Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-11-05
2001-11-27
Kifle, Bruck (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S220000, C540S555000, C540S560000, C540S561000, C540S562000
Reexamination Certificate
active
06323197
ABSTRACT:
The invention relates to new 2,3-benzodiazepine derivatives, their production and use as pharmaceutical agents.
It is already known that selected 2,3-benzodiazepine derivatives have modulatory activity at quisqualate receptors and owing to this property are suitable as pharmaceutical agents for treating diseases of the central nervous system.
It has now been found that the 2,3-benzodiazepine derivatives according to the invention are also suitable for treating diseases of the central nervous system, whereby the compounds are distinguished by better properties compared to the above-mentioned prior art.
The invention relates to the compounds of formula I
in which
R
1
and R
2
are the same or different and mean hydrogen, C
1
-C
6
alkyl, nitro, halogen, cyano, the group —NR
8
R
9
, —O—C
1-4
alkyl, —CF
3
, OH or C
1-6
alkanoyloxy,
R
3
and R
4
are the same or different and mean hydrogen, halogen, C
1
-C
6
alkoxy, hydroxy, thiocyanato, C
1
-C
6
alkylthio, cyano, COOR
12
, PO
3
R
13
R
14
, C
1-6
alkanoyl, C
1-6
alkanoyloxy, C
2-6
alkynyl optionally substituted with C
1-4
alkoxy or phenyl, C
2-6
alkenyl optionally substituted with C
1-4
alkoxy or phenyl; C
1
-C
6
alkyl optionally substituted by halogen, hydroxy, C
1
-C
6
alkoxy, C
1
-C
6
thioalkyl, NR
10
—R
11
; C
3-7
cycloalkyl, or an optionally substituted aryl or hetaryl radical,
R
8
and R
9
are the same or different and mean hydrogen, C
1
-C
6
alkyl or the group —CO—C
1-6
alkyl,
R
10
and R
11
are the same or different and mean hydrogen, C
1
-C
6
alkyl or C
1-6
alkanoyl or together with the nitrogen atom form a 5- to 7-membered saturated heterocyle, which can contain another oxygen, sulfur or nitrogen atom and can be substituted,
R
12
, R
13
, R
14
are the same or different and mean H or C
1
-C
6
alkyl,
X means hydrogen or halogen,
Y means C
1-6
alkoxy or X and Y together mean —O—(CH
2
)
n
—O—,
n means 1, 2 or 3, and
A together with the nitrogen forms a saturated or unsaturated five-membered heterocycle, which can contain 1-3 nitrogen atoms and/or an oxygen atom and/or one or two carbonyl groups or their isomers or physiologically compatible salts.
Alkyl is defined in each case as a straight-chain or branched alkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl or hexyl.
R
3
and R
4
in the meaning of C
2-6
alkenyl contain at least one double bond such as, for example, vinyl, propenyl, buten-1-yl, isobutenyl, penten-1-yl, 2,2-dimethyl-buten-1-yl, 3-methylbuten-1-yl, hexen-1-yl. If R
3
or R
4
means C
2-6
alkynyl, at least 1 triple bond is present, such as, for example, ethynyl, propynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl. The alkenyl and alkinyl radicals can be substituted, e.g., with C
1-4
alkoxy or phenyl, which can be substituted with halogen. If a halogenated alkyl radical is present, the latter can be halogenated or perhalogenated in one or more places like CF
3
.
Halogen is defined in each case as fluorine, chlorine, bromine and iodine.
The aryl and hetaryl radicals R
3
and R
4
can be substituted in one to three places in the same way or differently with halogen, C
1-4
alkoxy or C
1-4
alkyl.
The aryl and hetaryl radicals can be present as monocyclic or bicyclic compounds and can contain 5-12 ring atoms, preferably 5-9 ring atoms, such as, for example, phenyl, biphenyl, naphthyl, indenyl as an aryl radical, and thienyl, furyl, pyranyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, oxazolyl, iso-oxazolyl, thiazolyl, isothiazolyl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazolyl-5-yl, 1,2,4-oxadiazol-3-yl, quinolyl, isoquinolyl, benzo[1]thienyl, benzofuranyl as a hetaryl radical with 1-3 heteroatoms such as sulfur, oxygen and/or nitrogen. 2-Thienyl, 3-thienyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl and phenyl can be mentioned as preferred.
