Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2000-04-07
2002-06-25
Barts, Samuel (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S342000, C546S192000, C546S236000, C549S074000, C549S365000, C549S491000, C560S042000, C514S317000, C514S538000, C514S471000, C514S465000, C514S649000, C514S438000
Reexamination Certificate
active
06410790
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to substituted 3-amino-3-arylpropan-1-ols of the general formula I,
wherein
R
1
, R
2
denote, in each case independently of one another, C
1-6
alkyl or R
1
and R
2
together denote a (CH
2
)
2-6
ring that may also be substituted by phenyl,
R
3
denotes C
3-6
alkyl, C
3-6
cycloalkyl, aryl with optionally heteroatoms in the ring system and the substituents R
6
to R
8
on the aryl ring, or a substituted C
1-3
alkylphenyl of the formula XII,
wherein
n=1, 2 or 3
R
4
, R
5
denote, in each case independently of one another, C
1-6
alkyl, C
3-6
cycloalkyl, phenyl, benzyl, phenethyl or R
4
and R
5
together form a (CH
2
)
3-6
ring or CH
2
CH
2
OCH
2
CH
2
ring,
R
6
to R
8
denote, in each case independently of one another, H, F, Cl, Br, CHF
2
, CF
3
, OH, OCF
3
, OR
14
, NR
15
R
16
, SR
14
, phenyl, SO
2
CH
3
, SO
2
CF
3
, C
1-6
alkyl, CN, COOR
14
, CONR
15
R
16
or R
6
and R
7
together form a OCH
2
O, OCH
2
CH
2
O, CH═CHO, CH═C(CH
3
)O or (CH
2
) ring, wherein
R
14
denotes C
1-6
alkyl, phenyl, benzyl, phenethyl and
R
15
, R
16
denote, in each case independently of one another, H, C1-6 alkyl, phenyl, benzyl, phenethyl, and
A denotes an aryl radical that may optionally contain heteroatoms in the ring system and/or that may optionally be substituted,
and their diastereomers or enantiomers in the form of their bases or salts of physiologically compatible acids, whereas 1-benzyl-2-(dimethylaminophenylmethyl)cyclohexanol, its diastereomers and its enantiomers in the form of their bases and its reaction product with methyliodide are disclaimed, as well as their preparation and use as medicinal drugs.
The treatment of chronic and non-chronic painful states is extremely important in medicine since pain is one of the basic symptoms encountered in clinical practice. At the present time there is a worldwide demand for additional, not exclusively opioid, but highly effective pain treatments.
The urgent need for a patient-friendly and targeted treatment of chronic and non-chronic painful states, by which is meant the successful and satisfactory management of pain for the patient, is documented in the large number of scientific articles that have recently appeared in the field of applied analgesics and fundamental research in nociception.
Conventional opioids such as for example morphine are extremely effective in treating severe to extremely severe pain. Their use is limited however by the known side effects, for example respiratory depression, vomiting, sedation, constipation, addiction, dependence and development of tolerance. Accordingly they can be administered over a prolonged period or in relatively high doses only if particular safety precautions, for example special regulatory provisions, are observed (Goodman, Gilman, The Pharmacological Basis of Therapeutics, Pergamon Press, New York, 1990). Furthermore, they are less effective in some painful states, in particular in the case of neuropathic pain.
SUMMARY OF THE INVENTION
The object forming the basis of the present invention is to provide a new structural class of analgesically effective substances that are suitable for treating pain. Further objects of the invention are to provide active agents that are also suitable for use as a local anaesthetic and/or anti-arrythmic and/or anti-emetic and/or nootropic (neurotropic) and/or for the treatment/therapy of cardiovascular conditions and/or urinary incontinence and/or diarrhoea and/or pruritis and/or alcohol and/or narcotics and/or drug dependence and/or inflammation. As a rule the substances are also suitable for treating depression and/or for improving alertness and attentiveness, and/or improving libido.
