WO2017137528A1 - Agoniste du récepteur a1 de l'adénosine pour utilisation dans le traitement de l'état de mal épileptique - Google Patents

Agoniste du récepteur a1 de l'adénosine pour utilisation dans le traitement de l'état de mal épileptique Download PDF

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WO2017137528A1
WO2017137528A1 PCT/EP2017/052942 EP2017052942W WO2017137528A1 WO 2017137528 A1 WO2017137528 A1 WO 2017137528A1 EP 2017052942 W EP2017052942 W EP 2017052942W WO 2017137528 A1 WO2017137528 A1 WO 2017137528A1
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adenosine
receptor agonist
treatment
receptor
pharmaceutically acceptable
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PCT/EP2017/052942
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English (en)
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Zoltan GEREVICH
Zin-juan KLAFT
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Charité - Universitätsmedizin Berlin
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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • 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
    • A61K31/435—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
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • 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

  • Adenosine A1 receptor agonist for use in treatment of status epilepticus
  • TLE Temporal lobe epilepsy
  • AEDs antiepileptic drugs
  • TLE Temporal lobe epilepsy
  • Patients suffering status epilepticus present with similarly high rates of resistance to first-line treatment with benzodiazepines. Therefore, alternative anticonvulsant substances are required and interfering with purinergic signaling may be a viable option.
  • Adenosine triphosphate is (co-)released in an activity-dependent manner from astrocytes and neurons and is subject to extracellular enzymatic degradation to adenosine. Also direct release of adenosine has been described. ATP/ADP and adenosine have been shown to modulate synaptic transmission and neuronal network activity in models of physiological and pathological network oscillations by activating P2 and A-i and A 2a receptors, respectively. Purinergic receptors have also been implicated in epileptogenic processes. While only few studies describe acute effects of P2 receptor activation on network activity adenosine receptor-mediated effects have been extensively studied.
  • Anticonvulsant properties of adenosine have been known for some time and are mediated by reduced presynaptic transmitter release probability and postsynaptic hyperpolarization. Additionally, adenosine acts proconvulsantly via A 2a receptors. However, due to the lower affinity of adenosine to A 2a receptors, its acute net effect is a reduction or suppression of epileptiform activity in different model systems presumably serving as an intrinsic anticonvulsant. However, there remains a need for further means and modalities for treatment of status epilepticus and in particular for treatment of status epilepticus refractory to treatment with known anticonvulsive drugs like e.g. benzodiazepines, carbamazepine (CBZ), valproate (VPA) and/or phenytoin (PHT).
  • CBZ carbamazepine
  • VPA valproate
  • PHT phenytoin
  • known anticonvulsive drugs like e.g. benzodiazepines, carbamazepine (CBZ), valproate (VPA) and/or phenytoin (PHT).
  • the present invention relates to adenosine A1 receptor agonists or pharmaceutically acceptable salts thereof for use in the treatment of status epilepticus.
  • adenosine A1 receptor agonists are particularly effective in treatment of status epilepticus being refractory to treatment with known anticonvulsive drugs like e.g. benzodiazepines, carbamazepine (CBZ), valproate (VPA) and/or phenytoin (PHT).
  • known anticonvulsive drugs like e.g. benzodiazepines, carbamazepine (CBZ), valproate (VPA) and/or phenytoin (PHT).
  • Activating A-i receptors with a specific agonist completely suppressed seizure-like events (SLEs) in 73 % of human temporal cortex slices. In the remaining slices incidence of SLEs was markedly reduced. Also in slices insensitive to a high dose of carbamazepine (50 ⁇ ) the adenosine A-i agonist was equally efficient.
  • the adenosine A-i receptor is one member of the adenosine receptor group of G protein- coupled receptors with adenosine as endogenous ligand.
  • Activation of the adenosine A-i receptor by an agonist causes binding of Gn/2/3 or G 0 protein. Binding of Gn/2/3 causes an inhibition of adenylate cyclase and, therefore, a decrease in the cAMP concentration.
  • An increase of the inositol triphosphate/diacylglycerol concentration is caused by an activation of phospholipase C, whereas the elevated levels of arachidonic acid are mediated by DAG lipase, which cleaves DAG to form arachidonic acid.
