g (69%) of a light grey solid, mp 123.degree.-124.degree. C. 
Analysis calculated for: C.sub.24 H.sub.22 N.sub.2 SO.sub.2 F.sub.2 : C, 
65.44; H, 5.03; N, 6.36. Found: C, 65.15; H, 4.97; N, 6.31. 
PREATION 6 
N,.alpha.-Bis(4-fluorophenyl)-1-(phenylsulfonyl)-4-piperidine-methanamine 
A mixture of 9.20 g (0.021 mol) of 
N-.alpha.-bis(4-fluorophenyl)-1-(phenylsulfonyl)-4-piperidinethanimine and 
2.70 g (0.071 mol) of LiAlH.sub.4 in 250 mL of dry THF (distilled from 
sodium/benzophenone ketyl) and under an atmosphere of nitrogen was stirred 
at room temperature for 17 h. The reaction was quenched with 10% NaOH. 
Water and CH.sub.2 Cl.sub.2 were added, and the mixture was filtered 
through Celite.RTM.. The phases were separated, and the organic phases was 
extracted with water and was dried (Na.sub.2 SO.sub.4). The solvent was 
removed in vacuo, and the residue was subjected to flash chromatography 
(silica gel, elution with CH.sub.2 Cl.sub.2) to give a solid. This was 
recrystallized from CH.sub.2 Cl.sub.2 /hexane to give 5.77 g (62.3%) of 
white solid, mp 175.degree.-176.degree. C. 
Analysis calculated for: C.sub.24 H.sub.24 N.sub.2 O.sub.2 SF.sub.2 : C, 
65.14; H, 5.47; N, 6.33. Found: C, 65.04; H, 5.47; N, 6.30. 
PREATION 7 
.alpha.-(4-Fluorophenyl)-N-[(4-fluorophenyl)methyl]-1-(phenylsulfonyl)-4-pi 
peridinemethanimine 
A solution of 22.26 g (0.064 mol) of 
(4-fluorophenyl)[1-(phenylsulfonyl)-4-piperidinyl]methanone, 12.51 g (0.10 
mol) of 4-fluorobenzylamine, and 0.76 g (0.0048 mol) of benzenesulfonic 
acid in 400 mL of xylene was heated at reflux for 25.5 h. Water was 
removed with a Dean-Stark trap. The solvent was removed in vacuo, and the 
residue was partitioned between CH.sub.2 Cl.sub.2 and dilute NaOH. The 
CH.sub.2 Cl.sub.2 solution was dried (Na.sub.2 SO.sub.4), and the solvent 
was removed in vacuo. The residue was recrystallized from CH.sub.2 
Cl.sub.2 -hexane to give 18.49 g (63.68%) of white crystalline solid, mp 
114.degree.-116.degree. C. A second crop of 3.27 g (11.28%) of product was 
isolated from the filtrate as a white solid, mp 110.degree.-112.degree. C. 
Analysis calculated for: C.sub.25 H.sub.24 N.sub.2 O.sub.2 F.sub.2 S: C, 
66.06; H, 5.32; N, 6.16. Found: C, 66.04; H, 5.26; N, 6.14. 
PREATION 8 
.alpha.-(4-Fluorophenyl)-N-[(4-fluorophenyl)methyl]-1-(phenylsulfonyl)-4-pi 
peridinemethanamine (E)-2-butenedioate (1:1) 
A mixture of 17.0 g (0.037 mol) of 
.alpha.-(4-fluorophenyl)-N-[(4-fluorophenyl)methyl]-1-(phenylsulfonyl)-4-p 
iperidinemethanimine and 1.60 g (0.042 mol) of LiAlH.sub.4 in 200 mL of dry 
THF (distilled from sodium-benzophenone ketyl) and under an atmosphere of 
nitrogen was stirred at room temperature for 23 h. The reaction was 
quenched with 10% NaOH. CH.sub.2 Cl.sub.2 was added, and the mixture was 
filtered through Celite. The filtrate was extracted with water and was 
dried (Na.sub.2 SO.sub.4). The resulting oil was purified with flash 
chromatography (silica gel, eluted with CH.sub.2 Cl.sub.2 and 1% CH.sub.3 
OH in CH.sub.2 Cl.sub.2) to give an oil. This was converted to the 
fumarate salt, and the salt was recrystallized from CH.sub.3 OH/ether to 
give 14.37 g (67.8%) of white solid, mp 213.degree.-214.degree. C. 
Analysis calculated for: C.sub.29 H.sub.30 N.sub.2 O.sub.6 F.sub.2 S: C, 
60.83; H, 5.28; N, 4.89. Found: C, 60.81; H, 5.26; N, 4.92. 
PREATION 9 
4-(p-Fluorobenzoyl)-1-(3-phenoxypropyl)piperidine hydrochloride hemihydrate 
A mixture of 12.2 g (0.05 mole) of 4-(p-fluorobenzoyl)piperidine 
hydrochloride, 11.8 g (0.055 mole) of 3-phenoxypropyl bromide and 30.4 g 
(0.022 mole) of anhydrous potassium carbonate in 150 mL of 1-butanol was 
refluxed for 20 hours. The mixture was filtered, and the filtrate was 
concentrated. The solid residue which remained was dissolved in 
isopropanol and an excess of ethereal HCl was added. The hydrochloride 
salt crystallized upon cooling of the solution. Recrystallization from 
2-propanol gave 10.9 g (58%) of the hydrochloride salt which melted at 
196.degree.-198.degree. C. 
Analysis calculated for: C.sub.42 H.sub.52 N.sub.2 Cl.sub.2 F.sub.2 O.sub.5 
: C, 65.19; H, 6.51; N, 3.62. Found: C, 65.57; H, 6.68, N, 3.67. 
PREATION 10 
(4-Fluorophenyl)[1-(3-phenoxypropyl)-4-piperidinyl]methanone oxime 
A solution of the HCl salt of 
4-(p-fluorobenzoyl)-1-(3-phenoxypropyl)piperidine (7.54 g, 0.02 mol) and 
hydroxylamine hydrochloride (2.44 g, 0.035 mol) was prepared in 75 mL of 
95% ethanol. To this solution was added 10 mL of water to produce a 
suspension. Next, sodium hydroxide (8.0 g, 0.2 mol) dissolved in 15 mL of 
water was added dropwise with stirring. The resultant was heated at reflux 
for an hour, and two separate phases resulted. The suspension was diluted 
to 1500 mL with water and extracted with chloroform. The chloroform layer 
was back extracted with water and 5% sodium hydroxide. The chloroform 
layer was dried (Na.sub.2 SO.sub.4) and filtered. When chloroform was 
removed, a white solid was obtained (6.54 g, 91.9%). A one gram sample was 
recrystallized from methylene chloride-isopropyl ether. A white solid was 
isolated and dried in vacuo overnight at 80.degree. C. This process 
furnished 0.68 g (62.5%) of white crystalline solid, mp 163.5.degree.- 
166.5.degree. C. 
Analysis calculated for: C.sub.21 H.sub.25 N.sub.2 O.sub.2 F.0.25H.sub.2 O: 
C, 69.88; H, 7.12; N, 7.76. Found: C, 69.61; H, 7.00; N, 7.68. 
PREATION 11 
.alpha.-(4-Fluorophenyl)-1-(3-phenoxypropyl)-4-piperidinemethanamine 
dihydrochloride hemihydrate 
A suspension of the 
(4-fluorophenyl)[1-(3-phenoxypropyl)-4-piperidinyl]methanone oxime (5.00 
g, 0.014 mol) in 100 mL of ethanol was subjected to hydrogenation (52 psi) 
in the presence of Raney nickel for 16 hours at room temperature. The 
catalyst was removed by filtration, and ethanol was removed by the rotary 
evaporator to give a clear oil. This oil was converted to the HCl salt in 
methanol using ethereal HCl. A white solid was isolated and dried in vacuo 
16 hours at 80.degree. C. in the presence of phosphorus pentoxide. This 
process provided 3.22 g (54.2%) of white crystalline solid, mp 
247.degree.-248.degree. C. (dec). 
Analysis calculated for: C.sub.21 H.sub.27 FN.sub.2 O.2HCl.0.5H.sub.2 O: C, 
59.43; H, 7.13; N, 6.60. Found: C, 59.47; H, 7.14; N, 6.59. 
PREATION 12 
4-(p-Fluorobenzoyl)-1-phenethylpiperidine hydrochloride 
A mixture of 12.2 g (0.05 mole) of 4-(p-fluorobenzoyl)piperidine 
hydrochloride, 10.2 g (0.055 mole) of phenethyl bromide, and 27.6 g (0.2 
mole) of potassium carbonate in 150 mL of 1-butanol was allowed to reflux 
for 2 hours. The mixture was filtered, and the filtrate concentrated. The 
solid residue which remained weighed 14.8 g (95%). The hydrochloride salt 
was prepared in the usual manner and after recrystallization from 
isopropanol, melted at 254.degree.-257.degree. C. 
Analysis calculated for: C.sub.20 H.sub.23 ClFNO: C, 69.05; H, 6.66; N, 
4.03. Found: C, 69.02; H, 6.62; N, 4.03. 
PREATION 13 
2-[(Ethoxycarbonyl)amino]benzoic acid ethyl ester 
A mixture of ethyl 2-aminobenzoate (ethyl anthranilate) (50.0 g, 0.30 mole) 
and ethyl chloroformate (32.8 g, 0.30 mole) in 400 mL of xylenes was 
heated at reflux for 8 hours. The xylene was removed and the residue was 
dissolved in chloroform. The chloroform layer was extracted with 5% sodium 
hydroxide, dried (Na.sub.2 SO.sub.4), filtered, and the chloroform removed 
to give an oil which crystallized. The solid was triturated with isopropyl 
ether and placed in the freezer. Two crops of white solid were obtained 
and dried in vacuo overnight at room temperature. This provided 67.95 g 
(97.6% yield) of white crystalline solid, mp 41.degree.-42.degree. C. 
Analysis calculated for: C.sub.12 H.sub.15 NO.sub.4 : C, 60.75; H, 6.37; N, 
5.90. Found: C, 60.68; H, 6.41; N, 5.92. 
PREATION 14 
3-(2-Hydroxyethyl)-2,4(1H,3H)-quinazolinedione 
A mixture of 2-[(ethoxycarbonyl)amino]benzoic acid ethyl ester (65.75 g, 
0.277 mol) and 2-aminoethanol (16.9 g, 0.277 mol) was refluxed for 2.5 
days in 350 mL of xylenes. The reaction was cooled to room temperature and 
xylene was removed. Chloroform was added to the residue and a brown solid 
crystallized. The brown solid was filtered from the solution. The 
chloroform layer was extracted with water, dried (Na.sub.2 SO.sub.4), 
filtered and the solvent was removed. The residue was placed in the 
freezer in isopropyl alcohol. The brown solid was triturated with 
isopropyl alcohol. Both produced a crystalline white solid which was dried 
in vacuo overnight at 80.degree. C. This gave a total of 40.70 g (71.3% 
yield) of white crystalline solid, mp 250.degree.-252.degree. C. 
Analysis calculated for: C.sub.10 H.sub.10 N.sub.2 O.sub.3 : C, 58.25; H, 
9.89; N, 13.59. Found: C, 58.14; H, 4.84; N, 13.50. 
PREATION 15 
3-(2-Chloroethyl-2,4(1H,3H)-quinazolinedione 
A solution of 3-(2-hydroxyethyl)-2,4(1H,3H)-quinazolinedione (16.23 g, 
0.079 mole) and thionyl chloride (9.76 g, 0.082 mole) was heated at reflux 
for 22 hours in 300 mL of chloroform. The solution was concentrated to 
dryness and a white solid was obtained. The solid was triturated with 
diethyl ether and placed in the refrigerator freezer. The white solid was 
filtered and washed with diethyl ether. The solid was dried in vacuo 
overnight at 80.degree. C. This provided 26.50 g (93.2% yield) of white 
crystalline solid, mp 189.degree.-192.degree. C. 
Analysis calculated for: C.sub.10 H.sub.9 N.sub.2 O.sub.2 Cl: C, 53.47; H, 
4.04; N, 12.47. Found: C, 53.24; H, 4.05; N, 12.34. 
PREATION 16 
4-(3-Chloropropoxy)benzoic acid 1,1-dimethylethyl ester 
A mixture of 4-hydroxybenzoic acid 1,1-dimethylethyl ester (U.S. Pat. No. 
3,625,954) (35.0 g, 0.1804 mol), 3-chlorobromopropane (56.81 g, 0.361 
mol), and potassium carbonate (69.1 g, 0.5 mol) was heated 20 h at reflux 
in 600 mL of acetone. The mixture was cooled to room temperature and 
filtered. The solvent was removed in vacuo to give an oil. The oil was 
dissolved in hexanes (400 mL), and the solution was chilled in the 
freezer. A white solid crystallized and was separated. The solid was dried 
in vacuo for 6 h at room temperature. This procedure furnished 39.46 g 
(81%) of a white crystalline solid, mp 57.5.degree.-58.5.degree. C. 
Analysis calculated for: C.sub.14 H.sub.19 O.sub.3 Cl: C, 62.11; H, 7.07. 
Found: C, 62.02; H, 7.24. 
PREATION 17 
(4-Fluorophenyl)[1-(1-methylethyl)-4-piperidinyl]methanone 
A mixture of 34.16 g (0.165 mol) of the 4-(4-fluorobenzoyl)piperidine, 
33.80 g (0.199 mol) of isopropyl iodide and excessive sodium bicarbonate 
in 600 mL of acetonitrile was heated at reflux for 14 h. The solvent was 
removed in vacuo, and the residue was partitioned between CH.sub.2 
Cl.sub.2 and dilute NaOH. The CH.sub.2 Cl.sub.2 solution was dried 
(Na.sub.2 SO.sub.4), and the solvent was removed in vacuo to give a solid. 
This was recrystallized from CH.sub.2 Cl.sub.2 /hexane to give 31.89 g 
(77.6%) of crystalline solid, mp 120.degree.-121.degree. C. 
Analysis calculated for: C.sub.15 H.sub.20 NOF: C, 72.26; H, 8.09; N, 5.62. 
Found: C, 72.21; H, 8.16; N, 5.64. 
PREATION 18 
2-Benzoyl-1-(3-phenoxypropyl)piperidine 
Following the procedure of Preparation 9, the title compound is prepared 
from 2-benzoylpiperidine [U.S. Pat. No. 3,459,750; Helv. Chim. Acta. 38, 
134-40 (1955)]. 
PREATION 19 
1-(3-Phenoxypropyl)-3-(3-trifluoromethylbenzoyl)pyrroldine 
Following the procedure of Preparation 9, the title compound is prepared 
from 3-(3-trifluoromethylbenzoyl)pyrroldine (U.S. Pat. No. 3,489,769) and 
3-phenoxypropyl bromide. 
PREATION 20 
2-Cyano-1-(3-phenoxypropyl)piperidine 
Following the procedure of Preparation 9, the title compound is prepared 
from 3-phenoxypropyl bromide and 2-cyanopiperidine [Chem. Ber. 92, 
1608-1613 (1959), Helv. Chim. Acta 46(4), 1190-1206 (1963)]. 
PREATION 21 
2-Cyano-1-(3-phenoxypropyl)pyrrolidine 
Following the procedure of Preparation 9, the title compound is prepared 
from 2-cyanopyrrolidine [Helv. Chim. Acta 50(8), 2520-2531 (1967)] and 
3-phenoxypropyl bromide. 
PREATION 22 
3-(4-Fluorobenzoyl)azetidine 
Following the procedure for the preparation of 
1-benzyl-3-benzoylpyrrolidine (U.S. Pat. No. 3,479,370) and using 
1-benzhydryl-3-cyanoazetidine [J.O.C. 37(24), 3953-55, (1972)] and 
4-fluorophenylmagnesium bromide, 1-benzhydryl-3-(4-fluorobenzoyl)azetidine 
is obtained. The benzhydryl group is removed by catalytic hydrogenation 
using palladium on carbon to obtain the title compound. 
PREATION 23 
2-(4-Fluorobenzoyl)azetidine 
Following the procedure for the preparation of 
1-benzyl-3-benzoyl-pyrrolidine (U.S. Pat. No. 3,479,370) and using 
1-benzhydryl-2-cyanoazetidine (G.B. 1,517,934) and 4-fluorophenylmagnesium 
bromide, 1-benzhydryl-2(4-fluorobenzoyl)azetidine is obtained. The 
benzhydryl group is removed by catalytic hydrogenation using palladium on 
carbon to obtain the title compound. 
PREATION 24 
(S)-2-(4-Fluorobenzoyl)pyrrolidine 
Using procedures given in J. Chem. Soc. Perkin Trans. I, 1987, 1469, 
(S)-1-ethoxycarbonylproline is reacted with diphenylphosphinoyl chloride 
in the presence of triethylamine to form the mixed anhydride. The mixed 
anhydride is treated with 4-fluorophenylmagnesium bromide to obtain 
(S)-1-ethoxycarbonyl-2-(4-fluorobenzoyl)pyrrolidine. Hydrolysis with 
methanotic potassium hydroxide gives the title compound. 
PREATION 25 
2-(4-Fluorobenzoyl)-1-(3-phenoxypropyl)pyrrolidine 
Following the procedure for the preparation of 
1-benzyl-3-benzoylpyrrolidine (U.S. Pat. No. 3,479,370) the title compound 
is prepared from 2-cyano-1-(3-phenoxypropyl)pyrrolidine and 
4-fluorophenylmagnesium bromide. 
PREATION 26 
2(4-Fluorobenzoyl)-1-(3-phenoxypropyl)piperidine 
Following the same procedure as Preparation 25, the title compound is 
prepared from 2-cyano-1-(3-phenoxypropyl)piperidine and 
4-fluorophenylmagnesium bromide. 
PREATION 27 
3-(4-Fluorobenzoyl)-1-(2-naphthalenylmethyl)azetidine 
Following the procedure of Preparation 9, the title compound is prepared 
from 2-bromomethylnaphthalene and 3-(4-fluorobenzoyl)azetidine. 
PREATION 28 
2-(4-Fluorobenzoyl)-1-(3-phenoxypropyl)azetidine 
Following the procedure of Preparation 9, the title compound is obtained 
from 2-(4-fluorobenzoyl)azetidine and 3-phenoxypropyl bromide. 
