Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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1-PHENYL-2-DIMETHYLAMINOMETHYLCYCLOHEXANE COMPOUNDS FOR
THERAPY OF DEPRESSIVE SYMPTOMS, PAIN AND INCONTINENCE
The invention relates to metabolites of [2-(3-
methoxyphenyl)-cyclohexylmethyl]-dimethylamine as free
bases and/or in the form of physiologically acceptable
salts, corresponding medicaments and the use of [2-(3-
methoxyphenyl)-cyclohexylmethyl]-dimethylamine and its
metabolites for the preparation of a medicament for
treatment of depressions and methods for treatment of
depressions.
Depression is an affectivity disorder with which a
depressive syndrome occupies the foreground, depressive
meaning associated with depression or of sad mood. The
antidepressants used for therapy are also important
adjuvants for pain therapy (R. van Schayck et al. 1998,
MMP, 10, 304-313; Jung et al. 1997, J. Gen. Intern.
Med. 12, 384-389; Onghena and Van Houdenhove 1992,
Pain, 49, 205-219; Feuerstein 1997, Diagnostik and
Therapie, 3, 213-225; Rowbotham 1997, The Pain Medicine
Journal Club Journal, 3, 119-122), in particular in cases
of chronic states of pain, since the lasting pain load can
lead to a depressive mood in the patient. This is
particularly often the case with cancer pain patients
(Berard 1996, Int. Med. J., 3, 257-259). Since there has
hitherto been no painkiller with a clinically relevant
antidepressant action component, antidepressants must be
added to the administration of analgesics as additional
medication. Since chronic pain patients often require a
large number of various medicaments, the additional
administration of the antidepressant leads to a further
stress on the organism. For this reason and to improve
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compliance, an antidepressant action component already
present in an analgesic substance would be of particular
advantage.
The basis of the antidepressant action is the inhibition of
the reuptake of noradrenaline and serotonin. Opioids
having a moderate inhibition of the uptake, such as e.g.
tramadol, have been known for a relatively long time and
are employed therapeutically as potent analgesics having a
low addiction and dependency potential (Raffa et al. 1992,
Journal of Pharmacology and experimental Therapeutics, 260,
278-285; Raffa and Friderichs 1996, Pain Review, 3, 249-
271). However, the uptake-inhibiting component is not
potent enough to be able to initiate a clinically relevant
antidepressant effect.
In addition to the actual antidepressant action, inhibition
of the reuptake of noradrenaline and serotonin also leads
to an independent analgesic action, in that descending pain
inhibition pathways are activated at the level of the
spinal marrow. In combination with opiates, which also
inhibit transmission of pain at the spinal marrow level,
this leads to a mutual potentiation of the pain inhibition
mechanisms and therefore to a particularly effective
analgesia.
An opioid substance having a relatively potent NA and/or
5HT uptake-inhibiting component which displays an
antidepressant activity (e. g. demonstrated in a suitable
behaviour model in animal studies) would therefore be
particularly favourable in this indication, in particular
f ; F
r f
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treatment of depressions, precisely also in combination
with pain therapy.
The object of the present invention was therefore to
discover substances, in particular opiod substances, which
are suitable for treatment of depressions, in particular
those which combine this activity with analgesic activity.
It has now been found, surprisingly, that 2-(3-
methoxyphenyl)-cyclohexylmethyl)-dimethylamine and also its
metabolites, and in this context in particular 3-(2-
dimethylaminomethyl-cyclohexyl)-phenol, have a
therapeutically relevant antidepressant action component.