Cycloalkyl is defined in each case as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, especially C
3-5
cycloalkyl.
As alkanoyl radicals, straight-chain or branched aliphatic carboxylic acid radicals, such as formyl, acetyl, propionyl, butanoyl, isopropylcarbonyl, caproyl, valeroyl, trimethylacetyl, i.a., are suitable.
If R
10
and R
11
together with the nitrogen atom form a heterocycle, for example, piperidine, pyrrolidine, thiomorpholine, hexahydroazepine, morpholine, piperazine, imidazolidine, hexahydrodiazepine is mentioned. If the heterocycle is substituted, the substituent C
1-4
alkyl or phenyl can be in one to two places, such as, for example, N-methyl-piperazine, N-phenyl-piperazine, 2,6-dimethylmorpholine.
If A together with the nitrogen atom forms a saturated heterocycle, the latter can be substituted at the carbon atom or at another nitrogen atom. In this case, A means, for example, C
3
alkylene, which can be substituted with R
3
and R
4
, and in which 1, 2 or 3 alkylene groups can be replaced by oxygen, carbonyl or —NR
3
—, such as, for example, —(CH
2
)
3
—, —CH
2
—NR
3
—CH
2
—, —CH
2
—O—CH
2
—, —CH
2
—O—CO—, —CH
2
—NR
3
—CO—, —CO—NR
3
—Co— or CH
2
—O—CR
3
R
4
, whereby the carbonyl group is bonded to the nitrogen atom of the benzodiazepine, and R
3
and R
4
preferably mean C
1-4
alkyl. These compounds of formula I contain a chiral center in the 4-position of the 2,3-benzodiazepine skeleton and can be present as a racemate or optical isomers.
If A together with the nitrogen atom forms an unsaturated 5-membered heterocycle, it thus is not a chiral carbon atom, but rather an exocyclic double bond that is present in the 4-position of the 2,3-benzodiazepine skeleton. The unsaturated 5-membered heterocycle can be present partially unsaturated or aromatic. Preferred are heteroaromatic compounds with 1-3 nitrogen atoms, in which A has, for example, the following meaning:
The physiologically compatible salts are derived from inorganic and organic acids. Suitable are inorganic acids, such as, for example, hydrohalic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or organic acids such as, for example, aliphatic or aromatic mono- or dicarboxylic acids such as formic acid, acetic acid, maleic acid, fumaric acid, succinic acid, lactic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid or sulfonic acids, for example, C
1-4
alkanesulfonic acids such as methanesulfonic acid or benzenesulfonic acids that are optionally substituted by halogen or C
1-4
alkyl, such as p-toluenesulfonic acid.
The compounds of formula I also comprise all possible stereoisomers and their mixtures, such as diastereomers, racemates and enantiomers.
Preferred are compounds of general formula I in which R
2
means hydrogen.
The compounds of general formula I as well as their physiologically compatible salts can be used as pharmaceutical agents owing to their non-competitive inhibition of the AMPA receptors. Owing to their profile of action, the compounds according to the invention are suitable for treating diseases that are caused by hyperactivity of excitatory amino acids, such as, for example, glutamate or aspartate. Since the new compounds act as non-competitive antagonists of excitatory amino acids, they are suitable especially for treating those diseases that are influenced by the receptors of excitatory amino acids, especially the AMPA receptor.
The pharmacological action of the compounds of formula I was determined by means of the tests described below:
Male NMRI mice weighing 18-22 g were kept under controlled conditions (0600-1800 hours light/dark cycle, with free access to food and water) and their assignment to groups was randomized. The groups consisted of 5-16 animals. The observation of the animals was performed between 0800 and 1300 hours.
AMPA was sprayed into the left ventricles of mice that were allowed to move freely. The applicator consisted of a cannula with a device made of stainless steel, which limits the depth of injection to 3.2 mm. The applicator was connected to an injection pump. The injection needle was inserted perpendicular to the surface of the skull accordin
Abraham Gizella
Andrasi Ferenc
Berzsenyi Pal
Csuzdi Ernese
Gal Melinda
Kifle Bruck
Millen White Zelano & Branigan
Schering Aktiengesellschaft
LandOfFree
Condensed 2,3-benzodiazepine derivatives and their use as... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Condensed 2,3-benzodiazepine derivatives and their use as..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Condensed 2,3-benzodiazepine derivatives and their use as... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2608081