WO2016188816A1 - Treatment of epilepsy - Google Patents

Treatment of epilepsy Download PDF

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WO2016188816A1
WO2016188816A1 PCT/EP2016/061110 EP2016061110W WO2016188816A1 WO 2016188816 A1 WO2016188816 A1 WO 2016188816A1 EP 2016061110 W EP2016061110 W EP 2016061110W WO 2016188816 A1 WO2016188816 A1 WO 2016188816A1
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pyridin
ylmethyl
fluoro
pyrrolo
lower alkyl
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Rafal Marian KAMINSKI
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UCB Biopharma SRL
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants

Definitions

  • Epilepsy refers to a clinical phenomenon rather than a single disease entity and describes a condition in which a person has recurrent seizures due to a chronic, underlying process.
  • Four subdivisions of epilepsy are recognized: grand mal epilepsy (with subgroups:
  • epilepsy is one of the foremost examples of a seizure-related disorder
  • a wide variety of neurological and psychiatric symptoms and disorders may have, as their etiology, seizures or related seizure-like neurological phenomenon.
  • a seizure or a related seizure-like neurological phenomenon is a single discrete clinical event caused by an excessive electrical discharge from a collection of neurons or a seizure susceptible group of neurons through a process termed "ictogenesis.”
  • ictogenesis As such, ictogenic seizures may be merely the symptom of a disease.
  • epilepsy and other analogous seizure-related disorders are dynamic and often progressive diseases, with a maturation process characterized by a complex and poorly understood sequence of pathological transformations.
  • epileptogenic focus whereby the collections of abnormally discharging neurons or neurons susceptible to seizures form localized groups or “epileptogenic zones” interspersed throughout the cortical tissue.
  • the epileptogenic zones are biochemically inter-connected such that an abnormal ictogenic discharge is able to cascade from zone to zone.
  • epileptogenesis progresses, the involved areas of the nervous system become more excitable and it becomes easier for a seizure to be triggered, resulting in progressively debilitating symptoms of the seizure or seizure-related disorder.
  • Ictogenesis is the initiation and propagation of a seizure in a discrete time and space, a rapid and definitive electrical/chemical event that occurs over a period of time ranging from seconds to minutes.
  • epileptogenesis is a gradual biochemical or neuronal restructuring process whereby the normal brain is transformed by ictogenic events into an epileptogenically focused brain, having neuronal circuitry that becomes sensitized and responsive to ictogenic events, making an individual increasingly susceptible to the recurrence of spontaneous, episodic, time- limited seizures, resulting in progressively debilitating symptoms of the seizure or seizure-related disorder and progressive non-responsiveness to treatment.
  • the maturation of an "epileptogenic focus” is a slow biochemical and/or structural process that generally occur over months to years.
  • Phase 1 epileptogenesis is the initiation of the epileptogenic process prior to the first epileptic seizure or symptom of an analogous seizure-related disorder, and is often the result of some kind of injury or trauma to the brain, i.e., stroke, disease (e.g., infection such as meningitis), or trauma, such as an accidental blow to the head or a surgical procedure performed on the brain.
  • Phase 2 epileptogenesis refers to the process during which brain tissue that is already susceptible to epileptic seizures or seizure related phenomena of an analogous seizure- related disorder, becomes still more susceptible to seizures of increasing frequency and/or severity and/or becomes less responsive to treatment.
  • medication used to manage the epileptic seizures or symptoms of an analogous seizure-related disorder is required for extended periods of time, and in some cases, a patient must continue to take such prescription medication for life. Furthermore, such drugs are only effective for the management of symptoms and have side effects associated with chronic, prolonged usage.
  • AEDs anticonvulsant agents or, more properly termed, anti-epileptic drugs (AEDs), wherein the term “anti-epileptic” is synonymous with “anti-seizure” or “anti-ictogenic”. These drugs therapeutically suppress seizures by blocking the initiation of a single ictogenic event. But those AEDs now clinically available, do not prevent the process of epileptogenesis. In treating seizures or related symptoms of analogous seizure-related disorders, that is for diseases and disorders with seizure-like neurological phenomenon that may apparently be related to seizures disorders, such as mood cycling in Bipolar Disorder, impulsive behavior in patients with Impulse Control Disorders or for seizures resulting from brain injury, some AEDs may also be
  • epileptogenesis to an epileptogenic focus that also characterizes analogous seizure-related disorders.
  • AEDs are available for the management of epileptic seizures and include older agents such as phenytoin, valproate and carbamazepine, as well as newer agents such as felbamate, gabapentin, topiramate, levetiracetam, lacosamide and tiagabine.
  • the present invention relates to a new treatment of an epileptic disorder, in particular of epilepsy, epileptogenesis, seizure disorders and convulsions.
  • Figure 1 shows the effects of a test compound on the daily frequency of spontaneous recurrent seizures in the pilocarpine model of temporal lobe epilepsy.
  • Baseline seizure frequency was determined during 2-week video-accelerometry monitoring, followed by 2- week treatment phase with 3 and 30 mg/kg (p.o., once daily). * P ⁇ 0.05 vs. baseline (i-test).
  • Figure 2 shows the effects of a test compound on cumulative duration of hippocampal paroxysmal discharges (HPD) in the intra-hippocampal kainate model of temporal lobe epilepsy. D5 and D8 - days 5 and 8 after baseline readout, respectively. The test compound (30 mg/kg) was given once daily (p.o.) for 4 days after baseline HPD readout. 120 min. EEG recording was used to calculate the cumulative duration of HPD. * P ⁇ 0.05 vs. baseline (i-test). DETAILED DESCRIPTION OF THE INVENTION
  • the present invention relates to compounds of Formula ⁇ for the treatment of an epileptic disorder :
  • Formula ⁇ also comprises the compounds in their salt form, a prodrug, a tautomer or a stereoisomer thereof.
