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WO2022060978A1 - Méthodes de traitement de la maladie de parkinson et de troubles apparentés avec des inhibiteurs de pde10a - Google Patents

Méthodes de traitement de la maladie de parkinson et de troubles apparentés avec des inhibiteurs de pde10a Download PDF

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WO2022060978A1
WO2022060978A1 PCT/US2021/050662 US2021050662W WO2022060978A1 WO 2022060978 A1 WO2022060978 A1 WO 2022060978A1 US 2021050662 W US2021050662 W US 2021050662W WO 2022060978 A1 WO2022060978 A1 WO 2022060978A1
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pharmaceutically acceptable
parkinson
acceptable salt
disease
treating
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Matthew During
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Matador Therapeutics Inc
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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
    • A61K31/495—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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines 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
    • A61K31/495—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs

Definitions

  • Methods and compositions for treating Parkinson’s disease related disorders with a PDE10A inhibitor More particularly, provided are methods and compositions for treating levodopa induced dyskinesia, off episodes associated with Parkinson’s disease, and Parkinson’s disease psychosis with a PDE10A inhibitor, e.g., l-[2-fluoro-4-(lH-pyrazol-l-yl)phenyl]-5-methoxy-3- ( 1 -phenyl- 1 H-pyrazol -5 -yl)-pyridazin-4( 1 H)-one.
  • a PDE10A inhibitor e.g., l-[2-fluoro-4-(lH-pyrazol-l-yl)phenyl]-5-methoxy-3- ( 1 -phenyl- 1 H-pyrazol -5 -yl)-pyridazin-4( 1 H)-one.
  • PDE10A is of the known 12 families of phosphodiesterases, the one with the most restricted expression, largely confined to the brain. It is a dual specificity enzyme with both cAMP and cGMP as substrates. As such, PDE10A inhibition increases the levels of both these second messengers and therefore augments receptors and signaling positively coupled to either PKA or PKG. The functional consequences of such inhibition are dependent on both the expression pattern or localization of the enzyme, as well as the activity of the relevant network of neurons.
  • PDE10A expression is most highly expressed in the caudate and putamen (also referred to as the striatum in lower species), the emphasis of the vast majority of investigators has been on the effect of PDE10A inhibition in disorders with altered caudate/putamen function, specifically schizophrenia and Huntington’s Disease (HD).
  • the enzyme is however more widely expressed, including cortex, hippocampus, prefrontal cortex and outside the CNS, the testis.
  • Parkinson's disease is a progressive neurodeg enerative disease with a primary symptom of extrapy rami dal function abnormality. Pathologically, loss of dopaminergic neurons and alpha-synuclein deposition in the substantia nigra pars compacta are observed.
  • levodopa L-DOPA
  • L-DOPA levodopa
  • the period when levodopa has a positive effect on Parkinson’s symptoms is ‘on-time’.
  • an ‘off-episode’ starts, where symptoms recur.
  • levodopa would be given to prevent off-episodes between doses.
  • the problem is that with prolonged use, the body’s ability to convert levodopa into dopamine decreases lowering the medication’s efficacy. This can be compensated, to a certain degree, by increasing the dose of levodopa or by increasing the dosing frequency.
  • LID Levodopa Induced Dyskinesia
  • the current therapeutic and preventative strategies for LID include using a lower dosage of levodopa, employing dopamine agonists as initial therapy in Parkinson's disease, amantadine, which is an NMDA antagonist, and neurosurgery.
  • Parkinson's disease employing dopamine agonists as initial therapy in Parkinson's disease, amantadine, which is an NMDA antagonist, and neurosurgery.
  • the methods include treating movement disorders including dyskinesia, dystonia, akinesia, bradykinesia, tardive dyskinesia, dopamine replacement therapy induced dyskinesia, levodopa induced dyskinesia, ataxia, akathisia, dystonia, essential tremor, myoclonus, chorea, balhsmus, athetosis, and tics.
  • the methods include treatments of levodopa induced dyskinesia.
  • the methods include treatments for off-episodes associated with Parkinson’s disease.
  • the methods include treatments for Parkinson’s disease psychosis.
  • the methods and compositions include a PDE10A inhibitor incorporating l-[2-fluoro-4-(lH-pyrazol-l-yl)phenyl]-5-methoxy-3- ( 1 -phenyl- 1 H-pyrazol -5 -yl)-pyridazin-4( 1 H)-one, 1 - (4 - (3 -(4-( 1/7- Benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-l-yl)ethanone, 2-[4-(l -Methyl -4-pyridin-4-yl-lH-pyrazol-3-yl)-phenoxymethyl]-quinoline, and/or 6-chloro-N-((2,4-dimethylthiazol-5-yl)methyl)-5-methyl-2-(3- (quinolin-2-yl) propoxy)pyrimidin-4-amine.
  • compositions including from O.lmg to lOOmg of a PDE10A inhibitor or a pharmaceutically acceptable salt thereof are provided.
  • the compositions and methods include lOmg, 20mg or 30mg of a PDE10A inhibitor or a pharmaceutically acceptable salt thereof.
  • compositions including a PDE10A inhibitor or a pharmaceutically acceptable salt thereof are administered from one to four times a day.
