3-amino-3-arylpropan-1-ol-compounds, their preparation and use

Details 3-amino-3-arylpropan-1-ol-compounds, their preparation and use 3-amino-3-arylpropan-1-ol-compounds, their preparation and use

2000-04-07

2001-09-11

Barts, Samuel (Department: 1621)

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

Organic compounds

Amino nitrogen containing

C564S384000, C564S389000, C560S073000, C514S534000, C514S655000

Reexamination Certificate

active

06288278

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to 3-amino-3-arylpropan-1-ol derivatives corresponding to the formula formula I
wherein
R
1
, R
2
each independently of one another denote C
1-6
-alkyl, or R
1
and R
2
together form a (CH
2
)
2-6
ring, which can also be benzo-fused or phenyl-substituted,
R
3
denotes H or methyl,
R
4
, R
5
each independently of one another denote C
1-6
-alkyl, C
3-6
-cycloalkyl, phenyl, benzyl or phenethyl, or R
4
and R
5
together form a (CH
2
)
3-6
or CH
2
CH
2
OCH
2
CH
2
ring,
A denotes an aryl radical, which optionally may contain heteroatoms in the ring system and/or may be substituted,
X denotes a substituted benzyl of the formula XI
 or a substituted benzoyl of the formula XII
 wherein
R
12
to R
14
in each independently of one another denote H, F, Cl, Br, CHF
2
, CF
3
, OR
11
, SR
11
, OCF
3
, SO
2
CH
3
, SO
2
CF
3
, C
1-6
-alkyl, phenyl, CN, COOR
11
or NO
2
, where
R
11
denotes H, C
1-6
-alkyl, phenyl, benzyl or phenethyl,
and diastereomers or enantiomers thereof, in the form of their bases or salts of physiologically tolerated acids, and their preparation and use as medicaments.
BACKGROUND OF THE INVENTION
The treatment of chronic and non-chronic states of pain is of great importance in medicine since pain is clinically one of the basic symptoms. There is currently a worldwide demand for additional pain treatment which is not exclusively opioid but has a good efficacy. The urgent need for action in respect of patient-relevant and target-oriented treatment of chronic and non-chronic states of pain, this being understood as meaning successful and satisfactory pain treatment for the patient, is documented in the large number of scientific works which have recently appeared in the field of applied analgesia and fundamental research into nociception.
Conventional opioids, such as e.g. morphine, have a good action in the treatment of severe to very severe pain. However, their use is limited due to the known side effects, e.g. respiratory depression, vomiting, sedation, constipation, addiction, dependency and development of tolerance. They can therefore be administered over a relatively long period of time or in relatively high dosages only with particular safety precautions, such as e.g. specific prescription instructions (Goodman, Gilman, The Pharmacological Basis of Therapeutics, Pergamon Press, New York 1990). Furthermore, they are not very effective for some states of pain, in particular neuropathic pain.
SUMMARY OF THE INVENTION
The object of the invention was to provide a new structural class of analgesically active substances which are suitable for treatment of pain.
A further object was to discover active compounds which are also suitable for use as a local anaesthetic and/or antiarrhythmic and/or antiemetic and/or nootropic (neurotropic) and/or for treatment or therapy of cardiovascular diseases and/or urinary incontinence and/or diarrhea and/or pruritus and/or alcohol, drug or medicament dependency and/or inflammations.
It has been found that the class of compounds corresponding to formula I is distinguished by a pronounced analgesic action. The compounds of the general formula I furthermore show a clear affinity for bonding site 2 of the sodium channel (BTX bonding) and for the benzothiazepine bonding site of the L-type calcium channel (diltiazem bonding). As a result, the class of compounds of formula I is also suitable for use as (i.e., for the preparation of a medicament for) a local anaesthetic and/or antiarrhythmic and/or antiemetic and/or nootropic (neurotropic) and/or for treatment/therapy of cardiovascular diseases and/or urinary incontinence and/or diarrhea and/or pruritus and/or alcohol and/or drug or medicament dependency and/or inflammations.
