Apomorphine prodrugs and uses thereof

Abstract

The present invention relates to a compound of formula (I) which is an apomorphine phosphate or a pharmaceutically acceptable salt thereof. The Apomorphine phosphates of the present invention exhibit significantly advantageous properties as therapeutic agents, including advantageous tolerance, improved side effect properties, particularly reduced nodule formation of the skin and the occurrence of lipiditis when administered subcutaneously, and pharmacokinetic and metabolic properties making them particularly suitable as Apomorphine prodrugs. The invention also relates to compounds of formula (I) for use as a medicament, in particular for the treatment of Parkinson's disease.

Description

[0001] The present invention relates to a compound of formula (I), which is apomorphine phosphate or a pharmaceutically acceptable salt thereof. The apomorphine phosphate of the present invention exhibits significant advantageous properties as a therapeutic agent, including favorable tolerability, an improved side effect profile, particularly reduced occurrence of skin nodule formation and panniculitis when administered subcutaneously, and pharmacokinetic and metabolic properties that make it particularly suitable as apomorphine prodrug. The present invention also relates to a compound of formula (I) for use as a medicament, particularly for the treatment of Parkinson's disease.

[0002] Idiopathic Parkinson's disease is the second most common neurodegenerative disease worldwide. Although there are no available therapies that can alter the underlying neurodegenerative process, symptomatic treatment can improve patients' quality of life. It is estimated that 7 to 10 million people worldwide suffer from Parkinson's disease (Parkinson's Disease Foundation, Statistics on Parkinson). The average age of onset of Parkinson's disease (PD) is approximately 62 years. Most cases of PD are sporadic and the cause is unknown.

[0003] Clinically, Parkinson's disease is characterized by resting tremor, rigidity, bradykinesia, and gait disturbances, which are referred to as the "cardinal features" of the disease. Other features include freezing of gait, postural instability, speech difficulties, autonomic dysfunction, sensory changes, mood disorders, sleep dysfunction, cognitive impairment, and dementia, all of which are referred to 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 feature of Parkinson's disease is the degeneration of pigmented midbrain dopaminergic neurons connecting the substantia nigra (pars compacta) and the neostriatum (caudate nucleus and putamen). Other affected pigmented nuclei may include the locus coeruleus and the dorsal motor nucleus of the vagus, as well as intracytoplasmic protein inclusions called Lewy bodies. These are composed of misfolded and aggregated proteins. Mutations in α-syn promote protein misfolding and the formation of oligomers and aggregates, which are thought to be involved in cell death processes (Olanow and Schapira. Ann Neurol. 2013 Sep;74(3):337-47).

[0004] Early in the disease course, dopamine deficiency is the primary neurochemical abnormality. As the disease progresses, involvement of nondopaminergic brain regions leads to motor and nonmotor symptoms that are levodopa-resistant. Therefore, dopamine replacement with levodopa is the gold standard for initial treatment of Parkinson's disease. Despite levodopa's reputation in the early stages of the disease, disabling fluctuations in motor responses and dyskinesias are a major threat during long-term therapy.

[0005] Among Parkinson's disease patients treated with oral levodopa for >5 years, >50% eventually experience fluctuations in motor performance. In addition, many patients experience other unpleasant "off-period" phenomena, including mood instability, delusions, anxiety, and painful dystonias consistent with the motor states (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, these response oscillations exhibit a predictable pattern related to the timing of levodopa intake (the "wear and tear" phenomenon) and can be managed by shortening the interval between levodopa doses, adding monoamine oxidase (MAO) B inhibitors (such as selegiline / deprenil) or amine receptor agonists, and administering controlled-release formulations of levodopa or catecholamine-O-methyltransferase inhibitors (e.g., entacapone). However, in advanced stages of the disease, patients experience complex and unpredictable motor oscillations, known as "on-off" phenomena, which 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 pharmacokinetics of peripheral levodopa, which is characterized by a plasma half-life of 1–1.5 hours. Although the peripheral pharmacokinetics of levodopa remain unchanged throughout the course of the disease, presynaptic nigrostriatal nerve terminals gradually lose the ability to store dopamine. However, there is evidence that the basis for the development of motor complications is much more complex, possibly related to chronic, nonphysiological, pulsed stimulation of dopamine receptors and involving alterations in striatal gene expression and, subsequently, alterations in basal ganglia firing patterns.

[0007] Motor complications are divided into motor fluctuations and dyskinesias. As PD progresses, patients' motor abilities may begin to fluctuate, a condition known as a "wear-off" (end-of-dose) effect, as motor improvements after a levodopa dose become less persistent and parkinsonism reappears. A minority of patients may experience biphasic dyskinesias, in which they exhibit dyskinesias when they start turning "on" and / or when they start turning "off," but they have different, less severe, or absent dyskinesias when the levodopa effect reaches its peak. Ultimately, patients may experience rapid and unpredictable fluctuations between "on" and "off" periods, known as an "on-off" phenomenon.

[0008] The management of motor fluctuations aims to prolong the effect of individual levodopa doses by adding adjunctive medications, such as catecholamine-O-methyltransferase (COMT) and monoamine oxidase B (MAO-B) inhibitors, as well as by modifying the intake interval and advising patients to avoid taking levodopa with meals. In addition, transdermal dopamine agonists are added to the medication regimen or their dose is increased. In some patients, attempts to adjust oral and transdermal medications in the presence of disabling fluctuations and dyskinesias fail after months or years. Other options include deep brain stimulation, pump systems that deliver levodopa to the jejunum via a gastric tube, and intermittent or continuous subcutaneous delivery of the dopamine agonist apomorphine, all of which are treatment options for patients with advanced PD who experience motor fluctuations.

[0009] Apomorphine is the oldest dopamine agonist used in clinical practice and is indicated for the treatment of motor symptoms associated with advanced Parkinson's disease, particularly acute, intermittent hypokinesia, "off" episodes ("end-of-dose wear-off" and unpredictable "on / off" episodes) associated with advanced Parkinson's disease, and as an adjunct / supplemental therapy to standard levodopa therapy. It was first used in patients with Parkinson's disease in 1951, but interest waned with the introduction of oral levodopa. Apomorphine was further studied with the recognition of long-term complications associated with levodopa therapy and the advent of the antiemetic domperidone (apomorphine can cause severe vomiting), which prevents most peripheral dopaminergic side effects, before apomorphine became available. Apomorphine was administered at a dose of 10–30 mg TDS for 72 hours.

[0010] Apomorphine is ineffective when taken orally due to extensive 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 stimulation of postsynaptic D2 receptors in the caudate putamen, a brain structure that supports motor function.

[0011] There are currently two different methods of administering apomorphine: a subcutaneous bolus dose and a continuous infusion. When administered subcutaneously, its bioavailability reaches nearly 100%, and the injection can effectively and quickly resolve abnormal states in patients with motor fluctuations. But when given as a single dose, the symptom relief is equivalent to oral levodopa, with a faster onset (5 to 15 minutes) and a shorter duration (average of 40 minutes). Intermittent apomorphine infusions can be used to reduce off-time in PD patients with severe motor complications. Continuous subcutaneous apomorphine infusions can be used to reduce "off" time and movement disorders in Parkinson's patients with severe motor complications. Subcutaneous infusions of apomorphine are suitable for PD patients for whom repeated boluses are inappropriate and there are too many intermittent cycles.

[0012] Apomorphine, synthesized from morphine by heating it as a catechol derivative with HCl, is known to be sensitive to oxidation. Under the influence of oxygen, apomorphine solutions turn green, indicating the formation of oxidation products with a "quinone-background" (Neef C et al. Clin Pharmacokinet. 1999. 37(3): 257-71). Electrochemical oxidation experiments have confirmed that the oxidative degradation of apomorphine is pH-dependent. The amount of degradation products increases with increasing pH, leading to spontaneous autooxidation at neutral pH (Garrido JM et al. Bioelectrochemistry. 2002. 55(1-2): 113-4).

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

[0014] Many routes of administration of apomorphine have been tried in clinical practice, resulting in therapeutically effective applications 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 cause adverse reactions at the site of administration, such as skin changes, irritation at the injection site, and subcutaneous nodules or panniculitis (inflammation of the subcutaneous fatty 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 cause allergic reactions in some patients. In addition, sodium metabisulfite tends to react irreversibly with carbon-oxygen double bonds in aldehydes and ketones. This is evident, for example, in the case of epinephrine, which, like apomorphine, contains two aromatic hydroxyl groups bonded in the ortho position, leading to the formation of quinones 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 have demonstrated that apomorphine induces melanin-positive pigmentation in the sc area (Loewe R et al. Hautarzt. 2003. 54: 58-63). Other data support that nodules formed at the injection site are panniculitis with infiltration of eosinophils and neutrophils, but no increase in IgE infiltration (Acland KM et al. Br J Dermatol. 1998. 138 (3): 480-2). These irritations led to 70% of patients receiving subcutaneous apomorphine infusions discontinuing therapy within one year.

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

[0019] However, even with the presence of symptom descriptions, the definitive underlying cause of nodule formation remains unclear. For example, Edwards et al. recently noted that "there are few studies on apomorphine nodule formation, and thus little is known about its etiology or natural history." (Edwards H et al. Ultrasound. 2008. 16(3): 155-9). Allergic reactions, hygienic reasons, effects caused by excipients (EDTA or sodium metabisulfite), and dopamine resistance have been discussed as underlying causes of nodule formation, but there is no clear evidence for 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 Vénéréologie. 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 J et al. 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] Several studies have been conducted in the past to elucidate the cellular basis of the neurotoxic effects of apomorphine. The results of these studies, described below, may help to understand the mechanism by which apomorphine preparations produce these side effects at the subcutaneous injection site. In cytotoxicity studies, apomorphine has been shown to have an antiproliferative effect and to induce apoptosis in the CHO-K1 cell line (Maggio R et al. Neurotox Res. 2000. 1(4): 285-97; Pardini C et al. Neuropharmacology. 2003. 45(2): 182-9). Other studies on rat glioma C6 cells and cultured rat neurons have shown that apomorphine promotes loss of cell membrane integrity, degradation of cytoplasmic organelles (especially mitochondria), DNA fragmentation and necrosis in vitro, which may occur through the formation of oxidative degradation products of apomorphine (quinones) (El-Bachá RS et al. Neuroscience Letters. 1999. 263: 25-8; dos Santos El-Bachá R et al. Biochem Pharmacol. 2001. 61 (1): 73-85). Apomorphine has also been shown to have antiproliferative effects 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] Apomorphine also exhibits genotoxic activity in vitro and in vivo, which may be related to its ability to intercalate into DNA or its prooxidative effects or the generation of superoxide radicals during autooxidation, thereby promoting frameshift mutations and inducing oxidative mutagenesis. These mutagenic and clastogenic effects are likely due to the formation of quinone products upon oxidation of apomorphine (reviewed in the following literature: 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), as quinone products are more aromatic and have a planar structure that favors intercalation into DNA (Cheng H et al. Analytical Chemistry. 1979. 51(13): 2243-6; Kalyanaraman B. Methods Enzymol. 1990. 186: 333-43). Quinones are known to be metabolically active intermediates with toxicological potential, resulting in several toxic effects in vivo (Garrido JM et al. J Chem Soc, Perkin Trans 2. 2002. 10: 1713-7). Apomorphine was not significantly genotoxic in the in vivo studies performed; however, the genotoxic effects of apomorphine and / or its oxidation products and their ability to intercalate into DNA could lead to cell death and may be one explanation for the cytotoxic and antiproliferative effects of apomorphine observed in the above studies.

