Novel medical uses of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime

Abstract

The present invention relates to the compound golexanolone for use in the treatment of Parkinson's disease (PD) or for use in the treatment of L-dopa-induced dyskinesia (LID) in Parkinson's disease (PD) patients. Furthermore, the present invention relates to the compound golexanolone or a pharmaceutically acceptable salt thereof for use in the treatment of Parkinson's disease (PD) patients, particularly PD patients exhibiting L-dopa-induced dyskinesia (LID).

Description

Detailed Description of the Invention

[0001] [Field of the Invention] The present invention relates to the compound golexanolone for use in the treatment of Parkinson's disease (PD) or for use in the treatment of L-dopa-induced dyskinesia (LID) in Parkinson's disease (PD) patients. Furthermore, the present invention relates to the compound golexanolone for use in the treatment of Parkinson's disease (PD) patients, in particular PD patients exhibiting L-dopa-induced dyskinesia (LID).

[0002] [Background of the invention] Parkinson's disease (PD) is a degenerative brain disorder associated with motor symptoms (bradykinesia, tremor, muscle rigidity, gait, and balance disorders) and various non-motor complications (fatigue, cognitive impairment, psychiatric disorders such as depression and anxiety, sleep disorders, and other sensory disturbances) (Lewitt, AP. and Chaudhuri, KR. 2020. Parkinsonism and Related Disorders, 80:S7-S12). Movement disorders such as dyskinesia (involuntary movements) and dystonia (painful involuntary muscle contractions) contribute to limitations in speech, mobility, and many areas of life. Progression of these symptoms leads to increased rates of disability and the need for care. PD patients also frequently develop dementia during the course of the disease (WHO 13 June 2022: Parkinson's disease (who.int) .

[0003] Although PD is the most common movement disorder, other movement disorders include multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and atypical parkinsonian syndromes such as dementia with Lewy bodies (DLB) (Przewodowska, D. et al. 2021. Frontiers in Molecular Neuroscience. August 2021, Vol. 14, Article 720220). Some movement disorders share symptoms similar to PD, such as tremor, bradykinesia, and rigidity. All movement disorders share similar challenges to PD regarding diagnostic and treatment gaps and access to medicines, especially in low- and middle-income countries (LMICs) (WHO 13 June 2022: Parkinson's disease (who.int) .

[0004] Risk factors for PD include aging, although younger people can be affected as well. Men are more likely to be affected than women. The cause of PD is unknown, but it is thought to result from a complex interaction between genetic factors and lifelong exposure to environmental factors such as pesticides, solvents, and air pollution (WHO 13 June 2022: Parkinson's disease (who.int) Levo-dihydroxyphenylalanine (L-DOPA) is the most effective treatment for Parkinson's disease, but most patients develop uncontrollable, abnormal involuntary movements known as L-DOPA-induced dyskinesia (Nishijima H et al.: Neurobiology of Disease 143(2020);pp.1-13;104979).

[0005] Levodopa-induced dyskinesia (LID) is Parkinson's disease Used to treat Levodopa Related to (L-DOPA) dyskinesia Levodopa-induced dyskinesia is a type of Chorea , dystonia , and Athetosis Hyperkinesis, including cerebrospinal fluid (CFL), is often observed (Gerlach M et al.: December 2011; Journal of Neural Transmission. 118(12):1659-1660).

[0006] In the setting of Parkinson's disease (PD), dyskinesias often occur as a consequence of long-term dopamine therapy. These motor fluctuations occur in up to 80% of PD patients 5–10 years after initiating L-DOPA treatment (Ahlskog JE et al. 2001; Mov Disord. 16(3):448–458), with the proportion of affected patients increasing over time (Obeso JA et al. 2000; Neurology. 55(S4):S13–S20).

[0007] Given the relationship with levodopa administration, dyskinesias most commonly occur at peak L-DOPA plasma concentrations; Peak-dose dyskinesia This condition is called PDD (Procedure-Specific Disorders of the Diabetic Retinopathy). As the condition progresses, patients may develop symptoms of biphasic dyskinesia (DD), which occurs when drug concentrations increase or decrease, and "OFF" dystonia, which involves persistent spasms and posturing when L-DOPA exposure decreases (Fabbrini, A. and Guerra, A. 2021. Journal of Experimental Pharmacology, 13:469-485). If dyskinesia is very severe or reduces the patient's quality of life, L-dopa dosage reduction may be necessary, but this can lead to a deterioration in motor function and the onset of "OFF" dystonia. Therefore, once L-DOPA develops, it is difficult to treat (Thanvi B et al. 2007: Postgraduate Medical Journal, 83(980):384-388).

[0008] In 2017, the FDA approved amantadine (Gocovri®, Adamas Pharmaceuticals) as a first-line treatment for levodopa-induced dyskinesia (LID) in patients with Parkinson's disease.

[0009] Parkinson's disease (PD) is a neurodegenerative disorder involving multiple nervous systems, readily apparent from the wide variety of motor and non-motor symptoms that PD patients develop over time (Terkelsen, M.H. et al., 2022. Current Neurology and Neuroscience Reports., doi.org / 10.1007 / s11910-022-01245-z). However, the clinical diagnosis of PD is based on the typical motor symptoms of bradykinesia, rigidity, and resting tremor, which result from the loss of dopaminergic projections from the substantia nigra pars compacta (SNc) to the striatum, the primary input of the motor corticostriatal pathway. Parkinsonism is also a key feature of atypical parkinsonism, a highly heterogeneous group of neurodegenerative disorders, which may be misdiagnosed as PD in the early stages. In the basal ganglia, dopaminergic neurons in the substantia nigra pars compacta (SNc) regulate two neural pathways, the direct and indirect pathways, connecting the striatum and thalamus, reducing overall inhibitory output and thereby refining brain processing. Inhibitory projection neurons in both of these pathways, projection medium spiny neurons, and the output pathway of the globus pallidus use gamma-aminobutyric acid (GABA) as a transmitter. In fact, one-third of all brain synapses use GABA for inhibition.

[0010] Several reports support the idea that increased GABAergic neurotransmission contributes to the pathogenesis of Parkinson's disease and the associated motor symptoms. In particular, a report by Heo et al. (Curr. Biol. 2020 January 20; 30(2): 276-291) showed that GABA levels increased in the substantia nigra pars compacta, particularly in activated astrocytes, in an animal model of Parkinson's disease. Increased GABA levels lead to increased GABA levels. A The receptor activity is enhanced and neuronal expression of tyrosine hydroxylase is decreased, resulting in movement disorders in these animal models.

