Substituted indole sulfonamides as anitviral agents

Details Substituted indole sulfonamides as anitviral agents Substituted indole sulfonamides as anitviral agents

2002-02-27

2002-12-24

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C548S491000, C548S503000

Reexamination Certificate

active

06498183

ABSTRACT:

This application is a 371 of PCT/EP00/03492 filed Apr. 18, 2000.
The present invention relates to novel compounds which are suitable as pharmaceuticals, to processes for their preparation and to their use as pharmaceuticals, in particular as antiviral agents.
&agr;,&bgr;-Naphthyl-linked phenylsulphonamides are mainly disclosed in photographic publications [compare in this connection JP-06 122 669-A2, EP-684 515-A1; JP-59 174 836-A2, DE-2 902 074, U.S. Pat. No. 3,925,347, U.S. Pat. No. 4,035,401, U.S. Pat. No. 3,622,603, U.S. Pat. No. 3,482,971, EP-284 130].
WO 90/09 787 dicloses sulphonamides as radio- or chemosensitizing agents and their use in the treatment of tumours.
In addition, the compound N-[4-[[[5-(dimethylamino)-1-naphthalenyl]sulphonyl]-amino]phenyl]acetamide is known (J. Inst. Chem. (India) (1976), 48, Pt 6, 280-5).
The invention relates to compounds of the general formula (I)
in which
R
1
represents a group which is selected from the following formulae
 in which
----
represents a single or double bond,
R
3
represents hydrogen, (C
1
-C
6
)alkyl or (C
3
-C
6
)cycloalkyl, each of which may be substituted by 1 to 3 substituents selected from the group consisting of hydroxyl, halogen, amino, mono- or di(C
1
-C
6
)-alkylamino, (C
1
-C
6
)alkanoylamino, (C
1
-C6)alkanoyloxy, (C
1
-C
6
)alkanoyl, carboxyl, (C
1
-C
6
)alkoxycarbonyl, carbamoyl, mono- or di(C
1
-C
6
)alkylaminocarbonyl and cyano, or
R
3
represents (C
6
-C
10
)arylsulphonyl, (C
6
-C
10
)arylcarbonyl, the (C
6
-C
10
)aryl group of which in each case can be substituted by 1 to 3 substituents selected from the group consisting of halogen, (C
1
-C
3
)alkyl, carboxyl, (C
1
-C
3
)alkoxycarbonyl, carbamoyl, mono- or di(C
1
-C
6
)alkylaminocarbonyl, cyano, hydroxyl and (C
1
-C
3
)alkoxy, or
R
3
represents (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkylsulphonyl, (C
3
-C
6
)cycloalkylcarbonyl, camphorsulphonyl or (C
3
-C
6
)cycloalkylsulphonyl, or
R
3
represents R
4
—X—CO—or R
4
—X—CS— in which
X represents O, S, NR
5
in which R
5
represents hydrogen or (C
1
-C
3
)alkyl, and
R
4
represents (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
6
-C
10
)aryl or 5- to 10-membered heteroaryl, and
R
2
represents
 in which
R
6
is (C
2
-C
6
)alkenyl or (C
1
-C
8
)alkyl which is optionally substituted once to three times, identically or differently, by amino, protected amino, (C
1
-C
4
)alkylamino, hydroxyl, cyano, halogen, azido, nitro, trifluoromethyl, carboxyl or phenyl, where phenyl in turn can be substituted up to twice, identically or differently, by nitro, halogen, hydroxyl, (C
1
-C
4
)alkyl or (C
1
-C
4
)alkoxy, or
R
6
represents radicals of the formulae
or
r—L—O—LO—Q,
 in which
L represents a straight-chain or branched alkanediyl group with up to 6 carbon atoms,
Q represents (C
1
-C
6
)alkyl which is optionally substituted by carboxyl, or
 represents radicals of the formulae
 in which
a denotes the number 1 or 2,
R
8
denotes hydrogen,
R
9
denotes (C
3
-C
8
)cycloalkyl, (C
6
-C
10
)aryl or hydrogen, or denotes (C
1
-C
8
)alkyl,
 where the (C
1
-C
8
)alkyl is optionally substituted by cyano, methylthio, hydroxyl, mercapto, guanidyl or by a group of the formula —NR
12
R
13
or R
14
—OC—,
 in which
 R
12
and R
13
denote, independently of one another, hydrogen, (C
1
-C
8
)alkyl or phenyl,
 and
 R
14
denotes hydroxyl, benzyloxyl, (C
1
-C
6
)alkoxy or the abovementioned group —NR
12
R
13
,
 or the (C
1
-C
8
)alkyl is optionally substituted by (C
3
-C
8
)-cycloalkyl or by (C
6
-C
10
)aryl which is in turn substituted by hydroxyl, halogen, nitro, (C
1
-C
8
)alkoxy or by the group —NR
12
R
13
,
 in which R
12
and R
13
have the meaning indicated above,
