The present invention relates to an oral pharmaceutical preparation.
The present invention relates to the use of pyridine-2-yl-methylamine derivatives for the preparation of a drug intended for the curative treatment of neuropathic and psychogenic chronic pain symptoms.
In international patent application WC 98/22459, the Applicant described compounds of general formula (I):
(Formula Removed)

Compounds of general formula (I) are characterized by their affinity and selectivity for 5-HTlA receptor subtypes, as well as by their capacity to provoke a specific element of serotonin syndrome (i.e., lower lip retraction) in the rat after oral administration. For this reason, compounds of formula (I) are claimed as potentially useful drugs for the treatment of depression and pain.
One aim of. the present invention is to improve existing analgesic techniques and treatments by means of compounds of general formula (I)- The claimed improvements open new therapeutic prospects for the preventive and./or curative treatment of chronic pain symptoms for which there is not, currently, a satisfactory therapeutic solution.
In general, three types of chronic pain are classified according to the mechanism implicated, namely, pain that results from excess nociceptive stimulation, neuropathic pain (or neurogenic or from deafferentation}, and psychogenic pain. However, some pain possesses characteristics common to several types of pain.

The expression "chronic pain" used within the scope of
this patent application encompasses pair, syndromes whose
development lasts beyond three months, but whose intensity may
vary over time.
Within the scope of the present invention, pain is
defined as an abnormal sensory and emotional experience which
ranges from unpleasant to painful, and which is perceived and
integrated at the highest level of the cerebral cortex where
its emotional and affective tone are imparted.
Within i:he scope of the present invention, the expression
"neuropathic pain" targets all pain that originates from one
or more lesions and/or dysfunctions of the central or
peripheral nervous system.
Within the scope of -he present invention, the expression
"psychogenic pain" indicates, in general, pain which does not
have an apparent pathological cause. This is pain without a
true anatomical foundation, which is to say, without an
objective lesion, and it is primarily psychological or
psychical. Thus, it may be an issue known as "phantom" pain,
i.e., an initial organic pain that persists after the causal
lesion (pain memory) disappears, or a true hallucination of
pain (pain felt in an amputated body part), or an organic pain
for which no lesion is discovered. This type of pain may be
perceived in various regions of the body and with widely
diverse manifestations and intensities.
Thus, the present invention targets the treatment of
symptoms of "erratic" pain, i.e., pain that frequently changes
location.
The present invention also targets the treatment of other
pain such as: "heavy" pain, i.e., pain accompanied by a
feeling of heaviness; "stabbing" pain, i.e., pain comparable
with that which would be caused by a stab; "dull" pain, i.e.,
light but continuous pain; vtensive" pain, i.e., pain
accompanied by a feeling by distension; and "terebrant" pain,
i.e., intense, deep pain that the patient perceives as if it
were produced by a pointed object inserted into the patient's
body.
By "analgesic drugs" is meant drugs which relieve or
suppress pain without the loss of sensation or consciousness.
In summary, the present invention targets the treatment
of symptoms not which correspond to pain nhat results fron
excess nociceptive stimulation, but for which neuropathic and
psychogenic pain no longer has any physiological role but
which has become truly pathological, in the form of a signal,
for example.
Thus, the present invention relates to the preparation of
drugs intended for the preventive and/or curative treatment of
chronic pain symptoms of neuropathic or psychogenic origin.
The drugs used in clinical practice to treat chronic pain
are derived from three distinct pharmacological families whose
best-known members include: morphine, aspirin, and
acetaminophen. Morphine acts on the central nervous system and
remains the central analgesic of reference. Aspirin acts on
the peripheral nervous system, directly on the cause of pain.
Acetaminophen acts similarly to aspirin but may also involve s.
central action. The drugs that belong to these various
families are effective against pain that results from excess
nociceptive stimulation, but little or not at all for the
other zypes of pain (i.e., neuropathic pain and psychogenic
pain). So to relieve certain neuropathic pain of low or
moderate intensity there is, in practice, recourse to
antidepressant agents, primarily to those members of the class
of tricyclics (amitriptyline and imipramine, for example).
Other auxiliary drugs such as anxiolytics, ar.ticonvulsants
(gabapentine and carbamazepine, for example), sodium channel
blockers (lidocaine, mexiletine), or glucocorticoids are also
prescribed in association with both morphine and non-morphine
based analgesics. In addition to uhe relatively limited
effectiveness of current drugs, their chronic use is
accompanied, moreover, by undesirable side effects. Examples
of side effects include: tolerance and dependence problems
related to the use of the major morphines (morphine and
pethidine, for example); digestive tcxicity (aspirin and
salicylated derivatives, for example); hypotension, sedation,
and weight gain (tricyclic antidepressants), etc.
In comparison to the drugs used in clinical practice, a
number of compounds which use different mechanisms of action
are at various stages of study as analgesics. These include,
for example, 5-HTlfi agonists {WO 98/22459, for example);
serotonin reuptake inhibitors (E-5296); serotonin and
adrenalin reuptake inhibirors (venlafaxine); cholinergic
agonists (levetiracetam); NMDA antagonists (memantine, CNS-
5161); glutamate antagonists (tcpiramate); nicotinic receptor
modulators (ABT-594); CCK antagonists (colykcde, devacade);
capsaicin derivatives (DA-5018, BL-1832); cannabinoids
derivatives(CT-3); nociceptin antagonists (JTC-801), etc.
These compounds are, for the most part, claimed as agents for
the symptomatic treatment of neuropathic pain.
Thus, it emerges overall that:
• currant chronic pain treatments are essentially founded
on treating the cause (anti-inflammatories, for example)
and, as a result, have little or no effect on neuropathic
and psychogenic pain;
• therapeutic approaches which address the problems of
neuropathic and psychogenic pain (antidepressants and
morphine, for example) relieve symptoms at best but do
not have any curative action; their use, moreover, is
limited by their side effects;
• new approaches may benefit from a wider range of action
than with conventional agents with respect to symptomatic
treatment of chronic pain, but there are no claims of an
effect which in any way resembles a curative effect.