The invention therefore relates to 3-amino-3-arylpropan-1-ol derivatives corresponding to the formula I and diastereomers or enantiomers thereof, in the form of their bases or salts of physiologically acceptable acids.
Preferred compounds are:
compounds of formula I in which R
1
and R
2
together form a (CH
2
)
2-6
-ring, which can also be benzo-fused or phenyl-substituted, and R
3
to R
5
, A and X have the meanings according to the definition of the general formula I, or
compounds of formula I in which R
1
and R
2
together form a (CH
2
)
4
ring, which may also be benzo-fused or phenyl-substituted, and R
3
to R
5
, A and X have the meanings according to the definition of the general formula I, or
compounds of formula I in which R
3
represents hydrogen and R
1
, R
2
, R
4
, R
5
, A and X have the meanings according to the definition of the general formula I, or
compounds of formula I in which A denotes a substituted phenyl of formula XIII
 wherein
R
6
to R
10
each independently of one another denote H, F, Cl, Br, I, CF
3
, OH, OR
11
, OCF
3
, SR
11
, SO
2
CH
3
, SO
2
CF
3
, C
1-6
-alkyl, phenyl, CN, COOR
11
or NO
2
, or R
6
and R
7
or R
7
and R
8
together form an OCH
2
O or OCH
2
CH
2
O ring, and
R
11
denotes C
1-6
-alkyl, phenyl, benzyl or phenethyl, or a substituted or unsubstituted thiophene radical or furan radical, and R
1
to R
5
and X have the meanings according to the definition of the general formula I, or
compounds of formula I in which R
1
and R
2
together form a (CH
2
)
2-6
ring, which can also be benzo-fused or phenyl-substituted, R
3
represents hydrogen, and R
4
, R
5
, A and X have the meanings according to the definition of the general formula I, or
compounds of formula I in which R
1
and R
2
together form a (CH
2
)
4
ring, which can also be benzo-fused or phenyl-substituted, A represents a substituted phenyl group of formula XIII or a substituted or unsubstituted thiophene radical or furan radical, R
3
represents hydrogen, and R
4
, R
5
and X have the meanings according to the definition of the general formula I, or
compounds of formula I in which R
1
and R
2
together form a (CH
2
)
4
ring, A represents a substituted phenyl group of formula XIII or a substituted or unsubstituted thiophene radical or furan radical, R
3
represents hydrogen, and R
4
, R
5
and X have the meanings according to the definition of the general formula I, or
compounds of formula I in which R
1
and R
2
together form a (CH
2
)
4
ring, A represents a substituted or unsubstituted thiophene radical, R
3
represents hydrogen, and R
4
, R
5
and X have the meanings according to the definition of the general formula I, or
compounds of formula I in which R
1
and R
2
together form a (CH
2
)
4
ring, A represents a substituted or unsubstituted furan radical, R
3
represents hydrogen, and R
4
, R
5
and X have the meanings according to the definition of the general formula I, or
compounds of formula I in which X represents a substituted benzyl radical of formula XI, and R
1
to R
5
and A have the meanings according to the definition of general formula I.
Further preferred compounds include:
dimethyl-{[2-(2-methylbenzyloxy)cyclohexyl]phenylmethyl}-amine and the corresponding hydrochloride;
[2-(dimethylaminophenylmethyl)cyclohexyl]4-trifluoro-methylbenzoate and the corresponding hydrochloride;
[2-(dimethylaminophenylmethyl)cyclohexyl]4-methoxybenzoate and the corresponding hydrochloride;
{[2-(2-chlorobenzyloxy)cyclohexyl]-(2-chlorophenyl)-methyl}-dimethylamine and the corresponding hydrochloride;
{(2-chlorophenyl)-[2-(4-methylbenzyloxy)cyclohexyl]methyl}-dimethylamine and the corresponding hydrochloride;
{[2-(4-fluorobenzyloxy)cyclohexyl]phenylmethyl}-dimethylamine and the corresponding hydrochloride.
In a particular embodiment of the invention, the enantiomers of a compound according to the invention are employed in a non-equimolar ratio, the content of one enantiomer in the enantiomer mixture preferably being 5 to 45 per cent by weight, as an active compound in a medicament, which can optionally comprise further active compounds.
In the context of the present invention, the term “C
1-6
-alkyl”, denotes straight-chain or branched hydrocarbons h

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