(2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid and its intermediates

Abstract

The present invention relates to a compound represented by the following formula (Id): [Formula 1] TIFF2022533317000054.tif41170 The present invention relates to a process for preparing (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid having the formula (Id) and pharmaceutically acceptable salts thereof. The compound of formula (Id) is a prodrug of catecholamines for use in the treatment of neurodegenerative diseases and disorders, such as Parkinson's disease. The present invention also relates to new intermediates of said process.

Description

[Technical field]

[0001] The present invention relates to a process for the preparation of the compound (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid for use in the treatment of neurodegenerative diseases and disorders, such as Parkinson's disease. The present invention also relates to new intermediates in said process and to the preparation of said intermediates. [Background technology]

[0002] Parkinson's disease (PD) is a common neurodegenerative disorder that becomes more prevalent with age and affects an estimated 7-10 million people worldwide. Parkinson's disease is a multifaceted disease characterized by both motor and non-motor symptoms. Motor symptoms include resting tremor, bradykinesia / akinesia (slowness and lack of movement), muscular rigidity, postural stability and gait dysfunction, and non-motor symptoms include neuropsychiatric disorders (e.g., depression, psychotic symptoms, anxiety, apathy, mild cognitive impairment and dementia) as well as autonomic and sleep disorders (Poewe et al., Nature Review, (2017) vol3 article 17013:1-21).

[0003] An important hallmark of the pathophysiology of Parkinson's disease is the loss of pigmented dopaminergic neurons in the substantia nigra pars compacta, which provides dopaminergic innervation to the striatum and other brain regions. Such progressive neurodegeneration leads to a decline in striatal levels of dopamine, which ultimately results in a series of changes in the basal ganglia circuitry, ultimately resulting in the four cardinal motor features of Parkinson's disease. The primary targets of dopamine in the striatum consist of medium spiny GABAergic neurons (MSNs) with prominent topographic processes that selectively express D1 or D2 receptors. GABAergic MSNs projecting to the lateral pallidum, also called the striatopallidal "indirect pathway", express D2 receptors (MSN-2). GABAergic-MSNs projecting to the substantia nigra pars reticulata and medial pallidum, also called the striatopallidal "direct pathway", express D1 receptors (MSN-1). Lack of dopamine due to neuronal loss leads to an imbalance in the activity of the two pathways, resulting in a marked decrease in thalamic and cortical output activity and ultimately in motor dysfunction (Gerfen et al, Science (1990) 250:1429-32; Delong, (1990) Trends in Neuroscience 13:281-5; Alexander et Crutcher, (1990) Trends in Neuroscience 13:266-71 and for review see Poewe et al., Nature Review (2017) vol.3 article 17013:1-21).

[0004] The most effective therapeutic strategies available for patients suffering from Parkinson's disease and aiming to control motor symptoms are mainly indirect and direct dopamine agonists. Classical and gold standard therapy includes chronic oral intake of L-3,4-dihydroxyphenylalanine (L-DOPA), which is decarboxylated in the brain to form dopamine. Other approaches include administration of dopamine receptor agonists such as apomorphine, which acts on both D1 and D2 receptor subtypes, or pramipexole, ropinirole, and other agonists that are predominantly directed against the D2 receptor subtype. Due to the activation of both D1 and D2 receptor subtypes and the holistic rebalancing of the indirect-direct pathway (i.e., only D2 agonists reverse the dysfunction of the indirect pathway), optimal MR (relief of symptoms with movement) is obtained with the use of both L-DOPA and apomorphine.

[0005] L-DOPA and apomorphine, whose structures are shown below, are currently the most effective PD drugs in clinical use. [ka]

[0006] L-DOPA is a prodrug of dopamine and remains the most effective drug in the treatment of motor Parkinson's disease. However, after several years of treatment (i.e., honeymoon period), complications occur due to the inherent progression of the disease (i.e., sustained loss of dopaminergic neurons) and the poor pharmacokinetic (PK) profile of L-DOPA. These complications include 1) dyskinesia, which is an abnormal involuntary movement that occurs during the optimal "timely effect" of the drug, and 2) out-of-phase periods during which the positive effects of L-DOPA gradually decrease and symptoms return or worsen (Sprenger and Poewe, CNS Drugs (2013), 27:259-272).

[0007] Direct dopamine receptor agonists can activate dopamine autoreceptors as well as postsynaptic dopamine receptors located on medium spiny neurons MSN-1 and MSN-2. Apomorphine belongs to a class of dopamine agonists that have a 1,2-dihydroxybenzene (catechol) moiety. When combined with a phenethylamine motif, catecholamines often have low or no oral bioavailability, as is the case with apomorphine. Clinically, apomorphine is used to treat PD, albeit with parenteral delivery (generally intermittent subcutaneous administration or continuous daytime parenteral infusion via pump). For apomorphine, animal studies have shown that transdermal delivery or implantation could provide a potential form of administration. However, when delivery of apomorphine from implants was studied in monkeys (Bibbiani et al., Chase Experimental Neurology (2005), 192:73-78), it was found that in most cases the animals had to be treated with the immunosuppressant dexamethasone to prevent local irritation and other complications after the implant procedure. Alternative delivery strategies for apomorphine therapy in PD, such as inhaled and sublingual formulations, have been extensively explored (see, for example, Grosset et al., Acta Neurol Scand. (2013), 128:166-171 and Hauser et al., Movement Disorders (2016), Vol. 32(9):1367-1372). However, these attempts have not yet been clinically implemented for the treatment of PD.

[0008] An alternative to parenteral formulation of catecholamines involves the use of prodrugs that mask the free catechol hydroxyl group to allow oral administration. However, a known problem with developing prodrugs for clinical use is the difficulty associated with predicting conversion to the parent compound in humans.

[0009] Various ester prodrugs of catecholamines have been reported in the literature, such as monopivaloyl esters of N-propyl-noraporphine (NPA) and apomorphine (see, e.g., WO 02 / 100377) fully coated for duodenal delivery, as well as the diacetyl prodrug of the D1-like agonist Adrogolide, A-86929 (Giardina and Williams; CNS Drug Reviews (2001), Vol. 7(3): 305-316). Adrogolide undergoes extensive hepatic first-pass metabolism in men after oral administration, resulting in low oral bioavailability (about 4%). In PD patients, intravenous (IV) Adrogolide has antiparkinsonian efficacy comparable to L-DOPA (Giardina and Williams; CNS Drug Reviews (2001), Vol. 7(3): 305-316).

[0010] In addition to ester prodrugs of catecholamines, an alternative prodrug approach involves masking the two catechol hydroxyl groups as the corresponding methylene-dioxy or di-acetalyl derivatives. The principle of this prodrug is described, for example, in Campbell et al., Neuropharmacology (1982); 21(10): 953-961, as well as in U.S. Pat. No. 4,543,256, WO 2009 / 026934 and WO 2009 / 026935.

[0011] Another proposed approach to catecholamine prodrugs is the formation of enone derivatives as proposed, for example, in WO 2001 / 078713 and Liu et al., Bioorganic Med. Chem. (2008), 16:3438-3444. For further examples of catecholamine prodrugs, see, for example, Sozio et al., Exp. Opin. Drug Disc. (2012); 7(5): 385-406.

[0012] The compound (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol, hereinafter referred to as Compound (I), is disclosed in WO 2009 / 026934. The trans isomer was previously disclosed in Liu et al., J. Med. Chem. (2006), 49:1494-1498, followed by Liu et al., Bioorganic Med. Chem. (2008), 16:3438-3444, with pharmacological data suggesting that the compound has low oral bioavailability in rats. The racemic compound was first disclosed in Cannon et al., J. Heterocyclic Chem. (1980); 17:1633-1636. [ka]

[0013] Compound (I) is a dopamine receptor agonist with mixed D1 and D2 activity. Several prodrug derivatives of Compound (I) are known in the art.

[0014] Liu et al., J. Med. Chem. (2006), 49:1494-1498 and Liu et al., Bioorganic Med. Chem. (2008), 16:3438-3444 disclose an enone derivative of formula (Ia), shown below, which was shown to be converted to the active compound (I) in rats. [ka]

[0015] WO 2009 / 026934 and WO 2009 / 026935 disclose two prodrug derivatives of compound (I), including a compound having the following formula (Ib): [ka]

[0016] The conversion of compound (Ib) to compound (I) in rat and human hepatocytes has been demonstrated in WO 2010 / 097092. Furthermore, the in vivo pharmacology of compounds (Ia) and (Ib) and the active "parent compound" (I) has been tested in various animal models for Parkinson's disease (WO 2010 / 097092). Both compound (I) and compounds (Ia) and (Ib) have been found to be effective, and it has been shown that compounds (Ia) and (Ib) are converted to compound (I) in vivo. All three compounds have been reported to have a longer duration of action than that observed for L-dopa and apomorphine.

[0017] Other prodrugs of compound (I) disclosed in WO 2009 / 026934 and WO 2009 / 026935 are conventional ester prodrugs of formula (Ic): [ka]

[0018] Despite longstanding interest in this field, there remains a clear unmet need for the development of effective, well-tolerated and orally active drugs for the treatment of PD. Prodrug derivatives of mixed D1 / D2 agonists that provide a stable PK profile capable of providing continuous dopaminergic stimulation could fulfill this unmet need.

[0019] Consequently, there is also a need for methods of producing such drugs, particularly methods that are suitable for large-scale production and result in high yields of the compound of formula (Id). Summary of the Invention

[0020] The present invention relates to a compound represented by the following formula (Id): [ka] and reacting the (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid having the following formula (I): [ka] The present invention relates to a novel process for the preparation of the compound having the formula (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol.

[0021] The overall process starting from compound (I) is shown in Scheme 1 below. [ka]

[0022] In one embodiment, the present invention provides a method for preparing compound (Id), or a pharma- ceutically acceptable salt thereof, from compound (I), comprising the steps of: (1) reacting compound (Id) with a phenyl group; [ka] reacting compound (A2) with (2S,3S,4S,5R,6R)-2-(methoxycarbonyl)-6-(2,2,2-trichloro-1-iminoethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate to obtain compound (A3) according to the formula: The reaction is carried out in an aprotic solvent in the presence of a Lewis acid.