The present application claims an improvement in the
treatments and techniques for chronic pain syndromes of
neuropathic or psychogenic origin for which therapeutic need
is significant. The advantages of the technical improvements
which are the subject of the application are:
• that the analgesia obtained by means of a 5-HTlfl agonist
of formula (I) extends beyond the classical symptomatic
treatment for chronic pain of neuropathic or psychogenic
origin;
• that the analgesia obtained by means of a 5-HTlA agonist
of formula (I) over time decreased, even permanently, the
pain intensity level perceived in the context of
neuropathic and psychogenic pain;
• that the activity of compounds of general formula (I) may
be similar in curative action for chronic pain of
neuropathic or psychogenic origin; to date, no action of
this type has been reported for any another agent that
possesses analgesic properties including, among others,
5-HTlA agonists.
With respect to a symptomatic pain syndrome treatment
plan, some compounds of general formula (I) possess a powerful
analgesic activity in representative animal models of
neuropathic pain. In fact, it has already been established
that their analgesic activity generally surpasses the activity
produced by reference analgesics. However, during the study of
the analgesic activity of compounds of formula (I) in
subchronic and chronic administration, the inventors
demonstrated unexpected properties of considerable scope in
terns of therapeutic application for the treatment of chronic
pain.
Indeed, regardless of the mode of action, all analgesic
agents present typical similar in vivo activity profiles,
which can be described as symptomatic as shown in figures 1
and 2 in the appendix. However, in addition to the classical
symptomatic analgesia phase, compounds of formula (I) produce
a curative phase of analgesia not previously reported for any
analgesic agent or regime. The nature of this specific
analgesia phase is detailed below.
In practice, two temporally different treatment plans may
be distinguished:
a) the active analgesic agent is administered during the
chronic pain phase;
b) administration of the active analgesic agent precedes
the appearance of chronic pain.
a} the active analgesic agent is administered during the
chronic pain phase
In animals that have developed chronic pain (hyperalgia
or allodynia) of maximum amplitude intensity, such as
presented in figure 1 in the appendix, chronic administration
of an active analgesic agent results in a significant, and in
theory dose dependant, decrease in the intensity of perceived
synptoms (i.e., symptomatic analgesia). The intensity of
perceived symptoms of pain may be objectified by measuring
various behavioral, physiological, conscious, and unconscious
parameters. The analgesic effect is maintained as long as
circulating levels of the analgesic agen~ are sufficient to
exert analgesic influence. When treatment is interrupted, the
intensity of perceived pain increases and tends to settle at a
level near its initial level (i.e., the pre-treatment pain
threshold). The intensity of perceived pain may also increase
during the treatment phase if a phenomenon of tolerance to the
analgesic agent develops (treatment with major morphines, for
example).
In the case of the chronic administration of certain
compounds of general formula (I), the classical dose dependant
decrease of the intensity of perceived symptoms (i.e.,
classical symptomatic analgesia) is also observed during the
treatment phase. However, contrary to other analgesics, the
intensity of perceived pain does not tend to find its initial
level when the treatment is interrupted, such as appears in
figure 1 in the appendix. Thus, quite surprisingly, not only
does analgesia persist in spite of the end of treatment but it
is maintained at a stable level at the same amplitude as that
reached at the treatment's end. The phenomenon observed is all
the more interesting because compound (I) is not no longer
present in the animals' bodies during the subsequent analgesia
phase at the treatment's end, and because it has no effect on
the causes of chronic pain (lesion and inflammation, for
example). Under these conditions, the actions of compound (I)
perhaps qualify as curative. The mechanisms implied in the
specific mode of action of compounds of formula (I),
downstream from the activation of £-HTlA receptors, remain
unknown.
b) administration of che active analgesic agent precedes
the appearance of chronic pain
The classical analgesic activity profile of an active
compound, when chronic treatment in the animal is initiated
before the induction of pain (such as appears in figure 2 in
the appendix), shows that the perceived intensity of pain
following the lesion reaches a amplitude threshold that is
lower than the threshold reached in the absence of treatment
(i.e., the classical symptomatic analgesic effect). This phase
of symptomatic analgesia disappears systematically when
treatment is interrupted (such as appears in figure 2 in the
appendix).
In the case of -he chronic administration of certain
compounds of general formula (I), when treatment is initiated
before the induction of pain, the phase of symptomatic
analgesia characteristic of active analgesics is also
observed. However, as in case a) the analgesia produced by
compounds of formula (I) persists and is maintained at a
stable level in spite of the treatment's end (such as appears
in figure 2 in the appendix). During this specific phase of
analgesia, compound (I) is no longer present in the animals'
bodies and has no effect on the cause of chronic pain. Thus, a
treatment by means of a compound (I) which precedes the
appearance of chronic pain tends to prevent or strongly
attenuate later pain development. This specific aspect of the
activity of compounds of formula (I) is potentially
advantageous for the preventive treatment of postoperative
pain. Such a treatment may also be useful for certain nervous
system attacks in which a more or less significant delay
separates the lesion from the appearance of pain (rachidian
lesions and phantom pain, for example).
The unique and unexpected analgesic activity development
profile of compounds of formula (I), in particular by their
curative action and regardless of the treatment plan (i.e.,
before or after pain develops), represents a substantial
improvement in the current state of the art.
Thus, compounds of the invention make it possible,
potentially, to respond to a therapeutic need in the field of
treatment of chronic pain of neuropathic and/or psychogenic
origin in which the drugs available prove to have little or no
effectiveness or prove of limited utility due to their side
effects.
