(4,5-DIHYDRO-5-OXO-1H-TETRAZOL-1-YL)ETHYL-4-[(1-OXO- PROPYL)PHENYLAMINO]-4-PIPERIDINE CARBOXYLATE COMPOUNDS

TRADUCTION NON-DISPONIBLE

English Abstract

JAB - 239
N-PHENYL-N-(4-PIPERIDINYL)AMIDES.
ABSTRACT OF THE DISCLOSURE:
Novel compounds of the series of N-phenyl-N-(4-pipe-
ridinyl)amindes having a (4,5-dihydro-4R-5-oxo-1H-tetrazol-1-
yl)alkyl or (4,5-dihydro-4-R-5-thioxo-1H-tetrazol-1-yl)alkyl
substituent group in the 1-position of the piperidine nucleus, said
compounds being useful as analgesic agents.

Claims

The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:
1. A process for preparing a chemical compound
selected from the group consisting of a N-phenyl-N-(4-piperidinyl)-
amide derivative having the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
wherein:
R is a member selected from the group consisting of hydrogen,
lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl,
(lower alkyl)oxy(lower alkyl), aryl and aryl(lower alkyl);
R1 is a member selected from the group consisting of hydrogen,
lower alkyl and aryl;
R2 is a member selected from the group consisting of hydrogen and
lower alkyl;
R3 is a member selected from the group consisting of lower alkyl-
oxy-carbonyl, lower alkyloxymethyl and lower alkylcar-
bonyl;
R4 is a member selected from the group consisting of lower alkyl,
cycloalkyl, lower alkenyl, lower alkyloxy and arylmethyl;
R5 is a member selected from the group consisting of hydrogen and
lower alkyl;
34

R6 is a member selected from the group consisting of hydrogen,
halo, lower alkyl, lower alkyloxy and trifluoromethyl;
Z is a member selected from the group consisting of O and S;
and
n is the integer 0 or 1;
wherein said aryl as used in the foregoing definitions is
selected from the group consisting of phenyl, substi-
tuted phenyl, thienyl and pyridinyl, said substituted
phenyl having from 1 to 2 substituents independently
selected from the group consisting of halo, lower
alkyl, lower alkyloxy, and trifluoromethyl, character-
ized by
a) reacting a compound having the formula
<IMG> (II)
with a N-phenyl-N-(4-piperidinyl)amide of the formula
<IMG> (III)
wherein R, R3, R4, R5 and R6 are as above-defined and either
X1 is hydrogen and X is a radical of the formula
<IMG> (IV)

or X is hydrogen and X1 is a radical of the formula
<IMG> (V)
and wherein Y is a reactive ester residue, said reaction being
conducted, at elevated temperatures, in a reaction inert organic
solvent in the presence of a base; or
b) N-acylating a compound having the formula
<IMG> (VI)
to prepare a compound having the formula
<IMG> (I-a)
or c) preparing compounds having the formula (I) wherein Z is
S, by reacting the corresponding compound of formula (I) where-
in z is 0 with a sulfurating agent while stirring and heating
the reactants together in a reaction-inert organic solvent
or d) debenzylating compounds of the formula I wherein R
represents phenylmethyl to prepare compounds wherein R repre-
sents hydrogen and, if desired, preparing pharmaceutically ac-
ceptable acid addition salts of the products of steps a) to d),
or also, if desired resolving racemic mixtures into their stereo-
chemically pure isomeric forms by known resolution techniques.
2. A process for preparing a chemical compound
selected from the group consisting of N-{1-[2-(4-ethyl-
4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl]-4-(methoxymethyl)-4-
piperidinyl}-N-phenylpropanamide and the pharmaceutically ac-
ceptable acid addition salts thereof, characterized by reacting
36

1-(2-chloroethyl)-4-ethyl-1,4-dihydro-5H-tetrazol-5-one, with
N-[4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide, and,
if desired, preparing pharmaceutically acceptable acid addition
salts of the product thereof.
3. A process for preparing a chemical compound
selected from the group consisting of methyl 1-[2-(4,5-dihydro-
4-methyl-5-oxo-1H-tetrazol-1-yl)ethyl]-4[(1-oxopropyl)phenyl-
amino]-4-piperidinecarboxylate and the pharmaceutically accept-
able acid addition salts thereof, characterized by reacting 1-
(2-chloroethyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one with
methyl 4-[N-(1-oxopropyl)-N-phenylamino]-4-piperidinecarboxylate
hydrochloride, and, if desired, preparing pharmaceutically ac-
ceptable acid addition salts of the product thereof.
4. A process for preparing a chemical compound
selected from the group consisting of methyl 1-[2-(4-ethyl-
4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl]-4-[(1-oxopropyl)-
phenylamino]-4-piperidinecarboxylate and the pharmaceutically
acceptable acid addition salts thereof, characterized by react-
ing 1-(2-chloroethyl)-4-ethyl-1,4-dihydro-5H-tetrazol-5-one
with methyl 4-[N-(1-oxopropyl)-N-phenylamino] 4-piperidinecarboxy-
late hydrochloride, and if desired, preparing pharmaceutically
acceptable acid addition salts of the product thereof.
5. A process for preparing a chemical compound
selected from the group consisting of methyl 1-[2-(4,5-dihydro-
5-oxo-4-propyl-1H-tetrazol-1-yl)ethyl]-4-[(1-oxopropyl)phenylamino]-
4-piperidinecarboxylate and the pharmaceutically acceptable
acid addition salts thereof, characterized by reacting 1-(2-
chloroethyl)-4-propyl-1,4 dihydro-5H-tetrazol-5-one with methyl
4-(N-(1-oxopropyl)-N-phenylamino]-4-piperidinecarboxylate hydro-
chloride.
37

6. A process for preparing a chemical compound
selected from the group consisting of N-{1-[2-(4,5-dihydro-4-
methyl-5-oxo-1H-tetrazol-1-yl)ethyl]-4-(methoxymethyl)-4-
piperidinyl}-N-phenylpropanamide and the pharmaceutically accept-
able acid addition salts thereof, characterized by reacting
1,4-dihydro-1-(2-iodoethyl)-4-methyl-5H-tetrazol-5-one with N-
[4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide and, if
38

desired, preparing pharmaceutically acceptable acid addition
salts of the products thereof.
7. A process for preparing a chemical compound
selected from the group consisting of N-{1-[2-(4-ethyl-4,5-
dihydro-5-oxo-1H-tetrazol-1-yl)-1-methylethyl]-4-(methoxymethyl)
4-piperidinyl}-N-phenylpropanamide and the pharmaceutically
acceptable acid addition salts thereof, characterized by
reacting 1-ethyl-1,4-dihydro-5H-tetrazol-5-one with N-[1-(2-
chloropropyl)-4-(methoxymethyl)-4-piperidinyl]-N-phenylpropan-
amide, and, if desired, preparing pharmaceutically acceptable
acid addition salts of the product thereof.
8. A chemical compound selected from the group
consisting of a N-phenyl-N-(4-piperidinyl)amide derivative having
the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
wherein:
R is a member selected from the group consisting of hydrogen,
lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl,
(lower alkyl)oxy(lower alkyl), aryl and aryl(lower
alkyl);
R1 is a member selected from the group consisting of hydrogen,
lower alkyl and aryl;
R2 is a member selected from the group consisting of hydrogen
and lower alkyl;
39

R3 is a member selected from the group consisting of lower alkyloxy-
carbonyl, lower alkyloxymethyl and lower alkylcarbonyl;
R4 is a member selected from the group consisting of lower alkyl,
cycloalkyl, lower alkenyl, lower alkyloxy and aryl-
methyl;
R5 is a member selected from the group consisting of hydrogen and
lower alkyl;
R6 is a member selected from the group consisting of hydrogen, halo,
lower alkyl, lower alkyloxy and trifluoromethyl;
Z is a member selected from the group consisting of O and S;
and
n is the integer 0 or 1;
wherein said aryl as used in the foregoing definitions is selected
from the group consisting of phenyl, substituted
phenyl, thienyl and pyridinyl, said substituted
phenyl having from 1 to 2 substituents independently
selected from the group consisting of halo, lower
alkyl, lower alkyloxy, and trifluoromethyl, whenever
prepared or produced by the process of claim 1 or by any chemical
equivalent thereof.
9. A chemical compound selected from the group con-
sisting of N-{1-[2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)-
ethyl]-4-(methoxymethyl)-4-piperidinyl}-N-phenylpropanamide and
the pharmaceutically acceptable acid addition salts thereof, when-
ever prepared or produced by the process of claim 2 or by any
chemical equivalent thereof.

