US20120101101A1 - Therapeutic agent for motor disorders - Google Patents

Therapeutic agent for motor disorders Download PDF

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US20120101101A1
US20120101101A1 US13/266,152 US201013266152A US2012101101A1 US 20120101101 A1 US20120101101 A1 US 20120101101A1 US 201013266152 A US201013266152 A US 201013266152A US 2012101101 A1 US2012101101 A1 US 2012101101A1
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pharmaceutically acceptable
acceptable salt
dopa
optionally substituted
pyridyl
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Noriaki Uesaka
Takashi Sawada
Tomoyuki Kanda
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Kyowa Kirin Co Ltd
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Kyowa Hakko Kirin Co Ltd
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    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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    • A61K31/4365—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 having sulfur as a ring hetero atom, e.g. ticlopidine
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to an agent for the treatment and/or prophylaxis of a movement disorder, an agent for the treatment and/or prophylaxis of Parkinson's disease and the like.
  • Parkinson's disease is a brain disease characterized by tremor, bradykinesia, difficulty in gait and coordinated movement and the like. This disease is associated with damage of a part of brain which governs muscle movements.
  • the first symptom of Parkinson's disease is a limb tremor (shaking or trembling) particularly when the body is at rest. Tremor often begins in the hemibody, and frequently occurs in one of the hands.
  • Other common symptoms include slow movement (bradykinesia), an inability to move (akinesia), a rigidity of trunk and limbs, a shuffling gait, and a stooped posture and the like.
  • Patients with Parkinson's disease are poor in facial expression, and tend to speak in a soft voice.
  • Parkinson's disease can cause secondary symptoms such as depression, anxiety, personality change, cognitive impairment, dementia, sleep disturbances, speech impairments or sexual dysfunction.
  • the drug therapy of Parkinson's disease currently employed clinically mainly controls the parkinsonian symptoms by controlling the imbalance among neurotransmitters.
  • Early stage patients of Parkinson's disease mostly respond well to a symptomatic therapy by a dopamine replacement therapy; however, the disability increases with progression of the disease.
  • L-DOPA Although more than thirty years have passed since discovering L-DOPA, it is still the best agent for treatment of Parkinson's disease. In the early stages of Parkinson's disease, patients usually enjoy a good response to L-DOPA. As the disease progresses, however, L-DOPA tends to become less helpful. This is not due to the loss of efficacy of L-DOPA, but rather, for example, to development of motor complications such as end-of-dose deterioration or adverse fluctuation in motor response including “wearing-off phenomenon”, “on-off fluctuations”, and dyskinesias.
  • the “on-off fluctuations” is an event wherein therapeutic benefit of a medication (“on” state, during which the patients are relatively free from the symptoms of Parkinson's disease) is suddenly and unacceptably lost, and the parkinsonian state (“off” state) appears.
  • Such condition occurs when patients with Parkinson's disease are under L-DOPA therapy and exposed to L-DOPA in an amount sufficient to express the efficacy.
  • the treatment effect may recover all of a sudden.
  • the “wearing-off phenomenon” is a phenomenon wherein the duration of L-DOPA action is decreased in patients with Parkinson's disease, even though they are under L-DOPA therapy and exposed to L-DOPA in an amount sufficient to express the efficacy.
  • the phenomenon is characterized by the gradual reappearance of the “off” state, and shortening of the “on” state. That is, it refers to a phenomenon where the duration of the treatment effect of L-DOPA gradually becomes shorter (duration of the treatment effect after administration of L-DOPA becomes shorter), which is remarkably seen in an advanced stage of the disease in patients with Parkinson's disease under L-DOPA therapy.
  • Dyskinesia can be broadly classified into chorea-like symptoms (hyperactive, purposeless dance-like movement) and dystonia (sustained, abnormal muscle contraction).
  • Duvoisin first focused on these abnormal involuntary movements, and found that half or more of patients with Parkinson's disease develop dyskinesia within 6 months of the treatment. With increasing period of treatment, both the frequency and severity of dyskinesia increase.
  • DATATOP trial L-DOPA induced dyskinesia was observed in 20-30% of patients who received L-DOPA treatment for a mean of 20.5 months.
  • dyskinesia occurs when L-DOPA or other dopamine receptor agonists have a concentration in the brain that is sufficient to hypersensitive dopamine receptors in the putamen (peak dose dyskinesia).
  • dyskinesia also occurs when the dopamine concentration is low (off-dystonia), or in a stage wherein the concentration of dopamine rises or falls (biphasic dyskinesia).
  • adenosine is widely distributed in the whole body, and exhibits a variety of physiological actions on the central nervous system, the cardiac muscle, the kidneys, the smooth muscle, and the like through its receptors (see non-patent document 1), and that an antagonist thereof is useful for the treatment and/or prophylaxis of various diseases.
  • adenosine A 1 antagonists are known to facilitate defecation (The Japanese Journal of Pharmacology (Jpn. J. Pharmacol.), Vol. 68, p. 119 (1995)).
  • the adenosine A 2A receptors are known to be involved particularly in the central nervous system, and the antagonists of the adenosine A 2A receptors are known to be useful as, for example, therapeutic drugs for Parkinson's disease etc. (see non-patent document 2), therapeutic drugs for sleep disturbance (see Nature Neuroscience, p. 858 (2005); patent document 1) and the like.
  • There are many reports concerning the relationship between adenosine receptors and Parkinson's disease see, for example, non-patent documents 3 and 4).
  • a method of reducing or suppressing side effects of L-DOPA therapy (i) a treatment method by reducing the dose of L-DOPA in L-DOPA therapy, (iii) a method of prolonging the duration of effectiveness of the treatment of Parkinson's disease in L-DOPA therapy, (iv) a method of treating a movement disorder and the like, each using an adenosine A 2A receptor antagonist, are known (see patent document 2).
  • movement disorders such as tremor, bradykinesia, gait disturbance, akinesia and the like can be suppressed by administering an adenosine A 2A receptor antagonist represented by the formula (A) and L-DOPA to patients with Parkinson's disease, and adenosine A 2A receptor antagonist represented by the formula (A) suppresses dyskinesia developed by administration of L-DOPA, and the like.
  • an adenosine A 2A receptor antagonist represented by the formula (A) shows an antiparkinson effect in MPTP-treated common marmoset (see non-patent document 5), does not provoke dyskinesia (see non-patent document 6), and does not provoke dyskinesia but potentiates an antiparkinson effect when used in combination with L-DOPA and/or a dopamine agonist (see non-patent document 7).
  • An object of the present invention is to provide an agent for the treatment and/or prophylaxis of a movement disorder such as a motor control disorder (e.g., extrapyramidal syndrome or the like), hypermobility (e.g., dystonia, dyskinesia, tardive dyskinesia, tremor, chorea, ballism, akathisia, athetosis, bradykinesia, gait disturbance, freezing, rigidity, postural instability, myoclonus, tics or Tourette syndrome, postural reflex disorder or the like), side effects of L-DOPA and/or dopamine agonist therapy (e.g., wearing-off phenomenon, dyskinesia or the like), or the like, an agent for the treatment and/or prophylaxis of Parkinson's disease and the like.
  • Another object is to provide a thiazole derivative or a pharmaceutically acceptable salt thereof having a selective adenosine A 2A antagonist, and useful as the above-mentioned agent for the
  • the present invention relates to the following (1)-(100).
  • An agent for the treatment and/or prophylaxis of a movement disorder comprising a thiazole derivative represented by the formula (I)
  • R 1 represents aryl, aralkyl, an aromatic heterocyclic group, aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl or tetrahydropyranyloxy, each of which is optionally substituted by 1 to 3 substituents selected from the group consisting of halogen; lower alkyl optionally substituted by lower alkoxy or morpholino; lower alkoxy; lower alkanoyl; and vinyl, and R 2 represents pyridyl or tetrahydropyranyl, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • R 1 is phenyl, pyridyl, pyrimidinyl, 5,6-dihydro-2H-pyridylmethyl or tetrahydropyranyloxy, each of which is optionally substituted by 1 to 3 substituents selected from a fluorine atom, a chlorine atom, a bromine atom, methyl, ethyl, methoxy and ethoxy, and R 2 is pyridyl or tetrahydropyranyl.