Compounds (I) are represented, in base form, by general
formula (I):
(Figure Removed)
represents a hydrogen atom or a methyl radical under
the condition that when u is a methyl radical then v
and w represent hydrogen atoms;
represents a hydrogen atom, a chlorine atom, or a
methyl radical under the condition that when v is a
methyl radical then u and w represent hydrogen
atoms;
represents a hydrogen atom, a fluorine atom, or a
methyl radical under the condition that when w is a
methyl radical then u and v represent hydrogen
atoms;
represents an atom of hydrogen or fluorine;
represents a chlorine atom or a methyl radical;
represents an atom of hydrogen, fluorine, or
chlorine, or a methyl radical;
represents:
an atom of hydrogen, fluorine, or chlorine;
- a C1-C5 alkyl radical, i.e., straight or branched
saturated aliphatic hydrocarbon waste that
contains 1 to 5 carbon atoms such as methyl,
ethyl, propyl, butyl, pentyl, isopropyl, 1-methylethyl,
1-methyl-propyl, 1-methyl-butyl, 2-methylpropyl,
2-methyl-butyl or 3-methyl-butyl, 1-ethylpropyl,
and 2-ethyl-propyl;
a fluoroalkyl radical such as monofluoromethyl (-
CH2F), difluoromethyl (-CHF2) , trifluoromethyl (-
CF3), 1-fluoro-l-ethyl (-CHFCH3), or 1,1-dif luoro-
1-ethyl (-CF2CH3);
a cyclopropyl, cyclobutyl, or cyclopenzyl radical;
an aromatic heterocyclic group with 5 links,
substituted or not, that contain 1, 2, 3, or 4
heteroatoms selected from among nitrogen, oxygen,
and sulfur, with no more than one atom of sulfur
or oxygen present in heterocycle A.
The aromatic heterocycles are preferably:
furar.-2-yl, (O.CH:CH.CH:C-) or
furan-3-yl, (CH:CH.O.CH:C-) or
lH-pyrrol-2-yl, (NH.CH:CH.CH:C-) or
lH-pyrrol-3-yl, (CH:CH.NH.CH:C-) or
l-methyl-pyrrol-2-yl, (N(CHS).CH:CH.CH:C-) or
l-methyl-pyrrol-3-yl, (CHrCH.N(CH3).CH:C-) or
thiophen-2-yl, (S.CH:CH.CH.C-) or
thiophen-3-yl, (CH:CH.S.CH:C-) or
pyrazole-1-yl, !N:CH.CHrCH.N-) or
lH-pyrazole-3-yl, (CHrCH.NH.N:C-) or
lH-pyrazole-4-yl, (CH:N.NH.CH:C-) or
l-methyl-pyrazole-3-yl, (CHrCH.N(CH3).N:C-) or
imidazol-1-yl (CHrN.CHrCH.N-) or
lH-imidazol-2-yl, (NH.CHrCH.N:C-) or
lH-in\idazol-4-yl, (N: CH.NH. CH:C-) or
oxazol-2-yl, (O.CHrCH.NrC-) or
oxazol-4-yl, (NrCH.O.CHrC-) or
oxazol-5-yl, (O.CH:N.CH:C-) or
xsoxazol-5-yl (O.NrCH.CHrC-) or
isoxazol-4-yl, (CHrN.O.CH:C-) or
isoxazol-3-yl, (CHrCH.O.NrC-) or
1C
uhiazol-2-yl, (S.CH:CH.N:C-) or
thiazol-4-yl, (N:CH.S.CH:C-) or
thiazol-5-yl, (S.CH:N.CH:C-) or
isothiazoi-5-yl, (S.N:CH.CH:C-) or
isothiazol-4-yl, (CH:N.S.CH:C-) or
isothiazol-3-yi, (CH:CH.S.N:C-) or
[l,2,4]triazolyl-lyl, (CH:N.CH:N.N-) or
lH-[l,2,4]triazol-3-yl, (N:CH.NH.N:C-) or
[l,2,4]oxadiazol-3-yl, (N:CH.O.N:C-) or
[l,2,4]oxadiazol-5-yl, (O.N:CH.N:C-) or
5-methyl-11,2,4]oxadiazol-3-ylr (N:C(CH3).O.N:C-)
or
lH-tetrazol-5-yi, (NH.N:N.N:C-);
an alkoxy (RiO-) or alkylthio (RiS-) group in
which radical R! represents:
a CI-GS alkyl radical as previously defined,
a monofluoromethyl or trifluoromethyl
radical,
a cyclopropyl, cyclobutyl, or cyclopentyl
radical;
a amino group of type II
in which R2 and R3, identical or different,
represent hydrogen, a Ci-C5 alkyl radical as
previously defined, a cyclopropyl group, or a
trifluoromethyl group;
a saturated cyclic amino group of type III
- (m)
in which n may be whole numbers 1 or 2;
- an alkoxycarbonyl group, preferably a
methoxycarbcnyl group (CH30CO-), or an
ethoxycarbonyl group (CH3CH2OCO-) .
The invention also extends to additive salts from
compounds of aforementioned formula I, with pharmaceutically
acceptable mineral or organic acids.
