Aryl sulfonamides and analogues thereof and their use in the...

Details Aryl sulfonamides and analogues thereof and their use in the... Aryl sulfonamides and analogues thereof and their use in the...

1999-11-15

2001-07-17

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C558S054000

Reexamination Certificate

active

06262112

ABSTRACT:

The present invention relates to new arylsulfonamides and analogues, processes for their preparation and their use for the prophylaxis and treatment of neuro-degenerative disorders, in particular for the treatment of cerebral apoplexy and craniocerebral trauma.
&Dgr;
9
-Tetrahydrocannabinol (&Dgr;
9
-THC) and, to a small extent, also &Dgr;
8
-THC are the biologically active constituents in extracts of the plant Cannabis sativa (marihuana, hashish) and are responsible for the effects on the human central nervous system (CNS). Potential historical and contemporary therapeutic uses of cannabis preparations include, inter alia, analgesia, emesis, anorexia, glaucoma and mobility disorders.
Until now, two subtypes of cannabinoid receptors and a splice variant have been identified. The CB1 receptor (Nature 1990, 346, 561) and a splice variant CB1a (J. Biol. Chem. 1995, 270, 3726) are mainly localized in the central nervous system. The CB2 receptor was mainly found in the peripheral tissue, in particular in leucocytes, spleen and macrophages (Eur. J. Biochem. 1995, 232, 54).
CB1 and CB2 receptors have seven transmembrane regions and belong to the family of G protein receptors. Both receptors are negatively coupled via G
i
/G
o
protein to adenylate cyclase and possibly negatively coupled to the presynaptic release of glutamates (J. Neurosci. 1996, 16, 4322). CB1 receptors are moreover positively coupled to potassium channels and also negatively coupled to N- and Q-type calcium channels.
Four classes of CB1 receptor agonists are known to date; classical cannabinoids, such as, for example, &Dgr;
9
-THC, non-classical cannabinoids, aminoalkylindoles and eicosanoids. The latter include the generally accepted endogenous CB1 receptor agonist anandamide.
It is additionally known that cerebral apoplexy is a consequence of a sudden circulatory disorder of a human brain region with subsequent functional losses, with corresponding neurological and/or physiological symptoms. The causes of cerebral apoplexy can lie in cerebral haemorrhages (e.g. after a vascular tear in hypertension, arteriosclerosis and aneurysms) and ischaemia (e.g. due to a blood pressure fall crisis or embolism). The functional losses in the brain lead to a degeneration or destruction of the brain cells (Journal of Cerebral Blood Flow and Metabolism 1981, 1, 155; Chem. Eng. News 1996 (May 13), 41; Trends Pharmacol. Sci. 1996, 17, 227)). Cranial cerebral trauma is understood as meaning covered and open cranial injuries with involvement of the brain.
The present invention relates to compounds of the general formula (I)
R
1
—A—D—E—G—L—R
2
(I)
in which
R
1
represents (C
6
-C
10
)-aryl, quinolyl, isoquinolyl or a radical of the formula
in which
a denotes a number 1 or 2,
R
3
denotes hydrogen, (C
2
-C
6
)-alkenyl, (C
1
-C
6
)-alkyl or (C
1
-C
6
)-acyl, and where all the abovementioned ring systems and radicals are optionally substituted, if appropriate geminally, by one or more, identical or different substituents which are selected from the group which consists of:
halogen, carboxyl, hydroxyl, phenyl, (C
1
-C
6
)-alkoxy, (C
1
-C
6
)-alkoxycarbonyl, (C
1
-C
8
)-alkyl, which, for its part, can be substituted by halogen, (C
1
-C
6
)-alkylsulphonyloxy, azide, amino, mono(C
1
-C
6
)-alkylamino, di(C
1
-C
6
)-alkylamino or hydroxyl,
a group of the formula —(CO)
b
—NR
4
R
5
,
in which
b denotes a number 0 or 1,
R
4
and R
5
are identical or different and independently of one another denote hydrogen, phenyl, (C
1
-C
6
)-acyl, cyclo(C
4
-C
7
)-acyl, benzoyl or (C
1
-C
6
)-alkyl which is optionally substituted by amino, mono(C
1
-C
6
)-alkylamino, di(C
1
-C
6
)-alkylamino, or
R
4
and R
5
, together with the nitrogen atom, form a 5- or -membered saturated heterocycle which can optionally contain one or more further heteroatoms from the group consisting of S and O and/or one or more radicals of the formula —NR
8