10. A chemical compound selected from the group
consisting of methyl 1-[2-(4,5-dihydro-4-methyl-5-oxo-1H-tetrazol-
1-yl)ethyl]-4-[(1-oxopropyl)phenylamino]-4-piperidinecarboxylate
and the pharmaceutically acceptable acid addition salts thereof,
whenever prepared or produced by the process of claim 3 or by any
chemical equivalent thereof.
11. A chemical compound selected from the group
consisting of methyl 1-[2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-
yl)ethyl]-4-[(1-oxopropyl)phenylamino]-4-piperidinecarboxylate and
the pharmaceutically acceptable acid addition salts thereof, whenever
prepared or produced by the process of claim 4 or by any chemical
equivalent thereof.
12. A chemical compound selected from the group con-
sisting of methyl 1-[2-(4,5-dihydro-5-oxo-4-propyl-1H-tetrazol-1-yl)-
ethyl]-4-[(1-oxopropyl)phenylamino]-4-piperidinecarboxylate and the
pharmaceutically acceptable acid addition salts thereof, whenever
prepared or produced by the process of claim 5 or by any chemical
equivalent thereof.
41

13. A chemical compound selected from the group con-
sisting of N-{1-[2-(4,5-dihydro-4-methyl-5-oxo-1H-tera-
zol-1-yl)ethyl]-4-(methoxymethyl)-4-piperidinyl}-N-
phenylpropanamide and the pharmaceutically acceptable
acid addition salts thereof, whenever prepared or produced
by the process of claim 6 or by any chemical equivalent thereof.
14. A chemical compound selected from the group con-
sisting of N-{1-[2-(4-ethyl-4,5-dihydro-5-oxo-1H-terazol-
1-yl)-1-methylethyl]-4-(methoxymethyl)-4-piperidinyl}-N-
phenylpropanamide and the pharmaceutically acceptable
acid addition salts thereof, whenever prepared or produced
by the process of claim 7 or by any chemical equivalent thereof.
42

Description

I0
BACXGROl:~D OF T~E I~tENTION:.
~'tJ.S.~at. No. 3,99~,834 there a~e de4cr~ed a rlu~ber
of N~ yl-N-(4-piperi~yl)a~ide~ g analge~ic propertIes.
T~e- compou~d-~ of t}~ rer~tio~ di~er frorQ the forego~g e~sentially
15 by ~he ~ e o~ the (4, ~-d;hydro-4-R-5-o~o~ tetsazol-l-yl)alk~l
or (4,5-di}syd~o-4-R-5~ oxo-lH tetrazol-l-yl)aLkyl group prese~t
n th~ ositio~ of ths pipersdsn~ ~ucleu~.
~3' ' ' '' ~
:~ .
r~..t.~

D~:SCRIPTION OF THl~:.PREFERRED EMBODIMENTS:
Thi~ inventio~ is coIlcerned with novel N-phenyl~N-(4-piperi-
di~yl)amides which rnay be represented by the structural formula:
R5
Z 1 R3
R -N--I~N- CH-(C~2 ) _ CH-O(N_C _R 4 ( 1 )
and the pharmaceutically accept~ble acid additio~ salts thereof, wherei~:
R is a member selected from the group consisti~g of hydrogen, lower
alk~rl, cycloalkyl, lower al~cenyl, lower alkynyl, (lower alkyl)-
oxy(lower a~}cyl), aryl and aryl(lower z~yl);
R i9 a member ~elected frorrL the group consisti~g of hydroge~, lower
alkyl and aryl;
RZ is a member selected ~om the group cor~sisting of hydrogen and
lo~er alkyl;
R i9 a member 5elected from the group consi~ting o lower a~ylo:xy
carbonyl, lower alkyloxymethyl and lower aLlcylcarbonyl;
R iq a member qelected f~rom the group cor~isti~Lg of lower alkyl,
cycIoalkyl, lower alXe~yl, lower a~Xyloxy a~d arylmethyl;
R is a me~nber 9elected from t~e group con3i~ti~g of hydroge~ and
lower alkyl;
R i8 a mernber selected from the group cor~isting of hydrogen, halo,
low~ alkyl, lower alkyloxy ~d trifluoro~nethyl;

Z is a member selected from the group consisting of O and S; a~d
n i9 the integer O or I;
wherein said aryl as used in the foregoing defi~itio~s i9 selected
from the group consisting of phenyl, substituted phenyl, thie~yl a~d
pyridi~yl, said substituted phenyl having from 1 to 2 substituents
i~dependently selected from the group conssting of halo, lower
alkyl, lower alkyloxy and tri1uoromethyl.
The term "lower aLkyl" a~ used herèin i9 meant to include
straight and branch chairLed alkyl radicals having from 1 to 6 carbo~l
Iû atoms, such as, or example, ~nethyl, ethyl, I-methylethyl, 1,1- -
dimethylethyl, propyl, butyl, pentyl, hexyl and the like; the term
"cycloaLtcyl " refers to cycloalkyl radicals havi~g from 3 to 6 carborL
atoms, e. g., cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;
~ower al~e~yl"refers to alkenyl radicals having from 3 to 6 carbon
lS atoms such as, for example, 2-propenyl, 2-buteD.yl, 3-perLtenyl, 2-
hex~nyl and the like; and lower alkynyl refers to alXyrLyl radicals
having from 3 to 6 c~rboll atoms such as, or example, 2-propynyl,
2-butynyl and the lilce.

5gt69L
The compourLds of formula (I) wherein Z is 0, (I-a), can
generally be prepared by the reaction of a 4~ 5 dihydro~ tetrazol-
5~one derivative of the formula
R--N~--X ( I I )
N=N
with a N-phenyl-N-(4-piperidinyl )amide of the for-
mula
R5.
X1 N~(R3 1l_R4 ( III )
wherein R, ~ R4~ R5 a;~ld R6 re a~ above-defIned and either X
is hydrogen and X is a r~dical o~ the ~ormula
.
c1 (C~2)n-CH-y (I~
or X is hydrogen a~d X1 is a radical of the ~o:rmula .
Y-CH-(C~2)n-CH (V)
. - ' ~.
,

~ 5~
' In th~ above formulae(IV) and (V) R1,R~ and n have the
prè~iously indicated meaning and Y is a reactive ester
residue, such as, ~or example, h~lo, more particularly
chloro, bromo or iodo, or a sulfonyloxy group, such as,
~or example, methylsulfonyloxy or 4-methylphenyls~ oYyl-
oxy.
The reaction o (II) with (III) may be carried out fol-
lo~ing standard N-alXylating-procedures as sener~lly
known in the art. Said reaction is ad~antage~usly con-
ducted in an appropriate, reaction-inert organic solvent,
such as, ~or example, a~ arom~tic hydrocarbon, e.~.,
benzene, methylbenzene, dimethylbenzene and the li~e;
a low~r alkanol`, e.g., methanol, ethanol, 2-propanol,
1-butanol and the like; ~ ketone, e~g., 4-methyl-2-
p~ntanone and the like; an ether, e.g., 1,4-dioxane, 1,~
oxybisethane and the like; N,N-dimethyl~ormamide; nitro-
benzenè; and the like.
The addition to the xeaction mixture o& an appropriate
ba5e, such~as, for example, an alkali metal carbona~e or
2Q hydrogen carbonate, or an organic base, such as, for
examp~e, N,~-diethyletha~amine or N~ me~hyle~hyl)-2-
propanamine may be utilized ~o pic}c up the acid that is
liberated during the course o ~he reaction. In some cases
the addition o~ an iodide salt, preferably an al~ali metal
~5 iodide, is appropriate. Somewhat elevated temper~tures
are ad~antageously employed ~o enhance the reaction ra~e.
In some circums~anees, especiall~ ~hen one o.& the sub-
stituPnts R1 and R2 is methyl and the other is hydrogen,
a partial re~r:ra~gement may occur during the reactioIl
. 3Q ~ielding a mixture of p~sition isomers wherein respec-
tively Rl is methyl and R2 is hydrogen and i~versely R1
is hydrogen and R2 is meth~l. Such position isomexs an
easily be separated from each other by known isolation
techr.ique~ such as, for example, selective`cxystallisation
- 35 rom an appropriate solve~t system or col~n-chroma~o-
g~aphy.