PREATION 29 
.alpha.,.beta.-(Benzoyloxy)-4-[(4-fluorophenyl)[(4-fluorophenyl)amino]methy 
l]-oxo-1-piperidinebutanoic acid hemihydrate 
A solution of N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamine (5.0 g, 
0.017 mol) in 50 mL of warm dioxane (previously dried over basic alumina) 
was added to a solution of dibenzoyl-L-tartaric anhydride (5.78 g, 0.017 
mol) in dried dioxane (50 mL). The reaction was heated to 70.degree. C. 
for 2 h. At that time TLC analysis (EtOAc:MeOH:NH.sub.4 OH, 7:2:1) 
indicated the reaction was complete. The dioxane was evaporated thoroughly 
and the crystalline residue dissolved in hot isopropyl alcohol (30 mL) and 
allowed to cool. The crystals which precipitated upon cooling were 
collected and recrystallized again from hot isopropyl alcohol (25 mL). 
After cooling the solid was collected and dried to obtain 1.24 g (11.4% 
yield), mp 147.degree.-150.degree. C., [.alpha.].sub.D =-61.6 (C=1, MeOH). 
Analysis calc'd for: C.sub.36 H.sub.32 N.sub.2 O7F.sub.2.O.sub.7 
F.sub.2.0.5H.sub.2 O: C, 66.35; H, 5.10; N, 4.30. Found: C, 66.24; H, 
4.94; N, 4.24. 
PREATION 30 
(+)-.alpha.,.beta.-Bis(benzoyloxy)-4-[(4-fluorophenyl)[(4-fluorophenyl)[(4- 
fluorophenyl)amino]methyl]-gamma-oxo-1-piperidinebutanoic acid hemihydrate 
A solution of N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamine (8.33 
g, 0.028 mol) in warm dry dioxane (50 mL) was combined with a solution of 
dibenzoyl-D-tartaric anhydride (9.38 g, 0.028 mol) in dioxane (50 mL). The 
reaction stirred at room temperature overnight. At that time TLC analysis 
(EtOAe: MeOH:NH.sub.4 OH 7:2:1) indicated the reaction was complete. The 
solvent was evaporated thoroughly and the crystalline residue was 
dissolved in hot isopropyl alcohol (180 mL) and allowed to cool slowly. 
Crystals precipitated upon cooling and were collected and dried then 
recrystallized again from isopropyl alcohol (50 mL). The crystals obtained 
after cooling were collected, rinsed with cold isopropyl alcohol and dried 
(3.0 g, 16.7%), mp 147.degree.-150.degree. C., [.alpha.].sub.D.sup.22 
=+61.5 (C=1, MeOH). 
Analysis calc'd for: C.sub.36 H.sub.32 N.sub.2 O.sub.7 F.sub.2.0.5H.sub.2 
O: C, 66.35; H, 5.10; N, 4.30. Found: C, 66.49; H, 4.90; N, 4.33. 
PREATION 31 
(4-Fluorophenyl)[1-(2-naphthalenylmethyl)-4-piperidinyl]methanone 
A mixture of 15.1 g (0.062 mol) 4-(4-fluorobenzoyl)piperidine 
hydrochloride, 13.77 g (0.062 mol) of 2-(bromomethyl)naphthalene and 13.6 
g (0.16 mol) of sodium bicarbonate in 500 mL of absolute ethanol was 
stirred at room temperature for 16 hr. The solvent was partitioned between 
CH.sub.2 Cl.sub.2 and dilute NaOH. The CH.sub.2 Cl.sub.2 solution was 
dried (Na.sub.2 SO.sub.4), and the solvent was removed in vacuo. The 
residue was recrystallized from 400 mL of methanol to give 11.81 g (54.9%) 
of white crystalline solid, mp 131.degree.-134.degree. C. The filtrate was 
subjected to flash chromatography (silica gel, gradiently eluted with 
CH.sub.3 OH/CH.sub.2 Cl.sub.2) to give an additional 2.84 g (13.2%) of the 
title compound. 
Analysis calculated for: C.sub.23 H.sub.22 NOF: C, 79.51; H, 6.38; N, 4.03. 
Found: C, 79.50; H, 6.38; N, 4.08. 
PREATION 32 
Following the procedure of Preparation 31 using 2-(bromomethyl)naphthalene 
and 
a. 4-benzoylpiperidine 
b. 4-(4-trifluoromethylbenzoyl)piperidine 
c. 4-(4-methoxybenzoyl)piperidine 
there are obtained respectively: 
a. 4-benzoyl-1-(2-naphthalenylmethyl)piperidine 
b. 1-(2-naphthalenylmethyl)-4-(4-trifluoromethylbenzoyl)piperidine 
c. 4-(4-methoxybenzoyl)-1-(2-naphthalenylmethyl)piperidine. 
PREATION 33 
1-Chloro-4-[(3-chloropropyl)sulfinyl]benzene 
To a stirred solution of 206.76 g (0.44 mol) of 
1-chloro-4-[(3-chloropropyl)thio]benzene (J.A.C.S. 82, 2505, 1960) and 
111.50 g of 30% H.sub.2 O.sub.2 (0.98 mol) in 1 L of acetone chilled in a 
dry ice acetone bath was added 90 mL of concentrated sulfuric acid. The 
ice bath was removed and the mixture stirred at ambient temperature for 16 
hr. The mixture was diluted with 1 L of water and extracted with two 500 
mL portions of CH.sub.2 Cl.sub.2. The extracts were dried (MgSO.sub.4) and 
concentrated separately and the residual material from both extractions 
shown to be a mixture of product and starting material. The impure product 
was chromatographed on Florisil (4.times.75 cm) using petroleum 
ether-chloroform for elution. The yield was 50.36 g. 
PREATION 34 
1-Chloro-4-[(3-chloropropyl)sulfonyl]benzene 
To a stirred solution of 58.50 g (0.266 mol) of 
1-chloro-4-[(3-chloropropyl)thio]benzene in 125 mL of glacial acetic acid 
cooled in an ice bath was added 69 g of 30% H.sub.2 O.sub.2 (0.609 mol). 
The mixture was stirred for 0.5 hr at ice bath temperature and then 
stirred at ambient temperature for 24 hr. The mixture was then heated at 
80.degree. C. for 20 hr. The reaction mixture was generated by addition of 
water (300 mL) and chloroform (300 mL). The mixture was stirred for 10 
minutes and the phases separated. The organic layer was washed with an 
aqueous solution of sodium sulfite and then with aqueous 1M NaOH solution. 
The organic solution was dried (MgSO.sub.4) and concentrated to give a 
white solid. The solid was recrystallized from chloroform-ether at freezer 
temperature to obtain 57.74 g (86%), mp 72.5-73.5. The filtrate was 
concentrated to an oil which was triturated with ether and chilled in a 
freezer to obtain a second crop of 4.53 g (6.8%), mp 69.degree.-72.degree. 
C. The total yield was 62.27 g (92.8%). 
PREATION 35 
4-(3,4-Difluorobenzoyl)piperidine 
Following the procedure for the preparation of 
1-acetyl-4(4-fluorobenzoyl)piperidine (U.S. Pat. No. 3,576,810), 
1-acetyl-4(3,4-difluorobenzoyl)piperidine is prepared from 
1-acetylisonipecotic acid chloride and 1,2-difluorobenzene. The acetyl 
group is removed by hydrolysis in dilute hydrochloric acid. Basification 
followed by extraction with a suitable solvent yields the title compound. 
PREATION 36 
4-(4-Trifluoromethylbenzoyl)piperidine 
The title compound is prepared from 1-acetyl-4-cyanopiperidine and 
4-trifluoromethylphenylmagnesium bromide according to the procedure given 
for 4-(3-trifluoromethylbenzoyl)piperidine in J. Med. Chem. 13, 1-6 
(1970). 
PREATION 37 
4-(3,4-Difluorobenzoyl)-1-(2-naphthalenylmethyl)piperidine 
Following the procedure of Example 31, the title compound is obtained from 
4-(3,4-difluorobenzoyl)piperidine and 2-bromomethylnaphthalene. 
PREATION 38 
2-(4-Fluorobenzoyl)-1-(3-phenoxypropyl)pyrrolidine 
2-Cyano-1-(3-phenoxypropyl)pyrrolidine is reacted with 
4-fluorophenylmagnesium bromide according to the usual procedures to 
obtain the title compound. 
PREATION 39 
2-(4-Fluorobenzoyl)-1-(3-phenoxypropyl)piperidine 
The title compound is obtained from a reaction of 4-fluorophenylmagnesium 
bromide with 2-cyano-1-(3-phenoxypropyl)piperidine. 
PREATION 40 
(3,4-Dichlorophenyl)(1-acetylpiperidin-4-yl)methanone 
To a slurry of 53.2 g (0.4 mol) of aluminum chloride in 80 mL of 
diclorobenzene was added portionwise 38.0 g (0.2 mol) of 
N-acetylisonipecotic acid chloride (by closed addition method) so as to 
maintain at 5.degree.-10.degree.. During the addition a total of 50 mL of 
methylene chloride was added as needed. After the addition was complete 
the mixture was allowed to come to room temperature and stirred for two 
days. The mixture was poured onto an excess of crushed ice. The aqueous 
mixture was extracted several times with chloroform. The collected 
extracts were dried over anhydrous sodium sulfate and the mixture was 
filtered. The filtrate was concentrated under reduced pressure and the 
residue was triturated in isopropyl ether. The residue crystallized and 22 
g (36.5%) of crude product was obtained. A 5-g sample was recrystallized 
from acetone-water after treatment with charcoal. After air-drying the 
off-white solid was recrystallized from isopropyl ether-methanol, mp 
134.degree.-136.degree.. 
Analysis calculated for: C.sub.14 H.sub.15 Cl.sub.2 NO.sub.2 : C, 56.01; H, 
5.04; N, 4.67. Found: C, 55.83; H, 5.03; N, 4.62. 
PREATION 41 
(3,4-Dichlorophenyl)(4-piperidinyl)methanone hydrochloride hemihydrate 
A slurry of 15 g (0.05 mol) of 1-acetyl-4-(3,4-dichlorobenzoyl)piperidine 
in 150 mL of 6N hydrochloric acid was heated at mild reflux for 23 hr. The 
mixture was cooled and neutralized using 50% sodium hydroxide solution and 
ice. The mixture was extracted several times with benzene and the 
collected extracts were dried over anhydrous sodium sulfate. The mixture 
was filtered and the filtrate was concentrated under reduced pressure. The 
residue obtained weighed 11.1 g (86%). The hydrochloride salt was made in 
the usual manner on 5 g of the free base. Recrystallization from isopropyl 
alcohol-ether gave a crystalline solid, mp 221-223. 
Analysis calculated for: C.sub.24 H.sub.30 Cl.sub.6 N.sub.2 O.sub.3 : C, 
47.62; H, 5.00; N, 4.62. Found: C, 47.46; H, 4.86; N, 4.58. 
PREATION 42 
2-(3-Chloropropyloxy)naphthalene 
A mixture of 2-naphthol (72.07 g, 0.5 mol), 1-chloro-3-bromopropane (78.72 
g, 0.5 mol), and potassium carbonate (103.65 g, 0.75 mol) was heated at 
reflux 16 hr in 750 mL of acetone. The mixture was cooled to room 
temperature and filtered. The reaction was concentrated to a viscous oil 
using a rotary evaporator. The oil was dissolved in chloroform and washed 
with 5% sodium hydroxide and water. The chloroform was dried (Na.sub.2 
SO.sub.4) and filtered. Chloroform was removed to give a brown solid. A 
ten-gram sample was subjected to flash chromatography on silica gel using 
2% ethyl acetate-hexanes, 3% ethylacetate-hexanes, 5% ethyl 
acetate-hexanes, and 10% ethyl acetate-hexanes for elution. Fractions of 
similar purity were combined and solvents removed. A clear oil was 
obtained and dried 16 hr at 80.degree. C. A white crystalline solid was 
formed on standing at room temperature. This procedure provided 7.01 g 
(52.2%) of white crystalline solid, mp 46.degree.-49.degree. C. 
Analysis calculated for: C.sub.13 H.sub.13 OCl: C, 70.75; H, 5.74. Found: 
C, 70.79; H, 5.89. 
PREATION 43 
3-(4-Fluorobenzoyl)pyrrolidine 
1-Benzyl-3-(4-fluorobenzoyl)pyrrolidine is prepared by reacting 
1-benzyl-3-cyanopyrrolidine with 4-fluorophenylmagnesium bromide by well 
known procedures. Removal of the benzyl group by catalytic debenzylation 
gives the title compound. 
PREATION 44 
3-(4-Fluorobenzoyl)piperidine 
Reaction of 1-acetylnipecotoyl chloride with fluorobenzene by the 
procedures used to prepare the compound of Preparation 1 gives the title 
compound. 
PREATION 45 
.alpha.-(4-Fluorophenyl)-N-(phenylmethyl)-1-(phenylsulfonyl)-4-piperidineme 
thanimine 
A mixture of 10.32 g (0.0297 mol) of 
N-benzenesulfonyl-4-(p-fluorobenzoyl)piperidine, 5.4 g (0.0505 mol) of 
benzylamine and 0.5 g (0.0032 mol) of benzenesulfonic acid in 500 mL of 
toluene was heated at reflux. Water was removed from the reaction mixture 
with a Dean-Stark trap. After 134.5 h, the solvent was removed in vacuo, 
and the residue was partitioned between CH.sub.2 Cl.sub.2 and dilute NaOH. 
The CH.sub.2 Cl.sub.2 solution was dried (MgSO.sub.4), the volume was 
reduced to 100 mL, and 200 mL of ether was added. A precipitate was 
collected to give 10.0 g (77.1%) of the title compound as a white 
crystalline solid, mp 153.degree.-155.degree.C. 
Analysis calculated for: C.sub.25 H.sub.25 N.sub.2 SO.sub.2 F: C, 68.78; H, 
5.77; N, 6.42. Found: C, 68.63; H, 5.76; N, 6.39. 
EXAMPLE 1 
N,.alpha.-Bis(4-fluorophenyl)-4-piperidinemethanamine (E)-2-butendioate 
(1:1) hemihydrate 
A mixture of 31.6 g (0.072 mol) of 
N,.alpha.-bis(4-fluorophenyl)-1-(phenylsulfonyl)-4-piperidinemethanamine 
and 32 g (0.34 mol) of phenol in 200 mL 48% HBr was heated at reflux for 2 
hr and then was poured over ice. The mixture was made basic with 50% NaOH, 
and the basic mixture was extracted with CH.sub.2 Cl.sub.2. The CH.sub.2 
Cl.sub.2 solution was dried (Na.sub.2 SO.sub.4), and the solvent was 
removed in vacuo to give a gum. This was subjected to flash chromatography 
(silica gel, eluted with 5% NH.sub.4 OH in CH.sub.3 OH) to give 6.81 g 
(28.7%) of the desired product as the nonsalt form. This was converted to 
the fumarate salt, and the salt was recrystallized from methanol/ether to 
give 5.59 g (18%) of the title compound as a white crystalline solid, mp 
136.degree.-141.degree. C. 
Analysis calculated for: C.sub.22 H.sub.25 N.sub.2 F.sub.2 O.sub.4.5 : C, 
61.82; H, 5.90; N, 6.55. Found: C, 62.13; H, 5.72; N, 6.48. 
EXAMPLE 2 
1-[4-[3-[4-[(4-Fluorophenyl)[4-fluorophenyl)amino]methyl]-1-piperidinyl]pro 
poxy]-3-methoxyphenyl]ethanone hemihydrate 
A mixture of 3.22 g (10.8 mmol) of 
N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamine, 2.90 g (12.0 mmol) 
of 3-chloro-1-(4-acetyl-2-methoxyphenoxy) propane, and 2.90 g (35 mmol) of 
sodium bicarbonate in 400 mL of 1-butanol was heated at reflux for 17.5 h. 
The solvent was removed in vacuo, and the residue was partitioned between 
CH.sub.2 Cl.sub.2 and diluted NaOH. The CH.sub.2 Cl.sub.2 solution was 
dried (Na.sub.2 SO.sub.4), and the solvent was removed in vacuo to give an 
oil. This was subjected to flash chromatography by (silica gel, eluted 
gradiently with 1% to 5% CH.sub.3 OH in CH.sub.2 Cl.sub.2) to give 3.53 g 
(63.1%) of the title compound as a noncrystalline solid. 
Analysis calculated for: C.sub.30 H.sub.35 N.sub.2 O.sub.3.5 : C, 69.61; H, 
6.82; N, 5.41. Found: C, 69.88; H, 6.67; N, 5.43. 
EXAMPLE 3 
4-[(4-Fluorophenyl)[(4-fluorophenyl)amino]methyl]-1,1-bis(3-phenyl-2-propen 
yl)piperidinium chloride 
A mixture of 34.41 g (11.3 mmol) of 
N-.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamine, 1.85 g (12.1 mmol) 
of cinnamyl chloride and 2.00 g (19 mmol) of sodium carbonate in 300 mL of 
acetonitrile was stirred at room temp overnight. The solvent was removed 
in vacuo, and the residue was partitioned between CH.sub.2 Cl.sub.2 and 
dilute NaOH. The residue was recrystallized from CH.sub.2 Cl.sub.2 /hexane 
to give 1.25 g (19.4%) of a white crystalline solid, mp 
215.degree.-216.degree. C. 
Analysis calculated for: C.sub.36 H.sub.37 N.sub.2 F.sub.2 Cl: C, 75.71; H, 
6.53; N, 4.91. Found: C, 75.07; H, 6.48; N, 4.85. 
EXAMPLE 4 
N,.alpha.-Bis(4-fluorophenyl)-1-(1-methylethyl)-4-piperidinemethanamine 
dihydrochloride monohydrate 
A mixture of 29.36 g (0.103 mol) of 
(4-fluorophenyl)[1-(1-methylethyl)-4-piperidinyl]methanone hydrochloride, 
28.9 g (0.260 mol) of 4-fluoroaniline and 0.61 g (3.9 mmol) of 
benzenesulfonic acid in 500 mL of xylene was heated at reflux for 20 h. 
Water was removed with a Dean-Stark trap. The solvent was removed in 
vacuo. The residue was reacted with 6.0 g (0.16 mol) of LiAlH.sub.4 in 400 
mL of THF at room temperature. After 23 h, dilute NaOH and then water were 
added slowly. The mixture was filtered through Celite.RTM., and CH.sub.2 
Cl.sub.2 (400 mL) was added to the filtrate. The mixture was extracted 
with several portions of water and was dried (Na.sub.2 SO.sub.4). The 
solvent was removed in vacuo. The residue was dissolved in CH.sub.3 OH and 
treated with an excess of ethereal HCl. The hydrochloride salt was 
collected to give 13.8 g (32.1%) of the title compound as a white solid, 
mp 225.degree.-228.degree. C. An additional 4.58 g (10.2%) of product was 
collected from the filtrate. 
