Aryl sulphonamide amino acid esters and analogues

Details Aryl sulphonamide amino acid esters and analogues Aryl sulphonamide amino acid esters and analogues

2001-02-16

2003-04-08

Seaman, D. Margaret (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Radical -xh acid, or anhydride, acid halide or salt thereof...

C514S417000, C514S576000, C548S473000, C560S015000, C560S051000

Reexamination Certificate

active

06545050

ABSTRACT:

A The present invention relates to novel amino acid esters of arylsulphonamides and analogues, to processes for their preparation and to their use for the prophylaxis and treatment of neurodegenerative disorders, in particular for the treatment of cerebral apoplexy, craniocerebral trauma, pain and spasticity.
&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 found mainly in 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 glutamate (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 anandarnide.
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 psychological symptoms. The causes of cerebral apoplexy can lie in cerebral haemorrhages (e.g. after a vascular tear in hypertension, arteriosclerosis and appoplectic aneurysm) and ischaemias (e.g. due to a drop in blood pressure or embolism). The functional losses in the brain lead to a degeneration or destruction of 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). Craniocerebral 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 a radical of the formula
 in which
a represents a number 1 or 2,
R
3
represents hydrogen, (C
2
-C
6
)-alkenyl, (C
1
-C
6
)-alkyl or (C
1
-C
6
)-acyl,
and where all of the phenyl ring systems listed above are optionally substituted, optionally geminally, by one or more identical or different substituents selected from the group consisting of:
halogen, carboxyl, hydroxyl, phenyl, (C
1
-C
6
)-alkoxy, (C
1
-C
6
)-alkoxycarbonyl, (C
1
-C
8
)-alkyl, which for its part may 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 represents a number 0 or 1,
R
4
and R
5
are identical or different and independently of one another represent 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 6-membered saturated heterocycle which may optionally contain one or more further heteroatom(s) from the group consisting of S and O and/or one or more radical(s) of the formula —NR
8
,
in which
R
8
represents 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
represents hydrogen, phenyl, (C
1
-C
6
)-alkyl or (C
1
-C
6
)-acyl,
R
7
represents phenyl or (C
1
-C
6
)-alkyl,
Q represents a radical of the formula
 in which
represents a number 1, 2, 3, 4, 5 or 6,
R
9
and R
10
are identical or different and represent hydrogen or (C
1
-C
6
)-alkyl,
T represents a radical of the formula —(CH
2
)
d
—,
in which
d represents a number 1, 2, 3, 4, 5, 6, 7 or 8, or
T represents a moiety of an amino acid radical of the formula
 in which
R
13
and R
14
are identical or different and represent hydrogen or methyl, or
R
13
represents hydrogen or methyl and
R
14
represents (C
3
-C
8
)-cycloalkyl or (C
6
-C
10
)-aryl or hydrogen, or (C
1
-C
8
)-alkyl,
where the (C
1
-C
8
)-alkyl is optionally substituted by methlythio, hydroxyl, mercapto, guanidyl or by a group of the formula —NR
15
R
16
or —NR
17
—OC—,
in which
R
15
and R
16
independently of one another represent hydrogen, (C
1
-C
8
)-alkyl or phenyl and
R
17
represents hydroxyl, benzyloxy, (C
1
-C
8
)-alkoxy or the group —NR
15
R
16
listed above,
or the (C
1
-C
8
)-alkyl is optionally substituted by (C
3
-C
6
)-cycloalkyl or phenyl, which for its part is substituted by hydroxyl, halogen or (C
1
-C
6
)-alkoxy or amino,
or the (C
1
-C
8
)-alkyl is optionally substituted by imidazolyl or indolyl, in which the corresponding —NH functions are optionally protected by (C
1
-C
6
)-alkyl or by an amino protective group,
R
11
and R
12
are identical or different and represent hydrogen, (C
1
-C
6
)-alkyl or a typical amino protective group, or
R
11
and R
12
together with the nitrogen atom form a 5- to 6-membered saturated heterocycle, which may optionally contain a further heteroatom from the group consisting of S and O or a radical of the formula —NR
18
,
in which
R
18
represents hydrogen, (C
1
-C
6
)-alkyl or phenyl,
A and E are identical or different and represent a bond or represent (C
1
-C
4
)-alkylene,
D represents an oxygen atom or represents a radical of the formula —S(O)
e
—or —N(R
19
)—,
in which
e represents a number 0, 1 or 2,
R
9
represents hydrogen, (C
1
-C
6
)-alkyl or (C
1
-C
6
)-acyl,
G represents doubly attached (C
6
-C
10
)-aryl or represents a doubly attached 5- to 7-membered aromatic heterocycle having up to 3 heteroatoms from the group consisting of S, N and O, which are optionally substituted by one or more identical or different substituents selected from the group consisting 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 groups of the formulae —CO—O—(CH
2
)
f
—NR
20
R
21
, —NR
22
—SO
2
R
23
, —(CH
2
)
g
—(CO)
h
—NR
24
R
25
and —OR
26
,
in which
f represents a number 1, 2, 3 or 4,
g and h are identical or different and represent a number 0 or 1,
R
20
and R
21
have the meaning of R
4
and R
5
given above and are identical to or different from this meaning,
R
22
has the meaning of R
6
given above and is identical to or different from this meaning,
R
23
has the meaning of R
7
given above and is identical to or different from this meaning,
R
24
and R
25
have the meaning of R
4
and R
5
given above and are identical to or different from this meaning,
or independently of one another represent a radical of the formula
—(CH
2
)
i
—NR
27
R
28
,
 in which
i represents a number 1, 2, 3 or 4, and
R
27
and R
28
have the meaning of R
4
and R
5
given above and are identical to or different from this meaning,
R
26
represents (C
6
-C
10
)-aryl,
L represents a radical of the formula —O—, —NH—,
where the left-hand side of the radicals is attached to G,
and in which R
29
, R
30
, R
31
, R
32
, R
33
, R
34
, R
35
, R
36
and R
37
are identical or different and represent hydrogen or (C
1
-C
4
)-alkyl, or
R
29
represents a radical of the formula —SO
2
R
2
,
R
2
represents (C
6
-C
10
)-aryl or represents a 5- to 7-membered saturated or aromatic heterocycle having up to 3 heteroatoms from the group consisting of S, N and O, which are optionally substituted by one or more iden

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