  • administering a composition including a PDE10A inhibitor or pharmaceutically acceptable salt thereof may be accomplished via one or more of the following routes: oral, buccal, sublingual, rectal, topical, intranasal, and parenteral.
  • the methods and compositions for treating levodopa induced dyskinesia include a compound according to Formula I or a pharmaceutically acceptable salt thereof in an amount of 1 mg to 100 mg.
  • the methods and compositions include a compound according to Formula I or a pharmaceutically acceptable salt thereof in an amount of lOmg, 20mg or 30mg.
  • Parkinson’s disease related disorders include movement disorders, such as, dyskinesia, dystonia, akinesia, bradykinesia, tardive dyskinesia, dopamine replacement therapy induced dyskinesia, levodopa induced dyskinesia, ataxia, akathisia, dystonia, essential tremor, myoclonus, chorea, ballismus, athetosis, and tics.
  • the methods include treatments of levodopa induced dyskinesia.
  • the methods include treatments for off-episodes.
  • compositions and methods for treating, improving, suppressing the progression, or preventing motor complications associated with levodopa therapy, especially levodopa induced dyskinesia referred to as LID or PD-LID.
  • compositions and methods for treating, improving, suppressing, or preventing off-episodes associated with Parkinson's disease are also provided.
  • compositions and methods for treating, improving, suppressing, or preventing Parkinson's disease are provided.
  • PDElOa inhibitors include l-[2-fluoro-4-(lH-pyrazol-l-yl)phenyl]-5- m ethoxy-3 -( 1 -phenyl- 1 H-pyrazol -5 -yl)-pyridazin-4( 1 H)-one, l-(4-(3-(4-(I77- Benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-l-yl)ethanone, 2-[4-(l -Methyl -4-pyridin-4-yl-lH-pyrazol-3-yl)-phenoxymethyl]-quinoline, 6-chloro-N-((2,4-dimethylthiazol-5-yl)methyl)-5-methyl-2- (3-(quinolin-2-yl)propoxy)pyrimidin-4-amine.
  • PDE10A inhibitors are described in Hu et al., J. Med. Chem. 2014, 57, 6632-6641; Buijnsters et al., ACS Med. Chem. Lett. 2014, 5, 1049-1053; Shipe et al., J. Med. Chem. 2015, 58, 7888-7894, the disclosures of which are incorporated herein in their entirety.
  • compositions for treating Parkinson’s disease and Parkinson’s disease related disorders by administering to a subject in need thereof a pharmaceutical composition including an effective amount of l-[2-fluoro-4-(lH-pyrazol-l-yl)phenyl]-5- methoxy-3-(l-phenyl-lH-pyrazol-5-yl)-pyridazin-4(lH)-one or a pharmaceutically acceptable salt thereof.
  • compositions for treating Parkinson’s disease and Parkinson’s disease related disorders by administering to a subject in need thereof a pharmaceutical composition including an effective amount of l-(4-(3-(4-(l/7-Benzo[ ]imidazole-2- carbonyl)phenoxy)pyrazin-2-yl)piperidin-l-yl)ethanone or a pharmaceutically acceptable salt thereof.
  • compositions for treating Parkinson’s disease and Parkinson’s disease related disorders by administering to a subject in need thereof a pharmaceutical composition including an effective amount of 2-[4-(l -Methyl -4-pyridin-4-yl-lH-pyrazol-3- yl)-phenoxymethyl]-quinoline or a pharmaceutically acceptable salt thereof.
  • compositions and methods herein are also suitable for the treatment of Parkinson's disease or Parkinson’s disease related disorders such as, psychosis, dementia, dementia associated psychosis, dyskinesia, akinesia, dystonia, depression, fatigue, and other neuropsychiatric complications of Parkinson's disease.
  • Parkinson's disease or Parkinson’s disease related disorders such as, psychosis, dementia, dementia associated psychosis, dyskinesia, akinesia, dystonia, depression, fatigue, and other neuropsychiatric complications of Parkinson's disease.
  • compositions for treating Parkinson’s disease and Parkinson’s disease related disorders by administering to a subject in need thereof a pharmaceutical composition including an effective amount of 6-chloro-N-((2,4-dimethylthiazol-5- yl)methyl)-5-methyl-2-(3-(quinolin-2-yl)propoxy)pyrimidin-4-amine or a pharmaceutically acceptable salt thereof.
  • the methods may reduce severity of OFF periods, such that the patient experiences less motor fluctuations or fewer side effects during OFF periods.
  • the methods may reduce duration of OFF periods by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% compared with the duration of OFF periods after the same L-Dopa treatment but in the absence of the disclosed treatments.
  • the methods may reduce frequency of OFF periods by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% compared with the frequency of OFF periods after the same L-Dopa treatment but in the absence of the disclosed treatments.
  • methods and compositions that reduce the severity, duration, and/or frequency of motor fluctuations, a common motor symptom during OFF periods.
  • Motor fluctuations result from variable responses to the therapeutic being administered, such as L-Dopa, reflecting the wearing off of therapeutic efficacy between doses and resulting in oscillating ON/OFF periods. Motor fluctuations may correspond to predictable wearing-off of a therapeutic, unpredictable ON/OFF or sudden OFF periods.
