IMINOMETHYLPIPERIDINES SUBSTITUEES EN N

SUBSTITUTED N-IMINOMETHYLPIPERIDINES

Abrégé anglais

ABSTRACT
SUBSTITUTED N-IMINOMETHYLPIPERIDINES
Substituted N-iminomethylpiperidines are dis-
closed which are useful for the inhibition of gastric
acid secretion.

Revendications

The embodiments of the invention in which an exclusive property
or privilege is claimed are defined as follows:
1. A process for preparing a member selected from the group
consisting of a substituted N-iminomethyl-piperidine of formula
(I):
<IMG>
(I)
and the corresponding non-toxic acid addition salts thereof,
wherein:
R1 taken individually is a member selected from the group
consisting of hydrogen; phenyl; phenyl substituted with from one
to three members each selected from the group consisting of
loweralkyl, loweralkoxy, hydroxy and halo; phenyl (C1-C4) lower-
alkyl; l-phenyl (C7-C9) loweralkyl; phenyl (C1-C4) loweralkyl
and l-phenyl (C7-C9) loweralkyl in which said phenyl is substi-
tuted with from one to three members each selected from the
group consisting of loweralkyl, loweralkoxy, hydroxy, halo, and
phenyl, provided that no more than one member is phenyl; diphenyl
(C1-C4) loweralkyl; diphenyl-(C1-C4) loweralkyl wherein at least
one of said phenyls is substituted with from one to three members
each selected from the group consisting of loweralkyl, lower-
alkoxy, halo, hydroxy, and phenyl, provided that no more than one
member is phenyl; diphenylhydroxymethyl; diphenylhydroxymethyl
wherein at least one of said phenyls is substituted with from
one to three members each selected from the group consisting of
loweralkyl, loweralkoxy, hydroxy, halo, and phenyl, provided
that no more than one member is phenyl; and compounds of formulae
52

<IMG> and <IMG>
wherein n is 0, 1, or 2 and E is H or OH;
A taken individually is a member selected from hydrogen,
acetyl, and phenyl, provided that when A is acetyl or phenyl, R1
is a member selected from the group consisting of phenyl or phenyl
substituted with from one to three members each selected from the
group consisting of loweralkyl, loweralkoxy, hydroxy and halo;
R1 and A taken together is a member selected from the
group consisting of benzhydrylidene and compounds of formulae:
<IMG> and <IMG>
wherein n is 0, 1, or 2;
R1' taken individually is a member selected from the
group consisting of hydrogen; methyl; diphenylmethyl; diphenyl-
methyl wherein at least one of the phenyl groups is substituted
with from one to three members each selected from the group con-
sisting of loweralkyl, loweralkoxy, hydroxy, halo, and phenyl,
provided that no more than one member is phenyl; diphenylhydroxy-
methyl; diphenylhydroxymethyl wherein at least one of said
phenyls is substituted with from one to three members each sel-
ected from the group consisting of loweralkyl, loweralkoxy, halo,
hydroxy, and phenyl, provided that no more than one member is
phenyl; and a compound of formula:
53

<IMG>
wherein n is 0, 1, or 2 and E is H or OH;
B taken individually is hydrogen;
R1' and s taken together is a member selected from the
group consisting of benzhydrylidene and a compound of formula:
<IMG>
wherein n is 0, 1, or 2.
R1" taken individually is a member selected from the
group consisting of hydrogen, diphenylmethyl; diphenylmethyl
wherein at least one of said phenyls is substituted with from
one to three members each selected from the group consisting of
loweralkyl, loweralkoxy, halo, hydroxy, and phenyl, provided
that no more than one member is phenyl; diphenylhydroxymethyl;
diphenylhydroxymethyl wherein at least one of said phenyls is
substituted with from one to three members each selected from
the group consisting of loweralkyl, loweralkoxy, hydroxy, halo,
and phenyl, provided that no more than one member is phenyl; and
compounds of formulae:
<IMG> and <IMG>
54

wherein n is 0, 1, or 2;
D taken individually is hydrogen;
R1" and D taken together is benzhydrylidene;
R2 is a member selected from the group consisting of
hydrogen and C1-C4 loweralkyl; and
R3 is a member selected from the group consisting of
hydrogen; alkyl; cycloalkyl; phenylloweralkyl; phenyllower-
alkyl in which said phenyl is substituted with from one to three
members each selected from the group consisting of loweralkyl,
loweralkoxy, hydroxy, and halo; diphenyl (C1-C4) loweralkyl; di-
phenyl (C1-C4) loweralkyl wherein at least one of said phenyls
is substituted with from one to three members each selected from
the group consisting of loweralkyl, loweralkoxy, halo, hydroxy,
and phenyl, provided that no more than one member is phenyl;
alkenyl; and alkynyl; provided that at least one of said R1,
R1' and R1" is other than hydrogen, and further provided that
when R1" is other than hydrogen R1 and R'1 and A are each hydro-
gen; when R'1 is hydrogen only one of R1 and R"1 is other than
hydrogen; when R'1 is other than hydrogen and R"1 is hydrogen;
and when R'1 is other than hydrogen or ethyl R1, R"1 and A are
each hydrogen, characterized by a) i) reacting a compound of
formula
<IMG>
(II)
with a compound of the formula Z? = NR3 (III)
or the acid addition salt form of the latter, namely,
Z? = NR3 - HX
in a suitable organic solvent at a temperature between 0°C and
50°C, wherein A, B, D, R1, R1', R1, R2, and R3 are as previously
defined, Z is selected from the group consisting of loweralkoxy,

loweralkyl-S-, chloro, and C12(O)PO-, and X is a member selected
from the group consisting of halide, BF4, FSO3, and CH3OSO3,
and additionally, when Z is loweralkyl-S-, X may also be a member
selected from the group consisting of (4-methylphenyl)SO3,
CH3SO3, and CF3SO3 in order to prepare a compound of the formula
(I);
or ii) reacting a compound of formula (II)
with a compound of the formula R3N=C=S (IIIA)
under similar reaction conditions to step a) i) in order to
prepare the corresponding thiourea which is then reduced in
order to prepare a compound of the formula (I), wherein R2 is
hydrogen;
or iii) reacting a compound of formula (II)
with a compound of the formula R3N=C (IIIB) in the presence
of silver chloride as a catalyst in order to prepare a compound
of the formula (I),
wherein R2 is hydrogen; or
b) i) reacting a compound of the formula
<IMG>
X-
with a compound of the formula R3NH2 (VII), wherein R1, R1',
R1, R2, R3, A, B, D, Z, and X are as defined above, in order to
prepare a compound of the formula (I); or ii) in the instance
wherein Z in compound (VI) is (loweralkyl)-S- and R2 is H, re-
acting said compound of the formula
<IMG>
56

with a compound of the formula R3N=C-O (VIII)
in a suitahle solvent, preferably at reflux temperature, in order
to prepare a compound of the formula (I), wherein R2 is hydrogen;
and, if desired, preparing non-toxic acid addition salts thereof.
2. A process for preparing a member selected from the group
consisting of 4-diphenylmethyl-1-iminomethylpiperidine and the
non-toxic acid addition salts thereof, characterized by reacting
ethyl formimidate with diphenyl-4-piperidylmethane.
3. A process for preparing a member selected from the group
consisting of 4-(diphenylmethyl)-1-[(isopropylimino)methyl]-
piperidine and the non-toxic acid addition salts thereof, char-
acterized by reacting N-formyl-4-diphenylmethylpiperidine with
dimethylsulfate and reacting the product with isopropylamine.
4. A process for preparing a member selected from the group
consisting of l-[N-(benzyl)iminomethyl]-4-diphenylmethylpiper-
idine and the non-toxic acid addition salts thereof, characterized
by reacting N-formyl-4-diphenylmethylpiperidine with dimethyl-
sulfate and reacting the product with benzylamine.
5. A process for preparing a member selected from the group
consisting of l-[N-(phenethyl)iminomethyl]-4-diphenylmethylpiper-
idine and the non-toxic acid addition salts thereof, character-
ized by reacting N-formyl-4-diphenylmethylpiperidine with di-
methyl sulfate and then reacting the product with phenethylamine.
6. A process for preparing a member selected from the group
consisting of 1-[N-(n-decyl)iminomethyl]-4-diphenylmethylpiper-
idine and the non-toxic acid addition salts thereof, character-
ized by reacting N-formyl-4-diphenylmethylpiperidine with di-
methyl sulfate and then reacting the product with n-decylamine.
7. A process for preparing a member selected from the group
consisting of 4-(diphenylmethyl)-1 [octylimino)methyl]piperidine
and the non-toxic acid addition salts thereof, characterized by
reacting N-formyl-4-diphenylmethylpiperidine with phosgene and
57

then reacting the product with octylamine.
8. A process for preparing a member selected from the group
consisting of 4-(diphenylmethyl)-1-[(2-propynylimino)methyl]-
piperidine and the non-toxic acid addition salts thereof, char-
acterized by reacting 4-(diphenylmethyl)-1-piperidinocarbothioal-
dehyde with methyl iodide and reacting the product with 2-propy-
nylamine.
9. A process for preparing a member selected from the group
consisting of 4-benzhydrylidene-1-[(octylimino)methy] piperidine
and the non-toxic acid addition salts thereof, characterized by
reacting 4-benzhydrylidene-1-piperidinecarbothioaldehyde with
methyl iodide and then reacting the product with n-octylamine.
10. A process for preparing a member selected from the group
consisting of 4-(diphenylmethyl)-1-[(ethylimino)methyl] piper-
idine and the non-toxic acid addition salts thereof, character-
ized by reacting ethylpropionimidate hydrochloride with diphenyl-
4-piperidylmethane.
11. A process for preparing a member selected from the group
consisting of 4-(diphenylmethyl)-1-[(hexylimino)methyl] piperidine
and the non-toxic acid addition salts thereof, characterized by
reacting N-formyl-4-diphenylmethylpiperidine with dimethyl sul-
fate and then reacting the product with hexylamine.
12. A process for preparing a member selected from the group
consisting of 1-[(4-chlorobenzylimino)methyl]-4-(diphenylmethyl)-
piperidine and the non-toxic acid addition salts thereof, char-
acterized by reacting N-formyl-4-diphenylmethylpiperidine with
dimethyl sulfate and then reacting the product with 4-chloro-
benzylamine.
13. A process for preparing a member selected from the group
consisting of 4[1-(4-methoxyphenyl)benzyl]-1-[(octylimino)-
methyl]-piperidine and the non-toxic acid addition salts there-
of, characterized by reacting N-formyl-4 [1-(4-methoxyphenyl)-
benzyl] -piperidine with dimethyl sulfate and then reacting the
58

product with octylamine.
14. A process for preparing a member selected from the group
consisting of 4[l-[4-chlorophenyl)benzyl]-l-iminomethylpiperi-
dine and the non-toxic acid addition salts thereof, character-
ized by reacting ethyl formidate hydrochloride with 4-[.alpha.-(4-
chlorophenyl)benzyl] piperidine.
15. A process for preparing a member selected from the group
consisting of 4(9-fluorenyl)-1-[(octylimino)methyl]piperidine
and the non-toxic acid addition salts thereof, characterized by
reacting 4(9-fluorenyl)-1-piperidinecarbothioaldehyde with methyl
iodide and then reacting the product with octylamine.
16. A process for preparing a member selected from the group
consisting of 4-(diphenylmethyl)-1-[methyl(octylimino)methyl]-
piperidine and the non-toxic acid addition salts thereof, char-
acterized by reacting triethyloxoniumfluoroborate with N-(n-
octyl)acetamide and reacting the product with 4-diphenylmethyl-
piperidine.
17. A process for preparing a member selected from the group
consisting of N-[4-(diphenylmethyl)-1-piperidinyl]methylene
benzenebutylimine and the non-toxic acid addition salts thereof,
characterized by reacting N-formyl-4-diphenylmethylpiperidine
with dimethyl sulfate and then reacting the product with phenyl-
butylamine.
59

18 . A process for preparing a member selected from
the group consisting of 3-(diphenylmethyl)-1-[(octyl-
imino)methyl]piperidine and the non-toxic acid addition
salts thereof, characterized by reacting 3-(diphenyl-
methyl)-l-piperidinecarbothioaldehyde with methyliodide
and then reacting the product with octylamine.
19. A process for preparing 4-(hydroxydiphenylmethyl)-1-
[(octylimino)methyl]piperidine(E)-2-butenedioate,
characterized by reacting 4-(hydroxydiphenylmethyl)-1-
piperidinecarbothioaldehyde with methyliodide and then
reacting the product with octylamine.
20. A process for preparing 3-(diphenylmethyl)-1-
(iminomethyl)piperidine(E)-2-butenedioate hydrate,
characterized by reacting 3-(diphenylmethyl)-1-
piperidinecarbothioaldehyde with methyl iodide and
aminating the product.
21. A process for preparing 4-[4-hydroxyphenyl)phenyl-
methyl]-1-[octylimino)methyl]piperidine 2-naphthalene-
sulfonate, characterized by treating 4-[(4-methoxyphenyl)
phenylmethyl]-1-[(octylimino)methyl]piperidine with
hydrobromic acid and converting the obtained product to
its 2-naphthalenesulfonic acid salt.

