阅读说明：本技术 用于治疗共核蛋白病的nk1-拮抗剂组合和方法 (NK 1-antagonist combinations and methods for treating synucleinopathies ) 是由 T·N·蔡斯 K·E·克拉伦斯-史密斯 于 2018-04-09 设计创作，主要内容包括：本发明描述了NK1-拮抗剂与6-丙基氨基-4,5,6,7-四氢-1,3-苯并噻唑-2-胺组合的用途,其通过使治疗有效的6-丙基氨基-4,5,6,7-四氢-1,3-苯并噻唑-2-胺日剂量发挥作用而没有普拉克索二盐酸盐一水合物单独施用时引起的典型的不良作用来促进治疗患有共核蛋白病的患者。(The present invention describes the use of an NK 1-antagonist in combination with 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine to facilitate treatment of patients with synucleinopathies by allowing a therapeutically effective daily dose of 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine to act without the typical adverse effects caused by pramipexole dihydrochloride monohydrate when administered alone.)

1. A method for treating synucleinopathy in a patient, the method comprising administering to the patient in need of such treatment an effective daily dose of an NK 1-antagonist in combination with an effective daily dose of 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine.

2. The method of claim 1, wherein the effective daily dose of the NK 1-antagonist is from 1 μ g to 600 mg.

3. The method of claim 1, wherein the effective daily dose of the NK 1-antagonist is 1mg to 600 mg.

4. The method of claim 1, wherein the NK 1-antagonist is aprepitant or a pharmaceutically acceptable salt or solvate thereof.

5. The method of claim 1, wherein the NK 1-antagonist is rolipidem or a pharmaceutically acceptable salt or solvate thereof.

6. The method of claim 1, wherein the NK 1-antagonist is aprepitant and the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine is pramipexole dihydrochloride monohydrate.

7. The method of claim 1, wherein the NK 1-antagonist is aprepitant and the effective daily dose is 10mg to 250mg and the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine is pramipexole dihydrochloride monohydrate and the effective daily dose is 1.5mg to 45 mg.

8. The method of claim 1, wherein the NK 1-antagonist and the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine are each formulated as a pharmaceutical composition in dosage unit form comprising the NK 1-antagonist and the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine, respectively, each in admixture with a pharmaceutical carrier or vehicle.

9. The method of claim 1, wherein the NK 1-antagonist and the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine are each formulated as a pharmaceutical composition in dosage unit form comprising each in admixture with a pharmaceutical carrier or vehicle,

the NK 1-antagonist in an amount per unit form of 1 μ g to 600 mg; and

the amount of 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine per unit form is 0.125mg to 3000 mg.

10. The method of claim 1, wherein the NK 1-antagonist and the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine are each formulated as a pharmaceutical composition in dosage unit form, said pharmaceutical compositions comprising said NK 1-antagonist and said 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine, respectively, the amount of the NK 1-antagonist per unit form is 1mg to 600mg, and the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine is pramipexole dihydrochloride monohydrate, which is in an amount per unit form of greater than 4.5mg to 45 mg.

11. The process of claim 10, wherein the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine is pramipexole dihydrochloride monohydrate in an amount per unit form of from greater than 6mg to 45 mg.

12. The process of claim 10, wherein the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine is pramipexole dihydrochloride monohydrate in an amount per unit form from 6.5mg to 45 mg.

13. The method of claim 1, wherein the NK 1-antagonist and the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine are co-formulated into a pharmaceutical composition in dosage unit form comprising the NK 1-antagonist and the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine in an amount of from 1 μ g to 600mg per unit form of the NK 1-antagonist and from 0.125mg to 3000mg per unit form of the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine, in admixture with a pharmaceutical carrier or vehicle.

14. The method of claim 1, wherein said NK 1-antagonist and said 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine are co-formulated into a pharmaceutical composition in dosage unit form comprising said NK 1-antagonist and said 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine in an amount of 1 μ g to 600mg per unit form of said NK 1-antagonist, said 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine being selected from pramipexole and pharmaceutically acceptable salts and solvates thereof, in an amount per unit form equivalent to 0.125mg to 45mg of pramipexole dihydrochloride monohydrate.

15. The method of claim 14, wherein in the composition the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine is pramipexole dihydrochloride monohydrate in an amount per unit form of from greater than 4.5mg to 45 mg.

16. The method of claim 14, wherein in the composition the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine is pramipexole dihydrochloride monohydrate in an amount per unit form of from greater than 6mg to 45 mg.

17. The method of claim 14, wherein, in said composition, said NK 1-antagonist is aprepitant in an amount per unit form of 10 to 250 mg; the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine is pramipexole dihydrochloride monohydrate in an amount of 0.125mg to 45mg per unit form.

18. The method of claim 1, wherein the synucleinopathy is selected from the group consisting of parkinson's disease, Lewy body dementia, a glucocerebrosidase gene mutation, alzheimer's disease, Lewy body variants of alzheimer's disease, multiple system atrophy, neurodegeneration caused by brain iron accumulation, and parkinson's disease associated with a Glucocerebrosidase (GBA) mutation.

19. A pharmaceutical composition in dosage unit form comprising, in admixture with a pharmaceutical carrier or vehicle:

(a) an NK 1-antagonist in an amount per unit form of 1 μ g to 600 mg; and

(b) 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine selected from:

-the racemate or a pharmaceutically acceptable salt thereof, in an amount corresponding, per unit form, to 0.25mg to 90mg of pramipexole dihydrochloride monohydrate;

-pramipexole or a pharmaceutically acceptable salt thereof in an amount equivalent to 0.125mg to 45mg pramipexole dihydrochloride monohydrate; and

the amount of (R)/(S) -mixture per unit form is between 50mg and 3000mg, including the amount of (S) -enantiomer per unit form corresponding to between 0.125mg and 45mg pramipexole dihydrochloride monohydrate.

20. The composition of claim 19, wherein the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine is pramipexole or a pharmaceutically acceptable salt thereof in an amount per unit form equivalent to greater than 4.5mg to 45mg pramipexole dihydrochloride monohydrate.

21. The composition of claim 19, wherein the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine is pramipexole or a pharmaceutically acceptable salt thereof in an amount per unit form equivalent to greater than 6mg to 45mg pramipexole dihydrochloride monohydrate.

22. The composition of claim 19, wherein the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine is pramipexole or a pharmaceutically acceptable salt thereof in an amount per unit form equivalent to 6.5mg to 45mg pramipexole dihydrochloride monohydrate.

23. The composition of claim 19, wherein the NK 1-antagonist is aprepitant in an amount per unit form of 10 to 250 mg; the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine is pramipexole dihydrochloride monohydrate in an amount of 0.125mg to 45mg per unit form.

Technical Field

The present invention relates to the field of the treatment of synucleinopathies, i.e. neurodegenerative diseases of the human central nervous system, and in particular to the treatment of neurotoxic processes due to α -synuclein oligomerization and aggregation.

Objects of the invention

The present invention relates to pharmaceutical combinations (including fixed dose combinations) comprising 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof and a neurokinin receptor subtype 1 antagonist ("NK 1-antagonist"), and their use for the treatment of synucleopathies, in particular the CNS neurotoxic effects of alpha-synuclein in human subjects exhibiting abnormal plasma exosome/total alpha-synuclein ratios in the blood.

Definition of

- "CNS": the central nervous system.

- "IR": immediate release of the active ingredient from the composition.

- "ER": prolonged release of the active ingredient from the composition.

- "GI": gastrointestinal.

- "AE": adverse reaction.

- "SNCA Gene": a synuclein-alpha gene or an alpha-synuclein gene.

- "MSA": multiple systems atrophy.

- "PD": parkinson's disease.

- "LBD": dementia with Lewy bodies.

- "AD": alzheimer's disease.

- "Coucleinopathies": diseases characterized by abnormal accumulation, processing and spread of alpha-synuclein (alpha-synuclein) within the brain. That is, α -synuclein is deposited in the central, peripheral and autonomic nervous systems. Synucleinopathies (also known as α -synucleinopathies) are neurodegenerative diseases, including but not limited to parkinson's disease, dementia with Lewy Bodies (LBD) or dementia with Lewy bodies (DLB), alzheimer's disease, Lewy body variants of AD, multiple system atrophy, neurodegeneration caused by brain iron accumulation, and parkinson's disease associated with Glucocerebrosidase (GBA) mutations.

- "TTS": transdermal therapeutic systems.

"effective daily dose of NK 1-antagonist": as used herein, the expression refers to a dose of the NK 1-antagonist that is at least as high as the dose used to prevent or treat nausea and vomiting in a pediatric or adult patient receiving cancer chemotherapy according to the regimen currently used for such treatment. The daily dose is usually 1mg to 600 mg.

- "6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine": a chiral compound, obtainable in the form of: racemate, chemical name is (R, S) -6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine; (R) -stereoisomer, chemical name (R) -6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine ("d-pramipexole", INN); and the (S) -stereoisomer, whose chemical name is (S) -6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine ("pramipexole", INN). These three chemical entities are basic materials that can be isolated as their acid addition salts and solvates, respectively. Pramipexole dihydrochloride monohydrate is also known as its USAN "pramipexole hydrochloride". As used herein, "6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine" is a general term and, unless otherwise specified, refers to a member selected from the group consisting of pramipexole, the racemate, and a pramipexole/dexpramipexole mixture.

- "(R)/(S) -mixture": the term denotes a physical mixture of dexpramipexole/pramipexole for use as an active ingredient according to the invention.

- "(S) -enantiomer": this term is used herein with respect to the dose (daily or per unit form) of 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine which means that the (S) -stereoisomer included in the dose is primarily responsible for the dopaminergic effect counteracted by the NK 1-antagonist at the dose of the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine form. More specifically, the S-enantiomer is used herein to denote the S-stereoisomer present as racemate or a pharmaceutically acceptable salt thereof, and is similarly used to denote pramipexole or a pharmaceutically acceptable salt thereof present in the (R)/(S) -mixture as the (S) -component, to distinguish it from pramipexole used alone.

The terms "6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine", "(R) -6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine", "d-pramipexole", "S) -6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine", "(S) -enantiomer", "racemate" and "(R)/(S) -mixture" include the free base and pharmaceutically acceptable salts thereof (unless otherwise specified); the relative doses (daily or per unit form) are given as equivalents of pramipexole dihydrochloride monohydrate.

"effective daily dose of pramipexole" or of the "(S) -enantiomer": a daily dose of pramipexole or its pharmaceutically acceptable salts and solvates effective in pediatric or adult humans that is at least equivalent to a daily dose of pramipexole dihydrochloride monohydrate approved for the treatment of PD.

- "effective pramipexole amount per unit form" or (S) -effective amount per unit form of the enantiomer ": pramipexole or a pharmaceutically acceptable salt or solvate thereof in an amount per unit form that is at least equivalent to the amount of pramipexole dihydrochloride monohydrate per unit form approved for the treatment of PD. More specifically, said amount per unit form corresponds to 0.125mg to 45mg of pramipexole dihydrochloride monohydrate. As described above and as used herein, "pramipexole" and "(S) -enantiomer" refer to the same chemical entity, but the term "(S) -enantiomer" is generally used when describing the composition of the racemate and the (R)/(S) -mixture.

Background

Alpha-synuclein is a 140 amino acid protein encoded by the SNCA gene, expressed in large amounts in the human brain, mainly at the ends of neurons, especially in the cortex, hippocampus, substantia nigra and cerebellum, where it helps to regulate neurotransmitter release and is secreted in the blood (Marques and Outeiro,2012), packaged in CNS-derived exosomes (Shi et al, 2014).

Under normal conditions, this soluble protein forms a stably folded tetramer that is resistant to aggregation. However, in certain pathological cases, for unknown reasons, α -synuclein oligomerizes and aggregates (with fibril formation or "fibrillation"), and its conformation therefore changes in an abnormal manner to a tertiary toxic conformation, also secreted in the blood.

