Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-12-18
2004-05-18
Rao, Deepak (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252100, C514S256000, C514S357000, C514S365000, C514S400000, C514S427000, C514S438000, C514S471000, C544S224000, C544S294000, C544S336000, C546S285000, C548S202000, C548S335500, C548S528000
Reexamination Certificate
active
06737423
ABSTRACT:
This application claims the benefit of the filing date of German Patent Application Number 10063294.7-44, filed on Dec. 19, 2000, which application is hereby incorporated by reference.
One embodiment of the invention relates to substituted heterocyclo-norbomylamino derivatives having: a) an exo-configuration nitrogen and an endo-fused five-membered or six-membered ring of the formula (I), or b) an exo-configuration nitrogen and an exo-fused five-membered or six-membered ring of the formula (I a),
wherein:
A is (C
1
-C
4
)-alkylene;
T is (C
1
-C
4
)-alkyl or H;
B is a saturated or unsaturated carbon five-membered or six-membered ring, which is unsubstituted or is substituted, having 1-3 substituents chosen from oxo, hydroxyl, (C
1
-C
4
)-alkoxy, and (C
1
-C
4
)-alkyl;
Het is a 5- or 6-membered, saturated or unsaturated, heterocycle that contains up to four identical or different heteroatoms chosen from O, S, N, and Se;
R is OH, F, Cl, Br, I, CN, NO
2
, phenyl, CO
2
R1, (C
1
-C
4
)-alkyl, (C
1
-C
4
)-alkoxy, amino, (C
1
-C
4
)-alkylamino, di(C
1
-C
4
)-alkylamino, or amino-(C
1
-C
4
)-alkyl,
wherein the alkyl radicals are unsubstituted or are completely or partly substituted by fluorine;
R
1
is H or (C
1
-C
4
)-alkyl, which is unsubstituted or completely or partly substituted by fluorine;
n0, 1, 2, 3 or 4,
wherein, if n=2, 3 or 4, the substituents R are chosen independently of one another;
and their pharmaceutically tolerable salts or trifluoracetates.
Examples of compounds of the invention include those compounds having an exo-configuration nitrogen and endo-fused carbon five-membered or six-membered ring of the formula (I) and those compounds having an exo-configuration nitrogen and exo-fused carbon five-membered or six-membered ring of the formula (I a), wherein:
A is (C
1
-C
2
)-alkylene;
T is H or methyl;
B is a saturated or unsaturated carbon five-membered or six-membered ring;
Het is a 5- or 6-membered, saturated or unsaturated, heterocycle that contains up to three identical or different heteroatoms chosen from O, S, and N;
R is F, Cl, Br, iodine, amino, hydroxymethyl, OH, phenyl, CO
2
R1, (C
1
-C
4
)-alkyl, or (C
1
-C
4
)-alkoxy,
wherein the alkyl radicals are unsubstituted or completely or partly substituted by fluorine;
R
1
is H or (C
1
-C
4
)-alkyl, wherein the alkyl radical is unsubstituted or completely or partly substituted by fluorine;
n0, 1, 2 or 3,
wherein, if n=2 or 3, the corresponding substituents R are chosen independently of one another;
and their pharmaceutically tolerable salts or trifluoracetates.
Further examples of compounds of the invention include those compounds having an exo-configuration nitrogen and endo-fused carbon five-membered or six-membered ring of the formula (I) and those compounds having an exo-configuration nitrogen and exo-fused carbon five-membered or six-membered ring of the formula (I a), wherein:
A is (C
1
-C
2
)-alkylene;
T is hydrogen;
B is a saturated or unsaturated carbon five-membered or six-membered ring;
Het is a 5- or 6-membered, saturated or unsaturated, heterocycle that contains up to two identical or different heteroatoms chosen from O, S, and N
R is F, Cl, Br, (C
1
-C
4
)-alkoxy or (C
1
-C
4
)-alkyl,
wherein the alkyl radicals are unsubstituted or completely or partly substituted by fluorine;
nis 0, 1 or 2, wherein, if n=2, the corresponding substituents R are chosen independently of one another;
and their pharmaceutically tolerable salts or trifluoracetates.
