U.S. patent application number 12/682760 was filed with the patent office on 2011-03-10 for cgrp antagonists.
This patent application is currently assigned to BOEHRINGER INGELHEIM INTERNATIONAL GMBH. Invention is credited to Georg Dahmann, Henri Doods, Dirk Gottschling, Annekatrin Heimann, Stephan Georg Mueller, Klaus Rudolf, Gerhard Schaenzle, Dirk Stenkamp.
Application Number | 20110059954 12/682760 |
Document ID | / |
Family ID | 39167163 |
Filed Date | 2011-03-10 |
United States Patent
Application |
20110059954 |
Kind Code |
A1 |
Gottschling; Dirk ; et
al. |
March 10, 2011 |
CGRP ANTAGONISTS
Abstract
The present invention relates to new CGRP-antagonists of general
formula I ##STR00001## wherein U, V, X, Y, R.sup.1, R.sup.2 and
R.sup.3 are defined as stated hereinafter, the tautomers, the
isomers, the diastereomers, the enantiomers, the hydrates, the
mixtures thereof and the salts thereof and the hydrates of the
salts, particularly the physiologically acceptable salts thereof
with inorganic or organic acids or bases, pharmaceutical
compositions containing these compounds, their use and processes
for preparing them.
Inventors: |
Gottschling; Dirk;
(Mittelbiberach, DE) ; Dahmann; Georg;
(Attenweiler, DE) ; Doods; Henri; (Warthausen,
DE) ; Heimann; Annekatrin; (Biberach, DE) ;
Mueller; Stephan Georg; (Warthausen, DE) ; Rudolf;
Klaus; (Warthausen, DE) ; Schaenzle; Gerhard;
(Biberach, DE) ; Stenkamp; Dirk; (Biberach,
DE) |
Assignee: |
BOEHRINGER INGELHEIM INTERNATIONAL
GMBH
Ingelheim am Rhein
DE
|
Family ID: |
39167163 |
Appl. No.: |
12/682760 |
Filed: |
October 16, 2008 |
PCT Filed: |
October 16, 2008 |
PCT NO: |
PCT/EP2008/063965 |
371 Date: |
July 23, 2010 |
Current U.S.
Class: |
514/221 ;
514/256; 514/303; 540/500; 544/328; 546/118 |
Current CPC
Class: |
A61P 3/10 20180101; A61P
29/00 20180101; C07D 405/14 20130101; A61P 43/00 20180101; A61P
11/00 20180101; C07D 471/04 20130101; A61P 25/04 20180101; C07D
401/14 20130101; A61P 15/12 20180101; A61P 1/12 20180101; A61P
11/02 20180101; A61P 19/02 20180101; C07D 417/14 20130101; C07D
413/14 20130101; A61P 17/00 20180101; A61P 9/00 20180101; A61P
25/06 20180101; A61P 31/04 20180101; A61P 25/36 20180101; A61P
37/08 20180101; A61P 1/02 20180101; A61P 11/06 20180101 |
Class at
Publication: |
514/221 ;
544/328; 514/256; 540/500; 546/118; 514/303 |
International
Class: |
A61K 31/5513 20060101
A61K031/5513; C07D 401/14 20060101 C07D401/14; A61K 31/506 20060101
A61K031/506; C07D 471/04 20060101 C07D471/04; A61K 31/437 20060101
A61K031/437; A61P 25/06 20060101 A61P025/06 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 18, 2007 |
EP |
07118809.8 |
Claims
1. A compound of the formula I ##STR00441## wherein R.sup.1 denotes
a group of the formula II ##STR00442## wherein G-L denotes N,
N--C(R.sup.4.1).sub.2, C.dbd.C(R.sup.4.1), C.dbd.N, C(R.sup.4.1),
C(R.sup.4.1)--C(R.sup.4.1).sub.2,
C(R.sup.4.1)--C(R.sup.4.1).sub.2--C(R.sup.4.1).sub.2,
C.dbd.C(R.sup.4.1)--C(R.sup.4.1).sub.2,
C(R.sup.4.1)--C(R.sup.4.1).dbd.C(R.sup.4.1),
C(R.sup.4.1)--C(R.sup.4.1).sub.2--N(R.sup.4.2),
C.dbd.C(R.sup.4.1)--N(R.sup.4.2), C(R.sup.4.1)--C(R.sup.4.1).dbd.N,
C(R.sup.4.1)--N(R.sup.4.2)--C(R.sup.4.1).sub.2,
C.dbd.N--C(R.sup.4.1).sub.2, C(R.sup.4.1)--N.dbd.C(R.sup.4.1),
C(R.sup.4.1)--N(R.sup.4.2)--N(R.sup.4.2), C.dbd.N--N(R.sup.4.2),
N--C(R.sup.4.1).sub.2--C(R.sup.4.1).sub.2,
N--C(R.sup.4.1).dbd.C(R.sup.4.1),
N--C(R.sup.4.1).sub.2--N(R.sup.4.2), N--C(R.sup.4.1).dbd.N,
N--N(R.sup.4.2)--C(R.sup.4.1).sub.2 or N--N.dbd.C(R.sup.4.1), Q-T
denotes C(R.sup.5).sub.2--C(R.sup.5).sub.2,
C(R.sup.5).dbd.C(R.sup.5), N.dbd.C(R.sup.5),
C(R.sup.5).sub.2--C(.dbd.O), C(.dbd.O)--C(R.sup.5).sub.2,
C(R.sup.5).sub.2--S(O).sub.m or C(R.sup.s).sub.2--N(R.sup.5),
wherein a group C(R.sup.5).sub.2 contained in Q-T may also denote a
cyclic group which is selected from among C.sub.3-6-cycloalkyl,
C.sub.5-6-cycloalkenyl or heterocyclyl, or wherein in a group
C(R.sup.5).sub.2--C(R.sup.5).sub.2, C(R.sup.5).dbd.C(R.sup.5) or
C(R.sup.5).sub.2--N(R.sup.5) contained in Q-T in each case a group
R.sup.5 together with an adjacent group R.sup.5 and the atoms to
which these groups are bound may also denote a
C.sub.3-6-cycloalkyl, C.sub.5-6-cycloalkenyl, heterocyclyl, aryl or
heteroaryl group, which may be substituted independently of one
another by 1, 2 or 3 substituents R.sup.5.1, R.sup.2 denotes (a) H,
(b) F, --CN, C.sub.1-3-alkyl, --CO.sub.2--R.sup.2.1 or (c) a
C.sub.1-3-alkyl group wherein each methylene group is substituted
by up to two fluorine atoms and each methyl group is substituted by
up to three fluorine atoms, R.sup.2.1 denotes H or C.sub.1-6-alkyl,
R.sup.3 denotes a 6 or 10-membered aryl group substituted by the
groups R.sup.3.1, R.sup.3.2 and R.sup.3.3 or a 6-membered
heteroaryl group substituted by the groups R.sup.3.1, R.sup.3.2 and
R.sup.3.3 which is attached via a carbon atom, R.sup.3.1 denotes
(a) H, (b) halogen, --NH.sub.2, C.sub.1-4-alkyl-NH--,
(C.sub.1-4-alkyl).sub.2N--, C.sub.1-3-alkyl-C(O)--NH--,
C.sub.1-3-alkyl-S(O.sub.2)--NH--, --CN, --OH,
--O--C(O)--NH--C.sub.1-3-alkyl, (c) C.sub.1-4-alkyl,
R.sup.3.1,1--C.sub.1-3-alkylene, C.sub.2-4-alkenyl,
C.sub.2-4-alkynyl, C.sub.1-3-alkyl-O--,
C.sub.1-3-alkyl-S(O).sub.m--, cyclopropyl, (d) a C.sub.1-3-alkyl or
C.sub.1-3-alkyl-O-- group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, (e) --C(O)--R.sup.3.1.2,
(f) --S(O).sub.2--R.sup.3.1.3, R.sup.3.1.1 denotes (a) H, (b)
C.sub.3-6-cycloalkyl, C.sub.5-6-cycloalkenyl, (c)
(R.sup.3.1.1.1).sub.2N, (d) a saturated, mono- or diunsaturated 5-
or 6-membered heterocyclic group which is substituted at a nitrogen
atom by a group R.sup.3.1.1.1 and is substituted at a carbon atom
by one or two groups R.sup.3.1.1.2, or (e) a heteroaryl group which
is substituted at a carbon atom by a group R.sup.3.1.1.2,
R.sup.3.1.1.1 independently of one another denotes (a) H,
C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl, (b) heterocyclyl, (c)
aryl-C.sub.0-3-alkylene or heteroaryl-C.sub.0-3-alkylene,
R.sup.3.1.1.2 independently of one another denotes (a) H, F,
C.sub.1-3-alkyl, --CN, --OH, --O--C.sub.1-3-alkyl,
--CO(O)R.sup.3.1.1.2.1, H.sub.2N--, (C.sub.1-4-alkyl)-NH--,
(C.sub.1-4-alkyl).sub.2N--, (b) phenyl or phenyl-CH.sub.2--, (c) a
C.sub.1-3-alkyl or --O--C.sub.1-3-alkyl group wherein each
methylene group is substituted by up to two fluorine atoms and each
methyl group is substituted by up to three fluorine atoms, or
R.sup.3.1.1.2.1 denotes H, C.sub.1-6-alkyl, benzyl, R.sup.3.1.2
denotes --O--C.sub.1-3-alkyl, --OH, --NR.sup.3.1.2.1R.sup.3.1.2.2,
R.sup.3.1.2.1 denotes H, C.sub.1-3-alkyl, R.sup.3.1.2.2 denotes H,
C.sub.1-3-alkyl, R.sup.3.1.2.1 and R.sup.3.1.2.1 together may also
form a ring which is selected from among azetidinyl, pyrrolidinyl,
piperidinyl, piperazinyl and morpholinyl, R.sup.3.1.3 denotes
--O--C.sub.1-3-alkyl, --NR.sup.3.1.3.1R.sup.3.1.3.2, R.sup.3.1.3.1
denotes H, C.sub.1-3-alkyl, R.sup.3.1.3.2 denotes H,
C.sub.1-3-alkyl, R.sup.3.1.3.1 and R.sup.3.1.3.1 together may also
form a ring which is selected from among azetidinyl, pyrrolidinyl,
piperidinyl, piperazinyl and morpholinyl, R.sup.3.2 denotes (a) H,
(b) halogen, --NH.sub.2, C.sub.1-4-alkyl-NH--,
(C.sub.1-4-alkyl).sub.2N--, C.sub.1-3-alkyl-C(O)--NH--,
C.sub.1-3-alkyl-S(O.sub.2)--NH--, --CN, --OH,
--O--C(O)--NH--C.sub.1-3-alkyl, (c) C.sub.1-4-alkyl,
C.sub.2-4-alkenyl, C.sub.2-4-alkynyl, C.sub.1-3-alkyl-O,
C.sub.1-3-alkyl-S(O).sub.m--, cyclopropyl, (d) a C.sub.1-3-alkyl or
C.sub.1-3-alkyl-O-- group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, (e) --C(O)--R.sup.3.2.1,
(f) --S(O).sub.2--R.sup.3.2.2, R.sup.3.2.1 denotes
--O--C.sub.1-3-alkyl, --OH, --NR.sup.3.2.1.1R.sup.3.2.1.2,
R.sup.3.2.1.1 denotes H, C.sub.1-3-alkyl, R.sup.3.2.1.2 denotes H,
C.sub.1-3-alkyl, R.sup.3.2.1.1 and R.sup.3.2.1.2 together may also
form a ring which is selected from among azetidinyl, pyrrolidinyl,
piperidinyl, piperazinyl and morpholinyl, R.sup.3.2.2 denotes
--NR.sup.3.2,2,1R.sup.3.2,2,2, R.sup.3.2,2,1 denotes H,
C.sub.1-3-alkyl, R.sup.3.2,2,2 denotes H, C.sub.1-3-alkyl,
R.sup.3.2,2,1 and R.sup.3.2,2,2 together may also form a ring which
is selected from among azetidinyl, pyrrolidinyl, piperidinyl,
piperazinyl and morpholinyl, R.sup.3.3 denotes (a) H, (b) halogen,
--NH.sub.2, C.sub.1-4-alkyl-NH--, (C.sub.1-4-alkyl).sub.2N--,
C.sub.1-3-alkyl-C(O)--NH--, C.sub.1-3-alkyl-S(O.sub.2)--NH--, --CN,
--OH, --O--C(O)--NH--C.sub.1-3-alkyl, (c) C.sub.1-4-alkyl,
C.sub.2-4-alkenyl, C.sub.2-4-alkynyl, C.sub.1-3-alkyl-O,
C.sub.1-3-alkyl-S(O).sub.m--, cyclopropyl, (d) a C.sub.1-3-alkyl-
or C.sub.1-3-alkyl-O-- group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, (e) --C(O)--R.sup.3.3.1,
(f) --S(O).sub.2--R.sup.3.3.2, R.sup.3.3.1 denotes
--O--C.sub.1-3-alkyl, --OH, --NR.sup.3.3.1.1R.sup.3.3.1.2,
R.sup.3.3.1.1 denotes H, C.sub.1-3-alkyl, R.sup.3.3.1.2 denotes H,
C.sub.1-3-alkyl, R.sup.3.3.1.1 and R.sup.3.3.1.2 together may also
form a ring which is selected from among azetidinyl, pyrrolidinyl,
piperidinyl, piperazinyl and morpholinyl, R.sup.3.3.2 denotes
--O--C.sub.1-3-alkyl, --NR.sup.3.3.2.1R.sup.3.3.2.2, R.sup.3.3.2.1
denotes H, C.sub.1-3-alkyl, R.sup.3.3.2.2 denotes H,
C.sub.1-3-alkyl, R.sup.3.3.2.1 and R.sup.3.3.2.2 together may also
form a ring which is selected from among azetidinyl, pyrrolidinyl,
piperidinyl, piperazinyl and morpholinyl, or R.sup.3.2 and
R.sup.3.3 together with the carbon atoms to which they are attached
form a monounsaturated 5-membered or a mono- or diunsaturated
6-membered heterocyclic group or a 5- to 6-membered heteroaryl
group, while the heterocycles mentioned previously may contain a
carbonyl, thiocarbonyl or cyanimino group adjacent to a nitrogen
atom, and may optionally each additionally be substituted at one or
two nitrogen atoms by a group R.sup.3.3.3 and may optionally each
additionally be substituted at one or two carbon atoms by one or
two groups R.sup.3.3.4, R.sup.3.3.3 independently of one another
denote (a) C.sub.1-4-alkyl or (b) C.sub.3-6-cycloalkyl, R.sup.3.3.4
independently of one another denote (a) C.sub.1-4-alkyl or (b)
C.sub.3-6-cycloalkyl, (c) halogen, CN, --O--C.sub.1-3-alkyl,
--NH.sub.2, (d) a C.sub.1-3-alkyl- or C.sub.1-3-alkyl-O-- group
wherein each methylene group is substituted by up to two and each
methyl group is substituted by up to three fluorine atoms,
R.sup.4.1 independently of one another denote (a) H, (b)
C.sub.1-6-alkyl, --CN, --OH, --O--C.sub.1-3-alkyl, (c) a
C.sub.1-3-alkyl- or C.sub.1-3-alkyl-O-- group wherein each
methylene group is substituted by up to two fluorine atoms and each
methyl group is substituted by up to three fluorine atoms,
R.sup.4.2 denotes H or C.sub.1-6-alkyl, R.sup.5 independently of
one another denote (a) H, C.sub.1-6-alkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, C.sub.3-6-cycloalkyl, (b) an aryl group
optionally substituted by 1, 2 or 3 substituents R.sup.5.2, wherein
the substituents R.sup.5.2 may be identical or different, (c) a
heteroaryl group optionally substituted by 1, 2 or 3 substituents
R.sup.5.2, wherein the substituents R.sup.5.2 may be identical or
different, (d) a heterocyclic group optionally substituted by 1, 2
or 3 substituents R.sup.5.2, wherein the substituents R.sup.5.2 may
be identical or different, R.sup.5.1 independently of one another
denote (a) H, halogen, C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, (b)
--O--C.sub.1-6-alkylene-NR.sup.7R.sup.8, --O--R.sup.6,
--O--(CH.sub.2).sub.s--O--R.sup.6, --CO.sub.2--R.sup.6,
--C(O)--NR.sup.7R.sup.8, --O--C(O)--NR.sup.7R.sup.8,
--NR.sup.6--C(O)--NR.sup.7R.sup.8, --NR.sup.7--C(O)--R.sup.8,
--NR.sup.7--C(O)--O--R.sup.8, --SO.sub.2--NR.sup.7R.sup.8,
--NR.sup.7--SO.sub.2--R.sup.8, --S(O).sub.m--R.sup.7, --CN,
--NR.sup.7R.sup.8, --NR.sup.6--C(O)--NR.sup.7R.sup.8,
--O--C(O)--R.sup.6, (c) a C.sub.1-3-alkyl- or C.sub.1-3-alkyl-O--
group wherein each methylene group is substituted by up to two
fluorine atoms and each methyl group is substituted by up to three
fluorine atoms, (d) an aryl group substituted by 1, 2 or 3
substituents R.sup.6, wherein the substituents R.sup.6 may be
identical or different, (e) a heteroaryl group substituted by 1, 2
or 3 substituents R.sup.6, wherein the substituents R.sup.6 may be
identical or different, (f) a heterocyclic group substituted by 1,
2 or 3 substituents R.sup.6, wherein the substituents R.sup.6 may
be identical or different, R.sup.5.2 independently of one another
denote (a) halogen, C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, (b)
--O--R.sup.6, --O--(CH.sub.2).sub.s--O--R.sup.6, --CO.sub.2R.sup.6,
--C(O)--NR.sup.7R.sup.8, --O--(CO)--NR.sup.7R.sup.8,
--N(R.sup.6)--C(O)--NR.sup.7R.sup.8, --N(R.sup.7)--C(O)--R.sup.8,
--N(R.sup.7)--C(O)--O--R.sup.8, --SO.sub.2--NR.sup.7R.sup.8,
--N(R.sup.7)--SO.sub.2--R.sup.8, --S(O).sub.m--R.sup.7, --CN,
--NR.sup.7R.sup.8, --N(R.sup.6)--C(O)--NR.sup.7R.sup.8,
--O--C(O)--R.sup.6 or (c) a C.sub.1-3-alkyl group wherein each
methylene group is substituted by up to two fluorine atoms and each
methyl group is substituted by up to three fluorine atoms, R.sup.6
denotes (a) H, (b) C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, aryl,
heteroaryl, benzyl, which may be substituted by a group R.sup.6.1,
or (c) a C.sub.1-3-alkyl group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, R.sup.6.1 denotes
halogen, HO-- or C.sub.1-6-alkyl-O--, R.sup.7 denotes (a) H, (b)
C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, aryl, heteroaryl or benzyl,
while the groups are unsubstituted or may be substituted by
halogen, HO-- or C.sub.1-6-alkyl-O--, or (c) a C.sub.1-3-alkyl
group wherein each methylene group is substituted by up to two
fluorine atoms and each methyl group is substituted by up to three
fluorine atoms, R.sup.8 denotes (a) H, (b) C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, aryl, heteroaryl or benzyl, while the groups
are unsubstituted or may be substituted by halogen, HO-- or
C.sub.1-6-alkyl-O--, or (c) a C.sub.1-3-alkyl group wherein each
methylene group is substituted by up to two fluorine atoms and each
methyl group is substituted by up to three fluorine atoms, or
R.sup.7 and R.sup.8 together may also form a ring which is selected
from among azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and
morpholinyl, wherein the ring may be unsubstituted or substituted
by 1, 2 or 3 substituents R.sup.6 or fluorine, wherein the
substituents R.sup.6 are independent of one another, m denotes one
of the numbers 0, 1 or 2, s denotes one of the numbers 1, 2 or 3, U
denotes N,N-oxide or C--R.sup.9, V denotes N,N-oxide or
C--R.sup.10, X denotes N,N-oxide or CR.sup.11, Y denotes N or
C--R.sup.12, while at most three of the previously mentioned groups
U, V, X or Y simultaneously denote a nitrogen atom, R.sup.9 denotes
(a) H, (b) a C.sub.1-6-alkyl- or C.sub.1-3-alkyl-O-- group which
may each be substituted by a group R.sup.9.1, (c)
R.sup.9.2R.sup.9.3N, R.sup.9.2R.sup.9.3N--C.sub.1-3-alkylene-, (d)
halogen, --CN, --OH, --COOH, C.sub.1-3-alkyl-O--C.sub.1-3-alkylene,
C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkyl-C.sub.1-4-alkylene-,
C.sub.1-3-alkyl-C(O)--O--C.sub.1-3-alkylene, (e) a C.sub.1-3-alkyl
or C.sub.1-3-alkyl-O-- group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, R.sup.9.1 denotes H, OH
or --O--CH.sub.3, R.sup.9.2 denotes H or C.sub.1-3-alkyl, R.sup.9.3
denotes H or C.sub.1-3-alkyl, or R.sup.9.2 and R.sup.9.3 together
with the nitrogen atom to which they are attached denote a 3- to
6-membered heterocyclic group, R.sup.10 denotes (a) H, (b) a
C.sub.1-6-alkyl- or C.sub.1-3-alkyl-O-- group which may each be
substituted by a group R.sup.10.1. (c) --NR.sup.10.2R.sup.10.3,
NR.sup.10.2R.sup.10.3--C.sub.1-3-alkylene-, (d) halogen, --CN,
--OH, C.sub.1-3-alkyl-O--C.sub.1-3-alkylene, C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyl-C.sub.1-4-alkylene,
C.sub.1-3-alkyl-C(O)--O--C.sub.1-3-alkylene, (e) an
aryl-C.sub.0-3-alkylene-O-- group, (f) a C.sub.1-3-alkyl or
C.sub.1-3-alkyl-O-- group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, R.sup.10.1 denotes H, OH
or --O--CH.sub.3, R.sup.10.2 denotes H or C.sub.1-6-alkyl,
R.sup.10.3 denotes H, C.sub.1-6-alkyl or
--SO.sub.2--C.sub.1-3-alkyl, or R.sup.10.2 and R.sup.10.3 together
with the nitrogen atom to which they are attached denote a 3- to
6-membered heterocyclic group, R.sup.11 denotes (a) H, (b) a
C.sub.1-6-alkyl- or C.sub.1-3-alkyl-O-- group which may each be
substituted by a group R.sup.11.1, (c) R.sup.11.2R.sup.11.3N,
R.sup.11.2R.sup.11.3N--C.sub.1-3-alkylene-, (d) halogen, --CN,
--OH, --COOH, C.sub.1-3-alkyl-O--C.sub.1-3-alkylene-,
C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkyl-C.sub.1-4-alkylene-,
C.sub.1-3-alkyl-C(O)--O--C.sub.1-3-alkylene, (e) a C.sub.1-3-alkyl-
or C.sub.1-3-alkyl-O-- group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, R.sup.11.1 denotes H, OH
or --O--CH.sub.3, R.sup.11.2 denotes H or C.sub.1-3-alkyl,
R.sup.11.3 denotes H or C.sub.1-3-alkyl, or R.sup.11.2 and
R.sup.11.3 together with the nitrogen atom to which they are
attached denote a 3- to 6-membered heterocyclic group, and R.sup.12
denotes H, halogen or C.sub.1-3-alkyl, or a tautomer or salt
thereof.
2. A compound of the formula I according to claim 1, wherein
R.sup.1 denotes a group of the formula II ##STR00443## wherein G-L
denotes N, N--C(R.sup.4.1).sub.2, C.dbd.C(R.sup.4.1), C.dbd.N,
C(R.sup.4.1), C(R.sup.4.1)--C(R.sup.4.1).sub.2,
C(R.sup.4.1)C(R.sup.4.1).sub.2--C(R.sup.4.1).sub.2,
C.dbd.C(R.sup.4.1)--C(R.sup.4.1).sub.2,
C(R.sup.4.1)--C(R.sup.4.1).dbd.C(R.sup.4.1),
C(R.sup.4.1)--C(R.sup.4.1).sub.2--N(R.sup.4.2),
C.dbd.C(R.sup.4.1)--N(R.sup.4.2), C(R.sup.4.1)--C(R.sup.4.1).dbd.N,
C(R.sup.4.1)--N(R.sup.4.2)--C(R.sup.4.1).sub.2,
C.dbd.N--C(R.sup.4.1).sub.2, C(R.sup.4.1)--N.dbd.C(R.sup.4.1),
C(R.sup.4.1)--N(R.sup.4.2)--N(R.sup.4.2), C.dbd.N--N(R.sup.4.2),
N--C(R.sup.4.1).sub.2--C(R.sup.4.1).sub.2,
N--C(R.sup.4.1).dbd.C(R.sup.4.1),
N--C(R.sup.4.1).sub.2--N(R.sup.4.2), N--C(R.sup.4.1)=N,
N--N(R.sup.4.2)--C(R.sup.4.1).sub.2 or N--N.dbd.C(R.sup.4.1), Q-T
denotes C(R.sup.5).sub.2--C(R.sup.5).sub.2,
C(R.sup.5).dbd.C(R.sup.5), N.dbd.C(R.sup.5),
C(R.sup.5).sub.2--C(.dbd.O), C(.dbd.O)--C(R.sup.5).sub.2,
C(R.sup.5).sub.2--S(O).sub.m or C(R.sup.5).sub.2--N(R.sup.5), while
a group C(R.sup.5).sub.2 contained in Q-T may also denote a cyclic
group which is selected from among cyclobutyl, cyclopentyl,
cyclohexyl, cyclopentenyl, cyclohexenyl, dioxanyl, morpholinyl,
thiomorpholinyl, thiomorpholine-S-oxide, thiomorpholine-S-dioxide,
azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl,
tetrahydropyranyl and piperazinyl, or in a group
C(R.sup.5).sub.2--C(R.sup.5).sub.2, C(R.sup.5).dbd.C(R.sup.5) or
C(R.sup.5).sub.2--N(R.sup.5) contained in Q-T in each case a group
R.sup.5 together with an adjacent group R.sup.5 and the atoms to
which these groups are attached may also denote a group selected
from cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl,
cyclohexenyl, dioxanyl, phenyl, naphthyl, thienyl, thiazolyl,
thiazolinyl, oxazolyl, oxazolinyl, imidazolyl, imidazolinyl,
imidazolidinyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,
pyrrolyl, pyrrolinyl, quinolinyl, isoquinolinyl, morpholinyl,
thiomorpholinyl, thiomorpholine-S-oxide, thiomorpholine-S-dioxide,
azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl,
tetrahydropyranyl, tetrahydropyridyl, furanyl, dihydrofuranyl,
dihydropyranyl and piperazinyl, which may be substituted
independently of one another by 1, 2 or 3 substituents R.sup.5.1,
R.sup.4.1 denotes (a) H, (b) C.sub.1-6-alkyl, --CN, --OH,
--O--C.sub.1-3-alkyl, (c) a C.sub.1-3-alkyl or C.sub.1-3-alkyl-O--
group wherein each methylene group is substituted by up to two
fluorine atoms and each methyl group is substituted by up to three
fluorine atoms, R.sup.4.2 denotes H or C.sub.1-6-alkyl, R.sup.5
denotes (a) H, C.sub.1-6-alkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, C.sub.3-6-cycloalkyl, (b) an aryl group
optionally substituted by 1, 2 or 3 substituents R.sup.5.2, wherein
the substituents R.sup.5.2 may be identical or different, (c) a
heteroaryl group optionally substituted by 1, 2 or 3 substituents
R.sup.5.2, wherein the substituents R.sup.5.2 may be identical or
different, (d) a heterocyclic group optionally substituted by 1, 2
or 3 substituents R.sup.5.2, wherein the substituents R.sup.5.2 may
be identical or different, R.sup.5.1 denotes (a) H, halogen,
C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, (b)
--O--C.sub.1-6-alkylene-NR.sup.7R.sup.8, --O--R.sup.6,
--O--(CH.sub.2).sub.s--O--R.sup.6, --CO.sub.2--R.sup.6,
C(O)--NR.sup.7R.sup.8, --O--C(O)--NR.sup.7R.sup.8,
--NR.sup.7--C(O)--NR.sup.7R.sup.8, --NR.sup.7--C(O)--R.sup.8,
--NR.sup.7--C(O)--O--R.sup.8, --SO.sub.2--NR.sup.7R.sup.8,
--NR.sup.7--SO.sub.2--R.sup.8, --S(O).sub.m--R.sup.7, --CN,
--NR.sup.7R.sup.8, --NR.sup.6--C(O)--NR.sup.7R.sup.8,
--O--C(O)--R.sup.6, (c) a C.sub.1-3-alkyl- or C.sub.1-3-alkyl-O--
group wherein each methylene group is substituted by up to two
fluorine atoms and each methyl group is substituted by up to three
fluorine atoms, (d) an aryl group substituted by 1, 2 or 3
substituents R.sup.6, wherein the substituents R.sup.6 may be
identical or different, (e) a heteroaryl group substituted by 1, 2
or 3 substituents R.sup.6, wherein the substituents R.sup.6 may be
identical or different, (f) a heterocyclic group substituted by 1,
2 or 3 substituents R.sup.6, wherein the substituents R.sup.6 may
be identical or different, R.sup.5.2 denotes (a) halogen,
C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, (b) --O--R.sup.6,
--O--(CH.sub.2).sub.s--O--R.sup.6, --CO.sub.2R.sup.6,
--C(O)--NR.sup.7R.sup.8, --O--(CO)--NR.sup.7R.sup.8,
--N(R.sup.6)--C(O)--NR.sup.7R.sup.8, --N(R.sup.7)--C(O)--R.sup.8,
--N(R.sup.7)--C(O)--O--R.sup.8, --SO.sub.2--NR.sup.7R.sup.8,
--N(R.sup.7)--SO.sub.2--R.sup.8, --S(O).sub.m--R.sup.7, CN,
NR.sup.7R.sup.8, --N(R.sup.6)--C(O)--NR.sup.7R.sup.8,
--O--C(O)--R.sup.6 or (c) a C.sub.1-3-alkyl group wherein each
methylene group is substituted by up to two fluorine atoms and each
methyl group is substituted by up to three fluorine atoms, R.sup.6
denotes (a) H, (b) C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, aryl,
heteroaryl, benzyl, which may be substituted by a group R.sup.6.1,
or (c) a C.sub.1-3-alkyl group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, R.sup.6.1 denotes
halogen, HO or C.sub.1-6-alkyl-O--, R.sup.7 denotes (a) H, (b)
C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, aryl, heteroaryl or benzyl,
while the groups are unsubstituted or may be substituted by
halogen, HO-- or C.sub.1-6-alkyl-O--, or (c) a C.sub.1-3-alkyl
group wherein each methylene group is substituted by up to two
fluorine atoms and each methyl group is substituted by up to three
fluorine atoms, R.sup.8 denotes (a) H, (b) C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, aryl, heteroaryl or benzyl, while the groups
are unsubstituted or may be substituted by halogen, HO-- or
C.sub.1-6-alkyl-O--, or (c) a C.sub.1-3-alkyl group wherein each
methylene group is substituted by up to two fluorine atoms and each
methyl group is substituted by up to three fluorine atoms, or
R.sup.7 and R.sup.8 together may also form a ring which is selected
from among azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and
morpholinyl, wherein the ring may be unsubstituted or substituted
by 1, 2 or 3 substituents R.sup.6 or fluorine, wherein the
substituents R.sup.6 are independent of one another, m denotes one
of the numbers 0, 1 or 2 and s denotes one of the numbers 1, 2 or
3, or a tautomer or salt thereof.
3. A compound of the formula I according to claim 1, wherein
R.sup.1 denotes a group of the formulae ##STR00444## wherein Q-T
denotes C(R.sup.5).sub.2--C(R.sup.5).sub.2,
C(R.sup.5).dbd.C(R.sup.5), N.dbd.C(R.sup.5),
C(R.sup.5).sub.2--C(.dbd.O), C(.dbd.O)--C(R.sup.5).sub.2,
C(R.sup.5).sub.2--S(O).sub.m or C(R.sup.5).sub.2--N(R.sup.5), while
in a group C(R.sup.5).sub.2--C(R.sup.5).sub.2,
C(R.sup.5).dbd.C(R.sup.5) or C(R.sup.5).sub.2--N(R.sup.5) contained
in Q-T in each case a group R.sup.5 together with an adjacent group
R.sup.5 and the atoms to which these groups are attached may also
denote a group selected from cyclobutyl, cyclopentyl, cyclohexyl,
cyclopentenyl, cyclohexenyl, dioxanyl, phenyl, naphthyl, thienyl,
thiazolyl, thiazolinyl, oxazolyl, oxazolinyl, imidazolyl,
imidazolinyl, imidazolidinyl, pyridyl, pyrimidyl, pyrazinyl,
pyridazinyl, pyrrolyl, pyrrolinyl, quinolinyl, isoquinolinyl,
morpholinyl, thiomorpholinyl, thiomorpholine S-oxide,
thiomorpholine S-dioxide, azetidinyl, pyrrolidinyl, piperidinyl,
tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridyl, furanyl,
dihydrofuranyl, dihydropyranyl and piperazinyl, which may be
substituted independently of one another by 1, 2 or 3 substituents
R.sup.5.1, R.sup.4.1 denotes (a) H, (b) C.sub.1-6-alkyl, --CN,
--OH, --O--C.sub.1-3-alkyl, (c) a C.sub.1-3-alkyl or
C.sub.1-3-alkyl-O-- group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, R.sup.5 independently of
one another denote (a) H, C.sub.1-6-alkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, C.sub.3-6-cycloalkyl, (b) an aryl group
optionally substituted by 1, 2 or 3 substituents R.sup.5.2, wherein
the substituents R.sup.5.2 may be identical or different, (c) a
heteroaryl group optionally substituted by 1, 2 or 3 substituents
R.sup.5.2, wherein the substituents R.sup.5.2 may be identical or
different, (d) a heterocyclic group optionally substituted by 1, 2
or 3 substituents R.sup.5.2, wherein the substituents R.sup.5.2 may
be identical or different, R.sup.5.1 denotes (a) H, halogen,
C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, (b)
--O--C.sub.1-6-alkylene-NR.sup.7R.sup.8, --O--R.sup.6,
--CO.sub.2R.sup.6, --C(O)NR.sup.7R.sup.8,
--SO.sub.2--NR.sup.7R.sup.8, --N(R.sup.7)--SO.sub.2--R.sup.8,
--S(O).sub.m--R.sup.7, --CN, --NR.sup.7R.sup.8, --O--C(O)--R.sup.6
or (c) a C.sub.1-3-alkyl group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, R.sup.5.2 denotes (a)
halogen, C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, (b) --O--R.sup.6,
--O--(CH.sub.2).sub.s--O--R.sup.6, --CO.sub.2R.sup.6,
--S(O).sub.m--R.sup.7, --CN, --O--C(O)--R.sup.6 or (c) a
C.sub.1-3-alkyl group wherein each methylene group is substituted
by up to two fluorine atoms and each methyl group is substituted by
up to three fluorine atoms, R.sup.6 denotes (a) H, (b)
C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, aryl, heteroaryl, benzyl,
which may be substituted by a group R.sup.6.1, or (c) a
C.sub.1-3-alkyl group wherein each methylene group is substituted
by up to two fluorine atoms and each methyl group is substituted by
up to three fluorine atoms, R.sup.6.1 denotes halogen, HO-- or
C.sub.1-6-alkyl-O--, R.sup.7 denotes (a) H, (b) C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, aryl, heteroaryl, or benzyl, while the groups
are unsubstituted or may be substituted by halogen, HO-- or
C.sub.1-6-alkyl-O--, or (c) a C.sub.1-3-alkyl group wherein each
methylene group is substituted by up to two fluorine atoms and each
methyl group is substituted by up to three fluorine atoms, R.sup.8
denotes (a) H, (b) C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, aryl,
heteroaryl, or benzyl, while the groups are unsubstituted or may be
substituted by halogen, HO-- or C.sub.1-6-alkyl-O--, or (c) a
C.sub.1-3-alkyl group wherein each methylene group is substituted
by up to two fluorine atoms and each methyl group is substituted by
up to three fluorine atoms, or R.sup.7 and R.sup.8 together may
also form a ring which is selected from among azetidinyl,
pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, wherein the
ring may be unsubstituted or substituted by 1, 2 or 3 substituents
R.sup.6, wherein the substituents R.sup.6 are independent of one
another, m denotes one of the numbers 0, 1 or 2 and s denotes one
of the numbers 1, 2 or 3, or a tautomer or salt thereof.
4. A compound of the formula I according to claim 1, wherein
R.sup.1 denotes a group of the formulae ##STR00445## wherein Q-T
denotes C(R.sup.5).sub.2--C(R.sup.5).sub.2,
C(R.sup.5).dbd.C(R.sup.5), N.dbd.C(R.sup.5),
C(R.sup.5).sub.2--C(.dbd.O), C(.dbd.O)--C(R.sup.5).sub.2,
C(R.sup.5).sub.2--S(O).sub.m or C(R.sup.5).sub.2--N(R.sup.5), while
in a group C(R.sup.5).sub.2--C(R.sup.5).sub.2,
C(R.sup.5).dbd.C(R.sup.5) or C(R.sup.5).sub.2--N(R.sup.5) contained
in Q-T in each case a group R.sup.5 together with an adjacent group
R.sup.5 and the atoms to which these groups are attached may also
denote a group selected from cyclopentyl, cyclohexyl,
cyclopentenyl, cyclohexenyl, dioxanyl, phenyl, naphthyl, thienyl,
pyridyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl,
morpholinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl,
tetrahydropyranyl and piperazinyl, which may be substituted
independently of one another by 1, 2 or 3 substituents R.sup.5.1,
R.sup.4.1 denotes (a) H, (b) C.sub.1-6-alkyl, --CN, --OH,
--O--C.sub.1-3-alkyl, (c) a C.sub.1-3-alkyl or C.sub.1-3-alkyl-O--
group wherein each methylene group is substituted by up to two
fluorine atoms and each methyl group is substituted by up to three
fluorine atoms, R.sup.5 independently of one another denote (a) H,
C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, (b) an aryl group optionally
substituted by 1, 2 or 3 substituents R.sup.5.2, wherein the
substituents R.sup.5.2 may be identical or different, (c) a
heteroaryl group optionally substituted by 1, 2 or 3 substituents
R.sup.5.2, wherein the substituents R.sup.5.2 may be identical or
different, (d) a heterocyclic group optionally substituted by 1, 2
or 3 substituents R.sup.5.2 wherein the substituents R.sup.5.2 may
be identical or different, R.sup.5.1 denotes (a) H, halogen,
C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, (b)
--O--C.sub.1-6-alkylene-NR.sup.7R.sup.8, --O--R.sup.6,
--CO.sub.2R.sup.6, --C(O)--NR.sup.7R.sup.8,
--SO.sub.2--NR.sup.7R.sup.8, --NR.sup.7--SO.sub.2--R.sup.8,
--S(O).sub.m--R.sup.7, --CN, --NR.sup.7R.sup.8, --O--C(O)--R.sup.6
or (c) a C.sub.1-3-alkyl group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, R.sup.5.2 denotes (a)
halogen, C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, (b) --O--R.sup.6,
--O--(CH.sub.2).sub.s--OR.sup.6, --CO.sub.2R.sup.6,
--S(O).sub.m--R.sup.6, --CN, --O--C(O)--R.sup.6 or (c) a
C.sub.1-3-alkyl group wherein each methylene group is substituted
by up to two fluorine atoms and each methyl group is substituted by
up to three fluorine atoms, R.sup.6 denotes (a) H, (b)
C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, aryl, heteroaryl, benzyl,
which may be substituted by a group R.sup.6.1, or (c) a
C.sub.1-3-alkyl group wherein each methylene group is substituted
by up to two fluorine atoms and each methyl group is substituted by
up to three fluorine atoms, R.sup.6.1 denotes halogen, HO-- or
C.sub.1-6-alkyl-O--, R.sup.7 denotes (a) H, (b) C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, aryl, heteroaryl, or benzyl, while the groups
are unsubstituted or may be substituted by halogen, HO-- or
C.sub.1-6-alkyl-O--, or (c) a C.sub.1-3-alkyl group wherein each
methylene group is substituted by up to two fluorine atoms and each
methyl group is substituted by up to three fluorine atoms, R.sup.8
denotes (a) H, (b) C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, aryl,
heteroaryl, or benzyl, while the groups are unsubstituted or may be
substituted by halogen, HO-- or C.sub.1-6-alkyl-O--, or (c) a
C.sub.1-3-alkyl group wherein each methylene group is substituted
by up to two fluorine atoms and each methyl group is substituted by
up to three fluorine atoms, or R.sup.7 and R.sup.8 together may
also form a ring which is selected from among azetidinyl,
pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, wherein the
ring may be unsubstituted or substituted by 1, 2 or 3 substituents
R.sup.6, wherein the substituents R.sup.6 are independent of one
another, m denotes one of the numbers 0, 1 or 2 and s denotes one
of the numbers 1, 2 or 3, or a tautomer or salt thereof.
5. A compound of the formula I according to claim 1, wherein
R.sup.1 denotes a group of the formula ##STR00446## ##STR00447##
wherein R.sup.4.1 denotes (a) H, (b) C.sub.1-3-alkyl, --OH,
--O--C.sub.1-3-alkyl, (c) a C.sub.1-3-alkyl- or C.sub.1-3-alkyl-O--
group wherein each methylene group is substituted by up to two
fluorine atoms and each methyl group is substituted by up to three
fluorine atoms, R.sup.5 denotes (a) H, C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, (b) a phenyl group optionally substituted by
1, 2, or 3 substituents R.sup.5.2, wherein the substituents
R.sup.5.2 may be identical or different, (c) a heteroaryl group
optionally substituted by 1, 2 or 3 substituents R.sup.5.2 which is
selected from among benzimidazole, benzothiophene, furan,
imidazole, indole, isoxazole, oxazole, pyrazine, pyrazole,
pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene and
triazole, wherein the substituents R.sup.5.2 may be identical or
different, (d) a heterocyclic group optionally substituted by 1, 2
or 3 substituents R.sup.5.2, wherein the substituents R.sup.5.2 may
be identical or different, R.sup.5.1 denotes (a) H, halogen,
C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, (b)
--O--C.sub.1-6-alkylene-NR.sup.7R.sup.8, --O--R.sup.6,
--CO.sub.2R.sup.6, --C(O)--NR.sup.7R.sup.8,
--SO.sub.2--NR.sup.7R.sup.8, --NR.sup.7--SO.sub.2--R.sup.8,
--S(O).sub.m--R.sup.7, --CN, --NR.sup.7R.sup.8, --O--C(O)--R.sup.6
or (c) a C.sub.1-3-alkyl or C.sub.1-3-alkyl-O-- group wherein each
methylene group is substituted by up to two fluorine atoms and each
methyl group is substituted by up to three fluorine atoms,
R.sup.5.2 denotes (a) halogen, C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, (b) --O--R.sup.6,
--O--(CH.sub.2).sub.s--O--R.sup.6, --CO.sub.2R.sup.6,
--S(O).sub.m--R.sup.6, --CN, --O--C(O)--R.sup.6 or (c) a
C.sub.1-3-alkyl group wherein each methylene group is substituted
by up to two fluorine atoms and each methyl group is substituted by
up to three fluorine atoms, R.sup.6 denotes (a) H, (b)
C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, aryl, heteroaryl, benzyl,
which may be substituted by a group R.sup.6.1, or (c) a
C.sub.1-3-alkyl group wherein each methylene group is substituted
by up to two fluorine atoms and each methyl group is substituted by
up to three fluorine atoms, R.sup.6.1 denotes HO-- or
C.sub.1-6-alkyl-O--, R.sup.7 denotes (a) H, (b) C.sub.1-3-alkyl,
phenyl or benzyl, while the groups are unsubstituted or may be
substituted by halogen, HO-- or H.sub.3C--O--, R.sup.8 denotes (a)
H, (b) C.sub.1-3-alkyl, phenyl or benzyl, while the groups are
unsubstituted or may be substituted by halogen, HO-- or
H.sub.3C--O--, or R.sup.7 and R.sup.8 together may also form a ring
which is selected from among azetidinyl, pyrrolidinyl, piperidinyl,
piperazinyl and morpholinyl, while the ring may be unsubstituted or
substituted by a substituent R.sup.6, m denotes one of the numbers
0, 1 or 2, and s denotes one of the numbers 1, 2 or 3, or a
tautomer or salt thereof.
6. A compound of the formula I according to claim 1, wherein
R.sup.1 denotes a group of the formula ##STR00448## or a tautomer
or salt thereof.
7. A compound of the formula I according to claim 1, wherein
R.sup.2 denotes a hydrogen atom, or a tautomer or salt thereof.
8. A compound of the formula I according to claim 1, wherein
R.sup.3 denotes a group of the formula III ##STR00449## A
independently of one another denote CH or N, R.sup.3.1 denotes (a)
H, (b) halogen, --NH.sub.2, C.sub.1-4-alkyl-NH--,
(C.sub.1-4-alkyl).sub.2N--, C.sub.1-3-alkyl-C(O)--NH--,
C.sub.1-3-alkyl-S(O).sub.2--NH--, --CN, --OH,
--O--C(O)--NH--C.sub.1-3-alkyl, (c) C.sub.1-4-alkyl,
R.sup.3.1.1--C.sub.1-3-alkylene, C.sub.2-4-alkenyl,
C.sub.2-4-alkynyl, C.sub.1-3-alkyl-O--, C.sub.1-3-alkyl-S--, (d) a
C.sub.1-3-alkyl or C.sub.1-3-alkyl-O-- group wherein each methylene
group is substituted by up to two fluorine atoms and each methyl
group is substituted by up to three fluorine atoms, (e)
--C(O)--R.sup.3.1.2, (f) --S(O).sub.2--R.sup.3.1.3, R.sup.3.1.1
denotes (a) H, (b) C.sub.3-6-cycloalkyl, C.sub.5-6-cycloalkenyl,
(c) (R.sup.3.1.1.1).sub.2N--, (d) a saturated, mono- or
diunsaturated 5- or 6-membered heterocyclic group, which is
substituted at a nitrogen atom by a group R.sup.3.1.1.1 and at a
carbon atom by one or two groups R.sup.3.1.1.2, or (e) a heteroaryl
group which is substituted at a carbon atom by a group
R.sup.3.1.1.2, R.sup.3.1.1.1 independently of one another denote
(a) H, C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl, (b) heterocyclyl, (c)
aryl-C.sub.0-3-alkylene or heteroaryl-C.sub.0-3-alkylene,
R.sup.3.1.1.2 independently of one another denote (a) H, F,
C.sub.1-3-alkyl, --CN, --OH, --O--C.sub.1-3-alkyl,
--CO(O)R.sup.3.1.1.2.1, H.sub.2N, (C.sub.1-4-alkyl)-NH--,
(C.sub.1-4-alkyl).sub.2N--, (b) phenyl or phenyl-CH.sub.2--, (c) a
C.sub.1-3-alkyl or --O--C.sub.1-3-alkyl group wherein each
methylene group is substituted by up to two fluorine atoms and each
methyl group is substituted by up to three fluorine atoms, or
R.sup.3.1.1.2.1 denotes H, C.sub.1-6-alkyl, benzyl, R.sup.3.1.2
denotes --O--C.sub.1-3-alkyl, --OH, --NR.sup.3.1.2.1R.sup.3.1.2.2,
R.sup.3.1.2.1 denotes H, C.sub.1-3-alkyl, R.sup.3.1.2.2 denotes H,
C.sub.1-3-alkyl, R.sup.3.1.3 denotes --NR.sup.3.1.3.1R.sup.3.1.3.2,
R.sup.3.1.3.1 denotes H, C.sub.1-3-alkyl, R.sup.3.1.3.2 denotes H,
C.sub.1-3-alkyl, R.sup.3.2 denotes (a) H, (b) halogen, --NH.sub.2,
C.sub.1-4-alkyl-NH--, (C.sub.1-4-alkyl).sub.2N--,
C.sub.1-3-alkyl-C(O)--NH--, C.sub.1-3-alkyl-S(O).sub.2--NH--, --CN,
--OH, --O--C(O)--NH--C.sub.1-3-alkyl, (c) C.sub.1-4-alkyl,
C.sub.2-4-alkenyl, C.sub.2-4-alkynyl, C.sub.1-3-alkyl-O--,
C.sub.1-3-alkyl-S--, (d) a C.sub.1-3-alkyl or C.sub.1-3-alkyl-O--
group wherein each methylene group is substituted by up to two
fluorine atoms and each methyl group is substituted by up to three
fluorine atoms, (e) --C(O)--R.sup.3.2.1, (f)
--S(O).sub.2--R.sup.3.2.2, R.sup.3.2.1 denotes
--O--C.sub.1-3-alkyl, --OH, --NR.sup.3.2.1.1R.sup.3.2.1.2,
R.sup.3.2.1.1 denotes H, C.sub.1-3-alkyl, R.sup.3.2.1.2 denotes H,
C.sub.1-3-alkyl, R.sup.3.2.2 denotes --NR.sup.3.2,2,1R.sup.3.2,2,2,
R.sup.3.2,2,1 denotes H, C.sub.1-3-alkyl, R.sup.3.2,2,2 denotes H,
C.sub.1-3-alkyl, R.sup.3.3 denotes (a) H, (b) halogen, --NH.sub.2,
C.sub.1-4-alkyl-NH--, (C.sub.1-4-alkyl).sub.2N,
C.sub.1-3-alkyl-C(O)--NH--, C.sub.1-3-alkyl-S(O).sub.2--NH--, --CN,
--OH, --O--C(O)--NH--C.sub.1-3-alkyl, (c) C.sub.1-4-alkyl,
C.sub.2-4-alkenyl, C.sub.2-4-alkynyl, C.sub.1-3-alkyl-O--,
C.sub.1-3-alkyl-S--, (d) a C.sub.1-3-alkyl or C.sub.1-3-alkyl-O--
group wherein each methylene group is substituted by up to two
fluorine atoms and each methyl group is substituted by up to three
fluorine atoms, (e) --C(O)--R.sup.3.3.1, (f)
--S(O).sub.2--R.sup.3.3.2, R.sup.3.3.1 denotes
--O--C.sub.1-3-alkyl, --OH, --NR.sup.3.3.1.1R.sup.3.3.1.2,
R.sup.3.3.1.1 denotes H, C.sub.1-3-alkyl, R.sup.3.3.1.2 denotes H,
C.sub.1-3-alkyl, R.sup.3.3.2 denotes --O--C.sub.1-3-alkyl,
--NR.sup.3.3.2.1R.sup.3.3.2.2, R.sup.3.3.2.1 denotes H,
C.sub.1-3-alkyl, R.sup.3.3.2.2 denotes H, C.sub.1-3-alkyl, or
R.sup.3.2 and R.sup.3.3 together with the carbon atoms to which
they are attached form a monounsaturated 5-membered or a mono- or
diunsaturated 6-membered heterocyclic group or a 5- to 6-membered
heteroaryl group, while the heterocycles mentioned previously may
contain a carbonyl, thiocarbonyl or cyanimino group adjacent to a
nitrogen atom, and may optionally each additionally be substituted
at one or two nitrogen atoms by a group R.sup.3.3.3 and may
optionally each additionally be substituted at one or two carbon
atoms by one or two groups R.sup.3.3.4, R.sup.3.3.3 independently
of one another denote (a) C.sub.1-4-alkyl or (b)
C.sub.3-6-cycloalkyl, and R.sup.3.3.4 independently of one another
denote (a) C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl, (b) halogen, CN,
C.sub.1-3-alkyl-O, --NH.sub.2, (c) a C.sub.1-3-alkyl or
C.sub.1-3-alkyl-O-- group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, or a tautomer or salt
thereof.
