Title: Sulfur substituted sulfonylaminocarboxylic acid N-arylamides, their preparation, their use and pharmaceutical preparations comprising them
Abstract: The present invention relates to compounds of the formula I ##STR1##wherein A.sup.1, A.sup.2, R.sup.1, R.sup.2, R.sup.3, X and n are as defined in the claims, which are valuable pharmaceutically active compounds for the therapy and prophylaxis of diseases, for example of cardiovascular diseases such as hypertension, angina pectoris, cardiac insufficiency, thromboses or atherosclerosis. The compounds of the formula I are capable of modulating the body's production of cyclic guanosine monophosphate (cGMP) and are generally suitable for the therapy and prophylaxis of diseases which are associated with a disturbed cGMP balance. The invention furthermore relates to processes for preparing compounds of the formula I, to their use for the therapy and prophylaxis of the abovementioned diseases and for preparing pharmaceuticals for this purpose, and to pharmaceutical preparations which comprise compounds of the formula I.
Patent Number: 6,881,735 Issued on 04/19/2005 to Schindler, et al.
| Inventors:
|
Schindler; Ursula (Bad Soden, DE);
Schonafinger; Karl (Alzenau, DE);
Strobel; Hartmut (Liederbach, DE)
|
| Assignee:
|
Aventis Pharma Deutschland GmbH (Frankfurt am Main, DE)
|
| Appl. No.:
|
994730 |
| Filed:
|
November 28, 2001 |
Foreign Application Priority Data
| Jul 08, 1998[DE] | 198 30 430 |
| Jan 27, 1999[DE] | 199 03 126 |
| Current U.S. Class: |
514/227.8; 514/230.8; 514/235.5; 514/318; 514/352; 514/407; 514/447; 544/58.7; 544/131; 544/146; 546/194; 546/309; 548/371.7; 549/68 |
| Intern'l Class: |
A61K 031//54; C07D 279//12 |
| Field of Search: |
544/58.7,131,146
546/194,309
548/371.7
549/68
514/227.8,230.8,235.5,318,352,407,447
|
References Cited [Referenced By]
U.S. Patent Documents
| 6150356 | Nov., 2000 | Lloyd et al. | 514/218.
|
| 6511977 | Jan., 2003 | Lloyd et al. | 514/233.
|
| 6548547 | Apr., 2003 | Schindler et al. | 514/604.
|
| Foreign Patent Documents |
| 197 44 027 | Apr., 1999 | DE.
| |
| 0 908 456 | Apr., 1999 | EP.
| |
| 2201083 | Apr., 1974 | FR.
| |
| 876526 | Sep., 1961 | GB.
| |
| 96/31492 | Oct., 1996 | WO.
| |
Other References
Lloyd et al., Chemical Abstracts, vol. 132:207763, 2000.*
Ferlux-Chimie S.A., Chemical Abstracts, vol. 82:16861, 1975.*
Alexander Mulsch, et al., "Purification of Heme-Containing Soluble Guanylyl
Cyclase," Methods in Enzymology, vol. 195, pp. 377-383, 1991.
Hirano et al., "Silver Halide Photographic Material," Chemical Abstracts,
119:105757f:726, 1993.
Nagaoka et al., "Color Photographic Material With Good Sharpness and Low
Minimum Density," Chemical Abstracts, 120:41858a:807, 1994.
Fukagawa et al., "Direct Positive Color Photographic Material For Color
Image Formation and Color Proof," Chemical Abstracts, 123:70224h:1043,
1995.
Matsumoto et al., "Silver Halide Color Photographic Material With Excellent
Color Reproduction, Sharpness and Storage Stability," Chemical Abstracts,
126:257007u:1075, 1997.
Vesely, D.L., "B complex vitamins activate rat guanylate cyclase and
increase cyclic GMP levels," European Journal of Clinical Investigation,
1985, 15:258-262.
Vesely, D.L., "Phencyclidine Stimulates Guanylate Cyclase Activity,"
Biochemical and Biophysical Research Communications, 1979, 88:4:1244-1248.
Ignarro, L.J., "Regulation of Cytosolic Guanylyl Cylase by Porphyrins and
Metalloporphyrins," Advances in Pharmacology, 1994, 26:35-65.
Pettibone, D.J., et al., "A Structurally Novel Stimulator of Guanylate
Cyclase With Long-Lasting Hypotensive Activity In The Dog," European
Journal of Pharmacology, 1985, 116:307-312.
Yu, S.M., et al., "Vasorelaxant effect of isoliquiritigenin, a novel
soluble guanylate cyclase activator, in rat aorta,"British Journal of
Pharmacology, 1995, 114:1587-1594.
Ko, F.N., et al., "YC-1, a Novel Activator of Platelet Guanylate Cyclase,"
Blood, 1994, 84:12:4226-4233.
Yu, S.M., et al., "Mechanism of anti-proliferation caused by YC-1, an
indazole derivative, in cultured rat A10 vascular smooth-muscle cells,"
Biochem. J., 1995, 306:787-792.
Wu, C.C., et al., "YC-1 inhibited human platelet aggregation through
No-independent activation of soluble guanylate cyclase," British Journal
of Pharmacology, 1995, 116:1973-1978.
Konishiroku Photo Industry Co., Chemical Abstracts, vol. 102, abstract
140722, 1985.
Ikegami, Chemical Abstracts, vol. 122, abstract 92744, 1995.
|
Primary Examiner: Raymond; Richard L.
Attorney, Agent or Firm: Finnegan, Henderson, Farabow, Garrett & Dunner, L.L.P.
Parent Case Text
The present application is a divisional application of U.S. application
Ser. No. 09/349,933 filed on Jul. 8, 1999, and issued on Jan. 1, 2002 as
U.S. Pat. No. 6,335,334, which claims priority under 35 U.S.C. .sctn. 119
to German patent applications No. 19830430.7 filed on Jul. 8, 1998, and
No. 19903126.6 filed on Jan. 27, 1999; all three prior applications are
incorporated herein in their entirety by specific reference.
Claims
We claim:
1. A compound of formula I, a stereoisomeric form thereof, or a
physiologically acceptable salt thereof:
##STR11##
wherein
A.sup.1 is a divalent residue chosen from phenylene, naphthylene, and
heteroarylene, and is unsubstituted or substituted by one or more
identical or different substituents chosen from halogen, (C.sub.1
-C.sub.5)-alkyl, phenyl, tolyl, CF.sub.3, NO.sub.2, OH, --O--(C.sub.1
-C.sub.5)-alkyl, --O--(C.sub.2 -C.sub.4)-alkyl-O--(C.sub.1
-C.sub.3)-alkyl, (C.sub.1 -C.sub.2)-alkylenedioxy, NH.sub.2,
--NH--(C.sub.1 -C.sub.3)-alkyl, --N((C.sub.1 -C.sub.3)-alkyl).sub.2,
--NH--CHO, --NH--CO--(C.sub.1 -C.sub.5)-alkyl, --CN, --CO--NH.sub.2,
--CO--NH--(C.sub.1 -C.sub.3)-alkyl, --CO--N((C.sub.1
-C.sub.3)-alkyl).sub.2, --CO--OH, --CO--O--(C.sub.1 -C.sub.5)-alkyl,
heterocyclyl, CHO, --CO--(C.sub.1 -C.sub.5)-alkyl, --S(O).sub.n --(C.sub.1
-C.sub.4)-alkyl, --S(O).sub.n -phenyl, and --S(O).sub.n -tolyl;
A.sup.2, which comprises the two carbon atoms bonded to the groups
C(.dbd.X)--NH-- and NH--SO.sub.2 R.sup.2, is
a saturated or partially unsaturated or aromatic monocyclic 5-membered to
7-membered heterocycle which comprises one or more ring heteroatoms chosen
from nitrogen, oxygen, and sulfur, or
a saturated or partially unsaturated or aromatic bicyclic 8-membered to
10-membered heterocycle which comprises one or more ring heteroatoms
chosen from nitrogen, oxygen, and sulfur;
R.sup.1, when n in the group R.sup.1 --S(O).sub.n -- is 0, is aryl,
heterocyclyl, or (C.sub.1 -C.sub.18)-alkyl which is unsubstituted or
substituted by one or more identical or different residues R.sup.4, or is
--CN, or
when n in the group R.sup.1 --S(O).sub.n -- is 1, R.sup.1 is aryl,
heterocyclyl, or (C.sub.1 -C.sub.18)-alkyl which is unsubstituted or
substituted by one or more identical or different residues R.sup.4, or
when n in the group R.sup.1 --S(O).sub.n -- is 2, R.sup.1 is aryl,
heterocyclyl, or (C.sub.1 -C.sub.18)-alkyl which is unsubstituted or
substituted by one or more identical or different residues R.sup.4, or