  • methods provided herein reduce the variability of response to a levodopa, e.g., lengthening ON periods and/or reducing delayed responses, thus reducing oscillations between ON/OFF periods during doses.
  • Non-motor symptoms of OFF periods may also include sleep disorders, such as sleep apnea and REM sleep behavior disorder.
  • non-motor symptoms of OFF periods include psychosis, such as hallucinations and delusions.
  • the instant methods reduce or alleviate symptoms of psychosis, such as hallucinations and/or delusions, in particular, hallucinations and delusions associated with OFF periods.
  • hallucinations In Parkinson s patients, hallucinations often are benign at first, such as involving visions of children or animals around the home. During later stages, however, patients may experience serious psychosis, involving delusions (false or illogical beliefs) and paranoia (such as becoming convinced that others are spying on them).
  • methods provided herein delay, reduce, or alleviate hallucinations and/or delusions.
  • kits for treating levodopa induced dyskinesia by administering to a subject in need thereof a pharmaceutical composition including an effective amount of a PDE10A inhibitor.
  • the PDE10A inhibitor is l-[2-fluoro-4- (IH-pyrazol- l-yl)phenyl]-5-methoxy-3-(l -phenyl- lH-pyrazol-5-yl)- pyridazin-4(lH)-one or a pharmaceutically acceptable salt thereof.
  • levodopa induced dyskinesia refers to involuntary movement of the hand, leg, or body unintentionally weaving, which is induced by levodopa. It is known that dyskinesia is readily manifested if a large amount of levodopa is dosed and it is very difficult to control once it is manifested, even if the dosage of levodopa is subsequently increased or decreased to various levels. Peak-dose dyskinesia is known as an exemplary symptom of LID. The symptom is manifested on the face, tongue, neck, limbs, body trunk, or the like when the blood levodopa concentration is high.
  • a PDE10A inhibitor or a pharmaceutically acceptable salt thereof to treat a subject having levodopa induced dyskinesia.
  • the subject may be an animal, e.g., mammal, e.g., human, etc.
  • the terms “treat”, “treatment” or “treating” encompass any manner in which the symptoms or pathology of a condition, disorder or disease are ameliorated or otherwise beneficially altered.
  • the benefit to a subject being treated may be statistically significant, mathematically significant, or at least perceptible to the subject and/or the physician.
  • levodopa of “L-dopa” is (L-3,4- dihydroxyphenylalanine (TUPAC nomenclature is (S)-2-amino-3-(3,4- dihydroxyphenyljpropanoic acid).
  • TUPAC nomenclature is (S)-2-amino-3-(3,4- dihydroxyphenyljpropanoic acid).
  • esters of L-3,4-dihydroxyphenylalanine and salts thereof are examples of esters of L-3,4-dihydroxyphenylalanine and salts thereof.
  • esters of L-3,4-dihydroxyphenylalanine include levodopa ethyl ester (LDEE); ethyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate), levodopa propyl ester; levodopa propyl ester (propyl(2S)-2-amino-3-(3,4- dihydroxyphenyljpropanoate), levodopa methyl ester (methyl(2S)-2-amino-3- (3,4-dihydroxyphenyl)propanoate), and the like.
  • LEE levodopa ethyl ester
  • levodopa propyl ester levodopa propyl ester (propyl(2S)-2-amino-3-(3,4
  • An ester of L-3,4- dihydroxyphenylalanine can be, for example, a salt including hydrated salt.
  • a salt of levodopa ester can include, but is not limited to, one of octanoate, myristate, succinate, succinate dihydrate, fumarate, fumarate dihydrate, mesylate, tartrate, and hydrochloride.
  • succinate dehydrate or succinate of ester of L-3,4-dihydroxyphenylalanine include levodopa ethyl ester succinate (LDEE-S) and levodopa ethyl ester succinate dehydrate (LDEE-S-dihydrate or LDEE-S(d))
  • the terms "effective amount” or “therapeutically effective amount” refer to an amount of a compound, material, composition, medicament, or other material that is effective to achieve a particular pharmacological and/or physiologic effect.
  • effective amount refers to an amount which may be suitable to improve the involuntary movement associated with levodopa therapy.
  • the effect of improvement on levodopa induced dyskinesia in Parkinson's disease may be clinically confirmed using a patient diary or a clinical evaluation scale such as Unified Dyskinesia Rating Scale (UDysRS), Clinical Dyskinesia Rating Scale (CDRS), or Abnormal Involuntary Movement Scale (AIMS).
  • the effect of improving dyskinesia can also be confirmed by dyskinesia-like abnormal involuntary movement behavior evaluation in a non-clinical model LID rat model.
  • the improvement, suppression of progression, or prevention of levodopa induced dyskinesia symptoms, as well as reduction in the period of levodopa induced dyskinesia manifestation can be measured by using, e.g., the Unified Dyskinesia Rating Scale (UDysRS), Movement Disorder Society- Unified Parkinson's Disease Rating Scale (MDS-UPDRS), part Ill-motor score, Bradykinesia, MDS-UPDRS part I, II, and IV, UDysRS part 1 and 2, and /or a PD Motor Diary.
