Substituted cyclohexanols as central nervous system agents

Substituted cyclohexanols are described, as well as methods for the preparation and pharmaceutical composition of same, which are useful as central nervous system agents and are particularly useful as dopaminergic, antipsychotic, and antihypertensive agents as well as for treating hyperprolactinaemia-related conditions and central nervous system disorders.

BACKGROUND OF THE INVENTION 
The present invention relates to novel substituted cyclohexanols useful as 
pharmaceutical agents, to methods for their production, to pharmaceutical 
compositions which include these compounds and a pharmaceutically 
acceptable carrier, and to pharmaceutical methods of treatment. The novel 
compounds of the present invention are central nervous system agents. More 
particularly, the novel compounds of the present invention are 
dopaminergic agents. 
A series of 1-(4-arylcyclohexyl)piperidines which may structurally be 
represented by the formula 
##STR1## 
the pharmaceutically acceptable acid addition salts and the 
stereochemically isomeric forms thereof, wherein 
Ar.sup.1 is a member selected from the group consisting of aryl and 
1,3-benzodioxolyl; 
R is a member selected from the group consisting of hydrogen and lower 
alkyl; 
R.sup.1 is a member selected from the group consisting of hydrogen, cyano, 
carboxyl, lower alkyloxycarbonyl, aryllower alkyloxycarbonyl, 
aminocarbonyl, mono- and di(lower alkyl)aminocarbonyl, mono- and 
di(aryllower alkyl)aminocarbonyl, (aryllower alkyl)lower alkylamino 
carbonyl, hydroxy, lower alkyloxy, lower alkylcarbonyloxy, formyl, lower 
alkylcarbonyl, arylcarbonyl, aryllower alkylcarbonyl, lower alkyl, lower 
alkenyl, lower alkynyl and cyclohexyl; and 
A is a bivalent radical, having the formula 
##STR2## 
wherein 
R.sup.2 and R.sup.3 are each independently selected from the group 
consisting of hydrogen, halo, trifluoromethyl, lower alkyl, and lower 
alkyloxy; or 
A is a bivalent radical, having the formula 
##STR3## 
wherein 
Ar.sup.2 is aryl, and 
R.sup.4 is a member selected from the group consisting of hydrogen, lower 
alkyl, aryllower alkyl, cyanolower alkyl, aminolower alkyl, mono- and 
di(lower alkyl) aminolower alkyl, mono- and di(aryllower alkyl)aminolower 
alkyl, [(aryllower alkyl)lower alkylamino]lower alkyl, hydroxylower alkyl, 
mercaptolower alkyl, lower alkyloxylower alkyl, lower alkylthiolower 
alkyl, aryloxylower alkyl, arylthiolower alkyl, aryllower alkyloxylower 
alkyl, aryllower alkylthiolower alkyl, and a radical of formula 
##STR4## 
wherein 
n is 0 or an integer of from 1 to 6 inclusive, Q is O, S or NR.sup.6, p is 
0 or 1, X is O or S, R.sup.5 is hydrogen, lower alkyl, aryl or aryllower 
alkyl, m is 0 or 1 and Y is O, S or NR.sup.6, wherein R.sup.6 as used in 
the definition of Q and Y is hydrogen, lower alkyl, aryl or aryllower 
alkyl; 
provided that when Y is O and m and p are each 1, then R.sup.5 is other 
than hydrogen and provided that when p is 1 then n is other than 0: 
wherein aryl is a member selected from the group consisting of phenyl, 
thienyl, pyridinyl, naphthalenyl and substituted phenyl, said substituted 
phenyl having from 1 to 3 substituents each independently selected from 
the group consisting of halo, lower alkyl, lower alkyloxy, phenyl lower 
alkyloxy, trifluoromethyl, nitro, amino and hydroxy are disclosed in U.S. 
Pat. No. 4,329,353 as having psychotropic and antiemetic activity. 
A series of 4-alkoxy-4-(substituted phenyl)cyclohexylamines of formula 
##STR5## 
where the sign indicates the cis or trans configuration the condition 
that when the R.sub.3 O bond is cis with respect to the amino group the 
bond joining the phenyl and cyclohexyl rings is trans and vice versa; 
R=1-4C alkyl, Cl, F, Br, CF.sub.3, or 1-4C alkoxy; R'=R or H; R.sub.1 =H 
or 1-4C alkyl; R.sub.2 =H, 1-4C alkyl, aroylalkyl (monosubstituted on the 
aryl ring by a group R or 6-10C aryl) or bis-arylalkyl (monosubstituted on 
the ring by a group R' or 6-10C aryl) or R.sub.1 and R.sub.2 together with 
the N atom form a saturated heterocyclic chosen from pyrrolidino, 
piperidino, hexamethyleneimino, morpholino, and piperazino (optionally 
monosubstituted); R.sub.3 =1-4C alkyl; are disclosed in Belgium Patent No. 
790836 as having central nervous system depressant activity. 
However, the 1-(4-arylcyclohexyl)piperidines disclosed in U.S. Pat. No. 
4,329,353 and the 4-alkoxy-4-(substituted phenyl)-cyclohexylamines 
disclosed in Belgium Patent 790836 do not disclose or suggest the 
combination of structural variations of the compounds of the present 
invention described hereinafter. 
SUMMARY OF THE INVENTION 
Accordingly, the present invention is a compound of Formula I 
##STR6## 
wherein 
R is --OR.sup.3, wherein R.sup.3 is hydrogen, lower alkyl, aryl lower 
alkyl, lower alkanoyl, aroyl, or aryl lower alkanoyl, 
##STR7## 
wherein R.sup.4 and R.sup.5 are each independently hydrogen, lower alkyl, 
aryl, aryl lower alkyl, lower alkanoyl, aryl lower alkanoyl, aroyl, or 
R.sup.4 and R.sup.5 are taken together with the nitrogen atom to which 
they are attached to form a ring denoted by 
##STR8## 
wherein p is zero or an integer from 1 to 4 and R.sup.6 is hydrogen or 
lower alkyl, 
##STR9## 
wherein X is oxygen or sulfur or 
##STR10## 
wherein R.sup.6 is as defined above, or 
##STR11## 
wherein R.sup.4 and R.sup.5 are each independently hydrogen, lower alkyl, 
aryl, aryl lower alkyl, lower alkanoyl, aryl lower alkanoyl, aroyl, or 
R.sup.4 and R.sup.5 are taken together with the oxygen and nitrogen atoms 
to which they are attached to form a ring denoted by 
##STR12## 
wherein q is an integer from 2 to 3 and R.sup.6 is as defined above; 
m is zero or an integer from 1 to 2; 
R.sup.1 is aryl, 2-, 3-, or 4-pyridinyl or 2-, 3-, or 4-pyridinyl 
substituted by lower alkyl, lower alkoxy, or halogen, 2-, 4-, or 
5-pyrimidinyl or 2-, 4-, or 5-pyrimidinyl substituted by lower alkyl, 
lower alkoxy, or halogen, 2-pyrazinyl or 2-pyrazinyl substituted by lower 
alkyl, lower alkoxy, or halogen, 2- or 3-thienyl or 2- or 3-thienyl 
substituted by lower alkyl or halogen, 2- or 3-furanyl or 2- or 3-furanyl 
substituted by lower alkyl or halogen, 2-, 4-, or 5-thiazolyl or 2-, 4-, 
or 5-thiazolyl substituted by lower alkyl or halogen; 
n is zero or an integer from 1 to 4; 
R.sup.2 is 
##STR13## 
wherein R.sup.1 is as defined above; and the corresponding cis and trans 
isomers thereof; or a pharmaceutically acceptable acid addition salt 
thereof. 