  • Several types of potassium channels are activated but N-, P-, and Q-type calcium channels are inhibited.
  • A1 -receptor activation generally attenuates synaptic signaling.
  • the present invention is directed to the use of adenosine A1 receptor agonists for treatment of status epilepticus.
  • the term "adenosine A1 receptor agonist” is used in its art recognized meaning and refers to small molecules which are capable of activating the adenosine A1 receptor in vivo.
  • the term "adenosine A1 receptor agonist” refers to the active compound as such and to a pharmaceutically acceptable salt thereof.
  • the adenosine A1 receptor agonist of the present invention exhibits an IC 50 value of 1 ⁇ or less with regard to the activation of human adenosine A1 receptor in vitro.
  • the present invention is not limited to the use of a particular adenosine A1 receptor agonist but is independent from the actual choice of adenosine A1 receptor agonist provided said adenosine A1 receptor agonist is capable of activating the adenosine A1 receptor.
  • the adenosine A1 receptor agonist is selective for adenosine A1 receptor compared to other types of adenosine receptors like e.g. adenosine A2 receptor.
  • an adenosine A1 receptor agonist is selective for adenosine A1 receptor if said agonist exhibits an IC 50 value for activation of adenosine A1 receptor which is 2x, preferably 5x, more preferably 10x lower than the IC 50 value for activation of adenosine A2 receptor.
  • adenosine A1 receptor agonists In the prior art, a huge number of different adenosine A1 receptor agonists is known. Exemplary embodiments of suitable adenosine A1 receptor agonists of the present invention are disclosed and derivable from US 4,843,066, US 4,985,409, US 2014/0241990, WO 2001/045715, US 9,040,566 and WO 2008/130520. 9.
  • the adenosine A1 receptor agonist for use of the present invention can be selected e.g.
  • exemplary embodiments are disclosed in WO 2008/130520, and substituted 3,5- dicyano-4-phenylpyridines, exemplary embodiments of which are disclosed in WO 03/53441 , WO 2009/015776, WO 2009/01581 1 , WO 2009/015812, WO 2010/072314, WO 2010/072315 and WO 2010/086101.
  • the adenosine A1 receptor agonist for use according to the present invention is:
  • CCPA 2-chloro-N(6)-cyclopentyladenosine
  • N6-cyclohexyl-adenosine (CHA)
  • R(-)-N6-(2-phenylisopropyl)adenosine R-PIA
  • the adenosine A1 receptor agonist for use of the present invention is N-cyclohexyl-2'-0-methyladenosine (SDZ WAG 994).
  • the adenosine A1 receptor agonist for use of the present invention can comprise one particular type of adenosine A1 receptor agonist or may comprise a combination of two or more different adenosine A1 receptor agonists.
  • the adenosine A1 receptor agonists of the present invention may be presented in form of a pharmaceutically acceptable salt thereof.
  • pharmaceutically acceptable salt includes acid addition salts and base addition salts.
  • Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of an adenosine A1 receptor agonist with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo or by freeze-drying).
  • the compounds can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the adenosine A1 receptor agonist with a pharmaceutically acceptable inorganic or organic acid, e.g.
  • hydrohalides such as hydrochloride, hydrobromide, hydroiodide
  • other mineral acids and their corresponding salts such as sulfate, nitrate, phosphate, etc.
  • alkyl- and monoarylsulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate
  • other organic acids and their corresponding salts such as acetate, tartrate, maleate, succinate, citrate, benzoate, salicylate and ascorbate.
  • Further acid addition salts include adipate, alginate, arginate, aspartate, benxenesulfonate (hesylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dini- trobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galacterate (from mucic acid), galacturonate, glucoheptaoate, glucorrate, glutamate, glycerophosplrate, hemisueci- nate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionat
  • a pharmaceutically acceptable base addition salt can be prepared by reacting the free acid form of the adenosine A1 receptor agonist with a pharmaceutically acceptable inorganic or organic base.
  • bases include alkali metal hydroxides including potassium, sodium and lithium hydroxides; alkaline earth metal hydroxides such as barium and calcium hydroxides; alkali metal alkoxides, e.g. potassium ethanolate and sodium propanolate; and various organic bases such as ammonium hydroxide, piperidine, diethanolamine and N-methylglutamine.
