Sulphoxybenzamides

Details Sulphoxybenzamides Sulphoxybenzamides

2001-10-23

2002-12-03

Powers, Flona T. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C558S037000

Reexamination Certificate

active

06489359

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to new sulphoxybenzamides of formula I,
wherein the groups R
1
, R
2
, R
3
, A
1
, A
2
, Z
0
, Z
1
, Z
2
, m and n have the meanings given in the claims and specification, processes for preparing them as well as their use as medicaments, particularly as leukotriene B
4
(LTB
4
) antagonists.
BACKGROUND TO THE INVENTION
Benzamidine derivatives are known from the prior art as active substances with valuable pharmaceutical properties. Thus, for example, International Patent Applications WO 97/21670 (corresponding to U.S. Pat. No. 6,127,423) and WO 98/11062 (corresponding to U.S. Pat. No. 6,197,824 B1) disclose inter alia benzamidines which have free hydroxy groups. They contain no references of any kind to benzamidines containing sulphate groups.
The aim of the present invention is to prepare new LTB
4
antagonists which, by virtue of their LTB
4
antagonistic properties, have many possible uses in the therapeutic field.
DETAILED DESCRIPTION OF THE INVENTION
Surprisingly, it has been found that benzamidine derivatives containing sulphate groups, of general formula (I)
wherein the groups R
1
, R
2
, R
3
, A
1
, A
2
, Z
0
, Z
1
, Z
2
, m and n have the meanings given in the claims and specification, have an LTB
4
antagonistic activity and may be used according to the invention for the prevention and treatment of diseases in which LTB
4
antagonists may provide a therapeutic benefit.
The invention thus relates to sulphoxybenzamides of general formula I
wherein
Z
0
denotes a group selected from the formulae —X
1
—(CH
2
)
r
—X
2
— and —CR
4
R
5
—,
A
1
and A
2
independently of one another each denote a 1,4-phenylene- or 1,3-phenylene group optionally substituted by one or more halogen atoms, C
1
-C
8
-alkyl groups, C
2
-C
8
-alkenyl groups, C
1
-C
8
-haloalkyl groups or C
1
-C
8
-alkoxy groups,
Z
1
and Z
2
independently of one another each denote a group of formula —X
3
—(CH
2
)
s
—X
4
— or a single bond,
R
1
denotes hydrogen, hydroxy, —COO—C
1
-C
8
-alkyl or —COO—C
1
-C
4
-alkyl-phenyl, whilst in the abovementioned group the phenyl ring in each case may be substituted by C
1
-C
4
-alkyl or C
1
-C
4
-alkoxy,
R
2
and R
3
independently of one another each denote a hydrogen or halogen atom, or a C
1
-C
8
-alkyl, C
1
-C
8
-haloalkyl, C
1
-C
8
-alkoxy, aryl, aryloxy or aralkyl group,
R
4
and R
5
independently of one another each denote hydrogen or C
1
-C
4
-alkyl,
X
1
and X
2
independently of one another each denote —O, —S, —NH— or a single bond,
X
3
and X
4
independently of one another each denote —O, —S, —NH— or a single bond,
m and n independently of one another each denote 0 or 1, and
r and s independently of one another denote an integer from 1 to 8,
optionally in the form of the tautomers, racemates, enantiomers, diastereomers and mixtures thereof, as well as optionally the pharmacologically acceptable salts thereof.
Preferred compounds are those of formula I wherein
Z
0
denotes a group selected from the formulae —X
1
—(CH
2
)
r
—X
2
— and —CR
4
R
5
—,
A
1
and A
2
independently of one another each denote a 1,4-phenylene or 1,3-phenylene group optionally substituted by a C
1
-C
4
-alkyl group or C
2
-C
4
-alkenyl group,
Z
1
and Z
2
independently of one another each denote a group of formula —X
3
—(CH
2
)
s
—X
4
— or a single bond,
R
1
denotes hydrogen,
R
2
and R
3
each denote a hydrogen atom,
R
4
and R
5
independently of one another each denote C
1
-C
4
-alkyl,
X
1
and X
2
independently of one another each denote —O— a single bond,
X
3
and X
4
independently of one another each denote —O— or a single bond,
m and n independently of one another each denote 0 or 1, and