[0011] This effect occurs in neurons that have not yet died, and therefore, acting on these mechanisms can improve movement disorders and quality of life in patients. Heo et al. (Curr. Biol. 2020 Jan 20;30(2):276-291) also show that inhibiting MAOb (monoamine oxidase b) reduces GABA levels and restores neuronal expression of tyrosine hydroxylase, resulting in improvement of movement disorders. Expression of tyrosine hydroxylase is linked to the α5 subunit of GABA. A It can also be restored by blocking the receptors, so GABA A Enhanced receptor activity promotes inhibition of tyrosine hydroxylase expression and movement disorders.

[0012] Other reports support the idea that degeneration of the substantia nigra pars compacta spreads to other brain regions, leading to cerebellar degeneration (Wu et al. Brain. 2013 March;136(Pt 3):696-709; Rusholt et al. Brain Pathol. 2020 May;30(3):576-588). Cerebellar degeneration is associated with decreased tyrosine hydroxylase levels (Hurley et al. Eur J Neurosci. 2003 Nov;18(9):2668-2672), and the appearance of alpha-synuclein aggregates (Seidel et al., Ann Neurol. 2017 Jun;81(6):898-903), which are associated with anxiety (Wang et al., Transl Neurosci. 2021 Oct 29;12(1):415-424), motor function (Ballanger et al., J Neurol Neurosurg Psychiatry. 2008 Oct;79(10):1110-1116); (Lewis et al., Can J Neurol Sci. 2013 May;40(3):299-306); (Seidel et al., Ann Neurol. 2017 Jun;81(6):898-903), and cognitive impairment in patients and animal models of Parkinson's disease. Neurol. 2017 June;81(6):898-903).

[0013] In addition to motor impairments, patients and animal models of Parkinson's disease also exhibit cognitive dysfunction (Lindgren et al. Eur J Neurosci. 2012 June;35(12):1894-1907; (Leao et al., 2021 Behav Brain Res. 2021 July 23;410:113349); (Schneider et al.; Exp Neurol. 2021 January;335:113514); and (Tian et al.; Oxid Med Cell Longev. 2022 January 4;2022:2792348).

[0014] All neurodegenerative diseases are characterized by selective neuronal loss, which is associated with microglial and astrocytic activity (Dickson, DW Cold Spring Harb. Perspect. Med., 2(8), a009258, 2012). Neuroinflammation, associated with microglial and astrocytic activity, plays an important role in the pathogenesis of Parkinson's disease and other α-synucleinopathies (Kam TI, et al.; Neurobiol Dis. 2020 October; 144:105028; (Stefanova N; J. Parkinson's Dis., 12(s1), S105-S112; 2022); and (Chen K et al. Brain Sci., 13(4), 634; 2023). Neuroinflammation is associated with the accumulation and aggregation of α-synuclein (alphaSyn), a key pathological feature of Parkinson's disease.

[0015] The motor symptoms of Parkinson's disease are due to dopamine depletion caused by neurodegeneration and widespread loss of dopaminergic neurons in the substantia nigra, resulting in the loss of tyrosine hydroxylase (TH), the main dopamine-synthesizing enzyme (Zhou, ZD et al. 2022; Cell. Mol. Life Sci., 79(12), 599). The gold standard marker for identifying dopaminergic neurons is tyrosine hydroxylase (TH), and a decrease in TH is an indicator of dopaminergic neuron loss (Nagatsu T et al. J Neural Transm. 2019 Apr;126(4):397-409).

[0016] Furthermore, the pathogenesis of LID is complex, and various neurotransmitters, such as dopamine, glutamine, adenosine, and gamma-aminobutyric acid, play a key role in altering the normal physiological function of the direct and indirect pathways of the cortico-basal ganglia-thalamic loop, which is responsible for fine motor control (Pandey and Srivanitchapoom, 2017, Ann Indian Acad Neurol. 20:190-198). Several reports support the involvement of increased GABAergic neurotransmission in the pathogenesis of L-DOPA-induced dyskinesia in Parkinson's disease and the associated motor symptoms. In particular, a report from Nishijima et al. (Nishijima H et al.: Neurobiology of Disease 143(2020);pp.1-13;104979) showed that GABA levels in an animal model of Parkinson's disease were increased in the medial pallidum, which corresponds to the internal pallidum in humans.

[0017] Nishijima et al. (Nishijima H et al.: Neurobiology of Disease 143(2020);pp.1-13;104979) also showed that blocking GABAA receptors with the experimental GABAA receptor antagonist bicuculline alleviated LID in Parkinson's disease model rats pretreated with L-DOPA.

[0018] In summary, according to the classical basal ganglia network model, neuronal degeneration in the SNc (substantia nigra pars compacta) leads to an imbalance of GABA and glutamate neurotransmission in the nigrostriatal system in Parkinson's disease, resulting in movement disorders and other behavioral symptoms. This contrasts with liver diseases such as cirrhosis, in which increased blood ammonia levels and inflammation can lead to cerebellar dysfunction, resulting in ataxia, as described by Balzano et al. (Biomedicines. 2021 Aug 12;9(8):1002. doi:10.3390 / biomedicines9081002.).

[0019] The compound golexanolone, chemically named 3α-ethynyl-3β-hydroxyandrostan-17-one oxime, is currently undergoing Phase II clinical trials for the treatment of hepatic encephalopathy (HE). This compound is disclosed in International Publication No. WO 2008 / 063128 for use in various CNS disorders. International Publication No. WO 2015 / 114308 discloses the use of the compound 3α-ethynyl-3β-hydroxyandrostan-17-one oxime for the treatment of hepatic encephalopathy (HE). U.S. Patent Application Publication No. 2017 / 0348323 discloses a method for treating hypersomnia by administering the compound 3α-ethynyl-3β-hydroxyandrostan-17-one oxime. International Publication No. WO 2019 / 102040 discloses pharmaceutical formulations of the compound golexanolone. WO 2022 / 223526 discloses the compound 3α-ethynyl-3β-hydroxyandrostan-17-one oxime for use in chronic liver disease and associated symptoms.

[0020] [Description of the Invention] One aspect of the present invention is a compound of formula (I) for use in the treatment of Parkinson's disease (PD). [ka] The compound golexanolone (3α-ethynyl-3β-hydroxyandrostan-17-one oxime) of formula (I) or a pharmaceutically acceptable salt thereof.

[0021] In another embodiment of the invention, treatment is administered in Parkinson's disease (PD) patients who present with L-dopa-induced dyskinesia (LID).

[0022] A further aspect of the present invention is a compound of formula (I) for use in treating patients with Parkinson's disease (PD). [ka] The compound golexanolone (3α-ethynyl-3β-hydroxyandrostan-17-one oxime) of formula (I) or a pharmaceutically acceptable salt thereof.

[0023] In another embodiment of the present invention, the PD patient to be treated exhibits L-dopa-induced dyskinesia (LID).

[0024] A further aspect of the present invention is a compound of formula (I) for use in the treatment of L-dopa-induced dyskinesia (LID) in PD patients. [ka] The compound golexanolone (3α-ethynyl-3β-hydroxyandrostan-17-one oxime) of formula (I) or a pharmaceutically acceptable salt thereof.

