U.S. patent application number 12/511474 was filed with the patent office on 2009-12-31 for substituted 1,2-ethylenediamines, methods for preparing them and uses thereof.
This patent application is currently assigned to Boehringer Ingelheim International GmbH. Invention is credited to Cornelia Dorner-Ciossek, Christian Eickmeier, Klaus Fuchs, Sandra Handschuh, Niklas Heine, Klaus Klinder, Marcus Kostka, Stefan Peters.
Application Number | 20090325940 12/511474 |
Document ID | / |
Family ID | 36545049 |
Filed Date | 2009-12-31 |
United States Patent
Application |
20090325940 |
Kind Code |
A1 |
Eickmeier; Christian ; et
al. |
December 31, 2009 |
Substituted 1,2-ethylenediamines, Methods for Preparing Them and
Uses Thereof
Abstract
The present invention relates to substituted
1,2-ethylenediamines of general formula (I) ##STR00001## wherein
the groups R.sup.1 to R.sup.15, A, B, L, i as well as
X.sup.1-X.sup.4 are defined as in the specification and claims and
the use thereof for the treatment of Alzheimer's disease (AD) and
similar diseases.
Inventors: |
Eickmeier; Christian;
(Mittelbiberach, DE) ; Peters; Stefan; (Biberach,
DE) ; Fuchs; Klaus; (Mittelbiberach, DE) ;
Heine; Niklas; (Biberach, DE) ; Handschuh;
Sandra; (Warthausen, DE) ; Dorner-Ciossek;
Cornelia; (Ravensburg, DE) ; Klinder; Klaus;
(Oggelshausen, DE) ; Kostka; Marcus; (Biberach,
DE) |
Correspondence
Address: |
MICHAEL P. MORRIS;BOEHRINGER INGELHEIM USA CORPORATION
900 RIDGEBURY RD, P O BOX 368
RIDGEFIELD
CT
06877-0368
US
|
Assignee: |
Boehringer Ingelheim International
GmbH
Ingelheim
DE
|
Family ID: |
36545049 |
Appl. No.: |
12/511474 |
Filed: |
July 29, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11278059 |
Mar 30, 2006 |
|
|
|
12511474 |
|
|
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|
Current U.S.
Class: |
514/222.5 ;
514/231.2; 514/616; 544/173; 544/8; 564/153 |
Current CPC
Class: |
C07K 5/06191 20130101;
C07K 5/06026 20130101; C07K 5/0808 20130101; A61P 9/00 20180101;
A61P 35/00 20180101; C07K 5/0812 20130101; A61P 1/18 20180101; A61P
3/10 20180101; A61P 25/28 20180101; A61P 35/04 20180101; A61P 21/00
20180101; A61P 25/00 20180101; C07K 5/0821 20130101; A61P 9/10
20180101; C07K 5/06034 20130101; A61P 43/00 20180101 |
Class at
Publication: |
514/222.5 ;
514/231.2; 514/616; 544/8; 544/173; 564/153 |
International
Class: |
A61K 31/54 20060101
A61K031/54; A61K 31/535 20060101 A61K031/535; A61K 31/16 20060101
A61K031/16; C07D 285/16 20060101 C07D285/16; C07D 265/32 20060101
C07D265/32; C07C 237/02 20060101 C07C237/02 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 30, 2005 |
EP |
05006939.2 |
Claims
1. A compound of formula (I): ##STR00752## wherein: A is aryl or
heteroaryl, optionally substituted by one or more fluorine atoms; L
are each independently hydrogen, fluorine, chlorine, bromine,
iodine, hydroxy, carboxy, formyl, cyano, nitro, F.sub.3C,
HF.sub.2C, FH.sub.2C, C.sub.1-6-alkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, C.sub.1-6-alkyl-S,
C.sub.1-6-alkyl-S--C.sub.1-3-alkyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkenyl, C.sub.3-7-cycloalkyl-C.sub.1-6-alkyl,
C.sub.3-7-cycloalkyl-C.sub.2-6-alkenyl,
C.sub.3-7-cycloalkyl-C.sub.2-6-alkynyl,
C.sub.3-7-cycloalkenyl-C.sub.1-6-alkyl,
C.sub.3-7-cycloalkenyl-C.sub.2-6-alkenyl,
C.sub.3-7-cycloalkenyl-C.sub.2-6-alkynyl, aryl,
aryl-C.sub.1-6-alkyl, aryl-C.sub.2-6-alkenyl,
aryl-C.sub.2-6-alkynyl, heterocyclyl, heterocyclyl-C.sub.1-6-alkyl,
heterocyclyl-C.sub.2-6-alkenyl, heterocyclyl-C.sub.2-6-alkynyl,
heteroaryl, heteroaryl-C.sub.1-6-alkyl,
heteroaryl-C.sub.2-6-alkenyl, heteroaryl-C.sub.2-6-alkynyl,
R.sup.15--O, R.sup.15--O--C.sub.1-3-alkyl, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--CO, R.sup.14--CO--(R.sup.14)N,
(R.sup.14).sub.2N--CO--(R.sup.14)N,
R.sup.14--SO.sub.2--(R.sup.14)N, (R.sup.14).sub.2N--SO.sub.2 or
R.sup.14--SO.sub.2, wherein the above-mentioned groups are
optionally substituted independently of one another by one or more
groups selected from fluorine, chlorine, bromine, iodine, hydroxy,
oxo, carboxy, formyl, cyano, nitro, F.sub.3C, HF.sub.2C, FH.sub.2C,
hydroxy-C.sub.1-6-alkyl, C.sub.1-3-alkyl, C.sub.1-6-alkoxy,
(R.sup.14).sub.2N, (R.sup.14).sub.2N--C.sub.1-3-alkyl,
(R.sup.14).sub.2N--CO and HOSO.sub.2--; i is 0, 1, 2 or 3; B is a
C.sub.1-4-alkylene bridge, optionally substituted by one or more
groups selected from fluorine, chlorine, bromine, iodine, hydroxy,
oxo, carboxy, cyano, nitro, F.sub.3C, HF.sub.2C, FH.sub.2C,
C.sub.1-4-alkyl, C.sub.1-6-alkyl-S--C.sub.1-3-alkyl,
C.sub.3-7-cycloalkyl, C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl, aryl,
aryl-C.sub.1-3-alkyl, heteroaryl, heteroaryl-C.sub.1-3-alkyl,
R.sup.15--O, (R.sup.14).sub.2N--SO.sub.2, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--C.sub.1-3-alkyl, (R.sup.14).sub.2N--CO,
R.sup.14--SO.sub.2, R.sup.14--CO--(R.sup.14)N,
R.sup.14--SO.sub.2(R.sup.14)N, (R.sup.14).sub.2N--SO.sub.2,
R.sup.14--CO-- and R.sup.14--SO--, wherein two C.sub.1-4-alkyl
groups bound to the same carbon atom of the C.sub.1-4-alkylene
bridge may be joined together to form a C.sub.3-7-cycloalkyl group,
and each of the above-mentioned groups and the C.sub.3-7-cycloalkyl
group formed from the C.sub.1-4-alkyl groups are optionally
substituted independently of one another by one or more groups
selected from fluorine, chlorine, bromine, iodine, hydroxy, oxo,
carboxy, formyl, cyano, nitro, F.sub.3C, HF.sub.2C, FH.sub.2C,
C.sub.1-3-alkyl, C.sub.1-3-alkoxy, R.sup.15--O--C.sub.1-3-alkyl,
R.sup.14--CO(R.sup.14)N, R.sup.14--SO.sub.2(R.sup.14)N,
(R.sup.14).sub.2N, (R.sup.14).sub.2N--C.sub.1-3-alkyl,
(R.sup.14).sub.2N--CO, (R.sup.14).sub.2N--SO.sub.2-- and
HOSO.sub.2--, and wherein when B is a C.sub.3-4-alkylene bridge,
the CH.sub.2 group of the C.sub.3-4-alkylene bridge, which is bound
to the group A, is optionally replaced by --O--; R.sup.1 is
hydrogen, C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.3-7-cycloalkyl, C.sub.3-7-cycloalkyl-C.sub.1-6-alkyl,
C.sub.3-7-cycloalkyl-C.sub.2-6-alkenyl,
C.sub.3-7-cycloalkyl-C.sub.2-6-alkynyl, C.sub.3-7-cycloalkenyl,
C.sub.3-7-cycloalkenyl-C.sub.1-6-alkyl,
C.sub.3-7-cycloalkenyl-C.sub.2-6-alkenyl,
C.sub.3-7-cycloalkenyl-C.sub.2-6-alkynyl, aryl,
aryl-C.sub.1-6-alkyl, aryl-C.sub.2-6-alkenyl,
aryl-C.sub.2-6-alkynyl, heterocyclyl, heterocyclyl-C.sub.1-6-alkyl,
heterocyclyl-C.sub.2-6-alkenyl, heterocyclyl-C.sub.2-6-alkynyl,
heteroaryl, heteroaryl-C.sub.1-6-alkyl,
heteroaryl-C.sub.2-6-alkenyl or heteroaryl-C.sub.2-6-alkynyl,
wherein the above-mentioned groups are optionally substituted
independently of one another by one or more groups selected from
fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl,
cyano, nitro, F.sub.3C, HF.sub.2C, FH.sub.2C, C.sub.1-3-alkyl,
C.sub.1-3-alkoxy, hydroxy-C.sub.1-6-alkyl, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--C.sub.1-3-alkyl,
(R.sup.14).sub.2N--CO--(R.sup.14).sub.2N--SO.sub.2,
R.sup.14--CO--(R.sup.14)N, R.sup.14--SO.sub.2--(R.sup.14)N and
HOSO.sub.2--; X.sup.1, is nitrogen or C(R.sup.10); X.sup.2,
X.sup.3, X.sup.4 are each independently nitrogen or C(R.sup.11),
with the proviso that 0, 1, 2 or 3 of the groups X.sup.1, X.sup.2,
X.sup.3 and X.sup.4 are nitrogen; R.sup.2 is C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, R.sup.15--O--C.sub.1-3-alkyl,
C.sub.1-6-alkyl-S--C.sub.1-3-alkyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.2-6-alkynyl, C.sub.3-7-cycloalkenyl,
C.sub.3-7-cycloalkenyl-C.sub.1-6-alkyl,
C.sub.3-7-cycloalkenyl-C.sub.2-6-alkenyl,
C.sub.3-7-cycloalkenyl-C.sub.2-6-alkynyl, heterocyclyl,
C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl, heterocyclyl-C.sub.1-3-alkyl,
C.sub.3-7-cycloalkyl-C.sub.2-3-alkenyl,
heterocyclyl-C.sub.2-3-alkenyl, heterocyclyl-C.sub.2-3-alkynyl,
aryl, heteroaryl, aryl-C.sub.1-3-alkyl, heteroaryl-C.sub.1-3-alkyl,
aryl-C.sub.2-3-alkenyl, aryl-C.sub.2-3-alkynyl,
heteroaryl-C.sub.2-3-alkenyl or heteroaryl-C.sub.2-3-alkynyl,
wherein the above-mentioned groups are optionally substituted
independently of one another by one or more groups selected from
fluorine, chlorine, bromine, iodine, F.sub.3C, HF.sub.2C,
FH.sub.2C, hydroxy, oxo, carboxy, formyl, cyano, nitro,
(R.sup.14).sub.2N, HOSO.sub.2--, C.sub.1-3-alkyl,
C.sub.1-6-alkyl-S--C.sub.1-3-alkyl, (R.sup.14).sub.2N--SO.sub.2--,
R.sup.14--CO--(R.sup.14)N, R.sup.14--SO.sub.2--(R.sup.14)N,
(R.sup.14).sub.2N--C.sub.1-3-alkyl, (R.sup.14).sub.2N--CO,
R.sup.5--O and R.sup.15--O--C.sub.1-3-alkyl; R.sup.3, R.sup.4 are
each independently hydrogen, C.sub.1-6-alkyl, fluorine, F.sub.3C,
HF.sub.2C or FH.sub.2C; R.sup.5, R.sup.7 are each independently
hydrogen, C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.3-7-cycloalkyl, heterocyclyl,
C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl,
C.sub.3-7-cycloalkyl-C.sub.2-6-alkynyl,
heterocyclyl-C.sub.1-3-alkyl,
C.sub.3-7-cycloalkyl-C.sub.2-4-alkenyl,
heterocyclyl-C.sub.2-4-alkenyl, heterocyclyl-C.sub.2-4-alkynyl,
C.sub.3-7-cycloalkenyl, C.sub.3-7-cycloalkenyl-C.sub.1-6-alkyl,
C.sub.3-7-cycloalkenyl-C.sub.2-6-alkenyl,
C.sub.3-7-cycloalkenyl-C.sub.2-6-alkynyl, aryl, heteroaryl,
aryl-C.sub.1-3-alkyl, heteroaryl-C.sub.1-3-alkyl,
aryl-C.sub.2-3-alkenyl, heteroaryl-C.sub.2-3-alkenyl,
aryl-C.sub.2-3-alkynyl or heteroaryl-C.sub.2-3-alkynyl, wherein the
above-mentioned groups are optionally substituted independently of
one another by one or more groups selected from fluorine, chlorine,
bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro,
C.sub.1-3-alkyl, R.sup.15--O, C.sub.1-3-alkyl-S, aryl, heteroaryl,
heteroaryl-C.sub.1-3-alkyl, aryl-C.sub.1-6-alkyl,
R.sup.14--CO--(R.sup.14)N, R.sup.14--SO.sub.2--(R.sup.14)N,
(R.sup.14).sub.2N--SO.sub.2--, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--C.sub.1-3-alkyl, (R.sup.14).sub.2N--CO and
HOSO.sub.2--; R.sup.6, R.sup.9 are each independently hydrogen,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy-C.sub.1-3-alkyl,
C.sub.3-7-cycloalkyl, C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl,
C.sub.2-6-alkenyl, heterocyclyl-C.sub.1-3-alkyl, heteroaryl,
heteroaryl-C.sub.1-3-alkyl or C.sub.2-6-alkynyl, wherein the
above-mentioned groups are optionally substituted independently of
one another by one or more groups selected from among fluorine,
chlorine, bromine, iodine, cyano, C.sub.1-3-alkyl,
C.sub.1-6-alkoxy- and (R.sup.14).sub.2N; R.sup.8 is hydrogen,
C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.3-7-cycloalkyl, C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl,
C.sub.3-7-cycloalkyl-C.sub.2-4-alkenyl,
C.sub.3-7-cycloalkyl-C.sub.2-4-alkynyl, C.sub.3-7-cycloalkenyl,
C.sub.3-7-cycloalkenyl-C.sub.1-6-alkyl,
C.sub.3-7-cycloalkenyl-C.sub.2-6-alkenyl,
C.sub.3-7-cycloalkenyl-C.sub.2-6-alkynyl, heterocyclyl,
heterocyclyl-C.sub.1-3-alkyl, heterocyclyl-C.sub.2-4-alkenyl,
heterocyclyl-C.sub.2-4-alkynyl, aryl, aryl-C.sub.1-3-alkyl,
aryl-C.sub.2-4-alkenyl, aryl-C.sub.2-4-alkynyl, heteroaryl,
heteroaryl-C.sub.1-3-alkyl, heteroaryl-C.sub.2-4-alkenyl or
heteroaryl-C.sub.2-4-alkynyl, wherein the above-mentioned groups
are optionally substituted independently of one another by one or
more groups selected from fluorine, chlorine, bromine, iodine,
hydroxy, oxo, carboxy, formyl, cyano, nitro, C.sub.1-3-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl, R.sup.15--O,
R.sup.15--O--C.sub.1-3-alkyl, R.sup.15--S,
R.sup.15--S--C.sub.1-3-alkyl, aryl, heteroaryl,
heteroaryl-C.sub.1-3-alkyl, aryl-C.sub.1-6-alkyl,
(R.sup.14).sub.2N, (R.sup.14).sub.2N--C.sub.1-3-alkyl,
(R.sup.14).sub.2N--CO, (R.sup.14).sub.2N--CO--N(R.sup.14)--,
(R.sup.14).sub.2N--SO.sub.2-- and HOSO.sub.2--; R.sup.10 is
hydrogen, fluorine, chlorine, bromine, iodine, cyano,
C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.3-7-cycloalkyl, C.sub.3-7-cycloalkyl-C.sub.1-6-alkyl,
C.sub.3-7-cycloalkyl-C.sub.2-6-alkynyl, heterocyclyl,
heterocyclyl-C.sub.1-6-alkyl, heterocyclyl-C.sub.2-6-alkenyl,
heterocyclyl-C.sub.2-6-alkynyl,
C.sub.3-7-cycloalkyl-C.sub.2-6-alkenyl,
heterocyclyl-C.sub.2-4-alkenyl, C.sub.3-7-cycloalkenyl,
C.sub.3-7-cycloalkenyl-C.sub.1-6-alkyl,
C.sub.3-7-cycloalkenyl-C.sub.2-6-alkenyl,
C.sub.3-7-cycloalkenyl-C.sub.2-6-alkynyl, aryl,
aryl-C.sub.1-6-alkyl, heteroaryl, heteroaryl-C.sub.1-6-alkyl,
aryl-C.sub.2-6-alkenyl, heteroaryl-C.sub.2-6-alkenyl,
aryl-C.sub.2-6-alkynyl or heteroaryl-C.sub.2-6-alkynyl,
R.sup.15--O, R.sup.15--O--C.sub.1-3-alkyl,
R.sup.12--SO.sub.2--(R.sup.13)N or R.sup.12--CO--(R.sup.13)N
wherein the above-mentioned groups are optionally substituted
independently of one another by one or more groups selected from
among fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy,
formyl, cyano, nitro, C.sub.1-6-alkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, C.sub.1-6-alkyl-S,
C.sub.1-6-alkyl-S--C.sub.1-3-alkyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-6-alkyl, aryl, aryl-C.sub.1-6-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-6-alkyl, heteroaryl,
heteroaryl-C.sub.1-6-alkyl, R.sup.15--O, R.sup.15--O--CO,
R.sup.15--CO, R.sup.15--O--CO-- (R.sup.14)N,
(R.sup.14).sub.2N--CO--O, R.sup.15--O--C.sub.1-3-alkyl,
(R.sup.14).sub.2N, (R.sup.14).sub.2N--CO,
R.sup.14--CO--(R.sup.14)N, (R.sup.14).sub.2N--CO--(R.sup.14)N,
(R.sup.14).sub.2N--SO.sub.2--,
(R.sup.14).sub.2N--SO.sub.2--(R.sup.14)N, R.sup.14--SO.sub.2--,
F.sub.3C, HF.sub.2C, FH.sub.2C, F.sub.3C--O, HF.sub.2C--O,
FH.sub.2C--O and R.sup.14--SO.sub.2--(R.sup.14)N; R.sup.11 are each
independently hydrogen, fluorine, chlorine, bromine, iodine,
R.sup.15--O, (R.sup.14).sub.2N or C.sub.1-3-alkyl, wherein the
C.sub.1-3-alkyl group is optionally substituted by one or more
fluorine atoms; R.sup.12 is C.sub.1-6-alkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, C.sub.3-7-cycloalkyl-C.sub.2-6-alkenyl,
aryl-C.sub.2-3-alkenyl, heteroaryl-C.sub.2-4-alkenyl,
heterocyclyl-C.sub.2-4-alkenyl, aryl-C.sub.2-3-alkynyl,
C.sub.3-7-cycloalkyl-C.sub.2-4-alkynyl,
heterocyclyl-C.sub.2-4-alkynyl-heteroaryl-C.sub.2-3-alkynyl,
C.sub.3-7-cycloalkyl, C.sub.3-7-cycloalkyl-C.sub.1-6-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-4-alkyl, C.sub.3-7-cycloalkenyl,
C.sub.3-7-cycloalkenyl-C.sub.1-6-alkyl,
C.sub.3-7-cycloalkenyl-C.sub.2-6-alkenyl,
C.sub.3-7-cycloalkenyl-C.sub.2-6-alkynyl, aryl,
aryl-C.sub.1-4-alkyl, heteroaryl, heteroaryl-C.sub.1-3-alkyl or
(R.sup.14).sub.2N, wherein the above-mentioned groups are
optionally substituted independently of one another by one or more
groups selected from among fluorine, chlorine, bromine, hydroxy,
oxo, carboxy, formyl, cyano, nitro, C.sub.1-3-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-3-alkyl, R.sup.15--O,
R.sup.15--O--C.sub.1-3-alkyl, R.sup.14--CO(R.sup.14)N,
R.sup.14--SO.sub.2(R.sup.14)N, (R.sup.14).sub.2N--SO.sub.2--,
R.sup.14--SO.sub.2--, R.sup.14--SO, R.sup.14--S, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--C.sub.1-3-alkyl and (R.sup.14).sub.2N--CO;
R.sup.13 is hydrogen, C.sub.1-6-alkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl, aryl, aryl-C.sub.1-3-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl,
heterocyclyl-C.sub.2-3-alkenyl, heterocyclyl-C.sub.2-3-alkynyl,
heteroaryl, heteroaryl-C.sub.2-3-alkenyl,
heteroaryl-C.sub.2-3-alkynyl or heteroaryl-C.sub.1-3-alkyl, wherein
the above-mentioned groups are optionally substituted independently
of one another by one or more groups selected from among fluorine,
chlorine, bromine, hydroxy, oxo, carboxy, formyl, cyano, nitro,
C.sub.1-3-alkyl, heterocyclyl, heterocyclyl-C.sub.1-3-alkyl,
R.sup.15--O, R.sup.15--O--C.sub.1-3-alkyl, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--C.sub.1-3-alkyl and R.sup.14CO; or R.sup.12 and
R.sup.13 together form a C.sub.2-6-alkylene bridge, so that with
the inclusion of the nitrogen atom linked to R.sup.13 and the
SO.sub.2-- or CO group linked to R.sup.12, a heterocyclic ring is
formed, wherein one or two CH.sub.2 groups of the
C.sub.2-6-alkylene bridge are optionally replaced independently of
one another by O, S, SO, SO.sub.2 or N(R.sup.14) in such a way that
in each case two O or S atoms or an 0 and an S atom are not joined
together directly, and the C atoms of the above-mentioned
C.sub.2-6-alkylene bridge are optionally substituted by one or more
groups selected from fluorine, chlorine, bromine, hydroxy, carboxy,
formyl, cyano, F.sub.3C, HF.sub.2C, FH.sub.2C, C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, oxo and nitro; R.sup.14 are each independently
hydrogen, C.sub.1-6-alkyl, C.sub.1-6-alkoxy-C.sub.1-3-alkyl,
C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl, aryl or
aryl-C.sub.1-3-alkyl, heterocyclyl, heterocyclyl-C.sub.1-3-alkyl,
heteroaryl or heteroaryl-C.sub.1-3-alkyl, wherein two
C.sub.1-6-alkyl groups bound to the same nitrogen atom together may
form a C.sub.2-6-alkylene bridge, so that with the inclusion of the
nitrogen atom bound to the groups R.sup.14 a heterocyclic ring is
formed, wherein a CH.sub.2 group of the C.sub.2-6-alkylene bridge
may be replaced by O, S or N(R.sup.14), and the above-mentioned
groups and the heterocyclic ring are optionally substituted
independently of one another by one or more groups selected from
among fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy,
formyl, cyano, nitro, C.sub.1-3-alkyl, hydroxy-C.sub.1-3-alkyl,
C.sub.1-3-alkoxy, (R.sup.15).sub.2N--CO or (R.sup.15).sub.2N, and
R.sup.15 are each independently hydrogen, C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl, aryl, aryl-C.sub.1-3-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl, heteroaryl or
heteroaryl-C.sub.1-3-alkyl, wherein the above-mentioned groups are
optionally substituted independently of one another by one or more
groups selected from fluorine, chlorine, bromine, iodine, hydroxy,
oxo, carboxy, formyl, cyano, nitro, C.sub.1-3-alkyl- and
C.sub.1-3-alkoxy; and tautomers, diastereomers, enantiomers,
mixtures thereof and salts thereof.
2. The compound according to claim 1, wherein A is phenyl,
biphenyl, naphthyl or a 5-, 6-, 7-, 8-, 9- or 10-membered aromatic
mono- or bicyclic heteroaryl group which contains 1-4 heteroatoms
selected from the group consisting of N, O and S.
3. The compound according to claim 1, wherein the group
##STR00753## is selected from the group consisting of:
##STR00754##
4. The compound according to claim 1, wherein A is phenyl, thienyl,
thiazolyl or pyridyl.
5. The compound according to claim 1, wherein L are each
independently hydrogen, fluorine, chlorine, bromine, iodine,
hydroxy, carboxy, cyano, nitro, F.sub.3C, HF.sub.2C, FH.sub.2C,
C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.3-7-cycloalkyl, C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl, aryl,
aryl-C.sub.1-3-alkyl, heterocyclyl, heterocyclyl-C.sub.1-3-alkyl,
heteroaryl, heteroaryl-C.sub.1-3-alkyl, R.sup.15--O,
R.sup.15--O--C.sub.1-3-alkyl, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--CO, R.sup.14--CO--(R.sup.14)N,
(R.sup.14).sub.2N--CO--(R.sup.14)N, (R.sup.14).sub.2N--SO.sub.2--,
R.sup.14--SO.sub.2--(R.sup.14)N or C.sub.1-3-alkyl-SO.sub.2--,
wherein the above-mentioned groups are optionally substituted
independently of one another by one or more groups selected from
fluorine, chlorine, bromine, hydroxy, oxo, carboxy, cyano, nitro,
F.sub.3C, HF.sub.2C, FH.sub.2C, hydroxy-C.sub.1-3-alkyl,
C.sub.1-3-alkyl, C.sub.1-3-alkoxy, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--C.sub.1-3-alkyl and (R.sup.14).sub.2N--CO; and i
is 0, 1 or 2.
6. The compound according to claim 1, wherein L are each
independently hydrogen, fluorine, chlorine, bromine, iodine, cyano,
hydroxy, C.sub.1-6-alkyl, C.sub.1-6-alkoxy, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl, phenyl, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--CO, R.sup.14--CO--(R.sup.14)N,
(R.sup.14).sub.2N--CO--(R.sup.14)N, R.sup.14--SO.sub.2--(R.sup.14)N
or (R.sup.14).sub.2N--SO.sub.2--, wherein the above-mentioned
groups are optionally substituted by one or more fluorine atoms,
and i is 0, 1 or 2.
7. The compound according to claim 1, wherein L are each
independently hydrogen, fluorine, chlorine, bromine, hydroxy,
C.sub.1-4-alkyl or C.sub.1-4-alkoxy, wherein the above-mentioned
groups are optionally substituted by one or more fluorine atoms,
and i is 0, 1 or 2.
8. The compound according to claim 1, wherein B is a
C.sub.1-4-alkylene bridge, wherein the C.sub.1-4-alkylene bridge is
optionally substituted by one or more groups selected from
fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, cyano,
nitro, F.sub.3C, HF.sub.2C, FH.sub.2C, C.sub.1-4-alkyl,
C.sub.1-6-alkyl-S--C.sub.1-3-alkyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-3-alkyl, aryl, aryl-C.sub.1-3-alkyl,
heteroaryl, heteroaryl-C.sub.1-3-alkyl, R.sup.15--O,
(R.sup.14).sub.2N--SO.sub.2--, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--C.sub.1-3-alkyl, (R.sup.14).sub.2N--CO,
R.sup.14--SO.sub.2--, R.sup.14--CO--(R.sup.14)N,
R.sup.14--SO.sub.2(R.sup.14)N, (R.sup.14).sub.2N--SO.sub.2--,
R.sup.14--CO and R.sup.14--SO, and wherein two C.sub.1-4-alkyl
groups bound to the same carbon atom of the C.sub.1-4-alkylene
bridge are optionally joined together forming a
C.sub.3-7-cycloalkyl group, and wherein the above-mentioned groups
and the C.sub.3-7-cycloalkyl group formed from the C.sub.1-4-alkyl
groups are optionally substituted independently of one another by
one or more groups selected from among fluorine, chlorine, bromine,
iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, F.sub.3C,
HF.sub.2C, FH.sub.2C, C.sub.1-3-alkyl, C.sub.1-3-alkoxy,
R.sup.15--O--C.sub.1-3-alkyl, R.sup.14--CO(R.sup.14)N,
R.sup.14--SO.sub.2(R.sup.14)N, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--C.sub.1-3-alkyl, (R.sup.14).sub.2N--CO,
(R.sup.14).sub.2N--SO.sub.2-- and HOSO.sub.2--.
9. The compound according to claim 1, wherein B is a
C.sub.1-4-alkylene bridge, wherein the C.sub.1-4-alkylene bridge is
optionally substituted independently of one another by one or more
groups selected from among fluorine, hydroxy, carboxy, cyano,
nitro, F.sub.3C, HF.sub.2C, FH.sub.2C, C.sub.1-4-alkyl,
C.sub.3-7-cycloalkyl, C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl, aryl,
aryl-C.sub.1-3-alkyl, heteroaryl, heteroaryl-C.sub.1-3-alkyl,
R.sup.15--O, (R.sup.14).sub.2N--SO.sub.2-- and (R.sup.14).sub.2N,
and wherein two C.sub.1-4-alkyl groups bound to the same carbon
atom of the C.sub.1-4-alkylene bridge are optionally joined
together forming a C.sub.3-7-cycloalkyl group, and wherein the
above-mentioned groups and the C.sub.3-7-cycloalkyl group formed
from the C.sub.1-4-alkyl groups are optionally substituted
independently of one another by one or more groups selected from
fluorine, chlorine, bromine, hydroxy, carboxy, cyano, F.sub.3C,
HF.sub.2C, FH.sub.2C, C.sub.1-3-alkyl, C.sub.1-3-alkoxy and
R.sup.15--O--C.sub.1-3-alkyl.
10. The compound according to claim 1, wherein B is a
C.sub.1-4-alkylene bridge, wherein the C.sub.1-4-alkylene bridge is
optionally substituted independently of one another by one or more
groups selected from among C.sub.1-4-alkyl, phenyl or benzyl, and
wherein two C.sub.1-4-alkyl groups bound to the same carbon atom of
the C.sub.1-4-alkylene bridge are optionally joined together
forming a C.sub.3-6-cycloalkyl group, and wherein the
above-mentioned groups and the C.sub.3-6-cycloalkyl group formed
from the C.sub.1-4-alkyl groups are optionally substituted
independently of one another by one or more groups selected from
fluorine, hydroxy and C.sub.1-3-alkoxy.
11. The compound according to claim 1, wherein B is selected from
the group consisting of: ##STR00755## wherein one or more hydrogen
atoms are optionally replaced by fluorine.
12. The compound according to claim 1, wherein B is a
C.sub.1-2-alkylene bridge, wherein the C.sub.1-2-alkylene bridge is
optionally substituted by one or more C.sub.1-4-alkyl groups, and
wherein two C.sub.1-4-alkyl groups bound to the same carbon atom of
the C.sub.1-2-alkylene bridge may be joined together forming a
cyclopropyl group, and wherein one or more hydrogen atoms of the
above-mentioned C.sub.1-2-alkylene bridge and/or the
C.sub.1-4-alkyl groups and/or the cyclopropyl group formed
therefrom are optionally replaced by one or more fluorine
atoms.
13. The compound according to claim 1, wherein partial formula (II)
##STR00756## is selected from the group consisting of: ##STR00757##
##STR00758## ##STR00759## ##STR00760## ##STR00761## ##STR00762##
##STR00763##
14. The compound according to claim 1, wherein R.sup.1 is hydrogen,
C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.3-7-cycloalkyl, C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl, aryl,
aryl-C.sub.1-3-alkyl, heteroaryl or heteroaryl-C.sub.1-3-alkyl,
wherein the above-mentioned groups are optionally substituted
independently of one another by one or more groups selected from
fluorine, chlorine, bromine, hydroxy, carboxy, cyano, nitro,
F.sub.3C, HF.sub.2C, FH.sub.2C, C.sub.1-3-alkyl, C.sub.1-3-alkoxy
and hydroxy-C.sub.1-3-alkyl.
15. The compound according to claim 1, wherein R.sup.1 is hydrogen,
C.sub.1-4-alkyl, C.sub.3-4-alkenyl, C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl, wherein the above-mentioned
groups are optionally substituted independently of one another by
one or more groups selected from among fluorine, hydroxy and
C.sub.1-3-alkoxy.
16. The compound according to claim 1, wherein R.sup.2 is
C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.1-6-alkoxy-C.sub.1-3-alkyl,
C.sub.1-6-alkyl-S--C.sub.1-3-alkyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkenyl-C.sub.1-3-alkyl,
C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-3-alkyl, aryl, aryl-C.sub.1-3-alkyl,
heteroaryl or heteroaryl-C.sub.1-3-alkyl, wherein the
above-mentioned groups are optionally substituted independently of
one another by one or more groups selected from fluorine, chlorine,
bromine, iodine, F.sub.3C, HF.sub.2C, FH.sub.2C, hydroxy, carboxy,
cyano, nitro, C.sub.1-3-alkyl, (R.sup.14).sub.2N--SO.sub.2--,
(R.sup.14).sub.2N, R.sup.14--CO--(R.sup.14)N,
R.sup.14--SO.sub.2(R.sup.14)N, (R.sup.14).sub.2N--C.sub.1-3-alkyl,
(R.sup.14).sub.2N--CO, R.sup.15--O and
R.sup.15--O--C.sub.1-3-alkyl.
17. The compound according to claim 1, wherein R.sup.2 is
C.sub.1-6-alkyl, C.sub.2-6-alkynyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl, heterocyclyl-C.sub.1-3-alkyl,
phenyl, phenyl-C.sub.1-3-alkyl, heteroaryl or
heteroaryl-C.sub.1-3-alkyl, wherein the heteroaryl groups are 5- or
6-membered aromatic heteroaryl groups which contain 1, 2 or 3
heteroatoms selected from N, O and S, and wherein the
above-mentioned groups are optionally substituted independently of
one another by one or more groups selected from among fluorine,
chlorine, bromine, iodine, cyano, hydroxy, C.sub.1-3-alkyl,
F.sub.3C, HF.sub.2C, FH.sub.2C, C.sub.1-3-alkoxy and
(R.sup.14).sub.2N.
18. The compound according to claim 1, wherein R.sup.2 is n-propyl,
n-butyl, 2-propynyl, 2-butynyl, benzyl, 2-phenylethyl,
pyridylmethyl, furanylmethyl, thienylmethyl or thiazolylmethyl,
wherein the above-mentioned propyl, butyl, propynyl and butynyl
groups are optionally substituted by one or more fluorine atoms and
the benzyl, and 2-phenylethyl, furanylmethyl, thienylmethyl or
thiazolylmethyl are optionally substituted independently of one
another by one or more groups selected from fluorine, chlorine,
bromine, methyl, F.sub.3C, HF.sub.2C, FH.sub.2C and H.sub.2N.
19. The compound according to claim 1, wherein R.sup.3 is hydrogen,
C.sub.1-6-alkyl, fluorine, F.sub.3C, HF.sub.2C or FH.sub.2C; and
R.sup.4 is hydrogen.
20. The compound according to claim 1, wherein R.sup.8 is hydrogen,
C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.3-7-cycloalkyl, C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl,
C.sub.3-7-cycloalkenyl, C.sub.3-7-cycloalkenyl-C.sub.1-3-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl, aryl,
aryl-C.sub.1-3-alkyl, heteroaryl or heteroaryl-C.sub.1-3-alkyl,
wherein the above-mentioned groups are optionally substituted
independently of one another by one or more groups selected from
fluorine, chlorine, bromine, iodine, hydroxy, carboxy, cyano,
nitro, C.sub.1-3-alkyl, heterocyclyl, heterocyclyl-C.sub.1-3-alkyl,
aryl, aryl-C.sub.1-3-alkyl, heteroaryl, heteroaryl-C.sub.1-3-alkyl,
(R.sup.14).sub.2N, (R.sup.14).sub.2N--C.sub.1-3-alkyl,
(R.sup.14).sub.2N--CO, (R.sup.14).sub.2N--CO--N(R.sup.14)--,
(R.sup.14).sub.2N--SO.sub.2--, R.sup.15--O,
R.sup.15--O--C.sub.1-3-alkyl, R.sup.15--S and
R.sup.15--S--C.sub.1-3-alkyl.
21. The compound according to claim 1, wherein R.sup.8 is hydrogen,
C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl, phenyl,
phenyl-C.sub.1-3-alkyl, heteroaryl or heteroaryl-C.sub.1-3-alkyl,
wherein the heteroaryl groups are 5- or 6-membered aromatic
heteroaryl groups which contain 1, 2 or 3 heteroatoms selected from
the group consisting of N, O and S, and wherein the above-mentioned
groups are optionally substituted independently of one another by
one or more groups selected from fluorine, chlorine, bromine,
carboxy, hydroxy, cyano, C.sub.1-3-alkyl, C.sub.1-3-alkoxy,
C.sub.1-3-alkoxy-C.sub.1-3-alkyl, C.sub.1-3-alkyl-S,
C.sub.1-3-alkyl-S--C.sub.1-3-alkyl, hydroxy-C.sub.1-3-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--C.sub.1-3-alkyl,
(R.sup.14).sub.2N--CO--N(R.sup.14)-- and
(R.sup.14).sub.2N--SO.sub.2--.
22. The compound according to claim 1, wherein R.sup.8 is hydrogen,
C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl, phenyl-C.sub.1-3-alkyl or
tetrahydropyranyl-C.sub.1-3-alkyl, wherein the above-mentioned
groups are optionally substituted independently of one another by
one or more groups selected from fluorine, chlorine, bromine,
pyrrolidin-1-ylmethyl, hydroxy, cyano, C.sub.1-3-alkyl,
C.sub.1-3-alkoxy, C.sub.1-3-alkyl-S, hydroxy-C.sub.1-3-alkyl,
(R.sup.14).sub.2N, (R.sup.14).sub.2N--C.sub.1-3-alkyl,
(R.sup.14).sub.2N--CO--N(R.sup.14)-- and
(R.sup.14).sub.2N--SO.sub.2--.
23. The compound according to claim 1, wherein R.sup.5, R.sup.7 are
each independently hydrogen, C.sub.1-6-alkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, C.sub.3-7-cycloalkyl, heterocyclyl,
C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl, heterocyclyl-C.sub.1-3-alkyl,
C.sub.3-7-cycloalkenyl, C.sub.3-7-cycloalkenyl-C.sub.1-3-alkyl,
aryl, heteroaryl, aryl-C.sub.1-3-alkyl or
heteroaryl-C.sub.1-3-alkyl, wherein the above-mentioned groups are
optionally substituted independently of one another by one or more
groups selected from fluorine, chlorine, bromine, iodine, hydroxy,
carboxy, cyano, nitro, C.sub.1-3-alkyl, C.sub.1-3-alkoxy,
C.sub.1-3-alkyl-S, aryl, heteroaryl, heteroaryl-C.sub.1-3-alkyl,
aryl-C.sub.1-3-alkyl, (R.sup.14).sub.2N--SO.sub.2--,
(R.sup.14).sub.2N, (R.sup.14).sub.2N--C.sub.1-3-alkyl and
(R.sup.14).sub.2N--CO.