5~
.
The compounds of formula (I-a) ca:~l also be prepared by acylating
an appropriate 4-piperidinamine o~ the formula
~5
R-N~ fH-(CHZ)n f
R R ~R6
(VI )
Said acylation reaction i9 con~renieIltly carried out according to k~own
N-acylat~on procedures, for example, by reactirLg (VI) with an appropriate
acyl halide, R4-~:O-halo, representing respecti~ely a lower allcylcarborlyl
halide, a cycIoalkylcarbonyl halide, a~ arylacetyl halide or a lower
alkyl carbonohalidate, following }~ethodologies k~ow~ in the art.
W~en R4represents lower alkyl or cycloalkyl the acylation m~y al~o be
carried out with an a2~hydride deri~red from the acid R4CoC)H.
.
I0The compounds of formula (I) wherein Z i9 S, (I-b), can generally
be deri~red from the corre~ponding (I-a) by react~g the latter with an
appropriate ~uLfurating age~t s~ch aq, for examplet P2S5. The reactio~
may be co~veniently carried out by stirring a~ heati~g the reacta:~lt~
together in an appropria.te reactio~ ert organic sol~rer~t such aa, for
lSexample, an aromatic hydrocarbon such as, ber~zene, methylbenzene, di~
methylbenzene and the li~ce.
.
The compou~ds of forr~ula (I~ whe~ein R repre~ent~ hydrogerl are
preferably deri~ed fro~:L the corresponding (I) whereiD R repre~ants
p~enylmethyl by debe~zylati~g the latter i~ t:he usual man~er, e. g.,
20 by catalytic hydrogenatioIl u~i~g an appropriate cataLy9t suoh a~
paIladius~-o~- char coal .
~6

In the foregoing and subse~uent preparations, ~he
reaction products are isolated ~rom the reaction mixture,
and, if nece5szry, urther puriied by ~h~ applicatiorL of
common isolation and purification procedures as ge}lerally
known in the art~
A number o~ the compounds within the scope of ~ormula
(I) ha~e one or more asymmetric carbon a~oms within their -
structure and co~sequently exist under di~erent stereo-
chemically isomeric ~orms. More partieularly ~hen ~1 or
R are other than ~ydrogen, ~he carbon atoms ~o which they
are at~ached zr~ asymmetric, while additional asymmetric
carbon atoms may be present in the lower alkyl ~roups
comprised in R, R~ and R4.
While in the above preparations ~he~e are obtained essen~
lS tially mixtures, including racemic mixtures, o~ such
stereochemlcal isomers, such mixtu*es can generally be
resolYed into their stereochemically pure isomeric ~orms
by the applic~tion o~ known resolution techniques, e.g.,
by salt ~orma~ion with optical isomers of asymmetric acids
and select~Ye crystallisation of the salts thus ob~ained.
The stereochemically isomeric forms o~ ~om~ounds o~ ~or-
mula (I) are included within the scope o~ formula (I).
As a result of their basic proper~ies, the compounds
o~ ~ormula (I) C~l be converted to the~r therapeutically
active, non-toxic acid addition sal~ ~orm by trea~ment
wi~h an apprapriate acid, such as, ~or example, an i~
orga~ic acid, such as hydrohalic acid, e.g., hydrochloric,
hydrobromic, and the li~e 9 a~d sul~uric acid, nitrlc acldf
. phosphori~ acid and the like, or an organic acid, such as,
.30 ~or example, acetic, propanoic, hydroxyacetic, 2~hydro~y~
propanoic, 2-oxopropanoic, propa~edioic, butanedioic,
~Z)-2-butenedioic, (E)~2-butenedioic, 2-hydro~ybutanedioic,
2~3-~ihydroxybutanedioic, 2-hydroxy~1,2 9 3 prop~netr~
carboxylic, benzoic, 3 phenyl~2 propenoic, ~ ydroxybenzene~
~5 acetic, methanesulfonic, ethanesul~onic, be~zenesulfonic~

~ 5 ~ ~
4-me~h~lbenzenesulEonic, cyclo~exznesul~mic, o,-h~droi~-
ben~oic, 4-amino-2-hydroxybenzoic and the like acids.
Conversely, tlle salt ~orm can be converted b~ treatment
with alkali into the free base fo~m.
The starting materials of formula (II) wherein X i5
hydrogen, (II-a), can easily be prepared by the reac~ion
o~ a~ appropriate isocyanate o~ the ~ormula (V~) or an
acylc'nloride of the ~ormula (VII) with sodium azide in t~e
presence o aluminium chloride in an appropriate organic
solvent, preferably an ether such as tetrah~Jdrofuran
(THF),
~-N=C-O
(VI~
or Na~3/ A1Cl3 R-N
~f~ T~. Na~
R~
a3
(VII~
~ The reaction is co~venien~ly carried out by s~irring
and heating the reactznts together in the solvent ~or
; several hours~ When an acyl chloride o~ crmula ~VII.) is S
used as a reactant at least 2 molar equivalents of the
- azide ha~e to be employed and the use of an addi~ional t
e~cess thereo~ is generally ~ound appropriate.
`
Starting ma~erials o ~ormula (II) ~herein X is a t
~ radical o~ the rormula (I~) t (II-b)j can be ob~ained
by in~roducing said radical into the corresponding (II~a)
by ~nown me~hods. -
t
... ~
.
'

. ~ -
In general, said st~rting ma~erials (II-b) can be
prepared by carryi~g out the steps o~:
i) reac~ins the ~ppropriate ( II-a) with ~ haloalkanol
derivative o~ the formula
halo-f H- ( CH2 ) n-CH-OH
R R
(VIII )
~ollowing generally Xnown ~-alk~la~ins procedu~es
as pre~iously described '~ er~in, to obtai~ an i2lter-
mediate o~ the ~ormula
~, ~I CH-(CH2)n-~H-OH
~N ~ 2
. .
~ IX)
and;
,
ii) subse~uently cor~ ing the hydrox3r group of the
thus obtained (IX) iXltO a reactive ester group ~ollo-
~ing~ art~no~rn procedures of preparing reactive esters
starting ~rom the correspondillg alcohols.
.
reacti~e ester ~ll~
(IX) ~ R-N N--C~ (CH2)~cH~Y
~ormation ~ 2
~ .
.
~9