MN 335
22. A member selected from the group consisting
of a substituted N-iminomethylpiperidine of formula (I):
<IMG>
(I)
and the corresponding non-toxic acid addition salts
thereof, wherein:
R1 taken individually is a member selected
from the group consisting of hydrogen; phenyl;
phenyl substituted with from one to three members each
selected from the group consisting of loweralkyl, lower-
alkoxy, hydroxy and halo; phenyl (C1-C4)loweralkyl;
l-phenyl(C7-C9)loweralkyl; phenyl(C1-C4)lowaralkyl and
l-phenyl(C7-C9)loweralkyl in which said phenyl is sub-
stituted with from one to three members each selected
from the group consisting of loweralkyl, loweralkoxy,
hydroxy, halo, and phenyl, provided that no more than one
member is phenyl; diphenyl(C1-C4)loweralkyl; diphenyl-
(C1-C4)loweralkyl wherein at least one of said phenyls
is substituted with from one to three members each
selected from the group consisting of loweralkyl,
loweralkoxy, halo, hydroxy, and phenyl, provided that
no more than one member is phenyl; diphenylhydroxymethyl;
diphenylhydroxymethyl wherein at least one of said
phenyls is substituted with from one to three members
each selected from the group consisting of loweralkyl,
loweralXoxy, hydroxy, halo, and phenyl, provided that no
more than one member is phenyl; and compounds of formulae:
<IMG> and <IMG>
61

wherein n is 0, 1, or 2 and E is H or OH;
A taken individually is a member selected from
hydrogen, acetyl, and phenyl, provided that when A is
acetyl or phenyl, R1 is a member selected from the group
consisting of phenyl or phenyl substituted with from one
to three members each selected from the group consisting
of loweralkyl, loweralkoxy, hydroxy and halo;
R1 and A taken together is a member selected
from the group consisting of benzhydrylidene and compounds
of formulae:
<IMG> and <IMG>
wherein n is 0, 1, or 2;
R1' taken individually is a member selected from the group
consisting of hydrogen; methyl; diphenylmethyl, diphenyl-
methyl wherein at least one of the phenyl groups is sub-
stituted with from one to three members each selected
from the group consisting of loweralkyl, loweralkoxy,
hydroxy, halo, and phenyl, provided that no more than
one member is phenyl; diphenylhydroxymethyl; diphenyl-
hydroxymethyl wherein at least one of said phenyls is
substituted with from one to three members each selected
from the group consisting of loweralkyl, loweralkoxy,
halo, hydroxy, and phenyl, provided that no more than
one member is phenyl; and a compound of formula:
<IMG>
wherein n is 0, 1, or 2 and E is H or OH;
62

B taken individually is hydrogen
R1' and B taken together is a member selected
from the group consisting of benzhydrylidene and a compound
of formula
<IMG>
wherein n i8 0, 1, or 2
R1" taken individually is a member selected from the group
consisting of hydrogen, diphenylmethyl; diphenylmethyl wherein at
least one of said phenyls is substituted with from one to
three members each selected from the group consisting of
loweralkyl, loweralkoxy, halo, hydroxy, and phenyl, pro-
vided that no more than one member is phenyl; diphenyl-
hydroxymethyl; diphenylhydroxymethyl wherein at least
one of said phenyls is substituted with from one of three
members each selected from the group consisting of lower-
alkyl, loweralkoxy, hydroxy, halo, and phenyl, provided
that no more than one member is phenyl; and compounds
of formulae:
<IMG> and <IMG>
wherein n is 0, 1, or 2;
D taken individually is hydrogen;
R; and D taken together is benzhydrylidene;
R2 is a member selected from the group con-
sisting of hydkogen and C1-C4 loweralkyl; and
R3 is a member selected from the group con-
sisting of hydrogen alkyl; cycloalkyl; phenylloweralkyl;
phenylloweralkyl in which said phenyl is substituted
63

with from one to three members each selected from the group
consisting of loweralkyl, loweralkoxy, hydroxy, and halo; di-
phenyl(C1-C4)loweralkyl; diphenyl(C1-C4)loweralkyl wherein at
least one of said phenyls is substituted with from one to three
members each selected from the group consisting of loweralkyl,
loweralkoxy, halo, hydroxy, and phenyl, provided that no more
than one member is phenyl; alkenyl; and alkynyl; provided that
at least one of said R1, R1', and R1" is other than hydrogen and
further provided that when R1" is other than hydrogen R1, and R'1, and A are
each hydrogen; when R'1 is hydrogen only one of R1 and R"1 is
other than hydrogen; when R'1 is other than hydrogen or ethyl R1,
R"1 and A are each hydrogen whenever prepared or produced by
the process of claim 1 or by any chemical equivalent thereof.
23. A member selected from the group consisting of 4-diphenyl-
methyl-l-iminomethylpiperidine and the non-toxic acid addition
salts thereof, whenever prepared or produced by the process of
Claim 2 or by any chemical equivalent thereof.
24. A member selected from the group consisting of 4-(diphenyl-
methyl-l- [(isopropylimino)methyl] piperidine and the non-toxic
acid addition salts thereof, whenever prepared or produced by
the process of Claim 3 or by any chemical equivalent thereof.
25. A member selected from the group consisting of l-[N-
(benzyl)iminomethyl]-4-diphenylmethylpiperidine and the non-
toxic acid addition salts thereof, whenever prepared or produced
by the process of Claim 4 or by any chemical equivalent thereof.
26. A member selected from the group consisting of l-[N-
(phenethyl)iminomethyl]-4-diphenylmethylpiperidine and the non-
toxic acid addition salts thereof, whenever prepared or produced
by the process of Claim 5 or by any chemical equivalent thereof.
27. A member selected from the group consisting of l-[N-(n-
decyl)iminomethyl]-4-diphenylmethylpiperidine and the non-toxic
acid additions salts thereof, whenever prepared or produced by
the process of Claim 6 or by any chemical equivalent thereof.
64

28. A member selected from the group consisting of 4-(diphenyl-
methyl)-l- [(octylimino)methyl] piperidine and the non-toxic acid
addition salts thereof, whenever prepared or produced by the
process of Claim 7 or by any chemical equivalent thereof.
29. A member selected from the group consisting of 4-(diphenyl-
methyl)-l-[(ethylimino)methyl]piperidine and the non-toxic acid
addition salts thereof, whenever prepared or produced by the
process of Claim 10 or by any chemical equivalent thereof.
30. A member selected from the group consisting of 4-(diphenyl-
methyl)-l-[(hexylimino)methyl] piperidine and the non-toxic acid
addition salts thereof, whenever prepared or produced by the
process of Claim 11 or by any chemical equivalent thereof.
31. A member selected from the group consisting of 1-[(4-
chlorobenzylimino)methyl]-4-(diphenylmethyl)-piperidine and the
non-toxic acid addition salts thereof, whenever prepared or
produced by the process of Claim 12 or by any chemical equivalent
thereof.
32. A member selected from the group consisting of 4-(diphenyl-
methyl)-l-[(2-propynylimino)methyl]-piperidine and the non-toxic
acid addition salts thereof, whenever prepared or produced by
the process of Claim 8 or by any chemical equivalent thereof.
33. A member selected from the group consisting of 4[1-(4-
methoxyphenyl)benzyl]-1-[(octylimino)methyl]-piperidine and the
non-toxic acid addition salts thereof, whenever prepared or pro-
duced by the process of Claim 13 or by any chemical equivalent
thereof.
34. A member selected from the group consisting of 4[1-(4-
chlorophenyl)benzyl]-l-iminomethylpiperidine and the non-toxic
acid addition salts thereof, whenever prepared or produced by
the process of Clalm 14 or by any chemical equivalent thereof.
35. A member selected from the group consisting of 4(9-fluo-
renyl)-l-[(octylimino)methyl] piperidine and the non-toxic acid

addition salts thereof, whenever prepared or produced by the
process of Claim 15 or by any chemical equivalent thereof.
36. A member selected from the group consisting of 4-(diphenyl-
methyl)-l-[methyl(octylimino)methyl]-piperidine and the non-toxic
acid addition salts thereof, prepared or produced by the process
of Claim 16 or by any chemical equivalent thereof.
37. A member selected from the group consisting of N-[4-(di-
phenylmethyl)-l-piperidinyl] methylene benzenebutylimine and the
non-toxic acid addition salts thereof, whenever prepared or pro-
duced by the process of Claim 17 or by any chemical equivalent
thereof.
38. A member selected from the group consisting of 4-benzhydry-
lidene-l-[(octylimino)methyl]piperidine and the non-toxic acid
addition salts thereof, whenever prepared or produced by the
process of Claim 9 or by any chemical equivalent thereof.
39. A member selected from the group consisting of 3-(diphenyl-
methyl)-1-[(octylimino)methyl] piperidine and the non-toxic acid
addition salts thereof, whenever prepared or produced by the
process of Claim 18 or by any chemical equivalent thereof.
66

40. A member selected from the group consisting of
4-(hydroxydiphenylmethyl)-1-[(octylimino)methyl]
piperidine(E)-2-butenedioate and the non-toxic addition
salts thereof , whenever prepared or produced by the
process of Claim 19 or by any chemical equivalent thereof.
41. A member selected from the group consisting of
3-(diphenylmethyl)-1-(iminomethyl)piperidine(E)-2-
butenedioate hydrate, and the non-toxic addition salts
thereof , whenever prepared or produced by the process of
Claim 20 or by any chemical equivalent thereof.
42. A member selected from the group consisting of
4-[(4-hydroxyphenyl)phenylmethyl]-1-[(octylimino)methyl]
piperidine 2-naphthalenesulfonate or the non-toxic
addition salts thereof, whenever prepared or produced by
the process of Claim 21 or by any chemical eauivalent
thereof.
67

Description

~401.1~3 -
SUBSTITUTED N-IMINOMETXYLPIPERIDINES
. .
BACKGRO~ND o~ TEE INVENTION
.
Unsubstituted ~-iminomethylpiperidine is dis-
closed in United States Patent No. 2,615,023, but said
compound does not inhibit gastric acid secretion even
at dose~ four times or greater than those at which the
subject compounds are active. It has now surprisingly
been discovered t~at certain substituted N-Lminomethyl-
piperidines are effective inhibitors of gastric acid
secretion.
SUMMARY OF THE INVENTION
Description of the Compounds~
The present invention comprises substituted
N-iminomethylpiperidines of Formula ~
R
Rl
>~ NC=NR3
. A ~ R2 (I)
wherein:
Rl taken individually is a member selected
from the group consisting of hydrogen; phenyl;
phenyl substituted with from one to three members each
selected from the group consisting of loweralkyl, lower-
alkoxy, h~X~ and halo; ~yl(Cl~C4tloweraIkyl; l-phenyl(C7-Cg)-
loweralkyl; p~enyltCl-C4Sloweralkyl and l-phenyl(C7-C9~-
loweralkyl in which said phenyl is substituted with from

114V~
one to three members each selected from the group con-
sisting of loweralXyl, loweralkoxy, hydroxy, halo, and
phenyl, ~rovided that no more than one member is phenyl;
diphenyl(Cl-C4~loweralkyl; diphenyl(Cl-C4)loweralkyl
S wherein at least one of said phenyls is substituted with
from one to three memhers each selected from the group
consisting of loweralkyl, loweralkoxy, halo, hydroxy,
and phenyl, provided that no more than one member is
pheny}; diphenylhydroxymethyl; diphenylhydroxymethyl
wherein at least one of said phenyls i5 gubstituted with
from one to three members each selected from the group
consi~ting of loweralkyl, loweralkoxy, hydroxy, halo,
and phenyl, provided that no more than one member is
phenyl; and compounds of formulae:
~C ~ and
wherein n is 0, 1, or 2 and E is H or OH;
A t~ in~ivi~E~ly is a memker selected frcm the ~roup
conslcting of ~x~en, acetyl, an~ phenyl, provided that when A is
acetyl or phenyl, Rl i5 a member selected from the group
consisting of phenyl or phenyl substituted with from one
to three members each selected from the group consisting
of loweralkyl, loweralkoxy, hydroxy and halo;
Rl and A taXen together is a member selected
~rom the group consisting o~ benzhydrylidene and compounds
of ~ormulae:
(C ~ and
wherein n is 0, 1, or 2;