24. The compound according to claim 1, wherein R.sup.5 is
C.sub.1-6-alkyl, cyclopropyl, C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl
or phenyl-C.sub.1-3-alkyl, wherein the above-mentioned groups are
optionally substituted independently of one another by one or more
groups selected from fluorine, chlorine, bromine, iodine, cyano,
hydroxy, carboxy, C.sub.1-3-alkyl, C.sub.1-3-alkoxy and
(R.sup.14).sub.2N, and R.sup.7 is C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl, phenyl
or phenyl-C.sub.1-3-alkyl, wherein the above-mentioned groups are
optionally substituted independently of one another by one or more
groups selected from fluorine, chlorine, bromine, iodine, cyano,
hydroxy, carboxy, C.sub.1-3-alkyl, C.sub.1-3-alkoxy and
(R.sup.14).sub.2N.
25. The compound according to claim 1, wherein R.sup.5, R.sup.7 are
each independently C.sub.1-4-alkyl or cyclopropyl, wherein one or
more hydrogen atoms of the above-mentioned groups are optionally
replaced by fluorine atoms.
26. The compound according to claim 1, wherein R.sup.6 is hydrogen,
and R.sup.9 is hydrogen or C.sub.1-4-alkyl, wherein one or more
hydrogen atoms of the C.sub.1-4-alkyl group are optionally replaced
by fluorine.
27. The compound according to claim 1, wherein R.sup.10 is
hydrogen, fluorine, chlorine, bromine, cyano, C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-6-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-6-alkyl, C.sub.3-7-cycloalkenyl, aryl,
aryl-C.sub.1-6-alkyl, heteroaryl, heteroaryl-C.sub.1-6-alkyl,
R.sup.15--O, R.sup.15--O--C.sub.1-3-alkyl,
R.sup.12--SO.sub.2--(R.sup.13)N or R.sup.12--CO--(R.sup.13)N,
wherein the above-mentioned groups are optionally substituted
independently of one another by one or more groups selected from
fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl,
cyano, nitro, C.sub.3-7-cycloalkyl, heterocyclyl,
(R.sup.14).sub.2N, (R.sup.14).sub.2N--CO, R.sup.15--CO,
R.sup.15--O--CO, R.sup.14--CO--(R.sup.14)N,
(R.sup.14).sub.2N--CO--(R.sup.14)N, (R.sup.14).sub.2N--SO.sub.2--,
(R.sup.14).sub.2N--SO.sub.2--(R.sup.14)N, R.sup.14--SO.sub.2--,
C.sub.1-4-alkyl, R.sup.15--O, C.sub.1-4-alkyl-S, F.sub.3C,
HF.sub.2C, FH.sub.2C, F.sub.3C--O, HF.sub.2C--O, FH.sub.2C--O and
R.sup.14--SO.sub.2--(R.sup.14)N; and R.sup.11 each independently
denotes hydrogen, fluorine, chlorine, bromine, iodine, methyl or
F.sub.3C.
28. The compound according to claim 1, wherein R.sup.10 is
hydrogen, fluorine, chlorine, bromine, cyano, C.sub.1-4-alkyl,
C.sub.1-4-alkoxy, C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkyl-oxy,
C.sub.3-6-cycloalkyl-C.sub.1-3-alkoxy,
1,3-diazacyclohexan-2-on-1-yl, 2-oxo-1,3-oxazinan-3-yl,
3-oxomorpholino, 1,1-dioxo-[1,2,6]thiadiazinan-2-yl, phenyl,
pyridyl, thienyl, furyl, R.sup.12--CO--(R.sup.13)N or
R.sup.12--SO.sub.2--(R.sup.13)N, wherein the above-mentioned groups
are optionally substituted independently of one another by one or
more groups selected from fluorine, chlorine, bromine, carboxy,
cyano, C.sub.1-4-alkyl, C.sub.1-4-alkoxy, C.sub.1-4-alkyl-S,
R.sup.15--CO, R.sup.15--O--CO, R.sup.14--SO.sub.2--, F.sub.3C,
HF.sub.2C, FH.sub.2C, F.sub.3C--O, HF.sub.2C--O, FH.sub.2C--O and
(R.sup.14).sub.2N--CO; and R.sup.11 are each independently
hydrogen, fluorine, chlorine, or bromine.
29. The compound according to claim 1, wherein R.sup.10 is
R.sup.12--CO--(R.sup.13)N, R.sup.12--SO.sub.2--(R.sup.13)N,
cyanophenyl or cyanothienyl, wherein the above-mentioned
cyanophenyl and cyanothienyl groups are optionally substituted
independently of one another by one or more groups selected from
fluorine, chlorine, bromine, C.sub.1-4-alkyl, C.sub.1-4-alkoxy,
F.sub.3C, HF.sub.2C, FH.sub.2C, F.sub.3C--O, HF.sub.2C--O and
FH.sub.2C--O; and R.sup.11 are each independently hydrogen,
fluorine, chlorine, or bromine.
30. The compound according to claim 1, wherein R.sup.12 is
C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.3-7-cycloalkyl, C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl, C.sub.3-7-cycloalkenyl,
C.sub.3-7-cycloalkenyl-C.sub.1-3-alkyl, aryl, aryl-C.sub.1-3-alkyl,
heteroaryl, heteroaryl-C.sub.1-3-alkyl or (R.sup.14).sub.2N,
wherein the above-mentioned groups are optionally substituted by
one or more groups selected from fluorine, chlorine, bromine,
hydroxy, carboxy, cyano, nitro, C.sub.1-3-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-3-alkyl, C.sub.1-3-alkoxy,
hydroxy-C.sub.1-3-alkyl, R.sup.14--CO(R.sup.14)N,
R.sup.14--SO.sub.2(R.sup.14)N, (R.sup.14).sub.2N--SO.sub.2--,
R.sup.14--SO.sub.2--R.sup.14--SO, R.sup.14--S, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--C.sub.1-3-alkyl and (R.sup.14).sub.2N--CO; and
R.sup.13 is hydrogen, C.sub.1-6-alkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl, aryl, aryl-C.sub.1-3-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl, heteroaryl or
heteroaryl-C.sub.1-3-alkyl, wherein the above-mentioned groups are
optionally substituted independently of one another by one or more
groups selected from fluorine, chlorine, bromine, hydroxy, cyano,
C.sub.1-3-alkyl, C.sub.1-3-alkoxy, hydroxy-C.sub.1-3-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl, (R.sup.14).sub.2N-- and
(R.sup.14).sub.2N--C.sub.1-3-alkyl, or R.sup.12 and R.sup.13
together form a C.sub.2-6-alkylene bridge, so that with the
inclusion of the nitrogen atom attached to R.sup.13 and the
SO.sub.2 or CO group attached to R.sup.12 a heterocyclic ring is
formed, wherein one or two CH.sub.2 groups of the
C.sub.2-6-alkylene bridge are optionally replaced independently of
one another by O, S, SO, SO.sub.2 or N(R.sup.14) in such a way that
in each case two O or S atoms or one O atom and an S atom are not
directly joined together, and wherein the C atoms of the
above-mentioned C.sub.2-6-alkylene bridge are optionally
substituted independently of one another by one or more groups
selected from among fluorine, hydroxy, carboxy, F.sub.3C,
HF.sub.2C, FH.sub.2C, C.sub.1-3-alkyl and C.sub.1-3-alkoxy.
31. The compound according to claim 1, wherein R.sup.12 is
C.sub.1-6-alkyl, heterocyclyl, phenyl, phenyl-C.sub.1-3-alkyl,
heteroaryl, heteroaryl-C.sub.1-3-alkyl or (R.sup.14).sub.2N,
wherein the heteroaryl groups are 5- or 6-membered aromatic
heteroaryl groups which contain 1 or 2 heteroatoms selected from
the group consisting of N, O and S, wherein a maximum of one O or S
atom may be present, and wherein the above-mentioned groups are
optionally substituted independently of one another by one or more
groups selected from fluorine, chlorine, bromine, hydroxy, cyano,
C.sub.1-3-alkyl, C.sub.1-3-alkoxy, heterocyclyl,
heterocyclyl-C.sub.1-3-alkyl, hydroxy-C.sub.1-3-alkyl,
(R.sup.14).sub.2N and (R.sup.14).sub.2N--C.sub.1-3-alkyl; and
R.sup.13 is hydrogen, C.sub.1-6-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-3-alkyl, C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl, phenyl,
phenyl-C.sub.1-3-alkyl, heteroaryl or heteroaryl-C.sub.1-3-alkyl,
wherein the heteroaryl groups are 5- or 6-membered aromatic
heteroaryl groups which contain 1 or 2 heteroatoms selected from
the group consisting of N, O and S, wherein a maximum of one O or S
atom may be present, and wherein the above-mentioned groups are
optionally substituted independently of one another by one or more
groups selected from a fluorine, chlorine, bromine, hydroxy, cyano,
C.sub.1-3-alkyl, C.sub.1-3-alkoxy, hydroxy-C.sub.1-3-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl, (R.sup.14).sub.2N-- and
(R.sup.14).sub.2N--C.sub.1-3-alkyl; or R.sup.12 and R.sup.13
together form a C.sub.2-6-alkylene bridge, so that with the
inclusion of the nitrogen atom attached to R.sup.13 and the
SO.sub.2 or CO group attached to R.sup.12 a heterocyclic ring is
formed, wherein one or two CH.sub.2 groups of the
C.sub.2-6-alkylene bridge may be replaced independently of one
another by O, S, SO, SO.sub.2 or N(R.sup.14) in such a way that in
each case two O or S atoms or an O atom and an S atom are not
directly joined together, and wherein the C atoms of the
above-mentioned C.sub.2-6-alkylene bridge are optionally
substituted independently of one another by one or more groups
selected from among fluorine, hydroxy, carboxy, F.sub.3C,
HF.sub.2C, FH.sub.2C, C.sub.1-3-alkyl and C.sub.1-3-alkoxy.
32. The compound according to claim 1, wherein R.sup.12 is
C.sub.1-4-alkyl, morpholinyl, phenyl, benzyl, pyridyl or
(CH.sub.3).sub.2N, wherein the above-mentioned groups are
optionally substituted independently of one another by one or more
groups selected from fluorine, chlorine and bromine; R.sup.13 is
hydrogen, methyl, ethyl, phenyl or 4-fluorophenyl wherein the
above-mentioned groups are optionally substituted independently of
one another by one or more groups selected from fluorine, chlorine
and bromine; or R.sup.12 and R.sup.13 with the inclusion of the
nitrogen atom attached to R.sup.13 and the SO.sub.2 or CO group
attached to R.sup.12 together form a heterocyclic ring of formulae
(IIa), (IIb), (IIc) or (IId) ##STR00764##
33. The compound according to claim 1, wherein R.sup.12 and
R.sup.13 together form a C.sub.2-6-alkylene bridge, so that with
the inclusion of the nitrogen atom attached to R.sup.13 and the
SO.sub.2 or CO group attached to R.sup.12 a heterocyclic ring is
formed, wherein one or two CH.sub.2 groups of the
C.sub.2-6-alkylene bridge are optionally replaced independently of
one another by O, S, SO, SO.sub.2 or N(R.sup.14) in such a way that
in each case two O or S atoms or an O atom and an S atom are not
directly joined together, and wherein the C atoms of the
above-mentioned C.sub.2-6-alkylene bridge are optionally
substituted independently of one another by one or more groups
selected from fluorine, hydroxy, carboxy, F.sub.3C, HF.sub.2C,
FH.sub.2C, C.sub.1-3-alkyl and C.sub.1-3-alkoxy.
34. The compound according to claim 1, wherein R.sup.12 and
R.sup.13 with the inclusion of the nitrogen atom attached to
R.sup.13 and the SO.sub.2 or CO group attached to R.sup.12 together
form a heterocyclic ring of formulae (IIa), (IIb), (IIc) or (IId)
##STR00765##
35. The compound according to claim 1, wherein R.sup.14 is hydrogen
or C.sub.1-6-alkyl, wherein one or more hydrogen atoms of the
C.sub.1-6-alkyl group are optionally replaced by fluorine.
36. The compound according to claim 1, wherein R.sup.15 is hydrogen
or C.sub.1-3-alkyl.
37. The compound according to claim 1, wherein compound is of
formula (Ia), (Ib), (Ic), (Id) or (Ie): ##STR00766## wherein A, B,
L, x.sup.2, x.sup.3, x.sup.4, i, R.sup.1, R.sup.2, R.sup.3,
R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14 and R.sup.15 are as defined in claim
1.
38. A physiologically acceptable salt of the compound according to
claim 1.
39. A pharmaceutical composition comprising a compound according to
claim 1 and one or more inert carriers and/or diluents.
40. The pharmaceutical composition according to claim 39, further
comprising one or more medicinally effective active substances
selected from beta-secretase inhibitors, gamma-secretase
inhibitors, amyloid aggregation inhibitors, directly or indirectly
acting neuroprotective substances, anti-oxidants, Cox inhibitors,
NSAIDs additionally or exclusively having A.beta. lowering
properties, HMG-CoA reductase inhibitors, acetylcholinesterase
inhibitors, NMDA receptor antagonists, AMPA agonists, substances
modulating the concentration or release of neurotransmitters,
substances inducing the secretion of growth hormone, CB-1 receptor
antagonists or inverse agonists, antibiotics, PDE-IV inhibitors,
PDE-IX inhibitors, GABA.sub.A inverse agonists, nicotinic agonists,
histamine H3 antagonists, 5 HAT-4 agonists or partial agonists,
5HT-6 antagonists, a2-adrenoreceptor antagonists, muscarinic M1
agonists, muscarinic M2 antagonists and metabotropic
glutamate-receptor 5 positive modulators.
41. The pharmaceutical composition according to claim 39, further
comprising one or more medicinally effective active substances
selected from alzhemed, vitamin E, ginkolide, donepezil,
rivastigmine, tacrine, galantamine, memantine, NS-2330, ibutamoren
mesylate, capromorelin, minocyclin and rifampicin.
42. A method for treating or preventing a disease or condition
associated with an abnormal processing of Amyloid Precursor Protein
(APP) or aggregation of Abeta peptide, comprising administering to
a patient in need thereof a compound according to claim 1.
43. A method for treating or preventing diseases or conditions
influenced by inhibiting the .beta.-secretase activity, comprising
administering to a patient in need thereof a compound according to
claim 1, wherein the compound acts as a .beta.-secretase
Inhibitor.
44. A method for treating or preventing diseases or conditions
influenced by inhibiting the aspartylprotease cathepsin D,
comprising administering to a patient in need thereof a compound
according to claim 1.
45. A method for preventing the metastasisation of tumour cells,
comprising administering to a patient in need thereof a compound
according to claim 1.
46. A method for treating or preventing a disease or condition
selected from the group consisting of: Alzheimer's disease (AD),
MCI ("mild cognitive impairment"), trisomy 21 (Down's syndrome),
cerebral amyloid angiopathy, degenerative dementias, hereditary
cerebral haemorrhage with amyloidosis, Dutch type (HCHWA-D),
Alzheimer's dementia with Lewy bodies, trauma, stroke,
pancreatitis, Inclusion Body Myositis (IBM), and other peripheral
amyloidoses, diabetes or arteriosclerosis, comprising administering
to a patient in need thereof a compound according to claim 1.
47. A method for treating or preventing Alzheimer's disease (AD),
comprising administering to a patient in need thereof a compound
according to claim 1.
48. A method for inhibiting .beta.-secretase activity, comprising
contacting .beta.-secretase with an effective inhibitory amount of
a compound according to claim 1.
Description
RELATED APPLICATIONS
[0001] This application is a divisional of U.S. Ser. No.
11/278,059, filed Mar. 30, 2006. This application claims priority
to European Patent Application No. 05 006 939.2, filed Mar. 30,
2005. The contents of each of the above are incorporated herein by
reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to substituted
1,2-ethylenediamines of general formula (I)
##STR00002##
wherein the groups R.sup.1 to R.sup.15, A, B, L, i and
X.sup.1-X.sup.4 are defined below, including the tautomers, the
stereoisomers, the mixtures thereof and the salts thereof. A
further object of this invention relates to pharmaceutical
compositions containing a compound of formula (I) according to the
invention and the use of a compound according to the invention for
preparing a pharmaceutical composition for the treatment and/or
prevention of Alzheimer's disease (AD) and other diseases
associated with abnormal processing of Amyloid Precursor Protein
(APP) or aggregation of the Abeta peptide, as well as diseases
which can be treated or prevented by the inhibition of
.beta.-secretase. Such diseases include MCI ("mild cognitive
impairment"), trisomy 21 (Down's syndrome), cerebral amyloid
angiopathy, degenerative dementias, hereditary cerebral haemorrhage
with amyloidosis, Dutch type (HCHWA-D), Alzheimer's dementia with
Lewy bodies, trauma, stroke, pancreatitis, Inclusion Body Myositis
(IBM), and other peripheral amyloidoses, diabetes and
arteriosclerosis.
[0003] The compounds according to the invention also inhibit the
aspartylprotease cathepsin D and are therefore suitable for
suppressing the metastasisation of tumour cells.
[0004] The invention further relates to processes for preparing a
pharmaceutical composition and a compound according to the
invention.
BACKGROUND OF THE INVENTION
[0005] EP 652 009 A1 describes inhibitors of aspartate protease
which inhibit the production of beta-amyloid peptides in cell
culture and in vivo.
[0006] WO 00/69262 discloses a beta-secretase and the use thereof
in assays for finding potential active substances for the treatment
of AD.
[0007] WO 01/00663 discloses memapsin 2 (human beta-secretase) as
well as a recombinant catalytically active enzyme. Methods of
identifying inhibitors of memapsin 2 are also described.
[0008] WO 01/00665 discloses inhibitors of memapsin 2 for the
treatment of AD.
[0009] WO 03/057721 discloses substituted aminocarboxamides for the
treatment of AD.
[0010] At present there are no effective treatment methods capable
of preventing, stopping or reversing AD.
[0011] The objective of the present invention is therefore to
provide new substituted 1,2-ethylenediamines which inhibit the
cleaving of APP (Amyloid Precursor Protein) mediated by
.beta.-secretase.
[0012] A further objective of the present invention is to provide
physiologically acceptable salts of the compounds according to the
invention with inorganic or organic acids.
[0013] Another objective of the present invention is to provide
pharmaceutical compositions containing at least one compound
according to the invention or a physiologically acceptable salt
according to the invention, optionally together with one or more
inert carriers and/or diluents.
[0014] The present invention further relates to pharmaceutical
compositions containing one or more, preferably one active
substance, which is selected from the compounds according to the
invention and/or the corresponding salts, as well as one or more,
preferably one additional active substance optionally together with
one or more inert carriers and/or diluents.
[0015] This invention further relates to the use of at least one of
the compounds according to the invention for inhibiting
.beta.-secretase.
[0016] The invention also sets out to provide new pharmaceutical
compositions which are suitable for the treatment or prevention of
diseases or conditions associated with the abnormal processing of
Amyloid Precursor Protein (APP) or aggregation of Abeta
peptide.
[0017] The invention also sets out to provide new pharmaceutical
compositions which are suitable for the treatment or prevention of
diseases or conditions which can be influenced by inhibiting the
.beta.-secretase activity.
[0018] The invention also sets out to provide new pharmaceutical
compositions which are suitable for the treatment and/or prevention
of Alzheimer's disease (AD) and other diseases which are associated
with the abnormal processing of APP or aggregation of Abeta
peptide, as well as diseases which can be treated or prevented by
the inhibition of .beta.-secretase, particularly AD.
[0019] The invention also relates to a method of inhibiting
.beta.-secretase activity.
[0020] Further objectives of the present invention will be apparent
to the skilled man immediately from the foregoing remarks and those
made hereinafter.
SUMMARY OF THE INVENTION
[0021] In a first aspect the present invention relates to
substituted 1,2-ethylenediamines of general formula (I)
##STR00003##
wherein [0022] A denotes aryl or heteroaryl, [0023] wherein the
group A in addition to the groups L may optionally be substituted
by one or more fluorine atoms, [0024] L denotes in each case
independently of one another hydrogen, fluorine, chlorine, bromine,
iodine, hydroxy, carboxy, formyl, cyano, nitro, F.sub.3C,
HF.sub.2C, FH.sub.2C, C.sub.1-6-alkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, C.sub.1-6-alkyl-S,
C.sub.1-6-alkyl-S--C.sub.1-3-alkyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkenyl, C.sub.3-7-cycloalkyl-C.sub.1-6-alkyl,
C.sub.3-7-cycloalkyl-C.sub.2-6-alkenyl,
C.sub.3-7-cycloalkyl-C.sub.2-6-alkynyl,
C.sub.3-7-cycloalkenyl-C.sub.1-6-alkyl,
C.sub.3-7-cycloalkenyl-C.sub.2-6-alkenyl,
C.sub.3-7-cycloalkenyl-C.sub.2-6-alkynyl, aryl,
aryl-C.sub.1-6-alkyl, aryl-C.sub.2-6-alkenyl,
aryl-C.sub.2-6-alkynyl, heterocyclyl, heterocyclyl-C.sub.1-6-alkyl,
heterocyclyl-C.sub.2-6-alkenyl, heterocyclyl-C.sub.2-6-alkynyl,
heteroaryl, heteroaryl-C.sub.1-6-alkyl,
heteroaryl-C.sub.2-6-alkenyl, heteroaryl-C.sub.2-6-alkynyl,
R.sup.15--O, R.sup.15--O--C.sub.1-3-alkyl, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--CO, R.sup.14--CO--(R.sup.14)N,
(R.sup.14).sub.2N--CO--(R.sup.14)N,
R.sup.14--SO.sub.2--(R.sup.14)N, (R.sup.14).sub.2N--SO.sub.2 or
R.sup.14--SO.sub.2, [0025] wherein the above-mentioned groups may
optionally be substituted independently of one another by one or
more groups selected from among fluorine, chlorine, bromine,
iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, F.sub.3C,
HF.sub.2C, FH.sub.2C, hydroxy-C.sub.1-6-alkyl, C.sub.1-3-alkyl,
C.sub.1-6-alkoxy, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--C.sub.1-3-alkyl, (R.sup.14).sub.2N--CO and
HOSO.sub.2--, [0026] denotes 0, 1, 2 or 3, [0027] B denotes a
C.sub.1-4-alkylene bridge, [0028] wherein in the case of a
C.sub.3-4-alkylene bridge the CH.sub.2 group of the
C.sub.3-4-alkylene bridge, which is bound to the group A, may be
replaced by --O--, and the C.sub.1-4-alkylene bridge may optionally
be substituted by one or more groups selected from among fluorine,
chlorine, bromine, iodine, hydroxy, oxo, carboxy, cyano, nitro,
F.sub.3C, HF.sub.2C, FH.sub.2C, C.sub.1-4-alkyl,
C.sub.1-6-alkyl-S--C.sub.1-3-alkyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-3-alkyl, aryl, aryl-C.sub.1-3-alkyl,
heteroaryl, heteroaryl-C.sub.1-3-alkyl, R.sup.15--O,
(R.sup.14).sub.2N--SO.sub.2, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--C.sub.1-3-alkyl, (R.sup.14).sub.2N--CO,
R.sup.14--SO.sub.2, R.sup.14--CO--(R.sup.14)N,
R.sup.14--SO.sub.2(R.sup.14)N, (R.sup.14).sub.2N--SO.sub.2,
R.sup.14--CO-- and R.sup.14--SO--, and [0029] two C.sub.1-4-alkyl
groups bound to the same carbon atom of the C.sub.1-4-alkylene
bridge may be joined together forming a C.sub.3-7-cycloalkyl group,
and [0030] the above-mentioned groups and the C.sub.3-7-cycloalkyl
group formed from the C.sub.1-4-alkyl groups may optionally be
substituted independently of one another by one or more groups
selected from among fluorine, chlorine, bromine, iodine, hydroxy,
oxo, carboxy, formyl, cyano, nitro, F.sub.3C, HF.sub.2C, FH.sub.2C,
C.sub.1-3-alkyl, C.sub.1-3-alkoxy, R.sup.15--O--C.sub.1-3-alkyl,
R.sup.14--CO(R.sup.14)N, R.sup.14--SO.sub.2(R.sup.14)N,
(R.sup.14).sub.2N, (R.sup.14).sub.2N--C.sub.1-3-alkyl,
(R.sup.14).sub.2N--CO, (R.sup.14).sub.2N--SO.sub.2-- and
HOSO.sub.2--, [0031] R.sup.1 denotes hydrogen, C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-6-alkyl,
C.sub.3-7-cycloalkyl-C.sub.2-6-alkenyl,
C.sub.3-7-cycloalkyl-C.sub.2-6-alkynyl, C.sub.3-7-cycloalkenyl,
C.sub.3-7-cycloalkenyl-C.sub.1-6-alkyl,
C.sub.3-7-cycloalkenyl-C.sub.2-6-alkenyl,
C.sub.3-7-cycloalkenyl-C.sub.2-6-alkynyl, aryl,
aryl-C.sub.1-6-alkyl, aryl-C.sub.2-6-alkenyl,
aryl-C.sub.2-6-alkynyl, heterocyclyl, heterocyclyl-C.sub.1-6-alkyl,
heterocyclyl-C.sub.2-6-alkenyl, heterocyclyl-C.sub.2-6-alkynyl,
heteroaryl, heteroaryl-C.sub.1-6-alkyl,
heteroaryl-C.sub.2-6-alkenyl or heteroaryl-C.sub.2-6-alkynyl,
[0032] wherein the above-mentioned groups may optionally be
substituted independently of one another by one or more groups
selected from among fluorine, chlorine, bromine, iodine, hydroxy,
oxo, carboxy, formyl, cyano, nitro, F.sub.3C, HF.sub.2C, FH.sub.2C,
C.sub.1-3-alkyl, C.sub.1-3-alkoxy, hydroxy-C.sub.1-6-alkyl,
(R.sup.14).sub.2N, (R.sup.14).sub.2N--C.sub.1-3-alkyl,
(R.sup.14).sub.2N--CO-- (R.sup.14).sub.2N--SO.sub.2,
R.sup.14--CO--(R.sup.14)N, R.sup.14--SO.sub.2--(R.sup.14)N and
HOSO.sub.2--, [0033] X.sup.1, denotes nitrogen or C(R.sup.10),
[0034] X.sup.2, X.sup.3, X.sup.4 each independently of one another
denote nitrogen or C(R.sup.11) with the proviso that 0, 1, 2 or 3
of the groups X.sup.1, X.sup.2, X.sup.3 and X.sup.4 may be
nitrogen, [0035] R.sup.2 denotes C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, R.sup.15--O--C.sub.1-3-alkyl,
C.sub.1-6-alkyl-S--C.sub.1-3-alkyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.2-6-alkynyl, C.sub.3-7-cycloalkenyl,
C.sub.3-7-cycloalkenyl-C.sub.1-6-alkyl,
C.sub.3-7-cycloalkenyl-C.sub.2-6-alkenyl,
C.sub.3-7-cycloalkenyl-C.sub.2-6-alkynyl, heterocyclyl,
C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl, heterocyclyl-C.sub.1-3-alkyl,
C.sub.3-7-cycloalkyl-C.sub.2-3-alkenyl,
heterocyclyl-C.sub.2-3-alkenyl, heterocyclyl-C.sub.2-3-alkynyl,
aryl, heteroaryl, aryl-C.sub.1-3-alkyl, heteroaryl-C.sub.1-3-alkyl,
aryl-C.sub.2-3-alkenyl, aryl-C.sub.2-3-alkynyl,
heteroaryl-C.sub.2-3-alkenyl or heteroaryl-C.sub.2-3-alkynyl,
[0036] wherein the above-mentioned groups may optionally be
substituted independently of one another by one or more groups
selected from among fluorine, chlorine, bromine, iodine, F.sub.3C,
HF.sub.2C, FH.sub.2C, hydroxy, oxo, carboxy, formyl, cyano, nitro,
(R.sup.14).sub.2N, HOSO.sub.2--, C.sub.1-3-alkyl,
C.sub.1-6-alkyl-S--C.sub.1-3-alkyl, (R.sup.14).sub.2N--SO.sub.2--,
R.sup.14--CO--(R.sup.14)N, R.sup.14--SO.sub.2--(R.sup.14)N,
(R.sup.14).sub.2N--C.sub.1-3-alkyl, (R.sup.14).sub.2N--CO,
R.sup.15--O and R.sup.15--O--C.sub.1-3-alkyl, [0037] R.sup.3,
R.sup.4 each independently of one another denote hydrogen,
C.sub.1-6-alkyl, fluorine, F.sub.3C, HF.sub.2C or FH.sub.2C, [0038]
R.sup.5, R.sup.7 each independently of one another denote hydrogen,
C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.3-7-cycloalkyl, heterocyclyl,
C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl,
C.sub.3-7-cycloalkyl-C.sub.2-6-alkynyl,
heterocyclyl-C.sub.1-3-alkyl,
C.sub.3-7-cycloalkyl-C.sub.2-4-alkenyl,
heterocyclyl-C.sub.2-4-alkenyl, heterocyclyl-C.sub.2-4-alkynyl,
C.sub.3-7-cycloalkenyl, C.sub.3-7-cycloalkenyl-C.sub.1-6-alkyl,
C.sub.3-7-cycloalkenyl-C.sub.2-6-alkenyl,
C.sub.3-7-cycloalkenyl-C.sub.2-6-alkynyl, aryl, heteroaryl,
aryl-C.sub.1-3-alkyl, heteroaryl-C.sub.1-3-alkyl,
aryl-C.sub.2-3-alkenyl, heteroaryl-C.sub.2-3-alkenyl,
aryl-C.sub.2-3-alkynyl or heteroaryl-C.sub.2-3-alkynyl, [0039]
wherein the above-mentioned groups may optionally be substituted
independently of one another by one or more groups selected from
among fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy,
formyl, cyano, nitro, C.sub.1-3-alkyl, R.sup.15--O,
C.sub.1-3-alkyl-S, aryl, heteroaryl, heteroaryl-C.sub.1-3-alkyl,
aryl-C.sub.1-6-alkyl, R.sup.14--CO--(R.sup.14)N,
R.sup.14--SO.sub.2--(R.sup.14)N, (R.sup.14).sub.2N--SO.sub.2--,
(R.sup.14).sub.2N, (R.sup.14).sub.2N--C.sub.1-3-alkyl,
(R.sup.14).sub.2N--CO and HOSO.sub.2--, [0040] R.sup.6, R.sup.9
each independently of one another denote hydrogen, C.sub.1-6-alkyl,
C.sub.1-6-alkoxy-C.sub.1-3-alkyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl, C.sub.2-6-alkenyl,
heterocyclyl-C.sub.1-3-alkyl, heteroaryl,
heteroaryl-C.sub.1-3-alkyl or C.sub.2-6-alkynyl, [0041] wherein the
above-mentioned groups may optionally be substituted independently
of one another by one or more groups selected from among fluorine,
chlorine, bromine, iodine, cyano, C.sub.1-3-alkyl,
C.sub.1-6-alkoxy- and (R.sup.14).sub.2N, [0042] R.sup.8 denotes
hydrogen, C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.3-7-cycloalkyl, C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl,
C.sub.3-7-cycloalkyl-C.sub.2-4-alkenyl,
C.sub.3-7-cycloalkyl-C.sub.2-4-alkynyl, C.sub.3-7-cycloalkenyl,
C.sub.3-7-cycloalkenyl-C.sub.1-6-alkyl,
C.sub.3-7-cycloalkenyl-C.sub.2-6-alkenyl,
C.sub.3-7-cycloalkenyl-C.sub.2-6-alkynyl, heterocyclyl,
heterocyclyl-C.sub.1-3-alkyl, heterocyclyl-C.sub.2-4-alkenyl,
heterocyclyl-C.sub.2-4-alkynyl, aryl, aryl-C.sub.1-3-alkyl,
aryl-C.sub.2-4-alkenyl, aryl-C.sub.2-4-alkynyl, heteroaryl,
heteroaryl-C.sub.1-3-alkyl, heteroaryl-C.sub.2-4-alkenyl or
heteroaryl-C.sub.2-4-alkynyl, [0043] wherein the above-mentioned
groups may optionally be substituted independently of one another
by one or more groups selected from among fluorine, chlorine,
bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro,
C.sub.1-3-alkyl, heterocyclyl, heterocyclyl-C.sub.1-3-alkyl,
R.sup.15--O, R.sup.15--O--C.sub.1-3-alkyl, R.sup.15--S,
R.sup.15--S--C.sub.1-3-alkyl, aryl, heteroaryl,
heteroaryl-C.sub.1-3-alkyl, aryl-C.sub.1-6-alkyl,
(R.sup.14).sub.2N, (R.sup.14).sub.2N--C.sub.1-3-alkyl,
(R.sup.14).sub.2N--CO, (R.sup.14).sub.2N--CO--N(R.sup.14)--,
(R.sup.14).sub.2N--SO.sub.2-- and HOSO.sub.2--, [0044] R.sup.10
denotes hydrogen, fluorine, chlorine, bromine, iodine, cyano,
C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.3-7-cycloalkyl, C.sub.3-7-cycloalkyl-C.sub.1-6-alkyl,
C.sub.3-7-cycloalkyl-C.sub.2-6-alkynyl, heterocyclyl,
heterocyclyl-C.sub.1-6-alkyl, heterocyclyl-C.sub.2-6-alkenyl,
heterocyclyl-C.sub.2-6-alkynyl,
C.sub.3-7-cycloalkyl-C.sub.2-6-alkenyl,
heterocyclyl-C.sub.2-4-alkenyl, C.sub.3-7-cycloalkenyl,
C.sub.3-7-cycloalkenyl-C.sub.1-6-alkyl,
C.sub.3-7-cycloalkenyl-C.sub.2-6-alkenyl,
C.sub.3-7-cycloalkenyl-C.sub.2-6-alkynyl, aryl,
aryl-C.sub.1-6-alkyl, heteroaryl, heteroaryl-C.sub.1-6-alkyl,
aryl-C.sub.2-6-alkenyl, heteroaryl-C.sub.2-6-alkenyl,
aryl-C.sub.2-6-alkynyl or heteroaryl-C.sub.2-6-alkynyl,
R.sup.15--O, R.sup.15--O--C.sub.1-3-alkyl,
R.sup.12--SO.sub.2--(R.sup.13)N or R.sup.12--CO--(R.sup.13)N,
[0045] wherein the above-mentioned groups may optionally be
substituted independently of one another by one or more groups
selected from among fluorine, chlorine, bromine, iodine, hydroxy,
oxo, carboxy, formyl, cyano, nitro, C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, C.sub.1-6-alkyl-S,
C.sub.1-6-alkyl-S--C.sub.1-3-alkyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-6-alkyl, aryl, aryl-C.sub.1-6-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-6-alkyl, heteroaryl,
heteroaryl-C.sub.1-6-alkyl, R.sup.15--O, R.sup.15--O--CO,
R.sup.15--CO, R.sup.15--O--CO--(R.sup.14)N,
(R.sup.14).sub.2N--CO--O, R.sup.14--O--C.sub.1-3-alkyl,
(R.sup.14).sub.2N, (R.sup.14).sub.2N--CO,
R.sup.14--CO--(R.sup.14)N, (R.sup.14).sub.2N--CO--(R.sup.14)N,
(R.sup.14).sub.2N--SO.sub.2--,
(R.sup.14).sub.2N--SO.sub.2--(R.sup.14)N, R.sup.14--SO.sub.2--,
F.sub.3C, HF.sub.2C, FH.sub.2C, F.sub.3C--O, HF.sub.2C--O,
FH.sub.2C--O and R.sup.14--SO.sub.2--(R.sup.14)N, [0046] R.sup.11
each independently of one another denote hydrogen, fluorine,
chlorine, bromine, iodine, R.sup.15--O, (R.sup.14).sub.2N or
C.sub.1-3-alkyl, [0047] wherein the C.sub.1-3-alkyl group may
optionally be substituted by one or more fluorine atoms, [0048]
R.sup.12 denotes C.sub.1-6-alkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, C.sub.3-7-cycloalkyl-C.sub.2-6-alkenyl,
aryl-C.sub.2-3-alkenyl, heteroaryl-C.sub.2-4-alkenyl,
heterocyclyl-C.sub.2-4-alkenyl, aryl-C.sub.2-3-alkynyl,
C.sub.3-7-cycloalkyl-C.sub.2-4-alkynyl,
heterocyclyl-C.sub.2-4-alkynyl-heteroaryl-C.sub.2-3-alkynyl,
C.sub.3-7-cycloalkyl, C.sub.3-7-cycloalkyl-C.sub.1-6-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-4-alkyl, C.sub.3-7-cycloalkenyl,
C.sub.3-7-cycloalkenyl-C.sub.1-6-alkyl,
C.sub.3-7-cycloalkenyl-C.sub.2-6-alkenyl,
C.sub.3-7-cycloalkenyl-C.sub.2-6-alkynyl, aryl,
aryl-C.sub.1-4-alkyl, heteroaryl, heteroaryl-C.sub.1-3-alkyl or
(R.sup.14).sub.2N, [0049] wherein the above-mentioned groups may
optionally be substituted independently of one another by one or
more groups selected from among fluorine, chlorine, bromine,
hydroxy, oxo, carboxy, formyl, cyano, nitro, C.sub.1-3-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl, R.sup.15--O,
R.sup.15--O--C.sub.1-3-alkyl, R.sup.14--CO(R.sup.14)N,
R.sup.14--SO.sub.2(R.sup.14)N, (R.sup.14).sub.2N--SO.sub.2--,
R.sup.14--SO.sub.2--, R.sup.14--SO, R.sup.14--S, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--C.sub.1-3-alkyl and (R.sup.14).sub.2N--CO,
[0050] R.sup.13 denotes hydrogen, C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl, aryl, aryl-C.sub.1-3-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl,
heterocyclyl-C.sub.2-3-alkenyl, heterocyclyl-C.sub.2-3-alkynyl,
heteroaryl, heteroaryl-C.sub.2-3-alkenyl,
heteroaryl-C.sub.2-3-alkynyl or heteroaryl-C.sub.1-3-alkyl, [0051]
wherein the above-mentioned groups may optionally be substituted
independently of one another by one or more groups selected from
among fluorine, chlorine, bromine, hydroxy, oxo, carboxy, formyl,
cyano, nitro, C.sub.1-3-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-3-alkyl, R.sup.15--O,
R.sup.15--O--C.sub.1-3-alkyl, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--C.sub.1-3-alkyl and R.sup.14CO, [0052] or [0053]
R.sup.12 and R.sup.13 together form a C.sub.2-6-alkylene bridge, so
that with the inclusion of the nitrogen atom linked to R.sup.13 and
the SO.sub.2-- or CO group linked to R.sup.12 a heterocyclic ring
is formed, [0054] wherein one or two CH.sub.2 groups of the
C.sub.2-6-alkylene bridge may be replaced independently of one
another by O, S, SO, SO.sub.2 or N(R.sup.14) in such a way that in
each case two O or S atoms or an 0 and an S atom are not joined
together directly, and [0055] the C atoms of the above-mentioned
C.sub.2-6-alkylene bridge may optionally be substituted by one or
more groups selected from among fluorine, chlorine, bromine,
hydroxy, carboxy, formyl, cyano, F.sub.3C, HF.sub.2C, FH.sub.2C,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, oxo and nitro, R.sup.14 each
independently of one another denote hydrogen, C.sub.1-6-alkyl,
C.sub.1-6-alkoxy-C.sub.1-3-alkyl, C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl, aryl or aryl-C.sub.1-3-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl, heteroaryl or
heteroaryl-C.sub.1-3-alkyl, wherein [0056] two C.sub.1-6-alkyl
groups bound to the same nitrogen atom together may form a
C.sub.2-6-alkylene bridge, so that with the inclusion of the
nitrogen atom bound to the groups R.sup.14 a heterocyclic ring is
formed, [0057] wherein a CH.sub.2 group of the C.sub.2-6-alkylene
bridge may be replaced by O, S or N(R.sup.14), and [0058] the
above-mentioned groups and the heterocyclic ring may optionally be
substituted independently of one another by one or more groups
selected from among fluorine, chlorine, bromine, iodine, hydroxy,
oxo, carboxy, formyl, cyano, nitro, C.sub.1-3-alkyl,
hydroxy-C.sub.1-3-alkyl, C.sub.1-3-alkoxy, (R.sup.15).sub.2N--CO--
and (R
.sup.15).sub.2N--, and [0059] R.sup.15 each independently of one
another denote hydrogen, C.sub.1-6-alkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl, aryl, aryl-C.sub.1-3-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl, heteroaryl or
heteroaryl-C.sub.1-3-alkyl, [0060] wherein the above-mentioned
groups may optionally be substituted independently of one another
by one or more groups selected from among fluorine, chlorine,
bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro,
C.sub.1-3-alkyl- and C.sub.1-3-alkoxy, the tautomers, the
stereoisomers, the mixtures thereof and the salts thereof,
particularly the physiologically acceptable salts thereof.