As dopaminergic agents, the compounds of Formula 1 are useful as 
antipsychotic agents for treating psychoses such as schizophrenia. They 
are also useful as antihypertensives and for the treatment of disorders 
which respond to dopaminergic activation. Thus, other embodiments of the 
present invention include the treatment, by a compound of Formula I, of 
hyperprolactinaemia-related conditions, such as galactorrhea, amenorrhea, 
menstrual disorders and sexual dysfunction, and several central nervous 
system disorders such as Parkinson's disease, Huntington's chorea, and 
depression. In addition, like many known antipsychotics, these compounds 
are high affinity ligands for the central nervous system sigma binding 
site. 
A still further embodiment of the present invention is a pharmaceutical 
composition for administering an effective amount of a compound of Formula 
I in unit dosage form in the treatment methods mentioned above. 
Finally, the present invention is directed to methods for production of a 
compound of Formula I. 
DETAILED DESCRIPTION OF THE INVENTION 
In the compounds of Formula I, the term "lower alkyl" means a straight or 
branched hydrocarbon radical having from one to six carbon atoms and 
includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, 
sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like. 
The term "aryl" means an aromatic radical which is a phenyl group or phenyl 
group substituted by one to four substituents selected from lower alkyl, 
lower alkoxy, lower thioalkoxy, halogen or trifluoroethyl such as, for 
example, benzyl, phenethyl, and the like. 
The term "aryl lower alkyl" means an aromatic radical, as defined above, 
attached to a lower alkyl group as defined above. 
The term "lower alkanoyl" means a lower alkyl group as defined above 
attached to a carbonyl group which is then attached to the parent 
molecular residue. 
The term "aryl lower alkanoyl" means an aromatic radical, as defined above, 
attached to a lower alkanoyl group as defined above. 
The term "aroyl" means an aromatic radical as defined above attached to a 
carbonyl group which is then attached to the parent molecular residue. 
"Lower alkoxy" and "thioalkoxy" are O-alkyl or S-alkyl of from one to six 
carbon atoms as defined above for "lower alkyl." 
"Halogen" is fluorine, chlorine, bromine, or iodine. 
"Alkali metal" is a metal in Group IA of the periodic table and includes, 
for example, lithium, sodium, potassium, and the like. 
"Alkaline-earth metal" is a metal in Group IIA of the periodic table and 
includes, for example, calcium, barium, strontium, magnesium and the like. 
Pharmaceutically acceptable acid addition salts of the compounds of Formula 
1 include salts derived from nontoxic inorganic acids, such as 
hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, 
phosphorous, and the like, as well as the salts derived from nontoxic 
organic acids, such as aliphatic mono- and dicarboxylic acids, 
phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic 
acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such 
salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, 
nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, 
metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, 
propionate, caprylate, isobutyrate, oxalate, malonate, succinate, 
suberate, sebacate, fumarate, maleate, mandelate, benzoate, 
chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, 
benzenesulfonate, toluenesufonate, phenylacetate, citrate, lactate, 
maleate, tartrate, methanesulfonate, and the like. Also contemplated are 
salts of amino acids such as arginate and the like and gluconate, 
galacturonate (see, for example, Berge, S. M., et al, "Pharmaceutical 
Salts," Journal of Pharmaceutical Science, Vol. 66, pages 1-19 (1977)). 
The acid addition salts of said basic compounds are prepared by contacting 
the free base form with a sufficient amount of the desired acid to produce 
the salt in the conventional manner. The free base form may be regenerated 
by contacting the salt form with a base and isolating the free base in the 
conventional manner. The free base forms differ from their respective salt 
forms somewhat in certain physical properties such as solubility in polar 
solvents, but otherwise the salts are equivalent to their respective free 
base for purposes of the present invention. 
Certain of the compounds of the present invention can exist in unsolvated 
forms as well as solvated forms, including hydrated forms. In general, the 
solvated forms, including hydrated forms, are equivalent to unsolvated 
forms and are intended to be encompassed within the scope of the present 
invention. 
The compounds of the present invention may exist as a mixture of cis and 
trans isomers or as the individual cis and trans isomers. The mixture of 
isomers as well as the individual isomers are intended to be encompassed 
within the scope of the present invention. 
A preferred compound of Formula I is one wherein R is --OR.sup.3, wherein 
R.sup.3 is hydrogen or lower alkanoyl, 
##STR14## 
wherein R.sup.4 is hydrogen or lower alkanoyl and R.sup.5 is hydrogen or 
##STR15## 
wherein one of R.sup.4 or R.sup.5 is hydrogen and the other is hydrogen, 
lower alkyl, aryl, or lower alkanoyl; 
m is zero; 
R.sup.1 is phenyl, phenyl substituted by para lower alkyl, para lower 
alkoxy, para lower thioalkoxy, or para halogen, 2-, 3-, or 4-pyridinyl, 
2-, or 3-furanyl, 2- or 3-thienyl, 2-, 4-, or 5-thiazolyl, or 2-, 4-, or 
5-pyrimidinyl; 
n is zero or an integer from 1 to 3; and 
R.sup.2 is 
##STR16## 
wherein R.sup.1 is as defined above. 