Even more examples of the compounds of the invention include those compounds having an exo-configuration nitrogen and endo-fused carbon five-membered or six-membered ring of the formula (I) and those compounds having an exo-configuration nitrogen and exo-fused carbon five-membered ring of the formula (I a) such as, for example:
exo/exo-(octahydro-4,7-methanoinden-5-yl)pyridin-3-ylmethylamine,
(rac)-exo/endo-(octahydro-4,7-methanoinden-5-yl)pyrid in-3-ylmethylamine,
(+)-exo/endo-(octahydro-4,7-methanoinden-5-yl)pyridin-3-ylmethylamine,
(−)-exo/endo-(octahydro-4,7-methanoinden-5-yl)pyridin-3-ylmethylamine,
(rac)-exo/endo-(octahydro-4,7-methanoinden-5-yl)pyrazin-2-ylmethylamine,
(+)-exo/endo-(octahydro-4,7-methanoinden-5-yl)pyrazin-2-ylmethylamine,
(−)-exo/endo-(octahydro-4,7-methanoinden-5-yl)pyrazin-2-ylmethylamine,
exo/endo-(decahydro-1,4-methanonaphthalen-2-yl)pyrazin-2-ylmethyl-amine,
exo/endo-(octahydro-4,7-methanoinden-5-yl)thiophen-2-ylmethylamine,
exo/endo-(octahydro-4,7-methanoinden-5-yl)thiophen-3-ylmethylamine,
exo/endo-(3a,4,5,6,7,7a-hexahydro-3H-4,7-methanoinden-5-yl)pyridin-3-ylmethylamine,
exo/endo-(3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-yl)pyridin-3-ylmethylamine,
exo/endo-furan-3-ylmethyl-(octahydro-4,7-methanoinden-5-yl)amine,
exo/endo-furan-2-ylmethyl-(octahydro-4,7-methanoinden-5-yl)amine,
exo/endo-(decahydro-1,4-methanonaphthalen-2-yl)pyridin-3-ylmethylamine,
exo/endo-(octahydro-4,7-methanoinden-5-yl)-(1 H-pyrrol-2-ylmethyl)amine,
exo/endo-(octahydro-4,7-methanoinden-5-yl)-pyrimidin-5-ylmethylamine
and their pharmaceutically tolerable salts or trifluoracetates.
More examples of compounds of the invention include those compounds having an exo-configuration nitrogen and endo-fused carbon five-membered or six-membered ring of the formula (I) and those compounds having an exo-configuration nitrogen and exo-fused carbon five-membered ring of the formula (I a) such as, for example:
exo/exo-(octahydro-4,7-methanoinden-5-yl)pyridin-3-ylmethylamine,
(rac)-exo/endo-(octahydro-4,7-methanoinden-5-yl)pyridin-3-ylmethylamine,
(+)-exo/endo-(octahydro-4,7-methanoinden-5-yl)pyridin-3-ylmethylamine,
(−)-exo/endo-(octahydro-4,7-methanoinden-5-yl)pyridin-3-ylmethylamine,
(rac)-exo/endo-(octahydro-4,7-methanoinden-5-yl)pyrazin-2-ylmethylamine,
(+)-exo/endo-(octahydro-4,7-methanoinden-5-yl)pyrazin-2-ylmethylamine,
exo/endo-(octahydro-4,7-methanoinden-5-yl)thiophen-2-ylmethylamine,
exo/endo-(3a,4,5,6,7,7a-hexahydro-3H-4,7-methanoinden-5-y l)pyrimidin-3-ylmethylamine,
exo/endo-(3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-yl)pyridin-3-ylmethylamine,
exo/endo-(decahydro-1,4-methanonaphthalen-2-yl)pyridin-3-ylmethylamine,
exo/endo-(octahydro-4,7-methanoinden-5-yl)-(1H-pyrrol-2-ylmethyl)amine,
exo/endo-(octahydro-4,7-methanoinden-5-yl)-pyrimidin-5-ylmethylamine
and their pharmaceutically tolerable salts or trifluoracetates.
Suitable acid addition salts of the compounds of the invention include salts of pharmacologically tolerable acids, for example halides (such as hydrochlorides), lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates, p-toluenesulfonates, adipates, fumarates, gluconates, glutamates, glycerophosphates, maleates, and pamoates. This group also exemplifies some of the physiologically acceptable anions, in addition to trifluoracetates.
If a compound of the formula (I) or (I a) contains one or more asymmetric centers, these centers can have either the S or the R configuration. The compounds can be present as optical isomers, diastereomers, racemates, or mixtures thereof. However, the amino substituent on the norbornyl system must be exo and the ring endo- or exo-fused
The alkyl or alkylene radicals mentioned can be either straight-chain or branched.
Suitable heterocycles include, inter alia:
Another embodiment of the invention relates to a process for the preparation of the compounds of the formula (I) or (I a), which comprises
a) reacting a compound of the formula (II) or (II a)
with a compound of the formula (III)
in the presence of suitable reductants and possibly also Lewis acids directly to give compounds of the formula (I) or (I a),
wherein T, B, Het and R
n
have the meanings indicated above; independently of one another A′ corresponds to a bond or (C
1
-C
3
)-alkyl and A″ corresponds to H or (C
1
-C
3
)-alkyl; and A′ and A″, together with the carbon atom of the carbonyl group, represent as many carbon atoms as A represents in formula (I) or (I a);
or
b) isolating an intermediate of the formula (IV) or (IV a), formed from reacting
Heinelt Uwe
Jansen Hans-Willi
Lang Hans-Jochen
Wirth Klaus
Aventis Pharma Deutschland GmbH
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Rao Deepak
LandOfFree
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