R.sup.1 is NR.sup.5 R.sup.6 ;
R.sup.2 is aryl, heterocyclyl, NR.sup.5 R.sup.6, or (C.sub.1
-C.sub.10)-alkyl which is unsubstituted or substituted by one or more
identical or different residues R.sup.4 ;
R.sup.3 is one or more identical or different residues chosen from
hydrogen, halogen, CF.sub.3, OH, --O--(C.sub.1 -C.sub.7)-alkyl,
--O--(C.sub.2 -C.sub.4)-alkyl-O--(C.sub.1 -C.sub.7)-alkyl, --O-aryl,
(C.sub.1 -C.sub.2)-alkylenedioxy, NO.sub.2, --CN, NR.sup.7 R.sup.8,
--CO--NR.sup.7 R.sup.8, --CO--OH, --CO--O--(C.sub.1 -C.sub.5)-alkyl,
heterocyclyl, --S(O).sub.n --(C.sub.1 -C.sub.5)-alkyl, and (C.sub.1
-C.sub.5)-alkyl which is unsubstituted or substituted by one or more
identical or different residues R.sup.4 ;
R.sup.4 is fluorine, OH, --O--(C.sub.1 -C.sub.10)-alkyl, --O--(C.sub.2
-C.sub.4)-alkyl-O--(C.sub.1 -C.sub.7)-alkyl, --O-aryl, --CN, NR.sup.7
R.sup.8, --CO--NH.sub.2, --CO--NH--(C.sub.1 -C.sub.3)-alkyl,
--CO--N((C.sub.1 -C.sub.3)-alkyl).sub.2, --CO--OH, --CO--O--(C.sub.1
-C.sub.5)-alkyl, heterocyclyl, or oxo;
R.sup.5 is hydrogen, (C.sub.1 -C.sub.10)-alkyl which is unsubstituted or
substituted by one or more identical or different substituents chosen from
R.sup.4 and aryl, or is aryl, heterocyclyl, --CO--NR.sup.7 R.sup.8,
--CO-aryl, or --CO--(C.sub.1 -C.sub.10)-alkyl wherein the alkyl residue is
unsubstituted or substituted by one or more identical or different
residues R.sup.4 ;
R.sup.6 is hydrogen, (C.sub.1 -C.sub.10)-alkyl which is unsubstituted or
substituted by one or more identical or different substituents chosen from
R.sup.4 and aryl, or is aryl, heterocyclyl, --CO--NR.sup.7 R.sup.8,
--CO-aryl, or --CO--(C.sub.1 -C.sub.10)-alkyl wherein the alkyl residue is
unsubstituted or substituted by one or more identical or different
residues R.sup.4 ;
or R.sup.5 and R.sup.6 together with the nitrogen atom to which they are
bonded form a 5-membered to 8-membered saturated or partially unsaturated
ring, wherein said ring optionally further comprises one or more ring
heteroatoms chosen from nitrogen, oxygen, and sulfur, and wherein said
ring is unsubstituted or substituted by one or more identical or different
substituents chosen from fluorine, (C.sub.1 -C.sub.5)-alkyl,
hydroxy-(C.sub.1 -C.sub.3)-alkyl-, --(C.sub.1 -C.sub.3)-alkyl-O--(C.sub.1
-C.sub.4)-alkyl, aryl, CF.sub.3, OH, --O--(C.sub.1 -C.sub.7)-alkyl,
--O-aryl, --O--(C.sub.2 -C.sub.4)-alkyl-O--(C.sub.1 -C.sub.7)-alkyl,
(C.sub.2 -C.sub.3)-alkylenedioxy, NR.sup.7 R.sup.8, --CN, --CO--NH.sub.2,
--CO--NH--(C.sub.1 -C.sub.3)-alkyl, --CO--N((C.sub.1
-C.sub.3)-alkyl).sub.2, --CO--OH, --CO--O--(C.sub.1 -C.sub.5)-alkyl, CHO,
--CO--(C.sub.1 -C.sub.5)-alkyl, --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
--S(O).sub.n --NH.sub.2, --S(O).sub.n --NH--(C.sub.1 -C.sub.3)-alkyl,
--S(O).sub.n --N((C.sub.1 -C.sub.3)-alkyl).sub.2, oxo, --(CH.sub.2).sub.m
--NH.sub.2, --(CH.sub.2).sub.m --NH--(C.sub.1 -C.sub.4)-alkyl, and
--(CH.sub.2).sub.m --N((C.sub.1 -C.sub.4)-alkyl).sub.2 where in the
substituent --(CH.sub.2).sub.m --N((C.sub.1 -C.sub.4)-alkyl).sub.2 the two
alkyl groups are independent, identical or different, or are connected by
a single bond and together with the nitrogen atom to which they are bonded
form a 5-membered to 7-membered ring, which optionally further comprises
an oxygen atom, sulfur atom, or a group NR.sup.5 as a ring member;
R.sup.7 is hydrogen or (C.sub.1 -C.sub.7)-alkyl which is unsubstituted or
substituted by one or more identical or different substituents chosen from
OH, --O--(C.sub.1 -C.sub.5)-alkyl, NH.sub.2, --NH--(C.sub.1
-C.sub.4)-alkyl, and --N((C.sub.1 -C.sub.4)-alkyl).sub.2 where in the
substituent N((C.sub.1 -C.sub.4)-alkyl).sub.2 the two alkyl groups are
independent, identical or different, or are connected by a single bond and
together with the nitrogen atom to which they are bonded form a 5-membered
to 7-membered ring, wherein said ring optionally further comprises an
oxygen atom, sulfur atom, or a group NR.sup.5 as a ring member;
R.sup.8 is hydrogen, --CO--(C.sub.1 -C.sub.4)-alkyl, or (C.sub.1
-C.sub.7)-alkyl which is unsubstituted or substituted by one or more
identical or different substituents chosen from OH, --O--(C.sub.1
-C.sub.5)-alkyl, NH.sub.2, --NH--(C.sub.1 -C.sub.4)-alkyl, and
--N((C.sub.1 -C.sub.4)-alkyl).sub.2 where in the substituent N((C.sub.1
-C.sub.4)-alkyl).sub.2 the two alkyl groups are independent, identical or
different, or are connected by a single bond and together with the
nitrogen atom to which they are bonded form a 5-membered to 7-membered
ring which optionally further comprises an oxygen atom, a sulfur atom, or
a group NR.sup.5 as ring member;
aryl is phenyl, naphthyl, or heteroaryl, and is unsubstituted or
substituted by one or more identical or different substituents chosen from
halogen, (C.sub.1 -C.sub.5)-alkyl, phenyl, tolyl, CF.sub.3, --O--CF.sub.3,
NO.sub.2, OH, --O--(C.sub.1 -C.sub.5)-alkyl, --O--(C.sub.2
-C.sub.4)-alkyl-O--(C.sub.1 -C.sub.3)-alkyl, (C.sub.1
-C.sub.2)-alkylenedioxy, NH.sub.2, --NH--(C.sub.1 -C.sub.3)-alkyl,
--N((C.sub.1 -C.sub.3)-alkyl).sub.2, --NH--CHO, --NH--CO--(C.sub.1
-C.sub.5)-alkyl, --CN, --CO--NH.sub.2, --CO--NH--(C.sub.1 -C.sub.3)-alkyl,
--CO--N((C.sub.1 -C.sub.3)-alkyl).sub.2, --CO--OH, --CO--O--(C.sub.1
-C.sub.5)-alkyl, heterocyclyl, CHO, --CO--(C.sub.1 -C.sub.5)-alkyl,
--S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl, --S(O).sub.n -phenyl, and
--S(O).sub.n -tolyl;
heteroaryl and heteroarylene, independently of each other, are a residue of
a monocyclic 5-membered or 6-membered aromatic heterocycle or of a
bicyclic 8-membered to 10-membered aromatic heterocycle, wherein said
heterocycles comprise one or more ring heteroatoms chosen from nitrogen,
oxygen, and sulfur;
heterocyclyl is a residue of a monocyclic or polycyclic 5-membered to
11-membered saturated or partially unsaturated heterocycle which comprises
one or more ring heteroatoms chosen from nitrogen, oxygen, and sulfur, and
which is unsubstituted or substituted by one or more identical or
different substituents chosen from fluorine, (C.sub.1 -C.sub.5)-alkyl, OH,
--O--(C.sub.1 -C.sub.5)-alkyl, --O--(C.sub.2 -C.sub.4)-alkyl-O--(C.sub.1
-C.sub.3)-alkyl, NH.sub.2, --NH--(C.sub.1 -C.sub.3)-alkyl, --N((C.sub.1
-C.sub.3)-alkyl).sub.2, --CN, --CO--NH.sub.2, --CO--NH--(C.sub.1
-C.sub.3)-alkyl, --CO--N((C.sub.1 -C.sub.3)-alkyl).sub.2, --CO--OH, and
--CO--O--(C.sub.1 -C.sub.5)-alkyl;
n is 0, 1, or 2;
m is 2, 3, or 4; and
X is oxygen or NH, or X is a nitrogen atom which via a single bond is
attached to a ring carbon atom in the group A.sup.1 which ring carbon atom
is directly adjacent to the carbon atom in A.sup.1 bonded to the group
--NH--C(.dbd.X)-- so that the group --NH--C(.dbd.X)-- together with the
carbon atoms in A.sup.1 bonded to it forms an anellated imidazole ring.
2. The compound of the formula I as claimed in claim 1, wherein A.sup.1 is
a phenylene residue or a 5-membered or 6-membered heteroarylene residue,
wherein said residues are unsubstituted or substituted as set forth in
claim 1.