[0061] The compounds according to the invention of general formula
(I) and the physiologically acceptable salts thereof have valuable
pharmacological properties, particularly an inhibiting effect on
.beta.-secretase activity, particularly the .beta.-secretase
mediated cleaving of APP. In addition, the compounds of the present
invention are characterised by a surprisingly good cellular
activity.
[0062] In view of the inhibitory properties of the compounds
according to the invention on cathepsin D activity, the compounds
are also suitable for suppressing the metastasisation of tumour
cells. The present invention also relates to the physiologically
acceptable salts of the compounds according to the invention with
inorganic or organic acids.
[0063] The invention therefore also relates to the use of the
compounds according to the invention, including the physiologically
acceptable salts, as medicaments.
[0064] The invention further relates to pharmaceutical compositions
containing at least one compound according to the invention or a
physiologically acceptable salt according to the invention
optionally together with one or more inert carriers and/or
diluents.
[0065] This invention further relates to pharmaceutical
compositions containing one or more, preferably one active
substance, which is selected from the compounds according to the
invention and/or the corresponding salts, as well as one or more,
preferably one active substance, selected for example from among
the beta-secretase inhibitors; gamma-secretase inhibitors; amyloid
aggregation inhibitors such as e.g. alzhemed; directly or
indirectly acting neuroprotective substances; anti-oxidants, such
as e.g. vitamin E or ginkolide; anti-inflammatory substances, such
as e.g. Cox inhibitors, NSAIDs additionally or exclusively having
A.beta. lowering properties; HMG-CoA reductase inhibitors
(statins); acetylcholinesterase inhibitors, such as donepezil,
rivastigmine, tacrine, galantamine; NMDA receptor antagonists such
as e.g. memantine; AMPA agonists; substances modulating the
concentration or release of neurotransmitters such as NS-2330;
substances inducing the secretion of growth hormone such as
ibutamoren mesylate and capromorelin; CB-1 receptor antagonists or
inverse agonists; antibiotics such as minocyclin or rifampicin;
PDE-IV and PDE-IX inhibitors, GABA.sub.A inverse agonists,
nicotinic agonists, histamine H3 antagonists, 5 HAT-4 agonists or
partial agonists, 5HT-6 antagonists, a2-adrenoreceptor antagonists,
muscarinic M1 agonists, muscarinic M2 antagonists, metabotropic
glutamate-receptor 5 positive modulators, and other substances that
modulate receptors or enzymes in a manner such that the efficacy
and/or safety of the compounds according to the invention is
increased and/or unwanted side effects are reduced, optionally
together with one or more inert carriers and/or diluents.
[0066] This invention further relates to pharmaceutical
compositions containing one or more, preferably one active
substance, which is selected from the compounds according to the
invention and/or the corresponding salts, as well as one or more,
preferably one active substance selected from among alzhemed,
vitamin E, ginkolide, donepezil, rivastigmine, tacrine,
galantamine, memantine, NS-2330, ibutamoren mesylate, capromorelin,
minocyclin and/or rifampicin, optionally together with one or more
inert carriers and/or diluents.
[0067] This invention further relates to the use of at least one of
the compounds according to the invention for inhibiting
.beta.-secretase.
[0068] This invention also relates to the use of at least one
compound according to the invention or a physiologically acceptable
salt of such a compound for preparing a pharmaceutical composition,
which is suitable for the treatment or prophylaxis of diseases or
conditions associated with the abnormal processing of Amyloid
Precursor Protein (APP) or aggregation of the Abeta peptide.
[0069] This invention also relates to the use of at least one
compound according to the invention or a physiologically acceptable
salt of such a compound for preparing a pharmaceutical composition
which is suitable for the treatment or prophylaxis of diseases or
conditions which can be influenced by inhibiting the
.beta.-secretase activity.
[0070] This invention also relates to the use of at least one
compound according to the invention or a pharmaceutical composition
according to the invention for preparing a medicament which is
suitable for the treatment and/or prevention of Alzheimer's disease
(AD) and other diseases which are associated with the abnormal
processing of APP or aggregation of Abeta peptide, as well as
diseases which can be treated or prevented by the inhibition of
.beta.-secretase, particularly AD. Such diseases include MCI ("mild
cognitive impairment"), trisomy 21 (Down's syndrome), cerebral
amyloid angiopathy, degenerative dementias, hereditary cerebral
haemorrhage with amyloidosis, Dutch type (HCHWA-D), Alzheimer's
dementia with Lewy bodies, trauma, stroke, pancreatitis, Inclusion
Body Myositis (IBM), and other peripheral amyloidoses, diabetes and
arteriosclerosis.
[0071] This invention further relates to a method of inhibiting
.beta.-secretase activity, characterised in that .beta.-secretase
is brought into contact with an inhibitory amount of one of the
compounds according to the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0072] Unless otherwise stated the groups, residues and
substituents R.sup.1 to R.sup.15, A, B, L, i and X.sup.1-X.sup.4
have the meanings given hereinbefore and below.
[0073] If residues, substituents or groups occur more than once in
a compound, they may have the same or different meanings.
[0074] In a preferred embodiment of the compounds of the present
invention the group
##STR00004##
denotes a phenyl, biphenyl, naphthyl or a 5-, 6-, 7-, 8-, 9- or
10-membered aromatic mono- or bicyclic heteroaryl group which
contains 1-4 heteroatoms selected from N, O and S.
[0075] In another preferred embodiment of the compounds of the
present invention the group
##STR00005##
denotes a phenyl ring or a 5- or 6-membered aromatic heteroaryl
group which contains 1 or 2 heteroatoms selected from N, O and S,
wherein a maximum of one O or S atom may be present.
[0076] In another preferred embodiment the group
##STR00006##
has the following meanings:
##STR00007##
[0077] In a particularly preferred embodiment the group
##STR00008##
denotes a phenyl, thienyl, thiazolyl, particularly 2-thiazolyl, or
a pyridyl group, wherein the phenyl, the thienyl, particularly the
3-thienyl, and the pyridyl group, particularly the 2-pyridyl group,
are deemed to be particularly preferred.
[0078] Preferably the substituent L denotes independently of one
another in each case hydrogen, fluorine, chlorine, bromine, iodine,
hydroxy, carboxy, cyano, nitro, F.sub.3C, HF.sub.2C, FH.sub.2C,
C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.3-7-cycloalkyl, C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl, aryl,
aryl-C.sub.1-3-alkyl, heterocyclyl, heterocyclyl-C.sub.1-3-alkyl,
heteroaryl, heteroaryl-C.sub.1-3-alkyl, R.sup.15--O,
R.sup.15--O--C.sub.1-3-alkyl, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--CO, R.sup.14--CO--(R.sup.14)N,
(R.sup.14).sub.2N--CO--(R.sup.14)N, (R.sup.14).sub.2N--SO.sub.2--,
R.sup.14--SO.sub.2--(R.sup.14)N or C.sub.1-3-alkyl-SO.sub.2--,
wherein the above-mentioned groups may optionally be substituted
independently of one another by one or more groups selected from
among fluorine, chlorine, bromine, hydroxy, oxo, carboxy, cyano,
nitro, F.sub.3C, HF.sub.2C, FH.sub.2C, hydroxy-C.sub.1-3-alkyl,
C.sub.1-3-alkyl, C.sub.1-3-alkoxy, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--C.sub.1-3-alkyl and (R.sup.14).sub.2N--CO.
[0079] Particularly preferably the substituent L denotes
independently of one another in each case hydrogen, fluorine,
chlorine, bromine, iodine, cyano, hydroxy, C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl, phenyl, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--CO, R.sup.14--CO(R.sup.14)N,
(R.sup.14).sub.2N--CO--(R.sup.14)N, R.sup.14--SO.sub.2--(R.sup.14)N
or (R.sup.14).sub.2N--SO.sub.2--, wherein the above-mentioned
groups may optionally be substituted by one or more fluorine
atoms.
[0080] Most particularly preferred meanings for the substituent L,
independently of one another in each case, are hydrogen, fluorine,
chlorine, bromine, hydroxy, C.sub.1-4-alkyl or C.sub.1-4-alkoxy,
wherein the above-mentioned groups may optionally be substituted by
one or more fluorine atoms.
[0081] Particularly preferred meanings for the substituent L,
independently of one another in each case, are hydrogen, fluorine,
chlorine, trifluoromethyl, trifluoromethoxy, methyl and
methoxy.
[0082] Preferably the index i may assume the values 0, 1 or 2. In
particularly preferred embodiments the value of the index i is 0 or
1.
[0083] In a preferred embodiment of the compounds according to the
invention the group B represents a C.sub.1-4-alkylene bridge which
may optionally be substituted independently of one another by one
or more groups selected from among fluorine, chlorine, bromine,
iodine, hydroxy, oxo, carboxy, cyano, nitro, F.sub.3C, HF.sub.2C,
FH.sub.2C, C.sub.1-4-alkyl, C.sub.1-6-alkyl-S--C.sub.1-3-alkyl,
C.sub.3-7-cycloalkyl, C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl, aryl,
aryl-C.sub.1-3-alkyl, heteroaryl, heteroaryl-C.sub.1-3-alkyl,
R.sup.15--O, (R.sup.14).sub.2N--SO.sub.2--, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--C.sub.1-3-alkyl, (R.sup.14).sub.2N--CO,
R.sup.14--SO.sub.2--, R.sup.14--CO--(R.sup.14)N,
R.sup.14--SO.sub.2(R.sup.14)N, (R.sup.14).sub.2N--SO.sub.2--,
R.sup.14--CO and R.sup.14--SO, and wherein two C.sub.1-4-alkyl
groups bound to the same carbon atom of the C.sub.1-4-alkylene
bridge may be joined together forming a C.sub.3-7-cycloalkyl group,
and the above-mentioned groups and the C.sub.3-7-cycloalkyl group
formed from the C.sub.1-4-alkyl groups may optionally be
substituted independently of one another by one or more groups
selected from among fluorine, chlorine, bromine, iodine, hydroxy,
oxo, carboxy, formyl, cyano, nitro, F.sub.3C, HF.sub.2C, FH.sub.2C,
C.sub.1-3-alkyl, C.sub.1-3-alkoxy, R.sup.15--O--C.sub.1-3-alkyl,
R.sup.14--CO(R.sup.14)N, R.sup.14--SO.sub.2(R.sup.14)N,
(R.sup.14).sub.2N, (R.sup.14).sub.2N--C.sub.1-3-alkyl,
(R.sup.14).sub.2N--CO, (R.sup.14).sub.2N--SO.sub.2-- and
HOSO.sub.2--.
[0084] In another preferred embodiment of the compounds according
to the invention the group B represents a C.sub.1-4-alkylene
bridge, which may optionally be substituted independently of one
another by one or more groups selected from among fluorine,
hydroxy, carboxy, cyano, nitro, F.sub.3C, HF.sub.2C, FH.sub.2C,
C.sub.1-4-alkyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-3-alkyl, aryl, aryl-C.sub.1-3-alkyl,
heteroaryl, heteroaryl-C.sub.1-3-alkyl, R.sup.15--O,
(R.sup.14).sub.2N--SO.sub.2-- and (R.sup.14).sub.2N, and two
C.sub.1-4-alkyl groups bound to the same carbon atom of the
C.sub.1-4-alkylene bridge may be joined together forming a
C.sub.3-7-cycloalkyl group, and the above-mentioned groups and the
C.sub.3-7-cycloalkyl group formed from the C.sub.1-4-alkyl groups
may optionally be substituted independently of one another by one
or more groups selected from among fluorine, chlorine, bromine,
hydroxy, carboxy, cyano, F.sub.3C, HF.sub.2C, FH.sub.2C,
C.sub.1-3-alkyl, C.sub.1-3-alkoxy- and
R.sup.15--O--C.sub.1-3-alkyl.
[0085] Particularly preferably the group B denotes a
C.sub.1-4-alkylene bridge, wherein the C.sub.1-4-alkylene bridge
may optionally be substituted independently of one another by one
or more groups selected from among C.sub.1-4-alkyl, phenyl- and
benzyl, and two C.sub.1-4-alkyl groups bound to the same carbon
atom of the C.sub.1-4-alkylene bridge may be joined together
forming a C.sub.3-6-cycloalkyl group, and the above-mentioned
groups and the C.sub.3-7-cycloalkyl group formed from the
C.sub.1-4-alkyl groups may optionally be substituted independently
of one another by one or more groups selected from among fluorine,
hydroxy and C.sub.1-3-alkoxy.
[0086] Most particularly preferred are the compounds according to
the invention wherein the group B is selected from among
##STR00009##
wherein one or more hydrogen atoms may optionally be replaced by
fluorine.
[0087] In another most particularly preferred embodiment B is a
C.sub.1-2-alkylene bridge which may optionally be substituted by
one or more C.sub.1-4-alkyl groups, and wherein two C.sub.1-4-alkyl
groups bound to the same carbon atom of the C.sub.1-2-alkylene
bridge may be joined together forming a cyclopropyl group, and one
or more hydrogen atoms of the above-mentioned C.sub.1-2-alkylene
bridge and/or the C.sub.1-4-alkyl groups and/or the cyclopropyl
group formed therefrom may optionally be replaced by one or more
fluorine atoms.
[0088] Particularly preferred are those compounds according to the
invention wherein the group B is selected from among
##STR00010##
wherein one or more hydrogen atoms may optionally be replaced by
fluorine.
[0089] Another preferred embodiment comprises those compounds
according to the invention wherein the partial formula (II)
##STR00011##
is selected from among
##STR00012## ##STR00013## ##STR00014## ##STR00015## ##STR00016##
##STR00017##
[0090] Preferably the group R.sup.1 is selected from among
hydrogen, C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.3-7-cycloalkyl, C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl, aryl,
aryl-C.sub.1-3-alkyl, heteroaryl and heteroaryl-C.sub.1-3-alkyl,
wherein the above-mentioned groups may optionally be substituted
independently of one another by one or more groups selected from
among fluorine, chlorine, bromine, hydroxy, carboxy, cyano, nitro,
F.sub.3C, HF.sub.2C, FH.sub.2C, C.sub.1-3-alkyl, C.sub.1-3-alkoxy
and hydroxy-C.sub.1-3-alkyl.
[0091] Particularly preferred are those groups R.sup.1 selected
from among hydrogen, C.sub.1-4-alkyl, C.sub.3-4-alkenyl,
C.sub.3-6-cycloalkyl- and C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl,
wherein the above-mentioned groups may optionally be substituted
independently of one another by one or more groups selected from
among fluorine, hydroxy and C.sub.1-3-alkoxy.
[0092] Most particularly preferred are the groups R.sup.1 selected
from among hydrogen and C.sub.1-4-alkyl, wherein the
C.sub.1-4-alkyl group may be substituted by one or more fluorine
atoms.
[0093] Particularly preferred are those compounds according to the
invention wherein R.sup.1 is hydrogen.
[0094] In a preferred embodiment X.sup.1 is C(R.sup.10) and
X.sup.2, X.sup.3, X.sup.4 each independently of one another denote
C(R.sup.11), wherein the groups R.sup.1 may each be selected
independently of one another from the definitions given for
R.sup.11 hereinbefore and below.
[0095] In a particularly preferred embodiment X.sup.1 is
C(R.sup.10) and X.sup.2, X.sup.3, X.sup.4 in each case denote a
.dbd.CH-- group.
[0096] Preferred groups R.sup.2 are groups selected from among
C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.1-6-alkoxy-C.sub.1-3-alkyl,
C.sub.1-6-alkyl-S--C.sub.1-3-alkyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkenyl-C.sub.1-3-alkyl,
C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-3-alkyl, aryl, aryl-C.sub.1-3-alkyl,
heteroaryl and heteroaryl-C.sub.1-3-alkyl, wherein the
above-mentioned groups may optionally be substituted independently
of one another by one or more groups selected from among fluorine,
chlorine, bromine, iodine, F.sub.3C, HF.sub.2C, FH.sub.2C, hydroxy,
carboxy, cyano, nitro, C.sub.1-3-alkyl,
(R.sup.14).sub.2N--SO.sub.2--, (R.sup.14).sub.2N,
R.sup.14--CO--(R.sup.14)N, R.sup.14--SO.sub.2(R.sup.14)N,
(R.sup.14).sub.2N--C.sub.1-3-alkyl, (R.sup.14).sub.2N--CO,
R.sup.15--O and R.sup.15--O--C.sub.1-3-alkyl.
[0097] Particularly preferred groups R.sup.2 are groups selected
from among C.sub.1-6-alkyl, C.sub.2-6-alkynyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl, heterocyclyl-C.sub.1-3-alkyl,
phenyl, phenyl-C.sub.1-3-alkyl, heteroaryl and
heteroaryl-C.sub.1-3-alkyl, wherein by the above-mentioned
heteroaryl groups are meant 5- or 6-membered aromatic heteroaryl
groups, which contain 1, 2 or 3 heteroatoms selected from N, O and
S, and wherein the above-mentioned groups may optionally be
substituted independently of one another by one or more groups
selected from among fluorine, chlorine, bromine, iodine, cyano,
hydroxy, C.sub.1-3-alkyl, F.sub.3C, HF.sub.2C, FH.sub.2C,
C.sub.1-3-alkoxy and (R.sup.14).sub.2N.
[0098] Other particularly preferred groups R.sup.2 are groups
selected from among C.sub.1-6-alkyl, C.sub.2-6-alkynyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl, heterocyclyl-C.sub.1-3-alkyl,
phenyl, phenyl-C.sub.1-3-alkyl, heteroaryl and
heteroaryl-C.sub.1-3-alkyl, wherein by the above-mentioned
heteroaryl groups are meant 5- or 6-membered aromatic heteroaryl
groups, which contain 1 or 2 heteroatoms selected from N, O and S,
wherein a maximum of one O or S atom may be present, and wherein
the above-mentioned groups may optionally be substituted
independently of one another by one or more groups selected from
among fluorine, chlorine, bromine, iodine, cyano, hydroxy,
C.sub.1-3-alkyl, F.sub.3C, HF.sub.2C, FH.sub.2C, C.sub.1-3-alkoxy
and (R.sup.14).sub.2N.
[0099] Most particularly preferred are those groups R.sup.2 which
are selected from among n-propyl, n-butyl, 2-propynyl, 2-butynyl,
benzyl, 2-phenylethyl, pyridylmethyl, particularly 3-pyridylmethyl,
furanylmethyl, thienylmethyl and thiazolylmethyl,
wherein the above-mentioned propyl, butyl, propynyl and butynyl
groups may optionally be substituted by one or more fluorine atoms
and the benzyl, 2-phenylethyl, furanylmethyl, thienylmethyl or
thiazolylmethyl groups may optionally be substituted independently
of one another by one or more groups selected from among fluorine,
chlorine, bromine, methyl, F.sub.3C, HF.sub.2C, FH.sub.2C and
H.sub.2N.
[0100] Also most particularly preferred are those groups R.sup.2
which are selected from among n-butyl, benzyl, 2-phenylethyl,
pyridylmethyl, particularly 3-pyridylmethyl, thienylmethyl and
thiazolylmethyl, wherein the above-mentioned phenyl groups of the
benzyl and 2-phenylethyl groups may optionally be substituted by
one or more fluorine atoms.
[0101] Particularly preferred are those groups R.sup.2 which are
selected from among benzyl, 3,5-difluorobenzyl, thienylmethyl,
particularly 3-thienylmethyl- and n-butyl, the benzyl group being
the most preferred group.
[0102] Preferably the group R.sup.3 denotes hydrogen,
C.sub.1-6-alkyl, fluorine, F.sub.3C, HF.sub.2C or FH.sub.2C-- and
particularly preferably R.sup.3 is hydrogen.
[0103] The group R.sup.4 is preferably hydrogen.
[0104] In a particularly preferred embodiment of the compounds
according to the invention the group R.sup.3 is selected from among
hydrogen, C.sub.1-6-alkyl, fluorine, F.sub.3C, HF.sub.2C or
FH.sub.2C and the group R.sup.4 is hydrogen.
[0105] In a most particularly preferred embodiment of the compounds
according to the invention the groups R.sup.3 and R.sup.4 are
hydrogen.
[0106] Preferred groups R.sup.8 are groups selected from among
hydrogen, C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.3-7-cycloalkyl, C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl,
C.sub.3-7-cycloalkenyl, C.sub.3-7-cycloalkenyl-C.sub.1-3-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl, aryl,
aryl-C.sub.1-3-alkyl, heteroaryl and heteroaryl-C.sub.1-3-alkyl,
wherein the above-mentioned groups may optionally be substituted
independently of one another by one or more groups selected from
among fluorine, chlorine, bromine, iodine, hydroxy, carboxy, cyano,
nitro, C.sub.1-3-alkyl, heterocyclyl, heterocyclyl-C.sub.1-3-alkyl,
aryl, aryl-C.sub.1-3-alkyl, heteroaryl, heteroaryl-C.sub.1-3-alkyl,
(R.sup.14).sub.2N, (R.sup.14).sub.2N--C.sub.1-3-alkyl,
(R.sup.14).sub.2N--CO, (R.sup.14).sub.2N--CO--N(R.sup.14)--,
(R.sup.14).sub.2N--SO.sub.2, R.sup.5--O,
R.sup.15--O--C.sub.1-3-alkyl, R.sup.15--S and
R.sup.15--S--C.sub.1-3-alkyl.
[0107] Particularly preferred groups R.sup.8 are groups selected
from among hydrogen, C.sub.1-6-alkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-3-alkyl, phenyl, phenyl-C.sub.1-3-alkyl,
heteroaryl and heteroaryl-C.sub.1-3-alkyl, wherein by the
above-mentioned heteroaryl groups are meant 5- or 6-membered
aromatic heteroaryl groups which contain 1, 2 or 3 heteroatoms
selected from N, O and S, and wherein the above-mentioned groups
may optionally be substituted independently of one another by one
or more groups selected from among fluorine, chlorine, bromine,
carboxy, hydroxy, cyano, C.sub.1-3-alkyl, C.sub.1-3-alkoxy,
C.sub.1-3-alkoxy-C.sub.1-3-alkyl, C.sub.1-3-alkyl-S,
C.sub.1-3-alkyl-S--C.sub.1-3-alkyl, hydroxy-C.sub.1-3-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--C.sub.1-3-alkyl,
(R.sup.14).sub.2N--CO--N(R.sup.14)-- and
(R.sup.14).sub.2N--SO.sub.2--.
[0108] Other particularly preferred groups R.sup.8 are groups
selected from among hydrogen, C.sub.1-6-alkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-3-alkyl, phenyl, phenyl-C.sub.1-3-alkyl,
heteroaryl and heteroaryl-C.sub.1-3-alkyl, wherein by the
above-mentioned heteroaryl groups are meant 5- or 6-membered
aromatic heteroaryl groups which contain 1 or 2 heteroatoms
selected from N, O and S, wherein a maximum of one O or S atom may
be present, and wherein the above-mentioned groups may optionally
be substituted independently of one another by one or more groups
selected from among fluorine, chlorine, bromine, carboxy, hydroxy,
cyano, C.sub.1-3-alkyl, C.sub.1-3-alkoxy,
C.sub.1-3-alkoxy-C.sub.1-3-alkyl, C.sub.1-3-alkyl-S,
C.sub.1-3-alkyl-S--C.sub.1-3-alkyl, hydroxy-C.sub.1-3-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--C.sub.1-3-alkyl,
(R.sup.14).sub.2N--CO--N(R.sup.14)-- and
(R.sup.14).sub.2N--SO.sub.2--.
[0109] Most particularly preferred are those groups R.sup.8 which
are selected from among hydrogen, C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl,
phenyl-C.sub.1-3-alkyl or tetrahydropyranyl-C.sub.1-3-alkyl,
particularly 4-tetrahydropyranyl-C.sub.1-3-alkyl, wherein the
above-mentioned groups may optionally be substituted independently
of one another by one or more groups selected from among fluorine,
chlorine, bromine, pyrrolidin-1-ylmethyl, hydroxy, cyano,
C.sub.1-3-alkyl, C.sub.1-3-alkoxy, C.sub.1-3-alkyl-S,
hydroxy-C.sub.1-3-alkyl, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--C.sub.1-3-alkyl,
(R.sup.14).sub.2N--CO--N(R.sup.14)-- and
(R.sup.14).sub.2N--SO.sub.2--.
[0110] Particularly preferred as the group R.sup.8 is
C.sub.1-6-alkyl, particularly C.sub.1-4-alkyl,
C.sub.3-5-cycloalkyl-C.sub.1-2-alkyl, wherein R.sup.8 in its most
preferred embodiment denotes a methyl or ethyl group.
[0111] Preferred groups R.sup.5 and R.sup.7 are each selected
independently of one another from among hydrogen, C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, C.sub.3-7-cycloalkyl,
heterocyclyl, C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl,
heterocyclyl-C.sub.1-3-alkyl, C.sub.3-7-cycloalkenyl,
C.sub.3-7-cycloalkenyl-C.sub.1-3-alkyl, aryl, heteroaryl,
aryl-C.sub.1-3-alkyl- and heteroaryl-C.sub.1-3-alkyl, wherein the
above-mentioned groups may optionally be substituted independently
of one another by one or more groups selected from among fluorine,
chlorine, bromine, iodine, hydroxy, carboxy, cyano, nitro,
C.sub.1-3-alkyl, C.sub.1-3-alkoxy, C.sub.1-3-alkyl-S, aryl,
heteroaryl, heteroaryl-C.sub.1-3-alkyl, aryl-C.sub.1-3-alkyl,
(R.sup.14).sub.2N--SO.sub.2--, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--C.sub.1-3-alkyl and (R.sup.14).sub.2N--CO.
[0112] Particularly preferred groups R.sup.5 are selected from
among C.sub.1-6-alkyl, cyclopropyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl and phenyl-C.sub.1-3-alkyl,
wherein the above-mentioned groups may optionally be substituted
independently of one another by one or more groups selected from
among fluorine, chlorine, bromine, iodine, cyano, hydroxy, carboxy,
C.sub.1-3-alkyl, C.sub.1-3-alkoxy and (R.sup.14).sub.2N.
[0113] Particularly preferred groups R.sup.7 are selected from
among C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl, phenyl and
phenyl-C.sub.1-3-alkyl, wherein the above-mentioned groups may
optionally be substituted independently of one another by one or
more groups selected from among fluorine, chlorine, bromine,
iodine, cyano, hydroxy, carboxy, C.sub.1-3-alkyl, C.sub.1-3-alkoxy
and (R.sup.14).sub.2N.
[0114] In a most particularly preferred embodiment of the compounds
according to the invention R.sup.5 is selected from among
C.sub.1-6-alkyl, cyclopropyl, C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl
and phenyl-C.sub.1-3-alkyl, wherein the above-mentioned groups may
optionally be substituted independently of one another by one or
more groups selected from among fluorine, chlorine, bromine,
iodine, cyano, hydroxy, carboxy, C.sub.1-3-alkyl, C.sub.1-3-alkoxy
and (R.sup.14).sub.2N, and R.sup.7 is selected from among
C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl, phenyl and
phenyl-C.sub.1-3-alkyl, wherein the above-mentioned groups may
optionally be substituted independently of one another by one or
more groups selected from among fluorine, chlorine, bromine,
iodine, cyano, hydroxy, carboxy, C.sub.1-3-alkyl, C.sub.1-3-alkoxy
and (R.sup.14).sub.2N.
[0115] Particularly preferred compounds are those wherein R.sup.5
and R.sup.7 each independently of one another denote
C.sub.1-4-alkyl or cyclopropyl groups, wherein one or more hydrogen
atoms of the above-mentioned groups may optionally be replaced by
fluorine atoms.
[0116] Particularly preferred compounds are those wherein R.sup.5
and R.sup.7 each independently of one another denote
C.sub.1-4-alkyl groups, wherein one or more hydrogen atoms of the
C.sub.1-4-alkyl groups may optionally be replaced by fluorine
atoms, wherein R.sup.5 is most preferably a methyl group and
R.sup.7 is most preferably an ethyl or isopropyl group.
[0117] Preferred groups R.sup.6 and R.sup.9 are in each case
selected independently of one another from among hydrogen,
C.sub.1-6-alkyl, C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl,
C.sub.2-6-alkenyl and C.sub.2-6-alkynyl, wherein one or more
hydrogen atoms of the above-mentioned groups may be replaced by
fluorine.
[0118] In a particularly preferred embodiment of the compounds
according to the invention R.sup.6 is hydrogen and R.sup.9 is
selected from among hydrogen and C.sub.1-4-alkyl, wherein one or
more hydrogen atoms of the C.sub.1-4-alkyl group may be replaced by
fluorine.
[0119] In a most particularly preferred embodiment of the compounds
according to the invention the groups R.sup.6 and R.sup.9 are
hydrogen.
[0120] Preferred groups R.sup.10 are groups selected from among
hydrogen, fluorine, chlorine, bromine, cyano, C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-6-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-6-alkyl, C.sub.3-7-cycloalkenyl, aryl,
aryl-C.sub.1-6-alkyl, heteroaryl, heteroaryl-C.sub.1-6-alkyl,
R.sup.15--O, R.sup.15--O--C.sub.1-3-alkyl,
R.sup.12--SO.sub.2--(R.sup.12)N and R.sup.13--CO--(R.sup.12)N,
wherein the above-mentioned groups may optionally be substituted
independently of one another by one or more groups selected from
among fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy,
formyl, cyano, nitro, C.sub.3-7-cycloalkyl, heterocyclyl,
(R.sup.14).sub.2N, (R.sup.14).sub.2N--CO, R.sup.15--CO,
R.sup.15--O--CO, R.sup.14--CO--(R.sup.14)N,
(R.sup.14).sub.2N--CO--(R.sup.14)N, (R.sup.14).sub.2N--SO.sub.2--,
(R.sup.14).sub.2N--SO.sub.2--(R.sup.14)N, R.sup.14--SO.sub.2--,
C.sub.1-4-alkyl, R.sup.14--O, C.sub.1-4-alkyl-S, F.sub.3C,
HF.sub.2C, FH.sub.2C, F.sub.3C--O, HF.sub.2C--O, FH.sub.2C--O and
R.sup.14--SO.sub.2--(R.sup.14)N.
[0121] Particularly preferred groups R.sup.10 are groups selected
from among hydrogen, fluorine, chlorine, bromine, cyano,
C.sub.1-4-alkyl, C.sub.1-4-alkoxy, C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyl-oxy, C.sub.3-6-cycloalkyl-C.sub.1-3-alkoxy,
1,3-diazacyclohexan-2-on-1-yl, 2-oxo-1,3-oxazinan-3-yl,
3-oxomorpholino, 1,1-dioxo-[1,2,6]thiadiazinan-2-yl, phenyl,
pyridyl, thienyl, furyl, R.sup.12--CO--(R.sup.13)N and
R.sup.2--SO.sub.2--(R.sup.13)N, wherein the above-mentioned groups
may optionally be substituted independently of one another by one
or more groups selected from among fluorine, chlorine, bromine,
carboxy, cyano, C.sub.1-4-alkyl, C.sub.1-4-alkoxy,
C.sub.1-4-alkyl-S, R.sup.15--CO, R.sup.15--O--CO,
R.sup.14--SO.sub.2--, F.sub.3C, HF.sub.2C, FH.sub.2C, F.sub.3C--O,
HF.sub.2C--O, FH.sub.2C--O and (R.sup.14).sub.2N--CO.
[0122] Other particularly preferred groups R.sup.10 are groups
selected from among R.sup.12--CO--(R.sup.13)N,
R.sup.12--SO.sub.2--(R.sup.13)N, cyanophenyl, particularly
o-cyanophenyl, and cyanothienyl, particularly o-cyanothienyl,
wherein the above-mentioned cyanophenyl and cyanothienyl groups may
optionally be substituted independently of one another by one or
more groups selected from among fluorine, chlorine, bromine,
C.sub.1-4-alkyl, C.sub.1-4-alkoxy, F.sub.3C, HF.sub.2C, FH.sub.2C,
F.sub.3C--O, HF.sub.2C--O and FH.sub.2C--O.
[0123] In another most particularly preferred embodiment of the
compounds according to the invention the group R.sup.10 denotes
R.sup.12--SO.sub.2--(R.sup.13)N or o-cyanophenyl, wherein the
o-cyanophenyl group may optionally be substituted by a
C.sub.1-4-alkyl or C.sub.1-4-alkoxy group.
[0124] Preferred groups R.sup.11 are in each case selected
independently of one another from among hydrogen, fluorine,
chlorine, bromine, iodine, methyl and F.sub.3C, wherein the groups
hydrogen, fluorine, chlorine and bromine are particularly
preferred, and the group hydrogen is most preferred.
[0125] Also preferred according to the invention are those
compounds wherein R.sup.10 denotes hydrogen, fluorine, chlorine,
bromine, cyano, C.sub.1-6-alkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-6-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-6-alkyl, C.sub.3-7-cycloalkenyl, aryl,
aryl-C.sub.1-6-alkyl, heteroaryl, heteroaryl-C.sub.1-6-alkyl,
R.sup.15--O, R.sup.15--O--C.sub.1-3-alkyl,
R.sup.12--SO.sub.2--(R.sup.13)N or R.sup.12--CO--(R.sup.13)N,
wherein the above-mentioned groups may optionally be substituted
independently of one another by one or more groups selected from
among fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy,
formyl, cyano, nitro, C.sub.3-7-cycloalkyl, heterocyclyl,
(R.sup.14).sub.2N, (R.sup.14).sub.2N--CO, R.sup.15--CO,
R.sup.15--O--CO, R.sup.14--CO--(R.sup.14)N,
(R.sup.14).sub.2N--CO--(R.sup.14)N, (R.sup.14).sub.2N--SO.sub.2--,
(R.sup.14).sub.2N--SO.sub.2--(R.sup.14)N, R.sup.14--SO.sub.2--,
C.sub.1-4-alkyl, R.sup.15--O, C.sub.1-4-alkyl-S, F.sub.3C,
HF.sub.2C, FH.sub.2C, F.sub.3C--O, HF.sub.2C--O, FH.sub.2C--O and
R.sup.14--SO.sub.2--(R.sup.14)N, and R.sup.11 each independently of
one another denote hydrogen, fluorine, chlorine, bromine, iodine,
methyl or F.sub.3C.
[0126] Particularly preferred are those compounds according to the
invention wherein R.sup.10 denotes hydrogen, fluorine, chlorine,
bromine, cyano, C.sub.1-4-alkyl, C.sub.1-4-alkoxy,
C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkyl-oxy,
C.sub.3-6-cycloalkyl-C.sub.1-3-alkoxy,
1,3-diazacyclohexan-2-on-1-yl, 2-oxo-1,3-oxazinan-3-yl,
3-oxomorpholino, 1,1-dioxo-[1,2,6]thiadiazinan-2-yl, phenyl,
pyridyl, thienyl, furyl, R.sup.12--CO--(R.sup.13)N or
R.sup.12--SO.sub.2--(R.sup.13)N, wherein the above-mentioned groups
may optionally be substituted independently of one another by one
or more groups selected from among fluorine, chlorine, bromine,
carboxy, cyano, C.sub.1-4-alkyl, C.sub.1-4-alkoxy,
C.sub.1-4-alkyl-S, R.sup.15--CO, R.sup.15--O--CO,
R.sup.14--SO.sub.2--, F.sub.3C, HF.sub.2C, FH.sub.2C, F.sub.3C--O,
HF.sub.2C--O, FH.sub.2C--O and (R.sup.14).sub.2N--CO, and R.sup.11
each independently of one another denote hydrogen, fluorine,
chlorine or bromine.
[0127] Most particularly preferred are those compounds according to
the invention wherein R.sup.10 denotes the group
R.sup.12--CO--(R.sup.13)N, R.sup.12--SO.sub.2--(R.sup.13)N,
cyanophenyl, particularly o-cyanophenyl, or cyanothienyl,
particularly o-cyanothienyl, wherein the above-mentioned
cyanophenyl and cyanothienyl groups may optionally be substituted
independently of one another by one or more groups selected from
among fluorine, chlorine, bromine, C.sub.1-4-alkyl,
C.sub.1-4-alkoxy, F.sub.3C, HF.sub.2C, FH.sub.2C, F.sub.3C--O,
HF.sub.2C--O and FH.sub.2C--O, and R.sup.11 each independently of
one another denote hydrogen, fluorine, chlorine or bromine,
particularly hydrogen.
[0128] Most particularly preferred are those compounds according to
the invention wherein R.sup.10 denotes the group
R.sup.12--SO.sub.2--(R.sup.13)N or o-cyanophenyl, wherein the
o-cyanophenyl group may optionally be substituted by a
C.sub.1-4-alkyl or C.sub.1-4-alkoxy group, and R.sup.11 each
independently of one another denote hydrogen, fluorine, chlorine or
bromine, particularly hydrogen.