  • R 1 is pyridyl or pyrimidinyl, each of which is optionally substituted by 1 to 3 substituents selected from the group consisting of halogen; lower alkyl optionally substituted by lower alkoxy or morpholino; lower alkoxy; lower alkanoyl; and vinyl.
  • R 2 is pyridyl.
  • R 2 is tetrahydropyranyl.
  • thiazole derivative represented by the formula (I) is a compound represented by any one of the following formulas (IA)-(IAA).
  • the agent of any one of (1)-(6), wherein the movement disorder is an extrapyramidal syndrome.
  • the agent of any one of (1)-(6), wherein the movement disorder is bradykinesia, gait disturbance, dystonia, dyskinesia or tardive dyskinesia.
  • the agent of any one of (1)-(6), wherein the movement disorder is a side effect of L-DOPA and/or dopamine agonist therapy.
  • the agent of (9), wherein the side effect is a motor complication.
  • the agent of (10), wherein the motor complication is wearing-off phenomenon.
  • the agent of (10), wherein the motor complication is on-off fluctuation.
  • a pharmaceutical composition comprising (a) a thiazole derivative represented by the formula (I)
  • R 1 represents aryl, aralkyl, an aromatic heterocyclic group, aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl or tetrahydropyranyloxy, each of which is optionally substituted by 1 to 3 substituents selected from the group consisting of halogen; lower alkyl optionally substituted by lower alkoxy or morpholino; lower alkoxy; lower alkanoyl; and vinyl, and R 2 represents pyridyl or tetrahydropyranyl, or a pharmaceutically acceptable salt thereof, and (b) L-DOPA and/or a dopamine agonist.
  • An agent for the treatment and/or prophylaxis of Parkinson's disease comprising (a) a thiazole derivative represented by the formula (I)
  • R 1 represents aryl, aralkyl, an aromatic heterocyclic group, aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl or tetrahydropyranyloxy, each of which is optionally substituted by 1 to 3 substituents selected from the group consisting of halogen; lower alkyl optionally substituted by lower alkoxy or morpholino; lower alkoxy; lower alkanoyl; and vinyl, and R 2 represents pyridyl or tetrahydropyranyl, or a pharmaceutically acceptable salt thereof, and (b) L-DOPA and/or a dopamine agonist in combination.
  • R 1 is phenyl, pyridyl, pyrimidinyl, 5,6-dihydro-2H-pyridylmethyl or tetrahydropyranyloxy, each of which is optionally substituted by 1 to 3 substituents selected from a fluorine atom, a chlorine atom, a bromine atom, methyl, ethyl, methoxy and ethoxy, and R 2 is pyridyl or tetrahydropyranyl.
  • a kit comprising (a) a first component comprising a thiazole derivative represented by the formula (I)
  • R 1 represents aryl, aralkyl, an aromatic heterocyclic group, aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl or tetrahydropyranyloxy, each of which is optionally substituted by 1 to 3 substituents selected from the group consisting of halogen; lower alkyl optionally substituted by lower alkoxy or morpholino; lower alkoxy; lower alkanoyl; and vinyl
  • R 2 represents pyridyl or tetrahydropyranyl, or a pharmaceutically acceptable salt thereof
  • a second component comprising L-DOPA and/or a dopamine agonist.
  • a method of treating and/or preventing a movement disorder comprising administering an effective amount of a thiazole derivative represented by the formula (I)
  • R 1 represents aryl, aralkyl, an aromatic heterocyclic group, aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl or tetrahydropyranyloxy, each of which is optionally substituted by 1 to 3 substituents selected from the group consisting of halogen; lower alkyl optionally substituted by lower alkoxy or morpholino; lower alkoxy; lower alkanoyl; and vinyl, and R 2 represents pyridyl or tetrahydropyranyl, or a pharmaceutically acceptable salt thereof.
  • R 1 is phenyl, pyridyl, pyrimidinyl, 5,6-dihydro-2H-pyridylmethyl or tetrahydropyranyloxy, each of which is optionally substituted by 1 to 3 substituents selected from a fluorine atom, a chlorine atom, a bromine atom, methyl, ethyl, methoxy and ethoxy, and R 2 is pyridyl or tetrahydropyranyl.
  • the method of any one of (35)-(40), wherein the movement disorder is extrapyramidal syndrome.
  • the method of any one of (35)-(40), wherein the movement disorder is bradykinesia, gait disturbance, dystonia, dyskinesia or tardive dyskinesia.
  • the method of any one of (35)-(40), wherein the movement disorder is a side effect of L-DOPA and/or dopamine agonist therapy.
  • the method of (43), wherein the side effect is a motor complication.
  • the method of (44), wherein the motor complication is wearing-off phenomenon.
  • the method of (44), wherein the motor complication is on-off fluctuation.
  • R 1 represents aryl, aralkyl, an aromatic heterocyclic group, aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl or tetrahydropyranyloxy, each of which is optionally substituted by 1 to 3 substituents selected from the group consisting of halogen; lower alkyl optionally substituted by lower alkoxy or morpholino; lower alkoxy; lower alkanoyl; and vinyl
  • R 2 represents pyridyl or tetrahydropyranyl, or a pharmaceutically acceptable salt thereof, and (b) an effective amount of L-DOPA and/or a dopamine agonist, simultaneously or separately at an interval.
  • R 1 is phenyl, pyridyl, pyrimidinyl, 5,6-dihydro-2H-pyridylmethyl or tetrahydropyranyloxy, each of which is optionally substituted by 1 to 3 substituents selected from a fluorine atom, a chlorine atom, a bromine atom, methyl, ethyl, methoxy and ethoxy, and R 2 is pyridyl or tetrahydropyranyl.
  • R 1 represents aryl, aralkyl, an aromatic heterocyclic group, aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl or tetrahydropyranyloxy, each of which is optionally substituted by 1 to 3 substituents selected from the group consisting of halogen; lower alkyl optionally substituted by lower alkoxy or morpholino; lower alkoxy; lower alkanoyl; and vinyl
  • R 2 represents pyridyl or tetrahydropyranyl, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prophylaxis of a movement disorder.
  • R 1 represents aryl, aralkyl, an aromatic heterocyclic group, aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl or tetrahydropyranyloxy, each of which is optionally substituted by 1 to 3 substituents selected from the group consisting of halogen; lower alkyl optionally substituted by lower alkoxy or morpholino; lower alkoxy; lower alkanoyl; and vinyl, and R 2 represents pyridyl or tetrahydropyranyl, or a pharmaceutically acceptable salt thereof, and (b) L-DOPA and/or a dopamine agonist, for use in the treatment and/or prophylaxis of Parkinson's disease.
  • R 1 represents aryl, aralkyl, an aromatic heterocyclic group, aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl or tetrahydropyranyloxy, each of which is optionally substituted by 1 to 3 substituents selected from the group consisting of halogen; lower alkyl optionally substituted by lower alkoxy or morpholino; lower alkoxy; lower alkanoyl; and vinyl
  • R 2 represents pyridyl or tetrahydropyranyl, or a pharmaceutically acceptable salt thereof, for the manufacture of an agent for the treatment and/or prophylaxis of a movement disorder.
  • R 1 represents aryl, aralkyl, an aromatic heterocyclic group, aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl or tetrahydropyranyloxy, each of which is optionally substituted by 1 to 3 substituents selected from the group consisting of halogen; lower alkyl optionally substituted by lower alkoxy or morpholino; lower alkoxy; lower alkanoyl; and vinyl, and R 2 represents pyridyl or tetrahydropyranyl, or a pharmaceutically acceptable salt thereof, and (b) L-DOPA and/or a dopamine agonist for the manufacture of an agent for the treatment and/or prophylaxis of Parkinson's disease.
  • the present invention provides an agent for the treatment and/or prophylaxis of a movement disorder, comprising a thiazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient; a pharmaceutical composition comprising (a) a thiazole derivative or a pharmaceutically acceptable salt thereof and (b) L-DOPA and/or a dopamine agonist; an agent for the treatment and/or prophylaxis of Parkinson's disease comprising (a) a thiazole derivative or a pharmaceutically acceptable salt thereof and (b) L-DOPA and/or a dopamine agonist in combination; a kit comprising (a) a first component comprising a thiazole derivative or a pharmaceutically acceptable salt thereof and (b) a second component comprising L-DOPA and/or a dopamine agonist; a thiazole derivative or a pharmaceutically acceptable salt thereof, which has a selective adenosine A 2A antagonistic activity and is useful for the treatment of a movement disorder, and the like.