Alpha-synuclein oligomerization and aggregation are thought to be responsible for synucleinopathies, particularly PD, LBD, Parkinson's disease associated with mutations in the glucocerebrosidase Gene (GBA), MSA, some forms of Alzheimer's disease, and several other diseases, collectively referred to as "synucleinopathies". Alpha-synuclein is a ubiquitous protein, particularly abundant in the brain, and is thought to play a central role in the pathogenesis of Parkinson's Disease (PD), Alzheimer's disease, and other neurodegenerative diseases (Kim et al 2004).

Abnormal plasma exosome/total alpha-synuclein ratio in the patient's blood is a diagnostic marker for synucleinopathies.

PD is a common neurodegenerative disease of the human CNS, first described by James Parkinson in 1817. It has three major clinical signs: resting tremor, bradykinesia, and muscular rigidity. In addition, postural instability and various neurobehavioral disorders may occur. In the united states alone, it is estimated that more than one million people are afflicted with this relentless progressive disease. Furthermore, as the U.S. population generally ages, PD prevalence continues to rise. It is now believed that signs of parkinson reflect to a large extent the progressive loss of dopaminergic neurons within the nigrostriatal system. The reason for this degenerative process is not completely understood, but now appears to involve misprocessing of alpha-synuclein into abnormal neurotoxic substances.

Dementia with Lewy bodies (Lewy body dementia, LBD) is one of the most common types of progressive dementia. The main features of LBD include progressive cognitive decline, hallucinations, and parkinsonian motor symptoms such as bradykinesia, difficulty walking, and myotonia. Some people may also suffer from depression. Symptoms of LBD are due to the selective loss of nerve cells, which may be the result of misprocessing of synuclein and are associated with the establishment of Lewy bodies (accumulation of globular synuclein within many degenerated neurons). The investigators did not know why alpha-synuclein accumulated into Lewy bodies or how the synuclein material could cause LBD symptoms. Formation of LBD has been considered as a marker for PD; however, LBD (Al-Mansoor et al.2013) is also observed in as many as 60% of sporadic and familial cases of Alzheimer's Disease (AD). Thus, it has been strongly suggested that aggregation of α -synuclein is a key step in the development of neurodegenerative diseases (Al-Mansoor et al.2013).

Sporadic PD or brainstem dominated LBD and dementia with Lewy bodies (DLB) are the two most common alpha-synucleinopathies and are progressive multi-system neurodegenerative diseases with a widespread alpha-synuclein deposition in the central, peripheral and autonomic nervous systems (jellinger ka 2008). Considerable clinical and pathological overlap between PD (with or without dementia) and DLB (or LBD) corresponding to Braak LB 5 and 6 phases, both of which are commonly associated with variable alzheimer's disease types, is reported (Jellinger KA 2008 a). Dementia is usually not associated with the progressive stages of the LB pathology, but may also be associated with the accompanying alzheimer lesion or mixed pathology (Jellinger KA,2008 a).

Alzheimer's Disease (AD) is reported to be characterized by deposition of beta-amyloid peptide, phosphorylated tau protein (3-and 4-repeat tau) and alpha-synuclein (aSyn) deposition (JellingerKA,2008 b). Lewy Body Disease (LBD), such as sporadic Parkinson's Disease (PD) and dementia with Lewy bodies (DLB), shows aSyn-positive deposits in neurons, neurites, glia and common anterior terminals, while frontotemporal dementia is tau-positive and tau-negative, ubiquitin-positive and TDP-43-positive neurons and glial inclusion bodies (Jellinger KA,2008 b). Molecular interactions between major proteins may occur in the same brain in various distribution patterns associated with multiple phenotypes and mixed pathologies, such as AD with aSyn pathology in the brainstem and amygdala, PD and DLB with AD pathology, frontotemporal dementia with a mixture of multiple deposits, while other features are one of the main pathological features without other pathologies (e.g., tangle-dominant dementia type, pure PD, brainstem-dominant LBD) (Jellinger KA,2008 b).

MSA with orthostatic hypotension is the current term for neurological diseases, once known as Shy-Drager syndrome. Progressive diseases of the central and autonomic nervous systems, characterized by orthostatic hypotension (excessive drop in blood pressure while standing), which causes dizziness or fainting. Multiple system atrophy may occur in the absence of orthostatic hypotension, but instead with urinary tract involvement (urgency/incontinence). Neurologists classify this disease into 3 types: parkinson's type, including symptoms of parkinson's disease such as motor retardation, muscle rigidity, and tremor; cerebellar type, which causes coordination and speech problems; combined, symptoms including parkinson's disease and cerebellar failure. Problems with male urinary incontinence, constipation and impotence occur early in the disease. Other symptoms include general weakness, double vision or other visual disorders, difficulty breathing and swallowing, sleep disorders, and reduced sweating. Because the disease is similar to other diseases, correct diagnosis may take years.

Mutations in the glucocerebrosidase Gene (GBA) can lead to the autosomal recessive hereditary disease gaucher disease. Different evidence suggests that mutated GBA may be a risk factor for parkinson's disease. GBA mutations are now considered to be the single greatest risk factor for the development of idiopathic PD. Clinically, GBA PD is nearly identical to idiopathic PD in imaging and pharmacology (O' Regan et al, 2017). The molecular mechanism leading to this increased risk of PD in carriers of GBA mutations has not been fully elucidated, but has been shown to be associated with the accumulation of synuclein (Soria et al, 2017).

Although less frequently, several other diseases are also considered synucleinopathies. These include Hallevorden-Spatz syndrome, neuronal axonal dystrophy and some cases of craniocerebral injury. For Hallevorden-Spatz syndrome, symptoms include paralysis agitans, dystonia, dysphagia/dysarthria, sclerosis/stiffness of the extremities, dementia and spasticity.

Many now believe that the process leading to synuclein aggregation may be critical for neuronal damage and destruction that occurs in these diseases.

The mechanism of aggregation in these synucleinopathies is still uncertain. Current evidence suggests that the conversion of the alpha helical structure to the beta sheet conformation and subsequent oligomerization may be pathogenic precursors to synuclein fibrillation and aggregation. These features are similar to the abnormal processing of raney proteins, which may also become highly neurotoxic. Phosphorylation of alpha-synuclein at serine-129 residues has been implicated as a contributing factor (Chen et al.2016). According to the authors, the prion form of alpha-synuclein may be the causative agent, especially for multiple system atrophy. Raney proteins are small proteins that can also misfold, oligomerize, aggregate and spread to other cells. The result in the brain is a profound and widespread neurotoxic process.

Accordingly, inhibiting misfolding, oligomerization, and aggregation of synuclein may be beneficial in slowing or even preventing the progression of synucleinopathies.

As described above, α -synuclein is readily secreted into the extracellular space and has been identified in cerebrospinal fluid, blood, urine and saliva (Marques and Outeiro, 2012). The mechanism of secretion of α -synuclein is not completely understood, but studies have shown that secretion of at least a portion of α -synuclein is associated with exosomes (endocytic-derived 40 to 100nm membrane vesicles) (reviewed in Shiet al 2014). Plasma exosome alpha-synuclein has been shown to be significantly associated with disease severity (Shi et al 2014), suggesting that plasma exosome alpha-synuclein may help monitor disease progression. Similarly, the level of exosome α -synuclein correlates with the severity of lesions in cross-sectional samples of LBD patients (stuondl et al.2016).

Based on the above, agents that lower plasma exosomes/total alpha-synuclein should slow or even stop the neurodegenerative processes associated with synucleinopathies.

Various compositions for treating PD-associated synucleinopathies and related diseases have been proposed, which target the synuclein aggregation pathway. The discovery process is mainly related to cellular and animal models of the neurodegenerative degeneration caused by prion and synuclein (Prusiner et al 2015). Unfortunately, none of these models has been validated and all are considered uncertain predictors of human influence. However, without more reliable discovery techniques, these models continue to be widely used.

Currently proposed agents to consider include, for example, small molecules such as (S) -6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine (pramipexole) and its analogs, alone or in combination with various drugs.

Pramipexole is a synthetic aminothiazole derivative described in US 4,886,812, the contents of which are incorporated herein by reference in their entirety. It is a non-ergoline dopamine autoreceptor agonist (Schneider et al,1987), approved for symptomatic treatment of Parkinson's Disease (PD) in the late 90 s of the 20 th century, at doses ranging from 0.375 mg/day to 4.5 mg/day, given in 3 equal doses (Mirapex prescription information, 2016 month 7). Pramipexole as an immediate release tablet containing 0.125mg, 0.25mg, 0.5mg, 1mg and 1.5mg pramipexole dihydrochloride monohydrate; and sustained release tablets containing 4.5mg pramipexole dihydrochloride monohydrate.

Despite its widespread use in alleviating the symptoms of parkinson's disease, its potential as a disease modifier has made it a target of research interest.

Pramipexole was reported to reduce the formation of synuclein oligomers in vitro (Ono et al.2013). Relevant studies show that pramipexole inhibits the toxic effect of rotenone on dopaminergic neurons in a mouse PD model, and simultaneously reduces immunoreactivity on alpha-synuclein; in addition, pramipexole reduces H₂O₂+ cytochrome c results in vitro oligomerization of human wild-type α -synuclein (Inden et al 2009). Pulak has also been observedSoxhibits the aggregation of alpha-synuclein in human neuroblastoma SH-SY5Y cells (Kakimura et al 2009). Importantly, the relative expression of α -synuclein in serum exosomes has been found to decrease during pramipexole treatment of PD-type patients (Luo et al.2016).

Unfortunately, limitations associated with administration of pramipexole to synucleinopathies limit its use to potentially higher neuroprotective doses as predicted by some animal models. First, the mechanisms explaining their putative beneficial effects on synuclein-associated neurotoxicity remain elusive to a full understanding. Second, the magnitude of the effect in animal model studies tends to be small and occurs only at relatively high drug doses. Both of these cases were also observed in the pramipexole-induced change in exosome synuclein report for PD patients described above, which was associated with administration of pramipexole at recommended/approved doses up to-4.5 mg/day (Mirapex package insert; revised 2016, month 7).

In the Luo et al (2016) report, although treatment of Parkinson's disease patients with pramipexole at therapeutic doses approved for treatment of motor symptoms of PD significantly reduced the relative expression of alpha-synuclein (compared to pre-treatment values), the magnitude of the effect was small. Higher doses of pramipexole may be more effective in nature, but side effects such as vomiting and severe nausea preclude the use of higher doses. For example, Corrigan et al (2000) reported that a pramipexole dose of 5 mg/day, just above the maximum recommended dose of 4.5 mg/day (pramipexole FDA approved package insert), caused nausea in 76% of patients and vomiting in 39% of patients. Furthermore, 36% of patients may be unable to complete the study due to intolerable GI adverse events.

Recently, pramipexole has been reported to exert neuroprotective effects in various in vitro cellular and in vivo animal models of PD. The mechanisms by which these protections may occur remain uncertain. Unfortunately, the protective effect of pramipexole in animal models is generally small and requires higher doses than those considered safe and tolerable for human administration. Therefore, it is not surprising that pramipexole at doses approved for the treatment of motor symptoms of PD failed to demonstrate its neuroprotective (i.e., disease modifying) activity in a randomized, controlled clinical trial involving 535 PD patients (Schapira et al.2013).

In US 2008/0014259 there is disclosed an (R)/(S) -mixture consisting of a pharmaceutical composition for the treatment of PD comprising a therapeutically effective amount of dexpramipexole or pharmaceutically acceptable salts and solvates thereof and a therapeutically effective amount of pramipexole or pharmaceutically acceptable salts and solvates thereof, the contents of which are incorporated herein by reference in their entirety.

According to US 2008/0014259, both enantiomers are able to confer neuroprotective effects by their ability to accumulate in brain cells, spinal cord and mitochondria, where they have a positive effect on neural function that is independent of pramipexole's dopamine agonist activity. In particular, the document proposes the composition as a neuroprotective agent and a therapeutically effective amount of pramipexole of about 0.0625mg to about 6mg in combination with up to 5000mg of dexpramipexole. However, this document emphasizes the side effects of pramipexole due to its dopaminergic effect and tends to lower the dose of pramipexole, as also demonstrated by the same applicant in WO 2008/113003, of almost contemporary date, the contents of which are incorporated herein by reference in their entirety.

