U.S. patent application number 09/915558 was filed with the patent office on 2002-05-30 for n-triazolymethyl-piperazine compounds with neurokinin-receptor antagonist activity.
Invention is credited to Brueckner, Reinhard, Eeckhout, Christian, Jasserand, Daniel, Sann, Holger, Schoen, Uwe.
Application Number | 20020065276 09/915558 |
Document ID | / |
Family ID | 7650544 |
Filed Date | 2002-05-30 |
United States Patent
Application |
20020065276 |
Kind Code |
A1 |
Jasserand, Daniel ; et
al. |
May 30, 2002 |
N-triazolymethyl-piperazine compounds with neurokinin-receptor
antagonist activity
Abstract
N-triazolylmethyl-piperazine compounds which exhibit neurokinin
receptor antagonistic activity corresponding to the formula I: 1
wherein R.sup.1, R.sup.2 and R.sup.3 have the meanings given in the
specification; pharmaceutical compositions containing these
compounds; a process for preparing these compounds, and
intermediate products of this process.
Inventors: |
Jasserand, Daniel;
(Hannover, DE) ; Schoen, Uwe; (Burgdorf, DE)
; Sann, Holger; (Hannover, DE) ; Brueckner,
Reinhard; (Hannover, DE) ; Eeckhout, Christian;
(Lindwedel, DE) |
Correspondence
Address: |
CROWELL & MORING LLP
INTELLECTUAL PROPERTY GROUP
P.O. BOX 14300
WASHINGTON
DC
20044-4300
US
|
Family ID: |
7650544 |
Appl. No.: |
09/915558 |
Filed: |
July 27, 2001 |
Current U.S.
Class: |
514/233.5 ;
514/253.09; 514/254.05; 544/121; 544/360; 544/366 |
Current CPC
Class: |
A61P 25/00 20180101;
C07D 403/06 20130101; C07D 403/14 20130101; A61P 43/00 20180101;
A61P 1/04 20180101; A61P 1/00 20180101; A61P 29/00 20180101; A61P
1/06 20180101 |
Class at
Publication: |
514/233.5 ;
514/254.05; 514/253.09; 544/121; 544/360; 544/366 |
International
Class: |
C07D 413/14; A61K
031/5377; A61K 031/496; C07D 43/14 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 28, 2000 |
DE |
100 36 818.2 |
Claims
What is claimed is:
1. A compound corresponding to the formula I: 13wherein R.sup.1 is
hydrogen or lower alkyl, R.sup.2 is lower alkyl,
di-lower-alkylamino lower alkyl, lower-alkoxycarbonyl lower alkyl;
cyclo(hetero)alkyl having 5-6 ring atoms, which may optionally be
substituted once or twice by lower alkyl and which optionally
contains 1-2 double bonds; (hetero)phenyl lower alkyl optionally
substituted once or twice in the (hetero)phenyl ring by halogen,
lower alkyl and/or lower alkoxy, the lower-alkyl chain of which
(hetero)phenyl lower alkyl is optionally substituted once or twice
by lower alkyl or by spiro-C.sub.4-C.sub.5-alky- lene; or phenyl
lower alkoxy optionally substituted once or twice in the phenyl
ring by halogen, lower alkyl and/or lower alkoxy, and R.sup.3 is
lower alkyl, lower-alkoxycarbonyl lower alkyl or cyclo(hetero)alkyl
with 5-6 ring atoms which is optionally substituted once or twice
by lower alkyl, or R.sup.2 and R.sup.3, together with the nitrogen
to which they are bonded, form a cyclic group of formula a:
14wherein A is nitrogen, oxygen, methylene or methylidene, the
double bond of which, together with the adjacent carbon, is formed
in position 3 of group a, n is a whole number from 1 to 3, R.sup.4
is hydrogen, lower alkyl, lower-alkoxy lower alkyl, lower
alkoxycarbonyl, lower-alkoxycarbonyl lower alkyl,
di-lower-alkylamino lower alkyl; (hetero)phenyl optionally
substituted once or twice by halogen, lower alkyl and/or lower
alkoxy; (hetero)phenyl lower alkyl optionally substituted once or
twice in the (hetero)phenyl ring by halogen, lower alkyl and/or
lower alkoxy, the lower-alkyl chain of which (hetero)phenyl lower
alkyl is optionally substituted once or twice by lower alkyl;
cyclo(hetero)alkyl with 5-6 ring atoms, or cyclo(hetero)alkyl lower
alkyl, the cyclo(hetero)alkyl group of which has 5-6 ring atoms,
and R.sup.5 is hydrogen, lower alkyl or lower-alkoxy lower alkyl,
or R.sup.4 and R.sup.5 together are spiroethylenedioxy bonded to a
carbon of group a; C.sub.3-C.sub.4-alkylene bonded to two adjacent
atoms of group a; or phenyl fused via two adjacent carbons of group
a, or R.sup.2 and R.sup.3, together with the nitrogen to which they
are bonded, form a pyrrolidine ring which is substituted twice by
C.sub.4-alkylene which is bonded each time via two adjacent carbon
atoms, or a physiologically compatible acid addition salts
thereof.
2. A compound according to claim 1, wherein: R.sup.1 is hydrogen,
R.sup.2 is lower alkyl, di-lower-alkylamino lower alkyl,
lower-alkoxycarbonyl lower alkyl; cyclo(hetero)alkyl with 5-6 ring
atoms, optionally substituted once by lower alkyl; heterophenyl
lower alkyl optionally substituted once or twice in the
heterophenyl ring by lower alkyl or lower alkoxy, or
phenyl-C.sub.2-C.sub.4-alkyl substituted once or twice in the
phenyl ring by lower alkyl or lower alkoxy, and R.sup.3 is lower
alkyl or lower-alkoxycarbonyl lower alkyl, with the proviso that
R.sup.2 and R.sup.3 do not simultaneously stand for isobutyl, or
R.sup.2 and R.sup.3, together with the nitrogen to which they are
bonded, form a cyclic group of formula a, wherein n is a whole
number from 1 to 3, with the proviso that n stands for 2 or 3,
provided that R.sup.4 and R.sup.5 are both hydrogen and at the same
time A stands for methylene, R.sup.4 is hydrogen, lower alkyl,
lower-alkoxy lower alkyl, lower-alkoxycarbonyl lower alkyl,
di-lower-alkylamino lower alkyl; (hetero)phenyl optionally
substituted once by lower alkyl or lower alkoxy; (hetero)phenyl
lower alkyl optionally substituted once in the (hetero)phenyl ring
by halogen, lower alkyl or lower alkoxy; cyclo(hetero)alkyl with
5-6 ring atoms, or cyclo(hetero)alkyl lower alkyl, the
cyclo(hetero)alkyl radical of which has 5-6 ring atoms, and R.sup.5
is hydrogen, lower alkyl or lower alkoxy lower alkyl, with the
proviso that R.sup.4 and R.sup.5 are not bonded to the same ring
atom of group a, or R.sup.4 and R.sup.5 together are
spiroethylenedioxy bonded to a carbon of group a; or
C.sub.3-C.sub.4-alkylene bonded to two adjacent ring atoms of group
a.
3. A compound according to claim 1, wherein the carbon C-2 of the
piperazine ring which bears the 1H-indol-3-yl-methyl radical is in
the R configuration.
4. A compound according to claim 1, comprising group a which
represents pyrrolidine substituted by R.sup.4 and R.sup.5, wherein
R.sup.4 and R.sup.5 are not both simultaneously hydrogen, or a
represents 2,5-dihydropyrrole, piperidine, piperazine, morpholine
or diazepan, each substituted by R.sup.4 and R.sup.5.
5.
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-{[5--
(morpholinomethyl)-2H-1,2,3-triazol-4-yl]methyl}piperazine
according to claim 4.
6.
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-{[5--
(morpholinomethyl)-2H-1,2,3-triazol-4-yl]methyl}piperazine
dihydrochloride according to claim 4.
7. A pharmaceutical composition comprising a pharmacologically
active amount of a compound according to claim 1 and at least one
pharmaceutical carrier or adjuvant.