[0023] In one embodiment, the present invention provides a compound represented by the following formula (A3): [ka] or a salt thereof.

[0024] In one embodiment, the present invention provides a process for preparing compound (Id), or a pharma- ceutically acceptable salt thereof, from compound (I), comprising the steps of: Steps below 3) Deprotecting compound (A3) by contacting compound (A3) with a nucleophile according to Reaction Scheme 3 to obtain compound (Id), or a pharma- ceutically acceptable salt thereof. The present invention relates to a method comprising the steps of:

[0025] In a specific embodiment of the invention, the nucleophile used in step 3 is a base, for example, KOH or NaOH. [ka]

[0026] Individual aspects of the present invention relate to each of the method steps 1), 2) and 3).

[0027] Other individual aspects of the present invention relate to new intermediates of the process. Thus, a further aspect of the present invention relates to compounds (A2) and (A3) and their salts, which are useful intermediates in the process for preparing compound (Id), or a pharma- ceutically acceptable salt thereof, respectively.

[0028] The overall process provided by the present invention, as well as each individual process step and intermediate, are useful for the large scale production of compound (Id), or a pharma- ceutically acceptable salt thereof.

[0029] definition Compound References References to Compound (I), Compound (Id), (A2) and (A3) include the free substances (zwitterions) of said compounds, salts of said compounds, such as acid addition salts or base addition salts, as well as compounds in solution and solid form, including polymorphic and amorphous forms of the compounds of the invention and their salts. Furthermore, said compounds and their salts may potentially exist in unsolvated and solvated states with pharma- ceutically acceptable solvents such as water, ethanol, and the like.

[0030] Pharmaceutically acceptable salts In the context of this invention, pharma- ceutically acceptable salts are intended to denote non-toxic, ie physiologically acceptable salts.

[0031] The term "pharmaceutically acceptable salts" includes pharmaceutically acceptable acid addition salts, which are salts formed with inorganic and / or organic acids on a nitrogen atom in the parent molecule. The acids may be selected from, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitrous acid, sulfuric acid, benzoic acid, citric acid, gluconic acid, lactic acid, maleic acid, succinic acid, tartaric acid, acetic acid, propionic acid, oxalic acid, malonic acid, fumaric acid, glutamic acid, pyroglutamic acid, salicylic acid, gentisic acid, saccharin, and sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, naphthalene-2-sulfonic acid, 2-hydroxyethanesulfonic acid, and benzenesulfonic acid.

[0032] Other examples of acids and bases useful for forming pharma- ceutically acceptable salts are described, for example, in Stahl and Wermuth (Eds), Handbook of Pharmaceutical salts. Properties, selection, and use, Wiley-VCH2008.

[0033] The compounds of the present invention can be used as intermediates for the preparation of compound (Id), or a pharma- ceutically acceptable salt thereof. Thus, the salt forms of the intermediates disclosed herein are not limited to their pharma- ceutically acceptable salts. Nevertheless, the pharma- ceutically acceptable salts of the intermediates can also be advantageously used in the preparation of compound (Id), or a pharma- ceutically acceptable salt thereof. Thus, in one embodiment of the present invention, the salt of compound (I), A2, A3, or compound (Id) is a pharma- ceutically acceptable salt.

[0034] Prodrug In the context of the present invention, the term "prodrug" or "prodrug derivative" refers to a compound that is converted into a pharmacologically active site in the body after administration to a living subject, such as a mammal, preferably a human. The conversion preferably occurs in a mammal, such as a mouse, a rat, a dog, a miniature pig, a rabbit, a monkey and / or a human. In the context of the present invention, a "prodrug of the compound (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol" or a "prodrug of the compound of formula (I)" or a "prodrug of the compound (I)" is understood to be a compound that is converted into the compound (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol in the body after administration. The administration may be by conventional routes of administration of pharmaceutical compositions known in the art, preferably oral administration.

[0035] In the context of the present invention, the terms "parent compound" and "parent molecule" refer to the pharmacologically active moiety obtained upon conversion of the corresponding prodrug. For example, the "parent compound" of compound (Id) is understood to be the compound of formula (I).

[0036] Pharmacokinetic Definitions and Abbreviations As used herein, "PK profile" is an abbreviation for "pharmacokinetic profile." The pharmacokinetic profile and pharmacokinetic parameters described herein are based on plasma concentration-time data obtained for the compound of formula (I) after oral administration of the compound of the present invention (Id) using non-compartmental modeling. The omitted PK parameters are Cmax (maximum concentration); tmax (time to reach Cmax); t1 / 2 (half-life); AUC0-24 (area under the curve from the time of administration to 24 hours after administration), and "24-hour exposure" is the concentration measured 24 hours after administration.

[0037] Therapeutically Effective Dose In the context of the present invention, the term "therapeutically effective amount" of a compound means an amount sufficient to alleviate, prevent, partially prevent, eliminate or delay the clinical symptoms of a given disease and its complications in a therapeutic intervention involving the administration of said compound. An amount adequate to achieve this is defined as a "therapeutically effective amount". The amount effective for each purpose will vary depending, for example, on the severity of the disease or injury and the weight and general condition of the subject.

[0038] In the context of the present invention, a "therapeutically effective amount" of compound (Id) means an amount of said compound of the present invention which, when administered, preferably by the oral route, to a mammal, preferably a human, is capable of providing an amount of compound (I) sufficient to alleviate, prevent, partially prevent, eliminate or delay the clinical symptoms of a given disease and its complications.

[0039] Treatment and Procedures In the context of the present invention, "treatment" or "treatment" is intended to indicate the management and care of the patient for the purpose of alleviating, preventing, partially preventing, eliminating or slowing the progression of the clinical symptoms of the disease. The patient to be treated is preferably a mammal, in particular a human being.

[0040] Symptoms for treatment The compounds obtainable by the methods of the present invention are intended for the treatment of neurodegenerative or neuropsychiatric diseases and disorders, such as Parkinson's disease and / or other conditions where treatment with a dopamine agonist is therapeutically beneficial.

[0041] Indications for treatment include various central nervous system disorders characterized by motor and / or non-motor disorders and part of the underlying pathophysiology is dysfunction of striatal-mediated circuitry. Such functional disorders are found in neurodegenerative disorders such as, but not limited to, Parkinson's disease (PD), restless legs syndrome, Huntington's disease, and Alzheimer's disease, as well as in neuropsychiatric disorders such as, but not limited to, schizophrenia, attention deficit hyperactivity disorder, and drug addiction.

[0042] In addition to neurodegenerative diseases and disorders, in other conditions where increasing dopaminergic turnover may be beneficial, mental function, including various aspects of cognition, is improved.It may also have a positive effect in depressed patients, and may be used as an appetite suppressant in the treatment of obesity and in the treatment of drug addiction.It may improve the potentially negative, positive and cognitive symptoms of microcerebrovascular disorder (MBD), narcolepsy, attention deficit hyperactivity disorder and schizophrenia.

[0043] Restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) are other indications that are clinically treated with dopamine agonists. In addition, impotence, erectile dysfunction, SSRI-induced sexual dysfunction, ovarian hyperstimulation syndrome (OHSS) and certain pituitary tumors (prolactinomas) may also be improved by treating with dopamine agonists. Dopamine is involved in the regulation of the circulatory and renal systems, therefore renal failure and hypertension may be considered as alternative indications for compound (Id).

[0044] The present invention encompasses the use of compound (Id) obtained by the method of the present invention for the treatment of the above mentioned diseases and disorders.

[0045] Route of administration Pharmaceutical compositions containing the compounds of formula (Id), either as the sole active compound or in combination with other active compounds, may be specifically formulated for administration by any suitable route, such as oral, rectal, nasal, buccal, sublingual, pulmonary, transdermal and parenteral (e.g. subcutaneous, intramuscular and intravenous) routes. In the context of the present invention, the oral route is the preferred route of administration.

[0046] It will be appreciated that the route will vary depending on the general condition and age of the subject being treated, the nature of the condition being treated and the active ingredient.

[0047] Pharmaceutical Formulations and Excipients Hereinafter, the term "excipient" or "pharmaceutical acceptable excipient" means pharmaceutical excipients such as, but not limited to, carriers, fillers, diluents, antiadherents, binders, coatings, colorants, disintegrants, flavors, glidants, lubricants, preservatives, adsorbents, sweeteners, solvents, vehicles and auxiliary agents.

[0048] The present invention also provides a pharmaceutical composition comprising a compound of formula (Id), i.e., compound (Id), or a pharma- ceutically acceptable salt thereof, directly obtainable by the method of the present invention, for example as disclosed in the experimental section herein. The present invention also provides a method for preparing a pharmaceutical composition comprising a compound of formula (Id), or a pharma- ceutically acceptable salt thereof, e.g., compound (Id), or a pharma- ceutically acceptable salt thereof, directly obtainable by the method of the present invention. The pharmaceutical composition according to the present invention may be formulated using pharma- ceutically acceptable excipients according to conventional techniques, such as those disclosed in Remington, The Science and Practice of Pharmacy, 22nd edition (2013), Edited by Allen, Loyd V., Jr.

[0049] The pharmaceutical composition comprising the compound of the present invention is preferably for oral administration.The pharmaceutical composition for oral administration includes solid oral dosage forms such as tablets, capsules, powders and granules, and liquid oral dosage forms such as liquids, emulsions, suspensions and syrups, and powders and granules that are dissolved or suspended in suitable liquids.

[0050] The solid oral dosage form can be provided as individual units (e.g., tablets or hard or soft capsules), each containing a predetermined amount of active ingredient, preferably one or more suitable excipients.If appropriate, the solid dosage form can be prepared with a coating, such as an enteric coating, or can be formulated to provide controlled release of the active ingredient, such as delayed or sustained release, according to methods well known in the art.If appropriate, the solid dosage form can also be a dosage form that disintegrates in saliva, such as, for example, an orodispersible tablet.