:~;
5gL6~
.
Halides are conveniently obtained by t~e rezction o~
(IX) ~ith an appropriate halogenating agent, such as,
for e~ample, sul~inyl chloride, sulfuryl chloride, p~os-
phor pentachlorid2~ phosphor pentabromide, phosporyl
chloride and the like. When the reactive ester i5 aY
iodide, it is preferably derived from the correspon-
ding chloride or bromide by the replaceme~t o~ that
halogen with iodine. Reactive sulfonate esters such as
methanesul~onates and 4-methylbenze~esul~onate~ are
con~en~ently prepared by reactirg the alcohol with an
appropriate sul~onyl halide such as, ~or example, methane-
sulfonyl chloride and 4-methylben~enesul~or.yl chloride
respectively.
~en Y in (II-b) is chloro, (II-b-1), the in~ro-
tS duc~ion of the chloroal~yl chain can also be per~ormed
by the reaction o~ an appropriate (II-a) ~ith an
- appropriate bromo-chloroal~ane derivative o~ the formula
(X) ~ollowing s~andard N-alkylating procedures to obtain
the corresponding (II-b~
.
(II-a) I Br-fH (CH2)n-~X-C~
R1 ~2
;. (~)
(CH2~n-1H`Gl
~ b-1)

s~
` Al~ernativel~, the st~ting matericls (II-b~ ere-
in R is o~her than hydrogenorphenylcan be obtainedbyintroducing
the R-substituellt into a precursor of tl1e ~ormula
o
`N-CH-(CH2)~-CH-Cl
N- N R1 . p2
(XI)
Said introduction of R is con~eniently carried out by
the reaction of ~XI) with an appropriate re~ctive es~er
~Y wherein Ri~ a9 previouslyde~i~edbutother than hydrogen or
phe~yl, follo~ting standard N alX~lating procedures as
descri~ed 'nereina~ove. It is to be noted that w~en said
Y in said RY is iodo, the chloro substituent of (XI) may
be replaced during the reaction by iodo, especiall~ ~hen
an excess o the alkylating iodide is employed.
The precursor compounds o formula (XI) may b~ prepared
following ~he procedures described in Tetrahe~ron, 31,
765 (19~5) wherein t~e compound o ormula (XI~ wherPin
. 15 ~l and R2 are both hydrosen and n is 1 is speci~ically
described.
The starting materials o formula ~III) ~therein X1
is hydrogen, (III-a), can be prepared according to t~e
- procedures outlined in U.SOPat. No~ 3,9g8,83~ wherein a
number o~ such startIng materials and theIr preparation
are ~escribed. . ¦,
. il
The starting materials of ~ormula (III) wherein X1 1
is a radical of the ormu1a (V), (III b), can be prepared 1.
- by-N-alkylating a piperidine derivative o the ~ormula
(III-a) with a haloalka~ol of t~e ~or~ula (XII) in the
usual manner to obtain an intermediate of che ~ormula
.

:
5~L~4
,
(XIII) and therea~ter converting the hydroxy group o~
the la~ter into a reactive es.er group as previously
described.
(CH2)n IH halo + ~)(N-e-R4 >
(XII) ~R6
( III~a )
... . ~1-~R3
HO I H- ~ CX2 ) n~CEI~N~,~N~ R4
. ~R 6
(XIII )
.
reactive ester formation
1 2 N-l~-R
R
(III--b)
' ~
Inte~mediates of formula (XIII) herein w~erein n ls
- - O can also be obt~ined by the reac~ion o~ (III-a) wit:h
an appropriately substituted oxirane o~ the ~rmula
CH--CEI (XIV~
~1 R2 ` .1
~.

5~
It is to be noted that ~hen in ormula (XIV) one o r the
radicals ~1 and R2 is met~yl, the other being hydrogen,
there is substantially ob~ained an interme~late (XIII)
wherein the metl1yl sub~ituent i5 loca~ed at the
~- posi~ion ~ith respect to the pipe~idine nitrogen.
Intermedi~tes of ~ormula (XIII) wherein R1 is phenyl and
n is zero and methods of preparing them are also described
in U.S.Pat. No. 3,998,8340
The reaction o (XIV) with (III-a) is convenien~ly
carried out b~ s~irring and heating the re~ctants toge~lner
in ~n appropriate organic solvent, such as, ~or example,
an aromatic hydrocarbon, e.g. r benzene, methyl~enzene,
dimethylbe~2ene, and the li~e; a ~nalogenated hydrocarbon,
e.g., dichloromethane and trichloromethare; or a lower
alkanol, e.g., methanol, ethanol, 2-propanol and the li~e;
znd preferably in a mixture of an aromatic ~ydrocarbon and
a lower alkanol. The reaction may be promo~ed by the addition
of an appropriate base, such as, for eXample, an al~ali
metal carbonate or hydrogen carbonate.
Starting materials o ~ormula (III-b) wherein Y is chlorq
tIII-b -1), can al50 be prepared directly by the reaction
o (III-a) with a bromo-chloroalkane of the formula (XV)
~ollowing methods s~milar to ~hose described herein for the
preparation o~ starting materi~ls (II b 1) starting rom
tII~a).
_ Cl IC~~(CH2~n-fH~Br ~ a)
R-1 ' R2
(XV~ Cl-CH-(CHz)n-C}~6
(III-b~1)
_13~

5~
Tha starti~g materials of ormula (VI) hereln can generally
be prepared by the :reaction of a reacti~re ester of the formula (II)
whereiu R represents a radical of the formula (IV) with a ~-piperi-
dinamine of the for~ la R5
~ R 3
~
~R~
( XVI )
following similar procedures as d~scribed herein for the preparation
of the compounds ( I-a) 3tarting from ( II) a~d ( III ).
The 4-piperidinamines of formula (XVI) u~ed as 3t~rtir~g mate-
rial9 herei~ cau also be prepared followiIlg the procedures described
U. S. Pat. No. 3, ~98, 834 wherein a number of such compounds- are
specificalIy de~cribed.
.
The ultimate starti~g materials in each o:E the above proce~ures
are ge~erally known and they may all be prepared following art-
lcnown procedures as are de~crbed i~l the literature for preparing
such known compound~ .
~ I 40

5~
The compourlds of formula ( I ) and the pharmaceutically
acceptable acid addition salts thereof have very interesting
pharmacological properties. More particularly they are potent
morphine-like analgesic~ and as such they ca~ be used to
depre~s pain in warm blooded animal~.
The useful analgesic properties of the compour~d~ of
formula ( I ) and acid addition salt~ thereof a~e clearly evidenced
by the results obtained ~ the rat tail withdrawal . test, described
in Arzneimittel-For~chung, I3, 50Z (1963~ a~d Zl, 862 ~1971).
The re3ult~ iu the table I below indicate the LED, i. e.
the lowest 100~ effective dose i~ mg~cg upon intravenous
administration, and the duration (expressed irL mi~utei) of this
effect at the stated do3e.
.: .

-
~s~
.,~
~ c~ . ~ ~ O O u~ ~ ~ ~1 ~'1 ~ d'
.. _......... ... _ .
U
., . ~n ~ ~ ~ , o ~ ~ ~
. ~ ~ O O O ~ CU C~J~7 0 0 0 3 00 N
. . . _ _ . ......... _ . ~
0--0~ O ~ C ~ O C~~ C 1 N X
:C cu~c~ C4. o ~ O o O ~ ! :C D j N 5
_. ~ X
~-- ~ -- ~
~ ~ ~ X
C~ ~4 ~ ~ ~ U ~ C ) U~ ~ N C~
,- _ . __
c~ C) C) ~ 3 0 0 C:~ C) 0 ~5
g g g o 8 ~
'. " " C~ , V ~ , U
., .... :.
~Y . .
e 1; ~ 3~ æ
u~ ~ 3 c~ ~ ~0 x ~
' ' ' _ ~
~ . ~ .
. ~C~J
.,
E~ --~L~. e~
~.
.

