Catecholamine carbamate prodrugs for use in the treatment of Parkinson's disease

Abstract

The present invention provides compounds of formula (Id) which are prodrugs of catecholamines for use in the treatment of neurodegenerative diseases and disorders. The present invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of treating neurodegenerative or neuropsychiatric diseases and disorders, particularly Parkinson's disease, using the compounds of the invention.

Description

Technical Field

[0001] The present invention provides a carbamate derivative and a prodrug of the dopamine agonist (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol, and its use in the treatment of Parkinson's disease and / or, but not limited to, restless legs syndrome, Huntington's disease, Alzheimer's disease, etc., and also, but not limited to, neuropsychiatric diseases and disorders such as schizophrenia, attention deficit hyperactivity disorder, and drug addiction, etc., in the treatment of other symptoms for which treatment with a dopamine agonist is therapeutically beneficial. The present invention also provides a pharmaceutical composition comprising a compound of the present invention.

Background Art

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

[0003] A significant and prominent feature of the pathophysiology of Parkinson's disease is the loss of pigmented dopaminergic neurons in the substantia nigra pars compacta, which provides dopaminergic innervation to the striatum and other brain regions. Such progressive neurodegeneration causes a decrease in striatal dopamine levels, which ultimately leads to a series of changes in the basal ganglia circuitry and finally the emergence of the four major motor features of Parkinson's disease. The main targets of dopamine in the striatum consist of medium spiny GABAergic neurons (MSNs) that selectively express either D1 or D2 receptors, with prominent dendritic arbors. GABAergic MSNs that project to the external globus pallidus, also known as the striatopallidal "indirect pathway", express D2 receptors (MSN-2). GABAergic-MSNs that project to the substantia nigra reticulata and the internal globus pallidus, also known as the striatonigral "direct pathway", express D1 receptors (MSN-1). The lack of dopamine due to neuronal loss causes an imbalance in the activity of the two pathways, resulting in a significant decrease in thalamic and cortical output activity and ultimately motor dysfunction (Gerfen et al, Science (1990) 250:1429-32; Delong, (1990) Trends in Neuroscience 13:281-5; Alexander et Crutcher, (1990) Trends in Neuroscience 13:266-71 and for reviews see Poewe et al., Nature Review (2017) vol.3 article 17013:1-21).

[0004] The most effective treatment strategies available for patients suffering from Parkinson's disease and aiming at the control of motor symptoms are mainly indirect and direct dopamine agonists. The classical and gold standard therapy is the chronic oral intake of L-3,4-dihydroxyphenylalanine (L-DOPA) which is decarboxylated in the brain to form dopamine. Other approaches include the administration of dopamine receptor agonists such as apomorphine or pramipexole, ropinirole which act on both D1 and D2 receptor subtypes, and other agonists preferentially directed towards the D2 receptor subtype. Optimal MR (symptoms are reduced when moving) is obtained with the use of both L-DOPA and apomorphine, for the activation of both D1 and D2 receptor subtypes and for the global rebalancing of the indirect-direct pathway (i.e. only D2 agonists reverse the dysfunction of the indirect pathway).

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

Chemical formula

[0006] L-DOPA is a prodrug of dopamine and continues to be the most effective drug in 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 (i.e. the continued decrease of dopaminergic neurons) and the poor pharmacokinetic (PK) profile of L-DOPA. The complications include 1) dyskinesia, abnormal involuntary movements that occur during the optimal 'on-time effect' of the drug, and 2) off-periods where the positive effect of L-DOPA gradually decreases during that period and symptoms reappear or worsen (Sprenger and Poewe, CNS Drugs (2013), 27:259-272).

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

[0008] Alternatives to parenteral formulations of catecholamines include the use of prodrugs that mask the free catechol hydroxyl groups so that they can be administered orally. However, a known problem associated with the development of prodrugs for clinical use is the difficulty in predicting conversion to the parent compound in humans.

[0009] Various ester prodrugs of catecholamines, such as the overall coated N-propyl-noraporphine (NPA) for duodenal delivery and the monopivaloyl ester of apomorphine (International Publication No. 02 / 100377 pamphlet), and the D1-like agonist adrogolide, the diacetyl prodrug of A-86929 (Giardina and Williams; CNS Drug Reviews (2001), Vol. 7(3): 305-316), etc., have been reported in the literature. Adrogolide undergoes extensive first-pass hepatic metabolism in men after oral administration, resulting in low oral bioavailability (about 4%). In PD patients, intravenous (IV) adrogolide has anti-Parkinson efficacy equivalent to L-DOPA (Giardina and Williams; CNS Drug Reviews (2001), Vol. 7(3): 305-316).

[0010] In addition to the ester prodrugs of catecholamines, alternative prodrug approaches involve masking of the two catechol hydroxyl groups as the corresponding methylene-dioxy derivatives or di-acetalyl derivatives. The principle of this prodrug is described, for example, in Campbell et al., Neuropharmacology (1982); 21(10): 953-961 and U.S. Patent No. 4543256, International Publication No. 2009 / 026934 pamphlet and International Publication No. 2009 / 026935 pamphlet.

[0011] Another proposed approach for catecholamine prodrugs is, for example, the formation of enone derivatives proposed in International Publication No. 02 / 100377 pamphlet and Liu et al., Bioorganic Med.Chem. (2008), 16: 3438-3444. For further examples of catecholamine prodrugs, see, for example, Sozio et al., Exp.Opin.Drug Disc. (2012); 7(5): 385-406.

[0012] The compound (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol, shown as compound (I) below, is disclosed in International Publication No. WO 2009 / 026934 pamphlet. The trans isomer was previously disclosed in Liu et al., J. Med. Chem. (2006), 49:1494-1498, which contains pharmacological data suggesting that the compound has low oral bioavailability in rats, and then in Liu et al., Bioorganic Med. Chem. (2008), 16:3438-3444. First, the racemic compound was disclosed in Cannon et al., J. Heterocyclic Chem. (1980); 17:1633-1636. [Chemical formula] Compound (I) is a dopamine receptor agonist having mixed D1 and D2 activities. Three prodrug derivatives of compound (I) are known in the art.

[0013] Liu et al., J. Med. Chem. (2006), 49:1494-1498 and Liu et al., Bioorganic Med. Chem. (2008), 16:3438-3444 disclose enone derivatives of the following formula (Ia) which have been shown to be converted to the active compound (I) in rats. [Chemical formula]

[0014] International Publication No. WO 2009 / 026934 pamphlet and International Publication No. WO 2009 / 026935 pamphlet disclose two prodrug derivatives of compound (I) including (6aR,10aR)-7-propyl-6,6a,7,8,9,10,10a,11-octahydro-[1,3]dioxolo[4’,5’:5,6]benzo[1,2-g]quinoline, a methylenedioxy (MDO) derivative having the following formula (Ib). [Chemical formula]

[0015] The conversion of compound (Ib) to compound (I) in rat and human hepatocytes has been demonstrated in WO 2010 / 097092 pamphlet. Further, the in vivo pharmacology of compounds (Ia) and (Ib) and the active “parent compound” (I) has been tested in various animal models for Parkinson's disease (WO 2010 / 097092 pamphlet). Both compound (I) and both compounds (Ia) and (Ib) have been found to be effective, and compounds (Ia) and (Ib) have been shown to be converted to compound (I) in vivo. All three compounds have been reported to have a longer duration of action than that confirmed for L-dopa and apomorphine.

[0016] Other prodrugs of compound (I) disclosed in WO 2009 / 026934 pamphlet and WO 2009 / 026935 pamphlet are conventional ester prodrugs of formula (Ic). [Chemical formula]

[0017] Despite being a subject of interest in this field for many years, the need for the development of an efficient, well-tolerated and orally acting drug for the treatment of PD remains clearly unaddressed. Prodrug derivatives of mixed D1 / D2 agonists that can provide continuous dopaminergic stimulation and give a stable PK profile may meet such unaddressed needs.

[0018] Carbamate derivatives as prodrug components have been previously proposed and investigated for various compounds containing a catechol moiety. Carbamate derivatives of apomorphine and N-n-propylnorapomorphine have been proposed as prodrug derivatives decades ago (Edward et al. (1976). J. Pharm Sci. 65(11):1682-1685). Apomorphine (dimethylcarbamate) has been synthesized and tested in mice, suggesting that the conversion to apomorphine is very slow, despite its very limited pharmacological effects compared to apomorphine itself. European Patent No. 0352815 shows the oral bioavailability of a carbamate derivative of gamma-L-glutamyl-L-dopa in the treatment of Parkinson's disease.

[0019] Prodrugs targeting various amino acid or peptide transporters are known in the art (see, for example, Vale et al. 2018, Amino acids in the development of prodrugs, Molecules, 23(9), 2318). Further, Ninomiya et al. (2011) disclosed amino acid conjugates of tricine and referred to improved bioavailability after oral administration. Further, it has been reported by Kim et al. that quercetin - amino acid derivatives exhibit favorable cell permeability in vitro through interaction with the peptide transporter PEPT1 ((In vitro solubility, stability and permeability of novel quercetin - amino acid (Kim, M.K.; Park, K.-S.; Yeo, W.-S.; Choo, H.; Chong, Y. In vitro solubility, stability and permeability of novel quercetin - amino acid conjugates. Bioorg. Med. Chem. 2009, 17, 1164 - 1171.). International Publication No. 06014429 pamphlet discloses a prodrug for sitafovir containing an amino acid residue or peptide and having an affinity for hPEPT1. However, none of these documents disclose a catecholamine prodrug containing an amino acid or peptide moiety.

Summary of the Invention

[0020] The present invention relates to novel compounds for the treatment of Parkinson's disease. More specifically, the present invention relates to novel carbamate prodrug derivatives of the compound (4aR,10aR)-1 - propyl - 1,2,3,4,4a,5,10,10a - octahydro - benzo[g]quinoline - 6,7 - diol (Compound (I)). Representative compounds (1)-(3) of the present invention have been proven to be particularly useful for oral delivery of Compound (I).

[0021] Accordingly, in a first aspect, the formula (Ie) [Chemical formula] (wherein Y is H and the following formula CONR1R2 [Chemical formula] selected from the carbamoyl groups of, X is H and the following formula CONR3NR4 [Chemical formula] selected from the carbamoyl groups of, Y and X are not both H, R1, R2, R3 and R4 are each independently selected from the group consisting of H, C 1~6 alkyl, amino acids, amino acid residues and peptides) There is provided a compound according to or a pharmaceutically acceptable salt thereof.

[0022] In another aspect, 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.

[0023] A further aspect of the present invention relates to a compound according to formula (Id) for use as a medicament.