[0051] Examples of excipients suitable for solid oral dosage forms include, but are not limited to, microcrystalline cellulose, corn starch, lactose, mannitol, povidone, croscarmellose sodium, sucrose, cyclodextrin, talcum, gelatin, pectin, magnesium stearate, stearic acid, and lower alkyl ethers of cellulose. Similarly, solid formulations may contain excipients for delayed or sustained release formulations known in the art, such as glyceryl monostearate or hypromellose. When solid materials are used for oral administration, the formulations may be prepared, for example, by mixing the active ingredient with a solid excipient and then compressing the mixture with conventional tableting equipment, or the formulations may be placed in hard capsules, for example, in powder, pellet, or mini-tablet form. The amount of solid excipients may vary widely, but usually ranges from about 25 mg to about 1 g per dosage unit.

[0052] Liquid oral dosage forms can be provided, for example, as elixirs, syrups, oral drops, or liquid-filled capsules. Liquid oral dosage forms can also be provided as powders for solution or suspension in aqueous or non-aqueous liquids. Examples of excipients suitable for liquid oral dosage forms include, but are not limited to, ethanol, propylene glycol, glycerol, polyethylene glycol, poloxamer, sorbitol, polysorbate, mono- and diglycerides, cyclodextrin, coconut oil, palm oil, and water. Liquid oral dosage forms can be prepared, for example, by dissolving or suspending the active ingredient in an aqueous or non-aqueous liquid, or by incorporating the active ingredient into an oil-in-water or water-in-oil liquid emulsion.

[0053] Additional excipients such as colorants, flavors and preservatives may be used in both solid and liquid oral formulations.

[0054] Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous solutions, dispersions, suspensions or emulsions for injection or infusion, concentrates for injection or infusion, and sterile powders that are dissolved in a sterile solution or dispersion for injection or infusion before use. Examples of excipients suitable for parenteral formulations include, but are not limited to, water, coconut oil, palm oil, and cyclodextrin solutions. Aqueous formulations should be appropriately buffered if necessary and rendered isotonic with sufficient saline or glucose.

[0055] Other types of pharmaceutical compositions include suppositories, inhalants, creams, gels, transdermal patches, implants, and formulations for buccal or sublingual administration.

[0056] Excipients used in pharmaceutical formulations should be compatible with the intended route of administration and with the active ingredient.

[0057] dose In one embodiment, compound (Id) obtained by the method of the present invention, or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 0.0001 to about 5 mg / kg body weight per day. In particular, the daily dose may range from 0.001 to about 1 mg / kg body weight per day. The exact dosage will vary depending on the frequency and mode of administration of the subject to be treated, the sex, age, weight and general condition of the subject, the nature and severity of the condition to be treated, the associated disease to be treated, the desired effect of the treatment, and other factors known to those skilled in the art.

[0058] A typical oral dosage for an adult is in the range of 0.1-100 mg / day of a compound of the invention, for example 0.05-50 mg / day, 0.1-10 mg / day or 0.1-5 mg / day. Conveniently, the compound of the invention is administered in a unit dosage form containing said compound in an amount of about 0.01-50 mg, for example 0.05 mg, 0.1 mg, 0.2 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg or up to 50 mg. [Brief description of the drawings]

[0059] [Figure 1] PK profiles in Wistar rats obtained after oral administration according to Example 7. Profiles are based on the average plasma concentrations from 3 subjects for each compound. X-axis: time (hours); Y-axis: plasma concentrations of compound (I) (pg / mL) obtained after administration of the following compounds: ●: compound (Ia); ▲: compound (Ib); ◆: compound (Id). [Diagram 2]Figures 2 and 3: Locomotor activity time course (Figure 2) and total distance traveled (Figure 3) after treatment with vehicle (HO, orally) or compound (Id-ia) (10, 30, 100 or 300 μg / kg, orally) and compared to standard of care (SoC): apomorphine (APO, 3 mg / kg, subcutaneous), pramipexole (PPX, 0.3 mg / kg, subcutaneous). Animals were dosed at t = 60 min after a habituation period in the test chamber of 60 min and activity was then monitored for 350 min. Data were evaluated using Kruskal-Wallis tests with Dunn's multiple comparison test, giving an overall P value < 0.0001. Figure 2: X-axis: time (min); Y-axis: distance traveled (cm) ± SEM / 5 min-bins. Figure 3: Y-axis: total distance traveled (cm) ± SEM. Significance levels for post-hoc comparisons (vs. vehicle group) are indicated: *<0.05, **<0.01, ***<0.001, ****<0.0001. [Diagram 3] Same as above. [Figure 4] Figures 4 and 5: Relationship between plasma concentrations of compound (Id) and compound (I) and hyperactivity induced by compound (Id) (100 μg / kg, oral) (Figure 4) and the corresponding relationship between plasma apomorphine concentrations and hyperactivity induced by apomorphine (3 mg / kg, subcutaneous) (Figure 5). X-axis time (min); Y-axis left: distance traveled (cm) ± SEM / 5-min-bins; Y-axis right (Figure 4): plasma concentration of compound (I) (pg / mL); Y-axis right (Figure 5): plasma concentration of apomorphine (ng / mL). □: distance traveled (cm) ● plasma concentration. [Diagram 5] Same as above. [Figure 6] Conversion of compound (Id) to compound (I) in rat (6a) and human (6b) hepatocytes. X-axis: time (min); Y-axis: concentration of compound (I) (pg / mL). [Figure 7] Conversion of compound (Id) in rat (7a) and human (7b) whole blood. X-axis: time (min); Y-axis: concentration of compound (I) (pg / mL). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0060] Detailed Description of the Invention The present invention relates to a compound represented by the following formula (Id): [ka] The present invention relates to a method for producing the compound (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid having the formula:

[0061] The compound of formula (Id) is a prodrug of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol [Compound (I)], a dual D1 / D2 agonist having in vitro data as set forth in Table 2.

[0062] The present inventors have observed that compound (I) is conjugated with sulfate and glucuronide derivatives, including compound (Id), in rat and human hepatocytes, and the conjugates have been shown to be converted to compound (I) by conjugation and deconjugation in vivo.

[0063] Glucuronide and sulfate derivatives are generally known to be unstable in the intestine. The derivatives are formed as highly polar and soluble metabolites, facilitating the removal of the compounds from the body, and are therefore easily excreted. For example, in bile duct cannulated rats, glucuronide and sulfate conjugates are often found in the bile, and the deconjugates (i.e., the parent compound) are found in the feces. Back-conversion of glucuronide and sulfate conjugates in the intestine to the parent compound, which is sometimes subsequently reabsorbed, is known as part of the enterohepatic recycling process. As mentioned above, oral administration of phenethylcatecholamines such as apomorphine has generally proven unsuccessful due to low bioavailability. Similarly, compound (I) also has low oral bioavailability (Liu et al., Bioorganic Med.Chem.(2008),16:3438-3444). With this in mind, and taking into account the instability of the glucuronide and sulfate conjugates in the gastrointestinal tract, it would not be expected that sufficient plasma exposure of the compound could be achieved using oral administration of the glucuronide conjugate of Compound (I).

[0064] The principle of applying glucuronide derivatives as prodrugs for oral delivery has been discussed for retinoic acid (Goswami et al., J. Nutritional Biochem. (2003) 14:703-709) and for morphine (Stain-Texier et al., Drug Metab. and Disposition (1998) 26(5):383-387). Both studies showed very low levels of exposure to the parent compound after oral administration of the derivatives. Other studies have suggested the use of budesonide-β-D-glucuronide as a prodrug for local delivery of budesonide to the large intestine for the treatment of ulcerative colitis, based on poor absorption of the prodrug from the intestinal system itself (Nolen et al., J. Pharm Sci. (1995), 84(6):677-681).

[0065] Nevertheless, it was unexpectedly observed that oral administration of compound (Id), identified as a metabolite of compound (I) in rats and minipigs, provided systemic exposure of compound (I) in plasma, suggesting the utility of said compound as an orally active prodrug of compound (I).

[0066] The plasma profile of compound (I) obtained from oral administration of compounds (Ia) and (Ib) and oral administration of compound (Id) to Wistar rats according to Example 7 is shown in Figure 1. For all compounds, the dose was corrected by molecular weight to equal a dose of 300 μg / kg of compound (Ib) corresponding to 287 μg / kg of compound (I). The inventors found that oral administration of compounds (Ia) and (Ib) to Wistar rats results in early and high peak concentrations of compound (I). Such high peak concentrations may be associated with dopaminergic side effects in humans, such as nausea, vomiting and dizziness. In contrast, administration of compound (Id) results in a slower absorption rate, preventing rapid peak concentrations with sustained exposure of compound (I) in plasma. Furthermore, although the resulting AUC of compound (I) is generally lower than the AUC obtained after administration of compound (Ib), the plasma exposure of compound (I) in Wistar rats is maintained throughout 24 hours. However, due to the low peak concentration of compound (I) expected to induce side effects, a higher dose of compound (Id) could potentially be administered to achieve a higher total plasma concentration of compound (I) compared to the concentration achievable from administering compounds (Ia) and (Ib). When investigating the PK properties of compound (Ic), the inventors found that the plasma concentration of compound (I) was very low, making compound (Ic) unsuitable as a prodrug of compound (I) for oral administration, and the oral bioavailability suggested by compound (Id) was found to be very unpredictable. The PK parameters for the PK study in Wistar rats are listed in Table 3.

[0067] The in vivo conversion of compound (Id) to compound (I) was also observed following oral administration of compound (Id) in minipigs.

[0068] Bioconversion of compound (Id) in humans is supported by the experiments in Example 4a and Example 4b, which showed conversion to the compound of formula (I) in rat and human hepatocytes and in rat and human blood (Figures 6 and 7).

[0069] Thus, in conclusion, compound (Id) has been demonstrated in rats to be useful as an orally active prodrug of compound (I) and to provide a PK profile that avoids the peak Cmax observed with known prodrugs (Ia) and (Ib) and results in a significantly higher AUC for compound (I) than compound (Ic).

