Neocatecholamine prodrugs for treatment of parkinson's disease

Abstract

The present invention provides prodrugs as catecholamines for use in the treatment of neurodegenerative diseases and disorders. The invention also provides pharmaceutical compositions comprising the compounds of the invention, and uses of the compounds of the invention in the preparation of treatment of neurodegenerative or neuropsychiatric diseases and disorders, especially Parkinson's disease.

Description

[0001] This application is a divisional application of the Chinese invention patent application with application number 202080031106.1, application date May 19, 2020, and invention name “New catecholamine prodrugs for treating Parkinson’s disease”. Technical Field

[0002] The present invention provides compounds that are phosphate, phosphonooxymethyl and ether derivative prodrugs of the dopamine agonist (4aR, 10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol, and their use in the treatment of Parkinson's disease and / or other conditions for which treatment with dopamine agonists is therapeutically beneficial, such as, but not limited to, restless leg syndrome, Huntington's disease and Alzheimer's disease; and also neuropsychiatric diseases and disorders, such as, but not limited to, schizophrenia, attention deficit hyperactivity disorder and drug addiction. The present invention also provides pharmaceutical compositions comprising the compounds of the present invention. Background Art

[0003] Parkinson's disease (PD) is a common neurodegenerative disorder that becomes more and more common with age, and affects an estimated population of seven to ten million in the world. Parkinson's disease is a multifaceted disease characterized by both motor symptoms and non-motor symptoms. Motor symptoms include resting tremor (tremor), bradykinesia / akinesia (slowness and difficulty of movement), muscle rigidity, postural instability and gait disorders; and non-motor symptoms include neuropsychiatric disorders (such as depression, psychotic symptoms, anxiety, emotional indifference, mild cognitive impairment and dementia) and autonomic dysfunction and sleep disorders (Poewe et al., Nature Review [Natural Review], (2017) Vol. 3 Entry 17013: 1-21).

[0004] A key hallmark of Parkinson's disease pathophysiology is the loss of pigmented dopaminergic neurons in the substantia nigra pars compacta, which provide dopaminergic innervation to the striatum and other brain regions. This progressive neurodegeneration results in a decrease in striatal levels of dopamine, which ultimately leads to a series of changes in the basal ganglia circuitry, culminating in the development of the four cardinal motor features of Parkinson's disease. The primary targets of dopamine in the striatum consist of medium-sized spiny GABAergic neurons (MSNs) that selectively express either D1 or D2 receptors awaiting localized projection. GABAergic MSNs that project to the lateral globus pallidus (also known as the striato-pallido- 'indirect pathway') express D2 receptors (MSN-2); whereas GABAergic MSNs that project to the substantia nigra pars compacta and lateral globus pallidus (also known as the striato-nigra 'direct pathway') express D1 receptors (MSN-1). Depletion of dopamine due to neuronal loss results in unbalanced activity of the two pathways, leading to a significant reduction in thalamic and cortical output activity and, ultimately, movement disorders (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, Poewe et al., Nature Review (2017) Vol. 3 Entry 17013: 1-21).

[0005] The most effective treatment strategies available for patients with Parkinson's disease and aimed at controlling motor symptoms are mainly indirect and direct dopamine agonists. The classic standard and gold standard treatment regimen includes chronic oral intake of L-3,4-dihydroxyphenylalanine (L-DOPA), which is decarboxylated in the brain to form dopamine. Other approaches are to administer dopamine receptor agonists such as apomorphine (apomorphine works on both D1 and D2 receptor subtypes), or pramipexole, ropinirole, etc., which are mainly directed against the D2 receptor subtype. The best motor relief obtained with L-DOPA and apomorphine is due to their activation of both D1 and D2 receptor subtypes, and overall rebalancing of the indirect-direct pathway (i.e., while the D2 agonist only reverses the indirect pathway disorder).

[0006] L-DOPA and apomorphine, which have the structures depicted below, are currently the most effective PD drugs in clinical use.

[0007]

[0008] L-DOPA is a prodrug of dopamine and remains the most effective drug for the treatment of motor Parkinson's disease. However, after several years of treatment (i.e., the honeymoon period), complications occur due to the inherent progression of the disease (persistent loss of dopaminergic neurons) and the poor pharmacokinetic (PK) profile of L-DOPA. Those complications include: 1) dyskinesia, which is abnormal involuntary movement that occurs during the best "duration effect" of the drug; and 2) fluctuations, during which the positive effect of L-DOPA disappears and symptoms reappear or worsen (Sprenger and Poewe, CNS Drugs [CNS Drugs] (2013), 27: 259-272).

[0009] Direct dopamine receptor agonists can activate dopamine autoreceptors and postsynaptic dopamine receptors located on medium spiny neurons MSN-1 and MSN-2. Apomorphine belongs to a class of dopamine agonists with 1,2-dihydroxybenzene (catechol) parts. When combined with the phenylethylamine motif, catecholamines generally have low oral bioavailability or do not have oral bioavailability, such as apomorphine. Although it is delivered non-orally (typically intermittent subcutaneous administration via a pump or continuous parenteral infusion during the day), apomorphine is used clinically in PD treatment. For apomorphine, animal studies have shown that transdermal delivery or implants can provide possible forms of administration. However, when studying the delivery of apomorphine from implants in monkeys (Bibbiani et al., Chase Experimental Neurology [experimental neurology] (2005), 192: 73-78), it was found that in most cases, animals must be treated with the immunosuppressant dexamethasone to prevent local irritation and other complications after implantation surgery. Alternative delivery strategies for apomorphine treatment in PD, such as inhaled and sublingual formulations, have been extensively developed (see, e.g., Grosset et al., Acta Neurol Scand. (2013), 128:166-171 and Hauser et al., Movement Disorders (2016), Vol. 32(9):1367-1372). However, these efforts have not yet been used in clinical applications to treat PD.

[0010] An alternative approach to non-oral formulation of catecholamines involves the use of prodrugs that mask the free catechol hydroxyl groups to enable oral administration. However, a known problem associated with the development of prodrugs for clinical use is the difficulty associated with predicting conversion to the parent compound in humans.

[0011] Different ester prodrugs of catecholamines have been reported in the literature, such as enteric-coated N-propyl-noraporphine (NPA) and monopivaloyl esters of apomorphine for duodenal delivery (see, e.g., WO 02 / 100377) and the D1-like agonist adralide (diacetyl prodrug of A-86929) (Giardina and Williams; CNS Drug Reviews (2001), Vol. 7(3):305-316). In humans, adralide undergoes extensive hepatic first-pass metabolism after oral administration and, as a result, has a low oral bioavailability (approximately 4%). In PD patients, intravenous (IV) adralide has antiparkinsonian efficacy comparable to that of L-DOPA (Giardina and Williams; CNS Drug Reviews (2001), Vol. 7(3):305-316).

[0012] In addition to ester prodrugs of catecholamines, an alternative prodrug approach involves masking the two catechol hydroxyl groups as the corresponding methylenedioxy derivatives, or as diacetal derivatives. This prodrug principle has been described, for example, in Campbell et al., Neuropharmacology (1982); 21(10):953-961 and US 4543256, WO 2009 / 026934 and WO 2009 / 026935.

[0013] For catecholamine prodrugs, yet another proposed approach is to form enone derivatives, as suggested in, for example, 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.

[0014] The compound (4aR, 10aR)-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol described as the following 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 and then in Liu et al., Bioorganic Med. Chem. (2008), 16: 3438-3444, which included pharmacological data indicating that the compound had low oral bioavailability in rats. The racemate was first disclosed in Cannon et al., J. Heterocyclic Chem. (1980); 17: 1633-1636.

[0015]

[0016] Compound (I) is a dopamine receptor agonist with mixed D1 and D2 activities. Three prodrug derivatives of Compound (I) are known in the art.

[0017] Liu et al., J. Med. Chem. (2006), 49: 1494-1498 and Liu et al., Bioorganic Med. Chem. (2008), 16: 3438-3444 disclosed enone derivatives having formula (Ia) described below, which were shown to be converted into active compounds (I) in rats.

[0018]

[0019] WO 2009 / 026934 and WO 2009 / 026935 disclose two types of prodrug derivatives of compound (I), including (6aR, 10aR)-7-propyl-6,6a,7,8,9,10,10a,11-octahydro-[1,3]dioxol[4',5':5,6]benzo[1,2-g]quinoline, a methylenedioxy (MDO) derivative having the following formula (Ib):

[0020]

[0021] It has been demonstrated in WO 2010 / 097092 that compound (Ib) is converted to compound (I) in rat and human hepatocytes. In addition, the in vivo pharmacology of compounds (Ia) and (Ib) and the active "parent compound" (I) has been tested in different animal models for Parkinson's disease (WO 2010 / 097092). Compound (I) and both compounds (Ia) and (Ib) were found to be effective, indicating 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.

[0022] Other prodrugs of compound (I) disclosed in WO 2009 / 026934 and WO 2009 / 026935 are conventional ester prodrugs having the formula (Ic) shown below:

[0023]

[0024] Despite the long-standing interest in this area, there is clearly an unmet need for the development of highly effective, well-tolerated and orally active drugs for the treatment of PD. Prodrug derivatives of mixed D1 / D2 agonists that can provide continuous dopaminergic stimulation, giving a stable PK profile, may meet such unmet needs.

[0025] For various compounds containing catechol moieties, phosphate derivatives have been proposed and explored as prodrug principles. EP 0167204 discloses that the oral absorption of L-DOPA can be improved by phosphorylation of a hydroxyphenol group. This is demonstrated by showing an increase in renal blood flow in anesthetized dogs. US 3132171 discloses that the diphosphate derivatization of L-DOPA provides a water-soluble and stable composition that is converted to L-DOPA when administered parenterally in rats. US 5073547 discloses monophosphorylated L-DOPA esters and shows that these provide high bioavailability via the oral route (based on intraperitoneal administration), which is believed to be caused by reduced peripheral decarboxylation of the compound.

[0026] Recently, phosphate and bisphosphate derivatives of carbidopa and levodopa were disclosed in WO 2016 / 065019, the purpose of which is to increase the water solubility of these compounds. The plasma concentration curves of levodopa and carbidopa show the conversion of phosphate derivatives of carbidopa and levodopa after intravenous and subcutaneous administration.

[0027] Phosphonooxymethyl derivatization of amines is considered a prodrug principle for amine compounds other than catecholamines.