  • Ar is selected from the group consisting of:
  • R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of-H, halogen, lower alkyi, halogen substituted lower alkyi, halogen substituted lower alkoxy, alkoxy substituted lower alkyi, cycloalkylamino, -CN, -O-R 40 , -S(0) 2 -R 41 , -S(0) 2 -N(H)-R 42 , - N(H)-R 42 , -N(R 42 ) 2 , and -N(H)-S(0) 2 -R 43 , wherein:
  • R 40 is lower alkyi, fluoro substituted lower alkyi, methoxy substituted lower alkyi, or cycloalkyl
  • R 41 , R 42 and R 43 are lower alkyi
  • R 5 is selected from the group consisting of -H, -F, -CI, -Br, lower alkyi, halogen substituted alkyi, lower alkenyl, lower alkynyl, cycloalkyl, phenyl, pyrazolyl, -CN, -O-R 10 , -C(0)-N(H)- 11 , -C(0)-0-R 11 , -S(0) 2 -R 12 , -S(0) 2 -N(H)-R 12 , -N(H)-C(0)-R 12 , and -N(H)-S(0) 2 -R 12 , wherein pyrazolyl is optionally substituted with lower alkyl or heterocycloalkyl;
  • R 6 is selected from the group consisting of H, halogen, lower alkyl, halogen substituted alkyl, lower alkenyl, lower alkynyl, cycloalkyl, phenyl, pyrazolyl, -CN, -O-R 13 , -C(0)-N(H)- R 14 , -C(0)-0-R 14 , -S(0) 2 -R 15 , -S(0) 2 -N(H)-R 14 , -N(H)-C(0)-R 15 , and -N(H)-S(0) 2 -R 15 , wherein pyrazolyl is optionally substituted with lower alkyl or heterocycloalkyl;
  • R 7 is H, halogen or lower alkyl
  • R 8 is H, halogen or lower alkoxy
  • R 9 is H or halogen
  • R 10 and R 13 are independently -H, lower alkyl, lower alkyl substituted with -0-CH 3 , lower alkyl substituted with di-alkylamine, or lower alkyl substituted with heterocycloalkyl;
  • R 11 and R 14 are independently hydrogen or lower alkyl
  • R 12 and R 15 are each independently lower alkyl, In a specific embodiment, Ar is a pyridyl moiety.
  • R 6 is selected from a halogen, lower alkyl, halogen substituted alkyl.
  • R 5 is selected from a halogen, lower alkyl, halogen substituted alkyl.
  • one of R 1 , R 2 , R 3 and R 4 is selected from a halogen, lower alkyl, halogen substituted lower alkyl, whereas the others are hydrogen.
  • the compound for the treatment according to this invention has the following structure in its salt form or in its free base form :
  • Halogen or “Halo” refers to all halogens, that is, chloro (CI), fluoro (F), bromo (Br), or iodo (I).
  • Lower alkyl alone or in combination means an alkane-derived radical containing from 1 to 6 carbon atoms (unless specifically defined) that includes a straight chain alkyl or branched alkyl.
  • a lower alkyl is a straight or branched alkyl group containing from 1 -6, 1 -4, or 1 -2, carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and the like.
  • a lower alkyl may be independently substituted as described herein, unless indicated otherwise, with one or more, preferably 1 , 2, 3, 4 or 5, also 1 , 2, or 3 substituents, wherein the substituents are as indicated.
  • halo substituted lower alkyl denotes a lower alkyl group substituted with one or more halogen atoms, where preferably the lower alkyl is substituted with 1 , 2, 3, 4 or 5 halogen atoms, also 1 , 2, or 3 halogen atoms.
  • possible substitutions are attached at any available atom to produce a stable compound.
  • fluoro substituted lower alkyl denotes a lower alkyl group substituted with one or more fluoro atoms, such as
  • perfluoroalkyl where preferably the lower alkyl is substituted with 1 , 2, 3, 4 or 5 fluoro atoms, also 1 , 2, or 3 fluoro atoms.
  • exemplary fluoro substituted lower alkyl includes, but is not limited to, CF 3 , CF 2 CF 3 , CH 2 CF 3 , and the like. It is understood that substitutions are chemically feasible and attached at any available atom to provide a stable compound.
  • Lower alkoxy refers to those lower alkyl groups as defined herein attached to the remainder of the molecule via an oxygen atom.
  • Representative alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, n-pentoxy, n-heptoxy, and the like, as well as isomers thereof.
  • “Lower alkenyl” alone or in combination means a straight or branched hydrocarbon containing 2-6 carbon atoms (unless specifically defined) and at least one, preferably 1 -3, more preferably 1 -2, most preferably one, carbon to carbon double bond. Carbon to carbon double bonds may be either contained within a straight chain or branched portion.
  • the straight chain or branched lower alkenyl group is chemically feasible and attached at any available point to provide a stable compound. Examples of lower alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, and the like.
  • “Lower alkynyl” alone or in combination means a straight or branched hydrocarbon containing 2-6 carbon atoms (unless specifically defined) containing at least one, preferably one, carbon to carbon triple bond.
  • the straight chain or branched lower alkynyl group is chemically feasible and attached at any available point to provide a stable compound. Examples of alkynyl groups include ethynyl, propynyl, butynyl, and the like.
  • Cycloalkyl refers to saturated or unsaturated, non-aromatic monocyclic, bicyclic or tricyclic carbon ring systems of 3-10, also 3-8, more preferably 3-6, ring members per ring, such as cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, and the like.
  • Heterocycloalkyl refers to a saturated or unsaturated non-aromatic cycloalkyl group having from 5 to 10 atoms in which from 1 to 3 carbon atoms in the ring are replaced by heteroatoms of O, S or N, and are optionally fused with benzo or heteroaryl of 5-6 ring members. Heterocycloalkyl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. Heterocycloalkyl is also intended to include compounds in which a ring carbon may be oxo substituted, i.e.
  • the ring carbon is a carbonyl group, such as lactones and lactams.
  • the point of attachment of the heterocycloalkyl ring is at a carbon or nitrogen atom such that a stable ring is retained.
  • heterocycloalkyl groups include, but are not limited to, morpholino, tetrahydrofuranyl,
  • the compounds claimed herein may be obtained according to the methods described in WO 2008/064265 and WO 201 1/057022.
  • Example 1 Pilocarpine mouse of model of temporal lobe epilepsy
  • the pilocarpine model of temporal lobe epilepsy and epileptogenesis was performed as previously described (Mazzuferi et al., 2012). Male NMRI mice (Charles River, France) weighing 28-32 g were used for all experiments. Procedures involving animals and their care were conducted in accordance with current European Community regulations. N- Methylscopolamine was dissolved in saline and injected ip 30 min (1 mg/kg) before administration of pilocarpine 300 mg/kg, ip. Within minutes after injection of pilocarpine the mice start to develop convulsive seizures and ⁇ 30-40% of the animals will develop a long-lasting continuous seizure (i.e. status epilepticus; SE).
  • SE status epilepticus
  • SRSs spontaneous recurrent seizures
  • Example 2 Intra-hippocampal kainate model of temporal love epilepsy
  • KA kainate
  • CA1 CA3 areas and hilus, mossy fiber sprouting and dispersion of the dentate gyrus, which are all features of human temporal lobe epilepsy.
  • HPD hippocampal paroxysmal discharges
  • Mice receive 50 nl of the KA solution (1 nmol) over 1 min using a micro-pump. After injection, the cannula is left in place for an additional 1 -min period to avoid reflux along the cannula track.