[0129] Preferred groups R.sup.12 are groups selected from among
C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.3-7-cycloalkyl, C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl, C.sub.3-7-cycloalkenyl,
C.sub.3-7-cycloalkenyl-C.sub.1-3-alkyl, aryl, aryl-C.sub.1-3-alkyl,
heteroaryl, heteroaryl-C.sub.1-3-alkyl and (R.sup.14).sub.2N,
wherein the above-mentioned groups may optionally be substituted
independently of one another by one or more groups selected from
among fluorine, chlorine, bromine, hydroxy, carboxy, cyano, nitro,
C.sub.1-3-alkyl, heterocyclyl, heterocyclyl-C.sub.1-3-alkyl,
C.sub.1-3-alkoxy, hydroxy-C.sub.1-3-alkyl, R.sup.14--CO(R.sup.14)N,
R.sup.14--SO.sub.2(R.sup.14)N, (R.sup.14).sub.2N--SO.sub.2--,
R.sup.14--SO.sub.2--, R.sup.14--SO, R.sup.14--S, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--C.sub.1-3-alkyl and (R.sup.14).sub.2N--CO.
[0130] Particularly preferred groups R.sup.12 are groups selected
from among C.sub.1-6-alkyl, heterocyclyl, phenyl,
phenyl-C.sub.1-3-alkyl, heteroaryl, heteroaryl-C.sub.1-3-alkyl- and
(R.sup.14).sub.2N, wherein by the above-mentioned heteroaryl groups
are meant 5- or 6-membered aromatic heteroaryl groups which contain
1 or 2 heteroatoms selected from N, O and S, wherein a maximum of
one O or S atom may be present, and wherein the above-mentioned
groups may optionally be substituted independently of one another
by one or more groups selected from among fluorine, chlorine,
bromine, hydroxy, cyano, C.sub.1-3-alkyl, C.sub.1-3-alkoxy,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl,
hydroxy-C.sub.1-3-alkyl, (R.sup.14).sub.2N and
(R.sup.14).sub.2N--C.sub.1-3-alkyl.
[0131] Most particularly preferred groups R.sup.12 are groups
selected from among C.sub.1-4-alkyl, particularly methyl or ethyl,
morpholinyl, phenyl, benzyl, pyridyl, particularly 3-pyridyl, and
(CH.sub.3).sub.2N, wherein the above-mentioned groups may
optionally be substituted independently of one another by one or
more groups selected from among fluorine, chlorine and bromine.
[0132] Preferred groups R.sup.13 are groups selected from among
hydrogen, C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.3-7-cycloalkyl, C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl, aryl,
aryl-C.sub.1-3-alkyl, heterocyclyl, heterocyclyl-C.sub.1-3-alkyl,
heteroaryl and heteroaryl-C.sub.1-3-alkyl, wherein the
above-mentioned groups may optionally be substituted independently
of one another by one or more groups selected from among fluorine,
chlorine, bromine, hydroxy, cyano, C.sub.1-3-alkyl,
C.sub.1-3-alkoxy, hydroxy-C.sub.1-3-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-3-alkyl, (R.sup.14).sub.2N and
(R.sup.14).sub.2N--C.sub.1-3-alkyl.
[0133] Particularly preferred groups R.sup.13 are groups selected
from among hydrogen, C.sub.1-6-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-3-alkyl, C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl, phenyl,
phenyl-C.sub.1-3-alkyl, heteroaryl and heteroaryl-C.sub.1-3-alkyl,
wherein by the above-mentioned heteroaryl groups are meant 5- or
6-membered aromatic heteroaryl groups which contain 1 or 2
heteroatoms selected from N, O and S, wherein a maximum of one O or
S atom may be present, and wherein the above-mentioned groups may
optionally be substituted independently of one another by one or
more groups selected from among fluorine, chlorine, bromine,
hydroxy, cyano, C.sub.1-3-alkyl, C.sub.1-3-alkoxy,
hydroxy-C.sub.1-3-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-3-alkyl, (R.sup.14).sub.2N and
(R.sup.14).sub.2N--C.sub.1-3-alkyl.
[0134] Most particularly preferred groups R.sup.13 are groups
selected from among hydrogen, methyl, ethyl, phenyl and
4-fluorophenyl, wherein the above-mentioned groups may optionally
be substituted independently of one another by one or more groups
selected from among fluorine, chlorine and bromine.
[0135] Also preferred according to the invention are those
compounds wherein R.sup.12 is selected from among C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-3-alkyl, C.sub.3-7-cycloalkenyl,
C.sub.3-7-cycloalkenyl-C.sub.1-3-alkyl, aryl, aryl-C.sub.1-3-alkyl,
heteroaryl, heteroaryl-C.sub.1-3-alkyl and (R.sup.14).sub.2N,
wherein the above-mentioned groups may optionally be substituted
independently of one another by one or more groups selected from
among fluorine, chlorine, bromine, hydroxy, carboxy, cyano, nitro,
C.sub.1-3-alkyl, heterocyclyl, heterocyclyl-C.sub.1-3-alkyl,
C.sub.1-3-alkoxy, hydroxy-C.sub.1-3-alkyl, R.sup.14--CO(R.sup.14)N,
R.sup.14--SO.sub.2(R.sup.14)N, (R.sup.14).sub.2N--SO.sub.2--,
R.sup.14--SO.sub.2--, R.sup.14--SO, R.sup.14--S, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--C.sub.1-3-alkyl and (R.sup.14).sub.2N--CO,
and
R.sup.13 is selected from among hydrogen, C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl, aryl, aryl-C.sub.1-3-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl, heteroaryl and
heteroaryl-C.sub.1-3-alkyl, wherein the above-mentioned groups may
optionally be substituted independently of one another by one or
more groups selected from among fluorine, chlorine, bromine,
hydroxy, cyano, C.sub.1-3-alkyl, C.sub.1-3-alkoxy,
hydroxy-C.sub.1-3-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-3-alkyl, (R.sup.14).sub.2N and
(R.sup.14).sub.2N--C.sub.1-3-alkyl.
[0136] Also particularly preferred are those compounds wherein
R.sup.12 is selected from among C.sub.1-6-alkyl, heterocyclyl,
phenyl, phenyl-C.sub.1-3-alkyl, heteroaryl,
heteroaryl-C.sub.1-3-alkyl- and (R.sup.14).sub.2N, wherein by the
above-mentioned heteroaryl groups are meant 5- or 6-membered
aromatic heteroaryl groups which contain 1 or 2 heteroatoms
selected from N, O and S, wherein a maximum of one O or S atom may
be present, and wherein the above-mentioned groups may optionally
be substituted independently of one another by one or more groups
selected from among fluorine, chlorine, bromine, hydroxy, cyano,
C.sub.1-3-alkyl, C.sub.1-3-alkoxy, heterocyclyl,
heterocyclyl-C.sub.1-3-alkyl, hydroxy-C.sub.1-3-alkyl,
(R.sup.14).sub.2N and (R.sup.14).sub.2N--C.sub.1-3-alkyl, and
R.sup.13 is selected from among hydrogen, C.sub.1-6-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl, C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl, phenyl,
phenyl-C.sub.1-3-alkyl, heteroaryl and
heteroaryl-C.sub.1-3-alkyl,
wherein by the above-mentioned heteroaryl groups are meant 5- or
6-membered aromatic heteroaryl groups, which contain 1 or 2
heteroatoms selected from N, O and S, wherein a maximum of one O or
S atom may be present, and wherein the above-mentioned groups may
optionally be substituted independently of one another by one or
more groups selected from among fluorine, chlorine, bromine,
hydroxy, cyano, C.sub.1-3-alkyl, C.sub.1-3-alkoxy,
hydroxy-C.sub.1-3-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-3-alkyl, (R.sup.14).sub.2N and
(R.sup.14).sub.2N--C.sub.1-3-alkyl.
[0137] Also particularly preferred are those compounds according to
claim 1 wherein R.sup.12 denotes C.sub.1-4-alkyl, particularly
methyl or ethyl, morpholinyl, phenyl, benzyl, pyridyl, particularly
3-pyridyl, and (CH.sub.3).sub.2N, wherein the above-mentioned
groups may optionally be substituted independently of one another
by one or more groups selected from among fluorine, chlorine and
bromine, and R.sup.13 denotes hydrogen, methyl, ethyl, phenyl and
4-fluorophenyl, wherein the above-mentioned groups may optionally
be substituted independently of one another by one or more groups
selected from among fluorine, chlorine and bromine.
[0138] If R.sup.12 and R.sup.13 together form an alkylene bridge, a
C.sub.2-6-alkylene bridge is preferred, so that with the inclusion
of the nitrogen atom linked to R.sup.13 and the SO.sub.2 or CO
group linked to R.sup.12 a heterocyclic ring is formed, wherein one
or two CH.sub.2 groups of the C.sub.2-6-alkylene bridge may be
replaced independently of one another by O, S, SO, SO.sub.2 or
N(R.sup.14) in such a way that in each case two O or S atoms or an
O atom and an S atom are not directly joined together, and wherein
the C atoms of the above-mentioned C.sub.2-6-alkylene bridge may
optionally be substituted independently of one another by one or
more groups selected from among fluorine, hydroxy, carboxy,
F.sub.3C, HF.sub.2C, FH.sub.2C, C.sub.1-3-alkyl and
C.sub.1-3-alkoxy.
[0139] If R.sup.12 and R.sup.13 together form an alkylene bridge, a
C.sub.2-4-alkylene bridge is particularly preferred, so that with
the inclusion of the nitrogen atom linked to R.sup.13 and the
SO.sub.2 or CO group linked to R.sup.12 a heterocyclic ring is
formed, wherein one or two CH.sub.2 groups of the
C.sub.2-4-alkylene bridge may be replaced independently of one
another by O, S or N(R.sup.14) in such a way that in each case two
O, S or N atoms or an 0 and an S atom are not joined together
directly, and wherein the C atoms of the above-mentioned
C.sub.2-4-alkylene bridge may optionally be substituted by one or
more fluorine atoms.
[0140] Particularly preferred are those compounds wherein R.sup.12
and R.sup.13 together form the heterocyclic rings of formulae
(IIa), (IIb), (IIc) or (IId)
##STR00018##
[0141] Preferred groups R.sup.14 are groups which are in each case
selected independently from among hydrogen, C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl, aryl,
aryl-C.sub.1-3-alkyl, heterocyclyl, heterocyclyl-C.sub.1-3-alkyl,
heteroaryl and heteroaryl-C.sub.1-3-alkyl, wherein the
above-mentioned groups may optionally be substituted independently
of one another by one or more groups selected from among fluorine,
chlorine, bromine, hydroxy, carboxy, cyano, nitro, C.sub.1-3-alkyl,
hydroxy-C.sub.1-3-alkyl and C.sub.1-3-alkoxy.
[0142] Also preferred are those compounds of general formula (I)
wherein two groups R.sup.14 bound to the same nitrogen atom each
denote a C.sub.1-6-alkyl group which together form a
C.sub.2-6-alkylene bridge, so that with the inclusion of the
nitrogen atom linked to the groups R.sup.14 a heterocyclic ring is
formed, wherein a CH.sub.2 group of the C.sub.2-6-alkylene bridge
independently of one another may be replaced by O, S or
N(R.sup.14), and the heterocyclic ring may optionally be
substituted independently of one another by one or more groups
selected from among fluorine, chlorine, bromine, hydroxy, carboxy,
cyano, nitro, C.sub.1-3-alkyl, hydroxy-C.sub.1-3-alkyl and
C.sub.1-3-alkoxy.
[0143] Particularly preferred groups R.sup.14 independently of one
another are hydrogen or C.sub.1-6-alkyl groups, particularly
hydrogen or a methyl group, wherein one or more hydrogen atoms of
the C.sub.1-6-alkyl group may be replaced by fluorine.
[0144] Preferably in each case R.sup.15 is selected independently
of one another from among hydrogen, C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl, aryl, aryl-C.sub.1-3-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl, heteroaryl and
heteroaryl-C.sub.1-3-alkyl, wherein the above-mentioned groups may
optionally be substituted independently of one another by one or
more groups selected from among fluorine, chlorine, bromine,
hydroxy, carboxy, cyano, nitro, C.sub.1-3-alkyl and
C.sub.1-3-alkoxy.
[0145] Particularly preferred groups R.sup.15 independently of one
another are hydrogen or C.sub.1-3-alkyl groups, particularly
hydrogen or a methyl group.
[0146] Particularly preferred compounds according to the invention
are listed in the following group of formulae (Ia), (Ib), (Ic),
(Id) and (Ie):
##STR00019##
wherein A, B, L, X.sup.2, X.sup.3, X.sup.4, i, R.sup.1, R.sup.2,
R.sup.3, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10,
R.sup.11, R.sup.12, R.sup.13, R.sup.14 and R.sup.15 have the
meanings given hereinbefore.
[0147] Particularly preferred are compounds of formula (Ia)
according to the invention,
##STR00020##
wherein [0148] A denotes aryl or heteroaryl, [0149] wherein the
group A in addition to the groups L may optionally be substituted
by one or more fluorine atoms, [0150] L denotes in each case
independently of one another hydrogen, fluorine, chlorine, bromine,
iodine, hydroxy, carboxy, cyano, nitro, F.sub.3C, HF.sub.2C,
FH.sub.2C, C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.3-7-cycloalkyl, C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl, aryl,
aryl-C.sub.1-3-alkyl, heterocyclyl, heterocyclyl-C.sub.1-3-alkyl,
heteroaryl, heteroaryl-C.sub.1-3-alkyl, R.sup.15--O,
R.sup.15--O--C.sub.1-3-alkyl, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--CO, R.sup.14--CO--(R.sup.14)N,
(R.sup.14).sub.2N--CO--(R.sup.14)N, (R.sup.14).sub.2N--SO.sub.2--,
R.sup.14--SO.sub.2--(R.sup.14)N or C.sub.1-3-alkyl-SO.sub.2--
[0151] wherein the above-mentioned groups may optionally be
substituted independently of one another by one or more groups
selected from among fluorine, chlorine, bromine, hydroxy, oxo,
carboxy, cyano, nitro, F.sub.3C, HF.sub.2C, FH.sub.2C,
hydroxy-C.sub.1-3-alkyl, C.sub.1-3-alkyl, C.sub.1-3-alkoxy,
(R.sup.14).sub.2N, (R.sup.14).sub.2N--C.sub.1-3-alkyl and
(R.sup.14).sub.2N--CO, and [0152] i denotes 0, 1 or 2, [0153] B
denotes a C.sub.1-4-alkylene bridge, [0154] wherein the
C.sub.1-4-alkylene bridge may optionally be substituted by one or
more groups selected from among fluorine, chlorine, bromine,
iodine, hydroxy, oxo, carboxy, cyano, nitro, F.sub.3C, HF.sub.2C,
FH.sub.2C, C.sub.1-4-alkyl, C.sub.1-6-alkyl-S--C.sub.1-3-alkyl,
C.sub.3-7-cycloalkyl, C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl, aryl,
aryl-C.sub.1-3-alkyl, heteroaryl, heteroaryl-C.sub.1-3-alkyl,
R.sup.15--O, (R.sup.14).sub.2N--SO.sub.2--, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--C.sub.1-3-alkyl, (R.sup.14).sub.2N--CO,
R.sup.14--SO.sub.2--, R.sup.14--CO--(R.sup.14)N,
R.sup.14--SO.sub.2(R.sup.14)N, (R.sup.14).sub.2N--SO.sub.2--,
R.sup.14--CO and R.sup.14--SO, and [0155] wherein two
C.sub.1-4-alkyl groups bound to the same carbon atom of the
C.sub.1-4-alkylene bridge may be joined together forming a
C.sub.3-7-cycloalkyl group, and [0156] wherein the above-mentioned
groups and the C.sub.3-7-cycloalkyl group formed from the
C.sub.1-4-alkyl groups may optionally be substituted independently
of one another by one or more groups selected from among fluorine,
chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano,
nitro, F.sub.3C, HF.sub.2C, FH.sub.2C, C.sub.1-3-alkyl,
C.sub.1-3-alkoxy, R.sup.15--O--C.sub.1-3-alkyl,
R.sup.14--CO(R.sup.14)N, R.sup.14--SO.sub.2(R.sup.14)N,
(R.sup.14).sub.2N, (R.sup.14).sub.2N--C.sub.1-3-alkyl,
(R.sup.14).sub.2N--CO, (R.sup.14).sub.2N--SO.sub.2-- and
HOSO.sub.2--, [0157] R.sup.1 denotes hydrogen, C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-3-alkyl, aryl, aryl-C.sub.1-3-alkyl,
heteroaryl or heteroaryl-C.sub.1-3-alkyl, [0158] wherein the
above-mentioned groups may optionally be substituted independently
of one another by one or more groups selected from among fluorine,
chlorine, bromine, hydroxy, carboxy, cyano, nitro, F.sub.3C,
HF.sub.2C, FH.sub.2C, C.sub.1-3-alkyl, C.sub.1-3-alkoxy and
hydroxy-C.sub.1-3-alkyl, [0159] X.sup.2, X.sup.3, X.sup.4 may each
independently of one another be nitrogen or C(R.sup.11), preferably
C(R.sup.11), [0160] R.sup.2 denotes C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.1-6-alkoxy-C.sub.1-3-alkyl,
C.sub.1-6-alkyl-S--C.sub.1-3-alkyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkenyl-C.sub.1-3-alkyl,
C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-3-alkyl, aryl, aryl-C.sub.1-3-alkyl,
heteroaryl or heteroaryl-C.sub.1-3-alkyl, [0161] wherein the
above-mentioned groups may optionally be substituted independently
of one another by one or more groups selected from among fluorine,
chlorine, bromine, iodine, F.sub.3C, HF.sub.2C, FH.sub.2C, hydroxy,
carboxy, cyano, nitro, C.sub.1-3-alkyl,
(R.sup.14).sub.2N--SO.sub.2--, (R.sup.14).sub.2N,
R.sup.14--CO--(R.sup.14)N, R.sup.14--SO.sub.2(R.sup.14)N,
(R.sup.14).sub.2N--C.sub.1-3-alkyl, (R.sup.14).sub.2N--CO,
R.sup.15--O and R.sup.15--O--C.sub.1-3-alkyl, [0162] R.sup.3
denotes hydrogen, C.sub.1-6-alkyl, fluorine, F.sub.3C, HF.sub.2C or
FH.sub.2C, [0163] R.sup.8 denotes hydrogen, C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl, C.sub.3-7-cycloalkenyl,
C.sub.3-7-cycloalkenyl-C.sub.1-3-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-3-alkyl, aryl, aryl-C.sub.1-3-alkyl,
heteroaryl and heteroaryl-C.sub.1-3-alkyl, [0164] wherein the
above-mentioned groups may optionally be substituted independently
of one another by one or more groups selected from among fluorine,
chlorine, bromine, iodine, hydroxy, carboxy, cyano, nitro,
C.sub.1-3-alkyl, heterocyclyl, heterocyclyl-C.sub.1-3-alkyl, aryl,
aryl-C.sub.1-3-alkyl, heteroaryl, heteroaryl-C.sub.1-3-alkyl,
(R.sup.14).sub.2N, (R.sup.14).sub.2N--C.sub.1-3-alkyl,
(R.sup.14).sub.2N--CO, (R.sup.14).sub.2N--CO--N(R.sup.14),
(R.sup.14).sub.2N--SO.sub.2--, R.sup.5--O,
R.sup.15--O--C.sub.1-3-alkyl, R.sup.15--S and
R.sup.15--S--C.sub.1-3-alkyl, [0165] R.sup.5, R.sup.7 each
independently of one another denote hydrogen, C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, C.sub.3-7-cycloalkyl,
heterocyclyl, C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl,
heterocyclyl-C.sub.1-3-alkyl, C.sub.3-7-cycloalkenyl,
C.sub.3-7-cycloalkenyl-C.sub.1-3-alkyl, aryl, heteroaryl,
aryl-C.sub.1-3-alkyl or heteroaryl-C.sub.1-3-alkyl, [0166] wherein
the above-mentioned groups may optionally be substituted
independently of one another by one or more groups selected from
among fluorine, chlorine, bromine, iodine, hydroxy, carboxy, cyano,
nitro, C.sub.1-3-alkyl, C.sub.1-3-alkoxy, C.sub.1-3-alkyl-S, aryl,
heteroaryl, heteroaryl-C.sub.1-3-alkyl, aryl-C.sub.1-3-alkyl,
(R.sup.14).sub.2N--SO.sub.2--, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--C.sub.1-3-alkyl and (R.sup.14).sub.2N--CO,
[0167] R.sup.6, R.sup.9 each independently of one another denote
hydrogen, C.sub.1-6-alkyl, C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl,
C.sub.2-6-alkenyl or C.sub.2-6-alkynyl, [0168] wherein one or more
hydrogen atoms of the above-mentioned groups may be replaced by
fluorine, [0169] R.sup.10 denotes hydrogen, fluorine, chlorine,
bromine, cyano, C.sub.1-6-alkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-6-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-6-alkyl, C.sub.3-7-cycloalkenyl, aryl,
aryl-C.sub.1-6-alkyl, heteroaryl, heteroaryl-C.sub.1-6-alkyl,
R.sup.15--O, R.sup.15--O--C.sub.1-3-alkyl,
R.sup.12--SO.sub.2--(R.sup.13)N or R.sup.12--CO--(R.sup.13)N,
[0170] wherein the above-mentioned groups may optionally be
substituted independently of one another by one or more groups
selected from among fluorine, chlorine, bromine, iodine, hydroxy,
oxo, carboxy, formyl, cyano, nitro, C.sub.3-7-cycloalkyl,
heterocyclyl, (R.sup.14).sub.2N, (R.sup.14).sub.2N--CO,
R.sup.15--CO, R.sup.15--O--CO, R.sup.14--CO--(R.sup.14)N,
(R.sup.14).sub.2N--CO--(R.sup.14)N, (R.sup.14).sub.2N--SO.sub.2--,
(R.sup.14).sub.2N--SO.sub.2--(R.sup.14)N, R.sup.14--SO.sub.2--,
C.sub.1-4-alkyl, R.sup.15--O, C.sub.1-4-alkyl-S, F.sub.3C,
HF.sub.2C, FH.sub.2C, F.sub.3C--O, HF.sub.2C--O, FH.sub.2C--O and
R.sup.14--SO.sub.2--(R.sup.14)N, and [0171] R.sup.11 each
independently of one another denote hydrogen, fluorine, chlorine,
bromine, iodine, methyl or F.sub.3C, [0172] R.sup.12 denotes
C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.3-7-cycloalkyl, C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl, C.sub.3-7-cycloalkenyl,
C.sub.3-7-cycloalkenyl-C.sub.1-3-alkyl, aryl, aryl-C.sub.1-3-alkyl,
heteroaryl, heteroaryl-C.sub.1-3-alkyl or (R.sup.14).sub.2N, [0173]
wherein the above-mentioned groups may optionally be substituted
independently of one another by one or more groups selected from
among fluorine, chlorine, bromine, hydroxy, carboxy, cyano, nitro,
C.sub.1-3-alkyl, heterocyclyl, heterocyclyl-C.sub.1-3-alkyl,
C.sub.1-3-alkoxy, hydroxy-C.sub.1-3-alkyl, R.sup.14--CO(R.sup.14)N,
R.sup.14--SO.sub.2(R.sup.14)N, (R.sup.14).sub.2N--SO.sub.2--,
R.sup.14--SO.sub.2--, R.sup.14--SO, R.sup.14--S, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--C.sub.1-3-alkyl and (R.sup.14).sub.2N--CO, and
[0174] R.sup.13 denotes hydrogen, C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl, aryl, aryl-C.sub.1-3-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl, heteroaryl or
heteroaryl-C.sub.1-3-alkyl, [0175] wherein the above-mentioned
groups may optionally be substituted independently of one another
by one or more groups selected from among fluorine, chlorine,
bromine, hydroxy, cyano, C.sub.1-3-alkyl, C.sub.1-3-alkoxy,
hydroxy-C.sub.1-3-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-3-alkyl, (R.sup.14).sub.2N and
(R.sup.14).sub.2N--C.sub.1-3-alkyl, or [0176] R.sup.12 and R.sup.13
together form a C.sub.2-6-alkylene bridge, so that with the
inclusion of the nitrogen atom linked to R.sup.13 and the
SO.sub.2-- or CO group linked to R.sup.12 a heterocyclic ring is
formed, [0177] wherein one or two CH.sub.2 groups of the
C.sub.2-6-alkylene bridge may be replaced independently of one
another by O, S, SO, SO.sub.2 or N(R.sup.14) in such a way that in
each case two O or S atoms or an O atom and an S atom are not
directly joined together, and [0178] wherein the C atoms of the
above-mentioned C.sub.2-6-alkylene bridge may optionally be
substituted independently of one another by one or more groups
selected from among fluorine, hydroxy, carboxy, F.sub.3C,
HF.sub.2C, FH.sub.2C, C.sub.1-3-alkyl and C.sub.1-3-alkoxy, [0179]
R.sup.14 each independently of one another denote hydrogen,
C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl, aryl, aryl-C.sub.1-3-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl, heteroaryl or
heteroaryl-C.sub.1-3-alkyl, or two C.sub.1-6-alkyl groups bound to
the same nitrogen atom may together form a C.sub.2-6-alkylene
bridge, so that with the inclusion of the nitrogen atom bound to
the groups R.sup.14 a heterocyclic ring is formed, [0180] wherein a
CH.sub.2 group of the C.sub.2-6-alkylene bridge may be replaced
independently of one another by O, S or N(R.sup.14), and [0181]
wherein the above-mentioned groups and the heterocyclic ring may
optionally be substituted independently of one another by one or
more groups selected from among fluorine, chlorine, bromine,
hydroxy, carboxy, cyano, C.sub.1-3-alkyl, hydroxy-C.sub.1-3-alkyl
and C.sub.1-3-alkoxy, and [0182] R.sup.15 each independently of one
another denote hydrogen, C.sub.1-6-alkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl, aryl, aryl-C.sub.1-3-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl, heteroaryl or
heteroaryl-C.sub.1-3-alkyl, [0183] wherein the above-mentioned
groups may optionally be substituted independently of one another
by one or more groups selected from among fluorine, chlorine,
bromine, hydroxy, carboxy, cyano, nitro, C.sub.1-3-alkyl and
C.sub.1-3-alkoxy.
[0184] Also particularly preferred are those compounds of formula
(Ib) according to the invention,
##STR00021##
wherein [0185] A denotes phenyl, biphenyl, naphthyl or a 5-, 6-,
7-, 8-, 9- or 10-membered aromatic mono- or bicyclic heteroaryl
group which contains 1-4 heteroatoms selected from N, O and S, or
[0186] phenyl or a 5- or 6-membered aromatic heteroaryl group which
contains 1 or 2 heteroatoms selected from N, O and S, wherein a
maximum of one O or S atom may be present, [0187] L denotes in each
case independently of one another hydrogen, fluorine, chlorine,
bromine, iodine, cyano, hydroxy, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
C.sub.3-7-cycloalkyl, C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl, phenyl,
(R.sup.14).sub.2N, (R.sup.14).sub.2N--CO,
R.sup.14--CO--(R.sup.14)N, (R.sup.14).sub.2N--CO--(R.sup.14)N,
R.sup.14--SO.sub.2--(R.sup.14)N or (R.sup.14).sub.2N--SO.sub.2--,
[0188] wherein the above-mentioned groups may optionally be
substituted by one or more fluorine atoms, and [0189] i denotes 0,
1 or 2, [0190] B denotes a C.sub.1-4-alkylene bridge, [0191]
wherein the C.sub.1-4-alkylene bridge may optionally be substituted
independently of one another by one or more groups selected from
among fluorine, hydroxy, carboxy, cyano, nitro, F.sub.3C,
HF.sub.2C, FH.sub.2C, C.sub.1-4-alkyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-3-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-3-alkyl, aryl, aryl-C.sub.1-3-alkyl,
heteroaryl, heteroaryl-C.sub.1-3-alkyl, R.sup.15--O,
(R.sup.14).sub.2N--SO.sub.2-- and (R.sup.14).sub.2N, and [0192]
wherein two C.sub.1-4-alkyl groups bound to the same carbon atom of
the C.sub.1-4-alkylene bridge may be joined together forming a
C.sub.3-7-cycloalkyl group, and [0193] wherein the above-mentioned
groups and the C.sub.3-7-cycloalkyl group formed from the
C.sub.1-4-alkyl groups may optionally be substituted independently
of one another by one or more groups selected from among fluorine,
chlorine, bromine, hydroxy, carboxy, cyano, F.sub.3C, HF.sub.2C,
FH.sub.2C, C.sub.1-3-alkyl, C.sub.1-3-alkoxy- and
R.sup.15--O--C.sub.1-3-alkyl, [0194] R.sup.1 denotes hydrogen,
C.sub.1-4-alkyl, C.sub.3-4-alkenyl, C.sub.3-6-cycloalkyl or
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl, [0195] wherein the
above-mentioned groups may optionally be substituted independently
of one another by one or more groups selected from among fluorine,
hydroxy and C.sub.1-3-alkoxy, [0196] R.sup.2 denotes
C.sub.1-6-alkyl, C.sub.2-6-alkynyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl, heterocyclyl-C.sub.1-3-alkyl,
phenyl, phenyl-C.sub.1-3-alkyl, heteroaryl or
heteroaryl-C.sub.1-3-alkyl, wherein by the above-mentioned
heteroaryl groups are meant 5- or 6-membered aromatic heteroaryl
groups, which contain 1, 2 or 3 heteroatoms selected from N, O and
S, and [0197] wherein the above-mentioned groups may optionally be
substituted independently of one another by one or more groups
selected from among fluorine, chlorine, bromine, iodine, cyano,
hydroxy, C.sub.1-3-alkyl, F.sub.3C, HF.sub.2C, FH.sub.2C,
C.sub.1-3-alkoxy and (R.sup.14).sub.2N, [0198] R.sup.8 denotes
hydrogen, C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl, phenyl,
phenyl-C.sub.1-3-alkyl, heteroaryl and heteroaryl-C.sub.1-3-alkyl,
wherein by the above-mentioned heteroaryl groups are meant 5- or
6-membered aromatic heteroaryl groups, which contain 1, 2 or 3
heteroatoms selected from N, O and S, and [0199] wherein the
above-mentioned groups may optionally be substituted independently
of one another by one or more groups selected from among fluorine,
chlorine, bromine, carboxy, hydroxy, cyano, C.sub.1-3-alkyl,
C.sub.1-3-alkoxy, C.sub.1-3-alkoxy-C.sub.1-3-alkyl,
C.sub.1-3-alkyl-S, C.sub.1-3-alkyl-S--C.sub.1-3-alkyl,
hydroxy-C.sub.1-3-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-3-alkyl, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--C.sub.1-3-alkyl,
(R.sup.14).sub.2N--CO--N(R.sup.14)-- and
(R.sup.14).sub.2N--SO.sub.2--, [0200] R.sup.5 denotes
C.sub.1-6-alkyl, cyclopropyl, C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl
or phenyl-C.sub.1-3-alkyl, [0201] wherein the above-mentioned
groups may optionally be substituted independently of one another
by one or more groups selected from among fluorine, chlorine,
bromine, iodine, cyano, hydroxy, carboxy, C.sub.1-3-alkyl,
C.sub.1-3-alkoxy and (R.sup.14).sub.2N, and [0202] R.sup.7 denotes
C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl, phenyl and
phenyl-C.sub.1-3-alkyl, [0203] wherein the above-mentioned groups
may optionally be substituted independently of one another by one
or more groups selected from among fluorine, chlorine, bromine,
iodine, cyano, hydroxy, carboxy, C.sub.1-3-alkyl, C.sub.1-3-alkoxy
and (R.sup.14).sub.2N, [0204] R.sup.9 denotes hydrogen or
C.sub.1-4-alkyl, [0205] wherein one or more hydrogen atoms of the
C.sub.1-4-alkyl group may be replaced by fluorine, [0206] R.sup.10
denotes hydrogen, fluorine, chlorine, bromine, cyano,
C.sub.1-4-alkyl, C.sub.1-4-alkoxy, C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyl-oxy, C.sub.3-6-cycloalkyl-C.sub.1-3-alkoxy,
1,3-diazacyclohexan-2-on-1-yl, 2-oxo-1,3-oxazinan-3-yl,
3-oxomorpholino, 1,1-dioxo-[1,2,6]thiadiazinan-2-yl, phenyl,
pyridyl, thienyl, furyl, R.sup.12--CO--(R.sup.13)N or
R.sup.12SO.sub.2--(R.sup.13)N, [0207] wherein the above-mentioned
groups may optionally be substituted independently of one another
by one or more groups selected from among fluorine, chlorine,
bromine, carboxy, cyano, C.sub.1-4-alkyl, C.sub.1-4-alkoxy,
C.sub.1-4-alkyl-S, R.sup.15--CO, R.sup.15--O--CO,
R.sup.14--SO.sub.2--, F.sub.3C, HF.sub.2C, FH.sub.2C, F.sub.3C--O,
HF.sub.2C--O, FH.sub.2C--O and (R.sup.14).sub.2N--CO, [0208]
R.sup.11 each independently of one another denote hydrogen,
fluorine, chlorine or bromine [0209] R.sup.12 denotes
C.sub.1-6-alkyl, heterocyclyl, phenyl, phenyl-C.sub.1-3-alkyl,
heteroaryl, heteroaryl-C.sub.1-3-alkyl or (R.sup.14).sub.2N, [0210]
wherein by the above-mentioned heteroaryl groups are meant 5- or
6-membered aromatic heteroaryl groups which contain 1 or 2
heteroatoms selected from N, O and S, wherein a maximum of one O or
S atom may be present, and [0211] wherein the above-mentioned
groups may optionally be substituted independently of one another
by one or more groups selected from among fluorine, chlorine,
bromine, hydroxy, cyano, C.sub.1-3-alkyl, C.sub.1-3-alkoxy,
heterocyclyl, heterocyclyl-C.sub.1-3-alkyl,
hydroxy-C.sub.1-3-alkyl, (R.sup.14).sub.2N and
(R.sup.14).sub.2N--C.sub.1-3-alkyl, [0212] R.sup.13 denotes
hydrogen, C.sub.1-6-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-3-alkyl, C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl, phenyl,
phenyl-C.sub.1-3-alkyl, heteroaryl and heteroaryl-C.sub.1-3-alkyl,
[0213] wherein by the above-mentioned heteroaryl groups are meant
5- or 6-membered aromatic heteroaryl groups which contain 1 or 2
heteroatoms selected from N, O and S, wherein a maximum of one O or
S atom may be present, and [0214] wherein the above-mentioned
groups may optionally be substituted independently of one another
by one or more groups selected from among fluorine, chlorine,
bromine, hydroxy, cyano, C.sub.1-3-alkyl, C.sub.1-3-alkoxy,
hydroxy-C.sub.1-3-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-3-alkyl, (R.sup.14).sub.2N and
(R.sup.14).sub.2N--C.sub.1-3-alkyl, or [0215] R.sup.12 and R.sup.13
together form a C.sub.2-4-alkylene bridge, so that with the
inclusion of the nitrogen atom linked to R.sup.13 and the SO.sub.2
or CO group linked to R.sup.12 a heterocyclic ring is formed,
[0216] wherein one or two CH.sub.2 groups of the C.sub.2-4-alkylene
bridge may be replaced independently of one another by O, S or
N(R.sup.14) in such a way that in each case two O, S or N atoms or
an O and an S atom are not joined together directly, and [0217]
wherein the C atoms of the above-mentioned C.sub.2-4-alkylene
bridge may optionally be substituted by one or more fluorine atoms,
and [0218] R.sup.14 denotes hydrogen or C.sub.1-6-alkyl, [0219]
wherein one or more hydrogen atoms of the C.sub.1-6-alkyl group may
be replaced by fluorine.
[0220] Also particularly preferred are those compounds according to
the invention of formula (Ic),
##STR00022##
wherein [0221] A denotes phenyl, thienyl, thiazolyl or pyridyl,
[0222] L denotes in each case independently of one another
hydrogen, fluorine, chlorine, bromine, hydroxy, C.sub.1-4-alkyl or
C.sub.1-4-alkoxy, [0223] wherein the above-mentioned groups may
optionally be substituted by one or more fluorine atoms, and [0224]
i denotes 0, 1 or 2, [0225] B denotes a C.sub.1-2-alkylene bridge,
[0226] wherein the C.sub.1-2-alkylene bridge may optionally be
substituted by one or more C.sub.1-4-alkyl groups, and [0227]
wherein two C.sub.1-4-alkyl groups bound to the same carbon atom of
the C.sub.1-2-alkylene bridge may be joined together forming a
cyclopropyl group, and [0228] wherein one or more hydrogen atoms of
the above-mentioned C.sub.1-2-alkylene bridge or of the
C.sub.1-4-alkyl groups or of the cyclopropyl group formed therefrom
may optionally be replaced by one or more fluorine atoms, [0229]
R.sup.1 denotes hydrogen or C.sub.1-4-alkyl, [0230] wherein the
C.sub.1-4-alkyl group may optionally be substituted by one or more
fluorine atoms, [0231] R.sup.2 denotes n-propyl, n-butyl,
2-propynyl, 2-butynyl, benzyl, 2-phenylethyl, pyridylmethyl,
particularly 3-pyridylmethyl, furanylmethyl, thienylmethyl,
particularly 3-thienylmethyl, or thiazolylmethyl, particularly
4-thiazolylmethyl, [0232] wherein thiazolylmethyl and
4-thiazolylmethyl are most particularly preferred, and [0233]
wherein the above-mentioned propyl, butyl, propynyl and butynyl
groups may optionally be substituted by one or more fluorine atoms
and the benzyl, 2-phenylethyl, furanylmethyl, thienylmethyl or
thiazolylmethyl groups may optionally be substituted independently
of one another by one or more groups selected from among fluorine,
chlorine, bromine, methyl, F.sub.3C, HF.sub.2C, FH.sub.2C and
H.sub.2N, [0234] R.sup.8 denotes hydrogen, C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl,
phenyl-C.sub.1-3-alkyl and tetrahydropyranyl-C.sub.1-3-alkyl,
preferably 4-tetrahydropyranylmethyl, [0235] wherein the
above-mentioned groups may optionally be substituted independently
of one another by one or more groups selected from among fluorine,
chlorine, bromine, pyrrolidin-1-ylmethyl, hydroxy, cyano,
C.sub.1-3-alkyl, C.sub.1-3-alkoxy, C.sub.1-3-alkyl-S,
hydroxy-C.sub.1-3-alkyl, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--C.sub.1-3-alkyl,
(R.sup.14).sub.2N--CO--N(R.sup.14)-- and
(R.sup.14).sub.2N--SO.sub.2--, [0236] R.sup.5, R.sup.7 each
independently of one another denote C.sub.1-4-alkyl or cyclopropyl,
[0237] wherein one or more hydrogen atoms of the above-mentioned
groups may optionally be replaced by fluorine atoms, [0238]
R.sup.12 denotes C.sub.1-4-alkyl, particularly methyl or ethyl,
morpholinyl, phenyl, benzyl, pyridyl, particularly 3-pyridyl or
(CH.sub.3).sub.2N, [0239] wherein the above-mentioned groups may
optionally be substituted independently of one another by one or
more groups selected from among fluorine, chlorine and bromine,
[0240] R.sup.13 denotes hydrogen, methyl, ethyl, phenyl or
4-fluorophenyl, [0241] wherein the above-mentioned groups may
optionally be substituted independently of one another by one or
more groups selected from among fluorine, chlorine and bromine, or
[0242] R.sup.12 and R.sup.13 together form, with the inclusion of
the nitrogen atom linked to R.sup.13 and the SO.sub.2 or CO group
linked to R.sup.12, a heterocyclic ring of formulae (Ia), (IIb),
(IIc) or (IId)
[0242] ##STR00023## [0243] and [0244] R.sup.14 denotes hydrogen or
C.sub.1-6-alkyl, [0245] wherein one or more hydrogen atoms of the
C.sub.1-6-alkyl group may be replaced by fluorine.