3. The compound of the formula I as claimed in claim 1, wherein A.sup.2 is
an aromatic ring.
4. The compound of the formula I as claimed in claim 1, wherein X is
oxygen.
5. The compound of the formula I as claimed in claim 1, wherein R.sup.2 is
aryl and is unsubstituted or substituted as set forth in claim 1.
6. The compound of the formula I as claimed in claim 1, wherein R.sup.1 is
(C.sub.1 -C.sub.7)-alkyl, aryl, or NR.sup.5 R.sup.6, and is unsubstituted
or substituted as set forth in claim 1.
7. The compound of the formula I as claimed in claim 1, wherein R.sup.1 is
NR.sup.5 R.sup.6 and R.sup.5 and R.sup.6 independently of one another are
hydrogen, (C.sub.1 -C.sub.9)-alkyl, (C.sub.1 -C.sub.4)-alkyl-O--(C.sub.1
-C.sub.3)-alkyl-, or 5-membered or 6-membered aryl or R.sup.5 and R.sup.6
together with the nitrogen atom to which they are bonded form a 5-membered
to 7-membered heterocycle which optionally further comprises an additional
ring heteroatom chosen from nitrogen, oxygen, and sulfur, wherein said
heterocycle is unsubstituted or substituted by one or more identical or
different residues chosen from (C.sub.1 -C.sub.3)-alkyl, hydroxy-(C.sub.1
-C.sub.3)-alkyl-, 5-membered or 6-membered aryl, carbamoyl, hydroxy, and
oxo.
8. The compound of the formula I as claimed in claim 1, wherein
A.sup.1 is phenylene or heteroarylene, and is unsubstituted or substituted
by one or more identical or different substituents chosen from halogen,
(C.sub.1 -C.sub.4)-alkyl, CF.sub.3, --O--(C.sub.1 -C.sub.4)-alkyl, and
--CN;
A.sup.2 is an aromatic ring;
R.sup.1, when n in the group R.sup.1 --S(O).sub.n -- is 1, is (C.sub.1
-C.sub.7)-alkyl which is unsubstituted or substituted by one or more
identical or different residues R.sup.4, or R.sup.1 is aryl, or
when n in the group R.sup.1 --S(O).sub.n -- is 2, R.sup.1 is aryl, or
(C.sub.1 -C.sub.7)-alkyl which is unsubstituted or substituted by one or
more identical or different residues R.sup.4, or R.sup.1 is NR.sup.5
R.sup.6 ;
R.sup.2 is aryl;
R.sup.3 is one or more identical or different residues chosen from
hydrogen, halogen, CF.sub.3, OH, --O--(C.sub.1 -C.sub.4)-alkyl,
--O--(C.sub.2 -C.sub.4)-alkyl-O--(C.sub.1 -C.sub.4)-alkyl, --O-aryl,
NO.sub.2, --CN, NR.sup.7 R.sup.8, --CO--NR.sup.7 R.sup.8, --CO--OH,
--CO--O--(C.sub.1 -C.sub.4)-alkyl, heterocyclyl, --S(O).sub.n --(C.sub.1
-C.sub.4)-alkyl, and (C.sub.1 -C.sub.4)-alkyl which is unsubstituted or
substituted by one or more identical or different residues R.sup.4 ;
R.sup.4 is fluorine, OH, --O--(C.sub.1 -C.sub.10)-alkyl, --O--(C.sub.2
-C.sub.4)-alkyl-O--(C.sub.1 -C.sub.7)-alkyl, --O-aryl, --CN, NR.sup.7
R.sup.8, --CO--NH.sub.2, --CO--NH--(C.sub.1 -C.sub.3)-alkyl,
--CO--N((C.sub.1 -C.sub.3)-alkyl).sub.2, --CO--OH, --CO--O--(C.sub.1
-C.sub.4)-alkyl, heterocyclyl, or oxo;
R.sup.5 and R.sup.6 independently of one another are hydrogen, (C.sub.1
-C.sub.9)-alkyl, (C.sub.1 -C.sub.4)-alkyl-O--(C.sub.1 -C.sub.3)-alkyl-, or
aryl, or
R.sup.5 and R.sup.6 together with the nitrogen to which they are bonded
form a 5-membered, 6-membered, or 7-membered heterocycle, wherein said
heterocycle optionally further comprises an additional ring heteroatom
chosen from nitrogen, oxygen, and sulfur, and wherein said heterocycle is
unsubstituted or substituted by one or more identical or different
residues chosen from (C.sub.1 -C.sub.3)-alkyl, hydroxy-(C.sub.1
-C.sub.3)-alkyl-, aryl, carbamoyl, hydroxy, and oxo;
R.sup.7 is hydrogen, (C.sub.1 -C.sub.3)-alkyl, ((C.sub.1
-C.sub.4)-alkyl).sub.2 N--(C.sub.1 -C.sub.3)-alkyl-, or (C.sub.1
-C.sub.4)-alkyl-O--(C.sub.1 -C.sub.3)-alkyl-;
R.sup.8 is hydrogen, (C.sub.1 -C.sub.3)-alkyl, or acetyl;
aryl is phenyl or heteroaryl, and is unsubstituted or substituted by one or
more identical or different substituents chosen from halogen, (C.sub.1
-C.sub.4)-alkyl, phenyl, CF.sub.3, NO.sub.2, --O--(C.sub.1
-C.sub.4)-alkyl, (C.sub.1 -C.sub.2)-alkylenedioxy, NH.sub.2,
--NH--CO--(C.sub.1 -C.sub.4)-alkyl, --CN, --CO--NH.sub.2, --CO--OH, and
--CO--O--(C.sub.1 -C.sub.4)-alkyl;
heteroaryl and heteroarylene are a residue of a monocyclic 5-membered or
6-membered aromatic heterocycle which comprises one or more identical or
different ring heteroatoms chosen from nitrogen, oxygen, and sulfur;
heterocyclyl is a residue of a monocyclic 5-membered or 6-membered
saturated heterocycle which comprises one or more identical or different
ring heteroatoms chosen from nitrogen, oxygen, and sulfur, and which is
unsubstituted or substituted by one or more identical or different
substituents chosen from fluorine, (C.sub.1 -C.sub.4)-alkyl, OH,
--O--(C.sub.1 -C.sub.4)-alkyl, NH.sub.2, --CN, --CO--NH.sub.2, --CO--OH,
and --CO--O--(C.sub.1 -C.sub.4)-alkyl;
n is 0, 1, or 2; and
X is oxygen.