  • mice were implanted with a bipolar electrode in the ipsilateral dorsal hippocampus and a reference electrode over the cerebellum.
  • test compound according to Formula ⁇ was
  • HPD hippocampal paroxysmal discharges
  • results As shown in Figure 1 , the test compound produced dose-dependent reduction in the daily frequency of SRSs, when compared to baseline values in the pilocarpine model of temporal lobe epilepsy. This effects reached statistical significance (P ⁇ 0.05, t-test) at the dose of 30 mg/kg.

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Abstract

The present invention relates to the compounds of formula I' for use in the treatment of epilepsy, epileptogenesis, seizure disorders and convulsions.

Description

Treatment of Epilepsy
INTRODUCTION
Epilepsy refers to a clinical phenomenon rather than a single disease entity and describes a condition in which a person has recurrent seizures due to a chronic, underlying process. Four subdivisions of epilepsy are recognized: grand mal epilepsy (with subgroups:
generalized, focal, jacksonian), petit mal epilepsy, psychomotor or temporal lobe epilepsy (with subgroups: psychomotor proper or tonic with adversive or torsion movements or masticatory phenomenon, automatic with amnesia, or sensory with hallucinations or dream states) and autonomic or diencephalic epilepsy (with flushing, pallor, tachycardia, hypertension, perspiration or other visceral symptoms).
While epilepsy is one of the foremost examples of a seizure-related disorder, a wide variety of neurological and psychiatric symptoms and disorders may have, as their etiology, seizures or related seizure-like neurological phenomenon. In simple terms, a seizure or a related seizure-like neurological phenomenon is a single discrete clinical event caused by an excessive electrical discharge from a collection of neurons or a seizure susceptible group of neurons through a process termed "ictogenesis." As such, ictogenic seizures may be merely the symptom of a disease. However, epilepsy and other analogous seizure-related disorders are dynamic and often progressive diseases, with a maturation process characterized by a complex and poorly understood sequence of pathological transformations.
The development and maturation of such changes is the process of "epileptogenesis," whereby the larger collection of neurons that is the normal brain is altered and
subsequently becomes capable of generating abnormal, spontaneous, sudden, recurrent, excessive electrical discharges, i.e., seizures. The maturation of the epileptogenic process results in the development of an "epileptogenic focus," whereby the collections of abnormally discharging neurons or neurons susceptible to seizures form localized groups or "epileptogenic zones" interspersed throughout the cortical tissue. The epileptogenic zones are biochemically inter-connected such that an abnormal ictogenic discharge is able to cascade from zone to zone. As epileptogenesis progresses, the involved areas of the nervous system become more excitable and it becomes easier for a seizure to be triggered, resulting in progressively debilitating symptoms of the seizure or seizure-related disorder. While ictogenesis and epileptogenesis may have a common origin in certain biochemical phenomenon and common neuronal pathways in various diseases, the two processes are not identical. Ictogenesis is the initiation and propagation of a seizure in a discrete time and space, a rapid and definitive electrical/chemical event that occurs over a period of time ranging from seconds to minutes.
Comparatively, epileptogenesis is a gradual biochemical or neuronal restructuring process whereby the normal brain is transformed by ictogenic events into an epileptogenically focused brain, having neuronal circuitry that becomes sensitized and responsive to ictogenic events, making an individual increasingly susceptible to the recurrence of spontaneous, episodic, time- limited seizures, resulting in progressively debilitating symptoms of the seizure or seizure-related disorder and progressive non-responsiveness to treatment. The maturation of an "epileptogenic focus" is a slow biochemical and/or structural process that generally occur over months to years. Epileptogenesis is a Two Phase Process: "Phase 1 epileptogenesis" is the initiation of the epileptogenic process prior to the first epileptic seizure or symptom of an analogous seizure-related disorder, and is often the result of some kind of injury or trauma to the brain, i.e., stroke, disease (e.g., infection such as meningitis), or trauma, such as an accidental blow to the head or a surgical procedure performed on the brain. "Phase 2 epileptogenesis" refers to the process during which brain tissue that is already susceptible to epileptic seizures or seizure related phenomena of an analogous seizure- related disorder, becomes still more susceptible to seizures of increasing frequency and/or severity and/or becomes less responsive to treatment. While the processes involved in epileptogenesis have not been clearly identified, it is believed by many scientists that the up regulation of excitatory coupling between neurons, mediated by N- methyl-D-aspartate (NMDA) receptors, is involved. Other scientists implicate down regulation of inhibitory coupling between neurons, mediated by gamma-amino-butyric acid (GABA) receptors. Many other factors may be involved in this process relating to the presence, concentration or activity of NO (nitric oxide) or iron, calcium or zinc ions. Although epileptic seizures are rarely fatal, large numbers of patients require medication to avoid the disruptive, and potentially dangerous consequences of seizures. In many cases, medication used to manage the epileptic seizures or symptoms of an analogous seizure-related disorder is required for extended periods of time, and in some cases, a patient must continue to take such prescription medication for life. Furthermore, such drugs are only effective for the management of symptoms and have side effects associated with chronic, prolonged usage.
Accepted drugs for the treatment of epilepsy are anticonvulsant agents or, more properly termed, anti-epileptic drugs (AEDs), wherein the term "anti-epileptic" is synonymous with "anti-seizure" or "anti-ictogenic". These drugs therapeutically suppress seizures by blocking the initiation of a single ictogenic event. But those AEDs now clinically available, do not prevent the process of epileptogenesis. In treating seizures or related symptoms of analogous seizure-related disorders, that is for diseases and disorders with seizure-like neurological phenomenon that may apparently be related to seizures disorders, such as mood cycling in Bipolar Disorder, impulsive behavior in patients with Impulse Control Disorders or for seizures resulting from brain injury, some AEDs may also be
therapeutically useful. However, those AEDs now approved are unable to prophylactically or therapeutically prevent the initial development or progressive maturation of
epileptogenesis to an epileptogenic focus that also characterizes analogous seizure- related disorders.
A wide variety of AEDs are available for the management of epileptic seizures and include older agents such as phenytoin, valproate and carbamazepine, as well as newer agents such as felbamate, gabapentin, topiramate, levetiracetam, lacosamide and tiagabine.
SUMMARY OF THE INVENTION The present invention relates to a new treatment of an epileptic disorder, in particular of epilepsy, epileptogenesis, seizure disorders and convulsions.
FIGURES
Figure 1 shows the effects of a test compound on the daily frequency of spontaneous recurrent seizures in the pilocarpine model of temporal lobe epilepsy. Baseline seizure frequency was determined during 2-week video-accelerometry monitoring, followed by 2- week treatment phase with 3 and 30 mg/kg (p.o., once daily). *P<0.05 vs. baseline (i-test).
