U.S. patent application number 13/441085 was filed with the patent office on 2012-08-02 for new compounds.
This patent application is currently assigned to Boehringer Ingelheim International GmbH. Invention is credited to Kirsten ARNDT, Henri DOODS, Klaus KLINDER, Raimund KUELZER, Dimitrijs LUBRIKS, Juergen MACK, Benjamin PELCMAN, Roland PFAU, Henning PRIEPKE, Robert ROENN, Dirk STENKAMP, Edgars SUNA.
Application Number | 20120196897 13/441085 |
Document ID | / |
Family ID | 42111729 |
Filed Date | 2012-08-02 |
United States Patent
Application |
20120196897 |
Kind Code |
A1 |
PFAU; Roland ; et
al. |
August 2, 2012 |
NEW COMPOUNDS
Abstract
The present invention relates to compounds of general formula I
##STR00001## in which A, L, M, Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1,
R.sup.5, R.sup.a, R.sup.b, R.sup.c, W, X, Y, Z.sup.1, Z.sup.2,
Z.sup.3 are defined in the description, the salts thereof,
particularly the physiologically acceptable salts thereof. The
compounds are of potential utility in the treatment and/or
prevention of inflammatory diseases and associated conditions, in
particular, in the treatment and/or prevention of pain. The
invention also relates to the use of such compounds as medicaments,
to pharmaceutical compositions containing them, and to their
preparation.
Inventors: |
PFAU; Roland; (Biberach an
der Riss, DE) ; ARNDT; Kirsten; (Ravensburg, DE)
; DOODS; Henri; (Warthausen, DE) ; KLINDER;
Klaus; (Oggelshausen, DE) ; KUELZER; Raimund;
(Mittelbiberach, DE) ; LUBRIKS; Dimitrijs; (Riga,
LV) ; MACK; Juergen; (Biberach an der Riss, DE)
; PELCMAN; Benjamin; (Uppsala, SE) ; PRIEPKE;
Henning; (Warthausen, DE) ; ROENN; Robert;
(Uppsala, SE) ; STENKAMP; Dirk; (Biberach an der
Riss, DE) ; SUNA; Edgars; (Riga, LV) |
Assignee: |
Boehringer Ingelheim International
GmbH
Ingelheim am Rhein
DE
|
Family ID: |
42111729 |
Appl. No.: |
13/441085 |
Filed: |
April 6, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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12717407 |
Mar 4, 2010 |
|
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13441085 |
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Current U.S.
Class: |
514/322 ;
514/338; 514/395; 546/199; 546/273.4; 548/304.7; 548/306.1;
548/307.4 |
Current CPC
Class: |
C07D 403/12 20130101;
A61P 11/00 20180101; C07D 235/30 20130101; A61P 29/00 20180101;
C07D 405/12 20130101; A61P 25/04 20180101; C07D 409/12 20130101;
C07D 401/12 20130101 |
Class at
Publication: |
514/322 ;
548/307.4; 514/395; 548/306.1; 548/304.7; 546/199; 546/273.4;
514/338 |
International
Class: |
A61K 31/454 20060101
A61K031/454; A61K 31/4184 20060101 A61K031/4184; C07D 403/10
20060101 C07D403/10; C07D 409/12 20060101 C07D409/12; A61K 31/4439
20060101 A61K031/4439; C07D 405/10 20060101 C07D405/10; C07D 405/12
20060101 C07D405/12; C07D 403/12 20060101 C07D403/12; A61P 29/00
20060101 A61P029/00; C07D 235/30 20060101 C07D235/30; C07D 401/12
20060101 C07D401/12 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 5, 2009 |
EP |
09154414.8 |
Dec 17, 2009 |
EP |
09179618.5 |
Claims
1. A compound of formula I: ##STR00123## one of X and Y represents
--N(R.sup.6)--; and the other represents --N.dbd.; one of Z.sup.1,
Z.sup.2 and Z.sup.3 independently represents --C(R.sup.7).dbd. or
--N.dbd.; and the other two of Z.sup.1, Z.sup.2 and Z.sup.3
represent --C(R.sup.7).dbd.; Q.sup.2, Q.sup.3 and Q.sup.4
respectively represent --C(R.sup.2).dbd., --C(R.sup.3).dbd. and
--C(R.sup.4).dbd.; or any one or two of Q.sup.2, Q.sup.3 or Q.sup.4
may alternatively and independently represent --N.dbd.; R.sup.1
represents halo, OH, --CN; C.sub.1-3 alkyl, C.sub.2-6 alkynyl,
OC.sub.1-3 alkyl, which latter three groups are optionally
substituted by one or more substituents selected from fluoro, --CN,
.dbd.O, OH, --OCH.sub.3, --OCF.sub.3; R.sup.2, R.sup.3 and R.sup.4
independently represent hydrogen, halo, --CN; C.sub.1-3 alkyl,
OC.sub.1-3 alkyl, which latter two groups are optionally
substituted by one or more substituents selected from fluoro, --CN,
.dbd.O, OH, --OCH.sub.3, --OCF.sub.3; R.sup.a, R.sup.b
independently represent hydrogen, C.sub.1-3 alkyl, or both together
with the carbon atom which they are bound to, form a C.sub.3-7
cycloalkylene ring, or a 4-6 membered heterocycloalkylene ring;
R.sup.c represents hydrogen or C.sub.1-3 alkyl; W represents
--C(O)--, --S(O)--, --S(O).sub.2--, --C(O)O--, or --C(O)NR.sup.d--,
which groups are bound to the nitrogen of the --NR.sup.c-- moiety
via carbon or sulfur atom; R.sup.d represents hydrogen or C.sub.1-3
alkyl; M represents C.sub.1-7, alkyl, C.sub.3-7 cycloalkyl, both of
which groups are optionally substituted by one or more groups
selected from fluoro, --OH, --CN, --NH.sub.2, --NH(C.sub.1-3
alkyl), N(C.sub.1-3 alkyl).sub.2, --OC.sub.1-3 alkyl, --SC.sub.1-3
alkyl, aryl, heteroaryl [which latter two groups can be substituted
by one or more substituents selected from halo, OH, --CN, C.sub.1-3
alkyl, OC.sub.1-3 alkyl (which latter two alkyl groups are
optionally substituted by one or more fluoro atoms)], C.sub.1-7
alkyl, C.sub.2-7 alkynyl, C.sub.3-7 cycloalkyl-C.sub.0-2 alkyl, 4-7
membered heterocycloalkyl-C.sub.0-2 alkyl (which latter alkyl,
alkynyl, heterocycloalkyl or cycloalkyl groups are optionally
substituted by one or more substituents selected from fluoro, --CN,
.dbd.O, --NH.sub.2, --NH(C.sub.1-3 alkyl), --N(C.sub.1-3
alkyl).sub.2, --OH, --OC.sub.1-3 alkyl); or aryl, heteroaryl, 4-7
membered heterocycloalkyl, all of which groups are optionally
substituted by one or more substituents selected from halo, --OH,
--CN, --NH.sub.2, --NH(C.sub.1-3 alkyl), --N(C.sub.1-3
alkyl).sub.2, --OC.sub.1-3 alkyl, --SC.sub.1-3 alkyl, aryl,
heteroaryl [which latter two groups can be substituted by one or
more substituents selected from halo, OH, --CN, C.sub.1-3 alkyl,
--OC.sub.1-3 alkyl (which latter two alkyl groups are optionally
substituted by one or more fluoro atoms)], C.sub.1-7 alkyl,
C.sub.2-7 alkynyl, C.sub.3-7 cycloalkyl, 4-7 membered
heterocycloalkyl (which latter alkyl, alkynyl, heterocycloalkyl or
cycloalkyl groups are optionally substituted by one or more
substituents selected from fluoro, --CN, .dbd.O, --NH.sub.2,
--NH(C.sub.1-3 alkyl), N(C.sub.1-3 alkyl).sub.2, --OH,
--OC.sub.1-3alkyl)]; R.sup.5 represents hydrogen; or C.sub.1-3
alkyl; R.sup.6 represents hydrogen; C.sub.1-5 alkyl, C.sub.3-6
alkynyl, 4-7 membered heterocycloalkyl-C.sub.0-2 alkyl or
C.sub.3-7cycloalkyl-C.sub.0-2 alkyl (which latter four groups are
optionally substituted by one or more substituents selected from
fluoro, --CN, .dbd.O, C.sub.1-3 alkyl, --OH, --OC.sub.1-3 alkyl,
--NH.sub.2, --NH(C.sub.1-3 alkyl), N(C.sub.1-3 alkyl).sub.2); each
R.sup.7 independently represents hydrogen, halo, --CN, C.sub.1-7
alkyl, C.sub.2-7 alkynyl, C.sub.3-7 cycloalkyl, C.sub.1-5
alkyl-O--, C.sub.3-7 cycloalkyl- C.sub.0-2 alkyl-O--, 4-7 membered
heterocycloalkyl-C.sub.0-2 alkyl-O--, (in which latter six groups
the alkyl, alkynyl, cycloalkyl or heterocycloalkyl fragments are
optionally substituted by one or more substituents selected from
fluoro, --CN, .dbd.O, OH, --OC.sub.1-3 alkyl, --NH.sub.2,
--NH--C.sub.1-3 alkyl, N(C.sub.1-3 alkyl).sub.2 or by one or more
C.sub.1-3 alkyl groups, which can be optionally substituted by one
or more fluoro atoms); or aryl or heteroaryl, which latter two
groups can be substituted by one or more substituents selected from
halo, OH, --CN, C.sub.1-3 alkyl, --OC.sub.1-3 alkyl (in which
latter two groups the alkyl fragments are optionally substituted by
one or more fluoro atoms); L represents --C(O)N(R.sup.8)--,
--N(R.sup.8)C(O)--, --S(O).sub.2N(R.sup.8)--,
--N(R.sup.8)S(O).sub.2--, N(R.sup.8)C(O)N(R.sup.8)--,
--OC(O)N(R.sup.8)-- or --N(R.sup.8)C(O)O--; A represents hydrogen,
C.sub.1-8 alkyl, C.sub.3-8 alkynyl, aryl, heteroaryl,
aryl-C.sub.1-3alkyl-, C.sub.3-8cycloalkyl-C.sub.0-3alkyl-, 4-7
membered heterocycloalkyl-C.sub.0-3alkyl-,
heteroaryl-C.sub.1-3alkyl-, in which groups the alkyl-, alkynyl-,
cycloalkyl- and heterocycloalkyl-fragments are optionally
substituted by one or more substituents selected from R.sup.9a and
the aryl and heteroaryl fragments are optionally substituted by one
or more substituents selected from R.sup.9b; or A-L- together
represent one of the following groups ##STR00124## in which V
represents a bond, --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, wherein in each of the latter
alkylene groups one methylene [--(CH.sub.2)--] unit can optionally
be replaced by an oxygen atom, a --NH-- or --N(C.sub.1-3 alkyl)-
group and each methylene unit can optionally and independently be
substituted by one or two of the following groups: fluoro, --CN,
.dbd.O, --NH.sub.2, --NH(C.sub.1-3 alkyl), N(C.sub.1-3
alkyl).sub.2, --OH, --OC.sub.1-3alkyl); each R.sup.8 independently
represents hydrogen, or C.sub.1-3 alkyl; each R.sup.9a
independently represents fluoro, --OH, --CN, .dbd.O, --NH.sub.2,
--NH(C.sub.1-3 alkyl), --N(C.sub.1-3 alkyl).sub.2,
--OC.sub.1-6alkyl, C.sub.1-6alkyl, (in which latter four groups the
alkyl, fragments are optionally substituted by one or more
substituents selected from fluoro, --CN, .dbd.O, --NH.sub.2,
--NH(C.sub.1-3 alkyl), N(C.sub.1-3 alkyl).sub.2, --OH, --OC.sub.1-3
alkyl) or aryl, heteroaryl [which latter two groups can be
substituted by one or more substituents selected from halo, OH,
--CN, C.sub.1-3 alkyl, OC.sub.1-3 alkyl (which latter two alkyl
groups are optionally substituted by one or more fluoro atoms)];
each R.sup.9b represents independently halo, --OH, --CN,
--NH.sub.2, --NH(C.sub.1-3 alkyl), --N(C.sub.1-3 alkyl).sub.2,
--OC.sub.1-3 alkyl, --SO.sub.1-3 alkyl, aryl, heteroaryl [which
latter two groups can be substituted by one or more substituents
selected from halo, OH, --CN, C.sub.1-3 alkyl, OC.sub.1-3 alkyl
(which latter two alkyl groups are optionally substituted by one or
more fluoro atoms)], C.sub.1-7 alkyl, C.sub.2-7 alkynyl, C.sub.3-7
cycloalkyl, 4-7 membered heterocycloalkyl (which latter alkyl,
alkynyl, heterocycloalkyl or cycloalkyl groups are optionally
substituted by one or more substituents selected from fluoro, --CN,
.dbd.O, --NH.sub.2, --NH(C.sub.1-3 alkyl), N(C.sub.1-3
alkyl).sub.2, --OH, OC.sub.1-3alkyl); or a salt thereof.
2. A compound according to claim 1 having formula Ia: ##STR00125##
in which A, L, M, Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1, R.sup.6,
R.sup.a, R.sup.b, R.sup.c, W, Z.sup.1, Z.sup.2, Z.sup.3 have the
same meaning as defined in claim 1, or a salt thereof.
3. A compound according to claim 1 having formula Ib: ##STR00126##
in which A, L, M, Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1, R.sup.6,
R.sup.7, R.sup.a, R.sup.b, R.sup.c, W have the same meaning as
defined in claim 1, or a salt thereof.
4. A compound according to claim 1 having formula Ic: ##STR00127##
in which A, L, M, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6,
R.sup.a, R.sup.b, R.sup.c, W, Z.sup.1, Z.sup.2, Z.sup.3 have the
same meaning as defined in claim 1, or a salt thereof.
5. A compound according to claim 1 having formula Id: ##STR00128##
in which A, L, M, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6,
R.sup.7, R.sup.a, R.sup.b, R.sup.c, W have the same meaning as
defined in claim 1, or a salt thereof.
6. A compound according to claim 1, wherein W represents --C(O)--,
--S(O).sub.2--, which groups are bound to the nitrogen of the
--NR.sup.c-- moiety via carbon or sulfur atom; or a salt
thereof.
7. A compound according to claim 1, wherein M represents C.sub.1-7
alkyl, C.sub.3-7 cycloalkyl, both of which groups are optionally
substituted by one or more groups selected from: fluoro, --OH,
--CN, --NH.sub.2, --OC.sub.1-3 alkyl, --SC.sub.1-3 alkyl, aryl
[which latter aryl group can be substituted by one or more
substituents selected from halo, OH, --CN, C.sub.1-3 alkyl,
OC.sub.1-3 alkyl (which latter two alkyl groups are optionally
substituted by one or more fluoro atoms)], C.sub.1-7 alkyl,
C.sub.3-7 cycloalkyl-C.sub.0-2-alkyl (which latter alkyl and
cycloalkyl groups are optionally substituted by one or more
substituents selected from fluoro, --CN, .dbd.O, --NH.sub.2,
--NH(C.sub.1-3 alkyl), --N(C.sub.1-3 alkyl).sub.2, --OH,
--OC.sub.1-3 alkyl); or aryl, heteroaryl, 4-7 membered
heterocycloalkyl, all of which groups are optionally substituted by
one or more substituents selected from halo, --CN, --OC.sub.1-3
alkyl, C.sub.1-7 alkyl, C.sub.3-7 cycloalkyl, (which latter alkyl
and cycloalkyl groups are optionally substituted by one or more
substituents selected from fluoro, --CN, --OC.sub.1-3alkyl); or a
salt thereof.
8. A compound according to claim 1, wherein R.sup.6 represents
hydrogen; C.sub.1-5 alkyl, C.sub.3-5cycloalkyl-C.sub.0-1 alkyl,
which latter two groups are optionally substituted by one or more
substituents selected from fluoro, --OCH.sub.3, --NH(C.sub.1-3
alkyl), N(C.sub.1-3 alkyl).sub.2; or a salt thereof.
9. A compound according to claim 1, wherein R.sup.2, R.sup.3 and
R.sup.4 independently represent hydrogen, fluoro, chloro- or
--CH.sub.3 optionally substituted by one or more fluorine atoms; or
a salt thereof.
10. A compound according to claim 1, wherein L represents
--C(O)NH-- or --S(O).sub.2NH--, which groups are bound to the
9-membered fused heteroaromatic scaffold via the carbon or sulfur
atom, respectively; or a salt thereof.
11. A compound according to claim 1, wherein each R.sup.7
represents hydrogen, halo, C.sub.1-5 alkyl-O--,
C.sub.3-5cycloalkyl-C.sub.0-2 alkyl-O--, 4-5-membered
heterocycloalkyl-C.sub.0-2 alkyl-O-- (in which latter three groups
the alkyl, cycloalkyl or heterocycloalkyl fragments are optionally
substituted by one or more substituents selected from fluoro,
--OC.sub.1-3 alkyl or by one or more C.sub.1-3 alkyl groups, which
can be optionally substituted by one or more fluoro atoms); or a
salt thereof.
12. A compound according to claim 1, wherein A represents hydrogen,
O.sub.1-6 alkyl, C.sub.3-6 alkynyl, phenyl, 5-6-membered
heteroaryl, C.sub.3-6cycloalkyl-C.sub.0-2alkyl-, 4-6-membered
heterocycloalkyl-C.sub.0-2alkyl, phenyl-C.sub.1-3alkyl-,
5-6-membered heteroaryl-C.sub.1-3alkyl in which groups the alkyl-,
alkynyl-, cycloalkyl- and heterocycloalkyl-fragments are optionally
substituted by one or two substituents selected from R.sup.9a and
the phenyl, thienyl and pyridyl fragments are optionally
substituted by one or two substituents selected from R.sup.9b; each
R.sup.9a independently represents fluoro, phenyl, C.sub.1-2alkyl,
--OC.sub.1-4alkyl which latter two groups are optionally
substituted by one to three fluoro atoms; each R.sup.9b represents
independently fluoro, chloro, bromo, C.sub.1-2 alkyl, --OC.sub.1-2
alkyl which latter two groups are optionally substituted by one or
more fluoro; or a salt thereof.
13. A compound according to claim 1, wherein M represents C.sub.1-6
alkyl, C.sub.3-6 cycloalkyl, 4-6-membered heterocycloalkyl, all of
which groups are optionally substituted by one or more groups
selected from fluoro, --OH, --CN, --NH.sub.2, phenyl, --CF.sub.3,
O.sub.1-2 alkyl, C.sub.3-5 cycloalkyl-C.sub.0-1 alkyl; or phenyl,
5-6-membered heteroaryl both of which are optionally substituted by
one or more substituents independently selected from fluoro,
chloro, methyl, --CF.sub.3, --OCH.sub.3; or a salt thereof.
14. A compound according to claim 1, having formula Ie:
##STR00129## in which A represents hydrogen, C.sub.1-6 alkyl,
phenylpropargyl, phenyl, C.sub.3-6cycloalkyl-C.sub.0-2alkyl-,
tetrahydrofuranyl-C.sub.0-2alkyl, pyrrolidinyl- C.sub.0-2 alkyl,
piperidin-C.sub.0-2alkyl, pyridyl-C.sub.1-2alkyl-, in which groups
the alkyl-, alkynyl-, cycloalkyl- and heterocycloalkyl fragments
are optionally substituted by one or more substituents selected
from R.sup.9a and the phenyl and pyridyl fragments are optionally
substituted by one or more substituents selected from R.sup.9b;
each R.sup.9a independently represents fluoro, C.sub.1-2alkyl,
--OC.sub.1-4alkyl in which latter two groups the alkyl fragments
are optionally substituted by one or more fluoro atoms; each
R.sup.9b represents independently fluoro, chloro, bromo, L
represents --C(O)NH-- or --S(O).sub.2NH--, which groups are bound
to the 9-membered fused heteroaromatic scaffold via the carbon or
sulfur atom, respectively; W represents --C(O)--, --S(O).sub.2--; M
represents C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl which latter two
groups are optionally substituted by one or more groups selected
from fluoro, --OH, --CN, --NH.sub.2, phenyl, CF.sub.3, C.sub.1-2
alkyl, cyclopropyl-methyl; or represents oxetanyl or
tetrahydrofuranyl, both of which groups are optionally substituted
by a CH.sub.3-group; or phenyl, thienyl both of which are
optionally substituted by one or two substituents independently
selected from fluoro or chloro, R.sup.1 represents fluoro, chloro,
bromo, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3, --OCH.sub.3;
R.sup.4 represents hydrogen or fluoro; R.sup.6 represents hydrogen,
C.sub.1-3 alkyl, C.sub.3-5cycloalkyl-C.sub.0-1 alkyl, which latter
two groups are optionally substituted by one or more substituents
selected from fluoro, --OCH.sub.3, --NH(C.sub.1-3 alkyl),
N(C.sub.1-3 alkyl).sub.2; R.sup.7-Z2 represents hydrogen, halo,
--OC.sub.1-5alkyl, in which latter group the alkyl is optionally
substituted by one or more fluoro atoms; R.sup.7-Z1 and R.sup.7-Z3
independently represent hydrogen or fluoro; or a salt thereof.
15. A compound according to claim 1, selected from the following
Examples 1 to 100: TABLE-US-00016 Example Structure 1 ##STR00130##
2 ##STR00131## 3 ##STR00132## 4 ##STR00133## 5 ##STR00134## 6
##STR00135## 7 ##STR00136## 8 ##STR00137## 9 ##STR00138## 10
##STR00139## 11 ##STR00140## 12 ##STR00141## 13 ##STR00142## 14
##STR00143## 15 ##STR00144## 16 ##STR00145## 17 ##STR00146## 18
##STR00147## 19 ##STR00148## 20 ##STR00149## 21 ##STR00150## 22
##STR00151## 23 ##STR00152## 24 ##STR00153## 25 ##STR00154## 26
##STR00155## 27 ##STR00156## 28 ##STR00157## 29 ##STR00158## 30
##STR00159## 31 ##STR00160## 32 ##STR00161## 33 ##STR00162## 34
##STR00163## 35 ##STR00164## 36 ##STR00165## 37 ##STR00166## 38
##STR00167## 39 ##STR00168## 40 ##STR00169## 41 ##STR00170## 42
##STR00171## 43 ##STR00172## 44 ##STR00173## 45 ##STR00174## 46
##STR00175## 47 ##STR00176## 48 ##STR00177## 49 ##STR00178## 50
##STR00179## 51 ##STR00180## 52 ##STR00181## 53 ##STR00182## 54
##STR00183## 55 ##STR00184## 56 ##STR00185## 57 ##STR00186## 58
##STR00187## 59 ##STR00188## 60 ##STR00189## 61 ##STR00190## 62
##STR00191## 63 ##STR00192## 64 ##STR00193## 65 ##STR00194## 66
##STR00195## 67 ##STR00196## 68 ##STR00197## 69 ##STR00198## 70
##STR00199## 71 ##STR00200## 72 ##STR00201## 73 ##STR00202## 74
##STR00203## 75 ##STR00204## 76 ##STR00205## 77 ##STR00206## 78
##STR00207## 79 ##STR00208## 80 ##STR00209## 81 ##STR00210## 82
##STR00211## 83 ##STR00212## 84 ##STR00213## 85 ##STR00214## 85
##STR00215## 86 ##STR00216## 87 ##STR00217## 88 ##STR00218## 89
##STR00219## 90 ##STR00220## 91 ##STR00221## 92 ##STR00222## 93
##STR00223## 94 ##STR00224## 95 ##STR00225## 96 ##STR00226## 97
##STR00227## 98 ##STR00228## 99 ##STR00229## 100 ##STR00230##
or a pharmaceutically acceptable salt of any of the above Examples
1 to 100.
16. A pharmaceutical composition comprising at least one compound
according to claim 1 and a pharmaceutically acceptable adjuvant,
diluent or carrier.
17. A method for treating or preventing an inflammatory disease or
associated condition in a patient comprising administering to said
patient a therapeutically effective amount of a compound according
to claim 1 or a pharmaceutically acceptable salt thereof.
18. A method according to claim 17, wherein the condition to be
treated or to prevented is pain.
Description
FIELD OF THE INVENTION
[0001] This invention relates to novel compounds, which are
inhibitors of the microsomal prostaglandin E.sub.2 synthase-1
(mPGES-1), pharmaceutical compositions containing them, and their
use as medicaments for the treatment and/or prevention of
inflammatory diseases and associated conditions.
BACKGROUND OF THE INVENTION
[0002] There are many acute and chronic diseases/disorders that are
inflammatory in their nature including but not limited to
rheumatoid diseases e.g. rheumatoid arthritis, osteoarthritis,
diseases of the visceral system e.g. inflammatory bowel syndrome,
autoimmune diseases, e.g. lupus erythematodes, lung diseases like
asthma and COPD. Current treatment with non-steroidal
anti-inflammatory drugs (NSAIDs) and Cyclooxygenase (COX)-2
inhibitors are efficacious, but show a prevalence for
gastrointestinal and cardiovascular side effects. There is a high
need for new treatment options showing equivalent efficacy with an
improved side effect profile.
[0003] NSAIDs and COX-2 inhibitors reduce inflammation and pain
through inhibition of one or both isoformes of COX enzymes. The
cyclooxygenase (COX) enzyme exists in two forms, one that is
constitutively expressed in many cells and tissues (COX-1), and one
that in most cells and tissues is induced by pro-inflammatory
stimuli, such as cytokines, during an inflammatory response
(COX-2). COXs metabolise arachidonic acid to the unstable
intermediate prostaglandin H.sub.2 (PGH.sub.2). PGH.sub.2 is
further metabolized to other prostaglandins including PGE.sub.2,
PGF.sub.2.alpha., PGD.sub.2, prostacyclin and thromboxane A.sub.2.
These arachidonic acid metabolites are known to have pronounced
physiological and pathophysiological activity including
pro-inflammatory effects. PGE.sub.2 in particular is known to be a
strong pro-inflammatory mediator, and is also known to induce
fever, inflammation and pain.
[0004] Consequently, numerous drugs were developed with a view to
inhibiting the formation of PGE.sub.2, including "NSAIDs"
(non-steroidal antiinflammatory drugs) and "coxibs" (selective
COX-2 inhibitors). These drugs act predominantly by inhibition of
COX-1 and/or COX-2, thereby reducing the formation of
PGE.sub.2.
[0005] However, the inhibition of COXs has the disadvantage that it
results in the reduction of the formation of all metabolites
downstream of PGH.sub.2, some of which are known to have beneficial
properties. In view of this, drugs which act by inhibition of COXs
are therefore known/suspected to cause adverse biological
effects.
[0006] For example, the non-selective inhibition of COXs by NSAIDs
may give rise to gastrointestinal side-effects and affect platelet
and renal function. Even the selective inhibition of COX-2 by
coxibs, whilst reducing such gastrointestinal side-effects, is
believed to give rise to cardiovascular problems.
[0007] An alternative treatment of inflammatory diseases that does
not give rise to the above-mentioned side effects would thus be of
real benefit in the clinic. In particular, a drug that preferably
selectively inhibits the transformation of PGH.sub.2 to the
pro-inflammatory mediator PGE.sub.2 might be expected to reduce the
inflammatory response in the absence of a corresponding reduction
of the formation of other, beneficial arachidonic acid metabolites.
Such inhibition would accordingly be expected to alleviate the
undesirable side-effects mentioned above.
[0008] PGH.sub.2 may be transformed to PGE.sub.2 by prostaglandin E
synthases (PGES). Two microsomal prostaglandin E synthases (mPGES-1
and mPGES-2), and one cytosolic prostaglandin E synthase (cPGES)
have been described.
[0009] The leukotrienes (LTs) are formed from arachidonic acid by a
set of enzymes distinct from those in the COX/PGES pathway.
Leukotriene B.sub.4 is known to be a strong proinflammatory
mediator, while the cysteinyl-containing leukotrienes O.sub.4,
D.sub.4 and E.sub.4 (CysLTs) are mainly very potent
bronchoconstrictors and have thus been implicated in the
pathobiology of asthma. The biological activities of the CysLTs are
mediated through two receptors designated CysLT.sub.1 and
CysLT.sub.2. As an alternative to steroids, leukotriene receptor
antagonists (LTRas) have been developed in the treatment of asthma.
These drugs may be given orally, but do not control inflammation
satisfactorily. The presently used LTRas are highly selective for
CysLT.sub.1. It may be hypothesised that better control of asthma,
and possibly also COPD, may be attained if the activity of both of
the CysLT receptors could be reduced. This may be achieved by
developing unselective LTRas, but also by inhibiting the activity
of proteins, e.g. enzymes, involved in the synthesis of the CysLTs.
Among these proteins, 5-lipoxygenase, 5-lipoxygenase-activating
protein (FLAP), and leukotriene O.sub.4 synthase may be mentioned.
A FLAP inhibitor would also decrease the formation of the
proinflammatory LTB.sub.4.
[0010] mPGES-1, FLAP and leukotriene O.sub.4 synthase belong to the
membrane-associated proteins in the eicosanoid and glutathione
metabolism (MAPEG) family. Other members of this family include the
microsomal glutathione S-transferases (MGST1, MGST2 and MGST3). For
a review, c.f. P.-J. Jacobsson et al in Am. J. Respir. Crit. Care
Med. 161, S20 (2000). It is well known that compounds prepared as
antagonists to one of the MAPEGs may also exhibit inhibitory
activity towards other family members, c.f. J. H Hutchinson et al
in J. Med. Chem. 38, 4538 (1995) and D. Claveau et al in J.
Immunol. 170, 4738 (2003). The former is paper also describes that
such compounds may also display notable cross-reactivity with
proteins in the arachidonic acid cascade that do not belong to the
MAPEG family, e.g. 5-lipoxygenase.
[0011] Thus, agents that are capable of inhibiting the action of
mPGES-1, and thus reducing the formation of the specific
arachidonic acid metabolite PGE.sub.2, are likely to be of benefit
in the treatment of inflammation. Further, agents that are capable
of inhibiting the action of the proteins involved in the synthesis
of the leukotrienes are also likely to be of benefit in the
treatment of asthma and COPD.
[0012] In addition to their anti-inflammatory effect, mPGES-1
inhibitors are also known to be of potential use in treating or
preventing a neoplasia, for example as described in international
patent application WO 2007/124589. The rationale behind this may
stem from the fact that the production of PGE2 is believed to
promote the formation, growth and/or metastasis of neoplasias. As
mPGES-1 is often expressed with COX-2 in benign and cancerous
neoplasias, the inhibition of mPGES-1 (rather than COX-2) may cause
the reduction of PGE2 and therefore mPGES-1 inhibitors may be
useful for the treatment of benign or malignant neoplasias.
[0013] The listing or discussion of an apparently prior-published
document in this specification should not necessarily be taken as
an acknowledgement that the document is part of the state of the
art or is common general knowledge.
