Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-09-27
2001-02-13
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S639000, C514S640000, C514S641000, C549S074000, C564S251000, C564S253000, C564S256000
Reexamination Certificate
active
06187808
ABSTRACT:
FIELD OF THE INVENTION
This invention provides 6-amino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one oximes and hydrazones which are useful in treating Parkinson's disease.
BACKGROUND OF THE INVENTION
Parkinson's disease is a degenerative disorder caused by the loss of dopaminergic neurons in the part of the brain that controls motor function. The disease is characterized by progressive motor dysfunction, cognitive disability, and death. Conventional treatments employ 3-hydroxy-L-tyrosine, commonly referred to as levodopa or L-DOPA. L-DOPA is a precursor in the natural production of dopamine, and it enhances levels of dopamine in the central nervous system. Unfortunately, L-DOPA loses its efficacy after prolonged use, presumably because of the continued degeneration of the neurons that convert it to dopamine. Prolonged treatment generally requires the use of additional dopaminergic agonists be used in combination with L-DOPA. Typical agents commonly utilized in adjunctive therapy with L-DOPA include pergolide and bromocryptine. Such agents often cause undesirable side-effects such as adverse cardiac effects, increased states of confusion and hallucinations, and exacerbation of pre-existing dyskinesia.
The need continues to find new agents that are useful to treat Parkinson's disease. Ideally, an agent
will replace the use of L-DOPA completely, and be sufficiently effective and safe such that adjunctive
therapy with additional drugs is obviated. We have now discovered a series of oxime and hydrazone derivatives of a naphthalenone which exhibit good in vivo agonist activity at both the D1 and the D2 dopamine receptors. The compounds are thus useful for treating Parkinson's disease.
SUMMARY OF THE INVENTION
This invention provides 6-amino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one oximes and hydrazones having Formula I
wherein:
R
1
is hydrogen, C
1-C
6
alkyl, (CH
2
)
n
phenyl, or (CH
2
)
n
-substituted phenyl;
R
2
is hydrogen, C
1
-C
6
alkyl, (CH
2
)
n
phenyl, (CH
2
)
n
-substituted phenyl, or (CH)
n
-thienyl;
R
3
is hydrogen or C
1
-C
6
alkyl;
X is O or N;
n is 1, 2, or 3; and the pharmaceutically acceptable acid addition salts thereof.
In a preferred embodiment, R
2
and R
3
both are lower alkyl, especially propyl.
Especially preferred compounds are the oximes of Formula 1, where X is O. Within this group, R
1
is preferably hydrogen or lower alkyl such as methyl, ethyl, or propyl.
Particularly preferred compounds of this invention include the following:
(±)-6-Dipropylamino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one;
6-Dipropylamino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one oxime;
6-Dipropylamino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one O-methyl oxime;
6-amino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one oxime;
6-methylamino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one oxime;
6-ethylamino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one oxime; 6-n-propylamino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one oxime;
6-iso butylamino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one oxime;
6-(2-phenylethyl)amino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one oxime;
6-(2-(2-thienyl)ethyl)amino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one oxime;
6-(N-methyl-N-n-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one oxime;
6-(N-ethyl-N-isopropylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one oxime;
6-(N-n-butyl-N-n-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one oxime;
6-(N-(2-(2-thienyl)ethyl)-N-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one oxime;
6-(N-(2-phenylethyl)-N-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one oxime;
6-dimethylamino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one oxime;
6-diethylamino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one oxime;
6-di-n-butylamino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one oxime;
6-di(2-phenylethyl)amino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one oxime;
6-di(2-(2-thienyl)ethyl)amino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one oxime;
6-amino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one O-methyl oxime;
6-methylamino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one O-methyl oxime;
6-ethylamino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one O-methyl oxime;
6-n-propylamino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one O-methyl oxime;
6-tert-butylamino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one O-methyl oxime;
6-(2-phenylethyl)amino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one O-methyl oxime;
6-(2-(2-thienyl)ethyl)amino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one O-methyl oxime;
6-(N-methyl-N-n-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one O-methyl oxime;
6-(N-ethyl-N-n-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one O-methyl oxime;
6-(N-n-butyl-N-n-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one O-methyl oxime;
6-(N-(2-(2-thienyl)ethyl)-N-isopropylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one O-methyl oxime;
6-(N-(2-phenylethyl)-N-n-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one O-methyl oxime;
6-dimethylamino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one O-methyl oxime;
6-diethylamino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one O-methyl oxime;
6-di-n-butylamino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one O-methyl oxime;
6-di(2-phenylethyl)amino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one O-methyl oxime;
6-di(2-(2-thienyl)ethyl)amino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one O-methyl oxime;
6-di-n-propylamino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one O-ethyl oxime;
6-diisopropylamino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one O-propyl oxime;
6-di-n-propylamino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one O-butyl oxime;
6-diisopropylamino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one O-pentyl oxime;
6-n-dipropylamino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one O-hexyl oxime;
6-di-n-propylamino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one O-phenyl oxime;
6-di-n-propylamino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one O-benzyl oxime;
6-di-n-propylamino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one O-phenethyl oxime;
6-di-n-propylamino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one hydrazone;
6-di-n-propylamino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one N-methylhydrazone; and
6-di-n-propylamino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one N,N-dimethylhydrazone.
The invention additionally provides a pharmaceutical formulation comprising a compound of Formula I admixed with a pharmaceutically acceptable diluent, excipient, or carrier thereof.
Another embodiment of this invention is a method for treating Parkinson's disease comprising administering to a human having Parkinson's disease and in need of treatment an effective amount of a compound of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
R
1
in Formula I includes “C
1
-C
6
alkyl,” which term means a straight or branched hydrocarbon moiety having from one to six carbon atoms. Typical of such groups include methyl, ethyl, n-propyl, isopropyl, sec-butyl, tert-butyl, n-pentyl, 1,1-dimethylbutyl, and 1ethylbutyl. The term “(CH
2
)
n
phenyl” means phenylmethyl, 2-phenylethyl, and 3phenylpropyl. The term “(CH
2
)
n
-substituted phenyl” means the foregoing groups wherein the phenyl is substituted with 1, 2, or 3 groups selected from hydroxy, C
1
-C
6
alkoxy, halo (chloro, fluoro, bromo, or iodo), C
1
-C
6
alkyl, nitro, amino, C
1
-C
6
alkylamino, or di-C
1
-C
6
alkylamino.
R
2
in Formula I can be alkyl, alkylphenyl, and alkyl-substituted phenyl, as well as (CH
2
)
n
-thienyl. The latter term means a C
1
-C
3
alkylene group having a terminal thienyl substituent, for example, a 2-thienyl or 3-thienyl group. Typical examples include 3-thienylmethyl, 2-(2-thienyl)ethyl, and 3-(2-thienyl)propyl.
The compounds of Formula I can be prepared from readily available starting materials, utilizing routine synthetic procedures well known to organic chemists. Both the oximes and the hydrazones are preferably prepared from the corresponding hexahydro naphthyl ketone, a compound having the formula
The ketone is readily prepared by reacting 1,3-cyclohexanedione, paraformaldehyde, acetone, and an amine of the Formula HNR
2
R
3
to form an eneamine, followed by reduction with agents such as sodium cyanoborohydride.
Oxime
Johnson Stephen Joseph
Meltzer Leonard Theodore
Wise Lawrence David
Ashbrook Charles W.
McKane Joseph K.
Solola Taofiq A.
Warner-Lambert & Company
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