Another preferred embodiment is a compound of Formula I wherein 
R is --OH, --NH.sub.2, or 
--NHOR.sup.4, wherein R.sup.4 is hydrogen, lower alkyl, aryl, or lower 
alkanoyl; 
m is zero; 
R.sup.1 is phenyl, phenyl substituted by para lower alkoxy or para halogen, 
2-, 3-, or 4-pyridinyl, 2- or 3-thienyl, 2-, 4-, or 5-thiazolyl, or 2-, 
4-, or 5-pyrimidinyl; 
n is zero or an integer from 1 to 2; and 
R.sup.2 is 
##STR17## 
wherein R.sup.1 is as defined above. 
Particularly valuable are: 
4-[2-[4-(2Pyridinyl)-1-piperazinyl]ethyl]-1-(2-thienyl)cyclohexanol 
(mixture of cis/trans); 
cis-4-[2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]-1-(2-thienyl)cyclohexanol; 
trans-4-[2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]-1-(2-thienyl)cyclohexanol; 
1-Phenyl-4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexanol (mixture of 
cis/trans); 
1-(2-Pyridinyl)-4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexanol 
(mixture of cis/trans); 
1-(4-Fluorophenyl)-4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexanol 
(mixture of cis/trans); 
cis-1-(4-Methoxyphenyl)-4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexa 
nol; 
trans-1-(4-Methoxyphenyl)-4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohe 
xanol; 
4-[2-4-(2-Pyridinyl)-1-piperazinyl]ethyl]-1-(2-thiazolyl)cyclohexanol 
(mixture of cis/trans); 
1-(3-Pyridinyl)-4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexanol 
(mixture of cis/trans); 
cis-1-(2-Pyridinyl)-4-[2-[3,6-dihydro-4-phenyl-1(2H)-pyridinyl]ethyl]cycloh 
exanol; 
cis-1-(3-Pyridinyl)-4-[2-[3,6-dihydro-4-phenyl-1(2H)-pyridinyl]ethyl]cycloh 
exanol; 
cis-4-[2-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)ethyl]-1-(2-thienyl)cyclohex 
anol; 
4-[2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]-1-(3-thienyl)cyclohexanol 
(mixture of cis/trans); 
trans-4-[[4-(2-Pyridinyl)-1-piperazinyl]methyl]-1-(2-thienyl)cyclohexanol; 
cis-4-[[4-(2-Pyridinyl)-1-piperazinyl]methyl]-1-(2-thienyl)cyclohexanol; 
trans-1-(2-Pyridinyl)-4-[4-(2-pyrimidinyl)-1-piperazinyl]cyclohexanol; 
cis-1-(2-Pyridinyl)-4-[4-(2-pyrimidinyl)-1-piperazinyl]cyclohexanol; 
trans-1-(2-Pyridinyl)-4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexanol; 
cis-1-(2-Pyridinyl)-4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexanol; 
trans-1-(3-Pyridinyl)-4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexanol; 
cis-1-(3-Pyridinyl)-4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexanol; 
4-[4-(2-Pyridinyl)-1-piperazinyl]-1-(2-thienyl)cyclohexanol (mixture of 
cis/trans); 
4-[4-(2-Pyridinyl)-1-piperazinyl]-1-(3-thienyl)cyclohexanol (mixture of 
cis/trans); 
trans-1-(4-Chlorophenyl)-4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexanol; 
cis-1-(4-Chlorophenyl)-4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexanol 
1-Methoxyphenyl-4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexanol (mixture of 
cis/trans); 
1-Phenyl-4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexanol (mixture of 
cis/trans); 
4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)-1-(2-pyridinyl)cyclohexanol 
(mixture of cis/trans); 
trans-4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)-1-(3-pyridinyl)cyclohexanol; 
and 
cis-4-[3,6-Dihydro-4-phenyl-1(2H)-pyridinyl]-1-(3-pyridinyl)cyclohexanol; 
or a pharmaceutically acceptable acid addition salt thereof. 
The compounds of Formula I are valuable dopaminergic agents. The tests 
employed indicate that compounds of Formula I possess dopaminergic 
activity. Thus, the compounds of Formula I were tested for their ability 
to inhibit locomotor activity in mice according to the assay described by 
J. R. McLean, et al, Pharmacology, Biochemistry and Behavior, Volume 8, 
pages 97-99 (1978); for their ability to inhibit [.sup.3 H]-spiroperidol 
binding in a receptor assay described by D. Grigoriadis and P. Seeman, 
Journal of Neurochemistry, Volume 44, pages 1925-1935 (1985); and for 
their ability to inhibit dopamine synthesis in rats according to the 
protocol described by J. R. Walters and R. H. Roth, Naunyn-Schmiedeberg's 
Archives of Pharmacology, Volume 296, pages 5-14 (1976). The above test 
methods are incorporated herein by reference. The data in the table show 
the dopaminergic activity of representative compounds of Formula I. 
Additionally, the compounds of Formula I are ligands for the sigma opiate 
binding site. The data in the table show the inhibition of [.sup. 3 H]DTG 
(ditoluoyl guanidine; a sigma ligand) binding by representative compounds 
of Formula I, according to the method of E. Weber, et al, Proceedings of 
the National Academy of Sciences, USA, Volume 83, pages 8784-8788 (1986). 