~ '~ individhally is a ms~ sel~ from the
grDUD oonsi~ing of ~XX~n; methyl; diphenylmethy~; diphenyl--
methyl wher~in at least one of the phenyl groups is sub-
stituted with from one to three mem~ers each selected
from the group consisting of loweralkyl, loweralkoxy,
hydroxy, halo, and phenyl, provided that no more than
one member is phenyl; diphenylhydroxymethyl; diphenyl~
hydroxymethyl wherein at least one of said phenyls is
su~stituted with from one to three members each selected
from ~he group consisting of loweralkyl, loweralkoxy,
halo, hydroxy, and phenyl, provided that no more than
one member i~ phenyl; and a compound of formula:
~.
~C~
wherein n is 0, 1, or 2 and E is H or OH;
B taken individually is hydrogen;
Rl' and B taken together is a member selected
from the group consisting of ~enzhydrylidene and a compound
of ~ormula:
(CH
wherein n i3 0, l, or 2.
Rl'taken individually is a m3mber sele~ fLal~the
grou~ consistmg of hy~ , diphenylmet~yl; diphenylmethyl wherein
at least one of said phenyls is substituted with frcm one to
three members each selected from the group consisting of
loweralkyl, loweralkoxy, halo, hydroxy, and phenyl, pro-
vided that no more than one m~oer is phenyl; diphenyl-
hydroxymethyl; diphenylhydroxymethyl wherein at least

~40~ 18
one of sa~d phenyls is substituted with from one to three
members each selected ~rom the group consisting of loweralkyl,
loweralko~y, hydroxy, halo, and phenyl, provided that no more
than one mernber is phenyl; and compounds of formulae:
~ H and ~ H
wherein n is 0, 1, or 2:
D taken individually is hydrogen;
Rl" and D taken together is benzhydrylidene.
R2 is a member selected from the group consisting of
hydrogen and Cl-C4 loweralkyl; and
R3 is a member selected from the group consisting of
hydrogen; alkyl; cycloalkyl; phenylloweralkyl; phenylloweralkyl
in which said phenyl is substituted with from one to three
members each selected from the group consisting of loweralkyl,
loweralkoxy, hydroxy, and halo; diphenyl(Cl-C4)10weralkyl; di-
phenyl(Cl-C4)loweralkyl in which at least one of said phenyls is
substituted with from one to three members each selected from
the group consisting of loweralkyl, loweralkoxy, hydroxy, halo,
and phenyl, provided that no more than one member is phenyl;
alkenyl; and alkynyl; provided that at least one of said Rl,
R'l and R"l is other than hydrogen and further provided that
when R"l is other than hydrogen Rl, and R'l, and A are each
hydrogen; when R'l is hydrogen only one of Rl and R"l is other
than hydrogen; when R'l is methyl Rl is other than hydrogen and
R"l is hydrogen; and when R'l is other than hydrogen or ethyl
Rl, R"l and A are each hydrogen.
As used herein~loweralkyl and loweralkoxy may be straight
or branched chain saturated aliphatic hydrocarbons having from
one to eight carbon atoms, such as for example, methyl, ethyl,
propyl, isopropyl, butyl, t-butyl, pentyl, and the like lower-
alkyls, and, respectively, the corresponding loweralkoxys, e.g.,
methoxy,

r~ ~
1~L~V~.18
ethoxy, propoxy, isopropoxy, butoxy, pentoxy, and the
liXe. The term "Cl-C4 loweralkyl" includes those lower-
alkyls having from one to four carbon atoms, such as for
example, methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, sec butyl, and the like. The terms "phenyl-
(Cl-C4)loweralkyl" and "diphenyl(Cl-C4)loweralkyl" include
only those compounds where the phenyl group( 5 ) are bonded
to the terminal carbon atom of a straight chain loweralkyl,
such as 2-phenethyl, 4-phenylbutyl, 4,4-diphenylbutyl,
3,3-diphenylpropyl, and the like. The term n l-phenyl-
(C7-Cg)loweralkyl" includes groups having the following
general formula:
~1
(C~ 2)m
c~3
where m is 5, 6,~r 7. me tenm "alkyl" includes straight or
branched chain saturated aliphatic hydrocarbons having up
to about sixteen carbon atoms, such as for example, the
a~o~e mentioned loweralkyls and fsrther such radicals
as hexyl, heptyl, octyl, nonyl, decyl, dodecyl, hexadecyl,
and the like. The term "cycloalkyl" includes mono-, bi-,
and tricyclic saturated and unsaturated aliphatic hydro-
carbons having up to about ten carbon atoms, such as for
example, cyclohexyl, adamantyl, l-adamantyl-methyl,
exo-norbornyl, endo-norbornyl, noradamantyl, anti-7-
norbornenyl, and the like. The terms "alkenyl" and
"alkynyl" include straight and branched chain hydro-
carbons having from two to about eighteen carbon atoms
and at least one double or triple bond, respectively,
such as for example, allyl, methallyl, l-propargyl
(l-propynyl), 2-pentenyl, and the like. The term "halo"
includes fluoro, chloro, bromo and iodo.
Methods of Preparation
The compounds of Formula I may generally be
prepared by reacting together: a) an appropriately-
6ubstituted piperidine of Formula (II) with an appropriate
activated amide (Formula III), or b) an appropriate
primary amine of Formula (VII) with an activated N-acyl

~Vt ~
piperidine of Formula (VI), said activation in either
case having been achieved by treatment of the respective
amide with a suitable activating agent selected from,
for example, phosgene, Me30 BF4 , Et30 BF4 , (MeO)2S0
MeOS02F, POCl~, PC15 and the like.
Included in the terms n amide n and "N-acyl-
piperidine" as used herein are the corresponding thio
derivatives in which the carbonyl oxygen has been re-
placed by sulfur. In the case of the thio derivatives,
there are additional suitable activating agents which
may be employed, such as for example, loweralkyl halides
(methyl halide being preferred), methyl tosylate, methyl
sulfonic acid esters te.g., methyl methanesulfonate)
methyl trifluoromethylsulfonate, and the like.
The activated reactant o~ Formula (III) may be
in either free base or acid addition salt form.
Specific preparative routes are given below:
~ ) The compounds of Formula (I) may be pre-
pared by reacting the appropriately-substituted piperidine
of Formula (IT) with an appropriate imidate ester of
Formula (III). The methyl and ethyl esters are preferred.
The substituted piperidine and the imidate ester (which
may be present in either free base or acid addition salt
form, the latter being shown) are stirred together in a
suitable oryanic solvent such as, for example, a halo-
carbon (e.g., carbon tetrachloride, chloroform, 1,2-
dichloroethane, and the like), a loweralkanol (e.g.,
methanol, ethanol, isopropanol, and the like), an aromatic
hydrocar~on (e.g., benzene, xylene, toluene, and the like),
dimethylsu~foxide, and the like. The temperature of the
reaction is preferably from about 0 to about 25C, and
in some cases may be carried out as high as 50C, but in
any event the temperature of the reaction must not be
high enough to decompose significant amounts of the
imidate e~ter. The resulting product may be isolated
and purified by techni~ues known in the art, e.g., by
stripping off the solvent and recrystallizing the desired
produet in the free base or acid addition salt form.
The above reaction ~cheme may be illustrated by the

1147~ 18
following~ wherein Al B, D, Rl, Rl', Rln, R2, and R3 are
as previously defined, Z is selected from the group con-
sisting of loweralkoxy (preferably methoxy and ethoxy),
loweralkyl-S- (preferably methylthio), chloro, and
C12(0)P0-, and X is a member selected from the group
consisting o~ halid~, BF4, FS03, and CH30S03. Addi-
tionally, when Z is loweral~yl-S-, X may also be a member
selected from the group consisting of (4-methylphenyl)S03,
CH3S03, and CF3S03.
Rl' B 1 Rl~ B Ri
~ D \~ ~ D
Rl ~ NH + ZC=NR3 HX 3 ~ NC2NR3
~ III) tI)
The compounds of Formula tI) wherein R2 is
hydrogen may also be-prepared ~y an analogous route by
substituting an appropriate compound of Formula (IIIA)
or (IIIB) for the imidate ester of Formula (III). If
the former is used, the resulting thiourea is then re-
duced (e.g., with Raney nickel) to give the desired com-
pound. If the latter is used, silver c~loride is em-
ployed as catalyst. These reaction schemes are illus-
trated by the following:
....
R ' B'`l
R ~
A ~ NH + R3N'C=S ~--_~thiOurcl reduction)(I) (R
(II) (IIIA)
~ ..
R ' B'`l
R~
A ~ NH + R3N-C cat~l~ti~ l ) (I) (R2=H)
tII) (IIIB)

M~ 335
1~4V~l~
B) The compounds of Formula (I) may also be
prepared by reac~i~g a suitably-substi~uted piperidine
of ~ormula (II) with acetic formic anhydride or N,N-
diloweralkylthioformamide (for R2=H~ or a Cl-C4 loweralkyl
anhydride ~for R2=Cl-C4 loweralkyl), the anhydride pre-
ferably being present in excess. The piperidine and
anhydride or thio~n~m~de are combined with cooling and æe
allowed to stir for about 18 hours. The resulting reac-
tion mixture, either dissolved in an organic solvent
~elected from t~e aforementioned halocarhon and alipha-
tic hydrocarhon ~olvents or ~ithout the addition of solvent,
is then treated ~lt~ an aqueous solution of a ~eak.~ase
~.g~, sodium bicarbonatel until the aqueous layer i5
neutral Cfor the. a~ydride routel or is ~ash~ wit~
water Cfor th~. amide route.l. The organic layer i5
separated and any solvent present is removed to ohtain
the respective intermediate amides CrVl, CrVAl, and CVl~
The intermediate. amide.lc treated either neat or in the
prese~ce of an organic solvent such as, for example, a
h~locarbon CCx~l3~ C ~ C12) or a hydrocar~on U~enzene,
toluen~) at 25~ to 100C with a suitahle activating
agent, 5 describ~d previously, for about t~o to three
hours, to produce the activated derivative (.VI~, after
which the reaction mixture is allowed to cool. Addition
of the appropriate primary amine CVII~ yields the de-
sired product of Formula ~I~ which may be isolated and
purified by known methods dis~ussed above. Th.e above
reaction scheme may be illustrated by the following,
.Rl, R1, Rl, R2, R3, A, B, D, Z, and X are as
originally defined:

v~
Rl'~ D
Il ~ A~_J ~c~tl~l~t~ng
IV ~nt
s~ D ~1 ~ D
R ~ tC113 ) 2 ~ ~ng Rl / ~ a
~7 ~ nt ~;N~ R3N112
SVA ~ VI
R ~1~,D ~ ctl~tlng
r~lcyl~ 20 ~ r~~g~nt
A~ lv.l r-lJcyl R ~ 1
V 7~ NR3
~ hen Z is Uo~eralkyl~-S-~ the compounds of
Formula CI2 wherein R2SH may also be obtained iy reacting
the activated intermediate ~VI) with. the appropriate
isocyanate of Formula (VIII), pre~erably at the reflux
temperature of the solvent (e.g., toluene) for about
nine days. This reac~ion scheme is illustrated by the
following:
R B Rl
1~JL---L~D
1 ~ ~ lo~eralkyl
A ~ N=C' H + R3N=C=0 ~ I~R2
VI VIII
Because the subject compounds CIl possess a
basic amidine group, they may be converted into the
corresponding acid addition salts.
The acid addition salts may be prepared by
reaction with an appropriate acid, as for example an
inorganic acid such as a hydrohalic acid, i~e , hydro-
chloric, hydro~romic or hydriodic acid; sulfuric or
nitric acid; phosphoric acid; an organic acid such.as
acetic, propionic, glycolic, pamoic, pyruvic, oxalic,
malonic, succinic, maleic, picric, fumaric, malic,
tartaric, citric, ~enzoic, cinnamic, mandelic, methane-
sulfonic, ethanesulfonic, benzenesulfonic, E~toluenesulfonic,

salicylic, 2-naphthalenesulfonic or ~-aminosalicylic
acid. The therapeutically active, non-toxic acid addi-
tion salts of subject compounds (I) are included within
the scope of the present invention.
The starting materials of Formulas ~II), ~III),
(IV), (IV~), (V), (VI), (VII), and (VIII) are known or
may be prepared by known methods. See generally R. C.
Elderfield, ~eterocyclic Compounds, Vol. 1, Ch. 9, pp
617-77 (1950). Preparative methods for compounds (II)
are described in, for example, articles by F. Ravenna,
Farmaco (Pavia) Ed. Sci., 14, 473-82 (1959) and E. Sury
and R. Hoffman, Helv. Chim. Acta., 248, 2133 (1954).
Preparative methods for compounds (III) and (IV) are des-
cribed in, for example, articles by R. Ohme and E. Schmitz,
Angew. Chem Intern. Ed., 6, 566 (1967), F. Snydam,
et al., J. Org. Chem., 34, 292 (1969), and R. Sechinger,
Helv. Chim. Acta., 56, 776 (1973). Preparative methods
for compounds (V) and (VI) are described in, for example,
C. A. Buehler and D. E. Pearson, Sur~ey of Or~anic Syn-
theses, Cho 18~ p 894 (1970).
Method of Testing
The compounds of the invention are useful for
inhibition of gastric acid secretion as measured by the
following test. Female Sprague-Dawley rats are fasted
twenty-four hours before testing and are given water ad
libidum while being kept in individual cages. On the
.
day of testing~ the rats are weighed and are selected
80 that the rats in each test weigh within a range of
+ 20 grams.
Surgery is carried out under light ether
anesthesia. As soon as the rat is anesthetized its teeth
are removed and a mid-line incision is made on the ab-
domen about 1 1/2 inches in length and the stomach and
duodenl~m are exposed. If at this point the stomach is
filled with food or fecal material, the rat is discarded.
If the condition of the stomach is acceptable, a purse
string stitch is placed on the fundic portion of the
stomach with a suture, taking care not to pierce any
blood vessels in the area. A small nick is then made

