The present invention concerns derivatives of
aminocyclobutane as well as their method of preparation and
their use in human therapy.
5 Glutamate receptors of the NMDA subtype (N-methyl-D-
10
aspartic acid) are ionotropic receptors, mainly permeable to
Ca'+ ions. Physiologically, their activation triggers the
opening of an ion channel and the production of an incoming
current which is only slowly inactivated. Stimulation of
this receptor requires the simultaneous presence of
glutamate (endogenous agonist) and glycine or D-serine
(endogenous co-agonists) as well as depolarisation of the
plasma membrane initiated by non-NMDA currents. The NMDA
receptors are widely spread throughout the central nervous
15 system and are also present at the periphery. They are found
in the neurones, astrocytes and oligodendrocytes (Karadottir
et al., 2005, Nature, 438, 1162-1166). At the neuronal
level, they are located mainly in the post-synapse but also
in extra-synaptic regions along the axons. The NMDA
20 receptors play a key role in communication and in neuronal
plasticity as well as in excitotoxicity.
The physiological activity of the NMDA receptors is
essential for normal neuronal function (Chen and Lipton,
2006, J. Neurochem., 97, 1611-1626). On the other hand, over
25 activation of these receptors is involved both in acute
neuronal disorders, for example strokes or cranial traumas,
and in chronic stress conditions, for
neurodegenerative di\sorders. It is also one of
causes of hyperexcitation leading to epilepsy
example
the main
seizures.
30 There are numerous pathologies considered to be associated
with NMDA receptor hyperactivity and therefore potentially
sensitive to NMDA antagonists. The following can be given as
examples: epilepsy, neurodegenerative disorders such as
Huntington's disease, Parkinson's disease, Alzheimer's
disease, strokes, amylotrophic lateral sclerosis or multiple
5 sclerosis, AIDS-related dementia, anxiety, depression and
pain syndromes.
10
In the present invention, the Applicant focuses in
particular on the anti-depressant and analgesic properties
of NMDA receptor antagonists of formula (1) .
In the context of the present invention, the term
"chronic pain" designates painful syndromes which progress
over a period of more than three months but whose severity
can vary over the course of time. On the other hand, the
term "acute pain" designates pain which lasts less than
15 three months.
Within the scope of the present invention, pain is
defined as an abnormal, unpleasant, even distressing,
sensory and emotional experience which is perceived and
integrated at the highest level of the cerebral cortex,
20 which gives it an emotional and affective nature. By
"analgesia", we refer to a decrease in the intensity of the
pain felt in response to a painful stimulus. By "analgesic
medication" (or "analgesics"), we refer to a medication
which relieves or suppresses the pain without leading to a
25 loss of sensation or consciousness.
Pain of differing
therapeutic strategies.
aetiologies
In general,
requires different
there are several
categories of pain depending on the mechanisms involved:
pain due to excessive nociception resulting from
30 lesions or excitation (for example inflammation) of the
peripheral or visceral tissuesi
lesion
4
neuropathic (or neurogenic)
or to dysfunctioning or
pain is related
disruption of
to a
the
somatosensory system; it differs from nociceptive pain in
that it has a different semiology;
5 - psychogenic (or idiopathic pain) is pain which exists
in the absence of lesions. The physiological mechanisms of
this type of pain are not clearly defined. It is generally
resistant to analgesics.
Nevertheless, certain pains have characteristics that
10 are common to several types of pain. For example, this is
the case for lower back or cancer pain which present in the
form of pain caused by excessive nociception, or in the form
of neuropathic pain or, in most cases, a mixture of the two.
Depression is defined in psychiatry as a mood disorder.
15 It is characterised by a loss of motivation associated or
not with different symptoms such as hopelessness, low selfesteem,
anxiety, anguish and, in extreme cases,
hallucinations. It is often multi-factorial and generally
has multiple causes.
20 It is reported that approximately 7 % of Europeans
suffer from depression and that a third of these are
resistant to clinically used antidepressants. The cost of
depression in the 15-44 year old age group for society is
among the highest of all known pathologies. One objective of
25 the present invention is to describe new NMDA antagonists
which have advantageous properties in this indication for
which existing treatments are not entirely satisfactory.
30
It has been shown in mice that chronic administration
of antidepressants which have different mechanisms of action
(monoamine oxidase
reuptake inhibitors
inhibitors,
(SSRI) , or
tricyclics, serotonin
mixed serotonin and
5
noradrenalin reuptake inhibitors) modifies the distribution
and density of the NMDA receptors. In rats, acute
administration by intraperitoneal route of ketamine, an NMDA
receptor antagonist, reduces the immobility time in the
5 forced swimming test, a recognised pre-clinical model for
detecting the antidepressant activity of molecules. In
addition, recent studies indicate that ketamine has
antidepressant properties in humans. Thus administration of
a single sub-anaesthetic dose of ketamine by intravenous
10 route to patients with resistant depression significantly
improves their condition and this just 2 hours after
injection. The antidepressant effects obtained moreover last
over a week (Zarate et al., 2006, Arch. Gen. Psychiatry, 63,
856-864). The rapidity of this action contrasts with the
15 time taken for a reaction to occur with conventional
antidepressants, in other words first-generation tricyclics,
and the SSRis or SNRis which require several weeks of
treatment before any beneficial effect is obtained. It
therefore seems that NMDA receptor antagonists, and in
20 particular ketamine, are effective in the treatment of
depression, especially in the treatment of depression
resistant to existing medications.
The therapeutic requirements of pain treatment are
considerable. In fact, an incalculable number of individuals
25 suffer from acute pain and over one in five adults both in
Europe and the United States suffer from chronic pain
(Johannes et al., 2010, J. Pain, 11, 1230-1239). The object
of the present invention is to describe the advantageous
analgesic properties that the compounds of formula (1)
30 possess as well as the therapeutic perspectives they open up
in the treatment of acute and chronic pain.
6
Many studies on animals and humans have shown that NMDA
receptor antagonists such as ketamine can alleviate many
aetiological types of pain such as, for example,
neuropathic, postoperative or cancer pain (Cohen et al.,
5 2011, Adv. Psychosom. Med., 30, 139-161) Thus ketamine by
intravenous route reduces neuropathic pain in patients
resistant to treatment by conventional antidepressants. It
also improves allodynia and hyperalgia in patients with CRPS
(complex regional pain syndrome) (Finch et al., 2009, Pain,
10 146, 18-25). As an adjuvant, perioperative administration of
a low dose of ketamine reduces the consumption of analgesics
and limits acute morphine tolerance following surgery (Elia
et Tramer, 2005, Pain, 113, 61-70). As preventive treatment,
ketamine and dextromethorpan (another NMDA antagonist)
15 improve the management of postoperative pain (Muir, 2006,
Current Opinion in Pharmacology, 6, 53-60). Ketamine also
seems to prevent the occurrence of chronic postoperative
pain (Wilder-Smith et al., 2002, Pain, 97, 189-194). The
results obtained with other NMDA antagonists such as
20 amantadine or MK-81 in neuropathic pain are nonetheless nonconclusive
(Muir, 2006, already cited).
Opening of the NMDA channels causes an increase in
intracellular calcium which activates, among others, NO
synthetase and type II cyclooxygenase, leading to
25 prostaglandin synthesis (PGs). By inhibiting the PGs,
especially PGE2, NMDA antagonists thus have a direct impact
on the regulation of .inflammatory conditions (Beloeil et
al., 2009, Anesth. Analg., 109, 943-950). This complementary
anti-inflammatory activity of the NMDA antagonists can be
30 advantageous in the treatment of acute or chronic pain of
inflammatory origin. Similarly, NMDA receptors are expressed
7
in the chondrocytes and contribute to the mechanical
function of cells (Salter et al., 2004, Biorheology, 41,
273-281). In particular, they appear to be involved in their
proliferation and in inflammation leading to the destruction
5 of joint cartilage (Piepoli et al., 2009, Osteoarthritis and
Cartilage, 17, 1076-1083). As the latter is not regenerated
in adults, use of an NMDA antagonist therefore seems to be
particularly advantageous in preventing or slowing down the
destruction of joint cartilage that accompanies certain
10 pathological conditions, such as, for example, inflammatory
monoarthri tis, rheumatoid arthritis, septic arthritis,
osteoarthritis, rheumatoid arthritis, gout,
spondylarthritis, acute abarticular rheumatism.
Nevertheless, the clinical usefulness of NMDA
15 antagonists in humans is limited by their unwanted effects,
in particular on the central nervous system, and especially
in the course of repeated treatment. Among the side effects
of NMDA antagonists, we can cite for example:
hallucinations, confusion, personality disorders,
20 nightmares, agitation, lack of concentration, mood changes,
convulsions, sedation, somnolence,
Tymianski, 2003, Biochem. Pharmacal.,
nausea (Aarts et
66, 877-886). These
side effects result from the fact that NMDA antagonists
block not only the excessive activation of the
25 glutamate/NMDA system but also disrupt its normal
physiological function. It therefore appears to be essential
in practice to improve the risk-benefit ratio of clinically
available NMDA antagonists.
When the type of pain to be treated is sui table, for
30 example in the case of arthritis, the risk-benefit ratio of
the NMDA antagonist can be improved by limiting its action
8
on the central nervous system, for, example by means of
topical application. The concentration of the compound in
the target tissue is therefore very much higher than its
concentration in the blood, thus reducing the risk of
5 toxicity. Consequently, several NMDA antagonists have been
studied by epidural or topical route. Ketamine applied
locally has been shown to be effective in the treatment of
neuropathic pain not alleviated by conventional medications.
Different associations of an NMDA antagonist and one or more
10 other analgesic agents have also been studied in local
application. For example, ketamine or other NMDA antagonists
have been combined with antidepressants or antihypertensives
(US 6 387 957); anti-epileptics (WO 03/061656, WO 98/07447,
WO 99/12537, US 20040204366, WO 2010036937); adrenergic
15 agonists (US 20040101582); or opioids (WO 2000003716).
Given the vi tal role played by NMDA receptors in a
number of psychiatric and neurological disorders, they have
been the subject of intensive research and a multi tude of
antagonists/blockers/modulators have been described. They
20 can be broadly claS'sified in three main groups as a function
of their site of action on the NMDA receptor. They therefore
include:
1. Competitive antagonists targeting either the
glutamate binding site, for example selfotel, perzinfotel
25 and the prodrugs (WO 2009029618) or the glycine binding
sites for example gavestinel, GV-196771 (Wallace et al. ,
2002, Neurology, 59, 1694-1700) and the quinolines reported
in patent application WO 2010037533. This category also
includes partial agonists of the glycine sites such as D-
30 cycloserine (US 2011160260) .
9
2) Non-competitive (or allosteric) antagonists which
act on many modulator sites of receptor regulation, such as,
for example, the polyamine and phenyl ethanolamine sites.
Compounds belonging to this family are currently the most
5 clinically studied. One of the top contenders is ifenprodil
( 23 210-56-2) and more selective derivatives of the latter
for the NMDA receptor are currently undergoing clinical
evaluation such as, for example, traxodopril, RGH-896, MK-
0657, EVT-101 and EVT-103
10 Pharmacal., 157, 1301-1317).
(Mony et al., 2009, Br. J.
15
3) Non-competitive antagonists, channel pore blockers.
This is the family which has had the most success clinically
because ketamine (9 (Ketalar , anaesthetic/analgesic) ,
dextromethorphan (Atuxane"', antitussive), memantine (Ebixa®,
anti-Alzheimer) , amantadine (Mantadix®, antiviral then
antiparkinsonian) , felbamate ® (Taloxa , anticonvulsant) are
commercially available. Phencyclidine ® (Sernyl ) developed as
an anaesthetic has been withdrawn from the market and
dizocilpine (MK-801) is not commercially available as a
20 medication.
The compounds of the invention belong to this latter
family of non-competitive antagonists which block the NMDA
receptor channels. A major advantage of compounds of this
type resides in the fact that they do not block the channel
25 except when it is open; they are therefore more effective
the more excessive the NMDA receptor activity. We can also
easily see that the biophysical characteristics of the
blocker/antagonist, which affects the frequency and duration
of channel opening, will play a critical role in its
30 pharmacological activity and its risk/benefit ratio. Several
compounds of this type have been clinically studied such as,
10
for example, CNS-5161 (160754-76-7), neramexane (219810-59-
0), dimiracetam (126100-97-8), V-3381 (1104525-45-2), NEU-
2000 (640290-67-1). Others are at the pre-clinical stage,
among which we cite as examples the oxazolidines claimed in
5 patent application WO 2009092324, indanes (WO 2009069610),
10
15
diarylethylamines
(WO 2010142890) I
(WO 2010074647) I arylcyclohexylamines
ketamine and phencyclidine analogues
(Zarantonello et al., 2011, Bioorg. Med. Chem. Lett., 21,
2059-2063).