8. A process for preparing a compound corresponding to formula I:
15wherein R.sup.1 is hydrogen or lower alkyl, R.sup.2 is lower
alkyl, di-lower-alkylamino lower alkyl, lower-alkoxycarbonyl lower
alkyl; cyclo(hetero)alkyl having 5-6 ring atoms, which may
optionally be substituted once or twice by lower alkyl and which
optionally contains 1-2 double bonds; (hetero)phenyl lower alkyl
optionally substituted once or twice in the (hetero)phenyl ring by
halogen, lower alkyl and/or lower alkoxy, the lower-alkyl chain of
which (hetero)phenyl lower alkyl is optionally substituted once or
twice by lower alkyl or by spiro-C.sub.4-C.sub.5-alkylene; or
phenyl lower alkoxy optionally substituted once or twice in the
phenyl ring by halogen, lower alkyl and/or lower alkoxy, and
R.sup.3 is lower alkyl, lower-alkoxycarbonyl lower alkyl or
cyclo(hetero)alkyl with 5-6 ring atoms which is optionally
substituted once or twice by lower alkyl, or R.sup.2 and R.sup.3,
together with the nitrogen to which they are bonded, form a cyclic
group of formula a, 16wherein A is nitrogen, oxygen, methylene or
methylidene, the double bond of which, together with the adjacent
carbon, is formed in position 3 of group a, n is a whole number
from 1 to 3, R.sup.4 is hydrogen, lower alkyl, lower-alkoxy lower
alkyl, lower alkoxycarbonyl, lower-alkoxycarbonyl lower alkyl,
di-lower-alkylamino lower alkyl, (hetero)phenyl optionally
substituted once or twice by halogen, lower alkyl and/or lower
alkoxy; (hetero)phenyl lower alkyl optionally substituted once or
twice in the (hetero)phenyl ring by halogen, lower alkyl and/or
lower alkoxy, the lower-alkyl chain of which (hetero)phenyl lower
alkyl is optionally substituted once or twice by lower alkyl;
cyclo(hetero)alkyl with 5-6 ring atoms, or cyclo(hetero)alkyl lower
alkyl, the cyclo(hetero)alkyl group of which has 5-6 ring atoms,
and R.sup.5 is hydrogen, lower alkyl or lower-alkoxy lower alkyl,
or R.sup.4 and R.sup.5 together are spiroethylenedioxy bonded to a
carbon of group a; C.sub.3-C.sub.4-alkylene bonded to two adjacent
atoms of group a; or phenyl fused via two adjacent carbons of group
a, or R.sup.2 and R.sup.3, together with the nitrogen to which they
are bonded, form a pyrrolidine ring which is substituted twice by
C.sub.4-alkylene which is bonded each time via two adjacent carbon
atoms, or a physiologically compatible acid addition salt thereof,
said process comprising: a) reacting a compound corresponding to
formula II: 17 wherein R.sup.1 has the above meaning, with a
compound corresponding to formula III: 18 wherein R.sup.2 and
R.sup.3 have the above meanings, and wherein any reactive groups
present are blocked by suitable protective groups, or b) reacting a
compound corresponding to formula IV: 19 wherein R.sup.1 has the
above meaning, with a compound corresponding to formula V: 20
wherein R.sup.2 and R.sup.3 have the above meanings, and wherein
any reactive groups present are blocked by suitable protective
groups, and subsequently cleaving off any protective groups present
therein, and optionally converting a resulting compound of Formula
I into a corresponding acid addition salt, or converting an acid
addition salt into a free compound of Formula I.
9. A compound corresponding to the formula IV: 21wherein R.sup.1 is
hydrogen or lower alkyl.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to novel
2-indolylmethyl-piperazine derivatives which are antagonistic to
neurokinin receptors and which are substituted at a nitrogen of the
piperazine parent structure by a triazolylmethyl radical.
Furthermore, the invention relates to medicaments containing these
novel N-triazolylmethyl-piperazine derivatives. Furthermore, the
invention relates to a process for the preparation of the novel
piperazine derivatives and also intermediate products of this
process.
[0002] Compounds which are structurally similar to the compounds of
the present invention are already known from WO 98/57954, which
compounds are ascribed general properties which are antagonistic to
tachykinin, neurokinin A or alternatively neurokinin B and which
are capable of influencing the central nervous system (=CNS).
[0003] 2-Indolylmethyl-piperazine derivatives having a different
substitution pattern from the compounds of the present invention
and which have properties which are antagonistic to neurokinin
receptors are described in EP 0 899 270 A1.
[0004] Furthermore, additional 2-indolylmethyl-piperazine
derivatives having a different substitution pattern from the
compounds of the present invention are known from EP 0 655 442 A1
which are ascribed properties which generally are antagonistic to
tachykinin, neurokinin A or alternatively neurokinin B and which
are regarded as being suitable to influence the CNS.
SUMMARY OF THE INVENTION
[0005] It was an object of the present invention to provide novel
active substances having properties antagonistic to neurokinin
(=NK) receptors.
[0006] Another object of the invention was to provide compounds
with neurokinin receptor antagonistic properties and an improved
activity profile.
[0007] A further object of the invention was to provide compounds
with neurokinin receptor antagonistic properties which are suitable
for treating peripheral disturbances such as functional and
inflammatory disturbances of the gastrointestinal tract.
[0008] These and other objects of the invention have been achieved
by providing a compound corresponding to the formula I: 2
[0009] wherein
[0010] R.sup.1 is hydrogen or lower alkyl,
[0011] R.sup.2 is lower alkyl, di-lower-alkylamino lower alkyl,
lower-alkoxycarbonyl lower alkyl; cyclo(hetero)alkyl having 5-6
ring atoms, which may optionally be substituted once or twice by
lower alkyl and which optionally contains 1-2 double bonds;
(hetero)phenyl lower alkyl optionally substituted once or twice in
the (hetero)phenyl ring by halogen, lower alkyl and/or lower
alkoxy, the lower-alkyl chain of which (hetero)phenyl lower alkyl
is optionally substituted once or twice by lower alkyl or by
spiro-C.sub.4-C.sub.5-alkylene; or phenyl lower alkoxy optionally
substituted once or twice in the phenyl ring by halogen, lower
alkyl and/or lower alkoxy, and
[0012] R.sup.3 is lower alkyl, lower-alkoxycarbonyl lower alkyl or
cyclo(hetero)alkyl with 5-6 ring atoms which is optionally
substituted once or twice by lower alkyl, or
[0013] R.sup.2 and R.sup.3, together with the nitrogen to which
they are bonded, form a cyclic group of formula a: 3
[0014] wherein
[0015] A is nitrogen, oxygen, methylene or methylidene, the double
bond of which, together with the adjacent carbon, is formed in
position 3 of group a,
[0016] n is a whole number from 1 to 3,
[0017] R.sup.4 is hydrogen, lower alkyl, lower-alkoxy lower alkyl,
lower alkoxycarbonyl, lower-alkoxycarbonyl lower alkyl,
di-lower-alkylamino lower alkyl; (hetero)phenyl optionally
substituted once or twice by halogen, lower alkyl and/or lower
alkoxy; (hetero)phenyl lower alkyl optionally substituted once or
twice in the (hetero)phenyl ring by halogen, lower alkyl and/or
lower alkoxy, the lower-alkyl chain of which (hetero)phenyl lower
alkyl is optionally substituted once or twice by lower alkyl;
cyclo(hetero)alkyl with 5-6 ring atoms, or cyclo(hetero)alkyl lower
alkyl, the cyclo(hetero)alkyl group of which has 5-6 ring atoms,
and
[0018] R.sup.5 is hydrogen, lower alkyl or lower-alkoxy lower
alkyl, or
[0019] R.sup.4 and R.sup.5 together are spiroethylenedioxy bonded
to a carbon of group a; C.sub.3-C.sub.4-alkylene bonded to two
adjacent atoms of group a; or phenyl fused via two adjacent carbons
of group a, or
[0020] R.sup.2 and R.sup.3, together with the nitrogen to which
they are bonded, form a pyrrolidine ring which is substituted twice
by C.sub.4-alkylene which is bonded each time via two adjacent
carbon atoms,
[0021] or a physiologically compatible acid addition salts
thereof.
[0022] It has now surprisingly been discovered that one group of
novel N-triazolylmethyl-piperazine derivatives is distinguished by
specific properties antagonistic to NK-1 receptors and exerts its
action preferentially in the peripheral region. Accordingly, the
group of compounds according to the invention appears particularly
suitable for the treatment of peripheral disturbances induced by
NK-1, in particular for the treatment of functional and
inflammatory disturbances of the gastrointestinal tract.