  • UDysRS Unified Dyskinesia Rating Scale
  • MDS-UPDRS Movement Disorder Society- Unified Parkinson's Disease Rating Scale
  • part Ill-motor score Bradykinesia
  • administration of a composition to a Parkinson's disease patient may result in a significant reduction in levodopa induced dyskinesia (LID).
  • administration of the compositions result in about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or 80% reduction in levodopa induced dyskinesia.
  • the reduction in levodopa induced dyskinesia is measured on a numeric scale that is used by the FDA to evaluate effectiveness of drugs indicated to reduce LID.
  • the scale used in measuring the reduction in LID could be UDysRS, UPDRS Part IV (subscores 32, 33), Dyskinesia Rating Scale (DRS), Abnormal Involuntary Movement Scale (AIMS), or other scales developed for this purpose.
  • administration of a composition to a Parkinson's disease patient may result reducing or suppressing the adverse effects of L-DOPA.
  • the compounds provided herein may reduce the patients' amount of awake time in an "OFF" state.
  • An OFF state in this context means the period of time where the therapeutic benefit of a dose of a parkinsonian medication have worn off, such that the patient experiences symptoms of Parkinson's disease such as are classified by the Unified Parkinson's Disease Rating Scale (UPDRS) and the Hoehn and Yahr (HY) scale, for example.
  • the methods and compositions are also directed to reducing the adverse effects of L-DOPA by increasing the proportion of the patients' awake time in an "ON" state.
  • ON state is meant, the period of time following a dose of a parkinsonian medication during which the patient is relatively free of the symptoms of Parkinson's Disease as classified by the UPDRS and the HY scale.
  • Patients treatable by the methods provided herein include patients at early, intermediate and advanced stages of Parkinson's disease with or without motor complications as determined by the Parkinson Dyskinesia Scale (PDS).
  • Dyskinesias can be separately measured by the UPDRS, modified Goetz Dyskinesia Rating Scale (MGDRS), and/or Abnormal Involuntary Movement Scale (AIMS).
  • the treatment contemplated herein is especially effective in patients suffering from advanced Parkinson's disease.
  • the dosage amount can vary according to a variety of factors such as subject-dependent variables (e.g., age, immune system, health, etc.), the disease or disorder being treated, as well as the route of administration and the pharmacokinetics of the agent being administered.
  • methods include treating a Parkinson’s disease related disorders, e.g., psychosis, levodopa induced dyskinesia and/or off episodes, by administering to a patient in need thereof a pharmaceutical composition including about 5 mg to about 100 mg of a PDE10A inhibitor, e.g. , 1 - [2-fluoro-4-( 1 H-pyrazol- 1 -yl)phenyl] -5 -methoxy-3 -( 1 -phenyl - 1 H- pyrazol-5-yl)-pyridazin-4(lH)-one or a pharmaceutically acceptable salt thereof).
  • a PDE10A inhibitor e.g. , 1 - [2-fluoro-4-( 1 H-pyrazol- 1 -yl)phenyl] -5 -methoxy-3 -( 1 -phenyl - 1 H- pyrazol-5-yl)-pyridazin-4(lH)-one or a pharmaceutically acceptable
  • doses may be, e.g, 5mg, lOmg, 15mg, 25mg, or 30mg. In embodiments, doses may be in the range of about 0.1 to 100 mg, 0.1 to 75 mg, 0.1 to 50 mg, 0.1 to 30 mg, 0.1 to 25 mg, 0.1 to 20 mg, 0.1 to 15 mg, 0.1 to 10 mg, 0.1 to 5 mg, 0.1 to Img, 1 to 100 mg, 1 to 75 mg, 1 to 50 mg, 1 to 30 mg, 1 to 25 mg, 1 to 20 mg, 1 to 15 mg, 1 to 10 mg, 1 to 5 mg, 5 to 100 mg, 5 to 75 mg, 5 to 50 mg, 5 to 30 mg, 5 to 25 mg, 5 to 20 mg, 5 to 15 mg, 5 to 10 mg, 10 to 150 mg, 10 to 125 mg, 10 to 100 mg, 10 to 75 mg, 10 to 50 mg, 10 to 30 mg, 10 to 25 mg, 10 to 20 mg, 10 to 15 mg, 15 to 200 mg, 15 to 175 mg, 15 to 150
  • the methods and compositions include treating a Parkinson’s disease related disorders, e.g., psychosis, levodopa induced dyskinesia and/or off-episodes, by administering l-[2-fluoro-4-(lH-pyrazol-l- yl)phenyl]-5-methoxy-3-(l-phenyl-lH-pyrazol-5-yl)-pyridazin-4(lH)-one or a pharmaceutically acceptable salt thereof.
  • Parkinson’s disease related disorders e.g., psychosis, levodopa induced dyskinesia and/or off-episodes
  • doses may include 1 to 100 mg l-[2-fluoro-4-(lH-pyrazol-l-yl)phenyl]-5-methoxy-3-(l-phenyl- lH-pyrazol-5-yl)-pyridazin-4(lH)-one, e.g., 10 mg , 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg.