__________________________________________________________________________ 
Biological Activity of Compounds of Formula I 
Inhibition 
Effects on 
Inhibiton of 
of Locomotor 
Brain Striatal 
Inhibition 
[.sup.3 H]-Spiroperidol 
Activity 
Dopamine Synthesis 
of [.sup.3 H]DT 
Example Binding in Mice in Rats at 
Binding 
Number 
Compound IC.sub.50 nM 
ED.sub.50, mg/kg, IP 
10 mg/kg, IP 
IC.sub.50 
__________________________________________________________________________ 
nM 
1 trans-1-(4-Chlorophenyl)-4-[4-(2- 
333 2.3 
pyridinyl)-1-piperazinyl]cyclohexanol 
1a cis-1-(4-Chlorophenyl)-4-[4-(2- 
816 0.86 
pyridinyl)-1-piperazinyl]cyclohexanol 
3 cis-4-[2-]4-(2-Pyridinyl)-1-piperazinyl]- 
262 1.3 67% inhibition 
6.0 
ethyl]-1-(2-thienyl)cyclohexanol 
4 trans-4-[2-[4-(2-Pyridinyl)-1-piperazinyl]- 
341 1.1 47% inhibition 
5.0 
ethyl]-1-(2-thienyl)cyclohexanol 
5 1-Phenyl-4-[2-[4-(2-pyridinyl)-1- 
537 1.8 35% inhibition 
piperazinyl]ethyl]cylcohexanol (mixture 
of cis/trans) 
6 1-(2-Pyridinyl)-4-[2-[4-(2-pyridinyl)- 
1047 0.34 
1-piperazinyl]ethyl]cyclohexanol 
(mixture of cis/trans) 
7 1-(4-Fluorophenyl)-4-[2-[4-(2- 
94% inhibition 
0.64 48% inhibition 
16.5 
pyridinyl)-1-piperazinyl]ethyl]- 
at 10.sup.-5 M 
cyclohexanol (mixture of cis/trans) 
8 cis-1-(4-Methoxyphenyl)-4-[2-[4-(2- 
169 0.9 88% inhibition 
pyridinyl)-1-piperazinyl]ethyl]- 
cyclohexanol 
9 4-[2-[4-(2-Pyridinyl)-1-piperazinyl]- 
1550 1.0 
ethyl]-1-(2-thiazolyl)cyclohexanol 
(mixture of cis/trans) 
10 1-(3-Pyridinyl)-4-[2-[4-(2-pyridinyl)- 
847 0.37 
1-piperazinyl]ethyl]cyclohexanol 
(mixture of cis/trans) 
11 cis-1-(2-Pyridinyl)-4-[2-[3,6-dihydro- 
156 0.64 3.5 
4-phenyl-1(2H)-pyridinyl]ethyl]cyclo- 
hexanol 
12 cis-1-(3-Pyridinyl)-4-[2-[3,6-dihydro- 
116 0.25 79% inhibition 
4-phenyl-1(2H)-pyridinyl]ethyl]cyclo- 
hexanol 
13 cis-4-[2-(3,6-Dihydro-4-phenyl-1(2H)- 
51 2 
pyridinyl)ethyl]-1-(2-thienyl)cyclo- 
hexanol 
14 4-[2-[4-(2-Pyridinyl)-1-piperazinyl]- 
312 0.48 37% inhibition 
4.5 
ethyl]-1-(3-thienyl)cyclohexanol 
(mixture of cis/trans) 
15 trans-1-(4-Methoxyphenyl)-4-[2-[4- 
932 0.3 52% inhibition 
(2-pyridinyl)-1-piperazinyl]ethyl]- 
cyclohexanol 
16 trans-4-[[4-(2-Pyridinyl)-1-piperazinyl]- 
4.3 
methyl]-1-(2-thienyl)cyclohexanol 
17 cis-4-[[4-(2-Pyridinyl)-1-piperazinyl]- 
3900 5.2 
methyl]-1-(2-thienyl)cyclohexanol 
18 trans-1-(2-Pyridinyl)-4-[4-(2- 
&gt;30 
pyrimidinyl)-1-piperazinyl]cyclohexanol 
19 cis-1-(2-Pyridinyl)-4-[4-(2-pyridinyl)- 
13.0 
1-piperazinyl]cyclohexanol 
20 trans-1-(2-Pyridinyl)-4-[4-(2-pyridinyl)- 
&gt;30 
1-piperazinyl]cyclohexanol 
21 cis-1-(2-Pyridinyl)-4-[4-(2-pyridinyl)- 
2785 2.3 
1-piperazinyl]cyclohexanol 
22 trans-1-(3-Pyridinyl)-4-[4-(2-pyridinyl)- 
12500 30 
1-piperazinyl]cyclohexanol 
23 cis-1-(3-Pyridinyl)-4-[4-(2-pyridinyl)- 
1155 1.6 
1-piperazinyl]cyclohexanol 
24 4-[4-(2-Pyridinyl)-1-piperazinyl]-1- 
&gt;30 
(2-thienyl)cyclohexanol (mixture of 
cis/trans) 
25 4-[4-(2-Pyridinyl)-1-piperazinyl]-1- 
2700 2.4 
(3-thienyl)cyclohexanol (mixture of 
cis/trans) 
26 1-(4-Methoxyphenyl)-4-[4-(2-pyridinyl)- 
670 0.3 
1-piperazinyl]cyclohexanol (mixture of 
cis/trans) 
27 1-Phenyl-4-[4-(2-pyridinyl)-1- 
1660 0.83 
piperazinyl]cyclohexanol (mixture of 
cis/trans) 
28 4-(3,6-Dihydro-4-phenyl-1(2H)- 
1.8 
pyridinyl)-1-(2-pyridinyl)cyclohexanol 
(mixture of cis/trans) 
29 trans-4-(3,6-Dihyrdo-4-phenyl-1(2H)- 
25.6 
pyridinyl)-1-(3-pyridinyl)cyclohexanol 
30 cis-4-(3,6-Dihydro-4-phenyl-1(2H)- 
1250 1.3 
pyridinyl)-1-(3-pyridinyl)cyclohexanol 
__________________________________________________________________________ 
A compound of Formula Ia 
##STR18## 
wherein 
R is --OH, 
##STR19## 
wherein R.sup.4 is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower 
alkanoyl, aryl lower alkanoyl, or aroyl, 
##STR20## 
wherein R.sup.4 is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower 
alkanoyl, aryl lower alkanoyl, or aroyl; 
m is zero or an integer from 1 to 2; 
R.sup.1 is aryl, 2-, 3-, or 4-pyridinyl or 2-, 3-, or 4-pyridinyl 
substituted by lower alkyl, lower alkoxy, or halogen, 2-, 4-, or 
5-pyrimidinyl or 2-, 4-, or 5-pyrimidinyl substituted by lower alkyl, 
lower alkoxy, or halogen, 2-pyrazinyl or 2-pyrazinyl substituted by lower 
alkyl, lower alkoxy, or halogen, 2- or 3-thienyl or 2- or 3-thienyl 
substituted by lower alkyl or halogen, 2- or 3-furanyl or 2- or 3-furanyl 
substituted by lower alkyl or halogen, 2-, 4-, or 5-thiazolyl or 2-, 4-, 
or 5-thiazolyl substituted by lower alkyl or halogen; 
n is zero or an integer from 1 to 4; 
R.sup.2 is 
##STR21## 
wherein R.sup.1 is as defined above; and the corresponding cis and trans 
isomers thereof; or a pharmaceutically acceptable acid addition salt 
thereof may be prepared by reacting a compound of Formula II 
##STR22## 
wherein 
A is O, 
N--R.sup.4 wherein R.sup.4 is as defined above, or 
N--OR.sup.4 wherein R.sup.4 is as defined above, and 
R.sup.2 and n are as defined above with a compound of Formula III 
##STR23## 
wherein M is magnesium-Hal, wherein Hal is halogen or M is lithium and 
R.sup.1 and m are as defined above, in the presence of a solvent such as, 
for example, tetrahydrofuran, diethyl ether, and the like at about 
-78.degree. C. to about the reflux temperature of the solvent for about 
0.5 to about 24 hours to give a compound of Formula Ia. 