[0070] Compound (Id) was further investigated in rat locomotor activity assay according to Example 8. The assay demonstrated the dopaminergic effect obtained after oral administration of compound (Id) (see Figures 2, 3 and 4). (Id) Compound (Id) does not retain in vitro dopaminergic activity (see Example 5 and Table 2), further indicating that the effect of compound (Id) in rat locomotor activity assay is obtained by conversion of compound (Id) to compound (I).

[0071] Finally, the important problem with compound (Ib) of the prior art is that this compound is an agonist of 5-HT2B receptor.The association of 5-HT2B receptor agonism with the pathogenesis of valvular heart disease (VHD) after long-term exposure makes such compound unsuitable for use in the treatment of chronic diseases (Rothman et al., Circulation (2000), 102:2836-2841 and Cavero and Guillon, J. Pharmacol. Toxicol. Methods (2014), 69:150-161).Therefore, a further advantage of compound (Id) is that it is not a 5-HT2B agonist (see Example 6 and Table 2).

[0072] Compound (Id) is useful in the treatment of neurodegenerative diseases and disorders, such as Parkinson's disease and / or other conditions in which treatment with dopamine agonists is therapeutically beneficial. Compounds suitable for oral administration have the potential to provide a novel treatment paradigm in Parkinson's disease.

[0073] The present invention provides a scalable synthesis of compound (Id). The key step is the direct glucuronide conjugation reaction on compound (A2) using (2S,3S,4S,5R,6R)-2-(methoxycarbonyl)-6-(2,2,2-trichloro-1-iminoethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate as the conjugate donor. The present invention also includes a deprotection step that utilizes sodium hydroxide in methanol / water, thereby avoiding the use of, for example, toxic KCN. The overall method starting from compound (I) is simply shown in Scheme 4 below. [ka]

[0074] A method for producing compound (I) to be used in step 1) is disclosed in WO 2009 / 026934. WO 2019 / 101917 discloses a method for producing compound A2 and compound (Id).

[0075] Table 1 below provides an overview of the intermediate compounds (A2) and (A3) having the following respective compound names:

[0076] [Table 1]

[0077] The reactant triisopropylsilyl chloride used in step 1) can be purchased from Sigma-Aldrich (CAS number: 13154-24-0).

[0078] The reactant (2S,3S,4S,5R,6R)-2-(methoxycarbonyl)-6-(2,2,2-trichloro-1-iminoethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate used in step 2) can be purchased from Sigma-Aldrich (CAS number: 92420-89-8).

[0079] In step 1), compound (I) is selectively protected with a triisopropylsilyl (TIPS) protecting group to give compound (A2). [ka]

[0080] Compound (I) is reacted with triisopropylsilyl chloride in an aprotic solvent in the presence of a base. The inventors have found that carrying out the reaction in an aprotic solvent, such as dichloromethane (CH2Cl2), sulfolane or methyl-isobutyl ketone (MIBK), in the presence of a base, such as N,N-diisopropylethylamine (DIPEA) or triethylamine, results in high conversion and selectivity. High conversion was observed when 4-5 equivalents of DIPEA were used and the reaction was carried out at room temperature.

[0081] In one embodiment of the present invention, step 1 is carried out using dichloromethane (CH2Cl2) as a solvent.

[0082] In another embodiment of the invention, step 1 is carried out using sulfolane as a solvent.

[0083] In yet another embodiment of the present invention, step 1 is carried out using methyl-isobutyl ketone (MIBK) as the solvent.

[0084] In step 2), compound (A2) is conjugated with (2S,3S,4S,5R,6R)-2-(methoxycarbonyl)-6-(2,2,2-trichloro-1-iminoethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate. [ka]

[0085] The reaction is carried out in an aprotic solvent, preferably dichloromethane or benzotrifluoride, in the presence of a Lewis acid, such as boron trifluoride diethyl etherate.

[0086] In step 3), compound (A3) is deprotected with a suitable nucleophile to give compound (Id) or a pharma- ceutically acceptable salt thereof. [ka]

[0087] The deprotection is carried out in a solvent such as a mixture of methanol (MeOH) and water in the presence of a suitable nucleophile, such as a base, preferably a hydroxide base, such as potassium hydroxide (KOH) or sodium hydroxide (NaOH).

[0088] In one embodiment, step 3) is carried out in the presence of a solvent, such as a mixture of methanol (MeOH) and water.

[0089] In one embodiment of the present invention, step 3 is carried out using one or more suitable nucleophiles, such as a hydroxide base and NHF. More specifically, step 3 can be carried out using a combination of NHF and potassium hydroxide (KOH) or sodium hydroxide (NaOH).

[0090] In a specific embodiment, step 3 is carried out using potassium hydroxide (KOH) and NH4F.

[0091] EMBODIMENTS OF THE PRESENT DISCLOSURE In the following, embodiments of the present invention are disclosed, a first embodiment is denoted E1 and a second embodiment is denoted E2.

[0092] E1. The following formula: [ka] Compound (Id) having the formula [ka] A process for preparing a compound (I) having the formula Steps below 2) The following reaction scheme [ka] Compound (A2) is reacted with (2S,3S,4S,5R,6R)-2-(methoxycarbonyl)-6-(2,2,2-trichloro-1-iminoethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate according to the procedure described above to obtain compound (A3). Including, The reaction is carried out in an aprotic solvent in the presence of a Lewis acid.

[0093] E2. A method for producing the following compound (A3): Steps below 2) The following reaction scheme [ka] Compound (A2) is reacted with (2S,3S,4S,5R,6R)-2-(methoxycarbonyl)-6-(2,2,2-trichloro-1-iminoethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate according to the procedure described above to obtain compound (A3). Including, The reaction is carried out in an aprotic solvent in the presence of a Lewis acid.

[0094] The method of any of the preceding embodiments, wherein the aprotic solvent used in step 2) is dichloromethane.

[0095] E4. The method of any of the preceding embodiments, wherein the Lewis acid used in step 2) is boron trifluoride diethyl etherate.

[0096] E5. The method of any of embodiments 1-4, wherein the aprotic solvent is dichloromethane and the Lewis acid is boron trifluoride diethyl etherate.

[0097] E6. The following formula (A3): [ka] or a salt thereof.

[0098] E7. Use of a compound according to embodiment 6 in a method for producing a compound of formula (Id).

[0099] E8. The following formula: [ka] Compound (Id) having the formula [ka] A process for preparing a compound (I) having the formula Steps below 3) The following reaction scheme [ka] Compound (A3) is contacted with a base to deprotect compound (3) to obtain compound (Id) according to the formula: The method includes:

[0100] E9. Step 2) and then the following steps 3) The following reaction scheme [ka] Compound (A3) is deprotected by contacting compound (A3) with a base according to the formula (Id). The method according to any one of embodiments 1 and 3 to 5,

[0101] E10. The method according to any of embodiments 8-9, wherein the base used in step 3) is selected from potassium hydroxide and sodium hydroxide.

[0102] E11. The method of any of embodiments 8-10, wherein the deprotection is carried out in a mixture of methanol and water.

[0103] E12. Compound (A2) can be prepared by the following steps: 1) The following reaction scheme [ka] Compound (I) is reacted with triisopropylsilyl chloride to obtain compound (A2) according to the following procedure: It was obtained by The method according to any one of embodiments 1 to 5 and 9 to 11, wherein the reaction is carried out in an aprotic solvent in the presence of a base.

[0104] E13. The method of embodiment 12, wherein the aprotic solvent used in step 1) is dichloromethane.

[0105] E14. The method of any of embodiments 12-13, wherein the base used in step 1) is N,N-diisopropylethylamine (DIPEA).

[0106] E15. The method of any of embodiments 12-14, wherein the aprotic solvent is dichloromethane and the base is N,N-diisopropylethylamine (DIPEA).

[0107] E16. The method of any of embodiments 14-15, wherein said N,N-diisopropylethylamine (DIPEA) is present in an amount of 4-5 equivalents relative to compound (I).

[0108] E17. The method of any of embodiments 14-16, wherein said N,N-diisopropylethylamine (DIPEA) is present in an amount of about 4.6 equivalents relative to compound (I).

[0109] E18. A method for producing compound (Id) from compound (I), comprising the steps of: Step 2) according to any one of embodiments 1 and 3 to 5; Step 3) according to any one of embodiments 8 and 10 to 11 Including, The compound A2 used in step 2) is Step 1) according to any one of embodiments 12 to 17 The method is obtained by

[0110] E19. A compound of the formula: [ka] The compound (Id) has the formula:

[0111] E20. The method of any one of embodiments 1, 3-5, 8, 10-11, and 12-17, comprising the additional step of formulating compound Id into a solid oral dosage form.

[0112] term The following sections serve to describe the invention and its embodiments.

[0113] Term 1. The following formula [ka] or a pharma- ceutically acceptable salt thereof, [ka] A process for preparing a compound (I) having the formula Steps below 2) The following reaction scheme [ka] Compound (A2) is reacted with (2S,3S,4S,5R,6R)-2-(methoxycarbonyl)-6-(2,2,2-trichloro-1-iminoethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate according to the procedure described above to obtain compound (A3). Including, The reaction is carried out in an aprotic solvent in the presence of a Lewis acid.

[0114] Item 2. A method for producing the following compound (A3), comprising the steps of: 2) The following reaction scheme [ka] Compound (A2) is reacted with (2S,3S,4S,5R,6R)-2-(methoxycarbonyl)-6-(2,2,2-trichloro-1-iminoethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate according to the procedure described above to obtain compound (A3). Including, The reaction is carried out in an aprotic solvent in the presence of a Lewis acid.

[0115] Item 3. The method according to any one of Items 1 to 2, wherein step 2) comprises isolating compound (A3).

[0116] Item 4. The method according to any one of Items 1 to 3, wherein the aprotic solvent is dichloromethane or benzotrifluoride.

[0117] Item 5. The method according to any one of Items 1 to 4, wherein the aprotic solvent is dichloromethane and the Lewis acid is boron trifluoride diethyl etherate.

[0118] Item 6. The method according to any one of Items 1 to 4, wherein the aprotic solvent is benzotrifluoride and the Lewis acid is boron trifluoride diethyl etherate.

[0119] Item 7. The following formula (A3) [ka] or a salt thereof.

