Apomorphine prodrugs and their use

Abstract

The present invention relates to a compound of formula (I) which is an apomorphine phosphate ester or a pharmaceutically acceptable salt thereof. The apomorphine phosphate ester according to the present invention exhibits significantly advantageous properties as a therapeutic agent, including good tolerance, an improved side effect profile, in particular a reduction in the occurrence of skin nodules and panniculitis when administered subcutaneously, and pharmacokinetic and metabolic properties that are particularly suitable as an apomorphine prodrug. The present invention further relates to a compound of formula (I) for use as a medicament, in particular for the treatment of Parkinson's disease.

Description

Technical Field

[0001] The present invention relates to a compound of formula (I) which is a phosphate ester of apomorphine or a pharmaceutically acceptable salt thereof. The apomorphine phosphate esters according to the invention exhibit significantly advantageous properties as therapeutic agents, including good tolerability, an improved side effect profile, in particular a reduction in the occurrence of skin nodules and panniculitis when administered subcutaneously, and pharmacokinetic and metabolic properties that make them particularly suitable as apomorphine prodrugs. The invention further relates to a compound of formula (I) for use as a medicament, in particular for the treatment of Parkinson's disease.

Background Art

[0002] Idiopathic Parkinson's disease is the second most common neurodegenerative disease in the world. Although there is no cure that can change the underlying neurodegenerative process, the quality of life of patients can be improved by symptomatic treatment. It is estimated that 7 to 10 million people worldwide live with Parkinson's disease (Parkinson's Disease Foundation, Statistics on Parkinson). The average age of onset of Parkinson's disease (PD) is about 62 years. Most cases of PD occur sporadically and the cause is unknown.

[0003] Clinically, Parkinson's disease is characterized by resting tremor, rigidity, akinesia, and gait disturbances, which are known as the "cardinal features" of Parkinson's disease. Additional features include dystonic feet, postural instability, dysarthria, autonomic dysfunction, sensory changes, mood disorders, sleep dysfunction, cognitive impairment, and dementia, all of which are known as non-dopaminergic features because they do not fully respond to dopaminergic therapy (Olanow and Schapira. Ann Neurol. 2013 Sep;74(3):337-47). Pathologically, the hallmark of PD is the degeneration of the pigmented midbrain dopaminergic neurons that connect the substantia nigra (pars compacta) to the neostriatum (caudate nucleus and putamen). Other affected pigmented nuclei may include the locus coeruleus and the dorsal motor nucleus of the vagus nerve, as well as cytoplasmic proteinaceous inclusions known as Lewy bodies. These are composed of misfolded and aggregated proteins. Mutations in α-synuclein are thought to promote protein misfolding and the formation of oligomers and aggregates that are involved in the process of cell death (Olanow and Schapira. Ann Neurol. 2013 Sep;74(3):337-47).

[0004] In the early stages of the disease course, dopamine deficiency is the dominant neurochemical abnormality. As the disease progresses, the involvement of non-dopaminergic brain regions gives rise to levodopa-resistant motor and non-motor symptoms. As a result, dopamine replacement therapy with levodopa is the gold standard for the initial treatment of Parkinson's disease. Despite the excellent reputation of levodopa in the early stages of the disease, motor response fluctuations and dyskinesias that are disabling become a major threat in long-term treatment.

[0005] Fluctuations in movement in motor ability ultimately occur in >50% of Parkinson's disease patients treated with oral levodopa for over 5 years. Furthermore, many patients also experience other unpleasant "off-period" phenomena, including mood fluctuations, delusions, anxiety, and painful dystonia that coincide with their motor state (Cantello R, et al. Neurol Neurosurg Psychiatry. 1986 Oct;49(10):1182-90; Hardie RJ, et al. Brain. 1984 Jun;107(Pt 2):487-506; Nissenbaum H, et al. Psychol Med. 1987 Nov;17(4):899-904; Quinn NP, et al. Lancet. 1986;327(8494):1366-1369). Initially, the fluctuations in these responses show a predictable pattern related to the timing of levodopa administration (the "wearing-off" phenomenon) and can be managed by shortening the levodopa dosing interval, adding a monoamine oxidase (MAO)-B inhibitor (such as selegiline / deprenyl) or a dopamine receptor agonist, and administering a controlled-release preparation of levodopa or a catechol-O-methyl-transferase inhibitor (e.g., entacapone). However, in the advanced stages of the disease, patients experience complex and unpredictable motor fluctuations called the "on-off" phenomenon that are refractory to these conventional treatment strategies (Marsden CD, et al. Lancet. 1977 Feb 12;1(8007):345-9).

[0006] Ultimately, the clinical response closely reflects the peripheral L-dopa pharmacokinetics, which is characterized by a plasma half-life of 1 - 1.5 hours. The peripheral pharmacokinetics of L-dopa remains unchanged throughout the course of the disease, but the presynaptic substantia nigra-striatal nerve terminals gradually lose their ability to store dopamine. However, there is evidence for a much more complex basis for the development of motor complications, including changes in striatal gene expression and associated changes in the firing patterns of the basal ganglia, which may be related to long-term non-physiological pulsatile stimulation of dopamine receptors.

[0007] Motor complications are divided into motor fluctuations and dyskinesia. As PD progresses, patients begin to experience fluctuations in their motor abilities, i.e., the duration of motor improvement after levodopa dosing becomes shorter and parkinsonism reappears, so they may start to experience the "wearing-off" (the end of a scheduled analgesic) effect. A small number of patients may experience biphasic dyskinesia, where the patient shows dyskinesia when starting to be "on" and / or when starting to be "off", but shows a different and less severe dyskinesia or no dyskinesia at the peak of the levodopa effect. Eventually, patients may experience rapid and unpredictable fluctuations between "on" and "off", known as the "on-off" phenomenon.

[0008] The management of motor fluctuations aims to extend the effect of individual levodopa doses by not only adding adjuvant medications such as catechol-O-methyltransferase (COMT) and monoamine oxidase B (MAO-B) inhibitors, but also changing the dosing intervals and advising patients not to take L-dopa with meals. In addition, transdermal dopamine agonists are added to the dosing regimen or their doses are increased. In some patients, attempts to adjust oral and transdermal medications in the presence of disabling fluctuations and dyskinesia fail after several months or years. Further options, including deep brain stimulation therapy, a pump system that delivers L-dopa to the jejunum via a gastrostomy tube, and intermittent or continuous subcutaneous delivery of the dopamine agonist apomorphine, are treatment options for late-stage PD patients suffering from motor fluctuations.

[0009] Apomorphine is the oldest dopamine agonist used clinically and is indicated for the treatment of motor symptoms associated with advanced Parkinson's disease, particularly bradykinesia associated with advanced Parkinson's disease, acute intermittent treatment of "off" episodes ("wearing off" at the end of regular analgesics and unpredictable "on / off" episodes), and as an adjunct / supplementary therapy to standard levodopa therapy. Apomorphine was first applied to PD patients in 1951, but interest waned with the introduction of oral L-dopa. The long-term complications associated with L-dopa therapy were recognized, and apomorphine was further studied when the antiemetic domperidone, which can prevent most peripheral dopamineergic side effects at a dose of 10 - 30 mg three times a day 72 hours before apomorphine (apomorphine causes severe vomiting), became available.

[0010] Apomorphine is not effective orally because of its high first-pass metabolism in the liver. The exact mechanism of action of apomorphine as a treatment for Parkinson's disease is unknown, but it is thought to be due to the stimulation of postsynaptic D2 receptors in the caudate putamen, a brain structure that supports motor function.

[0011] Currently, there are two different methods of administering apomorphine: subcutaneous bolus dosing and continuous infusion. In the case of subcutaneous injection, its bioavailability reaches almost 100%, and the injection can be effective in rapidly resolving the off state in patients with motor fluctuations. When administered as a single dose, symptom relief is comparable to oral L-dopa, the onset of effect is quite rapid (5 - 15 minutes), and the duration is short (average 40 minutes). In PD patients with severe motor complications, intermittent injections of apomorphine may be used to shorten off time. In PD patients with severe motor complications, continuous subcutaneous infusion of apomorphine may be used to reduce "off" time and dyskinesia. Subcutaneous infusion of apomorphine is appropriate for PD patients with a very high off period when repeated bolus injections are inappropriate.

[0012] As a catechol derivative, apomorphine, which is synthesized from morphine by heating with HCl, is known to be sensitive to oxidation. Under the influence of oxygen, the solution of apomorphine turns green, which indicates the formation of "quinone background" oxidation products (Neef C, et al. Clin Pharmacokinet. 1999. 37(3):257-71). Electrochemical oxidation experiments have shown that the oxidative decomposition of apomorphine is pH-dependent. The decomposition products increase with the increase in pH and lead to spontaneous auto-oxidation at neutral pH (Garrido JM, et al. Bioelectrochemistry. 2002. 55(1-2):113-4).

[0013] The water solubility of apomorphine is 20 mg / ml in pure water at acidic pH, but in NaCl solution, the solubility decreases to less than 10 mg / ml. The pK a values are 7.2 and 8.9, respectively. The UV absorption maximum of a 0.1 mM HCl solution is 273 nm, with a small shoulder at 305 nm (Muhtadi FJ, et al. Analytical Profiles of Drug Substances. 1991. 20:121-171; confirmed with our own data).

[0014] In clinical approaches, numerous administration routes of apomorphine have been tried, resulting in effective therapeutic uses as subcutaneous, sublingual, nasal, or rectal administration. Currently, only subcutaneous formulations are used in clinical routine (Neef C, et al. Clin Pharmacokinet. 1999. 37(3):257-71).

[0015] When administered subcutaneously, apomorphine is known to induce side effects at the administration site, such as skin changes, irritation at the injection site, and subcutaneous nodules or panniculitis (inflammation of subcutaneous adipose tissue).

[0016] Commercially available apomorphine formulations are stabilized by a low pH (3 - 4) and sodium metabisulfite as an antioxidant. In some cases, sulfites can induce allergic reactions in some patients. Furthermore, sodium metabisulfite has a tendency to react irreversibly with the carbon - oxygen double bond found in aldehydes and ketones. This is evaluated, for example, in epinephrine which, like apomorphine, contains two aromatic hydroxyl - binding groups in the ortho - position that lead to quinone formation during oxidation (Gupta PK, et al. (eds.). Injectable drug development: techniques to reduce pain and irritation. Taylor and Francis Group. 1999. 409).

[0017] Histological data shows that apomorphine induces melanin - positive pigmentation in the s.c. region (Loewe R, et al. Hautarzt. 2003. 54:58 - 63). Further data supports nodule formation at the injection site, described as panniculitis with eosinophil and neutrophil infiltration without an increase in IgE infiltration (Acland KM, et al. Br J Dermatol. 1998. 138(3):480 - 2). Due to these irritations, 70% of patients administered apomorphine by subcutaneous injection discontinue treatment within one year.