A compound of Formula Ib 
##STR24## 
wherein 
R.sup.a is --OR.sup.3, wherein R.sup.3 is lower alkyl, or aryl lower alkyl; 
m is zero or an integer from 1 to 2; 
R.sup.1 is aryl, 2-, 3-, or 4-pyridinyl or 2-, 3-, or 4-pyridinyl 
substituted by lower alkyl, lower alkoxy, or halogen, 2-, 4-, or 
5-pyrimidinyl or 2-, 4-, or 5-pyrimidinyl substituted by lower alkyl, 
lower alkoxy, or halogen, 2-pyrazinyl or 2-pyrazinyl substituted by lower 
alkyl, lower alkoxy, or halogen, 2- or 3-thienyl or 2- or 3-thienyl 
substituted by lower alkyl or halogen, 2- or 3-furanyl or 2- or 3-furanyl 
substituted by lower alkyl or halogen, 2-, 4-, or 5-thiazolyl or 2-, 4-, 
or 5-thiazolyl substituted by lower alkyl or halogen; 
n is zero or an integer from 1 to 4; 
R.sup.2 is 
##STR25## 
wherein R.sup.1 is as defined above; and the corresponding cis and trans 
isomers thereof; or a pharmaceutically acceptable acid addition salt 
thereof may be prepared by reacting a compound of Formula Ic 
##STR26## 
wherein R.sup.1, m, n, and R.sup.2 are as defined above with a compound of 
Formula IV 
##STR27## 
wherein Hal is halogen and R.sup.3 is as defined above in the presence of 
a base such as an organic base, for example, triethylamine, pyridine and 
the like, an inorganic base, for example, an alkali metal or alkaline 
earth metal hydroxide or carbonate, alkali metal hydride and the like and 
a solvent such as, for example, dichloromethane, and the like at about 
-78.degree. C. to about the reflux temperature of the solvent for about 
0.5 to about 24 hours to give a compound of Formula Ib. 
A compound of Formula Id 
##STR28## 
wherein 
R.sup.b is --OR.sup.3.spsp.a, wherein R.sup.3.spsp.a is lower alkanoyl, 
aroyl, or aryl lower alkanoyl; 
m is zero or an integer from 1 to 2; 
R.sup.1 is aryl, 2-, 3-, or 4-pyridinyl or 2-, 3-, or 4-pyridinyl 
substituted by lower alkyl, lower alkoxy, or halogen, 2-, 4-, or 
5-pyrimidinyl or 2-, 4-, or 5-pyrimidinyl substituted by lower alkyl, 
lower alkoxy, or halogen, 2-pyrazinyl or 2-pyrazinyl substituted by lower 
alkyl, lower alkoxy, or halogen, 2- or 3-thienyl or 2- or 3-thienyl 
substituted by lower alkyl or halogen, 2- or 3-furanyl or 2- or 3-furanyl 
substituted by lower alkyl or halogen, 2-, 4-, or 5-thiazolyl or 2-, 4-, 
or 5-thiazolyl substituted by lower alkyl or halogen; 
n is zero or an integer from 1 to 4; 
R.sup.2 is 
##STR29## 
wherein R.sup.1 is as defined above; and the corresponding cis and trans 
isomers thereof; or a pharmaceutically acceptable acid addition salt 
thereof may be prepared by reacting a compound of Formula Ic with a 
compound of Formula V 
##STR30## 
wherein Hal is halogen and R.sup.3.spsp.a is as defined above using the 
methodology used to prepare a compound of Formula Ib from a compound of 
Formula Ic and a compound of Formula IV to give a compound of Formula Id. 
A compound of Formula Ie 
##STR31## 
wherein R.sup.c is 
##STR32## 
wherein R.sup.4 and R.sup.5 are each independently hydrogen, lower alkyl, 
aryl, aryl lower alkyl, lower alkanoyl, aryl lower alkanoyl, aroyl, or 
R.sup.4 and R.sup.5 are taken together with the nitrogen atom to which 
they are attached to form a ring denoted by 
##STR33## 
wherein p is zero or an integer from 1 to 4 and R.sup.6 is hydrogen or 
lower alkyl, 
##STR34## 
wherein X is oxygen or sulfur or 
##STR35## 
wherein R.sup.6 is as defined above, or 
##STR36## 
wherein R.sup.4 and R.sup.5 are each independently hydrogen, lower alkyl, 
aryl, aryl lower alkyl, lower alkanoyl, aryl lower alkanoyl, aroyl, or 
R.sup.4 and R.sup.5 are taken together with the oxygen and nitrogen atoms 
to which they are attached to form a ring denoted by 
##STR37## 
wherein q is an integer from 2 to 3 and R.sup.6 is as defined above; 
m is zero or an integer from 1 to 2; 
R.sup.1 is aryl, 2-, 3-, or 4-pyridinyl or 2-, 3-, or 4-pyridinyl 
substituted by lower alkyl, lower alkoxy, or halogen, 2-, 4-, or 
5-pyrimidinyl or 2-, 4-, or 5-pyrimidinyl substituted by lower alkyl, 
lower alkoxy, or halogen, 2-pyrazinyl or 2-pyrazinyl substituted by lower 
alkyl, lower alkoxy, or halogen, 2- or 3-thienyl or 2- or 3-thienyl 
substituted by lower alkyl or halogen, 2- or 3-furanyl or 2- or 3-furanyl 
substituted by lower alkyl or halogen, 2-, 4-, or 5-thiazolyl or 2-, 4-, 
or 5-thiazolyl substituted by lower alkyl or halogen; 
n is zero or an integer from 1 to 4; 
R.sup.2 is 
##STR38## 
wherein R.sup.1 is as defined above; and the corresponding cis and trans 
isomers thereof; or a pharmaceutically acceptable acid addition salt 
thereof may be prepared by reacting a compound of Formula VI 
##STR39## 
wherein R.sup.c, R.sup.2, and n are as defined above with a compound of 
Formula III wherein M, R.sup.1, and m are as defined above in the presence 
of a solvent such as, for example, tetrahydrofuran and the like at about 
0.degree. C. for about 0.5 to about 24 hours to give a compound of Formula 
Ie. 