[0028] Masking of the catechol hydroxyl group of carbidopa derivatives with benzyl or small alkyl groups to improve intestinal absorption has been proposed in WO 2004 / 052841, but the prodrug potential of such compounds has not been demonstrated. Summary of the invention

[0029] The present invention relates to novel compounds for the treatment of Parkinson's disease. More specifically, the present invention relates to novel prodrug derivatives of compound (4aR, 10aR)-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol (compound (I)). It has been demonstrated that the compounds of the present invention are particularly useful for oral delivery of compound (I). In a first aspect, the present invention provides a compound according to formula (Id)

[0030]

[0031] Wherein R1, R2 and R3 are according to the following a) or b):

[0032] a) R1 and R2 are each independently selected from H, C1-C6 alkyl, benzyl and the following substituent (i), and R3 is absent,

[0033]

[0034] Where * indicates the attachment point,

[0035] The premise is that R1 and R2 cannot both be H;

[0036] or

[0037] b) R1 and R2 are both H, and R3 is a substituent (ii) below,

[0038]

[0039] Where * indicates the attachment point;

[0040] and wherein R4 and R5 are each independently selected from H, C1-C6 alkyl, phenyl, benzyl, C3-C6 cycloalkyl, and methyl substituted by C3-C6 cycloalkyl;

[0041] or a pharmaceutically acceptable salt thereof.

[0042] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound according to formula (Id) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0043] Another aspect of the present invention relates to compounds according to formula (Id) for use as medicaments.

[0044] Another aspect of the present invention relates to a compound according to formula (Id) or a pharmaceutically acceptable salt thereof, for use in the treatment of a neurodegenerative disease or disorder, such as Parkinson's disease, Huntington's disease, restless leg syndrome or Alzheimer's disease; or for use in the treatment of a neuropsychiatric disease or disorder, such as schizophrenia, attention deficit hyperactivity disorder or drug addiction.

[0045] Another aspect of the present invention relates to a method for treating a neurodegenerative disease or disorder, such as Parkinson's disease, Huntington's disease, restless leg syndrome or Alzheimer's disease; or a neuropsychiatric disease or disorder, such as schizophrenia, attention deficit hyperactivity disorder or drug addiction; the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (Id) or a pharmaceutically acceptable salt thereof.

[0046] Another aspect of the present invention relates to the use of a compound according to formula (Id) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a neurodegenerative disease or disorder, such as Parkinson's disease, Huntington's disease, restless leg syndrome or Alzheimer's disease; or for treating a neuropsychiatric disease or disorder, such as schizophrenia, attention deficit hyperactivity disorder or drug addiction.

[0047] definition

[0048] Attachment Point

[0049] In the context of the present invention, it is understood that the carbon atom at the point of attachment on substituent (i) is at the anomeric position of (i). Similarly, the carbon atom at the point of attachment on substituent (ii) is at the anomeric position of (ii).

[0050] Compounds of the present invention

[0051] References to compounds encompassed by the present invention include free species of the compounds of the present invention (e.g., free base or zwitter ion), pharmaceutically acceptable salts of the compounds of the present invention, such as acid addition salts or base addition salts, and polymorphic and amorphous forms of the compounds of the present invention and their pharmaceutically acceptable salts. In addition, the compounds of the present invention and their pharmaceutically acceptable salts can potentially exist in unsolvated forms as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. The present invention encompasses both solvated and unsolvated forms.

[0052] Pharmaceutically acceptable salts

[0053] In the context of the present invention, pharmaceutically acceptable salts are intended to indicate non-toxic, ie physiologically acceptable salts.

[0054] The term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts, which are salts formed with inorganic and / or organic acids on the nitrogen atom in the parent molecule. The acid can 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.

[0055] The term pharmaceutically acceptable salts also includes pharmaceutically acceptable base addition salts, which are salts formed with inorganic and / or organic bases on the acid groups of compounds of formula (Id). The base may be selected from, for example, zinc hydroxide, and alkali metal bases such as sodium hydroxide, lithium hydroxide, potassium hydroxide, and alkaline earth metal bases such as calcium hydroxide and magnesium hydroxide, and organic bases such as choline, diethylamine, trimethylamine and triethylamine.

[0056] Further examples of useful acids and bases that form pharmaceutically acceptable salts can be found, for example, in Stahl and Wermuth (eds.) “Handbook of Pharmaceutical salts. Properties, selection, and use”, Wiley-VCH, 2008.

[0057] Prodrug

[0058] In the context of the present invention, the term "prodrug" or "prodrug derivative" indicates a compound that is converted into a pharmacologically active moiety in vivo after administration to a living subject, such as a mammal, preferably a human. This conversion preferably occurs in vivo in a mammal, such as in a mouse, rat, dog, minipig, rabbit, monkey and / or human. In the context of the present invention, "a prodrug of compound (4aR, 10aR)-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol", or "a prodrug of a compound of formula (I)", or "a prodrug of compound (I)" is understood to be a compound that is converted into compound (4aR, 10aR)-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol in vivo after administration. The administration may be by conventional routes of administration of pharmaceutical compositions known in the art, preferably by oral administration.

[0059] In the context of the present invention, the terms "parent compound" and "parent molecule" indicate the pharmacologically active portion obtained after conversion of the corresponding prodrug. For example, the "parent compound" of one of compounds (Ia), (Ib), (Ic) or any of the compounds of the present invention is understood to be a compound of formula (I).

[0060] Substituents

[0061] In the context of the present invention, "-" (dash) or "to" may be used interchangeably to indicate a given range, for example the term "C1-C6 alkyl" is equivalent to "C1 to C6 alkyl".

[0062] The term "alkyl" refers to a straight chain (i.e., unbranched) or branched saturated hydrocarbon having from 1 to 6 carbon atoms (including end values). Examples of such groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2-methyl-1-butyl and n-hexyl.

[0063] As used herein, the term "cycloalkyl" refers to a saturated ring system containing all carbon atoms as ring members and 0 double bonds. The cycloalkyl can be a monocyclic cycloalkyl (e.g., cyclopropyl). Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0064] Pharmacokinetic Definitions and Abbreviations

[0065] As used herein, "PK profile" is an abbreviation for "pharmacokinetic profile". The pharmacokinetic profiles and pharmacokinetic parameters described herein are based on plasma concentration-time data for a compound of formula (I) obtained using a non-compartmental model following oral administration of the compound of the invention. The abbreviated PK parameters are: C max (maximum concentration); t max (reach C max time); t 1 / 2 (half-life); AUC 0-24 (area under the curve from the time of dosing and up to 24 hours post-dose) and "exposure at 24 hours" is the plasma concentration of the compound of formula (I) as measured 24 hours post-dose.

[0066] Therapeutically effective amount

[0067] In the context of the present invention, the term "therapeutically effective amount" of a compound of the present invention means an amount sufficient to alleviate, retard, partially retard, remove or delay the clinical manifestations of a given disease and its complications in a therapeutic intervention comprising the administration of the compound. An amount sufficient to achieve this purpose is defined as a "therapeutically effective amount". The effective amount for each purpose will depend, for example, on the severity of the disease or injury and the weight and general state of the subject. It should be understood that determining an appropriate dose can be achieved using routine experimentation by constructing a matrix of values ​​and testing different points in the matrix, all within the ordinary skill of a trained physician.

[0068] In the context of the present invention, a "therapeutically effective amount" of a compound of the present invention indicates an amount of the compound of the present invention which, when administered (preferably by oral route) to a mammal (preferably a human), is able to provide an amount of compound (I) sufficient to alleviate, arrest, partially arrest, eliminate or delay the clinical manifestations of a given disease and its complications.

[0069] Treatment and treating

[0070] In the context of the present invention, "treatment" or "treating" is intended to indicate the management and care of a patient with the purpose of alleviating, arresting, partially arresting, eliminating the clinical manifestations of a disease or delaying its progression. The patient to be treated is preferably a mammal, in particular a human being.

[0071] Conditions treated

[0072] The compounds of the present invention are intended for use in the treatment of neurodegenerative diseases and disorders, such as Parkinson's disease and / or other conditions for which treatment with a dopamine agonist is therapeutically beneficial.

[0073] Therapeutic indications include various central nervous system disorders characterized by motor and / or non-motor disorders and for which part of the underlying pathophysiology is a disorder of striatal-mediated circuits. Such dysfunctions can be seen in neurodegenerative diseases such as, but not limited to, Parkinson's disease (PD), restless leg syndrome, Huntington's disease, and Alzheimer's disease, as well as neuropsychiatric disorders such as, but not limited to, schizophrenia, attention deficit hyperactivity disorder, and drug addiction.

[0074] In addition to neurodegenerative diseases and disorders, other conditions where an increase in dopaminergic turnover may be beneficial have improvements in different aspects of mental function, including cognition. In patients with depression, it may also have a positive effect, and it may also be used as an appetite suppressant to treat obesity, and for the treatment of drug addiction. It may improve negative, positive, and cognitive symptoms of mild brain dysfunction (MBD), sleeping sickness, attention deficit hyperactivity disorder, and potentially, schizophrenia.

[0075] Restless leg syndrome (RLS) and periodic limb movement disorder (PLMD) are alternative indications for treatment with dopamine agonists in the clinic. In addition, impotence, erectile dysfunction, SSRI-induced sexual dysfunction, ovarian hyperstimulation syndrome (OHSS) and certain pituitary tumors (prolactinomas) may also be improved by treatment with dopamine agonists. Dopamine is involved in the regulation of the cardiovascular and renal systems, and therefore renal failure and hypertension can be considered as alternative indications for the compounds of the present invention.

[0076] The present invention encompasses the use of the compounds of the present invention for the treatment of the diseases and disorders listed above.

[0077] combination

[0078] In one embodiment of the invention, the compound of formula (Id) is used as a stand-alone treatment as the sole active compound. In another embodiment of the invention, the compound of formula (Id) can be used in combination with other agents that can be used for neurodegenerative diseases or disorders, such as Parkinson's disease. As used herein in the context of the method of the present invention (including the combined administration of a therapeutically effective amount of a compound of formula (Id) and another compound, which can be used to treat neurodegenerative diseases or disorders), the terms "combined use", "combined with..." and "combination of..." etc. are intended to mean that the compound of formula (Id) is administered simultaneously or sequentially (in any order) with the other compounds.