, in which
R
8
denotes hydrogen, (C
1
-C
6
)-alkyl or (C
1
-C
6
)-acyl,
and
a group of the formula —NR
6
—SO
2
—R
7
in which
R
6
denotes hydrogen, phenyl, (C
1
-C
6
)-alkyl or (C
1
-C
6
)acyl,
R
7
denotes phenyl or (C
1
-C
6
)-alkyl,
A and E are identical or different and represent a bond or (C
1
-C
4
)-alkylene,
D represents an oxygen atom or a radical of the formula —S(O)
c
— or —N(R
9
)—,
in which
c denotes a number 0, 1 or 2,
R
9
denotes hydrogen, (C
1
-C
6
)-alkyl or (C
1
-C
6
)-acyl,
G represents doubly bonded (C
6
-C
10
)-aryl or a doubly bonded 5- to 7-membered aromatic heterocycle having up to 3 heteroatoms from the group consisting of S, N and/or O, each of which is optionally substituted by one or more, identical or different substituents which are selected from the group which consists of:
hydroxyl, trifluoromethyl, carboxyl, halogen, (C
1
-C
6
)-alkyl, hydroxy(C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy, (C
1
-C
6
)-alkoxycarbonyl,
and also groups of the formulae
—CO—O—(CH
2
)
d
—NR
10
—R
11
, —NR
2
—SOR
13
,
—(CH
2
)
e
—(CO)
f
—NR
14
R
15
and —OR
6
,
in which
d denotes a number 1, 2, 3 or 4,
e and f are identical or different and denote a number 0 or 1,
R
10
and R
11
have the meaning of R
4
and R
5
indicated above and are identical to or different from this,
R
12
has the meaning of R
6
indicated above and is identical to or different from this,
R
13
has the meaning of R
7
indicated above and is identical to or different from this,
R
14
and R
15
have the meaning of R
4
and R
5
indicated above and are identical to or different from this,
or independently of one another represents a radical of the formula
—(CH
2
)
g
—NR
17
R
18
,
in which
g denotes a number 1, 2, 3 or 4, and
R
17
and R
18
have the meaning of R
4
and R
5
indicated above and are identical to or different from this,
R
16
denotes (C
6
-C
10
)-aryl,
L represents a radical of the formula
—O—, —NH—,
where the bonding of the radicals to G takes place at the left bond,
and in which R
19
, R
20
, R
21
, R
22
, R
23
, R
24
, R
25
, R
26
and R
27
are identical or different and denote hydrogen or (C
1
-C
4
)-alkyl, or
R
19
denotes a radical of the formula —SO
2
R
2
,
R
2
represents (C
6
-C
10
)-aryl or a 5- to 7-membered saturated or aromatic heterocycle having up to 3 heteroatoms from the group consisting of S, N and/or O, each of which is optionally substituted by one or more, identical or different substituents which are selected from the group which consists of:
halogen, trifluoromethyl, nitro, amino and (C
1
-C
6
)-alkyl, or
represents the radical of the formula
or morpholine, or
represents C
3
-C
8
-cycloalkyl, or
represents (C
1
-C
12
)-alkyl, (C
2
-C
12
)-alkenyl or (C
2
-C
12
)-alkinyl, each of which is optionally substituted by one or more, identical or different substituents which are selected from the group which consists of:
halogen, trifluoromethyl, hydroxyl, cyano, azido, (C
1
-C
6
)-alkoxy, (C
1
-C
6
)-perfluoroalkoxy, partially fluorinated (C
1
-C
6
)-alkoxy, a radical of the formula
in which R
28
and R
29
have the meaning of R
4
and R
5
indicated above and are identical to or different from this,
phenyl, optionally substituted by one or more, identical or different substituents which are selected from the group which consists of:
halogen, nitro, hydroxyl, (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy and a group of the formula —NR
30
R
31
,
in which R
30
and R
31
are identical or different and denote hydrogen or (C
1
-C
6
)-alkyl or (C
1
-C
6
)-acyl,
and a 5- to 6-membered aromatic heterocycle having up to three heteroatoms from the group consisting of S, N and/or O, optionally substituted by one or more, identical or different substituents which are selected from the group which consists of:
halogen, nitro, hydroxyl, (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy and a group of the formula —NR
30
R
31
,
in which R
30
and R
31
are as defined above, or
L and R
2
together represent a radical of the formula
and their salts
Preferred compounds of the formula (I) are those in which
R
1
represents phenyl, naphthyl, quinolyl, isoquinolyl or a radical of the formula
in which
a denotes a number 1 or 2,
R
3
denotes hydrogen, (C
2
-C

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