9. A method for preparing a compound of formula I, comprising:
converting a cyclic aminocarboxylic acid compound of formula II into a
sulfonylaminocarboxylic acid compound of formula III; and
converting the sulfonylaminocarboxylic acid compound of formula III into a
compound of formula I:
##STR12##
wherein, in the compounds of formulae I, II, and III:
A.sup.1 is a divalent residue chosen from phenylene, naphthylene, and
heteroarylene, and is unsubstituted or substituted by one or more
identical or different substituents chosen from halogen, (C.sub.1
-C.sub.5)-alkyl, phenyl, tolyl, CF.sub.3, NO.sub.2, OH, --O--(C.sub.1
-C.sub.5)-alkyl, --O--(C.sub.2 -C.sub.4)-alkyl-O--(C.sub.1
-C.sub.3)-alkyl, (C.sub.1 -C.sub.2)-alkylenedioxy, NH.sub.2,
--NH--(C.sub.1 -C.sub.3)-alkyl, --N((C.sub.1 -C.sub.3)-alkyl).sub.2,
--NH--CHO, --NH--CO--(C.sub.1 -C.sub.5)-alkyl, --CN, --CO--NH.sub.2,
--CO--NH--(C.sub.1 -C.sub.3)-alkyl, --CO--N((C.sub.1
-C.sub.3)-alkyl).sub.2, --CO--OH, --CO--O--(C.sub.1 -C.sub.5)-alkyl,
heterocyclyl, CHO, --CO--(C.sub.1 -C.sub.5)-alkyl, --S(O).sub.n --(C.sub.1
-C.sub.4)-alkyl, --S(O).sub.n -phenyl, and --S(O).sub.n -tolyl;
A.sup.2, which comprises the two carbon atoms bonded to the groups
C(.dbd.X)--NH-- and NH--SO.sub.2 R.sup.2, is
a saturated or partially unsaturated or aromatic monocyclic 5-membered to
7-membered heterocycle which comprises one or more ring heteroatoms chosen
from nitrogen, oxygen, and sulfur, or
a saturated or partially unsaturated or aromatic bicyclic 8-membered to
10-membered heterocycle which comprises one or more ring heteroatoms
chosen from nitrogen, oxygen, and sulfur;
R.sup.1, when n in the group R.sup.1 --S(O).sub.n -- is 0, is aryl,
heterocyclyl, or (C.sub.1 -C.sub.18)-alkyl which is unsubstituted or
substituted by one or more identical or different residues R.sup.4, or is
--CN, or
when n in the group R.sup.1 --S(O).sub.n -- is 1, R.sup.1 is aryl,
heterocyclyl, or (C.sub.1 -C.sub.18)-alkyl which is unsubstituted or
substituted by one or more identical or different residues R.sup.4, or
when n in the group R.sup.1 --S(O).sub.n -- is 2, R.sup.1 is aryl,
heterocyclyl, or (C.sub.1 -C.sub.18)-alkyl which is unsubstituted or
substituted by one or more identical or different residues R.sup.4, or
R.sup.1 is NR.sup.5 R.sup.6 ;
R.sup.2 is aryl, heterocyclyl, NR.sup.5 R.sup.6, or (C.sub.1
-C.sub.10)-alkyl which is unsubstituted or substituted by one or more
identical or different residues R.sup.4 ;
R.sup.3 is one or more identical or different residues chosen from
hydrogen, halogen, CF.sub.3, OH, --O--(C.sub.1 -C.sub.7)-alkyl,
--O--(C.sub.2 -C.sub.4)-alkyl-O--(C.sub.1 -C.sub.7)-alkyl, --O-aryl,
(C.sub.1 -C.sub.2)-alkylenedioxy, NO.sub.2, --CN, NR.sup.7 R.sup.8,
--CO--NR.sup.7 R.sup.8, --CO--OH, --CO--O--(C.sub.1 -C.sub.5)-alkyl,
heterocyclyl, --S(O).sub.n --(C.sub.1 -C.sub.5)-alkyl, and (C.sub.1
-C.sub.5)-alkyl which is unsubstituted or substituted by one or more
identical or different residues R.sup.4 ;
R.sup.4 is fluorine, OH, --O--(C.sub.1 -C.sub.10)-alkyl, --O--(C.sub.2
-C.sub.4)-alkyl-O--(C.sub.1 -C.sub.7)-alkyl, --O-aryl, --CN, NR.sup.7
R.sup.8, --CO--NH.sub.2, --CO--NH--(C.sub.1 -C.sub.3)-alkyl,
--CO--N((C.sub.1 -C.sub.3)-alkyl).sub.2, --CO--OH, --CO--O--(C.sub.1
-C.sub.5)-alkyl, heterocyclyl, or oxo;
R.sup.5 is hydrogen, (C.sub.1 -C.sub.10)-alkyl which is unsubstituted or
substituted by one or more identical or different substituents chosen from
R.sup.4 and aryl, or is aryl, heterocyclyl, --CO--NR.sup.7 R.sup.8,
--CO-aryl, or --CO--(C.sub.1 -C.sub.10)-alkyl wherein the alkyl residue is
unsubstituted or substituted by one or more identical or different
residues R.sup.4 ;
R.sup.6 is hydrogen, (C.sub.1 -C.sub.10)-alkyl which is unsubstituted or
substituted by one or more identical or different substituents chosen from
R.sup.4 and aryl, or is aryl, heterocyclyl, --CO--NR.sup.7 R.sup.8,
--CO-aryl, or --CO--(C.sub.1 -C.sub.10)-alkyl wherein the alkyl residue is
unsubstituted or substituted by one or more identical or different
residues R.sup.4 ;
or R.sup.5 and R.sup.6 together with the nitrogen atom to which they are
bonded form a 5-membered to 8-membered saturated or partially unsaturated
ring, wherein said ring optionally further comprises one or more ring
heteroatoms chosen from nitrogen, oxygen, and sulfur, and wherein said
ring is unsubstituted or substituted by one or more identical or different
substituents chosen from fluorine, (C.sub.1 -C.sub.5)-alkyl,
hydroxy-(C.sub.1 -C.sub.3)-alkyl-, --(C.sub.1 -C.sub.3)-alkyl-O--(C.sub.1
-C.sub.4)-alkyl, aryl, CF.sub.3, OH, --O--(C.sub.1 -C.sub.7)-alkyl,
--O-aryl, --O--(C.sub.2 -C.sub.4)-alkyl-O--(C.sub.1 -C.sub.7)-alkyl,
(C.sub.2 -C.sub.3)-alkylenedioxy, NR.sup.7 R.sup.8, --CN, --CO--NH.sub.2,
--CO--NH--(C.sub.1 -C.sub.3)-alkyl, --CO--N((C.sub.1
-C.sub.3)-alkyl).sub.2, --CO--OH, --CO--O--(C.sub.1 -C.sub.5)-alkyl, CHO,
--CO--(C.sub.1 -C.sub.5)-alkyl, --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
--S(O).sub.n --NH.sub.2, --S(O).sub.n --NH--(C.sub.1 -C.sub.3)-alkyl,
--S(O).sub.n --N((C.sub.1 -C.sub.3)alkyl).sub.2, oxo, --(CH.sub.2).sub.m
--NH.sub.2, --(CH.sub.2).sub.m --NH--(C.sub.1 -C.sub.4)-alkyl, and
--(CH.sub.2).sub.m --N((C.sub.1 -C.sub.4)-alkyl).sub.2 where in the
substituent --(CH.sub.2).sub.m --N((C.sub.1 -C.sub.4)-alkyl).sub.2 the two
alkyl groups are independent, identical or different, or are connected by
a single bond and together with the nitrogen atom to which they are bonded
form a 5-membered to 7-membered ring, which optionally further comprises
an oxygen atom, sulfur atom, or a group NR.sup.5 as a ring member;
R.sup.7 is hydrogen or (C.sub.1 -C.sub.7)-alkyl which is unsubstituted or
substituted by one or more identical or different substituents chosen from
OH, --O--(C.sub.1 -C.sub.5)-alkyl, NH.sub.2, --NH--(C.sub.1
-C.sub.4)-alkyl, and --N((C.sub.1 -C.sub.4)-alkyl).sub.2 where in the
substituent N((C.sub.1 -C.sub.4)-alkyl).sub.2 the two alkyl groups are
independent, identical or different, or are connected by a single bond and
together with the nitrogen atom to which they are bonded form a 5-membered
to 7-membered ring, wherein said ring optionally further comprises an
oxygen atom, sulfur atom, or a group NR.sup.5 as a ring member;
R.sup.8 is hydrogen, --CO--(C.sub.1 -C.sub.4)-alkyl, or (C.sub.1
-C.sub.7)-alkyl which is unsubstituted or substituted by one or more
identical or different substituents chosen from OH, --O--(C.sub.1
-C.sub.5)-alkyl, NH.sub.2, --NH--(C.sub.1 -C.sub.4)-alkyl, and
--N((C.sub.1 -C.sub.4)-alkyl).sub.2 where in the substituent N((C.sub.1
-C.sub.4)-alkyl).sub.2 the two alkyl groups are independent, identical or
different, or are connected by a single bond and together with the
nitrogen atom to which they are bonded form a 5-membered to 7-membered
ring which optionally further comprises an oxygen atom, a sulfur atom, or
a group NR.sup.5 as ring member;
aryl is phenyl, naphthyl, or heteroaryl, and is unsubstituted or
substituted by one or more identical or different substituents chosen from
halogen, (C.sub.1 -C.sub.5)-alkyl, phenyl, tolyl, CF.sub.3, --O--CF.sub.3,
NO.sub.2, OH, --O--(C.sub.1 -C.sub.5)-alkyl, --O--(C.sub.2
-C.sub.4)-alkyl-O--(C.sub.1 -C.sub.3)-alkyl, (C.sub.1
-C.sub.2)-alkylenedioxy, NH.sub.2, --NH--(C.sub.1 -C.sub.3)-alkyl,
--N((C.sub.1 -C.sub.3)-alkyl).sub.2, --NH--CHO, --NH--CO--(C.sub.1
-C.sub.5)-alkyl, --CN, --CO--NH.sub.2, --CO--NH--(C.sub.1 -C.sub.3)-alkyl,
--CO--N((C.sub.1 -C.sub.3)-alkyl).sub.2, --CO--OH, --CO--O--(C.sub.1
-C.sub.5)-alkyl, heterocyclyl, CHO, --CO--(C.sub.1 -C.sub.5)-alkyl,
--S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl, --S(O).sub.n -phenyl, and
--S(O).sub.n -tolyl;
heteroaryl and heteroarylene, independently of each other, are a residue of
a monocyclic 5-membered or 6-membered aromatic heterocycle or of a
bicyclic 8-membered to 10-membered aromatic heterocycle, wherein said
heterocycles comprise one or more ring heteroatoms chosen from nitrogen,
oxygen, and sulfur;
heterocyclyl is a residue of a monocyclic or polycyclic 5-membered to
11-membered saturated or partially unsaturated heterocycle which comprises
one or more ring heteroatoms chosen from nitrogen, oxygen, and sulfur, and
which is unsubstituted or substituted by one or more identical or
different substituents chosen from fluorine, (C.sub.1 -C.sub.5)-alkyl, OH,
--O--(C.sub.1 -C.sub.5)-alkyl, --O--(C.sub.2 -C.sub.4)-alkyl-O--(C.sub.1
-C.sub.3)-alkyl, NH.sub.2, --NH--(C.sub.1 -C.sub.3)-alkyl, --N((C.sub.1
-C.sub.3)-alkyl).sub.2, --CN, --CO--NH.sub.2, --CO--NH--(C.sub.1
-C.sub.3)-alkyl, --CO--N((C.sub.1 -C.sub.3)-alkyl).sub.2, --CO--OH, and
--CO--O--(C.sub.1 -C.sub.5)-alkyl;
n is 0, 1, or 2;
m is 2, 3, or 4; and
X is oxygen or NH, or X is a nitrogen atom which via a single bond is
attached to a ring carbon atom in the group A.sup.1 which ring carbon atom
is directly adjacent to the carbon atom in A.sup.1 bonded to the group
--NH--C(.dbd.X)-- so that the group --NH--C(.dbd.X)-- together with the
carbon atoms in A.sup.1 bonded to it forms an anellated imidazole ring;
or when one or more of said residues, independent of each other, are
present in protected form or in a form of precursor groups.