Figure 2 shows the effects of a test compound on cumulative duration of hippocampal paroxysmal discharges (HPD) in the intra-hippocampal kainate model of temporal lobe epilepsy. D5 and D8 - days 5 and 8 after baseline readout, respectively. The test compound (30 mg/kg) was given once daily (p.o.) for 4 days after baseline HPD readout. 120 min. EEG recording was used to calculate the cumulative duration of HPD. *P<0.05 vs. baseline (i-test). DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to compounds of Formula Γ for the treatment of an epileptic disorder :
Figure imgf000005_0001
Formula Γ also comprises the compounds in their salt form, a prodrug, a tautomer or a stereoisomer thereof.
In Formula Γ, Ar is selected from the group consisting of:
Figure imgf000005_0002
, and ; wherein
s the point of attachment of Ar to -CH2- of Formula Γ and wherein
Figure imgf000005_0003
indicates the point of attachment of Ar to -NH- of Formula Γ;
R1, R2, R3 and R4 are each independently selected from the group consisting of-H, halogen, lower alkyi, halogen substituted lower alkyi, halogen substituted lower alkoxy, alkoxy substituted lower alkyi, cycloalkylamino, -CN, -O-R40, -S(0)2-R41, -S(0)2-N(H)-R42, - N(H)-R42, -N(R42)2, and -N(H)-S(0)2-R43, wherein:
R40 is lower alkyi, fluoro substituted lower alkyi, methoxy substituted lower alkyi, or cycloalkyl;
R41, R42 and R43 are lower alkyi;
R5 is selected from the group consisting of -H, -F, -CI, -Br, lower alkyi, halogen substituted alkyi, lower alkenyl, lower alkynyl, cycloalkyl, phenyl, pyrazolyl, -CN, -O-R10, -C(0)-N(H)-11, -C(0)-0-R11, -S(0)2-R12, -S(0)2-N(H)-R12, -N(H)-C(0)-R12, and -N(H)-S(0)2-R12, wherein pyrazolyl is optionally substituted with lower alkyl or heterocycloalkyl;
R6 is selected from the group consisting of H, halogen, lower alkyl, halogen substituted alkyl, lower alkenyl, lower alkynyl, cycloalkyl, phenyl, pyrazolyl, -CN, -O-R13, -C(0)-N(H)- R14, -C(0)-0-R14, -S(0)2-R15, -S(0)2-N(H)-R14, -N(H)-C(0)-R15, and -N(H)-S(0)2-R15, wherein pyrazolyl is optionally substituted with lower alkyl or heterocycloalkyl;
R7 is H, halogen or lower alkyl;
R8 is H, halogen or lower alkoxy;
R9 is H or halogen;
R10 and R13 are independently -H, lower alkyl, lower alkyl substituted with -0-CH3, lower alkyl substituted with di-alkylamine, or lower alkyl substituted with heterocycloalkyl;
R11 and R14 are independently hydrogen or lower alkyl; and
R12 and R15 are each independently lower alkyl, In a specific embodiment, Ar is a pyridyl moiety.
In a specific embodiment, R6 is selected from a halogen, lower alkyl, halogen substituted alkyl.
In a specific embodiment, R5 is selected from a halogen, lower alkyl, halogen substituted alkyl.
In a specific embodiment, one of R1, R2, R3 and R4 is selected from a halogen, lower alkyl, halogen substituted lower alkyl, whereas the others are hydrogen.
In a specific embodiment, the compound for the treatment according to this invention has the following structure in its salt form or in its free base form :
Figure imgf000006_0001
Further compounds according to Formula Γ that are useful for the treatment of an epileptic disorder are the following : [5-(5-Chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2,6-dimethoxy- pyridin-3-yl methyl) amine
[6-Fluoro-5-(5-fluoro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy- pyridin-3-ylmethyl) amine
N-(3-{2-Fluoro-6-[(5-fluoro-2-methoxy-pyhdin-3-ylmethyl)-amino] -pyridin-3-yl- methyl}-1 H-pyrrolo[2,3-b]pyridin-5-yl) acetamide
N-(3-{6-[(6-Chloro-pyridin-3-ylmethyl)-amino]-2-fluoro-pyhdin-3-ylmethyl}-1 H- pyrrolo[2,3-b]pyridin-5-yl)-methanesulfonamide
[5-(5-Chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(5-fluoro- pyridin-3-ylmethyl) amine
[6-Fluoro-5-(5-methoxy-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyhdin-2-yl]-(5-fluoro- pyridin-3-ylmethyl) amine
[6-Fluoro-5-(5-methyl-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy pyridin-3-ylmethyl) amine
[6-Fluoro-5-(5-methoxy-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyhdin-2-yl]-(6- methoxy-pyhdin-3-ylmethyl) amine
[5-(5-Chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyhmidin-2-yl]-(6-methoxy- pyridin-3-ylmethyl) amine
[6-Fluoro-5-(5-methoxy-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyhdin-2-yl]-(2- methoxy-pyhdin-3-yl-methyl) amine
[6-Fluoro-5-(1 H-pyrrolo[2,3-b]pyhdin-3-ylmethyl)-pyridin-2-yl]-(2-methoxy-pyridin-3 ylmethyl) amine
(5-Fluoro-6-methoxy-pyhdin-3-ylmethyl)-[6-fluoro-5-(5-methyl-1 H-pyrrolo[2,3- b]pyridin-3-ylmethyl)-pyhdin-2-yl]-amine
(5-Fluoro-2-methoxy-pyhdin-3-ylmethyl)-[6-fluoro-5-(5-methyl-1 H-pyrrolo[2,3- b]pyhdin-3-ylmethyl)-pyhdin-2-yl]-amine
[6-Fluoro-5-(5-methyl-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-methoxy pyridin-3 -ylmethyl) amine (6-Methoxy-pyridin-3 -yl-methyl)- [5 -(5-methyl-1 H-pyrrolo [2,3 -b]pyridin-3 - ylmethyl)- pyrimidin-2-yl] amine
(5-Fluoro-2-methoxy-pyridin-3-ylmethyl)-[5-(5-methyl-1 H-pyrrolo[2,3-b]pyridin-3- ylmethyl)-pyrimidin-2-yl] amine
[6-Fluoro-5-(5-methyl-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4- trifluoromethyl-pyhdin-3 -ylmethyl) amine
[5-(5 -Chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyhdin-2-yl]-(4-trifluoromethyl- pyridin-3-ylmethyl) amine
[5-(5-Chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyhmidin-2-yl]-(5-fluoro-2- methoxy- pyhdin-3-ylmethyl) amine
[6-Fluoro-5-(5-methyl-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-methyl- pyridin-4-ylmethyl) amine
[5-(5 -Methyl-1 H-pyrrolo [2,3 -b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-trifluoromethyl- pyridin-3-ylmethyl) amine
(5-Fluoro-2-methoxy-pyridin-4-ylmethyl)-[6-fluoro-5-(5-methyl-1 H-pyrrolo[2,3- b]pyridin-3-ylmethyl)-pyridin-2-yl] amine