  • FIG. 1 shows the effect of compound (IC) on the motor disability score in the Test Example 3.
  • the vertical axis shows the motor disability score, and the horizontal axis shows time (min) after administration.
  • ⁇ shows a combination of solvent and L-DOPA
  • ⁇ shows a combination of compound (IC) and L-DOPA.
  • FIG. 2 shows the effect of compound (IC) on the maximum action (minimum motor disability score) in the Test Example 3.
  • the vertical axis shows the minimum motor disability score, and the horizontal axis shows the L-DOPA dasage.
  • ⁇ shows a combination of solvent and L-DOPA, and ⁇ shows a combination of compound (IC) and L-DOPA.
  • the movement disorder is a neurological condition characterized by motor control disorder such as paucity or lack of movement, extrapyramidal syndrome or the like, hypermobilities (e.g., dystonia, dyskinesia, tardive dyskinesia, tremor, chorea, ballism, akathisia, athetosis, bradykinesia, gait disturbance, freezing, rigidity, postural instability, myoclonus, tics or Tourette syndrome, postural reflex disorder or the like) or the like.
  • motor control disorder such as paucity or lack of movement, extrapyramidal syndrome or the like, hypermobilities (e.g., dystonia, dyskinesia, tardive dyskinesia, tremor, chorea, ballism, akathisia, athetosis, bradykinesia, gait disturbance, freezing, rigidity, postural instability, myoclonus, tics or Tourette syndrome, postural reflex disorder or the like) or the like.
  • the movement disorder in the agent for the treatment and/or prophylaxis of a movement disorder of the present invention means the above-mentioned movement disorder, and preferably means, for example, motor control disorder such as extrapyramidal syndrome or the like, tremor, chorea, athetosis, bradykinesia, gait disturbance, dystonia, dyskinesia, tardive dyskinesia, postural reflex disorder or the like.
  • motor control disorder such as extrapyramidal syndrome or the like, tremor, chorea, athetosis, bradykinesia, gait disturbance, dystonia, dyskinesia, tardive dyskinesia, postural reflex disorder or the like.
  • the agent for the treatment and/or prophylaxis of a movement disorder of the present invention can treat and/or prevent or reduce or suppress these diseases and/or symptoms (e.g., motor control disorder such as extrapyramidal syndrome or the like, tremor, chorea, athetosis, bradykinesia, gait disturbance, dystonia, dyskinesia, tardive dyskinesia, postural reflex disorder or the like, preferably, for example, extrapyramidal syndrome, bradykinesia, gait disturbance, dystonia, dyskinesia, tardive dyskinesia, postural reflex disorder or the like, and more preferably, extrapyramidal syndrome, bradykinesia, gait disturbance, dystonia, dyskinesia, tardive dyskinesia or the like).
  • motor control disorder such as extrapyramidal syndrome or the like, tremor, chorea, athetosis, bradykinesia, gait disturbance, dystonia, dysk
  • the movement disorder in the agent for the treatment and/or prophylaxis of a movement disorder of the present invention also encompasses side effects of L-DOPA and/or dopamine agonist therapy (e.g., motor complications such as wearing-off phenomenon, on-off fluctuation, dyskinesia or the like).
  • L-DOPA provides robust and rapid therapeutic benefits in Parkinson's disease, eventually, severe and uncomfortable adverse reactions including motor complications such as wearing-off phenomenon, on-off fluctuation, dyskinesia and the like appear (Marsden et al., “Fluctuat ionsind is ability in Parkinson's disease: clinical aspects” In: Marsden, C D, Fahn S., eds. Movement disorders. New York: Butterworth Scientific, p. 96-122 (1982)). It is also known that an administration of L-DOPA alone causes side effects such as nausea, vomiting, anorexia and the like.
  • a dopamine agonist can also induce dyskinesia.
  • Use of a dopamine agonist is often limited due to neuropsychiatric side effects, particularly, hallucination and psychosis.
  • a dopamine agonist provides advantages when used as the adjunct in the treatment with L-DOPA, control thereby of motor complication caused by L-DOPA is extremely difficult or even impossible, as mentioned above (Olanow, Watts and Kollereds., An Algorithm (Decision Tree) for the Management of Parkinson's Disease: Treatment Guidelines, Neurology 56, Suppl. 5 (2001)).
  • L-DOPA Long adot alpha-1
  • the side effects in the L-DOPA and/or dopamine agonist therapy in the present invention refer to the above-mentioned side effects that occur in the treatment and/or prophylaxis of Parkinson's disease and the like using L-DOPA and/or a dopamine agonist.
  • they include motor complications such as wearing-off phenomenon, on-off fluctuation, dyskinesia and the like, nausea, vomiting, anorexia, hallucination and psychological symptom, excessive daytime sleepiness, preferably, motor complications such as wearing-off phenomenon, on-off fluctuation, dyskinesia and the like, and the like.
  • the agent for the treatment and/or prophylaxis of a movement disorder of the present invention can reduce or suppress a side effect that appears on administration of L-DOPA and/or a dopamine agonist, specifically, a motor complication such as wearing-off phenomenon, on-off fluctuation, dyskinesia or the like, nausea, vomiting, anorexia, hallucination and psychological symptom, or excessive daytime sleepiness, preferably, a motor complication such as wearing-off phenomenon, on-off fluctuation, dyskinesia or the like, more preferably, a symptom such as wearing-off phenomenon, dyskinesia or the like.
  • a motor complication such as wearing-off phenomenon, on-off fluctuation, dyskinesia or the like, nausea, vomiting, anorexia, hallucination and psychological symptom, or excessive daytime sleepiness
  • a motor complication such as wearing-off phenomenon, on-off fluctuation, dyskinesia or the like, more preferably, a symptom such as
  • the agent for the treatment and/or prophylaxis of a movement disorder of the present invention can extend the effective time of the treatment with L-DOPA and/or a dopamine agonist by reducing or suppressing the above-mentioned side effects.
  • the agent for the treatment and/or prophylaxis of a movement disorder of the present invention can effectively suppress the wearing-off phenomenon or the like, which are problematic in L-DOPA therapy of patients with Parkinson's disease in an advanced stage.
  • L-DOPA used for the above-mentioned L-DOPA and/or dopamine agonist therapy may contain L-DOPA or a salt, hydrate, prodrug or the like thereof as an active ingredient, and examples thereof include preparations containing these as an active ingredient and the like.
  • examples of the commercially available product include Menesit (registered trade mark), EC Doparl (registered trade mark), Doparl (registered trade mark), Madopar (registered trade mark) and the like.
  • the dopamine agonist may contain a dopamine agonist or a salt, hydrate, prodrug or the like thereof as an active ingredient, and examples thereof include preparations containing pramipexole, talipexole, ropinirole, cabergoline, pergolide or the like, or a hydrochloride, mesylate or prodrug thereof or the like as an active ingredient, and the like.
  • Examples of the commercially available product include Domin (registered trade mark), Permax (registered trade mark), Cabaser (registered trade mark) and the like.
  • the agent for the treatment and/or prophylaxis of Parkinson's disease of the present invention characteristically comprises a thiazole derivative or a pharmaceutically acceptable salt thereof and L-DOPA and/or a dopamine agonist in combination, and not only can reduce or suppress each symptom of Parkinson's disease, but also can delay the onset of the side effect caused by the administration of the aforementioned L-DOPA and/or a dopamine agonist (e.g., wearing-off phenomenon, on-off fluctuation, dyskinesia or the like) or suppress the symptoms.
  • Examples of the lower alkyl moiety of the lower alkyl, the lower alkoxy and the lower alkanoyl include straight or branched alkyl having 1 to 10 carbon atoms, and more specific examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like.
  • aralkyl examples include aralkyl having 7 to 16 carbon atoms, and more specific examples thereof include benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, phenylheptyl, phenyloctyl, phenylnonyl, phenyldecyl, naphthylmethyl, naphthylethyl, naphthylpropyl, naphthylbutyl, naphthylpentyl, naphthylhexyl, anthrylmethyl, anthrylethyl and the like.
  • aryl examples include aryl having 6 to 14 carbon atoms, and more specific examples thereof include phenyl, naphthyl, azulenyl, anthryl and the like.