[0025] In particular, the present invention relates to the following embodiments: i) A compound of formula (I) for use in the treatment of Parkinson's disease (PD) [ka] The compound golexanolone (3α-ethynyl-3β-hydroxyandrostan-17-one oxime) or a pharmaceutically acceptable salt thereof.

[0026] ii) The compound golexanolone for use according to i), wherein the treatment is carried out in Parkinson's disease (PD) patients presenting with L-dopa-induced dyskinesia (LID).

[0027] iii) A compound of formula (I) for use in treating patients with Parkinson's disease (PD) [ka] The compound golexanolone (3α-ethynyl-3β-hydroxyandrostan-17-one oxime) or a pharmaceutically acceptable salt thereof.

[0028] iv) The compound golexanolone for use according to iii), wherein Parkinson's disease (PD) patients present with L-dopa-induced dyskinesia (LID).

[0029] v) A compound of formula (I) for use in the treatment of L-dopa-induced dyskinesia (LID) in patients with Parkinson's disease (PD). [ka] The compound golexanolone (3α-ethynyl-3β-hydroxyandrostan-17-one oxime) or a pharmaceutically acceptable salt thereof.

[0030] vi) The compound golexanolone for use according to any one of i) to v), wherein Parkinson's disease (PD) comprises movement disorders.

[0031] vii) The compound golexanolone for use according to vi), wherein the movement disorder is selected from any one or combination of bradykinesia, tremor, posture, dexterity, gait and balance disorders, communication skills, rigidity, gait and balance disorders.

[0032] viii) The compound golexanolone for use according to vi), wherein the movement disorder is selected from any one or combination of bradykinesia, gait pattern and balance function, and gait and balance disorders.

[0033] ix) The compound golexanolone for use according to any one of claims i) to v), wherein the Parkinson's disease (PD) comprises non-motor complications.

[0034] x) The compound golexanolone for use according to ix), wherein the non-motor complication is selected from any one or combination of cognitive impairment, psychiatric disorders such as depression or anxiety, sleep disorders, pain and sensory disorders.

[0035] xi) The compound golexanolone for use according to ix), wherein the non-motor complication is selected from any one or combination of cognitive impairment, psychiatric disorders such as depression or anxiety, and sleep disorders.

[0036] xii) The compound golexanolone for use according to vi), wherein the movement disorder is dyskinesia (involuntary movements).

[0037] xiii) The compound golexanolone for use according to vi), wherein the movement disorder is dystonia (painful involuntary muscle contractions).

[0038] xiv) The compound golexanolone for use according to vi), wherein the movement disorder is bradykinesia and / or rigidity.

[0039] xv) The compound golexanolone for use according to vi), wherein the movement disorder is freezing of gait.

[0040] xvi) The compound golexanolone for use according to x) or xi), wherein the sleep disorder is excessive daytime sleepiness (EDS).

[0041] xvii) The compound golexanolone for use according to any one of ii), iv) or v), wherein the L-dopa-induced dyskinesia (LID) comprises hyperkinesia.

[0042] xviii) The compound golexanolone for use according to xvii), wherein the hyperkinesia comprises any one or combination of chorea, dystonia or athetosis.

[0043] xix) The compound golexanolone for use according to any one of ii), iv) or v), wherein the L-dopa-induced dyskinesia (LID) is peak dose dyskinesia (PDD).

[0044] xx) The compound golexanolone for use according to any one of ii), iv) or v), wherein the L-dopa-induced dyskinesia (LID) is biphasic dyskinesia (DD).

[0045] xxi) The compound golexanolone for use according to any one of ii), iv) or v), wherein the L-dopa-induced dyskinesia (LID) is off-dyskinesia.

[0046] xxii) A method for treating Parkinson's disease (PD), comprising administering to a patient of formula (I) [ka] or a pharmaceutically acceptable salt thereof to a subject in need of such treatment.

[0047] xxiii) The method according to xxii), wherein the subject exhibits L-dopa-induced dyskinesia (LID).

[0048] xxiv) A compound of formula (I) for the manufacture of a medicament for the treatment of Parkinson's disease (PD). [ka] 2. Use of the compound golexanolone (3α-ethynyl-3β-hydroxyandrostan-17-one oxime) or a pharmaceutically acceptable salt thereof.

[0049] xxv) The use according to xxiv), wherein the treatment is carried out in PD patients exhibiting L-dopa-induced dyskinesia (LID).

[0050] xxvi) A compound of formula (I) for the manufacture of a medicament for the treatment of patients with Parkinson's disease (PD). [ka] 2. Use of the compound golexanolone (3α-ethynyl-3β-hydroxyandrostan-17-one oxime) or a pharmaceutically acceptable salt thereof.

[0051] xxvii) The use according to xxvi), wherein the PD patient exhibits L-dopa-induced dyskinesia (LID). [Brief explanation of the drawings]

[0052] [Figure 1] FIG. 1 is a schematic diagram of the experimental design used herein with rats having various symptoms of Parkinson's disease (PD). [Figure 2A] FIG. 10 is a diagram showing fatigue test results. [Figure 2B] FIG. 10 is a diagram showing fatigue test results. [Figure 3A] FIG. 1 shows the results of a motor coordination test. [Figure 3B] FIG. 1 shows the horizontal ladder that rats have to cross in the catwalk test. [Figure 4A] FIG. 1 shows test results for the initial double support phase in the catwalk test. [Figure 4B] FIG. 1 shows test results for the initial double support phase in the catwalk test. [Figure 4C] FIG. 1 shows test results for the initial double support phase in the catwalk test. [Figure 5A] FIG. 1 shows test results for the swing phase of walking in the catwalk test. [Figure 5B] FIG. 1 shows test results for the swing phase of walking in the catwalk test. [Figure 6] FIG. 1 shows test results in the Object Place Memory Test (OLM). [Figure 7] FIG. 1 shows test results of a short-term spatial memory test. [Figure 8] FIG. 1 shows test results for anxiety tests. [Figure 9] FIG. 1 shows test results of depression tests. [Figure 10]FIG. 1 shows the results of a tyrosine hydroxylase (TH) study in 6-OHDA rats. [Figure 11] FIG. 1 shows the results of a study of α-synuclein in 6-OHDA rats. [Figure 12] FIG. 1 shows microglial activity in the striatum of 6-OHDA rats. [Figure 13] FIG. 1 shows astrocyte activity in the striatum of 6-OHDA rats. [Figure 14] FIG. 1 shows the rat experimental setup for L-dopa-induced dyskinesia (LID). [Figure 15] FIG. 1 shows the evaluation of AIM in L-dopa-induced dyskinesia (LID). [Figure 16] FIG. 1 shows all AIMs during the 3-hour period following placebo and golexanolone administration, respectively.