According to US 2013/0116292 (the contents of which are incorporated herein by reference in their entirety), dexpramipexole, or pharmaceutically acceptable salts and solvates thereof, acts by slowing the progression of neuronal degeneration and/or by preventing neuronal cell death. However, this possible noteworthy role of dexpramipexole is not further mentioned in this document.

The synthesis of dexpramipexole and its pharmaceutically acceptable salts, particularly dexpramipexole dihydrochloride monohydrate, is described in US 2012/0253047, the contents of which are incorporated herein by reference in their entirety.

Despite the extensive literature, pramipexole continues to provide only a small amount of activity in the treatment of parkinson's disease.

Thus, the problem of providing safe, long-term, effective treatment with pramipexole to patients with synucleinopathies remains unsolved.

Disclosure of Invention

The present invention stems from the idea that increasing the therapeutic window of pramipexole can safely bring its full efficacy to a degree that delays onset and/or slows progression of symptoms to a clinically significant degree in patients with PD-like disease, when still considering neuroprotective intent.

The present invention shows that increasing the tolerable dose of pramipexole to an unexpected level safely allows its full efficacy to a degree that delays onset and/or slows progression of symptoms to a clinically significant degree in patients with PD-like disease.

It has now been found that drugs such as aprepitant, netupitant and rolipidant may confer pramipexole an improved synucleinopathy potential by reducing or even eliminating the GI side effects of high doses of pramipexole, particularly nausea and vomiting.

It has also been found that by using an NK 1-receptor antagonist (also known as an NK1 receptor inhibitor or simply as an NK 1-antagonist) in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof, patients suffering from synucleinopathies can be treated by maintaining a therapeutically effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof with minimal adverse effects.

In addition, it has been found that the NK 1-antagonist allows for the safe administration of 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine at daily doses containing (S) -enantiomer doses that may be higher, even much higher, than the maximum daily dose of pramipexole recommended for the alleviation of motor symptoms of parkinson' S disease. Thus, an improvement in the condition of patients suffering from synucleinopathies, in particular PD, Lewy body disease, parkinson's disease associated with Glucocerebrosidase (GBA) mutations, and MSA is obtained.

The combination of an NK 1-antagonist (such as aprepitant, rollepitant or netupitant) as component (a) and 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine as component (b) acts in a manner that results in the normalization of abnormal ratios of monomeric to oligomeric synuclein species in plasma exosomes derived from the CNS of patients with synucleinopathies.

Accordingly, the present invention provides a combination of an NK 1-antagonist (for use in the treatment of synucleinopathies in patients in need of such treatment) and 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine. The combination functions in a manner that tends to normalize abnormal ratios of monomeric to oligomeric synuclein species in CNS-derived plasma exosomes.

The invention also provides a method of treating a synucleinopathy patient comprising treating the patient with an effective dose of an NK 1-antagonist in combination with 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine.

According to one embodiment, the NK 1-antagonist and the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine are each formulated in a pharmaceutical composition in admixture with a pharmaceutical carrier and administered separately to a patient in need of treatment with the combination.

According to another embodiment, the NK 1-antagonist and the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine are mixed together and formulated into a pharmaceutical composition (fixed dose combination) in admixture with a pharmaceutical carrier for administration to a patient in need of such treatment.

Any NK 1-antagonist that is effective in preventing nausea and vomiting can be used in combination with a dose, or higher doses, even much higher doses, of 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine, including the (S) -enantiomer doses currently commonly used in the treatment of PD. A number of suitable NK 1-antagonists are disclosed in the literature. The long-term use of such a combination ameliorates the symptoms of synucleinopathies by simultaneously reducing or even eliminating the adverse effects caused by the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine.

As stated in the definition, 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine represents the active ingredient per se, irrespective of the salt or solvate of the active ingredient. Similarly, for any recited NK 1-antagonist or 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine, the expression "salt or solvate thereof" and "salt and solvate thereof" means that any said NK 1-antagonist or salt of said 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine can be solvated with a solvent, typically water.

According to the present invention, preferably, the NK 1-antagonists used are those approved for the prevention of nausea and vomiting following cancer chemotherapy. In fact, surprisingly, NK1 receptor inhibitors known to block nausea, vomiting and diarrhea caused by chemotherapeutic drugs have been shown to also block the gastrointestinal side effects of the (S) -enantiomer contained in the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine without affecting its efficacy in treating the synucleinopathies.

This finding is also surprising because both the NK 1-antagonist and the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine are two series of products that have been used for over a decade, each with its own indications, but none have thought to be used in combination for the treatment of synucleinopathies. In particular, to date, no one has suggested that the condition of patients with synucleinopathies can be safely improved by combining an effective dose of an NK 1-antagonist with an effective anti-synucleinopathic dose of 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine. In addition, no one suspects that in the case of pramipexole, such a combination would normally allow the administration of the maximum recommended daily dose of pramipexole, even allowing the possible increase in the dose of pramipexole dihydrochloride monohydrate.

More specifically, it has been found that in the case of pramipexole dihydrochloride monohydrate, its combination with an NK 1-antagonist allows the administration of therapeutically effective anti-synucleinopathy doses, which in many patients will significantly exceed the maximum recommended dose of pramipexole dihydrochloride monohydrate (4.5 mg/day) for the treatment of motor symptoms of PD, thus increasing its efficacy in the treatment of patients suffering from synucleinopathy (e.g. PD), including an unexpected and substantial slowing of the progression of the disease.

Accordingly, the present invention provides a method of treating synucleinopathies comprising administering to a patient in need of such treatment an effective daily dose of an NK 1-antagonist in combination with an effective daily dose of 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine.

Pharmaceutically acceptable salts of 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine are also included in the present invention.

According to one embodiment, the present invention provides a pharmaceutical combination comprising an NK 1-antagonist in a daily dose generally at least as high as the dose approved for the prevention or treatment of post-operative nausea and vomiting or for the prevention of chemotherapy-induced nausea and vomiting, and an effective daily dose of 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine.

More specifically, according to this embodiment, said 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine is pramipexole or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of synucleinopathies in patients in need of such treatment, administered at a daily dose equivalent to 0.375mg to 45mg of pramipexole dihydrochloride monohydrate.

According to another embodiment, the present invention provides said NK 1-antagonist in a pharmaceutical composition component (a) comprising as an active ingredient an NK 1-antagonist in admixture with a pharmaceutical carrier or vehicle, for administration in combination with 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine which is also in admixture with a pharmaceutical carrier or vehicle in a pharmaceutical composition component (b).

The amount of the NK 1-antagonist in the composition is in the range of 1 μ g to 600mg, typically 1mg to 600mg, and the amount of 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine in the composition is in the range of 0.125mg to 3000 mg.

According to this embodiment, the NK 1-antagonist is preferably present in said composition in an amount/unit form at least as high as the dose/unit form approved for the prevention or treatment of post-operative nausea and vomiting or for the prevention of chemotherapy-induced nausea and vomiting, in admixture with a pharmaceutical carrier, for the prevention or treatment of adverse effects of pramipexole administered for the treatment of synucleopathies in the form of a pharmaceutical composition comprising said pramipexole or a pharmaceutically acceptable salt thereof in an amount/unit form equivalent to 0.125mg to 45mg, preferably 0.125mg to 40-42mg of pramipexole dihydrochloride monohydrate.

According to another aspect of this embodiment, the present invention provides a pharmaceutical combination comprising

(a) An NK 1-antagonist in admixture with a pharmaceutical carrier or vehicle in a pharmaceutical composition comprising as active ingredient said NK 1-antagonist in an amount at least as high as the dose/unit form approved for the prevention or treatment of postoperative nausea and vomiting or for the prevention of chemotherapy-induced nausea and vomiting; and

(b) pramipexole dihydrochloride monohydrate admixed with a pharmaceutical carrier or vehicle in a pharmaceutical composition comprising said pramipexole dihydrochloride monohydrate as active ingredient in an amount per unit form that is at least as high as the approved dose per unit form for the treatment of parkinson's disease.

In such a combination, component (a) is present in the composition in an amount of from 1 μ g to 600mg, typically from 1mg to 600mg or from 1mg to 300mg, and component (b) is present in the form of pramipexole dihydrochloride monohydrate in an amount of from 0.125mg to 45mg, preferably from 0.125mg to 40-42mg, typically from 0.125mg to 20-21 mg.

According to another embodiment, the present invention provides the use of an NK 1-antagonist for the manufacture of a medicament for the treatment of synucleinopathies, consisting of a pharmaceutical composition comprising said NK 1-antagonist as active ingredient in admixture with a pharmaceutical carrier, for the prevention or treatment of the adverse effects of 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine or a pharmaceutically acceptable salt and/or solvate thereof, in an amount per unit form that is at least as high as the dose approved for the prevention or treatment of postoperative nausea and vomiting or for the prevention of chemotherapy-induced nausea and vomiting.

As mentioned above, the amount per unit form of the NK 1-antagonist is at least as high as the dose approved for the prevention or treatment of postoperative nausea and vomiting or for the prevention of chemotherapy-induced nausea and vomiting, and may be up to 6 times or more the dose, and the amount per unit form of 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine is from 0.125mg to 3000 mg.

According to yet another embodiment, the present invention provides a pharmaceutical fixed dose combination consisting of a pharmaceutical composition comprising an effective dose per unit form of an NK 1-antagonist as component (a) and an effective dose per unit form of 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine as component (b) in admixture with a pharmaceutical carrier or vehicle.

The amount of 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine per IR-unit form is equivalent to 0.125mg to 1500mg pramipexole dihydrochloride monohydrate, depending on safety and tolerability (in combination with NK 1-antagonist).

Typically, if the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine in the IR formulation is pramipexole dihydrochloride monohydrate, the dosage range is 0.125mg to 30mg, preferably 0.125mg to 22.5mg, usually 0.125mg to 20mg or 0.125mg to 10mg per unit form, depending on safety and tolerability (in combination with NK 1-antagonist).

The dosage/unit form of 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine in ER formulations (including sustained release compositions and transdermal therapeutic systems such as transdermal patches) is from 1.5mg to 3000mg, depending on tolerability (in combination with NK 1-antagonist). Typically, if the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine is pramipexole dihydrochloride monohydrate, the dosage range/unit form is 1.5mg to 45mg, preferably 1.5mg to 40-42mg, or 3mg to 40-42mg, typically 3mg to 20-21 mg.

The dose per IR-unit form of 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine in the form of a (R)/(S) mixture ranges from 50mg to 1500mg, depending on safety and tolerability (in combination with NK 1-antagonist). The above ranges include (S) -enantiomer amounts of 0.125mg to 10mg per IR-unit form. For pramipexole administered at higher doses, the above range is 0.125mg to 22.5mg, typically 0.125mg to 20mg, advantageously 6.5mg to 20mg per IR unit form.

Typically, if the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine is pramipexole dihydrochloride monohydrate, the dose per IR-unit form ranges from 0.125mg to 10mg, advantageously from 1.5mg to 10mg or from 6.5mg to 10mg, depending on safety and tolerability (in combination with NK 1-antagonist). For pramipexole administered at higher doses, the dose range is 0.125mg to 20mg, typically 6.5mg to 20 mg.

The dosage/unit form of 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine in ER formulations (including sustained release compositions and transdermal therapeutic systems such as transdermal patches) is from 3mg to 3000mg, depending on tolerability (in combination with NK 1-antagonist).

The dose/unit form of 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine in the form of an (R)/(S) -mixture in ER formulations (including sustained release compositions and transdermal therapeutic systems such as transdermal patches) ranges from 150mg to 3000mg, typically from 300mg to 3000mg pramipexole dihydrochloride monohydrate, including the (S) -enantiomer dose/unit form equivalent to 0.375mg to 45mg, typically 0.375mg to 40-42mg, or greater than 6mg to 40-42mg pramipexole dihydrochloride monohydrate, preferably 0.375mg to 40-42mg, or greater than 6mg to 40-42mg pramipexole dihydrochloride monohydrate, depending on tolerance (in combination with NK 1-antagonist).