10. A method for preparing a compound of formula I, comprising:
converting a cyclic nitrocarboxylic acid compound of formula IX into a
nitrocarboxamide compound of formula XII; and
converting the nitrocarboxamide compound of the formula XII into a compound
of formula I by
reducing the nitro group to an amino group, and sulfonylating the amino
group:
##STR13##
wherein, in the compounds of formulae IX, XII, and I:
A.sup.1 is a divalent residue chosen from phenylene, naphthylene, and
heteroarylene, and is unsubstituted or substituted by one or more
identical or different substituents chosen from halogen, (C.sub.1
-C.sub.5)-alkyl, phenyl, tolyl, CF.sub.3, NO.sub.2, OH, --O--(C.sub.1
-C.sub.5)-alkyl, --O--(C.sub.2 -C.sub.4)-alkyl-O--(C.sub.1
-C.sub.3)-alkyl, (C.sub.1 -C.sub.2)-alkylenedioxy, NH.sub.2,
--NH--(C.sub.1 -C.sub.3)-alkyl, --N((C.sub.1 -C.sub.3)-alkyl).sub.2,
--NH--CHO, --NH--CO--(C.sub.1 -C.sub.5)-alkyl, --CN, --CO--NH.sub.2,
--CO--NH--(C.sub.1 -C.sub.3)-alkyl, --CO--N((C.sub.1
-C.sub.3)-alkyl).sub.2, --CO--OH, --CO--O--(C.sub.1 -C.sub.5)-alkyl,
heterocyclyl, CHO, --CO--(C.sub.1 -C.sub.5)-alkyl, --S(O).sub.n --(C.sub.1
-C.sub.4)-alkyl, --S(O).sub.n -phenyl, and --S(O).sub.n -tolyl;
A.sup.2, which comprises the two carbon atoms bonded to the groups
C(.dbd.X)--NH-- and NH--SO.sub.2 R.sup.2, is
a saturated or partially unsaturated or aromatic monocyclic 5-membered to
7-membered heterocycle which comprises one or more ring heteroatoms chosen
from nitrogen, oxygen, and sulfur, or
a saturated or partially unsaturated or aromatic bicyclic 8-membered to
10-membered heterocycle which comprises one or more ring heteroatoms
chosen from nitrogen, oxygen, and sulfur;
R.sup.1, when n in the group R.sup.1 --S(O).sub.n -- is 0, is aryl,
heterocyclyl, or (C.sub.1 -C.sub.18)-alkyl which is unsubstituted or
substituted by one or more identical or different residues R.sup.4, or is
--CN, or
when n in the group R.sup.1 --S(O).sub.n -- is 1, R.sup.1 is aryl,
heterocyclyl, or (C.sub.1 -C.sub.18)-alkyl which is unsubstituted or
substituted by one or more identical or different residues R.sup.4, or
when n in the group R.sup.1 --S(O).sub.n -- is 2, R.sup.1 is aryl,
heterocyclyl, or (C.sub.1 -C.sub.18)-alkyl which is unsubstituted or
substituted by one or more identical or different residues R.sup.4, or
R.sup.1 is NR.sup.5 R.sup.6 ;
R.sup.2 is aryl, heterocyclyl, NR.sup.5 R.sup.6, or (C.sub.1
-C.sub.10)-alkyl which is unsubstituted or substituted by one or more
identical or different residues R.sup.4 ;
R.sup.3 is one or more identical or different residues chosen from
hydrogen, halogen, CF.sub.3, OH, --O--(C.sub.1 -C.sub.7)-alkyl,
--O--(C.sub.2 -C.sub.4)-alkyl-O--(C.sub.1 -C.sub.7)-alkyl, --O-aryl,
(C.sub.1 -C.sub.2)-alkylenedioxy, NO.sub.2, --CN, NR.sup.7 R.sup.8,
--CO--NR.sup.7 R.sup.8, --CO--OH, --CO--O--(C.sub.1 -C.sub.5)-alkyl,
heterocyclyl, --S(O).sub.n --(C.sub.1 -C.sub.5)-alkyl, and (C.sub.1
-C.sub.5)-alkyl which is unsubstituted or substituted by one or more
identical or different residues R.sup.4 ;
R.sup.4 is fluorine, OH, --O--(C.sub.1 -C.sub.10)-alkyl, --O--(C.sub.2
-C.sub.4)-alkyl-O--(C.sub.1 -C.sub.7)-alkyl, --O-aryl, --CN, NR.sup.7
R.sup.8, --CO--NH.sub.2, --CO--NH--(C.sub.1 -C.sub.3)-alkyl,
--CO--N((C.sub.1 -C.sub.3)-alkyl).sub.2, --CO--OH, --CO--O--(C.sub.1
-C.sub.5)-alkyl, heterocyclyl, or oxo;
R.sup.5 is hydrogen, (C.sub.1 -C.sub.10)-alkyl which is unsubstituted or
substituted by one or more identical or different substituents chosen from
R.sup.4 and aryl, or is aryl, heterocyclyl, --CO--NR.sup.7 R.sup.8,
--CO-aryl, or --CO--(C.sub.1 -C.sub.10)-alkyl wherein the alkyl residue is
unsubstituted or substituted by one or more identical or different
residues R.sup.4 ;
R.sup.6 is hydrogen, (C.sub.1 -C.sub.10)-alkyl which is unsubstituted or
substituted by one or more identical or different substituents chosen from
R.sup.4 and aryl, or is aryl, heterocyclyl, --CO--NR.sup.7 R.sup.8,
--CO-aryl, or --CO--(C.sub.1 -C.sub.10)-alkyl wherein the alkyl residue is
unsubstituted or substituted by one or more identical or different
residues R.sup.4 ;
or R.sup.5 and R.sup.6 together with the nitrogen atom to which they are
bonded form a 5-membered to 8-membered saturated or partially unsaturated
ring, wherein said ring optionally further comprises one or more ring
heteroatoms chosen from nitrogen, oxygen, and sulfur, and wherein said
ring is unsubstituted or substituted by one or more identical or different
substituents chosen from fluorine, (C.sub.1 -C.sub.5)-alkyl,
hydroxy-(C.sub.1 -C.sub.3)-alkyl-, --(C.sub.1 -C.sub.3)-alkyl-O--(C.sub.1
-C.sub.4)-alkyl, aryl, CF.sub.3, OH, --O--(C.sub.1 -C.sub.7)-alkyl,
--O-aryl, --O--(C.sub.2 -C.sub.4)-alkyl-O--(C.sub.1 -C.sub.7)-alkyl,
(C.sub.2 -C.sub.3)-alkylenedioxy, NR.sup.7 R.sup.8, --CN, --CO--NH.sub.2,
--CO--NH--(C.sub.1 -C.sub.3)-alkyl, --CO--N((C.sub.1
-C.sub.3)-alkyl).sub.2, --CO--OH, --CO--O--(C.sub.1 -C.sub.5)-alkyl, CHO,
--CO--(C.sub.1 -C.sub.5)-alkyl, --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
--S(O).sub.n --NH.sub.2, --S(O).sub.n --NH--(C.sub.1 -C.sub.3)-alkyl,
--S(O).sub.n --N((C.sub.1 -C.sub.3)-alkyl).sub.2, oxo, --(CH.sub.2).sub.m
--NH.sub.2, --(CH.sub.2).sub.m --NH--(C.sub.1 -C.sub.4)-alkyl, and
--(CH.sub.2).sub.m --N((C.sub.1 -C.sub.4)-alkyl).sub.2 where in the
substituent --(CH.sub.2).sub.m --N((C.sub.1 -C.sub.4)-alkyl).sub.2 the two
alkyl groups are independent, identical or different, or are connected by
a single bond and together with the nitrogen atom to which they are bonded
form a 5-membered to 7-membered ring, which optionally further comprises
an oxygen atom, sulfur atom, or a group NR.sup.5 as a ring member;
R.sup.7 is hydrogen or (C.sub.1 -C.sub.7)-alkyl which is unsubstituted or
substituted by one or more identical or different substituents chosen from
OH, --O--(C.sub.1 -C.sub.5)-alkyl, NH.sub.2, --NH--(C.sub.1
-C.sub.4)-alkyl, and --N((C.sub.1 -C.sub.4)-alkyl).sub.2 where in the
substituent N((C.sub.1 -C.sub.4)-alkyl).sub.2 the two alkyl groups are
independent, identical or different, or are connected by a single bond and
together with the nitrogen atom to which they are bonded form a 5-membered
to 7-membered ring, wherein said ring optionally further comprises an
oxygen atom, sulfur atom, or a group NR.sup.5 as a ring member;
R.sup.8 is hydrogen, --CO--(C.sub.1 -C.sub.4)-alkyl, or (C.sub.1
-C.sub.7)-alkyl which is unsubstituted or substituted by one or more
identical or different substituents chosen from OH, --O--(C.sub.1
-C.sub.5)-alkyl, NH.sub.2, --NH--(C.sub.1 -C.sub.4)-alkyl, and
--N((C.sub.1 -C.sub.4)-alkyl).sub.2 where in the substituent N((C.sub.2
-C.sub.4)-alkyl).sub.2 the two alkyl groups are independent, identical or
different, or are connected by a single bond and together with the