[0022] Apomorphine can undergo spontaneous autooxidation 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 in this oxidative mechanism. However, even in acidic guest solutions, in the absence of antioxidants, apomorphine undergoes significant oxidative degradation, resulting in a green solution within a day. At pH < 7, the major degradation product is oxo-apomorphine, while at pH > 7, apomorphine-p-quinone is the major degradation product (Udvardy A et al. Journal of molecular structure. 2011. 1002(1): 37-44). Thus, the above data from in vitro studies are consistent with the common adverse reactions of apomorphine at the site of administration, such as skin changes, irritation at the injection site, and subcutaneous nodules and panniculitis, since subcutaneous oxidation of apomorphine and the generation of apomorphine oxidation products such as quinones or semiquinones could constitute a mechanism leading to loss of cell integrity and cell death (necrosis), subsequently initiating the inflammatory process and nodule formation observed around the injection site.

[0023] Various attempts have been made to improve the tolerability, stability and / or pharmacokinetic properties of apomorphine. In particular, specific formulations of apomorphine have been proposed, for example in EP-A-2545905, US 5,939,094, US 6,121,276, US 8,772,309, WO 99 / 66916, WO 02 / 100377, WO 2009 / 019463, WO 2009 / 056851, WO 2013 / 007381, WO 2013 / 183055 and WO 2017 / 055337. In addition, certain prodrugs of apomorphine have been proposed, but none have resulted in any approved drug products; see, for example, WO 2003 / 080074; WO 2005 / 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 Biopharm. Sci, 2018, 13(6): 507-517, doi: 10.1016 / j.ajps.2017.11.004.

[0024] WO 2019 / 101917 discloses apomorphine prodrugs in the form of sulfate esters with modified 10- and 11-hydroxyl groups or both. These compounds are disclosed as reference examples and are considered unsuitable for use as orally bioavailable prodrugs.

[0025] Park Hyejin et al. (ACS Medicinal Chemistry Letters, Vol. 11, No. 3, March 12, 2020, pp. 385-392) disclosed several types of apomorphine prodrugs, including di-acetate derivatives, =di-MOM ether derivatives, and methylene acetal derivatives.

[0026] Thus, there remains a strong and unmet need for new therapeutic approaches that provide apomorphine with improved safety and tolerability and an improved side effect profile.

[0027] The present invention addresses this need and provides a novel prodrug of apomorphine that can be administered subcutaneously with a highly favorable safety and tolerability profile and a particularly beneficial side effect profile, which can prevent or reduce the occurrence of inflammatory reactions, nodule formation and panniculitis in the subcutaneous tissue at the site of administration.

[0028] Thus, in the context of the present invention, it has been surprisingly found that apomorphine phosphates, particularly compounds of formula (I) and pharmaceutically acceptable salts thereof, are advantageously water-soluble compared to apomorphine or its pharmaceutically acceptable salts. The inventors have also surprisingly found that compounds of formula (I) and pharmaceutically acceptable salts thereof are physiologically stable, particularly in human blood and subcutaneous tissue, but are readily metabolized to apomorphine by human hepatocytes (as also demonstrated in Example 6), making them particularly suitable as prodrugs. Thus, it has been found that compounds of formula (I) are very advantageous because they exhibit excellent tolerability, improved stability under storage conditions and under physiological conditions of blood and subcutaneous tissue, and an improved side effect profile, particularly a significant reduction in the occurrence of inflammation and panniculitis at the subcutaneous administration site, which greatly promotes patient acceptability and compliance. This is further supported by the data shown in Example 7, which show that pigs treated with the apomorphine prodrug of the present invention had reduced nodule development compared to commercially available prior art apomorphine formulations.

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

[0030]

[0031] In formula (I), the group R 1 and R 2 are each independently -OH or -OP(=O)(-OH)(-OH), provided that R 1 and R 2 At least one of them is -OP(=O)(-OH)(-OH).

[0032] In a second aspect, the present invention relates to a pharmaceutical composition comprising a compound of the first aspect and a pharmaceutically acceptable excipient.

[0033] In a third aspect, the invention relates to a compound of the first aspect or a pharmaceutical composition of the second aspect for use as a medicament (or for use in therapy). According to this third aspect, the invention also relates to the use of a compound of the first aspect in the preparation of a medicament.

[0034] In a fourth aspect, the present invention relates to the compound of the first aspect or the pharmaceutical composition of the second aspect for use in treating neurodegenerative diseases / disorders. In this fourth aspect, the present invention also relates to the use of the compound of the first aspect in the preparation of a medicament for treating neurodegenerative diseases / disorders. The present invention also provides a method for treating neurodegenerative diseases / disorders, the method comprising administering to a subject (e.g., a human) in need thereof a therapeutically effective amount of the compound of the first aspect or the pharmaceutical composition of the second aspect. 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), and more preferably Parkinson's disease.

[0035] The present invention particularly relates to a method for treating Parkinson's disease using the compound of the first aspect or the pharmaceutical composition of the second aspect as described and defined herein. Therefore, in a fifth aspect, the present invention relates to a compound of the first aspect or the pharmaceutical composition of the second aspect for use in treating Parkinson's disease (e.g., idiopathic Parkinson's disease, acquired Parkinson's disease, or hereditary Parkinson's disease), preferably in humans. In this aspect, the present invention also relates to the use of the compound of the first aspect in the preparation of a medicament for treating Parkinson's disease. In a fifth aspect, the present invention also provides a method for treating Parkinson's disease, the method comprising administering a therapeutically effective amount of the compound of the first aspect to a subject (e.g., a human) in need thereof.

[0036] The compound of the first aspect of the present invention or the pharmaceutical composition of the second aspect of the present invention can also be used as a rescue treatment for subjects with Parkinson's disease. In particular, the compound or the pharmaceutical composition comprising the compound can be used as an emergency treatment for subjects with Parkinson's disease who have received a drug (particularly a long-term drug) other than apomorphine and who have an emergency rest period. Therefore, when subjects receiving different Parkinson's disease treatments (e.g., levodopa) experience motor fluctuations between regular treatment doses (e.g., between regular levodopa doses), the compound or pharmaceutical composition can be administered as needed. The compound or pharmaceutical composition can also be administered to subjects suffering from a rest period exceeding about 30 min.

[0037] Therefore, in a sixth aspect, the present invention relates to a compound of the first aspect or a pharmaceutical composition of the second aspect for use in treating refractory motor fluctuations / oscillations in Parkinson's disease, telogen retardation in Parkinson's disease, akinesia in Parkinson's disease (particularly peak dose dyskinesia) or akinesia in Parkinson's disease. In this sixth aspect, the present invention also relates to the use of a compound of the first aspect in the preparation of a medicament for treating refractory motor fluctuations / oscillations in Parkinson's disease, telogen retardation in Parkinson's disease, dyskinesia in Parkinson's disease or akinesia in Parkinson's disease. The present invention also relates to a method for treating refractory motor fluctuations / oscillations in Parkinson's disease, telogen retardation in Parkinson's disease, dyskinesia in Parkinson's disease or akinesia in Parkinson's disease, the method comprising administering a therapeutically effective amount of a compound of the first aspect or a pharmaceutical composition of the second aspect to a subject (e.g., a human) in need thereof.

[0038] In a seventh aspect, the present invention provides a compound of the first aspect or a pharmaceutical composition of the second aspect for treating sexual dysfunction or impotence (including male or female sexual dysfunction, in particular male erectile dysfunction), preferably in a human subject. According to this seventh aspect, the present invention thus particularly relates to a compound of the first aspect or a pharmaceutical composition of the second aspect for treating male erectile dysfunction in a human subject. In this seventh aspect, the present invention also relates to the use of a compound of the first aspect in the preparation of a medicament for treating sexual dysfunction or impotence, in particular for treating male erectile dysfunction. The present invention also provides a method for treating sexual dysfunction or impotence, comprising administering a therapeutically effective amount of a compound of the first aspect or a pharmaceutical composition of the second aspect to a subject in need thereof (e.g., a human). In particular, the present invention provides a method for treating male erectile dysfunction, comprising administering a therapeutically effective amount of a compound of the first aspect or a pharmaceutical composition of the second aspect to a human subject in need thereof.

[0039] In an eighth aspect, the present invention relates to a compound of the first aspect or a pharmaceutical composition of the second aspect for use in treating restless legs syndrome. According to this eighth aspect, the present invention also provides the use of a compound of the first aspect in the preparation of a medicament for treating restless legs syndrome. Similarly, the present invention provides a method for treating restless legs syndrome, the method comprising administering a therapeutically effective amount of a compound of the first aspect or a pharmaceutical composition of the second aspect to a subject (e.g., a human) in need thereof.