DETAILED DESCRIPTION OF THE INVENTION
[0014] In a first embodiment, in the general formula I,
##STR00002## [0015] one of X and Y represents --N(R.sup.6)--; and
[0016] the other represents --N.dbd.; [0017] one of Z.sup.1,
Z.sup.2 and Z.sup.3 independently represents --C(R.sup.7).dbd. or
--N.dbd.; and the other two of Z.sup.1, Z.sup.2 and Z.sup.3
represent --C(R.sup.7).dbd.; [0018] Q.sup.2, Q.sup.3 and Q.sup.4
respectively represent --C(R.sup.2).dbd., --C(R.sup.3).dbd. and
--C(R.sup.4).dbd.; or any one or two of Q.sup.2, Q.sup.3 or Q.sup.4
may alternatively and independently represent --N.dbd.; [0019]
R.sup.1 represents halo, OH, --CN; C.sub.1-3 alkyl, C.sub.2-6
alkynyl, OC.sub.1-3 alkyl, which latter three groups are optionally
substituted by one or more substituents selected from fluoro, --CN,
.dbd.O, OH, --OCH.sub.3, --OCF.sub.3; [0020] R.sup.2, R.sup.3 and
R.sup.4 independently represent hydrogen, halo, --CN; C.sub.1-3
alkyl, OC.sub.1-3 alkyl, which latter two groups are optionally
substituted by one or more substituents selected from fluoro, --CN,
.dbd.O, OH, --OCH.sub.3, --OCF.sub.3; [0021] R.sup.a, R.sup.b
independently represent hydrogen, C.sub.1-3 alkyl, or both together
with the carbon atom which they are bound to, form a C.sub.3-7
cycloalkylene ring, or a 4-6 membered heterocycloalkylene ring;
[0022] R.sup.c represents hydrogen or C.sub.1-3 alkyl; [0023] W
represents --C(O)--, --S(O)--, --S(O).sub.2--, --C(O)O--, or
--C(O)NR.sup.d--, which groups are bound to the nitrogen of the
--NR.sup.c-- moiety via carbon or sulfur atom; [0024] R.sup.d
represents hydrogen or C.sub.1-3 alkyl; [0025] M represents
C.sub.1-7 alkyl, C.sub.3-7 cycloalkyl, both of which groups are
optionally substituted by one or more groups selected from: fluoro,
--OH, --CN, --NH.sub.2, --NH(C.sub.1-3 alkyl), N(C.sub.1-3
alkyl).sub.2, --OC.sub.1-3 alkyl, [0026] --SC.sub.1-3 alkyl, aryl,
heteroaryl [which latter two groups can be substituted by one or
more substituents selected from halo, OH, [0027] --CN, C.sub.1-3
alkyl, OC.sub.1-3 alkyl (which latter two alkyl groups are
optionally substituted by one or more fluoro atoms)], [0028]
C.sub.1-7 alkyl, C.sub.2-7 alkynyl, C.sub.3-7 cycloalkyl-C.sub.0-2
alkyl, 4-7 membered heterocycloalkyl-C.sub.0-2 alkyl (which latter
alkyl, alkynyl, heterocycloalkyl or cycloalkyl groups are
optionally substituted by one or more substituents selected from
fluoro, --CN, .dbd.O, --NH.sub.2, [0029] --NH(C.sub.1-3 alkyl),
--N(C.sub.1-3 alkyl).sub.2, --OH, --OC.sub.1-3 alkyl); or [0030]
aryl, heteroaryl, 4-7 membered heterocycloalkyl, all of which
groups are optionally substituted by one or more substituents
selected from: [0031] halo, --OH, --CN, --NH.sub.2, --NH(C.sub.1-3
alkyl), --N(C.sub.1-3 alkyl).sub.2, alkyl, [0032] --SC.sub.1-3
alkyl, aryl, heteroaryl [which latter two groups can be substituted
by one or more substituents selected from halo, OH, [0033] --CN,
C.sub.1-3 alkyl, --OC.sub.1-3 alkyl (which latter two alkyl groups
are optionally substituted by one or more fluoro atoms)], C.sub.1-7
alkyl, C.sub.2-7 alkynyl, C.sub.3-7 cycloalkyl, 4-7 membered
heterocycloalkyl (which latter alkyl, alkynyl, heterocycloalkyl or
cycloalkyl groups are optionally substituted by one or more
substituents selected from fluoro, --CN, .dbd.O, --NH.sub.2,
--NH(C.sub.1-3 alkyl), N(C.sub.1-3 alkyl).sub.2, --OH, [0034]
--OC.sub.1-3alkyl)]; [0035] R.sup.5 represents hydrogen; or
C.sub.1-3 alkyl; [0036] R.sup.6 represents hydrogen; C.sub.1-5
alkyl, C.sub.3-6 alkynyl, 4-7 membered heterocycloalkyl-C.sub.0-2
alkyl or C.sub.3-7cycloalkyl-C.sub.0-2 alkyl (which latter four
groups are optionally substituted by one or more substituents
selected from fluoro, --CN, .dbd.O, C.sub.1-3 alkyl, --OH,
OC.sub.1-3 alkyl, --NH.sub.2, [0037] --NH(C.sub.1-3 alkyl),
N(C.sub.1-3 alkyl).sub.2); [0038] each R.sup.7 independently
represents hydrogen, halo, --CN, C.sub.1-7 alkyl, C.sub.2-7
alkynyl, C.sub.3-7 cycloalkyl, C.sub.1-5 alkyl-O--,
C.sub.3-7cycloalkyl- [0039] C.sub.0-2 alkyl-O--, 4-7 membered
heterocycloalkyl-C.sub.0-2 alkyl-O--, (in which latter six groups
the alkyl, alkynyl, cycloalkyl or heterocycloalkyl fragments are
optionally substituted by one or more substituents selected from
fluoro, --CN, .dbd.O, OH, --OC.sub.1-3 alkyl, --NH.sub.2,
--NH--C.sub.1-3 alkyl, N(C.sub.1-3 alkyl).sub.2 or by one or more
C.sub.1-3 alkyl groups, which can be optionally substituted by one
or more fluoro atoms); [0040] or [0041] aryl or heteroaryl, which
latter two groups can be substituted by one or more substituents
selected from halo, OH, --CN, C.sub.1-3 alkyl, [0042] --OC.sub.1-3
alkyl (in which latter two groups the alkyl fragments are
optionally substituted by one or more fluoro atoms); [0043] L
represents --C(O)N(R.sup.8)--, --N(R.sup.8)C(O)--,
--S(O).sub.2N(R.sup.8)--, --N(R.sup.8)S(O).sub.2--, [0044]
N(R.sup.8)C(O)N(R.sup.8)--, --OC(O)N(R.sup.8)-- or
--N(R.sup.8)C(O)O--; [0045] A represents hydrogen, O.sub.1-8 alkyl,
O.sub.3-8 alkynyl, aryl, heteroaryl, aryl-C.sub.1-3alkyl-,
C.sub.3-8cycloalkyl-C.sub.0-3alkyl-, 4-7 membered
heterocycloalkyl-C.sub.0-3alkyl-, heteroaryl-C.sub.1-3alkyl-, in
which groups the alkyl-, alkynyl-, cycloalkyl- and
heterocycloalkyl-fragments are optionally substituted by one or
more substituents selected from R.sup.9a and the aryl and
heteroaryl fragments are optionally substituted by one or more
substituents selected from R.sup.9b; or [0046] A-L- together
represent one of the following groups
##STR00003##
[0046] in which [0047] V represents a bond, --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, wherein in each of the latter
alkylene groups one methylene [--(CH.sub.2)--] unit can optionally
be replaced by an oxygen atom, a --NH-- or --N(C.sub.1-3 alkyl)-
group and each methylene unit can optionally and independently be
substituted by one or two of the following groups: fluoro, --CN,
.dbd.O, [0048] --NH.sub.2, --NH(C.sub.1-3 alkyl), N(C.sub.1-3
alkyl).sub.2, --OH, --OC.sub.1-3alkyl); [0049] each R.sup.8
independently represents hydrogen, or C.sub.1-3 alkyl; [0050] each
R.sup.9a independently represents fluoro, --OH, [0051] --CN,
.dbd.O, --NH.sub.2, --NH(C.sub.1-3 alkyl), --N(C.sub.1-3
alkyl).sub.2, --OC.sub.1-6alkyl, C.sub.1-6alkyl, (in which latter
four groups the alkyl, fragments are optionally substituted by one
or more substituents selected from fluoro, --CN, .dbd.O,
--NH.sub.2, --NH(C.sub.1-3 alkyl), N(C.sub.1-3 alkyl).sub.2, --OH,
--OC.sub.1-3 alkyl) or aryl, heteroaryl [which latter two groups
can be substituted by one or more substituents selected from halo,
OH, --CN, C.sub.1-3 alkyl, OC.sub.1-3 alkyl (which latter two alkyl
groups are optionally substituted by one or more fluoro atoms)];
[0052] each R.sup.9b represents independently halo, --OH, --CN,
--NH.sub.2, --NH(C.sub.1-3 alkyl), [0053] --N(C.sub.1-3
alkyl).sub.2, --OC.sub.1-3 alkyl, --SO.sub.1-3 alkyl, [0054] aryl,
heteroaryl [which latter two groups can be substituted by one or
more substituents selected from halo, OH, --CN, C.sub.1-3 alkyl,
OC.sub.1-3 alkyl (which latter two alkyl groups are optionally
substituted by one or more fluoro atoms)], C.sub.1-7 alkyl,
C.sub.2-7 alkynyl, C.sub.3-7 cycloalkyl, [0055] 4-7 membered
heterocycloalkyl (which latter alkyl, alkynyl, heterocycloalkyl or
cycloalkyl groups are optionally substituted by one or more
substituents selected from fluoro, --CN, .dbd.O, --NH.sub.2, [0056]
--NH(C.sub.1-3 alkyl), N(C.sub.1-3 alkyl).sub.2, --OH,
OC.sub.1-3alkyl); the salts thereof, particularly the
physiologically acceptable salts thereof with organic or inorganic
acids or bases.
[0057] In a second embodiment, in the general formula I,
##STR00004##
in which [0058] one of X and Y represents --N(R.sup.6)--; and
[0059] the other represents --N.dbd.; [0060] one of Z.sup.1,
Z.sup.2 and Z.sup.3 independently represents --C(R.sup.7).dbd. or
--N.dbd.; and the other two of Z.sup.1, Z.sup.2 and Z.sup.3
represent --C(R.sup.7).dbd.; [0061] Q.sup.2, Q.sup.3 and Q.sup.4
respectively represent --C(R.sup.2).dbd., --C(R.sup.3).dbd. and
--C(R.sup.4).dbd.; [0062] or any one or two of Q.sup.2, Q.sup.3 or
Q.sup.4 may alternatively and independently represent --N.dbd.;
[0063] R.sup.1 represents halo, OH, --CN; [0064] C.sub.1-3 alkyl,
C.sub.2-6 alkynyl, OC.sub.1-3 alkyl, which latter three groups are
optionally substituted by one or more substituents selected from
fluoro, --CN, .dbd.O, OH, --OCH.sub.3, --OCF.sub.3; [0065] R.sup.2,
R.sup.3 and R.sup.4 independently represent hydrogen, halo, --CN;
[0066] C.sub.1-3 alkyl, OC.sub.1-3 alkyl, which latter two groups
are optionally substituted by one or more substituents selected
from fluoro, --CN, .dbd.O, OH, --OCH.sub.3, --OCF.sub.3; [0067]
R.sup.a, R.sup.b independently represent hydrogen, C.sub.1-3 alkyl,
[0068] or both together with the carbon atom which they are bound
to, form a C.sub.3-7 cycloalkylene ring, or a 4-6 membered
heterocycloalkylene ring; [0069] R.sup.c independently represents
hydrogen or C.sub.1-3 alkyl; [0070] W represents --C(O)--,
--S(O)--, --S(O).sub.2--, --C(O)O--, or [0071] --C(O)NR.sup.c--,
which groups are bound to the nitrogen of the --NR.sup.c-- moiety
via carbon or sulfur atom; [0072] M represents C.sub.1-7 alkyl,
C.sub.3-7 cycloalkyl, both of which groups are either unsubstituted
or substituted by one or more fluoro atoms; [0073] or [0074]
C.sub.1-7 alkyl, C.sub.3-7 cycloalkyl both of which groups are
substituted by one or more groups selected from [0075] --OH, --CN,
--NH.sub.2, --NH(C.sub.1-3 alkyl), N(C.sub.1-3 alkyl).sub.2,
--OC.sub.1-3 alkyl, --SC.sub.1-3 alkyl, aryl, heteroaryl [which
latter two groups can be substituted by one or more substituents
selected from halo, OH, [0076] --CN, C.sub.1-3 alkyl, OC.sub.1-3
alkyl (which latter two alkyl groups are optionally substituted by
one or more fluoro atoms)], [0077] C.sub.1-7 alkyl, C.sub.2-7
alkynyl, C.sub.3-7 cycloalkyl, heterocycloalkyl (which latter
alkyl, alkynyl, heterocycloalkyl or cycloalkyl groups are
optionally substituted by one or more substituents selected from
fluoro, --CN, .dbd.O, --NH.sub.2, --NH(C.sub.1-3 alkyl),
--N(C.sub.1-3 alkyl).sub.2, --OH, --OC.sub.1-3 alkyl); [0078] or
[0079] aryl, heteroaryl, heterocycloalkyl, all of which groups are
optionally substituted by one or more substituents selected from
halo, --OH, [0080] --CN, --NH.sub.2, --NH(C.sub.1-3 alkyl),
--N(C.sub.1-3 alkyl).sub.2, [0081] --OC.sub.1-3 alkyl, --SO.sub.1-3
alkyl, [0082] aryl, heteroaryl (which latter two groups can be
substituted by one or more substituents selected from halo, OH,
--CN, C.sub.1-3 alkyl, OC.sub.1-3 alkyl (which latter two alkyl
groups are optionally substituted by one or more fluoro atoms)],
[0083] C.sub.1-7 alkyl, C.sub.2-7 alkynyl, C.sub.3-7 cycloalkyl,
heterocycloalkyl (which latter alkyl, alkynyl, heterocycloalkyl or
cycloalkyl groups are optionally substituted by one or more
substituents selected from fluoro, --CN, .dbd.O, --NH.sub.2,
--NH(C.sub.1-3 alkyl), N(C.sub.1-3 alkyl).sub.2, --OH,
--OC.sub.1-3alkyl); [0084] R.sup.5 represents hydrogen; or
C.sub.1-3 alkyl; [0085] R.sup.6 represents hydrogen; C.sub.1-3
alkyl, C.sub.3-6 alkynyl, heterocycloalkyl, or cycloalkyl (which
latter four groups are optionally substituted by one or more
substituents selected from fluoro, --CN, .dbd.O, C.sub.1-3 alkyl,
[0086] --OC.sub.1-3 alkyl); [0087] each R.sup.7 independently
represents hydrogen, halo, --CN, C.sub.1-7 alkyl, C.sub.2-7
alkynyl, C.sub.3-7 cycloalkyl, --OC.sub.1-3 alkyl,
--OC.sub.3-7cycloalkyl, --OC.sub.3-7heterocycloalkyl, in which
groups the alkyl fragments are optionally substituted by one or
more substituents selected from fluoro, --CN, .dbd.O, OH,
--OC.sub.1-3 alkyl, --NH.sub.2, --NH--C.sub.1-3 alkyl,
--N(C.sub.1-3 alkyl).sub.2); or [0088] aryl or heteroaryl, which
latter two groups can be substituted by one or more substituents
selected from halo, OH, --CN, C.sub.1-3 alkyl, [0089] --OC.sub.1-3
alkyl (in which latter two groups the alkyl fragments are
optionally substituted by one or more fluoro atoms); [0090] L
represents --C(O)N(R.sup.8)--, --N(R.sup.8)C(O)--,
--S(O).sub.2N(R.sup.8)--, --N(R.sup.8)S(O).sub.2--, [0091]
--N(R.sup.8)C(O)N(R.sup.8)--, --OC(O)N(R.sup.8)-- or
--N(R.sup.8)C(O)O--; [0092] A represents C.sub.1-8 alkyl, C.sub.3-8
alkynyl, aryl, heteroaryl, aryl-C.sub.1-3alkylene,
C.sub.3-8cycloalkyl-C.sub.0-3alkylene,
heterocycloalkyl-C.sub.0-3alkyl, heteroaryl-C.sub.1-3alkylene, in
which groups the alkyl-, alkynyl-, cycloalkyl- and
heterocycloalkyl-fragments are optionally substituted by one or
more substituents selected from R.sup.9a and the aryl and
heteroaryl fragments are optionally substituted by R.sup.9b; or
[0093] A-L- together represent one of the following groups
##STR00005##
[0093] in which [0094] V represents a bond, --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--, wherein in each
of the latter alkylene groups one methylene [--(CH.sub.2)--] unit
can optionally be replaced by an oxygen atom, a --NH-- or
--NH(C.sub.1-3 alkyl) group and each methylene unit can optionally
and independently be substituted by one or two of the following
groups: fluoro, --CN, .dbd.O, --NH.sub.2, --NH(C.sub.1-3 alkyl),
N(C.sub.1-3 alkyl).sub.2, --OH, [0095] OC.sub.1-3alkyl); [0096]
each R.sup.8 independently represents hydrogen, or C.sub.1-3 alkyl;
[0097] each R.sup.9a independently represents fluoro, --CN, .dbd.O,
--NH.sub.2, --OH, C.sub.1-3alkyl, --OC.sub.1-3alkyl, --NH(C.sub.1-3
alkyl), --N(C.sub.1-3 alkyl).sub.2 in which latter three groups the
alkyl fragments are optionally substituted by one or more
substituents selected from fluoro, --CN, .dbd.O, --NH.sub.2, [0098]
--NH(C.sub.1-3 alkyl), N(C.sub.1-3 alkyl).sub.2, --OH, --OC.sub.1-3
alkyl; [0099] each R.sup.9b represents independently halo, --OH,
--CN, --NH.sub.2, --NH(C.sub.1-3 alkyl), [0100] --N(C.sub.1-3
alkyl).sub.2, --OC.sub.1-3 alkyl, --SC.sub.1-3 alkyl, [0101] aryl,
heteroaryl [which latter two groups can be substituted by one or
more substituents selected from halo, OH, --CN, C.sub.1-3 alkyl,
OC.sub.1-3 alkyl (which latter two alkyl groups are optionally
substituted by one or more fluoro atoms)], C.sub.1-7 alkyl,
C.sub.2-7 alkynyl, C.sub.3-7 cycloalkyl, heterocycloalkyl (which
latter alkyl, alkynyl, heterocycloalkyl or cycloalkyl groups are
optionally substituted by one or more substituents selected from
fluoro, --ON, .dbd.O, --NH.sub.2, --NH(C.sub.1-3 alkyl),
N(C.sub.1-3 alkyl).sub.2, --OH, OC.sub.1-3alkyl); the salts
thereof, particularly the physiologically acceptable salts thereof
with organic or inorganic acids or bases.
[0102] A further embodiment of the present invention comprises
compounds of the general formula I, namely compounds of formula
Ia
##STR00006##
in which A, L, M, Q.sub.2, Q.sup.3, Q.sup.4, R.sup.1, R.sup.6,
R.sup.a, R.sup.b, R.sup.c, W, Z.sup.1, Z.sup.2, Z.sup.3 have the
same meaning as defined in any of the preceding embodiments, the
salts thereof, particularly the physiologically acceptable salts
thereof with organic or inorganic acids or bases.
[0103] A further embodiment of the present invention comprises
compounds of the formula I, namely compounds of formula Ib
##STR00007##
in which A, L, M, Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1, R.sup.6,
R.sup.7, R.sup.a, R.sup.b, R.sup.c, W have the same meaning as
defined in any of the preceding embodiments, the salts thereof,
particularly the physiologically acceptable salts thereof with
organic or inorganic acids or bases.
[0104] A further embodiment of the present invention comprises
compounds of the formula I, namely compounds of formula Ic
##STR00008##
in which A, L, M, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6,
R.sup.a, R.sup.b, Fr, W, Z.sup.1, Z.sup.2, Z.sup.3 have the same
meaning as defined in any of the preceding embodiments, the salts
thereof, particularly the physiologically acceptable salts thereof
with organic or inorganic acids or bases.
[0105] A further embodiment of the present invention comprises
compounds of the formula I, namely compounds of formula Id
##STR00009##
in which A, L, M, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6,
R.sup.7, R.sup.a, R.sup.b, R.sup.c, W have the same meaning as
defined in any of the preceding embodiments, the salts thereof,
particularly the physiologically acceptable salts thereof with
organic or inorganic acids or bases.
[0106] In a further embodiment, in the general formula I, A, L, M,
Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.a, R.sup.b, R.sup.c, X, Y,
Z.sup.1, Z.sup.2, Z.sup.3 have the same meaning as defined in any
of the preceding embodiments and [0107] W represents --C(O)--,
--S(O).sub.2--, which groups are bound to the nitrogen of the
--NR.sup.c-- moiety via the carbon or sulfur atom; the salts
thereof, particularly the physiologically acceptable salts thereof
with organic or inorganic acids or bases.
[0108] In a further embodiment, in the general formula I, A, L,
Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.a, R.sup.b, R.sup.c, W, X, Y,
Z.sup.1, Z.sup.2, Z.sup.3 have the same meaning as defined in any
of the preceding embodiments and [0109] M represents C.sub.1-7
alkyl, C.sub.3-7 cycloalkyl, both of which groups are optionally
substituted by one or more groups selected from fluoro, --OH, --CN,
--NH.sub.2, --OC.sub.1-3 alkyl, --SC.sub.1-3 alkyl, aryl [which
latter aryl group can be substituted by one or more substituents
selected from halo, OH, --CN, C.sub.1-3 alkyl, OC.sub.1-3 alkyl
(which latter two alkyl groups are optionally substituted by one or
more fluoro atoms)], [0110] C.sub.1-7, alkyl, C.sub.3-7
cycloalkyl-C.sub.0-2-alkyl (which latter alkyl and cycloalkyl
groups are optionally substituted by one or more substituents
selected from fluoro, --CN, .dbd.O, --NH.sub.2, --NH.sub.2,
--NH(C.sub.1-3 alkyl), --N(C.sub.1-3 alkyl).sub.2, [0111] --OH,
--OC.sub.1-3 alkyl); [0112] or [0113] aryl, heteroaryl, 4-7
membered heterocycloalkyl, all of which groups are optionally
substituted by one or more substituents selected from halo, --CN,
[0114] --OC.sub.1-3 alkyl, C.sub.1-7 alkyl, C.sub.3-7 cycloalkyl,
(which latter alkyl and cycloalkyl groups are optionally
substituted by one or more substituents selected from fluoro, --CN,
--OC.sub.1-3alkyl); the salts thereof, particularly the
physiologically acceptable salts thereof with organic or inorganic
acids or bases.
[0115] In a further embodiment, in the general formula I, A, L, M,
Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.7, R.sup.a, R.sup.b, R.sup.c, W, X, Y, Z.sup.1,
Z.sup.2, Z.sup.3 have the same meaning as defined in any of the
preceding embodiments and [0116] R.sup.6 represents hydrogen,
C.sub.1-5 alkyl, C.sub.3-5cycloalkyl-C.sub.0-1 alkyl, which latter
two groups are optionally substituted by one or more substituents
selected from fluoro, --OCH.sub.3, --NH(C.sub.1-3 alkyl),
N(C.sub.1-3 alkyl).sub.2; the salts thereof, particularly the
physiologically acceptable salts thereof with organic or inorganic
acids or bases.
[0117] In a further embodiment, in the general formula I, A, L, M,
Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1, R.sup.5, R.sup.6, R.sup.7,
R.sup.9a, R.sup.9b, R.sup.a, R.sup.b, R.sup.c, W, X, Y, Z.sup.1,
Z.sup.2, Z.sup.3 have the same meaning as defined in any of the
preceding embodiments and [0118] R.sup.2, R.sup.3 and R.sup.4
independently represent hydrogen, fluoro, chloro- or --CH.sub.3
optionally substituted by one or more fluorine atoms; the salts
thereof, particularly the physiologically acceptable salts thereof
with organic or inorganic acids or bases.
[0119] In a further embodiment, in the general formula I, A, L, M,
Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.a, R.sup.b, R.sup.c, W, X, Y,
Z.sup.1, Z.sup.2, Z.sup.3 have the same meaning as defined in any
of the preceding embodiments and [0120] each R.sup.9a independently
represents fluoro, --CN, C.sub.1-6alkyl, --OC.sub.1-6alkyl in which
latter two groups the alkyl fragments are optionally substituted by
one or more fluoro atoms; [0121] each R.sup.9b represents
independently halo, --CN, --OC.sub.1-3 alkyl, C.sub.1-7 alkyl
(which latter two groups are optionally substituted by one or more
fluoro atoms; the salts thereof, particularly the physiologically
acceptable salts thereof with organic or inorganic acids or
bases.
[0122] In a further embodiment, in the general formula I, A, L, M,
Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.a, R.sup.b, R.sup.c, W, X, Y,
Z.sup.1, Z.sup.2, Z.sup.3 have the same meaning as defined in any
of the preceding embodiments and [0123] each R.sup.9a independently
represents fluoro, --CN, C.sub.1-3alkyl, --OC.sub.1-3alkyl in which
latter two groups the alkyl fragments are optionally substituted by
one or more fluoro atoms; [0124] each R.sup.9b represents
independently halo, --CN, --OC.sub.1-3 alkyl, C.sub.1-7 alkyl
(which latter two groups are optionally substituted by one or more
fluoro atoms; the salts thereof, particularly the physiologically
acceptable salts thereof with organic or inorganic acids or
bases.
[0125] In a further embodiment, in the general formula I, A, M,
Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.a, R.sup.b, R.sup.c, W, X, Y,
Z.sup.1, Z.sup.2, Z.sup.3 have the same meaning as defined in any
of the preceding embodiments and [0126] L represents
--C(O)N(R.sup.8)-- or --S(O).sub.2N(R.sup.8)--, which groups are
bound to the 9-membered fused heteroaromatic scaffold via the
carbon or sulfur atom, respectively; or [0127] A-L- together
represent one of the following groups
##STR00010##
[0127] in which [0128] V represents a bond, --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--, which latter
alkylene groups can optionally be substituted by one or two of the
following groups: fluoro, --CN, --OC.sub.1-3alkyl); the salts
thereof, particularly the physiologically acceptable salts thereof
with organic or inorganic acids or bases.
[0129] In a further embodiment, in the general formula I, A, M,
Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.a, R.sup.b, R.sup.c, W, X, Y,
Z.sup.1, Z.sup.2, Z.sup.3 have the same meaning as defined in any
of the preceding embodiments and [0130] L represents --C(O)NH-- or
--S(O).sub.2NH--, which groups are bound to the 9-membered fused
heteroaromatic scaffold via the carbon or sulfur atom,
respectively; the salts thereof, particularly the physiologically
acceptable salts thereof with organic or inorganic acids or
bases.
[0131] In a further embodiment, in the general formula I, L, A, M,
Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.a, R.sup.b, R.sup.c, W, X, Y, Z.sup.1,
Z.sup.2, Z.sup.3 have the same meaning as defined in any of the
preceding embodiments and each R.sup.7 represents hydrogen, halo,
C.sub.1-5 alkyl-O--, C.sub.3-5cycloalkyl-C.sub.0-2 alkyl-O--,
4-5-membered heterocycloalkyl-C.sub.0-2 alkyl-O-- (in which latter
three groups the alkyl, cycloalkyl or heterocycloalkyl fragments
are optionally substituted by one or more substituents selected
from fluoro, --OC.sub.1-3 alkyl or by one or more C.sub.1-3 alkyl
groups, which can be optionally substituted by one or more fluoro
atoms);
the salts thereof, particularly the physiologically acceptable
salts thereof with organic or inorganic acids or bases.
[0132] In a further embodiment, in the general formula I, L, M,
Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.a, R.sup.b, R.sup.c, W, X, Y,
Z.sup.1, Z.sup.2, Z.sup.3 have the same meaning as defined in any
of the preceding embodiments and [0133] A represents hydrogen,
C.sub.1-6 alkyl, C.sub.3-6 alkynyl, phenyl, 5-6-membered
heteroaryl, [0134] C.sub.3-6cycloalkyl-C.sub.0-2alkyl-,
4-6-membered heterocycloalkyl-C.sub.0-2alkyl,
phenyl-C.sub.1-3alkyl-, 5-6-membered heteroaryl-C.sub.1-3alkyl in
which groups the alkyl-, alkynyl-, cycloalkyl- and [0135]
heterocycloalkyl-fragments are optionally substituted by one or two
substituents selected from R.sup.9a and the phenyl, thienyl and
pyridyl fragments are optionally substituted by one or two
substituents selected from R.sup.9b; [0136] each R.sup.9a
independently represents fluoro, phenyl, C.sub.1-2alkyl,
--OC.sub.1-4alkyl which latter two groups are optionally
substituted by one to three fluoro atoms; [0137] each R.sup.9b
represents independently fluoro, chloro, bromo, C.sub.1-2 alkyl,
--OC.sub.1-2 alkyl which latter two groups are optionally
substituted by one or more fluoro; the salts thereof, particularly
the physiologically acceptable salts thereof with organic or
inorganic acids or bases.
[0138] In a further embodiment, in the general formula I, A, L,
Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.a, R.sup.b, R.sup.c, W, X, Y,
Z.sup.1, Z.sup.2, Z.sup.3 have the same meaning as defined in any
of the preceding embodiments and [0139] M represents C.sub.1-6
alkyl, C.sub.3-6 cycloalkyl, 4-6-membered heterocycloalkyl, all of
which groups are optionally substituted by one or more groups
selected from fluoro, --OH, --CN, --NH.sub.2, phenyl, --CF.sub.3,
C.sub.1-2 alkyl, [0140] C.sub.3-5 cycloalkyl-C.sub.0-1 alkyl;
[0141] or phenyl, 5-6-membered heteroaryl both of which are
optionally substituted by one or more substituents independently
selected from fluoro, chloro, methyl, --CF.sub.3, methoxy; the
salts thereof, particularly the physiologically acceptable salts
thereof with organic or inorganic acids or bases.
[0142] In a further embodiment, in the general formula I, A, L, M,
Q.sup.2, Q.sup.3, Q.sup.4, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.a, R.sup.b, R.sup.c, W, X, Y, Z.sup.1,
Z.sup.2, Z.sup.3 have the same meaning as defined in the any of the
preceding embodiments and [0143] R.sup.1 represents fluoro, chloro,
bromo, C.sub.1-2 alkyl, C.sub.1-2 alkoxy, the latter two groups of
which are optionally substituted by one or more fluoro; the salts
thereof, particularly the physiologically acceptable salts thereof
with organic or inorganic acids or bases.
[0144] In a further embodiment, in the general formula I, A, L, M,
Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, W, X, Y, Z.sup.1, Z.sup.2, Z.sup.3 have
the same meaning as defined in any of the preceding embodiments and
[0145] R.sup.a, R.sup.b and R.sup.c represent hydrogen, the salts
thereof, particularly the physiologically acceptable salts thereof
with organic or inorganic acids or bases.
[0146] A further embodiment of the present invention comprises
compounds of the formula I, namely compounds of formula Ie
##STR00011##
in which [0147] A represents hydrogen, O.sub.1-6 alkyl,
phenylpropargyl, phenyl, C.sub.3-6cycloalkyl-C.sub.0-2alkyl-,
tetrahydrofuranyl-C.sub.0-2alkyl, pyrrolidinyl- [0148]
C.sub.0-2alkyl, piperidin-C.sub.0-2alkyl, pyridyl-C.sub.1-2alkyl-,
in which groups the alkyl-, alkynyl-, cycloalkyl- and
heterocycloalkyl-fragments are optionally substituted by one or
more substituents selected from R.sup.9a and the phenyl and pyridyl
fragments are optionally substituted by one or more substituents
selected from R.sup.9b; [0149] each R.sup.9a independently
represents fluoro, C.sub.1-2alkyl, --OC.sub.1-4alkyl in which
latter two groups the alkyl fragments are optionally substituted by
one or more fluoro atoms; [0150] each R.sup.9b represents
independently fluoro, chloro, bromo, [0151] L represents --C(O)NH--
or --S(O).sub.2NH--, which groups are bound to the [0152]
9-membered fused heteroaromatic scaffold via the carbon or sulfur
atom, respectively; [0153] W represents --C(O)--, --S(O).sub.2--;
[0154] M represents C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl which
latter two groups are optionally substituted by one or more groups
selected from fluoro, [0155] --OH, --CN, --NH.sub.2, phenyl,
CF.sub.3, C.sub.1-2 alkyl, cyclopropyl-methyl; [0156] or [0157]
represents oxetanyl or tetrahydrofuranyl, both of which groups are
optionally substituted by a CH.sub.3-group; or phenyl, thienyl both
of which are optionally substituted by one or two substituents
independently selected from fluoro or chloro, [0158] R.sup.1
represents fluoro, chloro, bromo, CH.sub.3, CH.sub.2F, CHF.sub.2,
CF.sub.3, --OCH.sub.3; [0159] R.sup.4 represents hydrogen or
fluoro; [0160] R.sup.6 represents hydrogen; C.sub.1-3 alkyl,
C.sub.3-5cycloalkyl-C.sub.0-1 alkyl, which latter two groups are
optionally substituted by one or more substituents selected form
fluror, --OCH.sub.3, --NH(C.sub.1-3 alkyl), N(C.sub.1-3
alkyl).sub.2; [0161] R.sup.7-Z2 represents hydrogen, halo,
--OC.sub.1-5alkyl, in which latter group the alkyl is optionally
substituted by one or more fluoro atoms; [0162] R.sup.7-Z1 and
R.sup.7-Z3 independently represent hydrogen or fluoro; the salts
thereof, particularly the physiologically acceptable salts thereof
with organic or inorganic acids or bases.
Terms and Definitions Used
[0163] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication commensurate with a reasonable
benefit/risk ratio.
[0164] As used herein, "pharmaceutically acceptable salts" refer to
derivatives of the disclosed compounds wherein the parent compound
is modified by making acid or base salts thereof. Examples of
pharmaceutically acceptable salts include, but are not limited to,
mineral or organic acid salts of basic residues such as amines;
alkali or organic salts of acidic residues such as carboxylic
acids; and the like. The pharmaceutically acceptable salts include
the conventional non-toxic salts or the quaternary ammonium salts
of the parent compound formed, for example, from non-toxic
inorganic or organic acids.
[0165] The pharmaceutically acceptable salts of the present
invention can be synthesized from the parent compound which
contains a basic or acidic moiety by conventional chemical methods.
Generally, such salts can be prepared by reacting the free acid or
base forms of theses compounds with a stoichiometric amount of the
appropriate base or acid in water or in an organic solvent, or in a
mixture of the two; generally, nonaqueous media like ether, ethyl
acetate, ethanol isopropanol, or acetonitrile are preferred. Lists
of suitable salts are found in Remington's Pharmaceutical Sciences,
17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the
disclosure of which is hereby incorporated by reference.
[0166] Examples of pharmaceutically active salts for each of the
compounds which are the subject of this description include,
without being restricted thereto, salts which are prepared from
pharmaceutically acceptable acids or bases, including organic and
inorganic acids and bases. If the preferred compound is basic,
salts may be prepared from pharmaceutically acceptable acids. When
selecting the most preferred salt, or to clarify whether a salt or
the neutral compound is used, properties such as bioavailability,
ease of manufacture, workability and shelf life are taken into
consideration, inter alia.
[0167] Suitable pharmaceutically acceptable acids include acetic
acid, benzenesulphonic acid (besylate), benzoic acid,
p-bromophenylsulphonic acid, camphorsulphonic acid, carbonic acid,
citric acid, ethanesulphonic acid, fumaric acid, gluconic acid,
glutamic acid, hydrobromic acid, hydrochloric acid, hydriodic acid,
isethionic acid, lactic acid, maleic acid, malic acid, mandelic
acid, methanesulphonic acid (mesylate), mucinic acid, nitric acid,
oxalic acid, pamoic acid, pantothenic acid, phosphoric acid,
succinic acid, sulphuric acid, tartaric acid, p-toluenesulphonic
acid and the like. Examples of pharmaceutically acceptable salts
include, without being restricted thereto, acetate, benzoate,
hydroxybutyrate, bisulphate, bisulphite, bromide,
butyne-1,4-dioate, caproate, chloride, chlorobenzoate, citrate,
dihydrogen phosphate, dinitrobenzoate, fumarate, glutaminate,
glycollate, is heptanoate, hexyne-1,6-dioate, hydroxybenzoate,
iodide, lactate, maleate, malonate, mandelate, metaphosphate,
methanesulphonate, methoxybenzoate, methylbenzoate, monohydrogen
phosphate, naphthalene-1-sulphonate, naphthalene-2-sulphonate,
oxalate, phenylbutyrate, phenylproprionate, phosphate, phthalate,
phenylacetate, propanesulphonate, propiolate, propionate,
pyroglutaminate, pyrophosphate, pyrosulphate, sebacate, suberate,
succinate, sulphate, sulphite, sulphonate, tartrate,
trifluoroacetate, xylenesulphonate and the like.
[0168] "Isomers": It will be appreciated that the compounds of the
present invention may contain one or more asymmetrically
substituted carbon atoms and therefore they may be isolated in
racemic or in optically active forms (i.e. in form of their
corresponding enantiomers or diasteromers).
[0169] In certain instances, an enantiomer or a diastereomer of a
compound of Formula I may display superior activity compared with
the other. When required, diastereomers may be separated from
diastereomeric mixture of the compounds using conventional, e.g.
fractional crystallisation or HPLC techniques. The desired
enantiomers may be obtained by methods well known to the skilled
man in the art i.e. by reaction of the appropriate optically active
starting materials under conditions which will not cause
racemisation or epimerisation (i.e. a `chiral pool` method), by
reaction of the appropriate starting material with a `chiral
auxiliary` which can subsequently be removed at a suitable stage,
by derivatisation (i.e. a resolution, including a dynamic
resolution), for example with a homochiral acid followed by
separation of the diastereomeric derivatives by conventional means
such as chromatography (see for example Thomas J. Tucker, et al, J.
Med. Chem. 1994, 37, 2437-2444), or by reaction with an appropriate
chiral reagent or chiral catalyst all under conditions known to the
skilled person (e.g. Mark A. Huffman, et al, J. org. Chem. 1995, 60
1590-1594).
[0170] Compounds of the invention may contain double bonds and may
thus exist as E (entgegen) and Z (zusammen) geometric isomers about
each individual double bond. All such isomers and mixtures thereof
are included within the scope of the invention.
[0171] Compounds of the invention may also exhibit tautomerism. All
tautomeric forms and mixtures thereof are included within the scope
of the invention. For instance, a compound containing the moiety
"1H-benzimidazole" may be considered to be identical to a
corresponding compound containing a "3H-benzimidazole" moiety.
[0172] All chiral, enantiomeric, diastereomeric, racemic forms,
tautomeric and all geometric isomeric forms of a structure are
included within the scope of invention, unless the specific
stereochemistry or isomer form is specifically indicated.
Obviously, the isomer which is pharmacologically most effective and
most free from side effects is preferred.
[0173] The subject-matter of this invention also includes
deuterated compounds of general formula I, i.e. in which one or
more hydrogen atoms, for example one, two, three, four or five
hydrogen atoms, are replaced by the hydrogen isotope deuterium.