[0023] The invention thus relates to new compounds corresponding to
the formula I: 4
[0024] wherein
[0025] R.sup.1 is hydrogen or lower alkyl,
[0026] R.sup.2 is lower alkyl, di-lower-alkylamino lower alkyl,
lower-alkoxycarbonyl lower alkyl; cyclo(hetero)alkyl having 5-6
ring atoms, which may optionally be substituted once or twice by
lower alkyl and which optionally contains 1-2 double bonds;
(hetero)phenyl lower alkyl optionally substituted once or twice in
the (hetero)phenyl ring by halogen, lower alkyl and/or lower
alkoxy, the lower-alkyl chain of which (hetero)phenyl lower alkyl
is optionally substituted once or twice by lower alkyl or by
spiro-C.sub.4-C.sub.5-alkylene; or phenyl lower alkoxy optionally
substituted once or twice in the phenyl ring by halogen, lower
alkyl and/or lower alkoxy, and
[0027] R.sup.3 is lower alkyl, lower-alkoxycarbonyl lower alkyl or
cyclo(hetero)alkyl with 5-6 ring atoms which is optionally
substituted once or twice by lower alkyl, or
[0028] R.sup.2 and R.sup.3, together with the nitrogen to which
they are bonded, form a cyclic group of formula a: 5
[0029] wherein
[0030] A is nitrogen, oxygen, methylene or methylidene, the double
bond of which, together with the adjacent carbon, is formed in
position 3 of group a,
[0031] n is a whole number from 1 to 3,
[0032] R.sup.4 is hydrogen, lower alkyl, lower-alkoxy lower alkyl,
lower alkoxycarbonyl, lower-alkoxycarbonyl lower alkyl,
di-lower-alkylamino lower alkyl; (hetero)phenyl optionally
substituted once or twice by halogen, lower alkyl and/or lower
alkoxy; (hetero)phenyl lower alkyl optionally substituted once or
twice in the (hetero)phenyl ring by halogen, lower alkyl and/or
lower alkoxy, the lower-alkyl chain of which (hetero)phenyl lower
alkyl is optionally substituted once or twice by lower alkyl;
cyclo(hetero)alkyl with 5-6 ring atoms, or cyclo(hetero)alkyl lower
alkyl, the cyclo(hetero)alkyl group of which has 5-6 ring atoms,
and
[0033] R.sup.5 is hydrogen, lower alkyl or lower-alkoxy lower
alkyl, or
[0034] R.sup.4 and R.sup.5 together are spiroethylenedioxy bonded
to a carbon of group a, C.sub.3-C.sub.4-alkylene bonded to two
adjacent atoms of group a, or phenyl fused via two adjacent carbons
of group a; or
[0035] R.sup.2 and R.sup.3, together with the nitrogen to which
they are bonded, form a pyrrolidine ring which is substituted twice
by C.sub.4-alkylene which is bonded each time via two adjacent
carbon atoms,
[0036] and physiologically compatible acid addition salts of
compounds of Formula I.
[0037] Furthermore, the invention also relates to pharmaceutical
compositions containing the compounds of Formula I.
[0038] In addition, the invention relates to a process for
preparing the compounds of Formula I and intermediate products of
this process.
[0039] Whenever in the compounds of Formula I the substituents are
or contain lower alkyl or alkoxy groups, these may be
straight-chain or branched and contain 1 to 4 carbon atoms.
[0040] Whenever the substituents contain halogen, in particular
fluorine, chlorine or bromine, preferably fluorine or chlorine, are
used.
[0041] Whenever the substituents of the compounds of Formula I are
or contain cyclo(hetero)alkyl, this may be a pure carbocyclic
group, or it may also represent carbocyclic compounds in which in
each case 1 to 3 ring carbon atoms are replaced by nitrogen, oxygen
and/or sulfur. Nitrogen and oxygen are preferred heteroatoms.
[0042] Whenever the substituents of the compounds of Formula I are
or contain (hetero)phenyl, this may stand for phenyl, or may also
represent phenyl wherein in each case 1 to 3 ring carbon atoms are
replaced by nitrogen.
[0043] Whenever the substituents of the compounds of Formula I are
or contain heterophenyl, this stands for phenyl in which in each
case 1 to 3 ring carbon atoms are replaced by nitrogen.
[0044] R.sup.1 preferably stands for hydrogen. Where R.sup.1 stands
for lower alkyl, methyl is preferred.
[0045] R.sup.2 preferably stands for lower alkyl, in particular
methyl, ethyl, isopropyl or tert. butyl; for di-lower-alkylamino
lower-alkyl, in particular dimethylaminoethyl or
dimethylamino-n-propyl; for lower-alkoxycarbonyl lower alkyl, in
particular ethoxycarbonylmethyl; for cyclo(hetero)alkyl having 5 to
6 ring atoms, optionally substituted once by lower alkyl, in
particular methyl, in particular for optionally substituted
cyclopentyl, cyclohexyl or piperidinyl; for heterophenyl lower
alkyl optionally substituted once or twice in the heterophenyl ring
by lower alkyl, in particular methyl, or by lower alkoxy, in
particular methoxy, in particular for optionally substituted
pyridyl; or for phenyl-C.sub.2-C.sub.4-alkyl substituted once or
twice in the phenyl ring by lower alkyl, in particular methyl, or
by lower alkoxy, in particular methoxy.
[0046] R.sup.3 preferably represents lower alkyl, in particular
methyl, ethyl or isopropyl; or for lower-alkoxycarbonyl lower
alkyl, in particular ethoxycarbonylmethyl.
[0047] Those compounds of Formula I wherein R.sup.2 and R.sup.3 are
not simultaneously isobutyl are preferred.
[0048] Whenever R.sup.2 and R.sup.3, together with the nitrogen to
which they are bonded, form a group of formula a, R.sup.4
preferably stands for hydrogen; for lower alkyl, in particular
methyl or isopropyl; for lower-alkoxy lower alkyl, in particular
methoxymethyl; for lower-alkoxycarbonyl lower alkyl, in particular
ethoxycarbonylmethyl; for di-lower-alkylamino lower alkyl, in
particular dimethylaminoethyl; for (hetero)phenyl optionally
substituted once by lower alkyl, in particular methyl, or by lower
alkoxy, in particular methoxy, in particular for optionally
substituted phenyl, pyridyl, pyrimidyl or pyrazolyl; for
(hetero)phenyl lower alkyl optionally substituted once in the
(hetero)phenyl ring by halogen, lower alkyl, in particular methyl,
or by lower alkoxy, in particular methoxy, in particular for
optionally substituted benzyl or pyridyl lower alkyl; for
cyclo(hetero)alkyl having 5 to 6 ring atoms, in particular for
cyclohexyl, pyrrolidinyl or piperidinyl; or for cyclo(hetero)alkyl
lower alkyl, the cyclo(hetero)alkyl ring of which has 5 to 6 ring
atoms, in particular for pyrrolidinyl-C.sub.1-C.sub.2-alkyl,
morpholinoethyl or cyclohexylmethyl.
[0049] In any group of Formula a which may be present, R.sup.5
preferably stands for hydrogen; for lower alkyl, in particular
methyl; or for lower-alkoxy lower alkyl, in particular
methoxymethyl.
[0050] Preferred compounds of Formula I are those in which in any
group of Formula a which may be present, R.sup.4 and R.sup.5 are
not bonded to the same atom of group a, with the exception of the
preferred compounds of Formula I in which R.sup.4 and R.sup.5
together are spiroethylenedioxy bonded to a carbon of group a.
Likewise, compounds of Formula I are preferred in which R.sup.4 and
R.sup.5 are C.sub.3-C.sub.4-alkylene bonded to two adjacent ring
atoms of group a.
[0051] In any group of Formula a which may be present, n stands for
a whole number from 1 to 3. Where R.sup.4 and R.sup.5 are both
hydrogen and at the same time A stands for methylene, n preferably
stands for 2 or 3.
[0052] Generally, the substituents R.sup.4 and R.sup.5 of group a
may be bonded to each ring atom of the group, including the ring
atoms formed by A, which do not stand for oxygen. Where a ring atom
of group a is substituted by R.sup.4 or R.sup.5, R.sup.4 or R.sup.5
replaces a hydrogen atom otherwise present at the same place, so
that the usual valencies of the ring atoms of group a are retained.
Where A stands for methylidene, the double bond thereof is
preferably formed with the adjacent carbon in position 3 of group
a, which in this case likewise forms a methylidene group.
[0053] Preferred are compounds of Formula I, in which an optionally
present group a stands for pyrrolidine substituted by R.sup.4 and
R.sup.5, wherein R.sup.4 and R.sup.5 are not both simultaneously
hydrogen, or wherein an optionally present group a stands for
2,5-dihydropyrrole, piperidine, piperazine, morpholine or diazepan,
each substituted by R.sup.4 and R.sup.5.
[0054] Particularly preferred is the compound
(2R)-1-[3,5-bis(trifluoromet-
hyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-{[5-(morpholinomethyl)-2H-1,2,3-tri-
azol-4-yl]methyl}piperazine of Formula I.
