U.S. patent application number 15/077422 was filed with the patent office on 2016-09-22 for acylamino-substituted fused cyclopentanecarboxylic acid derivatives and their use as pharmaceuticals.
The applicant listed for this patent is SANOFI. Invention is credited to L. Charlie CHEN, Werngard CZECHTIZKY, Dieter KADEREIT, Marcel PATEK, Josef PERNERSTORFER, Alena SAFAROVA, Matthias SCHAEFER, Hartmut STROBEL, Aleksandra WEICHSEL.
Application Number | 20160272577 15/077422 |
Document ID | / |
Family ID | 39870123 |
Filed Date | 2016-09-22 |
United States Patent
Application |
20160272577 |
Kind Code |
A1 |
SCHAEFER; Matthias ; et
al. |
September 22, 2016 |
ACYLAMINO-SUBSTITUTED FUSED CYCLOPENTANECARBOXYLIC ACID DERIVATIVES
AND THEIR USE AS PHARMACEUTICALS
Abstract
The present invention relates to compounds of the formula I,
##STR00001## wherein A, Y, Z, R.sup.3 to R.sup.6, R.sup.20 to
R.sup.22 and R.sup.50 have the meanings indicated in the claims,
which are valuable pharmaceutical active compounds. Specifically,
they are inhibitors of the endothelial differentiation gene
receptor 2 (Edg-2, EDG2), which is activated by lysophosphatidic
acid (LPA) and is also termed as LPA.sub.1 receptor, and are useful
for the treatment of diseases such as atherosclerosis, myocardial
infarction and heart failure, for example. The invention
furthermore relates to processes for the preparation of the
compounds of the formula I, their use and pharmaceutical
compositions comprising them.
Inventors: |
SCHAEFER; Matthias;
(Frankfurt am Main, DE) ; PERNERSTORFER; Josef;
(Frankfurt am Main, DE) ; KADEREIT; Dieter;
(Frankfurt am Main, DE) ; STROBEL; Hartmut;
(Frankfurt am Main, DE) ; CZECHTIZKY; Werngard;
(Frankfurt am Main, DE) ; CHEN; L. Charlie;
(Tucson, AZ) ; SAFAROVA; Alena; (Tucson, AZ)
; WEICHSEL; Aleksandra; (Tucson, AZ) ; PATEK;
Marcel; (Tucson, AZ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SANOFI |
Paris |
|
FR |
|
|
Family ID: |
39870123 |
Appl. No.: |
15/077422 |
Filed: |
March 22, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14314780 |
Jun 25, 2014 |
9328071 |
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15077422 |
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13867293 |
Apr 22, 2013 |
8802720 |
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14314780 |
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13632546 |
Oct 1, 2012 |
8445530 |
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13867293 |
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12939650 |
Nov 4, 2010 |
8362073 |
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13632546 |
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PCT/EP2009/002917 |
Apr 22, 2009 |
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12939650 |
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61117336 |
Nov 24, 2008 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/44 20130101;
A61P 9/12 20180101; C07C 323/62 20130101; C07D 213/81 20130101;
C07D 233/64 20130101; C07D 471/08 20130101; A61P 25/02 20180101;
C07C 321/26 20130101; C07D 235/12 20130101; C07D 333/78 20130101;
A61P 11/00 20180101; A61P 37/08 20180101; C07D 319/06 20130101;
C07C 315/04 20130101; A61P 7/02 20180101; A61P 13/00 20180101; A61P
9/04 20180101; A61P 17/06 20180101; A61P 25/18 20180101; A61P 35/04
20180101; A61P 5/16 20180101; C07C 2601/02 20170501; A61P 37/02
20180101; C07D 319/12 20130101; C07D 319/20 20130101; A61P 17/00
20180101; A61P 13/12 20180101; C07D 213/74 20130101; C07D 333/38
20130101; C07D 207/09 20130101; A61P 1/16 20180101; C07C 311/08
20130101; A61P 11/16 20180101; C07D 211/22 20130101; A61K 31/196
20130101; A61K 31/439 20130101; A61P 43/00 20180101; C07D 209/12
20130101; C07C 319/20 20130101; C07D 241/38 20130101; C07C 255/54
20130101; C07C 317/22 20130101; A61P 25/00 20180101; A61P 25/28
20180101; C07D 213/30 20130101; C07D 213/75 20130101; C07D 221/04
20130101; C07D 413/04 20130101; C07D 235/18 20130101; C07D 249/06
20130101; A61P 11/06 20180101; C07D 213/65 20130101; C07D 417/04
20130101; A61K 31/4409 20130101; A61K 31/216 20130101; A61P 25/04
20180101; A61P 37/00 20180101; C07C 235/54 20130101; C07C 307/10
20130101; C07C 317/46 20130101; C07C 323/19 20130101; C07D 263/32
20130101; C07D 305/06 20130101; A61P 9/08 20180101; A61P 5/00
20180101; C07D 231/12 20130101; C07D 261/04 20130101; C07D 271/08
20130101; C07D 295/20 20130101; A61P 35/00 20180101; A61P 19/00
20180101; C07C 235/62 20130101; C07D 207/08 20130101; C07D 285/06
20130101; A61P 9/14 20180101; A61P 5/14 20180101; C07D 333/16
20130101; C07C 2601/14 20170501; C07D 233/84 20130101; A61P 9/10
20180101; A61P 17/02 20180101; C07C 323/42 20130101; A61P 9/00
20180101; C07D 277/24 20130101; A61K 31/4965 20130101; C07C 255/58
20130101; C07D 213/73 20130101; C07D 277/56 20130101; C07C 319/12
20130101; C07C 2601/08 20170501; C07D 233/54 20130101; A61P 27/02
20180101; A61K 31/381 20130101; C07C 255/57 20130101; C07D 207/263
20130101; C07D 307/12 20130101; C07C 231/02 20130101; C07D 309/06
20130101; C07C 237/38 20130101; C07D 209/44 20130101; C07D 453/02
20130101; C07C 323/12 20130101; A61K 31/277 20130101; A61P 19/02
20180101; A61P 3/00 20180101; C07D 295/08 20130101; A61K 31/445
20130101; A61K 31/495 20130101; A61P 29/00 20180101; C07C 235/84
20130101; C07D 261/20 20130101; C07D 213/82 20130101; C07D 213/68
20130101; C07C 309/73 20130101; A61P 17/04 20180101; C07C 2602/08
20170501; C07D 333/56 20130101 |
International
Class: |
C07C 235/54 20060101
C07C235/54; C07C 321/26 20060101 C07C321/26; C07C 319/12 20060101
C07C319/12; C07C 317/46 20060101 C07C317/46; C07C 315/04 20060101
C07C315/04; C07D 213/30 20060101 C07D213/30; C07D 209/12 20060101
C07D209/12; C07D 307/12 20060101 C07D307/12; C07D 319/20 20060101
C07D319/20; C07D 211/22 20060101 C07D211/22; C07D 213/81 20060101
C07D213/81; C07D 213/65 20060101 C07D213/65; C07D 261/04 20060101
C07D261/04; C07D 319/06 20060101 C07D319/06; C07D 453/02 20060101
C07D453/02; C07D 207/08 20060101 C07D207/08; C07D 207/263 20060101
C07D207/263; C07D 235/18 20060101 C07D235/18; C07D 263/32 20060101
C07D263/32; C07D 231/12 20060101 C07D231/12; C07D 333/56 20060101
C07D333/56; C07D 233/64 20060101 C07D233/64; C07D 417/04 20060101
C07D417/04; C07D 233/84 20060101 C07D233/84; C07D 213/73 20060101
C07D213/73; C07D 249/06 20060101 C07D249/06; C07D 285/06 20060101
C07D285/06; C07D 413/04 20060101 C07D413/04; C07D 221/04 20060101
C07D221/04; C07C 231/02 20060101 C07C231/02 |
Foreign Application Data
Date |
Code |
Application Number |
May 5, 2008 |
EP |
08290427.7 |
Claims
1. A compound of formula I, ##STR00294## wherein ring A is a
3-membered to 7-membered cycloalkane ring, a benzene ring, or a
monocyclic 5-membered or 6-membered aromatic heterocyclic ring
which comprises 1 or 2 identical or different hetero ring members
chosen from the series consisting of N, N(R.sup.0), O and S,
wherein the cycloalkane ring is optionally substituted by one or
more identical or different substituents chosen from the series
consisting of fluorine and (C.sub.1-C.sub.4)-alkyl, and the benzene
ring and the heterocyclic rings are optionally substituted by one
or more identical or different substituents chosen from the series
consisting of halogen, R.sup.1, HO--, R.sup.1--O--,
R.sup.1--C(O)--O--, R.sup.1--S(O).sub.2--O--,
R.sup.1--S(O).sub.m--, H.sub.2N--, R.sup.1--NH--,
R.sup.1--N(R.sup.1)--, R.sup.1--C(O)--NH--,
R.sup.1--C(O)--N(R.sup.71)--, R.sup.1--S(O).sub.2--NH--,
R.sup.1--S(O).sub.2--N(R.sup.71)--, R.sup.1--C(O)--, HO--C(O)--,
R.sup.1--O--C(O)--, H.sub.2N--C(O)--, R.sup.1--NH--C(O)--,
R.sup.1--N(R.sup.1)--C(O)--, H.sub.2N--S(O).sub.2--,
R.sup.1--NH--S(O).sub.2--, R.sup.1--N(R.sup.1)--S(O).sub.2--, NC--,
O.sub.2N--, phenyl and Het; Y is chosen from the series consisting
of N(R.sup.10), S, O, C(R.sup.12).dbd.C(R.sup.13),
N.dbd.C(R.sup.14) and C(R.sup.15).dbd.N; Z is chosen from the
series consisting of N and C(R.sup.16); R.sup.0 is chosen from the
series consisting of hydrogen and R.sup.2; R.sup.1, R.sup.2,
R.sup.11, R.sup.30, R.sup.33, R.sup.35, R.sup.54, R.sup.55,
R.sup.57 and R.sup.58 are, independently of each other group
R.sup.1, R.sup.2, R.sup.11, R.sup.30, R.sup.33, R.sup.35, R.sup.54,
R.sup.55, R.sup.57 and R.sup.58, chosen from the series consisting
of (C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, (C.sub.3-C.sub.7)-cycloalkyl and
(C.sub.3-C.sub.7)-cycloalkyl-(C.sub.1-C.sub.4)-alkyl- which are all
optionally substituted by one or more identical or different
substituents R.sup.70; R.sup.3 and R.sup.5 are independently of
each other chosen from the series consisting of hydrogen,
(C.sub.1-C.sub.4)-alkyl, phenyl-(C.sub.1-C.sub.4)-alkyl-, phenyl
and hydroxy; R.sup.4 and R.sup.6 are independently of each other
chosen from the series consisting of hydrogen and
(C.sub.1-C.sub.4)-alkyl; R.sup.10 is chosen from the series
consisting of hydrogen and R.sup.11; R.sup.12, R.sup.13, R.sup.14,
R.sup.15 and R.sup.16 are independently of each other chosen from
the series consisting of hydrogen, halogen,
(C.sub.1-C.sub.4)-alkyl, HO--(C.sub.1-C.sub.4)-alkyl-,
(C.sub.1-C.sub.4)-alkyl-O--, (C.sub.1-C.sub.4)-alkyl-S(O).sub.m--,
H.sub.2N--, (C.sub.1-C.sub.4)-alkyl-NH--,
(C.sub.1-C.sub.4)-alkyl-N((C.sub.1-C.sub.4)-alkyl)-,
(C.sub.1-C.sub.4)-alkyl-C(O)--, NC-- and O.sub.2N--; R.sup.20 is
chosen from the series consisting of hydrogen and
(C.sub.1-C.sub.4)-alkyl; one of the groups R.sup.21 and R.sup.22 is
a group of the formula II R.sup.24--R.sup.23-- II and the other of
the groups R.sup.21 and R.sup.22 is chosen from the series
consisting of hydrogen, halogen, R.sup.30, HO--, R.sup.30--O--,
R.sup.30--C(O)--O--, R.sup.30--S(O).sub.2--O--,
R.sup.30--S(O).sub.m--, H.sub.2N--, R.sup.30--NH--,
R.sup.30--N(R.sup.30)--, R.sup.30--C(O)--NH--,
R.sup.30--C(O)--N(R.sup.71)--, R.sup.30--S(O).sub.2--NH--,
R.sup.30--S(O).sub.2--N(R.sup.71)--, R.sup.30--C(O)--, HO--C(O)--,
R.sup.30--O--C(O)--, H.sub.2N--C(O)--, R.sup.30--NH--C(O)--,
R.sup.30--N(R.sup.30)--C(O)--, H.sub.2N--S(O).sub.2--,
R.sup.30--NH--S(O).sub.2--, R.sup.30--N(R.sup.30)--S(O).sub.2--,
NC--, O.sub.2N-- and Het.sup.1; R.sup.23 is a direct bond or a
chain consisting of 1 to 5 chain members of which 0, 1 or 2 chain
members are identical or different hetero chain members chosen from
the series consisting of N(R.sup.25), O, S, S(O) and S(O).sub.2,
but two hetero chain members can be present in adjacent positions
only if one of them is chosen from the series consisting of S(O)
and S(O).sub.2 and the other is chosen from the series consisting
of N(R.sup.25), O and S, and the other chain members are identical
or different groups C(R.sup.26)(R.sup.26), wherein two adjacent
groups C(R.sup.26)(R.sup.26) can be connected to each other by a
double bond or a triple bond; R.sup.24 is chosen from the series
consisting of hydrogen, R.sup.31, HO--, R.sup.31--O--,
R.sup.31--C(O)--O--, R.sup.31--S(O).sub.m--, H.sub.2N--,
R.sup.31--NH--, R.sup.31--N(R.sup.31)--, R.sup.31--C(O)--NH--,
R.sup.31--C(O)--N(R.sup.71)--, R.sup.31--S(O).sub.2--NH--,
R.sup.31--S(O).sub.2--N(R.sup.71)--, R.sup.31--C(O)--, HO--C(O)--,
R.sup.31--O--C(O)--, H.sub.2N--C(O)--, R.sup.31--NH--C(O)--,
R.sup.31--N(R.sup.31)--C(O)--, H.sub.2N--S(O).sub.2--,
R.sup.31--NH--S(O).sub.2--, R.sup.31--N(R.sup.31)--S(O).sub.2--,
NC-- and a 3-membered to 10-membered, monocyclic, bicyclic or
tricyclic ring which is saturated or unsaturated and contains 0, 1,
2 or 3 identical or different hetero ring members chosen from the
series consisting of N, N(R.sup.32), O, S, S(O) and S(O).sub.2,
which ring is optionally substituted on ring carbon atoms by one or
more identical or different substituents chosen from the series
consisting of halogen, R.sup.33, HO--, R.sup.33--O--,
R.sup.33--C(O)--O--, R.sup.33--S(O).sub.2--O--,
R.sup.33--S(O).sub.m--, H.sub.2N--, R.sup.33--NH--,
R.sup.33--N(R.sup.33)--, R.sup.33--C(O)--NH--,
R.sup.33--C(O)--N(R.sup.71)--, R.sup.33--S(O).sub.2--NH--,
R.sup.33--S(O).sub.2--N(R.sup.71)--, H.sub.2N--S(O).sub.2--NH--,
R.sup.33--NH--S(O).sub.2--NH--,
R.sup.33--N(R.sup.33)--S(O).sub.2--NH--,
H.sub.2N--S(O).sub.2--N(R.sup.71)--,
R.sup.33--NH--S(O).sub.2--N(R.sup.71)--,
R.sup.33--N(R.sup.33)--S(O).sub.2--N(R.sup.71)--, R.sup.33--C(O)--,
HO--C(O)--, R.sup.33--O--C(O)--, H.sub.2N--C(O)--,
R.sup.33--NH--C(O)--, R.sup.33--N(R.sup.33)--C(O)--,
H.sub.2N--S(O).sub.2--, R.sup.33--NH--S(O).sub.2--,
R.sup.33--N(R.sup.33)--S(O).sub.2--, NC--, O.sub.2N--, oxo, phenyl
and Het, provided that the total number of C, N, O and S atoms
which is present in the two groups R.sup.23 and R.sup.24, is at
least 5; R.sup.25 is chosen from the series consisting of hydrogen
and (C.sub.1-C.sub.4)-alkyl; R.sup.26, independently of each other
group R.sup.26, is chosen from the series consisting of hydrogen,
fluorine, (C.sub.1-C.sub.4)-alkyl and HO--, or two groups R.sup.26
bonded to the same carbon atom together are oxo, or two of the
groups R.sup.26 or one group R.sup.25 and one group R.sup.26,
together with the comprised chain members, form a 3-membered to
7-membered monocyclic ring which is saturated and contains 0, 1 or
2 identical or different hetero ring members chosen from the series
consisting of N, N(R.sup.34), O, S, S(O) and S(O).sub.2, which ring
is optionally substituted on ring carbon atoms by one more
identical or different substituents chosen from the series
consisting of fluorine and (C.sub.1-C.sub.4)-alkyl; R.sup.31 is
chosen from the series consisting of (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.6)-alkenyl and (C.sub.2-C.sub.6)-alkynyl which are
all optionally substituted by one or more identical or different
substituents R.sup.70; R.sup.32 and R.sup.34 are independently of
each other chosen from the series consisting of hydrogen, R.sup.35,
R.sup.35--S(O).sub.2--, R.sup.35--C(O)--, R.sup.35--O--C(O)--,
phenyl and Het; R.sup.50 is chosen from the series consisting of
R.sup.51--O-- and R.sup.52--N(R.sup.53)--; R.sup.51 is chosen from
the series consisting of hydrogen and R.sup.54; R.sup.52 is chosen
from the series consisting of hydrogen, R.sup.55, NC-- and
R.sup.56--S(O).sub.2--; R.sup.53 is chosen from the series
consisting of hydrogen and R.sup.57; R.sup.56 is chosen from the
series consisting of R.sup.58 and phenyl; R.sup.60, independently
of each other group R.sup.60, is chosen from the series consisting
of hydrogen and (C.sub.1-C.sub.4)-alkyl; R.sup.70 is chosen from
the series consisting of HO--, R.sup.71--O--, R.sup.71--C(O)--O--,
R.sup.71--S(O).sub.m--, H.sub.2N--, R.sup.71--NH--,
R.sup.71--N(R.sup.71)--, R.sup.71--C(O)--NH--,
R.sup.71--C(O)--N(R.sup.71)--, R.sup.71--S(O).sub.2--NH--,
R.sup.71--S(O).sub.2--N(R.sup.71)--, HO--C(O)--,
R.sup.71--O--C(O)--, H.sub.2N--C(O)--, R.sup.71--NH--C(O)--,
R.sup.71--N(R.sup.71)--C(O)--, H.sub.2N--S(O).sub.2--,
R.sup.71--NH--S(O).sub.2--, R.sup.71--N(R.sup.71)--S(O).sub.2--,
NC--, oxo, phenyl and Het.sup.2; R.sup.71, independently of each
other group R.sup.71, is chosen from (C.sub.1-C.sub.4)-alkyl,
(C.sub.3-C.sub.4)-cycloalkyl and
(C.sub.3-C.sub.4)-cycloalkyl-(C.sub.1-C.sub.2)-alkyl-; Het,
independently of each other group Het, is a monocyclic 4-membered
to 7-membered heterocyclic ring which comprises 1, 2 or 3 identical
or different hetero ring members chosen from the series consisting
of N, N(R.sup.60), O, S, S(O) and S(O).sub.2, which ring is
saturated or unsaturated and is optionally substituted by one or
more identical or different substituents chosen from the series
consisting of halogen, (C.sub.1-C.sub.4)-alkyl and R.sup.70;
Het.sup.1 is a monocyclic 4-membered to 7-membered heterocyclic
ring which comprises 1 or 2 identical or different hetero ring
members chosen from the series consisting of N, N(R.sup.60), O, S,
S(O) and S(O).sub.2, which ring is saturated and is optionally
substituted by one or more identical or different substituents
chosen from the series consisting of fluorine and
(C.sub.1-C.sub.4)-alkyl; Het.sup.2 is a monocyclic 5-membered or
6-membered heterocyclic ring which comprises 1, 2 or 3 identical or
different hetero ring members chosen from the series consisting of
N, N(R.sup.60), O and S, which ring is aromatic and is optionally
substituted by one or more identical or different substituents
chosen from the series consisting of halogen,
(C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkyl-O-- and NC--; m,
independently of each other number m, is an integer chosen from the
series consisting of 0, 1 and 2; phenyl, independently of each
other group phenyl, is optionally substituted by one or more
identical or different substituents chosen from the series
consisting of halogen, (C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.4)-alkyl-O-- and NC--, unless specified otherwise;
cycloalkyl, independently of each other group cycloalkyl, and
independently of any other substituents on cycloalkyl, is
optionally substituted by one or more identical or different
substituents chosen from fluorine and (C.sub.1-C.sub.4)-alkyl; and
alkyl, alkenyl and alkynyl, independently of each other group
alkyl, alkenyl and alkynyl, and independently of any other
substituents on alkyl, alkenyl and alkynyl, is optionally
substituted by one or more fluorine substituents; in any of its
stereoisomeric forms or a mixture of stereoisomeric forms in any
ratio, or a physiologically acceptable salt thereof, or a
physiologically acceptable solvate of any of them, provided that
the compound of the formula I is not
2-[(6,2',4'-trichlorobiphenyl-3-carbonyl)amino]indane-2-carboxylic
acid,
2-[6-chloro-[1,1',4',1'']terphenyl-3-carbonyl)amino]indane-2-carboxylic
acid, 2-(4-chloro-3-phenylethynyl-benzoylamino)-indane-2-carboxylic
acid,
5-(4-chloro-phenyl)-2-[4-(2-methyl-1H-benzoimidazol-1-ylmethyl)-benzoylam-
ino]-indane-2-carboxylic acid or
5-(4-chloro-phenyl)-2-[4-(2-methyl-1H-benzoimidazol-1-ylmethyl)-benzoylam-
ino]-indane-2-carboxylic acid ethyl ester.
2. The compound according to claim 1, wherein: R.sup.3 and R.sup.5
are independently of each other chosen from the series consisting
of hydrogen, (C.sub.1-C.sub.4)-alkyl,
phenyl-(C.sub.1-C.sub.4)-alkyl- and phenyl; in any of its
stereoisomeric forms or a mixture of stereoisomeric forms in any
ratio, or a physiologically acceptable salt thereof, or a
physiologically acceptable solvate of any of them.
3. The compound according to claim 1, wherein: ring A is a
cyclohexane ring, a benzene ring, a pyridine ring, a pyridazine
ring or a thiophene ring, wherein the cyclohexane ring is
optionally substituted by one or more identical or different
substituents chosen from the series consisting of fluorine and
(C.sub.1-C.sub.4)-alkyl, and the benzene ring, the pyridine ring,
the pyridazine ring and the thiophene ring are optionally
substituted by one or more identical or different substituents
chosen from the series consisting of halogen, R.sup.1, HO--,
R.sup.1--O--, R.sup.1--C(O)--O--, R.sup.1--S(O).sub.2--O--,
R.sup.1--S(O).sub.m--, H.sub.2N--, R.sup.1--NH--,
R.sup.1--N(R.sup.1)--, R.sup.1--C(O)--NH--,
R.sup.1--C(O)--N(R.sup.71)--, R.sup.1--S(O).sub.2--NH--,
R.sup.1--S(O).sub.2--N(R.sup.71)--, R.sup.1--C(O)--, HO--C(O)--,
R.sup.1--O--C(O)--, H.sub.2N--C(O)--, R.sup.1--NH--C(O)--,
R.sup.1--N(R.sup.1)--C(O)--, H.sub.2N--S(O).sub.2--,
R.sup.1--NH--S(O).sub.2--, R.sup.1--N(R.sup.1)--S(O).sub.2--, NC--
and O.sub.2N--; Y is chosen from the series consisting of S,
C(R.sup.12).dbd.C(R.sup.13), and C(R.sup.15).dbd.N; and Z is
C(R.sup.16); in any of its stereoisomeric forms or a mixture of
stereoisomeric forms in any ratio, or a physiologically acceptable
salt thereof, or a physiologically acceptable solvate of any of
them.
4. The compound according to claim 1, wherein: ring A is a benzene
ring, a pyridine ring, a pyrazine or a thiophene ring which rings
are all optionally substituted by one or two identical or different
substituents chosen from the series consisting of halogen,
(C.sub.1-C.sub.4)-alkyl and (C.sub.1-C.sub.4)-alkyl-O--; Y is
chosen from the series consisting of S, C(R.sup.12).dbd.C(R.sup.13)
and C(R.sup.15).dbd.N; Z is C(R.sup.16); R.sup.3 and R.sup.5 are
independently of each other chosen from the series consisting of
hydrogen and (C.sub.1-C.sub.4)-alkyl; R.sup.4 and R.sup.6 are
hydrogen; R.sup.12, R.sup.13, R.sup.15 and R.sup.16 are
independently of each other chosen from the series consisting of
hydrogen, halogen (C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.4)-alkyl-O-- and NC--; and R.sup.20 is hydrogen; in
any of its stereoisomeric forms or a mixture of stereoisomeric
forms in any ratio, or a physiologically acceptable salt thereof,
or a physiologically acceptable solvate of any of them.
5. The compound according to claim 1, wherein: R.sup.21 is chosen
from the series consisting of hydrogen, halogen,
(C.sub.1-C.sub.4)-alkyl, HO--(C.sub.1-C.sub.4)-alkyl-,
(C.sub.1-C.sub.4)-alkyl-O--, (C.sub.1-C.sub.4)-alkyl-S(O).sub.m--,
H.sub.2N--, (C.sub.1-C.sub.4)-alkyl-NH--,
di((C.sub.1-C.sub.4)-alkyl)N--, (C.sub.1-C.sub.4)-alkyl-C(O)-- and
NC--; R.sup.22 is a group of the formula II; R.sup.24--R.sup.23--
II R.sup.23 is a direct bond or a chain consisting of 2, 3 or 4
chain members of which 0 or 1 chain members are hetero chain
members chosen from the series consisting of N(R.sup.25), O, S,
S(O) and S(O).sub.2, and the other chain members are identical or
different groups C(R.sup.26)(R.sup.26), wherein two adjacent groups
C(R.sup.26)(R.sup.26) can be connected to each other by a double
bond or a triple bond; in any of its stereoisomeric forms or a
mixture of stereoisomeric forms in any ratio, or a physiologically
acceptable salt thereof, or a physiologically acceptable solvate of
any of them.
6. The compound according to claim 1, wherein: R.sup.24 is a
3-membered to 7-membered monocyclic ring or a 7-membered to
10-membered bicyclic ring, which rings are saturated or unsaturated
and contain 0, 1 or 2 identical or different hetero ring members
chosen from the series consisting of N, N(R.sup.32), O, S, S(O) and
S(O).sub.2, and which rings are optionally substituted on ring
carbon atoms by one or more identical or different substituents
chosen from the series consisting of halogen, R.sup.33, HO--,
R.sup.33--O--, R.sup.33--S(O).sub.m--, H.sub.2N--, R.sup.33--NH--,
R.sup.33--N(R.sup.33)--, R.sup.33--C(O)--NH--,
R.sup.33--C(O)--N(R.sup.71)--, R.sup.33--S(O).sub.2--NH--,
R.sup.33--S(O).sub.2--N(R.sup.71)--, H.sub.2N--S(O).sub.2--NH--,
R.sup.33--NH--S(O).sub.2--NH--,
R.sup.33--N(R.sup.33)--S(O).sub.2--NH--,
H.sub.2N--S(O).sub.2--N(R.sup.71)--,
R.sup.33--NH--S(O).sub.2--N(R.sup.71)--,
R.sup.33--N(R.sup.33)--S(O).sub.2--N(R.sup.71)--, HO--C(O)--,
R.sup.33--O--C(O)--, H.sub.2N--C(O)--, R.sup.33--NH--C(O)--,
R.sup.33--N(R.sup.33)--C(O)--, NC--, oxo, phenyl and Het; and
R.sup.32 is chosen from the series consisting of hydrogen,
R.sup.35, R.sup.35--C(O)--, R.sup.35--O--C(O)-- and phenyl; in any
of its stereoisomeric forms or a mixture of stereoisomeric forms in
any ratio, or a physiologically acceptable salt thereof, or a
physiologically acceptable solvate of any of them.
7. The compound according to claim 1, wherein: ring A is a benzene
ring, a pyridine ring, a pyrazine or a thiophene ring which rings
are all optionally substituted by one or two identical or different
substituents chosen from the series consisting of halogen,
(C.sub.1-C.sub.4)-alkyl and (C.sub.1-C.sub.4)-alkyl-O--; Y is
chosen from the series consisting of S, C(R.sup.12).dbd.C(R.sup.13)
and C(R.sup.15).dbd.N; Z is C(R.sup.16); R.sup.3 and R.sup.5 are
independently of each other chosen from the series consisting of
hydrogen and (C.sub.1-C.sub.4)-alkyl; R.sup.4 and R.sup.6 are
hydrogen; R.sup.12, R.sup.13, R.sup.15 and R.sup.16 are
independently of each other chosen from the series consisting of
hydrogen, halogen (C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.4)-alkyl-O-- and NC--; R.sup.20 is hydrogen;
R.sup.21 is chosen from the series consisting of hydrogen, halogen,
(C.sub.1-C.sub.4)-alkyl, HO--(C.sub.1-C.sub.4)-alkyl-,
(C.sub.1-C.sub.4)-alkyl-O--, (C.sub.1-C.sub.4)-alkyl-S(O).sub.m--,
H.sub.2N--, (C.sub.1-C.sub.4)-alkyl-NH--,
di((C.sub.1-C.sub.4)-alkyl)N--, (C.sub.1-C.sub.4)-alkyl-C(O)-- and
NC--; R.sup.22 is a group of the formula II; R.sup.24--R.sup.23--
II R.sup.23 is a direct bond or a chain consisting of 2, 3 or 4
chain members of which 0 or 1 chain members are hetero chain
members chosen from the series consisting of N(R.sup.25), O, S,
S(O) and S(O).sub.2, and the other chain members are identical or
different groups C(R.sup.26)(R.sup.26), wherein two adjacent groups
C(R.sup.26)(R.sup.26) can be connected to each other by a double
bond or a triple bond; R.sup.24 is a 3-membered to 7-membered
monocyclic ring or a 7-membered to 10-membered bicyclic ring, which
rings are saturated or unsaturated and contains 0, 1 or 2 identical
or different hetero ring members chosen from the series consisting
of N, N(R.sup.32), O, S, S(O) and S(O).sub.2, which ring is
optionally substituted on ring carbon atoms by one or more
identical or different substituents chosen from the series
consisting of halogen, R.sup.33, HO--, R.sup.33--O--,
R.sup.33--S(O).sub.m--, H.sub.2N--, R.sup.33--NH--,
R.sup.33--N(R.sup.33)--, R.sup.33--C(O)--NH--,
R.sup.33--C(O)--N(R.sup.71)--, R.sup.33--S(O).sub.2--NH--,
R.sup.33--S(O).sub.2--N(R.sup.71)--, HO--C(O)--,
R.sup.33--O--C(O)--, H.sub.2N--C(O)--, R.sup.33--NH--C(O)--,
R.sup.33--N(R.sup.33)--C(O)--, NC--, oxo, phenyl and Het; and
R.sup.32 is chosen from the series consisting of hydrogen,
R.sup.35, R.sup.35--C(O)--, R.sup.35--O--C(O)-- and phenyl; in any
of its stereoisomeric forms or a mixture of stereoisomeric forms in
any ratio, or a physiologically acceptable salt thereof, or a
physiologically acceptable solvate of any of them.
8. The compound according to claim 1, wherein ring A is a benzene
ring which is optionally substituted by one or two identical or
different substituents chosen from the series consisting of
halogen, (C.sub.1-C.sub.4)-alkyl and (C.sub.1-C.sub.4)-alkyl-O--; Y
is C(R.sup.12).dbd.C(R.sup.13); Z is C(R.sup.16); R.sup.3, R.sup.4,
R.sup.5 and R.sup.6 are hydrogen; R.sup.12, R.sup.13 and R.sup.16
are independently of each other chosen from the series consisting
of hydrogen, halogen, (C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.4)-alkyl-O-- and NC--; R.sup.20 is hydrogen;
R.sup.21 is chosen from the series consisting of hydrogen, halogen,
(C.sub.1-C.sub.4)-alkyl, HO--(C.sub.1-C.sub.4)-alkyl-,
(C.sub.1-C.sub.4)-alkyl-O--, (C.sub.1-C.sub.4)-alkyl-S(O).sub.m--,
(C.sub.1-C.sub.4)-alkyl-C(O)-- and NC--; R.sup.22 is a group of the
formula II; R.sup.24--R.sup.23-- II R.sup.23 is a direct bond or a
chain consisting of 2, 3 or 4 chain members of which 0 or 1 chain
members are hetero chain members chosen from the series consisting
of N(R.sup.25), O, S, S(O) and S(O).sub.2, and the other chain
members are identical or different groups C(R.sup.26)(R.sup.26);
R.sup.24 is a benzene ring which is optionally substituted by one
or more identical or different substituents chosen from the series
consisting of halogen, R.sup.33, HO--, R.sup.33--O--,
R.sup.33--S(O).sub.m--, H.sub.2N--, R.sup.33--NH--,
R.sup.33--N(R.sup.33)--, R.sup.33--C(O)--NH--,
R.sup.33--S(O).sub.2--NH--, HO--C(O)--, R.sup.33--O--C(O)--,
H.sub.2N--C(O)--, R.sup.33--NH--C(O)--,
R.sup.33--N(R.sup.33)--C(O)-- and NC--; provided that the total
number of C, N, O and S atoms which is present in the two groups
R.sup.23 and R.sup.24, is at least 5; R.sup.25 is chosen from the
series consisting of hydrogen and (C.sub.1-C.sub.4)-alkyl;
R.sup.26, independently of each other group R.sup.26, is chosen
from the series consisting of hydrogen, fluorine,
(C.sub.1-C.sub.4)-alkyl and HO--, or two of the groups R.sup.26
which are bonded to the same carbon atom in the chain, together
with the carbon atom carrying them, form a cyclopropane ring;
R.sup.33 is, independently of each other group R.sup.33, chosen
from the series consisting of (C.sub.3-C.sub.7)-cycloalkyl and
(C.sub.3-C.sub.7)-cycloalkyl-(C.sub.1-C.sub.2)-alkyl-, which are
all optionally substituted by one or more identical or different
substituents R.sup.70; R.sup.50 is chosen from the series
consisting of R.sup.51--O-- and R.sup.52--N(R.sup.53)--; R.sup.51
is chosen from the series consisting of hydrogen and
(C.sub.1-C.sub.4)-alkyl; R.sup.52 is chosen from the series
consisting of hydrogen and (C.sub.1-C.sub.4)-alkyl; R.sup.53 is
chosen from the series consisting of hydrogen and
(C.sub.1-C.sub.4)-alkyl; R.sup.70 is chosen from the series
consisting of HO-- and R.sup.71--O--; R.sup.71 is
(C.sub.1-C.sub.4)-alkyl; m, independently of each other number m,
is an integer chosen from the series consisting of 0 and 2;
cycloalkyl, independently of each other group cycloalkyl, and
independently of any other substituents on cycloalkyl, is
optionally substituted by one or more identical or different
substituents chosen from fluorine and (C.sub.1-C.sub.4)-alkyl; and
alkyl, independently of each other group alkyl, and independently
of any other substituents on alkyl, is optionally substituted by
one or more fluorine substituents; in any of its stereoisomeric
forms or a mixture of stereoisomeric forms in any ratio, or a
physiologically acceptable salt thereof, or a physiologically
acceptable solvate of any of them.
9. The compound according to claim 1, which is
2-[4-methylsulfanyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxyli-
c acid,
2-[4-acetyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid,
2-[4-ethyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid,
2-[4-ethoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid,
2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid,
2-{4-methoxy-3-[2-(3-trifluoromethylsulfanyl-phenyl)-ethoxy]-benzoy-
lamino}-indane-2-carboxylic acid,
2-[4-methoxy-3-(1-m-tolyl-cyclopropylmethoxy)-benzoylamino]-indane-2-carb-
oxylic acid,
2-{3-[2-(3-cyano-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxy-
lic acid,
5-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-5,6-dihydro-4H-c-
yclopenta[b]thiophene-5-carboxylic acid,
2-{[5-acetyl-4-(2-m-tolyl-ethoxy)-thiophene-2-carbonyl]-amino}-indane-2-c-
arboxylic acid,
2-[3-fluoro-4-methoxy-5-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxy-
lic acid,
2-[4-methoxy-3-(2-m-tolyloxy-ethyl)-benzoylamino]-indane-2-carbo-
xylic acid,
2-[4-methoxy-3-(3-m-tolyl-propyl)-benzoylamino]-indane-2-carboxylic
acid,
5-fluoro-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxy-
lic acid,
2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-5,6-dimethyl-ind-
ane-2-carboxylic acid,
2-[4-cyano-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid,
2-[4-methoxy-3-(2-m-tolyl-ethylamino)-benzoylamino]-indane-2-carboxylic
acid,
2-{3-[2-(3-chloro-phenyl)-ethoxy]-4-methyl-benzoylamino}-indane-2-c-
arboxylic acid,
2-[4-methoxy-3-(2-m-tolyl-ethylsulfanyl)-benzoylamino]-indane-2-carboxyli-
c acid,
2-[3-(2-m-tolyl-ethoxy)-4-trifluoromethyl-benzoylamino]-indane-2-c-
arboxylic acid,
2-{3-[2-(2-fluoro-5-methyl-phenyl)-ethoxy]-4-trifluoromethyl-benzoylamino-
}-indane-2-carboxylic acid,
2-(3-{2-[3-(2-hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-inda-
ne-2-carboxylic acid,
2-{[6-methoxy-5-(2-m-tolyl-ethoxy)-pyridine-3-carbonyl]-amino}-indane-2-c-
arboxylic acid,
2-[(3'-methanesulfonylamino-6-methoxy-biphenyl-3-carbonyl)-amino]-indane--
2-carboxylic acid,
2-[(3'-dimethylaminosulfonylamino-6-methoxy-biphenyl-3-carbonyl)-amino]-i-
ndane-2-carboxylic acid,
2-[(6-methoxy-3'-trifluoromethoxy-biphenyl-3-carbonyl)-amino]-indane-2-ca-
rboxylic acid,
2-[(3'-cyanomethyl-6-methoxy-biphenyl-3-carbonyl)-amino]-indane-2-carboxy-
lic acid,
2-[(3'-isopropyl-6-methoxy-biphenyl-3-carbonyl)-amino]-indane-2--
carboxylic acid,
2-[(3-chloro-6-methoxy-Z-methyl-biphenyl-3-carbonyl)-amino]-indane-2-carb-
oxylic acid,
2-{[5-(3-chloro-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-indane-2-ca-
rboxylic acid, or
2-[3-(2,2-difluoro-2-phenyl-ethoxy)-4-methoxy-benzoylamino]-indane-2-carb-
oxylic acid; in any of its stereoisomeric forms or a mixture of
stereoisomeric forms in any ratio, or a physiologically acceptable
salt thereof, or a physiologically acceptable solvate of any of
them.
10. A process for the compound according to claim 1, comprising
reacting a compound of formula III with a compound of the formula
IV, ##STR00295## wherein the ring A and the groups Y, Z, R.sup.3 to
R.sup.6, R.sup.20 to R.sup.22 and R.sup.50 in the compounds of the
formulae III and IV are defined as in claim 1 and additionally
functional groups can be present in protected form or in the form
of a precursor group, and the group G in the compound of the
formula IV is HO--, (C.sub.1-C.sub.4)-alkyl-O-- or halogen.
11. A pharmaceutical composition comprising the compound according
to claim 1, in any of its stereoisomeric forms or a mixture of
stereoisomeric forms in any ratio, or a physiologically acceptable
salt thereof, or a physiologically acceptable solvate of any of
them, and a pharmaceutically acceptable carrier.
12. A pharmaceutical composition comprising the compound according
to claim 9, in any of its stereoisomeric forms or a mixture of
stereoisomeric forms in any ratio, or a physiologically acceptable
salt thereof, or a physiologically acceptable solvate of any of
them, and a pharmaceutically acceptable carrier.
13. A method for treating a cardiovascular disease, heart failure,
cardiomyopathy, myocardial infarction, myocardial remodeling,
vascular remodeling, hypertension, atherosclerosis, peripheral
arterial occlusive disease, restenosis, thrombosis, vascular
permeability disorder, an inflammatory disease, rheumatoid
arthritis, osteoarthritis, renal disease, renal papillary necrosis,
renal failure, a pulmonary disease, chronic obstructive pulmonary
disease, asthma, acute respiratory dystress syndrome, an
immunological disease, an allergic disease, tumor growth,
metastasis, a metabolic disease, a fibrotic disease, pulmonary
fibrosis, cardiac fibrosis, vascular fibrosis, perivascular
fibrosis, renal fibrosis, liver fibrosis, fibrosing skin condition,
psoriasis, pain, pruritus, retinal ischemia, reperfusion damage,
macular degeneration, a psychiatric disorder, a neurodegenerative
disease, a cerebral nerve disorder, a peripheral nerve disorder, an
endocrinic disorder, hyperthyroidism, a scarring disorder or a
would healing disorder, or for cardioprotection or renoprotection,
in a patient in need thereof, comprising administering to the
patient a pharmaceutically effective amount of the compound
according to claim 1, in any of its stereoisomeric forms or a
mixture of stereoisomeric forms in any ratio, or a physiologically
acceptable salt thereof, or a physiologically acceptable solvate of
any of them.
14. A method for treating a cardiovascular disease, heart failure,
cardiomyopathy, myocardial infarction, myocardial remodeling,
vascular remodeling, hypertension, atherosclerosis, peripheral
arterial occlusive disease, restenosis, thrombosis, vascular
permeability disorder, an inflammatory disease, rheumatoid
arthritis, osteoarthritis, renal disease, renal papillary necrosis,
renal failure, a pulmonary disease, chronic obstructive pulmonary
disease, asthma, acute respiratory dystress syndrome, an
immunological disease, an allergic disease, tumor growth,
metastasis, a metabolic disease, a fibrotic disease, pulmonary
fibrosis, cardiac fibrosis, vascular fibrosis, perivascular
fibrosis, renal fibrosis, liver fibrosis, fibrosing skin condition,
psoriasis, pain, pruritus, retinal ischemia, reperfusion damage,
macular degeneration, a psychiatric disorder, a neurodegenerative
disease, a cerebral nerve disorder, a peripheral nerve disorder, an
endocrinic disorder, hyperthyroidism, a scarring disorder or a
would healing disorder, or for cardioprotection or renoprotection,
in a patient in need thereof, comprising administering to the
patient a pharmaceutically effective amount of the compound
according to claim 9, in any of its stereoisomeric forms or a
mixture of stereoisomeric forms in any ratio, or a physiologically
acceptable salt thereof, or a physiologically acceptable solvate of
any of them.
Description
[0001] The present invention relates to compounds of the formula
I,
##STR00002##
wherein A, Y, Z, R.sup.3 to R.sup.6, R.sup.20 to R.sup.22 and
R.sup.50 have the meanings indicated below, which are valuable
pharmaceutical active compounds. Specifically, they are inhibitors
of the endothelial differentiation gene receptor 2 (Edg-2, EDG2),
which is activated by lysophosphatidic acid (LPA) and is also
termed as LPA.sub.1 receptor, and are useful for the treatment of
diseases such as atherosclerosis, myocardial infarction and heart
failure, for example. The invention furthermore relates to
processes for the preparation of the compounds of the formula I,
their use and pharmaceutical compositions comprising them.
[0002] LPA is a group of endogenous lysophospholipid derivatives
including 1-oleoyl-sn-glycerol 3-phosphate, for example. LPA
activates G-protein-coupled receptors (GPCR's) from the endothelial
differentiation gene receptor family which belong to the
lysophospholipid receptors. LPA signaling exerts a variety of
pleiotropic biological responses on many different cell types which
interfere with processes such as cell proliferation, cell growth,
cell hypertrophy, re-differentiation, cell retraction, cell
contraction, cell migration, cell survival or inflammation. The Edg
receptor family, originally identified as a family of orphan
GPCR's, currently comprises eight different members which were
recently termed according to their respective ligand as LPA
receptors or S1P receptors (sphingosine-1-phosphate receptors).
According to the nomenclature of the International Union of Basic
and Clinical Pharmacology (IUPHAR), LPA receptors Edg-2, Edg-4 and
Edg-7 are now also termed as LPA.sub.1, LPA.sub.2 and LPA.sub.3
receptor (cf. I. Ishii et al., Annu. Rev. Biochem. 73 (2004),
321-354).
[0003] LPA is generated mainly in the extracellular compartment by
different pathways predominantly by the cancer cell motility factor
autotaxin which was recently found to be identical with
lysophospholipase D. LPA can also be generated by alternative
routes involving phospholipase hydrolysis (PLA.sub.1 and PLA.sub.2)
or other mechanisms such as de novo phospholipid synthesis.
Although LPA, in contrast to other phospholipids, is highly soluble
in water, in plasma it is carried by different binding proteins
such as albumin and gelsolin which display a high affinity to LPA
and from which it can be released. Under pathophysiological
conditions, levels of LPA can be elevated to an undesirable amount
and thus increase LPA-mediated signaling and lead to detrimental
processes such as abnormal cell proliferation, for example.
Blocking LPA signaling, for example by Edg-2 inhibitors, allows to
prevent such processes.
[0004] For example, increased liberation of LPA was observed during
platelet activation and blood clotting and at sites of inflammation
(T. Sano et. al., J. Biol. Chem. 277 (2002), 21197-21206). After
acute myocardial infarction (AMI) in humans, LPA serum levels were
significantly raised in humans to about 6-fold higher
concentrations, and LPA was regarded to be involved in the
pathophysiological processes in the cardiovascular system related
to AMI (X. Chen et al., Scand. J. Clin. Lab. Invest. 63 (2003),
497-503). The importance of LPA and its receptor Edg-2 for the
pathophysiological processes after myocardial infarction such as
cardiac remodeling and for the prevention of cardiac hypertrophy
and heart failure was confirmed in further investigations (J. Chen
et al., J. Cell. Biochem. 103 (2008), 1718-1731). LPA was shown to
be generated during mild oxidation of low density lipoprotein (LDL)
particles and to be accumulated in the lipid core of human
atherosclerotic plaques (W. Siess et al., Proc. Natl. Acad. Sci. 96
(1999), 6931-6936). Furthermore, LPA was identified as an important
bioactive component of moxLDL (mildly oxidized low density
lipoprotein) leading to platelet activation, and it was shown that
the effects of LPA, moxLDL or lipid core extracts from human
atherosclerotic plaques on platelet activation could be abrogated
by the Edg-2/Edg-7 receptor inhibitor dioctanoylglycerol
pyrophosphate DGPP(8:0), implicating a causative role of
LPA-mediated Edg receptor signaling in platelet aggregation and
usefulness of such LPA receptor inhibitors in the treatment of
cardiovascular diseases (E. Rother et al., Circulation 108 (2003),
741-747).
[0005] Further findings underline the detrimental role of LPA
during initiation and progression of cardiovascular diseases such
as atherosclerosis, left ventricular remodeling and heart failure.
LPA leads to pertussis toxin-sensitive, NF.kappa.B (nuclear factor
kappa B)-mediated pro-inflammatory responses of endothelial cells
including upregulation of chemokines like monocyte chemoattractant
protein-1 (MCP-1) and interleukin-8 (IL8) (A. Palmetshofer et al.,
Thromb. Haemost. 82 (1999), 1532-1537) and exposure of endothelial
cell adhesion molecules like E-selectin or intercellular adhesion
molecule-1 (ICAM-1) (H. Lee et al., Am. J. Physiol. 287 (2004),
C1657-C1666). Direct evidence for the involvement of Edg-2
receptors arises from recent studies which demonstrate that LPA
induces oxidative stress in vascular smooth muscle cells and
endothelial cells which was attenuated by pharmacological
inhibition by DGPP(8:0) or THG1603, a specific Edg-2 receptor
antagonist (U. Kaneyuki et al., Vascular Pharmacology 46 (2007),
286-292; S. Brault et al., Am. J. Physiol. Regul. Integr. Comp.
Physiol. 292 (2007), R1174-R1183). In vascular smooth muscle cells,
LPA leads to pertussis toxin-sensitive Ca.sup.2+ release from
internal stores, to activation of 42 kDa mitogen-activated protein
kinase (p42MAPK) and to cell proliferation (S. Seewald et al.,
Atherosclerosis 130 (1997), 121-131). Intravascular injection of
LPA was shown to induce neointima formation in vivo (K. Yoshida et
al., Circulation 108 (2003), 1746-1752). On isolated adult cardiac
myocytes, LPA leads to cellular hypertrophy and to activation of
different kinases known to be relevant for a hypertrophic response
(Y.-J. Xu et al., Biochemical Pharmacology 59 (2000), 1163-1171).
Studies on neonatal myocytes confirmed a role of LPA in the
induction of hypertrophy and revealed the relevance of a rho
kinase-dependent pathway (R. Hilal-Dandan et al., J. Mol. Cell.
Cardiol. 36 (2004), 481-493). The relevance of rho kinase
underlines the involvement of the Edg-2 receptors which, in
contrast to Edg-7 receptors, are coupled to G.sub..alpha.12/13
proteins. LPA furthermore attenuates the force of contraction in
human myocardial ventricular and atrial preparations and impairs
isoprenaline-induced fractional shortening of isolated adult rat
ventricular myocytes. The latter effects were reverted after
pre-incubation with pertussis toxin indicating the relevance of a
GPCR-mediated and G.sub..alpha.i/0-mediated pathway (B. Cremers et
al., J. Mol. Cell. Cardiol. 35 (2003), 71-80). LPA was also found
to lead to enhanced matrix generation and proliferation of cardiac
fibroblasts (J. Chen et al., FEBS Letters 580 (2006),
4737-4745).
[0006] The importance of influencing Edg-2 receptor signaling and
LPA-mediated effects for many diseases was confirmed by
pharmacological approaches using specific tool compounds or Edg-2
receptor knock-out mice or by experimental silencing of the Edg-2
receptors. For example, the relevance of LPA-activated Edg
receptors for renal diseases was demonstrated by different kinds of
Edg-2/Edg-7 receptor inhibitors. In one approach, it was shown that
the LPA-induced proliferative response of mesangial cells could be
inhibited by the compound DGPP(8:0) (Y. Xing et al., Am. J.
Physiol. Cell Physiol. 287 (2004), F1250-F1257). In another
approach using the Edg-2/Edg-7 receptor inhibitor VPC12249 it was
demonstrated in an in vivo model of mouse renal ischemia
reperfusion that LPA displays a dual role in renoprotection. While
Edg-4 receptor signaling was shown to be beneficial, Edg-2 and
Edg-7 receptor signaling aggravated renal injury, most probably due
to enhanced infiltration of leukocytes into the renal tissue, and
should therefore be blocked for treating or preventing
ischemia/reperfusion-induced acute renal failure (M. D. Okusa et
al., Am. J. Physiol. Renal Physiol. 285 (2003), F565-F574). The
crucial role of Edg-2 receptors in the development of
tubulointerstitial fibrosis was confirmed in a model of unilateral
ureteral obstruction (J. P. Pradere et al., J. Am. Soc. Nephrol. 18
(2007), 3110-3118). In this model, renal injury was attenuated in
Edg-2 receptor knock-out mice or by pharmacological treatment with
the Edg-2/Edg-7 receptor inhibitor Ki16425. The impact of the
LPA/Edg-2 receptor system in pulmonary fibrosis and vascular
leakage was recently confirmed by the finding that the bioactive
content of LPA was increased in bronchoalveolar fluid of humans
suffering from idiopathic pulmonary fibrosis. Edg-2 receptor
knock-out mice were protected from bleomycin-induced lung injury
and vascular leakage, as compared to wild-type littermates (A. M.
Tager et al., Nat. Med. 14 (2008), 45-54).
[0007] Direct involvement of Edg-2 receptors was recently
demonstrated for the progression of bone metastasis in vivo.
Progression was reduced under pharmacological treatment with the
Edg-2/Edg-7 receptor inhibitor Ki16425 as well as after specific
silencing of the Edg-2 receptors in the same order of magnitude (A.
Boucharaba et al., Proc. Natl. Acad. Sci. 103 (2006), 9643-9648).
The relevance of Edg-2 receptors was also shown in vitro with
respect to prostate cancer cell proliferation and metastatic
potential of human colon carcinoma cells (R. Guo et al.,
Endocrinology 147 (2006), 4883-4892; D. Shida et al., Cancer Res.
63 (2003), 1706-1711).
[0008] The relevance of LPA-mediated Edg-2 receptor signaling was
also demonstrated in an in vivo model of neuropathic pain.
Intrathecal injection of LPA mimicked behavioral, morphological and
biochemical alterations similar to those observed after peripheral
nerve injury. Non-redundant function of Edg-2 receptors was
demonstrated in Edg-2 receptor deficient mice which did not develop
signs of neuropathic pain after nerve injury. Therefore, Edg-2
receptor signaling is regarded as crucial in the initiation of
neuropathic pain (M. Inoue et al., Nat. Med. 10 (2004), 712-718).
Thus, it is evident that inhibition of the Edg-2 receptor and the
effects of LPA by suitable inhibitors is an attractive approach for
treating various diseases.
[0009] Certain compounds which exhibit Edg-2 inhibitory activity,
have already been described. For example, as compounds which are
structurally related to LPA, the above-mentioned compounds
DGPP(8:0) or VPC12249 may be mentioned. In WO 02/29001 and WO
2005/115150 amino compounds comprising a phosphate group,
phosphonate group or hydroxy group are described which have
activity as agonists or antagonists of LPA receptors. LPA receptor
antagonistic azole compounds which are characterized by a carbamate
group in the 4-position of the azole ring, are described in EP
1258484. The use of azole compounds, further heterocycles and other
compounds for modulating the Edg-2, Edg-3, Edg-4 and Edg-7 receptor
is described in WO 03/062392. Compounds which have LPA receptor,
especially Edg-2, antagonistic activity and which comprise a
.beta.-alanine moiety carrying a biphenyl-2-carbonyl group on the
amino group, or an alcohol group and at least three cyclic groups,
are described in EP 1533294 and EP 1695955, respectively. But there
still is a need for further Edg-2 inhibitors which exhibit a
favorable property profile and can be used in the treatment of
diseases such as the above-mentioned ones and other diseases in
which LPA signaling and Edg-2 receptors play a role. The present
invention satisfies this need by providing the
acylamino-substituted fused cyclopentanecarboxylic acid derivatives
of the formula I defined below.
[0010] Certain acylamino-substituted fused cyclopentanecarboxylic
acid derivatives which structurally differ from the compounds of
the invention, have already been described, such as the compound
2-benzoylamino-indane-2-carboxylic acid in R. Lohmar et al., Chem.
Ber. 113 (1980), 3706-3715. 2-Acylamino-indane-2-carboxylic acids
which are characterized by an aryl or heteroaryl substituent on the
benzene ring of the indane moiety and which control the function of
the GPR34 receptor and thereby inhibit histamine release, have been
described in WO 2006/088246 (EP 1849465), among them the compounds
of the formula I in which the fused cyclopentane ring depicted in
formula I together with ring A is an indane ring which carries a
4-chlorophenyl substituent in the 5-position, the groups R.sup.3 to
R.sup.6 and R.sup.20 are hydrogen, the group R.sup.50 is hydroxy or
ethoxy and the cyclic residue containing the groups Y, Z, R.sup.21
and R.sup.22 is 4-(2-methyl-1H-benzoimidazol-1-ylmethyl)-phenyl,
which residue may also be designated as
4-(2-methyl-benzoimidazol-1-ylmethyl)-phenyl. The compounds of the
formula I in which the fused cyclopentane ring depicted in formula
I together with ring A is an unsubstituted indane ring, the groups
R.sup.3 to R.sup.6 and R.sup.20 are hydrogen, the group R.sup.50 is
hydroxy and the cyclic residue containing the groups Y, Z, R.sup.21
and R.sup.22 is 6,2',4'-trichlorobiphenyl-3-yl,
6-chloro-[1,1',4',1'']terphenyl-3-yl or
4-chloro-3-(2-phenylethynyl)-phenyl, have been described in WO
2006/044975 which relates to anti-tumor agents.
[0011] A subject of the present invention is a compound of the
formula I, in any of its stereoisomeric forms or a mixture of
stereoisomeric forms in any ratio, or a physiologically acceptable
salt thereof, or a physiologically acceptable solvate of any of
them,
##STR00003##
wherein ring A is a 3-membered to 7-membered cycloalkane ring, a
benzene ring, or a monocyclic 5-membered or 6-membered aromatic
heterocyclic ring which comprises 1 or 2 identical or different
hetero ring members chosen from the series consisting of N,
N(R.sup.0), O and S, wherein the cycloalkane ring is optionally
substituted by one or more identical or different substituents
chosen from the series consisting of fluorine and
(C.sub.1-C.sub.4)-alkyl, and the benzene ring and the heterocyclic
rings are optionally substituted by one or more identical or
different substituents chosen from the series consisting of
halogen, R.sup.1, HO--, R.sup.1--O--, R.sup.1--C(O)--O--,
R.sup.1--S(O).sub.2--O--, R.sup.1--S(O).sub.m--, H.sub.2N--,
R.sup.1--NH--, R.sup.1--N(R.sup.1)--, R.sup.1--C(O)--NH--,
R.sup.1--C(O)--N(R.sup.71)--, R.sup.1--S(O).sub.2--NH--,
R.sup.1--S(O).sub.2--N(R.sup.71)--, R.sup.1--C(O)--, HO--C(O)--,
R.sup.1--O--C(O)--, H.sub.2N--C(O)--, R.sup.1--NH--C(O)--,
R.sup.1--N(R.sup.1)--C(O)--, H.sub.2N--S(O).sub.2--,
R.sup.1--NH--S(O).sub.2--, R.sup.1--N(R.sup.1)--S(O).sub.2--, NC--,
O.sub.2N--, phenyl and Het;
[0012] Y is chosen from the series consisting of N(R.sup.10), S, O,
C(R.sup.12).dbd.C(R.sup.13), N.dbd.C(R.sup.14) and
C(R.sup.15).dbd.N;
[0013] Z is chosen from the series consisting of N and
C(R.sup.16);
[0014] R.sup.0 is chosen from the series consisting of hydrogen and
R.sup.2;
[0015] R.sup.1, R.sup.2, R.sup.11, R.sup.30, R.sup.33, R.sup.35,
R.sup.54, R.sup.55, R.sup.57 and R.sup.58 are, independently of
each other group R.sup.1, R.sup.2, R.sup.11, R.sup.30, R.sup.33,
R.sup.35, R.sup.54, R.sup.55, R.sup.57 and R.sup.58, chosen from
the series consisting of (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
(C.sub.3-C.sub.7)-cycloalkyl and
(C.sub.3-C.sub.7)-cycloalkyl-(C.sub.1-C.sub.4)-alkyl-which are all
optionally substituted by one or more identical or different
substituents R.sup.70;
[0016] R.sup.3 and R.sup.5 are independently of each other chosen
from the series consisting of hydrogen, (C.sub.1-C.sub.4)-alkyl,
phenyl-(C.sub.1-C.sub.4)-alkyl-, phenyl and hydroxy;
[0017] R.sup.4 and R.sup.6 are independently of each other chosen
from the series consisting of hydrogen and
(C.sub.1-C.sub.4)-alkyl;
[0018] R.sup.10 is chosen from the series consisting of hydrogen
and R.sup.11;
[0019] R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are
independently of each other chosen from the series consisting of
hydrogen, halogen, (C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.4)-alkyl-S(O).sub.m--, H.sub.2N--,
(C.sub.1-C.sub.4)-alkyl-NH--,
(C.sub.1-C.sub.4)-alkyl-N((C.sub.1-C.sub.4)-alkyl)-,
(C.sub.1-C.sub.4)-alkyl-C(O)--, NC-- and O.sub.2N--;
[0020] R.sup.20 is chosen from the series consisting of hydrogen
and (C.sub.1-C.sub.4)-alkyl;
[0021] one of the groups R.sup.21 and R.sup.22 is a group of the
formula II
R.sup.24--R.sup.23-- II
and the other of the groups R.sup.21 and R.sup.22 is chosen from
the series consisting of hydrogen, halogen, R.sup.30, HO--,
R.sup.30--O--, R.sup.30--C(O)--O--, R.sup.30--S(O).sub.2--O--,
R.sup.30--S(O).sub.m--, H.sub.2N--, R.sup.30--NH--,
R.sup.30--N(R.sup.30)--, R.sup.30--C(O)--NH--,
R.sup.30--C(O)--N(R.sup.71)--, R.sup.30--S(O).sub.2--NH--,
R.sup.30--S(O).sub.2--N(R.sup.71)--, R.sup.30--C(O)--, HO--C(O)--,
R.sup.30--O--C(O)--, H.sub.2N--C(O)--, R.sup.30--NH--C(O)--,
R.sup.30--N(R.sup.30)--C(O)--, H.sub.2N--S(O).sub.2--,
R.sup.30--NH--S(O).sub.2--, R.sup.30--N(R.sup.30)--S(O).sub.2--,
NC--, O.sub.2N-- and Het.sup.1;
[0022] R.sup.23 is a direct bond or a chain consisting of 1 to 5
chain members of which 0, 1 or 2 chain members are identical or
different hetero chain members chosen from the series consisting of
N(R.sup.25), O, S, S(O) and S(O).sub.2, but two hetero chain
members can be present in adjacent positions only if one of them is
chosen from the series consisting of S(O) and S(O).sub.2 and the
other is chosen from the series consisting of N(R.sup.25), O and S,
and the other chain members are identical or different groups
C(R.sup.26)(R.sup.26), wherein two adjacent groups
C(R.sup.26)(R.sup.26) can be connected to each other by a double
bond or a triple bond;
[0023] R.sup.24 is chosen from the series consisting of hydrogen,
R.sup.31, HO--, R.sup.31--O--, R.sup.31--C(O)--O--,
R.sup.31--S(O).sub.m--, H.sub.2N--, R.sup.31--NH--,
R.sup.31--N(R.sup.31)--, R.sup.31--C(O)--NH--,
R.sup.31--C(O)--N(R.sup.71)--, R.sup.31--S(O).sub.2--NH--,
R.sup.31--S(O).sub.2--N(R.sup.71)--, R.sup.31--C(O)--, HO--C(O)--,
R.sup.31--O--C(O)--, H.sub.2N--C(O)--, R.sup.31--NH--C(O)--,
R.sup.31--N(R.sup.31)--C(O)--, H.sub.2N--S(O).sub.2--,
R.sup.31--NH--S(O).sub.2--, R.sup.31--N(R.sup.31)--S(O).sub.2--,
NC-- and a 3-membered to 10-membered, monocyclic, bicyclic or
tricyclic ring which is saturated or unsaturated and contains 0, 1,
2 or 3 identical or different hetero ring members chosen from the
series consisting of N, N(R.sup.32), O, S, S(O) and S(O).sub.2,
which ring is optionally substituted on ring carbon atoms by one or
more identical or different substituents chosen from the series
consisting of halogen, R.sup.33, HO--, R.sup.33--O--,
R.sup.33--C(O)--O--, R.sup.33--S(O).sub.2--O--,
R.sup.33--S(O).sub.m--, H.sub.2N--, R.sup.33--NH--,
R.sup.33--N(R.sup.33)--, R.sup.33--C(O)--NH--,
R.sup.33--C(O)--N(R.sup.71)--, R.sup.33--S(O).sub.2--NH--,
R.sup.33--S(O).sub.2--N(R.sup.71)--, H.sub.2N--S(O).sub.2--NH--,
R.sup.33--NH--S(O).sub.2--NH--,
R.sup.33--N(R.sup.33)--S(O).sub.2--NH--,
H.sub.2N--S(O).sub.2--N(R.sup.71)--,
R.sup.33--NH--S(O).sub.2--N(R.sup.71)--,
R.sup.33--N(R.sup.33)--S(O).sub.2--N(R.sup.71)--, R.sup.33--C(O)--,
HO--C(O)--, R.sup.33--O--C(O)--, H.sub.2N--C(O)--,
R.sup.33--NH--C(O)--, R.sup.33--N(R.sup.33)--C(O)--,
H.sub.2N--S(O).sub.2--, R.sup.33--NH--S(O).sub.2--,
R.sup.33--N(R.sup.33)--S(O).sub.2--, NC--, O.sub.2N--, oxo, phenyl
and Het,
[0024] provided that the total number of C, N, O and S atoms which
is present in the two groups R.sup.23 and R.sup.24, is at least
5;
[0025] R.sup.25 is chosen from the series consisting of hydrogen
and (C.sub.1-C.sub.4)-alkyl;
[0026] R.sup.26, independently of each other group R.sup.26, is
chosen from the series consisting of hydrogen, fluorine,
(C.sub.1-C.sub.4)-alkyl and HO--, or two groups R.sup.26 bonded to
the same carbon atom together are oxo, or two of the groups
R.sup.26 or one group R.sup.25 and one group R.sup.26, together
with the comprised chain members, form a 3-membered to 7-membered
monocyclic ring which is saturated and contains 0, 1 or 2 identical
or different hetero ring members chosen from the series consisting
of N, N(R.sup.34), O, S, S(O) and S(O).sub.2, which ring is
optionally substituted on ring carbon atoms by one more identical
or different substituents chosen from the series consisting of
fluorine and (C.sub.1-C.sub.4)-alkyl;
[0027] R.sup.31 is chosen from the series consisting of
(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkenyl and
(C.sub.2-C.sub.6)-alkynyl which are all optionally substituted by
one or more identical or different substituents R.sup.70;
[0028] R.sup.32 and R.sup.34 are independently of each other chosen
from the series consisting of hydrogen, R.sup.35,
R.sup.35--S(O).sub.2--, R.sup.35--C(O)--, R.sup.35--O--C(O)--,
phenyl and Het;
[0029] R.sup.50 is chosen from the series consisting of
R.sup.51--O-- and R.sup.52--N(R.sup.53)--;
[0030] R.sup.51 is chosen from the series consisting of hydrogen
and R.sup.54;
[0031] R.sup.52 is chosen from the series consisting of hydrogen,
R.sup.55, NC-- and R.sup.56--S(O).sub.2--;
[0032] R.sup.53 is chosen from the series consisting of hydrogen
and R.sup.57;
[0033] R.sup.56 is chosen from the series consisting of R.sup.58
and phenyl;
[0034] R.sup.60, independently of each other group R.sup.60, is
chosen from the series consisting of hydrogen and
(C.sub.1-C.sub.4)-alkyl;
[0035] R.sup.70 is chosen from the series consisting of HO--,
R.sup.71--O--, R.sup.71--C(O)--O--, R.sup.71--S(O).sub.m--,
H.sub.2N--, R.sup.71--NH--, R.sup.71--N(R.sup.71)--,
R.sup.71--C(O)--NH--, R.sup.71--C(O)--N(R.sup.71)--,
R.sup.71--S(O).sub.2--NH--, R.sup.71--S(O).sub.2--N(R.sup.71)--,
HO--C(O)--, R.sup.71--O--C(O)--, H.sub.2N--C(O)--,
R.sup.71--NH--C(O)--, R.sup.71--N(R.sup.17)--C(O)--,
H.sub.2N--S(O).sub.2--, R.sup.71--NH--S(O).sub.2--,
R.sup.71--N(R.sup.71)--S(O).sub.2--, NC--, oxo, phenyl and
Het.sup.2;
[0036] R.sup.71, independently of each other group R.sup.71, is
chosen from (C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.4)-cycloalkyl
and (C.sub.3-C.sub.4)-cycloalkyl-(C.sub.1-C.sub.2)-alkyl-;
[0037] Het, independently of each other group Het, is a monocyclic
4-membered to 7-membered heterocyclic ring which comprises 1, 2 or
3 identical or different hetero ring members chosen from the series
consisting of N, N(R.sup.60), O, S, S(O) and S(O).sub.2, which ring
is saturated or unsaturated and is optionally substituted by one or
more identical or different substituents chosen from the series
consisting of halogen, (C.sub.1-C.sub.4)-alkyl and R.sup.70;
[0038] Het.sup.1 is a monocyclic 4-membered to 7-membered
heterocyclic ring which comprises 1 or 2 identical or different
hetero ring members chosen from the series consisting of N,
N(R.sup.60), O, S, S(O) and S(O).sub.2, which ring is saturated and
is optionally substituted by one or more identical or different
substituents chosen from the series consisting of fluorine and
(C.sub.1-C.sub.4)-alkyl;
[0039] Het.sup.2 is a monocyclic 5-membered or 6-membered
heterocyclic ring which comprises 1, 2 or 3 identical or different
hetero ring members chosen from the series consisting of N,
N(R.sup.60), O and S, which ring is aromatic and is optionally
substituted by one or more identical or different substituents
chosen from the series consisting of halogen,
(C.sub.1-C.sub.4)-alkyl-O-- and NC--;
[0040] m, independently of each other number m, is an integer
chosen from the series consisting of 0, 1 and 2;
[0041] phenyl, independently of each other group phenyl, is
optionally substituted by one or more identical or different
substituents chosen from the series consisting of halogen,
(C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkyl-O-- and NC--,
unless specified otherwise;
[0042] cycloalkyl, independently of each other group cycloalkyl,
and independently of any other substituents on cycloalkyl, is
optionally substituted by one or more identical or different
substituents chosen from fluorine and (C.sub.1-C.sub.4)-alkyl;
[0043] alkyl, alkenyl and alkynyl, independently of each other
group alkyl, alkenyl and alkynyl, and independently of any other
substituents on alkyl, alkenyl and alkynyl, is optionally
substituted by one or more fluorine substituents;
[0044] provided that the compound of the formula I is not
2-[(6,2',4'-trichlorobiphenyl-3-carbonyl)amino]indane-2-carboxylic
acid,
2-[6-chloro-[1,1',4',1'']terphenyl-3-carbonyl)amino]indane-2-carboxylic
acid, 2-(4-chloro-3-phenylethynyl-benzoylamino)-indane-2-carboxylic
acid,
5-(4-chloro-phenyl)-2-[4-(2-methyl-1H-benzoimidazol-1-ylmethyl)-benzoylam-
ino]-indane-2-carboxylic acid or
5-(4-chloro-phenyl)-2-[4-(2-methyl-1H-benzoimidazol-1-ylmethyl)-benzoylam-
ino]-indane-2-carboxylic acid ethyl ester.
