&bgr;-amyloid inhibitors, processes for preparing them, and...

Details &bgr;-amyloid inhibitors, processes for preparing them, and... &bgr;-amyloid inhibitors, processes for preparing them, and...

2001-07-24

2003-02-04

Raymond, Richard L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C546S199000, C544S129000, C544S364000, C514S322000, C514S253090

Reexamination Certificate

active

06514969

ABSTRACT:

The present invention relates to compounds of general formula (I)
wherein the groups A, Het, R
1
, R
2
, and R
3
may have the meanings given in the following description and in the claims, processes for preparing them and the use of compounds of general formula (I) as pharmaceutical compositions, particularly as pharmaceutical compositions with a beta-amyloid-inhibiting activity.
BACKGROUND OF THE INVENTION
The aggregation and precipitation of proteins are implicated in the origins of various neurodegenerative disorders such as Alzheimer's, Parkinson's, and St. Vitus' dance (“Huntington's Chorea”). In Alzheimer's disease, the amyloid-&bgr;-peptide (A&bgr;) aggregates and leads to insoluble senile plaques which constitute one of the pathological markers of the disease. A&bgr; is formed by the proteolytic cleaving of a precursor protein, amyloid precursor protein (APP). Two methods of metabolizing APP have been detected, the non-amyloidogenic method and the amyloidogenic method.
In the non-amyloidogenic metabolism of APP, &agr;-secretase cleaves within the A&bgr; region of the APP and thus leads to the secretion of the soluble N-terminal region of the protein (&agr;-APPs) and, after the &ggr;-secretase cutting has taken place, to the release of p3. By contrast, the amyloidogenic route leads to the formation of AP, two proteases generating the N-terminus (&bgr;-secretase), and the C-terminus (&ggr;-secretase), respectively, of A&bgr;.
A&bgr; can be detected in human plasma and cerebrospinal fluid in vivo. In cell culture, too, secreted A&bgr; can be detected in the cell culture supernatant of various types of cells which express or overexpress APP or fragments thereof endogenously.
The problem of the present invention is to prepare compounds which are capable of interfering (preferably in an inhibitory capacity) in the process of the formation of A&bgr; or its release from cells, or of reducing the activity of A&bgr; by inhibiting it. Finally, the present invention is based on the further objective of preparing compounds which can be used effectively for the prevention or treatment of Alzheimer's disease.
DETAILED DESCRIPTION OF THE INVENTION
The problems set forth above are solved by the compounds of general formula (I) defined as follows.
The compounds according to the invention are compounds of general formula (I)
wherein
A denotes —CH
2
—, —CH
2
—CH
2
—, —CH
2
—CH
2
—CH
2
—, —CH
2
—CH
2
—CH
2
—CH
2
—, —CH
2
—CO—, —CH
2
—CH
2
—CO—, or —CH═CH—CO—;
Het denotes piperidinyl, piperazinyl, or dihydrobenzimidazolonyl;
R
1
denotes hydrogen or halogen, preferably hydrogen;
R
2
denotes hydrogen, C
1
-C
4
-alkyl, CF
3
, or a phenyl group which may optionally be substituted by halogen, C
1
-C
4
-alkyl, or C
1
-C
4
-alkyloxy; and
R
3
denotes hydrogen, C
1
-C
4
-alkyl, HO—C
1
-C
4
-alkyl, C
2
-C
4
-alkenyl, or a group selected from among phenyl, benzyl, and phenylethyl, which may optionally be substituted by halogen, CF
3
, C
1
-C
4
-alkyl, or C
1
-C
4
-alkyloxy, or a heterocycle selected from among morpholine, piperidine, piperazine, and dihydrobenzimidazolone, which may be linked directly or via a C
1
-C
4
-alkylene bridge.
Preferred compounds of general formula (I) are those wherein:
A denotes —CH
2
—CH
2
—, —CH
2
—CH
2
—CH
2
—, —CH
2
—CO—, or —CH═CH—CO—;
Het denotes piperidinyl, piperazinyl, or dihydrobenzimidazolonyl;
R
1
denotes hydrogen or halogen, preferably hydrogen;
R
2
denotes hydrogen, C
1
-C
4
-alkyl, phenyl, halogen-substituted phenyl, C
1
-C
4
-alkyloxy-substituted phenyl, or CF
3
; and
R
3
denotes C
1
-C
4
-alkyl, HO—C
1
-C
4
-alkyl, C
2
-C
4
-alkenyl, phenyl, benzyl, phenylethyl, halogen-substituted phenyl, halogen-substituted benzyl, or a heterocycle selected from among morpholine and dihydrobenzimidazolone, which may be linked directly or via a C
