Note: Descriptions are shown in the official language in which they were submitted.
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-1-
Lacosamide for add-on-therapy
Description
The present invention is directed to the use of a class of peptide compounds '
for the prevention, alleviation or/and treatment of a disease that is treated
with antipsychotics, in particular psychosis, more particular schizophrenia,
in
an add-on therapy to at least one antipsychotic.
Particularly, the present invention is directed to the use of a class of
peptide
compounds for the prevention, alleviation or/and treatment of schizophrenia,
bipolar disorder, autism, attention deficit hyperactivity disorder, psychosis,
psychosis associated with schizophrenia, bipolar disorder, autism,
Alzheimer's disease, attention deficit hyperactivity disorder, drug or/and
alcohol abuse, affective disorders, dyskinesias and related disorders,
dementia, mental retardation, polydipsia/hyponatraemia, severe personality
disorder, acute episodes of mania, obsessive compulsive disorder,
intractable chronic insomnia, Huntington's Disease, Tourette's syndrom,
Parkinson's disease, or/and dopaminergic therapy of Parkinson's disease,
preferably wherein psychosis is associated with schizophrenia, in an add-on
therapy-to at least one antipsychotic.
Certain peptides are known to exhibit central nervous system (CNS) activity
and are useful in the treatment of epilepsy and other CNS disorders. These
peptides which are described in the U.S. Patent No. 5,378,729 have the
Formula (la):
30
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-2-
R2
I
R NH--[-C CNH -],-C R,
0 9 0
R3
Formula (la)
wherein
R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower
alkyl,
heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower
cycloalkyl, lower cycloalkyl lower alkyl, and R is unsubstituted or is
substituted with at least one electron withdrawing group or electron donating
group;
R, is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl,
aryl, heterocyclic lower alkyl, heterocyclic, lower cycloalkyl, lower
cycloalkyl
lower alkyl, each unsubstituted or substituted with an electron donating
group or an electron withdrawing group; and
R2 and R3 are independently hydrogen, lower alkyl, lower alkenyl, lower
alkynyl, aryl lower alkyl, aryl, heterocyclic; heterocyclic lower alkyl, lower
alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, or Z-Y
wherein R2 and Rs may be unsubstituted or substituted with at least one
electron withdrawing group or electron donating group;
Z is 0, S, S(O)a, NR4, PR4 or a chemical bond;
Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower
alkynyl,
halo, heterocyclic, heterocyclic lower alkyl, and Y may be unsubstituted or
substituted with an electron donating group or an electron withdrawing
group, provided that when Y is halo, Z is a chemical bond, or
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-3-
ZY taken together is NR4NR5R7, NR4OR5, ONR4R7, OPR4R5, PR4OR5,
SNR4R7, NR4SR7, SPRaR5 or PR4SR7, NR4PR5R6or PR4NR5R,,
NR4C-R5, SCR5, NRaC-ORs, SC-ORs;
O O O 11 IOI
R4, R5 and R6 are independently hydrogen, lower alkyl, aryl, aryl lower alkyl,
lower alkenyl, or lower alkynyl, wherein R4, R5 and Rs may be unsubstituted
or substituted with an electron withdrawing group or an electron donating
group; and
R7 is R6 or COORs or CORs;
R8 is hydrogen or lower alkyl, or aryl lower alkyl, and the aryl or alkyl
group
may be unsubstituted or substituted with an electron withdrawing group or
an electron donating group; and
n is 1-4; and
a is 1-3.
U.S. Patent No. 5,773,475 also discloses additional compounds useful for
treating CNS disorders. These compounds are N-benzyl-2-amino-3-
methoxy-propionamide having the Formula (Ila):
H H H
I I I
Ar-CHr-N-G-C-N-C-Ri
1 11
O CH2 O
1
R3
Formula (Ila)
wherein
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-4-
Ar is aryl which is unsubstituted or substituted with halo; R3 is lower
alkoxy;
and R, is methyl.
However, neither the U.S. patent No. US 5,378,729 nor the U.S. patent No.
US 5,773,475 describe the use of these compounds for treating psychosis,
in particular for treating psychosis associated with schizophrenia, in an add-
on therapy to at least one antipsychotic.
WO 02/074297 relates to the use of a compound according to Formula (Ila)
wherein Ar is phenyl which may be substituted by at least one halo, R3 is
lower alkoxy containing 1-3 carbon atoms and R, is methyl for the
preparation of pharmaceutical compositions useful for the treatment of
allodynia related to peripheral neuropathic pain.
WO 02/074784 relates to the use of a compound having Formula (la) or/and
Formula (Ila) showing antinociceptive properties for treating different types
and symptoms of acute and chronic pain, especially non neuropathic
inflammatory pain, e.g. rheumatoid arthritic pain or/and secondary
inflammatory osteo-arthritic pain.
Psychosis, in particular schizophrenia, is a state of mental impairment
marked by following symptoms:
= Distorted Perceptions of Reality
People with psychosis may have perceptions of reality that are strikingly
different from the reality seen and shared by others around them.
= Hallucinations and Illusions
Hallucinations are perceptions that occur without connection to an
appropriate source. Hallucinations can occur in any sensory form - auditory
(sound), visual (sight), tactile (touch), gustatory (taste), and olfactory
(smell).
Auditory hallucinations, particularly the experience of hearing voices that
other people do not hear, are a common and often prominent feature of
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-5-
psychosis.
= Delusions
Delusions are false personal beliefs that are not subject to reason or
contradictory evidence and are not explained by a person's usual cultural
concepts.
= Disordered Thinking
Psychosis often affects a person's ability to "think straight." Thoughts may
come and go rapidly; the person may not be able to concentrate on one
thought for very long and may be easily distracted, unable to focus attention.
Disordered thinking is classified largely by its effect on speech and writing.
Psychosis is considered to be a symptom of severe mental illness, but not a
diagnosis in itself. Although it is not exclusively linked to any particular
psychological or physical state, it is particularly associated with
schizophrenia, bipolar disorder and severe clinical depression. There are
also several physical circumstances that can induce a psychotic state,
including electrolyte disorder, urinary tract infections in the elderly, pain
syndromes, drug toxicity, and drug withdrawal (especially alcohol,
barbiturates, and sometimes benzodiazepines) as well as infections of or
injuries to the brain (these psychoses are now more commonly referred to as
organic mental disorders).
Chronic psychological stress is also known to cause psychotic states, though
the exact mechanism is uncertain. Short-lived psychosis triggered by stress
is known as brief reactive psychosis.
There are also some non-psychiatric conditions which are linked particularly
to psychosis, which may include brain tumor, dementia with Lewy bodies,
hypoglycemia, intoxication, multiple sclerosis, systemic lupus
erythematosus, or/and sarcoidosis.
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-6-
Psychosis is a common condition in schizophrenia, marked by the typical,
above mentioned symptoms. In addition, people with schizophrenia often
show "blunted" or "flat" affect. This refers to a severe reduction in
emotional
expressiveness.
Schizophrenia is a chronic, severe, and disabling brain disease found all
over the world. Approximately 1 percent of the population develops
schizophrenia during their lifetime. The severity of the symptoms and long-
lasting, chronic pattern of schizophrenia often cause a high degree of
disability. People with schizophrenia have a higher rate of suicide than the
general population. Approximately 10 percent of people with schizophrenia
(especially younger adult males) commit suicide. The first signs of
schizophrenia often appear as confusing, or even shocking, changes in
behavior. This sudden onset of severe psychotic symptoms is referred to as
an "acute" phase of schizophrenia.
Some people have only one such psychotic episode; others have many
episodes during a lifetime, but lead relatively normal lives during the
interim
periods. However, the individual with "chronic" schizophrenia, or a
continuous or recurring pattern of illness, often does not fully recover
normal
functioning and typically requires long-term treatment, generally including
medication, to control the symptoms.
There is no known single cause of schizophrenia. Many diseases, such as
heart disease, result from interplay of genetic, behavioral, and other
factors;
and this may be the case for schizophrenia as well. It has long been known
that schizophrenia runs in families. Scientists are studying genetic factors
in
schizophrenia. It appears likely that multiple genes are involved in creating
a
predisposition to develop the disorder. In addition, factors such as prenatal
difficulties like intrauterine starvation or - viral infections, perinatal
complications, and various nonspecific stressors, seem to influence the
development of schizophrenia. However, it is not yet understood how the
genetic predisposition is transmitted, and it cannot yet be accurately
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-7-
predicted whether a given person will or will not develop the disorder.
Basic knowledge about brain chemistry and its link to schizophrenia is
expanding rapidly. It is likely, although not yet certain, that the disorder
is
associated with some imbalance of the complex, interrelated chemical
systems of the brain, perhaps involving the neurotransmitters dopamine and
glutamate.
Many studies of people with schizophrenia have found abnormalities in brain
structure (for example, enlargement of the fluid-filled cavities, called the
ventricles, in the interior of the brain,. and decreased size of certain brain
regions) or function (for example, decreased metabolic activity in certain
brain regions). It should be emphasized that these abnormalities are quite
subtle and are not characteristic of all people with schizophrenia, nor do
they
occur only in individuals with this illness. Microscopic studies of brain
tissue
after death have also shown small changes in distribution or number of brain
cells in people with schizophrenia. It appears that many (but probably not
all)
of these changes are present before an individual becomes ill, and
schizophrenia may be, in part, a disorder in development of the brain.
Available treatments can relieve many symptoms, but most people with
schizophrenia continue to suffer some symptoms throughout their lives; it
has been estimated that no more than one in five individuals recovers
completely. Medications and other treatments for schizophrenia can help
reduce and control the distressing symptoms of the illness. However, some
people are not greatly helped by available treatments or may prematurely
discontinue treatment because of unpleasant side effects. Since
schizophrenia may not be a single condition and its causes are not yet
known, current treatment methods are based on both clinical research and
experience. These approaches are chosen on the basis of their ability to
reduce the symptoms of schizophrenia and to lessen the chances that
symptoms will return.
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-8-
Antipsychotic medications have been available since the mid-1950s but they
do not "cure" the underlying disease such as schizophrenia or ensure that
there will be no further psychotic episodes. Clinically effective
antipsychotic
agents include tricyclic phenothiazines, thioxanthenes, and dibenzepines, as
well as butyrophenones and congeners, other heterocyclics and
experimental benzamides. Virtually all of these drugs block D2-dopamine
receptors and reduce dopamine neurotransmission in forebrain; some of
these drugs, in particular the atypical antipsychotics, also interact with D,-
and D4-dopaminergic, 5-HT2A- and 5-HT2c-serotonergic and alpha-adrenergic
receptors (Goodman & Gilman's, The Pharmacological Basis of
Therapeutics, 10th edition, McGraw-Hill, 2001: Summary of chapter 20 (p.
485)). Antagonism of dopamine-mediated synaptic neurotransmission is an
important action of antipsychotic drugs (same document, p. 493, left column,
2nd para).