(5-Fluoro-6-methoxy-pyridin-3-ylmethyl)-[5-(5-methyl-1 H-pyrrolo[2,3-b]pyridin-3- ylmethyl)-pyrimidin-2-yl] amine
[5-(5-Chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(2-methyl- pyridin-4-ylmethyl) amine
(6-Chloro-pyridin-3-ylmethyl)-[5-(5-methyl-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)- pyrimidin-2-yl] amine
(6-Chloro-pyridin-3 -ylmethyl)-[6-fluoro-5-(5-methyl-1 H-pyrrolo[2,3-b]pyridin-3- ylmethyl)- pyridin-2-yl] amine
(2,6-Dimethoxy-pyridin-3-ylmethyl)-[6-fluoro-5-(5-methyl-1 H-pyrrolo[2,3-b]pyridin- 3-ylmethyl)-pyridin-2-yl] amine
[6-Fluoro-5-(5-methyl-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-fluoro- pyridin- 3-ylmethyl) amine [6-Fluoro-5-(5-methyl-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-fluoro- pyridin-4-ylmethyl) amine
(2-Methoxy-pyridin-3-ylnnethyl)-[5-(5-nnethyl-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)- pyrimidin-2-yl] -amine
3-{[5-(5-Chloro-1 H-pyrrolo [2,3 -b]pyridin-3-ylmethyl)-pyrimidin-2-ylamino]-methyl} -5-fluoro-1 -methyl-1 H-pyridin-2-one
[5-(5-Chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(5-fluoro-6- methoxy-pyridin-3-ylmethyl) amine
[5-(5-Chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(5-fluoro-pyridin-3- ylmethyl) amine
3-{2-Fluoro-6-[(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}- 1 H-pyrrolo[2,3-b]pyridine-5-carbonitrile
5- [(5-bromo-1 H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-6-fluoro-N-[(5-fluoro-6-methoxy- 3-pyridyl)methyl]pyridin-2-amine
3-[[2-fluoro-6-[(5-fluoro-6-methoxy-3-pyridyl)methylamino]-3-pyridyl]methyl]-1 H- pyrrolo[2,3-b]pyridine-5-carbonitrile
6- chloro-N-[(5-fluoro-2-methoxy-3-pyridyl)methyl]-5-[(5-methyl-1 H-pyrrolo[2,3- b]pyridin-3-yl)methyl]pyridin-2-amine
6-fluoro-N-[(5-fluoro-6-methoxy-3-pyridyl)methyl]-5-[[5-(trifluoromethyl)-1 H-pyrrolo- [2,3- b]pyridin-3-yl]methyl]pyridin-2-amine
(6-Methoxy-pyridin-3-yl-methyl)-[3-methyl-5-(5-methyl-1 H-pyrrolo[2,3-b]pyridin-3- ylmethyl)-pyridin-2-yl] amine
[3-Fluoro-5-(5-methyl-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy- pyridin-3-ylmethyl) amine
(6-Chloro-pyridin-3-ylmethyl)-[5-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)- pyridin-2-yl] amine
[5-(5-Chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-fluoro-pyridin-3-yl- methyl) amine [5-(5-Chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3,4-d
benzyl) amine
[5-(5-Chloro-1 H-pyrrolo [2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3-methyl-benzyl) amine
[5-(5-Methyl-1 H-pyrrolo [2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl- pyridin-3-ylmethyl) amine
[6-Fluoro-5-(5-methyl-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6- trifluoromethyl-pyridin-3-ylmethyl) amine
(4-Chloro-benzyl)-[6-fluoro-5-(5-methoxy-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)- pyridin-2-yl] amine
(4-Chloro-benzyl)-[6-fluoro-5-(4-methoxy-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)- pyridin-2-yl]-amine
(6-Methyl-pyridin-2-ylmethyl)-[5-(5-methyl-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)- pyrimidin-2-yl] -amine
[5-(5-Methyl-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(6-morpholin-4-yl- pyridin-2-ylmethyl) amine
[5-(5-Methyl-1 H-pyrrolo [2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(6-pyrrolidin-1 -yl- pyridin-2-ylmethyl) amine
[6-Fluoro-5-(5-methyl-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(5-methyl- pyridin-2 -ylmethyl)-amine
[3-Fluoro-5-(5-methyl-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6- trifluoromethyl-pyridin-3 -ylmethyl) amine
[3-Fluoro-5-(5-methoxy-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6- trifluoromethyl-pyridin-3-ylmethyl) amine
(2-Cyclopentyloxy-pyridin-3-ylmethyl)-[5-(5-methyl-1 H-pyrrolo [2,3-b]pyridin-3- ylmethyl)- pyrimidin-2-yl] amine
[5-(5-Chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methoxy-pyridin- 3- ylmethyl) amine [5-(5-Chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methoxy-pyridin-
2- ylmethyl) amine
[5-(5-Chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3-fluoro-pyridin-2-yl]-(6- trifluoromethyl- pyridin-3-ylnnethyl) amine
Ethanesulfonic acid (2- {[6-fluoro-5-(5-methyl-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)- pyridin- 2-ylamino]-methyl}-phenyl) amide
Ethanesulfonic acid (3-fluoro-5-{[6-fluoro-5-(5-methyl-1 H-pyrrolo[2,3-b]pyridin-3- ylmethyl)-pyhdin-2-ylamino]-methyl}-phenyl) amide
(6-Trifluoromethyl-pyridin-3-ylmethyl)-[5-(5-trifluoromethyl-1 H-pyrrolo[2,3-b]pyridin-
3- ylmethyl)-pyridin-2-yl]-amine
(5-Fluoro-6-methoxy-pyhdin-3-ylmethyl)-[6-fluoro-5-(5-trifluoromethyl-1 H- pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyhdin-2-yl] amine
[5-(5-Cyclopropyl-1 H-pyrrolo[2,3-b]pyhdin-3-ylmethyl)-pyhdin-2-yl]-(6- trifluoromethyl-pyhdin-3-ylmethyl) amine
(6-Chloro-pyridin-3-ylmethyl)-[5-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)- pyridinyl] amine
[5-(5-Chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyhdin-2-yl]-(6-fluoro-pyhdin-3- ylmethyl) amine
[5-(5-Chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyhmidin-2-yl]-(3-fluoro-5- trifluoromethyl-benzyl) amine
[5-(5-Methyl-1 H-pyrrolo [2,3-b]pyridin-3-yl-methyl)-pyridin-2-yl]-(6-trifluoromethyl- pyridin-3-ylmethyl) amine
[6-Fluoro-5-(5-methyl-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy- pyridin-3-ylmethyl) amine
[6-Fluoro-5-(5-methoxy-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyhdin-2-yl]-(6- methoxy-pyhdin-3-ylmethyl) amine
[6-Fluoro-5-(5-methyl-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6- trifluoromethyl-pyhdin-3-ylmethyl) amine (4-Chloro-benzyl)-[6-fluoro-5-(5-methoxy-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)- pyridin-2-yl] amine
(2-Chloro-benzyl)-[6-fluoro-5-(5-methoxy-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)- pyridin-2-yl] amine