The present invention concerns the derivatives
represented by general formula (1):
( 1)
wherein:
20 - X1 represents a hydrogen atom or fluorine atom;
- X2 is a hydrogen atom or fluorine atom or chlorine
atom;
- R1 represents a hydrogen atom or fluorine atom or
chlorine atom or methyl group or methoxy group or cyano
25 group;
- R2 represents independently or together a methyl
group or ethyl group.
Preferably, the compounds of general formula (1)
according to the invention are those in which:
30 - X1 represents a hydrogen atom or fluorine atom;
11
- X/. is a hydrogen atom or fluorine atom or chlorine
atom;
- R1 a hydrogen atom or fluorine atom or chlorine atom
or methyl group or methoxy group or cyano group;
5 - R2 is an ethyl group.
The compounds of the invention may intervene as pure
diastereoisomers or as mixtures of diastereoisomers. More
specifically, the invention relates to pure diastereoisomers
in which the 1-carboxamide group and the 3-amino group
10 occupy opposite sides of the plane defined by cyclobutane.
15
This stereochemical relationship between said substituents
is termed 'trans' in the present invention. The invention
therefore relates to pure trans diastereoisomers of the
following products:
- trans-3-amino-N,N-diethyl-1-
phenylcyclobutanecarboxamide,
- trans~3-amino-N,N-dimethyl-1-
phenylcyclobutanecarboxamide
- trans-3-amino-N,N-diethyl-1-(2-fluorophenyl)-
20 cyclobutanecarboxamide,
- trans-3-amino-N,N-diethyl-1-(3-methoxyphenyl)cyclobutanecarboxamide,
- trans-3-amino-N,N-diethyl-1-(3-fluorophenyl)cyclobutanecarboxamide,
25 - trans-3-amino-N,N-diethyl-1-(3-chlorophenyl)-
cyclobutanecarboxamide,
- trans-3-amino-N,N-diethyl-1-(3-methylphenyl)cyclobutanecarboxamide,
- trans-3-amino-N,N-diethyl-1-(3-cyanophenyl)-
30 cyclobutanecarboxamide,
5
10
12
- trans-3-amino-N,N-diethyl-1-(2-fluoro-3-
chlorophenyl)-cyclobutanecarboxamide,
- trans-3-amino-N,N-diethyl-1-(2,5-difluorophenyl)cyclobutanecarboxamide,
- trans-3-amino-N,N-diethyl-1-(3,5-difluorophenyl)-
cyclobutanecarboxamide,
- trans-3-amino-N,N-diethyl-1-(3,5-dichlorophenyl)cyclobutanecarboxamide.
as well as their pharmaceutically acceptable salts.
The term "pure diastereoisomers" designates that the
'trans' diastereoisomer of the compound of general formula
(1) contains less than 5 % of the 'cis' diastereoisomer, in
other words the one in which the 1-carboxamide group and the
3-amino group occupy the same half-space of the plane
15 defined by cyclobutane.
The term "diastereoisomers" designates in the context
of the present invention stereoisomers which are not mirror
images of each other.
The term "steroisomers" designates in the context of
20 the present invention isomers of identical constitution but
which differ in terms of the arrangement of their atoms in
space.
The closest state of the technique is represented by
the derivatives described in patent application
25 WO 2003063.797 and having the following formula:
30
wherein:
13
m and p are independently equal to 0, 1, 2 or 3;
The dotted line represents a double bond when R1a is
absent;
R1 can be a NR6R7 group with R6 and R7 possibly
5 representing a hydrogen atom;
R1a can be a hydrogen atom;
R2 can be an aryl group substituted or unsubstituted;
J can be a bond;
R3 can be a -C (Z,) -R, group with possibly_
10 representing a NR6aR7a group;
and possibly represent an alkyl group
substituted or unsubstituted and Z1 possibly represents a
carbonyl group (C=O);
Rx can be one or several substituted or non-attached
15 group(s) to all the available carbon atoms in the ring but
also a hydrogen atom.
This patent application therefore covers a considerable
number of compounds, the large majority of which are of the
cyclobutane type (m = 0 and p = 1) . Among the latter only
20 four are given as examples in said patent. This concerns the
compounds of the following formula:
F
25
30 wherein G is a or
/
0
~~ H
or or
14
The compounds in this patent application are

claimed as
inhibitors of the current produced by type Kv1 voltagedependent
potassium channels and in particular the current
produced by isoform Kv1.5.
5 They are presented as useful in a broad range of
indications that does not include the treatment of
depression or pain.
It is important to mention that the compounds of the
present invention do not interact with the potassium
10 channels and in particular with type Kv1.5 channels.
Moreover, the NMDA antagonist activity of the compounds of
the invention is found to be highly sensitive to structural
changes in the compounds of formula ( 1) . Thus the NMDA
antagonist activity is suppressed when:
15 1) The 1-carboxamide group is reduced to a 1-
aminomethyl group, such as that of the cyclobutane compounds
of patent WO 2003/063797;
2) The amino group in position 3 on cyclobutane is
different from a primary amine group (NH2 ) . In patent
20 application WO 2003063797, the 3-amino group is substituted
by a C(G)=NCN group;
3) The "cis" stereochemistry between the 1-aryl and 3-
amino groups is not present. In fact when the 1-aryl and 3-
amino groups are in "trans" stereochemistry, the
25 corresponding compounds have no affinity for the NMDA
receptor.
30
The state of the technique is also represented by the
derivatives described in patent application WO 99/52848 and
corresponding to the following formula:
R3
X
5
15
wherein:
X is different from a hydrogen atom;
A can be an NR7 group with R7 different from a hydrogen
atom;
R3 can be a C ( 0) NR8R10 group in which R8 and R1o can be
C1-C4 alkyl chains. Said compounds are claimed as being
10 selective inhibitors of type 4 phosphodiesterases, useful
for treating inflammatory and autoimmune diseases. The
compounds of the present invention therefore differ from
those described in application wo 99/52848 in terms of both
their chemical structure and their pharmacological activity.
15
20
25
The state of the technique is also represented by the
derivatives described in patent application WO 2010/112597
and having the general formula:
wherein:
a can be a single bond;
Ar represents a phenyl group substituted or
unsubstituted, or a pyridine-3-yl core substituted by one or
more halogen atom or alkyl groups or alkoxide groups or by a
cyano group;
R1 and R2 can represent independently or together a cl-
30 c6 alkyl group.
16
Contrary to the compounds of patent application
WO 2010/112597, those of the present invention do not have
affinity for the serotonin and noradrenalin reuptake sites.
The compounds of formula ( 1) therefore differ from those
5 described in application WO 2010/112597 not only in terms of
their chemical structure but also in terms of their
pharmacological activity.
The state of the technique is finally represented by the
compounds described in patent application WO 2000/051607 and
10 having the general formula:
R2
15
N
I
R1
R12
R13
wherein R12 and R13 represent a C1 -C6 alkyl group or a C2-C6
20 alkenyl group or a C2-C6 alkynyl group substituted or
unsubstituted.
Said derivatives are chemokine modulators useful in the
prevention or treatment of certain inflammatory or immune
system diseases. Here again the compounds of the present
25 invention thus differ from those described in application
WO 2000/051607, in terms of both their chemical structure
and their pharmacological activity.
The present invention also covers salts of the
derivatives of general formula (1) with pharmaceutically
30 acceptable organic or mineral acids. In the present
invention, the term "pharmaceutically acceptable" refers to
17
molecular entities and compositions which have no adverse or
allergic effect or any unwanted reaction when administered
to humans. When used here, the term "pharmaceutically
acceptable excipient" includes any diluents, adjuvants or
5 excipients, such as preservatives, fillers, disintegrating
agents, wetting agents, emulsifiers, dispersing agents,
antibacterial or antifungal agents, or even agents which
help delay intestinal and digestive absorption and
resorption. The use of these media or carriers is well known
10 to the person skilled in the art. The term "pharmaceutically
acceptable salts" of a compound refers to the salts defined
here and which possess the pharmacological activity of the
parent compound. Such salts include: acid addition salts
formed with mineral acids, such as hydrochloric acid,
15 hydrobromic acid, sulphuric acid, nitric acid, phosphoric
acid and similar, or formed with organic salts, such as
acetic acid, benzensulphonic acid, benzoic acid,
camphorsulphonic acid, citric acid, ethanesulphonic acid,
fumaric acid, glucoheptonic acid, gluconic acid, glutamic
20 acid, glycolic acid, hydroxynaphtoic acid, 2-
hydroxyethanesulphonic acid, lactic acid, maleic acid, malic
acid, mandelic acid, methanesulphonic acid, muconic acid, 2-
napthalenesulphonic acid, proprionic acid, salicylic acid,
succinic acid, dibenzoyl-L-tartic acid, tartric acid, p-
25 toluenesulphonic acid, trimethylacetic acid, trifluoroacetic
acid and similar.
The pharmaceutically acceptable
solvent (solvates) addition forms or
(polymorphs), such as defined here,
30 addition salt.
salts also include
crystalline forms
of the same acid
18
The present invention also covers compounds of formula
(1) as well as their pharmaceutically acceptable salts for
use as medication.
The present invention concerns compounds of formula (1)
5 as well as their pharmaceutically acceptable salts for use
as NMDA receptor antagonists.
The present invention also concerns compounds of formula
(1) as well as their pharmaceutically acceptable salts for
use as medication intended for the treatment and/or
10 prevention of depression.
The present invention also concerns compounds of formula
(1) as well as their pharmaceutically acceptable salts for
use as medication for the treatment of pain, especially pain
due to excessive nociception, neuropathic pain and mixed
15 pain.
Among the types of pain potentially sensitive to the
action of compounds of general formula (1), we can cite more
particularly as non-limiting examples:
Peripheral or central neuropathic pain resulting from
20 nerve lesions of traumatic origin (for example stroke),
metabolic· origin (for example diabetes), infectious origin
(for example HIV, shingles, herpes) , trigeminal neuralgia,
pain due to chemotherapy and/or radiotherapy;
- inflammatory pain, for example rheumatoid arthritis,
25 septic arthritis, osteoarthritis, polyarthritis, gout,.
spondylarthritis, acute abarticular rheumatism, visceral
pain, for example irritable bowel syndrome, Crohn's disease;
Pain due to excessive nociception, such as
posttraumatic pain, postoperative pain, burns,
30 twisting/distension, renal or hepatic colic attacks, joint
pain, arthritis, spondylarthropathies;
19
- Mixed pain such as cancer pain, back and lower back
pain or other types of pain that are difficult to classify
such as headaches, fibromyalgia,
vascular/ischemic problems such
5 disease.
pain associated with
as angina, Reynaud's
The present invention also concerns compounds of formula
(1) as well as their pharmaceutically acceptable salts for
use as medication for the treatment and/or prevention of
inflammation of the joints. Among the types of inflammation
10 potentially sensitive to the action of the compounds of
general formula (1), we can more particularly cite as a nonlimiting
examples:
arthritis, septic
polyarthritis, gout,
15 rheumatism.
inflammatory monoarthritis, rheumatoid
arthritis, osteoarthritis rheumatoid
spondylarthritis, acute abartricular
The present invention moreover concerns a pharmaceutical
composition characterised in that it contains at least one
compound of general formula (1) or one of its
pharmaceutically acceptable salts as the active principle.
20 The invention also covers a pharmaceutical composition
characterised in that it includes at least one compound of
general formula ( 1) or one of its pharmaceutically
acceptable salts and at least one pharmaceutically
acceptable excipient.
25 The invention also covers a pharmaceutical. composition
for use as a medication for the treatment and/or prevention
of depression.
The invention further covers a pharmaceutical
composition for use as a medication for the treatment of
30 pain, particularly pain caused by excessive nociception, and
neuropathic and mixed pain.
20
The pharmaceutical compositions according to the present
invention can be formulated for administration to humans.
These compositions
administered by
are produced such that
oral, sublingual,
they can be
subcutaneous,
5 intramuscular, intravenous, transdermal, local or rectal
route. In this case, the active ingredient can be
administered in administration unit forms, mixed with
conventional pharmaceutical supports, to
Suitable administration unit forms include
human beings.
forms by oral
10 route such as tablets, capsules, powders, granules and oral
solutions or suspensions, sublingual and buccal forms of
administration,
intravenous,
subcutaneous,
intranasal or
topical, intramuscular,
intraocular forms of
administration and rectal forms of administration.
15 Advantageously, the pharmaceutical composition according
20
to the present invention is formulated for administration by
oral or topical route. Administration by topical route is
the preferred route for the treatment of certain types of
pain, such as for example joint pain.
The term topical administration refers to local
administration to the skin or mucous membrane.
Suitable formulations for the administration form chosen
are known to the person skilled in the art and are described
for example in: Remington, The Science and Practice of
25 Pharmacy, 19th edition, 1995, Mack Publishing Company.
30
When a solid composition in the form of tablets is
prepared, the principle active ingredient is mixed with a
pharmaceutical carrier such as gelatine, starch, lactose,
magnesium stearate, talc, gum arabica, silica or similar.