  • aluminum salts of the adenosine A1 receptor agonists of the present invention are also included.
  • Further base salts include copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium and zinc salts.
  • Organic base salts include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, e.g., arginine, betaine, caffeine, chloroprocaine, choline, ⁇ , ⁇ '-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, Z-dimethylami- noethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, iso-propylamine, lidocaine, lysine, meglumine, N -methyl- D-glucamine, morph
  • Salts may also be prepared by exchanging a counter-ion of an adenosine A1 receptor agonist of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
  • the salt form may confer improved pharmacokinetic properties on the adenosine A1 receptor agonist as compared to the free form of the compound.
  • the pharmaceutically acceptable salt form may also positively affect the pharmacodynamics of the compound with respect to its therapeutic activity in the body.
  • An example of a pharmacodynamic property that may be favorably affected is the manner in which the compound is transported across cell membranes, which in turn may directly and positively affect the adsorption, distribution, biotransformation and excretion of the compound.
  • the adenosine A1 receptor agonist or a pharmaceutically acceptable salt thereof is used in the treatment of status epilepticus.
  • the present invention also relates to the use of an adenosine A1 receptor agonist or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of status epilepticus.
  • the present invention also relates to a method of treating status epilepticus, wherein a patient in need of such therapy is administered a therapeutically effective dose of an adenosine A1 receptor agonist or a pharmaceutically acceptable salt thereof.
  • SE Status epilepticus
  • HCSNA highly coherent/synchronous network activity
  • SE is a separate seizure/HCSNA disorder and is classified in ICD-10 as G41 .
  • Drug resistance rates in SE are around 30-40 %. Convulsive and non-convulsive SE exists, whereas non-convulsive SE tends to be more often resistant to pharmacological treatment.
  • SE requires ictogenesis, but not necessarily epileptogenesis.
  • ictogenesis describes an acute process that, in a short time scale, directly leads to a seizure/HCSNA (the ictus).
  • HCSNA the ictus
  • ictogenic substances like high potassium artificial cerebrospinal fluid combined with a GABA receptor antagonist
  • a healthy brain can be pushed to have a seizure/ictus/HCSNA and a brain suffering from epilepsy can be pushed more "easily" to have a seizure/ictus/HCSNA.
  • ictogenesis describes the acute process causing a seizure.
  • epileptogenesis describes a chronic process, witnessed across species, where in a healthy brain an initiating event occurs and the subject ultimately develops epilepsy later on. During the days/weeks (rodents, cats, dogs) and years (human) following the initial event no seizures/HCSNA are apparent. However, during this latent period network changes occur. After the latent period comes the chronic period which is characterized by repeated and "gradually" occurring clinically relevant seizures/HCSNAs. During the chronic period and after repeated seizures patients are usually diagnosed with epilepsy. Epileptogenesis, thus, describes the processes needed to transform a healthy brain into an epileptic brain and is a long-term process characterized by reproducible anatomical changes in multiple brain regions. Epileptogenesis describes a chronic process, comprising occurrence of reproducible anatomical changes in multiple brain regions, that ultimately leads to spontaneously recurring seizures/HCSNAs.
  • the status epilepticus to be treated according to the present invention is a status epilepticus without prior epileptogenesis.
  • SE can occur without prior epileptogenesis e.g. as a spontaneous result of an acute insult like e.g. traumatic brain injury, stroke, metabolic abnormalities, hypoxia, systemic infection, anoxia, drug overdose, CNS infection, CNS hemorrhage and/or intoxication.
  • an acute insult like e.g. traumatic brain injury, stroke, metabolic abnormalities, hypoxia, systemic infection, anoxia, drug overdose, CNS infection, CNS hemorrhage and/or intoxication.
  • Such SE patients do have an acute or unknown event (ictogenesis) that leads to a long lasting seizure or a series of seizures without recovery to baseline conditions which cannot be stopped through endogenous brain mechanisms.
  • SE in epilepsy patients tends to respond very well to treatment with anticonvulsive drugs whereas (acute) SE without prior epileptogenesis tends to be often difficult to treat.
  • the adenosine A1 receptor agonist or a pharmaceutically acceptable salt thereof is used for treatment of status epilepticus, wherein the status epilepticus is refractory to treatment with one or more anticonvulsive drugs.