[0018] Nodule formation induced by subcutaneous application of apomorphine is one of the most frequently described side - effects in apomorphine injection or infusion therapy. In a meta - analysis, the incidence of nodule formation was determined to be 70% in subcutaneous infusion therapy with apomorphine (Deleu D, et al. Drugs Aging. 2004. 21(11):687 - 709). This side - effect is also described in all Summary of Product Characteristics (SmPC) of approved apomorphine solutions.

[0019] However, even with descriptions of symptoms, the exact underlying cause of nodule formation remains unknown. For example, Edwards et al. recently pointed out that "little research has been done on the formation of apomorphine nodules, and as a result, little is known about its etiology or natural history" (Edwards H, et al. Ultrasound. 2008. 16(3):155-9). Allergic reactions, hygiene reasons, effects induced by excipients (EDTA or sodium metabisulfite), and dopamine toxicity have been considered as possible underlying causes of nodule formation, but there is no clear evidence for any of these hypotheses (Acland KM, et al. Br J Dermatol. 1998. 138(3):480-2; Boyle A, et al. CNS Drugs. 2015. 29:83-9; Dadban A, et al. Annales de Dermatologie et de Venereologie. 2010. 137(11):730-5; Deleu D, et al. Drugs Aging. 2004. 21(11):687-709; Edwards H, et al. Ultrasound. 2008. 16(3):155-9; Ganesaligam J, et al. Movement Disorders. 2011. 26(12):2182; Henriksen T. Neurodegen. Dis. Manage. 2014. 4(3):271-82; Hughes AJ, et al. Movement Disorders. 1993. 8(2):165-70; Loewe R, et al. Hautarzt. 2003. 54:58-63; Martinez-Martin P, et al. Movement Disorder. 2015. 30(14):510-6; Neef C, et al. Clin Pharmacokinet. 1999. 37(3):257-71; Rosei MA, et al. Biochemistry and Molecular Biology International. 1995. 35(6):1253-9).

[0020] To explain the neurotoxic effects of apomorphine on a cellular basis, several attempts have been made in the past. The results of these studies, described below, may help to understand the mechanisms underlying the reported side effects of apomorphine formulations at the subcutaneous injection site. In cytotoxicity tests, apomorphine has been shown to have an anti-proliferative effect on the CHO-K1 cell line and to induce apoptosis (Maggio R, et al. Neurotox Res. 2000. 1(4):285-97; Pardini C, et al. Neuropharmacology. 2003. 45(2):182-9). In other tests on rat glioma C6 cells and rat cultured neurons, apomorphine has been shown to promote in vitro the loss of cell membrane integrity, the degeneration of cytoplasmic organelles (especially mitochondria), DNA fragmentation, and necrosis, probably through the formation of oxidized degradation products (quinones) of apomorphine (El-Bacha RS, et al. Neuroscience Letters. 1999. 263:25-8; dos Santos El-Bacha R, et al. Biochem Pharmacol. 2001. 61(1):73-85). Furthermore, apomorphine has been shown to have an anti-proliferative effect on several tumor cell lines (Kondo Y, et al. J Pharmacobiodyn. 1990. 13(7):426-31; Schrell UM, et al. J Clin Endocrinol Metab. 1990. 71(6):1669-71).

[0021] Furthermore, the genotoxic activity of apomorphine has been shown in vitro and in vivo, and is related to its ability to intercalate into DNA, or its pro-oxidant action, or the generation of superoxide radicals during auto-oxidation, and thus may promote frameshift mutations and induce oxidative mutagenicity. These mutagenic and chromosome aberration-inducing effects are likely due to the quinone products formed by the oxidation of apomorphine (Reviews: Picada JN, et al. Brazilian journal of medical and biological research. 2005. 38:477-86; Picada JN, et al. Mutat Res. 2003. 539(1-2):29-41; Picada JN, et al. Brain Res Mol Brain Res. 2003. 114(1):80-5), which is because the more aromatic and planar structure of the quinone products is favorable for intercalation into DNA (Cheng H, et al. Analytical Chemistry. 1979. 51(13):2243-6; Kalyanaraman B. Methods Enzymol. 1990. 186:333-43). In general, quinones are known to be metabolic active intermediates with toxicological potential to cause several toxic effects in vivo (Garrido JM, et al. J Chem Soc, Perkin Trans 2. 2002. 10:1713-7). In the in vivo tests conducted, apomorphine was clearly not genotoxic, but the genotoxic effects of apomorphine and / or its oxidation products, as well as its ability to intercalate into DNA, may lead to cell death and may explain the cytotoxic and anti-proliferative effects of apomorphine observed in the above tests.

[0022] Apomorphine can undergo spontaneous auto-oxidation in neutral and alkaline solutions (Kaul PN. J Pharm Sci. 1961. 50:266-7), which reflects the physiological environment of subcutaneous tissue, and reactive metabolites such as quinones and reactive oxygen species (ROS) may be generated during this oxidation mechanism. However, even in acidic solutions, significant oxidative decomposition of apomorphine occurs in the absence of antioxidants, and the solution turns green within one day. At pH < 7, the main decomposition product is oxoapomorphine, and at pH > 7, apomorphine-paraquione is the main decomposition product (Udvardy A, et al. Journal of molecular structure. 2011. 1002(1):37-44). Therefore, the data from the above in vitro tests are consistent with the side effects of apomorphine commonly observed at the administration site such as skin changes, irritation at the injection site, and subcutaneous nodules and panniculitis, which is due to the oxidation of apomorphine subcutaneously and the generation of oxidation products of apomorphine such as quinones or semiquinones, which may constitute a mechanism leading to the loss of cell integrity and cell death (necrosis) that causes the development of the inflammatory process and nodule formation observed in the surrounding area of the injection site later.

[0023] Various attempts have been made to improve the tolerance, stability and / or pharmacokinetic properties of apomorphine. In particular, certain formulations of apomorphine have been proposed in, for example, EP-A-2545905, US5,939,094, US6,121,276, US8,772,309, WO99 / 66916, WO02 / 100377, WO2009 / 019463, WO2009 / 056851, WO2013 / 007381, WO2013 / 183055 and WO2017 / 055337. Furthermore, certain prodrugs of apomorphine have been proposed, but have not reached approved pharmaceuticals. See, for example, WO2003 / 080074; WO2005 / 041966; Borgman RJ et al., J Med Chem, 1976, 19(5):717-19, doi: 10.1021 / jm00227a026; Liu KS et al., Eur J Pharm Biopharm, 2011, 78(3):422-31, doi: 10.1016 / j.ejpb.2011.01.024; Borkar N et al., Eur J Pharm Biopharm, 2015, 89:216-23, doi: 10.1016 / j.ejpb.2014.12.014; and Borkar N et al., Asian J Pharm Sci, 2018, 13(6):507-517, doi: 10.1016 / j.ajps.2017.11.004.

[0024] WO2019 / 101917 discloses prodrugs of apomorphine in the form of sulfates in which one or both of the 10- and 11-hydroxy groups are modified. These compounds are disclosed as reference examples that are considered not suitable for oral use as bioavailable prodrugs.

[0025] Park Hyejin et al. (ACS Medicinal Chemistry Letters, vol. 11, no. 3, 12 March 2020, pp. 385 - 392) disclose several prodrugs of apomorphine, including diacetate derivatives, dimethyl orthoformate (diMOM) ether derivatives, and methylene acetal derivatives. Summary of the Invention Problems to be Solved by the Invention

[0026] Therefore, there remains a strong unmet need for new therapeutic approaches to provide apomorphine with improved safety and tolerability and an improved side - effect profile. Means for Solving the Problems

[0027] The present invention addresses this need by providing novel prodrugs of apomorphine that are subcutaneously administrable and have highly advantageous safety and tolerability, as well as a particularly beneficial side - effect profile, thereby preventing or reducing the occurrence of inflammatory reactions, nodule formation, and panniculitis in the subcutaneous tissue at the administration site.

[0028] Thus, surprisingly, in the context of the present invention, apomorphine esters, in particular the compounds of formula (I) and their pharmaceutically acceptable salts, have been found to be advantageously water-soluble compared to apomorphine or its pharmaceutically acceptable salts. The inventors have further surprisingly found that the compounds of formula (I) and their pharmaceutically acceptable salts are physiologically stable, particularly in human blood and subcutaneous tissue, but are readily metabolized to apomorphine by human hepatocytes (as also shown in Example 6), and are therefore particularly well-suited as prodrugs. Thus, the compounds of formula (I) exhibit excellent tolerance, improved stability both under storage conditions and under physiological conditions in blood and subcutaneous tissue, as well as an improved side effect profile, particularly a significantly reduced incidence of inflammation and steatitis at the subcutaneous administration site, thereby making it very advantageous as it greatly facilitates patient acceptance and compliance. This is further confirmed by the data shown in Example 7, which shows a reduction in the incidence of nodules in pigs treated with the apomorphine prodrug of the present invention compared to the latest commercially available apomorphine formulations.

[0029] Accordingly, in a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0030] [Chemical formula] In formula (I), the groups R 1 and R 2 are each independently -OH or -O-P(=O)(-OH)(-OH), provided that at least one of R 1 and R 2 is -O-P(=O)(-OH)(-OH).

[0031] In a second aspect, the present invention relates to a pharmaceutical composition comprising a compound according to the first aspect and a pharmaceutically acceptable excipient. In a third aspect, the present invention relates to a compound according to the first aspect or a pharmaceutical composition according to the second aspect for use as a medicament (or for use in therapy). According to this third aspect, the present invention also relates to the use of a compound according to the first aspect in the preparation of a medicament.

[0032] In a fourth aspect, the present invention refers to a compound according to the first aspect or a pharmaceutical composition according to the second aspect for use in the treatment of a neurodegenerative disease / disorder. In this fourth aspect, the present invention also relates to the use of a compound according to the first aspect in the preparation of a medicament for the treatment of a neurodegenerative disease / disorder. The present invention further provides a method of treating a neurodegenerative disease / disorder, the method comprising administering a therapeutically effective amount of a compound according to the first aspect or a pharmaceutical composition according to the second aspect to a subject (e.g., a human) in need thereof. According to the fourth aspect of the present invention, the neurodegenerative disease / disorder is preferably selected from Parkinson's disease, Alzheimer's disease, Huntington's disease, neuroleptic malignant syndrome, dystonia, and schizophrenia (e.g., chronic schizophrenia), more preferably Parkinson's disease.

[0033] The present invention particularly relates to the treatment of Parkinson's disease using a compound according to the first aspect or a pharmaceutical composition according to the second aspect as described and defined herein. Thus, in a fifth aspect, the present invention relates to a compound according to the first aspect or a pharmaceutical composition according to the second aspect for use in the treatment of Parkinson's disease, preferably in a human (e.g., idiopathic Parkinson's disease, acquired Parkinson's disease, or genetic Parkinson's disease). In this aspect, the present invention further refers to the use of a compound according to the first aspect in the preparation of a medicament for the treatment of Parkinson's disease. In the fifth aspect, the present invention similarly provides a method of treating Parkinson's disease, the method comprising administering a therapeutically effective amount of a compound according to the first aspect to a subject (e.g., a human) in need thereof.