[0024] A further 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 neurodegenerative diseases or disorders such as Parkinson's disease, Huntington's disease, restless legs syndrome or Alzheimer's disease or psychotic disorders such as schizophrenia, attention deficit hyperactivity disorder or drug addiction.

[0025] A further 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 legs 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.

[0026] A further aspect of the present invention relates to the use of a compound of formula (Id) 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 legs syndrome or Alzheimer's disease; or for the manufacture of a medicament for the treatment of a neuropsychiatric disease or disorder such as schizophrenia, attention deficit hyperactivity disorder or drug addiction.

[0027] Definitions Compounds of the present invention References to compounds encompassed by the present invention include the free forms of the compounds of the present invention (e.g., free base or zwitterion), pharmaceutically acceptable salts, acid addition salts or base addition salts of the compounds of the present invention, and polymorphic and amorphous forms of the compounds of the present invention and their pharmaceutically acceptable salts. Further, the compounds of the present invention and their pharmaceutically acceptable salts may potentially exist in unsolvated and solvated states with pharmaceutically acceptable solvents such as water, ethanol, etc. Both the solvated and unsolvated states are encompassed by the present invention.

[0028] Pharmaceutically acceptable salts In the context of the present invention, pharmaceutically acceptable salts are intended to represent non-toxic, i.e., physiologically acceptable salts.

[0029] The term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts which are salts formed with inorganic acids and / or organic acids on the nitrogen atom in the parent molecule. The acids can be selected, for example, from 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.

[0030] Other examples of acids useful for forming pharmaceutically acceptable salts are described, for example, in Stahl and Wermuth (Eds), Handbook of Pharmaceutical salts. Properties, selection, and use, Wiley-VCH 2008.

[0031] Prodrug In the context of the present invention, the term "prodrug" or "prodrug derivative" means a compound that is converted in vivo to a pharmacologically active moiety after administration to a biological subject such as a mammal, preferably a human. The conversion preferably occurs in a mammal such as a mouse, rat, dog, mini-pig, rabbit, monkey and / or human. In the context of the present invention, a "prodrug of the compound (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol", or a "prodrug of the compound of formula (I)", or a "prodrug of compound (I)" is understood to be a compound that is converted in vivo to the compound (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol after administration. The administration can be by a conventional route of administration of a pharmaceutical composition known in the art and can preferably be oral administration.

[0032] In connection with the present invention, the terms "parent compound" and "parent molecule" mean the pharmacologically active moiety obtained upon 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 the compound of formula (I).

[0033] Substituent In connection with the present invention, a given range is indicated without distinction by "-" (dash) or "~", for example, "C1-C6 alkyl" is equivalent to "C1~C6 alkyl".

[0034] The term "alkyl" means a straight-chain (i.e., unbranched) or branched saturated hydrocarbon having from 1 to 6 carbon atoms. 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.

[0035] Amino acid The amino acid can be based on any one of the 20 common amino acids found in naturally synthesized proteins, provided that the residue provides oral bioavailability of the compound (I) of the present invention. Common amino acids include arginine, lysine, aspartic acid, glutamic acid, glutamine, asparagine, histidine, serine, threonine, tyrosine, cysteine, tryptophan, methionine, alanine, isoleucine, leucine, phenylalanine, valine, proline, and glycine.

[0036] In some embodiments of the present invention, an alpha amino acid having both an amino group and a carboxylic acid group bonded to the first alpha carbon atom is preferred. The amino group bonded to the alpha carbon may be referred to as an α-amino group. Similarly, the carboxylic acid group bonded to the alpha carbon may be referred to as an α-carboxyl group. Except for the cyclic amino acid proline, α-amino acids generally have the general formula H2NC αIt has HXCOOH, where X is an organic substituent known as a "side chain", and the remaining part is known as the backbone, which has a (α-) carboxyl group and a (α-) amino group.

[0037] The term "amino acid residue" means an amino acid lacking a part of its structure. Thus, for example, when the term amino acid residue of glycine is mentioned in this specification, it will be understood that the amino acid residue is glycine lacking a part of its structure. Examples include α-amino acids lacking the OH part of the α-carboxyl group or the H part of the α-amino group. The definition of an amino acid residue also includes amino acids lacking a part of their side chains, such as serine amino acids lacking the H part of the side chain-OH group.

[0038] Amino acid residues can also be based on modified or abnormal amino acids. Examples of modified or abnormal amino acids include, but are not limited to, 2-aminoadipic acid, 3-aminoadipic acid, beta-alanine, 2-aminobutyric acid, pipecolic acid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid, 2-aminopimelic acid, 2,4-diaminobutyric acid, desmosine, 2,2'-diaminopimelic acid, 2,3-diaminopropionic acid, N-ethylglycine, N-ethylasparagine, hydroxylysine, allohydroxylysine, 3-hydroxyproline, 4-hydroxyproline, isodesmosine, isodesmosine, N-methylglycine, N-methylisoleucine, N-methylvaline, norvaline, norleucine, ornithine, and homoserine.

[0039] Similarly, peptides such as dipeptides or tripeptides can contain any of the 20 common amino acids and any of the modified or abnormal amino acids, as long as the peptide supports the oral bioavailability of the compound (I) - carbamate derivative.

[0040] Both the (D) and (L) stereoisomers of the amino acid residues can be incorporated into the compounds of the present invention. When the configuration is not specified, the amino acid or residue can have the configuration (D), (L), or (DL). For the purposes of the present application, unless otherwise specified, the designated amino acid is to be construed as including both stereoisomers of (D) or (L). In certain embodiments of the present invention, the amino acid residue is an L-amino acid and the peptide is prepared from L-amino acids.

[0041] A derivative of an amino acid residue is an amino acid residue in which a part of its structure is substituted by an atom or a group of molecules. Examples of such derivatives include, but are not limited to, ester derivatives having an -OR group instead of the α-carboxyl -OH group (R is an alkyl or alkenyl group). In certain embodiments, R is a C1-C20 alkyl or alkenyl group. A dipeptide or tripeptide derivative is a peptide that contains at least one derivative of an amino acid residue.

[0042] Pharmacokinetic Definitions and Abbreviations 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 obtained for the compounds of formula (I) after oral administration of the compounds of the present invention using non-compartmental modeling. The PK parameters that are omitted are C max (maximum concentration); t max (C max time to reach); t 1 / 2 (half-life); AUC 024 (area under the curve from the time of administration to 24 hours after administration, and "exposure at 24 hours" is the plasma concentration of the compound of formula (I) measured 24 hours after administration.

[0043] Therapeutically Effective Amount In connection with the present invention, the term "therapeutically effective amount" of a compound of the present invention means an amount sufficient to reduce, arrest, partially arrest, remove or delay the clinical symptoms of a given disease and its complications in a therapeutic intervention that includes administration of said compound. The amount suitable to achieve this is defined as a "therapeutically effective amount". The amount effective for each purpose will vary, for example, depending on the severity of the disease or injury and the body weight and general condition of the subject. It will be understood that determination of the appropriate dosage is accomplished by constructing a matrix of values and testing various points in that matrix using ordinary experimentation within the ordinary skill of a skilled physician.

[0044] In connection with the present invention, "therapeutically effective amount" of a compound of the present invention means an amount of the compound (I) of the present invention that can provide an amount of the compound of the present invention sufficient to reduce, arrest, partially arrest, remove or delay the clinical symptoms of a given disease and its complications when the said compound of the present invention is preferably administered to a mammal, preferably a human, by the oral route.

[0045] Treatment and Therapy In connection with the present invention, "treatment" or "therapy" is intended to denote the management and care of a patient for the purpose of alleviating, arresting, partially arresting, removing or delaying the progression of the clinical symptoms of a disease. The patient to be treated is preferably a mammal, particularly a human.

[0046] Symptoms for Treatment The compounds of the present invention are intended for the treatment of neurodegenerative diseases and disorders such as Parkinson's disease and / or other symptoms for which treatment with a dopamine agonist is therapeutically beneficial.

[0047] The indications for treatment include various central nervous system diseases characterized by motor and / or non-motor disorders, and in which part of the underlying pathophysiology is dysfunction of the striatal-mediated circuitry. Such functional disorders include, but are not limited to, neurodegenerative diseases such as Parkinson's disease (PD), restless leg syndrome, Huntington's disease and Alzheimer's disease, as well as, but not limited to, psychoneurological diseases such as schizophrenia, attention deficit hyperactivity disorder and drug addiction.

[0048] In addition to neurodegenerative diseases and disorders, mental functions, including various aspects of cognition, are improved in other conditions where an increase in dopaminergic metabolic turnover may be beneficial. It may also have a positive effect in patients with depression and can be used in the treatment of obesity and drug addiction as an anorectic agent. It may improve the potential negative, positive and cognitive symptoms of mild brain dysfunction (MBD), narcolepsy, attention deficit hyperactivity disorder and schizophrenia.

[0049] Restless leg syndrome (RLS) and periodic limb movement disorder (PLMD) are another indication clinically treated with dopamine agonists. Furthermore, sexual dysfunction, 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 circulatory and renal systems, and thus, renal insufficiency and hypertension may be considered alternative indications for the compounds of the present invention.

[0050] The present invention encompasses the use of the compounds of the present invention for treating the above-mentioned diseases and disorders.

[0051] Combination In one embodiment of the present invention, the compound of formula (Ie) is used in a stand-alone treatment as a single active compound. In other embodiments of the present invention, the compound of formula (Ie) can be used in combination with other agents useful for the treatment of neurodegenerative diseases or disorders such as Parkinson's disease. As used herein in connection with the methods of the present invention, terms such as "combined use", "in combination with", and "combination of" which include administering a therapeutically effective amount of the compound of formula (Ie) and another compound useful for the treatment of a neurodegenerative disease or disorder in combination are intended to mean administering the compound of formula (Ie) simultaneously or sequentially in either order together with the other compound.

[0052] The two compounds can be administered simultaneously or with a time interval between administrations of the two compounds. The two compounds can be administered as part of the same pharmaceutical formulation or composition or in separate pharmaceutical formulations or compositions. The two compounds can be administered on the same day or on different days. They can be by the same route, such as oral administration, subcutaneous injection, transdermal administration, depot, intramuscular injection or intravenous injection, etc., or by different routes where one compound is administered, for example, orally or by depot and the other compound is administered, for example, by infusion. The two compounds can be administered according to the same dosing schedule or interval, such as once or twice a day, once or twice a week or once or twice a month, or according to different dosing schedules, for example, one is administered once a day and the other is administered twice a day, or once a week, or once a month.

[0053] In some cases, the patient being treated can already be receiving treatment with one or more other compounds useful in the treatment of a neurodegenerative disease or disorder when treatment with the compound of formula (Ie) is initiated. In other cases, when treatment with one or more other compounds useful in the treatment of a neurodegenerative disease or disorder is initiated, the patient can already be receiving treatment with a compound of formula (Ie) or (Id). In other cases, treatment with the compound of formula (Ie) and treatment with one or more other compounds useful in the treatment of a neurodegenerative disease or disorder are initiated simultaneously.