[0079] The two compounds can be administered simultaneously or there is a time interval between the administration of the two compounds. The two compounds can be administered as part of the same pharmaceutical preparation or composition or in a separate pharmaceutical preparation or composition. The two compounds can be administered on the same day or on different days. They can be administered by the same route, such as by oral administration, subcutaneous injection, by transdermal administration, by depot type, by intramuscular injection or intravenous injection; or by different routes, wherein one compound is, for example, administered orally or placed by a depot, and another compound is, for example, injected. The two compounds can be administered by the same dosing regimen or intervals, such as once or twice a day, weekly, or monthly; or by different dosing regimens, such as wherein one compound is administered once a day, and another compound is administered twice a day or weekly or monthly.

[0080] In some cases, when treatment with a compound of formula (Id) is initiated, the patient to be treated may already be treated with one or more other compounds useful for treating a neurodegenerative disease or disorder. In other cases, when treatment with one or more other compounds useful for treating a neurodegenerative disease or disorder is initiated, the patient may already be treated with a compound of formula (Id). In other cases, treatment with a compound of formula (Id) and treatment with one or more other compounds useful for treating a neurodegenerative disease or disorder are initiated simultaneously.

[0081] Compounds for combination therapy

[0082] In the context of the present invention, the compound to be used in combination with the compound of formula (Id) may be selected, for example, from L-DOPA, droxidopa, foliglurax, MAO-B inhibitors such as selegiline or rasagiline, COMT inhibitors such as entacapone or tolcapone, adenosine 2a antagonists such as istradefylline, anti-glutamate agents such as amantadine or memantine, acetylcholinesterase inhibitors such as rivastigmine, donepezil or galantamine, and antipsychotics such as quetiapine, clozapine, risperidone, pimavanserin, olanzapine, haloperidol, aripiprazole or epiriprazole.

[0083] In addition to small molecules, compounds for combination may also include emerging biologic approaches in the treatment of neurodegenerative diseases or disorders, such as antibodies targeting α-synuclein, tau or A-β proteins.

[0084] Route of administration

[0085] Pharmaceutical compositions comprising a compound of formula (Id) (as the sole active compound or in combination with another active compound) can 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 a preferred route of administration.

[0086] It will be appreciated that the route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient.

[0087] Pharmaceutical preparations and excipients

[0088] Hereinafter, the term "excipient" or "pharmaceutically acceptable excipient" refers to pharmaceutical excipients, including but not limited to carriers, fillers, diluents, antiadherents, binders, coatings, colorants, disintegrants, flavoring agents, glidants, lubricants, preservatives, sorbents, sweeteners, solvents, carriers and adjuvants.

[0089] The present invention also provides a pharmaceutical composition comprising a compound of formula (Id) (such as one of the compounds disclosed in the experimental section herein). The present invention also provides a method for manufacturing a pharmaceutical composition comprising a compound of formula (Id). The pharmaceutical composition according to the present invention can be formulated with pharmaceutically acceptable excipients according to conventional techniques, such as those disclosed in: Remington, The Science and Practice of Pharmacy, 22nd edition (2013), editor Allen, Loyd V., Jr.

[0090] Preferably, the pharmaceutical composition comprising the compound of the present invention is a pharmaceutical composition for oral administration. Pharmaceutical compositions for oral administration include solid oral dosage forms, such as tablets, capsules, powders and granules; and liquid oral dosage forms, such as solutions, emulsions, suspensions and syrups, as well as powders and granules to be dissolved or suspended in appropriate liquids.

[0091] Solid oral dosage forms can be presented as discrete units (e.g., tablets or hard or soft capsules), each containing a predetermined amount of active ingredient and preferably one or more suitable excipients. Where appropriate, solid dosage forms can be prepared with coatings, such as enteric coatings, or they can be formulated to provide modified release of the active ingredient, such as delayed release or extended release, according to methods well known in the art. Where appropriate, solid dosage forms can be dosage forms that disintegrate in saliva, such as orodispersible tablets.

[0092] Examples of excipients suitable for solid oral preparations include, but are not limited to, microcrystalline cellulose, corn starch, lactose, mannitol, povidone, cross-linked sodium carboxymethylcellulose, sucrose, cyclodextrin, talc, gelatin, pectin, magnesium stearate, stearic acid, and lower alkyl ethers of cellulose. Similarly, solid preparations may include excipients known in the art for delayed or extended release preparations, such as glyceryl monostearate or hypromellose. If a solid material is used for oral administration, the preparation may be prepared, for example, by mixing the active ingredient with a solid excipient and then compressing the mixture in a conventional tablet press; or the preparation may be placed in a hard capsule, for example, in the form of a powder, pill, or mini tablet. The amount of solid excipient will vary widely, but will typically be in the range of from about 25 mg to about 1 g / dosage unit.

[0093] Liquid oral dosage forms can be presented as, for example, elixirs, syrups, oral drops or liquid-filled capsules. Liquid oral dosage forms can also be presented as powders for solutions or suspensions in aqueous or non-aqueous liquids. Examples of excipients suitable for liquid oral formulations include, but are not limited to, ethanol, propylene glycol, glycerol, polyethylene glycol, poloxamer, sorbitol, polysorbate, monoglycerides and diglycerides, cyclodextrins, 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.

[0094] Additional excipients (eg, coloring agents, flavoring agents, preservatives, etc.) may be used in both solid and liquid oral preparations.

[0095] 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 to be reconstituted in sterile solutions or dispersions for injection or infusion prior to 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 made isotonic with sufficient saline or glucose.

[0096] Other types of pharmaceutical compositions include suppositories, inhalants, creams, gels, skin patches, implants, and formulations for buccal or sublingual administration.

[0097] It is essential that the excipients used in any pharmaceutical formulation are suitable for the intended route of administration and are compatible with the active ingredient.

[0098] dose

[0099] In one embodiment, the compound of the invention is administered in an amount from about 0.0001 mg / kg body weight to about 5 mg / kg body weight per day. In particular, the daily dose may be in the range of 0.001 mg / kg body weight to about 2 mg / kg body weight per day. The exact dose will depend on the frequency and mode of administration, the sex, age, weight and general condition of the subject to be treated, the nature and severity of the condition to be treated, any concomitant disease to be treated, the desired therapeutic effect, and other factors known to those skilled in the art.

[0100] Typical oral dosages for adults will be in the following range: 0.01-100 mg / day of the compound of the invention, such as 0.05-50 mg / day, such as 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 the compound in an amount of about 0.01 to 50 mg, such as 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 of the compound of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0101] Figure 1 ： Scheme for the conversion of compounds of the present invention into compounds (Id).

[0102] Solid arrows: transformations demonstrated in vitro and in vivo. Dashed arrows: transformations demonstrated in vitro.

[0103] Figure 2 ： PK profiles in Wistar rats obtained after oral administration according to Example 3. The profiles are based on the mean plasma concentrations from 3 subjects for each compound.

[0104] 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 (9); ●: compound (8); X: compound (3) and ▲: compound (2). DETAILED DESCRIPTION

[0105] The inventors of the present invention have identified novel compounds which are prodrugs of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol [Compound (I)] that are dual D1 / D2 agonists (see, e.g., WO 2009 / 026934).

[0106] The compounds of the present invention are phosphate and phosphonooxymethyl derivatives and ether derivatives of compound (I).

[0107] Oral administration of representative compounds of the invention in Wistar rats was found to provide systemic exposure of Compound (I) in plasma, indicating the usefulness of the compounds as orally active prodrugs of Compound (I).

[0108] For all compounds, the doses were corrected by molecular weight to be equal to a dose of 300 μg / kg of Compound (Ib) (corresponding to 287 μg / kg of Compound (I)).

[0109] It has been observed that oral administration of compounds (Ia) and (Ib) to Wistar rats results in early and high peak plasma concentrations of compound (I). In humans, such high peak concentrations may be associated with the side effects of dopaminergic drugs (e.g., nausea, vomiting, and mild headaches). In contrast, for the compounds of the present invention, a slower absorption rate was observed, with the continued exposure of compound (I), avoiding rapid peak concentrations. Therefore, in Wistar rats, the plasma exposure of compound (I) was maintained for 24 hours, although the AUC obtained after administration of compounds (Ia) and (Ib) was generally lower. However, because the peak concentration of compound (I) driving side effects is expected to be lower, a higher dose of the compound of the present invention can be administered, thereby potentially achieving a higher overall plasma concentration of compound (I) compared to the results achievable from administration of compounds (Ia) and (Ib). When studying the PK properties of compound (Ic), the inventors of the present invention found that the plasma concentration of compound (I) was extremely low, making compound (Ic) unsuitable for oral administration as a prodrug of compound (I), and confirmed that the oral bioavailability of the compound of the present invention is highly unpredictable. The PK parameters used for PK studies in Wistar rats are listed in Table 4, and Figure 2 PK profiles are depicted in. All compounds evaluated in vivo showed conversion to compound (I).

[0110] Phosphate esters and phosphonooxymethyl derivatives are preferred embodiments of the present invention.

[0111] As described in Example 1, the bioconversion of the compounds of the invention to compounds of formula (Id) was also evaluated by incubation in human plasma and / or human hepatocytes. For the parent compound (I) itself, a short half-life was observed in the plasma assay, which may explain why the appearance of compound (I) was difficult to detect or only detected in very small amounts in some cases, because compound (I) may be metabolized while it is formed. For compound (6), the appearance of compound (I) was not observed, but since compound (8) was formed, it can be expected that compound (6) is converted to compound (I) via compound (8).

[0112] For the compounds of the present invention, the conversion rate was evaluated in vitro or both in vitro and in vitro, see Tables 1 and Figure 1 .

[0113] Table 1: In vitro and in vivo transformation of compounds of the invention

[0114]

[0115]

[0116] *nt: not tested; nd: not detected

[0117] Thus, in summary, the compounds of the present invention are useful as orally active prodrugs of compound (I) and have been observed in rats to provide a PK profile that avoids the peak C observed for known prodrugs (Ia) and (Ib). max , and provided a significantly higher AUC for Compound (I) compared to Compound (Ic).

[0118] Finally, an important issue associated with compound (Ib) is that the compound is an agonist of the 5-HT2B receptor. Since 5-HT2B receptor agonists have been implicated in the pathogenesis of valvular heart disease (VHD) after long-term exposure, such compounds are not suitable for 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, the compounds of the present invention have the additional advantage that these compounds are not 5-HT2B agonists, see Example 2 and Table 3.

[0119] The compounds of the invention are useful for treating neurodegenerative diseases and disorders, such as Parkinson's disease and / or other conditions for which treatment with a dopamine agonist is therapeutically beneficial. Compounds suitable for oral administration have the potential to provide a new treatment paradigm for Parkinson's disease.