Typically, if the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine is pramipexole dihydrochloride monohydrate, the dose range per ER-unit form is 3mg to 45 mg. Advantageously, if the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine is pramipexole or a pharmaceutically acceptable salt thereof, the dose range per ER-unit form will correspond to greater than 4.5mg to 45mg or greater than 6mg to 45mg, preferably, greater than 4.5mg to 40-42mg or greater than 6mg to 40-42mg, in some cases greater than 4.5mg to 22.5mg, preferably greater than 6mg to 20mg or 6.5mg to 20mg pramipexole dihydrochloride monohydrate. Preferably, the dosage range/ER-unit form will correspond to greater than 4.5mg to 40-42mg or greater than 6mg to 40-42mg, in some cases greater than 4.5mg to 20mg, preferably greater than 6mg to 20mg or 6.5mg to 20mg pramipexole dihydrochloride monohydrate.

If the NK 1-antagonist is aprepitant, the IR dose of aprepitant ranges from 10mg to 250mg, or in some embodiments, from 10mg to 125 mg.

If the NK 1-antagonist is fosaprepitant or a pharmaceutically acceptable salt or solvate thereof, the IR dose of the NK 1-antagonist is equivalent to 10mg to 250mg aprepitant.

If the NK 1-antagonist is Lapalutant, the dose/unit form in combination with the above-described dose/unit form of 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine in the IR formulation ranges from 15mg to 270 mg.

Typically, in the method (or use) of treatment of synucleinopathies according to the invention (in combination with an NK 1-antagonist), 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine, typically in a pharmaceutical composition, in admixture with a pharmaceutical carrier or vehicle, is administered to a patient in need of such treatment at a daily dose of 1.5mg to 3000 mg. In practice, the daily dose is selected from the group consisting of:

-pramipexole or a pharmaceutically acceptable salt thereof in a daily dose equivalent to 1.5mg to 45mg pramipexole dihydrochloride monohydrate;

-the racemate or a pharmaceutically acceptable salt thereof, in a daily dose ranging from 3mg to 90mg of pramipexole dihydrochloride monohydrate (thus obviously comprising a daily dose of (S) -6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine corresponding to a daily dose of 1.5mg to 45mg of pramipexole dihydrochloride monohydrate, and a daily dose of (R) -6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine corresponding to a daily dose of 1.5mg to 45mg of pramipexole dihydrochloride monohydrate); and

a daily dose of 150mg to 3000mg of (S) -enantiomer comprising a daily dose of (S) -enantiomer equivalent to 1.5mg to 45mg, preferably 1.5mg to 40-42mg of pramipexole dihydrochloride monohydrate (thus, it is clear that said daily dose consists of a dose of (S) -enantiomer equivalent to 1.5mg to 45mg, preferably 1.5mg to 40-42mg of pramipexole dihydrochloride monohydrate and a dose of (R) -6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine equivalent to 150mg to 3000mg (minus 1.5mg to 45mg, preferably 1.5mg to 40-42mg) of pramipexole dihydrochloride monohydrate).

In the method (or use) of treating synucleinopathies according to the invention, 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine in the form of a (R)/(S) -mixture is administered to a patient in need of such treatment, usually in a pharmaceutical composition mixed with a pharmaceutical carrier or vehicle, at a daily dose of 1.5mg to 3000mg or 3.0mg to 3000 mg; a daily dose of (S) -enantiomer comprising an amount of pramipexole dihydrochloride monohydrate equivalent to 0.375mg to 45mg, preferably a daily dose of (S) -enantiomer comprising an amount of pramipexole dihydrochloride monohydrate greater than 6mg to 45mg or 6.5mg to 45mg, more preferably a daily dose of (S) -enantiomer comprising an amount of pramipexole dihydrochloride monohydrate equivalent to 0.375mg to 40-42mg, greater than 6mg to 40-42mg or 6.5mg to 40-42 mg.

According to a specific embodiment, in the method (or use), the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine is pramipexole dihydrochloride monohydrate, which is administered to the patient at a daily dose of 1.5mg to 45mg, preferably 1.5mg to 40-42mg, typically 1.5mg to 20 mg. According to this embodiment, in the method (or use), 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine is administered to the patient in combination with an NK 1-antagonist.

If the NK 1-antagonist is aprepitant or fosaprepitant, the NK 1-antagonist is administered to the patient at a daily dose of 10mg to 250mg, or in some embodiments 10mg to 125mg, based on aprepitant.

If the NK 1-antagonist is rollipitan, administering said rollipitan to said patient at a daily dose of 15mg to 270 mg.

Detailed Description

As mentioned above, the present invention provides a combination comprising a fixed dose combination of an NK 1-antagonist component (a) and a 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine component (b), and its use in the treatment of synucleinopathies in patients. In particular, the invention provides

-a method of treating a patient with synucleinopathy comprising treating the patient with a combination of an NK 1-antagonist and a 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine component (b);

-NK 1-antagonist component (a) in combination with 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine component (b) for use in treating patients suffering from synucleinopathies;

-use of an NK 1-antagonist in combination with 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine for the preparation of a medicament for the treatment of synucleinopathies in a patient in need of such treatment; and

-a fixed dose combination comprising a pharmaceutical composition in dosage unit form comprising an NK 1-antagonist component (a) and a 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine component (b) in admixture with a pharmaceutical carrier or vehicle and its use in the treatment of synucleinopathies in patients.

NK 1-antagonist component (a).

As mentioned above, any NK 1-antagonist known to be useful as an antiemetic agent may be used in combination with 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine for the treatment of synucleinopathies.

Long term use of this combination slows the progression of synucleinopathies by reducing or even eliminating adverse effects caused by pramipexole such as the racemate or the (R)/(S) -enantiomer in the mixture, allowing the use of high and therefore more neuroprotective doses of pramipexole.

Advantageously, the NK 1-antagonist is selected from the group consisting of:

-5- [ [ (2R,3S) -2- [ (lR) -l- [3, 5-bis (trifluoromethyl) phenyl ] phenyl]Ethoxy radical]-3- (4-fluorophenyl) -4-morpholinyl]Methyl radical]-l, 2-dihydro-3H-l, 2, 4-triazol-3-one (aprepitant); described in US 5,719,147, 130mg aprepitant in 18ml of emulsion, in the form of a liquid oral formulation, in US 2017/0035774, and in the form of an injectable emulsion in monodose vials for intravenous use

Described in US9,808,465 (the contents of each patent being incorporated herein by reference in their entirety);

- [3- { [ (2R,3S) -2- [ (lR) -l- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] -3- (4-fluorophenyl) morpholin-4-yl ] methyl } -5-oxo-2H-1, 2, 4-triazol-1-yl ] phosphonic acid (fosaprepitant), disclosed for example as the meglumine salt in US 5,691,336 and as the bis (cyclohexylamine) salt in US 2016/0355533, the contents of each of which are incorporated herein by reference in their entirety;

- (2S,4S) -4- (4-acetyl-1-piperazinyl) -N- [ (lR) -l- [3, 5-bis (trifluoromethyl) phenyl ] ethyl ] -2- (4-fluoro-2-methylphenyl) -N-methyl-l-piperidinecarboxamide (casopropidem), described in US 7,294,630, the contents of which are incorporated herein by reference in their entirety;

- (2S) -l- [ (3aS,4S,7aS) -4-hydroxy-4- (2-methoxyphenyl) -7, 7-diphenyl-l, 3,3a,5,6,7 a-hexahydroisoindol-2-yl ] -2- (2-methoxyphenyl) propan-1-one (INN: dapitan);

- (2S,3S) -N- (5-tert-butyl-2-methoxybenzyl) -2- (diphenylmethyl) -l-azabicyclo [2.2.2] octan-3-amine (maropiptan), disclosed in u.s.5,807,867, WO2005/082416 and EP 3173071, the contents of each being incorporated herein by reference in its entirety;

- (2S,3S) -2-diphenylmethyl-3- [ (5-isopropyl-2-methoxybenzyl) amino ] quinuclidine (INN: epibatine), disclosed by: evangelista S (2001), "Ezlopitantt. Pfizer"; current Opinion in investigational Drugs:2(10): 1441-3; reviewed in Drugs, the Investigational drug journal 6(8):758-72, the contents of each of which are incorporated herein by reference in their entirety;

- (2S) -N- {2- [3, 5-bis (trifluoromethyl) phenyl ] ethyl } -2- [4- (cyclopropylmethyl) piperazin-1-yl ] -N-methyl-2-phenylacetamide (INN: phenanthroipitant);

-N- [ (2R) -l- [ acetyl- [ (2-methoxyphenyl) methyl ] amino ] -3- (lH-indol-3-yl) propan-2-yl ] -2- (4-piperidin-1-ylpiperidin-1-yl) acetamide (INN: lanepitan);

-2- [3, 5-bis (trifluoromethyl) phenyl ] -N, 2-dimethyl-N- [4- (2-methylphenyl) -6- (4-methyl-1-piperazinyl) -3-pyridinyl ] propionamide (netupitan), described in US 6,297,375, US 6,593,472, US 6,719,996, and in the form of an oral composition comprising 300mg of netupitan and palonosetron hydrochloride in an amount equivalent to 0.5mg of palonosetron base, hereinafter referred to as "netupitan-300/palonosetron-0.5", described in US 8,951,969, the contents of each of which are incorporated herein by reference in their entirety;

- (2R,4S) -4- [ (8aS) -6-oxo-l, 3,4,7,8,8 a-hexahydropyrrolo [ l,2-a ] pyrazin-2-yl ] -N- [ (lR) -l- [3, 5-bis (trifluoromethyl) phenyl ] ethyl ] -2- (4-fluoro-2-methylphenyl) -N-methylpiperidine-1-carboxamide (INN: orvepitant), disclosed in US 2005/0176715, and described in US 2011/0166150 aS a crystalline maleate ester, the contents of each being incorporated herein by reference in its entirety;

- (5S,8S) -8- ({ (lR) -l- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy } methyl) -8-phenyl-l, 7-diazaspiro [4.5] decan-2-one (lapitan), described in US 7,049,320 and, for its injectable form, in US9,101,615, the contents of each being incorporated herein by reference in its entirety;

-3- ((3aR,4R,5S,7aS) -5- [ (lR) -l- [3, 5-bis (trifluoromethylphenyl ] ethoxy ] -4- (4-fluorophenyl) -l,3,3a,4,5,6,7,7 a-octahydroisoindol-2-cyclopent-2-en-1-one (serlopitant), described in US 7,544,815 and US 7,217,731, the contents of each being incorporated herein by reference in its entirety;

-2- (S) - (4-fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid [ l- (R) - (3, 5-bis-trifluoromethyl-phenyl) -ethyl ] -methyl-amide (INN: virtipitant), described in WO 2001/25219, and in the form of an intravenous formulation with reduced tendency to cause hemolysis, described in WO 2012/175434, the contents of each of which are incorporated herein by reference in their entirety; and

- (2S,3S) -N- [ (2-methoxy-5- [5- (trifluoromethyl) tetrazol-1-yl ] phenylmethyl ] -2-phenylpiperidin-3-amine (INN: Waflurapine) disclosed by Gardner CJ et al, Regul Pept.1996 Aug 27; 65(l):45-53, the contents of which are incorporated herein by reference in their entirety.

Illustrative examples of pharmaceutically acceptable salts of basic favored NK 1-antagonists include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, phosphoric acid, and the like, as well as acid addition salts formed with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, methanesulfonic acid, ethanesulfonic acid, gluconic acid, aspartic acid, glutamic acid, and the like.

Illustrative examples of pharmaceutically acceptable salts of acidic NK 1-antagonists, such as fosaprepitant, include salts with inorganic bases, such as alkali metal or alkaline earth metal salts, and salts with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucosamine (meglumine) salts, and salts with amino acids, as described in US 5,691,336, the contents of which are incorporated herein by reference in their entirety.