9. A compound of the formula I according to claim 1, wherein
R.sup.3 denotes a group of the formulae III ##STR00450## A
independently of one another denotes CH or N, R.sup.3.1 denotes (a)
H, (b) halogen, --NH.sub.2, C.sub.1-4-alkyl-NH--,
(C.sub.1-4-alkyl).sub.2N--C.sub.1-3-alkyl-C(O)--NH--, --CN, --OH,
--O--C(O)--NH--C.sub.1-3-alkyl, (c) C.sub.1-4-alkyl,
C.sub.2-4-alkenyl, C.sub.2-4-alkynyl, C.sub.1-3-alkyl-O--,
C.sub.1-3-alkyl-S--, (d) a C.sub.1-3-alkyl- or C.sub.1-3-alkyl-O--
group wherein each methylene group is substituted by up to two
fluorine atoms and each methyl group is substituted by up to three
fluorine atoms, R.sup.3.2 denotes (a) H, (b) halogen, --NH.sub.2,
C.sub.1-4-alkyl-NH, (C.sub.1-4-alkyl).sub.2N--,
C.sub.1-3-alkyl-C(O)--NH--, --CN, --OH,
--O--C(O)--NH--C.sub.1-3-alkyl, (c) C.sub.1-4-alkyl,
C.sub.2-4-alkenyl, C.sub.2-4-alkynyl, C.sub.1-3-alkyl-O--,
C.sub.1-3-alkyl-S--, (d) a C.sub.1-3-alkyl or C.sub.1-3-alkyl-O--
group wherein each methylene group is substituted by up to two
fluorine atoms and each methyl group is substituted by up to three
fluorine atoms, R.sup.3.3 denotes (a) H, (b) halogen, --NH.sub.2,
C.sub.1-4-alkyl-NH--, (C.sub.1-4-alkyl).sub.2N--,
C.sub.1-3-alkyl-C(O)--NH--, --CN, --OH,
--O--C(O)--NH--C.sub.1-3-alkyl, (c) C.sub.1-4-alkyl,
C.sub.2-4-alkenyl, C.sub.2-4-alkynyl, C.sub.1-3-alkyl-O--,
C.sub.1-3-alkyl-S--, (d) a C.sub.1-3-alkyl or C.sub.1-3-alkyl-O--
group wherein each methylene group is substituted by up to two
fluorine atoms and each methyl group is substituted by up to three
fluorine atoms, R.sup.3.2 and R.sup.3.3 together with the carbon
atoms to which they are attached form a monounsaturated 5-membered
or a mono- or diunsaturated 6-membered heterocyclic group or a 5-
to 6-membered heteroaryl group, while the heterocycles mentioned
previously may contain a carbonyl, thiocarbonyl or cyanimino group
adjacent to a nitrogen atom, and may optionally each additionally
be substituted at one or two nitrogen atoms by a group R.sup.3.3.3
and may optionally each additionally be substituted at one or two
carbon atoms by one or two groups R.sup.3.3.4, R.sup.3.3.3
independently of one another denote (a) C.sub.1-4-alkyl or (b)
C.sub.3-6-cycloalkyl, and R.sup.3.3.4 independently of one another
denote (a) C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl, (b) halogen, CN,
C.sub.1-3-alkyl-O, --NH.sub.2, (c) a C.sub.1-3-alkyl- or
C.sub.1-3-alkyl-O-- group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, or a tautomer or salt
thereof.
10. A compound of the formula I according to claim 1, wherein
R.sup.3 denotes a group of the formulae III ##STR00451## R.sup.3.1
denotes (a) H, (b) F, Cl, Br, --NH.sub.2, C.sub.1-3-alkyl-NH,
(C.sub.1-3-alkyl).sub.2N, C.sub.1-3-alkyl-C(O)--NH, --CN, --OH, (c)
C.sub.1-4-alkyl, C.sub.2-4-alkenyl, C.sub.2-4-alkynyl,
C.sub.1-3-alkyl-O--, C.sub.1-3-alkyl-S--, (d) a C.sub.1-3-alkyl or
C.sub.1-3-alkyl-O-- group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, R.sup.3.2 denotes (a) H,
(b) F, Cl, Br, H.sub.2N--, (C.sub.1-4-alkyl)-NH--,
(C.sub.1-4-alkyl).sub.2N--, (C.sub.1-3-alkyl)-C(O)--NH--, --OH, (c)
C.sub.1-4-alkyl, (d) a C.sub.1-3-alkyl- or C.sub.1-3-alkyl-O--
group wherein each methylene group is substituted by up to two
fluorine atoms and each methyl group is substituted by up to three
fluorine atoms, R.sup.3.3 denotes (a) H, (b) F, Cl, Br, H.sub.2N--,
(C.sub.1-4-alkyl)-NH--, (C.sub.1-4-alkyl).sub.2N--,
(C.sub.1-3-alkyl)-C(O)--NH--, --OH, (c) C.sub.1-4-alkyl, (d) a
C.sub.1-3-alkyl- or C.sub.1-3-alkyl-O-- group wherein each
methylene group is substituted by up to two fluorine atoms and each
methyl group is substituted by up to three fluorine atoms,
R.sup.3.2 and R.sup.3.3 together with the carbon atoms to which
they are attached form a monounsaturated 5-membered or a mono- or
diunsaturated 6-membered heterocyclic group or a 5- to 6-membered
heteroaryl group, while the heterocycles mentioned previously may
contain a carbonyl, thiocarbonyl or cyanimino group adjacent to a
nitrogen atom, and may optionally each additionally be substituted
at one or two nitrogen atoms by a group R.sup.3.3.3 and may
optionally each additionally be substituted at one or two carbon
atoms by one or two groups R.sup.3.3.4, R.sup.3.3.3 independently
of one another denote (a) C.sub.1-4-alkyl or (b)
C.sub.3-6-cycloalkyl, and R.sup.3.3.4 independently of one another
denote (a) C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl, (b) halogen, CN,
C.sub.1-3-alkyl-O--, --NH.sub.2, (c) a C.sub.1-3-alkyl- or
C.sub.1-3-alkyl-O-- group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, or a tautomer or salt
thereof.
11. A compound of the formula I according to claim 1, wherein
R.sup.3 denotes a group of the formula ##STR00452## ##STR00453## or
a tautomer or salt thereof.
12. A compound of the formula I according to claim 1, wherein
R.sup.3 denotes a group of the formulae III ##STR00454## R.sup.3.1
denotes (a) H, (b) F, Cl, Br, --NH.sub.2, C.sub.1-3-alkyl-NH--,
(C.sub.1-3-alkyl).sub.2N, C.sub.1-3-alkyl-C(O)--NH--, --CN, --OH,
(c) C.sub.1-4-alkyl, C.sub.2-4-alkenyl, C.sub.2-4-alkynyl,
C.sub.1-3-alkyl-O--, C.sub.1-3-alkyl-S--, (d) a C.sub.1-3-alkyl- or
C.sub.1-3-alkyl-O-- group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, R.sup.3.2 and R.sup.3.3
together with the carbon atoms to which they are attached form a
monounsaturated 5-membered heterocyclic group or a mono- or
diunsaturated 6-membered heterocyclic group or a 5- to 6-membered
heteroaryl group, while the heterocycles mentioned previously may
contain a carbonyl, thiocarbonyl or cyanimino group adjacent to a
nitrogen atom, and may optionally each additionally be substituted
at one or two nitrogen atoms by a group R.sup.3.3.3 and may
optionally each additionally be substituted at one or two carbon
atoms by one or two groups R.sup.3.3.4, R.sup.3.3.3 independently
of one another denote (a) C.sub.1-4-alkyl or (b)
C.sub.3-6-cycloalkyl, and R.sup.3.3.4 independently of one another
denote (a) C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl, (b) halogen,
--CN, --O--C.sub.1-3-alkyl, --NH.sub.2, (c) a C.sub.1-3-alkyl- or
C.sub.1-3-alkyl-O-- group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, the tautomers, the
diastereomers, the enantiomers, the hydrates, the mixtures thereof
and the salts thereof as well as the hydrates of the salts,
particularly the physiologically acceptable salts thereof with
inorganic or organic acids or bases.
13. Compounds of general formula I according to claim 1, wherein U,
V, X, Y, R.sup.1 and R.sup.2 are defined as in claim 1, 2, 3, 4, 5,
6 or 7 and R.sup.3 denotes a group of general formulae III
##STR00455## R.sup.3.1 denotes (a) H, (b) F, Cl, Br, --NH.sub.2,
C.sub.1-3-alkyl-NH, (C.sub.1-3-alkyl).sub.2N,
C.sub.1-3-alkyl-C(O)--NH, --CN, --OH, (c) C.sub.1-4-alkyl,
C.sub.2-4-alkenyl, C.sub.2-4-alkynyl, C.sub.1-3-alkyl-O,
C.sub.1-3-alkyl-S, (d) a C.sub.1-3-alkyl- or C.sub.1-3-alkyl-O--
group wherein each methylene group is substituted by up to two
fluorine atoms and each methyl group is substituted by up to three
fluorine atoms, R.sup.3.2 and R.sup.3.3 together with the carbon
atoms to which they are attached form a monounsaturated 5-membered
heterocyclic group or a 5-membered heteroaryl group, wherein the
heterocycles mentioned previously may contain a carbonyl,
thiocarbonyl or cyanimino group adjacent to a nitrogen atom, and
may optionally each additionally be substituted at one or two
nitrogen atoms by a group R.sup.3.3.3 and may optionally each
additionally be substituted at one or two carbon atoms by one or
two groups R.sup.3.3.4, R.sup.3.3.3 independently of one another
denote (a) C.sub.1-4-alkyl- or (b) C.sub.3-6-cycloalkyl, and
R.sup.3.3.4 independently of one another denote (a)
C.sub.1-4-alkyl-, C.sub.3-6-cycloalkyl-, (b) halogen, --CN,
--O--C.sub.1-3-alkyl, --NH.sub.2, (c) a C.sub.1-3-alkyl or
C.sub.1-3-alkyl-O-- group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, or a tautomer or salt
thereof.
14. A compound of the formula I according to claim 1, wherein
R.sup.3 denotes a group of the formula IIIa ##STR00456## T denotes
O, S, CH.sub.2, NH or N--R.sup.3.3.3, R.sup.3.1 denotes (a) H, (b)
F, Cl, Br, --NH.sub.2, C.sub.1-3-alkyl-NH,
(C.sub.1-3-alkyl).sub.2N, C.sub.1-3-alkyl-C(O)--NH, --CN, --OH, (c)
C.sub.1-4-alkyl, C.sub.2-4-alkenyl, C.sub.2-4-alkynyl,
C.sub.1-3-alkyl-O, C.sub.1-3-alkyl-S--, (d) a C.sub.1-3-alkyl or
C.sub.1-3-alkyl-O-- group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, and R.sup.3.3.3
independently of one another denote (a) C.sub.1-4-alkyl or (b)
C.sub.3-6-cycloalkyl, or a tautomer or salt thereof.
115. A compound of the formula I according to claim 1, wherein
R.sup.3 denotes a group of the formula ##STR00457## or a tautomer
or salt thereof.
16. A compound of the formula I according to claim 1, wherein U-V-X
denotes --N.dbd.N--(C--R.sup.11).dbd.,
--N.dbd.(C--R.sup.10)--N.dbd., --N.dbd.(C--R.sup.10)--(C--H).dbd.,
--(N-oxide)=(C--R.sup.10)--(C--R.sup.11).dbd.,
--(CR.sup.9).dbd.N--N.dbd., --(CR.sup.9).dbd.N--(CR.sup.11).dbd.,
--(C--R.sup.9).dbd.N(oxide)-(C--R.sup.11).dbd.,
--(CR.sup.9).dbd.(C--R.sup.10)--N.dbd.,
--(CR.sup.9).dbd.(C--R.sup.0)--(N-oxide)=, or
--(CR.sup.9).dbd.(C--R.sup.10)--(CR.sup.11).dbd., R.sup.9 denotes
(a) H, (b) a C.sub.1-6-alkyl- or C.sub.1-3-alkyl-O-- group which
may each be substituted by a group R.sup.9.1, (c)
R.sup.9.2R.sup.9.3N, R.sup.9.2R.sup.9.3N--C.sub.1-3-alkylene-, (d)
halogen, --CN, --OH, --COOH,
C.sub.1-3-alkyl-O--C.sub.1-3-alkylene-, C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyl-C.sub.1-4-alkylene-,
C.sub.1-3-alkyl-C(O)--O--C.sub.1-3-alkylene, (e) a C.sub.1-3-alkyl
or C.sub.1-3-alkyl-O-- group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, R.sup.9.1 denotes H, OH
or --O--CH.sub.3, R.sup.9.2 denotes H or C.sub.1-3-alkyl, R.sup.9.3
denotes H or C.sub.1-3-alkyl, or R.sup.9.2 and R.sup.9.3 together
with the nitrogen atom to which they are attached denote a 3- to
6-membered heterocyclic group, R.sup.10 denotes (a) H, (b) a
C.sub.1-6-alkyl or C.sub.1-3-alkyl-CO-- group which may each be
substituted by a group R.sup.10.1, (c) --NR.sup.10.1R.sup.10.2,
NR.sup.10.1R.sup.10.2--C.sub.1-3-alkylene-, (d) halogen, --CN,
--OH, C.sub.1-3-alkyl-O--C.sub.1-3-alkylene, C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyl-C.sub.1-4-alkylene,
C.sub.1-3-alkyl-C(O)--O--C.sub.1-3-alkylene, (e)
aryl-C.sub.0-3-alkylene-O--, (f) a C.sub.1-3-alkyl or
C.sub.1-3-alkyl-O-- group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, R.sup.10.1 denotes H, OH
or --O--CH.sub.3, R.sup.10.2 denotes H or C.sub.1-6-alkyl,
R.sup.10.3 denotes H, C.sub.1-6-alkyl or
--SO.sub.2--C.sub.1-3-alkyl, R.sup.11 denotes (a) H, (b) a
C.sub.1-6-alkyl- or C.sub.1-3-alkyl-O-- group which may each be
substituted by a group R.sup.11.1, (c) R.sup.11.2R.sup.11.3N,
R.sup.11.2R.sup.11.3N--C.sub.1-3-alkylene-, (d) halogen, --CN,
--OH, --COOH, C.sub.1-3-alkyl-O--C.sub.1-3-alkylene,
C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkyl-C.sub.1-4-alkylene,
C.sub.1-3-alkyl-C(O)--O--C.sub.1-3-alkylene, (e) a C.sub.1-3-alkyl
or C.sub.1-3-alkyl-O-- group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, R.sup.11.1 denotes H, OH
or --O--CH.sub.3, R.sup.11.2 denotes H or C.sub.1-3-alkyl,
R.sup.11.3 denotes H or C.sub.1-3-alkyl, or R.sup.11.2 and
R.sup.11.3 together with the nitrogen atom to which they are
attached denote a 3- to 6-membered heterocyclic group, or a
tautomer or salt thereof.
17. A compound of the formula I according to claim 1, wherein the
ring ##STR00458## denotes a group of the formula ##STR00459##
##STR00460## or a tautomer or salt thereof.
18. A compound of the formula I according to claim 1, wherein
R.sup.1 denotes a group of the formula ##STR00461## R.sup.2 denotes
H and R.sup.3 denotes a group of the formula ##STR00462## and the
ring ##STR00463## denotes a group of the formula ##STR00464## or a
tautomer or salt thereof.
19. A compound according to claim 1 selected from the group
consisting of: TABLE-US-00020 No. Structure (1) ##STR00465## (2)
##STR00466## (3) ##STR00467## (4) ##STR00468## (5) ##STR00469## (6)
##STR00470## (7) ##STR00471## (8) ##STR00472## (9) ##STR00473##
(10) ##STR00474## (11) ##STR00475## (12) ##STR00476## (13)
##STR00477## (14) ##STR00478## (15) ##STR00479## (16) ##STR00480##
(17) ##STR00481## (18) ##STR00482## (19) ##STR00483## (20)
##STR00484## (21) ##STR00485## (22) ##STR00486## (23) ##STR00487##
(24) ##STR00488## (25) ##STR00489## (26) ##STR00490## (27)
##STR00491## (28) ##STR00492## (29) ##STR00493## (30) ##STR00494##
(31) ##STR00495## (32) ##STR00496## (33) ##STR00497## (34)
##STR00498## (35) ##STR00499## (36) ##STR00500## (37) ##STR00501##
(38) ##STR00502## (39) ##STR00503## (40) ##STR00504## (41)
##STR00505## (42) ##STR00506## (43) ##STR00507## (44) ##STR00508##
(45) ##STR00509## (46) ##STR00510## (47) ##STR00511## (48)
##STR00512## (49) ##STR00513## (50) ##STR00514## (51) ##STR00515##
(52) ##STR00516## (53) ##STR00517## (54) ##STR00518## (55)
##STR00519## (56) ##STR00520## (57) ##STR00521## (58) ##STR00522##
(59) ##STR00523## (60) ##STR00524## (61) ##STR00525## (62)
##STR00526## (63) ##STR00527## (64) ##STR00528## (65) ##STR00529##
(66) ##STR00530## (67) ##STR00531## (68) ##STR00532## (69)
##STR00533## (70) ##STR00534## (71) ##STR00535## (72) ##STR00536##
(73) ##STR00537## (74) ##STR00538## (75) ##STR00539## (76)
##STR00540## (77) ##STR00541## (78) ##STR00542## (79) ##STR00543##
(80) ##STR00544## (81) ##STR00545## (82) ##STR00546## (83)
##STR00547## (84) ##STR00548## (85) ##STR00549##
or a salt thereof.
20. A physiologically acceptable salt of a compound according to
any one of claims 1 to 18.
21. A pharmaceutical composition comprising a compound according to
any one of claims 1 to 18, or a physiologically acceptable salt
thereof, and a carrier or diluent.
22. A method of treating headache, migraine headache and cluster
headache which comprises administering to a host suffering from the
same a therapeutically effective amount of a compound according to
any one of claims 1 to 18, or a physiologically acceptable salt
thereof.
23-24. (canceled)
Description
[0001] The present invention relates to new CGRP-antagonists of
general formula I
##STR00002##
wherein U, V, X, Y, R.sup.1, R.sup.2 and R.sup.3 are defined as
mentioned hereinafter, the tautomers thereof, the isomers thereof,
the diastereomers thereof, the enantiomers thereof, the hydrates
thereof, the mixtures thereof and the salts thereof as well as the
hydrates of the salts, particularly the physiologically acceptable
salts thereof with inorganic or organic acids or bases,
pharmaceutical compositions containing these compounds, the use
thereof and processes for the preparation thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0002] In the above general formula I in a first embodiment [0003]
R.sup.1 denotes a group of general formula II
##STR00003##
[0003] wherein [0004] G-L denotes N, N--C(R.sup.4.1).sub.2,
C.dbd.C(R.sup.4.1), C.dbd.N, C(R.sup.4.1),
C(R.sup.4.1)--C(R.sup.4.1).sub.2,
C(R.sup.4.1)--C(R.sup.4.1).sub.2--C(R.sup.4.1).sub.2,
C.dbd.C(R.sup.4.1)--C(R.sup.4.1).sub.2,
C(R.sup.4.1)--C(R.sup.4.1).dbd.C(R.sup.4.1),
C(R.sup.4.1)--C(R.sup.4.1).sub.2--N(R.sup.4.2),
C.dbd.C(R.sup.4.1)--N(R.sup.4.2), C(R.sup.4.1)--C(R.sup.4.1).dbd.N,
C(R.sup.4.1)--N(R.sup.4.2)--C(R.sup.4.1).sub.2,
C.dbd.N--C(R.sup.4.1).sub.2, C(R.sup.4.1)--N.dbd.C(R.sup.4.1),
C(R.sup.4.1)--N(R.sup.4.2)--N(R.sup.4.2), C.dbd.N--N(R.sup.4.2),
N--C(R.sup.4.1).sub.2--C(R.sup.4.1).sub.2,
N--C(R.sup.4.1).dbd.C(R.sup.4.1),
N--C(R.sup.4.1).sub.2--N(R.sup.4.2), N--C(R.sup.4.1).dbd.N,
N--N(R.sup.4.2)--C(R.sup.4.1).sub.2 or N--N.dbd.C(R.sup.4.1),
[0005] Q-T denotes C(R.sup.5).sub.2--C(R.sup.5).sub.2,
C(R.sup.5).dbd.C(R.sup.5), N.dbd.C(R.sup.5),
C(R.sup.5).sub.2--C(.dbd.O), C(.dbd.O)--C(R.sup.5).sub.2,
C(R.sup.5).sub.2--S(O).sub.m-- or C(R.sup.5).sub.2--N(R.sup.5),
[0006] while a group C(R.sup.5).sub.2 contained in Q-T may also
denote a cyclic group which is selected from among
C.sub.3-6-cycloalkyl, C.sub.5-6-cycloalkenyl or heterocyclyl, or
[0007] in a group C(R.sup.5).sub.2--C(R.sup.5).sub.2,
C(R.sup.5).dbd.C(R.sup.5) or C(R.sup.5).sub.2--N(R.sup.5) contained
in Q-T in each case a group R.sup.5 together with an adjacent group
R.sup.5 and the atoms to which these groups are attached may also
denote a C.sub.3-6-cycloalkyl, C.sub.5-6-cycloalkenyl,
heterocyclyl, aryl or heteroaryl group, which may be substituted
independently of one another by 1, 2 or 3 substituents R.sup.5.1,
[0008] R.sup.2 denotes [0009] (a) H, [0010] (b) F, --CN,
C.sub.1-3-alkyl, --CO.sub.2--R.sup.2.1 or [0011] (c) a
C.sub.1-3-alkyl group wherein each methylene group is substituted
by up to two fluorine atoms and each methyl group is substituted by
up to three fluorine atoms, [0012] R.sup.2.1 denotes H or
C.sub.1-6-alkyl, [0013] R.sup.3 a 6 or 10-membered aryl group
substituted by the groups R.sup.3.1, R.sup.3.2 and R.sup.3.3 or a
6-membered heteroaryl group substituted by the groups R.sup.3.1,
R.sup.3.2 and R.sup.3.3 which is attached via a carbon atom, [0014]
R.sup.3.1 denotes [0015] (a) H, [0016] (b) halogen, --NH.sub.2,
C.sub.1-4-alkyl-NH, (C.sub.1-4-alkyl).sub.2N,
C.sub.1-3-alkyl-C(O)--NH, C.sub.1-3-alkyl-S(O.sub.2)--NH, --CN,
--OH, --O--C(O)--NH--C.sub.1.3-alkyl, [0017] (c) C.sub.1-4-alkyl,
R.sup.3.1.1--C.sub.1-3-alkylene, C.sub.2-4-alkenyl,
C.sub.2-4-alkynyl, C.sub.1-3-alkyl-O, C.sub.1-3-alkyl-S(O).sub.m--,
cyclopropyl, [0018] (d) a C.sub.1-3-alkyl or C.sub.1-3-alkyl-O--
group wherein each methylene group is substituted by up to two
fluorine atoms and each methyl group is substituted by up to three
fluorine atoms, [0019] (e) --C(O)--R.sup.3.1.2, [0020] (f)
--S(O).sub.2--R.sup.3.1.3, [0021] R.sup.3.1.1 denotes [0022] (a) H,
[0023] (b) C.sub.3-6-cycloalkyl, C.sub.5-6-cycloalkenyl, [0024] (c)
(R.sup.3.1.1.1).sub.2N, [0025] (d) a saturated, mono- or
diunsaturated 5- or 6-membered heterocyclic group, which is
substituted at a nitrogen atom by a group R.sup.3.1.1.1 and is
substituted at a carbon atom by one or two groups R.sup.3.1.1.2, or
[0026] (e) a heteroaryl group which is substituted at a carbon atom
by a group R.sup.3.1.1.2, [0027] R.sup.3.1.1.1 independently of one
another denote [0028] (a) H, C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl,
[0029] (b) heterocyclyl, [0030] (c) aryl-C.sub.0-3-alkylene or
heteroaryl-C.sub.0-3-alkylene, R.sup.3.1.1.2 independently of one
another denote [0031] (a) H, F, C.sub.1-3-alkyl, --CN, --OH,
--O--C.sub.1-3-alkyl, --CO(O)R.sup.3.1.1.2.1, H.sub.2N,
(C.sub.1-4-alkyl)-NH, (C.sub.1-4-alkyl).sub.2N, [0032] (b) phenyl
or phenyl-CH.sub.2, [0033] (c) a C.sub.1-3-alkyl or
--O--C.sub.1-3-alkyl group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, or [0034]
R.sup.3.1.1.2.1 denotes H, C.sub.1-6-alkyl, benzyl, [0035]
R.sup.3.1.2 denotes --O--C.sub.1-3-alkyl, --OH,
--NR.sup.3.1.2.1R.sup.3.1.2.2, [0036] R.sup.3.1.2.1 denotes H,
C.sub.1-3-alkyl, [0037] R.sup.3.1.2.2 denotes H, C.sub.1-3-alkyl,
[0038] R.sup.3.1.2.1 and R.sup.3.1.2.2 together may also form a
ring which is selected from among azetidinyl, pyrrolidinyl,
piperidinyl, piperazinyl and morpholinyl, [0039] R.sup.3.1.3
denotes --O--C.sub.1-3-alkyl, --NR.sup.3.1.3.1R.sup.3.1.3.2, [0040]
R.sup.3.1.3.1 denotes H, C.sub.1-3-alkyl, [0041] R.sup.3.1.3.2
denotes H, C.sub.1-3-alkyl, [0042] R.sup.3.1.3.1 and R.sup.3.1.3.2
together may also form a ring which is selected from among
azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl,
[0043] R.sup.3.2 denotes [0044] (a) H, [0045] (b) halogen,
--NH.sub.2, C.sub.1-4-alkyl-NH, (C.sub.1-4-alkyl).sub.2N,
C.sub.1-3-alkyl-C(O)--NH, C.sub.1-3-alkyl-S(O.sub.2)--NH, --CN,
--OH, --O--C(O)--NH--C.sub.1-3-alkyl, [0046] (c) C.sub.1-4-alkyl,
C.sub.2-4-alkenyl, C.sub.2-4-alkynyl, C.sub.1-3-alkyl-O,
C.sub.1-3alkyl-S(O).sub.m--, cyclopropyl, [0047] (d) a
C.sub.1-3-alkyl or C.sub.1-3-alkyl-O-- group wherein each methylene
group is substituted by up to two fluorine atoms and each methyl
group is substituted by up to three fluorine atoms, [0048] (e)
--C(O)--R.sup.3.2.1, [0049] (f) --S(O).sub.2--R.sup.3.2.2, [0050]
R.sup.3.2.1 denotes --O--C.sub.1-3-alkyl, --OH,
--NR.sup.3.2.1.1R.sup.3.2.1.2, [0051] R.sup.3.2.1.1 denotes H,
C.sub.1-3-alkyl, [0052] R.sup.3.2.1.2 denotes H, C.sub.1-3-alkyl,
[0053] R.sup.3.2.1.1 and R.sup.3.2.1.2 together may also form a
ring which is selected from among azetidinyl, pyrrolidinyl,
piperidinyl, piperazinyl and morpholinyl, [0054] R.sup.3.2.2
denotes --NR.sup.3.2,2,1R.sup.3.2,2,2, [0055] R.sup.3.2,2,1 denotes
H, C.sub.1-3-alkyl, [0056] R.sup.3.2,2,2 denotes H,
C.sub.1-3-alkyl, [0057] R.sup.3.2,2,1 and R.sup.3.2,2,2 together
may also form a ring which is selected from among azetidinyl,
pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, [0058]
R.sup.3.3 denotes [0059] (a) H, [0060] (b) halogen, --NH.sub.2,
C.sub.1-4-alkyl-NH, (C.sub.1-4-alkyl).sub.2N,
C.sub.1-3-alkyl-C(O)--NH, C.sub.1-3-alkyl-S(O.sub.2)--NH, --CN,
--OH, --O--C(O)--NH--C.sub.1-3-alkyl, [0061] (c) C.sub.1-4-alkyl,
C.sub.2-4-alkenyl, C.sub.2-4-alkynyl, C.sub.1-3-alkyl-O,
C.sub.1-3-alkyl-S(O).sub.m--, cyclopropyl, [0062] (d) a
C.sub.1-3-alkyl or C.sub.1-3-alkyl-O-- group wherein each methylene
group is substituted by up to two fluorine atoms and each methyl
group is substituted by up to three fluorine atoms, [0063] (e)
--C(O)--R.sup.3.3.1, [0064] (f) --S(O).sub.2--R.sup.3.3.2, [0065]
R.sup.3.3.1 denotes --O--C.sub.1-3-alkyl, --OH,
--NR.sup.3.3.1.1R.sup.3.3.1.2, [0066] R.sup.3.3.1.1 denotes H,
C.sub.1-3-alkyl, [0067] R.sup.3.3.1.2 denotes H, C.sub.1-3-alkyl,
[0068] R.sup.3.3.1.1 and R.sup.3.3.1.2 together may also form a
ring which is selected from among azetidinyl, pyrrolidinyl,
piperidinyl, piperazinyl and morpholinyl, [0069] R.sup.3.3.2
denotes --O--C.sub.1-3alkyl, --NR.sup.3.3.2.1R.sup.3.3.2.2, [0070]
R.sup.3.3.2.1 denotes H, C.sub.1-3-alkyl, [0071] R.sup.3.3.2.2
denotes H, C.sub.1-3-alkyl, [0072] R.sup.3.3.2.1 and R.sup.3.3.2.2
together may also form a ring which is selected from among
azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl,
or [0073] R.sup.3.2 and R.sup.3.3 together with the carbon atoms to
which they are attached form a monounsaturated 5-membered or a
mono- or diunsaturated 6-membered heterocyclic group or a 5- to
6-membered heteroaryl group, while [0074] the above-mentioned
heterocycles may contain a carbonyl, thiocarbonyl or cyanimino
group adjacent to a nitrogen atom, and [0075] may optionally
additionally be substituted at one or two nitrogen atoms by a group
R.sup.3.3.3 in each case and [0076] may optionally each
additionally be substituted at one or two carbon atoms by one or
two groups R.sup.3.3.4, [0077] R.sup.3.3.3 independently of one
another denote [0078] (a) C.sub.1-4-alkyl or [0079] (b)
C.sub.3-6-cycloalkyl, [0080] R.sup.3.3.4 independently of one
another denote [0081] (a) CO.sub.1-4-alkyl or [0082] (b)
C.sub.3-6-cycloalkyl, [0083] (c) halogen, CN, --O--C.sub.1-3-alkyl,
--NH.sub.2, [0084] (d) a C.sub.1-3-alkyl- or C.sub.1-3-alkyl-O--
group wherein each methylene group is substituted by up to two and
each methyl group is substituted by up to three fluorine atoms,
[0085] R.sup.4.1 independently of one another denote [0086] (a) H,
[0087] (b) C.sub.1-6-alkyl, --CN, --OH, --O--C.sub.1-3-alkyl,
[0088] (c) a C.sub.1-3-alkyl- or C.sub.1-3-alkyl-O-- group wherein
each methylene group is substituted by up to two fluorine atoms and
each methyl group is substituted by up to three fluorine atoms,
[0089] R.sup.4.2 denotes H or C.sub.1-6-alkyl, [0090] R.sup.5
independently of one another denote [0091] (a) H, C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, C.sub.3-6-cycloalkyl, [0092]
(b) an aryl group optionally substituted by 1, 2 or 3 substituents
R.sup.5.2, wherein the substituents R.sup.5.2 may be identical or
different, [0093] (c) a heteroaryl group optionally substituted by
1, 2 or 3 substituents R.sup.5.2, wherein the substituents
R.sup.5.2 may be identical or different, [0094] (d) a heterocyclic
group optionally substituted by 1, 2 or 3 substituents R.sup.5.2,
wherein the substituents R.sup.5.2 may be identical or different,
[0095] R.sup.5.1 independently of one another denote [0096] (a) H,
halogen, C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, [0097] (b)
--O--C.sub.1-6-alkylene-NR.sup.7R.sup.8, --O--R.sup.6,
--O--(CH.sub.2).sub.s--O--R.sup.6, --CO.sub.2--R.sup.6,
--C(O)--NR.sup.7R.sup.8, --O--C(O)--NR.sup.7R.sup.8,
--NR.sup.6--C(O)--NR.sup.7R.sup.8, --NR.sup.7--C(O)--R.sup.8,
--NR.sup.7--C(O)--O--R.sup.8, --SO.sub.2--NR.sup.7R.sup.8,
--NR.sup.7--SO.sub.2--R.sup.8, --S(O).sub.m--R.sup.7, --CN,
--NR.sup.7R.sup.8, --NR.sup.6--C(O)--NR.sup.7R.sup.8,
--O--C(O)--R.sup.6, [0098] (c) a C.sub.1-3-alkyl- or
C.sub.1-3-alkyl-O-- group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, [0099] (d) an aryl group
substituted by 1, 2 or 3 substituents R.sup.6, wherein the
substituents R.sup.6 may be identical or different, [0100] (e) a
heteroaryl group substituted by 1, 2 or 3 substituents R.sup.6,
wherein the substituents R.sup.6 may be identical or different,
[0101] (f) a heterocyclic group substituted by 1, 2 or 3
substituents R.sup.6, wherein the substituents R.sup.6 may be
identical or different, [0102] R.sup.5.2 independently of one
another denote [0103] (a) halogen, C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, [0104] (b) --O--R.sup.6,
--O--(CH.sub.2).sub.s--O--R.sup.6, --CO.sub.2R.sup.6,
--C(O)--NR.sup.7R.sup.8, --O--(CO)--NR.sup.7R.sup.8,
--N(R.sup.6)--C(O)--NR.sup.7R.sup.8, --N(R.sup.7)--C(O)--R.sup.8,
--N(R.sup.7)--C(O)--O--R.sup.8, --SO.sub.2--NR.sup.7R.sup.8,
--N(R.sup.7)--SO.sub.2--R.sup.8, --S(O).sub.m--R.sup.7, --CN,
--NR.sup.7R.sup.8, --N(R.sup.6)--C(O)--NR.sup.7R.sup.8,
--O--C(O)--R.sup.6 or [0105] (c) a C.sub.1-3-alkyl group wherein
each methylene group is substituted by up to two fluorine atoms and
each methyl group is substituted by up to three fluorine atoms,
[0106] R.sup.6 denotes [0107] (a) H, [0108] (b) C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, aryl, heteroaryl, benzyl, which may be
substituted by a group R.sup.6.1, or [0109] (c) a C.sub.1-3-alkyl
group wherein each methylene group is substituted by up to two
fluorine atoms and each methyl group is substituted by up to three
fluorine atoms, [0110] R.sup.6.1 denotes halogen, HO-- or
C.sub.1-6-alkyl-O--, [0111] R.sup.7 denotes [0112] (a) H, [0113]
(b) C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, aryl, heteroaryl or
benzyl, while the groups are unsubstituted or may be substituted by
halogen, HO-- or C.sub.1-6-alkyl-O--, or [0114] (c) a
C.sub.1-3-alkyl group wherein each methylene group is substituted
by up to two fluorine atoms and each methyl group is substituted by
up to three fluorine atoms, [0115] R.sup.8 denotes [0116] (a) H,
[0117] (b) C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, aryl, heteroaryl
or benzyl, while the groups are unsubstituted or may be substituted
by halogen, HO-- or C.sub.1-6-alkyl-O--, or [0118] (c) a
C.sub.1-3-alkyl group wherein each methylene group is substituted
by up to two fluorine atoms and each methyl group is substituted by
up to three fluorine atoms, or [0119] R.sup.7 and R.sup.8 together
may also form a ring which is selected from among azetidinyl,
pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, wherein the
ring may be unsubstituted or substituted by 1, 2 or 3 substituents
R.sup.6 or fluorine, wherein the substituents R.sup.6 are
independent of one another, [0120] m denotes one of the numbers 0,
1 or 2, [0121] s denotes one of the numbers 1, 2 or 3, [0122] U
denotes N,N-oxide or C--R.sup.9, [0123] V denotes N,N-oxide or
C--R.sup.10, [0124] X denotes N,N-oxide or CR.sup.11, [0125] Y
denotes N or C--R.sup.12, [0126] while at most three of the
previously mentioned groups U, V, X or Y simultaneously denote a
nitrogen atom, [0127] R.sup.9 denotes [0128] (a) H, [0129] (b) a
C.sub.1-6-alkyl- or C.sub.1-3-alkyl-O-- group which may each be
substituted by a group R.sup.9.1, [0130] (c) R.sup.9.2R.sup.9.3N,
R.sup.9.2R.sup.9.3N--C.sub.1-3-alkylene-, [0131] (d) halogen, --CN,
--OH, --COOH, C.sub.1-3-alkyl-O--C.sub.1-3-alkylene-,
C.sub.3-6-cycloalkyl-, C.sub.3-6-cycloalkyl-C.sub.1-4-alkylene-,
C.sub.1-3-alkyl-C(O)--O--C.sub.1-3-alkylene, [0132] (e) a
C.sub.1-3-alkyl- or C.sub.1-3-alkyl-O-- group wherein each
methylene group is substituted by up to two fluorine atoms and each
methyl group is substituted by up to three fluorine atoms, [0133]
R.sup.9.1 denotes H, OH or --O--CH.sub.3, [0134] R.sup.9.2 denotes
H or C.sub.1-3-alkyl, [0135] R.sup.9.3 denotes H or
C.sub.1-3-alkyl, or [0136] R.sup.9.2 and R.sup.9.3 together with
the nitrogen atom to which they are attached denote a 3- to
6-membered heterocyclic group, [0137] R.sup.10 denotes [0138] (a)
H, [0139] (b) a C.sub.1-6-alkyl or C.sub.1-3-alkyl-O-- group which
may each be substituted by a group R.sup.10.1, [0140] (c)
--NR.sup.10.2R.sup.10.3,
NR.sup.10.2R.sup.10.3--C.sub.1-3-alkylene-, [0141] (d) halogen,
--CN, --OH, C.sub.1-3-alkyl-O--C.sub.1-3-alkylene-,
C.sub.3-6-cycloalkyl-, C.sub.3-6-cycloalkyl-C.sub.1-4-alkylene-,
C.sub.1-3-alkyl-C(O)--O--C.sub.1-3-alkylene, [0142] (e) an
aryl-C.sub.0-3-alkylene-O-- group, [0143] (f) a C.sub.1-3-alkyl or
C.sub.1-3-alkyl-O-- group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, [0144] R.sup.10.1
denotes H, OH or --O--CH.sub.3, [0145] R.sup.10.2 denotes H or
C.sub.1-6-alkyl, [0146] R.sup.10.3 denotes H, C.sub.1-6-alkyl or
--SO.sub.2--C.sub.1-3-alkyl, or [0147] R.sup.10.2 and R.sup.10.3
together with the nitrogen atom to which they are attached denote a
3- to 6-membered heterocyclic group, [0148] R.sup.11 denotes [0149]
(a) H,
[0150] (b) a C.sub.1-6-alkyl or C.sub.1-3-alkyl-O-- group which may
each be substituted by a group R.sup.11.1, [0151] (c)
R.sup.11.2R.sup.11.3N, R.sup.11.2R.sup.11.3N--C.sub.1-3-alkylene,
[0152] (d) halogen, --CN, --OH, --COOH,
C.sub.1-3-alkyl-O--C.sub.1-3-alkylene-, C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyl-C.sub.1-4-alkylene-,
C.sub.1-3-alkyl-C(O)--O--C.sub.1-3-alkylene, [0153] (e) a
C.sub.1-3-alkyl- or C.sub.1-3-alkyl-O-- group wherein each
methylene group is substituted by up to two fluorine atoms and each
methyl group is substituted by up to three fluorine atoms, [0154]
R.sup.11.1 denotes H, OH or --O--CH.sub.3, [0155] R.sup.11.2
denotes H or C.sub.1-3-alkyl, [0156] R.sup.11.3 denotes H or
C.sub.1-3-alkyl, or [0157] R.sup.11.2 and R.sup.11.3 together with
the nitrogen atom to which they are attached denote a 3- to
6-membered heterocyclic group, and [0158] R.sup.12 denotes H,
halogen or C.sub.1-3-alkyl, the tautomers, the diastereomers, the
enantiomers, the hydrates, the mixtures thereof and the salts
thereof as well as the hydrates of the salts, particularly the
physiologically acceptable salts thereof with inorganic or organic
acids or bases.
[0159] A second embodiment of the present invention consists in the
compounds of the above general formula I, wherein U, V, X, Y,
R.sup.2 and R.sup.3 are defined as hereinbefore in the first
embodiment and [0160] R.sup.1 denotes a group of general formula
II
##STR00004##
[0160] wherein [0161] G-L denotes N, N--C(R.sup.4.1).sub.2,
C.dbd.C(R.sup.4.1), C.dbd.N, C(R.sup.4.1),
C(R.sup.4.1)--C(R.sup.4.1).sub.2,
C(R.sup.4.1)--C(R.sup.4.1).sub.2--C(R.sup.4.1).sub.2,
C.dbd.C(R.sup.4.1)--C(R.sup.4.1).sub.2,
C(R.sup.4.1)--C(R.sup.4.1).dbd.C(R.sup.4.1),
C(R.sup.4.1)--C(R.sup.4.1).sub.2--N(R.sup.4.2),
C.dbd.C(R.sup.4.1)--N(R.sup.4.2), C(R.sup.4.1)--C(R.sup.4.1).dbd.N,
C(R.sup.4.1)--N(R.sup.4.2)--C(R.sup.4.1).sub.2,
C.dbd.N--C(R.sup.4.1).sub.2, C(R.sup.4.1)--N.dbd.C(R.sup.4.1),
C(R.sup.4.1)--N(R.sup.4.2)--N(R.sup.4.2), C.dbd.N--N(R.sup.4.2),
N--C(R.sup.4.1).sub.2--C(R.sup.4.1).sub.2,
N--C(R.sup.4.1).dbd.C(R.sup.4.1),
N--C(R.sup.4.1).sub.2--N(R.sup.4.2), N--C(R.sup.4.1).dbd.N,
N--N(R.sup.4.2)--C(R.sup.4.1).sub.2 or N--N.dbd.C(R.sup.4.1),
[0162] Q-T denotes C(R.sup.5).sub.2--C(R.sup.5).sub.2,
C(R.sup.5).dbd.C(R.sup.5), N.dbd.C(R.sup.5),
C(R.sup.5).sub.2--C(.dbd.O), C(.dbd.O)--C(R.sup.5).sub.2,
C(R.sup.5).sub.2--S(O).sub.m or C(R.sup.5).sub.2--N(R.sup.5),
[0163] while a group C(R.sup.5).sub.2 contained in Q-T may also
denote a cyclic group which is selected from among cyclobutyl,
cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, dioxanyl,
morpholinyl, thiomorpholinyl, thiomorpholine-S-oxide,
thiomorpholine-S-dioxide, azetidinyl, pyrrolidinyl, piperidinyl,
tetrahydrofuranyl, tetrahydropyranyl and piperazinyl, or [0164] in
a group C(R.sup.5).sub.2--C(R.sup.5).sub.2,
C(R.sup.5).dbd.C(R.sup.5) or C(R.sup.5).sub.2--N(R.sup.5) contained
in Q-T in each case a group R.sup.5 together with an adjacent group
R.sup.5 and the atoms to which these groups are attached may also
denote a group selected from cyclobutyl, cyclopentyl, cyclohexyl,
cyclopentenyl, cyclohexenyl, dioxanyl, phenyl, naphthyl, thienyl,
thiazolyl, thiazolinyl, oxazolyl, oxazolinyl, imidazolyl,
imidazolinyl, imidazolidinyl, pyridyl, pyrimidyl, pyrazinyl,
pyridazinyl, pyrrolyl, pyrrolinyl, quinolinyl, isoquinolinyl,
morpholinyl, thiomorpholinyl, thiomorpholine-S-oxide,
thiomorpholine-S-dioxide, azetidinyl, pyrrolidinyl, piperidinyl,
tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridyl, furanyl,
dihydrofuranyl, dihydropyranyl and piperazinyl, which may be
substituted independently of one another by 1, 2 or 3 substituents
R.sup.5.1, [0165] R.sup.4.1 denotes [0166] (a) H, [0167] (b)
C.sub.1-6-alkyl, --CN, --OH, --O--C.sub.1-3-alkyl, [0168] (c) a
C.sub.1-3-alkyl- or C.sub.1-3-alkyl-O-- group wherein each
methylene group is substituted by up to two fluorine atoms and each
methyl group is substituted by up to three fluorine atoms, [0169]
R.sup.4.2 denotes H or C.sub.1-6-alkyl, [0170] R.sup.5 denotes
[0171] (a) H, C.sub.1-6-alkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, C.sub.3-6-cycloalkyl, [0172] (b) an aryl group
optionally substituted by 1, 2 or 3 substituents R.sup.5.2, wherein
the substituents R.sup.5.2 may be identical or different, [0173]
(c) a heteroaryl group optionally substituted by 1, 2 or 3
substituents R.sup.5.2, wherein the substituents R.sup.5.2 may be
identical or different, [0174] (d) a heterocyclic group optionally
substituted by 1, 2 or 3 substituents R.sup.5.2, wherein the
substituents R.sup.5.2 may be identical or different, [0175]
R.sup.5.1 denotes [0176] (a) H, halogen, C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, [0177] (b)
--O--C.sub.1-6-alkylene-NR.sup.7R.sup.8, --O--R.sup.6,
--O--(CH.sub.2).sub.s--O--R.sup.6, --CO.sub.2--R.sup.6,
C(O)--NR.sup.7R.sup.8, --O--C(O)--NR.sup.7R.sup.8,
--NR.sup.7--C(O)--NR.sup.7R.sup.8, --NR.sup.7--C(O)--R.sup.8,
--NR.sup.7--C(O)--O--R.sup.8, --SO.sub.2--NR.sup.7R.sup.8,
--NR.sup.7--SO.sub.2--R.sup.8, --S(O).sub.m--R.sup.7, --CN,
--NR.sup.7R.sup.8, --NR.sup.6--C(O)--NR.sup.7R.sup.8,
--O--C(O)--R.sup.6, [0178] (c) a C.sub.1-3-alkyl- or
C.sub.1-3-alkyl-O-- group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, [0179] (d) an aryl group
substituted by 1, 2 or 3 substituents R.sup.6, wherein the
substituents R.sup.6 may be identical or different, [0180] (e) a
heteroaryl group substituted by 1, 2 or 3 substituents R.sup.6,
wherein the substituents R.sup.6 may be identical or different,
[0181] (f) a heterocyclic group substituted by 1, 2 or 3
substituents R.sup.6, wherein the substituents R.sup.6 may be
identical or different, [0182] R.sup.5.2 denotes [0183] (a)
halogen, C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, [0184] (b)
--O--R.sup.6, --O--(CH.sub.2).sub.s--O--R.sup.6, --CO.sub.2R.sup.6,
--C(O)--NR.sup.7R.sup.8, --O--(CO)--NR.sup.7R.sup.8,
--N(R.sup.6)--C(O)--NR.sup.7R.sup.8, --N(R.sup.7)--C(O)--R.sup.8,
--N(R.sup.7)--C(O)--O--R.sup.8, --SO.sub.2--NR.sup.7R.sup.8,
--N(R.sup.7)--SO.sub.2--R.sup.8, --S(O).sub.m--R.sup.7, CN,
NR.sup.7R.sup.8, --N(R.sup.6)--C(O)--NR.sup.7R.sup.8,
--O--C(O)--R.sup.6 or [0185] (c) a C.sub.1-3-alkyl group wherein
each methylene group is substituted by up to two fluorine atoms and
each methyl group is substituted by up to three fluorine atoms,
[0186] R.sup.6 denotes [0187] (a) H, [0188] (b) C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, aryl, heteroaryl, benzyl, which may be
substituted by a group R.sup.6.1, or [0189] (c) a C.sub.1-3-alkyl
group wherein each methylene group is substituted by up to two
fluorine atoms and each methyl group is substituted by up to three
fluorine atoms, [0190] R.sup.6.1 denotes halogen, HO-- or
C.sub.1-6-alkyl-O--, [0191] R.sup.7 denotes [0192] (a) H, [0193]
(b) C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, aryl, heteroaryl or
benzyl, while the groups are unsubstituted or may be substituted by
halogen, HO-- or C.sub.1-6-alkyl-O--, or [0194] (c) a
C.sub.1-3-alkyl group wherein each methylene group is substituted
by up to two fluorine atoms and each methyl group is substituted by
up to three fluorine atoms, [0195] R.sup.8 denotes [0196] (a) H,
[0197] (b) C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, aryl, heteroaryl
or benzyl, while the groups are unsubstituted or may be substituted
by halogen, HO-- or C.sub.1-6-alkyl-O--, or [0198] (c) a
C.sub.1-3-alkyl group wherein each methylene group is substituted
by up to two fluorine atoms and each methyl group is substituted by
up to three fluorine atoms, or [0199] R.sup.7 and R.sup.8 together
may also form a ring which is selected from among azetidinyl,
pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, wherein the
ring may be unsubstituted or substituted by 1, 2 or 3 substituents
R.sup.6 or fluorine, wherein the substituents R.sup.6 are
independent of one another, [0200] m denotes one of the numbers 0,
1 or 2 and [0201] s denotes one of the numbers 1, 2 or 3, the
tautomers, the diastereomers, the enantiomers, the hydrates, the
mixtures thereof and the salts thereof as well as the hydrates of
the salts, particularly the physiologically acceptable salts
thereof with inorganic or organic acids or bases.
