Substituted norbornylamino derivatives, processes for their...

Details Substituted norbornylamino derivatives, processes for their... Substituted norbornylamino derivatives, processes for their...

2000-12-12

2004-11-30

Tsang, Cecilia (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S603000, C514S637000, C549S451000, C564S373000, C564S364000

Reexamination Certificate

active

06825231

ABSTRACT:

DESCRIPTION OF THE INVENTION
The invention relates to substituted norbornylamino derivatives having exo-configured nitrogen and an endo-fused five-, six- or seven-membered ring of the formula I, or having exo-configured nitrogen and an exo-fused five-, six- or seven-membered ring of the formula I a
in which:
A is (C
1
-C
4
)-alkylene;
S1 is a free electron pair or (C
1
-C
4
)-alkyl;
S2 is (C
1
-C
4
)-alkyl or H;
where, if S1 and S2 are alkyl, X in the resulting grouping [—N
+
(S1S2)-X
−
] corresponds to a pharmacologically acceptable anion or trifluoroacetate;
B is a saturated or unsaturated five-, six- or seven-membered carbon ring which may be mono- or, independently of one another, polysubstituted by oxo, hydroxyl, (C
1
-C
4
)-alkoxy and (C
1
-C
4
)-alkyl; and
R1, R2, R3, R4 and R5 are, independently of one another, H, OH, F, Cl, Br, I, CN, NO
2
, amidino, —CO
2
R(11), —CONR(11)R(12), —SO
r
R(11), —SO
s
NR(11)-R(12), (C
1
-C
4
)-alkyl, (C
1
-C
4
)-alkoxy, (C
1
-C
4
)-alkoxy-(C
1
-C
4
)-alkyl, (C
1
-C
4
)-alkoxy-(C
1
-C
4
)-alkyloxy, hydroxy-(C
1
-C
4
)-alkyl, (C
3
-C
7
)-cycloalkoxy or phenyloxy,
where phenyl is unsubstituted or substituted by up to three substituents, which are independent of one another and selected from the group consisting of F, Cl, Br and methoxy;
amino, (C
1
-C
4
)-alkylamino, di-(C
1
-C
4
)-alkylamino, amino-(C
1
-C
4
)-alkyl, di-(C
1
-C
4
)-alkylamino-(C
1
-C
4
)-alkyl, (C
1
-C
4
)-alkylamino-(C
1
-C
4
)-alkyl,
where some or all of the hydrogen atoms in the alkyl radicals may be substituted by fluorine;
R11 and R12 are, independently of one another, H or (C
1
-C
4
)-alkyl, where some or all of the hydrogen atoms in the alkyl radicals may be substituted by fluorine;
r is 0, 1 or 2;
s is 1 or 2; or
R1 and R2, R2 and R3, R3 and R4 or R4 and R5 in each case together are a group —O—(CH
2
)
n
—O—;
n is 1 or 2; and
the radicals R1, R2, R3, R4 or R5 which remain in each case are, independently of one another, H, OH, F, Cl, Br, I, CN, NO
2
, amidino, —CO
2
R(11), —CONR(11)R(12), —SO
r
R(11), —SO
s
NR(11)-R(12), (C
1
-C
4
)-alkyl, (C
1
-C
4
)-alkoxy, (C
1
-C
4
)-alkoxy-(C
1
-C
4
)-alkyl, (C
3
-C
7
)-cycloalkoxy, hydroxy-(C
1
-C
4
)-alkyl, amino, (C
1
-C
4
)-alkylamino, di-(C
1
-C
4
)-alkylamino, amino-(C
1
-C
4
)-alkyl, di-(C
1
-C
4
)-alkylamino-(C
1
-C
4
)-alkyl, (C
1
-C
4
)-alkylamino-(C
1
-C
4
)-alkyl, where some or all of the hydrogen atoms in the alkyl radicals may be substituted by fluorine;
R11 and R12 are, independently of one another, H or (C
1
-C
4
)-alkyl, where some or all of the hydrogen atoms in the alkyl radicals may be substituted by fluorine;
r is 0, 1 or2;
s is 1 or 2;
except for benzyl(octahydro-4,7-methanoinden-5-yl)amine,
and their pharmaceutically acceptable salts or trifluoroacetates.
Preference is given to compounds having exo-configured nitrogen and an endo-fused five- or six-membered ring of the formula I, or having exo-configured nitrogen and an exo-fused five- or six-membered ring of the formula I a, in which:
A is (C
1
-C
2
)-alkylene;
S1 is a free electron pair or methyl;
S2 is H;
B is a saturated or unsaturated five- or six-membered carbon ring;
R1, R2, R3, R4 and R5 are, independently of one another, H, amino, hydroxymethyl, OH, methoxy, F, Cl, Br or iodine; or
R2 and R3 together are —O—CH
2
—O—; and
the remaining radicals R1, R4 and R5 are, independently of one another, H, OH, F, Cl, Br, I, CN, NO
2
, (C
1
-C
2
)-alkoxy, amino, (C
1
-C
2
)-alkylamino or di-(C
1
-C
2
)-alkylamino, where some or all of the hydrogen atoms in the alkyl radicals may be substituted by fluorine;
except for benzyl(octahydro-4,7-methanoinden-5-yl)amine,
and their pharmaceutically acceptable salts or trifluoroacetates.