[0034] The compound according to the first aspect of the present invention or the pharmaceutical composition according to the second aspect of the present invention can also be used as a rescue treatment for a subject suffering from Parkinson's disease. In particular, the compound or the pharmaceutical composition containing it has received a drug therapy different from apomorphine (especially chronic drug therapy) and can be used as an acute treatment for a Parkinson's disease subject suffering from an acute off period. Thus, the compound or the pharmaceutical composition can be administered as needed when a subject receiving a different treatment for Parkinson's disease (e.g., levodopa) experiences motor fluctuations during regular treatment dosing intervals (e.g., during regular dosing intervals of levodopa). The compound or the pharmaceutical composition may also be administered to a subject suffering from an off period longer than about 30 minutes.

[0035] Thus, in a sixth aspect, the present invention relates to a compound according to the first aspect or a pharmaceutical composition according to the second aspect for use in the treatment of refractory motor fluctuations / tremors in Parkinson's disease, off periods in Parkinson's disease, refractory off periods in Parkinson's disease, dyskinesia in Parkinson's disease (especially peak-dose dyskinesia), or akinesia in Parkinson's disease. In this sixth aspect, the present invention further refers to the use of a compound according to the first aspect in the preparation of a medicament for the treatment of refractory motor fluctuations / tremors in Parkinson's disease, off periods in Parkinson's disease, refractory off periods in Parkinson's disease, dyskinesia in Parkinson's disease, or akinesia in Parkinson's disease. The present invention also relates to a method of treating refractory motor fluctuations / tremors in Parkinson's disease, off periods in Parkinson's disease, refractory off periods in Parkinson's disease, dyskinesia in Parkinson's disease, or akinesia in Parkinson's disease, the method comprising the step of administering a therapeutically effective amount of a compound according to the first aspect or a pharmaceutical composition according to the second aspect to a subject (e.g., a human) in need thereof.

[0036] In a seventh aspect, the invention provides a compound according to the first aspect or a pharmaceutical composition according to the second aspect for use in the treatment of sexual dysfunction or sexual impotence (including male or female sexual dysfunction, particularly male erectile dysfunction) in a human subject. Thus, according to this seventh aspect, the invention relates to a compound according to the first aspect or a pharmaceutical composition according to the second aspect for use particularly in the treatment of male erectile dysfunction in a human subject. In this seventh aspect, the invention also refers to the use of a compound according to the first aspect in the preparation of a medicament for the treatment of sexual dysfunction or sexual impotence, particularly male erectile dysfunction in a human subject. The invention also provides a method of treating sexual dysfunction or sexual impotence, the method comprising administering a therapeutically effective amount of a compound according to the first aspect or a pharmaceutical composition according to the second aspect to a subject (e.g., a human) in need thereof. In particular, the invention provides a method of treating male erectile dysfunction, the method comprising administering a therapeutically effective amount of a compound according to the first aspect or a pharmaceutical composition according to the second aspect to a human subject in need thereof.

[0037] In an eighth aspect, the invention relates to a compound according to the first aspect or a pharmaceutical composition according to the second aspect for use in the treatment of restless legs syndrome. According to this eighth aspect, the invention also provides the use of a compound according to the first aspect in the preparation of a medicament for the treatment of restless legs syndrome. Similarly, the invention provides a method of treating restless legs syndrome, the method comprising administering a therapeutically effective amount of a compound according to the first aspect or a pharmaceutical composition according to the second aspect to a subject (e.g., a human) in need thereof.

[0038] In a ninth aspect, the present invention relates to a compound according to the first aspect or a pharmaceutical composition according to the second aspect for use in the prevention, reduction or amelioration of panniculitis associated with subcutaneous administration of apomorphine, wherein the compound or pharmaceutical composition is administered subcutaneously. In this aspect, the present invention also relates to a compound according to the first aspect or a pharmaceutical composition according to the second aspect for use in the prevention, reduction or amelioration of the formation of subcutaneous nodules associated with subcutaneous administration of apomorphine, wherein the compound or pharmaceutical composition is administered subcutaneously. The present invention further relates to a compound according to the first aspect or a pharmaceutical composition according to the second aspect for use in the prevention, reduction or amelioration of skin inflammation and / or irritation associated with subcutaneous administration of apomorphine, wherein the compound or pharmaceutical composition is administered subcutaneously. According to the ninth aspect, the present invention further refers to (i) the use of a compound according to the first aspect in the preparation of a medicament for the prevention, reduction or amelioration of panniculitis associated with subcutaneous administration of apomorphine, wherein the medicament is administered subcutaneously, (ii) the use of a compound according to the first aspect in the preparation of a medicament for the prevention, reduction or amelioration of the formation of subcutaneous nodules associated with subcutaneous administration of apomorphine, wherein the medicament is administered subcutaneously, and further (iii) the use of a compound according to the first aspect in the preparation of a medicament for the prevention, reduction or amelioration of skin inflammation and / or irritation associated with subcutaneous administration of apomorphine, wherein the medicament is administered subcutaneously. In a ninth aspect, the present invention similarly refers to (i) a method for preventing, reducing or ameliorating panniculitis associated with subcutaneous administration of apomorphine, comprising the step of subcutaneously administering a therapeutically effective amount of a compound according to the first aspect or a pharmaceutical composition according to the second aspect to a subject (e.g., a human) in need thereof, (ii) a method for preventing, reducing or ameliorating the formation of subcutaneous nodules associated with subcutaneous administration of apomorphine, comprising the step of subcutaneously administering a therapeutically effective amount of a compound according to the first aspect or a pharmaceutical composition according to the second aspect to a subject (e.g., a human) in need thereof, and (iii) a method for preventing, reducing or ameliorating skin inflammation and / or irritation associated with subcutaneous administration of apomorphine, comprising the step of subcutaneously administering a therapeutically effective amount of a compound according to the first aspect or a pharmaceutical composition according to the second aspect to a subject (e.g., a human) in need thereof.

[0039] The present invention is further illustrated by the following exemplary figures.

Brief Description of the Drawings

[0040]

Figure 1-1

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Mode for Carrying Out the Invention

[0041] The following detailed description applies to all embodiments of the present invention, including all embodiments according to each one of the first, second, third, fourth, fifth, sixth, seventh, eighth, and ninth aspects described above in this specification.

[0042] In a first aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0043]

Chemical Formula

[0044] Accordingly, R 1 may be -OH, R 2 may be -O-P(=O)(-OH)(-OH), or R 1 may be -O-P(=O)(-OH)(-OH), R 2 may be -OH, or R 1 and R 2 may each be -O-P(=O)(-OH)(-OH). Accordingly, the compound of formula (I) can be, for example, a compound having any one of the following formulas, or a pharmaceutically acceptable salt thereof.

[0045]

Chemical Formula

[0046] More preferably, R 1 is -OH, and R 2 is -O-P(=O)(-OH)(-OH). Therefore, it is particularly preferred that the compound of formula (I) is a compound having the following formula or a pharmaceutically acceptable salt thereof.

[0047]

Chemical formula

[0048]

Chemical formula

[0049]

Chemical formula

[0050]

Chemical formula

[0051] The scope of the present invention encompasses all pharmaceutically acceptable salt forms of the compounds of formula (I) which can be formed, for example, by protonating an atom having an easily protonatable lone pair of electrons such as an amino group with an inorganic or organic acid, or as a salt of an acid group (e.g., phenolic -OH group or phosphate group) with a physiologically acceptable cation. Exemplary base addition salts include, for example, alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salt, meglumine salt, ethylenediamine salt, or choline salt; aralkylamine salts such as N,N - dibenzylethylenediamine salt, benzathine salt, benethamine salt; heterocyclic aromatic amine salts such as pyridine salt, picoline salt, quinoline salt, or isoquinoline salt; quaternary ammonium salts such as tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt, or tetrabutylammonium salt; and basic amino acid salts such as arginine salt, lysine salt or histidine salt.Exemplary acid addition salts include, for example, mineral salts such as hydrochloride, hydrobromide, hydroiodide, sulfate (such as sulfuric acid or bisulfate), nitrate, phosphate (such as phosphoric acid, hydrogen phosphate or dihydrogen phosphate), carbonate, bicarbonate, perchlorate, borate, or thiocyanate; organic acid salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipate, gluconate, glycolate, nicotinate, benzoate, salicylate, ascorbate, pamoate (embonate), camphorate, glucoheptanoate, or pivalate; sulfonate salts such as methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-naphthalenesulfonate (napsylate), 3-phenylsulfonate, or camphorsulfonate; glycerophosphate; and acidic amino acid salts such as aspartate or glutamate. Further pharmaceutically acceptable salts are described in the literature, for example, Stahl PH & Wermuth CG (eds.), "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Wiley-VCH, 2002 and the references cited therein. Preferred examples of pharmaceutically acceptable salts of the compounds of formula (I) include pharmaceutically acceptable alkali metal salts or pharmaceutically acceptable divalent metal cation salts. Particularly preferred examples of pharmaceutically acceptable salts of the compounds of formula (I) include sodium salt, potassium salt, ammonium (NH4. + ) salt, magnesium salt, calcium salt, zinc salt, copper salt (especially Cu(II) salt), or iron salt (especially Fe(II) salt). A particularly preferred example of a pharmaceutically acceptable salt of the compound of formula (I) is the sodium salt.

[0052] The present invention also relates, in particular, to a compound of formula (I) in non-salt form, comprising any one of the specific compounds of formula (I) described herein. The compound of formula (I) or a pharmaceutically acceptable salt thereof may also exist in any solvated form, including, in particular, as a solvate with water. Thus, the compound of formula (I) or a pharmaceutically acceptable salt thereof may also be in the form of a hydrate. Furthermore, the present invention encompasses all physical forms, including any amorphous or crystalline form (i.e., polymorph) of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0053] For the sake of brevity, when considering the compound of formula (I) or a pharmaceutically acceptable salt thereof hereinafter, reference is made to the "compound of formula (I)" (or "compound (I)"). It should be understood that such reference relates to the compound of formula (I) or a pharmaceutically acceptable salt thereof, and in particular to the corresponding compound in non-salt form or in the form of a pharmaceutically acceptable salt.

[0054] The scope of the present invention also encompasses compounds of formula (I) in which one or more atoms are replaced by specific isotopes of the corresponding atoms. For example, the present invention encompasses compounds of formula (I) in which one or more hydrogen atoms (or, for example, all hydrogen atoms) are replaced by deuterium atoms (i.e., 2 H; also referred to as "D"). Thus, the present invention also encompasses deuterium-enriched compounds of formula (I). Naturally occurring hydrogen consists of approximately 99.98 mol% hydrogen-1 ( 1 H) and approximately 0.0156 mol% deuterium ( 2It is an isotope mixture containing H or D). The deuterium content at one or more hydrogen positions in the compound of formula (I) can be increased using deuteration techniques known in the art. For example, the compound of formula (I), or a reactant or precursor used in the synthesis of the compound of formula (I), can be subjected to an H / D exchange reaction using, for example, heavy water (D2O). Further suitable deuteration techniques are described in Atzrodt J et al., Bioorg Med Chem, 20(18), 5658 - 5667, 2012; William JS et al., Journal of Labelled Compounds and Radiopharmaceuticals, 53(11 - 12), 635 - 644, 2010; Modvig A et al., J Org Chem, 79, 5861 - 5868, 2014. The deuterium content can be determined using, for example, mass spectrometry or NMR spectroscopy. Unless specifically indicated otherwise, the compounds of formula (I) are preferably not enriched in deuterium. Thus, it is preferred that hydrogen atoms or 1 H hydrogen atoms that occur naturally in the compound of formula (I) are present.