Advantageous NK 1-antagonists to be used in combination with 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine are selected from the group consisting of:

aprepitant and pharmaceutically acceptable salts and solvates thereof,

fosaprepitant and pharmaceutically acceptable salts and solvates thereof,

-casomoitan and pharmaceutically acceptable salts and solvates thereof,

-Marupitan and pharmaceutically acceptable salts and solvates thereof,

-eziopitant and pharmaceutically acceptable salts and solvates thereof,

-lanopiptan and pharmaceutically acceptable salts and solvates thereof,

-Netupidem and pharmaceutically acceptable salts and solvates thereof,

orvepitant and pharmaceutically acceptable salts and solvates thereof,

-Lapiaptan and pharmaceutically acceptable salts and solvates thereof,

-serlopitant and pharmaceutically acceptable salts and solvates thereof,

-valtipitant and pharmaceutically acceptable salts and solvates thereof,

-woflurbipitan and pharmaceutically acceptable salts and solvates thereof, and

-netupitant-300/palonosetron-0.5.

Aprepitant, fosaprepitant meglumine, fosaprepitant di (cyclohexylamine), rollepitant hydrochloride, and netupitant-300/palonosetron-0.5 are particularly advantageous NK 1-antagonists.

Antagonists of the NK1 receptor approved for the prevention or treatment of postoperative nausea and vomiting or for the prevention of chemotherapy-induced nausea and vomiting are particularly useful according to the present invention. The following are preferred NK 1-antagonists: aprepitant, commercially available in the form of capsules containing 40mg, 80mg or 125mg aprepitant

(ii) a Fosaprepitant meglumine, commercially available in the form of vials containing 115mg or 150mg fosaprepitant: (

Injections); lapidan, obtained as 90mg tablets

And Netopiram-300/Palonosetron-0.5, obtained as a fixed-dose combination in a capsule containing 300mg of Netopiram and 0.5mg of the NK 1-antagonist Palonosetron (in the form of its hydrochloride salt).

In the aforementioned methods, uses and combinations (including fixed dose combinations), the NK 1-antagonist is present in an amount per unit form and is administered in an amount of from 1 μ g to 600mg, typically in an amount of from 1mg to 600mg or in a daily dose of from 1mg to 300 mg.

More particularly, in said combination, said NK 1-antagonist is selected from the group consisting of: aprepitant and pharmaceutically acceptable salts and solvates thereof in a daily dose equivalent to 10mg to 250mg aprepitant; fosaprepitant and pharmaceutically acceptable salts and solvates thereof in a daily dose equivalent to 10mg to 250mg aprepitant; lapatitan and pharmaceutically acceptable salts and solvates thereof, the daily dose being equivalent to 15mg to 270mg Lapatitan; netupidem and pharmaceutically acceptable salts and solvates thereof, in a daily dose equivalent to 300mg to 600 mg; and netupitant-300/palonosetron-0.5.

For administration to patients with synucleinopathies in combination with 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine, each of the above NK 1-antagonists is formulated as a pharmaceutical composition in dosage unit form comprising as an active ingredient said NK 1-antagonist in admixture with a pharmaceutical carrier or vehicle.

In particular, said NK 1-antagonist active ingredient of said pharmaceutical composition is selected from the group consisting of: aprepitant and pharmaceutically acceptable salts and solvates thereof in an amount per unit form equivalent to 10mg to 250mg aprepitant; fosaprepitant and pharmaceutically acceptable salts and solvates thereof in an amount equivalent to 10mg to 250mg aprepitant per unit form; lapatitan and pharmaceutically acceptable salts and solvates thereof, in an amount per unit form equivalent to 15mg to 270mg Lapatitan; netupidem and pharmaceutically acceptable salts and solvates thereof, in an amount per unit form equivalent to 300mg to 600 mg; and netupitant-300/palonosetron-0.5.

Advantageously, the NK 1-antagonist is: aprepitant in an amount of 10mg to 250mg per unit form; fosaprepitant meglumine in an amount per unit form equivalent to 10mg to 250mg aprepitant; or rollipitan in an amount per unit form from 15mg to 270mg or from 30mg to 270 mg.

As described above, by using the NK 1-antagonist in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof, patients suffering from synucleinopathy can be treated by maintaining a therapeutically effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof with minimal adverse effects.

Thus, in order to ensure the definitive, safe and simultaneous administration of said NK 1-antagonist and said 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine, the present invention provides a fixed dose combination consisting of a pharmaceutical composition in dosage unit form comprising an effective amount per unit form of said NK 1-antagonist and an effective amount per unit form of said 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine, in admixture with a pharmaceutical carrier or vehicle.

These NK 1-antagonist/6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine fixed-dose combinations are illustrated in the "pharmaceutical compositions" section below.

6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine component (b).

As described in the above definitions, 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine is selected from:

-pramipexole, (S) -6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine, and pharmaceutically acceptable salts and solvates thereof;

-the racemate, namely (R, S) -6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine, and pharmaceutically acceptable salts and solvates thereof; and

the- (S)/(R) -mixture, i.e. the mixture of (R) -6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine and (S) -6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine, is typically in the form of a pharmaceutical composition, e.g. as described in US 2008/0014259 (the contents of which are incorporated herein by reference in their entirety), containing a therapeutically effective amount of the (S) -enantiomer in admixture with a pharmaceutical carrier or vehicle.

Illustrative examples of pharmaceutically acceptable salts and solvates of 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine are derived from inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, acetic acid, propionic acid, stearic acid, glycolic acid, oxalic acid, succinic acid, lactic acid, maleic acid, hydroxymaleic acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, 2-acetoxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid (isethionic acid), p-toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-amino-benzenesulfonic acid (sulfanilic acid), 2, 6-naphthalenedisulfonic acid, 1, 5-naphthalenedisulfonic acid, and pamoic acid (pamoic acid, an embonic acid). The solvating solvent is typically water.

In the case of pramipexole or a pharmaceutically acceptable salt or solvate thereof, the commercially available pramipexole dihydrochloride monohydrate is the preferred 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine. For example, stable pharmaceutical compositions comprising pramipexole dihydrochloride monohydrate disclosed in WO2012/0140604 and WO 2008/122638 (the contents of each of which are incorporated herein by reference in their entirety); and sustained release compositions comprising pramipexole dihydrochloride monohydrate, disclosed in US 8,399,016 (the contents of which are incorporated herein by reference in their entirety), may be used in combination with NK 1-antagonists for the treatment of synucleinopathies.

The racemate and pramipexole described in US 4.886,812 (the contents of which are incorporated herein by reference in their entirety) are each 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine useful in combination with an NK 1-antagonist for the treatment of synucleinopathies.

(S)/(R) -mixtures, i.e. pharmaceutical compositions comprising a therapeutically effective amount of (R) -6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine or pharmaceutically acceptable salts and solvates thereof and a therapeutically effective amount of (S) -6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine or pharmaceutically acceptable salts and solvates thereof (as disclosed in US 2008/0014259), are also 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine used in combination with NK 1-antagonists for the treatment of synucleinopathies.

For treatment of synucleinopathies, in combination with the NK 1-antagonist described in the section "NK 1-antagonist component (a)" above, 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine was formulated into a pharmaceutical composition comprising the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine in an amount equivalent to 0.125mg to 3000mg of pramipexole dihydrochloride monohydrate, admixed with a pharmaceutical carrier or vehicle. The composition is administered to a patient in need of such treatment at a daily dose of 0.375mg to 3000mg in combination with a NK 1-antagonist at a daily dose of 1 μ g to 600mg, usually 1mg to 600 mg.

According to the invention, 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine is preferably selected from the following group:

- (S) -6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine (INN: pramipexole) and pharmaceutically acceptable salts and solvates thereof, in particular the dihydrochloride monohydrate thereof (USAN: pramipexole hydrochloride), in a dose per unit form equivalent to 0.125mg to 45mg, preferably 0.125mg to 40-42mg of pramipexole dihydrochloride monohydrate;

- (R, S) -6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine (racemate) and pharmaceutically acceptable salts and solvates thereof, in a dosage per unit form corresponding to 0.25mg to 90mg of pramipexole dihydrochloride monohydrate (thus, it is apparent to include (S) -6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine in a dosage per unit form corresponding to 0.125mg to 45mg, preferably 0.125mg to 40-42mg of pramipexole dihydrochloride monohydrate, and (R) -6-propylamino-4 in a dosage per unit form corresponding to 0.125mg to 45mg, preferably 0.125mg to 40mg of pramipexole dihydrochloride monohydrate, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine), preferably 0.25 to 90mg, preferably 0.25 to 80-84mg pramipexole dihydrochloride monohydrate (thus, it is clear to include (S) -6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine in a dose per unit form corresponding to 0.125 to 40-42mg pramipexole dihydrochloride monohydrate and (R) -6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine in a dose per unit form corresponding to 0.125 to 40-42mg pramipexole dihydrochloride monohydrate); and

(R)/(S) mixture, pharmaceutical composition in unit dosage form comprising 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine, in a dosage amount equivalent to 50mg to 3000mg, preferably 150mg to 3000mg, per unit form of pramipexole dihydrochloride monohydrate, said amount per unit form comprising an (S) -enantiomer amount equivalent to 0.125mg to 45mg, preferably 0.125mg to 45mg, pramipexole dihydrate monohydrate (thus, obviously, said amount per unit form consists of an (R) -6-propan-ol-monohydrate equivalent to 0.125mg to 45mg, preferably 0.125mg to 40-42mg, pramipexole dihydrate monohydrate and an (R) -6-propan-ol-monohydrate equivalent to 50mg, preferably 150mg to 3000mg (minus 0.125mg to 45mg, usually 0.125 to 40-42mg), pramipexole dihydrate monohydrate Amount per unit form of amidoamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine), preferably 0.125mg to 40-42mg pramipexole dihydrochloride monohydrate (thus, obviously, the amount per unit form consists of an amount of (S) -enantiomer corresponding to 0.125mg to 45mg, preferably 0.125mg to 40-42mg, pramipexole dihydrochloride monohydrate and an amount per unit form of (R) -6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine corresponding to 50mg, preferably 150mg (minus 0.125mg to 45mg, preferably 0.125 to 40-42mg) pramipexole dihydrochloride monohydrate).

As defined herein, an effective daily dose of pramipexole or the (S) -enantiomer is a dose at least equivalent to the approved daily dose of pramipexole dihydrochloride monohydrate for the treatment of PD. The approved daily dose is 0.375mg to 4.5 mg. It is hereby stated, however, that the combination of an NK 1-antagonist and the pramipexole or (S) -enantiomer in accordance with the present invention allows the administration of an approved daily dose of pramipexole dihydrochloride monohydrate for the treatment of parkinson' S disease without any adverse effects, but also allows the administration of a higher, and much higher, daily dose of pramipexole dihydrochloride monohydrate than the approved dose.

In particular, pramipexole dihydrochloride monohydrate in combination with an NK 1-antagonist may be administered to patients, including pediatric patients, suffering from synucleinopathies at daily doses ranging from 0.375mg to 45mg, preferably from 0.375mg to 40-42mg, depending on tolerance (in combination with an NK 1-antagonist). According to the invention, a daily dose range of 0.375mg to 45mg, preferably 0.375mg to 40-42mg, comprises the low dose to be administered during titration. More particularly, the daily dosage range may be selected from: 1.5 to 45mg, 1.6 to 45mg, 1.625 to 45mg, 3 to 45mg, greater than 4.5 to 45mg, 4.8 to 45mg, greater than 6 to 45mg, and 6.5 to 45 mg. Preferably, the daily dosage range may be selected from: 1.5mg to 40-42mg, 1.6mg to 40-42mg, 1.625mg to 40-42mg, 3mg to 40-42mg, greater than 4.5mg to 40-42mg, 4.8mg to 40-42mg, greater than 6mg to 40-42mg, greater than 10mg to 40-42mg, 13.5mg to 30mg, and 13.5mg to 20-21mg, depending on tolerance (in combination with NK 1-antagonist).

For administration to patients with synucleinopathies in combination with an NK 1-antagonist as described above in the section "NK 1-antagonist component (a)", 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine is formulated as a pharmaceutical composition comprising said 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine as the active ingredient in admixture with a pharmaceutical carrier or vehicle.