[0120] Item 8. Use of the compound according to item 7 in a method for producing a compound of formula (Id) or a pharma- ceutically acceptable salt thereof.

[0121] Item 9. A compound (A3) which is directly obtained by the method according to any one of items 2 to 6.

[0122] Item 10. The following formula [ka] or a pharma- ceutically acceptable salt thereof, [ka] A process for preparing a compound (I) having the formula Steps below 3) The following reaction scheme [ka] and deprotecting compound (A3) by contacting compound (A3) with a nucleophilic reagent according to the formula: The method includes:

[0123] Section 11. Step 3) defined below 3) The following reaction scheme: [ka] and deprotecting compound (A3) by contacting compound (A3) with a nucleophilic reagent according to the formula: The method according to any one of items 1 to 6, comprising:

[0124] Item 12. The method according to any one of Items 10 to 11, wherein the deprotection is carried out in a mixture of methanol and water.

[0125] Item 13. The method according to any one of Items 10 to 12, wherein the nucleophilic reagent used in step 3) is selected from potassium hydroxide, potassium cyanide, and sodium hydroxide.

[0126] Item 14. The method according to any one of Items 10 to 13, wherein step 3) comprises isolating compound (Id) or a pharma- ceutically acceptable salt thereof.

[0127] Item 15. The method according to any one of items 13 to 14, wherein compound (Id) is obtained as a potassium salt of compound (Id), and potassium hydroxide or potassium cyanide is used as a nucleophilic reagent in step 3).

[0128] Item 16. The method according to any one of items 13 to 15, wherein compound (Id) is obtained as a potassium salt of compound (Id), and potassium hydroxide is used as a nucleophilic reagent in step 3).

[0129] Item 17. The method according to any one of items 10 to 14, wherein compound (Id) is obtained as a sodium salt of compound (Id), and sodium hydroxide is used as a nucleophilic reagent in step 3).

[0130] Item 18. The method according to any one of items 10 to 14, wherein the solution obtained in step 3) containing compound (Id) is subsequently neutralized with a strong acid.

[0131] Item 19. The method according to item 18, wherein the strong acid is HCl.

[0132] Item 20. The method according to any one of Items 18 to 19, wherein compound (Id) is obtained as (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid heptahydrate.

[0133] Item 21. Compound (A2) can be prepared by the following steps: 1) The following reaction scheme [ka] Compound (I) or a salt thereof is reacted with triisopropylsilyl chloride to obtain compound (A2) according to the following procedure: It was obtained by The method according to any one of Items 1 to 6 and Items 10 to 20, wherein the reaction is carried out in an aprotic solvent in the presence of a base.

[0134] Item 22. The method according to item 21, wherein the aprotic solvent is dichloromethane, sulfolane or methyl-isobutyl ketone.

[0135] Item 23. The method according to any one of Items 21 to 22, wherein the aprotic solvent is dichloromethane.

[0136] Item 24. The method according to any one of Items 21 to 22, wherein the aprotic solvent is sulfolane.

[0137] Item 25. The method according to any one of Items 21 to 22, wherein the aprotic solvent is methyl isobutyl ketone.

[0138] Item 26. The method according to any one of Items 21 to 25, wherein the base is N,N-diisopropylethylamine or triethylamine.

[0139] Item 27. The method according to item 21, wherein the aprotic solvent is dichloromethane and the base is N,N-diisopropylethylamine.

[0140] Item 28. The method according to any one of Items 26 to 27, wherein the N,N-diisopropylethylamine (DIPEA) is present in an amount of 4 to 5 equivalents relative to the amount of compound (I).

[0141] Item 29. The method according to any one of Items 21 to 28, wherein step 1) comprises isolating compound (A2).

[0142] Item 30. A method for producing compound (Id) or a pharma- ceutically acceptable salt thereof from compound (I), comprising the steps of: Step 2) described in any one of items 1 and 3 to 6); followed by Step 3) according to any one of items 11 to 20 Including, The compound (A2) used in step 2) is Step 1) according to any one of items 21 to 29 The method is obtained by

[0143] Item 30. A compound represented by the following formula, obtained by the method according to any one of items 1, 3 to 6, 11 to 20, and 21 to 29: [ka] or a pharma- ceutically acceptable salt thereof.

[0144] Item 31. The method according to any one of items 1, 3 to 6, 11 to 20, and 21 to 29, comprising the additional step of formulating compound (Id) or a pharma- ceutically acceptable salt thereof into a solid oral dosage form.

[0145] All references mentioned in this specification, including publications, patent applications, and patents, are incorporated by reference herein in their entirety and to the same extent as if each reference was individually and specifically indicated to be incorporated by reference and was set forth in its entirety (to the fullest extent permitted by law).

[0146] Headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.

[0147] Description herein of any aspect or embodiments of the invention using terms such as "comprising," "having," "including," or "containing" when referring to one or more elements is intended to provide support for similar aspects or embodiments of the invention that "consist," "consist essentially of," or "substantially comprise" that particular element or elements, unless otherwise specified or clearly contradicted by context (e.g., a composition described herein as comprising a particular element should be understood to also describe a composition consisting of that element, unless otherwise specified or clearly contradicted by context).

[0148] The use of any and all examples or exemplary terms in this specification (such as "for instance," "for example," "for example," "such as," and "per se") is intended merely to make the invention more clear and does not limit the scope of the invention unless otherwise specified.

[0149] It should be understood that the various aspects, embodiments, implementations, and features of the invention described herein may be claimed separately or in any combination.

[0150] This invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law.

[0151] Experimental Section Preparation of Compounds of Formula (Id) and Intermediates NMR method QNMR(600MHz): 1) Wait 40 seconds 2) Acquisition time 3.76 seconds 3) Time domain 64k 4) Size 32k 5) 4 dummy scans 6) Scan 8 times 7) Pulse 30deg

[0152] LC-MS method Method A: LC-MS was performed on a Waters Aquity UPLC-MS consisting of a Waters Aquity containing a column manager, a binary solvent manager, a sample organizer, a PDA detector (operating at 254 nM), an ELS detector and a TQ-MS equipped with an APPI source operated in positive ion mode. LC conditions: The column was an Acquity UPLC BEH C18 1.7 μm; 2.1×150 mm operated at 60° C. using a binary gradient of 0.6 ml / min consisting of water+0.05% trifluoroacetic acid (A) and acetonitrile / water (95:5)+0.05% trifluoroacetic acid. Gradient (Linear): 0.00 minutes 10%B 3.00 minutes 100%B 3.60 minutes 10%B Total execution time: 3.6 minutes

[0153] Method B: LC-MS was performed on an Agilent 1260 HPLC consisting of a single Q-MS equipped with a column compartment, a binary pump, a Hip sample, and an ESI source operated in positive ion mode. LC conditions: Column: Inertstain AQ-C18 HP 3.0 μm; 3.0×50 mm operated at 35° C. using a binary gradient of 1.2 ml / min consisting of water+0.05% trifluoroacetic acid (A) and acetonitrile+0.05% trifluoroacetic acid (B). Gradient (Linear): 0.00 minutes 0%B 3.00 minutes 95%B 4.00 minutes 95%B Total execution time: 4.0 minutes

[0154] LC-MS method C: Equipment: Shimadzu LCMS-2020 Column: Phenomenex Kinetex EVO C18, 100×2.1mm, 2.6μm, ULC-016, UV-Vis detector: 190-800nm, flow rate: 0.5ml / min, mobile phase A: H2O+0.1%HCOOH, mobile phase B: acetonitrile Gradient (Linear): 1.00 minutes 2%B 10.00 minutes 90%B 13.00 minutes 90%B 13.10 minutes 2%B Total execution time: 13.1 minutes

[0155] Preparative HPLC method A: Column: AQ gel, UV detector: 210 nm, flow rate: 1 L / min, mobile phase A: water (0.05% NH4HCO3), mobile phase B: acetonitrile. Gradient (Linear): 0.00 min 5%B 30.0 minutes 30%B Total execution time: 30.0 minutes

[0156] Preparative HPLC method B: Column: RP-C18, 360g column, flow rate: 150ml / min, UV detector wavelength: 210nm. Mobile phase A: water, mobile phase B: acetonitrile Gradient (Linear): 0.00 min 5%B 4.00 minutes 30%B Total execution time: 4.0 minutes

[0157] Quantitative HPLC: Column: Phenomenex Synergi Polar RP, 150 x 4,6 mm x 4,0 μm, Thermo-Dionex Ultimate 3000 pump, autosampler, column compartment, variable wavelength detector, flow rate: 1 ml / min, UV detector wavelength: 210 nm. Mobile phase A: water-acetonitrile 98:2 + 0.1% trifluoroacetic acid, mobile phase B: acetonitrile + 0.1% trifluoroacetonitrile. Gradient (Linear): 0.00 min 2%B 6.00 minutes 90%B 9.00 minutes 90%B 9.50 minutes 2%B 15.0 minutes 2%B Total execution time: 15.0 minutes

[0158] Example 1: Preparation of compound (A2) (Step 1) Example 1a: A 1 L three-neck flask was charged with 15 g (50.4 mmol, 1 equiv.) of the HCl salt of compound (I), 450 ml of dry dichloromethane, 40.4 ml (232 mmol) of N,N-diisopropylethylamine (DIPEA) and 20.5 ml (96 mmol, 1.9 equiv.) of triisopropylsilyl chloride. The mixture was stirred at 20-25°C under an inert atmosphere. After 48 h, the reaction mixture was cooled to 0-5°C and saturated NH4Cl solution was added (300 ml). The mixture was stirred for 10 min and then the phases were separated. The organic layer was washed with deionized water (2 x 150 ml), dried over Na2SO4 and evaporated to give compound (A2) (27.8 g). It was used directly in the next step (Example 2a). LC-MS (Method A): Retention time (RT) = 2.71 min, [M+H] + =418.2m / z.

