Substituted thiadiazolesulfonamides

Details Substituted thiadiazolesulfonamides Substituted thiadiazolesulfonamides

1999-10-14

2001-04-17

Gerstl, Robert (Department: 1613)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C544S134000, C544S367000, C546S209000, C548S129000

Reexamination Certificate

active

06218412

ABSTRACT:

Under the provisions of Section 119 of 35 U.S.C., Applicants hereby claim the benefit of the filing date of German Patent Application Number 19847823.2, filed Oct. 16, 1998, which Application is hereby incorporated by reference.
1. Field of the Invention
The invention relates to novel substituted thiadiazolesulfonamides, processes for their preparation, and the use thereof as pharmaceuticals.
2. Background of the Invention
The patents U.S. Pat. Nos. 4,758,578, 4,873,239 and 4,985,450 describe only those arylthiadiazolesulfonamides which are suitable for liberating sulfonamides unsubstituted on the nitrogen, and can therefore be used in particular for glaucoma treatment.
Some 1,2,4-thiadiazole-sulfonamide derivatives with a bactericidal action are known, for example, see N. M. Yousif et al., Egypt. J. Chem. 32 (1989) 607-614.
In efforts to develop more effective and better tolerated medicaments for treatment of rheumatic diseases, those compounds which are capable of influencing surplus or dysregulated cytokine production are gaining increasing importance. Annual Reports in Medicinal Chemistry volume 27, (1992), pages 209-218. Interleukin-I&bgr; (IL-1&bgr;) is to be noted in particular here as one of the most important pro-inflammatory cytokines. Its de novo synthesis takes place above all in the white blood cells and macrophages, where it must first be liberated from inactive pro-IL-1&bgr; in order to display its action. It plays a decisive role both in the control of the immune system and in inflammation processes, and thus has a causal relationship with the development of diseases, such as rheumatoid arthritis, arthrosis, various states of shock, or inflammatory bone diseases.
DETAILED DESCRIPTION OF THE INVENTION
According to the invention, it has now been found, surprisingly, that certain thiadiazolesulfonamides are potent inhibitors of cell interleukin-1&bgr; generation.
The invention relates to compounds of the formula (I):
and/or a stereoisomeric form of compounds of the formula (I) and/or a physiologically tolerated salt of any of the forgoing in which:
R
1
is
1. phenyl,
2. phenyl which is mono- to trisubstituted by:
2.1. —(C
1
-C
6
)-alkyl, wherein alkyl is straight-chain, cyclic or branched,
2.2. —OH,
2.3. —O—C(O)—(C
1
-C
6
)-alkyl-,
2.4. —O—(C
1
-C
6
)-alkyl,
2.5. methylenedioxo,
2.6. halogen,
2.7. —CF
3
,
2.8. —CN,
2.9. —NO
2
,
2.10. —C(O)—OH,
2.11. —C(O)—O—(C
1
-C
6
)-alkyl, or
2.12. R
3
—(R
4
)N—, wherein R
3
and R
4
are identical or different and are a hydrogen atom or (C
1
-C
6
)-alkyl, or
3. a heteroaromatic from the following group 3.1 to 3.15 (which is unsubstituted or substituted as described under 2.1 to 2.12):
3.1. pyrrole,
3.2. pyrazole,
3.3. imidazole,
3.4. triazole,
3.5. thiophene,
3.6. thiazole,
3.7. oxazole,
3.8. isoxazole,
3.9. pyridine,
3.10. pyrimidine,
3.11. indole,
3.12. benzothiophene,
3.13. benzimidazole,
3.14. benzoxazole, or
3.15. benzothiazole;
R
3
is
1. a hydrogen atom or
2. (C
1
-C
6
)-alkyl;
R
2
is
1. (C
1
-C
7
)-alkyl, wherein alkyl is branched or unbranched and is unsubstituted or is mono- or disubstituted as described above under 2.1 to 2.12 or is substituted by a heteroalkyl ring or by a (C
3
-C
7
)-cycloalkyl, wherein the heteroalkyl ring or the (C
3
-C
7
)-cycloalkyl is unsubstituted or is mono- or disubstituted as described above under 2.1 to 2.12,
2. —(C
2
-C
10
)-alkenyl, wherein alkenyl is straight-chain or branched,
3. (C
3
-C
7
)-cycloalkyl, wherein cycloalkyl is unsubstituted or is mono- or disubstituted as described above under 2.1 to 2.12,
4. phenyl, wherein phenyl is unsubstituted or mono- or disubstituted as described above under 2.1 to 2.12,
5. —(CH
2
)m-phenyl, wherein phenyl is unsubstituted or mono- or disubstituted as described above under 2.1 to 2.12, and m is the integer 1, 2, 3, 4, 5, or 6, or wherein one hydrogen atom of the —(CH
2
)m radical is replaced by —OH,