[0045] If structural elements such as groups, substituents or
numbers, for example, can occur several times in the compounds of
the formula I, they are all independent of each other and can in
each case have any of the indicated meanings, and they can in each
case be identical to or different from any other such element. In a
dialkylamino group, for example, the alkyl groups can be identical
or different.
[0046] Alkyl groups, i.e. saturated hydrocarbon residues, can be
linear (straight-chain) or branched. This also applies if these
groups are substituted or are part of another group, for example an
alkyl-O-- group (alkyloxy group, alkoxy group) or an HO-substituted
alkyl group (hydroxyalkyl group). Depending on the respective
definition, the number of carbon atoms in an alkyl group can be 1,
2, 3, 4, 5 or 6, or 1, 2, 3 or 4, or 1, 2 or 3, or 1 or 2, or 1.
Examples of alkyl are methyl, ethyl, propyl including n-propyl and
isopropyl, butyl including n-butyl, sec-butyl, isobutyl and
tert-butyl, pentyl including n-pentyl, 1-methylbutyl, isopentyl,
neopentyl and tert-pentyl, and hexyl including n-hexyl,
3,3-dimethylbutyl and isohexyl. Examples of alkyl-O-- groups are
methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,
tert-butoxy, n-pentoxy. Examples of alkyl-S(O).sub.m-- are
methylsulfanyl-(CH.sub.3--S--), methanesulfinyl-(CH.sub.3--S(O)--),
methanesulfonyl (CH.sub.3--S(O).sub.2--),
ethylsulfanyl-(CH.sub.3--CH.sub.2--S--),
ethanesulfinyl-(CH.sub.3--CH.sub.2--S(O)--), ethanesulfonyl
(CH.sub.3--CH.sub.2--S(O).sub.2--),
1-methylethylsulfanyl-((CH.sub.3).sub.2CH--S--),
1-methylethanesulfinyl-((CH.sub.3).sub.2CH--S(O)--),
1-methylethanesulfonyl ((CH.sub.3).sub.2CH--S(O).sub.2--). In one
embodiment of the invention the number m is chosen from 0 and 2,
wherein all numbers m are independent of each other and can be
identical or different. In another embodiment the number m in any
of its occurrences is, independent of its meaning in other
occurrences, 0. In another embodiment the number m in any of its
occurrences is, independent of its meaning in other occurrences,
2.
[0047] A substituted alkyl group can be substituted in any
positions, provided that the respective compound is sufficiently
stable and is suitable as a pharmaceutical active compound. The
prerequisite that a specific group and a compound of the formula I
are sufficiently stable and suitable as a pharmaceutical active
compound, applies in general with respect to the definitions of all
groups in the compounds of the formula I. An alkyl group which is
optionally substituted by one or more fluorine substituents can be
unsubstituted, i.e. not carry fluorine substituents, or
substituted, for example by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11
fluorine substituents, or by 1, 2, 3, 4 or 5 fluorine substituents,
which can be located in any positions. For example, in a
fluoro-substituted alkyl group one or more methyl groups can carry
three fluorine substituents each and be present as trifluoromethyl
groups, and/or one or more methylene groups (CH.sub.2) can carry
two fluorine substituents each and be present as difluoromethylene
groups. The explanations with respect to the substitution of a
group by fluorine also apply if the group additionally carries
other substituents and/or is part of another group, for example of
an alkyl-O-- group. Examples of fluoro-substituted alkyl groups are
trifluoromethyl, 2-fluoroethyl, 1-fluoroethyl, 1,1-difluoroethyl,
2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl,
2,2,3,3,3-pentafluoropropyl, 4,4,4-trifluorobutyl and
heptafluoroisopropyl. Examples of fluoro-substituted alkyl-O--
groups are trifluoromethoxy, 2,2,2-trifluoroethoxy,
pentafluoroethoxy and 3,3,3-trifluoropropoxy. Examples of
fluoro-substituted alkyl-S(O).sub.m-- groups are
trifluoromethylsulfanyl-(CF.sub.3--S--),
trifluoromethanesulfinyl-(CF.sub.3--S(O)--) and
trifluoromethanesulfonyl (CF.sub.3--S(O).sub.2--).
[0048] The above explanations with respect to alkyl groups apply
correspondingly to unsaturated hydrocarbon residues, i.e. alkenyl
groups, which in one embodiment of the invention contain one double
bond, and alkynyl groups, which in one embodiment of the invention
contain one triple bond. Thus, for example, alkenyl groups and
alkynyl groups can likewise be linear or branched, and substituted
alkenyl and alkynyl groups can be substituted in any positions,
provided that the resulting compound is sufficiently stable and is
suitable as a pharmaceutical active compound. Double bonds and
triple bonds can be present in any positions. The number of carbon
atoms in an alkenyl or alkynyl group can be 2, 3, 4, 5 or 6, for
example 2, 3, 4 or 5. Examples of alkenyl and alkynyl are ethenyl
(vinyl), prop-1-enyl, prop-2-enyl (allyl), but-2-enyl,
2-methylprop-2-enyl, 3-methylbut-2-enyl, hex-3-enyl, hex-4-enyl,
4-methylhex-4-enyl, prop-1-ynyl, prop-2-ynyl (propargyl),
but-2-ynyl, but-3-ynyl, 4-methylpent-2-ynyl, hex-4-ynyl and
hex-5-ynyl. In one embodiment of the invention, an alkenyl or
alkynyl group contains at least three carbon atoms and is bonded to
the remainder of the molecule via a carbon atom which is not part
of a double bond or triple bond.
[0049] The above explanations with respect to alkyl groups apply
correspondingly to alkanediyl groups (divalent alkyl groups)
including chains of one or more groups C(R.sup.26)(R.sup.26) which
latter groups as such and chains of such groups are alkanediyl
groups in case R.sup.26 is chosen from hydrogen and
(C.sub.1-C.sub.4)-alkyl, or are substituted alkanediyl groups in
case any of the groups R.sup.26 has a meaning different from
hydrogen and (C.sub.1-C.sub.4)-alkyl. Likewise, the alkyl part of a
substituted alkyl group can also be regarded as an alkanediyl
group. Thus, alkanediyl groups can also be linear or branched, the
bonds to the adjacent groups can be located in any positions and
can start from the same carbon atom or from different carbon atoms,
and they can be substituted by fluorine substituents. Examples of
alkanediyl groups are --CH.sub.2--, --CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
--CH(CH.sub.3)--, --C(CH.sub.3).sub.2--,
--CH(CH.sub.3)--CH.sub.2--, --CH.sub.2--CH(CH.sub.3)--,
--C(CH.sub.3).sub.2--CH.sub.2--, --CH.sub.2--C(CH.sub.3).sub.2--.
Examples of fluoro-substituted alkanediyl groups, which can contain
1 2, 3, 4, 5 or 6 fluorine substituents, for example, are --CHF--,
--CF.sub.2--, --CF.sub.2--CH.sub.2--, --CH.sub.2--CF.sub.2--,
--CF.sub.2--CF.sub.2--, --CF(CH.sub.3)--, --C(CF.sub.3).sub.2--,
--C(CH.sub.3).sub.2--CF.sub.2--, --CF.sub.2--C(CH.sub.3).sub.2--.
Further, the above explanations apply correspondingly to divalent
residues of unsaturated hydrocarbons, i.e. unsaturated alkanediyl
groups such as alkenediyl groups and alkynediyl groups, which
groups can occur in the group R.sup.23 in case two adjacent groups
C(R.sup.26)(R.sup.26) are connected to each other by a double bond
or triple bond and which groups in one embodiment of the invention
contain one double bond or one triple bond, respectively, which can
be present in any positions, and which groups are optionally
substituted by fluorine substituents. Examples of such unsaturated
divalent groups are --CH.dbd.CH--, --CH.sub.2--CH.dbd.CH--,
--CH.dbd.CH--CH.sub.2--, --CH.sub.2--CH.dbd.CH--CH.sub.2--,
--C.ident.C--, --CH.sub.2--C.ident.C--, --C.ident.C--CH.sub.2--,
--C(CH.sub.3).sub.2--C.ident.C--, --C.ident.C--C(CH.sub.3).sub.2--,
--CH.sub.2--C.ident.C--CH.sub.2--.
[0050] The number of ring carbon atoms in a
(C.sub.3-C.sub.7)-cycloalkyl group can be 3, 4, 5, 6 or 7. Examples
of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl
and cycloheptyl. Cycloalkyl groups which are optionally substituted
by one or more (C.sub.1-C.sub.4)-alkyl substituents, can be
unsubstituted, i.e. not carry alkyl substituents, or substituted,
for example by 1, 2, 3 or 4 identical or different
(C.sub.1-C.sub.4)-alkyl substituents, for example by methyl groups,
which substituents can be located in any positions. Examples of
such alkyl-substituted cycloalkyl groups are 1-methylcyclopropyl,
2,2-dimethylcyclopropyl, 1-methylcyclopentyl,
2,3-dimethylcyclopentyl, 1-methylcyclohexyl, 4-methylcyclohexyl,
4-isopropylcyclohexyl, 4-tert-butylcyclohexyl and
3,3,5,5-tetramethylcyclohexyl. Cycloalkyl groups which are
optionally substituted by one or more fluorine substituents, can be
unsubstituted, i.e. not carry fluorine substituents, or
substituted, for example by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11
fluorine substituents, or by 1, 2, 3, 4, 5 or 6 fluorine
substituents. The fluorine substituents can be located in any
positions of the cycloalkyl group and can also be located in an
alkyl substituent on the cycloalkyl group. Examples of
fluoro-substituted cycloalkyl groups are 1-fluorocyclopropyl,
2,2-difluorocyclopropyl, 3,3-difluorocyclobutyl,
1-fluorocyclohexyl, 4,4-difluorocyclohexyl and
3,3,4,4,5,5-hexafluorocyclohexyl. Cycloalkyl groups can also be
substituted simultaneously by fluorine and alkyl. Examples of the
group (C.sub.3-C.sub.7)-cycloalkyl-(C.sub.1-C.sub.4)-alkyl- are
cyclopropylmethyl-, cyclobutylmethyl-, cyclopentylmethyl-,
cyclohexylmethyl-, cycloheptylmethyl-, 1-cyclopropylethyl-,
2-cyclopropylethyl-, 1-cyclobutylethyl-, 2-cyclobutylethyl-,
1-cyclopentylethyl-, 2-cyclopentylethyl-, 1-cyclohexylethyl-,
2-cyclohexylethyl-, 1-cycloheptylethyl-, 2-cycloheptylethyl-. The
explanations with respect cycloalkyl groups apply correspondingly
to unsaturated cycloalkyl groups such as cycloalkenyl groups which
can occur in the group R.sup.24 and which in one embodiment of the
invention contain one double bond which can be present in any
positions, and divalent cycloalkyl groups (cycloalkanediyl groups),
which latter groups can occur in case two of the groups R.sup.26
together with the comprised chain members form a ring. Likewise,
the cycloalkyl part of a substituted cycloalkyl group can also be
regarded as a cycloalkanediyl group. Thus, for example, the bonds
through which a cycloalkanediyl group, such as a ring formed by two
of the groups R.sup.26 together with the comprised chain members,
is connected to the adjacent groups, can be located in any
positions and can start from the same ring carbon atom or from
different ring carbon atoms.
[0051] In substituted phenyl groups, including phenyl groups which
represent the 3-membered to 10-membered, monocyclic, bicyclic or
tricyclic ring representing R.sup.24, the substituents can be
located in any positions. In monosubstituted phenyl groups, the
substituent can be located in the 2-position, the 3-position or the
4-position. In disubstituted phenyl groups, the substituents can be
located in 2,3-position, 2,4-position, 2,5-position, 2,6-position,
3,4-position or 3,5-position. In trisubstituted phenyl groups, the
substituents can be located in 2,3,4-position, 2,3,5-position,
2,3,6-position, 2,4,5-position, 2,4,6-position or 3,4,5-position.
If a phenyl group carries four substituents, some of which can be
fluorine atoms, for example, the substituents can be located in
2,3,4,5-position, the 2,3,4,6-position or 2,3,5,6-position. If a
polysubstituted phenyl group or any other polysubstituted group
such as a heteroaryl group carries different substituents, each
substituent can be located in any suitable position, and the
present invention comprises all positional isomers. The number of
substituents in a substituted phenyl group can be 1, 2, 3, 4 or 5.
In one embodiment of the invention, a substituted phenyl group, and
likewise another substituted group such as a heteroaryl group,
carries 1, 2 or 3, for example 1 or 2, identical or different
substituents.
[0052] In heterocyclic groups, including the groups Het, Het.sup.1
and Het.sup.2 and heterocyclic rings which can be present in
structural elements in the compounds of the formula I such as the
ring A or the 3-membered to 10-membered ring representing R.sup.24
or a ring formed by a group R.sup.25 and a group R.sup.26 together
with the comprised chain members, for example, the hetero ring
members specified in the respective definition can be present in
any combination and located in any suitable ring positions,
provided that the resulting group and the compound of the formula I
are sufficiently stable and suitable as a pharmaceutical active
compound. In one embodiment of the invention two oxygen atoms in
any heterocyclic ring in the compounds of the formula I cannot be
present in adjacent ring positions. In another embodiment two
hetero ring members from the series consisting of O, S and N atoms
carrying a hydrogen atom or a substituent, cannot be present in
adjacent ring positions. Examples of such series are the hetero
ring members O, S and N(R.sup.32), or O, S and N(R.sup.34), or O, S
and N(R.sup.60). In another embodiment of the invention two hetero
ring members from the series consisting of S(O) and S(O).sub.2
cannot be present in adjacent ring positions. In an aromatic
heterocyclic ring the choice of hetero ring members and their
positions is limited by the prerequisite that the ring is aromatic,
i.e. it comprises a cyclic system of six delocalized pi electrons.
The residue of a monocyclic, 5-membered or 6-membered, aromatic
heterocyclic ring, which can occur in the groups Het, Het.sup.2 and
the 3-membered to 10 membered ring representing R.sup.24, for
example, can also be designated as monocyclic, 5-membered or
6-membered heteroaryl group. The ring nitrogen atom in such a
heteroaryl group which carries the group R.sup.32 or R.sup.60,
respectively, is the ring nitrogen atom in a 5-membered ring such
as pyrrole, pyrazole, imidazole or triazole to which an exocyclic
atom or group such as a hydrogen atom is bonded, and can be present
once only in a 5-membered aromatic ring just as the hetero ring
members O and S. Examples of rings from which such a heteroaryl
group can be derived are pyrrole, furan, thiophene, imidazole,
pyrazole, triazoles including [1,2,3]triazole and [1,2,4]triazole,
oxazole ([1,3]oxazole), isoxazole ([1,2]oxazole), thiazole
([1,3]thiazole), isothiazole ([1,2]thiazole), oxadiazoles including
[1,2,4]oxadiazole, [1,3,4]oxadiazole and [1,2,5]oxadiazole,
thiadiazoles including [1,3,4]thiadiazole, pyridine, pyridazine,
pyrimidine, pyrazine, triazines including [1,2,3]triazine,
[1,2,4]triazine and [1,3,5]triazine. These explanations with
respect to monocyclic, 5-membered or 6-membered heteroaryl groups
apply correspondingly to the monocyclic, 5-membered or 6-membered,
aromatic heterocyclic ring representing the ring A in formula I in
which the ring nitrogen atom carrying the group R.sup.0 can
likewise be present once only in a 5-membered ring such as pyrrole,
pyrazole or imidazole. Just so, the hetero ring members O and S can
be present once only in the ring A. In one embodiment of the
invention, a monocyclic, 5-membered or 6-membered heteroaryl group
comprises one or two identical or different hetero ring members, in
another embodiment of the invention such a heteroaryl group
comprises one hetero ring member, which are defined as indicated,
and in another embodiment of the invention such a heteroaryl is
chosen from thiophenyl, thiazolyl and pyridinyl. A monocyclic,
5-membered or 6-membered heteroaryl group can be bonded via any
ring carbon atom or, in the case of a 5-membered ring comprising a
hetero ring member N(R.sup.32) or N(R.sup.60), via a ring nitrogen
atom, wherein in the latter case the bond via which the heteroaryl
group is attached to the remainder of the molecule, replaces the
group R.sup.32 or R.sup.60. In one embodiment of the invention, a
monocyclic, 5-membered or 6-membered heteroaryl group is bonded via
a ring carbon atom. For example, a thiophenyl group (thienyl group)
can be thiophen-2-yl (2-thienyl) or thiophen-3-yl (3-thienyl),
furanyl can be furan-2-yl or furan-3-yl, pyridinyl (pyridyl) can be
pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, pyrazolyl can be
1H-pyrazol-3-yl, 1H-pyrazol-4-yl or 2H-pyrazol-3-yl, imidazolyl can
be 1H-imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl or
3H-imidazolyl-4-yl, thiazolyl can be thiazol-2-yl, thiazol-4-yl or
thiazol-5-yl.
[0053] In substituted monocyclic, 5-membered or 6-membered
heteroaryl groups, the substituents can be located in any
positions, for example in a thiophen-2-yl group or a furan-2-yl
group in the 3-position and/or in the 4-position and/or in the
5-position, in a thiophen-3-yl group or a furan-3-yl group in the
2-position and/or in the 4-position and/or in the 5-position, in a
pyridin-2-yl group in the 3-position and/or in the 4-position
and/or in the 5-position and/or in the 6-position, in a
pyridin-3-yl group in the 2-position and/or in the 4-position
and/or in the 5-position and/or in the 6-position, in a
pyridin-4-yl group in the 2-position and/or in the 3-position
and/or in the 5-position and/or in the 6-position. In one
embodiment of the invention, a substituted monocyclic, 5-membered
or 6-membered heteroaryl group is substituted by 1, 2 or 3, for
example 1 or 2, identical or different substituents. Generally,
besides optionally carrying the substituents indicated in the
definition of the group, suitable ring nitrogen atoms in a
monocyclic, 5-membered or 6-membered heteroaryl group as well as in
other heterocyclic groups, for example in a 3-membered to
10-membered, monocyclic, bicyclic or tricyclic ring representing
R.sup.24 or in the aromatic ring A or the aromatic ring comprising
the groups Y and Z which are depicted in formula I, for example the
nitrogen atom in a pyridinyl group or a nitrogen atom in a
[1,2,5]oxadiazolyl group, can also carry an oxido substituent
--O.sup.- and be present as an N-oxide.
[0054] The above explanations with respect to monocyclic,
5-membered or 6-membered aromatic heterocyclic groups apply
correspondingly to the bicyclic aromatic heterocyclic groups
discussed below which can occur in the 3-membered to 10-membered
ring representing R.sup.24 and which can also be designated as a
bicyclic heteroaryl group.
[0055] Besides monocyclic, 5-membered or 6-membered, aromatic
heterocyclic groups, the group Het comprises monocyclic, 4-membered
to 7-membered, partially unsaturated, i.e. non-aromatic,
heterocyclic groups and 4-membered to 7-membered, saturated,
heterocyclic groups. 4-membered to 7-membered, saturated,
heterocyclic groups are also comprised by the group Het'. The rings
of the groups Het and Het.sup.1 thus can be 4-membered, 5-membered,
6-membered or 7-membered, for example 5-membered or 6-membered. In
one embodiment of the invention, a partially unsaturated group Het
comprises one or two, in another embodiment one, double bonds
within the ring which can be present in any position. In one
embodiment of the invention, a 4-membered group Het is saturated.
In one embodiment of the invention, a group Het is a 4-membered to
7-membered saturated group or a 5-membered or 6-membered aromatic
group, in another embodiment a group Het is a is a 4-membered to
7-membered saturated group, and in another embodiment a group Het
is a 5-membered or 6-membered aromatic group. The groups Het and
Het.sup.1 can be bonded via any ring carbon atom or ring nitrogen
atom. Examples of groups Het and Het.sup.1 are azetidinyl including
azetidin-1-yl, oxetanyl including oxetan-3-yl, tetrahydrofuranyl
including tetrahydrofuran-2-yl and tetrahydrofuran-3-yl,
tetrahydrothiophenyl including tetrahydrothiophen-2-yl and
tetrahydrothiophen-3-yl, 1-oxo-tetrahydrothiophenyl including
1-oxo-tetrahydrothiophen-2-yl and 1-oxo-tetrahydrothiophen-3-yl,
1,1-dioxo-tetrahydrothiophenyl including
1,1-dioxo-tetrahydrothiophen-2-yl and
1,1-dioxo-tetrahydrothiophen-3-yl, pyrrolidinyl including
pyrrolidin-1-yl, pyrrolidin-2-yl and pyrrolidin-3-yl,
tetrahydropyranyl including tetrahydropyran-2-yl,
tetrahydropyran-3-yl and tetrahydropyran-4-yl,
tetrahydrothiopyranyl including tetrahydrothiopyran-2-yl,
tetrahydrothiopyran-3-yl and tetrahydrothiopyran-4-yl, piperidinyl
including piperidin-1-yl, piperidin-2-yl, piperidin-3-yl and
piperidin-4-yl, 1,2,3,4-tetrahydropyridinyl including
1,2,3,4-tetrahydropyridin-1-yl, 1,2,3,6-tetrahydropyridinyl
including 1,2,3,6-tetrahydropyridin-1-yl, oxepanyl including
oxepan-2-yl, oxepan-3-yl and oxepan-4-yl, azepanyl including
azepan-1-yl, azepan-2-yl, azepan-3-yl and azepan-4-yl,
1,3-dioxolanyl including 1,3-dioxolan-2-yl and 1,3-dioxolan-4-yl,
imidazolidinyl including imidazolidin-1-yl, imidazolidin-2-yl and
imidazolidin-4-yl, [1,3]oxazolidinyl including
[1,3]oxazolidin-2-yl, [1,3]oxazolidin-3-yl, [1,3]oxazolidin-4-yl
and [1,3]oxazolidin-5-yl, [1,3]thiazolidinyl including
[1,3]thiazolidin-2-yl, [1,3]thiazolidin-3-yl, [1,3]thiazolidin-4-yl
and [1,3]thiazolidin-5-yl, [1,3]dioxanyl including
[1,3]dioxan-2-yl, [1,3]dioxan-4-yl and [1,3]dioxan-5-yl,
[1,4]dioxanyl including [1,4]dioxan-2-yl, piperazinyl including
piperazin-1-yl and piperazin-2-yl, morpholinyl including
morpholin-2-yl, morpholin-3-yl and morpholin-4-yl, thiomorpholinyl
including thiomorpholin-2-yl, thiomorpholin-3-yl and
thiomorpholin-4-yl, 1-oxo-thiomorpholinyl including
1-oxo-thiomorpholin-2-yl, 1-oxo-thiomorpholin-3-yl and
1-oxo-thiomorpholin-4-yl, 1,1-dioxo-thiomorpholinyl including
1,1-dioxo-thiomorpholin-2-yl, 1,1-dioxo-thiomorpholin-3-yl and
1,1-dioxo-thiomorpholin-4-yl, [1,3]diazepanyl, [1,4]diazepanyl,
[1,4]oxazepanyl or [1,4]thiazepanyl. Besides by oxo groups in the
ring members S(O) and S(O).sub.2 and alkyl groups representing
R.sup.60, the groups Het and Het.sup.1 are optionally substituted
on ring carbon atoms by one or more, for example 1, 2, 3, 4 or 5,
or 1, 2, 3 or 4, or 1, 2 or 3, identical or different substituents
as indicated, which can be located in any positions.
[0056] The 3-membered to 10-membered, monocyclic, bicyclic or
tricyclic ring which is saturated or unsaturated and which contains
0, 1, 2 or 3 identical or different hetero ring members chosen from
the series consisting of N, N(R.sup.32), O, S, S(O) and S(O).sub.2,
which ring can represent R.sup.24, can comprise 3, 4, 5, 6, 7, 8, 9
or 10 ring members. In one embodiment of the invention, a bicyclic
and tricyclic ring is fused or bridged. An unsaturated ring can be
partially unsaturated and contain, for example, one or two double
bonds within the ring, or, in the case of a monocyclic or bicyclic
ring, be aromatic in one or both rings, and altogether the number
of double bonds within an unsaturated ring can be one, two, three,
four or five. In a bicyclic ring, the two individual rings can
independently of each other be saturated or partially unsaturated
or aromatic, and in a tricyclic ring the individual rings,
independently of each other, can in particular be saturated or
partially unsaturated. In one embodiment of the invention, a
3-membered or 4-membered ring is saturated. The 3-membered to
10-membered, monocyclic, bicyclic or tricyclic ring can be a
carbocyclic ring, i.e. contain 0 (zero) hetero ring members, or a
heterocyclic ring in which hetero ring members can be present as
indicated above. In a bicyclic heterocyclic ring one or both
individual rings can contain hetero ring members, and in a
tricyclic ring one or more individual rings can contain hetero ring
members. In case nitrogen atoms are present as hetero ring members
in a bicyclic or tricyclic ring, they can also be present at a
fusion position or a bridgehead position. The free bond via which
the ring is bonded to the group R.sup.23, can be located at any
suitable ring carbon atom or ring nitrogen atom. In one embodiment
of the invention the free bond is located at a ring carbon atom. In
general, besides by oxo groups in the ring members S(O) and
S(O).sub.2 and substituents R.sup.32 on ring nitrogen atoms, the
3-membered to 10 membered ring is optionally substituted on ring
carbon atoms by one or more, for example 1, 2, 3, 4 or 5, or 1, 2,
3 or 4, or 1, 2 or 3, identical or different substituents as
indicated, which can be located in any positions.
[0057] The 3-membered to 10-membered, monocyclic, bicyclic or
tricyclic ring comprises (C.sub.3-C.sub.7)-cycloalkyl groups,
phenyl groups, and monocyclic, 5-membered or 6-membered aromatic
heterocyclic groups and monocyclic 4-membered to 7-membered
partially unsaturated and saturated groups as are comprised by the
definitions of the groups Het, Het.sup.1 and Het.sup.2. All these
groups thus are examples of the said 3-membered to 10-membered
ring, and all explanations given above with respect to these groups
apply correspondingly to the said 3-membered to 10-membered ring
unless specified otherwise in the definition of the said 3-membered
to 10-membered ring. Thus, for example, the substituents in these
groups, such as in a phenyl group which represents the said
3-membered to 10-membered ring, or in a monocyclic 5-membered or
6-membered aromatic heterocyclic group representing the group Het
or Het.sup.2 which represents the said 3-membered to 10-membered
ring, can then be as is specified in the definition of R.sup.24. As
further examples of cyclic groups which are comprised by the said
3-membered to 10-membered ring, (C.sub.5-C.sub.7)-cycloalkenyl
groups, naphthalenyl groups and hydrogenated naphthalenyl groups,
indenyl groups and hydrogenated indenyl groups, bicyclic
heterocyclic groups, and bicycloalkyl, bicycloalkenyl and
tricycloalkyl groups and hetero analogs thereof may be
mentioned.
[0058] In a (C.sub.5-C.sub.7)-cycloalkenyl group representing
R.sup.24, the number of ring carbon atoms can be 5, 6 or 7.
Examples of cycloalkenyl groups are cyclopentenyl including
cyclopent-1-enyl, cyclopent-2-enyl and cyclopent-3-enyl, cyclohexyl
including cyclohex-1-enyl, cyclohex-2-enyl and cyclohex-3-enyl, and
cycloheptyl including cyclohept-1-enyl, cyclohept-2-enyl,
cyclohept-3-enyl and cyclohept-4-enyl. Cycloalkenyl groups
representing R.sup.24 can be unsubstituted or substituted as
indicated with respect to the 3-membered to 10-membered ring
representing R.sup.24, for example by one or more, or 1, 2, 3 or 4,
or 1, 2 or 3, identical or different (C.sub.1-C.sub.4)-alkyl
substituents, for example by methyl groups, which can be located in
any positions. Examples of such alkyl-substituted cycloalkenyl
groups are 1-methylcyclopent-2-enyl, 1-methylcyclopent-3-enyl,
2,3-dimethylcyclohex-2-enyl and 3,4-dimethylcyclohex-3-enyl.
Cycloalkenyl groups also are optionally substituted by one or more
fluorine substituents, i.e., they can be unsubstituted by fluorine
and not carry any fluorine substituents, or substituted, for
example by 1, 2, 3, 4, 5, 6 or 7, or by 1, 2, 3, 4 or 5, or by 1,
2, 3 or 4, fluorine substituents. Cycloalkenyl groups can also be
substituted simultaneously by fluorine and alkyl. The fluorine
atoms can be located in any positions of the cycloalkenyl group and
can also be located in an alkyl substituent on the cycloalkenyl
group. Examples of fluoro-substituted cycloalkyl groups are
1-fluorocyclohex-2-enyl, 1-fluorocyclohex-3-enyl and
4,4-difluorocyclohex-2-enyl.
[0059] Naphthalenyl groups (naphthyl groups) representing R.sup.24
can be naphthalen-1-yl (1-naphthyl) and naphthalen-2-yl
(2-naphthyl) groups, and are optionally substituted by one or more,
for example by 1, 2, 3, 4 or 5, or by 1, 2 or 3, for example by 1
or 2, identical or different substituents as indicated above. The
substituents in a substituted naphthalenyl group can be located in
any positions, for example in the 2-position, 3-position,
4-position, 5-position, 6-position, 7-position or 8-position in the
case of a monosubstituted naphthalen-1-yl group and in the
1-position, 3-position, 4-position, 5-position, 6-position,
7-position or 8-position in the case of a monosubstituted
naphthalen-2-yl group. Likewise, in a naphthalenyl group which
carries two or more substituents, the substituents can be located
in the ring to which the remainder of the molecule is bonded,
and/or in the other ring. Examples of hydrogenated naphthalenyl
groups representing R.sup.24 are dihydronaphthalenyl including
1,4-dihydronaphthalenyl, tetrahydronaphthalenyl including
1,2,3,4-tetrahydronaphthalenyl and 5,6,7,8-tetrahydronaphthalenyl,
octahydronaphthalenyl including
1,2,3,4,5,6,7,8-octahydronaphthalenyl, and decahydronaphthalenyl.
Hydrogenated naphthalenyl groups can be bonded to the remainder of
the molecule via any ring carbon atom in a saturated or partially
unsaturated or aromatic ring and are optionally substituted by one
or more, for example by 1, 2, 3, 4 or 5, or by 1, 2 or 3, for
example by 1 or 2, identical or different substituents as indicated
above which can be located in any positions.
[0060] Indenyl groups representing R.sup.24 can be 1H-inden-1-yl,
1H-inden-2-yl, 1H-inden-3-yl, 1H-inden-4-yl, 1H-inden-5-yl,
1H-inden-6-yl or 1H-inden-7-yl, for example, and are optionally
substituted by one or more, for example by 1, 2, 3, 4 or 5, or by
1, 2 or 3, for example by 1 or 2, identical or different
substituents as indicated above which can be located in any
positions. Examples of hydrogenated indenyl groups representing
R.sup.24 are indanyl (2,3-dihydro-1H-indenyl) and
octahydro-1H-indenyl, which can be bonded to the remainder of the
molecule via any ring carbon atom in a saturated or partially
unsaturated or aromatic ring, for example via the 1-position,
2-position, 4-position or 5-position in the case of an indanyl
group, and are optionally substituted by one or more, for example
by 1, 2, 3, 4 or 5, or by 1, 2 or 3, for example by 1 or 2,
identical or different substituents as indicated above which can be
located in any positions.
[0061] In one embodiment of the invention, bicyclic heterocyclic
groups representing R.sup.24 are fused bicyclic groups in which the
two rings have a bond in common, and can be saturated, partially
unsaturated or aromatic as indicated above with respect to the
3-membered to 10-membered ring representing R.sup.24 in general.
They can contain 1, 2, 3, 4 or 5 double bonds within the rings.
Both of the rings can be saturated, or one of the rings can be
saturated or partially unsaturated and the other ring partially
unsaturated or aromatic, or both rings can be aromatic, i.e.
comprise a cyclic system of six delocalized pi electrons. In one
embodiment of the invention, both rings are aromatic or one of the
rings is aromatic and the other ring is partially unsaturated and
comprises at least one double bond due to the condensation to the
aromatic ring. In one embodiment of the invention, a bicyclic
heterocyclic group comprises 8, 9 or 10 ring members and two fused
5-membered rings or two fused 6-membered rings or a 6-membered ring
fused to a 5-membered ring or a 7-membered ring fused to a
5-membered ring, in another embodiment 9 or 10 ring members and two
fused 6-membered rings or a 6-membered ring fused to a 5-membered
ring. Hetero ring members can be present in both rings of a
bicyclic heterocyclic group or in one of the rings only and the
other ring contain no hetero ring members. Ring nitrogen atoms can
also be common to both rings. Besides being a hetero ring member in
other 3-membered to 10-membered rings representing R.sup.24 such as
saturated rings, a ring nitrogen atom carrying a group R.sup.32 can
be the ring nitrogen atom in a fused 5-membered ring in an aromatic
bicyclic heterocyclic group, such as in a fused pyrrole, pyrazole,
imidazole or triazole, to which an exocyclic atom or group is
bonded. Examples of rings from which a fused bicyclic heterocyclic
group can be derived, are indole, isoindole, benzo[b]thiophene,
benzofuran, benzo[1,3]dioxole ([1,3]benzodioxole,
1,2-methylenedioxybenzene), benzo[1,3]oxazole, benzo[1,3]thiazole,
benzoimidazole, chromane, isochromane, benzo[1,4]dioxane
([1,4]benzodioxane, 1,2-ethylenedioxybenzene), quinoline,
isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine,
pyrroloazepines, imidazoazepines, thienothiophenes, thienopyrroles,
thienopyridines, naphthyridines, and the respective rings in which
one or some or all of the double bonds are hydrogenated, i.e.
replaced with single bonds, such as 2,3-dihydro-1H-indole,
2,3-dihydro-1H-isoindole, 2,3-dihydrobenzofuran,
1,2,3,4-tetrahydroquinoline, 5,6,7,8-tetrahydroquinoline,
decahydroquinoline, 1,2,3,4-tetrahydroisoquinoline,
5,6,7,8-tetrahydroisoquinoline, decahydroisoquinoline, for example.
A bicyclic heterocyclic group can be bonded via any ring carbon
atom or ring nitrogen atom. In one embodiment of the invention, a
bicyclic heteroaromatic group is bonded via a ring carbon atom. For
example, an indolyl group can be indol-1-yl, indol-2-yl,
indol-3-yl, indol-4-yl, indol-5-yl, indol-6- or indol-7-yl, a
benzoimidazolyl group can be 1H-benzoimidazol-1-yl,
1H-benzoimidazol-2-yl, 1H-benzoimidazol-4-yl,
1H-benzoimidazol-5-yl, 1H-benzoimidazol-6-yl or
1H-benzoimidazol-7-yl, a benzo[1,4]dioxanyl group can be
benzo[1,4]dioxan-2-yl, benzo[1,4]dioxan-5-yl or
benzo[1,4]dioxan-6-yl, a quinolinyl group (quinolyl group) can be
quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl,
quinolin-6-yl, quinolin-7-yl or quinolin-8-yl, an isoquinolinyl
group can be isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl,
isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl or
isoquinolin-8-yl. In a substituted bicyclic heteroaromatic group,
the substituents can be located in any desired positions such as,
for example, in an indol-2-yl group in the 1-position and/or the
3-position and/or the 4-position and/or the 5-position and/or the
6-position and/or the 7-position, in an indol-5-yl group in the
1-position and/or the 2-position and/or the 3-position and/or the
4-position and/or the 6-position and/or the 7-position, in a
1H-benzoimidazol-2-yl group in the 1-position and/or the 4-position
and/or the 5-position and/or the 6-position and/or the 7-position.
Generally, besides the substituents indicated above, a bicyclic
heterocyclic group can also carry on suitable ring nitrogen atoms
in aromatic rings, for example the nitrogen atom in a quinolinyl
group or isoquinolinyl group, an oxido substituent --O.sup.- and be
present as an N-oxide.
[0062] In one embodiment of the invention, bicycloalkyl,
bicycloalkenyl and tricycloalkyl groups representing R.sup.24 are
bridged 6-membered to 10-membered, in another embodiment 7-membered
to 10-membered, bicyclic and tricyclic groups which can contain
carbon atoms only as ring members, i.e. they can be derived from
carbocyclic bicycloalkanes, bicycloalkenes and tricycloalkanes, or
which can also contain hetero ring members as indicated above, i.e.
they can be derived from the respective heteroanalogous aza-, oxa-
and thia-bicycloalkanes, -bicycloalkenes and -tricycloalkanes. If
they contain hetero ring members, in one embodiment they contain
one or two hetero ring members, in another embodiment one hetero
ring member, for example ring members chosen from the series
consisting of N, N(R.sup.28) and O. The hetero ring members can be
present in any desired positions in the bicyclic or tricyclic
system including positions in the bridges and, in the case of
nitrogen atoms, positions at the bridgeheads. Bicycloalkenyl and
their hetero analogs can contain one or more double bonds within
the rings. In one embodiment of the invention they contain one or
two double bonds, in another embodiment one double bond, within the
ring. Bicycloalkyl, bicycloalkenyl and tricycloalkyl can be bonded
to the remainder of the molecule via any ring carbon atom or ring
nitrogen atom. The free bond can be located in any stereochemical
position, for example in an exo position or an endo position.
Bicycloalkyl, bicycloalkenyl and tricycloalkyl and their hetero
analogs are optionally substituted as indicated above, for example
by substituents chosen from the series consisting of
(C.sub.1-C.sub.4)-alkyl, (C.sub.2--O.sub.5)-alkenyl, HO--,
HO--CH.sub.2-- (hydroxymethyl-) and oxo, in any positions. Examples
of bicycloalkyl, bicycloalkenyl and tricycloalkyl groups and hetero
analogs thereof are norbornyl (bicyclo[2.2.1]heptyl),
bicyclo[3.1.1]heptyl, bicyclo[3.1.1]hept-2-enyl,
bicyclo[2.2.2]octyl, bicyclo[2.2.2]oct-2-enyl, bicyclo[3.2.1]octyl,
7-azabicylo[2.2.1]heptyl, 1-azabicyclo[2.2.2]octyl,
bicyclo[2.2.2.]oct-2-en-yl, tricyclo[4.4.0.0.sup.3,8]decyl),
adamantyl (tricyclo[3.3.1.1.sup.3,7]decyl), noradamantyl
(tricyclo[3.3.1.0.sup.3,7]nonyl),
tricyclo[2.2.1.0.sup.2,6]heptyl.
[0063] Halogen is fluorine, chlorine, bromine or iodine. In one
embodiment of the invention, halogen is fluorine, chlorine or
bromine, in another embodiment fluorine or chlorine.
[0064] An oxo group, i.e. a doubly bonded oxygen atom, when bonded
to a carbon atom, replaces two hydrogen atoms on a carbon atom of
the parent system. Thus, if a CH.sub.2 group is substituted by oxo,
it becomes a carbonyl group (C(O), C.dbd.O). An oxo group cannot
occur as a substituent on a carbon atom in an aromatic ring such as
in a phenyl group.
[0065] The present invention comprises all stereoisomeric forms of
the compounds of the formula I, for example all enantiomers and
diastereomers including cis/trans isomers. The invention likewise
comprises mixtures of two or more stereoisomeric forms, for example
mixtures of enantiomers and/or diastereomers including cis/trans
isomers, in all ratios. Asymmetric centers contained in the
compounds of the formula I, for example in unsubstituted or
substituted alkyl groups, can all independently of each other have
the S configuration or the R configuration. The invention relates
to enantiomers, both the levorotatory and the dextrorotatory
antipode, in enantiomerically pure form and essentially
enantiomerically pure form and in the form of racemates and in the
form of mixtures of the two enantiomers in all ratios. The
invention likewise relates to diastereomers in the form of pure and
essentially pure diastereomers and in the form of mixtures of two
or more diastereomers in all ratios. The invention also comprises
all cis/trans isomers of the compounds of the formula I in pure
form and essentially pure form and in the form of mixtures of the
cis isomer and the trans isomer in all ratios. Cis/trans isomerism
can occur in substituted rings and on double bonds, for example.
The preparation of individual stereoisomers, if desired, can be
carried out by resolution of a mixture according to customary
methods, for example, by chromatography or crystallization, or by
use of stereochemically uniform starting compounds in the synthesis
or by stereoselective reactions. Optionally, before a separation of
stereoisomers a derivatization can be carried out. The separation
of a mixture of stereoisomers can be carried out at the stage of
the compound of the formula I or at the stage of an intermediate in
the course of the synthesis. The invention also comprises all
tautomeric forms of the compounds of the formula I.
[0066] Physiologically acceptable salts, including pharmaceutically
utilizable salts, of the compounds of the formula I generally
comprise a nontoxic salt component. They can contain inorganic or
organic salt components. Such salts can be formed, for example,
from compounds of the formula I which contain an acidic group, for
example a carboxylic acid group (hydroxycarbonyl group,
HO--C(O)--), and nontoxic inorganic or organic bases. Suitable
bases are, for example, alkali metal compounds or alkaline earth
metal compounds, such as sodium hydroxide, potassium hydroxide,
sodium carbonate or sodium hydrogencarbonate, or ammonia, organic
amino compounds and quaternary ammonium hydroxides. Reactions of
compounds of the formula I with bases for the preparation of the
salts are in general carried out according to customary procedures
in a solvent or diluent. Examples of salts of acidic groups thus
are sodium, potassium, magnesium or calcium salts or ammonium salts
which can also carry one or more organic groups on the nitrogen
atom. Compounds of the formula I which contain a basic, i.e.
protonatable, group, for example an amino group or a basic
heterocycle, can be present in the form of their acid addition
salts with physiologically acceptable acids, for example as salt
with hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric
acid, acetic acid, benzoic acid, methanesulfonic acid,
p-toluenesulfonic acid, which in general can be prepared from the
compounds of the formula I by reaction with an acid in a solvent or
diluent according to customary procedures. If the compounds of the
formula I simultaneously contain an acidic and a basic group in the
molecule, the invention also includes internal salts (betaines,
zwitterions) in addition to the salt forms mentioned. The present
invention also comprises all salts of the compounds of the formula
I which, because of low physiological tolerability, are not
directly suitable for use as a pharmaceutical, but are suitable as
intermediates for chemical reactions or for the preparation of
physiologically acceptable salts, for example by means of anion
exchange or cation exchange. The present invention also comprises
all solvates of the compounds of the formula I and their salts,
including physiologically acceptable solvates, such as hydrates,
i.e. adducts with water, and adducts with alcohols like
(C.sub.1-C.sub.4)-alkanols, as well as active metabolites of
compounds of the formula I and prodrugs of the compounds of the
formula I, i.e. compounds which in vitro may not necessarily
exhibit pharmacological activity but which in vivo are converted
into pharmacologically active compounds of the formula I, for
example compounds which are converted by metabolic hydrolysis into
a compound of the formula I, such as compounds in which a
carboxylic acid group is present in esterified form or in the form
of an amide.
[0067] As indicated above, the hetero ring members in the ring A,
which ring includes the two carbon atoms which also are part of the
fused 5-membered ring depicted in formula I carrying the groups
R.sup.3 to R.sup.6, can be present in any combination and can be
located in any suitable position. For example, in the case of a
pyridine ring or a thiophene representing A, the ring nitrogen atom
or sulfur atom can be present in a position which is adjacent to
the said 5-membered ring, or in a position which is not adjacent to
the said 5-membered ring. In case the ring A is a 6-membered
heterocyclic ring which comprises two hetero ring members N, for
example, both hetero ring members can be present in the two
positions adjacent to the said 5-membered ring and the 6-membered
ring be a pyrazine ring, or one of them can be present in a
position adjacent to the said 5-membered ring and the other in a
non-adjacent position and the 6-membered ring be a pyrimidine ring
or a pyridazine ring, or both hetero ring members can be present in
non-adjacent positions and the 6-membered ring be a pyridazine
ring. In one embodiment of the invention, the hetero ring members
in a heterocyclic ring representing A are chosen from N and S, in
another embodiment they are N. In one embodiment of the invention,
a cycloalkane ring representing A is 5-membered, 6-membered or
7-membered, in another embodiment 5-membered or 6-membered, in
another embodiment 6-membered, and the cycloalkane ring thus is a
cyclopentane, cyclohexane or cycloheptane ring which can all be
substituted as indicated. In one embodiment of the invention the
ring A is a cyclohexane ring, a benzene ring, a pyridine ring, a
pyrazine ring or a monocyclic 5-membered aromatic heterocyclic ring
comprising 1 or 2 identical or different hetero ring members chosen
from the series consisting of N, N(R.sup.1), O and S, for example 1
hetero ring member chosen from the series consisting of N(R.sup.1),
O and S, such as a thiophene ring, which rings can all be
optionally substituted as indicated. In another embodiment the ring
A is a benzene ring, a pyridine ring, a pyrazine ring or a
monocyclic 5-membered aromatic heterocyclic ring comprising 1 or 2
identical or different hetero ring members chosen from the series
consisting of N, N(R.sup.1), O and S, for example 1 hetero ring
member chosen from the series consisting of N(R.sup.1), O and S,
such as a thiophene ring, which rings can all be optionally
substituted as indicated. In another embodiment the ring A is a
benzene ring or a monocyclic 5-membered aromatic heterocyclic ring
comprising 1 or 2 identical or different hetero ring members chosen
from the series consisting of N, N(R.sup.1), O and S, for example 1
hetero ring member chosen from the series consisting of N(R.sup.1),
O and S, such as a thiophene ring, which rings can all be
optionally substituted as indicated. In another embodiment the ring
A is a benzene ring, a pyrazine ring or a thiophene ring, in
another embodiment a benzene ring or a thiophene ring, which rings
can all be optionally substituted as indicated. In another
embodiment of the invention, the ring A is a benzene ring which is
optionally substituted as indicated. In another embodiment of the
invention, the ring A is a cycloalkane ring which is optionally
substituted as indicated.
[0068] The number of the substituents which can optionally be
present on the ring A, depends on the size and the kind of the ring
A and the number of hetero ring members. In one embodiment of the
invention the number of optional substituents is 1, 2, 3 or 4, in
another embodiment 1, 2 or 3, in another embodiment 1 or 2, in
another embodiment 1. For example, in the case of a benzene ring
representing A, which ring can be unsubstituted or substituted, the
number of optional substituents can be 1, 2, 3 or 4, or 1, 2 or 3,
or 1 or 2, for example 1. In the case of a pyridine ring, the
number of optional substituents can be 1, 2 or 3, or 1 or 2, for
example 1, in the case of pyrazine ring, it can be 1 or 2, for
example 1, in the case of a thiophene ring it can be 1 or 2, for
example 1, in the case of a thiazole ring it can be 1. In one
embodiment of the invention, a cycloalkane ring representing A is
not substituted by any substituents. In another embodiment of the
invention the ring A is not substituted by any substituents and the
ring carbon atoms thus carry hydrogen atoms. Substituents on the
ring A can be present in any suitable position. In one embodiment
of the invention, in compounds of the formula I in which the ring A
is an optionally substituted benzene ring, the substituents which
are optionally present in positions 5 and 6 of the indane ring
comprising the said benzene ring representing A, are chosen from
the series consisting of halogen, R.sup.1, HO--, R.sup.1--O--,
R.sup.1--C(O)--O--, R.sup.1--S(O).sub.2--O--,
R.sup.1--S(O).sub.m--, H.sub.2N--, R.sup.1--N(R.sup.1)--,
R.sup.1--C(O)--NH--, R.sup.1--C(O)--N(R.sup.71)--,
R.sup.1--S(O).sub.2--NH--, R.sup.1--S(O).sub.2--N(R.sup.71)--,
R.sup.1--C(O)--, HO--C(O)--, R.sup.1--O--C(O)--, H.sub.2N--C(O)--,
R.sup.1--NH--C(O)--, R.sup.1--N(R.sup.1)--C(O)--,
H.sub.2N--S(O).sub.2--, R.sup.1--NH--S(O).sub.2--,
R.sup.1--N(R.sup.1)--S(O).sub.2--, NC-- and O.sub.2N--. In another
embodiment of the invention, in compounds of the formula I in which
the ring A is an optionally substituted benzene ring, the
substituents which are optionally present in the ring A are chosen
from the series consisting of halogen, R.sup.1, HO--, R.sup.1--O--,
R.sup.1--C(O)--O--, R.sup.1--S(O).sub.2--O--,
R.sup.1--S(O).sub.m--, H.sub.2N--, R.sup.1--N(R.sup.1)--,
R.sup.1--C(O)--NH--, R.sup.1--C(O)--N(R.sup.71)--,
R.sup.1--S(O).sub.2--NH--, R.sup.1--S(O).sub.2--N(R.sup.71)--,
R.sup.1--C(O)--, HO--C(O)--, R.sup.1--O--C(O)--, H.sub.2N--C(O)--,
R.sup.1--NH--C(O)--, R.sup.1--N(R.sup.1)--C(O)--,
H.sub.2N--S(O).sub.2--, R.sup.1--NH--S(O).sub.2--,
R.sup.1--N(R.sup.1)--S(O).sub.2--, NC-- and O.sub.2N--. In another
embodiment of the invention, the substituents in a benzene ring or
a heterocyclic ring representing A are chosen from the series
consisting of halogen, R.sup.1, HO--, R.sup.1--O--,
R.sup.1--C(O)--O--, R.sup.1--S(O).sub.2--O--,
R.sup.1--S(O).sub.m--, H.sub.2N--, R.sup.1--NH--,
R.sup.1--N(R.sup.1)--, R.sup.1--C(O)--NH--,
R.sup.1--C(O)--N(R.sup.71)--, R.sup.1--S(O).sub.2--NH--,
R.sup.1--S(O).sub.2--N(R.sup.71)--, R.sup.1--C(O)--, HO--C(O)--,
R.sup.1--O--C(O)--, H.sub.2N--C(O)--, R.sup.1--NH--C(O)--,
R.sup.1--N(R.sup.1)--C(O)--, H.sub.2N--S(O).sub.2--,
R.sup.1--NH--S(O).sub.2--, R.sup.1--N(R.sup.1)--S(O).sub.2--, NC--
and O.sub.2N--, in another embodiment from the series consisting of
halogen, R.sup.1, HO--, R.sup.1--O--, R.sup.1--C(O)--O--,
R.sup.1--S(O).sub.m--, H.sub.2N--, R.sup.1--NH--,
R.sup.1--N(R.sup.1)--, R.sup.1--C(O)--NH--,
R.sup.1--C(O)--N(R.sup.71)--, R.sup.1--S(O).sub.2--NH--,
R.sup.1--S(O).sub.2--N(R.sup.71)--, NC-- and O.sub.2N--, in another
embodiment from the series consisting of halogen, R.sup.1,
R.sup.1--O--, R.sup.1--S(O).sub.m--, NC-- and O.sub.2N--, for
example from the series consisting of halogen,
(C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkyl-S(O).sub.m--, NC--
and O.sub.2N--, in another embodiment from the series consisting of
halogen, R.sup.1, R.sup.1--O--, R.sup.1--S(O).sub.m-- and NC--, for
example from the series consisting of halogen,
(C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkyl-S(O).sub.m-- and
NC--, in another embodiment from the series consisting of halogen,
R.sup.1, R.sup.1--O-- and NC--, for example from the series
consisting of halogen, (C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.4)-alkyl-O-- and NC--, in another embodiment from
the series consisting of halogen, R.sup.1 and R.sup.1--O--, for
example from the series consisting of halogen,
(C.sub.1-C.sub.4)-alkyl and (C.sub.1-C.sub.4)-alkyl-O--. In one
embodiment of the invention the substituents in a benzene ring or a
heterocyclic ring representing A are chosen from the series
consisting of halogen and (C.sub.1-C.sub.4)-alkyl. In one
embodiment of the invention, the number of nitro substituents
(O.sub.2N--) on the ring A is not greater than two, in another
embodiment not greater than one. In one embodiment of the
invention, the total number of nitro groups in a compound of the
formula I is not greater than two.
[0069] In case the ring A is a benzene ring, the compounds of the
formula I can also be represented by the formula Ia,
##STR00004##
wherein Y, Z, R.sup.3 to R.sup.6, R.sup.20 to R.sup.22 and R.sup.50
are defined as in the compounds of the formula I, R.sup.7 is
defined as the substituents which are optionally present in a
benzene ring representing the ring A in the compounds of the
formula I, i.e. R.sup.7 is chosen from the series consisting of
halogen, R.sup.1, HO--, R.sup.1--O--, R.sup.1--C(O)--O--,
R.sup.1--S(O).sub.2--O--, R.sup.1--S(O).sub.m--, H.sub.2N--,
R.sup.1--NH--, R.sup.1--N(R.sup.1)--, R.sup.1--C(O)--NH--,
R.sup.1--C(O)--N(R.sup.71)--, R.sup.1--S(O).sub.2--NH--,
R.sup.1--S(O).sub.2--N(R.sup.71)--, R.sup.1--C(O)--, HO--C(O)--,
R.sup.1--O--C(O)--, H.sub.2N--C(O)--, R.sup.1--NH--C(O)--,
R.sup.1--N(R.sup.1)--C(O)--, H.sub.2N--S(O).sub.2--,
R.sup.1--NH--S(O).sub.2--, R.sup.1--N(R.sup.1)--S(O).sub.2--, NC--,
O.sub.2N--, phenyl and Het, or from any of the other series of
substituents indicated herein, for example from the series
consisting of halogen, (C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.4)-alkyl-S(O).sub.m-- and NC--, or from the series
consisting of halogen and (C.sub.1-C.sub.4)-alkyl, and the number r
is 0, 1, 2, 3 or 4, or is 0, 1, 2 or 3, or is 0, 1 or 2, or is 0 or
1. In one embodiment of the invention, the number r in the
compounds of the formula Ia is 0, i.e. the benzene ring depicted in
formula Ia does not carry a substituent R.sup.7. The substituents
R.sup.7 can be present on any of the four carbon atoms of the
benzene ring depicted in formula Ia which are not part of the fused
5-membered ring carrying the groups R.sup.3 to R.sup.6. All other
such carbon atoms of the benzene ring which do not carry a
substituent R.sup.7, carry hydrogen atoms. I.e., in case the number
r is 0, for example, the benzene ring carries four hydrogen
atoms.
[0070] In a similar manner, in case the ring A is a pyridine ring,
a pyridazine ring, a thiophene ring, or a cyclohexane ring, for
example, the compounds of the formula I can be represented by the
formulae Ib-1, Ib-2, Ic, Id-1, Id-2 and Ie,
##STR00005##
wherein Y, Z, R.sup.3 to R.sup.6, R.sup.20 to R.sup.22 and R.sup.50
are defined as in the compounds of the formula I, R.sup.7 is
defined as the substituents which are optionally present in the
ring A in the compounds of the formula I, i.e. in the case of the
compounds of the formulae Ib-1, Ib-2, Ic, Id-1 and Id-2 R.sup.7 is
chosen from the series consisting of halogen, R.sup.1, HO--,
R.sup.1--O--, R.sup.1--C(O)--O--, R.sup.1--S(O).sub.2--O--,
R.sup.1--S(O).sub.m--, H.sub.2N--, R.sup.1--NH--,
R.sup.1--N(R.sup.1)--, R.sup.1--C(O)--NH--,
R.sup.1--C(O)--N(R.sup.71)--, R.sup.1--S(O).sub.2--NH--,
R.sup.1--S(O).sub.2--N(R.sup.71)--, R.sup.1--C(O)--, HO--C(O)--,
R.sup.1--O--C(O)--, H.sub.2N--C(O)--, R.sup.1--NH--C(O)--,
R.sup.1--N(R.sup.1)--C(O)--, H.sub.2N--S(O).sub.2--,
R.sup.1--NH--S(O).sub.2--, R.sup.1--N(R.sup.1)--S(O).sub.2--, NC--,
O.sub.2N--, phenyl and Het, or from any of the other series of
substituents indicated herein, for example from the series
consisting of halogen, (C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.4)-alkyl-O--, (C.sub.1-C.sub.4)-alkyl-S(O).sub.m--
and NC--, or from the series consisting of halogen and
(C.sub.1-C.sub.4)-alkyl, and in the case of the compounds of the
formula Ie R.sup.7 is chosen from the series consisting of fluorine
and (C.sub.1-C.sub.4)-alkyl, and the number r is 0, 1, 2 or 3, or
is 0, 1 or 2, or is 0 or 1, in the case of the compounds of the
formulae Ib-1 and Ib-2, and is or 0, 1 or 2, or is 0 or 1, in the
case of the compounds of the formulae Ic, Id-1 and Id-2, and is 0,
1, 2, 3, 4, 5, 6, 7 or 8, or is 0, 1, 2, 3 or 4, or is 0, 1 or 2,
for example, in the case of the compounds of the formula Ie. In one
embodiment of the invention, the number r in the compounds of the
formulae Ib-1, Ib-2, Ic, Id-1, Id-2 and Ie is 0, i.e. the pyridine
ring, pyridazine ring, thiophene ring and cyclohexane ring depicted
in the formulae do not carry a substituent R.sup.7. The
substituents R.sup.7 can be present on any ring carbon atoms, in
particular ring carbon atoms which are not part of the fused
5-membered ring carrying the groups R.sup.3 to R.sup.6. In
positions on ring carbon atoms in which no substituent R.sup.7 is
present, hydrogen atoms are present.
[0071] In the group C(R.sup.12).dbd.C(R.sup.13) representing the
divalent group Y, the carbon atom carrying the group R.sup.13 is
bonded to the ring carbon atom carrying the group R.sup.21 and the
carbon atom carrying the group R.sup.12 is bonded to the ring
carbon atom carrying the group C(O)--N(R.sup.20). In the group
N.dbd.C(R.sup.14), the carbon atom carrying the group R.sup.14 is
bonded to the ring carbon atom carrying the group R.sup.21 and the
nitrogen atom is bonded to the ring carbon atom carrying the group
C(O)--N(R.sup.20). In the group C(R.sup.15).dbd.N, the nitrogen
atom is bonded to the ring carbon atom carrying the group R.sup.21
and the carbon atom carrying the group R.sup.15 is bonded to the
ring carbon atom carrying the group C(O)--N(R.sup.20). In one
embodiment of the invention, Y is chosen from the series consisting
S, C(R.sup.12).dbd.C(R.sup.13), N.dbd.C(R.sup.14) and
C(R.sup.15).dbd.N, in another embodiment from the series consisting
S, C(R.sup.12).dbd.C(R.sup.13) and C(R.sup.15).dbd.N. In one
embodiment of the invention Y is chosen from the series consisting
of S and C(R.sup.12).dbd.C(R.sup.13),) in another embodiment from
the series consisting of C(R.sup.12).dbd.C(R.sup.13) and
C(R.sup.15).dbd.N. In another embodiment of the invention, Y is
C(R.sup.12).dbd.C(R.sup.13). In another embodiment of the
invention, Y is C(R.sup.15).dbd.N.