[0040] In a ninth aspect, the present invention relates to a compound of the first aspect or a pharmaceutical composition of the second aspect for use in preventing, alleviating, or ameliorating 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 of the first aspect or a pharmaceutical composition of the second aspect for use in preventing, alleviating, or ameliorating subcutaneous nodule formation associated with subcutaneous administration of apomorphine, wherein the compound or pharmaceutical composition is administered subcutaneously. The present invention also relates to a compound of the first aspect or a pharmaceutical composition of the second aspect for use in preventing, alleviating, or ameliorating 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 also relates to: (i) the use of the compound of the first aspect in the preparation of a medicament for preventing, alleviating or ameliorating panniculitis associated with subcutaneous administration of apomorphine, wherein the medicament is administered subcutaneously; (ii) the use of the compound of the first aspect in the preparation of a medicament for preventing, alleviating or ameliorating subcutaneous nodule formation associated with subcutaneous administration of apomorphine, wherein the medicament is administered subcutaneously; and (iii) the use of the compound of the first aspect in the preparation of a medicament for preventing, alleviating or ameliorating skin inflammation and / or irritation associated with subcutaneous administration of apomorphine, wherein the medicament is administered subcutaneously. In the ninth aspect, the present invention also relates to: (i) a method for preventing, alleviating or improving panniculitis associated with subcutaneous administration of apomorphine, which method comprises subcutaneously administering a therapeutically effective amount of the compound of the first aspect or the pharmaceutical composition of the second aspect to a subject (e.g., a human) in need thereof; (ii) a method for preventing, alleviating or improving subcutaneous nodule formation associated with subcutaneous administration of apomorphine, which method comprises subcutaneously administering a therapeutically effective amount of the compound of the first aspect or the pharmaceutical composition of the second aspect to a subject (e.g., a human) in need thereof; and (iii) a method for preventing, alleviating or improving skin inflammation and / or irritation associated with subcutaneous administration of apomorphine, which method comprises subcutaneously administering a therapeutically effective amount of the compound of the first aspect or the pharmaceutical composition of the second aspect to a subject (e.g., a human) in need thereof.

[0041] The invention is further described by means of the following exemplary drawings:

[0042] Figure 1: Part 1 and Part 2 show the apomorphine monophosphate isomer mixture obtained in Example 1 in D2O. 1 H and 13 C NMR spectrum. Part 3 shows the basis for the calculation of the molar ratio of the two isomers in the mixture obtained in Example 1.

[0043] Figure 2: HPLC-MS measurement value obtained from the mixture obtained in Example 1. Two structural isomers of apomorphine phosphate were present (ratio ∼2 / 1), m / z=348 [M (free acid)+H + ].

[0044] Figure 3: Part 1 - HPLC-MS analysis of the isolated apomorphine monophosphate isomer mixture from Example 2. Part 2 - HPLC-MS analysis of the isomers obtained in the first isolated peak. Part 3 - HPLC-MS analysis of the isomers contained in the first isolated peak. 1 H NMR analysis. Part 4 - Isomers contained in the first isolated peak 13 C NMR analysis. Part 5 - Isomers contained in the first isolated peak 31 P NMR analysis. Part 6 - HPLC-MS analysis of the isomers contained in the second isolated peak. Part 7 - HPLC-MS analysis of the isomers contained in the second isolated peak. 1 H NMR analysis. Part 8 - The second isolated peak contains isomers 13 CNMR analysis. Part 9 - The second separated peak contains isomers 31 PNMR analysis.

[0045] Figure 4: Part 1 - Isomer mixture obtained in Example 1 when pH is adjusted to 8 1 H NMR analysis. Part 2 - The isomer mixture obtained in Example 1 when the pH was adjusted to 4 1 H NMR analysis. Part 3 - The isomer mixture obtained in Example 1 when the pH was adjusted to 1 1 H NMR analysis. Part 4 - HPLC-MS analysis of the isomeric mixture obtained in Example 1 when the pH was adjusted to 1. Part 5 - HPLC-MS analysis of the isomeric mixture obtained in Example 1 when the pH was adjusted to 1 and when the isomeric mixture contained in the second isolated peak of Example 2 was spiked with a tracer.

[0046] Figure 5: Example 1 and K as shown in parts 1-4 respectively + NH4 + , Ca 2+ and Mg 2+ HPLC-MS analysis of the cation exchange product of a mixture of apomorphine monophosphate (sodium salt) isomers.

[0047] Figure 6: Part 1 - In vitro stability of apomorphine monophosphate in human hepatocytes. Part 2 - In vitro stability of apomorphine monophosphate in human hepatocyte control (no cell negative control). Part 3 - In vitro stability of apomorphine monophosphate in human liver S9 homogenate. No prodrug conversion was observed. Part 4 - In vitro stability of apomorphine HCl hemihydrate in human liver S9 homogenate. Apomorphine is rapidly metabolized in hepatocyte S9 cell extracts.

[0048] Figure 7: Part 1 - Summary of the total nodule score measured in the animal experiments as described in Example 7. Part 2 - Nodules formed in animal 22 treated with Dalcipton, as observed on day 8 of the study.

[0049] The following detailed description applies to all embodiments of the invention, including all embodiments according to each of the first, second, third, fourth, fifth, sixth, seventh, eighth and ninth aspects as described above.

[0050] In a first aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0051]

[0052] In formula (I), R 1 and R 2 are each independently -OH or -OP(=O)(-OH)(-OH), provided that R 1 and R 2 At least one of them is -OP(=O)(-OH)(-OH).

[0053] Therefore, R 1 Can be -OH, and R 2 It can be -OP(=O)(-OH)(-OH); or R 1 It can be -OP(=O)(-OH)(-OH), and R 2 Can be -OH; or R 1 and R 2 Each may be -OP(=O)(-OH)(-OH). The compound of formula (I) may be, for example, a compound having any one of the following formulae or a pharmaceutically acceptable salt thereof:

[0054]

[0055] Preferably, R 1 and R 2 One of them is -OP(=O)(-OH)(-OH), and R 1 and R 2 The other is -OH.

[0056] More preferably, R 1 is -OH, and R 2 Therefore, it is particularly preferred that the compound of formula (I) is a compound having the following formula or a pharmaceutically acceptable salt thereof:

[0057]

[0058] Furthermore, it is preferred that the compounds of formula (I) have the (R)-configuration at the stereocenter of formula (I), i.e. at the carbon ring atom adjacent to the nitrogen ring atom. Thus, it is preferred that the compounds of formula (I) have the following configuration:

[0059]

[0060] Therefore, it is preferred that the compound of formula (I) is a compound having any one of the following formulae or a pharmaceutically acceptable salt thereof:

[0061]

[0062] Even more preferably, the compound of formula (I) is a compound having the following formula or a pharmaceutically acceptable salt thereof:

[0063]

[0064] The compounds of formula (I) and their pharmaceutically acceptable salts can be prepared according to the synthesis and / or isolation methods described in the Examples section, in particular Examples 1 to 4. The present invention also particularly relates to each of the compounds described in the Examples section.

[0065] 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 carrying a lone electron pair prone to protonation (e.g. an amino group) with an inorganic or organic acid, or by protonating a salt of an acidic group (e.g. a phenolic-OH group or a 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; fatty amine salts, such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; arylalkylamine salts, such as N,N-dibenzylethylenediamine salts, benzathine penicillin salts, phenethylbenzylamine salts; heterocyclic aromatic amine salts, such as pyridinium salts, picolinium salts, quinolinium salts, or isoquinolinium salts; quaternary ammonium salts, such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts, or tetrabutylammonium salts; and basic amino acid salts, such as arginine salts, lysine salts, or histidine salts. Exemplary acid addition salts include, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydrogen iodide, sulfate (e.g., sulfate or hydrogen sulfate), nitrate, phosphate (e.g., phosphate, hydrogen phosphate, or dihydrogen phosphate), carbonate, bicarbonate, perchlorate, borate, or thiocyanate; organic acid salts such as acetate, propionate, butyrate, valerate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, Succinate, adipate, gluconate, glycolate, nicotinate, benzoate, salicylate, ascorbate, pamoate (pamoate), camphorate, glucoheptonate or pivalate; sulfonates, such as methanesulfonate (mesylate), ethanesulfonate (ethanesulfonate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (benzenesulfonate), p-toluenesulfonate (toluenesulfonate), 2-naphthalenesulfonate (naphthalenesulfonate), 3-benzenesulfonate or camphorsulfonate; glycerophosphate; and acidic amino acid salts, such as aspartate or glutamate. Other pharmaceutically acceptable salts are described in the literature, for example in Stahl PH & Wermuth CG (eds.), "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Wiley-VCH, 2002 and references cited therein. Preferred examples of pharmaceutically acceptable salts of the compound 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 compound of formula (I) include sodium salts, potassium salts, ammonium (NH4 +) salts, magnesium salts, calcium salts, zinc salts, copper salts (especially Cu(II) salts) or ionic salts (especially Fe(II) salts). Particularly preferred examples of pharmaceutically acceptable salts of the compound of formula (I) include sodium salts.

[0066] The present invention also particularly relates to compounds of formula (I) in non-salt form, including any of the specific compounds of formula (I) described herein.

[0067] The compound of formula (I) or its pharmaceutically acceptable salt can also exist in any solvated form, particularly including as a solvate with water. Therefore, the compound of formula (I) or its pharmaceutically acceptable salt can also be in the form of a hydrate. In addition, the present invention also encompasses all physical forms of the compound of formula (I) or its pharmaceutically acceptable salt, including any amorphous or crystalline form (i.e., polymorph).

[0068] For simplicity, when discussing compounds of formula (I) or pharmaceutically acceptable salts thereof hereinafter, reference will be made to "compounds of formula (I)" (or "compounds of formula (I)"). It will be understood that any such references are to compounds of formula (I) or pharmaceutically acceptable salts thereof, and particularly to the corresponding compounds in non-salt form or pharmaceutically acceptable salt form.

[0069] The scope of the present invention also includes 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") substitution. Therefore, the present invention also includes deuterium-enriched compounds of formula (I). Naturally occurring hydrogen is a compound containing about 99.98 mol% of hydrogen 1 ( 1 H) and about 0.0156 mol% deuterium ( 2H or D) isotopic mixtures. Deuteration techniques known in the art can be used to increase the deuterium content at one or more hydrogen positions in the compound of formula (I). For example, the compound of formula (I) or the reactants or precursors for synthesizing the compound of formula (I) can be subjected to an H / D exchange reaction using, for example, heavy water (DO). Other suitable deuteration techniques are described in the following literature: 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. For example, the deuterium content can be determined using mass spectrometry or NMR spectroscopy. Unless otherwise indicated, it is preferred that the compound of formula (I) is not enriched in deuterium. Therefore, it is preferred that the compounds of formula (I) contain naturally occurring hydrogen atoms or 1 H hydrogen atom.

[0070] The present invention also includes compounds of formula (I) wherein one or more atoms are replaced by positron-emitting isotopes of the corresponding atoms, e.g. 11 C. 13 N and / or 15 O. Such compounds can be used as tracers, tracking agents or imaging probes in positron emission tomography (PET). Thus, the present invention includes: (i) compounds of formula (I) wherein one or more carbon atoms (or, for example, all carbon atoms) are 11 C atom replacement; (ii) a compound of formula (I) wherein the nitrogen atom is 13 and (iii) compounds of formula (I) wherein one or more oxygen atoms (or, for example, all oxygen atoms) are replaced by 15 In general, it is preferred that none of the atoms in the compounds of formula (I) are replaced by a specific isotope.