[0202] A third embodiment of the present invention consists in the
compounds of the above general formula I, wherein U, V, X, Y,
R.sup.2 and R.sup.3 are defined as hereinbefore in the first
embodiment and [0203] R.sup.1 denotes a group of general
formulae
##STR00005##
[0203] wherein [0204] Q-T denotes
C(R.sup.5).sub.2--C(R.sup.5).sub.2, C(R.sup.5).dbd.C(R.sup.5),
N.dbd.C(R.sup.5), C(R.sup.5).sub.2--C(.dbd.O),
C(.dbd.O)--C(R.sup.5).sub.2, C(R.sup.5).sub.2--S(O).sub.m or
C(R.sup.5).sub.2--N(R.sup.5), [0205] while in a group
C(R.sup.5).sub.2--C(R.sup.5).sub.2, C(R.sup.5).dbd.C(R.sup.5) or
C(R.sup.5).sub.2--N(R.sup.5) contained in Q-T in each case a group
R.sup.5 together with an adjacent group R.sup.5 and the atoms to
which these groups are attached may also denote a group selected
from cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl,
cyclohexenyl, dioxanyl, phenyl, naphthyl, thienyl, thiazolyl,
thiazolinyl, oxazolyl, oxazolinyl, imidazolyl, imidazolinyl,
imidazolidinyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,
pyrrolyl, pyrrolinyl, quinolinyl, isoquinolinyl, morpholinyl,
thiomorpholinyl, thiomorpholine S-oxide, thiomorpholine S-dioxide,
azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl,
tetrahydropyranyl, tetrahydropyridyl, furanyl, dihydrofuranyl,
dihydropyranyl and piperazinyl, which may be substituted
independently of one another by 1, 2 or 3 substituents R.sup.5.1,
[0206] R.sup.4.1 denotes [0207] (a) H, [0208] (b) C.sub.1-6-alkyl,
--CN, --OH, --O--C.sub.1-3-alkyl, [0209] (c) a C.sub.1-3-alkyl- or
C.sub.1-3-alkyl-O-- group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, [0210] R.sup.5
independently of one another denote [0211] (a) H, C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, C.sub.3-6-cycloalkyl, [0212]
(b) an aryl group optionally substituted by 1, 2 or 3 substituents
R.sup.5.2, wherein the substituents R.sup.5.2 may be identical or
different, [0213] (c) a heteroaryl group optionally substituted by
1, 2 or 3 substituents R.sup.5.2, wherein the substituents
R.sup.5.2 may be identical or different, [0214] (d) a heterocyclic
group optionally substituted by 1, 2 or 3 substituents R.sup.5.2,
wherein the substituents R.sup.5.2 may be identical or different,
[0215] R.sup.5.1 denotes [0216] (a) H, halogen, C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, [0217] (b)
--O--C.sub.1-6-alkylene-NR.sup.7R.sup.8, --O--R.sup.6,
--CO.sub.2R.sup.6, --C(O)NR.sup.7R.sup.8,
--SO.sub.2--NR.sup.7R.sup.8, --N(R.sup.7)--SO.sub.2-- R.sup.8,
--S(O).sub.m--R.sup.7, --CN, --NR.sup.7R.sup.8, --O--C(O)--R.sup.6
or [0218] (c) a C.sub.1-3-alkyl group wherein each methylene group
is substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, [0219] R.sup.5.2 denotes
[0220] (a) halogen, C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, [0221]
(b) --O--R.sup.6, --O--(CH.sub.2).sub.s--O--R.sup.6,
--CO.sub.2R.sup.6, --S(O).sub.m--R.sup.7, --CN, --O--C(O)--R.sup.6
or [0222] (c) a C.sub.1-3-alkyl group wherein each methylene group
is substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, [0223] R.sup.6 denotes
[0224] (a) H, [0225] (b) C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl,
aryl, heteroaryl, benzyl, which may be substituted by a group
R.sup.6.1, or [0226] (c) a C.sub.1-3-alkyl group wherein each
methylene group is substituted by up to two fluorine atoms and each
methyl group is substituted by up to three fluorine atoms, [0227]
R.sup.6.1 denotes halogen, HO-- or C.sub.1-6-alkyl-O--, [0228]
R.sup.7 denotes [0229] (a) H, [0230] (b) C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, aryl, heteroaryl, or benzyl, while the groups
are unsubstituted or may be substituted by halogen, HO-- or
C.sub.1-6-alkyl-O--, or [0231] (c) a C.sub.1-3-alkyl group wherein
each methylene group is substituted by up to two fluorine atoms and
each methyl group is substituted by up to three fluorine atoms,
[0232] R.sup.8 denotes [0233] (a) H, [0234] (b) C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, aryl, heteroaryl, or benzyl, while the groups
are unsubstituted or may be substituted by halogen, HO-- or
C.sub.1-6-alkyl-O--, or [0235] (c) a C.sub.1-3-alkyl group wherein
each methylene group is substituted by up to two fluorine atoms and
each methyl group is substituted by up to three fluorine atoms, or
[0236] R.sup.7 and R.sup.8 together may also form a ring which is
selected from among azetidinyl, pyrrolidinyl, piperidinyl,
piperazinyl and morpholinyl, wherein the ring may be unsubstituted
or substituted by 1, 2 or 3 substituents R.sup.6, wherein the
substituents R.sup.6 are independent of one another, [0237] m
denotes one of the numbers 0, 1 or 2 and [0238] s denotes one of
the numbers 1, 2 or 3, the tautomers, the diastereomers, the
enantiomers, the hydrates, the mixtures thereof and the salts
thereof as well as the hydrates of the salts, particularly the
physiologically acceptable salts thereof with inorganic or organic
acids or bases.
[0239] A fourth embodiment of the present invention consists in the
compounds of the above general formula I, wherein U, V, X, Y,
R.sup.2 and R.sup.3 are defined as hereinbefore in the first
embodiment and [0240] R.sup.1 denotes a group of general
formulae
##STR00006##
[0240] wherein [0241] Q-T denotes
C(R.sup.5).sub.2--C(R.sup.5).sub.2, C(R.sup.5).dbd.C(R.sup.5),
N.dbd.C(R.sup.5), C(R.sup.5).sub.2--C(.dbd.O),
C(.dbd.O)--C(R.sup.5).sub.2, C(R.sup.5).sub.2--S(O).sub.m or
C(R.sup.5).sub.2--N(R.sup.5), [0242] while in a group
C(R.sup.5).sub.2--C(R.sup.5).sub.2, C(R.sup.5).dbd.C(R.sup.5) or
C(R.sup.5).sub.2--N(R.sup.5) contained in Q-T in each case a group
R.sup.5 together with an adjacent group R.sup.5 and the atoms to
which these groups are attached may also denote a group selected
from cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl,
dioxanyl, phenyl, naphthyl, thienyl, pyridyl, pyrazinyl,
pyridazinyl, quinolinyl, isoquinolinyl, morpholinyl, pyrrolidinyl,
piperidinyl, tetrahydrofuranyl, tetrahydropyranyl and piperazinyl,
which may be substituted independently of one another by 1, 2 or 3
substituents R.sup.5.1, R.sup.4.1 denotes [0243] (a) H, [0244] (b)
C.sub.1-6-alkyl, --CN, --OH, --O--C.sub.1-3-alkyl, [0245] (c) a
C.sub.1-3-alkyl- or C.sub.1-3-alkyl-O-- group wherein each
methylene group is substituted by up to two fluorine atoms and each
methyl group is substituted by up to three fluorine atoms, [0246]
R.sup.5 independently of one another denote [0247] (a) H,
C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, [0248] (b) an aryl group
optionally substituted by 1, 2 or 3 substituents R.sup.5.2, wherein
the substituents R.sup.5.2 may be identical or different, [0249]
(c) a heteroaryl group optionally substituted by 1, 2 or 3
substituents R.sup.5.2, wherein the substituents R.sup.5.2 may be
identical or different, [0250] (d) a heterocyclic group optionally
substituted by 1, 2 or 3 substituents R.sup.5.2, wherein the
substituents R.sup.5.2 may be identical or different, [0251]
R.sup.5.1 denotes [0252] (a) H, halogen, C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, [0253] (b)
--O--C.sub.1-6-alkylene-NR.sup.7R.sup.8, --O--R.sup.6,
--CO.sub.2R.sup.6, --C(O)--NR.sup.7R.sup.8,
--SO.sub.2--NR.sup.7R.sup.8, --NR.sup.7--SO.sub.2--R.sup.8,
--S(O).sub.m--R.sup.7, --CN, --NR.sup.7R.sup.8, --O--C(O)--R.sup.6
or [0254] (c) a C.sub.1-3-alkyl group wherein each methylene group
is substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, [0255] R.sup.5.2 denotes
[0256] (a) halogen, C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, [0257]
(b) --O--R.sup.6, --O--(CH.sub.2).sub.s--OR.sup.6,
--CO.sub.2R.sup.6, --S(O).sub.m--R.sup.6, --CN, --O--C(O)--R.sup.6
or [0258] (c) a C.sub.1-3-alkyl group wherein each methylene group
is substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, [0259] R.sup.6 denotes
[0260] (a) H, [0261] (b) C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl,
aryl, heteroaryl, benzyl, which may be substituted by a group
R.sup.6.1, or [0262] (c) a C.sub.1-3-alkyl group wherein each
methylene group is substituted by up to two fluorine atoms and each
methyl group is substituted by up to three fluorine atoms, [0263]
R.sup.6.1 denotes halogen, HO-- or C.sub.1-6-alkyl-O--, [0264]
R.sup.7 denotes [0265] (a) H, [0266] (b) C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, aryl, heteroaryl, or benzyl, while the groups
are unsubstituted or may be substituted by halogen, HO-- or
C.sub.1-6-alkyl-O--, or [0267] (c) a C.sub.1-3-alkyl group wherein
each methylene group is substituted by up to two fluorine atoms and
each methyl group is substituted by up to three fluorine atoms,
[0268] R.sup.8 denotes [0269] (a) H, [0270] (b) C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, aryl, heteroaryl, or benzyl, while the groups
are unsubstituted or may be substituted by halogen, HO-- or
C.sub.1-6-alkyl-O--, or [0271] (c) a C.sub.1-3-alkyl group wherein
each methylene group is substituted by up to two fluorine atoms and
each methyl group is substituted by up to three fluorine atoms, or
[0272] R.sup.7 and R.sup.8 together may also form a ring which is
selected from among azetidinyl, pyrrolidinyl, piperidinyl,
piperazinyl and morpholinyl, wherein the ring may be unsubstituted
or substituted by 1, 2 or 3 substituents R.sup.6, wherein the
substituents R.sup.6 are independent of one another, [0273] m
denotes one of the numbers 0, 1 or 2 and [0274] s denotes one of
the numbers 1, 2 or 3, the tautomers, the diastereomers, the
enantiomers, the hydrates, the mixtures thereof and the salts
thereof as well as the hydrates of the salts, particularly the
physiologically acceptable salts thereof with inorganic or organic
acids or bases.
[0275] A fifth embodiment of the present invention consists in the
compounds of the above general formula I, wherein U, V, X, Y,
R.sup.2 and R.sup.3 are defined as hereinbefore in the first
embodiment and [0276] R.sup.1 denotes a group of general
formula
##STR00007## ##STR00008##
[0276] wherein [0277] R.sup.4.1 denotes [0278] (a) H, [0279] (b)
C.sub.1-3-alkyl, --OH, --O--C.sub.1-3-alkyl, [0280] (c) a
C.sub.1-3-alkyl- or C.sub.1-3-alkyl-O-- group wherein each
methylene group is substituted by up to two fluorine atoms and each
methyl group is substituted by up to three fluorine atoms, [0281]
R.sup.5 denotes [0282] (a) H, C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, [0283] (b) a phenyl group optionally
substituted by 1, 2, or 3 substituents R.sup.5.2, wherein the
substituents R.sup.5.2 may be identical or different, [0284] (c) a
heteroaryl group optionally substituted by 1, 2 or 3 substituents
R.sup.5.2 which is selected from among benzimidazole,
benzothiophene, furan, imidazole, indole, isoxazole, oxazole,
pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,
thiazole, thiophene and triazole, wherein the substituents
R.sup.5.2 may be identical or different, [0285] (d) a heterocyclic
group optionally substituted by 1, 2 or 3 substituents R.sup.5.2,
wherein the substituents R.sup.5.2 may be identical or different,
[0286] R.sup.5.1 denotes [0287] (a) H, halogen, C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, [0288] (b)
--O--C.sub.1-6-alkylene-NR.sup.7R.sup.8, --O--R.sup.6,
--CO.sub.2R.sup.6, --C(O)--NR.sup.7R.sup.8,
--SO.sub.2--NR.sup.7R.sup.8, --NR.sup.7--SO.sub.2--R.sup.8,
--S(O).sub.m--R.sup.7, --CN, --NR.sup.7R.sup.8, --O--C(O)--R.sup.6
or [0289] (c) a C.sub.1-3-alkyl or C.sub.1-3-alkyl-O-- group
wherein each methylene group is substituted by up to two fluorine
atoms and each methyl group is substituted by up to three fluorine
atoms, [0290] R.sup.5.2 denotes [0291] (a) halogen,
C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, [0292] (b) --O--R.sup.6,
--O--(CH.sub.2).sub.s--O--R.sup.6, --CO.sub.2R.sup.6,
--S(O).sub.m--R.sup.6, --CN, --O--C(O)--R.sup.6 or [0293] (c) a
C.sub.1-3-alkyl group wherein each methylene group is substituted
by up to two fluorine atoms and each methyl group is substituted by
up to three fluorine atoms, [0294] R.sup.6 denotes [0295] (a) H,
[0296] (b) C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, aryl, heteroaryl,
benzyl, which may be substituted by a group R.sup.6.1, or [0297]
(c) a C.sub.1-3-alkyl group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, [0298] R.sup.6.1 denotes
HO-- or C.sub.1-6-alkyl-O--, [0299] R.sup.7 denotes [0300] (a) H,
[0301] (b) C.sub.1-3-alkyl, phenyl or benzyl, while the groups are
unsubstituted or may be substituted by halogen, HO-- or
H.sub.3C--O--, [0302] R.sup.8 denotes [0303] (a) H, [0304] (b)
C.sub.1-3-alkyl, phenyl or benzyl, while the groups are
unsubstituted or may be substituted by halogen, HO-- or
H.sub.3C--O--, or [0305] R.sup.7 and R.sup.8 together may also form
a ring which is selected from among azetidinyl, pyrrolidinyl,
piperidinyl, piperazinyl and morpholinyl, while the ring may be
unsubstituted or substituted by a substituent R.sup.6, [0306] m
denotes one of the numbers 0, 1 or 2, and [0307] s denotes one of
the numbers 1, 2 or 3, the tautomers, the diastereomers, the
enantiomers, the hydrates, the mixtures thereof and the salts
thereof as well as the hydrates of the salts, particularly the
physiologically acceptable salts thereof with inorganic or organic
acids or bases.
[0308] A sixth embodiment of the present invention consists in the
compounds of the above general formula I, wherein U, V, X, Y,
R.sup.2 and R.sup.3 are defined as hereinbefore in the first
embodiment and [0309] R.sup.1 denotes a group selected from
##STR00009##
[0309] the tautomers, the diastereomers, the enantiomers, the
hydrates, the mixtures thereof and the salts thereof as well as the
hydrates of the salts, particularly the physiologically acceptable
salts thereof with inorganic or organic acids or bases.
[0310] A seventh embodiment of the present invention consists in
the compounds of the above general formula I, wherein U, V, X, Y,
R.sup.1 and R.sup.3 are as hereinbefore defined in the first,
second, third, fourth, fifth or sixth embodiment and R.sup.2
denotes a hydrogen atom,
the tautomers, the diastereomers, the enantiomers, the hydrates,
the mixtures thereof and the salts thereof as well as the hydrates
of the salts, particularly the physiologically acceptable salts
thereof with inorganic or organic acids or bases.
[0311] An eighth embodiment of the present invention consists in
the compounds of the above general formula I, wherein U, V, X, Y,
R.sup.1 and R.sup.2 are as hereinbefore defined in the first,
second, third, fourth, fifth, sixth or seventh embodiment and
[0312] R.sup.3 denotes a group of general formula III
[0312] ##STR00010## [0313] A independently of one another denote CH
or N, [0314] R.sup.3.1 denotes [0315] (a) H, [0316] (b) halogen,
--NH.sub.2, C.sub.1-4-alkyl-NH, (C.sub.1-4-alkyl).sub.2N,
C.sub.1-3-alkyl-C(O)--NH--, C.sub.1-3-alkyl-S(O).sub.2--NH--, --CN,
--OH, --O--C(O)--NH--C.sub.1-3-alkyl, [0317] (c) C.sub.1-4-alkyl,
R.sup.3.1.1--C.sub.1-3-alkylene, C.sub.2-4-alkenyl,
C.sub.2-4-alkynyl, C.sub.1-3-alkyl-O--, C.sub.1-3-alkyl-S--, [0318]
(d) a C.sub.1-3-alkyl- or C.sub.1-3-alkyl-O-- group wherein each
methylene group is substituted by up to two fluorine atoms and each
methyl group is substituted by up to three fluorine atoms, [0319]
(e) --C(O)--R.sup.3.1.2, [0320] (f) --S(O).sub.2--R.sup.3.1.3,
[0321] R.sup.3.1.1 denotes [0322] (a) H, [0323] (b)
C.sub.3-6-cycloalkyl, C.sub.5-6-cycloalkenyl, [0324] (c)
(R.sup.3.1.1.1).sub.2N--, [0325] (d) a saturated, mono- or
diunsaturated 5- or 6-membered heterocyclic group, which is
substituted at a nitrogen atom by a group R.sup.3.1.1.1 and at a
carbon atom by one or two groups R.sup.3.1.1.2, or [0326] (e) a
heteroaryl group which is substituted at a carbon atom by a group
R.sup.3.1.1.2, [0327] R.sup.3.1.1.1 independently of one another
denote [0328] (a) H, C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl, [0329]
(b) heterocyclyl, [0330] (c) aryl-C.sub.0-3-alkylene or
heteroaryl-C.sub.0-3-alkylene, [0331] R.sup.3.1.1.2 independently
of one another denote [0332] (a) H, F, C.sub.1-3-alkyl, --CN, --OH,
--O--C.sub.1-3-alkyl, --CO(O)R.sup.3.1.1.2.1, H.sub.2N,
(C.sub.1-4-alkyl)-NH--, (C.sub.1-4-alkyl).sub.2N--, [0333] (b)
phenyl or phenyl-CH.sub.2--, [0334] (c) a C.sub.1-3-alkyl or
--O--C.sub.1-3-alkyl group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, or [0335]
R.sup.3.1.1.2.1 denotes H, C.sub.1-6-alkyl, benzyl, [0336]
R.sup.3.1.2 denotes --O--C.sub.1-3-alkyl, --OH,
--NR.sup.3.1.2.1R.sup.3.1.2.2, [0337] R.sup.3.1.2.1 denotes H,
C.sub.1-3-alkyl, [0338] R.sup.3.1.2.2 denotes H, C.sub.1-3-alkyl,
[0339] R.sup.3.1.3 denotes --NR.sup.3.1.3.1R.sup.3.1.3.2, [0340]
R.sup.3.1.3.1 denotes H, C.sub.1-3-alkyl, [0341] R.sup.3.1.3.2
denotes H, C.sub.1-3-alkyl, [0342] R.sup.3.2 denotes [0343] (a) H,
[0344] (b) halogen, --NH.sub.2, C.sub.1-4-alkyl-NH--,
(C.sub.1-4-alkyl).sub.2N--, C.sub.1-3-alkyl-C(O)--NH--,
C.sub.1-3-alkyl-S(O).sub.2--NH--, --CN, --OH,
--O--C(O)--NH--C.sub.1-3-alkyl, [0345] (c) C.sub.1-4-alkyl,
C.sub.2-4-alkenyl, C.sub.2-4-alkynyl, C.sub.1-3-alkyl-O,
C.sub.1-3-alkyl-S--, [0346] (d) a C.sub.1-3-alkyl- or
C.sub.1-3-alkyl-O-- group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, [0347] (e)
--C(O)--R.sup.3.2.1, [0348] (f) --S(O).sub.2--R.sup.3.2.2, [0349]
R.sup.3.2.1 denotes --O--C.sub.1-3-alkyl, --OH,
--NR.sup.3.2.1.1R.sup.3.2.1.2, [0350] R.sup.3.2.1.1 denotes H,
C.sub.1-3-alkyl, [0351] R.sup.3.2.1.2 denotes H, C.sub.1-3-alkyl,
[0352] R.sup.3.2.2 denotes --NR.sup.3.2,2,1R.sup.3.2,2,2, [0353]
R.sup.3.2,2,1 denotes H, C.sub.1-3-alkyl, [0354] R.sup.3.2,2,2
denotes H, C.sub.1-3-alkyl, [0355] R.sup.3.3 denotes [0356] (a) H,
[0357] (b) halogen, --NH.sub.2, C.sub.1-4-alkyl-NH--,
(C.sub.1-4-alkyl).sub.2N, C.sub.1-3-alkyl-C(O)--NH--,
C.sub.1-3-alkyl-S(O).sub.2--NH, --CN, --OH,
--O--C(O)--NH--C.sub.1-3-alkyl, [0358] (c) C.sub.1-4-alkyl,
C.sub.2-4-alkenyl, C.sub.2-4-alkynyl, C.sub.1-3-alkyl-O--,
C.sub.1-3-alkyl-S--, [0359] (d) a C.sub.1-3-alkyl or
C.sub.1-3-alkyl-O-- group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, [0360] (e)
--C(O)--R.sup.3.3.1, [0361] (f) --S(O).sub.2--R.sup.3.3.2, [0362]
R.sup.3.3.1 denotes --O--C.sub.1-3-alkyl, --OH,
--NR.sup.3.3.1.1R.sup.3.3.1.2, [0363] R.sup.3.3.1.1 denotes H,
C.sub.1-3-alkyl, [0364] R.sup.3.3.1.2 denotes H, C.sub.1-3-alkyl,
[0365] R.sup.3.3.2 denotes --O--C.sub.1-3alkyl,
--NR.sup.3.3.2.1R.sup.3.3.2.2, [0366] R.sup.3.3.2.1 denotes H,
C.sub.1-3-alkyl, [0367] R.sup.3.3.2.2 denotes H, C.sub.1-3-alkyl,
or [0368] R.sup.3.2 and R.sup.3.3 together with the carbon atoms to
which they are attached form a monounsaturated 5-membered or a
mono- or diunsaturated 6-membered heterocyclic group or a 5- to
6-membered heteroaryl group, while [0369] the heterocycles
mentioned previously may contain a carbonyl, thiocarbonyl or
cyanimino group adjacent to a nitrogen atom, and [0370] may
optionally each additionally be substituted at one or two nitrogen
atoms by a group R.sup.3.3.3 and [0371] may optionally each
additionally be substituted at one or two carbon atoms by one or
two groups R.sup.3.3.4, [0372] R.sup.3.3.3 independently of one
another denote [0373] (a) C.sub.1-4-alkyl or [0374] (b)
C.sub.3-6-cycloalkyl, and [0375] R.sup.3.3.4 independently of one
another denote [0376] (a) C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl,
[0377] (b) halogen, CN, C.sub.1-3-alkyl-O--, --NH.sub.2, [0378] (c)
a C.sub.1-3-alkyl or C.sub.1-3-alkyl-O-- group wherein each
methylene group is substituted by up to two fluorine atoms and each
methyl group is substituted by up to three fluorine atoms, the
tautomers, the diastereomers, the enantiomers, the hydrates, the
mixtures thereof and the salts thereof as well as the hydrates of
the salts, particularly the physiologically acceptable salts
thereof with inorganic or organic acids or bases.
[0379] A ninth embodiment of the present invention consists in the
compounds of the above general formula I, wherein U, V, X, Y,
R.sup.1 and R.sup.2 are as hereinbefore defined in the first,
second, third, fourth, fifth, sixth or seventh embodiment and
[0380] R.sup.3 denotes a group of general formulae III
[0380] ##STR00011## [0381] A independently of one another denotes
CH or N, [0382] R.sup.3.1 denotes [0383] (a) H, [0384] (b) halogen,
--NH.sub.2, C.sub.1-4-alkyl-NH--, (C.sub.1-4-alkyl).sub.2N--,
C.sub.1-3-alkyl-C(O)--NH, --CN, --OH,
--O--C(O)--NH--C.sub.1-3-alkyl, [0385] (c) C.sub.1-4-alkyl,
C.sub.2-4-alkenyl, C.sub.2-4-alkynyl, C.sub.1-3-alkyl-O--,
C.sub.1-3-alkyl-S--, [0386] (d) a C.sub.1-3-alkyl or
C.sub.1-3-alkyl-O-- group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, [0387] R.sup.3.2 denotes
[0388] (a) H, [0389] (b) halogen, --NH.sub.2, C.sub.1-4-alkyl-NH--,
(C.sub.1-4-alkyl).sub.2N--, C.sub.1-3-alkyl-C(O)--NH--, --CN, --OH,
--O--C(O)--NH--C.sub.1-3-alkyl, [0390] (c) C.sub.1-4-alkyl,
C.sub.2-4-alkenyl, C.sub.2-4-alkynyl, C.sub.1-3-alkyl-O--,
C.sub.1-3-alkyl-S--, [0391] (d) a C.sub.1-3-alkyl or
C.sub.1-3-alkyl-O-- group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, [0392] R.sup.3.3 denotes
[0393] (a) H, [0394] (b) halogen, --NH.sub.2, C.sub.1-4-alkyl-NH,
(C.sub.1-4-alkyl).sub.2N, C.sub.1-3-alkyl-C(O)--NH, --CN, --OH,
--O--C(O)--NH--C.sub.1-3-alkyl, [0395] (c) C.sub.1-4-alkyl,
C.sub.2-4-alkenyl, C.sub.2-4-alkynyl, C.sub.1-3-alkyl-O,
C.sub.1-3-alkyl-S--, [0396] (d) a C.sub.1-3-alkyl- or
C.sub.1-3-alkyl-O-- group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, [0397] R.sup.3.2 and
R.sup.3.3 together with the carbon atoms to which they are attached
form a monounsaturated 5-membered or a mono- or diunsaturated
6-membered heterocyclic group or a 5- to 6-membered heteroaryl
group, while [0398] the heterocycles mentioned previously may
contain a carbonyl, thiocarbonyl or cyanimino group adjacent to a
nitrogen atom, and [0399] may optionally each additionally be
substituted at one or two nitrogen atoms by a group R.sup.3.3.3 and
[0400] may optionally each additionally be substituted at one or
two carbon atoms by one or two groups R.sup.3.3.4, [0401]
R.sup.3.3.3 independently of one another denote [0402] (a)
C.sub.1-4-alkyl or [0403] (b) C.sub.3-6-cycloalkyl, and [0404]
R.sup.3.3.4 independently of one another denote [0405] (a)
C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl, [0406] (b) halogen, CN,
C.sub.1-3-alkyl-O--, --NH.sub.2, [0407] (c) a C.sub.1-3-alkyl or
C.sub.1-3-alkyl-O-- group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, the tautomers, the
diastereomers, the enantiomers, the hydrates, the mixtures thereof
and the salts thereof as well as the hydrates of the salts,
particularly the physiologically acceptable salts thereof with
inorganic or organic acids or bases.
[0408] A tenth embodiment of the present invention consists in the
compounds of the above general formula I, wherein U, V, X, Y,
R.sup.1 and R.sup.2 are as hereinbefore defined in the first,
second, third, fourth, fifth, sixth or seventh embodiment and
[0409] R.sup.3 denotes a group of general formulae III
[0409] ##STR00012## [0410] R.sup.3.1 denotes [0411] (a) H, [0412]
(b) F, Cl, Br, --NH.sub.2, C.sub.1-3-alkyl-NH,
(C.sub.1-3-alkyl).sub.2N, C.sub.1-3-alkyl-C(O)--NH, --CN, --OH,
[0413] (c) C.sub.1-4-alkyl, C.sub.2-4-alkenyl, C.sub.2-4-alkynyl,
C.sub.1-3-alkyl-O--, C.sub.1-3-alkyl-S--, [0414] (d) a
C.sub.1-3-alkyl or C.sub.1-3-alkyl-O-- group wherein each methylene
group is substituted by up to two fluorine atoms and each methyl
group is substituted by up to three fluorine atoms, [0415]
R.sup.3.2 denotes [0416] (a) H, [0417] (b) F, Cl, Br, H.sub.2N--,
(C.sub.1-4-alkyl)-NH--, (C.sub.1-4-alkyl).sub.2N--,
(C.sub.1-3-alkyl)-C(O)--NH--, --OH, [0418] (c) C.sub.1-4-alkyl,
[0419] (d) a C.sub.1-3-alkyl- or C.sub.1-3-alkyl-O-- group wherein
each methylene group is substituted by up to two fluorine atoms and
each methyl group is substituted by up to three fluorine atoms,
[0420] R.sup.3.3 denotes [0421] (a) H, [0422] (b) F, Cl, Br,
H.sub.2N--, (C.sub.1-4-alkyl)-NH--, (C.sub.1-4-alkyl).sub.2N--,
(C.sub.1-3-alkyl)-C(O)--NH--, --OH, [0423] (c) C.sub.1-4-alkyl,
[0424] (d) a C.sub.1-3-alkyl- or C.sub.1-3-alkyl-O-- group wherein
each methylene group is substituted by up to two fluorine atoms and
each methyl group is substituted by up to three fluorine atoms,
[0425] R.sup.3.2 and R.sup.3.3 together with the carbon atoms to
which they are attached form a monounsaturated 5-membered or a
mono- or diunsaturated 6-membered heterocyclic group or a 5- to
6-membered heteroaryl group, while [0426] the heterocycles
mentioned previously may contain a carbonyl, thiocarbonyl or
cyanimino group adjacent to a nitrogen atom, and [0427] may
optionally each additionally be substituted at one or two nitrogen
atoms by a group R.sup.3.3.3 and [0428] may optionally each
additionally be substituted at one or two carbon atoms by one or
two groups R.sup.3.3.4, [0429] R.sup.3.3.3 independently of one
another denote [0430] (a) C.sub.1-4-alkyl or [0431] (b)
C.sub.3-6-cycloalkyl, and [0432] R.sup.3.3.4 independently of one
another denote [0433] (a) C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl,
[0434] (b) halogen, CN, C.sub.1-3-alkyl-O--, --NH.sub.2, [0435] (c)
a C.sub.1-3-alkyl or C.sub.1-3-alkyl-O-- group wherein each
methylene group is substituted by up to two fluorine atoms and each
methyl group is substituted by up to three fluorine atoms, the
tautomers, the diastereomers, the enantiomers, the hydrates, the
mixtures thereof and the salts thereof as well as the hydrates of
the salts, particularly the physiologically acceptable salts
thereof with inorganic or organic acids or bases.
[0436] An eleventh embodiment of the present invention consists in
the compounds of the above general formula I, wherein U, V, X, Y,
R.sup.1 and R.sup.2 are as hereinbefore defined in the first,
second, third, fourth, fifth, sixth or seventh embodiment and
[0437] R.sup.3 denotes a group selected from
##STR00013## ##STR00014##
[0437] the tautomers, the diastereomers, the enantiomers, the
hydrates, the mixtures thereof and the salts thereof as well as the
hydrates of the salts, particularly the physiologically acceptable
salts thereof with inorganic or organic acids or bases.
[0438] A twelfth embodiment of the present invention consists in
the compounds of the above general formula I, wherein U, V, X, Y,
R.sup.1 and R.sup.2 are as hereinbefore defined in the first,
second, third, fourth, fifth, sixth or seventh embodiment and
[0439] R.sup.3 denotes a group of general formulae III
[0439] ##STR00015## [0440] R.sup.3.1 denotes [0441] (a) H, [0442]
(b) F, Cl, Br, --NH.sub.2, C.sub.1-3-alkyl-NH,
(C.sub.1-3-alkyl).sub.2N, C.sub.1-3-alkyl-C(O)--NH, --CN, --OH,
[0443] (c) C.sub.1-4-alkyl, C.sub.2-4-alkenyl, C.sub.2-4-alkynyl,
C.sub.1-3-alkyl-O--, C.sub.1-3-alkyl-S--, [0444] (d) a
C.sub.1-3-alkyl or C.sub.1-3-alkyl-O-- group wherein each methylene
group is substituted by up to two fluorine atoms and each methyl
group is substituted by up to three fluorine atoms, [0445]
R.sup.3.2 and R.sup.3.3 together with the carbon atoms to which
they are attached form a monounsaturated 5-membered heterocyclic
group or a mono- or diunsaturated 6-membered heterocyclic group or
a 5- to 6-membered heteroaryl group, while [0446] the heterocycles
mentioned previously may contain a carbonyl, thiocarbonyl or
cyanimino group adjacent to a nitrogen atom, and [0447] may
optionally each additionally be substituted at one or two nitrogen
atoms by a group R.sup.3.3.3 and [0448] may optionally each
additionally be substituted at one or two carbon atoms by one or
two groups R.sup.3.3.4, [0449] R.sup.3.3.3 independently of one
another denote [0450] (a) C.sub.1-4-alkyl or [0451] (b)
C.sub.3-6-cycloalkyl, and [0452] R.sup.3.3.4 independently of one
another denote [0453] (a) C.sub.1-4-alkyl-, C.sub.3-6-cycloalkyl-,
[0454] (b) halogen, --CN, --O--C.sub.1-3-alkyl, --NH.sub.2, [0455]
(c) a C.sub.1-3-alkyl- or C.sub.1-3-alkyl-O-- group wherein each
methylene group is substituted by up to two fluorine atoms and each
methyl group is substituted by up to three fluorine atoms, the
tautomers, the diastereomers, the enantiomers, the hydrates, the
mixtures thereof and the salts thereof as well as the hydrates of
the salts, particularly the physiologically acceptable salts
thereof with inorganic or organic acids or bases.
[0456] A thirteenth embodiment of the present invention consists in
the compounds of the above general formula I, wherein U, V, X, Y,
R.sup.1 and R.sup.2 are as hereinbefore defined in the first,
second, third, fourth, fifth, sixth or seventh embodiment and
[0457] R.sup.3 denotes a group of general formulae III
[0457] ##STR00016## [0458] R.sup.3.1 denotes [0459] (a) H, [0460]
(b) F, Cl, Br, --NH.sub.2, C.sub.1-3-alkyl-NH--,
(C.sub.1-3-alkyl).sub.2N--, C.sub.1-3-alkyl-C(O)--NH--, --CN, --OH,
[0461] (c) C.sub.1-4-alkyl, C.sub.2-4-alkenyl, C.sub.2-4-alkynyl,
C.sub.1-3-alkyl-O--, C.sub.1-3-alkyl-S--, [0462] (d) a
C.sub.1-3-alkyl- or C.sub.1-3-alkyl-O-- group wherein each
methylene group is substituted by up to two fluorine atoms and each
methyl group is substituted by up to three fluorine atoms, [0463]
R.sup.3.2 and R.sup.3.3 together with the carbon atoms to which
they are attached form a monounsaturated 5-membered heterocyclic
group or a 5-membered heteroaryl group, wherein [0464] the
heterocycles mentioned previously may contain a carbonyl,
thiocarbonyl or cyanimino group adjacent to a nitrogen atom, and
[0465] may optionally each additionally be substituted at one or
two nitrogen atoms by a group R.sup.3.3.3 and [0466] may optionally
each additionally be substituted at one or two carbon atoms by one
or two groups R.sup.3.3.4, [0467] R.sup.3.3.3 independently of one
another denote [0468] (a) C.sub.1-4-alkyl or [0469] (b)
C.sub.3-6-cycloalkyl, and [0470] R.sup.3.3.4 independently of one
another denote [0471] (a) C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl,
[0472] (b) halogen, --CN, --O--C.sub.1-3-alkyl, --NH.sub.2, [0473]
(c) a C.sub.1-3-alkyl- or C.sub.1-3-alkyl-O-- group wherein each
methylene group is substituted by up to two fluorine atoms and each
methyl group is substituted by up to three fluorine atoms, the
tautomers, the diastereomers, the enantiomers, the hydrates, the
mixtures thereof and the salts thereof as well as the hydrates of
the salts, particularly the physiologically acceptable salts
thereof with inorganic or organic acids or bases.
[0474] A fourteenth embodiment of the present invention consists in
the compounds of the above general formula I, wherein U, V, X, Y,
R.sup.1 and R.sup.2 are as hereinbefore defined in the first,
second, third, fourth, fifth, sixth or seventh embodiment and
[0475] R.sup.3 denotes a group of general formula IIIa
[0475] ##STR00017## [0476] T denotes O, S, CH.sub.2, NH or
N--R.sup.3.3.3, [0477] R.sup.3.1 denotes [0478] (a) H, [0479] (b)
F, Cl, Br, --NH.sub.2, C.sub.1-3-alkyl-NH--,
(C.sub.1-3-alkyl).sub.2N--, C.sub.1-3-alkyl-C(O)--NH--, --CN, --OH,
[0480] (c) C.sub.1-4-alkyl, C.sub.2-4-alkenyl, C.sub.2-4-alkynyl,
C.sub.1-3-alkyl-O--, C.sub.1-3-alkyl-S--, [0481] (d) a
C.sub.1-3-alkyl- or C.sub.1-3-alkyl-O-- group wherein each
methylene group is substituted by up to two fluorine atoms and each
methyl group is substituted by up to three fluorine atoms, and
[0482] R.sup.3.3.3 independently of one another denote [0483] (a)
C.sub.1-4-alkyl or [0484] (b) C.sub.3-6-cycloalkyl, the tautomers,
the diastereomers, the enantiomers, the hydrates, the mixtures
thereof and the salts thereof as well as the hydrates of the salts,
particularly the physiologically acceptable salts thereof with
inorganic or organic acids or bases.
[0485] A fifteenth embodiment of the present invention consists in
the compounds of the above general formula I, wherein U, V, X, Y,
R.sup.1 and R.sup.2 are as hereinbefore defined in the first,
second, third, fourth, fifth, sixth or seventh embodiment and
[0486] R.sup.3 denotes a group selected from
##STR00018##
[0486] the tautomers, the diastereomers, the enantiomers, the
hydrates, the mixtures thereof and the salts thereof as well as the
hydrates of the salts, particularly the physiologically acceptable
salts thereof with inorganic or organic acids or bases.
[0487] A sixteenth embodiment of the present invention consists in
the compounds of the above general formula I, wherein Y, R.sup.1,
R.sup.2 and R.sup.3 are as hereinbefore defined in the first,
second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth,
eleventh, twelfth, thirteenth, fourteenth or fifteenth embodiment
and [0488] U-V-X denotes a group selected from [0489]
--N.dbd.N--(C--R.sup.11).dbd., --N.dbd.(C--R.sup.10)--N.dbd.,
--N.dbd.(C--R.sup.10)--(C--R.sup.11).dbd.,
--(N-oxide)=(C--R.sup.10)--(C--R.sup.11).dbd.,
--(CR.sup.9).dbd.N--N.dbd., --(CR.sup.9).dbd.N--(CR.sup.11).dbd.,
--(C--R.sup.9).dbd.N(oxide)-(C--R.sup.11).dbd.,
--(CR.sup.9).dbd.(C--R.sup.10)--N.dbd.,
--(CR.sup.9).dbd.(C--R.sup.10)--(N-oxide).dbd.,
--(CR.sup.9).dbd.(C--R.sup.10)--(CR.sup.11).dbd., and [0490]
R.sup.9 denotes [0491] (a) H, [0492] (b) a C.sub.1-6-alkyl- or
C.sub.1-3-alkyl-O-- group which may each be substituted by a group
R.sup.9.1, [0493] (c) R.sup.9.2 R.sup.9.3N,
R.sup.9.2R.sup.9.3N--C.sub.1-3-alkylene-, [0494] (d) halogen, --CN,
--OH, --COOH, C.sub.1-3-alkyl-O--C.sub.1-3-alkylene-,
C.sub.3-6-cycloalkyl-, C.sub.3-6-cycloalkyl-C.sub.1-4-alkylene-,
C.sub.1-3-alkyl-C(O)--O--C.sub.1-3-alkylene, [0495] (e) a
C.sub.1-3-alkyl or C.sub.1-3-alkyl-O-- group wherein each methylene
group is substituted by up to two fluorine atoms and each methyl
group is substituted by up to three fluorine atoms, [0496]
R.sup.9.1 denotes H, OH or --O--CH.sub.3, [0497] R.sup.9.2 denotes
H or C.sub.1-3-alkyl, [0498] R.sup.9.3 denotes H or
C.sub.1-3-alkyl, or [0499] R.sup.9.2 and R.sup.9.3 together with
the nitrogen atom to which they are attached denote a 3- to
6-membered heterocyclic group, [0500] R.sup.10 denotes [0501] (a)
H, [0502] (b) a C.sub.1-6-alkyl or C.sub.1-3-alkyl-CO-- group which
may each be substituted by a group R.sup.10.1, [0503] (c)
--NR.sup.10.1R.sup.10.2,
NR.sup.10.1R.sup.10.2--C.sub.1-3-alkylene-, [0504] (d) halogen,
--CN, --OH, C.sub.1-3-alkyl-O--C.sub.1-3-alkylene-,
C.sub.3-6-cycloalkyl-, C.sub.3-6-cycloalkyl-C.sub.1-4-alkylene-,
C.sub.1-3-alkyl-C(O)--O--C.sub.1-3-alkylene, [0505] (e)
aryl-C.sub.1-3-alkylene-O--, [0506] (f) a C.sub.1-3-alkyl- or
C.sub.1-3-alkyl-O-- group wherein each methylene group is
substituted by up to two fluorine atoms and each methyl group is
substituted by up to three fluorine atoms, [0507] R.sup.10.1
denotes H, OH or --O--CH.sub.3, [0508] R.sup.10.2 denotes H or
C.sub.1-6-alkyl, [0509] R.sup.10.3 denotes H, C.sub.1-6-alkyl or
--SO.sub.2--C.sub.1-3-alkyl, [0510] R.sup.11 denotes [0511] (a) H,
[0512] (b) a C.sub.1-6-alkyl or C.sub.1-3-alkyl-O-- group which may
each be substituted by a group R.sup.11.1, [0513] (c)
R.sup.11.2R.sup.11.3N, R.sup.11.2R.sup.11.3N--C.sub.1-3-alkylene-,
[0514] (d) halogen, --CN, --OH, --COOH,
C.sub.1-3-alkyl-O--C.sub.1-3-alkylene-, C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyl-C.sub.1-4-alkylene-,
C.sub.1-3-alkyl-C(O)--O--C.sub.1-3-alkylene, [0515] (e) a
C.sub.1-3-alkyl- or C.sub.1-3-alkyl-O-- group wherein each
methylene group is substituted by up to two fluorine atoms and each
methyl group is substituted by up to three fluorine atoms, [0516]
R.sup.11.1 denotes H, OH or --O--CH.sub.3, [0517] R.sup.11.2
denotes H or C.sub.1-3-alkyl, [0518] R.sup.11.3 denotes H or
C.sub.1-3-alkyl, or [0519] R.sup.11.2 and R.sup.11.3 together with
the nitrogen atom to which they are attached denote a 3- to
6-membered heterocyclic group, the tautomers, the diastereomers,
the enantiomers, the hydrates, the mixtures thereof and the salts
thereof as well as the hydrates of the salts, particularly the
physiologically acceptable salts thereof with inorganic or organic
acids or bases.
[0520] A seventeenth embodiment of the present invention consists
in the compounds of the above general formula I, wherein Y,
R.sup.1, R.sup.2 and R.sup.3 are as hereinbefore defined in the
first, second, third, fourth, fifth, sixth, seventh, eighth, ninth,
tenth, eleventh, twelfth, thirteenth, fourteenth or fifteenth
embodiment and the ring
##STR00019##
denotes a group selected from
##STR00020## ##STR00021##
the tautomers, the diastereomers, the enantiomers, the hydrates,
the mixtures thereof and the salts thereof as well as the hydrates
of the salts, particularly the physiologically acceptable salts
thereof with inorganic or organic acids or bases.
[0521] An eighteenth embodiment of the present invention consists
in the compounds of the above general formula I wherein [0522]
R.sup.1 denotes a group selected from
[0522] ##STR00022## [0523] R.sup.2 denotes H and [0524] R.sup.3
denotes a group selected from
##STR00023##
[0524] and the ring
##STR00024##
denotes a group selected from
##STR00025##
the tautomers, the diastereomers, the enantiomers, the hydrates,
the mixtures thereof and the salts thereof as well as the hydrates
of the salts, particularly the physiologically acceptable salts
thereof with inorganic or organic acids or bases.
[0525] The following compounds are mentioned as examples of most
particularly preferred compounds of the above general formula
I:
TABLE-US-00001 No. Structure (1) ##STR00026## (2) ##STR00027## (3)
##STR00028## (4) ##STR00029## (5) ##STR00030## (6) ##STR00031## (7)
##STR00032## (8) ##STR00033## (9) ##STR00034## (10) ##STR00035##
(11) ##STR00036## (12) ##STR00037## (13) ##STR00038## (14)
##STR00039## (15) ##STR00040## (16) ##STR00041## (17) ##STR00042##
(18) ##STR00043## (19) ##STR00044## (20) ##STR00045## (21)
##STR00046## (22) ##STR00047## (23) ##STR00048## (24) ##STR00049##
(25) ##STR00050## (26) ##STR00051## (27) ##STR00052## (28)
##STR00053## (29) ##STR00054## (30) ##STR00055## (31) ##STR00056##
(32) ##STR00057## (33) ##STR00058## (34) ##STR00059## (35)
##STR00060## (36) ##STR00061## (37) ##STR00062## (38) ##STR00063##
(39) ##STR00064## (40) ##STR00065## (41) ##STR00066## (42)
##STR00067## (43) ##STR00068## (44) ##STR00069## (45) ##STR00070##
(46) ##STR00071## (47) ##STR00072## (48) ##STR00073## (49)
##STR00074## (50) ##STR00075## (51) ##STR00076## (52) ##STR00077##
(53) ##STR00078## (54) ##STR00079## (55) ##STR00080## (56)
##STR00081## (57) ##STR00082## (58) ##STR00083## (59) ##STR00084##
(60) ##STR00085## (61) ##STR00086## (62) ##STR00087## (63)
##STR00088## (64) ##STR00089## (65) ##STR00090## (66) ##STR00091##
(67) ##STR00092## (68) ##STR00093## (69) ##STR00094## (70)
##STR00095## (71) ##STR00096## (72) ##STR00097## (73) ##STR00098##
(74) ##STR00099## (75) ##STR00100## (76) ##STR00101## (77)
##STR00102## (78) ##STR00103## (79) ##STR00104## (80) ##STR00105##
(81) ##STR00106## (82) ##STR00107## (83) ##STR00108## (84)
##STR00109## (85) ##STR00110##
the enantiomers, the diastereomers, the hydrates, the mixtures
thereof and the salts thereof as well as the hydrates of the salts,
particularly the physiologically acceptable salts thereof with
inorganic or organic acids or bases.
[0526] The following compounds are mentioned as examples of more
preferred compounds of the above general formula I:
TABLE-US-00002 No. Structure (1) ##STR00111## (2) ##STR00112## (3)
##STR00113## (4) ##STR00114## (10) ##STR00115## (11) ##STR00116##
(12) ##STR00117## (13) ##STR00118## (14) ##STR00119## (15)
##STR00120## (16) ##STR00121## (17) ##STR00122## (18) ##STR00123##
(19) ##STR00124## (20) ##STR00125## (21) ##STR00126## (22)
##STR00127## (23) ##STR00128## (24) ##STR00129## (25) ##STR00130##
(26) ##STR00131## (27) ##STR00132## (28) ##STR00133## (29)
##STR00134## (30) ##STR00135## (31) ##STR00136## (32) ##STR00137##
(33) ##STR00138## (34) ##STR00139## (35) ##STR00140## (36)
##STR00141## (37) ##STR00142## (38) ##STR00143## (39) ##STR00144##
(40) ##STR00145## (42) ##STR00146## (43) ##STR00147## (44)
##STR00148## (45) ##STR00149## (46) ##STR00150## (47) ##STR00151##
(48) ##STR00152## (49) ##STR00153## (50) ##STR00154## (51)
##STR00155## (52) ##STR00156## (53) ##STR00157## (55) ##STR00158##
(58) ##STR00159## (59) ##STR00160## (60) ##STR00161## (61)
##STR00162## (63) ##STR00163## (64) ##STR00164## (67) ##STR00165##
(69) ##STR00166## (70) ##STR00167## (72) ##STR00168## (75)
##STR00169## (76) ##STR00170## (78) ##STR00171## (79) ##STR00172##
(80) ##STR00173## (81) ##STR00174## (82) ##STR00175## (83)
##STR00176## (84) ##STR00177## (85) ##STR00178##
the enantiomers, the diastereomers, the hydrates, the mixtures
thereof and the salts thereof as well as the hydrates of the salts,
particularly the physiologically acceptable salts thereof with
inorganic or organic acids or bases.
TERMS AND DEFINITIONS USED
[0527] The present specification of the invention is to be
interpreted in accordance with the conventions and rules of
chemical bonds.
[0528] The compounds included in this invention are those that are
also chemically stable.
[0529] Unless otherwise stated, all the substituents are
independent of one another. If for example there are a plurality of
C.sub.1-4-alkyl groups as substituents in one group, in the case of
three C.sub.1-4-alkyl substituents, independently of one another,
one may represent methyl, one ethyl and one n-propyl.
[0530] Within the scope of this application, in the definition of
possible substituents, these may also be represented in the form of
a structural formula. If present, an asterisk (*) in the structural
formula of the substituent is to be understood as being the linking
point to the rest of the molecule. For example a phenyl group is
shown as follows:
##STR00179##
[0531] Moreover, the atom of the substituent that follows the
linking point is understood as being the atom at position number
1.
[0532] The subject-matter of this invention also includes the
compounds according to the invention, including the salts thereof,
wherein one or more hydrogen atoms, for example one, two, three,
four or five hydrogen atoms, are replaced by deuterium.
[0533] By the term "C.sub.1-3-alkyl" (including those which are a
part of other groups) are meant branched and unbranched alkyl
groups with 1 to 3 carbon atoms, by the term "C.sub.1-4-alkyl" are
meant branched and unbranched alkyl groups with 1 to 4 carbon atoms
and by the term "C.sub.1-6-alkyl" are meant branched and unbranched
alkyl groups with 1 to 6 carbon atoms. Examples include: methyl,
ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,
tert-butyl, pentyl, neopentyl or n-hexyl. The abbreviations may
optionally also be used for the above-mentioned groups Me, Et,
n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. Unless stated otherwise, the
definitions propyl and butyl include all the possible isomeric
forms of the groups in question. Thus, for example, propyl includes
n-propyl and iso-propyl, butyl includes iso-butyl, sec-butyl and
tert-butyl etc.
[0534] By the term "C.sub.1-6-alkylene" (including those which are
a part of other groups) are meant branched and unbranched alkylene
groups with 1 to 6 carbon atoms and by the term
"C.sub.1-3-alkylene" are meant branched and unbranched alkylene
groups with 1 to 3 carbon atoms. Examples include: methylene,
ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene,
1,1-dimethylethylene, 1,2-dimethylethylene, pentylene,
1,1-dimethylpropylene, 2,2-dimethylpropylene,
1,2-dimethylpropylene, 1,3-dimethylpropylene or hexylene. Unless
stated otherwise, the definition propylene includes all the
possible isomeric forms of the groups in question with the same
number of carbons. Thus, for example, propyl also includes
1-methylethylene and butylene includes 1-methylpropylene,
1,1-dimethylethylene, 1,2-dimethylethylene.
[0535] The definition for C.sub.0-alkylene denotes a bond.
[0536] By the term "C.sub.2-6-alkenyl" (including those which are a
part of other groups) are meant branched and unbranched alkenyl
groups with 2 to 6 carbon atoms and by the term "C.sub.2-4-alkenyl"
are meant branched and unbranched alkenyl groups with 2 to 4 carbon
atoms, provided that they comprise at least one double bond.
Alkenyl groups with 2 to 4 carbon atoms are preferred. Examples
include: ethenyl or vinyl, propenyl, butenyl, pentenyl, or hexenyl.
Unless stated otherwise, the definitions propenyl, butenyl,
pentenyl and hexenyl include all the possible isomeric forms of the
groups in question. Thus, for example, propenyl includes 1-propenyl
and 2-propenyl, butenyl includes 1-, 2- and 3-butenyl,
1-methyl-1-propenyl, 1-methyl-2-propenyl etc.