[0055] The present invention also encompasses compounds of formula (I) in which one or more atoms are replaced by a positron-emitting isotope of the corresponding atom such as, for example, 11 C, 13 N and / or 15 O. Such compounds can be used as tracers, trackers or imaging probes in positron emission tomography (PET). Thus, the present invention includes (i) compounds of formula (I) in which one or more carbon atoms (or, for example, all carbon atoms) are replaced by 11 C atoms, (ii) compounds of formula (I) in which a nitrogen atom is replaced by 13 N atoms, and (iii) compounds of formula (I) in which one or more oxygen atoms (or, for example, all oxygen atoms) are replaced by 15 O atoms. In general, it is preferred that none of the atoms in the compounds of formula (I) are replaced by a specific isotope.

[0056] The present invention further relates to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable excipient. In particular, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament, and a pharmaceutically acceptable excipient. The pharmaceutical composition may comprise a single compound of formula (I) or a pharmaceutically acceptable salt thereof, or may comprise more than one compound of formula (I) or a pharmaceutically acceptable salt thereof. In particular, the present invention relates to (i) a compound of formula (I) (the "first compound") in which R 1 is -OH and R 2 is -O-P(=O)(-OH)(-OH), or a pharmaceutically acceptable salt thereof, (ii) a compound of formula (I) (the "second compound") in which R 1 is -O-P(=O)(-OH)(-OH) and R 2 is -OH, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. The molar ratio of the "first compound" to the "second compound" is not particularly limited and may be, for example, in the range of 10:1 to 1:10, preferably in the range of 5:1 to 1:5, more preferably in the range of 3:1 to 1:3, and even more preferably in the range of 2:1 to 1:2 (for example, about 1:1).

[0057] The compound of formula (I) provided herein may be administered as the compound itself or may be formulated as a medicament. The medicament / pharmaceutical composition may optionally comprise one or more pharmaceutically acceptable excipients such as carriers, diluents, fillers, disintegrants, lubricants, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and / or solubility enhancers.

[0058] The pharmaceutical composition may contain one or more solubility enhancers, such as poly(ethylene glycol) having a molecular weight in the range of about 200 to about 5,000 Da (e.g., PEG200, PEG300, PEG400, or PEG600), ethylene glycol, propylene glycol, glycerol, nonionic surfactants, tyloxapol, polysorbate 80, macrogol-15-hydroxystearate (e.g., Kolliphor® HS 15, CAS 70142-34-6), phospholipids, lecithin, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, cyclodextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, sulfobutyl ether-γ-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkylthioether, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, or any combination thereof.

[0059] The pharmaceutical composition may also contain one or more preservatives, particularly one or more antibacterial preservatives, for example, such as benzyl alcohol, chlorobutanol, 2-ethoxyethanol, m-cresol, chlorocresol (for example, 2-chloro-3-methyl-phenol or 4-chloro-3-methyl-phenol), benzalkonium chloride, benzethonium chloride, benzoic acid (or its pharmaceutically acceptable salts), sorbic acid (or its pharmaceutically acceptable salts), chlorhexidine, thimerosal, or any combination thereof. A preferred antibacterial preservative is benzyl alcohol.

[0060] The pharmaceutical composition can be formulated by techniques known to those skilled in the art, for example, the techniques disclosed in "Remington: The Science and Practice of Pharmacy", Pharmaceutical Press, 22nd edition. The pharmaceutical composition can be formulated as dosage forms for oral, parenteral, for example intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardiac, rectal, nasal, oral mucosa, buccal, sublingual, topical, aerosol or vaginal administration. Dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, troches, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, medicinal gums, chewable tablets, effervescent tablets, and sublingual films. Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersants and powders and granules for reconstitution. Emulsions are a preferred dosage form for parenteral administration. Dosage forms for rectal and vaginal administration include suppositories and vaginal suppositories. Dosage forms for nasal administration may be administered, for example, by inhalation and insufflation using a metered-dose inhaler. Dosage forms for topical administration include creams, gels, ointments, plasters, patches and transdermal delivery systems.

[0061] The pharmaceutical composition preferably contains a compound of formula (I) or a pharmaceutically acceptable salt thereof (preferably the sodium salt) in an amount of about 0.1 mg / ml to 50 mg / ml, more preferably in an amount of about 3 mg / ml to about 20 mg / ml, and even more preferably in an amount of about 5 mg / ml to about 10 mg / ml. It should be understood that the above-mentioned amount / concentration is based on the weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof, that is, it is not based on the weight of the non-salt form of the compound of formula (I) unless the compound of formula (I) is actually used in the non-salt form. For example, when the compound of formula (I) exists in the form of trisodium anhydrous salt, 5 mg / ml refers to the amount of 5 mg of the trisodium salt of the compound of formula (I) in 1 ml of the pharmaceutical composition. Therefore, it should be further understood that the above-mentioned amount / concentration is not based on the corresponding amount of apomorphine or a salt thereof obtained upon hydrolysis of the compound of formula (I) or a pharmaceutically acceptable salt thereof. The supply of a high concentration of the compound of formula (I) to the pharmaceutical composition can be promoted, for example, by including a solubilizing agent such as α-propylene glycol in the pharmaceutical composition.

[0062] The pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered directly by the subcutaneous route, such as by subcutaneous injection. An aqueous composition containing a higher concentration of the compound of formula (I) or a pharmaceutically acceptable salt thereof can be used, for example, for subcutaneous sustained infusion in which the aqueous composition can be diluted to the desired final concentration upon administration, or for subcutaneous administration by intermittent bolus injection using an injection pen in which the aqueous composition is pre-filled in a pen cartridge (also referred to as a "cartridge"). Therefore, the pharmaceutical composition of the present invention can be provided, for example, in a container (such as an injection vial) or a pen cartridge.

[0063] The pharmaceutical composition according to the present invention may also contain one or more antioxidants, for example, reduced glutathione (「GSH」, IUPAC name: (2S)-2-amino-4-{[(1R)-1-[(carboxymethyl)carbamoyl]-2-sulfanylethyl]carbamoyl}butanoic acid) or a pharmaceutically acceptable salt thereof (e.g., an alkali metal salt, especially the sodium salt), and / or ascorbic acid (especially L-ascorbic acid, i.e., (5R)-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxyfuran-2(5H)-one) or a pharmaceutically acceptable salt thereof (e.g., sodium ascorbate, potassium ascorbate, or calcium ascorbate). The pharmaceutical composition preferably contains both reduced glutathione (or a pharmaceutically acceptable salt thereof) and ascorbic acid (or a pharmaceutically acceptable salt thereof). Reduced glutathione (GSH) or a pharmaceutically acceptable salt thereof may be present in the pharmaceutical composition of the present invention in an amount of about 1 mg / ml to about 50 mg / ml, more preferably in an amount of about 1 mg / ml to about 20 mg / ml, even more preferably in an amount of about 2 mg / ml to about 10 mg / ml, and still more preferably in an amount of about 5 mg / ml. The pharmaceutical composition of the present invention may be present in the pharmaceutical composition of the present invention in an amount of about 2 mg / ml to about 50 mg / ml, more preferably in an amount of about 5 mg / ml to about 20 mg / ml, even more preferably in an amount of about 8 mg / ml to about 15 mg / ml, and still even more preferably in an amount of about 10 mg / ml.

[0064] The pharmaceutical composition of the present invention is preferably an aqueous pharmaceutical composition. Accordingly, the pharmaceutical composition preferably contains water, particularly at least about 60% (v / v) water, more preferably at least about 70% (v / v) water, even more preferably at least about 80% (v / v) water, even more preferably at least about 90% (v / v) water, and still even more preferably at least about 95% (v / v) water, based on the total volume of the pharmaceutical composition. The water in the pharmaceutical composition is preferably water for injection (e.g., as defined in the 8th edition of the European Pharmacopoeia (Ph.Eur.) as of July 1, 2015, including Addendum 8.6). Water for injection (WFI) can be prepared, for example, using techniques known in the art, such as distillation or membrane techniques (such as reverse osmosis or ultrafiltration), as described in Felton LA (ed.), Remington: Essentials of Pharmaceutics, Pharmaceutical Press, 2013.

[0065] The pharmaceutical composition may be, for example, an aqueous solution or an oil-in-water emulsion. In this regard, the pharmaceutical composition preferably has an oil content of less than about 5% (v / v), more preferably less than about 3% (v / v), even more preferably less than about 2% (v / v), even more preferably less than about 1% (v / v), and still even more preferably less than about 0.5% (v / v), and still even more preferably does not contain oil. Accordingly, it is preferred that the pharmaceutical composition is an aqueous solution.

[0066] Furthermore, the pharmaceutical composition preferably has a total content of lipophilic substances of less than about 5% (v / v), more preferably less than about 3% (v / v), even more preferably less than about 2% (v / v), even more preferably less than about 1% (v / v), and still even more preferably less than about 0.5% (v / v), and still even more preferably does not contain lipophilic substances.

[0067] The pharmaceutical composition is preferably an aqueous pharmaceutical composition having a pH of about 3 to about 7.4 (such as a pH of about 3.0, about 3.7, about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, or about 7.4). More preferably, the pharmaceutical composition has a pH of about 4 to about 7, more preferably a pH of about 5 to about 6 (such as about 5.0, about 5.5, or about 6.0), and even more preferably a pH of about 5.5.

[0068] The desired pH may be controlled by adjusting the pH by using a suitable buffer and adding an aqueous solution of HCl or NaOH as necessary. The buffer is not particularly limited, and examples thereof include malic acid buffer, formic acid buffer, succinic acid buffer, citric acid buffer, acetic acid buffer, pyridine buffer, MES buffer, tartaric acid buffer, oxalic acid buffer, ascorbic acid buffer, cacodylic acid buffer, dimethylglutaric acid buffer, carbonate buffer, Bis-Tris buffer, ADA buffer, pyrophosphate buffer, EDPS buffer, Bis-Tris propane buffer, PIPES buffer, ACES buffer, MOPSO buffer, imidazole buffer, histidine buffer, BES buffer, MOPS buffer, phosphate buffer, EMTA buffer, TES buffer, HEPES buffer, and DIPSO buffer (for example, as described in Stoll VS, et al. Buffers: principles and practice. Methods Enzymol. 1990. 182:24-38 or AppliChem, Biological Buffers, 2008). It is understood that a suitable buffer can be selected according to the pK a value of the buffer substance and the desired pH of the pharmaceutical composition.