  • doses may include 1 to 30 mg l-[2-fluoro-4-(lH-pyrazol-l-yl)phenyl]-5-methoxy-3- (l-phenyl-lH-pyrazol-5-yl)-pyridazin-4(lH)-one, e.g., 1 mg, 5 mg , lOmg, 15mg, 20 mg, 25mg, or 30 mg.
  • compositions may include a PDE10A inhibitor, e.g. , 1 -[2-fluoro-4-( 1 H-pyrazol- 1 -yl)phenyl] -5 -methoxy-3 -( 1 - phenyl-lH-pyrazol-5-yl)-pyridazin-4(lH)-one or a pharmaceutically acceptable salt thereof) in an amount as described herein.
  • a PDE10A inhibitor e.g. , 1 -[2-fluoro-4-( 1 H-pyrazol- 1 -yl)phenyl] -5 -methoxy-3 -( 1 - phenyl-lH-pyrazol-5-yl)-pyridazin-4(lH)-one or a pharmaceutically acceptable salt thereof
  • dosages may be administered to a subject once, twice, three or four times daily, every other day, once weekly, or once a month.
  • a PDE10 A inhibitor e.g., l-[2-fluoro-4-(lH-pyrazol-l- yl)phenyl]-5-methoxy-3-(l-phenyl-lH-pyrazol-5-yl)-pyridazin-4(lH)-one or a pharmaceutically acceptable salt thereof
  • a PDE10 A inhibitor e.g., l-[2-fluoro-4-(lH-pyrazol-l- yl)phenyl]-5-methoxy-3-(l-phenyl-lH-pyrazol-5-yl)-pyridazin-4(lH)-one or a pharmaceutically acceptable salt thereof
  • a PDE10A inhibitor e.g., l-[2-fluoro-4-(lH-pyrazol-l-yl)phenyl]-5-methoxy-3-(l -phenyl- 1H- pyrazol-5-yl)-pyridazin-4(lH)-one or a pharmaceutically acceptable salt thereof
  • a PDE10A inhibitor e.g., l-[2-fluoro-4-(lH-pyrazol-l-yl)phenyl]-5-methoxy-3-(l -phenyl- 1H- pyrazol-5-yl)-pyridazin-4(lH)-one or a pharmaceutically acceptable salt thereof
  • a subject once in the morning, and once in the evening.
  • a PDE10A inhibitor e.g., l-[2-fluoro-4-(lH- pyrazol - 1 -yljphenyl] -5 -methoxy-3 -( 1 -phenyl- 1 H-pyrazol -5 -yl)-pyridazin- 4(lH)-one or a pharmaceutically acceptable salt thereof
  • a subject three times a day (e.g., at breakfast, lunch, and dinner), at a dose, e.g., of 10 mg/administration (e.g., 30 mg/day).
  • a PDElOA inhibitor e.g., l-[2-fluoro-4-(lH-pyrazol- l-yl)phenyl]-5-methoxy-3-(l-phenyl-lH-pyrazol-5-yl)-pyridazin-4(lH)-one or a pharmaceutically acceptable salt thereof
  • a PDE10A inhibitor e.g., l-[2-fluoro-4-(lH-pyrazol- l-yl)phenyl]-5-methoxy-3-(l-phenyl-lH-pyrazol-5-yl)-pyridazin-4(lH)-one or a pharmaceutically acceptable salt thereof
  • a PDE10A inhibitor e.g.
  • 1 -[2-fluoro-4-( 1 H-pyrazol- 1 -yljphenyl] -5 -methoxy-3 -( 1 - phenyl-lH-pyrazol-5-yl)-pyridazin-4(lH)-one or a pharmaceutically acceptable salt thereof) is administered to a subject 10, 20, or 30 mg/per day in one or more doses.
  • the dosage of a PDE10A inhibitor (e.g, l-[2-fluoro- 4-( 1 H-pyrazol - 1 -yljphenyl] -5 -methoxy-3 -(1 -phenyl - 1 H-pyrazol -5 -y 1) - pyridazin-4(lH)-one or a pharmaceutically acceptable salt thereof) is 0.01-100 mg/kg, 0.5-50 mg/kg, 0.5-10 mg/kg or 25-50 mg/kg once, twice, three times or four times daily.
  • the dosage is 0.5 mg/kg, 1 mg/kg, 5 mg/kg, 7.5 mg/kg, or 10 mg/kg once, twice, three times or four times daily.
  • a subject is administered a total daily dose of 0.01 mg to 100 mg of a PDE10A inhibitor (e.g, l-[2-fhioro-4-(lH-pyrazol-l- yl)phenyl]-5-methoxy-3-(l-phenyl-lH-pyrazol-5-yl)-pyridazin-4(lH)-one or a pharmaceutically acceptable salt thereof) once, twice, three times, four times daily.
  • the total amount administered to a subject in 24-hour period is, e.g., 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 45 mg, 50 mg, 60 mg, 75 mg, 100 mg.
  • the subject may be started at a low dose and the dosage is escalated.
  • the subject may be started at a high dose and the dosage is decreased.