More particularly, the present invention targets zhe use
of compounds of formula I selected from among:
(3, 4-Dichloro-phenyl)-(4-{[(6-pyrazole-l-yl-pyridine-2-
ylmethy1)-ami no]-methyl}-piperidine-1-yl)-methanone
(3-Chloro-4-fluoro-phenyl)-(4-{[(6-pyrazole-l-yl-pyridine-2-
ylmethyl)-amino]-methyl}-piperidine-l-yl)-methanone
(4-Chloro-3-methyl-phenyl)-(4-{[(6-pyrazole-l-yl-pyridine-2-
ylmethyl)-ami no]-methyl}-piperidine-l-yl)-methanone
(3-Chloro-phenyl)-(4-{[(6-pyrazole-l-yl-pyridine-2-ylmethyl)-
aminoJ-methyl}-piperidine-1-yl)-methanone
(4-{ [(6-Pyrazole-l-yl-pyridine-2-ylmethyl)-amino]-methyl}-
piperidine-1-yl)-m-tolyl-methanone
(3, 4-Dichloro-phenyl)-{4-fluoro-4-{[(6-pyrazole-l-yl-pyridine-
2-ylmetnyl)-amino]-methyl)-piperidine-1-yl)-methanone
(3, 4-Dichloro-phenyl)-(4-{[(6-imidazol-l-yl-pyridine-2-
ylmethyl)amino]-methyl}-piperidine-1-yl)-methanone
(3,4-Dichloro-phenyl)-(4-{[(6[1,2, 4, ]triazol-l-yl-pyridine-2-
ylmethyl)-amino]-methyl}-piperidine-1-yl)-methanone
(3, 4-Dichloro-phenyl)-(4-{[(6-pyrrol-l-yl-pyridine-2-
ylmethyl)-ami no]-methyl}-piperidine-1-yl)-methanone
{3, 4-Dichloro-phenyl)-(4-{ [ (6-methylamino-pyridir.e-2-
ylmethyl)-amino]-methyl}-piperidine-1-yl)-methanone
12
(3,4-Dichloro-phenyl)-(4-fluoro-4-{[(6-methylamino-pyridine-2-
ylmethyl)-amino]-methyl}-piperidine-1-yl)-methanone
(3, 4-Dichloro-phenyl)-(4-{[(6-dimethylamino-pyridine-2-
ylmethyl)-amino]-methyl}-piperidine-1-yl)-methanone
(3-Chloro-4-fluoro-phenyl)-(4-{[(6-diraethylamino-pyridine-2-
ylmethyl)-amino]-methyl}-4-fluoro-piperidine-l-yl)-methanone
(3, 4-Dichloro-phenyl)-{4-{[(6-dimethylamino-pyridine-2-
ylmethyl)-amino]-methyl}-4-fluoro-piperidine-1-yl)-methanone
(3,4-Dichloro-phenyl)-[4-({[6-(ethyl-methyl-amino)-pyridine-2-
ylmezhyl]-amino}-methyl)-4-fluoro-piperidine-l-yl]-methanone
(3,4-Dichloro-phenyl)-[4({[6-(methyl-propyl-amino)-pyridine-2-
ylmethyl]-amino}-methyl)-piperidine-1-yl]-methanone
(4-{[(6~Azetidin-l-yl-pyridine-2-ylmethyl)-amino]-methyl}-
piperidine-1-yl)-(3,4-dichloro-phenyl)-methanone
{4-{[(6-Azetidin-l-yl-pyridine-2-ylmethyl)-aminc]-methyl}-4-
fluoro-piperidine-1-yl)-(3,4-dichloro-phenyl)-methanone
(4-{[(6-Cyclopentyl-pyridine-2-ylmethyl)-amino]-methyl}-
piperidine-1-yl}-(3, 4-dichloro-phenyl)-methanone
(4-{ [ (6-Chloro-pyridir.e-2-ylmethyl) -amino] -methyl} -piperidine-
1-yl) -(3, 4-dichloro-phenyl)-methanone
(3, 4-Dichloro-phenyl)-[4({[6-(lH-pyrazole-3-yl)-pyridine-2-
ylmethyl]-amino}-methyl)-piperidine-1-yl]-methanone
(3,4-Dichloro-phenyl)-[4-fluoro-4-{{[6-(lH-pyrazole-3-yl)-
pyridine-2-ylmethyl]-amino}-methyl)-piperidine-1-yl]-methanone
(3, 4-Dichloro-phenyl)-[4-fluoro-4-({[6-(l-methyl-pyrazole-3-
yl) -pyridine~2-ylmethyl]-amino}-methyl)-piperidine-1-yl]-
methanone
(3, 4-Dichloro-phenyl)-[4-({[6-(lH-imidazol-2-yl)-pyridine-2-
ylmethyl]-amino}-methyl)-piperidine-1-yl]-methanone
(3, 4-Dichloro-phenyl)-(4-{[(6-thiazol-2-yl-pyridine-2-
ylmethyl)-ami no]-methyl}-piperidine-1-yl)-methanone
(3,4-Dichloro-phenyl)-(4-fluoro-4-{[(6-thiazol-2-yl-pyridine-
2-ylmethyl)-amino]-methyl}-piperidine-1-yl)-methanone
(3, 4-Dichloro-phenyl)-[4-({[6-(lH-pyrrol-2-yl)-pyridine-2-
ylmethyl]-amino}-methyl)-piperidine-1-yl]-methanone
(3, 4-Dichloro-phenyl)-(4-{t(6-thiophen-2-yl-pyridine-2-
ylmethyl)amino]-methyl}-piperidine-1-yl)-methanone
(3,4-Dichloro-phenyl)-(4-fluoro-4-{[(6-thiophen-2-yl-pyridine-
2-ylmethyl)-amino]-methyl}-piperidine-1-yl)-methanone
(3,4-Dichloro-phenyl}-(4-{[(6-furan-2-yl-pyridine-2-ylmethyl)-
amino]-methyl}-piperidine-1-yl)-methanone
(3, 4-Dichloro-phenyl}-(4-fluoro-4-{[(6-furan-2-yl-pyridine-2-
ylnethyl) -araino] -methyl}-piperidine-1-yl) -methanone
(3-Chloro-4-fluoro-phenyl)-(4-fluoro-4-{[(6-furan-2-ylpyridine-
2-ylmethyl)-amino]-methyl}-piperidine-1-yl)-methanone
{3,4-Dichloro-phenyl)-{4-{[(6-oxazol-5-yl-pyridine-2-
ylmethyl)-amino]-methyl}-piperidine-1-yl)-methanone
(3, 4-Dichloro-phenyl)-(4-fluoro-4-{[(6-oxazol-5-yl-pyridine-2-
ylmethyl)-amino]-methyl}-piperidine-1-yl)-methanone
(3, 4-Dichloro-phenyl)-(4-fluoro-4-([(6-furan-3-yl-pyridine-2-
ylmezhyl)-amino]-methyl}-piperidine-1-yl)-methanone
(3,4-Dichloro-phenyl)-[4-({[6-(5-methyl[1,2,4]oxadiazol-3-yl)-
pyridine-2-ylmethyl]-amino}-methyl)-piperidine-1-yl]-methanone
(3,4-Dichloro-phenyl}-(4-{[(6-methyl-pyridine-2-ylmethyl)-
amino]-methyl}-piperidine-1-yl)-methanone
{3, 4-Dichloro-phenyl)-(4-{[(6-isopropyl-pyridine-2-ylmethyl)-
amino]-methyl}-piperidine-1-yl)-methanone
(3,4-Dichloro-phenyl)-(4-{[(6-cyclopropyl-pyridine-2-
ylmethyl)-amino]-methyl}-4-fluoro-piperidine-1-yl)-methanone
(3, 4-Dichloro-phenyl)-(4-fluoro-4-{[(6-fluoromethyl-pyridine-
2-ylmethyl)-amino]-methyl}-piperidine-1-yl)-methanone
(3, 4-Dichloro-phenyl)-(4-{[(6-difluoromethyl-pyridine-2-
ylmethyl)-arnino]-methyl}-piperidine-1-yl)-methanone