The tablets can be coated with saccharose or other
appropriate materials, or they can be treated such that they
21
have prolonged or delayed activity and release a
predetermined amount of active principle in a continuous
manner.
A capsule preparation is obtained by mixing the active
5 ingredient with a diluent and pouring the mixture obtained
into soft or hard capsules.
A preparation in the form of a syrup or elixir can
contain the active ingredient along with a sweetener and an
antiseptic, as well as a flavouring agent and a suitable
10 dye.
Powders or granules that are dispersible in water can
contain the active ingredient mixed with dispersing agents
or wetting agents, or suspending agents, as well as with
flavour correctors or sweeteners.
15 For rectal administration, suppositories are used which
are prepared with binding agents that dissolve at rectal
temperature, for example cocoa butter or polyethylene
glycols.
For parenteral (intravenous, intramuscular, intradermal,
20 subcutaneous) , intranasal or intraocular administration,
aqueous suspensions, isotonic saline solutions or sterile
and injectable solutions are used which contain dispersing
agents and/or pharmacologically compatible wetting agents.
The active ingredients can also be formulated as
25 microcapsules, possibly with one or more additive supports
if necessary.
Topical administration of the pharmaceutical composition
can be obtained by application of a solution, dispersion,
gel, lotion, milk, ointment, salve cream, drops or other
30 carrier used for topical application and well known to the
person skilled in the art. One possible method is the
22
administration of the pharmaceutical .composition by means of
an aerosol spray allowing fine liquid droplets to be sprayed
for distribution over the entire surface to be treated or,
to the contrary, to restrict this precisely to a particular
5 zone to be treated, or in a solid form such as a stick.
Another example is a patch or strip which allows continuous
release of the topical composition. The patch can be a
reservoir and a porous membrane or solid matrix well known
to the person skilled in the art. Other modes of
10 administration such as iontophoresis or electroporation can
also be used.
15
The compositions described in this invention can also
include ingredients or compounds usually mixed with such
topical preparations,
include additional
for example the compositions can also
ingredients
moisturisers, oils, fats, waxes,
agents, antioxidants, viscosity
such as
surfactants,
stabilisers,
carriers,
thickening
chelating
agents, buffers, preservatives, perfumes, colorants,
humectants, emollients, dispersing agents, sun creams with
20 compounds blocking radiation and particularly UV blockers,
antibacterials, antifungals, disinfectants, vitamins,
antibiotics or other anti-acne agents, as well as other
adapted substances with no harmful adverse effect on the
activity of the topical composition. For example, additional
25 ingredients can be used such as sodium acid phosphate, witch
hazel extract, glycerine, apricot kernel oil, maize oil. In
addition to the compounds described above, compositions of
the present invention can optionally contain other
ingredients. For example triethanolamine can be added as a
30 reticulating agent. A preservative such as butylated
hydroxytoluene can also be added. Other irritation reducing
23
agents can also be added; in this respect this includes but
is not limited to glycerol. For topical administration, the
compositions can contain conventional emollients and
emulsifiers including alginates, glyceryl stearate, PEG-100
5 stearate, ketyl alcohol, propylparaben, butylparaben,
sorbitols, ethoxylated anhydrosorbitol monostearate (TWEEN),
white petrolatum (Vaseline), triethaolamine, emu oil, aloe
vera, lanolin, cocoa butter and other extracts.
The compositions described can be applied to the
10 patient's skin area to be treated. The frequency of
application will depend on circumstances and the patient.
For example the compositions can be applied daily, twice a
day or even more frequently.
The doses of a compound of general formula (1) or one of
15 its pharmaceutically acceptable salts in the composition of
the invention can be adjusted in order to obtain a quantity
of substance that is effective in achieving the desired
therapeutic response for a composition specific to the
administration method. The effective dose of the compound of
20 the invention varies as a function of numerous parameters
such as, for example, the administration route chosen,
weight, age, sex, type of disease, sensitivity of the
individual to be treated. Consequently the optimum dosage
can be established by the specialists in the field as a
25 function of parameters the specialist considers to be
relevant. Although the effective doses can vary within broad
proportions, the daily doses can be scaled between 1 mg and
1000 mg per 24 h for an adult of average weight of 70 kg, in
one or more divided doses.
24
Finally the invention includes the method for synthesis
of products of the compounds of general formula (1) as well
as those of synthesis intermediates of formula (C) and (D) .
The compounds of general formula (1) can be obtained by
5 the process described in the reaction diagram hereafter.
(A)
EtOCOCI
(B)
(D)
Xz x1
iPrMgCI
0
~CI
XC02H
R1 y
avo
0
(F)
(B) OH
iPrMgCI
HN(R2)2
Reaction diagram
Xz
~x1o
R1V··~~-R2 y R2
OH
(D)
NH2
(1)
25
The preparation of the compounds of the invention uses
as starting material derivatives of benzeneacetic acid of
formula (A) that are commercially available such as:
5 benzeneacetic acid (RN 103-82-2); 2-fluorobenzene-acetic
acid (RN 451-82-1) ; 3-fluorobenzeneacetic acid (RN 331-25-
9); 3-chlorobenzeneacetic acid (RN 1878-65-5); 3-
methylbenzeneacetic acid (RN 621-36-3); 3-cyanobenzeneacetic
acid (RN 1878-71-3); 3-methoxybenzeneacetic acid (RN 1798-
10 09-0); 2,5-difluorobenzeneacetic acid (RN 85068-27-5); 3,5-
difluorobenzeneacetic
dichlorobenzeneacetic
acid
acid
(RN 105184-38-1); 3,5-
(RN 51719-65-4); 2-fluoro-3-
chlorobenzeneacetic acid (RN 261762-96-3) . The derivatives
of formula(A) are condensed with epichlorhydrin according to
15 a method adapted from that described in patent application
WO 2007/038452 to give derivatives of formula (B) in which
the alcohol and carboxylic acid groups show 'cis'
stereochemistry. Said patent does not describe the
intermediates of formula (B) . The lactones of formula (C)
20 are then formed from derivatives of formula (B) by using a
conventional method of activation of the acid group, for
example such as using an alkyl chloroformiate as described
in application WO 2008/092955. Opening of the lactone of
formula (C) is then advantageously carried out using the
25 magnesium salt of the appropriate secondary amine according
to Williams et al. (Tetrahedron Lett., 1995, 36, 5461-5464)
to produce the corresponding carboxamide of formula (D) .
Introduction of the primary amine group in position 3 of
cyclobutane with inversion of the stereochemistry can be
30 achieved through the intermediate of the azide of formula
(E) according to Soltani Rad et al. (Tetrahedron Lett.,
26
2007, 48, 3445-3449) . Reduction of the azido group to the
corresponding primary amine is then achieved either by
catalytic hydrogenation or by a Staudinger reaction.
Alternatively conversion of the compound of formula (D) into
5 the amine of formula ( 1) can be carried out through the
intermediate of phthalimide of formula (F) according to
Gabriel's conventional method (for example application WO
2006081179).
The following examples illustrate the invention without
10· being limiting. In the examples below:
(i) different crystalline shapes can give rise to
different melting points; the melting points reported in
this application are those of the products prepared
according to the methods described and are not corrected;
15 (ii) the structure of the products obtained according
20
to the invention is confirmed by the nuclear magnetic
resonance (NMR) spectra and by mass spectrometry; the purity
of the final product is verified by TLC and centesimal
analysis;
(iii) the NMR spectra
given: chemical shifts (8)
million (ppm) relative
multiplicity of signals is
doublet; t, triplet; q,
are recorded in the solvent
are expressed in parts per
to tetramethylsilane; the
indicated by: s, singulet; d,
quadruplet; qu, quintuplet,
25 m, multiplet; 1, large;
(iv) the different symbols for units have their usual
meaning: pg (microgram); mg (milligram); g (gram); mL
(millilitre); mv (millivolt); oc (degrees Celsius); mmol
(millimole; nmol (nanomol); em (centimetre); nm (nanometre);
30 min (minute); ms (millisecond), Hz (hertz);
1-
5
27
(v) the abbreviations have the following meaning: Mp
(melting point); Bp (boiling point);
(vi) the term "ambient temperature", refers to a
temperature between 20°C and 25°C.
Example 1: trans-3-amino-N,N-diethyl-1-
phenylcyclobutanecarboxamide (1a1)
Step 1: cis-1-phenyl-3-hydroxy-cyclobutanecarboxylic acid
10 (B1)
Place 2.2 eq of isopropylmagnesium chloride in a threenecked
flask and cool the reaction medium to 0°C. Add 1 eq
of phenylacetic acid diluted in THF; the temperature must be
kept between 40 and 50°C. Cool the medium to 20°C and add
15 1. 8 eq of epichlorhydrin; the temperature must be kept
between 20 and 25°C, and stir at this temperature for
45 min. Next, add 2 eq of isopropylmagnesium chloride (2M in
THF) dropwise and stir at room temperature for 2 h. Next
heat the reaction medium to 60°C for 19 h. Allow the medium
20 to cool then acidify with an HCl solution (1N) to pH 1. Add
dichloromethane (DCM) and extract. Decant, dry the organic
phase over Mg804 , then evaporate the DCM under reduced
pressure. Purify the residue by flash chromatography with
the following eluent: DCM, then DCM/methanol 70:30. The
25 title product is obtained in the form of a pale yellow solid
(yield = 70 %) .
30
CnH1203 (molecular weight = 192) .
1H-NMR (DMSO d 6 , 400 MHz) o (ppm) 2. 50
2H, J = 9.4 Hz), 3.32 (s 1 1H), 3.85 (qu,
7. 22-7.38 (m, SH) 1 12.21 (s 1 1H)
SM-ESI: 193.1 (MH+).
(ml 2H), 2.74 (t,
1H I J = 7. 2 Hz) ,
28
Step 2: 4-phenyl-2-oxabicyclo[2.1.1]hexane-3-one (C1)
Place 1 eq of compound B1) in a flask, dilute in THF
and 1.03 eq of triethylamine. Stir at room temperature until
dissolved then cool the reaction medium to 0°C. Add 1 eq of
5 ethyl chloroformiate and stir at this temperature for 1 h
then bring back to room temperature
Evaporate THF under reduced pressure,
with ethyl acetate (AcOEt). Decant,
MgS04 , then evaporate under reduced
10 residue by flash chromatography with
and stir for 20 h.
take up the residue
dry the acetate on
pressure. Purify the
the following eluant:
heptane, then heptane/AcOEt 60:40. The title product is
obtained in the form of a colourless oil (yield = 87 %) .
CuH1o02 (MW = 174) .
1H-NMR (CDC1 3 , 400 MHz) 8 (ppm): 2. 71 (m, 2H), 2. 89 (m, 2H),
15 4.97 (s, 1H), 7.31-7.42 (m, 5H).
SM-ESI: 175 (MH+).
Step 3: cis-3-hydroxy-N,N-diethyl-1-
phenylcyclobutanecarboxamide (D1a)
Place 1 eq of compound ( C1) , 2 eq of diethylamine and
20 THF in a three-necked flask. Cool the reaction medium to
-20°C, then add 3 eq of isopropylmagnesium chloride dropwise
(2M in THF) keeping the temperature below -5°C. Stir the
mixture for 2 h at a temperature between -10 and -20°C.
Hydrolyze the reaction medium with a saturated NaCl solution
25 then add an HCl solution (1N) and extract with AcOEt. Dry
the organic phase over MgS04 , filter and concentrate. Purify
the residue by flash chromatography with the following
mixture as the eluant: DCM/methanol 85:15. The title product
is obtained in the form a pale yellow solid (yield = 99 %) .
30 C1sH21N02 (MW = 247).
29
1H-NMR (CDC1 3 , 400 MHz) 8 (ppm): 0.63 (t, 3H, J = 7.2 Hz),
1.08 (t, 3H, J = 7.2 Hz), 2.72 (m, 2H), 2.82 (m, 2H), 2.90
(q, 2H, J = 7.2 Hz), 3.21 (q, 2H, J = 7.2 Hz), 4.36 (qu, 1H,
J = 7.4 Hz), 7.21-7.36 (m, 5H). The signal corresponding to
5 the H in OH is not visible on the spectrum.
SM-ESI: 248 (MH+).
Step 4: trans-3-azido-N,N-diethyl-1-
phenylcyclobutanecarboxamide (Ela)
Place 1 eq of compound (D1a) , 1. 5 eq of N- (p-
10 toluenesulfonyl)imidazole, 2 eq of triethylamine, 0.025 eq
of tetrabutylammonium iodide, 3 eq of sodium azide and DMF
in a flask. Stir and heat the reaction medium at 160°C for
4 h. Pour the reaction medium onto ice water and extract
with ethyl ether. Dry the organic phase over MgS04 , filter
15 and concentrate. Purify the residue by flash chromatography
with the following mixture as the eluant: heptane/AcOEt
70:30. The title product is obtained in the form of a
colourless oil (yield = 65 %) .