~14V~ ~l8
11
into the stomach in the center of the purse string, and
a cannula, consisting of a small vinyl tube with a flange
on one end, is put into the stomach, and the purse string
stitch is closed tightly around the flange. The test
compound is administered either i~b=YhIdona~ly ~d.l
immediately-aft r surgery or orally (~.o~l one hcur prior bo surgery
at doses gene~ally ranging from about 0.25 to about 160
mg/kg in a volume of 0.5 ml/100 grams rat. Control rats
receive the-test vehicle, Q.5% aoueous methyl cellulose.
After the surgery and (in the case of i.d. ~d-
ministration~ after administration of the test compound,
the abdominal wall and skin are clo~ed simultaneously
with three or four 18 mm wound clips and a collecting tube
is placed on the cannula. Each rat is then placed in a
box in which a longitudinal slit has been made to allow
the cannula to hang freely and to allow the rat to move
about unencumbered. After the rat has been allowed to
stabilize for thirty minutes, the collection tube on the
cannula is discarded and replaced with a clean tube to
receive the gastric juice. Collections are made at one
hour. At th~ end of the study, the cannula is removed and
the rat is sacrificed.
The sample of gastric contents collected is
drained into a centrifuge tube and centrifuged to pack
down the sedLment. The volume is read and a 1 ml ali-
quot of the sup~rnatant is put into a beaker containing
10 ml distilled water and is titrated to pH7 using 0.01
N sodium hydroxide. Results are determined for Volume,
Titrata~le Acid and Total Acid Output, where Volume
equals total ml of gastric juice minus sediment;
Titratable Acid (meq/l) equals amount of O.Ol N sodium
hydroxide needed to titrate the acid to pH7; and Total
Acid Output equals Titratable Acid times Volume. Results
are reported as the ED50 dose (mg/kg required to produce
an average of 50% inhibition in Total Acid Output versus
controls in all the animals tested for a particular oom-
pound) and as percent inhibition. The compound~ of the
invention all demonstrate a significant inhibition both

MN 335
12
i.d. an~ p.o. at less than 80 mg/kg, with preferred com
pounds having an ED50 ~ less than 20 mg/kg. In con-
trast, the prior art N-iminomethylpiperidine demonstrates
no inhibition whatsoever at a dose of 100 mg/kg ~ o. or at
80 mg/kg id.
It is well-known that excessive se~retion of
gastric hydrochloric acid leads to unneeded peptic activi-
ty and endangers the mucous lining of the stomach. The
use of gastric antisecretory agents is thus desirable as
an aid in the prevention and amelioration of distress
occasioned by high concentrations of stomach acid.
Description of the Preferred Embodiments
Preferred compounds of the invention are those
of Formula (I) wherein:
Rl is a ~ember selected from the group consisting
of phenyl; phenyl substituted with from one to three mem-
bers each selected from the group consisting of loweralkyl,
loweralkoxy, halo, and phenyl, provided that no more than
one member is p~enyl; phenyl(Cl-C4)loweralkyl; phenyl-
(Cl-C4)loweralkyl in which said phenyl is substituted
with from one to three members each selected from the group
consisting of loweralkyl, loweralkoxy and halo; diphenyl-
(Cl-C4)loweralkyl and diphenyl(Cl-C4)loweralkyl wherein
at least on~ of said phenyls is substituted with from
one to three members each selected from the group con-
sisting of loweralkyl, loweralkoxy, halo, and phenyl,
provided that no more than one member is phenyl;
R2 is a member selected from the group consisting
of hydrogen and methyl;
R3 is a member selected from the group consisting
of hydrogen; alkyl; cycloalkyl; phenylloweralkyl; phenyl-
loweralkyl in which said phenyl is substituted with from
one to three members each selected from the group consis-
ting of loweralkyl, loweralkoxy, and halo; alkenyl, and
alkynyl; and
Rl', Rl", A, B, and D are each hydrogen.
More preferred compounds of the invention are
those of Formula ~I) wherein:

1~4~)~1t3
13
Rl is a member selected from the group consisting
of diphenylmethyl and diphenylmethyl wherein at least one
of said phenyls is substituted with from one to three
m~hers each selected ~rom the group consisting of lower-
alkyl, lowera~oxy, and halo;
R2 is hydrogen;
R3 is a member selected ~rom the group consistingof hydrogen; alkyl; phenylloweralkyl; phenylloweralkyl
in which said phenyl i8 substituted with from Qne to three
members each selected from the group consisting of lower-
alkyl, loweralkoxy, and halo; alkenyl; and alkynyl; and
Rl', Rl", A, B, and D are hydrogen.
Most preferred compounds of the invention are
those of Formula (I) wherein Rl is a member selected from
the group consisting of diphenylmethyl and diphenylmethyl
wherein one of said phenyls is subs~itued in the ~
position with a mP~her selected from the group consisting
of loweralkyl, loweralkoxy, and halo; R2 is hydrogen; R3
is a mem~er selected from ~he group consisting of hydrogen,
straight chain alkyl, and phenylloweralkyl; and Rl', Rl"~
A, B, and D are all hydrogen.
Description of the Method of
Treatment and Pharmaceutical Compositions
In view of the antisecretory activity of the
subject compounds, there is further provided herein a
met~od of inhibiting gastric acid secretion which com-
prises internally admini~tering to a gastric hyperacidic
subject (man or animal) an effective gastric acid secretion
inhibiting amount of a substituted N-iminomethylpiperidine
of Formula tI~, in base or acid addition salt form, pref-
erably in admixtur~ with a pharmaceutically acce~tabl~carrier. If an acid addition sa}t form is used, said salt
must of couræe ~e pharmaceutically-acceptable and non-
toxic. Pharmaceutical compositions comprising a su~ject
compound (I~ are also considered a further aspect of thP
3s present invention.
To prepare the pharmaceutical compositions of
the present invention, a substituted N-iminomethylpiperidine
of Formula (I~ or an acid addition salt thereof is combined

M~ 335
ll~Q1 .18
14
as the active ingredient in intimate admixture with a
pharmaceutical carrier according to conventional pharma-
ceutical compounding techniques, which carrier may take
a wide variety of forms depending on the form of prepara-
tion desired for administration, e.g., oral or parenteral.In preparing the compositions in oral dosage form, any
of the usual pharmaceutical media may be employed, such as
for example, water, glycols, oils, alcohols, flavoring
agents, preservatives, coloring agents, and the like in
the case of oral liquid preparations such as for example,
suspensions, elixirs, and solutions; or carriers such as
starches, sugars, diluents, granulating agents, lubri-
cants, binders, disintegrating agents, ~nd the like in a
case of oral solid preparations, such as for example,
powders, capsules, and tablets. Because of their ease
in administration, tablets and capsules represent the
most advantageous oral dosage unit form, in which case
solid pharmaceutioal ~arriers are obviously employed.
If desired, tablets may be sugar coated or enteric coated
by ~tandard techniques. For parenterals, the carrier will
usually comprise sterile water, although other ingredients,
for example, to aid solubility or for preservative pur-
poses, may be included. Injectable suspensions may also
be prepared, in which case appropriate liquid carriers,
suspending agents, and the like may be employed. The
pharmaceutical compositions herein will contain, per
dosage unit, e.g., tablet, capsule, powder, injection,
teaspoonful, and the like, ~rom about ten to about five
hundred milligrams of the active ingredient, and prefer-
ably from about fifteen to about two hundred fifty milli-
grams.
The following examples are intended to illustrate
but not to limit the scope of the present invention.

EXAMPLE I
4-Diphenylmethyl-l-iminomethylpiperidine
~ ~ ochloride hydrate
A suspension of 27.39g (0.25 mole) of ethyl
formimidate hydrochloride ~prepared by the method of
Ohme, et al., Angew. Chem. ~ntl. Ed., 6, 566(1967)] and
52.71g (0.20 mole) of diphenyl-4-piperidylmethane in 80
ml of freshly-opened absolute ethanol was stirred mag-
netically under a calcium chloride tube overnight. The
suspension was filtered and diethylether was added to the
filtrate. The filtrate was stripped to dryness and the
resulting oil was crystallized from isopropanol. The
solid was then suspended in boiling ethyl acetate to
obtain a higher melting form. Two recrystallizations from
ethanol-ether yielded pure 4-diphenylmethyl-1-Lminomethyl-
piperidine hydrochloride hydrate; m.p. 220-221C.
EXAMPLE II
Following the procedure of Example I, but sub-
stituting for the ethyl formimidate hydrochloride and
diphenyl-4-piperidylmethane ~sed therein, equivalent
amounts of the appropriate starting materials, there are
prepared the following:
R ~
1 ~ NC=NR3 . Salt
A ~ ~2
Rl 5alt A R2 R3 m.p~ (C?
~ip~P~y~ yl ~Cl H C2H5 ~ 271.5-277.5
a-(4-m~h~yniE~y1) fumarate H H H 1~9.5-192.5
b~l ,
~-~,4-h~nyl)-a- HCl H H H 216 -218
hy~lr3~1
p~enyl HCl H H H 204 -205
benzyl ECl o H H H 199 -201.5
phenyl HCl C-CH3 H H 172 -175
a-U~on~E~ ~rate H H H 192.5-194.5
~yl

l8
16
EXAMPLE III
4-(DiphPnylmethyl)-l-N-ethyliminomethyl-
pip~ridine oxalate hemihydrate
A mixture of 8.00g (0.029 mole) of N-formyl-4-
diphenylmethy~piperidine and 3.51g (2.67 ml, 0.029 mole~
of dimethylsulfate was heated on a steam bath for two
hours to give a clear thick syrup. To this material
was then added 1.38g (2.00 ml, 0.031 mole) of ethylamine
in 15 ml of methylene chloride. The resulting solution
was stirred for 1.5 hours at 25, stripped, slurried in
ether, and treated with 28 ml of 3 N sodium hydroxide
solution. The ethereal layer was dried over potassium
carbonate, filtered through diatomaceous earth filter
aid and evaporated to give 8.77g of yellow li~uid. Treat-
ment of this material in isopropanol with 3.26g of oxalicacid dihydrate afforded 5.0g of white solid m.p. 165-
175C. Recrystallization from isopropanol afforded pure
4-(diphenylmethyl)-1-N-ethyliminomethylpiperidine oxalate
hemihydrate as a white solid; m.p. 185-187C.
EXAMPLE IV
Following the procedure of Example III, but
substituting for the ~-formyl-4-diphenylme~hylpiperidine
and ethylamine used therein, e~uivalent amounts of the
appropriate starting materials, there are prepared the
following:
R1 ~ NC=NR3 Salt
\J R2
_ R2 ~ Salt m.p. (C)
dipheny~ yl H -C~2C~=CX2 cycld~ane 179.5-181
~amate
n H i-p~l fumarate 175 -178
~ H n-butyl " 193.5-195
H n-hexyl ~ 179 -181.5
n H _-hepkyl ~ 175 -178
H n~x~yI " 157 -159
" H t-octyl " 227 -229
" H n-nonyl " 142 -144.5