A number of new antipsychotic agents (the so-called "atypical
antipsychotics") have been introduced since 1990. The first of these,
clozapine, has been shown to be more effective than other antipsychotics,
although the possibility of severe side effects - in particular, a condition
called agranulocytosis (loss of the white blood cells that fight infection) -
requires that patients be monitored with blood tests every one or two weeks.
Even newer antipsychotic agents, such as risperidone and olanzapine are
safer than the older drugs or clozapine, and they also may be better
tolerated. They may or may not treat the illness as well as clozapine,
however.
Antipsychotic agents are often very effective in treating certain symptoms of
schizophrenia, particularly hallucinations and delusions; unfortunately, the
drugs may not be as helpful with other symptoms, such as reduced
motivation and emotional expressiveness.
Current limitations of antipsychotic agent therapy of psychosis, especially
psychosis associated with schizophrenia, include limited efficacy, side
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-9-
effects and delayed onset of action. Valproate was shown to enhance the
onset of action of olanzapine or risperidone (Casey et al.,
Neuropsychopharmacology 28:182ff, 2003). Furthermore, another double-
blind placebo controlled clinical trial demonstrated that lamotrigine, when
added to clozapine, is beneficial for the treatment of treatment-resistant
schizophrenia (Tihohen et al., Biol Psychiatr. 54:1241ff, 2003). It is
estimated that currently up to 50% of hospitalized schizophrenic patients
receive adjunct therapy with anti-epileptic drugs (Citrome L.,
Psychopharmacology Bull 37(S2):p74ff, 2003) especially for enhancing the
onset of action, for controlling the positive symptoms, e.g. hallucinations,
the
affective symptoms, e.g. depression, as well as the cognitive symptoms, e.g.
attention deficit.
However, as described in Citrome L., Psychopharmacology Bull 37(S2):
p74ff, 2003, data on the use of anticonvulsahts for add-on therapy to
antipsychotics are inconsistent. Valproate and lamotrigine were shown to
preferentially reduce the positive symptoms of schizophrenia (same
document, p. 86, last para). A possible locus of action of valproate was said
to be direct effects on voltage gated sodium channels (same document,
page 78, 2nd para). However, the use of the anticonvulsant carbamazepine
as add-on to the antipsychotic agent haloperidol was associated with a
worse clinical outcome compared with antipsychotic monotherapy (same
document, page 80, first para). In another study on the use of
carbamazepine there was a failure to detect significant improvement on the
total BPRS (brief psychiatric rating scale). Adjunctive use of lamotrigine in
addition to clozapine resulted in improvement of positive, not negative
symptoms of schizophrenia (same document, page 85, 1St para). Reports on
the use of other anticonvulsants in schizophrenia report general worsening
of psychosis with gabapentin or deterioration in both positive and negative
symptoms of schizophrenia with topiramate (same document, page 85, 2nd
para).
The reported differences in the efficacy of anticonvulsants as add-on
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-10-
therapeutics to antipsychotics might be due to their, different modes of
action. In contrast to antipsychotic agents that share a common antagonistic
action on dopamine receptors, current anticonvulsants are believed to work
through diverse mechanisms of action. These mechanisms of action are e.g.
altering neuronal impulse propagation via interaction with voltage gated
sodium-, calcium-, or potassium channels or affecting neural transmission by
either potentiating inhibitory GABA systems or by inhibition of excitatory
glutamate systems.
In contrast to current anticonvulsants, lacosamide potentially has a unique
but yet unknown molecular mechanism of action. Lacosamide does not
directly interact with a variety of known GABA receptor subtypes, nor does it
directly interact with a variety of known glutamate receptor subtypes. In
particular, lacosamide does not inhibit voltage-gated sodium or calcium
channels and does not potentiate potassium currents.
In an article by Jann MW, Pharmacotherapy 2004;24(12):1759-1783, which
is directed to the cognitive symptoms of schizophrenia, add-on therapy of
antipsychotics to several other active agents is described, but no reference
is made to add-on therapy of antipsychotics to anticonvulsants.
The use of compounds of Formula (lb) or/and Formula (ilb) for treatment of
psychosis, in particular schizophrenia or/and psychosis associated with
schizophrenia, in an add-on therapy to at least one antipsychotic agent has
not been reported. Thus, the present invention concerns the use of said
compound(s) of Formulae (Ib) or/and (Ilb) for the preparation of a
pharmaceutical composition for the prevention, alleviation or/and treatment
of a disease treated with an antipsychotic, in particular psychosis, more
particular in the course of schizophrenia, in an add-on therapy to at least
one antipsychotic.
The application of lacosamide (international non-proprietory name, also
formerly called harkose(de or SPM 927) alone had no significant effect on
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-11-
prepulse inhibition in mice, which is a model of predictive validity for
psychosis, particularly for cognitive symptoms. Surprisingly, the compounds
(Ib) or/and (llb), particularly (R)-2-acetamide-N-benzyl-3-
methoxypropionamide (lacosamide) potentiated the increase of prepulse
inhibition of the antipsychotic agent, clozapine, when administered together.
Prepulse inhibition in mice is a model of predictive value for psychosis
associated with e.g. schizophrenia, bipolar disorder, autism, Alzheimer's
disease, attention deficit hyperactivity disorder, drug or/and alcohol abuse,
affective disorders, dyskinesias and related disorders, dementia, mental
retardation, polydipsia/hyponatraemia, severe personality disorder, acute
episodes of mania, obsessive compulsive disorder, intractable chronic
insomnia, Huntington's Disease, Tourette's syndrom, Parkinson's disease,
or/and dopaminergic therapy of Parkinson's disease.
Considering the prior art as outlined above, in particular the multitude of
modes of action of anticonvulsants, the conflicting results in the add-on
therapy of anticonvulsants and antipsychotics, the difference of the mode of
action of valproate, the only anticonvulsant with established usefulness in
add-on therapy with antipsychotics, as compared to lacosamide, and the
lack of mentioning of anticonvulsants in an article on add-on therapy of
cognitive symptoms of schizophrenia (Jann MW, see above), a person
skilled in the art would not, have expected the usefulness of lacosamide in
the therapy of psychosis in an add-on therapy to at least one antipsychotic.
In a broad sense, the term õantipsychotic agent" or õanti-psychotic" refers to
any compound known in the art for prevention, alleviation or treatment of
psychosis, including without limitation: (-)-isofloxythepin, (+-)-idazoxan
monohydrochloride, (+)-isofloxythepin, 1,2-benzisoxazole-3-
methanesulfonamide, monosodium salt, 1 H-isoindole-a,3(2H)-dione, 2-[4-[4-
(1,2-benzisothiazol-3-yl)-1-piperazinyl]buryl]-hexahydro-,
monohydrochloride, (3aR,7aS)-rel-, 2(1 H)-quinolinone, 1-[3-[4-(3-
chlorophenyl)-1-piperazinyl]propyl]-3,4-dihydro-5-methoxy- (OPC 14523), 2-
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-12-
propen-l-one, 1-(2-fluorophenyl)-3-(4-hydroxyphenyl)-O-[2-(dimethylamino)-
ethyl]oxime, (1 Z,2E)-, (2E)-2-butenedioate (2:1), 9H-xanthene-9-propanoic
acid, a-amino-a-[(1S,2S)-2-carboxycyclopropyl]-m(aS) (LY 341495),
abaperidone, acetophenazine, aminosultopride, amisuipride, ampalex,
aplindore fumarate, aripiprazole, asenapine maleate, benperidol,
benzquinamide, beta-uridine, bromoperidol, buramate, butaperazine,
carbadipimidine, carbamazepine, carphenazine, carpipramine, carpipramine
dihydrochloride, centbutindole, chlorpenthixol, chlorpromazine,
chlorpromazine hydrochloride, chlorprothixene, cis-clopenthixol, cis-
tramadol, cis-tramadol hydrochloride, citalopram hydrobromide,
clocapramine, clocapramine dihydrochloride, clomacran, clopenthixol,
clospirazine, clothiapine, clozapine, cyamemazine, devazepide, divalproex
sodium, dixyrazine, droperidol, duloxetine hydrochloride, ethyl loflazepate,
farampator, fluanisone, flubuperone, fluoxetine hydrochloride, flupentixol,
fluphenazine, fluphenazine decanoate, fluphenazine enanthate,
fluphenazine hydrochloride, fluspirilene, flutoprazepam, fluvoxamine,
fluvoxamine maleate, haloperidol, haloperidol and haloperidol decanoate,
iloperidone, isofloxythepin, lamotrigine, loxapine succinate, lurasidone
hydrochloride, melperone, melperone hydrochloride, mepazine,
mesoridazine, mesoridazine besylate, methoxypromazine, metofenazate,
mifepristone, minaprine, minaprine hydrochloride, moclobemide, molindone,
molindone hydrochloride, moperone, mosapramine, mosapramine
dihydrochloride, neboglamine, nemonapride, ocaperidone, octoclothepine,
olanzapine, opipramol, paroxetine, penfluridol, perazine, pericyazine,
perimethazine, perospirone, perphenazine, phenothiazines, pimozide,
piperacetazine, pipothiazine, pipothiazine palmitate, pipotiazine,
pramipexole, prochlorperazine, promazine, prothipendyl, quetiapine,
quetiapine fumarate, racemic idazoxan, remoxipride, risperidone,
sabcomeline, secretine, sertraline hydrochloride, spiperone, sulforidazine,
sulpiride, sultopride, talnetrant, tetrabenazine, thiapride, thiopropazate,
thioproperazine, thioridazine, thioridazine hydrochloride, thiothixene,
thiothixene hydrochloride, thioxanthenes, timeperone, topiramate,
trifluoperazine, trifluoperazine hydrochloride, trifluperidol,
triflupromazine,
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-13-
zaprasidone, ziprasidone hydrochloride, zonisamide, zotepine,
zuclopenthixol acetate, zuclopenthixol decanoate, enantiomers, racemates,
pharmaceutically acceptable salts, esters, amides, prodrugs and metabolites
thereof.