C15H2oN40 (MW = 272).
20 1H-NMR (CDCl3 , 400 MHz) 8 (ppm): 0.52 (t, 3H, J = 7.2 Hz),
1.11 (t, 3H, J = 7.2 Hz), 2.47 (m, 2H), 2.89 (q, 2H, J = 7.2
Hz), 3.14 (m, 2H), 3.34 (q, 2H, J = 7.2 Hz), 3.96 (qu, lH,
J = 7.8 Hz), 7.23 (m, 3H), 7.35 (m, 2H).
25
SM-ESI: 273 (M+H+)
Step 5: trans-3-amino-N,N-diethyl-1-
phenylcyclobutanecarboxamide (1al)
Dissolve 1 eq of compound (Ela) in methan.ol in a flask.
Degas the solution for 30 min with nitrogen then add Pd/C
30 (20 % weight). Purge the system (cycle: vacuum/H2 gas) and
hydrogenate the reaction medium for 3 h at room temperature
30
with stirring. Filter the catalyst and evaporate the
solvent. Purify the residue by flash chromatography with the
following mixture as the eluant: DCM/methanol/NH40H: 90:9:1.
The title product is obtained in the form of a colourless
5 oil (yield = 70 %) •
C15H22N20 (MW = 246).
1H-NMR (DMSO d 61 400 MHz) 8 (ppm): 0.50 (t 1 3HI J = 7.2 Hz) I
1.10 (t, 3H, J = 7.2 Hz), 2.11 (m, 2H), 2.92 (ql 2HI J = 6.8
Hz) 1 3.12 (m1 2H) 1 3.32 (q, 2H, J = 6.8 Hz), 3.46 (qui 1HI J
!0 = 8.0 Hz), 7.18-7.35 (m, 5H). The signal corresponding to
the H in NH2 is not visible on the spectrum.
SM-ESI: 247 (MH+).
Maleate of the title compound
Salification of the previous compound by means of
15 maleic acid leads to obtaining Maleate of the title compound
in the form of a white powder.
Mp: 185°C.
1H-NMR (DMSO d61 400 MHz) 8 (ppm): 0.42 (tl 3H, J = 7.0 Hz),
1. 02 (t, 3H 1 J 7.0 Hz), 2.56 (m, 2H) I 2.85-2.96 (ml 4H) I
20 3125 (q, 2H 1 J 6.8 Hz), 3.54 (qui 1H1 J = 8.4 Hz), 6.03
(sl 2H) I 7.26 (m, 3H) I 7.39 (t, 2H, J = 7.6 Hz) 1 8.00 (s,
2H) . The signal corresponding to the H in NH2 is not visible
on the spectrum.
13C-NMR (DMSO d 61 100 MHz) 8 (ppm): 12.021 12.151 36.931
25 39.191 40.071 41.19, 46.61, 124.87, 126.511 128.71, 136.021
142.69, 167.191 171.10.
%Theoretical: C 62.97, H 7.23, N 7.73.
%Found: C 63.00, H 7.17, N 7.78.
30 Example 2: trans-3-amino-N,N-dimethyl-1-
phenylcyclobutanecarboxamide (1a2)
3!
Step 3: cis-3-hydroxy-N,N-dimethyl-1-
phenylcyclobutanecarboxamide (D1b)
Identical to step 3 described in Example 1, using
dimethylamine instead of diethylamine. The title product is
5 obtained in the form of a colourless oil (yield = 89 %) .
1H-NMR (CDC13 , 400 MHz) 8 (ppm): 2.65 (m, 2H), 2.55 (s, 3H),
2.95 (s, 3H), 2.80 (m, 2H), 4.27 (qu, 1H, J = 7.8 Hz), 7.19-
I
7.35 (m, 5H). The signal corresponding to the H in OH is not
visible on the spectrum.
10 Step 4: trans-3-azido-N,N-dimethyl-1-
phenylcyclobutanecarboxamide (E1b)
Identical to step 4 described in Example 1. The title
product is obtained in the form of a beige solid (yield =
95 %) •
!5 1H-NMR (CDC13 , 400 MHz) 8 (ppm): 2.50 (m, 2H), 2.54 (s, 3H),
2.96 (s, 3H), 3.18 (m, 2H), 3.97 (qu, 1H, J = 7.8 Hz), 7.24
(m, 3H), 7. 36 (m, 2H).
Step 5: trans-3-amino-N,N-dimethyl-1-
phenylcyclobutanecarboxamide (1a2)
20 Identical to step 5 described in Example 1. The title
product is obtained in the form of a colourless oil (yield =
84 %) •
C13H18N20 (MW = 218) .
1H-NMR (CDC1 3 , 400 MHz) 8 (ppm): 2.13 (m, 2H), 2.55 (s, 3H),
25 2.95 (s, 3H), 3.15 (m, 2H), 3.47 (qu, 1H, J = 7.8 Hz), 7.19-
7. 3 5 (m, 5H) . The signal corresponding to the H in NH2 is
not visible on the spectrum.
SM-ESI: 219 (MH+).
Maleate of the title compound
32
Salification of the previous compound by means of
maleic acid leads to obtaining Maleate of the title compound
in the form of a white powder.
Mp: 163°C.
5 1H-NMR (DMSO d61 400 MHz) 8 (ppm): 2. 51 (m, 5H), 2. 86 (s,
3 H) , 2 . 9 8 ( m, 2 H) , 3 . 3 6 ( s , lH) I 3 . 53 ( qu, lH 1 J = 8 . 4 Hz) 1
6.03 (s, 2H), 7.26 (m, 3H), 7.39 (t, 2H, J = 7.6 Hz), 8.05
(s, 3H).
10
13C-NMR
39.91,
(DMSO d6, 100 MHZ) 8 (ppm): 35.80, 37.20,
46.54, 124.941 126.591 128.72,
167.15, 171.68.
%Theoretical: C 61.07, H 6.63, N 8.38.
% Found: c 60.73, H 6.43, N 8.15.
136.00,
37.34,
142.43,
15 Example 3: trans-3-amino-N,N-diethyl-1-(2-fluorophenyl)cyclobutanecarboxamide
(lb)
Step 1: cis-3-hydroxy-1-(2-fluorophenyl)cyclobutanecarboxylic
acid (B2)
Identical to step 1 described in 1, by using 2-
20 fluorophenylacetic acid as the starting product. The title
product is obtained in the form of a white solid (yield =
49 %) •
CnHnF03 (MW = 210).
1H-NMR (CDCl31 400 MHz) 8 (ppm): 2.80 (m1 2H), 2.97 (m, 2H),
25 4. 29 (qu, lH, J = 6. 4 Hz), 7. 04-7.23 (m, 4H) . The signals
corresponding to the H in OH in the alcohol and acid are not
visible on the spectrum.
SM-ESI: 211 (MH+).
Step 2: 4-(2-fluorophenyl)-2-oxabicyclo[2.l.l]hexane-3-one
30 (C2)
33
Identical to step 2 described in Example 1. The title
product is obtained in the form of a colourless oil (yield =
81 %) •
C11H9F02 (MW = 192) .
5 1H-NMR (CDC1 31 400 MHz) 8 (ppm): 2.75 (ml 2H) I 2.99 (ml 2H) 1
5.01 (s 1 1H) 1 7.07-7.42 (ml 4H).
SM-ESI: = 193 (MH+).
Step 3: cis-3-hydroxy-N1 N-diethyl-1-(2-fluorophenyl)cyclobutanecarboxamide
(D2a)
10 Identical to step 3 of Example 1. The title product is
15
obtained in the form of a white solid (yield = 85 %) .
C15H2oN02F (MW = 2 65) .
1H-NMR (CDC13 I 400 MHz) 8 (ppm): 0.47 (tl 3H 1 J = 6.8
1.10 (tl 3H 1 J = 6.8 Hz) 1 2.77-2.89 (ml 4H) I 2.95 (ml
3.31 (ml 2H) I 4.32 (qui 1H 1 J = 6.8 Hz) I 7.04 (tl 1H 1
7.8 Hz) I 7.15 (tl 1H 1 J = 7.8 Hz) I 7.26 (ml 1H) I 7.37
Hz) 1
2H) I
J =
(tl
1H1 J = 7.8 Hz). The signal corresponding to the H in OH is
not visible on the spectrum.
SM-ESI: 266 (MH+) .
20 Step 4: trans-3-azido-N1N-diethyl-1-(2-fluorophenyl)cyclobutanecarboxamide
(E2a)
Identical to step 4 described in 1. The title product
is obtained in the form of a colourless oil (yield = 75 %) .
C15H19N40F (MW = 2 90) ..
25 1H-NMR (CDC13 I 400 MHz) 8 (ppm): 0.42 (t 1 3H 1 J = 7.0
1.10 (tl 3H 1 J = 7.0 Hz) I 2.55 (ml 2H) I 2.98 (ql 2H 1
7.0 Hz) 1 3.19 (ml 2H) I 3.31 (ql 2H 1 J = 7.0 Hz) 1 4.02
1H1 J = 8.0 Hz) 1 7.03 (ml 1H) I 7.14-7.29 (ml 3H).
SM-ESI: 291 (MH+).
30 Step 5: trans-3-amino-N1N-diethyl-1-(2-fluorophenyl)cyclobutanecarboxamide
(1b)
Hz) 1
J =
(qui
34
Identical to step 5 described in example 1. The title
product obtained is in the form of a colourless oil (yield =
90 %) .
C15H21N20F (MW = 264).
5 1H-NMR (CDC13 , 400 MHz) 8 (ppm): 0.42 (t, 3H, J = 6.8 Hz),
1.10 (t, 3H, J = 6.8 Hz), 2.19 (m, 2H), 3.00 (q, 2H, J =
6.8 Hz), 3.17 (m, 2H), 3.31 (q, 2H, J = 6.8 Hz), 3.53 (qu,
1H, J 8.0 Hz), 7.00 (m, 1H) 7.11-7.31 (m, 3H). The
signal corresponding to the H in NH2 is not visible on the
10 spectrum.
SM-ESI: 265 (MH+).
Maleate of the title compound.
Salification of the previous compound by means of
maleic acid leads to obtaining Maleate of the title compound
15 in the form of a white powder.
Mp: 193°C.
1H-NMR (DMSO d 6 , 400 MHz) 8 (ppm) : 0. 01 (t, 3H, J = 6. 8 Hz) ,
0.77 (t, 3H, J = 6.8 HZ) 1 2.36 (m, 2H), 2.72 (m, 4H), 2.97
(q, 2H, J = 6.8 Hz), 3.22 (s, 1H), 3.38 (qu, 1H, J = 8.0
20 Hz), 5.81 (s, 2H), 6.94 (m, 1H), 7.04-7.14 (m, 2H), 7.33 (m,
1H) I 7 . 7 5 ( s I 3 H) .
13C-NMR (DMSO d 6 , 100 MHZ) 8 (ppm): 12.00, 12.20, 36.14,
39.97, 40.60, 41.19, 43.60, 115.71 (d, 2Jc-F =21Hz), 124.64
(d, 4Jc-F = 4 Hz), 128.00 (d, 3Jc-P = 5 Hz), 128.80 (d, 3Jc-F =
25 8Hz), 130.07 (d, 2Jc-l' =13Hz), 136.04, 158.52, 160.96,
167.14, 169.93.
%Theoretical: C 59.99, H 6.621 N 7.36.
%Found: C 60.15, H 6.48, N 7.20.
30 Example 4: trans-3-amino-N,N-diethyl-1-(3-fluorophenyl)cyclobutanecarboxamide
(1c)
35
Step 1: cis-3-hydroxy-1-(3-fluorophenyl)cyclobutanecarboxylic
acid (B3)
Identical to step 1 of Example 1 by using 3-
fluorophenylacetic acid as the starting acid. The title
5 product is obtained in the form of a white solid (yield =
52 %) •
CuHnF03 (MW = 210).
1H-NMR (DMSO d 6 , 400 MHz) 8 (ppm): 2. 50 (m, 2H), 2. 75 (m,
2H), 3.86 (qu, 1H, J = 7.2 Hz), 5.18 (s, 1H), 7.07-7.21 (m,
10 3H), 7.40 (m, 1H), 12.40 (s, 1H).
SM-ESI: 211 (MH+).
Step 2: 4-(3-fluorophenyl)-2-oxabicyclo[2.1.1]hexane-3-one
(C3)
Identical to step 2 described in Example 1. The title
15 product is obtained in the form of a colourless oil (yield =
91 %) .
CuH902F (MW = 192) .
1H-NMR (DMSO d 6 , 400 MHz) 8 (ppm): 2.83 (s, 4H), 5.09 (s,
1H) , 7 . 15-7 . 2 2 ( m, 3 H) , 7 . 3 8 -7 . 4 7 ( m, 1H) .
