Bis-basic compounds with tryptase-inhibitory activity

Details Bis-basic compounds with tryptase-inhibitory activity Bis-basic compounds with tryptase-inhibitory activity

2000-10-30

2004-08-24

McKane, Joseph K. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S334000, C544S360000, C546S191000

Reexamination Certificate

active

06780863

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to bis-basic compounds having tryptase-inhibiting activity, processes for preparing such compounds, their therapeutic use in the treatment of disease, and pharmaceutical compositions comprising such compounds.
SUMMARY OF THE INVENTION
Tryptase inhibitors may be used in the production of pharmaceutical compositions which are used to prevent and/or treat inflammatory and/or allergic conditions.
The object of the present invention is therefore to provide new compounds that have a tryptase-inhibiting activity and may be used to prevent and treat conditions in which tryptase inhibitors may have a therapeutic value.
DETAILED DESCRIPTION OF THE INVENTION
The compounds according to the invention are bis-basic compounds of general formula (I)
B
1
—Ar
1
—X
1
—Ar
2
—X
2
—A—X
3
—Ar
3
—X
4
—Ar
4
—B
2
  (I)
wherein
B
1
and B
2
which may be identical or different denote —C(═NR
1
)—NR
1′
H, —CH
2
NH
2
, —CH
2
CH
2
NH
2
or —NH—C(═NH)—NH
2
;
R
1
and R
1′
which may be identical or different denote hydrogen, OH, —COR
2
or —COOR
2
;
R
2
denotes hydrogen, C
1
-C
18
-alkyl, aryl or aryl-C
1
-C
6
-alkyl;
Ar
1
, Ar
2
, Ar
3
, Ar
4
and aryl which may be identical or different denote C
6
-C
10
-aryl, which may optionally be mono- to tetrasubstituted by one or more groups selected from among C
3
-C
10
-cycloalkyl, F, Cl , Br, I, OH, OR
3
, SR
3
, NR
3
R
4
, COOR
3
, C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl and C
2
-C
6
-alkynyl, whilst in the substituents C
1
-C
6
-alkyl and C
2
-C
6
-alkenyl one or more hydrogen atoms may optionally be replaced by F or OR
3
, or
 a 5-10-membered mono- or bicyclic heteroaryl ring, wherein up to three carbon atoms may be replaced by one or more heteroatoms selected from among oxygen, nitrogen and sulphur and which may optionally be mono- to tetrasubstituted by one or more groups selected from among C
1
-C
10
-cycloalkyl, F, Cl, Br, I, OH, OR
3
, SR
3
, NR
3
R
4
, COOR
3
, C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl and C
2
-C
6
-alkynyl, whilst in the substituents C
1
-C
6
-alkyl and C
2
-C
6
-alkenyl one or more hydrogen atoms may optionally be replaced by F or OR
3
;
R
3
and R
4
which may be identical or different denote hydrogen or a group selected from among C
1
-C
6
-alkyl and C
3
-C
6
-cycloalkyl wherein one or more hydrogen atoms may optionally be replaced by F;
X
1
, X
2
, X
3
and X
4
which may be identical or different denote a bridge selected from among —(CH
2
)
n
—, —(CH
2
)
n
O—, —(CH
2
)
n
—S—, —(CH
2
)
n
NR
3
— and —(CH
2
)
n
N
+
R
3
R
4
— where n=1 or 2;
A denotes a group selected from among C
2
-C
16
-alkylene and C
2
-C
16
-alkenylene, wherein optionally one or more hydrogen atoms may be replaced by one or more groups selected from among F, R
3
, OR
3
and COOR
3
, or A denotes C
2
-C
16
-alkynylene, or
A denotes —(CH
2
)
l
—D—(CH
2
)
m
—, whilst in the alkylene groups —(CH
2
)
l
— and —(CH
2
)
m
— one or two hydrogen atoms may optionally be replaced by C
1
-C
6
-alkyl and wherein
D denotes aryl or C
3
-C
10
-cycloalkyl wherein one or more hydrogen atoms may optionally be replaced by one or more groups selected from among F, R
3
and OR
3
and l and m, which may be identical or different, denote 0, 1, 2, 3 or 4,
or
D denotes —O—, —S— or —NR
3
— and l and m, which may be identical or different, denote 2, 3 or 4;
or
A denotes —G
1
—(CH
2
)
r
—G
2
—, if X
2
or X
3
denote —(CH
2
)
n
—, A may also denote —E
1
—(CH
2
)
r
—G
1
— or —E
1
—(CH
2
)
r
—E
2
—,
wherein
r denotes the number 0, 1, 2, 3, 4, 5 or 6,
G
1
and G
2
which may be identical or different denote a single bond or C
3
-C
10
-cycloalkyl, but if r=0 or r=1 G
1
and G
2
cannot simultaneously represent a single bond;
E
1
and E
2
which may be identical or different denote C
3
-C
10