It has now been found that the class of compounds of the general formula I is characterized by a pronounced analgesic action. Furthermore the compounds of the general formula I exhibit a marked affinity for the binding site 2 of the sodium channel (BTX binding), for the benzothiazepine and the phenylalkylamine binding site of the L-type calcium channel (diltiazem and verapamil binding), and inhibit synaptosomal noradrenaline uptake (NA uptake inhibition). Accordingly the class of compounds of the general formula I is also suitable for use as a local anaesthetic and/or anti-arrythmic and/or anti-emetic and/or nootropic (neurotropic) and/or for the treatment/therapy of cardiovascular conditions and/or urinary incontinence and/or diarrhoea and/or pruritis and/or alcohol and/or narcotics and/or drug dependence, and/or inflammation. As a rule the class of compounds of the general formula I is also suitable for improving alertness and attentiveness and/or improving libido and/or for treating depression.
The invention thus relates to substituted 3-amino-3-arylpropan-1-ols of the general formula I,
wherein the radicals R
1
to R
5
and A have the meanings given above,
and the corresponding diastereomers or enantiomers in the form of their bases or salts of physiologically compatible acids,
whereas 1-benzyl-2-(dimethylaminophenylmethyl)cyclohexanol, its diastereomers and its enantiomers in the form of their bases and its reaction product with methyliodide are disclaimed.
Preferred are compounds of the general formula I in which R
1
and R
2
together form a (CH
2
)
2-6
ring, in particular a (CH
2
)
4
ring, which is optionally substituted by phenyl, R
3
to R
5
and A have the meanings according to the definition of the general formula I, or
compounds of the general formula I in which R
3
denotes a substituted C
1-3
alkylphenyl of the formula XII, R
1
, R
2
, R
4
and R
5
and A have the meanings according to the definition of the general formula I, or
compounds of the general formula I in which R
3
denotes an aryl radical with optionally heteroatoms in the ring system and the substituents R
6
to R
8
on the aryl ring, R
1
, R
2
, R
4
and R
5
and A have the meanings according to the definition of the general formula I, or
compounds of the general formula I in which A denotes a radical from the group of substituted phenyl of the formula XI
wherein
R
9
to R
13
denote, in each case independently of one another, H, F, Cl, Br, I, CF
3
, OH, OR
14
, OCF
3
, SR
14
, SO
2
CH
3
, SO
2
CF
3
, C
1-6
alkyl, phenyl, CN, COOR
14
, NO
2
or R
9
and R
10
or R
10
and R
11
together form a OCH
2
O or OCH
2
CH
2
O ring,
R
14
denotes C
1-6
alkyl, phenyl, benzyl, phenethyl
or A denotes an unsubstituted or substituted thiophene or an unsubstituted or substituted furan, and the radicals R
1
to R
5
have the meanings according to the definition of the general formula I.
Also preferred are compounds of the general formula I in which R
1
and R
2
together form a (CH
2
)
2-6
ring, in particular a (CH
2
)
4
ring, which is optionally substituted by phenyl, R
3
denotes a substituted C
1-3
alkylphenyl of the formula XII, R
4
to R
5
and A have the meanings according to the definition of the general formula I, or
compounds of the general formula I in which R
1
and R
2
together form a (CH
2
)
2-6
ring, in particular a (CH
2
)
4
ring, which is optionally substituted by phenyl, R
3
denotes an aryl radical with optionally heteroatoms in the ring system and the substituents R
6
to R
8
on the aryl ring, and R
4
to R
5
and A have the meanings according to the definition of the general formula I, or
compounds of the general formula I in which R
1
and R
2
together form a (CH
2
)
4
ring, which is optionally substituted by phenyl, A denotes a radical from the group of substituted phenyl of the formula XI or unsubstituted or substituted thiophene or unsubstituted or substituted furan, R
3
denotes a substituted C
1-3
alkylphenyl of the formula XII, and R
4
to R
5
have the meanings according to the definition of the general formula I, or
compounds of the general formula I in which R
1
and R
2
together form a (CH
2
)
4
ring, which is optionally substituted by phenyl, A denotes a radical from the group of substituted phenyl of the formula XI or unsubstituted or substituted thiophene or unsubstitut
Buschmann Helmut
Hennies Hagen-Heinrich
Koegel Babette-Yvonne
Sundermann Bernd
Barts Samuel
Crowell & Moring LLP
Gruenenthal GmbH
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