~14V~
R2 R3 Salt m.p. (
diphenylmEthyl ~ nrdecyl succ~nate 106 -109
n H ~ 1 ~umarate 143 -145.5
~dra~e
~ H l-~mantyl fumarate 275 -276
n ~ benzyl cy~lohexane 164.5-166.5
n H ~1 n 141 -144
n H ~ 1 2-nLç~ ene 222 -224
~ul~anate
n H ~ 1 n 110.5-112.5
a- (4-r~eY~D~npYenyl) H n-octyl (E)-2-butene- 154.5-156
b~l dioate
10a- (4-methy1pheny1) H n-octyl n 161 -163.5
diphenylmethyl H 4 m~thyltEnzyl pt5~ or3te 242 -244
n H phenyl 4-tDluene- 285 -286
sulfonate
EXAMPLE IVA
A mixture of 4-[(4-methoxyphenyl)phenylmethyl]-
l-[~octylimino)methyl]piperidine (1.9Og, 0.0045 mole) and
42 ml of 47-49~ hydrobromic acid was refluxed one hour,
cooled, and the aqueous portion decanted from a thick
oil. The oil was dissolved in methylene chloride,
rendered neutral with a~ueous sodium bicar~onate, dried
and evaporated. The residue, 4-[(4-hydroxyphenyl)-
phenylmethyl]-l-[(octylLmino)methyl]piperidine was con-
verted to its 2~naphthalenesulfonio acid salt, m.p.
177.5-180C.
XAMPLE V
4-(Diphenylmethyl)-l-[(octyl$mino)methyl]-
Pi~eridine Fumarate Hvdrate
", , _
A ~olution of triethyl oxonium fluoroborate
[prepared from 104.6g (0.737 mole) of boron trifluoride
etherate and 56.04g ~47.37 ml, 0.606 mole) of epichloro-
hydrin] was dissolved in 800 ml of anhydrous methylene
chloride and the resulting solution treated with 81.0g
(0.516 mole) of N-(n-octyl) formamide and stirred over-
nigh~ at 25$. 4-Diphenylmethylpiperidine (130g, 0.518
mole) was added and the mixture was stirred for four
hours. A small amount of white solid was filtered off,

r~
18
the filtrate made basic with 3 N sodium hydroxide solu-
tion, separated, dried over potassium carbonate and
evaporated to a yellow oil. This material was dissolved
in isopropanol and treated with 6~g of fumaric acid with
warming. Addition of an equal volume of aceto~e followed
by ether caused a solid to form affording two crops of
material m.p. 152-157C. These were combined and re-
crystallized from ethanol-water to give two crops of
4-~diphenylmethyl)-1-[~octylimino)methyl]piperidine
fumarate hydrate: m.p. 157-159C.
EXAMPLE VI
. . .
4-(Diphenylmethyl)-l-pipe-r-idinecarbothioaldehyd-e
A solution o~ 20.0g (0.08 mole) of 4-diphenyl-
methylpiperidine, 14.2g (0.16 mole) of N,N-dimethylthio-
formamide and 50 ml of toluene was refluxed for 12 hours,
cooled, and washed with water. The organic layer was
separated, dried and stripped to an oil which was treated
with diethyl ether to give a solid. Recrystallization of
this material afforded a white crystalline solid, 4-(di-
phenylmethyl)-l-piperidinecarbothioaldehyde, m.p. 152-154C.
EXAMPLE VII
. .
Following the above procedure, but substituting
for 4-diphenylmethylpiperidine used therein, an equiva-
lent amount of an appropriate piperidine, there are pre-
pared the following: R '
Rl / \ S
A ~ NCH
/ , .
Rl A Rl' m p. (C)
9-fluorenyl H H 142 - 146
H H Ph2CH 115 - 120
-~ benzyhydrylidene------- H 131 - 134
diphenylhydroxymethyl H H 200 - 203
EXAMæLE VIII
4-(Diphenylmethyl) -1-N-
(n-dodecyliminomethyl)piperidine fumarate
35A solution of 5.54g (0.019 mole) of 4-(diphenyl-
methyl)-1-piperidinecarbothioaldehyde in 20 ml of

~l~V~ ~l8
lg
chloroform was treated with 2.65g tl.l6 ml, 0.019 mole)
of methyl iodide and refluxed for one hour. The result-
ing solution was treated with 3.49g (0.019 mole) of n-
dodecylamine, refluxed one and one half hours, cooled,
treated with aqueous sodium hydroxide and the organic
layer separated. After drying, evaporation yielded an
oil which was converted to the fumarate to yield 4-
(diphenylmethyl)-l-N-(n-dodecyliminomethyl)piperidine
fumarate; m.p. 143-145.5C.
EXAMPLE IX
Following the above procedure, but substituting
for the 4-(diphenylmethyl)-1-p$peridinecarbothioaldehyde
and n-dodecylamine used therein, equivalent amounts of
the appropriate starting.materials, there are prepared
15 the following: Rl'
Rl ~\
A ~ NCH=NR3
A ~' R3 Salt ~ p. ~C)
H H
di~Y~lmetbyl H ( ~ )8C=C- fumara~_ ~inter
(CH2)~CH3 hydrate 131 -13S
diphenylmethyl H H ~ C-CH HCl 117 -1l9
9H-flu~rg-yl H H n-C8H17 HCl 174 -177
H H diphenyl- n-C8H17 ~m~rate (sin~Pr 68.5)
methyl . hylrate 70 -72
-be1~*y~ryl~ H n-C8H17 te 167 -170
diphenylhy~x3ynethyl H H n-C8H17 f~ate (.s nter 145)
H H diF ~ 1- H fu~rate 185.5-187.5
methyl
EXAMPLE X
Alternate Preparative Routes Illustrated for
4-(Diphenylmethyl?-l-[(octylimino)methyl]Piperidine
1) A mixture of 2.90g (0.01 mole) of 4-(di-
phenylmethyl)-l-piperidinecarbothioaldehyde, 129g (0.01
mole) of n-octylamine, 0.60g (0.01 mole) of glacial
acetic acid and 20 ml of toluene was heated with stirring
at 60 for two days. The reaction mixture was made basic

~l~V~
and concentrated to give an oil which was identified as
4-(diphenylmethyl~-1-[(octylimino)methyl]piperidine by
vapor phase chromatography.
2) A mixture of 2.0g (0.0068 mole) of 4-(di-
phenylmethyl)-l-piperidinecar~othioaldehyde, O.9g
(0.0069 mole) of n-octylamine, 2.16g (0.010 mole) of
mercuric oxide and 15 ml of isopropanol was refluxed
overnight, filtered and concentrated. The residue was
treated with fumaric acid to give 4-(diphenylmethyl)-1-
[(octylimino)methyl3piperidine (E)-2-butenedioate
(1:1) hydrate which was identified by comparison with
an authentic sample by thin layer chromatography.
3) A solution of l.Og (0.0034 mole) of 4-(di-
phenylmethyl)-l-piperidinecarbothioaldehyde, 0.59g
(0.0038 mole) of n-octyl isocyanate and 6 ml toluene
were refluxed nine days. Vapor phase chromatography
in conjunction with mass spectral analysis showed
4-(dipheny}methyl)-1-[(octylimino)methyl]piperidine
in the amount of 17% in the reaction mixture.
4) A solution of l.Og (0.0034 mole), of 4-(di-
phenylmethyl)-l-piperidinecarbothioaldehyde, 0.45g
(0.0034 mole) of n-octylamine, and 6.0 ml isopropanol
was refluxed overnight. Vapor phase chromatography
analysis of the reaction mixture showed 4-(diphenylmethyl)-
l-[(ootylimino)methyl]piperidine to be present.
5) A solution of 6.0g (0.035 mole) of n-octyl-
isothiocyanate was dissolved in 25 ml of toluene, treated
with 8.80g (0.035 mole) of 4-diphenylmethylpiperidine
and stirred at 25 for twelve hours. The mixture was
cooled, filtered and evaporated. Chromatography of the
residue through silic~ gel using chloroform as an eluent
aforded a brown oil, 4-(diphenylmethyl)-N-octyl-l-
piperidinecarbothioamide. A mixture of l.Og (0.0024 mole~
of this material, 3g of Raney Nickel and 15 ml of iso-
propanol was refluxed three hours, cooled, and filtered.Evaporation of the filtrate afforded an oil which was
converted to a fumarate identified as 4-(diphenylmethyl)-
l-[(octylimino)methyl]piperidine (E)-2-butenedioate
(1:1) hydrate by thin layer chromatography.

114V
21
6) A solution of N-formyl-4-diphenylmethyl-
piperidine 40.0g (0.143 mole) and 50 ml of methylene
chloride was treated with pho~gene until gas evolution
ceased. After refluxing for one hour, the excess phosgene
was removed under reduced pressure, the reaction was
diluted with 50 ml of methylene chloride and ~4~8 ml
(0.145 mole) of n-octyl amine in 25 ml of methylene
chloride was introduced at such a rate as to maintain
mild reflux. ~riethyl amine (28 ml) was added 510wly,
the reaction stirred for ten minutes, and then poured
into water. The organic phase was separated, washed with
20% sodium hydroxide solution, dried, and stripped to an
oil which was converted to 4-(diphenylmethyl)-1-[(octyl-
imino)methyl]piperidine (E)-2-butenedioate (1:1) hydrate,
identified by thin layer chromatography.
7) A mixture of 5.60g (0.022 mole) of 4-di-
phenylmethylpiperidine, 3.50g (0.022 mole) of n-octyl~
isonitrile, 0.26g (0.002 mole) of silver chloride, and
10 ml of toluene was stirred 48 hours at 25, filtered,
stripped, and the residue dissolved i~ methylene chloride.
Extraction with 10% sodium hydroxide, drying and filtra-
tion of the organic layer followed by evaporation afforded
4-(diphenylmethyl) l-[(octylimino)methyl]piperidine
isolated as the fumarate salt, which was identified by
thin layer chromatography.
EXAMPLE XI
Following the test procedure previously des-
cribed, the following compounds were tested for their
antisecretory activity. The ED50 values for p.o.
administration and the percent inhibition for i.d.
administration at 20 mg/kg are tabulated below (Ri =
H except where noted):
~1
R~ R2
A~NC=NR3
. _ . . ... , _ _ _ .. _ . . , .. _ . . ~

MN
~4~ ~8
O O O O ~O O ~D ~ ~ ~ ~ a~ c o ~o o o ~ In ~
~ O O O O O 0~ G 0 t~ ~ t~ O O ~ t` ~0
o 8 '` ~ ~ co ~ .` 'D ~ ~D ~ o ~ ~ ~
u~ C ~r o o ~ CD CO ~ ~ u~ ~ CO ~ ~` ~O ~ ~ O O O
k~ ~ ~ A V
~N ~J
1 ~ t
~ I r : ~ e
.
~3'

r~
l.8
~3
a ~
o ~ O N t` C~ W 0~ ~
o o In ~ co I o ~ +~+U- ~
~I cl

~14V~ ~8
2~
EXA~?LE XII
Following the procadure described by Buehler
and Pearson [Survey of Organic Syntheses, Ch. 18, p 894
(1970)] and using the appropriate substituted piperidine
and anhydride, there are prepared the following piperidine
S amides, wherein the following substituents are in the two
(Rln), three ~Rl') or four ~Rl) position:
1~ Rl" ,
1 ~ .NC=O
A ~ R2
Position of
Substituent S~i~t ~ A
dipbeny~ yl 4 H H
c~ (4~11t~he~1)bq~1 n n n
(4~rethylEiher~1) b~l n ~ n
(4~1~9/~l)be~l n n n
ct~ (4--chl~phe~l)}~l 3
9--fluor~l ~ n n
d~hes~l n ~ n
ph~yl 4 n
phe~l n
4 ~ lar ~ yl " " H
4-chl~rcpheny~ " " phenyl
20 4-methcxypheny1 " " H
4-methcxyph~nyl " " phenyl
4-chlordbenzyl n n H
phenyl " methylphenyl
pbenyl n n-butyL phenyl
25 o!(l,4-bipbenyl)benzyl " H H
or(l~4-biphenyl)b#nzyl " methyl
o-(1,4-bipbenyl)henzyl " n-butyl n
2,2-dipheny1ethy1 " H "
2,2-diphenylethyl n methyl
30 2,2-diphenylethy1 ~ n-butyl "
10,11-cbhydrc-SH-dikenzo[a,d]-
cycloheptene-S-yl 2 H "

~4V~
25 ~ositic~n of
Su~tih~t Substituent ~ A
10,11~ ~5H~Z Ea~d] -
qk~hept~5-yl 2 ræt~yl H
n n rs--~l~l n
n- 4 H "
n " meff~yl
n n--but
4,4~1-n-}~1 4 H ~
4 ~ 4~1~ l n T~l n
4 ~ 4~ l nn--butyl n
4~th~1 n H ~
benzyl - - n
9--f Lu~l n n n
dip~3met~1ene n n -
~-(4~1)~1 " " "
--(4~1p~yl)bOE~ n
~~ (4~1) be~ tl n n n
dipe~l 3~ " "
Y~Y1
2 0 a--(4~hl~1) b~l n n n
pheryl 4 n n
9--fluore~l n n n
4--chlxo~ - n
4~1 n n ~
2 5 4~c~1zyl n 1~ n
4~e~1 1~
~zyl .. .. ..
dipher~ylmethylene n n n
a-(4~orc~yl)b~zyl " " "
(4~ctl~1) b~zyl ~' n ~
- (4~ret~1F~yl) b~zyl " " "
diE~henylme~yl 3 " "
9-flu~renyl 1. " "
~lw~l 4 " "
--(4--chlor~yl~b~zy1 3 n