[0174] The term "C.sub.1-3-alkyl" (including those which are part
of other groups) means alkyl groups with 1 to 3 carbon atoms, the
term "C.sub.1-4-alkyl" means branched and unbranched alkyl groups
with 1 to 4 carbon atoms, the term "C.sub.1-6-alkyl" means branched
and unbranched alkyl groups with 1 to 6 carbon atoms and the term
"C.sub.1-8-alkyl" means branched and unbranched alkyl groups with 1
to 8 carbon atoms. Examples include: methyl, ethyl, n-propyl,
iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl,
neopentyl, n-hexyl, n-heptyl and n-octyl. The abbreviations Me, Et,
n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. may optionally also be used for
the groups mentioned above. 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. The term "alkyl" also includes alkyl groups wherein 1-3
hydrogen atoms are replaced by fluorine atoms.
[0175] The term "C.sub.1-n-alkylene" wherein n is an integer 1 to
n, either alone or in combination with another radical, denotes an
acyclic, straight or branched chain divalent alkyl radical
containing from 1 to n carbon atoms. For example the term
C.sub.1-4-alkylene includes --(CH.sub.2)--, --(CH(CH.sub.3))--,
--(CH.sub.2--CH.sub.2--CH.sub.2)--, --(C(CH.sub.3).sub.2)--,
--(CH(CH.sub.2CH.sub.3))--, --(CH(CH.sup.3)--CH.sup.2)--,
--(CH.sub.2--CH(CH.sub.3))--,
--(CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2)--,
--(CH.sub.2--CH.sub.2--CH(CH.sub.3))--,
--(CH(CH.sub.3)--CH.sub.2--CH.sub.2)--,
--(CH.sub.2--CH(CH.sub.3)--CH.sub.2)--,
--(CH.sub.2--C(CH.sub.3).sub.2)--,
--(C(CH.sub.3).sub.2--CH.sub.2)--,
--(CH(CH.sub.3)--CH(CH.sub.3))--,
--(CH.sub.2--CH(CH.sub.2CH.sub.3))--,
(CH(CH.sub.2CH.sub.3)--CH.sub.2)--,
--(CH(CH.sub.2CH.sub.2CH.sub.3))--(CHCH(CH.sub.3).sub.2)-- and
--C(CH.sub.3)(CH.sub.2CH.sub.3)--.
[0176] The term "C.sub.3-8-cycloalkyl" (including those which are
part of other groups) means cyclic alkyl groups with 3 to 8 carbon
atoms and the term "C.sub.3-6-cycloalkyl" means cyclic alkyl groups
with 3 to 6 carbon atoms. Examples include: cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl and
also include the following structures
##STR00012##
[0177] 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. These cycloalkyls may additionally be annelated (i.e.
fused) to a benzene ring, so that nine- to twelve-membered bicyclic
heterocycles are formed.
[0178] The term "C.sub.2-6-alkenyl" (including those which are part
of other groups) means branched and unbranched alkenyl groups with
2 to 6 carbon atoms, provided that they have 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-butenyl,
2-butenyl and 3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl
etc.
[0179] The term "C.sub.2-7-alkynyl" (including those which are part
of other groups) means branched and unbranched alkynyl groups with
2 to 7 carbon atoms, provided that they have at least one triple
bond. Alkynyl groups with 2 to 4 carbon atoms are preferred.
Examples of these 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-butynyl,
2-butynyl and 3-butynyl, 1-methyl-1-propynyl, 1-methyl-2-propynyl
etc.
[0180] The term "halo" or "halogen", when used herein, includes
fluoro, chloro, bromo and iodo. Unless stated otherwise, fluorine,
chlorine and bromine are regarded as preferred halogens.
[0181] The term "4-7 membered heterocycloalkyl" means stable 4-,
5-, 6- or 7-membered monocyclic heterocyclic ring systems which may
be both saturated and monounsaturated. One or two of the ring
carbon atoms may independently be replaced by heteroatoms which are
selected from among oxygen, nitrogen and sulphur, the latter two of
which heteroatoms may optionally be oxidised (so forming N-oxide,
sulfoxide or sulfon). The previously mentioned heterocycles may be
linked to the rest of the molecule via a carbon atom or a nitrogen
atom. Examples for the 4-, 5-, 6- or 7-membered heterocyclic ring
systems include:
##STR00013##
[0182] These heterocycloalkyls may additionally be annelated (i.e.
fused) to a benzene ring, so that eight- or eleven-membered
bicyclic heterocycles are formed.
[0183] The term "aryl" (including those which are part of other
groups) means aromatic ring systems with 6 or 14 carbon atoms (e.g.
C.sub.6-10 aryl). Such groups may be monocyclic, bicyclic or
tricyclic and have between 6 and 14 ring carbon atoms.
[0184] Examples include phenyl, 1-naphthyl or 2-naphthyl. The
preferred aryl group is phenyl. Unless otherwise mentioned, the
aromatic groups may be substituted by one or more groups selected
from among methyl, ethyl, n-propyl, iso-propyl, tert-butyl,
hydroxy, methoxy, trifluoromethoxy, fluorine, chlorine, bromine and
iodine, while the groups may be identical or different.
[0185] The term "heteroaryl" means five- or six-membered
heterocyclic aromatic groups which may contain one, two, three or
four heteroatoms, selected from among oxygen, sulphur and nitrogen,
and which additionally contain a sufficient number of conjugated
double bonds to form an aromatic system. These heteroaryls may
additionally be annelated (i.e. fused) to a benzene ring, so that
nine- or ten-membered bicyclic heteroaryls are formed.
[0186] Examples for the five- or six-membered heterocyclic aromatic
groups include:
##STR00014##
[0187] Examples for the nine- or ten-membered heterocyclic aromatic
groups include:
##STR00015##
[0188] Unless otherwise stated, the heteroaryls mentioned
previously may be substituted by one or more groups selected from
among methyl, ethyl, n-propyl, iso-propyl, tert-butyl, hydroxy,
methoxy, trifluoromethoxy, fluorine, chlorine, bromine and iodine,
while the groups may be identical or different. In addition, a
nitrogen atom present in the heteroaryl group may be oxidised, thus
forming an N-oxide.
[0189] For the avoidance of doubt, in cases in which the identity
of two or more substituents in a compound of formula I may be the
same, the actual identities of the respective substituents are not
in any way interdependent. For example, in the situation in which
Z.sup.1 and Z.sup.2 both represent .dbd.C(R.sup.7)--, then the
respective .dbd.C(R.sup.7)-- groups in question may be the same or
different. Similarly, when groups are substituted by more than one
substituent as defined herein, the identities of those individual
substituents are not to be regarded as being interdependent. For
example, when the A group represents C.sub.1-8 alkyl substituted by
two R.sup.9a groups, in which, in both cases, R.sup.9a represents
--N(C.sub.1-3 alkyl).sub.2, then the identities of the two
--N(C.sub.1-3 alkyl).sub.2 groups are not to be regarded as being
interdependent, i.e. the two --N(C.sub.1-3 alkyl).sub.2 moieties
may be the same or different. Similarly, also the C.sub.1-3 alkyl
groups within one particular --N(C.sub.1-3 alkyl).sub.2 group are
independent of one another, i.e. they may be the same or different
from each other.
[0190] For the avoidance of doubt, when preferred features are
mentioned herein, then such features may be taken independently of
other preferred features or conjunctively with other preferred
features.
[0191] The skilled person will appreciate that compounds of formula
I that are the subject of this invention include those that are
stable. That is, compounds of the invention include those that are
sufficiently robust to survive isolation from e.g. a reaction
mixture to a useful degree of purity.
Methods of Preparation
[0192] Compounds of the present invention can be prepared in
accordance with techniques that are well known to those skilled in
the art, for example as described hereinafter and in the
experimental section. According to a further aspect of the
invention there is provided a process for the preparation of a
compound of formula I, which process can be performed for example
according to the following schemes A-E.
##STR00016##
[0193] The protecting group PG which is introduced in step a) is a
standard nitrogen protecting group, well known to those skilled in
the art, for example a nitrogen protecting group as described in
"Protective Groups in Organic Synthesis", 3.sup.rd edition, T.W.
Greene & P.G.M. Wutz, Wiley-Interscience (1999), for example a
tert-butoxycarbonyl-, benzyloxycarbonyl-, ethoxycarbonyl-,
methoxycarbonyl-, allyloxycarbonyl- or trifluormethylcarbonyl
group.
[0194] Step a) can be performed according to literature procedures
as described in "Protective Groups in Organic Synthesis", 3.sup.rd
edition, T.W. Greene & P.G.M. Wutz, Wiley-Interscience (1999)
for example with reagents like
2-(tert-Butoxycarbonyloxyimino)-2-phenylacetonitrile (BOC-ON),
Di-tert-butyl dicarbonate (BOC.sub.2O), Di-methyl dicarbonate,
Di-ethyl dicarbonate, Ethyl chloroformate, Methyl chloroformate,
Allyl chloroformate, Benzyl chloroformate or Trifluoroacetic acid
chloride under conditions which are known from the literature
preferably in presence of a base for example sodium hydroxide,
triethylamine, diisopropyl ethyl amine, 4-dimethylamino-pyridine.
Appropriate solvent for this step is for example is
dichloromethane, tetrahydrofuran (THF), acetonitrile,
dimethylformamide (DMF), dimethylacetamide, N methylpyrrolidone or
mixtures of the above mentioned solvents.
[0195] Step b) can be performed with H.sub.2/Raney-Nickel,
H.sub.2/Palladium on carbon, Fe-powder/aqueous NH.sub.4Cl.sub.1,
Fe/HCl, Zn/HCl, Na.sub.2S.sub.2O.sub.4, SnCl.sub.2/HCl, Zn/HCl or
NaBH.sub.4/CuCl or according to procedures described in the
literature for example R. Larock, Comprehensive Organic
Transformations, VCH Verlagsgemeinschaft, Weinheim (1989).
Appropriate solvent for this step is for example dichloromethane,
tetrahydrofuran (THF), acetonitrile, dimethylformamide (DMF),
dimethylacetamide, N methylpyrrolidone, ethanol, methanol,
isopropanol or mixtures of the above mentioned solvents.
[0196] Step c) can be performed according to standard literature
procedures for example with reagents such as
1,1'-thiocarbonyldi-2-pyridone or
1,1.varies.-thiocarbonyldiimidazole or with thiophosgene in a
solvent as for example dichloromethane or dimethylformamide and
optionally under addition of a base like 4-dimethylamino-pyridine
or triethylamine.
[0197] Step d) can be performed under standard conditions known to
those skilled in the art in presence of a suitable solvent such as
diethyl ether, dimethylformamide, dichloromethane, acetononitrile
and/or tetrahydrofuran. The coupling reaction is preferably
performed in the presence of a base such as NaOH, KOH, NaHCO.sub.3,
triethylamine, N-ethyldiisopropylamine, 4-dimethylamino-pyridine or
other appropriate bases.
[0198] Step e) is preferably performed in the presence of a
suitable `coupling` reagent. As `coupling` reagent for instance a
carbodiimide based compound such as dicyclohexylcarbodiimide (DCC),
1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (or salt, e.g.
hydrochloride, thereof) or N,N-diisopropylcarbodiimide (DIC) can be
used. The reaction may proceed at any suitable temperature (e.g.
one between about 0.degree. C. to about 200.degree. C.), and may
also be performed in the presence of an additive (such as
2,2,2-trifluoro-N,O-bis-(trimethylsilyl)-acetamide). Appropriate
co-solvent for this step is for example dichloromethane,
tetrahydrofuran (THF), acetonitrile, dimethylformamide (DMF),
dimethylacetamide, N methylpyrrolidone or mixtures of the above
mentioned solvents.
[0199] Step d and e can be performed in a step-wise reaction under
isolation of the intermediate XV or without isolation of XV.
[0200] Step f) Protecting groups may be removed in accordance with
techniques that are well known to those skilled in the art and as
described hereinafter. For example, protected
compounds/intermediates described herein may be converted
chemically to unprotected compounds using HCl or H.sub.2SO.sub.4
solutions, trifluoro acetic acid, KOH; Ba(OH).sub.2, Pd on carbon,
trimethylsilyl iodide or other conditions as described in
"Protective Groups in Organic Synthesis", 3.sup.rd edition, T.W.
Greene & P.G.M. Wutz, Wiley-Interscience (1999). Appropriate
co-solvent for this step is for example dichloromethane,
tetrahydrofuran (THF), acetonitrile, dimethylformamide (DMF),
dimethylacetamide, N methylpyrrolidone or mixtures of the above
mentioned solvents.
[0201] Step g): The coupling of the amine XVII with the acid XXa
can be performed with an additional in-situ activating agent like
1-propylphosphonic acid cyclic anhydride,
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate or hexafluorophosphate,
N,N'-dicyclohexylcarbodiimide,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, carbonyldiimidazole,
oxalyl chloride or other activating agents of the state of the
art.
[0202] The coupling reaction is preferably performed in the
presence of a base such as NaOH, KOH, NaHCO.sub.3, triethylamine,
N-ethyldiisopropylamine, N,N,-dimethylaminopyridine or other
appropriate bases of the state of the art and for example described
in described in Houben-Weyl, "Methods in Organic Synthesis", Vol.
E22a, p 425ff.
[0203] Alternatively, the coupling of the amine XVII can be
performed with an activated acid derivative XXb, where the leaving
group LG can be for example, a fluorine, chlorine, bromine, azide
or an isopropyloxy-C(O)--O anion. The coupling reaction is
preferably performed in the presence of a base such as NaOH, KOH,
NaHCO.sub.3, triethylamine, N-ethyldiisopropylamine,
4-dimethylamino-pyridine or other appropriate bases under
conditions which are for example described in Houben-Weyl, "Methods
in Organic Synthesis", Vol. E22a, p 425ff.
[0204] If step g) is carried out in presence of trimethylaluminium
or triethylaluminium the leaving group in XXb can also be a methoxy
or ethoxy group.
[0205] The above mentioned coupling reactions are performed in an
appropriate solvent for example like dichloromethane,
tetrahydrofuran (THF), acetonitrile, dimethylformamide (DMF),
dimethylacetamide, N methylpyrrolidone or in mixtures of the above
mentioned solvents.
##STR00017##
[0206] Step h) The reductive amination is performed according to
known procedures for example with sodium triacetoxyborohydride,
sodium borohydride or sodium cyanoborhydride in an appropriate
solvent like tetrahydrofuran or dichlormethane under addition of
acetic acid or trifluoro acetic acid if appropriate, or with
Palladium on charcoal under a hydrogen atmosphere in
tetrahydrofuran or ethanol or methanol or isopropanol or
dimethylformamide, preferably in the presence of acetic acid or
trifluoro acetic acid.
[0207] Step i) can be performed according to standard literature
procedures for example to with reagents such as thiophosgene in an
appropriate solvent as for example dichloromethane or
dimethylformamide optionally under addition of a base like
4-dimethylamino-pyridine or triethylamine.
[0208] Step j) can be performed under standard conditions known to
those skilled in the is art in presence of a suitable solvent such
as diethyl ether, dimethylformamide, dichloromethane,
acetononitrile and/or tetrahydrofuran). The coupling reaction is
preferably performed in the presence of a base such as NaOH, KOH,
NaHCO.sub.3, triethylamine, N-ethyldiisopropylamine,
4-dimethylamino-pyridine or other appropriate bases.
[0209] Step k) is preferably performed in the presence of a
suitable coupling reagent as for example a carbodiimide based
compound such as dicyclohexylcarbodiimide (DCC),
1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (or salt, e.g.
hydrochloride, thereof) or N,N-diisopropylcarbodiimide (DIC). The
reaction may proceed at any suitable temperature (e.g. one between
about 0.degree. C. to about 200.degree. C.), and may also be
performed in the presence of an additive (such as
2,2,2-trifluoro-N,O-bis-(trimethylsilyl)-acetamide). Appropriate
co-solvent for this step is for example dichloromethane,
tetrahydrofuran, acetonitrile, dimethylformamide,
dimethylacetamide, N methylpyrrolidone or mixtures of the above
mentioned solvents.
[0210] Step j and k can be performed in a step-wise reaction under
isolation of the intermediate XXI or without isolation of XXI.
[0211] Step I) Protecting groups may be removed in accordance with
techniques that are well known to those skilled in the art and as
described hereinafter. For example, protected
compounds/intermediates described herein may be converted
chemically to unprotected compounds using HCl or H.sub.2SO.sub.4
solutions, trifluoro acetic acid, KOH; Ba(OH).sub.2, Pd on carbon,
trimethylsilyl iodide or other conditions as described in
"Protective Groups in Organic Synthesis", 3.sup.rd edition, T.W.
Greene & P.G.M. Wutz, Wiley-Interscience (1999). T Appropriate
co-solvent for this step is for example dichloromethane,
tetrahydrofuran, acetonitrile, dimethylformamide,
dimethylacetamide, N methylpyrrolidone, methanol, ethanol or
mixtures of the above mentioned solvents.
[0212] Step m): The coupling of the amine XXIII with the acid XXa
can be performed with an additional in-situ activating agent like
1-propylphosphonic acid cyclic anhydride,
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate or hexafluorophosphate,
N,N'-dicyclohexylcarbodiimide,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, carbonyldiimidazole,
oxalyl chloride or other activating agents of the state of the
art.
[0213] The coupling reaction is preferably performed in the
presence of a base such as NaOH, KOH, NaHCO.sub.3, triethylamine,
N-ethyldiisopropylamine, N,N,-dimethylaminopyridine or other
appropriate bases of the state of the art and for example described
in described in Houben-Weyl, "Methods in Organic Synthesis", Vol.
E22a, p 425ff.
[0214] Alternatively, the coupling of the amine XXIII can be
performed with an activated acid derivative XXb, where the leaving
group LG can be for example, a fluorine, chlorine, bromine, azide
or an isopropyloxy-C(O)--O anion. The coupling reaction is
preferably performed in the presence of a base such as NaOH, KOH,
NaHCO.sub.3, triethylamine, N-ethyldiisopropylamine,
4-dimethylamino-pyridine or other appropriate bases under
conditions which are for example described in Houben-Weyl, "Methods
in Organic Synthesis", Vol. E22a, p 425ff.
[0215] If step g) is carried out in presence of trimethylaluminium
or triethylaluminium the leaving group in XXb can also be a methoxy
or ethoxy group.
[0216] The above mentioned coupling reactions are performed in an
appropriate solvent for example like dichloromethane,
tetrahydrofuran, acetonitrile, dimethylformamide (DMF),
dimethylacetamide, N methylpyrrolidone or in mixtures of the above
mentioned solvents.
##STR00018##
[0217] Step n) can be performed according to standard literature
procedures for example with reagents such as
1,1'-thiocarbonyldi-2-pyridone or 1,1'-thiocarbonyldiimidazole or
with thiophosgene in a solvent as for example dichloromethane or
dimethylformamide and optionally under addition of a base like
4-dimethylamino-pyridine or triethylamine.
[0218] Step o) can be performed under standard conditions known to
those skilled in the art in presence of a suitable solvent such as
diethyl ether, dimethylformamide, dichloromethane, acetononitrile
and/or tetrahydrofuran. The coupling reaction is preferably
performed in the presence of a base such as NaOH, KOH, NaHCO.sub.3,
triethylamine, N-ethyldiisopropylamine, 4-dimethylamino-pyridine or
other appropriate bases.
[0219] Step p) is preferably performed in the presence of a
suitable `coupling` reagent. As `coupling` reagent for instance a
carbodiimide based compound such as dicyclohexylcarbodiimide (DCC),
1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (or salt, e.g.
hydrochloride, thereof) or N,N-diisopropylcarbodiimide (DIC) can be
used. The reaction may proceed at any suitable temperature (e.g.
one between about 0.degree. C. to about 200.degree. C.), and may
also be performed in the presence of an additive (such as
2,2,2-trifluoro-N,O-bis-(trimethylsilyl)-acetamide). Appropriate
co-solvent for this step is for example dichloromethane,
tetrahydrofuran (THF), acetonitrile, dimethylformamide (DMF),
dimethylacetamide, N methylpyrrolidone or mixtures of the above
mentioned solvents.
[0220] Step o and p can be performed in a step-wise reaction under
isolation of the intermediate XXV or without isolation of XXV.
[0221] Building blocks XXIX-a or XXIX-b can also be used as
precursors according to Scheme D. (PG1=protecting group).
##STR00019##
##STR00020##
[0222] The protecting group PG.sup.1 is a standard nitrogen
protecting group, well known to those skilled in the art, for
example a nitrogen protecting group as described in "Protective
Groups in Organic Synthesis", 3.sup.rd edition, T.W. Greene &
P.G.M. Wutz, Wiley-Interscience (1999), for example a
tert-butoxycarbonyl-, benzyloxycarbonyl-, ethoxycarbonyl-,
methoxycarbonyl-, allyloxycarbonyl- or trifluormethylcarbonyl
group.
[0223] Step q) can be performed under standard conditions known to
those skilled in the art in presence of a suitable solvent such as
diethyl ether, dimethylformamide, dichloromethane, acetononitrile
and/or tetrahydrofuran. The coupling reaction is preferably
performed in the presence of a base such as NaOH, KOH, NaHCO.sub.3,
triethylamine, N-ethyldiisopropylamine, 4-dimethylamino-pyridine or
other to appropriate bases.
[0224] Step r) is preferably performed in the presence of a
suitable `coupling` reagent. As `coupling` reagent for instance a
carbodiimide based compound such as dicyclohexylcarbodiimide (DCC),
1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (or salt, e.g.
hydrochloride, thereof) or N,N-diisopropylcarbodiimide (DIC) can be
used. The reaction may proceed at any suitable temperature (e.g.
one between about 0.degree. C. to about 200.degree. C.), and may
also be performed in the presence of an additive (such as
2,2,2-trifluoro-N,O-bis-(trimethylsilyl)-acetamide). Appropriate
co-solvent for this step is for example dichloromethane,
tetrahydrofuran (THF), acetonitrile, dimethylformamide (DMF),
dimethylacetamide, N methylpyrrolidone or mixtures of the above
mentioned solvents.
[0225] Step q and r can be performed in a step-wise reaction under
isolation of the intermediate XXVII or without isolation of
XXVII.
[0226] Step s): The protecting group PG1 may be removed in
accordance with techniques that are well known to those skilled in
the art and as described hereinafter. For example, protected
compounds/intermediates described herein may be converted
chemically to unprotected compounds using HCl or H.sub.2SO.sub.4
solutions, trifluoro acetic acid, KOH; Ba(OH).sub.2, Pd on carbon,
trimethylsilyl iodide or other conditions as described in
"Protective Groups in Organic Synthesis", 3.sup.rd edition, T.W.
Greene & P.G.M. Wutz, Wiley-Interscience (1999). Appropriate
co-solvent for this step is for example dichloromethane,
tetrahydrofuran (THF), acetonitrile, dimethylformamide (DMF),
dimethylacetamide, N methylpyrrolidone, methanol, ethanol or
mixtures of the above mentioned solvents.
[0227] Step t): The coupling of the amine XXVIII with the acid
A-COOH can be performed with an additional in-situ activating agent
like 1-propylphosphonic acid cyclic anhydride,
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate or hexafluorophosphate,
N,N'-dicyclohexylcarbodiimide,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, carbonyldiimidazole,
oxalyl chloride or other activating agents of the state of the
art.
[0228] The coupling reaction is preferably performed in the
presence of a base such as NaOH, KOH, NaHCO.sub.3, triethylamine,
N-ethyldiisopropylamine, N,N,-dimethylaminopyridine or other
appropriate bases of the state of the art and for is example
described in described in Houben-Weyl, "Methods in Organic
Synthesis", Vol. E22a, p 425ff.
[0229] Alternatively, the coupling of the amine XXVIII can be
performed with an activated acid derivative A-C(O)-LG, where the
leaving group LG can be for example, a fluorine, chlorine, bromine,
azide or an isopropyloxy-C(O)--O anion or with A-SO.sub.2--Cl. The
coupling reaction is preferably performed in the presence of a base
such as NaOH, KOH, NaHCO.sub.3, triethylamine,
N-ethyldiisopropylamine, N,N,-dimethylaminopyridine or other
appropriate bases under conditions which are for example described
in Houben-Weyl, "Methods in Organic Synthesis", Vol. E22a, p
425ff.
[0230] The above mentioned coupling reactions are performed in an
appropriate solvent for example like dichloromethan,
tetrahydrofurane (THF), acetonitrile, dimethylformamide (DMF),
dimethylacetamide, N methylpyrrolidone or in mixtures of the above
mentioned solvents.
[0231] Building blocks XXX-a or XXX-b can also be used as
precursors according to Scheme E.
##STR00021##
##STR00022##
[0232] Step u) can be performed under standard conditions known to
those skilled in the art in presence of a suitable solvent such as
diethyl ether, dimethylformamide, dichloromethane, acetononitrile
and/or tetrahydrofuran. The coupling reaction is preferably
performed in the presence of a base such as NaOH, KOH, NaHCO.sub.3,
triethylamine, N-ethyldiisopropylamine, 4-dimethylamino-pyridine or
other appropriate bases.
[0233] Step v) is preferably performed in the presence of a
suitable `coupling` reagent. As `coupling` reagent for instance a
carbodiimide based compound such as dicyclohexylcarbodiimide (DCC),
1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (or salt, e.g.
hydrochloride, thereof) or N,N-diisopropylcarbodiimide (DIC) can be
used. The reaction may proceed at any suitable temperature (e.g.
one between about 0.degree. C. to about 200.degree. C.), and may
also be performed in the presence of an additive (such as
2,2,2-trifluoro-N,O-bis-(trimethylsilyl)-acetamide). Appropriate
co-solvent for this step is is for example dichloromethane,
tetrahydrofuran (THF), acetonitrile, dimethylformamide (DMF),
dimethylacetamide, N methylpyrrolidone or mixtures of the above
mentioned solvents.
[0234] Step u and v can be performed in a step-wise reaction under
isolation of the intermediate XXXI or without isolation of
XXXI.
[0235] Step w) can be performed under known saponification methods
for example with aquous NaOH or KOH in ethanol, methanol or
dioxane.
[0236] Step x) The coupling of the amine XXXIV with the acid XXXIII
can be performed with an additional in-situ activating agent like
1-propylphosphonic acid cyclic anhydride,
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate or hexafluorophosphate,
N,N'-dicyclohexylcarbodiimide,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, carbonyldiimidazole,
oxalyl chloride or other activating agents of the state of the
art.
[0237] The coupling reaction is preferably performed in the
presence of a base such as NaOH, KOH, NaHCO.sub.3, triethylamine,
N-ethyldiisopropylamine, N,N,-dimethylaminopyridine or other
appropriate bases of the state of the art and for example described
in described in Houben-Weyl, "Methods in Organic Synthesis", Vol.
E22a, p 425ff.
[0238] The above mentioned coupling reaction is performed in an
appropriate solvent for example dichloromethane, tetrahydrofuran
(THF), acetonitrile, dimethylformamide (DMF), dimethylacetamide, N
methylpyrrolidone or in mixtures of the above mentioned
solvents.
[0239] It will be appreciated by those skilled in the art that, in
the processes described above and hereinafter, the functional
groups of intermediate compounds may need to be protected by
protecting groups.
[0240] The protection and deprotection of functional groups may
take place before or after a reaction in the above-mentioned
schemes.
[0241] Protecting groups may be removed in accordance with
techniques that are well known to those skilled in the art and as
described hereinafter. For example, protected
compounds/intermediates described herein may be converted
chemically to unprotected compounds using standard deprotection
techniques.
[0242] The type of chemistry involved will dictate the need, and
type, of protecting groups as well as the sequence for
accomplishing the synthesis.
[0243] The use of protecting groups is fully described in
"Protective Groups in Organic Chemistry", edited by J W F McOmie,
Plenum Press (1973), and "Protective Groups in Organic Synthesis",
3.sup.rd edition, T.W. Greene & P.G.M. Wutz, Wiley-Interscience
(1999).
[0244] The conditions for all individual steps in the above
mentioned schemes e.g. protection/deprotection steps, reductive
aminations, amide formations and others are well known to the
expert and are described in the standard literature such as the
Houben-Weyl: Methoden der organischen Chemie, Georg-Thieme-Verlag,
Stuttgart and are exemplified in more detail in the experimental
section. Compounds of formula I (including I-1 through I-4) may be
isolated from their reaction mixtures using conventional
techniques.
Biological Assay
[0245] The basis of the assay used is to measure the inhibition of
microsomal prostaglandin E.sub.2 synthase-1 (mPGES-1) dependent
prostaglandin (PG) E.sub.2 formation from PGH.sub.2 by different
compounds. Thus, the formation of PGE.sub.2 is used as signal and a
lowering of this signal can be interpreted as inhibition of
mPGES-1. Similar assays to measure inhibition of mPGES-1 have
previously been described in the literature [1, 2].
List of Reagents Used:
[0246] Glutathione (Sigma, G-4251) [0247] Freeze culture in Rosetta
E coli expression strain. [0248] LB growth media with Ampillicillin
(Amp) final concentration in culture 50 .mu.g/ml [0249]
Chloroamphenicol stock 34 mg/ml (chloro) final concentration in
culture 34 .mu.g/ml [0250] Sterile growth flasks for 500 ml-1 liter
cultures [0251] 0.1 M KP, buffer pH 7.4 [0252] 9.25% HCl [0253]
PGH.sub.2 (0.25 mM) [0254] Fe (II) Cl.sub.2 tetrahydrate, 99%
(Sigma, 220229) [0255] 384-well plate with compounds [0256] 96-well
plate, polypropylene (Thermo fast 96 skirted VWR) [0257] 384-well
plate polypropylene PCR plate (Greiner 785201) [0258] Greiner
384-well plate pp (In vitro cat. no. 781280) [0259] Adhesive
sealing film for 96-well plates (Sigma-Aldrich) [0260] Aluminium
foil (PCR foil, 310-0030-127-471 from Labora) [0261] PBS (GIBCO
14040) [0262] Prostaglandin E.sub.2 Assay (Cisbio,cat.no. 62P2APEC)
[0263] Biomek FX robot (Beckman Coulter) [0264] Biomek NX robot
(Beckman Coulter) [0265] Multidrop; micro or combi
(ThermoLabsystems) [0266] Plate reader: Safire2 (Tecan)
[0267] Microsomes from Rosetta E. coli bacteria expressing
recombinant human mPGES-1 can be derived as described below:
[0268] Inoculate 5 ml LB with Amp and Chloro with bacteria from
freeze culture. Incubate over night at 37.degree. C. with 200 rpm.
Thereafter, inoculate 500-800 ml LB containing Amp and Chloro with
the 5 ml on culture and grow to OD640 of 0.6-0.8. Chill the culture
to +4.degree. C. before induction. Induce the culture with IPTG at
a final concentration of 400 .mu.M. Express the protein at room
temp 18-23.degree. C. with 200 rpm shaking over night.
[0269] The following steps can be performed on the following day:
[0270] 1. Spin down the cells in 250 ml centrifuge flasks for 15
min at 7000 rpm [0271] 2. Dissolve the pellet from 250 ml culture
in 12.5 ml homogenization buffer [0272] 3. Disintegrate the cells
by sonication, 4.times.10 seconds at 35% amplitude [0273] 4. Add
2.5 ml MgC12 (100 mM) and DNase 12.5 .mu.l (0.8 mg/ml) and incubate
on ice for 30 min [0274] 5. Spin down the bacteria debris and save
the supernatant, 7000 rpm for 15 min [0275] 6. Isolate the protein
containing membranes in the supernatant by ultracentrifugation
45000.times.g for 1 hour. [0276] 7. Discard the supernatant and
dissolve the pellet in 20 mM KPi buffer and aliquot the enzyme and
store aliquots at -80.degree. C.
[0277] Before each experiment is performed an aliquot of the enzyme
is thawed and it can then be dissolved in 0.1 M KP, pH 7.4 buffer
containing 2.5 mM GSH. 50 it of this enzyme solution is
subsequently dispensed in a 384-well plate at room temperature. 0.5
it of the inhibitor dissolved in DMSO is thereafter added to each
well and incubated for 25 minutes at room temperature.
Subsequently, 2 .mu.l of PGH.sub.2 dissolved in an appropriate
solvent is added to each well and after one minute at room
temperature, the acidified stop solution containing FeCl.sub.2 is
added. 4 .mu.l of the total volume is transferred to a separate
plate and diluted 750-fold in two separate steps before
quantification of PGE.sub.2.
[0278] In order to quantitate the amount of PGE.sub.2 that has been
formed, a homogenous time resolved fluorescent (HTRF) detection of
PGE.sub.2 can be performed by the use of a commercially available
kit from CisBio essentially according to the manufacturer's
protocol. Briefly, 10 .mu.l of the diluted sample is transferred to
a white 384-well plate and the following steps can be performed in
a sequential manner at room temperature or as indicated. [0279] 5
.mu.L reconstitution buffer as supplied by the manufacturer is
added to the negative control (NC) wells. [0280] The plate is
covered with adhesive sealing film. [0281] The plate can now be
centrifuged at 1200 rpm for 1 minute. [0282] The NC samples are
covered with sealing film. [0283] 250 .mu.l d2 labeled PGE.sub.2
(d2-PGE.sub.2) can be diluted in 4750 .mu.L reconstitution buffer
as supplied by the manufacturer [0284] 250 .mu.l Eu3+-cryptate can
be diluted in 4750 .mu.l reconstitution buffer as supplied by the
manufacturer [0285] 5 .mu.l d2-PGE.sub.2 can now be added to rows 1
to 24, by using a multidrop. The sealing film is thereafter removed
from the NC wells. [0286] 5 .mu.l Eu3+-cryptate labeled
anti-PGE.sub.2 can now be added to rows 1 to 24 by using a
Multidrop. [0287] The plate can now be covered with sealing film.
[0288] The plate can now be centrifuge at 1200 rpm for 1 minute and
place at 4.degree. C. overnight.
[0289] After the over night incubation the fluorescence is measured
by the use of an appropriate microplate reader. The fluorescence of
Eu3+-cryptate and d2-PGE.sub.2 are measured using the following
excitation and emission wavelength, europium cryptate:
.lamda..sub.max.sup.ex=307 nm, .lamda..sub.max.sup.em=620 nm and
d2: .lamda..sub.max.sup.ex=620 nm, .lamda..sub.max.sup.em=665 nm),
respectively. The extent of the specific HTRF is measured as a
ratio of the emission intensity at 665 nm vs. that at 620 nm. A
standard curve using synthetic PGE.sub.2 is used to quantify the
amount of PGE.sub.2 in unknown samples. The degree of inhibition
can be calculated as percent inhibition by dividing the amount of
PGE.sub.2 formed in unknown samples by the amount of PGE.sub.2
formed in control samples.
LITERATURE REFERENCES
[0290] 1. Riendeau, D., R. Aspiotis, D. Ethier, Y. Gareau, E.
Grimm, J. Guay, S. Guiral, H. Juteau, J. Mancini, N. Methot, J.
Rubin, and R. Friesen, Inhibitors of the inducible microsomal
prostaglandin E2 synthase (mPGES-1) derived from MK-886. Bioorg Med
Chem Lett, 2005. 15(14): p. 3352-3355. [0291] 2. Cote, B., L.
Boulet, C. Brideau, D. Claveau, D. Ethier, R. Frenette, M. Gagnon,
A. Giroux, J. Guay, S. Guiral, J. Mancini, E. Martins, F. Masse, N.
Methot, D. Riendeau, J. Rubin, D. Xu, H. Yu, Y. Ducharme, and R.
