Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-10-22
2003-07-08
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S137000, C548S241000
Reexamination Certificate
active
06589949
ABSTRACT:
The present invention relates to new 3-oxo-2,1-benzisoxazole-1(3H)-carboxamides, processes for their preparation and their use for the production of medicaments for the prophylaxis and/or treatment of disorders of the central nervous system, in particular cognitive disorders such as Alzheimer's disease and other forms of dementia, cerebral infarct, craniocerebral trauma and pain.
Acylpeptide hydrolase (ACPH) is a serine protease which cleaves N-acetylated amino acids of peptides. A function of ACPH is the degradation of N-acetylated hormones and neuropeptides. ACPH is inhibited by low concentrations of diisopropyl fluorophosphate (DFP) (WO-A-99/52516). Investigations in the ‘Morris test’, an animal model of learning and memory, showed that DFP has a promoting action on learning and memory processes (
J. Pharmacol. Exp. Ther
. 1996, 278, 697-708). The use of ACPH inhibitors for the treatment of Alzheimer's disease and for improving the cognitive power has been described beforehand (WO-A-99/52516).
WO-A-96/02537 discloses benzo-fused 5-membered heterocyclyl-carboxamides for the treatment of disorders of the central nervous system.
The synthesis and the antimicrobial and antileukemic action of 1-(1-mono-alkylamino-carbonyl)-2,1-benzisoxazol-3(1H)-ones has been described (
J. Med. Chem
. 1984,27, 1212-1215).
The present invention relates to compounds of the general formula (I),
in which
R
1
and R
2
are identical or different and independently of one another
represent hydrogen, halogen, (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy, (C
1
-C
3
)-perfluoroalkyl, (C
1
-C
3
)-perfluoroalkoxy or a radical-NR
5
R
6
,
in which
R
5
and R
6
are identical or different and represent hydrogen, (C
1
-C
4
)-alkyl, (C
1
-C
4
)-acyl, (C
1
-C
4
)-alkoxycarbonyl, carbamoyl, mono- or di-(C
1
-C
4
)-alkylaminocarbonyl,
R
3
and R
4
are identical or different and independently of one another
represent (C
1
-C
8
)-alkyl whose carbon chain is optionally interrupted by an oxygen or sulfur atom or by a radical NR
7
and which is optionally mono- or polysubstituted by radicals selected from the group consisting of (C
3
-C
6
)-cycloalkyl, (C
1
-C
4
)-alkoxy, hydroxyl, halogen or NR
8
R
9
,
represent (C
3
-C
8
)-cycloalkyl whose carbon chain is optionally interrupted by an oxygen or sulfur atom or by a radical NR
10
and which is optionally mono- or polysubstituted by radicals selected from the group consisting of (C
1
-C
4
)-alkoxy, hydroxyl, halogen or NR
11
R
12
,
in which
R
7
, R
8
, R
9
, R
10
, R
11
and R
12
are identical or different and independently of one another have the meaning mentioned for R
5
,
or
R
3
and R
4
, together with the nitrogen atom, form a saturated or partially unsaturated 3- to 10-membered, mono- or bicyclic heterocycle, which optionally contains up to two further heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and which is optionally substituted by radicals selected from the group consisting of (C
1
-C
4
)-alkyl, (C
1
-C
4
)-alkoxy, hydroxyl, halogen, COOR
13
or NR
14
R
15
,
in which
R
13
denotes hydrogen or (C
1
-C
4
)-alkyl, and
R
14
and R
15
are identical or different and independently of one another have the meaning mentioned for R
5
,
and
X represents oxygen or sulfur,
and their salts.
Halogen in the context of the invention in general represents fluorine, chlorine, bromine and iodine. Fluorine, chlorine and bromine are preferred. Fluorine and chlorine are particularly preferred.
(C
1
-C
6
-alkyl or (C
1
-C
4
)-alkyl in the context of the invention represent a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl. A straight-chain or branched alkyl radical having 1 to 4 carbon atoms is preferred. A straight-chain or branched alkyl radical having 1 to 3 carbon atoms is particularly preferred.