26
Positic~ of
Substitu~t S~ entR~ A
5~o[a,d]cyc~5-yl 2 H H
n n me~l n
n n--bu~yl
lO,ll~ydro ~a,d] ~yc~5-yl n E~ n
" " me~l "
n n n~ 5~1 n
E~Tl (oc~l)mEt~l 4 H n
n ~ yl n
" n-h~l
phe~l ~h~l)m~l ~ H
n }~1 n
n n ~b~l n
p~e~l n n n
W~l n ~ n
4-ræ~1 n 1~ n
be~l n n n
Wllc~l ~I n n
4~ _1 n n n
q~l 2 H n
diE~yl n ~1
di~ lmethyl n n-butyl
5H~szota,d]cycloh~J~s-~-yl 4 H n
5~-d~#~c[a,d]cyclohq~5-yl n methYl n
5~d~x~o[a,d~cycJ~ en-5-yl " n-butyl
EXAMPLE XIII
Following the procedure described by Buehler
and Pearson [Survey of Organic Syntheses, Ch. 18, p 894
(1970)] and using the appropriate substituted piperidine
and anhydride, there are prepared the following piperidine
amides:

,~,
s~
2)n
Po~ition of
Substituent n R2
4 0 H
n n CH3
S n n n--butyl
" 1 H
n ~ CH3
n n n-butyl
" 2 H
n n CH3
n 1l n-butyl-
3 0 H
n n CH3
" " n-butyl
" 1 H
n n CH3
n ~ n-butyl
" 2 H
" " CH3
2 0 n n n-butyl

1~4~
28
EXAMPLE XIV
Following the procedure of Example XIII, there
are prepared the following piperidine amides:
~,,
~ NC=O
wherein R2 = hydrogen, methyl~ or n-butyl.
EXAMPLE XV
Foll~wing the procedure of Example XIII, there
are prepared the following piperidine amides:
(C6HS)2C ~\
~`NC80
/ R2
10Position of Substituent R2
4 H
" CH3
" n-butyl
3 H
n CH3
n n-butyl
2 H
" CH3
n n-butyl

1~4~.8
29
EXAMPLE XVI
Following procedures describPd in the references
given above for compounds o~ Formula ~III), the following
are prepared: 1l IH
R2C-NR3
~2 R3
H -(CH2)llCH3
(CH2)7CH3
H -(CH2)l4CH3
H -(CH2~4CH-CHCH CH
Hcls-(cH2)5cH=cH(cH2)locH3
( 2)6C_CH
H 4-ClPh-
H 4-MeOPh-
H 4-MePh-
H -C~2C--CH
~ exo-2-norbornyl
H endo-2-norbornyl
Hl-decahydronaphthyl
H l-adamantyl
H2-bicyclo[2.2.2]octyl
Hanti-7-norbornenyl
Hendo-bicyclo[3.2.lloctyl
Hl-adamantylmethyl
Me H
Me -C2H5
Me -(CH2)5CH3
Me -(CH2)7CH3
Me -(CH2)l4CH3
Me-(CH2)4CH=CHCH2cH3
Meclg-(CH2)5CH=CH(CH2)loCH3
Me -CH~C-CH
Me (CH2)6C--CH
Me Ph
Me 4-ClPh-
Me 4-MeOPh-
Me 4-MePh-
Me PhCH2-
Me 4-ClPhCH2-
Me 4-MePhCH2-

M~ 335
~4(~
R2 R3
Me 4-MeOPhC~2-
Me 2CH2
Me exo-2-norbornyl
M~ endo-2-norbornyl
Me l-decahydronaphthyl
~e l-adamantyl
Me 2-bicyclo[2.2.2]octyl
Me anti-7-norbornenyl
Me endo-bicyclol3.2.1]octyl
Me 1-adamantylmethyl
n-Butyl H
l-nBU" )
Bu C2H5
Bu -CH2CH=CH2
Bu (CH2)7CH3
Bu (CH2)14CH3
Bu -(CH2)4CH=C~C2~5
Bu cis-(cH2)5C~=CH(cH2)locH3
Bu CH2C-CH
Bu ( 2)6C-H
Bu 4-ClPh
Bu 4-MeOPh
Bu 4-MePh
Bu Ph
Bu PhCH2
Bu 4-ClPhCH2-
Bu 4-MePhCH2-
~u 4-MeOPhCH2-
Bu PhCH2CH2
~u exo-2-norbornyl
Bu endo-2-norbornyl
Bu l-decahydronaphthyl
Bu l-adamantyl
Bu . 2-bicyclo[2.2.2]octyl
Bu anti-7-norbornenyl
Bu endo-bicyclo[3.2.1]octyl
Bu l-adamantylmethyl
H diphenylmethyl
Me diphenylmethyl
Bu diphenylmethyl
H 3,3-diphenyl-n-propyl
Me 3,3-diphenyl-n-propyl
Bu 3,3-diphenyl-n-propyl

~40~ 18
31
EXAMPLE XVII
Following the procedure of either Example I or
Example III, bu~ substituting for the ethyl formimidate
hydrochloride and diphenyl-4-piperidylmethane or N-formyl-
4-diphenylmetXylpiperidine and ethylamine, respectively,
used therein, equivalent amounts of the appropriate
starting materials such as described in Examples XII and
XVI, there are prepared the following, wherein the
following su~sti~uents are in the two (Rln), three (Rl'),
or four (Rl) positions:
Rl l Rl n
Rl ~<
A--\_~NC=NR3
R2
Posi--
tion of
S~x*itNent S~x~i-
~ ', or ~n) uent ~ R3 A
d~nylmethyl 2 H H H
dipheny~ yl 3 n ~ n
15 9-fluorenyl " n n n
c~--(4~1)berlz~1 n n n "
di~ f~Nymethyl 4 " " n
10,11-dihy~x~5~ ~zo "
[a,d]cycloh~en-5-yl
4--chlon~x~y1 n n
20 4~o~enyl
dipheny~E~l n n (~)11CH3
4~hlD~l n
a-(4-methylphenyl)benzyl " " " "
4-chlorokenzyl n n n
~--(4~hl~1)--tY-- l~ n
~ydm~1
a-(4-~ophenyl)ben2yl 3 " " "
9-fluorenyl ~ n
4-metbI~uy1 4 " -(CH2)7CH3
9-~luorenyl 3 " n
dipbenyl~y~s~ymethyl 2
a-(4~o~pY~y1)benzyl 3 " n

1~4V~
3Z
Posi--
~ o
n ) uent R2 R3 A
diph~nylhy~raxy~yl 4 H - (CH2) 7CH3 H
51~dikG~o[a,d3 n
~yc~hep~-5-yl
yl n
d~l (CH2) 14CH3
~1
cr ~4--chlon~pherlyl ) b~lzyl 3 " " n
9-flu~renyl 4 " " "
~ 14-methyl~henyl)benzy1 "
4~hloq:c~1 n n n n
~1 " l~ ,. "
di~henylmet~yl " -(CH2)4C~I2CH3
~E~l)benzyl n
d~l8~t~1 3
10~11~5~ y_ ~
5}~dil~lzo [a,d] cyt:ld~5-yl
9--fll~lyl n ~ n
di~ly~ret~lyl 4
ph~yl " " " "
~ ~l n ~ n
diphenyl~ thyl n ~ CLs--(CEI2) cE~(CH2)10CH3
c~~ (4~hla~?he~1)b~zyl 3
9-~9-flUDl~T1 4
--(4~hl~lyl) ~~ I- ~ n n
~1
4~et~:yl " " " "
2 5 berlzyl ll ll ll n
cr (4~1~ yl)be~1 n
dip~Iylmethyl n " (CH2) 6C{~
a- (4-chlor~pbenyl) benzyl " " " "
~1
3 0 9-fluar~nyl 3 " " "
a-(4-chlorop~enyl)benzyl " " " "
dip~ylTrethyl 2 .. " n

3 3
Posi--
~ o
S~nt S~
, R~ ', or Rln) uent ~2 .R3 A
}~1 4 H (C~z) 6C-CH . H
4--~leth~l n " n n
d~T~ E~l n n --CH2C ~{ H n
a--(4--leti~l)b~l n n
a--(4~tly1p~1) ~-- n ~ n n
~1
--(4~L)berlzyl 3 " n n
9--fll~l 4 n n n
[a,d] ~c1~5-y1
10 4~ethNyE~h~l n n n E~yl
4~hlo~c~1 n ~ n H
dipb~ n n exc~--2~1y1 n
a- (4~et~y1p~1) b~1 " " ~ n
a--(4~1)--a-- n n n n
~1
diF~lmet~l 3 n n n
9--flu~l ,. n
E~yl 4 " n n
4-chLor~ibenzyl n n ~ n
~-(4~hlar~yl)b~zy1 " " en~2-nor~ornyl "
diphe~ethyl " n n
di~enyl~ ~ethyl
a-(4-chlorop}~yl)benzyl 3
9--flu~l ~ .. n n
4~y~yl 4 " " "
b~zyl ~ .. "
di~enylIrethyl ~ nl--deca~ydr~phthyl n
a- (4~yl) b~zyl " n
~- (4-methylp~yl)--a- n
~b~l
dipheny~thyl 3 "
9--fluorenyl ~ .- n ~
p~enyl 4 " " "
4-chlor~l
~- (4-meth~yl)benzyl " " l~nantyl "

~14
34
Posi-
tian o~
Sl~bstituent Su~
(Rl, Rl', ar Rln) uent R2 R3 A
10 ,11--di3y~5-~dr~ 4 H1-ad~nan~yl H
5}}di~ ta,drc~yc~5-yl
~~ (4~hlo~l)_a_ n n ~ n
~1
a--(4~1)b0zy1 3 n n
9--flg~l n ~-
4--chl~l 4 n n F~l
n n n El
diph~et~l n n2-bic~yclo~2.2.2]oc~1
-(4-~retl~1)~enzy1 " " " "
d~ ~Crc~l " n n n
diphen~l 3 n n n
9--fluore~l 4 n n
E~l .. n n
4~etho~1 ~ n n n
15 dip} ~ ~rethS~l n a ~ -7-I
-~4-c~lk=~ enyl)benzyl " n n
~-(4 m~Lhylphenyl)-~- n n
~1
dipheny~mEthyl 3 n n -
9-fluorenyl " " " "
20 phenyl 4 n n
4-~hlorobenzy1 " " " "
diphenylmethyl " " enlo-bicy~10[3.2.1]octyl
o-(4-methylpheny1)benzy1 " " n n
diphenyIhydroxy=ethyl n n n ~
25 ~-(4-chlorcpbeny1)benzyl 3 " " "
9-fluorenyl n n
dipbenyIhydr=xymethyl 2 " " "
4-methcxypbenyl 4 " " "
b ~ zyl " n n
30 diphenylmethyl " "l-adamantylmethyl "
-(4-methcxyph~=yl)benzyl " " n n
a-(4-chlo ~ 1)_o_ n n
hydrax ~ l
a-(4-chlorc~henyl)benzyl 3

V~ ~ ~
Posi--
tion o
9-flu~l , 3 Hl-adamantyl~1 H
phe~l 4 n ~ . n
4--sw~l n ~ n n
diE~3~1m~1 laeth~l H n
--(4~1)~1 n n ~ n
a--(4--chl~Yl)~~ n n n n
~1
5--~51~di~1zo n n n n
[a,d] c:ycl~-5-yl
~ (4~yl)ber~ 1 3 ~ n
9--fluorer~1 n n n
diEhel~lmeff~l 2 n n ~
4--chlcl~l 4 n n 1
be~l n n 11 n
t~ (4--llethc~phe~l)be~l ~I n n n
a--(4~ylpt~nyl)--a-- n n ~ n
~1
dip~yl~ }~l 3 n 1~ n
9--h~r~9--flua~l 4 n n ~
4~th~y~yl " " " "
2 0 10 ,11 di~yd~5i}di~eDzo
[a,d] cycl~-5-yl
b~lzyl ~- n
(~(4~1phe~lyl)be~lzyl n --(CH2)7CH
dipher~llyd~ynet~yl n
a- (4~hlo~1)~1 3 n
2 5 9--fluor~l
p}~l 4 " " "
be2~zyl ~ n n
dipheny~nethyl " "(~ H2) 14CH3
a- (4~hl~phen~1)benzy1 " " "
3 0 a- (4~ret~y1) ~ " "
hydm~yl
dipherlyln~l 3 " " "
9-fluoren~l " " "