[0071] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable excipient. The present invention particularly relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, for use as a medicament. The pharmaceutical composition may comprise a single compound of formula (I) or a pharmaceutically acceptable salt thereof, or it may comprise more than one compound of formula (I) or a pharmaceutically acceptable salt thereof. In particular, the present invention relates to a pharmaceutical composition comprising: (i) a compound of formula (I), wherein R 1 is -OH, and R 2is -OP(=O)(-OH)(-OH) ("the first compound") or a pharmaceutically acceptable salt thereof; (ii) a compound of formula (I), wherein R 1 is -OP(=O)(-OH)(-OH), and R 2 is -OH ("second compound") 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 can be, for example, 10:1 to 1:10, preferably 5:1 to 1:5, more preferably 3:1 to 1:3, and even more preferably 2:1 to 1:2 (e.g., about 1:1).

[0072] The compounds of formula (I) provided herein can be administered as the compounds themselves or can be formulated into medicaments. The medicaments / pharmaceutical compositions may also contain one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricants, binders, colorants, pigments, stabilizers, preservatives, antioxidants and / or dissolution promoters.

[0073] The pharmaceutical composition may comprise one or more dissolution enhancers, such as poly(ethylene glycol), including poly(ethylene glycol) having a molecular weight of about 200 to about 5,000 Da (e.g., PEG 200, PEG 300, PEG 400, or PEG 600), ethylene glycol, propylene glycol, glycerol, nonionic surfactants, tyloxamer, polysorbate 80, polyethylene glycol-15-hydroxystearate (e.g., 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, carboxymethyl sulfide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, or any combination thereof.

[0074] The pharmaceutical composition may further comprise one or more preservatives, particularly one or more antimicrobial preservatives, such as benzyl alcohol, chlorobutanol, 2-ethoxyethanol, m-cresol, chlorocresol (e.g. 2-chloro-3-methylphenol or 4-chloro-3-methyl-phenol), benzalkonium chloride, benzethonium bromide, benzoic acid (or a pharmaceutically acceptable salt thereof), sorbic acid (or a medically acceptable salt thereof), chlorhexidine, thimerosal or any combination thereof. A preferred antimicrobial preservative is benzyl alcohol.

[0075] The pharmaceutical composition can be formulated by techniques known to those skilled in the art, such as those published in "Remington: The Science and Practice of Pharmacy," Pharmaceutical Press, 22nd edition. The pharmaceutical composition can be formulated into dosage forms for oral, parenteral, e.g., intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardiac, rectal, nasal, oral mucosal, buccal, sublingual, topical, aerosol, or vaginal administration. Dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, tablets, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, medicated chewing gum, chewable tablets, effervescent tablets, and sublingual films. Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersions, 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 pessaries. Dosage forms for nasal administration can be administered by inhalation or insufflation, for example, by a metered dose inhaler.Dosage forms for topical administration include creams, gels, ointments, salves, patches and transdermal delivery systems.

[0076] The pharmaceutical composition preferably comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof (preferably a 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 amounts / concentrations are based on the weight of the compound of formula (I) or its pharmaceutically acceptable salt, i.e., they are based on the weight of the non-salt form of the compound of formula (I), except where the compound of formula (I) is actually used in non-salt form. For example, if the compound of formula (I) is present in the form of a trisodium 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 also be understood that the above amounts / concentrations are not based on the corresponding amount of apomorphine or its salt that can be obtained when the compound of formula (I) or its pharmaceutically acceptable salt is hydrolyzed. For example, by including a dissolution promoter such as α-propylene glycol in the pharmaceutical composition, it can be advantageous to provide a high concentration of the compound of formula (I) in the pharmaceutical composition.

[0077] The pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof can be directly administered by subcutaneous route, for example, by subcutaneous injection. An aqueous composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in higher amounts can be used, for example, for subcutaneous continuous infusion, wherein the aqueous composition can be diluted to a desired final concentration when administered, or administered subcutaneously by intermittent rapid bolus injection using an injection pen, wherein the aqueous composition is pre-filled with a pen-type barrel (also referred to as "karpule"). Therefore, for example, the pharmaceutical composition of the present invention can be provided in a container (e.g., injection vial) or a pen-type barrel.

[0078] The pharmaceutical composition of the present invention may further comprise one or more antioxidants, such as 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, in particular a sodium salt and / or ascorbic acid (in particular, 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). Preferably, the pharmaceutical composition comprises 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 can 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 can comprise, or can 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.

[0079] The pharmaceutical composition of the present invention is preferably an aqueous pharmaceutical composition. Therefore, it is preferred that the pharmaceutical composition comprises water, in particular 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 by volume of the total pharmaceutical composition. The water in the pharmaceutical composition is preferably water for injection (e.g., as defined in the European Pharmacopoeia (Ph.Eur.), 8th edition, dated July 1, 2015, including Supplement 8.6). Water for injection (WFI) can be prepared using techniques known in the art, for example, by distillation or by membrane technology (e.g., reverse osmosis or ultrafiltration), as described, for example, in Felton LA (ed.), Remington: Essentials of Pharmaceutics, Pharmaceutical Press, 2013.

[0080] For example, the pharmaceutical composition can be an aqueous solution or an oil-in-water emulsion. In this regard, it is preferred that the pharmaceutical composition 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), even more preferably less than about 0.5% (v / v), and still even more preferably does not contain any oil. Therefore, it is preferred that the pharmaceutical composition is an aqueous solution.

[0081] Furthermore, it is preferred that the pharmaceutical composition 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), even more preferably less than about 0.5% (v / v), and still even more preferably does not contain any lipophilic substances.

[0082] The pharmaceutical composition is preferably an aqueous pharmaceutical composition having a pH of about 3 to about 7.4 (e.g., 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, it has a pH of about 4 to about 7, more preferably a pH of about 5 to about 6 (e.g., about 5.0, about 5.5, or about 6.0), and even more preferably a pH of about 5.5.

[0083] The desired pH can be controlled by using a suitable buffer, if necessary by adding an aqueous solution of HCl or NaOH to adjust the pH. The buffer is not particularly modern and can be selected from malate buffer, formate buffer, succinate buffer, citrate buffer, acetate buffer, pyridine buffer, MES buffer, tartrate buffer, oxalate buffer, ascorbate buffer, cacodylate buffer, dimethylglutarate 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 solution (as described, for example, in Stoll VS et al. Buffers: principles and practice. Methods Enzymol. 1990. 182: 24-38; or AppliChem, Biological Buffers, 2008). It will be appreciated that suitable buffers can be determined based on the pK a The pH value may be selected depending on the desired pH of the pharmaceutical composition.

[0084] The pharmaceutical composition of the present invention may further comprise α-propylene glycol (i.e., propylene-1,2-diol) and / or sodium chloride. These substances can be used as isotonic agents to make the pharmaceutical composition isotonic with human plasma. Thus, the pharmaceutical composition may comprise α-propylene glycol in an amount of, for example, about 1 mg / ml to about 25 mg / ml (or about 5 mg / ml to about 15 mg / ml), but if α-propylene glycol is used as an isotonic agent, the preferred amount of α-propylene glycol depends on the pH of the pharmaceutical composition (e.g., a pharmaceutical composition of the present invention having a pH of about 5 may preferably comprise α-propylene glycol in an amount of about 5 mg / ml to about 10 mg / ml). The pharmaceutical composition may comprise, for example, sodium chloride in an amount of about 3 mg / ml to about 8 mg / ml, but if sodium chloride is used as an isotonic agent, the preferred amount of sodium chloride depends on the pH of the pharmaceutical composition (e.g., a pharmaceutical composition of the present invention having a pH of about 5 may preferably comprise sodium chloride in an amount of about 4.5 mg / ml).

[0085] The pharmaceutical composition is preferably isotonic with human plasma. In particular, it is preferred that the pharmaceutical composition have an osmolality of about 280 mOsm / kg to about 305 mOsm / kg, more preferably an osmolality of about 290 mOsm / kg to about 300 mOsm / kg, and even more preferably an osmolality of about 296 mOsm / kg. Furthermore, as described above, it is preferred that the pharmaceutical composition be rendered isotonic (e.g., to any of the above-mentioned osmolality ranges or values) using α-propylene glycol and / or sodium chloride, more preferably using α-propylene glycol.

[0086] Typically, the compound of formula (I) or its pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition can be directly administered by any convenient route of administration. The corresponding route of administration includes, but is not limited to: oral (e.g., tablets, capsules or ingestible solutions), topical (e.g., transdermal, intranasal, ocular, oral and sublingual), parenteral (e.g., using injection techniques or infusion techniques, and including, for example, by injection, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid or intrasternal, e.g., by implanting a reservoir, e.g., by subcutaneous or intramuscular injection), pulmonary (e.g., by inhalation or insufflation therapy, e.g., aerosol, e.g., oral or nasal), gastrointestinal, intrauterine, intraocular, subcutaneous, ophthalmic (including intravitreal or intracameral), rectal or vaginal administration. The compound of formula (I) or pharmaceutical composition is preferably administered parenterally (e.g., by injection or infusion), more preferably by subcutaneous administration.

[0087] If the compound or pharmaceutical composition is administered parenterally, the example of such administration includes one or more of the following: intravenous, intraarterial, intraperitoneal, intrathecal, intracerebroventricular, intraurethral, ​​intrasternal, intracardial, intracranial, intramuscular or subcutaneous administration of the compound or pharmaceutical composition, and / or by using an infusion technique. Thus, for example, the parenteral administration of the compounds of the invention can be administered by subcutaneous injection or infusion. For parenteral administration, the compound is preferably used in the form of a sterile aqueous solution, which may contain other substances, for example, enough salt or glucose to make the solution isotonic with the blood. If necessary, the aqueous solution should be appropriately buffered (preferably reaching a pH value of 3 to 9). Preparing suitable parenteral formulations under sterile conditions is easy to complete by standard pharmaceutical techniques well known to those skilled in the art.