The invention accordingly provides the use of
~ 3-(2-dimethylaminomethyl-cyclohexyl)-phenol,
~ (1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)
phenol,
~ [2-(3-methoxyphenyl)-cyclohexylmethyl]-
dimethylamine,
~ (1R,2R)-[2-(3-methoxyphenyl)-cyclohexylmethyl]-
dimethylamine,
~ sulfuric acid mono-[3-(2-dimethylaminomethyl-
cyclohexyl)-phenyl] ester,
~ sulfuric acid mono- (1R, 2R) - [3- (2-
dimethylaminomethyl-cyclohexyl)-phenyl] ester,
~ 3-(2-methylaminomethyl-cyclohexyl)-phenol,
~ (1R,2R)-3-(2-methylaminomethyl-cyclohexyl)-phenol,
~ 3-(2-dimethylaminomethyl-cyclohexyl)-phenol N-
oxide,
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~ (1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-
phenol N-oxide,
~ 6-[3-(2-dimethylaminomethyl-cyclohexyl)-phenoxy]-
3,4,5-trihydroxy-tetrahydropyran-2-carboxylic
acid,
~ 6-[(1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-
phenoxy]-3,4,5-trihydroxy-tetrahydropyran-2-
carboxylic acid,
~ 4-(2-dimethylaminomethyl-cyclohexyl)-catechol,
~ (1R,2R)-4-(2-dimethylaminomethyl-cyclohexyl)-
catechol,
~ 3-(2-aminomethyl-cyclohexyl)-phenol,
~ (1R,2R)-3-(2-aminomethyl-cyclohexyl)-phenol,
~ 4-(2-dimethylaminomethyl-cyclohexyl)-benzene-1,2-
diol,
~ (1R,2R)-4-(2-dimethylaminomethyl-cyclohexyl)-
benzene-1,2-diol,
~ C-[2-(3-methoxy-phenyl)-cyclohexyl]-methylamine,
~ (1R, 2R) -C- [2- (3-methoxy-phenyl) -cyclohexyl] -
methylamine,
~ [2-(3-methoxy-phenyl)-cyclohexylmethyl]-methyl-
amine,
~ ( 1R, 2R) - [2 - ( 3 -methoxy-phenyl ) -cyclohexylmethyl ] -
methyl-amine,
~ [2-(3-methoxy-phenyl)-cyclohexylmethyl]-dimethyl-
amine; N-oxide or
~ (1R, 2R) - [2- (3-methoxy-phenyl) -cyclohexylmethyl] -
dimethyl-amine; N-oxide;
optionally in the form of their racemates, their pure
stereoisomers, in particular enantiomers or
diastereomers, or in the form of mixtures of the
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stereoisomers, in particular the enantiomers or
diastereomers, in any desired mixture ratio;
in the form shown or in the form of their acids or
their bases or in the form of their salts, in
5 particular the physiologically acceptable salts, or in
the form of their solvates, in particular the
hydrates;
for the preparation of a medicament for treatment of
depressions.
In this context it is particularly preferable if the
compounds used are in the form of R,R, preferably 1R,2R
stereoisomers.
The term salt is to be understood as meaning any form of
the active compound according to the invention in which
this assumes an ionic form or is charged and coupled with a
counter-ion (a cation or anion) or is in solution. This is
also to be understood as meaning complexes of the active
compound with other molecules and ions, in particular
complexes which are complexed via ionic interactions. In
particular, this is understood as meaning (and this is also
a preferred embodiment of this invention) physiologically
acceptable salts, in particular physiologically acceptable
salts with cations or bases and physiologically acceptable
salts with anions or acids or also a salt formed with a
physiologically acceptable acid or a physiologically
acceptable cation.
The preferred salt of the compounds used is the
hydrochloride.
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Physiologically acceptable is to be understood as meaning
that the substance, in particular the salt as such, is
acceptable when used in humans or mammals, that is to say,
for example, does not have a non-physiological (e. g. toxic)
action.
In the context of this invention, the term of
physiologically acceptable salt with anions or acids is
understood as meaning at least one of the compounds
according to the invention - usually protonated, for
example on the nitrogen - as the cation with at least one
anion, which are physiologically acceptable - especially
when used in humans and/or mammals. In particular, in the
context of this invention by this there is understood the
salt formed with a physiologically acceptable acid, namely
salts of the particular active compound with inorganic or
organic acids which are physiologically acceptable -
especially when used in humans and/or mammals. Examples of
physiologically acceptable salts of particular acids are
salts of: hydrochloric acid, hydrobromic acid, sulfuric
acid, methanesulfonic acid, formic acid, acetic acid,
oxalic acid, succinic acid, malic acid, tartaric acid,
mandelic acid, fumaric acid, lactic acid, citric acid,
glutamic acid, l,l-dioxo-1,2-dihydrolb6-benzo[d]isothiazol-
3-one (saccharic acid), monomethylsebacic acid, 5-oxo-
proline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or
4-aminobenzoic acid, 2,4,6-trimethyl-benzoic acid, a-
liponic acid, acetylglycine, acetylsalicylic acid, hippuric
acid and/or aspartic acid. The hydrochloride salt is
particularly preferred.
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In the context of this invention, the term of salt formed
with a physiologically acceptable acid is understood as
meaning salts of the particular active compound with
inorganic or organic acids which are physiologically
acceptable - especially when used in humans and/or mammals.
The hydrochloride is particularly preferred. Examples of
physiologically acceptable acids are: hydrochloric acid,
hydrobromic acid, sulfuric acid, methanesul.fonic acid,
formic acid, acetic acid, oxalic acid, succinic acid,
tartaric acid, mandelic acid, fumaric acid, lactic acid,
citric acid, glutamic acid, 1,1-dioxo-1,2-dihydrola6-
benzo[d]isothiazol-3-one (saccharic acid),
monomethylsebacic acid, 5-oxo-proline, hexane-1-sulfonic
acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-
trimethyl-benzoic acid, a-liponic acid, acetylglycine,
acetylsalicylic acid, hippuric acid and/or aspartic acid.