[0159] Example 1b: In a 3 L three-necked round bottom flask purged and maintained with an inert atmosphere of nitrogen, the HCl salt of compound (I) (68 g, 228 mmol), dichloromethane (1.8 L), N,N-diisopropylethylamine (DIPEA) (83.6 g) and triisopropylsilyl chloride (135.7 g, 704.0 mmol) were charged. The resulting solution was stirred at 25° C. for 2 days. The reaction was then quenched by the addition of 1000 mL of NH4Cl. The resulting solution was extracted with dichloromethane (2×1 L) and the organic layers were combined and concentrated under vacuum. The residue was purified using silica gel column chromatography (eluent: ethyl acetate / petroleum ether (1:1)). This gave compound (A2) (78 g) as an oil, which was used directly in the next step (Example 2b). LC-MS (Method B): RT=1.606 min, [M+H] + =418m / z 1 H NMR(CDCl3,ppm): δ 6.64(d,J=8.2Hz,1H),6.49(d,J=8.2Hz,1H),3.11(dd,J=15.5,5.0Hz,1H),2.97(dd,J=17.5,5.0Hz,1H),2.80-2.50(m,3H),2.23(dd,J= 17.5,11.5Hz,1H),1.95(d,J=13.0Hz,1H),1.80-1.65(m,3H),1.41-1.23(m,3H),1.16-1.03(m,33H,TIPS impurity included),0.91(t,J=7.5Hz,3H).

[0160] Example 2: Preparation of compound (A3) (Step 2) Example 2a: A 500 ml three-neck flask equipped with a CaCl2 tube was charged with compound (A2) (8.7 g, 21 mmol), anhydrous dichloromethane (260 mL) and (2S,3S,4S,5R,6R)-2-(methoxycarbonyl)-6-(2,2,2-trichloro-1-iminoethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (20 g, 42 mmol). The solution was cooled to 0-5°C and boron trifluoride diethyl etherate (5.2 mL, 42 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into an ice-cold saturated solution of NaHCO3 (770 mL). After 10 min of stirring, the phases were separated and the aqueous phase was extracted with dichloromethane (235 mL). The combined organic phases were dried over Na2SO4 and evaporated to dryness to give 27.9 g of crude product as an oil.

[0161] The crude material was purified by normal phase silica gel column chromatography to obtain compound (A3). (1st run: 7.2 g, purity >90% (quantitative HPLC) (2nd run: 2.2 g, purity approx. 80% (quantitative HPLC). LC-MS (Method C): RT=8.33 min, [M+H] + =418.4m / z 1 H NMR:(CDCl3,ppm):δ 6.98(d,J=8.5Hz,1H),6.84(d,J=8.5Hz,1H),5.38-5.30(m,3H),5.12(d,J=6.0Hz ,1H),4.26-4.17(m,1H),3.77(s,3H),3.18(dd,J=16.0,5.0Hz,1H),3.10-2.96(m ,2H),2.86-2.70(m,1H),2.31(s,3H),2.15-2.00(m,10H),1.91(d,J=13.0Hz,1H) ,1.55(q,J=7.5Hz,2H),1.35-1.20(m,3H),1.16-1.04(m,1H),1.01-0.90(m,24H).

[0162] Example 2b: In a 3 L three-necked round bottom flask purged and maintained with an inert atmosphere of nitrogen, compound (A2) (60.0 g, 144 mmol, 1.0 eq.), dichloromethane (1.2 L) and (2S,3S,4S,5R,6R)-2-(methoxycarbonyl)-6-(2,2,2-trichloro-1-iminoethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (351.3 g, 733.9 mmol) were charged. Boron trifluoride diethyl etherate (150 g, 1.25 eq.) was then added dropwise at room temperature. The resulting solution was stirred at 25° C. for 2 days. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was applied onto a silica gel column (eluent: ethyl acetate / petroleum ether (1:10)) to give compound (A3) (75 g) as a solid. LC-MS (Method B): RT=3.531 min, [M+H] + =720m / z 1 H NMR:(CDCl3,ppm):δ 6.98(d,J=8.5Hz,1H),6.84(d,J=8.5Hz,1H),5.38-5.30(m,3H),5.12(d,J=6.0Hz ,1H),4.26-4.17(m,1H),3.77(s,3H),3.18(dd,J=16.0,5.0Hz,1H),3.10-2.96(m ,2H),2.86-2.70(m,1H),2.31(s,3H),2.15-2.00(m,10H),1.91(d,J=13.0Hz,1H) ,1.55(q,J=7.5Hz,2H),1.35-1.20(m,3H),1.16-1.04(m,1H),1.01-0.90(m,24H).

[0163] Example 3: Preparation of Compound (Id) (Step 3) Example 3a (using KOH) In a 10 L three-necked round bottom flask purged and maintained with an inert atmosphere of nitrogen, compound (A3) (75 g, 102 mmol), methanol (4 L), and water (375 mL) were charged. This was followed by the addition of potassium hydroxide (28.7 g), NHF (3.8 g) at 0° C. The resulting solution was stirred at 25° C. overnight. The resulting solution was neutralized with 1N HCl (about 200 mL, pH was adjusted to 7.1) and concentrated under reduced pressure to obtain 250 mL of solution. The solution was purified by preparative HPLC (Method A) to obtain compound (Id) (40 g) as a solid. The resulting compound (Id) is obtained as the heptahydrate of compound (Id). LC-MS (Method B): RT=1.902 min, [M+H] + =438.3m / z. 1 H NMR(300MHz,D2O): δ 6.83(d,J=8.5Hz,1H),6.74(d,J=8.5Hz,1H),4.74(d,J=7.5Hz,1H),3.59-3.54(m,2H),3.54-3.45(m,3H) 3.36-3.13(m,4H),3.08-2.99(m,2H),2.72(dd,J=14.5,12.0Hz,1H),2.27(dd,J=17.5,11.5Hz,1H),1.95(t ,J=15.0Hz,2H),1.88-1.68(m,3H),1.68-1.58(m,1H),1.31(dq,J=13.5,3.5Hz,1H),0.91(t,J=7.5Hz,3H).

[0164] Example 3b (Comparative Example Using KCN) In a three-neck flask, 6.1 g (8.2 mmol) of compound (A3) was dissolved in 260 ml of a mixture of MeOH / water (12:1) and treated with 10.0 g (19 equiv.) of KCN at 0° C. After the addition, the reaction mixture was stirred at room temperature. After 16 h, the reaction mixture was filtered to remove insoluble inorganic salts. The filtrate was evaporated to dryness to give 15.2 g of crude compound (Id). The crude product was purified by preparative HPLC (Method B) to give compound (Id) (2.8 g) as a solid. The resulting compound (Id) is obtained as the potassium salt of compound (Id). LC-MS (Method C): RT=4.17 min, [M+H] +=438.3m / z.

[0165] In vitro and in vivo characterization of compound (Id) Example 4a: Conversion of the compound of formula (Id) in rat and human hepatocytes Compound (Id) was incubated at 1 μg / mL with hepatocytes from human or rat origin suspended in DMEM (Dulbecco's Modified Eagle's Medium) (pH 7.4) containing HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid). The cell concentration in the incubation was 1×106 viable cells / mL. Incubations were performed in glass tubes at 37° C. with a total incubation volume of 3.5 mL, and incubations were performed in duplicate for each test item. 3.5 mL of the hepatocyte suspension was equilibrated in a water bath set at 37° C. for 10 minutes, after which incubation was initiated by adding 3.5 μL of a stock solution of the test item in DMSO (dimethyl sulfoxide) and gently inverting the tube. The final solvent concentration in the incubation was 0.1% DMSO. After ensuring homogeneity of the hepatocyte suspension, 600 μL samples were taken from the incubation at predefined time points of 0.25, 5, 15, 30 and 60 min. The taken volume was added to a 1 mL Nunc cryotube on wet ice containing 60 μL of ice-cold ascorbic acid (100 mg / mL) and 30 μL of ice-cold 100 mM saccharic acid 1.4-lactone in 0.5 M citric acid. The tube was mixed and 35 μL of ice-cold 20% formic acid solution was added. The tube was mixed thoroughly and stored at -80°C awaiting analysis. The analytical method and equipment used for the analysis of (I) from administration of compound (Id) were the methods and equipment described in Example 7 in the section "Apparatus used for the analysis of compound (I) from administration of compound (Ic)".

[0166] FIG. 6 shows the time-dependent conversion of (Id) to compound (I) in both rat and human hepatocytes.

[0167] Example 4b: Conversion of compound (Id) in fresh rat and human blood The conversion of (Id) to (I) in human blood (average of 3 donors) and rat blood (average of 45 donors) was demonstrated in fresh blood spiked with (Id) 1 μg / mL at 37° C., and (I) was measured in isolated plasma at 0, 5, 15, 30 and 60 minutes. The analytical method and equipment are described in Example 7 below in the section "Apparatus used for the analysis of compound (I) from administration of compound (Ic)".

[0168] FIG. 7 shows the time-dependent conversion of (Id) to compound (I) in both rat and human blood.

[0169] Example 5: Dopamine agonist activity Dopamine D1 receptor agonism Dopamine D1 receptor agonism was measured using HTRF cAMP from CisBio using a protocol developed by HD Biosciences (China). Briefly, the assay is a homogeneous time-resolved fluorescence resonance energy transfer (HTRF) assay that measures the production of cAMP by cells in a competitive immunoassay between native cAMP produced by cells and cAMP labeled with XL-665. A cryptate-labeled anti-cAMP antibody visualizes the tracer. The assay was performed according to the manufacturer's instructions.

[0170] Test compounds were added to the wells of a microplate (384 format). HEK-293 cells expressing human D1 receptors were plated at 1000 cells / well and incubated for 30 min at room temperature. cAMP-d2 tracer was added to the wells, followed by anti-cAMP antibody-cryptate preparation and incubated for 1 h at room temperature in the dark. HTRF cAMP was measured by exciting the donor with a 337 nm laser ("TRF light unit") and then measuring cryptate and d2 emission at 615 nm and 665 nm over a 200 microsecond time window, time window 2000 microseconds / 100 flashes between repetitions (delay time 100 microseconds). HTRF measurements were performed on an Envision microplate reader (PerkinElmer). HTRF signal was calculated as the emission ratio at 665 nm to 615 nm. HTRF ratio readings for test compounds were normalized to 0% and 100% stimulation using control wells containing DMSO vehicle or 30 uM dopamine. Test compound potency (EC50) was estimated by nonlinear regression with a sigmoidal dose-response (variable slope) using Xlfit4 (IDBS, Guildford, Surrey, UK, model 205). y=(A+((BA) / (1+((C / x)^D)))) where y is the normalized HTRF ratio measurement for a given concentration of test compound, x is the concentration of test compound, A is the estimated potency at infinite compound dilution, and B is the maximum potency. C is the EC50 value, and D is the Hill slope coefficient. EC50 estimates were obtained from independent experiments and logarithmic means were calculated.