(4-Chloro-benzyl)-[6-fluoro-5-(4-methoxy-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)- pyridin-2-yl]amine
[5-(5-Chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyhmidin-2-yl]-(6-methoxy- pyridin-3-ylmethyl) amine
(5-Fluoro-6-methoxy-pyhdin-3-ylmethyl)-[6-fluoro-5-(5-methoxy-1 H-pyrrolo[2,3- b]pyridin-3-ylmethyl)-pyridin-2-yl] amine
(5-Fluoro-6-methoxy-pyhdin-3-ylmethyl)-[6-fluoro-5-(1 H-pyrrolo[2,3-b]pyridin-3- ylmethyl)- pyridin-2-yl] amine
(5-Chloro-pyridin-2-ylmethyl)-[6-fluoro-5-(1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)- pyridin-2-yl] amine
(5-Chloro-pyridin-2-ylmethyl)-[6-fluoro-5-(5-methyl-1 H-pyrrolo[2,3-b]pyridin-3- ylmethyl)- pyridin-2-yl] amine
(5-Fluoro-6-methoxy-pyhdin-3-ylmethyl)-[6-fluoro-5-(5-methyl-1 H-pyrrolo[2,3- b]pyridin-3-ylmethyl)-pyridin-2-yl] amine
(4-Chloro-benzyl)-[6-fluoro-5-(5-methyl-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)- pyridin-2-yl] amine
(6-Methoxy-pyhdin-3-ylmethyl)-[5-(5-methyl-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)- pyrimidin-2-yl] amine
[5-(5-Chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(5-fluoro-6- methoxy-pyhdin-3-ylmethyl) amine
All atoms designated within a Formula described herein, either within a structure provided, or within the definitions of variables related to the structure, is intended to include any isotope thereof, unless clearly indicated to the contrary. It is understood that for any given atom, the isotopes may be present essentially in ratios according to their natural occurrence, or one or more particular atoms may be enhanced with respect to one or more isotopes using synthetic methods known to one skilled in the art.
"Halogen" or "Halo" refers to all halogens, that is, chloro (CI), fluoro (F), bromo (Br), or iodo (I).
"Lower alkyl" alone or in combination means an alkane-derived radical containing from 1 to 6 carbon atoms (unless specifically defined) that includes a straight chain alkyl or branched alkyl. In many embodiments, a lower alkyl is a straight or branched alkyl group containing from 1 -6, 1 -4, or 1 -2, carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and the like. A lower alkyl may be independently substituted as described herein, unless indicated otherwise, with one or more, preferably 1 , 2, 3, 4 or 5, also 1 , 2, or 3 substituents, wherein the substituents are as indicated.
Furthermore, possible substitutions are attached at any available atom to produce a stable compound. For example "halo substituted lower alkyl" denotes a lower alkyl group substituted with one or more halogen atoms, where preferably the lower alkyl is substituted with 1 , 2, 3, 4 or 5 halogen atoms, also 1 , 2, or 3 halogen atoms. Furthermore, possible substitutions are attached at any available atom to produce a stable compound. For example "fluoro substituted lower alkyl" denotes a lower alkyl group substituted with one or more fluoro atoms, such as
perfluoroalkyl, where preferably the lower alkyl is substituted with 1 , 2, 3, 4 or 5 fluoro atoms, also 1 , 2, or 3 fluoro atoms. Exemplary fluoro substituted lower alkyl includes, but is not limited to, CF3, CF2CF3, CH2CF3, and the like. It is understood that substitutions are chemically feasible and attached at any available atom to provide a stable compound.
"Lower alkoxy" refers to those lower alkyl groups as defined herein attached to the remainder of the molecule via an oxygen atom. Representative alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, n-pentoxy, n-heptoxy, and the like, as well as isomers thereof.
"Lower alkenyl" alone or in combination means a straight or branched hydrocarbon containing 2-6 carbon atoms (unless specifically defined) and at least one, preferably 1 -3, more preferably 1 -2, most preferably one, carbon to carbon double bond. Carbon to carbon double bonds may be either contained within a straight chain or branched portion. The straight chain or branched lower alkenyl group is chemically feasible and attached at any available point to provide a stable compound. Examples of lower alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, and the like.
"Lower alkynyl" alone or in combination means a straight or branched hydrocarbon containing 2-6 carbon atoms (unless specifically defined) containing at least one, preferably one, carbon to carbon triple bond. The straight chain or branched lower alkynyl group is chemically feasible and attached at any available point to provide a stable compound. Examples of alkynyl groups include ethynyl, propynyl, butynyl, and the like.
"Cycloalkyl" refers to saturated or unsaturated, non-aromatic monocyclic, bicyclic or tricyclic carbon ring systems of 3-10, also 3-8, more preferably 3-6, ring members per ring, such as cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, and the like.
"Heterocycloalkyl" refers to a saturated or unsaturated non-aromatic cycloalkyl group having from 5 to 10 atoms in which from 1 to 3 carbon atoms in the ring are replaced by heteroatoms of O, S or N, and are optionally fused with benzo or heteroaryl of 5-6 ring members. Heterocycloalkyl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. Heterocycloalkyl is also intended to include compounds in which a ring carbon may be oxo substituted, i.e. the ring carbon is a carbonyl group, such as lactones and lactams. The point of attachment of the heterocycloalkyl ring is at a carbon or nitrogen atom such that a stable ring is retained. Examples of heterocycloalkyl groups include, but are not limited to, morpholino, tetrahydrofuranyl,
dihydropyridinyl, piperidinyl, pyrrolidinyl, pyrrolidonyl, piperazinyl,
The compounds claimed herein may be obtained according to the methods described in WO 2008/064265 and WO 201 1/057022.