In the context of this invention, the term of
physiologically acceptable salt with cations or bases is
understood as meaning salts of at least one of the
compounds according to the invention - usually of a
(deprotonated) acid - as the anion with at least one
preferably inorganic cation which are physiologically
acceptable - especially when used in humans and/or mammals.
The salts of the alkali metals and alkaline earth metals
and also with NH4+ are particularly preferred, but
especially (mono-) or (di-)sodium, (mono-) or
(di-)potassium, magnesium or calcium salts.
In the context of this invention, the term of salt formed
with a physiologically acceptable cation is understood as
meaning salts of at least one of the particular compounds
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as the anion with at least one inorganic cation which is
physiologically acceptable - especially when used in humans
and/or mammals. The salts of the alkali metals and
alkaline earth metals and also NH4+ are particularly
preferred, but especially (mono-) or (di-)sodium, (mono-)
or (di-)potassium, magnesium or calcium salts.
According to the present investigations, the substances
used, and in particular (1R,2R)-3-(2-dimethylaminomethyl-
cyclohexyl)-phenol, are potent analgesics and
antidepressants, that is to say have an additional and
clinically relevant antidepressant action component. In
particular, (1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-
phenol can be employed in cases of moderate to severe acute
and chronic pain and renders possible treatment of the
depressive concomitant symptoms with chronic states of
pain. It therefore leads to a significant improvement in
the treatment of chronic pain, since antidepressants
hitherto had to be added as additional medicaments to those
of pain therapy. (1R,2R)-3-(2-Dimethylaminomethyl-
cyclohexyl)-phenol and the other substances used according
to the invention can therefore also be used as genuine
antidepressants independently of their analgesic action.
The invention also provides metabolites, in particular of
[2-(3-methoxyphenyl)-cyclohexylmethyl]-dimethylamine and 3-
(2-dimethylaminomethyl-cyclohexyl)-phenol chosen from
~ sulfuric acid mono-[3-(2-dimethylaminomethyl-
cyclohexyl)-phenyl] ester,
~ sulfuric acid mono-(1R,2R)-[3-(2-
dimethylaminomethyl-cyclohexyl)-phenyl] ester,
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~ 3-(2-methylaminomethyl-cyclohexyl)-phenol,
~ (1R,2R)-3-(2-methylaminomethyl-cyclohexyl)-phenol,
~ 3-(2-dimethylaminomethyl-cyclohexyl)-phenol N-
oxide,
~ (1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-
phenol N-oxide,
~ 6-[3-(2-dimethylaminomethyl-cyclohexyl)-phenoxy]-
3,4,5-trihydroxy-tetrahydropyran-2-carboxylic
acid,
~ 6-[(1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-
phenoxy]-3,4,5-trihydroxy-tetrahydropyran-2-
carboxylic acid,
~ 4-(2-dimethylaminomethyl-cyclohexyl)-catechol,
~ (1R,2R)-4-(2-Dimethylaminomethyl-cyclohexyl)-
catechol,
~ 3-(2-aminomethyl-cyclohexyl)-phenol,
(1R,2R)-3-(2-aminomethyl-cyclohexyl)-phenol,
~ 4-(2-dimethylaminomethyl-cyclohexyl)-benzene-1,2-
diol,
~ (1R,2R)-4-(2-dimethylaminomethyl-cyclohexyl)-
benzene-1,2-diol,
~ C-[2-(3-methoxy-phenyl)-cyclohexyl]-methylamine,
~ (1R,2R)-C-[2-(3-methoxy-phenyl)-cyclohexyl]-
methylamine,
~ [2-(3-methoxy-phenyl)-cyclohexylmethyl]-methyl-
amine,
~ (1R, 2R) - [2- (3-methoxy-phenyl) -cyclohexylmethyl] -
methyl-amine,
~ [2-(3-methoxy-phenyl)-cyclohexylmethyl]-dimethyl-
amine; N-oxide or
~ (1R,2R)-[2-(3-methoxy-phenyl)-cyclohexylmethyl]-
dimethyl-amine N-oxide;
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optionally in the form of their racemates, their pure
stereoisomers, in particular enantiomers or
diastereomers, or in the form of mixtures of the
5 stereoisomers, in particular the enantiomers or
diastereomers, in any desired mixture ratio;
in the form shown or in the form of their acids or
their bases or in the form of their salts, in
particular the physiologically acceptable salts, or in
10 the form of their solvates, in particular the
hydrates.
Metabolites according to the invention which are in the
form of R,R, preferably 1R,2R stereoisomers are
particularly preferred.