(3, 4-Dichloro-phenyl)-(4-{[(6-difluoromethyl-pyridine-2-
ylmethyl)-arnino]-methyl}-4-fluoro-piperidine-1-yl)-methanone
{3, 4-Dichlcro-phenyl)-[4-fluoro-4-({[6-(1-fluoro-ethyl)-
pyridine-2-ylmethyl]-amino}-methyl)-piperidine-1-yl]-methanone
6-({ [1-(3,4-Dichloro-benzoyl)-piperidine-4-ylmethyl]-amino}-
methyl)-pyridine-2-carboxylicacidmethylester
6-({[1-(3,4-Dichloro-benzoyl)-piperidine-4-ylmethyl]-amino}-
methyl)-pyridine-2-carboxylicacidethylester
(3,4-D.i chloro-phenyl) - (4-{ [ (6-methoxy-pyridine-2-ylmethyl) -
amino]-methyl}-piperidine-1-yl)-methanone
(3,4-Cichloro-phenyl)-(4-fluoro-4-{[(6-methoxy-pyridine-2-
ylrnethyl) -amino] -methyl}-piperidine-l-yl) -methanone
(3, 4-Dichloro-phenyl)-(4-fluoro-4-{[(6-isopropyloxy-pyridine-
2-ylmethyl)-amino]-methyl}-piperidine-l-yl)-methanone
(4-{ [(6-Cyclopentyloxy-pyridine-2-ylmethyl)-amino]-methyl }-
piperidine-1-yl)-(3,4-dichloro-phenyl)-methanone
(3, 4-Dichloro-phenyl)-{4-{[(6-methylsulfanyl-pyridine-2-
ylmethyl)-amino]-methyl}-piperidine-1-yl)-methanone
(3,4-Dichloro-phenyl)-(4-{[(6-fluoro-pyridine-2-ylmethyl)-
amino]methyl}-piperidine-1-yl)-methancne
(3,4-Dichloro-phenyl)-(4-fluoro-4-{[(6-fluoro-pyridine-2-
ylmethyl)-amino]-methyl}-piperidine-1-yl)-methanone
(3, 4-Dichloro-phenyl)-(4-fluoro-{[(3-fluoro-pyridine-2-
ylmethyl)-amino]-methyl}-piperidine-1-yl)-methanone
(4- { [ (4-Chloro-pyriciine-2-ylmethyl) -amino] -methyl }-piperidine-
1-yl)-(3,4-dichloro-phenyl)-methanone
(3-Chloro-4-fluoro-phenyl)-(4-fluoro-4-{[(5-methyl-6-furan-2-
yl-pyr i dine-2-y line thyl) -amino] -methyl} -piperidine-1-yl) -
methanone
(3~Chloro-4-fluoro-phenyl)-[4-fluoro-4-({[5-methyl-6-(1Hpyrazole-
3-yl)-2-yl-pyridine-2-ylmethyl]-amino}-methyl)-
piperidine-1-yl]-methanone
(3-Chloro-4-fluoro-phenyl)-(4-fluoro-4-([(5-methyl-6-
methylamino~p)yridine-2-ylmethyl) -amino] -methyl}-piperidine-1-
yl) -methanone?
(4-{ [ (6-Azetidin-l-yl-pyridine-2-yl:nethyl) -amino] -methyl} -4-
fluoro-piperidine-1-yl)-(3-chloro-4-fluoro-pnenyl)-methanone
(3-Chloro--4-f luoro-phenyl)-(4-fluoro-4-{[(6-oxazol-S-ylpyridine-
2-ylmethyl)-amino]-methyl}-piperidine-1-yl)-methanone
(3-Chloro-~4-f luoro-phenyl) - (4-fluoro-4-{ [ (6-ethylaminopyridine-
2-ylmethyl)-amino]-methyl}-piperidine-1-yl)-methanone
(3-Chloro-4-fluoro-phenyl)-(4-fluoro-4-{[(6-methylaminopyridine-
2-ylmethyl)-amino]-methyl}-piperidine-1-yl)-methancne
(3-Chloro-4-methyl-phenyl)-(4-fluoro-4-{[(6-dimethylaminopyr
;di ne-2-ylmethyl)-amino]-methyl}-piperidine-1-yl)-methanone
(3-Chloro-4-fluoro-phenyl)-{4-fluoro-4-{[(5-methyl-6-
dimethylamino-pyridine-2-ylir.ethyl) -amino] -mezhyl} -piperidine-
1-yl) -methanone
(3-Chloro-4-fluoro-phenyl)-[4-fluoro-4-({[6-(lH-pyrazole-3-
yl)-pyridine-2-ylmethyl]-amino}-methyl)-piperidine-1-yl]-
methanone
(3,4-Dichloro-phenyl)-(4-fluoro-4-{[(3-methyl-6-dimethylaminopyridine-
2-ylmethyl)-amino]-methyl}-piperidine-1-yl)-methancne
(3-Chloro-4-fluoro-phenyl)-(4-fluoro-4-{[(6-pyrazole-l-ylpyridine-
2-ylmethyl)-amino]-methyl}-piperidine-1-yl)-methancne
(3, 4-Dichloro-phenyl)-(4-fluoro-4-{[(5-methyl-pyridine-2-
ylmethyl)-amino]-methyl}-piperidine-l-yl)-methanone
(3-Chloro-4-fluoro-phenyl)-(4-fluoro-4-{[(5-methyl-pyridine-2-
ylmethyl)-aminc]-methyl}-piperidine-1-yl)-methanone
(3-Chloro-4-fluoro-phenyl}-(4-fluoro-4-{[(6-diethylaminopyridine-
2-ylmethyl)-amino]-methyl}-piperidine-1-yl)-methanone
(3-Chloro-4-fluoro-methyl)-(4-fluoro-4-{[(5-methyl-6-chloropyridine-
2-ylmethyl) -amino] -methyl}-piperidine-l-yl) -methar.one
(3-Chloro-4-fluoro-phenyl)-(4-fluoro-4-{[(4-methyl-6-
dimethylamino-pyridine-2-ylmethyl}-amino]-methyl}-piperidine-
1-yl)-methanone
(3-Chloro-4-fluoro-phenyl) - (4-fluoro-4-{ t (5-inethyl-6-pyrazolel-
yl-pyridine-2-ylmethyl)-amino]-methyl}-piperidine-l-yl) -
methanone
(3-Chloro-phenyI)-(4-fluoro-4-{[(6-dimethylamino-pyridine-2-
ylmethyl)-amino]-methyl}-piperidine-l-yl)-methanone
Within the context of the present invention, the preferred
compounds of formula (I) are:
(3-Chloro-4-fluorophenyl)-[4-fluoro-{[(5-methyl-pyridine-2-
ylmethyl)-amino]-methyl}-piperidine-1-yl)-methanone,
with A = H, u = CH3, v and w = H, X = F, y = Cl, and z = F,
and
{3-Chloro-4-fluorophenyl)-(4-fluoro-{[(5-methyl-6-methylaminopyridine-
2-ylmethyl)-amino]-methyl}-piperidine-1-yl)-
methanone, with A = NHCH3, u = CH3, v and w = H, X = F, y =
Cl, and z = F
as well as their additive salts with pharmaceutically
acceptable mineral or organic acids. These compounds are
referred to hereafter as (la) and (Ib>.
The preparation of compounds (la) and (Ib) as well as
their analytical characteristics are reported in patent WO
02/064585.
The invention also extends to pharmaceutical compounds
that contain as an active ingredient at least one of the
derivatives of general formula (I) or one of its salts or
13
hydrates thereof in combination with one or more inert media
