Substituted 3-phenoxy- and...

Details Substituted 3-phenoxy- and... Substituted 3-phenoxy- and...

2000-02-18

2002-08-27

Barts, Samuel (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S347000, C564S346000, C564S366000, C514S317000, C514S277000, C514S651000, C514S427000, C514S428000, C514S408000, C514S471000, C546S192000, C548S570000, C549S490000

Reexamination Certificate

active

06441237

ABSTRACT:

The present patent application relates to new substituted 3-phenoxy- or 3-phenylalkyloxy-2-phenyl-propylamines of general formula 1, processes for preparing them and their use as pharmaceutical compositions.
wherein
R
1
and R
2
independently of one another may denote hydrogen, C
1
-C
8
-alkyl, benzyl, furylmethyl, cycloalkyl, cycloalkyl-methyl, C
2
-C
8
-alkenyl, C
2
-C
8
-alkynyl, C
1
-C
8
-alkoxy-(CH
2
)
1
—, C
3-C
8
-cycloalkoxy-(CH
2
)
m
— and
1 may denote an integer 1, 2, 3, 4, 5, 6, 7 or 8 and
m may denote an integer 0, 1, 2, 3, 4, 5, 6, 7 or 8 or
R
1
and R
2
together with the nitrogen atom form a 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclic ring which may optionally be substituted with 1-4 methyl groups or a dimethylene group; or
R
1
and R
2
together may denote a —CH
2
—(CH═CH)—(CH
2
)
2
-bridge;
n may denote an integer 0, 1, 2 or 3;
R
3
, R
3′
, R
4
and R
4′
independently of one another may denote hydrogen, fluorine, chlorine, bromine, hydroxy, methyl, ethyl, methoxy or CF
3
;
R
5
and R
6
independently of one another may denote hydrogen, fluorine, chlorine, bromine, methyl, ethyl or CF
3
or
R
5
and R
6
adjacent to each other may denote a fused-on aromatic ring;
R
7
may denote hydrogen, fluorine, chlorine, methyl, ethyl, methoxy or an aromatic ring fused on at the free vicinal position;
R
8
may denote hydrogen, fluorine, chlorine, methyl, ethyl or methoxy.
Preferred compounds of general formula 1 are those wherein
R
1
and R
2
independently of one another may denote hydrogen, C
1
-C
6
-alkyl, benzyl, furylmethyl, cycloalkyl, cycloalkyl-methyl, C
2-6
-alkenyl, preferably allyl, C
2
-C
6
-alkynyl, preferably propargyl, C
1
-C
6
-alkoxy-(CH
2
)
1
—, C
3
-
8
-cycloalkoxy-(CH
2
)
m
— and
1 denotes an integer 1, 2, 3 or 4, and
m denotes an integer 0, 1, 2, 3 or 4, or
R
1
and R
2
together with the nitrogen atom form a 5-, 6-, or 7-membered heterocyclic ring, which may optionally be substituted with 1-4 methyl groups or a dimethylene group;
n may denote an integer 0, 1, 2 or 3;
R
3
, R
4
and R
3′
independently of one another may denote hydrogen, fluorine, chlorine, bromine, hydroxy, methyl, ethyl, methoxy or CF
3
;
R
4′
may denote hydrogen;
R
5
and R
6
independently of one another may denote hydrogen, fluorine, chlorine, bromine, methyl or ethyl or
R
5
and R
6
adjacent to one another denote a fused-on aromatic ring;
R
7
and R
8
independently of one another may denote hydrogen, methyl, ethyl, methoxy or fluorine.
Particularly preferred are the compounds of general formula 1, wherein:
R
1
and R
2
independently of one another may denote hydrogen, C
1
-C
6
-alkyl, benzyl, furylmethyl, cycloalkyl, cycloalkyl-methyl, C
2
-C
6
-alkenyl, preferably allyl, C
2-6
-alkynyl, preferably propargyl, C
1-6
-alkoxy-(CH
2
)
1
—, C
3
-
8
-cycloalkoxy-(CH
2
)
m—
, and
1 denotes an integer 1, 2, 3 or 4, and
m denotes an integer 0, 1, 2, 3 or 4, or
R
1
and R
2
together with the nitrogen atom form a 5-, 6-, or 7-membered heterocyclic ring, which may optionally be substituted with 1-4 methyl groups or a dimethylene group;
n may denote an integer 0, 1, 2 or 3;
R
3
and R
4
independently of one another may denote hydrogen, fluorine, chlorine, bromine, hydroxy, methyl, ethyl, methoxy or CF
3
;
R
3′
and R
4′
may denote hydrogen;
R
5
and R
6
independently of one another may denote hydrogen, fluorine, chlorine, bromine, methyl or ethyl;
R
7
and R
8
independently of one another may denote hydrogen, methyl, ethyl, methoxy or fluorine.
Of particular interest according to the invention are compounds of general formula 1, wherein:
R
1
and R
2
independently of one another denote hydrogen, C
1
-
4
-alkyl, benzyl, furylmethyl, cycloalkyl, cycloalkyl-methyl, C
2
-
4
-alkenyl, preferably allyl, C
2
-C
4
-alkynyl, preferably propargyl, C
1
-C
4
-alkoxy-(CH
2
)
1
—, C
3
-C
6
-cycloalkoxy-(CH
2
)
m—
and
1 denotes an integer 1, 2 or 3, and
m denotes an integer 1, 2 or 3, or
R
1
and R
2
together with the nitrogen atom form a 5- or 6-membered heterocyclic ring which may optionally be substituted with 1, 2 or 3 methyl groups or a dimethylene group;
n may denote an integer 0, 1, 2 or 3;
R
3
may denote fluorine, chlorine or methyl, preferably in the ortho position;
R
4
may denote hydrogen, fluorine, chlorine or methyl, preferably in the ortho position;
R
3′
and R
4′
may denote hydrogen;
R
5
and R
6
independently of one another may denote hydrogen or methyl;
R
7
and R
8
independently of one another may denote methyl, ethyl or methoxy.
Most particularly preferred are compounds of general formula 1, wherein
R
1
and R
2
independently of one another denote hydrogen, methyl, ethyl, propyl, butyl, benzyl, furylmethyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, C
2
-C
4
-alkenyl, preferably allyl, C
2
-C
4
-alkynyl, preferably propargyl, C
1
-C
4
-alkoxy-(CH
2
)
1
—, C
3
-C
6
-cycloalkoxy-(CH
2
)
m
—, and
1 denotes an integer 1, 2 or 3 and
m denotes an integer 1, 2 or 3, or
R
1
and R
2
together with the nitrogen atom form a 5- or 6-membered heterocyclic ring which may optionally be substituted with 1 or 2 methyl groups or a dimethylene group;
n may denote 1;
R
3
may denote ortho-fluorine, ortho-chlorine or ortho-methyl;
R
4
may denote hydrogen, ortho-fluorine, ortho-chlorine or ortho-methyl;
R
3′
and R
4′
may denote hydrogen;
R
5
and R
6
may denote hydrogen;
R
7
and R
8
, which may be identical or different, may denote methyl or ethyl, preferably methyl.
The following compounds are mentioned as examples of compounds of particular interest according to the invention:
N-Pentamethylene-3-(2,6-difluorophenyl)methoxy-2-(2,6-dimethylphenyl)-propylamine;
N-Pentamethylene-3-(2-fluorophenyl)methoxy-2-(2,6-dimethylphenyl)-propylamine;
N-Pentamethylene-3-(2,6-dichlorophenyl)methoxy-2-(2,6-dimethylphenyl)-propylamine;
N-Pentamethylene-3-(2,6-dimethylphenyl)methoxy-2-(2,6-dimethylphenyl)-propylamine;
N-Cyclopropylmethyl-3-(2,6-difluorophenyl)methoxy-2-(2,6-dimethylphenyl)-propylamine;
N-Allyl-3-(2,6-difluorophenyl)methoxy-2-(2,6-dimethylphenyl)-propylamine;
N-(3,3-Dimethylallyl)-3-(2,6-difluorophenyl)methoxy-2-(2,6-dimethylphenyl)-propylamine;
N-(2-Methylallyl)-3-(2,6-difluorophenyl)methoxy-2-(2,6-dimethylphenyl)-propylamine;
N-(1-Methylallyl)-3-(2,6-difluorophenyl)methoxy-2-(2,6-dimethylphenyl)-propylamine.
The invention relates to the compounds in question, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates and in the form of the free bases or the corresponding acid addition salts thereof with pharmacologically acceptable acids—such as for example acid addition salts with hydrohalic acids—e.g. hydrochloric or hydrobromic acid—or organic acids—such as e.g. oxalic, fumaric or diglycolic acid or methanesulphonic acid.
Unless otherwise stated, the general definitions are used as follows:
C
1
-C
4
-alkyl or C
1
-C
8
-alkyl generally denotes a branched or unbranched hydrocarbon group having 1 to 4 carbon atom(s), which may optionally be substituted with one or more halogen atoms—preferably fluorine—, which may be identical to or different from one another. The following hydrocarbon groups are mentioned by way of example:
methyl, ethyl, propyl, 1-methylethyl(isopropyl), n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2,-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Unless otherwise specified, the preferred groups are lower alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl. The definitions propyl, butyl, pentyl, etc., always

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