20 SM-ESI: 193 (MH') .
Step 3: cis-3-hydroxy-N,N-diethyl-1-(3-fluorophenyl)cyclobutanecarboxamide
(D3a)
Identical to step 3 of Example 1. The title product is
obtained in the form of a white solid (yield = 92 %) .
25 C15H20N02F ( MW = 2 6 5) .
1H-NMR (DMSO d 6 , 400 MHz) 8 (ppm): 0.62 (t, 3H, J = 7.2 Hz),
0.97 (t, 3H, J = 7.2 Hz), 2.50 (m, 2H), 2.66 (m, 2H), 2.86
(q, 2H, J = 7.2 Hz), 3.19 (q, 2H, J = 7.2 Hz), 4.05 (m, 1H),
5.12 (d, 1H, J = 6. 8 Hz), 7. 04-7.15 (m, 3H), 7. 39 (m, 1H).
30 SM-ESI: 266 (MH+).
36
Step 4: trans-3-azido-N,N-diethyl-1-(3-fluorophenyl)cyclobutanecarboxamide
(E3a)
Identical to step 4 described in 1. The title product
is obtained in the form of a colourless oil (yield = 72 %) .
5 1H-NMR (DMSO d 6, 400 MHz) 8 (ppm): 0.59 (t, 3H, J = 7.2 Hz),
1.00 (t, 3H, J = 7.2 Hz), 2.40 (m, 2H), 2.86 (q, 2H, J = 7.2
Hz ) , 3 . 0 4 ( m, 2 H) , 3 . 2 4 ( q, 2 H, J = 7 . 2 Hz) , 4 . 0 7 ( m, 1H) ,
7 . 0 4-7 . 15 ( m, 3 H) , 7 . 3 9 ( m, 1H) .
Step 5: trans-3-amino-N,N-diethyl-1-(3-fluorophenyl)-
10 cyclobutanecarboxamide (1c)
Identical to step 5 described in Example 1. The title
product is obtained in the form of a colourless oil (yield =
93 %) •
C15H21N20F (MW = 264).
15 SM-ESI: 265 (MH+) .
Maleate of the title compound
Salification of the previous compound by means of
maleic acid leads to obtaining Maleate of the title compound
in the form of a white powder.
20 Mp : 17 4 ° C.
1H-NMR (DMSO d6, 400 MHz) 8 (ppm): 0.49 (t, 3H, J = 7.0 Hz),
1. 02 (t, 3H, J = 7.0 Hz), 2.56 (m, 2H), 2.91 (m, 4H), 3.26
(q, 2H, J 7.0 Hz), 3.35 ( s, 1H), 3.53 (qu, 1H, J = 8.4
Hz), 6.03 (s, 2H), 7.01 (d, 1H, J = 8.0 Hz), 7.09-7.20 (m,
25 2H), 7.42 (m, 1H), 7.99 (s, 3H) .
13C-NMR (DMSO d6, 100 MHz) 8 (ppm): 12.10, 36.93, 39.23,
39.91, 41.18, 46.40, 111.03 (d, 2' Jc-F = 22 Hz), 113.39 (d,
2
Jc-F = 21 Hz), 121.11 (d, 4
Jc-F = 2 Hz), 130.77 (d, 3
Jc-F =
9 Hz), 136.02, 145.55 (d, 3
Jc-F 7 Hz), 161.21, 163.64,
30 167.14, 170.60.
%Theoretical: C 59.99, H 6.62, N 7.36.
37
%Found: C 59.11, H 6.40, N 7.07.
Example 5: trans-3-amino-N,N-diethyl-1-(3-methoxyphenyl)cyclobutanecarboxamide
(1d)
5 Step 1: cis-3-hydroxy-1-(3-methoxyphenyl)cyclobutanecarboxylic
acid (B4)
Identical to step 1 of Example 1 by using 3-
methoxyphenylacetic instead of phenylacetic acid. The title
product is obtained in the form of a white solid (yield =
10 50 %) .
C12H1404 (MW = 222).
1H-NMR (DMSO d 6 , 400 MHz) 8 (ppm): 2. 50 (m, 2H), 2. 73 (m,
2H), 3.75 (s, 3H), 3.86 (qu, 1H, J = 7.2 Hz), 5.14 (s, 1H),
6.82 (dd, 1H, J = 8.0 Hz and J = 2.0 Hz), 6.87 (s, 1H), 6.93
IS (d, 1H, J = 8.0 Hz), 7.26 (t, 1H, J = 8.0 Hz), 12.23 (s,
1H).
SM-ESI: 222.
Step 2: 4-(3-methoxyphenyl)-2-oxabicyclo[2.1.l]hexane-3-one
(C4)
20 Identical to step 2 described in Example 1. The title
25
product is obtained in the form of a colourless oil (yield =
85 %) •
C12H1202 (MW = 188).
1H-NMR (DMSO d6 , 400 MHz) 8 (ppm):
3H), 5.06 (s, 1H), 6.87-6.91 (m,
8. 0 Hz) .
SM-ESI: 189 (MH+).
2.80 (m, 4H), 3.76 (s,
3H) I 7. 30 (t I 1H, J =
Step 3: cis-3-hydroxy-N,N-diethyl-1-(3-methoxyphenyl)-
cyclobutanecarboxamide (D4a)
38
Identical to step 3 described for Example 1. The title
product is obtained in the form of a white solid (yield =
92 %) .
C16H23N03 (MW = 2 7 7) .
5 1H-NMR (DMSO d 6, 400 MHz) 8 (ppm): 0.62 (t, 3H, J = 6.8 Hz),
0.97 (t, 3H, J = 6.8 Hz), 2.50 (m, 2H), 2.64 (m, 2H), 2.86
(q, 2H, J = 6.8 Hz), 3.19 (q, 2H, J 6.8 Hz), 3.73 (s, 3H),
4.06 (se, 1H, J = 7.6 Hz), 5.08 (d, 1H, J 7.2 Hz), 6.81
(m, 2H), 6.89 (d, 1H, J = 7.6 Hz), 7.27 (m, 1H).
10 SM-ESI: 278 (MH+).
Step 4: trans-3-azido-N,N-diethyl-1-(3-methoxyphenyl)cyclobutanecarboxamide
(E4a)
Identical to step 4 described for Example 1. The title
product is obtained in the form of a colourless oil (yield =
15 82 %) •
Cl6H22N402 (MW = 3 02) .
1H-NMR (DMSO d 6, 400 MHz) 8 (ppm): .0.59 (t, 3H, J = 6.8 Hz),
1.00 (t, 3H, J = 6.8 Hz), 2.40 (m, 2H), 2.86 (q, 2H, J = 6.8
Hz), 3.05 (m, 2H), 3.24 (q, 2H, J = 6.8 Hz), 3.74 (s, 3H),
20 3.95 (qu, 1H, J = 7.6 Hz), 6.76 (m, 1H), 6.83 (m, 2H), 7.30
(m, 1H).
SM-ESI: 303 (MH+).
Step 5: trans-3-amino-N,N-diethyl-1-(3-methoxyphenyl)cyclobutanecarboxamide
(1d)
25 Identical to step 5 described for Example 1. The title
30
product is obtained in the form of a colourless oil (yield =
88 %) •
C16H24N202 (MW = 276).
1 H~NMR (DMSO d 6 , 400 MHz) 8 (ppm): 0.50 (tl 3H, J = 7.0 Hz) 1
1. 00
(qu,
(t, 3H, J = 7.0 Hz), 2.02 (m, 2H) 1 2.83 (ml 4H)I 3.10
1H, J = 8. 0 Hz) , 3 . 2 3 ( q, 2H, J = 7. 2 Hz) I 3. 3 3 ( s,
39
2H), 3.73 (s, 3H), 6.73-6.79 (m, 3H), 7.25 (t, 1H, J 8.0
Hz) .
SM-ESI: 277 (MH+).
Maleate of the title compound
5 Salification of the previous compound by means of
maleic acid leads to obtaining Maleate of the title compound
in the form of a white powder.
Mp: 156°C.
1H-NMR (DMSO d 6 , 400 MHz) 8 (ppm): 0.47 (t, 3H, J = 6.8 Hz),
10 1.02 (t, 3H, J = 6.8 Hz), 2.55 (m, 2H), 2.89 (m, 4H), 3.26
(q, 2H, J = 6.8 Hz), 3.35 (s, 1H), 3.52 (qu, 1H, J = 8.4
Hz), 3.75 (s, 3H), 6.03 (s, 2H), 6.78-6.86 (m, 3H), 7.31 (t,
1H, J = 8.0 Hz), 7.98 (s, 3H).
13C-NMR (DMSO d 6 , 100 MHz) 8 (ppm): 12.11, 36.98, 39.23,
15 39.99, 41.23, 46.57, 55.03, 111.05, 111.54, 117.12, 129.89,
136.03, 144.22, 159.54, 167.12, 171.02.
% Theoretical: c 61.21, H 7.19, N 7.14.
% Found: C 61.38, H 7.09, N 6.98.
20 Example 6: trans-3-amino-N,N-diethyl-1-(3-chlorophenyl)cyclobutanecarboxamide
(1e)
Step 1: cis-3-hydroxy-1-(3-chlorophenyl)cyclobutanecarboxylic
acid (B5)
Identical to step 1 described in 1 by using 3-
25 chlorophenylacetic acid as the starting acid. The title
compound is obtained in the form of a white solid (yield =
52 %) .
CuHu03Cl (MW = 226.5).
1H-NMR (DMSO d 6 , 400 MHz) 8 (ppm): 2. 50 (m, 2H), 2. 75 (m,
30 2H), 3.86 (qu, 1H, J = 7.2 Hz), 5.19 (s, 1H), 7.31-7.40 (m,
4H), 12.44 (s, 1H).
40
Step 2: 4-(3-chlorophenyl)-2-oxabicyclo[2.1.1]hexane-3-one
(C5)
Identical to step 2 described in Example 1. The title
product is obtained in the form of a colourless oil (yield =
5 78 %) .
C11H902Cl (MW = 208).
1H-NMR (DMSO d 6 , 400 MHz) 8 (ppm)
1H), 7.29-7.45 (m, 4H).
SM-ESI: 209 (MH+).
2.84 (m, 4H), 5.09 (s,
10 Step 3: cis-3-hydroxy-N,N-diethyl-1-(3-chlorophenyl)-
cyclobutanecarboxamide (D5a)
Identical to step 3 described in example 1. The title
compound is obtained in the form of a white solid (yield =
99 %) .
15 C15H20N02Cl (MW = 281.5).
1H-NMR (DMSO d 6 , 400 MHz) 8 (ppm): 0.63 (t, 3H, J = 6.8 Hz),
0.96 (t, 3H, J = 6.8 Hz), 2.51 (m, 2H), 2.66 (m, 2H), 2.86
(q, 2H, J = 6.8 Hz), 3.19 (q, 2H, J = 6.8 Hz), 4.05 (qu, 1H,
J = 7.6 Hz), 5.13 (s, 1H), 7.29-7.41 (m, 4H).
20 SM-ESI: 282.1 (MH+) .
Step 4: trans-3-(dioxoisoindoline-2-yl)-N,N-diethyl-1-(3-
chlorophenyl)-cyclobutanecarboxamide (F5a).
In a flask under an atmosphere of nitrogen, add 1 eq of
compound (D5a) , 1. 1 eq of triphenylphosphine, 1. 05 eq of
25 phthalimide and THF. Next, add 1.2 eq of
diisopropyldiazodicarboxylate (DIAD) dropwise and stir at
room temperature for 16 h. Add water and extract with DCM.
Dry the organic phase over Na 2 SO~, filter and concentrate.
Purify the residue by flash chromatography with the
30 following mixture as the eluent: heptane/AcOEt: 80:20. The
title product is obtained.with a yield de 77 %.
41
C23H23N203Cl (MW = 410. 5).
1H-NMR (CDC13, 400 MHz) 8 (ppm): 0.67 (t, 3H, J = 7.2 Hz),
1.18 (t, 3H, J = 7.2 Hz), 2.91 (q, 2H, J 7.2 Hz), 3.11 (m,
2H), 3.35 (m, 2H), 3.42 (q, 2H, J = 7.2 Hz), 4.79 (qu, 1H,
5 J = 8.8 Hz), 7.23 (m, 1H), 7.32 (m, 2H), 7.41 (s, 1H), 7.73
(m, 2H) , 7. 83 (m, 2H)
SM-ESI: 411.1 (MH+).
Step 5: trans-3-amino-N,N-diethyl-1-(3-chlorophenyl)cyclobutanecarboxamide
(1e)
10 Place derivative (F5a) in solution in ethanolamine in a
flask. Heat the reaction medium at 60°C for 1 h 30. Add a
mixture of ice and water, stir for 15 min and extract with
AcOEt. Wash the organic phase with saturated NaCl solution
and decant. Dry the organic phase over MgS04, filter and
15 concentrate. Purify the residue by flash chromatography with
the following mixture as the eluent: DCM/methanol/NH40H:
90:9:1. The title product is obtained with a yield de 40 %.