[0054] Compounds for combination therapy In connection with the present invention, the compounds used in combination with the compounds of formula (Ie) can be selected, for example, from MAO-B inhibitors such as L-DOPA, droxidopa, foligraside, selegiline or rasagiline, COMT inhibitors such as entacapone or tolcapone, adenosine 2a antagonists such as istradefylline, antiglutamate 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 brexpiprazole.

[0055] In addition to small molecules, the compounds used in combination can also include emerging biologic approaches in the treatment of neurodegenerative diseases or disorders, such as antibody-targeted α-synuclein, Tau or A-β proteins.

[0056] Route of administration The pharmaceutical composition comprising a compound of formula (Ie), either as a single active compound or in combination with other active compounds, can be formulated specifically for administration by any suitable route, such as oral, rectal, nasal, buccal mucosa, sublingual, pulmonary, transdermal and parenteral (e.g., subcutaneous, intramuscular and intravenous) routes. In connection with the present invention, the oral route is the preferred route of administration.

[0057] It is understood that the route will vary depending on the general condition and age of the subject being treated, the nature of the condition being treated, and the active ingredient.

[0058] Pharmaceutical formulations and excipients In the following, the term "excipient" or "pharmaceutically acceptable excipient" means pharmaceutical excipients such as, but not limited to, carriers, fillers, diluents, antiadherents, binders, coatings, colorants, disintegrants, flavors, glidants, lubricants, preservatives, adsorbents, sweeteners, solvents, vehicles and adjuvants.

[0059] The present invention also provides a pharmaceutical composition comprising a compound of formula (Ie), such as one of the compounds disclosed in the experimental section herein. The present invention also provides a process for manufacturing a pharmaceutical composition comprising a compound of formula (Ie). The pharmaceutical composition according to the present invention can be formulated using pharmaceutically acceptable excipients according to conventional techniques, such as the techniques disclosed in Remington, The Science and Practice of Pharmacy, 22th edition (2012), Edited by Allen, Loyd V., Jr.

[0060] The pharmaceutical composition comprising the compound of the present invention is preferably a pharmaceutical composition for oral administration. Examples of pharmaceutical compositions for oral administration include solid oral dosage forms such as tablets, capsules, powders, and granules, liquid oral dosage forms such as solutions, emulsions, suspensions, and syrups, and powders and granules that are dissolved or suspended in a suitable liquid.

[0061] The solid oral dosage form can be provided as individual units (e.g., tablets or hard or soft capsules), each containing a predetermined amount of the active ingredient, preferably one or more suitable excipients. Where appropriate, the solid dosage form can be manufactured using a coating such as an enteric coating, or formulated to provide controlled release of the active ingredient, such as delayed or sustained release, according to methods well known in the art. Where appropriate, the solid dosage form can also be a dosage form that disintegrates in saliva, such as an orally dispersible tablet, for example.

[0062] Examples of excipients suitable for solid oral dosage forms include, but are not limited to, microcrystalline cellulose, corn starch, lactose, mannitol, povidone, croscarmellose sodium, sucrose, cyclodextrin, talcum, gelatin, pectin, magnesium stearate, stearic acid, and lower alkyl ethers of cellulose. Similarly, solid formulations may include excipients for delayed or sustained release formulations known in the art, such as glyceryl monostearate or hypromellose. When solid materials are used for oral administration, the formulation can be produced, for example, by mixing the active ingredient with a solid excipient and subsequently compressing the mixture with conventional tableting equipment, or a formulation in the form of, for example, powder, pellet, or mini-tablet can be placed in a hard capsule. The amount of solid excipient varies widely but is usually in the range of about 25 mg to about 1 g per dosage unit.

[0063] Liquid oral dosage forms can be provided, for example, as elixirs, syrups, oral drops, or liquid-filled capsules. Liquid oral dosage forms can also be provided as powders for solutions or suspensions in aqueous or non-aqueous liquids. Examples of excipients suitable for liquid oral dosage forms include, but are not limited to, ethanol, propylene glycol, glycerol, polyethylene glycol, poloxamer, sorbitol, polysorbate, monoglyceride and diglyceride, cyclodextrin, coconut oil, palm oil, and water. Liquid oral dosage forms can be produced, 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.

[0064] Additional excipients such as colorants, flavors, and preservatives can be used in solid and liquid oral formulations.

[0065] Examples of pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous solutions, dispersions, suspensions or emulsions for injection or infusion, concentrates for injection or infusion, and sterile powders that are dissolved in a sterile solution or dispersion for injection or infusion before use. Examples of excipients suitable for parenteral formulations include, but are not limited to, solutions of water, coconut oil, palm oil, and cyclodextrin. Aqueous formulations should be appropriately buffered and made isotonic with sufficient saline or glucose as necessary.

[0066] Examples of other types of pharmaceutical compositions include suppositories, inhalants, creams, gels, transdermal patches, implant tablets, and formulations for oral or sublingual administration.

[0067] The excipients used in pharmaceutical formulations must be compatible with the intended route of administration and the active ingredient.

[0068] Dosage In one embodiment, the compounds of the present invention are administered in an amount of about 0.0001 to about 5 mg / kg body weight per day. In particular, the daily dose can be in the range of 0.001 to about 2 mg / kg body weight per day. The exact dosage will vary depending on factors such as the frequency and form of administration, sex, age, weight and general condition of the subject to be treated, the nature and severity of the condition to be treated, the accompanying diseases to be treated, the desired effect of the treatment, and other factors known to those skilled in the art.

[0069] The typical oral dosage for an adult is in the range of 0.1 to 100 mg / day of the compound of the present invention, for example, in the range of 0.05 to 50 mg / day, 0.1 to 10 mg / day, or 0.1 to 5 mg / day. Conveniently, the compounds of the present invention are administered in unit dosage forms containing the compound in an amount of about 0.01 to 50 mg, for example, up to 0.05 mg, 0.1 mg, 0.2 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, or 50 mg.

Brief Description of the Drawings

[0070] [Figure 1]The conversion of the compounds (1) to (3) of the present invention to the compound (I) is illustrated. Solid arrows: Conversions demonstrated in vitro and in vivo. Hatched arrows: Conversions demonstrated in vivo.

Mode for Carrying Out the Invention

[0071] Detailed Description of the Invention The present inventors have identified novel compounds that are carbamate derivative prodrugs of the dual D1 / D2 agonist (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol [Compound (I)]. (See, for example, WO 2009 / 026934 pamphlet).

[0072] The compounds of the present invention are carbamate derivatives of Compound (I).

[0073] The inventors of the present invention have found that by orally administering representative compounds (1) to (3) of the present invention in Wistar rats, systemic exposure of Compound (I) in plasma is provided, suggesting the usefulness of said compounds as orally active prodrugs of Compound (I).

[0074] For the compounds tested in vivo, the dose was 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). Oral administration of compounds (Ia) and (Ib) to Wistar rats was found to result in initial and high peak concentrations of compound (I). Such high peak concentrations may be associated with dopaminergic side effects such as nausea, vomiting, and dizziness in humans. In contrast, for the compounds of the present invention, the absorption rate is slow with sustained exposure to compound (I), preventing rapid peak plasma concentrations. Furthermore, the obtained AUC of compound (I) was lower than the AUC obtained after administration of compounds (Ia) and (Ib), but the plasma exposure of compound (I) in Wistar rats was maintained throughout 24 hours. However, due to the low peak concentration of compound (I) that is expected to induce side effects, a higher dose of the compound of the present invention can be administered to potentially achieve a higher total plasma concentration of compound (I) compared to the concentration achievable by administering compounds (Ia) and (Ib). When investigating the PK characteristics of compound (Ic), the inventors found that the plasma concentration of compound (I) was very low and that compound (Ic) remained unsuitable as a prodrug of compound (I) for oral administration, and it was confirmed that the oral bioavailability of the compounds of the present invention is very unpredictable. The PK parameters for the PK study in Wistar rats are listed in Table 4.

[0075] The bioconversion of the compounds of the present invention to compounds (1) to (3) of formula (I) was also evaluated by incubation in human plasma as described in Example 1. For the parent compound (I) itself, a short half-life was observed in the plasma assay. This is likely to explain why the formation of compound (I) could not be determined because one of the compounds of the present invention may have been metabolized simultaneously as it was formed. For all compounds (1) to (3) of the present invention, the conversion to compound (I) was demonstrated in vivo or both in vivo and in vitro (see Table 1 and Figure 1 below).

[0076]

Table 1

[0077] As a conclusion, the compounds of the present invention represented by the compounds (1) to (3) are useful as oral active prodrugs of the compound (I), and peak C confirmed by the known prodrugs (Ia) and (Ib) max is avoided, and it was confirmed in rats that a PK profile can be provided in which the AUC of the compound (I) is significantly higher than that of the compound (Ic).

[0078] Finally, an important problem associated with the compound (Ib) is that this compound is an agonist of the 5-HT2B receptor. Since the etiology of valvular heart disease (VHD) after long-term exposure is related to 5-HT2B receptor agonists, such compounds are not suitable for use in the treatment of chronic diseases (Rothman et al., Circulation (2000), 102: 2836-2841 and Cavero and Guillon, J. Pharmacol. Toxicol. Methods (2014), 69: 150-161). Therefore, a further advantage of the compounds (1) to (3) of the present invention is that they are not 5-HT2B agonists (see Example 2 and Table 3).

[0079] Peptide transporters (PEPT1 and PEPT2), as well as LAT1 and LAT2, are used as targets for prodrugs, and amino acids or peptides are linked to the active compound by an ester or carbamate bond. L-type amino acid transporters 1 (LAT1) and 2 (LAT2) play a role in transporting large neutral amino acids from the extracellular fluid into cells. The natural substrates of LAT1 are large neutral amino acids such as L-leucine, L-tryptophan, and L-phenylalanine. Furthermore, PEPT1 is known to play an important role in the absorption of various drugs and prodrugs from the intestine. PEPT1 is located in the apical intestinal cell membrane of the upper small intestine, where it uses an electrochemical proton gradient as the driving force and functions as a cotransporter. Human PEPT1 (hPEPT1) contains 708 amino acids oriented in 12 transmembrane domains. Since PEPT1 is an important amino acid / di / tripeptide transporter in human intestinal cells, the transport of possible hundreds of different dipeptides, possible thousands of tripeptides, as well as various drugs and prodrugs, implies the broad substrate specificity of this transporter.

