Phenyl-and phenylalkyl-substituted ethanolamines and...

Details Phenyl-and phenylalkyl-substituted ethanolamines and... Phenyl-and phenylalkyl-substituted ethanolamines and...

2001-07-24

2004-08-03

Raymond, Richard (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S649000, C514S715000, C514S644000

Reexamination Certificate

active

06770636

ABSTRACT:

The present patent application relates to new compounds of general formula 1
wherein the groups A, X, R
1
, R
2
, R
3
, R
4
, R
5
, and R
6
have the meanings given in the specification and claims, processes for preparing them, and their use as pharmaceutical compositions, particularly as pharmaceutical compositions for the prevention or treatment of diseases the cause of which is based on a functional disorder caused by overstimulation.
BACKGROUND OF THE INVENTION
The aim of the present invention is to prepare new compounds which can be used as blockers of the voltage-dependent sodium channel. Compounds of this kind can be used to treat diseases which are caused by a functional disorder resulting from overstimulation. These include diseases such as arrhythmias, spasms, cardiac and cerebral ischemias, pain, and neurodegenerative diseases of various origins. These include, for example: epilepsy, hypoglycemia, hypoxia, anoxia, brain trauma, brain edema, cerebral stroke, perinatal asphyxia, degeneration of the cerebellum, amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclophrenia, hypotonia, cardiac infarction, heart rhythm disorders, angina pectoris, chronic pain, neuropathic pain, and local anesthesia.
DETAILED DESCRIPTION OF THE INVENTION
The problem stated above is solved by the compounds of general formula 1 disclosed in the description which follows.
The present patent application relates to new compounds of general formula 1
wherein:
R
1
denotes hydrogen, hydroxy, CF
3
, NO
2
, CN, halogen, C
1
-C
8
-alkyl, or C
1
-C
8
-alkoxy;
R
2
, R
3
, and R
4
independently of one another denote hydrogen, C
1
-C
8
-alkyl, hydroxy, NO
2
, CN, C
1
-C
8
-alkyloxy, CF
3
, or halogen;
R
5
and R
6
independently of one another denote hydrogen or a group selected from among C
1
-C
8
-alkyl, C
2
-C
8
-alkenyl, C
3
-C
8
-alkynyl, C
3
-C
8
-cycloalkyl, C
3
-C
8
-cycloalkyl-C
1
-C
6
-alkylene, C
5
-C
8
-cycloalkenyl, C
5
-C
8
-cycloalkenyl-C
1
-C
6
-alkylene, C
6
-C
10
-aryl, and C
6
-C
10
-aryl-C
1
-C
6
-alkylene, which may optionally be substituted by a group selected from among C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl, halogen, C
1
-C
6
-alkyloxy, —NH
2
, —NH(C
1
-C
4
-alkyl), —N(C
1
-C
4
-alkyl)
2
, hydroxy, ═O, —COOH, —CO—OC
1
-C
4
-alkyl, —CONH
2
, —CONH(C
1
-C
4
-alkyl), —CON(C
1
-C
4
-alkyl)
2
, and CF
3
, or
R
5
and R
6
together with the nitrogen atom denote a saturated or unsaturated 5-, 6-, 7-, or 8-membered heterocyclic group which optionally contains one or two further heteroatoms selected from sulfur, oxygen, and nitrogen and may optionally be mono-, di-, or trisubstituted by a group selected from C
1
-C
4
-alkyl, hydroxy, ═O, —COOH, —CO—OC
1
-C
4
-alkyl, —CONH
2
, —CONH(C
1
-C
4
-alkyl), —CON(C
1
-C
4
-alkyl)
2
, halogen, and benzyl;
X denotes oxygen, —NH—, —N(CHO)—, —N(CO—C
1
-C
6
-alkyl), —N(C
1
-C
6
-alkyl), or —N(C
3
-C
6
-cycloalkyl-C
1
-C
4
-alkylene), preferably oxygen or —NH—;
A denotes a group selected from C
1
-C
6
-alkylene, C
2
-C
6
-alkenylene, and C
3
-C
6
-alkynylene, which may optionally be substituted by a group selected from halogen, ═O, and hydroxy.
Preferred compounds of general formula 1 are those wherein
R
1
denotes hydrogen, halogen, C
1
-C
6
-alkyl, CF
3
, or methoxy;
R
2
, R
3
, and R
4
independently of one another denote hydrogen, C
1
-C
6
-alkyl, C
1
-C
6
-alkyloxy, CF
3
, or halogen;
R
5
and R
6
independently of one another denote hydrogen or a group selected from among C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl, C
3
-C
6
-alkynyl, C
3
-C
6
-cycloalkyl, C
3
-C
6
-cycloalkyl-C
1
-C
6
-alkylene, C
5
-C
6
-cycloalkenyl, C
5
-C
6
-cycloalkenyl-C
1
-C
6
-alkylene, phenyl, and phenyl-C
1
-C
6
-alkylene, which may optionally be substituted by a group selected from among C
1
-C
4
-alkyl, C
2
-C
4
-alkenyl, halogen, C
1
-C
4
-alkyloxy, hydroxy, —CONH