[0088] The compound or pharmaceutical composition can also be administered orally in the form of tablets, capsules, vaginal suppositories, elixirs, solutions or suspensions, which may contain flavoring agents or coloring agents and are suitable for immediate-, delayed-, modified-, sustained-, pulse- or controlled-release applications. Tablets can include excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate and glycine; disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, cross-linked sodium carboxymethyl cellulose and certain composite silicates; and granulation binders such as polyvinyl pyrrolidone, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), sucrose, gelatin and gum arabic. In addition, lubricants such as magnesium stearate, stearic acid, glyceryl behenate and talc may also be included. Similar types of solid compositions can also be used as fillers in gelatin capsules. In this regard, preferred excipients include lactose, starch, cellulose or high molecular weight polyethylene glycol. For aqueous suspensions and / or elixirs, the agent may be combined with various sweeteners or flavorings, colorants or dyes, emulsifiers and / or suspending agents, and diluents such as water, ethanol, propylene glycol, and glycerol, and combinations thereof. For oral administration, the compound or pharmaceutical composition may preferably be administered by oral ingestion, particularly by swallowing. Thus, the compound or pharmaceutical composition may be administered so as to enter the gastrointestinal tract through the mouth, which may also be referred to as "oro-enteral" administration.

[0089] Alternatively, the compound or pharmaceutical composition can be administered in the form of a suppository or pessary, or can be administered topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder. The compounds of the invention can also be administered dermally or transdermally, for example, by using a skin patch.

[0090] The compound or pharmaceutical composition can also be used by a sustained-release system. Suitable examples of sustained-release compositions include semipermeable polymer matrices of formed article form, such as films or microcapsules. Sustained-release matrices include, for example, copolymers of polylactide, L-glutamic acid and γ-ethyl-L-glutamate, poly-(2-hydroxyethyl methacrylate), ethylene-vinyl acetate or poly-D(-)-3-hydroxybutyric acid. Sustained-release pharmaceutical compositions also include liposome-embedded compounds. Therefore, the present invention further relates to liposomes comprising the compounds of this invention or their pharmaceutically acceptable salts.

[0091] The compounds or pharmaceutical compositions may also be administered via the pulmonary, rectal or ophthalmic routes. For ophthalmic use, they may be formulated as micronized suspensions in isotonic, pH-adjusted, sterile saline, or, preferably, as isotonic, pH-adjusted sterile saline solutions, optionally in combination with a preservative such as benzalkonium chloride. Alternatively, they may be formulated as an ointment such as petrolatum.

[0092] It is also contemplated to prepare dry powder formulations of compounds of formula (I) or pharmaceutically acceptable salts thereof for pulmonary administration, particularly inhalation. Such dry powders can be prepared by spray drying under conditions that produce large quantities of amorphous glassy or large quantities of crystalline biologically active powders. Thus, dry powders of the compounds of the invention can be prepared according to an emulsification / spray drying process.

[0093] For topical application to the skin, the compounds or pharmaceutical compositions may be formulated into a suitable ointment containing the active compound suspended or dissolved in a mixture of, for example, one or more of the following ingredients: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax, and water. Alternatively, they may be formulated into a suitable lotion or cream suspended or dissolved in a mixture of, for example, one or more of the following ingredients: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, 2-octyldodecanol, benzyl alcohol, and water.

[0094] Therefore, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein, wherein the corresponding compound or pharmaceutical composition is administered by any of the following routes: oral route; topical route, including transdermal, intranasal, ocular, oral or sublingual route; parenteral route using injection technology or infusion technology, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid, intrasternal, intraventricular, intraurethral or intracranial route; pulmonary route, including by inhalation or insufflation therapy; gastrointestinal tract; intrauterine route; intraocular route; subcutaneous route; ophthalmic route, including intravitreal or intracameral route; rectal route or vaginal route. Preferred routes of administration are parenteral administration, in particular subcutaneous administration (e.g., by subcutaneous injection or infusion) or intramuscular administration. Particularly preferred routes of administration are subcutaneous administration, for example, by subcutaneous injection or infusion. Therefore, for each compound or pharmaceutical composition provided herein, it is particularly preferred that the corresponding compound or pharmaceutical composition be administered subcutaneously (particularly by subcutaneous injection or infusion).

[0095] Typically, a clinician can determine the actual dosage that is most suitable for an individual subject. The specific dosage level and dosage frequency for any particular individual subject can vary and depend on various factors, including the activity of the specific compound used, the metabolic stability and duration of action of the compound, age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, severity of the particular condition, and the individual subject being treated.

[0096] For example, the compound or pharmaceutical composition of the present invention can be administered to a human subject (preferably a human subject aged 18 years or older) by intermittent subcutaneous bolus injection at a dose 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). For example, the corresponding dosage unit can be administered 1-2 times per day (preferably 1-10 times per day) until a maximum daily dose of, for example, about 100 mg is reached (preferably up to a maximum daily dose of about 50 mg, and more preferably up to a maximum daily dose of about 30 mg). Alternatively, the compound or pharmaceutical composition can be administered to a human subject (preferably a human subject 18 years of age or older) by subcutaneous continuous infusion (e.g., using a mini-pump and / or syringe delivery device) at an infusion rate of about 1 mg to about 4 mg of the active ingredient (i.e., a compound of formula (I) or a pharmaceutically acceptable salt thereof, which can be included in the pharmaceutical composition at a concentration of, for example, about 5 mg / ml) per hour, 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., a compound of formula (I) or a pharmaceutically acceptable salt thereof, which can be included in the pharmaceutical composition at a concentration of, for example, about 5 mg / ml). It may be necessary to routinely adjust the dosage according to the age and weight of the patient / subject and the severity of the disease to be treated. The exact dosage and route of administration will ultimately be determined by the attending physician (or assistant veterinarian).

[0097] Apomorphine has been used to treat 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 et al. Mov Disord. 2002. 11(5):789-794; and Manson AJ et al. Mov Disord. 2002. 11(6):1235-1241), 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 other neurodegenerative diseases / disorders (e.g., Kyriazis MJ AntiAging Med. 2003. 6(1):21-28; and Truong JG et al. Eur J Pharmacol. 2004. 492(2-3):143-147).The use of apomorphine in 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). Because the compound of formula (I) can be used as a prodrug of apomorphine, it can be used to treat any of the above-mentioned disorders as well as any other disorder for which the use of apomorphine has been proposed in the literature.

[0098] As used herein, the term "treatment" (or "treating") in relation to a disease or condition refers to the management and care of a patient with the goal of combating the disease or disorder, such as reversing, alleviating, inhibiting, or delaying the disease or disorder or one or more symptoms of such a disease or disorder. It also refers to the administration of a compound or composition with the goal of preventing the onset of symptoms of a disease or disorder, alleviating such symptoms, or eliminating the disease or disorder. "Treatment" can be preventative or non-preventative. Preferably, "treating" is curing, ameliorating, or alleviating.

[0099] The present invention can be used in the context of monotherapy or in combination with one or more other pharmaceutically active agents to comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active agent. If the pharmaceutical composition of the present invention is used in conjunction with another pharmaceutically active agent, and the pharmaceutically active agent is active against the same disease / disorder, a lower dose of each active agent can be used. The pharmaceutical composition of the present invention can be combined with one or more other pharmaceutically active agents to comprise simultaneous / accompanied administration of another pharmaceutically active agent and the pharmaceutical composition of the present invention. However, it is also concerned about sequential / single administration. When administered sequentially, any one of the pharmaceutical composition of the present invention or one or more other pharmaceutically active agents can be administered first. When administered simultaneously, one or more other pharmaceutically active agents can be included in the pharmaceutical composition of the present invention, or they can be administered in one or more different (independent) pharmaceutical compositions.

[0100] For the treatment of Parkinson's disease, the compound of formula (I) of the present invention (or its pharmaceutically acceptable salt) or pharmaceutical composition can be administered in combination with one or more additional anti-Parkinson's disease drugs, such as levodopa, droxidopa, levodopa, methyllevodopa, alindol, bromocriptine, cabergoline, ciradopa, dihydroergocryptine, lisuride, pardolu, pergolide, piribedil, pramipexole, ropironide, rotigotine, radotigib, lazabemide, mofegiline, pargyline, radoxime, radoxime, dapoxetine ... Saijilan, selegiline, entacapone, niticapol, tolcapone, benserazide, carbidopa, methyldopa, methyldopa, benztropine, biperiden, bonapril, chlorpheniramine, cyclamine, dextrobenzylamide, dimenhydrinate, diphenhydramine, ethyldiphenhydramine, ethylphenyltropine, mazatik, methixene, orphenadrine, fenagluamide, pyroheptine, procyclidine, profenamide, trihexyphenidyl, tripatepine, amantadine, budipine, memantine, methylxanthine, rimantadine, UWA-101 and any pharmaceutically acceptable salt of these medicines.Preferred antiparkinsonism drug is levodopa, carbidopa and biperiden.Particularly preferred antiparkinsonism drug is levodopa.

[0101] Thus, 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 the treatment of refractory motor fluctuations / oscillations in Parkinson's disease, telogen in Parkinson's disease, refractory telogen 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 wherein the composition or the pharmaceutical composition is administered in combination with one or more other anti-Parkinson's disease drugs (e.g., one or more of the specific anti-Parkinson's disease drugs described above). For example, the combined administration of the compound or the pharmaceutical composition and the one or more other anti-Parkinson's disease drugs may be by simultaneous / concomitant administration or sequential / separate administration. The one or more other anti-Parkinson's disease drugs are not necessarily administered subcutaneously but may be administered by any convenient route of administration.

[0102] Since the product of the hydrolysis of the compound of formula (I), apomorphine, may cause short-term nausea, particularly at the beginning of treatment, the compound of the present invention or the pharmaceutical composition of the present invention is preferably administered in combination with an antiemetic. For example, this combination therapy can be continued while administering the compound of the present invention or the drug combination, and the time limit of at least two weeks before the administration of the antiemetic can be terminated. For example, the antiemetic can be selected from alizapride, alosetron, aprepitant, atropine, azasetron, bemisetron, benzquinamine, bromide, bukeli, casopitant, cerium oxalate, chlorpromazine, cilansetron, clebopride, clozapine, seckel, cyproheptadine, dazopride, dexamethasone, dimenhydrinate, diphenhydramine, diphenidol, dolasetron, domperidone, dronabinol, elopitant, fosaprepitant, granisetron, haloperidol, hydroxyzine, scopolamine, itopride, lelisetron, lorazepam , maropitant, metoprololazine, metoclopramide, metopimazine, mianserin, midazolam, mirtazapine, nabilone, norcannabidiol, olanzapine, ondansetron, oxypentad, palonosetron, pipamazine, prochlorperazine, promethazine, propofol, quetiapine, ramosetron, licarsetron, risperidone, scopolamine, tetrahydrocannabinol, thiethylpyrrolidone, trimethobenzamide, tropisetron, viltepitant, zatosetron, ziprasidone, and pharmaceutically acceptable salts (e.g., hydrochlorides) of any of these drugs.