[0080] In one embodiment of the present invention, the carbamate derivative compound of compound (I) can be transported by one or more peptide transporters such as PEPT1, PEPT2, LAT1, and LAT2. In a more specific embodiment of the present invention, the carbamate derivative compound of compound (I) as defined herein can be transported by PEPT1.

[0081] PEPT1 has been shown to exhibit high affinity for L-amino acids or peptides containing L-amino acids. Therefore, in one embodiment of the present invention, the amino acid or amino acid residue is an L-amino acid or an L-amino acid residue. Similarly, in one embodiment of the present invention, the peptide contains or consists of L-amino acids.

[0082] The amino acid or amino acid residue according to the present invention can be any one of the 20 common amino acids found in naturally synthesized proteins. Thus, in one embodiment, the amino acid or amino acid residue is selected from the group consisting of arginine, lysine, aspartic acid, glutamic acid, glutamine, asparagine, histidine, serine, threonine, tyrosine, cysteine, tryptophan, methionine, alanine, isoleucine, leucine, phenylalanine, valine, proline, and glycine.

[0083] In one embodiment of the present invention, the peptide comprises two or more amino acid residues of an amino acid selected from the group consisting of arginine, lysine, aspartic acid, glutamic acid, glutamine, asparagine, histidine, serine, threonine, tyrosine, cysteine, tryptophan, methionine, alanine, isoleucine, leucine, phenylalanine, valine, proline, and glycine.

[0084] In some studies, PEPT1 has been found to have a preference for certain amino acids such as phenylalanine, valine, leucine, isoleucine, glycine, alanine, or peptides containing them. Thus, in one embodiment of the present invention, the amino acid is selected from the group consisting of phenylalanine, valine, leucine, isoleucine, glycine, and alanine, and the L-form of the amino acids in this group is preferred. In an even more specific embodiment of the present invention, the amino acid is selected from the group consisting of phenylalanine and glycine.

[0085] Similarly, in one embodiment, the peptide comprises or consists of one or more amino acids selected from the group consisting of phenylalanine, valine, leucine, isoleucine, glycine, and alanine, and the L-form of the amino acids in this group is preferred. In an even more specific embodiment of the present invention, the peptide comprises one or more amino acids selected from the group consisting of phenylalanine and glycine.

[0086] PEPT1 can transport single amino acid derivatives, as well as dipeptide derivatives and tripeptide derivatives of active compounds. Therefore, in one embodiment of the present invention, the carbamate derivative of compound (I) contains one amino acid residue.

[0087] In another embodiment of the present invention, the compound of the present invention contains a dipeptide or a tripeptide.

[0088] In one embodiment of the present invention, the compound of the present invention contains one or more amino acids selected from the group consisting of phenylalanine, valine, leucine, isoleucine, glycine and alanine or a dipeptide consisting of them, and the L-form of the amino acids in this group is preferred. In a specific embodiment of the present invention, the compound of the present invention contains one or more amino acids or amino acid residues selected from the group consisting of phenylalanine and glycine or a dipeptide consisting of them. In an even more specific embodiment of the present invention, the compound of the present invention contains a dipeptide containing a phenylalanine residue. In an even more specific embodiment of the present invention, the compound of the present invention contains a dipeptide containing a glycine residue. In a specific embodiment of the present invention, the dipeptide consists of phenylalanine and glycine residues.

[0089] In another specific embodiment of the present invention, the compound of the present invention contains or consists of a dipeptide containing at least two amino acid residues selected from the group consisting of phenylalanine, valine, leucine, isoleucine, glycine and alanine.

[0090] In a specific embodiment of the present invention, the dipeptide consists of two alanine residues, or two phenylalanine residues, or two leucine residues, or two isoleucine residues, or two valine residues.

[0091] In one embodiment of the present invention, the compound of the present invention comprises or consists of a tripeptide containing one or more amino acids selected from the group consisting of phenylalanine, valine, leucine, isoleucine, glycine and alanine, and the L-form of the amino acids in this group is preferred. In a specific embodiment of the present invention, the compound of the present invention comprises or consists of a tripeptide containing one or more amino acids or amino acid residues selected from the group consisting of phenylalanine and glycine.

[0092] In another specific embodiment, the compound of the present invention comprises or consists of a tripeptide containing at least two amino acid residues selected from the group consisting of phenylalanine, valine, leucine, isoleucine, glycine and alanine.

[0093] In another specific embodiment, the compound of the present invention comprises or consists of a tripeptide containing at least three amino acid residues selected from the group consisting of phenylalanine, valine, leucine, isoleucine, glycine and alanine.

[0094] In a specific embodiment of the present invention, the tripeptide consists of three alanine residues, or three phenylalanine residues, or three leucine residues, or three isoleucine residues, or three valine residues.

[0095] Thus, in a more specific embodiment, the tripeptide comprises or consists of the amino acid residues of phenylalanine, glycine and alanine.

[0096] In another more specific embodiment, the tripeptide comprises or consists of the amino acid residues of phenylalanine, glycine and isoleucine.

[0097] In another more specific embodiment, the tripeptide comprises or consists of the amino acid residues of phenylalanine, glycine and leucine.

[0098] In another more specific embodiment, the tripeptide comprises or consists of amino acid residues of phenylalanine, glycine and valine.

[0099] In another more specific embodiment, the tripeptide comprises or consists of amino acid residues of phenylalanine, alanine and isoleucine.

[0100] In another more specific embodiment, the tripeptide comprises or consists of amino acid residues of phenylalanine, alanine and leucine.

[0101] In another more specific embodiment, the tripeptide comprises or consists of amino acid residues of phenylalanine, alanine and valine.

[0102] In another more specific embodiment, the tripeptide comprises or consists of amino acid residues of phenylalanine, isoleucine and leucine.

[0103] In another more specific embodiment, the tripeptide comprises or consists of amino acid residues of phenylalanine, isoleucine and valine.

[0104] In another more specific embodiment, the tripeptide comprises or consists of amino acid residues of phenylalanine, leucine and valine.

[0105] In another more specific embodiment, the tripeptide comprises or consists of amino acid residues of phenylalanine, leucine and valine.

[0106] In another more specific embodiment, the tripeptide comprises or consists of amino acid residues of glycine, alanine and isoleucine.

[0107] In another more specific embodiment, the tripeptide comprises or consists of amino acid residues of glycine, alanine and leucine.

[0108] In another more specific embodiment, the tripeptide comprises or consists of amino acid residues of glycine, alanine and valine.

[0109] In another more specific embodiment, the tripeptide comprises or consists of amino acid residues of glycine, isoleucine and leucine.

[0110] In another more specific embodiment, the tripeptide comprises or consists of amino acid residues of glycine, isoleucine and valine.

[0111] In another more specific embodiment, the tripeptide comprises or consists of amino acid residues of glycine, leucine and valine.

[0112] In another more specific embodiment, the tripeptide comprises or consists of amino acid residues of isoleucine, leucine and valine.

[0113] As described above, peptide transporters such as hPEPT1 can transport dipeptides. In certain embodiments, the compounds of the present invention comprise a dipeptide comprising or consisting of at least two amino acid residues selected from the group consisting of phenylalanine, valine, leucine, isoleucine, glycine and alanine.

[0114] In another specific embodiment, the compounds of the present invention comprise a dipeptide consisting of two amino acid residues selected from the group consisting of phenylalanine, valine, leucine, isoleucine, glycine and alanine.

[0115] In certain embodiments of the present invention, the dipeptide consists of two alanine residues, or two phenylalanine residues, or two leucine residues, or two isoleucine residues, or two valine residues.

[0116] In certain embodiments, the compounds of the invention include dipeptides containing phenylalanine residues.

[0117] In another specific embodiment, the compounds of the invention include dipeptides containing glycine residues.

[0118] Thus, in more specific embodiments of the invention, the peptide comprises or consists of amino acid residues of phenylalanine and alanine.

[0119] In another more specific embodiment of the invention, the peptide consists of amino acid residues of phenylalanine and glycine.

[0120] In another more specific embodiment of the invention, the peptide comprises or consists of amino acid residues of phenylalanine and isoleucine.

[0121] In another more specific embodiment of the invention, the peptide comprises or consists of amino acid residues of phenylalanine and leucine.

[0122] In another more specific embodiment of the invention, the peptide comprises or consists of amino acid residues of phenylalanine and valine.

[0123] In another more specific embodiment of the invention, the peptide comprises or consists of amino acid residues of alanine and glycine.

[0124] In another more specific embodiment of the invention, the peptide comprises or consists of amino acid residues of alanine and isoleucine.

[0125] In another more specific embodiment of the invention, the peptide comprises or consists of amino acid residues of alanine and leucine.

[0126] In another more specific embodiment of the present invention, the peptide comprises or consists of amino acid residues of alanine and valine.

[0127] In another more specific embodiment of the present invention, the peptide comprises or consists of amino acid residues of glycine and isoleucine.

[0128] In another more specific embodiment of the present invention, the peptide comprises or consists of amino acid residues of glycine and leucine.

[0129] In another more specific embodiment of the present invention, the peptide comprises or consists of amino acid residues of glycine and valine.

[0130] In another more specific embodiment of the present invention, the peptide comprises or consists of amino acid residues of isoleucine and leucine.

[0131] In another more specific embodiment of the present invention, the peptide comprises or consists of amino acid residues of isoleucine and valine.

[0132] In another more specific embodiment of the present invention, the peptide comprises or consists of amino acid residues of leucine and valine.

[0133] In a specific embodiment of the present invention, one or more of R1, R2, R3, and R4 are amino acids, amino acid residues, or amino acids, amino acid derivatives, or peptides linked via the Cα atom of a peptide.

[0134] In a specific embodiment of the present invention, one or more of R1, R2, R3, and R4 are amino acids, amino acid residues, or peptides linked via the Cα atom of a glycine residue.

[0135] In a preferred embodiment of the present invention, one or more of R1, R2, R3 and R4 are amino acids, amino acid residues or amino acids, amino acid derivatives or peptides linked via the carboxyl group of a peptide.

[0136] In a preferred embodiment of the present invention, one or more of R1, R2, R3 and R4 are amino acids or amino acid derivatives linked via the backbone carboxyl group of an amino acid or amino acid residue.

[0137] In another embodiment of the present invention, one or more of R1, R2, R3 and R4 are phenylalanine or derivatives thereof linked via the benzyl group of the side chain of an amino acid or amino acid residue.

[0138] In another embodiment of the present invention, one or more of R1, R2, R3 and R4 are phenylalanine or residues thereof linked via the benzyl group of the side chain of an amino acid or amino acid residue.

[0139] In a preferred embodiment of the present invention, one or more of R1, R2, R3 and R4 are peptides linked via the carboxyl group at the C-terminus of the peptide backbone.