[0171] Dopamine D2 receptor agonism Dopamine D2 receptor agonism was measured using a calcium mobilization assay protocol developed by HD Biosciences (China). Briefly, HEK293 / G15 cells expressing human D2 receptors were plated in clear-bottom Matrigel-coated 384-well plates at a density of 15000 cells / well and grown for 24 h at 37 °C in the presence of 5% CO2. Cells were incubated with calcium-sensitive fluorescent dye Fluo8 for 60-90 min in the dark at 37 °C. Test compounds were prepared in 3x concentrated solutions in 1x HBSS buffer with Ca2+ and Mg2+. After compound addition from the compound plate to the cell plate of the FLIPR (Molecular Devices), calcium influx signals were recorded immediately. Fluorescence data were normalized to obtain responses to no stimulation (buffer) and full stimulation (dopamine 1 μM) for 0% and 100% stimulation, respectively. Test compound potencies (EC50) were estimated by non-linear regression with a sigmoidal dose-response (variable slope) using Xlfit4 (IDBS, Guildford, Surrey, UK, model 205). y=(A+((BA) / (1+((C / x)^D)))) where y is the normalized ratio measurement for a given concentration of the test compound, x is the concentration of the test compound, A is the estimated potency at infinite compound dilution, and B is the maximum potency. C is the EC50 value, and D is the Hill slope coefficient. EC50 estimates were obtained from independent experiments and logarithmic means were calculated.

[0172] Example 6: 5-HT2B agonist activity and binding assays 5-HT2B agonist activity assay The agonist activity of compounds (I), (Ia), (Ib), (Ic) and (Id) at human 5-HT2B receptor was evaluated by Eurofins / Cerep (France) using HTRF detection, measuring the effect of the compounds on inositol monophosphate (IP1) production. Briefly, human 5-HT2B receptor was expressed in transfected CHO cells. Cells were suspended in a buffer containing 10 mM Hepes / NaOH (pH 7.4), 4.2 mM KCl, 146 mM NaCl, 1 mM CaCl2, 0.5 mM MgCl2, 5.5 mM glucose and 50 mM LiCl, then distributed into microplates at a density of 4100 cells / well and incubated for 30 minutes at 37°C in the presence of buffer (basal control), test compound or reference agonist. For the measurement of stimulated control, each assay well contained 1 μM 5-HT. After incubation, cells were lysed and the fluorescent acceptor (fluorophen D2-labeled IP1) and fluorescent donor (anti-IP1 antibody labeled with europium cryptate) were added. After 60 min at room temperature, the fluorescence shift was measured using a microplate reader (Rubystar, BMG) at λ(Ex) 337 nm and λ(Em) 620 and 665 nm. The IP1 concentration was determined by dividing the signal measured at 665 nm by the signal measured at 620 nm (ratio). The results were expressed as a percentage of the control response to 1 μM 5-HT. The standard reference agonist was 5-HT, which was tested in each experiment at several concentrations to generate a concentration-response curve from which its EC50 value was calculated as described above for the dopamine functional assay.

[0173] 5-HT2B binding assay The affinity of compound (Id) for human 5-HT2B receptor was evaluated in a radioligand binding assay at Eurofins / Cerep (France). Membrane homogenates prepared from CHO cells expressing human 5HT2B receptor were incubated with 0.2 nM [125I] (±) DOI (1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine) for 60 min at room temperature in the absence or presence of test compound in a buffer containing 50 mM Tris-HCl (pH 7.4), 5 mM MgCl2, 10 μM pargyline and 0.1% ascorbic acid. Non-specific binding is determined in the presence of 1 μM (±) DOI. After incubation, samples were rapidly filtered under vacuum through glass fiber filters (GF / B, Packard) presoaked with 0.3% polyethyleneimine (PEI) and rinsed several times with ice-cold 50 mM Tris-HCl using a 96-sample cell harvester (Unifilter, Packard). Filters were dried and counted for radioactivity in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard). Results are expressed as percent inhibition of control radioligand-specific binding. The standard reference compound is (±) DOI, which is tested in each experiment at several concentrations to obtain a competition curve from which its IC50 is calculated.

[0174] [Table 2]

[0175] Example 7: PK studies in rats For all experiments, approximately 0.68 mL blood samples were collected from the tail or sublingual vein and placed in K3EDTA tubes that had been pre-chilled and prepared with a stabilizing solution consisting of 80 μL ascorbic acid and 40 μL 100 mM D-glyceric acid 1,4 lactone in water. The tubes were gently inverted 6-8 times to mix thoroughly and then placed on wet ice. Collection tubes were placed on wet ice for up to 30 min until centrifugation. Centrifugation was started immediately after removal from the wet ice. Samples were placed back on wet ice immediately after centrifugation was completed. Three subsamples of 130 μL plasma were transferred to each of three appropriately labeled cryotubes containing pre-chilled formic acid (20%) (tubes had been previously spiked and kept refrigerated prior to use). The tube caps were immediately replaced and the plasma solution was thoroughly mixed by gently inverting 6-8 times. Samples were stored frozen at nominally -70°C within 60 min after sampling. Centrifugation conditions were 3000G for 10 minutes at 4° C. After collection, plasma was placed on ice water. Final storage at approximately −70° C.

[0176] Plasma samples were analyzed by UPLC-MS / MS following solid phase extraction or direct protein precipitation. MS detection using electrospray in positive ion mode by monitoring the specific mass / charge transition of compound (I) using an internal standard to correct the response. Concentration-time data were analyzed using standard software with appropriate non-compartmental techniques to obtain estimates of derived PK parameters.

[0177] Equipment used for the analysis of compound (I) from administering compound (Ia): Mass spectrometer (LC-MS / MS): Waters Acquity-Sciex API 5000. Analytical column: Waters BEH UPLC Phenyl 100 x 2.1 mm column, particle size 1.7 μm. Mobile phase A: 20 mM ammonium formate (aqueous) + 0.5% formic acid. Mobile phase B: acetonitrile. Gradient moving from 95 / 5% to 2 / 98 in 6.1 min. Flow rate: 0.5 mL / min. MRM monitoring (multiple reaction monitoring) of test items and added analytical standards.

[0178] Dosing and Blood Sampling: Han Wistar rats were provided by Charles River Laboratories, Sulzfeld, Germany. An automatically controlled artificial 12-hour light and dark cycle was maintained. Rats were fed a standard laboratory diet (Altromin 1324 pellets) obtained from Brogaarden. Rats had free access to food. During the study (4-week toxicity study), rats were orally administered a dose of (Ia) once daily by gavage. Blood samples from rats administered 300 μg / kg (Ia) and from 3 male satellite animals) were taken at the following time points on day 29: 0.5, 1, 2, 4, 6, 8, 12 and 24 hours after administration.

[0179] Equipment used for the analysis of compound (I) from the administration of compound (Ib): Mass spectrometer (LC-MS / MS): Waters Acquity -Sciex API5000. Analytical column: Waters BEH UPLC Phenyl 100 x 2.1 mm column, particle size 1.7 μm. Mobile phase A: 20 mM ammonium formate (aqueous) + 0.5% formic acid. Mobile phase B: acetonitrile. Gradient moving from 95 / 5% to 2 / 98 in 6.1 min. Flow rate: 0.5 mL / min. MRM monitoring of test items and added analytical standards.

[0180] Dosing and Blood Sampling: Han Wistar rats were provided by Charles River Laboratories (UK). An automated artificial 12-hour light and dark cycle was maintained. Rats were fed a standard laboratory diet (Teklad 2014C Diet). Rats had free access to food. During the study (a 26-week toxicity study), rats were orally administered a dose of (Ib) once daily by gavage. From rats administered 300 μg / kg (Ib), blood samples from three male satellite animals were taken at the following time points on day 182: 0.5, 1, 2, 4, 8 and 24 hours post-dose.

[0181] Equipment used for the analysis of compound (I) from the administration of compounds (Ic) and (Id): Mass spectrometer (LC-MS / MS): Waters Acquity-Waters Xevo TQ-S. Analytical column: Acquity BEH C18 100 x 2.1 mm, 1.7 μm. Mobile phase A: 20 mM ammonium formate + 0.2% formic acid. Mobile phase B: acetonitrile + 0.2% formic acid. Gradient moving from 95 / 5% to 5 / 95% in 11.0 min. Flow rate: 0.3 mL / min. MRM monitoring of test items and added analytical standards.

[0182] Compound (Id) Administration and Blood Sampling: Han Wistar rats were provided by Charles River Laboratories, Wiga GmbH, German. An automatically controlled artificial 12-hour light and dark cycle was maintained. Rats were fed with standard laboratory chow (Altromin 1324 pellets) obtained from Brogaarden. Rats had free access to food. Compound (Id) was administered orally by gavage to male Han Wistar rats in a single oral gavage dose. From rats administered 633 μg / kg of compound (Id), blood samples from 3 male animals were taken on the first day at the following time points: 1, 2, 4, 6, 8 and 24 hours after administration.

[0183] Administration of Compound (Ic) and Blood Sampling: Han Wistar rats were supplied by Envigo, UK. An automated artificial 12-hour light and dark cycle was maintained. Rats were fed a standard laboratory diet Teklad 2014C. Rats had free access to food. (Ic) was administered to male Han Wistar rats by single oral gavage. Rats were dosed with 494 μg / kg (Ic). Blood samples from 3 male animals were taken at the following time points on day 1: 1, 2, 4, 6, 8 and 24 hours post-dosing.