More particularly, term "antipsychotic" or "antipsychotic agent" as used here
is meant to comprise classical or so-called typical antipsychotics, also
referred to as classical or typical neuroleptics, as well as atypical
antipsychotics, also referred to as atypical neuroleptics. Examples for
classical antipsychotics are acetophenazine, benperidol, benzquinamide,
biriperone, bromoperidol, butaperazine, butyrophenones, carphenazine,
centbutindole, chlorpromazine, chlorpromazine hydrochloride,
chlorprothixene, clomacran, clopenthixol, clothiapine, cyamemazine,
dibenzoxazepines, dihydroindolones, dixyrazine, droperidol, fluanisone,
flupentixol, fluphenazine, fluphenazine decanoate, fluphenazine enanthate,
fluphenazine hydrochloride, haloperidol, haloperidol decanoate,
isofloxythepin, levomepromazine, loxapine succinate, melperone, melperone
hydrochloride, mepazine, mesoridazine, mesoridazine besylate,
methotrimeprazine, methoxypromazine, metofenazate, molindone,
molindone hydrochloride, moperone, neboglamine, nemonapride,
octoclothepine, penfluridol, pericyazine, perimethazine, perphenazine,
phenothiazines, pimozide, pipamperone, pipothiazine, pipothiazine
paimitate, prochlorperazine, promazine, prothipendyl, spiperone,
sulforidazine, sultopride, talnetant, thiapride, thiopropazate,
thioproperazine,
thioridazine, thioridazine hydrochloride, thiothixene, thiothixene
hydrochloride, thioxanthenes, trifluoperazine, trifluoperazine hydrochloride,
trifluperidol, triflupromazine, zuclopenthixol acetate, zuclopenthixol
decanoate and enantiomers, racemates, pharmaceutically acceptable salts
and derivatives, particularly esters, amides, prodrugs and metabolites
thereof. Examples for . atypical antipsychotics are abaperidone,
aminosultopride, amisulpride, ampalex, aripiprazole, asenapine maleate,
clozapine, fluspirilene, iloperidone, mosapramine, mosapramine
dihydrochioride, ocaperidone, olanzapine, oxypertine, _ perazine,
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-14-
perospirone, piperacetazine; quetiapine, quetiapine fumarate, remoxipride,
risperidone, sertindole, suipiride, ziprasidone, ziprasidone hydrochloride,
zotepine and enantiomers, racemates, pharmaceutically acceptable salts
and derivatives, particularly esters, amides, prodrugs and metabolites
thereof. The term "antipsychotic" further comprises dopamine antagonists,
preferably D2 antagonists.
The term "antipsychotic" or "antipsychotic agent" as used here preferably
does not comprise drugs that, although they might also be used in the
therapy of psychosis, are no antipsychotics as defined above, such as for
example anticonvulsants (such as carbamazepine, valproate, lamotrigine),
antidepressants, such as tri- and tetracyclic antidepressants (for example
amitryptiline, clomipramine, doxepine, imipramine, trimipramine,
nortriptyline, desipramine, maprotiline, trazodone), selective serotonine-
reuptake inhibitors (for example citaloprame, fluoxetine, fluvoxamine,
paroxetine, sertraline), selective noradrenaline-reuptake inhibitors (for
example reboxetine), serotonine-noradrenaline-reuptake inhibitors (for
example venlafaxine, duloxetine), serotonine-noradrenaline-specific
antidepressants (for example mianserine, mirtazapine) or monoamine-
oxidase inhibitors (for example tranylcypromine, moclobemide), lithium salts
or benzodiazepines (for example alprazolame, lorazepame, diazepame).
Doses of typical dopamine antagonists which may be employed in the
present invention are:
Psychosis-treating
compound [CAS Mode of action Illustrative dose Reference
Ref.
Amisulpride Dopamine D2/D3 200-1200 http://en.wikipedia.org/
71675-85-9 antagonist mg/day wiki/Amisul ride
The recommended
starting and target http://www.healthyplace.com
dose is 10 or 15 /Communities/Thought
Aripiprazole Dopamine D2 mg/day
[129722-12-9] partial agonist administered on a Disorders/schizo/medication
once-a-day s/
schedule without aripiprazole.asp#DOSAGE
re ard to meals.
Biriperone Dopamine 3-4.5 mg/day p.o.
42021-34-1 antagonist
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-~5-
Psychosis-treating
compound ICAS Mode of action iliustrative dose Reference
Ref.]
Bromperidol Dopamine D2 3-18 mg/day http://chrom.tutms.tut.ac.jp/
[10457-90-6] antagonist JINNO/DRUGDATA/
46brom eridol.html
Carpipramine Dopamine D2
[5942-95-0; 7075-03- antagonist
8
Clocapramine Serotonin antagonist; targets http://chrom.tutms.tut.ac.jp/
[28058-62-0; dopamine D2 30-150 mg/day JINNO/DRUGDATA/
47739-98-0] receptor 57clocapramine.htmi
Clorotepine Dopamine
13448-22-1 antagonist
Achieve a target
dose of 300-450
mg/day by the end http:/Iwww.rxiist.com/cgi/
of 2 weeks. Adults generic3/clozapine ids.htm
Dopamine At frst, 12.5 mg
Clozapine [5786-21-0] antagonist once or twice a http://www.nlm.nih.gov/
day. However, the medlinepius/druginfo/uspdi/
dose usually is not 202157.html
more than 900 mg
a da.
Isofiloxythepin
[106819-39-0; Dopamine 5 mg/kg orally Psychopharmacology (13er1.)
106819-41-4; antagonist 1982; 76{4):389-4.
70931-18-9
Melperone Dopamine D2 Sumiyashi: Schizophrenia
[1622-79-3; 3575-80- antagonist 300 mg/day Research 62(2):65
2]
Mosapramine
[89419'-40-9, Dopamine D2
mgiday
98043-60-8] antagonist 6.25-25
Nemonapride Dopamine D2/D3 9-36 mg/day
75272-39-8 antagonist
Olanzapine Dopamine D2 http://www.mentalhealth.co
132539-06-1 anta onist 10 mg/day m/ dru / 30-oQ2.html
Dopamine J. Clin. Pharmacol.,
Penfluridol [26864-56- antagonist (D1 and 60-8Q mg once April 1, 1977;
17(4):252-
2] D2 weekly 258.
Perospirone. Dopamine D2
[129273-38-7; antagonist 8-48 mg/day
150915-41-6
The average
Pimozide [2062-78-4] Dopamine D2 maintenance dose http://home.intekom.com/
antagonist is 6 mg daily with pharm/janssen/orap-t.html
the usual range of
2 to 12 mg per da
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-16=
Psychosis-treating
compound [CAS Mode of action Illustrative dose Reference
Ref.]
To be administered
as an i.m. injection
only; it is frequently
Pipotiazine palmitate Dopamine possible to achieve http://www.mentalhealth.co
[37517-26-3; antagonist; adequate control m/drug/p30-
39860-99-6] targets dopamine with a dosage p03.html#Head_8
D2 receptor between 75 and
150 mg
administered every
4 weeks
Quetiapine fumarate University of Alberta website
[111974-69-7; Dopamine D2 Varies called 'DrugBank';
111974-72-2] antagonist http://www.rxiist.com/cgi/
eneric2/auetiap ids.htm#D
6 mg/day http://ajp.psychiatryonline.or
/c i/re rint/157/7/1178-a
Risperdal Consta:
Risperidone Dopamine D2 25-75m /da i.m.
[106266-06-2] antagonist Risperdal
Instasolv: http://www.rxiist.com/cgi/
mean modal dose generic/risperid_cp.htm#CP
mg/day
600-800 mg/day
i.m.; or 200-3200
Sulpiride [15676-16-1] Dopamine D2 mg/day in 2 or 3 http://www.mentalhealth.co
antagonist divided doses m/drug/p30-s06.html
orally
Sultopride [53583-79- Dopamine D2
2 antagonist
Usual final dose is http://www.spisdemo.com/
Tiapride [51012-32-9] Dopamine D2 200-300 mg/day, ~
antagonist continued for 1-2 ~~Display.aspx.qsRXID
months =RX22030204&qsSection=5
Timiperone Dopamine D2 4_8 mg/day
[57648-21-21 antagonist
Ziprasidone Dopamine D2 http://www.geodon.com/
[122883-93-6; antagonist Varies hcp_home.asp
146939-27-7
Dopamine http://www.ukmi.nhs.uk/
Zotepine [26615-21-4] antagonist 75-300 mg/day NewMaterial/htmi/docs/
zote ine. df
Zuclopenthixol The usual http://www.mentalhealth.co
[53772-83-1; 982-24- Dopamine D2 antagonist therapeutic range m/drug/p30-
1 is 20-60m /da z03.html#Head 8
50-150 mg i.m.,
repeated if
necessary every 2-
Zuclopenthixol 3 days; maximum http://www.vhpharmsci.com/
Dopamine D2 cumulative dose PDTM/Monographs/
acetate [85721 05-7] antagonist should not exceed zuclopenthixol%
400 mg and 20acetate.htm
number of
injections should
not exceed 4
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-17-
Psychosis-treating
compound [CAS Mode of action Illustrative dose Reference
Ref.
The minimum
effective dose of
Zuclopenthixol zuclopenthixol was pharmacopsychiatry 1994
decanoate Dopamine D2 200 mg/2 weeks May; 27(3):119-123
[64053-00-5] antagonist (range 60-400),
with a serum
concentration of 22
nmol/I (7.1-69.7).
In an especially preferred embodiment, the present invention refers to a
specific combination of lacosamide with at least one of the antipsychotics as
indicated above, more particular with at least one dopamine antagonist,
which may be at least one D2 antagonist, even more particular with at least
one atypical antipsychotic such as at least one atypical antipsychotic as
defined above, most particular clozapine, risperidone, aripiprazole,
quetiapine, olanzapine, ziprasidone, suipiride, amisuipride or/and zotepine.
An add-on therapy according to the present invention for the prevention,
alleviation or/and treatment of a disease treated with an antipsychotic, in
particular psychosis, more particular schizophrenia or/and psychosis
associated with schizophrenia, is the co-administration of at least one
compound of Formulae (Ib) or/and (ilb) with at least one antipsychotic agent
useful for the prevention, alleviation or/and treatment of psychosis, in
particular schizophrenia, in order to increase the efficacy, decrease the side
effects or/and enhance the onset of action of the antipsychotic medication,
for example.
The term "co-administration" refers to a plurality of agents that, when
administered to a subject together or separately, are co-active in bringing
therapeutic benefit to the subject. Such co-administration is also referred to
as "combination therapy," "co-therapy," "adjunctive therapy" or "add-on
therapy." For example, one agent can potentiate or enhance the therapeutic
effect of another, or reduce an adverse side effect of another, or one or more
agents can be effectively administered at a lower dose than when used
alone, or can provide greater therapeutic benefit than when used alone, or
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-18-
can complementarily address different aspects, symptoms or etiological
factors of a disease or condition.
Co-administration comprises administration of the agents in amounts
sufficient to achieve or/and maintain therapeutically effective
concentrations,
e.g. plasma concentrations, in the subject in need thereof. Co-administration
comprises simultaneous or/and subsequent administration. Simultaneous
administration comprises administration of the agents as a single or as
different compositions (see below) "at the same time" within the treatment
period. Subsequent administration comprises administration of the agents
"at intervals" within the treatment period.
Administration "at the same time" includes administration of the at least one
antipsychotic agent useful for the prevention, alleviation or/and treatment of
psychosis and the compound(s) of Formulae (lb) or/and (Ilb) literally "at the
same time", but also includes administration directly one after another.
Administration "at intervals" includes administration of the at least one
antipsychotic agent useful for the prevention, alleviation or/and treatment of
psychosis and the compound(s) of Formulae (Ib) or/and (Ilb) at an interval of
1 h at the maximum, preferably 6 h at the maximum, more preferably 12 h at
the maximum, even more preferably 1 day at the maximum, and most
preferably 1 month at the maximum.