 or the (C
1
-C
8
)alkyl is optionally substituted by a 5- to 6-membered nitrogen-containing heterocycle or by indolyl, in which the corresponding —NH functions are optionally substituted by (C
1
-C
6
)alkyl or are protected by an amino protective group,
R
10
and R
11
are identical or different and denote hydrogen or an amino protective group,
R
7
represents hydrogen or represents a radical of the formula
 in which
R
8′
, R
9′
, R
10′
and R
11′
have the meaning indicated above for R
8
,
R
9
, R
10
and R
11
and are identical to or different from the latter,
and the salts thereof.
The substances according to the invention may also be in the form of salts. Physiologically acceptable salts are preferred for the purposes of the invention.
Physiologically acceptable salts may be salts of the compounds according to the invention with inorganic or organic acids. Preference is given to salts with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid, or salts with organic carboxylic or sulphonic acids such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulphonic acid, ethanesulphonic acid, phenylsulphonic acid, toluenesulphonic acid or naphthalenedisulphonic acid.
Physiologically acceptable salts may likewise be metal or ammonium salts of the compounds according to the invention. Particularly preferred examples are sodium, potassium, magnesium or calcium salts, and ammonium salts derived from ammonia or organic amines such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
The compounds in accordance with the invention of the general formula (1) may occur in various stereochemical forms which either are related as image and mirror image (enantiomers) or are not related as image and mirror image (diastereomers). The invention relates both to the antipodes and to the racemic forms, and the mixtures of diastereomers. The racemic forms can, just like the diastereomers, be separated into the stereoisomerically homogeneous components in a known manner.
In addition, certain compounds may exist in tautomeric forms. This is known to the skilled person, and the scope of the invention likewise encompasses such compounds.
(C
1
-C
6
)Alkyl generally represents for the purposes of the invention straight-chain or branched hydrocarbon radicals with 1 to 6 carbon atoms. Correspondingly, (C
1
-C
4
)alkyl and (C
1
-C
3
)alkyl generally represent for the purposes of the invention straight-chain or branched hydrocarbon radicals with respectively 1 to 4 and 1 to 3 carbon atoms. Examples which may be mentioned are: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl.
(C
3
-C
6
)Cycloalkyl represents cycloalkyl group with 3 to 6 carbon atoms and includes, for example: cyclopropyl, cyclopentyl and cyclohexyl. Cyclopropyl is preferred.
The (C
1
-C
6
)alkoxy group used in the present invention and also used in the definitions of (C
1
-C
6
)alkoxycarbonyl includes, for example, straight-chain or branched alkoxy groups with 1 to 6 carbon atoms, particularly preferably alkoxy groups with 1 to 4 carbon atoms ((C
1
-C
4
)alkoxy), and more preferably alkoxy groups with 1 to 3 carbon atoms ((C
1
-C
3
)alkoxy). Examples which may be mentioned are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy and isohexoxy. Methoxy, ethoxy and propoxy are preferred.
Mono- or di(C
1
-C
6
)alkylamino includes for the purposes of the invention those whose alkyl groups have 1 to 6 carbon atoms. The alkylamino groups in this connection may be symmetrical or nonsymmetrical, such as, for example, dimethylamino, diethylamino, methylethylamino etc. This also applies to the mono- or di(C
1
-C
6
)alkylamino moiety in the mono- or di(C
1
-C
6
)alkylaminocarbonyl group.
(C
6
-C
10
)Aryl represents for the purposes of the invention an aromatic radical with 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.
5- to 10-membered heteroaryl represents for the purposes of the invention 5- to 10-membered heteroatom-containing rings

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