nitrogen atom to which they are bonded form a 5-membered to 7-membered
ring which optionally further comprises an oxygen atom, a sulfur atom, or
a group NR.sup.5 as ring member;
aryl is phenyl, naphthyl, or heteroaryl, and is unsubstituted or
substituted by one or more identical or different substituents chosen from
halogen, (C.sub.1 -C.sub.5)-alkyl, phenyl, tolyl, CF.sub.3, --O--CF.sub.3,
NO.sub.2, OH, --O--(C.sub.1 -C.sub.5)-alkyl, --O--(C.sub.2
-C.sub.4)-alkyl-O--(C.sub.1 -C.sub.3)-alkyl, (C.sub.1
-C.sub.2)-alkylenedioxy, NH.sub.2, --NH--(C.sub.1 -C.sub.3)-alkyl,
--N((C.sub.1 -C.sub.3)-alkyl).sub.2, --NH--CHO, --NH--CO--(C.sub.1
-C.sub.5)-alkyl, --CN, --CO--NH.sub.2, --CO--NH--(C.sub.1 -C.sub.3)-alkyl,
--CO--N((C.sub.1 -C.sub.3)-alkyl).sub.2, --CO--OH, --CO--O--(C.sub.1
-C.sub.5)-alkyl, heterocyclyl, CHO, --CO--(C.sub.1 -C.sub.5)-alkyl,
--S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl, --S(O).sub.n -phenyl, and
--S(O).sub.n -tolyl;
heteroaryl and heteroarylene, independently of each other, are a residue of
a monocyclic 5-membered or 6-membered aromatic heterocycle or of a
bicyclic 8-membered to 10-membered aromatic heterocycle, wherein said
heterocycles comprise one or more ring heteroatoms chosen from nitrogen,
oxygen, and sulfur;
heterocyclyl is a residue of a monocyclic or polycyclic 5-membered to
11-membered saturated or partially unsaturated heterocycle which comprises
one or more ring heteroatoms chosen from nitrogen, oxygen, and sulfur, and
which is unsubstituted or substituted by one or more identical or
different substituents chosen from fluorine, (C.sub.1 -C.sub.5)-alkyl, OH,
--O--(C.sub.1 -C.sub.5)-alkyl, --O--(C.sub.2 -C.sub.4)-alkyl-O--(C.sub.1
-C.sub.3)-alkyl, NH.sub.2, --NH--(C.sub.1 -C.sub.3)-alkyl, --N((C.sub.1
-C.sub.3)-alkyl).sub.2, --CN, --CO--NH.sub.2, --CO--NH--(C.sub.1
-C.sub.3)-alkyl, --CO--N((C.sub.1 -C.sub.3)-alkyl).sub.2, --CO--OH, and
--CO--O--(C.sub.1 -C.sub.5)-alkyl;
n is 0, 1, or 2;
m is 2, 3, or 4; and
X is oxygen or NH, or X is a nitrogen atom which via a single bond is
attached to a ring carbon atom in the group A.sup.1 which ring carbon atom
is directly adjacent to the carbon atom in A.sup.1 bonded to the group
--NH--C(.dbd.X)-- so that the group --NH--C(.dbd.X)-- together with the
carbon atoms in A.sup.1 bonded to it forms an anellated imidazole ring;
or when one or more of said residues, independent of each other, are
present in protected form or in a form of precursor groups.
11. A composition, comprising a compound of formula I:
##STR14##
wherein
A.sup.1 is a divalent residue chosen from phenylene, naphthylene, and
heteroarylene, and is unsubstituted or substituted by one or more
identical or different substituents chosen from halogen, (C.sub.1
-C.sub.5)-alkyl, phenyl, tolyl, CF.sub.3, NO.sub.2, OH, --O--(C.sub.1
-C.sub.5)-alkyl, --O--(C.sub.2 -C.sub.4)-alkyl-O--(C.sub.1
-C.sub.3)-alkyl, (C.sub.1 -C.sub.2)-alkylenedioxy, NH.sub.2,
--NH--(C.sub.1 -C.sub.3)-alkyl, --N((C.sub.1 -C.sub.3)-alkyl).sub.2,
--NH--CHO, --NH--CO--(C.sub.1 -C.sub.5)-alkyl, --CN, --CO--NH.sub.2,
--CO--NH--(C.sub.1 -C.sub.3)-alkyl, --CO--N((C.sub.1
-C.sub.3)-alkyl).sub.2, --CO--OH, --CO--O--(C.sub.1 -C.sub.5)-alkyl,
heterocyclyl, CHO, --CO--(C.sub.1 -C.sub.5)-alkyl, --S(O).sub.n --(C.sub.1
-C.sub.4)-alkyl, --S(O).sub.n -phenyl, and --S(O).sub.n -tolyl;
A.sup.2, which comprises the two carbon atoms bonded to the groups
C(.dbd.X)--NH-- and NH--SO.sub.2 R.sup.2, is
a saturated or partially unsaturated or aromatic monocyclic 5-membered to
7-membered heterocycle which comprises one or more ring heteroatoms chosen
from nitrogen, oxygen, and sulfur, or
a saturated or partially unsaturated or aromatic bicyclic 8-membered to
10-membered heterocycle which comprises one or more ring heteroatoms
chosen from nitrogen, oxygen, and sulfur;
R.sup.1, when n in the group R.sup.1 --S(O).sub.n -- is 0, is aryl,
heterocyclyl, or (C.sub.1 -C.sub.18)-alkyl which is unsubstituted or
substituted by one or more identical or different residues R.sup.4, or is
--CN, or
when n in the group R.sup.1 --S(O).sub.n -- is 1, R.sup.1 is aryl,
heterocyclyl, or (C.sub.1 -C.sub.18)-alkyl which is unsubstituted or
substituted by one or more identical or different residues R.sup.4, or
R.sup.1 is NR.sup.5 R.sup.6 ;
R.sup.2 is aryl, heterocyclyl, NR.sup.5 R.sup.6, or (C.sub.1
-C.sub.10)-alkyl which is unsubstituted or substituted by one or more
identical or different residues R.sup.4 ;
R.sup.3 is one or more identical or different residues chosen from
hydrogen, halogen, CF.sub.3, OH, --O--(C.sub.1 -C.sub.7)-alkyl,
--O--(C.sub.2 -C.sub.4)-alkyl-O--(C.sub.1 -C.sub.7)-alkyl, --O-aryl,
(C.sub.1 -C.sub.2)-alkylenedioxy, NO.sub.2, --CN, NR.sup.7 R.sup.8,
--CO--NR.sup.7 R.sup.8, --CO--OH, --CO--O--(C.sub.1 -C.sub.5)-alkyl,
heterocyclyl, --S(O).sub.n --(C.sub.1 -C.sub.5)-alkyl, and (C.sub.1
-C.sub.5)-alkyl which is unsubstituted or substituted by one or more
identical or different residues R.sup.4 ;
R.sup.4 is fluorine, OH, --O--(C.sub.1 -C.sub.10)-alkyl, --O--(C.sub.2
-C.sub.4)-alkyl-O--(C.sub.1 -C.sub.7)-alkyl, --O-aryl, --CN, NR.sup.7
R.sup.8, --CO--NH.sub.2, --CO--NH--(C.sub.1 -C.sub.3)-alkyl,
--CO--N((C.sub.1 -C.sub.3)-alkyl).sub.2, --CO--OH, --CO--O--(C.sub.1
-C.sub.5)-alkyl, heterocyclyl, or oxo;
R.sup.5 is hydrogen, (C.sub.1 -C.sub.10)-alkyl which is unsubstituted or
substituted by one or more identical or different substituents chosen from
R.sup.4 and aryl, or is aryl, heterocyclyl, --CO--NR.sup.7 R.sup.8,
--CO-aryl, or --CO--(C.sub.1 -C.sub.10)-alkyl wherein the alkyl residue is
unsubstituted or substituted by one or more identical or different
residues R.sup.4 ;
R.sup.6 is hydrogen, (C.sub.1 -C.sub.10)-alkyl which is unsubstituted or
substituted by one or more identical or different substituents chosen from
R.sup.4 and aryl, or is aryl, heterocyclyl, --CO--NR.sup.7 R.sup.8,
--CO-aryl, or --CO--(C.sub.1 -C.sub.10)-alkyl wherein the alkyl residue is
unsubstituted or substituted by one or more identical or different
residues R.sup.4 ;
or R.sup.5 and R.sup.6 together with the nitrogen atom to which they are
bonded form a 5-membered to 8-membered saturated or partially unsaturated
ring, wherein said ring optionally further comprises one or more ring
heteroatoms chosen from nitrogen, oxygen, and sulfur, and wherein said
ring is unsubstituted or substituted by one or more identical or different
substituents chosen from fluorine, (C.sub.1 -C.sub.5)-alkyl,
hydroxy-(C.sub.1 -C.sub.3)-alkyl-, --(C.sub.1 -C.sub.3)-alkyl-O--(C.sub.1
-C.sub.4)-alkyl, aryl, CF.sub.3, OH, --O--(C.sub.1 -C.sub.7)-alkyl,
--O-aryl, --O--(C.sub.2 -C.sub.4)-alkyl-O--(C.sub.1 -C.sub.7)-alkyl,
(C.sub.2 -C.sub.3)-alkylenedioxy, NR.sup.7 R.sup.8, --CN, --CO--NH.sub.2,