The at least one antipsychotic agent useful for the prevention, alleviation
or/and treatment of psychosis and the at least one compound of Formulae
(Ib) or/and (Ilb) may be formulated in one pharmaceutical preparation (single
dose form) for administration at the same time or may be formulated in two
distinct preparations (separate dose form) for administration at the same
time or at intervals, as described in the preferred embodiments below for
example. The two distinct preparations in the separate dose form may be
administered by the same route or by different routes.'
Separate dose forms can optionally be co-packaged, for example in a single
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-19-
coritainer or in a plurality of containers within a single outer package, or
co-
presented in separate packaging ("common presentation"). As an example
of co-packaging or common presentation, a kit is contemplated comprising,
in separate containers, the at least one antipsychotic and the at least one
compound of Formulae (Ib) or/and (Ilb). In another example, the at least
one antipsychotic and the at least one compound of Formulae (Ib) or/and
(Ilb) are separately packaged and available for sale independently of one
another, but are co-marketed or co-promoted for use according to the
invention. The separate dose forms may also be presented to a subject
separately and independently, for use according to the invention.
Depending on the dosage forms, which may be identical or different, e.g.
fast release dosage forms, controlled release dosage forms or/and depot
forms, the at least one antipsychotic agent useful for the prevention,
alleviation or/and treatment of psychosis and the compound(s) of Formulae
(lb) or/and (Ilb) may be administered with the same or with different
schedules on a daily, weekly or monthly basis. Therefore, the administration
interval of the at least one antipsychotic agent useful for the prevention,
alleviation or/and treatment of psychosis and the compound(s) of Formulae
(Ib) or/and (lib) may depend on the administration schedules or/and on the
dosage forms.
In a preferred embodiment, the compounds of Formulae (Ib) or/and (Ilb) are
used for the preparation of a pharmaceutical composition comprising
(a) at least one antipsychotic agent useful for the prevention, alleviation
or/and treatment of psychosis, and
(b) at least one compound of Formulae (Ib) or/and (Ilb).
In the use of the present invention, the at least one antipsychotic agent
useful for the prevention, alleviation or treatment of psychosis may be a
dopamine antagonist, preferably a D2 antagonist, more preferably an atypical
antipsychotic agent, even more preferably an atypical antipsychotic as
defined above, and most preferably the agent is clozapine, risperidone,
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
- 20 '-
aripiprazole, quetiapine, olanzapine, ziprasidone, suipiride, amisuipride
or/and zotepine.
In a further preferred embodiment, the compounds of Formulae (Ib) or/and
(Ilb) are used for the preparation of a pharmaceutical composition
comprising a single dose form comprising at least one compound according
to Formula (Ib) or/and Formula (lib) and at least one antipsychotic agent
useful for the prevention, alleviation or/and treatment of psychosis in the
form of one composition.
In another preferred embodiment, the compounds of Formulae (lb) or/and
(ilb) are used for the preparation of a pharmaceutical composition which is a
separate dose form comprising
(i) a first composition comprising at least one antipsychotic agent useful for
the prevention, alleviation or/and treatment of psychosis, and
(ii) a second composition comprising at least one compound of Formulae
(lb) or/and (Ilb).
In yet another preferred embodiment of the present invention, a
commercially available composition of an antipsychotic agent useful for
prevention, alleviation or/and treatment of psychosis may be administered to
a subject in need thereof. Therefore, in this preferred embodiment, the
compounds of Formulae (lb) or/and (ilb) are used for the preparation of a
pharmaceutical composition comprising at least one compound according to
Formula (lb) or/and Formula (lib) and not comprising an antipsychotic agent
useful for the prevention, alleviation or/and treatment of psychosis.
The use according to the present invention may comprise the preparation of
a pharmaceutical composition for administration of the at least one
compound of Formulae (Ib) or/and (ilb) and the at least orie antipsychotic
agent useful for the prevention, alleviation or/and treatment of psychosis at
the same time or at intervals, as defined above.
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-21 -
A compound according to the invention has the general Formula (Ib)
R2
1
R NH-[-C CNH-]õ-C R,
O 1 O
R3
Formula (lb)
wherein
R is hydrogen, alkyl, alkenyl, alkynyl, aryl, aryl alkyl, heterocyclic,
heterocyclic alkyl, alkyl heterocyclic, cycloalkyl or cycloalkyl alkyl, and R
is
unsubstituted or is substituted with at least one electron withdrawing group,
and/or at least one electron donating group;
R, is hydrogen or alkyl, alkenyl, alkynyl, aryl alkyl, aryl, heterocyclic
alkyl,
alkyl heterocyclic, heterocyclic, cycloalkyl, cycloalkyl alkyl, each
unsubstituted or substituted with at least one electron donating group and/or
at least one electron withdrawing group;
and
R2 and R3 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl alkyl,
aryl, halo, heterocyclic, heterocyclic alkyl, alkyl heterocyclic, cycloalkyl,
cycloalkyl alkyl, or Z-Y wherein R2 and R3 may be unsubstituted or
substituted with at least one electron withdrawing group and/or at least one
electron donating group;
Z is 0, S, S(O)a, NR4, NR'6, PR4 or a chemical bond;
Y is hydrogen, alkyl, aryl, aryl alkyl, alkenyl, alkynyl, halo, heterocyclic,
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-22-
heterocyclic alkyl, alkyl heterocyclic and Y may be unsubstituted or
substituted with at least one electron donating group and/or at least -one
electron withdrawing group, provided that when Y is halo, Z is a chemical
bond, r
ZY taken together is NR4NR5R7, NR4OR5, ONR4R7, OPR4R5, PR4OR5,
SNR4R7, NR4SR7, SPR4R5, PR4SR7, N R4PR5R6, PR4NR5R, or N+RsR6R7,
NR4C-R5, S I) R5, NR.4 I, -ORS, SC-OR5, NR4NR5- II-ORs';
0 0 0 O O
R'6 is hydrogen, alkyl, alkenyl, or alkynyl which may be unsubstituted or
substituted with at least one electron withdrawing group or/and at least one
electron donating group;
R4, R5 and R6 are independently hydrogen, alkyl, aryl, aryl alkyl, alkenyl, or
alkynyl, wherein R4, R5 and R6 may independently be unsubstituted or
substituted with at least one electron withdrawing group or/and at least one
electron donating group;
R7 is R6 or COORB or COR8, which R7 may be unsubstituted or substituted
with at least one electron withdrawing group or/and at least one electron
donating group;
R8 is hydrogen or alkyl, or aryl alkyl, and the aryl or alkyl group may be
unsubstituted or substituted with at least one electron withdrawing group
or/and at least one electron donating group; and
nis1-4;and
a is 1-3.
Preferably the compound according to the invention has the general Formula
(ilb)
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-23-
H H H
I ( i
Ar-CHz-N-C-C-N-C-R,
(p R3 O
Formula (llb)
wherein
Ar is aryl, especially phenyl, which is unsubstituted or substituted with at
least one substituent independently selected from the group consisting of
hydrogen, halo, alkyl, alkenyl, alkynyl, nitro, carboxy, formyl, carboxyamido,
aryl, quaternary ammonium, haloalkyl, aryl alkanoyl, hydroxy, alkoxy, amino,
alkylamino, dialkylamino, aryloxy, mercapto, alkylthio, alkylmercapto, and
disulfide;
R3 is selected from the group consisting of hydrogen, alkyl, alkoxy,
alkoxyalkyl, aryl, N-alkoxy-N-alkylamino, and N-alkoxyamino; and
R, is alkyl.
In particular, Ar is aryl, especially phenyl, which is unsubstituted or
substituted with at least one halo; R3 is -CH2-Q, wherein Q is lower alkoxy;
and R, is lower alkyl, especially methyl.
The present invention is also directed to a pharmaceutical composition
comprising at least one compound according to Formula (Ib) or/and Formula
(ilb) useful for the prevention, alleviation or/and treatment of a disease
that
can be treated with an antipsychotic, in particular psychosis, in an add-on
therapy to at least one antipsychotic agent.
In a preferred embodiment, the pharmaceutical composition comprises
(a) at least one antipsychotic agent useful for the prevention, alleviation
or/and treatment of psychosis, and
(b) at least one compound of Formulae (Ib) or/and (Ilb).
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-24-
In the pharmaceutical composition of the present invention, the at least one
antipsychotic agent useful for the prevention, alleviation or treatment of
psychosis may be a dopamine antagonist, preferably a D2 antagonist, more
preferably an atypical antipsychotic agent, even more preferably an atypical
antipsychotic as defined above, and most preferably the agent is clozapine,
risperidone, aripiprazole, quetiapine, olanzapine, ziprasidone, sulpiride,
amisulpride or/and zotepine.
In a further preferred embodiment, the pharmaceutical composition of the
present invention comprises a single dose form comprising at least one
compound according to Formula (Ib) or/and Formula (Ilb) and at least one
antipsychotic agent useful for the prevention, alleviation or/and treatment of
psychosis in the form of one composition.
In another preferred embodiment, the pharmaceutical composition of the
present invention comprises a separate dose form comprising
(i) a first composition comprising at least one antipsychotic agent useful for
the prevention, alleviation or/and treatment of psychosis, and
(ii) a second composition comprising at least one compound of Formulae
(Ib) or/and (Ilb).
In yet another preferred embodiment of the present invention, a
commercially available composition of an antipsychotic agent useful for the
prevention, alleviation or/and treatment of psychosis may be administered to
a subject in need thereof. Therefore, in this preferred embodiment, the
pharmaceutical composition of the present invention comprises at least one
compound according to Formula (lb) or/and Formula (Ilb) and does not
comprise an antipsychotic agent useful for the prevention, alleviation or/and
treatment of psychosis.
The pharmaceutical composition of the present invention may be prepared
for administration of the at least one compound of Formulae (Ib) or/and (Ilb)
and the at least one antipsychotic agent useful for the prevention,
alleviation
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-25-
or/and treatment of psychosis at the same time or at intervals, as defined
above.
The term "alkyl" (alone or in combination with another term(s)) means a
straight- or branched-chain saturated hydrocarbyl substituent preferably
containing from 1 to about 20 carbon atoms, more preferably from 1 to about
8 carbon atoms, and even more preferably from 1 to about 6 carbon atoms.
Most preferably, alkyl is lower alkyl as defined below.
The "lower alkyl" groups when used alone or in combination with other
groups, are lower alkyl containing from 1 to 6 carbon atoms, especially I to 3
carbon atoms, and may be straight chain or branched. These groups include
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, - tertiary butyl, pentyl
and
isomers of pentyl, hexyl and isomers of hexyl, and the like.
The term "alkoxy" (alone or in combination with another term(s)) means an
alkylether substituent, i.e., -0-alkyl.
The "lower alkoxy" groups are lower alkoxy containing from 1 to 6 carbon
atoms, especially 1 to 3 carbon atoms, and may be straight chain or
branched. These groups include methoxy, ethoxy, propoxy, butoxy,
isobutoxy, tert-butoxy, pentoxy, hexoxy and the like.
The "aryl alkyl" or "aryl lower alkyl" groups include, for example, benzyl,
phenylethyl, phenylpropyl, phenylisopropyl, phenylbutyl, diphenylmethyl, 1,1-
diphenylethyl, 1,2-diphenylethyl, and the like.