According to the invention, the pharmaceutical composition, component (b), comprises pramipexole or a pharmaceutically acceptable salt thereof as active ingredient in an IR-formulation in an amount per unit form corresponding to 0.125mg to 30mg or 20-21mg, typically 1.5mg to 10mg pramipexole dihydrochloride monohydrate, or in an ER formulation in an amount per unit form corresponding to 1.5 to 45mg, preferably 1.5mg to 40-42mg pramipexole dihydrochloride monohydrate.

More particularly, the pramipexole is present in the composition in an amount per unit form corresponding to an amount per unit form of pramipexole dihydrochloride monohydrate selected from the group consisting of: 0.125 to 45mg, preferably 1.5 to 45mg, 1.625 to 45mg, 3 to 45mg, greater than 4.5 to 45mg, 4.8 to 45mg, greater than 6 to 45mg, and greater than 10 to 45 mg. In particular, the pramipexole is present in the composition in an amount per unit form corresponding to the amount per unit form of pramipexole dihydrochloride monohydrate selected from the group consisting of: 0.125mg to 40-42mg, 0.125mg to 30mg, 0.125 to 20-21mg, 1.5mg to 40-42mg, 1.625mg to 40-42mg, 3mg to 40-42mg, greater than 4.5mg to 40-42mg, 4.8mg to 40-42mg, greater than 6mg to 40-42mg, and greater than 10mg to 40-42 mg.

In a preferred embodiment, the present invention provides a pharmaceutical composition in dosage unit form comprising pramipexole and its pharmaceutically acceptable salts and solvates as an active ingredient in an amount per unit form equivalent to 13.5mg to 45mg, 13.5mg to 40-42mg, 13.5mg to 30mg or 13.5mg to 20-21mg pramipexole dihydrochloride monohydrate in admixture with a pharmaceutical carrier or vehicle.

As described above, NK 1-antagonists in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof, can treat patients with synucleinopathies by maintaining a therapeutically effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof without adverse effects.

In order to provide for the simultaneous administration of the NK 1-antagonist and the pramipexole or a pharmaceutically acceptable salt or solvate thereof, the present invention provides a fixed dose combination consisting of a pharmaceutical composition in dosage unit form comprising as active ingredients an NK 1-antagonist and pramipexole and a pharmaceutically acceptable salt or solvate thereof, in admixture with a pharmaceutical carrier or vehicle.

The NK 1-antagonist/-6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine fixed dose combination will be illustrated in the "pharmaceutical composition" section below.

Certain aspects of the invention.

According to a first aspect, the invention comprises a method of safely slowing or even reversing the progression of disease in a patient suffering from synucleinopathy and treated with 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine by the simultaneous and chronic administration of an NK 1-antagonist to said patient.

More specifically, the present invention provides a method for treating synucleinopathies in a patient comprising administering to said patient in need of such treatment an effective daily dose of an NK 1-antagonist in combination with an effective daily dose of 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine.

According to the method of this aspect of the invention, any of the NK 1-antagonists described in the section "NK 1-antagonist component (a)" may be used.

In practicing the methods of the invention, the daily dose of these NK 1-antagonists is at least as high as the daily dose used for the prevention or treatment of nausea and vomiting in a patient undergoing surgery or cancer chemotherapy according to the current treatment or prevention regimen. The daily dose is from 1 μ g to 600mg, typically from 1mg to 600mg, or from 1mg to 300 mg.

NK 1-antagonists selected from aprepitant and pharmaceutically acceptable salts and solvates thereof and also from rollipitant and pharmaceutically acceptable salts and solvates thereof are particularly advantageous NK 1-antagonists.

As described above, 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine is selected from the group consisting of racemate, pramipexole and (R)/(S) -mixture, and pharmaceutically acceptable salts and solvates thereof.

The dosage per unit form and daily dosage of 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine are described above in the section "6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine". The dosage per unit form of the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine consists of or includes the following: amounts per unit form corresponding to from 0.125mg to 45mg, preferably from more than 6mg to 45mg, typically from 0.125mg to 40-42mg, preferably from more than 6mg to 40-42mg of the (S) -enantiomer of pramipexole dihydrochloride monohydrate.

According to one embodiment, the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine is selected from:

- (S) -6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine (INN: pramipexole) and pharmaceutically acceptable salts thereof, in particular the dihydrochloride monohydrate thereof (USAN: pramipexole hydrochloride), in a dosage per unit form equivalent to 0.125mg to 45mg, preferably 0.125mg to 40-42mg, pramipexole dihydrochloride monohydrate, administered in a daily dose equivalent to 0.375mg to 45mg, preferably greater than 6mg to 45mg or 6.5mg to 45mg, typically 0.375mg to 40-42mg, preferably greater than 6mg to 40-42mg or 6.5mg to 40-42mg, pramipexole dihydrochloride monohydrate;

- (R, S) -6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine (racemate) and pharmaceutically acceptable salts thereof in a dosage per unit form of 0.25 to 90mg, preferably greater than 12 to 90mg, usually 0.25 to 80mg, said dose comprises an amount per unit form corresponding to the S-enantiomer of pramipexole dihydrochloride monohydrate in the range of 0.125mg to 45mg, preferably in the range of more than 12mg to 45mg or in the range of 13mg to 45mg, typically in the range of 0.125mg to 40-42mg, preferably in the range of more than 12mg to 40-42mg or in the range of 13mg to 40-42mg, is administered in a daily dose equivalent to 0.375mg to 45mg, preferably greater than 12mg to 45mg or 13mg to 45mg, typically 0.375mg to 40-42mg, preferably greater than 12mg to 40-42mg or 13mg to 40-42mg pramipexole dihydrochloride monohydrate.

- (S)/(R) -mixture, which is a pharmaceutical composition comprising 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine in dosage unit form at a dose of 50mg to 3000mg, preferably 150mg to 3000mg per unit form, said dose comprising an amount corresponding to 0.125 to 45mg, preferably more than 6mg to 45mg or 6.5mg to 45mg, usually 0.125 to 40-42mg, preferably more than 6mg to 40-42mg or 6.5mg to 40-42mg of the S-enantiomer of pramipexole dihydrochloride monohydrate per unit form, at 150mg to 3000mg, preferably 300mg to 3000mg or 450mg (including an amount corresponding to 0.375 to 45mg, preferably more than 6mg to 45mg or 6.5mg to 45mg, usually 0.375mg to 40-42mg, preferably more than 6mg to 40-42mg or 6.5mg to 40-42mg of the (S) -enantiomer per unit form, usually 0.375mg to 40-42mg, preferably 6mg to 40-42mg Dose) a daily dose of pramipexole dihydrochloride monohydrate was administered.

In the method of treating synucleinopathies according to the present invention, the NK 1-antagonist is generally administered to a patient in need of such treatment in combination with pramipexole dihydrochloride monohydrate in the effective daily dose as described above. The pramipexole dihydrochloride monohydrate admixed in a pharmaceutical composition with a pharmaceutical carrier or vehicle is administered to the patient in a daily dose of 0.375mg to 45mg, preferably 0.375mg to 40-42 mg.

In accordance with one embodiment of the present invention,

the NK 1-antagonist is selected from: aprepitant and pharmaceutically acceptable salts and solvates thereof, fosaprepitant and pharmaceutically acceptable salts and solvates thereof, rollepitant and pharmaceutically acceptable salts and solvates thereof, netupitant and pharmaceutically acceptable salts and solvates thereof, each at a daily dose as described in the section "NK 1-antagonist"; and, netupitant-300/palonosetron-0.5, once daily or once every 2 to 4 days; and

the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazole-2-amine is selected from the following groups: pramipexole and pharmaceutically acceptable salts and solvates thereof in daily dosages as described above in section "6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine component (b)".

According to an advantageous embodiment, in the method of the invention, the NK 1-antagonist is aprepitant, fosaprepitant meglumine or lapitant, 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof is pramipexole dihydrochloride monohydrate, in the respective daily doses as described in the respective sections.

According to a particular embodiment, in said method (or use), said NK 1-antagonist is administered to said patient in an effective daily dose as described above in combination with a daily dose of 1.5mg to 45mg, typically 1.5mg to 45mg, preferably 1.5mg to 40-42mg, typically 1.5mg to 20-21mg of said pramipexole dihydrochloride monohydrate.

Preferably, in the method for treating synucleinopathies in a patient according to the invention,

the NK 1-antagonist is: aprepitant in a daily oral dose of 10mg to 250 mg; fosaprepitant meglumine injected daily at a dose equivalent to 10mg to 250mg aprepitant; or rollipintan at a daily oral dose of 15mg to 270mg or 30mg to 270 mg; or netupitant-300/palonosetron-0.5; and

the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine or pharmaceutically acceptable salt or solvate thereof is pramipexole dihydrochloride monohydrate, and an effective daily oral dose is 1.5mg to 45mg, usually 1.5mg to 22.5mg, preferably 1.5mg to 40-42mg, usually 1.5mg to 20-21 mg.

The NK 1-antagonist and the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine may also be co-formulated into a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle as described hereinafter.

The methods of the invention allow for the safe treatment of synucleinopathies such as Parkinson's disease, Lewy body dementia, glucocerebrosidase gene mutations, multiple system atrophy, Alzheimer's disease, Lewy body variant diseases of Alzheimer's disease, neurodegeneration with brain iron accumulation, and Parkinson's disease associated with Glucocerebrosidase (GBA) mutations.

According to a second aspect, the present invention provides an NK 1-antagonist for use in combination with 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine in the treatment of synucleinopathies in patients in need of such treatment.

According to this second aspect of the invention, any of the NK 1-antagonists shown in the section "NK 1-antagonist component (a)", may be used, typically in dosage unit form.

In particular, a second aspect of the invention provides an NK 1-antagonist in combination with a daily dose of 0.375mg to 3000mg of said 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine in an amount per unit form of 1 μ g to 600mg, typically 1mg to 600mg or 1mg to 300mg, for use in the treatment of synucleinopathies in patients in need of such treatment.

For use according to the invention, the daily dose of these NK 1-antagonists is at least as high as the daily dose for preventing or treating nausea and vomiting in a patient undergoing surgery or cancer chemotherapy according to the current treatment or prevention regimen. The daily dose is from 1 μ g to 600mg, typically from 1mg to 600mg or from 1mg to 300 mg.

For use in the treatment of synucleinopathies according to the invention, the NK 1-antagonist as indicated in the section "NK 1-antagonist component (a)" is administered to a patient in need of such treatment in combination with the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine as described in the section "6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine" at an effective daily dose as described above.

According to one embodiment, the NK 1-antagonist is typically used in combination with 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazole-2-amine in the form of an (R)/(S) -mixture in a daily dose comprising a dose of the (S) -enantiomer equivalent to 0.375mg to 45mg, preferably more than 6mg to 45mg or 6.5mg to 45mg, typically 0.375mg to 40-42mg, preferably more than 6mg to 40-42mg or 6.5mg to 40-42mg pramipexole dihydrochloride monohydrate, in an amount per unit form of 1 μ g to 600mg, typically 1mg to 600mg or 1mg to 300 mg.

The 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine may also be the racemate in a daily dose equivalent to 0.75 to 90mg, preferably greater than 12 to 90mg or 13 to 90mg, usually 0.75 to 80mg, preferably greater than 12 to 80mg or 13 to 80mg pramipexole dihydrochloride monohydrate, thereby delivering a daily dose of the (S) -enantiomer equivalent to 0.75 to 40-42mg, preferably greater than 12 to 40-42mg or 13 to 40-42mg, 0.75 to 40-42mg, preferably greater than 12 to 40-42mg or 13 to 40-42mg pramipexole dihydrochloride monohydrate.

Preferably, the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine is pramipexole or a pharmaceutically acceptable salt or solvate thereof in a daily dose equivalent to 1.5mg to 45mg, advantageously greater than 4.5mg to 45mg, more advantageously 4.8mg to 45mg, preferably greater than 6mg to 45mg or 6.5mg to 45mg, typically 1.5mg to 40-42mg, advantageously greater than 4.5mg to 40-42mg, more advantageously 4.8mg to 40-42mg, preferably greater than 6mg to 40-42mg or 6.5mg to 40-42mg pramipexole dihydrochloride monohydrate.