C15H21N20Cl (MW = 280. 5).
1H-NMR (CDCl3, 400 MHz) 8 (ppm): 0.58 (t, 3H, J = 7.2
20 1.10 (t, 3H, J = 7.2 Hz), 2.08 (m, 2H) I 2.91 (q, 2H,
7.2 Hz), 3.11 (m, 2H) I 3.34 (q, 2H, J
1H, J = 8,0 Hz), 7.12 (dd, 1H, J = 7.6
7.19 (m, 2H) I 7.26 (m, 1H). The signal
H in NH2 is not visible on the spectrum.
25 SM-ESI: 281.1 (MR'.) .
Maleate of the title compound
= 7.2 Hz), 3.46
Hz and J = 1.2
corresponding to
Hz),
J =
(qu,
Hz),
the
Salification of the previous compound by means of
maleic acid leads to obtaining Maleate of the title compound
in the form of a white powder.
30 Mp: 16 7 ° C.
5
42
1H-NMR (DMSO d 6, 400 MHz) 8 (ppm): 0.50 (t, 3H, J = 6.8 Hz),
1. 02 (t, 3H, J = 6.8 Hz), 2.56 (m, 2H), 2.86-2.95 (m, 4H),
3.26 (m, 2H), 3.34 (s, 1H), 3.54 (qu, 1H, J = 8.0 Hz), 6.03
(s, 2H), 7.15 (d, 1H, J = 7.6 Hz), 7.34-7.44 (m, 3H) , 8.00
(s, 3H).
13C-NMR (DMSO d6. 100 MHz) 8 (ppm); 12.09, 12.12, 36.88,
39.19, 39.90, 41.14, 46.37, 123.76, 124.94, 126.61, 130.65,
133.51, 136.00, 145.09, 167.14, 170.54.
%Theoretical: c 57.50, H 6.35, N 7.06.
I 0 % Found : C 57 . 3 6 , H 6 . 2 6 , N 6 . 6 8 .
Example 7: trans-3-amino-N,N-diethyl-1-(3-methylphenyl)cyclobutanecarboxamide
(1f)
Step 1: cis-3-hydroxy-1-(3-methylphenyl)-
15 cyclobutanecarboxylic acid (B6)
Identical to step 1 of Example 1 by using 3-
methylphenylacetic acid instead of phenylacetic acid. The
title product is obtained in the form of a white solid
(yield = 40 %) .
20 C12H14 0 3 (MW = 206).
1H-NMR (CDCl3 . 400 MHz) 8 (ppm): 2.35 (s, 3H), 2.73 (m, 2H),
2.94
7.6
(m, 2H) ,· 4. 21 (qu, lH,
Hz), 7.16 (s, 2H),
J = 6. 4 Hz) , 7. 0 8
7.24 (m, lH).
(d,
The
1H, J =
signals
corresponding to the H in OH in the alcohol and acid are not
25 visible on the spectrum.
SM-ESI: 205.
Step 2: 4-(3-methylphenyl)-2-oxabicyclo[2.1.1]hexane-3-one
(C6)
Identical to step 2 described in Example 1. The title
30 product is obtained in the form of a colourless oil (yield =
74 %) •
43
C12H1202 (MW = 188).
1H-NMR (DMSO d 6, 400 MHz) 8 (ppm): 2.37 (s, 3H), 2.70 (m,
2H), 2.87 (m, 2H), 4.96 (s, 1H), 7.09-7.30 (m, 4H).
SM-ESI: 189 (MH+).
5 Step 3: cis-3-hydroxy-N,N-diethyl-1-(3-methylphenyl)cyclobutanecarboxamide
(D6a)
Identical to step 3 described in example 1. The title
product is obtained with a yield de 77 %.
1H-NMR (CDC13 , 400 MHz) 8 (ppm): 0.65 (t, 3H, J = 7.2 Hz),
10 1.08 (t, 3H, J = 7.2 Hz), 2.69 (s, 3H), 2.73 (m, 2H), 2.81
(m, 2H), 2.90 (q, 2H, J = 7.2 Hz), 3.31 (q, 2H, J = 7.2 Hz),
4.35 (qu, 1H, J = 7.4 Hz), 7.04 (m, 1H), 7.11 (m, 2H), 7.23
(m, 1H) . The signal corresponding to the H in OH is not
visible on the spectrum.
15 Step 4: trans-3-azido-N,N-diethyl-1-(3-methylphenyl)cyclobutanecarboxamide
(E6a)
Identical to step 4 described in 1. The title product
is obtained with a yield de 70 %.
1H-NMR (CDC13 . 400 MHz) 8 (ppm): 0.54 (t, 3H, J = 7.2 Hz),
20 1.11 (t, 3H, J = 7.2 Hz), 2.34 (s, 3H), 2.47 (m, 2H), 2.89
(q, 2H, J = 7.2 Hz), 3.12 (m, 2H), 3.34 (q, 2H, J = 7.2 Hz),
3.95 (qu, 1H, J = 7.8 Hz), 7.04 (m, 3H), 7.23 (m, 1H).
Step 5: trans-3-amino-N,N-diethyl-1-(3-methylphenyl)cyclobutanecarboxamide
(1f)
25 Identical to step 5 described in Example 1. The title
product is obtained with a yield de 57 %.
C16H24N20 (MW =260).
1H-NMR (CDC13 , 400 MHz) 8 (ppm): 0,52 (t, 3H, J = 7,2 Hz),
1,10 (t, 3H, J = 7,2 Hz), 2,11 (m, 2H), 2,33 (s, 3H), 2,92
30 (q, 2H, J = 7,2 Hz), 3,10 (m, 2H), 3,33 (q, 2H, J = 7,2 Hz),
3,44 (qu, 1H, J = 8,0 Hz), 7,03 (m, 3H), 7,21 (m, 1H). The
44
signal corresponding to the H in NH2 is not visible on the
spectrum.
SM-ESI: 261 (MH+).
Maleate of the title compound
5 Salification of the previous compound by means of
maleic acid leads to obtaining Maleate of the title compound
in the form of a white powder.
Mp: 173°C.
1H-NMR (DMSO d 6 , 400 MHz) 8 (ppm): 0.45 (t, 3H, J = 6.8 Hz),
10 1.02 (t, 3H, J = 6.8 Hz), 2.31 (s, 3H), 2.52 (m, 2H), 2.89
(m, 4H), 3.25 (q, 2H, J = 6.8 Hz), 3.52 (qu, 1H, J = 8.4
Hz), 6.02 (s, 2H), 7.05 (m, 3H), 7.27 (t, 1H, J = 7.6 Hz),
8.00 (s, 2H). The signal corresponding to the H in NH2 is
not visible on the spectrum.
15 13C-NMR (DMSO d 6 , 100 MHz) 8 (ppm): 12.07, 12.13, 21.05,
36.97, 39.15, 40.09, 41.18, 46.56, 48.53, 121.99, 125.43,
127.15, 128.63, 136.07, 137.88, 142.66, 167.21, 171.19.
%Theoretical: C 63.81, H 7.50, N 7.44.
20
%Found: C 63.93, H 7.45, N 7.27.
Example 8: trans-3-amino-N,N-diethyl-1-(2-fluoro-3-
chlorophenyl)-cyclobutanecarboxamide (1g)
Step 1: cis-3-hydroxy-1-(2-fluoro-3-chlorophenyl)cyclobutanecarboxylic
acid (B7)
25 Identical to step 1 of Example 1 by using 2-fluoro-3-
chlorophenylacetic acid instead of phenylacetic acid. The
title product is obtained in the form of a white solid
(yield = 30 %) .
CuH1 oFCl03 (MW = 244. 5) .
45
1H-NMR (DMSO d 6 , 400 MHz) 6 (ppm): 2. 58 (m, 2H),
2H), 3.93 (qu, 1H, J 7.6 Hz), 5.33 (s, 1H), 7.22
7. 52 (m, 2H), 12.56 (m, 1H) .
SM-ESI: 243,0.
5 Step 2: 4-(2-fluoro-3-chlorophenyl)-2-
oxabicyclo[2.1.1]hexane-3-one (C7)
2.75 (m,
(m, 1H),
Identical to step 2 described in Example 1. The title
product is obtained in the form of a colourless oil (yield =
66 %) •
10 C11H80 2ClF (MW = 226. 5).
1H-NMR (DMSO d 6 , 400 MHz) 6 (ppm): 2.89 (s, 4H), 5.16 (s,
1H) , 7. 22-7.29 (m, 2H) , 7. 61 (m, 1H) .
SM-ESI: 227 (MH+).
Step 3: cis-3-hydroxy-N,N-diethyl-1-(2-fluoro-3-
15 chlorophenyl)-cyclobutanecarboxamide (D7a)
Identical to step 3 described in example 1. The title
product is obtained with a yield de 87 %.
C15H19N02ClF (MW = 299.5).
1H-NMR (DMSO d 6 , 400 MHz) 6 (ppm): 0.35 (t, 3H, J = 7.0 Hz),
20 0.96 (t, 3H, J = 7.0 Hz), 2.57 (m, 2H), 2.67 (m, 2H), 2.87
(q, 2H, J = 7.0 Hz), 3.16 (q, 2H, J = 7.0 Hz), 4.00 (se, 1H,
J = 8.0 Hz), 5.02 (d, 1H, J = 7.2 Hz), 7.27 (t, 1H, J = 8.0
Hz) , 7. 50 ( t, 1H, J
SM-ESI: 300 (MH+).
8 . 0 Hz) , 7. 6 5 ( t, 1H, J = 8. 0 Hz) .
25 Step 4: trans-3-(dioxoisoindoline-2-yl)-N,N-diethyl-1-(2-
fluoro-3-chlorophenyl)-cyclobutanecarboxamide (F7a)
Identical to step 4 described for Example 6. The title
product is obtained with a yield de 45 %.
C23H22FClN203 (MW = 428.5).
30 1H-NMR (CDC13, 400 MHz) 6 (ppm): 0.29 (t, 3H, J = 6.8 Hz),
1.04 (t, 3H, J = 6.8 Hz), 2.94-3.04 (m, 4H), 3.22-3.28 (m,
46
4H), 4.61 (qu, 1H, J = 8.8 Hz), 7.35 (t, 1H, J = 8.0 Hz),
7.54 (t, 1H, J = 8.4 Hz), 7.62 (t, 1H, J = 7.2 Hz), 7.83 (s,
4H).
SM-ESI: 429 (MH+).
5 Step 5: trans-3-amino-N,N-diethyl-1-(2-fluoro-3-
chlorophenyl)-cyclobutanecarboxamide (1g)
Identical to step 5 described for Example 6. The title
product is obtained with a yield de 93 %.
C1sH2oFClN20 (MW = 298. 5).
10 1H-NMR (DMSO d 6 , 400 MHz) 8 (ppm): 0.27 (t, 3H, J = 6.8 Hz),
0.97 (t, 3H, J = 6.8 Hz), 2.08 (m, 2H), 2.88-2.94 (m, 4H),
3.17-3.25 (m, 3H), 7.26 (t, 1H, J = 8.0 Hz), 7.44-7.49 (m,
2H) . The signal corresponding to the H in NH2 is not visible
on the spectrum.
15 SM-ESI: 299 (MH+).
Maleate of the title compound
Salification of the previous compound by means of
maleic acid leads to obtaining Maleate of the title compound
in the form of a white powder.
20 Mp: 179°C.
25
1H-NMR (DMSO d 6 , 400 MHz) 8 (ppm): 0.26 (t, 3H, J = 6.8 Hz),
0.99
3.20
8.4
(m,
(t,
(q,
Hz),
2H) I
3H, J
2H, J
6.8 Hz), 2.60 (m, 2H), 2.91-3.00 (m, 4H),
6.8 Hz), 3.34 (s, 1H), 3.61 (qu, 1H, J =
6 . 0 2 ( s I 2 H) I 7 . 3 2 ( t I 1H I J = 8 . 0 Hz) I 7 . 52-7 . 57
7.97 (s, 3H).
13C-NMR (DMSO d6 , 100 MHz) 8 (ppm): 12.15, 12.21, 36.19,
40.08, 40.56, 41.16, 43.81, 120.16, 125.59, 127.11, 129.12,
132.00, 136.11, 153.74, 156.22, 167.19, 169.48.
%Theoretical: C 55.01, H 5.83, N 6.75.
30 %Found: C 54.73, H 5.98, N 6.46.
47
Example 9: trans-3-amino-N,N-diethyl-1-(2,5-difluorophenyl)cyclobutanecarboxamide
(1h)
Step 1: cis-3-hydroxy-1-(2,5-difluorophenyl)cyclobutanecarboxylic
acid (B8)
5 Identical to step 1 described in 1 by using 2,5-
10
difluorophenylacetic acid as the starting acid. The title
product is obtained in the form of a white solid (yield = 69
%) .