Friesen, Substituted phenanthrene imidazoles as potent, selective,
and orally active mPGES-1 inhibitors. Bioorg Med Chem Lett, 2007.
17(24): p. 6816-6820.
Test Results:
[0292] Table 1 demonstrates the mPGES-1 inhibitory effect (in
%-inhibition) measured for selected compounds at a concentration of
10 (unless otherwise specified) in the HTRF assay as described
above. The examples show that 10 .mu.M of the compound inhibit
PGE.sub.2 production to the indicated degree. These data reflect a
successful mPGES-1 inhibition for the given compound examples.
TABLE-US-00001 TABLE 1 mPGES-1 inhibitory effect (in %-inhibition)
of compounds of the invention at a concentration of 10 .mu.M in the
HTRF assay Example # % inhibition 1 100 3 100 4 83 5 100 6 100 7 98
8 98 9 98 10 100 11 100 12 100 13 100 14 100 15 99 16 80 17 95 18
98 19 98 20 100 21 100 22 98 23 100 24 97 25 99 26 100 27 100 28
100 29 99 30 98 31 99 32 98 33 93 34 100 35 100 36 100 37 100 38
100 39 100 40 98 41 100 42 100 43 100 44 100 45 100 46 100 47 100
48 100 49 100 50 100 51 94 52 96 53 100 54 98 55 68
[0293] Table 2 demonstrates the mPGES-1 inhibitory effect
(IC.sub.50) measured for selected examples in the HTRF assay as
described above. These data reflect a successful mPGES-1 inhibition
for the given compound examples.
TABLE-US-00002 TABLE 2 mPGES-1 inhibitory effect (IC.sub.50 values
in nM) of compounds of the invention in the HTRF assay IC50 IC50
IC50 IC50 example [nM] example [nM] example [nM] example [nM] 59 2
69 1 79 4 87 2 60 1 70 3 80 9 88 2 61 1 71 2 81 2 89 2 62 1 72 3 82
3 90 1 63 2 73 3 83 3 91 4 64 2 74 4 84 4 92 7 65 300 75 3 85 2 93
2 66 3 76 3 86 1 94 3 67 2 77 4 57 1 95 1 68 3 78 3 58 3 96 1 97 5
98 6 99 >100 100 5
Method of Treatment
[0294] The present invention relates to compounds of formula I
which are useful in the prevention and/or treatment of a disease
and/or condition in which the inhibition of prostaglandin E
synthases, in particular that of the microsomal prostaglandin
E.sub.2 synthase-1 (mPGES-1) is of therapeutic benefit, including
but not limited to the treatment and/or prevention of inflammatory
diseases and/or associated conditions.
[0295] The term "inflammation" will be understood to include any
inflammatory disease, disorder or condition per se, any condition
that has an inflammatory component associated with it, and/or any
condition characterised by inflammation as a symptom, including
inter alia acute, chronic, ulcerative, specific, allergic and
necrotic inflammation, and other forms of inflammation known to
those skilled in the art. The term thus also includes, for the
purposes of this invention, inflammatory pain, pain generally
and/or fever.
[0296] Where a condition has an inflammatory component associated
with it, or a condition characterised by inflammation as a symptom,
the skilled person will appreciate that compounds of the invention
may be useful in the treatment of the inflammatory symptoms and/or
the inflammation associated with the condition. Compounds of the
invention may also have effects that are not linked to inflammatory
mechanisms, such as in the reduction of bone loss in a subject.
Such conditions include osteoporosis, osteoarthritis, Paget's
disease and/or periodontal diseases.
[0297] A further aspect of the present invention relates to a
compound of formula I as a medicament.
[0298] Another aspect of the present invention is the use of
compounds of formula I for the treatment and/or prevention of a
disease and/or condition in which the inhibition of the mPGES-1 is
of therapeutic benefit.
[0299] A further aspect of the present invention is the use of a
compound of formula I for the treatment and/or prevention of
inflammatory diseases and/or associated conditions.
[0300] The present invention also relates to the use of compounds
of formula I for the treatment and/or prevention of the following
diseases and conditions:
1. Rheumatic diseases or autoimmune diseases or muscoskeletal
diseases: all forms of rheumatic diseases including e.g. soft
tissue rheumatism, rheumatoid arthritis, polymyalgia rheumatica,
reactive arthritis, tenosynovitis, gout or metabolic arthritis,
bursitis, tendonitis, juvenile arthritis, spondyloarthropathies
like e.g. spondylitis, ankylosing spondylitis, psoriatric
arthropathy; sarcoidosis, fibromyalgia, myositis, polymyositis,
osteoarthritis, traumatic arthritis, collagenoses of any origin
e.g. systemic lupus erythematosus, scleroderma, dermatomyositis,
Still's Disease, Sjogren syndrome, Felty syndrome; rheumatic fever
and rheumatic heart disease, diseases of blood vessels like
vasculitis, polyarthritis nodosa, Behcet's syndrome, giant cell
arthritis, Wegener's granulomatosis, Henoch-Schonlein purpura;
psoriatic arthritis, fungal arthritis, in particular including pain
associated with any of the aforementioned conditions; 2. Headaches
such as migraines with and without aura, tension-type headaches,
cluster headaches and headaches with different origins; 3.
Sympathetically maintained pain like complex regional pain syndrome
Type I and II; 4. Neuropathic pain such as low back pain, hip pain,
leg pain, non-herpetic neuralgia, post herpetic neuralgia, diabetic
neuropathy, nerve injury-induced pain, acquired immune deficiency
syndrome (AIDS) related neuropathic pain, head trauma, toxin and
chemotherapy caused nerve injuries, phantom limb pain, multiple
sclerosis, root avulsions, painful traumatic mononeuropathy,
painful polyneuropathy, thalamic pain syndrome, post-stroke pain,
central nervous system injury, post surgical pain, carpal tunnel
syndrome, trigeminal neuralgia, post mastectomy syndrome,
postthoracotomy syndrome, stump pain, repetitive motion pain,
neuropathic pain associated hyperalgesia and allodynia, alcoholism
and other drug-induced pain; 5. Cancer pain induced by or
associated with tumors such as bone tumors, lymphatic leukemia;
Hodgkin's disease, malignant lymphoma; lymphogranulomatoses;
lymphosarcoma; solid malignant tumors; extensive metastases 6.
Visceral disorders such as chronic pelvic pain, pancreatitis,
peptic ulcer, interstitial cystitis, cystitis, renal colic, angina,
dysmenorrhoea, menstruation, gynaecological pain, irritable bowel
disease (IBS), inflammatory bowel disease, Crohn's disease and
ulcerative colitis, nephritis, prostatitis, vulvodynia, non-ulcer
dyspepsia, non-cardiac chest pain, myocardial ischemia; 7.
Inflammation associated diseases of ear, nose, mouth and throat
like influenza and viral/bacterial infections such as the common
cold, allergic rhinitis (seasonal and perennial), pharyngitis,
tonsillitis, gingivitis, larhyngitis, sinusitis, and vasomotor
rhinitis, fever, hay fever, thyroiditis, otitis, dental conditions
like toothache, perioperative and post-operative conditions,
trigeminal neuralgia, uveitis; iritis, allergic keratitis,
conjunctivitis, blepharitis, neuritis nervi optici, choroiditis,
glaucoma and sympathetic opthalmia, as well as pain thereof. 8.
Neurological diseases such as cerebral oedema and angioedema,
cerebral dementia like e.g. Parkinson's and Alzheimers disease,
senile dementia; multiple sclerosis, stroke, myasthenia gravis,
brain and meningeal infections like encephalomyelitis, meningitis,
including HIV as well as schizophrenia, delusional disorders,
autism, affective disorders and tic disorders; 9. Work-related
diseases like pneumoconiosis, including aluminosis, anthracosis,
asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis
and byssinosis; 10. Lung diseases such as asthma including allergic
asthma (atopic or non-atopic) as well as exercise-induced
bronchoconstriction, occupational asthma, viral- or bacterial
exacerbation of asthma, other non-allergic asthmas and
"wheezy-infant syndrome", Chronic obstructive pulmonary disease
(COPD) including emphysema, adult respiratory distress syndrome,
bronchitis, pneumonia, adult respiratory distress syndrome (ARDS),
pigeon fancier's disease, farmers lung; 11. Skin diseases such as
psoriasis and eczema, dermatitis, sunburn, burns as well as aprains
and strains and tissue trauma; 12. Vascular and heart diseases
which are inflammation--related like artheriosclerosis including
cardiac transplant atherosclerosis, panarteritis nodosa,
periarteritis nodosa, arteritis temporalis, Wegner granulomatosis,
giant cell arthritis, reperfusion injury and erythema nodosum,
thrombosis (e.g. deep vein thrombosis, renal, hepathic, portal vein
thrombosis); coronary artery disease, aneurysm, vascular rejection,
myocardial infarction, embolism, stroke, thrombosis including
venous thrombosis, angina including unstable angina, coronary
plaque inflammation, bacterial-induced inflammation including
Chlamydia-induced inflammation, viral induced inflammation, and
inflammation associated with to surgical procedures such as
vascular grafting including coronary artery bypass surgery,
revascularization procedures including angioplasty, stent
placement, endarterectomy, or other invasive procedures involving
arteries, veins and capillaries, artery restenosis; 13.
Diabetes-associated symptoms such as diabetic vasculopathy,
diabetic is neuropathy, diabetic retinopathy, post capillary
resistance or diabetic symptoms associated with insulitis (e.g.
hypergiycemia, diuresis, proteinuria and increased nitrite and
kallikrein urinary excretion); 14. Benign and malignant tumors and
neoplasia including cancer, such as colorectal cancer, brain
cancer, bone cancer, epithelial cell-derived neoplasia (epithelial
carcinoma) such as basal cell carcinoma, adenocarcinoma,
gastrointestinal cancer such as lip cancer, mouth cancer,
esophageal cancer, small bowel cancer, stomach cancer, colon
cancer, liver cancer, bladder cancer, pancreas cancer, ovary
cancer, cervical cancer, lung cancer, breast cancer, skin cancer
such as squamous cell and basal cell cancers, prostate cancer,
renal cell carcinoma, and other known cancers effecting epithelial
cells throughout the body; neoplasias like gastrointestinal cancer,
Barrett's esophagus, liver cancer, bladder cancer, pancreatic
cancer, ovarian cancer, prostate cancer, cervical cancer, lung
cancer, breast cancer and skin cancer; adenomatous polyps,
including familial adenomatous polyposis (FAP) as well preventing
polyps from forming in patients at risk of FAP. 15. Various other
disease states and conditions like epilepsy, septic shock e.g. as
antihypovolemic and/or antihypotensive agents, sepsis,
osteoporosis, benign prostatic hyperplasia and hyperactive bladder,
nephritis, pruritis, vitiligo, disturbances of visceral motility at
respiratory, genitourinary, gastrointestinal or vascular regions,
wounds, allergic skin reactions, mixed-vascular and non-vascular
syndromes, septic shock associated with bacterial infections or
with trauma, central nervous system injury, tissue damage and
postoperative fever, syndromes associated with itching.
[0301] Preferred according to the present invention is the use of a
compound of formula I for the treatment and/or prevention of pain;
in particular pain that is associated with any one of the diseases
or conditions listed above.
[0302] Another aspect of the present invention is a method for the
treatment and/or prevention of above mentioned diseases and
conditions, which method comprises the administration of an
effective amount of a compound of formula Ito a human being.
[0303] Compounds of the invention may also have the advantage that
they may be more efficacious than, be less toxic than, be longer
acting than, be more potent than, produce fewer side effects than,
be more easily absorbed than, and/or have a better pharmacokinetic
profile (e.g. higher oral bioavailability and/or lower clearance)
than, and/or have other useful pharmacological, physical, or
chemical properties over, compounds known in the prior art, whether
for use in the above-stated indications or otherwise.
Dosage
[0304] The term "effective amount" refers to an amount of a
compound, which confers a therapeutic effect on the treated
patient. The effect may be objective (i.e. measurable by some test
or marker) or subjective (i.e. the subject gives an indication of
or feels an effect).
[0305] Compounds of the invention may be administered at varying
doses. Oral, pulmonary and topical dosages may range from between
about 0.01 mg/kg of body weight per day (mg/kg/day) to about 100
mg/kg/day, preferably about 0.01 to about 100 mg/kg/day, and more
preferably about 0.1 to about 25 mg/kg/day. For e.g. oral
administration, the compositions typically contain between about
0.01 mg to about 5000 mg, and preferably between about 1 mg to
about 2000 mg, of the active ingredient. Intravenously, the most
preferred doses will range from about 0.001 to about 10 mg/kg/hour
during constant rate infusion. Advantageously, compounds may be
administered in a single daily dose, or the total daily dosage may
be administered in divided doses of two, three or four times
daily.
[0306] In any event, the physician, or the skilled person, will be
able to determine the actual dosage which will be most suitable for
an individual patient, which is likely to vary with the route of
administration, the type and severity of the condition that is to
be treated, as well as the species, age, weight, sex, renal
function, hepatic function and response of the particular patient
to be treated. The above-mentioned dosages are exemplary of the
average case; there can, of course, be individual instances where
higher or lower dosage ranges are merited, and such are within the
scope of this invention.
Pharmaceutical Formulations
[0307] Suitable preparations for administering the compounds of
formula will be apparent to those with ordinary skill in the art
and include for example tablets, pills, capsules, suppositories,
lozenges, troches, solutions, syrups, elixirs, sachets,
injectables, inhalatives and powders etc. Such formulations may be
prepared in accordance with standard and/or accepted pharmaceutical
practice.
[0308] Depending on e.g. potency and physical characteristics of
the compound of the invention (i.e. active ingredient), the content
of the pharmaceutically active compound(s) should be in the range
from 1 to 99 wt.-%, preferably 10 to 90 wt.-%, more preferably 20
to 70 wt.-%, of the composition as a whole.
[0309] Suitable tablets may be obtained, for example, by mixing one
or more compounds according to formula I with known excipients, for
example inert diluents, carriers, disintegrants, adjuvants,
surfactants, binders and/or lubricants. The tablets may also
consist of several layers.
[0310] A further aspect of the invention is a pharmaceutical
formulation including a compound of formula I in admixture with a
pharmaceutically acceptable adjuvant, diluent or carrier.
Combination Therapy
[0311] The compounds according to the present invention can be
combined with other treatment options known to be used in the art
in connection with a treatment of any of the indications the
treatment of which is in the focus of the present invention. Among
such treatment options that are considered suitable for combination
with the treatment according to the present inventions are: [0312]
non-steroidal antiinfiammatory drugs (NSAIDs) including COX-2
inhibitors; [0313] opiate receptor agonists; [0314] Cannabionoid
agonists; [0315] Sodium channel blockers; [0316] N-type calcium
channel blockers; [0317] serotonergic and noradrenergic modulators;
[0318] corticosteroids; [0319] histamine H1 receptor antagonists;
[0320] histamine H2 receptor antagonists; [0321] proton pump
inhibitors; [0322] leukotriene antagonists and 5-lipoxygenase
inhibitors; [0323] local anesthetics; [0324] VR1 agonists and
antagonists; [0325] Nicotinic acetylcholine receptor agonists;
[0326] P2X3 receptor antagonists; [0327] NGF agonists and
antagonists; [0328] NK1 and NK2 antagonists; [0329] NMDA
antagonist; [0330] potassium channel modulators; [0331] GABA
modulators; [0332] serotonergic and noradrenergic modulators [0333]
anti-migraine drugs.
[0334] Said list is not considered to have a limiting
character.
In the following representative examples of such treatment options
shall be given. [0335] Non-steroidal antiinflammatory drugs
(NSAIDs) including COX-2 inhibitors:propionic acid derivatives
(alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenhufen,
fenoprofen, flubiprofen, ibuprofen, indoprofen, ketoprofen,
miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen,
tiaprofenic acid, and tioxaprofen), acetic acid derivatives
(indomethacin, acemetacin, alclofenac, clidanac, diclofenac,
fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac,
isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and
zomepirac), fenamic acid derivatives (meclofenamic acid, mefenamic
acid, and tolfenamic acid), biphenyl-carboxylic acid derivatives,
oxicams (isoxicam, meloxicam, piroxicam, sudoxicam and tenoxican),
salicylates (acetyl salicylic acid, sulfasalazine) and the
pyrazolones (apazone, bezpiperylon, feprazone, mofebutazone,
oxyphenbutazone, phenylbutazone), and the coxibs (celecoxib,
valecoxib, rofecoxib and etoricoxib) and the like; [0336] Antiviral
drugs like acyclovir, tenovir, pleconaril, peramivir, pocosanol and
the like. [0337] Antibiotic drugs like gentamicin, streptomycin,
geldanamycin, doripenem, cephalexin, cefaclor, ceftazichine,
cefepime, erythromycin, vancomycin, aztreonam, amoxicillin,
bacitracin, enoxacin, mafenide, doxycycline, chloramphenicol and
the like; [0338] Opiate receptor agonists: morphine, propoxyphene
(Darvon), tramadol, buprenorphin and the like. [0339]
Glucocorticosteroids such as bethamethasone, budesonide,
dexamethasone, hydrocortisone, methylprednisolone, prednisolone,
prednisone, triamcinolone and deflazacort; [0340]
immunosuppressive, immunomodulatory, or cytsostatic drugs inlcuding
but not limited to hydroxychlorquine, D-penicillamine,
sulfasalizine, auranofin, gold mercaptopurine, tacrolimus,
sirolimus, mycophenolate mofetil, cyclosporine, leflunomide,
methotrexate, azathioprine, cyclophosphamide and glatiramer acetate
and novantrone, fingolimod (FTY720), minocycline and thalidomide
and the like; [0341] anti-TNF antibodies or TNF-receptor
antagonists such as but not limited to Etanercept, Infliximab,
Adalimumab (D2E7), CDP 571, and Ro 45-2081 (Lenercept), or biologic
agents directed against targets such as but not limited to CD-4,
CTLA-4, LFA-1, IL-6, ICAM-1, C5 and Natalizumab and the like;
[0342] IL-1 receptor antagonists such as but not limited to
Kineret; [0343] Sodium channel blockers: carbamazepine, mexiletine,
lamotrigine, tectin, lacosamide and the like. [0344] N-type calcium
channel blockers: Ziconotide and the like. [0345] Serotonergic and
noradrenergic modulators: paroxetine, duloxetine, clonidine,
amitriptyline, citalopram; [0346] Histamine H1 receptor
antagonists: bromophtniramint, chlorpheniramine,
dexchlorpheniramine, triprolidine, clemastine, diphenhydramine,
diphenylpyraline, tripelennamine, hydroxyzine, methdiJazine,
promethazine, trimeprazine, azatadine, cyproheptadine, antazoline,
pheniramine pyrilamine, astemizole, terfenadine, loratadine,
cetirizine, deslo-ratadine, fexofenadine and levocetirizine and the
like; [0347] Histamine H2 receptor antagonists: cimetidine,
famotidine and ranitidine and the like; [0348] Proton pump
inhibitors: omeprazole, pantoprazole and esomeprazole and the like;
[0349] Leukotriene antagonists and 5-lipoxygenase inhibitors:
zafirlukast, mon-telukast, pranlukast and zileuton and the like;
[0350] Local anesthetics such as ambroxol, lidocaine and the like;
[0351] Potassium channel modulators:like retigabine; [0352] GABA
modulators: lacosamide, pregabalin, gabapentin and the like; [0353]
Anti-migraine drugs: sumatriptan, zolmitriptan, naratriptan,
eletriptan, telcegepant and the like; [0354] NGF antibodies such as
RI-724 and the like.
[0355] Combination therapy is also possible with new principles for
the treatment of pain e.g. P2X3 antagonists, VR1 antagonists, NK1
and NK2 antagonists, NMDA antagonists, mGluR antagonists and the
like.
[0356] The combination of compounds is preferably a synergistic
combination. Synergy, as described for example by Chou and Talalay,
Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect of the
compounds when administered in combination is greater than the
additive effect of the compounds when administered alone as a
single agent. In general, a synergistic effect is most clearly
demonstrated at suboptimal concentrations of the compounds. Synergy
can be in terms of lower cytotoxicity, increased pharmacological
effect, or some other beneficial effect of the combination compared
with the individual components.
Experimental Section
Preparation of Examples for Compounds of the General Formula I
[0357] Unless otherwise stated, one or more tautomeric forms of
compounds of the examples described hereinafter may be prepared in
situ and/or isolated. All tautomeric forms of compounds of the
examples described hereinafter should be considered to be
disclosed.
[0358] The invention is illustrated by way of the following
examples, in which the following abbreviations may be employed:
ABBREVIATIONS
[0359] AcOH acetic acid [0360] aq aqueous [0361] BSTFA
(N,O-bis(trimethylsilyl)trifluoroacetamide [0362] Boc
tert.-butoxycarbonyl [0363] conc concentrated [0364] DCM
dichloromethane [0365] DIC diisopropylcarbodiimide [0366] DIPEA
N-ethyldiisopropylamine [0367] DMAP N,N-dimethylaminopyridine
[0368] DMSO dimethylsulphoxide [0369] DMF N,N-dimethylformamide
[0370] dppf (1,1'-Bis(diphenylphosphino)ferrocene [0371] EDC
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride [0372]
EtOAc ethyl acetate [0373] Et2O diethyl ether [0374] EtOH ethanol
[0375] HATU
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-hexafluoro-phosph-
ate [0376] HBTU O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate [0377] HPLC high performance liquid
chromatography [0378] i-PrOH isopropanol [0379] KOtBu potassium
tert.-butylate [0380] MeCN acetonitrile [0381] MeOH methanol [0382]
MS mass spectrometry [0383] MTBE methyl-tert-butyl ether [0384] NMR
nuclear magnetic resonance [0385] PE petrol ether [0386] PPA
1-propylphosphonic-acid cyclic anhydride [0387] RP reversed phase
[0388] rt room temperature [0389] R.sub.f retention factor [0390]
R.sub.t retention time sat saturated [0391] TBTU
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate [0392] TCDI thiocarbonyl diimidazole [0393] TEA
triethylamine [0394] THF tetrahydrofuran [0395] TFA trifluoroacetic
acid [0396] TLC thin layer chromatography
Analytical Methods
[0397] The TLC data was obtained by using the following tic plates
[0398] a) Silica gel plates 60 F254 Merck No 1.05714.0001
abbreviated in the experimental part as "silica gel" [0399] b)
Reversed phase plates: RP-8 F 254s Merck No: 1.15684.0001
abbreviated in the experimental part as "RP-8". [0400] c)
Aluminiumoxide plates 60 F254 Merck 1.05713.0001 abbreviated in the
experimental part as "Alox"
[0401] The R.sub.f values given were determined without chamber
saturation.
[0402] The HPLC/MS data, where specified, were obtained under the
following conditions:
[0403] Agilent 1100 with quarternary pump, Gilson G215 Autosampler,
HP diode array detector.
[0404] The diode array detection took place in a wavelength range
from 210-550 nm Range of mass-spectrometric detection: m/z 120 to
m/z 1000
[0405] The following methods were used:
Method A:
Mobile Phase:
[0406] E1: water with 0.15% formic acid E2: acetonitrile
Eluent Gradient C (Unpolar):
TABLE-US-00003 [0407] time in min % E1 % E2 flow rate in mL/min 0.0
95 5 1.6 2.00 10 90 1.6 5.00 10 90 1.6 5.50 90 10 1.6
[0408] The following column was used as the stationary phase:
(column temperature: constant at 25.degree. C.): Zorbax Stable Bond
C18, 1.8 .mu.m, 3.0.times.30 mm
Method B:
Mobile Phase:
[0409] E1: water with 0.15% formic acid E2: acetonitrile
Eluent Gradient C (Unpolar):
TABLE-US-00004 [0410] time in min % E1 % E2 flow rate in mL/min 0.0
95 5 1.6 2.00 10 90 1.6 5.00 10 90 1.6 5.50 90 10 1.6
[0411] The following column was used as the stationary phase:
(column temperature: constant at 25.degree. C.): Zorbax StableBond
C18, 4.6.times.75 mm
[0412] The following compounds are accompanied by structural
drawings. The skilled person will appreciate that the rules of
valency must be adhered to and hence there must be a certain number
of bonds attached to each atom, which may not necessarily be
depicted on the drawings. For example, in the case where a nitrogen
heteroatom is depicted with only one or two bonds attached to it,
the skilled person will realise that it should be attached to an
additional one or two bonds (a total of three), in which such bonds
are normally attached to one or two hydrogen atoms (so forming a
--NH.sub.2 or --N(H)-- moiety).
Example 1
2-[5-(1-Acetamidoethyl)-2-chlorophenylamino]-N-(4-bromophenyl)-1-methylben-
z-imidazole-5-carboxamide
##STR00023##
[0413] (a) 4-Chloro-.alpha.-methyl-3-nitrobenzylamine
[0414] Ammonium acetate (3.86 g, 50 mmol), NaBH.sub.3CN (0.22 g,
3.5 mmol), and 3 .ANG. molecular sieves (25 g) were added to a
mixture of 4-chloro-3-nitroacetophenone (1.00 g, 5 mmol) in MeOH
(15 mL) at rt. The mixture was stirred at rt for 20 h and
NaHCO.sub.3 (aq, sat) and EtOAc were added. The mixture was
filtered and the aq layer washed with EtOAc. The combined organic
phases were dried over Na.sub.2SO.sub.4 and concentrated to give
the sub-title compound. Yield: 0.27 g (27%).
(b) N-[1-(4-Chloro-3-nitrophenyl)ethyl]acetamide
[0415] TEA (0.28 mL, 2.0 mmol) followed by acetylchloride (96
.mu.L, 1.3 mmol) were added to
4-chloro-.alpha.-methyl-3-nitrobenzylamine (0.27 g, 1.3 mmol) in
THF (5 mL) at rt. The mixture was stirred at rt for 3.5 h and
additional acetylchloride (20 .mu.L, 0.27 mmol) was added. After 1
h at rt, NaHCO.sub.3 (aq, 5%) was added and the mixture extracted
with EtOAc.
[0416] The combined extracts were dried over Na.sub.2SO.sub.4 and
conc to give the sub-title compound. Yield: 0.30 g (92%).
(c) N-[1-(3-Amino-4-chlorophenyl)ethyl]acetamide
[0417] A solution of sodium dithionite (1.08 g, 6.1 mmol) in
H.sub.2O (4 mL) was added to a vigorously stirred mixture of
N-[1-(4-chloro-3-nitrophenyl)ethyl]acetamide (0.30 g, 1.2 mmol) in
EtOH (20 mL) at 55.degree. C. After 4 h at 55.degree. C. additional
sodium dithionite (0.20 g, 1.1 mmol) was added and stirring was
continued at 55.degree. C. for 1.5 h. The mixture was allowed to
cool and NaHCO.sub.3 (aq, sat) was added. The mixture was extracted
with EtOAc and the combined extracts were dried over
Na.sub.2SO.sub.4 and concentrated to give the sub-title
compound.
[0418] Yield: 90 mg (34%).
(d) N-[1-(4-Chloro-3-isothiocyanatophenyl)ethyl]acetamide
[0419] N-[1-(3-Amino-4-chlorophenyl)ethyl]acetamide (90 mg, 0.2
mmol) was added to a mixture of 1,1'-thiocarbonyldi-2-pyridone (69
mg, 0.2 mmol), DMAP (7 mg, 0.05 mmol) and DCM (2 mL) at rt. The
mixture was concentrated and used in the next step without further
purification.
(e) 3-Nitro-N-(4-bromophenyl)-4-methylaminobenzamide
[0420] A mixture of 3-Nitro-4-methylaminobenzoic acid (196 mg, 1.00
mmol), 20 ml DCM, 0.15 ml pyridine and 160 mg
1-Chloro-N,N,2-trimethylprop-1-enylamine was stirred until a clear
solution was obtained. 4-Bromoaniline (172 mg, 1.0 mmol) was added
and the mixture was stirred for 16 h. The mixture was filtered
through a pad of ALOX B and concentrated. 5 ml DMF and 20 ml
H.sub.2O were added and the precipitate was collected and dried.
Yield: 240 mg (68%).
(f) 3-Amino-N-(4-bromophenyl)-4-methylaminobenzamide
[0421] A mixture of
3-Nitro-N-(4-bromophenyl)-4-methylaminobenzamide (120 mg, 0.34
mmol), 10 ml THF, 10 ml MeOH and 30 mg 5%-Pt-on-carbon was stirred
for 4 h under a hydrogen atmosphere (3.5 bar). The catalyst was
removed by filtration and the mixture was concentrated and used in
the next step without further purification.
(g)
3-{3-[5-(1-Acetamidoethyl)-2-chlorophenyl]thioureido}-N-(4-bromophenyl-
)-4-(methylamino)benzamide
[0422] N-[1-(4-Chloro-3-isothiocyanatophenyl)ethyl]acetamide in DMF
(2 mL) was added to a mixture of
3-amino-N-(4-bromophenyl)-4-methylaminobenzamide (87 mg, 0.2 mmol,
crude material from the step above) in DMF (2 mL) at rt. The
mixture was stirred at rt overnight and concentrated. The residue
was purified by chromatography to give the sub-title compound.
Yield: 130 mg.
(h)
2-[5-(1-Acetamidoethyl)-2-chlorophenylamino]-N-(4-bromophenyl)-1-methy-
lbenzimidazole-5-carboxamide
[0423] N,N-Diisopropylcarbodiimide (46 .mu.L, 0.2 mmol) was added
to
3-{3-[5-(1-acetamidoethyl)-2-chlorophenyl]thioureido}-N-(4-bromophenyl)-4-
-(methylamino)benz-amide (130 mg, 0.2 mmol) in DMF (2 mL) at rt.
The mixture was stirred at 80.degree. C. for 2 h, cooled and
concentrated. The residue was purified by chromatography to give
the title compound. Yield: 30 mg (24%). MS m/z: 540
[M+H].sup.+.
[0424] HPLC-method A: R.sub.t=1.60 min
Example 2
2-[5-(tert.
Butylcarbonylaminomethyl)-2-chlorophenylamino]-6-chloro-N-(2,2,2-trifluor-
ethyl)-benzimidazole-5-carboxamide
##STR00024##
[0425] (a) tert-Butyl 4-chloro-3-nitrobenzylcarbamate
[0426] Di-tert-butyl dicarbonate (21.05 g, 96.5 mmol) in DCM (30
mL) was added to an ice-cooled mixture of
4-chloro-3-nitrobenzylamine (15 g, 80.4 mmol), DMAP (0.49 g, 4
mmol) and DCM (100 mL). The mixture was stirred at rt for 12 h,
poured into ammonia and extracted with DCM. The combined extracts
were washed with brine and concentrated.
[0427] The residue was washed with Et.sub.2O to give the sub-title
compound which was used directly in the next step without any
further purification.
(b) tert-Butyl 3-amino-4-chlorobenzylcarbamate
[0428] A mixture of tert-butyl 4-chloro-3-nitrobenzylcarbamate
(crude material from step (b)), Fe powder (17.65 g, 316 mmol),
NH.sub.4Cl (aq, sat, 100 mL) and EtOH (100 mL) was heated at
90.degree. C. for 4 h and allowed to cool. The pH was adjusted to
.about.10 and the mixture was filtered through Celite. The solids
were washed with EtOAc and EtOH and the combined filtrates
concentrated to remove the organic solvents. The residue was added
to ammonia and the mixture was extracted with DCM. The combined
extracts were washed with brine, dried over Na.sub.2SO.sub.4 and
concentrated. Crystallization from EtOAc/petroleum ether gave the
sub-title compound. Yield: 15.5 g (75% from
4-chloro-3-nitrobenzylamine).
(c) tert-Butyl 4-chloro-3-isothiocyanatobenzylcarbamate
[0429] The sub-title compound was prepared from tert-butyl
3-amino-4-chlorobenzyl-carbamate, in accordance with Example 1,
step (d).
(d)
Ethyl-2-[5-(tert.butoxycarbonylaminomethyl)-2-chlorophenylamino]-6-chl-
oro-benzimidazole-5-carboxylate
[0430] The sub-title compound was prepared in two steps from
tert-Butyl-4-chloro-3-isothiocyanatobenzylcarbamate and
Ethyl-2-chloro-4,5-diamino-benzoic acid in accordance with Example
1, step (g) with additional TEA and Example 1, step (h).
(e)
Ethyl-2-[5-(aminomethyl)-2-chlorophenylamino]-6-chloro-benzimidazole-5-
-carboxylate
[0431] A mixture of 1.15 g (2.4 mmol)
Ethyl-2-[5-(tert.butylcarbonylaminomethyl)-2-chlorophenylamino]-benzimida-
zole-5-carboxylate and 10 ml 4M HCl in Dioxane was stirred
overnight. The reaction mixture was concentrated under reduced
pressure to give the sub-title compound. Yield: 1.0 g (100%).
(f)
Ethyl-2-[5-(tert.butylcarbonylaminomethyl)-2-chlorophenylamino]-6-chlo-
ro-benzimidazole-5-carboxylate
[0432] A mixture of
Ethyl-2-[5-(aminomethyl)-2-chlorophenylamino]-6-chloro-benzimidazole-5-ca-
rboxylate (1.00 g, 2.4 mmol), pivaloyl chloride (0.296 ml, 2.4
mmol), 1.5 ml TEA and 50 ml THF were stirred for 18 h at rt. The
mixture was concentrated, diluted with EtOAc, washed 2.times. with
H.sub.2O, dried over Na.sub.2SO.sub.4 and concentrated. The residue
was purified by chromatography to give the sub-title compound.
Yield 0.92 g (83%).
(g)
2-[5-(tert.butylcarbonylaminomethyl)-2-chlorophenylamino]-6-chloro-ben-
zimidazole-5-carboxylic Acid
[0433] A mixture of
Ethyl-2-[5-(tert.butylcarbonylaminomethyl)-2-chlorophenylamino]-6-chloro--
benzimidazole-5-carboxylate (0.91 g, 1.9 mmol) in 20 ml EtOH was
treated with 1 N NaOH (3.9 ml+0.98 ml+0.98 ml) for 4 h at rt, for 5
h at 50.degree. C. and for 3 d at rt. The mixture was concentrated,
diluted with H.sub.20, acidified with 1 N HCl and cooled in an ice
bath. The precipitate was filtered, washed with ice water and dried
to give the sub-title compound. Yield 0.81 g (95%).
(h)
2-[5-(tert.Butylcarbonylaminomethyl)-2-chlorophenylamino]-6-chloro-N-(-
2,2,2-trifluorethyl)-benzimidazole-5-carboxamide
[0434] A mixture of
2-[5-(tertbutylcarbonylaminomethyl)-2-chlorophenylamino]-6-chloro-benzimi-
dazole-5-carboxylic acid (0.15 g, 0.345 mmol),
2,2,2-Trifluoroethylamine (2.times.0.027 ml, 0.345 mmol),
1-propylphosphonic-acid cyclic anhydride (PPA, 0.244 ml, 50% in
EtOAc), 0.12 ml TEA and 10 ml MeCN was stirred for 48 h at
60.degree. C. an concentrated. The residue was purified by
chromatography to give the title compound. Yield 17 mg (10%)
[0435] m/z: 516 [M+H].sup.+.
[0436] HPLC-method B: R.sub.t=2.35 min.
