Position-4 substituted 2-pyrrolidinone derivatives to reduce...

Details Position-4 substituted 2-pyrrolidinone derivatives to reduce... Position-4 substituted 2-pyrrolidinone derivatives to reduce...

2000-07-12

2002-05-07

Solola, T. A. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S424000, C548S408000, C548S543000

Reexamination Certificate

active

06384069

ABSTRACT:

Glutamate (Glu) is the essential excitatory transmitter in the central nervous system. High extracellular concentrations of Glu in the extracellular space lead to excitotoxic damage (Siesjö B K, Bengtsson F, Grampp W, Theander S, 1989, Calcium, excitotoxins, and neuronal death in the brain. Ann N Y Acad Sci 568:234-251). Examples of disorders of the central nervous system in which excitotoxicity is involved are stroke, hypoglycemia, hypoxia, trauma and epilepsy as acute disturbances, but also chronic disturbances in the sense of neurodegeneration such as Alzheimer's disease, AIDS-associated dementia, amyotrophic lateral sclerosis, Parkinson's disease, chronic alcoholism and others. In cases of chronic pain, an increased glutamatergic transmission (associated with elevated extracellular Glu concentrations) is responsible for plastic changes and is essentially involved in the pathogenesis of the “pain disorder” which is remote from the actual cause (Liu H T, Mantyh P W, Basbaum A I, 1997, NMDA-receptor regulation of substance P release from primary afferent nociceptors. Nature 386:721-724).
Substances which prevent the excitotoxicity of and the plastic changes due to Glu by reducing the extracellular Glu level would be a crucial advantage for the therapy and prophylaxis of the pathological states mentioned.
Several substances which (allegedly) influence glutamatergic transmission are known or already on the market as medicines. They include the Glu-release inhibitor riluzole (Bryson H M, Fulton B, Benfield P, 1996, Riluzole. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in amyotrophic lateral sclerosis. Drugs 52:549-563) and lamotrigine. However, the latter does not, despite assertions to the contrary originally, act as a specific inhibitor of Glu release (Waldmeier P C, Martin P, Stocklin K, Portet C, Schmutz M, 1996, Effect of carbamazepine, oxcarbazepine and lamotrigine on the increase in extracellular glutamate elicited by veratridine in rat cortex and striatum. Naunyn Schmiedeberg's Arch Pharmacol 354:164-172). The GABA derivative gabapentin is also said to inhibit Glu synthesis in the millimolar concentration range (Goldlust A, Su T Z, Welty D F, Taylor C P, Oxender D L, 1995, Effects of anticonvulsant drug gabapentin on the enzymes in metabolic pathways of glutamate and GABA. Epilepsy Res 22:1-11); however, these concentrations cannot be reached in vivo.
Some 1-, 3- and 5-substituted derivatives of 2-pyrrolidinone are known as substances having anticonvulsant activity and/or possibly influencing glutamatergic transmission (Nakamura J, Miwa T, Mori Y, Sasaki H, Shibasaki J, 1991, Comparative studies on the anticonvulsant activity of lipophilic derivatives of gamma-aminobutyric acid and 2-pyrrolidinone in mice. J Pharmacobiodyn 14:1-8; Reddy P A, Hsiang B C, Latifi T N, Hill M W, Woodward K E, Rothman S M, Ferrendelli J A, Covey D F, 1996, 3,3-Dialkyl- and 3-alkyl-3-benzyl-substituted 2-pyrrolidinones: a new class of anticonvulsant agents. J Med Chem 39:1898-1906; De la Mora M P, Tapia R, 1973, Anticonvulsant effect of 5-ethyl,5-phenyl,2-pyrrolidinone and its possible relationship to &ggr;-aminobutyric acid-dependent inhibitory mechanisms. Biochem Pharmacol 22:2635-2639).
The publication Arzneimittelforschung 10, 1960, page 243-250 discloses in Table I No. XVII the compound
However, this compound is not regarded as particularly active, as is evident from the discussion in the right-hand column on page 249 of this publication. Nor does the publication contain any reference to the use of this compound as pharmaceutical.
At present there is no satisfactory pharmaceutical which effectively reduces the extracellular glutamate level. Even the medicines riluzole and lamotrigine, which are already commercially available, have only low activity as inhibitors of Glu release and show side effects, through metabolism or their mechanism of action, which restricts their therapeutic use.