  • Anticonvulsant drugs are a diverse group of pharmacological agents used in the treatment of seizures. Anticonvulsant drugs suppress the rapid and excessive firing of neurons during seizures. Anticonvulsant drugs may also prevent the spread of a seizure within the brain.
  • Conventional anticonvulsive drugs may block sodium channels or enhance ⁇ -aminobutyric acid (GABA) function.
  • GABA ⁇ -aminobutyric acid
  • targets include but are not restricted to GABA A receptors, the GAT-1 GABA transporter, and GABA transaminase. Additional targets include voltage-gated calcium channels, its subunit ⁇ 2 ⁇ , and the synaptic vesicle protein SV2A.
  • Another potential target of antiepileptic drugs is the peroxisome proliferator-activated receptor alpha.
  • aldehydes e.g. paraldehyde
  • aromatic allylic alcohols e.g. stiripentol
  • barbiturates e.g. phenobarbital, methylphenobarbital, barbexaclone
  • benzodiazepines e.g. diazepam, midazolam, lorazepam, clobazam, clonazepam, clorazepate
  • diazepam, midazolam, lorazepam, clobazam, clonazepam, clorazepate e.g. diazepam, midazolam, lorazepam, clobazam, clonazepam, clorazepate
  • carbamates e.g. felbamate
  • carboxamides e.g. carbamazepine, oxcarbamazepine
  • - fatty acids e.g. valproates, valpryolamides, vigabatrin
  • GABA analogs e.g. gabapentin, pregabalin
  • hydantoins e.g. ethotoin, phenytoin, mephenytoin, fosphenytoin
  • oxazolidinediones e.g. paramethadione, trimethadione, ethadione
  • propionates e.g. beclamide
  • pyrimidinediones e.g. primidone
  • pyrrolidines e.g. brivaracetam, levetiracetam, seletracetam
  • succinimides e.g. ethosuximide, phensuximide, mesuximide
  • sulfonamides e.g. acetazolamide, sultiame, methazolamide, zonisamide
  • triazines e.g. lamotrigine
  • the status epilepticus is refractory to treatment with one or more of carbamazepine (CBZ), valproate (VPA) and/or phenytoin (PHT).
  • CBDZ carbamazepine
  • VPA valproate
  • PHT phenytoin
  • the status epilepticus to be treated is refractory to treatment with one or more modulators of GABA-A receptor signaling, preferably to treatment with an active agent of the class of benzodiazepines or dibenzazepines.
  • the adenosine A1 receptor agonist can be used in acute treatment of status epilepticus, which optionally is refractory to treatment with one or more known anticonvulsive drugs.
  • An acute treatment regime is characterized by administration of the pharmaceutical in a scheme that occurs at irregular, not predetermined time intervals, wherein one particular administration event is triggered and dependent from the presence or occurrence of an individual seizure event.
  • the term "acute” as used herein defines that each treatment or administration of the adenosine A1 receptor agonist is directly triggered by the presence or reasoned expectance of the onset of a particular seizure event or status epilepticus.
  • acute treatment refers to a self-administration by the patient of the adenosine A1 receptor agonist of the invention or a pharmaceutically acceptable salt thereof, wherein each self-administration is directly triggered upon self-perception by the patient of presence or reasoned expectance of the onset of a particular seizure event or status epilepticus.
  • each acute treatment or self-administration may be triggered by self-perception of signs of onset of a seizure event or status epilepticus by the patient, or by self-perception of an ongoing seizure event or status epilepticus.
  • the term "acute” encompasses a time window starting 2 hours before the expected onset of a seizure event or status epilepticus until any time point during the persistence of the seizure event or status epilepticus of a particular patient.
  • acute refers to a time window that begins not more than 1 hour before the expected onset of a particular seizure event or status epilepticus, most preferably not more than 30 min, 10 min or 5 min before the expected onset of a particular epileptic seizure event or status epilepticus.
  • the adenosine A1 receptor agonist can be used in chronic treatment of status epilepticus, preferably in chronic treatment of status epilepticus, which is refractory to treatment with one or more known anticonvulsive drugs.
  • a chronic treatment regime is characterized by administration of the pharmaceutical in a scheme that occurs at regular, predetermined time intervals, wherein a particular administration event is independent from the presence or absence of an individual seizure or status epilepticus.
