Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-12
2001-09-11
Owens, Amelia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S292000
Reexamination Certificate
active
06288109
ABSTRACT:
The invention relates to pyranones, the basic structure of which can be derived from lactones which occur in the plant
Piper methysticum
, methods of preparing the said compounds, including the resulting intermediate products, and medicaments which contain the said compounds.
The use of kava (
Piper methystium
) extracts for the therapy of anxiety and similar psychological diseases has been known for a long time. It is likewise known that the socalled kava pyrones (kawain, dihydrokawain, methysticin, dihydromethysticin and yangonin) form the active component of such extracts. Numerous pharmacological investigations have demonstrated the various biological effects of pure substances of this type as well as their anti-convulsive and neuro-protective properties [cf. R. Kretzschmar et al., Arch. Int. Pharmacodyn. Ther. 177, pp. 261 subsequ. (1969) and C. Backhauss et al., Europ. J. Pharmacol. 215, pp. 265 subsequ. (1992)]. Until now, however, the practical therapeutic application of kava pyrones as anti-epileptics or for treating neuro-degenerative diseases has not been known. We have found that the known kava pyrones are unsuitable for the therapy of epilepsy and neuro-degenerative diseases, since the active duration of these substances after oral administration is very short, and in addition the oral bio-availability of many of these natural substances is inadequate. Furthermore, a serious obstacle to the industrial production of suitable medicaments is the fact that the isolation of new natural substances from the kava root or other plants is very complicated, which would make therapy with such compounds very expensive and thus uneconomic. In addition, the industrial exploitation is subject to the problem that the natural substances are optically active, whereas racemates are involved in the case of the previously known derivatives of kava lactones which are produced by simpler synthesis. Since the effects of kava lactones depend upon their enantiomeric form, only those kava lactones which are synthesized stereo-selectively can be used for therapeutic purposes.
Until now, however, no stereo-specific synthesis methods of this type which can be applied commercially are known for this class of substances.
The object of the invention is therefore to provide novel pyranone derivatives which have a sufficiently strong anti-convulsive effect when administered orally and have an active duration of several hours and can be used as pharmaceutical active ingredients, in particular in the therapy of diseases of the central nervous system.
This object is attained by the preparation of the compounds and methods according to the invention as well as by the use of the said compounds as medicaments which have an anti-convulsive and anti-epileptic effect [when administered] orally.
The subject of the invention is thus:
2H-1-pyran-2-ones of the general formula I,
in which
R
1
represents an alkyl radical with from 2 to 5 C atoms, a cycloalkyl radical with from 4 to 6 C atoms, a cycloalkyl alkyl radical with from 4 to 8 C atoms or an alkoxyalkyl radical with altogether 3 to 5 C atoms, and
R
2
represents a 2-(3,4-methylene dioxyphenyl)ethyl radical or a 2-phenyl ethenyl radical substituted with R
3
, R
4
and R
5
in positions 3, 4 and 5 on the benzene ring, wherein, independently of one another,
R
3
and R
5
are methoxy or ethoxy, and
R
4
is a straight-chain or branched alkoxy radical with from 1 to 5 C atoms, an alkenyloxy radical with from 3 to 5 C atoms, a cycloalkoxy radical with from 4 to 6 C atoms, a cycloalkyl alkoxy radical with from 4 to 8 C atoms or an alkoxy alkoxy radical with altogether 3 to 5 C atoms.
The compounds according to the invention are novel.