2
, ═O, and CF
3
, or
R
5
and R
6
together with the nitrogen atom denote a saturated or unsaturated 5-, 6-, or 7-membered heterocyclic group which optionally contains one or two further heteroatoms selected from sulfur, oxygen, and nitrogen and may optionally be mono-, di-, or trisubstituted by C
1
-C
4
-alkyl, —CONH
2
, or hydroxy;
X denotes oxygen, —NH—, —N(CHO)—, —N(CO—C
1
-C
5
-alkyl), —N(C
1
-C
5
-alkyl), or —N(C
3
-C
6
-cycloalkyl-C
1
-C
4
-alkylene), preferably oxygen or —NH—; and
A denotes C
1
-C
5
-alkylene, C
2
-C
4
-alkenylene, or C
3
-C
4
-alkynylene, preferably C
1
-C
5
-alkylene.
Particularly preferred are compounds of general formula 1, wherein
R
1
denotes hydrogen, C
1
-C
4
-alkyl, or CF
3
;
R
2
, R
3
, and R
4
independently of one another denote hydrogen, C
1
-C
4
-alkyl, CF
3
, or halogen;
R
5
and R
6
independently of one another denote hydrogen, C
1
-C
6
-alkyl, CF
3
—C
1
-C
6
-alkylene, preferably selected from —CH
2
—CF
3
, —CH
2
—CH
2
—CF
3
, C
2
-C
6
-alkenyl, C
3
-C
C
6
-alkynyl, C
3
-C
6
-cycloalkyl, C
3
-C
6
-cycloalkyl-C
1
-C
6
-alkylene, preferably cyclopropylmethyl or cyclohexenemethyl, cyclohexenyl, cyclohexenyl-C
1
-C
6
-alkylene, propenyl-cyclohexenylene-C
1
-C
6
-alkylene, phenyl, or phenyl-C
1
-C
6
-alkylene, or
R
5
and R
6
together with the nitrogen atom denote a saturated or unsaturated 5-, 6-, or 7-membered heterocyclic group, which optionally contains another nitrogen atom and may optionally be mono-, di-, or trisubstituted by C
1
-C
4
-alkyl, —CONH
2
, or hydroxy;
X denotes oxygen, —NH—, —N(CHO)—, —N(CO-methyl), —N(CO-ethyl), —N(C
1
-C
5
-alkyl), or —N(C
3
-C
6
-cycloalkyl-methylene), preferably oxygen or —NH—; and
A denotes —CH
2
—, —CH
2
—CH
2
—, or —CH
2
—CH
2
—CH
2
—.
Also particularly preferred are compounds of general formula 1, wherein:
R
1
denotes hydrogen or methyl;
R
2
and R
3
independently of one another denote hydrogen, methyl, fluorine, chlorine, or bromine;
R
4
denotes hydrogen, fluorine, chlorine, or bromine;
R
5
and R
6
independently of one another denote hydrogen, C
1
-C
6
-alkyl, CF
3
-C
1
-C
6
-alkylene, preferably —CH
2
—CH
2
—CF
3
, C
2
-C
6
-alkenyl, butenyl, pentenyl, C
3
-C
6
-cycloalkyl, preferably cyclohexyl, C
3
-C
6
-cycloalkyl-C
1
-C
6
-alkylene, cyclopropylmethyl, or cyclohexenemethyl, cyclohexenyl, cyclohexenyl-C
1
-C
6
-alkylene, preferably cyclohexenyl-CH
2
—, or
R
5
and R
6
together with the nitrogen atom denote a heterocyclic group selected from among pyrrolidine, piperidine, 1,2,3,6-tetrahydropyridine, and azepan;
X denotes oxygen, —NH—, —N(CHO)—, —N(CO-methyl), —N(CO-ethyl), —N(methyl)-, —N(ethyl)-, —N(propyl)-, —N(butyl)-, —N(pentyl)-, or —N(cyclopropylmethylene)-, preferably oxygen or —NH—; and
A denotes —CH
2
—, —CH
2
—CH
2
—, or —CH
2
—CH
2
—CH
2
—.
Of particular importance according to the invention are compounds of general formula 1, wherein
R
1
denotes hydrogen or methyl;
R
2
and R
3
independently of one another denote hydrogen, methyl, fluorine, chlorine, or bromine;
R
4
denotes hydrogen, fluorine, chlorine, or bromine;
R
5
and R
6
independently of one another denote hydrogen, methyl, propyl, butyl, hexyl, cyclopropylmethyl, or cyclohexenemethyl, or
R
5
and R
6
together with the nitrogen atom denote a heterocyclic group selected from among pyrrolidine, piperidine, 1,2,3,6-tetrahydropyridine, and azepan;
X denotes oxygen, —NH—, —N(CHO)—, —N(CO-methyl), —N(CO-ethyl), —N(ethyl)-, —N(propyl)-, —N(butyl)-, —N(pentyl)-, or —N(cyclopropylmethylene)-, preferably oxygen or —NH—; and
A denotes —CH
2
—, —CH
2
—CH
2
—, or —CH
2
—CH
2
—CH
2
—.
Of outstanding importance according to the invention are compounds of general formula 1, wherein
R
1
denotes hydrogen or methyl;
R
2
and R
3
independently of one another denote hydrogen or fluorine;
R
4
denotes hydrogen;
R
5
and R
6
independently of one another denote hydrogen, butyl, hexyl, or cyclohexenemethyl, or
R
5
and R
6
together with the nitrogen atom denote piperidine and 1,2,3,6-tetrahydropyridine;
X denotes oxygen or —NH—; and
A denotes —CH
2
—CH
2
— or —CH
2
—CH
2
—CH
2
—.
Compounds of general formula 1, wherein R
1
denotes hydrogen, R
2
and R
3
are in the ortho position, and X, A,

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