For the treatment of synucleinopathies, the NK 1-antagonist and 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine are each formulated into a pharmaceutical composition in dosage unit form comprising said NK 1-antagonist and said 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine, respectively, each in admixture with a pharmaceutical carrier or vehicle.

Typically, the NK 1-antagonist and the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine are each formulated as a pharmaceutical composition in dosage unit form comprising, in admixture with a pharmaceutical carrier or vehicle, respectively:

the NK 1-antagonist in an amount per unit form of 1 μ g to 600 mg; and

the amount of 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine per unit form is 0.125mg to 3000 mg.

In particular, according to this second aspect, the present invention provides a pharmaceutical combination comprising:

component (a): an NK 1-antagonist in a pharmaceutical composition in dosage unit form in an amount of from 1 μ g to 600mg, typically from 1mg to 600mg or from 1mg to 300mg per unit form of said NK 1-antagonist as active ingredient, in admixture with a pharmaceutical carrier or vehicle; and

a component (b): 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine selected from pramipexole and pharmaceutically acceptable salts thereof in a daily dose equivalent to 0.375mg to 45mg, preferably 0.375mg to 40-42mg of pramipexole dihydrochloride monohydrate, for use in the treatment of synucleinopathies in a patient in need thereof.

Preferably, the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine is pramipexole dihydrochloride monohydrate, also present in the pharmaceutical composition in dosage unit form in an amount per unit form of 4.5mg to 45mg, greater than 6mg to 45mg, or 6.5mg to 45mg, preferably greater than 4.5mg to 40-42mg, greater than 6mg to 40-42mg, or 6.5mg to 40-42 mg.

Advantageously, said NK 1-antagonist component (a) is selected from: aprepitant and pharmaceutically acceptable salts and solvates thereof, fosaprepitant and pharmaceutically acceptable salts and solvates thereof, rollepitant and pharmaceutically acceptable salts and solvates thereof, and netupitant and pharmaceutically acceptable salts and solvates thereof, each in an amount per unit form as indicated in the section "NK 1-antagonist component (a)"; and netupitant-300/palonosetron-0.5.

Preferably, the NK 1-antagonist is aprepitant in a daily oral dose of 10mg to 250 mg; fosaprepitant meglumine, in an effective daily injectable dose equivalent to 10mg to 250mg aprepitant; lapiaptan, effective daily oral dosage from 15mg to 270mg or 30mg to 270 mg; or netupitant-300/palonosetron-0.5.

The use according to the invention is carried out under the conditions described above for carrying out the treatment method.

According to this second aspect, the invention also provides a pharmaceutical combination for the treatment of synucleinopathies, comprising

(a) An NK 1-antagonist; and

(b) 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine.

For this purpose, the method according to this aspect of the invention may use any of the NK 1-antagonists shown in the section "NK 1-antagonist component (a)".

Typically, the NK 1-antagonist component (a) is used in a dose at least as high as the dose approved for the prevention or treatment of postoperative nausea and vomiting or for the prevention of chemotherapy-induced nausea and vomiting; the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine component (b) is used according to a conventional protocol for treating synucleinopathies such as PD.

The amount per unit form and daily dose of the NK 1-antagonist and 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine are as described in the first aspect of the invention and in the second aspect above.

According to a third aspect, the present invention provides the use of an NK 1-antagonist in combination with an effective daily dose of 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine in the manufacture of a medicament for the treatment of synucleinopathies in a patient in need of such treatment.

For this use, the NK 1-antagonist is formulated as a pharmaceutical composition comprising as active ingredient the NK 1-antagonist in admixture with a pharmaceutical carrier or vehicle for simultaneous or sequential administration in combination with 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine for the treatment of synucleinopathies in patients in need of such treatment.

In the pharmaceutical composition, the NK 1-antagonist is mixed with a pharmaceutical carrier and formulated in unit form for oral, intravenous, transdermal, and/or transdermal administration, as described below.

Any of the NK 1-antagonists described in section "NK 1-antagonist component (a)" may be used as an active ingredient of a pharmaceutical composition for the treatment of synucleinopathies in combination with 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine described in section "6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine" according to the third aspect of the present invention.

According to an embodiment of this third aspect, the medicament is a pharmaceutical composition in dosage unit form comprising as active ingredient the NK 1-antagonist in an amount per unit form of 1 μ g to 600mg, typically 1mg to 600mg or 1mg to 300mg, in admixture with a pharmaceutical carrier or vehicle. The medicament is administered to a patient suffering from synucleinopathy in combination with a daily dose of 0.375mg to 3000mg (including (S) -enantiomer amounts of 0.375mg to 45mg, preferably 0.375mg to 40-42mg) of 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine.

These daily doses of 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine include the low daily dose of pramipexole for administration during the titration period. At the end of the titration period, the drug thus prepared allowed the safe intake of a daily dose of pramipexole (not combined with an NK 1-antagonist) as indicated in part (b), which has never been obtained so far.

In particular, the NK 1-antagonist active ingredient is selected from: aprepitant and pharmaceutically acceptable salts and solvates thereof in an amount per unit form equivalent to 10mg to 250mg aprepitant; fosaprepitant and pharmaceutically acceptable salts and solvates thereof in an amount equivalent to 10mg to 250mg aprepitant per unit form; lapatitan and pharmaceutically acceptable salts and solvates thereof, in an amount per unit form equivalent to 15mg to 270mg Lapatitan; netupidem and pharmaceutically acceptable salts and solvates thereof, in an amount per unit form of from 300mg to 600 mg; and netupitant-300/palonosetron-0.5.

Advantageously, the NK 1-antagonist is: aprepitant in an amount per unit form from 10mg to 250 mg; fosaprepitant meglumine in an amount per unit form equivalent to 10mg to 250mg aprepitant; or rollipintan in an amount per unit dose of 15mg to 270mg or 30mg to 270 mg.

In combination with the advantageous NK 1-antagonist in the pharmaceutical composition, the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine may be pramipexole or a pharmaceutically acceptable salt thereof, is safely administered to patients with synucleinopathies at the following daily doses: equivalent to 0.375mg to 45mg, advantageously greater than 4.5mg to 45mg, preferably greater than 6mg to 45mg or 6.5mg to 45mg, or in some cases equivalent to 1.5mg to 22.5mg, 1.6mg to 22.5mg, 1.625mg to 22.5mg, 3mg to 22.5mg, greater than 4.5mg to 22.5mg, 4.8mg to 22.5mg, greater than 6mg to 22.5mg or 6.5mg to 22.5mg pramipexole dihydrochloride monohydrate. Typically, the daily dose is equivalent to 0.375mg to 40-42mg, advantageously greater than 4.5mg to 40-42mg, preferably greater than 6mg to 40-42mg or 6.5mg to 40-42mg, or in some cases 1.5mg to 20-21mg, 1.6mg to 20-21mg, 1.625mg to 20-21mg, 3mg to 20-21mg, greater than 4.5mg to 20-21mg, 4.8mg to 20-21mg, greater than 6mg to 20-21mg or 6.5mg to 20-21mg pramipexole dihydrochloride monohydrate.

The advantageous NK 1-antagonists in the pharmaceutical compositions can also be used for the treatment of synucleinopathies with 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine in the form of a (R)/(S) -mixture in a daily dose of 150mg to 3000mg, usually 300mg to 3000mg, comprising a daily dose of (S) -enantiomer corresponding to 0.375mg to 45mg, preferably more than 6mg to 45mg or 6.5mg to 45mg, usually 0.375mg to 40-42mg, preferably more than 6mg to 40-42mg or 6.5mg to 40-42mg pramipexole dihydrochloride monohydrate, said 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine also being in the form of a dosage unit, mixed with a pharmaceutical carrier or vehicle.

The advantageous NK 1-antagonist of the pharmaceutical composition can also be combined with 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine in racemic form in a daily dose equivalent to 0.75 to 90mg, preferably greater than 12 to 90mg or 13 to 90mg, usually 0.75 to 80mg, preferably greater than 12 to 80mg or 13 to 80mg pramipexole dihydrochloride monohydrate, for the treatment of synucleinopathies, said 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine also being in pharmaceutical form in dosage unit form, mixed with a pharmaceutical carrier or vehicle.

For administration for the treatment of synucleinopathies, the NK 1-antagonist and 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine are each formulated into a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle.

In the treatment of synucleinopathies, the NK 1-antagonist and 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine are used in combination, and the two active ingredients may be co-administered simultaneously or sequentially or in fixed dose combinations comprising a pharmaceutical composition comprising the NK 1-antagonist and 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine in admixture with a pharmaceutical carrier or vehicle.

The NK 1-antagonist component (a) and the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine component (b) may be administered separately or together in any conventional oral or parenteral dosage unit form such as capsules, tablets, powders, cachets, suspensions, solutions or transdermal devices.

Where an effective amount of the NK 1-antagonist per unit form and an effective amount of the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine per unit form are administered separately (simultaneously or sequentially), each may be packaged in a kit comprising the NK 1-antagonist in admixture with a pharmaceutical carrier or vehicle in a container; and said 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine, preferably pramipexole, admixed with a pharmaceutical carrier or vehicle in another separate container.

For simultaneous administration for the treatment of synucleinopathies, the NK 1-antagonist and the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof may also be formulated together as a fixed dose combination consisting of a pharmaceutical composition comprising the NK 1-antagonist and the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine in admixture with a pharmaceutical carrier or vehicle.

Fixed dose combinations ensure safe, simultaneous administration of the NK 1-antagonist and 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine.

As mentioned above, the amount per unit form of the NK 1-antagonist is at least as high as, and up to 6 times as high as, a dose approved for the prevention or treatment of postoperative nausea and vomiting or for the prevention of chemotherapy-induced nausea and vomiting.

According to a fourth aspect, the present invention provides a pharmaceutical fixed dose combination consisting of a pharmaceutical composition in dosage unit form, said pharmaceutical composition comprising, in admixture with a pharmaceutical carrier or vehicle: an effective amount of an NK 1-antagonist as shown above or a pharmaceutically acceptable salt and solvate thereof as an active ingredient, as component (a); an effective amount per unit form of 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine as the second active ingredient, as component (b).

Advantageously, the amount per unit form of the NK 1-antagonist component (a) is at least as high as a dose approved for the prevention and treatment of postoperative nausea and vomiting or for the prevention of chemotherapy-induced nausea and vomiting.

The NK 1-antagonist component (a) is present in the fixed dose combination in an amount per unit form of from 1 μ g to 600mg, typically from 1mg to 600mg or from 1mg to 300 mg; the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine component (b) is present in an amount of 0.125mg to 3000mg per unit form in the fixed-dose combination.

In particular, according to this fourth aspect, the present invention provides a pharmaceutical composition in dosage unit form comprising a pharmaceutical carrier or vehicle in admixture with a pharmaceutically acceptable carrier or vehicle

(a) An NK 1-antagonist in an amount per unit form of 1 μ g to 600 mg; and

(b) 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine selected from the group consisting of: pramipexole or a pharmaceutically acceptable salt thereof in an amount equivalent to 0.125mg to 45mg, preferably 0.125mg to 40-42mg pramipexole dihydrochloride monohydrate; the racemate or a pharmaceutically acceptable salt thereof, in an amount per unit form equivalent to 0.25 to 90mg, preferably 0.25 to 80mg, of pramipexole dihydrochloride monohydrate; (R)/(S) -mixture in an amount per unit form of 50mg to 3000mg, including an amount per unit form of (S) -enantiomer equivalent to 0.125mg to 45mg, preferably 0.125mg to 40-42mg pramipexole dihydrochloride monohydrate.

Preferably, the amount per unit form of the NK 1-antagonist is at least as high as, and up to 6 times as high as, a pediatric or adult dose that shows efficacy or is approved for the prevention or treatment of postoperative nausea and vomiting or for the prevention of chemotherapy-induced nausea and vomiting.