--CO--NH--(C.sub.1 -C.sub.3)-alkyl, --CO--N((C.sub.1
-C.sub.3)-alkyl).sub.2, --CO--OH, --CO--O--(C.sub.1 -C.sub.5)-alkyl, CHO,
--CO--(C.sub.1 -C.sub.5)-alkyl, --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
--S(O).sub.n --NH.sub.2, --S(O).sub.n --NH--(C.sub.1 -C.sub.3)-alkyl,
--S(O).sub.n --N((C.sub.1 -C.sub.3)-alkyl).sub.2, oxo, --(CH.sub.2).sub.m
--NH.sub.2, --(CH.sub.2).sub.m --NH--(C.sub.1 -C.sub.4)-alkyl, and
--(CH.sub.2).sub.m --N((C.sub.1 -C.sub.4)-alkyl).sub.2 where in the
substituent --(CH.sub.2).sub.m --N((C.sub.1 -C.sub.4)-alkyl).sub.2 the two
alkyl groups are independent, identical or different, or are connected by
a single bond and together with the nitrogen atom to which they are bonded
form a 5-membered to 7-membered ring, which optionally further comprises
an oxygen atom, sulfur atom, or a group NR.sup.5 as a ring member;
R.sup.7 is hydrogen or (C.sub.1 -C.sub.7)-alkyl which is unsubstituted or
substituted by one or more identical or different substituents chosen from
OH, --O--(C.sub.1 -C.sub.5)-alkyl, NH.sub.2, --NH--(C.sub.1
-C.sub.4)-alkyl, and --N((C.sub.1 -C.sub.4)-alkyl).sub.2 where in the
substituent N((C.sub.1 -C.sub.4)-alkyl).sub.2 the two alkyl groups are
independent, identical or different, or are connected by a single bond and
together with the nitrogen atom to which they are bonded form a 5-membered
to 7-membered ring, wherein said ring optionally further comprises an
oxygen atom, sulfur atom, or a group NR.sup.5 as a ring member;
R.sup.8 is hydrogen, --CO--(C.sub.1 -C.sub.4)-alkyl, or (C.sub.1
-C.sub.7)-alkyl which is unsubstituted or substituted by one or more
identical or different substituents chosen from OH, --O--(C.sub.1
-C.sub.5)-alkyl, NH.sub.2, --NH--(C.sub.1 -C.sub.4)-alkyl, and
--N((C.sub.1 -C.sub.4)-alkyl).sub.2 where in the substituent N((C.sub.1
-C.sub.4)-alkyl).sub.2 the two alkyl groups are independent, identical or
different, or are connected by a single bond and together with the
nitrogen atom to which they are bonded form a 5-membered to 7-membered
ring which optionally further comprises an oxygen atom, a sulfur atom, or
a group NR.sup.5 as ring member;
aryl is phenyl, naphthyl, or heteroaryl, and is unsubstituted or
substituted by one or more identical or different substituents chosen from
halogen, (C.sub.1 -C.sub.5)-alkyl, phenyl, tolyl, CF.sub.3, --O--CF.sub.3,
NO.sub.2, OH, --O--(C.sub.1 -C.sub.5)-alkyl, --O--(C.sub.2
-C.sub.4)-alkyl-O--(C.sub.1 -C.sub.3)-alkyl, (C.sub.1
-C.sub.2)-alkylenedioxy, NH.sub.2, --NH--(C.sub.1 -C.sub.3)-alkyl,
--N((C.sub.1 -C.sub.3)-alkyl).sub.2, --NH--CHO, --NH--CO--(C.sub.1
-C.sub.5)-alkyl, --CN, --CO--NH.sub.2, --CO--NH--(C.sub.1 -C.sub.3)-alkyl,
--CO--N((C.sub.1 -C.sub.3)-alkyl).sub.2, --CO--OH, --CO--O--(C.sub.1
-C.sub.5)-alkyl, heterocyclyl, CHO, --CO--(C.sub.1 -C.sub.5)-alkyl,
--S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl, --S(O).sub.n -phenyl, and
--S(O).sub.n -tolyl;
heteroaryl and heteroarylene, independently of each other, are a residue of
a monocyclic 5-membered or 6-membered aromatic heterocycle or of a
bicyclic 8-membered to 10-membered aromatic heterocycle, wherein said
heterocycles comprise one or more ring heteroatoms chosen from nitrogen,
oxygen, and sulfur;
heterocyclyl is a residue of a monocyclic or polycyclic 5-membered to
11-membered saturated or partially unsaturated heterocycle which comprises
one or more ring heteroatoms chosen from nitrogen, oxygen, and sulfur, and
which is unsubstituted or substituted by one or more identical or
different substituents chosen from fluorine, (C.sub.1 -C.sub.5)-alkyl, OH,
--O--(C.sub.1 -C.sub.5)-alkyl, --O--(C.sub.2 -C.sub.4)-alkyl-O--(C.sub.1
-C.sub.3)-alkyl, NH.sub.2, --NH--(C.sub.1 -C.sub.3)-alkyl, --N((C.sub.1
-C.sub.3)-alkyl).sub.2, --CN, --CO--NH.sub.2, --CO--NH--(C.sub.1
-C.sub.3)-alkyl, --CO--N((C.sub.1 -C.sub.3)-alkyl).sub.2, --CO--OH, and
--CO--O--(C.sub.1 -C.sub.5)-alkyl;
n is 0, 1, or 2;
m is 2, 3, or 4; and
X is oxygen or NH, or X is a nitrogen atom which via a single bond is
attached to a ring carbon atom in the group A.sup.1 which ring carbon atom
is directly adjacent to the carbon atom in A.sup.1 bonded to the group
--NH--C(.dbd.X)-- so that the group --NH--C(.dbd.X)-- together with the
carbon atoms in A.sup.1 bonded to it forms an anellated imidazole ring;
or a stereoisomer thereof, or a physiologically acceptable salt thereof, or
a mixture of two or more of any of the foregoing; and
at least one pharmaceutically acceptable carrier.
12. A composition useful for the treatment or prevention of cardiovascular
diseases, endothelial dysfunction, diastolic dysfunction, atherosclerosis,
hypertension, angina pectoris, thromboses, restenoses, myocardial
infarction, strokes, cardiac insufficiency, pulmonary hypertonia, erectile
dysfunction, asthma bronchiale, chronic kidney insufficiency, diabetes or
cirrhosis of the liver, said composition comprising an amount efficacious
for said treatment or prevention of a compound of formula I as claimed in
claim 1, a stereoisomeric form thereof, or a physiologically acceptable
salt thereof, or a mixture of two or more of any of the foregoing, and a
pharmaceutically acceptable carrier.
13. A method for activating soluble guanylate cyclase, said method
comprising the step of administering an amount efficacious therefor of a
compound of formula I as claimed in claim 1, a stereoisomeric form
thereof, a physiologically acceptable salt thereof, or a mixture of any
two or more of the foregoing.
14. The method as claimed in claim 13, further comprising the step of
diagnosing a disease.
15. The method as claimed in claim 13, wherein said administering is to a
human or animal patient in need of such activating.
16. A method for treatment or prevention of cardiovascular diseases,
endothelial dysfunction, diastolic dysfunction, atherosclerosis,
hypertension, angina pectoris, thromboses, restenoses, myocardial
infarction, strokes, cardiac insufficiency, pulmonary hypertonia, erectile
dysfunction, asthma bronchiale, chronic kidney insufficiency, diabetes, or
cirrhosis of the liver in a human or animal patient, said method
comprising the step of administering to the patient an amount efficacious
for said treatment or prevention of a compound of formula I as claimed in
claim 1, a stereoisomeric form thereof, a physiologically acceptable salt
thereof, or a mixture of any two or more of the foregoing.
17. A method for improving restricted memory performance or ability to
learn in a human or animal patient, said method comprising the step of
administering an amount efficacious therefor to the patient of a compound
of formula I as claimed in claim 1, a stereoisomeric form thereof, a
physiologically acceptable salt thereof, or a mixture of any two or more
of the foregoing.