[0537] By the term "C.sub.2-6-alkynyl" (including those which are a
part of other groups) are meant branched and unbranched alkynyl
groups with 2 to 6 carbon atoms and by the term "C.sub.2-4-alkynyl"
are meant branched and unbranched alkynyl groups with 2 to 4 carbon
atoms, provided that they comprise at least one triple bond.
Examples include: ethynyl, propynyl, butynyl, pentynyl, or hexynyl.
Unless stated otherwise, the definitions propynyl, butynyl,
pentynyl and hexynyl include all the possible isomeric forms of the
groups in question. Thus, for example propynyl includes 1-propynyl
and 2-propynyl, butynyl includes 1-, 2- and 3-butynyl,
1-methyl-1-propynyl, 1-methyl-2-propynyl etc.
[0538] By the term "C.sub.3-6-cycloalkyl" (including those which
are a part of other groups) are meant cyclic alkyl groups with 3 to
6 carbon atoms and by the term "C.sub.5-6-cycloalkyl" are meant
cyclic alkyl groups with 5 to 6 carbon atoms. Examples include:
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Unless
otherwise stated, the cyclic alkyl groups may be substituted by one
or more groups selected from among methyl, ethyl, iso-propyl,
tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.
[0539] By the term "C.sub.5-6-cycloalkenyl" (including those which
are a part of other groups) are meant cyclic alkenyl groups with 5
or 6 carbon atoms, which contain an unsaturated bond. Examples
include: cyclopentenyl or cyclohexenyl. Unless otherwise stated,
the cyclic alkenyl groups may be substituted by one or more groups
selected from among methyl, ethyl, iso-propyl, tert-butyl, hydroxy,
fluorine, chlorine, bromine and iodine.
[0540] By the term "heterocyclyl" or "heterocyclic group" are
meant, unless otherwise described in the definitions, stable 5-, 6-
or 7-membered monocyclic or 8-, 9-, 10- or 11-membered bicyclic
heterocyclic ring systems, which do not form an aromatic ring
system in at least one ring and in addition to carbon atoms may
carry one to four heteroatoms selected from among nitrogen, oxygen
and sulphur. The two nitrogen atoms and also sulphur atoms may
optionally be oxidised and nitrogen atoms may be quaternised. The
heterocyclic ring may contain one or two carbonyl, thiocarbonyl or
cyanimino groups adjacent to a nitrogen atom. The heterocycles
mentioned previously may be linked to the rest of the molecule via
a carbon atom or a nitrogen atom.
[0541] Unless otherwise stated, the heterocycles may be substituted
by one or more groups selected from among: [0542] (a) OH, NO.sub.2,
CN, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, NH.sub.2, [0543] (b)
halogen, preferably fluorine or chlorine, [0544] (c)
C.sub.1-6-alkyl, preferably C.sub.1-3-alkyl, particularly
preferably ethyl, methyl, iso-propyl or tert-butyl, [0545] (d)
--SO.sub.2--O--C.sub.1-3-alkyl, preferably --O-methyl, [0546] (e)
--O--C.sub.1-3-alkyl, preferably --O-methyl or --O-ethyl, [0547]
(f) COOH, COO--C.sub.1-3-alkyl, preferably CO--O-methyl or
CO--O-ethyl, while the groups may be identical or different.
[0548] The following compounds are mentioned by way of example, but
the invention is not restricted to them: azetidine, oxetane,
thietane, thietane dioxide, tetrahydrofuran, dihydrofuran,
dioxolane, imidazolidine, imidazoline, imidazolidinone,
dihydroimidazolone, oxazoline, oxazolidine, oxazolidinone,
pyrrolidinone, dihydropyrazole, pyrrolidine, pyrroline, morpholine,
tetrahydropyridine, dihydropyran, tetrahydropyran, dioxane,
piperazine, piperidine, piperazinone, piperidinone, pyran,
thiomorpholine-S-oxide, thiomorpholine-S-dioxide, thiomorpholine,
dihydroxazine, morpholinedione, morpholinethione,
perhydrothiazinedioxide, {acute over (.epsilon.)}-caprolactam,
oxazepanone, diazepanone, thiazepanone, perhydroazepine,
dihydroquinazolinone, dihydroindole, dihydroisoindole,
benzoxazolone, benzimidazolone, chromanone, tetrahydroquinoline,
tetrahydrobenzoxazole, tetrahydrobenzisoxazole,
tetrahydrobenzothiophene, tetrahydrothieno-pyridine,
tetrahydrobenzofuran, tetrahydro-oxazolopyridine,
tetrahydro-isoxazolopyridine.
[0549] The following heterocycles are preferred according to the
invention:
##STR00180##
[0550] By the term "aryl" (including those which are a part of
other groups) are meant monocyclic aromatic ring systems with 6
carbon atoms or bicyclic aromatic ring systems with 10 carbon
atoms. Examples include phenyl, 1-naphthyl or 2-naphthyl; the
preferred aryl group is phenyl.
[0551] Unless otherwise stated, the aromatic groups may be
substituted by one or more groups selected from among: [0552] (a)
OH, NO.sub.2, CN, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, NH.sub.2,
[0553] (b) halogen, preferably fluorine or chlorine, [0554] (c)
C.sub.1-6-alkyl, preferably C.sub.1-3-alkyl, particularly
preferably ethyl, methyl, iso-propyl or tert-butyl, [0555] (d)
--SO.sub.2--O--C.sub.1-3-alkyl, preferably --O-methyl, [0556] (e)
--O--C.sub.1-3-alkyl, preferably --O-methyl or --O-ethyl, [0557]
(f) COOH, CO--O--C.sub.1-3-alkyl, preferably CO--O-methyl or
CO--O-ethyl, while the groups may be identical or different.
[0558] By the term "heteroaryl" are meant stable five- or
six-membered heterocyclic aromatic groups or 8- to 10-membered
bicyclic heteroaryl rings that may contain in each ring one, two or
three heteroatoms, selected from among oxygen, sulphur and
nitrogen, and additionally sufficient conjugated double bonds to
form an aromatic system. Examples of five- or six-membered
heterocyclic aromatic groups are as follows, but the invention is
not restricted to these:
furan, pyrrole, thiophene, pyrazole, imidazole, oxazole, thiazole,
isothiazole, isoxazole, oxadiazole, triazole, tetrazole, furazan,
thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine,
triazine.
[0559] The following five-membered heterocyclic aromatic groups are
preferred according to the invention:
##STR00181##
[0560] The following six-membered heterocyclic aromatic groups are
preferred according to the invention:
##STR00182##
[0561] Examples of 9- or 10-membered bicyclic heteroaryl rings are
as follows, but the invention is not restricted to these:
indole, isoindole, indazole, indolizine, benzofuran, benzthiophene,
benzimidazole, benzoxazole, benzothiazole, benzotriazole,
benzisoxazole, benzisothiazole, quinoline, isoquinoline, cinnoline,
phthalazine, quinoxaline, quinazoline, pyridopyrimidine,
pyridopyrazine, pyridopyridazine, pyrimidopyrimidine, pteridine,
purine, quinolizine, benzoxazolecarbonitrile, quinoline,
isoquinoline, quinolizine, pteridine, purine, quinolizine,
benzoxazole-carbonitrile.
[0562] The following bicyclic heteroaryl rings are preferred
according to this invention:
##STR00183##
[0563] Unless otherwise stated, the heteroaryls previously
mentioned may be substituted by one or more groups selected from
among: [0564] (a) OH, NO.sub.2, CN, OCF.sub.3, OCHF.sub.2,
OCH.sub.2F, NH.sub.2, [0565] (b) halogen, preferably fluorine or
chlorine, [0566] (c) C.sub.1-6-alkyl, preferably C.sub.1-3-alkyl,
particularly preferably ethyl, methyl, iso-propyl or tert-butyl,
[0567] (d) --SO.sub.2--O--C.sub.3-alkyl, preferably --O-methyl,
[0568] (e) --O--C.sub.1-3-alkyl, preferably --O-methyl or
--O-ethyl, [0569] (f) COOH, CO--O--C.sub.1-3-alkyl, preferably
CO--O-methyl or CO--O-ethyl, while the groups may be identical or
different.
[0570] Bicyclic heteroaryl rings may preferably be substituted in
the phenyl group.
[0571] By the term "halogen" are meant fluorine, chlorine, bromine
or iodine atoms.
[0572] Compounds of general formula I may have acid groups, mainly
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 for example hydrobromic acid, phosphoric acid, nitric acid,
hydrochloric acid, sulphuric acid, methanesulphonic acid,
ethanesulphonic acid, benzenesulphonic acid, p-toluenesulphonic
acid or organic acids such as for example malic acid, succinic
acid, acetic acid, fumaric acid, maleic acid, mandelic acid, lactic
acid, tartaric acid, citric acid or as salts with pharmaceutically
useable bases such as alkali or alkaline earth metal hydroxides,
e.g. sodium hydroxide or potassium hydroxide, or carbonates,
ammonia, zinc or ammonium hydroxides or organic amines such as e.g.
diethylamine, triethylamine, ethanolamine, diethanolamine,
triethanolamine, cyclohexylamine, dicyclohexylamine, inter
alia.
[0573] The compounds according to the invention may be present as
racemates, provided that they have only one chiral element, but may
also be obtained as pure enantiomers, i.e. in the (R) or (S)
form.
[0574] Compounds with a carbon double bond may be present in both
the E- and the Z-form.
[0575] The following nitrogen-containing heteroaryls may be present
in different tautomeric forms:
##STR00184##
[0576] This means that the compound prepared in each case is not
restricted to one tautomeric form, but encompasses all the
tautomeric forms.
[0577] However, the application also includes the individual
diastereomeric pairs of antipodes or mixtures thereof, which are
obtained if there is more than one chiral element in the compounds
of general formula I, as well as the individual optically active
enantiomers of which the above-mentioned racemates are made up.
[0578] The invention relates to the compounds in question,
optionally in the form of the individual optical isomers, mixtures
of the individual enantiomers or racemates, in the form of the
tautomers as well as in the form of the free bases or the
corresponding acid addition salts with pharmacologically
acceptable.
[0579] So-called prodrugs of compounds of general formula I are
also encompassed by this invention. The term prodrug is used to
denote any molecule that releases the active principle of general
formula I in-vivo after administration to mammals. The prodrug may
have little or no pharmacological activity per se, but releases the
active principle of general formula I in-vivo after administration
and this has the activity described. Prodrugs for compounds of
general formula I may be prepared by modifying suitable functional
groups in the compound of general formula I, as known to the
skilled man in this field. (H. Bundgaard (Editor), Design of
Prodrugs. (1986), Elsevier)
[0580] This invention also includes those metabolites that are
derived from the compounds of general formula I. By metabolites are
meant, in this context, compounds that are formed in-vivo from the
compound of general formula I after administration. Examples of
metabolites include: [0581] methyl groups of the compound of
general formula I may be converted into the corresponding
hydroxymethyl groups. (--CH.sub.3->--CH.sub.2OH) [0582] alkoxy
groups of the compound of general formula I may be converted into
the corresponding hydroxyl groups. (--OR->--OH) [0583] secondary
amines of the compound of general formula I may be converted into
the corresponding primary amines.
(--NR.sub.1R.sub.2->--NHR.sub.1 or --NHR.sub.2) [0584] nitrogen
atoms of the compound of general formula I may be converted into
the corresponding nitrogen oxides.
(.dbd.N--->.dbd.N.sup.+--(O.sup.-)--)
Methods of Preparation
[0585] The invention also relates to a process for preparing the
compounds of general formula I, wherein the substituents have the
meanings stated earlier.
[0586] Some methods of preparing the compounds of general formula I
according to the invention
##STR00185##
wherein U, V, X, Y, R.sup.1, R.sup.2 and R.sup.3 are as
hereinbefore defined, are illustrated in the following synthesis
schemes and Examples.
[0587] In some cases the order of carrying out the reaction schemes
may be varied in order to simplify the reactions or prevent
unwanted by-products. The Examples that follow are provided to make
the invention fully comprehensible. The Examples are intended to
illustrate the invention and should in no way restrict it.
[0588] In some cases the end product may be further derivatised,
e.g. by manipulation of the substituents. These manipulations may
be generally known to the skilled man, such as oxidation,
reduction, alkylation, acylation and hydrolysis, but need not be
restricted to the above.
[0589] The compounds according to the invention may be prepared
according to the schemes and specific examples provided or
corresponding modifications thereof. Modifications to these
reactions which are known to the skilled man but not described in
detail here may also be implemented. The general methods of
preparing the compounds according to the invention will become
apparent to the skilled man from a study of the following
schemes.
[0590] Starting compounds are commercially available or are
prepared by processes which are described in the literature, known
in the art or as described herein. Before the reaction is carried
out corresponding functional groups in the compounds may be
protected by conventional protective groups. These protective
groups may be cleaved again at a suitable stage within the reaction
sequence using methods familiar to the skilled man.
[0591] In the reactions described below, any reactive groups
present such as hydroxy, carboxy, amino, alkylamino, amide or imino
groups may be protected during the reaction by conventional
protective groups that are cleaved again after the reaction.
[0592] For example [0593] a suitable protective group for a hydroxy
group may be the methoxy, benzyloxy, trimethylsilyl, acetyl,
benzoyl, tert.-butyl, trityl, benzyl or tetrahydropyranyl group,
[0594] suitable protective groups for a carboxyl group may be the
trimethylsilyl, methyl, ethyl, tert.-butyl, benzyl or
tetrahydropyranyl group, and [0595] suitable protective groups for
an amide group may be the N-methoxymethyl-(MOM), N-benzyloxymethyl
(BOM), N-(trimethylsilyl)ethoxymethyl (SEM),
N-tert-butyldimethylsiloxymethyl, N-tert-butyldimethylsilyl
(TBDMS), N-triisopropylsilyl-(TIPS), N-benzyl, N-4-methoxybenzyl
(PMB), N-triphenylmethyl (Trt), N-tert-butoxycarbonyl (BOC),
N-benzyloxycarbonyl (Cbz) or N-trimethylsilylethylsulphonyl (SES)
[0596] a suitable protective group for an amino, alkylamino or
imino group may be the acetyl, trifluoroacetyl, benzoyl,
ethoxycarbonyl, tert.-butoxycarbonyl, benzyloxycarbonyl, benzyl,
methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for
the amino group, the phthalyl group.
[0597] Other protective groups and their cleavage are described in
T. W. Greene, P. G. M. Wuts, "Protective Groups in Organic
Synthesis", Wiley, 2006.
[0598] Any protecting group used is optionally subsequently cleaved
for example by hydrolysis in an aqueous solvent, e.g. in water,
isopropanol/water, tetrahydrofuran/water or dioxane/water, in the
presence of an acid such as trifluoroacetic acid, hydrochloric acid
or sulphuric acid or in the presence of an alkali metal base such
as lithium hydroxide, sodium hydroxide or potassium hydroxide, or
by ether splitting, e.g. in the presence of iodotrimethylsilane, at
temperatures between 0 and 100.degree. C., preferably at
temperatures between 10 and 50.degree. C.
[0599] However, a benzyl, methoxybenzyl or benzyloxycarbonyl group
is cleaved, for example, hydrogenolytically, e.g. with hydrogen in
the presence of a catalyst such as palladium/charcoal in a solvent
such as methanol, ethanol, ethyl acetate, dimethylformamide,
dimethylformamide/acetone or glacial acetic acid, optionally with
the addition of an acid such as hydrochloric acid at temperatures
between 0 and 50.degree. C., but preferably at ambient temperature,
and at a hydrogen pressure of 1 to 7 bar, but preferably 1 to 5
bar.
[0600] A methoxybenzyl group may also be cleaved in the presence of
an oxidising agent such as cerium(IV)ammonium nitrate in a solvent
such as methylene chloride, acetonitrile or acetonitrile/water at
temperatures of between 0 and 50.degree. C., but preferably at
ambient temperature.
[0601] A methoxy group is conveniently cleaved in the presence of
boron tribromide in a solvent such as methylene chloride at
temperatures between -35 and -25.degree. C.
[0602] A 2,4-dimethoxybenzyl group is preferably cleaved in
trifluoroacetic acid in the presence of anisole.
[0603] A tert. butyl or tert. butyloxycarbonyl group is preferably
cleaved by treating with an acid such as trifluoroacetic acid or
hydrochloric acid, optionally using a solvent such as methylene
chloride, dioxan or ether.
[0604] A phthalyl group is preferably cleaved in the presence of
hydrazine or a primary amine such as methylamine, ethylamine or
n-butylamine in a solvent such as methanol, ethanol, isopropanol,
toluene/water or dioxan at temperatures between 20 and 50.degree.
C.
[0605] A methoxymethyl group may be cleaved in the presence of an
acid such as concentrated hydrochloric acid in a solvent such as
dimethoxyethane. Alternatively an acid such as trifluoroacetic acid
may also be used without a solvent.
[0606] An N-(trimethylsilyl)ethoxymethyl group may be cleaved in
the presence of TBAF and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone. Alternatively the
SEM protective group may also be cleaved with an acid such as
hydrogen chloride in an organic solvent such as dioxane or
ethanol.
[0607] An allyloxycarbonyl group is cleaved by treating with a
catalytic amount of tetrakis-(triphenylphosphine)-palladium(0),
preferably in a solvent such as tetrahydrofuran and preferably in
the presence of an excess of a base such as morpholine at
temperatures between 0 and 100.degree. C., preferably at ambient
temperature and under an inert gas, or by treating with a catalytic
amount of tris-(triphenylphosphine)-rhodium(I)chloride in a solvent
such as aqueous ethanol and optionally in the presence of a base
such as 1,4-diazabicyclo[2,2,2]octane at temperatures between 20
and 70.degree. C.
[0608] The following methods of preparing the compounds of general
formula I according to the invention and their precursors have
proved particularly suitable:
[0609] An end compound of general formula I wherein U, V, X, Y,
R.sup.1, R.sup.2 and R.sup.3 are as hereinbefore defined may be
obtained by reacting a compound of general formula (1-1) with an
electron-poor compound of general formula (1-2) that has a leaving
group LG. Halides, preferably chlorides and bromides,
--SO.sub.2CH.sub.3, --OSO.sub.2CH.sub.3,
--OSO.sub.2C.sub.6H.sub.4--CH.sub.3 or --S--CH.sub.3 (--S--CH.sub.3
requires further reaction with an organic peroxide in order to be
converted into the actual leaving group) etc. may act as the
leaving group LG, but it is not restricted to this list. The use of
chlorides is most particularly preferred.
##STR00186##
[0610] The reaction may be carried out by nucleophilic aromatic
substitution in an inert solvent using an auxiliary base in a
temperature range of from 0.degree. C. to the reflux temperature of
the solvent. The reaction is carried out in a suitable inert
solvent, such as tetrahydrofuran, toluene, xylene, dialkylformamide
(particularly preferably dimethylformamide), cyclic amide
(particularly preferably N-methyl-pyrrolidone), 1,4-dioxane,
acetonitrile or in inert solvent mixtures. Suitable auxiliary bases
include tertiary amines such as triethylamine or
ethyldiisopropylamine, alkali metal carbonates such as potassium
carbonate or sodium carbonate, sodium hydride (NaH) or lithium
diisopropylamide (LDA). The inert solvent used must be compatible
with the base used. The reaction is preferably carried out in
dimethylformamide, at temperatures between ambient temperature and
the reflux temperature of the solvent, in the presence of a
tertiary amine base.
[0611] Alternatively the structures of general formula (1-3) shown
in Scheme 1 wherein U, V, X, Y, R.sup.1, R.sup.2 and R.sup.3 are as
hereinbefore defined may be synthesised by transition
metal-catalysed reactions. A compound of general formula (1-1) may
react with a compound of general formula (1-2) that has a leaving
group LG in an inert solvent in the presence of a catalyst and an
auxiliary base. In addition, a suitable ligand may be used for the
catalyst. Chlorides, bromides, iodides, trifluoroacetates,
trifluoromethanesulphonates, methanesulphonates and
toluenesulphonates, but this list is not restrictive. Xylene,
tetrahydrofuran, dimethylformamide, dimethoxyethane, toluene,
benzene, 1,4-dioxane, acetonitrile or solvent mixtures may be used
as inert solvents. The preferred solvent is xylene. Suitable bases
are particularly amine bases such as e.g. triethylamine or
diisopropylethylamine or also inorganic bases such as caesium
carbonate, caesium acetate, potassium carbonate, sodium carbonate
or potassium phosphate. Preferred reaction temperatures are from RT
to the reflux temperature of the solvent at normal pressure.
Typical catalysts are e.g. transition metal catalysts, such as e.g.
palladium catalysts of the
tris(dibenzylideneacetone)-dipalladium(0),
tetrakis-(triphenylphosphine)-palladium(0), palladium-(II)-acetate,
Pd(PPh.sub.3).sub.2Cl.sub.2, Pd(CH.sub.3CN).sub.2Cl.sub.2,
Pd(dppf)C.sub.2 or palladium(II)-chloride type. Typical ligands are
e.g. triphenylphosphine, triphenylarsene,
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP),
2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (XPhos),
4,5-bis-diphenylphosphanyl-9,9-dimethyl-9H-xanthene (XantPhos) or
2-(di-tert-butylphosphino)biphenyl.
[0612] Compounds of general formula (2-4), wherein U, V, X, Y,
R.sup.1, R.sup.2 and R.sup.3 are as hereinbefore defined, may be
prepared as shown in Scheme 2.
##STR00187##
[0613] The reaction starts from a compound of general formula (2-1)
wherein Hal denotes a halogen atom, preferably chlorine, bromine or
iodine. The Grignard or lithiated compound of general formula (2-2)
may be prepared from the correspondingly halogenated compound of
general formula (2-1) either by a so-called halogen-metal exchange
or by inserting the metal in a halogen-carbon bond. In order to
synthesise the corresponding lithiated compound of general formula
(2-2) the halogen-metal exchange may be carried out for example
with an organo-lithium compound such as e.g. n-, sec- or
tert.-butyllithium. The corresponding magnesium compounds (Grignard
compounds) may also be obtained by a halogen-metal exchange with a
corresponding Grignard reagent such as e.g. isopropyl- or
sec-butyl-magnesium bromide or chloride or diisopropyl- or
di-sec-butylmagnesium with or in the presence of a salt such as
e.g. lithium chloride (that may accelerate the metallisation
process). The corresponding transmetallising organo-magnesium
compound may also be synthesised in-situ from corresponding
precursors (cf. e.g. Angew. Chem. 2004, 116, 3396-3399 and Angew.
Chem. 2006, 118, 165-169 and references contained therein). In
addition, -ate complexes of the organo-magnesium compounds may also
be used, resulting from the combination of e.g. butylmagnesium
chloride or bromide or isopropyl-magnesium chloride or bromide and
butyllithium. (cf. Angew. Chem. 2000, 112, 2594-2596 and
Tetrahedron Lett. 2001, 42, 4841-4844 and references contained
therein). The halogen-metal exchange is preferably carried out
between -100.degree. C. and 40.degree. C., most particularly
preferred is a temperature range of from -80.degree. C. to
10.degree. C. in an inert solvent, preferably alkylether (most
particularly preferably diethyl ether), cyclic ether (most
particularly preferably 1,4-dioxane or tetrahydrofuran), toluene,
hexane or solvent mixtures thereof. The magnesium or organolithium
compounds thus obtained may optionally be transmetallised with
metal salts such as e.g. cerium trichloride, zinc chloride or
bromide, indium chloride or bromide, in order to synthesise
alternative organometallic compounds of general formula (2-2) that
are also suitable for the reaction described. Alternatively the
organo-metallic compound (2-2) may also be prepared by inserting a
metal into a carbon-halogen bond. Lithium or magnesium are suitable
elemental metals for this transformation. The insertion reaction is
preferably carried out between -80.degree. C. and 100.degree. C.,
while most particularly preferred is a temperature range from
-70.degree. C. to 40.degree. C. in an inert solvent, preferably
alkylether (most particularly preferably diethyl ether), cyclic
ether (most particularly preferably 1,4-dioxane or
tetrahydrofuran), toluene, hexane or solvent mixtures thereof. In
cases where no spontaneous reaction takes place it may be necessary
to activate the metal with e.g. 1,2-dibromoethane, iodine,
trimethyl-silyl chloride, acetic acid, hydrogen chloride or
ultrasound. The reaction of the organo-metallic compound of general
formula (2-2) with a compound (2-3) is preferably carried out in a
temperature range from -100.degree. C. to 100.degree. C., while a
temperature range from -80.degree. C. to 50.degree. C. is
particularly preferred. The reaction is carried out in an inert
solvent, such as e.g. preferably alkylether (most particularly
preferably diethyl ether, dimethoxyethane), cyclic ether (most
particularly preferably 1,4-dioxane or tetrahydrofuran), aromatic
hydrocarbons (most particularly preferably toluene or benzene),
hexane or solvent mixtures thereof. All the reactions may be
carried out in the air, but it is preferable to carry them out in a
protective gas atmosphere such as argon or nitrogen. It may prove
advantageous to temporarily protect the functional group in
compound (2-3). The lithium-substituted or magnesium-substituted
compound of general formula (2-2) may react with a compound of
general formula (2-3) that contains a carboxyl group or derivatives
thereof such as esters, nitriles, carboxylic acid chlorides or
amides, such as e.g. grapevine amides. These reactions may often be
carried out without any additional transition metal catalyst or
transmetallisation to another metal such as e.g. cerium, indium or
zinc. In some cases, however, the two modifications mentioned may
also prove advantageous. Aromatic boric acids, esters derived
therefrom, dialkylarylboranes or aryltrifluoroborates may be
reacted with acid chlorides or carboxylic acids in the presence of
a transition metal, such as e.g. palladium, as catalyst, to obtain
the corresponding ketones (V. Polackova, St. Toma, I. Augustinova,
Iveta; Tetrahedron; 2006; 62; 50; 11675-11678 and references cited
therein and R. Kakino, H. Narahashi, I. Shimizu, A. Yamamoto, Bull.
Chem. Soc. Jpn., 2002, 75, 1333-1345).
[0614] The corresponding boron-substituted compound, such as e.g.
boric acids, dialkylarylboranes or boric acid ester can be
synthesised from the metallised species by reaction with a boron
electrophil such as e.g. a boric acid ester or derivatives thereof.
Boron-substituted compounds may also be synthesised from the
halogenated or pseudohalogenated precursor molecules using a
transition metal catalyst, preferably palladium, and a boron or
borolan compound. (Tetrahedron Lett. 2003, 4895-4898 and references
cited therein).
[0615] The metallisation and/or coupling reaction may also be
carried out in microreactors and/or in the micromixer. The
reactions may be carried out without any further additions or, in
the case of unreactive reactants, promoters such as e.g.
BF.sub.3*OEt.sub.2 may also be added (cf. M. Schlosser,
Organometallics in Synthesis, John Wiley & Sons, Chichester/New
York/Brisbane/Toronto/Singapore, 1994).
[0616] The halogenated compounds of general formula (2-1) are
either commercially available or may be synthesised by methods
known in the field of organic chemistry or described in the
specialist literature (cf. e.g. J. March, Advanced Organic
Reactions, Reactions Mechanism, and Structure, 4th Edition, John
Wiley & Sons, Chichester/New York/Brisbane/Toronto/Singapore,
1992 and literature cited therein). The use of transition metals
and organometallic compounds for the synthesis is described in
detail in monographs (cf. e.g. L. Brandsma, S. F. Vasilevsky, H. D.
Verkruijsse, Application of Transition Metals Catalysts in Organic
Synthesis, Springer-Verlag, Berlin/Heidelberg, 1999; M. Schlosser,
Organometallics in Synthesis, John Wiley & Sons, Chichester/New
York/Brisbane/Toronto/Singapore, 1994, P. J. Stang, F. Diederich,
Metal-Catalyzed Cross-Coupling Reactions, Wiley-VCH, Weinheim, 1997
and references contained therein.)
[0617] A method of synthesising compounds of general formula (3-4)
wherein U, V, X, Y and R.sup.3 are as hereinbefore defined is
illustrated in Scheme 3.
##STR00188##
[0618] Starting from a halogenated compound (particularly preferred
are the chlorides, bromides and iodides) of general formula (3-1)
the corresponding lithium or magnesium-substituted compound may be
synthesised by a halogen-metal exchange reaction, e.g. with
butyllithium, isopropylmagnesium halide or diisopropylmagnesium or
by insertion of an elemental metal into the halogen-carbon bond.
The corresponding boron-substituted compounds, such as e.g. boric
acid, dialkylarylborane or boric acid ester, can be synthesised
from the metallised species by reaction with a boron electrophile
such as e.g. a boric acid ester or derivatives thereof.
Boron-substituted compounds may also be synthesised from the
halogenated or pseudohalogenated precursor molecules using a
transition metal catalyst, preferably palladium, and a boron or
borolan compound (Tetrahedron Lett. 2003, 4895-4898 and references
cited therein). The lithium-substituted or magnesium-substituted
compound of general formula (3-2) may be added to a compound of
general formula (3-3) that contains a carboxyl group or derivatives
thereof such as esters, nitriles, carboxylic acid chlorides or
amides, such as e.g. grapevine amides. These reactions may often be
carried out without any additional transition metal catalyst or
transmetallisation to another metal such as e.g. cerium, indium or
zinc. In some cases, however, the two modifications mentioned may
also prove advantageous. Aromatic boric acids, esters derived
therefrom, dialkylarylboranes or aryltrifluoroborates may be
reacted with acid chlorides or carboxylic acids in the presence of
a transition metal, such as e.g. palladium, as catalyst, to obtain
the corresponding ketones (V. Polackova, St. Toma, I. Augustinova,
Iveta; Tetrahedron; 2006; 62; 50; 11675-11678 and references cited
therein and R. Kakino, H. Narahashi, I. Shimizu, A. Yamamoto, Bull.
Chem. Soc. Jpn., 2002, 75, 1333-1345).
[0619] Compounds of general formula (4-3), wherein U, V, X, Y and
R.sup.3 are as hereinbefore defined, may be prepared as shown in
Scheme 4.
##STR00189##
[0620] A compound of general formula (4-1) that has a leaving group
LG and an acid halide group may be reacted with an aromatic
compound of general formula (4-2) under Friedel-Crafts acylation
conditions or variations thereof. Friedel-Crafts reactions are
carried out in the presence of a catalyst which is used in either
catalytic or stoichiometric amounts. Suitable catalysts are, in
particular, AlCl.sub.3, FeCl.sub.3, iodine, iron, ZnCl.sub.2,
sulphuric acid or trifluoromethanesulphonic acid. Instead of the
acid halide the corresponding carboxylic acid, anhydride, ester or
nitrile may also be used. The reaction is preferably carried out in
halogenated hydrocarbons. Dichloromethane and 1,2-dichloroethane
are particularly preferred. Friedel-Crafts reactions are carried
out in a temperature range of from -30.degree. C. to 120.degree.
C., preferably from 30.degree. C. to 100.degree. C. However, the
reactions may also be carried out without a solvent. The reactions
may also be carried out in the microwave.
[0621] Compounds of general formula (5-3), wherein U, V, X, Y,
R.sup.1, R.sup.2 and R.sup.3 are as hereinbefore defined, may be
prepared as shown in Scheme 5.
##STR00190##
[0622] Analogously to a method of T. Ishiyama et al. (J. Org.
Chem., 1998, 63, 4726) a compound of general formula (5-1) that has
a leaving group LG may be reacted with a boron-substituted
compound, such as boric acid (R.dbd.H), boric acid ester (R=alkyl)
dialkylarylborane in the presence of a catalyst and a base, in an
inert solvent and a carbon monoxide atmosphere, preferably in a
temperature range from ambient temperature to the reflux
temperature of the solvent. Preferably, elevated reaction
temperatures from 80.degree. C. to 110.degree. C. are used, under
elevated carbon monoxide pressure. A suitable ligand may
additionally be used for the catalyst. Alkali metal iodides such as
sodium iodide or potassium iodide may be added as additives.
Bromides, iodides, trifluoroacetates, trifluoromethanesulphonates,
methanesulphonates and toluenesulphonates may act as the leaving
group LG, although this list is not restrictive. The inert solvents
used may be xylene, tetrahydrofuran, dimethylformamide,
dimethoxyethane, toluene, benzene, anisole, 1,4-dioxane,
acetonitrile or solvent mixtures. The preferred solvent is anisole.
Suitable bases are inorganic bases such as caesium carbonate,
caesium acetate, potassium carbonate, sodium carbonate or potassium
phosphate. The reactions are carried out in a carbon monoxide
atmosphere, in which the carbon monoxide pressure may be 1 to 50
bar. Typical catalysts are e.g. palladium catalysts such as
tris-(dibenzylideneacetone)-dipalladium(0),
tetrakis-(triphenylphosphine)-palladium(0), palladium-(II)-acetate,
Pd(PPh.sub.3).sub.2Cl.sub.2, Pd(CH.sub.3CN).sub.2Cl.sub.2,
Pd(dppf)Cl.sub.2 or palladium(II)-chloride. Typical ligands are
e.g. triphenylphosphine, tricyclohexylphosphine,
tri-tert-butylphosphine, triphenylarsene, BINAP, XPhos, XantPhos,
or 2-(di-tert-butylphosphino)biphenyl,
1,1'-bis(diphenylphosphino)ferrocene (Dppf),
1,2-bis(diphenylphosphino)ethane (dppe),
1,3-bis(diphenylphosphino)propane(dppp) and
1,4-bis(diphenylphosphino)butane (dppb).
[0623] It is particularly preferable to use
Pd(PPh.sub.3).sub.2Cl.sub.2 as catalyst, potassium carbonate as
base, 1 bar of carbon monoxide, potassium iodide as additive and
anisole as solvent. The corresponding boron-substituted compounds
are either commercially obtainable or can be synthesised from
metallised compounds by reaction with a boron electrophil such as
e.g. a boric acid ester or a derivative thereof. Moreover, the
boron-substituted compounds may be prepared from the corresponding
halogenated or pseudohalogenated precursor molecules in a
transition metal-catalysed reaction, e.g. with palladium and a
diborolane or borolane compound. (Tetrahedron Lett. 2003, 4895-4898
and references cited therein).
[0624] A method of synthesising compounds of general formula (6-3),
wherein U, V, X, Y and R.sup.3 are as hereinbefore defined, is
shown in Scheme 6:
##STR00191##
[0625] Analogously to a method of A. Miyashita et al.
(Heterocycles, 1997, Vol. 45, No. 11, 2159-2173) compounds of
general formula (6-1) that have a leaving group LG can be reacted
with aromatic aldehydes in the presence of a catalyst and a base in
inert solvents to obtain compounds of general formula (6-3).
Fluorides, chlorides, bromides, iodides,
trifluoromethanesulphonates, methanesulphonates and
toluenesulphonates may act as the leaving group LG, but the list is
not restrictive. Particularly preferred are chlorides and bromides.
Cyclic ethers (preferably tetrahydrofuran) and dialkylformamides
(preferably dimethylformamide), may be used as inert solvents.
Suitable catalysts are azolium salts, such as
1,3-dimethylimidazolium iodide or 1,3-dimethylbenzimidazolium
iodide. Suitable bases are metal hydrides. Sodium hydride is most
particularly preferred. The reactions are carried out in a
temperature range from RT to the reflux temperature of the solvent.
Elevated temperatures are preferred.
[0626] The reaction may also be carried out with sodium
p-tolylsulphinate instead of azolium salts and base, in the
presence of an alkali metal cyanide (preferably potassium cyanide)
in an inert solvent at elevated temperatures. (A. Miyashita et al.,
Heterocycles, 1998, Vol. 47, No. 1, 407-414).
[0627] Compounds of general formula (7-4) wherein U, V, X, Y and
R.sup.3 are as hereinbefore defined, as shown in Scheme 7, may be
prepared analogously to A. Miyashita et al. (Heterocycles, 1997,
Vol. 45, No. 11, 2159-2173) and the literature cited therein.
##STR00192##
[0628] Compounds of general formula (7-1) that have a leaving group
LG may be reacted with 2-arylacetonitrile or
2-heteroarylacetonitrile in the presence of a base in an inert
solvent to obtain compounds of general formula (7-3). Fluorides,
chlorides, bromides, iodides, trifluoromethanesulphonates,
methanesulphonates and toluenesulphonates may act as the leaving
group LG, but the list is not restrictive. Particularly preferred
are chlorides and bromides. The inert solvent may be a
dialkylformamide (preferably dimethylformamide). Metal hydrides are
suitable as the base. Sodium hydride is most particularly
preferred.
[0629] The reactions are carried out in a temperature range from RT
to the reflux temperature of the solvent. Preferably the reactions
are carried out at elevated temperatures. The compounds of general
formula (7-4) are synthesised by oxidative decyanisation of
compounds of general formula (7-3). Oxidative decyanisations are
carried out in inert solvents through which oxygen gas is passed in
the presence of a base. Cyclic ethers (preferably tetrahydrofuran)
may be used as inert solvents. Suitable bases are metal hydrides.
Sodium hydride is most particularly preferred. The reactions are
carried out in a temperature range from -20.degree. C. to the
reflux temperature of the solvent. Reactions are preferably carried
out at RT.
[0630] The new compounds of general formula I according to the
invention may contain one or more chiral centres. If for example
there are two chiral centres present, the compounds may occur in
the form of two diastereomeric pairs of antipodes. The invention
includes the individual isomers as well as the mixtures thereof.
The diastereomers may be separated on the basis of their different
physico-chemical properties, e.g. by fractional crystallisation
from suitable solvents, by high pressure liquid or column
chromatography, using chiral or preferably non-chiral stationary
phases.
[0631] Racemates covered by general formula I may be separated for
example by HPLC on suitable chiral stationary phases (e.g. Chiral
AGP, Chiralpak AD). Racemates which contain a basic or acidic
function can also be separated via the diastereomeric, optically
active salts which are produced on reacting with an optically
active acid, for example (+) or (-)-tartaric acid, (+) or
(-)-diacetyl tartaric acid, (+) or (-)-monomethyl tartrate or (+)
or (-)-camphorsulphonic acid, or an optically active base, for
example with (R)-(+)-1-phenylethylamine, (S)-(-)-1-phenylethylamine
or (S)-brucine.
[0632] According to a conventional method of separating isomers,
the racemate of a compound of general formula I is reacted with one
of the abovementioned optically active acids or bases in equimolar
amounts in a solvent and the resulting crystalline, diastereomeric,
optically active salts thereof are separated using their different
solubilities. This reaction may be carried out in any type of
solvent provided that it is sufficiently different in terms of the
solubility of the salts. Preferably, methanol, ethanol or mixtures
thereof, for example in a ratio by volume of 50:50, are used. Then
each of the optically active salts is dissolved in water, carefully
neutralised with a base such as sodium carbonate or potassium
carbonate, or with a suitable acid, e.g. with dilute hydrochloric
acid or aqueous methanesulphonic acid, and in this way the
corresponding free compound is obtained in the (+) or (-) form.
[0633] The (R) or (S) enantiomer alone or a mixture of two
optically active diastereomeric compounds covered by general
formula I may also be obtained by performing the syntheses
described above with a suitable reaction component in the (R) or
(S) configuration.
[0634] The new compounds of general formula I and the
physiologically acceptable salts thereof have valuable
pharmacological properties, based on their selective
CGRP-antagonistic properties. The invention further relates to
pharmaceutical compositions containing these compounds, their use
and the preparation thereof.
[0635] The new compounds mentioned above and the physiologically
acceptable salts thereof have CGRP-antagonistic properties and
exhibit good affinities in CGRP receptor binding studies. The
compounds display CGRP-antagonistic properties in the
pharmacological test systems described hereinafter.
[0636] The following experiments were carried out to demonstrate
the affinity of the above-mentioned compounds for human
CGRP-receptors and their antagonistic properties:
A. Binding Studies with SK-N-MC Cells (Expressing the Human CGRP
Receptor)
[0637] SK-N-MC cells are cultivated in "Dulbecco's modified Eagle
medium". The medium is removed from confluent cultures. The cells
are washed twice with PBS buffer (Gibco 041-04190 M), detached by
the addition of PBS buffer mixed with 0.02% EDTA, and isolated by
centrifuging. After resuspension in 20 ml of "Balanced Salts
Solution" [BSS (in mM): NaCl 120, KCl 5.4, NaHCO.sub.3 16.2,
MgSO.sub.4 0.8, NaHPO.sub.4 1.0, CaCl.sub.2 1.8, D-glucose 5.5,
HEPES 30, pH 7.40] the cells are centrifuged twice at 100.times.g
and resuspended in BSS. After the number of cells has been
determined, the cells are homogenised using an Ultra-Turrax and
centrifuged for 10 minutes at 3000.times.g. The supernatant is
discarded and the pellet is recentrifuged in Tris buffer (10 mM
Tris, 50 mM NaCl, 5 mM MgCl.sub.2, 1 mM EDTA, pH 7.40) enriched
with 1% bovine serum albumin and 0.1% bacitracin, and resuspended
(1 ml/1000000 cells). The homogenised product is frozen at
-80.degree. C. The membrane preparations are stable for more than 6
weeks under these conditions.
[0638] After thawing, the homogenised product is diluted 1:10 with
assay buffer (50 mM Tris, 150 mM NaCl, 5 mM MgCl.sub.2, 1 mM EDTA,
pH 7.40) and homogenised for 30 seconds with an Ultra-Turrax. 230
.mu.l of the homogenised product are incubated for 180 minutes at
ambient temperature with 50 pM
.sup.125I-iodotyrosyl-Calcitonin-Gene-Related Peptide (Amersham)
and increasing concentrations of the test substances in a total
volume of 250 .mu.l. The incubation is ended by rapid filtration
through GF/B glass fibre filters treated with polyethyleneimine
(0.1%) using a cell harvester. The protein-bound radioactivity is
measured using a gamma counter. Non-specific binding is defined as
the bound radioactivity after the presence of 1 .mu.M human
CGRP-alpha during incubation. The concentration binding curves are
analysed using computer-aided non-linear curve fitting.
[0639] The compounds mentioned hereinbefore show Ki values
.ltoreq.50 .mu.M in the test described.
B. CGRP Antagonism in SK-N-MC Cells
[0640] SK-N-MC cells (1 million cells) are washed twice with 250
.mu.l incubation buffer (Hanks' HEPES, 1 mM
3-isobutyl-1-methylxanthine, 1% BSA, pH 7.4) and pre-incubated at
37.degree. C. for 15 minutes. After the addition of CGRP (10 .mu.l)
as agonist in increasing concentrations (10.sup.-11 to 10.sup.-6
M), or additionally the substance in 3 to 4 different
concentrations, the mixture is incubated for another 15
minutes.
[0641] Intracellular cAMP is then extracted by the addition of 20
.mu.l of 1M HCl and centrifugation (2000.times.g, 4.degree. C., for
15 minutes). The supernatants are frozen in liquid nitrogen and
stored at -20.degree. C.
[0642] The cAMP contents of the samples are determined by
radioimmunoassay (Messrs. Amersham) and the pA.sub.2 values of
antagonistically acting substances are determined graphically.
[0643] The compounds according to the invention exhibit
CGRP-antagonistic properties in the in vitro test model described,
in a dosage range between 10.sup.-12 and 10.sup.-4 M.
[0644] To demonstrate that the compounds of general formula I
exhibit good to very good CGRP-antagonistic activities with
different structural elements, the following Table gives the
K.sub.i values obtained according to the test procedure described
above. It should be noted that the compounds were selected for
their different structural elements and not in order to emphasise
specific compounds:
TABLE-US-00003 Example K.sub.i [nM] (1) 0.4 (3) 4 (4) 1
INDICATIONS
[0645] In view of their pharmacological properties the compounds
according to the invention and the salts thereof with
physiologically acceptable acids are thus suitable for the acute
and prophylactic treatment of headaches, particularly migraine or
cluster headaches and tension headaches. Moreover, the compounds
according to the invention also have a positive effect on the
following diseases: non-insulin-dependent diabetes mellitus
("NIDDM"), cardiovascular diseases, morphine tolerance, diarrhoea
caused by clostridium toxin, skin diseases, particularly thermal
and radiation-induced skin damage including sunburn, lichen,
pruritis, pruritic toxidermies and severe itching, inflammatory
diseases, e.g. inflammatory diseases of the joints (osteoarthritis,
rheumatoid arthritis, neurogenic arthritis), generalised
soft-tissue rheumatism (fibromyalgia), neurogenic inflammation of
the oral mucosa, inflammatory lung diseases, allergic rhinitis,
asthma, COPD, diseases accompanied by excessive vasodilatation and
resultant reduced blood supply to the tissues, e.g. shock and
sepsis, chronic pain, e.g. diabetic neuropathies, neuropathies
induced by chemotherapy, HIV-induced neuropathies, postherpetic
neuropathies, neuropathies induced by tissue trauma, trigeminal
neuralgias, temporomandibular dysfunctions, CRPS (complex regional
pain syndrome), back pain, and visceral complaints, such as e.g.
irritable bowel syndrome (IBS) and inflammatory bowel syndrome. In
addition, the compounds according to the invention have a general
pain-relieving effect. The symptoms of menopausal hot flushes
caused by vasodilatation and increased blood flow in
oestrogen-deficient women and hormone-treated patients with
prostate carcinoma and castrated men are favourably affected by the
CGRP antagonists of the present application in a preventive and
acute-therapeutic capacity, this therapeutic approach being
distinguished from hormone replacement by the absence of side
effects.
[0646] The dosage required to achieve a corresponding effect is
conveniently 0.0001 to 3 mg/kg of body weight, preferably 0.01 to 1
mg/kg of body weight, when administered intravenously or
subcutaneously, and 0.01 to 10 mg/kg of body weight, preferably 0.1
to mg/kg of body weight when administered orally, nasally or by
inhalation, 1 to 3.times. a day in each case.
[0647] If the treatment with CGRP antagonists and/or CGRP release
inhibitors is given as a supplement to conventional hormone
replacement, it is advisable to reduce the doses specified above,
in which case the dosage may be from 1/5 of the lower limits
mentioned above up to 1/1 of the upper limits specified.
[0648] The invention further relates to the use of the compounds
according to the invention as valuable adjuvants for the production
and purification (by affinity chromatography) of antibodies as well
as in RIA and ELISA assays, after suitable radioactive labelling,
for example by tritiation of suitable precursors, for example by
catalytic hydrogenation with tritium or replacing halogen atoms
with tritium, and as a diagnostic or analytical adjuvant in
neurotransmitter research.
Combinations
[0649] Categories of active substance which may be used in
combination include e.g. antiemetics, prokinetics, neuroleptics,
antidepressants, neurokinin antagonists, anticonvulsants,
histamine-H1-receptor antagonists, 3-blockers, a-agonists and
a-antagonists, ergot alkaloids, mild analgesics, non-steroidal
antiphlogistics, corticosteroids, calcium antagonists,
5-HT.sub.1B/1D-agonists or other anti-migraine agents which 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, polyvinyl
pyrrolidone, citric acid, tartaric acid, water, water/ethanol,
water/glycerol, water/sorbitol, water/polyethylene glycol,
propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or
fatty substances such as hard fat or suitable mixtures thereof,
into conventional galenic preparations such as plain or coated
tablets, capsules, powders, suspensions, solutions, metered dose
aerosols or suppositories.
[0650] Thus other active substances which may be used for the
combinations mentioned above include for example the non-steroidal
antiinflammatories aceclofenac, acemetacin, acetyl-salicylic acid,
acetaminophen (paracetamol), azathioprine, diclofenac, diflunisal,
fenbufen, fenoprofen, flurbiprofen, ibuprofen, indometacin,
ketoprofen, leflunomide, lornoxicam, mefenamic acid, naproxen,
phenylbutazone, piroxicam, sulphasalazine, zomepirac or the
pharmaceutically acceptable salts thereof as well as meloxicam and
other selective COX2-inhibitors, such as for example rofecoxib,
valdecoxib, parecoxib, etoricoxib and celecoxib, as well as
substances that inhibit earlier or later stages of prostaglandin
synthesis or prostaglandin receptor antagonists such as e.g.
EP2-receptor antagonists and IP-receptor antagonists.
[0651] It is also possible to use ergotamine, dihydroergotamine,
metoclopramide, domperidone, diphenhydramine, cyclizine,
promethazine, chlorpromazine, vigabatrin, timolol, isometheptene,
pizotifen, botox, gabapentin, pregabalin, duloxetine, topiramate,
riboflavin, montelukast, lisinopril, micardis, prochloroperazine,
dexamethasone, flunarizine, dextropropoxyphene, meperidine,
metoprolol, propranolol, nadolol, atenolol, clonidine, indoramin,
carbamazepine, phenyloin, valproate, amitryptiline, imipramine,
venlafaxine, lidocaine or diltiazem and other
5-HT.sub.1B/1D-agonists such as, for example, almotriptan,
avitriptan, eletriptan, frovatriptan, naratriptan, rizatriptan,
sumatriptan and zolmitriptan.
[0652] Furthermore, CGRP antagonists with vanilloid receptor
antagonists, such as e.g. VR-1 antagonists, glutamate receptor
antagonists, such as e.g. MGlu5 receptor antagonists, mGlu1
receptor antagonists, iGlu5 receptor antagonists, AMPA receptor
antagonists, purine receptor blockers, such as e.g. P2X3
antagonists, NO-synthase inhibitors, such as e.g. INOS inhibitors,
calcium channel blockers, such as e.g. PQ-type blockers, N-type
blockers, potassium channel openers, such as e.g. KCNQ channel
openers, sodium channel blockers, such as e.g. PN3 channel
blockers, NMDA receptor antagonists, acid-sensing ion channel
antagonists, such as e.g. ASIC3 antagonists, bradykinin receptor
antagonists such as e.g. B1 receptor antagonists, cannabinoid
receptor agonists, such as e.g. CB2 agonists, CB1 agonists,
somatostatin receptor agonists, such as e.g. Sst2 receptor agonists
may be added.
[0653] The dosage of these active substances is expediently 1/5 of
the lowest usually recommended dose to 1/1 of the normally
recommended dose, i.e. for example 20 to 100 mg of sumatriptan.
Formulations
[0654] The compounds prepared according to the invention may be
administered either on their own or optionally in combination with
other active substances for the treatment of migraine by
intravenous, subcutaneous, intramuscular, intraarticular,
intrarectal, intranasal route, by inhalation, topically,
transdermally or orally, while aerosol formulations are
particularly suitable for inhalation. The combinations may be
administered either simultaneously or sequentially.
[0655] Suitable forms for administration are for example tablets,
capsules, solutions, syrups, emulsions or inhalable powders or
aerosols. The content of the pharmaceutically effective compound(s)
in each case should be in the range from 0.1 to 90 wt. %,
preferably 0.5 to 50 wt. % of the total composition, i.e. In
amounts which are sufficient to achieve the dosage range specified
hereinafter.
[0656] The preparations may be administered orally in the form of a
tablet, as a powder, as a powder in a capsule (e.g. a hard gelatine
capsule), as a solution or suspension. When administered by
inhalation the active substance combination may be given as a
powder, as an aqueous or aqueous-ethanolic solution or using a
propellant gas formulation.
[0657] Preferably, therefore, pharmaceutical formulations are
characterised by the content of one or more compounds of formula I
according to the preferred embodiments above.