1H-NMR (DMSO d 6 , 400 MHz) 8 (ppm): 2. 55
2H), 3.94 (qu, 1H, J = 7.2 Hz), 5.32 (s,
2 H) , 7 . 41 ( m, 1H) , 12 . 4 8 ( s , 1H) .
(m, 2H) , 2. 71
1H) , 7. 12-7. 23
(m,
(m,
Step 2: 4-(2,5-difluophenyl)-2-oxabicyclo[2.1.1]hexane-3-one
(C8)
Identical to step 2 described in Example 1. The title
15 product is obtained in the form of a colourless oil (yield =
91 %) •
CnHsF202 (MW = 210).
1H-NMR (CDC13 , 400 MHz) 8 (ppm): 2. 77 (m, 2H), 2. 98 (m, 2H),
5 . 0 1 ( s , 1H) , 6 . 9 3 -7 . 0 8 ( m , 3 H) .
20 SM-ESI: 228 (M+NH4 +) .
Step 3: cis-3-hydroxy-N,N-diethyl-1-(2,5-difluorophenyl)cyclobutanecarboxamide
(D8a)
Identical to step 3 of Example 1. The title product is
obtained in the form of a white solid (yield = 100 %) .
25 C1sH19N02F2 (MW 283).
1H-NMR (CDC13 , 400 MHz) 8 (ppm): 0.56 (t, 3H, J = 6.8 Hz),
1.09 (t, 3H, J = 6.8 Hz), 2.82 (m, SH), 2.95 (q, 2H, J = 6.8
Hz), 3.31 (q, 2H, J = 6.8 Hz), 4.32 (qu, 1H, J = 7.2 Hz),
6. 91-7.11 (m, 3H) .
30 SM-ESI: 284 (MH+) .
48
Step 4: trans-3-azido-N,N-diethyl-1-(2,5-difluorophenyl)cyclobutanecarboxamide
(E8a)
Identical to step 4 described in 1. The title product
is obtained in the form of a colourless oil (yield = 76 %) .
5 C1sH1sNqOF2 (MW = 3 0 8) .
10
1H-NMR (CDCl3, 400 MHz) 8 (ppm): 0.51 (t, 3H, J = 7.2 Hz),
1,10 (t, 3H, J = 7,2 Hz), 2.51 (m, 2H) I 2.98 (q, 2H, J =
7.2 Hz), 3.19 (m, 2H) I 3.32 (q, 2H, J = 7.2 Hz), 4.02 (qu,
1H, J = 8.0 Hz), 6.90-7.04 (m, 3H).
SM-ESI: 309 (MR").
Step 5: trans-3-amino-N,N-diethyl-1-(2,5-difluorophenyl)cyclobutanecarboxamide
(1h)
Place 1 eq of compound (E8a) in a flask and dissolve in
20 volumes of THF. Stir under an atmosphere of nitrogen then
15 add 1 volume of water and 1. 5 eq of triphenylphosphine.
Carry on stirring overnight. Evaporate the THF under reduced
pressure and take up the residue obtained with water and
extract twice with DCM. Dry the organic phases on MgS04,
filter then evaporate the solvent under reduced pressure.
20 The oil obtained is purified by flash chromatography with
the following mixture as the eluant: DCM/methanol/NH40H
95:4.5:0.5. The title product is obtained in the form
colourless oil with a yield de 97 %.
C1sH2oN20F2 (MW = 282) .
25 1H-NMR (CDC13, 400 MHz) 8 (ppm): 0,51 (t, 3H, J = 6,8 Hz),
1,10 (t, 3H, J = 6,8 Hz), 2,15 (m, 2H), 2,99 (q, 2H, J =
6,8 Hz), 3,16 (m, 2H), 3,32 (q, 2H, J = 6,8 Hz), 3,52 (qu,
1H, J = 8,0 Hz), 6,85-7,02 (m, 3H). The signal corresponding
to the H in NH2 is not visible on the spectrum.
30 SM-ESI: 283 (MH+) .
Maleate of the title compound
5
10
49
Salification of the previous compound by means of
maleic acid leads to obtaining Maleate of the title compound
in the form of a white powder.
Mp:l84°C.
1H-NMR (DMSO d6, 400 MHz) 8 (ppm): 0.31 (t, 3H, J = 6.8 Hz),
0.99 (t, 3H, J 6.8 Hz), 2.58 (m, 2H), 2.93-2.97 (m, 4H),
3.20 (q, 2H, J 6.8 Hz), 3.34 (s, lH), 3.59 (qu, lH, J =
8.4 Hz), 6.02 (s, 2H), 7. 13-7. 3 0 (m, 2H), 7.49-7.53 (m, lH),
7.97 (s, 3H).
13C-NMR (DMSO d6, 100 MHZ) 8 (ppm): 12.04, 12.15, 36.08,
40.00, 40.61, 41.20, 43.48, 114.90, 117.2, 124.37, 132 .1,
136.00, 154.6, 157.05, 157.13, 159.51, 167.12, 169.41.
%Theoretical: C 57.28, H 6.07, N 7.03.
%Found C: 57.21, H 6.01, N 6.66.
15 Example 10: trans-3-amino-N,N~diethyl-1-(3,5-
dichlorophenyl)-cyclobutanecarboxamide (li)
Step 1: cis-3-hydroxy-1-(3,5-dichlorophenyl)cyclobutanecarboxylic
acid (B9)
Identical to step 1 described in 1 by synthesizing 3,5-
20 dichlorophenylacetic acid in advance after which it is used
as the starting acid. The title product is obtained in the
form of a white solid (yield = 50 %) .
CnH1oCl20 3 (MW = 261).
1H-NMR (DMSO d 6, 400 MHz) 8 (ppm): 2. 53 (m, 2H), 2. 77 (m,
25 2H), 3.87 (qu, lH, J 7.4 Hz), 5.23 (s, 1H) 1 7.38 (m 1 2H)I
7 . 51 ( m 1 lH) I 12 . 6 2 ( s I lH) .
SM-ESI: 259.
Step 2: 4-(3,5-dichlorophenyl)-2-oxabicyclo[2.l.l]hexane-3-
one (C9)
50
Identical to step 2 described in Example 1. The title
product is obtained in the form'of a colourless oil (yield=
87 %) .
CuH8Cl202 (MW = 243) .
5 1H-NMR (CDC1 3 , 400 MHz) 8 (ppm): 2.72 (m, 2H), 2.88 (m, 2H),
4.99 (s, 1H), 7.21 (m, 2H), 7.34 (m, lH).
SM-ESI: 244 (MH+).
Step 3: cis-3-hydroxy-N,N-diethyl-1-(3,5-dichlorophenyl)cyclobutanecarboxamide
(D9a)
10 Identical to step 3 of Example 1. The title product is
obtained in the form of a white solid (yield = 100 %) .
C1sH19Cl202N (MW = 316) .
1H-NMR (CDC1 3 , 400 MHz) o (ppm) : 0. 77 (t, 3H, J = 7. 2 Hz),
1.09 (t, 3H, J = 7.2 Hz), 2.58 (s, 1H), 2.75 (m, 4H), 2.88
15 (q, 2H, J = 7.2 Hz), 3.32 (q, 2H, J = 7.2 Hz), 4.34 (qu, 1H,
J = 7.6 Hz), 7.20-7.27 (m, 3H).
SM-ESI: 316.
Step 4: trans-3-azido-N,N-diethyl-1-(3,5-dichlorophenyl)cyclobutanecarboxamide
(E9a)
20 Identical to step 4 described in 1. The title product
is obtained in the form of a colourless oil (yield = 79 %) .
C1sH1sN40Cl2 (MW = 341).
1H-NMR (CDC1 3 , 400 MHz) o (ppm): 0.67 (t, 3H, J = 7.2 Hz),
1.12 (t, 3H, J = 7.2 Hz), 2.40 (m, 2H), 2.87 (q, 2H, J =
25 7.2 Hz), 3.15 (m, 2H), 3.36 (q, 2H, J = 7.2 Hz), 3.99 (qu,
1H, J = 7.6 Hz), 7.13 (m, 2H), 7.25 (m, 1H).
SM-ESI: 341.
Step 5: trans-3-amino-N,N-diethyl-1-(3,5-dichlorophenyl)cyclobutanecarboxamide
(1i)
30 Identical to step 5 of Example 9. The title product is
obtained in the form colourless oil with a yield de 78 %.
51
C1sH2oN20ClF (MW = 2 8 3) .
1H-NMR (DMSO d6, 400 MHz) 8 (ppm): 0.58 (t, 3H, J = 7.2 Hz),
1.00 (t, 3H, J = 7.2 Hz), 1.90 (s, 2H), 2.07 (m, 2H), 2.85
(m, 4H), 3.11 (qu, 1H, J = 8.0 Hz), 3.25 (q, 2H, J = 7.2
5 Hz), 7.23 (m, 2H), 7.48 (m, 1H).
SM-ESI: 283.
Maleate of the title compound
Salification of the previous compound by means of
maleic acid leads to obtaining Maleate of the title compound
10 in the form of a white powder.
15
Mp: 180°C.
1H-NMR (DMSO d6, 400 MHz) 8 (ppm): 0.57 (t 1 3H, J = 6.8 Hz),
1. 02 (t, 3H, J 6.8 Hz), 2.58 (m, 2H) I 2.85-2.96 (m, 4H) I
3.28 (q, 2H, J = 6.8 Hz), 3.54 (qu, 1H, J = 8.4 Hz), 6.02
(s, 2H) I 7.28 (s, 2H) I 7.56 (s, 1H) I 7.99 (s, 3H).
13C-NMR (DMSO d6, 100 MHz) 8 (ppm): 11.96, 12.19, 36.83,
39.20, 41.10, 46.2, 124.03, 126.38, 134.50, 136.02, 146.66,
167.12, 170,04.
%Theoretical: C 52.91 1 H 5.61, N 6.50.
20 %Found: c 53.01, H 5.53, N 6.11.
25
The following examples make it possible to understand
the invention better without in any way limiting its scope.
The compounds of general formula (1) as well as a
pharmaceutically acceptable source present remarkable
pharmacological properties: they are generally more powerful
than ketamine as NMDA channel blockers at the same time as
having fewer unwanted effects on the central nervous system
than ketamine.
30 We examined the effects of the compounds of the
invention on inhibition of the NMDA current in Xenop·e
52
(Xenopus laevis) expressing recombinant human NMDA receptors
constructed from NR1 and NR2B sub-units. The currents
produced by stimulation of these receptors by means of
endogenous agonists were studied according to the two
5 electrode voltage clamp technique reported by Planells-Cases
et al., 2002, J. Pharmacal. Exp. Ther., 302, 163-173.
Protocol: ovocytes were surgically removed from adults
xenopes, enzymatically defolliculated and stored at 17 oc in
10 a solution containing: 96 mM of NaCl, 2 mM of KCl, 1 mM of
MgC12 , 1. 8 mM of CaC12 and 5 mM of HEPES at pH 7. 5 (NaOH)
and 50 mg/L of gentamycin (Heusler et al., 2005,
Neuropharmacology, 49, 963-976) Complementary DNA (eDNA)
coding for the NR1 sub-unit was cloned by PCR using primers
15 targeted for start and end codons in the published sequence
(Genebank access number M 007327). eDNA coding for the NR2B
sub-unit was synthesised by Eurogentec (Seraing, Belgium)
according to the published sequence (gene bank access number
NM_000834) . The NR1 and NR2B eDNA was then sub-cloned in the
20 pGEMHE high expression carrier for in vitro transcription of
eDNA. cRNA coding for NR1 and NR2B was prepared according to
the method described by Heusler et al. (already cited) .
Aliquots of the cRNA solution were injected into the
ovocytes (20-500 pg/ovocyte for NR1 and 40-1000 pg/ovocyte
25 for NR2B) . Each ovocyte was injected with 100 nL of a
solution containing: 4 mM of Na+BAPTA (pH 7. 2) in order to
block all residual chlorine currents. After stabilisation,
NMDA currents were activated by superfusion of glutamate and
glycine each at a concentration of 10 pM. The compounds to
30 be tested were then superfused in a Ringer Ba++ solution at
increasing concentrations in the presence of glutamate and
53
glycine (4 to 5 concentrations were tested per ovocyte). The
concentration-response codes obtained are analysed for each
ovocyte by non-linear regression and a piC50 value was
calculated. piC50 designates the negative logarithm of the
5 compound concentration tested needed to reduce the amplitude
of the NMDA current by half.
Results: table 1 below gives the piC50 values for
certain compounds of the invention. It emerges that, under
the test conditions compounds (1a1), (1b), (1c), (1d) and
10 (1e) block ·the NMDA current in a concentration-dependant
15
manner and are more powerful than ketamine,
antagonist used clinically.
Table 1.