[0072] In one embodiment of the invention, the trivalent group Z is
C(R.sup.16). In another embodiment Z is C(R.sup.16) and Y is chosen
from the series consisting of S, C(R.sup.12).dbd.C(R.sup.13) and
C(R.sup.15).dbd.N. In another embodiment Z is C(R.sup.16) and Y is
chosen from the series consisting of S and
C(R.sup.12).dbd.C(R.sup.13).) In another embodiment Z is
C(R.sup.16) and Y is chosen from the series consisting of
C(R.sup.15).dbd.N and C(R.sup.12).dbd.C(R.sup.13). In this latter
embodiment, the aromatic ring in the compounds of the formula I
comprising the ring members Y and Z is a pyridine ring or a benzene
ring, respectively, and the compounds of the formula I are
compounds of the formula If or of the formula Ig,
##STR00006##
wherein A, R.sup.3 to R.sup.6, R.sup.12, R.sup.13, R.sup.15,
R.sup.16, R.sup.20 to R.sup.22 and R.sup.50 are defined as in the
compounds of the formula I or have any of their other indicated
meanings. In one embodiment of the invention the group Z is
C(R.sup.16) and the group Y is S. In another embodiment of the
invention the group Z is C(R.sup.16) and the group Y is
C(R.sup.15).dbd.N. In another embodiment of the invention the group
Z is C(R.sup.16) and the group Y is C(R.sup.12).dbd.C(R.sup.13),
i.e., in this embodiment the compounds of the formula I are
compounds of the formula Ig. In another embodiment of the
invention, in the compounds of the formula Ia the group Z is
C(R.sup.16) and the group Y is C(R.sup.12).dbd.C(R.sup.13), i.e.,
compounds of this embodiment are compounds of the formula Ih,
##STR00007##
wherein R.sup.3 to R.sup.6, R.sup.12, R.sup.13, R.sup.16, R.sup.20
to R.sup.22 and R.sup.50 are defined as in the compounds of the
formula I or have any of their other indicated meanings. R.sup.7
and r in the compounds of the formula Ih are defined as in the
compounds of the formula Ia and, like in the compounds of the
formula Ia, the substituents R.sup.7 can be present on any of the
four carbon atoms of the fused benzene ring depicted in formula Ih
which are not part of the fused 5-membered ring carrying the groups
R.sup.3 to R.sup.6, and all other such carbon atoms of the benzene
ring which do not carry a substituent R.sup.7 carry hydrogen atoms.
All explanations on groups and all definitions and embodiments
specified above or below with respect to the compounds of the
formula I apply correspondingly to the compounds of all formulae
which represent subgroups of the compounds of the formula I,
including the compounds of the formulae Ia to Ih.
[0073] In one embodiment of the invention, R.sup.0 is chosen from
the series consisting of hydrogen and (C.sub.1-C.sub.4)-alkyl, in
another embodiment from the series consisting of hydrogen and
methyl. In one embodiment of the invention, R.sup.0 is hydrogen. In
another embodiment of the invention R.sup.0 is
(C.sub.1-C.sub.4)-alkyl, for example methyl.
[0074] In one embodiment of the invention, R.sup.1, R.sup.2,
R.sup.11, R.sup.30, R.sup.33, R.sup.35, R.sup.54, R.sup.55,
R.sup.57 and R.sup.58 are, independently of each other group
R.sup.1, R.sup.2, R.sup.11, R.sup.30, R.sup.33, R.sup.35, R.sup.54,
R.sup.55, R.sup.57 and R.sup.58, chosen from the series consisting
of (C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.4)-alkenyl,
(C.sub.2-C.sub.4)-alkynyl, (C.sub.3-C.sub.7)-cycloalkyl and
(C.sub.3-C.sub.7)-cycloalkyl-(C.sub.1-C.sub.2)-alkyl-, in another
embodiment from the series consisting of (C.sub.1-C.sub.4)-alkyl,
(C.sub.2-C.sub.4)-alkenyl, (C.sub.2-C.sub.4)-alkynyl,
(C.sub.3-C.sub.7)-cycloalkyl and
(C.sub.3-C.sub.7)-cycloalkyl-(C.sub.1-C.sub.2)-alkyl-, in another
embodiment from the series consisting of (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl and
(C.sub.3-C.sub.7)-cycloalkyl-(C.sub.1-C.sub.2)-alkyl-, in another
embodiment from the series consisting of (C.sub.1-C.sub.4)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl and
(C.sub.3-C.sub.7)-cycloalkyl-(C.sub.1-C.sub.2)-alkyl-, in another
embodiment from the series consisting of (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl and
(C.sub.3-C.sub.7)-cycloalkyl-CH.sub.2-alkyl-, in another embodiment
from the series consisting of (C.sub.1-C.sub.6)-alkyl and
(C.sub.3-C.sub.7)-cycloalkyl, in another embodiment from the series
consisting of (C.sub.1-C.sub.4)-alkyl and
(C.sub.3-C.sub.7)-cycloalkyl, which are all optionally substituted
by one or more identical or different substituents R.sup.70,
wherein in these groups besides any substituents R.sup.70 one or
more fluorine substituents are optionally present and in cycloalkyl
groups one or more (C.sub.1-C.sub.4)-alkyl substituents are
optionally present as applies to alkyl, alkenyl, alkynyl and
cycloalkyl groups in general. In one embodiment of the invention
R.sup.1, R.sup.2, R.sup.11, R.sup.30, R.sup.33, R.sup.35, R.sup.54,
R.sup.55, R.sup.57 and R.sup.58 are, independently of each other
group R.sup.1, R.sup.2, R.sup.11, R.sup.30, R.sup.33, R.sup.35,
R.sup.54, R.sup.55, R.sup.57 and R.sup.58, chosen from the series
consisting of (C.sub.1-C.sub.6)-alkyl, in another embodiment from
the series consisting of (C.sub.1-C.sub.4)-alkyl, which are all
optionally substituted by one or more identical or different
substituents R.sup.70. In one embodiment of the invention,
(C.sub.3-C.sub.7)-cycloalkyl groups occurring in R.sup.1, R.sup.2,
R.sup.11, R.sup.30, R.sup.33, R.sup.35, R.sup.54, R.sup.55,
R.sup.57 and R.sup.58 are, independently of each other group
R.sup.1, R.sup.2, R.sup.11, R.sup.30, R.sup.33, R.sup.35, R.sup.54,
R.sup.55, R.sup.57 and R.sup.58, (C.sub.3-C.sub.6)-cycloalkyl, in
another embodiment (C.sub.3-C.sub.4)-cycloalkyl, for example
cyclopropyl, in another embodiment (C.sub.5-C.sub.6)-cycloalkyl,
for example cyclohexyl. In one embodiment of the invention, the
number of substituents R.sup.70 in any of the groups R.sup.1,
R.sup.2, R.sup.11, R.sup.30, R.sup.33, R.sup.35, R.sup.54,
R.sup.55, R.sup.57 and R.sup.58 is, independently of each other
group R.sup.1, R.sup.2, R.sup.11, R.sup.30, R.sup.33, R.sup.35,
R.sup.54, R.sup.55, R.sup.57 and R.sup.58, 0, 1, 2, 3 or 4, in
another embodiment 0, 1, 2 or 3, in another embodiment 0, 1 or 2,
in another embodiment 0 or 1. In one embodiment of the invention,
any of the groups R.sup.1, R.sup.2, R.sup.11, R.sup.30, R.sup.33,
R.sup.35, R.sup.54, R.sup.55, R.sup.57 and R.sup.58, independently
of each other group R.sup.1, R.sup.2, R.sup.11, R.sup.30, R.sup.33,
R.sup.35, R.sup.54, R.sup.55, R.sup.57 and R.sup.58, does not carry
a substituent R.sup.70, but merely is optionally substituted by one
or more fluorine substituents and, in the case of cycloalkyl
groups, one or more (C.sub.1-C.sub.4)-alkyl substituents. In
another embodiment of the invention, any of the groups R.sup.1,
R.sup.2, R.sup.11, R.sup.30, R.sup.33, R.sup.35, R.sup.54,
R.sup.55, R.sup.57 and R.sup.58, independently of each other group
R.sup.1, R.sup.2, R.sup.11, R.sup.30, R.sup.33, R.sup.35, R.sup.54,
R.sup.55, R.sup.57 and R.sup.58, does neither carry a substituent
R.sup.70 nor fluorine substituents nor, in the case of cycloalkyl
groups, (C.sub.1-C.sub.4)-alkyl substituents.
[0075] In one embodiment of the invention, a
phenyl-(C.sub.1-C.sub.4)-alkyl- group representing R.sup.3 or
R.sup.5 is a benzyl group wherein the phenyl moiety is optionally
substituted as indicated with respect to phenyl groups in general.
In one embodiment of the invention, one of the groups R.sup.3 and
R.sup.5 is chosen from the series consisting of hydrogen,
(C.sub.1-C.sub.4)-alkyl, phenyl-(C.sub.1-C.sub.4)-alkyl-, phenyl
and hydroxy and the other of the groups R.sup.3 and R.sup.5 is
chosen from the series consisting of hydrogen,
(C.sub.1-C.sub.4)-alkyl, phenyl-(C.sub.1-C.sub.4)-alkyl- and
phenyl. In one embodiment of the invention, the groups R.sup.3 and
R.sup.5 are independently of each other chosen from the series
consisting of hydrogen, (C.sub.1-C.sub.4)-alkyl,
phenyl-(C.sub.1-C.sub.4)-alkyl- and phenyl. In another embodiment,
R.sup.3 and R.sup.5 are independently of each other chosen from the
series consisting of hydrogen and (C.sub.1-C.sub.4)-alkyl, in
another embodiment from the series consisting of hydrogen and
methyl. In another embodiment, R.sup.3 and R.sup.5 are
hydrogen.
[0076] In one embodiment of the invention, R.sup.4 and R.sup.6 are
independently of each other chosen from the series consisting of
hydrogen and methyl. In another embodiment, R.sup.4 and R.sup.6 are
hydrogen.
[0077] In one embodiment of the invention, R.sup.3 and R.sup.4 are
identical and are chosen from the series consisting of hydrogen and
methyl, in another embodiment they both are hydrogen. In another
embodiment, R.sup.5 and R.sup.6 are identical and are chosen from
the series consisting of hydrogen and methyl, and in another
embodiment they both are hydrogen. In another embodiment R.sup.3,
R.sup.4, R.sup.5 and R.sup.6 are all identical and are chosen from
the series consisting of hydrogen and methyl. In another embodiment
R.sup.3, R.sup.4, R.sup.5 and R.sup.6 all are hydrogen.
[0078] In one embodiment of the invention, R.sup.10 is chosen from
the series consisting of hydrogen and methyl. In another embodiment
R.sup.10 is hydrogen. In another embodiment of the invention
R.sup.10 is (C.sub.1-C.sub.4)-alkyl, for example methyl.
[0079] In one embodiment of the invention, R.sup.12, R.sup.13,
R.sup.14, R.sup.15 and R.sup.16 are independently of each other
chosen from the series consisting of hydrogen, halogen,
(C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkyl-S(O).sub.m--,
H.sub.2N--, (C.sub.1-C.sub.4)-alkyl-NH--,
(C.sub.1-C.sub.4)-alkyl-N((C.sub.1-C.sub.4)-alkyl)-, NC-- and
O.sub.2N--, in another embodiment from the series consisting of
hydrogen, halogen, (C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.4)-alkyl-O--, NC-- and O.sub.2N--, in another
embodiment from the series consisting of hydrogen, halogen,
(C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkyl-O-- and
O.sub.2N--, in another embodiment from the series consisting of
hydrogen, halogen, (C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.4)-alkyl-O-- and NC--, in another embodiment from
the series consisting of hydrogen, halogen, (C.sub.1-C.sub.4)-alkyl
and (C.sub.1-C.sub.4)-alkyl-O--, in another embodiment from the
series consisting of hydrogen, halogen and (C.sub.1-C.sub.4)-alkyl.
In one embodiment of the invention, R.sup.12 and R.sup.13 are
independently of each other chosen from the series consisting of
hydrogen, halogen, (C.sub.1-C.sub.4)-alkyl, 0- and NC--, in another
embodiment from the series consisting of hydrogen, halogen,
(C.sub.1-C.sub.4)-alkyl and NC--, in another embodiment from the
series consisting of hydrogen, halogen and NC--, in another
embodiment from the series consisting of hydrogen and halogen, in
another embodiment from the series consisting of hydrogen, chlorine
and fluorine, in another embodiment from the series consisting of
hydrogen and fluorine. In one embodiment of the invention, R.sup.12
is hydrogen and R.sup.13 is fluorine or R.sup.12 is fluorine and
R.sup.13 is hydrogen. In another embodiment R.sup.12 and R.sup.13
are hydrogen. In one embodiment of the invention, R.sup.14 and
R.sup.15 are independently of each other chosen from the series
consisting of hydrogen, halogen, (C.sub.1-C.sub.4)-alkyl and
(C.sub.1-C.sub.4)-alkyl-O--, in another embodiment from the series
consisting of hydrogen, halogen and (C.sub.1-C.sub.4)-alkyl, in
another embodiment from the series consisting of hydrogen and
halogen, in another embodiment from the series consisting of
hydrogen, chlorine and fluorine. In another embodiment of the
invention, R.sup.14 and R.sup.15 are hydrogen. In one embodiment of
the invention, R.sup.16 is chosen from the series consisting of
hydrogen, halogen, (C.sub.1-C.sub.4)-alkyl and
(C.sub.1-C.sub.4)-alkyl-O--, in another embodiment from the series
consisting of hydrogen, halogen and (C.sub.1-C.sub.4)-alkyl, in
another embodiment from the series consisting of hydrogen and
halogen, in another embodiment from the series consisting of
hydrogen, chlorine and fluorine. In another embodiment of the
invention, R.sup.16 is hydrogen.
[0080] In one embodiment of the invention, R.sup.20 is chosen from
the series consisting of hydrogen and methyl. In another embodiment
R.sup.20 is hydrogen. In another embodiment R.sup.20 is
(C.sub.1-C.sub.4)-alkyl, for example methyl.
[0081] In one embodiment of the invention the group R.sup.21 is a
group of the formula II, i.e. of the formula R.sup.24--R.sup.23--,
which is bonded to the remainder of the molecule through the moiety
R.sup.23 as is symbolized with respect to this group and in general
by a terminal hyphen representing the free bond, and the group
R.sup.22 is chosen from the series consisting of hydrogen, halogen,
R.sup.30, HO--, R.sup.30--O--, R.sup.30--C(O)--O--,
R.sup.30--S(O).sub.2--O--, R.sup.30--S(O).sub.m--, H.sub.2N--,
R.sup.30--NH--, R.sup.30--N(R.sup.30)--, R.sup.30--C(O)--NH--,
R.sup.30--C(O)--N(R.sup.71)--, R.sup.30--S(O).sub.2--NH--,
R.sup.30--S(O).sub.2--N(R.sup.71)--, R.sup.30--C(O)--, HO--C(O)--,
R.sup.30--O--C(O)--, H.sub.2N--C(O)--, R.sup.30--NH--C(O)--,
R.sup.30--) N(R.sup.30--C(O)--, H.sub.2N--S(O).sub.2--,
R.sup.30--NH--S(O).sub.2--, R.sup.30--N(R.sup.30)--S(O).sub.2--,
NC--, O.sub.2N-- and Het'. In another embodiment, the group
R.sup.22 is a group of the formula II and the group R.sup.21 is
chosen from the series consisting of hydrogen, halogen, R.sup.30,
HO--, R.sup.30--O--, R.sup.30--C(O)--O--,
R.sup.30--S(O).sub.2--O--, R.sup.30--S(O).sub.m--, H.sub.2N--,
R.sup.30--NH--, R.sup.30--N(R.sup.30)--, R.sup.30--C(O)--NH--,
R.sup.30--C(O)--N(R.sup.71)--, R.sup.30--S(O).sub.2--NH--,
R.sup.30--S(O).sub.2--N(R.sup.71)--, R.sup.30--C(O)--, HO--C(O)--,
R.sup.30--O--C(O)--, H.sub.2N--C(O)--, R.sup.30--NH--C(O)--,
R.sup.30--N(R.sup.30)--C(O)--, H.sub.2N--S(O).sub.2--,
R.sup.30--NH--S(O).sub.2--, R.sup.30--N(R.sup.30)--S(O).sub.2--,
NC--, O.sub.2N-- and Het.sup.1.
[0082] In one embodiment of the invention, the one of the groups
R.sup.21 and R.sup.22 which is not a group of the formula II, is
chosen from the series consisting of hydrogen, halogen, R.sup.30,
R.sup.30--C(O)--O--, R.sup.30--S(O).sub.m--, H.sub.2N--,
R.sup.30--NH--, R.sup.30--N(R.sup.30)--, R.sup.30--C(O)--NH--,
R.sup.30--C(O)-- and NC--, in another embodiment from the series
consisting of hydrogen, halogen, (C.sub.1-C.sub.4)-alkyl,
HO--(C.sub.1-C.sub.4)-alkyl-, (C.sub.1-C.sub.4)-alkyl-S(O).sub.m--,
H.sub.2N--, (C.sub.1-C.sub.4)-alkyl-NH--,
di((C.sub.1-C.sub.4)-alkyl)N--, (C.sub.1-C.sub.4)-alkyl-C(O)-- and
NC--, in another embodiment from the series consisting of hydrogen,
halogen, (C.sub.1-C.sub.4)-alkyl, HO--(C.sub.1-C.sub.4)-alkyl-,
(C.sub.1-C.sub.4)-alkyl-O--, (C.sub.1-C.sub.4)-alkyl-S(O).sub.m--,
(C.sub.1-C.sub.4)-alkyl-C(O)-- and NC--, in another embodiment from
the series consisting of halogen, (C.sub.1-C.sub.4)-alkyl,
HO--(C.sub.1-C.sub.4)-alkyl-, (C.sub.1-C.sub.4)-alkyl-O--,
(C.sub.1-C.sub.4)-alkyl-S(O).sub.m--, H.sub.2N--,
(C.sub.1-C.sub.4)-alkyl-NH--, di((C.sub.1-C.sub.4)-alkyl)N--,
(C.sub.1-C.sub.4)-alkyl-C(O)-- and NC--, in another embodiment from
the series consisting of (C.sub.1-C.sub.4)-alkyl,
HO--(C.sub.1-C.sub.4)-alkyl-, (C.sub.1-C.sub.4)-alkyl-S(O).sub.m--,
H.sub.2N--, di((C.sub.1-C.sub.4)-alkyl)N--,
(C.sub.1-C.sub.4)-alkyl-C(O)-- and NC--, in another embodiment from
the series consisting of (C.sub.1-C.sub.4)-alkyl,
HO--(C.sub.1-C.sub.4)-alkyl-, (C.sub.1-C.sub.4)-alkyl-O--,
(C.sub.1-C.sub.4)-alkyl-S(O).sub.m--, (C.sub.1-C.sub.4)-alkyl-NH--,
di((C.sub.1-C.sub.4)-alkyl)N-- and (C.sub.1-C.sub.4)-alkyl-C(O)--.
In one embodiment of the invention, the one of the groups R.sup.21
and R.sup.22 which is not a group of the formula II, is chosen from
the series consisting of (C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.4)-alkyl-O--, (C.sub.1-C.sub.4)-alkyl-S(O).sub.m--,
(C.sub.1-C.sub.4)-alkyl-NH-- and di((C.sub.1-C.sub.4)-alkyl)N--, in
another embodiment from the series consisting of
(C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkyl-O-- and
(C.sub.1-C.sub.4)-alkyl-S(O).sub.m--, in another embodiment from
the series consisting of (C.sub.1-C.sub.4)-alkyl-O-- and
(C.sub.1-C.sub.4)-alkyl-S(O).sub.m--. In another embodiment, the
one of the groups R.sup.21 and R.sup.22 which is not a group of the
formula II, is chosen from the series consisting of
(C.sub.1-C.sub.4)-alkyl, HO--(C.sub.1-C.sub.4)-alkyl-,
(C.sub.1-C.sub.4)-alkyl-O-- and (C.sub.1-C.sub.4)-alkyl-C(O)--, in
another embodiment from the series consisting of
(C.sub.1-C.sub.4)-alkyl, HO--(C.sub.1-C.sub.4)-alkyl- and
(C.sub.1-C.sub.4)-alkyl-O--, in another embodiment from the series
consisting of (C.sub.1-C.sub.4)-alkyl and
(C.sub.1-C.sub.4)-alkyl-O--. In another embodiment, the one of the
groups R.sup.21 and R.sup.22 which is not a group of the formula
II, is (C.sub.1-C.sub.4)-alkyl-O--, for example methoxy or
ethoxy.
[0083] In one embodiment of the invention, in case the group
R.sup.21 is a group of the formula II, the group R.sup.22 is chosen
from the series consisting of (C.sub.1-C.sub.4)-alkyl and
(C.sub.1-C.sub.4)-alkyl-O--, and in another embodiment it is
(C.sub.1-C.sub.4)-alkyl-O--, and in case the group R.sup.22 is a
group of the formula II, the group R.sup.21 is chosen from the
series consisting of hydrogen, halogen, R.sup.30, HO--,
R.sup.30--O--, R.sup.30--C(O)--O--, R.sup.30--S(O).sub.2--O--,
R.sup.30--S(O).sub.m--, H.sub.2N--, R.sup.30--NH--,
R.sup.30--N(R.sup.30)--, R.sup.30--C(O)--NH--,
R.sup.30--C(O)--N(R.sup.71)--, R.sup.30--S(O).sub.2--NH--,
R.sup.30--S(O).sub.2--N(R.sup.71)--, R.sup.30--C(O)--, HO--C(O)--,
R.sup.30--O--C(O)--, H.sub.2N--C(O)--, R.sup.30--NH--C(O)--,
R.sup.30--N(R.sup.30)--C(O)--, H.sub.2N--S(O).sub.2--,
R.sup.30--NH--S(O).sub.2--, R.sup.30--N(R.sup.30)--S(O).sub.2--,
NC--, O.sub.2N-- and Het.sup.1, or is defined as in any of the
embodiments or other definitions of R.sup.21 specified herein.
[0084] The number of chain members in a chain representing R.sup.23
can be 1, 2, 3, 4 or 5. In one embodiment of the invention, the
divalent group R.sup.23 is a direct bond, i.e. the group R.sup.24
is directly bonded to the ring comprising the groups Y and Z which
is depicted in formula I. In another embodiment R.sup.23 is a
direct bond or a chain consisting of 1, 2, 3 or 4 chain members. In
another embodiment R.sup.23 is a direct bond or a chain consisting
of 2, 3 or 4 chain members, in another embodiment a direct bond or
a chain consisting of 2 or 3 chain members, in another embodiment a
direct bond or a chain consisting of 3 chain members, wherein in
these embodiments the chain members are defined as above or below.
In another embodiment R.sup.23 is a chain consisting of 1, 2, 3, 4
or 5 chain members, in another embodiment a chain consisting of 1,
2, 3 or 4 chain members, in another embodiment a chain consisting
of 2, 3 or 4 chain members, in another embodiment a chain
consisting of 2 or 3 chain members, in another embodiment a chain
consisting of 3 chain members, wherein in these embodiments the
chain members are defined as above or below. In one embodiment of
the invention, zero or one of the chain members in a chain
representing R.sup.23 is a hetero chain member, and in another
embodiment one of the chain members in a chain representing
R.sup.23 is a hetero chain member, wherein in these embodiments the
hetero chain members are defined as above or below. In another
embodiment of the invention, none of the chain members in a chain
representing R.sup.23 is a hetero chain member. In one embodiment
of the invention, the hetero chain members in a chain representing
R.sup.23 are chosen from the series consisting of N(R.sup.25), O, S
and S(O).sub.2. In another embodiment of the invention, the hetero
chain members in a chain representing R.sup.23 are chosen from the
series consisting of N(R.sup.25), O and S, in another embodiment
from the series consisting of N(R.sup.25) and O, in another
embodiment from the series consisting of O and S, in another
embodiment from the series consisting of N(R.sup.25), O and
S(O).sub.2, in another embodiment from the series consisting of
N(R.sup.25) and S(O).sub.2, in another embodiment from the series
consisting of O and S(O).sub.2. In another embodiment of the
invention, the hetero chain members which can be present in a chain
representing R.sup.23, are O (oxygen), and in another embodiment
the hetero chain members which can be present in a chain
representing R.sup.23, are N(R.sup.25). In another embodiment of
the invention, zero or one hetero chain member is present in a
chain representing R.sup.23 which is O (oxygen), and in another
embodiment one hetero chain member is present which is O. In
another embodiment of the invention, zero or one hetero chain
member is present in a chain representing R.sup.23 which is
N(R.sup.25), and in another embodiment one hetero chain member is
present which is N(R.sup.25).
[0085] Hetero chain members in a chain representing R.sup.23 can be
present in any positions of the chain provided that the resulting
moiety complies with the prerequisites specified above with respect
to R.sup.23 and the compounds of the invention in general. In case
two adjacent groups C(R.sup.26)(R.sup.26) in a chain representing
R.sup.23 are connected to each other by a double bond or triple
bond, in one embodiment of the invention hetero chain members are
not present in positions adjacent to such a double bond or triple
bond. Hetero chain members can be present at any one end or at both
ends of the chain, and can thus be directly bonded to the group
R.sup.24 and/or the ring comprising the groups Y and Z which is
depicted in formula I, and/or inside the chain. In case one or two
hetero chain members are present in a chain representing R.sup.23,
in one embodiment of the invention at least one of the terminal
chain members is a hetero chain member, and in another embodiment
the terminal chain member which is bonded to the group R.sup.24 is
a hetero chain member, and in another embodiment the terminal chain
member which is bonded to the ring comprising the groups Y and Z is
a hetero chain member. In one embodiment of the invention, one of
the chain members in a chain representing R.sup.23 is a hetero
chain member and this hetero chain member is the terminal chain
member bonded to the group R.sup.24. In another embodiment, one of
the chain members in a chain representing R.sup.23 is a hetero
chain member and this hetero chain member is the terminal chain
member bonded to the ring comprising the groups Y and Z which is
depicted in formula I.
[0086] If two adjacent groups C(R.sup.26)(R.sup.26) within a chain
representing R.sup.23 are connected to each other by a double bond
or a triple bond, the chain thus comprises an unsaturated divalent
group of the formula --C(R.sup.26).dbd.C(R.sup.26)--, wherein
R.sup.26 is defined as above and in one embodiment of the invention
is chosen from the series consisting of hydrogen and
(C.sub.1-C.sub.4)-alkyl, or an unsaturated group of the formula
--C.ident.C--. Chain members which are not connected to each other
by a double bond or triple bond, are connected to each other by a
single bond. If a double bond is present between two adjacent
groups C(R.sup.26)(R.sup.26), one of the groups R.sup.26 in each of
the two adjacent groups C(R.sup.26)(R.sup.26) can be regarded as
being a free bond, the two free bonds together then forming a
second bond between the respective carbon atoms. If a triple bond
is present between two adjacent groups C(R.sup.26)(R.sup.26), both
groups R.sup.26 in each of the two adjacent groups
C(R.sup.26)(R.sup.26) can be regarded as being a free bond, the two
pairs of free bonds together then forming a second and a third bond
between the respective carbon atoms. In one embodiment of the
invention, the said unsaturated group is present not more than once
in a chain representing R.sup.23. The said unsaturated group can be
present in any position of a chain representing R.sup.23 and occur
at any one end of the chain, and can thus be bonded directly to the
group R.sup.24 and/or the ring comprising the groups Y and Z which
is depicted in formula I, or occur inside the chain. In one
embodiment of the invention the said unsaturated group is not
adjacent to a hetero chain member. In one embodiment of the
invention, a chain representing R.sup.23 does not contain a double
bond or triple bond. In another embodiment it is possible for two
adjacent groups C(R.sup.26)(R.sup.26) to be connected to each other
by a double bond. In another embodiment it is possible for two
adjacent groups C(R.sup.26)(R.sup.26) to be connected to each other
by a triple bond. In another embodiment two adjacent groups
C(R.sup.26)(R.sup.26) are connected to each other by a triple bond,
i.e., in this embodiment a chain representing R.sup.23 comprises a
triple bond. In a another embodiment the group R.sup.23 is a group
of the formula --C.ident.C--.
[0087] In one embodiment of the invention R.sup.23 is chosen from a
direct bond and from any one or more of the chains which are
present in the following examples of groups of the formula II,
which groups are bonded to the ring comprising the groups Y and Z
which is depicted in formula I by the free bond represented by the
terminal hyphen, and from which groups of the formula II the groups
R.sup.23 themselves are obtained by removing the group R.sup.24:
[0088] R.sup.24--C.ident.C-- [0089]
R.sup.24--C(R.sup.26)(R.sup.26)--S--, [0090]
R.sup.24--S(O).sub.2--O--, [0091]
R.sup.24--C(R.sup.26).dbd.C(R.sup.26)--C(R.sup.26)(R.sup.26)--,
[0092] R.sup.24--O--C(R.sup.26)(R.sup.26)--C(R.sup.26)(R.sup.26)--,
[0093] R.sup.24--C(R.sup.26)(R.sup.26)--C(R.sup.26)(R.sup.26)--S--,
[0094] R.sup.24--S--C(R.sup.26)(R.sup.26)--C(R.sup.26)(R.sup.26)--,
[0095] R.sup.24--C(R.sup.26)(R.sup.26)--C(R.sup.26)(R.sup.26)--,
[0096] R.sup.24--C(R.sup.26)(R.sup.26)--O--, [0097]
R.sup.24--C(R.sup.26)(R.sup.26)--N(R.sup.25)--, [0098]
R.sup.24--C(R.sup.26)(R.sup.26)--C(R.sup.26)(R.sup.26)--C(R.sup.26)(R.sup-
.26)--, [0099]
R.sup.24--C(R.sup.26)(R.sup.26)--C(R.sup.26)(R.sup.26)--O--, [0100]
R.sup.24--C(R.sup.26)(R.sup.26)--O--C(R.sup.26)(R.sup.26)--, [0101]
R.sup.24--C(R.sup.26)(R.sup.26)--S--C(R.sup.26)(R.sup.26)--, [0102]
R.sup.24--C(R.sup.26)(R.sup.26)--C(R.sup.26)(R.sup.26)--N(R.sup.25)--,
wherein in these groups of the formula II the groups R.sup.24,
R.sup.25 and R.sup.26 are defined as above or below.
[0103] In one embodiment of the invention, R.sup.24 is chosen from
the series consisting of R.sup.31, R.sup.31--O--,
R.sup.31--S(O).sub.m--, H.sub.2N--, R.sup.31--NH--,
R.sup.31--N(R.sup.31)--, R.sup.31--C(O)--NH--,
R.sup.31--C(O)--N(R.sup.71)--, HO--C(O)--, R.sup.31--O--C(O)--,
H.sub.2N--C(O)--, R.sup.31--NH--C(O)--,
R.sup.31--N(R.sup.31)--C(O)--, NC-- and a 3-membered to
10-membered, monocyclic, bicyclic or tricyclic ring, in another
embodiment from the series consisting of R.sup.31, R.sup.31--O--,
R.sup.31--S(O).sub.m--, NC-- and a 3-membered to 10-membered,
monocyclic, bicyclic or tricyclic ring, in another embodiment from
the series consisting of R.sup.31, R.sup.31--O-- and a 3-membered
to 10-membered, monocyclic, bicyclic or tricyclic ring, in another
embodiment from the series consisting of (C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl-O-- and a 3-membered to 10-membered,
monocyclic, bicyclic or tricyclic ring, wherein in all these
embodiments the 3-membered to 10-membered, monocyclic, bicyclic or
tricyclic ring is defined as above or below and is saturated or
unsaturated and contains 0, 1, 2 or 3 identical or different hetero
ring members chosen from the series consisting of N, N(R.sup.32),
O, S, S(O) and S(O).sub.2 and is optionally substituted on ring
carbon atoms by one or more identical or different substituents
chosen from the series consisting of halogen, R.sup.33, HO--,
R.sup.33--O--, R.sup.33--C(O)--O--, R.sup.33--S(O).sub.2--O--,
R.sup.33--S(O).sub.m--, H.sub.2N--, R.sup.33--NH--,
R.sup.33--N(R.sup.33)--, R.sup.33--C(O)--NH--,
R.sup.33--C(O)--N(R.sup.71)--, R.sup.33--S(O).sub.2--NH--,
R.sup.33--S(O).sub.2--N(R.sup.71)--, H.sub.2N--S(O).sub.2--NH--,
R.sup.33--NH--S(O).sub.2--NH--,
R.sup.33--N(R.sup.33)--S(O).sub.2--NH--,
H.sub.2N--S(O).sub.2--N(R.sup.71)--,
R.sup.33--NH--S(O).sub.2--N(R.sup.71)--,
R.sup.33--N(R.sup.33)--S(O).sub.2--N(R.sup.71)--, R.sup.33--C(O)--,
HO--C(O)--, R.sup.33--O--C(O)--, H.sub.2N--C(O)--,
R.sup.33--NH--C(O)--, R.sup.33--N(R.sup.33)--C(O)--,
H.sub.2N--S(O).sub.2--, R.sup.33--NH--S(O).sub.2--,
R.sup.33--N(R.sup.33)--S(O).sub.2--, NC--, O.sub.2N--, oxo, phenyl
and Het, or has any of its other meanings indicated herein. In
another embodiment of the invention R.sup.24 is a 3-membered to
10-membered, monocyclic, bicyclic or tricyclic ring which is
defined as above or below and is saturated or unsaturated and
contains 0, 1, 2 or 3 identical or different hetero ring members
chosen from the series consisting of N, N(R.sup.32), O, S, S(O) and
S(O).sub.2, which ring is optionally substituted on ring carbon
atoms by one or more identical or different substituents chosen
from the series consisting of halogen, R.sup.33, HO--,
R.sup.33--O--, R.sup.33--C(O)--O--, R.sup.33--S(O).sub.2--O--,
R.sup.33--S(O).sub.m--, H.sub.2N--, R.sup.33--NH--,
R.sup.33--N(R.sup.33)--, R.sup.33--C(O)--NH--,
R.sup.33--C(O)--N(R.sup.71)--, R.sup.33--S(O).sub.2--NH--,
R.sup.33--S(O).sub.2--N(R.sup.71)--, H.sub.2N--S(O).sub.2--NH--,
R.sup.33--NH--S(O).sub.2--NH--,
R.sup.33--N(R.sup.33)--S(O).sub.2--NH--,
H.sub.2N--S(O).sub.2--N(R.sup.71)--,
R.sup.33--NH--S(O).sub.2--N(R.sup.71)--,
R.sup.33--N(R.sup.33)--S(O).sub.2--N(R.sup.71)--, R.sup.33--C(O)--,
HO--C(O)--, R.sup.33--O--C(O)--, H.sub.2N--C(O)--,
R.sup.33--NH--C(O)--, R.sup.33--N(R.sup.33)--C(O)--,
H.sub.2N--S(O).sub.2--, R.sup.33--NH--S(O).sub.2--,
R.sup.33--N(R.sup.33)--S(O).sub.2--, NC--, O.sub.2N--, oxo, phenyl
and Het, or has any of its other meanings indicated herein.
[0104] In one embodiment of the invention, a 3-membered to
10-membered, monocyclic, bicyclic or tricyclic ring representing
R.sup.24 is a monocyclic or bicyclic ring, and in another
embodiment it is a monocyclic ring, which rings are all optionally
substituted as indicated above or below. In one embodiment of the
invention, a monocyclic ring representing R.sup.24 is 3-membered to
7-membered, in another embodiment 3-membered or 5-membered to
7-membered, in another embodiment 3-membered, 5-membered or
6-membered, in another embodiment 5-membered or 6-membered, in
another embodiment 6-membered, which rings are all optionally
substituted as indicated above or below. In one embodiment of the
invention, a bicyclic or tricyclic ring representing R.sup.24 is
7-membered to 10-membered, which rings are all optionally
substituted as indicated above or below. In one embodiment of the
invention, a ring representing R.sup.24 is a saturated ring or an
unsaturated ring including a partially unsaturated, i.e.
non-aromatic, ring which contains zero, one, two or three, for
example zero, one or two, double bonds, within the ring, or an
aromatic ring, which rings are all optionally substituted as
indicated above or below. In another embodiment, a ring
representing R.sup.24 is a saturated ring or a partially
unsaturated ring which contains zero, one, two or three, for
example zero, one or two, double bonds within the ring, which rings
are all optionally substituted as indicated above or below. In
another embodiment of the invention, a ring representing R.sup.24
is an aromatic ring, in another embodiment an aromatic ring chosen
from benzene, aromatic 5-membered and 6-membered monocyclic
heterocycles, naphthalene and aromatic 9-membered and 10-membered
bicyclic heterocycles, in another embodiment an aromatic ring
chosen from benzene and aromatic 5-membered and 6-membered
monocyclic heterocycles, in another embodiment an aromatic ring
chosen from benzene and thiophene, which rings are all optionally
substituted as indicated above or below. In another embodiment, a
ring representing R.sup.24 is a benzene ring which is optionally
substituted as indicated above or below, i.e. by the substituents
specified above or below with respect to the 3-membered to
10-membered ring representing R.sup.24. In terms of residues, in
this latter embodiment R.sup.24 is a phenyl group which is
optionally substituted as indicated above or below, i.e. by the
substituents specified above or below with respect to the
3-membered to 10-membered ring representing R.sup.24.
[0105] In one embodiment of the invention, the number of hetero
ring members which can be present in a 3-membered to 10-membered
ring representing R.sup.24 is 0, 1 or 2, in another embodiment of
the invention the number of hetero ring members is 0 or 1, and in
another embodiment of the invention the number of hetero ring
members is 0 (zero), i.e., in this latter embodiment a 3-membered
to 10-membered ring representing R.sup.24 is a carbocyclic ring,
which rings are all optionally substituted as indicated above or
below. In one embodiment of the invention, the hetero ring members
which can be present in a 3-membered to 10-membered ring
representing R.sup.24 are chosen from N, N(R.sup.32), O, S and
S(O).sub.2, in another embodiment from N, N(R.sup.32), O and S, in
another embodiment from N, O and S, in another embodiment from
N(R.sup.32), O and S, in another embodiment from N and S.
[0106] In one embodiment of the invention, the number of
substituents which are optionally present on ring carbon atoms in a
3-membered to 10-membered ring representing R.sup.24 is 1, 2, 3, 4,
or 5, in another embodiment the number of substituents which are
optionally present on ring carbon atoms is 1, 2, 3 or 4, in another
embodiment the number of substituents which are optionally present
on ring carbon atoms is 1, 2 or 3, in another embodiment the number
of substituents which are optionally present on ring carbon atoms
is 1 or 2.
[0107] In one embodiment of the invention, the substituents which
are optionally present on ring carbon atoms in a 3-membered to
10-membered ring representing R.sup.24, including a benzene ring or
a phenyl group, respectively, representing R.sup.24, are chosen
from the series consisting of halogen, R.sup.33, HO--,
R.sup.33--O--, R.sup.33--S(O).sub.m--, H.sub.2N--, R.sup.33--NH--,
R.sup.33--N(R.sup.33)--, R.sup.33--C(O)--NH--,
R.sup.33--C(O)--N(R.sup.71)--, R.sup.33--S(O).sub.2--NH--,
R.sup.33--S(O).sub.2--N(R.sup.71)--, H.sub.2N--S(O).sub.2--NH--,
R.sup.33--NH--S(O).sub.2--NH--,
R.sup.33--N(R.sup.33)--S(O).sub.2--NH--,
H.sub.2N--S(O).sub.2--N(R.sup.71)--,
R.sup.33--NH--S(O).sub.2--N(R.sup.71)--,
R.sup.33--N(R.sup.33)--S(O).sub.2--N(R.sup.71)--, HO--C(O)--,
R.sup.33--O--C(O)--, H.sub.2N--C(O)--, R.sup.33--NH--C(O)--,
R.sup.33--N(R.sup.33)--C(O)--, NC--, oxo, phenyl and Het, in
another embodiment from the series consisting of halogen, R.sup.33,
HO--, R.sup.33--O--, R.sup.33--S(O).sub.m--, H.sub.2N--,
R.sup.33--NH--, R.sup.33--N(R.sup.33)--, R.sup.33--C(O)--NH--,
R.sup.33--C(O)--N(R.sup.71)--, R.sup.33--S(O).sub.2--NH--,
R.sup.33--S(O).sub.2--N(R.sup.71)--, H.sub.2N--S(O).sub.2--NH--,
R.sup.33--NH--S(O).sub.2--NH--,
R.sup.33--N(R.sup.33)--S(O).sub.2--NH--,
H.sub.2N--S(O).sub.2--N(R.sup.71)--,
R.sup.33--NH--S(O).sub.2--N(R.sup.71)--,
R.sup.33--N(R.sup.33)--S(O).sub.2--N(R.sup.71)--, HO--C(O)--,
R.sup.33--O--C(O)--, H.sub.2N--C(O)--, R.sup.33--NH--C(O)--,
R.sup.33--N(R.sup.33)--C(O)-- and NC--, in another embodiment from
the series consisting of halogen, R.sup.33, HO--, R.sup.33--O--,
R.sup.33--S(O).sub.m--, H.sub.2N--, R.sup.33--NH--,
R.sup.33--N(R.sup.33)--, R.sup.33--C(O)--NH--,
R.sup.33--S(O).sub.2--NH--, H.sub.2N--S(O).sub.2--NH--,
R.sup.33--NH--S(O).sub.2--NH--,
R.sup.33--N(R.sup.33)--S(O).sub.2--NH--, HO--C(O)--,
R.sup.33--O--C(O)--, H.sub.2N--C(O)--, R.sup.33--NH--C(O)--,
R.sup.33--N(R.sup.33)--C(O)-- and NC--, in another embodiment from
the series consisting of halogen, R.sup.33, HO--, R.sup.33--O--,
R.sup.33--S(O).sub.m--, H.sub.2N--, R.sup.33--NH--,
R.sup.33--N(R.sup.33)--, R.sup.33--C(O)--NH--,
R.sup.33--S(O).sub.2--NH--, H.sub.2N--S(O).sub.2--NH--,
R.sup.33--NH--S(O).sub.2--NH--,
R.sup.33--N(R.sup.33)--S(O).sub.2--NH--, H.sub.2N--C(O)--,
R.sup.33--NH--C(O)--, R.sup.33--N(R.sup.33)--C(O)-- and NC--, in
another embodiment from the series consisting of halogen, R.sup.33,
HO--, R.sup.33--O--, R.sup.33--S(O).sub.m--, H.sub.2N--,
R.sup.33--NH--, R.sup.33--N(R.sup.33)--, R.sup.33--C(O)--NH--,
R.sup.33--S(O).sub.2--NH--, H.sub.2N--C(O)--, R.sup.33--NH--C(O)--,
R.sup.33--N(R.sup.33)--C(O)-- and NC--, in another embodiment from
the series consisting of halogen, R.sup.33, HO--, R.sup.33--O--,
R.sup.33--S(O).sub.m--, H.sub.2N--, R.sup.33--NH--,
R.sup.33--N(R.sup.33)--, R.sup.33--C(O)--NH--,
R.sup.33--C(O)--N(R.sup.71)--, R.sup.33--S(O).sub.2--NH--,
R.sup.33--S(O).sub.2--N(R.sup.71)--, H.sub.2N--C(O)--,
R.sup.33--NH--C(O)--, R.sup.33--N(R.sup.33)--C(O)-- and NC--, in
another embodiment from the series consisting of halogen, R.sup.33,
HO--, R.sup.33--O--, R.sup.33--S(O).sub.m--, R.sup.33--C(O)--NH--,
R.sup.33--C(O)--N(R.sup.71)--, R.sup.33--S(O).sub.2--NH--,
R.sup.33--S(O).sub.2--N(R.sup.71)--, H.sub.2N--C(O)--,
R.sup.33--NH--C(O)--, R.sup.33--N(R.sup.33)--C(O)-- and NC--, in
another embodiment from the series consisting of halogen, R.sup.33,
HO--, R.sup.33--O--, R.sup.33--S(O).sub.m--, R.sup.33--C(O)--NH--,
R.sup.33--S(O).sub.2--NH--, H.sub.2N--C(O)--, R.sup.33--NH--C(O)--,
R.sup.33--N(R.sup.33)--C(O)-- and NC--, in another embodiment from
the series consisting of halogen, R.sup.33, HO--, R.sup.33--O--,
R.sup.33--C(O)--NH--, R.sup.33--S(O).sub.2--NH--, H.sub.2N--C(O)--,
R.sup.33--NH--C(O)--, R.sup.33--N(R.sup.33)--C(O)-- and NC--, in
another embodiment from the series consisting of halogen, R.sup.33,
R.sup.33--O--, R.sup.33--C(O)--NH--, R.sup.33--S(O).sub.2--NH--,
H.sub.2N--C(O)--, R.sup.33--NH--C(O)--,
R.sup.33--N(R.sup.33)--C(O)-- and NC--, in another embodiment from
the series consisting of halogen, R.sup.33, R.sup.33--O-- and NC--,
in another embodiment from the series consisting of halogen,
R.sup.33 and R.sup.33--O--, in another embodiment from the series
consisting of halogen and R.sup.33, wherein in all these
embodiments R.sup.33 and R.sup.71 are defined as indicated above or
below and R.sup.33 is optionally substituted by one or more
identical or different substituents R.sup.70. In one embodiment of
the invention, the groups R.sup.33 in these substituents on a ring
representing R.sup.24 are independently of each other chosen from
the series consisting of (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl and
(C.sub.3-C.sub.7)-cycloalkyl-(C.sub.1-C.sub.4)-alkyl-, in another
embodiment from the series consisting of (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl and
(C.sub.3-C.sub.6)-cycloalkyl-(C.sub.1-C.sub.2)-alkyl-, in another
embodiment from the series consisting of (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl and
(C.sub.3-C.sub.6)-cycloalkyl-CH.sub.2--, in another embodiment from
the series consisting of (C.sub.1-C.sub.6)-alkyl, cyclopropyl and
cyclopropyl-CH.sub.2--, for example from the series consisting of
(C.sub.1-C.sub.6)-alkyl, in another embodiment from the series
consisting of (C.sub.1-C.sub.4)-alkyl, cyclopropyl and
cyclopropyl-CH.sub.2--, for example from the series consisting of
(C.sub.1-C.sub.4)-alkyl. In one embodiment of the invention, the
number of substituents R.sup.70, which are optionally present in
these groups R.sup.33 besides any fluorine substituents and, in the
case of cycloalkyl groups, any (C.sub.1-C.sub.4)-alkyl
substituents, is independently of each other 0, 1, 2 or 3, in
another embodiment 0, 1 or 2, in another embodiment 0 or 1, in
another embodiment 0. In one embodiment of the invention, the
substituents R.sup.70 in these groups R.sup.33 are independently of
each other chosen from the series consisting of HO--,
R.sup.71--C(O)--O--, H.sub.2N--, R.sup.71--NH--,
R.sup.71--N(R.sup.71)--, R.sup.71--C(O)--NH--,
R.sup.71--C(O)--N(R.sup.71)--, R.sup.71--S(O).sub.2--NH-- and
R.sup.71--S(O).sub.2--N(R.sup.71)--, in another embodiment from the
series consisting of HO--, R.sup.71--C(O)--O--, H.sub.2N--,
R.sup.71--C(O)--NH-- and R.sup.71--S(O).sub.2--NH--, in another
embodiment from the series consisting of HO--, R.sup.71--C(O)--O--
and R.sup.71--C(O)--NH--, in another embodiment from the series
consisting of HO-- and R.sup.71--C(O)--NH--, in another embodiment
from the series consisting of HO-- and R.sup.71--O--, and in
another embodiment of the invention substituents R.sup.70 in these
groups R.sup.33 are HO--. In one embodiment of the invention, the
groups R.sup.71 present in these groups R.sup.33 are independently
of each other chosen from the series consisting of
(C.sub.1-C.sub.4)-alkyl, cyclopropyl and cyclopropyl-, in another
embodiment from the series consisting of (C.sub.1-C.sub.4)-alkyl
and cyclopropyl, in another embodiment from the series consisting
of (C.sub.1-C.sub.4)-alkyl. In one embodiment of the invention,
R.sup.24 is a benzene ring or a thiophene ring, for example a
benzene ring, or, in terms of the respective residues, R.sup.24 is
a phenyl group or a thiophenyl (thienyl) group, for example a
phenyl group, which are all optionally substituted as indicated
afore.
[0108] Examples of specific residues of benzene and thiophene
rings, i.e. of specific phenyl and thiophenyl groups, representing
R.sup.24, from any one or more of which examples the group R.sup.24
is chosen in one embodiment of the invention, are phenyl,
2-fluoro-phenyl, 3-fluoro-phenyl, 2-chloro-phenyl, 3-chloro-phenyl,
4-chloro-phenyl, 3-bromo-phenyl, 2,3-dichloro-phenyl,
3,4-dichloro-phenyl, 2,5-difluoro-phenyl, 2,5-dichloro-phenyl,
2-chloro-6-fluoro-phenyl, 3,4,5-trifluoro-phenyl, 3-methyl-phenyl
(m-tolyl), 3-ethyl-phenyl, 3-isopropyl-phenyl,
3-cyclopropyl-phenyl, 3-tert-butyl-5-methyl-phenyl,
3-trifluoromethyl-phenyl, 3-(2-hydroxyethyl)-phenyl,
3-(2-hydroxy-2-methyl-propyl)-phenyl,
3-(2-acetylaminoethyl)-phenyl, 2-fluoro-5-methyl-phenyl,
3-chloro-2-methyl-phenyl, 5-chloro-2-methyl-phenyl,
5-chloro-2-fluoro-3-methyl-phenyl,
2-fluoro-3-trifluoromethyl-phenyl,
2-fluoro-5-trifluoromethyl-phenyl,
4-fluoro-3-trifluoromethyl-phenyl,
5-fluoro-3-trifluoromethyl-phenyl,
3-chloro-4-trifluoromethyl-phenyl,
5-chloro-2-trifluoromethyl-phenyl,
5-chloro-3-trifluoromethyl-phenyl, 3-ethoxy-phenyl,
2-propoxy-phenyl, 3-isopropoxy-phenyl, 3-trifluoromethoxy-phenyl,
3-(2,2,2-trifluoroethoxy)-phenyl, 5-chloro-2-methoxy-phenyl,
3-chloro-4-methoxy-phenyl, 5-fluoro-3-isopropoxy-phenyl,
2-fluoro-3-trifluoromethoxy-phenyl, 4-methoxy-3,5-dimethyl-phenyl,
3-methoxy-5-trifluoromethyl-phenyl, 3-methylsulfanyl-phenyl,
3-ethylsulfanyl-phenyl, 3-trifluoromethylsulfanyl-phenyl,
3-ethanesulfonyl-phenyl, 3-acetylamino-phenyl,
3-methanesulfonylamino-phenyl, 3-dimethylaminosulfonylamino-phenyl,
3-cyano-phenyl, 2-thienyl, 3-thienyl, 4-methyl-2-thienyl,
5-methyl-3-thienyl.
[0109] In one embodiment of the invention, the total number of C,
N, O and S atoms which is present in the two groups R.sup.23 and
R.sup.24, i.e. in the substituent group R.sup.24--R.sup.23-- on the
ring comprising the groups Y and Z which is depicted in formula I,
is at least 6, in another embodiment at least 7, in another
embodiment at least 8, in another embodiment at least 9.
[0110] In one embodiment of the invention, R.sup.25 is chosen from
the series consisting of hydrogen and methyl, in another embodiment
R.sup.25 is hydrogen. In another embodiment of the invention
R.sup.25 is (C.sub.1-C.sub.4)-alkyl, for example methyl.
[0111] In one embodiment of the invention, R.sup.26, independently
of each other group R.sup.26, is chosen from the series consisting
of hydrogen, fluorine, methyl and HO--, in another embodiment from
the series consisting of hydrogen, fluorine and
(C.sub.1-C.sub.4)-alkyl, in another embodiment from the series
consisting of hydrogen, fluorine and methyl, in another embodiment
from the series consisting of hydrogen and fluorine, in another
embodiment from the series consisting of hydrogen and methyl, and
in another embodiment R.sup.26 is hydrogen, or in all these
embodiments two groups R.sup.26 bonded to the same carbon atom
together are oxo, or two of the groups R.sup.26 or one group
R.sup.25 and one group R.sup.26, together with the comprised chain
members, form a 3-membered to 7-membered monocyclic ring which is
saturated and contains 0, 1 or 2 identical or different hetero ring
members chosen from the series consisting of N, N(R.sup.34), O, S,
S(O) and S(O).sub.2, which ring is optionally substituted on ring
carbon atoms by one more identical or different substituents chosen
from the series consisting of fluorine and (C.sub.1-C.sub.4)-alkyl.
In another embodiment of the invention, R.sup.26, independently of
each other group R.sup.26, is chosen from the series consisting of
hydrogen, fluorine, methyl and HO--, in another embodiment from the
series consisting of hydrogen, fluorine and
(C.sub.1-C.sub.4)-alkyl, in another embodiment from the series
consisting of hydrogen, fluorine and methyl, in another embodiment
from the series consisting of hydrogen and fluorine, in another
embodiment from the series consisting of hydrogen and methyl, and
in another embodiment R.sup.26 is hydrogen, or in all these
embodiments two of the groups R.sup.26 or one group R.sup.25 and
one group R.sup.26, together with the comprised chain members, form
a 3-membered to 7-membered monocyclic ring which is saturated and
contains 0, 1 or 2 identical or different hetero ring members
chosen from the series consisting of N, N(R.sup.34), O, S, S(O) and
S(O).sub.2, which ring is optionally substituted on ring carbon
atoms by one more identical or different substituents chosen from
the series consisting of fluorine and (C.sub.1-C.sub.4)-alkyl. In
another embodiment of the invention, R.sup.26, independently of
each other group R.sup.26, is chosen from the series consisting of
hydrogen, fluorine, methyl and HO--, in another embodiment from the
series consisting of hydrogen, fluorine and
(C.sub.1-C.sub.4)-alkyl, in another embodiment from the series
consisting of hydrogen, fluorine and methyl, in another embodiment
from the series consisting of hydrogen and fluorine, in another
embodiment from the series consisting of hydrogen and methyl, and
in another embodiment all groups R.sup.26 are hydrogen.
[0112] In one embodiment of the invention, the number of groups
R.sup.26 in a chain representing R.sup.23 which are HO--, is zero,
one or two, in another embodiment zero or one, in another
embodiment zero, in another embodiment one. In one embodiment of
the invention, a HO-- group representing R.sup.26 is not present on
a carbon atom which is adjacent to a hetero chain member in a chain
representing R.sup.23. In another embodiment a HO-- group
representing R.sup.26 is not bonded to a carbon atom which is
connected to an adjacent group C(R.sup.26)(R.sup.26) by a double
bond. In one embodiment of the invention the number of groups
R.sup.26 in a chain representing R.sup.23 which are
(C.sub.1-C.sub.4)-alkyl such as methyl, is zero, one or two, in
another embodiment zero or one, in another embodiment zero, in
another embodiment one, in another embodiment two. In one
embodiment of the invention the number of groups R.sup.26 in a
chain representing R.sup.23 which are fluorine, is zero, one, two,
three or four, in another embodiment zero, one, two or three, in
another embodiment zero, one or two, in another embodiment zero or
one, in another embodiment zero, in another embodiment one, in
another embodiment two. In one embodiment of the invention, the
number of oxo substituents in a chain representing R.sup.23 which
are formed by two groups R.sup.26 bonded to the same carbon atom,
is zero, one or two, in another embodiment zero or one, in another
embodiment zero, in another embodiment one. In one embodiment of
the invention, an oxo substituent in a chain representing R.sup.23
is not present on a carbon atom which is adjacent to a hetero chain
member chosen from the series consisting of S(O) and S(O).sub.2, in
another embodiment from the series consisting of S, S(O) and
S(O).sub.2, in another embodiment from the series consisting of O,
S, S(O) and S(O).sub.2.
[0113] In one embodiment of the invention, the number of rings
which are formed by two of the groups R.sup.26 or one group
R.sup.25 and one group R.sup.26, together with the comprised chain
members, is zero, one or two, in another embodiment zero or one, in
another embodiment one, in another embodiment zero. In one
embodiment of the invention a ring formed by two of the groups
R.sup.26 or one group R.sup.25 and one group R.sup.26, together
with the comprised chain members, is a 3-membered, 4-membered,
5-membered or 6-membered ring, in another embodiment a 3-membered,
5-membered or 6-membered ring, in another embodiment a 3-membered
ring, in another embodiment a 5-membered or 6-membered ring. In one
embodiment of the invention, it is possible for two of the groups
R.sup.26, together with the comprised chain members, to form a
ring, but not for one group R.sup.25 and one group R.sup.26. In one
embodiment of the invention the number of chain members which is
comprised by a ring formed by two of the groups R.sup.26 or one
group R.sup.25 and one group R.sup.26, is one, two, three or four,
in another embodiment it is one, two or three, in another
embodiment it is one or two, in another embodiment it is one. In
case such ring comprises only one chain member, the two of the
groups R.sup.26 forming the ring are bonded to the same carbon atom
in the chain and the said one chain member is the carbon atom
carrying the two groups R.sup.26. Examples of rings, which are
formed by two groups R.sup.26 bonded to the same carbon atom and
the one comprised chain member, are cycloalkane rings such as
cyclopropane, cyclobutane, cyclopentane or cyclohexane, and
heterocyclic rings such as tetrahydrothiophene,
tetrahydrothiopyran, oxetane, tetrahydrofuran, tetrahydropyran,
azetidine, pyrrolidine or piperidine, for example cyclopropane,
which carry any adjacent chain members of a chain representing
R.sup.23 and/or the group R.sup.24 and/or the ring comprising the
groups Y and Z which is depicted in formula I, on the same ring
carbon atom, and which rings can all be substituted as indicated.
In case a ring formed by two of the groups R.sup.26 or one group
R.sup.25 and one group R.sup.26, together with the comprised chain
members, comprises two chain members, the two groups R.sup.26
forming the ring are bonded to two adjacent carbon atoms in the
chain or the one group R.sup.26 is bonded to a carbon atom which is
adjacent to the group N(R.sup.25), respectively. Examples of rings,
which are formed in such case, are likewise cycloalkane rings such
as cyclopropane, cyclobutane, cyclopentane or cyclohexane, and
heterocyclic rings such as tetrahydrothiophene,
tetrahydrothiopyran, oxetane, tetrahydrofuran, tetrahydropyran,
azetidine, pyrrolidine or piperidine, for example cyclopropane,
which carry any adjacent chain members of a chain representing
R.sup.23 and/or the group R.sup.24 and/or the ring comprising the
groups Y and Z which is depicted in formula I, on two adjacent ring
carbon atoms or on the ring nitrogen atom and an adjacent ring
carbon atom, and which rings can all be substituted as
indicated.
[0114] In case a ring formed by two of the groups R.sup.26 or one
group R.sup.25 and one group R.sup.26, together with the comprised
chain members, comprises more than one chain members, besides at
least one group C(R.sup.26)(R.sup.26) the comprised chain members
can also be hetero chain members including the group N(R.sup.25)
which then are hetero ring members of the formed ring. In one
embodiment of the invention, the total number of hetero ring
members in such a ring is zero, one or two, in another embodiment
zero or one, in another embodiment zero, in another embodiment one.
In one embodiment of the invention, hetero ring members in such a
ring are chosen from the series consisting of N, N(R.sup.34), O and
S, in another embodiment form the series consisting of N,
N(R.sup.34) and O, in another embodiment from the series consisting
of N and N(R.sup.34), in another embodiment from the series
consisting of N(R.sup.34) and O, in another embodiment from the
series consisting of N(R.sup.34), and in another embodiment hetero
ring members in such a ring are N, and in still another embodiment
hetero ring members in such a ring are 0, wherein a hetero ring
member N in a ring formed by two of the groups R.sup.26 or one
group R.sup.25 and one group R.sup.26, together with the comprised
chain members, is the nitrogen atom of a hetero chain member
N(R.sup.25).
[0115] In one embodiment of the invention, the number of
substituents which are optionally present in a ring formed by two
of the groups R.sup.26 or one group R.sup.25 and one group together
with the comprised chain members, is 0, 1, 2, 3 or 4, in another
embodiment 0, 1, 2 or 3, in another embodiment 0, 1 or 2, in
another embodiment 0 or 1, in another embodiment 0. In one
embodiment of the invention, (C.sub.1-C.sub.4)-alkyl substituents
which are present in a ring formed by two of the groups R.sup.26 or
one group R.sup.25 and one group R.sup.26, together with the
comprised chain members, are methyl. In one embodiment of the
invention substituents present in a ring formed by two of the
groups R.sup.26 or one group R.sup.25 and one group R.sup.26,
together with the comprised chain members, are fluorine, in another
embodiment they are identical or different (C.sub.1-C.sub.4)-alkyl
groups, for example methyl.
[0116] Examples of specific groups R.sup.23 including specific
groups R.sup.26 contained therein are given in the following
examples of groups of the formula II, which groups are bonded to
the ring comprising the groups Y and Z which is depicted in formula
I by the free bond represented by the terminal hyphen or the
terminal line in the structural formula, and from which groups of
the formula II the groups R.sup.23 themselves are obtained by
removing the group R.sup.24, wherein in these groups of the formula
II the group R.sup.24 is defined as above or below: [0117]
R.sup.24--CH.sub.2--, [0118] R.sup.24--CH.sub.2--CH.sub.2--,
[0118] ##STR00008## [0119] R.sup.24--C.ident.C--, [0120]
R.sup.24--CF.sub.2--O, [0121] R.sup.24--CH.sub.2--NH--, [0122]
R.sup.24--C(O)--NH--, [0123]
R.sup.24--CH.sub.2--CH.sub.2--CH.sub.2--, [0124]
R.sup.24--CF.sub.2--CH.sub.2--CH.sub.2--, [0125]
R.sup.24--CH.sub.2--CH.sub.2--CH(OH)--, [0126]
R.sup.24--C(CH.sub.3).sub.2--CH.sub.2--CH.sub.2--,
##STR00009##
[0126] ##STR00010## [0127] R.sup.24--CH.dbd.CH--CH(OH)--, [0128]
R.sup.24--CH.sub.2--CF.sub.2--O--, [0129]
R.sup.24--CF.sub.2--CH.sub.2--O--, [0130] R.sup.24--CF.sub.2--,
##STR00011##
[0130] ##STR00012## [0131] R.sup.24--CH.sub.2--O--, [0132]
R.sup.24--CH.sub.2--S--, [0133] R.sup.24--CH.sub.2--N(CH.sub.3)--,
[0134] R.sup.24--S(O).sub.2--O--, [0135]
R.sup.24--CH.sub.2--CH.sub.2--CF.sub.2--, [0136]
R.sup.24--CH(OH)--CH.sub.2--CH.sub.2--, [0137]
R.sup.24--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--,
##STR00013##
[0137] ##STR00014## [0138] R.sup.24--CH--.dbd.CH--CH.sub.2--,
[0139] R.sup.24--CH.sub.2--CH.sub.2--O--, [0140]
R.sup.24--CH(F)--CH.sub.2--O--, [0141]
R.sup.24--CF.sub.2--CF.sub.2--O--, [0142]
R.sup.24--CH(CH.sub.3)--CH.sub.2--O--,
##STR00015##
[0142] ##STR00016## [0143] R.sup.24--O--CF.sub.2--CH.sub.2--,
[0144] R.sup.24--O--CF.sub.2--CF.sub.2--,
[0144] ##STR00017## [0145] R.sup.24--CF.sub.2--O--CH.sub.2--,
[0145] ##STR00018## [0146] R.sup.24--CH.sub.2--CH.sub.2--S--,
[0147] R.sup.24--S--CH.sub.2--CH.sub.2--, [0148]
R.sup.24--CH.sub.2--CH.sub.2--N(CH.sub.3)--, [0149]
R.sup.24--C(CH.sub.3).sub.2--CH.sub.2--O--,
[0149] ##STR00019## [0150] R.sup.24--O--CH.sub.2--CH.sub.2--,
[0151] R.sup.24--O--CH.sub.2--CF.sub.2--,
[0151] ##STR00020## [0152] R.sup.24--CH.sub.2--O--CH.sub.2--,
[0153] R.sup.24--CH.sub.2--O--CF.sub.2--,
[0153] ##STR00021## [0154] R.sup.24--CH.sub.2--S--CH.sub.2--,
[0155] R.sup.24--CH.sub.2--CH.sub.2--NH--, [0156]
R.sup.24--CH.sub.2--C(O)--NH--.
[0157] In one embodiment of the invention, R.sup.23 is chosen from
a direct bond and any one or more of the chains R.sup.23 in the
preceding examples of groups of the formula II and, likewise, the
group of the formula II is chosen from the group R.sup.24 and any
one or more of the preceding examples of the groups of the formula
II.
[0158] In one embodiment of the invention, the number of
substituents R.sup.70 which are optionally present in the group
R.sup.31, is zero, one, two or three, in another embodiment zero,
one or two, in another embodiment zero or one, in another
embodiment zero. In one embodiment of the invention, R.sup.31 is
chosen from the series consisting of (C.sub.1-C.sub.6)-alkyl, in
another embodiment from the series consisting of
(C.sub.1-C.sub.4)-alkyl, which are all optionally substituted by
one or more identical or different substituents R.sup.70.
