Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-19
2003-08-05
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S579000, C514S659000
Reexamination Certificate
active
06602862
ABSTRACT:
FIELD OF INVENTION
New use of 1-amino-alkylcyclohexanes, i.e., as anti-parasitemial, anti-trypanosomiasis, or trypanocidal agents.
BACKGROUND OF THE INVENTION
Vector control and other public health measures have a successful history of containing African trypanosomiasis. However, war, civil unrest and economic problems have resulted in a breakdown of these interventions and the estimated annual incidence is now 300,000 cases. The causative agents of human trypanosomiasis are the tsetse fly-transmitted protozoan parasites
Trypanosoma brucei gambiense
(western and central Africa) and
Trypanosoma brucei rhodesiense
(eastern and southern Africa). In the bloodstream of infected individuals antigenic variation by the parasite prevents elimination by the immune system and the development of a vaccine is not considered feasible. The drugs used to treat trypanosomiasis are unsatisfactory. They all require hospitalization, are expensive, can fail to eradicate parasitemia and often have toxic side effects. Melarsoprol, which is used against the advanced stage of the disease that occurs once trypanosomes have invaded the central nervous system, causes 5 to 10% patient mortality due to arsenic encephalopathy. The only other drug available for clinical use against this stage of the disease, difluoromethylornithine (DFMO), has limited efficacy against
T.b. rhodesiense
infections and is very expensive. In the absence of treatment, trypanosomiasis is fatal and the development of new chemotherapeutic approaches is thus a priority.
PRIOR ART
The prior art is represented by our prior U.S. Pat. No. 6,034,134 of Mar. 7, 2000 and our published application WO 99/01416, PCT/EP98/04026, and Parsons et al. Neuropharmacology 38, 85-108 (1999), wherein the active compounds utilized according to the present invention are disclosed and disclosed to be NMDA receptor antagonists and anticonvulsants. We have subsequently disclosed them to be useful as 5HT
3
and neuronal nicotinic receptor antagonists.
THE PRESENT INVENTION
The present invention is directed to a new use of 1-amino-alkylcyclohexane compounds selected from the group consisting of those of the formula
wherein R* is —(CH
2
)
n
—(CR
6
R
7
)
m
—NR
8
R
9
wherein n+m=0, 1, or 2
wherein R
1
through R
7
are independently selected from the group consisting of hydrogen and lower-alkyl (1-6C), and
wherein R
8
and R
9
each represent hydrogen or lower-alkyl (1-6C) or together represent lower-alkylene —(CH
2
)
x
—
wherein x is 2 to 5, inclusive, and enantiomers, optical isomers, hydrates, and pharmaceutically-acceptable salts thereof, as well as pharmaceutical compositions thereof,
and the preparation and use of such compounds and compositions for the treatment of a living animal as antitrypanosomiasis agents and as trypanocides.
Representative of these compounds are as follows:
MRZ 579: 1-Amino-1,3,3,5,5-pentamethylcyclohexane,
580: 3,3,5,5-Tetramethylcyclohexylmethylamine,
601: 1-Amino-1-propyl-3,3,5,5-tetramethylcyclohexane,
607: 1-Amino-1,3,3,5(trans)-tetramethylcyclohexane (axial amino group),
614: 3-Propyl-1,3,5,5-Tetramethylcyclohexylamine semihydrate (mixture of diastereomers ~1:2)
615: 1-Amino-1,3,5,5-tetramethyl-3-ethylcyclohexane (mixture of diastereomers),
616: 1-Amino-1,3,5-trimethylcyclohexane (mixture of diastereomers),
617: 1-Amino-1,3-dimethyl-3-propylcyclohexane (mixture of diastereomers),
618: 1-Amino-1,3 (trans),5 (trans)-trimethyl-3(cis)-propylcyclohexane,
620: 1-Amino-1,3-dimethyl-3-ethylcyclohexane,
621: 1-Amino-1,3,3-trimethylcyclohexane,
622: cis-3-Ethyl-1, trans-3, trans-5-trimethylcyclohexamine,
625: 1-Amino-1,3 (trans)-dimethylcyclohexane,
626: 1,3,3-Trimethyl-5,5-dipropylcyclohexylamine,
627: 1-Amino-1-methyl-3 (trans) propylcyclohexane,
628: 1-Methyl-3-cis-propylcyclohexylamine,
629: 1-Amino-1-methyl-3 (trans) ethylcyclohexane,
632: 1-Amino-1,3,3-trimethyl-5 (cis) ethylcyclohexane,
633: 1-Amino-1,3,3-trimethyl-5 (trans) ethylcyclohexane,
634: cis-3-Propyl-1,5,5-trimethylcyclohexylamine,
635: trans-3-Propyl-1,5,5-trimethylcyclohexylamine
639: N-Ethyl-1,3,3,5,5-pentamethylcyclohexylamine,
640: N-methyl-1-Amino-1,3,3,5.5-pentamethylcyclohexane,