(C
1
-C
6
)-alkoxy in the context of the invention represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms. Examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy. A straight-chain or branched alkoxy radical having 1 to 4 carbon atoms is preferred. A straight-chain or branched alkoxy radical having 1 to 3 carbon atoms is particularly preferred.
(C
1
-C
3
)-perfluoroalkyl in the context of the invention represents a perfluorinated straight-chain or branched alkyl radical having 1 to 3 carbon atoms. Examples which may be mentioned are: trifluoromethyl, pentafluoroethyl and heptafluoroisopropyl. Trifluoromethyl is preferred.
(C
1
-C
3
)-perfluoroalkoxy in the context of the invention represents a perfluorinated straight-chain or branched alkoxy radical having 1 to 3 carbon atoms. Examples which may be mentioned are: trifluoromethoxy, pentafluoroethoxy and heptafluoroisopropoxy. Trifluoromethoxy is preferred.
(C
1
-C
4
)-acyl or (C
1
-C
3
)-acyl in the context of the invention represents a straight-chain or branched acyl radical having 1 to 4 or 1 to 3 carbon atoms. Examples which may be mentioned are: formyl, acetyl, propionyl, n-butyryl and iso-butyryl. Formyl, acetyl and propionyl are preferred.
(C
1
-C
4
)-alkoxycarbonyl in the context of the invention represents a straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.
Mono- or di-(C
1
-C
4
)-alkylaminocarbonyl in the context of the invention represents an amino group, which is linked via a carbonyl group and which contains a straight-chain or branched or two identical or different straight-chain or branched alkyl substituents in each case having 1 to 4 carbon atoms. Examples which may be mentioned are: methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, n-propyl-aminocarbonyl, isopropylmethylaminocarbonyl, tert-butylaminocarbonyl and tert-butyl-methylaminocarbonyl. A mono- or dialkylaminocarbonyl radical is preferred whose straight-chain or branched alkyl radical or whose identical or different straight-chain or branched alkyl radicals contain 1 to 3 carbon atoms.
(C
3
-C
8
)-cycloalkyl or (C
3
-C
6
)-cycloalkyl in the context of the invention represents a cycloalkyl radical having 3 to 8 or 3 to 6 carbon atoms. Examples which may be mentioned are: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclooctyl. Cyclopropyl, cyclopentyl and cyclohexyl are preferred.
(C
1
-C
18
)-alkyl, (C
1
-C
6
)-alkyl or (C
1
-C
4
)-alkyl whose carbon chain is optionally interrupted by an an oxygen or sulfur atom or by a radical NR
7
in the context of the invention represents a straight-chain or branched alkyl radical having 1 to 8, 1 to 6 or 1 to 4 carbon atoms, whose carbon chain contains an oxygen or sulfur atom or a radical NR
7
as a further chain member. A straight-chain or branched alkyl radical having 1 to 6 carbon atoms is preferred, whose carbon chain contains an oxygen or sulfur atom or a radical NR
7
as a further chain member. A straight-chain or branched alkyl radical having 1 to 4 carbon atoms is particularly preferred, whose carbon chain contains an oxygen atom as a further chain member.
(C
3
-C
8
)-cycloalkyl or (C
4
-C
6
)-cycloalkyl whose carbon chain is optionally interrupted by an oxygen or sulfur atom or by a radical NR
10
in the context of the invention represents a cycloalkyl radical having 3 to 8 or 4 to 6 carbon atoms, whose carbon chain contains an oxygen or sulfur atom or a radical NR
10
as a further ring member. A cycloalkyl radical having 4 to 6 carbon atoms is preferred, whose carbon chain contains an oxygen or sulfur atom or a radical NR
10
as a further ring member. A cycloalkyl radical having 4 to 6 carbon atoms is particularly preferred, whose carbon chain contains an oxygen atom or a radical NR
10
as a further ring member.
The saturated or partially unsaturated 3- to 10-membered, mono- or bicyclic heterocycle in the context of the invention represents a monocyclic or bicycl
Böss Frank
Ergüden Jens-Kerim
Fürstner Chantal
Moriwaki Toshiya
Riedl Bernd
Pellegrino Susan M.
Ramsuer Robert W.
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