[0120] In one embodiment of the invention, the compounds are used as a stand-alone treatment for a neurodegenerative disease or disorder. In another embodiment of the invention, the compounds are used in combination with other agents for the treatment of PD, such as compounds selected from the group consisting of L-DOPA, droxidopa, foliglurax, MAO-B inhibitors such as selegiline or rasagiline, COMT inhibitors such as entacapone or tolcapone, adenosine 2a antagonists such as istradefylline, anti-glutamate agents such as amantadine or memantine, acetylcholinesterase inhibitors such as rivastigmine, donepezil or galantamine, antipsychotics such as quetiapine, clozapine, risperidone, pimavanserin, olanzapine, haloperidol, aripiprazole or epiriprazole; or in combination with antibodies targeting alpha-synuclein, tau protein or A-beta protein.

[0121] Embodiments of the present invention

[0122] In the following, embodiments of the present invention are disclosed. The first embodiment is denoted as E1, the second embodiment is denoted as E2, and so on:

[0123] E1. A compound according to formula (Id)

[0124]

[0125] Wherein R1, R2 and R3 are according to the following a) or b):

[0126] a) R1 and R2 are each independently selected from H, C1-C6 alkyl, benzyl and the following substituent (i), and R3 is absent,

[0127]

[0128] and where * indicates the attachment point,

[0129] The premise is that R1 and R2 cannot both be H;

[0130] or

[0131] b) R1 and R2 are both H, and R3 is a substituent (ii) below, N is positively charged,

[0132]

[0133] and wherein * indicates the point of attachment;

[0134] And among them

[0135] R4 and R5 are each independently selected from H, C1-C6 alkyl, phenyl, benzyl, C3-C6 cycloalkyl and methyl substituted by C3-C6 cycloalkyl;

[0136] or a pharmaceutically acceptable salt thereof.

[0137] E2. A compound according to Embodiment E1, wherein the compound is a compound having formula (Ie),

[0138]

[0139] in

[0140] R1 and R2 are each independently selected from H, C1-C6 alkyl, benzyl and substituent (i);

[0141] The premise is that R1 and R2 cannot both be H;

[0142]

[0143] wherein * indicates an attachment point; and wherein

[0144] R4 and R5 are each independently selected from H, C1-C6 alkyl, phenyl, benzyl, C3-C6 cycloalkyl and methyl substituted by C3-C6 cycloalkyl;

[0145] or a pharmaceutically acceptable salt thereof.

[0146] E3. A compound according to Embodiment E1-E2 or a pharmaceutically acceptable salt thereof, wherein

[0147] R1 is a substituent (i).

[0148] E4. A compound according to Embodiment E1-E3 or a pharmaceutically acceptable salt thereof, wherein

[0149] R1 is a substituent (i); and

[0150] R2 is selected from H, C1-C6 alkyl, benzyl and substituent (i).

[0151] E5. A compound according to Embodiment E1-E4 or a pharmaceutically acceptable salt thereof, wherein

[0152] R1 is selected from H, C1-C6 alkyl, benzyl and substituent (i); and

[0153] R2 is a substituent (i).

[0154] E6. A compound according to Embodiment E1 or a pharmaceutically acceptable salt thereof, wherein

[0155] R1 is H and R2 is substituent (i) and R3 is absent.

[0156] E7. A compound according to Embodiment E1 or a pharmaceutically acceptable salt thereof, wherein

[0157] R1 is substituent (i) and R2 is H and R3 is absent.

[0158] E8. A compound according to Embodiment E1 or a pharmaceutically acceptable salt thereof, wherein

[0159] R1 and R2 are both represented by substituent (i), and R3 is absent.

[0160] E9. A compound according to Embodiment E1 or a pharmaceutically acceptable salt thereof, wherein

[0161] R1 and R2 are both H; and

[0162] R3 is a substituent (ii).

[0163] E10. A compound according to any one of embodiments E1 and E5, or a pharmaceutically acceptable salt thereof, wherein

[0164] R1 is benzyl.

[0165] E11. A compound according to Embodiment E1 or a pharmaceutically acceptable salt thereof, wherein

[0166] R1 is benzyl and R2 is selected from H, C1-C6 alkyl, benzyl and substituent (i).

[0167] E12. A compound according to Embodiment E1 or a pharmaceutically acceptable salt thereof, wherein

[0168] R1 is benzyl; and R2 is selected from H, C1-C6 alkyl, benzyl and substituent (i); and R3 is absent.

[0169] E13. A compound according to embodiment E1 or a pharmaceutically acceptable salt thereof, wherein

[0170] R1 is benzyl; and R2 is selected from H, C1-C6 alkyl, benzyl and substituent (i); and R3 is absent.

[0171] E14. A compound according to any one of embodiments E1-E13 or a pharmaceutically acceptable salt thereof, wherein

[0172] R4 and R5 are independently selected from H, C1-C6 alkyl, phenyl and benzyl.

[0173] E15. A compound according to any one of embodiments E1-E14 or a pharmaceutically acceptable salt thereof, wherein

[0174] R4 and R5 are independently selected from H and benzyl.

[0175] E16. A compound according to any one of embodiments E1-E15 or a pharmaceutically acceptable salt thereof, wherein

[0176] R4 and R5 are selected from H, C1-C6 alkyl, phenyl and benzyl;

[0177] And at least one of R4 and R5 is H.

[0178] E17. A compound according to any one of embodiments E1-E16 or a pharmaceutically acceptable salt thereof, wherein

[0179] R4 and R5 are both H.

[0180] E18. A compound according to any one of embodiments E1-E16 or a pharmaceutically acceptable salt thereof, wherein

[0181] At least one of R4 and R5 is a benzyl group.

[0182] E19. The compound according to embodiment E1, wherein the compound is selected from the group consisting of:

[0183] Compound 1): (4aR,10aR)-6,7-bis(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline;

[0184] Compound (2): (4aR,10aR)-7-(Benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol;

[0185] Compound (3): (4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol;

[0186] Compound (4): benzyl ((4aR, 10aR)-6-((bis(benzyloxy)phosphoryl)oxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl) hydrogen phosphate;

[0187] Compound (5): benzyl ((4aR, 10aR)-7-((bis(benzyloxy)phosphoryl)oxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl) hydrogen phosphate;

[0188] Compound (6): (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diyl bis(dihydrogen phosphate);

[0189] Compound (7): benzyl ((4aR, 10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl) hydrogen phosphate;

[0190] Compound (8): (4aR, 10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl dihydrogen phosphate; and

[0191] Compound (9): ((1S,4aR,10aR)-6,7-dihydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-1-ium-1-yl)methyl hydrogen phosphate;

[0192] or a pharmaceutically acceptable salt of any of these compounds.

[0193] E20. The compound according to embodiment E1, wherein the compound is selected from the group consisting of:

[0194] Compound (2): (4aR,10aR)-7-(Benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol;

[0195] Compound (3): (4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol;

[0196] Compound (6): (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diyl bis(dihydrogen phosphate);

[0197] Compound (8): (4aR, 10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl dihydrogen phosphate; and

[0198] Compound (9): ((1S,4aR,10aR)-6,7-dihydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-1-ium-1-yl)methyl hydrogen phosphate;

[0199] or a pharmaceutically acceptable salt of any of these compounds.

[0200] E21. The compound according to embodiment E1, wherein the compound is selected from the group consisting of:

[0201] Compound (6): (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diyl bis(dihydrogen phosphate);

[0202] Compound (8): (4aR, 10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl dihydrogen phosphate; and

[0203] Compound (9): ((1S,4aR,10aR)-6,7-dihydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-1-ium-1-yl)methyl hydrogen phosphate;

[0204] or a pharmaceutically acceptable salt of any of these compounds.

[0205] E22. The compound according to embodiment E1, wherein the compound is selected from the group consisting of:

[0206] Compound (6): (4aR, 10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diyl bis(dihydrogen phosphate); and

[0207] Compound (8): (4aR, 10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl dihydrogen phosphate;

[0208] or the sodium salt of any of these compounds.

[0209] E23. The compound according to embodiment E1, wherein the compound is selected from the group consisting of:

[0210] Compound (2): (4aR,10aR)-7-(Benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol;

[0211] Compound (3): (4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol;

[0212] or a pharmaceutically acceptable salt of any of these compounds.

[0213] E24. A compound having the formula

[0214]

[0215] or a pharmaceutically acceptable salt thereof.

[0216] E25. A compound having the formula

[0217]

[0218] or a pharmaceutically acceptable salt thereof.

[0219] E26. A compound having the formula

[0220]

[0221] or a pharmaceutically acceptable salt thereof.

[0222] E27. A compound having the formula

[0223]

[0224] or a pharmaceutically acceptable salt thereof.

[0225] E28. A compound having the formula

[0226]

[0227] or a pharmaceutically acceptable salt thereof.

[0228] E29. A compound having the formula

[0229]

[0230] or a pharmaceutically acceptable salt thereof.

[0231] E30. A compound according to any one of embodiments E1-E29, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0232] E31. A compound according to any one of embodiments E1-E29, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0233] E32. The compound according to embodiment E31 for use as a medicament, or a pharmaceutically acceptable salt thereof, wherein the medicament is an oral medicament, such as a tablet or capsule for oral administration.

[0234] E33. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of Embodiments E1-E29 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or diluents.

[0235] E34. The pharmaceutical composition according to embodiment E33, wherein the pharmaceutical composition is for oral administration.

[0236] E35. The pharmaceutical composition according to any one of embodiments E33-E34, wherein the pharmaceutical composition is an oral pharmaceutical composition.

[0237] E36. The pharmaceutical composition according to any one of embodiments E33-E35, wherein the pharmaceutical composition is a solid oral dosage form.

[0238] E37. The pharmaceutical composition according to any one of embodiments E33-E36, wherein the pharmaceutical composition is a tablet or capsule for oral administration.

[0239] E38. The pharmaceutical composition according to any one of embodiments E33-E37, wherein the pharmaceutical composition further comprises another agent useful for treating a neurodegenerative disease or disorder, such as Parkinson's disease.

[0240] E39. A pharmaceutical composition according to any one of embodiments E33-E38, wherein the pharmaceutical composition further comprises a compound selected from the group consisting of: L-DOPA, a MAO-B inhibitor such as selegiline or rasagiline, a COMT inhibitor such as entacapone or tolcapone, an adenosine 2a antagonist such as istradefylline, an anti-glutamate agent such as amantadine or memantine, an acetylcholinesterase inhibitor such as rivastigmine, donepezil or galantamine, an antipsychotic such as quetiapine, clozapine, risperidone, pimavanserin, olanzapine, haloperidol, aripiprazole or epiriprazole; or an antibody targeting α-synuclein, tau protein or A-β protein.