  • aromatic heterocyclic group examples include a 5-membered or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, a bicyclic or tricyclic fused aromatic heterocyclic group in which 3 to 8-membered rings are fused, having at least one atom selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and the like.
  • More specific examples thereof include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, isoindolyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, imidazopyridinyl, purinyl, quinolinyl, isoquinolin
  • aromatic heterocycle-alkyl examples include a group wherein an aromatic heterocyclic group is bonded to alkylene.
  • the aromatic heterocyclic group include those exemplified in the above-mentioned aromatic heterocyclic group
  • the alkylene include an alkylene having 1 to 10 carbon atoms, and specific examples thereof include methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene and the like.
  • aromatic heterocycle-alkyl examples include pyrrolylmethyl, pyrrolylethyl, thiazolylmethyl, pyridylmethyl, pyridylethyl, pyrimidinylmethyl, pyrimidinylethyl, indolylmethyl, benzimidazolylmethyl and the like.
  • Examples of the aliphatic heterocycle-alkyl include a group wherein the aliphatic heterocyclic group is bonded to alkylene.
  • Examples of the aliphatic heterocyclic group include a 5-membered or 6-membered monocyclic aliphatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, a bicyclic or tricyclic fused aliphatic heterocyclic group in which 3 to 8-membered rings are fused, having at least one atom selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and the like.
  • More specific examples thereof include aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperidinyl, azepanyl, 1,2,5,6-tetrahydropyridyl, imidazolidinyl, pyrazolidinyl, piperazinyl, homopiperazinyl, pyrazolinyl, oxiranyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyridyl, oxazolidinyl, morpholino, morpholinyl, thioxazolidinyl, thiomorpholinyl, 2H-oxazolyl, 2H-thioxazolyl, dihydroindolyl, dihydroisoindolyl, dihydrobenzofuranyl, benzimidazolidinyl,
  • alkylene examples include alkylene having 1 to 10 carbon atoms, and specific examples thereof include methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene and the like.
  • aliphatic heterocycle-alkyl examples include 5,6-dihydro-2H-pyridylmethyl, 5,6-dihydro-2H-pyridylethyl, tetrahydro-2H-pyranylmethyl, 5,6-dihydro-2H-pyranylmethyl, 5,6-dihydro-2H-pyranylethyl, morpholinomethyl, morpholinoethyl, piperazinylmethyl, oxazolidinylmethyl and the like.
  • the halogen means each atom of fluorine, chlorine, bromine and iodine.
  • Compound (I) or a pharmaceutically acceptable salt thereof of the present invention or used in the present invention is preferably a compound having a potent antagonistic activity against adenosine A 2A receptors from among various subtypes of adenosine receptors (e.g., adenosine A 1 , A 2A , A 2B and A 3 receptors).
  • Compound (I) or a pharmaceutically acceptable salt thereof of the present invention or used in the present invention is preferably a compound having a strong affinity for the adenosine A 2A receptors.
  • the compound is preferably one having an inhibitory activity of 50% or more at a test compound concentration of 3 ⁇ 10 ⁇ 8 mol/L, more preferably one having an inhibitory activity of 50% or more at a test compound concentration of 1 ⁇ 10 ⁇ 8 mol/L, still more preferably one having an inhibitory activity of 50% or more at a test compound concentration of 3 ⁇ 10 ⁇ 9 mol/L, further preferably one having an inhibitory activity of 50% or more at a test compound concentration of 1 ⁇ 10 ⁇ 9 mol/L, in the adenosine A 2A receptor binding test shown in the below-mentioned Test Example 1.
  • the compound is preferably one having an inhibitory activity of 30 nmol/L or less in an inhibitory constant (Ki value), more preferably one having an inhibitory activity of 10 nmol/L or less, still more preferably one having an inhibitory activity of 3 nmol/L or less, further preferably one having an inhibitory activity of 1 nmol/L or less.
  • Ki value inhibitory constant
  • Compound (I) or a pharmaceutically acceptable salt thereof of the present invention or used in the present invention is preferably a compound having selective affinity for the adenosine A 2A receptors from among various subtypes of the adenosine receptors.
  • a compound having a higher affinity for the adenosine A 2A receptors than that for the adenosine A 1 receptors is preferable.
  • the compound is preferably a compound having 5 times or more affinity, more preferably 10 times or more affinity, further preferably 50 times or more affinity, even more preferably 100 times or more affinity, most preferably 500 times or more affinity for the adenosine A 2A receptors than that for the adenosine A 1 receptors.
  • the affinity for adenosine receptors can be determined according to a conventional method, for example, according to the method of Test Example 1 to be mentioned below, or the methods described in, for example, a document [for example, Naunyn Schmiedebergs Arch Pharmacol., 355(1), p. 59 (1987); Naunyn Schmiedebergs Arch Pharmacol. 355(2), p. 204 (1987); Br. J. Pharmacol. 117(8), p. 1645 (1996) and the like].
  • Compound (I) is preferably a compound wherein R 1 is phenyl optionally substituted by 1 to 3 substituents selected from halogen, C 1-6 alkyl optionally substituted by C 1-6 alkoxy or morpholino, C 1-6 alkanoyl, vinyl and C 1-6 alkoxy; pyridyl optionally substituted by 1 to 3 substituents selected from halogen, C 1-6 alkyl optionally substituted by C 1-6 alkoxy or morpholino, C 1-6 alkanoyl, vinyl and C 1-6 alkoxy; pyrimidinyl optionally substituted by 1 to 3 substituents selected from halogen, C 1-6 alkyl optionally substituted by C 1-6 alkoxy or morpholino, C 1-6 alkanoyl, vinyl and C 1-6 alkoxy; 5,6-dihydro-2H-pyridylmethyl optionally substituted by 1 to 3 substituents selected from halogen, C 1-6 alkyl and C 1-6 alkoxy;
  • R 1 is phenyl optionally substituted by 1 to 3 substituents selected from a fluorine atom, a chlorine atom, methyl and methoxy; pyridyl optionally substituted by 1 to 3 substituents selected from a fluorine atom, a chlorine atom, methyl and methoxy; pyrimidinyl optionally substituted by 1 to 3 substituents selected from a fluorine atom, a chlorine atom, methyl and methoxy; 5,6-dihydro-2H-pyridylmethyl optionally substituted by 1 to 3 substituents selected from a fluorine atom, a chlorine atom, methyl and methoxy; or 2,3,4,5-tetrahydropyranyloxy, still more preferably a compound wherein R 1 is pyridyl substituted by 1 to 3 substituents selected from a chlorine atom, methyl and methoxy; pyrimidinyl substituted by 1 to 3 substituents selected from chlorine
  • the pharmaceutically acceptable salts of Compound (I) include, for example, pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like.
  • the pharmaceutically acceptable acid addition salts of Compound (I) include, for example, inorganic acid salts such as hydrochloride, hydrobromate, nitrate, sulfate, and phosphate; organic acid salts such as acetate, oxalate, maleate, fumarate, citrate, benzoate, and methane sulfonate, and the like.
  • Examples of the pharmaceutically acceptable metal salts include alkali metal salts such as a sodium salt, and a potassium salt; alkaline earth metal salts such as a magnesium salt, and a calcium salt; an aluminum salt; a zinc salt, and the like.
  • Examples of the pharmaceutically acceptable ammonium salts include salts of ammonium, tetramethylammonium, and the like.
  • Examples of the pharmaceutically acceptable organic amine addition salts include addition salts of morpholine, piperidine, or the like.
  • Examples of the pharmaceutically acceptable amino acid addition salts include addition salts of lysine, glycine, phenylalanine, aspartic acid, glutamic acid, or the like.
  • Compound (I) can be produced according to a known method, for example, the method described in WO 2005/063743 and the like.
  • R 1 and R 2 are as defined above, and X is a chlorine atom, a bromine atom or the like.