Analysis calculated for: C.sub.21 H.sub.30 N.sub.2 F.sub.2 Cl.sub.2 O: C, 
57.93; H, 6.95; N, 6.43. Found: C, 57.96; H, 6.91; N, 6.41. 
EXAMPLE 5 
N,.alpha.-bis(4-fluorophenyl)-1-(3-phenyl-2-propenyl)-4-piperidinemethanami 
ne dihydrochloride hemihydrate 
A mixture of 3.41 g (11.3 mmol) of the 
N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamine, 1.85 g (12.1 mmol) 
of cinnamyl chloride, and 2.00 g (19.0 mmol) of sodium carbonate in 300 mL 
of acetonitrile was stirred at room temperature overnight. The solvent was 
removed in vacuo, and the residue was partitioned between CH.sub.2 
Cl.sub.2 and dilute NaOH. An insoluble residue was removed by filtration. 
The CH.sub.2 Cl.sub.2 solution was subjected to flash chromatography 
(silica gel, eluted with 3% CH.sub.3 OH in CH.sub.2 Cl.sub.2) to give an 
oil. This was converted to the HCl salt, and the salt was recrystallized 
from CH.sub.3 OH/ether to give 1.83 g (32.7%) as a white crystalline 
solid, mp 239.degree.-241.degree. C. 
Analysis calculated for: C.sub.27 H.sub.31 N.sub.2 F.sub.2 Cl.sub.2 
O.sub.0.5 : C, 65.80; H, 6.24; N, 5.60. Found: C, 65.14; H, 6.13; N, 5.68. 
EXAMPLE 6 
4-[(4-Fluorophenyl)[(4-fluorophenyl)amino]methyl]-.alpha.-(phenoxymethyl)-1 
-piperidineethanol dihydrochloride hemihydrate 
A mixture of 3.41 g (11.3 mmol) of the 
N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamine and 2.20 g (14.7 
mmol) of 1,2-epoxy-3-phenoxypropane in 400 mL of acetonitrile was heated 
at reflux for 46 h. The solvent was removed in vacuo, and the residue was 
subjected to flash chromatography (silica gel, eluted with 3% CH.sub.3 OH 
in CH.sub.2 Cl.sub.2) to give an oil. This was converted to the HCl salt, 
and the salt was recrystallized from CH.sub.3 OH-ether to give give 3.20 g 
(53%) of a crystalline white solid, mp 229.degree.-232.degree. C. 
Analysis calculated for: C.sub.27 H.sub.30 N.sub.2 O.sub.2.2HCl.0.5H.sub.2 
O: C, 0.68; H, 6.22; N, 5.24. Found: C, 60.49; H, 6.15; N, 5.20. 
EXAMPLE 7 
4-[(4-Fluorophenyl)[(4-fluorophenyl)amino]methyl]-.alpha.-(phenoxymethyl)-1 
-piperidineethanol dihydrochloride hemihydrate 
In the preparation of the compound of Example 6, an additional crop of 
material was obtained from the mother liquers to give 0.53 g (8.8%) of 
white crystalline solid which was shown by .sup.13 C NMR to be a 
diastereomer of the compound of Example 6, mp 212.degree.-216.degree. C. 
Analysis calculated for: C.sub.27 H.sub.30 N.sub.2 O.2HCl.0.5H.sub.2 O: C, 
60.68; H, 6.22; N, 5.24. Found: C, 60.49; H, 6.15; N, 5.20. 
EXAMPLE 8 
N,.alpha.-bis(4-Fluorophenyl)-1-(3-phenoxypropyl)-4-piperidinemethanamine 
dihydrochloride hemihydrate 
A mixture of 3.92 g (10.5 mmol) of 
N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamine hydrochloride 
hydrate, 2.77 g (13.0 mmol) of 3-phenoxy propyl bromide, 3.80 g (36.0 
mmol) of sodium carbonate, and 0.61 g (3.7 mmol) of KI in 400 mL of 
1-butanol was heated at reflux for 69 h. The solvent was removed in vacuo, 
and the residue was partitioned between CH.sub.2 Cl.sub.2 and dilute NaOH. 
The CH.sub.2 Cl.sub.2 solution was dried (Na.sub.2 SO.sub.4), and the 
solvent was removed in vacuo. The residue was subjected to flash column 
chromatography (silica gel, elution with 1 to 3% CH.sub.3 OH in CH.sub.2 
Cl.sub.2) to give the free base of the title compound. This was converted 
to the HCl salt, and the salt was recrystallized from CH.sub.3 OH/ether to 
give 3.59 g (65.9%) of the title compound as a white crystalline solid, mp 
222.degree.-226.degree. C. 
Analysis calculated for: C.sub.27 H.sub.33 N.sub.2 O.sub.1.5 F.sub.2 
Cl.sub.2 : C, 62.55; H, 6.42; N, 5.40. Found: C, 62.18; H, 6.26; N, 5.39. 
EXAMPLE 9 
4-[(4-Fluorophenyl)[(4-fluorophenyl)amino]methyl]-N-methyl-1-piperidinecarb 
oxamide 
A mixture of 1.91 g (6.25 mmol) of the 
N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamine and 0.45 g (7.9 
mmol) of methyl isocyanate in 300 mL of CH.sub.2 Cl.sub.2 was stirred at 
room temperature overnight. The solvent was removed in vacuo, and the 
residue was subjected to flash column chromatography (silica gel, 
gradiently eluted with 1 to 4% CH.sub.3 OH in CH.sub.2 Cl.sub.2) to give 
1.54 g (68.6%) of white solid, mp 86.degree.-90.degree. C. 
Analysis calculated for: C.sub.20 H.sub.23 N.sub.3 OF.sub.2 : C, 66.84; H, 
6.45; N, 11.69. Found: C, 66.63; H, 6.49; N, 11.73. 
EXAMPLE 10 
4-[(4-Fluorophenyl)[(4-fluorophenyl)amino]methyl]-N-phenyl-1-piperidine 
carboxamide 
A solution of 2.20 g (7.28 mmol) of N,.alpha.-bis(4-piperidinemethanamine 
and 0.88 g (7.40 mmol) of phenyl isocyanate in 300 mL of CH.sub.2 Cl.sub.2 
was stirred at room temperature for 16 h. The solution was extracted with 
dilute NaOH and was dried (Na.sub.2 SO.sub.4). The solvent was removed in 
vacuo. The residue was subjected to flash chromatography (silica gel, 
elution witgh 1% CH.sub.3 OH in CH.sub.2 Cl.sub.2), which gave 2.71 g 
(88.3%) of the title compound as a white crystalline solid, mp 
96.degree.-101.degree. C. 
Analysis calculated for: C.sub.25 H.sub.25 N.sub.3 OF.sub.2 : C, 71.24; H, 
5.98; N, 9.976. Found: C, 70.98; H, 5.92; N, 9.95. 
EXAMPLE 11 
N,.alpha.-Bis(4-fluorophenyl)-1-(4-phenylbutyl)-4-piperidinemethanamine 
dihydrochloride 
A mixture of 2.10 g (5.6 mmol) of 
N,.alpha.-bis(4-fluorophenyl)4-piperidinemethanamine hydrochloride 
hydrate, 1.0 g (6.0 mmol) of 4-chlorobutylbenzene and 2.20 g (20.8 mmol) 
of sodium bicarbonate in 300 mL of 1-butanol was heated at reflux for 16 
h. The solvent was removed in vacuo, and the residue was partitioned 
between CH.sub.2 Cl.sub.2 and dilute NaOH. The CH.sub.2 Cl.sub.2 solution 
was dried (Na.sub.2 SO.sub.4), and the solvent was removed in vacuo to 
give an oil. This was subjected to flash chromatography (silica gel, 
eluted with 4%, CH.sub.3 OH in CH.sub.2 Cl.sub.2) to give 2.0 g of an oil. 
This was converted to the HCl salt, and the salt was recrystallized from 
CH.sub.3 OH/ether to give 1.55 g (54.4%) of the title compound as a white 
crystalline salt, mp 243.degree.-246.degree. C. 
Analysis calculated for: C.sub.28 H.sub.32 N.sub.2 F.sub.2.2HCl: C, 66.27; 
H, 6.75; N, 5.52. Found: C, 65.94; H, 6.95; H, 5.50. 
EXAMPLE 12 
N-[[1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-4-piperidinyl](4-fluorophenyl)m 
ethyl]-N-(4-fluorophenyl)acetamide ethanedioate hydrate (2:2:1) 
A solution of 4.51 g (8.9 mmol) of 
1-[4-[3-[(4-fluorophenyl)[(4-fluorophenyl)amino]methyl]-1-piperidinyl]prop 
oxy]-3-methoxyphenyl]ethanone hemihydrate, 1.0 g (13 mmol) of acetyl 
chloride and 2.0 g (20 mmol) of triethylamine in 250 mL of methylene 
chloride was stirred at room temperature for 5 days. The solvent was 
removed in vacuo, and a NMR analysis of the residue indicated that 
approximately a 60/40 mixture of the product and starting material was 
present. The material was dissolved in 150 mL of CH.sub.2 Cl.sub.2, 1.0 g 
(12.8 mmol) of acetyl chloride and 0.89 g (8.8 mmol) of triethylamine were 
added, and the mixture was stirred at room temperature for an additional 5 
days. The mixture was poured over ice, and the resulting aqueous mixture 
was made basic with dilute NaOH. the phases were separated, and the 
CH.sub.2 Cl.sub.2 phase was extracted with dilute NaOH. The organic phase 
was chilled (Na.sub. 2 SO.sub.4), and the solvent was removed in vacuo. 
The residue was subjected to flash chromatography (silica gel, eluted with 
2-4% CH.sub.3 OH in CH.sub.2 Cl.sub.2) to give the free base of the 
product. This was converted to the oxalate salt, and the salt was 
recrystallized from CH.sub.3 OH/diethyl ether to give 1.02 g (17.6%) of 
the title compound as a white, crystalline solid, mp 166.5-167.5 dec. 
Analysis calculated for: C.sub.32 H.sub.36 N.sub.2 O.sub.4.C.sub.2 
O.sub.4.0.5H.sub.2 O: C, 62.86; H, 6.05; H, 4.31. Found: C, 63.22; H, 
5.88; N, 4.09. 
EXAMPLE 13 
1-[3-[4-(1,1-Dimethylethyl)phenoxy]propyl]-N,.alpha.,bis(4-fluorophenyl)-4- 
piperidinemethanamine hemihydrate 
A mixture of 2.49 g (0.011 mol) of 1-(p-t-butylphenoxy)-3-chloropropane, 
3.10 g (0.0103 mol) of 
N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamine, 2.0 g (0.019 mol) 
of sodium carbonate, and 0.5 g (0.003 mol) of potassium iodide in 400 mL 
of 1-butanol was heated at reflux for 29 h. The solvent was removed in 
vacuo, and the residue was partitioned between CH.sub.2 Cl.sub.2 and 
dilute NaOH. The organic phase was dried (Na.sub.2 SO.sub.4), and solvent 
was removed in vacuo to give an oil. The oil was subjected to flash 
chromatography (silica gel, eluted with 1-3% CH.sub.3 OH in CH.sub.2 
Cl.sub.2) to give 2.79 g (55%) of the title compound as an oil. 
Analysis calculated for: C.sub.31 H.sub.38 N.sub.2 OF.sub.2.0.5H.sub.2 O: 
C, 64.80; H, 7.19; N, 4.88. Found: C, 65.02; H, 7.12; N, 4.91. 
EXAMPLE 14 
4-[3-[4-[(4-Fluorophenyl)amino]methyl]-1-piperidinyl]propoxy]benzoic acid 
1,1-dimethylethyl ester hemihydrate 
A mixture of the N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamine 
(6.70 g, 0.022 mol), 4-(3-chloropropoxy)benzoic acid 1,1-dimethylethyl 
ester (5.99 g, 0.022 mol), and potassium carbonate (5.53 g, 0.04 mol) was 
heated 16 h at reflux in 400 mL of 1-butanol containing sodium iodide (0.2 
g). The mixture was concentrated to dryness and partitioned between 
chloroform and water. The chloroform layer was dried (Na.sub.2 SO.sub.4) 
and filtered, and the solvent was removed to obtain a dark brown oil. This 
oil was dissolved in methylene chloride and placed on top of a silica gel 
column. Flash chromatography was carried out using 10% acetone-methylene 
chloride, 20% acetone-methylene chloride, and 50% acetone-methylene 
chloride for elution. Fractions of similar purity were combined, and 
solvents removed to give an oil. This oil was dried in vacuo 16 h at 
100.degree. C. This entire process furnished 7.17 g (59.7%) of the title 
compound as a glass-like material. 
Analysis calculated for: C.sub.32 H.sub.38 N.sub.2 O.sub.3 
F.sub.2.0.5H.sub.2 O: C, 70.44; H, 7.20; N, 5.13. Found: C, 70.84, H, 
7.13, N, 5.19. 
EXAMPLE 15 
N,.alpha.-Bis(4-fluorophenyl)-1-(2-naphthalenylmethyl)-4-piperidinemethanam 
ine 
A mixture of N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamine (6.47 g, 
0.0214 mol), 2-(bromomethyl)naphthalene (4.74 g, 0.0214 mol), and 
potassium carbonate (4.84 g, 0.035 mol) was heated 16 h at reflux in 400 
mL of 1-butanol containing sodium iodide (0.2 g). The reaction mixture was 
concentrated to dryness. The residue was partitioned with 5% sodium 
hydroxide. The chloroform layer was dried (Na.sub.2 SO.sub.4), filtered, 
and concentrated to give a dark brown oil. The oil was dissolved in 
methylene chloride and subjected to flash chromatography. Elution was 
accomplished using methylene chloride, 1% acetone-methylene chloride, 2% 
acetone-methylene chloride, 5% acetone-methylene chloride, and 10% 
acetone-methylene chloride. Fractions of similar purity were combined, and 
solvents were removed to give a viscous gum. This material was dried in 
vacuo 16 h at 100.degree. C. in the presence of phosphorus pentoxide. This 
procedure provided 3.40 g (36%) of white glass-like material. 
Analysis calculated for: C.sub.29 H.sub.28 N.sub.2 F.sub.2 : C, 78.71; H, 
6.38; N, 6.33. Found: C, 78.64; H, 6.54; N, 6.38. 
EXAMPLE 16 
N-[2-(Diethylamino)ethyl]-4-[(4-fluorophenyl)[(4-fluorophenyl)amino]methyl] 
-1-piperidinecarboxamide hemihydrate 
A solution of N,N-diethylethylenediamine (1.63 g, 0.014 mol) and 
1,1'-carbonyldiimidazole (2.43 g, 0.015 mol) in 100 mL of tetrahydrofuran 
was stirred at room temperature under nitrogen for 2 h. A solution of 
N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamine (3.76 g, 0.01245 
mol) was added. The resulting solution was heated at reflux 16 h under 
nitrogen. The solution was cooled to room temperature and concentrated to 
dryness. The brown residue obtained was dissolved in methylene chloride. 
The methylene chloride layer was extracted with water, dried (Na.sub.2 
SO.sub.4), and filtered. The methylene chloride was removed with a rotary 
evaporator to give a dark brown oil (5.63 g). This material was dissolved 
in methylene chloride and placed on a silica gel column for flash 
chromatography. The column was eluted with 20% methanol-ethyl acetate, 50% 
methanol-ethyl acetate, and methanol. Fractions of similar purity were 
combined and solvents removed to give a dark brown oil. This material was 
dried for 16 h at 100.degree. C. in the presence of phosphorus pentoxide. 
The procedure provided 4.21 g (74.2%) of a dark brown glass. 
Analysis calculated for: C.sub.25 H.sub.34 N.sub.4 OF.sub.2.0.5H.sub.2 O: 
C, 66.20; H, 7.78; N, 12.32. Found: C, 65.99; H, 7.81; N, 12.49. 
EXAMPLE 17 
N-.alpha.-Bis(4-fluorophenyl)-1-(2-pyrimidinyl)-4-piperidinemethanamine 
A mixture of N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamine (4.76 g, 
0.0157 mol), 2-chloropyrimidine (1.80 g, 0.01576 mol), and sodium 
bicarbonate was heated at reflux for 72 h in 200 mL of ethanol (200). The 
solvent was removed with a rotary evaporator, and the residue obtained was 
dissolved in methylene chloride. The methylene chloride layer was 
extracted with water and 5% sodium hydroxide. The methylene chloride was 
dried (Na.sub.2 SO.sub.4) and filtered, and the solvent removed to give a 
fluffy brownish-gray residue. This material was dissolved in methylene 
chloride and subjected to flash chromatography on silica gel using 
methylene chloride, 1% acetone-methylene chloride, 2% acetone-methylene 
chloride, 5% acetone-methylene chloride, and 10% acetone-methylene 
chloride for elution. Fractions of similar purity were combined and 
solvents removed to give a light yellow oil. This material was dried 16 h 
at 100.degree. C. in vacuo in the presence of phosphorus pentoxide. This 
process provided 4.07 g (67.9%) of light yellow oil shown to contain 0.25 
mole of water. 
Analysis calculated for C.sub.22 N.sub.22 N.sub.4 F.sub.2.0.25H.sub.2 O: C, 
68.64; H, 5.89; N, 14.55. Found: C, 68.95; H, 5.82; N, 14.53. 
EXAMPLE 18 
N,.alpha.-Bis(4-fluorophenyl)-1-(2-quinolinylmethyl)-4-piperidinemethanamin 
e ethanedioate hydrate (2:2:1) 
A mixture of N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamine (4.23 g, 
0.014 mol), 2-(chloromethyl)quinoline monohydrochloride (3.00 g, 0.014 
mol), and sodium bicarbonate (2.42 g, 0.029 mol) was stirred 32 h at room 
temperature in 350 mL of ethanol (200). The reaction was concentrated to 
dryness, and the residue obtained was dissolved in chloroform. The 
chloroform layer was extracted with water. The chloroform layer was dried 
(Na.sub.2 SO.sub.4) and filtered. When the chloroform was removed by 
rotary evaporator, a dark brown oil was obtained. This oil was dissolved 
in methylene chloride and subjected to flash chromatography on silica gel. 