MN 335
Posi
ti~l of
o~ Rln)uent R2 R3
4~etlcyphenyl, 4 I~etl~l(CH2) 14CH~ H
4--chlorobenzyl " n n n
d:i~y~hyl " n--CH2CE~=CH2 n
a--(4--~l~ti~l)b~ln n n n
l n r n Eh
~1 n n ~ H
a-~4~1)bq!1 3 " " n
9--flu~re~yl n n Il n
4--chlor~henyl 4
bq~l " " " "
dipe~lllet~l n n~ (CH2 ) 4CE~H2CH3
a--(4~ethylphe~1)be~1 n n n n
a--(.4~bl~Y1)~-- n u n n
~1
di.E~ylIIethyl 3 n n n
9~fluorenyl
l 4 n n n
4-chlorobenzyl " ~ n n
diphenylmeth yl ~- n Cis--(CH2~5C~=CH( ~ )10 3
a-(4-methDxyphenyl~ken2yl" " " n
diphenYlhydroxymethyl " " " "
g-flu~renyl 3 n
a-~4-chl~opheny1)benzyl " " n
4--me~/l 4 ~ n
25 b~lzyl ll 1' ~I ll
a--(4-methylphenyl)benzyl n l~ n
a-(4-chlorcphenyl)-a_ " "
}~1
phenYlmethyl 3 " n ll
30 g-hydroxy-9-fluorenyl 4 " " "
~yl "
4-metho~ybenzy1
dipbenylmethyl n n~ (CH2) 6C---CH n
a-(4-chlorophenyl)benzyl " " n
diphenyIhy~roYymet~yl " " " "

l8
Posi-
tion of
S~b~t S~
(R~., Rl', or Rl") uent ~ R3 A
dip~y~e~l 3 nE~yl--(CH2)6C~CH H
9--f luorer~l n n n n
diFbe~lly~3~1e~1 2 " n n
4~hlc3~ 4 ~ n
diphe~l~E*}~l n n benzyl n
a-(4~p~1)benzy1 " " 4-chlc~e~1 "
diphe~Tlh~ 4~
diEihe~y~l 3 " 4~1b~1 "
10 ~ dih~5--~n n n n
5}}dib~zo [a,d3 c:yc1at~5-yl
9--fluor~Tl - n "
-(4~yp~1)~enzyl 4 " 4~ora}~nzyl "
4--chlor~benzyl " ' benzyl n
diph~ny~ yl " " ~2~ ornyl n
a--~4~eth~1pbenyl) b~zyl n 1- n n
~Iyl ~ n n p~ enyl
diphe~ynet~l n ~ n H
diph~nylmRthyl 3
2 0 Eiber~l 4 n n
9--fluorenyl 3 ~. n
~1 4 ~ n
10,~ ydr~5E~dib~zo
[a,d] c~clo~p~-~yl
dip~ny~rethyl ~ " ~2-n~ornyl "
a-(4 chlorc~henyl)benzyl " " " "
--(4~net~1ph~nyl)~- n n n
h~dra~l
diF~y~rethyl 3 " " "
9--fluorenyl n n n n
4~reth~p~enyl 4 " " n
3 o 4~or~zy1 " " " "
dip~yl~thyl " " l--decalyd~p~thyl n
- (4-~y~l)benzyl " " " "
dip~y~t~l " " "
-(4 chl~1)benzyl 3 " " "

~ 335
1~4~
38
Posi-
ti~ of
Substituent Sl~bSti-
(Rl, Rl', or RLn) uent R2 R3 A
4~hlQ~yl 4 n n n
4--net~yb~1 n n n n
5di~lmet~l n n1 a~~
~- (4~hlom~y1~benzy1 n ~ n n
--(4t~ n n ll n
h~drax~l
dip~ylIl~l 3 n n n
9--flu~r~yl " " n n
E~l 4 " " "
benzyl
diphe~et~l n n2--bi~yclo[2.2.2]oc~yl "
dip~Dydr~l " " n n
15--(4--chlor~enyllbenzyl 3 "
9-flu~r~nyl 4 " "
4--chloropher~1 n n n n
4~ff~ny1 n n n n
dipher~y~rethyl " anti--7--r~yl ..
a--(4-methylphenyl)benzyl " n n 1-
diph~yllllet}~l 2
a- (4-chl~yl)b~1 3
phe~l 4 " " n
9--fluorenyl 3
4--me~1 4 " n
diphenylIrethyl " "d~icyclo[3.2.1]oct~
p~yl " " " p~wlyl
a--(4~hlo~yl) benzyl n n n H
3 0 diE~nylhy~t~yl " n n
dipl~y~rethyl 3 "
9--flucxrenyl n n n
4--chlor~yl 4 " n
b~yl " " " "
3 5 diph~ny~lrethyl 1~ "l-a~nnanty~thyl "

~3
Posi-
~ o~
- (4~ylp~yl)benzyl 4 met~l l-adanantylnethyl H
c~--(4--chl~Yi) ~-- n n n n
h~l
diF~l 3 n n ~
9--~qUQ~l n n n n
4~t~ypl~yl 4 n n n
W~l n n
d:iph~ eth~ 1~1 H l~
--(4--ll~th~l)bel~l n n n n
dipbe~l 3 n n n
9--fluor~l n n n n
pb~yl 4 ll ~ n
4~yl ll n ll
diE~y~et~Lyl " -C2H5 n
he~ yl n n n ~yl
a- (4~1) b~zyl " " " . H
a--(4--chl~yl)--a~ n n n n
~1
di~yl~thyl 2 " n n
~--(4--chlor~?henyl)b~1 3 n n n
9-fluorenyl ~ - n
4~t~ypenyl 4 " " "
n ll ll n
diph~ylmethyl " " --(CH ) 7CH n
c~--(4--chlo~henyl)b~zyl " n 3
d:i.Fberly~:e~Tl ~ n n ~-
dipherlyl~ thyl 3
9--flut~ren~l
~yl 4 n n
3 0 b~zyl
d:ipheI~yl~thyl " ' - (CH2) 4CH
a-(4-srethylph~yl)benzyl " " 1 3
cc--( 4--chlo~ophenyl ) b~l 3
3 5 9-fluDrenyl " " " "
. _ . . . _ .

M~ 335
~ 14V~.~8
Posi--
tio l o~
Substitu~nt Substi-
(Rl Rl' or Rln) uent . R~ R3 A
10,11 dilyd~ 3 n~ut~rl (C~2)14CEI3 H
5~di~z= [a,d] ~c~eptcr~yi
4~e1~ ~1 4 ~ n n
4~cro~zyl n n n n
d~henylmethyl ~2CE~=CH2 n
a--(4~hlcrc~yl)b~zyl n n n n
di.p}~y~d~l~l n n n n
--(4--chl~1)b~1 3 n n n
9--flu~yl n n n n
4~c~ henyl 4 n n n
b~l n n n n
d:i.ph2n~1mPthyl ~ C~2) 4 2~5
5--h~d~5E~di~o n
[a,d] cy~:lc~5-yl
a--(4--srethylp~yl)b~nzyl n n n ~
a--(4~y1)~ n n n
~yd~l
dipheny~ yl 3 n n n
9--fluorenyl " n 1~ I~
E~enyl 4 " " "
4--chlo~1 .. .. n . n
diph~Iyl~ ncis--(CH2)5C~H(CH2)10CH3
a--(4~71phenyl)b~rl n l~ n l~
dip}~31ydr~1 " " " "
a- (4-chlo~p~enyl)b~zSr1 3 " n 1~
9--flu~renyl " n ~ n
2 5 phenyl 4 ~ .. ..
4--~y~l " n n n
diPh~Y~rethyl " l-CH2C~
a--(4--Irethylp}~yl)benzyl n n n
diPhe~llyd~ycet~yl " " " "
3 0 10 ~ dilyd~5H-dib~zo n n n
[a,d] :yclo~5-yl
dip~31rethyl 3 " n
9--fluarenyl " " n 1~
4-n~h~yp~:yl 4 " " "

~ll401 ,~l8
41
Posi-
~ o~
&b~tituerltSl~bsti-
(Rl RL~ 0~ Rln) t~t R2 R3 A
benz5~1 ~ 4 n~ CH2C-~ H
d~et~l n ~ CH2) 6C~
a- (4~10r~1)benzyl
S phe~l n n 1~ phe~l
~ (4~tb~1)-a-- n n n H
~yl
a--(4--chlor~1)benzy1 3 n n n
9--flu~rl n n n l~
~yl 4 n n n
4~ n ~
d~l n ~ ?l n
a- (4-met}~tlphe~l)b~ylzyl n ~l 4-chlor~1 ..
a- (4~1O~-yl) ~- " n4-sr~Yl~Zyl "
~dss:~yl
di l~yl~ 1 2 . n
d~ ret~l 3 " 4~h~ny1
9--flua~enyl n n 1~ n
yl 4 b~tl n
4~reth~1 " "4~thylbenzy1 "
diph~l " " phenethyl
--(4--Iletb~l)benzyl " " n
~1 3 ~ n
9--~dr~9--fluorenyl 4
~ yl ~- n n n
2 5 4-chlor~benzyl
dip~lyllllethyl n n ex~2~ yl
~~(4~ylE~he~1)be~1zyl
diFa~y~EI hyl n ~I n n
a- (4-chlor~r1)b~zyl 3 " "
3 o 9--fluore~l n n
4~ cyE~yl 4
b~lzyl ~ n
diF~exlyl~l~thyl n 1~eI~2--rx)~o~lyl
~- (4-chl~1)benzyl " " " "

~ M~ 335
~L4~
42
tion of
tR~., R~', o~ Rln) uent_ R2 R3 A
a- (4-met~ 4n-}~u~l erx~2-nor~ l H
dip~ln~yl 3 " "
9--fluor~yl n n n n
5 Ehe~l 4 n 1~ n
~h5~1 n ~ n n
dip~nethyl n n l~th~l n
a--u~l)b~Tl " n n 1~
~x--(4~ph~lyl ) ~-- n n n n
10 phenyl .. n 1~ phenyl
o~--(4~1~æhenyl) ben~l 3 n n H
9--fluorenyl n n n n
p~l 4 n n n
benzyl n n n n
15 dipeny~Ilet~l " " l-a~an~tyl n
a--(4~eth~phes~1)benzyl " n n n
di~iheny1lyd~et~ n
diE~y~et hyl 3 n
9--f lul~renyl n n l~
20 4-chlor~yl 4 " " "
4--chl~yl " ~I - n
dip~yl~et}~l ~I n2--biCyclo[2.2~2]octyl
--(4~hylp~enyl)ben~1 " n ll n
a- t4-chl~rcphen~l)-a- " " "
~1
25 a- (4-chl~r~yl)b~zyl 3 n ll ll
9-flu~enyl " " " "
phE~lyl 4 n n n
4~e~1 1~ n
dip~ly~I~etbyl ~ ~ ~-7-~ yl
30 a-(4~l~1p~1yl)benzyl n ll
dip~eny~ rethyl " " n
diEibenyl~rethyl 3 " " "
9-flu~enyl
ethyl 2 n

r~
1~4V~
Posi--
tiOIl of
Substil:uentSubsti-
(Rl, Rl', c~r Rl") uent R2 R3 A
4tret~=y~y1 4 ~utyl an~i-7~y1 EI
4~hl~yl n n n
diFb~;ylllethyl " endo~i~yclo[3.2.11a~
--(4-ilet~E~l)~eslzyl n n n n
a--~4--Irethylphe~71~---- n n n n
IydmY~l ,
a--(4--chlarc~l)~lzyl 3 n n n
9--flu~c)~l n
E~yl 4 " n n
4--*eth~1 n " n n
dipb~yllr~thyl " "l--ad~ntyllrethyl
~~ (4--~letb~l)b~lzyl n l~
dipheny3~yd ~ y ~ ~hyl " " " n
diphenylmethyl 3 " n "
15 9~fluorenyl n ll
phenyl 4 ~ n
bg~z~l n n n n
~-(1,4-biphenyl)benzyl " H H "
~-~1,4-biphenyl)benzyl n C~ ~(CH2)7CH3 "
20 -(1,4-biphenyl)benzyl "n-butyl phenethyl n
2,2-dipbeny1ethy1 " H H "
2,2-diphenylethyl n CH3 -(CH2)7CH3
2,2-dipheny1ethyl "_-butyl phenethyl "
4,4-diphenyl-n-butyl " H H "
4,4-dip~enyl-nrbutyl n CH3 -(CH2)~CH3 "
4,4-diphenyl-n-butyl "nrbutylphenethyl "
diphenylmethyl " Hdiphenylmethyl
phenyl 3 CH3 " "
9-fluorenyl 4n-butyl " n
30 4-chic~obenzy1 " H3,3-diphenyl-n-prcpyl "
diphenylmethyl 3 CH3 " "
diphenyIhyd mxymethyl 4 n-butyl