It is therefore an object of the invention to provide novel medicinal substances and pharmaceuticals which are effective for disorders which are attributable to an elevated glutamate level and which can therefore be employed for the prophylaxis and treatment of disorders of the central nervous system such as stroke, hypoglycemia, hypoxia, trauma and epilepsy, Alzheimer's disease, AIDS-associated dementia, amyotrophic lateral sclerosis, Parkinson's disease and chronic alcoholism. It is intended that these novel pharmaceuticals not have the disadvantages of the pharmaceuticals disclosed in the prior art.
The pharmaceuticals are preferably able to influence glutamatergic transmission and reduce the extracellular glutamate level and/or prevent the depolarization and overexcitation of postsynaptic cells, for example by presynaptically released glutamate.
This object is achieved according to the invention by providing a 2-pyrrolidinone derivative of the general formula
in which
R
1
and R
2
are, independently of one another, hydrogen atoms, hydroxyl groups, amino groups, C
1
-C
10
alkoxy radicals, C
1
-C
10
alkyl radicals or C
1
-C
10
alkylamino radicals, or R
1
and R
2
together with the carbon atom in position 4 of the pyrrolidinone ring form a five- to ten-membered saturated or unsaturated ring which, besides carbon atoms, may have up to 2 heteroatoms selected from oxygen, sulfur and nitrogen atoms, and which is unsubstituted or is substituted by up to 3 substituents selected from hydroxyl groups, amino groups, C
1
-C
4
alkyl radicals, C
1
-C
4
alkoxy radicals and C
1
-C
4
alkylamino radicals, with the proviso that R
1
and R
2
are not both hydrogen atoms,
R
3
, R
4
, R
5
and R
6
are, each independently of one another, hydrogen atoms, halogen atoms, hydroxyl groups, amino groups, C
1
-C
10
alkyl radicals, C
1
-C
10
alkoxy radicals, C
1
-C
10
alkylamino radicals or C
6
-C
10
aryl radicals, and
R
7
is a hydrogen atom or a C
1
-C
10
alkyl radical or C
1
-C
10
acyl radical,
pharmacologically acceptable salts thereof and prodrugs thereof for use as therapeutic active ingredient.
The alkyl radicals as well as the alkyl constituents of the alkoxy radicals and alkylamino radicals may be straight-chain or branched.
It has been found, surprisingly, that 2-pyrrolidinone derivatives which have in position 4 at least one substituent as defined above have an excellent effect in reducing the extracellular glutamate level and can therefore be used for the prophylaxis and treatment of disorders of the central nervous system such as stroke, hypoglycemia, hypoxia, trauma and epilepsy, Alzheimer's disease, AIDS-associated dementia, amyotrophic lateral sclerosis, Parkinson's disease and chronic alcoholism. The compounds may likewise preferentially prevent depolarization and over-excitation of postsynaptic cells, for example by presynaptically released glutamate. Substitution of the 2-pyrrolidinone derivatives according to the invention in positions 3 and 5 of the pyrrolidinone ring is substantially uncritical as long as substitution in position 4 of the pyrrolidinone ring is ensured. Preferred 2-pyrrolidinone derivatives are unsubstituted in positions 3 and 5 or have one or two alkyl substituents with up to 10 carbon atoms, preferably up to 6 carbon atoms and/or one or two aryl substituents with 6 to 10 carbon atoms, preferably phenyl groups.
Substitution on the nitrogen atom of the 2-pyrrolidinone derivatives is also substantially uncritical, but the nitrogen atom of the 2-pyrrolidinone derivatives according to the invention is preferably unsubstituted or substituted by a C
1
-C
6
alkyl radical or a C
1
-C
6
acyl radical.
The substitution at position 4 of the pyrrolidinone ring is essential for the 2-pyrrolidinone derivatives according to the invention. It is therefore necessary for at least one of the radicals R
1
and R
2
to be different from hydrogen. One of the radicals R
1
and R
2
is preferably a hydrogen atom, and other radical is preferably a C
1
-C
10
alkyl radical, particularly preferably a C
1
-C
6
alkyl radical.

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