Elution was accomplished using methylene chloride, 1% methanol-methylene 
chloride, and 2% methanol-methylene chloride. Fractions of similar purity 
were combined, and the solvents were removed to give a brown oil. Attempts 
to prepare a crystalline HCl salt gave a substance which was extremely 
hydroscopic. This material was converted to the free base and subjected 
again to flash chromatography using the same solvent systems for elution. 
A brown oil was obtained and converted to the oxalate salt in 
methanol-diethyl ether. A white solid was isolated and dried in vacuo 16 h 
at 100.degree. C. This process furnished 1.36 g (17.9%) of white 
crystalline solid, mp 180.degree.-182.degree. C. 
Analysis calculated for C.sub.20 H.sub.27 N.sub.3 OF.sub.2.C.sub.2 H.sub.2 
O.sub.4.0.5H.sub.2 O: C, 66.41; H, 5.57; N, 7.74. Found: C, 66.77; H, 
5.40; N, 7.70. 
EXAMPLE 19 
1-Benzoyl-N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamine 
A solution of N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamine (3.21 
g, 0.0106 mol), triethylamine (2.5 g, 0.025 mol), and benzoyl chloride 
(1.70 g, 0.012 mol) in 400 mL of methylene chloride was stirred 16 h at 
room temperature. The reaction was concentrated to dryness and dissolved 
in chloroform. The chloroform layer was extracted successively with water, 
1N sulfuric acid, and 5% sodium hydroxide. The chloroform layer was dried 
(Na.sub.2 SO.sub.4) and filtered. The chloroform was removed to give a 
fluffy-white residue. This material was dissolved in methylene chloride 
and chromatographed by flash chromatography on silica gel. Elution was 
accomplished using methylene chloride, 1% acetone-methylene chloride, 2% 
acetone-methylene chloride, and 4% acetone-methylene chloride. Fractions 
of similar purity were combined, and solvents removed to give a 
fluffy-white residue. This material was triturated with isopropyl ether 
and chilled in a freezer. A white solid was isolated and dried, 16 h at 
78.degree. C. This furnished 1.40 g (32.5%) of white crystalline solid, mp 
157.degree.-158.degree. C. 
Analysis calc'd for: C.sub.25 H.sub.24 N.sub.2 OF.sub.2 : C, 73.87; H, 
5.95; N, 6.89. Found: C, 73.60; H, 5.88; N, 6.82. 
EXAMPLE 20 
N,.alpha.-Bis(4-Fluorophenyl)-1-[2(2-naphthalenyloxy)ethyl]-4-piperidinemet 
hanamine hydrochloride (1:2) 
A mixture of N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamine (3.42 g, 
0.0113 mol), 2-bromoethyl naphthyl ether (2.83 g, 0.0113 mol), and 
potassium carbonate (3.46 g, 0.025 mol) was heated at reflux 16 h in 350 
mL of 1-butanol containing sodium iodide (0.2 g). The reaction was 
concentrated to dryness, and the residue partitioned between chloroform 
and water. The chloroform layer was extracted with 5% sodium hydroxide. 
The organic layer was dried (Na.sub.2 SO.sub.4) and filtered. The 
chloroform was removed by rotary evaporator to give a brown residue. This 
material was subjected to flash chromatography on silica gel. Elution was 
accomplished using methylene chloride, 1% methanol-methylene chloride, and 
2% methanol-methylene chloride. Fractions of similar purity were combined 
and solvents removed. A brown residue was obtained and converted to the 
HCl salt in methanol-diethyl ether and placed in the freezer. A white 
solid was isolated and dried 16 h at 78.degree. C. This process provided 
2.24 g (36.3%) of white crystalline product mp 226.degree.-230.degree. C. 
(dec.). 
Analysis calc'd for: C.sub.30 H.sub.30 N.sub.2 OF.sub.2.2HCl: C, 66.06; H, 
5.91; N, 5.14. Found: C, 65.81; H, 5.92; N, 5.10. 
EXAMPLE 21 
(+)-N,.alpha.-Bis(4-fluorophenyl)-4-piperidinemethanamine hydrochloride 
(2:5) 
The compound of Preparation 29 (3.0 g, 0.0047 mole) was dissolved in 
methanol (30 mL). The stirred solution was treated with concentrated 
hydrochloric acid (30 mL) and the mixture heated at 50.degree. C. for 4 h. 
The mixture was stirred at room temperature under a nitrogen atmosphere 
for 18 hr. The mixture was partially concentrated to remove the methanol 
and the remaining solution diluted with water (100 mL). Some insoluble 
material was removed by filtration and the filtrate washed several times 
with methylene chloride. The aqueous solution was basified with 50% sodium 
hydroxide solution and extracted with a 1:1 mixture of ethyl 
acetate-acetonitrile. The aqueous layer was acidified, washed with 
methylene chloride, basified, and again extracted with 1:1 ethyl 
acetate-acetonitrile. The extracts were combined, concentrated, and the 
residue dissolved in absolute ethanol. After filtration to remove some 
solid, the filtrate was treated with a solution of HCl in 2-propanol. 
White crystals formed upon trituration which were collected and dried to 
give 0.48 g (30% yield), mp 215.degree. C. (decomposes), 
[.alpha.].sub.D.sup.22 =+50.5.degree. (c=1, MeOH). 
Analysis calculated for C.sub.18 H.sub.20 N.sub.2 F.sub.2.2.5HCl: C, 54.94; 
H, 5.76; N, 7.12. Found: C, 54.12: H, 5.95; N, 6.91. 
EXAMPLE 22 
(-)-N,.alpha.-Bis(4-fluorophenyl)-4-piperidinemethanamine hydrochloride 
(1:3) 
Following the procedure of Example 22, a 30 g portion of the compound of 
Preparation 30 was hydrolyzed, isolated and the hydrochloride salt 
prepared to obtain 0.25 g (15%), mp 208.degree.-212.degree. C. 
(decomposes), [.alpha.].sub.D.sup.22 =-41.1.degree. (c=1, MeOH). 
Analysis calculated for: C.sub.18 H.sub.20 N.sub.2 F.sub.2.3HCl: C, 52.51; 
H, 5.63; N, 6.80. Found: C, 52.22; H, 5.60; N, 6.58. 
EXAMPLE 23 
N,.alpha.-Bis(4-fluorophenyl)-1-(phenylmethyl)-4-piperidinemethanamine 
dihydrochloride 
A mixture of N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamine (3.30 g, 
0.0109 mol), benzylbromide (1.86 g, 0.0109 mol), and sodium bicarbonate 
(1.68 g, 0.02 mol) was stirred 16 h at room temperature in 300 mL of 
acetonitrile (dried over 4 A molecular sieves) containing sodium iodide 
(0.2 g). The mixture was then heated at reflux 16 h followed by stirring 
72 h at room temperature. The reaction was stripped to dryness and 
partitioned between chloroform and water. The chloroform layer was 
extracted with 5% sodium hydroxide and dried (Na.sub.2 SO.sub.4). The 
chloroform was removed to give a fluffy-brown residue. This material was 
dissolved in methylene chloride for flash chromatography on a silica gel 
column. Elution was accomplished using 1% acetone in methylene chloride, 
3% acetone in methylene chloride, and 5% acetone in methylene chloride. 
Fractions of similar purity were combined, and solvents removed to give an 
oil. This oil was converted to the HCl salt in an ethanol-diethyl ether 
mixture. The white solid obtained was then recrystallized from 
methanol-diethyl ether to give a white solid. The solid was dried 16 h at 
78.degree. C. in the presence of phosphorus pentoxide. This method 
provided 1.86 g (36.7%) of white crystalline solid, mp 
241.degree.-242.degree. C. (dec.). 
Analysis calculated for: C.sub.25 H.sub.26 N.sub.2 F.sub.2.2HCl: C, 64.52; 
H, 6.06; N, 6.02. Found: C, 64.35; H, 6.10; N, 6.05. 
EXAMPLE 24 
1-[4-[3-[4-[(4-Fluorophenyl)[(4-fluorophenyl)amino]methyl]-1-piperidinyl]pr 
opoxy]phenyl]-2-methyl-1-propanone dihydrochloride 
A mixture of N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamine (4.63 g, 
0.0153 mol), 1-[4-(3-chloropropoxy)phenyl]-2-methyl-1-propanone (3.69 g, 
0.0153 mol), and potassium carbonate (2.76 g, 0.02 mol) was heated at 
reflux 16 h in 350 mL 1-butanol containing sodium iodide (0.2 g). The 
reaction was concentrated to dryness and partitioned between chloroform 
and water. The chloroform layer was then extracted with 5% sodium 
hydroxide and dried (Na.sub.2 SO.sub.4). The chloroform was removed to 
give a red oil. This material was subjected to flash chromatography on 
silica gel using 2% methanol in methylene chloride to accomplish elution. 
Fractions of similar purities were combined, and solvents removed to give 
an oil. The oil was converted to the HCl salt and recrystallized from 
methanol-diethyl ether to give a white solid. This solid was dried 16 h at 
78.degree. C. in vacuo. The procedure utilized here furnished 5.26 g (59%) 
of white crystalline product, mp 221.degree. -223.degree. C. (dec.). 
Analysis calculated for: C.sub.31 H.sub.36 N.sub.2 O.sub.2 F.sub.2.2HCl: C, 
64.25; H, 6.61; N, 4.83. Found: C, 64.32; H, 6.64; N, 4.99. 
EXAMPLE 25 
3-[2-[4-[(4-Fluorophenyl)[(4-fluorophenyl)amino]methyl]-1-piperidinyl]ethyl 
]2,4(1H,3H)quinazolinedione dihydrochloride 
A mixture of 2.89 g (7.52 mmol) of 
N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamine hydrochloride 
hydrate, 1.74 g (7.75 mmol) of 
3-(2-chloroethyl)-2,4(1H,3H)quinazolinedione, 7.56 g (90 mmol) of sodium 
bicarbonate, and 0.20 g (1.20 mmol) of potassium iodide in 250 mL of 
1-butanol was heated at reflux for 20 h. The solvent was removed in vacuo, 
and the residue was partitioned between CH.sub.2 Cl.sub.2 and dilute NaOH. 
The organic phase was dried (Na.sub.2 SO.sub.4), and the solvent was 
removed in vacuo. The residue was subjected to flash chromatography 
(silica gel, eluted with 1-3% CH.sub.3 OH in CH.sub.2 Cl.sub.2) to give 
the free base of the product. This was converted to the HCl salt, and the 
salt was recrystallized from CH.sub.3 OH/diethyl ether to give 1.80 g 
(42.7%) of the title compound as a white solid, mp 213.degree.-220.degree. 
C. 
Analysis calculated for: C.sub.28 H.sub.28 N.sub.4 O.sub.2 F.sub.2.2HCl: C, 
59.69; H, 5.37; N, 9.94. Found: C, 59.73; H, 5.32; N, 9.90. 
EXAMPLE 26 
1-Cyclohexyl-N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethamine 
hydrochloride hydrate (2:4:1) 
A mixture of N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamine (9.34 g, 
0.0309271 mol), bromocyclohexane (5.04 g, 0.0309271 mol), and potassium 
carbonate (6.91 g, 0.05 mol) was heated 16 h at reflux in 350 mL of 
1-butanol containing potassium iodide (0.2 g). The butanol was removed by 
rotary evaporation, and the residue was partitioned between chloroform and 
water. The chloroform layer was extracted with water and 5% sodium 
hydroxide. The chloroform layer was dried (Na.sub.2 SO.sub.4), filtered, 
and then concentrated to give a dark brown material. Gas chromatographic 
analysis of this material showed 91% starting material and 8% of another 
material. This material was dissolved in methylene chloride and placed on 
a 300-g silica gel column. Elution was accomplished using methylene 
chloride, 1% methanol-methylene chloride, 2% methanolmethylene chloride, 
2.5% methanol-methylene chloride, 3% methanol-methylene chloride, and 3.5% 
methanol-methylene chloride. Fractions of similar purity were combined, 
and solvents were removed to give an oil (0.64 g). This oil was converted 
to the HCl salt, and the salt was recrystallized from 
(methanol-diethylether). A white solid was isolated and dried 16 h in 
vacuo at 78.degree. C. This procedure produced 0.85 g (5.89%) of white 
crystalline material, mp 245.degree. C. (dec.). 
Analysis calculated for C.sub.24 H.sub.30 N.sub.2 F.sub.2.2HCl.0.5H.sub.2 
O: C, 61.80; H, 7.13; N, 6.01. Found: C, 61.67; H, 7.04; N, 6.05. 
EXAMPLE 27 
N,.alpha.-Bis(4-fluorophenyl)-1-(2-methylpropyl)-4-piperidinemethanamine 
hydrochloride hydrate (2:4:1) 
A mixture of N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamine (4.87 g, 
0.016 mol), 1-bromo-2-methylpropane (2.21 g, 0.016 mol), and sodium 
bicarbonate (2.52 g, 0.03 mol) was stirred 72 hr under nitrogen in 250 mL 
of anhydrous acetonitrile. The reaction was heated at reflux 4 hr and then 
cooled to room temperature. The reaction was concentrated to dryness and 
partitioned between chloroform and water. The chloroform layer was 
extracted with 5% sodium hydroxide, dried (Na.sub.2 SO.sub.4) and 
filtered. The chloroform was removed to give a dark brown oil. This oil 
was subjected to flash chromatography on silica gel using methylene 
chloride and mixtures of methylene chloride-methanol for elution. 
Fractions of similar purity were combined, and solvents were removed to 
give a brown oil. This oil was converted to the hydrochloride and the salt 
was recrystallized from 2-propanol. A white solid was obtained and washed 
with diethyl ether. The white solid was dried in vacuo at 78.degree. C. 
This procedure furnished 1.61 g (21.9%) of white crystalline product, mp 
138.degree.-139.degree. C. (dec.) which contained 2-propanol. 
Analysis calculated for: C.sub.22 H.sub.28 N.sub.2 F.sub.2.2HCl.0.5H.sub.2 
O.0.3C.sub.3 H.sub.8 O: C, 60.00; H, 7.34; N, 6.11. Found: C, 60.17; H, 
7.30; N, 6.19. 
EXAMPLE 28 
N,.alpha.-Bis(4-fluorophenyl)-1-propyl-4-piperidinemethanamine 
hydrochloride hydrate (2:4:1) 
A mixture of N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamine (4.95 g, 
0.0163907 mol), n-propyl iodide (2.79 g, 0.0163907 mol), and sodium 
bicarbonate (3.36 g, 0.04 mol) was stirred 48 hr at room temperature. The 
mixture was then heated at reflux 4 h. The reaction was concentrated to 
dryness and then partitioned between chloroform and water. The chloroform 
layer was extracted with 5% sodium hydroxide and then dried (Na.sub.2 
SO.sub.4). The chloroform layer was filtered, and the chloroform solvent 
was removed by a rotary evaporator to give a brown oil. This oil was 
subjected to flash chromatography on silica gel. Elution was accomplished 
using mixtures of methanol and methylene chloride. Fractions of similar 
purity were combined and solvents were removed. The oil obtained was 
dissolved in methanol and converted to the hydrochloride salt using 
ethereal HCl. Recrystallization from methanol diethyl ether gave a white 
solid which was dried 16 h at 78.degree. C. This process provided 3.82 g 
(54.7%) of white crystalline material, mp 251.degree. C. 
Analysis calculated for: C.sub.21 H.sub.26 N.sub.2 F.sub.2.2HCl.0.5H.sub.2 
O: C, 59.16; H, 6.86; N, 6.57. Found: C, 59.17; H, 6.72; N, 6.58. 
EXAMPLE 29 
1-(2-Ethoxyethyl)-N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamine 
hydrochloride hydrate (2:4:1) 
A mixture of N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamine (3.33 g, 
0.011 mol), 2-bromoethyl ethyl ether (1.69 g, 0.011 mol), and sodium 
bicarbonate (1.68 g, 0.011 mol) was stirred under nitrogen 16 h at room 
temperature. The mixture was then heated at reflux for 4 h and stirred 16 
h at room temperature. The reaction was concentrated to dryness and 
partitioned between chloroform and water. The chloroform layer was back 
extracted with 5% sodium hydroxide. The chloroform layer was dried 
(Na.sub.2 SO.sub.4), filtered, and the chloroform was removed to give an 
oil. The oil was subjected to flash chromatography on silica gel using 
methanol-methylene chloride mixtures for elution. Fractions of similar 
purity were combined and solvents removed. A brown oil was obtained which 
crystallized to a brown solid. This material was converted to the 
hydrochloride salt and the salt was recrystallized from methanol-diethyl 
ether to give a white solid. The solid was dried 16 h in vacuo at 
78.degree. C. This process furnished 2.00 g (39.8%) of white crystalline 
solid mp 241.degree.-243.degree. C. (dec.). 
Analysis calculated for: C.sub.22 H.sub.28 N.sub.2 OF.sub.2.2HCl.0.5H.sub.2 
O: C, 57.90; H, 6.85; N, 6.14. Found: C, 57.88; H, 6.76; N, 6.14. 
EXAMPLE 30 
N,.alpha.-Bis(4-fluorophenyl)-4-piperidinemethanamine 
A stirred mixture of 4-(4-fluorobenzoyl)piperidine hydrochloride (40.0 g, 
0.164 mole), 4-fluoroaniline (22.0 g, 0.197 mole), and benzenesulfonic 
acid (0.14 g) in xylenes (820 mL) was heated at reflux temperature for 18 
hr during which time 3 mL of water was collected in a Dean-Stark trap. 
After cooling to 50.degree. C., sodium borohydride (12.5 g, 0.328 mole) 
was added slowly. Ethanol (100 mL) was added and the mixture heated at 
60.degree. C. for 1 h. After stirring for 18 h under a nitrogen atmosphere 
at room temperature, the mixture was chilled to 5.degree. C. with an ice 
bath and chilled water added cautiously. A rapid evolution of gas occurred 
causing a portion of the reaction mixture to spill over into the ice bath. 
The contents of the ice bath and the remainder of the reaction mixture 
were combined and basified with 50% sodium hydroxide solution, causing a 
viscous insoluble oil to separate from the mixture. The material was 
dissolved in ethyl acetate. The ethyl acetate solution and the xylene 
layer were combined and washed with additional dilute aqueous NaOH 
solution. The aqueous layers were combined and extracted with ethyl 
acetate-acetonitrile (60:40). The organic layers were combined and 
extracted twice with 300 mL portions of 3N HCl solution. The acid extract 
was basified with 50% sodium hydroxide solution and extracted twice with 
600 mL portions of ethyl acetate-acetonitrile (60:40). The extracts were 
combined, treated with charcoal, dried (MgSO.sub.4), and concentrated. The 
residual material was heated at 100.degree. C. under vacuum for 1 h to 
remove excess 4-fluoroaniline. The yield was 24.8 g (50.5%). 