  • Compound (I) can be produced, for example, by reacting compound (Ia) described in WO 2005/063743 with preferably 0.5 to 5 equivalents of compound (Ib) in a solvent such as methanol, dichloromethane, chloroform, toluene, ethyl acetate, acetonitrile, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), pyridine, water, or a mixed solvent thereof and the like, preferably in the presence of 1 to 5 equivalents of a condensing agent such as 1,3-dicyclohexanecarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) hydrochloride and the like, if necessary, in the presence of preferably 1 to 5 equivalents of 1-hydroxybenzotriazo
  • a solvent such as methanol, dichlorome
  • Compound (I) can also be produced, for example, by reacting compound (Ia) described in WO 2005/063743 with preferably 1 to 10 equivalents of compound (Ic) without solvent or in a solvent such as dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, THF, DMF, DMA, pyridine and the like, if necessary, in the presence of preferably 1 to 10 equivalents of a base such as potassium carbonate, triethylamine, 4-dimethylaminopyridine (DMAP) and the like, at a temperature between ⁇ 20° C. and 150° C., for 5 min to 72 hr.
  • a solvent such as dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, THF, DMF, DMA, pyridine and the like, if necessary
  • Compound (I) may exist as stereoisomers such as geometrical isomers or optical isomers, or tautomers.
  • the thiazole derivative or a pharmaceutically acceptable salt thereof of the present invention encompasses all possible isomers including those and mixtures thereof.
  • All possible isomers including those and mixtures thereof can be used for an agent for the treatment and/or prophylaxis of a movement disorder, a pharmaceutical composition, an agent for the treatment and/or prophylaxis of Parkinson's disease, a kit, a method for the treatment and/or prophylaxis of a movement disorder, a method for the treatment and/or prophylaxis of Parkinson's disease, a combination, use for the manufacture of an agent for the treatment and/or prophylaxis of a movement disorder and use for the manufacture of an agent for the treatment and/or prophylaxis of Parkinson's disease, of the present invention.
  • a salt of Compound (I) when the Compound (I) is obtained in the form of a salt, it may be purified as it is. Further, when the compound is obtained in a free form, the compound may be dissolved or suspended in a suitable solvent, followed by addition of an acid or a base to form a salt. Then, the resulting salt may be isolated and purified.
  • the Compound (I) or a pharmaceutically acceptable salt thereof may exist in the form of an adduct with water or various solvents.
  • adduct is also encompassed in the thiazole derivative or a pharmaceutically acceptable salt thereof of the present invention, and can be used for an agent for the treatment and/or prophylaxis of a movement disorder, a pharmaceutical composition, an agent for the treatment and/or prophylaxis of Parkinson's disease, a kit, a method for the treatment and/or prophylaxis of a movement disorder, a method for the treatment and/or prophylaxis of Parkinson's disease, a combination, use for the manufacture of an agent for the treatment and/or prophylaxis of a movement disorder and use for the manufacture of an agent for the treatment and/or prophylaxis of Parkinson's disease, of the present invention.
  • L-DOPA used for a pharmaceutical composition, an agent for the treatment and/or prophylaxis of Parkinson's disease, a kit, a method for the treatment and/or prophylaxis of Parkinson's disease, a combination and use for the manufacture of an agent for the treatment and/or prophylaxis of Parkinson's disease, of the present invention may contain, as an active ingredient, L-DOPA or a salt, hydrate, prodrug or the like thereof and, for example, a preparation and the like containing these as active ingredients can be used.
  • Such L-DOPA can be obtained, for example, as a commercially available product, or can be produced by a known method. Specific examples of the commercially available product include Menesit (registered trade mark), EC Doparl (registered trade mark), Doparl (registered trade mark), Madopar (registered trade mark) and the like.
  • the dopamine agonist used for a pharmaceutical composition, an agent for the treatment and/or prophylaxis of Parkinson's disease, a kit, a method for the treatment and/or prophylaxis of Parkinson's disease, a combination and use for the manufacture of an agent for the treatment and/or prophylaxis of Parkinson's disease, of the present invention may contain, as an active ingredient, a dopamine agonist or a salt, hydrate, prodrug or the like thereof and, for example, a preparation and the like containing these as active ingredients can be used.
  • Such dopamine agonist can be obtained, for example, as a commercially available product, or can be produced by a known method.
  • Specific examples of the commercially available product include Domin (registered trade mark), Permax (registered trade mark), Cabaser (registered trade mark) and the like.
  • the pharmaceutical preparation according to an agent for the treatment and/or prophylaxis of a movement disorder, a method for the treatment and/or prophylaxis of a movement disorder and use for the manufacture of an agent for the treatment and/or prophylaxis of a movement disorder, of the present invention may contain, as the active ingredient, Compound (I) or a pharmaceutically acceptable salt thereof either alone or as a mixture with any other therapeutic active ingredient.
  • these pharmaceutical preparations are prepared by mixing the active ingredient with one or more pharmaceutically acceptable carriers (for example, diluents, solvents, excipients, or the like), and then subjecting the mixture to any method well-known in the technical field of pharmaceutics.
  • the administration route it is preferable to select the most effective route of administration for treatment.
  • the administration route include oral administration, and parenteral administration, for example, such as intravenous or transdermal administration and the like.
  • Examples of the dosage form include tablets, injections, external preparations, and the like.
  • Suitable dosage forms for the oral administration can be prepared by using excipients such as lactose, disintegrators such as starch, lubricants such as magnesium stearate, or binders such as hydroxypropylcellulose, or the like.
  • Suitable dosage forms for the parenteral administration can be prepared by using diluents or solvents such as a saline solution, a glucose solution, or a mixture of brine and glucose solution, or the like.
  • a dosage form suitable for external preparation is not particularly limited and, for example, ointment, cream, liniment, lotion, cataplasm, plaster, tape and the like can be included.
  • ointment, cream and the like can be produced by, for example, dissolving or mixing-dispersing the active ingredient in a base such as white petrolatum and the like.
  • the dose and administration frequency of Compound (I) or a pharmaceutically acceptable salt thereof varies depending on the efficacy, dose and/or administration form, age and body weight of patients, properties or severity of the symptoms to be treated and the like.
  • 0.001-1000 mg, preferably 0.05-100 mg is administered to one adult in one to several portions a day.
  • parenteral administration such as intravenous administration and the like
  • 0.001-1000 mg, preferably 0.01-100 mg is generally administered to one adult in one to several portions a day.
  • transdermal administration an external preparation containing 0.001-10% of Compound (I) or a pharmaceutically acceptable salt thereof is generally applied once to several times a day.
  • these doses and administration frequencies vary depending on the aforementioned various conditions.
  • the agent for the treatment and/or prophylaxis of a movement disorder shows a superior therapeutic and/or prophylactic, or reducing and/or suppressive effect on a movement disorder such as extrapyramidal syndrome, bradykinesia, gait disturbance, dystonia, dyskinesia, tardive dyskinesia or the like; and a side effect of L-DOPA and/or dopamine agonist therapy such as wearing-off phenomenon, on-off fluctuation, dyskinesia or the like.
  • a superior therapeutic and/or prophylactic, or reducing and/or suppressive effect on the above-mentioned disease developed in Parkinson's disease in an advanced stage e.g., a movement disorder such as extrapyramidal syndrome, bradykinesia, gait disturbance, dystonia, dyskinesia, tardive dyskinesia or the like; and a side effect of L-DOPA and/or dopamine agonist therapy such as wearing-off phenomenon, on-off fluctuation, dyskinesia or the like).
  • Compound (I) or a pharmaceutically acceptable salt thereof may be used in combination with one or more other pharmaceutical components.
  • Examples of the other pharmaceutical components used in combination include known drugs useful as therapeutic and/or prophylactic drug for Parkinson's disease and the like, and the like, and the like (Iyaku (Medicine and Drug) Journal, vol. 44, p. 91 (2008)).
  • COMT inhibitors e.g., entacapone, tolcapone and the like
  • MAO inhibitors e.g., selegiline, rasagiline and the like
  • COMT inhibitors e.g., entacapone, tolcapone and the like
  • MAO inhibitors e.g., selegiline, rasagiline and the like
  • Compound (I) or a pharmaceutically acceptable salt thereof When Compound (I) or a pharmaceutically acceptable salt thereof is used in combination with other pharmaceutical component(s), Compound (I) or a pharmaceutically acceptable salt thereof, and other pharmaceutical component(s) may be administered simultaneously or separately at an interval.
  • the doses vary depending on the administration subject, the administration route, the disease, and the combinations of pharmaceutical component, and the like, and should be decided according to the doses used in the clinic.