[0140] In a preferred embodiment of the present invention, one or more of R1, R2, R3 and R4 are dipeptides linked via the carboxyl group at the C-terminus of the peptide backbone.

[0141] In a preferred embodiment of the present invention, one or more of R1, R2, R3 and R4 are tripeptides linked via the carboxyl group at the C-terminus of the peptide backbone.

[0142] The compounds of the present invention are useful in the treatment of neurodegenerative diseases and disorders such as Parkinson's disease and / or other conditions where treatment with a dopamine agonist is therapeutically beneficial. Compounds suitable for oral administration have the potential to provide a new therapeutic paradigm in Parkinson's disease.

[0143] In one embodiment of the present invention, the compound is used as a stand-alone treatment for neurodegenerative diseases or disorders. In other embodiments of the present invention, the compound is used in combination with other agents for the treatment of PD, such as MAO-B inhibitors such as L-DOPA, droxidopa, foligrax, selegiline or rasagiline, COMT inhibitors such as entacapone or tolcapone, adenosine 2a antagonists such as istradefylline, antiglutamate 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 brexpiprazole, or in combination with antibody-targeted α-synuclein, Tau or A-β protein.

[0144] Embodiments of the present invention In the following, some specific embodiments of the present invention are disclosed. The first embodiment is represented by E1, the second embodiment is represented by E2, and so on.

[0145] E1. A compound of formula (Id)

Chemical formula

[0146] E2. A compound according to embodiment E1 or a pharmaceutically acceptable salt thereof, wherein R1 = R3 and R2 = R4.

[0147] E3. R1 and R3 are both H, and R2 and R4 are the same C 1~6 alkyl; or R1 and R3 are the same C 1~6A compound according to any of embodiments E1 - E2 or a pharmaceutically acceptable salt thereof, wherein R1 and R3 are alkyl and R2 and R4 are both H.

[0148] E4. R1 and R3 are the same C 1~6 alkyl; and R2 and R4 are the same C 1~6 alkyl, a compound according to any of embodiments E1 - E2 or a pharmaceutically acceptable salt thereof.

[0149] E5. A compound according to any of embodiments E1 - E2 or a pharmaceutically acceptable salt thereof, wherein R1 and R3 are both H and R2 and R4 are both methyl or both ethyl; or R1 and R3 are both methyl or both ethyl and R2 and R4 are both H.

[0150] E6. A compound according to any of embodiments E1 - E2 or a pharmaceutically acceptable salt thereof, wherein R1 and R3 are both ethyl or both methyl; and R2 and R4 are both ethyl or both methyl.

[0151] E7. A compound according to embodiment E1 or a pharmaceutically acceptable salt of any of these compounds, selected from the group consisting of compound (1): (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diylbis(methylcarbamate), compound (2): (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diylbis(ethylcarbamate); and compound (3): (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diylbis(dimethylcarbamate). A compound according to embodiment E1 or a pharmaceutically acceptable salt of any of these compounds, selected from the group consisting of

[0152] A compound which is a prodrug of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol (Compound (I)), wherein when the prodrug is orally administered to Wistar rats at a dose corresponding to 287 μg / kg of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol, the prodrug has a PK profile in which the C max of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol is 25 to 200 pg / mL, for example 50 to 150 pg / mL, for example 50 to 100 pg / mL. The compound or a pharmaceutically acceptable salt of the compound.

[0153] A compound which is a prodrug of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol (Compound (I)), wherein when the prodrug is orally administered to Wistar rats at a dose corresponding to 287 μg / kg of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol, the prodrug has an AUC 0-24 of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol that exceeds 1000 pg*h / mL. The compound or a pharmaceutically acceptable salt thereof according to Embodiment E8.

[0154] The compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments E8 to E9, wherein the PK profile is obtained by the PK experiment described in Example 3 of this specification.

[0155] The compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments E1 to E10 for use in therapy.

[0156] A compound according to any of embodiments E1 to E10 or a pharmaceutically acceptable salt thereof for use as a medicament.

[0157] E13. A compound or pharmaceutically acceptable salt for use as a medicament according to embodiment E12, wherein the medicament is an oral medicament such as a tablet or capsule for oral administration.

[0158] E14. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any of embodiments E1 to E10 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0159] E15. A pharmaceutical composition according to embodiment E14, which is for oral administration.

[0160] E16. A pharmaceutical composition according to any of embodiments E14 to E15, which is an oral pharmaceutical composition.

[0161] E17. A pharmaceutical composition according to any of embodiments E14 to E16, which is a solid oral dosage form.

[0162] E18. A pharmaceutical composition according to any of embodiments E14 to E17, which is a tablet or capsule for oral administration.

[0163] E19. A pharmaceutical composition according to any of embodiments E14 to E18, further comprising another medicament useful in the treatment of neurodegenerative diseases or disorders such as Parkinson's disease.

[0164] A pharmaceutical composition according to any of embodiments E14 to E19, further comprising a compound selected from the group consisting of MAO-B inhibitors such as E20.L-DOPA, droxidopa, foligrax, selegiline or rasagiline, COMT inhibitors such as entacapone or tolcapone, adenosine 2a antagonists such as istradefylline, antiglutamate 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 brexpiprazole, or antibody-targeted α-synuclein, Tau or A-β protein.

[0165] E21. A compound according to any of embodiments E1 to E10 or a pharmaceutically acceptable salt thereof for use in the treatment of neurodegenerative diseases or disorders such as Parkinson's disease, Huntington's disease, restless legs syndrome or Alzheimer's disease; or for use in the treatment of neuropsychiatric diseases or disorders such as schizophrenia, attention deficit hyperactivity disorder or dimethyl.

[0166] E22. A compound according to any of embodiments E1 to E10 or a pharmaceutically acceptable salt thereof for use in the treatment according to embodiment E21, wherein the neurodegenerative disease or disorder is Parkinson's disease.

[0167] E23. A compound according to any of embodiments E1 to E10 or a pharmaceutically acceptable salt thereof for use in the treatment according to any of embodiments E21 to E22, wherein the compound is used in combination with other agents useful in the treatment of neurodegenerative diseases or disorders such as Parkinson's disease.

[0168] For use in the treatment according to any of Embodiments E21 to E23, wherein the compound is an MAO-B inhibitor such as L-DOPA, droxidopa, foligrasp, selegiline or rasagiline, a COMT inhibitor such as entacapone or tolcapone, an adenosine 2a antagonist such as istradefylline, an antiglutamate agent such as amantadine or memantine, an acetylcholinesterase inhibitor such as rivastigmine, donepezil or galantamine, and an antipsychotic drug such as quetiapine, clozapine, risperidone, pimavanserin, olanzapine, haloperidol, aripiprazole or brexpiprazole, used in combination with a compound selected from the group consisting of or in combination with an antibody-targeted α-synuclein, Tau or A-β protein, a compound according to any of Embodiments E1 to E10 or a pharmaceutically acceptable salt thereof.

[0169] E25. For use in the treatment according to any of Embodiments E21 to E24, wherein the treatment is carried out by oral administration of the compound, a compound according to any of Embodiments E1 to E10 or a pharmaceutically acceptable salt thereof.

[0170] E26. For use in the treatment according to any of Embodiments E21 to E25, wherein the compound is contained in an oral pharmaceutical composition such as tablets or capsules for oral administration, a compound according to any of Embodiments E1 to E10 or a pharmaceutically acceptable salt thereof.

[0171] E27. A method for the treatment of neurodegenerative diseases or disorders such as Parkinson's disease, Huntington's disease, restless legs syndrome or Alzheimer's disease or mental and neurological diseases or disorders such as schizophrenia, attention deficit hyperactivity disorder or drug addiction, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any of Embodiments E1 to E10 or a pharmaceutically acceptable salt thereof.

[0172] E28. The method according to Embodiment E27, wherein the neurodegenerative disease or disorder is Parkinson's disease.

[0173] The compound according to any one of Embodiments E1 to E10 or a pharmaceutically acceptable salt thereof is used in combination with other agents useful in the treatment of neurodegenerative diseases or disorders such as Parkinson's disease, by the method according to any one of Embodiments E27 to E28.

[0174] E30. The compound according to any one of Embodiments E1 to E10 or a pharmaceutically acceptable salt thereof is used in combination with a compound selected from the group consisting of MAO-B inhibitors such as L-DOPA, droxidopa, foligrasp, selegiline or rasagiline, COMT inhibitors such as entacapone or tolcapone, adenosine 2a antagonists such as istradefylline, antiglutamate 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 brexpiprazole, or in combination with antibody-targeted α-synuclein, Tau or A-β protein, by the method according to any one of Embodiments E27 to E29.

[0175] E31. The administration is carried out by the oral route, by the method according to any one of Embodiments E27 to E30.

[0176] E32. The compound according to any one of Embodiments E1 to E10 or a pharmaceutically acceptable salt thereof is included in an oral pharmaceutical composition such as tablets or capsules for oral administration, by the method according to any one of Embodiments E27 to E31.

[0177] E33. Use of a compound according to any one of Embodiments E1 to E10 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of neurodegenerative diseases or disorders such as Parkinson's disease, Huntington's disease, restless legs syndrome or Alzheimer's disease; or for the treatment of neuropsychiatric diseases or disorders such as schizophrenia, attention deficit hyperactivity disorder or drug addiction.

[0178] Use according to embodiment E33, wherein the neurodegenerative disease or disorder is Parkinson's disease.

[0179] Use according to any one of embodiments E33 - E34, wherein the agent is used in combination with other agents useful in the treatment of neurodegenerative diseases or disorders such as Parkinson's disease.

[0180] Use according to any one of embodiments E33 - E35, wherein the agent is used in combination with a compound selected from the group consisting of L - DOPA, droxidopa, foligraspax, MAO - B inhibitors such as selegiline or rasagiline, COMT inhibitors such as entacapone or tolcapone, adenosine 2a antagonists such as istradefylline, antiglutamate 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 brexpiprazole, or in combination with antibody - targeted α - synuclein, Tau or A - β protein.

[0181] Use according to any one of embodiments E33 - E36, wherein the agent is an oral medicament such as a tablet or capsule for oral administration.

[0182] Further embodiments of the present invention The following sections further illustrate embodiments and aspects of the present invention. The first embodiment is represented by EE1, the second embodiment is represented by EE2, and so on.

[0183] EE1. Formula (Ie) [Chemical formula] (wherein Y is H and the following formula (CONR1R2) [Chemical formula] selected from the carbamoyl groups of X is H and the following formula (CONR3R4)

Chemical formula

[0184] EE2.Y is a carbamoyl group of the formula (CONR1R2), and X is H, a compound according to embodiment EE1 or a pharmaceutically acceptable salt.

[0185] EE3.Y is H, and X is a carbamoyl group of the formula (CONR3R4), a compound according to embodiment EE1 or a pharmaceutically acceptable salt.