[0159] In one embodiment of the invention, R.sup.32 and R.sup.34
are independently of each other chosen from the series consisting
of hydrogen, R.sup.35, R.sup.35--C(O)--, R.sup.35--O--C(O)--,
phenyl and Het, in another embodiment from the series consisting of
hydrogen, R.sup.35, R.sup.35--C(O)--, R.sup.35--O--C(O)--, phenyl
and Het.sup.2, in another embodiment from the series consisting of
hydrogen, R.sup.35, R.sup.35--C(O)--, R.sup.35--O--C(O)-- and
phenyl, in another embodiment from the series consisting of
hydrogen, R.sup.35, R.sup.35--C(O)-- and R.sup.35--O--C(O)--, in
another embodiment from the series consisting of hydrogen, R.sup.35
and R.sup.35--C(O)--, in another embodiment from the series
consisting of hydrogen, R.sup.35, phenyl and Het, in another
embodiment from the series consisting of hydrogen, R.sup.35, phenyl
and Het.sup.2, in another embodiment from the series consisting of
hydrogen, R.sup.35 and phenyl, in another embodiment from the
series consisting of hydrogen and R.sup.35, wherein in these
embodiments a group Het or Het.sup.2 occurring in R.sup.32 and
R.sup.34 in one embodiment of the invention is chosen from
pyridinyl and thiophenyl. In one embodiment of the invention, the
groups R.sup.35 occurring in R.sup.32 and R.sup.34 are
independently of each other chosen from (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl and
(C.sub.3-C.sub.7)-cycloalkyl-(C.sub.1-C.sub.4)-alkyl-, in another
embodiment from (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl and
(C.sub.3-C.sub.7)-cycloalkyl-(C.sub.1-C.sub.2)-alkyl-, in another
embodiment from (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl and
(C.sub.3-C.sub.7)-cycloalkyl-CH.sub.2--, in another embodiment from
(C.sub.1-C.sub.6)-alkyl and (C.sub.3-C.sub.7)-cycloalkyl, in
another embodiment from (C.sub.1-C.sub.6)-alkyl, in another
embodiment from (C.sub.1-C.sub.4)-alkyl, which are all optionally
substituted by one or more identical or different substituents
R.sup.70 and wherein in these groups besides any substituents
R.sup.70 one or more fluorine substituents are optionally present
and in cycloalkyl groups one or more (C.sub.1-C.sub.4)-alkyl
substituents are optionally present as applies to alkyl and
cycloalkyl groups in general.
[0160] In one embodiment of the invention, the number of
substituents R.sup.70 which are optionally present in a group
R.sup.35 occurring in R.sup.32 and R.sup.34 besides any fluorine
substituents and, in the case of a cycloalkyl group, alkyl
substituents, is, independently of each other group, 0, 1, 2, 3 or
4, in another embodiment 0, 1, 2 or 3, in another embodiment 0, 1
or 2, in another embodiment 0 or 1, in another embodiment 0. In one
embodiment of the invention, substituents R.sup.70 which are
optionally present in a group R.sup.35 occurring in R.sup.32 and
R.sup.34 are, independently of each other group, chosen from the
series consisting of HO--, R.sup.71--O--, NC--, phenyl and
Het.sup.2, in another embodiment from the series consisting of
phenyl and Het.sup.2, in another from the series consisting of
phenyl, wherein phenyl and Het.sup.2 are defined and optionally
substituted as indicated.
[0161] In one embodiment of the invention, R.sup.50 is chosen from
R.sup.51--O-- and R.sup.52--NH--, in another embodiment from
R.sup.51--O-- and H.sub.2N--. In another embodiment R.sup.50 is
R.sup.51--O--.
[0162] In one embodiment of the invention, R.sup.51 is hydrogen. In
another embodiment of the invention, R.sup.51 is R.sup.54.
[0163] In one embodiment of the invention, R.sup.52 is chosen from
the series consisting of hydrogen, R.sup.55 and
R.sup.56--S(O).sub.2--, in another embodiment from the series
consisting of hydrogen, (C.sub.1-C.sub.4)-alkyl which is optionally
substituted by one or more identical or different substituents
R.sup.70, and R.sup.56--S(O).sub.2--, in another embodiment from
the series consisting of hydrogen, unsubstituted
(C.sub.1-C.sub.4)-alkyl and R.sup.56--S(O).sub.2--, in another
embodiment from the series consisting of hydrogen, unsubstituted
methyl and R.sup.56--S(O).sub.2--, in another embodiment from the
series consisting of hydrogen and (C.sub.1-C.sub.4)-alkyl which is
optionally substituted by one or more identical or different
substituents R.sup.70, in another embodiment from the series
consisting of hydrogen and unsubstituted (C.sub.1-C.sub.4)-alkyl,
in another embodiment from the series consisting of hydrogen and
unsubstituted methyl. In another embodiment of the invention,
R.sup.52 is hydrogen.
[0164] In one embodiment of the invention, R.sup.53 is chosen from
the series consisting of hydrogen and (C.sub.1-C.sub.4)-alkyl which
is optionally substituted by one or more identical or different
substituents R.sup.70, in another embodiment from the series
consisting of hydrogen and unsubstituted (C.sub.1-C.sub.4)-alkyl,
in another embodiment from the series consisting of hydrogen and
unsubstituted methyl. In another embodiment of the invention,
R.sup.53 is hydrogen.
[0165] In one embodiment of the invention, R.sup.54 is chosen from
(C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl and
(C.sub.3-C.sub.7)-cycloalkyl-(C.sub.1-C.sub.4)-alkyl-, in another
embodiment from (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl and
(C.sub.3-C.sub.7)-cycloalkyl-(C.sub.1-C.sub.2)-alkyl-, in another
embodiment from (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl and
(C.sub.3-C.sub.7)-cycloalkyl-CH.sub.2--, in another embodiment from
(C.sub.1-C.sub.6)-alkyl and (C.sub.3-C.sub.7)-cycloalkyl, in
another embodiment from (C.sub.1-C.sub.6)-alkyl, in another
embodiment from (C.sub.1-C.sub.4)-alkyl, in another embodiment from
(C.sub.1-C.sub.3)-alkyl, which are all optionally substituted by
one or more identical or different substituents R.sup.70 and
wherein in these groups besides any substituents R.sup.70 one or
more fluorine substituents are optionally present and in cycloalkyl
groups one or more (C.sub.1-C.sub.4)-alkyl substituents are
optionally present as applies to alkyl and cycloalkyl groups in
general. In one embodiment of the invention, the number of
substituents R.sup.70 which are optionally present in a group
R.sup.54 besides any fluorine substituents and, in the case of a
cycloalkyl group, any alkyl substituents, is 0, 1 or 2, in another
embodiment 0 or 1, in another embodiment 1, in another embodiment
0. In another embodiment of the invention, a group R.sup.54 is
neither substituted by R.sup.70 nor by fluorine substituents nor,
in the case of a cycloalkyl group, by alkyl substituents, and
R.sup.54 in this embodiment thus is chosen, for example, from the
series consisting of C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
(C.sub.3-C.sub.7)-cycloalkyl and
(C.sub.3-C.sub.7)-cycloalkyl-(C.sub.1-C.sub.4)-alkyl-, or from the
series consisting of (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl and
(C.sub.3-C.sub.7)-cycloalkyl-CH.sub.2--, or from the series
consisting of (C.sub.1-C.sub.6)-alkyl, or from the series
consisting of (C.sub.1-C.sub.4)-alkyl, or from the series
consisting of (C.sub.1-C.sub.3)-alkyl, which are all unsubstituted.
In one embodiment of the invention, substituents R.sup.70 which are
optionally present in a group R.sup.54, are independently of each
other chosen from the series consisting of HO--, R.sup.71--O--,
R.sup.71--C(O)--O--, HO--C(O)-- and R.sup.71--O--C(O)--, in another
embodiment from the series consisting of HO--, R.sup.71--O-- and
R.sup.71--C(O)--O--, in another embodiment from the series
consisting of HO-- and R.sup.71--C(O)--O--.
[0166] In one embodiment of the invention, R.sup.56 is chosen from
the series consisting of phenyl which is optionally substituted as
indicated above or below, and unsubstituted
(C.sub.1-C.sub.4)-alkyl, in another embodiment from the series
consisting of phenyl which is optionally substituted as indicated
above or below, and unsubstituted methyl, in another embodiment
from unsubstituted (C.sub.1-C.sub.4)-alkyl, in another embodiment
from unsubstituted(C.sub.1-C.sub.3)-alkyl. In another embodiment
R.sup.56 is unsubstituted methyl, in another embodiment phenyl
which is optionally substituted as indicated.
[0167] In one embodiment of the invention, R.sup.60 is chosen from
the series consisting of hydrogen and methyl. In another embodiment
R.sup.60 is hydrogen. In another embodiment R.sup.60 is
(C.sub.1-C.sub.4)-alkyl, for example methyl.
[0168] In one embodiment of the invention, a group R.sup.70 in any
of its occurrences is, independently of groups R.sup.70 in other
occurrences and unless specified otherwise, chosen from the series
consisting of HO--, R.sup.71--O--, R.sup.71--C(O)--O--,
R.sup.71--S(O).sub.m--, H.sub.2N--, R.sup.71--NH--,
R.sup.71--N(R.sup.71)--, R.sup.71--C(O)--NH--,
R.sup.71--C(O)--N(R.sup.71)--, R.sup.71--S(O).sub.2--NH--,
R.sup.71--S(O).sub.2--N(R.sup.71)--, HO--C(O)--,
R.sup.71--O--C(O)--, H.sub.2N--C(O)--, R.sup.71--NH--C(O)--,
R.sup.71--N(R.sup.17)--C(O)--, NC--, oxo, phenyl and Het.sup.2, in
another embodiment from the series consisting of HO--,
R.sup.71--O--, R.sup.71--C(O)--O--, R.sup.71--S(O).sub.m--,
H.sub.2N--, R.sup.71--NH--, R.sup.71--N(R.sup.71)--,
R.sup.71--C(O)--NH--, R.sup.71--S(O).sub.2--NH--, HO--C(O)--,
R.sup.71--O--C(O)--, H.sub.2N--C(O)--, R.sup.71--NH--C(O)--,
R.sup.71--N(R.sup.17)--C(O)--, NC--, oxo, phenyl and Het.sup.2, in
another embodiment from the series consisting of HO--,
R.sup.71--O--, R.sup.71--C(O)--O--, R.sup.71--S(O).sub.m--,
HO--C(O)--, R.sup.71--O--C(O)--, H.sub.2N--C(O)--,
R.sup.71--NH--C(O)--, R.sup.71--N(R.sup.17)--C(O)--, NC--, oxo,
phenyl and Het.sup.2, in another embodiment from the series
consisting of HO--, R.sup.71--O--, R.sup.71--C(O)--O--,
R.sup.71--S(O).sub.m--, H.sub.2N--, R.sup.71--NH--,
R.sup.71--N(R.sup.71)--, R.sup.71--C(O)--NH--,
R.sup.71--S(O).sub.2--NH--, NC--, oxo, phenyl and Het.sup.2, in
another embodiment from the series consisting of HO--,
R.sup.71--O--, R.sup.71--C(O)--O--, R.sup.71--S(O).sub.m--, NC--,
oxo, phenyl and Het.sup.2, in another embodiment from the series
consisting of HO--, R.sup.71--O--, R.sup.71--S(O).sub.m--, NC--,
oxo, phenyl and Het.sup.2, in another embodiment from the series
consisting of HO--, R.sup.71--O--, R.sup.71--C(O)--O--,
R.sup.71--S(O).sub.m--, NC--, phenyl and Het.sup.2, in another
embodiment from the series consisting of HO--, R.sup.71--O--, NC--,
phenyl and Het.sup.2, in another embodiment from the series
consisting of HO--, R.sup.71--O--, phenyl and Het.sup.2, in another
embodiment from the series consisting of HO--, R.sup.71--O-- and
phenyl, in another embodiment from the series consisting of HO--
and R.sup.71--O--, in another embodiment from the series consisting
of HO-- and R.sup.71--C(O)--O--, in another embodiment from the
series consisting of phenyl and Het.sup.2, in another embodiment
from the series consisting of phenyl, in another embodiment from
the series consisting of HO--C(O)--, R.sup.71--O--C(O)--,
H.sub.2N--C(O)--, R.sup.71--NH--C(O)--,
R.sup.71--N(R.sup.17)--C(O)--, in another embodiment from the
series consisting of HO--C(O)--, and R.sup.71--O--C(O)--, and in
another embodiment R.sup.70 is HO--, wherein R.sup.71, phenyl and
Het.sup.2 are defined and optionally substituted as indicated above
or below. In the latter embodiment, in which R.sup.70 is HO--, a
(C.sub.1-C.sub.6)-alkyl group, for example, which is optionally
substituted by the said R.sup.70, can among others be a group such
as (C.sub.1-C.sub.6)-alkyl, HO--(C.sub.1-C.sub.6)-alkyl-, i.e.
hydroxy-(C.sub.1-C.sub.6)-alkyl-,
(HO).sub.2(C.sub.2-C.sub.6)-alkyl-, i.e.
dihydroxy-(C.sub.2-C.sub.6)-alkyl-, and a (C.sub.1-C.sub.4)-alkyl
group which is optionally substituted by R.sup.70, can among others
be a group such as (C.sub.1-C.sub.4)-alkyl,
HO--(C.sub.1-C.sub.4)-alkyl-, i.e.
hydroxy-(C.sub.1-C.sub.4)-alkyl-,
(HO).sub.2(C.sub.2-C.sub.4)-alkyl-, i.e.
dihydroxy-(C.sub.2-C.sub.4)-alkyl-, wherein the alkyl groups are
optionally substituted by one or more fluorine substituents. In one
embodiment of the invention, a carbon atom does not carry more than
one HO-- group.
[0169] In one embodiment of the invention, R.sup.71 is chosen from
(C.sub.1-C.sub.4)-alkyl, cyclopropyl and cyclopropyl-CH.sub.2--, in
another embodiment from (C.sub.1-C.sub.4)-alkyl and cyclopropyl, in
another embodiment from (C.sub.1-C.sub.4)-alkyl, in another
embodiment from (C.sub.1-C.sub.3)-alkyl, unless specified
otherwise.
[0170] A subject of the invention are all compounds of the formula
I wherein any one or more structural elements such as groups,
substituents and numbers are defined as in any of the specified
embodiments or definitions of the elements or have one or more of
the specific meanings which are mentioned herein as examples of
elements, wherein all combinations of one or more specified
embodiments and/or definitions and/or specific meanings of the
elements are a subject of the present invention. Also with respect
to all such compounds of the formula I, all their stereoisomeric
forms and mixtures of stereoisomeric forms in any ratios, and their
physiologically acceptable salts, and the physiologically
acceptable solvates of any of them, are a subject of the present
invention.
[0171] Likewise, also with respect to all specific compounds
disclosed herein, such as the example compounds which represent
embodiments of the invention wherein the various groups and numbers
in the general definition of the compounds of the formula I have
the specific meanings present in the respective specific compound,
it applies that all their stereoisomeric forms and mixtures of
stereoisomeric forms in any ratio, and their physiologically
acceptable salts, and the physiologically acceptable solvates of
any of them are a subject of the present invention. A subject of
the invention also are all specific compounds disclosed herein,
irrespective thereof whether they are disclosed as a free compound
and/or as a specific salt, both in the form of the free compound
and in the form of all its physiologically acceptable salts, and if
a specific salt is disclosed, additionally in the form of this
specific salt, and the physiologically acceptable solvates of any
of them. For example, in the case of the specific compound
2-{2-chloro-5-[2-(3-chloro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-
-2-carboxylic acid which is disclosed in the form of the free
compound, a subject of the invention are
2-{2-chloro-5-[2-(3-chloro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-
-2-carboxylic acid and its physiologically acceptable salts and the
physiologically acceptable solvates of any of them.
[0172] Thus, a subject of the invention also is a compound of the
formula I which is chosen from any of the specific compounds of the
formula I which are disclosed herein, or is any one of the specific
compounds of the formula I which are disclosed herein, irrespective
thereof whether they are disclosed as a free compound and/or as a
specific salt, for example a compound of the formula I which is
chosen from [0173]
2-[4-methylsulfanyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxyli-
c acid, [0174]
2-[4-acetyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid, [0175]
2-[4-ethyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid, [0176]
2-[4-ethoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid, [0177]
2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxyli-
c acid, [0178]
2-{4-methoxy-3-[2-(3-trifluoromethylsulfanyl-phenyl)-ethoxy]-benzoylamino-
}-indane-2-carboxylic acid, [0179]
2-[4-methoxy-3-(1-m-tolyl-cyclopropylmethoxy)-benzoylamino]-indane-2-carb-
oxylic acid, [0180]
2-{3-[2-(3-cyano-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxy-
lic acid, [0181] 5-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-5,
6-dihydro-4H-cyclopenta[c]thiophene-5-carboxylic acid, [0182]
5-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-5,6-dihydro-4H-cyclopenta-
[b]thiophene-5-carboxylic acid, [0183]
2-{[5-acetyl-4-(2-m-tolyl-ethoxy)-thiophene-2-carbonyl]-amino}-indane-2-c-
arboxylic acid, [0184]
2-[3-fluoro-4-methoxy-5-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxy-
lic acid, [0185]
2-[4-methoxy-3-(2-m-tolyloxy-ethyl)-benzoylamino]-indane-2-carboxylic
acid, [0186]
2-[4-methoxy-3-(3-m-tolyl-propyl)-benzoylamino]-indane-2-carboxylic
acid, [0187]
5-fluoro-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2--
carboxylic acid, [0188]
2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-5,6-dimethyl-indane-2-car-
boxylic acid, [0189]
2-[4-cyano-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid, [0190]
2-[4-methoxy-3-(2-m-tolyl-ethylamino)-benzoylamino]-indane-2-carbo-
xylic acid, [0191]
2-{3-[2-(3-chloro-phenyl)-ethoxy]-4-methyl-benzoylamino}-indane-2-carboxy-
lic acid, [0192]
2-[4-methoxy-3-(2-m-tolyl-ethylsulfanyl)-benzoylamino]-indane-2-carboxyli-
c acid, [0193]
2-[3-(2-m-tolyl-ethoxy)-4-trifluoromethyl-benzoylamino]-indane-2-carboxyl-
ic acid, [0194]
2-{3-[2-(2-fluoro-5-methyl-phenyl)-ethoxy]-4-trifluoromethyl-benzoylamino-
}-indane-2-carboxylic acid, [0195]
2-(3-{2-[3-(2-hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-inda-
ne-2-carboxylic acid, [0196]
2-{[6-methoxy-5-(2-m-tolyl-ethoxy)-pyridine-3-carbonyl]-amino}-indane-2-c-
arboxylic acid [0197]
2-[(3'-methanesulfonylamino-6-methoxy-biphenyl-3-carbonyl)-amino]-indane--
2-carboxylic acid, [0198]
2-[(3'-dimethylaminosulfonylamino-6-methoxy-biphenyl-3-carbonyl)-amino]-i-
ndane-2-carboxylic acid, [0199]
2-[(6-methoxy-3'-trifluoromethoxy-biphenyl-3-carbonyl)-amino]-indane-2-ca-
rboxylic acid, [0200]
2-[(3'-cyanomethyl-6-methoxy-biphenyl-3-carbonyl)-amino]-indane-2-carboxy-
lic acid, [0201]
2-[(3'-isopropyl-6-methoxy-biphenyl-3-carbonyl)-amino]-indane-2-carboxyli-
c acid, [0202]
2-[(3'-chloro-6-methoxy-2'-methyl-biphenyl-3-carbonyl)-amino]-indane-2-ca-
rboxylic acid, [0203]
2-{[5-(3-chloro-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-indane-2-ca-
rboxylic acid, and [0204]
2-[3-(2,2-difluoro-2-phenyl-ethoxy)-4-methoxy-benzoylamino]-indane-2-carb-
oxylic acid, [0205] or which is any one of these compounds, or a
physiologically acceptable salt thereof, or physiologically
acceptable solvate of any of them, wherein the compound of the
formula I is a subject of the invention in any of its
stereoisomeric forms or a mixture of stereoisomeric forms in any
ratio where applicable.
[0206] As an example of compounds of the invention which with
respect to any structural elements are defined as in specified
embodiments of the invention or definitions of such elements,
compounds of the formula I may be mentioned wherein ring A is a
cyclohexane ring, a benzene ring, a pyridine ring, a pyridazine
ring or a thiophene ring, wherein the cyclohexane ring is
optionally substituted by one or more identical or different
substituents chosen from the series consisting of fluorine and
(C.sub.1-C.sub.4)-alkyl, and the benzene ring, the pyridine ring,
the pyridazine ring and the thiophene ring are optionally
substituted by one or more identical or different substituents
chosen from the series consisting of halogen, R.sup.1, HO--,
R.sup.1--O--, R.sup.1--C(O)--O--, R.sup.1--S(O).sub.2--O--,
R.sup.1--S(O).sub.m--, H.sub.2N--, R.sup.1--NH--,
R.sup.1--N(R.sup.1)--, R.sup.1--C(O)--NH--,
R.sup.1--C(O)--N(R.sup.71)--, R.sup.1--S(O).sub.2--NH--,
R.sup.1--S(O).sub.2--N(R.sup.71)--, R.sup.1--C(O)--, HO--C(O)--,
R.sup.1--O--C(O)--, H.sub.2N--C(O)--, R.sup.1--NH--C(O)--,
R.sup.1--N(R.sup.1)--C(O)--, H.sub.2N--S(O).sub.2--,
R.sup.1--NH--S(O).sub.2--, R.sup.1--N(R.sup.1)--S(O).sub.2--, NC--
and O.sub.2N--;
[0207] Y is chosen from the series consisting of S,
C(R.sup.12).dbd.C(R.sup.13), and C(R.sup.15).dbd.N;
[0208] Z is C(R.sup.16);
[0209] and all other groups and numbers are defined as in the
general definition of the compounds of the formula I or in any
specified embodiments of the invention or definitions of structural
elements, in any of their stereoisomeric forms or a mixture of
stereoisomeric forms in any ratio, and their physiologically
acceptable salts, and the physiologically acceptable solvates of
any of them.
[0210] As another such example compounds of the formula I may be
mentioned, wherein ring A is a benzene ring, a pyridine ring, a
pyrazine or a thiophene ring which rings are all optionally
substituted by one or two identical or different substituents
chosen from the series consisting of halogen,
(C.sub.1-C.sub.4)-alkyl and (C.sub.1-C.sub.4)-alkyl-O--;
[0211] Y is chosen from the series consisting of S,
C(R.sup.12).dbd.C(R.sup.13) and C(R.sup.15).dbd.N;
[0212] Z is C(R.sup.16);
[0213] R.sup.3 and R.sup.5 are independently of each other chosen
from the series consisting of hydrogen and
(C.sub.1-C.sub.4)-alkyl;
[0214] R.sup.4 and R.sup.6 are hydrogen;
[0215] R.sup.12, R.sup.13, R.sup.15 and R.sup.16 are independently
of each other chosen from the series consisting of hydrogen,
halogen (C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkyl-O-- and
NC--;
[0216] R.sup.20 is hydrogen;
[0217] and all other groups and numbers are defined as in the
general definition of the compounds of the formula I or in any
specified embodiments of the invention or definitions of structural
elements, in any of their stereoisomeric forms or a mixture of
stereoisomeric forms in any ratio, and their physiologically
acceptable salts, and the physiologically acceptable solvates of
any of them.
[0218] As another such example compounds of the formula I may be
mentioned, wherein
[0219] R.sup.21 is chosen from the series consisting of hydrogen,
halogen, (C.sub.1-C.sub.4)-alkyl, HO--(C.sub.1-C.sub.4)-alkyl-,
(C.sub.1-C.sub.4)-alkyl-O--, (C.sub.1-C.sub.4)-alkyl-S(O).sub.m--,
H.sub.2N--, di((C.sub.1-C.sub.4)-alkyl)N--,
(C.sub.1-C.sub.4)-alkyl-C(O)-- and NC--;
[0220] R.sup.22 is a group of the formula II;
R.sup.24--R.sup.23-- II
[0221] R.sup.23 is a direct bond or a chain consisting of 2, 3 or 4
chain members of which 0 or 1 chain members are hetero chain
members chosen from the series consisting of N(R.sup.25), O, S,
S(O) and S(O).sub.2 and the other chain members are identical or
different groups C(R.sup.26)(R.sup.26), wherein two adjacent groups
C(R.sup.26)(R.sup.26) can be connected to each other by a double
bond or a triple bond;
[0222] and all other groups and numbers are defined as in the
general definition of the compounds of the formula I or in any
specified embodiments of the invention or definitions of structural
elements, in any of their stereoisomeric forms or a mixture of
stereoisomeric forms in any ratio, and their physiologically
acceptable salts, and the physiologically acceptable solvates of
any of them.
[0223] As another such example compounds of the formula I may be
mentioned, wherein R.sup.24 is a 3-membered to 7-membered
monocyclic ring or a 7-membered to 10-membered bicyclic ring, which
rings are saturated or unsaturated and contain 0, 1 or 2 identical
or different hetero ring members chosen from the series consisting
of N, N(R.sup.32), O, S, S(O) and S(O).sub.2, and which rings are
optionally substituted on ring carbon atoms by one or more
identical or different substituents chosen from the series
consisting of halogen, R.sup.33, HO--, R.sup.33--O--,
R.sup.33--S(O).sub.m--, H.sub.2N--, R.sup.33--NH--,
R.sup.33--N(R.sup.33)--, R.sup.33--C(O)--NH--,
R.sup.33--C(O)--N(R.sup.71)--, R.sup.33--S(O).sub.2--NH--,
R.sup.33--S(O).sub.2--N(R.sup.71)--, H.sub.2N--S(O).sub.2--NH--,
R.sup.33--NH--S(O).sub.2--NH--,
R.sup.33--N(R.sup.33)--S(O).sub.2--NH--,
H.sub.2N--S(O).sub.2--N(R.sup.71)--,
R.sup.33--NH--S(O).sub.2--N(R.sup.71)--,
R.sup.33--N(R.sup.33)--S(O).sub.2--N(R.sup.71)--, HO--C(O)--,
R.sup.33--O--C(O)--, H.sub.2N--C(O)--, R.sup.33--NH--C(O)--,
R.sup.33--N(R.sup.33)--C(O)--, NC--, oxo, phenyl and Het;
[0224] R.sup.32 is chosen from the series consisting of hydrogen,
R.sup.35, R.sup.35--C(O)--, R.sup.35--O--C(O)-- and phenyl;
[0225] and all other groups and numbers are defined as in the
general definition of the compounds of the formula I or in any
specified embodiments of the invention or definitions of structural
elements, in any of their stereoisomeric forms or a mixture of
stereoisomeric forms in any ratio, and their physiologically
acceptable salts, and the physiologically acceptable solvates of
any of them.
[0226] As another such example compounds of the formula I may be
mentioned, wherein ring A is a benzene ring, a pyridine ring, a
pyrazine or a thiophene ring which rings are all optionally
substituted by one or two identical or different substituents
chosen from the series consisting of halogen,
(C.sub.1-C.sub.4)-alkyl and (C.sub.1-C.sub.4)-alkyl-O--;
[0227] Y is chosen from the series consisting of S,
C(R.sup.12).dbd.C(R.sup.13) and C(R.sup.15).dbd.N;
[0228] Z is C(R.sup.16);
[0229] R.sup.3 and R.sup.5 are independently of each other chosen
from the series consisting of hydrogen and
(C.sub.1-C.sub.4)-alkyl;
[0230] R.sup.4 and R.sup.6 are hydrogen;
[0231] R.sup.12, R.sup.13, R.sup.15 and R.sup.16 are independently
of each other chosen from the series consisting of hydrogen,
halogen (C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkyl-O-- and
NC--;
[0232] R.sup.20 is hydrogen;
[0233] R.sup.21 is chosen from the series consisting of hydrogen,
halogen, (C.sub.1-C.sub.4)-alkyl, HO--(C.sub.1-C.sub.4)-alkyl-,
(C.sub.1-C.sub.4)-alkyl-S(O).sub.m--, H.sub.2N--,
(C.sub.1-C.sub.4)-alkyl-NH--, di((C.sub.1-C.sub.4)-alkyl)N--,
(C.sub.1-C.sub.4)-alkyl-C(O)-- and NC--;
[0234] R.sup.22 is a group of the formula II;
R.sup.24--R.sup.23-- II
[0235] R.sup.23 is a direct bond or a chain consisting of 2, 3 or 4
chain members of which 0 or 1 chain members are hetero chain
members chosen from the series consisting of N(R.sup.25), O, S,
S(O) and S(O).sub.2, and the other chain members are identical or
different groups C(R.sup.26)(R.sup.26), wherein two adjacent groups
C(R.sup.26)(R.sup.26) can be connected to each other by a double
bond or a triple bond;
[0236] R.sup.24 is a 3-membered to 7-membered monocyclic ring or a
7-membered to 10-membered bicyclic ring, which rings are saturated
or unsaturated and contains 0, 1 or 2 identical or different hetero
ring members chosen from the series consisting of N, N(R.sup.32),
O, S, S(O) and S(O).sub.2, which ring is optionally substituted on
ring carbon atoms by one or more identical or different
substituents chosen from the series consisting of halogen,
R.sup.33, HO--, R.sup.33--O--, R.sup.33--S(O).sub.m--, H.sub.2N--,
R.sup.33--NH--, R.sup.33--N(R.sup.33)--, R.sup.33--C(O)--NH--,
R.sup.33--C(O)--N(R.sup.71)--, R.sup.33--S(O).sub.2--NH--,
R.sup.33--S(O).sub.2--N(R.sup.71)--, HO--C(O)--,
R.sup.33--O--C(O)--, H.sub.2N--C(O)--, R.sup.33--NH--C(O)--,
R.sup.33--N(R.sup.33)--C(O)--, NC--, oxo, phenyl and Het;
[0237] R.sup.32 is chosen from the series consisting of hydrogen,
R.sup.35, R.sup.35--C(O)--, R.sup.35--O--C(O)-- and phenyl;
[0238] and all other groups and numbers are defined as in the
general definition of the compounds of the formula I or in any
specified embodiments of the invention or definitions of structural
elements, in any of their stereoisomeric forms or a mixture of
stereoisomeric forms in any ratio, and their physiologically
acceptable salts, and the physiologically acceptable solvates of
any of them.
[0239] As another such example compounds of the formula I may be
mentioned, wherein ring A is a benzene ring which is optionally
substituted by one or two identical or different substituents
chosen from the series consisting of halogen,
(C.sub.1-C.sub.4)-alkyl and (C.sub.1-C.sub.4)-alkyl-O--;
[0240] Y is C(R.sup.12).dbd.C(R.sup.13);
[0241] Z is C(R.sup.16);
[0242] R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are hydrogen;
[0243] R.sup.12, R.sup.13 and R.sup.16 are independently of each
other chosen from the series consisting of hydrogen, halogen,
(C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkyl-O-- and NC--;
[0244] R.sup.20 is hydrogen;
[0245] R.sup.21 is chosen from the series consisting of hydrogen,
halogen, (C.sub.1-C.sub.4)-alkyl, HO--(C.sub.1-C.sub.4)-alkyl-,
(C.sub.1-C.sub.4)-alkyl-O--, (C.sub.1-C.sub.4)-alkyl-S(O).sub.m--,
(C.sub.1-C.sub.4)-alkyl-C(O)-- and NC--;
[0246] R.sup.22 is a group of the formula II;
R.sup.24--R.sup.23-- II
[0247] R.sup.23 is a direct bond or a chain consisting of 2, 3 or 4
chain members of which 0 or 1 chain members are hetero chain
members chosen from the series consisting of N(R.sup.25), O, S,
S(O) and S(O).sub.2, and the other chain members are identical or
different groups C(R.sup.26)(R.sup.26);
[0248] R.sup.24 is a benzene ring which is optionally substituted
by one or more identical or different substituents chosen from the
series consisting of halogen, R.sup.33, HO--, R.sup.33--O--,
R.sup.33--S(O).sub.m--, H.sub.2N--, R.sup.33--NH--,
R.sup.33--N(R.sup.33)--, R.sup.33--C(O)--NH--,
R.sup.33--S(O).sub.2--NH--, HO--C(O)--, R.sup.33--O--C(O)--,
H.sub.2N--C(O)--, R.sup.33--NH--C(O)--,
R.sup.33--N(R.sup.33)--C(O)-- and NC--;
[0249] provided that the total number of C, N, O and S atoms which
is present in the two groups R.sup.23 and R.sup.24, is at least
5;
[0250] R.sup.25 is chosen from the series consisting of hydrogen
and (C.sub.1-C.sub.4)-alkyl;
[0251] R.sup.26, independently of each other group R.sup.26, is
chosen from the series consisting of hydrogen, fluorine,
(C.sub.1-C.sub.4)-alkyl and HO--, or two of the groups R.sup.26
which are bonded to the same carbon atom in the chain, together
with the carbon atom carrying them, form a cyclopropane ring;
[0252] R.sup.33 is, independently of each other group R.sup.33,
chosen from the series consisting of (C.sub.1-C.sub.4)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl and
(C.sub.3-C.sub.7)-cycloalkyl-(C.sub.1-C.sub.2)-alkyl-, which are
all optionally substituted by one or more identical or different
substituents R.sup.70;
[0253] R.sup.50 is chosen from the series consisting of
R.sup.51--O-- and R.sup.52--N(R.sup.53)--;
[0254] R.sup.51 is chosen from the series consisting of hydrogen
and (C.sub.1-C.sub.4)-alkyl;
[0255] R.sup.52 is chosen from the series consisting of hydrogen
and (C.sub.1-C.sub.4)-alkyl;
[0256] R.sup.53 is chosen from the series consisting of hydrogen
and (C.sub.1-C.sub.4)-alkyl;
[0257] R.sup.70 is chosen from the series consisting of HO-- and
R.sup.71--O--;
[0258] R.sup.71 is (C.sub.1-C.sub.4)-alkyl;
[0259] m, independently of each other number m, is an integer
chosen from the series consisting of 0 and 2;
[0260] cycloalkyl, independently of each other group cycloalkyl,
and independently of any other substituents on cycloalkyl, is
optionally substituted by one or more identical or different
substituents chosen from fluorine and (C.sub.1-C.sub.4)-alkyl;
[0261] alkyl, independently of each other group alkyl, and
independently of any other substituents on alkyl, is optionally
substituted by one or more fluorine substituents; in any of their
stereoisomeric forms or a mixture of stereoisomeric forms in any
ratio, and their physiologically acceptable salts, and the
physiologically acceptable solvates of any of them.
[0262] Another subject of the present invention are processes for
the preparation of the compounds of the formula I which are
outlined below and by which the compounds are obtainable. For
example, the preparation of the compounds of the formula I can be
carried out by reacting a compound of the formula III with a
compound of the formula IV with formation of an amide bond.
##STR00022##
[0263] The ring A and the groups Y, Z, R.sup.3 to R.sup.6, R.sup.20
to R.sup.22 and R.sup.50 in the compounds of the formulae III and
IV are defined as in the compounds of the formula I and
additionally functional groups can be present in protected form or
in the form of a precursor group which is later converted into the
final group. The group G in the compounds of the formula IV can be
HO-- (hydroxy), i.e. the compound of the formula IV can thus be a
carboxylic acid, or another group which can be replaced by the
group N(R.sup.20) in the compound of the formula III in a
substitution reaction, for example an aryloxy group such as
optionally substituted phenoxy or an alkyloxy group such as a
(C.sub.1-C.sub.4)-alkyl-O-group, for example a
(C.sub.1-C.sub.3)-alkyl-O-- group like methoxy or ethoxy, or
halogen, for example chlorine or bromine, and the compound of the
formula IV can thus be a reactive ester like an aryl ester or alkyl
ester, for example a methyl ester or ethyl ester, or an acid
halide, for example an acid chloride or acid bromide, of the
respective carboxylic acid. The compound of the formula III and/or
the compound of the formula IV can also be employed, and the
compounds of the formula I obtained, in the form of a salt, for
example an acid addition salt such as an hydrohalide, for example a
hydrochloride, of the compound of the formula III and/or an
alkaline metal salt, for example a sodium salt, of a compound of
the formula IV in which G is HO--. Likewise, in all other reactions
in the preparation of the compounds of the formula I, including the
preparation of starting compounds, compounds can also be employed
and/or products obtained in the form a salt.
[0264] In case a compound of the formula IV is employed in which G
is HO--, the carboxylic acid group HO--C(O)-- is generally
activated in situ by means of a customary amide coupling reagent or
converted into a reactive carboxylic acid derivative which can be
prepared in situ or isolated. For example, the compound of the
formula IV in which G is HO-- can be converted into an acid halide,
e. g. the compound of the formula IV in which G is Cl or Br, by
treatment with thionyl chloride, phosphorus pentachloride,
phosphorus tribromide or oxalyl chloride, or treated with an alkyl
chloroformate like ethyl chloroformate or isobutyl chloroformate to
give a mixed anhydride. Customary coupling reagents which can be
employed, are propanephosphonic anhydride, N,N'-carbonyldiazoles
like N,N'-carbonyldiimidazole (CDI), carbodiimides like
1,3-diisopropylcarbodiimide (DIC), 1,3-dicyclohexylcarbodiimide
(DCC) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDC), carbodiim ides together with additives like
1-hydroxy-benzotriazole (HOBT) or 1-hydroxy-7-azabenzotriazole
(HOAT), uronium-based coupling reagents like
O-(7-azabenzotriazol-1-yl)-N,N,N',N-tetramethyluronium
hexafluorophosphate (HATU),
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HBTU) or
O-(cyano(ethoxycarbonyl)methyleneamino)-N, N, N',
N'-tetramethyluronium tetrafluoroborate (TOTU), and
phosphonium-based coupling reagents like
(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium
hexafluorophosphate (BOP),
(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate
(PyBOP) or bromotripyrrolidinophosphonium hexafluorophosphate
(PyBroP).
[0265] The reaction conditions for the preparation of the compounds
of the formula I from compounds of the formulae III and IV depend
on the particulars of the specific case, for example the meaning of
the group G or the employed coupling reagent, and are well known to
a skilled person in view of the general knowledge in the art. For
example, in case a compound of the formula IV in which G is
alkyl-O--, like methoxy or ethoxy, is reacted with a compound of
the formula III, generally the reaction is carried out in an inert
solvent, for example a hydrocarbon or chlorinated hydrocarbon like
benzene, toluene, xylene, chlorobenzene, dichloromethane,
chloroform or dichloroethane, an ether like tetrahydrofuran (THF),
dioxane, dibutyl ether, diisopropyl ether or dimethoxyethane (DME),
or a mixture of solvents, at elevated temperatures, for example at
temperatures from about 40.degree. C. to about 140.degree. C., in
particular at temperatures from about 50.degree. C. to about
120.degree. C., for example at about the boiling temperature of the
solvent. In case a compound of the formula IV in which G is
halogen, like chlorine or bromine, is reacted with a compound of
the formula III, generally the reaction is likewise carried out in
an inert solvent, for example a hydrocarbon or chlorinated
hydrocarbon or ether like the aforementioned ones, an ester like
ethyl acetate or butyl acetate, a nitrile like acetonitrile, or
water, or a mixture of solvents including a mixture of water and an
organic solvent which is miscible or immiscible with water, at
temperatures from about -10.degree. C. to about 100.degree. C., in
particular at temperatures from about 0.degree. C. to about
80.degree. C., for example at about room temperature. Favorably,
the reaction of a compound of the formula IV in which G is halogen
with a compound of the formula III is carried out in the presence
of a base such as a tertiary amine, like triethylamine,
ethyldiisopropylamine, N-methylmorpholine or pyridine, or an
inorganic base such as an alkaline metal hydroxide, carbonate or
hydrogencarbonate, like sodium hydroxide, potassium hydroxide,
sodium carbonate or sodium hydrogencarbonate.
[0266] In case a compound of the formula IV in which G is HO-- is
reacted with a compound of the formula III and the carboxylic acid
group is activated by means of an amide coupling reagent such as,
for example, a carbodiimide or TOTU, the reaction is generally
carried out under anhydrous conditions in an inert aprotic solvent,
for example an ether like THF, dioxane or DME, an amide like
N,N-dimethylformamide (DMF) or N-methylpyrrolidone (NMP), at
temperatures from about -10.degree. C. to about 40.degree. C., in
particular at temperatures from about 0.degree. C. to about
30.degree. C. in the presence of a base such as a tertiary amine,
like triethylamine, ethyldiisopropylamine or N-methylmorpholine. In
case the compound of the formula III is employed in the form of an
acid addition salt in the reaction with the compound of the formula
IV, usually a sufficient amount of a base is added in order to
liberate the free compound of the formula III.
[0267] As indicated above, during the formation of the amide bond
between the compounds of the formulae III and IV functional groups
in the compounds of the formulae III and IV can be present in
protected form or in the form of a precursor group. Depending on
the particulars of the specific case, it may be necessary or
advisable for avoiding an undesired course of the reaction or side
reactions to temporarily block any functional groups by protective
groups and remove them later, or to let functional groups be
present in the form of a precursor group which is later converted
into the desired final group. This applies correspondingly to all
reactions in the course of the synthesis of the compounds of the
formula I including the synthesis of intermediates outlined below
and the synthesis of starting compounds and building blocks.
Respective synthetic strategies are commonly used in the art.
Details about protective groups and their introduction and removal
are found in P. G. M. Wuts and T. W. Greene, Greene's Protective
Groups in Organic Synthesis, 4. ed. (2007), John Wiley & Sons,
for example. Examples of protective groups which may be mentioned,
are benzyl protective groups which may occur in the form of benzyl
ethers of hydroxy groups and benzyl esters of carboxylic acid
groups from which the benzyl group can be removed by catalytic
hydrogenation in the presence of a palladium catalyst, tert-butyl
protective groups which may occur in the form of tert-butyl esters
of carboxylic acid groups from which the tert-butyl group can be
removed by treatment with trifluoroacetic acid, acyl protective
groups which may be used to protect hydroxy groups and amino groups
in the form of esters and amides and which can be cleaved by acidic
or basic hydrolysis, and alkyloxycarbonyl protective groups which
may occur in the form of tert-butoxycarbonyl derivatives of amino
groups which can be cleaved by treatment with trifluoroacetic acid.
Undesired reactions of carboxylic acid groups, for example the
carboxylic acid group present in the compound of the formula III in
case R.sup.50 is HO--, can also be avoided by employing them in the
reaction of the compounds of the formulae III and IV in the form of
other esters, for example in the form of alkyl esters like the
methyl or ethyl ester which can be cleaved by hydrolysis, for
example by means of an alkaline metal hydroxide like sodium
hydroxide or lithium hydroxide. Examples of precursor groups which
may be mentioned, are nitro groups which can be converted into
amino groups by catalytic hydrogenation or by reduction with sodium
dithionite, for example, and cyano groups (NC--, N.ident.C--) which
can be converted to carboxamide groups and carboxylic acid groups
by hydrolysis. Another example of a precursor group is an oxo group
which represents the groups R.sup.3 and R.sup.4 together or the two
groups R.sup.5 and R.sup.6 together, and which may initially be
present in the course of the synthesis of compounds of the formula
I in which R.sup.3 or R.sup.5 is hydroxy. In an approach for the
synthesis of such compounds of the formula I, a compound of the
formula III in which the groups R.sup.3 and R.sup.4 together are
oxo or the groups R.sup.5 and R.sup.6 together are oxo, may be
obtained from the respective compound which contains a bromine atom
instead of the group R.sup.20--NH-- by reaction with sodium azide
and subsequently with tributyl tin hydride as described in L.
Benati et al., J. Org. Chem. 64 (1999), 7836-7841, the obtained
amino compound reacted with a compound of the formula IV, the oxo
group reduced, for example with a complex hydride such as sodium
borohydride, or reacted with an organometallic compound, for
example a Grignard compound, and finally any protective groups
removed. If any protective groups or precursor groups are present
in the compounds of the formulae III and IV and the direct product
of the reaction of the compounds of the formulae III and IV is not
yet the desired final compound, the removal of the protective group
or conversion into the desired compound can in general also be
carried out in situ.
[0268] The compounds of the formula III are commercially available
or can be obtained according to, or analogously to, procedures
described in the literature, for example by di-alkylation of an
aminoacetic acid derivative of the formula VI with a compound of
the formula V analogously as described in Kotha et al., J. Org.
Chem. 65 (2000), 1359-1365, for example.
##STR00023##
[0269] The ring A and the groups R.sup.3 to R.sup.6 in the compound
of the formula V are defined as in the compounds of the formula I
and additionally functional groups can be present in protected form
or in the form of a precursor group which is later converted into
the final group. The groups L.sup.1 in the alkylating compound of
the formula V are leaving groups such as halogen, for example
chlorine or bromine, or sulfonyloxy groups, for example
methanesulfonyloxy or trifluoromethanesulfonyloxy. The group
PG.sup.1 in the compound of the formula VI is a protective group of
the carboxylic acid group of aminoacetic acid and can be a group
such as (C.sub.1-C.sub.4)-alkyl, for example methyl, ethyl or
tert-butyl, or benzyl. The group PG.sup.2 in the compound of the
formula VI is a divalent protective group of the amino group of
aminoacetic acid and can be a carbon atom, and the group
--N=PG.sup.2 thus be the isocyano group --N.dbd.C, or a carbon atom
carrying two phenyl groups, and the group --N=PG.sup.2 thus be the
benzhydrylideneamino group --N.dbd.C(phenyl).sub.2, for example.
The alkylation reaction of the compound of the formula VI with the
compound of the formula V is carried out in the presence of base,
for example an alkaline metal alkoxide such as potassium
tert-butoxide, or an alkaline metal hydride such as sodium hydride,
or an alkaline metal carbonate such as potassium carbonate with
addition of a phase transfer catalyst such as tetrabutylammonium
hydrogensulfate under solid-liquid phase transfer conditions, in an
inert solvent such as an amide like DMF or NMP or a nitrile like
acetonitrile at temperatures from about -40.degree. C. to about
80.degree. C., depending on the particulars of the specific case.
Subsequent to the alkylation, the protective group PG.sup.2 is
cleaved, for example by treatment with hydrochloric acid in ethanol
in the case of a isocyano group or with aqueous hydrochloric acid
in the case of a benzhydrylideneamino group, optionally with
concomitant cleavage of the protective group PG.sup.1, to give a
compound of the formula III in which R.sup.50 is
(C.sub.1-C.sub.4)-alkyl-O--, for example methoxy, ethoxy or
tert-butoxy, or benzyloxy, or HO--, and R.sup.20 is hydrogen.
Compounds of the formula III in which R.sup.20 is different from
hydrogen, can be obtained from the compounds in which R.sup.20 is
hydrogen by alkylation or by acylation and subsequent reduction of
the obtained amide to the amine. If desired, compounds of the
formula III in which R.sup.50 is HO-- can be obtained by acidic or
basic hydrolysis from compounds in which R.sup.50 is
(C.sub.1-C.sub.4)-alkyl-O-- or by hydrogenation from compounds in
which R.sup.50 is benzyloxy, for example.
[0270] The starting compounds of the formula V can be obtained from
the respective dihydroxy compounds, which contain hydroxy groups
instead of the groups L.sup.1, by treatment with an halogenating
agent, for example thionyl chloride or phosphorus tribromide, or a
sulfonylating agent such as methanesulfonyl chloride or
trifluoromethanesulfonic anhydride, or from the respective
hydrocarbons which contain hydrogen atoms instead of the groups
L.sup.1, by benzylic bromination, for example with
N-bromosuccinimide. The said dihydroxy compounds can be obtained
from the respective dicarboxylic acids, which contain carboxylic
acid groups HO--C(O) instead of the groups
L.sup.1-C(R.sup.3)(R.sup.4)-- and L.sup.1-C(R.sup.5)(R.sup.6)--, or
esterified carboxylic acid groups, by reduction, for example with
lithium aluminium hydride, in case all groups R.sup.3 to R.sup.6
are hydrogen, or by reaction with an organometallic compound such
as a Grignard compound or an organolithium compound, for example
methyl lithium, and optionally by reduction, in case groups R.sup.3
to R.sup.6 are different from hydrogen. Compounds of the formula
III in which A is a cycloalkane ring, can additionally be obtained
by hydrogenation in the presence of a transition metal
hydrogenation catalyst such as a platinum catalyst, for example,
from the respective compounds in which ring A is an unsaturated
ring, in particular in the case of compounds of the formula III in
which A is a cyclohexane ring which can be obtained from the
respective compounds in which A is a benzene ring. In another
approach, compounds of the formula III can be obtained from the
respective ketones, i.e. the compounds of the formula III in which
the two groups R.sup.20--NH-- and R.sup.50--C(O)-- are replaced
with an oxo group, according to the classical routes for the
synthesis of amino acids like the Strecker synthesis or the
Bucherer-Bergs synthesis. All said reactions are standard reactions
which are well known to a person skilled in the art.
[0271] The compounds of the formula IV likewise are commercially
available or can be obtained according to, or analogously to,
procedures described in the literature. Customarily, in synthetic
procedures for the preparation of compounds of the formula IV
compounds are prepared in which the group G in the compounds of the
formula IV is a group like (C.sub.1-C.sub.4)-alkyl-O-- and the
group G-C(O)-- thus is a (C.sub.1-C.sub.4)-alkyl ester group, or
the group G-C(O)-- is any other ester group such as a benzyl ester
phenyl-CH.sub.2--O--C(O)-- and the group G thus is a benzyloxy
group. Compounds of the formula IV in which G is HO--, can be
obtained from such compounds of the formula IV by acidic or basic
hydrolysis of alkyl esters or by hydrogenation of benzyl esters
under standard conditions. Compounds of the formula IV in which G
is HO-- can then be converted into compounds of the formula IV in
which G is halogen as already explained above, which latter
compounds can be converted into compounds in which G is aryloxy,
for example by reaction with a hydroxyarene such as phenol. In the
following, various synthetic procedures for the preparation of
compounds of the formula IV in which the group R.sup.23 in the
group R.sup.24--R.sup.23--, i.e. in the group of the formula II
which represents one of the groups R.sup.21 and R.sup.22, has
different meanings, are exemplarily outlined.
[0272] In a procedure for the preparation of compounds of the
formula IV in which the group R.sup.23 is a chain wherein the
terminal chain member which is bonded to the ring comprising the
groups Y and Z, is a hetero chain member, a compound of the formula
VII is reacted with a compound of the formula VIII to give a
compound of the formula IVa.
##STR00024##
[0273] In the compounds of the formulae IVa, VII and VIII the
groups Y, Z and R.sup.24 are defined as in the compounds of the
formula I. The group R.sup.80 is chosen from the series consisting
of hydrogen, halogen, R.sup.30, HO--, R.sup.30--O--,
R.sup.30--C(O)--O--, R.sup.30--S(O).sub.2--O--,
R.sup.30--S(O).sub.m--, H.sub.2N--, R.sup.30--NH--,
R.sup.30--N(R.sup.30)--, R.sup.30--C(O)--NH--,
R.sup.30--C(O)--N(R.sup.71)--, R.sup.30--S(O).sub.2--NH--,
R.sup.30--S(O).sub.2--N(R.sup.71)--, R.sup.30--C(O)--, HO--C(O)--,
R.sup.30--O--C(O)--, H.sub.2N--C(O)--, R.sup.30--NH--C(O)--,
R.sup.30--N(R.sup.30)--C(O)--, H.sub.2N--S(O).sub.2--,
R.sup.30--NH--S(O).sub.2--, R.sup.30--N(R.sup.30)--S(O).sub.2--,
NC--, O.sub.2N-- and Het'; i.e. it has the meaning of the one of
the groups R.sup.21 and R.sup.22 in the compounds of the formula I
which is not a group of the formula II. Additionally, functional
groups in the compounds of the formulae IVa, VII and VIII can be
present in protected form or in the form of a precursor group which
is later converted into the final group. The group G.sup.1-C(O)--
is an ester group and the group G.sup.1 a group such as
(C.sub.1-C.sub.4)-alkyl-O-- or benzyloxy. The group X is a hetero
chain member as specified in the definition of R.sup.23, i.e. a
group chosen from the series consisting of N(R.sup.25), O, S, S(O)
and S(O).sub.2, in particular from the series consisting of
N(R.sup.25), O and S. The groups R.sup.23a and X together represent
the group R.sup.23 as specified above wherein a terminal chain
member which is a hetero chain member, is bonded to the ring
comprising the groups Y and Z. R.sup.23a thus is a direct bond or a
chain consisting of 1 to 4 chain members of which 0 or 1 chain
member is a hetero chain member chosen from the series consisting
of N(R.sup.25), O, S, S(O) and S(O).sub.2, provided that the
terminal chain member adjacent to the group L.sup.2 can only be a
hetero chain member which leads to the formation of compound of the
formula IVa in which one of the group X and the said terminal chain
member is chosen from the series consisting of S(O) and S(O).sub.2
and the other is chosen from the series consisting of N(R.sup.25),
O and S, and the other chain members are identical or different
groups C(R.sup.26)(R.sup.26), wherein two adjacent groups
C(R.sup.26)(R.sup.26) can be connected to each other by a double
bond or a triple bond. As is symbolized by the bonds connecting the
groups R.sup.80 and XH in the compounds of the formula VII, as well
as the groups R.sup.80 and X--R.sup.23a--R.sup.24 in the compounds
of the formula IVa, which bonds are not directed to a specific ring
carbon atom, each of the said two groups can be located in each of
the two positions of the moiety C.dbd.C in the ring comprising the
groups Y and Z which is depicted in the formulae. I.e., R.sup.80
can be located on the ring carbon which is adjacent to the group Y
and the other of the two groups on the ring carbon atom which is
adjacent to the group Z, as well as R.sup.80 can be located on the
ring carbon which is adjacent to the group Z and the other of the
two groups on the ring carbon atom which is adjacent to the group
Y. This applies to all compounds defined below containing a group
R.sup.80 and a second group in which the bonds connecting the group
to the ring comprising the groups Y and Z are not directed to a
specific ring carbon atoms. The group L.sup.2 in the compounds of
the formula VIII is a leaving group which can be replaced with the
group X, such as halogen, fore example chlorine or bromine, a
sulfonyloxy group, for example methanesulfonyloxy,
trifluoromethanesulfonyloxy or toluene-4-sulfonyloxy, or hydroxy,
for example.
[0274] The reaction of a compound of the formula VII with a
compound of the formula VIII is a nucleophilic substitution
reaction which can be carried out under standard conditions for
such reactions which are well known to a person skilled in the art.
Generally, the reaction is performed in an inert solvent, for
example a hydrocarbon or chlorinated hydrocarbon like benzene,
toluene, xylene, chlorobenzene, dichloromethane, chloroform or
dichloroethane, an ether like THF, dioxane, dibutyl ether,
diisopropyl ether or DME, an alcohol like methanol, ethanol or
isopropanol, a ketone like acetone or butan-2-one, an ester like
ethyl acetate or butyl acetate, a nitrile like acetonitrile, an
amide like DMF or NMP, a sulfoxide like DMSO or a sulfone like
sulfolane, or a mixture of solvents, at temperatures from about
-10.degree. C. to about 120.degree. C., in particular at
temperatures from about 0.degree. C. to about 100.degree. C.,
depending on the particulars of the specific case. In many cases it
is favorable for enhancing the nucleophilicity of the compound of
the formula VII and/or binding an acid which is liberated during
the reaction, to add a base, for example a tertiary amine, such as
triethylamine, ethyldiisopropylamine or N-methylmorpholine, or an
inorganic base such as an alkaline metal hydride, hydroxide,
carbonate or hydrogencarbonate like sodium hydride, sodium
hydroxide, potassium hydroxide, sodium carbonate, potassium
carbonate, cesium carbonate or sodium hydrogencarbonate, or an
alkoxide or amide such as sodium methoxide, sodium ethoxide,
potassium methoxide, potassium tert-butoxide, sodium amide or
lithium diisopropylamide. A compound of the formula VII can also be
treated with a base and converted into a salt in a separate step.
Compounds of the formula VIII in which the group L.sup.2 is hydroxy
can favorably be reacted with compounds of the formula VII under
the conditions of the Mitsunobu reaction in the presence of an
azodicarboxylate like diethyl azodicarboxylate or diisopropyl
azodicarboxylate and a phosphine like triphenylphosphine or
tributylphosphine in an inert aprotic solvent such as an ether like
THF or dioxane (cf. O. Mitsunobu, Synthesis (1981), 1-28).
[0275] In another procedure, compounds of the formula IVa can be
obtained by reacting a compound of the formula IX with a compound
of the formula X.
##STR00025##
[0276] In the compounds of the formulae IX and X the groups Y, Z
and R.sup.24 are defined as in the compounds of the formula I. The
group R.sup.80 is defined as in the compounds of the formulae IVa
and VII, i.e. it has the meaning of the one of the groups R.sup.21
and R.sup.22 in the compounds of the formula I which is not a group
of the formula II. Additionally, functional groups in the compounds
of the formulae IX and X can be present in protected form or in the
form of a precursor group which is later converted into the final
group. The group G.sup.1-C(O)-- is an ester group and the group
G.sup.1 a group such as (C.sub.1-C.sub.4)-alkyl-O-- or benzyloxy.
The group X is a hetero chain member as specified in the definition
of R.sup.23, i.e. a group chosen from the series consisting of
N(R.sup.25), O, S, S(O) and S(O).sub.2, in particular from the
series consisting of N(R.sup.25), O and S. In the compound of the
formula X the groups R.sup.23a and X together represent the group
R.sup.23 as specified above wherein a terminal chain member which
is a hetero chain member, is bonded to the ring comprising the
groups Y and Z in the obtained compounds of the formula IVa.
R.sup.23a thus is a direct bond or a chain consisting of 1 to 4
chain members of which 0 or 1 chain member is a hetero chain member
chosen from the series consisting of N(R.sup.25), O, S, S(O) and
S(O).sub.2, provided that the terminal chain member adjacent to the
group X can only be a hetero chain member if one of the group X and
the said terminal chain member is chosen from the series consisting
of S(O) and S(O).sub.2 and the other is chosen from the series
consisting of N(R.sup.25), O and S, and the other chain members are
identical or different groups C(R.sup.26)(R.sup.26), wherein two
adjacent groups C(R.sup.26)(R.sup.26) can be connected to each
other by a double bond or a triple bond. The group L.sup.3 in the
compounds of the formulae IX is a leaving group which can be
replaced with the group X, such as halogen like fluorine, chlorine,
bromine or iodine, or a sulfonyloxy group like methanesulfonyloxy
or trifluoromethanesulfonyloxy, for example. The reaction of a
compound of the formula IX with a compound of the formula X
formally is a nucleophilic substitution reaction at the ring
comprising the groups Y and Z which can in particular be performed
in case of compounds of the formulae IX which are susceptible to
such a reaction because of the presence of electron-withdrawing
substituents or ring hetero atoms. The reaction can be carried out
under standard conditions for such reactions which are well known
to a person skilled in the art. The explanations on the reaction
conditions such as solvents or bases which are favorably added,
which are given above with respect to the reaction of a compound of
the formula VII with a compound of the formula VIII apply
correspondingly to the reaction of a compound of the formula IX
with a compound of the formula X.
[0277] The explanations on the reaction of a compound of the
formula VII with a compound of the formula VIII also apply
correspondingly to reactions for the preparation of compounds of
the formula I in which a hetero chain member in the group R.sup.23
is not present in the terminal position of the chain which is
adjacent to the ring comprising the groups Y and Z, but is
separated from the said ring by one or more groups
C(R.sup.26)(R.sup.26), which reactions are of the same type as the
reactions outlined above. As an example, the preparation of a
compound of the formula IVb from a compound of the formula XI and a
compound of the formula XII may be illustrated.
##STR00026##
[0278] In the compounds of the formulae IVb, XI and XII the groups
Y, Z and R.sup.24 are defined as in the compounds of the formula I.
The group R.sup.80 is defined as in the compounds of the formulae
IVa and VII, i.e. it has the meaning of the one of the groups
R.sup.21 and R.sup.22 in the compounds of the formula I which is
not a group of the formula II. Additionally, functional groups in
the compounds of the formulae IX and X can be present in protected
form or in the form of a precursor group which is later converted
into the final group. Additionally, functional groups in the
compounds of the formulae IVb, XI and XII can be present in
protected form or in the form of a precursor group which is later
converted into the final group. The group G.sup.1-C(O)-- is an
ester group and the group G.sup.1 a group such as
(C.sub.1-C.sub.4)-alkyl-O-- or benzyloxy. The group X is a hetero
chain member as specified in the definition of R.sup.23, i.e. a
group chosen from the series consisting of N(R.sup.25), O, S, S(O)
and S(O).sub.2, in particular from the series consisting of
N(R.sup.25), O and S. The groups R.sup.23b, R.sup.23c and X in the
compounds of the formulae IVb together represent the group R.sup.23
as specified above wherein X is a said hetero chain member. In case
R.sup.23 comprises only one hetero chain member, the group
R.sup.23b in the compounds of the formulae IVb and XI is a chain
consisting of 1 to 4 identical or different groups
C(R.sup.26)(R.sup.26) and the group R.sup.23 in the compounds of
the formulae IVb and XII is a direct bond or a chain consisting of
1 to 3 identical or different groups C(R.sup.26)(R.sup.26),
provided that the total number of groups C(R.sup.26)(R.sup.26) is
not greater than 4, wherein two adjacent groups
C(R.sup.26)(R.sup.26) can be connected to each other by a double
bond or a triple bond. In the group R.sup.23 in the compounds of
the formulae IVb and XII a further hetero chain member chosen from
the series consisting of N(R.sup.25), O, S, S(O) and S(O).sub.2 can
be present instead of one of the groups C(R.sup.26)(R.sup.26),
provided that such further hetero chain member can only be present
in the terminal position adjacent to the group L.sup.2 if one of
the group X and the said chain member in the terminal position is
chosen from the series consisting of S(O) and S(O).sub.2 and the
other is chosen from the series consisting of N(R.sup.25), O and S.
The leaving group L.sup.2 in the compounds of the formula XII is
defined as in the compounds of the formula VIII. Correspondingly as
outlined above with respect to the synthesis of the compounds of
the formula IVa, which can be prepared by reacting a compound of
the formula VII with a compound of the formula VIII as well as by
reacting a compound of the formula IX with a compound of the
formula X, compounds of the formula IVb can also be prepared by
reacting a compound which is defined as the compound of the formula
XI but contains a group L.sup.2 instead of the group XH, with a
compound which is defined as the compound of the formula XII but
contains a group XH instead of the group L.sup.2.
[0279] In a procedure for the preparation of compounds of the
formula IV in which the group R.sup.23 is a chain which does not
comprise any hetero chain member, a carbonyl compound of the
formula XIII is condensed with a compound of the formula XIV to
give an olefin of the formula IVc which can subsequently be
hydrogenated to give a compound of the formula IVd, respectively,
or reacted with an organometallic compound of the formula XV to
give an alcohol of the formula IVe which likewise can subsequently
be hydrogenated to give a compound of the formula IVf.
##STR00027##
[0280] In the compounds of the formulae IVc to IVf, XIII, XIV and
XV the groups Y, Z and R.sup.24 are defined as in the compounds of
the formula I. The group R.sup.80 is defined as in the compounds of
the formulae IVa and VII, i.e. it has the meaning of the one of the
groups R.sup.21 and R.sup.22 in the compounds of the formula I
which is not a group of the formula II. Additionally, functional
groups in the compounds of the formulae IVc to IVf, XIII, XIV and
XV can be present in protected form or in the form of a precursor
group which is later converted into the final group. The group
G.sup.1-C(O)-- is an ester group and the group G.sup.1 a group such
as (C.sub.1-C.sub.4)-alkyl-O-- or benzyloxy. The groups R.sup.a and
R.sup.b are independently of each other chosen from hydrogen and
(C.sub.1-C.sub.4)-alkyl. The group R.sup.23d is a direct bond or a
chain consisting of 1 to 3 identical or different groups
C(R.sup.26)(R.sup.26), the group R.sup.23e a direct bond or a chain
consisting of 1 to 4 identical or different groups
C(R.sup.26)(R.sup.26). The group L.sup.4 in the compounds of the
formula XIV is group which allows for the formation of a double
bond between the carbon atom carrying the group L.sup.4 and the
carbon atom of the aldehyde group or ketone group carrying the
group R.sup.a in the compound of the formula XIII in a condensation
reaction. Examples of suitable condensation reactions are the
Wittig reaction and the Wittig-Horner reaction, and examples of
suitable groups L.sup.4 thus are trisubstituted phosphonio groups,
such as the triphenylphosphonio group, having an anion, such as a
halide anion, as counterion, and
di((C.sub.1-C.sub.4)-alkyl)phosphonyl groups, such as the
diethylphosphonyl group. The group L.sup.5 in the compounds of the
formula XV is a metal such as lithium or a magnesium halide group
like MgCl, MgBr or MgI, and the compound of the formula XV thus an
organolithium compound or a Grignard compound. The Wittig reaction
and Wittig-Horner reaction and the addition of the organometallic
compound of the formula XV to the compound of the formula XIII can
be performed under standard conditions in an inert solvent such as
a hydrocarbon like benzene or toluene or an ether like diethyl
ether, THF, dioxane or DME. The Wittig reaction and the
Wittig-Horner reaction are performed in the presence of a base such
as a hydride like sodium hydride, an amide like sodium amide or
lithium diisopropylamide, or an alkoxide like potassium
tert-butoxide. Depending on the particular case, instead of
employing a phosphonium salt and deprotonating it, also stable
phosphorus ylides can directly be employed in the reaction. The
hydrogenation of the double bond in the compounds of the formula
IVc to give the compounds of the formulae IVd, or of the benzylic
hydroxy group in the compounds of the formulae IVe to give the
compounds of the formulae IVf, can be performed in the presence of
a hydrogenation catalyst such as palladium on charcoal.