A compound of Formula VI is prepared from a compound of Formula IIa 
##STR40## 
wherein R.sup.2 and n are as defined above and a compound of Formula VII 
##STR41## 
wherein R.sup.c is as defined above in the presence of an alkali metal 
cyanide such as, for example, potassium cyanide and the like and about an 
equivalent of an acid such as an organic acid, for example, acetic acid 
and the like, an inorganic acid, for example, hydrochloric acid and the 
like, in the presence of a solvent such as, for example, methanol, ethanol 
and the like at about room temperature to give a compound of Formula VI. 
A compound of Formula IIa is prepared from a compound of Formula VIII 
##STR42## 
wherein R.sup.7 and R.sup.8 are alkyl of one to six carbon atoms or 
R.sup.7 and R.sup.8 together are 
##STR43## 
and R.sup.2 and n are as defined above by treatment with an acid such as, 
for example, a 10% aqueous solution of hydrochloric acid in the presence 
of a solvent such as, for example, acetone and the like to give a compound 
of Formula IIa. 
A compound of Formula VIIIa 
##STR44## 
wherein n is zero and R.sup.2, R.sup.7, and R.sup.8 are as defined above 
is prepared from a compound of Formula IX 
##STR45## 
wherein R.sup.2, R.sup.7, and R.sup.8 are as defined above by treatment 
with a reducing agent such as, for example, sodium cyanoborohydride and 
the like in a solvent such as, for example, methanol and the like in the 
presence of an acid such as, for example, hydrochloric acid and the like 
or, alternatively, reduction is carried out with hydrogen in the presence 
of a catalyst such as, for example, palladium on carbon in the presence of 
a solvent such as, for example, methanol and the like to give a compound 
of Formula VIIIa. 
A compound of Formula IX is prepared from a compound of Formula X 
##STR46## 
wherein R.sup.7 and R.sup.8 are as defined above in the presence of a 
catalytic amount of an acid such as, for example, para-toluenesulfonic 
acid and the like in the presence of a solvent suited for the azeotropic 
removal of water such as, for example, toluene and the like to give a 
compound of Formula IX. 
A compound of Formula VIIIb wherein n is an integer from 1 to 4 and 
R.sup.2, R.sup.7, and R.sup.8 are as defined above is prepared from a 
compound of Formula XI 
##STR47## 
wherein n is an integer from 1 to 4 and R.sup.2, R.sup.7, and R.sup.8 are 
as defined above by treatment with a reducing agent such as, for example, 
diborane, aluminum hydride and the like in a solvent such as, for example, 
tetrahydrofuran and the like to give a compound of Formula VIIIb. 
A compound of Formula XI is prepared from a compound of Formula XII 
##STR48## 
wherein n is an integer from 1 to 4 and R.sup.7 and R.sup.8 are as defined 
above and a compound of Formula XI. In order to obtain the reaction of 
these two compounds, a compound of Formula XII must be activated in the 
presence of a chloroformate such as, for example, isobutyl chloroformate 
and a base such as, for example, triethylamine, or alternatively, a 
coupling reagent such as, for example, dicyclohexylcarbodiimide, 
carbonyldiimidazole and the like in the presence of a solvent such as, for 
example, dichloromethane and the like to give a compound of Formula XI. 
A compound of Formula XII is prepared from a compound of Formula XIII 
##STR49## 
wherein n is an integer from 1 to 4, R.sup.9 is lower alkyl and R.sup.7 
and R.sup.8 are as defined above, by hydrolysis with a base such as, for 
example, potassium hydroxide and the like in an alcohol such as, for 
example, ethanol and the like to give a compound of Formula XII. 
A compound of Formula XIII is prepared from a compound of Formula XIV 
##STR50## 
wherein n is an integer from 1 to 4 and R.sup.9 is as defined above using 
conventional procedures known in the art. 
Alternatively, a compound of Formula VIIIb is prepared from a compound of 
Formula XV 
##STR51## 
wherein n is an integer from 1 to 4, L is halogen, CH.sub.3 SO.sub.2 O--, 
para-CH.sub.3 C.sub.6 H.sub.4 SO.sub.2 O--, and the like, and R.sup.7 and 
R.sup.8 are as defined above and a compound of Formula XVI 
##STR52## 
wherein R.sup.2 is as defined above in the presence of a base such as, for 
example, sodium bicarbonate and the like and a solvent such as, for 
example, dimethylformamide and the like to give a compound of Formula 
VIIIb. 
A compound of Formula XV is prepared from a compound of Formula XVII 
##STR53## 
wherein n is an integer from 1 to 4 and R.sup.7 and R.sup.8 are as defined 
above by treatment with thionyl chloride, thionyl bromide and the like in 
the presence of a solvent such as, for example, chloroform and the like 
or, alternatively, treatment with methanesulfonyl chloride, 
para-toluenesulfonyl chloride and the like in the presence of a base such 
as, for example, pyridine and the like to give a compound of Formula XV. 
A compound of Formula XVII is prepared from a compound of Formula XIV 
wherein n is an integer from 1 to 4 and R.sup.7, R.sup.8, and R.sup.9 are 
as defined above by treatment with a complex metal hydride such as, for 
example, diborane, lithium aluminum hydride and the like in the presence 
of a solvent such as, for example, tetrahydrofuran and the like to give a 
compound of Formula XVII. 
A compound of Formula IIb 
##STR54## 
wherein 
A.sup.a is N-R.sup.4 wherein R.sup.4 is as defined above, or 
N-OR.sup.4 wherein R.sup.4 is as defined above and R.sup.2 and n are as 
defined above is prepared from a compound of Formula IIa and a compound of 
Formula XVIII 
##STR55## 
wherein 
R.sup.d is 
##STR56## 
wherein R.sup.4 is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower 
alkanoyl, aryl lower alkanoyl or aroyl, 
##STR57## 
wherein R.sup.4 is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower 
alkanoyl, aryl lower alkanoyl or aroyl in the presence of an acid such as, 
for example, para-toluenesulfonic acid to give a compound of Formula IIb. 
Compounds of Formula III, Formula IV, Formula V, Formula VII, Formula X, 
Formula XI, Formula XIV, and Formula XVIII are either known or capable of 
being prepared by methods known in the art. A compound of Formula I may 
exist as a mixture of cis or trans isomers or as the separate cis or trans 
isomer. Accordingly, as another aspect of the present invention, a mixture 
of cis and trans isomers of Formula I may be separated into the individual 
cis or trans isomer by conventional methodology such as, for example, by 
fractional crystallization, chromatography and the like. 