The term "aryl", when used alone or in combination, refers to an aromatic
group which contains from 6 up to 18 ring carbon atoms and up to a total of
25 carbon atoms and includes the polynuclear aromatics. These aryl groups
may be monocyclic, bicyclic, tricyclic or polycyclic and are fused rings. A
polynuclear aromatic compound as used herein, is meant to encompass
bicyclic and tricyclic fused aromatic ring systems containing from 10-18 ring
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-26-
carbon atoms and up to a total of 25 carbon atoms. The aryl group includes
phenyl, and the polynuclear aromatics e.g., naphthyl, anthracenyl,
phenanthrenyl, azulenyl and the like. The aryl group also includes groups
like ferrocenyl. Aryl groups may be unsubstituted or mono or polysubstituted
with electron withdrawing or/and electron donating groups as described
below.
The term "alkenyl" (alone or in combination with another term(s)) means a
straight- or branched-chain hydrocarbyl substituent containing one or more
double bonds and preferably from 2 to about 20 carbon atoms, more
preferably from 2 to about 8 carbon atoms, and even more preferably from 2
to about 6 carbon atoms. The alkenyl groups, where asymmetric, can have
cis or trans configuration. Most preferably, alkenyl is lower alkenyl as
defined
below.
"Lower alkenyl" is an alkenyl group containing from 2 to 6 carbon atoms and
at least one double bond. These groups may be straight chained or
branched and may be in the Z or E form. Such groups include vinyl,
propenyl, 1-butenyl, isobutenyl, 2-butenyl, 1-pentenyl, (Z)-2-pentenyl, (E)-2-
pentenyl, (Z)-4-methyl-2-pentenyl, (E)-4-methyl-2-pentenyl, pentadienyl,
e.g., 1, 3 or 2,4-pentadienyl, and the like.
The term "alkynyl" (alone or in combination with another term(s)) means a
straight- or branched-chain hydrocarbyl substituent containing one or more
triple bonds and preferably from 2 to about 20 carbon atoms, more
preferably from 2 to about 8 carbon atoms, and even more preferably from 2
to about 6 carbon atoms. Most preferably, alkynyl is lower alkynyl as defined
below.
The term '9ower alkynyl" is an alkynyl group containing 2 to 6 carbon atoms
and may be straight chained as well as branched. It includes such groups as
ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-
pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl and the like.
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-27-
The term "lower cycloalkyl" or "cycioalkyl" when used alone or in
combination is a cycloalkyl group containing from 3 to 18 ring carbon atoms
and up to a total of 25 carbon atoms. The cycloalkyl groups may be
monocyclic, bicyclic, tricyclic, or polycyclic and the rings are fused. The
cycloalkyl may be completely saturated or partially saturated. Examples
include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, cyclodecyl, cyclohexenyl, cyclopentenyl, cyclooctenyl,
cycloheptenyl, decalinyl, hydroindanyl, indanyl, fenchyl, pinenyl, adamantyl,
and the like. Cycloalkyl includes the cis or trans forms. Cycloalkyl groups
may be unsubstituted or mono or polysubstituted with electron withdrawing
or/and electron donating groups as described below. Furthermore, the
substituents may either be in endo or exo positions in the bridged bicyclic
systems.
The terms "electron-withdrawing" and "electron donating" refer to the ability
of a substituent to withdraw or donate electrons, respectively, relative to
that
of hydrogen if the hydrogen atom occupied the same position in the
molecule. These terms are well understood by one skilled in the art and are
discussed in Advanced Organic Chemistry, by J. March, John Wiley and
Sons, New York, NY, pp.16-18 (1985) and the discussion therein is
incorporated herein by reference. Electron withdrawing groups include halo,
including bromo, fluoro, chloro, iodo and the like; nitro, carboxy, alkenyl,
alkynyl, formyl, carboxyamido, aryl, quaternary ammonium, haloalkyl such as
trifluoromethyl, aryl alkanoyl, carbalkoxy and the like. Electron donating
groups include such groups as hydroxy, alkoxy, including methoxy, ethoxy
and the like; alkyl, such as methyl, ethyl, and the like; amino, alkylamino,
di
(alkyl) amino, aryloxy such as phenoxy, mercapto, alkylthio, alkylmercapto,
disulfide (alkyldithio) and the like. One of ordinary skill in the art will
appreciate that some of the aforesaid substituents may be considered to be
electron donating or electron withdrawing under different chemical
conditions. Moreover, the present invention contemplates any combination
of substituents selected from the above-identified groups.
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-28-
"Carbalkoxy" refers to -CO-O-alkyl, wherein alkyl may be lower alkyl as
defined above.
The term "halo" includes fluoro, chloro, bromo, and iodo.
"Alkanoyl" alone or in combination with another term(s) means a straight or
branched chain alkanoyl substituent preferably containing from 1 to about 20
carbon atoms, more preferably from 1 to about 8 carbon atoms, even more
preferably from 1 to about 6 carbon atoms.
The term "acyl" includes lower alkanoyl containing from 1 to 6 carbon atoms
and may be straight chains or branched. These groups include, for example,
formyl, acetyl, propionyl, butyryl, isobutyryl, tertiary butyryl, pentanoyl
and
isomers of pentanoyl, and hexanoyl and isomers of hexanoyl.
As employed herein, a heterocyclic group contains at least one sulfur,
nitrogen or oxygen ring atom, but also may include several of said atoms in
the ring. The heterocyclic groups contemplated by the present invention
include heteroaromatics and saturated and partially saturated heterocyclic
compounds. These heterocyclics may be monocyclic, bicyclic, tricyclic or
polycyclic and are e.g. fused rings. They may preferably contain up to 18
ring atoms and up to a total of 17 ring carbon atoms and a total of up to 25
carbon atoms. The heterocyclics are also intended to include the so-called
benzoheterocyclics. Representative heterocyclics include furyl, thienyl,
pyrazolyl, pyrrolyl, methylpyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl,
isothiazolyl, isoxazolyi, piperidyl, pyrrolinyl, piperazinyl, quinolyl,
triazolyl,
tetrazolyl, isoquinolyl, benzofuryl, benzothienyl, morpholinyl, benzoxazolyl,
tetrahydrofuryl, pyranyl, indazolyl, purinyl, indolinyl, pyrazolindinyl,
imidazolinyl, imadazolindinyl, pyrrolidinyl, furazanyl, N-methylindolyl,
methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl, epoxy, aziridino,
oxetanyl, azetidinyl, the N-oxides of the nitrogen containing heterocycles,
such as the N-oxides of pyridyl, pyrazinyl, and pyrimidinyl and the like.
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-29-
Heterocyclic groups may be unsubstituted or mono or polysubstituted with
electron withdrawing or/and electron donating groups.
The preferred heterocyclics are thienyl, furyl, pyrrolyi, benzofuryl,
benzothienyl, indolyl, methylpyrrolyl, morpholinyl; pyridiyl, pyrazinyl,
imidazolyl, pyrimidinyl, or pyridazinyl. The preferred heterocyclic is a 5 or
6-
membered heterocyclic compound. The especially preferred heterocyclic is
furyl, pyridyl, pyrazinyl, imidazolyl, pyrimidinyl, or pyridazinyl. The most
preferred heterocyclics are furyl and pyridyl.
The preferred compounds are those wherein n is 1, but di (n=2), tri (n=3)
and tetrapeptides (n=4) are also contemplated to be within the scope of the
invention.
The preferred values of R is aryl lower alkyl, especially benzyl especially
those wherein the phenyl ring thereof is unsubstituted or substituted with
electron donating groups or/and electron withdrawing groups, such as halo
(e.g., F).
The preferred R, is H or lower alkyl. The most preferred R, group is methyl.
The preferred electron donating substituents or/and electron withdrawing
substituents are halo, nitro, alkanoyl, formyl, aryialkanoyl, aryloyl,
carboxyl,
carbalkoxy, carboxamido, cyano, sulfonyl, sulfoxide, heterocyclic, guanidine,
quaternary ammonium, alkenyl, alkynyl, sulfonium salts, hydroxy, alkoxy,
alkyl, amino, alkylamino, di(alkyl)amino, amino alkyl, mercapto,
mercaptoalkyl, alkylthio, and alkyldithio. The term "sulfide" encompasses
mercapto, mercapto alkyl and alkylthio, while the term disulfide
encompasses alkyldithio. Especially preferred electron donating or/and
electron withdrawing groups are halo or alkoxy, e.g. lower alkoxy, most
preferred are fluoro or methoxy. These preferred substituents may be
present on any one of the groups in Formula (lb) or/and (lib), e.g. R, R,, R2,
R3, R4, R5, R6, R'6, R7, Rs and/or R5o as defined herein.
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-30-
The ZY groups representative of R2 and R3 include hydroxy, alkoxy, such as
methoxy, ethoxy, aryloxy, such as phenoxy; thioalkoxy, such as thiomethoxy,
thioethoxy; thioaryloxy such as thiophenoxy; amino; alkylamino, such as
methylamino, ethylamino; arylamino, such as anilino; lower dialkylamino,
such as, dimethylamino; trialkyl ammonium salt, hydrazino; alkylhydrazino
and arylhydrazino, such as N-methylhydrazino, N-phenylhydrazino,
carbalkoxy hydrazino, aralkoxycarbonyl hydrazino, aryloxycarbonyl
hydrazino, hydroxylamino, such as N-hydroxylamino (-NH-OH), alkoxy
amino [(NHOR,B) wherein R18 is alkyl], N-alkylhydroxyl amino [(NR,a)OH
wherein R,B is alkyl], N-alkyl-O-a{ky{hydroxyamino, i.e., [N(R,a)OR,s wherein
R18 and R,s are independently alkyl], and 0-hydroxylamino (-O-NH2);
alkylamido such as acetamido; trifluoroacetamido; alkoxyamino, (e.g., NH
(OCH3); and heterocyclicamino, such as pyrazoylamino.
The preferred heterocyclic groups representative of R2 and R3 are
monocyclic 5- or 6-membered heterocyclic moieties of the formula:
A
E
f ~ -- Rse
G L
(CH), /
or those corresponding partially or fully saturated form thereof wherein n is
0
or 1; and
R50 is H or an electron withdrawing group or electron donating group;
A, E, L, J and G are independently CH, or a heteroatom selected from the
group consisting of N, 0, S;
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-31-
but when n is 0, G is CH, or a heteroatom selected from the group consisting
of NH, 0 and S with the proviso that at most two of A, E, L, J and G are
heteroatoms.
When n is 0, the above heteroaromatic moiety is a five membered ring, while
if n is 1, the heterocyclic moiety is a six membered monocyclic heterocyclic
moiety. The preferred heterocyclic moieties are those aforementioned
heterocyclics which are monocyclic.
If the ring depicted hereinabove contains a nitrogen ring atom, then the N-
oxide forms are also contemplated to be within the scope of the invention.