[0241] E40. A compound according to any one of embodiments E1-E29, or a pharmaceutically acceptable salt thereof, for use in treating a neurodegenerative disease or disorder, such as Parkinson's disease, Huntington's disease, restless leg syndrome or Alzheimer's disease; or a neuropsychiatric disease or disorder, such as schizophrenia, attention deficit hyperactivity disorder or drug addiction.

[0242] E41. A compound according to any one of embodiments E1-E29, or a pharmaceutically acceptable salt thereof, for use in the treatment according to embodiment E40, wherein the neurodegenerative disease or disorder is Parkinson's disease.

[0243] E42. A compound according to any one of embodiments E1-E29, or a pharmaceutically acceptable salt thereof, for use in the treatment according to any one of embodiments E40-E41, wherein the compound is to be used in combination with another agent useful for treating a neurodegenerative disease or disorder, such as Parkinson's disease.

[0244] E43. A compound according to any one of embodiments E1-E29, or a pharmaceutically acceptable salt thereof, for use in the treatment according to any one of embodiments E40-E42, wherein the compound is to be used in combination with a compound selected from the group consisting of L-DOPA, droxidopa, foliglurax, MAO-B inhibitors such as selegiline or rasagiline, COMT inhibitors such as entacapone or tolcapone, adenosine 2a antagonists such as istradefylline, anti-glutamate agents such as amantadine or memantine, acetylcholinesterase inhibitors such as rivastigmine, donepezil or galantamine, antipsychotics such as quetiapine, clozapine, risperidone, pimavanserin, olanzapine, haloperidol, aripiprazole or epiriprazole; or in combination with antibodies targeting alpha-synuclein, tau protein or A-beta protein.

[0245] E44. A compound according to any one of embodiments E1-E29, or a pharmaceutically acceptable salt thereof, for use in the treatment according to any one of embodiments E40-E43, wherein the treatment is performed by oral administration of the compound.

[0246] E45. A compound according to any one of embodiments E1-E29, or a pharmaceutically acceptable salt thereof, for use in the treatment according to any one of embodiments E40-E44, wherein the compound is contained in an oral pharmaceutical composition, such as a tablet or capsule for oral administration.

[0247] E46. A method for treating a neurodegenerative disease or disorder such as Parkinson's disease, Huntington's disease, restless leg syndrome or Alzheimer's disease; or for treating a neuropsychiatric disease or disorder such as schizophrenia, attention deficit hyperactivity disorder or drug addiction; the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of Examples E1-E29 or a pharmaceutically acceptable salt thereof.

[0248] E47. The method according to embodiment E46, wherein the neurodegenerative disease or disorder is Parkinson's disease.

[0249] E48. The method according to any one of embodiments E46-E47, wherein the compound according to any one of embodiments E1-E29 or a pharmaceutically acceptable salt thereof is used in combination with another agent useful for treating a neurodegenerative disease or disorder, such as Parkinson's disease.

[0250] E49. The method according to any one of embodiments E46-E48, wherein the compound according to any one of embodiments E1-E29 or a pharmaceutically acceptable salt thereof is used in combination with a compound selected from the group consisting of: L-DOPA, droxidopa, foliglurax, MAO-B inhibitors such as selegiline or rasagiline, COMT inhibitors such as entacapone or tolcapone, adenosine 2a antagonists such as istradefylline, anti-glutamate agents such as amantadine or memantine, acetylcholinesterase inhibitors such as rivastigmine, donepezil or galantamine, antipsychotics such as quetiapine, clozapine, risperidone, pimavanserin, olanzapine, haloperidol, aripiprazole or epiriprazole; or in combination with antibodies targeting alpha-synuclein, tau protein or A-beta protein.

[0251] E50. The method according to any one of embodiments E46-E49, wherein said administration is performed by oral route.

[0252] E51. The method according to any one of embodiments E46-E50, wherein the compound according to any one of embodiments E1-E29 or a pharmaceutically acceptable salt thereof is contained in an oral pharmaceutical composition, such as a tablet or capsule for oral administration.

[0253] E52. Use of a compound according to any one of embodiments E1-E29 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a neurodegenerative disease or disorder such as Parkinson's disease, Huntington's disease, restless leg syndrome or Alzheimer's disease; or for the treatment of a neuropsychiatric disease or disorder such as schizophrenia, attention deficit hyperactivity disorder or drug addiction.

[0254] E53. The use according to embodiment E52, wherein the neurodegenerative disease or disorder is Parkinson's disease.

[0255] E54. The use according to any one of embodiments E52-E53, wherein the agent is used in combination with another agent useful for treating a neurodegenerative disease or disorder, such as Parkinson's disease.

[0256] E55. The use according to any one of embodiments E52-E54, wherein the agent is used in combination with a compound selected from the group consisting of: L-DOPA, droxidopa, foliglurax, MAO-B inhibitors such as selegiline or rasagiline, COMT inhibitors such as entacapone or tolcapone, adenosine 2a antagonists such as istradefylline, anti-glutamate agents such as amantadine or memantine, acetylcholinesterase inhibitors such as rivastigmine, donepezil or galantamine, antipsychotics such as quetiapine, clozapine, risperidone, pimavanserin, olanzapine, haloperidol, aripiprazole or epiriprazole; or in combination with antibodies targeting alpha-synuclein, tau protein or A-beta protein.

[0257] E56. The use according to any one of embodiments E52-E55, wherein the medicament is an oral medicament, such as a tablet or capsule for oral administration.

[0258] In the context of the present invention, it is understood that the carbon atom at the point of attachment on substituent (ii) (depicted in Example El) is at the anomeric position of (ii).

[0259] All documents (including publications, patent applications, and patents) cited herein are hereby incorporated by reference in their entirety and to the same extent as if each document were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein (to the maximum extent permitted by law).

[0260] Headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.

[0261] Unless stated otherwise or clearly contradicted by context, descriptions of any aspect or aspects of the invention herein using terms such as “comprising,” “having,” “including,” or “containing” referring to one or more elements are intended to provide support for the similar aspect or aspects of the invention “consisting of,” “consisting essentially of,” or “consisting essentially of,” the specified one or more elements (e.g., a composition described herein as comprising a specified element is to be understood to also describe a composition consisting of that element, unless stated otherwise or clearly contradicted by context).

[0262] Unless otherwise indicated, any and all examples or exemplary language (including "for instance", "for example", "eg", "such as", and "as such") used in this specification are intended merely to better illuminate the invention and do not pose a limitation on the scope of the invention.

[0263] It should be understood that the various aspects, embodiments, implementations and features of the invention mentioned herein may be claimed individually or in any combination.

[0264] This invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law.

[0265] Compounds of the present invention

[0266] Table 2: Exemplary compounds of the invention

[0267]

[0268]

[0269]

[0270] Experimental Section

[0271] Preparation of the compounds of the present invention

[0272] Compounds with formula (Id) can be prepared by the method described below and synthetic methods known in the field of organic chemistry or modifications familiar to those of ordinary skill in the art. The starting material used in this article is commercially available or can be prepared by conventional methods known in the art, such as those described in standard reference books (such as "Compendium of Organic Synthetic Methods [Organic Synthesis Methods Compendium], Volumes I-XII" (Wiley International Science Company (Wiley-Interscience) publishes)). Preferred methods include but are not limited to those described below.

[0273] These schemes are representative of methods that can be used to synthesize the compounds of the invention. They are not intended to limit the scope of the invention in any way.

[0274] LC-MS method

[0275] Analytical LC-MS data were obtained using the following identified method.

[0276] Method 25: MS: Ion source: (APPI), temperature 450℃ OR / RNG 20 / 200V OR / RNG 5 / 100V

[0277] Quality: 100-1000amu

[0278] HPLC: Column: dC-18 4.6 x 30 mm 3 μm Atlantis (Waters)

[0279] Column temperature: 40°C, gradient, reverse phase with ion pair

[0280] Solvent A: 100% H2O 0.05% TFA

[0281] Solvent B: 95% ACN 5% H2O 0.035% TFA

[0282] Flow rate: 3.3 ml / min, injection volume: 15 μl

[0283] Gradient: 2% B to 100% B in 2.4 min, 2% B 0.4 min, total run time: 2.8 min, UV: 254 nm.

[0284] ELSD: glass tube: 21 °C, evaporation chamber: 40 °C, pressure: 2.3 bar.

[0285] Method 550: LC-MS was run on a Waters Aquity UPLC-MS consisting of a Waters Aquity including 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 operating in positive ion mode.

[0286] LC-conditions: The column was Acquity UPLC BEH C18 1.7 μm; 2.1 x 50 mm, operated at 60°C with a binary gradient consisting of water + 0.05% trifluoroacetic acid (A) and acetonitrile / water (95:5) + 0.05% trifluoroacetic acid at 1.2 ml / min.

[0287] gradient:

[0288]

[0289] Total running time: 1.15 minutes

[0290] Method 551: LC-MS was run on a Waters Aquity UPLC-MS consisting of a Waters Aquity including 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 operating in positive ion mode.

[0291] LC-conditions: The column was Acquity UPLC HSS T3 1.8 μm; 2.1 x 50 mm, operated at 60°C with a binary gradient consisting of water + 0.05% trifluoroacetic acid (A) and acetonitrile / water (95:5) + 0.05% trifluoroacetic acid at 1.2 ml / min.

[0292] gradient:

[0293] 0.00min 2% B

[0294] 1.00min 100% B

[0295] 1.15min 2% B

[0296] Total running time: 1.15 minutes

[0297] Method 0-30 HPLC-AB (Agilent XDB):

[0298]

[0299] 0-30 HPLC-AB-conditions: The column was an Agilent XDB-C18 4.6*50 mm column (1.8 μm particles), operated at 40°C with a binary gradient of 0.6 mL / min consisting of water+0.037% trifluoroacetic acid (A) and acetonitrile+0.018% trifluoroacetic acid (B).

[0300] gradient:

[0301] 0.01-2.00min 0-30% B

[0302] 2.00-4.00min 30% B

[0303] 4.00-4.01min 0%-0% B

[0304] Total running time: 4.00 minutes

[0305] Method AB01 (Agilent 1200 & 6120):

[0306]

[0307]

[0308] LC-conditions: The column was Luna-C18 (2) 2.0*50 mm, 5 μm, operated at 40° C. with a binary gradient of 0.8 ml / min consisting of water+0.037% trifluoroacetic acid (A) and acetonitrile+0.018% trifluoroacetic acid (B).