  • compositions (a) Compound (I) or a pharmaceutically acceptable salt thereof and (b) L-DOPA and/or a dopamine agonist used for the pharmaceutical composition, the agent for the treatment and/or prophylaxis of Parkinson's disease, the kit, the method for the treatment and/or prophylaxis of Parkinson's disease, the combination and the use for the manufacture of an agent for the treatment and/or prophylaxis of Parkinson's disease, of the present invention may be used or administered as a single preparation (combination agent) or as a combination of more than one preparation, provided that these preparations are formulated together with, for example, a pharmaceutically acceptable carrier to contain these active ingredients.
  • a combination of two or more preparations is preferred.
  • the preparations When used or administered as a combination of more than one preparation, the preparations may be used or administered simultaneously or separately at an interval.
  • these preparations are used in the form of, for example, tablets, injections, external preparations or the like.
  • the dose ratio (weight/weight) of (a) Compound (I) or a pharmaceutically acceptable salt thereof and (b) L-DOPA and/or a dopamine agonist can be appropriately adjusted according to a combination of (a) Compound (I) or a pharmaceutically acceptable salt thereof and (b) L-DOPA and/or a dopamine agonist used, efficacy of each of (a) Compound (I) or a pharmaceutically acceptable salt thereof and (b) L-DOPA and/or a dopamine agonist and the like.
  • it is 1/100000 ((a) Compound (I) or a pharmaceutically acceptable salt thereof/(b) L-DOPA and/or a dopamine agonist)-1000/1, preferably 1/50000-500/1, more preferably 1/6000-100/1, further more preferably 1/4000-15/1, still further more preferably 1/1000-10/1, most preferably 1/100-10/1.
  • preparations are prepared by mixing the active ingredient with one or more pharmaceutically acceptable carriers (for example, diluents, solvents, excipients, or the like), and then subjecting the mixture to any method well known in the technical field of pharmaceutics.
  • pharmaceutically acceptable carriers for example, diluents, solvents, excipients, or the like
  • Suitable dosage forms for the oral administration can be prepared by using excipients such as lactose, disintegrators such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, or the like.
  • Suitable dosage forms for the parenteral administration can be prepared by using diluents or solvents such as a saline solution, a glucose solution, or a mixture of brine and glucose solution, or the like.
  • a dosage form suitable for external preparation is not particularly limited to and, for example, ointment, cream, liniment, lotion, cataplasm, plaster, tape and the like can be included.
  • ointment, cream and the like can be produced by, for example, dissolving or mixing-dispersing the active ingredient in a base such as white petrolatum and the like.
  • a first component comprising Compound (I) or a pharmaceutically acceptable salt thereof, and (b) a second component comprising L-DOPA and/or a dopamine agonist may be separately prepared into a kit, and may be administered to the same subject in the same route or in different routes simultaneously or separately at an interval, using the kit.
  • kits for example, a kit comprising contents and two or more containers (for example, vials, bags, etc.) whose material, shape, and so on are not particularly limited as long as the containers do not cause degeneration of the components which are the contents due to external temperature or light nor cause elution of chemical components from the containers during storage, and having a form which enables the administration of the above first and second components which are the contents through separate routes (for example, tubes, etc.) or the same route is used.
  • Specific examples thereof include tablet kits, injection kits, and the like.
  • the dose and administration frequency vary depending on the efficacy of each active ingredient, dosage form, age and body weight of a patient, symptom, and the like. It is preferable to administer each of (a) Compound (I) or a pharmaceutically acceptable salt thereof and (b) L-DOPA and/or a dopamine agonist usually at the following dose per day.
  • Compound (I) or a pharmaceutically acceptable salt thereof and (b) L-DOPA and/or a dopamine agonist are administered at 0.1-1000 mg and 0.1-10000 mg, preferably 0.1-500 mg and 0.1-5000 mg, more preferably 0.5-500 mg and 1-3000 mg, still more preferably 0.5-300 mg and 1-2000 mg, respectively, per one adult simultaneously or separately at an interval in one to several portions a day usually.
  • compositions (a) Compound (I) or a pharmaceutically acceptable salt thereof and (b) L-DOPA and/or a dopamine agonist are administered at 0.1-1000 mg and 0.1-10000 mg, preferably 0.1-500 mg and 0.1-5000 mg, more preferably 0.5-500 mg and 1-3000 mg, still more preferably 0.5-300 mg and 1-2000 mg, respectively, per one adult simultaneously or separately at an interval in one to several portions a day usually.
  • the dose and administration frequency vary depending on the efficacy of each active ingredient, dosage form, age and body weight of a patient, symptom, and the like. It is preferable to prepare one preparation containing each dose in the use or administration of a combination of the above-mentioned plural preparations, and use or administer same.
  • a pharmaceutical composition, an agent for the treatment and/or prophylaxis of Parkinson's disease, a kit, a method for the treatment and/or prophylaxis of Parkinson's disease, and a combination of the present invention can be used for, for example, the treatment and/or prophylaxis of Parkinson's disease, more specifically, for patients, for example, patients with Parkinson's disease in an advanced stage, patients with Parkinson's disease who developed symptoms of on-off fluctuation, wearing-off phenomenon, dyskinesia or the like due to L-DOPA therapy or the like, and the like, and can effectively treat these diseases.
  • test can be performed according to, for example, the method of Varani et al. (British Journal of Pharmacology, 1996, 117, p. 1693).
  • human recombinant receptors are expressed in HEK-293 cells.
  • the cell membranes of the receptor-expressing cells are collected, and a cell membrane suspension is prepared.
  • Tris HCl tris(hydroxymethyl)-aminomethane hydrochloride
  • tritium-labeled CGS-21680 3 H-2-[p-(2-carboxyethyl)phenethylamino]-5′-(N-ethylcarboxamido)adenosine: 50 mmol/L
  • a test compound solution dimethyl sulfoxide solution of the test compound
  • the mixture is subjected to rapid suction filtration using glass-fiber filter paper, and the radioactivity of the glass-fiber filter paper is measured.
  • the inhibitory rate of the test compound for the human adenosine A 2A receptor binding 3 H-CGS21680 binding
  • test can also be performed according to the method of Bruns et al. (Molecular Pharmacology, Vol. 29, p. 331, 1986).
  • rat striatum is suspended in 50 ml of ice-cooled Tris HCl buffer (50 mmol/L, pH 7.7) using a Polytron homogenizer and the suspension is centrifuged. The resulting precipitate is resuspended by adding Tris HCl buffer (50 mmol/L) thereto, followed by centrifugation in the same manner. The resulting final precipitate is suspended in Tris HCl buffer (50 mmol/L) [containing magnesium chloride (10 mmol/L), and adenosine deaminase (0.02 units/mg tissue)] to prepare the suspension at the tissue concentration of 5 mg (wet weight)/mL.
  • Tris HCl buffer 50 mmol/L
  • Tris HCl buffer 50 mmol/L
  • adenosine deaminase 0.02 units/mg tissue
  • Tritium-labeled CGS-21680 final concentration of 6.0 mmol/L
  • test compound solution dimethylsulfoxide solution of test compound diluted with Tris HCl buffer
  • the mixture is allowed to stand at 25° C. for 120 minutes, followed by rapid suction filtration using glass-fiber filter paper, and then immediately washed with ice-cooled Tris HCl buffer (50 mmol/L).
  • the glass-fiber filter paper is then placed in a vial, and MicroScinti (PKI) is added. Then, the radioactivity is measured with a TopCount (PerkinElmer), whereby the inhibitory rate for rat adenosine A 2A receptor binding ( 3 H-CGS21680 binding) of the test compound can be determined.
  • TopCount PerkinElmer
  • the inhibitory rate can be calculated by the following equation.
  • Inhibitory ⁇ ⁇ rate ⁇ ⁇ ( % ) ( 1 - Amount ⁇ ⁇ of ⁇ ⁇ binding ⁇ ⁇ in ⁇ ⁇ the ⁇ ⁇ presence ⁇ ⁇ of ⁇ ⁇ drug - amount ⁇ ⁇ of ⁇ ⁇ non ⁇ - ⁇ specific ⁇ ⁇ binding Total ⁇ ⁇ amount ⁇ ⁇ ⁇ of ⁇ ⁇ binding - amount ⁇ ⁇ of ⁇ ⁇ non ⁇ - ⁇ specific ⁇ ⁇ binding ) ⁇ 100
  • the total amount of binding refers to the bound radioactivity of 3 H-CGS21680 in the absence of the test compound.