641: 1-Amino-1-methylcyclohexane,
642: N,N-dimethyl-1-amino-1,3,3,5,5-pentamethylcyclohexane,
644: 2-(3,3,5,5-Tetramethylcyclohexyl)ethylamine,
645: 2-Methyl-1-(3,3,5,5-tetramethylcyclohexyl)propyl-2-amine,
662: 2-(1,3,3,5,5-Pentamethylcyclohexyl-1) ethylamine, semihydrate
705: N-(1,3,3,5,5-pentamethylcyclohexyl) pyrrolidine,
680: 1-amino-1,3(trans),5(trans)-trimethylcyclohexane,
681: 1-amino-1,3(cis),5(cis)-trimethylcyclohexane, .H
2
O,
682: 1-amino-(1R,5S)trans-5-ethyl-1,3,3-trimethylcyclohexane,
683: 1-amino-(1S,5S)cis-5-ethyl-1,3,3-trimethylcyclohexane, .H
2
O,
1-Amino-1,5,5-trimethyl-3(cis)-isopropyl-cyclohexane,
1-Amino-1,5,5-trimethyl-3(trans)-isopropyl-cyclohexane,
1-Amino-1-methyl-3 (cis)-ethyl-cyclohexane,
1-Amino-1-methyl-3(cis)-methyl-cyclohexane,
1-Amino-5,5-diethyl-1,3,3-trimethyl-cyclohexane, and
Also, 1-amino-1,3,3,5,5-pentamethylcyclohexane,
1-amino-1,5,5-trimethyl-3,3-diethylcyclohexane,
1-amino-1-ethyl-3,3,5,5-tetramethylcyclohexane,
N-ethyl-1-amino-1,3,3,5,5-pentamethylcyclohexane,
N-(1,3,5-trimethylcyclohexyl)pyrrolidine or piperidine,
N-[1,3(trans),5(trans)-trimethylcyclohexyl]pyrrolidine or piperidine,
N-[1,3(cis),5(cis)-trimethylcyclohexyl]pyrrolidine or piperidine,
N-(1,3,3,5-tetramethylcyclohexyl)pyrrolidine or piperidine,
N-(1,3,3,5,5-pentamethylcyclohexyl)pyrrolidine or piperidine,
N-(1,3,5,5-tetramethyl-3-ethylcyclohexyl)pyrrolidine or piperidine,
N-(1,5,5-trimethyl-3,3-diethylcyclohexyl)pyrrolidine or piperidine,
N-(1,3,3-trimethyl-cis-5-ethylcyclohexyl)pyrrolidine or piperidine,
N-[(1S,5S)cis-5-ethyl-1,3,3-trimethylcyclohexyl] pyrrolidine or piperidine,
N-(1,3,3-trimethyl-trans-5-ethylcyclohexyl)pyrrolidine or piperidine,
N-[(1R,5S)trans-5-ethyl-1,3,3-trimethylcyclohexyl] pyrrolidine or piperidine,
N-(1-ethyl-3,3,5,5-tetramethylcyclohexyl)pyrrolidine or piperidine, and
N-(1-propyl-3,3,5,5-tetramethylcyclohexyl)pyrrolidine or piperidine,
and optical isomers, enantiomers, and the hydrochloride, hydrobromide, hydrochloride hydrate, or other pharmaceutically-acceptable salts of any of the foregoing.
Of particular interest are compounds of the foregoing formula wherein at least R
1
, R
4
, and R
5
are lower-alkyl and those compounds wherein R
1
through R
5
are methyl, those wherein x is 4 or 5, and in particular the compound N-(1,3,3,5,5-pentamethylcyclohexyl) pyrrolidine, and optical isomers, enantiomers, hydrates and pharmaceutically-acceptable salts thereof.
In our U.S. Pat. No. 6,034,134 of Mar. 7, 2000, we disclosed compounds of the foregoing formula, pharmaceutical compositions thereof, and their use as NMDA-receptor antagonists and anticonvulsants. It has now been found that compounds of the foregoing formula and optical isomers, enantiomers, hydrates and pharmaceutically-acceptable salts thereof, in addition to their NMDA antagonist and anticonvulsant properties, quite unpredictably possess a high degree of anti-trypanosomiasis activity, making them useful in the treatment of trypanosomiasis and as trypanocides.
SUMMARY OF THE INVENTION
What we therefore believe to be comprised by our present invention may be summarized, inter alia, in the following words:
A method-of-treating a living animal for inhibition of progression or alleviation of a condition which is alleviated by an anti-trypanosomiasis agent or trypanocide, comprising the step of administering to the said living animal an amount of a 1-aminoalkylcyclohexane compound selected from the group consisting of those of the formula
wherein R* is —(CH
2
)
n
—(CR
6
R
7
)
m
—NR
8
R
9
wherein n+m=0, 1, or 2
wherein R
1
through R
7
are independently selected from the group consisting of hydrogen and lower-alkyl (1-6C),
wherein R
8
and R
9
are independently selected from the group consisting of hydrogen and lower-alkyl (1-6C) or together represent lower-alkylene —(CH
2
)
x
—wherein x is 2 to 5, inclusive, and optical isomers,
Gold Markus
Jirgensons Aigars
Kalvinsh Ivars
Kauss Valerjans
Kelly John M.
Jagoe Donna
Krass Frederick
Merz Pharma GmbH & Co. KGAA
The Firm of Hueschen and Sage
LandOfFree
1-Amino-alkylcyclohexanes as trypanocidal agents does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 1-Amino-alkylcyclohexanes as trypanocidal agents, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 1-Amino-alkylcyclohexanes as trypanocidal agents will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3121822