[0053] Throughout the figures, the following abbreviations used have the following meanings: SHAM VH or SMVH refers to sham-operated rats administered with vehicle. SHAM GR or SMGR refers to sham-operated rats administered with golexanolone. PARK VH or PKVH refers to Parkinson's disease rats administered with vehicle. PARK GR or PKGR refers to Parkinson's disease rats administered with golexanolone.

[0054] Detailed Description of the Invention One aspect of the present invention is a compound of formula (I) for use in the treatment of Parkinson's disease (PD). [ka] The compound golexanolone (3α-ethynyl-3β-hydroxyandrostan-17-one oxime) of formula (I) or a pharmaceutically acceptable salt thereof.

[0055] In another embodiment of the invention, treatment is carried out in Parkinson's disease (PD) patients who present with L-dopa-induced dyskinesia (LID).

[0056] A further aspect of the present invention is a compound of formula (I) for use in treating patients with Parkinson's disease (PD). [ka] The compound golexanolone (3α-ethynyl-3β-hydroxyandrostan-17-one oxime) of formula (I) or a pharmaceutically acceptable salt thereof.

[0057] In another embodiment of the present invention, the PD patient to be treated exhibits L-dopa-induced dyskinesia (LID).

[0058] A further aspect of the present invention is a compound of formula (I) for use in the treatment of L-dopa-induced dyskinesia (LID) in PD patients. [ka] The compound golexanolone (3α-ethynyl-3β-hydroxyandrostan-17-one oxime) of formula (I) or a pharmaceutically acceptable salt thereof.

[0059] One aspect of the present invention is the compound golexanolone for use in the treatment of Parkinson's disease (PD), including movement disorders.

[0060] One aspect of the present invention is the compound golexanolone for use in the treatment of Parkinson's disease (PD), including movement disorders selected from any one or combination of bradykinesia, tremor, posture, dexterity, gait and balance, communication skills, rigidity, freezing of gait, gait and balance disorders.

[0061] One aspect of the present invention is the compound golexanolone for use in the treatment of Parkinson's disease (PD), including non-motor complications.

[0062] One aspect of the present invention is the compound golexanolone for use in the treatment of Parkinson's disease (PD), including non-motor complications selected from any one or combination of cognitive impairment, psychiatric disorders such as depression or anxiety, sleep disorders, pain, and sensory disorders.

[0063] One aspect of the present invention is the compound golexanolone for use in the treatment of Parkinson's disease (PD), including the movement disorder dyskinesia (involuntary movements).

[0064] One aspect of the present invention is the compound golexanolone for use in the treatment of Parkinson's disease (PD), including the movement disorder dystonia (painful involuntary muscle contractions).

[0065] One aspect of the present invention is the compound golexanolone for use in the treatment of Parkinson's disease (PD), including the movement disorders bradykinesia or rigidity, or a combination of bradykinesia and rigidity.

[0066] One aspect of the present invention is the compound golexanolone for use in the treatment of L-dopa-induced dyskinesia (LID) in PD patients, including hyperkinesia.

[0067] One aspect of the present invention is the compound golexanolone for use in the treatment of L-dopa-induced dyskinesia (LID) in PD patients, including hyperkinesia selected from chorea, dystonia and athetosis, or a combination thereof.

[0068] One aspect of the present invention is the compound golexanolone for use in the treatment of L-dopa-induced dyskinesia (LID), which is peak dose dyskinesia (PDD) in PD patients.

[0069] One aspect of the present invention is the compound golexanolone for use in the treatment of L-dopa-induced dyskinesia (LID), a biphasic dyskinesia (DD) in PD patients.

[0070] One aspect of the present invention is the compound golexanolone for use in the treatment of L-dopa-induced dyskinesia (LID), an off-dyskinesia in PD patients.

[0071] One aspect of the present invention is the compound golexanolone for use in preventing or alleviating AIM (abnormal involuntary movements) in subjects with symptoms of L-dopa (levodopa)-induced dyskinesia (LID).

[0072] One aspect of the present invention is the compound golexanolone for use in Parkinson's disease, including sleep disorders such as excessive daytime sleepiness (EDS).

[0073] One aspect of the present invention is a method of treating Parkinson's disease (PD), comprising administering a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof to a subject in need of such treatment.

[0074] In one aspect of the invention, the subject to be treated exhibits L-dopa-induced dyskinesia (LID).

[0075] One aspect of the present invention is a method for the preparation of a compound of formula (I) for the treatment of Parkinson's disease (PD). [ka] The present invention relates to the use of the compound golexanolone (3α-ethynyl-3β-hydroxyandrostan-17-one oxime) of formula (I) or a pharmaceutically acceptable salt thereof.

[0076] In one aspect of the invention, treatment is carried out in PD patients who exhibit L-dopa-induced dyskinesia (LID).

[0077] One aspect of the present invention is a method for the preparation of a medicament for the treatment of patients with Parkinson's disease (PD), comprising administering to said patient a compound of formula (I) [ka] The present invention relates to the use of the compound golexanolone (3α-ethynyl-3β-hydroxyandrostan-17-one oxime) of formula (I) or a pharmaceutically acceptable salt thereof.

[0078] In one aspect of the present invention, the PD patient exhibits L-dopa-induced dyskinesia (LID).

[0079] definition As used throughout this specification and claims, the compound golexanolone refers to a compound of the chemical formula (I): [ka] It is a compound with the chemical name 3α-ethynyl-3β-hydroxyandrostan-17-one oxime,

[0080] The international nonproprietary name (INN) is "golexanolone" and the CAS number is 2089238-18-4.

[0081] Also included within the scope of this invention are pharmaceutically acceptable salts of the compound golexanolone for the uses described and claimed herein.

[0082] The compound golexanolone (3α-ethynyl-3β-hydroxyandrostan-17-one oxime) can be prepared according to the preparation method disclosed in WO 2008 / 063128.

[0083] The term Parkinson's disease (PD) is used herein as defined by the WHO as of June 13, 2022 (WHO 13 June 2022: Parkinson's disease (who.int)and refers to a degenerative brain disorder accompanied by motor symptoms (movement disorders) such as bradykinesia, tremor, rigidity, gait, and balance problems, or any combination thereof.

[0084] The term motor symptoms (movement disorders) refers to dyskinesias (involuntary movements) and dystonias (painful involuntary muscle contractions). Movement disorders may include bradykinesia, tremors, posture abnormalities, clumsiness, gait and balance abnormalities (equilibrium disorders), communication (speech) disorders, rigidity problems, or gait disorders, or any combination thereof.

[0085] The term dyskinesia refers to involuntary, irregular, jerking movements of the face, arms, legs, or trunk, and may include sustained muscle spasms, or any combination thereof.