[0186] EE4.Y is a carbamoyl group of the formula (CONR1R2), and X is a carbamoyl group of the formula (CONR3R4), a compound according to embodiment EE1 or a pharmaceutically acceptable salt.

[0187] EE5.At least one of R1, R2, R3 and R4 is an amino acid, an amino acid residue or a peptide, a compound according to any one of embodiments EE1 to EE4 or a pharmaceutically acceptable salt.

[0188] EE6.At least one of R1, R2, R3 and R4 is an amino acid, an amino acid residue or a peptide, and the amino acid, amino acid residue or peptide has an L configuration, a compound according to any one of embodiments EE1 to EE5 or a pharmaceutically acceptable salt.

[0189] At least one of R1, R2, R3, and R4 is an amino acid, amino acid residue, or peptide, and N is a compound according to any one of Embodiments EE1 to EE6 or a pharmaceutically acceptable salt thereof, which is bonded to the amino acid backbone atom of the amino acid, amino acid residue, or peptide.

[0190] At least one of R1, R2, R3, and R4 is an amino acid, amino acid residue, or peptide, and N is a compound according to any one of Embodiments EE1 to EE6 or a pharmaceutically acceptable salt thereof, which is bonded to the Cα atom of the amino acid, amino acid residue, or peptide.

[0191] At least one of R1, R2, R3, and R4 is an amino acid, amino acid residue, or peptide, and N is a compound according to any one of Embodiments EE1 to EE6 or a pharmaceutically acceptable salt thereof, which is bonded to the backbone carbonyl group of the amino acid, amino acid residue, or peptide.

[0192] At least one of R1, R2, R3, and R4 is an amino acid, amino acid residue, or peptide, and N is a compound according to any one of Embodiments EE1 to EE6 or a pharmaceutically acceptable salt thereof, which is bonded to the side chain atom of the amino acid, amino acid residue, or peptide.

[0193] At least one of R1, R2, R3, and R4 is an amino acid, amino acid residue, or peptide, and N is a compound according to any one of Embodiments EE1 to EE6 or a pharmaceutically acceptable salt thereof, which is bonded to the Cβ atom of the amino acid, amino acid residue, or peptide.

[0194] At least one of R1, R2, R3, and R4 is an amino acid, amino acid residue, or peptide, and N is a compound according to any one of Embodiments EE1 to EE6 or a pharmaceutically acceptable salt thereof, which is bonded to the Cγ side chain atom of the amino acid, amino acid residue, or peptide.

[0195] At least one of R1, R2, R3, and R4 is an amino acid, an amino acid residue, or a peptide, and N is a compound or a pharmaceutically acceptable salt according to any one of Embodiments EE1 to EE6, which is bonded to the Cδ side chain atom of the amino acid, amino acid residue, or peptide.

[0196] At least one of R1, R2, R3, and R4 is an amino acid, an amino acid residue, or a peptide, and N is a compound or a pharmaceutically acceptable salt according to any one of Embodiments EE1 to EE6, which is bonded to the Cε side chain atom of the amino acid, amino acid residue, or peptide.

[0197] At least one of R1, R2, R3, and R4 is an amino acid, an amino acid residue, or a peptide, and N is a compound or a pharmaceutically acceptable salt according to any one of Embodiments EE1 to EE6, which is bonded to the Cζ side chain atom of the amino acid, amino acid residue, or peptide.

[0198] At least one of R1, R2, R3, and R4 is an amino acid, an amino acid residue, or a peptide, and N is a compound or a pharmaceutically acceptable salt according to any one of Embodiments EE1 to EE6, which is bonded to the side chain oxygen atom of the amino acid, amino acid residue, or peptide.

[0199] At least one of R1, R2, R3, and R4 is an amino acid, an amino acid residue, or a peptide, and N is a compound or a pharmaceutically acceptable salt according to any one of Embodiments EE1 to EE6, which is bonded to the side chain nitrogen atom of the amino acid, amino acid residue, or peptide.

[0200] At least one of R1, R2, R3, and R4 is an amino acid, an amino acid residue, or a peptide, and N is a compound or a pharmaceutically acceptable salt according to any one of Embodiments EE1 to EE6, which is bonded to the side chain sulfur atom of the amino acid, amino acid residue, or peptide.

[0201] R1 and R3 are both methyl, and At least one of R2 and R4 is an amino acid, amino acid residue or peptide; or R2 and R4 are both H, and A compound or pharmaceutically acceptable salt according to any one of embodiments EE1 to EE18, wherein at least one of R1 and R3 is an amino acid, amino acid residue or peptide.

[0202] EE20.EE23.R1 and R3 are both methyl, and Only one of R2 and R4 is an amino acid, amino acid residue or peptide; or R2 and R4 are both H, and A compound or pharmaceutically acceptable salt according to any one of embodiments EE1 to EE18, wherein only one of R1 and R3 is an amino acid, amino acid residue or peptide.

[0203] EE21.R1 and R3 are both H, One of R2 and R4 is an amino acid, amino acid residue or peptide, and One of R2 and R4 is H; or R2 and R4 are both H, and One of R1 and R3 is an amino acid, amino acid residue or peptide, and One of R1 and R3 is H, a compound or pharmaceutically acceptable salt according to any one of embodiments EE1 to EE18.

[0204] EE22.R1, R2 and R3 are H, and R4 is an amino acid, amino acid residue or peptide, a compound or pharmaceutically acceptable salt according to any one of embodiments EE1 to EE21.

[0205] EE23.R1, R2 and R4 are H, and R3 is an amino acid, amino acid residue or peptide, a compound or pharmaceutically acceptable salt according to any one of embodiments EE1 to 21.

[0206] EE24. R1, R3, and R4 are H, and R2 is an amino acid, amino acid residue, or peptide, a compound according to any one of Embodiments EE1 to EE21, or a pharmaceutically acceptable salt.

[0207] EE25. R2, R3, and R4 are H, and R1 is an amino acid, amino acid residue, or peptide, a compound according to any one of Embodiments EE1 to EE21, or a pharmaceutically acceptable salt.

[0208] EE26. R1 is an amino acid residue, a compound according to any one of Embodiments EE1 to EE21, or a pharmaceutically acceptable salt.

[0209] EE27. R2 is an amino acid residue, a compound according to any one of Embodiments EE1 to EE26, or a pharmaceutically acceptable salt.

[0210] EE28. R3 is an amino acid residue, a compound according to any one of Embodiments EE1 to EE27, or a pharmaceutically acceptable salt.

[0211] EE29. R4 is an amino acid residue, a compound according to any one of Embodiments EE1 to EE28, or a pharmaceutically acceptable salt.

[0212] EE30. Both R1 and R3 are H, and at least one of R2 and R4 is an amino acid residue; or Both R2 and R4 are H, and at least one of R1 and R3 is an amino acid residue, a compound according to any one of Embodiments EE1 to EE21, or a pharmaceutically acceptable salt.

[0213] EE31. Both R1 and R3 are H, one of R2 and R4 is an amino acid residue, and one of R2 and R4 is H; or R2 and R4 are both H, one of R1 and R3 is an amino acid residue, and one of R1 and R3 is H. A compound or a pharmaceutically acceptable salt according to any one of embodiments EE1 to EE2, EE7 to EE21.

[0214] EE32. The amino acid is selected from the group consisting of arginine, lysine, aspartic acid, glutamic acid, glutamine, asparagine, histidine, serine, threonine, tyrosine, cysteine, tryptophan, methionine, alanine, isoleucine, leucine, phenylalanine, valine, proline, and glycine. A compound or a pharmaceutically acceptable salt according to any one of embodiments EE1 to EE31.

[0215] EE33. The amino acid residue is selected from the group consisting of amino acid residues of arginine, lysine, aspartic acid, glutamic acid, glutamine, asparagine, histidine, serine, threonine, tyrosine, cysteine, tryptophan, methionine, alanine, isoleucine, leucine, phenylalanine, valine, proline, and glycine. A compound or a pharmaceutically acceptable salt according to any one of embodiments EE1 to EE32.

[0216] EE34. The amino acid residue is selected from the group consisting of phenylalanine, valine, leucine, isoleucine, glycine, and alanine. A compound or a pharmaceutically acceptable salt according to any one of embodiments EE1 to EE33.

[0217] EE35. The amino acid residue is selected from the group consisting of phenylalanine and glycine. A compound or a pharmaceutically acceptable salt according to any one of embodiments EE1 to EE34.

[0218] EE36. Both R1 and R3 are H, and at least one of R2 and R4 is a peptide; or both R2 and R4 are H, and at least one of R1 and R3 is a peptide. A compound or a pharmaceutically acceptable salt according to any one of embodiments EE1 to EE25.

[0219] In EE37, both R1 and R3 are H, one of R2 and R4 is a peptide, and one of R2 and R4 is H; or R2 and R4 are both H, one of R1 and R3 is a peptide, and one of R1 and R3 is H, a compound or a pharmaceutically acceptable salt according to any one of Embodiments EE1 to EE25.

[0220] In EE38, R2, R3 and R4 are H, and R1 is a peptide, a compound or a pharmaceutically acceptable salt according to any one of Embodiments EE1 to EE25.

[0221] In EE39, R1, R3 and R4 are H, and R2 is a peptide, a compound or a pharmaceutically acceptable salt according to any one of Embodiments EE1 to EE25.

[0222] In EE40, R1, R2 and R4 are H, and R3 is a peptide, a compound or a pharmaceutically acceptable salt according to any one of Embodiments EE1 to EE25.

[0223] In EE41, R1, R2 and R3 are H, and R4 is a peptide, a compound or a pharmaceutically acceptable salt according to any one of Embodiments EE1 to EE25.

[0224] In EE42, the peptide is a dipeptide, a tripeptide or a derivative of a dipeptide or a tripeptide, a compound or a pharmaceutically acceptable salt according to any one of Embodiments EE1 to EE25 and EE36 to EE41.

[0225] EE43. The peptide is a compound or a pharmaceutically acceptable salt according to any one of Embodiments EE1 to EE25 and EE36 to EE42, comprising two or more amino acid residues selected from the group consisting of arginine, lysine, aspartic acid, glutamic acid, glutamine, asparagine, histidine, serine, threonine, tyrosine, cysteine, tryptophan, methionine, alanine, isoleucine, leucine, phenylalanine, valine, proline, and glycine residues.

[0226] EE44. The peptide is a compound or a pharmaceutically acceptable salt according to any one of Embodiments EE1 to EE25 and EE36 to EE43, comprising or consisting of two or more amino acids selected from the group consisting of phenylalanine, valine, leucine, isoleucine, glycine, and alanine.