335
44
Posi-
tion of
Sub6tit~ent Substi-
~ ', or ~ ~) uent ~ ~ A
phenyl(octyl)methyl 4 H H H
10,11-dihydro-5H-dltenzo 2 " -( ~ ) ~ n
[a,d]eyclcheF~er-S-yl 3
5~-diben~o[a,d] n ~ n
eye1 ~ 5-yl
5 pbenylnhByl)methyl 4 n (~) 6 n
E~l (hexyl)~l n mB~yl~ (C82) 4CE~ OE H2CH3 n
10,11-dbhy~e-5H ~ o 2 " -(C ~) C~rH "
[a,d]eye1 ~ -5-yl 6
5E-dlte~zo[a,d] " " " n
eyelQheptEn-5-y1
lO,ll~yd~5E~di~zD n ~h~l ~2C3 n
[a~d]cyclohept2nr5-yl
10 5H-dikenzo[a,d] " " n
cyclQhept~n-5-yl
phe~yl(octyl)~ethyl 4 " F~ yl n

~ 5
~40~l.8
4s
Example XVIII
Following t~Q procedure of either Example I or
Example III, but substituting for the ethyl formimidate
hydrochloride and 4-diphenylmethylpiperidine or N-formyl-
5 4-diphenylmethylpiperidine and ethylamine, respectively,
used therein, e~uivalent amounts of the appropriate
starting materials suc~ as described in Examples XIII
and XVI, there are prepared the following:
(C~2)n ~
~ ~ NC-NR
Position of
10 Su~stituent n ~ R
_ 2 3
3 0 H H
3 0 H n-octyl
3 0 H _-dodecyl
4 0 H n-hexadecyl
4 CH3 n-octyl
4 0 n-butyl n-octyl
3 1 H H
3 1 H n-octyl
3 1 H n-dodecyl
4 1 H n-hexadecyl
4 1 CH3 n-octyl
4 1 n-butyl n-octyl
3 2 . H H
3 Z H n-octyl
3 2 H n-dodecyl
4 2 H n-hexadecyl
4 2 CH3 n-octyl
4 2 n-butyl n-octyl

~4~
46
EXAMPLE XIX
Following the procPdure of either Example I or
Example III, but suhstituting for the ethyl formimidate
hydrochloride and 4-diphenylmethylpiperidine or N-formyl-
4-diphenylmethylpiperidine and ethylamine, respectively,
used therein, equival~nt amounts of the appropriate
starting materials such as descri~ed in Examples XIV
and XVI, there are prepared the following:
\ /
. A~
~ NC--NR3
~O>
R2 R3
~ H
H n-octyl
H n-dodecyl
H n-hexadecyl
c~3 n-octyl
n-butyl n-octyl
H H
H n-octyl
H n-dodecyl
H n-hexadecyl
CH3 n-octyl
n-butyl n-octyl
H H
H n-octyl
~ n-dodecyl
H n-hexadecyl
CH3 n-octyl
n-butyl n-octyl

MN.335
1~4V1 18
47
EXAMPLE XX
Following ~he procedure of either Example I or
Example III, but substituting for the ethyl formimidate
hydrochloride and ~-diphenylmethylpiperidine or N-formyl-
4-diphenylmethylpiperidine and ethylamine, respectively,
used therein, e~uivalent amounts of the appropriate
starting materials suc~ as described in Examples XV and
XVI, there are prepared the following:
(C6H5) 2C~\
\ NC=NR3
/ R2
Position of
10 Substituent n R2 R3
2 0 H H
2 0 H _-octyl
3 0 H _-dodecyl
3 0 H n-hexadecyl
4 0 CH3 n-octyl
4 0 n-butyl n-octyl
2 1 H H
2 1 H _-octyl
3 1 H n-dodecyl
3 1 H n-hexadecyl
4 1 CH3 n-octyl
4 1 n-butyl n-octyl
2 2 H H
2 2 H n-octyl
3 2 H n-dodecyl
3 2 . H n-hexadecyl
4 2 c~3 n-octyl
4 2 n-butyl n-octyl

MN 335
114()
48
EXAMPLE XXI
N-[4-(Diphenylmethyl3-1-piperidinyl]
methYlene benzenebutanamine (E)-2-Butenedioate Hvdrate
,
A ~ixture of 4.40g (0.016 mole) of N-formyl-4-
(diphenylmethyl)piperidine and 1.47 ml (2.00g, 0.015 mole)
of dimethyl sulfate was heated in a steam bath for three
hours at 100C under anhydrous conditions until homo-
geneous. The mixture was cooled, dissolved in 30 ml
of methylene chloride and treated with 2.50 ml (2.36 g,
O.016 mole) of phenylbutylamine. The resulting solution
was stirred for three hours and treated with 6 ml 3 N
sodium hydroxide solution with vigorous stirring at 0.
The organic layer wa~ separated, dried over potassium
carbonate, filtered and evaporated ~o an oil. This
material was dissolved in isopropanol, treated with
1.84g of fumaric acid and cooled. There was filtered
off a white crystalline solid which was recrystallized
from ethanol to give N-14-(diphenylmethyl)-1-piperidinyl]-
methylene benzenebutanamine (E)-2-butenedioate hydrate
as a white crystalline solid, m.p. 207-208.5C.
EXAMPLE XXII
~-(Diphenylmethyl)-l- l-[me~hyl(octylimino)
methyl]-piperidine Monoperchlorate
.
A mixture of the fluoroborate salt of N-octyl-
acetimidic acid ethyl ester ~generated from 5.68g [Q~04
molel of boron trifluoride etherate, 2.77g [0.03 mole]
of epichlorohydrin, and 5,80g t~.~34 mole] of N-octyl
acetamide) and 5~ ml of ether was treated with 4 ml
~2.92g, 0.029 mole~ of triethyl amine~ Filtratio~ and
evaporation of the filtrate afforded a liquid residue
whic~ ~as dissolved in 120 ml dry toluene~ To this
solution was added 6.00g ~0.024 mole) of glacial acetic
acid and the resulting solution was stirred at 50C
over 4A molecular sieves under a nitrogen atmosphere
for four days. The reaction mixture was cooled and
neutralized by ~haking with 3 N sodium hydroxide solu-
tion. The organic layer was separated, dried over X2C03,
filtered and stripped to an oil which was distilled.
5--

M~ 33s
l~LV~
4g
The pot residue was dissolved in ether and perchloric
acid and methanol added. Cooling the solution pro-
duced a solid fraction. Filtration afforded a crystal-
line solid whi.ch was recrystallized three times from
S methanol to give 4-(Diphenylmethyl)-l- l-[methyl(octylimino)-
methy]~piperidine Monoperchlorate as a white crystalline
solid, m.p. 119-121.5C.
EXAMPLE XXIII
a-(4-Methylphenyl ? -a-Phenvl-4-~yridine Methanol
A solution of 0.05 le of 4-methylphenyl
magnesium bromide in 500 ml of anhydrous ether was
treated with 4-benzoylpyridine in S00 ml anhydrous ether.
After stirring the n~lting m~re for 1.5 hc~rs at 25, an ~æ~s
soluticn of a~L~ium ~ik~ide was ~ causing a solid to form
which waQ filtered. Recrystallization of thi~ material
~rom 95% ethanol afforded the desired ~-(4-methylphenyl)-
a-phenyl-4-pyridine methanol, ~.p. 192-135C. The
corresponding 4-chlorophenyl (~.p. 198-202C) and 4-
methoxyphenyl (~pO 204-206C) derivatives were also
prepared by the same method, using equivalent amounts
of the appropriate starting materials.
EXAMPLE XXIV
x-(4-Methylphenyl)-a-Phenyl-4-Piperidine
A solution of 25~0g (0.09 mole) a-(4-methyl-
phenyl~-a-phenyl-4-pyridine methanol, 55 ml of 47-Sl~
hydriodic acid and 180 ml of acetic acid was refluxed
overnight, cooled, and poured into aqueous sodium
bisulfite. This solution was made basic with sodium
hydroxide and extracted with methylene chloride. From
the organic layer there was isolated an oil which was
reduced at 40 psi over platinum oxide at 60-65C in
acetic acid following the method of United States Patent
No. 3,267,108. The excess acid was removed and the
residue made ba~ic to give a-(4-methylphenyl)-a-phenyl-
4-piperidine which was characterized as its fumarate
salt, m.p. 157.5-161.5C (Hoover). The corresponding
4-chlorophenyl (m.p. 175-178C; fumarate salt) and
~,

~14
sn
4-methoxyphenyl (m.p. 94-98C; free base3 derivatives
were also prepared by the same method, using equivalent
amounts of the appropriate star~ing materials.
. EXAMPLE XXV
s -(1,4'-Biphenyl)~l--phenyl-4-pyridinemethanol
A solution of 111.0g (0.50 ~ole) of 4-biphenyl
bromide in 200 ml of dry ~etrahydrofuran ~THF) was added
slowly to a mixture of 12.10g (0.5 gram-atom) of mag-
nesium, 2 ml o~ ethylenedibromide and 200 ml of T~F at
such a rate as to maintain reflux. After addition the
mixture was refluxed for 0.5 hours, cooled and treated
over 0.5 hours with a solution of 82.3g (0.45 mole) of
4-benzoylpyridine in 600 ml THF. The resulting slurry
was stirred 0.5 hours at 25C and treated with 1000 ml
20% ammonium chloride solution. The organic layer was
separated, filtered, the filtrate dried, filtered and
stripped. The residue was triturated with ether and
filtered. This solid was recrystallized ~rom ethanol,
chloroform, and finally toluene to give a-(1,4'-biphenyl)-
yl-a-phenyl-4-pyridin methanol as a white solid, m.p.
after drying in vacuo at 70C; 173.5-175.5C.
EXAMPLE XXVI
_
a-(1~4'-Biphenyl)yl-a-phenyl-4-~iperidinemethanol
A solution of 10.00g (0.030 mole) of a-(1,4'-
biphenyl)yl-a-phenyl-4-pyridine and 160 ml of acetic
acid was hydrogenated in the presence of platinum oxide
(1.Og) at 25-35 psi at 70-90 on a Paar shaker. After
hydrogen uptake ceased, the mixture was filtered through
dicalite and evaporated to a solid residue. This residue
was slurried in water, made basic with 3 N NaOH and ex-
tracted with chloroform. The chloroform layer was dried
over potassium carbonate, filtered through dicalite and
evaporated. The residue was dissolved in toluene and
cooled. The resulting solid was filtered and recrystal-
lized from toluene to give a-~1,4'-biphenyl)yl-a-phenyl-
4-piperidinemethanol as a white solid; m.p. 185-186.5C.

MN 335
481.1)3
51
EXAMPLE XXVII
9-(4'-~ eridinYll-9-fluorenol
A sslution of 13.0g (0.05 mole) of 9-(4'-
pyridyl)-9-flu~renol in 200 ml of glacial acetic acid
was hydrogenated over 0.8g of platinum oxide at 40 psi.
The mixture was filtered, stripped, and the residue
made bas~c affording 9-(4'-piperidinyl)-9-fluorenol.
EXAMPLE XXVIII
4-Fluorenylidenepiperidine
A suspen~ion of 13.0g (0.05 mole) of 9-(4'-
piperidinyl)-9-fluorenol in 70 ml of 48% sulfuric acid
was heated on a steam bath for ~even hours and poured on
to ice. The resulting solid was filtered, made basic
with sodium hydroxide solution and extracted with methylene
chloride. The organic layer was qeparated, dried over
potassium carbonate, filtered and stripped to give 4-
fluorenylidenepiperidine.
EXAMPLE XXIX
9-(4'-Pyridyl)fluorene
A solution of 1.35g (0.005 mole1 of ~,a diphenyl-
4-pyridine methanol in 18.5 ml of 97% formic acid was
treated dropwise with 8 ml of concentrated sulfuric acid.
The r~action was refluxed ten minutes, cooled and made
basic with 6 N sodium hydroxide solution causing a solid
to separate. This material was filtered and recrystallized
from me~hanol to give 9-(4'-pyridyl)fluorene, m.p. 141-
143C (Hoover).
EXAMPLE_XXX
9-(4'-PiPeridYl)fluorene fumarate
A solution of 54.75g (0.225 mole) of 9-(4'-
pyridyl)fluorene in 600 ml of acetic acid was hydro-
genated over S.Og of platinum oxide at 40 psi and 25C.
The mixture was filtered, stripped and made basic, afford-
ing 9-(4'-piperidyl)fluorene, which was crystallized as
the fumarate salt, m.p. 228-230C (dec).