The compounds of the present invention can be prepared and administered in 
a wide variety of oral and parenteral dosage forms. It will be obvious to 
those skilled in the art that the following dosage forms may comprise as 
the active component, either a compound of Formula I or a corresponding 
pharmaceutically acceptable salt of a compound of Formula I. 
For preparing pharmaceutical compositions from the compounds of the present 
invention, pharmaceutically acceptable carriers can be either solid or 
liquid. Solid form preparations include powders, tablets, pills, capsules, 
cachets, suppositories, and dispersible granules. A solid carrier can be 
one or more substances which may also act as diluents, flavoring agents, 
solubilizers, lubricants, suspending agents, binders, preservatives, 
tablet disintegrating agents, or an encapsulating material. 
In powders, the carrier is a finely divided solid which is in a mixture 
with the finely divided active component. 
In tablets, the active component is mixed with the carrier having the 
necessary binding properties in suitable proportions and compacted in the 
shape and size desired. 
The powders and tablets preferably contain from five or ten to about 
seventy percent of the active compound. Suitable carriers are magnesium 
carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, 
starch, gelatin, tragacanth, methylcellulose, sodium 
carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The 
term "preparation" is intended to include the formulation of the active 
compound with encapsulating material as a carrier providing a capsule in 
which the active component, with or without other carriers, is surrounded 
by a carrier, which is thus in association with it. Similarly, cachets and 
lozenges are included. Tablets, powders, capsules, pills, cachets, and 
lozenges can be used as solid dosage forms suitable for oral 
administration. 
For preparing suppositories, a low melting wax, such as a mixture of fatty 
acid glycerides or cocoa butter, is first melted and the active component 
is dispersed homogeneously therein, as by stirring. The molten homogenous 
mixture is then poured into convenient sized molds, allowed to cool, and 
thereby to solidify. 
Liquid form preparations include solutions, suspensions, and emulsions, for 
example, water or water propylene glycol solutions. For parenteral 
injection liquid preparations can be formulated in solution in aqueous 
polyethylene glycol solution. 
Aqueous solutions suitable for oral use can be prepared by dissolving the 
active component in water and adding suitable colorants, flavors, 
stabilizing and thickening agents as desired. 
Aqueous suspensions suitable for oral use can be made by dispersing the 
finely divided active component in water with viscous material, such as 
natural or synthetic gums, resins, methylcellulose, sodium 
carboxymethylcellulose, and other well-known suspending agents 
Also included are solid form preparations which are intended to be 
converted, shortly before use, to liquid form preparations for oral 
administration. Such liquid forms include solutions, suspensions, and 
emulsions. These preparations may contain, in addition to the active 
component, colorants, flavors, stabilizers, buffers, artificial and 
natural sweeteners, dispersants, thickeners, solubilizing agents, and the 
like. 
The pharmaceutical preparation is preferably in unit dosage form. In such 
form, the preparation is subdivided into unit doses containing appropriate 
quantities of the active component. The unit dosage form can be a packaged 
preparation, the package containing discrete quantities of preparation, 
such as packeted tablets, capsules, and powders in vials or ampoules. 
Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge 
itself, or it can be the appropriate number of any of these in packaged 
form. 
The quantity of active component in a unit dose preparation may be varied 
or adjusted from 1 mg to 1000 mg preferably 10 mg to 100 mg according to 
the particular application and the potency of the active component. The 
composition can, if desired, also contain other compatible therapeutic 
agents. 
In therapeutic use as antipsychotic agents, the compounds utilized in the 
pharmaceutical method of this invention are administered at the initial 
dosage of about 1 mg to about 50 mg per kilogram daily. A daily dose range 
of about 5 mg to about 25 mg per kilogram is preferred. The dosages, 
however, may be varied depending upon the requirements of the patient, the 
severity of the condition being treated, and the compound being employed. 
Determination of the proper dosage for a particular situation is within 
the skill of the art. Generally, treatment is initiated with smaller 
dosages which are less than the optimum dose of the compound. Thereafter, 
the dosage is increased by small increments until the optimum effect under 
the circumstances is reached. For convenience, the total daily dosage may 
be divided and administered in portions during the day if desired

The following nonlimiting examples illustrate the inventors' preferred 
methods for preparing the compounds of the invention. 
EXAMPLE 1 AND EXAMPLE 1a 
cis- and 
trans-1-(4-Chlorophenyl)-4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexanol. 
A solution of 5.74 g of 1-bromo-4-chlorobenzene in 100 ml anhydrous 
tetrahydrofuran is cooled to -78.degree. C. under a nitrogen atmosphere. 
n-Butyllithium (18.75 ml of a 1.6M hexane solution) is added dropwise via 
syringe. The resulting suspension is stirred at -78.degree. C. for one 
hour. To this solution is added a solution of 5.19 g of 
4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexanone (Example A) in 175 ml of 
tetrahydrofuran from an addition funnel. The addition of the ketone takes 
about 15 minutes. The mixture is allowed to warm to room temperature and 
quenched with 50 ml of saturated ammonium chloride solution. The 
tetrahydrofuran is evaporated under vacuum and the residue is partitioned 
into water/dichloromethane. The organic phase is separated, dried over 
magnesium sulfate, and evaporated in vacuo. The residue is chromatographed 
on silica gel using 3% methanol:97% dichloromethane as eluant. The less 
polar isomer in this solvent system is characterized as 
trans-1-(4-chlorophenyl)-4-[4-(2 -pyridinyl)-1-piperazinylcyclohexanol 
containing 0.15 molecules of chloroform; mp 224.degree.-225.degree. C. 
(Example 1) and the more polar component is identified as 
cis-1-(4-chlorophenyl)-4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexanol; mp 
183.degree.-185.degree. C. (Example 1a). 
In a process analogous to Example 1 and Example 1a using appropriate 
starting materials the corresponding compounds of Formula I (Examples 2 to 
30) are prepared as follows: 
EXAMPLE 2 
4-[2-4-(2-Pyridinyl)-1-piperazinyl]ethyl]-1-(2-thienyl)cyclohexanol 
(mixture of cis/trans), containing 0.33 molecules of chloroform; mp 
124.degree.-140.degree. C. 
EXAMPLE 3 
cis-4-[2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]-1-(2-thienyl)cyclohexanol, 
hemihydrate; mp 151.degree.-154.degree. C. 
EXAMPLE 4 
trans-4-[2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]-1-(2-thienyl)cyclohexanol; 
mp 108.degree.-109.degree. C. 