[0246] Also particularly preferred are those compounds according to
the invention of formulae (Id) or (Ie),
##STR00024##
wherein, where applicable [0247] A denotes phenyl, thienyl,
preferably 3-thienyl, thiazolyl, particularly 2-thiazolyl, or
pyridyl, preferably 2-pyridyl, [0248] L denotes hydrogen, fluorine,
chlorine, trifluoromethyl, trifluoromethoxy, methyl and methoxy,
[0249] i denotes 0 or 1, [0250] B is selected from among
[0250] ##STR00025## [0251] wherein one or more hydrogen atoms may
optionally be replaced by fluorine, [0252] R.sup.2 denotes
n-propyl, n-butyl, 2-propynyl, 2-butynyl, benzyl,
3,5-difluorobenzyl, 2-phenylethyl, pyridylmethyl, particularly
3-pyridylmethyl, furanylmethyl, thienylmethyl, particularly
3-thienylmethyl, or thiazolylmethyl, particularly
4-thiazolylmethyl, wherein thiazolylmethyl or 4-thiazolylmethyl is
most particularly preferred, [0253] wherein the above-mentioned
propyl, butyl, propynyl and butynyl groups may optionally be
substituted by one or more fluorine atoms and the benzyl,
2-phenylethyl, furanylmethyl, thienylmethyl or thiazolylmethyl
groups may optionally be substituted independently of one another
by one or more groups selected from among fluorine, chlorine,
bromine, methyl, F.sub.3C, HF.sub.2C, FH.sub.2C and 5H.sub.2N,
[0254] R.sup.8 denotes hydrogen, C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl,
phenyl-C.sub.1-3-alkyl and tetrahydropyranyl-C.sub.1-3-alkyl,
preferably 4-tetrahydropyranylmethyl, [0255] wherein the
above-mentioned groups may optionally be substituted independently
of one another by one or more groups selected from among fluorine,
chlorine, bromine, pyrrolidin-1-ylmethyl, hydroxy, cyano,
C.sub.1-3-alkyl, C.sub.1-3-alkoxy, C.sub.1-3-alkyl-S,
hydroxy-C.sub.1-3-alkyl, (R.sup.14).sub.2N,
(R.sup.14).sub.2N--C.sub.1-3-alkyl,
(R.sup.14).sub.2N--CO--N(R.sup.14)-- and
(R.sup.14).sub.2N--SO.sub.2--, [0256] R.sup.5 denotes
C.sub.1-4-alkyl or cyclopropyl, [0257] wherein one or more hydrogen
atoms of the above-mentioned groups may optionally be replaced by
fluorine atoms, [0258] R.sup.7 denotes C.sub.1-4-alkyl, preferably
ethyl or isopropyl, or cyclopropyl, [0259] wherein one or more
hydrogen atoms of the above-mentioned groups may optionally be
replaced by fluorine atoms, [0260] R.sup.12 denotes
C.sub.1-4-alkyl, particularly methyl or ethyl, morpholinyl, phenyl,
benzyl, pyridyl, particularly 3-pyridyl or (CH.sub.3).sub.2N,
[0261] wherein the above-mentioned groups may optionally be
substituted independently of one another by one or more groups
selected from among fluorine, chlorine and bromine, [0262] R.sup.13
denotes hydrogen, methyl, ethyl, phenyl or 4-fluorophenyl, [0263]
wherein the above-mentioned groups may optionally be substituted
independently of one another by one or more groups selected from
among fluorine, chlorine and bromine, [0264] or [0265] R.sup.12 and
R.sup.13 together form, with the inclusion of the nitrogen atom
bound to R.sup.13 and the SO.sub.2 or CO group bound to R.sup.12, a
heterocyclic ring of formulae (Ia), (IIb), (IIc) or (IId)
##STR00026##
[0266] Particularly preferred individual compounds are selected
from among:
##STR00027## ##STR00028## ##STR00029## ##STR00030## ##STR00031##
##STR00032## ##STR00033## ##STR00034## ##STR00035## ##STR00036##
##STR00037## ##STR00038## ##STR00039## ##STR00040## ##STR00041##
##STR00042## ##STR00043## ##STR00044## ##STR00045## ##STR00046##
##STR00047## ##STR00048## ##STR00049## ##STR00050## ##STR00051##
##STR00052## ##STR00053## ##STR00054## ##STR00055## ##STR00056##
##STR00057## ##STR00058## ##STR00059## ##STR00060## ##STR00061##
##STR00062## ##STR00063## ##STR00064## ##STR00065## ##STR00066##
##STR00067## ##STR00068## ##STR00069## ##STR00070## ##STR00071##
##STR00072## ##STR00073## ##STR00074## ##STR00075## ##STR00076##
##STR00077## ##STR00078## ##STR00079## ##STR00080## ##STR00081##
##STR00082## ##STR00083## ##STR00084## ##STR00085## ##STR00086##
##STR00087## ##STR00088## ##STR00089## ##STR00090## ##STR00091##
##STR00092## ##STR00093## ##STR00094## ##STR00095## ##STR00096##
##STR00097## ##STR00098## ##STR00099## ##STR00100## ##STR00101##
##STR00102## ##STR00103## ##STR00104## ##STR00105## ##STR00106##
##STR00107## ##STR00108## ##STR00109## ##STR00110## ##STR00111##
##STR00112## ##STR00113## ##STR00114## ##STR00115## ##STR00116##
##STR00117## ##STR00118## ##STR00119## ##STR00120##
[0267] Some terms which are used hereinbefore and hereinafter to
describe the compounds according to the invention will now be
defined in more detail.
[0268] The term halogen denotes an atom selected from among F, Cl,
Br and I.
[0269] The term C.sub.1-n-alkyl, wherein n may have a value from 1
to 10, denotes a saturated, branched or unbranched hydrocarbon
group with 1 to n C atoms. Examples of such groups include methyl,
ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl,
tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, n-hexyl,
iso-hexyl etc.
[0270] The term C.sub.2-n-alkenyl, wherein n has a value of 3 to 6,
denotes a branched or unbranched hydrocarbon group with 2 to n C
atoms and a C.dbd.C double bond. Examples of such groups include
ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 1-butenyl,
2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl,
3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl,
3-hexenyl, 4-hexenyl, 5-hexenyl etc.
[0271] The term C.sub.2-n-alkynyl, wherein n has a value of 3 to 6,
denotes a branched or unbranched hydrocarbon group with 2 to n C
atoms and a C.ident.C triple bond. Examples of such groups include
ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,
1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl,
2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl etc.
[0272] The term C.sub.1-n-alkoxy or C.sub.1-n-alkyloxy denotes a
C.sub.1-n-alkyl-O group, wherein C.sub.1-n-alkyl is defined as
above. Examples of such groups include methoxy, ethoxy, n-propoxy,
iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy,
n-pentoxy, iso-pentoxy, neo-pentoxy, tert-pentoxy, n-hexoxy,
iso-hexoxy etc.
[0273] The term C.sub.3-n-cycloalkyl denotes a saturated monocyclic
group with 3 to n C atoms. Examples of such groups include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl
etc.
[0274] The term C.sub.3-n-cycloalkyloxy denotes a
C.sub.3-n-cycloalkyl-O group wherein C.sub.3-n-cycloalkyl is
defined as above. Examples of such groups include cyclopropyloxy,
cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy
etc.
[0275] The term C.sub.3-n-cycloalkyl-C.sub.1-n-alkoxy denotes a
C.sub.3-n-cycloalkyl group wherein C.sub.3-n-cycloalkyl is defined
as above and which is linked to a C.sub.1-n-alkoxy group through a
carbon atom of the C.sub.1-n-alkoxy group. Examples of such groups
include cyclopropylmethyloxy, cyclobutylethyloxy,
cyclopentylmethyloxy, cyclohexylmethyloxy, cyclohexylethyloxy
etc.
[0276] The term C.sub.3-n-cycloalkenyl denotes a
C.sub.3-n-cycloalkyl group which is defined as above and
additionally has at least one C.dbd.C double bond, but is not
aromatic by nature.
[0277] The term heterocyclyl used in this application denotes a
saturated five-, six- or seven-membered ring system or a 5-12
membered bicyclic ring system which includes one, two, three or
four heteroatoms, selected from N, O and/or S, such as for example
a morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl,
oxathianyl, dithianyl, dioxanyl, pyrrolidinyl, tetrahydrofuranyl,
dioxolanyl, oxathiolanyl, imidazolidinyl, tetrahydropyranyl,
pyrrolinyl, tetrahydrothienyl, oxazolidinyl, homopiperazinyl,
homopiperidinyl, homomorpholinyl, homothiomorpholinyl, azetidinyl,
1,3-diazacyclohexanyl or pyrazolidinyl group.
[0278] The term aryl used in this application denotes a phenyl,
biphenyl, indanyl, indenyl, 6,7,8,9-tetrahydrobenzocycloheptenyl,
1,2,3,4-tetrahydronaphthyl or naphthyl group.
[0279] The term heteroaryl used in this application denotes a
heterocyclic, mono- or bicyclic aromatic ring system which includes
in addition to at least one C atom one or more heteroatoms selected
from N, O and/or S, wherein the term heteroaryl also includes the
partially hydrogenated heterocyclic, aromatic ring systems.
Examples of such groups are pyrrolyl, furanyl, thienyl,
pyridyl-N-oxide, thiazolyl, imidazolyl, oxazolyl, triazinyl,
triazolyl, 1,2,4-oxadiazoyl, 1,3,4-oxadiazoyl, 1,2,5-oxadiazoyl,
isothiazolyl, isoxazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,
1,2,5-thiadiazolyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl,
tetrazolyl, pyridyl, indolyl, isoindoyl, indolizinyl,
imidazopyridinyl, imidazo[1,2-a]pyridinyl, pyrrolopyrimidinyl,
purinyl, pyridopyrimidinyl, pteridinyl, pyrimidopyrimidinyl,
benzofuranyl, benzothienyl, quinolinyl, isoquinolinyl,
quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl,
isobenzofuranyl, isobenzothienyl, thieno[3,2-b]thiophenyl,
thieno[3,2-b]pyrrolyl, thieno[2,3-d]imidazolyl, naphthyridinyl,
indazolyl, pyrrolopyridinyl, oxazolopyridinyl, benzimidazolyl,
benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl,
benzoxadiazolyl, benzothiadiazolyl, 1,3-benzodioxolyl,
2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl,
2,3-dihydrobenzo[1,4]dioxinyl, 3,4-dihydrobenzo[1,4]oxazinyl,
benzo[1,4]-oxazinyl, 2,3-dihydroindolyl, 2,3-dihydroisoindolyl,
1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,
2-oxo-2,3-dihydrobenzimidazolyl, 2-oxo-2,3-dihydroindolyl,
pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, chromanyl,
chromenyl, chromonyl, isochromenyl, isochromanyl,
dihydroquinolin-4-onyl, dihydroquinolin-2-onyl, quinolin-4-onyl,
isoquinolin-2-onyl, imidazo[1,2-a]pyrazinyl, 1-oxoindanyl,
benzoxazol-2-onyl, imidazo[4,5-d]thiazolyl or
6,7-dihydropyrrolizinyl groups.
[0280] Preferred heteroaryl groups are furanyl, thienyl, thiazolyl,
imidazolyl, isoxazolyl, pyrazolyl, pyridyl, indolyl, benzofuranyl,
1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl and
2,3-dihydrobenzo[1,4]dioxinyl.
[0281] The definition pyrazole includes the isomers 1H-, 3H- and
4H-pyrazole. Preferably pyrazolyl denotes 1H-pyrazolyl.
[0282] The definition imidazole includes the isomers 1H-, 2H- and
4H-imidazole. A preferred definition of imidazolyl is
1H-imidazolyl.
[0283] The definition triazole includes the isomers 1H-, 3H- and
4H-[1,2,4]-triazole as well as 1H-, 2H- and 4H-[1,2,3]-triazole.
The definition triazolyl therefore includes 1H-[1,2,4]-triazol-1-,
-3- and -5-yl, 3H-[1,2,4]-triazol-3- and -5-yl,
4H-[1,2,4]-triazol-3-, -4- and -5-yl, 1H-[1,2,3]-triazol-1-, -4-
and -5-yl, 2H-[1,2,3]-triazol-2-, -4- and -5-yl as well as
4H-[1,2,3]-triazol-4- and -5-yl.
[0284] The term tetrazole includes the isomers 1H-, 2H- and
5H-tetrazole. The definition tetrazolyl therefore includes
1H-tetrazol-1- and -5-yl, 2H-tetrazol-2- and -5-yl and
5H-tetrazol-5-yl.
[0285] The definition indole includes the isomers 1H- and
3H-indole. The term indolyl preferably denotes 1H-indol-1-yl.
[0286] The term isoindole includes the isomers 1H- and
2H-isoindole.
[0287] In general, the bond to one of the above-mentioned
heterocyclic or heteroaromatic groups may be effected via a C atom
or optionally an N atom.
[0288] Within the scope of this application, in the definition of
possible substituents, these may also be represented in the form of
a structural formula. An asterisk (*) in the structural formula of
the substituent is to be understood as being the linking point to
the rest of the molecule. Thus, for example, the groups
N-piperidinyl (a), 4-piperidinyl (b), 2-tolyl (c), 3-tolyl (d) and
4-tolyl (e) are represented as follows:
##STR00121##
[0289] If there is no asterisk (*) in the structural formula of the
substituent each hydrogen atom may be removed from the substituent
and the valency thus freed may be used as a bonding point to the
rest of a molecule. Thus, for example, (f)
##STR00122##
may denote 2-tolyl, 3-tolyl, 4-tolyl and benzyl.
[0290] The style of writing used in which in the group
##STR00123##
a bond of a substituent is shown towards the centre of the group A
denotes, unless stated otherwise, that this substituent may be
bound to every free position of the group A carrying an H atom.
[0291] The term "optionally substituted" used in this application
denotes that the group thus referred to is either unsubstituted or
mono- or polysubstituted by the substituents specified. If the
group in question is polysubstituted, the substituents may be
identical or different.
[0292] The groups and substituents described hereinbefore may be
mono- or polysubstituted by fluorine in the manner described.
Preferred fluorinated alkyl groups are fluoromethyl, difluoromethyl
and trifluoromethyl. Preferred fluorinated alkoxy groups are
fluoromethoxy, difluoromethoxy and trifluoromethoxy. Preferred
fluorinated alkylsulphinyl and alkylsulphonyl groups are
trifluoromethylsulphinyl and trifluoromethylsulphonyl.
[0293] The compounds of general formula (I) according to the
invention may have acid groups, chiefly carboxyl groups, and/or
basic groups such as e.g. amino functions. Compounds of general
formula (I) may therefore be present as internal salts, as salts
with pharmaceutically useable inorganic acids such as hydrochloric
acid, sulphuric acid, phosphoric acid, sulphonic acid or organic
acids (such as for example maleic acid, fumaric acid, citric acid,
tartaric acid or acetic acid) or as salts with pharmaceutically
useable bases such as alkali or alkaline earth metal hydroxides or
carbonates, zinc or ammonium hydroxides or organic amines such as
e.g. diethylamine, triethylamine, triethanolamine, inter alia.
[0294] The compounds according to the invention may be obtained
using the methods of synthesis known in principle from starting
compounds known to the skilled man (cf. for example: Houben
Weyl--Methods of Organic Chemistry, Vol. E22, Synthesis of Peptides
and Peptidomimetics, M. Goodman, A. Felix, L. Moroder, C. Toniolo
Eds., Georg Thieme Verlag Stuttgart, New York). The skilled man
knowing the structure of the compounds according to the invention
will be able to synthesise them from known starting materials
without any further information. Thus, the compounds may be
obtained by the methods of preparation described hereinafter.
##STR00124##
[0295] Diagram A illustrates by way of example the synthesis of the
compounds according to the invention. Starting from a Boc-protected
amino acid an amide is prepared by standard coupling methods. After
deprotection coupling is carried out with another Boc-protected
amino acid. The amine obtained after repeated deprotection is
reductively aminated with a Boc-protected aminoaldehyde. The amine
obtained after repeated deprotection is coupled with an isophthalic
acid monoamide component to yield the end product.
##STR00125## ##STR00126##
[0296] Diagram B illustrates by way of example the solid phase
synthesis of compounds of formula 19. The synthesis is carried out
according to normal standard methods described in the literature
(Houben-Weyl--Methods of Organic Chemistry, Vol. E22, Synthesis of
Peptides and Peptidomimetics, M. Goodman, A. Felix, L. Moroder, C.
Toniolo Eds., Georg Thieme Verlag Stuttgart, New York).
[0297] For the solid phase synthesis a commercially obtainable
(formylindolyl)acetamidomethylpolystyrene resin is used. In the
first reaction reductive alkylation is carried out between the
aldehyde group and 4-chloro-benzylamine. The secondary amine formed
is then acylated with the first amino acid (Fmoc-Val). The
acylation is carried out according to standard methods of peptide
chemistry, e.g. with HATU as coupling reagent. After the cleaving
of the Fmoc group with piperidine in DMF the second Fmoc amino acid
(Fmoc-Ala) is coupled in the presence of TBTU/HOBt as coupling
reagent. After a repeat cleaving of the Fmoc group the second
reductive alkylation is carried out with an Fmoc amino acid
aldehyde, in this case Fmoc-phenylalaninal. The resulting secondary
amine is then protected with Boc-anhydride. After cleaving of the
Fmoc group the acylation is carried out with the isophthalic acid
in the presence of TBTU/HOBt and Dipea. The cleaving of the product
from the solid phase is carried out under acidic conditions with
trifluoroacetic acid.
##STR00127##
[0298] Diagram C illustrates by way of example the synthesis of the
compounds according to the invention based on aryl-substituted
isophthalic acids. The aryl-substituted isophthalic acid monoamide
needed is obtained by Suzuki coupling, followed by
monosaponification, amide coupling and a repeat saponification. It
is coupled with an amine component (cf Diagram A) to yield the end
product.
[0299] As stated previously, the compounds of formula (I) may be
converted into the salts thereof, particularly for pharmaceutical
use into the physiologically and pharmacologically acceptable salts
thereof. On the one hand these salts may be present as
physiologically and pharmacologically acceptable acid addition
salts of the compounds of formula (I) with inorganic or organic
acids. On the other hand, in the case of acidically bound hydrogen,
the compound of formula (I) may also be converted by reaction with
inorganic bases into physiologically and pharmacologically
acceptable salts with alkali or alkaline earth metal cations as
counter-ion. Acids which may be used to prepare the acid addition
salts include for example hydrochloric acid, hydrobromic acid,
sulphuric acid, phosphoric acid, methanesulphonic acid, acetic
acid, fumaric acid, succinic acid, lactic acid, citric acid,
tartaric acid or maleic acid. Mixtures of the above acids may also
be used. For preparing the alkali and alkaline earth metal salts of
the compound of formula (I) with acidically bound hydrogen it is
preferable to use the alkali or alkaline earth metal hydroxides and
hydrides, of which the hydroxides and hydrides of the alkali
metals, particularly of sodium and potassium, are preferred, and
sodium and potassium hydroxide are particularly preferred.
[0300] The compounds according to the invention of general formula
(I) and the corresponding pharmaceutically acceptable salts thereof
are chiefly suitable for the treatment and/or prevention of all
those conditions or ailments which are characterised by a
pathological form of the .beta.-amyloid peptide, such as for
example .beta.-amyloid plaques, or which can be influenced by
inhibition of .beta.-secretase. For example the compounds according
to the invention are particularly suitable for the prevention,
treatment or slowing down of the progress of diseases such as
Alzheimer's disease (AD) and other diseases associated with
abnormal processing of Amyloid Precursor Protein (APP) or
aggregation of the Abeta peptide, as well as diseases which can be
treated or prevented by the inhibition of .beta.-secretase or
cathepsin D. Such diseases include MCI ("mild cognitive
impairment"), trisomy 21 (Down's syndrome), cerebral amyloid
angiopathy, degenerative dementias, hereditary cerebral haemorrhage
with amyloidosis, Dutch type (HCHWA-D), Alzheimer's dementia with
Lewy bodies, trauma, stroke, pancreatitis, Inclusion Body Myositis
(IBM), and other peripheral amyloidoses, diabetes and
arteriosclerosis.
[0301] The compounds are preferably suitable for the prevention and
treatment of Alzheimer's disease. The compounds according to the
invention may be used as a monotherapy and also in combination with
other compounds which may be administered for the treatment of the
above-mentioned diseases.
[0302] The compounds according to the invention are particularly
suitable for administration to mammals, preferably primates,
particularly preferably humans, for the treatment and/or prevention
of the above-mentioned conditions and diseases.
[0303] The compounds according to the invention may be administered
by oral, parenteral (intravenous, intramuscular etc.), intranasal,
sublingual, inhalative, intrathecal, topical or rectal route.
[0304] When administered orally, as is preferred, the compounds
according to the invention may be formulated such that the
compounds according to the invention do not come into contact with
the acidic gastric juices. Suitable oral formulations may for
example have gastric juice-resistant coatings which only release
the active substances on reaching the small intestine. Such tablet
coats are known in the art.
[0305] Suitable pharmaceutical formulations for administering the
compounds according to the invention are for example tablets,
pellets, coated tablets, capsules, powders, suppositories,
solutions, elixirs, active substance plasters, aerosols and
suspensions.
[0306] Approximately 0.1 to 1000 mg of one of the compounds
according to the invention or of a mixture of several of these
compounds is formulated on its own or together with
pharmaceutically conventional excipients such as carriers,
diluents, binders, stabilisers, preservatives, dispersants etc. to
form a dosage unit in a manner known to the skilled man.
[0307] A dosage unit (e.g. a tablet) preferably contains between 2
and 250 mg, particularly preferably between 10 and 100 mg of the
compounds according to the invention.
[0308] Preferably, the pharmaceutical formulations are administered
1, 2, 3 or 4 times, particularly preferably 1-2 times, most
preferably once a day.
[0309] The dosage required to achieve a corresponding effect with
the treatment or prevention usually depends on the compound which
is to be administered, the patient, the nature and gravity of the
disease or condition and the method and frequency of administration
and is for the doctor prescribing the treatment to decide.
[0310] Expediently, the amount of the compounds according to the
invention administered is in the range from 0.1 to 1000 mg/day,
preferably 2 to 250 mg/day, particularly preferably 5 to 100
mg/day, when administered orally. For this purpose, the compounds
of formula (I) prepared according to the invention, optionally in
combination with other active substances, may be formulated
together with one or more inert conventional carriers and/or
diluents, e.g. with corn starch, lactose, glucose, microcrystalline
cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid,
tartaric acid, water, water/ethanol, water/glycerol,
water/sorbitol, water/polyethyleneglycol, propyleneglycol,
cetylstearylalcohol, carboxymethylcellulose or fatty substances
such as hard fat or suitable mixtures thereof into conventional
galenic preparations such as tablets, pellets, coated tablets,
capsules, powders, suppositories, solutions, elixirs, active
substance plasters, aerosols and suspensions.
[0311] The compounds according to the invention may also be used in
combination with other active substances, particularly for the
treatment and/or prevention of the diseases and conditions
mentioned hereinbefore. Other active substances which may be used
for such combinations include in particular those which, for
example, potentiate the therapeutic effect of a compound according
to the invention in respect of one of the indications mentioned
and/or enable the dosage of a compound according to the invention
to be reduced. Therapeutic agents suitable for such a combination
include, for example, beta-secretase inhibitors; gamma-secretase
inhibitors; amyloid aggregation inhibitors such as e.g. alzhemed;
directly or indirectly acting neuroprotective substances;
anti-oxidants, such as e.g. vitamin E or ginkolide;
anti-inflammatory substances, such as e.g. Cox inhibitors, NSAIDs
additionally or exclusively having A.beta. lowering properties;
HMG-CoA reductase inhibitors (statins); acetylcholinesterase
inhibitors, such as donepezil, rivastigmine, tacrine, galantamine;
NMDA receptor antagonists such as e.g. memantine; AMPA agonists;
substances modulating the concentration or release of
neurotransmitters such as NS-2330; substances inducing the
secretion of growth hormone such as ibutamoren mesylate and
capromorelin; CB-1 receptor antagonists or inverse agonists;
antibiotics such as minocyclin or rifampicin; PDE-IV and PDE-IX
inhibitors, GABA.sub.A inverse agonists, nicotinic agonists,
histamine H3 antagonists, 5 HAT-4 agonists or partial agonists,
5HT-6 antagonists, a2-adrenoreceptor antagonists, muscarinic M1
agonists, muscarinic M2 antagonists, metabotropic
glutamate-receptor 5 positive modulators, and other substances that
modulate receptors or enzymes in a manner such that the efficacy
and/or safety of the compounds according to the invention is
increased and/or unwanted side effects are reduced.
[0312] Preferred are those combinations which consist of one or
more of the compounds according to the invention with one or more
of the following substances selected from among alzhemed, vitamin
E, ginkolide, donepezil, rivastigmine, tacrine, galantamine,
memantine, NS-2330, ibutamoren mesylate, capromorelin, minocyclin
and/or rifampicin.
[0313] The compounds according to the invention, or the
physiologically acceptable salts thereof, and the other active
substances to be combined with them may be contained together in a
dosage unit, for example a tablet or capsule, or separately in two
identical or different dosage units, for example as a so-called
kit-of-parts.
[0314] The compounds according to the invention may also be used in
combination with immunotherapies such as e.g. active immunisation
with Abeta or parts thereof or passive immunisation with humanised
anti-Abeta antibodies for the treatment of the above-mentioned
diseases and conditions.
[0315] The dosage for the above-mentioned combination partners is
expediently 1/5 of the normally recommended lowest dose up to 1/1
of the normally recommended dose.
[0316] Therefore in another aspect the invention relates to the use
of a compound according to the invention or a physiologically
acceptable salt of such a compound combined with at least one of
the active substances described above as combination partners for
preparing a pharmaceutical composition which is suitable for the
treatment or prevention of diseases or conditions which can be
influenced by the inhibition of .beta.-secretase.
[0317] The compound according to the invention, or a
physiologically acceptable salt thereof, in combination with
another active substance may be used simultaneously or at staggered
times, but particularly close together in time. If administered
simultaneously, the two active substances are given to the patient
together; if administered at staggered times the two active
substances are given to the patient successively within a period of
less than or equal to 12, particularly less than or equal to 6
hours.
[0318] Consequently, in another aspect, the invention relates to a
pharmaceutical composition which contains a compound according to
the invention or a physiologically acceptable salt of such a
compound and at least one of the active substances described
hereinbefore as combination partners, optionally together with one
or more inert carriers and/or diluents.
[0319] Thus, for example, a pharmaceutical composition according to
the invention contains a combination of a compound according to the
invention of formula (I) or a physiologically acceptable salt of
such a compound as well as at least one other of the
above-mentioned active substances optionally together with one or
more inert carriers and/or diluents.
[0320] The compounds according to the invention inhibit the
proteolysis of the APP protein between the amino acids Met595 and
Asp596 (the numbering relates to the APP695 isoform) or the
proteolysis of other APP isoforms such as APP751 and APP770 or
mutated APP at the corresponding site, which is also referred to as
the .beta.-secretase cleavage site. The inhibition of the
.beta.-secretase should therefore lead to a reduced production of
the .beta.-amyloid peptide (A.beta.).
[0321] The activity of the .beta.-secretase may be investigated in
assays based on different detection techniques. In the test set-up
a catalytically active form of .beta.-secretase is incubated with a
potential substrate in a suitable buffer. The reduction in the
substrate concentration or the increase in the product
concentration may be monitored using various technologies as a
function of the substrate used: HPLS-MS analysis, fluorescence
assays, fluorescence-quenching assays, luminescence assays are a
non-representative selection of the various possibilities. Assay
systems in which the effectiveness of a compound can be
demonstrated are described e.g. in U.S. Pat. No. 5,942,400 and U.S.
Pat. No. 5,744,346 and hereinafter. An alternative assay format
comprises displacing a known .beta.-secretase ligand with a test
substance (US 2003/0125257).
[0322] As the substrate, either the APP protein or parts thereof or
any amino acid sequence which can be hydrolysed by .beta.-secretase
may be used. A selection of such sequences can be found for example
in Tomasselli et al. 2003 in J. Neurochem 84: 1006. A peptide
sequence of this kind may be coupled to suitable dyes which make it
possible to detect proteolysis indirectly. The enzyme source used
may be the total .beta.-secretase enzyme or mutants with a
catalytic activity or just parts of the .beta.-secretase which
still contain the catalytically active domain. Various forms of
.beta.-secretase are known and available and may be used as the
enzyme source in a corresponding test set-up. This includes the
native enzyme as well as the recombinant or synthetic enzyme. Human
.beta.-secretase is known by the name Beta Site APP Cleaving Enzyme
(BACE), Asp2 and memapsin 2 and is described e.g. in U.S. Pat. No.
5,744,346 and in Patent Applications WO 98/22597, WO 00/03819, WO
01/23533, and WO 00/17369, as well as in the scientific literature
(Hussain et. al., 1999, Mol. Cell. Neurosci. 14: 419-427; Vassar
et. al., 1999, Science 286: 735-741; Yan et. al., 1999, Nature 402:
533-537; Sinha et. al., 1999, Nature 40: 537-540; and Lin et. al.,
2000, PNAS USA 97: 1456-1460). Synthetic forms of the enzyme have
also been described (WO 98/22597 and WO 00/17369). .beta.-secretase
may be extracted and purified for example from human brain tissue
or produced recombinantly in mammalian cell cultures, insect cell
cultures, yeasts or bacteria.
[0323] To calculate the IC50 value of a substance different amounts
of substance are incubated with the .beta.-secretase in an assay.
The IC50 value of a compound is defined as the concentration of
substance at which a 50% reduction in the detected signal is
measured, compared with the mixture without the test compound.
Substances are evaluated as inhibiting .beta.-secretase if under
these conditions their IC50 value is less than 50 mM, preferably
less than 10 mM, particularly preferably less than 1 mM and most
particularly preferably less than 100 nM.
[0324] In detail, an assay for detecting .beta.-secretase activity
may be as follows:
[0325] The ectodomain of BACE (amino acids 1-454) fused to the
recognition sequence for an anti-Myc antibody and a poly-histidine
is secreted overnight by HE 293/APP/BACE.sub.ect. cells in
OptiMEM.RTM. (Invitrogen). A 10 .mu.l aliquot of this cell culture
supernatant is used as the enzyme source. The enzyme is stable over
more than 3 months' storage at 4.degree. C. or -20.degree. C. in
OptiMEM.RTM.. The substrate used is a peptide with the amino acid
sequence SEVNLDAEFK, to which the Cy3 fluorophore (Amersham) is
coupled N-terminally and the Cy5Q fluorophore (Amersham) is coupled
C-terminally. The substrate is dissolved in DMSO in a concentration
of 1 mg/ml and used in the experiment in a concentration of 1
.mu.M. The test mixture also contains 20 mM NaOAc, pH 4.4 and a
maximum of 1% DMSO. The test is carried out in a 96-well plate in a
total volume of 200 .mu.l for 30 minutes at 30.degree. C. The
cleaving of the substrate is recorded kinetically in a fluorimeter
(ex: 530 nm, em: 590 nm). The assay is started by adding the
substrate.
[0326] Mixtures without enzyme or without inhibitor are included in
each plate as controls.
[0327] The IC.sub.50 value for the test compound is calculated
using standard software (e.g. GraphPad Prism.RTM.) from the
percentage inhibition of the substance at different test
concentrations. The relative inhibition is calculated from the
reduction in signal intensity in the presence of the substance,
compared with the signal intensity without the substance.
[0328] The compounds (1)-(458) listed in the preceding Table have
IC.sub.50 values of less than 30 .mu.M, measured using the test
described hereinbefore.
[0329] The activity of the .beta.-secretase may also be
investigated in cellular systems. As APP is a substrate for
.beta.-secretase and A.beta. is secreted by the cells after
processing of APP by .beta.-secretase has taken place, cellular
test systems for detecting .beta.-secretase activity are based on
the detection of the amount of A.beta. formed over a defined
period.
[0330] A selection of suitable cells includes, but is not
restricted to, human embryonic kidney fibroblasts 293 (HEK293),
Chinese Hamster Ovary cells (CHO), human H4 neuroglioma cells,
human U373 MG astrocytoma glioblastoma cells, murine neuroblastoma
N2a cells, which stably or transiently express APP or mutated forms
of APP, such as e.g. the Swedish or London or Indiana mutation. The
transfection of the cells is carried out e.g. by cloning the cDNA
from human APP into an expression vector such as e.g. pcDNA3
(Invitrogen) and adding it to the cells with a transfection reagent
such as e.g. lipofectamine (Invitrogen) in accordance with the
manufacturer's instructions.
[0331] The secretion of A.beta. may also be measured from cells
without genetic modification with a suitably sensitive A.beta.
detection assay such as e.g. ELISA or HTRF. Cells which may be used
for this may be for example human IMR32 neuroblastoma cells,
besides various other cells.
[0332] The secretion of A.beta. may also be investigated in cells
obtained from the brains of embryos or the young of APP transgenic
mice, e.g. in those of Hsiao et al 1996 Science 274: 99-102, or
from other organisms such as e.g. guinea pigs or rats.
[0333] Substances are evaluated as inhibiting .beta.-secretase if
under these conditions their IC.sub.50 value is less than 50 mM,
preferably less than 10 mM, particularly preferably less than 1
.mu.M and most preferably less than 100 nM.
[0334] An example of the method used to carry out a cell assay is
described below: U373-MG cells which stably express APP (isoform
751) are cultivated in a culture medium such as DMEM+glucose,
sodium pyruvate, glutamine and 10% FCS at 37.degree. C. in a
steam-saturated atmosphere with 5% CO.sub.2. In order to
investigate the .beta.-secretase inhibiting activity of substances
the cells are incubated with different concentrations of the
compound between 50 mM and 50 .mu.M for 12-24 h. The substance is
dissolved in DMSO and diluted for the assay in culture medium such
that the DMSO concentration does not exceed 0.5%. The production of
A.beta. during this period is determined using an ELISA which uses
the antibodies 6E10 (Senentek) and SGY3160 (C. Eckman, Mayo Clinic,
Jacksonville, Fla., USA) as capturing antibodies which are bound to
the microtitre plate and A.beta.40 and A.beta.42-specific
antibodies (Nanotools, Germany), coupled to alkaline phosphatase as
detection antibodies. Non-specific binding of proteins to the
microtitre plate is prevented by blocking with Block Ace (Serotec)
before the addition of the A.beta.-containing culture supernatant.
The amounts of A.beta. contained in the cell supernatant are
quantified by adding the substrate for alkaline phosphatase
CSPD/Sapphire II (Applied Biosystems) in accordance with the
manufacturer's instructions. Possible non-specific effects of the
test compound on the vitality of the cell are ruled out by
determining this by AlamarBlue (Resazurin) reduction over a period
of 60 minutes. The potency of non-toxic substances is determined by
calculating the concentration which results in a 50% reduction in
the amount of A.beta. secreted by comparison with untreated
cells.
[0335] In addition, various animal models may be used to
investigate the .beta.-secretase activity and/or the APP processing
and the release of A.beta.. Thus, for example, transgenic animals
which express APP and/or .beta.-secretase are used to test the
inhibitory activity of compounds of this invention. Corresponding
transgenic animals are described e.g. in U.S. Pat. No. 5,877,399,
U.S. Pat. No. 5,612,486, U.S. Pat. No. 5,387,742, U.S. Pat. No.
5,720,936, U.S. Pat. No. 5,850,003, U.S. Pat. No. 5,877,015 and
U.S. Pat. No. 5,811,633, and in Games et. al., 1995, Nature 373:
523. It is preferable to use animal models which exhibit some of
the characteristics of AD pathology. The addition of
.beta.-secretase inhibitors according to this invention and
subsequent investigation of the pathology of the animals is another
alternative for demonstrating the .beta.-secretase inhibition by
the compounds. The compounds are administered in such a way that
they are able to reach their site of activity in a pharmaceutically
effective form and amount.
[0336] The test for detecting cathepsin D (EC: 3.4.23.5) inhibition
was carried out as follows: 20 mU of recombinant cathepsin D
(Calbiochem, Cat. No. 219401) in 20 mM sodium acetate buffer pH 4.5
with 5 mM substrate peptide and various concentrations of the test
substance are incubated at 37.degree. C. in a 96-well dish and the
conversion is recorded over 60 minutes in a fluorescence measuring
device (emission: 535 nm, extinction: 340 nm). The peptide
substrate used has the following sequence:
NH.sub.2-Arg-Glu(Edans)-Glu-Val-Asn-Leu-Asp-Ala-Glu-Phe-Lys(Dab-
cyl)-Arg-COOH (Bachem). However, it is also possible to use a
peptide or protein substrate with a sequence that can be cleaved
proteolytically by cathepsin D. The test substances are dissolved
in DMSO and used in the assay after being diluted to a maximum 1%
DMSO.
[0337] The assay is started by adding the substrate.
[0338] Mixtures without enzyme or without inhibitor are included in
each plate as controls.
[0339] The IC.sub.50 value for the test compound is calculated
using standard software (e.g. GraphPad Prism.RTM.) from the
percentage inhibition of the substance at different test
concentrations. The relative inhibition is calculated from the
reduction in signal intensity in the presence of the substance,
compared with the signal intensity without the substance.
[0340] The compounds (1)-(458) listed in the Table hereinbefore had
an inhibitory effect on cathepsin D in the test described here.
[0341] The Examples that follow are intended to illustrate the
invention, without restricting it thereto.
EXAMPLES
[0342] The following abbreviations are used in the test
descriptions:
BOC tert.-butoxycarbonyl
DIPEAN-ethyl-diisopropylamine
[0343] DMF dimethylformamide ES-MS electrospray mass spectrometry
HPLC high pressure liquid chromatography HPLC-MS high pressure
liquid chromatography with mass detection sat. saturated HOBt
1-hydroxy-benzotriazole-hydrate i. vac. in vacuo conc. concentrated
MPLC medium pressure liquid chromatography RF retention factor RT
retention time TBTU
O-(benzotriazol-1-yl)-N,N,N','-tetramethyluronium tetrafluoroborate
TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran
.fwdarw.* indicates the binding site of a group -* indicates the
binding site of a group
[0344] The HPLC 1-data were produced under the following
conditions:
TABLE-US-00001 Waters Alliance 2695 HPLC, Waters 2700 Autosampler,
Waters 2996 diode array detector The mobile phase used is: A: water
with 0.13% TFA B: acetonitrile with 0.10% TFA time in min % A % B
flow rate in ml/min 0.0 95 5 1.00 0.7 95 5 1.00 5.2 2 98 1.00 5.7 2
98 1.00 6.0 95 5 1.00 6.5 95 5 1.00
[0345] The stationary phase used was a Varian column, Microsorb 100
C.sub.18 3 .mu.m, 4.6 mm.times.50 mm, batch no. 2231108 (column
temperature: constant at 25.degree. C.).