  • Suitable dosage forms for a PDE10A inhibitor include, but are not limited to oral forms, such as tablets, hard or soft gelatin capsules, powders, granules and oral solutions, syrups or suspensions, as well as the sublingual, buccal, intratracheal, intraocular, intranasal forms, forms adapted to inhalation, topical, transdermal, and implants for release of medication, parenteral forms, for example, intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethrally, intrasternal, intracranial, intramuscularly or subcutaneously.
  • parenteral forms for example, intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethrally, intrasternal, intracranial, intramuscularly or subcutaneously.
  • compositions herein may be provided with immediate release, delayed release, extended release, or modified release profiles.
  • a delayed release dosage form is one that releases a drug (or drugs) at a time other than promptly after administration.
  • an extended release dosage form is one that allows at least a twofold reduction in dosing frequency as compared to that drug presented as a conventional dosage form (e.g., as a solution or prompt drug-releasing, conventional solid dosage form).
  • a modified release dosage form is one for which the drug release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as solutions, ointments, or promptly dissolving dosage forms. Delayed release and extended release dosage forms and their combinations may be considered as types of modified release dosage forms.
  • compositions with different drug release profiles may be combined to create a two-phase or three-phase release profile.
  • pharmaceutical compositions may be provided with an immediate release and an extended release profile.
  • pharmaceutical compositions may be provided with an extended release and delayed release profile.
  • Such composition may be provided as pulsatile formulations, multilayer tablets, or capsules containing tablets, beads, granules, etc.
  • Compositions may be prepared using a pharmaceutically acceptable “carrier” composed of materials that are considered safe and effective.
  • the “carrier” includes all components present in the pharmaceutical formulation other than the active ingredient or ingredients.
  • carrier includes, but is not limited to, diluents, binders, lubricants, glidants, disintegrants, fillers, and coating compositions.
  • the term “pharmaceutically acceptable” refers to molecular entities and compositions that are "generally regarded as safe", e.g., that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction when administered to a human.
  • this term refers to molecular entities and compositions approved by a regulatory agency of the federal or a state government, as the GRAS list under section 204(s) and 409 of the Federal Food, Drug and Cosmetic Act, that is subject to premarket review and approval by the FDA or similar lists, the U.S. Pharmacopeia or another generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • pharmaceutically acceptable salts includes acid addition salts, addition salts of free bases, wherein the compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include but are not limited to mineral or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids.
  • Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • Such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, tolunesulfonic, naphthalenesulfonic, methanesulfonic, ethane disulfonic, and oxalic salts.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic
  • eplivanserin or pharmaceutically acceptable salts may include a hemifumarate salt.
  • the pharmaceutically acceptable salts of a compound of the PDE10A inhibitors can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods.
  • the PDE10A inhibitor (e.g., l-[2-fhioro-4-(lH-pyrazol-l-yl)phenyl]- 5-methoxy-3-(l-phenyl-lH-pyrazol-5-yl)-pyridazin-4(lH)-one or a pharmaceutically acceptable salt thereof) may be racemic and/or optically active isomers thereof.
  • some of the compounds can have asymmetric carbon atoms, and therefore, can exist either as racemic mixtures or as individual optical isomers (enantiomers).
  • compositions described herein that contain a chiral center include all possible stereoisomers of the compound, including compositions including the racemic mixture of the two enantiomers, as well as compositions including each enantiomer individually, substantially free of the other enantiomer.
  • contemplated herein is a composition including the S enantiomer of a compound substantially free of the R enantiomer, or the R enantiomer substantially free of the S enantiomer.
  • the scope of the present disclosure also includes compositions including mixtures of varying proportions between the diastereomers, as well as compositions including one or more diastereomers substantially free of one or more of the other diastereomers.
  • substantially free it is meant that the composition includes less than 25%, 15%, 10%, 8%, 5%, 3%, or less than 1% of the minor enantiomer or diastereomer(s).
  • Plasma concentrations of l-[2-fluoro-4-(lH-pyrazol-l- yl)phenyl]-5-methoxy-3-(l-phenyl-lH-pyrazol-5-yl)-pyridazin-4(lH)-one were subsequently measured by validated liquid chromatography-tandem mass spectrometry with a validated range of 0.5 to 1000 ng/mL.
  • the PK parameters analyzed for l-[2-fluoro-4-(lH-pyrazol-l-yl)phenyl]-5-methoxy-3- (l-phenyl-lH-pyrazol-5-yl)-pyridazin-4(lH)-one in plasma and urine included area under the plasma concentration-time curve from time 0 to infinity (AUC (o-ini)), maximum observed plasma concentration (C max), time to reach C max (T max), terminal elimination half-life (T 1/2), oral clearance (CL/F), volume of distribution (V z /F), and renal clearance (CL r ). Metabolite-to-parent ratios were estimated from C max and AUC (o-ini) data.
  • l-[2-fluoro-4-(lH-pyrazol-l-yl)phenyl]-5-methoxy-3-(l-phenyl-lH- pyrazol-5-yl)-pyridazin-4(lH)-one may then be administered simultaneously with the levodopa, at doses equivalent to human doses (e.g., lOmg, 20mg and 30mg). The reduction in symptoms including dyskinesia may then be measured.