EXAMPLE 31 
4-[[(3,4-Difluorophenyl)amino](4-fluorophenyl)methyl]piperidine 
hydrochloride hydrate (1:2:1) 
A mixture of 50.7 g (0.21 mol) of 4-(4-fluorobenzoyl)piperidine 
hydrochloride, 40.0 g (0.31 mol) of 3,4-difluoroaniline and 0.80 g (0.0051 
mol) of benzenesulfonic acid in 1 L of xylenes was heated at reflux for 4 
days with water being removed with Dean-Stark trap. The mixture was cooled 
to room temperature and 500 mL of dry THF was added. The mixture was 
cooled in an ice bath and was swept with a stream of nitrogen. To this 
mixture was slowly added 40.0 g (1.1 mol) of LiAlH.sub.4, and the mixture 
was stirred mechanically at room temperature overnight. Dilute NaOH was 
added slowly over 1 h, and the resulting mixture was filtered through a 
pad of Celite. The solvent was removed from the filtrate in vacuo, and the 
residue was partitioned between CH.sub.2 Cl.sub.2 and water. The CH.sub.2 
Cl.sub.2 solution was dried (Na.sub.2 SO.sub.4), and the solvent was 
removed in vacuo. The residue was dissolved in CH.sub.3 OH, an excess of 
ethereal HCl was added, and anhydrous ether was added until the solution 
became cloudy. The solution stood at room temperature overnight and 28.72 
g (33.3%) of product was collected. The filtrate yielded an additional 
4.51 g (5.2%) of product. A small portion of this was reccrystallized from 
CH.sub.3 OH/ether to give an analytically pure sample of the title 
compound as a white crystalline solid, mp 210.degree.-213.degree. C. 
Analysis calculated for: C.sub.18 H.sub.19 N.sub.2 F.sub.3.2HCl.H.sub.2 O: 
C, 52.57; H, 5.64; N, 6.81. Found: C, 52.93; H, 5.61; N, 6.83. 
EXAMPLE 32 
N-(3,4-Difluorophenyl)-.alpha.-(4-fluorophenyl)-1-(3-phenoxypropyl)-4-piper 
idinemethanamine ethanedioate (1:1) 
A mixture of 
4-[[(3,4-difluorophenyl)amino](4-fluorophenyl)methyl]piperidine (6.15 g, 
0.015 mol), phenoxypropyl bromide (3.23 g, 0.015 mol), and potassium 
carbonate (6.22 g, 0.045 mol) was heated at reflux 16 hr in 1-butanol 
containing sodium iodide (0.2 g). The reaction was concentrated to dryness 
and the residue obtained was partitioned between chloroform and water. The 
chloroform layer was dried (Na.sub.2 SO.sub.4) and filtered. When the 
chloroform was removed by rotary evaporation, a brown oil was obtained. 
This oil was dissolved in methylene chloride and subjected to flash 
chromatography on silica gel. Elution was carried out using methylene 
chloride, 1% methanol-methylene chloride, and 2% methanol-methylene. 
Fractions of similar purity were combined, and solvents were removed to 
give an oil. The oil was converted to oxalate salt in methanol-diethyl 
ether. A white solid was isolated and dried in vacuo at 100.degree. C. for 
16 hr. This process furnished 4.76 g (58.3%) of white crystalline solid, 
mp (89.degree. C. glass; 157.degree. C. melted). 
Analysis calculated for: C.sub.27 H.sub.29 N.sub.2 OF.sub.3.C.sub.2 H.sub.2 
O.sub.4 : C, 63.96; H, 5.74; N, 5.14. Found: C, 63.62; H, 5.71; N, 5.16. 
EXAMPLE 33 
N-(3,4-Difluorophenyl)-.alpha.-(4-fluorophenyl)-1-(2-quinolinylmethyl)-4-pi 
peridinemethanamine ethanedioate hydrate (2:2:1) 
A mixture of 3.60 g (8.8 mmol) of 
4-[[(3,4-difluorophenyl)amino](4-fluorophenyl)methyl]piperidine 
hydrochloride hydrate, 2.04 g (9.5 mmol) of 2-chloromethylquinoline and 
3.0 g (28.3 mmol) of sodium carbonate in 200 mL of absolute ethanol was 
stirred at room temperature for 66 h. The solvent was removed in vacuo to 
give an oil. This was partitioned between CH.sub.2 Cl.sub.2 and dilute 
NaOH. The CH.sub.2 Cl.sub.2 solution was dried (Na.sub.2 SO.sub.4), and 
the solvent was removed in vacuo to give an oil. A solution of the oil in 
methanol was treated with an excess of oxalic acid. Anhydrous ether was 
added, and 2.53 g (51.3%) of title compound was collected as a crystalline 
solid, mp. 139.degree.-140.degree. C. 
Analysis calculated for: C.sub.28 H.sub.26 N.sub.3 F.sub.3.C.sub.2 H.sub.2 
O.sub.4.0.5H.sub.2 O: C, 64.28; H, 5.21; N, 7.50. Found: C, 64.20; H, 
4.98; N, 7.41. 
EXAMPLE 34 
N-(3,4-Difluorophenyl)-.alpha.-(4-fluorophenyl)-1-(2-naphthalenylmethyl)-4- 
piperidinemethanamine dihydrochloride 
A mixture of 3.10 g (7.5 mmol) of 
4-[[(3,4-difluorophenyl)amino](4-fluorophenyl)methyl]piperidine 
hydrochloride hydrate, 1.70 g (7.7 mmol) of 2-bromomethylnaphthalene and 
5.1 g (60.7 mmol) of sodium bicarbonate in 200 mL of absolute ethanol was 
stirred at room temperature for 20 h. The solvent was removed in vacuo, 
and the residue was partitioned between methylene chloride and dilute 
NaOH. The organic phase was dried (Na.sub.2 SO.sub.4), and the solvent was 
removed in vacuo. The residue was subjected to flash chromatography 
(silica gel, elution with 1-4% MeOH in CH.sub.2 Cl.sub.2) to give an oil. 
This was converted to the HCl salt, and the salt was recrystallized from a 
mixture of methanol and diethylether to give 1.53 g (38.3%) of the title 
compound as a crystalline solid, mp 187.degree.-190.degree. C. 
Analysis calculated for: C.sub.29 H.sub.27 N.sub.2 F.sub.3.2HCl.0.25H.sub.2 
O: C, 64.75; H, 5.53; N, 5.21. C, 64.82; H, 5.41; N, 5.23. 
EXAMPLE 35 
N-(3,4-Difluorophenyl)-.alpha.-(4-fluorophenyl)-1-[2-(2-naphthalenyloxy)eth 
yl]-4-piperidinemethanamine dihydrochloride 
A mixture of 4.20 g (0.010 mol) of 
4-[[(3,4-difluorophenyl)amino](4-fluorophenyl)methyl]piperidine, 2.90 g 
(0.012 mol) of 2-(2-bromoethoxy)naphthalene, 8.1 g (0.096 mol) of sodium 
bicarbonate, and a trace of sodium iodide in 400 mL of 1-butanol was 
heated at reflux for 16 h. The solvent was removed in vacuo, and the 
residue was partitioned between CH.sub.2 Cl.sub.2 and dilute NaOH. The 
CH.sub.2 Cl.sub.2 solution was dried (Na.sub.2 SO4), and the solvent was 
removed in vacuo to give a gum. This was subjected to flash column 
chromatography (silica gel, eluted with CH.sub.2 Cl.sub.2 and 1-2% MeOH in 
CH.sub.2 Cl.sub.2) to give the free base. This was converted to the HCl 
salt, and the salt was recrystallized from diethyl ether/MeOH to give 3.05 
g (54.1%) as a white crystalline solid: mp 210.degree.-215.degree. C. 
Analysis calculated for: C.sub.30 H.sub.29 N.sub.2 F.sub.3 O.2HCl: C, 
63.95; H, 5.55; N, 4.97. Found: C, 63.90; H, 5.55; N, 4.93. 
EXAMPLE 36 
.alpha.-(4-Fluorophenyl)-N-[(4-fluorophenyl)methyl]-4-piperidinemethanamine 
hydrochloride hydrate (2:4:3) 
A mixture of 9.54 g (0.021 mol) of the 
.alpha.-(4-fluorophenyl)-N-[(4-fluorophenyl)methyl]-1-phenylfulfonyl-4-pip 
eridinemethaneamine, 8.20 g (0.087 mol) of phenol and 150 mL of 48% HBr was 
heated at reflux for 8 h. The reaction was poured over ice, and the 
mixture was made basic with 50% NaOH. The basic mixture was extracted with 
CH.sub.2 Cl.sub.2, and the CH.sub.2 Cl.sub.2 extract was dried (Na.sub.2 
SO.sub.4). The solvent was removed in vacuo to give an oil. This was 
dissolved in CH.sub.3 OH, treated with 4.87 g (0.042 mol) of fumaric acid, 
and anhydrous ether was added. This produced 7.69 g of a white solid, 
which was partitioned between CH.sub.2 Cl.sub.2 and dilute NaOH. The 
CH.sub.2 Cl.sub.2 solution was dried (Na.sub.2 SO.sub.4), and the solvent 
was removed in vacuo. The residue was dissolved in CH.sub.3 OH, excess 
ethereal HCl was added, and 2.24 g (25.1%) of the title compound was 
collected as a white solid, mp 238.degree.-240.degree. C. 
Analysis calculated for: C.sub.19 H.sub.27 N.sub.2 F.sub.2 Cl.sub.2 : C, 
54.81; H, 6.54; N, 6.73. Found: C, 54.93; H, 6.11; N, 6.72. 
EXAMPLE 37 
.alpha.-(4-Fluorophenyl)-N-[(4-fluorophenyl)methyl]-1-(2-phenylethyl)-4-pip 
eridinemethanamine (E)-2-butenedioate (2:3) 
A mixture of 11.4 g (0.037 mol) of 
N-(2-phenylethyl)-4-(4-fluorobenzoyl)piperidine, 6.79 g (0.054 mol) of 
4-fluorobenzylamine and 0.54 g (0.0034 mol) of benzenesulfonic acid in 400 
mL of xylene was heated at reflux for 24 h. Water was removed from the 
reaction mixture with a Dean-Stark trap. The solvent was removed in vacuo, 
and the residue was partitioned between CH.sub.2 Cl.sub.2 and dilute NaOH. 
The CH.sub.2 Cl.sub.2 solution was dried (Na.sub.2 SO.sub.4), and the 
solvent was removed in vacuo to give 12.46 g (81.2%) 
a-(4-fluorophenyl)-N-[(4-fluorophenyl)methyl]-1-(2-phenylethyl)-4-piperidi 
nemethanimine as an oil. 
A mixture of 7.85 g (0.0188 mol) of 
.alpha.-(4-fluorophenyl)-N-[(4-fluorophenyl)methyl]-1-(2-phenylethyl)-4-pi 
peridinemethanimine and 1.30 g (0.034 mol) of lithium aluminum hydride in 
200 mL of dry THF (distilled from sodium-benzophenone ketyl) and under an 
atmosphere of nitrogen was stirred at room temp for 14 h. A solution of 5% 
NaOH was added dropwise to the mixture and 20 mL of water was added. 
Methylene chloride was added and the mixture was filtered through Celite. 
The filtrate was extracted with water and was dried (Na.sub.2 SO.sub.4). 
The solvent was removed in vacuo to give an oil. This was dissolved in 
methanol, treated with 4.41 g (0.038 mol) of fumaric acid, and anhydrous 
ether was added. A precipitate formed to give 7.45 g (65.4%) of the title 
compound as a white solid, mp 177.degree.-179.degree. C. 
Analysis calculated for: C.sub.33 H.sub.37 N.sub.2 F.sub.2 O.sub.6.5 : C, 
65.66; H, 6.18; N, 4.64. Found: C, 65.65; H, 6.06; N, 4.63. 
EXAMPLE 38 
N[(4-Fluorophenyl)methyl]-N-[(4-fluorophenyl)[1-(2-phenylethyl)-4-piperidin 
yl]methyl]acetamide (E)-2-butendioate (1:1) monohydrate 
A mixture of 1.37 g (3.25 mmol) of 
.alpha.-(4-fluorophenyl)-N-[(4-fluorophenyl)methyl]-1-(2-phenylethyl)-4-pi 
peridinemethanamine, 1.0 g (13 mmol) of acetyl chloride and 0.90 g (9 mmol) 
of triethylamine in 150 mL of CH.sub.2 Cl.sub.2 was stirred at room temp 
for 16 h. The reaction mixture was poured over ice. The mixture was then 
extracted with the following in sequence: dilute NaOH, dilute H.sub.2 
SO.sub.4 and dilute NaOH. The CH.sub.2 Cl.sub.2 solution was dried 
(Na.sub.2 SO.sub.4), and the solvent was removed in vacuo to give an oil. 
This was treated with a methanolic solution of fumaric acid, ether was 
added, and a precipitate was collected to give 1.0 g (51.6%) of the title 
compound as a white crystalline solid, mp 206.degree.-208.degree. C., dec. 
Analysis calculated for: C.sub.33 H.sub.36 N.sub.2 O.sub.6 F.sub.2 : C, 
66.43; H, 6.42; N, 4.70. Found: C, 66.60; H, 6.12; N, 4.69. 
EXAMPLE 39 
N-[(4-Fluorophenyl)methyl]-N-[(4-fluorophenyl)[1-(2-phenylethyl)-4-piperidi 
nyl]methyl]-N'-methylurea (E)-2-butenedioate (2:3) 
A mixture of 1.37 g (0.0033 mol) of the 
.alpha.-(4-fluorophenyl)-N-[(4-fluorophenyl)methyl]-1-(2-phenylethyl)-4-pi 
peridinemethanamine and 1.0 g (0.0175 mol) of methyl isocyanate in 150 mL 
of CH.sub.2 Cl.sub.2 was stirred at room temperature overnight. The 
reaction mixture was extracted with water and was dried (Na.sub.2 
SO.sub.4). The solvent was removed in vacuo, and the residue was converted 
to the fumarate salt. The salt was recrystallized from CH.sub.3 OH/ether 
to give 1.62 g (76.5%) of a white solid, mp 136.degree.-140.degree. C. 
Analysis calculated for: C.sub.35 H.sub.39 N.sub.3 O.sub.7 F.sub.2 : C, 
64.51; H, 6.03; N, 6.45. Found: C, 64.92; H, 6.15; N, 6.75. 
EXAMPLE 40 
.alpha.-(4-Fluorophenyl)-N-[(4-fluorophenyl)methyl]-1-(3-phenoxypropyl-4-pi 
peridinemethanamine dihydrochloride hemihydrate 
A solution of 20.23 g (59 mmol) of 
4-(p-fluorobenzoyl)-1-(3-phenoxypropyl)piperidine, 9.80 g (78 mmol) of 
4-fluorobenzylamine and 1.0 g (7.9 mmol) of benzenesulfonic acid in 500 mL 
of xylene was heated at reflux for 5 days with water being removed from 
the reaction mixture with a Dean-Stark trap. The solvent was removed in 
vacuo, and the residue was partitioned between CH.sub.2 Cl.sub.2 and 
dilute NaOH. The CH.sub.2 Cl.sub.2 solution was dried (Na.sub.2 SO.sub.4), 
and the solvent was removed in vacuo to give a gum. This was reacted for 
16 h with 8.1 g (210 mmol) of LiAlH.sub.4 in 500 mL of THF at room 
temperature and under an atmosphere of nitrogen. Dilute NaOH was then 
added followed by the addition of 100 mL of water. CH.sub.2 Cl.sub.2 was 
added, and the mixture was filtered through Celite. The phases were 
separated, and the organic phase was extracted with several portions of 
water. The organic phase was dried (Na.sub.2 SO.sub.4), and the solvent 
was removed in vacuo to give an oil. This was dissolved in methanol, 
excess ethereal HCl was added, and anhydrous ether was added until the 
solution became cloudy. A white precipitate was collected to give 14.44 g 
(46.0%) of white, crystalline solid, mp 236.degree.-237.degree. C. 
Analysis calculated for: C.sub.28 H.sub.35 N.sub.2 O.sub.1.5 F.sub.2 
Cl.sub.2 : C, 63.16; H, 6.63; N, 5.26. Found: C, 63.41; H, 6.60; N, 5.31. 
EXAMPLE 41 
1-[4-[3-[4-[(4-Fluorophenyl)[[(4-fluorophenyl)methyl]amino]methyl]-1-piperi 
dinyl]propoxy]-3-methoxyphenyl]ethanone dihydrochloride hemihydrate 
A mixture of 3.03 g (7.81 mmol) of 
.alpha.-(4-fluorophenyl)-N-[(4-fluorophenyl)methyl]-4-piperidinemethanamin 
e hydrochloride hydrate, 1.95 g (8.1 mmol) of 
3-chloro-1-(4-acetyl-2-methoxyphenoxy)propane and 2.86 g (27 mmol) of 
sodium carbonate in 400 mL of 1-butanol was heated at reflux for 16 h. The 
solvent was removed in vacuo, and the residue was partitioned between 
CH.sub.2 Cl.sub.2 and dilute NaOH. The CH.sub.2 Cl.sub.2 solution was 
dried (Na.sub.2 SO.sub.4), and the solvent was removed in vacuo to give an 
oil. This was subjected to flash chromatography (silica gel, 3% CH.sub.3 
OH in CH.sub.2 Cl.sub.2) to give 2.26 g of an oil. The oil was converted 
to the hydrochloride salt, and the salt was recrystallized from 
methanol/ether to give 2.03 g (43%) of the title compound as a crystalline 
solid, mp 239.degree.-240.degree. C. 
Analysis calculated for: C.sub.31 H.sub.39 N.sub.2 O.sub.3.5 F.sub.2 
Cl.sub.2 : C, 61.59; H, 6.50; N, 4.63. Found: C, 61.50; H, 6.40; N, 4.62. 
EXAMPLE 42 
4-[(4-Fluorophenyl)[[(4-fluorophenyl)methyl]amino]methyl]-N-methyl-1-piperi 
dinecarboxamide (E)-2-butendioate (1:1) 
A solution of 3.57 g (9.20 mmol) of 
.alpha.-(4-fluorophenyl)-N-[(4-fluorophenyl)methyl]-4-piperidinemethanamin 
e and 0.68 g (12.0 mmol) of methyl isocyanate in 400 mL of CH.sub.2 
Cl.sub.2 was stirred at room temperature overnight. The solvent was 
removed in vacuo to give as an oil. This was converted to the fumarate 
salt, and the salt was recrystallized from methanol/ether to give 0.96 g 
(21.3%) of the title compound as a white crystalline solid, mp 
101.degree.-105.degree. C. A second crop of solid was collected from the 
filtrate to give 1.24 g (27.0%) of the monohydrate of the title compound, 
mp 98.degree.-102.degree. C. 