[0103] Therefore, 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 wherein the compound or the pharmaceutical composition is administered in combination with an antiemetic (e.g., any of the antiemetics listed above, preferably domperidone). For example, the combined administration of the compound or the pharmaceutical composition and the antiemetic can be performed by simultaneous / concomitant administration of the antiemetic with the compound or the pharmaceutical composition, or by sequential / separate administration thereof. When administered sequentially, the compound / pharmaceutical composition of the present invention may be included in the pharmaceutical composition or may be administered in different (separate) pharmaceutical compositions. If provided as a separate pharmaceutical composition, the antiemetic need not be administered subcutaneously, but rather by any convenient route of administration.

[0104] The present invention also relates to the administration of a compound or pharmaceutical composition of the present invention in combination with an antiemetic (as described above) and with one or more additional antiparkinsonian agents (as described above).

[0105] The subject or patient treated according to the present invention can 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., male or female) or a non-human mammal (e.g., a guinea pig, hamster, rat, mouse, rabbit, dog, cat, horse, monkey, ape, marmoset, baboon, gorilla, chimpanzee, orangutan, gibbon, sheep, cattle, or pig). Most preferably, the subject / patient treated according to the present invention is a human.

[0106] As used herein, the term "about" preferably refers to ±10% of the indicated numerical value, more preferably ±5% of the indicated numerical value, and especially refers to the exact numerical value indicated.

[0107] The terms "optional," "optionally," and "may" indicate that the indicated feature may be present, but may also be absent. Whenever the terms "optional," "optionally," or "may" are used, the present invention specifically contemplates both possibilities, i.e., the presence of the corresponding feature, or the absence of the corresponding feature. For example, if an ingredient of a composition is indicated as "optional," the present invention specifically contemplates both possibilities, i.e., the presence of the corresponding ingredient (included in the composition) or the absence of the corresponding ingredient in the composition.

[0108] Unless expressly indicated otherwise or contradicted by the context, the term "comprising" (or "comprise," "comprises," "contains," or "containing") has the meaning of "comprising, among other things," i.e., "comprising, in addition to other optional elements,..." In addition, the term also includes the narrow meanings of "consisting essentially of" and "consisting of." For example, the term "A comprising B and C" has the meaning of "comprising A in addition to B and C," where A may include other optional elements (e.g., "A comprising B, C, and D" may also be included), but the term also includes the meanings of "A consisting essentially of B and C" and "A consisting of B and C" (i.e., A does not contain elements other than B and C).

[0109] Any parameter referred to herein (including any amount / concentration expressed as "mg / ml" or "% (v / v)", and any pH value) is preferably measured under standard ambient temperature and pressure conditions, in particular at a temperature of 25°C (298.15K) and an absolute pressure of 1 atm (101.325 kPa).

[0110] It will be understood that the present invention is specifically directed to each and every combination of features and embodiments described herein, including any combination of typical and / or preferred features / embodiments.

[0111] Throughout this specification, numerous references, including patent applications and scientific literature, are cited. Although the disclosures of these references are not considered relevant to the patentability of the present invention, their entire contents are incorporated herein by reference. More specifically, all cited references are incorporated by reference to the same extent as if each individual reference were specifically and individually indicated to be incorporated by reference.

[0112] The present invention will now be described with reference to the following examples, which are illustrative only and should not be construed as limiting the scope of the invention. Example

[0113] Example 1: Synthesis of apomorphine monophosphate

[0114]

[0115] In a flame-dried, argon-purged Schlenk flask, a suspension of apomorphine hydrochloride hemihydrate (10.0 g, 32.0 mmol) in anhydrous CHCl (80 mL) was cooled to 0°C in an ice / water bath and deprotonated using EtN (13.5 mL, 9.86 g, 97.4 mmol). After stirring at 0°C for 20 min, phosphorus oxychloride (6.40 mL, 10.8 g, 70.1 mmol) was added and the resulting pale yellow suspension was heated at reflux for 66 h. After cooling to room temperature (rt), the solvent was removed under reduced pressure (rotary evaporator) and the residue was dissolved in water (100 mL). The pH was adjusted to pH ~11 by adding 3M NaOH aqueous solution. The resulting dark green suspension was filtered through a sintered glass frit, and the filtrate was directly applied to a reverse phase silica gel column (50 mL C18 silica gel, 400-200 mesh; eluent: HO; fraction size: 15 mL; fraction analysis: HPLC). Fractions containing the desired product were pooled and the pH was adjusted to pH ~5 by adding 1 M HCl to obtain a yellow-white suspension. The resulting precipitate (protonated apomorphine monophosphate) was collected by filtration, suspended in 100 mL HO, and deprotonated with 3 M NaOH (pH ~ 10). The resulting dark green solution was lyophilized to obtain the desired product.

[0116] Yield 4.60 g (11.1 mmol, 35%), light brown powder, C 17 H 15 NNa3O5P[413.25]

[0117] Mp>210℃ decomposition (Na-sodium)

[0118] HRMS[C 17 H 18 NO5P-H +]Calculated value (M / z): 348.0995; found value: 348.1000.

[0119] The NMR spectrum of the obtained product is shown in FIG1 .

[0120] 1 H NMR (300.36 MHz, D2O) δ = 8.38 (d, J = 7.6 Hz, 1H, two isomers), 7.37 (s, 1H, isomer a), 7.29 (t, J = 7.7 Hz, 1H, isomer b), 7.23-7.07 (m, 2H, two isomers), 7.00 (s, 1H, isomer a), 6.86 (d, J = 8.1 Hz, 1H, isomer b). H, isomer a), 6.56 (d, J = 7.9 Hz, 1H, isomer b), 3.25-3.03 (m, 4H, two isomers), 2.80 (d, J = 16.4 Hz, 1H, two isomers), 2.66-2.55 (m, 1H, two isomers), 2.50 (s, 3H, two isomers), 2.37 (m, 1H, two isomers) ppm.

[0121] 13 C NMR (75.53 MHz, D2O) δ = 148.3, 143.9, 134.5, 133.7, 133.4, 132.7, 132.6, 131.6, 131.0, 129.0, 128.0, 126.8, 126.7, 126.4, 125.6, 123.5, 122.2, 119.0, 117.1, 114.5, 61.9, 61.7, 52.0 (two isomers), 42.6, 42.5, 33.9, 33.4, 28.0 (two isomers) ppm.

[0122] HPLC-MS analysis:

[0123] Column: Agilent Technologies' 120SB-C18, 3.0 x 100 mm, 2.7 μm "type C-18-reversed phase column. Flow rate: constant flow rate 0.7 mL / min, T = 35 ° C. HPLC-MS analysis as shown Figure 2 As shown in .

[0124] 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.

[0125] Example 2: Separation of Regioisomers of Apomorphine Monophosphate

[0126] 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 100-5C18ec column (125×21 mm, 5 μm). Signals were detected at 210 nm and 254 nm. Acetonitrile (VWR HiPerSolv, HPLC grade) containing trifluoroacetic acid and water (Barnstead Ultrapure water system). Use the following method: Nucleodur C18 005TFA02to50: 0.0-3.0 min: 98% H2O (0.05% TFA) and 2% CH3CN; 3.0-13.0 min: linear gradient - 50% H2O (0.05% TFA) and 50% CH3CN; 13.0-14.0 min: linear gradient - 100% CH3CN; 14.0-15.0 min: 100% CH3CN; 15.0-16.0 min: linear gradient - 98% H2O (0.05% TFA) and 2% CH3CN; 16.0-19.0 min: 98% H2O (0.05% TFA) and 2% CH3CN; flow rate: 15.00 mL min -1 ; T = 30℃.

[0127] HPLC-MS analysis of the mixture:

[0128] Column: Agilent Technologies' 120SB-C18, 3.0 x 100 mm, 2.7 μm "type C-18-reversed phase column. Flow rate: constant flow rate 0.7 mL / min, T = 35°C.

[0129] 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.

[0130] The analysis results are as follows Figure 3 Part 1 As shown in .

[0131] HPLC-MS analysis of isolated peak 1:

[0132] Column: Agilent Technologies' 120SB-C18, 3.0 x 100 mm, 2.7 μm "type C-18-reversed phase column. Flow rate: constant flow rate 0.7 mL / min, T = 35°C.

[0133] 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.

[0134] The analysis results are as follows Figure 3 Part 2 As shown in .

[0135] NMR analysis of isolated peak 1

[0136]

[0137] 1 H NMR (300.36MHz, D2O) δ=8.29 (d, J=7.6Hz, 1H), 7.19 (t, J=7.3Hz, 1H), 6.98 (d, J=7.5Hz, 1H), 6.71 (d, J=7.7Hz, 2H) , 3.73 (d, J = 12.5Hz, 1H), 3.55 (d, J = 7.1Hz, 1H), 3.39-3.23 (m, 1H), 3.07-2.72 (m, 6H), 2.41 (t, J = 13.6Hz, 1H) ppm.

[0138] 13 C NMR (75.53MHz, D2O) δ=148.5, 138.8, 131.2, 129.2, 127.9, 127.9, 127.8, 127.3, 125.9, 125.5, 123.8, 117.3, 61.2, 51.5, 30.9, 25.2ppm.

[0139] 31 P NMR (202.35MHz, D2O) δ = 2.47ppm.

[0140] 1 H. 13 C and 31 The P NMR spectra are shown in Figure 3, parts 3-5, respectively.

[0141] HPLC-MS analysis of isolated peak 2:

[0142] Column: Agilent Technologies' 120SB-C18, 3.0 x 100 mm, 2.7 μm "type C-18-reversed phase column. Flow rate: constant flow rate 0.7 mL / min, T = 35°C.

[0143] 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.

[0144] The analysis results are as follows Figure 3 Part 6 As shown in .

[0145] NMR analysis of isolated peak 2

[0146]

[0147] 1 H NMR (300.36MHz, D2O) δ = 8.19 (d, J = 7.7Hz, 1H), 7.30 (t, J = 7.7Hz, 1H), 7.12 (d, J = 7.4Hz, 1H), 7.01 (d, J = 7.9Hz, 1H), 6.70 (d, J=8.0Hz, 1H), 3.45-3.28 (m, 2H), 3.23-3.04 (m, 2H), 2.84 (d, J=13.9Hz, 2H), 2.72 (s, 3H), 2.41 (t, J=13.8Hz, 1H) ppm.

[0148] 13 C NMR (75.53MHz, D2O) δ = 145.7, 141.8, 141.7, 131.6, 131.1, 130.6, 130.1, 1 27.7, 127.4, 126.5, 121.5, 121.1, 119.7, 61.4, 51.8, 41.1, 32.0, 26.2ppm.