When R2 or R3 is a heterocyclic of the above formula, it may be bonded to
the main chain by a ring carbon atom. When n is 0, R2 or R3 may additionally
be bonded to the main chain by a nitrogen ring atom.
Other preferred moieties of R2 and R3 are hydrogen, aryl, e.g., phenyl, aryl
alkyl, e.g., benzyl and alkyl.
It is to be understood that the preferred groups of R2 and R3 may be
unsubstituted or mono or poly substituted with electron donating or/and
electron withdrawing groups. It is preferred that R2 and R3 are independently
hydrogen, alkyl, which is either unsubstituted or substituted with electron
withdrawing groups or/and electron donating groups, such as alkoxy (e.g.,
methoxy, ethoxy, and the like), N-hydroxylamino, N-alkylhydroxyamino, N-
alkyl-O-alkyl and alkylhydroxyamino.
It is preferred that one of R2 and R3 is hydrogen.
It is preferred that n is one.
It is more preferred that n=1 and one of R2 and R3 is hydrogen. It is
especially preferred that in this embodiment, R2 is hydrogen and R3 is lower
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-32-
alkyl or ZY;
Z is 0, NR4 or PR4; Y is hydrogen or alkyl, e.g. lower alkyl; ZY is NR4NR5R7,
NR4OR5,
ONR4R7, NR4C-R5 or NR~C-OR5.
11 11
O 0
In another especially preferred embodiment, n=1, R2 is hydrogen and R3 is
alkyl, e.g. lower alkyl which may be substituted or unsubstituted with an
electron donating or electron withdrawing group, NR4OR5, or ONR4R7,
In yet another especially preferred embodiment, n= 1, R2 is hydrogen and
R3 is alkyl, e.g. lower alkyl which is unsubstituted or substituted with
hydroxy
or loweralkoxy, NR4OR5 or ONR4R7, wherein R4, R5 and R7 are
independently hydrogen or alkyl, R is aryl alkyl, which aryl group may be
unsubstituted or substituted with an electron withdrawing group and R, is
alkyl, e.g. lower alkyl. In this embodiment it is most preferred that aryl is
phenyl, which is unsubstituted or substituted with halo.
It is preferred that R2 is hydrogen and R3 is hydrogen, an alkyl group which
is
unsubstituted or substituted by at least an electron donating or electron
withdrawing group or ZY. In this preferred embodiment, it is more preferred
that R3 is hydrogen, an alkyl group such as methyl, which is unsubstituted or
substituted by an electron donating group, or NR4OR5 or ONR4R7, wherein
R4, R5 and R7 are independently hydrogen or lower alkyl. It is preferred that
the electron donating group is alkoxy, e.g. lower alkoxy, and especially
methoxy or ethoxy.
It is preferred that R2 and R3 are independently hydrogen, alkyl, e.g. lower
alkyl, or ZY;
Z is 0, NR4 or PR4;
Y is hydrogen or alkyl, e.g. lower alkyl or
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-33-
ZY is NR4R5R7, NR4OR5, ONR4R7, NR4C-R5 or NR4C-OR5.
0 0
It is also preferred that R is aryl alkyl, e.g. aryl lower alkyl. The most
preferred aryl for R is phenyl. The most preferred R group is benzyl. In a
preferred embodiment, the aryl group may be unsubstituted or substituted
with an electron donating or electron withdrawing group. If the aryl ring in R
is substituted, it is most preferred that it is substituted with an electron
withdrawing group, especially on the aryl ring. The most preferred electron
withdrawing group for R is halo, especially fluoro.
The preferred R, is lower alkyl, especially methyl.
It is more preferred that R is aryl lower alkyl and R, is lower alkyl.
Further preferred compounds are compounds of Formula (lb) wherein n is 1;
R2 is hydrogen; R3 is hydrogen, an alkyl group, e.g. a lower alkyl group,
especially methyl which is substituted by an electron donating or electron
withdrawing group or ZY; R is aryl alkyl, e.g. aryl lower alkyl, such as
benzyl,
wherein the aryl group is unsubstituted or substituted with an electron
donating or electron withdrawing group and R, is alkyl, e.g. lower alkyl. In
this embodiment, it is more preferred that. R3 is hydrogen, an alkyl group,
e.g. a lower alkyl group, especially methyl, which may be substituted by
electron donating group, such as alkoxy, e.g. lower alkoxy, (e.g., methoxy,
ethoxy and the like), NR4OR5 or ONR4R7 wherein these groups are defined
hereinabove.
The most preferred compounds utilized are those of the Formula (lib):
H H H
I I I
Ar-CHr-N-C-C-N-C-Ri
O R3 O
Formula (lib)
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-34-
wherein
Ar is aryl, especially phenyl, which is unsubstituted or substituted with at
least one electron donating group or electron withdrawing group, especially
halo,
R, is alkyl, especially containing 1=3 carbon atoms; and
R3 is as defined herein, but especially hydrogen, alkyl, e.g. lower alkyl,
which
is unsubstituted or substituted by at least an electron donating group or
electron withdrawing group or ZY. It is even more preferred that R3 is, in
this
embodiment, hydrogen, an alkyl group which is unsubstituted or substituted
by an electron donating group, NR4OR5 or ONR4R7. It is most preferred that
R3 is CH2-Q, wherein Q is alkoxy, e.g. lower alkoxy, especially containing 1-3
carbon atoms; NR4OR5 or ONR4R7 wherein R4 is hydrogen or alkyl
containing 1-3 carbon atoms, R5 is hydrogen or alkyl containing 1-3 carbon
atoms, and R, is hydrogen or alkyl containing 1-3 carbon atoms.
The most preferred R, is CH3. The most preferred R3 is CH2-Q, wherein Q is
methoxy.
The most preferred aryl is phenyl. The most preferred halo is fluoro.
The most preferred compounds include:
(R)-2-acetamido-N-benzyl-3-methoxy-propionamide;
(R)-2-acetamido-N-benzyl-3-ethoxy-propionamide;
O-methyl-N-acetyl-D-serine-m-fluorobenzyl-amide;
O-methyl-N-acetyl-D-seri ne-p-fluorobenzyl-am ide;
N-acetyl-D-phenylglycine benzylamide;
D-1,2-(N,O-dimethylhydroxylamino)-2-acetamide acetic acid benzylamide;
D-1,2-(O-methylhydroxylamino)-2-acetamido acetic acid benzylamide.
It is to be understood that the various combinations and permutations of the
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-35-
Markush groups of R,, R2, R3, R and n described herein are contemplated to
be within the scope of the present invention. Moreover, the present invention
also encompasses compounds and compositions which contain one or more
elements of each of the Markush groupings in R,, R2, R3, n and R and the
various combinations thereof. Thus, for example, the present invention
contemplates that R, may be one or more of the substituents listed
hereinabove in combination with any and all of the substituents of R2, R3,
and R with respect to each value of n.
The compounds utilized in the present invention may contain one or more
asymmetric carbons and may exist in racemic and optically active forms.
The configuration around each asymmetric carbon can be either the D or L
form. It is well known in the art that the configuration around a chiral
carbon
atoms can also be described as R or S in the Cahn-Prelog-Ingold
nomenclature system. All of the various configurations around each
asymmetric carbon, including the various enantiomers and diastereomers as
well as racemic mixtures and mixtures of enantiomers, diastereomers or
both are contemplated by the present invention.
In the principal chain, there exists asymmetry at the carbon atom to which
the groups R2 and R3 are attached. When n is 1, the compounds of the
present invention is of the formula
R2 0
1 H 11
R-NH-C-C-N-C-R1
O R3
wherein R, R,, R2, R3, R4, R5, R6, R'6, R7, R8, R5o Z and Y are as defined
previously.
As used herein, the term configuration shall refer to the configuration around
the carbon atom to which R2 and R3 are attached, even though other chiral
centers may be present in the molecule. Therefore, when referring to a
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-36-
particular configuration, such as D or L, it is to be understood to mean the D
or L stereoisomer at the carbon atom to which R2 and R3 are attached.
However, it also includes all possible enantiomers and diastereomers at
other chiral centers, if any, present in the compound.
The compounds of the present invention are directed to all the optical
isomers, i.e., the compounds of the present invention are either the L-
stereoisomer or the D-stereoisomer (at the carbon atom to which R2 and R3
are attached). These stereoisomers may be found in mixtures of the L and D
stereoisomer, e.g., racemic mixtures. The D stereoisomer is preferred. In
lacosamide, the D steroisomer corresponds to the R enantiomer according
to the R, S terminology.
The compounds of Formulae (lb) or/and (Ilb), in particular lacosamide, may
be substantially enantiopure. As used herein, the term "substantially
enantiopure" means preferably at least 88%, more preferably at least 90%,
most preferably at least 95, 96, 97, 98, or 99% enantiomeric purity.
Depending upon the substituents, the present compounds may form addition
salts as well. All of these forms are contemplated to be within the scope of
this invention including mixtures of the stereoisomeric forms.
The manufacture of the utilized compounds is described in U.S. Patent Nos.
5,378,729 and 5,773,475, the contents of both of which are incorporated by
reference.
The compounds utilized in the present invention are useful as such as
depicted in the Formulae (lb) or/and (Ilb) or can be employed in the form of
salts in view of its basic nature by the presence of the free amino group.
Thus, the compounds of Formulae (Ib) or/and (ilb) form salts with a wide
variety of acids, inorganic and organic, including pharmaceutically
acceptable acids. The salts with therapeutically acceptable acids are of
course useful in the preparation of formulation where enhanced water
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
- -37-
solubility is most advantageous.
These pharmaceutically acceptable salts have also therapeutic efficacy.
These saits include salts of inorganic acids such as hydrochloric, hydroiodic,
hydrobromic, phosphoric, metaphosphoric, nitric acid and sulfuric acids as
well as salts of organic acids, such as tartaric, acetic, citric, malic,
benzoic,
perchloric, glycolic, gluconic, succinic, aryl sulfonic, (e.g., p-toluene
sulfonic
acids, benzenesulfonic), phosphoric, malonic, and the like.
The present invention is further directed to a method for the prevention,
alleviation or/and treatment of a disease that is treated with an
antipsychotic,
in particular psychosis, more particular schizophrenia, in an add-on therapy
to at least one antipsychotic agent by administration of at least one
compound of Formulae (Ib) or/and (Ilb) to a subject in need thereof.
In a preferred embodiment, the method of the present invention comprises
(a) the administration of at least one antipsychotic agent useful for the
prevention, alleviation or/and treatment of psychosis, and
(b) the administration of at least one compound of Formulae (lb) or/and (Ilb)
in an add-on therapy in addition to the at least one agent of (a),
to a subject in need thereof.
In the method of the present invention, the at least one antipsychotic agent
useful for the prevention, alleviation or treatment of psychosis may be a
dopamine antagonist, preferably a D2 antagonist, more preferably an atypical
antipsychotic agent, even more preferably an atypical antipsychotic as
defined above, and most preferably the agent is clozapine, risperidone,
aripiprazole, quetiapine, olanzapine, ziprasidone, sulpiride, amisuipride
or/and zotepine.