  • the adenosine A1 receptor agonist or a pharmaceutically acceptable salt thereof is preferably administered in combination with another pharmaceutically active agent.
  • This other pharmaceutically active agent may be an anticonvulsive drug, an active agent for treatment of a concomitant disease or medical state or an active agent for treatment or prevention of side effects associated with the administration of the adenosine A1 receptor agonist of the invention.
  • the adenosine A1 receptor agonist is administered in combination with a non blood-brain-barrier permeable A1 antagonist.
  • non blood-brain-barrier permeable A1 receptor antagonists are 8- Sulphophenyltheophylline (8-SPT) und 8-Sulphophenylxanthine (DPCPX/8-SPX). Since the expression of adenosine A1 receptor is not specific to the brain, systemic treatment with an adenosine A1 receptor agonist may lead to side effects due to specific interaction with adenosine A1 receptor in the body periphery. In order to prevent or treat such side effects, it is beneficial to use an adenosine A1 receptor antagonist which does not cross the blood- brain barrier.
  • the activating effect of the adenosine A1 receptor agonist is counterbalanced in the body periphery by co-administration of a non blood-brain-barrier permeable A1 antagonist, while still allowing for specific activation of adenosine A1 receptor in the brain.
  • treating encompasses to reversing, alleviating or inhibiting the progress of a disease, disorder or condition, or improvement of one or more symptoms of such disease, disorder or condition, to which such term applies.
  • “treating” or “treatment” may also refer to decreasing the probability or incidence of the occurrence of a disease, disorder or condition in a mammal as compared to an untreated control population, or as compared to the same mammal prior to treatment.
  • “treating” or “treatment” may refer to preventing a disease, disorder or condition, and may include delaying or preventing the onset of a disease, disorder or condition, or delaying or preventing the symptoms associated with a disease, disorder or condition.
  • treating may also refer to reducing the severity of a disease, disorder or condition or symptoms associated with such disease, disorder or condition prior to a mammal's affliction with the disease, disorder or condition. Such prevention or reduction of the severity of a disease, disorder or condition prior to affliction relates to the administration of the adenosine A1 receptor agonist of the present invention, as described herein, to a subject that is not at the time of administration afflicted with the disease, disorder or condition.
  • the term “treating” or “treatment” may also refer to preventing the recurrence of a disease, disorder or condition or of one or more symptoms associated with such disease, disorder or condition.
  • treating refers to treatment of an individual, preferably of an animal, more preferably of a mammal, even more preferably of a human.
  • the individual to be treated is preferably in need of such treatment and may suffer from status epilepticus, preferably from status epilepticus refractory to treatment with an anticonvulsive drug.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as an active ingredient an adenosine A1 receptor agonist or a pharmaceutically acceptable salt thereof for use according to the present invention.
  • Such pharmaceutical compositions may comprise, in addition to the adenosine A1 receptor agonist of the invention or their pharmaceutically acceptable salts, one or more pharmaceutically acceptable excipients.
  • excipient is used herein to describe any ingredient other than the adenosine A1 receptor agonist of the invention. The choice of excipient will to a large extent depend on the particular mode of administration. Excipients can e.g.
  • Suitable carriers retardants, boosters, prolonging substances, adjuvants, stabilizers, binders, emulsifiers, surface active agents, penetration enhancers suspending agents, disintegrants, buffers, salts, dilutents, solvents, dispersion media, fillers, lubricants, propellants, preservatives, flavours or mixtures thereof.
  • the adenosine A1 receptor agonists are administered preferably at an effective dose.
  • An "effective dose” is the dose of an adenosine A1 receptor agonist that upon administration to a patient yields a measurable therapeutic effect with regard to the disease of interest.
  • an effective dose is the dose of an adenosine A1 receptor agonist that upon administration to a patient yields a therapeutic effect with regard to at least one disease related symptom in a patient or patients suffering from a disease as specified above.
  • the adenosine A1 receptor agonist of the invention is administered at a dose of not more than 500 mg/kg/d.
  • the adenosine A1 receptor agonist can be administered at a dose of 1 Mg/kg/d to 400 mg/kg/d, preferably of 20 Mg/kg/d to 150 mg/kg/d.