[0149] 31 P NMR (202.35MHz, D2O) δ=2.61ppm.

[0150] Example 3: Ionization State of Apomorphine Monophosphate

[0151] The pKa value of apomorphine monophosphate was estimated / predicted as follows (only one isomer of the compound is shown for better presentation):

[0152]

[0153] When the pH value was adjusted to the specified value by dropwise addition of 1 M apomorphine monophosphate in aqueous HCl (trisodium salt, pH of the solution ~11, as obtained in Example 1) and lyophilized, the following compounds were isolated:

[0154] pH 8:

[0155]

[0156] VIR-1-097-pH8

[0157] C 17 H 16 NNa2O5P[391.27]

[0158] Moderately lower solubility compared to the trisodium salt

[0159] 1 H NMR (300.36 MHz, DMSO-d6) δ = 8.44 (d, J = 7.4 Hz, 1H, isomer 1), 8.22 (d, J = 7.7 Hz, 1H, isomer 2), 7.15 (dd, J = 15.2, 7.6 Hz, 1H, two isomers), 6.98 (d, J = 7.1 Hz, 1H, two isomers), 6.87-6.55 (m, 2H, two isomers), 3.11-2.93 (m, 5H, two isomers), 2.69 (d, J = 16.7 Hz, 1H, two isomers), 2.45 (s, 3H, two isomers), 2.37-2.19 (m, 2H, two isomers) ppm.

[0160] The corresponding 1 The H NMR spectrum is shown in Figure 4, part 1.

[0161] pH 4:

[0162]

[0163] VIR-1-097-pH4

[0164] C 17 H 18 NO5P[347.31]

[0165] Insoluble in water (inner salt, completely neutral)

[0166] 1H NMR (300.36 MHz, DMSO-d6) δ = 8.56 (d, J = 7.7 Hz, 1H, isomer 1), 8.33 (d, J = 7.7 Hz, 1H, isomer 2), 7.29 (dd, J = 15.5, 7.6 Hz, 1H, two isomers), 7.11 (d, J = 6.9 Hz, 1H, two isomers), 6.91-6.61 (m, 2H, two isomers), 4.11 (s, 2H, two isomers), 3.43-3.23 (m, 5H, two isomers), 2.92 (s, 3H, two isomers), 2.82-2.68 (m, 1H, two isomers) ppm.

[0167] The corresponding 1 The H NMR spectrum is shown in Figure 4, part 1.2.

[0168] pH < 1:

[0169]

[0170] VIR-1-097-pH1

[0171] C 17 H 19 ClNO5P[383.76]

[0172] Solubility in water decreases (increases at higher temperatures)

[0173] Only one isomer remains (or is formed by interconversion)

[0174] 1 H NMR (300.36MHz, CD3OD) δ=8.41 (d, J=7.9Hz, 1H), 7.38 (t, J=7.7Hz, 1H), 7.21 (d, J=7.7Hz, 2H), 6.90 (d, J=8.1Hz, 1H), 4.3 4 (d, J=11.1Hz, 1H), 3.83 (d, J=7.3Hz, 1H), 3.61-3.42 (m, 3H), 3.21 (s, 3H), 3.13 (d, J=14.0Hz, 1H), 2.97-2.84 (m, 1H)ppm.

[0175] Corresponding in CD3OD 1 The H NMR spectrum is shown in Figure 4, part 1.3.

[0176] HPLC-MS analysis of VIR-1-097-pH1:

[0177] Column: Agilent Technologies' 120SB-C18, 3.0 x 100 mm, 2.7 μm "type C-18-reversed phase column. Flow rate: constant flow rate 0.7 mL / min, T = 35°C.

[0178] 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 was performed at 254.8 nm.

[0179] The results are as follows Figure 4 Part 4 As shown in .

[0180] As shown in the second peak in Example 2, spiked with the isolated isomer, it was shown that after adjusting the aqueous isomer mixture to pH <1 with 1M HCl, only this isomer remained as the hydrochloride salt. The results are shown in Part 5 of Figure 4. Since free apomorphine was not found in the HPLC chromatogram, it can be inferred that this was not caused by the decomposition of another isomer (as in the isolated peak 1 in Example 1), but rather occurred through an acid-mediated transesterification reaction.

[0181] Example 4: Cation Exchange of Apomorphine Monophosphate

[0182] Using Different Forms of Amberlite TM Cation exchange chromatography was performed using IR-120 ion exchange resin (0.6-0.8 mm particle size, total capacity as Na-form >1.8 eq / L). TM IR-120 Na-form ion exchange resin with the desired cation (K + NH4 + , Ca 2+ Mg 2+) of the corresponding chloride or iodide salt was pre-equilibrated for 3 h. The pre-equilibrated resin was then loaded into a column (diameter: 1 cm, height: 10 cm; resin volume: 7.9 mL; total capacity: >14 mmol) and rinsed twice with 25 mL of a saturated aqueous solution of the corresponding salt. The resin was then thoroughly washed with deionized water (3 x 50 mL) to remove any adhering salts. Subsequently, 100 mg of apomorphine monophosphate ("VIR-1-097") (0.242 mmol; Na-form) was dissolved in 1 mL of H2O, and the solution was applied to the ion exchange resin and then eluted (eluent: H2O; fraction size: 2 mL; fraction analysis: HPLC). The fractions containing the desired product were pooled and lyophilized to obtain a cation exchange product.

[0183] Apomorphine monophosphate potassium salt (VIR-1-097-K)

[0184]

[0185] 111 mg (0.240 mmol, 99%), ochre solid, C 17 H 15 K3NO5P[461.58]

[0186] Hygroscopic, highly soluble in water.

[0187] Apomorphine monophosphate ammonium salt (VIR-1-097-NH4)

[0188]

[0189] 87 mg (0.218 mmol, 90%), brown solid, C 17 H 27 N4O5P[398.40]

[0190] Its solubility in water is slightly lower than that of the sodium salt.

[0191] Apomorphine monophosphate calcium salt (VIR-1-097-Ca)

[0192]

[0193] 80 mg (0.198 mmol, 82%), gray solid, C 17 H 15 Ca 1.5 NO5P[404.40]

[0194] The solubility in water decreases.

[0195] Apomorphine magnesium monophosphate (VIR-1-097-Mg)

[0196]

[0197] 67 mg (0.176 mmol, 73%), yellow-white solid, C 17 H 15 Mg 1.5 NO5P[380.74]

[0198] The solubility in water decreases.

[0199] HPLC analysis of apomorphine monophosphate (VIR-1-097) salt:

[0200] Column: Agilent Technologies' 120SB-C18, 3.0 x 100 mm, 2.7 μm "type C-18-reversed phase column. Flow rate: constant flow rate 0.7 mL / min, T = 35°C.

[0201] 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 was performed at 254.8 nm.

[0202] The results are shown in Figure 5.

[0203] Example 5: Preparation of an injectable solution of apomorphine monophosphate trisodium salt

[0204] 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 the antioxidant was completely dissolved, the pH value was measured for information (pH 4.49).

[0205] 5.62 g of apomorphine trisodium monophosphate (mixture of isomers, containing approximately 5.9% water) was weighed and added to the compounding mixture under magnetic stirring. A clear amber solution was obtained. The pH was adjusted to 7.50 ± 0.1 with 1 M HCl. The mixture was then filled to a final weight of 800 g, stirred, and the pH was checked again (pH 7.62). The compounding vessel was then transferred to a glove box with a controlled oxygen-free atmosphere.

[0206] Final concentration: 6.61 g / L (anhydrous basis) of apomorphine trisodium monophosphate, equivalent to 0.016 mol / L (MW: 413.25 g / mol).

[0207] With Wfi washing glass bottle and rubber stopper, and sterilize by autoclaving.By sterilizing bottle and stopper transfer in glove box.Make compounding solution pass through sterile filter membrane (PALL 25mm Fluorodyne IIPVDF).Filtrate is filled in 20R glass bottle according to the part of 20.5ml, in the oxygen-free atmosphere (oxygen<100ppm) in glove box, stopper with rubber stopper.With aluminum crimping cover sealing band stopper bottle.

[0208] The filled vials gave the following analytical results:

[0209]

[0210] The filled vials are suitable for use in animal studies for further investigation. They have the same pH, the same sulfite content (0.5 mg / mL), and are equimolar to a commercial injectable solution of apomorphine 5 mg / ml (Dacepton).

[0211] A placebo product was prepared in a similar manner, but without the use of apomorphine trisodium monophosphate.

[0212] Example 6: Metabolic stabilization of apomorphine monophosphate (mixture of isomers) when incubated with human hepatocytes In vitro test results

[0213] The metabolic conversion of apomorphine monophosphate (mixture of isomers) obtained as in Example 1 to apomorphine was studied in a standardized human hepatocyte assay. Upon incubation with human hepatocytes, apomorphine monophosphate was rapidly cleared from the reaction mixture. Within 10 min, approximately 30% was converted to apomorphine; within 60 min, approximately 75% of apomorphine monophosphate was consumed (see Figure 6 Part 1 The half-life of apomorphine monophosphate in this assay was calculated to be 33 min.

[0214] The cell-free control (negative control) showed no significant formation of apomorphine (see Figure 6, part 3). This confirmed that the observed apomorphine formation was indeed caused by hepatocytes and not the result of nonspecific degradation during the assay.

[0215] Apomorphine was detected at all sampling points, with the highest levels detected after 10 minutes. At this time, the amount of apomorphine correlated with the disappearance of apomorphine monophosphate. Thereafter, the amount of apomorphine detected decreased.

[0216] It is well known that apomorphine is metabolized in the liver, and this is also reflected in the in vitro stability assay in human liver (see Figure 6 Part 4 ).

[0217] In vitro assays with hepatocytes confirmed that apomorphine monophosphate, as a prodrug, can be rapidly converted to apomorphine. In further in vitro testing, it was demonstrated that human plasma, human whole blood, and human liver S9 fractions do not convert apomorphine monophosphate to apomorphine to any significant extent. This confirms that the release of apomorphine from the apomorphine prodrug is caused by liver metabolism and enzymatic reactions located in functional hepatocytes.

[0218] As a phosphate prodrug, the enzymatic activation of apomorphine monophosphate 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 (e.g., alkaline phosphatase) confirms and rationalizes the in vitro assay results.