It is further preferred that the at least one compound of Formulae (lb) or/and
(ilb) and the at least one antipsychotic agent useful for the prevention,
alleviation or/and treatment of psychosis is administered in the form of one
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-38-
composition (single dose form).
In another preferred embodiment, the method of the present invention
comprises the administration of a separate dose form comprising
(i) a first composition comprising at least one antipsychotic agent useful for
the prevention, alleviation or/and treatment of psychosis, and
(ii) a second composition comprising at least one compound of Formulae
(Ib) or/and (Ilb).
to a subject in need thereof.
In yet another preferred embodiment of the present invention, a
commercially available composition of an antipsychotic agent useful for
prevention, alleviation or/and treatment of psychosis may be administered to
a subject in need thereof. Therefore, in this preferred embodiment, the
method of the present invention for prevention, alleviation or/and treatment
of a disease that is treated with an antipsychotic, in particular psychosis,
comprises administration of a pharmaceutical composition comprising at
least one compound according to Formula (Ib) or/and Formula (lib) and not
comprising an antipsychotic agent useful for the prevention, alleviation
or/and treatment of psychosis to a subject receiving a commercially available
composition containing an antipsychotic agent for prevention, alleviation
or/and treatment of psychosis.
The compounds according to Formulae (Ib) or/and (Ilb) may also be useful
in an add-on therapy for disorders or/and diseases other than schizophrenia
which are treated by antipsychotic agents. Therefore, yet another subject of
the present invention is an add-on therapy for the prevention, alleviation
or/and treatment of bipolar disorder, autism, psychosis in diseases other
than schizophrenia, e.g. in Alzheimer's disease, or/and attention deficit
hyperactivity disorder, by administration of a pharmaceutical composition of
the present invention. The compounds according to Formulae (Ib) or/and
(lib) may also be used for the preparation of a pharmaceutical composition
useful for the prevention, alleviation or/and treatment in an add-on therapy
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-39-
for disorders or/and diseases other than schizophrenia which can be treated
by antipsychotic agents, such as bipolar disorder, autism, psychosis in
diseases other than schizophrenia, e.g. in Alzheimer's disease, or/and
attention deficit hyperactivity disorder. The pharmaceutical composition of
the present invention as described herein for treatment of schizophrenia
may also be used for the prevention, alleviation or/and treatment in an add-
on therapy for disorders or/and diseases other than schizophrenia which can
be treated by antipsychotic agents, such as bipolar disorder, autism,
psychosis in diseases other than schizophrenia, e.g. in Alzheimer's disease,
or/and attention deficit hyperactivity disorder.
The compounds according to Formulae (Ib) or/and (Ilb) may also be useful
in an add-on therapy to at least one antipsychotic agent for the treatment of
psychosis other than psychosis in schizophrenia. Therefore, yet another
subject of the present invention is an add-on therapy to at least one
antipsychotic agent for the prevention, alleviation or/and treatment of
psychosis associated with e.g. bipolar disorder, autism, Alzheimer's disease,
attention deficit hyperactivity disorder, drug or/and alcohol abuse, affective
disorders, dyskinesias and related disorders, dementia, mental retardation,
polydipsia/hyponatraemia, severe personality disorder, acute episodes of
mania, obsessive compulsive disorder, intractable chronic insomnia,
Huntington's Disease, Tourette's syndrom, Parkinson's disease or/and
dopaminergic therapy of Parkinson's disease, by administration of a
pharmaceutical composition of the present invention. The compounds
according to Formulae (Ib) or/and (Ilb) may also be used for the preparation
of a pharmaceutical composition useful for the prevention, alleviation or/and
treatment in an add-on therapy to at least one antipsychotic agent for the
treatment of psychosis associated with e.g. bipolar disorder, autism,
Alzheimer's disease, attention deficit hyperactivity disorder, drug or/and
alcohol abuse, affective disorders, dyskinesias and related disorders,
dementia, mental retardation, polydipsia/hyponatraemia, severe personality
disorder, acute episodes of mania, obsessive compulsive disorder,
intractable chronic insomnia, Huntington's Disease, Tourette's syndrom,
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
- 40 -
Parkinson's disease or/and dopaminergic therapy of Parkinson's disease.
The pharmaceutical composition of the present invention as described
herein may also be used for the prevention, alleviation or/and treatment in
an add-on therapy for the treatment of psychosis associated with e.g. bipolar
disorder, autism, Alzheimer's disease, attention deficit hyperactivity
disorder,
drug or/and alcohol abuse, affective disorders, dyskinesias and 'related
disorders, dementia, mental retardation, polydipsia/hyponatraemia, severe
personality disorder, acute episodes of mania, obsessive compulsive
disorder, intractable chronic insomnia, Huntington's Disease, Tourette's
syndrom, Parkinson's disease, or/and dopaminergic therapy of Parkinson's
disease.
It is preferred that the compound utilized in the present invention is used in
therapeutically effective amounts.
The physician will determine the dosage of the present therapeutic agents
which will be most suitable and it will vary with the form of administration
and
the particular compound chosen, and furthermore, it will vary with the patient
under treatment, the age of the patient, the type of malady being treated. He
will generally wish to initiate treatment with small dosages substantially
less
than the optimum dose of the compound and increase the dosage by small
increments until the optimum effect under the circumstances is reached.
When the composition is administered orally, larger quantities of the active
agent will be required to produce the same effect as a smaller quantity given
parenterally. The compounds are useful in the same manner as comparable
therapeutic agents and the dosage level is of the same order of magnitude
as is generally employed with these other therapeutic agents.
Typical doses of antipsychotic agents administered to a subject in need
thereof in the add-on therapy to at least one antipsychotic agent of the
present invention are the doses of the dopamine antagonists as given above
or are the following doses: olanzapine 5-20 mg/day, clozapine 100-900
mg/day, quetiapine 100-800 mg/day, risperidone 1-16 mg/day, aripiprazole
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-41-
3-30 mg/day, ziprasidone 40-160 mg/day, suipiride 300-1600 mg/day,
amisuipride 50-1200 mg/day, zotepine 75-450 mg/day. Such doses may also
be included in the pharmaceutical composition of the present invention,
or/and may be used for the preparation of a pharmaceutical composition of
the present invention.
The physician is able to determine the administration route of the at least
one agent useful for the prevention, alleviation or/and treatment of
psychosis, which may be the same or different to the administration route of
the at least one compound of the present invention of Formulae (Ib) or/and
(Ilb). Typical administration routes of the at least one antipsychotic agent
useful for the prevention, alleviation or/and treatment of psychosis are oral,
intravenous, intramuscular, intrathecal or subcutaneous routes. Oral or/and
intravenous administration is preferred.
In a preferred embodiment, the compounds of Formulae (lb) or/and (Ilb) of
the present invention are administered in amounts ranging from about 1 mg
to about 10 mg per kilogram of body weight per day. This dosage regimen
may be adjusted by the physician to provide the optimum therapeutic
response. Patients in need thereof may be treated with doses of the
compound of the present invention of at least 50 mg/day, preferably of at
least 100 mg, more preferably at least 200 mg/day, even more preferably of
at least 300 mg/day and most preferably of at least 400 mg/day. Generally, a
patient in need thereof may be treated with doses at a maximum of 6 g/day,
more preferably a maximum of 1 g/day and most preferably a maximum of
600 mg/day. In some cases, however, higher or lower doses may be
needed.
In another preferred embodiment, the daily doses are increased until a
predetermined daily dose is reached which is maintained during the further
treatment.
In yet another preferred embodiment, several divided doses may be
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-42-
administered daily. For example, three doses per day may be administered,
preferably two doses per day. It is more preferred to administer a single
dose per day.
In yet another preferred embodiment, an amount of the compounds of the
present invention may be administered which results in a plasma
concentration of 0.1 to 15 pg/ml (trough) and 5 to 18.5 pg/mI (peak),
calculated as an average over a plurality of treated subjects.
The compounds of Formulae (Ib) or/and (Ilb) may be administered in a
convenient manner, such as by oral, intravenous (where water soluble),
intramuscular, intrathecal or subcutaneous routes. Oral or/and i.v.
administration is preferred.
The pharmaceutical composition of the present invention may be prepared
for the treatment regimen as described above, in particular for the treatment
with doses as described above, to effect plasma concentrations as
described above, for administration periods or/and administration routes as
specified in the embodiments of the present invention as described above.
The pharmaceutical compositions of the present invention comprising the at
least one antipsychotic agent for the prevention, alleviation orland treatment
of psychosis, in particular schizophrenia, is formulated with common
carriers, diluents or/and -auxiliary substances known to a person skilled in
the art. In the case of a separate dose form, the first composition comprising
at least one antipsychotic agent useful for the prevention, alleviation or/and
treatment of psychosis and the second composition comprising at least one
compound of Formulae (lb) or/and (llb) may comprise carriers, diluents
or/and auxiliary substances which are independently from each other,
identical or different in the first composition comprising at least one
antipsychotic agent useful for the prevention, alleviation or/and treatment of
psychosis and the second composition comprising at least one compound of
Formulae (lb) or/and (Ilb).
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-43-
The compounds of Formulae (lb) or/and (ilb) may be orally administered, for
example, with an inert diluent or with an assimilable edible carrier, or it
may
be enclosed in hard or soft shell gelatin capsules, or it may be compressed
into tablets, or it may be incorporated directly into the food or the diet.
For
oral therapeutic administration, the active compound of Formulae (lb) or/and
(Ilb) may be incorporated with excipients and used in the form of ingestible
tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups,
wafers, and the like. Such compositions and preparations should contain at
least 1% of active compound of Formulae (lb) or/and (Ilb). The percentage
of the compositions and preparations may, of course, be varied and may
conveniently be between about 5 to about 80% of the weight of the unit. The
amount of active compound of Formulae (Ib) or/and (Ilb) in such
therapeutically useful compositions is such that a suitable dosage will be
obtained. Preferred compositions or preparations according to the present
invention contains between about 10 mg and 6 g active compound of
Formulae (Ib) or/and (Ilb).
The tablets, troches, pills, capsules and the like may also contain the
following: A binder such as gum tragacanth, acacia, corn starch or gelatin;
excipients such as dicalcium phosphate; a disintegrating agent such as corn
starch, potato starch, alginic acid and the like; a lubricant such as
magnesium stearate; and a sweetening agent such as sucrose, lactose or
saccharin may be added or a flavoring agent such as peppermint, oil of
wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it
may contain, in addition to materials of the above type, a liquid carrier.
Various other materials may be present as coatings or otherwise modify the
physical form of the dosage unit. For instance, tablets, pills, or capsules
may
be coated with shellac, sugar or both. A syrup or elixir may contain the
active compound, sucrose as a sweetening agent, methyl and
propylparabens as preservatives, a dye and flavoring such as cherry or
orange flavor. Of course, any material used in preparing any dosage unit
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-44-
form should be pharmaceutically pure and substantially non-toxic in the
amounts employed. In addition, the active compound may be incorporated
into sustained-release preparations and formulations. For example,
sustained release dosage forms are contemplated wherein the active
ingredient is bound to an ion exchange resin which, optionally, can be
coated with a diffusion barrier coating to modify the release properties of
the
resin.