A pre~erred group o~ com~ounds wi~hin tlne scope of ~or-
mula` (I) is represented by those wherein R is a lo~rer
al~yl radical. In ~act these preferred compounds are
highly potent analgesics ha~ing a ahort duration of action.
Analgesics having such a short duration of action are
highly desirable in ci-cums~ances where acute severe
pai~ has to be eliminated over a short period, e.g., in
anaestl1esiology.
In vie~ of their analgesic activity, the subject com-
pounds may be formula~ed into various pharmaceutlcal forms
~or admir~istration purposes. To prepare the pharmaceu~i-
cal composi.ions o~ thls invention, an e~ective analgesic
amount o~ the particular compound, in base or acid-
addition salt ~orm, as the acti~e ingredlent i5 combined
in intImate admixture with a pharmaceu~iczlly acceptable
carrier~ which carrier may ta~e a wide ~arie~y of ~orms
depending on the form of preparation desired for admini-
stration. These pharmaceutical compositions are desira~le
in unitary dosage ~orm suitable, prefera~ly, ~or admini-
stration orally, rectally o~ by pærenteral i~JectionO
For example, in preparing the compostions in oral dosage
form, any o~ the usual pharmaceutica~ media may be em-
ployed, such as, for example, water, glycols, Oilsa~ alcohols
and the li~e in the case of oral liquid preparations ,uch
as suspensions, syrups, elixirs and solutions; or solid
carriers such as st~rches, sugaxs, Xaolin, lubricanta,
binders, disintegrating agents and the like in the case o
powders, pills, capsule~ and tablets. Because of ~heir
ease in adminis~ra~ion, table~s and capsules represent the
3~ most advantageous oral dosage unit ~orm, in which case ,~
solid pharmaceutical carriers are ob~iously employed. For
parenteral compositions, the carrier will usually comprise
sterile water, at least in large part, though other in~
gredients, for example, to aid solubility, may be included.
Injectable solutions, for example may be prepared in whieh
!

_17~

~5~6~
the carrier comprises saline solution, glucose solution or a
mix~ure o~ saline and glucose solution. lnjectable suspensi-
ons may also be prepared in which case appropriate liquid
carriers, suspending agents and the like may be employedO
S Acid addi.ion salts of (I), due to their increased water sol-
ubility over the corresponding base form, are obviously more
suitable in the preparation of aqueous compositions.
It is especially advantageous to ~ormulate the aforemen-
tioned pharmaceutical compositions in dosage unit form ~or
ease oE administration and uni~ormity of dosage. Dosage unit
form as used in the specification and claims herein re~ers to
physically discrete units suitable as unitary dosages~ each
unit containing a predetermined quantity o~ acti~e ingredient
calculated to produce the desired therapeutic effect in asso-
`ciation with the required pharmaceutical carrier. Examples
o~ such dosage unit ~orms are tablets (including scored or
coated tablets), capsules~ pills, powder pac~ets, wa~ers9
injectable solutions or suspensions, teaspaonuls, table-
spoonfuls and the li~e, and segregated multiples t!hereo~O
. .
; 20 In view of the ~nalgesic activity of the subjec~ com-
pounds, it is evident that ~he present invention provides
a method of preventing or combatting pain in wa~m-blooded
animals, by the systemic administ~ation of an ef~ective
analgesic amount of a compound of formula (I) or a pharma~
2S ceutically acceptable acid addition salt thereo~ in ad;
mixture ~ith a pharmaceu~ical carrier~
Al~hough the amount of acti~e i~gr~dien~ t~ be administered
may ~ar~ withi~ rather wide limits, depending on the par~
ticular circumstances of the case, doses o~ Erom about
0.01 mg/Xg to about 1 mg/kg, ~dministered once or re-
peatedly ~re generzlly ound e~fecti~eO
.
The ~ollowing examples axe i~tended ~o illustrate and
~o~ to limit the scope o the presen~ erltion. ~nless
ot~erwise stated all par~s therein are by weigh~
~lg ~ ,

:
EX~LE
To a s~irred mixture of 14.2 parts o~ isocyanato-
ethane, 29.2 parts o~ sodiu~ azide and 135 parts o~ dry
tet~lydrof~an is added a solution o~ 39 parts of
- 5 aluminium chloride in 225 parts o~ dry tetrahydro~uran.
Stirrias is continued overnig~l~ at reflux temperature.
The reaction mi~ture is cooled and acidi~ied with a
hydrochloric acid solution 6N. The whole is evaporated
to dry and the produc~ is ex.rac.ed ~o~ times wit~
tO 2-propanone. The combined extrac~s are dried, fil~ered
` and evaporated. The residue i, dried overnight, yielding
t8 parts (65%) of 1-ethyl-1,4-dihydro-5H-tetr~zol-5-oneO
EXA~PLE _ I
Following the procedure of ~xample I and usi~g an
equivalent amount of respectively isocyanatooyclohexane
and 2-îsocyanatopropane as a starting material there
are obtained:
1-cyclohexyl-1 ,4-dihydro-5H-tetrazol-5-one; and
1 ~4-dihydro~1-(l-met~let~tlyl)-5H-tetraæol-5-ane as a resi~
due~
I~XAMPL~ III
.
To ggO parts of te~ahydroura~,- cooled in 2n ice-
bath, are added portion~rise 156 parts o~ aluminium
chloride and ~he whole ls stirred vigorously till al~
solid e~ters solution. This solution is added quic~ly
2S ~ to a stirred suspensio~ o~ 208 part~ o sodium azide
in 225 parts of ~etrahydrouran a~d s~ir~ing is con~
ti~ued for 1 hour at relux temper~ture. A~ter cooling ~o
l9~ ..

5~
room ~e~perzture, t~ere is added droptJise a sol~ltion of
54 parts o~ butanoyl chloride in 225 parts o~ tetra-
hydrofuran at a temperature below 30Co T~e whole is
heated slowly to .elux ~nd stirring is con~inued over-
night at reflux temperature. While cooling, the reaction
mixture is acidified ~rith 800 par~s o~ a hydrochloric
acid solution 6N ~nd the solvent is evaporated. The
- residue is s~irred in a sodium hydrogen carbonate solu-
tion, tric~llorome~hane is added and ~he layers are
separated. The aa~ueous phase is acidified with concen-
trated hydrochloric acid ~nd the solve~t is evapora.ed.
The residue is stirred in 2-propanone. The precipitate
is ~iltered of~ and the ~iltrate is evaporated, yielding
32 parts o~ 1,4~di~ydro-1-propyl-5H-tetrazol-5-one as
; 15 a residue.
.1
'~ ~
~XA~LE IV
~ ~.... . _ .
Following the procedure o Example III and using an
e~ui~alent amount o an appropriate ac~l chloride as a
starting material, the following compounds are obtained:
t-(1,1-dimethylethyl)-1,4-di~ydro-5H-tetrazol-S-one as a
residue,
,
1,4-di~ydro 1-pe~tyl-SH-tetrazol-5-~ne;
- ' ~
- - 1,4-dihydro-1(2-phenylethyl)~5H~tetr~zol 5-o~e as a E
solid residue; - ~
~.
1,4-dihydro-1-(phe~ylm~thyl)-5H~tetrazol-5 one; mp. 152G; and
.. ~.
I eyeloPropyl~1,4-dihydro5~-tetrazol 5~orle; mp. 128C.
` .
_.

~5~4
EX~L~.IPLE V
~ ,
A mLYture of 22 parts of I-ethyl-I,4-dihydro~5H-tetrazol-5-
one, 45 parts of I~bromo-2-chloroethane, 26 parts of sodium earbonate,
0. 3 parts of potassium iodide and 240 parts of 4-methyl-2-pentanone i9
stirred and refluxed o~rernight with water-separator The reaction
mixture i9 cooled, water i~ added and the layers are separated The
aqueous phas~ i9 extracted three times with dichloromethane. The
combined organic pha~es are dried, filtered and e~raporated. The
residue i9 purified by column-chromatography o~rer silica gel u~ing
trichloromethane as eluent. The pure fractions are collected and
the eluent is e-raporated, yielding 28 . g parts ~80%) of I -(2-chloro-
ethyl)-4- ethyl- 1, 4-dihydro -5H-tetrazol-5 ~one as ~ residue .
}CX~MPLE Vl
FoLtowi~g the procedure o E~a~nple V and using equi~ralent
15~ amous~ts of re~pecti~ely an appropriate l, 4-dihydro-5H-tetrazol-5-
one and an appropriate bromochloroalkane as starting material~ the
following l-(chloroal~yl) 1,4-dihydro-5H-tetrazol-5-ones are
obtaisLed:
1-(2-chloroethyl)-1,4 dihydro-4 propyl-5H-tetrazol-5-o~e as a
resid~e;
.
I -~2-chloroethyl)-1, 4-dihydro-4-(l methylethyl)-5H-tetraæol_5_one
as a re idue;
1_(2-chlQroethyl)-g-(I, I-dimethylethyl)-l, 4dihydro~5H-tetra201-5~or~e
as a re~idue;
I~(2 chloroethyl)-I, a-di~ydro 4-pentyl 25H-tetrazol~5~0ne as a
residue;
l-(2 cllloroethyl)-4~cyclohe~yl~Ip4~dihydro~5H~tetrazol~5 one a~
a residue;