-aza-cycloalkyl which contains one or two nitrogen atoms, wherein at least one N-atom is bound to X
2
or X
3
=(CH
2
)
n
,
optionally in the form of their racemates, enantiomers, diastereomers, tautomers and mixtures thereof, and optionally the pharmacologically harmless acid addition salts thereof.
Preferred compounds of general formula (I) are those wherein
B
1
and B
2
which may be identical or different denote —C(═NR
1
)—NR
1′
H, —CH
2
NH
2
, —CH
2
CH
2
NH
2
or —NH—C(═NH)—NH
2
;
R
1
and R
1′
which may be identical or different denote hydrogen, OH, —COR
2
or —COOR
2
;
R
2
denotes hydrogen, C
1
-C
14
-alkyl, aryl or aryl-C
1
-C
6
-alkyl;
Ar
1
, Ar
2
, Ar
3
, Ar
4
and aryl which may be identical or different, denote C
6
-C
10
-aryl which may optionally be mono- to tetrasubstituted by one or more groups selected from among C
3
-C
8
-cycloalkyl, F, Cl, Br, I, OH, OR
3
, NR
3
R
4
, COOR
3
, C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl and C
2
-C
6
-alkynyl, whilst in the substituents C
1
-C
6
-alkyl and C
2
-C
6
-alkenyl one or more hydrogen atoms may optionally be replaced by F, or
 a 5-10-membered mono- or bicyclic heteroaryl ring, wherein up to three carbon atoms may be replaced by one or more heteroatoms selected from among oxygen, nitrogen and sulphur and which may optionally be mono- to tetrasubstituted by one or more groups selected from among F, OR
3
, COOR
3
or C
1
-C
6
-alkyl, wherein in the substituent C
1
-C
6
-alkyl one or more hydrogen atoms may optionally be replaced by F;
R
3
and R
4
which may be identical or different denote hydrogen or a group selected from among C
1
-C
6
-alkyl and C
3
-C
6
-cycloalkyl wherein one or more hydrogen atoms may optionally be replaced by F;
X
1
, X
2
, X
3
and X
4
which may be identical or different denote a bridge selected from among —(CH
2
)
n
—, —(CH
2
)
n
O—, —(CH
2
)
n
—S—, —(CH
2
)
n
NR
3
— and —(CH
2
)
n
N
+
R
3
R
4
— where n=1 or 2;
A denotes a group selected from among C
2
-C
14
-alkylene and C
2
-C
10
-alkenylene, wherein optionally one or more hydrogen atoms may be replaced by one or more groups selected from among F, R
3
, OR
3
and COOR
3
, or A denotes C
2
-C
10
-alkynylene, or
A denotes —(CH
2
)
l
—D—(CH
2
)
m
—, whilst in the alkylene groups —(CH
2
)
l
— and —(CH
2
)
m
— one or two hydrogen atoms may optionally be replaced by C
1
-C
6
-alkyl and wherein
D denotes aryl or C
3
-C
8
-cycloalkyl wherein one or more hydrogen atoms may optionally be replaced by one or more groups selected from among F, R
3
and OR
3
and l and m, which may be identical or different, denote 0, 1, 2, 3 or 4,
or
D denotes —O—, —S— or —NR
3
— and l and m, which may be identical or different, denote 2, 3 or 4;
or
A denotes —G
1
—(CH
2
)
r
—G
2
—,
if X
2
or X
3
represents —(CH
2
)
n
—, A also denotes —E
1
—(CH
2
)
r
—G
1
— or —E
1
—(CH
2
)
r
—E
2
—,
wherein
r denotes the number 0, 1, 2, 3, 4, 5 or 6,
G
1
and G
2
which may be identical or different denote a single bond or C
3
-C
8
-cycloalkyl, but if r=0 or r=1 G
1
and G
2
cannot simultaneously represent a single bond;
E
1
and E
2
which may be identical or different denote C
3
-C
8
-aza-cycloalkyl which contains one or two nitrogen atoms, wherein at least one N-atom is bound to X
2
or X
3
=(CH
2
)
n
,
optionally in the form of their racemates, enantiomers, diastereomers, tautomers and mixtures thereof, and optionally the pharmacologically harmless acid addition salts thereof.
Particularly preferred are compounds of general formula (I), wherein
B
1
and B
2
which may be identical or different denote —C(═NR
1
)—NR
1′
H, —CH
2
NH
2
, —CH
2
CH
2
NH
2
or —NH—C(═NH)—NH
2
;
R
1
and R
1′
which may be identical or different denote hydrogen, OH, —COR
2
or —COOR
2
;
R
2
denotes hydrogen, C
1
-C
10
-alkyl or aryl-C
1
-C
4
-alkyl;
Ar
1
, Ar
2
, Ar
3
, Ar
4
and aryl which may be identical or different, denote phenyl or naphthyl which may optionally be mono-, di— or trisubstituted by one or more groups selected from among F, OR
3
, NR
3
R
4
, COOR
3
or C
1
-C
6
-alkyl, wherein in the substituent C
1
-C
6
-alkyl one or more hydrogen atoms may optionally be replaced by F or OR
3
;
R
3
and R
4
which may be identical or different denote

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