[0055] The compounds of Formula I and their acid addition salts may
be prepared by
[0056] a) reacting a compound corresponding to formula II: 6
[0057] wherein R.sup.1 has the above meaning, with a compound
corresponding to formula III: 7
[0058] wherein R.sup.2 and R.sup.3 have the above meanings, and
wherein any reactive groups present are blocked by suitable
protective groups, or
[0059] b) reacting a compound corresponding to formula IV: 8
[0060] wherein R.sup.1 has the above meaning, with a compound
corresponding to formula V: 9
[0061] wherein R.sup.2 and R.sup.3 have the above meanings, and
wherein any reactive groups present are blocked by suitable
protective groups,
[0062] and subsequently cleaving off any protective groups which
may be present. If desired, a resulting compound of Formula I may
be converted into a corresponding acid addition salt, or an acid
addition salt may be converted into a free compound of Formula
I.
[0063] According to process variant a), a secondary amino function
of a substituted piperazine derivative of Formula II can be reacted
with an N,N-disubstituted azidobutinamine of Formula III to obtain
a compound of Formula I. The reaction can be carried out in a
solvent which is inert under the reaction conditions, such as a
dipolar-aprotic solvent, for example ethyl acetate or dimethyl
formamide (=DMF), or preferably in a mixture of such solvents. A
mixture of ethyl acetate and DMF is particularly preferred.
Suitable reaction temperatures are between room temperature and the
boiling temperature of the solvent or of the solvent mixture. Where
compounds of Formula III are used which have additional functional
groups which are reactive under the reaction conditions, these
additional functional groups are expediently blocked by known
protective groups. Suitable protective groups, which can be
introduced using known methods and later can be cleaved off again
using known methods, are known, for example, from J. A. W. McOmie
"Protective Groups in Organic Chemistry", Plenum Press 1973, or
from T. W. Green and P. G. M. Wuts "Protective Groups in Organic
Synthesis", Wiley and Sons 1991. The person skilled in the art can
select suitable protective groups for each case by routine
methods.
[0064] The compounds of Formula II and their stereoisomeric forms
are known from EP 0 655 442 A1, and can be prepared according to
the processes described in this patent application or analogously
to these processes.
[0065] Compounds of Formula III can be prepared by reacting a
compound of formula VI: 10
[0066] wherein R.sup.2 and R.sup.3 have the above meanings and Y
stands for a cleavable leaving group, with an alkali metal azide,
preferably sodium azide, in a manner known for azide formation.
Suitable leaving groups Y include, in particular, halogen,
preferably chlorine, or alternatively sulfonyloxy groups, which
form good leaving groups, for example lower-alkane sulfonyloxy such
as methanesulfonyloxy, or benzenesulfonyloxy optionally substituted
in the benzene ring by halogen or lower alkyl, such as
p-toluenesulfonyloxy.
[0067] Compounds of Formula VI can be prepared by reacting a
compound of Formula V in known manner with a compound corresponding
to formula VII: 11
[0068] wherein Y has the above meaning. Resulting compounds of
Formula VI may also be purified if desired. For purification,
compounds of Formula VI may for example be converted into suitable
salts, such as oxalates, and be purified according to known
crystallisation methods. The above salts of the compounds of
Formula VI may also be used directly for further reactions.
[0069] Secondary amines of Formula V are known per se. The
compounds of Formula VII are likewise known per se. Preferably
1,4-dichloro-2-butine can be used as the compound of Formula
VII.
[0070] According to process variant b), a piperazine-N-butinazide
of Formula IV may be reacted with a secondary amine of Formula V to
obtain a compound of Formula I. The reaction can be performed in
known manner, for example in accordance with a method known from K.
Banert, Chemische Berichte 122 (1989) 1963-1967 or by methods
analogous thereto, in a solvent which is inert under the reaction
conditions such as ethyl acetate or an ether, for example
tetrahydrofuran (=THF) or dioxane. If applicable, in a preferred
process variant the secondary amine of Formula V itself, for
example morpholine, may be used as solvent. A suitable reaction
temperature must be selected depending on the secondary amine of
Formula V which is used. If the amine of Formula V is liquid or
solid at room temperature, usually operation is possible at
temperatures between room temperature and the boiling point of
conventional solvents, for example up to 100.degree. C. Where
readily volatile amines of Formula V are used, for example
dimethylamine or diethylamine, it is advantageous to operate at low
temperatures, for example between -78.degree. C. and -10.degree.
C., and preferably at elevated pressure, for example at 1.5 to 3
bar. Reactions at elevated pressure can be performed in known
autoclaves. Where amines of Formula V are used which have
additional functional groups which are reactive under the reaction
conditions--for example a secondary amino function, if piperazine
is used--these additional functional groups are desirably blocked
by known protective groups. Suitable protective groups, which can
be introduced using known methods and later can be cleaved off
again using known methods, are known, for example, from the
publications mentioned above in process variant a). Where
piperazine is used as the amine of Formula V, the tert.
butoxycarbonyl group is preferred as protective group. Persons
skilled in the art can select suitable protective groups for each
case by routine methods.
[0071] Compounds of Formula IV are novel compounds which are
suitable as intermediate products for the preparation of novel
active substances, for example for the preparation of the compounds
of Formula I. The compounds of Formula IV can be prepared by
reacting compounds of the formula VIII: 12
[0072] wherein R.sup.1 and Y have the above meanings,
[0073] with an alkali metal azide, preferably sodium azide, in a
manner known for azide formation.
[0074] Compounds of Formula VIII can be prepared by reacting
compounds of Formula II with compounds of Formula VII in known
manner.
[0075] The compounds of Formula I may be isolated from the reaction
mixture and purified in known manner. Acid addition salts can be
converted into the free bases in conventional manner, and these may
if desired be converted in known manner into physiologically
compatible acid addition salts.
[0076] Physiologically compatible salts of compounds of Formula I
are their salts with inorganic acids, for example sulfuric acid,
phosphoric acids or hydrohalic acids, preferably hydrochloric acid,
or with organic acids, for example lower aliphatic monocarboxylic,
dicarboxylic or tricarboxylic acids such as maleic acid, fumaric
acid, lactic acid, tartaric acid, citric acid, or with sulfonic
acids, for example lower alkanesulfonic acids such as
methanesulfonic acid or benzenesulfonic acids optionally
substituted in the benzene ring by halogen or lower alkyl, such as
p-toluenesulfonic acid. A preferred salt of a compound of Formula I
is (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmet-
hyl)-4-{[5-(morpholinomethyl)-2H-1,2,3-triazol-4-yl]methyl}piperazine-dihy-
drochloride, since it is comparatively readily soluble in
water.
[0077] The compounds of Formula I at any rate contain a chiral
(asymmetric) carbon atom, namely the carbon atom bearing the
1H-indol-3-ylmethyl radical in position 2 of the piperazine parent
structure. The compounds of Formula I can thus exist in several
stereoisomeric forms. The present invention comprises both the
mixtures of optical isomers and the isomerically pure compounds of
Formula I. Preferred are compounds of Formula I in which the
indolylmethyl radical is located in position 2R of the piperazine
ring. If mixtures of optical isomers of the starting compound, for
example the compounds of Formula II or the compounds of Formula IV
are used in the synthesis of compounds of Formula I, the compounds
of Formula I are also obtained in the form of mixtures of optical
isomers. Starting from stereochemically uniform forms of the
starting compound, stereochemically uniform compounds of Formula I
can also be obtained. The stereochemically uniform compounds of
Formula I can be obtained from the mixtures of optical isomers by
known techniques, for example by chromatographic separation on
chiral separating materials or by reaction with suitable optically
active acids, for example tartaric acid or 10-camphorsulfonic acid,
and subsequent separation into their optically active antipodes by
fractional crystallisation of the resulting diastereomeric
salts.
[0078] In the compounds of Formula I, the 1,2,3-triazole ring may
be present in several tautomeric forms, so the hydrogen atom may be
bonded to different atoms of the 1,2,3-triazole ring. Within the
scope of the present invention, the compounds of Formula I should
jointly comprise all possible tautomers of the triazole ring.
[0079] The compounds of Formula I and their acid addition salts
have properties which are antagonistic to neurokinin (=NK)
receptors and are suitable for the treatment of pathological
conditions in larger mammals, particularly humans, in which
neurokinins are involved as transfer agents. In this case, the
group of compounds according to the invention is distinguished by a
particularly beneficial action profile which is characterised by a
high selective affinity to NK-1 receptors. Furthermore, the group
of compounds according to the invention is distinguished by good
compatibility even over prolonged periods of administration, and by
comparatively good oral bioavailability.
[0080] Due to their activity profile and to their selective and
reversible ability to bond to NK-1-receptors, the compounds
according to the invention are particularly suitable for inhibiting
processes involving neurokinins, such as Substance P, which bind to
NK-1 receptors. Thus the compounds are selectively suitable for the
treatment of pathological conditions in which Substance P is
involved. Substance P plays a part, for example, in the
transmission of pain, emesis, neurogenic inflammations, bladder
inflammation, inflammatory joint diseases and asthmatic complaints.