The metabolites according to the invention are
physiologically acceptable. The invention therefore also
provides a medicament comprising as the active compound at
least one metabolite according to the invention and
optionally additives and auxiliary substances. In
particular, the invention accordingly provides a medicament
comprising as the active compound at least one compound
chosen from
~ sulfuric acid mono-[3-(2-dimethylaminomethyl-
cyclohexyl)-phenyl] ester,
~ sulfuric acid mono- (1R,2R) - [3- (2-
dimethylaminomethyl-cyclohexyl)-phenyl] ester,
~ 3-(2-methylaminomethyl-cyclohexyl)-phenol,
~ (1R,2R)-3-(2-methylaminomethyl-cyclohexyl)-phenol,
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~ 3-(2-dimethylaminomethyl-cyclohexyl)-phenol N-
oxide,
~ (1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-
phenol N-oxide,
~ 6-[3-(2-dimethylaminomethyl-cyclohexyl)-phenoxy]-
3,4,5-trihydroxy-tetrahydropyran-2-carboxylic
acid,
~ 6-[(1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-
phenoxy]-3,4,5-trihydroxy-tetrahydropyran-2-
carboxylic acid,
~ 4-(2-dimethylaminomethyl-cyclohexyl)-catechol,
~ (1R, 2R) -4- (2-Dimethylaminomethyl-cyclohexyl) -
catechol,
~ 3-(2-aminomethyl-cyclohexyl)-phenol,
~ (1R,2R)-3-(2-aminomethyl-cyclohexyl)-phenol,
~ 4-(2-dimethylaminomethyl-cyclohexyl)-benzene-1,2-
diol,
~ (1R,2R)-4-(2-dimethylaminomethyl-cyclohexyl)-
benzene-1,2-diol,
~ C- [2- (3-methoxy-phenyl) -cyclohexyl] -methylamine,
(1R, 2R) -C- [2- (3-methoxy-phenyl) -cyclohexyl] -
methylamine,
~ [2-(3-methoxy-phenyl)-cyclohexylmethyl]-methyl-
amine,
~ (1R, 2R) - [2- (3-methoxy-phenyl) -cyclohexylmethyl] -
methyl-amine,
~ [2-(3-methoxy-phenyl)-cyclohexylmethyl]-dimethyl-
amine; N-oxide or
(1R, 2R) - [2- (3-methoxy-phenyl) -cyclohexylmethyl] -
dimethyl-amine N-oxide;
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optionally in the form of their racemates, their pure
stereoisomers, in particular enantiomers or
diastereomers, or in the form of mixtures of the
stereoisomers, in particular the enantiomers or
diastereomers, in any desired mixture ratio;
in the form shown or in the form of their acids or
their bases or in the form of their salts, in
particular the physiologically acceptable salts, or in
the form of their solvates, in particular the
hydrates;
and optionally additives and/or auxiliary substances.
It is particularly preferable if the compounds contained
therein are in the form of R,R, preferably 1R,2R
stereoisomers.
Suitable additives and/or auxiliary substances in the
context of this invention are all the substances known to
the expert from the prior art for achieving galenical
formulations. The choice of these auxiliary substances and
the amounts thereof to be employed depend on whether the
medicament is to be administered orally, intravenously,
intraperitoneally, intradermally, intramuscularly,
intranasally, buccally or locally. Formulations in the
form of tablets, chewable tablets, coated tablets,
capsules, granules, drops, juices or syrups are suitable
for oral administration, and solutions, suspensions, easily
reconstitutable dry formulations and sprays are suitable
for parenteral, topical and inhalatory administration.
Suppositories for use in the rectum are a further
possibility. The use in a depot in dissolved form, a
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carrier film or a patch, optionally with the addition of
agents which promote penetration through the skin, are
examples of suitable forms for percutaneous administration.
Examples of auxiliary substances and additives for the oral
administration forms are disintegrating agents, lubricants,
binders, fillers, mould release agents, optionally
solvents, flavourings, sugars, in particular carrier
agents, diluents, dyestuffs, antioxidants etc. For
suppositories, inter alia, waxes and fatty acid esters can
be used, and for compositions for parental administration
carrier substances, preservatives, suspension auxiliaries
etc. can be used. The amounts of active compound to be
administered to patients vary as a function of the weight
of the patient, the mode of administration and the severity
of the disease. The compounds used according to the
invention can be released in a delayed manner from
formulation forms which can be used orally, rectally or
percutaneously. Corresponding sustained-release
formulations, in particular in the form of a "once daily"
preparation which has to be taken only once a day, are
particularly preferred for the indication according to the
invention.
Medicaments which comprise at least 0.05 to 90.0 % of the
active compound, in particular low active dosages, in order
to avoid side effects or analgesic actions, are preferred.
0.1 to 5,000 mg/kg, in particular 1 to 500 mg/kg,
preferably 2 to 250 mg/kg of body weight of a least one
compound used according to the invention are conventionally
administered. However, the administration of 0.01 -
5 mg/kg, preferably 0.03 to 2 mg/kg, in particular 0.05 to
1 mg/kg, is also preferred and conventional.