According to a first embodiment, the NK 1-antagonist component (a) is aprepitant in an amount of from 10mg to 125mg per IR unit form, or is rolipidem in a dose of from 15mg to 270mg per unit form, 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine being present in the composition in an amount of from 0.125mg to 1500mg per IR-unit form (in the fixed-dose combination with the NK 1-antagonist).

Preferably, in said pharmaceutical composition, said NK 1-antagonist component (a) is aprepitant and the IR dose in the IR formulation ranges from 10mg to 125 mg.

The dose per IR-unit form of 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine component (b) is generally from 0.125mg to 1500mg, advantageously from 1.6mg to 1500mg, preferably from 1.625mg to 1500mg, depending on safety and tolerability (in combination with NK 1-antagonist component (a)).

The dose per IR-unit form of the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine generally ranges from 1.5mg to 1500mg, depending on safety and tolerability (in combination with NK 1-antagonist).

According to this first embodiment, if the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine component (b) of the fixed-dose combination is pramipexole or a pharmaceutically acceptable salt or solvate, the dose range per IR-unit form will correspond to 0.125mg to 30mg, typically 0.125mg to 22.5mg, 0.125mg to 11.25mg, preferably 0.125mg to 30mg or 0.125mg to 20-21mg, typically 0.125mg to 10mg pramipexole dihydrochloride monohydrate, depending on safety and tolerability (in combination with NK 1-antagonist). Typically, if the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine in the IR formulation is pramipexole dihydrochloride monohydrate, the dose range/IR unit form is 0.125mg to 30mg or 0.125mg to 20-21mg, typically 0.125mg to 10mg, depending on safety and tolerability (in combination with NK 1-antagonist). If the NK 1-antagonist is aprepitant, the dose of aprepitant per IR unit form combined with pramipexole dihydrochloride monohydrate will be from 10mg to 125mg aprepitant.

If the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine component (b) of the fixed-dose combination is the racemate, the dose per IR-unit ranges from 0.25mg to 45mg, preferably from 0.25mg to 40-42mg, thus containing the (S) -enantiomer of pramipexole dihydrochloride monohydrate in an amount equivalent to 0.125mg to 22.5mg, preferably from 0.125mg to 20-21mg, per unit form, and (R) -6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine in an amount equivalent to 0.125mg to 20-21mg of pramipexole dihydrochloride monohydrate per unit form.

If the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine component (b) of a fixed dose combination in an IR-formulation is an (R)/(S) -mixture, the dose range/IR-unit form will be from 50mg to 1500mg, including the (S) -enantiomer/unit form corresponding to 0.125mg to 22.5mg, preferably 0.125mg to 20-21mg pramipexole dihydrochloride monohydrate, thus containing the (S) -enantiomer/unit form corresponding to 0.125mg to 22.5mg, preferably 0.125mg to 20-21mg pramipexole dihydrochloride monohydrate, and the amount/unit form corresponding to 50mg to 1500mg (minus 0.125mg to 22.5mg, preferably 0.125mg to 20-21mg) pramipexole dihydrochloride monohydrate (R) -6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine.

The dose/ERIR unit form of the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine component (b) is generally from 0.375mg to 3000mg, advantageously from more than 4.5mg to 3000mg, preferably from 6.5mg to 3000mg, depending on safety and tolerability (in combination with the NK 1-antagonist component (a)).

If the fixed dose combination of the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine component (b) in an ER formulation (including sustained release compositions and transdermal therapeutic systems such as transdermal patches) is pramipexole or a pharmaceutically acceptable salt or solvate thereof, the amount per unit form thereof will correspond to a range of 1.5mg to 45mg, 3mg to 45mg or 3mg to 22.5mg, preferably 1.5mg to 40-42mg, 3mg to 40-42mg or 3mg to 20-21mg pramipexole dihydrochloride monohydrate, depending on tolerability (in combination with an NK 1-antagonist). In particular, if the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine is pramipexole dihydrochloride monohydrate, the dosage range/unit form is 1.5mg to 45mg, typically 3mg to 45mg, or 3mg to 22.5mg, preferably 1.5mg to 40-42mg, typically 3mg to 40-42mg or 3mg to 20-21 mg.

If the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine component (b) combined in fixed dose in an ER formulation (including sustained release compositions and transdermal therapeutic systems such as transdermal patches) is an (R)/(S) mixture, the dose range/ER-unit is from 150mg to 3000mg or 300mg to 3000mg, including the (S) -enantiomer/unit form equivalent to 3mg to 45mg, preferably greater than 4.5mg to 45mg, greater than 6mg to 45 or 6.5mg to 45mg, typically 3mg to 40-42mg, preferably greater than 4.5mg to 40-42mg, greater than 6mg to 40-42 or 6.5mg to 40-42mg pramipexole dihydrochloride monohydrate, depending on tolerability (in combination with NK 1-antagonist), thus in the case of a dosage range of 3mg to 40-42mg, the (S) -enantiomer of pramipexole dihydrochloride monohydrate is contained in an amount per unit form equivalent to 3mg to 45mg, preferably 3mg to 40-42mg, and (R) -6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine of pramipexole dihydrochloride monohydrate in an amount per unit form equivalent to 150mg to 3000mg or 300mg to 3000mg (minus 3mg to 45mg, preferably 3mg to 40-42 mg).

If the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine component (b) in a fixed-dose combination is the racemate, the dosage range/ER-unit form is selected from the following ranges: corresponding to 6mg to 90mg, preferably greater than 9mg to 90mg, greater than 12mg to 90mg or 13mg to 90mg, generally 6mg to 80mg, preferably greater than 9mg to 80mg, greater than 12mg to 80mg or 13mg to 80mg of pramipexole dihydrochloride dihydrate monohydrate, depending on tolerance, in combination with an NK 1-antagonist, thus, for example, in the case of a 6-80 mg-dose range, containing, for example, the (S) -enantiomer/unit form corresponding to pramipexole dihydrochloride monohydrate in an amount of from 3mg to 45mg, preferably from 3mg to 40-42mg, and (R) -6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine in an amount per unit form equivalent to 3mg to 45mg, preferably 3mg to 40-42mg of pramipexole dihydrochloride monohydrate.

The specific amounts/unit forms of the NK 1-antagonist and 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine active ingredients, respectively, in particular the sub-ranges of the amounts/unit forms of said component (a) and said component (b), are illustrated in the section "NK 1-antagonist component (a)" and "6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine component (b)".

If the NK 1-antagonist is aprepitant, the range of dose/unit form will be from 10mg to 250 mg.

If the NK 1-antagonist is rollepin, the dose/unit form in combination with the above dose/unit form of 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine will be from 30mg to 270 mg.

Preparation

For the intended use in combination with 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine for the treatment of synucleinopathies, the NK 1-antagonist is formulated into a pharmaceutical composition, wherein the NK 1-antagonist is in admixture with a pharmaceutical carrier or vehicle. For such treatment, 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine is also formulated into a pharmaceutical composition in which the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine is mixed with a pharmaceutical carrier or vehicle.

In the pharmaceutical compositions of the invention for oral, subcutaneous, intravenous, transdermal or topical administration, the active ingredient is preferably administered in the form of a dosage unit in admixture with a classical pharmaceutical carrier or vehicle, as described above.

The dosage, i.e. the amount (amount/unit form) of the active ingredient of a single dose to be administered to a patient, may vary widely depending on the age, weight and health of the patient. The dose comprises administering a dose of 1 μ g to 600mg, usually 1mg to 600mg or 1mg to 300mg (depending on the potency of each NK 1-antagonist and the age of the patient), and 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine in an amount equivalent to 0.125mg to 45mg, preferably 0.125mg to 40-42mg of pramipexole dihydrochloride monohydrate (depending on the age of the patient), by intravenous, subcutaneous, oral or transdermal administration 1 to 3 times per day, depending on the dosage strength of each active ingredient.

If the NK 1-antagonist is aprepitant, the dose range is 10mg to 250 mg; if the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine is pramipexole dihydrochloride monohydrate, the dose range is 0.125mg to 45mg, preferably 0.125mg to 40-42 mg.

If the NK 1-antagonist is rollipitan, the dose range is 15mg to 270 mg; if the 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine is pramipexole dihydrochloride monohydrate, the dose range is 0.125mg to 45mg, preferably 0.125mg to 40-42 mg.

As mentioned above, the pharmaceutical compositions of the present invention are in unit form formulated with classical excipients suitable for different modes of administration. The unit forms are manufactured according to conventional techniques allowing, for example, formulating the NK 1-antagonist in the IR-form and pramipexole dihydrochloride monohydrate in the same unit form in the ER-form. Particularly advantageous are formulations in the form: tablets, multinucleated tablets, multilayer tablets, coated tablets, orally disintegrating tablets, sustained release tablets, hard or soft capsules, multi-compartment capsules, sustained release capsules, transdermal patches, liquid oral solutions, syrups or suspensions in predetermined unit form, and vials for intravenous or subcutaneous administration.

The pharmaceutical compositions may be formulated in oral unit form, such as tablets or gelatin capsules, wherein the active ingredients of 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine or NK 1-antagonist, or both, are mixed with a carrier or vehicle which may include: diluents such as cellulose, dextrose, lactose, mannitol, sorbitol or sucrose; lubricants such as acid, calcium or magnesium stearate, polyethylene glycol, silica or talc; binders such as magnesium aluminum silicate, gelatin, methylcellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone are included, if desired.

The oral unit form may be a tablet coated with sucrose or various polymers for immediate release, or the tablet may be manufactured by using: carriers such as acrylic and methacrylic acid polymers and copolymers; cellulose derivatives such as hydroxypropyl ethyl cellulose; or other suitable material to have a prolonged or delayed activity by gradually releasing predetermined amounts of NK 1-antagonist or 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine or both active ingredients. The oral formulation may also be in the form of a capsule allowing for the extended release of the NK 1-antagonist or 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine or both active ingredients.

The oral unit form can also be a tablet or capsule, wherein one of the active ingredients is in the form of an IR-formulation and the other is in the form of an ER-formulation. For example, the unit forms include aprepitant or rollepitant in the form of an IR-formulation, pramipexole dihydrochloride monohydrate in the form of an ER-formulation, each present in the amounts/unit forms described above.

The pharmaceutical composition may also be formulated as a TTS, such as a patch, wherein the active ingredient or the mixture of active ingredients may comprise adjuvants such as D-sorbitol, gelatin, kaolin, methylparaben, polysorbate 80, propylene glycol, propylparaben, povidone, sodium carboxymethylcellulose, sodium polyacrylate, tartaric acid, titanium dioxide and purified water. The patch may also contain a skin penetration enhancer such as lactate (e.g., lauryl lactate), triacetin or diethylene glycol monoethyl ether.

In the above pharmaceutical composition, the preferred NK 1-antagonist active ingredient is aprepitant, fosaprepitant, rollepitant, or netupitant-300/palonosetron-0.5, and the preferred 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine active ingredient is pramipexole base or its dihydrochloride monohydrate.

Thus, for example, the pharmaceutical composition of the invention is administered in long-term combination with 6-propylamino-4, 5,6, 7-tetrahydro-1, 3-benzothiazol-2-amine, preferably pramipexole dihydrochloride monohydrate, in the case of IR-preparations in an amount per unit form of 0.125mg to 30mg or 1.5mg to 22.5mg, typically 1.5mg to 11.25mg, preferably 0.125mg to 20mg, typically 1.5mg to 10mg, or in the case of ER-preparations in an amount per unit form of 1.5mg to 45mg, preferably 1.5mg to 40-42mg, in a daily dose of 1.5mg to 45mg, typically 3mg to 22.5mg, 1.5mg to 40-42mg, typically 3mg to 20-21mg, which preferably comprises: aprepitant in an amount/unit form of 10mg to 250mg in the form of a once daily administration formulation; or rollipintan in an amount per unit form of 15mg to 270mg in the form of a once daily administration formulation.

In the case of pediatric or obese patients, the daily dosage of the NK 1-antagonist can be determined based on body weight. Thus, for example, aprepitant may be administered at a daily dose of 0.16mg/kg to 4.2mg/kg, and rollepitant may be administered at a daily dose of 0.25mg/kg to 4.5 mg/kg.