Owing to the action which is advantageously directed at the
peripheral region, the action profile of the compounds is suitable
for the treatment of peripheral pathological disturbances, in
particular for the treatment of functional and inflammatory
disturbances in the gastrointestinal tract. The functional
disturbances which can be treated by the compounds according to the
invention include in particular the disturbances of the lower
intestinal tracts known as so-called "irritable bowel syndrome"
(=IBS). The essential symptoms of IBS are pains in the lower
abdomen, which appear to be due to hypersensitivity of the visceral
afferent nervous system, and anomalies in bowel movement, in
particular abnormally accelerated passage of the stool in the
colon. The increased visceral sensitivity to pain with respect to
mechanical or chemical irritants in the intestinal tract results in
IBS patients suffering severe visceral pains even upon only
physiological slight distension of the colon owing to digestion,
e.g. even upon slight gas formation and slight flatulence, which
are scarcely noticed by healthy individuals. Inflammatory
disturbances in the gastrointestinal tract which can be favourably
influenced by the compounds according to the invention include the
inflammatory disturbances in the small intestine and large
intestine regions generally grouped under the term IBD
(=inflammatory bowel disease), including ulcerative colitis and
Crohn's disease. The action profile of the compounds is
distinguished by comparatively good oral bioavailability with
beneficial selectivity of the actions antagonistic to neurokinin
receptors with respect to unwanted side-effects, particularly in
therapeutic procedures directed at the peripheral region. Thus, in
dose ranges which block the NK-1 receptor, in pharmacological tests
no cardiovascular calcium-antagonistic action was detected.
Furthermore, it can be assumed of the compounds according to the
invention that they have no significant side-effects on the central
nervous system.
[0081] Description of the Pharmacological Test Methods
[0082] The example numbers given for the compounds used as test
substances in the pharmacological tests relate to the subsequent
preparation examples.
[0083] 1. Determination of the Binding Power of the Test Substances
to NK-1 Receptors In Vitro.
[0084] The affinity of the test substances to human NK-1 receptors
was measured in vitro. The inhibition of the binding of the
physiological neurokinin (Substance P) to neurokinin-1 receptors
was determined.
[0085] The receptor binding studies were performed with
[.sup.3H]-Substance P as ligand. For the binding test, different
samples of a membrane preparation of CHO cells (=egg cells of the
Chinese hamster, Chinese hamster oocytes), which express the human
NK-1 receptor ("Accession Number" of the associated nucleic acid
sequence=M74290; "Accession Number" of the associated protein
sequence=P25103; cf. Takeda, Y.; Chou, K. B., Takeda, J.; Sachais,
B. S. and Krause, J. E; Biochemical and Biophysical Research
Communications, 179(3) (1991) 1232-1240) were incubated with a
solution of the marked ligand, with the incubation mixtures
containing no test substance or additions of different
concentrations of test substance. Then, separation of bound and
free ligands was performed in each of the samples with the aid of
glass-fibre filtration. The fraction remaining in the filter was
washed several times with buffer solution and then the
radioactivity of the fraction remaining in the filter was measured
using a beta scintillation counter.
[0086] For the compounds of Examples 1 and 8 to 65, the affinity to
human NK-1 receptors was determined in each case by a single
measurement of the test substances in a concentration of 10.sup.-7
mol/l. All the above test substances in this test model exhibited
displacement of the physiological NK-receptor ligand Substance P of
.gtoreq.75%. The compounds of Examples 1, 8-15, 17-29, 34-47,
49-55, 57, 59-60 and 62-65 each exhibited a displacement of
.gtoreq.90%.
[0087] For the compounds of Examples 2 and 4-6, that concentration
which effects half maximum displacement of the bound ligand was
determined as IC.sub.50 of the respective test substance. From
this, the corresponding inhibition constant (K.sub.i value) of the
test substance was calculated, and was stated as the negative
common logarithm of the K.sub.i value (=pK.sub.i value). The
pK.sub.i avalue is a measurement of the affinity of the test
substances to human NK-1 receptors. In this test model, the test
substances set forth in the following Table 1 exhibited the given
pK.sub.i values:
1TABLE 1 Affinity of the test substances to human NK-1 receptors
Example No. pKi 2 8.4 4 8.3 5 8.3 6 8.4
[0088] 2. Determination of the Functional NK-1 Antagonism of the
Test Substances on Isolated Guinea Pig Tissue In Vitro.
[0089] The action antagonistic to NK-1 receptors of the test
substances was measured in vitro on isolated ring preparations,
kept in an oxygenated nutrient solution, of the aortas of
Pirbright-White guinea pigs. The inhibition by the test substances
of the relaxation of tone of the aorta preparations, caused after
stimulation with the NK-1 agonist Substance P, was determined.
[0090] In order to measure the contraction of the vessel muscles,
the preparations were fixed to a hook, joined by a thread to a
force measuring apparatus and the contractions were recorded in
each case on a plotter. The aorta preparations were tonicised with
phenylephrine. Then before and after the administration of the test
substance the NK-1 receptors of the preparations were stimulated
with 0.01 .mu.mol Substance P, which caused relaxation of the tone.
The relaxations before and after the administration of the test
substance were quantified in percent. The effective concentration
of the half maximum inhibition of the relaxation of the tone
(=EC.sub.50) was calculated. The negative common logarithm of the
EC.sub.50 value (=pEC.sub.50) was given as characteristic variable.
The pEC.sub.50 value is a measurement of the functional
effectiveness of the test substances on NK-1 receptors. In this
test model, the test substances set forth in the following Table 2
exhibited the given pEC.sub.50 values:
2TABLE 2 Functional NK-1 antagonism of the test substances on
isolated guinea pig tissue. Example No. pEC.sub.50 1 9.0 2 9.1 3
8.4 4 8.6 5 8.7 6 8.9
[0091] 3. Determination of the Substance-P-antagonistic Action of
the Test Substances In Vivo.
[0092] In order to demonstrate the substance-P-antagonistic action
of the test substances, the transient hypotension caused by
intravenous (=i.v.) administration of Substance P in guinea pigs
was used as the standard test model for Substance P-induced
pharmacological effects. The inhibiting effect of the test
substances was determined with respect to vasodepression induced by
Substance P on one hand after i.v. and on the other hand after oral
(=p.o.) administration of the test substances.
[0093] Male guinea pigs each had a catheter implanted in a common
carotid artery and a jugular vein under anaesthesia (ketamine 67
mg/kg, xylazine 13 mg/kg). The arterial catheter served to measure
the blood pressure. The administration of Substance P and, in the
case of i.v. administration, also the administration of the test
substance, was effected by means of the venous access. After a
20-minute equilibration phase, 50 pmol/animal of Substance P were
administered (bolus, i.v.) as a test stimulus. One minute after
administration of the test stimulus, in each case the maximum drop
in blood pressure induced thereby was determined as a control for
the later stimulation of the NK-1 receptors by the test substance.
Then the test substance was administered. For the i.v.
investigation, the test substance was administered in metered doses
of 0.01 to 0.1 .mu.mol/kg. For the p.o. investigation, the test
substance was administered in metered doses of 0.1 to 3.2
.mu.mol/kg. Tylose or Tylose/ethanol was used as the vehicle for
the p.o. investigations. Then, in each case the extent of the
vasodepression inhibited by the test substance was measured,
starting 1 minute after administration of test substance, up to 90
minutes after administration of test substance, at intervals of 15
minutes each time. The doses at which, dependent on the time, just
50% inhibition of the Substance P-induced vasodepression occurs due
to the test substance were determined from these measured values as
ED.sub.50 values. The negative common logarithm of the ED.sub.50
value (=pED.sub.50) was given as characteristic variable.
[0094] In this test model, the test substance of Example 1
exhibited a pED.sub.50 value of 7.6 one hour after i.v.
administration. The same test substance of Example 1 showed a
pED.sub.50 value of 6.2 one hour after p.o. administration. The
compound of Example 6 showed a pED.sub.50 value of 7.0 one hour
after i.v. administration. These values prove the high
pharmacological potency of the compounds of Formula I, in
particular also for oral administration.
[0095] In the same test model, the test substances were also
investigated for vasodepressive effects based on
calcium-antagonistic properties. To this end, the action of the
test substances on the basal blood pressure was investigated. The
substance of Example 1 exhibited no significant vasodepression in
the dose range investigated (i.v. doses of up to 0.1 .mu.mol/kg and
p.o. doses of up to 3.2 .mu.mol/kg). This is an indication that no
calcium-antagonistic side-effects occurred in this dose range. The
low calcium-antagonistic side-effects of the compounds according to
the invention can also be demonstrated by in vitro standard test
models, for example on isolated ileum tissue of guinea pigs.
[0096] In a standard test to determine CNS-permeable compounds
having an NK-1-antagonistic effect ("gerbil foot tapping test", cf.