[0219] Example 7: Animal Experiment - Testing the Skin Reaction of the Apomorphine Prodrug of the Invention in Pigs Materials and Methods

[0220] The animal research application for the current in vivo experiments was approved by the institutional ethics and welfare committee and the national authorities according to section 26 et seq. of the Austrian Animal Experiments Act (Tierversuchsgesetz 2012; approval number 2021-0.746.730).

[0221] The purpose of this study was to test the effects of two apomorphine formulations on pig skin: the apomorphine prodrug of the present invention and formulated in Example 5 (APO PD22-03; VIR-1-097, the sodium salt described in Example 1), formulated at a concentration of 6.61 mg / mL, pH 7.5 ± 0.2, and also containing 0.5 mg / mL metabisulfite; and a commercially available reference apomorphine formulation (Dasipton), which contains apomorphine hydrochloride hemihydrate at a concentration of 5 mg / mL, pH 3.8 ± 0.2, and also contains 1.0 mg / mL sodium metabisulfite and 0.8 mg / mL NaCl. The 6.61 mg / mL apomorphine prodrug concentration corresponds to the same molar concentration as the 5 mg / mL apomorphine hydrochloride hemihydrate concentration contained in the Dasipton formulation. Both drugs were injected subcutaneously daily over 12 hours on the right side of the neck over a 14-day period. In addition, blood was collected via a central venous catheter on selected study days.

[0222] For this experiment, 10 sows with an average initial weight of 55 kg were used. After an acclimatization period and daily training with positive conditioning, the six most docile animals and two spare animals (one animal was lost during the first week) were tattooed on the right side of the neck and a central venous catheter was placed in the jugular vein under general anesthesia.

[0223] On the right side of the neck, 8 application areas were tattooed, each divided into 2 quadrants, which determine the needle fixation position on a specific day (see Figure 7). In addition, the letters (IP) were tattooed below the corresponding application area. In addition, there was a control area where a needle was inserted and fixed for 12 hours twice every 7 days without catheter and drug administration. The needle insertion position on a specific day was defined by the area in the tattoo. This allows any injection site changes observed to be assigned to the injection on a specific day. Before inserting the needle, the application area was cleaned of dirt with a dressing and disinfected with alcohol.

[0224] Under general anesthesia, ketamine hydrochloride ( 10mg / kg body weight) and azaperone ( 1.3 mg / kg body weight) for induction, propofol (2.5-4.0 mg / kg) for maintenance of anesthesia, and methadone (0.3 mg / kg, twice every 4 hours) was administered to the animals for safety analgesia during surgery. To avoid pain and infection after catheter placement, analgesics ( 0.4 mg / kg body weight) and antibiotics (Baytril 7.5 mg / kg body weight). A central venous catheter extension was performed via a subcutaneous tunnel. External access was connected to the nape of the neck and, to protect this extension, was secured in a pouch secured at the nape of the neck with skin sutures.

[0225] Since apomorphine is an antiemetic, the animals were orally administered an antiemetic (morphine 10 mg film-coated tablets, JANSSEN-CILAG Pharma GmbH, 1020 Vienna, Austria) before the start of drug administration, at noon, and shortly before the end of drug administration. The tablets were hidden in grapes and thus ingested by the animals without any problems.

[0226] Drugs were administered via a pump administration system (D-mine pump; Fa. EVER Neuro Pharma, Unterach, Austria) using a subcutaneous infusion needle (Neria G27, 6 mm, Unomedic A ConVaTec Company, Denmark). This short needle (6 mm) was chosen so as not to penetrate the muscle. The needle was secured with tape (Animal Polster, Fa. Snogg, Vennesla, Norway).

[0227] The animals were divided into two groups. Animals numbered 17, 18, and 19 received an apomorphine prodrug (APO PD22-03; VIR-1-097) injected into the right side of the neck. On the other hand, animals 20, 21, and 22 received a commercially available apomorphine formulation (Dasipton) as a control. Since blood could no longer be drawn from animals 18 and 19 via the central venous catheter on study day 7 (due to catheter blockage), animals 23 and 24 were included in the study from study day 7 and received the drug APO PD22-03 until study day 14. Both drugs were administered at the same molar concentration—in the case of 45 mg of Dasipton, the daily dose = 3.7 mg / h = 8.88 ml for 12 hours—and the corresponding molar amount of APO PD22-03.

[0228] During the acclimation and experimental period, all animals were kept on straw and had free access to pelleted commercial feed and drinking water. The animals were trained to wear a dog harness with a pump enclosed in a pocket on the back all day. During the 14-day experimental period, the animals were housed in individual pens to minimize the risk of animals rubbing against each other's harnesses and / or securing the pumps. To reduce symptoms of social stress, the animals were allowed direct nose and eye contact at all times.

[0229] The study started with six animals included in the study. All animals were clinically examined daily in the morning, internal body temperatures were measured, and the animals were weighed once a week.

[0230] Macroscopic assessment of the injection site

[0231] The injection site was assessed daily before and after administration. The assessed injection site was photographed and recorded in the morning and evening. In order to evaluate drug-administration-derived side effects (such as skin lesions and nodule formation), the affected skin area was examined and the observations were recorded. The size and extent of skin lesions were assessed by two different scores, namely according to the extent of skin lesions (such as: 0-undetectable / present, 1-minimal, 2-low, 3-medium, 4-high) and the size of skin lesions (such as: 0-no skin reaction detected, 1-<10% of the area changed, 2-10-25% of the area changed, 3-26-50% of the area changed, 4-51-75% of the area changed, 5-76-100% of the area changed). The incidence of nodules was calculated separately using the score of the number of nodules (0-no nodules detected; 1-isolated, 1 nodule; 2-low grade, 2-5 nodules; 3-medium grade, 6-10 nodules; 4-high grade, >10 nodules) and the size of the nodules (in centimeters) was assessed.

[0232] After the start of the administration, check the animal every hour to detect premature needle dislodgement. If the needle has not completely dislodged and there is no leakage, repair by re-application is permitted. If the needle completely dislodges during the first 8 hours, a new catheter must be attached, the needle reinserted into the skin, and the pump restarted. If the needle dislodges after 8 hours, re-application is not necessary.

[0233] As shown in FIG7 , the total nodule score for each neck consists of the nodule score (0-4) for each of the 14 application sites tested twice daily (in this case, the maximum possible score is 56).

[0234] result

[0235] During this experiment, animals 17-24 did not experience any abnormalities during clinical examination. Antiemetics were administered three times daily without any problems, and no vomiting occurred in any of the animals. Weekly weighing of the animals revealed a sustained increase in weight and an average daily gain within normal limits. At the start of the experiment, the animals weighed between 50 and 70 kg, and at the end of the experiment (after two weeks), they weighed between 59 and 74 kg.

[0236] nodules

[0237] Animals 20-22 (Dasipton) showed nodules on almost every single injection day. However, the average recovery time for these animals ranged from 5 to 5.14 days. Animal 20 had nodules for an average of 5.14 days, while animals 21 and 22 had nodules for an average of exactly 5 days. Animal 20 developed nodules after 11 of the 14 days of injection, animal 21 developed a total of 12 nodules over the 14 days, and animal 22 developed nodules after 13 of the 14 days of injection.

[0238] In animals 17-19 (APO PD22-03), significantly fewer nodules were visible. The average time to nodule recovery was 3 days in animal 17, 1 day in animal 18, and 2.5 days in animal 19. Animal 17 had a total of 3 nodules, animal 18 displayed 6 nodules, and animal 19 had only 1 nodule. Animals 23 and 24 were injected with drug starting on study day 7, and after study day 10, both animals displayed 1 nodule each, which was observable at one observation time point.

[0239] Animals 17-19, which received the APO PD22-03 formulation, had few nodules. In these animals, nodules were mostly 1 cm in size at the first observation time point (only animal 19 had a 1.5 cm nodule at the first observation time point) and subsequently decreased in size (0.5 cm) or disappeared. In animals 20-22, nodules were mostly 1 cm in size initially and remained at 1 cm in diameter. Animal 22 had a larger nodule (2 cm) at the first observation time point. Animals 23 and 24 had one nodule, measuring 0.5 cm at one observation time point.

[0240] In the control area, where all animals were given needles once a week without any medication, no nodules appeared in any of the animals.

[0241] There was a significant difference in the total nodule score between the two drugs. Animals 17-19 had fewer nodules on each side of the neck. Animal 21 had the highest total score, with 15 nodules present on day 14 of injection. The data are summarized in Figure 7.

[0242] in conclusion

[0243] These results indicate that the formulations comprising the novel apomorphine prodrug of the present invention exhibit favorable improvements in local tolerability, particularly advantageously reduced skin reactions, compared to the commercial apomorphine formulation (Dasipton) used in this animal study.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: Where R 1 and R 2 are each independently -OH or -OP(=O)(-OH)(-OH), provided that R 1 and R 2 At least one of them is -OP(=O)(-OH)(-OH).

2. The compound of claim 1, wherein R 1 and R 2 One of them is -OP(=O)(-OH)(-OH), and R 1 and R 2 The other is -OH.

3. The compound of claim 1, wherein R 1 is -OH, and R 2 It is -OP(=O)(-OH)(-OH).

4. The compound of claim 1, wherein R 1 is -OP(=O)(-OH)(-OH), and R 2 It is -OH.

5. The compound of claim 1, wherein R 1 and R 2 Each is -OP(=O)(-OH)(-OH).

6. The compound of any one of claims 1 to 5, wherein the compound has the following configuration:

7. The compound according to any one of claims 1 to 6, which is a pharmaceutically acceptable salt of the compound of formula (I), preferably a sodium salt.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 and a pharmaceutically acceptable excipient.

9. A compound according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 8 for use as a medicament.

10. A compound according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 8 for use in the treatment of a neurodegenerative disease / disorder.

11. A compound for use according to claim 10 or a pharmaceutical composition for use according to claim 10, wherein the neurodegenerative disease / disorder is selected from Parkinson's disease, Alzheimer's disease, Huntington's disease, neuroleptic malignant syndrome, dystonia and schizophrenia.

12. A compound according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 8 for use in the treatment of Parkinson's disease.

13. A compound for use according to claim 11 or 12 or a pharmaceutical composition for use according to claim 11 or 12, wherein said compound or said pharmaceutical composition is administered in combination with one or more additional antiparkinsonian and / or antiemetic agents.

14. A compound according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 8 for use in the treatment of sexual dysfunction or impotence, or for use in the treatment of restless retreat syndrome.

15. A compound for use according to any one of claims 9 to 14 or a pharmaceutical composition for use according to any one of claims 9 to 14, wherein the compound or the pharmaceutical composition is administered subcutaneously, and / or wherein the compound or the pharmaceutical composition is administered to a human subject.

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