  • the physician or the skilled person will be able to determine the actual dose which will be suitable for an individual patient, which is likely to vary with the age, weight, sex, and concomitant illnesses such as e.g. renal or hepatic dysfunction and response of the particular patient to be treated.
  • the above mentioned dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are appropriate, and such are within the scope of the invention.
  • adenosine A1 receptor agonists of the present invention are preferably administered orally, intravenously, subcutaneously, bucally, rectally, dermally, nasally, tracheally, bronchially or by any other parenteral route or via inhalation in a pharmaceutically acceptable dosage form.
  • the adenosine A1 receptor agonist of the present invention may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include: solid formulations such as tablets; capsules containing particulates, liquids, or powders; lozenges (including liquid-filled); and chews; multi- and nano-particulates; gels; solid solutions; liposomes; films, ovules, sprays and liquid formulations.
  • Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • the adenosine A1 receptor agonist may make up from 0.1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form.
  • tablets generally contain a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl- substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate.
  • the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form.
  • Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
  • lactose monohydrate, spray-dried monohydrate, anhydrous and the like
  • mannitol xylitol
  • dextrose sucrose
  • sorbitol microcrystalline cellulose
  • starch dibasic calcium phosphate dihydrate
  • Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
  • surface active agents such as sodium lauryl sulfate and polysorbate 80
  • glidants such as silicon dioxide and talc.
  • surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet.
  • Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet.
  • ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.
  • Exemplary tablets contain up to about 80% compound, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant.
  • the adenosine A1 receptor agonist of the present invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intracerebroventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • a suitable vehicle such as sterile, pyrogen-free water.
  • the preparation of parenteral formulations under sterile conditions for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • the adenosine A1 receptor agonist of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
  • the adenosine A1 receptor agonist of the present invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3, 3-heptafluoropropane.
  • a suitable propellant such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3, 3-heptafluoro
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the adenosine A1 receptor agonist of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • adenosine A1 receptor agonist in the treatment of status epilepticus may have the advantage that such compounds may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbable than, have better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over compounds known in the prior art for treatment of said diseases.
  • Fig. 2 Exogenous and endogenous ATP signaling and SLEs.
  • Fig. 4 Specific A1 agonist during SLEs and comparison of purinergic SLE block efficacy.
  • C Proportional differences in efficacy to suppress SLEs with ATP, adenosine or the specific A1 agonist. ( * : p ⁇ 0.05; ** : p ⁇ 0.01 )
  • Fig. 5 SLE suppression in CBZ resistant human cortical slices.
  • a Upper grey trace represents SLEs sensitive to perfusion of CBZ (no subsequent A1 agonist) while lower trace is an example for CBZ resistance of SLEs in human cortical slices.
  • TLE Temporal lobe epilepsy
  • AEDs antiepileptic drugs
  • TLE Temporal lobe epilepsy
  • Studies from our and other labs have previously shown that slice preparations from resected human tissue are suitable to study pharmacological properties of induced epileptiform activities.
  • SLEs seizure-like events
  • CBZ carbamazepine
  • VPA valproate
  • PHT phenytoin
  • temporal neocortex specimen were incubated in cold (1 ° - 4° C) carbogenated (95 % 0 2 and 5 % C0 2 ) transport solution containing (in mM) KCI 3, NaH 2 P0 4 1 .25, glucose 10, sucrose 200, MgS0 4 2, MgCI 2 1 .6, CaCI 2 1 .6 and a-tocopherol 0.1 (pH 7.4, osmolality 304 mosmol/kg).
  • a-Tocopherol was dissolved in ethanol yielding a final ethanol concentration of 0.005 v%. Tissue was rapidly transported to the laboratory and dissected into 500 ⁇ thick slices in transport solution.
  • Field potential recordings were obtained in DC mode using electrodes filled with ACSF (3 - 10 mOhm) positioned in layer VA I of neocortex. Signals were digitized and saved on a computer hard drive at a sampling rate of 10 kHz with a 3 kHz low pass filter. SLEs were induced by perfusing slices with ACSF containing 8 mM K + and 50 ⁇ bicuculline-methiodide (high-K + -Bic-ACSF). Pharmacological experiments began earliest 30 minutes after SLEs had appeared to allow for stabilization and registration of a sufficient prewash control time-period.