[0227] EE45. The peptide is a compound or a pharmaceutically acceptable salt according to any one of Embodiments EE1 to EE25 and EE36 to EE44, comprising or consisting of two or more L - amino acids.

[0228] EE46. The peptide is a dipeptide, which is a compound or a pharmaceutically acceptable salt according to any one of Embodiments EE1 to EE25 and EE36 to EE45.

[0229] EE47. The peptide is a tripeptide, which is a compound or a pharmaceutically acceptable salt according to any one of Embodiments EE1 to EE2 and EE36 to EE46.

[0230] EE48. The peptide is a compound or a pharmaceutically acceptable salt according to any one of Embodiments EE1 to EE25 and EE36 to EE47, comprising one or more amino acid residues selected from the group consisting of phenylalanine and glycine.

[0231] The compound or pharmaceutically acceptable salt according to any one of Embodiments EE1 to EE25 and EE36 to EE48, wherein the peptide is a dipeptide containing one or more amino acid residues selected from the group consisting of phenylalanine and glycine.

[0232] The compound or pharmaceutically acceptable salt according to any one of Embodiments EE1 to EE35, wherein one of R1, R2, R3 and R4 is a glycine residue.

[0233] The compound or pharmaceutically acceptable salt according to any one of Embodiments EE1 to EE35 and EE50, wherein one of R1, R2, R3 and R4 is a glycine residue and three of R1, R2, R3 and R4 are H.

[0234] The compound or pharmaceutically acceptable salt according to any one of Embodiments EE1 to EE35 and EE50 to EE51, wherein one of R1, R2, R3 and R4 is CH2COOH.

[0235] The compound or pharmaceutically acceptable salt according to any one of Embodiments EE1 to EE35 and EE50 to EE52, wherein one of R1, R2, R3 and R4 is CH2COOH and three of R1, R2, R3 and R4 are H.

[0236] The compound or pharmaceutically acceptable salt according to any one of Embodiments EE1 to EE35, EE50 and EE52, wherein one of R1, R2, R3 and R4 is a phenylalanine residue.

[0237] The compound or pharmaceutically acceptable salt according to any one of Embodiments EE1 to EE35 and EE54, wherein one of R1, R2, R3 and R4 is a phenylalanine residue and three of R1, R2, R3 and R4 are H.

[0238] EE56. R1 is H and R2 is C 1~6 alkyl; or R1 is C1~6 A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments EE1, EE2 and EE4, wherein R1 is alkyl and R2 is H.

[0239] EE57. R1 and R2 are the same C 1~6 A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments EE1, EE2 and EE4, wherein R1 and R2 are alkyl.

[0240] EE58. R1 is H and R2 is methyl or ethyl; or R1 is methyl or ethyl and R2 is H, a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments EE1, EE2 and EE4.

[0241] EE59. R1 and R2 are independently selected from methyl and ethyl, a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments EE1, EE2 and EE4.

[0242] EE60. R1 and R2 are both methyl, a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments EE1, EE2 and EE4.

[0243] EE61. R1 and R2 are both ethyl, a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments EE1, EE2 and EE4.

[0244] EE62. R3 is H, R4 is, and C 1~6 alkyl; or R3 is C 1~6 alkyl and R4 is H, a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments EE1, EE3 and EE4.

[0245] EE63. R3 and R4 are the same C 1~6 alkyl, a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments EE1, EE3 and EE4.

[0246] EE64. R3 is H, and R4 is methyl or ethyl; or a compound or pharmaceutically acceptable salt thereof according to any one of embodiments EE1, EE3 and EE4, wherein R3 is methyl or ethyl, and R4 is H.

[0247] EE65. A compound or pharmaceutically acceptable salt thereof according to any one of embodiments EE1, EE3 and EE4, wherein R3 and R4 are independently selected from methyl and ethyl.

[0248] EE66. A compound or pharmaceutically acceptable salt thereof according to any one of embodiments EE1, EE3 and EE4, wherein both R3 and R4 are methyl.

[0249] EE67. A compound or pharmaceutically acceptable salt thereof according to any one of embodiments EE1, EE3 and EE4, wherein both R3 and R4 are ethyl.

[0250] EE68. The compound is of the following formula (Id)

Chemical formula

[0251] EE69. A compound or pharmaceutically acceptable salt thereof according to embodiment EE68, wherein R1, R2, R3 and R4 are each independently selected from the group consisting of H, straight-chain C 1~6 alkyl, amino acids, amino acid residues and peptides.

[0252] EE70. A compound or pharmaceutically acceptable salt thereof according to embodiments EE68 - EE69, wherein R1 = R3 and R2 = R4.

[0253] EE71. Both R1 and R3 are H, and R2 and R4 are both C 1~6 alkyl; or R1 and R3 are the same C 1~6 alkyl, and R2 and R4 are both H, a compound according to embodiments EE68 - EE70 or a pharmaceutically acceptable salt thereof.

[0254] EE72. R1 and R3 are the same C 1~6 alkyl; and R2 and R4 are the same C 1~6 alkyl, a compound according to embodiments EE68 - EE71 or a pharmaceutically acceptable salt thereof.

[0255] EE73. R1 and R3 are the same straight - chain C 1~6 alkyl; and R2 and R4 are the same straight - chain C 1~6 alkyl, a compound according to embodiments EE68 - EE72 or a pharmaceutically acceptable salt thereof.

[0256] EE74. Both R1 and R3 are H, and R2 and R4 are both methyl or both ethyl; or R1 and R3 are both methyl or both ethyl, and R2 and R4 are both H, a compound according to embodiments EE68 - EE71 or a pharmaceutically acceptable salt thereof.

[0257] EE75. Both R1 and R3 are ethyl or both methyl, and R2 and R4 are both ethyl or both methyl, a compound according to embodiments EE68 - EE73 or a pharmaceutically acceptable salt thereof.

[0258] EE76. Compound (1): (4aR,10aR) - 1 - propyl - 1,2,3,4,4a,5,10,10a - octahydrobenzo[g]quinoline - 6,7 - diylbis(methylcarbamate), Compound (2): (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diyl bis(ethylcarbamate); and Compound (3): (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diyl bis(dimethylcarbamate); Compound (4): ((((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)carbonyl)glycine; Compound (5): ((((4aR,10aR)-6-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl)oxy)carbonyl)glycine; Compound (6): (S)-2-amino-3-(3-(((((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)carbonyl)amino)phenyl)propanoic acid A compound according to Embodiment EE1 selected from the group consisting of and pharmaceutically acceptable salts of any of these compounds.

[0259] EE77. Compound (1): (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diyl bis(methylcarbamate), Compound (2): (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diyl bis(ethylcarbamate); and Compound (3): (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diyl bis(dimethylcarbamate) A compound according to Embodiment EE1 selected from the group consisting of and pharmaceutically acceptable salts of any of these compounds.

[0260] A compound according to any one of embodiments EE1 to EE77 or a pharmaceutically acceptable salt thereof for use in therapy.

[0261] A compound according to any one of embodiments EE1 to EE77 or a pharmaceutically acceptable salt thereof for use as a medicament.

[0262] A compound or pharmaceutically acceptable salt for use as a medicament according to EE79, wherein the medicament is an oral medicament such as a tablet or capsule for oral administration.

[0263] A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of embodiments EE1 to EE77 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0264] A pharmaceutical composition according to embodiment EE81, which is for oral administration.

[0265] A pharmaceutical composition according to any one of embodiments EE81 to EE82, which is an oral pharmaceutical composition.

[0266] A pharmaceutical composition according to any one of embodiments EE81 to EE83, which is a solid oral dosage form.

[0267] A pharmaceutical composition according to any one of embodiments EE81 to EE84, which is a tablet or capsule for oral administration.

[0268] A pharmaceutical composition according to any one of embodiments EE81 to EE85, further comprising another medicament useful in the treatment of neurodegenerative diseases or disorders such as Parkinson's disease.

[0269] A pharmaceutical composition according to any one of embodiments EE81 to EE86, further comprising a compound selected from the group consisting of MAO-B inhibitors such as EE87.L-DOPA, droxidopa, foligrax, selegiline or rasagiline, COMT inhibitors such as entacapone or tolcapone, adenosine 2a antagonists such as istradefylline, antiglutamate 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 brexpiprazole, or an antibody targeting α-synuclein, Tau or A-β protein.

[0270] EE88. A compound according to any one of embodiments EE1 to EE77 or a pharmaceutically acceptable salt thereof for use in the treatment of neurodegenerative diseases or disorders such as Parkinson's disease, Huntington's disease, restless legs syndrome or Alzheimer's disease, or for use in the treatment of neuropsychiatric diseases or disorders such as schizophrenia, attention deficit hyperactivity disorder or drug addiction.

[0271] EE89. A compound according to any one of embodiments EE1 to EE77 or a pharmaceutically acceptable salt thereof for use in the treatment according to embodiment EE88, wherein the neurodegenerative disease or disorder is Parkinson's disease.

[0272] EE90. A compound according to any one of embodiments EE1 to EE77 or a pharmaceutically acceptable salt thereof for use in the treatment according to any one of embodiments EE88 to EE89, wherein the compound is used in combination with other agents useful in the treatment of neurodegenerative diseases or disorders such as Parkinson's disease.

[0273] It is for use in the treatment according to any one of Embodiments EE88 to EE90, and the compound is an MAO-B inhibitor such as L-DOPA, droxidopa, foligrasp, selegiline or rasagiline, a COMT inhibitor such as entacapone or tolcapone, an adenosine 2a antagonist such as istradefylline, an antiglutamate agent such as amantadine or memantine, an acetylcholinesterase inhibitor such as rivastigmine, donepezil or galantamine, and an antipsychotic such as quetiapine, clozapine, risperidone, pimavanserin, olanzapine, haloperidol, aripiprazole or brexpiprazole. The compound according to any one of Embodiments EE1 to EE77 or a pharmaceutically acceptable salt thereof, used in combination with a compound selected from the group consisting of or in combination with an antibody-targeted α-synuclein, Tau or A-β protein.

[0274] EE92. It is for use in the treatment according to any one of Embodiments EE88 to EE90, and the treatment is carried out by oral administration of the compound. The compound according to any one of Embodiments EE1 to EE77 or a pharmaceutically acceptable salt thereof.

[0275] EE93. It is for use in the treatment according to any one of Embodiments EE88 to EE92, and the compound is contained in a pharmaceutical composition such as a tablet or capsule for oral administration. The compound according to any one of Embodiments EE1 to EE77 or a pharmaceutically acceptable salt thereof.

[0276] EE94. A method for the treatment of neurodegenerative diseases or disorders such as Parkinson's disease, Huntington's disease, restless legs syndrome or Alzheimer's disease or mental and neurological diseases or disorders such as schizophrenia, attention deficit hyperactivity disorder or drug addiction, comprising administering to a patient in need thereof a therapeutically effective amount of the compound according to any one of Examples EE1 to EE77 or a pharmaceutically acceptable salt thereof.