[0069] The pharmaceutical composition according to the present invention may further contain α - propylene glycol (i.e., propane - 1,2 - diol) and / or sodium chloride. These substances can be used as tonicity agents to make the pharmaceutical composition isotonic with human plasma. Thus, the pharmaceutical composition may contain, for example, α - propylene glycol in an amount of about 1 mg / ml to about 25 mg / ml (or about 5 mg / ml to about 15 mg / ml), but when α - propylene glycol is used as a tonicity agent, the preferred amount of α - propylene glycol depends on the pH of the pharmaceutical composition (for example, the pharmaceutical composition according to the present invention having a pH of about 5 may preferably contain α - propylene glycol in an amount of about 5 mg / ml to about 10 mg / ml). The pharmaceutical composition may contain, for example, sodium chloride in an amount of about 3 mg / ml to about 8 mg / ml, but when sodium chloride is used as a tonicity agent, the preferred amount of sodium chloride depends on the pH of the pharmaceutical composition (for example, the pharmaceutical composition according to the present invention having a pH of about 5 may preferably contain sodium chloride in an amount of about 4.5 mg / ml).

[0070] It is preferred that the pharmaceutical composition is isotonic with human plasma. In particular, it is preferred that the pharmaceutical composition has an osmotic pressure of about 280 mOsm / kg to about 305 mOsm / kg, more preferably about 290 mOsm / kg to about 300 mOsm / kg, and even more preferably about 296 mOsm / kg. Further, the pharmaceutical composition is preferably made isotonic using α - propylene glycol and / or sodium chloride as described above herein, more preferably using α - propylene glycol (for example, to any of the aforementioned osmotic pressure ranges or values).

[0071] In principle, the compound of formula (I) or its pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition may be administered to a subject by any convenient route of administration. Corresponding routes of administration include oral (e.g., as tablets, capsules, or ingestible solutions), topical (e.g., transdermal, intranasal, ocular, buccal, and sublingual), parenteral (e.g., using injection techniques or infusion techniques, e.g., by injection, e.g., subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intra-articular, subarachnoid, or intrasternal, e.g., by implantation of a depot, e.g., subcutaneous or intramuscular), pulmonary (e.g., using an aerosol, e.g., by inhalation or insufflation therapy from the mouth or nose), gastrointestinal, intrauterine, intraocular, subcutaneous, ophthalmic (including intravitreal or intracameral), rectal, or intravaginal administration, but are not limited thereto. The compound of formula (I) or the pharmaceutical composition is preferably administered parenterally (e.g., by injection or infusion), more preferably subcutaneously.

[0072] When the compound or pharmaceutical composition is administered parenterally, examples of such administration include intravenous, intra-arterial, intraperitoneal, intrathecal, intracerebroventricular, intraurethral, intrasternal, intracardiac, intracranial, intramuscular, or subcutaneous administration of the compound or pharmaceutical composition, and / or administration by use of one or more of infusion techniques. Thus, for example, parenteral administration of the compounds of the present invention may be by subcutaneous injection or infusion. In the case of parenteral administration, the compound is optimally used in the form of a sterile aqueous solution, which may contain other substances, e.g., salts or glucose sufficient to render the solution isotonic with blood. The aqueous solution should preferably be buffered as appropriate (preferably to pH 3 to 9). Preparation of suitable parenteral formulations under sterile conditions can be readily achieved by standard pharmaceutical techniques well known to those skilled in the art.

[0073] Alternatively, the compound or pharmaceutical composition may be orally administered in the form of tablets, capsules, vaginal suppositories, elixirs, solutions or suspensions which may contain flavoring or coloring agents for immediate, delayed, modified, sustained, pulsed or controlled release applications. Tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulating binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricants such as magnesium stearate, stearic acid, glyceryl behenate, and talc may be included. Solid compositions of the same type may also be used as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, cellulose, or high molecular weight polyethylene glycol. In the case of aqueous suspensions and / or elixirs, the drug may be combined with various sweetening or flavoring agents, coloring substances or dyes, emulsifying and / or suspending agents, and diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof. For oral administration, the compound or pharmaceutical composition is preferably administered by oral ingestion, particularly by swallowing. Thus, the compound or pharmaceutical composition may pass through the mouth and be administered to the gastrointestinal tract, which may also be referred to as "oral gastrointestinal tract" administration.

[0074] Alternatively, the compound or pharmaceutical composition may be administered in the form of suppositories or pessaries, or may be topically applied in the form of gels, hydrogels, lotions, solutions, creams, ointments or sprays. The compounds of the present invention may also be administered to the skin or transdermally, for example by using a skin patch.

[0075] The compound or pharmaceutical composition may also be administered by a sustained release system. Suitable examples of sustained release compositions include shaped articles such as films, or semipermeable polymer matrices in the form of microcapsules. Examples of sustained release matrices include, for example, polylactic acid, copolymers of L-glutamic acid and gamma-ethyl-L-glutamic acid, poly(2-hydroxyethyl methacrylate), ethylene vinyl acetate, or poly D(-)-3-hydroxybutyric acid. Sustained release pharmaceutical compositions also include compounds encapsulated in liposomes. Accordingly, the present invention also relates to liposomes containing the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0076] The compound or pharmaceutical composition may also be administered by the pulmonary route, rectal route, or ocular route. For ophthalmic use, they may be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline or preferably as a solution in isotonic, pH-adjusted, sterile saline, optionally in combination with a preservative such as benzalkonium chloride. Alternatively, they may be formulated into an ointment such as petrolatum.

[0077] For pulmonary administration, particularly inhalation, it is also contemplated to prepare dry powder formulations of the compound of formula (I) or a pharmaceutically acceptable salt thereof. Such dry powders may be prepared by spray drying under conditions that result in a substantially amorphous glassy or substantially crystalline bioactive powder. Accordingly, the dry powder of the compound of the present invention may be made according to an emulsification / spray drying process.

[0078] For topical application to the skin, the compound or pharmaceutical composition may be formulated as a suitable ointment containing the active compound suspended or dissolved, for example, in a mixture of one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax, and water. Alternatively, they may be formulated as a suitable lotion or cream containing the active compound suspended or dissolved, for example, in a mixture of one or more of the following: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl ester wax, 2-octyldodecanol, benzyl alcohol, and water.

[0079] Accordingly, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, wherein the corresponding compound or pharmaceutical composition is administered by any one of the following routes: oral route; topical routes including transdermal, intranasal, ocular, buccal, or sublingual routes; parenteral routes using injection or infusion techniques including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intraarticular, subarachnoid, intrasternal, intraventricular, intraurethral, or intracranial routes; pulmonary routes including inhalation or insufflation therapy; gastrointestinal routes; intrauterine routes; intraocular routes; subcutaneous routes; ophthalmic routes including intravitreal or intracameral routes; rectal routes; or vaginal routes. Preferred routes of administration are parenteral administration, particularly subcutaneous administration (e.g., by subcutaneous injection or infusion) or intramuscular administration. Particularly preferred routes of administration are, for example, subcutaneous administration by subcutaneous injection or infusion. Accordingly, for each of the compounds or pharmaceutical compositions provided herein, it is particularly preferred that each compound or pharmaceutical composition be administered subcutaneously (particularly by subcutaneous injection or infusion).

[0080] Typically, a physician determines the most suitable actual dosage for an individual subject. The specific dosage levels and dosing frequencies for a particular individual subject may vary and depend on various factors including the activity of the specific compound utilized, the metabolic stability and duration of action of that compound, age, weight, general health status, gender, diet, mode and time of administration, rate of excretion, drug combinations, the severity of the particular condition, and the individual subject being treated.

[0081] For example, a compound or pharmaceutical composition according to the present invention may be administered to a human subject (preferably a human subject 18 years of age or older) by subcutaneous intermittent bolus injection at a dosage of about 1 mg to about 10 mg of the active ingredient (i.e., the compound of formula (I) or a pharmaceutically acceptable salt thereof). The corresponding unit dosage may be administered subcutaneously, for example, 1 to 12 times per day (preferably 1 to 10 times per day), up to a maximum daily dosage of, for example, about 100 mg (preferably up to a maximum daily dosage of about 50 mg, more preferably up to a maximum daily dosage of about 30 mg). Alternatively, the compound or pharmaceutical composition may also be administered to a human subject (preferably a human subject 18 years of age or older) by subcutaneous continuous infusion at an infusion rate of about 1 mg to about 4 mg of the active ingredient per hour (i.e., the compound of formula (I) or a pharmaceutically acceptable salt thereof that may be contained in the pharmaceutical composition at a concentration of, for example, about 5 mg / ml), or at an infusion rate of about 0.015 mg / kg / hour to about 0.06 mg / kg / hour of the active ingredient (i.e., the compound of formula (I) or a pharmaceutically acceptable salt thereof that may be contained in the pharmaceutical composition at a concentration of, for example, about 5 mg / ml) (e.g., using a minipump and / or syringe driver). It is understood that the dosage may need to be adjusted daily depending on the age and weight of the patient / subject and the severity of the condition being treated. The exact dosage, as well as the route of administration, is ultimately at the discretion of the attending physician (or attending veterinarian).

[0082] Apomorphine has been described as useful in the treatment of Parkinson's disease (e.g., Schwab RS, et al. Trans Am Neurol Assoc. 1951. 56:251-253; Cotzias GC, et al. N Engl J Med. 1970. 282:31-33; Poewe W, et al. Mov Disord. 2000. 15(5):789-794; and Manson AJ, et al. Mov Disord. 2002. 17(6):1235-1241), Alzheimer's disease (e.g., Lashuel HA, et al. J Biol Chem. 2002. 277(45):42881-42890; Steele JW, et al. Ann Neurol. 2011. 69(2):221-225; and Himeno E, et al. Ann Neurol. 2011. 69(2):248-256), Huntington's disease (e.g., Corsini GU, et al. Arch Neurol. 1978. 35(1):27-30; Colosimo C, et al. Clin Neuropharmacol. 1994. 17(3):243-259; and Albanese A, et al. Clin Neuropharmacol. 1995. 18(5):427-434), neuroleptic malignant syndrome (e.g., Colosimo C, et al. Clin Neuropharmacol. 1994. 17(3):243-259; and Wang HC, et al. Mov Disord. 2001. 16(4):765-767), dystonia (e.g., Colosimo C, et al. Clin Neuropharmacol. 1994. 17(3):243-259), schizophrenia (e.g., Smith RC, et al. J Neural Transm. 1977. 40(2):171-176; and Tamminga CA, et al. Science. 1978. 200(4341):567-568), and additional neurodegenerative diseases / disorders (e.g., Kyriazis M. J Anti Aging Med. 2003. 6(1):21-28; and Truong JG, et al. Eur J Pharmacol. 2004. 492(2-3):143-147).The use of apomorphine for the treatment of erectile dysfunction and impotence has also been described in the literature (e.g., Heaton JP, et al. Urology. 1995. 45(2):200-206; O’Sullivan JD, et al. Mov Disord. 1998. 13(3):536-539; Dula E, et al. Urology. 2000. 56(1):130-135; and Rampin O. BJU Int. 2001. 88 Suppl. 3:22-24). Since the compounds of formula (I) can be used as prodrugs of apomorphine, they can be used for the treatment of the above disorders, as well as other disorders for which the use of apomorphine has been proposed in the literature.