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Auxiliary substances can be, for example: water, ethanol,
2-propanol, glycerol, ethylene glycol, propylene glycol,
polyethylene glycol, polypropylene glycol, glucose,
fructose, lactose, sucrose, dextrose, molasses, starch,
modified starch, gelatine, sorbitol, inositol, mannitol,
microcrystalline cellulose, methylcellulose,
carboxymethylcellulose, cellulose acetate, .shellac, cetyl
alcohol, polyvinylpyrrolidone, paraffins, waxes, naturally
occurring and synthetic gums, gum acacia, alginates,
dextran, saturated and unsaturated fatty acids, stearic
acid, magnesium stearate, zinc stearate, glyceryl stearate,
sodium lauryl sulfate, edible oils, sesame oil, coconut
oil, groundnut oil, Soya bean oil, lecithin, sodium
lactate, polyoxyethylene and -propylene fatty acid esters,
sorbitan fatty acid esters, sorbic acid, benzoic acid,
citric acid, ascorbic acid, tannic acid, sodium chloride,
potassium chloride, magnesium chloride, calcium chloride,
magnesium oxide, zinc oxide, silicon dioxide, titanium
oxide, titanium dioxide, magnesium sulfate, zinc sulfate,
calcium sulfate, potash, calcium phosphate, dicalcium
phosphate, potassium bromide, potassium iodide, talc,
kaolin, pectin, crospovidone, agar and bentonite.
The medicaments and pharmaceutical compositions according
to the invention are prepared with the aid of means,
devices, methods and processes which are well-known in the
prior art of pharmaceutical formulation, such as are
described, for example, in "Remington's Pharmaceutical
Sciences", ed. A. R. Gennaro, 17th ed., Mack Publishing
Company, Easton, Pa. (1985), in particular in part 8,
chapter 76 to 93.
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Thus e.g. for a solid formulation, such as a tablet, the
active compound of the medicament, i.e. a compound of the
general structure I or one of its pharmaceutically
5 acceptable salts, can be granulated with a pharmaceutical
carrier, e.g. conventional tablet constituents, such as
maize starch, lactose, sucrose, sorbitol, talc, magnesium
stearate, dicalcium phosphate or pharmaceutically
acceptable gums, and pharmaceutical diluents, such as e.g.
10 water, in order to form a solid composition which comprises
a compound according to the invention or a pharmaceutically
acceptable salt thereof in homogeneous distribution.
Homogeneous distribution is understood here as meaning that
the active compound is uniformly distributed over the
15 entire composition, so that this can easily be divided into
unit dose forms, such as tablets, pills or capsules, having
the same activity. The solid composition is then divided
into unit does forms. The tablets or pills of the
medicament according to the invention or of the
compositions according to the invention can also be coated
or compounded in another manner in order to provide a dose
form with delayed release. Suitable coating compositions
are, inter alia, polymeric acids and mixtures of polymeric
acids with materials such as e.g. shellac, cetyl alcohol
and/or cellulose acetate.
Although the medicaments according to the invention show
only few side effects, it may be of advantage - should this
be necessary at all - for example to avoid certain forms of
dependency, also to use morphine antagonists, in particular
naloxone, naltrexone and/or levallorphan, in addition to
the compounds used.
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Since the compounds according to the invention - as stated
above - have an analgesic action, the invention also
provides the use of a compound according to the invention
or of a metabolit according to the invention for the
preparation of a medicament for treatment of pain, in
particular acute, visceral, chronic or neuropathic pain or
cancer pain.
Since the compounds according to the invention moreover
also show an activity in cases of urinary incontinence, the
inventiona also provides the use of a compound according to
the invention or of a metabolite according to the invention
for the preparation of a medicament for treatment of an
increased urge to urinate or urinary incontinence.
The invention furthermore also relates to a method for
treatment of depression, in which the compounds used
according to the invention are used.
The invention likewise also relates to a method for
treatment of pain, in particular acute, visceral, chronic
or neuropathic pain or cancer pain, in which the compounds
or metabolites according to the invention are used.
The invention likewise also relates to a method for
treatment of an increased urge to urinate or urinary
incontinence, in which the compounds or metabolites
according to the invention are used.
2-(3-Methoxyphenyl)-cyclohexylmethyl)-dimethylamine and
(1R,2R)-[2-(3-methoxyphenyl)-cyclohexylmethyl)-
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dimethylamine] and their preparation are known from DE 195
25 137 A1 Example 8 and US 5,733,936 Example 8, where the
absolute stereochemistry of the compound (-6) prepared
according to Example 8 is certainly correctly (1R,2R) and
not (1R,2S). 3-(2-Dimethylaminomethyl-cyclohexyl)-phenol
and(1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol and
their preparation are also known from DE 195 25 137 A1
Example 10 and US 5,733,936, Example 10, where the absolute
stereochemistry of the compound (-7) prepared according to
Example 10 is certainly correctly (1R,2R) and not (1R,2S).
The compounds which, and the preparation of which, are not
yet known from DE 195 2S 137 A1 or US 5,733,936 were
prepared in accordance with the examples.