  • the amount of non-specific binding refers to the bound radioactivity of 3 H-CGS21680 in the presence of 50 ⁇ mol/L of 5′-N-ethylcarboxamideadenosine (NECA) or 100 ⁇ mol/L of cyclopentyladenosine (CPA).
  • the amount of binding in the presence of drug refers to the bound radioactivity of 3 H-CGS21680 in the presence of the test compound.
  • the inhibitory rate for the adenosine A 2A receptor at different concentrations of the test compound or a pharmaceutically acceptable salt thereof, and the test compound concentration at which the test compound inhibits binding by 50% (IC 50 ) can be calculated by appropriately adjusting the concentration of the test compound.
  • the inhibition constant (Ki value) of the test compound for the adenosine A 2A receptor binding can be calculated according to the following equation.
  • Ki IC 50 /(1+ L/Kd )
  • L denotes the concentration of the 3 H-CGS21680 used in the test
  • Kd is the dissociation constant of the 3 H-CGS21680 used in the test.
  • 3 H-SCH58261 3 H-5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine) and the like may be used.
  • the inhibition constant (Ki value) of the test compound for the adenosine A 1 receptor can be calculated in the same manner as in (1), using the materials below.
  • human A 1 receptor-expressing CHO cell membranes are used, and, as the labeled compound, for example, tritium-labeled DPCPX (1,3-dipropyl-8-cyclopentylxanthine) is used.
  • the amount of non-specific binding can be determined by measuring the 3 H-DPCPX bound radioactivity in the presence of, for example, 100 ⁇ mol/L of R( ⁇ )-PIA(( ⁇ )-N 6 -2-phenylisopropyl adenosine). The affinity of the test compound for the human adenosine A 1 receptors can be confirmed in this manner.
  • rat A 1 receptor-expressing cell membrane PerkinElmer
  • labeled compound for example, tritium-labeled CHA (N 6 -cyclohexyladenosine) is used.
  • 3 H-CHA bound radioactivity is measured in the presence of, for example, 10 ⁇ mol/L of DPCPX, and the affinity of the test compound for the rat adenosine A 1 receptor can be confirmed.
  • Parkinson's disease is a disease based on the progressive degeneration and loss of dopaminergic neuron in substantia nigra-striatum.
  • a treatment with MPTP which is a dopamine neurotoxin, causes selective degeneration and loss of dopaminergic neuron in substantia nigra-striatum and induces symptoms of akinesia, muscle rigidity and the like.
  • the primates treated with MPTP are known as the model of Parkinson's disease [Proceedings of the National Academy of Science USA, vol. 80, p. 4546 (1983)].
  • All compounds were used as a suspension in 0.5% MC400, 10% aqueous sucrose solution.
  • the subject animal was placed in an observation cage (with locomotor activity measuring apparatus) one day before the test compound administration for preconditioning to the environment.
  • the symptoms of Parkinson's disease were continuously monitored through one-way mirror and disability score was scored each 10 min for 6 hr.
  • the locomotor activity was automatically measured using a computer by a measuring apparatus with a photocell.
  • L-DOPA dopa decarboxylase inhibitor (benserazide hydrochloride)
  • IC dopa decarboxylase inhibitor
  • Compound (I) is considered to have effects of enhancing the therapeutic effect of L-DOPA on Parkinson's disease and prolonging the duration of therapeutic effect of L-DOPA on Parkinson's disease.
  • L-DOPA 10 mg/kg of L-DOPA (containing 2.5 mg/kg of benserazide hydrochloride) was administered by gavage to common marmoset that developed chronic parkinsonian symptoms by treatment with MPTP by the method described in Test Example 3 (MPTP-treated marmoset) twice a day at about 6 hr intervals.
  • L-DOPA was repeatedly administered for more than 3 weeks to induction of motor complication (dyskinesia symptom, wearing-off phenomenon, on-off fluctuation and the like) in MPTP-treated marmoset in addition to parkinsonian symptoms, and the marmoset was used for the test.
  • the parkinsonian symptoms were judged using rating scale described in a previous report [Annales of Neurology, vol. 43, p.
  • the locomotor activity was automatically measured using a computer by a measuring apparatus with a photocell. All compounds were used as a suspension in 0.5% MC400, 10% aqueous sucrose solution. The subject animal was placed in an observation cage (with locomotor activity measuring apparatus) one day before the test compound administration for preconditioning to the environment. The symptoms of Parkinson's disease were continuously monitored through one-way mirror and disability score was scored each 10 min for 6 hr. When 2.5 mg/kg or 10 mg/kg of L-DOPA (containing 2.5 or 0.625 mg/kg of benserazide hydrochloride) was administered, the parkinsonian symptoms in MPTP-treated marmoset decreased with the increasement of dosage.
  • L-DOPA containing 2.5 or 0.625 mg/kg of benserazide hydrochloride
  • L-DOPA 10 mg/kg of L-DOPA (containing 2.5 mg/kg of benserazide hydrochloride) was administered to common marmoset that developed chronic parkinsonian symptoms by treatment with MPTP by the method described in Test Example 3 (MPTP-treated marmoset) twice a day at about 6 hr intervals.
  • L-DOPA was repeatedly administered for more than 3 weeks to induction of motor complication (dyskinesia symptom, wearing-off phenomenon, on-off fluctuation and the like) in MPTP-treated marmoset in addition to parkinsonian symptoms, and the marmoset was used for the test.
  • the dyskinesia severity was rating using the rating scale described in a previous report [Annales of Neurology, vol. 43, p.
  • Test Example 2 As in Test Example 2. The evaluation items and scores are shown in Table 3. All compounds were used as a suspension of 0.5% MC400, 10% aqueous sucrose solution. The subject animal was placed in an observation cage (with locomotor activity measuring apparatus) one day before the test compound administration for preconditioning to the environment. The dyskinesia symptoms were observed through one-way mirror and scored each 20 min for 6 hr.
  • the locomotor activity was automatically measured using a computer by a measuring apparatus with a photocell.
  • L-DOPA each containing 0.3125, 0.625, 1.25, 1.875 and 2.5 mg/kg of benserazide hydrochloride, respectively
  • dyskinesia was induced in MPTP-treated marmoset with increasing dose of L-DOPA.
  • a combination of 1 mg/kg of compound (IC) and L-DOPA was simultaneously administered orally.
  • composition comprising of Compound (I) or a pharmaceutically acceptable salt thereof is considered to suppress or reduce side effects (e.g., wearing-off phenomenon, on-off fluctuation, dyskinesia or the like) of L-DOPA and/or dopamine agonist therapy for Parkinson's disease or the like.
  • side effects e.g., wearing-off phenomenon, on-off fluctuation, dyskinesia or the like
  • Compound (I) or a pharmaceutically acceptable salt thereof is considered to be effective for the reducing wearing-off phenomenon in L-DOPA and/or dopamine agonist therapy.
  • a combined use of Compound (I) or a pharmaceutically acceptable salt thereof and L-DOPA is considered to effectively treat parkinsonian symptoms (movement disorders relating to bradykinesia, gait, akinesia, or the like).
  • parkinsonian symptoms movement disorders relating to bradykinesia, gait, akinesia, or the like.
  • Compound (I) or a pharmaceutically acceptable salt thereof is used in combination with L-DOPA, an improving effect on parkinsonian symptoms and locomotor activity becomes stronger than that by the use of L-DOPA alone.
  • a combined use of Compound (I) or a pharmaceutically acceptable salt thereof and L-DOPA can reduce the dose of L-DOPA necessary for achieving the same improvement level as a treatment with L-DOPA alone, and can suppress or delay expression of side effects in the circulatory and gastrointestinal systems, as well as the onset of dyskinesia and motor complication due to L-DOPA.
  • Tablets having the following formulations are prepared according to the conventional manner.
  • Compound (IA) 40 g
  • potato starch 60 g
  • a 10% aqueous solution of hydroxypropylcellulose 120 g
  • the resulting mixture is kneaded according to the conventional manner, granulated, and dried to form granules for tableting.
  • magnesium stearate After adding thereto 1.2 g of magnesium stearate followed by mixing, the mixture is punched with a tableting machine having a punch measuring 8 mm in diameter (Model RT-15; Kikusui) to obtain tablets (containing 20 mg of an active ingredient per tablet).
  • Tablets having the following formulation are prepared according to the conventional manner.