[0281] Depending on the particulars of the specific case, various
other reactions can be used for preparing compounds of the formula
IV. As an example of the preparation of compounds in which the
group R.sup.23 is a chain comprising three groups
C(R.sup.26)(R.sup.26) and no hetero chain members, an aldol-type
reaction of a compound of the formula XIIIa, which is a compound of
the formula XIII in which the group R.sup.a is methyl, with an
aldehyde of the formula XVI may be mentioned which leads to a
compound of the formula IVg or the formula IVm which can be reduced
to a compound of the formula IVh, IVk or IVn, for example.
##STR00028##
[0282] In the compounds of the formulae IVg to IVn and XIIIa the
groups Y and Z are defined as in the compounds of the formula I.
The group R.sup.24a in the compounds of the formulae IVg to IVn and
XVI is a group R.sup.31 or a 3-membered to 10-membered ring as it
can represent the group R.sup.24 in the compounds of the formula I
which is bonded via a ring carbon atom, in particular an aromatic
ring such as an optionally substituted phenyl, naphthyl or
heteroaryl group. The group R.sup.80 is defined as in the compounds
of the formulae IVa and VII, i.e. it has the meaning of the one of
the groups R.sup.21 and R.sup.22 in the compounds of the formula I
which is not a group of the formula II. Additionally, functional
groups in the compounds of the formulae IVg to IVn, XIIIa and XVI
can be present in protected form or in the form of a precursor
group which is later converted into the final group. The group
G.sup.1-C(O)-- is an ester group and the group G.sup.1 a group such
as (C.sub.1-C.sub.4)-alkyl-O-- or benzyloxy.
[0283] The reaction of a compound of the formula XIIIa with a
compound of the formula XIV to give an aldol addition product of
the formula IVm or a condensation product of the formula IVg can be
carried under standard conditions for the aldol reaction in the
presence of a base, such as an alkaline metal hydroxide like sodium
hydroxide or potassium hydroxide, an alkoxide like sodium methoxide
or sodium ethoxide or an amide like lithium diisopropylamide, in a
solvent such as an alcohol like methanol or ethanol or an ether
like diethyl ether, THF or dioxane. At lower temperatures, for
example at temperatures from about -80.degree. C. to about
-30.degree. C., the compound of the formula IVm can be obtained, at
higher temperatures, for example at temperatures from about
10.degree. C. to about 60.degree. C., or by treatment of the
compound of the formula IVm with an acid, the compound of the
formula IVg can be obtained. The ketone function in the compounds
of the formulae IVg and IVm can be reduced to an alcohol function,
for example with a complex hydride such as a borohydride like
lithium borohydride or sodium borohydride, to give a compound of
the formula IVh or IVn, respectively, which can be converted into a
compound of the formula IVk by dehydration in the presence of an
acid and/or hydrogenation in the presence of a catalyst such as
palladium on charcoal, for example.
[0284] As a further example of reactions which can be used for
preparing compounds of the formula IV, transition metal-catalyzed
C--C coupling reactions may be mentioned by which compounds can be
obtained wherein the group R.sup.23 is a direct bond or comprises a
chain of two groups C(R.sup.26)(R.sup.26), which are connected to
each other by a triple bond, i.e. a group of the formula
--C.ident.C--, in a position adjacent to the ring comprising the
groups Y and Z. Such compounds can be obtained from a compound of
the formula IX and a boronic acid, for example an optionally
substituted phenylboronic acid, cycloalkylboronic acid or
heteroarylboronic acid, or an ethyne, for example an optionally
substituted phenylethyne. As catalyst in such reactions, a
palladium compound such as bis(triphenylphosphine)palladium(II)
chloride or tetrakis(triphenylphosphine)palladium(0) and a copper
compound such as copper(I) iodide can be used. Further details on
such reactions are found in N. Miyaura et al., Chem. Rev. 95
(1995), 2457-2483; and R. Chinchilla et al., Chem. Rev. 107 (2007),
874-922, for example.
[0285] The order in which groups are introduced in the course of
the synthesis of a compound of the formula I, can also be different
from the ones outlined above. For example, instead of first
preparing a compound of the formula IVa from a compound of the
formula VII and a compound of the formula VIII, or from a compound
of the formula IX and a compound of the formula X, and then
reacting the compound of the formula IVa with a compound of the
formula III to give a compound of the formula I, a compound of the
formula III can also be reacted with a compound of the formula VII
or a compound of the formula IX and the obtained compound of the
formula XVII or XVIII reacted with a compound of the formula VIII
or X, respectively, to give a compound of the formula Ik.
##STR00029##
[0286] In the compounds of the formulae Ik, XVII and XVIII the ring
A and the groups Y, Z, R.sup.3 to R.sup.6, R.sup.20, R.sup.24 and
R.sup.50 are defined as in the compounds of the formula I. The
groups X, R.sup.23a and R.sup.80 are defined as in the compounds of
the formula IVa. Thus, R.sup.80 has the meaning of the one of the
groups R.sup.21 and R.sup.22 in the compounds of the formula I
which is not a group of the formula II. The group X is a hetero
chain member as specified in the definition of R.sup.23, i.e. a
group chosen from the series consisting of N(R.sup.25), O, S, S(O)
and S(O).sub.2, in particular from the series consisting of
N(R.sup.25), O and S. The groups R.sup.23a and X together represent
the group R.sup.23 as specified above wherein a terminal chain
member which is a hetero chain member, is bonded to the ring
comprising the groups Y and Z. R.sup.23a thus is a direct bond or a
chain consisting of 1 to 4 chain members of which 0 or 1 chain
member is a hetero chain member chosen from the series consisting
of N(R.sup.25), O, S, S(O) and S(O).sub.2, provided that the
terminal chain member adjacent to the group X can only be a hetero
chain member if one of the group X and the said terminal chain
member is chosen from the series consisting of S(O) and S(O).sub.2
and the other is chosen from the series consisting of N(R.sup.25),
O and S, and the other chain members are identical or different
groups C(R.sup.26)(R.sup.26), wherein two adjacent groups
C(R.sup.26)(R.sup.26) can be connected to each other by a double
bond or a triple bond. Additionally, functional groups in the
compounds of the formulae Ik, XVII and XVIII can be present in
protected form or in the form of a precursor group which is later
converted into the final group. As indicated above and as applies
to all compounds which contain a group R.sup.80 and another group
which are connected to the ring comprising the groups Y and Z by
bonds which are not directed to a specific ring carbon atom, the
groups R.sup.80 and X in the compounds of the formula XVII, the
groups R.sup.80 and L.sup.3 in the compounds of the formula XVIII,
and the groups R.sup.80 and X--R.sup.23a--R.sup.24 in the compounds
of the formula Ik can be located in each of the two positions of
the moiety C.dbd.C in the ring comprising the groups Y and Z. The
explanations given above with respect to the reaction of a compound
of the formula III with a compound of the formula IV, the reaction
of a compound of the formula VII with a compound of the formula
VIII, and the reaction of a compound of the formula IX with a
compound of the formula X apply correspondingly to the reaction of
a compound of the formula III with a compound of the formula VII or
a compound of the formula IX, the reaction of a compound of the
formula XVII with a compound of the formula VIII, and the reaction
of a compound of the formula XVIII with a compound of the formula
X. The order in which groups are introduced in the course of the
synthesis of a compound of the formula I, can also be varied with
respect to other reactions. For example, a compound of the formula
XVIII can be employed in a transition-metal catalyzed C--C coupling
reaction as referred to above, or a compound of the formula XIIIa
can be reacted with a compound of the formula III and the obtained
compound modified at the CH.sub.3--C(O)-- group to give a compound
of the formula I.
[0287] The starting compounds and building blocks for the synthesis
of the compounds of the formula I are commercially available or can
be prepared according to procedures described in the literature or
analogously to such procedures. Exemplarily the preparation of
compounds of the formula VIII in which R.sup.24 is an optionally
substituted phenyl or naphthyl group, R.sup.23a is an optionally
alkyl-substituted CH.sub.2CH.sub.2 group and L.sup.2 is a hydroxy
group, may be mentioned in which use can be made of the procedure
for the coupling of aryl halides with ester enolates described by
M. Jorgensen et al., J. Am. Chem. Soc. 124 (2002), 12557-12565. In
the said procedure an optionally alkyl-substituted acetic acid
ester, for example acetic acid tert-butyl ester or isobutyric acid
methyl ester, is deprotonated with a base such as lithium
dicyclohexylamide and reacted with an optionally substituted aryl
bromide in the presence of a palladium compound such as
bis(dibenzylideneacetone)palladium or
tris(dibenzylideneactone)dipalladium and tri(tert-butyl)phosphine
to give a 2-(optionally substituted aryl)acetic acid ester which is
optionally alkyl-substituted in the 2-position of the acetic acid
moiety. Reduction of the ester function under standard conditions,
for example with lithium aluminium hydride, then affords the
2-(optionally substituted aryl)ethanol which is optionally
alkyl-substituted in the 2-position.
[0288] For obtaining further compounds of the formula I, various
transformations of functional groups can be carried out under
standard conditions in compounds of the formula I or intermediates
or starting compounds in the synthesis of the compounds of the
formula I. For example, a hydroxy group can be esterified to give a
carboxylic acid ester or a sulfonic acid ester, or etherified.
Etherifications of hydroxy groups can favorably be performed by
alkylation with the respective halogen compound, for example a
bromide or iodide, in the presence of a base such an alkali metal
carbonate like potassium carbonate or cesium carbonate in an inert
solvent such as an amide like DMF or NMP or a ketone like acetone
or butan-2-one, or with the respective alcohol under the conditions
of the Mitsunobu reaction referred to above. A hydroxy group can be
converted into a halide by treatment with a halogenating agent. A
halogen atom can be replaced with a variety of groups in a
substitution reaction which may also be a transition-metal
catalyzed reaction. A nitro group can be reduced to an amino group,
for example by catalytic hydrogenation. An amino group can be
modified under standard conditions for alkylation, for example by
reaction with a halogen compound or by reductive amination of a
carbonyl compound, or for acylation or sulfonylation, for example
by reaction with an activated carboxylic acid or a carboxylic acid
derivate like an acid chloride or anhydride or a sulfonic acid
chloride. A carboxylic ester group can be hydrolyzed under acidic
or basic conditions to give a carboxylic acid. A carboxylic acid
group can be activated or converted into a reactive derivative as
outlined above with respect to the compounds of the formula IX and
reacted with an alcohol or an amine or ammonia to give an ester or
amide. A primary amide can be dehydrated to give a nitrile. A
sulfur atom in an alkyl-S-- group or in a heterocyclic ring or a
sulfur atom occurring in a chain representing the group R.sup.23
can be oxidized with a peroxide like hydrogen peroxide or a peracid
to give a sulfoxide moiety S(O) or a sulfone moiety S(O).sub.2. A
carboxylic acid group, carboxylic acid ester group and a ketone
group can be reduced to an alcohol, for example with a complex
hydride such al lithium aluminium hydride, lithium borohydride or
sodium borohydride. All reactions in the preparation of the
compounds of the formula I are known per se and can be carried out
in a manner familiar to a person skilled in the art according to,
or analogously, to procedures which are described in the standard
literature, for example in Houben-Weyl, Methods of Organic
Chemistry, Thieme; or Organic Reactions, John Wiley & Sons; or
R. C. Larock, Comprehensive Organic Transformations: A Guide to
Functional Group Preparations, 2. ed. (1999), John Wiley &
Sons, and the references quoted therein. Furthermore, besides by
techniques of solution chemistry, the compounds of the formula I
can also be obtained by solid phase chemistry.
[0289] Another subject of the present invention are the novel
starting compounds and intermediates occurring in the synthesis of
the compounds of the formula I, including the compounds of the
formulae III, IV, IV, IVb, IVc, IVd, IVe, IVf, IVg, IVh, IVk, IVm,
IVn, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII and
XVIII, wherein the ring A and the groups G, G.sup.1, L.sup.1,
L.sup.2, L.sup.3, PG.sup.1, PG.sup.2, X, Y, Z, R.sup.3 to R.sup.6,
R.sup.20 to R.sup.23, R.sup.23a, R.sup.23b, R.sup.23c, R.sup.24,
R.sup.24a, R.sup.50, R.sup.80, R.sup.a and R.sup.b are defined as
above, in any of their stereoisomeric forms or a mixture of
stereoisomeric forms in any ratio, and their salts, and solvates of
any of them, and their use as synthetic intermediates or starting
compounds. All general explanations, specifications of embodiments
and definitions of numbers and groups given above with respect to
the compounds of the formula I apply correspondingly to the said
intermediates and starting compounds. A subject of the invention
are in particular the novel specific starting compounds and
intermediates described herein. Independently thereof whether they
are described as a free compound and/or as a specific salt, they
are a subject of the invention both in the form of the free
compounds and in the form of their salts, and if a specific salt is
described, additionally in the form of this specific salt.
[0290] The compounds of the formula I inhibit the Edg-2 receptor
(LPA.sub.1 receptor) as can be demonstrated in the pharmacological
test described below and in other tests which are known to a person
skilled in the art. The compounds of the formula I and their
physiologically acceptable salts and solvates therefore are
valuable pharmaceutical active compounds. The compounds of the
formula I and their physiologically acceptable salts and solvates
can be used for the treatment of cardiovascular diseases such as
heart failure including systolic heart failure, diastolic heart
failure, diabetic heart failure and heart failure with preserved
ejection fraction, cardiomyopathy, myocardial infarction,
myocardial remodeling including myocardial remodeling after
infarction or after cardiac surgery, vascular remodeling including
vascular stiffness, hypertension including pulmonary hypertension,
portal hypertension and systolic hypertension, atherosclerosis,
peripheral arterial occlusive disease (PAOD), restenosis,
thrombosis or vascular permeability disorders, for cardioprotection
such as cardioprotection after myocardial infarction or after
cardiac surgery, for renoprotection, or for the treatment of
inflammation or inflammatory diseases such as rheumatoid arthritis,
osteoarthritis, renal diseases such as renal papillary necrosis or
renal failure including renal failure after ischemia/reperfusion,
pulmonary diseases such as chronic obstructive pulmonary disease
(COPD), asthma or acute respiratory dystress syndrome (ARDS),
immunological diseases, allergic diseases, tumor growth,
metastasis, metabolic diseases, fibrotic diseases such as pulmonary
fibrosis including idiopathic lung fibrosis, cardiac fibrosis,
vascular fibrosis, perivascular fibrosis, renal fibrosis including
renal tubulointerstitial fibrosis, liver fibrosis, fibrosing skin
conditions including keloid formation, collagenosis, scleroderma,
progressive systemic sclerosis and nephrogenic fibrosing
dermopathy, or other types of fibrosis including Dupuytren's
contracture, psoriasis, pain such as neuropathic pain, diabetic
pain or inflammatory pain, pruritus, retinal ischemia/reperfusion
damage, macular degeneration, psychiatric disorders,
neurodegenerative diseases, cerebral nerve disorders, peripheral
nerve disorders, endocrinic disorders such as hyperthyroidism,
scarring disorders or wound healing disorders, for example. The
treatment of diseases is to be understood as meaning both the
therapy of existing pathological changes or malfunctions of the
organism or of existing symptoms with the aim of relief,
alleviation or cure, and the prophylaxis or prevention of
pathological changes or malfunctions of the organism or of symptoms
in humans or animals which are susceptible thereto and are in need
of such a prophylaxis or prevention, with the aim of a prevention
or suppression of their occurrence or of an attenuation in the case
of their occurrence. For example, in patients who on account of
their disease history are susceptible to myocardial infarction, by
means of the prophylactic or preventive medicinal treatment the
occurrence or re-occurrence of a myocardial infarction can be
prevented or its extent and sequelae decreased, or in patients who
are susceptible to disturbed wound healing, by means of the
prophylactic or preventive medicinal treatment wound healing after
surgery can favorably be influenced. The treatment of diseases can
occur both in acute cases and in chronic cases. The efficacy of the
compounds of the formula I can be demonstrated in the
pharmacological tests described below and in other tests which are
known to a person skilled in the art
[0291] The compounds of the formula I and their physiologically
acceptable salts and solvates can therefore be used in animals, in
particular in mammals and specifically in humans, as a
pharmaceutical or medicament on their own, in mixtures with one
another or in the form of pharmaceutical compositions. A subject of
the present invention also are the compounds of the formula I and
their physiologically acceptable salts and solvates for use as a
pharmaceutical, as well as pharmaceutical compositions and
medicaments which comprise an efficacious dose of at least one
compound of the formula I and/or a physiologically acceptable salt
thereof and/or solvate thereof as an active ingredient and a
pharmaceutically acceptable carrier, i.e. one or more
pharmaceutically innocuous, or nonhazardous, vehicles and/or
excipients, and optionally one or more other pharmaceutical active
compounds. A subject of the present invention furthermore are the
compounds of the formula I and their physiologically acceptable
salts and solvates for use in the treatment of the diseases
mentioned above or below, including the treatment of any one of the
mentioned diseases, for example heart failure or fibrotic diseases
such as pulmonary fibrosis, cardiac fibrosis, vascular fibrosis,
perivascular fibrosis, renal fibrosis, liver fibrosis or fibrosing
skin conditions, the use of the compounds of the formula I and
their physiologically acceptable salts and solvates for the
manufacture of a medicament for the treatment of the diseases
mentioned above or below, including the treatment of any one of the
mentioned diseases, for example heart failure or fibrotic diseases
such as pulmonary fibrosis, cardiac fibrosis, vascular fibrosis,
perivascular fibrosis, renal fibrosis, liver fibrosis or fibrosing
skin conditions, wherein the treatment of diseases comprises their
therapy and prophylaxis as mentioned above, as well as their use
for the manufacture of a medicament for the inhibition of the Edg-2
receptor (LPA.sub.1 receptor). A subject of the invention also are
methods for the treatment of the diseases mentioned above or below,
including the treatment of any one of the mentioned diseases, for
example heart failure or fibrotic diseases such as pulmonary
fibrosis, cardiac fibrosis, vascular fibrosis, perivascular
fibrosis, renal fibrosis, liver fibrosis or fibrosing skin
conditions, which comprise administering an efficacious amount of
at least one compound of the formula I and/or a physiologically
acceptable salt thereof and/or solvate thereof to a human or an
animal which is in need thereof. The compounds of the formula I and
pharmaceutical compositions and medicaments comprising them can be
administered enterally, for example by oral, sublingual or rectal
administration, parenterally, for example by intravenous,
intramuscular, subcutaneous or intraperitoneal injection or
infusion, or by another type of administration such as topical,
percutaneous, transdermal, intra-articular, intranasal or
intraocular administration.
[0292] The compounds of the formula I and their physiologically
acceptable salts and solvates can also be used in combination with
other pharmaceutical active compounds, wherein in such a
combination use the compounds of the formula I and/or their
physiologically acceptable salts and/or solvates and one or more
other pharmaceutical active compounds can be present in one and the
same pharmaceutical composition or in two or more pharmaceutical
compositions for separate, simultaneous or sequential
administration. Examples of such other pharmaceutical active
compounds are angiotensin converting enzyme (ACE) inhibitors,
ramipril, angiotensin II receptor subtype 1 (AT1) antagonists,
irbesartan, antiarrhythmics, dronedarone, peroxisome
proliferator-activated receptor-alpha (PPAR-.alpha.) activators,
peroxisome proliferator-activated receptor-gamma (PPAR-.gamma.)
activators, pioglitazone, rosiglitazone, prostanoids, endothelin
receptor antagonists, bosentan, elastase inhibitors, calcium
antagonists, beta blockers, diuretics, aldosterone receptor
antagonists, eplerenone, renin inhibitors, rho kinase inhibitors,
soluble guanylate cyclase (sGC) activators, sGC sensitizers,
phosphodiesterase (PDE) inhibitors, phosphodiesterase type 5 (PDE5)
inhibitors, NO donors, digitalis drugs, angiotensin converting
enzyme/neutral endopeptidase (ACE/NEP) inhibitors, statins, bile
acid reuptake inhibitors, platelet derived growth factor (PDGF)
receptor antagonists, vasopressin antagonists, aquaretics, sodium
hydrogen exchanger subtype 1 (NHE1) inhibitors, factor II/factor
IIa antagonists, factor IX/factor IXa antagonists, factor X/factor
Xa antagonists, factor XIII/factor XIIIa antagonists,
anticoagulants, antithrombotics, platelet inhibitors,
profibrinolytics, thrombin-activatable fibrinolysis inhibitors
(TAFI), plasminogen activator inhibitor-1 (PAI 1), coumarins,
heparins, thromboxane antagonists, serotonin antagonists,
cyclooxygenase inhibitors, acetylsalicylic acid, therapeutic
antibodies, glycoprotein IIb/IIIa (GPIIb/IIIa) antagonists
including abciximab, chymase inhibitors, cytostatics, taxanes,
paclitaxel, docetaxel, aromatase inhibitors, estrogen receptor
antagonists, selective estrogen receptor modulators (SERM),
tyrosine kinase inhibitors, imatinib, receptor tyrosine kinase
inhibitors, RAF kinase inhibitors, p38 mitogen-activated protein
kinase (p38 MAPK) inhibitors, pirfenidone, multi-kinase inhibitors,
and sorafenib. A subject of the present invention also is the said
combination use of any one or more of the compounds of the formula
I disclosed herein and their physiologically acceptable salts and
solvates, with any one or more, for example one or two, of the
mentioned other pharmaceutical active compounds.
[0293] The pharmaceutical compositions and medicaments according to
the invention normally contain from about 0.5 to about 90 percent
by weight of compounds of the formula I and/or physiologically
acceptable salts and/or solvates thereof, and an amount of active
ingredient of the formula I and/or its physiologically acceptable
salt and/or solvate which in general is from about 0.2 mg to about
1000 mg, in particular from about 0.2 mg to about 500 mg, for
example from about 1 mg to about 300 mg, per unit dose. Depending
on the kind of the pharmaceutical composition and other particulars
of the specific case, the amount may deviate from the indicated
ones. The production of the pharmaceutical compositions and
medicaments can be carried out in a manner known per se. For this,
the compounds of the formula I and/or their physiologically
acceptable salts and/or solvates are mixed together with one or
more solid or liquid vehicles and/or excipients, if desired also in
combination with one or more other pharmaceutical active compounds
such as those mentioned above, and brought into a suitable form for
dosage and administration, which can then be used in human medicine
or veterinary medicine.
[0294] As vehicles, which may also be looked upon as diluents or
bulking agents, and excipients suitable organic and inorganic
substances can be used which do not react in an undesired manner
with the compounds of the formula I. As examples of types of
excipients, or additives, which can be contained in the
pharmaceutical compositions and medicaments, lubricants,
preservatives, thickeners, stabilizers, disintegrants, wetting
agents, agents for achieving a depot effect, emulsifiers, salts,
for example for influencing the osmotic pressure, buffer
substances, colorants, flavorings and aromatic substances may be
mentioned. Examples of vehicles and excipients are water, vegetable
oils, waxes, alcohols such as ethanol, isopropanol,
1,2-propanediol, benzyl alcohols, glycerol, polyols, polyethylene
glycols or polypropylene glycols, glycerol triacetate,
polyvinylpyrrolidone, gelatin, cellulose, carbohydrates such as
lactose or starch like corn starch, sodium chloride, stearic acid
and its salts such as magnesium stearate, talc, lanolin, petroleum
jelly, or mixtures thereof, for example saline or mixtures of water
with one or more organic solvents such as mixtures of water with
alcohols. For oral and rectal use, pharmaceutical forms such as,
for example, tablets, film-coated tablets, sugar-coated tablets,
granules, hard and soft gelatin capsules, suppositories, solutions,
including oily, alcoholic or aqueous solutions, syrups, juices or
drops, furthermore suspensions or emulsions, can be used. For
parenteral use, for example by injection or infusion,
pharmaceutical forms such as solutions, for example aqueous
solutions, can be used. For topical use, pharmaceutical forms such
as ointments, creams, pastes, lotions, gels, sprays, foams,
aerosols, solutions or powders can be used. Further suitable
pharmaceutical forms are, for example, implants and patches and
forms adapted to inhalation. The compounds of the formula I and
their physiologically acceptable salts can also be lyophilized and
the obtained lyophilizates used, for example, for the production of
injectable compositions. In particular for topical application,
also liposomal compositions are suitable. The pharmaceutical
compositions and medicaments can also contain one or more other
active ingredients and/or, for example, one or more vitamins.
[0295] As usual, the dosage of the compounds of the formula I
depends on the circumstances of the specific case and is adjusted
by the physician according to the customary rules and procedures.
It depends, for example, on the compound of the formula I
administered and its potency and duration of action, on the nature
and severity of the individual syndrome, on the sex, age, weight
and the individual responsiveness of the human or animal to be
treated, on whether the treatment is acute or chronic or
prophylactic, or on whether further pharmaceutical active compounds
are administered in addition to a compound of the formula I.
Normally, in the case of administration to an adult weighing about
75 kg, a dose from about 0.1 mg to about 100 mg per kg per day, in
particular from about 1 mg to about 10 mg per kg per day (in each
case in mg per kg of body weight), is sufficient. The daily dose
can be administered in the form of a single dose or divided into a
number of individual doses, for example two, three or four
individual doses. The administration can also be carried out
continuously, for example by continuous injection or infusion.
Depending on the individual behavior in a specific case, it may be
necessary to deviate upward or downward from the indicated
dosages.
[0296] Besides as a pharmaceutical active compound in human
medicine and veterinary medicine, the compounds of the formula I
can also be employed as an aid in biochemical investigations or as
a scientific tool or for diagnostic purposes, for example in
in-vitro diagnoses of biological samples, if an inhibition of the
Edg-2 receptor is intended. The compounds of the formula I and
their salts can also be used as intermediates for the preparation
of further pharmaceutical active substances.
[0297] The following examples illustrate the invention.
ABBREVIATIONS
[0298] ACN acetonitrile [0299] DCM dichloromethane [0300] DIAD
diisopropyl azodicarboxylate [0301] DIC 1,3-diisopropylcarbodiimide
[0302] DMF dimethylformamide [0303] DMSO dimethyl sulfoxide [0304]
EA ethyl acetate [0305] EDIA N-ethyldiisopropylamine [0306] EDC
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride [0307]
FMOC fluoren-9-ylmethoxycarbonyl [0308] HEP heptane [0309] HOBT
1-hydroxy-benzotriazole [0310] NMM N-methyl-morpholine [0311] TFA
trifluoroacetic acid [0312] THF tetrahydrofuran
[0313] In general, reactions were carried out under argon. When
example compounds containing a basic group were purified by
preparative high pressure liquid chromatography (HPLC) on reversed
phase (RP) column material and, as customary, the eluent was a
gradient mixture of water and acetonitrile containing
trifluoroacetic acid, they were in part obtained in the form of
their acid addition salts with trifluoroacetic acid, depending on
the details of the workup such as evaporation or lyophilization
conditions. In the names of the example compounds and the
structural formulae such contained trifluoroacetic acid is not
specified.
[0314] The prepared compounds were in general characterized by
spectroscopic data and chromatographic data, in particular mass
spectra (MS) and HPLC retention times (Rt; in min) which were
obtained by combined analytical HPLC/MS characterization (LC/MS),
and/or nuclear magnetic resonance (NMR) spectra. Unless specified
otherwise, .sup.1H-NMR spectra were recorded at 500 MHz in
D.sub.6-DMSO as solvent at 298 K. In the NMR characterization, the
chemical shift .delta. (in ppm), the number of hydrogen atoms (H)
and the multiplicity (s: singlet, d: doublet, dd: double doublet,
t: triplet, dt: double triplet, q: quartet, m: multiplet; br:
broad) of the peaks as determined on printouts are given. In the MS
characterization, in general the mass number (m/z) of the peak of
the molecular ion [M], e.g. [M.sup.+], or of a related ion such as
the ion [M+1], e.g. [(M+1).sup.+], i.e. the protonated molecular
ion [(M+H).sup.+] abbreviated as [MH.sup.+], or the ion [M-1], e.g.
[(M-1).sup.-], i.e. the deprotonated molecular ion [(M-H).sup.-],
which was formed depending on the ionization method used, is given.
Generally, the ionization method was electrospray ionization (ESI)
or atmospheric pressure chemical ionization (APCl). The particulars
of the LC/MS methods used are as follows.
Method LC1
[0315] Column: YMC J'sphere H80, 20.times.2.1 mm, 4 .mu.m;
30.degree. C.; flow: 1.0 ml/min; eluent A: ACN; eluent B:
water+0.05% TFA; gradient: from 4% A+96% B to 95% A+5% B within 2.4
min, then to 4% A+96% B within 0.05 min, then 4% A+96% B for 0.05
min; MS ionization method: ESI.sup.+
Method LC2
[0316] Column: YMC J'sphere H80, 20.times.2.1 mm, 4 .mu.m;
30.degree. C.; flow: 1.0 ml/min; eluent A: ACN; eluent B:
water+0.05% TFA; gradient: from 4% A+96% B to 95% A+5% B within 2.4
min, then to 4% A+96% B within 0.05 min, then 4% A+96% B for 0.05
min; MS ionization method: ESI.sup.+
Method LC3
[0317] Column: YMC J'sphere H80, 33.times.2.1 mm, 4 .mu.m; flow:
1.3 ml/min; eluent A: ACN+0.05% TFA; eluent B: water+0.05% TFA;
gradient: from 5% A+95% B to 95% A+5% B within 2.5 min, then 95%
A+5% B for 0.5 min; then to 5% A+95% B within 0.2 min; MS
ionization method: ESI.sup.+
Method LC4
[0318] Column: YMC J'sphere H80, 33.times.2.1 mm, 4 .mu.m; flow:
1.0 ml/min; eluent A: ACN+0.05% TFA; eluent B: water+0.05% TFA;
gradient: from 5% A+95% B to 95% A+5% B within 3.4 min, then 95%
A+5% B for 1.0 min, then to 5% A+95% B within 0.2 min, then 5%
A+95% B for 0.5 min; MS ionization method: ESI.sup.+
Method LC5
[0319] Column: YMC J'sphere H80, 33.times.2.1 mm, 4 .mu.m; flow:
1.3 ml/min; eluent A: ACN+0.08% formic acid; eluent B: water+0.1%
formic acid; gradient: from 5% A+95% B to 95% A+5% B within 2.5
min, then 95% A+5% B for 0.5 min; MS ionization method:
ESI.sup.+
Method LC6
[0320] Column: YMC J'sphere H80, 33.times.2.1 mm, 4 .mu.m; flow:
1.3 ml/min; eluent A: ACN+0.05% TFA; eluent B: water+0.05% TFA;
gradient: from 5% A+95% B to 95% A+5% B within 2.5 min, then to 5%
A+95% B within 0.5 min; MS ionization method: ESI.sup.+
Method LC7
[0321] Column: Thermo Javelin C18, 40.times.2.1 mm, 5 .mu.m; flow:
1.0 ml/min; eluent A: ACN+0.1% TFA; eluent B: water+0.1% TFA;
gradient: from 2% A+98% B to 80% A+20% B within 7.0 min, then to
100% A+0% B within 0.2 min, then 100% A+0% B for 1.0 min, then to
2% A+98% B within 0.3 min, then 2% A+98% B for 0.5 min; MS
ionization method: ESI.sup.+
Method LC8
[0322] Column: Thermo Javelin C18, 40.times.2.1 mm, 5 .mu.m; flow:
1.0 ml/min; eluent A: ACN+0.1% TFA; eluent B: water+0.1% TFA;
gradient: from 2% A+98% B to 80% A+20% B within 5.0 min, then to
100% A+0% B within 0.2 min, then 100% A+0% B for 1.0 min, then to
2% A+98% B within 0.3 min, then 2% A+98% B for 0.5 min; MS
ionization method: ESI.sup.+
Method LC9
[0323] Column: HP Waters Atlantis dC18, 50.times.2.1 mm, 5 .mu.m;
flow: 0.6 ml/min; eluent A: ACN+0.1% TFA; eluent B: water+0.1% TFA;
gradient: from 2% A+98% B to 80% A+20% B within 5.0 min, then to
100% A+0 B within 0.2 min, then 100% A+0% B for 1.0 min, then to 2%
A+98% B within 0.3 min, then 2% A+98% B for 0.5 min; MS ionization
method: ESI.sup.+
Method LC10
[0324] Column: YMC J'sphere H80, 33.times.2.1 mm, 4 .mu.m; flow:
1.3 ml/min; eluent A: ACN+0.05% TFA; eluent B: water+0.05% TFA;
gradient: 5% A+95% B for 0.5 min, then to 95% A+5% B within 3.0
min, then to 5% A+95% B within 0.5 min; MS ionization method:
ESI.sup.+
Method LC11
[0325] Column: YMC J'sphere H80, 33.times.2.1 mm, 4 .mu.m; flow:
1.3 ml/min; eluent A: ACN+0.05% TFA; eluent B: water+0.05% TFA;
gradient: from 5% A+95% B to 95% A+5% B within 2.5 min, then 95%
A+5% B for 0.5 min; MS ionization method: ESI.sup.+
Method LC12
[0326] Column: YMC J'sphere H80, 33.times.2.1 mm, 4 .mu.m; flow: 1
ml/min; eluent A: ACN+0.05% TFA; eluent B: water+0.05% TFA;
gradient: 2% A+98% B for 1 min, then to 95% A+5% B within 4 min,
then 95% A+5% B for 1.25 min; MS ionization method: ESI.sup.+
Method LC13
[0327] Column: YMC J'sphere H80, 33.times.2.1 mm, 4 .mu.m; flow:
1.3 ml/min; eluent A: ACN+0.05% TFA; eluent B: water+0.05% TFA;
gradient: 5% A+95% B for 0.5 min, then to 95% A+5% B within 3 min,
then 95% A+5% B for 0.5 min; MS ionization method: ESI.sup.+
Method LC14
[0328] Column: Waters XBridge C18, 50.times.4.6 mm, 2.5 .mu.m;
flow: 1.3 ml/min, 50.degree. C.; eluent A: ACN+0.05% TFA; eluent B:
water+0.05% TFA; gradient: 5% A+95% B for 0.3 min, then to 95% A+5%
B within 3.2 min, then 95% A+5% B for 0.5 min; MS ionization
method: ESI.sup.+
Method LC15
[0329] Column: Waters XBridge C18, 50.times.4.6 mm, 2.5 .mu.m;
flow: 1.3 ml/min, 50.degree. C.; eluent A: ACN+0.1% formic acid;
eluent B: water+0.1% formic acid; gradient: from 3% A+97% B to 60%
A+40% B within 3.5 min, then to 98% A+2% B within 0.5 min, then 98%
A+2% B for 1 min, then to 3% A+97% B within 0.2 min, then 3% A+97%
B for 1.3 min; MS ionization method: APCl.sup.+
Method LC16
[0330] Column: Waters XBridge C18, 50.times.4.6 mm, 2.5 .mu.m;
flow: 1.3 ml/min, eluent A: ACN+0.08% formic acid; eluent B:
water+0.1% formic acid; gradient: from 3% A+97% B to 60% A+40% B
within 3.5 min, then to 98% A+2% B within 0.5 min, then 98% A+2% B
for 1 min, then to 3% A+97% B within 0.2 min, then 3% A+97% B for
1.3 min; MS ionization method: ESI.sup.-
Method LC17
[0331] Column: Waters XBridge C18, 50.times.4.6 mm, 2.5 .mu.m;
flow: 1.3 ml/min, eluent A: ACN+0.08% formic acid; eluent B:
water+0.1% formic acid; gradient: from 3% A+97% B to 60% A+40% B
within 3.5 min, then to 98% A+2% B within 0.5 min, then 98% A+2% B
for 1 min, then to 3% A+97% B within 0.2 min, then 3% A+97% B for
1.3 min; MS ionization method: ESI.sup.+
Method LC18
[0332] Column: Waters XBridge C18, 50.times.4.6 mm, 2.5 .mu.m;
flow: 1.7 ml/min, 50.degree. C., eluent A: ACN+0.05% TFA; eluent B:
water+0.05% TFA; gradient: 5% A+95% B for 0.2 min, then to 95% A+5%
B within 2.2 min, then 95% A+5% B for 1.1 min, then to 5% A+95% B
within 0.1 min, then 5% A+95% B for 0.9 min; MS ionization method:
ESI.sup.+
Method LC19
[0333] Column: Waters XBridge C18, 50.times.4.6 mm, 2.5 .mu.m;
flow: 1.3 ml/min, 50.degree. C., eluent A: ACN+0.1% formic acid;
eluent B: water+0.1% formic acid; gradient: from 3% A+97% B to 60%
A+40% B within 3.5 min, then to 98% A+2% B within 0.5 min, then 98%
A+2% B for 1 min, then to 3% A+97% B within 0.2 min, then 3% A+97%
B for 1.3 min; MS ionization method: ESI.sup.+
Method LC20
[0334] Column: Waters XBridge C18, 50.times.4.6 mm, 2.5 .mu.m;
flow: 1.3 ml/min, eluent A: ACN+0.08% formic acid; eluent B:
water+0.1% formic acid; gradient: from 3% A+97% B to 98% A+2% B
within 18 min, then 98% A+2% B for 1 min, then to 3% A+97% B within
0.5 min, then 3% A+97% B for 0.5 min; MS ionization method:
ESI.sup.+
Method LC21
[0335] Column: Waters XBridge C18, 50.times.4.6 mm, 2.5 .mu.m;
flow: 1.3 ml/min, 50.degree. C., eluent A: ACN+0.1% formic acid;
eluent B: water+0.1% formic acid; gradient: from 3% A+97% B to 60%
A+40% B within 3.5 min, then to 98% A+2% B within 0.5 min, then 98%
A+2% B for 1 min, then to 3% A+97% B within 0.2 min, then 3% A+97%
B for 1.3 min; MS ionization method: ESI.sup.-
Method LC22
[0336] Column: YMC J'sphere H80, 33.times.2.1 mm, 4 .mu.m; flow: 1
ml/min; eluent A: ACN+0.05% TFA; eluent B: water+0.05% TFA;
gradient: from 5% A+95% B to 95% A+5% B within 3.7 min; MS
ionization method: ESI.sup.+
EXAMPLE 1
2-[4-Bromo-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid methyl ester
##STR00030##
[0337] Step 1: 4-Bromo-3-(2-m-tolyl-ethoxy)-benzoic acid methyl
ester
[0338] 4-Bromo-3-hydroxy-benzoic acid methyl ester (1.00 g, 4.32
mmol) and triphenylphosphine (1.36 g, 5.19 mmol) were dissolved in
THF. 2-(3-Methylphenyl)-ethanol (2-m-tolyl-ethanol) (0.707 g, 5.19
mmol) was added, the mixture was cooled in an ice bath, and DIAD
(1.05 g, 5.19 mmol) was added slowly with stirring. The ice bath
was removed and stirring continued overnight at room temperature.
The volatiles were evaporated in vacuo, and the residue was
purified by silica gel chromatography (HEP/EA gradient) to give
1.55 g of the title compound.
Step 2: 4-Bromo-3-(2-m-tolyl-ethoxy)-benzoic acid
[0339] The compound of step 1 (0.50 g, 1.43 mmol) was dissolved in
dioxane (5 ml), lithium hydroxide (7.1 ml of an aqueous 1 M (i.e. 1
mol per liter) solution) was added, and the mixture was reacted
overnight. The mixture was partitioned between 2 N hydrochloric
acid and EA, the aqueous phase extracted with EA, and the organic
extracts were dried over sodium sulfate, filtered and evaporated to
dryness in vacuo to give 0.414 g of the title compound.
[0340] .sup.1H-NMR: .delta.=13.2 (br s, 1H); 7.7 (d, 1H); 7.52 (d,
1H); 7.42 (dd, 1H); 7.22-7.11 (m, 3H); 7.02 (d, 1H); 4.30 (t, 2H);
3.03 (t, 2H); 2.29 (s, 3H)
Step 3:
2-[4-Bromo-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid methyl ester
[0341] The compound of step 2 (0.410 g, 1.22 mmol) was dissolved in
DMF (5 ml), EDIA (0.790 g, 6.12 mmol), HOBT (33 mg, 0.244 mmol),
and 2-amino-indane-2-carboxylic acid methyl ester hydrochloride
(0.246 g, 1.47 mmol) were added, the mixture was cooled in an ice
bath and EDC (352 mg, 1.84 mmol) was added. The mixture was stirred
overnight. The volatiles were evaporated in vacuo, the mixture was
partitioned between 2 N hydrochloric acid and EA, the organic phase
was dried over magnesium sulfate and evaporated to dryness. The
residue was purified by silica gel chromatography (HEP/EA gradient)
to give 0.56 g of the title compound.
[0342] LC/MS (Method LC1): Rt=1.98 min; m/z=508.1/510.1
[MH.sup.+]
EXAMPLE 2
2-[4-Bromo-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid
##STR00031##
[0344] The compound of example 1 (60 mg, 0.118 mmol) was dissolved
in dioxane (1.5 ml), lithium hydroxide (0.59 ml of an aqueous 1 M
solution) was added and the mixture was reacted for 20 min at
60.degree. C. The mixture was partitioned between 2 N hydrochloric
acid and EA, the aqueous phase extracted with EA, and the organic
extracts were dried over sodium sulfate, filtered and evaporated to
dryness in vacuo. The residue was stirred overnight with a mixture
of diethyl ether and HEP, filtered, and the solid was dried in
vacuo to give 43 mg of the title compound.
[0345] .sup.1H-NMR: .delta.=12.45 (br s, 1H); 8.87 (s, 1H); 7.64
(d, 1H); 7.46 (d, 1H); 7.37 (dd, 1H); 7.25-7.11 (m, 7H); 7.02 (d,
1H); 4.27 (t, 2H); 3.60 (d, 2H); 3.37 (d, 2H); 3.02 (t, 2H); 2.28
(s, 3H)
EXAMPLE 3
2-[4-Methylsulfanyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid methyl ester
##STR00032##
[0346] Step 1: 4-Nitro-3-(2-m-tolyl-ethoxy)-benzoic acid methyl
ester
[0347] 3-Hydroxy-4-nitro-benzoic acid methyl ester (1.00 g, 5.07
mmol) and 2-(3-methylphenyl)-ethanol (0.829 g, 6.09 mmol) were
reacted in analogy to step 1 of example 1 to give 1.39 g of the
title compound.
[0348] .sup.1H-NMR: .delta.=7.96 (d, 1H); 7.75 (s, 1H); 7.63 (d,
1H); 7.18 (t, 1H); 7.11 (s, 1H); 7.08 (d, 1H); 7.03 (d, 1H); 4.41
(t, 2H); 3.89 (s, 3H); 3.01 (t, 2H); 2.28 (s, 3H)
Step 2: 4-Methylsulfanyl-3-(2-m-tolyl-ethoxy)-benzoic acid methyl
ester
[0349] The compound of step 1 (900 mg, 2.85 mmol) was dissolved in
1,3-dimethyl-2-imidazolidinone (6 ml), and sodium methanethiolate
(0.23 g, 3.29 mmol) was added. The mixture was reacted at room
temperature for 60 h, then partitioned between a saturated sodium
chloride solution and EA, and the aqueous phase extracted with EA.
The organic extracts were dried over sodium sulfate, filtered and
evaporated to dryness. The residue was purified by silica gel
chromatography (HEP/EA gradient) to give 600 mg of the title
compound.
[0350] .sup.1H-NMR: .delta.=7.56 (d, 1H); 7.39 (s, 1H); 7.23 (d,
1H); 7.21-7.12 (m, 3H); 7.02 (d, 1H); 4.25 (t, 2H); 3.82 (s, 3H);
3.01 (t, 2H); 2.41 (s, 3H); 2.29 (s, 3H)
Step 3: 4-Methylsulfanyl-3-(2-m-tolyl-ethoxy)-benzoic acid
[0351] The compound of step 2 (450 mg, 1.42 mmol) was hydrolyzed in
analogy to example 2 to give 395 mg of the title compound.
[0352] .sup.1H-NMR: .delta.=12.8 (br s, 1H); 7.55 (d, 1H); 7.38 (s,
1H); 7.23-7.10 (m, 4H); 7.02 (d, 1H); 4.25 (t, 2H); 3.82 (s, 3H);
3.00 (t, 2H); 2.41 (s, 3H); 2.29 (s, 3H)
Step 4:
2-[4-Methylsulfanyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-ca-
rboxylic acid methyl ester
[0353] The compound of step 3 (395 mg, 1.31 mmol) was dissolved in
DCM (5 ml). DMF (29 mg, 0.39 mmol) and oxalyl chloride (3.9 ml of a
2 M solution in DCM) were added at room temperature. The mixture
was stirred for 60 min, evaporated to dryness in vacuo, dissolved
in dioxane and evaporated again. The residue was dissolved in DCM
(2 ml) and the solution was slowly added with stirring to an
ice-cooled mixture of 2-amino-indane-2-carboxylic acid methyl ester
hydrochloride (5.42 g, 23.8 mmol), EA and an excess of saturated
aqueous sodium hydrogencarbonate solution. After 2 h, the organic
layer was separated, washed with a saturated sodium chloride
solution, dried over sodium sulfate, filtered and evaporated to
dryness. 582 mg of the title compound were obtained.
[0354] .sup.1H-NMR: .delta.=8.86 (s, 1H); 7.5 (dd, 1H); 7.36 (d,
1H); 7.25-7.11 (m, 8H); 7.02 (d, 1H); 4.23 (t, 2H); 3.61 (d, 2H);
3.60 (s, 3H); 3.37 (d, 2H); 3.01 (t, 2H); 2.39 (s, 3H); 2.28 (s,
3H)
EXAMPLE 4
2-[4-Methylsulfanyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid
##STR00033##
[0356] The compound of example 3 (580 mg, 1.22 mmol) was hydrolyzed
in analogy to example 2 to give 480 mg of the title compound.
[0357] .sup.1H-NMR: .delta.=12.4 (br s, 1H); 8.73 (s, 1H); 7.50
(dd, 1H); 7.35 (d, 1H); 7.24-7.11 (m, 8H); 7.02 (d, 1H); 4.24 (t,
2H); 3.59 (d, 2H); 3.37 (d, 2H); 3.01 (t, 2H); 2.39 (s, 3H); 2.28
(s, 3H)
EXAMPLE 5
2-[4-Methanesulfinyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxyli-
c acid
##STR00034##
[0359] The compound of example 4 (100 mg, 0.216 mmol) was dissolved
in acetic acid (7.5 ml), hydrogen peroxide (74 mg of a 30% solution
in water, 0.65 mmol) was added, and the mixture was reacted at room
temperature for 9 h. The mixture was partitioned between EA and a
1% aqueous sodium sulfite solution, the aqueous phase extracted
with EA, and the organic extracts were dried over sodium sulfate,
filtered and evaporated to dryness. The residue was stirred with
diethyl ether, filtered, and dried in vacuo to give 79 mg of the
title compound.
[0360] LC/MS (Method LC1): Rt=1.48 min; m/z=478.2 [MH.sup.+]
EXAMPLE 6
2-[4-Methanesulfonyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxyli-
c acid
##STR00035##
[0362] The compound of example 4 (140 mg, 0.30 mmol) was dissolved
in acetic acid (7.5 ml), hydrogen peroxide (103 mg of a 30%
solution in water, 0.91 mmol) was added and the mixture was reacted
at 70.degree. C. for 8 h. The mixture was partitioned between EA
and 1% aqueous sodium sulfite solution, the aqueous phase extracted
with EA, and the organic extracts were dried over sodium sulfate,
filtered and evaporated to dryness. The residue was stirred with
diethyl ether, filtered, and dried in vacuo to give 143 mg of the
title compound.
[0363] LC/MS (Method LC1): Rt=1.55 min; m/z=494.0 [MH.sup.+]
EXAMPLE 7
2-[4-Acetyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid methyl ester
##STR00036##
[0365] 4-Acetyl-3-hydroxy-benzoic acid (M. E. Zwaagstra et. al., J.
Med. Chem. 40 (1997), 1075-1089) was reacted with
2-amino-indane-2-carboxylic acid methyl ester hydrochloride in
analogy to step 3 of example 1. From the obtained
2-[4-acetyl-3-hydroxy-benzoylamino]-indane-2-carboxylic acid methyl
ester, the title compound was obtained by reaction with
2-(3-methylphenyl)-ethanol in analogy to step 1 of example 1.
[0366] LC/MS (Method LC1): Rt=1.83 min; m/z=472.2 [MH.sup.+]
EXAMPLE 8
2-[4-Acetyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid
##STR00037##
[0368] From the compound of example 7, the title compound was
obtained by hydrolysis with lithium hydroxide in analogy to example
2.
[0369] LC/MS (Method LC1): Rt=1.67 min; m/z=458.0 [MH.sup.+]
EXAMPLE 9
2-[4-(1-Hydroxy-ethyl)-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxy-
lic acid
##STR00038##
[0371] The compound of example 7 (300 mg, 0.636 mmol) was dissolved
in 3 ml of ethanol, the mixture was cooled in an ice bath and
sodium borohydride (24.1 mg, 0.636 mmol) was added. The reaction
mixture was allowed to warm to room temperature and stirring was
continued for 4 h. The mixture was partitioned between EA and a
saturated aqueous sodium hydrogencarbonate solution, the aqueous
phase extracted with EA, and the organic extracts were dried over
sodium sulfate, filtered and evaporated to dryness. The residue was
purified by preparative RP HPLC (water/ACN gradient) to give a
mixture of
2-[4-(1-hydroxy-ethyl)-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carbox-
ylic acid methyl ester and
2-[4-(1-hydroxy-ethyl)-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carbox-
ylic acid ethyl ester.
[0372] LC/MS (Method LC1): Rt=1.70 min; m/z=474.2 [MH.sup.+]
(2-[4-(1-hydroxy-ethyl)-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carbo-
xylic acid methyl ester)
[0373] LC/MS (Method LC1): Rt=1.76 min; m/z=488.2 [MH.sup.+]
(2-[4-(1-hydroxy-ethyl)-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carbo-
xylic acid ethyl ester)
[0374] From the mixture of the methyl ester and the ethyl ester,
the title compound was obtained by hydrolysis with lithium
hydroxide in analogy to example 2.
[0375] LC/MS (Method LC1): Rt=1.54 min; m/z=460.2 [MH.sup.+]
EXAMPLE 10
2-[4-Ethyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid
##STR00039##
[0377] The compound of example 9 (80 mg, 0.174 mmol) was dissolved
in methanol and hydrogenated in an H-Cube.TM. hydrogenation reactor
(ThalesNano, Budapest, Hungary) at a hydrogen pressure of 100 bar
over a 10% palladium on charcoal cartridge. The reaction mixture
was evaporated to dryness and the residue purified by preparative
RP HPLC (water/ACN gradient).
[0378] .sup.1H-NMR: .delta.=12.3 (br s, 1H); 8.72 (s, 1H);
7.40-7.33 (m, 2H); 7.25-7.12 (m, 7H); 7.10 (d, 1H); 7.02 (d, 1H);
4.20 (t, 2H); 3.59 (d, 2H); 3.37 (d, 2H); 3.02 (t, 2H); 2.56-2.51
(m, 2H); 2.27 (s, 3H); 1.02 (t, 3H)
EXAMPLE 11
2-[4-(1-Fluoro-ethyl)-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxyl-
ic acid
##STR00040##
[0380] The mixture of
2-[4-(1-hydroxy-ethyl)-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carbox-
ylic acid methyl ester and
2-[4-(1-hydroxy-ethyl)-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carbox-
ylic acid ethyl ester obtained in example 9 (50 mg) was dissolved
in DCM, and diethylaminosulfur trifluoride (33 mg, 0.204 mmol) was
added in two portions (second portion after 3.5 h). After complete
conversion as detected by HPLC, the mixture was partitioned between
EA and a saturated aqueous sodium hydrogencarbonate solution and
the aqueous phase extracted with EA. The combined organic extracts
were dried over sodium sulfate, filtered and evaporated to dryness.
The residue was stirred with a HEP/diethyl ether mixture, filtered,
and dried in vacuo. The obtained ester was hydrolyzed in analogy to
example 2 to give 12 mg of the title compound.
[0381] .sup.1H-NMR: .delta.=12.4 (br s, 1H); 8.82 (s, 1H); 7.49 (d,
1H); 7.41 (s, 1H); 7.37 (d, 1H); 7.25-7.12 (m, 6H); 7.10 (d, 1H);
7.03 (d, 1H); 5.83/5.74 (dq, 1H); 4.26 (t, 2H); 3.58 (d, 2H); 3.39
(d, 2H); 3.02 (d, 2H); 2.27 (s, 3H); 1.40/1.35 (dd, 3H)
EXAMPLE 12
2-[4-Ethoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid
##STR00041##
[0382] Step 1: 4-Ethoxy-3-hydroxy-benzoic acid ethyl ester
[0383] 3,4-Dihydroxybenzoic acid ethyl ester (3.00 g, 16.0 mmol)
was suspended in DMF (10 ml), potassium carbonate (2.21 g, 16.0
mmol) was added, the mixture was stirred for 5 min at room
temperature, and then iodoethane (2.49 g, 16.0 mmol) was added. The
mixture was stirred overnight, the addition of potassium carbonate
and of iodoethane was repeated, and the mixture was stirred
overnight again. The mixture was partitioned between 2 N
hydrochloric acid and EA, the aqueous phase extracted with EA, and
the combined organic extracts were washed with a saturated sodium
hydrogencarbonate solution and a saturated sodium chloride
solution, dried over sodium sulfate, filtered, and evaporated to
dryness. The residue was purified by silica gel chromatography
(HEP/EA gradient).
[0384] LC/MS (Method LC1): Rt=1.28 min; m/z=211.1 [MH.sup.+]
Step 2:
2-[4-Ethoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid
[0385] From the compound of step 1, the title compound was obtained
by reaction with 2-(3-methylphenyl)-ethanol in analogy to step 1 of
example 1, hydrolysis of the ester group in analogy to example 2,
reaction of the obtained carboxylic acid with
2-amino-indane-2-carboxylic acid methyl ester hydrochloride in
analogy to step 1 of example 15, and hydrolysis of the ester group
in analogy to example 2.
[0386] .sup.1H-NMR: .delta.=12.4 (br s, 1H); 8.64 (s, 1H); 7.46 (d,
1H); 7.41 (s, 1H); 7.22-7.10 (m, 7H); 7.02 (d, 1H); 6.99 (d, 1H);
4.16 (t, 2H); 4.04 (q, 2H); 3.53 (d, 2H); 3.3-3.4 (2H); 2.98 (t,
2H); 2.28 (s, 3H); 1.32 (t, 3H)
EXAMPLE 13
2-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid methyl ester
##STR00042##
[0387] Step 1: 4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid
[0388] From 3-hydroxy-4-methoxy-benzoic acid methyl ester, the
title compound was obtained by reaction with
2-(3-methylphenyl)-ethanol in analogy to step 1 of example 1 and
hydrolysis of the ester group in analogy to example 2.
[0389] .sup.1H-NMR: .delta.=12.65 (br s, 1H); 7.56 (dd, 1H); 7.44
(d, 1H); 7.19 (t, 1H); 7.17-7.15 (m, 1H); 7.12 (d, 1H); 7.06-7.02
(m, 2H); 4.19 (t, 2H); 3.83 (s, 3H); 3.01 (t, 2H); 2.29 (s, 3H)
Step 2:
2-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxyli-
c acid methyl ester
[0390] The compound of step 1 (1.98 g, 6.91 mmol) was dissolved in
thionyl chloride (10 ml) and stirred for 20 min at 60.degree. C.
The solution was evaporated to dryness in vacuo and the residue was
evaporated twice with dioxane in vacuo. The residue was dissolved
in a little DCM and added to a well-stirred mixture of
2-amino-indane-2-carboxylic acid methyl ester hydrochloride (1.50
g, 6.58 mmol) in EA and an excess of a saturated aqueous sodium
hydrogencarbonate solution. The mixture was stirred for 30 min at
room temperature. The layers were separated, the aqueous phase was
extracted with EA, the combined organic phases were washed with
brine, dried over sodium sulfate, filtered and evaporated to
dryness. This residue was stirred with diethyl ether overnight,
filtered and dried in vacuo to give 1.92 g of the title
compound.
[0391] .sup.1H-NMR: .delta.=8.78 (s, 1H); 7.50 (dd, 1H); 7.43 (d,
1H); 7.24-7.14 (m, 6H); 7.11 (d, 1H); 7.03 (d, 1H); 7.01 (d, 1H);
4.17 (t, 2H); 3.80 (s, 3H); 3.59 (d, 2H); 3.59 (s, 3H); 3.36 (d,
2H); 3.00 (t, 2H); 2.28 (s, 3H)
EXAMPLE 14
2-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid
##STR00043##
[0393] The compound of example 13 (1.92 g, 4.18 mmol) was dissolved
in dioxane (40 ml), lithium hydroxide (10 ml, 1 M solution in
water) was added and the mixture was stirred for 30 min at
60.degree. C. The mixture was partitioned between 2 N hydrochloric
acid and EA, the aqueous phase extracted with EA, and the combined
organic extracts were washed with brine, dried over sodium sulfate,
filtered and evaporated to dryness. The residue was stirred
overnight in EA, filtered, and the crystals were dried in vacuo to
give 1.35 g of the title compound.
[0394] .sup.1H-NMR: .delta.=12.36 (br s, 1H); 8.63 (s, 1H); 7.50
(dd, 1H); 7.43 (d, 1H); 7.23-7.13 (m, 6H); 7.11 (d, 1H); 7.03 (d,
1H); 7.00 (d, 1H); 4.17 (t, 2H); 3.79 (s, 3H); 3.58 (d, 2H); 3.37
(d, 2H); 3.00 (t, 2H); 2.28 (s, 3H)
EXAMPLE 15
2-{4-Methoxy-3-[2-(3-methylsulfanyl-phenyl)-ethoxy]-benzoylamino}-indane-2-
-carboxylic acid methyl ester
##STR00044##
[0395] Step 1:
2-(3-Acetoxy-4-methoxy-benzoylamino)-indane-2-carboxylic acid
methyl ester
[0396] 3-Acetoxy-4-methoxy-benzoic acid (5.00 g, 23.8 mmol) was
dissolved in DCM (50 ml). DMF (167 mg, 2.38 mmol) and oxalyl
chloride (35.6 ml of a 2 M solution in DCM) were added at room
temperature. The mixture was stirred for 20 min, evaporated to
dryness in vacuo, the residue redissolved in DCM and evaporated
again. The residue was dissolved in DCM and slowly added to a
stirred mixture of 2-amino-indane-2-carboxylic acid methyl ester
hydrochloride (5.42 g, 23.8 mmol), EA and an excess of a saturated
aqueous sodium hydrogencarbonate solution. After 90 min the organic
layer was separated and washed with a saturated sodium
hydrogencarbonate solution, 2 M hydrochloric acid and a saturated
sodium chloride solution, dried over sodium sulfate, filtered and
evaporated to dryness to give 8.95 g of the title compound.
[0397] .sup.1H-NMR: .delta.=8.88 (s, 1H); 7.80 (dd, 1H); 7.62 (d,
1H); 7.28-7.13 (m, 5H); 3.81 (s, 3H); 3.60 (s, 3H); 3.58 (d, 2H);
3.37 (d, 2H); 2.27 (s, 3H)
Step 2: 2-(3-Hydroxy-4-methoxy-benzoylamino)-indane-2-carboxylic
acid methyl ester
[0398] The compound of step 1 (3.44 g, 8.97 mmol) was dissolved in
methanol (50 ml), potassium carbonate (248 mg, 1.79 mmol) was added
and the mixture was stirred for 2 h at room temperature. The
mixture was evaporated to dryness, the residue partitioned between
EA and 1 N hydrochloric acid and the aqueous phase extracted with
EA. The combined organic extracts were dried over magnesium
sulfate, filtered and evaporated to dryness to give 2.80 g of the
title compound.
[0399] .sup.1H-NMR: .delta.=9.14 (s, 1H); 8.71 (s, 1H); 7.32 (dd,
1H); 7.29 (d, 1H); 7.24-7.20 (m, 2H); 7.19-7.13 (m, 2H); 6.93 (d,
2H); 3.80 (s, 3H); 3.60 (s, 3H); 3.56 (d, 2H); 3.38 (d, 2H)
Step 3:
2-{4-Methoxy-3-[2-(3-methylsulfanyl-phenyl)-ethoxy]-benzoylamino}--
indane-2-carboxylic acid methyl ester
[0400] The compound of step 2 (0.380 g, 1.11 mmol) and
triphenylphosphine (0.461 g, 1.67 mmol) were dissolved in THF.
2-(3-Methylsulfanyl-phenyl)-ethanol (0.281 g, 1.67 mmol) and DIAD
(0.359 g, 1.67 mmol) were added and the reaction mixture was
stirred at room temperature for 2 h. The volatiles were evaporated
in vacuo and the residue was purified by preparative RP HPLC
(water/ACN gradient) to give 0.217 g of the title compound.
[0401] .sup.1H-NMR: .delta.=8.78 (s, 1H); 7.50 (d, 1H); 7.41 (s,
1H); 7.28-7.20 (m, 4H); 7.20-7.13 (m, 2H); 7.13-7.08 (m, 2H); 7.00
(d, 1H); 4.18 (t, 2H); 3.79 (s, 3H); 3.62-3.55 (m, 5H); 3.38 (d,
2H); 3.01 (t, 2H); 2.45 (s, 3H)
EXAMPLE 16
2-{4-Methoxy-3-[2-(3-methylsulfanyl-phenyl)-ethoxy]-benzoylamino}-indane-2-
-carboxylic acid
##STR00045##
[0403] The compound of example 15 (195 mg, 0.397 mmol) was
dissolved in dioxane (2 ml), lithium hydroxide (1.99 ml of an
aqueous 1 M solution, 1.99 mmol) was added, and the mixture was
stirred at 60.degree. C. for 1 h. The mixture was partitioned
between 2 N hydrochloric acid and EA, the aqueous phase extracted
with EA, and the combined organic extracts were dried over sodium
sulfate, filtered and evaporated to dryness to give 180 mg of the
title compound.
[0404] .sup.1H-NMR: .delta.=12.37 (br s, 1H); 8.65 (s, 1H); 7.47
(d, 1H); 7.41 (s, 1H); 7.29-7.18 (m, 4H); 7.18-7.08 (m, 4H); 7.01
(d, 1H); 4.17 (t, 2H); 3.79 (s, 3H); 3.54 (d, 2H); 3.37 (d, 2H);
3.01 (t, 2H); 2.45 (s, 3H)
EXAMPLE 17
2-{3-[2-(3-Methanesulfinyl-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane--
2-carboxylic acid
##STR00046##
[0406] The compound of example 16 (35 mg, 0.078 mmol) was dissolved
in acetic acid (2.5 ml), hydrogen peroxide (43 mg of a 30% solution
in water, 0.38 mmol) was added and the mixture was stirred at room
temperature for 2 h. The mixture was partitioned between EA and a
1% aqueous sodium sulfite solution, the aqueous phase extracted
with EA, and the combined organic extracts were dried over sodium
sulfate, filtered and evaporated to dryness to give 36 mg of the
title compound.
[0407] .sup.1H-NMR: .delta.=12.3 (br s, 1H); 8.62 (s, 1H); 7.65 (s,
1H); 7.56-7.47 (m, 4H); 7.43 (d, 1H); 7.23-7.19 (m, 2H); 7.17-7.12
(m, 2H); 7.00 (d, 1H); 4.24 (t, 2H); 3.80 (s, 3H); 3.57 (d, 2H);
3.38 (d, 2H); 3.14 (t, 2H); 2.72 (s, 3H)
EXAMPLE 18
2-{3-[2-(3-Methanesulfonyl-phenyl)-ethoxy]-4-methoxy-benzoylamamino}-indan-
e-2-carboxylic acid
##STR00047##
[0409] The title compound was synthesized in analogy to example 17
except that the reaction temperature was 70.degree. C. Yield: 36
mg.