or other pharmaceutically acceptable vehicles.
Pharmaceutical compounds according to the invention may
be, for example, compounds that can be administered by the
oral, nasal, sublingual, rectal, transcutaneous, and
parenteral routes. As examples of compounds that may be
administered by the oral route, the most common include
tablets, gelatin capsules, granules, powders, and oral
solutions and suspensions. Pharmaceutical examples of
compounds that contain products of formula (I) are reported in
patent WO 98/22459.
The effective dose of a compound of the invention varies
as a function of a number of parameters such as, for example:
the administration route chosen; the subject's weight, age,
and sex; the state of advancement of the pathology under
treatment; and the sensitivity of the treated individual. As a
consequence, the optimal dosage must be determined as a
function of the parameters deemed relevant by the specialist
in the art.
As illustrative examples of chronic neuropathic and
psychogenic pain that is potentially sensitive to the action
of compounds of general formula (I), the following may be
cited more specifically: peripheral or central neuropathic
pain that results from nerve lesions of traumatic origin (a
cerebral vascular accident, for example), of metabolic origin
(diabetes, for example), infectious origin (HIV, shingles, and
herpes, fcr example), toxic origin (arsenic and lead, for
example), invasive origin (cancer pain), or congenital origin;
pain from phantom limbs; cephalgias; noninflammatory articular
pain (osteoarthritis, for example); fibromyalgia; rachidian
pain; postoperative pain; and from other causes of neuropathic
pain such as multiple sclerosis and chronic pain. Pain is
considered to be chronic when the patient reports suffering
for a period thai: exceeds six months. Among chronic pain, in
addition to pain associated with fibromyalgia, it would be
appropriate to cite as illustrative and non-limiting examples
pain arising from fibrous tissues, muscles, tendons, ligaments
and other sites, abdominal pain, diarrhea (notably in the case
of irritable bowel syndrome), and chronic back pain.
In particular, the present invention targets the
treatment of fibromyalgia syndrome. Fibromyalgia is a chronic
syndrome characterized by a morning sensation of pain or
burning and stiffness, primarily involving fibrous, articular,
and periarticular tissue, and by a feeling of profound
fatigue. It is appropriate here to recall that fibromyalgia
presents a set of symptoms which include nonrestorative sleep,
headaches, digestive disorders, depressed state, muscle
spasms, face pain, and numbness.
The invention also targets the treatment cf certain
symptoms of chronic fatigue syndrome, which is characterized
by a state of exhaustion or fatigue that most notably results
in muscle spasms and/or pain.
Study of the pharmacological properties of compounds of
formula (I)
Measuring the analgesic activity of products (la) and
(Ib} makes it possible to demonstrate:
the effectiveness of compounds of formula (I) in
representative animal models of neuropathic pain; and
their unique analgesic activity profile.
Thus are illustrated the improvements in analgesic techniques
and treatments which are the subject of the present invention.
As examples, we describe the analgesic activities of
products (la) and (Ib) obtained in tests of peripheral and
central neuropathy. These examples in no way limit the scope
of the invention.
An illustration of the curative aspect of the analgesic
effect produced by compounds of formula (I)
Case 1: treatment with compound (la) once chronic pain is
established
The central neuropathy test used is conducted in ~he rat
according to a method analogous to that described by Hao and
Xu in Pain 1996, 66, 279-286. The product to be tested is
delivered at a constant rate by means cf an osmotic pump
(Alzet, model 2ML2) for 14 days. The pumps are implanted 28
days after spinal cord lesion and then explanted at the
treatment's end. In this no-del, it was established that at 28
days post-lesion the animal is in a phase of chronic
hypersensitivity which then lasts for several months. In this
experinent, the hypersensitivity of the lesioned animals
treated with compound (la) or with saline solution was
measured. The pain threshold was objectified by the animal's
persistent vocalization in response to a stimulation of
increasing intensity in the sensitive region by means of von
Frey hairs. Thus, analgesia is all the more effective as the
vocalization amplitude threshold is raised. The fumaraze of
compound (la) is administered at 0.63 mg/rat/day. The pumps
implanted in the group of lesioned control animals release a
0.9 % NaCl solution (saline)/rat/day.