[0083] As used herein, the term "treatment" (or "treating") in relation to a disease or disorder refers to the management and care of a patient for the purpose of combating the disease or disorder, such as reversing, alleviating, suppressing or delaying the disease or disorder, or one or more symptoms thereof. The term also refers to the administration of a compound or composition for the purpose of preventing the onset of symptoms of a disease or disorder, alleviating such symptoms, or eliminating the disease or disorder. "Treatment" may be prophylactic or non-prophylactic. Preferably, "treatment" is curative, ameliorative or palliative.

[0084] The pharmaceutical composition according to the invention, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active agent, may be administered in the context of monotherapy or in combination with one or more further pharmaceutical active agents. When the pharmaceutical composition according to the invention is used in combination with a further pharmaceutical active agent that is active against the same disease / disorder, lower doses of each agent can be used. The combination of the pharmaceutical composition according to the invention with one or more further pharmaceutical active agents may include simultaneous / concomitant administration of the further pharmaceutical active agent and the pharmaceutical composition according to the invention. However, sequential / separated administration is also envisaged. If the administration is sequential, either the pharmaceutical composition according to the invention or one or more of the further pharmaceutical active agents can be administered first. If the administration is simultaneous, the one or more further pharmaceutical active agents may be included in the pharmaceutical composition according to the invention or may be administered in one or more different (separate) pharmaceutical compositions.

[0085] For the treatment of Parkinson's disease, the compound of formula (I) (or a pharmaceutically acceptable salt thereof) or the pharmaceutical composition according to the invention can be administered in combination with one or more further anti-Parkinson's agents which can be selected from, for example, etilevodopa, droxidopa, levodopa, melevodopa, aplindore, bromocriptine, cabergoline, siradopa, dihydroergocriptine, lisuride, pardoprunox, pergolide, piribedil, pramipexole, ropinirole, rotigotine, ladostigil, lazabemide, mofegiline, pargyline, rasagiline, selegiline, entacapone, nitecapone, tolcapone, benserazide, carbidopa, methyldopa, benzatropine, biperiden, bornaprine, chlorphenoxamine, cyclimine, dextethimide, dimenhydrinate, diphenhydramine, etanautine, etibenzatropine, mazaticol, methixene, orphenadrine, phenglutarimide, pyroheptin, procyclidine, profenamine, trihexyphenidyl, tropatepine, amantadine, budipine, memantine, methylxanthine, rimantadine, UWA-101, and pharmaceutically acceptable salts of any of these agents. Preferred anti-Parkinson's agents are levodopa, carbidopa and biperiden. A particularly preferred anti-Parkinson's agent is levodopa.

[0086] Accordingly, the present invention relates to a compound of the first aspect or a pharmaceutical composition of the second aspect as described and defined herein for use in the treatment of Parkinson's disease (or for use in the treatment of refractory motor fluctuations / tremors in Parkinson's disease, off-periods in Parkinson's disease, refractory off-periods in Parkinson's disease, dyskinesia in Parkinson's disease, and / or akinesia in Parkinson's disease), wherein the compound or the pharmaceutical composition is administered subcutaneously, and the compound or the pharmaceutical composition is administered in combination with one or more additional anti-Parkinson's disease agents (e.g., one or more of the specific anti-Parkinson's disease agents described above). The combined administration of the compound or the pharmaceutical composition with one or more additional anti-Parkinson's disease agents can be carried out, for example, by simultaneous / concurrent administration or sequential / separate administration. The one or more additional anti-Parkinson's disease agents do not necessarily have to be administered subcutaneously, but rather may be administered by any convenient route of administration.

[0087] Apomorphine, which is a hydrolysis product of the compound of formula (I), may cause short-term nausea, especially at the beginning of treatment. Therefore, the compound of the present invention or the pharmaceutical composition according to the present invention is preferably administered in combination with an antiemetic. Such combination treatment may be administered, for example, for a period of at least two weeks, and then the administration of the antiemetic may be terminated while continuing the administration of the compound or pharmaceutical composition of the present invention. The antiemetic may be selected, for example, from alizapride, alosetron, aprepitant, atropine, azasetron, bemestron, benzquinamine, bromopride, buclizine, casopitant, cerium oxalate, chlorpromazine, cilansetron, clebopride, clozapine, cyclizine, cyproheptadine, dazopride, dexamethasone, dimenhydrinate, diphenhydramine, diphenidol, dolasetron, domperidone, dronabinol, ezlopitant, fosaprepitant, granisetron, haloperidol, hydroxyzine, hyoscyamine, itopride, ramosetron, ricisetron, risperidone, scopolamine, tetrahydrocannabinol, thiethylperazine, trimethobenzamide, tropisetron, vestipitant, zatsetron, diprasidone, and pharmaceutically acceptable salts (e.g., hydrochloride) of any of these agents. A particularly preferred antiemetic is domperidone.

[0088] Accordingly, the present invention relates to a compound of formula (I) as described and defined herein or a pharmaceutical composition comprising the same, wherein the compound or the pharmaceutical composition is administered subcutaneously, and the compound or the pharmaceutical composition is administered in combination with an antiemetic (e.g., any one of the antiemetics listed above, preferably domperidone). The combined administration of the compound or pharmaceutical composition and the antiemetic may be effected, for example, by simultaneous / concurrent administration of the antiemetic and the compound or pharmaceutical composition, or by sequential / separate administration. If the administration is sequential, either the compound / pharmaceutical composition of the present invention or the antiemetic may be administered first. If the administration is simultaneous, the antiemetic may be included in the pharmaceutical composition or may be administered in a different (separate) pharmaceutical composition. When provided in a separate pharmaceutical composition, the antiemetic need not be administered subcutaneously and may rather be administered by any convenient route of administration.

[0089] The present invention also relates to the combined administration of a compound or pharmaceutical composition of the present invention with an antiemetic (as described above) and one or more additional anti-Parkinson's agents (as described above). The subject or patient to be treated according to the present invention may be an animal (e.g., a non-human animal). Preferably, the subject / patient is a mammal. More preferably, the subject / patient is a human (e.g., a male human or a female human) or a non-human mammal (e.g., guinea pig, hamster, rat, mouse, rabbit, dog, cat, horse, monkey, ape, marmoset, baboon, gorilla, chimpanzee, orangutan, langur, sheep, cow, or pig, etc.). Most preferably, the subject / patient to be treated according to the present invention is a human.

[0090] As used herein, the term "about" preferably refers to ±10% of the indicated numerical value, more preferably ±5% of the indicated numerical value, particularly the indicated numerical value being exactly accurate. The terms "optional", "optionally" and "may be" indicate that the indicated feature may or may not be present. Whenever the terms "optional", "optionally", or "may be" are used, the present invention specifically relates to both possibilities, namely, the corresponding feature being present or the corresponding feature being absent. For example, when a component of a composition is indicated as "optional", the present invention specifically relates to both possibilities, namely, the corresponding component being present (included in the composition) or the corresponding component being absent from the composition.

[0091] The term "comprising" (or "comprise", "comprises", "contain", "contains" or "containing") has the meaning of "including in particular", i.e., "including... among further optional elements", unless explicitly indicated otherwise or unless inconsistent with the context. In addition to this, this term also includes the narrower meanings of "consisting essentially of" and "consisting of". For example, the term "A comprising B and C" has the meaning of "A including in particular B and C", and A may contain further optional elements (e.g., "A containing B, C and D" is also included), but this term also includes the meaning of "A consisting essentially of B and C" and the meaning of "A consisting of B and C" (i.e., components other than B and C are not included in A).

[0092] Any parameter referred to herein (including any amount / concentration indicated by, for example, "mg / ml" or " %(v / v)", and any pH value) is preferably determined under standard ambient temperature and pressure conditions, in particular at a temperature of 25 °C (298.15 K) and an absolute pressure of 1 atm (101.325 kPa).

[0093] It should be understood that the present invention specifically relates to each and every combination of the features and embodiments described herein, including any combination of general and / or preferred features / embodiments.

[0094] In this specification, many documents are cited, including patent applications and scientific literature. The disclosures of these documents are not considered relevant to the patentability of the present invention, but are incorporated herein by reference in their entirety. More specifically, all of the documents cited are incorporated by reference to the same extent as if each individual document had been specifically and individually indicated to be incorporated by reference.

[0095] Next, the present invention will be described with reference to the following examples, which are merely illustrative and should not be construed as limiting the scope of the present invention.

Example

[0096] Example 1: Synthesis of Apomorphine Monophosphate

[0097]

Chemical formula

[0098] The NMR spectrum of the obtained product is shown in Figure 1.

[0099]

Number

[0100] Method: 0.0 - 0.1 min, isocratic, 2% MeCN (98% H2O + 0.05% TFA); 0.1 - 8.0 min, linear, 2% - 100% MeCN (98% - 0% H2O + 0.05% TFA); 8.0 - 11.1 min, isocratic, 100% MeCN; 11.1 - 11.3 min, linear, 100% - 2% MeCN (0% - 98% H2O + 0.05% TFA); 11.3 - 12.0 min, isocratic, 2% MeCN (98% H2O + 0.05% TFA). UV detection at 254.8 nm.

[0101] Example 2: Separation of Positional Isomers of Apomorphine Monophosphate Purification was performed using a "Thermo Scientific Dionex UltiMate 3000" system equipped with an UltiMate 3000 pump, an UltiMate 3000 autosampler, an UltiMate 3000 column compartment, an UltiMate 3000 diode array detector (deuterium lamp, λ = 190 - 380 nm), and an UltiMate 3000 automatic fraction collector. The components were separated using a Macherey-Nagel VP 125 / 21 Nucleodur (registered trademark) 100-5 C18ec column (125×21mm, 5μm). The signal was detected at 210 nm and 254 nm. Acetonitrile (VWR HiPerSolv, HPLC grade) and water containing trifluoroacetic acid (Barnstead NANOpure (registered trademark), ultrapure water system) were used as the mobile phase. The following method was used.

[0102] Nucleodur C18_005TFA_02to50: 0.0 - 3.0 minutes: 98% H2O (0.05% TFA) and 2% CH3CN; 3.0 - 13.0 minutes: linear gradient to 50% H2O (0.05% TFA) and 50% CH3CN; 13.0 - 14.0 minutes: linear gradient to 100% CH3CN; 14.0 - 15.0 minutes: 100% CH3CN; 15.0 - 16.0 minutes: linear gradient to 98% H2O (0.05% TFA) and 2% CH3CN; 16.0 - 19.0 minutes: 98% H2O (0.05% TFA) and 2% CH3CN; Flow rate: 15.00 mL·min -1 ; T = 30 °C. HPLC - MS analysis of the mixture: Column: C - 18 reverse - phase column of the type "Poroshell® 120 SB - C18, 3.0×100 mm, 2.7 μm" by Agilent Technologies. Flow rate: constant flow rate 0.7 mL / min, T = 35 °C.