1-(2-chloroethyl)-I, 4-dihydro-4-(2-phenylethyl)-5H-tetrazol 5-one
a~ a residue;
1-(3-chloropropyl)-4~ethyl-I,4-dihydro-5H-tetrazol-5-one as
a residue;
1 (2-chloroethyl~-1, 4~dihydro-4-(phenylmethyl)-5H-tetrazol-5-one
as a re~idue; and
I-t2-chloroethyl)~4-cyclopropyl-1, 4-dihydro-5H-tetrazol-5~on~e
as a re3idue
EXAMPLE ~II
A mixture of 49 parts of iodomethane, I0. 5 pa~ts of I-(2-
chloroethyl)-1,4-dihydro 5H-tetrazol-5-one, 15 parts of sodium
carbo~ate, 0.2 parts o~ pota3 9iU~1 iodid~ and Z40 parts of 4-rnethyl-
2-pentanone i5 stirred and reflux~d o~rernight with w~ter-sepalator.
The reaction mixture is cooled, 100 parts of water are added and the
layeri are 9eparated. The aqueous phase i9 extracted with dichloro-
methane. The combiAed organic pha3es are dried, filtered and
evapora,ted. The residue is purified by column-chromatography ov~r
silica gel using trichloromethane a9 eluent. The pure fraction~ are
collected and the eluent i~ evaporated, y~elding 15 part3 (85~)
of I,4-dihydro-1-(2-iodoethyl)-4 methy~-5H tetrazol;5-on~ as a
re~idue.
~2Z

~5~
EXA~h~LE VIII
.
A mixture o 19.6 parts o ~ -(2-~hien~l)eb~l-rl7
4-methylbenzenesulfonate, 10 pa~ts of 1-(2-chloro-
ethyl)-1,4-dihydro-5~-tetrazol-5-one, 10 parts of
sodi~ carbonate a~d 90 parts o~ N,N-dimethylform-
amide is stirred and heated overnight at 70C. The
reaction mixture is cooled, 100 parts of ~ater are
added and the product is ex~racted three times with
methylbenzene. The combined extracts are dried, filtered
and e~aporated. The residue is purified by column-
chromatography over silica gel using a mixture of
trichloromethane and petrol~umether (70:30 by volume)
as eluent, The pure ~rac~ions are collected and ~he
eluen~ is evaporated, yielding 15 parts (46.5,'o) of
1-(2-chloroet~yl)-1,4-dihydro-4-~2-(2-thienyl)et~y~
5H-tetrazol-5~ane as a residue.
.. . .
EXAMPLE IX
.
To 4.5 parts o~ sul~inyl chloride is added drop-
~ise a mixture of 13 parts o N-~ -(2-hydro~y-2-
phenylethyl)-4~(~e~hoxymethyl)-4-piperidinyl7-N-
phenylpropan~mide ~1ydrochloride and 260 par~s o~ di~
chl~romethane. Upo~ completion, the ~hole is stirred
and refluxed or a fe~ hours. The reaction mixture is
cooled and the solven~ is evaporated. The ~esidue is
tak~ up in 2~propanone. Th mixtu:re is ~iltered znd the
filt~ate is ~re~ted ~rith activated charccal. The. la~:ter
is ~iltered o~ and the iltrate is evaporated. The
resiàue is crystallized Erom a mi~e of 2~ropanone
and 2,2l-o~s:ybisprop2ne. The produc~ is .Qil~ered of~
and dried, yielding 9q2 parts ~61~7%) o~ N ~ (2-chlox~o~
2-phenylethyl) 4-(metho~ymethyl) 4 piperidi~yl7 N-
phenylpropanamide monoh~ ochloride; mp~ 145~3~1Go
.
~23- ~

~ 5~
.
E.YAM:PLE X
A mixture of 35 parts of 2~metnyloxirane, 83
parts o~ N-~4-(methoxymethyl)-4-piperidiny ~N-
phenylprop~lamide, 25 parts of sodium hydrogen car-
bonate, 450 parts o~ ~enze~e and 80 parts o~ methanol
is stirred and refluxed overnight. The reaction mix-
ture is evaporated ~ld t~e residue is tahen up in
water. The product is extracted with trichloromethæ~e.
The extract is dried, ~iltered and evaporated. The
residue is conver~ed into ~he hydrochloride salt in
2-propanol. The salt is filtered off and crystallized
~rom a mixture o 2,2~-o~ybispropa~e and 2-prop~nol,
yielding 41O5 parts (37%) o N-~-(2-hyaroxypropyl )-
4-(methoxymethyl)-4-piperidiny ~-N-phenylpropanamide
monohydrochlorideO
14 Parts o~ sul~inyl chloride are s tirred ~ld
there is added dropwise a solution o~ 37 parts of
N- ~-(2-hydrox~propyl)-4-(methoxymethyl)-4-piperi-
din~ phe~lylpropanamide monohydrochloride in
360 parts of dichloromethane~ Upon completion, stirriny
is continued overnisht at re1ux temper~ture. The
reaction mixture is evaporated and the residue i5 SUS-
pended in 2 proparlone. The product is filtered o~f and
dried, yielding 31.5 parts (~5%) o~ N-~ -(2-chloro-
propyl)-4-(me~hox~met~ 4-piperidinyl~-N-pheYlyl~
propanamide monohydrochloride.
24-
t

~ 5 ~ ~
.
EX~LE ~I
A mixture o~ 1~8 parts of 1-(2-chloroethyl)~4-
ethyl-1,¢~dihydro-5H-te~razol-5-one, 3.45 parts o~
N- r-(metho~methyl)-4-piperid~n~ -N~phenylpropana-
mide, 5 parts o~ sodiu~ carbonate, 002 parts o~ pota5-
sium iodide and 2~0 parts of 4-meth~l-2-pe;ltanone is
stirred and refluxed overr.ight with water-separator.
The reaction mixture is poured onto water and t~e
layers are separated. The organic phase is dxied,
filtered and evaporated. The residue is puri~ied by
column-chromatography ov-er silica gel using a mixt~re
of trichloromethane ard met1lanol (97:3 by volume) as
~luent. The pure Pr~ctions are collected ænd ~he
eluent is evaporated. T~e residue is corverte~ into
the hydrochloride sal- in 2-prop~none. The sal~ is
Piltered off and c~ystallized from 2-propanone, yielding
1.5 parts (33.3,0) of N~ ~ -(4-ethyl-4,5-dihydro-5-
oxo-1H-te~ra20l-1-yl)ethy~ -4-(methoxymethyl)-~-
piperidinyl~- N-phenylpropanamide monohydrochloride
monohydxate; mp~ 140~8~C.
.
.
EX~LE XII
Follawing the procedure o~ Example XI and using
- equi~alent amounts o the appropriate starti~g materi~
als, the ~ollowing co~npounds are obtained a~ acid
addition sal~s a~ter treatme~t o~ ~h~ ree base form
~ith an appropriate acid.
N {,1 ~2-(4,5-dihyd~o-5 oxo~4 propyl-1H-tetr~zol ~
yl)e~hyl~-(methoxymethyl)~4~piperidinyl}~ N~phellyl;
propanamide ethanedioa ~e ( 1: ~ ) monohydrate ; mp
30-~ 103.8C.
N~ 2 ~,5-dihydro~ ~2thylethyl)-5-oxo~lH tetrazol~l^y~
ethyl~ 4 (methox ~ ethyl) 4-piperidi~y~ N phonylpropa~amid~