Example 3
6-Chloro-2-{2-chloro-5-[(1-methylcyclohexylamido)methyl]phenylamino}-N-cyc-
lopentyl-1-methylbenzimidazole-5-carboxamide
##STR00025##
[0437] (a) 2-Chloro-N-cyclopentyl-4-fluoro-5-nitrobenzamide and
2-Chloro-N-cyclopentyl-4-cyclopentylamino-5-nitrobenzamide
[0438] 2-Chloro-4-fluoro-5-nitrobenzoyl chloride (1.5 g, 6.30 mmol)
was added to a mixture of cyclopentylamine (430 .mu.L, 12.6 mmol),
TEA (1.76 mL, 12.6 mmol) and DCM (30 mL) at -20.degree. C. After 12
h at rt, the mixture was diluted with DCM and washed with
NH.sub.4OH (aq sat). The organic layer was washed with H.sub.2O and
brine, dried over Na.sub.2SO.sub.4, concentrated and purified by
HPLC to afford 510 mg (28%) of
2-chloro-N-cyclopentyl-4-fluoro-5-nitrobenzamide and 300 mg (14%)
of 2-chloro-N-cyclopentyl-4-cyclopentylamino-5-nitro-benzamide.
(b) 2-Chloro-N-cyclopentyl-4-methylamino-5-nitrobenzamide
[0439] N-Methylamine in MeOH (2 M, 2.0 mL, 4.0 mmol) was added to
2-chloro-N-cyclopentyl-4-fluoro-5-nitrobenzamide (230 mg, 0.79
mmol) in EtOH. The mixture was heated at 50.degree. C. for 12 h in
a sealed vessel, cooled and concentrated. The residue was purified
by chromatography to give the sub-title compound. Yield: 150 mg
(64%).
(c) 5-Amino-2-chloro-N-cyclopentyl-4-methylaminobenzamide
[0440] The sub-title compound was prepared from
2-chloro-N-cyclopentyl-4-methylamino-5-nitrobenzamide in accordance
with Example 2, step (b).
(d) 3-Amino-4-chloro-benzylamine
[0441] A mixture of 3-Amino-4-chloro-benzonitrile (1.32 g, 8.33
mmol), Ra-Nickel (0.25 g) and 80 ml NH.sub.3 in MeOH was stirred
for 4 h at rt under H.sub.2-atmosphere (3 bar). The mixture was
filtered and concentrated and the sub-title compound was used
without further purification.
(e) N-(4-Chloro-3-aminobenzyl)-1-methylcyclohexylamide
[0442] A mixture of 3-Amino-4-chloro-benzylamine (0.69 g, 4.17
mmol), 1-Methyl-cyclohexane-1-carboxylic acid (0.59 g, 4.17 mmol),
1.47 g TBTU, 1.45 ml TEA and 30 ml THF was stirred for 6 h at rt.
The mixture was concentrated, diluted with EtOAc, washed 2.times.
with 2M NaOH and 1.times. with brine, dried with Na.sub.2SO.sub.4
filtered and concentrated to give the sub-title compound. Yield:
1.17 g (100%).
(f) N-(4-Chloro-3-isothiocyanatobenzyl)-1-methylcyclohexylamide
[0443] The sub-title compound was prepared from
N-(4-Chloro-3-aminobenzyl)-1-methylcyclohexylamide analogous to
Example 1, step (d) but with 1,1'-thiocarbonyl-diimidazole instead
of 1,1'-thiocarbonyldi-2-pyridone.
(g)
6-Chloro-2-{2-chloro-5-[(1-methylcyclohexylamido)methyl]phenylamino}-N-
-cyclopentyl-1-methylbenzimidazole-5-carboxamide
[0444] The title compound was prepared from
N-(4-chloro-3-isothiocyanatobenzyl)-1-methylcyclohexylamide and
5-amino-2-chloro-N-cyclopentyl-4-methylaminobenzamide analogous to
Example 1, steps (g and h), but without isolation of the thioureido
derivative and with EDC as coupling reagent instead of
N,N-diisopropylcarbodiimide. 200 MHz 1H-NMR (DMSO-d.sub.6, ppm)
.delta. 8.43 (1H, s) 8.20 (1H, d, J=7.4 Hz) 8.10 (1H, t, J=5.6 Hz)
7.84-7.78 (1H, m) 7.52-7.48 (1H, m) 7.42 (1H, d, J=8.2 Hz)
7.26-7.22 (1H, m) 7.00-6.91 (1H, m) 4.31-4.08 (3H, m) 3.69 (3H, s)
1.98-1.76 (4H, m) 1.68-1.16 (14H, m) 1.06 (3H, s). MS m/z: 556
[M+H].sup.+.
Example 4
N-{4-Chloro-3-[5-(1-byrrolidinylcarbonyl)-2-benzimidazolylamino]benzyl}-1--
methylcyclohexylamide
##STR00026##
[0445] (a)
2-{2-Chloro-5-[(1-methylcyclohexylamido)methyl]phenylamino}-ben-
zimidazole-5-carboxylic Acid
[0446] A mixture of methyl
2-{2-chloro-5-[(1-methylcyclohexylamido)methyl]phenyl-amino}benzimidazole-
-5-carboxylate (910 mg, 2.0 mmol), NaOH (aq, 2 M, 3.0 mL, 6.0 mmol)
and dioxane (15 mL) was heated at 90.degree. C. for 12 h and
concentrated. The residue was partitioned between NaOH (aq, 2 M)
and MTBE. The aq phase was acidified to pH .about.4-5 with HCl (aq,
4 M). The precipitate was collected, washed with H.sub.2O and dried
to give the sub-title compound. Yield: 873 mg (99%).
(b)
N-{4-Chloro-3-[5-(1-pyrrolidinylcarbonyl)-2-benzimidazolylamino]benzyl-
}-1-methylcyclohexylamide
[0447] TEA (130 .mu.L; 0.91 mmol) followed by HBTU (171 mg, 0.45
mmol) was added to
2-{2-chloro-5-[(1-methylcyclohexylamido)methyl]phenylamino}benzi-
midazole-5-carboxylic acid (200 mg, 0.45 mmol) in DMF (3 mL). After
10 min at rt, pyrrolidine (37 .mu.L, 0.45 mmol) in DMF (1 mL) was
added. After 12 h at rt, the mixture was concentrated and the
residue partitioned between water and DCM. The aq layer was
extracted with DCM and the combined extracts were washed with
brine, dried over Na.sub.2SO.sub.4 and concentrated. The residue
was purified by chromatography to give the title compound. Yield
127 mg (57%).
[0448] 400 MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 11.22-11.08
(1H, m) 8.83-8.69 (1H, m) 8.55 (1H, s) 8.12 (1H, t, J=5.8 Hz)
7.58-7.44 (1H, m) 7.41-7.28 (2H, m) 7.26-7.18 (1H, m) 6.89-6.82
(1H, m) 4.28 (2H, d, J=5.8 Hz) 3.50-3.41 (4H, m) 2.01-1.91 (2H, m)
1.89-1.75 (4H, m) 1.47-1.16 (8H, m) 1.12 (3H, s). MS m/z: 494
[M+H].sup.+.
Example 5
tert-Butyl
5-chloro-2-{2-chloro-5-[(1-methylcyclohexylamido)methyl]phenyla-
mino}-1-methyl-6-benzimidazolylcarbamate
##STR00027##
[0449] (a)
Di-tert-butyl-2,5-dichloro-4-nitrophenylimidodicarbonate
[0450] Di-tert-butyldicarbonate (4.58 g, 21.0 mmol) was added in
portions to a mixture of 2,5-dichloro-4-nitroaniline (2.07 g, 10.0
mmol), DMAP (61.1 mg, 0.5 mmol) and THF (15 mL). After 12 h at rt
the mixture was concentrated and the residue partitioned between
EtOAc and citric acid (aq, 1 M). The organic layer was washed with
brine, dried over Na.sub.2SO.sub.4 and concentrated. The residue
was washed with petroleum ether to give the sub-title compound.
Yield 3.67 g (91%).
(b) tert-Butyl 2-chloro-5-(methylamino)-4-nitrophenylcarbamate
[0451] The sub-title compound was prepared from
di-tert-butyl-2,5-dichloro-4-nitro-phenylimidodicarbonate in
accordance with Example 3, step (b).
(c) tert-Butyl 4-amino-2-chloro-5-(methylamino)phenylcarbamate)
[0452] The sub-title compound was prepared from tert-butyl
2-chloro-5-(methylamino)-4-nitrophenylcarbamate in accordance with
Example 2, step (b).
(d) tert-Butyl
5-chloro-2-{2-chloro-5-[(1-methylcyclohexylamido)methyl]-phenylamino}-1-m-
ethyl-6-benzimidazolylcarbamate
[0453] The title compound was prepared from
N-(4-chloro-3-isothiocyanatobenzyl)-1-methylcyclohexylamide and
tert-butyl 4-amino-2-chloro-5-(methylamino)phenylcarbamate) in
accordance to the procedures described above 200 MHz .sup.1H-NMR
(DMSO-d.sub.6, ppm) .delta. 8.55 (1H, s) 8.40 (1H, s) 8.12 (1H, t,
J=5.2) 7.80-7.74 (1H, m) 7.48-7.29 (3H, m) 7.01-6.89 (1H, m) 4.26
(2H, d, J=6.0) 3.66 is (3H, s) 2.00-1.85 (2H, m) 1.46 (9H, s)
1.42-1.10 (8H, m) 1.06 (3H, s).
[0454] MS m/z: 560 [M+H].sup.+.
Example 6
N-{4-chloro-3-[5-chloro-6-(cyclopentylamido)-1-methyl-2-benzimidazolylamin-
o]-benzyl}-1-methylcyclohexylamide
##STR00028##
[0455] (a)
N-[4-Chloro-3-(6-amino-5-chloro-1-methyl-2-benzimidazolylamino)-
benzyl]-1-methylcyclohexylamide
[0456] A mixture of tert-butyl
5-chloro-2-{2-chloro-5-[(1-methylcyclohexylamido)methyl]-phenylamino}-1-m-
ethyl-6-benzimidazolylcarbamate (400 mg, 0.71 mmol), TFA (0.5 mL;
6.7 mmol) and DCM (10 mL) was heated at 80.degree. C. for 3 h in a
sealed tube. The mixture was cooled, diluted with DCM and washed
with NaHCO.sub.3 (aq, sat; Caution: gas evolution!) and dried over
Na.sub.2SO.sub.4. Concentration gave the sub-title compound. Yield:
320 mg (98%).
(b)
N-{4-chloro-3-[5-chloro-6-(cyclopentylamido)-1-methyl-2-benzimidazolyl-
-amino]benzyl}-1-methylcyclohexylamide
[0457] The title compound was prepared from
N-[4-chloro-3-(6-amino-5-chloro-1-methyl-2-benzimidazolylamino)benzyl]-1--
methylcyclohexylamide and cyclopentylcarbox-ylic acid and HBTU in
accordance with Example 4, step (b).
[0458] 200 MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 9.37 (1H, s)
8.42 (1H, s) 8.12 (1H, t, J=5.8 Hz) 7.84-7.72 (1H, m) 7.51 (1H, s)
7.43 (1H, d, J=8.2 Hz) 7.36 (1H, s) 6.96 (1H, dd, J=8.2, 1.2 Hz)
4.27 (2H, d, J=5.8 Hz) 3.67 (3H, s) 2.98-2.79 (1H, m) 2.04-1.0
(21H, m). MS m/z: 556 [M+H].sup.+.
Example 7
N-{4-Chloro-3-[5-(N-cyclopentylsulfamoyl)-1-methyl-2-benzimidazolylamino]--
benzyl}-1-methylcyclohexylamide
##STR00029##
[0459] (a) 4-Chloro-N-cyclopentyl-3-nitrobenzenesulfonamide
[0460] Cyclopentylamine (1.5 mL, 15.6 mmol) in MeCN (10 mL) was
added over 10 min to an ice-cooled solution of
4-chloro-3-nitrobenzenesulfonyl chloride (2.0 g, 7.8 mmol) in MeCN
(20 mL). After 1 h at rt the mixture was poured into ice-water and
extracted with EtOAc. The combined extracts were washed with brine,
dried over Na.sub.2SO.sub.4 and concentrated to give the sub-title
compound. Yield 2.2 g (92%).
(b) N-Cyclopentyl-4-methylamino-3-nitrobenzenesulfonamide
[0461] The sub-title compound was prepared from
4-chloro-N-cyclopentyl-3-nitro-benzenesulfonamide and methylamine
in accordance with Example 3, step (b).
(c) 3-Amino-N-cyclopentyl-4-methylaminobenzenesulfonamide
[0462] The sub-title compound was prepared from
N-cyclopentyl-4-methylamino-3-nitro-benzenesulfonamide in
accordanced with Example 2, step (b).
(d)
N-{4-Chloro-3-[5-(N-cyclopentylsulfamoyl)-1-methyl-2-benzimidazolyl-am-
ino]benzyl}-1-methylcyclohexylamide
[0463] The title compound was prepared from
N-(4-chloro-3-isothiocyanatobenzyl)-1-methylcyclohexylamide and
3-amino-N-cyclopentyl-4-methylaminobenzene-sulfonamide) in
accordance with Example 3, step (g).
[0464] 200 MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 8.51 (1H, s)
8.13 (1H, t, J=6.0) 7.87-7.81 (1H, m) 7.58-7.39 (4H, m) 7.04-6.94
(1H, m) 4.28 (2H, d, J=6.0) 3.47 (3H, s) 3.38-3.28 (1H, m,
overlapped with H.sub.2O) 2.01-1.86 (2H, m) 1.60-1.11 (16H, m) 1.06
(3H, s). MS m/z: 558 [M+H].sup.+.
Example 8
2-{2-Chloro-5-[(1-methylcyclopropylamido)methyl]phenylamino}-N-cyclohexyl--
methyl-1-methylbenzimidazole-5-carboxamide
##STR00030##
[0465] (a)
2-(5-Aminomethy-1-2-chlorophenylamino)-N-cyclohexylmethyl-1-met-
hyl-benzimidazole-5-carboxamide
[0466] A mixture of
2-(2-chloro-5-cyanophenylamino)-N-cyclohexylmethyl-1-methylbenz-imidazole-
-5-carboxamide (500 mg, 1.19 mmol, prepared in analogy to the
experimental procedures described above) and EtOH (20 mL) was
saturated with ammonia. Freshly prepared Raney-Nickel (7 mg, 0.12
mmol) was added and the mixture was hydrogenated (rt, 70 atm) for
48 h. The mixture was filtered through Celite and the filter cake
washed with EtOAc. The combined filtrates were concentrated and the
residue treated with a mixture of petroleum ether and diethyl ether
to give the sub-title compound. Yield: 500 mg (98%).
(h)
2-{(2-Chloro-5-[(1-methylcyclopropylamido)methyl]phenylamino}-N-cyclo--
hexylmethyl-1-methylbenzimidazole-5-carboxamide
[0467] The title compound was prepared from
2-(5-aminomethyl-2-chlorophenylamino)-N-cyclohexylmethyl-1-methylbenzimid-
azole-5-carboxamide and 1-methylcyclo-propylcarboxylic acid and
HBTU in accordance with Example 4, step (b). 200 MHz .sup.1H-NMR
(DMSO-d.sub.6, ppm) .delta. 8.38 (1H, s) 8.33-8.22 (1H, m)
8.19-8.08 (1H, m) 7.91-7.80 (2H, m) 7.66-7.57 (1H, m) 7.42 (1H, d,
J=8.2 Hz) 7.37 (1H, d, J=8.2 Hz) 7.00-6.89 (1H, m) 4.24 (2H, d,
J=5.6 Hz) 3.71 (3H, s) 3.15-2.99 (2H, m) 1.79-1.45 (7H, m) 1.27
(3H, s) 1.21-1.06 (3H, m) 1.00-0.80 (5H, m). MS m/z: 508
[M+H].sup.+.
Example 9
2-{(2-Chloro-5-[(2-thienylsulfonamido)methyl]phenylamino}-N-cyclohexylmeth-
yl-1-methylbenzimidazole-5-carboxamide
##STR00031##
[0469] Thiophene-2-sulfonyl chloride (64 mg, 0.35 mmol) in MeCN (1
mL) was added to a mixture of
2-(5-aminomethyl-2-chlorophenylamino)-N-cyclohexylmethyl-1-methylbenzimid-
azole-5-carboxamide (150 mg, 0.35 mmol), TEA (150 .mu.L, 1.1 mmol)
and MeCN (2 mL). After 12 h at rt the mixture was diluted with DCM
and washed with NH.sub.3 (aq, sat) and brine, dried over
Na.sub.2SO.sub.4 and concentrated. The residue was purified by
chromatography to give the title compound. Yield: 36 mg (18%). 200
MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 8.50-8.36 (2H, m)
8.35-8.22 (1H, m) 7.94-7.82 (3H, m) 7.69-7.57 (2H, m) 7.42 (1H, d,
J=8.2 Hz) 7.37 (1H, d, J=8.2 Hz) 7.18-7.11 (1H, m) 7.04-6.95 (1H,
m) 4.09-3.96 (2H, m) 3.71 (3H, s) 3.14-3.00 (2H, m) 1.77-1.47 (7H,
m) 1.29-1.07 (4H, m). MS m/z: 572 [M+H].sup.+.
Example 10
4-Bromo-N-(2-{2-chloro-5-[(1-methylcyclopropylamido)methyl]phenylamino}-1--
methyl-5-benzimidazolyl)benzamide
##STR00032##
[0470] (a)
2-[5-(Aminomethyl)-2-chlorophenylamino]-N-(4-bromophenyl)-1-met-
hyl-benzimidazole-5-carboxamide
[0471] TFA (1.5 mL) was added to tert-butyl
3-[5-(4-bromophenylcarbamoyl)-1-methyl-2-benzimidazolylamino]-4-chloroben-
zylcarbamate (960 mg. 1.7 mmol prepared in analogy to the
experimental procedures described above) in DCM (20 mL) at rt.
After 16 h at rt TFA (2 mL) was added and the mixture was stirred
at rt for 16 h, diluted with DCM and washed with NaHCO.sub.3 (aq,
sat) and brine, dried and concentrated to give the sub-title
compound which was used in the next step without further
purification. Yield: 706 mg (90%)
(b)
4-Bromo-N-(2-{2-chloro-5-[(1-methylcyclopropylamido)methyl]phenyl-amin-
o}-1-methyl-5-benzimidazolyl)benzamide
[0472] The title compound was synthesized from
2-[5-(aminomethyl)-2-chlorophenyl-amino]-N-(4-bromophenyl)-1-methylbenzim-
idazole-5-carboxamide and 1-methyl-cyclopropyl carboxylic acid and
HBTU in accordance with Example 4, step (b). 200 MHz .sup.1H-NMR
(DMSO-d.sub.6, ppm) .delta. 10.24 (1H, s) 8.53-8.47 (1H, m) 8.17
(1H, t, J=6.0 Hz) 8.03 (1H, d, J=1.2 Hz) 7.89-7.71 (4H, m)
7.60-7.40 (4H, m) 7.00 (1H, dd, J=8.2, 1.8 Hz) 4.27 (2H, d, J=6.0
Hz) 3.76 (3H, s) 1.29 (3H, s) 1.00-0.93 (2H, m) 0.55-0.48 (2H, m).
MS m/z: 566 [M+H].sup.+.
Example 11
2-{2-chloro-5-[(1-trifluoromethylcyclopropylamido)methyl]phenylamino}-N-cy-
clo-propylmethyl-1-methylbenzimidazole-5-carboxamide
##STR00033##
[0473] (a) 4-Methylamino-3-nitrobenzoic Acid
[0474] TEA (13 mL) and methylamine (2 M in MeOH, 35 mL, 70 mmol)
was added to 3,4-dinitrobenzoic acid (10 g, 47.2 mmol) in EtOH (50
mL) at rt. After 24 h at rt the mixture was concentrated and
H.sub.2O was added to the residue. The mixture was filtered and
acidified with AcOH. The solids were collected and dried to give
the sub-title compound. Yield: 7.5 g (81%).
(b) Methyl 4-methylamino-3-nitrobenzoate
[0475] HCl was bubbled through a mixture of
4-methylamino-3-nitrobenzoic acid (7.41 g, 37.8 mmol), DMF (60 mL)
and MeOH (250 mL) at reflux for 10 h. The mixture was allowed to
cool, filtered and concentrated. NaHCO.sub.3 (aq, sat) was added to
the residue which was extracted with EtOAc. The combined extracts
were washed with brine, dried and concentrated to give the
sub-title compound.
[0476] Yield: 2.5 g (32%).
[0477] (c) Methyl 3-amino-4-methylaminobenzoate
[0478] Fe powder (3.4 g, 60 mmol) was added to a mixture of methyl
4-methylamino-3-nitrobenzoate (2.5 g, 12.0 mmol), AcOH (10 mL) and
MeOH (100 mL) at reflux. The mixture was heated at reflux for 30
min and allowed to cool to rt. The pH was adjusted to -8 by
addition of NaHCO.sub.3 (aq, sat) and the mixture was filtered
through Celite. The filter cake was washed with EtOH and the
combined filtrates were concentrated and the residue extracted with
EtOAc. The combined extracts were washed with brine, dried and
concentrated to give the sub-title compound. Yield: 1.91 g
(88%)
(d) Methyl
2-{5-[(tert-Butoxycarbonylamino)methyl]-2-chlorophenylamino}-1--
methylbenzimidazole-5-carboxylate
[0479] The sub-title compound was prepared from tert-butyl
4-chloro-3-isothiocyanato-benzylcarbamate (see Example 2d) and
methyl 3-amino-4-methylaminobenzoate according to Example 3, step
(g).
(e) Methyl
2-[5-(aminomethyl)-2-chlorophenylamino]-1-methylbenzo[d]-imidaz-
ole-5-carboxylate
[0480] The sub-title compound was prepared from methyl
2-{5-[(tert-butoxycarbonyl-amino)methyl]-2-chlorophenylamino}-1-methylben-
zimidazole-5-carboxylate in accordance with the procedure in
Example 10, step (a).
(f) Methyl
2-{2-chloro-5-[(1-trifluoromethylcyclopropylamido)methyl]phenyl-
-amino}-1-methylbenzimidazole-5-carboxylate
[0481] The sub-title compound was prepared from methyl
2-[5-(aminomethyl)-2-chloro-phenylamino]-1-methylbenzo[d]imidazole-5-carb-
oxylate, and 1-trifluoromethylcyc-lopropylcarboxylic acid and TBTU
in accordance with the procedure in Example 3, step (e).
(g)
2-{2-Chloro-5-[(1-trifluoromethylcyclopropylamido)methyl]phenylamino}--
1-methylbenzimidazole-5-carboxylic acid
[0482] A mixture of methyl
2-{2-chloro-5-[(1-trifluoromethylcyclopropylamido)methyl]-phenylamino}-1--
methylbenzimidazole-5-carboxylate (1.36 g, 2.8 mmol), NaOH (aq, 2
M, 15 mL) and dioxane (15 mL) was heated at reflux for 45 min. The
mixture was allowed to cool and concentrated, and HCl (aq, 1 M) was
added. The solids were collected, washed with H.sub.2O, and dried
to give the sub-title compound. Yield: 1.01 g (77%).
(h)
2-{2-chloro-5-[(1-trifluoromethylcyclopropylamido)methyl]phenylamino}--
N-cyclopropylmethyl-1-methylbenzimidazole-5-carboxamide
[0483] The title compound was prepared from
2-{2-chloro-5-[(1-trifluoromethylcyclo-propylamido)methyl]phenylamino}-1--
methylbenzimidazole-5-carboxylic acid and cyclopropylmethylamine
and TBTU in accordance with the procedure in Example 3, step
(e).
[0484] 400 MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) 8 (signals of minor
tautomer are not assigned) 8.50-8.34 (3H, m) 7.95-7.89 (1H, m)
7.88-7.82 (1H, m) 7.70-7.63 (1H, m) 7.45 (1H, d, J=8.2 Hz) 7.40
(1H, d, J=8.4 Hz) 6.99-6.92 (1H, m) 4.28 (2H, d, J=5.8 Hz) 3.73
(3H, s) 3.18-3.11 (2H, m) 1.40-0.98 (5H, m) 0.45-0.38 (2H, m)
0.26-0.20 (2H, m). MS m/z: 520 [M+H].sup.+.
[0485] The following compounds were synthesized in analogy to the
methods of preparation described above in detail.
TABLE-US-00005 Chemical structure MS m/z [M + H].sup.+ Name Ex.
.sup.1H-NMR 12 ##STR00034## 508
N-{4-Chloro-3-[1-methyl-5-(1-pyrrolidinylcarbonyl)-2-
benzimidazolylamino]benzyl}-1-methylcyclohexylamide 400 MHz
.sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 8.43-8.27 (1H, br s) 8.12-
8.03 (1H, m) 7.82-7.68 (1H, br s) 7.46-7.21 (4H, m) 6.97-6.88 (1H,
m) 4.25 (2H, d, J = 6.0 Hz) 3.76-3.59 (3H, br s) 3.49-3.39 (4H, m)
1.94-1.75 (6H, m) 1.40-1.14 (8H, m) 1.04 (3H, s) 13 ##STR00035##
508 2-{2-Chloro-5-[(1-methylcyclohexylamido)methyl]phenylamino}-N-
cyclopentylbenzimidazole-5-carboxamide 400 MHz .sup.1H-NMR
(DMSO-d.sub.6, ppm) .delta. 11.22-11.11 (1H, m) 8.83- 8.72 (1H, m)
8.58 (1H, s) 8.14-8.05 (2H, m) 7.94-7.83 (1H, m) 7.61-7.54 (1H, m)
7.42-7.27 (2H, m) 6.89-6.83 (1H, m) 4.31-4.17 (3H, m) 1.99-1.82
(4H, m) 1.73-1.65 (2H, m) 1.57-1.19 (12H, m) 1.11 (3H, s) 14
##STR00036## 522
2-{2-Chloro-5-[(1-methylcyclohexylamido)methyl]phenylamino}-N-
cyclopentyl-1-methylbenzimidazole-5-carboxamide 400 MHz .sup.1H-NMR
(DMSO-d.sub.6, ppm) .delta. 8.31 (1H, s) 8.12-8.04 (2H, m) 7.89
(1H, d, J = 1.4 Hz) 7.83 (1H, d, J = 1.8 Hz) 7.63 (1H, dd, J = 8.4,
1.4 Hz) 7.41 (1H, d, J = 8.2 Hz) 7.36 (1H, d, J = 8.4 Hz) 6.93 (1H,
dd, J = 8.2, 1.8 Hz) 4.25 (2H, d, J = 6.0 Hz) 3.70 (3H, s)
1.93-1.83 (4H, m) 1.71-1.66 (2H, m) 1.56-1.49 (4H, m) 1.41-1.16
(8H, m) 1.04 (3H, s) 15 ##STR00037## 554
N-(2-tert-Butoxyethyl)-2-{2-chloro-5-[(1-
methylcyclohexylamido)methyl]phenylamino}-1-
methylbenzimidazole-5-carboxamide 200 MHz .sup.1H-NMR
(DMSO-d.sub.6, ppm) .delta. 8.38-8.25 (2H, m) 8.09 (1H, t, J = 6.0
Hz) 7.87-7.82 (1H, m) 7.78 (1H, d, J = 1.6 Hz) 7.67-7.58 (1H, m)
7.42 (1H, d, J = 8.2 Hz) 7.37 (1H, d, J = 8.4 Hz) 6.94 (1H, dd, J =
8.2, 1.6 Hz) 4.25 (2H, d, J = 6.0 Hz) 3.69 (3H, s) 3.46-3.33 (4H,
m, overlapped with H.sub.2O) 1.98-1.82 (2H, m) 1.40-1.09 (19H, m)
1.03 (3H, s) 16 ##STR00038## 550
2-{2-Chloro-5-[(1-methylcyclohexylamido)methyl]phenylamino}-N-
cyclohexylmethyl-1-methylbenzimidazole-5-carboxamide 200 MHz
.sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 8.37-8.22 (2H, m) 8.08 (1H,
t, J = 5.8 Hz) 7.89-7.79 (2H, m) 7.66-7.58 (1H, m) 7.42 (1H, d, J =
8.2 Hz) 7.37 (1H, d, J = 8.4 Hz) 6.93 (1H, dd, J = 8.2, 1.6 Hz)
4.25 (2H, d, J = 5.8 Hz) 3.70 (3H, s) 3.08 (2H, t, J = 6.0 Hz)
1.98-1.83 (2H, m) 1.80-0.77 (24H, m) 17 ##STR00039## 565
2-{2-Chloro-5-[(1-methylcyclohexylamido)methyl]phenylamino}-1-
methyl-N-[2-(1-piperidinyl)ethyl]benzimidazole-5-carboxamide 200
MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 8.35 (1H, s) 8.26-8.17
(1H, m) 8.14-8.04 (1H, m) 7.87-7.76 (2H, m) 7.65-7.56 (1H, m) 7.45-
7.33 (2H, m) 6.98-6.89 (1H, m) 4.25 (2H, d, J = 5.8 Hz) 3.70 (3H,
s) 3.41-3.24 (2H, m, overlapped with water) 2.44-2.30 (6H, m)
1.96-1.83 (2H, m) 1.53-1.15 (14H, m) 1.04 (3H, s) 18 ##STR00040##
538 2-{2-Chloro-5-[(1-methylcyclohexylamido)methyl]phenylamino}-1-
methyl-N-[(2-tetrahydrofuryl)methyl]benzimidazole-5-carboxamide 200
MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 8.41-8.29 (2H, m)
8.15-8.03 (1H, m) 7.90-7.74 (2H, m) 7.69-7.58 (1H, m) 7.45-7.31
(2H, m) 6.99-6.85 (1H, m) 4.25 (2H, d, J = 5.8 Hz) 4.06-3.88 (1H,
m) 3.83- 3.53 (5H, m) 1.99-1.72 (6H, m) 1.68-1.50 (1H, m) 1.45-1.10
(9H, m) 1.04 (3H, s) 19 ##STR00041## 565
2-{2-Chloro-5-[(1-methylcyclohexylamido)methyl]phenylamino}-1-
methyl-N-[(1-methyl-2-piperidinyl)methyl]benzimidazole-5-carboxamide
200 MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 8.41-8.34 (1H, m)
8.31-8.20 (1H, m) 8.15-8.03 (1H, m) 7.90-7.77 (2H, m) 7.67-7.57
(1H, m) 7.46-7.33 (2H, m) 6.99-6.88 (1H, m) 4.25 (2H, d, J = 6.0
Hz) 3.70 (3H, s) 3.64-3.46 (2H, m) 3.38-3.22 (2H, overlapped with
H.sub.2O) 3.03-2.89 (1H, m) 2.50 (3H, s, overlapped with DMSO)
1.98-1.83 (2H, m) 1.78-1.18 (14H, m) 1.04 (3H, s) 20 ##STR00042##
545 2-{2-Chloro-5-[(1-methylcyclohexylamido)methyl]phenylamino}-1-
methyl-N-(2-pyridinylmethyl)benzimidazole-5-carboxamide 200 MHz
.sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 8.96 (1H, t, J = 5.8 Hz)
8.53- 8.46 (1H, m) 8.42-8.32 (1H, m) 8.15-8.02 (1H, m) 7.99-7.88
(1H, m) 7.85-7.64 (3H, m) 7.47-7.19 (4H, m) 6.99-6.86 (1H, m) 4.56
(2H, d, J = 5.4 Hz) 4.25 (2H, d, J = 5.8 Hz) 3.71 (3H, s) 1.98-1.83
(2H, m) 1.43-1.12 (8H, m) 1.04 (3H, s) 21 ##STR00043## 608
N-(4-Bromophenyl)-2-{2-chloro-5-[(1-
methylcyclohexylamido)methyl]phenylamino}-1-
methylbenzimidazole-5-carboxamide 200 MHz .sup.1H-NMR
(DMSO-d.sub.6, ppm) .delta. 10.23 (1H, s) 8.43 (1H, s) 8.10 (1H, t,
J . 6.0 Hz) 8.04-7.98 (1H, m) 7.86-7.70 (4H, m) 7.56- 7.39 (4H, m)
6.96 (1H, dd, J = 8.2, 1.8 Hz) 4.26 (2H, d, J = 6.0 Hz) 3.73 (3H,
s) 1.98-1.85 (2H, m) 1.43-1.13 (8H, m) 1.04 (3H, s) 22 ##STR00044##
536 2-{2-Chloro-5-[(1-methylcyclohexylamido)methyl]phenylamino}-N-
cyclopentyl-N,1-dimethylbenzimidazole-5-carboxamide 200 MHz
.sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 8.35 (1H, s) 8.10 (1H, t, J
= 5.8 Hz) 7.78-7.72 (1H, m) 7.46-7.32 (2H, m) 7.28-7.22 (1H, m)
7.11-7.02 (1H, m) 6.98-6.89 (1H, m) 4.42-4.16 (3H, m) 3.69 (3H, s)
2.81 (3H, s) 1.97-1.84 (2H, m) 1.74-1.55 (7H, m) 1.46-1.12 (11H, m)
1.03 (3H, s) 23 ##STR00045## 610
6-Chloro-2-{2-chloro-5-[(1-methylcyclohexylamido)methyl]
phenylamino}-N,1-dicyclopentylbenzimidazole-5-carboxamide 200 MHz
.sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 8.47 (1H, s) 8.24-8.03 (2H,
m) 7.56-7.20 (4H, m) 7.02-6.89 (1H, m) 5.05-4.82 (1H, m) 4.32- 4.05
(3H, m) 2.09-1.20 (26H, m) 1.03 (3H, s) 24 ##STR00046## 542
6-Chloro-2-{2-chloro-5-[(1-methylcyclohexylamido)
methyl]phenylamino}-N-cyclopentylbenzimidazole-5-carboxamide 200
MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 11.16 (1H, s) 8.98-8.84
(1H, m) 8.59-8.51 (1H, m) 8.27-8.06 (2H, m) 7.50-7.23 (3H, m) 6.91-
6.82 (1H, m) 4.36-4.07 (3H, m) 2.02-1.76 (4H, m) 1.71-1.19 (14H, m)
1.12 (3H, s) 25 ##STR00047## 642
4-Bromo-N-(5-chloro-2-{2-chloro-5-[(1-methylcyclohexylamido)
methyl]phenylamino}-1-methyl-6-benzimidazolyl)benzamide 200 MHz
.sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 10.15 (1H, s) 8.48 (1H, s)
8.14 (1H, t, J = 5.8 Hz) 8.03-7.91 (2H, m) 7.85-7.72 (3H, m) 7.55
(1H, s) 7.49-7.40 (2H, m) 6.98 (1H, dd, J = 8.2, 1.8 Hz) 4.28 (2H,
d, J = 5.8 Hz) 3.70 (3H, s) 2.02-1.84 (2H, m) 1.52-1.10 (8H, m)