[0410] .sup.1H-NMR: .delta.=12.35 (br s, 1H); 8.64 (s, 1H); 7.92
(s, 1H); 7.78 (d, 1H); 7.70 (d, 1H); 7.58 (dd, 1H); 7.49 (dd, 1H);
7.42 (d, 1H); 7.22-7.19 (m, 2H); 7.18-7.12 (m, 2H); 7.00 (d, 1H);
4.24 (t, 2H); 3.79 (s, 3H); 3.56 (d, 2H); 3.37 (d, 2H); 3.19 (s,
3H); 3.18 (t, 2H)
[0411] In analogy to the above examples, the example compounds of
the formula Im listed in table 1 were prepared. In the formulae of
the groups R.sup.90 in table 1 the line crossed with the symbol
represents the free bond via which the group R.sup.90 is bonded to
the oxygen atom which is attached to the 3-position of the benzoyl
group depicted in formula Im. I.e., in the formula of the complete
molecule the terminal endpoint of the line crossed with the said
symbol ends at the oxygen atom attached to the 3-position of the
benzoyl group. The compounds can be named as
2-[3-(R.sup.90-oxy)-4-methoxy-benzoylamino]-indane-2-carboxylic
acid, for example as
2-{3-[2-(3-cyclopropyl-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-c-
arboxylic acid in the case of example 21.
##STR00048##
TABLE-US-00001 TABLE 1 Example compounds of the formula Im Example
##STR00049## LC/MS Method m/z [MH.sup.+] Retention time [min] 19
##STR00050## LC3 532.09 2.04 20 ##STR00051## LC1 464.20 1.62 21
##STR00052## LC1 472.2 1.68 22 ##STR00053## LC1 460.2 1.70 23
##STR00054## LC1 460.2 1.65 24 ##STR00055## LC1 472.2 1.70 25
##STR00056## LC1 474.2 1.75 26 ##STR00057## LC2 457.1 1.48 27
##STR00058## LC1 476.2 1.35 28 ##STR00059## LC3 430.3 1.41 29
##STR00060## LC3 462.35 1.82 30 ##STR00061## LC3 438.36 2.04 31
##STR00062## LC3 419.28 1.15 32 ##STR00063## LC4 471.27 2.14 33
##STR00064## LC3 386.28 1.41 34 ##STR00065## LC3 460.38 1.96 35
##STR00066## LC3 384.31 1.73 36 ##STR00067## LC3 398.36 1.81 37
##STR00068## LC4 398.25 2.29 38 ##STR00069## LC3 412.31 1.45 39
##STR00070## LC3 452.30 1.86 40 ##STR00071## LC3 474.39 2.06 41
##STR00072## LC3 446.34 1.93 42 ##STR00073## LC3 410.34 1.85 43
##STR00074## LC3 412.33 1.92 44 ##STR00075## LC3 482.36 1.97 45
##STR00076## LC3 444.33 1.86 46 ##STR00077## LC3 476.33 1.80 47
##STR00078## LC3 500.31 1.94 48 ##STR00079## LC4 439.29 1.22 49
##STR00080## LC3 441.35 1.18 50 ##STR00081## LC3 422.33 1.87 51
##STR00082## LC3 520.35 1.48 52 ##STR00083## LC3 483.26 1.60 53
##STR00084## LC3 515.37 1.81 54 ##STR00085## LC4 533.25 2.37 55
##STR00086## LC4 449.26 1.24 56 ##STR00087## LC4 456.27 2.09 57
##STR00088## LC3 438.36 2.06 58 ##STR00089## LC3 477.26 1.28 59
##STR00090## LC3 426.35 2.03 60 ##STR00091## LC3 490.37 1.94 61
##STR00092## LC3 452.38 2.16 62 ##STR00093## LC3 480.31 2.00 63
##STR00094## LC3 461.32 1.25 64 ##STR00095## LC3 439.33 1.16 65
##STR00096## LC3 446.33 1.91 66 ##STR00097## LC4 529.34 1.49 67
##STR00098## LC3 512.38 1.23 68 ##STR00099## LC3 453.34 1.38 69
##STR00100## LC3 472.22 1.27 70 ##STR00101## LC3 513.35 1.85 71
##STR00102## LC4 436.26 1.42 72 ##STR00103## LC3 474.30 1.89 73
##STR00104## LC3 484.33 1.24 74 ##STR00105## LC3 506.28 1.64 75
##STR00106## LC4 468.24 1.32 76 ##STR00107## LC3 488.23 1.25 77
##STR00108## LC3 504.23 1.22 78 ##STR00109## LC3 454.22 1.49 79
##STR00110## LC3 485.19 1.64 80 ##STR00111## LC3 436.23 1.44 81
##STR00112## LC3 476.26 2.19 82 ##STR00113## LC3 396.20 1.72 83
##STR00114## LC3 501.24 1.33 84 ##STR00115## LC3 442.21 1.49 85
##STR00116## LC3 453.23 1.19 86 ##STR00117## LC3 396.20 1.75 87
##STR00118## LC3 434.22 1.89 88 ##STR00119## LC3 437.2 1.55 89
##STR00120## LC3 502.18 1.82 90 ##STR00121## LC3 488.21 1.46 91
##STR00122## LC3 516.31 1.26
EXAMPLE 92
Starting Compound
(1-m-Tolyl-cyclopropyl)-methanol
##STR00123##
[0413] m-Tolylacetonitrile (1.00 g, 7.62 mmol) and
1,2-dibromoethane (1.86 g, 9.91 mmol) were dissolved in DMF (5 ml).
The mixture was cooled in an ice bath and potassium tert-butoxide
(855 mg, 19.1 mmol) was added slowly with stirring. After stirring
for 30 min, the mixture was partitioned between EA and water. The
organic layer was washed with water, dried over sodium chloride,
decanted and evaporated to dryness.
[0414] After silica gel chromatography of the residue (HEP/EA
gradient), an approximately 1:1 mixture of
1-m-tolyl-cyclopropanecarbonitrile and the starting compound
m-tolylacetonitrile was obtained.
[0415] The obtained mixture of nitriles (500 mg) was dissolved in
ethanol (2 ml) and 50% aqueous potassium hydroxide (2 ml). The
mixture was reacted with microwave-heating at 140.degree. C. for 4
h in a tightly closed vial. Then the mixture was partitioned
between EA and 2 N hydrochloric acid, the aqueous phase extracted
with EA, and the combined organic extracts dried over sodium
chloride, decanted and evaporated to dryness to give a mixture of
1-m-tolyl-cyclopropanecarboxylic acid amide and
m-tolyl-acetamide.
[0416] The obtained mixture of amides (600 mg) was dissolved in
acetic acid (8.5 ml) and acetic anhydride (14.5 ml), the mixture
was cooled in an ice bath, sodium nitrite (1.97 g, 28.5 mmol) was
added, and the mixture was stirred for 2 h at room temperature.
Water (15 ml) was added and the mixture was heated to 60.degree. C.
for 30 min. After evaporation to dryness in vacuo, the residue was
partitioned between EA and 2 N hydrochloric acid, the aqueous phase
extracted with EA, and the combined organic extracts were dried
over sodium sulfate, decanted and evaporated to dryness to yield an
approximately 1:1 mixture of 1-m-tolyl-cyclopropanecarboxylic acid
and m-tolyl-acetic acid.
[0417] The obtained mixture of acids (430 mg) was dissolved in
dimethoxyethane (8 ml), NMM (272 mg, 2.68 mmol) and isobutyl
chloroformate (367 mg, 2.68 mmol) were added with stirring. After a
few minutes, the mixture was filtered and sodium borohydride (369
mg, 9.76 mmol) was added to the clear filtrate. After cautious
addition of water (4 ml; violent formation of hydrogen) stirring
was continued for a few minutes until the reaction ceased, the
mixture was partitioned between EA and 2 N hydrochloric acid, the
aqueous phase extracted with EA, and the combined organic extracts
were dried over sodium sulfate, decanted and evaporated to dryness.
This residue was purified by preparative RP HPLC (water/ACN
gradient) to give 133 mg of the title compound.
[0418] .sup.1H-NMR: .delta.=7.18-7.06 (m, 3H); 6.98 (d, 1H); 4.59
(t, 1H); 3.51 (d, 2H); 0.83-0.78 (m, 2H); 0.70-0.67 (m, 2H)
EXAMPLE 93
Starting Compound
2-(2-Fluoro-5-methyl-phenyl)-ethanol
##STR00124##
[0420] In analogy to the procedure described in M. Jorgensen et
al., J. Am. Chem. Soc. 124 (2002), 12557-12565, in a first flask,
dicyclohexylamine (3.06 g, 16.9 mmol) was dissolved in toluene and
cooled in an ice bath. n-Butyllithium (6.14 ml, 2.5 M solution in
hexane) was added. After 5 min, tert-butyl acetate (1.78 g, 15.3
mmol) was added slowly. A second flask was charged with
tri-(tert-butyl)phosphonium tetrafluoroborate (83 mg, 0.30 mmol)
and tris(dibenzylideneacetone)dipalladium(0) (146 mg, 0.153 mmol)
and thoroughly flushed with argon. Toluene (100 ml) was added,
followed by 3-bromo-4-fluoro-toluene (2.90 g, 15.3 mmol) and by the
contents of the first flask. After stirring overnight, the formed
suspension was filtered over a small plug of silica gel which was
washed repeatedly with diethyl ether. The filtrates were evaporated
in vacuo and the residue was purified by silica gel chromatography
(HEP/EA gradient) to give 2.81 g of
(2-fluoro-5-methyl-phenyl)-acetic acid tert-butyl ester.
[0421] .sup.1H-NMR: .delta.=7.12-7.07 (m, 2H); 7.03 (t, 1H); 3.54
(s, 2H); 2.25 (s, 3H); 1.39 (s, 9H)
[0422] A flask was charged with lithium aluminium hydride (0.846 g,
22.3 mmol) and flushed with argon. THF (8 ml) was added, and the
obtained (2-fluoro-5-methyl-phenyl)-acetic acid tert-butyl ester
was slowly added with stirring. The reaction took place
immediately. After 2 min, diethyl ether (30 ml) and EA (2.5 ml)
were added. Then water was added cautiously and slowly with
stirring until a greyish precipitate formed.
[0423] The solution was decanted and the precipitate was washed
with EA. The combined solutions were dried over sodium sulfate,
filtered and evaporated to dryness. The residue was purified by
silica gel chromatography (HEP/EA gradient) to give 0.55 g of the
title compound.
[0424] .sup.1H-NMR: .delta.=7.10 (d, 1H); 7.05-6.96 (m, 2H); 4.70
(t, 1H); 3.56 (dt, 2H); 2.71 (t, 2H); 2.25 (s, 3H)
EXAMPLE 94
2-{3-[2-(3-Cyano-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxyl-
ic acid
##STR00125##
[0425] Step 1: 3-[2-(3-Bromo-phenyl)-ethoxy]-4-methoxy-benzoic acid
methyl ester
[0426] Methyl 3-hydroxy-4-methoxybenzoate (500 mg, 2.75 mmol) and
triphenylphosphine (1.08 g, 4.12 mmol) were dissolved in THF (13
ml), the solution was cooled in an ice bath and
2-(3-bromophenyl)-ethanol (662 mg, 3.29 mmol) and DIAD (886 mg,
4.12 mmol) were added sequentially. Stirring was continued for 3 h
at room temperature. The reaction mixture was evaporated to dryness
and the residue purified by preparative RP HPLC (water/ACN
gradient) to give 900 mg of the title compound.
[0427] .sup.1H-NMR: .delta.=7.62-7.58 (m, 2H); 7.45 (d, 1H); 7.41
(d, 1H); 7.35 (d, 1H); 7.28 (dd, 1H); 7.08 (d, 1H); 4.22 (t, 2H);
3.83 (s, 3H); 3.80 (s, 3H); 3.01 (t, 2H)
Step 2: 3-[2-(3-Cyano-phenyl)-ethoxy]-4-methoxy-benzoic acid methyl
ester
[0428] A flask was charged with zinc cyanide (129 mg, 1.10 mmol)
and tetrakis(triphenylphosphine)palladium(0) (63 mg, 0.0547 mmol).
Under an atmosphere of argon, a solution of the compound of step 1
(400 mg, 1.10 mmol) in DMF (1.9 ml) was added to the mixture. After
stirring at 150.degree. C. for 1 h and cooling, the mixture was
diluted with methyl tert-butyl ether and filtered over celite. The
filtrate was washed with water, dried over magnesium sulfate,
filtered and evaporated to dryness to give 275 mg of the title
compound.
[0429] .sup.1H-NMR: .delta.=7.85 (s, 1H); 7.70 (dd, 1H); 7.58 (dd,
1H); 7.51 (dd, 1H); 7.44 (d, 1H); 7.07 (d, 1H); 4.26 (t, 2H); 3.82
(s, 3H); 3.80 (s, 3H); 3.11 (t, 2H)
Step 3: 3-[2-(3-Cyano-phenyl)-ethoxy]-4-methoxy-benzoic acid
[0430] The compound of step 2 (274 mg, 0.883 mmol) was dissolved in
dioxane (4.5 ml), lithium hydroxide (4.42 ml of a 1 M aqueous
solution, 4.42 mmol) was added, and the mixture was stirred at
60.degree. C. for 30 min. The mixture was partitioned between 2 N
hydrochloric acid and EA, the aqueous phase extracted with EA, and
the combined organic extracts were dried over sodium sulfate,
filtered and evaporated to dryness. The residue was purified by
preparative RP HPLC (water/ACN gradient) to give 160 mg of the
title compound.
[0431] .sup.1H-NMR: .delta.=12.65 (br s, 1H); 7.83 (s, 1H);
7.73-7.68 (m, 2H); 7.60-7.50 (m, 2H); 7.45 (d, 1H); 7.04 (d, 1H);
4.25 (t, 2H); 3.81 (s, 3H); 3.11 (t, 2H)
Step 4:
2-{3-[2-(3-Cyano-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2--
carboxylic acid methyl ester
[0432] From the compound of step 3 and 2-amino-indane-2-carboxylic
acid methyl ester hydrochloride, the title compound was obtained in
a yield of 79% in analogy to step 1 of example 15.
[0433] LC/MS (Method LC2): Rt=1.63 min; m/z=471.1 [MH.sup.+]
Step 5:
2-{3-[2-(3-Cyano-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2--
carboxylic acid
[0434] From the compound of step 4, the title compound was obtained
in a yield of 37% by hydrolysis with lithium hydroxide in analogy
to step 3 except that the reaction was performed at room
temperature.
[0435] .sup.1H-NMR: .delta.=12.35 (br s, 1H); 8.61 (s, 1H); 7.84
(s, 1H); 7.72-7.68 (2d, 2H); 7.54-7.49 (m, 2H); 7.43 (d, 1H);
7.24-7.20 (m, 2H); 7.18-7.13 (m, 2H); 7.00 (d, 1H); 4.22 (t, 2H);
3.79 (s, 3H); 3.58 (d, 2H); 3.37 (d, 2H); 3.11 (t, 2H)
EXAMPLE 95
2-{3-[2-(3-Carbamoyl-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carb-
oxylic acid
##STR00126##
[0437] The compound of example 94 was reacted with lithium
hydroxide at 60.degree. C. for 50 min in analogy to step 3 of
example 94. The obtained mixture of the title compound and
2-{3-[2-(3-carboxy-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carbo-
xylic acid (example 96) was separated by preparative RP HPLC
(water/ACN gradient).
[0438] .sup.1H-NMR: .delta.=12.3 (s, 1H); 8.61 (s, 1H); 7.91 (s,
1H); 7.83 (s, 1H); 7.72 (d, 1H); 7.53-7.47 (m, 2H); 7.45 (d, 1H);
7.37 (t, 1H); 7.31 (s, 1H); 7.23-7.19 (m, 2H); 7.17-7.12 (m, 2H);
7.00 (d, 1H); 4.22 (t, 2H); 3.78 (s, 3H); 3.59 (d, 2H); 3.38 (d,
2H); 3.10 (t, 2H)
EXAMPLE 96
2-{3-[2-(3-Carboxy-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carbox-
ylic acid
##STR00127##
[0440] The title compound was prepared as described in Example
95.
[0441] .sup.1H-NMR: .delta.=13.0-12.2 (br, 2H); 8.62 (s, 1H); 7.94
(s, 1H); 7.80 (d, 1H); 7.58 (d, 1H); 7.50 (dd, 1H); 7.47-7.42 (m,
2H); 7.22-7.19 (m, 2H); 7.17-7.12 (m, 2H); 7.00 (d, 1H); 4.22 (t,
2H); 3.78 (s, 3H); 3.59 (d, 2H); 3.37 (d, 2H); 3.12 (t, 2H)
EXAMPLE 97
5-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-5,
6-dihydro-4H-cyclopenta[c]thiophene-5-carboxylic acid ethyl
ester
##STR00128##
[0443] (Benzhydrylidene-amino)-acetic acid ethyl ester (0.113 g,
0.414 mmol) was dissolved in DMF (3 ml) and cooled in an ice bath.
Potassium tert-butoxide (94.8 mg, 0.828 mmol) was added, and the
mixture was stirred for 10 min. The mixture was cooled to
-30.degree. C., and 3,4-bis-chloromethyl-thiophene (50 mg, 0.276
mmol) was added in one portion. The mixture was then placed into an
ice bath again, and the reaction allowed to proceed for 20 min. The
mixture was acidified with 2 N hydrochloric acid, stirred for 10
min and partitioned between water and diethyl ether. The aqueous
phase was neutralized with a saturated sodium hydrogencarbonate
solution and extracted with EA. The combined EA extracts were
washed with a saturated sodium chloride solution, dried over sodium
sulfate, filtered and evaporated to dryness. The residue was
dissolved in diethyl ether, filtered, evaporated to dryness,
acidified with hydrogen chloride in methanol and evaporated to
dryness. The residue was stirred with an diethyl ether/HEP mixture,
and the solid was filtered and dried in vacuo to give crude
5-amino-5,6-dihydro-4H-cyclopenta[c]thiophene-5-carboxylic acid
ethyl ester hydrochloride. A part of the crude compound (27 mg,
0.109 mmol) was reacted without further purification with
4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid in analogy to step 1 of
example 15. After purification by preparative RP HPLC (water/ACN
gradient), 23 mg of the title compound were obtained.
[0444] .sup.1H-NMR: .delta.=8.78 (s, 1H); 7.50 (dd, 1H); 7.41 (d,
1H); 7.22-7.14 (m, 2H); 7.11 (d, 1H); 7.08-6.99 (m, 4H); 4.18 (t,
2H); 4.05 (q, 2H); 3.80 (s, 3H); 3.33 (d, 2H); 3.13 (d, 2H); 3.00
(t, 2H); 2.28 (s, 3H); 1.09 (t, 3H)
EXAMPLE 98
5-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-5,
6-dihydro-4H-cyclopenta[c]thiophene-5-carboxylic acid
##STR00129##
[0446] The compound of example 97 (21 mg, 0.0438 mmol) was
hydrolyzed in analogy to step 3 of example 94. After evaporation to
dryness, the residue was stirred with diethyl ether, filtered and
dried in vacuo to give 16 mg of the title compound.
[0447] .sup.1H-NMR: .delta.=8.69 (s, 1H); 7.48 (d, 1H); 7.41 (s,
1H); 7.21-7.09 (m, 3H); 7.05-6.98 (m, 4H); 4.19 (t, 2H); 3.80 (s,
3H); 3.30 (d, 2H); 3.11 (d, 2H); 3.00 (t, 2H); 2.29 (s, 3H)
EXAMPLE 99
5-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-5,6-dihydro-4H-cyclopenta[-
b]thiophene-5-carboxylic acid
##STR00130##
[0449] Starting from 2,3-bis-chloromethyl-thiophene, the title
compound was obtained in analogy to examples 97 and 98.
[0450] LC/MS (Method LC1): Rt=1.60 min; m/z=452.0 [MH.sup.+]
EXAMPLE 100
2-Chloro-5-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-5,6-dihydro-4H-cy-
clopenta[b]thiophene-5-carboxylic acid
##STR00131##
[0451] Step 1: 5-Chloro-2,3-bis-chloromethyl-thiophene
[0452] 2,3-Bis-chloromethyl-thiophene (500 mg, 2.76 mmol) was
dissolved in acetic acid (10 ml). Sulfuryl chloride (372 mg, 2.76
mmol) was added and the mixture was stirred for 1 h at room
temperature. The mixture was partitioned between EA, water and an
excess of solid sodium hydrogencarbonate and the aqueous phase
extracted with EA. The combined organic extracts were dried over
magnesium sulfate, filtered and evaporated to dryness to give 240
mg of the title compound.
[0453] .sup.1H-NMR: .delta.=7.13 (s, 1H); 5.16 (s, 2H); 4.76 (s,
2H)
Step 2:
2-Chloro-5-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-5,6-dihyd-
ro-4H-cyclopenta[b]thiophene-5-carboxylic acid
[0454] From the compound of step 1, the title compound was obtained
by reaction with (benzhydrylidene-amino)-acetic acid ethyl ester in
analogy to example 97, step 1, reaction with
4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid in analogy to step 3 of
example 1, and ester hydrolysis in analogy to example 2.
[0455] LC/MS (Method LC1): Rt=1.74 min; m/z=486.0/488.0
[MH.sup.+]
EXAMPLE 101
6-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-6,
7-dihydro-5H-[1]pyrindine-6-carboxylic acid
##STR00132##
[0456] Step 1:
6-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-6,7-dihydro-5H-[1]pyrindi-
ne-6-carboxylic acid ethyl ester
[0457] Isocyano-acetic acid methyl ester (112 mg, 1.13 mmol) and
2,3-bis-chloromethyl-pyridine (200 mg, 1.14 mmol) were dissolved in
DMF. Potassium tert-butoxide (0.255 g, 2.27 mmol) was added and the
reaction mixture was stirred for 1 h at room temperature. The
mixture was partitioned between EA and a saturated aqueous sodium
hydrogencarbonate solution, the aqueous phase extracted with EA,
and the organic extracts were dried over sodium sulfate, filtered
and evaporated to dryness. The residue was purified by silica gel
chromatography (HEP/EA gradient) to give
6-isocyano-6,7-dihydro-5H-[1]pyrindine-6-carboxylic acid methyl
ester. This compound was added to a solution of thionyl chloride
(147 mg, 1.23 mmol) in ethanol (1 ml) and refluxed overnight. The
mixture was evaporated to dryness, and the residue was stirred with
HEP, filtered and dried in vacuo. The obtained product was reacted
with 4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid in analogy to step
1 of example 15 and the title compound purified by preparative RP
HPLC (water/ACN gradient).
[0458] LC/MS (Method LC1): Rt=1.22 min; m/z=475.2 [MH.sup.+]
Step 2:
6-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-6,7-dihydro-5H-[1]-
pyrindine-6-carboxylic acid
[0459] The compound of step 1 was hydrolyzed with lithium hydroxide
in analogy to step 3 of example 94 to give 5 mg of the title
compound.
[0460] LC/MS (Method LC1): Rt=1.11 min; m/z=447.1 [MH.sup.+]
EXAMPLE 102
2-{[5-Acetyl-4-(2-m-tolyl-ethoxy)-thiophene-2-carbonyl]amino}-indane-2-car-
boxylic acid
##STR00133##
[0462] The title compound was synthesized by reaction of
5-acetyl-4-hydroxy-thiophene-2-carboxylic acid methyl ester with
2-(3-methylphenyl)-ethanol in analogy to step 1 of example 1,
subsequent ester hydrolysis in analogy to example 2, reaction with
2-amino-indane-2-carboxylic acid methyl ester hydrochloride in
analogy to step 1 of example 15, and ester hydrolysis in analogy to
example 2.
[0463] LC/MS (Method LC1): Rt=1.66 min; m/z=464.0 [MH.sup.+]
EXAMPLE 103
2-{5-[2-(3-Chloro-phenyl)-ethoxy]-4-methoxy-2-nitro-benzoylamino}-indane-2-
-carboxylic acid
##STR00134##
[0464] Step 1:
5-[2-(3-Chloro-phenyl)-ethoxy]-4-methoxy-2-nitro-benzoic acid
methyl ester
[0465] Methyl 3-hydroxy-4-methoxybenzoate and
2-(3-chlorophenyl)-ethanol were reacted in analogy to step 1 of
example 1. The obtained
3-[2-(3-chloro-phenyl)-ethoxy]-4-methoxy-benzoic acid methyl ester
(0.750 g, 2.34 mmol) was added slowly to ice-cooled 100% nitric
acid (10 ml). The ice bath was removed and stirring was continued
overnight. The mixture was cautiously transferred into a stirred
mixture of EA, water and an excess of sodium hydrogencarbonate and
extracted with EA. The combined organic extracts were washed with a
saturated sodium chloride solution, dried over sodium sulfate,
filtered and evaporated to dryness. The solid residue was extracted
with diethyl ether, and the ethereal solution was evaporated. The
residue was stirred with HEP, and the solid was filtered and dried
in vacuo to give 0.680 g of the title compound.
[0466] .sup.1H-NMR: .delta.=7.63 (s, 1H); 7.45 (s, 1H); 7.37 (s,
1H); 7.37-7.27 (m, 3H); 4.36 (t, 2H); 3.90 (s, 3H); 3.81 (s, 3H);
3.10 (t, 2H)
Step 2:
2-{5-[2-(3-Chloro-phenyl)-ethoxy]-4-methoxy-2-nitro-benzoylamino}--
indane-2-carboxylic acid
[0467] From the compound of step 1, the title compound was obtained
by hydrolysis of the ester group in analogy to example 2, reaction
of the obtained carboxylic acid with 2-amino-indane-2-carboxylic
acid methyl ester hydrochloride in analogy to step 1 of example 15,
and hydrolysis of the ester group in analogy to example 2.
[0468] .sup.1H-NMR: .delta.=12.5 (s, 1H); 9.08 (s, 1H); 7.59 (s,
1H); 7.45 (s, 1H); 7.38-7.28 (m, 3H); 7.25-7.20 (m, 2H); 7.18-7.12
(m, 2H); 6.97 (s, 1H); 4.31 (t, 2H); 3.87 (s, 3H); 3.56 (d, 2H);
3.3 (d, 2H); 3.10 (t, 2H)
EXAMPLE 104
2-{2-Bromo-5-[2-(3-chloro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-
-carboxylic acid
##STR00135##
[0469] Step 1:
2-Bromo-5-[2-(3-chloro-phenyl)-ethoxy]-4-methoxy-benzoic acid
methyl ester
[0470] Methyl 3-hydroxy-4-methoxybenzoate and
2-(3-chlorophenyl)-ethanol were reacted in analogy to step 1 of
example 1. The obtained
3-[2-(3-chloro-phenyl)-ethoxy]-4-methoxy-benzoic acid methyl ester
(300 mg, 0.935 mmol) and sodium acetate (230 mg, 2.81 mmol) were
dissolved in acetic acid (10 ml), bromine (224 mg, 1.40 mmol) was
added, and the mixture was stirred at 95.degree. C. with reaction
control every hour. When the reaction did no more proceed, further
bromine was added. After 5 h the reaction was completed. The
volatiles were evaporated in vacuo, the residue was partitioned
between EA and a saturated aqueous sodium hydrogencarbonate
solution, and the aqueous phase extracted with EA. The combined
organic extracts were washed with a saturated sodium chloride
solution, dried over sodium sulfate, filtered and evaporated to
dryness. This residue was purified by silica chromatography (HEP/EA
gradient) to give 180 mg of the title compound.
[0471] .sup.1H-NMR: .delta.=7.45-7.42 (m, 1H); 7.38 (s, 1H);
7.36-7.26 (m, 3H); 7.25 (s, 1H); 4.21 (t, 2H); 3.85 (s, 3H); 3.80
(s, 3H); 3.04 (t, 2H)
Step 2:
2-{2-Bromo-5-[2-(3-chloro-phenyl)-ethoxy]-4-methoxy-benzoylamino}--
indane-2-carboxylic acid
[0472] From the compound of step 1, the title compound was obtained
by hydrolysis of the ester group in analogy to example 2, reaction
of the obtained carboxylic acid with 2-amino-indane-2-carboxylic
acid methyl ester hydrochloride in analogy to step 1 of example 15,
and hydrolysis of the ester group in analogy to example 2.
[0473] LC/MS (Method LC1): Rt=1.64 min; m/z=544.0/546.0
[MH.sup.+]
EXAMPLE 105
2-{2-Chloro-5-[2-(3-chloro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane--
2-carboxylic acid
##STR00136##
[0474] Step 1:
2-Chloro-5-[2-(3-chloro-phenyl)-ethoxy]-4-methoxy-benzoic acid
methyl ester
[0475] Methyl 3-hydroxy-4-methoxybenzoate and
2-(3-chlorophenyl)-ethanol were reacted in analogy to step 1 of
example 1. The obtained
3-[2-(3-chloro-phenyl)-ethoxy]-4-methoxy-benzoic acid methyl ester
(300 mg, 0.935 mmol), N-chloro-succinimide (381 mg, 2.81 mmol), and
zirconium tetrachloride (129 mg, 0.57 mmol) were suspended in DCM
(4 ml) and the mixture was stirred under reflux for 5 h until the
starting material was used up. The mixture was partitioned between
EA and a saturated aqueous sodium hydrogencarbonate solution, the
aqueous phase extracted with EA, and the combined organic extracts
were dried over sodium sulfate, filtered and evaporated to dryness.
The residue was purified by silica chromatography (HEP/EA gradient)
to give 118 mg of the title compound.
[0476] LC/MS (Method LC1): Rt=1.82 min; m/z=355.0/357.0
[MH.sup.+]
Step 2:
2-{2-Chloro-5-[2-(3-chloro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-
-indane-2-carboxylic acid
[0477] From the compound of step 1, the title compound was obtained
by hydrolysis of the ester group in analogy to example 2, reaction
of the obtained carboxylic acid with 2-amino-indane-2-carboxylic
acid methyl ester hydrochloride in analogy to step 1 of example 15,
and hydrolysis of the ester group in analogy to example 2.
[0478] LC/MS (Method LC1): Rt=1.64 min; m/z=500.1/502.1
[MH.sup.+]
EXAMPLE 106
2-[3-Fluoro-4-methoxy-5-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxyl-
ic acid
##STR00137##
[0479] Step 1: 3-Acetoxy-5-amino-4-methoxy-benzoic acid
[0480] 3-Acetoxy-4-methoxy-5-nitro-benzoic acid (4.50 g, 17.6 mmol)
(R. T. Borchardt et al., J. Med. Chem. 25 (1982), 312-323; F.
Tiemann et al., Ber. dt. Chem. Ges. 9 (1876), 937) was dissolved in
ethanol (180 ml) and 0.5 M hydrogen chloride in methanol (4 ml) and
hydrogenated in an H-Cube.TM. hydrogenation reactor with 100 bar
hydrogen at 40.degree. C. over a 10% palladium on charcoal
cartridge. The mixture was evaporated to dryness to give 4.1 g of
the title compound.
[0481] LC/MS (Method LC1): Rt=0.75 min; m/z=226.0 [MH.sup.+]
Step 2: 3-Fluoro-5-hydroxy-4-methoxy-benzoic acid
[0482] The compound of step 1 (2.0 g, 8.88 mmol) was dissolved in
aqueous tetrafluoroboric acid (48%, 4.5 ml), sodium nitrite (612
mg, 8.88 mmol) was added at 0.degree. C., and the mixture was
stirred at room temperature for 60 min. The volatiles were
evaporated, toluene was added to the oily residue and the mixture
was heated at 100.degree. C. for 4 h. The mixture was partitioned
between EA and 2 N hydrochloric acid, the aqueous phase extracted
with EA, and the combined organic extracts were dried over sodium
chloride, decanted and evaporated to dryness. The residue was
purified by preparative RP HPLC (water/ACN gradient) to give 170 mg
of the title compound.
[0483] .sup.1H-NMR: .delta.=12.9 (br s, 1H); 10.1 (s, 1H); 7.29 (d,
1H); 7.18 (dd, 1H); 3.85 (s, 3H)
Step 3: 3-Acetoxy-5-fluoro-4-methoxy-benzoic acid
[0484] The compound of step 2 (169 mg, 913 mmol) was suspended in
acetic anhydride (1.75 ml) and heated at 100.degree. C. for 3 h.
The solution was cooled, water (2 ml) was added, and the mixture
was stirred at 60.degree. C. for 1 h. Upon cooling, crystals formed
which were filtered off and dried in vacuo to give 120 mg of the
title compound.
[0485] .sup.1H-NMR: .delta.=13 (br s, 1H); 7.67 (dd, 1H); 7.55 (d,
1H); 3.92 (s, 3H); 2.32 (s, 3H)
Step 4:
2-(3-Fluoro-5-hydroxy-4-methoxy-benzoylamino)-indane-2-carboxylic
acid methyl ester
[0486] The compound of step 3 (120 mg, 0.526 mmol) was reacted with
2-amino-indane-2-carboxylic acid methyl ester hydrochloride in
analogy to step 1 of example 15. The obtained product was dissolved
in methanol (0.77 ml), potassium carbonate (2 mg) was added, and
the mixture was stirred at room temperature for 30 min. The solvent
was evaporated, the residue was partitioned between EA and a
saturated sodium chloride solution, and the aqueous phase extracted
with EA. The combined organic extracts were dried over sodium
sulfate, filtered and evaporated to dryness to give 60 mg of the
title compound.
[0487] LC/MS (Method LC1): Rt=1.35 min; m/z=360.0 [MH.sup.+]
Step 5:
2-[3-Fluoro-4-methoxy-5-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2--
carboxylic acid
[0488] From the compound of step 4, the title compound was obtained
by reaction with 2-(3-methylphenyl)-ethanol in analogy to step 1 of
example 1 and hydrolysis in analogy to example 2.
[0489] .sup.1H-NMR: .delta.=12.4 (br s, 1H); 8.76 (s, 1H);
7.92-7.84 (m, 2H); 7.25-7.09 (m, 7H); 7.03 (d, 1H); 4.27 (t, 2H);
3.73 (s, 3H); 3.60 (d, 2H); 3.37 (d, 2H); 3.05 (t, 2H); 2.28 (s,
3H)
EXAMPLE 107
2-[4-Methoxy-3-nitro-5-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxyli-
c acid
##STR00138##
[0491] The title compound was obtained from
3-acetoxy-4-methoxy-5-nitro-benzoic acid by reaction with
2-amino-indane-2-carboxylic acid methyl ester hydrochloride,
hydrolysis of the acetoxy group in analogy to step 4 of example
106, and reaction of the obtained product with
2-(3-methylphenyl)-ethanol and subsequent ester hydrolysis in
analogy to step 5 of example 106.
[0492] LC/MS (Method LC1): Rt=1.77 min; m/z=491.0 [MH.sup.+]
EXAMPLE 108
2-{[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoyl]-methyl-amino}-indane-2-carboxy-
lic acid
##STR00139##
[0493] Step 1:
1,3-Dimethyl-spiro(imidazolidin-5,2'-indane)-2,4-dione
[0494] Spiro[imidazolidine-4,2'-indane]-2,5-dione (2-indanone
hydantoin) (200 mg, 0.989 mmol) and potassium tert-butoxide (255
mg, 2.28 mmol) were suspended in DMF (2 ml) and stirred for 20 min
at room temperature. Iodomethane (323 mg, 2.28 mmol) was added and
the mixture was stirred overnight. The addition of potassium
tert-butoxide, stirring for 20 min, addition of iodomethane and
stirring overnight at room temperature were repeated. Then the
reaction mixture was partitioned between EA and 2 N hydrochloric
acid, the aqueous phase extracted with EA, and the combined organic
extracts were dried over sodium chloride, decanted and evaporated
to dryness. Purification of the residue by silica gel
chromatography gave a mixture of the mono-methylated and the
di-methylated product. This mixture was dissolved in a 3:1 mixture
of 0.3 N potassium hydroxide solution and dioxane and stirred
overnight at room temperature. The mixture was partitioned between
EA and water and the aqueous phase extracted with EA. The combined
organic extracts were dried over sodium chloride, decanted and
evaporated to dryness to give 90 mg of the title compound.
[0495] LC/MS (Method LC1): Rt=1.10 min; m/z=231.1 [MH.sup.+]
Step 2:
2-{[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoyl]-methyl-amino}-indane-2-
-carboxylic acid
[0496] The compound of step 1 (90 mg, 0.391 mmol) was dissolved in
a mixture of methanol and 50% sodium hydroxide solution and stirred
in a microwave reactor at 140.degree. C. for about 3 h until
hydrolysis was complete. The mixture was evaporated to dryness and
the residue suspended in a mixture of water (6 ml) and dioxane (3
ml) and cooled in an ice bath. An excess of
4-methoxy-3-(2-m-tolyl-ethoxy)-benzoyl chloride, which had been
freshly prepared by dissolving the corresponding benzoic acid in
thionyl chloride, stirring the mixture at 60.degree. C. for 20 min,
evaporating to dryness and dissolving the residue in dioxane, was
slowly added to the mixture with stirring. The reaction mixture was
stirred for 1 h in the ice bath. Then the mixture was partitioned
between 2 N hydrochloric acid and EA, the aqueous phase extracted
with EA, and the combined organic extracts were dried over sodium
chloride, decanted and evaporated to dryness in vacuo. The residue
was purified by silica gel chromatography (DCM/methanol/ammonium
hydroxide gradient).
[0497] .sup.1H-NMR: .delta.=12.3 (br s, 1H); 7.25-7.08 (m, 7H);
7.05-6.97 (m, 4H); 4.15 (t, 2H); 3.79 (s, 3H); 3.63 (d, 2H); 3.40
(d, 2H); 3.00 (t, 2H); 2.98 (s, 3H); 2.27 (s, 3H)
EXAMPLE 109
2-(3-Benzenesulfonyloxy-4-methoxy-benzoylamino)-indane-2-carboxylic
acid
##STR00140##
[0499] The compound of step 2 of example 15 (200 mg, 0.586 mmol)
was dissolved in ACN (3 ml), potassium carbonate (243 mg, 1.7 mmol)
and benzenesulfonyl chloride (155 mg, 0.88 mmol) were added, and
the mixture was stirred for 30 min. The mixture was partitioned
between EA and saturated sodium chloride solution, the aqueous
phase extracted with EA, and the combined organic extracts were
dried over magnesium sulfate, filtered, and evaporated to dryness.
The residue was dissolved in dioxane (0.8 ml), lithium hydroxide
(0.8 ml of a 1 N aqueous solution) was added, and the mixture was
stirred at room temperature for 2.5 h. The mixture was partitioned
between 2 N hydrochloric acid and EA, the aqueous phase extracted
with EA, and the combined organic extracts were dried over
magnesium sulfate, filtered and evaporated to dryness. The residue
was purified by preparative RP HPLC (water/ACN gradient) to give
115 mg of the title compound.
[0500] .sup.1H-NMR: .delta.=12.4 (s, 1H); 8.77 (s, 1H); 7.87-7.77
(m, 4H); 7.72 (d, 1H); 7.67-7.61 (m, 2H); 7.76-7.71 (m, 2H);
7.21-7.16 (m, 2H); 7.10 (d, 1H); 3.57 (d, 2H); 3.48 (s, 3H); 3.38
(d, 2H)
[0501] In analogy to example 109, the example compounds of the
formula In listed in table 2 were prepared. The compounds can be
named as
2-[3-(R.sup.91-sulfonyloxy)-4-methoxy-benzoylamino]-indane-2-carboxylic
acid, for example as
2-[3-(toluene-3-sulfonyloxy)-4-methoxy-benzoylamino]-indane-2-carboxylic
acid in the case of example 111.
##STR00141##
TABLE-US-00002 TABLE 2 Example compounds of the formula In m/z
Retention Example R.sup.91 LC/MS Method [MH.sup.+] time [min] 110
4-methyl-phenyl LC2 482.0 1.54 111 3-methyl-phenyl LC2 482.0 1.54
112 2-methyl-phenyl LC2 482.0 1.55
EXAMPLE 113
2-[4-Methoxy-3-(2-m-tolyloxy-acetyl)-benzoylamino]-indane-2-carboxylic
acid
##STR00142##
[0502] Step 1: 3-(2-Bromo-acetyl)-4-methoxy-benzoic acid methyl
ester
[0503] 3-Acetyl-4-methoxy-benzoic acid methyl ester (T. Nagano et
al., J. Am. Chem. Soc. 75 (1953), 6237-6238) (1.25 g) was dissolved
in a mixture of acetic acid (7 ml) and hydrobromic acid (3 ml), the
solution was cooled in an ice bath, and bromine (0.961 g) added.
The mixture was allowed to slowly warm to room temperature and
react for 2 h. Then the mixture was evaporated to dryness in vacuo,
the residue was partitioned between EA and a saturated aqueous
sodium hydrogencarbonate solution, the aqueous phase extracted with
EA, and the combined organic extracts were dried over sodium
sulfate, filtered and evaporated to dryness. Upon stirring with a
mixture of EA and HEP, part of the title compound crystallized and
was filtered off. The filtrate was evaporated to dryness and the
residue purified by preparative RP HPLC (water/ACN gradient).
Altogether, 1.18 g of the title compound were obtained.
[0504] LC/MS (Method LC2): Rt=1.40 min; m/z=287.0/289.0
[MH.sup.+]
Step 2: 4-Methoxy-3-(2-m-tolyloxy-acetyl)-benzoic acid methyl
ester
[0505] The compound of step 1 (1.18 g, 4.12 mmol) and potassium
carbonate (1.72 g, 12.4 mmol) were suspended in DMF (10 ml),
m-cresol (450 mg, 4.12 mmol) was added, and the mixture was stirred
at room temperature for 2 h. The volatiles were evaporated in
vacuo, the residue was partitioned between EA and water, and the
aqueous phase extracted with EA. The combined organic extracts were
washed with a sodium chloride solution, dried over sodium sulfate,
filtered and evaporated to dryness. The residue was purified by
preparative RP HPLC (water/ACN gradient) to give 0.49 g of the
title compound.
[0506] .sup.1H-NMR: .delta.=8.28 (d, 1H); 8.18 (dd, 1H); 7.37 (d,
1H); 7.13 (dd, 1H); 6.74 (d, 1H); 6.72 (s, 1H); 6.67 (d, 1H); 5.30
(s, 2H); 4.03 (s, 3H); 3.85 (s, 3H); 2.26 (s, 3H)
Step 3:
2-[4-Methoxy-3-(2-m-tolyloxy-acetyl)-benzoylamino]-indane-2-carbox-
ylic acid
[0507] From the compound of step 2, the title compound was obtained
by hydrolysis of the ester group in analogy to example 2, reaction
of the obtained carboxylic acid with 2-amino-indane-2-carboxylic
acid methyl ester hydrochloride in analogy to step 1 of example 15,
and hydrolysis of the ester group in analogy to example 2.
[0508] .sup.1H-NMR: .delta.=12.4 (s, 1H); 8.88 (s, 1H); 8.22 (d,
1H); 8.10 (dd, 1H); 7.29 (d, 1H); 7.23-7.19 (m, 2H); 7.18-7.10 (m,
3H); 6.73 (d, 1H); 6.70 (s, 1H); 6.65 (d, 1H); 5.28 (s, 2H); 3.98
(s, 3H); 3.57 (d, 2H); 3.40 (d, 2H); 2.24 (s, 3H)
EXAMPLE 114
2-[3-(1-Hydroxy-2-m-tolyloxy-ethyl)-4-methoxy-benzoylamino]-indane-2-carbo-
xylic acid
##STR00143##
[0510] The compound of example 113 (113 mg, 0.246 mmol) was
dissolved in a mixture of methanol (2 ml) and ethanol (2 ml). With
cooling in an ice bath, sodium borohydride (28 mg, 0.738 mmol) was
added to the stirred solution, and the mixture was stirred in an
ice bath for 2 h. The volatiles were evaporated, the residue was
partitioned between diethyl ether and diluted hydrochloric acid,
the aqueous phase extracted with diethyl ether, the combined
organic extracts filtered over a small plug of silica gel, dried
with sodium sulfate, filtered and evaporated to dryness. The
residue was stirred with a mixture of EA and HEP and filtered to
give 112 mg of the title compound.
[0511] LC/MS (Method LC2): Rt=1.51 min; m/z=462.1 [MH.sup.+]
EXAMPLE 115
2-[4-Methoxy-3-(2-m-tolyloxy-ethyl)-benzoylamino]-indane-2-carboxylic
acid
##STR00144##
[0513] The compound of example 114 (20 mg, 0.043 mmol) was
dissolved in ethanol (2 ml), a 0.5 M solution of hydrogen chloride
in methanol (0.2 ml) was added and the mixture was hydrogenated
overnight in the presence of palladium on charcoal (10%) at room
temperature at a hydrogen pressure of 5 bar (complete conversion of
the starting compound). After filtration over a small plug of
silica gel and evaporation, the residue was purified by preparative
RP HPLC (water/ACN gradient).
[0514] LC/MS (Method LC2): Rt=1.69 min; m/z=446.0 [MH.sup.+]
EXAMPLE 116
2-[4-Methoxy-3-(3-m-tolyl-propyl)-benzoylamino]-indane-2-carboxylic
acid
##STR00145##
[0515] Step 1: 3-(1,3-Dihydroxy-3-m-tolyl-propyl)-4-methoxy-benzoic
acid methyl ester
[0516] 3-Acetyl-4-methoxy-benzoic acid methyl ester (150 mg, 0.720
mmol) was dissolved in THF (3 ml), cooled to -78.degree. C., and a
freshly prepared solution of lithium diisopropylamide (obtained by
addition of n-butyllithium in n-hexane (0.317 ml, 2.5 M solution)
to diisopropylamine (80.1 mg, 0.792 mmol) in THF (3 ml) at
0.degree. C. and stirring for 10 min) was slowly added with
stirring. After 10 min, 3-methylbenzaldehyde (86.5 mg, 0.720 mmol)
was added at -78.degree. C. After 30 min at -78.degree. C., 2 N
hydrochloric acid and EA were added, the cooling bath was removed,
the mixture was brought to room temperature. The phases were
separated, the aqueous phase was extracted three times with EA, the
combined organic extracts were dried over sodium chloride, decanted
and evaporated to dryness. The residue was dissolved in methanol (5
ml), sodium borohydride (28.7 mg, 0.761 mmol) was added, and the
mixture was stirred at room temperature for 30 min. The mixture was
evaporated to dryness and the residue was purified by silica gel
chromatography (HEP/EA gradient) to give 140 mg of the title
compound as a mixture of diastereomers.
[0517] LC/MS (Method LC1): Rt=1.32 min; m/z=353.1 [MNa.sup.+],
683.2 [2MNa.sup.+]
Step 2: 4-Methoxy-3-(3-m-tolyl-propyl)-benzoic acid methyl
ester
[0518] The compound of step 1 (140 mg, 0.424 mmol) was dissolved in
ethanol (10 ml) and 12 N hydrochloric acid (0.2 ml), palladium on
charcoal (10%) was added, and the mixture was hydrogenated at a
hydrogen pressure of 6 bar at room temperature overnight. After
filtration and evaporation, the residue was purified by silica gel
chromatography (HEP/EA gradient) to give 80 mg of the title
compound.
[0519] .sup.1H-NMR: .delta.=7.83 (dd, 1H); 7.72 (d, 1H); 7.16 (dd,
1H); 7.06 (d, 1H); 7.03-6.96 (m, 3H); 3.85 (s, 3H); 3.80 (s, 3H);
2.65-2.53 (m, 4H); 2.27 (s, 3H); 1.82 (m, 2H)
Step 3:
2-[4-Methoxy-3-(3-m-tolyl-propyl)-benzoylamino]-indane-2-carboxyli-
c acid
[0520] From the compound of step 2, the title compound was obtained
by hydrolysis of the ester group in analogy to example 2, reaction
of the obtained carboxylic acid with 2-amino-indane-2-carboxylic
acid methyl ester hydrochloride in analogy to step 1 of example 15,
and hydrolysis of the ester group in analogy to example 2.
[0521] .sup.1H-NMR: .delta.=12.3 (br s, 1H); 8.61 (s, 1H); 7.73
(dd, 1H); 7.66 (d, 1H); 7.25-7.20 (m, 2H); 7.19-7.12 (m, 3H); 3.81
(s, 3H); 3.57 (d, 2H); 3.38 (d, 2H); 2.61-2.52 (m, 4H); 2.26 (s,
3H); 1.86-1.78 (m, 2H)
EXAMPLE 117
2-(4-Methoxy-3-phenylacetylamino-benzoylamino)-indane-2-carboxylic
acid
##STR00146##
[0522] Step 1:
2-(4-Methoxy-3-nitro-benzoylamino)-indane-2-carboxylic acid methyl
ester
[0523] To 2-amino-indane-2-carboxylic acid methyl ester
hydrochloride (0.40 g, 1.77 mmol) and 4-methoxy-3-nitrobenzoic acid
(0.35 g, 1.77 mmol) in 4 ml of DMF were added NMM (0.59 ml, 5.32
mmol), HOBT (0.31 g, 2.31 mmol) and EDC (0.44 g, 2.31 mmol). The
mixture was stirred at 60.degree. C. until LC/MS analysis showed
complete conversion. The crude product was purified by silica gel
chromatography (HEP/EA gradient) to give 0.43 g of the title
compound.
Step 2: 2-(3-Amino-4-methoxy-benzoylamino)-indane-2-carboxylic acid
methyl ester
[0524] The compound of step 1 (0.43 g, 1.16 mmol) was dissolved in
methanol (30 ml), 10% palladium on charcoal (200 mg) was added, and
the flask flushed with argon. A balloon filled with hydrogen was
connected, and the mixture was stirred at room temperature
overnight. The balloon was removed, the flask flushed with argon,
the catalyst filtered off over Celite, and the filtrate was
evaporated in vacuo to give 0.38 g of the title compound.
Step 3:
2-(4-Methoxy-3-phenylacetylamino-benzoylamino)-indane-2-carboxylic
acid methyl ester
[0525] The compound of step 2 (0.042 g, 0.12 mmol) and phenylacetic
acid (0.013 g, 0.092 mmol) were dissolved in DCM (3 ml) and DMF (1
ml), NMM (0.031 ml, 0.28 mmol), HOBT (0.016 g, 0.12 mmol) and EDC
(0.021 g, 0.12 mmol) were added, and the mixture was stirred
overnight. LC/MS analysis showed complete conversion. The mixture
was filtered, the filtrate subjected to preparative RP HPLC
(water/ACN gradient), and the fractions containing the title
compound freeze-dried. Yield: 0.042 g.
Step 4:
2-(4-Methoxy-3-phenylacetylamino-benzoylamino)-indane-2-carboxylic
acid
[0526] The compound of step 3 (42 mg, 0.091 mmol) was dissolved in
methanol (3 ml) and water (1 ml), lithium hydroxide hydrate (5.3
mg, 0.12 mmol) was added, and the mixture was reacted at room
temperature overnight. LC/MS analysis showed complete conversion.
The mixture was filtered, the filtrate subjected to preparative RP
HPLC (water/ACN gradient), and the fractions containing the title
compound freeze-dried. Yield: 27 mg.
[0527] LC/MS (Method LC5): Rt=1.95 min; m/z=445.48 [MH.sup.+]
[0528] .sup.1H-NMR: .delta.=12.4 (br s, 1H); 9.39 (s, 1H); 8.67 (s,
1H); 8.31 (s, 1H); 7.62 (d, 1H); 7.38-7.30 (m, 4H); 7.28-7.20 (m,
3H); 7.18-7.12 (m, 2H); 7.08 (d, 1H); 3.87 (s, 3H); 3.72 (s, 2H);
3.55 (d, 2H); 3.35 (d, 2H)
[0529] In analogy to example 117, the example compounds of the
formula Ip listed in table 3 were prepared. The compounds can be
named as
2-[3-(R.sup.92-carbonyl-amino)-4-methoxy-benzoylamino)-indane-2-carboxyli-
c acid, for example as
2-[3-[3-fluoro-benzoylamino)-4-methoxy-benzoylamino)-indane-2-carboxylic
acid in the case of example 120.
##STR00147##
TABLE-US-00003 TABLE 3 Example compounds of the formula Ip m/z
Retention Example R.sup.92 LC/MS Method [MH.sup.+] time [min] 118
3-bromo-benzyl LC6 523.04 1.75 119 3-chloro-benzyl LC6 479.08 1.72
120 3-fluoro-phenyl LC6 449.12 1.66
EXAMPLE 121
2-[3-(4-Fluoro-benzylamino)-4-methoxy-benzoylamino]-indane-2-carboxylic
acid
##STR00148##
[0530] Step 1:
2-[3-(4-Fluoro-benzylamino)-4-methoxy-benzoylamino]-indane-2-carboxylic
acid methyl ester
[0531] The compound of example 117, step 2 (0.042 g, 0.12 mmol) and
4-fluorobenzaldehyde (0.0115 g, 0.092 mmol) were dissolved in THF
(3 ml) and acetic acid (0.5 ml). Resin-bound sodium
cyanoborohydride (0.2 mmol) was added, and the mixture was stirred
at room temperature until LC/MS analysis showed complete
conversion. The resin was filtered off, the filtrate was subjected
to preparative RP HPLC (water/ACN gradient), and the fractions
containing the title compound freeze-dried to give 33 mg of the
title compound.
Step 2:
2-[3-(4-Fluoro-benzylamino)-4-methoxy-benzoylamino]-indane-2-carbo-
xylic acid
[0532] The compound of step 1 (30 mg, 0.053 mmol) was dissolved in
methanol (3 ml) and water (1 ml). Lithium hydroxide hydrate (3.8
mg, 0.09 mmol) was added, and the mixture was stirred at room
temperature until LC/MS analysis showed complete conversion. The
mixture was filtered, the filtrate subjected to preparative RP HPLC
(water/ACN gradient), and the fractions containing the title
compound freeze-dried to give 19 mg of the title compound.
[0533] LC/MS (Method LC6): Rt=1.66 min; m/z=435.19 [MH.sup.+]
[0534] .sup.1H-NMR: .delta.=12.2 (br s, 1H); 8.45 (s, 1H);
7.38-7.32 (m, 2H); 7.22-7.20 (m, 2H); 7.20-7.14 (m, 3H); 7.14-7.09
(m, 2H); 6.92 (s, 1H); 6.81 (d, 1H); 4.32 (s, 2H); 3.80 (s, 3H);
3.72 (s, 2H); 3.53 (d, 2H); 3.32 (d, 2H)
[0535] In analogy to example 121, the example compounds of the
formula Ir listed in table 4 were prepared. The compounds can be
named as
2-[3-(R.sup.93-amino)-4-methoxy-benzoylamino]-indane-2-carboxylic
acid, for example as
2-[3-[2-phenyl-ethylamino)-4-methoxy-benzoylamino)-indane-2-carboxylic
acid in the case of example 122.
##STR00149##
TABLE-US-00004 TABLE 4 Example compounds of the formula Ir m/z
Retention Example R.sup.93 LC/MS Method [MH.sup.+] time [min] 122
2-phenyl-ethyl LC6 431.13 1.61 123 3-chloro-benzyl LC6 451.07 1.79
124 2-phenyl-propyl LC6 445.13 1.76
EXAMPLE 125
General Procedure for Solid Phase Synthesis
[0536] 0.5 g of Polystyrene AM RAM resin with FMOC-protected linker
(0.5 mmol/g or 0.75 mmol/g, respectively; Rapp Polymere GmbH,
Tubingen, Germany) were treated with a 50% solution of piperidine
in DMF for 20 min and washed extensively with DMF. The respective
FMOC-protected 2-amino-indane-2-carboxylic acid (5 equivalents),
HOBT (5 equivalents) and DIC (5 equivalents) were dissolved in DMF
(5 ml) and added to the resin. The mixture was shaken overnight at
room temperature. The resin was repeatedly washed with DMF and the
FMOC protecting group was removed by treatment of the resin with a
50% solution of piperidine in DMF for 20 min. The resin was
repeatedly washed with DMF.
[0537] For acylation of the amino group, a solution of the
respective hydroxy-substituted benzoic acid (5 equivalents), HOBT
(5 equivalents) and DIC (5 equivalents) in DMF (5 ml) was added to
the resin and the mixture was shaken overnight at room temperature.
The resin was washed with DMF and treated with a 2 N solution of
dimethylamine in THF overnight, or in some cases with a 50%
solution of piperidine in DMF for 2 h, for hydrolyzing the ester
formed by acylation of the hydroxy group. The resin was washed
extensively with DMF, DCM and THF.
[0538] For the Mitsunobu reaction on the hydroxy group,
triphenylphosphine (10 equivalents) and the respective alcohol (10
equivalents) were dissolved in 5 ml of dry THF and added to the
resin. The slurry was cooled to 0.degree. C. and DIAD (10
equivalents) was added to the cooled mixture which was allowed to
react overnight at room temperature. The resin was washed
repeatedly with DCM.
[0539] For cleavage of the obtained compound, the resin was treated
with neat TFA for 2 h. TFA was removed in vacuo, and the residue
was purified by preparative RP HPLC (water/ACN gradient). In most
cases the carboxylic acid was isolated after the TFA cleavage. In
some cases the carboxylic acid amide was isolated which was
converted into the carboxylic acid by hydrolysis in 50% aqueous TFA
at 60.degree. C. overnight, partial removal of the TFA in vacuo and
lyophilization of the aqueous solution.
[0540] According to the general procedure described in example 125,
the compounds of the formula Is listed in table 5 were synthesized.
In the formulae of the groups R.sup.95 in table 5 the line crossed
with the symbol represents the free bond via which the group
R.sup.95 is bonded to the oxygen atom which is attached to the
3-position of the benzoyl group depicted in formula Is. I.e., in
the formula of the complete molecule the terminal endpoint of the
line crossed with the said symbol ends at the oxygen atom attached
to the 3-position of the benzoyl group. The compounds can be named
as 2-[3-(R.sup.95-oxy)-4-R.sup.94-benzoylamino]-indane-2-carboxylic
acid, for example as
2-{4-methoxy-3-[2-(3-trifluoromethyl-phenyl)-ethoxy]-benzoylamino}-indane-
-2-carboxylic acid in the case of example 127.
##STR00150##
TABLE-US-00005 TABLE 5 Example compounds of the formula Is Example
R.sup.94-- ##STR00151## LC/MS Method m/z [MH.sup.+] Retention time
[min] 126 CH.sub.3O-- ##STR00152## LC9 432.2 4.32 127 CH.sub.3O--
##STR00153## LC8 500.2 4.39 128 Cl-- ##STR00154## LC8 504.1/ 506.1
4.80 129 CH.sub.3-- ##STR00155## LC9 430.2 5.14 130 CH.sub.3O--
##STR00156## LC9 432.2 4.51 131 CH.sub.3O-- ##STR00157## LC9 450.2
4.58 132 CH.sub.3O-- ##STR00158## LC9 466.1/ 468.1 4.74 133
CH.sub.3O-- ##STR00159## LC9 462.2 4.48 134 CH.sub.3O--
##STR00160## LC9 446.2 4.65 135 CH.sub.3O-- ##STR00161## LC9 446.2
4.69 136 CH.sub.3O-- ##STR00162## LC9 450.2 4.55 137 CH.sub.3O--
##STR00163## LC9 462.2 4.48 138 CH.sub.3O-- ##STR00164## LC9 462.2
4.57 139 CH.sub.3O-- ##STR00165## LC9 450.2 4.55 140 CH.sub.3O--
##STR00166## LC9 460.2 4.91 141 H-- ##STR00167## LC7 416.2 4.50 142
CH.sub.3O-- ##STR00168## LC7 446.2 4.56 143 CH.sub.3O--
##STR00169## LC7 510.1/ 512.1 5.28 144 CH.sub.3O-- ##STR00170## LC7
446.2 5.14 145 F-- ##STR00171## LC7 434.2 4.89 146 CH.sub.3O--
##STR00172## LC7 438.1 4.35 147 CH.sub.3O-- ##STR00173## LC7 438.1
4.34 148 CH.sub.3O-- ##STR00174## LC7 433.2 2.56 149 CH.sub.3O--
##STR00175## LC7 466.1/ 468.1 4.64 150 CH.sub.3O-- ##STR00176## LC7
424.2 4.72 151 CH.sub.3O-- ##STR00177## LC7 446.2 4.58 152
CH.sub.3O-- ##STR00178## LC9 484.1/ 486.1 4.71 153 CH.sub.3O--
##STR00179## LC9 484.1/ 486.1 4.77 154 CH.sub.3O-- ##STR00180## LC9
518.2 4.86 155 CH.sub.3O-- ##STR00181## LC9 518.2 8.87
EXAMPLE 156
5-Bromo-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxyli-
c acid
##STR00182##
[0542] The title compound was prepared according to the general
procedure described in example 125.
[0543] LC/MS (Method LC7): Rt=5.06 min; m/z=524.1/526.1
[MH.sup.+]
EXAMPLE 157
5-Fluoro-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxyl-
ic acid
##STR00183##
[0545] The title compound was prepared according to the general
procedure described in example 125.
[0546] LC/MS (Method LC7): Rt=4.74 min; m/z=464.2 [MH.sup.+]
EXAMPLE 158
[0547]
2-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-5,6-dimethyl-indane-
-2-carboxylic acid
##STR00184##
[0548] The title compound was prepared according to the general
procedure described in example 125.
[0549] LC/MS (Method LC7): Rt=5.03 min; m/z=474.2 [MH.sup.+]
EXAMPLE 159
5-Methoxy-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxy-
lic acid
##STR00185##
[0551] The title compound was prepared according to the general
procedure described in example 125.
[0552] LC/MS (Method LC7): Rt=4.60 min; m/z=476.2 [MH.sup.+]
EXAMPLE 160
2-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid amide
##STR00186##
[0554] The compound of example 14 (100 mg, 0.224 mmol) was added to
thionyl chloride (0.5 ml) and stirred for 30 min at 60.degree. C.
The volatiles were evaporated, dioxane (1 ml) was added and the
mixture was evaporated to dryness again. The obtained raw acid
chloride was dissolved in DCM and added to a stirred mixture of EA,
a saturated sodium hydrogencarbonate solution and ammonia (30% in
water, 0.015 ml). After stirring at room temperature for 90 min,
the layers were separated and the aqueous layer was extracted with
EA. The combined organic extracts were dried over sodium sulfate
and evaporated to dryness. The residue was purified by preparative
RP HPLC (water/ACN gradient).
[0555] LC/MS (Method LC1): Rt=1.55 min; m/z=445.1 [MH.sup.+]
EXAMPLE 161
2-{4-[2-(3-Chloro-phenyl)-ethoxy]-3-methoxy-benzoylamino}-indane-2-carboxy-
lic acid
##STR00187##
[0557] The title compound was prepared according to the general
procedure described in example 125.
[0558] LC/MS (Method LC7): Rt=4.70 min; m/z=466.1/468.1
[MH.sup.+]
EXAMPLE 162
2-{4-[2-(2-Chloro-phenyl)-ethoxy]-3-methoxy-benzoylamino}-indane-2-carboxy-
lic acid
##STR00188##
[0560] The title compound was prepared according to the general
procedure described in example 125.
[0561] LC/MS (Method LC7): Rt=4.69 min; m/z=466.1/468.1
[MH.sup.+]
EXAMPLE 163
2-[4-Amino-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid
##STR00189##
[0563] The title compound was prepared according to the general
procedure described in example 125 using 0.1 g of resin (0.5
mmol/g). In the acylation step, 3-hydroxy-4-nitro-benzoic acid was
employed. In the final step the nitro group was reduced with a 1 M
solution of tin(II) chloride dihydrate in DMF overnight at room
temperature. The resin was washed extensively with DMF, methanol,
and DCM, and the product was cleaved from the resin by treatment
with TFA for 2 h. TFA was removed in vacuo, and the residue was
purified by preparative RP HPLC (water/ACN gradient). Yield: 12.4
mg.
[0564] LC/MS (Method LC9): Rt=4.33 min; m/z=431.2 [MH.sup.+]
[0565] .sup.1H-NMR (300 MHz, D.sub.6-DMSO+2% TFA): .delta.=2.29 (s,
3H); 3.06 (t, J=6.97 Hz, 2H); 3.30-3.43 (m, 2H); 3.54-3.65 (m, 2H);
4.28 (t, J=7.06 Hz, 2H); 7.04 (d, J=7.35 Hz, 1H); 7.09-7.26 (m,
8H); 7.43-7.54 (m, 2H); 8.71 (s, 1H)
EXAMPLE 164
2-[4-Methylamino-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid
##STR00190##
[0567] The title compound was prepared in analogy to example 163
using 0.12 g of resin (0.5 mmol/g). After reduction of the nitro
group, the amino group was methylated using a 37% aqueous
formaldehyde solution (10 equivalents) and sodium cyanoborohydride
(8 equivalents, 1 M solution in THF) in a mixture of DCM and ACN
(3:1) containing 2% of acetic acid. The mixture was shaken
overnight, then the resin was washed and the procedure was repeated
with fresh reagents. For cleavage, the resin was treated with TFA
for 2 h, TFA was removed in vacuo and the residue was dissolved in
50% aqueous TFA. The solution was heated to 50.degree. C. for 48 h,
TFA was partially removed in vacuo and the aqueous solution was
lyophilized. The residue was purified by preparative RP HPLC
(water/ACN gradient). Yield: 9.8 mg.