:
mononitrate monohydrate; mp. 1 04. 5 C;
methyl I ~ 4, 5-dihydro-5-oxo-4-~-(2-thienyl)etky~7-IH-tetrazol-
I -yl ~ ethy~;7-4- ¢I -oxopropyl)phenylamino7-4 - piperidinecarboxylate
ethanedioate (I :1) mp. I62. 9C;
N- ~ (4-ethyl-4, 5-dihydro-5-oxo-lH-tetrazol-1 -yl)propy.l7-4-
(met~o~ethyl)-4-pipe~idinyl,}-N-phenylpropanamide hydrochloride
hemihydrate; mp. 182C; and
N~ 2-~4, 5-dihydro-5-oxo-4-(phenylmethyl)-lH-tetra~ol-l-y~-
ethyl}-4-(methoxymethyl)-4-piperidiny~ N~he~Lylpropa~amide
I0 etha~edioate (1:1); mp, 166~ 4C.
l;XAM PLE XIII
A mixture of 3. 6 parts of I-(Z-chloroethyl)-4-ethyl-I, 4-
dihydro-5H-tetrazol-5-one, 6.4 parts of methyl 4-~-(1-oxopropyl)~
N-phenylam~o~ piperidi~ecarboxylate hydrochloride, 4 partY of
~odium carbonate, 0.1 part~ of potas~ium iodide ~Ild 240 part~ of 4-
methyl-2-pe~tanone i9 stirred and refllLYed overIlight with water -
~eparator. The reactio~ mixture i8 cooled a~d pou~ed onto water.
The or~allic pha~e i3 9eparated, dried, filtered and e~raporated. The
residue is purified by column-chromatography over silica gel u9ing
a m~xture of trichloromethane and methanol (97:3 by ~rolume) a~
eluent. Tha pure fractions are collected and the eluent iB e~raporated.
Th~ residue is con~rerted irLto the etha~edioate sal~ in 2-propa~one,
The alt i~ f;ltered o~f and d~ied, yield~g I . 5 part~ (I3~) of ~eth~l
(4-ethyl-4, 5-dihydro-5-oxo-l~-tetra301-l -rl)ethy~7-4-~_oxo~
propyl)phenylamino7-4-piperidinecarbo:~ylate etharledioate (2:3);
; mp, 158. ~C.
o~6 C~ .

EXAMPLE _XIV
Following the procedure of Example X~II and using
equivalent amounts o~ the appropriate star~ing materi-
als, ~he ~ollowing et~anedioate sal~s are obtained:
methyl 1-~-(4,5-di~ydro-5-oxo-4-p~opyl-~H-tetra-
zol-1-yl)ethy~ -4- ~1-oxoprop~Jl)phe~ylamin~ -4-
piperi~inecarboxy}ate ethanedioa~e (1:1); mp.
168.4C;
.~ methyl 1-~2-~5~dihydro-4-(1-methylethyl)-5-oxo-1H-
tetra20l-1-y ~ethyl}-4- ~1-oxopropyl)phenylamin ~-4
piperidinecarboxylate e~h~nedioate (1:1);mp, 184.2C;
methyl 1-~2-~4-(1,1-dimethylethyl)-4,5-dihydro-5-
oxo-1H-tet~azol-1-y~ethyl}-4-~ 1-oxcpropyl)phenyl-
- amin ~-4-piperidinecarboxylate ethane~ioate (1:1);mp.
lS 168~1C;
methyl 1-r-~4,5-dihydro-5-oxo-4-pentyl 1~-tetrazol-
1-yl)ethy ~-4~ oxopropyl)phenylamin~ -~-piperidine-
~arboxylate ethanedioate (1;1); mp. 153~5C;
~ methyl 1- C~ ~JC10heXY1-4,5 di~ydro-5-oxo~
~e~razol-1-yl)e~hy~-4~ oxopr~pyl)phenylamin ~4 ~,;
piperidinecarboxylate ethanedioate ~1:1); mp, 173C; ¦.
` '
meth~ 2-r4,5~di~ydro-5-oxo-4~2-phe~yle~hyl)~H-
~ tetrazol-1-yl7ethyl}-4 a1 oxopropyl)phenylamin ~ ~
piperidinec~rboxylate ethanedioate (2:3); mp. 162~2C;
methyl I-{2~ di~ydro 5-oxo-4w(phenyi~ethyl) I~-tetrazol- t
I -yl7ethyl~ -4- ~ -oæopropyl)ph~ylamin~7_4W piper~di~eearboxylate
ethanedioate( l:I); mp, 19I.7C;
--27--
,.

S~L69~
.
methyl I -~-(4-cyclopropyl)-4, 5-dihydro-5-oxo-lH-tetrazol-l -yl)-
ethy~7~4-~1-oxopropyl)phe~ylamin~7-4-piperidinecarboxylate ethane-
dioate (Z:3~ hemihydrate; mp, I55. 9~C; and
methyl I-~ (4-ethyl-4, 5-dihydro-5-oxo-lH-t~trazol-l-yl)eth~7-4-
~phenylamino)-4-piperidinecarboxylate ethanedioate (2:3); rnp. I72C.
EXAMPLE XV
A mixture of 2. 55 parts of 1, 4-dihydso-1 -(2-iodoethyl)-4-
methyl-5H tetrazol-5-one, ~. 45 partq of N-~-(methoxyrnethyl)-4-
piperidiny~7-N-phenylpropanamide, 2 part~ of sodium carborlate, 0. 2
parts of potassium iodide and 160 parts of 4-m~thyl-2-pentanone i9
stirred and refluxed over~ig~ with water-separator. The reaction
mixture i~ cooled, 100 part~ of water are added and the layers are
9eparated. The aqueou~ phase i9 e.~ctracted with dichlorometha:ae. The.
combined orga~ic phase5 are tried, fil~ered a~d evaporated. The residue
i9 purified by coli~n~-chromatography over silica gel using a mixture of
tsichloromethane a~d methaD.ol (97:3 by ~rollLme) as elue~t. The pure
fraction9 are collected and the elue~t iY evaporated. The re~idue i~
converted Lnto the etha~edioate salt in 2-propa~orLe. The salt i~
filt,ered off and cry9tallized from 2-propa~one, yi.eldi~g 2.1 parts (42'1o)
of N- [ 1 -~-(4, 5 -dihydro-4-methyl-5 -oxo -1 H -tetra~ol- 1 -yl)ethy~7-4-
(methoxymethyl)-4-piperidi~yl}-N-phenylpropanamide etha:~edioate
(1:1 ); mp. 155 . 9 C.
L3 ~VI
Followingthe procedure of:Example XV thereis prepared methyl
1_ ~-(4,5-dihydro-~-n~thyl-5-oxo-lH_tetra~ol-l_yl)ethy~ -4. ~ ~
oxopropyl~phenylanninoJ-4-piperidL~ecarboxylate ethanedioate(I:I);
mp. I85.9~C;bythe reactio~ ofI,4-dihydxo-I-(2-iodoethyl)-4-methyl~
SH-tetrazol-5-one with methyl 4-~1-oxopropyl)phenylamlr?.oJ 4-piperi~
dinecarboxylate.