The following examples are intended to explain the
invention without the subject matter of the invention being
limited thereto.
Examples
Generally, the purification and the separation of
enantiomers in all the processes mentioned as an example is
carried out at the various stages with column
chromatography, and predominantly HPLC.
Example 1: Preparation of (1R,2R)-[2-(3-methoxyphenyl)-
cyclohexylmethyl]-methylamine, hydrochloride
[2-(3-Methoxyphenyl)-cyclohexylmethyl]-methylamine, and
(1R,2R)-[2-(3-methoxyphenyl)-cyclohexylmethyl]-methylamine,
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in particular the hydrochloride salt thereof, are prepared
as follows:
5.67 g (22 . 9 mmol) (1R, 2R) - [2- (3-methoxyphenyl) -
cyclohexylmethyl]-dimethylamine as the free base were
heated in 389.64 ml toluene with 3.16 ml (25.2 mmol) phenyl
chloroformate for 3 h. After cooling and washing, the
organic residue was concentrated and stirred at 110 °C with
192.53 ml ethylene glycol and a total of 45.84 ml 5 N NaOH
for a total of 8.5 h, with occasional stirring. (1R,2R)-
[2-(3-Methoxyphenyl)-cyclohexylmethyl]-methylamine was
formed. This was worked up and precipitated as the
hydrochloride with TMCS.
Example 2: Preparation of (1R,2R)-3-(2-methylaminomethyl-
cyclohexyl)-phenol, hydrochloride
3.55 g (15.2 mmol) of the hydrochloride salt of the
(1R,2R)-[2-(3-methoxy-phenyl)-cyclohexylmethyl]-methyl-
amines according to Example 1 were stirred under reflux in
4.59 ml (47-48 %) aqueous HBr for 7.5 h and the mixture was
cooled overnight. (1R,2R)-3-(2-Methylaminomethyl-
cyclohexyl)-phenol is formed. This was worked up and
precipitated as the hydrochloride with TMCS.
Example 3: Preparation of sulfuric acid mono-(1R,2R)-[3-(2-
dimethylaminomethyl-cyclohexyl)-phenyl] ester
Sulfuric acid mono-[3-(2-dimethylaminomethyl-cyclohexyl)-
phenyl] ester or sulfuric acid mono-(1R,2R)-[3-(2-
dimethylaminomethyl-cyclohexyl)-phenyl] ester was prepared
as follows:
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(1R,2R)-3-(2-Dimethylaminomethyl-cyclohexyl)-phenol;
hydrochloride was treated with dicyclohexylcarbodiimide
(DCC) in H2S04. Sulfuric acid mono- (1R, 2R) - [3- (2-
dimethylaminomethyl-cyclohexyl)-phenyl] ester was formed.
Example 4: Preparation of 6-[(1R,2R)-3-(2-
dimethylaminomethyl-cyclohexyl)-phenoxy]-3,4,5-trihydroxy-
tetrahydropyran-2-carboxylic acid
6-[3-(2-Dimethylaminomethyl-cyclohexyl)-phenoxy]-3,4,5-
trihydroxy-tetrahydropyran-2-carboxylic acid or 6-[(1R,2R)-
3-(2-dimethylaminomethyl-cyclohexyl)-phenoxy]-3,4,5-
trihydroxy-tetrahydropyran-2-carboxylic acid was prepared
as follows:
(1R,2R)-3-(2-Dimethylaminomethyl-cyclohexyl)-phenol;
hydrochloride was treated with 3,4,5-tri-O-acetyl-1-a-
bromo-D-glucoronic acid methyl ester with 1. LiOH and 2.
HOAc. 6-[(1R,2R)-3-(2-Dimethylaminomethyl-cyclohexyl)-
phenoxy]-3,4,5-trihydroxy-tetrahydropyran-2-carboxylic acid
was formed. Purification was carried out via a Lobar-
Lichoprep RP128 column MeOH:H20 system with subsequent HPLC
separation.
Example 5: Preparation of [2-(3-methoxy-phenyl)-
cyclohexylmethyl]-dimethyl-amine; N-oxide
[2-(3-Methoxy-phenyl)-cyclohexylmethyl]-dimethyl-amine; N-
oxide or (1R, 2R) - [2- (3-methoxy-phenyl) -cyclohexylmethyl] -
dimethyl-amine; N-oxide was prepared as follows:
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(1R, 2R) - [2- (3-Methoxy-phenyl) -cyclohexylmethyl] -dimethyl-
amine; hydrochloride was dissolved, and treated with H20z at
room temperature. (1R,2R)-[2-(3-Methoxy-phenyl)-
cyclohexylmethyl]-dimethyl-amine; N-oxide was formed.