[0086] Dyskinesia is a complication of treatment with anti-Parkinson's disease drugs, such as levodopa, and usually appears after several years of levodopa administration. This dyskinesia is defined as L-dopa (levodopa)-induced dyskinesia (LID).

[0087] The term AIM refers to abnormal involuntary movements that are symptoms of L-dopa (levodopa)-induced dyskinesia (LID), and includes axial AIM, limb AIM, migratory AIM, and orolingual AIM.

[0088] The term excessive daytime sleepiness (EDS) refers to the inability to maintain wakefulness and alertness during major waking episodes of the day, resulting in an irresistible desire to sleep or involuntary transitions into drowsiness or sleep.

[0089] The term dystonia refers to painful, involuntary muscle contractions.

[0090] As used herein, Parkinson's disease (PD) may further include non-motor complications such as fatigue, cognitive impairment, psychiatric disorders such as depression and anxiety, sleep disorders and pain, and other sensory disturbances, as described in LeWitt AP et al. 2020:Parkinsonism and Related Disorders, 80:S7-S12.

[0091] The term non-motor comorbidities as used herein is defined according to LeWitt AP et al. 2020:Parkinsonism and Related Disorders, 80:S7-S12 and includes any one or a combination of cognitive impairment, psychiatric disorders such as depression or anxiety, sleep disorders, pain, and sensory disorders.

[0092] The term L-dopa-induced dyskinesia (LID) includes hyperkinesia. LID can develop during long-term administration of levodopa. LID can also develop in patients with Parkinson's disease (PD) after short-term administration of levodopa for days or months.

[0093] L-dopa-induced dyskinesia (LID) is generally classified as peak-dose dyskinesia, wearing-off or off-phase dyskinesia, and biphasic dyskinesia. Examples of hyperkinesia include chorea, dystonia, and athetosis, or a combination thereof. The various types of dyskinesia in L-dopa-induced dyskinesia (LID) are defined in Annals of the Indian Academy of Neurology; Vol. 20; No. 3; July-September 2017; pp. 190-198 and Fabrini et al.: Journal of Experimental Pharmacology 2021:13; pp. 469-485.

[0094] The term peak-dose dyskinesia (PDD) refers to the most common type of dyskinesia (80%), which occurs at the peak of levodopa plasma concentrations and is characterized by stereotypic movements of the head, chorea of ​​the trunk, ballistic limb movements, and rarely myoclonus (involuntary jerking movements) which may involve the eye, respiratory, or abdominal muscles.

[0095] The term off-wearing, also called off-dyskinesia, is the second most common type (30%) of L-dopa-induced dyskinesia (LID), which typically manifests as morning dystonia before the first dose of levodopa and is usually accompanied by persistent jerking and posturing of the legs or feet.

[0096] The term biphasic dyskinesia (DD), also known as dyskinesia-improving dyskinesia (DID), is the least common type (20%), characterized by ipsilateral leg movements beginning 10-15 minutes after levodopa ingestion, followed by contralateral leg movements, followed by improvement of parkinsonian symptoms for several hours, with dyskinesia reappearing as levodopa levels decrease. This type of LID can occur when blood levels of levodopa increase or decrease.

[0097] The term athetosis refers to a condition characterized by slow, involuntary, complex, writhing movements of the fingers, hands, toes, and feet, and sometimes the arms, legs, neck, and tongue.

[0098] Pharmaceutical Formulations and Routes of Administration In certain aspects of the present invention, the compound golexanolone (3α-ethynyl-3β-hydroxyandrostan-17-one oxime), as used throughout this specification and claims, can be administered in the form of a pharmaceutical composition in admixture with one or more pharmaceutically acceptable adjuvants, diluents, and / or carriers. Examples of such pharmaceutically acceptable excipients, carriers, and / or diluents useful in formulating the compound golexanolone (3α-ethynyl-3β-hydroxyandrostan-17-one oxime) for use in accordance with the present invention are thickeners, flavorings, diluents, emulsifiers, dispersing agents, carrier substances, lubricants, or binders. Typical pharmaceutical carriers include, but are not limited to, binders (e.g., pregelatinized maize starch), excipients (e.g., lactose, glucose, sucrose and other sugars, microcrystalline cellulose, pectin, gelatin, calcium sulfate, ethyl cellulose, polyacrylates, or calcium hydrogen phosphate, and the like), lubricants (e.g., magnesium stearate, talc, silica, colloidal silicon dioxide, stearic acid, metallic stearates, hydrogenated vegetable oils, corn starch, polyethylene glycol, sodium benzoate, sodium acetate, and the like), disintegrants (e.g., starch and sodium starch glycolate), wetting agents, diluents, colorants, emulsifiers, pH buffers, preservatives, and mixtures thereof.

[0099] In one aspect of the present invention, the compound golexanolone (3α-ethynyl-3β-hydroxyandrostan-17-one oxime), when used as disclosed and claimed herein, can be administered enterally. Examples of enteral administration include administration to the esophagus, stomach, and small and large intestines (i.e., the digestive tract). Methods of administration include oral, sublingual (dissolving the drug under the tongue), and rectal.

[0100] This allows physicians to determine the actual dosage of the compound golexanolone (3α-ethynyl-3β-hydroxyandrostan-17-one oxime) that may be appropriate for an individual patient to treat Parkinson's disease (PD), including L-dopa-induced dyskinesia (LID). The dosage may vary depending on the route of administration, the severity of the disease, and the type of disease, age, weight, and sex of the patient.

[0101] In one aspect of the present invention, the compound golexanolone (3α-ethynyl-3β hydroxyandrostan-17-one oxime) can be administered in a daily dosage of 1 mg to 200 mg, 10 mg to 100 mg, 3 mg to 30 mg, 30 to 60 mg, 50 to 100 mg, 20 mg to 160 mg, 40 mg to 160 mg, or 80 mg to 160 mg.

[0102] The term "daily dose" can refer to the administration of the compound golexanolone (3α-ethynyl-3β-hydroxyandrostan-17-one oxime) once daily (QD) or twice daily (BID). Twice daily (BID) administration means that the total daily dose is divided into two doses that add up to the daily dose. For example, a daily dose of 1 mg to 200 mg may be administered as a 1 to 200 mg dose once daily (QD) or as a 0.5 to 100 mg dose twice daily (BID).

[0103] In one aspect of the invention, the daily dosage of the compound golexanolone (3α-ethynyl-3β hydroxyandrostan-17-one oxime) that may be useful according to the present invention may be selected from any one of 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, and 160 mg.

[0104] [Example] Manufacturing of the compound Golexanolone The compound golexanolone (3α-ethynyl-3β-hydroxyandrostan-17-one oxime) can be prepared according to the preparation method disclosed in WO 2008 / 063128.

[0105] Golexanolone formulations used in this study In the experiments described below, either vehicle or the compound golexanolone (3α-ethynyl-3β-hydroxyandrostan-17-one oxime) was used.