5~
.
~ . EXAMPLE ~VII
,
A mixture o 3 parts of 1-ethyl-1 ,4-dihydro-5H-
tetrazol-5-one, 9. 4 part~ of N-~- (2-chloropropyl)_4_
(methoxy~ethyl)-4-piperidinyl7~N-phenylprop~n~.,ide,
2.5 parts o~ sodium c~rbonate, 2.5 parts o~ N,N-diethyl-
: ethana~ine and ~0 parts o~ N,N-dimet~yl~ormamide is
stirred and heated overnight at 70C. The reacti~n
mix~ure is cGoled, 100 parts o~ water axe added and the
~ product is extracted t~ee times with methylbenzene.
The combined extracts are dried, iltered and evapcrated.
The residue is puri~ied twice by column-cnromatography
over silica gel ucing ~irst a mix~ure o~ trichloromethane
and methanol (97:3 by volume) and.then a mixture of
ethyl acetate and ethanol (9~:1 by ~olume) as eluent.
The pure ractions are collected and .he eluent is e~a-
porated. The residue is converted into ~e hydrochlo~ide
salt in 2-propanone and 2,2'~oxybispropane. The salt is
iltered of and dried, yieldi~g 2.1 parts (18%) of
N~ 2-(4~ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)-
1-methylethyl~-4-(methox~methyl)~4-piperidinyl}-N~phenyl-
propanamide monohydrochloride; mpO 1850.C.
EXA~D?L~ . XVIII .
- '' i
A mixture of 1.2 parts of 1-et~ 1,4-dihydro-5H- i
tetrazol-5~one, 3.9 parts o~ N-~ -(2-chloroprQpyl)-4- .
(methoxymeth~ 4~piperidinyl7-N-phenylpropanamide mono~ .
hyd~ochloride, 2 parts oE sodiwn carbonate, 0~1 parZ:s
o~ pota,sium iodide ~nd 120 parts of 4-me~hyl-2~penta-
none is stirred and refluxed overnigh~ wi~h ~ra~
separator. The reaction mixture is cooled, poured onto
water and the layers a~e sepa~ated. The organic phase is
.
- 2 9 - ~

~ 59~64~
~ried, ~iltered and evaporated. T~le residue is
puri~ied b~j col~n-c~1romztog~ap}ly over silica gel
usin~ a mixture o~ trichlo~omethane ~nd methz~l
(9~:1 by ~olume) as eluent. The pure ~ractions are
colle~ted ænd the eluent is evaporated. T~e resiaue
is con~erted into the nitrate salt in 2-pro~none.
The salt is ~ilt~red of ~d cr~stallized t~ice: ~irst
~rom a mixture of 2, 2 '-oxybisprop~ne and 2-propanone
and then ~rom 2-propanone, yielding 1~5 parts (30,')
o~ N-{1-~ -(4-eth~l-4,5-dihydro-5-oxo-1H-tetrazol-1
yl)-1-methylethy ~ -4-(methox~nethyl)-4-piperidinyl}-N-
phen~lpropanamide mononitra~e; mp~ 146.6C~
EXAMPLE XIX
Followins the procedure o~ Example XVIII there is
prepared N-~1-~2-(4,5-dihydro-5-oxo-a-phenyl-1H-~etra-
zol-1-yl)-1-methylethy ~ -~ (methoxymethyl)-4~piperidin~J~-
N-phenylpropanamide mononitrate; mp~ 151.2C; by ~he
reaction o~ 1,4-di~lydro-1-phenyl-5H-~etrazoI-5-o~e
with N~ -(2-chloropropyl)-4-(methoxymethyl~-4-piperidi
nyl7-N-phenylpropan~mide monohydrochloride.
.
EXA~iD?LE XX
A mixture of 3 parts o~ 1-ethyl-1,4-dihydro-5H-tetra~
æol-5-one, 8 parts o~ N-~ -(2-chloro=2 phenylet~ 4-
- (methoxymethyl)-4-piperidiny~ ~N-phenylpropanamide, 0~2
parts of potassium iodide, 5 part~ o~ sodium earbonate
and 135 par~s o N,N-dimethyl~ormamide is stirred and
heated overnigh~ at 70C. The reactio-a mix*ure ia cooled
- - ~o room t~mperature and 150 parts o~ ~ater are ~ddedO
.
-30

-
`
The product is ex~racted t~ee times ~th me~lyl-
benzene. The combined ext~ac~s are dried, filtered and
evapora.ed. The solid residue is pu~iied b~ column~
ch~omatogr~phy over silica gel using a mixture Or
trichlorometllane and methanol (97:3 by volume) as eluent.
The pure fractions are collected and the eluent is
evaporated. The residue is crystallized from a mixture
of pe~roleumether and 2,2'-o~bispropa~e. The product
is ~iltered o~f and dried, yieldlng 5.7 parts (6S%)
o~ N-~ (4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-
yl)-2-phenylethy~ -4-(methoxymethyl)-4-~iperidin~ N-
phenylpropan~mide; mp. 125 . 7 C .
. .
~X~LE XXI
.
A mixture of 3 parts of 1-ethyl-1,4-dihydro-5H-
tetrazol~5-one, 9.4 parts of N- ~ -(2-chloropropy~
(methoxymethyl)-4-piperidiny ~ -N-phenylpropanamide
monohydrochloride, 2.5 parts o~ N,N-diet~ylethanamine,
2.5 parts of sodium carbonate and ~0 parts of N,N-di
methyl~ormamide is stirred and heated overnight at 70DC.
The reaction mixtuxe is cooled and 100 parts of water
are added. The product is extracted three times with
methylbenzene. The combined ext~acts are dried, f iltered
and evaporated. The residue is pu~i~ied twice by column~
chromatography o~rer silica gel using ~irst a mix~ure o
l:richlorome~har.e and methanol ~97:3 by volume) and then
.- a mixture of ethyl acetate and ethanol (99:1 by vollame),
as eluent~, The pure ~ractions are collected and ,he
elue~t is e~raporated. T~e resi~ue is comrerted into the
hydrochloride salt in 2 propanone and 2, 2 ~-o~bispropaneO
- ~0 The salt is ~iltered o~ and dried, yieldi~g 3. 9 part:5
(33.4%) of ~-{1-~2-(4-et~Jl-4,5~dihydro-5 oxo-1EI tetrazol~
yl )propy~ (methoxymethyl ) ~ pipe:ridirLyl} -N-pherlyl
propanamide monohydrochloride; mp. 192.7C.
31~
.

~5
.
EXAMPLE XXII
A mixture o ~. 7 parts of methyl 1~ ethyl-~, 5~dihydro-
S-oxo-lH-tetrazol-I -yl)ethyl7-4-(phenyla~nino)-4-piperidinecarbo~-
ylate, 1. 9 parts of cyclopropanecarbonyl chloride, 2. 7 parts of N, N-
S diethyletha~amine and 68 par~s of methylben:z;ene i9 stirred and renuxed
over~ight. The reaction mixture i9 cs~oled, 100 parts of water are
added and the layer~ are separated. ~he organic phase is dried,
flltered and evaporated. The residu~ is purified by column-chromato-
graphy over silica gel u~ing a mixture of trichloromethane and methanol
IO (98 :2 by volume) as eluent. The pure :Eraction~ are collected and
treated with 1 part of ethanedioic acid. The formed ethanedioate salt
i9 filtered of and cry~tallized from a mixture of Z-propanone and
2,2'-oxybiapropane, yielding 1.5 part~ (17.5%) of methyl 4~cyclo-
propylcarbonyl)phenylamino7~ (4-ethyl-4, 5-dihydro-5-oxo-lH
15 tetr~2;ol-l-yl)ethy~ 4 piperidlrLecarboxylate ethanedioate (Z:3);
mp. 181. 5C.
~ .
,
EXA_PLE XXIII
Following the proceduIes described herein and using appropriate
starti~g materials the ~ollo~ g compounds of formula I ca~ still
20. be prepared:
~32 O

~ g
~o w ~ o
--
u~ ~ X ~ X V
: ~ ~ ~
5~
. ~ 0 `D
X ~ A
~;
V O V V ~ W ~ V U
- - ----
~ Ln Lll ~ U~
~ ~ ~ ~ x 5: ~ ~ ~
X
V O O U ~ O U X X O ~ V V O ~
~; O o ~ o ~ V ~ o V U o ~ o o o o o
O o ~ o a o o o o o o ~ o o o o o
~ U O V V O ~ t~ V ~ U V ~ U
..... . . . .... ~
. ~~'X X ' ~ X ~ .
.. . _.` - . _ .
~; X ~ X
~ O _, O O ~ ~ ~ C ~ C O C~ O C O ~ _,
., . , ~.
.... .. .. . ... _~
~` ~ o v~ o a a o o o o o o o o ~ o o ~n
. .. _ ~
U V ~ v ,~
~33 ~