[0568] LC/MS (Method LC7): Rt=4.41 min; m/z=445.2 [MH.sup.+]
[0569] .sup.1H-NMR (300 MHz, D.sub.6-DMSO+2% TFA): .delta.=2.28 (s,
3H); 2.75 (s, 3H); 3.04 (t, J=6.78 Hz, 2H); 3.30-3.41 (m, 2H);
3.52-3.63 (m, 2H); 4.21 (t, J=6.88 Hz, 2H); 6.61-6.71 (m, 1H); 7.03
(d, J=7.16 Hz, 1H); 7.10-7.25 (m, 7H); 7.37 (d, J=1.70 Hz, 1H);
7.47 (dd, J=8.19/1.79 Hz, 1H); 8.49 (br s, 1H)
EXAMPLE 165
2-[4-Dimethylamino-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid
##STR00191##
[0571] The title compound was prepared in analogy to example 164
using 0.12 g of resin (0.5 mmol/g) and repeating the methylation
procedure three more times with fresh reagents for complete
conversion of intermediary methylamino compound into the
dimethylamino compound. Yield: 6.6 mg.
[0572] LC/MS (Method LC7): Rt=3.37 min; m/z=459.2 [MH.sup.+]
[0573] .sup.1H-NMR (300 MHz, D.sub.6-DMSO+2% TFA): .delta.=2.28 (s,
3H); 3.04 (s, 6H); 3.12 (t, J=6.50 Hz, 2H); 3.33-3.44 (m, 2H); 3.62
(d, J=16.77 Hz, 2H); 4.43 (t, J=6.69 Hz, 2H); 7.04 (d, J=6.97 Hz,
1H); 7.11-7.27 (m, 7H); 7.55-7.71 (m, 3H); 8.93 (s, 1H)
EXAMPLE 166
2-[4-Isopropylamino-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid
##STR00192##
[0575] The title compound was prepared in analogy to example 163
using 0.25 g of resin (0.5 mmol/g). After reduction of the nitro
group, the amino group was alkylated using 2-methoxypropene (10
equivalents) in 2 ml of a mixture of DCM and ACN (3:1) containing
2% of acetic acid and 1 ml of a 1 M solution of sodium
cyanoborohydride in THF. The alkylation was repeated three times
with fresh reagents. Cleavage and work-up were performed in analogy
to example 164. Yield: 13.4 mg.
[0576] LC/MS (Method LC7): Rt=4.19 min; m/z=473.2 [MH.sup.+]
EXAMPLE 167
2-{3-[2-(2-Fluoro-phenyl)-2-hydroxy-ethoxy]-4-methoxy-benzoylamino}-indane-
-2-carboxylic acid
##STR00193##
[0578] The title compound was prepared according to the general
procedure described in example 125 using 0.25 g of resin (0.5
mmol/g). Attachment of the 2-amino-indane-2-carboxylic acid moiety
to the resin was followed by acylation with
3-hydroxy-4-methoxy-benzoic acid and treatment with 50% piperidine
in DMF for 2 h. After extensive washing with DMF and DCM the resin
was reacted with 2-bromo-1-(2-fluoro-phenyl)-ethanone (3
equivalents) in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU; 3 equivalents) in 3 ml of DCM overnight at room temperature.
The compound was cleaved from the resin with neat TFA for 2 h, and
TFA was evaporated in vacuo. The crude intermediate product was
dissolved in 4 ml of THF, 10 mg of lithium borohydride were added
and the reaction mixture was shaken for 3 h. Then the reaction
mixture was quenched with acetic acid, evaporated to dryness, and
the residue was purified by preparative RP HPLC (water/ACN
gradient). Yield: 3.7 mg.
[0579] LC/MS (Method LC7): Rt=4.01 min; m/z=466.2 [MH.sup.+]
EXAMPLE 168
2-[4-Cyano-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid
##STR00194##
[0581] The title compound was prepared according to the general
procedure described in example 125 using 0.3 g of resin (0.75
mmol/g). 3-Hydroxy-4-iodo-benzoic acid was used in the acylation
step. Finally, the resin with the iodo compound was treated with
zinc cyanide and tetrakis(triphenylphosphine)palladium(0) in 5 ml
of DMF/EDIA (2:1) in a microwave reactor (90 W) at 150.degree. C.
for 10 min. The resin was decanted with DCM, then extensively
washed with DMF and DCM, and the product was cleaved with neat TFA
for 2 h. TFA was removed in vacuo, and the residue was dissolved in
50% aqueous TFA and heated at 50.degree. C. overnight. The TFA was
partially evaporated and the aqueous solution was lyophilized. The
compound was purified by preparative RP HPLC (water/ACN gradient).
Yield: 11.4 mg.
[0582] LC/MS (Method LC7): Rt=4.78 min; m/z=441.2 [MH.sup.+]
[0583] .sup.1H-NMR (300 MHz, D.sub.6-DMSO+2% TFA): .delta.=2.28 (s,
3H); 3.05 (t, J=6.69 Hz, 2H); 3.33-3.43 (m, 2H); 3.55-3.65 (m, 2H);
4.36 (t, J=6.59 Hz, 2H); 7.03 (d, J=7.16 Hz, 1H); 7.09-7.26 (m,
7H); 7.49-7.58 (m, 2H); 7.80 (d, J=7.91 Hz, 1H); 9.04 (s, 1H)
EXAMPLE 169
2-[4-Methoxy-3-(3-phenyl-propyl)-benzoylamino]-indane-2-carboxylic
acid
##STR00195##
[0585] The title compound was prepared according to the general
procedure described in example 125 using 0.3 g of resin (0.75
mmol/g). 3-Iodo-4-methoxy-benzoic acid was used as the acylation
agent in place of the hydroxy-substituted benzoic acid. Finally,
the resin with the iodo compound was reacted under Sonogashira
conditions with 3-phenyl-1-propyne (10 equivalents) dissolved in 4
ml of DMF together with triethylamine (20 equivalents), copper(I)
iodide (0.1 equivalents) and bis(triphenylphosphine)palladium(II)
chloride (0.1 equivalents). The reaction mixture was shaken at room
temperature for 48 h. The resin was washed with DMF, DCM and the
intermediate product was cleaved with neat TFA for 2 h. TFA was
removed in vacuo, and residue was dissolved in water/ACN (3:2) and
lyophilized. The isolated intermediate product was dissolved in 6
ml of methanol, 100 mg of 10% palladium on charcoal were added, and
the mixture was hydrogenated in a Parr reactor at about 3.5 bar for
2 h. After filtration, methanol was evaporated and the residue was
purified by preparative RP HPLC (water/ACN gradient). Yield: 13.7
mg.
[0586] LC/MS (Method LC7): Rt=4.97 min; m/z=430.2 [MH.sup.+]
[0587] .sup.1H-NMR (300 MHz, D.sub.6-DMSO+2% TFA): .delta.=1.83
(dq, J=7.91, 7.66 Hz, 2H); 2.59 (q, J=7.72 Hz, 4H); 3.31-3.45 (m,
2H); 3.52-3.63 (m, 2H); 3.81 (s, 3H); 6.98 (d, J=8.67 Hz, 1H);
7.08-7.32 (m, 10H); 7.66 (d, J=2.26 Hz, 1H); 7.74 (dd, J=8.48/2.26
Hz, 1H); 8.62 (s, 1H)
EXAMPLE 170
2-[4-Acetyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid
##STR00196##
[0589] The title compound was prepared according to the general
procedure described in example 125 using 0.3 g of resin (0.75
mmol/g). 3-Hydroxy-4-iodo-benzoic acid was used in the acylation
step. Finally, the resin with the iodo compound was reacted with
trimethylsilylacetylene (10 equivalents) dissolved in 4 ml of DMF
together with triethylamine (20 equivalents), copper(I) iodide (0.1
equivalents) and bis(triphenylphosphine)palladium(II) chloride (0.1
equivalents) overnight at room temperature. The resin was washed
with DMF and THF and treated with a 1 M solution of
tetrabutylammonium fluoride in THF for 30 min. After extensive
washing with DCM, 10% acetic acid in DCM and DCM the compound was
cleaved from the resin with neat TFA for 2 h. The carboxylic acid
amide was converted into the carboxylic acid as described in the
general procedure in example 125 and the title compound purified by
preparative RP HPLC (water/ACN gradient). Yield: 5.8 mg.
[0590] LC/MS (Method LC7): Rt=4.77 min; m/z=458.2 [MH.sup.+]
EXAMPLE 171
2-[4-Methoxy-3-(2-m-tolyl-ethylamino)-benzoylamino]-indane-2-carboxylic
acid
##STR00197##
[0592] The title compound was prepared according to the general
procedure described in example 125 using 0.5 g of resin (0.75
mmol/g). 4-Methoxy-3-nitro-benzoic acid in place of the
hydroxy-substituted benzoic acid was used in the acylation step,
and the nitro group was subsequently reduced with a 1 M solution of
tin(II) chloride dihydrate in DMF overnight. The resin was washed
with DMF, DCM and reacted with 2,4-dinitro-benzenesulfonyl chloride
(5 equivalents) and 2,6-lutidine (10 equivalents) dissolved in 5 ml
of DCM for 5 h. After washing with DCM and THF, a solution of
triphenylphosphine (10 equivalents) and 2-(3-methylphenyl)-ethanol
(10 equivalents) in THF was added to the resin and the slurry was
cooled to 0.degree. C. DIAD was added to the cooled mixture and the
reaction mixture was shaken overnight at room temperature. The
resin was washed with DCM and treated with mercaptoacetic acid (5
equivalents) and triethylamine (10 equivalents) in DCM for 10 min.
The step was repeated with a fresh solution. The resin was washed
with DMF and DCM. The compound was cleaved from the resin with neat
TFA for 2 h, the carboxylic acid amide was converted into the
carboxylic acid as described in the general procedure in example
125 and the title compound purified by preparative RP HPLC
(water/ACN gradient). Yield: 36.4 mg.
[0593] LC/MS (Method LC7): Rt=3.80 min; m/z=445.2 [MH.sup.+]
[0594] .sup.1H-NMR (300 MHz, D.sub.6-DMSO+2% TFA): .delta.=2.27 (s,
3H); 2.83-2.92 (m, 2H); 3.33-3.48 (m, 4H); 3.53-3.64 (m, 2H); 3.90
(s, 3H); 6.99-7.25 (m, 10H); 7.56 (s, 1H); 7.63 (s, 1H); 8.72 (s,
1H)
EXAMPLE 172
2-{4-Methoxy-3-[methyl-(2-m-tolyl-ethyl)-amino]-benzoylamino}-indane-2-car-
boxylic acid
##STR00198##
[0596] First, the synthesis was carried out as described in example
171 using 0.25 g of resin (0.75 mmol/g). Subsequently, for the
N-methylation, the resin was treated with a 37% aqueous solution of
formaldehyde (10 equivalents) in DCM/ACN (3:1) containing 2% of
acetic acid and 1.5 ml of a 1 M sodium cyanoborohydride solution in
THF overnight. The methylation reaction was repeated three times
with fresh reagents. The cleavage, isolation and purification of
the compound were performed as described in example 171. Yield:
21.4 mg.
[0597] LC/MS (Method LC7): Rt=3.19 min; m/z=459.2 [MH.sup.+]
[0598] .sup.1H-NMR (300 MHz, D.sub.6-DMSO+2% TFA): .delta.=2.22 (s,
3H); 2.72 (t, J=7.82 Hz, 2H); 3.23 (s, 3H); 3.34-3.45 (m, 2H); 3.63
(d, J=16.95 Hz, 2H); 3.78 (t, J=8.67 Hz, 2H); 3.99 (s, 3H);
6.89-6.96 (m, 2H); 7.00 (d, J=7.91 Hz, 1H); 7.10-7.29 (m, 6H); 7.33
(d, J=8.85 Hz, 1H); 8.04 (dd, J=8.67/1.70 Hz, 1H); 8.16 (s, 1H);
8.84 (s, 1H)
EXAMPLE 173
2-[4-Cyano-3-(2-m-tolyl-ethylamino)-benzoylamino]-indane-2-carboxylic
acid
##STR00199##
[0600] 0.1 g of PL Wang resin (Polymer Laboratories, Amherst,
Mass., USA; 1.7 mmol/g) was acylated with FMOC-protected
2-amino-indane-2-carboxylic acid (3 equivalents) in the presence of
DIC (3 equivalents), HOBT (3 equivalents) and 1-methylimidazole in
DMF overnight. The FMOC protecting group was removed by treatment
with 50% piperidine in DMF, and the obtained amino acid was
acylated with 4-cyano-3-fluorobenzoic acid (3 equivalents) in the
presence of DIC (3 equivalents) and HOBT (3 equivalents) in DMF.
The resin was treated with a 1 M solution of
2-(3-methyl-phenyl)-ethylamine in DMF overnight at room
temperature. The reaction was repeated with fresh amine solution.
The resin was washed with DMF and DCM and the compound was cleaved
from the resin with neat TFA for 1.5 h. TFA was removed in vacuo
and the compound was purified by preparative RP HPLC (water/ACN
gradient). Yield: 9.7 mg.
[0601] LC/MS (Method LC7): Rt=4.66 min; m/z=440.2 [MH.sup.+]
[0602] .sup.1H-NMR (300 MHz, D.sub.6-DMSO+2% TFA): .delta.=2.27 (s,
3H); 2.83 (t, J=7.44 Hz, 2H); 3.33-3.47 (m, 4H); 3.54-3.65 (m, 2H);
6.98-7.11 (m, 4H); 7.11-7.26 (m, 7H); 7.54 (d, J=8.10 Hz, 1H); 8.95
(s, 1H)
EXAMPLE 174
2-[4-Cyano-3-[3-phenyl-pyrrolidin-1-yl)-benzoylamino]-indane-2-carboxylic
acid
##STR00200##
[0604] The synthesis was carried out as described in example 174
using 0.15 g of PL Wang resin (1.7 mmol/g). Instead of with
2-(3-methyl-phenyl)-ethylamine, in the last step the resin was
reacted with 3-phenyl-pyrrolidine (8 equivalents) in
dimethylacetamide at 90.degree. C. overnight. The compound was
cleaved, isolated and purified as described in example 173.
[0605] Yield: 11.3 mg.
[0606] LC/MS (Method LC7): Rt=4.82 min; m/z=452.2 [MH.sup.+]
EXAMPLE 175
2-{4-Cyano-3-[2-(2-fluoro-phenyl)-ethylamino]-benzoylamino}-indane-2-carbo-
xylic acid
##STR00201##
[0608] The synthesis was carried out as described in example 173
using 0.1 g of PL Wang resin (1.7 mmol/g). Instead of with
2-(3-methyl-phenyl)-ethylamine, in the last step the resin was
reacted with 2-(2-fluorophenyl)-ethylamine (10 equivalents) in
dimethylacetamide in a microwave reactor at 150.degree. C. for 1 h.
The compound was cleaved, isolated and purified as described in
example 173.
[0609] Yield: 1.7 mg.
[0610] LC/MS (Method LC7): Rt=4.51 min; m/z=444.2 [MH.sup.+]
EXAMPLE 176
2-{3-[2-(3-Chloro-phenyl)-ethoxy]-4-methyl-benzoylamino}-indane-2-carboxyl-
ic acid
##STR00202##
[0612] The synthesis was carried out on 0.15 g of PL Wang resin
(1.7 mmol/g). The attachment of 2-amino-indane-2-carboxylic acid
and the acylation with 3-hydroxy-4-methylbenzoic acid were
performed as in described in example 173. After the acylation step,
the resin was washed with THF and a solution of triphenylphosphine
(10 equivalents) and 2-(3-chlorophenyl)-ethanol (10 equivalents) in
THF was added to the resin. The slurry was cooled to 0.degree. C.,
DIAD (10 equivalents) was added to the cooled mixture, and the
reaction mixture was shaken overnight at room temperature. The
resin was washed with DCM. The compound was cleaved, isolated and
purified as in described in example 173. Yield: 2.3 mg.
[0613] LC/MS (Method LC7): Rt=5.11 min; m/z=450.2 [MH.sup.+]
EXAMPLE 177
2-{3-[2-(2-Fluoro-phenyl)-ethoxy]-4-methyl-benzoylamino}-indane-2-carboxyl-
ic acid
##STR00203##
[0615] The title compound was prepared as described in example 176.
Yield: 3.8 mg.
[0616] LC/MS (Method LC7): Rt=4.87 min; m/z=434.2 [MH.sup.+]
EXAMPLE 178
2-[4-Ethoxy-3-(2-m-tolyl-ethylamino)-benzoylamino]-indane-2-carboxylic
acid
##STR00204##
[0618] The synthesis was carried out on 0.15 g of PL Wang resin
(1.7 mmol/g). The attachment of 2-amino-indane-2-carboxylic acid
and the acylation step using 4-fluoro-3-nitro-benzoic acid were
performed as described in example 173. After the acylation step,
the resin was shaken with ethanol (5 equivalents) in the presence
of sodium bis(trimethylsilyl)amide (5 equivalents) in 3 ml of
dimethylacetamide. The resin was washed with DMF, 10% acetic
acid/DMF, DMF and finally with DCM. The reduction of the nitro
group with tin(II) chloride, sulfonylation with
2,4-dinitro-benzenesulfonyl chloride, alkylation with
2-(3-methylphenyl)-ethanol and removal of the sulfonyl group were
performed as described in example 171 and the compound purified by
preparative RP HPLC (water/ACN gradient). Yield: 2.4 mg.
[0619] LC/MS (Method LC7): Rt=3.73 min; m/z=459.2 [MH.sup.+]
EXAMPLE 179
2-[4-Hydroxy-3-(2-m-tolyl-ethylamino)-benzoylamino]-indane-2-carboxylic
acid
##STR00205##
[0621] 10 mg of the compound of example 171 were dissolved in DCM
and treated with 200 .mu.l of a 1 M solution of boron tribromide in
DCM for 5 h. A 2 M solution of sodium carbonate was added, and the
mixture was evaporated in vacuo. The product was purified by
preparative RP HPLC (water/ACN gradient).
[0622] LC/MS (Method LC7): Rt=3.34; m/z=431.2 [MH.sup.+]
[0623] .sup.1H-NMR (300 MHz, D.sub.6-DMSO+2% TFA): .delta.=2.21 (s,
3H); 2.81-2.92 (m, 2H); 3.24-3.37 (m, 2H); 3.37-3.48 (m, 2H);
3.48-3.60 (m, 2H); 6.88-7.04 (m, 5H); 7.04-7.21 (m, 6H); 7.66-7.79
(m, 2H); 8.66 (s, 1H)
EXAMPLE 180
2-[4-Methoxy-3-(2-m-tolyl-ethylsulfanyl)-benzoylamino]-indane-2-carboxylic
acid
##STR00206##
[0624] Step 1:
3-(5-Carboxy-2-methoxy-phenyldisulfanyl)-4-methoxy-benzoic acid
[0625] 45 g (179.5 mmol) of 3-chlorosulfonyl-4-methoxy-benzoic acid
were suspended in 200 ml of acetic acid and warmed to 40.degree. C.
Then a solution of 85.1 g (448.8 mmol) tin(II) chloride in 100 ml
of hydrochloric acid was added within 15 min and the mixture was
stirred for 2 h under reflux. The hot solution was added dropwise
to 2000 ml of ice/water. The formed precipitate was collected by
suction, washed with water and dried. 32.8 g of the title compound
were obtained.
Step 2: 4-Methoxy-3-(2-m-tolyl-ethylsulfanyl)-benzoic acid
[0626] 732.8 mg (2 mmol) of the compound of step 1 were dissolved
in 30 ml of absolute methanol and 151.3 mg (4 mmol) of sodium
borohydride were added slowly in portions. After stirring
overnight, a solution of 796.4 mg (4 mmol) of
1-(2-bromo-ethyl)-3-methyl-benzene in 10 ml of DCM was added and
the mixture was stirred overnight. Then 202.4 mg (4 mmol) of
triethylamine were added and stirring was continued for 2 h at room
temperature and for 2 h at 40.degree. C. After cooling, the mixture
was extracted with a sodium hydrogencarbonate solution and the
organic phase was dried and evaporated. The residue was used in the
subsequent step without further purification.
Step 3:
2-[4-Methoxy-3-(2-m-tolyl-ethylsulfanyl)-benzoylamino]-indane-2-ca-
rboxylic acid
[0627] 700 mg of the crude compound of step 2 were dissolved in 5
ml of DMF and 598 mg (4.63 mmol) of EDIA and 968 mg (2.55 mmol) of
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate were added. Then a solution of 527 mg (2.32
mmol) of 2-amino-indane-2-carboxylic acid methyl ester
hydrochloride in 5 ml of DMF was added. After stirring overnight,
EA and an aqueous solution of lithium chloride (4%) were added, the
organic phase was separated, washed once with a solution of lithium
chloride and twice with a solution of sodium hydrogencarbonate,
dried and evaporated. The solid residue was dissolved in 10 ml of a
9:1 mixture of THF and water, and 131 mg (5.47 mmol) of lithium
hydroxide were added. After stirring overnight, the mixture was
evaporated to dryness. The residue was purified by preparative RP
HPLC (water/ACN gradient) to give 222 mg of the title compound.
[0628] LC/MS (Method LC3): Rt=1.97 min; m/z=462.23 [MH.sup.+]
[0629] .sup.1H-NMR: .delta.=12.45 (br s, 1H); 8.87 (s, 1H); 7.78
(s, 1H); 7.74 (d, 1H); 7.20-7.26 (m, 2H); 7.13-7.20 (m, 3H); 7.09
(s, 1H); 6.98-7.08 (m, 3H); 3.87 (s, 3H); 3.60 (d, 2H); 3.18 (d,
2H); 2.82 (t, 2H); 2.29 (s, 3H)
EXAMPLE 181
2-{3-[2-(3-Chloro-phenyl)-ethylsulfanyl]-4-methoxy-benzoylamino}-indane-2--
carboxylic acid
##STR00207##
[0631] The title compound was obtained in analogy to example 180 by
using 1-(2-bromo-ethyl)-3-chloro-benzene instead of
1-(2-bromo-ethyl)-3-methyl-benzene in step 2.
[0632] LC/MS (Method LC3): Rt=1.97 min; m/z=482.19 [MH.sup.+]
EXAMPLE 182
2-(3-Benzylsulfanyl-4-methoxy-benzoylamino)-indane-2-carboxylic
acid
##STR00208##
[0634] The title compound was obtained in analogy to example 180 by
using benzyl bromide instead of 1-(2-bromo-ethyl)-3-methyl-benzene
in step 2.
[0635] LC/MS (Method LC3): Rt=1.80 min; m/z=434.26 [MH.sup.+]
EXAMPLE 183
2-[4-Methoxy-3-(2-m-tolyl-ethanesulfonyl)-benzoylamino]-indane-2-carboxyli-
c acid
##STR00209##
[0637] 55 mg (119.2 mmol) of the compound of example 180 were
dissolved in 5 ml of DCM and treated with a solution of 88.2 mg
(357.6 mmol) of 3-chloroperbenzoic acid in 5 ml of DCM. After
stirring at room temperature overnight, the solvent was evaporated
and the residue was purified by preparative RP HPLC (water/ACN
gradient) to give 28 mg of the title compound.
[0638] LC/MS (Method LC3): Rt=1.68 min; m/z=494.25 [MH.sup.+]
[0639] .sup.1H-NMR: .delta.=12.45 (br s, 1H); 9.00 (s, 1H); 8.30
(s, 1H); 7.21-7.28 (m, 3H); 7.13-7.20 (m, 2H); 7.08 (t, 1H);
6.90-6.95 (m, 2H); 6.88 (s, 1H); 3.94 (s, 3H); 3.70 (t, 2H); 3.60
(d, 2H); 3.42 (d, 2H); 2.82 (t, 2H); 2.18 (s, 3H)
EXAMPLE 184
2-{3-[2-(3-Chloro-phenyl)-ethanesulfonyl]-4-methoxy-benzoylamino}-indane-2-
-carboxylic acid
##STR00210##
[0641] The title compound was obtained in analogy to example 183,
starting from the compound of example 181.
[0642] LC/MS (Method LC3): Rt=1.69 min; m/z=514.20 [MH.sup.+]
EXAMPLE 185
2-[3-(2-m-Tolyl-ethoxy)-4-trifluoromethyl-benzoylamino]-indane-2-carboxyli-
c acid
##STR00211##
[0643] Step 1: 3-Acetoxy-4-trifluoromethyl-benzoic acid
[0644] 3.5 g (17 mmol) of 3-hydroxy-4-trifluoromethyl-benzoic acid
(prepared as described in WO 2006/128184) were dissolved in 35 ml
of acetic acid anhydride and heated to reflux for 3 h. 60 ml of
water were added and heating to reflux was continued for 10 min.
After cooling and stirring overnight, the formed precipitate was
collected by suction and dried to give 3.0 g of the title
compound.
Step 2:
2-(3-Acetoxy-4-trifluoromethyl-benzoylamino)-indane-2-carboxylic
acid methyl ester
[0645] To a solution of 2.7 g (10.9 mmol) of the compound of step 1
in 16.3 ml of a 2 M solution of oxalyl chloride in DCM (32.6 mmol),
80 mg of DMF were added and the mixture was stirred for 30 min at
room temperature. The solvent was evaporated, 20 ml of DCM were
added and the mixture was evaporated again. The residue was
dissolved in 20 ml of DCM and the solution added within 5 min at
0.degree. C. to a solution of 2.48 g (10.9 mmol) of
2-amino-indane-2-carboxylic acid methyl ester hydrochloride in 50
ml of DCM and 30 ml of a saturated sodium hydrogencarbonate
solution. After stirring overnight, the phases were separated, the
organic phase was dried over sodium sulfate, evaporated, and the
residue was purified by silica gel chromatography (HEP/EA
gradient). 1.1 g of the title compound were obtained.
Step 3:
2-[3-(2-m-Tolyl-ethoxy)-4-trifluoromethyl-benzoylamino]-indane-2-c-
arboxylic acid methyl ester
[0646] 200 mg (0.48 mmol) of the compound of step 2 were dissolved
in 5 ml of methanol, 13.1 mg (0.1 mmol) of potassium carbonate were
added and the mixture was stirred for 30 min. The mixture was
acidified with 1 N hydrochloric acid and extracted three times with
20 ml portions of EA. The combined organic phases were dried and
evaporated. The residue was dissolved in 5 ml of THF, 96.9 mg (0.71
mmol) of 2-(3-methylphenyl)-ethanol and 186.7 mg (0.71 mmol) of
triphenylphosphine were added, the mixture was cooled in an ice
bath, and 191.9 mg (0.95 mmol) of DIAD were added. After stirring
overnight, the mixture was evaporated to dryness and the residue
was purified by preparative RP HPLC (water/ACN gradient). 104 mg of
the title compound were obtained.
Step 4:
2-[3-(2-m-Tolyl-ethoxy)-4-trifluoromethyl-benzoylamino]-indane-2-c-
arboxylic acid
[0647] The title compound was obtained from the compound of step 3
by hydrolysis with lithium hydroxide in analogy to example 180,
step 3.
[0648] LC/MS (Method LC3): Rt=2.15 min; m/z=484.19 [MH.sup.+]
[0649] .sup.1H-NMR: .delta.=12.50 (br s, 1H); 9.00 (s, 1H); 7.69
(d, 1H); 7.59 (s, 1H); 7.55 (d, 1H); 7.20-7.26 (m, 2H); 7.13-7.20
(m, 4H); 7.11 (d, 1H); 7.03 (d, 1H); 4.35 (t, 2H); 3.60 (d, 2H);
3.39 (d, 2H); 3.02 (t, 2H); 2.29 (s, 3H)
[0650] In analogy to example 185, the example compounds of the
formula It listed in table 6 were prepared by using the respective
2-(substituted phenyl)-ethanol instead of
2-(3-methylphenyl)-ethanol in step 3. The compounds can be named as
2-{3-[2-(R.sup.96)-ethoxy]-4-trifluoromethyl-benzoylamino}-indane-2-carbo-
xylic acid, for example as
2-{3-[2-(3-chloro-phenyl)-ethoxy]-4-trifluoromethyl-benzoylamino}-indane--
2-carboxylic acid in the case of example 186.
##STR00212##
TABLE-US-00006 TABLE 6 Example compounds of the formula It Exam-
LC/ m/z Retention ple R.sup.96 MS Method [MH.sup.+] time [min] 186
3-chloro-phenyl LC3 504.24 2.15 187 2-chloro-6-fluoro-phenyl LC3
522.04 2.10 188 2,5-difluoro-phenyl LC3 506.07 2.03 189
5-chloro-2-fluoro-phenyl LC3 522.06 2.12 190 3-methyl-pyrazin-2-yl
LC3 486.23 1.67 191 2-fluoro-5-trifluoromethyl- LC3 556.26 2.14
phenyl 192 2-fluoro-5-methyl-phenyl LC4 502.17 2.67
EXAMPLE 193
2-{3-[2-(5-Chloro-2-fluoro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane--
2-carboxylic acid
##STR00213##
[0651] Step 1: 2-(5-Chloro-2-fluoro-phenyl)-ethanol
[0652] A solution of 5 g (26.51 mmol) of
5-chloro-2-fluoro-phenylacetic acid in 60 ml of THF was added
dropped to a suspension of 2.012 g (53.02 mmol) of lithium
aluminium hydride in 26.5 ml of THF. 30 ml of THF were added, and
the mixture was heated under reflux for 3 h. After cooling to
0.degree. C., a solution of 929.7 mg (16.57 mmol) of potassium
hydroxide in 4 ml of water was cautiously added and the mixture was
stirred overnight at room temperature. The formed precipitate was
filtered off with suction and washed with THF. The combined
filtrates were dried over sodium sulfate, filtered and evaporated
to dryness. The residue was purified by silica gel chromatography
(DCM/methanol 98:2) to give 3.8 g of the title compound.
Step 2:
2-{3-[2-(5-Chloro-2-fluoro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-
-indane-2-carboxylic acid
[0653] The title compound was obtained in analogy to example 185 by
using in 2-(5-chloro-2-fluoro-phenyl)-ethanol instead of
2-(3-methylphenyl)-ethanol in step 3.
[0654] LC/MS (Method LC4): Rt=2.35 min; m/z=484.13 [MH.sup.+]
[0655] .sup.1H-NMR: .delta.=12.45 (br s, 1H); 8.61 (s, 1H); 7.55
(m, 1H) 7.50 (d, 1H); 7.45 (s, 1H); 7.30-7.37 (m, 1H); 7.18-7.26
(m, 3H); 7.11-7.19 (m, 2H); 7.00 (d, 1H); 4.21 (t, 2H); 3.80 (s,
3H); 3.59 (d, 2H); 3.35 (d, 2H); 3.06 (t, 2H)
EXAMPLE 194
2-[4-Methoxy-3-(4-trifluoromethyl-phenylethynyl)-benzoylamino]-indane-2-ca-
rboxylic acid
##STR00214##
[0656] Step 1:
2-(3-Bromo-4-methoxy-benzoylamino)-indane-2-carboxylic acid methyl
ester
[0657] 3-Bromo-4-methoxybenzoic acid (22.8 g, 98.8 mmol) was
dissolved in thionyl chloride (42 ml) and stirred at 60.degree. C.
for 30 min. The volatiles were evaporated in vacuo and the residue
was stripped with dioxane. The obtained acid chloride was dissolved
in DCM (50 ml). 2-Amino-indane-2-carboxylic acid methyl ester
hydrochloride (15.0 g, 65.9 mmol) was suspended in DCM (100 ml),
EDIA (10.2 g, 79.1 mmol) was added, the mixture was cooled in an
ice bath, and the solution of the acid chloride was slowly added.
The mixture was stirred overnight at room temperature and
evaporated to dryness. The residue was purified by silica gel
chromatography (DCM/methanol gradient) and subsequent
crystallization from EA to give 21.8 g of the title compound.
[0658] LC/MS (Method LC3): Rt=1.495 min; m/z=404.0/406.0
[MH.sup.+]
Step 2:
2-[4-Methoxy-3-(4-trifluoromethyl-phenylethynyl)-benzoylamino]-ind-
ane-2-carboxylic acid methyl ester
[0659] 300 mg (0.74 mmol) of the compound of step 1 and 90.1 mg
(0.89 mmol) of triethylamine were dissolved in 10 ml of dry
toluene. 171.5 mg (148 .mu.mol) of
tetrakis(triphenylphosphine)palladium(0) and 14.1 mg (74 .mu.mol)
of copper(I) iodide were added, and the mixture was stirred for 30
min. Subsequently 126.2 mg (0.74 mmol) of
1-ethynyl-4-trifluoromethyl-benzene were added and the mixture was
heated to 100.degree. C. for 10 h. The mixture was filtered, the
solvent was evaporated and the residue was purified by preparative
RP HPLC (water/ACN gradient) to give 40 mg of the title
compound.
Step 3:
2-[4-Methoxy-3-(4-trifluoromethyl-phenylethynyl)-benzoylamino]-ind-
ane-2-carboxylic acid
[0660] From the compound of step 2, the title compound was obtained
by hydrolysis with lithium hydroxide in analogy to example 180,
step 3, and purification by silica gel chromatography (DCM/methanol
98:2). Yield: 32 mg.
[0661] LC/MS (Method LC4): Rt=2.57 min; m/z=480.17 [MH.sup.+]
[0662] .sup.1H-NMR: .delta.=12.45 (br s, 1H); 8.80 (s, 1H); 8.09
(s, 1H); 7.94 (d, 1H); 7.80 (d, 2H); 7.74 (d, 2H); 7.60-7.65 (m,
1H); 7.13-7.25 (m, 4H); 3.91 (s, 3H); 3.57 (d, 2H); 3.40 (d,
2H)
EXAMPLE 195
2-[3-(4-tert-Butyl-phenylethynyl)-4-methoxy-benzoylamino]-indane-2-carboxy-
lic acid
##STR00215##
[0664] The title compound was obtained in analogy to example 194 by
using 1-tert-butyl-4-ethynyl-benzene instead of
1-ethynyl-4-trifluoromethyl-benzene.
[0665] LC/MS (Method LC4): Rt=2.79 min; m/z=486.24 [MH.sup.+]
EXAMPLE 196
2-[(3'-Isopropyl-6-methoxy-biphenyl-3-carbonyl)-amino]-indane-2-carboxylic
acid
##STR00216##
[0667] 250 mg (0.62 mmol) of the compound of example 194, step 1,
and 152.1 mg (0.93 mmol) of 3-isopropylphenylboronic acid were
dissolved in 5 ml of DMF and 5 ml of toluene under an argon
atmosphere. 187.9 mg (1.24 mmol) of cesium fluoride and 35.73 mg
(0.05 mmol) of tetrakis(triphenylphosphine)palladium(0) were added,
and the mixture was stirred overnight at 100.degree. C. After
cooling, the mixture was filtered and the solvent was evaporated.
The obtained
2-[(3'-isopropyl-6-methoxy-biphenyl-3-carbonyl)-amino]-indane-2-carboxyli-
c acid methyl ester was dissolved in 10 ml of a mixture of THF and
water (9:1), 42.2 mg (1.80 mmol) of lithium hydroxide were added
and the mixture was stirred overnight. The solvent was evaporated
and the residue was purified by preparative RP HPLC (water/ACN
gradient). 71 mg of the title compound were obtained.
[0668] LC/MS (Method LC4): Rt=2.50 min; m/z=430.30 [MH.sup.+]
[0669] .sup.1H-NMR: .delta.=12.5 (br s, 1H); 8.72 (s, 1H); 7.89 (d,
1H); 7.80 (s, 1H); 7.13-7.37 (m, 9H); 3.81 (s, 3H); 3.60 (d, 2H);
2.92 (m, 1H); 1.24 (d, 6H)
[0670] In analogy to example 196, the example compounds of the
formula Iu listed in table 7 were prepared by using the respective
substituted phenylboronic acid instead of 3-isopropylphenylboronic
acid. In the case of examples 198 and 199, the intermediary
2-[(substituted biphenyl-3-carbonyl)-amino]-indane-2-carboxylic
acid methyl ester was purified by preparative RP HPLC (water/ACN
gradient) before hydrolysis. The compounds can be named as
2-[(substituted biphenyl-3-carbonyl)-amino]-indane-2-carboxylic
acid, for example as
2-[(3'-cyanomethyl-6-methoxy-biphenyl-3-carbonyl)-amino]-indane-2-carboxy-
lic acid in the case of example 199 in which the group R.sup.97 is
3-cyanomethyl-phenyl and, in view of the rules of nomenclature, the
group 3-(R.sup.97)-4-methoxy-phenyl-C(O) depicted in formula Iu
thus is named 3'-cyanomethyl-6-methoxy-biphenyl-3-carbonyl.
##STR00217##
TABLE-US-00007 TABLE 7 Example compounds of the formula Iu Exam-
LC/ m/z Retention ple R.sup.97 MS Method [MH.sup.+] time [min] 197
4-isobutyl-phenyl LC4 444.32 2.70 198 3-chloro-phenyl LC4 422.22
2.32 199 3-cyanomethyl-phenyl LC4 427.27 1.99 200
3-trifluoromethyl-phenyl LC4 456.24 2.38 201 4-tert-butyl-phenyl
LC4 444.32 2.63 202 3-ethyl-phenyl LC3 416.32 1.95 203
3-dimethylaminosulfonyl- LC10 510.22 2.30 amino-phenyl
EXAMPLE 204
2-{3-[2-(2,5-Difluoro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-car-
boxylic acid
##STR00218##
[0671] Step 1:
2-{3-[2-(2,5-Difluoro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-ca-
rboxylic acid methyl ester
[0672] 300.1 mg (0.88 mmol) of
2-(3-hydroxy-4-methoxy-benzoylamino)-indane-2-carboxylic acid
methyl ester, 208.6 mg (1.32 mmol) of
2-(2,5-difluoro-phenyl)-ethanol and 346 mg (1.32 mmol) of
triphenylphosphine were dissolved in 10 ml of THF. The mixture was
cooled in an ice bath, and 355.5 mg (1.76 mmol) of DIAD were added.
After stirring overnight, the mixture was evaporated to dryness and
the residue was purified by preparative RP HPLC (water/ACN
gradient). 340 mg of the title compound were obtained.
Step 2:
2-{3-[2-(2,5-Difluoro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-inda-
ne-2-carboxylic acid
[0673] From the compound of step 1, the title compound was obtained
by hydrolysis with lithium hydroxide in analogy to example 180,
step 3, and purification by preparative RP HPLC (water/ACN
gradient). Yield: 260 mg.
[0674] LC/MS (Method LC3): Rt=1.81 min; m/z=468.11 [MH.sup.+]
[0675] .sup.1H-NMR: .delta.=12.5 (br s, 1H); 8.63 (s, 1H); 7.51 (d,
1H); 7.44 (s, 1H); 7.30-7.10 (m, 6H); 7.00 (d, 1H); 4.22 (t, 2H);
3.79 (s, 3H); 3.59 (d, 2H); 3.38 (d, 2H); 3.08 (t, 2H)
EXAMPLE 205
2-{3-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-ca-
rboxylic acid
##STR00219##
[0677] The title compound was obtained in analogy to example 204 by
using 2-(5-ethyl-pyridin-2-yl)-ethanol instead
2-(2,5-difluoro-phenyl)-ethanol in step 1.
[0678] LC/MS (Method LC3): Rt=1.22 min; m/z=461.34 [MH.sup.+]
EXAMPLE 206
2-{4-Methoxy-3-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzoylamino}-indane-2-c-
arboxylic acid
##STR00220##
[0680] The title compound was obtained in analogy to example 204
using 2-(4-methyl-thiazol-5-yl)-ethanol instead
2-(2,5-difluoro-phenyl)-ethanol in step 1.
[0681] LC/MS (Method LC4): Rt=2.70 min; m/z=453.11 [MH.sup.+]
EXAMPLE 207
6-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-6,
7-dihydro-5H-cyclopentapyrazine-6-carboxylic acid
##STR00221##
[0683] The title compound was obtained from
2,3-bis-chloromethyl-pyrazine (K. Yoshiizumi et al., Bioorg. Med.
Chem. 11 (2003), 433-450) in analogy to examples 97 and 98, using
N-methylpyrrolidone instead of DMF as solvent in the initial
cyclization step. The intermediary amino acid ester was not
purified, but used as raw material.
[0684] LC/MS (Method LC1): Rt=1.32 min; m/z=448.0 [MH.sup.+]
EXAMPLE 208
2-{[6-Methoxy-5-(2-m-tolyl-ethoxy)-pyridine-3-carbonyl]-amino}-indane-2-ca-
rboxylic acid
##STR00222##
[0686] 6-Chloro-5-nitro-nicotinic acid methyl ester was prepared
according to the procedure described in WO 2005/021544 and
transformed into 5-hydroxy-6-methoxy-nicotinic acid methyl ester
according to the procedure described in WO 95/04045, which was then
transformed into the title compound by etherification with
2-m-tolyl-ethanol in analogy to step 1 of example 1, hydrolysis of
the ester group in analogy to example 2, reaction of the obtained
carboxylic acid with 2-amino-indane-2-carboxylic acid methyl ester
hydrochloride in analogy to step 1 of example 15, and hydrolysis of
the ester group in analogy to example 2.
[0687] .sup.1H-NMR: .delta.=12.5 (s, 1H); 8.75 (s, 1H); 8.21 (d,
1H); 7.63 (d, 1H); 7.75-7.13 (m, 6H); 7.11 (d, 1H); 7.02 (d, 1H);
4.21 (t, 2H); 3.91 (s, 3H); 3.61 (d, 2H); 3.37 (d, 2H); 3.01 (t,
2H); 2.28 (s, 3H)
EXAMPLE 209
2-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-1-methyl-indane-2-carboxyl-
ic acid
##STR00223##
[0688] Step 1: 1-(1-Chloro-ethyl)-2-chloromethyl-benzene
[0689] 1-(2-Hydroxymethyl-phenyl)-ethanol (prepared according to
the procedure described in P. Canonne et al., Tetrahedron 44
(1988), 2903-2912) (0.376 g, 2.47 mmol) was dissolved in DCM.
Thionyl chloride (2.94 g, 24 mmol) was added and allowed to react
for 1 h. The mixture was partitioned between EA and an excess of an
aqueous sodium hydrogencarbonate solution. The combined organic
extracts were dried over sodium sulfate, filtered and evaporated to
dryness in vacuo. The residue was purified by silica gel
chromatography with HEP to yield 0.228 g of the title compound.
[0690] .sup.1H-NMR: .delta.=7.68 (dd, 1H); 7.46-7.41 (m, 2H); 7.35
(dd, 1H); 5.66 (q, 1H); 4.95 (d, 1H); 4.90 (d, 1H); 1.82 (d,
3H)
Step 2:
2-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-1-methyl-indane-2--
carboxylic acid
[0691] The title compound was obtained from the compound of step 1
in analogy to examples 97 and 98, using N-methylpyrrolidone instead
of DMF as solvent in the initial cyclization step. The intermediary
amino acid ester was not purified, but used as raw material.
[0692] LC/MS (Method LC1): Rt=1.66 min; m/z=460.2 [MH.sup.+]
EXAMPLE 210
2-(3-{2-[3-(2-Hydroxy-1-hydroxymethyl-1-methyl-ethyl)-phenyl]-ethoxy}-4-me-
thoxy-benzoylamino)-indane-2-carboxylic acid
##STR00224##
[0693] Step 1: 2-(3-Methoxycarbonylmethyl-phenyl)-malonic acid
dimethyl ester
[0694] Tris(dibenzylideneacetone)dipalladium(0) (0.104 g, 0.113
mmol), tri-(tert-butyl)phosphonium tetrafluoroborate (65.8 mg,
0.227 mmol) and sodium hydride (295 mg, 60% dispersion in mineral
oil) were charged into a flask under an argon atmosphere.
(3-Bromophenyl)acetic acid methyl ester (1.30 g, 5.67 mmol) was
dissolved in THF (10 ml) and added to the mixture. Subsequently,
dimethyl malonate (0.995 g, 7.37 mmol) was added and the mixture
stirred under reflux overnight. The mixture was filtered over a
small plug of silica gel, evaporated to dryness and the residue
purified by silica gel chromatography (HEP/EA gradient) to yield
0.704 g of the title compound.
[0695] LC/MS (Method LC1): Rt=1.28 min; m/z=281.1 [MH.sup.+]
Step 2: 2-(3-Methoxycarbonylmethyl-phenyl)-2-methyl-malonic acid
dimethyl ester
[0696] The compound of step 1 (0.353 g, 1.26 mmol) was dissolved in
DMF (1.5 ml), potassium tert-butoxide (151 mg, 1.32 mmol) was
added, the mixture stirred at room temperature for 10 min, and then
iodomethane (0.542 g, 3.78 mmol) was added. The mixture was stirred
at room temperature for 3 h and partitioned between EA and 2 N
hydrochloric acid. The combined extracts were washed with a
saturated aqueous sodium chloride solution, dried over sodium
sulfate and evaporated to dryness. The residue was purified by
preparative RP HPLC (water/ACN gradient) to yield 0.128 g of the
title compound.
[0697] LC/MS (Method LC1): Rt=1.36 min; m/z=295.0 [MH.sup.+]
Step 3:
2-[3-(2-Hydroxy-ethyl)-phenyl]-2-methyl-propane-1,3-diol
[0698] The compound of step 2 (0.128 g, 0.435 mmol) was dissolved
in 2 ml of THF and cautiously added to an ice-cold suspension of
lithium aluminium hydride (174 mg, 4.35 mmol) in THF. After a few
minutes, diethyl ether (12 ml) was added and thereafter 200 .mu.l
of EA. Subsequently, water was added slowly and cautiously until
the alumina salts formed a light grey mass at the bottom of the
flask. The supernatant was decanted and the residue washed with EA.
The combined extracts were dried over sodium sulfate and evaporated
to dryness. The residue was used in the next step without further
purification.
[0699] LC/MS (Method LC1): Rt=0.69 min; m/z=228.1
[MNH.sub.4.sup.+]
Step 4:
2-(3-{2-[3-(2-Hydroxy-1-hydroxymethyl-1-methyl-ethyl)-phenyl]-etho-
xy}-4-methoxy-benzoylamino)-indane-2-carboxylic acid
[0700] The compound of step 3 was reacted with methyl
3-hydroxy-4-methoxybenzoate in analogy to step 1 of example 94.
From the obtained intermediate the title compound was prepared in
analogy to step 1 of example 15.
[0701] LC/MS (Method LC1): Rt=1.28 min; m/z=520.1 [MH.sup.+]
EXAMPLE 211
2-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-octahydro-indene-2-carboxy-
lic acid
##STR00225##
[0703] Acetyl chloride (22 mg, 0.282 mmol) was cautiously dissolved
in ethanol (2 ml). 2-Amino-indane-2-carboxylic acid (50 mg, 0.282
mmol) and platinum dioxide (25 mg) were added, and the mixture was
hydrogenated at room temperature at a hydrogen pressure of 5 bar
for 5 h. The solution was filtered over a small plug of celite and
evaporated to dryness. For conversion into
2-amino-octahydroindene-2-carboxylic acid methyl ester, the residue
was suspended in methanol (2 ml), thionyl chloride (0.5 ml) was
added and the mixture was stirred overnight at room temperature.
The mixture was evaporated to dryness to yield 99 mg of raw
material which was used in the next step without further
purification. From the obtained intermediate, the title compound
was prepared in analogy to step 1 of example 15 and hydrolysis of
the ester group in analogy to example 2.
[0704] .sup.1H-NMR: .delta.=12.0 (s, 1H); 8.40 (s, 1H); 7.48 (dd,
1H); 7.41 (dd, 1H); 7.22-7.16 (m, 2H); 7.11 (d, 1H); 7.04 (d, 1H);
7.00 (d, 1H); 4.18 (t, 2H); 3.80 (s, 3H); 3.01 (t, 2H); 2.29 (s,
3H); 2.20-2.00 (m, 6H); 1.53-1.40 (m, 6H); 1.32-1.20 (m, 2H)
EXAMPLE 212
2-{3-[2-(3-Chloro-phenyl)-2,2-difluoro-ethoxy]-4-methoxy-benzoylamino}-ind-
ane-2-carboxylic acid
##STR00226##
[0705] Step 1: 2-(3-Chloro-phenyl)-2,2-difluoro-ethanol
[0706] 1.00 g (4.26 mmol) (3-chloro-phenyl)-difluoro-acetic acid
ethyl ester (prepared according to the procedure described in WO
2006/122788) were dissolved in 100 ml of methanol and treated in an
ice bath with 120 mg (0.75 mmol) of sodium borohydride. After
stirring overnight the mixture was evaporated and the residue was
purified by silica gel chromatography (DCM/methanol 98:2) to give
700 mg of the title compound.
Step 2: Trifluoromethanesulfonic acid
2-(3-chloro-phenyl)-2,2-difluoro-ethyl ester
[0707] 700 mg (3.64 mmol) of the compound of step 1 were dissolved
in 10 ml of DCM and treated at 0.degree. C. with 78 .mu.l (4.36
mmol) of EDIA and 1.23 g (4.36 mmol) of trifluoromethanesulfonic
acid anhydride. After completion of the reaction (monitored by thin
layer chromatography (DCM/methanol 98:2), the mixture was poured on
water and the phases were separated. The organic phase was washed
once with a saturated sodium chloride solution, dried over sodium
sulfate and evaporated to dryness. The residue was purified by
silica gel chromatography (DCM) to give 450 mg of the title
compound.
Step 3:
2-{3-[2-(3-Chloro-phenyl)-2,2-difluoro-ethoxy]-4-methoxy-benzoylam-
ino}-indane-2-indane-2-carboxylic acid methyl ester
[0708] To a mixture of 230 mg (0.67 mmol) of
2-(3-hydroxy-4-methoxy-benzoylamino)-indane-2-carboxylic acid
methyl ester and 227 mg (1.62 mmol) of potassium carbonate in 6 ml
of acetone and 1.7 ml of DMF was added slowly a solution of 437 mg
(1.65 mmol) of the compound of step 2. The reaction mixture was
stirred for 3 d at room temperature and then evaporated. The
residue was purified by preparative RP HPLC (water/ACN gradient) to
give 20 mg of the title compound.
Step 4:
2-{3-[2-(3-Chloro-phenyl)-2,2-difluoro-ethoxy]-4-methoxy-benzoylam-
ino}-indane-2-carboxylic acid
[0709] 20 mg of the compound of step 3 were dissolved in 5 ml of a
mixture of THF and water (9:1), and 1.9 mg (77.5 .mu.mol) of
lithium hydroxide were added. After stirring at room temperature
for 3 d, the mixture was acidified with 1 M hydrochloric acid and
evaporated. The residue was purified by silica gel chromatography
(DCM/methanol 95:5) and RP HPLC (water/ACN gradient) to give 8 mg
of the title compound.
[0710] LC/MS (Method LC1): Rt=1.64 min; m/z=502.10 [MH.sup.+]
[0711] .sup.1H-NMR: .delta.=12.45 (br s, 1H); 8.62 (s, 1H); 7.75
(s, 1H); 7.50-7.65 (m, 4H); 7.48 (s, 1H); 7.23 (m, 2H) 7.17 (m,
2H); 7.04 (d, 1H); 4.65 (t, 2H); 3.80 (s, 3H); 3.59 (d, 2H); 3.38
(d, 2H)
EXAMPLE 213
2-[3-(2,2-Difluoro-2-phenyl-ethoxy)-4-methoxy-benzoylamino]-indane-2-carbo-
xylic acid
##STR00227##
[0713] The title compound was obtained in analogy to example 212,
starting from 2,2-difluoro-2-phenyl-ethanol.
[0714] LC/MS (Method LC1): Rt=1.53 min; m/z=468.15 [MH.sup.+]
[0715] .sup.1H-NMR: .delta.=12.45 (br s, 1H); 8.62 (s, 1H); 7.64
(d, 2H); 7.46-7.59 (m, 5H); 7.22 (m, 2H) 7.17 (m, 2H); 7.04 (d,
1H); 4.60 (t, 2H); 3.80 (s, 3H); 3.58 (d, 2H); 3.38 (d, 2H)
EXAMPLE 214
4,
7-Difluoro-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-car-
boxylic acid
##STR00228##
[0716] Step 1: (3,6-Difluoro-2-hydroxymethyl-phenyl)-methanol
[0717] Lithium aluminium hydride (792 mg, 19.8 mmol) was suspended
in THF (6 ml) and cooled in an ice bath. A solution of
4,7-difluoro-isobenzofuran-1,3-dione (730 mg, 3.97 mmol) in THF (6
ml) was added during 5 min. After completion of the reaction (5
min), diethyl ether (30 ml) was added. Subsequently, 2 ml of EA
were added in order to decompose excess of lithium aluminium
hydride, and thereafter water was slowly added until the alumina
salts precipitated. The supernatant was decanted and the
precipitate washed twice with EA. The combined extracts were dried
over sodium sulfate, filtered and evaporated to dryness to yield
360 mg of the title compound.
[0718] .sup.1H-NMR: .delta.=7.16 (t, 2H); 5.13 (t, 2H); 4.60 (d,
4H)
Step 2: 2,3-Bis-chloromethyl-1,4-difluoro-benzene
[0719] The compound of step 1 (360 mg, 2.07 mmol) was dissolved in
acetyl chloride (2.3 ml) in a vial. After 10 min, zinc chloride
(843 mg, 6.21 mmol) was added and the mixture was heated to
130.degree. C. in a microwave reactor for 30 min. After cooling,
the mixture was partitioned between diethyl ether and saturated
sodium hydrogencarbonate solution and the aqueous phase extracted
with diethyl ether. The combined organic phases were dried over
sodium sulfate, filtered and evaporated to dryness to yield 200 mg
of the title compound.
[0720] .sup.1H-NMR: .delta.=7.40 (t, 2H); 4.90 (s, 4H)
Step 3:
4,7-Difluoro-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indan-
e-2-carboxylic acid
[0721] The compound of step 2 was transformed into the title
compound in analogy to examples 97 and 98.
[0722] LC/MS (Method LC13): Rt=2.60 min; m/z=482.2 [MH.sup.+]
EXAMPLE 215
4-Fluoro-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxyl-
ic acid
##STR00229##
[0724] The title compound was prepared in analogy to example 214,
starting from (3-fluoro-2-hydroxymethyl-phenyl)-methanol.
[0725] LC/MS (Method LC11): Rt=1.91 min; m/z=464.2 [MH.sup.+]
EXAMPLE 216
2-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-methyl-indane-2-carboxyl-
ic acid
##STR00230##
[0727] The title compound was prepared in analogy to example 214,
starting from 4-methyl-isobenzofuran-1,3-dione.
[0728] LC/MS (Method LC12): Rt=3.74 min; m/z=460.2 [MH.sup.+]
EXAMPLE 217
4-Chloro-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxyl-
ic acid
##STR00231##
[0730] The title compound was prepared in analogy to example 214,
starting from 4-chloro-isobenzofuran-1,3-dione.
[0731] LC/MS (Method LC13): Rt=2.67 min; m/z=480.2 [MH.sup.+]
EXAMPLE 218
5-Cyano-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxyli-
c acid
##STR00232##
[0732] Step 1:
5-Bromo-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxyl-
ic acid ethyl ester
[0733] Starting from 5-bromo-3H-isobenzofuran-1-one, the
intermediate 4-bromo-1,2-bis-chloromethyl-benzene was prepared in
analogy to steps 1 and 2 of example 214.
[0734] This intermediate was transformed into the title compound in
analogy to example 97.
[0735] LC/MS (Method LC13): Rt=3.03 min; m/z=552.2 [MH.sup.+]
Step 2:
5-Cyano-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-c-
arboxylic acid ethyl ester
[0736] The compound of step 1 (50 mg, 0.091 mmol) was added to a
mixture of zinc cyanide (10.6 mg, 0.091 mmol) and
tetrakis(triphenylphosphine)palladium(0) (5.2 mg, 0.004 mmol) in
DMF (0.16 ml) at 150.degree. C. and stirred for 2 h. After cooling,
tert-butyl methyl ether was added and the mixture was filtered over
celite. The filtrate was washed with water, the organic phase dried
over magnesium sulfate, filtered and evaporated to dryness to yield
the title compound which was used without further purification.
Step 3:
5-Cyano-2-[4-methyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-ca-
rboxylic acid
[0737] The compound of step 2 was transformed into the title
compound by hydrolysis in analogy to step 3 of example 94.
[0738] LC/MS (Method LC13): Rt=2.54 min; m/z=471.3 [MH.sup.+]
EXAMPLE 219
5-Carbamoyl-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carbo-
xylic acid
##STR00233##
[0740] The compound of step 2 of example 218 was transformed into
the title compound by hydrolysis in analogy to example 98
(hydrolysis time 3 h).
[0741] LC/MS (Method LC14): Rt=3.68 min; m/z=489.3 [MH.sup.+]
EXAMPLE 220
1-Hydroxy-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxy-
lic acid
##STR00234##
[0742] Step 1:
2-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-1-oxo-indane-2-carboxylic
acid ethyl ester
[0743] 2-Amino-1-oxo-indane-2-carboxylic acid ethyl ester (L.
Benati et al., J. Org. Chem. 64 (1999), 7836-7841) (460 mg, 2.10
mmol) was reacted with 4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid
in analogy to step 2 of example 13 to yield 0.331 g of the title
compound.
[0744] LC/MS (Method LC12): Rt=4.09 min; m/z=488.2 [MH.sup.+]
Step 2:
1-Hydroxy-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-
-carboxylic acid ethyl ester
[0745] The compound of step 1 (0.439 g, 0.900 mmol) was dissolved
in THF (4 ml). The mixture was cooled to -30.degree. C. and sodium
borohydride (35 mg, 0.90 mmol) was added followed by dropwise
addition of methanol. After 30 min, the mixture was partitioned
between diethyl ether and 2 N hydrochloric acid, the aqueous phase
was extracted with diethyl ether, the combined organic phases were
dried over sodium sulfate and evaporated to dryness. The residue
was purified by silica gel chromatography (HEP/EA gradient) to
yield the title compound as a mixture of stereoisomers.
[0746] LC/MS (Method LC12): Rt=3.77 min; m/z=490.3 [MH.sup.+]
Step 3:
1-Hydroxy-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-
-carboxylic acid
[0747] The compound of step 2 was hydrolyzed in analogy to example
2. Purification by RP HPLC (water/ACN gradient) gave one of the
diastereomers (diastereomer A) of the title compound in pure form
(as the racemate) and a mixture of the other diastereomer with
diastereomer A (relative stereochemistry of the diastereomers
unknown).
[0748] Diastereomer A:
[0749] LC/MS (Method LC12): Rt=3.43 min; m/z=462.2 [MH.sup.+]
[0750] .sup.1H-NMR: .delta.=12.1 (br s, 1H); 8.43 (s, 1H); 7.48
(dd, 1H); 7.41 (d, 1H); 7.32 (dd, 1H); 7.28-7.13 (m, 5H); 7.10 (d,
1H); 7.02 (d, 1H); 7.00 (d, 1H); 5.70 (br s, 1H); 5.40 (s, 1H);
4.16 (t, 2H); 3.90 (d, 1H); 3.09 (d, 1H); 3.00 (t, 2H); 2.28 (s,
3H)
EXAMPLE 221
2-{[5-(3-Isopropyl-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-indane-2--
carboxylic acid
##STR00235##
[0751] Step 1: 5-(3-Isopropyl-phenyl)-6-methoxy-nicotinic acid
methyl ester
[0752] Under an atmosphere of argon, a mixture of
5-bromo-6-methoxy-nicotinic acid methyl ester (W. J. Thompson and
J. Gaudino, J. Org. Chem. 49 (1984), 5237-5243) (100 mg, 0.406
mmol), 3-isopropylphenylboronic acid (73 mg, 0.447 mmol),
tri-(tert-butyl)phosphonium tetrafluoroborate (7 mg, 0.024 mmol),
tris(dibenzylideneacetone)dipalladium(0) (11 mg, 0.012 mmol) and
potassium fluoride (78 mg, 1.34 mmol) in a flask was suspended in
dioxane (1.5 ml) and heated to 45.degree. C. for 3 h. After
cooling, it was filtered over a small plug of silica gel and
evaporated to dryness. Purification of the residue by silica gel
chromatography (HEP/EA gradient) and subsequent RP HPLC (water/ACN
gradient) yielded 63 mg of the title compound.
[0753] LC/MS (Method LC13): Rt=2.95 min; m/z=286.1 [MH.sup.+]
Step 2: 5-(3-Isopropyl-phenyl)-6-methoxy-nicotinic acid
[0754] The compound of step 1 (60 mg, 0.63 mmol) was hydrolyzed in
analogy to step 3 of example 94 to yield 57 mg of the title
compound.
[0755] LC/MS (Method LC13): Rt=2.48 min; m/z=272.1 [MH.sup.+]
Step 3:
2-{[5-(3-Isopropyl-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-i-
ndane-2-carboxylic acid
[0756] The compound of step 2 was reacted with
2-amino-indane-2-carboxylic acid methyl ester hydrochloride in
analogy to step 2 of example 13, and the obtained ester hydrolyzed
in analogy to example 2.
[0757] LC/MS (Method LC14): Rt=3.52 min; m/z=431.2 [MH.sup.+]
EXAMPLE 222
2-{[6-Methoxy-5-(3-methylsulfanyl-phenyl)-pyridine-3-carbonyl]-amino}-inda-
ne-2-carboxylic acid
##STR00236##
[0758] Step 1:
2-[(5-Bromo-6-methoxy-pyridine-3-carbonyl)-amino]-indane-2-carboxylic
acid methyl ester
[0759] 5-Bromo-6-methoxy-nicotinic acid methyl ester (W. J.
Thompson and J. Gaudino, J. Org. Chem. 49 (1984), 5237-5243) (2.00
g, 8.13 mmol) was hydrolyzed in analogy to example 2. The obtained
acid was reacted with 2-amino-indane-2-carboxylic acid methyl ester
hydrochloride in analogy to step 2 of example 13.
[0760] LC/MS (Method LC14): Rt=3.28 min; m/z=405.0 [MH.sup.+]
Step 2:
2-{[6-Methoxy-5-(3-methylsulfanyl-phenyl)-pyridine-3-carbonyl]-ami-
no}-indane-2-carboxylic acid
[0761] The compound of step 1 was reacted with
3-methylsulfanyl-phenylboronic acid in analogy to step 1 of example
221. The intermediate ester was hydrolyzed in analogy to example
2.
[0762] LC/MS (Method LC14): Rt=3.30 min; m/z=435.1 [MH.sup.+]
[0763] In analogy to example 221 and example 222, respectively, the
example compounds of the formula Iv listed in table 8 were prepared
by using the respective substituted phenylboronic acid. If the
initial palladium coupling reaction in the preparation analogously
to example 221 did not proceed satisfactorily, it was repeated once
more. The compounds can be named as 2-{[5-(substituted
phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-indane-2-carboxylic
acid, for example as
2-{[6-methoxy-5-(3-methyl-phenyl)-pyridine-3-carbonyl]-amino}-indane-2-ca-
rboxylic acid in the case of example 224.
##STR00237##
TABLE-US-00008 TABLE 8 Example compounds of the formula Iv LC/MS
m/z Retention Example R.sup.98 Preparation Method [MH.sup.+] time
[min] 223 3-chloro-phenyl (a) LC14 423.1 3.00 224 3-methyl-phenyl
(a) LC12 403.1 3.57 225 2-chloro-phenyl (a) LC12 423.0 3.49 226
4-chloro-phenyl (a) LC17 423.3 4.79 227
2-chloro-3-trifluoromethyl-phenyl (a) LC14 457.1 3.43 228
2,3-dichloro-phenyl (a) LC12 457.1 3.65 229 3,4,5-trifluoro-phenyl
(b) LC12 443.2 3.68 230 2-fluoro-3-trifluoromethyl-phenyl (b) LC14
475.1 3.46 231 3-dimethylaminosulfonylamino- (b) LC14 511.2 2.94
phenyl 232 3-chloro-4-trifluoromethyl-phenyl (b) LC16 978.9 (c)
4.99 233 3-ethylsulfanyl-phenyl (b) LC12 449.2 3.70 234
3-trifluoromethoxy-phenyl (b) LC17 473.2 4.89 235
3-chloro-5-trifluoromethyl-phenyl (b) LC14 491.2 3.71 236
3-cyano-phenyl (b) LC12 414.2 3.30 (a) preparation in analogy to
example 221 (b) preparation in analogy to example 222 (c) [(2M -
H).sup.-] instead of [MH.sup.+]
EXAMPLE 237
2-{[5-(3-Ethanesulfonyl-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-inda-
ne-2-carboxylic acid
##STR00238##
[0765] The compound of example 233 (50 mg, 0.11 mmol) was dissolved
in acetic acid (3.8 ml). Hydrogen peroxide (30% solution in water,
0.034 ml, 0.33 mmol) was added and the mixture was reacted at room
temperature for 72 h. The mixture was partitioned between EA and an
aqueous solution of sodium sulfite (about 1% strength). The organic
phase was dried over magnesium sulfate, filtered and evaporated to
dryness. The residue was purified by RP HPLC (water/ACN gradient).