The active compound may also be administered parenterally or
intraperitoneally. Dispersions can also be prepared in glycerol, liquid,
polyethylene glycols, and mixtures thereof and in oils. Under ordinary
conditions of storage and use, these preparations may contain a
preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous
solutions (where water soluble) or dispersions and sterile powders for the
extemporaneous preparation of sterile injectable solutions or dispersions. In
ali cases the form must be sterile and must be fluid to the extent that easy
syringability exists. It must be stable under the conditions of manufacture
and storage and must be preserved against the contaminating action of
microorganisms such as bacteria and fungi. The carrier can be a solvent or
dispersion medium containing, for example, water, ethanol, polyol (for
example, glycerol, propylene glycol, and liquid polyethylene glycol, and the
like), suitable mixtures thereof, and vegetable oils. The proper fluidity can
be
maintained, for example, by the use of a coating such as lecithin, by the
maintenance of the required particle size in the case of dispersions and by
the use of surfactants. The prevention of the action of microorganisms can
be brought about by various antibacterial and antifungal agents, for
example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the
like. In many cases, it will be preferable to include isotonic agents, for
example, sugars or sodium chloride. Prolonged absorption of the injectable
compositions can be brought about by the use in the compositions of agents
delaying absorption, for example, aluminium monostearate and gelatin.
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
- 45 -
Sterile injectable solutions are prepared by incorporating the active
compound in the required amount in the appropriate solvent with various of
the other ingredients enumerated above, as required, followed by filtered
sterilization. Generally, dispersions are prepared by incorporating the
various 'sterilized active ingredient into a sterile vehicle which contains
the
basic dispersion medium and the required other ingredients from those
enumerated above. In the case of sterile powders for the preparation of
sterile injectable solutions, the preferred methods of preparation are vacuum
drying the freeze-drying technique plus any additional desired ingredient
from previously sterile-filtered solution thereof.
As used herein, "pharmaceutically acceptable carrier" includes any and all
solvents, dispersion media, coatings, antibacterial and antifungal agent,
isotonic and absorption delaying agents for pharmaceutical active
substances as well known in the art. Except insofar as any conventional
media or agent is incompatible with the active ingredient, its use in the
therapeutic compositions is contemplated. Supplementary active ingredients
can also be incorporated into the compositions.
It is especially advantageous to formulate parenteral compositions in dosage
unit form for ease of administration and uniformity of dosage. Dosage unit
form as used herein refers to physically discrete units suited as unitary
dosages for the mammalian subjects to be treated; each unit containing a
predetermined quantity of active material calculated to produce the desired
therapeutic effect in association with -the required pharmaceutical carrier.
The specifics for the novel dosage unit forms of the invention are dictated by
and directly dependent on (a) the unique characteristics of the active
material an the particular therapeutic effect to be achieved, and (b) the
limitations inherent in the art of compounding such as active material for the
treatment of disease in living subjects having a diseased condition in which
bodily health is impaired as herein disclosed in detail.
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-46-
The principal active ingredient is compounded for convenient and effective
administration in effective amounts with a suitable pharmaceutically
acceptable carrier in dosage unit form as hereinbefore described. A unit
dosage form can, for example, contain the principal active compound in
amounts ranging from about 10 mg to about 6 g. Expressed in proportions,
the active compound is generally present in the carrier in an amount from
about 1 to about 750 mg/mi of carrier. In the case of compositions containing
supplementary active ingredients, the dosages are determined by reference
to the usual dose and manner of administration of the said ingredients.
As used herein the term "patient" or "subject" refers to a warm blooded
animal, and preferably mammals, such as, for example, cats, dogs, horses,
cows, pigs, mice, rats and primates, including humans. The preferred patient
is a human.
The term "treat" refers to preventing, curing or alleviating the patient's
disease or condition.
The compounds of the present invention are administered to a patient
suffering from the aforementioned type of disorder in an effective amount.
These amounts are equivalent to the therapeutically effective amounts
described hereinabove.
The following example shows the properties of lacosamide, formerly called
Harkoseride, or SPM 927, potentiating the prepulse inhibition of the
antipsychotic agent clozapine in mice when administered together.
The used substance was lacosamide. The standard chemical nomenclature
is (R)-2-acetamide-N-benzyl-3-methoxypropionamide.
Example
The effects of lacosamide alone and in combination with clozapine in
an animal model for schizophrenia.
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-47-
Some anticonvulsants have proven pre-clinical and/or clinical efficacy as
add-on therapy to antipsychotics for schizophrenia. Lacosamide was tested
in a simple animal model with predictive validity for psychosos such as
schizophrenia (i.e. prepulse inhibition (PPI) of the acoustic startle reflex).
Lacosamide was tested alone and in combination with the atypical
antipsychotic agent clozapine.
It should be noted that prepulse inhibition is a general model of psychosis
and therefore indicative for psychosis associated with other diseases or
conditions, such as psychosis associated with schizophrenia, bipolar
disorder, autism, Alzheimer's disease, attention deficit hyperactivity
disorder,
drug or/and alcohol abuse, affective disorders, dyskinesias and related
disorders, dementia, mental retardation, polydipsia/hyponatraemia, severe
personality disorder, acute episodes of mania, obsessive compulsive
disorder, intractable chronic insomnia, Huntington's Disease, Tourette's
syndrom, Parkinson's disease, or/and dopaminergic therapy of Parkinson's
disease.
The acoustic startle is an unconditioned reflex response to an external
auditory stimulation. PPI refers to the reduction in the startle response
caused by the presentation of a low-intensity auditory stimulus prior to the
startle stimulus. The PPI paradigm is the choice for the study of
schizophrenia and antipsychotic action due to the similarities between the
results from human and rodent studies. Antipsychotic agents, such as
clozapine, result in a dose-dependent increase in PPI in mice. Thus, an
increase of PPI in normal mice may be indicative of antipsychotic efficacy.
C57BL/6J mice obtained from the Jackson Laboratory, Bar Harbor, Maine
were received at the age of 6 weeks and were assigned unique identification
numbers (tail marked). Animals were housed 4 per cage in polycarbonate
cages with filter tops and acclimated for 7 days. All animals were examined,
handled, and weighed prior to initiation of the study to assure adequate
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-48-
health and suitability and to minimize non-specific stress associated with
manipulation.
During the course of the study, 12/12 light/dark cycles and a room
temperature of 20 to 23 C were maintained with a relative humidity
maintained around 50%. Chow and water were provided ad libitum for the
duration of the study. Each mouse was randomly assigned across the
treatment groups and balanced by cage numbers. The test was performed
during the animal's light cycle phase. Twelve animals were used in each
treatment group.
Lacosamide was dissolved in Saline (0.9% NaCI in sterile H20). Clozapine
was dissolved in 1% Tween 80 in sterile H20 at a final pH of 6Ø All
compounds were administered intraperitoneal (ip) (volume injection: 10
ml/kg). Lacosamide was administered at doses of 1, 10 and 30 mg/kg and
Clozapine at a dose of 3 mg/kg. Doses are expressed as mg of salt. Control
mice were administered saline (vehicle 1, VEH 1) or 1% Tween 80 (vehicle
2, VEH 2) at a pH of 6Ø The drug treatments were balanced across days
and the animals only used once. All tests were conducted blind. All
compounds were administered 30 min prior to testing.
Animals were placed in the PPI chambers (Med Associates) for a 5 min
session of white noise (70 dB) habituation. After the acclimation period the
test session was automatically started. The session started with an
habituation block of 6 presentations of the startle stimulus alone, followed
by
10 PPI blocks of 6 different types of trials. Trial types are: null (no
stimuli),
startle (120 dB), startle plus prepulse (4, 8 and 12 dB over background noise
i.e. 74, 78 or 82 dB) and prepulse alone (82 dB). Trial types were presented
at random within each block. Each trial started with a 50 ms null period
during which baseline movements are recorded. There was a subsequent 20
ms period during which prepulse stimuli were presented and responses to
the prepulse measured. After further 100 ms the startle stimuli were
presented for 40 ms and responses recorded for 100 ms from startle onset.
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-49-
Responses were sampled every ms. The inter-trial interval was variable with
an average of 15 s (range from 10 to 20 s). In startle alone trials the basic
auditory startle is measured and in prepulse plus startle trials the amount of
inhibition of the normal startle is determined and expressed as a percentage
of the basic startle response (from startle alone trials), excluding the
startle
response of the first habituation block. Eight animals were tested at one
time.
Twelve animals were tested in each group. A total of 108 mice were tested
using following design:
VEH1NEH2
lacosamide [3 mg/kg] / VEH2
lacosamide [10 mg/kg] / VEH2
lacosamide [30 mg/kg] / VEH2
VEH1 / Clozapine [3 mg/kg]
lacosamide [3 mg/kg] / Clozapine [3 mg/kg]
lacosamide [10 mg/kg] / Clozapine [3 mg/kg]
lacosamide [30 mg/kg] / Clozapine [3 mg/kg]
A two-way ANOVA (analysis of variance) with treatments as independent
factor and pre-pulse intensities as dependent factor (i.e. repeated measure)
was performed. This was followed by the post-hoc Newman Keuls test
where indicated. A p < 0.05 was considered significant. The Newman Keuis
test allows for the comparison of two independent samples.
Animals injected with clozapine (3 mg/kg) showed a significant improvement
in prepulse inhibition in comparison to animals receiving vehicle (p<0.05,
table 1). When administered alone, lacosamide did not have any significant
effect on prepulse inhibition at any dose tested, when compared to vehicle.
The administration of lacosamide (at 30 mg/kg but not at 3 or 10 mg/kg) in
combination with clozapine however, did potentiate the effect of clozapine
alone on prepulse inhibition i.e. the prepulse inhibition was significantly
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-50-
higher than the effect of clozapine alone (p<0.05).
The data obtained provide a basis for clinical trials in humans using
lacosamide as an add-on therapy for the treatment of psychosis, in particular
of schizophrenia or psychosis associated with schizophrenia or/and other
diseases or conditions.
Table I
Effects of lacosamide alone and in combination with clozapine on prepulse
inhibition of the acoustic startle response (PPI)
Treatment Mean PPI
VEH 1NEH 2 29 3
VEH 1/CLOZ [3 mg/kg] 45 2*
lacosamide [3 mg/kg]NEH 2 29 3
lacosamide [10 mg/kg]NEH 2 34 3
lacosamide [30 mg/kg]NEH 2 27 2
lacosamide [3 mg/kg]/ CLOZ [3 43 2*
mg/kg]
lacosamide [10 mg/kg]/ CLOZ [3 45 2*
mg/kg]
lacosamide [30 mg/kg]/ CLOZ [3 57 5*,#
mg/kg]
CA 02595330 2007-07-19
WO 2006/079547 PCT/EP2006/000722
-51 -
* p<0.05 for comparison to VEHNEH group
# p<0.05 for comparison to VEH/CLOZ group