[0106] Golexanolone was administered to rats as a pharmaceutical formulation containing golexanolone incorporated into a mixture of capric / caprylic mono- and diglycerides (Capmul® MCM EP / NF; Barentz ApS Odense, Denmark).

[0107] (i) Golexanolone is administered at a dose of 50 mg / kg as a 1.25 mL / kg solution (40 mg / mL golexanolone in the mixture of capric / caprylic monoglycerides and diglycerides described above).

[0108] (ii) Vehicle (placebo) is the mixture of capric / caprylic mono- and diglycerides described above without golexanolone, administered in a volume of 1.25 mL / kg.

[0109] Biological evaluation Study design We use the 6-OHDA rat model described by Heo et al. (Curr. Biol. 2020 Jan 20;30(2):276-291) and Carvalho et al. (Mol. Neurodegener. 2013, 8:14: Behavioral characterization of the 6-hydroxypamine model of Parkinson's disease and pharmacological rescuing of non-motor deficits).

[0110] The 6-OHDA rat model 1) Whether daily administration of golexanolone improves motor symptoms (motor coordination, gait pattern) and non-motor symptoms (cognitive function, fatigue, anxiety, and depression) 2) whether golexanolone is associated with improved microglial and astrocyte activity, tyrosine hydroxylase (TH) expression, and reduced α-synuclein in the striatum; was used to assess the

[0111] Neuroinflammation, in relation to microglial and astrocytic activity, is a target for suppressing disease progression, while α-synuclein and tyrosine hydroxylase (TH) are pathophysiological biomarkers associated with neurodegeneration and dopaminergic neurons, respectively (Carvalho, MM 2013. Mol. Neurodegener., 8, 14: Behavioral characterization of the 6-hydroxydopamine model of Parkinson's disease and pharmacological rescuing of non-motor deficits).

[0112] Under general anesthesia, all rats received a unilateral injection of 8 μg of 6-OHDA (Sigma Aldrich) in 4 μL of saline containing 0.1% ascorbic acid into the right medial forebrain bundle (AP -2.2 mm, L +1.5 mm, V -8.0 mm from the dura, relative to bregma) (Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates. 4. San Diego, USA: Academic; 1998) with the tooth bar set at +4.5 mm.

[0113] To confirm the success of the 6-OHDA model, an apomorphine (0.25 mg / kg, subcutaneous, Sigma Aldrich)-induced rotation test was performed and manually counted. The inclusion criterion was >6 rpm.

[0114] I. Surgery: Unilateral 6-OHDA injury A unilateral 6-hydroxydopamine (6-OHDA) rat model was used, following Carvalho M et al. in Molecular Neurodegeneration 2013, 8:14; pp. 1–11.

[0115] Fifty-six 8-week-old male Wistar-Han rats (Charles River, Barcelona) were housed two per cage under standard laboratory conditions: 12-h light / dark cycle, 22°C room temperature, 55% relative humidity, and free access to food and water. All procedures were performed in accordance with local regulations (European Union Directive 2010 / 63 / EU).

[0116] Animals anesthetized with isoflurane (induction 5%, then 2%) were placed in a stereotaxic apparatus (Stoelting, USA) with atraumatic ear fixation rods, and vehicle (sham group, n = 20) or 6-OHDA hydrochloride (Sigma, USA) (6-OHDA group, n = 40) was injected directly into one side of the medial forebrain bundle (left hemisphere) using a Hamilton syringe (Hamilton Company, Switzerland) with a 30-gauge needle (Bregma reference coordinates, AP = -4.4 mm, ML = -1.0 mm, DV = -7.8 mm according to (Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates. 4. San Diego, USA: Academic; 1998).

[0117] Sham-operated animals received 2 μl of 0.2 mg / ml ascorbic acid in 0.9% NaCl, and 6-OHDA animals received 2 μl of 6-OHDA hydrochloride (4 μg / μl) containing 0.2 mg / ml ascorbic acid in 0.9% NaCl at a rate of 1 μl / min. After injection, the syringe was left in place for 10 min to allow diffusion. II. Experimental design to verify the effect of golexanolone on Parkinson's disease (PD) symptoms The experimental design is illustrated in Figure 1.

[0118] Twenty rats with a positive apomorphine-induced rotation test were enrolled in the study along with 20 sham-operated controls. Four weeks after surgery, golexanolone (50 mg / kg, intragastrically administered daily) and vehicle administration as a negative control were initiated. The apomorphine test is well known as an indicator of therapeutic response to dopaminergic agents and is a reliable evaluation tool for the differential diagnosis of Parkinson's disease. The rats were divided into four groups: sham-operated rats administered vehicle, sham-operated rats administered golexanolone, Parkinson's disease rats administered vehicle, and Parkinson's disease rats administered golexanolone.

[0119] The following symptoms were evaluated in Parkinson's disease rats.

[0120] Example 1 Fatigue was assessed on a treadmill consisting of a motorized conveyor belt separated into two parallel compartments by an electric grid. To avoid foot shocks (0.5 mV, 1 mA, 0.3 Hz), animals had to walk forward without falling off the belt. Animals were pretrained at room temperature for 1 day, allowing the first 3 minutes of inactivity for exploration. Then, animals were trained at 10 cm / s for 5 minutes, followed by 20 cm / s for 5 minutes. Testing took place the following day. Animals were placed on a stationary belt with a 5° incline, and the speed was gradually increased to 30 cm / s over 5 minutes, and maintained at that speed for another 15 minutes (total 20 minutes). Time spent on the belt was measured by a sensor. The values ​​recorded during the final 15 minutes of each test (as well as the time spent falling onto the grid) were recorded. (Butterworth RF, Lalonde R, Power C, Baker GB, Gamrani H, Ahboucha S. Dehydroepiandrosterone sulphate improves cholestasis-associated fatigue in bile duct ligated rats. Neurogastroenterol Motil. December 2009;21(12):1319~1325).

[0121] A reduction in treadmill time (A) indicates increased fatigue, which is also reflected in the prolonged duration of exposure to the electric shock (B). As shown in Figure 2A and Figure 2B, golexanolone improved fatigue 5 weeks after surgery and 9 days after golexanolone administration.

[0122] Example 2 Motor coordination was assessed using the Motorater test (Zorner B, Filli L, Starkey ML, Gonzenbach R, Kasper H, Rothlisberger M, et al. Profiling locomotor recovery: comprehensive quantification of impairments after CNS damage in rodents. Nat Methods. 2010;7(9):701-708). In this test, rats are required to traverse a horizontal ladder (Figure 3B). Motor function is then analyzed kinematically using a MotoRater device (TSE Systems, Germany). Briefly, rats were trained to traverse an illuminated glass-enclosed rung and reach a dark escape box at the end. 24 hours later, rats were asked to traverse the ladder. Their movements during the test were recorded from the bottom with a mobile high-speed camera at 200 frames per second. The number of failed attempts to place their feet on the ladder rungs was counted. Figure 3A shows the results in Parkinson's disease rats 7 weeks after surgery and 3 weeks after treatment. As shown in Figure 3A, rats treated with golexanolone made fewer mistakes while crossing the ladder than did rats in the control group.