Description
The present invention relates to compounds of the formula I
##STR2##
wherein A.sup.1, A.sup.2, R.sup.1, R.sup.2, R.sup.3, X and n are as defined
below, which are valuable pharmaceutically active compounds for the
therapy and prophylaxis of diseases, for example for cardiovascular
diseases such as hypertension, angina pectoris, cardiac insufficiency,
thromboses or atherosclerosis. The compounds of the formula I are capable
of modulating the body's production of cyclic guanosine monophosphate
("cGMP") and are generally suitable for the therapy and prophylaxis of
diseases which are associated with a disturbed cGMP balance. The invention
furthermore relates to processes for preparing compounds of the formula I,
to their use for the therapy and prophylaxis of the abovementioned
diseases and for preparing pharmaceuticals for this purpose, and to
pharmaceutical preparations which comprise compounds of the formula I.
cGMP is an important intracellular messenger which triggers a multitude of
different effects via the modulation of cGMP-dependent protein kinases,
phosphodiesterases and ion channels. Examples are the relaxation of smooth
muscles, the inhibition of thrombocyte activation and the inhibition of
the proliferation of smooth-muscle cells and of leukocyte adhesion. cGMP
is produced by particulate and soluble guanylate cyclases as a response to
a number of extracellular and intracellular stimuli. In the case of the
particulate guanylate cyclases, stimulation is essentially effected by
peptidic messengers, such as the atrial natriuretic peptide or the
cerebral natriuretic peptide. The soluble guanylate cyclases ("sGC"),
which are cytosolic heterodimeric heme proteins, in contrast, are
essentially regulated by a family of low-molecular-weight factors which
are formed enzymatically. The most important stimulant is nitrogen
monoxide ("NO") or a closely related species. The function of other
factors such as carbon monoxide or the hydroxyl radical is still largely
unclear. The binding of NO to the heme with formation of a
penta-coordinate heme-nitrosyl complex is being discussed as activation
mechanism of the activation by NO. The associated release of the histidine
which is bound in the basal state to the iron converts the enzyme into the
active conformation.
Active soluble guanylate cyclases are composed of an .alpha. and a .beta.
subunit each. Several subunit subtypes have been described which differ
from one another with respect to sequence, tissue-specific distribution
and expression in different development stages. The subtypes .alpha..sub.1
and .beta..sub.1 are mainly expressed in brain and lung, while
.beta..sub.2 is found in particular in liver and kidney. The subtype
.alpha..sub.2 was shown to be present in human fetal brain. The subunits
referred to as .alpha..sub.3 and .beta..sub.3 were isolated from human
brain and are homologous to .alpha..sub.1 and .beta..sub.1. More recent
works indicate an .alpha..sub.2i subunit which contains an insert in the
catalytic domain. All subunits show great homologies in the region of the
catalytic domain. The enzymes presumably contain one heme per heterodimer,
which is bound via .beta..sub.1 -Cys-78 and/or .beta..sub.1 -His-105 and
is part of the regulatory center.
Under pathologic conditions, the formation of guanylate-cyclase-activating
factors can be reduced, or their degradation may be promoted owing to the
increased occurrence of free radicals. The resulting reduced activation of
the sGC leads, via a weakening of the respective cGMP-mediated cellular
response, for example to an increase of the blood pressure, to platelet
activation or to increased cell proliferation and cell adhesion. As a
consequence, formation of endothelial dysfunction, atherosclerosis,
hypertension, stable or unstable angina pectoris, thromboses, myocardial
infarction, strokes or erectile dysfunction results. Pharmacological
stimulation of sGC offers a possibility to normalize cGMP production and
therefore makes possible the treatment and/or prevention of such
disorders.
For the pharmacological stimulation of the sGC, use has hitherto almost
exclusively been made of compounds whose activity is based on an
intermediate NO release, for example organic nitrates. The drawback of
this treatment is the development of tolerance and a reduction of
activity, and the higher dosage which is required because of this.
Various sGC stimulators which do not act via NO release were described by
Vesely in a series of publications. However, the compounds, most of which
are hormones, plant hormones, vitamins or natural compounds such as, for
example, lizard poisons predominantly only have weak effects on the cGMP
formation in cell lysates. D. L. Vesely, Eur. J. Clin. Invest, vol. 15,
1985, p. 258; D. L. Vesely, Biochem. Biophys. Res. Comm., vol. 88, 1979,
p. 1244. A stimulation of heme-free guanylate cyclase by protoporphyrin IX
was demonstrated by Ignarro et al., Adv. Pharmacol., vol. 26, 1994, p. 35.
Pettibone et al., Eur. J. Pharmacol., vol. 116, 1985 p. 307, described an
antihypertensive action of diphenyliodonium hexafluorophosphate and
attributed this to a stimulation of sGC. According to Yu et al., Brit. J.
Pharmacol., vol. 114, 1995, p. 1587, isoliquiritigenin, which has a
relaxing action on isolated rat aortas, also activates sGC. Ko et al.,
Blood vol. 84, 1994, p. 4226, Yu et al., Biochem. J. vol. 306, 1995, p.
787, and Wu et al., Brit. J. Pharmacol. vol. 116, 1995, p. 1973,
demonstrated a sGC-stimulating activity of
1-benzyl-3-(5-hydroxymethyl-2-furyl)indazole and demonstrated an
antiproliferative and thrombocyte-inhibiting action. Pyrazoles and fused
pyrazoles which exhibit a sGC-stimulating activity are described in
European Patent Application No. 908,456 and German Patent Application No.
19,744,027.
A series of 2-sulfonylaminobenzoic acid N-arylamides, the N-aryl group of
which carries a thio substituent, have been mentioned in the literature.
These compounds in which the N-aryl group generally carries as further
substituents groups which are readily oxidizable such as, for example, two
hydroxy groups being in para position with respect to one another and
which in this case can be regarded as hydroquinone derivatives, are
auxiliaries for the preparation of photographic materials (see, for
example, Chemical Abstracts 119, 105757; 120, 41858; 123, 70224; or 126,
257007). If isolated structural elements are considered then the N-aryl
group in these known compounds corresponds to the group R.sup.1
--S(O).sub.n --A.sup.1 in formula I in case A.sup.1 denotes a
1,4-phenylene residue which in positions 2 and 5 carries hydroxy groups
(or oxy substituents), and the number n is 0. British patent publication
No. 876,526 (Chemical Abstracts 56, 15432e) discloses
3,5-dichloro-2-methylsulfonylaminobenzoic acid
N-(5-chloro-2-(4-chlorophenylmercapto)-phenyl)-amide which can be used for
the protection of wool against moths. Compounds covered by British patent
publication No. 876,526 correspond to compounds of the formula I if
simultaneously the ring A.sup.1 which comprises the carbon atoms which
carry the groups C(.dbd.X)--NH-- and NH--SO.sub.2 R.sup.2, together with
the residues R.sup.3, is a benzene ring which carries one to four halogen
atoms from the series chlorine and bromine, R.sup.2 is (C.sub.1
-C.sub.4)-alkyl, X is oxygen and the group R.sup.1 --S(O).sub.n --A.sup.1
-- is a phenylmercaptophenyl-residue (.dbd.phenylthiophenyl-) which is
substituted by halogen and/or trifluoromethyl and which can also be
substituted by methyl or (C.sub.1 -C.sub.4)-alkoxy, and the total number
of halogen atoms and trifluoromethyl groups is greater than two.
Pharmacological activities of these known 2-sulfonylaminobenzoic acid
N-arylamides are not disclosed.
Surprisingly, it has now been found that the compounds of the present
invention effect a strong activation of guanylate cyclase and are
therefore suitable for the therapy and prophylaxis of disorders which are
associated with a low cGMP level.
Thus, the present invention relates to compounds of the formula I:
##STR3##
wherein
A.sup.1 is a divalent residue from the series phenylene, naphthylene and
heteroarylene which can all be substituted by one or more identical or
different substituents from the series halogen, (C.sub.1 -C.sub.5)-alkyl,
phenyl, tolyl, CF.sub.3, NO.sub.2, OH, --O--(C.sub.1 -C.sub.5)-alkyl,
--O--(C.sub.2 -C.sub.4)-alkyl-O--(C.sub.1 -C.sub.3)-alkyl, (C.sub.1
-C.sub.2)-alkylenedioxy, NH.sub.2, --NH--(C.sub.1 -C.sub.3)-alkyl,
--N((C.sub.1 -C.sub.3)-alkyl).sub.2, --NH--CHO, --NH--CO--(C.sub.1
-C.sub.5)-alkyl, --CN, --CO--NH.sub.2, --CO--NH--(C.sub.1 -C.sub.3)-alkyl,
--CO--N((C.sub.1 -C.sub.3)-alkyl).sub.2, --CO--OH, --CO--O--(C.sub.1
-C.sub.5)-alkyl, heterocyclyl, CHO, --CO--(C.sub.1 -C.sub.5)-alkyl, 13
S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl, --S(O).sub.n -phenyl and
--S(O).sub.n -tolyl;
the ring A.sup.2 which comprises the carbon atoms which carry the groups
C(.dbd.X)--NH-- and NH--SO.sub.2 R.sup.2 is a benzene ring, a naphthalene
ring, a saturated or partially unsaturated 3-membered to 7-membered
carbocycle, a saturated or partially unsaturated or aromatic monocyclic
5-membered to 7-membered heterocycle which contains one or more ring
heteroatoms from the series N, O and S, or a saturated or partially
unsaturated or aromatic bicyc