N. M. Rupniak, A. R. Williams, European Journal of Pharmacology 265
(1994) 179-183), the compound of Example 1 did not exhibit any
typical effects of CNS-permeable NK-1 antagonists even at high
doses of up to 30 mg/kg p. o.
[0097] The compounds of Formula I may be administered in
conventional pharmaceutical preparations. The doses to be used may
vary individually and will naturally vary according to the type of
condition to be treated and the substance used. In general,
however, medicinal forms with an active substance content of 0.1 to
80 mg, in particular 1 to 10 mg, active substance per individual
dose are suitable for administration to humans and larger
mammals.
[0098] The compounds may be contained according to the invention,
together with conventional pharmaceutical auxiliaries and/or
carriers, in solid or liquid pharmaceutical preparations. Examples
of solid preparations are preparations which can be administered
orally, such as tablets, coated tablets, capsules, powders or
granules, or alternatively suppositories. These preparations may
contain conventional pharmaceutical inorganic and/or organic
carriers, such as talcum, lactose or starch, in addition to
conventional pharmaceutical auxiliaries, for example lubricants or
tablet disintegrating agents. Liquid preparations such as
suspensions or emulsions of the active substances may contain the
usual diluents such as water, oils and/or suspension agents such as
polyethylene glycols and the like. Other auxiliaries may
additionally be added, such as preservatives, taste correctives and
the like.
[0099] The active substances may be mixed and formulated with the
pharmaceutical auxiliaries and/or carriers in known manner. For the
production of solid medicament forms, the active substances may for
example be mixed with the auxiliaries and/or carriers in
conventional manner and may be wet or dry granulated. The granules
or powder can be poured directly into capsules or be pressed into
tablet cores in conventional manner. These can be coated in known
manner if desired.
[0100] The following examples are intended to illustrate the
invention in further detail, without limiting its scope.
EXAMPLE 1
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-{[5-(mo-
rpholinomethyl)-2H-1,2,3-triazol-4-yl]methyl}piperazine
[0101] Synthesis Method 1
[0102] A) 22 ml 1,4-dichloro-2-butine was added to a suspension of
43 g K.sub.2CO.sub.3 in 100 ml DMF at 20.degree. C. under a
protective gas atmosphere. The mixture was heated to 50.degree. C.
and then a solution of 50 g
(2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(1H-indol-3-ylmethyl)-
piperazine in 200 ml DMF was added dropwise to this receiving
solution. The resulting mixture was stirred for 5 hours at
50.degree. C. Stirring was continued overnight at room temperature,
undissolved precipitate was filtered out, and the precipitate was
washed twice with 200 ml portions of ethyl acetate. The combined
filtrates were evaporated to dryness in a vacuum, and the resulting
oil was purified by column chromatography (silica gel; mobile
solvent: n-hexane/ethyl acetate 60/40 to 30/70). The combined
product fractions were again evaporated to dryness. 40.4 g of
(2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]2-(1H-indol-3-ylmethyl]-4-(4-chl-
oro-2-butin-1-yl)piperazine was obtained as an amorphous yellowish
solid, which was used for the next synthesis stage without further
purification.
[0103] B) 5.76 g NaN.sub.3 were added to a solution of 40.0 g of
the chlorobutinyl-piperazine derivative obtained above under 1A) in
200 ml dimethyl sulfoxide (=DMSO) at room temperature and under a
protective gas atmosphere. The resulting mixture was stirred
further for 24 hours under a protective gas atmosphere at room
temperature. A solution of 50 g ammonium chloride in 300 ml water
was added to this receiving solution. Then the aqueous phase was
extracted with 500 ml methyl-tert. butyl ether (=MTBE). The organic
phase was washed in succession with 200 ml saturated common salt
solution and 200 ml water, dried over sodium sulfate and finally
evaporated to dryness in a vacuum. The remaining yellowish foam was
purified by column chromatography (silica gel; mobile solvent:
ethyl acetate/n-hexane 65/35 to 80/20). The combined product
fractions were again evaporated to dryness. 33.2 g
(2R)-1-[3,5-bis(trifluoromethyl)benzo-
yl]2-(1H-indol-3-ylmethyl]-4-(4-azido-2-butin-1-yl)piperazine were
obtained as a yellowish solid, which was used for the next
synthesis stage without further purification.
[0104] C) 25.5 g of the azido derivative obtained above under 1B)
were dissolved in 10 ml morpholine and were heated to 80.degree. C.
for 4 hours under a protective gas atmosphere. The reaction mixture
was stirred further overnight at room temperature and was then
evaporated to dryness in a vacuum. The residue was taken up in 500
ml ethyl acetate and again evaporated to dryness in a vacuum. The
resulting foam was purified by column chromatography (silica gel;
mobile solvent: ethyl acetate/ethanol 100/0 to 85/15). The combined
product fractions were evaporated to dryness. 22.0 g of the title
compound were obtained as a yellowish amorphous solid, melting
point=92.degree. to 98.degree. C. (glass transition temperature),
[.alpha.].sub.D.sup.20=5.degree. (c=1.0 in methanol).
[0105] D) 20 ml absolute ethanol were added to a solution of 39.0 g
of the title compound obtained above under 1C) in 100 ml MTBE under
a protective gas atmosphere. The resulting reaction mixture was
heated to 40.degree. to 50.degree. C. and 81 ml of a 1.6 N HCl in
isopropanol was added to this receiving solution. The reaction
mixture was stirred for another 10 minutes at 50.degree. C. Then
1,000 ml MTBE were added slowly, whereupon the salt began to
precipitate. Stirring was continued for 2 hours at room temperature
to complete the precipitation, the precipitate was filtered out
from the liquid phase and the salt was washed twice with MTBE.
After drying in a vacuum, 39.5 g of the solid title compound was
obtained as a white to beige dihydrochloride, melting
point.=213.degree. to 216.degree. C.;
[.alpha.].sub.D.sup.20=-3.60.degree. (c=1.0 in methanol).
[0106] Synthesis Method 2
[0107] A) 17.0 ml of 1,4-dichloro-2-butine were dissolved in 100 ml
toluene under a protective gas atmosphere, and 42.6 g
K.sub.2CO.sub.3 were added to the solution. Once the resulting
suspension had been heated to 50.degree. C., a solution of 10 ml
morpholine in 100 ml toluene was slowly added dropwise to this
receiving solution. The resulting reaction mixture was stirred for
another 5 hours at 50.degree. C. and then overnight at room
temperature. The K.sub.2CO.sub.3 was filtered out, subsequently
washed twice with 100 ml toluene each time and the combined
filtrates were reduced in a vacuum. The residue was taken up with
about 100 ml toluene and the organic phase was washed in succession
with saturated aqueous solutions of NaHCO.sub.3 and NaCl. The
organic phase was evaporated to dryness in a vacuum. 14.3 g crude
1-(4-chloro-2-butin-1-yl)morpholine was obtained as an oil, which
was converted into the monooxalate for purification.
[0108] For purification, 14.0 g of the crude compound obtained
above were taken up in 80 ml MTBE. The precipitate was filtered out
and subsequently washed twice with 100 ml portions of MTBE. The
combined filtrates were heated to 50.degree. C. under a protective
gas atmosphere. A solution at 50.degree. C. of 10.0 g oxalic acid
in 40 ml ethanol was added to this receiving solution. After
cooling to room temperature, the reaction mixture was stirred
overnight. The resulting oxalate was filtered out, and the solid
was subsequently washed three more times with 20 ml portions of
MTBE. 13.0 g [1-(4-chloro-2-butin-1-yl)morpholine]-monooxalat- e
were obtained, melting point=144-146.degree. C.
[0109] B) 510 g of the oxalic acid salt obtained above under
Example 1/Synthesis method 2A) were dissolved in 10 ml DMF at room
temperature under a protective gas atmosphere. 154 mg NaN.sub.3
were added to this receiving solution, and the solution was stirred
for 10 minutes. Then 0.6 ml triethylamine was added. The resulting
suspension was stirred further for another 15 hours, and the
resulting 1-(4-azido-2-butin-1-yl)morpholin- e was used directly in
the suspension without further working-up or characterization for
the next synthesis stage.
[0110] C) The suspension of the azido compound obtained above under
Example 1/Synthesis method 2B) was diluted with 60 ml ethyl
acetate. 1.5 ml of a 55% by weight solution of (2R)-1-[3,5-bis
(trifluoromethyl)benzoy- l]-2-(1H-indol-3-ylmethyl)piperazine in
THF were added to this receiving solution, and the resulting
mixture was heated to boiling point for 15 hours and was then
stirred further for another 3 days at room temperature. The
resulting solution was washed 3 times with 50 ml portions of water,
and the organic phase was dried over sodium sulfate. The residue
remaining after evaporation and drying in a high vacuum was
identified as the title compound by combined liquid
chromatography/mass spectroscopy (=LC/MS).