After evaporation of the product fraction, the residue was stirred
with a mixture of diethyl ether/HEP, filtered and dried in
vacuo.
[0766] LC/MS (Method LC14): Rt=3.88 min; m/z=481.2 [MH.sup.+]
EXAMPLE 238
2-(4-Methoxy-3-o-tolyloxy-benzoylamino)-indane-2-carboxylic
acid
##STR00239##
[0767] Step 1: 4-Methoxy-3-o-tolyloxy-benzoic acid
[0768] Potassium carbonate (1.20 g, 8.66 mmol), o-cresol (468 mg,
4.33 mmol), copper powder (28 mg, 0.43 mmol) and
3-bromo-4-methoxybenzoic acid (1.00 g, 4.33 mmol) were suspended in
DMF (5 ml) and heated to 165.degree. C. overnight. Potassium
carbonate (1.20 g, 8.66 mmol) and o-cresol (468 mg, 4.33 mmol) were
added once again and heating was continued for another 2 h. The
crude mixture was partitioned between EA and 2 N hydrochloric acid,
the aqueous phase extracted with EA, and the combined organic
phases were dried over magnesium sulfate, filtered and evaporated
to dryness. The residue was purified by silica gel chromatography
(HEP/EA gradient) to yield 600 mg of the title compound.
[0769] LC/MS (Method LC14): Rt=3.00 min; m/z=300.1
[(M+CH.sub.3CN+H).sup.+]
Step 2: 2-(4-Methoxy-3-o-tolyloxy-benzoylamino)-indane-2-carboxylic
acid
[0770] The compound of step 1 was reacted with
2-amino-indane-2-carboxylic acid methyl ester hydrochloride in
analogy to step 2 of example 13. The obtained ester was hydrolyzed
in analogy to example 2.
[0771] LC/MS (Method LC12): Rt=3.57 min; m/z=418.1 [MH.sup.+]
EXAMPLE 239
2-(4-Methoxy-3-m-tolyloxy-benzoylamino)-indane-2-carboxylic
acid
##STR00240##
[0773] The title compound was prepared in analogy to example 238
using m-cresol instead of o-cresol.
[0774] LC/MS (Method LC12): Rt=3.54 min; m/z=418.1 [MH.sup.+]
EXAMPLE 240
2-[4-Methoxy-3-(2-methyl-benzoyl)-benzoylamino]-indane-2-carboxylic
acid
##STR00241##
[0775] Step 1: 4-Methoxy-3-(2-methyl-benzoyl)-benzoic acid methyl
ester
[0776] 4-Methoxybenzoic acid methyl ester (5.00 g, 30.1 mmol) and
2-methylbenzoyl chloride (4.88 g, 31.6 mmol) were dissolved in
chlorobenzene (10 ml), tin(IV) chloride (9.41 g, 36.1 mmol) was
added cautiously, and the mixture was heated to 140.degree. C. for
3 h. The addition of the acid chloride and tin tetrachloride was
repeated twice, and the mixture subsequently heated to 140.degree.
C. for 3 h each time. The mixture was poured onto 300 ml of
ice/water and extracted with DCM. The combined extracts were dried
over magnesium sulfate, filtered and evaporated to dryness. The
residue was purified by silica gel chromatography (HEP/EA gradient)
and subsequently by RP HPLC (water/ACN gradient) to yield 200 mg of
the title compound.
[0777] .sup.1H-NMR: .delta.=8.12 (dd, 1H); 7.91 (d, 1H); 7.71 (d,
1H); 7.50-7.41 (m, 1H); 7.31-7.22 (m, 2H); 7.06 (d, 1H); 3.81 (s,
3H); 3.72 (s, 3H); 2.42 (s, 3H)
Step 2:
2-[4-Methoxy-3-(2-methyl-benzoyl)-benzoylamino]-indane-2-carboxyli-
c acid
[0778] The compound of step 1 was hydrolyzed in analogy to example
2 and the obtained acid reacted with 2-amino-indane-2-carboxylic
acid methyl ester hydrochloride in analogy to step 2 of example 13.
The obtained ester was hydrolyzed in analogy to example 2.
[0779] LC/MS (Method LC14): Rt=3.16 min; m/z=430.1 [MH.sup.+]
EXAMPLE 241
2-[3-(Hydroxy-o-tolyl-methyl)-4-methoxy-benzoylamino]-indane-2-carboxylic
acid
##STR00242##
[0781] The compound of example 240 (70 mg, 0.163 mmol) was
dissolved in a mixture of methanol (1.5 ml) and ethanol (1.5 ml)
and cooled in an ice bath. Sodium borohydride (18.9 mg, 0.49 mmol)
was added in two batches and the mixture reacted with ice cooling
until completion (3 h). The volatiles were evaporated and the
residue was partitioned between diethyl ether and 1 N hydrochloric
acid. The aqueous phase was extracted with diethyl ether, and the
combined organic phases were dried and evaporated. The residue was
purified by RP HPLC (water/ACN gradient) to yield 13 mg of the
title compound.
[0782] LC/MS (Method LC12): Rt=3.22 min; m/z=432.2 [MH.sup.+]
EXAMPLE 242
2-[4-Methoxy-3-(2-methyl-benzyl)-benzoylamino]-indane-2-carboxylic
acid
##STR00243##
[0784] The compound of example 241 (32 mg, 0.074 mmol) was
dissolved in ethanol (10 ml), palladium (10%) on charcoal (10 mg)
was added, and the mixture was hydrogenated at room temperature for
1 h at a hydrogen pressure of 5 bar. After completion of the
reaction, the mixture was filtered over silica gel and evaporated
to dryness. The residue was triturated with diethyl ether, filtered
and dried in vacuo to yield 25 mg of the title compound.
[0785] LC/MS (Method LC14): Rt=3.45 min; m/z=416.3 [MH.sup.+]
EXAMPLE 243
2-[4-Methoxy-3-benzyl-benzoylamino]-indane-2-carboxylic acid
##STR00244##
[0787] The title compound was prepared in analogy to examples 240,
241 and 242.
[0788] LC/MS (Method LC14): Rt=3.33 min; m/z=402.2 [MH.sup.+]
EXAMPLE 244
2-[4-Methoxy-3-(3-methyl-benzyl)-benzoylamino]-indane-2-carboxylic
acid
##STR00245##
[0790] The title compound was prepared in analogy to examples 240,
241 and 242.
[0791] LC/MS (Method LC12): Rt=3.74 min; m/z=416.1 [MH.sup.+]
EXAMPLE 245
2-[4-Methoxy-3-(4-methyl-benzyl)-benzoylamino]-indane-2-carboxylic
acid
##STR00246##
[0793] The title compound was prepared in analogy to examples 240,
241 and 242.
[0794] LC/MS (Method LC12): Rt=3.68 min; m/z=416.2 [MH.sup.+]
EXAMPLE 246
2-(3-{2-[3-(2-Amino-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-indane--
2-carboxylic acid
##STR00247##
[0795] Step 1:
2-(3-{2-[3-(2-Azido-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-indane-
-2-carboxylic acid methyl ester
[0796] 300 mg (0.613 mmol) of
2-(3-{2-[3-(2-hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-inda-
ne-2-carboxylic acid methyl ester (methyl ester intermediate of
example 27) and triphenylphosphine (0.241 g, 0.920 mmol) were
dissolved in THF (5 ml) and cooled in an ice bath.
Diphenylphosphoryl azide (0.258 g, 0.920 mmol) and DIAD (0.198 g,
0.920 mmol) were added sequentially, the ice bath was removed and
the mixture was stirred for 2 h at room temperature. The mixture
was evaporated to dryness and purified by silica gel chromatography
(HEP/EA gradient) to yield 0.188 g of the title compound.
[0797] LC/MS (Method LC14): Rt=3.68 min; m/z=515.3 [MH.sup.+]
Step 2:
2-(3-{2-[3-(2-Amino-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-
-indane-2-carboxylic acid methyl ester
[0798] The compound of step 1 (0.185 g, 0.360 mmol) and
triphenylphosphine (0.149 g, 0.539 mmol) were dissolved in a
mixture of 3 ml of THF and 3 ml of water, and the solution was
stirred overnight at room temperature. The mixture was evaporated
to dryness and purified by silica gel chromatography
(DCM/methanol/28% ammonia gradient, 70:30:0 to 0:100:0 to 0:90:10)
to yield 0.17 g of the title compound.
[0799] LC/MS (Method LC14): Rt=2.68 min; m/z=489.2 [MH.sup.+]
Step 3:
2-(3-{2-[3-(2-Amino-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-
-indane-2-carboxylic acid
[0800] The compound of step 2 (85 mg, 0.174 mmol) was hydrolyzed in
analogy to example 2 to yield 31 mg of the title compound.
[0801] LC/MS (Method LC12): Rt=2.68 min; m/z=475.2 [MH.sup.+]
EXAMPLE 247
2-(3-{2-[3-(2-Acetylamino-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-i-
ndane-2-carboxylic acid
##STR00248##
[0803] The compound of Step 2 of example 246 (85 mg, 0.174 mmol)
was dissolved in acetic anhydride and stirred under reflux for 30
min. Water was added in excess and the mixture was refluxed for 10
min. After cooling, the mixture was extracted with EA, the combined
extracts were dried over sodium sulfate and evaporated to dryness.
The residue was purified by RP HPLC (water/ACN gradient) to yield
the methyl ester of the title compound. Hydrolysis of this ester in
analogy to example 2 yielded 17 mg of the title compound.
[0804] LC/MS (Method LC16): Rt=3.95 min; m/z=1031.2
[(2M-H).sup.-]
EXAMPLE 248
2-{3-[2-(3-Carbamoylmethyl-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane--
2-carboxylic acid
##STR00249##
[0805] Step 1: (3-Methoxycarbonylmethyl-phenyl)-acetic acid
[0806] (3-Carboxymethyl-phenyl)-acetic acid (7.4 g, 38.1 mmol) was
suspended in methanol (20 ml). Thionyl chloride (4.5 g, 38 mmol)
was added at about -30.degree. C. (vigorous reaction), and the
mixture subsequently stirred at room temperature for 90 min. After
completion of the reaction, the mixture was evaporated to dryness
to yield the diester as a yellow oil. This material was dissolved
in methanol (20 ml), solid lithium hydroxide (0.948 g, 1
equivalent) was added and the mixture stirred at room temperature
for 1 h. After evaporation of the methanol, the residue was
partitioned between 2 N hydrochloric acid and EA and the aqueous
phase extracted with EA. The combined organic phases were dried
over sodium sulfate and evaporated to dryness. The crude mixture of
diester, monoester and dicarboxylic acid was purified by RP HPLC
(water/ACN gradient) to yield 3.1 g of the title compound.
[0807] LC/MS (Method LC16): Rt=3.18 min; m/z=415.3
[(2M-H).sup.-]
Step 2: (3-Carbamoylmethyl-phenyl)-acetic acid methyl ester
[0808] The compound of step 1 (0.4 g, 1.92 mmol) was dissolved in
thionyl chloride (2.7 ml) and stirred at 60.degree. C. for 1 h. The
volatiles were evaporated, and the residue was dissolved in DCM and
added to a stirred mixture of EA and 28% aqueous ammonia. After
completion of the reaction, the mixture was partitioned between
water and EA and the aqueous phase extracted with EA. The combined
organic phases were dried over sodium sulfate and evaporated to
dryness to yield 0.278 g of the title compound.
[0809] LC/MS (Method LC16): Rt=2.56 min; m/z=252.0
[(M+HCOOH--H).sup.-]
Step 3: 2-[3-(2-Hydroxy-ethyl)-phenyl]-acetamide
[0810] The compound of step 2 (0.151 g, 0.729 mmol) was dissolved
in 0.5 ml of THF and added to a suspension of lithium aluminium
hydride (58 mg, 1.46 mmol) in THF (1.5 ml) at -78.degree. C. After
2 min, diethyl ether (6 ml) was added, followed by EA (0.2 ml).
After warming to room temperature, water was added slowly until the
alumina salts formed a thick slurry from which the supernatant
could be decanted easily. The slurry was washed repeatedly with EA.
The combined extracts were dried with sodium sulfate and evaporated
to dryness to yield 0.101 g of the title compound.
[0811] LC/MS (Method LC15): Rt=2.40 min; m/z=180.2 [MH.sup.+]
Step 4:
2-{3-[2-(3-Carbamoylmethyl-phenyl)-ethoxy]-4-methoxy-benzoylamino}-
-indane-2-carboxylic acid
[0812] The compound of step 3 was transformed into the title
compound in analogy to step 3 of example 15, followed by hydrolysis
in analogy to example 2.
[0813] LC/MS (Method LC12): Rt=2.93 min; m/z=489.3 [MH.sup.+]
EXAMPLE 249
2-(3-{2-[3-(2-Hydroxy-2-methyl-propyl)-phenyl]-ethoxy}-4-methoxy-benzoylam-
ino)-indane-2-carboxylic acid
##STR00250##
[0814] Step 1: [3-(2-Hydroxy-2-methyl-propyl)-phenyl]-acetic
acid
[0815] (3-Methoxycarbonylmethyl-phenyl)-acetic acid (500 mg, 2.40
mmol) was dissolved in THF (3.5 ml) and methylmagnesium chloride
(2.8 ml, 3 M solution in THF) was added slowly at room temperature.
After stirring for 30 min the reaction was completed. Water was
added cautiously and the mixture was partitioned between EA and 2 N
hydrochloric acid. The aqueous phase was extracted with EA and the
combined organic phases were dried over sodium sulfate and
evaporated to dryness. The residue was purified by RP HPLC
(water/ACN gradient) to yield 0.34 g of the title compound.
[0816] LC/MS (Method LC16): Rt=2.92 min; m/z=415.2
[(2M-H].sup.-]
Step 2: 1-[3-(2-Hydroxy-ethyl)-phenyl]-2-methyl-propan-2-ol
[0817] The compound of step 1 (0.132 g, 0.634 mmol) was dissolved
in THF (0.5 ml) and added to a refluxing suspension of lithium
aluminium hydride (122 mg, 3.1 mmol) in THF (1 ml). The mixture was
stirred for 1 h under reflux and cooled to room temperature.
Diethyl ether (6 ml) was added, followed by EA (0.4 ml).
Subsequently, water was added slowly until the alumina salts formed
a thick slurry from which the supernatant could be decanted easily.
The slurry was repeatedly washed with EA, the combined extracts
were dried with sodium sulfate and evaporated to dryness. The
residue was purified by RP HPLC (water/ACN gradient) to yield 49 mg
of the title compound.
[0818] .sup.1H-NMR: .delta.=7.15 (t, 1H); 7.06-7.00 (m, 3H); 4.59
(t, 1H); 4.23 (s, 1H); 3.58 (dt, 2H); 2.69 (t, 2H); 2.60 (s, 2H);
1.04 (s, 6H)
Step 3:
2-(3-{2-[3-(2-Hydroxy-2-methyl-propyl)-phenyl]-ethoxy}-4-methoxy-b-
enzoylamino)-indane-2-carboxylic acid
[0819] The compound of step 2 was transformed into the title
compound in analogy to step 3 of example 15, followed by hydrolysis
in analogy to example 2.
[0820] LC/MS (Method LC14): Rt=3.05 min; m/z=504.2 [MH.sup.+]
EXAMPLE 250
2-[4-Methoxy-3-(3-phenyl-oxetan-3-ylmethoxy)-benzoylamino]-indane-2-carbox-
ylic acid
##STR00251##
[0822] The compound of step 2 of example 15 and
(3-phenyl-oxetan-3-yl)-methanol (S. Kanoh et al., Tetrahedron 58
(2002), 7065-7074) were reacted in analogy to step 3 of example 15,
and the obtained methyl ester was hydrolyzed in analogy to example
16.
[0823] LC/MS (Method LC14): Rt=3.10 min; m/z=474.4 [MH.sup.+]
EXAMPLE 251
2-{3-[2-(3-Hydroxy-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carbox-
ylic acid
##STR00252##
[0824] Step 1: Acetic acid 3-(2-hydroxy-ethyl)-phenyl ester
[0825] 2-(3-Hydroxyphenyl)ethanol (400 mg, 2.90 mmol) was dissolved
in a mixture of 4 ml of dioxane and 4 ml of water, and sodium
hydrogencarbonate (2.43 g, 29 mmol) was added followed by acetic
anhydride (2.96 g, 29 mmol) with ice cooling. The mixture was
stirred overnight at room temperature and then partitioned between
2 N hydrochloric acid and EA. The aqueous phase was extracted with
EA, the combined organic phases were dried over sodium sulfate and
evaporated to dryness to yield the crude title compound which was
used without further purification.
Step 2:
2-{3-[2-(3-Hydroxy-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane--
2-carboxylic acid
[0826] The compound of step 1 and the compound of step 2 of example
15 were reacted in analogy to step 3 of example 15 and the obtained
ester hydrolyzed in analogy to example 16.
[0827] LC/MS (Method LC12): Rt=3.17 min; m/z=448.2 [MH.sup.+]
EXAMPLE 252
2-[3-Methoxy-4-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid
##STR00253##
[0828] Step 1: 3-Acetoxy-4-hydroxy-benzoic acid ethyl ester
[0829] 3,4-Dihydroxy-benzoic acid ethyl ester (550 mg, 3.02 mmol)
was dissolved in DMF (5 ml), potassium tert-butoxide (210 mg, 2.87
mmol) was added and the mixture stirred for 10 min. Acetic
anhydride (339 mg, 3.32 mmol) was added and stirring continued for
10 min. The mixture was partitioned between EA and 2 N hydrochloric
acid, and the aqueous phase extracted with EA. The combined organic
phases were dried over sodium chloride, decanted and evaporated to
dryness. The residue was purified by RP HPLC (water/ACN
gradient).
[0830] LC/MS (Method LC15): Rt=3.97 min; m/z=225.2 [MH.sup.+]
Step 2: 3-Acetoxy-4-(2-m-tolyl-ethoxy)-benzoic acid ethyl ester
[0831] The compound of step 1 (350 mg, 1.56 mmol) was reacted with
2-m-tolyl-ethanol in analogy to step 3 of example 15 to yield 450
mg of the title compound.
[0832] LC/MS (Method LC14): Rt=3.86 min; m/z=343.2 [MH.sup.+]
Step 3: 3-Methoxy-4-(2-m-tolyl-ethoxy)-benzoic acid methyl
ester
[0833] The compound of step 2 (150 mg, 0.438 mmol) was dissolved in
methanol (3 ml), potassium tert-butoxide (73 mg, 0.657 mmol) was
added and the mixture was stirred overnight under reflux. Potassium
carbonate (60 mg, 0.44 mmol) and iodomethane (124 mg, 0.876 mmol)
were then added repeatedly, at intervals of 1 h, with stirring
under reflux until completion of the reaction. The volatiles were
evaporated in vacuo, the residue was partitioned between EA and 2 N
hydrochloric acid, and the aqueous phase was extracted with EA. The
combined organic phases were dried over sodium chloride, decanted
and evaporated to dryness to yield the title compound.
[0834] LC/MS (Method LC15): Rt=5.27 min; m/z=301.2 [MH.sup.+]
Step 4:
2-[3-Methoxy-4-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxyli-
c acid
[0835] The compound of step 3 was hydrolyzed in analogy to example
2, the obtained carboxylic acid reacted with
2-amino-indane-2-carboxylic acid methyl ester in analogy to step 1
of example 15, and the obtained ester hydrolyzed in analogy to
example 2.
[0836] LC/MS (Method LC14): Rt=3.41 min; m/z=446.1 [MH.sup.+]
EXAMPLE 253
2-[4-Benzyloxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid
##STR00254##
[0837] Step 1: 3-Acetoxy-4-benzyloxy-benzoic acid ethyl ester
[0838] The compound of step 1 of example 252 (20 g, 89.2 mmol) was
dissolved in DMF (100 ml) and cooled in an ice bath. Potassium
carbonate (18.4 g, 134 mmol) and, immediately thereafter, benzyl
bromide (15.2 g, 89.2 mmol) were added. The mixture was stirred for
30 min at room temperature, filtered into a mixture of 2 N
hydrochloric acid and diethyl ether. The solid was washed
repeatedly with diethyl ether. The combined ethereal phases were
washed with water, dried over sodium chloride, decanted and
evaporated to dryness. The residue was purified by silica gel
chromatography (HEP/EA gradient) to yield 21 g of the title
compound.
[0839] LC/MS (Method LC14): Rt=3.68 min; m/z=315.1 [MH.sup.+]
Step 2: 4-Benzyloxy-3-hydroxy-benzoic acid ethyl ester
[0840] The compound of step 1 (10 g, 31.8 mmol) was dissolved in
methanol, potassium carbonate (88 mg, 0.636 mmol) was added and the
mixture was stirred for 2 h under reflux. After evaporation to
dryness, the residue was used without further purification in the
subsequent step.
[0841] LC/MS (Method LC14): Rt=3.32 min; m/z=273.1 [MH.sup.+]
Step 3:
2-[4-Benzyloxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxy-
lic acid methyl ester
[0842] The compound of step 2 was reacted with 2-m-tolyl-ethanol in
analogy to step 1 of example 1, and the obtained ester was
hydrolyzed in analogy to example 2. The obtained carboxylic acid
was reacted with 2-amino-indane-2-carboxylic acid methyl ester in
analogy to step 2 of example 13.
[0843] LC/MS (Method LC14): Rt=4.05 min; m/z=536.3 [MH.sup.+]
Step 4:
2-[4-Benzyloxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxy-
lic acid
[0844] The compound of step 3 was hydrolyzed in analogy to example
2.
[0845] LC/MS (Method LC14): Rt=3.79 min; m/z=522.2 [MH.sup.+]
EXAMPLE 254
2-[4-Hydroxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid
##STR00255##
[0846] Step 1:
2-[4-Hydroxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid methyl ester
[0847] The compound of step 3 of example 253 (800 mg, 1.49 mmol)
was dissolved in EA (15 ml) and hydrogenated in the presence of
palladium (10%) on charcoal (200 mg) at a hydrogen pressure of 5
bar and room temperature for 6 h. The mixture was filtered over
silica gel and evaporated to dryness. The residue was purified by
RP HPLC (water/ACN gradient) to yield 300 mg of the title
compound.
[0848] LC/MS (Method LC14): Rt=3.47 min; m/z=446.2 [MH.sup.+]
Step 2:
2-[4-Hydroxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxyli-
c acid
[0849] The compound of step 1 was hydrolyzed in analogy to example
2.
[0850] LC/MS (Method LC14): Rt=3.22 min; m/z=432.2 [MH.sup.+]
EXAMPLE 255
2-[4-Isopropoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid
##STR00256##
[0852] The compound of step 1 of example 254 was reacted with
2-propanol in analogy to step 1 of example 1 and the obtained ester
hydrolyzed in analogy to example 2.
[0853] LC/MS (Method LC14): Rt=3.71 min; m/z=474.2 [MH.sup.+]
[0854] In analogy to example 255, the following example compounds
of the formula Iw listed in table 9 were prepared by using the
respective alcohol instead of 2-propanol. In the formulae of the
groups R.sup.99 in table 9 the line crossed with the symbol
represents the free bond via which the group R.sup.99 is bonded to
the oxygen atom which is attached to the 4-position of the benzoyl
group depicted in formula Iw. I.e., in the formula of the complete
molecule the terminal endpoint of the line crossed with the said
symbol ends at the oxygen atom attached to the 4-position of the
benzoyl group. The compounds can be named as
2-[4-(R.sup.99-oxy)-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxyli-
c acid, for example as
2-[4-cyclopropylmethoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carbo-
xylic acid in the case of example 266.
##STR00257##
TABLE-US-00009 TABLE 9 Example compounds of the formula Iw Example
##STR00258## LC/MS Method m/z [MH.sup.+] Retention time [min] 256
##STR00259## LC21 488.3 (a) 4.67 257 ##STR00260## LC21 526.4 (a)
5.15 258 ##STR00261## LC21 514.3 (a) 4.69 259 ##STR00262## LC21
530.3 (a) 4.88 260 ##STR00263## LC21 526.2 (a) 4.82 261
##STR00264## LC2 516.2 4.42 262 ##STR00265## LC2 500.2 4.29 263
##STR00266## LC12 502.2 4.35 264 ##STR00267## LC12 530.2 3.95 265
##STR00268## LC12 503.2 2.87 266 ##STR00269## LC12 486.2 3.93 267
##STR00270## LC12 506.2 3.97 268 ##STR00271## LC20 478.2 11.26 269
##STR00272## LC12 472.2 3.93 (a) [(M-H).sup.-] instead of
[MH.sup.+]
EXAMPLE 270
2-[4-(2-Hydroxy-ethoxy)-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carbox-
ylic acid
##STR00273##
[0855] Step 1:
2-[4-(2-Acetoxy-ethoxy)-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carbo-
xylic acid
[0856] The compound of step 1 of example 254 (70 mg, 0.157 mmol)
was dissolved in DMF (1 ml). Potassium carbonate (108 mg, 0.786
mmol) was added and subsequently 2-bromoethyl acetate (39 mg, 0.235
mmol). The mixture was stirred at room temperature for 2 h and then
partitioned between EA and water. The aqueous phase was extracted
with EA, and the combined organic phases were dried over sodium
sulfate and evaporated to dryness. The residue was purified by RP
HPLC (water/ACN gradient).
[0857] LC/MS (Method LC18): Rt=2.59 min; m/z=532.2 [MH.sup.+]
Step 2:
2-[4-(2-Hydroxy-ethoxy)-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane--
2-carboxylic acid
[0858] The compound of step 1 was hydrolyzed in analogy to example
2 using 6 equivalents lithium hydroxide.
[0859] LC/MS (Method LC18): Rt=2.21 min; m/z=476.2 [MH.sup.+]
EXAMPLE 271
2-[4-Carboxymethoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid
##STR00274##
[0861] The title compound was prepared in analogy to example 270
from the compound of step 1 of example 254 and 2-bromo-acetamide.
In the final hydrolysis step, 6 equivalents of lithium hydroxide
were used, resulting in the hydrolysis of the ester moiety and the
acetamide moiety.
[0862] LC/MS (Method LC18): Rt=2.23 min; m/z=490.1 [MH.sup.+]
EXAMPLE 272
2-[4-Cyclopropoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic
acid
##STR00275##
[0863] Step 1:
2-[4-(1-Phenylsulfanyl-cyclopropoxy)-3-(2-m-tolyl-ethoxy)-benzoylamino]-i-
ndane-2-carboxylic acid
[0864] The compound of step 1 of example 254 (50 mg, 0.116 mmol),
(1-iodo-cyclopropylsulfanyl)-benzene (G. J. Hollingworth et al.,
Tetrahedron Lett. 40 (1999), 2633-2636) (64 mg, 0.232 mmol) and
silver carbonate (64 mg, 0.232 mmol) in toluene (1 ml) were stirred
overnight at 50.degree. C. The mixture was filtered, the filtrate
evaporated to dryness and the residue purified by silica gel
chromatography (HEP/EA gradient) to yield 44 mg of the title
compound.
[0865] LC/MS (Method LC14): Rt=4.23 min; m/z=594.2 [MH.sup.+]
Step 2:
2-[4-Cyclopropoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carb-
oxylic acid
[0866] 3-Chloroperbenzoic acid (43 mg, 0.177 mmol) was added to the
compound of step 1 (35 mg, 0.059 mmol) in DCM (2 ml) and saturated
aqueous sodium hydrogencarbonate solution (2 ml). The mixture was
stirred for 30 min at room temperature and then partitioned between
EA and a sodium carbonate solution. The aqueous phase was extracted
with EA and the combined organic phases were dried over sodium
sulfate and evaporated to dryness. The residue (44 mg) was
dissolved in a mixture of 0.5 ml of THF and 1 ml of methanol.
Disodium hydrogenphosphate (40 mg, 0.28 mmol) and sodium mercury
amalgam (5% sodium) (250 mg) were added and the mixture was stirred
for 30 min at room temperature and stored for 6 days at 5.degree.
C. Then the mixture was partitioned between 2 N hydrochloric acid
and EA, the aqueous phase extracted with EA, and the combined
organic extracts were dried over sodium chloride, decanted and
evaporated to dryness. The residue was purified by silica gel
chromatography (DCM/methanol/28% ammonia gradient, 90:10:1 to
85:15:1.5). The product fractions were evaporated to dryness and
the residue partitioned between 2 N hydrochloric acid and EA. The
aqueous phase was extracted with EA, and the combined organic
extracts were dried over sodium chloride, decanted and evaporated
to dryness.
[0867] LC/MS (Method LC14): Rt=3.60 min; m/z=472.2 [MH.sup.+]
EXAMPLE 273
2-{[5-Ethyl-4-(2-m-tolyl-ethoxy)-thiazole-2-carbonyl]-amino}-indane-2-carb-
oxylic acid
##STR00276##
[0869] 5-Ethyl-4-hydroxy-thiazole-2-carboxylic acid ethyl ester (F.
A. J. Kerdesky et al., J. Med. Chem. 34 (1991), 2158-2165) (100 mg,
0.497 mmol) was reacted with 2-m-tolyl-ethanol in analogy to step 1
of example 1 and subsequently the ester moiety hydrolyzed in
analogy to example 2. The obtained carboxylic acid was reacted with
2-amino-indane-2-carboxylic acid methyl ester hydrochloride in
analogy to step 2 of example 13 and the obtained ester hydrolyzed
in analogy to example 2.
[0870] LC/MS (Method LC12): Rt=4.17 min; m/z=451.2 [MH.sup.+]
EXAMPLE 274
2-({5-[2-(2-Fluoro-5-methyl-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-
-amino)-indane-2-carboxylic acid
##STR00277##
[0872] The title compound was prepared in analogy to example 208
using 2-(2-fluoro-5-methyl-phenyl)-ethanol instead of
2-m-tolyl-ethanol.
[0873] LC/MS (Method LC12): Rt=3.64 min; m/z=465.2 [MH.sup.+]
EXAMPLE 275
2-[(5-{2-[3-(2-Hydroxy-ethyl)-phenyl]-ethoxy}-6-methoxy-pyridine-3-carbony-
l)-amino]-indane-2-carboxylic acid
##STR00278##
[0875] 6-Chloro-5-nitro-nicotinic acid methyl ester was prepared
according to the procedure described in WO 2005/021544 and
transformed into 5-hydroxy-6-methoxy-nicotinic acid methyl ester
according to the procedure described in WO 95/04045. The latter
compound was transformed into the title compound by etherification
with 2-[3-(2-hydroxy-ethyl)-phenyl]-ethanol in analogy to step 1 of
example 1, hydrolysis of the ester group in analogy to example 2,
reaction of the obtained carboxylic acid with
2-amino-indane-2-carboxylic acid methyl ester hydrochloride in
analogy to step 3 of example 1, and hydrolysis of the ester group
in analogy to example 2.
[0876] LC/MS (Method LC14): Rt=2.90 min; m/z=477.2 [MH.sup.+]
EXAMPLE 276
2-(3-Fluoro-5-{2-[3-(2-hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylami-
no)-indane-2-carboxylic acid
##STR00279##
[0877] Step 1: Acetic acid 2-[3-(2-hydroxy-ethyl)-phenyl]-ethyl
ester
[0878] 2-[3-(2-Hydroxy-ethyl)-phenyl]-ethanol (2.49 g, 15.0 mmol)
was dissolved in ACN (5 ml) and acetic anhydride (3.06 g, 30 mmol)
added. The mixture was stirred under reflux for 1 h and then
evaporated to dryness. Silica gel chromatography (HEP/EA gradient)
of the residue yielded 1.30 g of the title compound
(mono-acetylated product).
[0879] .sup.1H-NMR: .delta.=7.20 (t, 1H); 7.10-7.05 (m, 3H); 4.61
(t, 1H); 4.19 (t, 2H); 3.59 (dt, 2H); 2.82 (t, 2H); 2.69 (t, 2H);
1.98 (s, 3H)
Step 2: 2-Fluoro-3-hydroxy-4-methoxybenzoic acid methyl ester and
3-fluoro-5-hydroxy-4-methoxybenzoic acid methyl ester
[0880] 3-Acetoxy-4-methoxy-benzoic acid methyl ester (WO
2005/009389) (3.58 g, 16.0 mmol) and
1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane
bis(tetrafluoroborate) (Selectfluor.RTM.) (14.1 g, 39.9 mmol) in
ACN were batchwise (7 batches) heated to 170.degree. C. for 7 min
in a microwave reactor. The combined batches were partitioned
between 2 N hydrochloric acid and diethyl ether. The aqueous phase
was extracted with diethyl ether, the combined organic phases were
dried over sodium sulfate, filtered and evaporated to dryness. The
residue was purified by silica gel chromatography (HEP/EA gradient)
to yield 0.7 g of a mixture of the isomeric fluorinated compounds
with and without an acetyl group. This mixture was dissolved in
methanol (5 ml) and, after addition of potassium carbonate (80 mg),
heated under reflux for 3 h. After evaporation to dryness, the
residue was partitioned between 2 N hydrochloric acid and EA, the
aqueous phase extracted with EA, and the combined extracts were
dried over sodium sulfate and evaporated to dryness. The residue
was separated by RP HPLC (water/ACN gradient) to yield 0.14 g of
2-fluoro-3-hydroxy-4-methoxybenzoic acid methyl ester and 0.27 g of
3-fluoro-5-hydroxy-4-methoxybenzoic acid methyl ester.
2-Fluoro-3-hydroxy-4-methoxybenzoic acid methyl ester
[0881] .sup.1H-NMR: .delta.=10.55 (s, 1H); 7.61 (dd, 1H); 6.80 (dd,
1H); 3.90 (s, 3H); 3.88 (s, 3H)
3-Fluoro-5-hydroxy-4-methoxybenzoic acid methyl ester
[0882] .sup.1H-NMR: .delta.=10.25 (s, 1H); 7.30 (br s, 1H); 7.21
(dd, 1H); 3.87 (s, 3H); 3.81 (s, 3H)
Step 3:
2-(3-Fluoro-5-{2-[3-(2-hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-be-
nzoylamino)-indane-2-carboxylic acid
[0883] The title compound was prepared from
3-fluoro-5-hydroxy-4-methoxybenzoic acid methyl ester by
etherification with the compound of step 1 in analogy to step 1 of
example 1, hydrolysis of both ester moieties of the obtained
compound with 6 equivalents of lithium hydroxide in analogy to
example 2, reaction of the obtained carboxylic acid with
2-amino-indane-2-carboxylic acid methyl ester hydrochloride in
analogy to step 3 of example 1, and hydrolysis of the methyl ester
in analogy to example 2.
[0884] LC/MS (Method LC14): Rt=3.11 min; m/z=494.2 [MH.sup.+]
EXAMPLE 277
2-[2-Fluoro-4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxyl-
ic acid
##STR00280##
[0886] 2-Fluoro-3-hydroxy-4-methoxybenzoic acid methyl ester was
etherified with 2-m-tolyl-ethanol in analogy to step 1 of example
1, the obtained ester hydrolyzed in analogy to example 2, the
obtained carboxylic acid reacted with 2-amino-indane-2-carboxylic
acid methyl ester hydrochloride in analogy to step 3 of example 1,
and the methyl ester hydrolyzed in analogy to example 2.
[0887] LC/MS (Method LC14): Rt=3.92 min; m/z=464.2 [MH.sup.+]
EXAMPLE 278
2-{4-Methoxy-3-[2-(3-methyl-cyclohexyl)-ethoxy]-benzoylamino}-indane-2-car-
boxylic acid
##STR00281##
[0888] Step 1: 4-Methoxy-3-[2-(3-methyl-cyclohexyl)-ethoxy]-benzoic
acid
[0889] The compound of step 1 of example 13 (100 mg) was dissolved
in ethanol (5 ml). Platinum(IV) oxide (12 mg) was added, the
mixture was hydrogenated for 1 h at room temperature at a hydrogen
pressure of 1 bar, filtered over celite and evaporated to dryness
to yield 99 mg of the title compound.
[0890] LC/MS (Method LC12): Rt=3.87 min; m/z=334.2
[(M+CH.sub.3CN+H)+]
Step 2:
2-{4-Methoxy-3-[2-(3-methyl-cyclohexyl)-ethoxy]-benzoylamino}-inda-
ne-2-carboxylic acid
[0891] The compound of step 1 was reacted with
2-amino-indane-2-carboxylic acid methyl ester hydrochloride in
analogy to step 4 of example 3 and the obtained ester hydrolyzed in
analogy to example 2.
[0892] LC/MS (Method LC18): Rt=2.72 min; m/z=452.2 [MH.sup.+]
EXAMPLE 279
2-[4-Methoxy-3-(3-methyl-benzyloxymethyl)-benzoylamino]-indane-2-carboxyli-
c acid
##STR00282##
[0893] Step 1:
2-(3-Formyl-4-methoxy-benzoylamino)-indane-2-carboxylic acid methyl
ester
[0894] 3-Formyl-4-methoxy-benzoic acid (F. D. Chattaway and F.
Calvet, J. Chem. Soc. (1928), 2913-2918) (1.017 g, 5.65 mmol) was
reacted with 2-amino-indane-2-carboxylic acid methyl ester
hydrochloride in analogy to step 4 of example 3. The obtained
product (1.895 g) was dissolved in acetic acid (20 ml), sodium
acetate (0.57 g, 6.96 mmol) was added and the mixture was stirred
under reflux for 24 h. The volatiles were evaporated in vacuo, the
residue partitioned between a saturated sodium hydrogencarbonate
solution and EA, and the aqueous phase extracted with EA. The
combined organic phases were dried over sodium sulfate and
evaporated to dryness to yield 1.52 g of the title compound.
[0895] LC/MS (Method LC14): Rt=3.00 min; m/z=354.1 [MH.sup.+]
Step 2:
2-(3-Hydroxymethyl-4-methoxy-benzoylamino)-indane-2-carboxylic acid
methyl ester
[0896] The compound of step 1 (0.500 g, 1.42 mmol) was dissolved in
THF (5 ml) and cooled in an ice bath. Sodium borohydride (0.164 g,
4.25 mmol) was added. Subsequently methanol (2 ml) was added
dropwise. After 1 h, the volatiles were evaporated, the residue was
partitioned between diethyl ether and a saturated sodium
hydrogencarbonate solution, and the aqueous phase extracted with
diethyl ether. The combined organic phases were dried over sodium
sulfate and evaporated to dryness.
[0897] LC/MS (Method LC14): Rt=2.74 min; m/z=356.1 [MH.sup.+]
Step 3:
2-[4-Methoxy-3-(3-methyl-benzyloxymethyl)-benzoylamino]-indane-2-c-
arboxylic acid
[0898] The compound of step 2 (50 mg, 0.14 mmol)) was dissolved in
DMF (3 ml) and sodium hydride (60% dispersion in mineral oil, 6.2
mg, 0.15 mmol) was added followed by 1-bromomethyl-3-methyl-benzene
(27 mg, 0.14 mmol). The mixture was stirred overnight. Then lithium
hydroxide (1 M solution in water, 0.42 ml) and dioxane (1 ml) were
added and the mixture heated to 60.degree. C. for 1 h. The residue
was partitioned between 2 N hydrochloric acid and EA and the
aqueous phase was extracted with EA. The combined organic phases
were dried over sodium sulfate and evaporated to dryness. The
residue was purified by RP HPLC (water/ACN gradient) to yield 5 mg
of the title compound.
[0899] LC/MS (Method LC14): Rt=3.44 min; m/z=446.2 [MH.sup.+]
[0900] In analogy to example 196, the example compounds of the
formula Iu listed in table 10 were prepared by using the respective
substituted phenylboronic acid instead of 3-isopropylphenylboronic
acid. In the case of examples 282, 283 and 284, the intermediary
2-[3-(R.sup.97)-4-methoxy-benzoylamino]-indane-2-carboxylic acid
methyl ester was purified by preparative RP HPLC (water/ACN
gradient) before hydrolysis. The compounds can be named as
2-[3-(R.sup.97)-4-methoxy-benzoylamino]-indane-2-carboxylic acid,
for example as
2-[3-(5-chloro-pyridin-3-yl)-4-methoxy-benzoylamino]-indane-2-carboxylic
acid in the case of example 282.
##STR00283##
TABLE-US-00010 TABLE 10 Example compounds of the formula Iu LC/MS
m/z Retention Example R.sup.97 Method [MH.sup.+] time [min] 280
4-chloro-phenyl LC22 422.22 2.37 281 2-chloro-phenyl LC22 422.22
2.17 282 5-chloro-pyridin-3-yl LC14 423.08 2.93 283
6-cyano-pyridin-2-yl LC12 414.19 3.17 284 5-cyano-pyridin-3-yl LC14
414.15 2.85
EXAMPLE 285
General procedure for the preparation of
2-(3-aryl-4-methoxy-benzoylamino)-indane-2-carboxylic acids
[0901] 0.3 mmol of the respective boronic acid were weighed into a
microwave reaction vial. 0.2 mmol of
2-(3-bromo-4-methoxy-benzoylamino)-indane-2-carboxylic acid methyl
ester in 2 ml of 1,2-dimethoxyethane and 0.4 mmol of cesium
fluoride in 1 ml of methanol were added, followed by 0.01 mmol of
tetrakis(triphenylphosphine)palladium(0) in 0.5 ml of methanol. The
vial was closed with a crimp cap and irradiated in a microwave
reactor at 130.degree. C. for 5 min. The cooled solution was
treated with 0.25 ml of 4 N aqueous sodium hydroxide and irradiated
for another 5 min at 130.degree. C. in a microwave reactor. The
cooled solution was neutralized with 0.25 ml of 4 N aqueous
hydrochloric acid and evaporated. The residue was dissolved in 2 ml
of DMF, filtered and submitted to preparative RP HPLC (water/ACN
gradient).
[0902] According to the general procedure described in example 285,
the compounds of the formula Iu listed in table 11 were prepared.
They can be named as
2-[3-(R.sup.97)-4-methoxy-benzoylamino]-indane-2-carboxylic acid,
for example as
2-[(3'-ethanesulfonyl-6-methoxy-biphenyl-3-carbonyl)-amino]-indane-2-carb-
oxylic acid in the case of example 312 in which the group R.sup.97
is 3-ethanesulfonyl-phenyl and, in view of the rules of
nomenclature, the group 3-(R.sup.97)-4-methoxy-phenyl-C(O) depicted
in formula Iu thus is named
3'-ethanesulfonyl-6-methoxy-biphenyl-3-carbonyl.
##STR00284##
TABLE-US-00011 TABLE 11 Example compounds of the formula Iu Ex- am-
LC/MS m/z Retention ple R.sup.97 Method [MH+] time [min] 286
3-methyl-phenyl LC13 402.21 2.55 287 3-acetylamino-phenyl LC13
445.23 2.14 288 3-ethoxy-phenyl LC13 432.21 2.55 289
2-chloro-5-trifluoromethyl-phenyl LC13 490.12 2.70 290
4-propyl-phenyl LC13 430.22 2.80 291 3,4-dimethyl-phenyl LC13
416.22 2.63 292 3,4-dichloro-phenyl LC13 456.12 2.75 293
2,3-dichloro-phenyl LC13 456.12 2.61 294
4-methoxy-3,5-dimethyl-phenyl LC13 446.22 2.57 295
benzo[b]thiophen-3-yl LC12 444.2 3.65 296 5-chloro-2-methoxy-phenyl
LC13 452.17 2.53 297 3-cyano-phenyl LC13 413.19 2.39 298
3-dimethylamino-phenyl LC13 472.27 1.88 299
2-dimethylaminomethyl-phenyl LC13 445.22 1.87 300
4-methyl-thiophen-2-yl LC13 408.16 2.54 301 3-methylsulfanyl-phenyl
LC13 434.18 2.56 302 3-trifluoromethoxy-phenyl LC13 472.14 2.70 303
2,5-dichloro-phenyl LC13 456.12 2.64 304 5-fluoro-2-methoxy-phenyl
LC13 436.18 2.43 305 3-benzyloxy-phenyl LC13 494.24 2.76 306
3,4,5-trifluoro-phenyl LC13 442.14 2.63 307
3-methanesulfonylamino-phenyl LC13 481.19 2.20 308
3-ethylsulfanyl-phenyl LC13 448.19 2.67 309
3-methanesulfonyl-phenyl LC13 466.18 2.21 310
4-chloro-3-trifluoromethyl-phenyl LC13 490.12 2.79 311
3-(pyrrolidin-1-yl)-phenyl LC13 498.27 2.22 312
3-ethanesulfonyl-phenyl LC13 480.19 2.28 313
3-tert-butyl-5-methyl-phenyl LC13 458.25 2.91 314
5-chloro-2-methyl-phenyl LC12 436.19 3.74 315
3-methoxymethyl-phenyl LC13 432.21 2.40 316 2-methoxymethyl-phenyl
LC12 432.25 3.34 317 2,4,5-trimethyl-phenyl LC13 430.22 2.69 318
3-propoxy-phenyl LC13 446.23 2.68 319 3-isopropoxy-phenyl LC13
446.18 2.58 320 2-fluoro-5-trifluoromethyl-phenyl LC13 474.01 2.60
321 3-chloro-4-propoxy-phenyl LC13 480.08 2.76 322
3-chloro-4-trifluoromethyl-phenyl LC13 490.01 2.75 323
3-methylcarbamoyl-phenyl LC13 445.12 2.08 324
3-cyclopropylmethoxy-phenyl LC13 458.12 2.61 325
3-chloro-4-methoxy-phenyl LC13 452.12 2.49 326 benzofuran-5-yl LC13
428.14 2.46 327 3-chloro-2-methyl-phenyl LC13 436.12 2.61 328
3-(2-carboxy-ethyl)-phenyl LC13 460.22 2.21 329
2-chloro-thiophen-3-yl LC13 428.09 2.45 330 1-methyl-1H-indol-5-yl
LC13 441.21 2.44 331 2-ethoxy-naphthalen-1-yl LC13 482.21 2.58 332
5-chloro-2-fluoro-phenyl LC13 440.11 2.53 333
5-chloro-2-fluoro-3-methyl-phenyl LC13 454.12 2.63 334
3-(pyrazol-1-yl)-phenyl LC13 454.16 2.37 335
5-fluoro-2-isopropoxy-phenyl LC13 464.19 2.56 336
2-fluoro-5-isopropoxy-phenyl LC13 464.16 2.57 337
5-fluoro-3-trifluoromethyl-phenyl LC13 474.09 2.68 338
3-dimethylaminomethyl-phenyl LC13 445.18 1.84 339
3-(acetylamino-methyl)-phenyl LC13 459.23 2.11 340
4-ethoxy-3-methyl-phenyl LC13 446.23 2.69 341
4-isopropoxy-3-methyl-phenyl LC13 460.24 2.78 342
3-chloro-5-fluoro-phenyl LC13 440.13 2.66 343
5-fluoro-3-isopropoxy-phenyl LC13 464.21 2.71 344
5-fluoro-3-isobutoxy-phenyl LC13 478.22 2.88 345
4-fluoro-3-trifluoromethyl-phenyl LC13 474.17 2.68 346
3-(2,2,2-trifluoro-ethoxy)-phenyl LC12 486.22 3.68 347
5-chloro-3-trifluoromethyl-phenyl LC13 490.13 2.83 348
2-fluoro-3-trifluoromethyl-phenyl LC13 474.13 2.63 349
5-methoxy-3-trifluoromethyl- LC13 486.16 2.69 phenyl 350
3-isobutyrylamino-phenyl LC12 473.28 3.30 351
5-chloro-2-trifluoromethyl-phenyl LC13 490.12 2.68
[0903] In analogy to the examples listed in table 1, the example
compounds of the formula Im listed in table 12 were prepared. In
the formulae of the groups R.sup.90 in table 12 the line crossed
with the symbol represents the free bond via which the group
R.sup.90 is bonded to the oxygen atom which is attached to the
3-position of the benzoyl group depicted in formula Im. I.e., in
the formula of the complete molecule the terminal endpoint of the
line crossed with the said symbol ends at the oxygen atom attached
to the 3-position of the benzoyl group. The compounds can be named
as 2-[3-(R.sup.90-oxy)-4-methoxy-benzoylamino]-indane-2-carboxylic
acid, for example as
2-{3-[2-(2-fluoro-5-trifluoromethoxy-phenyl)-ethoxy]-4-methoxy-benzoylami-
no}-indane-2-carboxylic acid in the case of example 355.
##STR00285##
TABLE-US-00012 TABLE 12 Example compounds of the formula Im Ex-
ample ##STR00286## LC/MS Method m/z [MH.sup.+] Reten- tion time
[min] 352 ##STR00287## LC13 500.04 2.77 353 ##STR00288## LC13
438.13 2.25 354 ##STR00289## LC13 473.18 2.37 355 ##STR00290## LC12
534.07 3.84
EXAMPLE 356
Starting Compound
2-(2-Fluoro-5-trifluoromethoxy-phenyl)-ethanol
[0904] 3.00 g (12.6 mmol) of
2-(2-fluoro-5-trifluoromethoxy-phenyl)-acetic acid were dissolved
in 50 ml of dry THF and dropped at 0.degree. C. into a suspension
of 956 mg (25.2 mmol) of lithium aluminium hydride in 11 ml of THF.
After stirring overnight, 150 ml of THF were added followed by 3 ml
of EA. 15 ml water were added dropwise and the supernatant decanted
from the resulting slurry. The slurry was extracted three times
with 20 ml of EA. The combined organic phases were dried over
sodium sulfate and evaporated. The remaining oil (2.5 g) was used
for the next step without further purification.
[0905] In analogy to example 356, the starting compounds
2-(benzo[d]isoxazol-3-yl)-ethanol and
2-(4-methyl-furazan-3-yl)-ethanol were prepared from
2-(benzo[d]isoxazol-3-yl)-acetic acid and
2-(4-methyl-furazan-3-yl)-acetic acid, respectively.
EXAMPLE 357
2-[(3'-Ethanesulfonyl-5-fluoro-6-methoxy-biphenyl-3-carbonyl)-amino]-indan-
e-2-carboxylic acid
##STR00291##
[0906] Step 1: 3-Bromo-5-fluoro-4-hydroxy-benzoic acid methyl
ester
[0907] During 30 min, 5.64 g (35.27 mmol) of bromine were added to
a solution of 5.00 g (29.39 mmol) of 3-fluoro-4-hydroxy-benzoic
acid methyl ester in 30 ml of DCM and 30 ml of acetic acid at
0.degree. C. After stirring overnight, 200 ml of methyl acetate
were added. The resulting solution was extracted with a solution of
7.56 g (60 mmol) of sodium sulfite in 50 ml of water, a saturated
sodium chloride solution and water. The organic phase was dried
over sodium sulfate, filtered and evaporated. The resulting white
solid (7.2 g) was used in the next step without further
purification.
Step 2: 3-Bromo-5-fluoro-4-methoxy-benzoic acid methyl ester
[0908] 6 g (24.09 mmol) of the product obtained in step 1 were
dissolved in 60 ml of acetone, 10.13 g (2.270 mmol) of potassium
carbonate and 6.84 g (48.18 mmol) of iodomethane were added, and
the mixture was stirred for 4 days. Then is was filtered and
evaporated. The resulting product (5.8 g) was used in the next step
without further purification.
Step 3: 3-Bromo-5-fluoro-4-methoxy-benzoic acid
[0909] 5.8 g of the product obtained in step 2 were dissolved in
100 ml of a mixture of THF and water (9:1), 1.06 g (44.1 mmol) of
lithium hydroxide were added and the mixture was stirred for 3
days. The solvent was evaporated and the residue was purified by
preparative RP HPLC (water/ACN gradient). 2.9 g of the title
compound were obtained.
Step 4:
2-(3-Bromo-5-fluoro-4-methoxy-benzoylamino)-indane-2-carboxylic
acid methyl ester
[0910] 2.4 g (9.64 mmol) of the compound of step 3 were dissolved
in 40 ml of DMF and 2.49 g (19.27 mmol) of EDIA and 4.03 g (10.60
mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate were added. Then a solution of 2.19 g (9.64
mmol) of 2-amino-indane-2-carboxylic acid methyl ester
hydrochloride in 10 ml of DMF was added. After stirring overnight,
the mixture was evaporated to dryness and the residue purified by
preparative RP HPLC (water/ACN gradient). 3.6 g of the title
compound were obtained.
Step 5:
2-[(3-Ethanesulfonyl-5-fluoro-6-methoxy-biphenyl-3-carbonyl)-amino-
]-indane-2-carboxylic acid
[0911] 300 mg (0.71 mmol) of the compound of step 4 and 175 mg
(1.07 mmol) of 3-ethanesulfonylphenylboronic acid were dissolved in
4 ml of DMF and 4 ml of 1,2-dimethoxyethane under an argon
atmosphere. 216 mg (1.42 mmol) of cesium fluoride and 41.08 mg
(0.04 mmol) of tetrakis(triphenylphosphine)palladium(0) were added,
and the mixture was heated to 130.degree. C. in a microwave reactor
for 15 min. After cooling, the solvent was evaporated and the
residue purified by preparative RP HPLC (water/ACN gradient) to
yield the methyl ester of the title compound. 135.1 mg (0.26 mmol)
methyl ester were dissolved in 5 ml of a mixture of THF and water
(9:1), 12.65 mg (0.53 mmol) of lithium hydroxide were added and the
mixture was stirred for 3 days. The solvent was evaporated and the
residue was purified by preparative RP HPLC (water/ACN gradient).
123 mg of the title compound were obtained.
[0912] LC/MS (Method LC14): Rt=3.07 min; m/z=498.19 [MH.sup.+]
[0913] 1H-NMR: .delta.=12.5 (br s, 1H); 8.90 (s, 1H); 7.98 (s, 1H);
7.75-7.95 (m, 6H); 7.28 (d, 4H); 3.30-3.64 (m, 6H); 1.13 (t,
3H)
[0914] In analogy to example 357, the example compounds of the
formula Ix listed in table 13 were prepared by using the respective
substituted phenylboronic acid instead of
3-ethanesulfonylphenylboronic acid. They can be named as
2-[3-(R.sup.100)-5-fluoro-4-methoxy-benzoylamino]-indane-2-carboxylic
acid, for example as
2-[(5-fluoro-3'-isopropyl-6-methoxy-biphenyl-3-carbonyl)-amino]-indane-2--
carboxylic acid in the case of example 360 in which the group
R.sup.100 is 3-isopropyl-phenyl and, in view of the rules of
nomenclature, the group
3-(R.sup.100)-5-fluoro-4-methoxy-phenyl-C(O) depicted in formula Ix
thus is named
5-fluoro-3'-isopropyl-6-methoxy-biphenyl-3-carbonyl.
##STR00292##
TABLE-US-00013 TABLE 13 Example compounds of the formula Ix Exam-
LC/MS m/z Retention ple R.sup.100 Method [MH.sup.+] time [min] 358
4-chloro-phenyl LC14 440.15 3.53 359 3-methanesulfonylamino- LC14
499.19 2.96 phenyl 360 3-isopropyl-phenyl LC14 448.22 4.08 361
3-dimethylaminosulfonylamino- LC14 528.21 3.28 phenyl
EXAMPLE 362
2-{3-[2-(2,
5-Dichloro-phenyl)-ethoxy]-4-trifluoromethyl-benzoylamino}-indane-2-carbo-
xylic acid
##STR00293##
[0916] The title compound was synthesized in analogy to example 185
by using 2,5-dichloro-phenyl-ethanol instead of
2-(3-methyl-phenyl)-ethanol in step 3.
[0917] LC/MS (Method LC13): Rt=538.01 min; m/z=3.06 min
[MH.sup.+]
Pharmacological Tests
A) Determination of Edg-2 Receptor Inhibition by Fluorescence
Imaging Plate Reader (FLIPR) Measurements
[0918] The inhibition of the Edg-2 receptor (LPA.sub.1 receptor) by
the compounds of the invention was quantified by the inhibitory
effect on the LPA-mediated calcium liberation in a cell-based
calcium fluorescence assay by use of Chinese hamster ovarian (CHO)
cells in which the human Edg-2 receptor was stably overexpressed
(Flp-In system, Invitrogen). In order to enforce G-Protein coupling
and to direct signaling towards Ca.sup.2+ liberation, the
overexpressed receptor additionally had a C-terminal sequence of a
modified G-protein (G.sub..alpha.i4qi4) (WO 02/04665). Changes in
intracellular calcium were determined by fluorescence measurement
with the calcium-sensitive dye fluo-4 (Invitrogen) in a
fluorescence imaging plate reader (FLIPR, Molecular Dynamics).
[0919] CHO cells stably overexpressing the human Edg-2 receptor
were seeded (40.000 per well) in black clear-bottomed
poly-D-lysine-coated 96 well plates (Becton Dickinson, Biocoat
cellware) approximately 18-24 h prior to the experiments. Cells
were grown in an incubator at 37.degree. C., 5% carbon dioxide and
95% humidity in cell culture media based on F-12 glutamax media
(Gibco, #31765) supplemented with 1% (vol/vol)
penicilline/streptomycine (PAN, #P06-07100), 10% (vol/vol) fetal
calf serum (FCS, PAA, #A15-151) and hygromycin B (Invitrogen,
#10687-010) 300 mg/I (final concentrations).
[0920] Prior to the FLIPR experiment, cells were loaded with fluo-4
acetoxymethyl ester (fluo-4 AM, Invitrogen, #F14202) for 60 min in
an incubator at 37.degree. C., 5% carbon dioxide and 95% humidity
in dye-loading buffer consisting of Hanks' Balanced Salt Solution
(HBSS, Invitrogen, #14065049) supplemented with fluo-4 AM at 2
.mu.M (all data given for final concentration), Pluronic.RTM. F-127
0.05% (vol/vol) (Invitrogen, #P-3000MP), HEPES 20 mM (Gibco,
#15630), probenecid 2.5 mM (Sigma, #P-8761) and bovine serum
albumin 0.05% (BSA, Sigma, #A-6003), adjusted to pH 7.5 with sodium
hydroxide. During cell loading, fluo-4 AM is cleaved by
intracellular esterase resulting in trapping of the dye fluo-4
within the cells. Loading was terminated by washing of the cells in
a cell washer (Tecan Power washer) three times with the buffer
specified afore but without fluo-4 AM and BSA. This latter buffer
was also used as the buffer in the subsequent cell fluorescence
measurements.
[0921] The dye-loaded and washed cells were pre-incubated for
approximately 5 min with various concentrations of the test
compound added as a solution in DMSO (0.3% vol/vol maximum final
concentration of DMSO), or with DMSO in the respective
concentration only (positive control). Subsequent addition of LPA
(18:1, 1-oleoyl-sn-glycerol 3-phosphate; 100 nM final
concentration) leads to liberation of intracellular calcium from
internal stores resulting in a large transient increase of the
fluo-4 fluorescence signal which was monitored over approximately 3
min. The percent inhibition caused by the test compound was
determined from the maximum fluorescence response after LPA
addition to cells pre-incubated with the compound as compared to
the maximum fluorescence response after LPA addition to cells
pre-incubated with DMSO only. All fluorescence values were
corrected for the baseline fluorescence values obtained with cells
which were pre-incubated with DMSO only and were not treated with
LPA (baseline control). All measurements were performed in
triplicate. From the percent inhibitions the inhibitory
concentration IC.sub.50 was determined.
[0922] Inhibitory concentrations IC.sub.50 of various example
compounds are given in table 14, wherein "a" denotes an IC.sub.50
of less than 0.1 .mu.M, "b" denotes an IC.sub.50 between 0.1 .mu.M
and 1 .mu.M, and "c" denotes an IC.sub.50 between 1 .mu.M and 30
.mu.M.
TABLE-US-00014 TABLE 14 Inhibitory concentrations IC.sub.50 for
inhibition of the Edg-2 receptor Example IC.sub.50 2 a 4 a 5 c 6 c
8 b 9 b 10 a 11 a 12 a 14 a 16 a 17 c 18 c 19 a 20 a 21 a 22 c 23 a
24 a 25 a 26 c 27 a 28 c 29 c 30 c 31 c 32 c 33 c 34 c 35 c 36 c 37
c 38 c 39 c 40 c 41 c 42 c 43 c 44 c 45 c 46 b 47 c 48 c 49 c 50 b
51 c 52 c 53 c 54 c 55 c 56 c 57 c 58 c 59 c 60 c 61 c 62 c 63 c 64
c 65 c 66 c 67 c 68 c 69 c 70 c 71 c 72 c 73 c 74 c 75 c 76 c 77 c
78 c 79 c 80 c 81 a 82 c 83 c 84 c 85 c 86 c 87 c 88 c 89 c 90 c 91
c 94 a 95 c 96 c 98 a 99 a 100 a 101 c 102 b 103 c 104 c 105 b 106
a 107 c 108 b 109 c 110 c 111 c 112 c 113 c 114 c 115 c 116 a 117 b
118 c 119 c 120 c 121 c 122 b 123 c 124 b 126 c 127 a 128 b 129 b
130 a 131 a 132 a 133 b 134 c 135 c 136 c 137 c 138 c 139 b 140 c
141 c 142 c 143 a 144 a 145 b 146 b 147 b 148 c 149 a 150 c 151 c
152 a 153 b 154 a 155 c 156 a 157 a 158 b 159 a 161 c 162 c 163 b
164 a 165 b 166 b 167 c 168 a 169 b 171 a 172 c 173 c 174 c 175 c
176 a 177 b 178 c 179 b 180 a 181 a 182 c 183 c 184 c 185 a 186 a
187 a 188 a 189 a 190 c 191 a 192 a 193 a 194 c 195 b 196 a 197 c
198 a 199 a 200 a 201 c 202 a 203 a 204 a 205 c 206 c 207 c 208 a
209 a 210 b 211 a 212 a 213 a 214 a 215 a 216 a 217 a 218 a 219 c
220 a 221 a 222 a 223 a 224 a 225 b 226 a 227 a 228 a 229 a 230 a
231 a 232 a 233 a 234 a 235 a 236 a 237 b 238 b 239 c 240 c 241 c
242 b 243 c 244 b 245 a 246 c 247 b 248 a 249 a 250 a 251 c 252 b
253 a 254 c 255 a 256 a
257 a 258 a 259 a 260 b 261 b 262 a 263 a 264 a 265 b 266 a 267 a
268 a 269 a 270 a 271 b 272 b 273 b 274 a 275 a 276 a 277 c 278 c
279 b 280 b 281 c 282 b 283 c 284 a 286 a 287 b 288 b 289 b 290 c
291 b 292 a 293 a 294 a 295 a 296 a 297 a 298 b 299 c 300 b 301 a
302 a 303 a 304 a 305 b 306 a 307 a 308 a 309 b 310 b 311 c 312 b
313 a 314 a 315 a 316 b 317 b 318 a 319 b 320 a 321 c 322 a 323 c
324 c 325 a 326 b 327 a 328 b 329 c 330 c 331 b 332 b 333 a 334 b
335 a 336 c 337 a 338 c 339 b 340 b 341 c 342 a 343 a 344 b 345 a
346 b 347 a 348 a 349 a 350 c 351 a 352 a 353 c 354 c 355 a 357 a
358 a 359 a 360 a 361 a 362 a
B) In Vivo Antihypertrophic and Renoprotective Activity
[0923] The in vivo pharmacological activity of the compounds of the
invention can be investigated, for example, in the model of
DOCA-salt sensitive rats with unilateral nephrectomy. Briefly, in
this model unilateral nephrectomy of the left kidney (UNX) is
performed on Sprague Dawley rats of 150 g to 200 g of body weight.
After the operation as well as at the beginning of each of the
following weeks 30 mg/kg of body weight of DOCA
(desoxycorticosterone acetate) are administered to the rats by
subcutaneous injection. The nephrectomized rats treated with DOCA
are supplied with drinking water containing 1% of sodium chloride
(UNX/DOCA rats). The UNX/DOCA rats develop high blood pressure,
endothelial dysfunction, myocardial hypertrophy and fibrosis as
well as renal dysfunction. In the test group (UNX/DOCA Test) and
the placebo group (UNX/DOCA Placebo), which consist of randomized
UNX/DOCA rats, the rats are treated orally by gavage in two part
administrations at 6 a.m. and 6 p.m. with the daily dose of the
test compound (for example 10 mg/kg of body weight dissolved in
vehicle) or with vehicle only, respectively. In a control group
(control), which consists of animals which have not been subjected
to UNX and DOCA administration, the animals receive normal drinking
water and are treated with vehicle only. After five weeks of
treatment, systolic blood pressure (SBP) and heart rate (HR) are
measured non-invasively via the tail cuff method. For determination
of albuminuria and creatinine, 24 h urine is collected on metabolic
cages. Endothelial function is assessed in excised rings of the
thoracic aorta as described previously (W. Linz et al., JRAAS
(Journal of the renin-angiotensin-aldosterone system) 7 (2006),
155-161). As a measure of myocardial hypertrophy and fibrosis,
heart weight, left ventricular weight and the relation of
hydroxyproline and proline are determined in excised hearts.
* * * * *