Analysis of calculated for: C.sub.25 H.sub.29 N.sub.3 O.sub.5 F.sub.2 : C, 
61.34; H, 5.97; N, 8.58. Found: C, 61.22; H, 6.10; N, 8.84. 
Analysis calculated for: C.sub.25 H.sub.29 N.sub.3 O.sub.5 
F.sub.2.0.5H.sub.2 O: C, 60.23; H, 6.07; N, 8.43. Found: C, 60.10; H, 
6.06; N, 8.85. 
EXAMPLE 43 
N-[(4-Fluorophenyl)methyl]-N-[(4-fluorophenyl)[1-[(methylamino)carbonyl]-4- 
piperidinyl]methyl]-N'-methylurea 
A solution of 2.06 g (6.5 mmol) of 
.alpha.-(4-fluorophenyl)-N-[(4-fluorophenyl)methyl]-4-piperidinemethanamin 
e and 3.1 g (54.4 mmol) of methyl isocyanate in 300 mL of CH.sub.2 Cl.sub.2 
was stirred at room temperature for 18 h. The solvent was removed in vacuo 
to give a white solid. The solid was recrystallized from methylene 
chloride/ether to give 2.65 g (94.8%) of a white, crystalline solid 
containing 0.15 mole of CH.sub.2 Cl.sub.2, mp 120.degree.-162.degree. C. 
Analysis calculated for: C.sub.23 H.sub.28 N.sub.4 O.sub.2 F.sub.2 
+0.15CH.sub.2 Cl.sub.2 : C, 62.73; H, 6.44; N, 12.64. Found: C, 62.73; H, 
6.48; N, 12.57. 
EXAMPLE 44 
N-[(4-Fluorophenyl)methyl]-N-[(4-fluorophenyl)[1-(3-phenoxypropyl)-4-piperi 
dinyl]methyl]acetamide (E)-2-butenedioate (1:1) 
A solution of 2.21 g (4.2 mmol) of the compound of Example 40, 0.59 g (7.5 
mmol) of acetyl chloride, and 1.0 g (9.9 mmol) of triethylamine in 300 mL 
of CH.sub.2 Cl.sub.2 was stirred at room temperature for 104 h. The 
solution was extracted with several portions of dilute NaOH and was dried 
(Na.sub.2 SO.sub.4). The solvent was removed in vacuo to give an oil. The 
oil was reacted with excess fumaric acid in CH.sub.3 OH. Excess anhydrous 
ether was added, and 2.19 g (85.7%) of the title compound was collected as 
a white, crystalline solid, mp 141.degree.-143.degree. C. 
Analysis calculated for: C.sub.34 H.sub.38 N.sub.2 O.sub.6 F.sub.2 : C, 
67.09; H, 6.29; N, 4.60. Found: C, 67.05; H, 6.31; N, 4.60. 
EXAMPLE 45 
N-[(4-Fluorophenyl)methyl]-N-[(4-fluorophenyl)[(phenylamino)carbonyl]-4-pip 
eridinyl]methyl]-N'-phenylurea 
A solution of 1.55 g (4.9 mmol) of 
N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamine and 1.43 g (12.0 
mmol) of phenyl isocyanate in 300 mL of CH.sub.2 Cl.sub.2 was stirred at 
room temperature overnight. The solvent was removed in vacuo, and the 
residue was recrystallized from CH.sub.2 Cl.sub.2 /ether to give 2.32 g 
(85.4%) of white, crystalline solid, mp 229.degree.-230.degree. C. 
Analysis calculated for: C.sub.33 H.sub.32 N.sub.4 O.sub.2 F.sub.2 : C, 
71.46; H, 5.82; N, 10.10. Found: C, 71.15; H, 5.83; N, 10.02. 
EXAMPLE 46 
.alpha.-(4-Fluorophenyl)-N-(2-phenylethyl)-4-piperidinemethanamine 
(E)-2-butenedioate (1:2) hemihydrate 
A mixture of 2.15 g (4.8 mmol) of 
.alpha.-(4-fluorophenyl)-N-(2-phenylethyl)-1-(phenylsulfonyl)-4-piperidine 
methanamine and 3.5 g (37 mmol) of phenol in 60 mL of 48% HBr was refluxed 
for 3 h and then was stirred at ambient temperature for 14 h. The mixture 
was poured over ice, and the mixture was made basic with 50% NaOH. The 
basic mixture was extracted with CH.sub.2 Cl.sub.2. The CH.sub.2 Cl.sub.2 
solution was dried (MgSO.sub.4), and the solvent was removed in vacuo to 
give an oil. This was dissolved in CH.sub.3 OH, 2 equivalents of fumaric 
acid was added, and ether was added. A white precipitate was collected to 
give 1.59 g (59.8%) of the title compound as a white, crystalline solid, 
mp 189.5.degree.-191.degree. C. 
Analysis calculated for: C.sub.28 H.sub.34 N.sub.2 FO.sub.8.5 : C, 60.75; 
H, 6.19; N, 5.06. Found: C, 60.67; H, 6.01; N, 5.08. 
EXAMPLE 47 
1-[4-[3-[4-[(4-Fluorophenyl)[(2-phenylethyl)amino]methyl]-1-piperidinyl]pro 
poxy]-3-methoxyphenyl]ethanone (E)-2-butenedioate (1:1) monohydrate 
A mixture of 4.52 g (0.0145 mol of 
.alpha.-(4-fluorophenyl)-N-(2-phenylethyl)-4-piperidinemethanamine, 3.51 g 
(0.0145 mol) of 3-(4-acetyl-2-methoxyphenoxy)-1-chloropropane, 0.41 g 
(0.0025 mol) of KI and 8.2 g (0.098 mol) of sodium carbonate in 400 mL of 
1-butanol was heated at reflux for 18 h. The solvent was removed in vacuo 
to give an oil. To a solution of this oil in 100 mL of CH.sub.3 OH was 
added 3.40 g (0.029 mol) of fumaric acid. A precipitate was collected. 
This was recrystallized from CH.sub.3 OH-ether to give 5.77 g (61%) of 
white solid, mp 70.degree.-74.degree. C. 
Analysis calculated for: C.sub.36 H.sub.45 N.sub.2 O.sub.8 F: C, 66.24; H, 
6.95; N, 4.29. Found: C, 66.10; H, 6.73; N, 4.33. 
EXAMPLE 48 
4-[(4-Fluorophenyl)[(2-phenylethyl)amino]methyl]-N-phenyl-1-piperidinecarbo 
xamide (E)-2-butenedioate (4:3)hemihydrate 
A solution of 2.22 g (7:1 mmol) of 
.alpha.-(4-fluorophenyl)-N-(2-phenylethyl)-4-piperidinemethanamine and 
0.87 g (7.3 mmol) of phenyl isocyanate in 100 mL of CH.sub.2 Cl.sub.2 was 
stirred at room temperature overnight. Water was added, and the mixture 
was stirred for 0.5 h. The phases were separated, and the CH.sub.2 
Cl.sub.2 solution was extracted with water. The solution was dried 
(Na.sub.2 SO.sub.4), and the solvent was removed in vacuo to give a glass. 
This was converted to the fumarate salt, and the salt was recrystallized 
from CH.sub.3 OH/ether to give 1.79 g (47.8%) of the title compound as a 
white solid, mp 155.degree.-156.5.degree. C. dec. 
Analysis calculated for: C.sub.30 H.sub.34 N.sub.3 O.sub.4.5 F: C, 68.28; 
H, 6.50; N, 7.96. Found: C, 68.64; H, 6.21; N, 7.95. 
EXAMPLE 49 
4-[(4-Fluorophenyl)[(2-phenylethyl)amino]methyl]-N-methyl-1-piperidinecarbo 
xamide (E)-2-butanedioate (2:1) hemihydrate 
A solution of 1.84 g (5.9 mmol) of 
.alpha.-(4-fluorophenyl)-N-(2-phenylethyl)-4-piperidinemethanamine and 
0.28 g (5.1 mmol) of methyl isocyanate in 200 mL of CH.sub.2 Cl.sub.2 was 
stirred at room temp overnight. The solvent was removed in vacuo. The 
residue was dissolved in 30 mL of CH.sub.3 OH, and 0.68 g (5.9 mol) of 
fumaric acid was added. The solution was placed in the freezer, and 1.12 g 
(43.5%) of a white crystalline solid was collected. An additional 0.29 g 
(11.3%) of solid was collected from the filtrate to give a total of 1.41 g 
(54.8%) of the title compound as a white solid, mp 104.degree.-107.degree. 
C. 
Analysis calculated for: C.sub.24 H.sub.31 N.sub.3 O.sub.3.5 : C. 66.04; H, 
7.16; N, 9.63. Found: C, 65.93; H, 7.05; N, 9.43. 
EXAMPLE 50 
N-[(4-Fluorophenyl)[1-[(methylamino)carbonyl]-4-piperidinyl]methyl]-N'-meth 
yl-N-(2-phenylethyl)urea 
A solution of 2.25 g (0.0072 mol) of 
.alpha.-(4-fluorophenyl)-N-(2-phenylethyl)-4-piperidinemethanamine and 
2.50 g (0.044 mol) of methyl isocyanate in 200 mL of methylene chloride 
was stirred at room temperature overnight. The solvent was removed in 
vacuo to give a solid. This was triturated with anhydrous ether, and the 
solid was collected to give 2.43 g (79.1%) of white solid, mp 
186.degree.-188.degree. C. 
Analysis calculated for: C.sub.24 H.sub.31 N.sub.4 O.sub.2 F: C, 67.58; H, 
7.33; N, 13.14. Found: C, 67.45; H, 7.45; N, 12.97. 
EXAMPLE 51 
Following the procedure of Example 4 and using aniline and 
a. 4-benzoyl-1-(2-naphthalenylmethyl)piperidine 
b. 1-(2-naphthalenylmethyl)-4-(4-trifluoromethylbenzoyl)piperidine 
c. 4-(4-methoxybenzoyl)-1-(2-naphthalenylmethyl)piperidine 
d. 4-(4-fluorobenzoyl)-1-(2-naphthalenylmethyl)piperidine 
there are obtained respectively 
a. 1-(2-naphthalenylmethyl)-N,.alpha.-diphenyl-4-piperidinemethanamine 
b. 
1-(2-naphthalenylmethyl)-N-phenyl-.alpha.-[4-(trifluoromethyl)phenyl]-4-pi 
peridinemethanamine 
c. 
.alpha.-(4-methoxyphenyl)-1-(2-naphthalenylmethyl)-N-phenyl-4-piperidineme 
thanamine 
d. 
.alpha.-(4-fluorophenyl)-1-(2-naphthalenylmethyl)-N-phenyl-4-piperidinemet 
hanamine. 
EXAMPLE 52 
.alpha.-(4-Fluorophenyl)-N-(2-pyridinyl)-1-(3-phenoxypropyl)-4-piperidineme 
thanamine 
Following the procedure of Example 4, the title compound is obtained from 
2-aminopyridine and 4-(4-fluorobenzoyl)-1-(3-phenoxypropyl)piperidine. 
EXAMPLE 53 
4-[(4-Fluorophenyl)[(4-fluorophenyl)amino]methyl]-1-piperidinecarboximidami 
de 
N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamine and 
S-methylisothiouronium sulfate are reacted together according to the 
procedure of J. Amer. Chem. Soc. 71, 2476 (1949) to obtain the title 
compound. 
EXAMPLE 54 
1-(3-Chloropropyl)-N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamine 
Following the procedure of Example 2, the title compound is obtained from 
3-bromo-1-chloropropane and 
N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethylamine. 
EXAMPLE 55 
N-[3-[4-[(4-Fluorophenyl)[(4-fluorophenyl)amino]methyl]-1-piperidinyl]propy 
l]-2-pyrimidinamine 
A mixture of equivalent amounts of 
1-(3-chloropropyl)-N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamine, 
2-aminopyrimidine, and sodium bicarbonate in 1-butanol is heated at reflux 
temperature until the reaction is complete. The solvent is removed and the 
residual material partitioned between water and methylene chloride. The 
methylene chloride layer is dried and concentrated to obtain the title 
compound. 
EXAMPLE 56 
N,.alpha.-bis(4-Fluorophenyl)-1-[3-(phenylamino)propyl]-4-piperidinemethana 
mine 
1-(3-Chloropropyl)-N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamine 
and excess aniline are heated together until the reaction is complete. 
Excess aniline is distilled off and the residual material partitioned 
between dilute aqueous sodium hydroxide and methylene chloride. The 
methylene chloride solution is dried and concentrated to obtain the title 
compound. 
EXAMPLE 57 
N,.alpha.-bis(4-Fluorophenyl)-1-[3-(4-phenyl-1-piperazinyl)propyl]-4-piperi 
dinemethanamine 
Following the procedure of Example 55 and substituting 1-phenylpiperazine 
for 2-aminopyrimidine, the title compound is obtained. 
EXAMPLE 58 
2-[3-[4-[(4-Fluorophenyl)[(4-fluorophenyl)amino]methyl]-1-piperidinyl]propy 
l]-1H-isoindole-1,3-(2H)dione 
Following the procedure of Example 2, the title compound is obtained from 
N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamine and 
N-(3-bromopropyl)phthalimide. 
EXAMPLE 59 
4-[(4-Fluorophenyl)[(4-fluorophenyl)amino]methyl]-1-piperidinepropanamine 
Equimolar amounts of 
N,.alpha.-bis(4-fluorophenyl)-1-(3-phthalimido)propyl-4-piperidinemethanam 
ine and 85% hydrazine hydrate are heated together in absolute ethanol until 
the reaction is complete. The mixture is cooled, diluted with water, 
acidified, filtered, concentrated, and the residue partitioned between 
dilute aqueous sodium hydroxide and methylene chloride. The methylene 
chloride solution is dried and concentrated to obtain the title compound. 
EXAMPLE 60 
N-[3-[4-[(4-Fluorophenyl)[(4-fluorophenyl)amino]methyl]-1-piperidinyl]propy 
l]-N'-methylurea 
The compound of Example 59 is reacted with methyl isocyanate in an aprotic 
solvent to obtain the title compound. 
EXAMPLE 61 
N-[3-[4-[(4-Fluorophenyl)[(4-fluorophenyl)amino]methyl]-1-piperidinyl]propy 
l]-N'-phenylurea 
The compound of Example 59 is reacted with phenyl isocyanate in an aprotic 
solvent to obtain the title compound. 
EXAMPLE 62 
Following the procedure of Example 2, and substituting for 
3-chloro-1-(4-acetyl-2-methoxyphenoxy)propane 
a. cyclopropylmethylbromide 
b. 1-iodo-2,2,2-trifluoroethane 
c. 2-bromoethanol 
d. 4-bromo-2-methyl-2-butene 
e. 3-bromopropene 
f. 6-(2-chloroethyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidine-5-one (EP 
0110435) 
g. 1-benzyl-3-chloroethylimidozolidin-2-one (Neth. Appl. 6,410,202; CA 63 
11572b) 
there is correspondingly obtained 
a. 
1-(cyclopropylmethyl)-N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamin 
e 
b. 
N,.alpha.-bis(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-4-piperidinemethana 
mine 
c. 4-[(4-fluorophenyl)[(4-fluorophenyl)amino]methyl]-1-piperidineethanol 
d. 
N,.alpha.-bis(4-fluorophenyl)-1-(3-methyl-2-butenyl)-4-piperidinemethanami 
ne 
e. N,.alpha.-bis(4-fluorophenyl)-1-(2-propenyl)-4-piperidinemethanamine 
f. 
6-[2-[4-[(4-fluorophenyl)[(4-fluorophenyl)amino]methyl]-1-piperidinyl]ethy 
l]-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 
g. 
1-[2-[4-[(4-fluorophenyl)](4-fluorophenyl)amino]methyl]-1-piperidinyl]ethy 
l-3-(phenylmethyl)-2,3-dihydro-1H-benzimidazol-2-one. 
EXAMPLE 63 
4-[[4-(3,4-Difluorophenyl)amino](4-fluorophenyl)methyl]-1-piperidinyl]-1-(4 
-fluorophenyl)-1-butanone 
Following the procedure of Example 2, the title compound is prepared by 
first reacting 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane with 
N-(3,4-difluorophenyl)-.alpha.-(4-fluorophenyl)-4-piperidinemethanamine 
followed by hydrolysis of the ethyleneglycol ketal with dilute acid. 
EXAMPLE 64 
4-[[(3,4-Difluorophenyl)amino](4-fluorophenyl)methyl]-.alpha.-(4-fluorophen 
yl)-1-piperidinebutanol 
The compound of Example 63 is reduced with sodium borohydride by procedures 
known to those skilled in the art to obtain the title compound. 
EXAMPLE 65 
1-[3-[(4-Chlorophenyl)thio]propyl]-N-(3,4-difluorophenyl)-.alpha.-(4-fluoro 
phenyl)-4-piperidinemethanamine 
Following the procedure of Example 2, the title compound is prepared from 
1-chloro-4[(3-chloropropyl)thio]benzene [J. Amer. Chem. Soc. 82, 2505 
(1960)] and 
N-(3,4-dichlorophenyl)-.alpha.-(4-fluorophenyl)-4-piperidinemethanamine. 
EXAMPLE 66 
1-[3-[(4-Chlorophenyl)sulfinyl]propyl]-N-(3,4-difluorophenyl)-.alpha.-(4-fl 
uorophenyl)-4-piperidinemethanamine 
Following the procedure of Example 2, the title compound is prepared from 
1-chloro-4-[(3-chloropropyl)sulfinyl]benzene and 
N-(3,4-difluorophenyl)-.alpha.-(4-fluorophenyl)-4-piperidinemethanamine. 
EXAMPLE 67 
1-[3-[(4-Chlorophenyl)sulfonyl]propyl]-N-(3,4-difluorophenyl)-.alpha.-(4-fl 
uorophenyl)-4-piperidinemethanamine 
Following the procedure of Example 2, the title compound is prepared from 
1-chloro-4-[(3-chloropropyl)sulfonyl]benzene and 
N-(3,4-difluorophenyl)-.alpha.-(4-fluorophenyl)-4-piperidinemethanamine. 