[0123] Experimental Example 3 Motor coordination was further investigated using the Catwalk system (Lucas EK, Reid CS, McMeekin LJ, Dougherty SE, Floyd CL, Cowell RM. Cerebellar transcriptional alterations with Purkinje cell dysfunction and loss in mice lacking PGC-1α. Front Cell Neurosci. 2015;8:441) (Examples 3 and 4). The CatWalk™ system measures various aspects of gait patterns. Multiple parameters are calculated based on the position, pressure, and surface area of ​​each paw. Trials in which the animal remained stationary or turned were excluded from subsequent analysis. Trials were performed three times consecutively. CatWalk analysis software (version 7.1) was used to assign names to footprints and analyze the data. The initial double support phase was evaluated using the catwalk test. The initial double support distance is the time during which both hind or forepaws simultaneously contact the ground during each walk. As shown in Figures 4A, 4B, and 4C, golexanolone improved the initial double support phase in the catwalk test.

[0124] Example 4 The swing phase of walking was assessed using the catwalk test. Figures 5A and 5B show the effects in Parkinson's disease rats 7 weeks after surgery and 3 weeks after treatment. The swing phase is the time when one foot is not in contact with the ground. As shown in Figure 5, rats treated with golexanolone showed improved swing phase. The increase in the initial double support phase and the decrease in the swing phase indicate that Parkinson's disease rats spend less time with their feet raised in each step than sham-operated rats. Golexanolone improves this change.

[0125] Example 5 The object place memory (OLM) test assesses spatial location memory. Rats are placed in a room containing two identical objects. After two hours, one object is replaced. Analysis is performed based on the time spent exploring each object. The discrimination ratio is calculated as (exploration time for the object in the novel location - exploration time for the object in the familiar location) / total object exploration time. A lower ratio indicates impaired spatial location memory. As shown in Figure 6, Parkinson's disease rats treated with golexanolone performed better than the control group, suggesting that golexanolone improves object place memory (OLM). This test was performed 6 weeks after surgery and 2 weeks after treatment.

[0126] Example 6 Rats are asked to explore a Y-maze with one of the three arms closed. The closed arm is then opened, and the rat is returned to the maze after one minute. They should explore the newly opened arm for longer. If short-term memory is impaired, the preference for the "new" arm decreases. We calculate the ratio (time spent in the new arm - time spent in the existing arm) / total exploration time. A lower ratio indicates a worsening of short-term spatial memory. This test was conducted 7 weeks after surgery and 3 weeks after administration. This is shown in Figure 7.

[0127] Example 7 Anxiety was assessed by measuring the time the rats spent in the center of the box, rather than near the walls where they felt safer, during a 5-minute period in the open arena. A shorter time in the center indicates increased anxiety-like behavior. This test was conducted 5 weeks after surgery and 10 days after administration. As shown in Figure 8, golexanolone-administered rats showed improved anxiety.

[0128] Example 8 This test was conducted 7 weeks after surgery and 3 weeks after administration. The sucrose preference test evaluates anhedonia, a depressive symptom. This test consists of measuring the preference for drinking a 1% sucrose solution compared to water. The sucrose preference test is conducted after the rats have been fasted overnight. The percentage of ml of sucrose solution consumed out of the total ml of liquid consumed over a 2-hour period is shown. In rats, a decreased preference for sucrose solution indicates anhedonia (depression). As shown in Figure 9, rats treated with golexanolone showed improved depression.

[0129] Example 9 Analysis of tyrosine hydroxylase content Analysis of tyrosine hydroxylase (TH) was performed according to Heo et al. (Curr. Biol. 2020, Jan. 20;30(2):276-291). Immunohistochemical staining for TH was performed 5 weeks after surgery.

[0130] Five weeks after surgery, TH staining in the striatum of 6-OHDA rats was reduced (36±4% of the sham-operated group, p<0.0001). Golexanolone administration significantly prevented the reduction in TH staining in 6-OHDA rats (62±11% of the sham-operated group, p<0.05 compared with untreated 6-OHDA rats, p<0.01 compared with the sham-operated group). The results are shown in Figure 10.

[0131] Example 10 Analysis of α-synuclein content by Western blotting Alpha-synuclein content was analyzed by Western blotting. Animals were euthanized by decapitation 10 weeks after surgery. The striatum was dissected and homogenized by sonication. Samples were electrophoresed and immunoblotted using an alpha-synuclein antibody (1:1000, Proteintech) according to Felipo et al.; "Induction of rat brain tubulin following ammonium ingestion." J. Neurochem.; 51(4), pp. 1041–1405. Membranes were scanned using a ScanJet 5300C (Hewlett-Packard, Amsterdam, The Netherlands), and band intensity was quantified using an Alpha Imager 2200 version 3.1.3 (Alpha Innotech Corporation). Results are expressed as a percentage of the sham-operated group.

[0132] Ten weeks after surgery, α-synuclein levels were increased in the lesioned striatum of 6-OHDA rats (195±35% of the sham-operated group, p<0.05). The increase in α-synuclein was suppressed by golexanolone (99±9% of the sham-operated group, p<0.05 compared to untreated 6-OHDA rats). The results are shown in Figure 11.

[0133] Example 11 Analysis of microglial activity In a Parkinson's disease model, microglial activity was analyzed 5 weeks after surgery by measuring the perimeter of individual Iba1-stained cells using IpWin2 software. Microglia were significantly activated in the injured striatum of 6-OHDA rats at 5 weeks (217 ± 8 μm, p < 0.05 compared with 254 ± 1 μm in the sham-operated group). Golexanolone suppressed microglial activity in the injured striatum at 5 weeks (250 ± 8 μm, p < 0.05 compared with untreated 6-OHDA rats). The results are shown in Figure 12.

[0134] Example 12 Analysis of astrocyte activity Astrocyte activity was assessed 5 weeks after surgery by measuring the total GFAP-positive area using Image J software. The results were expressed as a percentage of the sham-operated group.

[0135] Astrocyte activity in the striatum was analyzed by immunohistochemistry. Astrocytes were significantly activated in the injured striatum of 6-OHDA rats (123±10% of the sham-operated group, p<0.05), and golexanolone inhibited the increase in astrocyte activity (92±4% of the sham-operated group, p<0.05 compared with untreated 6-OHDA rats). The results are shown in Figure 13.