Inhibition of NMDA
current
Compound piCso
1a1 6.3
1b 6.3
1c 6.8
1d 6.4
1e 7.1
ketamine 6.1
the NMDA
Given the low bioavailability of ketamine by oral route,
we chose the intraperitoneal (ip) route as the sole
administration route for in vivo experiments. The analgesic
activity of compounds of formula (1) and of ketamine, chosen
20 as the reference compound, were determined in a classical
acute inflammatory pain model, intradermal injection of
formaldehyde (Bardin et al., 2001, Eur. J. Pharmacal., 421,
109-114) .
54
Protocol: Male rats (Sprague-Dawley Iffa Credo, France)
were placed in Plexiglas observation boxes above an angled
mirror to facilitate observation of their hind paws. After
30 minutes of acclimatisation, the animals received a
5 formaldehyde injection diluted to 2.5 % on the plantar
surface of the right hind paw. Injection of formaldehyde
produces behavioural responses which occur in two phases:
an early phase, 0 to 5 minutes after injection of
formaldehyde, corresponding to stimulation of the receptors
10 specialised in the transmission of nociceptive stimulii
a late phase which occurs 20 to 30 minutes after
injection. This phase corresponds to stimulation of the
receptors by inflammatory mediators and/or to
hyperexcitation of the dorsal horn induced during the first
15 phase. This later phase therefore brings into play central
sensitisation of the pain neurotransmission system in which
the glutamate/NMDA system plays a major role. As a result of
'
this, the pain in the second phase is more representative of
neuropathic pain than the pain which occurs during the first
20 phase. For this reason, only results obtained in this later
phase are taken into consideration in this application.
We selected licking of the paw which received the
injection as a behavioural parameter for quantification of
pain and chose as the observation periods those periods
25 corresponding to the later phase (in other words, 22.5-27.5
min post-formaldehyde injection) During this 5 min phase,
animals are observed every 3 0 seconds in order to note
whether or not the animal is licking the "injected" pawi
thus the maximum score is 10. The products of the invention
30 or the carrier are administered by ip route 15 min prior to
the injection of formaldehyde.
55
Results: In this test, the compounds of formula ( 1a1)
and (1e), representative of compounds of the invention, have
remarkable analgesic effect (table 2) . Thus the minimum
significant dose (MSD, the dose needed to significantly
5 reduce licking of the injected paw) for the compounds of
formula (la1) and (le) is less than that for ketamine.
Another advantage of the compounds of formula (1a1) and (1e)
compared to ketamine relates to the amplitude of the
analgesic effect. In fact we note that at a dose of 40
10 mg/kg, paw licking is completely inhibited with compounds
(1a1) and (le) whereas it only reaches a 74 % reduction with
ketamine. Compounds (lal) and (1e) are therefore more
powerful and more effective than ketamine.
15 Table 2.
Paw licking
Compound % reduction
MSD (mg/kg)
at 40 mg/kg
1a1 10 100
1e 10 100
ketamine 40 75
To summarise, the analgesic effect of compounds (1a1)
and (1e), representative of compounds of formula (1), is
higher than that produced by ketamine in the acute
20 inflammatory pain model in the rat.
We also show that the compounds of the invention have an
antidepressant activity in vivo. The antidepressant
activities of compounds of formula (1) and of ketamine were
determined in a forced swimming model in the rat, a model
56
that is widely used as it is predictive of antidepressant
activity in humans.
Protocol: Male rats (Sprague-Dawley Iffa Credo, France)
were placed in a cylinder (height 45 em and diameter 20 em)
S filled with water at 25°C ± 0. 5°C up to a height of 17 em.
This height allows the rats to swim or to float without
their paws touching the base of the cylinder. 24 hours
before the test day, the rats are placed in the cylinder for
15 min, after which time they no longer attempt to escape
I 0 and remain immobile at the surface. On the test day, the
compound to be tested or the carrier is injected (ip) into
the animal which is placed in the cylinder 30 min later. The
duration of immobility (defined when the rat simply floats
and only makes small movements to stay at the surface) is
IS measured with an accuracy of 0.1 s for 5 minutes.
Results: In the forced swimming test, the compounds of
formulas (1c) and 1(e), representative of the series,
significantly reduce the animal's immobility time. When the
ED50 are compared, that is the doses which reduce immobility
20 time by half relative to control animals, we find that these
are lower than for ketamine for compounds (1c) and 1(e), see
Table 3. Similarly the amplitude of the anti-immobility
effect observed at a dose of 20 mg/kg is greater with
compounds (1c) and 1(e) than that obtained with ketamine.
25
Table 3.
Immobility time
Compound % reduction at 20
ED so (mg/kg)
mg/kg
1c 13 83
- --
1e 15 77
ketamine 20 50
57
To summarise, compounds (1c) and 1(e), representative of
compounds of formula (1), are more powerful and more
effective than ketamine in a test predicting antidepressant
5 activity.
We have already highlighted the importance of
normalising the NMDA receptor function, in other words
blocking its excessive activity without interfering, or
interfering as little as possible, with its normal
I 0 physiological functioning. As a marker of the interaction
between the products of the invention and the normal
functioning of the NMDA receptors, we chose the pre-pulse
inhibition test for the jolt reflex (PPI) This test
represents a measurement of the organism's capacity ·to
15 filter non-essential information. Non-competitive and
competitive antagonists as well as channel blockers reduce
PPI in the rat (Depoortere et al., 1999, Behav. Pharmacal.,
10, 51-62), such a reduction being considered to be
predictive of the psychotomimetic effects of NMDA
20 antagonists in humans.
Protocol: Male rats (Sprague-Dawley Iffa
Oncins, France) were placed in 18.4 em by 8.8
Credo, Les
em diameter
cylinders resting on a base below which a piezoelectric
accelerometer, is fixed to act as a detector of the jolt
25 reaction. This is enclosed in a box with a loudspeaker
attached to the ceiling to deliver sound pulses and prepulses,
and is acoustically isolated (SR LAB, San Diego
Instruments, San Diego, USA). All the events are controlled
by means of software. The animals first undergo a 13 minute
30 pre-test to habituate them to the procedure and to eliminate
rats which do not respond to a series of minimum reaction
58
criteria. Three types of sound stimuli (white noise) are
delivered; 1) a pulse of 118 dB (P, duration 40 msec); 2) a
pre-pulse of 78 dB (duration 20 msec) followed by a pulse of
118 dB (pP); and 3) no pre-pulse or pulse (NP). The interval
5 between the beginning of the pre-pulse and the beginning of
the pulse is 100 msec, with background noise at 70 dB. The
jolt reaction is recorded for 100 ms, 100 ms after the
beginning of the stimulus (pP or NP) by a numerical/analogue
acquisition card (12 bits) The session starts with a
10 stimulus-free period of 5 min after which animals are
exposed to 10 P (separated on average by 15 s and intended
to stabilise the jolt reaction) . The reactions recorded with
these 10 P are not used for the calculation. After this,
10 P, 10 pP and 3 NP are delivered in a semi-random order
15 with an average interval of 15 s in between. At the end of
this pre-test, rats undergo an ip injection of the compounds
to be tested or physiological serum as a control and are
returned to their cages. The actual test session (similar on
every point to the pre-test) is carried out 60 minutes
20 later. The percentage inhibition of the pre-pulse is
calculated using data from this test session according to
the formula:
25
(median amplitude P - median amplitude pP)
x 100/(median amplitude P).
Results: According to figure 1 in the appendix, it
appears that compound (l'al) does not disrupt inhibition of
the jolt reflex induced by the pre-pulse (PPI) except from a
dose of 20 mg/kg. Nevertheless, surprisingly the reduction
30 in PPI is much less pronounced than that observed with
ketamine. In fact at a dose of 20 mg/kg ip, ketamine leads
59
to the total disappearance of PPI whereas compound ( lal)
only causes a 30 % reduction. The PPI reduction nonetheless
remains modest even at a dose of 40 mg/kg. Consequently
compound (lal) has a clearly less pronounced tendency than
5 ketamine to cause side effects of central origins.
In summary, the compounds of the invention possess
analgesic and antidepressant activity that is superior to
that of ketamine in the animal model described above.
Surprisingly the compounds of the invention only cause very
10 moderate central effects. It therefore emerges from these
experiments that the risk/benefit ratio of the compounds of
the invention is clearly more favourable than that of
ketamine. As a result of this, the compounds of the present
invention as well as pharmaceutical compositions containing
IS a compound of general formula (1) as the active principle or
one of its pharmaceutically acceptable salts are potentially
useful as medications, particularly in the treatment of
certain diseases such as, for example, depression and pain,
especially acute or chronic pain, areas in which therapeutic
20 needs are not fully met and for which the discovery of new
treatments is therefore highly desirable.

We claim:
1. Compound of the following general formula (1)
(1)
or pharmaceutically acceptable salt or solvate thereof,
wherein:
- X1 represents a hydrogen atom or fluorine atom;
- X2 is a hydrogen atom or fluorine atom or chlorine
15 atom;
- R1 represents a hydrogen atom or fluorine atom or
chlorine atom or methyl group or methoxy group or cyano
group;
- R2 represents independently or together a methyl
20 group or ethyl group.
25
30
2. Compound according to claim 1, characterised in
that:
- X1 represents a hydrogen atom or fluorine atom;
- X2 is a hydrogen atom or fluorine atom or chlorine
atom;
- Rl a hydrogen atom or fluorine atom or chlorine atom
or methyl group or methoxy group or cyano group;
- R2 is an ethyl group.
61
3. Compound according to any one of claims 1 or 2,
characterised in that it s chosen from among the following
compounds:
- trans-3-amino-N,N-diethyl-1-
5 phenylcyclobutanecarboxamide,
- trans-3-amino-N,N-dimethyl-1-
phenylcyclobutanecarboxamide
- trans-3-amino-N,N-diethyl-1-(2-fluorophenyl)cyclobutanecarboxamide,
10 - trans-3-amino-N,N-diethyl-1-(3-methoxyphenyl)-
cyclobutanecarboxamide,
- trans-3-amino-N,N-diethyl-1-(3-fluorophenyl)cyclobutanecarboxamide,
- trans-3-amino-N,N-diethyl-1-(3-chlorophenyl)-
15 cyclobutanecarboxamide,
- trans-3-amino-N,N-diethyl-1-(3-methylphenyl)cyclobutanecarboxamide,
- trans-3-amino-N,N-diethyl-1-(3-cyanophenyl)cyclobutanecarboxamide,
20 - trans-3-amino-N,N-diethyl-1-(2-fluoro-3-
chlorophenyl)-cyclobutanecarboxamide,
- trans-3-amino-N,N-diethyl-1-(2,5-difluorophenyl)cyclobutanecarboxamide,
- trans-3-amino-N,N-diethyl-1-(3,5-difluorophenyl)-
25 cyclobutanecarboxamide,
- trans-3-amino-N,N-diethyl-1-(3,5-dichlorophenyl)cyclobutanecarboxamide
4. Compound according to any one of claims 1 to 3 for
30 use as a medication.
62
5. Compound according to any one of claims 1 to 3 for
use as medication for the treatment of depression.
6. Compound according to any one of claims 1 to 3 for
5 use as medication for the treatment of pain, particularly
pain due to excessive nociception, neuropathic pain and
mixed pain.
7. Pharmaceutical composition comprising at least one
10 compound of general formula (1) according to any one of
claims 1 to 3, and at least once pharmaceutically acceptable
excipient.
8. Pharmaceutical composition according to claim 7 for
15 use as medication for the treatment and/or prevention of
depression.
9. Pharmaceutical composition according to claim 7 for
use as medication for the treatment of pain, particularly
20 pain due to excessive nociception, neuropathic pain and
mixed pain.
10. Pharmaceutical composition according to any one of
claims 7 to 9, characterised in that it is formulated for
25 oral administration.
30
11. Pharmaceutical composition according to any one of
claims 7 to 9, characterised in that it is formulated for
topical administration.
5
10
15
20
63
12. Pharmaceutical composition according to any one of
claims 8 to 11 1 characterised in that it is presented in the
form of a daily dosage unit of a compound of general formula
(1) between 1 and 1000 mg.
13. Method for the preparation of compounds of general
formula ( 1) as defined in one of claims 1 to 3 1
characterised in that a secondary amine of formula (R2) 2NH
is reacted with a compound of formula (C)
to give the compound of formula (D)
the compound of formula (D) is then converted into an amine
25 of formula ( 1) 1 the R1 1 R2 1 X1 and X2 radicals present in the
reagents above-mentioned being as defined in claim 1.
30
14. Synthesis intermediates of formula (D)
x2
~x1 0
R1~--~~-R2 y R2
OH
(D)
64
wherein R1, R2, X1 and X2 are as defined in claim l, used
for the preparation of compounds of general formula (1) such
5 as defined in claims 1 to 3.
15. Synthesis intermediates of formula (C)
10
wherein Rl, X1 and X2 are as defined in claim 1, used for
the prepa~ation of compounds of general formula (D) such as
15 defined in claim 14.