[0103] Method: 0.0 - 0.1 minutes, isocratic, 2% MeCN (98% H2O + 0.05% TFA); 0.1 - 10.0 minutes, linear gradient, 2% - 50% MeCN (98% - 0% H2O + 0.05% TFA); 10.0 - 10.5 minutes, linear gradient, 50% - 100% MeCN (0% - 98% H2O + 0.05% TFA); 10.5 - 12.0 minutes, isocratic, 100% MeCN; 12.0 - 12.5 minutes, linear gradient, 100% - 2% MeCN (0% - 98% H2O + 0.05% TFA); isocratic, 12.5 - 14.0 minutes, isocratic, 2% MeCN (98% H2O + 0.05% TFA). UV detection at 254.8 nm.

[0104] The analysis results are shown in Part 1 of Figure 3. HPLC - MS analysis of the separated peak 1: Column: C - 18 reverse - phase column of the type "Poroshell® 120 SB - C18, 3.0×100 mm, 2.7 μm" by Agilent Technologies. Flow rate: constant flow rate 0.7 mL / min, T = 35 °C.

[0105] Method: 0.0 - 0.1 min, isocratic, 2% MeCN (98% H2O + 0.05% TFA); 0.1 - 10.0 min, linear gradient, 2% - 50% MeCN (98% - 0% H2O + 0.05% TFA); 10.0 - 10.5 min, linear gradient, 50% - 100% MeCN (0% - 98% H2O + 0.05% TFA); 10.5 - 12.0 min, isocratic, 100% MeCN; 12.0 - 12.5 min, linear gradient, 100% - 2% MeCN (0% - 98% H2O + 0.05% TFA); isocratic, 12.5 - 14.0 min, isocratic, 2% MeCN (98% H2O + 0.05% TFA). UV detection at 254.8 nm.

[0106] The analysis results are shown in Part 2 of Figure 3. NMR analysis of separated peak 1

[0107]

Chem.

[0108]

Math.

[0109] Method: 0.0 - 0.1 min, isocratic, 2% MeCN (98% H2O + 0.05% TFA); 0.1 - 10.0 min, linear gradient, 2% - 50% MeCN (98% - 0% H2O + 0.05% TFA); 10.0 - 10.5 min, linear gradient, 50% - 100% MeCN (0% - 98% H2O + 0.05% TFA); 10.5 - 12.0 min, isocratic, 100% MeCN; 12.0 - 12.5 min, linear gradient, 100% - 2% MeCN (0% - 98% H2O + 0.05% TFA); isocratic, 12.5 - 14.0 min, isocratic, 2% MeCN (98% H2O + 0.05% TFA). UV detection at 254.8 nm.

[0110] The analysis results are shown in Part 6 of Figure 3. NMR analysis of separated peak 2

[0111]

Chem.

[0112]

Math.

[0113]

Chem.

[0114]

Chem.

[0115]

Number

[0116]

Chemistry

[0117]

Number

[0118]

Chemistry

[0119]

Number

[0120] Method: 0.0 - 0.1 min, isocratic, 2% MeCN (98% H2O + 0.05% TFA); 0.1 - 10.0 min, linear gradient, 2% - 50% MeCN (98% - 0% H2O + 0.05% TFA); 10.0 - 10.5 min, linear gradient, 50% - 100% MeCN (0% - 98% H2O + 0.05% TFA); 10.5 - 12.0 min, isocratic, 100% MeCN; 12.0 - 12.5 min, linear gradient, 100% - 2% MeCN (0% - 98% H2O + 0.05% TFA); isocratic, 12.5 - 14.0 min, isocratic, 2% MeCN (98% H2O + 0.05% TFA). UV detection at 254.8 nm.

[0121] The results are shown in Part 4 of Figure 4. When spiking the isomers separated like the second peak in Example 2, it was shown that only the hydrochloride of this isomer remained after adjusting the aqueous isomer mixture to pH < 1 with 1M HCl. The results are shown in Part 5 of Figure 4. Since free apomorphine was not found in the HPLC chromatogram, this is not due to the decomposition of other isomers (like the separated peak 1 in Example 1), and it can be presumed to be caused by an ester exchange reaction via an acid.

[0122] Example 4: Cation Exchange of Apomorphine Monophosphate Cation exchange chromatography was performed using different forms of Amberlite (trademark) IR-120 ion exchange resin (particle size 0.6 - 0.8 mm, total capacity > 1.8 eq / L in Na form). For this purpose, the Amberlite (trademark) IR-120 Na form ion exchange resin was used with the desired cations (K + , NH4 + , Ca 2+ , Mg 2+) was pre-equilibrated for 3 hours with a saturated aqueous solution of the corresponding chloride or iodide salt. Next, the pre-equilibrated resin was loaded into a column (diameter: 1 cm, height: 10 cm, resin volume: 7.9 mL; total volume: >14 mmol) and washed twice with 25 mL of a saturated aqueous solution of the corresponding salt. Next, the resin was thoroughly washed with deionized water (3 x 50 mL) to remove the adhering salt. Thereafter, 100 mg of apomorphine-phosphoric acid (“VIR-1-097”) (0.242 mmol, Na form) was dissolved in 1 mL of H2O, the solution was loaded onto the ion exchange resin and eluted (eluent: H2O, fraction size: 2 mL, fraction analysis: HPLC). The fractions containing the desired product were pooled and lyophilized to obtain the cation exchange product. Potassium apomorphine-phosphate (VIR-1-097-K)

[0123]

Chemical formula

[0124] Ammonium apomorphine-phosphate (VIR-1-097-NH4)

[0125]

Chemical formula

[0126]

Chemical formula

[0127]

Chem.

[0128] Method: 0.0 - 0.1 min, isocratic, 2% MeCN (98% H2O + 0.05% TFA); 0.1 - 8.0 min, linear, 2% - 100% MeCN (98% - 0% H2O + 0.05% TFA); 8.0 - 11.1 min, isocratic, 100% MeCN; 11.1 - 11.3 min, linear, 100% - 2% MeCN (0% - 98% H2O + 0.05% TFA); 11.3 - 12.0 min, isocratic, 2% MeCN (98% H2O + 0.05% TFA). UV detection at 254.8 nm.

[0129] The results are shown in Figure 5. Example 5: Preparation of Injection Solution of Trisodium Salt of Apomorphine Monophosphate 720.0 g of water for injection (WfI) was weighed into a glass bottle and degassed with a nitrogen stream to remove dissolved oxygen. 400 mg of sodium metabisulfite was added to the compounding vessel under magnetic stirring. After complete dissolution of the antioxidant, the pH was measured for reference (pH 4.49).

[0130] 5.62 g of trisodium apomorphine monophosphate (mixture of isomers, containing about 5.9% water) was weighed and added to the formulation mixture under magnetic stirring. A clear amber solution was obtained. The pH was adjusted to 7.50 ± 0.1 with 1M HCl. Then, the mixture was filled to a final weight of 800 g, stirred, and the pH was confirmed again (pH 7.62). Then, the formulation container was transferred to a glove box with a controlled atmosphere free of oxygen.

[0131] Final concentration: 6.61 g / L (anhydrous basis) of trisodium apomorphine monophosphate corresponding to 0.016 mol / L (MW: 413.25 g / mol) Glass vials and rubber stoppers were washed with WfI and sterilized by autoclave. The sterilized vials and stoppers were transferred to the glove box. The formulation solution was passed through a sterile filter membrane (PALL 25 mm Fluorodyne II PVDF). The filtrate was filled into 20R glass vials in 20.5 ml aliquots and stoppered with rubber stoppers under an oxygen-free atmosphere (oxygen < 100 ppm) in the glove box. The stoppered vials were sealed with aluminum crimp caps.

[0132] The filled vials showed the following analytical results.

[0133]

Table 1

[0134] The placebo product was prepared in the same manner but without trisodium apomorphine monophosphate. Example 6: in vitro Test Results of Metabolic Stability of Apomorphine Monophosphate (Isomer Mixture) in Incubation with Human Hepatocytes The metabolic conversion of apomorphine monophosphate (isomer mixture) obtained in Example 1 to apomorphine was tested in a standardized human hepatocyte assay. When incubated with human hepatocytes, apomorphine monophosphate was rapidly removed from the reaction mixture. Approximately 30% was converted to apomorphine within 10 minutes, and approximately 75% of apomorphine monophosphate was consumed within 60 minutes (see Part 1 of Figure 6). The half-life of apomorphine monophosphate in this assay was calculated to be 33 minutes.

[0135] The cell-free control group (negative control) did not show significant formation of apomorphine (see Part 3 of Figure 6). This supports that the observed formation of apomorphine is actually caused by hepatocytes and not the result of non-specific degradation in the assay.

[0136] Apomorphine was found at all sample points, and the maximum amount was found after 10 minutes. At this time point, the amount of apomorphine correlates with the disappearance of apomorphine monophosphate. Thereafter, the detected amount of apomorphine decreased.

[0137] It is known that apomorphine is metabolized in the liver, and this is also reflected in the in vitro stability test of the human liver (see Part 4 of Figure 6). The hepatocyte in vitro assay supports that apomorphine monophosphate as a prodrug is rapidly converted to apomorphine. Further in vitro tests may show that human plasma, human whole blood, and human liver S9 fraction do not convert apomorphine monophosphate to apomorphine to a significant extent. This supports that the release of apomorphine from the apomorphine prodrug is caused by liver metabolism and enzymatic reactions present in functional hepatocytes.

[0138] As a phosphate prodrug, the enzymatic activation of apomorphine - phosphate is promoted by phosphotransferases. One of the most prominent and highly expressed phosphotransferases in the human body is alkaline phosphatase. High expression levels and abundance of alkaline phosphatase can be found in human hepatocytes. Therefore, the activation of apomorphine prodrugs promoted by liver metabolism and phosphatases such as alkaline phosphatase supports and rationalizes the in vitro assay results.

[0139] Example 7: Animal Test - Test of Skin Reaction of Apomorphine Prodrug of the Present Invention in Pigs Materials and Methods The animal experiment application for the current in vivo tests was approved by the institution's ethics and welfare committee and the national authorities in accordance with Article 26 et seq. of the Austrian Animal Experiment Act (Tierversuchsgesetz 2012; approval number 2021 - 0.746.730).

[0140] The purpose of this study was to test the skin reactions of two formulations of an apomorphine preparation in pigs: the prodrug of apomorphine formulated according to the present invention at a concentration of 6.61 mg / mL at pH 7.5 ± 0.2, further containing 0.5 mg / mL of metabisulfite, formulated in Example 5 (APO PD22 - 03; VIR - 1 - 097, i.e., the sodium salt described in Example 1), and a commercially available reference apomorphine formulation (Dacepton) containing apomorphine hydrochloride hemihydrate at a concentration of 5 mg / ml at pH 3.8 ± 0.2, further containing 1.0 mg / mL of metabisulfite and 0.8 mg / mL of NaCl. The concentration of 6.61 mg / mL of the apomorphine prodrug corresponds to the same molar concentration as the concentration of 5 mg / mL of apomorphine hydrochloride hemihydrate contained in the Dacepton formulation. Both drugs were administered subcutaneously to the right side of the animals' necks for 12 hours a day for 14 days. Additionally, blood samples were taken by a central venous catheter on selected test days.