  • This may be a two arm study, treatment and placebo arms and may include one or more treatment doses e.g., lOmg, 20mg and/or 30mg l-[2-fluoro-4-(lH- pyrazol - 1 -yl)phenyl] -5 -methoxy-3 -( 1 -phenyl- 1 H-pyrazol -5 -yl)-pyridazin- 4(lH)-one).
  • the primary efficacy endpoints may include Parkinsonian symptoms and dyskinesias scored every 10 minutes by a masked neurologist using an abbreviated LTPDRS-3 rating scale.
  • a modified abnormal movement scale (AIMS) describing involuntary movements in all extremities and trunk and face on a scale from 1-4.
  • Secondary Efficacy Endpoints may include validated motor function scales. Safety is monitored by means of frequent clinical evaluations and laboratory tests.
  • the primary efficacy endpoint may include change from baseline to, e.g., week 12, or 24, in the Unified Dyskinesia Rating Scale (UDysRS) score.
  • Key secondary endpoints may include: ON time without troublesome dyskinesia (ON time without dyskinesia plus ON with non- troublesome dyskinesia), based on a standardized PD home diary Unified Parkinson's Disease Rating Scale (MDS-UPDRS).
  • Fatigue may be measured by the Fatigue Severity Scale (FSS). This scale includes 9 questions that are completed by the patient using a rating scale from 1 (strongly disagree) to 7 (strongly agree).
  • the following mixture of traditional and new scales may also be used with or witout the Unified Dyskinesia Rating Scale (UDysRS) as the primary outcome measure.
  • the UDysRS scale has four parts, and a total possible score of 104: 1: Historical Disability (patient perceptions) of On-Dyskinesia impact II: Historical Disability (patient perceptions) of Off-Dystonia impact III: Objective Impairment (dyskinesia severity, anatomic distribution, and type, based on 4 observed activities) IV: Objective Disability based on Part III activities ON time without troublesome dyskinesia, based on a standardized Parkinson's Disease home diary.
  • Unified Parkinson's Disease Rating Scale UPDS
  • This scale is a traditional scale used in PD for many years and these items have been utilized in most LID studies.
  • the purpose of this study is to evaluate the effect of l-[2-fluoro-4-(lH- pyrazol - 1 -yl)phenyl] -5 -methoxy-3 -( 1 -phenyl- 1 H-pyrazol -5 -yl)-pyridazin- 4(1H)- in subjects on symptoms of levodopa induced dyskinesia (LID), on time, and off time.
  • LID levodopa induced dyskinesia
  • This may be a multiple arm study, treatment and placebo arms that include one or more treatment doses (e.g., 10mg, 20mg and/ or 3 Omg 1 - [2-fluoro-4-( 1 H-pyrazol- 1 -yl)phenyl] -5 -m ethoxy-3 -(1 -phenyl- 1 H-pyrazol -5 -yl)-pyridazin-4( 1 H)-one).
  • one or more treatment doses e.g., 10mg, 20mg and/ or 3 Omg 1 - [2-fluoro-4-( 1 H-pyrazol- 1 -yl)phenyl] -5 -m ethoxy-3 -(1 -phenyl- 1 H-pyrazol -5 -yl)-pyridazin-4( 1 H)-one).
  • Outcome measures may include assessment of the Change from Baseline to a predefined period (e.g., Week 26) in levodopa induced dyskinesia based on UDysRS total score.
  • the UDysRS is a dyskinesia rating scale from 0-104; it evaluates involuntary movements associated with PD. A higher score indicates more severe PD.
  • Outcome measures may also include assessment of the “ON time” with No Dyskinesia. Change from Baseline (Day 1 prior to start of study intervention) to a predefined period (e.g., Week 26) total daily ON time with No dyskinesia based on PD Home Diary. A PD home diary is used to score 5 different conditions : ASLEEP, OFF, ON (ie, had adequate control of PD symptoms) without dyskinesia, ON with non-troublesome dyskinesia, and ON with troublesome dyskinesia. Outcome measures may also include assessment of sleep time and/or ON time with non-troublesome dyskinesia.
  • a PD home diary is used to score 5 different conditions : ASLEEP, OFF, ON (ie, had adequate control of PD symptoms) without dyskinesia, ON with non-troublesome dyskinesia, and ON with troublesome dyskinesia.
  • Outcome measures may also include assessment of Movement Disorder Society-Sponsored Unified Parkinson's Disease Rating Scale (MDS- UPDRS) total score and sub-scores.
  • MDS- UPDRS Movement Disorder Society-Sponsored Unified Parkinson's Disease Rating Scale
  • MDS- UPDRS Change from Baseline (Day 1 prior to start of study intervention) to a predefined period (e.g., Week 26) in MDS- UPDRS total score and sub-scores.
  • the MDS-UPDRS is divided into 4 parts. In each part, all items are rated on a scale from 0 (normal) to 4 (severe impairment); Part I assesses 15 items of non-motor aspects of experiences of daily living; Part II comprises 13 items evaluating the impact of PD on patients' activities of daily living (ADL) over the week prior to the visit such as speech, salivation, swallowing, eating, handwriting, dressing, turning in bed, walking; part III assesses the motor abilities in PD patients at the time of the visit; Part IV assesses motor complications of therapy, such as dyskinesias, motor fluctuations.