[0658] It is particularly preferable if the compounds of formula I
are administered orally, and it is also particularly preferable if
they are administered once or twice a day. Suitable tablets may be
obtained, for example, by mixing the active substance(s) with known
excipients, for example inert diluents such as calcium carbonate,
calcium phosphate or lactose, disintegrants such as corn starch or
alginic acid, binders such as starch or gelatine, lubricants such
as magnesium stearate or talc and/or agents for delaying release,
such as carboxymethyl cellulose, cellulose acetate phthalate, or
polyvinyl acetate. The tablets may also comprise several
layers.
[0659] Coated tablets may be prepared accordingly by coating cores
produced analogously to the tablets with substances normally used
for tablet coatings, for example collidone or shellac, gum arabic,
talc, titanium dioxide or sugar. To achieve delayed release or
prevent incompatibilities the core may also consist of a number of
layers. Similarly the tablet coating may consist of a number of
layers to achieve delayed release, possibly using the excipients
mentioned above for the tablets.
[0660] Syrups containing the active substances or combinations
thereof according to the invention may additionally contain a
sweetener such as saccharine, cyclamate, glycerol or sugar and a
flavour enhancer, e.g. a flavouring such as vanillin or orange
extract. They may also contain suspension adjuvants or thickeners
such as sodium carboxymethyl cellulose, wetting agents such as, for
example, condensation products of fatty alcohols with ethylene
oxide, or preservatives such as p-hydroxybenzoates.
[0661] Capsules containing one or more active substances or
combinations of active substances may for example be prepared by
mixing the active substances with inert carriers such as lactose or
sorbitol and packing them into gelatine capsules.
[0662] Suitable suppositories may be made for example by mixing
with carriers provided for this purpose, such as neutral fats or
polyethyleneglycol or the derivatives thereof.
[0663] Excipients which may be used include, for example, water,
pharmaceutically acceptable organic solvents such as paraffins
(e.g. petroleum fractions), vegetable oils (e.g. groundnut or
sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or
glycerol), carriers such as e.g. natural mineral powders (e.g.
kaolins, clays, talc, chalk), synthetic mineral powders (e.g.
highly dispersed silicic acid and silicates), sugars (e.g. cane
sugar, lactose and glucose), emulsifiers (e.g. lignin, spent
sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone)
and lubricants (e.g. magnesium stearate, talc, stearic acid and
sodium lauryl sulphate).
[0664] For oral administration the tablets may, of course, contain,
apart from the abovementioned carriers, additives such as sodium
citrate, calcium carbonate and dicalcium phosphate together with
various additives such as starch, preferably potato starch,
gelatine and the like. Moreover, lubricants such as magnesium
stearate, sodium lauryl sulphate and talc may be used at the same
time for the tabletting process. In the case of aqueous suspensions
the active substances may be combined with various flavour
enhancers or colourings in addition to the excipients mentioned
above.
[0665] It is also preferred if the compounds of formula I are
administered by inhalation, particularly preferably if they are
administered once or twice a day. For this purpose, the compounds
of formula I have to be made available in forms suitable for
inhalation. Inhalable preparations include inhalable powders,
propellant-containing metered-dose aerosols or propellant-free
inhalable solutions, which are optionally present in admixture with
conventional physiologically acceptable excipients.
[0666] Within the scope of the present invention, the term
propellant-free inhalable solutions also includes concentrates or
sterile ready-to-use inhalable solutions. The preparations which
may be used according to the invention are described in more detail
in the next part of the specification.
EXPERIMENTAL SECTION
[0667] As a rule IR, .sup.1H-NMR and/or mass spectra have been
obtained for the compounds prepared. Unless stated otherwise,
R.sub.f values are determined using ready-made TLC silica gel
plates 60 F254 (E. Merck, Darmstadt, Item no. 1.05714) without
chamber saturation. The ratios given for the eluants relate to
units by volume of the particular solvents. The units by volume
given for NH.sub.3 relate to a concentrated solution of NH.sub.3 in
water.
[0668] Unless stated otherwise, the acid, base and salt solutions
used in working up the reaction solutions are aqueous systems of
the specified concentrations. Silica gel made by Millipore
(MATREX.TM., 35-70 .mu.m) is used for chromatographic
purifications.
[0669] The HPLC data provided are measured under the parameters
listed below and using the columns mentioned:
Columns Used:
[0670] (column temperature: 30.degree. C.; Injection volume: 5
.mu.L; detection at 254 nm)
TABLE-US-00004 S1 Zorbax column (Agilent Technologies), SB (Stable
Bond) C18; 3.5 .mu.m; 4.6 .times. 75 mm S2 Zorbax column (Agilent
Technologies), SB (Stable Bond) C18; 1.8 .mu.m; 3.0 .times. 30 mm
S3 Zorbax column (Agilent Technologies), SB (Stable Bond) C18; 5
.mu.m; 4.6 .times. 75 mm S4 Xbridge (Waters) C18; 3.0 .times. 30
mm, 2.5 .mu.m S5 Sunfire C18 (Waters); 3.5 .mu.m; 4.6 .times. 75 mm
S6 Symmetry C18 (Waters); 4.6 .times. 75 mm, 3.5 .mu.m
Solvents Used:
[0671] solvent A: water (with 0.1% formic acid), solvent B:
acetonitrile (with 0.1% formic acid), solvent C: water (with 0.1%
ammonia), solvent D: acetonitrile (with 0.1% ammonia).
[0672] The percentages stated refer to the total volume
Gradients:
TABLE-US-00005 [0673] time gradient [min] % A % B G1 0.00 95 5 (1.6
mL/min) 0.10 95 5 1.75 5 95 1.90 5 95 1.95 95 5 2.00 95 5 G2 0.00
95 5 (1.6 mL/min) 4.50 10 90 5.00 10 90 5.50 95 5 G3 0.00 95 5 (1.6
mL/min) 4.00 50 50 4.50 10 90 5.00 10 90 5.50 95 5 G4 0.00 95 5
(1.6 mL/min) 1.00 10 90 2.50 50 50 2.75 95 5 G5 0.00 95 5 (1.6
mL/min) 2.00 10 90 5.00 10 90 5.50 95 5 time gradient [min] % C % D
G6 0.00 95 5 (1.4 mL/min) 1.80 10 90 2.00 10 90 2.20 95 5 G7 0.00
95 5 (1.6 mL/min) 2.00 50 50 2.25 10 90 2.50 10 90 2.75 95 5 time
gradient [min] % A % B G8 0.00 95 5 (1.4 mL/min) 2.00 00 100 3.00
00 100 3.40 95 5
Methods:
TABLE-US-00006 [0674] column gradient method A S1 G1 method B S2 G1
method C S1 G2 method D S1 G3 method E S2 G4 method F S1 G5 method
G S4 G6 method H S2 G7 method I S5 G3 method K S5 G2 method L S6 G3
method M S6 G8
[0675] In preparative HPLC purifications as a rule the same
gradients are used as were used to obtain the analytical HPLC data.
The products are collected under mass control, the fractions
containing product are combined and freeze-dried.
[0676] In the absence of any more information regarding the
configuration, it is unclear whether there are pure enantiomers
involved or whether partial or even total racemisation has taken
place.
[0677] The following abbreviations are used in the test
descriptions:
18-crown-6 crown ether (1,4,7,10,13,16-hexaoxacyclooctadecan) AcOH
acetic acid AIBN 2,2'-azobis(2-methylpropionitrile) BINAP
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl BOC
tert.-butyloxycarbonyl CAD circulating air dryer Cyc cyclohexane
CDI 1,1'-carbonyldiimidazole DCM dichloromethane DIPE
diisopropylether DIPEA diisopropylethylamine
DMF N,N-dimethylformamide
[0678] of theoretical of theory D-water deionised water EI electron
jet ionisation (at MS) ESI electrospray ionisation (at MS) EtOAc
ethyl acetate EtOH ethanol el eluant HCl hydrogen chloride HCOOH
formic acid HPLC High Performance Liquid chromatography HPLC-MS
HPLC coupled mass spectrometry i. vac. in vacuo (under vacuum)
conc. concentrated MeOH methanol MS mass spectrometry MW molecular
weight [g/mol] NaOH sodium hydroxide NH.sub.4 OH ammonium hydroxide
(aqueous ammonia solution, 30%) NMP N-methyl-2-pyrrolidine
Pd.sub.2dba.sub.3 bis(dibenzylideneacetone) palladium (0) PE
petroleum ether R.sub.f retention index (in TLC) RT ambient
temperature R.sub.t retention time (in HPLC) TEA triethylamine TFA
trifluoroacetic acid THF tetrahydrofuran
Preparation of the Starting Compounds
Intermediate 1a
1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one-dihydrochloride
##STR00193##
[0680] This compound and its precursors were synthesised as
described in WO 2005/013894.
[0681] ESI-MS: m/z=219 (M+H).sup.+
[0682] R.sub.f: 0.11 (silica gel, DCM/MeOH/NH.sub.4OH=80:20:2)
Intermediate 1b
1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one
##STR00194##
[0683] Step 1: benzyl
4-(2-chloro-pyridin-3-yl-amino)-piperidine-1-carboxylate
##STR00195##
[0685] 560 mL (7.25 mol) TFA were added dropwise to 930 g (3.99
mol) N-benzyloxycarbonyl-4-piperidone and 466 g (3.63 mol)
2-chloro-3-aminopyridine in 9.5 L isopropyl acetate at approx.
15.degree. C. 922 g (4.35 mol) sodium triacetoxyborohydride were
added batchwise. The mixture was stirred until the reaction was
complete. At RT the reaction mixture was combined with 860 mL
sodium hydroxide solution (2 mol/L). The organic phase was
separated off, washed with 5 L water and evaporated down.
[0686] Yield: 1250 g (roughly 100% of theoretical)
[0687] ESI-MS: m/z=346 (M+H).sup.+
Step 2: benzyl
4-[1-(2-chloro-pyridin-3-yl)-ureido]-piperidine-1-carboxylate
##STR00196##
[0689] 530 mL (6.1 mol) chlorosulphonyl isocyanate were placed in 6
L THF and cooled to -15.degree. C. A solution of 1.25 kg (3.63 mol)
benzyl 4-(2-chloro-pyridin-3-yl-amino)-piperidine-1-carboxylate in
7 L THF was then added dropwise to this mixture within one hour
such that the temperature of the reaction mixture did not exceed
-7.degree. C. The mixture was stirred for 90 minutes at approx.
-8.degree. C. and then 700 mL water were added dropwise within 30
minutes. The mixture was stirred for 30 minutes at approx.
10.degree. C. and then slowly combined with 8.1 L sodium hydroxide
solution (2 mol/L). The reaction mixture was then heated to
50.degree. C. and the phases were separated. The organic phase was
washed with 2 L water. Then 10 L solvent were distilled off from
the organic phase, 15 L butyl acetate were added to the residue and
another 8 L were distilled off. The product was crystallised by
slow cooling to 0.degree. C. The precipitate was suction filtered,
washed with 2 L butyl acetate and dried at 40.degree. C.
[0690] Yield: 1108 g (78.8% of theoretical)
[0691] ESI-MS: m/z=389/391(M+H).sup.+
Step 3: benzyl
4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidine-1-carboxylate
##STR00197##
[0693] 1108 g (2.85 mol) benzyl
4-[1-(2-chloro-pyridin-3-yl)-ureido]-piperidine-1-carboxylate were
refluxed with 720 g (8.57 mol) sodium hydrogen carbonate in 14.5 L
tert-amylalcohol. 3 L solvent were distilled off. The reaction
mixture was cooled to 35.degree. C. and combined with 11 mL water.
Then 13 g (0.058 mol) palladium acetate and 49 g (0.115 mol)
1,4-bis-(diphenylphosphino)-butane (DPPB) were added and the
mixture was heated to reflux temperature. It was stirred at
100.degree. C. until the reaction was complete, cooled to RT and
7.5 L of water were added. The organic phase was separated off,
washed with 5 L water and then evaporated down. The oily residue
was mixed twice with 3 L isopropyl acetate and distilled off. Then
the residue was dissolved hot in 7 L isopropyl acetate and slowly
cooled to ambient temperature. The solid that crystallised out was
suction filtered, washed with 2 L isopropyl acetate and
tert.-butyl-methylether and dried at 50.degree. C.
[0694] Yield: 690 g (69% of theoretical)
[0695] ESI-MS: m/z=353 (M+H).sup.+
Step 4:
1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one
##STR00198##
[0697] 690 g (1.96 mol) benzyl
4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidine-1-carboxylate
were dissolved in 5.4 L methanol and hydrogenated with the addition
of 46 g Pd/C (10%; 6.6% by weight) at 60.degree. C. under a
hydrogen pressure of 60 psi until all the hydrogen had been taken
up. The catalyst was filtered off. 4 L methanol were distilled off
from the filtrate. 2 L methylcyclohexane were added and a further
1.5 L solvent were distilled off. The suspension thus obtained was
suction filtered, the residue was washed with methylcyclohexane and
dried at 40.degree. C.
[0698] Yield: 446 g (100% of theoretical)
[0699] ESI-MS: m/z=219 (M+H).sup.+
Intermediate 2
3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one
##STR00199##
[0701] This compound and its precursors were synthesised as
described in European Patent Application No. 1 619 187.
[0702] ESI-MS: m/z=246.2 (M+H).sup.+
Intermediate 3
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one
##STR00200##
[0703] Step 1: (5-methoxy-2-nitrophenyl)-acetonitrile
##STR00201##
[0705] 24.0 g (214 mmol) potassium-tert-butoxide in 100 mL DMF were
slowly added dropwise to a solution of 13.17 g (86.0 mmol)
4-nitroanisole and 18.0 g (107 mmol) 4-chlorophenoxyacetonitrile in
50 mL DMF. The reaction mixture was stirred for 30 min at
-10.degree. C. and then poured into 300 g of a 1:1 mixture of conc.
HCl and ice. After extraction with EtOAc the organic phase was
washed with water, dried and concentrated to dryness by rotary
evaporation in vacuo with gentle heating. The residue was treated
with a 1:1 mixture of PE/EtOAc and the product that crystallised
out was suction filtered. After washing with a 1:1 mixture of
PE/EtOAc the crystals were dried in the air. 6.5 g of the desired
product was obtained.
[0706] Yield: 6.5 g (39% of theoretical)
[0707] ESI-MS: m/z=210 (M+NH.sub.4).sup.+
[0708] R.sub.f: 0.45 (silica gel; PE/EtOAc=1:1)
Step 2: 2-(5-methoxy-2-nitrophenyl)-ethylamine
##STR00202##
[0710] Under a nitrogen atmosphere 200 mL (200 mmol) of a 1M borane
in THF solution were slowly added dropwise at RT to 12.6 g (65.7
mmol) (5-methoxy-2-nitrophenyl)-acetonitrile in 380 mL THF. The
reaction mixture was refluxed for 2 h. After cooling, 30 mL
methanol were added dropwise within 20 min. At the same time the
temperature was maintained at 10.degree. C. to 20.degree. C. with
an ice bath. The reaction mixture was stirred for 30 min at RT and
then within 30 min 45 mL of a 2M HCl solution were added dropwise
thereto. The reaction mixture was concentrated by rotary
evaporation i. vac. with gentle heating. The residue was diluted to
approx. 200 mL with water and extracted with 200 mL EtOAc. The
aqueous phase was made alkaline with a 15% (w/v) aqueous potassium
carbonate solution and continuously extracted with diethyl ether
overnight using a rotary perforator according to Ludwig (Messrs
Normag). The organic extract was concentrated to dryness by rotary
evaporation. 9.98 g of the desired product was obtained.
[0711] Yield: 9.98 g (77% of theoretical)
[0712] ESI-MS: m/z=197 (M+H).sup.+
[0713] R.sub.t (HPLC)=2.13 min (Method C)
Step 3:
(1-benzylpiperidin-4-yl)-[2-(5-methoxy-2-nitrophenyl)-ethyl]-amine
##STR00203##
[0715] Under a nitrogen atmosphere a mixture of 9.98 g (50.9 mmol)
2-(5-methoxy-2-nitrophenyl)-ethylamine, 9.80 mL (54.9 mmol)
N-benzylpiperidone and 6.30 mL (114 mmol) acetic acid in 270 mL DCM
was cooled to 0.degree. C. in an ice bath. At this temperature 14.2
g (67.0 mmol) sodium triacetoxyborohydride were added batchwise
within 20 min. The reaction mixture was stirred for a further 4 h
at 0.degree. C. and left to warm up to RT overnight. Then the
mixture was combined with 400 mL of a 15% (w/v) aqueous potassium
carbonate solution and stirred for 1 h at RT. The organic phase was
separated off, dried and concentrated by rotary evaporation. 18.8 g
of the desired product were obtained.
[0716] Yield: 18.8 g (quantitative)
[0717] ESI-MS: m/z=370 (M+H).sup.+
[0718] R.sub.t (HPLC)=1.93 min (Method C)
Step 4:
[2-(2-amino-5-methoxyphenyl)-ethyl]-(1-benzylpiperidin-4-yl)-amine
##STR00204##
[0720] 26.0 g (70.3 mmol)
(1-benzylpiperidin-4-yl)-[2-(5-methoxy-2-nitrophenyl)-ethyl]-amine
were hydrogenated with 5.00 g (2.45 mmol) rhodium charcoal (5%,
moistened with water) in 350 mL methanol in a 3 bar hydrogen
atmosphere for 3 h at RT. The catalyst was removed by suction
filtering and the solution was concentrated by rotary evaporation.
23.9 g of residue was obtained, which was immediately reacted
further without any further purification.
[0721] Yield: 23.9 g (quantitative)
[0722] R.sub.t (HPLC)=R.sub.t=0.99 min (Method D)
Step 5:
3-(1-benzylpiperidin-4-yl)-7-methoxy-1,3,4,5-tetrahydro-1,3-benzod-
iazepin-2-one
##STR00205##
[0724] 35.0 g (216 mmol) N,N'-carbonyldiimidazole were added to
23.9 g (70.3 mmol)
[2-(2-amino-5-methoxyphenyl)-ethyl]-(1-benzylpiperidin-4-yl)-amine
in 175 mL DMF and the mixture was stirred for 2 h at 100.degree. C.
The reaction mixture was poured onto approx. 1 kg of ice water and
stirred overnight. The precipitated product was suction filtered,
washed with 100 mL water and dried at 45.degree. C. in the CAD. The
residue was stirred with 150 mL DIPE and suction filtered. The
solid product was washed with 50 mL DIPE. After drying in the CAD
at 35.degree. C., 21.6 g of the desired product were obtained.
[0725] Yield: 21.6 g (84% of theoretical)
[0726] ESI-MS: m/z=366 (M+H).sup.+
[0727] R.sub.t (HPLC)=2.12 min (Method C)
Step 6:
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2--
one
##STR00206##
[0729] A mixture of 21.6 g (59.2 mmol)
3-(1-benzyl-piperidin-4-yl)-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepi-
n-2-one and 2.5 g palladium on charcoal (10%) in 300 mL methanol
was hydrogenated in a 3 bar hydrogen atmosphere at 50.degree. C.
until the reaction was complete. The catalyst was removed by
suction filtering and the mother liquor was concentrated by rotary
evaporation. The residue was triturated with 150 mL DIPE, suction
filtered, washed with 100 mL DIPE and dried at 40.degree. C. in the
CAD. 13.2 g of the desired product was obtained.
[0730] Yield: 13.2 g (81% of theoretical)
[0731] ESI-MS: m/z=276 (M+H).sup.+
[0732] R.sub.t (HPLC)=0.73 min (Method A)
Intermediate 4
3-piperidin-4-yl-1,3-dihydroimidazo[4,5-c]quinolin-2-one
##STR00207##
[0733] Step 1: 3-bromoquinoline-1-oxide
##STR00208##
[0735] A solution of 72% 3-chloroperbenzoic acid (97.8 g (0.408
mol) dissolved in 1000 mL DCM, dried on sodium sulphate and
filtered off) was added dropwise to a solution of 85.0 g (0.409
mol) 3-bromoquinoline in 100 mL DCM which had been cooled to
5.degree. C. Care was taken to ensure that the temperature of the
reaction mixture did not exceed 10.degree. C. After the addition
had ended the mixture was stirred for 5 h, then a solution of 72%
3-chloroperbenzoic acid (25.0 g (0.104 mol) dissolved in 200 mL
DCM, dried on sodium sulphate and filtered off) was again added
dropwise and the mixture was stirred overnight at RT. Saturated
aqueous sodium carbonate solution was added, the phases were
separated and the organic phase was dried on sodium sulphate. The
solution was filtered through activated charcoal and then
evaporated down i. vac.
[0736] Yield: 224 g (99% of theoretical)
[0737] ESI-MS: m/z=223/225 (Br)
[0738] R.sub.f=0.15 (silica gel, PE/EtOAc=2:1)
Step 2: 3-bromo-4-nitroquinoline-1-oxide
##STR00209##
[0740] A solution of 190 g (0.848 mol) 3-bromoquinoline-1-oxide in
500 mL concentrated sulphuric acid was heated to 90.degree. C. Then
120 g (1.19 mol) potassium nitrate was added in small batches such
that the temperature of the reaction did not exceed 95.degree. C.
The mixture was stirred for 3 h at 90.degree. C., left to cool to
RT and the mixture was poured onto ice. The precipitated product
was filtered off and the filter cake was washed with water. The
residue was dissolved in DCM and washed with saturated, aqueous
sodium hydrogen carbonate solution until the solution reacted in
alkaline manner. The phases were separated and the aqueous phase
was extracted with DCM. The combined organic phases were dried on
sodium sulphate and evaporated down i. vac. After comminution of
the residue and exhaustive drying i. vac. The product was obtained
as a yellow solid.
[0741] Yield: 104 g (46% of theoretical)
[0742] ESI-MS: m/z=268/270 (M+H).sup.+ (Br)
[0743] R.sub.f=0.77 (silica gel, EtOAc)
Step 3
(1-benzylpiperidin-4-yl)-(4-nitro-1-oxyquinolin-3-yl)-amine
##STR00210##
[0745] 104 g (0.387 mol) 3-bromo-4-nitroquinoline-1-oxide were
added to 320 mL (1.54 mol) 4-amino-1-benzylpiperidine. Then 500 mL
THF were added and the mixture was heated until the substances were
fully dissolved. Then it was stirred for 3 h at 70.degree. C. and
the reaction mixture was then evaporated down i. vac. The residue
obtained was dissolved in 2.5 L DCM and washed with saturated
aqueous sodium hydrogen carbonate solution.
[0746] The aqueous phase was extracted with 300 mL DCM. Then the
organic phases were combined, dried on sodium sulphate and
evaporated down i. vac. The residue was dissolved in 250 mL
methanol. The product precipitated as a solid was suction filtered
and dried i. vac.
[0747] Yield: 104 g (71% of theoretical)
[0748] ESI-MS: m/z=379 (M+H).sup.+
[0749] R.sub.f=0.75 (silica gel, EtOAc)
Step 4
N.sup..beta.-(1-benzylpiperidin-4-yl)quinoline-3,4-diamine
##STR00211##
[0751] 12.0 g rhodium charcoal (5%, moistened with water) were
added to 76.0 g (0.20 mol)
(1-benzylpiperidin-4-yl)-(4-nitro-1-oxyquinolin-3-yl)-amine in 1.0
L THF. The reaction was shaken for 4.5 h under a hydrogen
atmosphere (50 psi) at RT. The catalyst was filtered off and the
solvent was eliminated i. vac. Because of its proneness to
oxidation the crude product was used immediately for the next
step.
[0752] Yield: 66.0 g
[0753] R.sub.f=0.30 (silica gel,
DCM/MeOH/Cyc/NH.sub.4OH=70:15:15:2)
Step 5
3-(1-benzylpiperidin-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one
##STR00212##
[0755] 22.6 g (139 mmol) 1,1'-carbonyldiimidazole were added to
9.00 g (27.1 mmol)
N.sup.3-(1-benzylpiperidin-4-yl)-quinoline-3,4-diamine in 100 mL
DMF. The mixture was heated to 100.degree. C. and stirred for 1.5
h. After the reaction mixture had cooled it was poured onto 300 mL
water. The precipitated solid was filtered off, washed with water
and dried i. vac. At 30.degree. C. The residue was triturated with
diethyl ether, suction filtered and the solid product was dried i.
vac.
[0756] Yield: 7.42 g (77% of theoretical)
[0757] ESI-MS: m/z=359 (M+H).sup.+
[0758] R.sub.t (HPLC)=1.57 min (Method C)
Step 6 3-piperidin-4-yl-1,3-dihydroimidazo[4,5-c]quinolin-2-one
##STR00213##
[0760] A mixture of 44.0 g (0.123 mol)
3-(1-benzylpiperidin-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one
and 10.0 g palladium on charcoal (Pd/C 10%) in 500 mL methanol was
hydrogenated for 16 h at 50.degree. C. in a hydrogen atmosphere of
50 psi. After filtration of the reaction mixture the solvent was
eliminated in vacuo. Adding isopropanol caused the product to be
precipitated out. This was filtered off and then dried in
vacuo.
[0761] Yield: 31.2 g (95% of theoretical)
[0762] ESI-MS: m/z=269 (M+H).sup.+
[0763] R.sub.f=0.20 (silica gel,
DCM/MeOH/Cyc/NH.sub.4OH=70:15:15:2)
Intermediate 5
6-chloropyrimidine-4-carboxylic acid chloride
##STR00214##
[0764] Step 1: 6-hydroxypyrimidine-4-carboxylic acid
##STR00215##
[0766] 63.5 g (287 mmol) sodium diethyl-oxalacetate and 30.2 g (287
mmol) formamidine acetate were added to 24.1 g (597 mmol) NaOH in
3.6 L water. The mixture was stirred overnight at RT. Then
activated charcoal was added and the mixture was refluxed for 1 h.
It was filtered hot and after cooling acidified with aqueous HCl.
The solution was concentrated to dryness by rotary evaporation. The
residue contained the desired product and was used in the next step
without further purification.
[0767] Yield: 83.0 g
Step 2: 6-chloropyrimidine-4-carboxylic acid chloride
##STR00216##
[0769] 50 g (0.35 mol) 6-hydroxypyrimidine-4-carboxylic acid was
taken and 500 mL phosphorus oxychloride was added. Then 150 g
(0.720 mol) phosphorus pentachloride was added batchwise with
stirring. The reaction mixture was refluxed for 5 h. The phosphorus
oxychloride was distilled off and the residue was purified by
vacuum distillation through a column.
[0770] Yield: 52 (83% of theoretical)
[0771] ESI-MS: m/z=176/178/180 (M).sup.+ (2 Cl)
Intermediate 6
4-methyl-3H-benzoxazol-2-one
##STR00217##
[0773] 25.0 g (200 mmol) 2-amino-m-cresol and 70.4 mL (400 mmol)
DIPEA were placed in 1.0 L DCM and cooled to 0.degree. C. To this a
solution of 38.0 g (227 mmol) CDI was added dropwise over 30 min.
The mixture was stirred for 30 min at 0.degree. C., then stirred
overnight at RT. After evaporation of the reaction mixture i. vac.
down to half the volume, the aqueous phase was washed with water
(2.times.250 mL), 1M aqueous potassium hydrogen sulphate solution
(1.times.250 mL) and again water (1.times.250 mL). The organic
phase was evaporated down i. vac. The crude product left as a solid
was triturated with a mixture of diethyl ether and PE, the
precipitated solid was suction filtered, washed with PE and dried
i. vac.
[0774] Yield: 25.0 g (86% of theoretical)
[0775] ESI-MS: m/z=150(M+H).sup.+
[0776] R.sub.t (HPLC)=2.67 min (Method C)
Intermediate 7
6-(6-chloropyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one
##STR00218##
[0778] A well stirred mixture of 2.34 g (13.2 mmol)
6-chloropyrimidine-4-carboxylic acid chloride, 8.00 g (60.0 mmol)
aluminium trichloride and 1.79 g (12.0 mmol)
4-methyl-3H-benzoxazol-2-one was heated to 130.degree. C. for 1.5
h. After cooling to RT the mixture was decomposed with ice water,
then extracted with ethyl acetate, the organic phase was dried on
sodium sulphate and evaporated down i. vac. The crude product left
as a solid was triturated with diethyl ether, suction filtered and
dried in the air.
[0779] Yield: 2.00 g (52% of theoretical)
[0780] ESI-MS: m/z=290/292 (M+H).sup.+ (Cl)
[0781] R.sub.t (HPLC)=3.17 min (Method C)
Intermediate 8
6-(6-chloropyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one
##STR00219##
[0783] 0.35 g (8.0 mmol) sodium hydride (55%, suspension in mineral
oil) were added to 2.2 g (7.6 mmol) of
6-(6-chloropyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one in
10 mL N,N'-dimethylformamide. The reaction mixture was stirred for
30 min at RT. Then 0.95 mL (15.0 mmol) iodomethane were added and
the mixture was stirred for 1 h at RT. The reaction mixture was
combined with ice water, the aqueous phase was extracted several
times with EtOAc. The combined organic phases were dried on sodium
sulphate, filtered and concentrated to dryness by rotary
evaporation. The residue was triturated with diethyl ether, suction
filtered and dried.
[0784] Yield: 1.6 g (69% of theoretical)
[0785] ESI-MS: m/z=304/306 (Cl) (M+H).sup.+
[0786] R.sub.t (HPLC) 3.55 min (Method C)
Intermediate 9
(6-chloro-pyrimidin-4-yl)-(3,4-dichloro-phenyl)-methanone
##STR00220##
[0788] 3.00 g (17.0 mmol) 6-chloro-pyrimidine-4-carboxylic acid
chloride, 11.3 g (84.8 mmol) aluminium trichloride and 1.80 mL
(16.0 mmol) o-dichlorobenzene were heated for 1.5 h to 130.degree.
C. After cooling to RT the mixture was mixed with ice water, then
extracted with EtOAc, the organic phase was dried on magnesium
sulphate and evaporated down i. vac. The residue was triturated
with DIPE, suction filtered and dried.
[0789] Yield: 2.40 g (49% of theoretical)
[0790] EI-MS: m/z=286/288/290/292 (3.times.Cl) (M.sup.+)
[0791] R.sub.f: 0.76 (silica gel, PE/EtOAc=2/1)
Intermediate 10
(6-chloro-pyrimidin-4-yl)-(3,4-dimethyl-phenyl)-methanone
##STR00221##
[0793] 1.0 g (5.7 mmol) 6-chloro-pyrimidine-4-carboxylic acid
chloride were dissolved in 10 mL DCM, added to 3.7 g (28 mmol)
aluminium trichloride in 10 mL DCM and the mixture was stirred for
30 min at RT. Then 0.70 mL (5.8 mmol) xylene (dissolved in 10 mL
DCM) were slowly added dropwise to the reaction mixture and this
was stirred for 14 h at RT. It was then combined with DCM and 15%
potassium carbonate solution and the aqueous phase was extracted
several times with DCM. The organic phases were combined, dried on
magnesium sulphate and evaporated down i. vac.
[0794] Yield: 0.88 g (63% of theoretical)
[0795] ESI-MS: m/z=247/249 (Cl) (M+H).sup.+
[0796] R.sub.f: 0.71 (silica gel, PE/EtOAc=2/1)
Intermediate 11
(6-chloro-pyrimidin-4-yl)-(3,4-diethyl-phenyl)-methanone
##STR00222##
[0798] 1.0 g (5.7 mmol) 6-chloro-pyrimidine-4-carboxylic acid
chloride were dissolved in 10 mL DCM, added to 3.7 g (28 mmol)
aluminium trichloride in 10 mL DCM and the mixture was stirred for
30 min at RT. Then 0.93 mL (5.5 mmol) 1,2-diethylbenzene (dissolved
in 10 mL DCM) were slowly added dropwise to the reaction mixture
and this was stirred for 14 h at RT. It was then combined with DCM
and 15% potassium carbonate solution and the aqueous phase was
extracted several times with DCM. The organic phases were combined,
dried on magnesium sulphate and evaporated down i. vac.
[0799] Yield: 1.4 g (90% of theoretical)
[0800] ESI-MS: m/z=275 (M+H).sup.+
[0801] R.sub.f: 0.77 (silica gel, PE/EtOAc=2/1)
Intermediate 12
(6-chloro-pyrimidin-4-yl)-(3,4,5-trimethyl-phenyl)-methanone
##STR00223##
[0803] 1.0 g (5.7 mmol) 6-chloro-pyrimidine-4-carboxylic acid
chloride were dissolved in 10 mL DCM, added to 3.7 g (28 mmol)
aluminium trichloride in 10 mL DCM and the mixture was stirred for
30 min at RT. Then 0.70 g (5.8 mmol) 1,2,3-trimethylbenzene
(dissolved in 10 mL DCM) were slowly added dropwise to the reaction
mixture and this was stirred for 14 h at RT. It was then combined
with DCM and 15% potassium carbonate solution and the aqueous phase
was extracted several times with DCM. The organic phases were
combined, dried on magnesium sulphate and evaporated down i.
vac.
[0804] Yield: 0.90 g (61% of theoretical)
[0805] ESI-MS: m/z=261/263 (Cl) (M+H).sup.+
[0806] R.sub.f: 0.71 (silica gel, PE/EtOAc=2/1)
Intermediate 13
3-{1-[6-(4-benzyloxy-35-dimethyl-benzoyl)-pyrimidin-4-yl]-piperidin-4-yl}--
7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one
##STR00224##
[0807] Step 1:
(4-benzyloxy-3,5-dimethyl-phenyl)-(6-chloro-pyrimidin-4-yl)-methanone
##STR00225##
[0809] 150 mg (1.00 mmol) 4,6-dichloropyrimidine, 367 mg (1.50
mmol) 4-benzyloxy-3,5-dimethylbenzaldehyde and 166 mg (0.600 mmol)
1,3-dimethyl-3H-benzimidazol-1-ium-iodide (Chem. Pharm. Bull. 1990,
1147-52) in 10.0 mL THF were stirred at RT. Then 73.0 mg (1.51
mmol) sodium hydride (50% in mineral oil) were added and the
reaction mixture was refluxed for 2.5 h. The reaction mixture was
added to ice water and extracted with DCM. The organic phase was
dried and evaporated down.
[0810] Yield: 100 mg (28% of theoretical)
[0811] ESI-MS: m/z=353/55 (Cl) (M+H).sup.+
Step 2:
3-{1-[6-(4-benzyloxy-3,5-dimethyl-benzoyl)-pyrimidin-4-yl]-piperid-
in-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one
##STR00226##
[0813] 200 mg (0.730 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,
240 mg (0.680 mmol)
(4-benzyloxy-3,5-dimethyl-phenyl)-(6-chloro-pyrimidin-4-yl)-methanone
and 0.400 mL (2.30 mmol) DIPEA were combined in 2.0 mL DMF and
stirred for 3 h at RT. The mixture was added to ice water, the
precipitate was suction filtered and dried.
[0814] Yield: 400 mg (89% of theoretical)
[0815] Purity: 90%
[0816] ESI-MS: m/z=592 (M+H).sup.+
[0817] R.sub.t (HPLC): 5.0 min (method C)
Intermediate 14
6-chloro-pyrimidine-4-carboxylic acid methoxy-methyl-amide
##STR00227##
[0819] 20.7 mL (0.120 mol) DIPEA were added at 0.degree. C. to 10.7
g (54.4 mmol) 6-chloropyrimidine-4-carboxylic acid chloride and
5.50 g (56.4 mmol) N,O-dimethylhydroxylamine in 150 mL DCM and
stirred for 1 h at 0.degree. C. and 1 h at RT. The mixture was
diluted with DCM and washed with water. The organic phase was dried
on sodium sulphate, filtered and evaporated down.
[0820] Yield: 11.8 g (100% of theoretical)
[0821] Purity: 93%
Intermediate 15
6-(4-chloro-pyridin-2-carbonyl)-4-methyl-3H-benzoxazol-2-one
##STR00228##
[0823] 2.80 mL (38.1 mmol) thionyl chloride and 0.50 mL DMF were
added to 2.00 g (12.7 mmol) 4-chloropicolinic acid in 30 mL DCM and
the mixture was refluxed for 2 h. The reaction mixture was
evaporated to dryness and coevaporated twice with toluene. The
residue was mixed with 8.00 g (60.0 mmol) aluminium trichloride and
1.79 g (12.0 mmol) 4-methyl-3H-benzoxazol-2-one and stirred at
130.degree. C. The mixture was decomposed with ice water and
extracted twice with EtOAc. The organic phases were combined, dried
on magnesium sulphate, filtered and evaporated down i. vac. The
residue was triturated with DiPE and suction filtered. For further
purification the residue was purified by preparative HPLC-MS.
[0824] The fractions containing the product were combined and
freeze-dried.
[0825] Yield: 30 mg (1% of theoretical)
[0826] ESI-MS: m/z=289/291 (Cl) (M+H).sup.+
[0827] m/z=287/289 (Cl) (M-H).sup.-
[0828] R.sub.f: 0.17 (silica gel, PE/EtOAc=2/1)
Intermediate 16
5-phenyl-2-piperidin-4-yl-2,4-dihydro-[1,2,4]triazol-3-one
##STR00229##
[0830] This compound and its precursors were synthesised
analogously to US2001/36946 A1 (US2001-789391).
[0831] R.sub.f: 0.28 (silica gel,
DCM/Cyc/MeOH/NH.sub.4OH=70/15/15/2)
Intermediate 17
1-{1-[6-(4-benzyloxy-3,5-dimethyl-benzoyl)-pyrimidin-4-yl]-piperidin-4-yl}-
-1,3-dihydro-imidazo[4,5-b]pyridin-2-one
##STR00230##
[0832] Step 1: 2-benzyloxy-5-bromo-1,3-dimethyl-benzene
##STR00231##
[0834] 11.7 mL (96.5 mmol) benzylbromide were added dropwise to 20
g (96.5 mmol) 2,6-dimethyl-4-bromophenol and 16.5 g (118 mmol)
potassium carbonate in 300 mL acetone and stirred overnight at RT.
The precipitate formed was suction filtered, washed with acetone
and the filtrate was evaporated down. The residue was dissolved in
DCM, filtered through Alox and washed with DCM. The filtrate was
evaporated down.
[0835] Yield: 28.5 g (99% of theoretical)
[0836] Purity: 98%
[0837] R.sub.t (HPLC): 1.43 min (method E)
Step 2:
(4-benzyloxy-3,5-dimethyl-phenyl)-(6-chloro-pyrimidin-4-yl)-methan-
one
##STR00232##
[0839] Under an argon atmosphere 2.8 mL (4.5 mmol) of a 1.6 M
n-butyllithium solution were added to a mixture of 1.2 g (4.0 mmol)
2-benzyloxy-5-bromo-1,3-dimethyl-benzene in mL THF cooled to
-75.degree. C. and the mixture was stirred for 1 h at -75.degree.
C. Then 0.96 g (4.3 mmol) 6-chloro-pyrimidine-4-carboxylic
acidmethoxy-methyl-amide, dissolved in 10 mL THF, were added
dropwise. After another 30 min stirring at -75.degree. C. the
reaction mixture was slowly heated to 0.degree. C. The mixture was
combined with saturated sodium hydrogen carbonate solution and
extracted with diethyl ether. The organic phase was dried and
evaporated down. The residue was purified by flash
chromatography.
[0840] Yield: 0.43 g (29% of theoretical)
Step 3:
1-{1-[6-(4-benzyloxy-3,5-dimethyl-benzoyl)-pyrimidin-4-yl]-piperid-
in-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one
##STR00233##
[0842] 170 mg (0.779 mmol)
1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one, 270 mg
(0.727 mmol)
(4-benzyloxy-3,5-dimethyl-phenyl)-(6-chloro-pyrimidin-4-yl)-methano-
ne and 0.200 mL (1.42 mmol) TEA were combined in 2.0 mL DMF and
stirred overnight at RT. The reaction mixture was stirred into ice
water, the precipitate was suction filtered and dried.
[0843] Yield: 390 mg (95% of theoretical)
Intermediate 18
7-methoxy-3-(1-{6-[7-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-
e-5-carbonyl]-pyrimidin-4-yl}-piperidin-4-yl)-1,3,4,5-tetrahydro-benzo[d][-
1,3]diazepin-2-one
##STR00234##
[0844] Step 1: 4-bromo-2,6-dimethylphenyldiazonium
tetrafluoroborate
##STR00235##
[0846] 21.2 g (0.104 mol) 4-bromo-2,6-dimethylaniline in 58.0 mL
(0.444 mol) tetrafluoroboric acid (48% in water) were diluted with
water to form a stirrable suspension. 7.18 g (0.104 mol) sodium
nitrite, dissolved in water, were slowly added dropwise to the
reaction mixture which was cooled to 0.degree. C. After the
addition had ended the mixture was stirred for 1 h at RT. The
product precipitated as a solid was suction filtered, washed three
times with diethyl ether and dried.
[0847] Yield: 26.5 g (85% of theoretical)
Step 2: 5-bromo-7-methyl-1H-indazole
##STR00236##
[0849] 39.0 g (0.130 mol)
4-bromo-2,6-dimethylphenyldiazonium-tetrafluoroborate were added
batchwise to 25.5 g (0.260 mol) potassium acetate and 1.72 g (6.50
mmol) 18-crown-6 in 700 mL chloroform with mechanical stirring,
stirred for a further 3 h at RT and then left to stand overnight at
RT. The precipitated product was suction filtered and washed with
100 mL chloroform. The precipitate was stirred with 500 mL water
and extracted with 800 mL DCM. The organic phase was dried and
evaporated down i. vac. The remaining filtrate was washed with 1 L
water, dried on sodium sulphate and evaporated down. The residue
was combined with DIPE, the precipitated substance was suction
filtered, washed again with DIPE and dried. The solids obtained
were combined.
[0850] Yield: 19.8 g (72% of theoretical)
[0851] ESI-MS: m/z=209/211 (Br) (M-H).sup.-
[0852] R.sub.f: 0.5 (silica gel, DCM/MeOH=90/10)
Step 3:
5-bromo-7-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole
##STR00237##
[0854] 1.95 mL (11.0 mmol) (2-chloromethoxy-ethyl)-trimethyl-silane
were added to 2.11 g (10.0 mmol) 5-bromo-7-methyl-1H-indazole and
1.80 mL (12.3 mmol) N-methyldicyclohexylamine in 50 mL THF and
stirred overnight at RT. The precipitate formed was filtered off
and the filtrate was evaporated down. The residue was purified by
flash chromatography.
[0855] Yield: 0.78 g (23% of theoretical)
[0856] ESI-MS: m/z=341/343 (Br) (M+H).sup.+
[0857] R.sub.t (HPLC): 1.6 min (method E)
Step 4:
(6-chloro-pyrimidin-4-yl)-[7-methyl-1-(2-trimethylsilanyl-ethoxyme-
thyl)-1H-indazol-5-yl]-methanone
##STR00238##
[0859] Under an argon atmosphere 0.34 g (1.00 mmol)
5-bromo-7-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole in
10 mL THF were cooled to -75.degree. C., mixed with 0.70 mL (1.1
mmol) of a 1.6 molar n-butyllithium solution and stirred for 1 h at
-75.degree. C. Then 0.25 g (1.1 mmol)
6-chloro-pyrimidine-4-carboxylic acidmethoxy-methyl-amide,
dissolved in a little THF, were added dropwise. The cooling bath
was removed and the mixture was heated to 0.degree. C. and stirred
for a further hour in the ice bath. The mixture was stirred with
saturated sodium hydrogen carbonate solution, extracted with EtOAc,
the organic phase was dried and evaporated down. The residue was
purified by flash chromatography.
[0860] Yield: 58 mg (14% of theoretical)
[0861] R.sub.t (HPLC): 1.4 min (method E)
Step 5:
7-methoxy-3-(1-{6-[7-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-
-indazole-5-carbonyl]-pyrimidin-4-yl}-piperidin-4-yl)-1,3,4,5-tetrahydro-b-
enzo[d][1,3]diazepin-2-one
##STR00239##
[0863] 36 mg (0.13 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,
50 mg (0.12 mmol)
(6-chloro-pyrimidin-4-yl)-[7-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1-
H-indazol-5-yl]-methanone and 30 .mu.L (0.21 mmol) TEA were
combined in 0.5 mL DMF and stirred overnight at RT. The reaction
mixture was mixed with ice water, the product precipitated as a
solid was filtered off and dried.
[0864] Yield: 71 mg (84% of theoretical)
[0865] ESI-MS: m/z=642 (M+H).sup.+
[0866] R.sub.t (HPLC): 1.78 min (method B)
Intermediate 19
6-(6-chloro-pyrimidine-4-carbonyl)-3-methyl-3H-benzoxazol-2-one
##STR00240##
[0867] Step 1:
6-(6-chloro-pyrimidine-4-carbonyl)-3H-benzoxazol-2-one
##STR00241##
[0869] 3.93 g (22.2 mmol) 6-chloropyrimidine-4-carboxylic acid
chloride, 3.00 g (22.2 mmol) 2-benzoxazolinone and 14.8 g (111
mmol) aluminium trichloride were combined and heated for 3 h to
130.degree. C. Then the mixture was combined with ice water and
EtOAc, the solid was suction filtered and the phases were
separated. The aqueous phase was extracted twice with EtOAc, the
organic phases were combined, dried and evaporated down. The
residue was triturated in DIPE, suction filtered and dried.
[0870] Yield: 1.4 g (23% of theoretical)
[0871] ESI-MS: m/z=274/276 (M-H).sup.-
[0872] R.sub.t (HPLC): 1.17 min (method B)
Step 2:
6-(6-chloro-pyrimidine-4-carbonyl)-3-methyl-3H-benzoxazol-2-one
##STR00242##
[0874] 135 mg (3.10 mmol) sodium hydride (55%, suspension in
mineral oil) were added to 800 mg (2.90 mmol)
6-(6-chloro-pyrimidine-4-carbonyl)-3H-benzoxazol-2-one in 10 mL DMF
and the mixture was stirred for 30 min at RT. Then 0.368 mL (5.80
mmol) iodomethane were added and the mixture was stirred for a
further hour at RT. The mixture was mixed with ice water and
extracted twice with EtOAc. The organic phases were combined,
washed with water, dried and evaporated down. The residue was
triturated with DIPE, suction filtered and dried.
[0875] Yield: 600 mg (71% of theoretical)
[0876] ESI-MS: m/z=290/292 (M+H).sup.+
[0877] R.sub.t (HPLC): 1.33 min (method B)
Intermediate 20
5-(6-chloro-pyrimidine-4-carbonyl)-1,3-dihydro-indol-2-one
##STR00243##
[0879] 3.93 g (22.2 mmol) 6-chloropyrimidine-4-carboxylic acid
chloride, 2.96 g (22.2 mmol) 2-oxoindole and 14.8 g (111 mmol)
aluminium trichloride were combined and heated for 3 h to
130.degree. C. Then the mixture was mixed with ice water and
extracted twice with EtOAc. The organic phases were combined, dried
and evaporated down. The residue was triturated in DIPE, suction
filtered, washed and dried.
[0880] Yield: 1.4 g (23% of theoretical)
[0881] ESI-MS: m/z=272/274 (M-H).sup.-
[0882] R.sub.t (HPLC): 1.12 min (method B)
Intermediate 21
6-(2-bromo-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one
##STR00244##
[0884] 2.20 mL (30.0 mmol) thionyl chloride and 0.390 mL (4.80
mmol) DMF were added to 2.00 g (9.90 mmol)
2-bromopyridine-4-carboxylic acid in 30 mL DCM and refluxed for 2
h. The reaction mixture was evaporated to dryness and coevaporated
twice with toluene. The residue was combined with 6.24 g (46.8
mmol) aluminium trichloride and 1.50 g (10.1 mmol)
4-methyl-3H-benzoxazol-2-one and the mixture obtained was stirred
overnight at 110.degree. C. and for 5 hours at 130.degree. C. The
mixture was decomposed with ice water and extracted twice with DCM.
The organic phases were dried on magnesium sulphate, filtered and
evaporated down i. vac. The residue was triturated with DIPE/MeOH
and suction filtered. The product obtained is a mixture of the
corresponding bromine and chlorine compound (40/60).
[0885] Yield: 1.0 g (.about.30% of theoretical)
Intermediate 22
7-chloro-3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one
##STR00245##
[0887] 801 mg (6.00 mmol) N-chlorosuccinimide were added to 1.23 g
(5.00 mmol)
3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one in
10.0 mL carbon tetrachloride and the mixture was refluxed for 72 h.
The solvent was eliminated i. vac. and the crude product was
purified by flash chromatography. The fractions containing the
product were concentrated by rotary evaporation and purified by
preparative HPLC.
[0888] Yield: 420 mg (30% of theoretical)
[0889] ESI-MS: m/z=280/282 (Cl) (M+H).sup.+
[0890] R.sub.t (HPLC): 1.96 min (method C)
Intermediate 23
6-(6-chloro-pyrimidine-4-carbonyl)-3-ethyl-4-methyl-3H-benzoxazol-2-one
##STR00246##
[0892] 44 mg (1.0 mmol) sodium hydride (55%, suspension in mineral
oil) were added to 0.25 g (0.86 mmol)
6-(6-chloropyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one in
2.0 mL DMF and the mixture was stirred for 30 min at RT. Then 98
.mu.L (1.2 mmol) ethyl iodide were added and the mixture was
stirred for 1 h at RT. The reaction mixture was diluted with ice
water and extracted with EtOAc. The organic phase was washed with
water, dried on sodium sulphate, filtered and evaporated down i.
vac. The residue was purified by flash chromatography. The
fractions containing the product were combined and evaporated
down.
[0893] Yield: 110 mg (40% of theoretical)
[0894] R.sub.t (HPLC): 3.83 min (method C)
Intermediate 24
6-(6-chloro-pyrimidine-4-carbonyl)-4-methyl-3H-benzothiazol-2-one
##STR00247##
[0895] Step 1: 4-methyl-3H-benzothiazol-2-one
##STR00248##
[0897] 5.00 g (30.5 mmol) 2-amino-4-methylbenzothiazole in 15.0 mL
formic acid, 6.10 mL glacial acetic acid and 112 mL conc.
hydrochloric acid were cooled to -5.degree. C. with stirring and
slowly combined with a solution of 2.10 g (30.5 mmol) sodium
nitrite in 5.0 mL water. The reaction mixture was stirred for 20
min at this temperature, then heated to RT and then refluxed
overnight. The cooled mixture was then mixed with water and
extracted several times with EtOAc. The combined organic phases
were washed with saturated sodium chloride solution, dried on
sodium sulphate, filtered and the filtrate was evaporated down.
[0898] Yield: 3.70 g (74% of theoretical)
[0899] ESI-MS: m/z=164 (M-H).sup.-
[0900] R.sub.t (HPLC): 0.89 min (method B)
Step 2:
6-(6-chloro-pyrimidine-4-carbonyl)-4-methyl-3H-benzothiazol-2-one
##STR00249##
[0902] 1.93 g (10.0 mmol) 6-chloropyrimidine-4-carboxylic acid
chloride, 1.80 g (10.9 mmol) 4-methyl-3H-benzothiazol-2-one and
7.33 g (55.0 mmol) aluminium trichloride were combined and heated
to 130.degree. C. for 3 h with stirring. The mixture was combined
with ice water and EtOAc, the flakes formed were suction filtered
and the phases were separated. The aqueous phase was extracted with
EtOAc. The organic phases were combined, dried on sodium sulphate,
filtered and the filtrate was evaporated down i. vac. The residue
was triturated with DIPE, the precipitate was suction filtered and
dried.