The stimulation sensitivity tests by means of von Frey
hairs are conducted 3 days after implantation of the osmotic
pump and continue regularly for 28 days. The doses refer to
the weight of non-salified compound.
The effects obtained with compound (la) in comparison
with those of the lesioned control animals that received
saline solution are represented in figure 3 in the appendix.
In this model, antidepressant and anti-inflammatory agents, as
well as morphine compounds, are inactive.
Results
In the lesioned animals treated with saline solution the
stimulation that initiates vocalization is of very low
intensity and remains so throughout the experiment (i.e., 28
days post-lesion). Thus, the lesioned animals have developed
chronic hypersensitivity. The animals treated by means of
compound (la) tolerated stimulation of higher intensity that
did the control animals and this was the case at all
measurement points throughout the treatment. This state,
sinilar to analgesia, is statistically significant as of the
tenth day of treatment. Thus, compound la possesses
symptomatic analgesic activity. After treatment is interrupted
(i.e., after day 15 in figure 3 in the appendix), analgesia
persists and is maintained at the same level as that attained
at the treatment's end, in fact significantly at all
measurement times throughout the remainder of the experiment
(i.e., 14 days following pump explantation).
Thus, compound (la) also possesses a curative analgesic
activity.
The results of the experiment show that treatments using
compounds of formula (I) produce:
a phase of symptomatic analgesia;
a phase of curative analgesia.
Case 2: treatment with compounds (la) and (Ib) when pain
has yet to develop
The peripheral neuropathy test used was conducted in the
rat according to a method analogous to that described by Vos
in J. Neurosci. 1994, 14, 2708-2723. The product to be tested
is delivered at a constant rate (0.12 ml/day) by means of an
osmotic pump (Alzet, model 2ML2) for 14 days. The pumps are
implanted 24 hours before lesion (unilateral ligature of the
infraorbital nerve) and then explanted at the treatment's end.
The pumps are implanted subcutaneously via a transverse
incision made in the dorsal skin of the rat. Evaluation of the
intensity of perceived pain is objectified from a series of
behavioral signs observed in response to mechanical
stimulation of the region lesioned by means of von Frey hairs.
Stimulations are applied in order of increasing intensity.
Intensity of perceived pain is evaluated from the following
criteria: 0, no response by the animal; 1, detection (i.e.,
the rat turns its head towards the object used for
stimulation;,- 2, withdrawal (i.e., the rat turns away or makes
a withdrawal movement with its head to avoid the object used
for stimulation); 3, flight or attack (i.e., the rat avoids
the object by moving its body or deliberately attacks the
object used for stimulation); 4, face rubbing (i.e., the rat
rubs the area of stimulation three times in succession) . The
response level by the non-lesioned animals was 0 or 1.
The fumarate of compound (la) is administered at
0.63 rr.g/rat/day; the glycolate of compound (Ib) at
0.16 mg/rat/day; morphine hydrochloride at 5 mg/rat/day, and
baclofen at 1.06 mg/rat/day. All the compounds are
administered in solution in distilled water. The pumps
implanted in the control animals release a 0.9 % NaCl solution
(saline)/rat/day; the doses refer to the weight of nonsalified
compound.
The effects obtained with compounds (la), (Ib), and che
products chosen as references are represented in figures 4 to
8 in the appendix. Figures 4 to 7 represent the analgesic
effects of the various products evaluated at days 4, 6, 8, 11,
and 13 of treatment and 1 day following explantation of the
pump (day 15). Figure 8 represents the analgesic effects of
the various products measured at day 21, which is 6 days
following the treatment's end. In this model, it has been
established previously that antidepressant agents are inactive
whereas baclofen is the agent with the highest activity.
The individual scores of each animal represent the
average (± standard error) obtained after application of the
von Frey hairs. The comparison of the results between the
various groups as well as the progress of the values obtained
over time are performed using an analysis of variance test
(ANOVA), followed by a Dunnett's multiple comparison test.
Results
The analgesic effects observed vary differently over the
ccurse of the time as a function of the products evaluated.
The resolution of the evaluation system adopted (evaluation
criteria from 0 to 4) has as a consequence small relative
variation between the amplitudes of the analgesic effects
observed.
The comparison between product (la) and saline shows that
compound (la) reduced the animal's hypersensitivity
(allodynia) to stimulation (comparable to an analgesic
effect), and did so significantly after day 11 (figure 4).
Compound (Ib) reduced hypersensitivity significantly only
after day 13 (figure 5) . Morphine was inactive under the
experimental conditions (figure 6) whereas baclofen also had a
significant analgesic effect after day 11 {figure 7).
Six days after the treatment's end, the animals treated
with compounds (la) and (Ib) continued to show a significant
analgesic effect, whereas the effect of morphine and of
baclofen disappeared completely (figure 8). Moreover, the
amplitude of the analgesia produced by compounds (la) and (Ib)
measured 6 days after the treatment's end is not statistically
different from the amplitude measured at the treatment' s end
(i.e., day 15).
The results of the experiment show that a treatment by
means of compounds (la) and (Ib):
decreases perceived pain intensity after a nerve lesion
of peripheral origin and does so with an amplitude at
least equivalent to that of the reference product
recognized as the most effective in this neuropathic
pain model 'i.e., baclofen);
produces an analgesic effect that persists and remains
stable for at least 6 days following the treatment's
end which is contrary to that observed with baclofen.
It arises from the studies that certain compounds of
formula (I), as well as their additive salts with
pharmaceutically acceptable mineral or organic acids, are
effective in the treatment of chronic neuropathic pain of
peripheral and central origin. The analgesia that they
provide, moreover, has a single and completely renarkable
development profile. Thus, the analgesia persists and is
maintained at a stable level far beyond the treatment period
and does so regardless of the treatment plan (pre- cr postlesion)
. This specific analgesia phase, referred to as
"curative" in the present invention, is, contrary to the
symptomatic phase, specific to compounds of formula (I) . Such
an analgesic development profile has never before been
demonstrated, not only with 5-HTla agonists but also with other
agents that possess analgesic properties. For this reason,
compounds of formula (I) clearly make possible improvements in
current analgesia treatment.