EXAMPLE 68 
Following the procedure of Example 35 and substituting for 
2-(2-bromoethoxy)naphthalene, 
a. 4-(3-chloropropyloxy)benzoic acid 1-methylethyl ester 
b. 2-(2-bromoethyl)naphthalene 
there is obtained respectively 
a. 
4-[3-[4-[[(3,4-difluorophenyl)amino](4-fluorophenyl)methyl]-1-piperidinyl] 
propoxy]benzoic acid 1-methylethyl ester 
b. 
N-(3,4-difluorophenyl)-.alpha.-(4-fluorophenyl)-1-[2-(2-naphthylenyl)ethyl 
]-4-piperidinemethanamine. 
EXAMPLE 69 
N,.alpha.-bis(3,4-Difluorophenyl)-1-(2-naphthalenylmethyl)-4-piperidinemeth 
anamine 
Following the procedure of Example 4, the title compound is obtained from 
4-(3,4-difluorobenzoyl)-1-(2-naphthalenylmethyl)-4-piperidinemethanamine 
and 3,4-difluoroaniline. 
EXAMPLE 70 
.alpha.-(3,4-Difluorophenyl)-N-(4-fluorophenyl)-1-(2-naphthalenylmethyl)-4- 
piperidinemethanamine 
Following the procedure of Example 4, the title compound is obtained from 
4-(3,4-difluorobenzoyl)-1-(2-naphthalenylmethyl)-4-piperidinemethanamine 
and 4-fluoroaniline. 
EXAMPLE 71 
N-[(4-Fluorophenyl)[1-(3-phenoxypropyl)-4-piperidinyl]methyl]-2-pyrimidinam 
ine 
.alpha.-(4-Fluorophenyl)-1-(3-phenoxypropyl)-4-piperidinemethanamine and 
2-chloropyrimidine (equimolar quantities) are heated together in 
tetrahydrofuran at reflux temperature until the reaction is judged 
complete. The reaction mixture is concentrated and the residual material 
is partitioned between 1N NaOH solution and methylene chloride. The 
methylene chloride layer is dried and concentrated to obtain the title 
compound. 
EXAMPLE 72 
Following the procedure of Example 4, there is obtained from 
(4-fluorophenyl)[1-(2-naphthalenylmethyl)-4-piperidinyl]methanone and 
a. 4-methoxyaniline 
b. 4-chloroaniline 
c. 2,4-difluoroaniline 
d. 4-trifluoromethylaniline 
the following compounds respectively: 
a. 
.alpha.-(4-fluorophenyl)-N-(4-methoxyphenyl)-1-(2-naphthalenylmethyl)-4-pi 
peridinemethanamine 
b. 
N-(4-chlorophenyl)-.alpha.-(4-fluorophenyl)-1-(2-naphthalenylmethyl)-4-pip 
eridinemethanamine 
c. 
N-(2,4-difluorophenyl-.alpha.-(4-fluorophenyl)-1-(2-naphthalenylmethyl)-4- 
piperidinemethanamine 
d. 
.alpha.-(4-fluorophenyl)-1-(2-naphthalenylmenthyl)-N-(4-trifluoromethylphe 
nyl)-4-piperidinemethanamine. 
EXAMPLE 73 
Following the procedure of Example 4 and substituting for 
4-(4-fluorophenyl)[1-(1-methylethyl)-4-piperidinyl]methanone hydrochloride 
the following: 
a. 1-(3-phenoxypropyl)-3-(3-trifluoromethylbenzoyl)pyrrolidine 
b. 3-(4-fluorobenzoyl)-1-(2-naphthalenylmethyl)azetidine 
c. 2-(4-fluorobenzoyl)-1-(3-phenoxypropyl)azetidine 
d. 1-benzyl-3-(4-fluorobenzoyl)pyrrolidine 
e. 1-benzyl-3-(3-trifluoromethylbenzoyl)pyrrolidine 
f. 1-(2-ethoxyethyl)-3-(4-fluorobenzoyl)pyrrolidine 
there are obtained respectively: 
a. 
N-(4-fluorophenyl)-1-(3-phenoxypropyl)-.alpha.-(3-trifluoromethoxyphenyl)- 
3-pyrrolidinemethanamine 
b. 
N,.alpha.-bis(4-fluorophenyl)-1-(2-naphthalenylmethyl)-3-azetidinemethanam 
ine 
c. N,.alpha.-bis(4-fluorophenyl)-1-(3-phenoxypropyl)-2-azetidinemethanamine 
d. 1-benzyl-N,.alpha.-bis(4-fluorophenyl)-3-pyrrolidinemethanamine 
e. 
1-benzyl-N-(4-fluorophenyl)-.alpha.-(3-trifluoromethylphenyl)-3-pyrrolidin 
emethanamine 
f. 
1-(2-ethoxyethyl)-N,.alpha.-bis(4-fluorophenyl)-3-pyrrolidinemethanamine. 
EXAMPLE 74 
Following the procedure of Example 4 and substituting for 
4-(4-fluorophenyl)[1-(1-methylethyl)-4-piperidinyl]methanone hydrochloride 
the following: 
a. 2-(4-fluorobenzoyl)-1-(3-phenoxypropyl)pyrrolidine 
b. 2-(4-fluorobenzoyl)-1-(3-phenoxypropyl)piperidine 
there are obtained respectively: 
a. 
N,.alpha.-bis(4-fluorophenyl)-1-(3-phenoxypropyl)-2-pyrrolidinemethanamine 
b. 
N,.alpha.-bis(4-fluorophenyl)-1-(3-phenoxypropyl)-2-piperidinemethanamine. 
EXAMPLE 75 
N-[3-[4-[(4-Fluorophenyl)[4-fluorophenyl)amino]methyl]-1-piperidinyl]propyl 
]guanidine 
The compound of Example 59 and S-methylisothiouronium sulfate are reacted 
together according to the procedure of J. Amer. Chem. Soc. 71, 2476 (1979) 
to obtain the title compound. 
EXAMPLE 76 
.alpha.-(3,4-dichlorophenyl)-N-(4-fluorophenyl)-4-piperidinemethanamine 
The title compound is obtained following the procedure of Example 31 and 
using 4-(3,4-dichlorobenzoyl)piperidine hydrochloride and 4-fluoroaniline. 
EXAMPLE 77 
Following the procedure of Example 2 and using 
.alpha.-(3,4-dichlorophenyl)-N-(4-fluorophenyl)-4-piperidinemethanamine 
and the following: 
a. 3-chloropropyloxybenzene 
b. 2-bromomethylnaphthalene 
there are obtained respectively: 
a. 
.alpha.-(3,4-dichlorophenyl)-N-(4-fluorophenyl)-1-(3-phenoxypropyl)-4-pipe 
ridinemethanamine 
b. 
.alpha.-(3,4-dichlorophenyl)-N-(4-fluorophenyl)-1-(2-naphthylenylmethyl)-4 
-piperidinemethanamine. 
EXAMPLE 78 
N-(4-Fluorophenyl)-.alpha.-phenyl-3-piperidinemethanamine 
The title compound is obtained from 4-fluoroaniline and 3-benzoylpiperidine 
hydrochloride using the procedure of Example 31. 
EXAMPLE 79 
1-[4-[3-[3-[[(4-Fluorophenyl)amino]phenylmethyl]-1-piperidinyl]propoxy]-3-m 
ethoxyphenyl]ethanone 
Following the procedure of Example 2, the title compound is obtained where 
N-(4-fluorophenyl)-.alpha.-phenyl-3-piperidinemethanamine is substituted 
for N,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanamine. 
EXAMPLE 80 
N-(3,4-Difluorophenyl)-.alpha.-(4-fluorophenyl)-1-[3-(2-naphthalenyloxy)pro 
pyl]-4-piperidinemethanamine dihydrochloride 
A mixture of 
4-[[(3,4-difluorophenyl)amino](4-fluorophenyl)methyl]piperidine (4.70 g, 
0.0147 mol), 2-(3-chloropropyloxy)naphthalene) (3.23 g, 0.0147 mol), and 
sodium bicarbonate (5.53 g, 0.0658 mol) in 350 mL of 1-butanol containing 
sodium iodide was heated at reflux for 24 h. The butanol was removed by 
rotary evaporator and the residue partitioned between chloroform and 
water. The chloroform layer was washed with 5% sodium hydroxide, dried 
(Na.sub.2 SO.sub.4) and filtered. Chloroform was removed to give a brown 
oil. This oil was dissolved in methylene chloride and placed on a 300 g 
silica gel column for flash chromatography. Elution was accomplshed using 
methylene chloride, 1% methanol-methylene chloride, and 2% 
methanol-methylene chloride. Fractions of similar purity were combined and 
solvents removed to give a dark brown oil. This material was converted to 
the HCl salt and recrystallized from methanol-diethyl ether. A white solid 
was isolated and dried 16 h in vacuo at 80.degree. C. This procedure 
produced 5.08 g (59.8%) of white crystalline solid, mp 
225.degree.-226.degree. C. 
Analysis calculated for: C.sub.31 H.sub.31 N.sub.2 OF.sub.3.2HCl: C, 64.47; 
H, 5.76; N, 4.85. Found: C, 64.53; H, 5.89; N, 4.80. 
EXAMPLE 81 
N-(3,4-Difluorophenyl)-.alpha.-(4-fluorophenyl)-1-[2-(1-naphthalenyloxy)eth 
yl]-4-piperidinemethanamine dihydrochloride 
A mixture of 
4-[[(3,4-difluorophenyl)amino](4-fluorophenyl)methyl]piperidine (5.41 g, 
0.0169 mol), 1-(2-bromoethoxy)naphthalene (4.23 g, 0.0169 mol) and sodium 
bicarbonate (5.53 g, 0.059 mol) in 350 mL of 1-butanol containing sodium 
iodide (0.2 g) was heated 20 h at reflux. The reaction was concentrated to 
dryness and partitioned between chloroform and water. The chloroform layer 
was washed with 5% sodium hydroxide and dried (Na.sub.2 SO.sub.4). 
Chloroform was removed to give a brown oil. The oil was dissolved in 
methylene chloride and placed on a silica gel column for flash 
chromatography. Elution was accomplished using 1% methanol-methylene 
chloride and 2% methanol-methylene chloride. Fractions of similar purity 
were combined and solvents removed to give a fluffy grey material. This 
material was converted to the HCl salt and the salt was recrystallized 
from methanol-diethyl ether to give a whitish-grey solid. The material was 
dried 16 h in vacuo at 80.degree. C. This process provided 5.06 g (53.1%) 
of greyish material, mp 212.degree.-215.degree. C. (dec). 
Analysis calculated for: C.sub.30 H.sub.29 N.sub.2 OF.sub.3.2HCl: C, 63.95; 
H, 5.54; N, 4.97. Found: C, 63.78; H, 5.63; N, 4.95. 
EXAMPLE 82 
N-(3,4-Difluorophenyl)-.alpha.-(4-fluorophenyl)-1-(2-phenoxyethyl)-4-piperi 
dinemethanamine dihydrochloride 
A mixture of 
N-(3,4-difluorophenyl)-.alpha.-(4-fluorophenyl)-4-piperidinemethanamine 
(5.45 g, 0.0170 mol), 2-bromoethylphenyl ether (3.42 g, 0.0170 mol) and 
sodium bicarbonate (5.53 g, 0.0658 mol) in 1-butanol (350 mL) containing 
sodium iodide (0.2 g) was heated 16 h at reflux. The solvent was removed 
and the residue partitioned between water and chlorform. The chloroform 
layer was washed with water and 5% sodium hydroxide. The chloroform was 
dried (Na.sub.2 SO.sub.4), filtered and the chloroform was removed to give 
a brown oil. This material was subjected to flash chromatography on silica 
gel. Elution was accomplished using 1% methanol-methylene chloride and 2% 
methanol-methylene chloride. Fractions of similar purity were combined and 
solvents removed to give a brown oil. This material was converted to the 
hydrochloride salt and recrystallized from methanol-diethyl ether. A white 
solid was isolated and dried 16 h in vacuo at 80.degree. C. This process 
provided 5.55 g (63.6%) of white crystalline solid, mp 211.degree.- 
215.degree. C. 
Analysis calculated for: C.sub.26 H.sub.27 F.sub.3 N.sub.2 O.2HCl: C, 
60.82; H, 5.69; N, 5.46. Found: C, 60.47; H, 5.77; N, 5.41. 
EXAMPLE 83 
N,.alpha.-bis(4-Fluorophenyl)-3-pyrrolidinemethanamine 
The title compound is prepared from 4-fluoroaniline and 
3-(4-fluorobenzoyl)pyrrolidine hydrochloride according to the procedure of 
Example 31. 
EXAMPLE 84 
N,.alpha.-bis(4-Fluorophenyl)-3-piperidinemethanamine 
The title compound is prepared from 4-fluoroaniline and 
3-(4-fluorobenzoyl)piperidine hydrochloride according to the procedure of 
Example 31. 
EXAMPLE 85 
N,.alpha.-bis(4-Fluorophenyl)-1-(3-phenoxypropyl)-3-pyrrolidinemethanamine 
The title compound is prepared from 
N,.alpha.-bis(4-fluorophenyl)-3-pyrrolidinemethanamine hydrochloride and 
3-phenoxypropylbromide according to the procedure of Example 8. 
EXAMPLE 86 
N,.alpha.-bis(4-Fluorophenyl)-1-(3-phenoxypropyl)-3-piperidinemethanamine 
The title compound is prepared from 
N,.alpha.-bis(4-fluorophenyl)-3-pyrrolidinemethanamine hydrochloride and 
3-phenoxypropyl bromide according to the procedure of Example 8. 
EXAMPLE 87 
Using the procedures of Example 8 and replacing 3-phenoxypropyl bromide 
with 
a. 1-(2-chloroethyl)-3-methyl-2-imidazolidinone 
b. 1-(2-chloroethyl)-3-butyl-2-imidazolidinone 
c. 1-(2-chloroethyl)-2-imidazolidinone 
d. 1-(3-chloropropyl)-2-imidazolidinone 
e. 1-(2-chloroethyl)-2-benzimidazolidinone 
there are obtained respectively 
a. 
1-[2-[4-[(4-fluorophenyl)[(4-fluorophenyl)amino]methyl]-1-piperidinyl]ethy 
l]-3-methyl-2-imidazolidinone 
b. 
1-[2-[4-[(4-fluorophenyl)[(4-fluorophenyl)amino]methyl]-1-piperidinyl]ethy 
l]-3-butyl-2-imidazolidinone 
c. 
1-[2-[4-[(4-fluorophenyl)[(4-fluorophenyl)amino]methyl]-1-piperidinyl]ethy 
l]-2-imidazolidinone 
d. 
1-[3-[4-[(4-fluorophenyl)[(4-fluorophenyl)amino]methyl]-1-piperidinyl]prop 
yl]-2-imidazolidinone 
e. 
1-[2-[4-[(4-fluorophenyl)[(4-fluorophenyl)amino]methyl]-1-piperidinyl]ethy 
l]-1,3-dihydro-2H-benzimidazol-2-one. 
EXAMPLE 88 
N,.alpha.-bis(4-fluorophenyl)-N-methyl-1-(3-phenoxypropyl)-4-piperidinylmet 
hanamine 
The title compound is prepared from 
N,.alpha.-bis(4-fluorophenyl)-1-(3-phenoxypropyl)-4-piperidinemethanamine 
and methyl iodide by usual alkylation conditions known to those skilled in 
the art. 