  • ADL activities of daily living
  • Outcome measures may also include assessment of Clinician Global Impression of Change (CGIc) based on a predefined period (e.g, Week 26).
  • CGI-C is a 7-point scale used by Investigator to rate patient's overall improvement using a range of responses from 1 (very much improved) through to 7 (very much worse).
  • Outcome measures may also include assessment on Patient Global Impression of Change (PGIc).
  • PGI-C is a 7- point scale depicting a patient's rating of overall improvement using a range of responses from 1 (very much improved) to 7 (very much worse).
  • Outcome measures may also include assessment of the Change from Baseline (Day 1 prior to start of study intervention) to a predefined period (e.g, Week 26) in PDQ-39 summary index.
  • the PDQ-39 is a specific tool to assess quality of life in PD.
  • ADLs activities of daily living
  • emotional well-being stigma
  • social support social support
  • cognition communication
  • physical discomfort where scores range from 0-100, with the higher, the worse the perception of quality of life.
  • the purpose of this study will be to evaluate the effect of l-[2-fluoro-4- (lH-pyrazol-l-yl)phenyl]-5-methoxy-3-(l-phenyl-lH-pyrazol-5-yl)-pyridazin- 4(1H)- in subjects as a treatment of hallucinations and delusions associated with Parkinson’s disease psychosis.
  • This study will be a multi-center, randomized, placebo-controlled, double blind trial in which patients meeting entrance criteria will be randomly assigned to receive placebo or active drug for the study period, e.g., 6-weeks.
  • Patients will be randomized in a 1 :1 ratio to active drug (e.g., lOmg, 20mg or 30mg) or placebo once daily.
  • Study patients male or female and aged 40 years or older will include those having a diagnosis of Parkinson’s disease (PD) established at least 1 year prior to study entry and having psychotic symptoms (hallucinations and/or delusions) that started after the PD diagnosis, and that were severe and frequent enough to warrant treatment with an antipsychotic.
  • PD Parkinson’s disease
  • psychotic symptoms hallucinations and/or delusions
  • patients may be required to have a Mini -Mental State Examination (MMSE) score >21 and be able to self-report symptoms.
  • MMSE Mini -Mental State Examination
  • the majority of patients may be taking PD medications and use of these medications must be stable for at least 30 days prior to study start and throughout the study period.
  • SAPS-PD The PD-adapted Scale for the Assessment of Positive Symptoms
  • SAPS- PD is a 9-item scale adapted for PD from the Hallucinations and Delusions domains of the SAPS. Each item is scored on a scale of 0-5, with 0 being none and 5 representing severe and frequent symptoms. Therefore, the SAPS-PD total score can range from 0 to 45 with higher scores reflecting greater severity of illness. A negative change in score indicates improvement.
  • Primary efficacy will be evaluated based on change from baseline to the end of the study period, e.g., 6-weeks, in SAPS-PD total score.

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Abstract

L'invention concerne des procédés et des compositions pour le traitement de la maladie de Parkinson et/ou de troubles associés à la maladie de Parkinson avec un inhibiteur de PDE10A. Plus particulièrement, l'invention concerne des procédés et des compositions pour le traitement de la dyskinésie induite par la lévodopa, d'épisodes "off" associés à la maladie de Parkinson, et de la psychose de la maladie de Parkinson, avec un inhibiteur de PDE10A, par ex., 1-[2-fluoro-4-(1H-pyrazol-1-yl)phényl]-5-methoxy-3-(1-phényl-1H-pyrazol-5-yl)-pyridazin-4(1H)-one.
PCT/US2021/050662 2020-09-16 2021-09-16 Méthodes de traitement de la maladie de parkinson et de troubles apparentés avec des inhibiteurs de pde10a Ceased WO2022060978A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190247394A1 (en) * 2018-02-15 2019-08-15 Ovid Therapeutics Inc. Methods of treating developmental syndromes with pde10a inhibitors
WO2020094591A1 (fr) * 2018-11-06 2020-05-14 H. Lundbeck A/S Inhibiteurs de pde10a pour le traitement de symptômes négatifs et de troubles cognitifs chez un patient souffrant de schizophrénie

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190247394A1 (en) * 2018-02-15 2019-08-15 Ovid Therapeutics Inc. Methods of treating developmental syndromes with pde10a inhibitors
WO2020094591A1 (fr) * 2018-11-06 2020-05-14 H. Lundbeck A/S Inhibiteurs de pde10a pour le traitement de symptômes négatifs et de troubles cognitifs chez un patient souffrant de schizophrénie

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BECK ET AL.: "A Selective Phosphodiesterase 10A Inhibitor Reduces L-Dopa-Induced Dyskinesias in Parkinsonian Monkeys", MOV DISORD, vol. 33, no. 5, 2018, pages 805 - 814 *
DELHAYE ET AL.: "Role of phosphodiesterases in the pathophysiology of neurodevelopmental disorders", MOLECULAR PSYCHIATRY, vol. 26, 7 January 2021 (2021-01-07), pages 4570 - 4582, XP037616469, DOI: 10.1038/s41380-020-00997-9 *

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