[0136] Example 13 The ability of golexanolone to reduce or eliminate L-dopa-induced dyskinesia (LID) was analyzed, and this study is depicted in Figure 14.

[0137] L-dopa-induced dyskinesia (LID) was induced in a rat model described by Loiodice et al. in ACS Chem Neurosci. 2018 Apr 18;9(4):762-772. Abnormal involuntary movements (AIMs) were measured.

[0138] Rats with a positive apomorphine test were administered L-DOPA daily starting 4 weeks after surgery and orally administered golexanolone starting 7 weeks after surgery. The experimental setup is shown in Figure 14.

[0139] The experiment included the following groups: 1) L-DOPA- and vehicle-administered 6-OHDA rats, 2) Golexanolone- and L-DOPA-treated 6-OHDA rats (n=12 per group). AIM expression was analyzed after 6 weeks of daily L-DOPA injections and 3 weeks of golexanolone treatment as described in Lundblad M et al.; Eur J Neurosci. 2002 Jan;15(1):120-132 and Loiodice et al. in ACS Chem Neurosci. 2018 Apr;9(4):762-772.

[0140] Axial, limb, oral-lingual, and locomotor AIMs were assessed. As shown in Figure 15, L-DOPA was injected 1 hour after daily golexanolone administration, and AIMs were analyzed every 20 minutes for a total of 3 hours.

[0141] Figure 16 shows the time course of all AIMs (axial, limb, oral-lingual, and locomotor) over a 3-hour period. As shown in this graph, animals treated with golexanolone had fewer AIMs than those treated with L-DOPA alone.

[0142] statistical analysis Data are expressed as mean ± SEM. All statistical analyses were performed using GraphPad Prism software version 9.0. Data were tested for normality (Kolmogorov-Smirnov or Shapiro-Wilk test) and homogeneity of variance. Statistical analysis was performed using one-way analysis of variance and Tukey's or Fisher's multiple comparison test, or two-way analysis of variance, when appropriate. When data did not pass the normality test, the nonparametric Kruskal-Wallis test was used, and Dunn's test was used for multiple comparisons. When standard deviations (SD) were not equal, Welch's analysis of variance was used.

Claims

1. A compound of formula (I) for use in the treatment of Parkinson's disease (PD) 【Chemistry 1】 The compound golexanolone (3α-ethynyl-3β-hydroxyandrostan-17-one oxime) of formula (I) or a pharmaceutically acceptable salt thereof.

2. The compound golexanolone for use according to claim 1, wherein said treatment is carried out in Parkinson's disease (PD) patients presenting with L-dopa-induced dyskinesia (LID).

3. A compound of formula (I) for use in treating patients with Parkinson's disease (PD) 【Chemistry 2】 The compound golexanolone (3α-ethynyl-3β-hydroxyandrostan-17-one oxime) of formula (I) or a pharmaceutically acceptable salt thereof.

4. The compound golexanolone for use according to claim 3, wherein said Parkinson's disease (PD) patient presents with L-dopa-induced dyskinesia (LID).

5. 1. A compound of formula (I) for use in the treatment of L-dopa-induced dyskinesia (LID) in patients with Parkinson's disease (PD). 【Transformation 3】 The compound golexanolone (3α-ethynyl-3β-hydroxyandrostan-17-one oxime) of formula (I) or a pharmaceutically acceptable salt thereof.

6. The compound golexanolone for use according to any one of claims 1 to 5, wherein Parkinson's disease (PD) comprises movement disorders.

7. 7. The compound golexanolone for use according to claim 6, wherein said movement disorder is selected from any one or combination of bradykinesia, tremor, posture, dexterity, gait and balance disorders, communication skills, muscle rigidity, gait and balance disorders.

8. 7. The compound golexanolone for use according to claim 6, wherein said movement disorder is selected from any one or combination of bradykinesia, gait and balance function, and gait and balance disorders.

9. The compound golexanolone for use according to any one of claims 1 to 5, wherein the Parkinson's disease (PD) includes non-motor complications.

10. 10. The compound golexanolone for use according to claim 9, wherein said non-motor complication is selected from any one or combination of cognitive impairment, psychiatric disorders such as depression or anxiety, sleep disorders, pain and sensory disorders.

11. 10. The compound golexanolone for use according to claim 9, wherein said non-motor complication is selected from any one or combination of cognitive impairment, psychiatric disorders such as depression or anxiety, and sleep disorders.

12. The compound golexanolone for use according to claim 6, wherein said movement disorder is dyskinesia (involuntary movements).

13. The compound golexanolone for use according to claim 6, wherein said movement disorder is dystonia (painful involuntary muscle contractions).

14. The compound golexanolone for use according to claim 6, wherein said movement disorder is bradykinesia and / or rigidity.

15. 7. The compound golexanolone for use according to claim 6, wherein said movement disorder is freezing of gait.

16. 12. The compound golexanolone for use according to claim 10 or 11, wherein said sleep disorder is excessive daytime sleepiness (EDS).

17. 6. The compound golexanolone for use according to any one of claims 2, 4 or 5, wherein said L-dopa-induced dyskinesia (LID) comprises hyperkinesia.

18. 18. The compound golexanolone for use according to claim 17, wherein said hyperkinesia comprises any one or combination of chorea, dystonia or athetosis.

19. The compound golexanolone for use according to any one of claims 2, 4 or 5, wherein said L-dopa-induced dyskinesia (LID) is peak dose dyskinesia (PDD).

20. The compound golexanolone for use according to any one of claims 2, 4 or 5, wherein said L-dopa-induced dyskinesia (LID) is diphasic dyskinesia (DD).

21. The compound golexanolone for use according to any one of claims 2, 4 or 5, wherein said L-dopa-induced dyskinesia (LID) is off-dyskinesia.

22. A method for treating Parkinson's disease (PD), comprising administering to a patient a compound of formula (I): 【Chemistry 4】 or a pharmaceutically acceptable salt thereof to a subject in need of such treatment.

23. 23. The method of claim 22, wherein the subject exhibits L-dopa-induced dyskinesia (LID).

24. A compound of formula (I) for the manufacture of a medicament for the treatment of Parkinson's disease (PD). 【Transformation 5】 The use of the compound golexanolone (3α-ethynyl-3β-hydroxyandrostan-17-one oxime) of formula (I) or a pharmaceutically acceptable salt thereof.

25. 25. The use according to claim 24, wherein the treatment is in PD patients presenting with L-dopa-induced dyskinesia (LID).

26. A compound of formula (I) for the manufacture of a medicament for the treatment of patients with Parkinson's disease (PD). 【Transformation 6】 The use of the compound golexanolone (3α-ethynyl-3β-hydroxyandrostan-17-one oxime) of formula (I) or a pharmaceutically acceptable salt thereof.

27. 27. The use according to claim 26, wherein the PD patient exhibits L-dopa-induced dyskinesia (LID).

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