5
Example 6: Preparation of (1R,2R)-3-(2-dimethylaminomethyl-
cychlohexyl)-phenol N-oxide
3-(2-Dimethylaminomethyl-cychlohexyl)-phenol N-oxide or
10 (1R,2R)-3-(2-dimethylaminomethyl-cychlohexyl)-phenol N-
oxide was prepared as follows:
(1R,2R)-3-(2-Dimethylaminomethyl-cychlohexyl)-phenol;
hydrochloride was dissolved, and treated with H202 at room
15 temperature. (1R,2R)-3-(2-Dimethylaminomethyl-
cychlohexyl)-phenol N-oxide was formed.
Example 7: Preparation of 4-(2-dimethylaminomethyl-
cyclohexyl)-catechol or 4-(2-dimethylaminomethyl-
20 cyclohexyl)-benzene-1,2-diol.
4-(2-Dimethylaminomethyl-cyclohexyl)-catechol or 4-(2-
dimethylaminomethyl-cyclohexyl)-benzene-1,2-diol was
prepared in accordance with the following reaction
equation:
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~O
O O
N / Method 1: Buli
Method 2: Grignard N ~
aqueous 48~ HBr solution
O at -5 °C
O
/
N~
I) H2, Pd/C catalyst,
MeOH, HC1 salt
or
II) H2, Pd/C catalyst,
EtOH, base
O OH
aqueous
O~ 48~ HBr OH
solution
at 25 °C
N~
In this, in addition, Method 1 BuLi designates the
synthesis via BuLi reagents which is well-known to the
expert, and Method 2 Grignard designates the synthesis via
S Mg reagents which is well-known to the expert.
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Example 8: Preparation of C-[2-(3-methoxy-phenyl)-
cyclohexyl]-methylamine.
The preparation of C-[2-(3-methoxy-phenyl)-cyclohexyl]-
methylamine was carried out in accordance with the
following reaction equation:
Bn ~ w t ~ ~\
O O ~ ~- ~ O \
polyformaldehyde
snZrrxzcl MgBr
~NBnz NO
Tetrahydrofuran ~Bn2
~O\ ~O\
r
NBnz / NBn
z
Hz,
Pd-C catalyst,
EtOH
-NHz
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Example 9: Preparation of (1R,2R)-3-(2-aminomethyl-
cyclohexyl)-phenol.
3-(2-Aminomethyl-cyclohexyl)-phenol or (1R,2R)-3-(2-
aminomethyl-cyclohexyl)-phenol was prepared in accordance
with the following reaction equation:
O
Bn = ~ ~ ~ \
O polyformaldehyde ~ /
SnzNHzCl
MgBr /
' NBnz HO
Tetrahydrofuran '~~~\ N B n
2
~O\ ~0\
/
NBn2 / NBn
z
column chromatography to
give the desired 1,6-
olefin
di-isobutyl-aluminium
hydride (DiSAH)
OH ~ OH
Hz,
~NBnz Pd-C catalyst, 'NHZ
base,
EtOH
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Example 10 In vitro isolation of the metabolites:
[2-(3-Methoxyphenyl)-cyclohexylmethyl]-dimethylamine;
hydrochloride and in another example (1R,2R)-3-(2-
dimethylaminomethyl-cyclohexyl)-phenol; hydrochloride was
dissolved in TRIS/HCl buffer pH 7.4. MgCl and, where
appropriate, the other necessary cofactors, known from the
literature, for cytochrome P450 (CytP450) were then added
and the batch was incubated with CytP450 3A4 (N-
demethylation) and/or CytP450 2D6 (O-demethylation) at 37
°C. The batch was then separated via HPLC and the
metabolites in the fractions were identified via NMR and
then isolated from the fractions.
Example 11 In vivo isolation of the metabolites:
[2-(3-Methoxyphenyl)-cyclohexylmethyl]-dimethylamine;
hydrochloride and in a further example (1R,2R)-3-(2-
dimethylaminomethyl-cyclohexyl)phenol; hydrochloride were
injected into a mammal. Blood was taken from the mammal
and, after the corpuscular constituents had been separated
off, this was separated via HPLC and the metabolites in the
fractions were identified via NMR and then isolated from
the fractions.