EXAMPLE 5 
1-Phenyl-4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexanol (mixture of 
cis/trans), containing 0.1 molecules of water; mp 158.degree.-163.degree. 
C. 
EXAMPLE 6 
1-(2-Pyridinyl)-4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexanol 
(mixture of cis/trans), containing 0.25 molecules of water; mp 
100.degree.-105.degree. C. 
EXAMPLE 7 
1-(4-Fluorophenyl)-4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexanol 
(mixture of cis/trans); mp 172.degree.-177.degree. C. 
EXAMPLE 8 
cis 
1-(4-Methoxyphenyl)-4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexanol 
, containing 0.2 molecules of water; mp 142.degree.-144.degree. C. 
EXAMPLE 9 
4-[2-4-(2-Pyridinyl)-1-piperazinyl]ethyl]-1-(2-thiazolyl)cyclohexanol 
(mixture of cis/trans), containing 0.75 molecules of chloroform; mp 
65.degree.-80.degree. C. 
EXAMPLE 10 
1-(3-Pyridinyl)-4-2-4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexanol 
(mixture of cis/trans), containing 0.2 molecules of water; mp 
128.degree.-148.degree. C. 
EXAMPLE 11 
cis-1-(2-Pyridinyl]-4-[2-[3,6-dihydro-4-phenyl-1H(2H)-pyridinyl]ethyl]cyclo 
hexanol; mp 153.degree.-156.degree. C. 
EXAMPLE 12 
cis-1-(3-Pyridinyl)-4-[2-[3,6-dihydro-4-phenyl-1(2H)-pyridinyl]ethyl]cycloh 
exanol; mp 160.degree.-163.degree. C. 
EXAMPLE 13 
cis-4-[2-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)ethyl]-1-(2-thienyl)cyclohex 
anol, containing 0.1 molecules of water; mp 164.degree.-170.degree. C. 
EXAMPLE 14 
4-[2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]-1-(3-thienyl)cyclohexanol 
(mixture of cis/trans), containing 0.2 molecules of water; mp 
115.degree.-129.degree. C. 
EXAMPLE 15 
trans-1-(4-Methoxyphenyl)-4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohe 
xanol, containing 0.2 molecules of water; mp 127.degree.-131.degree. C. 
EXAMPLE 16 
trans-4-[[4-(2-Pyridinyl)-1-piperazinyl]methyl]-1-(2-thienyl)cyclohexanol; 
mp 50.degree.-52.degree. C. 
EXAMPLE 17 
cis -4-[[4-(2-Pyridinyl)-1-piperazinyl]methyl]-1-2-thienyl)cyclohexanol, 
trihydrochloride, containing 2.5 molecules of water; mp 
114.degree.-117.degree. C. 
EXAMPLE 18 
trans-1-(2-Pyridinyl)-4-[4-(2-pyrimidinyl)-1-piperazinyl]cyclohexanol; mp 
240.degree.-242.degree. C. 
EXAMPLE 19 
cis-1-(2-Pyridinyl)-4-[4-(2-pyrimidinyl)-1-piperazinyl]cyclohexanol, 
trihydrochloride, containing 3.5 molecules of water; mp 
138.degree.-140.degree. C. 
EXAMPLE 20 
trans-1-(2-Pyridinyl)-4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexanol, 
containing 0.25 molecules of water; mp 86.degree.-93.degree. C. 
EXAMPLE 21 
cis-1-(2-Pyridinyl)-4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexanol, 
containing 0.4 molecules of water; mp 130.degree.-134.degree. C. 
EXAMPLE 22 
trans-1-(3-Pyridinyl)-4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexanol; mp 
153.degree.-158.degree. C. 
EXAMPLE 23 
cis -1-(3-Pyridinyl)-4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexanol, 
hemihydrate; mp 175.degree.-179.degree. C. 
EXAMPLE 24 
4-[4-(2-Pyridinyl)-1-piperazinyl]-1-(2-thienyl)cyclohexanol (mixture of 
cis/trans); mp 130.degree.-135.degree. C. 
EXAMPLE 25 
4-[4-(2-Pyridinyl)-1-piperazinyl]-1-(3-thienyl)cyclohexanol (mixture of 
cis/trans); mp 140.degree.-155.degree. C. 
EXAMPLE 26 
1-(4-Methoxyphenyl)-4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexanol (mixture 
of cis/trans); mp 154.degree.-157.degree. C. 
EXAMPLE 27 
1-Phenyl-4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexanol (mixture of 
cis/trans), containing 0.25 molecules of water; mp 164.degree.-172.degree. 
C. 
EXAMPLE 28 
4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)-1-(2-pyridinyl)cyclohexanol 
(mixture of cis/trans); mp 157.degree.-159.degree. C. 
EXAMPLE 29 
trans-4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)-1-(3-pyridinyl)cyclohexanol; 
mp 124.degree.-125.degree. C. 
EXAMPLE 30 
cis-4-[3,6-Dihydro-4-phenyl-1(2H)-pyridinyl]-1-(3-pyridinyl)cyclohexanol; 
mp 199.degree.-200.degree. C. 
PREATION OF STARTING MATERIALS 
EXAMPLE A 
4-[4-(2-Pyridinyl)-1-piperazinyl]cyclohexanone. 
A solution of 1,4-cyclohexanedione monoethyleneketa (50.0 g), 
1-(2-pyridyl)piperazine (52.16 g), and p-toluenesulfonic acid (0.5 g) in 
500 ml of toluene is refluxed with a Dean-Stark trap until the theoretical 
amount of water is collected (about four hours). The solvent is evaporated 
in vacuo and the residue is dissolved in 750 ml of methanol. This solution 
is cooled in an ice bath and sodium cyanoborohydride (30.1 g) is added in 
small portions over a two-minute period. The resulting suspension is 
stirred mechanically and over the next 30 minutes enough concentrated 
hydrochloric acid solution is added dropwise to the reaction mixture to 
maintain a pH of about 4. The solvent is removed in vacuo to leave a 
semisolid residue which is dissolved in 300 ml of a 10% solution of 
hydrochloric acid in a well ventilated fume hood. This solution is diluted 
with an equal volume of acetone and refluxed for two hours. The volatile 
components of the mixture are removed in vacuo and the residue is cooled 
in an ice bath and made basic with concentrated ammonium hydroxide. The 
white solid which forms is recrystallized from ethyl acetate-heptane to 
give 52.4 g of the title compound; mp 142.degree.-144.degree. C.