  • SLEs from the last 10 min of drug application or corresponding control phases were analyzed with regard to incidence (events per minute, Fig 1 A, right panel), duration (s) and two amplitude values, namely, slow field potential (SFP; in mV; slow DC shift without superimposed faster activity) and maximum amplitude (xAmp; in mV, maximum amplitude of SLE including fast transients).
  • Duration of SLEs is defined as the time between the initial fast deflection from baseline and the time point where the signal has recovered 2/3 towards baseline of the slow field potential. Data are reported as mean ⁇ SD.
  • ATP disodium salt, adenosine, the A-i receptor antagonist DPCPX, the A-i receptor agonist SDZ WAG 994, the P2Y-, receptor antagonist MRS2179, the ⁇ 2 ⁇ ,, P2X 3 and P2X 2/3 receptor antagonist TNP-ATP, the P2X 7 receptor antagonists A740003 and A804598 were purchased from Tocris (Bristol, United Kingdom) and the broadband adenosine receptor antagonist CGS-15943, the GABA-A receptor antagonist bicuculline-methiodide, otocopherol and CBZ were purchased from Sigma (St. Louis, MO, USA). All drugs were added to the bath solution (high-K + -Bic-ACSF).
  • A740003, DPCPX, SDZ WAG 994 and CGS15943 were pre-dissolved in dimethyl sulfoxide (DMSO) before adding to ACSF with a final DMSO concentration of ⁇ 0.02 v%.
  • the two slices with SLE suppression were excluded from statistical analysis of the following SLE parameters.
  • Ai receptor agonist efficacy is maintained in slices with proven resistance to CBZ
  • adenosine A-i agonists like e.g. SDZ WAG 994 are sufficient to suppress seizure-like activity in human neocortical slices and, in addition, are equally effective in blocking SLEs that are CBZ-resistant.
  • A-i receptor mediated modulation of presynaptic transmitter release and postsynaptic hyperpolarization is sufficient to control CBZ-resistant seizure-like activity in a large proportion of slices form patients with pharmacoresistant epilepsy.
  • CBZ concentrations in our slice experiments were on the upper end of the maximal CBZ concentrations found in brain tissue of TLE patients. This condition may point to a superior efficacy of the A-i agonist inhibiting epileptiform activity in slices compared to CBZ.
  • adenosine still activates A 2a receptors which are known to mediate proconvulsant effects by facilitating glutamate release and NMDA-receptor activation.
  • SDZ WAG 994 1 ⁇
  • intraslice drug concentrations are expected to be considerably lower than bath concentrations due to slow diffusional equilibration and possible metabolic or uptake processes.
  • Fast metabolism and activation of proconvulsant adenosine receptors may be responsible for less efficient SLE control by adenosine compared to selective A-i receptor agonists.
  • Our comparison of adenosine and SDZ WAG 994 suggests higher efficacy of the A-i agonist.
  • inflammatory processes may play a major role in epileptogenesis and adenosine differentially modulates immune responses via A-i and A 2a receptors, it seems preferable to directly target the A-i receptor for its anticonvulsant and antiepileptogenic functions.
  • Adenosine A1 agonists are very efficient in blocking seizure-like events shown to be insensitive in vitro to a high dose of carbamazepine.
  • Efficacy in suppressing seizure-like events is significantly higher with the specific A1 agonist compared to adenosine or ATP application.
  • SDZ WAG 994 is expected to be efficient in stopping status epilepticus with tolerable side effects in patients where first and second line treatments are not efficient.

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Abstract

La présente invention concerne un agoniste du récepteur A1 de l'adénosine pour utilisation dans le traitement de l'état de mal épileptique, en particulier l'utilisation de N-cyclohexyl-2'-O-méthyladénosine (SDZ WAG 994) à des fins de traitement de l'état de mal épileptique sans épileptogenèse préalable et réfractaire au traitement par un médicament antiépileptique.
PCT/EP2017/052942 2016-02-12 2017-02-10 Agoniste du récepteur a1 de l'adénosine pour utilisation dans le traitement de l'état de mal épileptique WO2017137528A1 (fr)

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GB2582361A (en) * 2019-03-21 2020-09-23 Univ Warwick Adenosine receptor agonists

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