1
-C
4
-alkylene bridge.
Particularly preferred compounds of general formula (I) are those wherein:
A denotes —CH
2
—CH
2
—, —CH
2
—CH
2
—CH
2
—, —CH
2
—CO—, or —CH═CH—CO—;
Het denotes piperidinyl, piperazinyl, or dihydrobenzimidazolonyl;
R
1
denotes hydrogen or chlorine, preferably hydrogen;
R
2
denotes hydrogen, methyl, phenyl, or 4-chlorophenyl; and
R
3
denotes C
1
-C
4
-alkyl, HO—C
1
-C
4
-alkyl, C
2
-C
4
-alkenyl, phenyl, benzyl, halogen-substituted benzyl, or a heterocycle selected from morpholine and dihydrobenzimidazolone, which may be linked directly or via a C
1
-C
4
-alkylene bridge.
Of particular importance according to the invention are compounds of general formula (I), wherein:
A denotes —CH
2
—CH
2
—, —CH
2
—CH
2
—CH
2
—, or —CH═CH—CO—;
Het denotes piperidinyl or piperazinyl;
R
1
denotes hydrogen or chlorine, preferably hydrogen;
R
2
denotes hydrogen, methyl, phenyl, or 4-chlorophenyl; and
R
3
denotes 2-hydroxyethyl, phenyl, benzyl, 4-chlorobenzyl, or 1,3-dihydrobenzimidazol-2-on-1-yl.
Also preferred are compounds of general formula (I) wherein:
A denotes —CH
2
—CH
2
—, —CH
2
—CH
2
—CH
2
—, or —CH═CH—CO—;
Het denotes piperidinyl or piperazinyl;
R
1
denotes hydrogen;
R
2
denotes hydrogen, methyl, phenyl, or 4-chlorophenyl; and
R
3
denotes benzyl, 4-chlorobenzyl, or 1,3-dihydrobenzimidazol-2-on-1-yl.
Of exceptional importance according to the invention are the compounds of general formula (I), wherein the group —Het—R
3
denotes
The compounds listed below are mentioned as being particularly important within the scope of the present invention:
(a) 1-{1-[2-(2-methylimidazo[1,2-a]pyridin-3-yl)ethyl]piperidin-4-yl}-1,3-dihydrobenzimidazol-2-one;
(b) 1-[1-(3-imidazo[1,2-a]pyridin-3-ylpropyl)piperidin-4-yl]-1,3-dihydrobenzimidazol-2-one;
(c) 1-[1-(2-imidazo[1,2-a]pyridin-3-ylethyl)piperidin-4-yl]-1,3-dihydrobenzimidazol-2-one; and
(d) 1-{1-[3-(2-phenylimidazo[1,2-a]pyridin-3-yl)propyl]piperidin-4-yl}-1,3-dihydrobenzimidazol-2-one.
The invention relates to the compounds in question, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, in the form of the tautomers and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids, such as, for example, acid addition salts with hydrohalic acids, e.g., hydrochloric or hydrobromic acid, or organic acids, such as oxalic, fumaric, diglycolic, or methanesulfonic acid.
The term alkyl groups (including those which are part of other groups) denotes branched and unbranched alkyl groups with 1 to 4 carbon atoms, unless otherwise specified. Examples include: methyl, ethyl, propyl, and butyl. Unless otherwise stated, the above terms propyl and butyl also include all the possible isomeric forms. For example, the term propyl also includes the two isomeric groups n-propyl and isopropyl and the term butyl includes n-butyl, isobutyl, sec-butyl, and tert-butyl. In some cases common abbreviations are also used to denote the abovementioned alkyl groups, such as Me for methyl, Et for ethyl, etc.
The term alkylene groups denotes branched and unbranched alkylene bridges with 1 to 4 carbon atoms. Examples include: methylene, ethylene, propylene, and butylene. Unless otherwise stated, the terms propylene and butylene used above also include all the possible isomeric forms. Accordingly, the term propylene also includes the two isomeric bridges n-propylene and dimethylmethylene and the term butylene includes the isomeric bridges n-butylene, 1-methylpropylene, 2-methylpropylene, 1,1-dimethylethylene, and 1,2-dimethylethylene.
The term alkenyl groups (including those which are part of other groups) denotes branched and unbranched alkenyl groups with 2 to 4 carbon atoms, provided that they have at least one double bond, such as, for example, vinyl (provided that no unstable enamines or enolethers are formed), propenyl, isopropenyl, and butenyl.
The term halogen generally denotes fluorine, chlorine, bromine, or iodine. Unless otherwise specified, chlorine is preferred within the scope of the present invention.
“═O” denotes an

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