[0903] Yield: 1.10 g (33% of theoretical)
[0904] R.sub.t (HPLC): 1.40 min (method B)
Intermediate 25
6-(2-chloro-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one
##STR00250##
[0905] Step 1:
6-(2-chloro-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one
##STR00251##
[0907] 2.80 mL (38.1 mmol) thionyl chloride and 0.50 mL DMF were
added to 2.10 g (12.9 mmol) 2-chloroisonicotinic acid in 30.0 mL
DCM and the mixture was refluxed for 2 h. The reaction mixture was
evaporated to dryness and coevaporated twice with toluene. The
residue was combined with 8.00 g (60.0 mmol) aluminium trichloride
and 1.79 g (12.0 mmol) 4-methyl-3H-benzoxazol-2-one and stirred
overnight at 130.degree. C. The mixture was decomposed with ice
water and extracted twice with EtOAc. The organic phases were
combined, dried on magnesium sulphate, filtered and evaporated down
i. vac. The residue was triturated with DIPE and isopropanol,
suction filtered and dried.
[0908] Yield: 1.70 g (46% of theoretical)
[0909] ESI-MS: m/z=287/289 (Cl) (M-H).sup.-
[0910] R.sub.f: 0.13 (silica gel, PE/EtOAc=2/1)
Step 2:
6-(2-chloro-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one
##STR00252##
[0912] 220 mg (1.94 mmol) potassium-tert-butoxide were added to 500
mg (1.73 mmol)
6-(2-chloro-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one in
10.0 mL THF and the mixture was stirred for 30 min at RT. Then
0.220 mL (3.46 mmol) methyl iodide were added and the mixture was
stirred overnight at RT. The reaction mixture was diluted with
EtOAc and washed several times with saturated sodium chloride
solution. The organic phase was dried on magnesium sulphate,
filtered and evaporated down i. vac. The residue was triturated
with DIPE and suction filtered.
[0913] Yield: 390 mg (74% of theoretical)
[0914] ESI-MS: m/z=303/5 (Cl) (M+H).sup.+
[0915] R.sub.t (HPLC): 1.42 min (method B)
Intermediate 26
3-(3-fluoro-piperidin-4-yl)-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diaz-
epin-2-one
##STR00253##
[0916] Step 1: (5-methoxy-2-nitro-phenyl)-acetonitrile
##STR00254##
[0918] A solution of 110 g (0.653 mol)
4-(chloro-phenoxy)-acetonitrile and 100 g (0.653 mol)
1-methoxy-4-nitrobenzene in DMF were added dropwise to 161 g (1.44
mol) potassium-tert-butoxide in 1.50 L DMF within 1.5 h at
-30.degree. C. The reaction mixture was stirred for 30 min at
-30.degree. C., then poured into 2.0 L of a 2N aqueous hydrochloric
acid solution and stirred for 1 h. The precipitate formed was
suction filtered, washed with water and then dissolved in EtOAc.
This solution was dried on sodium sulphate, filtered and the
filtrate was evaporated down. The residue was added to EtOAc/PE=1/1
and cooled. The product precipitated as a solid was suction
filtered, washed with DIPE and dried.
[0919] Yield: 55 g (44% of theoretical)
[0920] ESI-MS: m/z=191 (M-H).sup.-
[0921] R.sub.1: 0.4 (silica gel: EtOAc/PE=1/9)
Step 2: 2-(5-methoxy-2-nitro-phenyl)-ethylamine
##STR00255##
[0923] 1.5 L of a 1 M borane solution in THF were slowly added
dropwise at 10.degree. C. to 110 g (0.572 mol)
(5-methoxy-2-nitro-phenyl)-acetonitrile in 0.5 L THF and the
mixture was stirred for 16 h at RT. The reaction mixture was
combined at 0.degree. C. with 250 ml MeOH and the mixture was
stirred for 1 h at RT. Then 250 mL of a 2N aqueous hydrochloric
acid solution were added and the excess THF was evaporated down.
The aqueous phase was extracted with EtOAc, then made basic with
saturated sodium carbonate solution and then extracted with EtOAc.
The organic phase was washed with water and saturated NaCl
solution, dried on sodium sulphate, filtered and the filtrate was
evaporated down.
[0924] Yield: 67.0 g (60% of theoretical)
[0925] ESI-MS: m/z=197 (M+H).sup.+
[0926] R.sub.f: 0.3 (silica gel: MeOH/chloroform=1/9)
Step 3: tert-butyl
3-fluoro-4-[2-(5-methoxy-2-nitro-phenyl)-ethylamino]-piperidine-1-carboxy-
late
##STR00256##
[0928] 1.00 mL (17.7 mmol) acetic acid and 2.09 g (9.86 mmol)
sodium triacetoxyborohydride were added at 0.degree. C. to 1.50 g
(7.65 mmol) 2-(5-methoxy-2-nitro-phenyl)-ethylamine and 1.80 g
(8.29 mmol) tert-butyl 3-fluoro-4-oxo-piperidine-1-carboxylate in
25 mL DCM and then the mixture was stirred for 3 h at RT. The
reaction mixture was combined at 0.degree. C. with a saturated
potassium carbonate solution and the aqueous phase was extracted
several times with DCM. The combined organic phases were washed
with water and saturated sodium chloride solution, dried on sodium
sulphate, filtered and the filtrate was evaporated down. The
residue was purified by flash chromatography.
[0929] Yield: 1.75 g (58% of theoretical)
[0930] R.sub.f: 0.65 (silica gel: MeOH/chloroform=1/9)
Step 4: tert-butyl
4-[2-(2-amino-5-methoxy-phenyl)-ethylamino]-3-fluoro-piperidine-1-carboxy-
late
##STR00257##
[0932] 3.50 g (8.81 mmol) tert-butyl
3-fluoro-4-[2-(5-methoxy-2-nitro-phenyl)-ethylamino]-piperidine-1-carboxy-
late were stirred with 0.8 g palladium on charcoal (Pd/C 10%) and
17.5 mL (359 mmol) hydrazine hydrate in 50 mL EtOH for 16 h at RT.
The catalyst was suction filtered through kieselguhr and the
solution was concentrated by rotary evaporation.
[0933] Yield: 3 g (93% of theoretical)
[0934] R.sub.f: 0.5 (silica gel: MeOH/chloroform 1/9)
Step 5: tert-butyl
3-fluoro-4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl-
)-piperidine-1-carboxylate
##STR00258##
[0936] 3.97 g (24.5 mmol) CDI were added to 3.00 g (8.16 mmol)
tert-butyl
4-[2-(2-amino-5-methoxy-phenyl)-ethylamino]-3-fluoro-piperidine-1-carboxy-
late in 20 mL DMF and the mixture was refluxed for 2 h. The
reaction mixture was cooled and mixed with ice water. The aqueous
phase was extracted several times with EtOAc, the organic phases
were combined, dried on sodium sulphate, filtered and the filtrate
was evaporated down. The residue was purified by flash
chromatography.
[0937] Yield: 2.10 g (65% of theoretical)
[0938] ESI-MS: m/z=394 (M+H).sup.+
[0939] R.sub.f: 0.65 (silica gel: MeOH/chloroform=1/9)
Step 6:
3-(3-fluoro-piperidin-4-yl)-7-methoxy-1,3,4,5-tetrahydro-benzo[d][-
1,3]diazepin-2-one
##STR00259##
[0941] 3.20 g (8.13 mmol) tert-butyl
3-fluoro-4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl-
)-piperidine-1-carboxylate were cooled to 0.degree. C. and at this
temperature slowly combined with 50 mL of a hydrochloric acid
solution (4 M in dioxane). Then the mixture was heated to RT and
stirred for 16 h at RT. The precipitate formed was suction
filtered, washed with diethyl ether and dried.
[0942] Yield: 2.20 g (92% of theoretical)
[0943] ESI-MS: m/z=294 (M+H).sup.+
[0944] R.sub.f: 0.2 (silica gel: MeOH/chloroform=1/9)
Intermediate 27
7-methoxy-3-(3-methyl-piperidin-4-yl)-1,3,4,5-tetrahydro-benzo[d][1,3]diaz-
epin-2-one
##STR00260##
[0945] Step 1: tert-butyl
4-[2-(5-methoxy-2-nitro-phenyl)-ethylamino]-3-methyl-piperidine-1-carboxy-
late
##STR00261##
[0947] 1.74 mL (29.0 mmol) acetic acid and 3.48 g (16.4 mmol)
sodium triacetoxyborohydride were added at 0.degree. C. to 2.50 g
(12.7 mmol) 2-(5-methoxy-2-nitro-phenyl)-ethylamine and 2.93 g
(13.7 mmol) tert-butyl 3-methyl-4-oxo-piperidine-1-carboxylate
(WO2004/41777) in 75 mL DCM and the mixture was stirred for 3 h at
RT. The reaction mixture was combined at 0.degree. C. with a
saturated potassium carbonate solution and the aqueous phase was
extracted several times with DCM. The combined organic phases were
washed with water and saturated sodium chloride solution, dried on
sodium sulphate, filtered and the filtrate was evaporated down. The
residue was purified by flash chromatography.
[0948] Yield: 4.50 g (90% of theoretical)
[0949] ESI-MS: m/z=394 (M+H).sup.+
[0950] R.sub.f: 0.65 (silica gel: MeOH/chloroform=1/9)
Step 2: tert-butyl
4-[2-(2-amino-5-methoxy-phenyl)-ethylamino]-3-methyl-piperidine-1-carboxy-
late
##STR00262##
[0952] 4.50 g (11.4 mmol) tert-butyl
4-[2-(5-methoxy-2-nitro-phenyl)-ethylamino]-3-methyl-piperidine-1-carboxy-
late were stirred with 0.6 g palladium on charcoal (Pd/C 10%) and
22.5 mL (460 mmol) hydrazine hydrate in 100 mL EtOH for 16 h at RT.
The catalyst was suction filtered through kieselguhr and the
filtrate was evaporated down i. vac.
[0953] Yield: 4 g (96% of theoretical)
[0954] ESI-MS: m/z=364 (M+H).sup.+
[0955] R.sub.f: 0.5 (silica gel: MeOH/chloroform=1/9)
Step 3: tert-butyl
4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-3-methy-
l-piperidine-1-carboxylate
##STR00263##
[0957] 7.20 g (44.4 mmol) CDI were added to 5.40 g (14.9 mmol)
tert-butyl
4-[2-(2-amino-5-methoxy-phenyl)-ethylamino]-3-methyl-piperidine-1-carboxy-
late in 75 mL DMF and the mixture was refluxed for 2 h. The
reaction mixture was cooled to RT and stirred for 16 h. After the
addition of ice water the aqueous phase was extracted several times
with EtOAc. The organic phase was dried on sodium sulphate,
filtered and the filtrate was evaporated down i. vac. The residue
obtained was purified by flash chromatography.
[0958] Yield: 4.00 g (69% of theoretical)
[0959] R.sub.f: 0.65 (silica gel: MeOH/chloroform=1/9)
Step 4:
7-methoxy-3-(3-methyl-piperidin-4-yl)-1,3,4,5-tetrahydro-benzo[d][-
1,3]diazepin-2-one
##STR00264##
[0961] 2.50 g (6.42 mmol) tert-butyl
4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-3-methy-
l-piperidine-1-carboxylate were slowly combined with 50 mL
hydrochloric acid solution (4 M in dioxane) at 0.degree. C. Then
the mixture was heated to RT and stirred for 16 h. The precipitate
formed was suction filtered, washed with diethyl ether and
dried.
[0962] Yield: 1.50 g (81% of theoretical)
[0963] ESI-MS: m/z=290 (M+H).sup.+
[0964] R.sub.f: 0.2 (silica gel: MeOH/chloroform=1/9)
Intermediate 28
7-methoxy-3-(2-methyl-piperidin-4-yl)-1,3,4,5-tetrahydro-benzo[d][1,3]diaz-
epin-2-one
##STR00265##
[0965] Step 1: benzyl
4-[2-(5-methoxy-2-nitro-phenyl)-ethylamino]-2-methyl-piperidine-1-carboxy-
late
##STR00266##
[0967] At 0.degree. C. 1.04 mL (17.3 mmol) acetic acid and 2.09 g
(9.86 mmol) sodium triacetoxyborohydride were added to 1.50 g (7.65
mmol) 2-(5-methoxy-2-nitro-phenyl)-ethylamine and 2.04 g (8.25
mmol) benzyl 2-methyl-4-oxo-piperidine-1-carboxylate (WO2007/11810)
in 75 mL DCM and the mixture was stirred for 3 h at RT. Then the
reaction mixture was combined at 0.degree. C. with a saturated
potassium carbonate solution and the aqueous phase was extracted
several times with DCM. The combined organic phases were washed
with water and saturated sodium chloride solution, dried on sodium
sulphate, filtered and the filtrate was evaporated down. The
residue was purified by flash chromatography.
[0968] Yield: 3.00 g (92% of theoretical)
[0969] ESI-MS: m/z=428 (M+H).sup.+
[0970] R.sub.f: 0.6 (silica gel: MeOH/chloroform=1/9)
Step 2: benzyl
4-[2-(2-amino-5-methoxy-phenyl)-ethylamino]-2-methyl-piperidine-1-carboxy-
late
##STR00267##
[0972] 5.30 g (12.4 mmol) benzyl
4-[2-(5-methoxy-2-nitro-phenyl)-ethylamino]-2-methyl-piperidine-1-carboxy-
late were stirred with 1.5 g palladium on charcoal (Pd/C 10%) and
24.3 mL (499 mmol) hydrazine hydrate in 100 mL EtOH for 16 h at RT.
The catalyst was suction filtered through kieselguhr and the
filtrate was evaporated down i. vac.
[0973] Yield: 4.60 g (93% of theoretical)
[0974] ESI-MS: m/z=398 (M+H).sup.+
[0975] R.sub.f: 0.5 (silica gel: MeOH/chloroform=1/9)
Step 3: benzyl
4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-2-methy-
l-piperidine-1-carboxylate
##STR00268##
[0977] 3.17 g (19.6 mmol) CDI were added to 2.60 g (6.54 mmol)
benzyl
4-[2-(2-amino-5-methoxy-phenyl)-ethylamino]-2-methyl-piperidine-1-carboxy-
late in 20 mL DMF and the mixture was refluxed for 2 h. The
reaction mixture was cooled to RT and stirred for 16 h. Then ice
water was added. The aqueous phase was extracted several times with
EtOAc.
[0978] The organic phases were combined, dried on sodium sulphate,
filtered and the filtrate was evaporated down i. vac. The residue
was purified by flash chromatography.
[0979] Yield: 2.24 g (81% of theoretical)
[0980] ESI-MS: m/z=424 (M+H).sup.+
[0981] R.sub.f: 0.65 (silica gel: MeOH/chloroform=1/9)
Step 4:
7-methoxy-3-(2-methyl-piperidin-4-yl)-1,3,4,5-tetrahydrobenzo[d][1-
,3]diazepin-2-one
##STR00269##
[0983] 2.00 g (4.88 mmol) benzyl
4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-2-methy-
l-piperidine-1-carboxylate were cooled to 0.degree. C. and at this
temperature 50 mL hydrochloric acid solution (4 M in dioxane) were
slowly added. Then the mixture was heated to RT and stirred for 16
h. The precipitate formed was suction filtered, washed with diethyl
ether and dried.
[0984] Yield: 1.20 g (85% of theoretical)
[0985] ESI-MS: m/z=290 (M+H).sup.+
[0986] R.sub.f: 0.2 (silica gel: MeOH/chloroform=1/9)
Intermediate 29
6-(2,6-dichloro-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one
##STR00270##
[0987] Step 1:
6-(2,6-dichloro-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one
##STR00271##
[0989] 3.00 g (14.3 mmol) 2,6-dichloropyridine-4-carboxylic acid
chloride, 1.80 g (11.0 mmol) 4-methyl-3H-benzoxazol-2-one and 9.47
g (71.0 mmol) aluminium trichloride were combined and heated for 2
h to 125.degree. C. with stirring. Then the mixture was decomposed
with ice water and EtOAc and the phases were separated. The aqueous
phase was extracted several times with EtOAc. The organic phases
were combined, dried on sodium sulphate, filtered and the filtrate
was evaporated down i. vac. The residue was triturated with diethyl
ether, the precipitate was suction filtered and dried i. vac.
[0990] Yield: 2.90 g (63% of theoretical)
[0991] ESI-MS: m/z=321/323/325 (2.times.Cl) (M+H).sup.+
[0992] R.sub.t(HPLC): 1.49 min (method B)
Step 2:
6-(2,6-dichloro-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2--
one
##STR00272##
[0994] Under a nitrogen atmosphere 2.30 g (7.12 mmol)
6-(2,6-dichloro-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one
in 10 mL DMF were combined at 0.degree. C. with 310 mg (7.10 mmol)
sodium hydride (55%, suspension in mineral oil). The reaction
mixture was stirred for 30 min at RT. Then 0.44 mL (7.10 mmol)
iodomethane were added and the mixture was stirred overnight at RT.
The reaction mixture was poured onto water and the precipitated
product was suction filtered, washed with water and dried.
[0995] Yield: 2.40 g (quantitative)
[0996] ESI-MS: m/z=409/411 (2.times.Cl) (M+H).sup.+
[0997] R.sub.t(HPLC): 1.59 min (method B)
Intermediate 30
6-(2-benzyloxy-6-chloro-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2--
one
##STR00273##
[0998] Step 1:
6-(2-benzyloxy-6-chloro-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one
##STR00274##
[1000] 3.85 mL (3.85 mmol) sodium benzylate solution (1M in
benzylalcohol) were added to 1.24 g (3.85 mmol)
6-(2,6-dichloro-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one
in 50 mL THF and stirred overnight at RT. The reaction mixture was
combined with saturated sodium hydrogen carbonate solution and
extracted with EtOAc. The combined organic phases were dried and
evaporated down i. vac.
[1001] Yield: 1.10 g (72% of theoretical)
[1002] R.sub.t(HPLC): 2.60 min (method F)
Step 2:
6-(2-benzyloxy-6-chloro-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzo-
xazol-2-one
##STR00275##
[1004] Under a nitrogen atmosphere and while cooling with ice 220
mg (5.06 mmol) sodium hydride (55%, suspension in mineral oil) were
added to 2.00 g (5.07 mmol)
6-(2-benzyl-oxy-6-chloro-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-on-
e in 10 mL DMF. The reaction mixture was stirred for 30 min at RT.
Then 0.312 mL (5.06 mmol) iodomethane were added and the mixture
was stirred overnight at RT. The reaction mixture was poured onto
water and the precipitated product was suction filtered, washed
with water and dried. The residue was stirred with diethyl ether,
suction filtered and dried.
[1005] Yield: 2.00 g (97% of theoretical)
[1006] ESI-MS: m/z=409 (Cl) (M+H).sup.+
[1007] R.sub.t(HPLC): 1.80 min (method B)
Intermediate 31
6-(3-bromo-benzoyl)-3,4-dimethyl-3H-benzoxazol-2-one
##STR00276##
[1008] Step 1: 6-(3-bromo-benzoyl)-4-methyl-3H-benzoxazol-2-one
##STR00277##
[1010] 2.08 g (9.48 mmol) 3-bromo-benzoic acid chloride, 1.41 g
(9.48 mmol) 4-methyl-3H-benz-oxazol-2-one and 5.33 g (40.0 mmol)
aluminium trichloride were heated to 125.degree. C. with stirring
for 1.5 h. Then the mixture was mixed with ice water and the grease
precipitated was separated from the solvent by decanting. The
residue was dissolved in EtOAc, evaporated down and a little MeOH
was triturated. The precipitate formed was suction filtered, washed
with diethyl ether and dried i. vac.
[1011] Yield: 1.00 g (32% of theoretical)
[1012] ESI-MS: m/z=332 (M+H).sup.+
[1013] R.sub.t(HPLC): 1.53 min (method B)
Step 2: 6-(3-bromo-benzoyl)-3,4-dimethyl-3H-benzoxazol-2-one
##STR00278##
[1015] 144 mg (3.30 mmol) sodium hydride (55%, suspension in
mineral oil) were added at RT to 1.00 g (3.01 mmol)
6-(3-bromo-benzoyl)-4-methyl-3H-benzoxazol-2-one in 4 mL DMF. The
reaction mixture was stirred for 30 min at RT. Then 0.285 mL (4.50
mmol) iodomethane were added and the mixture was stirred for 1 h at
RT. The reaction mixture was poured onto ice water and the
precipitate formed was suction filtered, washed with water and
dried i. vac.
[1016] Yield: 0.98 g (94% of theoretical)
[1017] ESI-MS: m/z=346 (M+H).sup.+
[1018] R.sub.t(HPLC): 1.61 min (method B)
Intermediate 32
6-methoxy-3-piperidin-4-yl-1H-quinolin-2-one
##STR00279##
[1019] Step 1:
1-benzyl-4-(2-chloro-6-methoxy-quinoline-3-yl)-piperidin-4-ol
##STR00280##
[1021] Under an argon atmosphere 14.0 mL (28.0 mmol) of a 2 M
lithium diisopropylamide solution in 50 mL THF were cooled to
-78.degree. C. and combined with stirring with a solution of 5.00 g
(25.1 mmol) of 2-chloro-6-methoxy-quinoline in THF. After 1 h
stirring at -78.degree. C., 4.5 mL (25.2 mmol) N-benzylpiperidone
were added dropwise. After 1 h stirring at -78.degree. C. the
mixture was allowed to come up to RT and stirred overnight. The
mixture was evaporated down i. vac. and purified by flash
chromatography through Alox. The fractions containing the product
were combined and evaporated down.
[1022] Yield: 2.10 g (13% of theoretical)
[1023] Purity: 60%
[1024] ESI-MS: m/z=383 (M+H).sup.+
[1025] R.sub.t(HPLC): 1.14 min (method B)
Step 2:
3-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-6-methoxy-quinolin-2--
ol
##STR00281##
[1027] 1.90 g (4.96 mmol)
1-benzyl-4-(2-chloro-6-methoxy-quinoline-3-yl)-piperidin-4-ol were
added to 25 mL of a 4N aqueous hydrochloric acid solution and
stirred overnight at 100.degree. C. Then 15 ml of a concentrated
aqueous hydrochloric acid solution were added dropwise and the
mixture was again stirred overnight. The mixture was evaporated
down by half i. vac., diluted with water and extracted with EtOAc.
The organic phase was dried on sodium sulphate, filtered and
evaporated down. The residue was triturated with PE/EtOAc and the
product remaining as a solid was suction filtered and dried.
[1028] Yield: 165 mg (8% of theoretical)
[1029] Purity: 80%
[1030] ESI-MS: m/z=347 (M+H).sup.+
Step 3: 6-methoxy-3-piperidin-4-yl-1H-quinolin-2-one
##STR00282##
[1032] A mixture of 160 mg (0.462 mmol)
3-(1-benzyl-1.2.3.6-tetrahydro-pyridin-4-yl)-6-methoxy-quinolin-2-ol
and 20 mg palladium on charcoal (Pd/C 10%) in 30 mL MeOH was first
of all hydrogenated for 17.5 h at 50.degree. C. in a hydrogen
atmosphere of 50 psi. Then 10 mL THF and 20 mg palladium on
charcoal (Pd/C 10%) were added and hydrogenation continued for a
further 2 h under the same conditions. Another 20 mg palladium on
charcoal (Pd/C 10%) were added and the mixture was hydrogenated
overnight at 50.degree. C. in a hydrogen atmosphere of 60 psi. Then
the reaction mixture was filtered, washed with DMF and the filtrate
was evaporated down. The residue was added to EtOAc, triturated
with PE and filtered. The precipitate was washed with DIPE and
dried.
[1033] Yield: 56 mg (35% of theoretical)
[1034] Purity: 75%
[1035] ESI-MS: m/z=259 (M+H).sup.30
[1036] R.sub.t(HPLC): 0.90 min (method B)
Intermediate 33
6-(3,6-dichloro-pyridazine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one
##STR00283##
[1038] 2.00 mL (27.4 mmol) thionyl chloride were added to 1.92 g
(9.95 mmol) 3,6-dichloro-pyridazine-4-carboxylic acid in 10 mL
1,2-dichloroethane and the mixture was refluxed for 2 h. The
reaction mixture was evaporated to dryness and coevaporated with
1,2-dichloroethane. Then 5.30 g (39.8 mmol) aluminium trichloride
and 1.56 g (10.5 mmol) 4-methyl-3H-benzoxazol-2-one were added and
the mixture was stirred for 1 h at 100.degree. C. under a nitrogen
atmosphere. Then it was stirred for a further 2 h at 120.degree.
C., 3 h at 130.degree. C. and then cooled for 48 h at RT. The
mixture was decomposed with ice water and extracted with DCM. The
organic phases were combined, washed with water, dried on sodium
sulphate, filtered and evaporated down i. vac. The residue was
triturated with DIPE, suction filtered and dried.
[1039] Yield: 0.660 g (18% of theoretical)
[1040] ESI-MS: m/z=324 (M+H).sup.+
[1041] R.sub.t(HPLC): 1.43 min (method B)
Intermediate 34
6-(5-bromo-1-oxy-pyridin-3-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one
##STR00284##
[1042] Step 1: 5-bromo-nicotinic acid chloride hydrochloride
##STR00285##
[1044] 2.00 g (9.90 mmol) 5-bromonicotinic acid were mixed with 20
mL thionyl chloride and boiled for 4 h. The mixture was evaporated
to dryness i. vac. and coevaporated twice with toluene. The residue
was reacted further as the crude product.
[1045] Yield: 2.35 g (92% of theoretical)
Step 2:
6-(5-bromo-pyridin-3-carbonyl)-4-methyl-3H-benzoxazol-2-one
##STR00286##
[1047] 2.57 g (10.0 mmol) 5-bromo-nicotinic acid chloride
hydrochloride, 1.49 g (10.0 mmol) 4-methyl-3H-benzoxazol-2-one and
5.33 g (40.0 mmol) aluminium trichloride were heated to 125.degree.
C. with stirring for 1.5 h. After cooling to RT the mixture was
mixed with ice water. The precipitate formed was suction filtered,
washed with water and dried i. vac.
[1048] Yield: 2.30 g (69% of theoretical)
[1049] ESI-MS: m/z=333 (M+H).sup.+
[1050] R.sub.t(HPLC): 1.41 min (method B)
Step 3:
6-(5-bromo-pyridin-3-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one
##STR00287##
[1052] 0.18 g (4.00 mmol) sodium hydride (55%, suspension in
mineral oil) were added at RT to 1.27 g (3.80 mmol)
6-(5-bromo-pyridin-3-carbonyl)-4-methyl-3H-benzoxazol-2-one in 5 mL
DMF. The reaction mixture was stirred for 30 min at RT. Then 0.32
mL (5.00 mmol) iodomethane were added and the mixture was stirred
overnight at RT. The reaction mixture was poured onto ice water and
the precipitate formed was suction filtered, washed with water and
dried i. vac.
[1053] Yield: 1.15 g (87% of theoretical)
[1054] ESI-MS: m/z=347 (M+H).sup.+
[1055] R.sub.t(HPLC): 1.54 min (method B)
Step 4:
6-(5-bromo-1-oxy-pyridin-3-carbonyl)-3,4-dimethyl-3H-benzoxazol-2--
one
##STR00288##
[1057] 0.690 g (4.00 mmol) m-chloro-perbenzoic acid were added to
1.05 g (3.03 mmol)
6-(5-bromo-pyridin-3-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one in
15 mL DCM and the mixture was stirred for 4 h at RT. After the
addition of another 100 mg of m-chloro-perbenzoic acid the reaction
mixture was stirred overnight at RT. Then it was diluted with DCM
and extracted twice with 1N aqueous sodium hydroxide solution. The
organic phase was dried on sodium sulphate, filtered and evaporated
down i. vac. and the residue obtained was dried.
[1058] Yield: 1.05 g (96% of theoretical)
[1059] ESI-MS: m/z=363 (M+H).sup.+
[1060] R.sub.t(HPLC): 1.27 min (method B)
Intermediate 35
6-(2-chloro-6-methoxy-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-on-
e
##STR00289##
[1061] Step 1:
6-(2,6-dichloro-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one
##STR00290##
[1063] 10.0 g (47.5 mmol) 2,6-dichloropyridine-4-carboxylic acid
chloride, 7.08 g (47.5 mmol) 4-methyl-3H-benzoxazol-2-one and 32.0
g (240 mmol) aluminium trichloride were heated to 120.degree. C.
for 1 h with stirring. The mixture was mixed with ice water and
extracted several times with EtOAc. The solid precipitated from
EtOAc was suction filtered and washed with EtOAc. The organic phase
remaining was separated off, dried on sodium sulphate, filtered and
evaporated down. The residue was combined with a little EtOAc, the
precipitated solid was suction filtered and washed with a little
EtOAc. For further purification the mixture was recrystallised from
EtOAc.
[1064] Yield: 7.00 g (46% of theoretical)
[1065] ESI-MS: m/z=323 (M+H).sup.+
[1066] R.sub.t(HPLC): 1.6 min (method B)
Step 2:
6-(2-chloro-6-methoxy-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol--
2-one
##STR00291##
[1068] Under a nitrogen atmosphere 0.21 g (9.3 mmol) sodium were
added batchwise to 50 mL MeOH. After the sodium had dissolved
completely, 1.0 g (3.1 mmol) of
6-(2,6-dichloro-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one
were added and the mixture was refluxed for 5 h. Then the reaction
mixture was evaporated down i. vac., the residue was combined with
50 mL water and the precipitated solid was suction filtered. This
was washed with a little water and dried.
[1069] Yield: 0.9 g (91% of theoretical)
[1070] ESI-MS: m/z=319 (M+H).sup.+
[1071] R.sub.t(HPLC): 1.45 min (method B)
Step 3:
6-(2-chloro-6-methoxy-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxa-
zol-2-one
##STR00292##
[1073] Under a nitrogen atmosphere 0.13 g (2.9 mmol) sodium hydride
(55%, suspension in mineral oil) were added 0.90 g (2.8 mmol)
6-(2-chloro-6-methoxy-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one
in 10 mL DMF at RT. The reaction mixture was stirred for 30 min at
RT. Then 0.18 mL (5.0 mmol) iodomethane in 1 mL DMF were added
dropwise and the mixture was stirred overnight at RT. The reaction
mixture was poured onto water and the precipitate formed was
suction filtered and washed with water. The residue was extracted
with diethyl ether, suction filtered and dried.
[1074] Yield: 0.84 g (89% of theoretical)
[1075] ESI-MS: m/z=333 (M+H).sup.+
[1076] R.sub.t(HPLC): 1.70 min (method B)
Intermediate 36
3-(1-{5-[hydroxy-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-yl)-methyl]-pyri-
dazin-3-yl}-piperidin-4-yl)-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diaz-
epin-2-one
##STR00293##
[1078] A mixture of 0.25 g (0.40 mmol)
3-{1-[6-chloro-5-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-pyri-
dazin-3-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diaz-
epin-2-one, 0.10 mL (0.71 mmol)TEA and 50 mg palladium on charcoal
(Pd/C 10%) in MeOH was hydrogenated for 3 h at 50.degree. C. in a
hydrogen atmosphere of 50 psi. After filtration of the reaction
mixture the filtrate was evaporated down to approx. 3 mL and mixed
with a little ice water. The precipitate formed was suction
filtered and dried. The residue contained the desired product in
the mixture and was used in the next step without further
purification.
[1079] Yield: 130 mg (12% of theoretical)
[1080] Purity: 20%
Intermediate 37
6-(3-bromo-4-fluoro-benzoyl)-3,4-dimethyl-3H-benzoxazol-2-one
##STR00294##
[1081] Step 1: 3-bromo-4-fluoro-benzoic acid chloride
##STR00295##
[1083] 2.17 g (9.41 mmol) 3-bromo-4-fluorobenzoic acid were mixed
with 20 mL thionyl chloride and then boiled for 2 h. The reaction
mixture was evaporated to dryness and coevaporated twice with
toluene. The residue was reacted further as the crude product.
[1084] Yield: 2.23 g
Step 2:
6-(3-bromo-4-fluoro-benzoyl)-4-methyl-3H-benzoxazol-2-one
##STR00296##
[1086] 2.23 g (9.40 mmol) 3-bromo-4-fluoro-benzoic acid chloride,
1.40 g (9.40 mmol) 4-methyl-3H-benzoxazol-2-one and 5.01 g (37.60
mmol) aluminium trichloride were heated to 125.degree. C. for 1.5 h
with stirring. After cooling to RT the mixture was mixed with ice
water. The precipitate formed was suction filtered and washed with
water. Then the precipitate was triturated with MeOH, suction
filtered, washed with MeOH and dried i. vac.
[1087] Yield: 1.90 g (58% of theoretical)
[1088] ESI-MS: m/z=350 (M+H).sup.+
[1089] R.sub.t(HPLC): 3.89 min (method C)
Step 3:
6-(3-bromo-4-fluoro-benzoyl)-3,4-dimethyl-3H-benzoxazol-2-one
##STR00297##
[1091] 0.175 g (4.00 mmol) sodium hydride (55%, suspension in
mineral oil) were added at RT to 1.33 g (3.80 mmol)
6-(3-bromo-4-fluoro-benzoyl)-4-methyl-3H-benzoxazol-2-one in 5 mL
DMF. The reaction mixture was stirred for 30 min at RT. Then 0.317
mL (5.00 mmol) iodomethane were added and the mixture was stirred
for 1 h at RT. Then 0.100 mL (15.8 mmol) iodomethane were added and
the mixture was stirred overnight at RT. After the addition of ice
water the reaction mixture was extracted with EtOAc. The organic
phase was washed with water, dried on sodium sulphate and
evaporated down i. vac. The residue was purified by flash
chromatography. The fractions containing the product were combined,
evaporated down and dried i. vac.
[1092] Yield: 1.38 g (quantitative)
[1093] ESI-MS: m/z=364 (M+H).sup.+
[1094] R.sub.t(HPLC): 1.32 min (method E)
Intermediate 38
3-{1-[6-chloro-5-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-p-
yridazin-3-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]d-
iazepin-2-one
##STR00298##
[1095] Step 1:
6-(3,6-dichloro-pyridazine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one
##STR00299##
[1097] 85 mg (2.1 mmol) sodium hydride (55%, suspension in mineral
oil) were added to 0.65 g (2.0 mmol)
6-(3,6-dichloro-pyridazine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one
in 10 mL DMF while cooling with ice. The reaction mixture was
stirred for 20 min. Then 0.19 mL (3.1 mmol) iodomethane were added
while cooling with ice and the mixture was stirred for 2 h at RT.
The reaction mixture was mixed with ice water, the precipitate
formed was suction filtered and dried.
[1098] Yield: 0.62 g (82% of theoretical)
Step 2:
3-{1-[6-chloro-5-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-car-
bonyl)-pyridazin-3-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[-
d][1,3]diazepin-2-one
##STR00300##
[1100] 550 mg (2.00 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one-
, 610 mg (1.80 mmol)
6-(3.6-dichloro-pyridazine-4-carbonyl)-3,4-dimethyl-3H-benz-oxazol-2-one,
630 mg (4.39 mmol) copper(I)bromide and 430 mL (2.50 mmol) DIPEA in
5 mL DMF were stirred for 2 h at 110.degree. C., then cooled and
filtered. The filtrate was combined with 1 mL of a 1N aqueous
hydrochloric acid solution and precipitated with 40 mL ice water.
The precipitate was suction filtered, washed with water and dried.
The solid was stirred with 120 mL DCM/MeOH (11:1), filtered through
silica gel and washed with DCM/MeOH. The filtrate was evaporated
down. The residue was triturated with diethyl ether, suction
filtered and dried. A mixture of isomers was obtained which was
further reacted.
[1101] Yield: 870 mg (50% of theoretical)
[1102] Purity: 60%
[1103] ESI-MS: m/z=575(M-H).sup.-
[1104] R.sub.t(HPLC): 3.70 min (method C)
Intermediate 39
6-(3,5-difluoro-benzoyl)-3,4-dimethyl-3H-benzoxazol-2-one
##STR00301##
[1105] Step 1: 3,5-difluoro-benzoic acid chloride
##STR00302##
[1107] 1.63 g (10.00 mmol) 3,5-difluoro-benzoic acid were mixed
with 20 mL thionyl chloride and boiled for 2 h. The reaction
mixture was evaporated to dryness and coevaporated twice with
toluene. The residue was reacted further as the crude product.
[1108] Yield: 1.45 g (82% of theoretical)
Step 2: 6-(3,5-difluoro-benzoyl)-4-methyl-3H-benzoxazol-2-one
##STR00303##
[1110] 1.45 g (8.21 mmol) 3,5-difluorobenzoic acid chloride, 1.22 g
(8.21 mmol) 4-methyl-3H-benzoxazol-2-one and 4.40 g (33.0 mmol)
aluminium trichloride were heated to 125.degree. C. for 1.5 h with
stirring. The mixture was mixed with ice water and the product
precipitated as a solid was suction filtered and washed with water.
After trituration of the precipitate with MeOH it was suction
filtered, washed with MeOH and dried i. vac.
[1111] Yield: 2.20 g (93% of theoretical)
[1112] ESI-MS: m/z=290 (M+H).sup.+
[1113] R.sub.t(HPLC): 1.61 min (method B)
Step 3:
6-(3,5-difluoro-benzoyl)-3,4-dimethyl-3H-benzoxazol-2-one
##STR00304##
[1115] 0.349 g (8.00 mmol) sodium hydride (55%, suspension in
mineral oil) were added at RT to 2.20 g (7.61 mmol)
6-(3,5-difluoro-benzoyl)-4-methyl-3H-benzoxazol-2-one in 10 mL DMF.
The reaction mixture was stirred for 30 min at RT. Then 0.634 mL
(10.0 mmol) iodomethane were added and the mixture was stirred for
1 h at RT. Then another 0.1 mL iodomethane were added and the
mixture was stirred further at RT. After the addition of ice water
the mixture was extracted with EtOAc. The organic phase was washed
with water, dried on sodium sulphate and evaporated down i. vac.
The residue was purified by flash chromatography. The fractions
containing the product were combined, evaporated down and dried i.
vac.
[1116] Yield: 1.00 g (43% of theoretical)
[1117] ESI-MS: m/z=304 (M+H).sup.+
[1118] R.sub.t(HPLC): 1.68 min (method B)
Intermediate 40
6-(6-chloro-pyrimidine-4-carbonyl)-3-methyl-4-pyrazol-1-ylmethyl-3H-benzox-
azol-2-one
##STR00305##
[1120] Under a nitrogen atmosphere 0.15 g (0.49 mmol)
6-(6-chloropyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one,
95 mg (0.53 mmol) N-bromosuccinimide and 5.0 mg (30 mmol)
2,2'-azobis-isobutyronitrile (AIBN) in 15 mL carbon tetrachloride
were combined refluxed for 4 h. The precipitate formed was filtered
off and the filtrate was combined with 20 .mu.L isopropanol. After
brief stirring 36 mg (0.53 mmol) pyrazole and 0.17 mL (0.99 mmol)
DIPEA were added and the mixture was refluxed for 6 h. Then the
reaction mixture was filtered through silica gel and washed with
DCM/EtOAc (1/1). The filtrate was evaporated down i. vac. and the
residue was reacted further as the crude product.
[1121] Yield: 210 mg (58% of theoretical)
[1122] Purity: 50%
[1123] R.sub.t(HPLC): 3.35 min (method C)
Intermediate 41
4-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-2-fluoro-benzoni-
trile
##STR00306##
[1124] Step 1: 4-cyano-3-fluoro-benzoic acid chloride
##STR00307##
[1126] 0.66 g (4.0 mmol) 4-cyano-3-fluoro-benzoic acid were mixed
with 10 mL thionyl chloride and boiled for 2 h. The mixture was
evaporated to dryness and coevaporated twice with toluene. The
residue was reacted further as the crude product.
[1127] Yield: 0.73 g (quantitative)
Step 2:
2-fluoro-4-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-ben-
zonitrile
##STR00308##
[1129] 0.73 g (4.0 mmol) 4-cyano-3-fluoro-benzoic acid chloride,
0.60 g (4.0 mmol) 4-methyl-3H-benzoxazol-2-one and 2.1 g (16 mmol)
aluminium trichloride were heated to 125.degree. C. for 1.5 h with
stirring. After cooling to RT the mixture was combined with ice
water. The precipitate formed was suction filtered, washed with
water and dried i. vac.
[1130] Yield: 1.2 g (quantitative)
[1131] ESI-MS: m/z=295 (M-H).sup.-
[1132] R.sub.t(HPLC): 1.45 min (method B)
Step 3:
4-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-2-fluoro-
-benzonitrile
##STR00309##
[1134] 0.190 g (4.30 mmol) sodium hydride (55%, suspension in
mineral oil) were added to 1.15 g (3.88 mmol)
2-fluoro-4-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-benzonitri-
le in 5.0 mL DMF at RT. The reaction mixture was stirred for 30 min
at RT. Then 0.320 mL (5.00 mmol) iodomethane were added and the
mixture was stirred for 1 h at RT. Then another 0.1 mL iodomethane
were added and stirring was continued at RT. Ice water was added to
the reaction mixture and the precipitate formed was suction
filtered. The residue was purified by flash chromatography. The
fractions containing the product were combined, evaporated down,
triturated with diethyl ether, suction filtered and again washed
with diethyl ether. The residue was dried i. vac.
[1135] Yield: 0.60 g (50% of theoretical)
[1136] ESI-MS: m/z=311 (M+H).sup.+
[1137] R.sub.t(HPLC): 1.54 min (method B)
Intermediate 42
6-(6-chloro-2-methyl-pyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one
##STR00310##
[1138] Step 1: 6-chloro-2-methyl-pyrimidine-4-carboxylic acid
chloride
##STR00311##
[1140] 2.00 g (13.0 mmol) 6-hydroxy-2-methylpyrimidine-4-carboxylic
acid were refluxed for 2 h with 11.9 mL (130 mmol) phosphorus
oxychloride. After cooling to RT, 2.70 g (13.0 mmol)
phosphorus-(V)-chloride were added and the mixture was boiled for 2
h. The reaction mixture was cooled to RT, evaporated to dryness i.
vac. and coevaporated twice with toluene. The residue was
triturated several times with DCM and the excess DCM was decanted
off. The combined DCM phases were evaporated down and the residue
was reacted further as the crude product.
[1141] Yield: 2.48 g (quantitative)
Step 2:
6-(6-chloro-2-methyl-pyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-
-2-one
##STR00312##
[1143] 2.48 g (13.0 mmol) 6-chloro-2-methyl-pyrimidine-4-carboxylic
acid chloride, 1.94 g (13.0 mmol) 4-methyl-3H-benzoxazol-2-one and
6.93 g (52.0 mmol) aluminium trichloride were heated to 125.degree.
C. for 1.5 h with stirring. The mixture was combined with ice water
and the precipitate formed was suction filtered and washed with
water. Then the precipitate was dissolved in MeOH/DCM and filtered
through silica gel suction. The filtrate was evaporated down and
the residue was purified by flash chromatography. The fractions
containing the product were combined, evaporated down and
triturated with diethyl ether.
[1144] The precipitate was suction filtered, washed with diethyl
ether and dried i. vac.
[1145] Yield: 0.600 g (15% of theoretical)
[1146] ESI-MS: m/z=304 (M+H).sup.+
[1147] R.sub.t(HPLC): 1.42 min (method B)
Intermediate 43
6-(6-chloro-2-methyl-pyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-o-
ne
##STR00313##
[1149] 59 mg (1.4 mmol) sodium hydride (55%, suspension in mineral
oil) were added at RT to 0.37 g (1.2 mmol)
6-(6-chloro-2-methyl-pyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one
in 5.0 mL DMF. The reaction mixture was stirred for 30 min at RT.
Then 0.10 mL (1.60 mmol) iodomethane were added and the mixture was
stirred for 1 h at RT. Then another 0.10 mL (1.60 mmol) iodomethane
were added and the mixture was stirred overnight at RT. The
reaction mixture was diluted with ice water and the precipitate
formed was suction filtered. The residue was washed with water and
dried i. vac.
[1150] Yield: 0.37 g (96% of theoretical)
[1151] ESI-MS: m/z=318 (M+H).sup.+
[1152] R.sub.t(HPLC): 1.53 min (method B)
Intermediate 44
6-(2-chloro-5-methyl-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one
##STR00314##
[1153] Step 1:
6-(2-chloro-5-methyl-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one
##STR00315##
[1155] 1.53 g (10.0 mmol) 3-methyl-1-oxy-isonicotinic acid were
stirred with 9.32 mL (100 mmol) phosphorus oxychloride and boiled
for 4 h. The reaction mixture was evaporated to dryness i. vac. and
coevaporated twice with toluene. The crude product thus obtained
(which was present in admixture with 2-chloro-3-methyl-isonicotinic
acid chloride) was combined with 1.49 g (10.0 mmol)
4-methyl-3H-benzoxazol-2-one and 5.33 g (40.0 mmol) aluminium
trichloride and heated to 125.degree. C. for 1.5 h with stirring.
Then the mixture was mixed with ice water and the precipitated
grease was separated from the solvent by decanting. The residue was
triturated with MeOH. The precipitate formed was suction filtered,
washed with MeOH and diethyl ether and dried i. vac. The product
thus obtained, which was present in admixture with
6-(2-chloro-3-methyl-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one,
was reacted further without further purification.
[1156] Yield: 400 mg (13%)
[1157] ESI-MS: m/z=303 (M+H).sup.+
[1158] R.sub.t(HPLC): 1.40 min (method B)
Step 2:
6-(2-chloro-5-methyl-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxaz-
ol-2-one
##STR00316##
[1160] 0.10 g (2.2 mmol) sodium hydride (55%, suspension in mineral
oil) were added to 0.61 g (2.0 mmol)
6-(2-chloro-5-methyl-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one
in admixture with
6-(2-chloro-3-methyl-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one
in 5 mL DMF at RT. The reaction mixture was stirred for 30 min at
RT. Then 0.17 mL (2.6 mmol) iodomethane were added and the mixture
was stirred for 1 h at RT. Then a further 0.1 mL iodomethane were
added and the mixture was stirred further at RT. Ice water was
added to the reaction mixture and the precipitate formed was
suction filtered. The residue was purified by flash chromatography.
The fractions containing the product were combined, evaporated
down, triturated with diethyl ether, suction filtered and dried.
The product was obtained in admixture with
6-(2-chloro-3-methyl-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-on-
e and reacted further as such.
[1161] Yield: 0.60 g (94% of theoretical) as mixture
[1162] ESI-MS: m/z=311 (M+H).sup.+
[1163] R.sub.t(HPLC): 1.46 min (method B)
Intermediate 45
3-fluoro-5-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-benzonitril-
e
##STR00317##
[1164] Step 1: 3-cyano-5-fluoro-benzoic acid chloride
##STR00318##
[1166] 1.65 g (10.0 mmol) 3-cyano-5-fluorobenzoic acid were boiled
for 2 h with 7.27 mL (100 mmol) thionyl chloride with stirring. The
reaction mixture was evaporated to dryness i. vac. and coevaporated
twice with toluene. The residue was reacted further as the crude
product.
[1167] Yield: 1.84 g (quantitative)
Step 2:
3-fluoro-5-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-ben-
zonitrile
##STR00319##
[1169] 1.84 g (10.0 mmol) 3-cyano-5-fluoro-benzoic acid chloride,
1.49 g (10.0 mmol) 4-methyl-3H-benzoxazol-2-one and 5.33 g (40.0
mmol) aluminium trichloride were heated to 125.degree. C. for 1.5 h
with stirring. Then the mixture was mixed with ice water. The
precipitate formed was suction filtered, washed with water and
dried i. vac.
[1170] Yield: 1.75 g (59% of theoretical)
[1171] ESI-MS: m/z=295 (M-H).sup.-
[1172] R.sub.t(HPLC): 1.33 min (method B)
Intermediate 46
9-fluoro-3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one
##STR00320##
[1173] Step 1: dimethyl 2-(3-fluoro-2-nitro-phenyl)-malonate
##STR00321##
[1175] 5.40 g (38.3 mmol) potassium carbonate and 4.50 mL (38.0
mmol) dimethylmalonate were added successively to 6.00 g (37.7
mmol) 2,6-difluoronitrobenzene in 60 mL DMF and the mixture was
stirred overnight at 65.degree. C. Then the reaction mixture was
cooled to RT and slowly poured onto 75 mL of 1N aqueous
hydrochloric acid solution. The aqueous phase was extracted several
times with EtOAc. The combined organic phases were washed with
water and saturated sodium chloride solution, dried on magnesium
sulphate, filtered and evaporated down i. vac. The residue was
stirred with n-hexane, suction filtered and dried.
[1176] Yield: 2.18 g (21% of theoretical)
[1177] ESI-MS: m/z=272 (M+H).sup.+
[1178] R.sub.f: 0.32 (silica gel; PE/EtOAc=2/1)
Step 2: (3-fluoro-2-nitro-phenyl)-acetic acid
##STR00322##
[1180] 28.0 g (103 mmol) dimethyl
2-(3-fluoro-2-nitro-phenyl)-malonate were added to 120 mL water and
120 mL conc. hydrochloric acid and refluxed for 5 h. The mixture
was cooled to RT and extracted several times with EtOAc. The
combined organic phases were dried on magnesium sulphate, filtered
and evaporated down i. vac. The residue was triturated with
PE/EtOAc=3/1 and suction filtered.
[1181] Yield: 17.3 g (84% of theoretical)
[1182] ESI-MS: m/z=217 (M+NH.sub.4).sup.+
[1183] R.sub.t(HPLC): 1.13 min (method B)
Step 3:
N-(1-benzyl-piperidin-4-yl)-2-(3-fluoro-2-nitro-phenyl)-acetamide
##STR00323##
[1185] 17.0 g (102 mmol) CDI were added at RT to 18.3 g (91.9 mmol)
(3-fluoro-2-nitro-phenyl)-acetic acid in 500 mL THF and stirred for
30 min. Then 20.0 mL (95.8 mmol) 4-amino-1-benzylpiperidine were
added and the mixture was stirred for a further 2 h. The reaction
mixture was diluted with EtOAc and the organic phase was washed
with water and saturated sodium chloride solution. The organic
phase was dried on magnesium sulphate, filtered and evaporated down
i. vac. The residue was triturated with DIPE and suction
filtered.
[1186] Yield: 33.0 g (97% of theoretical)
[1187] ESI-MS: m/z=372 (M+H).sup.+
[1188] R.sub.t(HPLC): 1.29 min (method B)
Step 4:
(1-benzyl-piperidin-4-yl)-[2-(3-fluoro-2-nitro-phenyl)-ethyl]-amin-
e
##STR00324##
[1190] 23.4 mL (183 mmol) chlorotrimethylsilane were slowly added
dropwise, with stirring, to 18.9 g (50.9 mmol) of
N-(1-benzyl-piperidin-4-yl)-2-(3-fluoro-2-nitro-phenyl)-acetamide
in 500 mL of THF. The mixture was stirred for 1 h at RT. Then 2.70
g (124 mmol) lithium borohydride were added batchwise and the
mixture was stirred for 1 h at RT. Then the mixture was refluxed
for 5 h and cooled to RT overnight. 16 mL MeOH, 40 mL water and mL
conc. hydrochloric acid were added dropwise with stirring and after
they had all been added the reaction mixture was refluxed for 3 h.