[0309] gradient:

[0310]

[0311] Total running time: 4.50 minutes

[0312] List of abbreviations for chemical compounds

[0313] BnCl: benzyl chloride

[0314] CCl4: Carbon tetrachloride

[0315] DIPEA: diisopropylethylamine

[0316] DMAP: 4-dimethylaminopyridine

[0317] DMF: dimethylformamide

[0318] EtOAc: ethyl acetate

[0319] NaH: Sodium hydride

[0320] MeCN: Acetonitrile

[0321] MeI: methyl iodide

[0322] MeOH: Methanol

[0323] MOM-Cl: Chloromethyl methyl ether

[0324] Pd / C: Palladium on carbon

[0325] THF: Tetrahydrofuran

[0326] TMSCH2N2: trimethylsilyldiazomethane

[0327] TMSI: trimethylsilane iodide

[0328] Preparation of Compounds of the Invention - General Methods

[0329] (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol hydrochloride [Compound (I)] (which can be prepared, for example, as disclosed in WO 2009 / 026934) is a substrate for the synthesis of compounds of the present invention.

[0330]

[0331] Prodrugs with two phosphate moieties on the catechol hydroxyl groups can be prepared from (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol hydrochloride by reaction with dibenzyl phosphonate and a suitable base (like, but not limited to, K2CO3 or DIPEA) followed by overall deprotection as described for (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diyl bis(phosphate). In a similar manner, the two monobenzylated catechol derivatives can be converted to the corresponding monophosphates as described for (4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl phosphate.

[0332]

[0333] Treatment of compound (I) with BnCl and a base (such as, but not limited to, triethylamine or K2CO3) will provide a mixture of (4aR,10aR)-6-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-ol and (4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol; these regioisomers can be separated. Using MeI instead of BnCl will provide a mixture of the corresponding methyl ethers, which can be separated.

[0334]

[0335] Provided herein are selective pathways to (4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol and (4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol.

[0336]

[0337] Using these four compounds as substrates for reaction with dibenzyl phosphonate or di-tert-butyl phosphate and a suitable base (like, but not limited to, K2CO3 or DIPEA), followed by overall deprotection such as by hydrogenolysis or acid treatment will give mixed prodrugs like (4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl phosphate and (4aR,10aR)-6-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl phosphate as shown above.

[0338] Prodrugs in which the phosphate is attached to the N atom via a linker can be prepared as described for ((1S,4aR,10aR)-6,7-dihydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-1-ium-1-yl)methyl hydrogen phosphate.

[0339]

[0340] Mixed O-bound and N-bound prodrugs can be prepared using similar chemistry as described above to give compounds like ((1S,4aR,10aR)-6-hydroxy-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-1-ium-1-yl)methyl hydrogen phosphate.

[0341]

[0342] Using an alternative protecting group strategy, mixed N-bonded phosphate and O-benzyl prodrugs like ((1S,4aR,10aR)-7-(benzyloxy)-6-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-1-ium-1-yl)methyl hydrogen phosphate can be prepared.

[0343]

[0344] Exemplary compounds of the present invention

[0345]

[0346] Compound (1): (4aR, 10aR)-6,7-bis(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline

[0347] (4aR, 10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol hydrochloride (10.75 g) and K2CO3 (17.5 g) were added to a flask, which was degassed under vacuum and purged with N2, after which DMF (107 mL) and benzyl chloride (8.55 mL) were added and the mixture was stirred at room temperature for 18 hours, then at 100° C. for 5 hours, and at room temperature for 19 hours. K2CO3 (7.48 g) and benzyl chloride (6.29 mL) were added, and the mixture was stirred at 100° C. for 5 hours. After cooling to room temperature, the mixture was partitioned between water (500 mL) and heptane (250 mL). The aqueous phase was washed with heptane (3 x 100 mL), and the combined organic phases were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to give the title compound (14.6 g).

[0348] Compound (2): (4aR,10aR)-7-(Benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol hydroiodide

[0349] (4aR,10aR)-6,7-bis(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline (11.9 g) was added to a flask, evaporated and purged with N2, followed by the addition of MeCN (180 mL). The mixture was stirred until homogeneous, followed by the addition of trimethylsilyl iodide (10.0 mL) and the mixture was stirred at room temperature under N2 for 2 hours. MeOH (5.5 mL) was added and the mixture was stirred for 1 hour. Isopropyl acetate / heptane (10 / 150 mL) was added and the mixture was cooled to 0°C and stirred for 1 hour. The solid was collected, washed with isopropyl acetate / heptane (3 / 47 mL), and dried to give the title compound (7.6 g).

[0350] 1H NMR (600MHz, CDCl3) δ10.42(bs,1H),7.43-7.33(m,4H),7.26(d,J=1.0Hz,1H),6.78(d,J=8.3Hz,1H),6.58( d,J=8.3Hz,1H),5.72(s,1H),5.08(s,2H),3.71(dd,J=11.70,15.0Hz,1H),3.58(d,J=11.70,1H),3.25-3.11 (m,4H),2.94-2.86(m,1H),2.77-2.57(m,2H),2.26(dd,J=11.70Hz,17.0Hz1H),2.19(d,J=13.80,1H),2.01- 1.92(m,2H),1.80-1.69(m,1H),1.56-1.53(m,1H),1.39(qd,J=3.60Hz,13.30Hz,1H),1.06(t,J=7.2Hz,3H).

[0351] LCMS (Method 550), retention time = 0.55 min, [M+H] + =352.5m / z.

[0352]

[0353] Compound (3): (4aR, 10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol

[0354] Step 1

[0355] (A1): (4aR, 10aR)-7-(Benzyloxy)-6-(methoxymethoxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline

[0356] To a mixture of (4aR, 10aR) -7- (benzyloxy) -1-propyl -1,2,3,4,4a,5,10,10a- octahydrobenzo [g] quinolin-6-ol hydroiodide (20 g) in DMF (400 mL) was slowly added NaH (4.17 g, 60% dispersion) at 0 ° C under N2. The mixture was stirred at 0 ° C for 30 minutes, after which MOMCl (3.5 mL) was added dropwise at 0 ° C. The mixture was stirred at room temperature for 1 hour, after which it was poured into water (400 mL) and stirred for 20 minutes, and then extracted with EtOAc (300 mL × 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated to give the title compound (20 g).

[0357] Step 2

[0358] (A2): (4aR, 10aR)-6-(methoxymethoxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-ol

[0359] To a solution of (4aR,10aR)-7-(benzyloxy)-6-(methoxymethoxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline (20 g) in MeOH (140 mL) was added Pd / C (10%, 30 g) under N2. The suspension was degassed under vacuum and purged with H2. The mixture was stirred at room temperature under H2 (50 psi) for 12 hours, after which the catalyst was filtered off. The filtrate was concentrated to give the title compound (15.4 g).

[0360] Step 3

[0361] (A3): (4aR, 10aR)-7-methoxy-6-(methoxymethoxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline

[0362] To a solution of (4aR,10aR)-6-(methoxymethoxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-ol (15 g) in MeOH (150 mL) was added (trimethylsilyl)diazomethane (2M in ether, 246 mL) dropwise at room temperature over 0.5 h. The mixture was concentrated to give the title compound (15 g).

[0363] Step 4

[0364] Compound (3): (4aR, 10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol

[0365] A solution of (4aR, 10aR) -7- methoxy -6- (methoxymethoxy) -1- propyl -1,2,3,4,4a,5,10,10a- octahydrobenzo [g] quinoline (15g) in 4M HCl in MeOH (150mL) was stirred at room temperature for 1 hour and then concentrated. The residue was dissolved in water (100mL) and the aqueous layer was alkalized to pH 7-8 with NaHCO. The aqueous layer was extracted with EtOAc (100mL and 50mL). The combined organic layers were washed with brine (100mL), dried over NaSO, filtered and concentrated to obtain the title compound (7g).

[0366] LCMS (Method 25), retention time = 0.95 min, 94.0% purity, [M+H] + =276.1m / z.

[0367] 1 H NMR(400MHz, CDCl3) δ6.70(d,J=8.4Hz,1H),6.62(d,J=8.0Hz,1H),5.71(brs,1H),3 .86(s,3H),3.07-3.18(m,2H),3.01(dd,J=5.2,17.6Hz,1H),2.72-2.89(m,2H),2.58 -2.68(m,1H),2.29-2.44(m,2H),2.24(dd,J=12.0,17.6Hz,1H),1.97(d,J=13.2Hz, 1H), 1.70-1.92 (m, 3H), 1.54-1.63 (m, 2H), 1.10-1.23 (m, 1H), 0.93 (t, J = 7.2Hz, 3H).

[0368]

[0369] Compound (4): Benzyl ((4aR, 10aR)-6-((bis(benzyloxy)phosphoryl)oxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl) hydrogen phosphate and / or benzyl ((4aR, 10aR)-7-((bis(benzyloxy)phosphoryl)oxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl) hydrogen phosphate [Compound (5)]

[0370] (4aR, 10aR) -1-propyl -1,2,3,4,4a,5,10,10a- octahydrobenzo [g] quinoline -6,7- diol hydrochloride (1 g) and DMAP (117 mg) were added to a flask and degassed under vacuum and purged with Ar before adding CCl4 (3 mL). The reaction mixture was cooled to 0 ° C before adding MeCN (15 mL), DIPEA (6.66 mL) and dibenzyl phosphate (5.02 g). The mixture was stirred at 0 ° C for 2 hours before being distributed between a KH2PO4 aqueous solution (0.5 M, 50 mL) and EtOAc (20 mL, 30 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC using a Shimadzu LC20AP instrument (Phenomenex Luna C18 250*50 mm, 10 μm particle column, operated at room temperature with a gradient of 80 mL / min of water + 0.1% TFA (A) and MeCN (B): 0-20 minutes 20% B to 50% B; 20.1-25 minutes 100% B; 25.1-30 minutes 20% B). Crude tetrabenzyl ((4aR, 10aR) -1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo [g] quinoline-6,7-diyl) bis (phosphate) (1.6 g) was obtained. The crude product was repurified by preparative HPLC using a Shimadzu LC20AP instrument (Phenomenex Luna C18 250*50 mm, 10 μm particle column, which was operated at room temperature with a gradient of 80 mL / min of water+0.1% TFA (A) and MeCN (B): 0-20 minutes 20% B to 50% B; 20.1-25 minutes 100% B; 25.1-30 minutes 20% B) to give one or more title compounds (0.4 g).