The compound 4-methoxy-6-[2-(3,4-methylene dioxyphenyl)ethyl]-2H-pyran-2-one is known (H. J. Meyer and R. Kretzschmar,
Arzneim
.-
Forsch
. [Medicinal Research] 19, 617 (1969)) and its moderately anti-convulsive effect with i.v. administration. The naturally occurring kava lactones are also known—methysticin (E-(+)-6-[2-(1,3-benzo-dioxol-5-yl)ethenyl]-5,6-dihydro-4-methoxy-2H-pyran-2-one), dihydromethysticin ((+)-6-[2-(1,3-benzodioxol-5-yl)ethyl]-5,6-dihydro-4-methoxy-2H-pyran-2-one), kawain (E-(+)-5,6-dihydro-4-methoxy-6-(2-phenylethenyl)-2H-pyran-2-one), dihydrokawain ((+)-5,6-dihydro-4-methoxy-6-(2-phenylethyl)-2H-pyran-2-one), yangonin (E-4-methoxy-6-[2-(4-methoxyphenyl)ethenyl]-2H-pyran-2-one) and desmethoxy-yangonin (E-4-meth-oxy-6(2-phenylethenyl)-2H-pyran-2-one), as well as their anti-convulsive effect with oral administration (R. Kretzschmar and H. J. Meyer, Arch. Int. Pharmacodyn. Ther. 177, 261 (1969)). These compounds are hardly effective, however, in the MES test after 3 h.
With respect to this prior art, it was surprising and in no way predictable to the person skilled in the art that the compounds of the general formula I according to the invention have a good anti-convulsive and anti-epileptic effect which lasts over several hours with oral administration, and so in many cases they have a longer active duration than the kava lactones occurring naturally. An important advantage achieved according to the invention is that it is possible to dispense with the complicated isolation of natural substances and to use simple processes of synthesis which do not require any stereoselective process performance, since the novel substances are achiral, i.e. do not have any asymmetric centres.
Compounds of the general formula I preferred according to the invention are those in which
R
1
represents an alkyl radical with from 2 to 5 C atoms, a cyclopropylmethyl radical or a methoxyethyl radical, and
R
2
represents a 2-(3,4-methylene dioxyphenyl)ethyl radical or a 2-phenyl ethenyl radical substituted with R
3
, R
4
and R
5
in positions 3, 4 and 5 on the benzene ring, wherein, independently of one another,
R
3
and R
5
are methoxy, and
R
4
is a straight-chain or branched alkoxy radical with from 1 to 5 C atoms, an allyloxy radical, a cyclopentyloxy radical, a cyclopropyl methoxy radical or a methoxyethoxy radical.
In the process according to the invention for preparing the compounds of the general formula I, in the case of R
2
=2-(3,4-methylene dioxyphenyl)ethyl a compound of the general formula II,
in which R
1
has the value indicated above, is reacted with hydrogen in the presence of a catalyst.
Alternatively, 6-[2-(1,3-benzodioxol-5-yl)ethyl]-4-hydroxy-2H-pyran-2-one can also be alkylated with R
1
X, in which R
1
has the value indicated above.
The compounds of the general formula I, in which R
2
is a 2-phenyl ethenyl radical substituted with R
3
, R
4
and R
5
in positions 3, 4 and 5 on the benzene ring, and the compounds of the general formula II are prepared by condensation of the pyranone of the general formula III—substituted accordingly with R
1
—with piperonal (3,4-methylene dioxybenzaldehyde) or with a benzaldehyde of the general formula IV substituted with R
3
, R
4
and R
5
in positions 3, 4 and 5, in which R
3
, R4 and R
5
have the values indicated above.
The compounds of the general formula III are obtained by alkylation of 4-hydroxy-6-methyl-2H-pyran-2-one with R
1
X.
The compounds of the general formula IV are obtained by O-alkylation of a benzaldehyde substituted accordingly with R
3
, R
4
and R
5
and in which one or two of the radicals R
3
to R
5
have the value indicated above and the remaining radicals R
3
to R
5
are hydroxy.
The intermediate products II and III, insofar as they are novel, likewise constitute the subject matter of the invention.
In addition, subjects of the invention are orally effective medicaments which contain one or more of the compounds of the general formula I according to the invention as the active ingredient and optionally, in addition, pharmacologically inert adjuvants, such as for example water, vegetable oils, polyethylene glycols, glycerin esters, gelatins, carbohydrates such as lactose or starch, magnesium stereate, talc, Vaseline®, preservatives, wett
Chatterjee Shyam Sunder
Hauer Hermann
Dr. Willmar Schwabe GmbH & Co.
Frost Brown Todd LLC
Owens Amelia
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