EXAMPLES
Example 1 : Pilocarpine mouse of model of temporal lobe epilepsy
The pilocarpine model of temporal lobe epilepsy and epileptogenesis was performed as previously described (Mazzuferi et al., 2012). Male NMRI mice (Charles River, France) weighing 28-32 g were used for all experiments. Procedures involving animals and their care were conducted in accordance with current European Community regulations. N- Methylscopolamine was dissolved in saline and injected ip 30 min (1 mg/kg) before administration of pilocarpine 300 mg/kg, ip. Within minutes after injection of pilocarpine the mice start to develop convulsive seizures and ± 30-40% of the animals will develop a long-lasting continuous seizure (i.e. status epilepticus; SE). SE was stopped after 3-h duration by bolus (ip) injection of diazepam (10 mg/kg). The mice surviving SE develop spontaneous recurrent seizures (SRSs) starting from 24-72 h after SE. These initial SRSs are typically stage 3/4 on Racine's seizure severity scale and fairly frequent (4-5 seizures per 24 h), then after 1-2 weeks the seizures become more severe (stage 4/5 mainly), but less frequent (1-2 seizures per week).
Example 2 : Intra-hippocampal kainate model of temporal love epilepsy
Unilateral injection of a small dose of kainate (KA) in the dorsal hippocampus of mice results in neuronal losses in CA1 , CA3 areas and hilus, mossy fiber sprouting and dispersion of the dentate gyrus, which are all features of human temporal lobe epilepsy. Three weeks after KA injection, spontaneous and recurrent hippocampal paroxysmal discharges (HPD), lasting about 15-20 s, are observed in the EEG concomitantly with behavioral arrest and/or automatisms. These focal seizures typically remain stable during the rest of the life of the animals and occur regularly at a frequency of about 40/h
(Bouilleret et al., 1999 and Riban et al., 2002).
In this study C57/BL6 mice, from Janvier (France) were used. After surgery, animals were housed in individual cages with access to food and water ad libitum under a 12/12h light and dark cycle (light on at 8:00 a.m). Procedures involving animals and their care were conducted in accordance with current European Community regulations. Stereotaxic injection and implantation of electrodes were performed under general anaesthesia using isoflurane (3% in oxygen). A stainless steel cannula (outer diameter, 0.28 mm) connected to a 0.5 μΙ micro-syringe via PE20 tubing containing distilled water, is filled with a 20 mM kainic acid solution (KA; Sigma, Lyon, France) in 0.9% sterile NaCI and positioned in the right dorsal hippocampus (AP = - 2, ML = -1.5, DV = - 2 mm with bregma as reference (Paxinos and Franklin, 2001 ). Mice receive 50 nl of the KA solution (1 nmol) over 1 min using a micro-pump. After injection, the cannula is left in place for an additional 1 -min period to avoid reflux along the cannula track. After KA injection, mice were implanted with a bipolar electrode in the ipsilateral dorsal hippocampus and a reference electrode over the cerebellum.
The test compound according to Formula Γ was
Figure imgf000016_0001
which was synthesized by UCB Biopharma Sprl, dissolved in in methylcellulose 1 %, Tween 80 0.1 %, silicone Antifoam 1510 0.1 % in water to concentrations of 0.326 and 3.26 mg/ml Testing:
Pilocarpine model
A stable seizure number and typical clustering of SRSs are observed from 6-8 weeks onwards in the pilocarpine model (Mazzuferi et al., 2012). Therefore 6 weeks after SE, the mice were screened during 2 weeks monitoring by video-accelerometry to confirm presence of SRSs and their frequency. Only the mice that reliably displayed SRSs were then selected for the next part of the experiment. At this time they were divided into three groups (N=20) and monitored for 2 weeks by continuous video-accelerometry to establish their SRS baseline frequency. After this period each group of animals received either vehicle (p.o.) or the above test compound (PLX-3397) (p.o) at either 10 or 30 mg/kg (single daily administration for 2 weeks). Pilot pharmacokinetics data indicated that p.o. administration of the test compound (10 mg/kg) in NMRI mice produced brain exposures of—1.1 μΜ in mice and brain/plasma ratios were equal to -0.25 at 2h and -0.5 at 6h following the drug administration.
Kainate model
One baseline EEG recording (2 hours duration) was performed 4 weeks after kainate (KA) injection and before the beginning of chronic treatment (DO). Only mice with confirmed and stable spontaneous and recurrent hippocampal paroxysmal discharges (HPD) were selected for the study (i.e. with a mean number of -40 hippocampal discharges/hour). Then these mice (n=8) were given the test compound at 30 mg/kg p.o. (one injection per day between 8 and 9 AM) for four consecutive days. An EEG recording (2 hours) was performed on the fifth day (i.e the day after the last drug treatment). A washout period of 2 days was then allowed and an additional EEG recording (2 hours) was performed on D8.
Results: As shown in Figure 1 , the test compound produced dose-dependent reduction in the daily frequency of SRSs, when compared to baseline values in the pilocarpine model of temporal lobe epilepsy. This effects reached statistical significance (P<0.05, t-test) at the dose of 30 mg/kg.
Treatment with the test compound at 30 mg/kg produced a significant decrease in cumulative duration of HPD in the kainate model when compared to the baseline period at D5 (P<0.05; i-test). This effect was no longer seen on D8 and the cumulative duration of HPD returned to the baseline value (Figure 2).
REFERENCES
Bouilleret V, Ridoux V, Depaulis A, Marescaux C, Nehlig A,Le Salle G.G.
Recurrent seizures and hippocampal sclerosis following intrahippocampal kainate injection in adult mice: electroencephalography, histopathology and synaptic reorganization similar to mesial temporal lobe epilepsy. Neuroscience 1999; 89:
717-29.
Mazzuferi M, Kumar G, Rospo C, Kaminski RM. Rapid epileptogenesis in the mouse pilocarpine model: video-EEG, pharmacokinetic and histopathological characterization. Exp Neurol. 2012; 238: 156-167.
Riban, V., Bouilleret, V., Pham-Le, B., & Fritschy, J. (2002) Evolution of hippocampal epileptic activity during the development of hippocampal sclerosis in a mouse model of temporal lobe epilepsy. Neuroscience 2002; 1 12: 101 -1 1 1.