[0371] Compound (6): Tetrasodium (4aR, 10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diyl bis(phosphate)

[0372] To a mixture of Pd / C (0.2 g, 50% (w / w)) in THF (20 mL) and water (5 mL) under N2 was added benzyl ((4aR, 10aR)-6-((bis(benzyloxy)phosphoryl)oxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl) hydrogen phosphate and / or benzyl ((4aR, 10aR)-7-((bis(benzyloxy)phosphoryl)oxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl) hydrogen phosphate (0.4 g) and NaHCO3 (91 mg). The suspension was degassed under vacuum and purged with H2. The mixture was stirred at room temperature under H2 (50 psi) for 12 h, after which the catalyst was filtered off. The filtrate was concentrated to give the title compound (0.22 g).

[0373] 1 H NMR(400MHz,D2O)δ7.17(d,J=8.4Hz,1H),6.84(d,J=8.8Hz,1H),3.55(d,J=12.0Hz,1H),3.39(d,J=15.2Hz,1H),3.23-3.32(m,3 H),3.11-3.14(m,2H),2.83(m,1H),2.48(m,1H),1.81-2.08(m,5H),1.69-1.71(m,1H),1.40-1.43(m,1H),0.97(t,J=7.2Hz,3H).

[0374] QC-LCMS (method 0-30 HPLC-AB), retention time = 2.74 minutes, [M+H] + =422.1m / z.

[0375]

[0376] Compound (7): Benzyl ((4aR, 10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl) hydrogen phosphate

[0377] To an oven dried microwave flask was added (4aR, 10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol hydroiodide (2 g) and DMAP (174 mg). The flask was degassed under vacuum and purged with argon before MeCN (30 mL) was added. The reaction mixture was cooled to 0 °C before CCl4 (6 mL), DIPEA (9.91 mL), and dibenzyl phosphate (7.46 g) were added. The mixture was stirred at 0 °C for 2 hours before being partitioned between aqueous KH2PO4 solution (0.5 M, 50 mL) and EtOAc (20 mL and 30 mL). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified twice by preparative HPLC using a Shimadzu LC20AP instrument (Run 1: Phenomenex Luna C18 250*50 mm, 10 μm particle column, which was operated at room temperature with a gradient of water + 0.1% TFA (A) and MeCN (B) at 80 mL / min: 0-20 minutes 25% B to 55% B; 20.1-25 minutes 100% B; 25.1-30 minutes 25% B. Run 2: Phenomenex Luna C18 250*40 mm, 10 μm particle column, which was operated at room temperature with a gradient of water + 0.1% TFA (A) and MeCN (B) at 60 mL / min: 0-10 minutes 35% B to 55% B; 10.1-12 minutes 100% B; 12.1-15 minutes 35% B) to give the title compound (0.2 g).

[0378] Compound (8): Disodium (4aR, 10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl phosphate

[0379] To a mixture of Pd / C (0.1 g, 50% (w / w)) in H2O (2 mL) and THF (10 mL) under N2 was added benzyl ((4aR, 10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl) hydrogen phosphate (0.2 g) and NaHCO3 (59 mg). The suspension was degassed under vacuum and purged with H2. The mixture was stirred at room temperature under H2 (50 psi) for 36 h. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated to give the title compound (120 mg).

[0380] QC-LCMS (method AB01), retention time = 1.87 min, [M+H] + =342.1m / z.

[0381] 1 H NMR (400MHz, DMSO-d6) δ6.53(d,J=8.8Hz,1H),6.42(d,J=8.0Hz,1H),2.93-3.06(m,2H),2.89(d,J=10.8Hz,1H),2.61-2.73(m,1H),2.22-2.40(m,2H) ),2.12(t,J=14.0Hz,2H),1.95-2.02(m,1H),1.80(d,J=12.8Hz,1H),1.31 -1.60(m,4H),1.20-1.25(m,1H),0.99-1.08(m,1H),0.84(t,J=7.2Hz,3H).

[0382]

[0383] Compound (9) ((1S,4aR,10aR)-6,7-dihydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-1-ium-1-yl)methyl hydrogen phosphate

[0384] Step 1: (4aR,10aR)-6,7-bis(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline

[0385] To a vacuum dried 100 mL round bottom flask equipped with a magnetic stir bar was added (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol hydrochloride (0.8 g). The flask was sealed with a septum and evacuated and backfilled with argon (this procedure was repeated 3 times). Degassed methanol (80 mL) was added followed by benzyl bromide (1.60 mL) and NaOH (1.07 g). The mixture was stirred at room temperature for 10 minutes under an argon atmosphere, then heated to 60 °C and stirred for an additional 90 minutes. The mixture was cooled to room temperature and concentrated under reduced pressure, then diluted with aqueous sodium bicarbonate (100 mL) and EtOAc (100 mL). The phases were separated and the EtOAc phase was washed with water and brine (2×50 mL), and the combined aqueous phases were extracted with EtOAc (2×50 mL). The combined EtOAc phases were dried over Na2SO4, filtered and purified by combiflash to give the title compound (623 mg).

[0386] LCMS (Method 450): retention time = 0.73 min; [M+H] + =442.3m / z.

[0387] Step 2: Benzyl (((1S,4aR,10aR)-6,7-bis(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-1-ium-1-yl)methyl) phosphate

[0388] (4aR, 10aR) -6,7-bis (benzyloxy) -1- propyl -1,2,3,4,4a,5,10,10a- octahydrobenzo [g] quinoline (200mg), dibenzyl chloromethyl phosphate (296mg), NaI (272mg, 1.812mmol) and cesium carbonate (443mg, 1.36mmol) were dissolved in anhydrous acetonitrile (5.0mL), and the resulting solution was stirred at 40 ° C for 90 minutes under an argon atmosphere. The reaction mixture was diluted with EtOAc (50mL), water (25mL) and saline (25mL), and the two phases were separated. The EtOAc phase was washed with water (25mL) and saline (25mL). The aqueous phase was extracted with EtOAc (2x 25mL) and the combined EtOAc phase was concentrated. The residue was ground by ether to produce a solid, which was collected and purified by preparative HPLC to obtain the title compound (80mg).

[0389] LCMS (Method 551): RT = 0.89 min; [M+H] + =642.7m / z.

[0390] Step 3: ((1S,4aR,10aR)-6,7-dihydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-1-ium-1-yl)methyl hydrogen phosphate

[0391] A solution of benzyl (((1S,4aR,10aR)-6,7-bis(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-1-ium-1-yl)methyl) phosphate (78 mg) in 20 mL of methanol and 2 mL of water was passed through an H-Cube (10% Pd / C) at room temperature, 5 bar and a flow rate of 1.0 mL / min. The title compound (32 mg) was obtained.

[0392] 1H NMR (600MHz, methanol-d4) δ6.66(d,J=8.0Hz,1H),6.49(d,J=8.0Hz,1H),5.28(s,1H),5.03(s,1H ),3.78(d,J=12.5Hz,1H),3.69-3.59(m,2H),3.51-3.41(m,1H),3.41-3.34(m,1H),3.16(d d,J=16.9,5.0Hz,2H),2.99(t,J=13.6Hz,1H),2.34(dd,J=17.4,10.5Hz,1H),2.30-2.15(m ,2H),2.12(d,J=13.4Hz,1H),1.98-1.78(m,3H),1.52-1.41(m,1H),1.05(t,J=7.2Hz,3H).

[0393] Diastereochemistry was demonstrated by NMR ROESY correlation.

[0394] QC-LCMS (Method 551): retention time = 0.35 min; [M+H] + =372.4m / z.

[0395] In vitro and in vivo characterization of compounds of the invention

[0396] Example 1: Transformation of compounds in human plasma and hepatocytes

[0397] Example 1a: Conversion of compounds of the invention in human plasma

[0398] The human plasma of freezing is thawed, and then centrifuged for 5 minutes with 3200x g to remove debris.Then the pH value of the supernatant is measured and adjusted to 7.4 ± 0.1 by adding 1% phosphoric acid or 1N sodium hydroxide.2 μL dosing solutions (50 μM for test compound and 100 μM (propantheline bromide) for positive control) are mixed with 98 μL blank plasma, to obtain the ultimate concentration of 1 μM test compound and 2 μM positive control.At 37 ℃ in a water bath, the mixture is incubated, and samples (in duplicate) are taken out at the predetermined time point of 0,0.5,1,2,4 and 6 hours from the incubation.10 μL inhibitors and 20 μL ascorbic acid and 2 μL formic acid (20%) are added at each corresponding time point, and then 400 μL " stop solution " (200ng / mL tolbutamide plus 200ng / mL labetalol in 50% ACN / MeOH) are added to precipitate protein. The material was mixed thoroughly and thereafter centrifuged at 4,000 rpm for 20 minutes. An aliquot of the supernatant (50 μL) was then transferred from each well to a sample plate and mixed with 100 μL of ultrapure water. The plate was shaken at 800 rpm for approximately 10 minutes before being subjected to LC-MS / MS analysis.

[0399] Example 1b: Transformation of the compounds of the invention in human hepatocytes

[0400] Incubate in 96-well plates with 1 μM compound concentration, in duplicate. Hepatocyte cell concentration is 0.5 × 106 cells / mL, for final incubation at 37 ° C in an incubator with 5% CO2 95% relative humidity. In the absence of cells, culture medium control samples are added at 0 minutes and 60 minutes. In the final incubation, total organic concentration is ≤1% (DMSO≤0.1%). Control (7-ethoxycoumarin and 7-hydroxycoumarin) is incubated in parallel with 3 μM. 2 μL dosing solution (50 μM for test compound and 100 μM for positive control) is mixed with 98 μL of 100mM PBS to obtain a final concentration of 1 μM test compound and 2 μM positive control. At 37 ° C in a water bath, the mixture is incubated, and samples (in duplicate) are taken out from the incubation at 0, 0.5, 1, 2, 4 and 6 hours at predetermined time points. To each sample, 10 μL of inhibitor and 20 μL of ascorbic acid and 2 μL of formic acid (20%) were added, followed by 400 μL of stop solution (200 ng / mL tolbutamide plus 200 ng / mL labetalol in 50% ACN / MeOH). The material was mixed thoroughly and thereafter centrifuged at 4,000 rpm for 20 minutes. An aliquot of the supernatant (50 μL) from each well was transferred to a sample plate and mixed with 100 μL of ultrapure water. The plate was shaken at 800 rpm for approximately 10 minutes before being subjected to LC-MS / MS analysis.