  • Compound (IA) 40 g
  • L-DOPA 40 g
  • lactose (246.8 g)
  • potato starch 60 g
  • a 10% aqueous solution of hydroxypropylcellulose 120 g
  • the resulting mixture is kneaded according to the conventional manner, granulated, and dried to form granules for tableting.
  • Injections having the following formulation are prepared according to the conventional manner.
  • Compound (IA) (1 g) is added to distilled water for injection followed by mixing.
  • the total volume is adjusted to 1,000 mL with distilled water for injection.
  • the resulting mixture is aseptically charged into glass vials in 2-mL portions to obtain injections (containing 2 mg of an active ingredient per vial).
  • Injections having the following formulation are prepared according to the conventional manner.
  • Compound IA (1 g) and L-DOPA (1 g) are added to distilled water for injection followed by mixing.
  • the resulting mixture is aseptically charged into glass vials in 2-mL portions to obtain injections (containing compound (IA) (2 mg) and L-DOPA (2 mg) per vial).
  • Injections having the following formulation are prepared in the same manner as in Example 10.
  • step 1 Methyl 6-chloronicotinate (1.51 g, 8.79 mmol) was dissolved in DMF (35 mL), vinyltributyltin (3.32 mL, 11.4 mmol), dichlorobis(tri-o-tolylphosphine)palladium (206 mg, 0.262 mmol) and lithium chloride (554 mg, 13.1 mmol) were added and the mixture was stirred at 100° C. for 2 hr. The mixture was allowed to cool to room temperature, and an aqueous potassium fluoride solution was added thereto. The mixture was filtered through celite and the residue was washed with ethyl acetate.
  • step 2 Methyl 6-vinylnicotinate (491 mg, 2.97 mmol) obtained above was dissolved in a 50% methanol aqueous solution (8 mL). Lithium hydroxide monohydrate (276 mg, 6.57 mmol) was added thereto and the mixture was stirred at room temperature for 1 hr. The mixture was cooled to 0° C., then 3 mol/L hydrochloric acid (3 mL) was added, and the precipitated solid was collected by filtration to give 6-vinylnicotinic acid (309 mg, 70%) as a white solid.
  • step 2 2-(Chloromethyl)-N-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]pyridine-4-carboxamide (70.0 mg, 0.162 mmol) obtained in step 1 was dissolved in acetonitrile (2.0 mL), then morpholine (70.0 ⁇ L, 2.15 mmol) was added thereto, and the mixture was stirred with heating under reflux for 1 hr. The mixture was allowed to cool to room temperature, water and a saturated aqueous sodium hydrogen carbonate solution were added thereto.
  • step 1 Sodium hydride (2.06 g, 51.5 mmol) was suspended in diethyl ether (40 mL), and methanol (2.1 ml, 51.8 mmol) was added slowly at ⁇ 5° C. thereto. To the mixture was added ethanol (6 mL), and the mixture was stirred at room temperature for 5 min, and cooled to 0° C. A mixture of tetrahydro-4H-pyran-4-one (4.61 mL, 49.9 mmol) and ethyl formate (4.11 ml, 51.1 mmol) was slowly added thereto. The mixture was stirred at room temperature for 2 hr, and the resultant product was extracted with water (30 ml) (aqueous solution A).
  • an aqueous piperidine-acettic acid solution prepared by dissolving acetic acid (1.5 mL) in water (3.5 mL) and adding piperidine (2.6 mL) thereto, and 2-cyanoacetamide (4.62 g, 54.9 mmol) were added to the above-mentioned aqueous solution A, and the mixture was stirred with heating under reflux for 4 hr. To the mixture was added acetic acid (3.6 mL) and, after cooling 0° C., the precipitated solid was collected by filtration to give 2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridine-3-carbonitrile (1.72 g, 20%) as a white solid.
  • step 2 2-Oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridine-3-carbonitrile (2.50 g, 14.4 mmol) obtained in step 1 was dissolved in phosphoryl chloride (20 mL), and the mixture was stirred with heating under reflux for 4 hr. The mixture was allowed to cool to room temperature, and slowly added to a saturated aqueous sodium hydrogen carbonate solution at 0° C., then the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • step 3 2-Chloro-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile (1.77 g, 9.09 mmol) obtained in step 2 was dissolved in ethanol (30 mL), acetic acid (9 mL) and zinc (2.60 g) were added thereto, and the mixture was stirred with heating under reflux for 4 hr. The mixture was allowed to cool to room temperature, then filtered through celite, and the filtrate was concentrated under reduced pressure. To the obtained residue was added a saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • step 4 In the same manner as in step 1 of Example 24, 7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carboxylic acid (318 mg, 47%) was obtained as a white solid from 7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile (609 mg, 3.80 mmol) obtained above.
  • step 1 In the same manner as in step 1 of Example 12, methyl 6-(1-propenyl)nicotinate (327 mg, 37%) was obtained as a colorless transparent oil from methyl 6-chloronicotinate (862 mg, 6.48 mmol) and allyltributyltin (2.20 ml, 7.09 mmol).
  • step 2 In the same manner as in step 2 of Example 12, 6-(1-propenyl)nicotinic acid (251 mg, 84%) was obtained as milk-white crystals from methyl 6-(1-propenyl)nicotinate (326 mg, 1.84 mmol) obtained above.
  • step 4 In the same manner as in Example 29, the title Compound IW (96.0 mg, 76%) was obtained as white crystals from N-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-6-(1-propenyl)pyridine-3-carboxamide (125 mg, 0.296 mmol) obtained above.
  • step 1 In the same manner as in step 1 of Example 26, 2-oxo-1,5,7,8-tetrahydro-5H-thiopyrano[4,3-b]pyridine-3-carbonitrile (3.06 g, 37%) was obtained as a pale-yellow solid from tetrahydro-4H-thiopyran-4-one (5.00 g, 43.0 mmol).
  • step 2 In the same manner as in step 2 of Example 26, 2-chloro-7,8-dihydro-5H-thiopyrano[4,3-b]pyridine-3-carbonitrile (1.75 g, 58%) was obtained from 2-oxo-1,5,7,8-tetrahydro-5H-thiopyrano[4,3-b]pyridine-3-carbonitrile (2.78 g, 14.4 mmol) obtained above.
  • step 3 In the same manner as in step 3 of Example 26, 7,8-dihydro-5H-thiopyrano[4,3-b]pyridine-3-carbonitrile (804 mg, 55%) was obtained from 2-chloro-7,8-dihydro-5H-thiopyrano[4,3-b]pyridine-3-carbonitrile (1.75 g, 8.31 mmol) obtained above.
  • step 4 In the same manner as in step 1 of Example 27, 7,8-dihydro-5H-thiopyrano[4,3-b]pyridine-3-carboxylic acid hydrochloride (901 mg, 78%) was obtained from 7,8-dihydro-5H-thiopyrano[4,3-b]pyridine-3-carbonitrile (874 mg, 4.96 mmol) obtained above.
  • step 1 In the same manner as in step 2 of Example 12, 5-acetyl-6-methylpyridine-3-carboxylic acid (462 mg, quantitative) was obtained as a yellow solid from ethyl 5-acetyl-6-methylpyridine-3-carboxylate (561 mg, 2.71 mmol) obtained by the method described in Synthesis, vol. 5, p. 400 (1986).
  • DMF 0.5 ml
  • DIPEA diisopropylethylamine
  • DIPEA diisopropylethylamine
  • 5-acetyl-6-methylpyridine-3-carboxylic acid 93.2 mg, 0.520
  • the present invention can be utilized for the treatment and/or prophylaxis of, for example, movement disorders (specifically, for example, extrapyramidal syndrome, side effects of L-DOPA and/or dopamine agonist therapy and the like), or the treatment and/or prophylaxis of Parkinson's disease.
  • movement disorders specifically, for example, extrapyramidal syndrome, side effects of L-DOPA and/or dopamine agonist therapy and the like
  • prophylaxis of Parkinson's disease for example, movement disorders (specifically, for example, extrapyramidal syndrome, side effects of L-DOPA and/or dopamine agonist therapy and the like), or the treatment and/or prophylaxis of Parkinson's disease.

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US10214523B2 (en) 2015-01-09 2019-02-26 Kyowa Hakko Kirin Co., Ltd. Production method of thiazole derivative

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