Example 12 p-Opioid receptor affinity and NA and 5HT
uptake-inhibiting components:
In addition to the binding to the p-opioid receptor, which
is decisive for an opiod substance, the NA and 5HT uptake-
inhibiting components were also investigated for two
antidepressants which are used clinically, fluoxetine and
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desipramine. The results of these standard tests, the
procedure of which is adequately known in the literature,
are summarized in Table 1:
5 Table l: Uptake inhibition and opioid receptor binding
(1R,2R)-3- (1R,2R)-3- Fluoxetine Desipramine
(2-Dimethyl- (2-Methyl-
aminomethyl- aminomethyl-
cyclohexyl)- cyclohexyl)-
phenol; phenol;
hydro- hydro-
chloride chloride
K; values
(~ZM)
p-Opioid 0.038 (rat) 0.91 (human)inactive inactive
receptor
NA uptake 0.16 0.56 0.53 0.0011
inhibition
5HT uptake 0.05 9.41 0.026 1.44
inhibition
The 5HT reuptake inhibition precisely of (1R,2R)-3-(2-
dimethylaminomethyl-cyclohexyl)-phenol is of the same order
10 of magnitude as the ~.z-opioid receptor binding of the
substance. The substance thus has an exactly balanced
ratio of ~Z-opioid component and uptake inhibition and
therefore also has the potential for a particularly
effective pain inhibition. The uptake inhibition is of the
15 order of magnitude of antidepressants used clinically and
thus leads to an independent antidepressant action
component, the substance having a relatively potent
inhibiting action on the noradrenaline and, in particular,
serotonin reuptake.
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Example 13 Tail suspension test:
The tail suspension test detects antidepressant and
anxiolytic activity and follows the method of Porsolt et
al. (Porsolt R. D., Bertin A., Jalfre M., Behaviourial
despair in mice: a primary screening test for
antidepressants. Arch. Int. Pharmacodyn. Ther., 229, 327-
336, 1977) and Steru at al. (Steru L., Chermat R., Thierry
B, Simon P. The Tail Suspension Test: a new method for
screening antidepressants in mice. Psychopharmacology, 85,
367-370, 1985). Rodents left hanging by the tail rapidly
become immobile. Antidepressants reduce the duration of
the immobility, while tranquilizers prolong the duration of
the immobility. The behaviour of the animals was observed
for 6 minutes, preferably with a computerized apparatus
(Itemac-TST) developed by Steru et al. (1985) (see above).
Several mice were investigated in parallel and the duration
of immobility determined. This parameter is analogous to
that in the behavioural despair test (Steru L., Chermat R.,
Thierry B., Mico J. A., Lenegre A., Steru M., Simon P.
Porsolt R. D., The automated Tail Suspension Test: a
computerized device which differentiates psychotropic
drugs. Prog. Neuropsychopharmacol. Exp. Psychiatry, 11,
659-671, 1987). 10-20 mice were investigated per group.
Morphine, (1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-
phenol; hydrochloride and desipramine were administered
i.p. 30 minutes before the test and naloxone i.v..
This behavioural model is capable of demonstrating the
antidepressant action of the uptake inhibition component in
the simultaneous presence of an opioid action. In this
behavioural model, antidepressants, as also in other
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behavioural models, lead to a shortening of the immobility
phase, while opioids such as morphine prolong the
immobility phase. If both action components are present
the two effects overlap, so that only a slight change in
motility results. This was eliminated by the opiate
component being blocked by pretreatment with naloxone.
After the pretreatment with naloxone, the stimulating
action of (1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-
phenol, which was only slight without pretreatment,
manifested itself clearly. The substance is therefore very
suitable, especially in combination with a pain therapy.
The results of these investigations together with reference
substances are summarized in Table 2.
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Table 2: Action of (1R,2R)-3-(2-dimethylaminomethyl-
cyclohexyl)-phenol, imipramine and morphine in the tail
suspension test on mice (10 - 20 animals/group)
Substance Dose Duration of
(mg/kg i.p.) immobility
change compared
with the solvent
control
(1R, 2R) -3- (2- 4.64 +6
Dimethylaminomethyl- 10.0 +12
cyclohexyl)-phenol; 21.5 +9 %
hydrochloride 31.6 -13 %
(1R, 2R) -3- (2- 21 . 5 -90
Dimethylaminomethyl- 31.6 -85
cyclohexyl)-phenol;
hydrochloride +
1.0 mg/kg i.v.
naloxone
Naloxone 1.0 mg/kg - -15 %
i.v.
Morphine 4.64 +90%
10.0 +145
21.5 +169
-Imipramine ~ 31.6 -61
Tab. 2 shows that (1R,2R)-3-(2-dimethylaminomethyl-
cyclohexyl)-phenol; hydrochloride causes a marked decrease
in the duration of immobility, such as was also found with
imipramine, only after pretreatment with naloxone. As
20 shown for morphine, opioids lead to a prolonging of the
duration of immobility. This explains why (1R,2R)-3-(2-
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dimethylaminomethyl-cyclohexyl)-phenol without naloxone
pretreatment causes, as the net effect of uptake inhibition
and opioid action, only a slight change in the duration of
immobility compared with the solvent control.
According to the present findings, (1R,2R)-3-(2-
dimethylaminomethyl-cyclohexyl)-phenol surprisingly is the
first opiod analgesic to have a relevant and evidently also
clinically useful antidepressant action component.
Example 14: Parenteral administration form
1 g (1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol;
hydrochloride is dissolved in 1 1 of water for injection
purposes at room temperature and the solution is then
adjusted to isotonic conditions by addition of NaCl.