1.08 (3H, s) 26 ##STR00048## 572
N-{4-Chloro-3-[5-(N-cyclopentyl-N-methylsulfamoyl)-1-methyl-2-
benzimidazolylamino]benzyl}-1-methylcyclohexylamide 200 MHz
.sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 8.54 (1H, s) 8.14 (1H, t, J
= 5.2) 7.91-7.85 (1H, m) 7.66-7.61 (1H, m) 7.55-7.40 (3H, m) 7.05-
6.95 (1H, m) 4.34-4.12 (3H, m) 3.75 (3H, s) 2.61 (3H, s) 2.02-1.87
(2H, m) 1.54-1.11 (16H, m) 1.08 (3H, s) 27 ##STR00049## 582
2-{2-Chloro-5-[(2-chloro-6-fluorobenzamido)methyl]phenylamino}-
N-cyclohexylmethyl-1-methylbenzimidazole-5-carboxamide 200 MHz
.sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 9.27 (1H, t, J = 5.6 Hz)
8.37- 8.24 (1H, m) 7.94-7.59 (3H, m) 7.55-7.20 (6H, m) 7.18-7.05
(1H, m) 4.46 (2H, d, J = 5.6 Hz) 3.69 (3H, s) 3.08 (2H, t, J = 6.0
Hz) 1.79-1.42 (7H, m) 1.33-1.04 (4H, m) 28 ##STR00050## 524
2-{2-Chloro-5-[(2-tetrahydrofurylamido)methyl]phenylamino}-N-
cyclohexylmethyl-1-methylbenzimidazole-5-carboxamide 200 MHz
.sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 8.42-8.26 (3H, m) 7.93-7.80
(2H, m) 7.65-7.61 (1H, m) 7.44-7.35 (2H, m) 6.97-6.93 (1H, m)
4.35-4.13 (3H, m) 3.92-3.68 (2H, m, overlapped with H.sub.2O) 3.32
(3H, s) 3.12-3.05 (2H, m) 2.17-1.97 (1H, m) 1.89-1.50 (8H, m)
1.27-1.07 (4H, m) 0.98-0.82 (2H, m) 29 ##STR00051## 530
N-(2-{2-Chloro-5-[(cyclopropylsulfonamido)methyl]phenylamino}-1-
methyl-5-benzimidazolyl)cyclohexylacetamide 200 MHz .sup.1H-NMR
(DMSO-d.sub.6, ppm) .delta. 8.39 (1H, s) 8.31-8.23 (1H, m)
7.90-7.85 (1H, m) 7.83-7.76 (1H, m) 7.66-7.57 (1H, m) 7.47- 7.31
(3H, m) 6.99-6.90 (1H, m) 4.10 (2H, d, J = 5.8 Hz) 3.70 (3H, s)
3.13-3.02 (2H, m) 1.76-1.54 (6H, m) 1.28-1.13 (4H, m) 0.99-0.86
(6H, m) 30 ##STR00052## 562
2-{2-chloro-5-[(1-trifluoromethylcyclopropylamido)methyl]phenyl-
amino}-N-cyclohexylmethyl-1-methylbenzimidazole-5-carboxamide 200
MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 8.47-8.34 (2H, m)
8.33-8.24 (1H, m) 7.91-7.82 (2H, m) 7.67-7.58 (1H, m) 7.43 (1H, d,
J = 8.2 Hz) 7.38 (1H, d, J = 8.2 Hz) 6.98-6.87 (1H, m) 4.26 (2H, d,
J = 6.0 Hz) 3.71 (3H, s) 3.14-3.02 (2H, m) 1.77-1.53 (6H, m)
1.38-1.10 (7H, m) 1.00-0.82 (2H, m) 31 ##STR00053## 536
2-{2-Chloro-5-[(1-methylcyclopentylamido)methyl]phenylamino}-N-
cyclohexylmethyl-1-methylbenzimidazole-5-carboxamide 200 MHz
.sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 8.37-8.22 (2H, m) 8.16-8.04
(1H, m) 7.90-7.78 (2H, m) 7.67-7.56 (1H, m) 7.45-7.31 (2H, m)
6.97-6.84 (1H, m) 4.24 (2H, d, J = 5.8 Hz) 3.70 (3H, s) 3.13-3.02
(2H, m) 2.04-1.89 (2H, m) 1.72-1.47 (10H, m) 1.42-1.29 (2H, m)
1.22-1.08 (6H, m) 1.00-0.81 (2H, m) 32 ##STR00054## 468
2-[5-(Acetamidomethyl)-2-chlorophenylamino]-N-cyclohexylmethyl-
1-methylbenzimidazole-5-carboxamide 200 MHz .sup.1H-NMR
(DMSO-d.sub.6, ppm) .delta. 8.46-8.36 (2H, m) 8.34-8.22 (1H, m)
7.91-7.80 (2H, m) 7.67-7.57 (1H, m) 7.47-7.30 (2H, m) 7.03-6.92
(1H, m) 4.22 (2H, d, J = 5.2 Hz) 3.71 (3H, s) 3.14-3.00 (2H, m)
1.86 (3H, s) 1.77-1.51 (6H, m) 1.25-1.07 (3H, m) 1.00-0.80 (2H, m)
33 ##STR00055## 526
tert-Butyl-4-chloro-3-[5-(cyclohexylmethylcarbamoyl)-1-methyl-2-
benzimidazolylamino]benzylcarbamate 200 MHz .sup.1H-NMR
(DMSO-d.sub.6, ppm) .delta. 8.39 (1H, s) 8.31-8.23 (1H, m)
7.90-7.85 (1H, m) 7.83-7.76 (1H, m) 7.66-7.57 (1H, m) 7.47- 7.31
(3H, m) 6.99-6.90 (1H, m) 4.10 (2H, d, J = 5.8 Hz) 3.70 (3H, s)
3.13-3.02 (2H, m) 1.76-1.54 (6H, m) 1.35 (9H, s) 1.24-1.08 (3H, m)
1.02-0.79 (2H, m) 34 ##STR00056## 584 tert-Butyl
3-[5-(4-bromophenylcarbamoyl)-1-methyl-2-
benzimidazolylamino]-4-chlorobenzylcarbamate 200 MHz .sup.1H-NMR
(DMSO-d.sub.6, ppm) .delta. 10.22 (1H, s) 8.48 (1H,
s) 8.08-8.00 (1H, m) 7.86-7.70 (4H, m) 7.54-7.39 (5H, m) 7.03-6.93
(1H, m) 4.11 (2H, d, J = 5.8 Hz) 3.74 (3H, s) 1.36 (9H, s). 35
##STR00057## 630
N-(4-Bromophenyl)-2-{2-chloro-5-[(4,4-difluorocyclohexylamido)-
methyl]phenylamino}-1-methylbenzimidazole-5-carboxamide 200 MHz
.sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 10.25 (1H, s) 8.56-8.40
(2H, m) 8.02 (1H, d, J = 1.0 Hz) 7.90-7.70 (4H, m) 7.59-7.42 (4H,
m) 6.97 (1H, dd, J = 8.2, 1.8 Hz) 4.27 (2H, d, J = 6.0 Hz) 3.76
(3H, s) 2.69-1.50 (9H, m, overlapped with DMSO) 36 ##STR00058## 640
N-(4-Bromophenyl)-2-{2-chloro-5-[(2-chloro-6-
fluorobenzamido)methyl]phenylamino}-1-methylbenzimidazole-5-carboxamide
200 MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 10.25 (1H, s) 9.30
(1H, t, J = 5.8 Hz) 8.55 (1H, s) 8.08-8.02 (1H, m) 7.96-7.90 (1H,
m) 7.85-7.72 (3H, m) 7.56-7.22 (7H, m) 7.18-7.10 (1H, m) 4.48 (2H,
d, J = 5.8 Hz) 3.77 (3H, s) 37 ##STR00059## 620
N-(4-Bromophenyl)-2-{2-chloro-5-[(1-
trifluoromethylcyclopropylamido)methyl]phenylamino}-1-
methylbenzimidazole-5-carboxamide 200 MHz .sup.1H-NMR
(DMSO-d.sub.6, ppm) .delta. 10.23 (1H, s) 8.50-8.36 (2H, m) 8.01
(1H, s) 7.86-7.68 (4H, m) 7.54-7.38 (4H, m) 6.99-6.90 (1H, m) 4.26
(2H, d, J = 5.8 Hz) 3.73 (3H, s) 1.39-1.16 (4H, m) 38 ##STR00060##
577 N-(4-Bromophenyl)-2-{2-chloro-5-[(1-
cyanocyclopropylamido)methyl]phenylamino}-1-
methylbenzimidazole-5-carboxamide 200 MHz .sup.1H-NMR
(DMSO-d.sub.6, ppm) .delta. 10.23 (1H, s) 8.23 (1H, t, J = 5.6 Hz)
8.50 (1H, s) 8.05-7.98 (1H, m) 7.85-7.69 (4H, m) 7.54-7.40 (4H, m)
7.00 (1H, dd, J = 8.2, 1.8 Hz) 4.28 (2H, d, J = 5.6 Hz) 3.74 (3H,
s) 1.60-1.46 (4H, m) 39 ##STR00061## 628
N-(4-Bromophenyl)-2-{2-chloro-5-[(trans-2-
phenylcyclopropylamido)methyl]phenylamino}-1-
methylbenzimidazole-5-carboxamide 200 MHz .sup.1H-NMR
(DMSO-d.sub.6, ppm) .delta. 10.22 (1H, s) 8.73-8.63 (1H, m) 8.50
(1H, s) 8.05-8.00 (1H, m) 7.87-7.68 (4H, m) 7.53-7.41 (4H, m)
7.23-7.00 (6H, m) 4.34-4.22 (2H, m) 3.73 (3H, s) 2.32-2.18 (1H, m)
1.96-1.83 (1H, m) 1.42-1.29 (1H, m) 1.26-1.14 (1H, m) 40
##STR00062## 582 N-(4-Bromophenyl)-2-{2-chloro-5-[(3-methyl-3-
oxetanylamido)methyl]phenylamino}-1-methylbenzimidazole-5-carboxamide
200 MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 10.24 (1H, s)
8.58-8.44 (2H, m) 8.03-7.98 (1H, m) 7.91-7.86 (1H, m) 7.84-7.70
(3H, m) 7.54- 7.40 (4H, m) 7.03-6.93 (1H, m) 4.76 (2H, d, J = 6.0
Hz) 4.32-4.19 (4H, m) 3.74 (3H, s) 1.51 (3H, s) 41 ##STR00063## 594
N-(4-Bromophenyl)-2-{2-chloro-5-[(1-
methylcyclopentylamido)methyl]phenylamino}-1-
methylbenzimidazole-5-carboxamide 200 MHz .sup.1H-NMR
(DMSO-d.sub.6, ppm) .delta. 10.23 (1H, s) 8.42 (1H, s) 8.17-8.07
(1H, m) 8.02-7.98 (1H, m) 7.86-7.69 (4H, m) 7.54-7.39 (4H, m)
6.98-6.89 (1H, m) 4.24 (2H, d, J = 6.0 Hz) 3.73 (3H, s) 2.06-1.87
(2H, m) 1.6-1.27 (6H, m) 1.15 (3H, s) 42 ##STR00064## 605
N-(4-Bromophenyl)-2-{2-chloro-5-[(1-
cyanocyclopentylamido)methyl]phenylamino}-1-
methylbenzimidazole-5-carboxamide 200 MHz .sup.1H-NMR
(DMSO-d.sub.6, ppm) .delta. 10.23 (1H, s) 8.93 (1H, t, J = 6.0 Hz)
8.45 (1H, s) 8.03-7.97 (1H, m) 7.88-7.70 (4H, m) 7.55-7.40 (4H, m)
7.01-6.93 (1H, m) 4.30 (2H, d, J = 6.0 Hz) 3.74 (3H, s) 2.20-2.10
(4H, m) 1.74-1.63 (4H, m) 43 ##STR00065## 526
2-[5-(Acetamidomethyl)-2-chlorophenylamino]-N-(4-bromophenyl)-
1-methylbenzimidazole-5-carboxamide 200 MHz .sup.1H-NMR
(DMSO-d.sub.6, ppm) .delta. 10.22 (1H, s) 8.50 (1H, s) 8.41 (1H, t,
J = 6.0 Hz) 8.04-7.99 (1H, m) 7.85-7.69 (4H, m) 7.53- 7.40 (4H, m)
7.03-6.95 (1H, m) 4.23 (2H, d, J = 6.0 Hz) 3.74 (3H, s) 1.85 (3H,
s) 44 ##STR00066## 630 N-(4-Bromophenyl)-2-{2-chloro-5-[(2-
thienylsulfonamido)methyl]phenylamino}-1-methylbenzimidazole-5-carboxamid-
e 200 MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 10.25 (1H, s)
8.54 (1H, s) 8.45 (1H, t, J = 6.4 Hz) 8.08-8.03 (1H, m) 7.96-7.70
(5H, m) 7.63 (1H, dd, J = 3.7, 1.1 Hz) 7.59-7.41 (4H, m) 7.17 (1H,
dd, J = 5.1, 3.7 Hz) 7.04 (1H, dd, J = 8.2, 1.8 Hz) 4.06 (2H, d, J
= 6.4 Hz) 3.76 (3H, s) 45 ##STR00067## 588
N-(4-Bromophenyl)-2-{2-chloro-5-
[(cyclopropylsulfonamido)methyl]phenylamino}-1-
methylbenzimidazole-5-carboxamide 200 MHz .sup.1H-NMR
(DMSO-d.sub.6, ppm) .delta. 10.25 (1H, s) 8.55 (1H, s) 8.05-7.98
(1H, m) 7.97-7.93 (1H, m) 7.85-7.71 (4H, m) 7.57-7.45 (4H, m)
7.20-7.08 (1H, m) 4.20 (2H, d, J = 5.8 Hz) 3.77 (3H, s) 0.94-0.86
(4H, m) 46 ##STR00068## 608 N-(4-Bromophenyl)-2-{2-chloro-5-[(1-
ethylcyclopentylamido)methyl]phenylamino}-1-
methylbenzimidazole-5-carboxamide 200 MHz .sup.1H-NMR
(DMSO-d.sub.6, ppm) .delta. 10.23 (1H, s) 8.43 (1H, s) 8.17-8.07
(1H, m) 8.04-7.98 (1H, m) 7.86-7.70 (4H, m) 7.55-7.38 (4H, m)
7.00-6.91 (1H, m) 4.25 (2H, d, J = 5.6 Hz) 3.73 (3H, s) 2.08-1.92
(2H, m) 1.61-1.30 (8H, m) 0.74-0.60 (3H, m) 47 ##STR00069## 626
N-(4-Bromophenyl)-2-{2-chloro-5-[(1-methylthiocyclopentylamido)-
methyl]phenylamino}-1-methylbenzimidazole-5-carboxamide 200 MHz
.sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 10.22 (1H, s) 8.48-8.32
(2H, m) 8.04-7.97 (1H, m) 7.86-7.70 (4H, m) 7.54-7.38 (4H, m) 7.04-
6.94 (1H, m) 4.27 (2H, d, J = 5.6 Hz) 3.73 (3H, s) 2.17-2.05 (2H,
m) 1.88 (3H, s) 1.77-1.54 (6H, m) 48 ##STR00070## 634
N-(4-Bromophenyl)-2-{2-chloro-5-[(1-
cyclopropylmethylcyclopentylamido)methyl]phenylamino}-1-
methylbenzimidazole-5-carboxamide 200 MHz .sup.1H-NMR
(DMSO-d.sub.6, ppm) .delta. 10.22 (1H, s) 8.43 (1H, s) 8.15-8.05
(1H, m) 8.03-7.97 (1H, m) 7.87-7.70 (4H, m) 7.54-7.39 (4H, m)
7.02-6.92 (1H, m) 4.25 (2H, d, J = 5.6 Hz) 3.73 (3H, s) 2.09-1.94
(2H, m) 1.55-1.38 (8H, m) 0.58-0.39 (1H, m) 0.30-0.18 (2H, m)
-0.04-[-0.16] (2H, m) 49 ##STR00071## 596
N-(4-Bromophenyl)-2-{2-chloro-5-[(2-methyl-2-
tetrahydrofurylamido)methyl]phenylamino}-1-methylbenzimidazole-5-carboxam-
ide 200 MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 10.18 (1H, s)
8.38 (1H, s) 8.37-8.33 (1H, m) 7.98-7.95 (1H, m) 7.78-7.68 (4H, m)
7.48-7.44 (2H, m) 7.42 (1H, d, J = 8.2 Hz) 7.39 (1H, d, J = 8.2 Hz)
6.91 (1H, dd, J = 8.2 Hz, 1.8 Hz) 4.26-4.14 (2H, m) 3.81-3.75 (2H,
m) 3.69 (3H, s) 2.13-2.04 (1H, m) 1.78-1.59 (3H, m) 1.25 (3H, s) 50
##STR00072## 581 2-(5-{[1-(Aminomethyl)cyclopropylamido]methyl}-2-
chlorophenylamino)-N-(4-bromophenyl)-1-methylbenzimidazole-5-carboxamide
200 MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 10.19 (1H, s) 8.40
(1H, s) 8.19-8.13 (1H, m) 7.99-7.95 (1H, m) 7.86-7.82 (1H, m)
7.78-7.69 (3H, m) 7.49-7.36 (5H, m) 6.96-6.90 (1H, m) 4.22 (2H, d,
J = 5.8 Hz) 3.71 (3H, s) 2.89 (2H, s) 1.25-1.17 (2H, m) 0.94-0.88
(2H, m) 51 ##STR00073## 644
N-(4-Bromophenyl)-2-{2-chloro-5-[(4,4-difluoro-1-
methylcyclohexylamido)methyl]phenylamino}-1-
methylbenzimidazole-5-carboxamide 52 ##STR00074## 566
N-(2-tert-Butoxyethyl)-2-{2-chloro-5-[(1-trifluoromethylcyclopropyl-
amido)methyl]phenylamino}-1-methylbenzimidazole-5-carboxamide 400
MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. (signals of minor
tautomer are not assigned) 8.48-8.26 (3H, m) 7.92-7.85 (1H, m)
7.85-7.78 (1H, m) 7.68-7.61 (1H, m) 7.44 (1H, d, J = 8.2 Hz) 7.40
(1H, d, J = 8.4 Hz) 7.00-6.91 (1H, m) 4.28 (2H, d, J = 5.8 Hz) 3.72
(3H, s) 3.46-3.39 (2H, m) 3.37-3.30 (2H, m, overlapped with water)
1.40-1.20 (4H, m) 1.13 (9H, s) 53 ##STR00075## 578
2-{2-Chloro-5-[(1-trifluoromethylcyclopropylamido)methyl]phenylamino}-
1-methyl-N-(4,4,4-trifluorobutyl)benzimidazole-5-carboxamide 400
MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. (signals of minor
tautomer are not assigned) 8.46-8.36 (3H, m) 7.90 (1H, d, J = 1.7
Hz) 7.84 (1H, d, J = 2.1 Hz) 7.65 (1H, dd, J = 8.3, 1.7 Hz) 7.45
(1H, d, J = 8.3 Hz) 7.41 (1H, d, J = 8.3 Hz) 6.95 (1H, dd, J = 8.3,
2.1 Hz) 4.28 (2H, d, J = 5.8 Hz) 3.73 (3H, s) 3.38-3.29 (2H, m,
overlapped with water) 2.40-2.24 (2H, m) 1.81-1.70 (2H, m)
1.40-1.13 (4H, m) 54 ##STR00076## 586
2-{2-chloro-5-[(1-trifluoromethylcyclopropylamido)methyl]phenylamino}-
N-(4,4-difluorocyclohexyl)-1-methylbenzimidazole-5-carboxamide 400
MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. (signals of minor
tautomer are not assigned) 8.42 (1H, t, J = 5.9 Hz) 8.38 (1H, s)
8.16 (1H, d, J = 7.8 Hz) 7.93 (1H, d, J = 1.3 Hz) 7.87 (1H, d, J =
2.1 Hz) 7.66 (1H, dd, J = 8.3, 1.3 Hz) 7.45 (1H, d, J = 8.4 Hz)
7.40 (1H, d, J = 8.3 Hz) 6.95 (1H, dd, J = 8.3, 2.1 Hz) 4.28 (2H,
d, J = 5.9 Hz) 4.05- 3.91 (1H, m) 3.73 (3H, s) 2.15-1.80 (6H, m)
1.73-1.59 (2H, m) 1.39-1.12 (4H, m) 55 ##STR00077## 579
2-{2-chloro-5-[(1-trifluoromethylcyclopropylamido)methyl]phenylamino}-
1-methyl-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]benzimidazole-5-carboxamide
400 MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. (signals of minor
tautomer are not assigned) 8.46-8.30 (3H, m) 7.90-7.85 (1H, m)
7.85-7.80 (1H, m) 7.66-7.58 (1H, m) 7.44 (1H, d, J = 8.0 Hz) 7.41
(1H, d, J = 8.2 Hz) 6.99-6.91 (1H, m) 4.28 (2H, d, J = 5.8 Hz) 3.73
(3H, s) 2.98-2.87 (1H, m) 2.55-2.35 (2H, m, overlapped with DMSO)
2.21 (3H, s) 2.10-1.81 (4H, m) 1.68-1.55 (2H, m) 1.50-1.11 (6H, m)
56 ##STR00078## 524
N-{4-Chloro-3-[6-chloro-5-(3,3-difluoro-pyrrolidin-1-ylcarbonyl)-2-
benzimidazolylamino]benzyl}-pivaloylamide HPLC-Method B: R.sub.t =
2.56 min 57 ##STR00079## 568 N-(4-Bromophenyl)-2-{2-chloro-5-
[(tert.butylcarbonylamino)methyl]phenylamino}-1-
methylbenzimidazole-5-carboxamide 58 ##STR00080## 606
N-(4-Bromophenyl)-2-{2-chloro-5-[((1-trifluoromethyl-
cyclopropanecarbonyl)amino)-methyl]phenylarnino}-
benzimidazole-5-carboxamide
Example 59
N-(4-Bromo-phenyl)-2-(2-chloro-5-{[(1-trifluoromethyl-cyclopropanecarbonyl-
)-amino]-methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimid-
azole-5-carboxylic Acid Amide
##STR00081##
[0486] (aa) (4-Chloro-3-nitrophenyl)methylamine Hydrochloride
[0487] BH.sub.3/THF (279 mL; 279 mmol) was added to a solution of
4-chloro-3-nitrobenzonitrile (30 g; 164 mmol) in THF (100 mL) over
30 min at 0.degree. C. and the resulting mixture was stirred over
night and allowed to reach rt. MeOH (150 mL) and conc. HCl (60 mL)
was added and the resulting mixture was refluxed for 4 h and
thereafter concentrated. The residue was treated with water (500
mL) and the resulting precipitate was filtered off. The filtrate
was treated with NaCl (120 g) and heated and the resulting
precipitate was filtered off to give the sub-title compound. Yield:
24.059 g (65%).
(a)
N-(4-Chloro-3-nitrobenzyl)-1-(trifluoromethyl)cyclopropanecarboxamide
[0488] TEA (21.7 mL; 156 mmol) was added to a mixture of
1-(trifluoromethyl)-cyclopropanecarboxylic acid (8.00 g; 51.9 mmol)
and TBTU (16.7 g; 52 mmol) in DMF (40 mL). After 1 h at rt, a
solution of (4-chloro-3-nitrophenyl)methylamine hydrochloride (11.6
g; 52 mmol) in DMF (70 mL) was added dropwise over 30 min. After 17
h at rt, the mixture was concentrated and the residue partitioned
between water and MTBE. The organic layer was washed with water,
dried over Na.sub.2SO.sub.4 and concentrated. The residue was
purified by column chromatography to give the sub-title compound.
Yield: 13.191 g (78%).
(b)
N-(3-Amino-4-chlorobenzyl)-1-(trifluoromethyl)cyclopropanecarboxamide
[0489] The sub-title compound was prepared from
N-(4-chloro-3-nitrobenzyl)-1-(trifluoromethyl)cyclopropanecarboxamide
in accordance with Example 2, step (b). Yield: 11.586 g (98%).
(c)
N-(4-Chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane
Carboxamide
[0490] A solution of
N-(3-amino-4-chlorobenzyl)-1-(trifluoromethyl)cyclopropane
carboxamide (5.21 g; 17.79 mmol) in DCM (40 mL) was added to a
solution of TCDI (3.80 g; 21.34 mmol) in DCM (30 mL) at 0.degree.
C. After 12 h at rt, the mixture was concentrated and the residue
was purified by column chromatography to give the sub-title
compound. Yield: 5.00 g (84%).
(d) Ethyl 2,4-difluoro-5-nitrobenzoate
[0491] Conc. HNO.sub.3 (8 mL) was added dropwise to a mixture of
ethyl 2,4-difluorobenzoate (10.0 g; 53.7 mmol) in conc.
H.sub.2SO.sub.4 (8 mL) at 0.degree. C. After 2 h at 0.degree. C.,
the mixture was poured onto ice and extracted with EtOAc. The
organic extracts were washed with saturated NaHCO.sub.3 solution
(aq) and concentrated to give the sub-title compound. Yield: 11.8 g
(95%).
(e) Ethyl 2-fluoro-4-(methylamino)-5-nitrobenzoate
[0492] A solution of MeNH.sub.2 in THF (21.6 mL; 2 M; 43.3 mmol)
was added dropwise to a solution of ethyl
2,4-difluoro-5-nitrobenzoate (5.0 g; 21.6 mmol) in THF (70 mL) at
-5.degree. C. The mixture was left over night at rt whereafter an
additional portion of MeNH.sub.2 in THF (10.0 mL; 2 M; 21.6 mmol)
was added at 0.degree. C. After 3 h at rt, water is was added and
the mixture was concentrated. The resulting precipitate was
filtered off and dried to give the sub-title compound. Yield: 5.0 g
(96%).
(f) Ethyl
2-(2,2-difluoroethoxy)-4-(methylamino)-5-nitrobenzoate
[0493] A solution of 2,2-difluoroethanol (1.7 g; 20.6 mmol) in THF
(50 mL) was added to a solution of ethyl
2-fluoro-4-(methylamino)-5-nitrobenzoate (5.0 g; 20.6 mmol) in DMF
(100 mL). Sodium hydride (0.824 g; 60%; 20.6 mmol) was added in
portions and the mixture was stirred over night at rt. A solution
of TFA (30 mL; 0.45 M aq) was added and the mixture was
concentrated. The resulting precipitation was filtered off, washed
with water, dried and recrystallized from EtOH/water to give the
sub-title compound. Yield: 4.8 g (76%).
(g) Ethyl
5-amino-2-(2,2-difluoroethoxy)-4-(methylamino)benzoate
[0494] A mixture of ethyl
2-(2,2-difluoroethoxy)-4-(methylamino)-5-nitrobenzoate (2.0 g; 6.57
mmol), Ra--Ni (1.0 g) and THF (100 mL) was stirred under
H.sub.2-atmosphere (8 atm) over night at rt. Na.sub.2SO.sub.4 was
added and the mixture was stirred another 30 min under
H.sub.2-atmosphere. The mixture was filtered through celite and the
sub-title compound was used in the next step without further
purification.
(h) Ethyl
2-(2-chloro-5-{[(1-trifluoromethyl-cyclopropanecarbonyl)-amino]--
methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-c-
arboxylate
[0495] A mixture of ethyl
5-amino-2-(2,2-difluoroethoxy)-4-(methylamino)benzoate (0.737 g;
2.68 mmol; crude material from step (g)) and
N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane
carboxamide (0.900 g; 2.68 mmol) in THF (100 mL) was stirred over
night at rt. DIC (0.338 g; 2.68 mmol) was added and the mixture was
stirred for 6 h at rt. Another portion of DIC (0.169 g; 1.34 mmol)
was added and the mixture stirred for another 6 h at rt. The
mixture was concentrated and purified by column chromatography to
give the sub-title compound. Yield: 0.790 g (51%).
(i)
N-(4-Bromo-phenyl)-2-(2-chloro-5-{[(1-trifluoromethyl-cyclopropanecarb-
onyl)-amino]-methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benz-
imidazole-5-carboxylic Acid Amide
[0496] Me.sub.3Al in toluene (0.870 mL; 2 M; 1.74 mmol) was added
to a solution of 4-bromoaniline (0.180 g; 1.05 mmol) in 1,4-dioxane
(5 mL) and the mixture was stirred for 20 min at rt. The mixture
was then added via cannula to a warm (60.degree. C.) solution of
ethyl
2-(2-chloro-5-{[(1-trifluoromethyl-cyclopropanecarbonyl)-amino]-methyl}-p-
henylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylat-
e (0.200 g; 0.35 mmol) in 1,4-dioxane (5 mL). The resulting mixture
was stirred at 100.degree. C. over night, cooled to rt and then
poured into brine (20 mL) and extracted with EtOAc. The combined
extracts were washed with brine, dried over Na.sub.2SO.sub.4 and
concentrated. The residue was purified by column chromatography to
give the title compound. Yield: 0.134 g (55%). 400 MHz .sup.1H-NMR
(DMSO-d.sub.6, ppm) .delta. 12.3-11.1 (1H, br s) 10.16 (1H, s) 8.45
(1H, t, J=5.9 Hz) 7.69-7.57 (5H, m) 7.53-7.47 (2H, m) 7.45 (1H, d,
J=2.0 Hz) 7.34 (1H, dd, J=8.2, 2.0 Hz) 6.48 (1H, tt, J=54.4, 3.3
Hz) 4.53 (2H, td, J=14.5, 3.3 Hz) 4.30 (2H, d, J=5.6 Hz) 3.81 (3H,
s) 1.33-1.26 (2H, m) 1.25-1.19 (2H, m). MS m/z: 700, 702, 704
[M+H].sup.+.
[0497] The following compounds were synthesized in analogy to the
methods of preparation described above in detail.
TABLE-US-00006 Chemical structure Name Ex. .sup.1H-NMR MS m/z [M +
H].sup.+ 60 ##STR00082## 600, 602
N-(Cycloproylmethyl)-2-(2-chloro-5-{[(1-trifluoromethyl-
cyclopropanecarbonyl)-amino]-methyl}-phenylamino)-6-(2,2-
difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid amide
400 MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 11.7-11.2 (1H, br
s) 8.42 (1H, t, J = 5.9 Hz) 8.10 (1H, t, J = 5.3 Hz) 7.68-7.64 (2H,
m) 7.57- 7.55 (1H, m) 7.44 (1H, d, J = 2.0 Hz) 7.34 (1H, dd, J =
8.3, 2.0 Hz) 6.51 (1H, tt, J = 54.4, 3.2 Hz) 4.52 (2H, td, J =
14.5, 3.5 Hz) 4.30 (2H, d, J = 5.9 Hz) 3.80 (3H, s) 3.13 (2H, t, J
= 6.2 Hz) 1.34-1.26 (2H, m) 1.25-1.18 (2H, m) 1.01-0.92 (1H, m)
0.45-0.38 (2H, m) 0.22-0.16 (2H, m) 61 ##STR00083## 656, 658
N-(4,4,4-Trifluorobutyl)-2-(2-chloro-5-{[(1-trifluoromethyl-
cyclopropanecarbonyl)-amino]-methyl}-phenylamino)-6-(2,2-
difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid amide
400 MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 11.2-10.9 (1H, br
s) 8.51 (1H, t, J = 5.8 Hz) 8.22 (1H, t, J = 5.8 Hz) 7.74 (1H, d, J
= 8.2 Hz) 7.67-7.63 (2H, m) 7.52 (1H, d, J = 1.8 Hz) 7.43 (1H, dd,
J = 8.2, 2.0 Hz) 6.55 (1H, tt, J = 54.7, 3.4 Hz) 4.58 (2H, td, J =
14.6, 3.1 Hz) 4.39 (2H, d, J = 5.8 Hz) 3.89 (3H, s) 3.45-3.37 (2H,
m) 2.40-2.27 (2H, m) 1.84-1.75 (2H, m) 1.42-1.36 (2H, m) 1.32-1.26
(2H, m) 62 ##STR00084## 664, 666
N-(4,4-Difluorocyclohexyl)-2-(2-chloro-5-{[(1-trifluoromethyl-
cyclopropanecarbonyl)-amino]-methyl}-phenylamino)-6-(2,2-
difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid amide
400 MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 9.34-8.29 (2H, m)
7.99-7.95 (1H, m) 7.67-7.62 (3H, m) 7.45-7.42 (1H, m) 7.34 (1H, dd,
J = 8.3, 1.7 Hz) 6.62-6.30 (1H, m) 4.54-4.43 (2H, m) 4.30 (2H, d, J
= 5.9 Hz) 4.04-3.90 (1H, m) 3.79 (3H, s) 2.06-1.68 (5H, m)
1.60-1.46 (1H, m) 1.34-1.15 (6H, m)
Example 63
N-(4-Bromo-phenyl)-2-(2-chloro-5-{[(1-trifluoromethyl-cyclopropanecarbonyl-
)-amino]-methyl}-phenylamino)-6-methoxy-1-methyl-1H-benzimidazole-5-carbox-
ylic Acid Amide
##STR00085##
[0498] (aa) Methyl
2-methoxy-4-(N-methylacetamido)-5-nitrobenzoate
[0499] A mixture of methyl 4-acetamido-2-methoxy-5-nitrobenzoate
(2.0 g; 7.5 mmol), methyl methanesulfonate (0.85 g; 7.7 mmol) and
K.sub.2CO.sub.3 (2.0 g; 14.5 mmol) in DMF (20 mL) was stirred for
36 h at rt. The mixture was thereafter poured into brine and
extracted with EtOAc. The combined extracts were washed with brine,
dried over Na.sub.2SO.sub.4, filtered and concentrated to give the
crude sub-title compound.
(ab) 2-Methoxy-4-(methylamino)-5-nitrobenzoic Acid
[0500] A mixture of methyl
2-methoxy-4-(N-methylacetamido)-5-nitrobenzoate (2.1 g; 0.74 mmol),
aqueous NaOH (29 mL; 1 M; 29 mmol) and EtOH (30 mL) was refluxed
for 2 h. The mixture was thereafter concentrated and the remaining
is aqueous phase was acidified to strongly acidic pH with acetic
acid, sonicated and filtered to give the sub-title compound. Yield:
1.28 g (76%).
(ac) 5-Amino-2-methoxy-4-(methylamino)benzoic Acid
[0501] A mixture of 2-methoxy-4-(methylamino)-5-nitrobenzoic acid
(7.0 g; 31 mmol), Pd/C (1.0 g), MeOH (25 mL) and THF (75 mL) was
stirred under H.sub.2 atmosphere (8 atm) for 24 h at 50.degree. C.
A second portion of Pd/C (1.0 g) was added and the mixture
hydrogenated for additional 24 h. A third portion of Pd/C (0.5 g)
was added and the mixture hydrogenated over night. The suspension
was concentrated and the residue stored under argon and was used in
the next step without further purification.
(a)
2-(2-chloro-5-{[(1-trifluoromethyl-cyclopropanecarbonyl)-amino]-methyl-
}-phenylamino)-6-methoxy-1-methyl-1H-benzimidazole-5-carboxylic
Acid
[0502] A mixture of
N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane
carboxamide (1.71 g; 5.10 mmol) and
5-amino-2-methoxy-4-(methylamino)benzoic acid (1.00 g; 1.00 mmol)
in DMF (20 mL) was stirred over night at rt. The mixture was
thereafter heated to 60.degree. C. and BSTFA (1.44 g; 5.61 mmol)
was added and stirred for 1 h before the addition of DIC (0.772 g;
6.12 mmol). The resulting mixture was stirred at 80.degree. C. for
3 h. Acetic acid (2 mL) was added and the mixture was concentrated
and the residue poured in aqueous NaOH (2 M) and pH adjusted to
.about.3-4. The mixture was extracted with EtOAc and the organic
extracts were washed with brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated. The residue was recrystallized from
EtOAc/petroleum ether to give the sub-title compound. Yield: 0.570
g (22%).