[0346] The diode array detection took place at a wavelength range
of 210-300 nm.
[0347] The HPLC 2-data were produced under the following
conditions:
TABLE-US-00002 The mobile phase used is: A: water B: acetonitrile
time in min % A % B flow rate in ml/min 0.0 95 5 1.50 5.0 0 100
1.50 6.0 0 100 1.50 6.2 95 5 1.50
[0348] The stationary phase used was a Develosil RPAq. column 4.6
mm.times.50 mm,
[0349] The detection took place at wavelengths of 254 nm.
[0350] The HPLC 3-data were produced under the following
conditions:
TABLE-US-00003 Waters Alliance 2795 HPLC with integrated
Autosampler, Waters 2996 PDA, Waters ZQ mass spectrometer The
mobile phase used is: A: water with 0.10% TFA B: acetonitrile with
0.08% TFA time in min % A % B flow rate in ml/min 0.00 95 5 0.80
2.75 2 98 0.80 3.50 2 98 0.80 3.80 95 5 0.80 5.00 95 5 0.80 6.5 95
5 1.00
[0351] The stationary phase used was a Waters column, Xterra MS
C.sub.18, 3.5 .mu.m, 2.1 mm.times.50 mm (column temperature:
constant at 40.degree. C.).
[0352] The diode array detection took place at a wavelength range
of 210-500 nm.
[0353] The HPLC 4-data were produced under the following
conditions:
TABLE-US-00004 Abimed Gilson, Autoinjector 231 XL, Fraction
collector 202 C, Detector 118 UV/Vis, The mobile phase used is: A:
water with 0.10% TFA B: acetonitrile with 0.10% TFA time in min % A
% B flow rate in ml/min 0 90 10 20.00 5 90 10 20.00 16 50 50 20.00
25 50 50 20.00 31 0 100 20.00 32 90 10 20.00 37 90 10 20.00
[0354] The stationary phase used was a Varian column, Microsorb
C.sub.18 8 .mu.m, 21.2 mm.times.250 mm; the diode array detection
took place at a wavelength range of 210-300 nm.
[0355] The HPLC 5-data were produced under the following
conditions:
[0356] column: Waters Xterra MS. C18. 4.6.times.50 mm. 3.5
.mu.m.
[0357] column temperature. 40.degree. C.
[0358] flow rate 1 ml/min.
[0359] buffer A: water+0.1% TFA.
[0360] buffer B: MeCN+0.08% TFA.
[0361] gradient: from 95% A to 2% A in 4.50 min
[0362] The HPLC 6 data were produced under the following
conditions:
TABLE-US-00005 Waters ZQ2000 mass spectrometer, HP1100 HPLC + DAD,
Gilson 215 The mobile phase used is: A: water with 0.10% TFA B:
acetonitrile with 0.10% TFA time in min % A % B flow rate in ml/min
0.0 95 5 1.00 0.4 95 5 1.00 4.0 2 98 1.00 4.35 2 98 1.00 4.50 95 5
1.00
[0363] The stationary phase used was a column X-Terra MS C18, 3.5
.mu.m, 4.6 mm.times.50 mm, (column temperature: constant at
40.degree. C.).
[0364] The diode array detection took place at a wavelength range
of 210-500 nm.
[0365] The HPLC-MS-data were produced under the following
conditions:
TABLE-US-00006 Waters ZMD, Waters Alliance 2690 HPLC, Waters 2700
Autosampler, Waters 996 diode array detector The mobile phase used
is: A: water with 0.13% TFA B: acetonitrile with 0.10% TFA time in
min % A % B flow rate in ml/min 0.0 95 5 1.00 0.1 95 5 1.00 3.1 2
98 1.00 4.5 2 98 1.00 5.0 95 5 1.00
[0366] The stationary phase used was a Waters column, Xterra MS
C.sub.18 2.5 .mu.m, 4.6 mm.times.30 mm, (column temperature:
constant at 25.degree. C.).
[0367] The diode array detection took place at a wavelength range
of 210-500 nm.
Example 1
##STR00128##
[0368] a) Preparation of 1-a:
##STR00129##
[0370] 2.0 g (9.6 mmol) dimethyl 5-amino-isophthalate were
dissolved in 19 ml dichloromethane and combined with 1.5 ml (19.1
mmol) pyridine. The reaction solution was cooled to 0.degree. C.,
at this temperature 0.8 ml (10.5 mmol) methanesulphonyl chloride
was metered in and the mixture was stirred for 2 hours at ambient
temperature. Then the reaction solution was evaporated to dryness
i. vac., the residue was mixed with ethyl acetate, filtered off and
dried in the vacuum drying cupboard.
[0371] Yield 2.5 g (91%) white crystals 1-a.
[0372] ES-MS (M+H).sup.+=288
b) Preparation of 1-b:
##STR00130##
[0374] First of all 2.5 g (8.7 mmol) 1-a and then 1.3 ml (17.4
mmol) methyl iodide were added to a solution of 0.7 g (17.4 mmol)
sodium hydride (60% in mineral oil) in 10 ml DMF. The reaction
solution was stirred for 1 h at ambient temperature, combined with
100 ml of water and extracted with ethyl acetate. The combined
organic phases were dried and evaporated to dryness using the
rotary evaporator. Quantitative yield of 1-b as a yellow oil.
[0375] ES-MS (M+NH.sub.4).sup.+=319
c) Preparation of 1-c:
##STR00131##
[0377] 2.9 g (8.7 mmol) 1-b were dissolved in 25 ml of methanol and
25 ml THF, at 0.degree. C. 8.7 ml (8.7 mmol) 1N NaOH were added and
the reaction solution was stirred for 7 hours at ambient
temperature. Then the solvent was eliminated using the rotary
evaporator, the residue was dissolved in 30 ml 1N HCl and extracted
with ethyl acetate. The combined organic phases were dried and
purified by chromatography on silica gel with the eluant
(dichloromethane/methanol 95:5).
[0378] Yield 1.2 g (46%) white crystals 1-c.
[0379] ES-MS (M+H).sup.+=288
d) Preparation of 1-d:
##STR00132##
[0381] 500 mg (1.7 mmol) 1-c in 10 ml dichloromethane were combined
with 615 mg (1.9 mmol) TBTU and 1.2 ml (7.0 mmol) DIPEA, then 226
.mu.l (1.7 mmol) (R)-1-phenyl-ethylamine was added and the mixture
was stirred for 1 hour at ambient temperature.
[0382] The reaction solution was extracted with 20% KHCO.sub.3
solution and water. The organic phases were separated using a phase
separator cartridge and evaporated to dryness i. vac. The residue
was purified by chromatography on silica gel with the eluant (ethyl
acetate/heptane 9:1). Yield 580 mg (85%) beige crystals 1-d.
[0383] ES-MS (M+H).sup.+=391
e) Preparation of 1-e:
##STR00133##
[0385] 580 mg (1.5 mmol) 1-d were dissolved in 5 ml of methanol and
5 ml THF, 1.5 ml (3.0 mmol) 2N NaOH was added and the reaction
solution was stirred for 1 hour at 50.degree. C. Then the solvent
was eliminated i. vac., the residue was combined with 20 ml 1N HCl,
the precipitate was filtered off and dried at 50.degree. C. in the
vacuum drying cupboard.
[0386] Yield 270.0 mg (48%) white crystals 1-e.
[0387] ES-MS (M+H).sup.+=377
f) Preparation of 1-f:
##STR00134##
[0389] 25.9 g (119.2 mmol) Boc-L-valine in 250 ml dichloromethane
were combined with 38.3 g (119 mmol) TBTU and 63.0 ml (371 mmol)
DIPEA, while cooling with an ice bath, then 10.7 g (131 mmol)
ethylamine-hydrochloride was added. The reaction solution was
stirred for 5 hours at ambient temperature and then extracted with
20% KHCO.sub.3 solution and water. The organic phases were
separated using a phase separator cartridge and evaporated to
dryness i. vac. The residue was purified by chromatography on
silica gel with the eluant (ethyl acetate/heptane 7:3).
Quantitative yield of 1-f as white crystals.
[0390] ES-MS (M+H).sup.+=245
g) Preparation of 1-g:
##STR00135##
[0392] 29.0 g (0.1 mol) 1-f was dissolved in 130 ml dichloromethane
and combined with 100 ml (1.3 mol) trifluoroacetic acid. The
reaction solution was stirred for 1 h at ambient temperature, then
evaporated to dryness using the rotary evaporator.
[0393] Quantitative yield of 1-g as a yellow oil.
h) Preparation of 1-h:
##STR00136##
[0395] 1-h was prepared analogously to 1-d from Boc-Ala-OH and
1-g.
[0396] ES-MS (M+H).sup.+=316
i) Preparation of 1-i:
##STR00137##
[0398] 40.0 g (0.1 mol) 1-h were suspended in 800 ml of ethyl
acetate and combined with 100 ml (0.4 mol) 4N HCl in dioxane. The
reaction solution was stirred overnight at ambient temperature. The
precipitate was suction filtered, suspended in diethyl ether,
suction filtered again and then dried at 50.degree. C. in the
vacuum drying cupboard.
[0399] Yield 27.1 g (85%) white crystals 1-i.
[0400] ES(-)-MS (M-H).sup.-=250
j) Preparation of 1-j:
##STR00138##
[0402] 29.7 g (70.0 mmol) of Dess-Martin periodinane were suspended
in 150 ml dichloromethane, then within 40 minutes a solution of
16.0 g (63.7 mmol) Boc-phenyl-alaminol in 150 ml dichloromethane
was metered in. The reaction solution was stirred for 2 hours at
ambient temperature, then combined with 200 ml 20% KHCO.sub.3
solution and 200 ml 10% Na.sub.2S.sub.2O.sub.3 solution. The
mixture was stirred for 20 min at ambient temperature, the phases
were separated and the organic phase was washed with 20% KHCO.sub.3
solution and water. The organic phase was dried and evaporated to
dryness using the rotary evaporator. Quantitative yield of 1-j as
white crystals.
k) Preparation of 1-k:
##STR00139##
[0404] 15.4 g (61.2 mmol) 1-i were dissolved in 200 ml acetonitrile
and combined with 10.5 ml (61.2 mmol) DIPEA. The mixture was
stirred for 10 min at ambient temperature, 15.3 g (61.2 mmol) 1-j
was added and the mixture was cooled to 0.degree. C. Then the
reaction solution was combined with 7.0 ml (122 mmol) acetic acid
and 20.5 g (91.8 mmol) sodium triacetoxyborohydride and stirred
overnight at ambient temperature. The reaction solution was
evaporated to dryness using the rotary evaporator and the residue
was combined with dichloromethane and 1N NaHCO.sub.3 solution. The
phases were separated, the organic phase was dried and evaporated
to dryness i. vac. The residue was purified by chromatography on
silica gel with the eluant (ethyl acetate/heptane 7:3 to ethyl
acetate/heptane 1:0). Yield 13.1 g (43%) bright yellow crystals
1-k.
[0405] ES-MS (M+H).sup.+=449
l) Preparation of 1-l:
##STR00140##
[0407] 1-l was prepared analogously to Example 1-g from 1-k.
[0408] ES-MS (M+H).sup.+=349
m) Preparation of 1-m:
##STR00141##
[0410] 1-m was prepared analogously to 1-d from 1-e and 1-l.
[0411] ES-MS (M+H).sup.+=707
[0412] Analogously to Example 1 the following compounds were
prepared from 1-c and the corresponding amount of amine:
TABLE-US-00007 ##STR00142## Mass Example R spectrum 1.2
##STR00143## 725 [M + H].sup.+ 1.3 ##STR00144## 725 [M + H].sup.+
1.4 ##STR00145## 721 [M + H].sup.+ 1.5 ##STR00146## 721 [M +
H].sup.+ 1.6 ##STR00147## 721 [M + H].sup.+ 1.7 ##STR00148## 708 [M
+ H]+ 1.8 ##STR00149## 708 [M + H]+ 1.9 ##STR00150## 708 [M + H]+
1.10 ##STR00151## 713 [M + H]+ 1.11 ##STR00152## 707 [M + H]+ 1.12
##STR00153## 755/757 (chlorine isotopes) [M + H]+ 1.13 ##STR00154##
817 [M + H]+ 1.14 ##STR00155## 784 [M + H]+ 1.15 ##STR00156## 735
[M + H]+ 1.16 ##STR00157## 790 [M + H]+ 1.17 ##STR00158## 782 [M +
H]+ 1.18 ##STR00159## 737 [M + H]+ 1.19 ##STR00160## 785/787
(bromine isotopes) [M + H]+ 1.20 ##STR00161## 757 [M + H]+ 1.21
##STR00162## 721 [M + H]+ 1.22 ##STR00163## 721 [M + H]+ 1.23
##STR00164## 719 [M + H]+ 1.24 ##STR00165## 741/743 (chlorine
isotopes) [M + H]+ 1.25 ##STR00166## 737 [M + H]+ 1.26 ##STR00167##
735 [M + H]+ 1.27 ##STR00168## 721 [M + H]+ 1.27-b ##STR00169## 761
[M + H]+ 1.27-c ##STR00170## 694 [M + H]+ 1.27-d ##STR00171## 738
[M + H]+ 1.27-e ##STR00172## 730 [M + H]+ 1.27-f ##STR00173## 712
[M + H]+ 1.27-g ##STR00174## 708 [M + H]+ 1.27-h ##STR00175## 736
[M + H]+ 1.27-i ##STR00176## 743 [M + H]+ 1.27-j ##STR00177## 776
[M + H]+ 1.27-k ##STR00178## 712 [M + H]+ 1.27-l ##STR00179## 726
[M + H]+ 1.27-m ##STR00180## 710 [M + H]+ 1.27-n ##STR00181## 740
[M + H]+ 1.27-o ##STR00182## 724 [M + H]+ 1.27-p ##STR00183## 684
[M + H]+ 1.27-q ##STR00184## 700 [M + H]+ 1.27-r ##STR00185## 744
[M + H]+ 1.27-s ##STR00186## 722 [M + H]+ 1.27-t ##STR00187## 722
[M + H]+ 1.27-u ##STR00188## 765 [M + H]+ 1.27-v ##STR00189## 736
[M + H]+ 1.27-w ##STR00190## 787 [M + H]+ 1.27-x ##STR00191## 709
[M + H]+ 1.27-y ##STR00192## 747 [M + H]+ 1.27-z ##STR00193## 750
[M + H]+ 1.27-za ##STR00194## 761 [M + H]+ 1.27-zb ##STR00195## 712
[M + H]+
[0413] Analogously to Example 1 the following compounds were
prepared from dimethyl 5-amino-isophthalate and the corresponding
amount of sulphonyl chlorides:
TABLE-US-00008 ##STR00196## Retention Exam- Mass time ple R
Spectrum (method) 1.28 ##STR00197## 783 [M + H].sup.+ 4.84 min
(HPLC 1) 1.29 ##STR00198## 770 [M + H].sup.+ 4.57 min (HPLC 1) 1.30
##STR00199## 721 [M + H].sup.+ 4.54 min (HPLC 1) 1.31 ##STR00200##
736 [M + H].sup.+ 4.64 min (HPLC 1) 1.32 ##STR00201## 778 [M +
H].sup.+ 4.53 min (HPLC 1) 1.33 ##STR00202## 769 [M + H]+ 4.79
(HPLC1) 1.34 ##STR00203## 735 [M + H]+
[0414] Analogously to 1 the following compounds were prepared from
corresponding educts:
TABLE-US-00009 Exam- Mass Retention time ple spectrum (method)
1.34-a ##STR00204## 788 [M + H].sup.+ 1.34-b ##STR00205## 774 [M +
H].sup.+ 1.34-c ##STR00206## 746 [M + H].sup.+ 2.58 min (HPLS-MS)
1.34-d ##STR00207## 805 [M + H].sup.+ 1.34-e ##STR00208## 788 [M +
H].sup.+ 3.03 min (HPLC-MS) 1.34-f ##STR00209## 781 [M + H].sup.+
2.75 min (HPLC-MS) 1.34-g ##STR00210## 773 [M + H].sup.+ 2.70 min
(HPLC-MS) 1.34-h ##STR00211## 764 [M + H].sup.+ 1.34-i ##STR00212##
786 [M + H].sup.+ 2.14 min (HPLC-MS) 1.34-j ##STR00213## 864 [M +
H].sup.+ 2.71 min (HPLC-MS) 1.34-k ##STR00214## 785 [M + H].sup.+
4.17 min (HPLC 1) 1.34-l ##STR00215## 863 [M + H].sup.+ 5.01 min
(HPLC 1) 1.34-m ##STR00216## 865 [M + H].sup.+ 3.84 min (HPLC 1)
1.34-n ##STR00217## 943 [M + H].sup.+ 4.75 min (HPLC 1) 1.34-o
##STR00218## 864 [M + H].sup.+ 4.39 min (HPLC 1) 1.34-p
##STR00219## 942 [M + H].sup.+ 5.27 min (HPLC 1)
Example 1.35
##STR00220##
[0416] Example 1.35 was prepared analogously to Example 1, except
that iodoethane was used instead of methyl iodide.
[0417] ES-MS (M+H).sup.+=721
[0418] RT(HPLC 1)=4.57 min
Example 1.36
##STR00221##
[0420] Example 1.36 was prepared analogously to Example 1 from 1-e
and
(S)-2-{(S)-2-[(S)-2-amino-3-(1H-imidazol-4-yl)-propylamino]-propionylamin-
o}-N-ethyl-3-methyl-butyramide.
[0421] ES-MS (M+H).sup.+=697
Example 1.37
##STR00222##
[0423] Example 1.37 was prepared analogously to Example 1 from 1-e
and the corresponding amine component, by using
Boc-(S)-cyclohexylalaninal in step 1k) instead of
Boc-(S)-phenylalaninal.
[0424] ES-MS (M+H).sup.+=713
[0425] RT(HPLC 1)=4.90 min
[0426] RT(HPLC-MS)=2.87 min
Example 1.38
##STR00223##
[0428] Example 1.38 was prepared analogously to Example 1 from 1-e
and the corresponding amine component, by using Boc-(S)-norleucinal
in step 1k) instead of Boc-(S)-phenylalaninal.
[0429] ES-MS (M+H).sup.+=673
[0430] RT(HPLC 1)=5.55 min
[0431] RT(HPLC-MS)=2.76 min
Example 1.39
##STR00224##
[0433] Example 1.39 was prepared analogously to Example 1 from 1-e
and the corresponding amine component, by using
Boc-(S)-2-amino-4-cyclohexyl-butyraldehyde in step 1k) instead of
Boc-(S)-phenylalaninal.
[0434] ES-MS (M+H).sup.+=727
[0435] RT(HPLC 1)=5.06 min
[0436] RT(HPLC-MS)=2.97 min
Example 1.40
##STR00225##
[0438] Example 1.40 was prepared analogously to Example 1 from 1-e
and the corresponding amine component, by using
Boc-(S)-cyclopentylalaninal in step 1k) instead of
Boc-(S)-phenylalaninal.
[0439] ES-MS (M+H).sup.+=699
[0440] RT(HPLC 1)=4.74 min
[0441] RT(HPLC-MS)=2.88 min
Example 1.41
##STR00226##
[0443] Example 1.41 was prepared analogously to Example 1 from 1-e
and the corresponding amine component, by using
Boc-(S)-2-amino-3-benzyloxy-propionaldehyde in step 1k) instead of
Boc-(S)-phenylalaninal.
[0444] ES-MS (M+H).sup.+=737
[0445] RT(HPLC 1)=4.67 min
[0446] RT(HPLC-MS)=2.83 min
Example 1.42
##STR00227##
[0448] Example 1.42 was prepared analogously to Example 1 from 1-e
and the corresponding amine component, by using
Boc-(S)-2-amino-3-(4-trifluoromethylphenyl)-propionaldehyde in step
1k) instead of Boc-(S)-phenylalaninal.
[0449] ES-MS (M+H).sup.+=775
[0450] RT(HPLC 1)=4.81 min
[0451] RT(HPLC-MS)=2.95 min
[0452] Analogously to Example 1 the following compounds were
prepared, using the corresponding amine instead of ethylamine
analogously to the preparation of 1f:
TABLE-US-00010 ##STR00228## Mass Retention time Example R spectrum
(method) 1.43 ##STR00229## 719 [M + H].sup.+ 4.64 min (HPLC 1),
2.82 min (HPLC-MS) 1.44 ##STR00230## 693 [M + H].sup.+ 4.39 min
(HPLC 1) 1.44b ##STR00231## 761 [M + H].sup.+ 4.76 min (HPLC 1),
3.03 min (HPLC-MS)
Example 1.45
##STR00232##
[0454] Example 1.45 was prepared analogously to Example 1 from 1-e
and the corresponding amine component, by using
2-tert-butoxycarbonylamino-4,4,4-trifluoro-butyric acid in step 1f)
instead of Boc-L-valine.
[0455] ES-MS (M+H).sup.+=747
[0456] RT(HPLC-MS)=2.86 min
Example 1.46
##STR00233##
[0458] Example 1.46 was prepared analogously to Example 1 from 1-e
and the corresponding amine component, by using
Boc-(S)-2-aminobutyric acid in step 1 h) instead of
Boc-alanine.
[0459] ES-MS (M+H).sup.+=747
[0460] RT(HPLC-MS)=2.86 min
Example 1.47
##STR00234##
[0462] Example 1.47 was prepared analogously to Example 1.46, by
using Boc-(S)-2-aminohexanal instead of Boc-(S)-phenylalaninal
analogously to step 1k). The crude product was purified by
RP-HPLC.
[0463] ES-MS (M+H).sup.+=687
[0464] RT(HPLC 1)=4.61 min
Example 1.48
##STR00235##
[0466] Example 1.48 was prepared analogously to Example 1.38 from
1-e, by using Ala-Val-amide (Bachem AG) in step 1-h) instead of 1i.
The crude product was purified by RP-HPLC.
[0467] ES-MS (M+H).sup.+=645
[0468] RT(HPLC 1)=4.34 min
[0469] RT(HPLC-MS)=2.71 min
Example 1.49
##STR00236##
[0471] Example 1.49 was prepared analogously to Example 1.19, by
using Ala-Val-amide (Bachem AG) in step 1-h) instead of 1i. The
crude product was purified by RP-HPLC.
[0472] ES-MS (M+H).sup.+=757/759 (Br)
[0473] RT(HPLC 1)=4.67 min
[0474] RT(HPLC-MS)=1.93 min
Example 1.50
##STR00237##
[0476] Example 1.50 was prepared analogously to Example 1.19, by
using 2,2,2-trifluorethylamine instead of ethyl amine in step 1-f).
The crude product was purified by RP-HPLC.
[0477] ES-MS (M+H).sup.+=839/841 (Br)
[0478] RT(HPLC 1)=5.00 min
Example 1.51
##STR00238##
[0480] Example 1.51 was prepared analogously to Example 1.38, by
using methylamine in step 1-f) instead of ethylamine. The crude
product was purified by RP-HPLC.
[0481] ES-MS (M+H).sup.+=659
[0482] RT(HPLC 1)=4.26 min
[0483] RT(HPLC-MS)=2.69 min
Example 1.52
##STR00239##
[0484] a) Preparation of 1.52-a:
##STR00240##
[0486] 101 mg (0.34 mmol) 18.6-b dissolved in 5 ml of pyridine were
combined batchwise with 92 mg (0.34 mmol) dansyl chloride and the
mixture was stirred for 14 h at ambient temperature. Then it was
poured onto water, mixed with hydrochloric acid, extracted with
ethyl acetate, the organic phase was dried and evaporated down. By
trituration with ether 132 mg 1.52-a were obtained as a beige
solid.
[0487] ES-MS (M+H).sup.+=532
b) Preparation of 1.52-b:
##STR00241##
[0489] The saponification von 1.52-a to 1.52-b was carried out
analogously to step 18.6-d with sodium hydroxide solution in
methanol.
[0490] ES-MS (M+H).sup.+=518
c) Preparation of 1.52
##STR00242##
[0492] 1.52 was prepared analogously to Example 1.38 from 1.52-b,
by using Ala-Val-amide (Bachem AG) in step 1-h) instead of 1i. The
crude product was first of all chromatographed on silica gel
(dichloromethane/methanol 95:5) and then purified by RP-HPLC.
[0493] ES-MS (M+H).sup.+=786
[0494] RT(HPLC 1)=4.55 min
Example 1.53
##STR00243##
[0496] Example 1.53 was prepared analogously to Example 1 from 1-e
and the corresponding amine component, by using
Boc-L-cyclopropylglycine in step 1 h) instead of Boc-alanine.
[0497] ES-MS (M+H).sup.+=733
[0498] RT(HPLC-1)=4.66 min
Example 1.54
##STR00244##
[0500] Example 1.54 was prepared analogously to Example 1 from 1-e
and the corresponding amine component, by using Boc-L-norvaline in
step 1h) instead of Boc-alanine.
[0501] ES-MS (M+H).sup.+=735
[0502] RT(HPLC-MS)=2.91 min
[0503] The following Examples were prepared analogously to Example
1 using the corresponding educts:
TABLE-US-00011 Mass Retention time Example spectrum (method) 1.55
##STR00245## 732 [M + H].sup.+ 1.56 ##STR00246## 776 [M + H].sup.+
1.57 ##STR00247## 798 [M + H].sup.+ 4.99 min (HPLC 1) 1.58
##STR00248## 777 [M + H].sup.+ 2.96 min (HPLC-MS) 1.59 ##STR00249##
791 [M + H].sup.+ 3.04 (HPLC-MS) 1.60 ##STR00250## 763 [M +
H].sup.+ 2.87 min (HPLC-MS)
[0504] The following Examples were prepared analogously to Example
1 using 1.61-a and the corresponding educts:
Preparation of 1.61-a
##STR00251##
[0506] 2.00 g (6.96 mmol) 1-a were placed in 50 ml DMF in the
autoclave and 1.2 g KOH powder was added. Then 5 bar of
chlorodifluoromethane were added under pressure. The reaction
mixture was heated to 80.degree. C. and stirred for 14 h. A further
1.0 g KOH powder was added, chlorodifluoromethane was added under
pressure and the mixture was stirred for 14 h at 80.degree. C. The
solution was cooled, water was slowly added (vigorous foaming) and
the mixture was extracted with ethyl acetate. After evaporation
brown crystals were formed which were stirred out with MeOH and
suction filtered.
[0507] Yield: 400 mg (17%) 1.61-a as brown crystals
[0508] RT (HPLC-MS)=3.04 min
[0509] ES-MS (M).sup.+=337
TABLE-US-00012 Exam- Mass Retention time ple spectrum (method) 1.61
##STR00252## 762 [M + H].sup.+ 4.77 min (HPLC 1) 1.62 ##STR00253##
778 [M + H].sup.+ 4.93 min (HPLC 1) 1.63 ##STR00254## 737 [M +
H].sup.+ 4.28 min (HPLC 1)
Example 2
##STR00255##
[0510] a) Preparation of 2-a:
##STR00256##
[0512] 2-a was prepared analogously to 1-d from monomethyl
isophthalate and 1-l.
b) Preparation of 2-b:
##STR00257##
[0514] 450 mg (0.88 mmol) 2-a were dissolved in 5 ml of methanol,
then 5.0 ml (10.0 mmol) 2N NaOH was added and the reaction solution
was stirred for 5 hours at ambient temperature. The solvent was
eliminated using the rotary evaporator and the residue was combined
with 2N HCl. Then the aqueous phase was decanted off, the organic
phase was combined with diethyl ether and the precipitate was
filtered off.
[0515] Yield 320.0 mg (68%) white crystals 2-b.
[0516] ES-MS (M+H).sup.+=497
c) Preparation of 2-c:
##STR00258##
[0518] 2-c was prepared analogously to 1-d from 2-b and
benzylamine. The purification was carried out by chromatography on
silica gel with the eluant (dichloromethane/methanol 9:1).
[0519] ES-MS (M+H).sup.+=586
[0520] Analogously to Example 2 the following compounds were
prepared from 2-b and the corresponding amount of amines:
##STR00259##
TABLE-US-00013 Mass Retention time Example R spectrum (method) 2.2
##STR00260## 600 [M + H].sup.+ 2.3 ##STR00261## 628 [M + H].sup.+
2.97 min (HPLC-MS) 2.4 ##STR00262## 614 [M + H].sup.+ 2.81 min
(HPLC-MS) 2.5 ##STR00263## 680 [M + H].sup.+ 4.20 min (HPLC 2) 2.6
##STR00264## 658 [M + H].sup.+ 3.91 min (HPLC 2) 2.7 ##STR00265##
690 [M + H]+ 4.30 min (HPLC 2) 2.8 ##STR00266## 614 [M + H]+ 3.98
min (HPLC 2) 2.9 ##STR00267## 614 [M + H]+ 3.95 min (HPLC 2) 2.10
##STR00268## 650 [M + H]+ 4.25 min (HPLC 2) 2.11 ##STR00269## 632
[M + H]+ 3.62 min (HPLC 2) 2.12 ##STR00270## 639 [M + H]+ 4.03 min
(HPLC 2) 2.13 ##STR00271## 601 [M + H]+ 3.27 min (HPLC 2) 2.14
##STR00272## 634 [M + H]+ 4.19 min (HPLC 2) 2.15 ##STR00273## 630
[M + H]+ 4.09 min (HPLC 2) 2.16 ##STR00274## 630 [M + H]+ 4.05 min
(HPLC 2) 2.17 ##STR00275## 660 [M + H]+ 3.87 min (HPLC 2) 2.18
##STR00276## 680 [M + H]+ 4.26 min (HPLC 2) 2.19 ##STR00277## 634
[M + H]+ 4.23 min (HPLC 2) 2.20 ##STR00278## 616 [M + H]+ 3.74 min
(HPLC 2) 2.21 ##STR00279## 614 [M + H]+ 4.18 min (HPLC 2) 2.22
##STR00280## 679 [M + H]+ 3.65 min (HPLC 2) 2.23 ##STR00281## 645
[M + H]+ 4.06 min (HPLC 2) 2.24 ##STR00282## 668 [M + H]+ 4.27 min
(HPLC 2) 2.25 ##STR00283## 634 [M + H]+ 4.20 min (HPLC 2) 2.26
##STR00284## 606 [M + H]+ 4.00 min (HPLC 2) 2.27 ##STR00285## 652
[M + H]+ 4.21 min (HPLC 2) 2.28 ##STR00286## 668 [M + H]+ 4.31 min
(HPLC 2) 2.29 ##STR00287## 643 [M + H]+ 4.24 min (HPLC 2) 2.30
##STR00288## 660 [M + H]+ 4.05 min (HPLC 2) 2.31 ##STR00289## 644
[M + H]+ 4.19 min (HPLC 2) 2.32 ##STR00290## 653 [M + H]+ 4.15 min
(HPLC 2) 2.33 ##STR00291## 618 [M + H]+ 4.09 min (HPLC 2) 2.34
##STR00292## 618 [M + H]+ 4.07 min (HPLC 2) 2.35 ##STR00293## 710
[M + H]+ 4.20 min (HPLC 2) 2.36 ##STR00294## 601 [M + H]+ 3.27 min
(HPLC 2) 2.37 ##STR00295## 628 [M + H]+ 4.29 min (HPLC 2) 2.38
##STR00296## 650 [M + H]+ 4.32 min (HPLC 2) 2.39 ##STR00297## 668
[M + H]+ 4.28 min (HPLC 2) 2.40 ##STR00298## 636 [M + H]+ 4.11 min
(HPLC 2) 2.41 ##STR00299## 636 [M + H]+ 4.12 min (HPLC 2) 2.42
##STR00300## 636 [M + H]+ 4.10 min (HPLC 2) 2.43 ##STR00301## 636
[M + H]+ 4.14 min (HPLC 2) 2.44 ##STR00302## 636 [M + H]+ 4.09 min
(HPLC 2) 2.45 ##STR00303## 619 [M + H]+ 3.75 min (HPLC 2) 2.46
##STR00304## 618 [M + H]+ 3.37 min (HPLC 2) 2.47 ##STR00305## 671
[M + H]+ 3.46 min (HPLC 2) 2.48 ##STR00306## 590 [M + H]+ 3.87 min
(HPLC 2) 2.49 ##STR00307## 684 [M + H]+ 4.32 min (HPLC 2) 2.50
##STR00308## 618 [M + H]+ 3.55 min (HPLC 2) 2.51 ##STR00309## 668
[M + H]+ 4.28 min (HPLC 2) 2.52 ##STR00310## 604 [M + H]+ 3.62 min
(HPLC 2) 2.53 ##STR00311## 604 [M + H]+ 3.61 min (HPLC 2) 2.54
##STR00312## 618 [M + H]+ 3.73 min (HPLC 2) 2.55 ##STR00313## 636
[M + H]+ 4.21 min (HPLC 2) 2.56 ##STR00314## 630 [M + H]+ 3.87 min
(HPLC 2) 2.57 ##STR00315## 604 [M + H]+ 3.97 min (HPLC 2) 2.58
##STR00316## 620 [M + H]+ 4.07 min (HPLC 2) 2.59 ##STR00317## 656
[M + H]+ 4.29 min (HPLC 2) 2.60 ##STR00318## 600 [M + H]+ 4.06 min
(HPLC 2) 2.61 ##STR00319## 604 [M + H]+ 4.00 min (HPLC 2) 2.62
##STR00320## 616 [M + H]+ 3.94 min (HPLC 2) 2.63 ##STR00321## 600
[M + H]+ 4.07 min (HPLC 2) 2.64 ##STR00322## 622 [M + H]+ 3.95 min
(HPLC 2) 2.65 ##STR00323## 614 [M + H]+ 4.21 min (HPLC 2) 2.66
##STR00324## 628 [M + H]+ 3.95 min (HPLC 2) 2.67 ##STR00325## 644
[M + H]+ 3.88 min (HPLC 2) 2.68 ##STR00326## 652 [M + H]+ 3.91 min
(HPLC 2) 2.69 ##STR00327## 590 [M + H]+ 3.26 min (HPLC 2) 2.70
##STR00328## 668 [M + H]+ 4.27 min (HPLC 2) 2.71 ##STR00329## 668
[M + H]+ 4.26 min (HPLC 2) 2.72 ##STR00330## 654 [M + H]+ 4.28 min
(HPLC 2) 2.73 ##STR00331## 620 [M + H]+ 4.10 min (HPLC 2) 2.74
##STR00332## 628 [M + H]+ 4.32 min (HPLC 2) 2.75 ##STR00333## 622
[M + H]+ 4.05 min (HPLC 2) 2.76 ##STR00334## 629 [M + H]+ 3.34 min
(HPLC 2) 2.77 ##STR00335## 626 [M + H]+ 4.03 min (HPLC 2) 2.78
##STR00336## 622 [M + H]+ 4.05 min (HPLC 2) 2.79 ##STR00337## 622
[M + H]+ 4.02 min (HPLC 2)
Example 2.80
##STR00338##
[0521] a) Preparation of 2.80-a:
##STR00339##
[0523] 2.80-a was prepared analogously to 1-d from monomethyl
isophthalate and (R)-1-phenyl-ethylamine.
b) Preparation of 2.80-b:
##STR00340##
[0525] 2.80-b was prepared analogously to 2-b from 2.80-a.
[0526] ES-MS (M+H).sup.+=270
c) Preparation of 2.80-c:
##STR00341##
[0528] 2.80-c was prepared analogously to 1-d from 2.80-b and
1-l.
[0529] ES-MS (M+H).sup.+=600
Example 2.81
##STR00342##
[0531] Example 2.81 was prepared analogously to Example 2.80,
except that (S)-1-phenyl-ethylamine was used instead of
(R)-1-phenyl-ethylamine.
[0532] ES-MS (M+H).sup.+=600
Example 2.82
##STR00343##
[0534] Example 2.82 was prepared analogously to Example 2.80,
except that in the synthesis of the precursor analogous to 1-l the
corresponding benzylamine was used in step 1-f.
[0535] ES-MS (M+H).sup.+=748
[0536] RT(HPLC-MS)=2.75 min
Example 3
##STR00344##
[0537] a) Preparation of 3-a:
##STR00345##
[0539] 1.0 g (5.6 mmol) monomethyl isophthalate were combined in 30
ml THF with 1.8 g (5.6 mmol) TBTU and 781.0 .mu.l (5.6 mmol)
triethylamine, then 723 .mu.l (5.6 mmol) benzylmethylamine was
added and the mixture was stirred overnight at ambient temperature.
The reaction solution was extracted with sat. NaCl solution and
ethyl acetate. The organic phases were dried and evaporated to
dryness i. vac. Quantitative yield of 3-a.
[0540] RF=0.64 (silica gel; petroleum ether/ethyl acetate 1:1)
b) Preparation of 3-b:
##STR00346##
[0542] 1.6 g (5.6 mmol) 3-a were dissolved in 40 ml THF and 50 ml
of water, then 1.2 g (27.8 mmol) lithium hydroxide was added and
the reaction solution was stirred for 3 hours at ambient
temperature. The solvent was eliminated using the rotary
evaporator, the residue was combined with 30 ml 1N HCl and
extracted with ethyl acetate. The combined organic phases were
dried, evaporated down i. vac. and combined with petroleum
ether/ethyl acetate. The precipitate was suction filtered and
dried.
[0543] Yield 1.3 g (83%) 3-b.
[0544] RF=0.13 (silica gel; petroleum ether/ethyl acetate 1:1)
c) Preparation of 3-c:
##STR00347##
[0546] 3-c was prepared analogously to 1-j from BOC-L-leucinol.
d) Preparation of 3-d:
##STR00348##
[0548] 3-d was prepared analogously to 1-k from 3-c and 1-i.
[0549] ES-MS (M+H).sup.+=415
e) Preparation of 3-e:
##STR00349##
[0551] 3-e was prepared analogously to 1-g from 3-d.
f) Preparation of 3-f:
##STR00350##
[0553] 3-f was prepared analogously to 1-d from 3-b and 3-e.
[0554] RT(HPLC 3)=1.87 min
Example 4
##STR00351##
[0555] a) Preparation of 4-a:
##STR00352##
[0557] 4-a was prepared analogously to 1-d from 1-c and
R-1-(3-chlorophenyl)-ethylamine.
b) Preparation of 4-b:
##STR00353##
[0559] 4-b was prepared analogously to 2-b from 4-a.
c) Preparation of 4-c:
##STR00354##
[0561] 4-c was prepared analogously to 1-d from 4-b and
(S)-2-[(S)-2-((S)-2-amino-3-thiazol-4-yl-propylamino)-propionylamino]-N-e-
thyl-3-methyl-butyramide.