Particular preference is given to compounds having exo-configured nitrogen and an endo-fused five- or six-membered ring of the formula I, or having exo-configured nitrogen and an exo-fused five- or six-membered ring of the formula I a, in which:
A is (C
1
-C
2
)-alkylene;
S1 is a free electron pair;
S2 is H;
B is a saturated or unsaturated five- or six-membered carbon ring;
R1, R3 and R5 are hydrogen;
and R2 and R4 are, independently of one another, H, methoxy, F or Cl; or
R2 and R3 together are —O—CH
2
—O—; and
R1, R4 and R5 are hydrogen;
except for benzyl(octahydro)-4,7-methanoinden-5-yl)amine,
and their pharmaceutically acceptable salts or trifluoroacetates.
Very particular preference is given to the following compounds, having exo-configured nitrogen and an endo-fused five- or six-membered ring of the formula I, or having exo-configured nitrogen and an exo-fused five-membered ring of the formula I a:
exo/endo-(3-chlorobenzyl)(octahydro-4,7-methanoinden-5-yl)amine,
exo/endo-(3-fluorobenzyl)(octahydro-4,7-methanoinden-5-yl)amine,
exo/endo-benzo[1,3]dioxol-5-ylmethyl(octahydro-4,7-methanoinden-5-yl)-amine,
exo/endo-(rac)-(3-methoxybenzyl)(octahydro-4,7-methanoinden-5-yl)-amine,
exo/endo-(+)-(3-methoxybenzyl)(octahydro-4,7-methanoinden-5-yl)amine,
exo/endo-(−)-(3-methoxybenzyl)(octahydro-4,7-methanoinden-5-yl)amine,
exo/endo-[1-(3-methoxyphenyl)ethyl](octahydro-4,7-methanoinden-5-yl)-amine,
exo/endo-(3-fluorobenzyl)(3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-yl)amine,
exo/endo-(3-fluorobenzyl)(3a,4,5,6,7,7a-hexahydro-3H-4,7-methanoinden-5-yl)amine,
exo/endo-(3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-yl)(3-methoxybenzyl)amine,
exo/endo-(3a,4,5,6,7,7a-hexahydro-3H-4,7-methanoinden-5-yl)(3-methoxybenzyl)amine,
exo/endo-(decahydro-1,4-methanonaphthalen-2-yl)(3-methoxybenzyl)-amine,
exo/endo-(3,5-difluorobenzyl)(octahydro-4,7-methanoinden-5-yl)amine,
exo/exo-(3-fluorobenzyl)(octahydro-4,7-methanoinden-5-yl)amine, and
exo/exo-(3-methoxybenzyl)(octahydro-4,7-methanoinden-5-yl)amine,
and their pharmaceutically acceptable salts or trifluoroacetates.
Most particular preference is given to the following compounds, having exo-configured nitrogen and an endo-fused five- or six-membered ring of the formula I:
exo/endo-(3-chlorobenzyl)(octahydro-4,7-methanoinden-5-yl)amine,
exo/endo-(3-fluorobenzyl)(octahydro-4,7-methanoinden-5-yl)amine,
exo/endo-(3-fluorobenzyl)(3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-yl)amine,
exo/endo-(3-fluorobenzyl)(3a,4,5,6,7,7a-hexahydro-3H-4,7-methanoinden-5-yl)amine,
exo/endo-benzo[1,3]dioxol-5-ylmethyl(octahydro-4,7-methanoinden-5-yl)-amine,
exo/endo-(rac)-(3-methoxybenzyl)(octahydro-4,7-methanoinden-5-yl)amine,
exo/endo-(+)-(3-methoxybenzyl)(octahydro-4,7-methanoinden-5-yl)amine,
exo/endo-(decahydro-1,4-methanonaphthalen-2-yl)(3-methoxybenzyl)-amine,
exo/endo-(−)-(3-methoxybenzyl)(octahydro-4,7-methanoinden-5-yl)amine, and
exo/endo-(3,5-difluorobenzyl)(octahydro-4,7-methanoinden-5-yl)amine,
and their pharmaceutically acceptable salts or trifluoroacetates.
Suitable acid addition salts are the salts of all pharmacologically acceptable acids, for example halides, in particular hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates, p-toluene-sulfonates, adipates, fumarates, gluconates, glutamates, glycerol phosphates, maleates, and pamoates. This group also corresponds to the pharmacologically acceptable anions. However, trifluoroacetates are also suitable.
If the compound of the formula I or Ia contains one or more centers of asymmetry, these can be either S- or R-configured. The compounds can be present as optical isomers, diastereomers, racemates, or mixtures thereof. However, the amino substituent has to be in the exo position and the ring has to be endo- and exo-fused, respectively.
The alkyl or alkylene radicals mentioned can be straight-chain or branched.
The invention furthermore relates to a process for preparing 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 which S1, S2, B, R1, R2, R3, R4 and R5 are as defined above, while independently of one another A′ is a bond or (C
1
-C
3
)-alkylene and A″ is H or (C
1
-C
3
)-alkyl and A′ and A″ together with the carbon at

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