After cooling to RT the organic phase was separated off and the
aqueous phase was extracted several times with EtOAc. The combined
organic phases were washed with saturated sodium chloride solution,
dried on magnesium sulphate, filtered and evaporated down i. vac.
The residue was purified by flash chromatography. The fractions
containing the product were combined and evaporated down. (Product
in the form of a mixture!)
[1191] Yield: 14.4 g (79% of theoretical)
[1192] ESI-MS: m/z=358 (M+H).sup.+
[1193] R.sub.f: 0.39 (silica gel;
DCM/Cyc/MeOH/NH.sub.4OH=70/15/15/2)
Step 5:
[2-(2-amino-3-fluoro-phenyl)-ethyl]-(1-benzyl-piperidin-4-yl)-amin-
e
##STR00325##
[1195] 14.4 g (40.3 mmol)
(1-benzyl-piperidin-4-yl)-[2-(3-fluoro-2-nitro-phenyl)-ethyl]-amine
in 100 mL MeOH were stirred with 2.00 g rhodium charcoal (10%) and
shaken at RT under a hydrogen atmosphere (3 bar). The catalyst was
filtered off and the solvent was eliminated i. vac. The residue was
further reacted immediately as the crude product.
[1196] Yield: 13.1 g (99% of theoretical)
[1197] R.sub.t(HPLC): 0.64 min (method B)
Step 6:
3-(1-benzyl-piperidin-4-yl)-9-fluoro-1,3,4,5-tetrahydro-benzo[d][1-
,3]diazepin-2-one
##STR00326##
[1199] 11.0 g (65.8 mmol) CDI were added to 13.1 g (40.0 mmol)
[2-(2-amino-3-fluoro-phenyl)-ethyl]-(1-benzyl-piperidin-4-yl)-amine
in 120 mL DMF. The mixture was heated to 100.degree. C. and stirred
for 1 h. After the reaction mixture had cooled to RT it was poured
onto 300 mL ice water. The aqueous phase was extracted several
times with DCM, the organic phases were combined, dried on
magnesium sulphate, filtered and evaporated down i. vac. The
residue was purified by flash chromatography. The fractions
containing the product were combined and evaporated down.
[1200] Yield: 13.7 g (97% of theoretical)
[1201] ESI-MS: m/z=354 (M+H).sup.+
[1202] R.sub.t(HPLC): 1.00 min (method B)
Step 7:
9-fluoro-3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-
-2-one
##STR00327##
[1204] 13.7 g (38.8 mmol)
3-(1-benzyl-piperidin-4-yl)-9-fluoro-1,3,4,5-tetrahydro-benzo[d][1,3]diaz-
epin-2-one in 100 mL MeOH were shaken with 2.00 g palladium on
charcoal (Pd/C 10%) under a hydrogen atmosphere (3 bar) at RT. The
catalyst was filtered off and the solvent was evaporated down. The
residue was purified by flash chromatography. The fractions
containing the product were combined and evaporated down. The
residue was stirred with DIPE/EtOAc, suction filtered and
dried.
[1205] Yield: 3.10 g (30% of theoretical)
[1206] ESI-MS: m/z=264 (M+H).sup.+
[1207] R.sub.t(HPLC): 2.43 min (method B)
Intermediate 47
6-(2,6-dichloro-pyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one
##STR00328##
[1208] Step 1: 2,6-dihydroxy-pyrimidine-4-carboxylic acid
##STR00329##
[1210] 23.00 g (127.74 mmol) orotic acid lithium salt monohydrate
in 400 mL DMF were heated to 70.degree. C. and at this temperature
hydrochloric acid was added batchwise within 2 h. The reaction
mixture was stirred for a further hour at 70.degree. C. and then
evaporated down in vacuo. The residue was stirred with water,
suction filtered and dried at 50.degree. C. in the CAD.
[1211] Yield: 21.40 g (quantitative)
[1212] ESI-MS: m/z=155 (M-H).sup.-
Step 2: 2,6-dichloro-pyrimidine-4-carboxylic acid chloride
##STR00330##
[1214] 20 g (0.13 mol) 2,6-dihydroxy-pyrimidine-4-carboxylic acid
were refluxed together with 40 mL phosphorus oxychloride. After
cooling to RT 60 g (0.29 mol) phosphorus-(V)-chloride were added
and refluxing was continued for a further 3 h. The product was
obtained by fractional distillation.
[1215] Yield: 6.00 g (22% of theoretical)
Step 3:
6-(2,6-dichloro-pyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-on-
e
##STR00331##
[1217] 2.75 g (13.0 mmol) 2,6-dichloro-pyrimidine-4-carboxylic acid
chloride, 1.94 g (13.0 mmol) 4-methyl-3H-benzoxazol-2-one and 6.93
g (52.0 mmol) aluminium trichloride were heated to 125.degree. C.
for 1.5 h with stirring. The mixture combined with ice water and
the product precipitated as a solid was suction filtered, washed
with water and dried i. vac.
[1218] Yield: 3.70 g (88% of theoretical)
[1219] ESI-MS: m/z=322 (M-H).sup.-
[1220] R.sub.t(HPLC): 1.41 min (method B)
Intermediate 48
3-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-5-fluoro-benzoni-
trile
##STR00332##
[1222] 0.161 g (3.70 mmol) sodium hydride (55%, suspension in
mineral oil) were added to 1.00 g (3.38 mmol)
3-fluoro-5-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-benzonitri-
le in 5 mL DMF at RT and stirred for 30 min at RT. Then 0.317 mL
(5.00 mmol) iodomethane were added and the mixture was stirred for
1 h at RT. Then a further 0.1 mL iodomethane were added and
stirring was continued at RT. After dilution with ice water the
aqueous phase was extracted with EtOAc. The organic phase was
washed with water, dried on sodium sulphate, filtered and
evaporated down i. vac. The residue was purified by flash
chromatography. The fractions containing the product were combined,
evaporated down and dried i. vac.
[1223] Yield: 0.960 g (92% of theoretical)
[1224] ESI-MS: m/z=311 (M+H).sup.+
[1225] R.sub.t(HPLC): 1.47 min (method B)
Intermediate 49
5-(6-chloro-pyrimidine-4-carbonyl)-7-methyl-1,3-dihydro-indol-2-one
##STR00333##
[1226] Step 1: 7-methyl-1,3-dihydro-indol-2-one
##STR00334##
[1228] 5.00 g (31.0 mmol) 7-methyl-1H-indol-2,3-dione in 18.1 mL
(372 mmol) hydrazine hydrate were heated to 110.degree. C. for 3 h.
Then the reaction mixture was cooled, the precipitate formed was
suction filtered and washed with water. The precipitate was
suspended in water, acidified with conc. hydrochloric acid and
stirred for 10 min. Then the reaction mixture was stirred for a
further 30 min in the ice bath, the precipitate was suction
filtered, washed with water and dried.
[1229] Yield: 1.60 g (35% of theoretical)
[1230] ESI-MS: m/z=148 (M+H).sup.+
[1231] R.sub.t(HPLC): 2.72 min (method C)
Step 2:
5-(6-chloro-pyrimidine-4-carbonyl)-7-methyl-1,3-dihydro-indol-2-on-
e
##STR00335##
[1233] 1.92 g (10.9 mmol) 6-chloropyrimidine-4-carboxylic acid
chloride, 1.60 g (10.9 mmol) 7-methyl-1,3-dihydro-indol-2-one and
7.33 g (55.0 mmol) aluminium trichloride were heated to 130.degree.
C. for 3 h with stirring. The mixture was combined first with ice
water and then with EtOAc. The precipitate formed as black flakes
was suction filtered and the phases were separated. The aqueous
phase was extracted several times with EtOAc. The combined organic
phases were dried on sodium sulphate, filtered and evaporated down
i. vac.
[1234] Yield: 250 mg (8% of theoretical)
[1235] ESI-MS: m/z=288/90 (Cl) (M+H).sup.+
[1236] R.sub.t(HPLC): 1.25 min (method B)
Intermediate 50
3-[6'-benzyloxy-4'-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-
-3,4,5,6-tetra-hydro-2H-[1,2']bipyridinyl-4-yl]-7-methoxy-1,3,4,5-tetrahyd-
ro-benzo[d][1,3]diazepin-2-one
##STR00336##
[1238] 991 mg (3.60 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one
and 500 mg (1.22 mmol)
6-(2-benzyloxy-6-chloro-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-
-one were combined in 10 mL NMP and stirred overnight at
120.degree. C. The reaction mixture was purified by preparative
HPLC-MS. The fractions containing the product were combined and
evaporated down.
[1239] Yield: 130 mg (6% of theoretical)
[1240] ESI-MS: m/z=648 (M+H).sup.+
[1241] R.sub.t(HPLC): 1.80 min (method B)
Intermediate 51
(6-chloro-pyrimidin-4-yl)-(1,7-dimethyl-1H-indazol-5-yl)-methanone
##STR00337##
[1242] Step 1: 5-bromo-1,7-dimethyl-1H-indazole
##STR00338##
[1244] 2.11 g (10.0 mmol) 5-bromo-7-methyl-1H-indazole and 1.20 g
(10.7 mmol) potassium-tert-butoxide in 50 mL THF were stirred
overnight with 0.700 mL (11.2 mmol) iodomethane at RT. Then the
precipitate was filtered off and the filtrate was evaporated down
i. vac. The residue was purified by flash chromatography.
[1245] Yield: 1.92 g (43% of theoretical)
[1246] ESI-MS: m/z=225/27 (M+H).sup.+
[1247] R.sub.t(HPLC): 1.13 min (method E)
Step 2:
(6-chloro-pyrimidin-4-yl)-(1,7-dimethyl-1H-indazol-5-yl)-methanone
##STR00339##
[1249] Under an argon atmosphere 0.450 g (2.00 mmol)
5-bromo-1,7-dimethyl-1H-indazole in 25 mL THF were cooled to
-75.degree. C., combined with 1.40 mL (2.24 mmol) of a 1.6 molar
n-butyllithium solution and stirred for 1 h at -75.degree. C. Then
0.480 g (2.14 mmol) 6-chloro-pyrimidine-4-carboxylic acid
methoxy-methyl-amide were added dropwise. The mixture was brought
to 0.degree. C. and stirred for a further hour. Then saturated
sodium hydrogen carbonate solution was stirred in, the mixture was
extracted with EtOAc, the organic phase was dried and evaporated
down i. vac. The residue was triturated with DIPE, suction filtered
and dried. The precipitate was purified by flash chromatography
(Alox).
[1250] Yield: 100 mg (14% of theoretical)
[1251] R.sub.t(HPLC): 1.46 min (method B)
Intermediate 52
(6-iodo-pyrimidin-4-yl)-(8-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-metha-
none
##STR00340##
[1253] 0.131 g (3.00 mmol) sodium hydride (55%, suspension in
mineral oil) were added to 0.677 g (2.00 mmol)
4,6-diiodopyrimidine, 0.535 g (3.00 mmol)
8-methyl-2,3-dihydro-benzo[1,4]dioxin-6-carbaldehyde
(US2005/256099) and 0.133 g (1.00 mmol) 1,3-dimethyl-imidazolium
chloride in 10 mL THF and the mixture was refluxed for 4 h. Then
the reaction mixture was mixed with ice water and extracted with
EtOAc. The organic phase was dried on sodium sulphate, evaporated
down i. vac. and the residue was purified by preparative HPLC-MS.
The fractions containing the product were combined and the organic
solvent was evaporated down i. vac. The residue was made alkaline
with 1N aqueous sodium hydroxide solution and the grease
precipitated was extracted with EtOAc. The organic phase was dried
on sodium sulphate, filtered, evaporated down and dried i. vac.
[1254] Yield: 200 mg (26% of theoretical)
[1255] ESI-MS: m/z=383 (M+H).sup.+
[1256] R.sub.t (HPLC): 4.19 min (method B)
Intermediate 53
(6-chloro-pyrimidin-4-yl)-(7-methyl-2,3-dihydro-benzofuran-5-yl)-methanone
##STR00341##
[1257] Step 1: 7-methyl-2,3-dihydro-benzofuran-3-ol
##STR00342##
[1259] Under a nitrogen atmosphere 0.945 g (7.35 mmol)
trimethylsulphoxonium chloride were placed in 20 mL THF, and 0.300
g (7.50 mmol) sodium hydride (55%, suspension in mineral oil) were
added batchwise. The reaction mixture was refluxed for 2 h. Then
1.00 g (7.35 mmol) 2-hydroxy-3-methylbenzaldehyde in 20 mL THF were
added dropwise to the reaction mixture and it was refluxed
overnight. Then PE was added and the suspension obtained was
filtered. The filtrate was evaporated down i. vac. and purified by
flash chromatography. The fractions containing the product were
combined and evaporated down.
[1260] Yield: 0.615 g (56% of theoretical)
[1261] ESI-MS: m/z=133 (M-H.sub.2O+H).sup.+
[1262] R.sub.t (HPLC): 1.09 min (method B)
Step 2: 7-methyl-2,3-dihydro-benzofuran
##STR00343##
[1264] Under a nitrogen atmosphere 0.610 g (4.06 mmol)
7-methyl-2,3-dihydro-benzofuran-3-ol in 5 mL acetic acid were
refluxed for 2 h with 770 .mu.L (8.16 mmol) acetic anhydride. After
cooling to RT, 60 mg palladium on charcoal (Pd/C 10%) were added
and the mixture was hydrogenated for 3.5 h under a hydrogen
atmosphere (3 bar). The catalyst was filtered off and the solvent
was evaporated down.
[1265] Yield: 0.350 g (64% of theoretical)
[1266] ESI-MS: m/z=134 (M+)
Step 3:
(6-chloro-pyrimidin-4-yl)-(7-methyl-2,3-dihydro-benzofuran-5-yl)-m-
ethanone
##STR00344##
[1268] 0.396 g (2.24 mmol) 6-chloropyrimidine-4-carboxylic acid
chloride and 0.328 g (2.46 mmol) aluminium trichloride in 10 mL DCM
were stirred for 20 min at RT. Then 0.300 g (2.24 mmol)
7-methyl-2,3-dihydro-benzofuran in DCM were added dropwise to the
reaction mixture and this was stirred for 1.5 h at RT. After the
addition of water and DCM to the reaction mixture the phases were
separated and the aqueous phase was extracted with DCM. The
combined organic phases were washed with saturated aqueous sodium
hydrogen carbonate solution, dried on sodium sulphate, filtered and
evaporated down i. vac.
[1269] Yield: 0.550 g (62% of theoretical)
[1270] Purity: 70%
[1271] ESI-MS: m/z=275/277 (Cl) (M+H).sup.+
[1272] R.sub.t (HPLC): 1.54 min (method B)
Intermediate 54
(6-chloro-pyrimidin-4-yl)-(1,3,3,7-tetramethyl-2,3-dihydro-1H-indol-5-yl)--
methanone
##STR00345##
[1273] Step 1: 1,3,3,7-tetramethyl-1,3-dihydro-indol-2-one
##STR00346##
[1275] 2.00 g (50.0 mmol) sodium hydride (55%, suspension in
mineral oil) were added at 0.degree. C. to 2.34 g (3.58 mmol)
7-methyl-1,3-dihydro-indol-2-one in 20 mL DMF and the mixture was
stirred for 30 min. Then 3.00 mL (48.2 mmol) iodomethane were added
and the mixture was stirred for 2 h at RT. Ice water was added to
the reaction mixture, then it was extracted with DCM and aqueous
sodium hydrogen carbonate solution. The organic phase was dried on
sodium sulphate, filtered and evaporated down i. vac. The residue
was purified by preparative HPLC-MS. The fractions containing the
product were combined and freeze-dried.
[1276] Yield: 1.300 g (43% of theoretical)
[1277] Purity: 90%
[1278] ESI-MS: m/z=190 (M+H).sup.+
[1279] R.sub.t(HPLC): 1.41 min (method B)
Step 2: 1,3,3,7-tetramethyl-2,3-dihydro-1H-indole
##STR00347##
[1281] Under an argon atmosphere 5.71 mL of a 1 molar lithium
aluminium hydride solution in THF were added dropwise to 600 mg
(2.85 mmol) 1,3,3,7-tetramethyl-1,3-dihydro-indol-2-one in 20 mL
THF. The reaction mixture was stirred for 2.5 h at 60.degree. C.
and then cooled to RT. While cooling with the ice bath, saturated,
aqueous sodium sulphate solution was slowly added dropwise and the
resulting suspension was filtered through Celite. The filtrate was
combined with EtOAc and saturated sodium chloride solution. The
organic phase was dried on sodium sulphate, filtered and the
filtrate was evaporated down.
[1282] Yield: 520 mg (99% of theoretical)
[1283] Purity: 95%
[1284] ESI-MS: m/z=176 (M+H).sup.+
Step 3:
(6-chloro-pyrimidin-4-yl)-(1,3,3,7-tetramethyl-2,3-dihydro-1H-indo-
l-5-yl)-methanone
##STR00348##
[1286] Under an argon atmosphere 0.473 g (2.67 mmol)
6-chloropyrimidine-4-carboxylic acid chloride and 0.427 g (3.20
mmol) aluminium trichloride were stirred in 20 mL DCM for 30 min.
Then 0.520 g (2.67 mmol) 1,3,3,7-tetramethyl-2,3-dihydro-1H-indole
in DCM were added dropwise to the reaction mixture and it was
stirred for 45 min at RT, then for 45 min at 40.degree. C. Next,
the reaction mixture was decomposed with ice water/sodium hydroxide
solution, extracted with DCM and the organic phase was evaporated
down i. vac. The residue was taken up in MeOH and purified by
preparative HPLC-MS. The fractions containing the product were
combined and freeze-dried.
[1287] Yield: 170 mg (20% of theoretical)
[1288] ESI-MS: m/z=316 (M+H).sup.+
[1289] R.sub.t (HPLC): 1.70 min (method B)
Intermediate 55
tert-butyl
[4'-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-4-(-
2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2']-
bipyridinyl-6'-yl]-methyl-carbamate
##STR00349##
[1291] Under an argon atmosphere 13 mg (0.96 mmol) tert-butyl
methyl-carbamate, 11 mg (0.019 mmol) Xantphos, 8.8 mg (0.010 mmol)
Pd.sub.2 dba.sub.3 and 47 mg (0.15 mmol) caesium carbonate were
added to 50 mg (0.10 mmol)
1-[6'-chloro-4'-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-3-
,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]pyr-
idin-2-one in 1.00 mL dioxane and the mixture was refluxed for 15 h
with stirring. The reaction mixture was evaporated down i. vac. and
the residue obtained was used in the next step without further
purification.
[1292] Yield: 59 mg (quantitative)
[1293] R.sub.t (HPLC): 1.70 min (method B)
Intermediate 56
tert-butyl
[4'-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-4-(-
7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-3,4,5,6-tet-
rahydro-2H-[1,2']bipyridinyl-6'-yl]-carbamate
##STR00350##
[1295] Under an argon atmosphere 31 mg (0.26 mmol) tert-butyl
carbamate, 10 mg (0.017 mmol) Xantphos, 8.0 mg (0.009 mmol)
Pd.sub.2 dba.sub.3 and 42 mg (0.13 mmol) caesium carbonate were
added to 50 mg (0.10 mmol)
3-[6'-chloro-4'-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-3-
,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl]-7-methoxy-1,3,4,5-tetrahydro--
benzo[d][1,3]diazepin-2-one in 1.0 mL dioxane and the mixture was
refluxed for 15 h with stirring. The reaction mixture was
evaporated down i. vac. and the residue obtained was used in the
next step without further purification.
[1296] Yield: 57 mg (quantitative)
[1297] R.sub.t (HPLC): 1.72 min (method B)
Intermediate 57
(6-chloro-pyrimidin-4-yl)-phenyl-methanone
##STR00351##
[1299] 250 mg (1.68 mmol) 4,6-dichloropyrimidine, 258 mg (2.52
mmol) benzaldehyde and 152 mg (0.56 mmol)
1,3-dimethyl-3H-benzimidazol-1-ium-iodide (Chem. Pharm. Bull. 1990,
1147-52) in 3.0 mL THF were stirred at RT. Then 121 mg (2.52 mmol)
50% sodium hydride (suspension in mineral oil) was added and the
reaction mixture was stirred for 30 min at RT and then refluxed.
The reaction mixture was evaporated down i. vac., the residue was
mixed with ice water and the product was extracted with DCM. The
organic phases were combined, dried and filtered through silica
gel. The filtrate was evaporated down i. vac. and the residue
reacted further as the crude product.
[1300] Yield: 300 mg (39% of theoretical)
[1301] Purity: 48%
[1302] ESI-MS: m/z=219/221 (Cl) (M+H).sup.+
[1303] R.sub.f: 0.5 (silica gel; cyclohexane/EtOAc 5/1)
Intermediate 58
6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piper-
idin-1-yl]-pyrimidine-4-carboxylic acidmethoxy-methyl-amide
##STR00352##
[1305] 0.20 g (0.99 mmol) 6-chloro-pyrimidine-4-carboxylic
acidmethoxy-methyl-amide, 0.28 g
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one
and 0.20 mL (1.16 mmol) DIPEA in 1.5 mL THF were heated to
120.degree. C. in the microwave for 30 min. The mixture was diluted
with water and extracted with DCM. The combined organic phases were
dried on sodium sulphate, filtered and evaporated down i. vac. The
residue was triturated with diethyl ether, suction filtered and
dried.
[1306] Yield: 290 mg (66% of theoretical)
[1307] ESI-MS: m/z=441 (M+H).sup.+
[1308] R.sub.t (HPLC): 1.06 min (method B)
Intermediate 59
5-(6-chloro-pyrimidine-4-carbonyl)-1,3-dimethyl-1,3-dihydro-benzimidazol-2-
-one
##STR00353##
[1309] Step 1:
5-(6-chloro-pyrimidine-4-carbonyl)-1,3-dihydro-benzimidazol-2-one
##STR00354##
[1311] 3.00 g (17.0 mmol) 6-chloro-pyrimidine-4-carboxylic acid
chloride, 11.1 g (83.2 mmol) aluminium trichloride and 2.40 g (17.4
mmol) benzimidazole were stirred for 3 h at 130.degree. C. Then the
reaction mixture was combined with DCM, water and 15% (w/v) aqueous
potassium carbonate solution and the phases were separated. The
aqueous phase was extracted several times with DCM. The combined
organic phases were combined, dried on magnesium sulphate, filtered
and evaporated down i. vac. The residue was triturated with DIPE
and isopropanol, suction filtered and dried i. vac.
[1312] Yield: 570 mg (12% of theoretical)
[1313] ESI-MS: m/z=273 (M-H).sup.-
[1314] R.sub.f: 0.61 (silica gel;
DCM/Cyc/MeOH/NH.sub.4OH=70/15/15/2)
Step 2:
5-(6-chloro-pyrimidine-4-carbonyl)-1,3-dimethyl-1,3-dihydro-benzim-
idazol-2-one
##STR00355##
[1316] 570 mg (2.08 mmol)
5-(6-chloro-pyrimidine-4-carbonyl)-1,3-dihydro-benzimidazol-2-one
in 10.0 mL DMF were combined at 0.degree. C. with 190 mg (4.35
mmol) sodium hydride (55%, suspension in mineral oil). After 1 h
stirring at 0.degree. C., 0.300 mL (4.73 mmol) iodomethane were
added. The reaction was allowed to come up to RT and stirred
overnight. Then iodomethane was added again and the mixture was
stirred for a further 2 h at RT. Then the reaction mixture was
added to water and stirred for 30 min. The precipitate formed was
suction filtered and dried i. vac.
[1317] Yield: 400 mg (64% of theoretical)
[1318] ESI-MS: m/z=303/305 (Cl) (M+H).sup.+
[1319] R.sub.f: 0.84 (silica gel;
DCM/Cyc/MeOH/NH.sub.4OH=70/15/15/2)
Preparation of the End Compounds
Example 1
1-{1-[6-(4-methyl-2-oxo-2,3-dihydrobenzoxazole-6-carbonyl)-pyrimidin-4-yl]-
-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one
##STR00356##
[1321] 64 mg (0.22 mmol)
1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one-dihydrochloride,
64 mg (0.221 mmol)
6-(6-chloropyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one and
0.174 mL (1.00 mmol) DIPEA were stirred overnight in 2.0 mL DMF at
RT. The mixture was purified by preparative HPLC-MS. The fractions
containing the product were combined, the organic solvent was
eliminated i. vac. and the aqueous phase remaining was neutralised
with 4N aqueous NaOH solution. The precipitate was suction
filtered, washed with water and dried in the CAD.
[1322] Yield: 56 mg (54% of theoretical)
[1323] ESI-MS: m/z=472 (M+H).sup.+
[1324] R.sub.t (HPLC): 2.37 min (method C)
Example 2
7-methoxy-3-{1-[6-(4-methyl-2-oxo-2,3-dihydrobenzoxazole-6-carbonyl)-pyrim-
idin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one
##STR00357##
[1326] 275 mg (1.00 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,
289 mg (1.00 mmol)
6-(6-chloropyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one and
0.348 mL (2.00 mmol) DIPEA were stirred overnight in 10 mL DMF at
RT. The mixture was purified by preparative HPLC-MS. The fractions
containing the product were combined, the organic solvent was
eliminated i. vac. and the aqueous phase remaining was neutralised
with 4N aqueous NaOH solution. The precipitate was suction
filtered, washed with water and dried in the CAD.
[1327] Yield: 270 mg (51% of theoretical)
[1328] ESI-MS: m/z=529 (M+H).sup.+
[1329] R.sub.t (HPLC): 2.86 min (method C)
Example 3
4-methyl-6-{6-[4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidin-
-1-yl]-pyrimidine-4-carbonyl}-3H-benzoxazol-2-one
##STR00358##
[1331] 378 mg (1.00 mmol)
5-phenyl-2-piperidin-4-yl-2,4-dihydro-1,2,4-triazol-3-one, 289 mg
(1.00 mmol)
6-(6-chloropyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one and
0.348 mL (2.0 mmol) DIPEA were stirred overnight in 10 mL DMF at
RT. The mixture was purified by preparative HPLC-MS. The fractions
containing the product were combined, the organic solvent was
eliminated i. vac. and the aqueous phase remaining was neutralised
with a 4N aqueous NaOH solution. The precipitate was suction
filtered, washed with water and dried in the CAD.
[1332] Yield: 280 mg (56% of theoretical)
[1333] ESI-MS: m/z=498 (M+H).sup.+
[1334] R.sub.t (HPLC)=2.72 min (method C)
Example 4
3-{1-[6-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-pyrimidin-4-yl-
]-piperidin-4-yl}-1,3-dihydroimidazo[4,5-c]quinolin-2-one
##STR00359##
[1336] 134 mg (0.500 mmol)
3-piperidin-4-yl-1,3-dihydroimidazo[4,5-c]quinolin-2-one, 145 mg
(0.500 mmol)
6-(6-chloropyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one and
0.174 mL (1.00 mmol) DIPEA were stirred overnight in 5 mL DMF at
RT. The mixture was purified by preparative HPLC-MS. The fractions
containing the product were combined, the organic solvent was
eliminated i. vac. and the aqueous phase remaining was neutralised
with a 4N aqueous NaOH solution. The precipitate was suction
filtered, washed with water and dried in the CAD.
[1337] Yield: 100 mg (38% of theoretical)
[1338] ESI-MS: m/z=522 (M+H).sup.+
[1339] R.sub.t (HPLC)=1.99 min (method C)
Example 5
1-{1-[6-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-pyrimidin--
4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one
##STR00360##
[1341] 72.8 mg (0.25 mmol)
1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one-dihydrochloride,
75 mg (0.25 mmol)
6-(6-chloropyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one
and 0.22 mL (1.25 mmol) DIPEA were stirred in 2 mL DMF for 2 h at
RT. The mixture was purified by preparative HPLC-MS. The fractions
containing the product were combined, the organic solvent was
eliminated i. vac. and the aqueous phase remaining was neutralised
with a 4N aqueous NaOH solution. The precipitate was suction
filtered, washed with water and dried in the CAD.
[1342] Yield: 71 mg (59% of theoretical)
[1343] ESI-MS: m/z=486 (M+H).sup.+
[1344] R.sub.t (HPLC) 2.67 min (method C)
Example 6
3-{1-[6-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-pyrimidin--
4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one
##STR00361##
[1346] 63.3 mg (0.23 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,
70 mg (0.23 mmol)
6-(6-chloropyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one
and 0.08 mL (0.46 mmol) DIPEA were stirred in 2 mL of DMF for 2 h
at RT. The mixture was diluted with methanol. The precipitate was
suction filtered, washed with methanol and diethyl ether and dried
in the CAD.
[1347] Yield: 85 mg (68% of theoretical)
[1348] ESI-MS: m/z=543 (M+H).sup.+
[1349] R.sub.t (HPLC) 3.2 min (method C)
Example 7
1-{1-[6-(3,4-dimethyl-benzoyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-
-imidazo[4,5-b]-pyridin-2-one
##STR00362##
[1351] 150 mg (0.515 mmol)
1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one-dihydrochloride,
150 mg (0.527 mmol)
(6-chloro-pyrimidin-4-yl)-(3,4-dimethyl-phenyl)-methanone and 0.300
mL (1.74 mmol) DIPEA were stirred overnight in 5.0 mL DMF at RT.
The reaction mixture was evaporated down i. vac., the residue was
mixed with water and stirred for 10 min. The precipitate was
suction filtered and purified by preparative HPLC-MS. The fractions
containing the product were combined and freeze-dried.
[1352] Yield: 125 mg (57% of theoretical)
[1353] ESI-MS: m/z=429 (M+H).sup.+
[1354] R.sub.f: 0.52 (silica gel,
DCM/Cyc/MeOH/NH.sub.4OH=70/15/15/2)
Example 8
1-{1-[6-(3,4-diethyl-benzoyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro--
imidazo[4,5-b]-pyridin-2-one
##STR00363##
[1356] 150 mg (0.515 mmol)
1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one-dihydrochloride,
150 mg (0.546 mmol)
(6-chloro-pyrimidin-4-yl)-(3,4-diethyl-phenyl)-methanone and 0.300
mL (1.74 mmol) DIPEA were stirred overnight in 5.0 mL DMF at RT.
The reaction mixture was evaporated down i. vac., the residue was
mixed with water and stirred for another 10 min. The precipitate
was suction filtered and purified by preparative HPLC-MS. The
fractions containing the product were combined and
freeze-dried.
[1357] Yield: 125 mg (53% of theoretical)
[1358] ESI-MS: m/z=457 (M+H).sup.+
[1359] R.sub.f: 0.53 (silica gel,
DCM/Cyc/MeOH/NH.sub.4OH=70/15/15/2)
Example 9
3-[1-(6-benzoyl-pyrimidin-4-yl)-piperidin-4-yl]-7-methoxy-1,3,4,5-tetrahyd-
ro-benzo[d]-[1,3]diazepin-2-one
##STR00364##
[1361] Under a nitrogen atmosphere 100 mg (0.227 mmol)
6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-pipe-
ridin-1-yl]-pyrimidine-4-carboxylic acidmethoxy-methyl-amide were
cooled to -10.degree. C. in 5.00 mL THF and combined with 0.400 mL
(0.400 mmol) phenylmagnesium bromide solution (1M in THF). The
mixture was stirred for 1 h at -10.degree. C. and then heated to
0.degree. C. Then 0.200 mL (0.200 mmol) phenylmagnesium bromide
solution (1M in THF) were added, the mixture was stirred for 1 h
and then heated to RT. The reaction mixture was combined with a
saturated ammonium chloride solution and extracted with EtOAc. The
combined organic phases were dried and evaporated down i. vac. The
residue was purified by preparative HPLC-MS. The fractions
containing the product were combined and evaporated down by half.
The precipitate formed was suction filtered and dried.
[1362] Yield: 19 mg (18% of theoretical)
[1363] ESI-MS: m/z=548 (M+H).sup.+
[1364] R.sub.t (HPLC): 3.24 min (method C)
Example 10
1-{1-[6-(3,4-dichloro-benzoyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-
-imidazo[4,5-b]-pyridin-2-one
##STR00365##
[1366] 150 mg (0.515 mmol)
1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one-dihydrochloride,
150 mg (0.522 mmol)
(6-chloro-pyrimidin-4-yl)-(3,4-dichloro-phenyl)-methanone and 0.300
mL (1.74 mmol) DIPEA were stirred overnight in 5.0 mL DMF at RT.
The reaction mixture was evaporated down i. vac., the residue was
mixed with water and stirred for another 10 min. Then the
precipitate was suction filtered and purified by preparative
HPLC-MS. The fractions containing the product were combined and
freeze-dried.
[1367] Yield: 125 mg (52% of theoretical)
[1368] ESI-MS: m/z=469/471/473 (2Cl) (M+H).sup.+
[1369] R.sub.f: 0.67 (silica gel,
DCM/Cyc/MeOH/NH.sub.4OH=70/15/15/2)
Example 11
3-[4'-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-6'-oxo-3,4,5-
,6.1'.6'-hexa-hydro-2H-[1,2']bipyridinyl-4-yl]-7-methoxy-1,3,4,5-tetrahydr-
o-benzo[d][1,3]diazepin-2-one
##STR00366##
[1371] 30 mg palladium on charcoal (Pd/C 10%), 30 mL THF and 30 mL
DCM were added to 0.13 g (0.20 mmol)
3-[6'-benzyloxy-4'-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl-
)-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl]-7-methoxy-1,3,4,5-tetrahyd-
ro-benzo[d][1,3]diazepin-2-one in 20 mL MeOH and the mixture was
hydrogenated for 1.5 h under a hydrogen atmosphere. After
filtration of the reaction mixture the solvent was evaporated down
i. vac. The residue was purified by preparative HPLC-MS. The
fractions containing the product were combined and
freeze-dried.
[1372] Yield: 3 mg (3% of theoretical)
[1373] ESI-MS: m/z=558(M+H).sup.+
[1374] R.sub.t (HPLC): 1.35 min (method B)
Example 12
7-methoxy-3-{1-[5-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-pyri-
dazin-3-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one
##STR00367##
[1376] 0.13 g (0.049 mmol)
3-(1-{5-[hydroxy-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-yl)-methyl]-pyr-
idazin-3-yl}-piperidin-4-yl)-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]dia-
zepin-2-one and 1.0 g (12 mmol) manganese(IV)-oxide in 100 mL DCM
were stirred overnight at RT. Then 500 mg manganese(IV)-oxide were
added and the mixture was stirred for a further 20 h. Then the
reaction mixture was combined with 10 mL MeOH, filtered off and
evaporated down. The residue was purified by preparative HPLC-MS.
The fractions containing the product were combined and
freeze-dried.
[1377] Yield: 5 mg (17% of theoretical)
[1378] ESI-MS: m/z=529 (M+H).sup.+
[1379] R.sub.t (HPLC): 1.23 min (method G)
Example 13
7-methoxy-3-{1-[2-methyl-6-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbo-
nyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d][1,3]diaze-
pin-2-one
##STR00368##
[1381] 83 mg (0.30 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,
91 mg (0.30 mmol)
6-(6-chloro-2-methyl-pyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one
and 0.11 mL (0.60 mmol) DIPEA were stirred together in 3 mL DMF
overnight at RT. Then the reaction mixture was purified by
preparative HPLC-MS. The fractions containing the product were
combined and the organic solvent was evaporated down. The residue
was neutralised with 4N aqueous sodium hydroxide solution, the
precipitate formed was suction filtered, washed with water and
dried i. vac.
[1382] Yield: 115 mg (71% of theoretical)
[1383] ESI-MS: m/z=543 (M+H).sup.+
[1384] R.sub.t (HPLC): 1.33 min (method B)
Example 14
3-[5'-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-1'-oxy-3,4,5-
,6-tetrahydro-2H-[1,3']bipyridinyl-4-yl]-7-methoxy-1,3,4,5-tetrahydro-benz-
o[d][1,3]diazepin-2-one
##STR00369##
[1386] Under an argon atmosphere 275 mg (1.00 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one-
, 363 mg (1.00 mmol)
6-(5-bromo-1-oxy-pyridin-3-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one
and 489 mg (1.50 mmol) caesium carbonate were combined in 16 mL
dioxane, then mixed with 63 mg (0.10 mmol) BINAP and 23 mg (0.10
mmol) palladium(II)acetate and stirred for 6 h at 120.degree. C.
The mixture was evaporated down i. vac. and the residue was
purified by preparative HPLC-MS. The fractions containing the
product were combined and the acetonitrile was eliminated i. vac.
The aqueous residue was made basic with 1N aqueous sodium hydroxide
solution, the precipitate formed was suction filtered and washed
with water and dried i. vac.
[1387] Yield: 35 mg (6% of theoretical)
[1388] ESI-MS: m/z=558 (M+H).sup.+
[1389] R.sub.t (HPLC): 1.38 min (method B)
Example 15
4'-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-4-(2-oxo-2,3-di-
hydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H,1'H-[1,2']bipyridi-
nyl-6'-one
##STR00370##
[1391] 20 mg (0.034 mmol)
1-[6'-benzyloxy-4'-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl-
)-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]-
pyridin-2-one in 0.10 g (0.87 mmol) pyridine hydrochloride were
kept in a melt for 4 min. After cooling the mixture was purified by
preparative HPLC-MS. The fractions containing the product were
combined and freeze-dried.
[1392] Yield: 11 mg (65% of theoretical)
[1393] ESI-MS: m/z=501(M+H).sup.+
[1394] R.sub.t (HPLC): 1.17 min (method B)
Example 16
3-{1-[2-chloro-6-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-pyrim-
idin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diaze-
pin-2-one
##STR00371##
[1396] 275 mg (1.00 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,
324 mg (1.00 mmol)
6-(2,6-dichloro-pyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one
and 0.348 mL (2.00 mmol) DIPEA in 5.00 mL DMF were stirred
overnight at RT. Then the mixture was purified by preparative
HPLC-MS. The fractions containing the product were combined and the
organic solvent was evaporated down i. vac. The residue was
neutralised with 4N aqueous sodium hydroxide solution and the
precipitate formed was suction filtered, washed with water and
dried.
[1397] Yield: 180 mg (32% of theoretical)
[1398] ESI-MS: m/z=563 (M+H).sup.+
[1399] R.sub.t (HPLC): 1.15 min (method B)
Example 17
7-methoxy-3-{1-[6-methoxy-5-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carb-
onyl)-pyridazin-3-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d][1,3]diaz-
epin-2-one
##STR00372##
[1401] 0.13 g (0.11 mmol) (purity 50%)
3-{1-[6-chloro-5-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-pyri-
dazin-3-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]-dia-
zepin-2-one and 0.050 mL (0.29 mmol) DIPEA were heated with 1 mL
MeOH in a microwave container for 2 h at 125.degree. C. Then
potassium-tert-butoxide was added and the mixture was stirred for
48 h at RT. Next, the reaction mixture was heated for a further 6 h
and then it was neutralised with acetic acid and purified by
preparative HPLC-MS.
[1402] Yield: 13 mg (20% of theoretical)
[1403] R.sub.t (HPLC): 2.14 min (method H)
Example 18
3-{1-[6-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-2-methyl-p-
yrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]d-
iazepin-2-one
##STR00373##
[1405] 83 mg (0.30 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,
95 mg (0.30 mmol)
6-(6-chloro-2-methyl-pyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2--
one and 0.11 mL (0.60 mmol) DIPEA were stirred overnight in 3 mL
DMF at RT. Then the reaction mixture was purified by preparative
HPLC-MS. The fractions containing the product were combined and the
organic solvent was evaporated down i. vac. The residue was
neutralised with 4N aqueous sodium hydroxide solution, the
precipitate formed was suction filtered, washed with water and
dried i. vac.
[1406] Yield: 115 mg (71% of theoretical)
[1407] ESI-MS: m/z=543 (M+H).sup.+
[1408] R.sub.t (HPLC): 1.33 min (method B)
Example 19
3-[4'-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-3,4,5,6-tetr-
ahydro-2H-[1,2']bipyridinyl-4-yl]-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,-
3]diazepin-2-one
##STR00374##
[1410] 350 mg (1.27 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one
and 180 mg (0.600 mmol)
6-(2-chloro-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one
were stirred overnight in 3 mL NMP at 120.degree. C. The reaction
mixture was diluted with MeOH and purified by preparative HPLC-MS.
The fractions containing the product were combined and
freeze-dried.
[1411] Yield: 60 mg (19% of theoretical)
[1412] ESI-MS: m/z=542 (M+H).sup.+
[1413] R.sub.t (HPLC): 4.24 min (method L)
Example 20
3-{1-[6-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-pyrimidin--
4-yl]-3-fluoro-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]d-
iazepin-2-one
##STR00375##
[1415] 60 mg (0.21 mmol)
3-(3-fluoro-piperidin-4-yl)-7-methoxy-1,3,4,5-tetrahydro-benzo[d]-[1,3]di-
azepin-2-one, 60 mg (0.20 mmol)
6-(6-chloro-pyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one
and 0.040 mL (0.30 mmol) TEA were stirred overnight in 1 mL DMF at
RT. The reaction mixture was combined with 2 mL MeOH and the
precipitate formed was suction filtered, washed with MeOH and
diethyl ether and dried.
[1416] Yield: 77 mg (70% of theoretical)
[1417] ESI-MS: m/z=561 (M+H).sup.+
[1418] R.sub.t (HPLC): 3.40 min (method C)
Example 21
1-{1-[2-methyl-6-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-pyrim-
idin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one
##STR00376##
[1420] 65 mg (0.30 mmol)
1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 91 mg
(0.30 mmol)
6-(6-chloro-2-methyl-pyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol--
2-one and 0.11 mL (0.60 mmol) DIPEA were stirred overnight in 3 mL
DMF at RT. Then the reaction mixture was purified by preparative
HPLC-MS. The fractions containing the product were combined and the
organic solvent evaporated down. The residue was neutralised with
4N aqueous sodium hydroxide solution, the precipitate formed was
suction filtered, washed with water and dried.
[1421] Yield: 90 mg (62% of theoretical)
[1422] ESI-MS: m/z=486 (M+H).sup.+
[1423] R.sub.t (HPLC): 1.17 min (method B)
Example 22
7-methoxy-3-[4'-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-3,4,5,-
6-tetrahydro-2H-[1,2']bipyridinyl-4-yl]-1,3,4,5-tetrahydro-benzo[d][1,3]di-
azepin-2-one
##STR00377##
[1425] Under a nitrogen atmosphere 0.21 g (0.80 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one-
, 0.38 g (1.2 mmol) caesium carbonate, 50 mg (0.10 mmol) BINAP and
25 mg (0.10 mmol) palladium(II)acetate were stirred in 20 mL xylene
for 10 min at RT. 0.25 g (0.80 mmol)
6-(2-bromo-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one were
added and the mixture was stirred overnight at 120.degree. C. The
mixture was evaporated down, the residue was mixed with 15 mL DMF
and 25 mg (0.11 mmol) palladium(II)acetate and 50 mg (0.10 mmol)
BINAP were added. The reaction mixture was stirred for 48 h at
120.degree. C. After cooling the solid was filtered off and the
filtrate was evaporated down i. vac. The residue was triturated
with EtOAc, suction filtered and dissolved in DMF. The product was
purified by preparative HPLC-MS. The fractions containing the
product were combined and freeze-dried.
[1426] Yield: 10 mg (3% of theoretical)
[1427] ESI-MS: m/z=528 (M+H).sup.+
[1428] R.sub.f: 0.57 (silica gel,
DCM/Cyc/MeOH/NH.sub.4OH=70/15/15/2)
Example 23
1-{1-[6-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-2-methyl-p-
yrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one
##STR00378##
[1430] 65 mg (0.30 mmol)
1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 95 mg
(0.30 mmol)
6-(6-chloro-2-methyl-pyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxa-
zol-2-one and 0.11 mL (0.60 mmol) DIPEA were stirred overnight in 3
mL DMF at RT. Then the reaction mixture was purified by preparative
HPLC-MS. The fractions containing the product were combined and the
organic solvent was evaporated down i. vac. The residue was
neutralised with 4N aqueous sodium hydroxide solution, the
precipitate formed was suction filtered, washed with water and
dried.
[1431] Yield: 80 mg (53% of theoretical)
[1432] ESI-MS: m/z=500 (M+H).sup.+
[1433] R.sub.t (HPLC): 1.24 min (method B)
Example 24
1-[4'-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-3,4,5,6-tetr-
ahydro-2H-[1,2']bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]pyridin-2-one
##STR00379##
[1435] 0.40 g (1.8 mmol)
1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one and 0.18 g
(0.60 mmol)
6-(2-chloro-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one
were stirred overnight in 3 mL NMP at 120.degree. C. The reaction
mixture was diluted with MeOH and purified by preparative HPLC-MS.
The fractions containing the product were combined and
freeze-dried.
[1436] Yield: 65 mg (23% of theoretical)
[1437] ESI-MS: m/z=485 (M+H).sup.+
[1438] R.sub.t (HPLC): 1.23 min (method B)
Example 25
3-{1-[6-chloro-5-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-pyrid-
azin-3-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diaze-
pin-2-one
##STR00380##
[1440] 360 mg (1.31 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,
480 mg (1.19 mmol)
6-(3.6-dichloro-pyridazine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one
and 0.300 mL (1.74 mmol) DIPEA were stirred in 3 mL DMF for 4 h at
100.degree. C. Then the reaction mixture was cooled, combined with
0.5 mL formic acid and 15 mL water, the precipitate formed was
suction filtered and dried. This was purified by preparative
HPLC-MS. The fractions containing the product were combined and
freeze-dried.
[1441] Yield: 10 mg (2% of theoretical)
[1442] ESI-MS: m/z=563 (M+H).sup.+
[1443] R.sub.t (HPLC): 1.31 min (method G)
Example 26
3-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piper-
idin-1-yl]-5-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-benzonitr-
ile
##STR00381##
[1445] 0.22 g (0.80 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one
and 0.12 g (0.40 mmol)
3-fluoro-5-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-benzonitri-
le were heated to 300.degree. C. for approx. 10 min. Then the
mixture was dissolved in DMF and purified by preparative HPLC-MS.
The fractions containing the product were combined and the organic
solvent was evaporated down. The residue was neutralised with 1N
aqueous sodium hydroxide solution, the precipitate formed was
suction filtered, washed with water and dried.
[1446] Yield: 30 mg (14% of theoretical)
[1447] ESI-MS: m/z=552 (M+H).sup.+
[1448] R.sub.t (HPLC): 1.48 min (method B)
Example 27
1-[1-(6-benzoyl-pyrimidin-4-yl)-piperidin-4-yl]-1,3-dihydro-imidazo[4,5-b]-
pyridin-2-one
##STR00382##
[1450] 0.20 g (0.67 mmol)
1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 0.15 g
(0.33 mmol) (6-chloro-pyrimidin-4-yl)-phenyl-methanone and 0.20 mL
(1.1 mmol) DIPEA in 3 mL DMF were heated to 80.degree. C. for 1 h.
Then the reaction mixture was purified by preparative HPLC-MS. The
fractions containing the product were combined and
freeze-dried.
[1451] Yield: 87 mg (66% of theoretical)
[1452] ESI-MS: m/z=401 (M+H).sup.+
[1453] R.sub.t (HPLC): 1.59 min (method M)
Example 28
3-{1-[6-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-pyrimidin--
4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one
##STR00383##
[1455] 98 mg (0.40 mmol)
3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 0.12 g
(0.40 mmol)
6-(6-chloropyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one
and 0.14 mL (0.80 mmol) DIPEA were stirred in 3 mL DMF for 2 h at
RT. The mixture was diluted with methanol, and the precipitate
formed was suction filtered, washed with MeOH diethyl ether and
dried.
[1456] Yield: 185 mg (90% of theoretical)
[1457] ESI-MS: m/z=513 (M+H).sup.+
[1458] R.sub.t (HPLC): 1.36 min (method B)
Example 29
7-methoxy-3-{1-[5-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-6-ox-
o-5.6-dihydro-pyridazin-3-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d][-
1,3]diazepin-2-one
##STR00384##
[1460] 0.10 g (1.0 mmol) potassium acetate were added to 0.13 g
(0.20 mmol)
3-{1-[6-chloro-5-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl-
)-pyridazin-3-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,-
3]diazepin-2-one (mixture) in 3 mL acetic acid and the mixture was
boiled under a nitrogen atmosphere for 7 h. Then the reaction
mixture was evaporated down and the residue was triturated with
water, suction filtered and dried. The residue was purified by
preparative HPLC-MS. The fractions containing the product were
combined and freeze-dried.
[1461] Yield: 1.5 mg (1% of theoretical)
[1462] ESI-MS: m/z=545 (M+H).sup.+
[1463] R.sub.t (HPLC): 4.22 min (method I)
Example 30
3-{1-[5-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-6-oxo-1,6--
dihydro-pyridazin-3-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo-
[d][1,3]diazepin-2-one
##STR00385##
[1465] 0.10 g (1.02 mmol) potassium acetate were added to 0.13 g
(0.20 mmol)
3-{1-[6-chloro-5-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carb-
onyl)-pyridazin-3-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d-
][1,3]diazepin-2-one (mixture) in 2 mL acetic acid and the mixture
was boiled for 16 h under a nitrogen atmosphere. Then the reaction
mixture was purified by preparative HPLC-MS. The fractions
containing the product were combined and freeze-dried.
[1466] Yield: 1.6 mg (13% of theoretical)
[1467] Purity: 90%
[1468] ESI-MS: m/z=559 (M+H).sup.+
[1469] R.sub.t (HPLC): 1.52 min (method K)
Example 31
7-chloro-3-{1-[6-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-p-
yrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2--
one
##STR00386##
[1471] 56 mg (0.20 mmol)
7-chloro-3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one,
61 mg (0.20 mmol)
6-(6-chloropyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one
and 0.070 mL (0.40 mmol) DIPEA were stirred overnight in 1.5 mL DMF
at RT. The mixture was diluted with 1.5 mL MeOH, suction filtered,
washed with DIPE and dried.
[1472] Yield: 87 mg (80% of theoretical)
[1473] ESI-MS: m/z=547/549 (M+H).sup.+
[1474] R.sub.t (HPLC): 3.6 min (method C)
Example 32
3-{1-[6-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-pyrimidin--
4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-c]quinolin-2-one
##STR00387##
[1476] 0.11 g (0.40 mmol)
3-piperidin-4-yl-1,3-dihydroimidazo[4,5-c]quinolin-2-one, 0.12 g
(0.40 mmol)
6-(6-chloropyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one
and 0.14 mL (0.80 mmol) DIPEA were stirred overnight in 3 mL DMF at
RT. The mixture was purified by preparative HPLC-MS. The fractions
containing the product were combined, the organic solvent was
eliminated i. vac. and the aqueous phase remaining was neutralised
with 4M aqueous NaOH solution. The precipitate was suction
filtered, washed with water and dried i. vac.
[1477] Yield: 150 mg (70% of theoretical)
[1478] ESI-MS: m/z=536 (M+H).sup.+
[1479] R.sub.t (HPLC): 1.0 min (method B)
Example 33
3-[6'-chloro-4'-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-3,-
4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl]-7-methoxy-1,3,4,5-tetrahydro-b-
enzo[d][1,3]diazepin-2-one
##STR00388##
[1481] 0.41 g (1.5 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one
and 0.20 g (0.49 mmol)
6-(2,6-dichloro-pyridine-4-carbonyl)-3,4-dimethyl-3H-benz-oxazol-2-one
were stirred in 3 mL NMP for 3 h at 120.degree. C. The reaction
mixture was purified by preparative HPLC. The fractions containing
the product were combined and freeze-dried.