[0184] Equipment used for the analysis of apomorphine: Mass spectrometer (UPCLC-MS / MS) Waters Acquity I-Class - Waters Xevo TQ-S. Analytical column Acquity HSS T3 C18 50 x 2.1 mm, 1.8 μm. Mobile phase A: 10 mM ammonium formate 0.2% formic acid:acetonitrile (95:5). Mobile phase B: 10 mM ammonium formate 0.2% formic acid:acetonitrile (5:95). Gradient moving from 95 / 5% to 5 / 95% in 2.40 min. Flow rate 0.3 mL / min. MRM detection of test items and added analytical standards.

[0185] Dosing and Blood Sampling for Apomorphine: The test animals were as described in Compound (Id) administration and blood sampling. In addition, rats were administered a single dose of apomorphine subcutaneously. From rats administered 3000 μg / kg (apomorphine), blood samples from 3 male animals were taken at the following times on day 1: 0.25, 0.5, 1, 1.5, 2, 3, 5 and 7 hours after administration of SC administration.

[0186] [Table 3]

[0187] Example 8: PK / PD of Compound (Id) / Compound (I) in the Rat Hyperactivity Assay animal A total of 206 male CD rats (Charles River, Germany) weighing 200-250 grams (165-190 grams on arrival) were used in the study. The animals were housed at standard temperature (22±1°C) and in a light-controlled environment (lights on from 7 am to 8 pm) with free access to food and water. The experiments described below were carried out in accordance with the standard operating procedures of Charles River Discovery Research Services Finland Ltd. and in accordance with The National Animal Experiment Board of Finland (Elainkoelautakunta, ELLA) authority for animal testing.

[0188] Locomotor activity test, open field The test device is a square Plexiglas area (measuring 40x40x40cm) within which the rat's travel path is recorded by an activity monitor (Med. Associates Inc.). Rats are allowed to habituate to their test cage for 60 minutes before the test period begins. Once habituation is complete, animals are treated with either compound or vehicle and placed back into the open field apparatus. The primary test parameter measured is distance traveled (recorded in 5 minute intervals). The overall measurement time after receiving the first treatment was 360 minutes. The total follow-up time for the study was 420 minutes, including 60 minutes of habituation.

[0189] result Oral administration of compound (Id) was evaluated in a rat locomotor activity assay, and this functional readout was then correlated with the plasma concentration of compound (I). Apomorphine and pramipexole were also tested simultaneously in this assay as a comparison (i.e., standard of care (SoC) known in the Parkinson's field), and plasma concentrations were analyzed for apomorphine.

[0190] As shown in Figure 2, compound (Id) (10-300 μg / kg, p.o.) increased locomotor activity with effects beginning approximately 2 hours after administration (at approximately 180 minutes) and continuing until the end of the recording (at 415 minutes). In contrast, the hyperactivity induced by apomorphine (3 mg / kg, s.c.) was immediate but only lasted a short time, as the effects disappeared 1.5 hours after administration (at 150 minutes). Pramipexole (0.3 mg / kg, s.c.) also induced an increase in activity, but the effects appeared approximately 1 hour after administration and disappeared 2.5 hours later (at 270 minutes). The total distance traveled, seen in Figure 3, demonstrates a significant increase in activity for both compound (Id) and the two comparators tested, an effect that is expected from a dopamine agonist.

[0191] In parallel with the locomotor activity assessment, plasma samples were taken from satellite animals at six different time points (1.5, 2, 3, 4, 5 and 7 hours post-dose for animals treated with compound (Id)). Pharmacokinetic analysis demonstrated that the behavioral effects of compound (Id) (100 μg / kg, orally) correlated with the plasma concentration of compound (I) (see FIG. 4), demonstrating that the behavioral effects of compound (Id) were induced by compound (I) and not by compound (Id) itself. Corresponding exposure analysis of apomorphine (at 1.25, 1.5, 2, 3, 5 and 7 hours post-dose) yielded a correlation between apomorphine plasma concentrations and hyperactivity behavior (see FIG. 5).

[0192] Reference List U.S. Pat. No. 4,543,256 International Publication No. 2001 / 078713 Brochure International Publication No. 02 / 100377 Brochure International Publication No. 2009 / 026934 Brochure International Publication No. 2009 / 026935 Brochure International Publication No. 2010 / 097092 Brochure International Publication No. 2019101917 Brochure Alexander et Crutcher,(1990)Trends in Neuroscience 13:266-71; Bibbiani et al.,Chase Experimental Neurology(2005),192:73-78; Campbell et al., Neuropharmacology(1982);21(10):953-961; Cannon et al., J. Heterocyclic Chem. (1980);17:1633-1636; Cavero and Guillon, J.Pharmacol.Toxicol.Methods(2014),69:150-161; Delong, (1990)Trends in Neuroscience 13:281-5; Gerfen et al,Science(1990)250:1429-32; Giardina and Williams;CNS Drug Reviews(2001),Vol.7(3):305-316; Goswami et al.,J.Nutritional Biochem.(2003)14:703-709; Grosset et al.,Acta Neurol Scand.(2013),128:166-171; Hauser et al.,Movement Disorders(2016),Vol.32(9):1367-1372; Liu et al.,J.Med.Chem.(2006),49:1494-1498; Liu et al.,Bioorganic Med.Chem.(2008),16:3438-3444; Nolen et al.,J.Pharm Sci.(1995),84(6):677-681; Poewe et al.,Nature Review,(2017)vol 3 article 17013:1-21; Remington,“The Science and Practice of Pharmacy”,22 th edition(2013),Edited by Allen,Loyd V.,Jr. Rothman et al.,Circulation(2000),102:2836-2841; Sprenger and Poewe,CNS Drugs(2013),27:259-272; Sozio et al.,Exp.Opin.Drug Disc.(2012);7(5):385-406; Stain-Texier et al.,Drug Metab.and Disposition(1998)26(5):383-387; Wiley-Interscience(publisher):Compendium of Organic Synthetic Methods,Vol.I-XII The present invention may include the following aspects. [1] The following formula:

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[10] Compound (A2) can be prepared by the following steps: 1) The following reaction scheme

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[11] 11. The method of claim 10, wherein the aprotic solvent is dichloromethane and the base is N,N-diisopropylethylamine (DIPEA).

[12] 12. The method of claim 11, wherein the N,N-diisopropylethylamine (DIPEA) is present in an amount of 4 to 5 equivalents relative to compound (I).

[13] A process for preparing compound (Id), or a pharma- ceutically acceptable salt thereof, from compound (I), comprising the steps of: Step 2) according to any one of claims 1 and 3; followed by Step 3) according to any one of claims 7 to 9 Including, The compound A2 used in step 2) is Step 1) according to any one of claims 10 to 12 The method is obtained by

[14] A compound of the formula:

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[15] The method of any one of claims 1 and 3, 6, 8-9, and 10-12, comprising the additional step of formulating compound (Id), or a pharma- ceutically acceptable salt thereof, into a solid oral dosage form.

Claims

1. The following formula: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, 【Chemistry 2】 A process for producing a compound (I) having the formula Steps below 2) The following reaction scheme 【Chemistry 3】 Compound (A2) is reacted with (2S,3S,4S,5R,6R)-2-(methoxycarbonyl)-6-(2,2,2-trichloro-1-iminoethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate according to the procedure described above to obtain compound (A3). Including, The reaction is carried out in an aprotic solvent in the presence of a Lewis acid.

2. A method for producing the following compound (A3), comprising the steps of: 2) The following reaction scheme 【Chemistry 4】 Compound (A2) is reacted with (2S,3S,4S,5R,6R)-2-(methoxycarbonyl)-6-(2,2,2-trichloro-1-iminoethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate according to the procedure described above to obtain compound (A3). Including, The reaction is carried out in an aprotic solvent in the presence of a Lewis acid.

3. 3. The method according to claim 1, wherein the aprotic solvent is dichloromethane or benzotrifluoride and the Lewis acid is boron trifluoride diethyl etherate.

4. The following formula (A3) 【Chemistry 5】 or a salt thereof.

5. The formula:

5. Use of a compound according to claim 4 in a process for preparing compound (Id), or a pharma- ceutically acceptable salt thereof, having the formula:

6. The following formula: 【Chemistry 6】 or a pharma- ceutically acceptable salt thereof, 【Chemistry 7】 A process for producing a compound (I) having the formula Steps below 3) The following reaction scheme 【Chemistry 8】 and deprotecting compound (A3) by contacting compound (A3) with a nucleophilic reagent according to the formula (Id), or a pharma- ceutically acceptable salt thereof. The method includes:

7. Step 2) is followed by the following steps: 3) The following reaction scheme 【Chemistry 9】 and deprotecting compound (A3) by contacting compound (A3) with a nucleophilic reagent according to the formula (Id), or a pharma- ceutically acceptable salt thereof. The method according to any one of claims 1 to 3, further comprising carrying out

8. 8. The method according to claim 6 or 7, wherein the nucleophile used in step 3) is selected from potassium hydroxide and sodium hydroxide.

9. The method according to any one of claims 6 to 8, wherein the deprotection is carried out in a mixture of methanol and water.

10. Compound (A2) can be prepared by the following steps: 1) The following reaction scheme 【Chemistry 10】 Compound (I) or a salt thereof is reacted with triisopropylsilyl chloride to obtain compound (A2) according to the following procedure: It was obtained by The process according to any one of claims 1 to 3 and 6 to 9, wherein the reaction is carried out in an aprotic solvent in the presence of a base.

11. The method of claim 10, wherein the aprotic solvent is dichloromethane and the base is N,N-diisopropylethylamine (DIPEA).

12. The method of claim 11, wherein the N,N-diisopropylethylamine (DIPEA) is present in an amount of 4 to 5 equivalents relative to compound (I).

13. The formula: or a pharma- ceutically acceptable salt thereof, A process for producing a compound (I) having the formula Step 2) according to any one of claims 1 and 3; followed by Step 3) according to any one of claims 7 to 9 Including, The compound A2 used in step 2) is Step 1) according to any one of claims 10 to 12 The method is obtained by

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