We Claim
1. The fumarate salt of a compound of formula (I)
(Formula Removed)

in which:
u represents a hydrogen atom or a methyl radical under the condition that when u is a methyl radical then v and w represent hydrogen atoms; v represents a hydrogen atom, a chlorine atom, or a methyl radical under the condition that when v is a methyl radical then u and u represent hydrogen atoms; w represents a hydrogen atom, a fluorine atom, or a methyl radical under the condition that when w is a methyl radical then u and v represent hydrogen atoms; x represents an atom of hydrogen or fluorine; y represents a chlorine atom or a methyl radical; z represents an atom of hydrogen, fluorine, or
chlorine, or a methyl radical; A represents:
an atom of hydrogen, fluorine, or chlorine;
a C1-C5 alkyl radical, i.e., straight or branched saturated aliphatic hydrocarbon waste that contains 1 to 5 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl, isopropyl, 1-methyl-ethyl, 1-methyl-propyl, 1-methyl-butyl, 2-methyl-propyl, 2-methyl-butyl or 3-methyl-butyl, 1-ethyl-propyl, and 2-ethyl-propyl;

a fluoroalkyl radical such as monofluoromethyl (-CH2F) , difluoromethyl (-CHF2) , trifluoromethyl (-CF3) , 1-fluoro-1-ethyl (-CHFCH3) , or 1,1-difluoro-l-ethyl (-CF2CH3);
a cyclopropyl, cyclobutyl, or cyclopentyl radical;
an aromatic heterocyclic group with 5 links, substituted or not, that contain 1, 2, 3, or 4 heteroatoms selected from among nitrogen, oxygen, and sulfur, with no more than one atom of sulfur or oxygen present in heterocycle A.
The aromatic heterocycles are preferably: furan-2-yl, (0.CH:CH.CH:C-) or furan-3-yl, (CH:CH.0.CH:C-) or lH-pyrrol-2-yl, (NH.CH:CH.CH:C-) or lH-pyrrol-3-yl, (CH:CH.NH.CH:C-) or L-methyl-pyrrol-2-yl, (N(CH3).CH:CH.CH:C-) or
L-methyl-pyrrol-3-yl, (CH:CH.N(CH3).CH:C-) or
thiophen-2-yl, (S.CH:CH.CH.C-) or thiophen-3-yl, (CH:CH.S.CH:C-) or pyrazole-1-yl, (NR:CH.CH:CH.N-) or lH-pyrazole-3-yl, (CH:CH.NH.N:C-) or lH-pyrazole-4-yl, (CH:N.NH.CH:C-) or L-methyl-pyrazole-3-yl, (CH:CH.N(CH3).N:C-) or
imidazol-1-yl (CH:N.CH:CH.N-) or lH-imidazol-2-yl, (NH.CH:CH.N:C-) or lH-imidazol-4-yl, (NR:CH.NH.CH:C-) or oxazol-2-yl, (0.CH:CH.N:C-) or oxazol-4-yl, (N:CH.0.CH:C-) or oxazol-5-yl, (0.CH:N.CH:C-) or isoxazol-5-yl (0.N:CH.CH:C-) or isoxazol-4-yl, (CH:N.0.CH:C-) or isoxazol-3-yl, (CH:CH.O.N:C-) or

thiazol-2-yl, (S.CH:CH.N:C-) or thiazol-4-yl, (N:CH.S.CH:C-) or thiazol-5-yl, (S.CH:N.CH:C-) or isothiazol-5-yl, (S.N:CH.CH:C-) or isothiazol-4-yl, (CH:N.S.CH:C-) or isothiazol-3-yl, (CH:CH.S.N:C-) or [l,2,4]triazolyl-lyl, (CH:N.CH:N.N-) or lH-[l,2,4]triazol-3-yl, (N:CH.NH.N:C-) or [l,2,4]oxadiazol-3-yl, (N:CH.O.N:C-) or [l,2,4]oxadiazol-5-yl, (O.N:CH.N:C-) or 5-methyl-[1,2,4]oxadiazol-3-yl, (N:C(CH3).O.N:C-) or lH-tetrazol-5-yl, (NH.N:N.N:C-); - an alkoxy (RiO-) or alkylthio (RiS-) group in which radical Ri represents:
a C1-C5 alkyl radical as previously
defined,
a monofluoromethyl or trifluoromethyl
radical,
a cyclopropyl, cyclobutyl, or
cyclopentyl radical;
a amino group of type II F2
R3
in which R2 and R3, identical or different, represent hydrogen, a C1-C5 alkyl radical as previously defined, a cyclopropyl group, or a trifluoromethyl group;
a saturated cyclic amino group of type
(Formula Removed)
in which n may be whole numbers 1 or 2;

an alkoxycarbonyl group, preferably a methoxycarbonyl group (CH30C0-), or an ethoxycarbonyl group (CH3CH2OCO-) ;
under a form adapted for an administration by oral route, for the curative treatment of chronic pain symptoms of neuropathic or psychogenic origin.
2. The fumarate salt, as claimed in claim 1, wherein compound (I) conforms to formula (I) in which: A is either a hydrogen atom or an aminomethyl group, u represents a methyl radical CH3, both v and w are hydrogen atoms, X represents a fluorine atom, y is a chlorine atom, and Z an atom of fluorine.
3. The fumarate salt, as claimed in claim 1, wherein compound (I) conforms to formula (I) in which: A is a hydrogen atom, u represents a methyl radical CH3, both v and w are hydrogen atoms, X represents a fluorine atom, y is a chlorine atom, and Z an atom of fluorine.
4. The fumarate salt, as claimed in claim 1, which is intended for the preventive and curative treatment of chronic pain symptoms of neuropathic or psychogenic origin.