[1482] Yield: 150 mg (53% of theoretical)
[1483] ESI-MS: m/z=576/78 (Cl) (M+H).sup.+
[1484] R.sub.t (HPLC): 1.67 min (method B)
Example 34
3-{1-[6-chloro-5-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-p-
yridazin-3-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]d-
iazepin-2-one
##STR00389##
[1486] 0.10 g (1.0 mmol) potassium acetate were added to 0.13 g
(0.20 mmol)
3-{1-[6-chloro-5-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carb-
onyl)-pyridazin-3-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d-
][1,3]diazepin-2-one (mixture) in 2 mL acetic acid and boiled for
16 h under a nitrogen atmosphere. Then the reaction mixture was
purified by preparative HPLC-MS. The fractions containing the
product were combined and freeze-dried.
[1487] Yield: 5 mg (4% of theoretical)
[1488] Purity: 90%
[1489] ESI-MS: m/z=577 (M+H).sup.+
[1490] R.sub.t (HPLC): 3.67 min (method C)
Example 35
1-[4'-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-3,4,5,6-tetrahyd-
ro-2H-[1,2']bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]pyridin-2-one
##STR00390##
[1492] 0.20 g (0.70 mmol)
1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one-dihydrochloride,
0.20 g (0.70 mmol)
6-(6-chloropyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one and
0.30 g (2.2 mmol) potassium carbonate were stirred in 3.0 mL NMP
overnight at 130.degree. C. The reaction mixture was filtered, the
filtrate was diluted with a little water and then purified by
preparative HPLC-MS. The fractions containing the product were
combined and freeze-dried.
[1493] Yield: 40 mg (12% of theoretical)
[1494] ESI-MS: m/z=471 (M+H).sup.+
[1495] R.sub.f: 0.62 (silica gel,
DCM/Cyc/MeOH/NH.sub.4OH=70/15/15/2)
Example 36
3-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-5-[4-(7-methoxy--
2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piperidin-1-yl]-benzo-
nitrile
##STR00391##
[1497] 0.22 g (0.80 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one
and 0.12 g (0.40 mmol)
3-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-5-fluoro-benzon-
itrile were combined and heated to 300.degree. C. for approx. 10
min. Then the mixture was dissolved in DMF and purified by
preparative HPLC-MS. The fractions containing the product were
combined and the organic solvent was evaporated down. The residue
was neutralised with 1N aqueous sodium hydroxide solution, the
precipitate formed was suction filtered, washed with water and
dried i. vac.
[1498] Yield: 25 mg (11% of theoretical)
[1499] ESI-MS: m/z=566 (M+H).sup.+
[1500] R.sub.t (HPLC): 1.56 min (method B)
Example 37
4-methyl-6-[4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-3,4,5,6-tetrahydro-2H-
-[1,4']bipyridinyl-2'-carbonyl]-3H-benzoxazol-2-one
##STR00392##
[1502] 0.20 g (0.90 mmol)
1-piperidin-4-yl-1,3-dihydro-benzimidazol-2-one, 0.25 g (0.90 mmol)
6-(4-chloro-pyridin-2-carbonyl)-4-methyl-3H-benzoxazol-2-one and
0.13 g (0.90 mmol) potassium carbonate were stirred in 3 mL NMP
overnight at 130.degree. C. The solid was filtered off, the
filtrate was diluted with DMF and purified by preparative HPLC-MS.
The fractions containing the product were combined and
freeze-dried.
[1503] Yield: 20 mg (5% of theoretical)
[1504] ESI-MS: m/z=471 (M+H).sup.+
[1505] R.sub.f: 0.51 (silica gel,
DCM/Cyc/MeOH/NH.sub.4OH=70/15/15/2)
Example 38
3-[4'-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-5'-methyl-3,-
4,5,6-tetra-hydro-2H-[1,2']bipyridinyl-4-yl]-7-methoxy-1,3,4,5-tetrahydro--
benzo[d][1,3]diazepin-2-one
##STR00393##
[1507] 0.33 g (1.2 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one
and 0.13 g (0.40 mmol)
6-(2-chloro-5-methyl-pyridine-4-carbonyl)-3,4-dimethyl-3H-benz-oxazol-2-o-
ne (mixture) were combined and heated to 300.degree. C. for approx.
10 min. Then the mixture was dissolved in DMF and purified by
preparative HPLC-MS. The fractions containing the product were
combined and the organic solvent was evaporated down. The residue
was neutralised with 1N aqueous sodium hydroxide solution, the
precipitate formed was suction filtered, washed with water and
dried i. vac.
[1508] Yield: 40 mg (18% of theoretical)
[1509] ESI-MS: m/z=556 (M+H).sup.+
[1510] R.sub.t (HPLC): 1.51 min (method B)
Example 39
3-{1-[3-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-5-fluoro-p-
henyl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin--
2-one
##STR00394##
[1512] 440 mg (1.60 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one
and 121 mg (0.40 mmol)
6-(3,5-difluoro-benzoyl)-3,4-dimethyl-3H-benzoxazol-2-one were
combined and heated to 300.degree. C. for approx. 10 min using the
hot gun. Then the mixture was dissolved in DMF and purified by
preparative HPLC-MS. The fractions containing the product were
combined and the organic solvent was evaporated down. The residue
was neutralised with 1N aqueous sodium hydroxide solution, the
precipitate formed was suction filtered, washed with water and
dried i. vac.
[1513] Yield: 50 mg (22% of theoretical)
[1514] ESI-MS: m/z=559 (M+H).sup.+
[1515] R.sub.t (HPLC): 1.77 min (method B)
Example 40
1-[6'-chloro-4'-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-3,-
4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]pyri-
din-2-one
##STR00395##
[1517] 0.33 g (1.5 mmol)
1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one and 0.20 g
(0.49 mmol)
6-(2,6-dichloro-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-o-
ne were stirred in 3 mL NMP for 3 h at 120.degree. C. The reaction
mixture was purified by preparative HPLC. The fractions containing
the product were combined and freeze-dried.
[1518] Yield: 160 mg (63% of theoretical)
[1519] ESI-MS: m/z=519/21(Cl) (M+H).sup.+
[1520] R.sub.t (HPLC): 1.54 min (method B)
Example 41
7-methoxy-3-{1-[6-(7-methyl-1H-indazole-5-carbonyl)-pyrimidin-4-yl]-piperi-
din-4-yl}-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one
##STR00396##
[1522] 65 mg (0.10 mmol)
7-methoxy-3-(1-{6-[7-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazo-
le-5-carbonyl]-pyrimidin-4-yl}-piperidin-4-yl)-1,3,4,5-tetrahydro-benzo[d]-
[1,3]diazepin-2-one in 0.4 mL MeOH and 0.6 mL (2.4 mmol) of a 4
molar HCl solution in dioxane was stirred overnight at RT. The
mixture was neutralised with 0.4 mL of a 6 molar methanolic ammonia
solution, mixed with some water and purified by preparative
HPLC-MS. The fractions containing the product were combined and
freeze-dried.
[1523] Yield: 16 mg (28% of theoretical)
[1524] Purity: 90%
[1525] ESI-MS: m/z=512 (M+H).sup.+
[1526] R.sub.t (HPLC): 2.76 min (method C)
Example 42
3-{1-[6-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-pyrimidin--
4-yl]-3-methyl-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]d-
iazepin-2-one
##STR00397##
[1528] 60 mg (0.21 mmol)
7-methoxy-3-(3-methyl-piperidin-4-yl)-1,3,4,5-tetrahydro-benzo[d]-[1,3]di-
azepin-2-one, 60 mg (0.20 mmol)
6-(6-chloro-pyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one
and 0.040 mL (0.29 mmol) TEA were stirred overnight in 1 mL DMF at
RT. Then the reaction mixture was combined with 2 mL MeOH, the
precipitate formed was suction filtered, washed with MeOH and
diethyl ether and dried.
[1529] Yield: 80 mg (66% of theoretical)
[1530] ESI-MS: m/z=557 (M+H).sup.+
[1531] R.sub.t (HPLC): 1.41 min (method C)
Example 43
4-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-2-[4-(7-methoxy--
2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piperidin-1-yl]-benzo-
nitrile
##STR00398##
[1533] 440 mg (1.60 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one
and 124 mg (0.400 mmol)
4-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-2-fluoro-benzon-
itrile were combined and heated to 300.degree. C. for approx. 10
min. Then the mixture was dissolved in DMF and purified by
preparative HPLC-MS. The fractions containing the product were
combined and the organic solvent was evaporated down. The residue
was neutralised with 1N aqueous sodium hydroxide solution, the
precipitate formed was suction filtered, washed with water and
dried.
[1534] Yield: 125 mg (55% of theoretical)
[1535] ESI-MS: m/z=566 (M+H).sup.+
[1536] R.sub.t (HPLC): 1.65 min (method B)
Example 44
7-methoxy-3-{1-[6-(4-methyl-2-oxo-2,3-dihydro-benzothiazole-6-carbonyl)-py-
rimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-o-
ne
##STR00399##
[1538] 63 mg (0.23 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one-
, 71 mg (0.23 mmol)
6-(6-chloro-pyrimidine-4-carbonyl)-4-methyl-3H-benzothiazol-2-one
and 0.047 mL (0.27 mmol) DIPEA were combined in 2 mL DMF and shaken
overnight at RT. The reaction mixture was taken up in
acetonitrile/water and purified by preparative HPLC. The fractions
containing the product were combined and freeze-dried.
[1539] Yield: 25 mg (20% of theoretical)
[1540] ESI-MS: m/z=545 (M+H).sup.+
[1541] R.sub.t (HPLC): 3.48 min (method C)
Example 45
3-{1-[3-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-phenyl]-pi-
peridin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one
##STR00400##
[1543] Under an argon atmosphere 330 mg (1.20 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one-
, 350 mg (1.01 mmol)
6-(3-bromo-benzoyl)-3,4-dimethyl-3H-benzoxazol-2-one and 586 mg
(1.80 mmol) caesium carbonate were stirred in 10 mL xylene, then
combined with 56 mg (0.090 mmol) BINAP and 20 mg (0.089 mmol)
palladium(II)acetate and stirred for 48 h at 100.degree. C. The
mixture was evaporated down i. vac., the residue was dissolved in
DMF/MeOH and purified by preparative HPLC-MS. The fractions
containing the product were combined and the acetonitrile was
evaporated down. The aqueous residue was made basic with 1N aqueous
sodium hydroxide solution, the precipitate formed was suction
filtered and washed with water and dried. The product was again
purified by preparative HPLC-MS. The fractions containing the
product were combined and freeze-dried.
[1544] Yield: 7 mg (1% of theoretical)
[1545] ESI-MS: m/z=541 (M+H).sup.+
[1546] R.sub.t (HPLC): 1.58 min (method B)
Example 46
4-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-2-[4-(2-oxo-2,3--
dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-benzonitrile
##STR00401##
[1548] 0.26 g (1.2 mmol)
1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one and 93 mg
(0.30 mmol)
4-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-2-fluoro--
benzonitrile were combined and heated to 300.degree. C. for approx.
10 min. Then the mixture was dissolved in DMF and purified by
preparative HPLC-MS. The fractions containing the product were
combined and the organic solvent was evaporated down. The residue
was neutralised with 1N aqueous sodium hydroxide solution, the
precipitate formed was suction filtered, washed with water and
dried.
[1549] Yield: 7 mg (5% of theoretical)
[1550] ESI-MS: m/z=509 (M+H).sup.+
[1551] R.sub.t (HPLC): 1.50 min (method B)
Example 47
1-[4'-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-6'-methoxy-3-
,4,5,6-tetra-hydro-2H-[1,2']bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]py-
ridin-2-one
##STR00402##
[1553] 785 mg (3.60 mmol)
1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one and 420 mg
(1.26 mmol)
6-(2-chloro-6-methoxy-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxaz-
ol-2-one were combined in 3 mL NMP and stirred for 12 h at
120.degree. C. The mixture was purified by preparative HPLC-MS. The
fractions containing the product were combined and the acetonitrile
was eliminated i. vac. The residue was diluted with water, the
precipitated solid was suction filtered, washed with water and
dried.
[1554] Yield: 180 mg (10% of theoretical)
[1555] ESI-MS: m/z=515 (M+H).sup.+
[1556] R.sub.t (HPLC): 1.60 min (method B)
Example 48
3-[4'-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-6'-methoxy-3-
,4,5,6-tetra-hydro-2H-[1,2']bipyridinyl-4-yl]-7-methoxy-1,3,4,5-tetrahydro-
-benzo[d][1,3]diazepin-2-one
##STR00403##
[1558] 991 mg (3.60 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one
and 420 mg (1.26 mmol)
6-(2-chloro-6-methoxy-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-o-
ne were combined in 3 mL NMP and stirred for 12 h at 120.degree. C.
The mixture was purified by preparative HPLC-MS. The fractions
containing the product were combined and the acetonitrile was
eliminated i. vac. The residue was diluted with water, the
precipitated solid was suction filtered, washed with water and
dried.
[1559] Yield: 290 mg (14% of theoretical)
[1560] ESI-MS: m/z=572 (M+H).sup.+
[1561] R.sub.t (HPLC): 1.70 min (method B)
Example 49
3-{1-[6-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-pyrimidin--
4-yl]-piperidin-4-yl}-1H-quinolin-2-one
##STR00404##
[1563] 60 mg (0.26 mmol) 3-piperidin-4-yl-1H-quinolin-2-one, 80 mg
(0.26 mmol)
6-(6-chloropyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one
and 0.15 mL (0.86 mmol) DIPEA were combined in 3 mL DMF and stirred
overnight at RT. The reaction mixture was added to water and the
precipitate formed was suction filtered, washed with MeOH and
dried.
[1564] Yield: 110 mg (80% of theoretical)
[1565] ESI-MS: m/z=496 (M+H).sup.+
[1566] R.sub.t (HPLC): 1.34 min (method B)
Example 50
3,4-dimethyl-6-{6-[4-(5-oxo-3-phenyl-4,5-dihydro-[1,2,4]triazol-1-yl)-pipe-
ridin-1-yl]-pyrimidine-4-carbonyl}-3H-benzoxazol-2-one
##STR00405##
[1568] 98 mg (0.40 mmol)
5-phenyl-2-piperidin-4-yl-2,4-dihydro-[1,2,4]triazol-3-one, 0.12 g
(0.40 mmol)
6-(6-chloro-pyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one
and 0.14 mL (0.80 mmol) DIPEA were combined in 3 mL DMF and stirred
for 48 h at RT. The mixture was diluted with MeOH, suction
filtered, washed with MeOH and diethyl ether and dried.
[1569] Yield: 158 mg (77% of theoretical)
[1570] ESI-MS: m/z=512 (M+H).sup.+
[1571] R.sub.t (HPLC): 1.27 min (method A)
Example 51
7-methoxy-3-{1-[6-(7-methyl-2-oxo-2,3-dihydro-1H-indol-5-carbonyl)-pyrimid-
in-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one
##STR00406##
[1573] 0.12 g (0.42 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,
0.12 g (0.42 mmol)
5-(6-chloro-pyrimidine-4-carbonyl)-7-methyl-1,3-dihydro-indol-2-one
and 0.08 mL (0.46 mmol) DIPEA were combined in 2 mL DMF and shaken
overnight at RT. Then the reaction mixture was taken up in
acetonitrile/water and purified by preparative HPLC-MS. The
fractions containing the product were combined and
freeze-dried.
[1574] Yield: 30 mg (14% of theoretical)
[1575] ESI-MS: m/z=527 (M+H).sup.+
[1576] R.sub.t (HPLC): 1.18 min (method B)
Example 52
1-[4'-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-5'-methyl-3,-
4,5,6-tetra-hydro-2H-[1,2']bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]pyr-
idin-2-one
##STR00407##
[1578] 0.26 g (1.2 mmol)
1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one and 0.13 g
(0.40 mmol)
6-(2-chloro-5-methyl-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazo-
l-2-one (mixture) were combined and heated to 250.degree. C. for
approx. 10 min. Then the mixture was dissolved in DMF and purified
by preparative HPLC-MS. The fractions containing the product were
combined and the organic solvent was evaporated down. The residue
was neutralised with 1N aqueous sodium hydroxide solution, the
precipitate formed was suction filtered, washed with water and
dried.
[1579] Yield: 52 mg (26% of theoretical)
[1580] ESI-MS: m/z=499 (M+H).sup.+
[1581] R.sub.t (HPLC): 1.34 min (method B)
Example 53
3-{1-[6-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-pyrimidin--
4-yl]-piperidin-4-yl}-6-methoxy-1H-quinolin-2-one
##STR00408##
[1583] 30 mg (0.087 mmol)
6-methoxy-3-piperidin-4-yl-1H-quinoline-2-one, 30 mg (0.10 mmol)
6-(6-chloro-pyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one
and 50 .mu.l (0.36 mmol) TEA were combined in 3 mL DMF and stirred
overnight at RT. Then the reaction mixture was added to water, the
precipitate formed was suction filtered and washed with MeOH. Next,
the precipitate was boiled in DMF/MeOH and the precipitate was
suction filtered.
[1584] Yield: 12 mg (24% of theoretical)
[1585] ESI-MS: m/z=526 (M+H).sup.+
[1586] R.sub.t (HPLC): 1.33 min (method B)
Example 54
3-{1-[6-(4-hydroxy-3,5-dimethyl-benzoyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-
-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one
##STR00409##
[1588] 70 mg (0.10 mmol)
3-{1-[6-(4-benzyloxy-3,5-dimethyl-benzoyl)-pyrimidin-4-yl]-piperidin-4-yl-
}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one and 20
mg palladium on charcoal (Pd/C 10%) in 10 mL MeOH were hydrogenated
for 30 min at RT in a hydrogen atmosphere of 10 psi. After
filtration of the reaction mixture the solvent was eliminated i.
vac. and the residue was purified by preparative HPLC-MS. The
fractions containing the product were combined and
freeze-dried.
[1589] Yield: 11 mg (21% of theoretical)
[1590] ESI-MS: m/z=502 (M+H).sup.+
[1591] R.sub.t (HPLC): 3.0 min (method C)
Example 55
1-{1-[6-(4-methyl-2-oxo-2,3-dihydro-benzothiazole-6-carbonyl)-pyrimidin-4--
yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one
##STR00410##
[1593] 50 mg (0.23 mmol)
1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 70.6 mg
(0.23 mmol)
6-(6-chloro-pyrimidine-4-carbonyl)-4-methyl-3H-benzothiazol-2-one
and 0.05 mL (0.27 mmol) DIPEA were combined in 2 mL DMF and shaken
overnight at RT. The reaction mixture was taken up in
acetonitrile/water and purified by preparative HPLC. The fractions
containing the product were combined and freeze-dried.
[1594] Yield: 12 mg (11% of theoretical)
[1595] ESI-MS: m/z=488 (M+H).sup.+
[1596] R.sub.t (HPLC): 2.80 min (method C)
Example 56
1-{1-[6-(4-hydroxy-3,5-dimethyl-benzoyl)-pyrimidin-4-yl]-piperidin-4-yl}-1-
,3-dihydro-imidazo[4,5-b]pyridin-2-one
##STR00411##
[1598] 50 mg palladium/charcoal (10%) were added to 390 mg (0.7
mmol)
1-{1-[6-(4-benzyloxy-3,5-dimethyl-benzoyl)-pyrimidin-4-yl]-piperidin-4-yl-
}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one in 50 mL MeOH and the
mixture was hydrogenated for 40 min in a 5 psi hydrogen atmosphere
at RT. The catalyst was removed by suction filtering and the
filtrate was evaporated down. The residue was triturated with some
MeOH, suction filtered and washed with diethyl ether. The suction
filtered catalyst was decocted with 120 mL MeOH for 1 h, filtered
hot and the filtrate was evaporated down. The residue was
triturated with a little MeOH, suction filtered and dried. The two
batches of solid were combined and purified by preparative HPLC-MS.
The fractions containing the product were combined and
freeze-dried.
[1599] Yield: 30 mg (10% of theoretical)
[1600] ESI-MS: m/z=445 (M+H).sup.+
[1601] R.sub.t (HPLC): 2.48 min (method C)
Example 57
3-{1-[6-(1,7-dimethyl-1H-indazole-5-carbonyl)-pyrimidin-4-yl]-piperidin-4--
yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one
##STR00412##
[1603] 33 mg (0.12 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,
45 mg (0.13 mmol)
(6-chloro-pyrimidin-4-yl)-(1,7-dimethyl-1H-indazol-5-yl)-methanone
and 25 .mu.L (0.18 mmol) TEA were combined in 1 mL DMF and stirred
overnight at RT. The reaction mixture was purified by preparative
HPLC. The fractions containing the product were combined and
evaporated down to approx. 10 mL. This residue was neutralised with
saturated sodium hydrogen carbonate solution, the precipitate
formed was suction filtered and dried.
[1604] Yield: 30 mg (48% of theoretical)
[1605] ESI-MS: m/z=526 (M+H).sup.+
[1606] R.sub.t (HPLC): 3.11 min (method C)
Example 58
3-{1-[6-(3-ethyl-4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-pyrimi-
din-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazep-
in-2-one
##STR00413##
[1608] 44 mg (0.20 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one-
, 50 mg (0.20 mmol)
6-(6-chloro-pyrimidine-4-carbonyl)-3-ethyl-4-methyl-3H-benzoxazol-2-one
and 56 .mu.L (0.30 mmol) DIPEA were combined in 2 mL DMF and
stirred overnight at RT. The reaction mixture was purified by
preparative HPLC. The fractions containing the product were
combined, the organic solvent was evaporated down and the residue
was neutralised with 1N aqueous sodium hydroxide solution. The
precipitate formed was suction filtered, washed with water and
dried.
[1609] Yield: 43 mg (48% of theoretical)
[1610] ESI-MS: m/z=557 (M+H).sup.+
[1611] R.sub.t (HPLC): 3.41 min (method C)
Example 59
7-methoxy-3-{1-[6-(3-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-pyri-
midin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one
##STR00414##
[1613] 99 mg (0.40 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,
0.10 g (0.40 mmol)
6-(6-chloro-pyrimidine-4-carbonyl)-3-methyl-3H-benzoxazol-2-one and
0.070 mL (0.40 mmol) DIPEA were combined in 2 mL DMF and shaken
overnight at RT. The mixture was diluted with acetonitrile/water
and purified by preparative HPLC-MS. The fractions containing the
product were combined and freeze-dried.
[1614] Yield: 140 mg (74% of theoretical)
[1615] ESI-MS: m/z=529 (M+H).sup.+
[1616] R.sub.t (HPLC): 1.27 min (method B)
Example 60
7-methoxy-3-{1-[6-(2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-pyrimidin-4-y-
l]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one
##STR00415##
[1618] 99 mg (0.40 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,
0.10 g (0.40 mmol)
6-(6-chloro-pyrimidine-4-carbonyl)-3H-benzoxazol-2-one and 0.07 mL
(0.40 mmol) DIPEA were combined in 2 mL DMF and shaken overnight at
RT. The mixture was diluted with acetonitrile/water and purified by
preparative HPLC-MS. The fractions containing the product were
combined and freeze-dried.
[1619] Yield: 105 mg (57% of theoretical)
[1620] ESI-MS: m/z=513 (M-H).sup.-
[1621] R.sub.t (HPLC): 1.18 min (method B)
Example 61
1-{1-[6-(7-methyl-2-oxo-2,3-dihydro-1H-indol-5-carbonyl)-pyrimidin-4-yl]-p-
iperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one
##STR00416##
[1623] 91 mg (0.42 mmol)
1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 120 mg
(0.42 mmol)
5-(6-chloro-pyrimidine-4-carbonyl)-7-methyl-1,3-dihydro-indol-2-one
and 0.080 mL (0.46 mmol) DIPEA were combined in 2 mL DMF and shaken
overnight at RT. Then the reaction mixture was in taken up
acetonitrile/water and purified by preparative HPLC-MS. The
fractions containing the product were combined and
freeze-dried.
[1624] Yield: 33 mg (17% of theoretical)
[1625] ESI-MS: m/z=468 (M-H).sup.-
[1626] R.sub.t (HPLC): 1.07 min (method B)
Example 62
1-{1-[6-(3,4,5-trimethyl-benzoyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihy-
dro-imidazo[4,5-b]-pyridin-2-one
##STR00417##
[1628] 0.20 g (0.70 mmol)
1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one-dihydrochloride,
0.18 g (0.70 mmol)
(6-chloro-pyrimidin-4-yl)-(3,4,5-trimethyl-phenyl)-methanone and
0.40 mL (2.3 mmol) DIPEA were combined in 10 mL DMF and stirred
overnight at RT. The reaction mixture was evaporated down i. vac.,
the residue was mixed with water and stirred for another 10 min.
The precipitate was suction filtered and purified by preparative
HPLC-MS. The fractions containing the product were combined and
freeze-dried.
[1629] Yield: 30 mg (10% of theoretical)
[1630] ESI-MS: m/z=443 (M+H).sup.+
[1631] R.sub.f: 0.66 (silica gel,
DCM/Cyc/MeOH/NH.sub.4OH=70/15/15/2)
Example 63
1-[6'-benzyloxy-4'-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-
-3,4,5,6-tetra-hydro-2H-[1,2']bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]-
pyridin-2-one
##STR00418##
[1633] 785 mg (3.60 mmol)
1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one and 500 mg
(1.22 mmol)
6-(2-benzyloxy-6-chloro-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzox-
azol-2-one (mixture) were combined in 5 mL NMP and stirred
overnight at 120.degree. C. The reaction mixture was purified by
preparative HPLC. The fractions containing the product were
combined and evaporated down. The residue was triturated with DIPE,
suction filtered, washed with DIPE and dried.
[1634] Yield: 300 mg (14% of theoretical)
[1635] ESI-MS: m/z=591 (M+H).sup.+
[1636] R.sub.t (HPLC): 1.70 min (method B)
Example 64
7-methoxy-3-{1-[6-(3-methyl-2-oxo-4-pyrazol-1-ylmethyl-2,3-dihydro-benzoxa-
zole-6-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[-
d][1,3]diazepin-2-one
##STR00419##
[1638] 140 mg (0.508 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,
210 mg (0.284 mmol)
6-(6-chloro-pyrimidine-4-carbonyl)-3-methyl-4-pyrazol-1-yl-methyl-3H-benz-
oxazol-2-one and 0.100 mL (0.581 mmol) DIPEA were combined in 1.0
mL DMF and stirred for 48 h at RT. Then the reaction mixture was
purified several times by preparative HPLC-MS. The fractions
containing the product were combined and freeze-dried.
[1639] Yield: 12 mg (6% of theoretical)
[1640] ESI-MS: m/z=609 (M+H).sup.+
[1641] R.sub.t (HPLC): 4.33 min (method D)
Example 65
1-{1-[6-(1,7-dimethyl-1H-indazole-5-carbonyl)-pyrimidin-4-yl]-piperidin-4--
yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one
##STR00420##
[1643] 25 mg (0.12 mmol)
1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 35 mg
(0.10 mmol)
(6-chloro-pyrimidin-4-yl)-(1,7-dimethyl-1H-indazol-5-yl)-methanone
and 25 .mu.L (0.18 mmol) TEA were combined in 1 mL DMF and stirred
overnight at RT. The reaction mixture was purified by preparative
HPLC. The fractions containing the product were combined evaporated
down to approx. 5 mL. This residue was neutralised with saturated
sodium hydrogen carbonate solution, the precipitate formed was
suction filtered and dried.
[1644] Yield: 20 mg (44% of theoretical)
[1645] ESI-MS: m/z=469 (M+H).sup.+
[1646] R.sub.t (HPLC): 2.63 min (method C)
Example 66
7-methoxy-3-{1-[6-(7-methyl-2,3-dihydro-benzofuran-5-carbonyl)-pyrimidin-4-
-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one
##STR00421##
[1648] 100 mg (0.363 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,
90.0 mg (0.229 mmol)
(6-chloro-pyrimidin-4-yl)-(7-methyl-2,3-dihydro-benzofuran-5-yl)-methanon-
e and 0.200 mL (1.16 mmol) DIPEA were combined in 1.5 mL DMF and
stirred for 48 h at RT. Then the reaction mixture was combined with
a few drops of hydrochloric acid and purified by preparative
HPLC-MS. The fractions containing the product were combined and
freeze-dried.
[1649] Yield: 75 mg (64% of theoretical)
[1650] ESI-MS: m/z=514 (M+H).sup.+
[1651] R.sub.t (HPLC): 1.3 min (method B)
Example 67
1-{1-[6-(3-ethyl-4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-pyrimi-
din-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one
##STR00422##
[1653] 47 mg (0.20 mmol)
1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one-dihydrochloride,
50 mg (0.20 mmol)
6-(6-chloro-pyrimidine-4-carbonyl)-3-ethyl-4-methyl-3H-benzoxazol-2-one
and 0.11 mL (0.64 mmol) DIPEA were combined in 2.0 mL DMF and
stirred overnight at RT. The reaction mixture was purified by
preparative HPLC. The fractions containing the product were
combined, the organic solvent was evaporated down and the residue
was neutralised with 1N aqueous sodium hydroxide solution. The
precipitate formed was suction filtered, washed with water and
dried.
[1654] Yield: 47 mg (59% of theoretical)
[1655] ESI-MS: m/z=500 (M+H).sup.+
[1656] R.sub.t (HPLC): 2.89 min (method C)
Example 68
7-methoxy-3-{1-[6-(1,3,3,7-tetramethyl-2,3-dihydro-1H-indol-5-carbonyl)-py-
rimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-o-
ne
##STR00423##
[1658] 48 mg (0.17 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,
55 mg (0.17 mmol)
(6-chloro-pyrimidin-4-yl)-(1,3,3,7-tetramethyl-2,3-dihydro-1H-indol-5-yl)-
-methanone and 0.050 mL (0.29 mmol) DIPEA were combined in 2 mL DMF
and stirred overnight at 40.degree. C. Then the reaction mixture
was purified by preparative HPLC-MS. The fractions containing the
product were combined and freeze-dried.
[1659] Yield: 50 mg (52% of theoretical)
[1660] ESI-MS: m/z=555 (M+H).sup.+
[1661] R.sub.t (HPLC): 1.39 min (method B)
Example 69
3-{1-[6-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-pyrimidin--
4-yl]-piperidin-4-yl}-9-fluoro-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2--
one
##STR00424##
[1663] 61 mg (0.23 mmol)
9-fluoro-3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one,
70 mg (0.23 mmol)
6-(6-chloropyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one
and 0.080 mL (0.46 mmol) DIPEA were combined in 2 mL DMF and
stirred for 2 h at RT. Then the reaction mixture was diluted with
MeOH, the precipitate formed was suction filtered, washed with MeOH
and diethyl ether and dried.
[1664] Yield: 78 mg (64% of theoretical)
[1665] ESI-MS: m/z=531 (M+H).sup.+
[1666] R.sub.t (HPLC): 1.38 min (method B)
Example 70
3-{1-[5-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-2-fluoro-p-
henyl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin--
2-one
##STR00425##
[1668] Under an argon atmosphere 330 mg (1.20 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one-
, 437 mg (1.20 mmol)
6-(3-bromo-4-fluoro-benzoyl)-3,4-dimethyl-3H-benzoxazol-2-one and
586 mg (1.80 mmol) caesium carbonate were combined in 10 mL
dioxane, then mixed with 75 mg (0.12 mmol) BINAP and 27 mg (0.12
mmol) palladium(II)acetate and stirred for 48 h at 100.degree. C.
The mixture was evaporated down, the residue was dissolved in
DMF/MeOH and purified by preparative HPLC-MS. The fractions
containing the product were combined and the acetonitrile was
evaporated down. The aqueous residue was made basic with 1N aqueous
sodium hydroxide solution, the precipitate formed was suction
filtered and washed with water and dried. As the product was still
contaminated, it was then purified again by preparative
HPLC-MS.
[1669] Yield: 40 mg (6% of theoretical)
[1670] ESI-MS: m/z=559 (M+H).sup.+
[1671] R.sub.t (HPLC): 4.21 min (method C)
Example 71
1-{1-[6-(7-methyl-2,3-dihydro-benzofuran-5-carbonyl)-pyrimidin-4-yl]-piper-
idin-4-yl}-1,3-di-hydro-imidazo[4,5-b]pyridin-2-one-formate
##STR00426##
[1673] 0.11 g (0.36 mmol)
1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one-dihydrochloride,
90 mg (0.23 mmol)
(6-chloro-pyrimidin-4-yl)-(7-methyl-2,3-dihydro-benzofuran-5-yl)-methanon-
e and 0.20 mL (1.16 mmol) DIPEA were combined in 1.5 mL DMF and
stirred for 48 h at RT. Then the reaction mixture was mixed with a
few drops of hydrochloric acid and purified by preparative HPLC-MS.
The fractions containing the product were combined and
freeze-dried.
[1674] Yield: 60 mg (52% of theoretical)
[1675] ESI-MS: m/z=457 (M+H).sup.+
[1676] R.sub.t (HPLC): 1.18 min (method B)
Example 72
1-{1-[6-(2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-pyrimidin-4-yl]-piperid-
in-4-yl}-1,3-di-hydro-imidazo[4,5-b]pyridin-2-one
##STR00427##
[1678] 78 mg (0.40 mmol)
1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one, 0.10 g
(0.40 mmol) 6-(6-chloro-pyrimidine-4-carbonyl)-3H-benzoxazol-2-one
and 0.070 mL (0.40 mmol) DIPEA were combined in 2 mL DMF and shaken
overnight at RT. The mixture was diluted with acetonitrile/water
and purified by preparative HPLC-MS. The fractions containing the
product were combined and freeze-dried.
[1679] Yield: 98 mg (60% of theoretical)
[1680] ESI-MS: m/z=456 (M-H).sup.-
[1681] R.sub.t (HPLC): 1.02 min (method B)
Example 73
7-methoxy-3-{1-[6-(8-methyl-2,3-dihydro-benzo[1,4]dioxin-6-carbonyl)-pyrim-
idin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one
##STR00428##
[1683] 61 mg (0.22 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,
84 mg (0.22 mmol)
(6-iodo-pyrimidin-4-yl)-(8-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-meth-
anone and 0.08 mL (0.44 mmol) DIPEA were combined in 2.5 mL DMF and
stirred overnight at RT. Then the reaction mixture was purified by
preparative HPLC-MS. The fractions containing the product were
combined and the organic solvent was evaporated down. The residue
was combined with 1N aqueous sodium hydroxide solution, the
precipitate formed was suction filtered, washed with water and
dried.
[1684] Yield: 65 mg (56% of theoretical)
[1685] ESI-MS: m/z=530 (M+H).sup.+
[1686] R.sub.t (HPLC): 3.38 min (method B)
Example 74
1-{1-[6-(8-methyl-2,3-dihydro-benzo[1,4]dioxin-6-carbonyl)-pyrimidin-4-yl]-
-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one
##STR00429##
[1688] 64 mg (0.22 mmol)
1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one-dihydrochloride,
84 mg (0.22 mmol)
(6-iodo-pyrimidin-4-yl)-(8-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-meth-
anone and 0.15 mL (0.88 mmol) DIPEA were combined in 2.5 mL DMF and
stirred overnight at RT. Then the reaction mixture was purified by
preparative HPLC-MS. The fractions containing the product were
combined and the organic solvent was evaporated down. The residue
was mixed with 1N aqueous sodium hydroxide solution, the
precipitate formed was suction filtered, washed with water and
dried.
[1689] Yield: 70 mg (67% of theoretical)
[1690] ESI-MS: m/z=473 (M+H).sup.+
[1691] R.sub.t (HPLC): 2.85 min (method B)
Example 75
1-{1-[6-(3-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-pyrimidin-4-yl-
]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one
##STR00430##
[1693] 78 mg (0.40 mmol)
1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one, 0.10 g
(0.40 mmol)
6-(6-chloro-pyrimidine-4-carbonyl)-3-methyl-3H-benzoxazol-2-one and
0.070 mL (0.40 mmol) DIPEA were combined in 2 mL DMF and shaken
overnight at RT. The mixture was diluted with acetonitrile/water
and purified by preparative HPLC-MS. The fractions containing the
product were combined and freeze-dried.
[1694] Yield: 126 mg (74% of theoretical)
[1695] ESI-MS: m/z=470 (M-H).sup.-
[1696] R.sub.t (HPLC): 1.1 min (method B)
Example 76
7-methoxy-3-{1-[6-(2-oxo-2,3-dihydro-1H-indol-5-carbonyl)-pyrimidin-4-yl]--
piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one
##STR00431##
[1698] 99 mg (0.40 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one-
, 98 mg (0.40 mmol)
5-(6-chloro-pyrimidine-4-carbonyl)-1,3-dihydro-indol-2-one and
0.070 mL (0.40 mmol) DIPEA were combined in 2 mL DMF and shaken
overnight at RT. The mixture was diluted with acetonitrile/water
and purified by preparative HPLC-MS. The fractions containing the
product were combined and freeze-dried.
[1699] Yield: 91 mg (49% of theoretical)
[1700] ESI-MS: m/z=511 (M-H).sup.-
[1701] R.sub.t (HPLC): 1.1 min (method B)
Example 77
1-{1-[6-(1,3,3,7-tetramethyl-2,3-dihydro-1H-indol-5-carbonyl)-pyrimidin-4--
yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one
##STR00432##
[1703] 38 mg (0.17 mmol)
1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 55 mg
(0.17 mmol)
(6-chloro-pyrimidin-4-yl)-(1,3,3,7-tetramethyl-2,3-dihydro-1H-indol-
-5-yl)-methanone and 0.050 mL (0.29 mmol) DIPEA were combined in 2
mL DMF and stirred overnight at 40.degree. C. Then the reaction
mixture was purified by preparative HPLC-MS. The fractions
containing the product were combined and freeze-dried.
[1704] Yield: 60 mg (69% of theoretical)
[1705] ESI-MS: m/z=498 (M+H).sup.+
[1706] R.sub.t (HPLC): 1.24 min (method B)
Example 78
3-{1-[6-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-pyrimidin--
4-yl]-2-methyl-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]d-
iazepin-2-one
##STR00433##
[1708] 60 mg (0.21 mmol)
7-methoxy-3-(2-methyl-piperidin-4-yl)-1,3,4,5-tetrahydro-benzo[d]-[1,3]di-
azepin-2-one, 60 mg (0.20 mmol)
6-(6-chloropyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one
and 0.040 mL (0.29 mmol) TEA were combined in 1 mL DMF and stirred
for three days at RT. Then
7-methoxy-3-(2-methyl-piperidin-4-yl)-1,3,4,5-tetrahydrobenzo[d][1,3]diaz-
epin-2-one was added again and the mixture was stirred for 3 h at
80.degree. C. The reaction mixture was purified by preparative
HPLC. The fractions containing the product were combined and the
solvent was evaporated down by half. The aqueous residue was
extracted with DCM, the combined organic phases were dried on
sodium sulphate, filtered and the filtrate was evaporated down.
[1709] Yield: 9 mg (8% of theoretical)
[1710] ESI-MS: m/z=557 (M+H).sup.+
[1711] R.sub.t (HPLC): 3.54 min (method C)
Example 79
1-{1-[6-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carbonyl)-pyrim-
idin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one
##STR00434##
[1713] 75 mg (0.34 mmol)
1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 0.10 g
(0.33 mmol)
5-(6-chloro-pyrimidine-4-carbonyl)-1,3-dimethyl-1,3-dihydro-benzimi-
dazol-2-one and 0.10 mL (0.58 mmol) DIPEA were combined in 5 mL DMF
and stirred overnight at RT. Then the reaction mixture was
evaporated down, the residue was mixed with water and stirred for
another 10 min. The precipitate formed was suction filtered,
dissolved in DMF and purified by preparative HPLC-MS. The fractions
containing the product were combined and freeze-dried.
[1714] Yield: 75 mg (45% of theoretical)
[1715] ESI-MS: m/z=485 (M+H).sup.+
[1716] R.sub.f: 0.59 (silica gel;
DCM/Cyc/MeOH/NH.sub.4OH=70/15/15/2)
Example 80
3-{1-[6-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carbonyl)-pyrim-
idin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diaze-
pin-2-one
##STR00435##
[1718] 90 mg (0.34 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,
0.10 g (0.33 mmol)
5-(6-chloro-pyrimidine-4-carbonyl)-1,3-dimethyl-1,3-dihydro-benzimidazol--
2-one and 0.10 mL (0.58 mmol) DIPEA in 5 mL DMF were combined and
stirred overnight at RT. Then the reaction mixture was evaporated
down, the residue was mixed with water and stirred for another 10
min. The precipitate formed was suction filtered, dissolved in DMF
and purified by preparative HPLC-MS. The fractions containing the
product were combined and freeze-dried.
[1719] Yield: 55 mg (31% of theoretical)
[1720] ESI-MS: m/z=542 (M+H).sup.+
[1721] R.sub.f: 0.64 (silica gel;
DCM/Cyc/MeOH/NH.sub.4OH=70/15/15/2)
Example 81
3-[6'-amino-4'-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-3,4-
,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl]-7-methoxy-1,3,4,5-tetrahydro-be-
nzo[d][1,3]diazepin-2-one
##STR00436##
[1723] 0.50 mL TFA were added to 57 mg (0.10 mmol) tert-butyl
[4'-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-4-(7-methoxy--
2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-3,4,5,6-tetrahydro-2H-
-[1,2']bipyridinyl-6'-yl]-carbamate in 5.00 mL DCM and stirred for
3 h at RT. Then another 0.50 mL TFA were added and the mixture was
stirred overnight at RT. Then the reaction mixture was evaporated
down, the residue was dissolved in DMF and purified by preparative
HPLC-MS. The fractions containing the product were combined and
freeze-dried.
[1724] Yield: 4 mg (8% of theoretical)
[1725] ESI-MS: m/z=557 (M+H).sup.+
[1726] R.sub.t (HPLC): 1.30 min (method B)
Example 82
3-{1-[6-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-2-methyl-p-
yrimidin-4-yl]-3-fluoro-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo-
[d][1,3]diazepin-2-one
##STR00437##
[1728] 82 mg (0.28 mmol)
3-(3-fluoro-piperidin-4-yl)-7-methoxy-1,3,4,5-tetrahydro-benzo[d]-[1,3]di-
azepin-2-one, 85 mg (0.27 mmol)
6-(6-chloro-2-methyl-pyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2--
one and 0.10 mL (0.56 mmol) DIPEA were combined in 2 mL DMF and
stirred overnight at RT. Then the reaction mixture was purified by
preparative HPLC-MS. The fractions containing the product were
combined and the organic solvent was evaporated down. The residue
was neutralised with 4N aqueous sodium hydroxide solution, the
precipitate formed was suction filtered, washed with water and
dried.
[1729] Yield: 64 mg (40% of theoretical)
[1730] ESI-MS: m/z=575 (M+H).sup.+
[1731] R.sub.t (HPLC): 1.32 min (method B)
Example 83
7-methoxy-3-[5'-methyl-4'-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbon-
yl)-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl]-1,3,4,5-tetrahydro-benzo-
[d][1,3]diazepin-2-one
##STR00438##
[1733] 688 mg (2.50 mmol)
7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one
and 378 mg (1.25 mmol)
6-(2-chloro-5-methyl-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one
(mixture) were combined and heated to 300.degree. C. for approx. 10
min. Then the mixture was dissolved in DMF and purified by
preparative HPLC-MS. The fractions containing the product were
combined and the organic solvent was evaporated down. The residue
was neutralised with 1N aqueous sodium hydroxide solution, the
precipitate formed was suction filtered, washed with water and
dried.
[1734] Yield: 115 mg (17% of theoretical)
[1735] ESI-MS: m/z=542 (M+H).sup.+
[1736] R.sub.t (HPLC): 1.15 min (method B)
Example 84
1-[4'-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-6'-methylami-
no-3.4.5.6-tetrahydro-2H-[1,2']bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b-
]pyridin-2-one
##STR00439##
[1738] 1.00 mL TFA were added to 59 mg (0.096 mmol) tert-butyl
[4'-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-4-(2-oxo-2,3--
dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2']bipyridiny-
l-6'-yl]-methyl-carbamate in 5.00 mL DCM and the mixture was
stirred for 3 h at RT. Then the reaction mixture was evaporated
down, the residue was dissolved in DMF and purified by preparative
HPLC-MS. The fractions containing the product were combined and
freeze-dried.
[1739] Yield: 3 mg (6% of theoretical)
[1740] ESI-MS: m/z=514 (M+H).sup.+
[1741] R.sub.t (HPLC): 1.28 min (method B)
Example 85
1-[2'-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-3,4,5,6-tetrahyd-
ro-2H-[1,4']bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]pyridin-2-one
##STR00440##
[1743] 32 mg (0.11 mmol)
1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 30 mg
(0.10 mmol)
6-(4-chloro-pyridin-2-carbonyl)-4-methyl-3H-benzoxazol-2-one and 45
mg (0.33 mmol) potassium carbonate were combined in 1 mL NMP and
stirred overnight at 130.degree. C. The reaction mixture was
filtered, the filtrate was diluted with 1 mL DMF and purified by
preparative HPLC-MS. The fractions containing the product were
combined and freeze-dried.
[1744] Yield: 10 mg (21% of theoretical)
[1745] ESI-MS: m/z=471 (M+H).sup.+
[1746] R.sub.f: 0.49 (silica gel,
DCM/Cyc/MeOH/NH.sub.4OH=70/15/15/2)
[1747] The following Examples describe the preparation of
pharmaceutical formulations that contain as active substance any
desired compound of general formula I:
Example I
Capsules for Powder Inhalation Containing 1 mg of Active
Ingredient
Composition:
[1748] 1 capsule for powder inhalation contains:
TABLE-US-00007 active ingredient 1.0 mg lactose 20.0 mg hard
gelatine capsules 50.0 mg 71.0 mg
Method of Preparation:
[1749] The active ingredient is ground to the particle size
required for inhaled substances. The ground active ingredient is
homogeneously mixed with the lactose. The mixture is transferred
into hard gelatine capsules.
Example II
Inhalable Solution for Respimat.RTM. Containing 1 mg of Active
Ingredient
Composition:
[1750] 1 puff contains:
TABLE-US-00008 active ingredient 1.0 mg benzalkonium chloride 0.002
mg disodium edetate 0.0075 mg purified water ad 15.0 .mu.l
Method of Preparation:
[1751] The active ingredient and benzalkonium chloride are
dissolved in water and transferred into Respimat.RTM.
cartridges.
Example III
Inhalable Solution for Nebulisers Containing 1 mg of Active
Ingredient
Composition:
[1752] 1 vial contains:
TABLE-US-00009 active ingredient 0.1 g sodium chloride 0.18 g
benzalkonium chloride 0.002 g purified water ad 20.0 ml
Method of Preparation:
[1753] The active ingredient, sodium chloride and benzalkonium
chloride are dissolved in water.
Example IV
Propellant Gas-Operated Metered Dose Aerosol Containing 1 mg of
Active Ingredient
Composition:
[1754] 1 puff contains:
TABLE-US-00010 active ingredient 1.0 mg lecithin 0.1% propellant
gas ad 50.0 .mu.l
Method of Preparation:
[1755] The micronised active ingredient is homogeneously suspended
in the mixture of lecithin and propellant gas. The suspension is
transferred into a pressurised container with a metering valve.
Example V
Nasal Spray Containing 1 mg of Active Ingredient
Composition:
TABLE-US-00011 [1756] active ingredient 1.0 mg sodium chloride 0.9
mg benzalkonium chloride 0.025 mg disodium edetate 0.05 mg purified
water ad 0.1 ml
Method of Preparation:
[1757] The active ingredient and the excipients are dissolved in
water and transferred into a suitable container.
Example VI
Injectable Solution Containing 5 mg of Active Substance Per 5
ml
Composition:
TABLE-US-00012 [1758] active substance 5 mg glucose 250 mg human
serum albumin 10 mg glycofurol 250 mg water for injections ad 5
ml
Preparation:
[1759] Glycofurol and glucose are dissolved in water for injections
(Wfl); human serum albumin is added; active ingredient is dissolved
with heating; made up to specified volume with Wfl; transferred
into ampoules under nitrogen gas.
Example VII
Injectable Solution Containing 100 mg of Active Substance Per 20
ml
Composition:
TABLE-US-00013 [1760] active substance 100 mg monopotassium
dihydrogen phosphate = KH.sub.2PO.sub.4 12 mg disodium hydrogen
phosphate = Na.sub.2HPO.sub.4*2H.sub.2O 2 mg sodium chloride 180 mg
human serum albumin 50 mg Polysorbate 80 20 mg water for injections
ad 10 ml
Preparation:
[1761] Polysorbate 80, sodium chloride, monopotassium dihydrogen
phosphate and disodium hydrogen phosphate are dissolved in water
for injections (Wfl); human serum albumin is added; active
ingredient is dissolved with heating; made up to specified volume
with Wfl; transferred into ampoules.
Example VIII
Lyophilisate Containing 10 mg of Active Substance
Composition:
TABLE-US-00014 [1762] Active substance 10 mg Mannitol 300 mg human
serum albumin 20 mg water for injections ad 2 ml
Preparation:
[1763] Mannitol is dissolved in water for injections (Wfl); human
serum albumin is added; active ingredient is dissolved with
heating; made up to specified volume with Wfl; transferred into
vials; freeze-dried.
Solvent for Lyophilisate:
TABLE-US-00015 [1764] Polysorbate 80 = Tween 80 20 mg mannitol 200
mg water for injections ad 10 ml
Preparation:
[1765] Polysorbate 80 and mannitol are dissolved in water for
injections (Wfl); transferred into ampoules.
Example IX
Tablets Containing 20 mg of Active Substance
Composition:
TABLE-US-00016 [1766] active substance 20 mg lactose 120 mg corn
starch 40 mg magnesium stearate 2 mg Povidone K 25 18 mg
Preparation:
[1767] Active substance, lactose and corn starch are homogeneously
mixed; granulated with an aqueous solution of Povidone; mixed with
magnesium stearate; compressed in a tablet press; weight of tablet
200 mg.
Example X
Capsules Containing 20 mg Active Substance
Composition:
TABLE-US-00017 [1768] active substance 20 mg corn starch 80 mg
highly dispersed silica 5 mg magnesium stearate 2.5 mg
Preparation:
[1769] Active substance, corn starch and silica are homogeneously
mixed; mixed with magnesium stearate; the mixture is packed into
size for 3 hard gelatine capsules in a capsule filling machine.
Example XI
Suppositories Containing 50 mg of Active Substance
Composition:
TABLE-US-00018 [1770] active substance 50 mg hard fat (Adeps
solidus) q.s. Ad 1700 mg
Preparation:
[1771] Hard fat is melted at about 38.degree. C.; ground active
substance is homogeneously dispersed in the molten hard fat; after
cooling to about 35.degree. C. it is poured into chilled
moulds.
Example XII
Injectable Solution Containing 10 mg of Active Substance Per 1
ml
Composition:
TABLE-US-00019 [1772] active substance 10 mg mannitol 50 mg human
serum albumin 10 mg water for injections ad 1 ml
Preparation:
[1773] Mannitol is dissolved in water for injections (Wfl); human
serum albumin is added; active ingredient is dissolved with
heating; made up to specified volume with Wfl; transferred into
ampoules under nitrogen gas.
* * * * *