[0562] ES-MS (M+H).sup.+=748/750 (chlorine isotopes)
[0563] RT(HPLC 1)=4.35 min
[0564] Analogously to Example 4 the following compounds were
prepared from 1-c and the corresponding amount of amines:
##STR00355##
TABLE-US-00014 Mass Retention time Example R spectrum (method) 4.2
##STR00356## 728 [M + H].sup.+ 4.27 min (HPLC 1) 4.3 ##STR00357##
720 [M + H].sup.+ 4.09 min (HPLC 1) 4.4 ##STR00358## 728 [M +
H].sup.+ 4.25 min (HPLC 1) 4.5 ##STR00359## 744 [M + H]+ 4.15 min
(HPLC 1)
Example 5
##STR00360##
[0565] a) Preparation of 5-a:
##STR00361##
[0567] 945 mg (24.9 mmol) lithium aluminium hydride were suspended
in 10 ml THF, cooled to 0.degree. C. and then 5.0 g (16.6 mmol)
Boc-L-3,5-difluorophenylalanine dissolved in 15 ml THF was slowly
metered in. The reaction solution was stirred overnight at ambient
temperature, then combined with 10 ml sat. diammonium tartrate
solution and magnesium sulphate, stirred for 30 minutes at ambient
temperature and filtered through silica gel. The filtrate was
evaporated to dryness i. vac. and separated by chromatography by
MPLC using the eluant (ethyl acetate/heptane 0:100 to 70:30). Yield
2.8 g (58%) white crystals 5-a.
[0568] RT(HPLC-MS)=2.92 min
b) Preparation of 5-b:
##STR00362##
[0570] 5-b was prepared analogously to 1-j from 5-a.
[0571] RF=0.7 (ethyl acetate/heptane 70:30)
c) Preparation of 5-c:
##STR00363##
[0573] 5-c was prepared analogously to 1-k from 1-i and 5-b.
[0574] RT(HPLC-MS)=2.65 min
d) Preparation of 5-d:
##STR00364##
[0576] 5-d was prepared analogously to 1-i from 5-c.
[0577] ES-MS (M+H).sup.+=385
[0578] RT(HPLC-MS)=2.12 min
e) Preparation of 5-e:
##STR00365##
[0580] 5-e was prepared analogously to 1-d from 1-e and 5-d.
[0581] ES-MS (M+H).sup.+=743
[0582] RT(HPLC 1)=4.58 min
[0583] Analogously to 5-e the following compounds were prepared
from 1-e and the corresponding amount of amines:
TABLE-US-00015 ##STR00366## Mass Example R spectrum 5.2
##STR00367## 721 [M + H].sup.+ 5.3 ##STR00368## 719 [M + H].sup.+
5.4 ##STR00369## 713 [M + H].sup.+ 5.5 ##STR00370## 708 [M +
H].sup.+ 5.6 ##STR00371## 708 [M + H].sup.+ 5.7 ##STR00372## 714 [M
+ H]+ 5.8 ##STR00373## 655 [M + H]+ 5.9 ##STR00374## 697 [M + H]+
5.10 ##STR00375## 697 [M + H]+ 5.11 ##STR00376## 713 [M + H]+ 5.12
##STR00377## 791/793 (Br) [M + H]+ 5.13 ##STR00378## 764 [M + H]+
5.14 ##STR00379## 714 [M + H]+ 5.15 ##STR00380## 670 [M + H]+ 5.16
##STR00381## 752 [M + H]+ 5.17 ##STR00382## 785/787 (Br) [M + H]+
5.18 ##STR00383## 722 [M + H]+ 5.19 ##STR00384## 741/743 (Cl) [M +
H]+ 5.20 ##STR00385## 747/749 (Cl) [M + H]+ 5.21 ##STR00386## 727
[M + H]+ 5.22 ##STR00387## 725 [M + H]+ 5.23 ##STR00388## 669 [M +
H]+ 5.24 ##STR00389## 712 [M + H]+ 5.25 ##STR00390## 659 [M +
H]+
[0584] Analogously to 5-e the following compounds were prepared
from the corresponding acids analogous to 1-e and amines analogous
to 5-d:
TABLE-US-00016 Mass Retention spectrum time Example structure [M +
H].sup.+ [method] 5.26 ##STR00391## 731 2.78 min [HPLC-MS] 5.27
##STR00392## 726 2.46 min [HPLC-MS] 5.28 ##STR00393## 726 2.40 min
[HPLC-MS] 5.29 ##STR00394## 742/744 (Cl) 2.53 min [HPLC-MS] 5.30
##STR00395## 742/744 (Cl) 2.49 min [HPLC-MS] 5.31 ##STR00396##
747/749 (Cl) 2.87 min [HPLC-MS] 5.32 ##STR00397## 727 2.83 min
[HPLC-MS] 5.33 ##STR00398## 722 4.00 min [HPLC- 1] 5.34
##STR00399## 722 2.42 min [HPLC-MS] 5.35 ##STR00400## 714 3.86 min
[HPLC- 1] 5.36 ##STR00401## 714 2.33 min [HPLC-MS] 5.37
##STR00402## 825/827/ 829 (Br/Cl) 5.38 ##STR00403## 798/800 (Cl)
2.85 min [HPLC-MS] 5.39 ##STR00404## 748/750 (Cl) 2.65 min
[HPLC-MS] 5.40 ##STR00405## 704/706 (Cl) 2.68 min [HPLC-MS]
Example 6
##STR00406##
[0585] a) Preparation of 6-a:
##STR00407##
[0587] 2.0 g (12.0 mmol) 3,5-pyridinedicarboxylic acid were
combined with 0.9 ml (12.0 mmol) thionyl chloride in 40 ml of
methanol while cooling with an ice bath. The reaction solution was
stirred first at ambient temperature, then at 50.degree. C.
overnight. Then the reaction solution was combined with water at
ambient temperature and 20% KHCO.sub.3 solution and extracted with
ethyl acetate. The aqueous phase was adjusted to pH 3 with 4N HCl
and extracted with ethyl acetate. The organic phase was dried and
evaporated to dryness using the rotary evaporator. The residue was
purified by chromatography on silica gel with the eluant
(dichloromethane/methanol/CH.sub.3COOH 95:5:0.1). Yield 1.0 g (46%)
white crystals 6-a.
[0588] ES-MS (M+H).sup.+=182
##STR00408##
[0589] 6-b was prepared analogously to 1-d from 6-a and
(R)-1-(4-fluoro-phenyl)-ethylamine.
c) Preparation of 6-c:
##STR00409##
[0591] 6-c was prepared analogously to 2-b from 6-b.
d) Preparation of 6-d:
##STR00410##
[0593] 6-d was prepared analogously to 1-d from 1-l and 6-c.
[0594] ES-MS (M+H).sup.+=619
Example 6.2
##STR00411##
[0596] Example 6.2 was prepared analogously to Example 6, except
that pyridine-2,6-dicarboxylic acid was used instead of
3,5-pyridinedicarboxylic acid.
[0597] ES-MS (M+H).sup.+=619
Example 6.3
##STR00412##
[0598] a) Preparation of 6.3-a:
##STR00413##
[0600] 30.0 g (133.2 mmol) monomethyl 5-nitro-isophthalate were
dissolved in 200 ml of methanol and combined with 3.0 g Pd/C (5%).
The mixture was hydrogenated for 2.5 hours in a Parr apparatus at
ambient temperature under a hydrogen pressure of 50 psi. Then the
catalyst was filtered off and the filtrate was evaporated down i.
vac. Yield 18.4 g (71%) 6.3-a.
[0601] RT(HPLC 1)=2.88 min
b) Preparation of 6.3-b:
##STR00414##
[0603] 14.0 g (62.7 mmol) copper-(II)-bromide and 12.0 ml (102.6
mmol) n-butylnitrite in 300 ml acetonitrile were combined with 10.0
g (51.2 mmol) 6.3-a, suspended in 300 ml acetonitrile, while
cooling with an ice bath. The reaction solution was stirred for 1.5
hours at 30.degree. C., then evaporated to dryness i. vac. Then the
residue was combined with dichloromethane and washed with 3N HCl
and water. The organic phase was dried and evaporated to dryness
using the rotary evaporator. The residue was combined with diethyl
ether and the precipitate was filtered off.
[0604] Yield 4.5 g (34%) 6.3-b.
[0605] ES-MS (M+H).sup.+=257/259 (bromine isotopes)
[0606] RT(HPLC-MS)=2.87 min
c) Preparation of 6.3-c:
##STR00415##
[0608] 6.3-c was prepared analogously to 1-d from 6.3-b and
(R)-1-(4-fluoro-phenyl)-ethylamine.
d) Preparation of 6.3-d:
##STR00416##
[0610] 6.3-d was prepared analogously to 2-b from 6.3-c.
e) Preparation of 6.3-e:
##STR00417##
[0612] 6.3-e was prepared analogously to Example 1-d from 1-l and
6.3-d.
[0613] ES-MS (M+H).sup.+=696/698 (bromine isotopes)
[0614] Analogously to 6.3-e the following compounds were prepared
from corresponding educts:
##STR00418##
[0615] ES-MS (M+H).sup.+=826/828 (Br)
[0616] RT(HPLC-MS)=2.84 min 198
Example 6.4
##STR00419##
[0617] a) Preparation of 6.4-a:
##STR00420##
[0619] 6.4-a was prepared analogously to 1-d from
2,4,5,6-tetrafluoro-isophthalic acid and
(R)-1-phenyl-ethylamine.
[0620] ES-MS (M+H).sup.+=342
[0621] RT(HPLC 1)=4.53 min
b) Preparation of 6.4-b:
##STR00421##
[0623] 6.4-b was prepared analogously to 1-d from 1-l and
6.4-a.
[0624] ES-MS (M+H).sup.+=672
Example 7
##STR00422##
[0625] a) Preparation of 7-a:
##STR00423##
[0627] 0.5 g (2.4 mmol) dimethyl 5-amino-isophthalate were refluxed
in 10.0 ml (127 mmol) acetyl chloride for 2 hours. The reaction
solution was evaporated to dryness i. vac. and combined with water.
The precipitate was filtered off and dried.
[0628] Yield 0.6 g (100%) white crystals 7-a.
b) Preparation of 7-b:
##STR00424##
[0630] 7-b was prepared analogously to 1-e from 7-a.
c) Preparation of 7-c:
##STR00425##
[0632] 7-c was prepared analogously to 1-d from 7-b and
(R)-1-phenyl-ethylamine.
d) Preparation of 7-d:
##STR00426##
[0634] 7-d was prepared analogously to 2-b from 7-c.
[0635] e) Preparation of 7-e:
##STR00427##
[0636] 7-e was prepared analogously to 1-d from 1-l and 7-d.
[0637] ES-MS (M+H).sup.+=657
[0638] Analogously to Example 7 the following compounds were
prepared from dimethyl 5-amino-isophthalate and the corresponding
amount of acid chlorides:
TABLE-US-00017 ##STR00428## Mass Example R spectrum 7.2
##STR00429## 719 [M + H].sup.+ 7.3 ##STR00430## 733 [M +
H].sup.+
[0639] Analogously to Example 7 the following compounds were
prepared from dimethyl 5-methylamino-isophthalate and the
corresponding educts:
TABLE-US-00018 Mass Example spectrum 7.4 ##STR00431## 672 [M +
H].sup.+ 7.5 ##STR00432## 630 [M + H].sup.+ 7.6 ##STR00433## 880 [M
+ H].sup.+ 7.7 ##STR00434## 794 [M + H].sup.+ 7.8 ##STR00435## 709
[M + H].sup.+ 7.9 ##STR00436## 822 [M + H].sup.+ 7.10 ##STR00437##
881 [M + H].sup.+
Example 8
##STR00438##
[0640] a) Preparation of 8-a:
##STR00439##
[0642] 300 mg (1.0 mmol) 1-a and 255 mg (2.1 mmol) phenylboric acid
in 10 ml dichloromethane were combined with 220 mg (1.2 mmol)
copper-(II)-acetate, 290 .mu.l (2.1 mmol) triethylamine and 150 mg
molecular sieve 4A. The reaction solution was stirred overnight at
ambient temperature and filtered through silica gel. The filtrate
was washed first with 2N HCl and then with sat. NaHCO.sub.3
solution. The organic phases were separated through phase
separation cartridges and evaporated to dryness. The residue was
purified by HPLC. Yield 60 mg (16%) 8-a.
[0643] ES-MS (M+NH.sub.4).sup.+=381
[0644] RT(HPLC 1)=4.84 min
b) Preparation of 8-b:
##STR00440##
[0646] 8-b was prepared analogously to 1-c from 8-a.
[0647] RT(HPLC 1)=4.67 min
c) Preparation of 8-c:
##STR00441##
[0649] 8-c was prepared analogously to 1-d from 8-b and
(R)-1-phenyl-ethylamine.
[0650] RT(HPLC 1)=5.03 min
d) Preparation of 8-d:
##STR00442##
[0652] 8-d was prepared analogously to 2-b from 8-c.
[0653] RT(HPLC 1)=4.57 min
e) Preparation of 8-e:
##STR00443##
[0655] 8-e was prepared analogously to 1-d from 8-d and 1-l.
[0656] ES-MS (M+H).sup.+=769
[0657] RT(HPLC 1)=4.73 min
Example 8.2
##STR00444##
[0659] Example 8.2 was prepared analogously to Example 8, except
that 4-fluorophenylboric acid was used instead of phenylboric
acid.
[0660] ES-MS (M+H).sup.+=787
[0661] RT(HPLC 1)=4.87 min
Example 8.3
##STR00445##
[0663] Example 8.3 was prepared analogously to Example 8.2 using
the corresponding educts.
[0664] ES-MS (M+H).sup.+=859
Example 9
##STR00446##
[0665] b) Preparation of 9-a:
##STR00447##
[0667] 2.5 g (18.6 mmol) copper-(II)-chloride and 3.6 ml (30.8
mmol) n-butylnitrite were dissolved in 50 ml acetonitrile. While
cooling with the ice bath a suspension of 3.0 g (15.4 mmol) 6.3-a
in 150 ml acetonitrile was slowly metered in and the reaction
solution was stirred for 2 hours at ambient temperature. After the
reaction had ended the mixture was evaporated down i. vac., the
residue was combined with dichloromethane and washed with 3N HCl
and water. The organic phase was evaporated to dryness using the
rotary evaporator, the residue was combined with diethyl ether, the
precipitate was filtered off and dried. Yield 1.6 g (47%) beige
crystals 9-a.
[0668] ES-MS (M+H).sup.+=215
c) Preparation of 9-b:
##STR00448##
[0670] 9-b was prepared analogously to 1-d from 9-a and
(R)-1-phenyl-ethylamine.
[0671] RT(HPLC 1)=5.17 min
d) Preparation of 9-c:
##STR00449##
[0673] 9-c was prepared analogously to 2-b from 9-b.
[0674] RT(HPLC 1)=4.62 min
e) Preparation of 9-d:
##STR00450##
[0676] 9-d was prepared analogously to 1-d from 9-c and 1-l.
[0677] ES-MS (M+H).sup.+=634/636 (chlorine isotopes)
[0678] RT(HPLC 1)=4.71 min
Example 9.2
##STR00451##
[0679] a) Preparation of 9.2-a:
##STR00452##
[0681] 9.2-a was prepared analogously to 1-d from 9-a and
(R)-1-(4-fluoro-phenyl)-ethylamine.
[0682] RT(HPLC 1)=5.16 min
b) Preparation of 9.2-b:
##STR00453##
[0684] 9.2-b was prepared analogously to 2-b from 9.2-a.
[0685] RT(HPLC 1)=4.61 min
c) Preparation of 9.2-c:
##STR00454##
[0687] 9.2-c was prepared analogously to 1-d from 9.2-b and
1-l.
[0688] ES-MS (M+H).sup.+=652/654 (chlorine isotopes)
[0689] RT(HPLC 1)=4.71 min
[0690] Analogously to Example 9.2 the following compounds were
prepared from 9-a and the corresponding amount of amines:
TABLE-US-00019 ##STR00455## Mass Retention time Example R spectrum
(method) 9.3 ##STR00456## 668/670 (chlorine isotopes) [M + H].sup.+
4.91 min (HPLC 1) 9.4 ##STR00457## 634 [M + H].sup.+ 4.68 min (HPLC
1) 9.5 ##STR00458## 640/642 (chlorine isotopes) [M + H].sup.+ 4.63
min (HPLC 1)
Example 9.6
##STR00459##
[0691] a) Preparation of 9.6-a:
##STR00460##
[0693] 9.6-a was prepared analogously to 1-d from 9-a and 1-l.
[0694] RT(HPLC 1)=4.44 min
b) Preparation of 9.6-b:
##STR00461##
[0696] 9.6-b was prepared analogously to 2-b from 9.6-a.
[0697] ES-MS (M+H).sup.+=531/533 (chlorine isotopes)
[0698] RT(HPLC 1)=4.14 min
c) Preparation of 9.6-c:
##STR00462##
[0700] 9.6-c was prepared analogously to 1-d from 9.6-b and
(R)-1-phenyl-propylamine.
[0701] ES-MS (M+H).sup.+=648/650 (chlorine isotopes)
[0702] RT(HPLC 1)=4.84 min
[0703] Analogously to 9.6-c the following compounds were prepared
from 9.6-b and the corresponding amount of amines:
TABLE-US-00020 ##STR00463## Retention Mass time Example R spectrum
(method) 9.7 ##STR00464## 635/637 (chlorine isotopes) [M + H].sup.+
3.81 min (HPLC 1) 9.8 ##STR00465## 664/666 (chlorine isotopes) [M +
H].sup.+ 4.63 min (HPLC 1) 9.9 ##STR00466## 662/664 (chlorine
isotopes) [M + H].sup.+ 4.93 min (HPLC 1) 9.10 ##STR00467## 664 [M
+ H].sup.+ 4.79 min (HPLC 1)
Example 10
##STR00468##
[0704] a) Preparation of 10-a:
##STR00469##
[0706] 1.8 g (8.4 mmol) dimethyl 5-amino-isophthalate were
dissolved in 15 ml THF and combined with 1.0 g (8.4 mmol)
1-chloro-3-isocyanate-propane and refluxed overnight with stirring.
Then the reaction solution was evaporated down i. vac. Yield 2.7 g
(69%) white crystals 10-a.
[0707] RT(HPLC 1)=4.49 min
b) Preparation of 10-b:
##STR00470##
[0709] 2.7 g (5.8 mmol) 10-a were dissolved in 25 ml DMF, combined
with 1.3 g (11.6 mmol) potassium tert-butoxide and stirred
overnight at 60.degree. C. Then the reaction solution was combined
with water and extracted with dichloromethane. The combined organic
phases were dried over MgSO.sub.4, filtered and the filtrate was
evaporated to dryness i. vac. The residue was purified by MPLC with
the eluant (ethyl acetate/heptane 7:3 up to pure methanol). Yield
870 mg (52%) 10-b as white crystals.
[0710] ES-MS (M+H).sup.+=293/294
[0711] RT(HPLC 1)=3.91 min
c) Preparation of 10-c:
##STR00471##
[0713] 10-c was prepared analogously to 1-c from 10-b.
[0714] RT(HPLC 1)=3.44 min
d) Preparation of 10-d:
##STR00472##
[0716] 10-d was prepared analogously to 1-d from 10-c and 1-l.
[0717] RT(HPLC 1)=3.96 min
e) Preparation of 10-e:
##STR00473##
[0719] 10-e was prepared analogously to 2-b from 10-d.
[0720] ES(-)-MS (M-H).sup.-=593
[0721] RT(HPLC 1)=3.74 min
f) Preparation of 10-f:
##STR00474##
[0723] 10-f was prepared analogously to 1-d from 10-e and
(R)-1-phenyl-ethylamine.
[0724] ES-MS (M+H).sup.+=698
[0725] RT(HPLC 1)=4.27 min
[0726] Analogously to 10-f the following compounds were prepared
from 10-e and the corresponding amount of amines:
TABLE-US-00021 ##STR00475## Retention Mass time Example R spectrum
(method) 10.2 ##STR00476## 732/734 (chlorine isotopes) [M +
H].sup.+ 4.50 min (HPLC 1) 10.3 ##STR00477## 728 [M + H].sup.+ 4.31
min (HPLC 1)
Example 11
##STR00478##
[0727] a) Preparation of 11-a:
##STR00479##
[0729] 1.3 ml (15.4 mmol) sulphuryl chloride were metered into a
solution of 1.0 g (7.7 mmol) 3-chloro-propylamine-hydrochloride in
10 ml acetonitrile while cooling with an ice bath and stirred
overnight at 85.degree. C. Then the reaction solution was
evaporated down i. vac. Quantitative yield of 11-a.
b) Preparation of 11-b:
##STR00480##
[0731] 1.0 g (4.8 mmol) dimethyl 5-amino-isophthalate were
suspended in 10 ml of pyridine and slowly combined with 1.5 g (7.8
mmol) 11-a and stirred overnight at ambient temperature. Then the
reaction solution was combined with dichloromethane and washed with
1N HCl and water, the organic phase was separated using a phase
separation cartridge and evaporated down i. vac.
[0732] Yield 1.1 g (41%) brown crystals 11-a.
[0733] RT(HPLC 1)=4.51 min
c) Preparation of 11-c:
##STR00481##
[0735] 11-c was prepared analogously to 10-b from 11-b.
[0736] ES-MS (M+H).sup.+=329
[0737] RT(HPLC 1)=4.29 min
d) Preparation of 11-d:
##STR00482##
[0739] 11-d was prepared analogously to 1-c from 11-c.
[0740] RT(HPLC 1)=3.79 min
e) Preparation of 11-e:
##STR00483##
[0742] 11-e was prepared analogously to 1-d from 11-d and 1-l.
[0743] RT(HPLC 1)=4.16 min
f) Preparation of 11-f:
##STR00484##
[0745] 11-f was prepared analogously to 2-b from 11-e.
[0746] ES(-)-MS (M-H).sup.-=629
[0747] RT(HPLC 1)=3.86 min
g) Preparation of 11-g:
##STR00485##
[0749] 11-g was prepared analogously to 1-d from 11-f and
(R)-1-phenyl-ethylamine.
[0750] ES-MS (M+H).sup.+=734
[0751] RT(HPLC 1)=4.46 min
[0752] Analogously to 11-g the following compounds were prepared
from 11-f and the corresponding amount of amines:
TABLE-US-00022 ##STR00486## Retention Mass time Example R spectrum
(method) 11.2 ##STR00487## 768/770 (chlorine isotopes) [M +
H].sup.+ 4.64 min (HPLC 1) 11.3 ##STR00488## 764 [M + H].sup.+ 4.39
min (HPLC 1) 11.4 ##STR00489## 753 [M + H].sup.+ 4.59 min (HPLC 1)
11.5 ##STR00490## 749 [M + H].sup.+ 2.79 min (HPLC-MS) 11.6
##STR00491## 739 [M + H].sup.+ 4.08 min (HPLC 1) 11.7 ##STR00492##
714 [M + H].sup.+ 3.99 min (HPLC 1) 11.8 ##STR00493## 815 [M +
H].sup.+ 4.80 min (HPLC 1) 11.9 ##STR00494## 735 [M + H].sup.+ 2.26
min (HPLC-MS)
[0753] Analogously to 11-9 the following compounds were prepared
from corresponding educts:
TABLE-US-00023 Retention Mass time Example spectrum (method) 11.10
##STR00495## 739[M + H].sup.+ 4.54 min (HPLC 1) 11.11 ##STR00496##
735[M + H].sup.+ 2.71 min (HPLC-MS) 11.12 ##STR00497## 725[M +
H].sup.+ 3.95 min (HPLC 1) 11.13 ##STR00498## 714[M + H].sup.+ 3.99
min (HPLC 1) 11.14 ##STR00499## 736[M + H].sup.+ 2.38 min (HPLC-MS)
11.15 ##STR00500## 816[M + H].sup.+ 2.52 min (HPLC-MS) 11.16
##STR00501## 742[M + H].sup.+ 4.26 min (HPLC 1) 11.17 ##STR00502##
821[M + H].sup.+ 4.51 min (HPLC 1) 11.18 ##STR00503## 743[M +
H].sup.+ 1.99 min (HPLC-MS)
##STR00504##
a) Preparation of 12-a:
##STR00505##
[0755] 15.0 g (70.3 mmol) dimethyl 5-amino-isophthalate were
dissolved in 150 ml of pyridine and slowly combined with 12.0 ml
(111.7 mmol) N,N-dimethylamidosulphonic acid chloride and stirred
overnight at 90.degree. C. Then the reaction solution was combined
at ambient temperature with 200 ml 4N HCl and the precipitate was
filtered off. The crystals were combined with diethyl ether,
filtered off again and dried at 40.degree. C. in the vacuum drying
cupboard. Yield 17.9 g (64%) beige crystals 12-a.
[0756] RT(HPLC 1)=4.14 min
b) Preparation of 12-b:
##STR00506##
[0758] First 17.9 g (56.6 mmol) 12-a in 250 ml DMF and then 9.3 ml
(124.5 mmol) methyl iodide were added to a solution of 5.0 g (125.1
mmol) sodium hydride (60% in mineral oil) in 250 ml DMF while
cooling with dry ice. The reaction solution was stirred for 3 h at
ambient temperature, combined with 500 ml of water and extracted
with ethyl acetate. The combined organic phases were dried over
MgSO.sub.4 and evaporated to dryness using the rotary evaporator.
The residue was combined with diethyl ether, the precipitate was
filtered off and dried.
[0759] Yield 12.5 g (57%) brown crystals 12-b.
[0760] RT(HPLC 1)=4.67 min
c) Preparation of 12-c:
##STR00507##
[0762] 12-c was prepared analogously to 1-c from 12-b.
[0763] RT(HPLC-MS)=2.58 min
d) Preparation of 12-d:
##STR00508##
[0765] 12-d was prepared analogously to 1-d from 12-c and 1-l.
[0766] RT(HPLC 1)=4.37 min
e) Preparation of 12-e:
##STR00509##
[0768] 12-e was prepared analogously to 2-b from 12-d.
[0769] ES-MS (M+H).sup.+=633
[0770] RT(HPLC-MS)=2.50 min
f) Preparation of 12-f:
##STR00510##
[0772] 12-f was prepared analogously to 1-d from 12-e and
(R)-1-(3-chloro-phenyl)-ethylamine.
[0773] ES-MS (M+H).sup.+=770/772 (chlorine isotopes)
[0774] RT(HPLC 1)=4.77 min
[0775] Analogously to 12-f the following compounds were prepared
from 12-e and the corresponding amount of amines:
TABLE-US-00024 ##STR00511## Mass Retention time Example R spectrum
(method) 12.2 ##STR00512## 754 [M + H].sup.+ 4.67 min (HPLC 1) 12.3
##STR00513## 766 [M + H].sup.+ 4.58 min (HPLC 1) 12.4 ##STR00514##
750 [M + H].sup.+ 4.68 min (HPLC 1) 12.5 ##STR00515## 750 [M +
H].sup.+ 4.66 min (HPLC 1) 12.6 ##STR00516## 737 [M + H].sup.+ 3.83
min (HPLC 1) 12.7 ##STR00517## 737 [M + H].sup.+ 3.89 min (HPLC 1)
12.8 ##STR00518## 742 [M + H].sup.+ 4.55 min (HPLC 1)
[0776] Analogously to 12-f the following compounds were prepared
from corresponding educts:
TABLE-US-00025 Mass Retention spectrum time Example structure [M +
H].sup.+ [method] 12.9 ##STR00519## 776/778 (Cl) 4.88 min [HPLC-1]
12.10 ##STR00520## 771/773 (Cl) 4.29 min [HPLC-1] 12.11
##STR00521## 771/773 (Cl) 4.22 min [HPLC-1] 12.12 ##STR00522## 742
4.67 min [HPLC-1] 12.13 ##STR00523## 737 4.11 min [HPLC-1] 12.14
##STR00524## 737 4.03 min [HPLC-1] 12.15 ##STR00525## 684 2.70 min
[MPLC-MS] 12.16 ##STR00526## 726 2.73 min [MPLC-MS] 12.17
##STR00527## 742 2.81 min [MPLC-MS] 12.18 ##STR00528## 820/822 (Br)
12.19 ##STR00529## 854/856/ 858 (Br/Cl) 5.07 min [HPLC-1] 12.20
##STR00530## 793 2.82 min [HPLC-MS]
Example 13
##STR00531##
[0777] a) Preparation of 13-a:
##STR00532##
[0779] 8.4 ml (96.4 mmol) morpholine in 12 ml acetonitrile were
metered into a solution of 4.0 ml (49.3 mmol) sulphuryl chloride in
12 ml acetonitrile while cooling with an ice bath and the
##STR00533##
[0780] 13-d was prepared analogously to 1-c from 13-c.
[0781] RT(HPLC 1)=4.01 min
e) Preparation of 13-e:
##STR00534##
[0783] 13-e was prepared analogously to 1-d from 13-d and 1-l.
[0784] RT(HPLC 1)=4.30 min
f) Preparation of 13-f:
##STR00535##
[0785] mixture was stirred overnight at 85.degree. C. Then the
reaction solution was evaporated down i. vac., the residue was
combined with diethyl ether, the precipitate was filtered off and
the filtrate was distilled under a pressure of 1 mbar and a head
temperature of 95-98.degree. C. Yield 3.7 g (40%) colourless oil
13-a.
b) Preparation of 13-b:
##STR00536##
[0787] 2.5 g (11.7 mmol) dimethyl 5-amino-isophthalate were
suspended in 40 ml of pyridine, slowly combined with 3.3 g (17.8
mmol) 13-a and stirred overnight at 90.degree. C. Then the reaction
solution was combined with 50 ml 4N HCl while cooling with an ice
bath and the precipitate was filtered off. The crystals were
dissolved in dichloromethane, filtered through a phase separation
cartridge and the filtrate was evaporated down i. vac. Yield 2.7 g
(64%) brown crystals 13-b.
[0788] RT(HPLC 1)=4.30 min
c) Preparation of 13-c:
##STR00537##
[0790] 13-c was prepared analogously to 1-b from 13-b.
[0791] RT(HPLC-MS)=2. 90 min
d) Preparation of 13-d: 229
[0792] 13-f was prepared analogously to 2-b from 13-e.
[0793] ES(-)-MS (M-H).sup.-=675
[0794] RT(HPLC 1)=4.05 min
f) Preparation of 13-g:
##STR00538##
[0796] 13-g was prepared analogously to 1-d from 13-f and
(R)-1-(3-chloro-phenyl)-ethylamine.
[0797] ES-MS (M+H).sup.+=812/814 (chlorine isotopes)
[0798] RT(HPLC-MS)=2.94 min
[0799] Analogously to 13-g the following compounds were prepared
from 13-f and the corresponding amount of amines:
TABLE-US-00026 ##STR00539## Retention Mass time Example R spectrum
(method) 13.2 ##STR00540## 796 [M + H].sup.+ 2.84 min (HPLC-MS)
13.3 ##STR00541## 808 [M + H].sup.+ 2.81 min (HPLC-MS) 13.4
##STR00542## 792 [M + H].sup.+ 2.88 min (HPLC-MS) 13.5 ##STR00543##
792 [M + H].sup.+ 2.90 min (HPLC-MS) 13.6 ##STR00544## 779
(chlorine isotopes) [M + H].sup.+ 2.40 min (HPLC-MS) 13.7
##STR00545## 779 [M + H].sup.+ 2.33 min (HPLC-MS) 13.8 ##STR00546##
784 [M + H].sup.+ 2.81 min (HPLC-MS)
Example 14
##STR00547##
[0800] a) Preparation of 14-a:
##STR00548##
[0802] 25.1 ml (120.0 mmol) 4-chlorobutyl acetate and 15.9 g (120
mmol) sodium sulphite were combined in 40 ml of water, then
refluxed for 20 hours with stirring. Then the reaction solution was
evaporated to dryness i. vac., the residue was combined with 30 ml
(conc.) hydrochloric acid and refluxed for a further 2 hours with
stirring. The mixture was cooled to ambient temperature, filtered
to remove the insoluble matter, the filtrate was neutralised with
4N NaOH and evaporated to dryness using the rotary evaporator.
Quantitative yield of 14-a.
[0803] ES(-)-MS (M-H).sup.-=153
b) Preparation of 14-b:
##STR00549##
[0805] 6.0 g (66%, 22.5 mmol) 14-a were added batchwise to 6 ml
phosphorus oxychloride while cooling with an ice bath. Then 9.3 g
(45.0 mmol) phosphorus pentachloride was also added batchwise and
the mixture was stirred for 24 hours at reflux temperature. It was
evaporated to dryness i. vac., the residue was combined with
diethyl ether and filtered to remove the insoluble matter. The
filtrate was distilled off under 1 mbar pressure at a bottom
temperature of 130-170.degree. C.
[0806] Yield 2.4 g (31%) 14-b (purity approx. 54%).
c) Preparation of 14-c:
##STR00550##
[0808] 14-c was prepared analogously to 11-b from 14-a and dimethyl
5-amino-isophthalate.
[0809] ES(-)-MS (M-H).sup.-=362/364 (chlorine isotopes)
d) Preparation of 14-d:
##STR00551##
[0811] 14-d was prepared analogously to 10-b from 14-c.
[0812] ES-MS (M+H).sup.+=328
[0813] RT(HPLC-MS)=2.86 min
e) Preparation of 14-e:
##STR00552##
[0815] 14-e was prepared analogously to 1-c from 14-d.
[0816] ES-MS (M+H).sup.+=314
f) Preparation of 14-f:
##STR00553##
[0818] 14-f was prepared analogously to 1-d from 14-e and
(R)-1-phenyl-ethylamine.
[0819] ES-MS (M+H).sup.+=417
g) Preparation of 14-g:
##STR00554##
[0821] 14-g was prepared analogously to 1-c from 14-f.
[0822] ES(-)-MS (M-H).sup.-=401
[0823] RT(HPLC-MS)=2.76 min
h) Preparation of 14-h:
##STR00555##
[0825] 14-h was prepared analogously to 1-d from 14-g and 1-l.
[0826] ES-MS (M+H).sup.+=733
Example 14.2
##STR00556##
[0828] Example 14.2 was prepared analogously to Example 14, except
that (R)-1-(3-chloro-phenyl)-ethylamine was used instead of
(R)-1-phenyl-ethylamine.
[0829] ES-MS (M+NH.sub.4).sup.+=468/470
Example 15
##STR00557##
[0830] a) Preparation of 15-a:
##STR00558##
[0832] 15-a was prepared analogously to 1-d from 1-c and
C-thiazol-2-yl-methylamine-hydrochloride.
b) Preparation of 15-b:
##STR00559##
[0834] 15-b was prepared analogously to 2-b from 15-a.
c) Preparation of 15-c:
##STR00560##
[0836] 15-c was prepared analogously to 1-d from 15-b and 1-l.
[0837] ES-MS (M+H).sup.+=700
[0838] Analogously to Example 15 the following compounds were
prepared from 1-c and the corresponding amount of amines:
TABLE-US-00027 ##STR00561## Mass Example R spectrum 15.2
##STR00562## 737 [M + H].sup.+ 15.3 ##STR00563## 765 [M + H].sup.+
15.4 ##STR00564## 751 [M + H].sup.+ 15.5 ##STR00565## 808 [M +
H].sup.+ 15.6 ##STR00566## 808 [M + H].sup.+ 15.7 ##STR00567## 794
[M + H].sup.+
Example 16
##STR00568##
[0839] a) Preparation of 16-a:
##STR00569##
[0841] 16-a was prepared analogously to 1-a from dimethyl
5-amino-isophthalate and ethanesulphonyl chloride.
[0842] ES(-)-MS (M-H).sup.-=300
c) Preparation of 16-b:
##STR00570##
[0844] 16-b was prepared analogously to 1-b from 16-a and methyl
iodide.
[0845] ES-MS (M+H).sup.+=316
[0846] RT(HPLC 1)=4.56 min
c) Preparation of 16-c:
##STR00571##
[0848] 16-c was prepared analogously to 1-c from 16-b.
[0849] RT(HPLC-MS)=2.50 min
d) Preparation of 16-d:
##STR00572##
[0851] 16-d was prepared analogously to 1-d from 16-c and
(R)-1-phenyl-ethylamine.
[0852] RT(HPLC 1)=4.79 min
e) Preparation of 16-e:
##STR00573##
[0854] 16-e was prepared analogously to 2-b from 16-d.
[0855] ES-MS (M+H).sup.+=391
[0856] RT(HPLC 1)=4.33 min
f) Preparation of 16-f:
##STR00574##
[0858] 16-f was prepared analogously to 1-d from 16-e and
(S)-2-[(S)-2-((S)-2-amino-3-thiazol-4-yl-propylamino)-propionylamino]-N-e-
thyl-3-methyl-butyramide.
[0859] ES-MS (M+H).sup.+=728
[0860] RT(HPLC 1)=4.22 min
Example 16.2
##STR00575##
[0862] Example 16.2 was prepared analogously to Example 16, except
that benzenesulphonyl chloride was used instead of ethanesulphonyl
chloride.
[0863] ES(-)-MS (M-H).sup.-=776
[0864] RT(HPLC 1)=4.52 min
[0865] Analogously to 16-2 the following compounds were prepared
from corresponding educts:
TABLE-US-00028 Mass Retention time Example spectrum (method) 16.3
##STR00576## 763 [M + H].sup.+ 16.4 ##STR00577## 795 [M + H].sup.+
16.5 ##STR00578## 770 [M + H].sup.+ 16.6 ##STR00579## 870 [M +
H].sup.+ 2.90 min (HPLC-MS) 16.7 ##STR00580## 792 [M + H].sup.+
2.32 min (HPLC-MS) 16.8 ##STR00581## 871 [M + H].sup.+ 4.11 min
(HPLC 1) 16.9 ##STR00582## 948 [M + H].sup.+ 5.06 min (HPLC 1)
Example 17
##STR00583##
[0866] a) Preparation of 17-a:
##STR00584##
[0868] A solution of 400 mg (1.9 mmol) dimethyl
5-amino-isophthalate in 5 ml THF was combined with 680 .mu.l (3.8
mmol) DIPEA and 164 mg (2.9 mmol) methyl isocyanate. The reaction
solution was stirred overnight at ambient temperature and
evaporated to dryness i. vac. The residue was combined with water
and dichloromethane, the phases were separated through a phase
separation cartridge and the organic phase was evaporated to
dryness i. vac. The residue was purified by MPLC with the eluant
(ethyl acetate/hexane 4:6 to ethyl acetate/hexane 1:0).
[0869] Yield 310 mg (61%) white crystals 17-a.
b) Preparation of 17-b:
##STR00585##
[0871] 17-b was prepared analogously to 1-e from 17-a.
c) Preparation of 17-c:
##STR00586##
[0873] 17-c was prepared analogously to 1-d from 17-b and
(R)-1-phenyl-ethylamine.
d) Preparation of 17-d:
##STR00587##
[0875] 17-d was prepared analogously to 1-e from 17-c.
[0876] e) Preparation of 17-e:
##STR00588##
[0877] 17-e was prepared analogously to 1-d from 17-d and 1-l.