(b)
N-(4-Bromo-phenyl)-2-(2-chloro-5-{[(1-trifluoromethyl-cyclopropanecarb-
onyl)-amino]-methyl}-phenylamino)-6-methoxy-1-methyl-1H-benzimidazole-5-ca-
rboxylic Acid Amide
[0503] The title compound was prepared from
2-(2-chloro-5-{[(1-trifluoromethyl-cyclopropanecarbonyl)-amino]-methyl}-p-
henylamino)-6-methoxy-1-methyl-1H-benzimidazole-5-carboxylic acid
(92 mg; 0.19 mmol) and 4-bromoaniline (33 mg; 0.19 mmol) in
accordance with Example 59, step (a). Yield: 73 mg (59%). 400 MHz
.sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 10.16 (1H, s) 8.40 (1H, t,
J=6.0 Hz) 8.25 (1H, s) 7.85-7.81 (1H, m) 7.76-7.68 (3H, m)
7.51-7.46 (2H, m) 7.40 (1H, d, J=8.2 Hz) 7.22-7.17 (1H, m)
6.92-6.86 (1H, m) 4.25 (2H, d, J=6.0 Hz) 3.97 (3H, s) 3.71 (3H, s)
1.37-1.32 (2H, m) 1.23-1.18 (2H, m). MS m/z: 650, 652, 654
[M+H].sup.+.
[0504] The following compounds were synthesized in analogy to the
methods of preparation described above in detail.
TABLE-US-00007 Chemical structure Name Ex. .sup.1H-NMR MS m/z [M +
H].sup.+ 64 ##STR00086## 550, 552
N-(cyclopropylmethyl)-2-(2-chloro-5-{[(1-trifluoromethyl-
cyclopropanecarbonyl)-amino]-methyl}-phenylamino)-6-methoxy-
1-methyl-1H-benzimidazole-5-carboxylic acid amide 400 MHz
.sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 8.41 (1H, t, J = 5.8 Hz)
8.25- 8.17 (2H, m) 7.89-7.82 (2H, m) 7.40 (1H, d, J = 8.2 Hz)
7.17-7.14 (1H, m) 6.92-6.86 (1H, m) 4.26 (2H, d, J = 5.8 Hz) 3.95
(3H, s) 3.70 (3H, s) 3.21-3.14 (2H, m) 1.39-1.33 (2H, m) 1.24-1.18
(2H, m) 1.06-0.99 (1H, m) 0.46-0.38 (2H, m) 0.26-0.19 (2H, m) 65
##STR00087## 496, 498
2-(2-chloro-5-{[(1-trifluoromethyl-cyclopropanecarbonyl)-amino]-
methyl}-phenylamino)-6-methoxy-1-methyl-1H-benzimidazole-5-
carboxylic acid amide 400 MHz .sup.1H-NMR (DMSO-d.sub.6, ppm)
.delta. 8.39 (1H, t, J = 5.8 Hz) 8.28- 8.18 (1H, m) 7.88 (1H, s)
7.82-7.77 (1H, m) 7.66-7.56 (1H, m) 7.39 (1H, d, J = 8.2 Hz)
7.35-7.29 (1H, m) 7.13 (1H, s) 6.88 (1H, dd, J = 8.2, 1.8 Hz) 4.24
(2H, d, J = 5.8 Hz) 3.93 (3H, s) 3.68 (3H, s) 1.37-1.31 (2H, m)
1.22-1.18 (2H, m)
Example 66
N-(4-Bromo-bhenyl)-2-(2-fluoro-5-{[(1-trifluoromethyl-cyclopropanecarbonyl-
)-amino]-methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimid-
azole-5-carboxylic Acid Amide
##STR00088##
[0505] (a) (4-Fluoro-3-nitrophenylmethylamine Hydrochloride
[0506] BH.sub.3/THF (120 mL; 120 mmol) was added to a solution of
4-fluoro-3-nitrobenzonitrile (10 g; 60 mmol) in THF (50 mL) over 30
min at 0.degree. C. and the resulting mixture was stirred at
0.degree. C. for 1 h and at rt for 3 h. The mixture was acidified
to pH .about.1, stirred for 1 h at rt, basicified to pH .about.7-8
and extracted with EtOAc. The organic extracts were dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
dissolved in Et.sub.2O and treated with a solution of HCl in
1,4-dioxane to give the sub-title compound. Yield: 8.7 g (70%).
(b)
N-(4-Fluoro-3-nitro-benzyl)-1-(trifluoromethyl)cyclopropanecarboxamide
[0507] The sub-title compound was prepared in accordance with the
procedure in Example 72, step (c) using
(4-fluoro-3-nitrophenyl)methylamine hydrochloride (3.0 g; 14.5
mmol), 1-(trifluoromethyl)-cyclopropanecarboxylic acid (2.5 g; 16.0
mmol), HBTU (6.07 g; 16.0 mmol), TEA (5.88 g; 58.1 mmol) and DMF
(50 mL). Yield: 3.8 g (85%).
(c)
N-(3-Amino-4-fluorobenzyl)-1-(trifluoromethyl)cyclopropanecarboxamide
[0508] The sub-title compound was prepared in accordance with the
procedure in Example 2, step (b) using
N-(4-fluoro-3-nitrobenzyl)-1-(trifluoromethyl)-cyclopropanecarboxamide
(3.77 g; 12.3 mmol), Fe (3.45 g; 61.6 mmol), (aq, sat, 30 mL) and
EtOH (30 mL). Yield: 3.2 g (76%).
(d)
N-(4-Fluoro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane
carboxamide
[0509] A mixture of
N-(3-amino-4-fluorobenzyl)-1-(trifluoromethyl)cyclopropanecarboxamide
(3.17 g; 11.5 mmol) and TCDI (3.07 g; 17.2 mmol) in DCM (50 mL) was
heated over night at 50.degree. C. The mixture was concentrated and
the residue purified by column chromatography to give the sub-title
compound. Yield: 3 g (82%).
(e) 2-(2,2-Difluoroethoxy)-4-(methylamino)-5-nitrobenzoic Acid
[0510] The sub-title compound was prepared in accordance with
Example 72, step (b) using ethyl
2-(2,2-difluoroethoxy)-4-(methylamino)-5-nitrobenzoate ((950 mg;
3.12 mmol) see Example 59, step (f)), NaOH (3.1 mL; 2 M aq; 6.2
mmol) and 1,4-dioxane (10 mL). Yield: 800 mg (93%).
(f)
N-(4-Bromophenyl)-2-(2,2-difluoroethoxy)-4-(methylamino)-5-nitrobenzam-
ide
[0511] The sub-title compound was prepared in accordance with
Example 72, step (c) using
2-(2,2-difluoroethoxy)-4-(methylamino)-5-nitrobenzoic acid (800 mg;
2.90 mmol), 4-bromoaniline (499 mg; 2.90 mmol), HBTU (1.10 g; 2.90
mmol), TEA (587 mg; 5.80 mmol) and DMF (15 mL). Yield: 1.01 g
(81%).
(g)
5-Amino-N-(4-bromophenyl)-2-(2,2-difluoroethoxy)-4-(methylamino)benzam-
ide
[0512] The sub-title compound was prepared by hydrogenation
according to procedure 3d using
N-(4-bromophenyl)-2-(2,2-difluoroethoxy)-4-(methylamino)-5-nitrobenzamide
(1.01 g; 2.34 mmol), Ra--Ni (14 mg), H.sub.2 (8 atm) and THF (50
mL). Yield: 905 mg (97%).
(h)
N-(4-Bromo-phenyl)-2-(2-fluoro-5-{[(1-trifluoromethyl-cyclopropanecarb-
onyl)-amino]-methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benz-
imidazole-5-carboxylic Acid Amide
[0513] The title compound was prepared in accordance with the
procedure in Example 72, step (a) using
N-(4-fluoro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane
carboxamide (160 mg; 0.50 mmol),
5-amino-N-(4-bromophenyl)-2-(2,2-difluoroethoxy)-4-(methylamino)benzamide
(200 mg; 0.50 mmol), DIC (63 mg; 0.50 mmol) and DMF (4 mL). Yield:
25 mg (7%). 400 MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 10.06
(1H, s) 8.61 (1H, s) 8.39 (1H, t, J=5.8 Hz) 7.87-7.81 (1H, m)
7.73-7.65 (3H, m) 7.52-7.48 (2H, m) 7.29-7.26 (1H, m) 7.21-7.14
(1H, m) 6.91-6.86 (1H, m) 6.65-6.36 (1H, m) 4.55-4.46 (2H, m) 4.24
(2H, d, J=5.8 Hz) 3.71 (3H, s) 1.39-1.32 (2H, m) 1.23-1.20 (2H, m).
MS m/z: 684, 686 [M+H].sup.+.
Example 67
N-(4-Bromo-phenyl)-2-(2-chloro-5-{[(1-trifluoromethyl-cyclopropanecarbonyl-
)-amino]-methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1H-benzimidazole-5-c-
arboxylic Acid Amide
##STR00089##
[0514] (a) Ethyl 4-amino-2-fluoro-5-nitrobenzoate
[0515] A mixture of ethyl 2,4-difluoro-5-nitrobenzoate (5.00 g;
21.6 mmol) (see Example 59 (d)) in THF (100 mL) was treated with
NH.sub.3 in THF (2.7 mL; 8 M; 21.6 mmol) at 0.degree. C. and the
mixture was stirred over night. Another portion of NH.sub.3 in THF
(1.0 mL; 8M; 8 mmol) was added and the mixture stirred over night.
Water (100 mL) was added and the mixture was concentrated. The
precipitate was filtered off and dried to give the sub-title
compound. Yield: 4.80 g (98%).
(b) Ethyl 4-amino-2-(2,2-difluoroethoxy)-5-nitrobenzoate
[0516] The sub-title compound was prepared in accordance with
Example 59 (f) using ethyl 4-amino-2-fluoro-5-nitrobenzoate (4.80
g; 21.0 mmol), 2,2-difluoroethanol (1.73 g; 21.0 mmol), sodium
hydride (0.841 g; 60%; 21.0 mmol), THF (100 mL) and DMF (50 mL).
Yield: 2.40 g (39%).
(c) Ethyl 4,5-diamino-2-(2,2-difluoroethoxy)benzoate
[0517] The sub-title compound was prepared in accordance with
Example 59 (g) using ethyl
4-amino-2-(2,2-difluoroethoxy)-5-nitrobenzoate (1.00 g; 3.44 mmol),
Ra--Ni (1.0 g) and THF (50 mL). The sub-title compound was used in
the next step without further purification.
(d) Ethyl
2-(2-chloro-5-{[(1-trifluoromethyl-cyclopropanecarbonyl)-amino]--
methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1H-benzimidazole-5-carboxylat-
e
[0518] The sub-title compound was prepared in accordance with
Example 59 (h) using ethyl
4,5-diamino-2-(2,2-difluoroethoxy)benzoate (0.466 g; 1.79 mmol;
crude material from step (c)),
N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane
carboxamide (0.600 g; 1.79 mmol), DIC (0.226 g; 1.79 mmol) and THF
(40 mL). Yield: 0.620 g (62%).
(e)
N-(4-Bromo-phenyl)-2-(2-chloro-5-{[(1-trifluoromethyl-cyclopropanecarb-
onyl)-amino]-methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1H-benzimidazole-
-5-carboxylic Acid Amide
[0519] The title compound was prepared in accordance with Example
59 (i) using ethyl
2-(2-chloro-5-{[(1-trifluoromethyl-cyclopropanecarbonyl)-amino]-methyl}-p-
henylamino)-6-(2,2-difluoro-ethoxy)-1H-benzimidazole-5-carboxylate
(0.200 g; 0.36 mmol), 4-bromoaniline (0.184 g; 1.07 mmol),
Me.sub.3Al in toluene (0.900 mL; 2 M; 1.80 mmol) and 1,4-dioxane
(10 mL). Yield: 0.115 g (47%). 400 MHz .sup.1H-NMR (DMSO-d.sub.6,
ppm) .delta. 11.3-11.1 (1H, br s) 10.17 (1H, s) 9.1-8.8 (1H, br s)
8.65-8.57 (1H, m) 8.53 (1H, t, J=5.8 Hz) 7.95-7.90 (1H, m)
7.80-7.73 (2H, m) 7.63-7.57 (2H, m) 7.49 (1H, d, J=8.4 Hz)
7.31-7.26 (1H, m) 6.94 (1H, dd, J=8.2, 1.6 Hz) 6.59 (1H, tt,
J=54.3, 3.1 Hz) 4.57 (2H, td, J=14.9, 3.0 Hz) 4.38 (2H, d, J=5.8
Hz) 1.54-1.47 (2H, m) 1.38-1.31 (2H, m). MS m/z: 686, 688, 690
[M+H].sup.+.
[0520] The following compounds were synthesized in analogy to the
methods of preparation described above in detail.
TABLE-US-00008 Chemical structure Name Ex. .sup.1H-NMR MS m/z [M +
H].sup.+ 68 ##STR00090## 586.588
N-(Cyclopropylmethyl)-2-(2-chloro-5-{[(1-trifluoromethyl-
cyclopropanecarbonyl)-amino]-methyl}-phenylamino)-6-(2,2-
difluoro-ethoxy)-1H-benzimidazole-5-carboxylic acid amide 400 MHz
.sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 11.0-10.7 (1H, br s)
8.8-8.5 (1H, br s) 8.36-8.29 (1H, m) 8.25 (1H, t, J = 5.8 Hz) 7.89
(1H, t, J = 5.2 Hz) 7.72-7.68 (1H, m) 7.20 (1H, d, J = 8.1 Hz)
6.97-6.90 (1H, m) 6.64 (1H, dd, J = 8.1, 1.8 Hz) 6.30 (1H, tt, J =
54.3, 3.1 Hz) 4.25 (2H, td, J = 14.8, 3.2 Hz) 4.09 (2H, d, J = 5.8
Hz) 3.00-2.94 (2H, m) 1.27-1.18 (2H, m) 1.09-1.02 (2H, m) 0.85-0.74
(1H, m) 0.28-0.20 (2H, m) 0.05-0.02 (2H, m)
Example 69
N-(4-Bromo-phenyl)-2-(2-chloro-5-{[(1-trifluoromethyl-cyclopropanecarbonyl-
)-amino]-methyl}-phenylamino)-6-methoxy-1H-benzimidazole-5-carboxylic
Acid Amide
##STR00091##
[0521] (a) 4-Amino-2-methoxy-5-nitrobenzoic Acid
[0522] A mixture of ethyl 4-acetamido-2-methoxy-5-nitrobenzoate
(4.0 g; 14.9 mmol) and NaOH (40 mL, 1 M aq; 40 mmol) in EtOH (80
mL) was refluxed for 2 h. The mixture was cooled to rt and water
(20 mL) was added. The mixture was acidified by HCl (6 M aq) and
the sub-title compound was filtered off. Yield: 3.0 g (95%).
(b) 4-Amino-N-(4-bromophenyl)-2-methoxy-5-nitrobenzamide
[0523] The sub-title compound was prepared in accordance with the
procedure in Example 59, step (a) using
4-amino-2-methoxy-5-nitrobenzoic acid (2.0 g; 9.43 mmol), TBTU
(3.33 g; 10.4 mmol), TEA (2.9 mL; 20.8 mmol), 4-bromoaniline (1.62
g; 9.43 mmol) and DMF (70 mL). Yield: 3.41 g (99%).
(c) 4,5-Diamino-N-(4-bromophenyl)-2-methoxybenzamide
[0524] A mixture of
4-amino-N-(4-bromophenyl)-2-methoxy-5-nitrobenzamide (1.30 g; 3.55
mmol), THF (80 mL) and EtOH (50 mL) was treated with AcOH (3 mL)
and stirred for 15 min at 100.degree. C. To the warm mixture, Fe
(1.30 g; 23.3 mmol) was carefully added in portions and the
resulting mixture was heated for 2 h at 100.degree. C. The mixture
was cooled, filtered through celite and concentrated to give the
crude sub-title compound.
(d)
N-(4-Bromo-phenyl)-2-(2-chloro-5-{[(1-trifluoromethyl-cyclopropanecarb-
onyl)-amino]-methyl}-phenylamino)-6-methoxy-1H-benzimidazole-5-carboxylic
Acid Amide
[0525] The title compound was prepared in accordance with the
procedure in Example 72, step (a) using
N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane
carboxamide ((200 mg; 0.60 mmol) see Example 59, step (c)),
4,5-diamino-N-(4-bromophenyl)-2-methoxybenzamide (202 mg; 0.60
mmol), DIC (76 mg; 0.60 mmol) and DMF (4 mL). Yield: 63 mg (16%).
400 MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 11.12 (0.36H, s,
minor tautomer) 11.00 (0.57H, s, major tautomer) 10.22-10.14 (1H,
m) 8.94 (0.57H, s, major tautomer) 8.76 (0.36H, s, minor tautomer)
8.61-8.52 (1H, m) 8.48-8.41 (1H, m) 7.86-7.69 (3H, m) 7.53-7.45
(2H, m) 7.42-7.35 (1H, m) 7.21 (0.38H, s, minor tautomer) 7.10
(0.59H, s, major tautomer) 6.87-6.79 (1H, m) 4.29 (2H, d, J=5.8 Hz)
3.93 (3H, s) 1.49-1.39 (2H, m) 1.28-1.23 (2H, m). MS m/z: 636, 638,
640 [M+H].sup.+.
Example 70
N-(4-Bromo-phenyl)-2-(2-chloro-5-{[(1-trifluoromethyl-cyclopropanecarbonyl-
)-amino]-methyl}-phenylamino)-1-(2-(dimethylamino)ethyl)-1H-benzimidazole--
5-carboxylic Acid Amide
##STR00092##
[0526] (a) N-(4-Bromophenyl)-4-fluoro-3-nitrobenzamide
[0527] A mixture of 4-fluoro-3-nitrobenzoic acid (10.0 g; 54.0
mmol), SOCl.sub.2 (20.0 mL; 270 mmol) and DMF (2-3 drops) was
refluxed for 4 h, concentrated and the residue was dissolved in DCM
(25 mL) and slowly added to a mixture of 4-bromoaniline (9.3 g;
54.1 mmol) and TEA (11.4 mL; 81.0 mmol) in DCM (50 mL) at 0.degree.
C. The mixture was stirred for 1 h at rt, concentrated, EtOAc was
added and the organic phase was washed with aqueous NaHCO.sub.3,
aqueous HCl (1 M), dried over Na.sub.2SO.sub.4, filtered and
concentrated to give the sub-title compound. Yield: 18.0 g
(98%).
(b)
N-(4-Bromophenyl)-4-(2-(dimethylamino)ethylamino)-3-nitrobenzamide
[0528] A mixture of N-(4-bromophenyl)-4-fluoro-3-nitrobenzamide
(400 mg; 1.18 mmol) and 2-dimethylamino ethylamine (208 mg; 2.36
mmol) in EtOH (5 mL) was stirred over night at 50.degree. C. The
mixture was then poured into aqueous NaHCO.sub.3 and extracted with
EtOAc. The organic layers were dried over Na.sub.2SO.sub.4,
filtered and concentrated. Recrystallization from EtOAc/petroleum
ether gave the crude sub-title compound (560 mg).
(c)
3-Amino-N-(4-bromophenyl)-4-(2-(dimethylamino)ethylamino)benzamide
[0529] The sub-title compound was prepared in accordance with the
procedure in Example 2, step (b) using
N-(4-bromophenyl)-4-(2-(dimethylamino)ethylamino)-3-nitrobenzamide
(560 mg; 1.38 mmol), Fe (384 mg; 6.88 mmol), NH.sub.4Cl (aq, sat,
10 mL) and EtOH (10 mL). Yield: 475 mg (91%).
(d)
N-(4-Bromo-phenyl)-2-(2-chloro-5-{[(1-trifluoromethyl-cyclopropanecarb-
onyl)-amino]-methyl}-phenylamino)-1-(2-(dimethylamino)ethyl)-1H-benzimidaz-
ole-5-carboxylic acid amide
[0530] The title compound was prepared in accordance with the
procedure in Example 72, step (a) using
N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane
carboxamide ((222 mg; 0.66 mmol) see Example 59, step (c)),
3-amino-N-(4-bromophenyl)-4-(2-(dimethylamino)ethylamino)benzamide
(250 mg; 0.66 mmol), DIC (83 mg; 0.66 mmol) and DMF (4 mL). Yield:
151 mg (34%). 400 MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 10.37
(1H, s) 10.22 (1H, s) 8.39 (1H, t, J=5.8 Hz) 8.10 (1H, d, J=1.8 Hz)
8.06 (1H, d, J=1.6 Hz) 7.82-7.71 (3H, m) 7.53-7.46 (3H, m) 7.40
(1H, d, J=8.2 Hz) 6.86 (1H, dd, J=8.2, 1.8 Hz) 4.32-4.21 (4H, m)
2.74-2.68 (2H, m) 2.29 (6H, s) 1.37-1.32 (2H, m) 1.23-1.19 (2H, m).
MS m/z: 677, 679, 681 [M+H].sup.+.
[0531] The following compounds were synthesized in analogy to the
methods of preparation described above in detail.
TABLE-US-00009 Chemical structure Name Ex. .sup.1H-NMR MS m/z [M +
H].sup.+ 71 ##STR00093## 664, 666, 668
N-(4-Bromo-phenyl)-2-(2-chloro-5-{[(1-trifluoromethyl-
cyclopropanecarbonyl)-amino]-methyl}-phenylamino)-1-(2-
methoxyethyl)-1H-benzimidazole-5-carboxylic acid amide 400 MHz
.sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 10.24 (1H, s) 8.64 (1H, s)
8.42 (1H, t, J = 6.0 Hz) 8.21 (1H, d, J = 2.0 Hz) 8.08 (1H, d, J =
1.6 Hz) 7.81-7.74 (3H, m) 7.54 (1H, d, J = 8.4 Hz) 7.52-7.47 (2H,
m) 7.43 (1H, d, J = 8.2 Hz) 6.88 (1H, dd, J = 8.2, 2.0 Hz)
4.45-4.38 (2H, m) 4.27 (2H, d, J = 6.0 Hz) 3.77-3.71 (2H, m) 3.34
(3H, s) 1.39-1.34 (2H, m) 1.24-1.19 (2H, m)
Example 72
N-(4-Bromo-phenyl)-2-(2-chloro-5-{[(1,1-difluoro-ethylcarbonyl)-amino]-met-
hyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carb-
oxylic Acid Amide
##STR00094##
[0532] (a)
Ethyl-2-(2-chloro-5-{[(tert-butoxycarbonyl)-amino]-methyl}-phen-
ylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylate
[0533] A mixture of tert-butyl
4-chloro-3-isothiocyanatobenzylcarbamate ((see Example 2, step (c))
974 mg; 3.26 mmol) and ethyl
5-amino-2-(2,2-difluoroethoxy)-4-(methylamino)benzoate ((see
Example 59, step (g)) 894 mg; 3.26 mmol) in DMF (10 mL) was stirred
over night at rt. DIC (411 mg; 3.26 mmol) was added and the mixture
was heated at 90.degree. C. for 1.5 h. The mixture was concentrated
and the residue was recrystallized from EtOAc/petroleum ether and
washed with Et.sub.2O to give the sub-title compound. Yield: 1.75 g
(99%).
(b)
2-(2-Chloro-5-{[(tert-butoxycarbonyl)-amino]-methyl}-phenylamino)-6-(2-
,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid
[0534] A mixture of
ethyl-2-(2-chloro-5-{[(tert-butoxycarbonyl)-amino]-methyl}-phenylamino)-6-
-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylate
(1.35 g; 2.50 mmol), NaOH (4 mL; 2 M aq; 8 mmol) and 1,4-dioxane
(15 mL) was refluxed for 3 h. After cooling to rt the mixture was
acidified to pH .about.5-6 and extracted with EtOAc. The organic
extracts were dried over Na.sub.2SO.sub.4, filtered and
concentrated. The residue was washed with Et.sub.2O to give the
sub-title compound. Yield: 1.12 g (88%).
(c)
N-(4-Bromo-phenyl)-2-(2-chloro-5-{[(tert-butoxycarbonyl)-amino]-methyl-
}-phenylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxy-
lic Acid Amide
[0535] A mixture of
2-(2-chloro-5-{[(tert-butoxycarbonyl)-amino]-methyl}-phenylamino)-6-(2,2--
difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid (1.12
g; 2.19 mmol), HBTU (831 mg; 2.19 mmol) and TEA (433 mg; 4.38 mmol)
in DMF (10 mL) was stirred for 30 min at rt and thereafter added to
a solution of 4-bromoaniline (377 mg; 2.19 mmol) in DMF (10 mL).
The resulting mixture was stirred over night at rt, poured into
brine and extracted with EtOAc. The organic extracts were dried
over Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by column chromatography to give the sub-title compound.
Yield: 1.35 g (93%).
(d)
N-(4-Bromo-phenyl)-2-(2-chloro-5-{[amino]-methyl}-phenylamino)-6-(2,2--
difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic Acid
Amide
[0536] A mixture of
N-(4-bromo-phenyl)-2-(2-chloro-5-{[(tert-butoxycarbonyl)-amino]-methyl}-p-
henylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic
acid amide (1.35 g; 2.03 mmol) and TFA (3.47 g; 30.5 mmol) in DCM
(75 mL) was stirred over night at rt. The mixture was cooled to
0.degree. C. and basicified to pH .about.10 and extracted with DCM.
The organic extracts were dried over Na.sub.2SO.sub.4, filtered and
concentrated. The residue was washed with a mixture of Et.sub.2O
and petroleum ether to give the sub-title compound. Yield: 1.15 g
(100%).
(e)
N-(4-Bromo-phenyl)-2-(2-chloro-5-{[(1,1-difluoro-ethylcarbonyl)-amino]-
-methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole-5--
carboxylic Acid Amide
[0537] The title compound was prepared in accordance with Example
72, step (c) using
N-(4-bromo-phenyl)-2-(2-chloro-5-{[amino]-methyl}-phenylamino)--
6-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid
amide (170 mg; 0.30 mmol), 2,2-difluoropropanoic acid (33 mg; 0.30
mmol), HBTU (114 mg; 0.30 mmol), TEA (61 mg; 0.60 mmol) and DMF (3
mL). Yield: 63 mg (32%). 400 MHz .sup.1H-NMR (DMSO-d.sub.6, ppm)
.delta. 10.07 (1H, s) 9.30 (1H, t, J=5.8 Hz) 8.35 (1H, s) 7.87-7.82
(1H, m) 7.73-7.60 (3H, m) 7.53-7.39 (3H, m) 7.33-7.27 (1H, m)
6.99-6.90 (1H, m) 6.66-6.34 (1H, m) 4.59-4.44 (2H, m) 4.30 (2H, d,
J=5.8 Hz) 3.71 (2.38H, s, major tautomer) 3.43 (0.41H, s, minor
tautomer) 1.74 (3H, t, J=19.6 Hz). MS m/z: 656, 658, 660
[M+H].sup.+.
[0538] The following compounds were synthesized in analogy to the
methods of preparation described above in detail.
TABLE-US-00010 Chemical structure Name Ex. .sup.1H-NMR MS m/z [M +
H].sup.+ 73 ##STR00095## 688, 690, 692
N-(4-Bromo-phenyl)-2-(2-chloro-5-{[(1-trifluoromethyl-ethyl-
carbonyl)-amino]-methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1-
methyl-1H-benzimidazole-5-carboxylic acid amide 400 MHz .sup.1H-NMR
(DMSO-d.sub.6, ppm) .delta. 10.06 (1H, s) 8.86-8.76 (1H, m) 8.34
(1H, s) 7.87-7.81 (1H, m) 7.76-7.59 (3H, m) 7.53-7.38 (3H, m)
7.34-7.27 (1H, m) 6.99-6.88 (1H, m) 6.67-6.33 (1H, m) 4.59-4.43
(2H, m) 4.35-4.21 (2H, m) 3.71 (2.61H, s, major tautomer) 3.42
(0.46H, s, minor tautomer) 3.37-3.30 (1H, m) 1.25 (3H, d, J = 7.0
Hz) 74 ##STR00096## 720.722, 724
N-(4-Bromo-phenyl)-2-(2-chloro-5-{[(2-chloro-6-
fluorophenylcarbonyl)-amino]-methyl}-phenylamino)-6-(2,2-
difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid amide
400 MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 10.11-9.95 (1H, m)
9.29- 9.12 (1H, m) 8.39 (1H, s) 7.94-7.81 (1H, m) 7.76-7.58 (3H, m)
7.54-7.38 (4H, m) 7.36-7.20 (3H, m) 7.12-7.02 (1H, m) 6.68-6.34
(1H, m) 4.57-4.39 (4H, m) 3.71 (2.48H, s, major tautomer) 3.43
(0.46H, s, minor tautomer) 75 ##STR00097## 703, 705, 707
N-(4-Bromo-phenyl)-2-(2-chloro-5-{[(1-amino-1-trifluoromethyl-
ethyl-carbonyl)-amino]-methyl}-phenylamino)-6-(2,2-difluoro-
ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid amide 400 MHz
.sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 10.09-9.96 (1H, m) 8.68
(1H, t, J = 6.2 Hz) 8.32 (1H, s) 7.85-7.77 (1H, m) 7.73-7.58 (3H,
m) 7.53- 7.45 (2H, m) 7.42 (1H, d, J = 8.2 Hz) 7.33-7.27 (1H, m)
6.98-6.91 (1H, m) 6.66-6.34 (1H, m) 4.57-4.44 (2H, m) 4.34-4.20
(2H, m) 3.70 (2.38H, s, major tautomer) 3.42 (0.43H, s, minor
tautomer) 2.55 (2H, s) 1.37 (3H, s) 76 ##STR00098## 648, 650, 652
N-(4-Bromo-phenyl)-2-(2-chloro-5-{[(1-
hydroxycyclopropanecarbonyl)-amino]-methyl}-phenylamino)-6-
(2,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid
amide 400 MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 10.11-9.95
(1H, m) 8.47 (1H, t, J = 6.2 Hz) 8.41-8.33 (1H, m) 7.79-7.59 (4H,
m) 7.53-7.47 (2H, m) 7.41 (1H, d, J = 8.2 Hz) 7.32-7.27 (1H, m)
7.03-6.96 (1H, m) 6.66- 6.35 (1H, m) 6.22 (1H, s) 4.56-4.44 (2H, m)
4.27 (2H, d, J = 6.2 Hz) 3.70 (2.64H, s, major tautomer) 3.43
(0.37H, s, minor tautomer) 1.03-0.95 (2H, m) 0.84-0.77 (2H, m) 77
##STR00099## 702, 704, 706
N-(4-Bromo-phenyl)-2-(2-chloro-5-{[(1-methyl-1-trifluoromethyl-
ethylcarbonyl)-amino]-methyl}-phenylamino)-6-(2,2-difluoro-
ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid amide 400 MHz
.sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 10.06 (1H, s) 8.62-8.50
(1H, m) 8.35-8.23 (1H, m) 7.91-7.82 (1H, m) 7.74-7.63 (3H, m) 7.53-
7.47 (2H, m) 7.43-7.38 (1H, m) 7.34-7.28 (1H, m) 6.95-6.85 (1H, m)
6.65-6.37 (1H, m) 4.56-4.47 (1H, m) 4.27 (2H, d, J = 5.6 Hz) 3.71
(3H, s) 1.36 (6H, s)
Example 78
N-(4-Bromo-phenyl)-2-(2-chloro-5-{[(tert-butylcarbonyl)-amino]-methyl}-phe-
nylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic
Acid Amide
##STR00100##
[0540] A solution of pivaloyl chloride (34 mg; 0.28 mmol) in DCM (1
mL) was added dropwise to a mixture of
N-(4-bromo-phenyl)-2-(2-chloro-5-{[amino]-methyl}-phenylamino)-6-(2,2-dif-
luoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid amide
((see Example 72, step (d)) 150 mg; 0.27 mmol), TEA (41 mg; 0.41
mmol) and DCM (2 mL) at 0.degree. C. The resulting mixture was
stirred over night at rt, poured into water and extracted with DCM.
The organic extracts were washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
recrystallized from EtOAc/petroleum ether to give the title
compound. Yield: 119 mg (68%). 400 MHz .sup.1H-NMR (DMSO-d.sub.6,
ppm) .delta. 10.09-9.96 (1H, m) 8.27 (1H, s) 8.10 (1H, t, J=5.8 Hz)
7.89-7.84 (1H, m) 7.75-7.61 (3H, m) 7.54-7.46 (2H, m) 7.39 (1H, d,
J=8.2 Hz) 7.33-7.27 (1H, m) 6.95-6.87 (1H, m) 6.67-6.35 (1H, m)
4.58-4.44 (2H, m) 4.22 (2H, d, J=5.8 Hz) 3.70 (2.63H, s, major
tautomer) 3.42 (0.33H, s, minor tautomer) 1.10 (9H, s). MS m/z:
648, 650, 652 [M+H].sup.+.
[0541] The following compounds were synthesized in analogy to the
methods of preparation described above in detail.
TABLE-US-00011 Chemical structure Name Ex. .sup.1H-NMR MS m/z [M +
H].sup.+ 79 ##STR00101## 606, 608, 610
N-(4-Bromo-phenyl)-2-(2-chloro-5-{[(methylcarbonyl)-amino]-
methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-
benzimidazole-5-carboxylic acid amide 400 MHz .sup.1H-NMR
(DMSO-d.sub.6, ppm) .delta. 10.09-9.96 (1H, m) 8.45- 8.24 (2H, m)
7.82-7.75 (1H, m) 7.74-7.59 (3H, m) 7.53-7.38 (3H, m) 7.33-7.26
(1H, m) 7.00-6.91 (1H, m) 6.68-6.31 (1H, m) 4.57- 4.43 (2H, m) 4.21
(2H, d, J = 6.0 Hz) 3.70 (2.58H, s, major tautomer) 3.42 (0.38H, s,
minor tautomer) 1.84 (3H, s) 80 ##STR00102## 632, 634, 636
N-(4-Bromo-phenyl)-2-(2-chloro-5-{[(cyclopropylcarbonyl)-amino]-
methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-
benzimidazole-5-carboxylic acid amide 400 MHz .sup.1H-NMR
(DMSO-d.sub.6, ppm) .delta. 10.09-9.96 (1H, m) 8.62- 8.56 (1H, m)
8.37 (1H, s) 7.80-7.76 (1H, m) 7.73-7.62 (3H, m) 7.53-7.47 (2H, m)
7.41 (1H, d, J = 8.2 Hz) 7.33-7.27 (1H, m) 6.98- 6.92 (1H, m)
6.65-6.35 (1H, m) 4.55-4.45 (2H, m) 4.24 (2H, d, J = 5.8 Hz) 3.70
(2.36H, s, major tautomer) 3.42 (0.47H, s, minor tautomer)
1.61-1.53 (1H, m) 0.69-0.59 (4H, m) 81 ##STR00103## 668, 670, 672
N-(4-Bromo-phenyl)-2-(2-chloro-5-{[(tert-butylsulfinyl)-amino]-
methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-
benzimidazole-5-carboxylic acid amide 400 MHz .sup.1H-NMR
(DMSO-d.sub.6, ppm) .delta. 10.10-9.95 (1H, m) 8.32 (1H, s) 8.01
(1H, s) 7.75-7.58 (3H, m) 7.56-7.36 (3H, m) 7.35-7.26 (1H, m)
7.14-6.98 (1H, m) 6.68-6.33 (1H, m) 5.84-5.73 (1H, m) 4.59-4.42
(2H, m) 4.24-4.03 (2H, m) 3.71 (2.53H, s, major tautomer) 3.43
(0.46H, s, minor tautomer) 1.12 (9H, s)
Example 82
N-(4-Bromo-phenyl)-2-(2-chloro-5-{[(tert-butylsulfonyl)-amino]-methyl}-phe-
nylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic
Acid Amide
##STR00104##
[0543] A mixture of
N-(4-bromo-phenyl)-2-(2-chloro-5-{[(tert-butylsulfinyl)-amino]-methyl}-ph-
enylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic
acid amide (100 mg; 0.15 mmol), m-chloroperoxybenzoic acid (28 mg;
0.16 mmol) and DCM (20 mL) was stirred over night at rt. The
mixture was basicified to pH .about.8-9 and extracted with EtOAc.