6. —(CH
2
)
n
-heteroaryl, wherein heteroaryl is as defined under 3.1. to 3.15. and is unsubstituted or substituted as described above under 2.1 to 2.12, and n is the integer zero, 1, 2, 3, 4, 5, or 6,
7. —(C
2
-C
6
)-alkyl-O—R
6
, wherein R
6
is a hydrogen atom, benzyl, allyl, or (C
1
-C
6
)-alkyl, and wherein the alkyl radical is straight-chain or branched,
8. —(C
2
-C
6
)alkyl-C(O)—OR
6
, wherein R
6
is as defined above,
9. —C(R
8
,R
7
)—C(O)—X, wherein R
8
has the same meaning as R
3
above, R
7
is the radical of an &agr;-amino acid, or R
8
and R
7
(together with the carbon atom to which they are bonded) form a 4- to 7-membered ring, and X is —OH, NHR
6
or —OR
6
, wherein R
6
is as defined above, or
10. R
2
and R
3
(together with the nitrogen to which they are bonded) form a 4- to 7-membered ring, wherein at least one of the carbon atoms is optionally replaced by —O—, —S— or
11. —NH—, and wherein one, two or three of the carbon atoms in the ring are unsubstituted or mono- or disubstituted by
10.1 (C
1
-C
2
)-alkyl,
10.2 phenyl,
10.3 —OH,
10.4 ═O,
10.5 —C(O)—O—(C
1
-C
6
)-alkyl,
10.6 —C(O)—phenyl, wherein phenyl is unsubstituted or substituted as described above under 2.1 to 2.12,
10.7 —C(O)—(C
1
-C
6
)-alkyl, or
10.8 —C—(O)—OR
3
, wherein R
3
is a hydrogen atom or (C
1
-C
6
)-alkyl, and/or
10.9 two carbon atoms in the ring form part of an additional phenyl radical, which is unsubstituted or substituted as described above under 2.1 to 2.12, or wherein the hydrogen atom in the —NH— optionally present is unsubstituted or is substituted by
(a) (C
1
-C
3
)-alkyl,
(b) —C(O)—R
3
, wherein R
3
is as defined above,
(c) —(CH
2
)
o
-phenyl, wherein phenyl is unsubstituted or mono- or disubstituted as described under 2.1 to 2.12, and o is the integer zero, one, or two,
(d) benzoyl, which is unsubstituted or substituted as described above under 2.1 to 2.12, or
(e) —C(O)—O—(C
1
-C
6
)-alkyl.
Currently preferred, are compounds of the formula (I) in which:
R
1
is phenyl which is unsubstituted or is monosubstituted by (C
1
-C
6
)-alkyl (wherein alkyl is straight-chain or branched),halogen,—O—(C
1
-C
3
)alkyl or —N—R
3
—(R
4
), wherein R
3
and R
4
are identical or different and are a hydrogen atom or (C
1
-C
6
)-alkyl;
R
3
is a hydrogen atom or methyl;
R
2
is
1. (C
1
-C
4
)-alkyl, wherein alkyl is branched or unbranched and is unsubstituted or is monosubstituted as described under 2.1. to 2.12 or by phenyl, or is substituted by a heteroalkyl ring or by a (C
3
-C
7
)-cycloalkyl, wherein the heteroalkyl ring or the (C
3
-C
7
)-cycloalkyl is unsubstituted or is mono- or disubstituted as described under 2.1 to 2.12,
2. cyclohexyl,
3. —C(R
8
,R
7
)—C(O)—X, wherein R
8
is a hydrogen atom, R
7
is the radical of an (&agr;-amino acid, or R
8
and R
7
(together with the carbon atom to which they are bonded) form a 4- to 7-membered ring, and X is—OH or —OR
6
, wherein R
6
is benzyl or (C
1
-C
3
)-alkyl, or
4. R
2
and R
3
(together with the nitrogen to which they are bonded) form a 4- to 7-membered ring, wherein one of the carbon atoms is optionally replaced by —O—, —S— or —NH—, and wherein one, two, or three of the carbon atoms in the ring are unsubstituted or are mono- or disubstituted by
4.1 phenyl, which is unsubstituted or substituted by halogen,
4.2 —OH,
4.3 ═O,
4.4 —C(O)—OH,
4.5 —C(O)—(C
1
-C
2
)-alkyl,
4.6 (C
1
-C
3
)-alkyl, or
4.7 —(O)—OR
3
and wherein R
3
is a hydrogen atom or (C
1
-C
6
)-alkyl,
 and optionally, two carbon atoms in the ring form part of an additional phenyl radical;
 and optionally wherein the hydrogen atom in the —NH— optionally present in the ring is substituted by
(a) (C
1
-C
3
)-alkyl,
(b) —C(O)—R
3
, wherein R
3
is a hydrogen atom or (C
1
-C
6
)-alkyl,
(c) phenyl-(CH
2
)o—, wherein phenyl is unsubstituted or mono- or disubstituted as described under 2.1. to 2.12. and o is the integer zero, one or two, or
(d) C(O)—O—(C
1
-C
3
)-alkyl.
Also currently preferred are compounds of the formula (I) in which:
R
1
is phenyl which is unsubstituted or is monosubstituted by (C
1
-C
3
)-alkyl (wherein alkyl is straight-chain or branched), chlorine, or —O—methyl;
R
3
is a hydrogen atom or methyl;
R
2
is
1. (

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