[0878] ES-MS (M-H).sup.+=672
[0879] Analogously to Example 17 the following compounds were
prepared from dimethyl 5-amino-isophthalate and the corresponding
amount of isocyanates:
TABLE-US-00029 ##STR00589## Mass Example R spectrum 17.2
##STR00590## 734 [M + H].sup.+ 17.3 ##STR00591## 748 [M +
H].sup.+
Example 18
##STR00592##
[0880] a) Preparation of 18-a:
##STR00593##
[0882] 24.8 ml (49.5 mmol) ethylamine, 8.6 ml (50.0 mmol) DIPEA
were metered at 5.degree. C. into a solution of 10.0 g (49.2 mmol)
(S)-2-tert-butoxycarbonylamino-butyric acid in 100 ml THF and then
16.1 g (50.0 mmol) TBTU and 6.8 g (50.0 mmol) HOBT were added
batchwise. The reaction solution was stirred overnight at ambient
temperature, evaporated to dryness i. vac., combined with ethyl
acetate and washed with NaHCO.sub.3 solution and NaCl solution. The
organic phase was dried and evaporated to dryness i. vac.
Quantitative yield of 18-a.
[0883] ES-MS (M+H).sup.+=118
[0884] RT(HPLC 1)=2.8 min
b) Preparation of 18-b:
##STR00594##
[0886] 18-b was prepared analogously to 1-i from 18-a.
[0887] ES-MS (M+H).sup.+=131
[0888] RT(HPLC-MS)=2.38 min
c) Preparation of 18-c:
##STR00595##
[0890] 18-c was prepared analogously to 1-d from 18-b and
Boc-L-alanine.
[0891] ES-MS (M+H).sup.+=302
[0892] RT(HPLC-MS)=2.34 min
d) Preparation of 18-d:
##STR00596##
[0894] 18-d was prepared analogously to 1-i from 18-c.
[0895] ES-MS (M+H).sup.+=202
[0896] RT(HPLC-MS)=2.33 min
e) Preparation of 18-e:
##STR00597##
[0898] 18-e was prepared analogously to 1-k from 18-d and
tert-butyl ((S)-1-benzyl-2-oxo-ethyl)-carbamate.
[0899] RT(HPLC-MS)=2.48 min
f) Preparation of 18-f:
##STR00598##
[0901] 18-f was prepared analogously to 1-g from 18-e.
[0902] ES-MS (M+H).sup.+=335
[0903] RT(HPLC-MS)=1.93 min
g) Preparation of 18-g:
##STR00599##
[0905] 18-g was prepared analogously to 1-d from 18-f and 1-e.
[0906] ES-MS (M+H).sup.+=693
[0907] RT(HPLC 4)=19.6 min
Example 18.1
##STR00600##
[0909] Example 18.1 was prepared analogously to Example 18 from
18-f and
(R)--N-[1-(4-fluorophenyl)-ethyl]-5-(methanesulphonylmethylamino)-isophth-
alic acid, which was obtained analogously to 1-e using
(R)-1-(4-fluorophenyl)-ethylamine.
[0910] ES-MS (M+H).sup.+=710
[0911] RT(HPLC 1)=4.48 min
[0912] RT(HPLC-MS)=2.79 min
Example 18.2
##STR00601##
[0914] Example 18.2 was prepared analogously to Example 18 from
18-f and
(R)--N-[1-(3-chlorophenyl)-ethyl]-5-(methanesulphonylmethylamino)-isophth-
alic acid, which was obtained analogously to 1-e using
(R)-1-(3-chlorophenyl)-ethylamine.
[0915] ES-MS (M+H).sup.+=727
[0916] RT(HPLC-MS)=2.86 min
Example 18.3
##STR00602##
[0918] Example 18.3 was prepared analogously to Example 18 from the
amine component, which was obtained using 18-d as well as
tert-butyl (S)-(2-oxo-1-thiophen-3-ylmethyl-ethyl)-carbamate, and
(R)--N-[1-(3-chlorophenyl)-ethyl]-5-(methanesulphonylmethylamino)-isophth-
alic acid, which was obtained analogously to 1-e using
(R)-1-(3-chlorophenyl)-ethylamine.
[0919] ES-MS (M+H).sup.+=733/735 (Cl)
[0920] RT(HPLC-MS)=3.20 min
Example 18.4
##STR00603##
[0922] Example 18.4 was prepared analogously to Example 18.3 from
the amine component, which was obtained using 18-d and tert-butyl
(S)-(2-oxo-1-thiophen-3-ylmethyl-ethyl)-carbamate, as well as
1-e.
[0923] ES-MS (M+H).sup.+=699
[0924] RT(HPLC 1)=4.44 min
[0925] RT(HPLC-MS)=2.90 min
Example 18.5
##STR00604##
[0927] Example 18.5 was prepared analogously to Example 18 using
18-d, by using (S)-Boc-2-aminohexanal in step 18-e) instead of
tert-butyl ((S)-1-benzyl-2-oxo-ethyl)-carbamate.
[0928] ES-MS (M+H).sup.+=659
[0929] RT(HPLC 1)=4.27 min
[0930] RT(HPLC-MS)=2.65 min
Example 18.6
##STR00605##
[0931] a) Preparation of 18.6-a:
##STR00606##
[0933] 10 g (44.0 mmol) monomethyl 5-nitro-isophthalate were
suspended in 100 ml dichloromethane, combined with 14.1 g (44.0
mmol) TBTU and 15 ml (88.0 mmol) DIPEA while cooling with ice and
stirred for 30 min at ambient temperature. Then 5.6 ml (44.0 mmol)
R-(+)-1-phenylethylamine were added and the mixture was stirred for
14 h. It was washed with water, potassium hydrogen carbonate
solution, the organic phase was dried and evaporated down. 14.1 g
of 18.6-a was obtained which was used in the next step without any
purification.
[0934] ES(-)-MS (M-H).sup.-=327
b) Preparation of 18.6-b:
##STR00607##
[0936] 14.1 g (43.0 mmol) 18.6-a were hydrogenated at 50 psi and
ambient temperature on palladium charcoal (5%) for 5 h. The
catalyst was separated off and the crude product was purified by
flash chromatography (dichloromethane/methanol 100:1). 6.86 g of
18.6-b was obtained by trituration with diethyl ether and
tert-butylmethylether.
[0937] ES-MS (M+H).sup.+=299
c) Preparation of 18.6-c:
##STR00608##
[0939] 500 mg (1.68 mmol) 18.6-b were dissolved in 14 ml
acetonitrile, combined with 2.36 g potassium carbonate and 2 mg
dimethylaminopyridine and stirred for 3 min at ambient temperature.
Then 0.25 ml (1.84 mmol) 5-bromovaleryl chloride dissolved in 3 ml
acetonitrile was added dropwise while being cooled and the mixture
was stirred for 4 h at ambient temperature. The solids were
separated off, the solution was evaporated down, and the residue
was taken up in ethyl acetate. The mixture was washed with water,
dried and evaporated down. 496 mg of colourless 18.6-c was obtained
which was used in the next step without any further
purification.
[0940] ES-MS (M+H).sup.+=381
d) Preparation of 18.6-d:
##STR00609##
[0942] 496 mg (1.30 mmol) of 18.6-c dissolved in 10 ml of methanol
were combined with 5 ml of 4 N sodium hydroxide solution and
stirred for 14 h at ambient temperature. The mixture was combined
with 5 ml hydrochloric acid. It was stirred out with
dichloromethane and ethyl acetate, dried and after evaporation 150
mg of 18.6-d was obtained as a solid, which was used in the next
step without any further purification.
[0943] ES-MS (M+H).sup.+=367
[0944] RT(HPLC-MS)=2.70 min
e) Preparation of 18.6:
##STR00610##
[0946] 54.2 mg (0.148 mmol) 18.6-d were dissolved in 5 ml THF and
combined with 52 mg TBTU (0.163 mmol) and 77.3 .mu.l (0.444 mmol)
DIPEA. After 10 min, 61.4 mg (0.148 mmol)
(S)-2-((S)-2-((S)-2-aminohexylamino)-propanamido)-N-ethylbutanamide
was added, which was prepared as described in Example 18.5. The
mixture was stirred for 14 h, evaporated down, the residue was
purified by RP-HPLC and in this way 5 mg of 18.6 was obtained as a
TFA salt.
[0947] ES-MS (M+H).sup.+=649
[0948] RT(HPLC 1)=4.32 min
[0949] RT(HPLC-MS)=2.62 min
Example 18.7
##STR00611##
[0951] Example 18.7 was prepared analogously to Example 18 using
18-d, by using (S)-Boc-2-aminohexanal in step 18-e) instead of
tert-butyl ((S)-1-benzyl-2-oxo-ethyl)-carbamate.
[0952] ES-MS (M+H).sup.+=659
[0953] RT(HPLC 1)=4.27 min
[0954] RT(HPLC-MS)=2.65 min
Example 18.8
##STR00612##
[0956] Example 18.8 was prepared analogously to Example 18, by
using cyclopropylmethylamine in step 18-a) instead of ethylamine.
The product was purified by RP-HPLC.
[0957] ES-MS (M+H).sup.+=719
[0958] RT(HPLC-MS)=3.00 min
Example 18.9
##STR00613##
[0959] a) Preparation of 18.9-a:
##STR00614##
[0961] 18.9-a was obtained analogously to 18.6-d as a white solid,
by using 4-bromobutyric acid chloride instead of 5-bromovaleryl
chloride analogously to step 18.6-c. The crude product was purified
by flash chromatography (dichloromethane/methanol/acetic acid
95:5:0.1).
[0962] ES-MS (M+NH.sub.4).sup.+=370
[0963] RT(HPLC-1)=4.19 min
b) Preparation of 18.9
##STR00615##
[0965] 18.9 was prepared analogously to Example 18.6, by using
18.9-a in step 18.6-e) instead of 18.d. The product was purified by
RP-HPLC. 17 mg (16%) were obtained as a white solid.
[0966] ES-MS (M+H).sup.+=297
[0967] RT(HPLC-1)=4.58 min
Example 19.4
##STR00616##
[0969] Example 19.4 was synthesised by standard solid phase peptide
synthesis on a 3-(formylindolyl)acetamidomethylpolystyrene resin
(100 mg, 0.1 mmol; load 1 mmol/g) (Novabiochem).
[0970] For the first reductive alkylation the resin was suspended
in DMF/TMOF (2:1, 2 ml) and reacted with a solution of
4-chlorobenzylamine (10 equiv.) in DMF/TMOF (2:1, 2 ml) and
Na(OAc).sub.3BH (10 Equiv.) in DMF (1M solution, 1 ml) overnight at
ambient temperature. Then the resin was carefully washed with DMF
and MeOH.
[0971] Fmoc cleavings were carried out by reacting the resin twice
(2 minutes and 20 minutes) with 30% piperidine/DMF solution. Then
the resin was carefully washed with DMF. The coupling of the first
amino acid was carried out overnight with HATU (5 equiv.), HOBt (5
equiv.), Dipea (15 equiv.) and Fmoc-valine (5 equiv.) in DMF as
solvent. The coupling of the second Fmoc-amino acid was carried out
with TBTU (5 equiv.), HOBt (5 equiv.), Dipea (15 equiv.) and
Fmoc-alanine (5 equiv.) in DMF.
[0972] After the coupling of the first two amino acids and the
cleaving of the Fmoc group reductive alkylation of the amino group
was carried out with a solution of freshly prepared
Fmoc-phenylalaninal (3.5 equiv.) and NaCNBH.sub.3 (10.5 equiv.) in
DMF/HOAc (99:1 ml) for 2.25 hours. The resin was then carefully
washed with DMF/HOAc (99:1), DMF, 5% Dipea in DMF and DMF. It was
then reacted for 16 hours with Boc.sub.2O (10 equiv.) and Dipea (10
equiv.) in DMF.
[0973] After a repeat cleaving of the Fmoc group and thorough
washing with DMF the resin was reacted with a solution of the
corresponding acid (prepared analogously to 1-e from 1-c and
(R)-1-(3-chlorophenyl)-ethylamine) (3 equiv.), TBTU (3 equiv.) and
Dipea (9 equiv.) in DMF.
[0974] In order to cleave the product from the resin and also
cleave any protective groups the resin was washed with DMF and
dichloromethane and dried and then mixed with TFA/water (95:5, 2
ml) for 1 hour at ambient temperature. The solution was filtered
off and the resin was washed twice more with dichloromethane (1
ml). The combined filtrates were evaporated down in vacuo and the
product was purified by preparative reversed phase HPLC.
[0975] The following Examples were obtained analogously to Example
19.4:
TABLE-US-00030 Mass Retention Ex- spectrum time am- [M + method ple
structure H].sup.+ HPLC 5 19 ##STR00617## 860.4 RT = 3.67 min 19.1
##STR00618## 811.4 RT = 3.63 min 19.2 ##STR00619## 817.4 RT = 3.97
min 19.3 ##STR00620## 713.3 RT = 3.62 min 19.4 ##STR00621## 837.4
RT = 3.99 min 19.5 ##STR00622## 833.4 RT = 4.33 min 19.6
##STR00623## 811.4 RT = 3.70 min 19.7 ##STR00624## 828.4 RT = 3.86
min 19.8 ##STR00625## 833.0 RT = 3.90 min 19.9 ##STR00626## 882.4
RT = 3.70 min 19.10 ##STR00627## 767.4 RT = 3.81 min 19.11
##STR00628## 753.4 RT = 3.73 min 19.12 ##STR00629## 818.4 RT = 3.44
min 19.13 ##STR00630## 444.0 [1/2 M + 1] RT = 3.49 min 19.14
##STR00631## 889.5 RT = 3.73 min
Example 20
##STR00632##
[0976] a) Preparation of 20-a:
##STR00633##
[0978] Compound 4-b (6.0 g; 14.6 mmol) was dissolved in DMF (60 ml)
and combined with TBTU (4.67 g; 14.6 mmol), HOBt (2.23 g; 14.6
mmol) and Dipea (7.5 ml; 43.6 mmol). After 5 minutes stirring
S-phenylalaminol (2.0 g; 13.2 mmol) was added and the mixture was
stirred overnight at RT. Then the solvent was eliminated i. vac.
and the remainder was taken up in ethyl acetate (200 ml). The org.
phase was extracted twice each with water, 0.5 M HCl, water, sat.
sodium carbonate solution, water and sat. NaCl solution and dried
over sodium sulphate. The org. phase was filtered through silica
gel and distilled off i. vac. The residue was triturated with
diethyl ether.
[0979] Yield 6.2 g (86% white crystals)
[0980] ES-MS (M+H).sup.+=544.6
b) Preparation of 20-b:
##STR00634##
[0982] The alcohol 20-a (6.2 g; 11.3 mmol) was dissolved in
dichloromethane and combined with Dess-Martin periodinane (10.1 g;
23.8 mmol) in two batches, with stirring. Then water (0.43 ml; 23.8
mmol) was added and the mixture was stirred for a further two
hours. It was combined with a solution of sodium hydrogen carbonate
(11.6 g; 138 mmol) and sodium thiosulphate-5-hydrate (14.1 g; 56.7
mmol) dissolved in water (200 ml) and stirred overnight. Then the
insoluble residue was filtered off and extracted with
dichloromethane. The organic phase was washed with sat. sodium
hydrogen carbonate solution and water, dried over sodium sulphate
and evaporated down i. vac. The residue was taken up in
acetonitrile and freeze-dried.
[0983] Yield 5.4 g
[0984] ES-MS (M+H).sup.+=542.5
c) Preparation of 20-c:
##STR00635##
[0986] (S)-alanine-tert.-butylester hydrochloride (1.44 g; 8 mmol)
was dissolved in dimethylacetamide (20 ml) and combined with
glacial acetic acid (0.62 ml; 10.3 mmol) and aldehyde 20-b (5.6 g;
10.3 mmol), dissolved in dimethylacetamide (10 ml). Then sodium
triacetoxyborohydride (10.1 g; 47.7 mmol) was added and the mixture
was stirred overnight at ambient temperature. The mixture was
evaporated down i. vac., taken up in dichloromethane (200 ml), the
organic phase was washed with sodium hydrogen carbonate solution
and water, dried with sodium sulphate and evaporated down i. vac.
The purification was carried out by chromatography on basic Alox
(eluant ethyl acetate/petroleum ether 1:1). The combined product
fractions were evaporated down i. vac. and combined with ethereal
hydrochloric acid. After 2 hours' stirring the crystals were
filtered off and washed with diethyl ether.
[0987] Yield 4.2 g (72%)
[0988] ES-MS (M+H).sup.+=615.6
d) Preparation of Compound 20-d:
##STR00636##
[0990] Aminopyrazine (190 mg; 2.0 mmol) was combined with a
solution of Boc-L-valine (434.5 mg; 2.0 mmol), HATU (380.2 mg; 2.0
mmol) and Dipea (685 .mu.l; 4.0 mmol) in DMF (4 ml) and shaken
overnight at ambient temperature. The mixture was evaporated down
i. vac. and purified by reversed phase HPLC.
[0991] Yield 87 mg (15%)
[0992] ES-MS (M+H).sup.+=294.4
e) Preparation of Compound 20-e:
##STR00637##
[0994] The Boc compound 20-d (37.8 mg; 0.1 mmol) was dissolved in
trifluoroacetic acid/water 95:5 (3 ml) and shaken for 2 hours at
ambient temperature. Then the solvent was eliminated i. vac. and
co-distilled with toluene. The crude product was further reacted
directly without purification.
f) Preparation of Compound 20
##STR00638##
[0996] The amine compound 20-e (0.1 mmol) was dissolved in DMF (1
ml) and combined with a solution of compound 20-c (61.5 mg; 0.1
mmol), TBTU (32.1 mg; 0.1 mmol), HOBt.times.H.sub.2O (15.3 mg; 0.1
mmol) and Dipea (85.6 .mu.l; 0.5 mmol) in DMF (1.0 ml). After the
addition of Dipea (200 .mu.l) the mixture was shaken for 72 hours
at ambient temperature. It was evaporated down i. vac. and purified
by preparative reversed phase HPLC.
[0997] Yield 13.5 mg (13.6%)
[0998] ES-MS (M+H).sup.+=791.4
[0999] RT=3.76 min (HPLC 6)
[1000] Analogously to Example 20 the following compounds were
prepared from 20-c and different amines 20-e, using different amine
components in step 20-d:
TABLE-US-00031 Mass spec- Retention Ex- trum time am- [M + method
ple structure H].sup.+ HPLC 6 20.2 ##STR00639## 875.7 3.65 min 20.3
##STR00640## 755.7 3.82 min 20.4 ##STR00641## 767.7 3.88 min 20.5
##STR00642## 769.7 3.95 min 20.6 ##STR00643## 871.7 4.10 min 20.7
##STR00644## 869.8 3.53 min 20.8 ##STR00645## 879.8 4.17 min 20.9
##STR00646## 846.8 3.67 min 20.10 ##STR00647## 860.7 3.76 min 20.11
##STR00648## 875.8 3.75 min 20.12 ##STR00649## 781.7 3.93 min 20.13
##STR00650## 831.7 4.06 min 20.14 ##STR00651## 803.7 3.96 min 20.15
##STR00652## 795.8 4.00 min 20.16 ##STR00653## 804.7 3.49 min 20.17
##STR00654## 789.7 3.98 min 20.18 ##STR00655## 837.7 4.04 min 20.19
##STR00656## 809.8 4.08 min 20.20 ##STR00657## 767.7 3.84 min 20.21
##STR00658## 769.8 3.93 min 20.22 ##STR00659## 771.4 3.75 min 20.23
##STR00660## 817.7 4.03 min 20.24 ##STR00661## 809.7 3.93 min 20.25
##STR00662## 797.7 3.79 min 20.26 ##STR00663## 783.8 3.98 min 20.27
##STR00664## 769.7 3.92 min 20.28 ##STR00665## 796.7 3.84 min 20.29
##STR00666## 804.7 3.51 min 20.30 ##STR00667## 817.7 4.00 min 20.31
##STR00668## 783.8 3.97 min 20.32 ##STR00669## 804.7 3.48 min 20.33
##STR00670## 741.7 3.78 min 20.34 ##STR00671## 804.7 3.90 min 20.35
##STR00672## 751.7 3.80 min 20.36 ##STR00673## 780.7 3.82 min 20.37
##STR00674## 817.7 4.00 min
Example 21
##STR00675##
[1001] a) Preparation of 21-a:
##STR00676##
[1003] 50 g (153 mmol) dimethyl 5-iodo-isophthalate were dissolved
in 300 ml THF under a nitrogen atmosphere. At -10.degree. C., 7.14
g (168 mmol) lithium chloride and 168 ml isopropylmagnesium
chloride (2.0 M in THF) were added. After 15 min. the mixture was
cooled to -60.degree. C., 79.5 ml (765 mmol) trimethylborate was
added and the mixture was slowly heated to 25.degree. C. After 12
h, 70 ml aqueous HCl (2.0 M) were added. The suspension is
evaporated down to 1/4 of the volume. The precipitate was suction
filtered and washed with water and cold dichloromethane. 34.0 g
(93%) of 21-a were obtained as a colourless solid.
[1004] RT (HPLC-MS)=2.39 min.
[1005] ES-MS (M+H).sup.+=239.1
b) Preparation of 21-b:
##STR00677##
[1007] 3.00 g (15.5 mmol) 3-bromothiophene-2-carbonitrile were
dissolved in 50 ml of toluene under a nitrogen atmosphere. 0.54 g
(0.46 mmol) tetrakistriphenylphosphine palladium(0), a solution of
5.53 g (23.2 mmol) 21-a in 25 ml of methanol and a solution of 1.80
g (17.0 mmol) sodium carbonate in 25 ml of water were added
successively. After 8 h at 100.degree. C. the mixture was cooled to
25.degree. C., the precipitate formed was filtered off and washed
with toluene, water and cold methanol. 4.00 g (86%) of 21-b were
obtained as a colourless solid.
[1008] RT (HPLC-MS)=3.26 min.
[1009] ES-MS (M+H).sup.+=302.1
c) Preparation of 21-c:
##STR00678##
[1011] 21-c was prepared analogously to 1-c from 21-b.
[1012] RT (HPLC-MS)=2.82 min.
d) Preparation of 21-d:
##STR00679##
[1014] 21-d was prepared analogously to 1-d from 21-c and
(R)-1-phenyl-ethylamine.
[1015] RT (HPLC-MS)=3.35 min.
[1016] ES-MS (M+H).sup.+=391.1
e) Preparation of 21-e:
##STR00680##
[1018] 21-e was prepared analogously to 1-e from 21-d.
f) Preparation of 21-f:
##STR00681##
[1020] 21-f was prepared analogously to 1-d from 21-e and 1-l.
[1021] RT (HPLC-MS)=2.90 min.
[1022] ES-MS (M+H).sup.+=707.1
g) Preparation of 21-g:
##STR00682##
[1024] 5.29 g (16.5 mmol) dimethyl 5-iodo-isophthalate was
dissolved in 80 ml DMF under a nitrogen atmosphere. 4.50 g (23.3
mmol) 2-[1,3,2]-dioxaborinan-2-yl-benzonitrile, 3.90 ml (28.0 mmol)
triethylamine, 3.0 ml of water, 0.10 mg (0.45 mmol) palladium
acetate as well as 0.13 g (0.43 mmol) tri-o-tolylphosphine were
added successively. After 2.5 h at 100.degree. C. the mixture was
cooled to 25.degree. C. The solvent was distilled off and the
residue was purified by preparative MPLC (SiO.sub.2, gradient:
cyclohexane to cyclohexane/ethyl acetate 5:95). 2.60 g (45%) 21-g
was obtained as a colourless solid.
[1025] RT (HPLC-MS)=3.19 min.
[1026] ES-MS (M-MeOH+H).sup.+=264.1
h) Preparation of 21-h:
##STR00683##
[1028] 21-h was prepared analogously to 1-c from 21-g.
[1029] RT (HPLC-MS)=2.81 min.
[1030] ES-MS (M-H.sub.2O+H).sup.+=264.1
i) Preparation of 21-i:
##STR00684##
[1032] 21-i was prepared analogously to 1-d from 21-h and
(R)-1-phenyl-ethylamine.
j) Preparation of 21-j:
##STR00685##
[1034] 21-j was prepared analogously to 1-e from 21-i.
[1035] Analogously to Example 21 the following compounds were
prepared from 1-l and 21-j or from acids which had been obtained
analogously to 21-e starting from corresponding arylhalides (step
21-b) and suitable amines (step 21-d):
TABLE-US-00032 Mass Retention time spectrum method Example
structure [M + H].sup.+ HPLC-MS 21.2 ##STR00686## 719 2.70 min 21.3
##STR00687## 701.1 2.96 min 21.4 ##STR00688## 701.2 2.94 min 21.5
##STR00689## 715.1 2.84 min 21.6 ##STR00690## 779/781 (Br) 3.12 min
21.7 ##STR00691## 715.1 3.01 min 21.8 ##STR00692## 729.1 2.98 min
21.9 ##STR00693## 694.1 2.65 min 21.10 ##STR00694## 735/737 (Cl)
3.08 min 21.11 ##STR00695## 715.2 2.93 min 21.12 ##STR00696## 755.1
2.99 min 21.13 ##STR00697## 702.1 2.39 min 21.14 ##STR00698## 715.1
2.94 min 21.15 ##STR00699## 731.1 2.88 min 21.16 ##STR00700## 731.1
2.90 min 21.17 ##STR00701## 715.1 3.00 min 21.18 ##STR00702## 677.1
2.95 min
[1036] Analogously to Example 21, the following compounds were
prepared from acids obtained analogously to 21-e starting from
corresponding aryl halides (step 21-b) and amines obtained
analogously to 1-l from suitable educts:
TABLE-US-00033 Mass Retention time spectrum method Example
structure [M + H].sup.+ HPLC-MS 21.19 ##STR00703## 687.1 1.99 min
21.20 ##STR00704## 667.1 3.01 min 21.21 ##STR00705## 755 2.14
min
Example 22
##STR00706##
[1038] Example 22 was synthesised by standard solid phase peptide
synthesis on a [3-((methyl-fmoc-amino)-methyl)-1-indol-1-yl]-acetyl
AM resin (367 mg, 0.25 mmol) (Novabiochem).
[1039] Fmoc cleavings were carried out by reacting the resin twice
(2 minutes and 20 minutes) with 30% piperidine/DMF solution. Then
the resin was washed ten times with DMF. The coupling of the first
amino acid was carried out with HATU (380 mg, 1.0 mmol), HOAt (0.5
molar solution, 2 ml, 1.0 mmol), Dipea (513 .mu.l, 3 mmol) and
Fmoc-valine (339 mg, 1 mmol) in DMF as solvent over 5 hours. The
coupling of the second Fmoc-amino acid was carried out analogously
with Fmoc-serine-tert.butyl ester (383 mg, 1 mmol).
[1040] After the coupling of the first two amino acids and the
cleaving of the Fmoc group reductive alkylation of the amino group
was carried out with a solution of freshly prepared
Fmoc-phenylalaninal (310 mg, 0.75 mmol) and NaBH(OAc).sub.3 (530
mg, 2.5 mmol) in DMF/HOAc (99:1, 2 ml) for 2.5 hours. Then the
resin was carefully washed with DMF/HOAc (99:1), DMF, 5% Dipea in
DMF and DMF. The resin was then reacted for 16 hours with
Boc.sub.2O (10 equiv.) and Dipea (10 equiv.) in DMF.
[1041] After a repeat cleaving of the Fmoc group and thorough
washing with DMF the resin was reacted with a solution of the
corresponding acid 4-b (376 mg, 1 mmol), HATU (380 mg, 1.0 mmol),
HOAt (0.5 molar solution, 2 ml, 1.0 mmol), Dipea (513 .mu.l, 3
mmol) in DMF.
[1042] In order to cleave the product from the resin and also
cleave any protective groups the resin was washed with DMF and
dichloromethane and dried and then mixed with TFA/water (95:5, 2
ml) for 1 hour at ambient temperature. The solution was filtered
off and the resin was washed twice more with dichloromethane (1
ml). The combined filtrates were evaporated down in vacuo and the
product was purified by preparative reversed phase HPLC.
[1043] Yield 35.1 mg
[1044] ES-MS (M+H).sup.+=709.5
[1045] RT=3.71 min (HPLC 6)
Example 23
##STR00707##
[1047] Example 23 was prepared analogously to Example 1 from 23-c
and the corresponding precursors.
[1048] ES-MS (M+H).sup.+=700
[1049] RT (HPLC-MS): 2.70 min
a) Preparation of 23-a:
##STR00708##
[1051] 10.46 g (50 mmol) dimethyl 5-amino-isophthalate were
dissolved in 200 ml of toluene and combined with 7.3 ml (60 mmol)
diphosgene. The reaction solution was refluxed for 1 h. Then the
reaction solution was evaporated down i. vac., twice combined with
toluene and distilled off again. The residue (10.6 g) was used in
23-b without being purified.
b) Preparation of 23-b:
##STR00709##
[1053] 10.6 g (45 mmol) 23-a were dissolved in 450 ml of toluene
and combined with 3.88 ml (45 mmol) 3-chloro-1-propanol. The
reaction solution was heated to 75.degree. C. for 1 h. Then the
reaction solution was evaporated down i. vac. The residue was
purified by chromatography on silica gel with the eluant (ethyl
acetate/heptane 7:3).
[1054] Yield 8.5 g of 23-a (57%)
[1055] ES-MS (M+H).sup.+=330
c) Preparation of 23-c:
##STR00710##
[1057] 8.49 g (25.8 mmol) 23-b were dissolved in 140 ml
acetonitrile, combined with 4.27 g (30.9 mmol) potassium carbonate
and refluxed for 2 h. Then the insoluble constituents were filtered
off, the reaction solution was evaporated down i. vac. and stirred
with ether. The crystals formed were filtered off and washed with
ether.
[1058] Yield 6.5 g 23-c (77%)
[1059] ES-MS (M+H).sup.+=294
[1060] Analogously to 23 the following compounds were prepared from
corresponding educts:
TABLE-US-00034 Mass Retention time Example spectrum (method) 23.2
##STR00711## 821 [M + H].sup.+ 2.39 min (HPLC-MS) 23.3 ##STR00712##
701 [M + H].sup.+ 2.12 min (HPLC-MS) 23.4 ##STR00713## 779 [M +
H].sup.+ 2.70 min (HPLC-MS) 23.5 ##STR00714## 745 [M + H].sup.+
2.64 min (HPLC-MS) 23.6 ##STR00715## 686 [M + H].sup.+ 2.54 min
(HPLC-MS) 23.7 ##STR00716## 715 [M + H].sup.+ 2.24 min (HPLC-MS)
23.8 ##STR00717## 780 [M + H].sup.+ 2.36 min (HPLC-MS) 23.9
##STR00718## 735 [M + H].sup.+ 2.58 min (HPLC-MS) 23.10
##STR00719## 786 [M + H].sup.+ 2.62 min (HPLC-MS) 23.11
##STR00720## 729 [M + H].sup.+ 2.40 min (HPLC-MS) 23.12
##STR00721## 728 [M + H].sup.+ 2.75 min (HPLC-MS) 23.13
##STR00722## 687 [M + H].sup.+ 2.21 min (HPLC-MS) 23.14
##STR00723## 693 [M + H].sup.+ 2.42 min (HPLC-MS) 23.15
##STR00724## 765 [M + H].sup.+ 4.72 min (HPLC 1) 23.16 ##STR00725##
766 [M + H].sup.+ 23.17 ##STR00726## 772 [M + H].sup.+ 23.18
##STR00727## 687 [M + H].sup.+ 1.45 min (HPLC-MS) 23.19
##STR00728## 694 [M + H].sup.+ 2.03 min (HPLC-MS) 23.20
##STR00729## 700 [M + H].sup.+ 4.59 min (HPLC 1) 23.21 ##STR00730##
701 [M + H].sup.+ 4.10 min (HPLC 1) 23.22 ##STR00731## 707 [M +
H].sup.+ 2.58 min (HPLC-MS) 23.23 ##STR00732## 779 [M + H].sup.+
2.93 min (HPLC-MS) 23.24 ##STR00733## 780 [M + H].sup.+ 4.33 min
(HPLC 1) 23.25 ##STR00734## 786 [M + H].sup.+ 4.59 min (HPLC 1)
23.26 ##STR00735## 702 [M + H].sup.+ 2.27 min (HPLC-MS) 23.27
##STR00736## 708 [M + H].sup.+ 3.59 min (HPLC 1) 23.28 ##STR00737##
700 [M + H].sup.+ 4.62 min (HPLC 1) 23.29 ##STR00738## 707 [M +
H].sup.+ 4.29 min (HPLC 1) 23.30 ##STR00739## 779 [M + H].sup.+
4.80 min (HPLC 1) 23.31 ##STR00740## 780 [M + H].sup.+ 4.28 min
(HPLC 1) 23.32 ##STR00741## 786 [M + H].sup.+ 4.58 min (HPLC 1)
23.33 ##STR00742## 701 [M + H].sup.+ 3.87 min (HPLC 1) 23.34
##STR00743## 701 [M + H].sup.+ 4.05 min (HPLC 1) 23.35 ##STR00744##
701 [M + H].sup.+ 23.36 ##STR00745## 686 [M + H].sup.+ 4.53 min
(HPLC 1)
Example 24
##STR00746##
[1062] Example 24 was prepared analogously to Example 1 from 24-e
and the corresponding precursors.
[1063] ES-MS (M+H).sup.+=700
[1064] RT (HPLC-MS): 2.70 min
a) Preparation of 24-a:
##STR00747##
[1066] 10.22 g (100 mmol) 2-dioxane were dissolved in 50 ml of
ethanol and combined with 14.5 ml (41.4 mmol) thionyl chloride,
while the temperature was kept below 30.degree. C. The reaction
solution was refluxed for 4 h and then evaporated down i. vac.
[1067] Yield 9.2 g of colourless liquid which was used further in
its crude state.
b) Preparation of 24-b:
##STR00748##
[1069] 9.2 g (41.4 mmol) 24-a were dissolved in 50 ml THF and
combined with 30 ml of 2N NaOH solution. The reaction solution was
stirred for 4 h at ambient temperature. Standard working up yielded
6.7 g of colourless oil.
c) Preparation of 24-c:
##STR00749##
[1071] 6.7 g (48.4 mmol) 23-c were combined with 25 ml of thionyl
chloride and stirred for 2 h at 60.degree. C. The mixture was then
evaporated down in vacuo and further reacted immediately in
24-d.
d) Preparation of 24-d:
##STR00750##
[1073] 9.3 g (44.6 mmol) dimethyl 5-amino-isophthalate were
dissolved in 30 ml of ethanol and combined with 18.5 ml (133.4
mmol) triethylamine. Subsequently 7.7 g (448.9 mmol) of 24-c
dissolved in 30 ml THF were slowly added dropwise while cooling
with ice. The reaction solution was refluxed for 2 h. Standard
working up yielded 12.6 g of 24-d as a beige solid (86%).
e) Preparation of 24-e:
##STR00751##
[1075] 7 g (21.2 mmol) 24-d and 7.15 g potassium-tert-butoxide were
dissolved in 40 ml DMF and stirred for 2 h at 60.degree. C. The
reaction solution was evaporated down in vacuo, combined with water
and extracted three times with ethyl acetate. After acidification
of the aqueous phase with 4N HCL solution the mixture was again
extracted three times with ethyl acetate. The combined organic
phases were dried over magnesium sulphate and distilled off in
vacuo. The residue was purified by MPLC (silica gel, methylene
chloride:methanol=10:1). Yield 1.6 g of 24-d as an orange oil
(27%).
[1076] RT (HPLC-MS)=2.16 min
[1077] Some examples of formulations will now be described, wherein
the term "active substance" denotes one or more compounds according
to the invention including the salts thereof. In the case of one of
the aforementioned combinations with one or more other active
substances the term "active substance" also includes the additional
active substances.
Example A
TABLE-US-00035 [1078] Tablets containing 100 mg of active substance
Composition: 1 tablet contains: active substance 100.0 mg lactose
80.0 mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium
stearate 2.0 mg 220.0 mg
Method of Preparation:
[1079] The active substance, lactose and starch are mixed together
and uniformly moistened with an aqueous solution of the
polyvinylpyrrolidone. After the moist composition has been screened
(2.0 mm mesh size) and dried in a rack-type drier at 50.degree. C.
it is screened again (1.5 mm mesh size) and the lubricant is added.
The finished mixture is compressed to form tablets.
[1080] Weight of tablet: 220 mg
[1081] Diameter: 10 mm, biplanar, facetted on both sides and
notched on one side.
Example B
TABLE-US-00036 [1082] Tablets containing 150 mg of active substance
Composition: 1 tablet contains: active substance 50.0 mg powdered
lactose 89.0 mg corn starch 40.0 mg colloidal silica 10.0 mg
polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg 300.0 mg
Preparation:
[1083] The active substance mixed with lactose, corn starch and
silica is moistened with a 20% aqueous polyvinylpyrrolidone
solution and passed through a screen with a mesh size of 1.5 mm.
The granules, dried at 45.degree. C., are passed through the same
screen again and mixed with the specified amount of magnesium
stearate. Tablets are pressed from the mixture.
[1084] Weight of tablet: 300 mg
[1085] die: 10 mm, flat
Example C
TABLE-US-00037 [1086] Hard gelatine capsules containing 150 mg of
active substance 1 capsule contains: active substance 50.0 mg corn
starch (dried) approx. 80.0 mg lactose (powdered) approx. 87.0 mg
magnesium stearate 3.0 mg approx. 420.0 mg
Preparation:
[1087] The active substance is mixed with the excipients, passed
through a screen with a mesh size of 0.75 mm and homogeneously
mixed using a suitable apparatus. The finished mixture is packed
into size 1 hard gelatine capsules.
[1088] Capsule filling: approx. 320 mg
[1089] Capsule shell: size 1 hard gelatine capsule.
Example D
TABLE-US-00038 [1090] Suppositories containing 150 mg of active
substance 1 suppository contains: active substance 150.0 mg
polyethyleneglycol 1500 550.0 mg polyethyleneglycol 6000 460.0 mg
polyoxyethylene sorbitan monostearate 840.0 mg 2,000.0 mg
Preparation:
[1091] After the suppository mass has been melted the active
substance is homogeneously distributed therein and the melt is
poured into chilled moulds.
Example E
TABLE-US-00039 [1092] Ampoules containing 10 mg active substance
Composition: active substance 10.0 mg 0.01 N hydrochloric acid q.s.
double-distilled water ad 2.0 ml
Preparation:
[1093] The active substance is dissolved in the necessary amount of
0.01 N HCl, made isotonic with common salt, filtered sterile and
transferred into 2 ml ampoules.
Example F
TABLE-US-00040 [1094] Ampoules containing 50 mg of active substance
Composition: active substance 50.0 mg 0.01 N hydrochloric acid q.s.
double-distilled water ad 10.0 ml
Preparation:
[1095] The active substance is dissolved in the necessary amount of
0.01 N HCl, made isotonic with common salt, filtered sterile and
transferred into 10 ml ampoules.
* * * * *