[0401] Instrumentation used to analyze plasma and hepatocyte incubation samples:

[0402] Mass spectrometer (LC-MS / MS): Shimadzu LC 20-AD Shimadzu UHPLC API 4000. Analytical column: ACQUITY BEH Phenyl 1.7 μm 2.1×50 mm. Mobile phase A: 0.1% formic acid in water. Mobile phase B: 0.1% formic acid in acetonitrile. Gradient was run from 95 / 5% to 5 / 95 over 2.0 minutes. Flow rate 0.7 mL / min. MRM monitoring (multiple reaction monitoring) of test items and added analytical standards (labetalol or tolbutamide).

[0403] Example 2: 5-HT2B agonist activity and binding assays

[0404] 5-HT2B agonist activity assay

[0405] The evaluation of the agonist activity of compounds (I), (Ia), (Ib), (Ic), compound (2), compound (3), compound (6), compound (8), and compound (9) at the human 5-HT2B receptor was performed by Eurofins / Cerep (France) using the HTRF detection method to measure the compound effect on inositol-phosphate (IP1) production. Briefly, the human 5-HT2B receptor was expressed in transfected CHO cells. The 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 plated in a microplate at a density of 4100 cells / well and incubated at 37°C for 30 minutes in the presence of buffer (basal control), test compound or reference agonist. For the control measurement of stimulation, a separate assay well contained 1 μM 5-HT. After incubation, the cells were lysed and a fluorescent acceptor (fluorobenzene D2-labeled IP1) and a fluorescent donor (anti-IP1 antibody labeled with a europium cryptate) were added. After 60 minutes at room temperature, fluorescence transfer was measured at λ(Ex) 337nm and λ(Em) 620 and 665nm using a microplate reader (Rubystar, BMG). The IP1 concentration was determined by dividing the signal measured at 665nm by the signal measured at 620nm (ratio). The results were expressed as a percentage of the control in response to 1 μM 5-HT. The standard reference agonist was 5-HT, which was tested at several concentrations in each experiment to generate a concentration-response curve, from which its EC was calculated as described above for the dopamine function assay. 50 value.

[0406] 5-HT2B binding assay

[0407] Evaluation of compound affinity for the human 5-HT2B receptor was determined in a radioligand binding assay at Eurofins / Cerep (France). Membrane homogenates prepared from CHO cells expressing the human 5HT2B receptor were incubated with 0.2 nM [125I] (±) DOI (1-(4-iodo-2,5-dimethoxyphenyl) propan-2-amine) in a buffer containing 50 mM Tris-HCl (pH 7.4), 5 mM MgCl2, 10 μM pargyline and 0.1% ascorbic acid at room temperature for 60 minutes in the absence or presence of test compounds. Nonspecific binding was determined in the presence of 1 μM (±) DOI. After incubation, the samples were quickly filtered under vacuum through glass fiber filters (GF / B, Packard) pre-soaked with 0.3% polyethyleneimine (PEI) using a 96 sample cell collector (Unifilter, Packard) and rinsed several times with ice-cold 50 mM Tris-HCl. The filters were dried and the radioactivity was counted in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard). The results were expressed as a percentage inhibition of specific binding of the control radioligand. The standard reference compound was (±) DOI, and in each experiment, it was tested at several concentrations to obtain a competition curve from which its IC was calculated. 50 .

[0408] Table 3. In vitro activities of the compounds of the present invention obtained according to Example 2

[0409]

[0410] *Indicates binding affinity (% inhibition of control, specific binding at indicated concentrations).

[0411] Example 3: PK study in rats

[0412] For all experiments, approximately 0.68 mL of blood samples were drawn from the tail vein or sublingual vein and placed in K3EDTA tubes that had been pre-cooled and prepared with a stabilizing solution consisting of 80 μL of ascorbic acid and 40 μL of 100 mM D-glucaric acid 1,4-lactone in water. These tubes were gently inverted 6-8 times to ensure thorough mixing and then placed in wet ice. The collection tubes were placed in wet ice for up to 30 minutes until centrifugation. Once removed from the wet ice, centrifugation was started immediately. The samples were immediately placed back on wet ice after the centrifugation was completed. Three subsamples of 130 μL of plasma were transferred to each of three appropriately labeled cryo tubes (pre-mixed and frozen storage before use) containing 6.5 μL of pre-cooled formic acid (20%). The tube caps were replaced immediately and the plasma solution was thoroughly mixed by gently inverting 6-8 times. Within 60 minutes after sampling, the samples were stored frozen at a nominal -70°C. Centrifugation conditions were at 3000G, at 4°C, for 10 minutes. After collection, the plasma was placed on water-ice. The final storage was at approximately -70°C.

[0413] Plasma samples were analyzed by solid phase extraction or direct protein precipitation followed by UPLC-MS / MS. Electrospray MS detection was used in positive ion mode, where specific mass-to-nuclear transitions of compound (I) were monitored and the reaction was calibrated using an internal standard. Concentration-time data were analyzed using standard software using appropriate non-compartmental techniques to obtain estimates of derived PK parameters.

[0414] Instrumental equipment for analysis of compound (I) from administration of compound (Ia):

[0415] Mass spectrometer (LC-MS / MS) Waters Acquity-Sciex API 5000. Analytical column Waters BEH UPLC Phenyl 100x 2.1 mm column, 1.7 μm particle size. Mobile phase A: 20 mM ammonium formate (aqueous) + 0.5% formic acid. Mobile phase B: acetonitrile. Gradient from 95% / 5% to 2 / 98 over 6.1 minutes. Flow rate 0.5 mL / min. MRM monitoring (multiple reaction monitoring) of test items and added analytical standards.

[0416] Drug administration and blood sampling:Han Wistar rats were provided by Charles River Laboratories, Sulzfeld, Germany. An artificial, automatically controlled, light-dark cycle of 12 hours was maintained. The rats received a standard laboratory diet from Brogaarden (Altromin 1324 pellets). The rats had received this diet without restriction. During the study period (4-week toxicity study), the rats received oral administration of (Ia) once a day by gavage. Blood samples from 3 male satellite animals were collected from rats given 300 μg / kg of (Ia) at the following time points on day 29 after administration: 0.5, 1, 2, 4, 6, 8, 12 and 24 hours.

[0417] Instrumental equipment for analysis of compound (I) from administration of compound (Ib):

[0418] Mass spectrometer (LC-MS / MS) Waters Acquity-Sciex API 5000. Analytical column Waters BEH UPLC Phenyl 100x 2.1 mm column, 1.7 μm particle size. Mobile phase A: 20 mM ammonium formate (aqueous) + 0.5% formic acid. Mobile phase B: acetonitrile. Gradient from 95% / 5% to 2 / 98 over 6.1 minutes. Flow rate 0.5 mL / min. MRM monitoring of test items and added analytical standards.

[0419] Drug administration and blood sampling: Han Wistar rats were provided by Charles River Laboratories, UK. An artificial, automatically controlled, light-dark cycle of 12 hours was maintained. Rats received a standard laboratory diet (Teklad 2014C diet). Rats have received this diet without restriction. During the study period (26-week toxicity study), rats received oral administration of (Ib) once a day by gavage. Blood samples from 3 male satellite animals were collected from rats given 300 μg / kg (Ib) at the following time points on day 182 after dosing: 0.5, 1, 2, 4, 8 and 24 hours.

[0420] Instrumentation for analysis of compound (I) from administration of compound (Ic), compound (2), compound (3), compound (8), and compound (9)

[0421] Mass spectrometer (LC-MS / MS) Waters Acquity-Waters Xevo TQ-S. Analytical column Acquity BEH C18 100x 2.1mm, 1.7μm. Mobile phase A: 20mM NH4-formate + 0.2% formic acid. Mobile phase B: acetonitrile + 0.2% formic acid. Gradient was run from 95% / 5% to 5% / 95% over 11.0 minutes. Flow rate 0.3mL / min. MRM monitoring of test items and added analytical standards.

[0422] Administration and blood sampling of compound (Ic), compound (2), compound (3), compound (8) and compound (9) Sample: Han Wistar rats were provided by Envigo, UK. A 12-hour artificial, automatically controlled, light-dark cycle was maintained. Rats received a standard laboratory diet, Teklad 2014C. Rats had received this diet without restriction. Male Han Wistar rats were administered a single oral gavage administration of the test compound by oral gavage. Rats were given 494 μg / kg (Ic), 392 μg / kg compound (8), 426 μg / kg compound (9), 359 μg / kg compound (3) and 551 μg / kg compound (2). Blood samples from 3 male animals were collected at the following time points on day 1 after dosing: 0.25, 0.5, 1, 2, 4, 8 and 24 hours.

[0423] Table 4. According to Example 3, 0.300 mg / kg (Ia), 0.300 mg / kg (Ib), 551 μg / kg of compound (2), 359 After oral administration to Wistar rats, (4aR,10aR)-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol (Compound (I)) PK parameters

[0424]

Claims

1. A compound represented by the following formula or a pharmaceutically acceptable salt thereof:

2. A pharmaceutical composition comprising a therapeutically effective amount of the following compound or a pharmaceutically acceptable salt thereof: (4aR,10aR)-6,7-bis(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline; (4aR,10aR)-7-(Benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol; (4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol; and one or more pharmaceutically acceptable carriers or diluents.

3. The pharmaceutical composition according to claim 2, wherein The compound is selected from: (4aR,10aR)-7-(Benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol; (4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol; or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical composition according to claim 2, wherein The pharmaceutical composition is a solid oral dosage form.

5. The pharmaceutical composition according to claim 3, wherein The pharmaceutical composition is a solid oral dosage form.

6. Use of a compound selected from the following or a pharmaceutically acceptable salt thereof for the manufacture of a medicament: (4aR,10aR)-6,7-bis(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline; (4aR,10aR)-7-(Benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol; (4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol; The agent is used to treat a neurodegenerative disease or disorder, including Parkinson's disease, Huntington's disease, restless leg syndrome, or Alzheimer's disease; or to treat a neuropsychiatric disease or disorder, including schizophrenia, attention deficit hyperactivity disorder, or drug addiction.

7. The use according to claim 6, wherein the medicament is used to treat Parkinson's disease.

8. The use according to claim 6, wherein the compound is selected from: (4aR,10aR)-7-(Benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol; (4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol; or a pharmaceutically acceptable salt thereof.

9. The use according to claim 7, wherein the compound is selected from: (4aR,10aR)-7-(Benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol; (4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol; or a pharmaceutically acceptable salt thereof.

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