3 TABLE 1 
##STR20## 
Ex. No. (X)m R Ring Position Ring Size (Q).sub.n 
Ar R' Salt 1 4-F H 4 6 4-FC.sub.6 H.sub.4 H 0.5 H.sub.2 O 
2 4-F H 4 6 4-FC.sub.6 
H.sub.4 
##STR21## 
0.5 H.sub.2 O 3 4-F H 4 6 4-FC.sub.6 H.sub.4 CH.sub.2 CHCHC.sub.6 
H.sub.5 C.sub.6 H.sub.5 CHCHCH.sub.2.sup..sym. Cl.sup..crclbar. 4 4-F H 
4 6 4-FC.sub.6 H.sub.4 CH(CH.sub.3).sub.2 2 HCl.H.sub.2 O 5 4-F H 4 6 
4-FC.sub.6 H.sub.4 CH.sub.2 CHCHC.sub.6 H.sub. 5 2 HCl.H.sub.2 O 6 4-F 
H 4 6 4-FC.sub.6 H.sub.4 CH.sub.2CH(OH)CH.sub.2 OC.sub.6 H.sub.5 2 
HCl.0.5 H.sub.2 O 7 4-F H 4 6 4-FC.sub.6 H.sub.4 CH.sub.2CH(OH)CH.sub.2 
OC.sub.6 H.sub.5 2 HCl.0.5 H.sub.2 O (low melting diasteriomers) 
8 4-F H 4 6 4-FC.sub.6 H.sub.4 (CH.sub.2).sub.3 OC.sub.6 H.sub.5 2 
HCl.0.5 H.sub.2 O 9 4-F H 4 6 4-FC.sub.6 
H.sub.4 
##STR22## 
-- 10 4-F H 4 6 4-FC.sub.6 
H.sub.4 
##STR23## 
-- 11 4-F H 4 6 4-FC.sub.6 H.sub.4 (CH.sub.2).sub.4 OC.sub.6 H.sub.5 2 
HCl 
12 4-F 
##STR24## 
4 6 4-FC.sub.6 
H.sub.4 
##STR25## 
oxalate.0.5 H.sub.2 O 13 4-F H 4 6 4-FC.sub.6 
H.sub.4 
##STR26## 
0.5 H.sub.2 O 14 4-F H 4 6 4-FC.sub.6 
H.sub.4 
##STR27## 
0.5 H.sub.2 O 15 4-F H 4 6 4-FC.sub.6 
H.sub.4 
##STR28## 
-- 16 4-F H 4 6 4-FC.sub.6 
H.sub.4 
##STR29## 
0.5 H.sub.2 O 17 4-F H 4 6 4-FC.sub.6 
H.sub.4 
##STR30## 
-- 18 4-F H 4 6 4-FC.sub.6 
H.sub.4 
##STR31## 
oxalate.0.5 H.sub.2 O 19 4-F H 4 6 4-FC.sub.6 
H.sub.4 
##STR32## 
-- 20 4-F H 4 6 4-FC.sub.6 
H.sub.4 
##STR33## 
2 HCl 21 4-F H 4 6 4-FC.sub.6 H.sub.4 H(+)isomer 2.5 HCl 22 4-F H 4 6 
4-FC.sub.6 H.sub.4 H(-)isomer 3 HCl 23 4-F H 4 6 4-FC.sub.6 H.sub.4 
CH.sub.2 C.sub.6 H.sub.5 2 HCl 24 4-F H 4 6 4-FC.sub.6 
H.sub.4 
##STR34## 
2 HCl 25 4-F H 4 6 4-FC.sub.6 
H.sub.4 
##STR35## 
2 HCl 26 4-F H 4 6 4-FC.sub.6 H.sub.4 cyclohexyl 2 HCl.0.5 H.sub.2 O 
27 4-F H 4 6 4-FC.sub.6 H.sub.4 CH.sub.2 CH(CH.sub.3).sub.2 2 HCl.0.5 
H.sub.2 O 28 4-F H 4 6 4-FC.sub.6 
H.sub.4 propyl 2 HCl.0.5 H.sub.2 O 29 
4-F H 4 6 4-FC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 OC.sub.2 H.sub.5 2 
HCl.0.5 H.sub.2 O 30 4-F H 4 6 4-FC.sub.6 H.sub.4 H -- 31 4-F H 4 6 
3,4-diFC.sub.6 H.sub.3 H 2 HCl.0.5 H.sub.2 O 32 4-F H 4 6 3,4-diFC.sub.6 
H.sub.3 (CH.sub.2).sub.3 OC.sub.6 H.sub.5 oxalate 
33 4-F H 4 6 3,4-diFC.sub.6 
H.sub.3 
##STR36## 
oxalate.0.5 H.sub.2 O 34 4-F H 4 6 3,4-diFC.sub.6 
H.sub.3 
##STR37## 
2 HCl 35 4-F H 4 6 3,4-diFC.sub.6 
H.sub.3 
##STR38## 
2 HCl 36 4-F H 4 6 4-FC.sub.6 H.sub.4CH.sub.2 H 2 HCl.1.5 H.sub.2 O 37 
4-F H 4 6 4-FC.sub.6 H.sub.4CH.sub.2 CH.sub.2 CH.sub.2 C.sub.6 H.sub.5 
1.5 fumarate 
38 4-F 
##STR39## 
4 6 4-FC.sub.6 H.sub.4CH.sub.2 CH.sub.2 CH.sub.2 C.sub.6 H.sub.5 
fumarate 
39 4-F 
##STR40## 
4 6 4-FC.sub.6 H.sub.4CH.sub.2 CH.sub.2 CH.sub.2 C.sub.6 H.sub.5 1.5 
fumarate 40 4-F H 4 6 4-FC.sub.6 H.sub.4CH.sub.2 (CH.sub.2).sub.3 
OC.sub.6 H.sub.5 2 HCl.0.5 H.sub.2 O 41 4-F H 4 6 4-FC.sub.6 
H.sub.4CH.sub.2 
##STR41## 
2 HCl.0.5 H.sub.2 O 42 4-F H 4 6 4-FC.sub.6 
H.sub.4CH.sub.2 C(O)NHCH.sub.3 fumarate 
43 4-F 
##STR42## 
4 6 4-FC.sub. 6 
H.sub.4CH.sub.2 
##STR43## 
-- 44 4-F CH.sub.3 C(O) 4 6 4-FC.sub.6 
H.sub.4CH.sub.2 (CH.sub.2).sub.3 OC.sub.6 H.sub.5 fumarate 45 4-F 
##STR44## 
4 6 4-FC.sub.6 
H.sub.4CH.sub.2 
##STR45## 
-- 46 4-F H 4 6 C.sub.6 H.sub.5CH.sub.2 CH.sub.2 H 2 fumarate.0.5 
H.sub.2 O 47 4-F H 4 6 C.sub.6 H.sub.5CH.sub.2 
CH.sub.2 
##STR46## 
2 fumarate.H.sub. 2 O 48 4-F H 4 6 C.sub.6 H.sub.5CH.sub.2 CH.sub.2 
##STR47## 
0.75 fumarate.0.5 H.sub.2 O 49 4-F H 4 6 C.sub.6 H.sub.5CH.sub.2 
CH.sub.2 
##STR48## 
0.5 fumarate.0.5 H.sub. 2 O 
50 4-F 
##STR49## 
4 6 C.sub.6 H.sub.5CH.sub.2 
CH.sub.2 
##STR50## 
-- 51a H H 4 6 C.sub.6 
H.sub.5 
##STR51## 
-- 51b 4-CF.sub.3 H 4 6 C.sub.6 
H.sub.5 
##STR52## 
-- 51c 4-CH.sub.3 O H 4 6 C.sub.6 
H.sub.5 
##STR53## 
-- 51d 4-F H 4 6 C.sub.6 
H.sub.5 
##STR54## 
-- 52 4-F H 4 6 2-pyridyl (CH.sub.2).sub.3OC.sub.6 H.sub.5 -- 53 4-F 
H 4 6 4FC.sub.6 
H.sub.4 
##STR55## 
-- 54 4-F H 4 6 4-FC.sub. 6 H.sub.4 (CH.sub.2).sub.3 Cl -- 55 4-F H 4 
6 4-FC.sub.6 
H.sub.4 
##STR56## 
-- 56 4-F H 4 6 4-FC.sub.6 H.sub.4 (CH.sub.2).sub.3 NHC.sub.6 H.sub.5 
-- 57 4-F H 4 6 4-FC.sub.6 
H.sub.4 
##STR57## 
-- 58 4-F H 4 6 4-FC.sub.6 
H.sub.4 
##STR58## 
-- 59 4-F H 4 6 4-FC.sub.6 H.sub.4 (CH.sub.2).sub.3 NH.sub.2 -- 60 
4-F H 4 6 4-FC.sub.6 
H.sub.4 
##STR59## 
-- 61 4-F H 4 6 4-FC.sub.6 
H.sub.4 
##STR60## 
-- 62a 4-F H 4 6 4-FC.sub.6 
H.sub.4 
##STR61## 
-- 62b 4-F H 4 6 4-FC.sub.6 H.sub.4 CH.sub.2 CF.sub.3 -- 62c 4-F H 4 
6 4-FC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 OH -- 62d 4-F H 4 6 4-FC.sub.6 
H.sub.4 CH.sub.2 CHC(CH.sub.3).sub.2 -- 62e 4-F H 4 6 4-FC.sub.6 
H.sub.4 CH.sub.2 CHCH.sub.2 -- 62f 4-F H 4 6 4-FC.sub.6 H.sub.4 
##STR62## 
-- 62g 4-F H 4 6 4-FC.sub.6 
H.sub.4 
##STR63## 
-- 63 4-F H 4 6 3,4-diFC.sub.6 
H.sub.3 
##STR64## 
-- 64 4-F H 4 6 3,4-diFC.sub.6 
H.sub.3 
##STR65## 
-- 65 4-F H 4 6 3,4-diFC.sub.6 
H.sub.3 
##STR66## 
-- 66 4-F H 4 6 3,4-diFC.sub.6 
H.sub.3 
##STR67## 
-- 67 4-F H 4 6 3,4-diFC.sub.6 
H.sub.3 
##STR68## 
-- 68a 4-F H 4 6 3,4-diFC.sub.6 
H.sub.3 
##STR69## 
-- 68b 4-F H 4 6 3,4-diFC.sub.6 
H.sub.3 
##STR70## 
-- 69 3,4-diF H 4 6 3,4-diFC.sub.6 
H.sub.3 
##STR71## 
-- 70 3,4-diF H 4 6 4-FC.sub.6 
H.sub.4 
##STR72## 
-- 
71 4-F H 4 6 
##STR73## 
(CH.sub.2).sub.3 OC.sub.6 H.sub.5 -- 72a 4-F H 4 6 4-CH.sub.3 
OC.sub.6 
H.sub.4 
##STR74## 
-- 72b 4-F H 4 6 4-ClC.sub.6 
H.sub.4 
##STR75## 
-- 72c 4-F H 4 6 3,4-diFC.sub.6 
H.sub.4 
##STR76## 
-- 72d 4-F H 4 6 4-CF.sub.3 C.sub.6 
H.sub.4 
##STR77## 
-- 73a 3-CF.sub.3 H 3 5 4-FC.sub.6 H.sub.4 (CH.sub.2).sub.3 OC.sub.6 
H.sub.5 -- 73b 4-F H 3 4 4-FC.sub.6 H.sub.4 (CH.sub.2).sub.3 OC.sub.6 
H.sub.5 -- 73c 4-F H 2 4 4-FC.sub.6 H.sub.4 (CH.sub.2).sub.3 OC.sub.6 
H.sub.5 -- 73d 4-F H 3 5 4-FC.sub.6 H.sub.4 CH.sub.2 C.sub.6 H.sub.5 -- 
73e 3-CF.sub.3 H 3 5 4-FC.sub.6 H.sub.4 CH.sub.2 C.sub.6 H.sub.5 -- 
73f 4-F H 3 5 4-FC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 OC.sub.2 H.sub.5 -- 
74a 4-F H 2 5 4-FC.sub.6 H.sub.4 (CH.sub.2).sub.3 OC.sub.6 H.sub.5 -- 
74b 4-F H 2 6 4-FC.sub.6 H.sub.4 (CH.sub.2).sub.3 OC.sub.6 H.sub.5 -- 
75 4-F H 4 6 4-FC.sub.6 
H.sub.4 
##STR78## 
-- 76a 3,4-diCl H 4 6 4-FC.sub.6 H.sub.4 H -- 77a 3,4-diCl H 4 6 
4-FC.sub.6 H.sub.4 (CH.sub.2).sub.3 OC.sub.6 H.sub.5 -- 77b 3,4-diCl H 
4 6 4-FC.sub.6 
H.sub.4 
##STR79## 
-- 78 H H 3 6 4-FC.sub.6 H.sub.4 H -- 79 H H 3 6 4-FC.sub.6 H.sub.4 
##STR80## 
-- 80 4-F H 4 6 3,4-diFC.sub.6 
H.sub.3 
##STR81## 
2 HCl 81 4-F H 4 6 3,4-diFC.sub.6 
H.sub.3 
##STR82## 
2 HCl 82 4-F H 4 6 3,4-diFC.sub.6 H.sub.3 (CH.sub.2).sub.2 OC.sub.6 
H.sub.5 2 HCl 83 4-F H 3 5 4-FC.sub.6 
H.sub.5 H -- 84 4-F H 3 6 4-FC.sub.6 
H.sub.4 H -- 85 4-F H 3 5 4-FC.sub.6 H.sub.4 (CH.sub.2).sub.3 OC.sub.6 
H.sub.5 -- 86 4-F H 3 6 4-FC.sub.6 H.sub.4 (CH.sub.2).sub.3 OC.sub.6 
H.sub.5 -- 87a 4-F H 4 6 4-FC.sub.6 
H.sub.4 
##STR83## 
-- 87b 4-F H 4 6 4-FC.sub.6 
H.sub.4 
##STR84## 
-- 87c 4-F H 4 6 4-FC.sub.6 
H.sub.4 
##STR85## 
-- 87d 4-F H 4 6 4-FC.sub.6 
H.sub.4 
##STR86## 
-- 87e 4-F H 4 6 4-FC.sub.6 
H.sub.4 
##STR87## 
-- 88 4-F CH.sub.3 4 6 4-FC.sub.6 H.sub.4 (CH.sub.2).sub.3 OC.sub.6 
H.sub.5 
PHARMACOLOGICAL METHODS 
Screening Method for Calcium Channel Blocking Activity in Isolated Rabbit 
Aorta 
Spiral strips of thoracic aorta are obtained from nonfasted New Zealand 
white rabbits killed by cervical dislocation. The aortic strips are 
prepared by the method of Furchgott, R. F. and Bhadrakom, S. (1953) J. 
Pharmacol. Exp. Ther. 108:129-143 and suspended in a modified Krebs 
solution aerated with a mixture of 95% oxygen and 5% carbon dioxide. 
Measurements of tissue isometric contractions are made with Grass 
force-displacement transducers (FT03C). Experiments were conducted 
according to the method of Godfraind, T. and Kaba, A. (1969) Br. J. 
Pharmacol. 6:549-560. Briefly, the strips were sequentially bathed in a 
modified Krebs solution containing calcium chloride, 2.6 mM; a 
calcium-free modified Krebs buffer: and then in a depolarizing 
calcium-free buffer containing 100 nM potassium chloride. Cumulative 
addition of calcium chloride to the last buffer induces isometric 
contractions of the tissue, which are measured and recorded on a Grass 
polygraph (Model 7). Contractile responses induced by calcium chloride are 
conducted in the absence and then followed by the presence of the test 
compound and then are compared. Responses of at least three aortic strips 
are used to calculate Pa.sub.2 values according to the method of Van 
Rossum, J. M. (1963) Arch. Int. Pharmacodyn. 143:299-330. 
In this test the more active compounds such as those of Examples 2, 6, and 
14 had pA.sub.2 values of 8.80, 7.99, and 8.49 respectively as compared to 
the reference compound verapamil (Pa.sub.2 =8.0). 
Test Method for Antihypertensive Effect of Orally Administered Drugs to 
Unanesthetized Spontaneously Hypertensive Rats 
At least 24 hours prior to compound administration, adult male 
spontaneously hypertensive rats (SHR) are anesthetized with sodium 
pentobarbital (50 mg/kg IP). A polyethylene catheter (PE-50) is implanted 
in a carotid artery or the abdominal aorta for the direct measurement of 
arterial blood pressure. The catheter is exteriorized at the nape of the 
neck and connected through a swivel device to a Statham P23(Id) pressure 
transducer. Blood pressure is displayed on a Grass polygraph (Model 7) and 
simultaneously digitized and collected with a Buxco Electronics 
Datalogger. Data are obtained from conscious, freely moving rats that are 
allowed free access to food and water. After obtaining baseline blood 
pressure data for 1-1.5 hours, compounds are administered orally as 
solutions or as uniform suspensions (30 mg/kg in 5 mL/kg of 0.5 Tween 80 
in distilled water or other suitable vehicle as necessary). Blood pressure 
are measured at 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 24 hours after dosing. The 
mean arterial blood pressure (MABP) values obtained at these intervals are 
used to calculate an average percent change from predose MABP for the 
0.5-2.0 hour, 3-6 hour, and 24 hour periods. Raw blood pressure are 
analyzed by a paired, one-tailed t-test. Decreases in MABP are considered 
statistically significant when &lt;0.05. 
The more active compounds such as those of Examples 20 and 35 are effective 
in lowering blood pressure in the spontaneously hypertensive rats. 
Procedure for Determinating Effect of Compounds on Coronary Blood Flow 
The procedure used to determine the effect of the aforementioned compounds 
on coronary arterial blood flow is described as follows. 
Mongrel dogs of either sex were anesthetized with phenobarbital sodium (100 
mg/kg) and pentobarbital sodium (100 mg total dose). The trachea was 
surgically exposed, a tracheal tube was inserted and the dog was 
artificially respired with room air using a Harvard Model 613 Respirator. 
The heart was exposed by a left thoracotomy at the fourth intercostal 
space. An approximately 1.5 cm segment of the left arterior descending 
coronary artery was exposed and a Statham electromagnetic blood flow probe 
was implanted around the vessel. The flow probe was implanted around the 
vessel. The flow probe cable was connected to a Statham Model 2201 Blood 
Flow Meter. Continuous recordings of carotid arterial blood pressure, and 
a coronary arterial blood flows, were obtained using a Grass Model 5 
Polygraph. 
The compounds were administered via a femoral vein. Changes in both 
magnitude and duration of change in coronary blood flow from pre-drug 
levels were determined. Generally, multiple doses of the compounds tested 
were administered to a single dog. Appropriate intervals between doses 
were allowed to permit the blood flow to return to control levels. 
Illustratively, the compounds of Examples 20 and 35 showed an increase in 
coronary arterial blood flow of about 75-120 mL/min at 1 mg/kg IV. 
Pharmaceutical Compositions and Administration 
Compositions for administration to living animals are comprised of at least 
one of the compounds of Formula I according to the methods of treatment of 
the invention in association with a pharmaceutical carrier or excipient. 
Effective quantities of the compounds may be administered in any one of 
various ways, for example, orally as in elixirs, capsules, tablets or 
coated tablets, parenterally in the form of sterile solutions suspensions 
and in some cases intravenously in the form of sterile solutions, 
intranasally and to the throat or bronchial region in the form of drops, 
gargles, syrups, powders, etc. or subcutaneously. Suitable tableting 
excipients include lactose, potato and maize starches, talc, gelatin, 
stearic, and silicic acids, magnesium stearate and polyvinyl pyrrolidone. 
For the parenteral administration, the carrier or excipient can be 
comprised of a sterile parenterally acceptable liquid, e.g., water or 
arachis oil contained in ampoules. 
Advantageously, the compositoins are formulated as dosage units, each unit 
being adapted to supply a fixed dose of active ingredients. Tablets, 
coated tablets, capsules, ampoules, sprays and suppositories are examples 
of preferred dosage forms. It is only necessary that the active ingredient 
constitute an effective amount such that a suitable effective dosage will 
be consistent with the dosage form employed, in multiples if necessary. 
The exact individual dosages, as well as daily dosages, will of course be 
determined according to standard medical principles under the direction of 
a physician or veterinarian. Generally, the following guide to projected 
human oral dosages is derived by knowledge of the activity obtained in 
animal screening tests for the various indications in the methods of the 
invention compared to activity of known agents in the field in the same 
animal screening tests. However, the amount of the active compounds 
administered need not be limited by these comparisons due to uncertainty 
in transposing comparative animal data to human treatments. 
Oral dosages projected for hypertension for an adult human of the order of 
40-300 mg/day divided into 2 or 3 doses. Thus, for example, two capsules 
each containing 10-50 mg active agent of Formula I could be administered 
2-3 times daily for blood pressure lowering. 
Oral dosages projected for use in the treatment of angina for an adult 
human are of the order of 60-400 mg/day divided into 2 or 3 doses. Thus, 
for example, two capsules each containing 10-30 mg active agent of Formula 
I could be administered 2-5 daily to increase coronary blood flow. 
Other routes of administration such as subcutaneous, intraperitoneal, 
intravenous, etc. are possible with dosage forms being adapted to the 
situation as will be obvious to one skilled in the art of medicine. 
Various modifications and equivalents will be apparent to one skilled in 
the art and may be made in the compounds, methods of treatment and 
compositions of the present invention without departing from the spirit or 
scope thereof, and it is therefore to be understood that the invention is 
to be limited only by the scope of the appended claims.