The organic extracts were dried over Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified by column chromatography to
give the title compound. Yield: 24 mg (23%). 200 MHz .sup.1H-NMR
(DMSO-d.sub.6, ppm) .delta. 10.06-10.02 (1H, m) 7.75-7.62 (4H, m)
7.54-7.44 (4H, m) 7.27-7.17 (2H, m) 6.95-6.84 (1H, m) 6.57-6.49
(1H, m) 4.58-4.42 (2H, m) 4.16-4.09 (2H, m) 3.57-3.51 (3H, m) 1.29
(9H, s). MS m/z: 684, 686, 690 [M+H].sup.+.
Example 83
N-(4-Bromo-phenyl)-2-(2-trifluoromethyl-5-{[(1-trifluoromethyl-cyclopropan-
ecarbonyl)-amino]-methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-
-benzimidazole-5-carboxylic Acid Amide
##STR00105##
[0544] (a) 3-Amino-4-(trifluoromethyl)benzonitrile
[0545] A closed pressure tube charged with
3-fluoro-4-(trifluoromethyl)benzonitrile (10.0 g; 52.9 mmol) and
liquid NH.sub.3 (60 mL) was heated for 6 days at 90.degree. C. The
tube was cooled to -60.degree. C. and opened. The mixture was
allowed to stir for 1 h at rt. The residue was treated with brine
and extracted with EtOAc to give the crude sub-title compound (10.2
g).
(b) tert-Butyl N-[5-cyano-2-(trifluoromethyl)phenyl]-carbamate
[0546] A mixture of 3-amino-4-(trifluoromethyl)benzonitrile (10.0
g; 53.7 mmol), DCM (100 mL) and TEA (8.2 mL; 59 mmol) was treated
dropwise with a solution of Boc.sub.2O (12.9 g; 59.1 mmol) in DCM
(50 mL) at 0.degree. C. and thereafter stirred over night. Another
portion of Boc.sub.2O in DCM and DMAP (656 mg; 5.37 mmol) was added
and the mixture was stirred for another 12 h at rt, washed with
water and brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified by column chromatography to
give the sub-title compound. Yield: 8.50 g (55%).
(c) tert-Butyl
N-[5-(aminomethyl)-2-(trifluoromethyl)phenyl]-carbamate
[0547] The sub-title compound was prepared in accordance with the
procedure in Example 59, step (g) using tert-butyl
N-[5-cyano-2-(trifluoromethyl)phenyl]-carbamate (8.5 g; 29.7 mmol),
Ra--Ni (174 mg; 2.97 mmol), H.sub.2 (5 atm) and THF (60 mL). Yield:
8 g (93%).
(d)
N-(3-Amino-4-(trifluoromethyl)-benzyl)-1-(trifluoromethyl)-cyclopropan-
ecarboxamide
[0548] The sub-title compound was prepared in accordance with the
procedures in Example 72, step (c) and Example 72, step (d) using
tert-butyl N-[5-(aminomethyl)-2-(trifluoromethyl)phenyl]-carbamate
(2.09 g; 7.20 mmol), 1-(trifluoromethyl)-cyclopropanecarboxylic
acid (1.11 g; 7.20 mmol), HBTU (2.73 g; 7.20 mmol), TEA (2.19 g;
21.6 mmol), DMF (25 mL), TFA (10 mL) and DCM (50 mL). Yield: 1.8 g
(77%).
(e)
N-(4-Trifluoromethyl-3-isothiocyanato-benzyl)-1-(trifluoromethyl)cyclo-
propane Carboxamide
[0549] A mixture of
N-(3-amino-4-(trifluoromethyl)-benzyl)-1-(trifluoromethyl)-cyclopropaneca-
rboxamide (1.60 g; 4.90 mmol), di-(2-pyridyl)thionocarbonate (1.71
g; 7.36 mmol) and THF (40 mL) was stirred in a pressure tube for 2
days at 60.degree. C. The mixture was concentrated and the residue
purified by column chromatography to give the sub-title compound.
Yield: 1.29 g (72%).
(f)
N-(4-Bromo-phenyl)-2-(2-trifluoromethyl-5-{[(1-trifluoromethyl-cyclopr-
opanecarbonyl)-amino]-methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1-methy-
l-1H-benzimidazole-5-carboxylic Acid Amide
[0550] The title compound was prepared in accordance with the
procedure in Example 72, step (a) using
N-(4-trifluoromethyl-3-isothiocyanato-benzyl)-1-(trifluoromethyl)cyclopro-
pane carboxamide (184 mg; 0.50 mmol),
5-amino-N-(4-bromophenyl)-2-(2,2-difluoroethoxy)-4-(methylamino)benzamide
(200 mg; 0.50 mmol), DIC (63 mg; 0.50 mmol) and DMF (4 mL). Yield:
59 mg (16%). 400 MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 10.62
(0.57H, s, major tautomer) 10.09-9.96 (1H, m) 8.47-8.41 (0.38H, m,
minor tautomer) 8.36-8.28 (1H, m) 7.72-7.61 (3H, m) 7.58-7.47 (3H,
m) 7.36-7.28 (1H, m) 7.12-6.84 (2H, m) 6.67-6.35 (1H, m) 4.58-4.45
(2H, m) 4.34-4.25 (2H, m) 3.64 (0.96H, s, minor tautomer) 3.41
(1.93H, s, major tautomer) 1.31-1.17 (4H, m). MS m/z: 734, 736
[M+H].sup.+.
Example 84
2-(2-Chloro-4-fluoro-5-{[(1-(trifluoromethyl)cyclopropanecarbonyl)amino]me-
thyl}-phenylamino)-6-(2,2-difluoroethoxy)-1-methyl-N-(trans-4-trifluoromet-
hyl-cyclohex-1-yl)-1H-benzo[d]imidazole-5-carboxamide
##STR00106##
[0551] (a) 4-Chloro-2-fluoro-5-nitrobenzonitrile
[0552] A mixture of 4-chloro-2-fluorobenzonitrile (4.62 g; 29.7
mmol) in conc. H.sub.2SO.sub.4 (42 mL) was treated dropwise with
conc. HNO.sub.3 (3.9 mL) at 1-2.degree. C. After stirring at
1-2.degree. C. for 2 h the mixture was poured into ice and filtered
to give the sub-title compound. Yield: 5.18 g (87%).
(b) 4-Chloro-2-fluoro-5-isothiocyanatobenzonitrile
[0553] H.sub.2 was passed through a mixture of
4-chloro-2-fluoro-5-nitrobenzonitrile (1.0 g; 5.0 mmol) and Ra--Ni
(29 mg, 0.50 mmol) in THF (50 mL) for 6 h. The mixture was filtered
through celite. CSCl.sub.2 (2.29 g; 19.9 mmol), K.sub.2CO.sub.3
(3.45 g; 25.0 mmol) was added and the resulting mixture was stirred
over night at rt and concentrated. The residue was purified by
column chromatography to give the sub-title compound.
[0554] Yield: 840 mg (79%).
(c)
2-[(2-Chloro-5-cyano-4-fluorophenyl)-amino]-6-(2,2-difluoroethoxy)-1-m-
ethyl-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-1H-benzo[d]imidazole-5-car-
boxamide
[0555] The sub-title compound was prepared in accordance with the
procedure in Example 72, step (a) using
4-chloro-2-fluoro-5-isothiocyanatobenzonitrile (270 mg; 1.27 mmol),
5-amino-2-(2,2-difluoroethoxy)-4-(methylamino)-N-((trans)-4-(trifluoromet-
hyl)cyclohexyl)benzamide [502 mg; 1.27 mmol, prepared from
4-trans-trifluoromethyl-cyclohexylamine and
2-(2,2-difluoroethoxy)-4-(methylamino)-5-nitrobenzoic acid in
analogy to Example 66, step (f+g)], DIC (160 mg; 1.27 mmol) and DMF
(10 mL). Yield: 210 mg (29%).
(d)
2-[5-(Aminomethyl)-2-chloro-4-fluoro-phenyl]amino-6-(2,2-difluoroethox-
y)-1-methyl-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-1H-benzo[d]imidazole-
-5-carboxamide
[0556] The sub-title compound was prepared in accordance with
Example 3d, using
2-[(2-chloro-5-cyano-4-fluoro-phenyl)-amino]-6-(2,2-difluoroethoxy)-
-1-methyl-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-1H-benzo[d]imidazole-5-
-carboxamide (210 mg; 0.37 mmol), Ra--Ni (3 mg), H.sub.2 (5 atm)
and THF (10 mL). Yield: 150 mg (70%).
(e)
2-(2-Chloro-4-fluoro-5-{[(1-(trifluoromethyl)cyclopropanecarbonyl)amin-
o]methyl}-phenylamino)-6-(2,2-difluoroethoxy)-1-methyl-N-(trans-4-trifluor-
omethyl-cyclohex-1-yl)-1H-benzo[d]imidazole-5-carboxamide
[0557] The title compound was prepared in accordance with the
procedure in Example 72, step (c) using
2-[5-(aminomethyl)-2-chloro-4-fluoro-phenyl]amino-6-(2,2-difluoroethoxy)--
1-methyl-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-1H-benzo[d]imidazole-5--
carboxamide (150 mg; 0.26 mmol),
1-(trifluoromethyl)-cyclopropanecarboxylic acid (40 mg; 0.26 mmol),
HBTU (99 mg; 0.26 mmol), TEA (53 mg; 0.52 mmol) and DMF (4 mL).
Yield: 39 mg (21%). 400 MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) .delta.
8.40 (1H, t, J=5.8 Hz) 8.32 (1H, s) 7.90-7.82 (2H, m) 7.78-7.74
(1H, m) 7.44 (1H, d, J=9.6 Hz) 7.23-7.19 (1H, m) 6.63-6.34 (1H, m)
4.51-4.40 (2H, m) 4.29 (2H, d, J=5.8 Hz) 3.78-3.65 (4H, m)
2.28-2.17 (1H, m) 2.03-1.97 (2H, m) 1.91-1.85 (2H, m) 1.39-1.19
(8H, m). MS m/z: 714, 716 [M+H].sup.+.
[0558] The following compounds were synthesized in analogy to the
methods of preparation described above in detail.
TABLE-US-00012 Chemical structure Name Ex. .sup.1H-NMR MS m/z [M +
H].sup.+ 85 ##STR00107## 718, 720, 722
N-(4-Bromophenyl)-2-(2-chloro-4-fluoro-5-{[(1-trifluoromethyl-
cyclopropanecarbonyl)amino]methyl}phenylamino)-6-(2,2-
difluoroethoxy)-1-methyl-1H-benzo[d]imidazole-5-carboxamide 400 MHz
.sup.1H-NMR (DMSO-d.sub.6, ppm) .delta. 10.09-9.94 (1H, m) 8.46-
8.22 (2H, m) 7.84 (1H, d, J = 7.6 Hz) 7.73-7.61 (3H, m) 7.53-7.42
(3H, m) 7.31-7.27 (1H, m) 6.66-6.36 (1H, m) 4.55-4.46 (2H, m) 4.29
(2H, d, J = 5.8 Hz) 3.70 (3H, s) 1.39-1.19 (4H, m)
Example 86
N-(3-Chloro-4-fluoro-phenyl)-2-(2-chloro-5-{[(tert-butylcarbonyl)-amino]-m-
ethyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-ca-
rboxylic Acid Amide
##STR00108##
[0559] (a) Ethyl 2-fluoro-4-methylamino-5-nitro-benzoate
[0560] A 2N solution of methylamine in THF (11.5 ml, 23.0 mmol) was
added at -5.degree. C. to ethyl-2,4-difluoro-5-nitro-benzoate (2.50
g, 10.8 mmol) in 20 ml THF and the cooling bath was removed. After
15 min at room temperature, the mixture was concentrated i.vac., 50
ml DCM were added, the organic phase was washed with water and
dried with MgSO.sub.4. After concentration i. vac. the crude
product was triturated with ethanol to give the cristalline
product. Yield: 1.72 g (66%); MS m/z: 243 [M+H].sup.+.
(b) Ethyl 2-(2,2-difluoroethoxy)-4-methylamino-5-nitro-benzoate
[0561] KOtBu (0.26 g, 95%, 2.39 mmol) was added to a mixture of
2,2-difluoroethanol (0.16 ml, 2.48 mmol) and 10 ml THF. It was
stirred for 15 min, ethyl 2-fluoro-4-methylamino-5-nitro-benzoate
(0.40 g, 1.65 mmol) was added and it was stirred for 3 d. The
mixture was diluted with water, concentrated i.vac. and the crude
product was collected by filtration.
[0562] Yield: 0.47 g (94%); TLC: silica gel, PE/EtOAc 60:40,
R.sub.f=0.35.
(c) Ethyl 2-(2,2-difluoroethoxy)-4-methylamino-5-amino-benzoate
[0563] Ethyl 2-(2,2-difluoroethoxy)-4-methylamino-5-nitro-benzoate
(0.47 g, 1.54 mmol) was hydrogenated with 10% Pd/C (50 mg) in 15 ml
MeOH for 18 h (50 psi H.sub.2), filtered and concentrated.
[0564] Yield: 0.35 g (83%); TLC: silica gel, DCM/EtOH 95:5,
R.sub.f=0.4.
(d) Ethyl
2-(2-chloro-5-{[(tert.butylcarbonyl)amino]methyl}phenylamino)-6--
(2,2-difluoroethoxy)-1-methyl-1H-benzo[d]imidazole-5-carboxylate
[0565] The sub-title compound was prepared from ethyl
2-(2,2-difluoroethoxy)-4-methylamino-5-amino-benzoate and
(4-chloro-3-isothiocyanatobenzyl)-2,2-dimethylpropionamide with DIC
in DMF at r.t. in analogy to example 72a. The crude material was
directly used in the next step.
(e)
2-(2-Chloro-5-{[(tert.butylcarbonyl)amino]methyl}phenylamino)-6-(2,2-d-
ifluoroethoxy)-1-methyl-1H-benzo[d]imidazole-5-carboxylic Acid
[0566] The sub-title compound was prepared from crude ethyl
2-(2-chloro-5-{[(tert.butylcarbonyl)amino]methyl}phenylamino)-6-(2,2-difl-
uoroethoxy)-1-methyl-1H-benzo[d]imidazole-5-carboxylate with NaOH
in analogy to example 2 g. Yield: (85% for two steps); TLC: silica
gel, DCM/EtOH 95:5, R.sub.f=0.2. MS m/z: 495/497 [M+H].sup.+.
(f)
N-(3-Chloro-4-fluoro-phenyl)-2-(2-chloro-5-{[(tert-butylcarbonyl)-amin-
o]-methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole--
5-carboxylic Acid Amide
[0567] The title compound was prepared from
2-(2-chloro-5-{[(tert.butylcarbonyl)amino]methyl}-phenylamino)-6-(2,2-dif-
luoroethoxy)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and
3-chloro-4-fluoro-aniline with HATU and TEA in THF in analogy to
example 3e and purified via flash chromatography. Yield: (57%);
[0568] TLC: silica gel, DCM/EtOH 95:5, R.sub.f=0.2. HPLC
R.sub.t=1.40 min (method A) MS m/z: 622/624 [M+H].sup.+.
[0569] The following compounds were synthesized in analogy to the
methods of preparation described above in detail.
TABLE-US-00013 Chemical structure Name Ex. .sup.1H-NMR MS m/z [M +
H].sup.+ 87 ##STR00109## 548
N-(Cyclopropylmethyl)-2-(2-chloro-5-{[(tert-butylcarbonyl)-amino]-
methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-
benzimidazole-5-carboxylic acid amide TLC: silica gel, DCM/EtOH
95:5, R.sub.f = 0.25. HPLC R.sub.t = 1.23 min (method A) 88
##STR00110## 576
N-(2,2-Dimethylcyclopropyl-methyl)-2-(2-chloro-5-{[(tert-
butylcarbonyl)-amino]-methyl}-phenylamino)-6-(2,2-difluoro-
ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid amide TLC:
silica gel, DCM/EtOH 95:5, R.sub.f = 0.32. 89 ##STR00111## 562
N-(Cyclobutylmethyl)-2-(2-chloro-5-{[(tert-butylcarbonyl)-amino]-
methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-
benzimidazole-5-carboxylic acid amide TLC: silica gel, DCM/EtOH
9:1, R.sub.f = 0.62. 90 ##STR00112## 608
N-(3-Phenylpropargyl)-2-(2-chloro-5-{[(tert-butylcarbonyl)-amino]-
methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-
benzimidazole-5-carboxylic acid amide TLC: silica gel, DCM/EtOH
95:5, R.sub.f = 0.3. HPLC R.sub.t = 1.34 min (method A)
Example 91
2-({5-[(tert.
Butoxycarbonyl)amino]methyl}-2-trifluoromethyl-phenylamino)-6-methoxy-N-(-
trans-4-trifluoromethyl-cyclohex-1-yl)-1H-benzo[d]imidazole-5-carboxamide
##STR00113##
[0570] (a) 3-Nitro-4-trifluoromethyl-benzoic Acid Amide
[0571] 3-Nitro-4-trifluoromethyl-benzoylchloride (5.32 g, 21 mmol)
in 30 ml THF was added dropwise into 30 ml of conc ammonia. The
mixture was stirred overnight, filtered and the precipitate was
washed with water.
[0572] Yield: 3.05 g (62%); MS m/z: 233 [M+H].sup.-. TLC: silica
gel, DCM/EtOH 95:5, R.sub.f=0.3.
(b) 3-Nitro-4-trifluoromethyl-benzylamine
[0573] A 1 M solution of Borane in THF (51 ml, 51 mmol) was added
at 0.degree. C. to 3-nitro-4-trifluoromethyl-benzoic acid amide
(3.00 g, 12.8 mmol) in 50 ml THF and it was stirred for 3 days.
Methanol was carefully added and it was stirred for 30 min at r.t
and 2 h at reflux. Then it was concentrated i.vac.; NaOH was added
(pH 8) and the mixture was extracted with EtOAc. The organic layer
was dried with Na.sub.2SO.sub.4, filtered and concentrated to
furnish the crude subtitle compound.
(c) tert.-Butyl-N-(3-nitro-4-trifluoromethyl-benzyl)carbamate
[0574] The sub-title compound was prepared from crude
3-nitro-4-trifluoromethyl-benzylamine with di-tertbutyl-dicarbonate
in analogy to example 2a.
[0575] TLC: silica gel, DCM/EtOH 95:5, R.sub.f=0.73. MS m/z: 321
[M+H].sup.+.
(d) tert.-Butyl-N-(3-amino-4-trifluoromethyl-benzyl)carbamate
[0576] The sub-title compound was prepared from
tert.-butyl-N-(3-nitro-4-trifluoromethyl-benzyl)carbamate with
powdered iron in analogy to example 2b.
[0577] TLC: silica gel, DCM/EtOH 95:5, R.sub.f=0.51. MS m/z: 291
[M+H].sup.+.
(e)
tert.-Butyl-N-(3-isothiocyanato-4-trifluoromethyl-benzyl)carbamate
[0578] The sub-title compound was prepared from
tert.-butyl-N-(3-amino-4-trifluoromethyl-benzyl)carbamate with
1,1'-thiocarbonyldi-2-pyridone in analogy to example 1d,
[0579] Yield: 86%; TLC: silica gel, DCM/EtOH 95:5, R.sub.f=0.8.
(f)
N-(trans-4-Trifluoromethyl-cyclohex-1-yl)-2-methoxy-4-amino-5-nitro
Benzoic Acid Amide
[0580] The sub-title compound was prepared from
2-methoxy-4-amino-5-nitro benzoic acid and
trans-4-trifluoromethyl-cyclohexylamine with TBTU and TEA in DMF in
analogy to example 3e. Yield: quantitative; TLC: silica gel,
DCM/EtOH 9:1, R.sub.f=0.68.
(g) N-(trans-4-Trifluoromethyl-cyclohex-1-yl)-2-methoxy-4,5-diamino
Benzoic Acid Amide
[0581] The sub-title compound was prepared from
N-(trans-4-trifluoromethyl-cyclohex-1-yl)-2-methoxy-4-amino-5-nitro
benzoic acid amide with Ra--Ni in analogy to example 59 g.
[0582] Yield: 99%; TLC: silica gel, DCM/EtOH 9:1, R.sub.f=0.40.
(h)
2-({5-[(tert.Butoxycarbonyl)amino]methyl}-2-trifluoromethyl-phenylamin-
o)-6-methoxy-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-1H-benzo[d]imidazol-
e-5-carboxamide
[0583] The title compound was prepared from
N-(trans-4-trifluoromethyl-cyclohex-1-yl)-2-methoxy-4,5-diamino
benzoic acid amide and
tert.-Butyl-N-(3-isothiocyanato-4-trifluoromethyl-benzyl)carbamate
with DIC in analogy to example 72a.
[0584] Yield: 77%; TLC: silica gel, DCM/EtOH 95:5, R.sub.f=0.3. MS
m/z: 630 [M+H].sup.+.
Example 92
2-({5-[(2-Amino-3,3,3-trifluoro-propionyl)amino]methyl}-2-trifluoromethyl--
phenylamino)-6-methoxy-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-1H-benzo[-
d]imidazole-5-carboxamide
##STR00114##
[0585] (a)
2-(5-Aminomethyl-2-trifluoromethyl-phenylamino)-6-methoxy-N-(tr-
ans-4-trifluoromethyl-cyclohex-1-yl)-1H-benzo[d]imidazole-5-carboxamide
[0586] The title compound was prepared from
2-({5-[(tert.butoxycarbonyl)amino]methyl}-2-trifluoromethyl-phenylamino)--
6-methoxy-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-1H-benzo[d]imidazole-5-
-carboxamide and 6M HCl in THF in analogy to example 2e,
[0587] Yield: 76%; TLC: silica gel, DCM/EtOH/NH.sub.3aq 90:10:1,
R.sub.f=0.2. MS m/z: 530 [M+H].sup.+.
(b)
2-(5-{[(2-tert.Butoxycarbonylamino-3,3,3-trifluoro-propionyl)amino]met-
hyl}-2-trifluoromethyl-phenylamino)-6-methoxy-N-(trans-4-trifluoromethyl-c-
yclohex-1-yl)-1H-benzo[d]imidazole-5-carboxamide
[0588] The title compound was prepared from
2-(5-aminomethyl-2-trifluoromethyl-phenylamino)-6-methoxy-N-(trans-4-trif-
luoromethyl-cyclohex-1-yl)-1H-benzo[d]imidazole-5-carboxamide and
2-tert.butoxycarbonylamino-3,3,3-trifluoro-propionic acid with
TBTU, and TEA in THF in analogy to example 3e.
[0589] Yield: 70%; HPLC Rt=1.38 min (method A). TLC: silica gel,
DCM/EtOH 95:5:1, R.sub.f=0.3. MS m/z: 755 [M+H].sup.+.
(c)
2-({5-[(2-Amino-3,3,3-trifluoropropionyl)amino]methyl}-2-trifluorometh-
yl-phenylamino)-6-methoxy-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-1H-ben-
zo[d]imidazole-5-carboxamide
[0590] The title compound was prepared from
2-(5-{[(2-tert.Butoxycarbonylamino-3,3,3-trifluoro-propionyhamino]methyl}-
-2-trifluoromethyl-phenylamino)-6-methoxy-N-(trans-4-trifluoromethyl-cyclo-
hex-1-yl)-1H-benzo[d]imidazole-5-carboxamide and 6M HCl in THF in
analogy to example 2e.
[0591] Yield: 99%; HPLC R.sub.t=1.23 min (method A). TLC: silica
gel, DCM/EtOH/aq.NH.sub.3 95:5:1, R.sub.f=0.55. MS m/z: 655
[M+H].sup.+.
[0592] The following compounds were synthesized in analogy to the
methods of preparation described above in detail.
TABLE-US-00014 Chemical structure Name Ex. .sup.1H-NMR MS m/z [M +
H].sup.+ 93 ##STR00115## 666
N-(trans-4-Trifluoromethyl-cyclohex-1-yl)-2-(2-trifluoromethyl-5-
{[(1-trifluoromethylcyclopropanecarbonyl)amino]-methyl}-
phenylamino)-6-methoxy-1H-benzimidazole-5-carboxylic acid amide
TLC: silica gel, DCM/EtOH/aq.cndot.NH.sub.3 90:10:1, R.sub.f =
0.65. HPLC R.sub.t = 1.32 min (method A) 94 ##STR00116## 614
N-(trans-4-Trifluoromethyl-cyclohex-1-yl)-2-(2-trifluoromethyl-5-
{[(1-hydroxy-cyclopropanecarbonyl)amino]-methyl}-phenylamino)-
6-methoxy-1H-benzimidazole-5-carboxylic acid amide TLC: silica gel,
DCM/EtOH/aq.cndot.NH.sub.3 90:10:1, R.sub.f = 0.55. HPLC R.sub.t =
1.22 min (method A)
Example 95
N-(trans-4-Trifluoromethyl-cyclohex-1-yl)-1-methyl-2-(2-trifluoromethyl-5--
{[(tert-butylcarbonyl)-amino]-methyl}-ohenylamino)-6-(2,2-difluoro-ethoxy)-
-1H-benzimidazole-5-carboxylic Acid Amide
##STR00117##
[0593] (a) 3-Amino-4-trifluoromethyl-benzylamine
[0594] The title compound was prepared from
tert.-butyl-N-(3-amino-4-trifluoromethyl-benzyl)carbamate and 6M
HCl in THF in analogy to example 2e.
[0595] Yield: 99%; HPLC R.sub.t=0.68 min (method A). MS m/z: 191
[M+H]+.
(b) N-(3-Amino-4-trifluoromethyl-benzyl)-pivaloyl Amide
[0596] The sub-title compound was prepared from
3-amino-4-trifluoromethyl-benzylamine and pivaloylchloride with TEA
in analogy to example 1b.
[0597] Yield: 96%; HPLC R.sub.t=1.31 min (method A). MS m/z: 275
[M+H]+.
(c) N-(3-Isothiocyanato-4-trifluoromethyl-benzyl)-pivaloylamide
[0598] The sub-title compound was prepared from
N-(3-amino-4-trifluoromethyl-benzyl)-piyaloyl amide with
1,1'-thiocarbonyldi-2-pyridone in analogy to example 1d. Yield:
72%; TLC: silica gel, DCM/EtOH 95:5, R.sub.f=0.75.
(d)
5-Nitro-2-fluoro-4-(methylamino)-N-(trans-4-trifluoromethyl.cyclohex-1-
-yl)-benzamide
[0599] The sub-title compound was prepared from
4-trans-trifluoromethyl-cyclohexylamine and
2-fluoro-4-(methylamino)-5-nitrobenzoic acid with DIPEA and TBTU in
analogy to example 3e.
[0600] Yield: 70%; HPLC R.sub.t=1.44 min (method A). MS m/z: 364
[M+H]+.
(e)
5-Nitro-2-(2,2-difluoroethoxy)-4-(methylamino)-N-(trans-4-trifluoromet-
hyl-cyclohex-1-yl)-benzamide
[0601] The sub-title compound was prepared from
5-nitro-2-fluoro-4-(methylamino)-N-(trans-4-trifluoromethyl.cyclohex-1-yl-
)-benzamide and 2,2-difluoroethanol with KOtBu in analogy to
example 86b.
[0602] Yield: 89%; HPLC R.sub.t=1.47 min (method A). MS m/z: 426
[M+H]+.
(f)
5-Amino-2-(2,2-difluoroethoxy)-4-(methylamino)-N-(trans-4-trifluoromet-
hyl-cyclohex-1-yl)-benzamide
[0603] The sub-title compound was prepared from
5-nitro-2-(2,2-difluoroethoxy)-4-(methylamino)-N-(trans-4-trifluoromethyl-
-cyclohex-1-yl)-benzamide, hydrogen and Pd/C in analogy to example
86c.
[0604] Yield: 98%; HPLC R.sub.t=1.24 min (method A). MS m/z: 396
[M+H]+.
(g)
N-(trans-4-Trifluoromethyl-cyclohex-1-yl)-1-methyl-2-(2-trifluoromethy-
l-5-{[(tert-butylcarbonyl)-amino]-methyl}-phenylamino)-6-(2,2-difluoro-eth-
oxy)-1H-benzimidazole-5-carboxylic Acid Amide
[0605] The sub-title compound was prepared from
5-amino-2-(2,2-difluoroethoxy)-4-(methylamino)-N-(trans-4-trifluoromethyl-
-cyclohex-1-yl)-benzamide and
N-(3-isothiocyanato-4-trifluoromethyl-benzyl)-pivaloylamide in
analogy to example 72a. Yield: 51%; HPLC R.sub.t=1.38 min (method
A). MS m/z: 678 [M+H]+. TLC: silica gel, DCM/EtOH 95:5,
R.sub.f=0.3.
[0606] The following compounds were synthesized in analogy to the
methods of preparation described above in detail.
TABLE-US-00015 Chemical structure Name Ex. .sup.1H-NMR MS m/z [M +
H].sup.+ 96 ##STR00118## 664
N-(trans-4-Trifluoromethyl-cyclohex-1-yl)-2-(2-trifluoromethyl-5-
{[(tert-butylcarbonyl)-amino]-methyl}-phenylamino)-6-(2,2-difluoro-
ethoxy)-1H-benzimidazole-5-carboxylic acid amide TLC: silica gel,
DCM/EtOH 95:5, R.sub.f = 0.25. HPLC R.sub.t = 1.35 min (method A)
97 ##STR00119## 626
N-(trans-4-Trifluoromethyl-cyclohex-1-yl)-1-methyl-2-(2-chloro-5-
{[(tert-butylcarbonyl)-amino]-methyl}-phenylamino)-6-(2-fluoro-
ethoxy)-1H-benzimidazole-5-carboxylic acid amide HPLC R.sub.t =
1.32 min (method A) 98 ##STR00120## 662
N-(trans-4-Trifluoromethyl-cyclohex-1-yl)-1-methyl-2-(2-chloro-5-
{[(tert-butylcarbonyl)-amino]-methyl}-phenylamino)-6-(2,2,2-
trifluoro-ethoxy)-1H-benzimidazole-5-carboxylic acid amide TLC:
silica gel, DCM/EtOH 95:5, R.sub.f = 0.43. HPLC R.sub.t = 1.37 min
(method A)
Example 99
N-(trans-4-Trifluoromethyl-cyclohex-1-yl)-2-(2-methoxy-5-{[(tert-butylcarb-
onyl)-amino]-methyl}-phenylamino)-6-chloro-1H-benzimidazole-5-carboxylic
Acid Amide
##STR00121##
[0607] (a) N-(3-Amino-4-methoxy-benzyl)-pivaloyl Amide
[0608] The sub-title compound was prepared from
3-amino-4-methoxy-benzylamine and pivaloylchloride with TEA in
analogy to example 1b. Yield: 30%; MS m/z: 237 [M+H]+.
(b) N-(3-lsothiocyanato-4-methoxy-benzyl)-pivaloylamide
[0609] The sub-title compound was prepared from
N-(3-amino-4-methoxy-benzyl)-pivaloyl amide with
1,1'-thiocarbonyldi-2-pyridone in analogy to example 1d.
[0610] Yield: 99%; MS m/z: 279 [M+H]+.
(c)
5-Nitro-2-chloro-4-fluoro-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-be-
nzamide
[0611] The sub-title compound was prepared from
2-chloro-4-fluoro-5-nitrobenzoic acid--which was converted into the
corresponding acid chloride with thionyl chloride- and
4-trans-trifluoromethyl-cyclohexylamine according to example
70a.
[0612] Yield: 100%; MS m/z: 369 [M+H]+.
(d)
5-Nitro-2-chloro-4-amino-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-ben-
zamide
[0613] Conc. ammonia (0.8 ml) was added portionwise at -10.degree.
C. to a mixture of
5-nitro-2-chloro-4-fluoro-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-benza-
mide (0.20 g, 0.54 mmol) and 10 ml THF and it was stirred overnight
at room temperature. Water was added and the mixture was conc.
i.vac. The residue was triturated with water and filtered. The
filter cake was washed with water and dried to obtain the crude
subtitle compound (MS m/z: 366 [M+H]+).
(e)
4,5-Diamino-2-chloro-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-benzami-
de
[0614]
5-Nitro-2-chloro-4-amino-N-(trans-4-trifluoromethyl-cyclohex-1-yl)--
benzamide was hydrogenated with Ra--Ni in analogy to example 66 g.
The crude material was directly used without further
purification.
(f)
N-(trans-4-Trifluoromethyl-cyclohex-1-yl)-2-(2-methoxy-5-{[(tert-butyl-
carbonyl)-amino]-methyl}-phenylamino)-6-chloro-1H-benzimidazole-5-carboxyl-
ic Acid Amide
[0615] The compound was prepared from
4,5-diamino-2-chloro-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-benzamide
and N-(3-isothiocyanato-4-methoxy-benzyl)-pivaloylamide in analogy
to example 72a.
[0616] Yield: 32%; MS m/z: 580 [M+H]+.
Example 100
N-(4-Bromo-phenyl)-2-(2-chloro-5-{[(tert-butylcarbonyl)-amino]-methyl}-phe-
nylamino)-6-(2,2-difluoro-ethoxy)-1-(2,2-difluoroethyl)-1H-benzimidazole-5-
-carboxylic Acid Amide
##STR00122##
[0618] Ethyl
2-(2-chloro-5-{[(tert.butylcarbonyl)amino]methyl}phenylamino)-6-(2,2-difl-
uoroethoxy)-1-(2,2-difluoroethyl)-1H-benzo[d]imidazole-5-carboxylate
(prepared in analogy to example 86a-d) and 4-bromoaniline where
coupled using trimethylaluminium in analogy to example 59i.
[0619] Yield: (57%). TLC: silica gel, DCM/EtOH 9:1, R.sub.f=0.6. MS
m/z: 698 [M+H].sup.+.
* * * * *