EXAMPLE 2
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-{[5-(pi-
perazinomethyl)-2H-1,2,3-triazol-4-yl) ]methyl }piperazine
[0111] A) 1.0 g
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylm-
ethyl)-4-[4-azido-2-butin-1-yl]piperazine (for preparation see
Example 1/Synthesis method 1B)) was dissolved in 50 ml ethyl
acetate under a protective gas atmosphere. 0.4 g tert.
butoxycarbonylpiperazine was added to this receiving solution, and
the resulting reaction mixture was heated for 8 hours to 80.degree.
C. under reflux cooling. Stirring was effected overnight at room
temperature, and the organic phase was then washed three times with
10 ml portions of water. The organic phase was dried over sodium
sulfate and evaporated to dryness in a vacuum. 1.4 g
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1-methyl-indol-3-ylmethyl)-4--
{[5-(4-tert.
butoxycarbonylpiperazin-1-yl)-2H-1,2,3-triazol-4-yl]methyl}pi-
perazine was obtained as a yellowy-brown foam, which was used
directly for the next synthesis stage without further
purification.
[0112] B) 330 mg of the compound obtained above under 2A) was
dissolved in 10 ml methanol. 10 ml of a 1.5 N HCl solution in
isopropanol was added to this receiving solution, and the resulting
reaction mixture was stirred overnight at room temperature. A
solution of 0.4 g NaOH in 10 ml water was then added to this
receiving solution. Evaporation virtually to dryness was effected
in a vacuum, and the residue was extracted with 50 ml
CH.sub.2Cl.sub.2. The organic phase was washed with 100 ml water
and evaporated to dryness in a vacuum. 270 mg of a hydrochloric
acid salt of the title compound were obtained as a foam, melting
point >200.degree. C.
[0113] EXAMPLE 3
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1-methyl-indol-3-methyl)-4-{[5-
-(morpholinomethyl)-2H-1,2,3-triazol-4-yl)]methyl}piperazine
[0114] A) First 50 ml of a 55% by weight solution of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-piperazi-
ne in THF and then 25 ml water were added to a suspension of 7.4 g
K.sub.2CO.sub.3 in 150 ml THF. A solution of 12.2 g tert.
butoxycarbonyl anhydride in 50 ml THF was added to this receiving
solution, and the mixture was stirred for 12 hours at room
temperature. After reduction of the reaction mixture in a vacuum,
the residue was taken up in 300 ml MTBE, and the organic phase was
washed, in succession, twice with 100 ml portions of water, once
with 50 ml of a 15% by weight aqueous tartaric acid solution and
another four times with 100 ml portions of water, and then dried
over sodium sulfate/SiO.sub.2. After filtering out the drying
agent, the filtrate was reduced in a vacuum, and the residue was
taken up in 20 ml MTBE. After heating to 60.degree. C., 120 ml
ligroin was added, and the volume was then reduced by approximately
100 ml by vacuum distillation. After another addition of 100 ml
ligroin, the mixture was left to stand for 3 days to precipitate.
The precipitated solid was filtered out, washed three times more
with 30 ml portions of ligroin and dried at 60.degree. C. in a
vacuum. 82.0 g of (2R)-1-[3,5-bis(trifluorome-
thyl)benzoyl]-2-(1H-indol-3-ylmethyl]-4-(tert.
butoxycarbonyl)piperazine were obtained as a solid, melting
point=155-156.degree. C.
[0115] B) 5.0 g of the BOC-protected piperazine derivative obtained
above under 3A) were dissolved in 100 ml dry DMF at room
temperature under a protective gas atmosphere. 0.2 g NaH (60%
strength in mineral oil) was added to this receiving solution and
the solution was stirred further for 10 minutes. Then a solution of
1.9 ml CH.sub.3I in 5 ml DMF was added dropwise, and stirring was
continued for 4 hours at room temperature once addition had been
completed. The reaction mixture was poured on to a mixture of 100 g
ice, 18 g Na.sub.2S.sub.2O.sub.3 and 50 ml water. The aqueous phase
was extracted with a mixture of 200 ml ethyl acetate and 100 ml
MTBE. The organic phase was washed once with water and was
evaporated to dryness in a vacuum. The oily residue was taken up in
100 ml methanol, washed with 50 ml diethylether and again
evaporated to dryness. 5.5 g
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1-methyl-indol-
-3-ylmethyl)-4-(tert. butoxycarbonyl)piperazine was obtained as a
glassy solid, which was used directly for the next synthesis stage
without purification or characterization.
[0116] C) 5.9 g of the indolyl-N-methylated piperazine derivative
obtained above under 3B) were dissolved in 60 ml methanol. A total
of 10 ml of an aqueous 1N HCl solution was added slowly to this
receiving solution and was stirred for 48 hours at room
temperature. The reaction mixture was taken up in 100 ml methanol
and washed twice with 20 ml portions of n-hexane. The methanol
phase was reduced in a vacuum, and the residue was taken up in a
mixture of 100 ml water and 100 ml MTBE and left to stand
overnight. Then the organic phase was decanted off as supernatant
from the aqueous phase and extracted 3 times with 30 ml portions of
0.1 N aqueous HCl. The organic phase was neutralized with a
saturated aqueous solution of K.sub.2CO.sub.3, whereupon a first
fraction
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1-methyl-indol-3-ylmethyl)pip-
erazine was produced as an amorphous solid, which was purified by
conversion into the oxalate and subsequent neutralization back to
the base. A further solid fraction was obtained by neutralizing the
aqueous phase. The combined solid fractions, which were obtained by
filtration from the organic and the aqueous phase, were dried in a
high vacuum. A total of 4.6 g of the above de-protected
indolyl-N-methylated piperazine derivative was obtained.
[0117] D) 0.52 ml 1,4-dichloro-2-butine was reacted with 1.2 g of
the de-protected indolyl-N-methylated piperazine derivative
obtained above under 3C) as described under Example 1/Synthesis
method 1A). After chromatography (silica gel, mobile solvent: ethyl
acetate/n-hexane 65/35 to 80/20), 840 mg
(2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(1-methyl-i-
ndol-3-ylmethyl]-4-(4-chlor-2-butin-1-yl) was obtained as a foam,
which was used for the next synthesis stage without further
purification.
[0118] E) 820 mg of the chlorobutinyl-piperazine derivative
obtained above under 3D) were reacted with 130 mg NaN.sub.3 as
described under Example 1/Synthesis method 1B). 760 mg
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-
-[1-methyl-indol-3-ylmethyl]-4-[4-azido-2-butin-1-yl]piperazine
were obtained as a foam, which was used for the next synthesis
stage without further purification.
[0119] F) 740 mg of the azido compound obtained above under 3E)
were dissolved in 15 ml of morpholine. The reaction mixture was
worked up as described under Example 1/Synthesis method 1C). After
chromatography (silica gel, mobile solvent:
CH.sub.2Cl.sub.2/ethanol), 470 mg of the title compound were
obtained as a white solid, which was used for the next synthesis
stage without further purification.
[0120] G) 440 mg of the title compound obtained above under 3F)
were converted into the HCl salt with 1 ml of a 1.6 N HCl solution
in isopropanol as described under Example 1/Synthesis method 1D).
425 mg of the dihydrochloride monohydrate of the title compound
were obtained as a solid, melting point=192.degree.-200.degree.
C.
EXAMPLE 4
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-{[5-(di-
methylaminomethyl)-2H-1,2,3-triazol-4-yl]methyl}piperazine
[0121] 660 mg
(2R)-1-3,5-bis(trifluoromethyl)benzoyl)-2-(1H-indol-3-ylmeth-
yl)-4-[4-azido-2-butin-1-yl]piperazine (for preparation see Example
1/Synthesis method 1B)) were poured into an autoclave precooled to
-20.degree. C. To this there was added a solution, cooled to
-20.degree. C., of 2 moles dimethylamine in 30 ml THF. Once the
autoclave had been closed, the mixture was stirred for one day at
70.degree. C. and at a pressure of 2.0 to 2.2 bar. Then stirring
was continued overnight at room temperature under conditions which
were otherwise unchanged. The reaction mixture was evaporated to
dryness in a vacuum, and 700 mg of the title compound were obtained
as foam.