Claims

Figure imgf000018_0001
or a salt, a prodrug, a tautomer or a stereoisomer thereof, wherei
Ar is selected from the group consisting of:
Figure imgf000018_0002
dicates the point of attachment of Ar to -CH2- of Formula Γ and wherein
Figure imgf000018_0003
indicates the point of attachment of Ar to -NH- of Formula Γ; R1, R2, R3 and R4 are each independently selected from the group consisting of-H, halogen, lower alkyi, halogen substituted lower alkyi, halogen substituted lower alkoxy, alkoxy substituted lower alkyi, cycloalkylamino, -CN, -O-R40, -S(0)2-R41, - S(0)2-N(H)-R42, -N(H)-R42, -N(R42)2, and -N(H)-S(0)2-R43, wherein:
R40 is lower alkyi, fluoro substituted lower alkyi, methoxy substituted lower alkyi, or cycloalkyl;
R41, R42 and R43 are lower alkyi;
R5 is selected from the group consisting of -H, -F, -CI, -Br, lower alkyi, halogen substituted alkyi, lower alkenyl, lower alkynyl, cycloalkyl, phenyl, pyrazolyl, -CN, -O- R10, -C(0)-N(H)-11, -C(0)-0-R11, -S(0)2-R12, -S(0)2-N(H)-R12, -N(H)-C(0)-R12, and - N(H)-S(0)2-R12, wherein pyrazolyl is optionally substituted with lower alkyl or heterocycloalkyl;
R6 is selected from the group consisting of H, halogen, lower alkyl, halogen substituted alkyl, lower alkenyl, lower alkynyl, cycloalkyl, phenyl, pyrazolyl, -CN, -O- R13, -C(0)-N(H)-R14, -C(0)-0-R14, -S(0)2-R15, -S(0)2-N(H)-R14, -N(H)-C(0)-R15, and -
N(H)-S(0)2-R15, wherein pyrazolyl is optionally substituted with lower alkyl or heterocycloalkyl;
R7 is H, halogen or lower alkyl;
R8 is H, halo gen or lower alkoxy;
R9 is H or halogen;
R10 and R13 are independently -H, lower alkyl, lower alkyl substituted with -0-CH3, lower alkyl substituted with di-alklylamine, or lower alkyl substituted with
heterocycloalkyl;
R11 and R14 are independently hydrogen or lower alkyl; and
R12 and R15 are each independently lower alkyl.
2. Compound according to claim 1 , wherein Ar is a pyridyl moiety.
3. Compound according to claim 1 or 2, wherein R6 is a halogen, lower alkyl, halogen substituted alkyl.
4. Compound according to any of claim 1 -3, wherein R5 is a halogen, lower alkyl,
halogen substituted alkyl.
5. Compound according to any of claim 1 -4, wherein one of R1, R2, R3 and R4 is a
halogen, lower alkyl, halogen substituted lower alkyl, whereas the others are hydrogen.
6. Compound according to any of claim 1 -5, wherein a lower alkyl is a methyl, ethyl, propyl, isopropyl, butyl, t-butyl group.
7. Compound according to any of claim 1 -5, wherein a lower alkyl is a methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, n-pentoxy, n-heptoxy group.
8. Compound according to any of claim 1 -7, having the following structure : 19
Figure imgf000020_0001
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109153677A (en) * 2016-06-17 2019-01-04 苏州科睿思制药有限公司 Hydrochloride Form of PLX3397 and its preparation method and application
WO2019023198A1 (en) * 2017-07-25 2019-01-31 Plexxikon Inc. Formulations of a compound modulating kinases

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008064265A2 (en) 2006-11-22 2008-05-29 Plexxikon, Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
WO2010055127A1 (en) * 2008-11-14 2010-05-20 Neurosearch A/S Benzimidazole derivatives and their use for modulating the gabaa receptor complex
WO2011057022A1 (en) 2009-11-06 2011-05-12 Plexxikon, Inc. Compounds and methods for kinase modulation, and indications therefor
WO2013142427A1 (en) * 2012-03-19 2013-09-26 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008064265A2 (en) 2006-11-22 2008-05-29 Plexxikon, Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
WO2010055127A1 (en) * 2008-11-14 2010-05-20 Neurosearch A/S Benzimidazole derivatives and their use for modulating the gabaa receptor complex
WO2011057022A1 (en) 2009-11-06 2011-05-12 Plexxikon, Inc. Compounds and methods for kinase modulation, and indications therefor
WO2013142427A1 (en) * 2012-03-19 2013-09-26 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BOUILLERET V; RIDOUX V; DEPAULIS A; MARESCAUX C; NEHLIG A; LE SALLE G.G: "Recurrent seizures and hippocampal sclerosis following intrahippocampal kainate injection in adult mice: electroencephalography, histopathology and synaptic reorganization similar to mesial temporal lobe epilepsy", NEUROSCIENCE, vol. 89, 1999, pages 717 - 29
CATHERINE C SMITH ET AL: "764: PLX3397 Is An Investigational Selective FLT3 Inhibitor That Retains Activity Against the Clinically-Relevant FLT3-ITD/F691L "Gatekeeper" Mutation in Vitro", BLOOD, vol. 118, no. 21, 18 November 2011 (2011-11-18) - 13 December 2011 (2011-12-13), US, pages 347, XP055193708, ISSN: 0006-4971 *
MAZZUFERI M; KUMAR G; ROSPO C; KAMINSKI RM: "Rapid epileptogenesis in the mouse pilocarpine model: video-EEG, pharmacokinetic and histopathological characterization", EXP NEUROL., vol. 238, 2012, pages 156 - 167
RIBAN, V.; BOUILLERET, V.; PHAM-LE, B.; FRITSCHY, J.: "Evolution of hippocampal epileptic activity during the development of hippocampal sclerosis in a mouse model of temporal lobe epilepsy", NEUROSCIENCE, vol. 112, 2002, pages 101 - 111

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109153677A (en) * 2016-06-17 2019-01-04 苏州科睿思制药有限公司 Hydrochloride Form of PLX3397 and its preparation method and application
CN109153677B (en) * 2016-06-17 2021-03-12 苏州科睿思制药有限公司 Hydrochloride crystal form of PLX3397 and preparation method and application thereof
WO2019023198A1 (en) * 2017-07-25 2019-01-31 Plexxikon Inc. Formulations of a compound modulating kinases
US10435404B2 (en) 2017-07-25 2019-10-08 Plexxikon Inc. Formulations of a compound modulating kinases
KR20200032683A (en) * 2017-07-25 2020-03-26 플렉시콘 인코퍼레이티드 Formulation of compounds that modulate kinase
JP2020528884A (en) * 2017-07-25 2020-10-01 プレキシコン インコーポレーテッドＰｌｅｘｘｉｋｏｎ Ｉｎｃ． Formulations of compounds that regulate kinases
US10941142B2 (en) 2017-07-25 2021-03-09 Plexxikon Inc. Formulations of a compound modulating kinases
US10961240B2 (en) 2017-07-25 2021-03-30 Plexxikon Inc. Formulations of a compound modulating kinases
JP7170030B2 (en) 2017-07-25 2022-11-11 プレキシコン インコーポレーテッド Formulations of compounds that modulate kinases
KR102615829B1 (en) 2017-07-25 2023-12-20 플렉시콘 인코퍼레이티드 Preparations of compounds that modulate kinases

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