[0141] In this experiment, 10 female pigs with an average initial weight of 55 kg were used. After the acclimation period and daily training with positive conditioning, the 6 most human - accustomed pigs and 2 as reserves (1 was lost in the first week) were tattooed on the right side of the neck, and a central venous catheter was inserted into the jugular vein under general anesthesia.

[0142] On the right side of the neck, 8 application areas divided into 2 compartments each were tattooed, thereby determining the needle - fixation position for a specific day (see Figure 7). Furthermore, the letters (I - P) were tattooed under each application area. Additionally, there was a control area where needles were inserted and fixed twice at 7 - day intervals for 12 hours without using a catheter and without applying drugs. The insertion position of the needle for a specific day was defined by the tattooed area. Thus, the observed changes in the injection site could be assigned to the injection on a specific day. Before needle insertion, the application area was soiled with a compressive gauze and disinfected with alcohol.

[0143] For tattooing the application area and inserting the central venous catheter (into the jugular vein) under general anesthesia, ketamine hydrochloride (Narketan®, 10 mg / kg body weight) and azaperone (Stresnil®, 1.3 mg / kg body weight) were administered intravenously for induction, and propofol (2.5 - 4.0 mg / kg) was administered intravenously for maintaining anesthesia. Methadone (0.3 mg / kg twice at 4 - hour intervals) was bolus - administered to the animals for safe intraoperative analgesia. To avoid pain and infection after catheter insertion, analgesics (Metacam®, 0.4 mg / kg body weight) and antibiotics (Baytril RSI®, 7.5 mg / kg body weight) were administered to the animals for the first 5 days after anesthesia. The extension of the central venous catheter was tunneled subcutaneously. The external access part was attached to the dorsal part of the neck and protected with a pocket on the dorsal part of the neck fixed by skin sutures to protect this extension.

[0144] Since apomorphine is emetic, an antiemetic agent was orally administered to the animals before the start of drug application, at noon, and immediately before the end of application (Motilium 10 mg film-coated tablets, JANSSEN-CILAG Pharma GmbH, 1020 Vienna, Austria). Since the tablets were hidden in grapes, the animals ingested them without problems.

[0145] The drug was applied using a subcutaneous injection needle (Neria G27, 6 mm, Unomedical A ConvaTec Company, Denmark) with a pump application system (D-mine pump; EVER Neuro Pharma, Unterach, Austria). A needle of this short length (6 mm) was selected to avoid penetrating the muscle. After fixation, the needle was taped (Animal Polster, Snogg, Vennesla, Norway).

[0146] The animals were divided into two groups. Animals 17, 18, and 19 were injected with the apomorphine prodrug (APO PD22-03; VIR-1-097) on the right side of the neck. On the other hand, animals 20, 21, and 22 were administered a commercially available apomorphine preparation (Dacepton) as a control. In animals 18 and 19, blood sampling via a central venous catheter became impossible on the 7th day of the test (due to catheter blockage), so animals 23 and 24 were incorporated into the test from the 7th day of the test and administered the drug APO PD22-03 until the 14th day of the test. The same molar concentration was administered for both drugs. In the case of Dacepton, the dose was 45 mg per day = 3.7 mg / h over 12 hours = 8.88 ml, and APO PD22-03 was the corresponding molar amount.

[0147] All animals were housed on straw during both the acclimation period and the experimental period and had free access to pelleted commercial feed and drinking water. The animals were trained to wear a dog harness with a pump housed in a dorsal pocket throughout the day. During the 14-day test period, the animals were housed individually in enclosures to minimize the risk of the animals rubbing against each other's harnesses and / or the fixed parts of the pumps. To reduce social stress symptoms, the animals were always allowed to directly touch noses and eyes.

[0148] The test was started by incorporating six animals into the test. All animals were clinically examined daily in the morning, their body temperature was measured, and their body weight was measured once a week. Macroscopic Evaluation of Injection Site The injection sites were evaluated daily before and after application. The evaluated injection sites were photographed in the morning and in the evening. For the evaluation of side effects resulting from drug application (e.g., skin lesions and nodule formation), the skin areas of the affected parts were examined and the observations were recorded. The size and extent of the skin lesions were evaluated using two different scores, namely, the degree of the skin lesion (as 0 - undetectable / absent, 1 - minimal, 2 - low, 3 - moderate, 4 - high) and the size of the skin lesion (as 0 - no detectable skin reaction, 1 - <10% area change, 2 - 10 - 25% area change, 3 - 26 - 50% area change, 4 - 51 - 75% area change, 5 - 76 - 100% area change). The occurrence of nodules was separately counted using a score of the number of nodules (0 - no detectable nodules; 1 - isolated, one nodule; 2 - low malignancy, 2 - 5 nodules; 3 - moderate malignancy, 6 - 10 nodules; 4 - high malignancy, >10 nodules), and the size of the nodules (in centimeters) was evaluated.

[0149] After the start of application, the animals were checked every hour to detect early needle detachment. If the needle had not completely come out and there was no fluid leakage, it was repaired by reapplication. If the needle completely came out within the first 8 hours, a new catheter had to be attached, the needle had to be reinserted into the skin, and the pump had to be restarted. If the needle came out after 8 hours, reapplication was not necessary.

[0150] As shown in Fig. 7, the total nodule score around the neck is composed of the nodule scores (0 - 4) of each of the 14 application sites tested twice a day (the maximum possible score is 56 in this case). Results During the experiment, animals 17 - 24 did not experience abnormalities in clinical examinations. The three - times - a - day application of the anti - emetic functioned without problems, and vomiting was not observed in any of the animals. By measuring the animals' weights weekly, a continuous increase in weight and an average daily weight gain within the normal range could be observed. The animals' weights were 50 - 70 kg at the start of the test and 59 - 74 kg at the end of the test (two weeks later). Nodule Animals 20 - 22 (Dacepton) showed nodules after almost all injection days. However, the average recovery time for these animals varied from 5 to 5.14 days. Animal 20 showed nodules for an average of 5.14 days, while animals 21 and 22 showed nodules for an average of exactly 5 days. Animal 20 showed nodules after 11 out of 14 injection days, animal 21 showed nodules in a total of 12 out of 14 possible days, and animal 22 showed nodules after 13 out of 14 injection days.

[0151] In animals 17 - 19 (APO PD22 - 03), significantly fewer nodules were visible. In animal 17, the average recovery time for nodules was 3 days, in animal 18 it was 1 day, and in animal 19 it was 2.5 days. Animal 17 showed a total of 3 nodules, animal 18 showed 6 nodules, and animal 19 showed only 1 nodule. Animals 23 and 24 started drug injection on the 7th day of the test, and both animals showed 1 nodule each after the 10th day of the test, but this was seen at only one observation point.

[0152] In animals 17 - 19 administered with formulation APO PD22 - 03, almost no nodules developed. In these animals, most nodules were only about 1 cm in size at the first observation point (only animal 19 had a nodule of 1.5 cm in size at the first observation point), and they became smaller (0.5 cm) or disappeared. In animals 20 - 22, most nodules were 1 cm in size at the start and remained 1 cm in diameter. Animal 22 showed a larger (2 cm) nodule at the first observation point. Animals 23 and 24 showed only one nodule, which was 0.5 cm at one observation point.

[0153] In the control area where all animals were pricked once a week without applying any drug, no nodules developed in any of the animals. There was a clear difference in the total nodule score between the two drugs. Animals 17 - 19 had fewer nodules per side of the neck. Animal 21 had 15 nodules on the 14th day after injection and had the highest total score. The data are summarized in Figure 7. Conclusion These results indicate that the formulation containing the novel apomorphine prodrug according to the present invention shows advantageously improved local tolerability, particularly advantageously reduced skin reactions, compared to the commercially available apomorphine formulation (Dacepton) used in this animal experiment.

Claims

1. Compounds of formula (I) or pharmaceutically acceptable salts thereof 【Chemistry 1】 In the formula, R １ and R ２ These are independently -OH or -O-P (=O)(-OH)( -OH) and where R １ and R ２ At least one of them is -O-P(=O)(-OH) (-OH)

2. R １ and R ２ One of them is -O-P (=O)(-OH)(-OH), and R １ and R ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the other of the two is -OH.

3. R １ is -OH, and R ２ is -O-P(=O)(-OH)(-OH), Claim 1 The compounds described or their pharmaceutically acceptable salts.

4. R １ is -O-P(=O)(-OH)(-OH), and R ２ Claim 1, where is -OH The compounds described or their pharmaceutically acceptable salts.

5. R １ and R ２ Claim 1, wherein each of them is -O-P(=O)(-OH)(-OH). The compound or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 or the pharmaceutically acceptable compound having the following stereoconfiguration Salt is acceptable. 【Chemistry 2】

7. The compound according to claim 1, which is a pharmaceutically acceptable salt of the compound of formula (I).

8. The compound according to claim 7, wherein the pharmaceutically acceptable salt is a sodium salt.

9. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof A pharmaceutical composition comprising the compound according to claim 7 or 8 and a pharmaceutically acceptable excipient. 。

10. The pharmaceutical composition according to claim 9 for the treatment of neurodegenerative diseases / disorders.

11. The aforementioned neurodegenerative diseases / disorders include Parkinson's disease, Alzheimer's disease, Huntington's disease, and The following is a description of a condition selected from neuroleptic malignant syndrome, dystonia, and schizophrenia, as described in claim 10. A pharmaceutical composition.

12. The pharmaceutical composition according to claim 9 for the treatment of Parkinson's disease.

13. The pharmaceutical composition is combined with one or more further antiparkinson's disease agents and / or antiemetic agents. The pharmaceutical composition according to claim 12, which is administered by hand.

14. Claim 9 for the treatment of sexual dysfunction, impotence, or restless legs syndrome The pharmaceutical composition described above.

15. A claim in which the pharmaceutical composition is administered subcutaneously and / or administered to a human subject. A pharmaceutical composition as described in any one of items 9 to 14.

16. Any one of claims 1 to 6, relating to the manufacture of a pharmaceutical product for the treatment of neurodegenerative diseases / disorders. The compound described in claim 7 or 8, or a pharmaceutically acceptable salt thereof, or the compound described in claim 7 or 8. Use of mixed ingredients.

17. The neurodegenerative disease / disorder is Parkinson's disease, Alzheimer's disease, Huntington's disease, The following is a description of a condition selected from neuroleptic malignant syndrome, dystonia, and schizophrenia, as described in claim 16. Use.

18. The manufacture of a pharmaceutical product for the treatment of Parkinson's disease, as described in any one of claims 1 to 6. The compound listed or a pharmaceutically acceptable salt thereof, or the compound described in claim 7 or 8. Use.

19. Manufacture of a pharmaceutical product for the treatment of sexual dysfunction, impotence, or restless legs syndrome. The compound described in any one of claims 1 to 6 or the pharmaceutically acceptable thereof Use of a salt or the compound described in claim 7 or 8.

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