[0122] For salt formation, 680 mg of the title compound were
dissolved in 10 ml methanol. 1.5 ml of a 1.5N HCl solution in
isopropanol were added to this receiving solution, and it was then
evaporated to dryness under a high vacuum. The residue was taken up
twice in 20 ml portions of methanol and each time evaporated again
to dryness. The remaining residue was suspended in 10 ml MTBE and
heated to boiling point for 2 hours with reflux cooling. After
cooling to room temperature and subsequent filtration, the solid
precipitate was washed three times with 10 ml portions of MTBE and
dried under a high vacuum. 670 mg of a dihydrochloride dihydrate
salt of the title compound were obtained as an amorphous solid,
which was characterized, inter alia, by elemental analysis.
[0123] The compounds of Formula I set forth in the following Table
3 can also be prepared according to the processes described in the
above examples or by processes analogous thereto. Whenever in
Tables 3 and 4 below the substituents R.sup.2 and R.sup.3 together
stand for "a", R.sup.2 and R.sup.3, together with the nitrogen to
which they are bonded, form a cyclic group of formula a as
described above in which R.sup.4, R.sup.5, A and n each have the
meanings set forth in the tables.
3TABLE 3 Further compounds of formula I Configuration at Ex. the
indolyl- No. piperazine C - 2 R.sup.1 R.sup.2 R.sup.3 R.sup.4
R.sup.5 A n 5 R H Et Et -- -- -- -- 6 R H i-Pr i-Pr -- -- -- -- 7 S
H .alpha. H H O 2 Abbreviations used: i-Pr = isopropyl; Et =
ethyl
[0124] The following compounds of Examples 8 to 65 were prepared
using an automated preparation process. For this, per batch a
solution of 0.03 mmol
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(-
4-azido-2-butin-1-yl)piperazine of Formula IV (for preparation see
Example 1/Synthesis method 1B)) in 1 ml ethyl acetate was reacted
each time with a solution of 0.03 mmol of the secondary amine of
Formula V provided as reaction participant in 1 ml ethyl acetate
and then diluted with 3 ml ethyl acetate. Nitrogen gas was poured
on to the reaction mixtures and they were each stirred for 6 hours
at 70.degree. C. The end point of the reaction was determined by
thin-layer chromatography. Once the reaction was completed, the
individual reaction mixtures were each evaporated to dryness in a
vacuum. Samples were each taken from the residue without further
purification for high-performance liquid chromatography (=HPLC) and
for automatic mass spectroscopy to determine the purity and to
confirm the structure.
[0125] The compounds of Formula I set forth in the following Table
4 can be prepared using the automated preparation process referred
to above. All the compounds of Formula I listed in Table 4 have the
R configuration at the carbon C-2 of the piperazine structure which
bears the indolylmethyl radical.
4TABLE 4 Further compounds of the general formula I Ex. No. R.sup.1
R.sup.2 R.sup.3 R.sup.4 R.sup.5 A n 8 H c-C.sub.6H.sub.11 Me -- --
-- -- 9 H a H H HC.dbd. 1 10 H a 2-Me 5-Me CH.sub.2 1 11 H a 4-Me H
N(R.sup.4) 2 12 H a 4-BzI H N(R.sup.4) 2 13 H a 3-Me 5-Me O 2 14 H
a 4O--(CH.sub.2).sub.2--O.paren close-st..sub.4 CR.sup.4R.sup.5 2
15 H a H H CH.sub.2 2 16 H a 3-COCEt H CH.sub.2 2 17 H a
4-(pyridyl-2) H N(R.sup.4) 2 18 H --(CH.sub.2).sub.2-(pyridyl-2) Me
-- -- -- -- 19 H a 4-(piperidinyl-1) H CHR.sup.4 2 20 H
(1-Me-piperidinyl-4) Me -- -- -- -- 21 H --(CH.sub.2).sub.2--NMe.s-
ub.2 Me -- -- -- -- 22 H --(CH.sub.2).sub.3--NMe.sub.2 Me -- -- --
-- 23 H a 2-(pyridyl-3) H CH.sub.2 1 24 H --CH.sub.2-(pyridyl-3) Me
-- -- -- -- 25 H --CH.sub.2-(pyridyl-4) Et -- -- -- -- 26 H i-Pr
t-Bu -- -- -- -- 27 H a (2S)-COOt-Bu H CH.sub.2 1 28 H a
4-(pyrrolidinyl-1) H CHR.sup.4 2 29 H a 2-(CH.sub.2).sub.4-3
CH.sub.2 2 30 H a 2-(.dbd.CH--CH.dbd.CH--CH.dbd.)-3 .dbd.C.dbd. 2
31 H Bzl i-Pr -- -- -- -- 32 H i-Bu i-Bu -- -- -- -- 33 H
c-C.sub.6H.sub.11 c-C.sub.6H.sub.11 -- -- -- -- 34 H a
(2S)-CH.sub.2-(pyrrolidinyl-1- ) H CH.sub.2 1 35 H a
4-CH(CH.sub.3)--Phe H N(R.sup.4) 2 36 H a 4-CH.sub.2--C(O)OEt H
N(R.sup.4) 2 37 H a 4-(CH.sub.2).sub.2--Phe H N(R.sup.4) 2 38 H a
4-(pyrimidyl-2) H N(R.sup.4) 2 39 H a 4-(pyrazolyl-2) H N(R.sup.4)
2 40 H --CH.sub.2--C(O)OEt --CH.sub.2--C(O)OEt -- -- -- -- 41 H
t-Bu Me -- -- -- -- 42 H a 4-c-C.sub.6H.sub.11 H N(R.sup.4) 2 43 H
a 4-Me H N(R.sup.4) 3 44 H --(CH.sub.2).sub.2-[3,4-Di(OMe)--Phe] Me
-- -- -- -- 45 H a 4-i-Pr H N(R.sup.4) 2 46 H a
4-(CH.sub.2).sub.2-(morpholinyl-1) H N(R.sup.4) 2 47 H a
(2R)-CH.sub.2Ome (5R)-CH.sub.2OMe CH.sub.2 1 48 H
--CH.sub.2-(furanyl-2) 2-(CH.sub.2).sub.2C(O)OEt -- -- -- -- 49 H a
4-[(2-OMe--)Phe] H CHR.sup.4 1 50 H a 4-Bzl H N(R.sup.4) 3 51 H a
4-(4-F--Bzl) H N(R.sup.4) 2 52 H a 4-CH.sub.2-c-C.sub.6H.s- ub.11 H
N(R.sup.4) 2 53 H a 4-Phe H CHR.sup.4 2 54 H
2-(CH.sub.2).sub.2--Phe Me -- -- -- -- 55 H a 2-Me H CH.sub.2 1 56
H --(CH.sub.2).sub.2--O--(4-Cl--Phe) Me -- -- -- -- 57 H
c-C.sub.5H.sub.9 Me -- -- -- -- 58 H dodecahydro-1H-carbazolyl-1-
Me -- -- -- -- 59 H --CH.sub.2-(3-Me-pyridyl-2) Me -- -- -- -- 60 H
a 2-CH.sub.2--NEt.sub.2 H CH.sub.2 2 61 H a 3-Phe 3-Me CH.sub.2 2
62 H a 4-(6-Me-pyridyl-2) H N(R.sup.4) 2 63 H a
4-CH.sub.2-(Pyridyl-4) H N(R.sup.4) 2 64 H a
4-(CH.sub.2).sub.3-(pyrrolidinyl-1) H N(R.sup.4) 2 65 H a
4-(3-Me--Bzl) H N(R.sup.4) 2 Abbreviations used: c = cyclo; Me =
methyl; Et = ethyl Phe = phenyl; Bzl = benzyl; i-Pr = isopropyl;
i-Pu = isobutyl; t-Bu = tert. butyl.
EXAMPLE I:
Capsules containing
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-
-ylmethyl)-4-[(5-(morpholino-methyl)-2H-1,2,3-triazol-4-yl)methyl]piperazi-
ne
[0126] Capsules with the following composition per capsule were
produced:
5 (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2- 20 mg
(1H-indol-3-ylmethyl)-4-[(5-(morpholinomethyl)-
2H-1,2,3-triazol-4-yl)methyl]piperazine Corn starch 60 mg Lactose
300 mg Ethyl acetate q.s.
[0127] The active substance, the corn starch and the lactose were
processed into a homogenous pasty mixture using ethyl acetate. The
paste was ground and the resulting granules were placed on a
suitable tray and dried at 45.degree. C. in order to remove the
solvent. The dried granules were passed through a crusher and mixed
in a mixer with the following auxiliaries:
6 Talcum 5 mg Magnesium stearate 5 mg Corn starch 9 mg
[0128] and then poured into 400 mg capsules (=capsule size 0).
[0129] The foregoing description and examples have been set forth
merely to illustrate the invention and are not intended to be
limiting. Since modifications of the disclosed embodiments
incorporating the spirit and substance of the invention may occur
to persons skilled in the art, the invention should be construed
broadly to include all variations falling within the scope of the
appended claims and equivalents thereof.
* * * * *