r and s independently of one another each denote an integer from 1 to 3.
Another preferred embodiment comprises the compounds of formula I, wherein
Z
0
denotes a group of formula —CR
4
R
5
—,
A
1
and A
2
independently of one another each denote a 1,4-phenylene or 1,3-phenylene group optionally substituted by a C
1
-C
4
-alkyl group or C
2
-C
4
-alkenyl group, and preferably A
1
denotes 1,4-phenylene and A
2
denotes 1,3-phenylene,
Z
1
and Z
2
independently of one another each denote a group of formula —X
3
—(CH
2
)
s
—X
4
—, and preferably Z
1
denotes —O—CH
2
— and Z
2
denotes —CH
2
—O—
R
1
denotes hydrogen,
R
2
and R
3
each denote a hydrogen atom,
R
4
and R
5
each denote methyl,
X
3
and X
4
independently of one another each denote —O— or a single bond,
m and n each denote 1, and
s denotes 1.
Also preferred are compounds of formula I wherein
Z
0
denotes a group of formula —X
1
—(CH
2
)
r
—X
2
—,
A
2
denotes a 1,4-phenylene group substituted by a C
1
-C
4
-alkyl group or C
2
-C
4
-alkenyl group, preferably a 1,4-phenylene group substituted by an n-propyl or allyl group,
Z
2
denotes a single bond,
R
1
denotes hydrogen,
R
2
and R
3
each denote a hydrogen atom,
X
1
and X
2
independently of one another each denote —O—,
m denotes 0,
n denotes 1, and
r denotes 2.
Unless specifically stated otherwise, the general definitions are used in the following sense: C
1
-C
8
-alkyl and C
1
-C
4
-alkyl generally denote a branched or unbranched hydrocarbon group with 1 to 4 or 8 carbon atom(s), which may optionally be substituted by one or more halogen atom(s), preferably flu orine, which may be identical to or different from one another. The following hydrocarbon groups are mentioned as examples:
methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Unless otherwise stated, lower alkyl groups with 1 to 4 carbon atoms are preferred, such as methyl; ethyl, n-propyl, iso-propyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl.
C
2
-C
8
-alkenyl and C
2
-C
4
-alkenyl generally denote a branched or unbranched unsaturated hydrocarbon group with 2 to 4 or 8 carbon atom(s), which may optionally be substituted by one or more halogen atom(s), preferably fluorine, which may be identical to or different from one another. The following hydrocarbon groups are mentioned as examples:
Vinyl, allyl, prop-1-enyl, butenyl, pentenyl, hexenyl, heptenyl and octenyl. Unless otherwise stated, lower alkenyl groups with 2 to 4 carbon atoms, such as vinyl or allyl, are preferred.
The group —(CH
2
)
r
— or —(CH
2
)
s
— denotes a branched or unbranched double-bonded hydrocarbon bridge with 1 to 8 carbon atoms, which may optionally be substituted by one or more halogen atom(s), preferably fluorine, which may be identical to or different from one another.
Aryl generally denotes an aromatic group with 6 to 10 carbon atoms, preferably phenyl, while the aromatic group may be substituted by one or more lower alkyl group(s), lower alkenyl group(s), trifluoromethyl group(s), cyano group(s), alkoxy group(s), nitro group(s), amino group(s) and/or one or. more halogen atom(s), which may be identical or different; the preferred aryl group is an optionally substituted phenyl group, the preferred substituents being halogen—such as fluorine, chlorine or bromine—as well as hydroxyl.
Alkoxy generally denotes a straight-chain or branched hydrocarbon group with 1 to 8 carbon atom(s) bound via an oxygen atom. A lower alkoxy group with 1 to 3 carbon atom(s) is preferred. The methoxy group is particularly preferred.
Aryloxy generally denotes an aromatic group with 6 to 10 carbon atoms bound via an oxygen, preferably phenoxy, whilst the aromatic group may be substituted by one or more lower alkyl group(s), lower alkenyl group(s), trifluoromethyl group(s), cyano group(s), alkoxy group(s), nitro group(s), amino group(s) and/or one or more halogen atom(s), which may be identical or differe

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