[0277] The method according to embodiment EE94, wherein the neurodegenerative disease or disorder is Parkinson's disease.

[0278] The method according to any one of embodiments EE94 - EE95, wherein the compound or a pharmaceutically acceptable salt thereof according to any one of embodiments EE1 - EE77 is used in combination with other agents useful in the treatment of neurodegenerative diseases or disorders such as Parkinson's disease.

[0279] The use according to any one of embodiments EE94 - EE96, wherein the compound or a pharmaceutically acceptable salt thereof according to any one of embodiments EE1 - EE77 is used in combination with a compound selected from the group consisting of L - DOPA, droxidopa, foligrasp, MAO - B inhibitors such as selegiline or rasagiline, COMT inhibitors such as entacapone or tolcapone, adenosine 2a antagonists such as istradefylline, antiglutamate 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 brexpiprazole, or in combination with antibody - targeted α - synuclein, Tau or A - β protein.

[0280] The method according to any one of embodiments EE94 - EE97, wherein the administration is by the oral route.

[0281] The method according to any one of embodiments EE94 - EE98, wherein the compound or a pharmaceutically acceptable salt thereof according to any one of embodiments EE1 - EE77 is included in an oral pharmaceutical composition such as tablets or capsules for oral administration.

[0282] Use of a compound according to any one of Embodiments EE1 to EE77 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of neurodegenerative diseases or disorders such as Parkinson's disease, Huntington's disease, restless legs syndrome or Alzheimer's disease; or for the treatment of neuropsychiatric diseases or disorders such as schizophrenia, attention deficit hyperactivity disorder or drug addiction.

[0283] EE101. Use according to Embodiment EE100, wherein the neurodegenerative disease or disorder is Parkinson's disease.

[0284] EE102. Use according to any one of Embodiments EE100 to EE101, wherein the medicament is used in combination with other medicaments useful in the treatment of neurodegenerative diseases or disorders such as Parkinson's disease.

[0285] EE103. Use according to any one of Embodiments EE100 to EE102, wherein the medicament is used in combination with a compound selected from the group consisting of L-DOPA, droxidopa, foligrasalax, MAO-B inhibitors such as selegiline or rasagiline, COMT inhibitors such as entacapone or tolcapone, adenosine 2a antagonists such as istradefylline, antiglutamate 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 brexpiprazole; or in combination with antibody-targeted α-synuclein, Tau or A-β protein.

[0286] EE104. Use according to any one of Embodiments EE100 to EE103, wherein the medicament is an oral medicament such as a tablet or capsule for oral administration.

[0287] All references, including publications, patent applications, and patents, cited herein are incorporated by reference herein in their entirety and to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety (to the maximum extent permitted by law).

[0288] Headings and subheadings are used herein for convenience only and should never be construed as limiting the invention.

[0289] In any aspect of the invention or in the description of aspects of the invention herein, when referring to one or more elements using terms such as "comprising," "having," "including," or "containing," such description is intended to provide support for the same aspect of the invention or aspects of the invention that "consist of," "consist essentially of," or "substantially contain" such one or more particular elements, unless otherwise specified or there is an express contradiction in the context (e.g., a composition described herein as containing a particular element should be understood to also describe a composition consisting of that element, unless otherwise specified or there is an express contradiction in the context).

[0290] The use of any and all examples or exemplary terms (such as "for instance," "for example," "as an example," and "itself") in this specification is merely intended to make the invention clearer and is not intended to limit the scope of the invention unless otherwise specified.

[0291] It should be understood that the various aspects, embodiments, implementations, and features of the invention described herein may be claimed separately or in any combination.

[0292] The invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto, as permitted by applicable law.

[0293] The compounds of the invention

[0294] [Table 2]

[0295] Experimental Section Preparation of the Compounds of the Invention The compounds of formula (Id) are prepared by the methods described below, together with synthetic methods known in the field of organic chemistry or modified forms well known to those skilled in the art. The starting materials used herein are either commercially available or can be prepared by conventional methods known in the art, such as the methods described in standard reference books such as "Compendium of Organic Synthetic Methods, Vol. I-XII" (published by Wiley-Interscience). Preferred methods include, but are not limited to, the following methods.

[0296] The schemes represent methods useful for the synthesis of the compounds of the invention. They are not intended to limit the scope of the invention in any way.

[0297] List of Compound Abbreviations BF3-OEt2: Boron Trifluoride Diethyl Etherate BnBr: Benzyl Bromide BnCl: Benzyl Chloride DCM: Dichloromethane DMF: Dimethylformamide ee: Enantiomeric Excess EtOAc: Ethyl Acetate MeCN: Acetonitrile MeOH: Methanol MeI: Methyl Iodide MOM-Cl: Chloromethyl Methyl Ether Pd / C: Palladium on Carbon Pyridine-HF: Pyridine Hydrogen Fluoride TBAF: Tetrabutylammonium Fluoride TFA: Trifluoroacetic Acid TMS-I: Trimethylsilyl Iodide

[0298] LC-MS method Analytical LC-MS data were acquired using the methods specified below, unless otherwise detailed in the following experimental protocol.

[0299] Method 550: LC-MS was performed 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 with an APPI source operating in positive ion mode. LC conditions: The column was an Acquity UPLC BEH C18 1.7 μm; 2.1×50 mm, operating at 60 °C using a binary gradient of water + 0.05% trifluoroacetic acid (A) and acetonitrile / water (95:5) + 0.05% trifluoroacetic acid at 1.2 ml / min. Gradient: 0.00 min 10% B 1.00 min 100% B 1.01 min 10% B 1.15 min 10% B Total run time: 1.15 min

[0300] Method 10-90AB (Shimadzu LC-20AD&MS 2010): Method name: 10-90AB Equipment: Shimadzu LC-20AD&MS 2020 MS mode: Positive MS range: 100 - 1000 CDL temperature 250 °C Heat block temperature 28 °C Spray gas flow rate 1.5 L / min

[0301] LC conditions: The column was Luna-C18(2) 2.0*30 mm (3 μm particles), operating at 40 °C using a gradient of water + 0.037% TFA (A) and MeCN + 0.018% TFA (B) at 0.8 mL / min (0.01 - 1.51 min) and 1.2 mL / min (1.52 - 2.00 min). Gradient: 0.01 min 10%B 0.01 - 1.15 min 10 - 90%B 1.15 - 1.65 min 90%B 1.65 - 1.66 min 90 - 10%B 1.66 - 2.00 min 10%B Total implementation time: 2.00 min

[0302] LC-MS method B: LC-MS was performed on an Agilent 1260 HPLC consisting of a column comp, binary pump, Hip sample and a single Q-MS equipped with an ESI source operating in positive ion mode.

[0303] LC conditions: Column: Inertsustain AQ-C18 HP 3.0μm; 3.0×50mm Operating at 35°C using a two-component gradient of water + 0.05% trifluoroacetic acid (A) and acetonitrile + 0.05% trifluoroacetic acid (B) at 1.2 ml / min. Gradient: 0.00 min 0%B 3.00 min 95%B 4.00 min 95%B Total implementation time: 4.0 min

[0304] General scheme for preparing compounds (1)-(3) of the present invention For example, (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol hydrochloride [Compound (I)], which can be produced as disclosed in WO 2009 / 026934 pamphlet, was used as a substrate for synthesizing compounds (1)-(3) of the present invention according to the following scheme.

Chemical formula

[0305] As described for (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diylbis(dimethylcarbamate), a prodrug having two identical carbamate groups can be prepared by treating compound (I) with a carbamoyl chloride such as N,N-dimethylcarbamoyl chloride in the presence of a base such as triethylamine or K2CO3. As described for (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diylbis(ethylcarbamate), compound (I) can be reacted with an isocyanate such as ethyl isocyanate and an appropriate base such as triethylamine or K2OC3.

Chemical formula

[0306] Prodrugs in which only one of the catechol hydroxyl groups is alkylated can be prepared by treating a compound such as (4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol (Compound A2) or (4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol (Compound A6) with either carbamoyl chloride or isocyanate in the presence or absence of a suitable base such as triethylamine, diethylisopropylamine or potassium carbonate. In these reactions, Compounds A2 and A6 can be used in the free form or as acid addition salts such as hydroiodide (A2-HI), hydrobromide, hydrochloride salt. The synthesis of the two precursors is described herein. The opposite positional isomers can be prepared in a similar manner from (4aR,10aR)-6-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-ol or (4aR,10aR)-6-benzyloxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-ol.

Chemical formula

[0307] When Compound (I) is treated with BnCl and a base such as triethylamine or K2CO3, 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 is obtained, and these positional isomers can be separated. When MeI is used instead of BnCl, the corresponding mixture of methyl ethers is obtained, which can be separated.

Chemical formula

[0308] (4aR,10aR)-7-(Benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol and a selective route to (4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol are provided herein.

[0309] (4aR,10aR)-6-Methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-ol can be prepared from (4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol by methylation followed by debenzylation or by use of a MOM-based protecting group strategy used in the synthesis of (4aR,10aR)-7-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol. [Chemical formula]

[0310] (4aR,10aR)-6-(Benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-ol alternative route can be obtained based on treating (4aR,10aR)-1-propyl-7-((triisopropylsilyl)oxy)-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol with benzyl 2,2,2-trichloroacetimidate in the presence of a suitable Lewis acid such as BF3-OEt2 and then cleaving the silyl protecting group with KOH, TBAF or pyridine-HF. [Chemical formula]

[0311] The intermediates of the present invention [Chemical formula] A1: (4aR,10aR)-6,7-bis(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline The hydrochloride (10.75 g) of compound (I) and K2CO3 (17.5 g) were placed in a one-necked 1 L round-bottom flask equipped with a magnetic stir bar. The flask was evacuated and refilled with nitrogen, and then dry DMF (107 mL) was introduced. Then, benzyl chloride (8.55 mL) was added, and the mixture was stirred at room temperature for 18 hours, then warmed to 100 °C for 5 hours, then cooled to room temperature, and further stirred for 19 hours. Then, K2CO3 (7.48 g) and benzyl chloride (6.29 mL) were further added, and the mixture was stirred at 100 °C for 5 hours. Next, the mixture was cooled to room temperature, and water (500 mL) and heptane (250 mL) were added. The aqueous phase was extracted with heptane (3 × 100 mL), the combined organic phases were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated to obtain the title compound (14.6 g).

[0312] A2-HI: (4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol hydrogen iodide A magnetic stir bar and (4aR,10aR)-6,7-bis(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline (11.9 g) were placed in a 1 L one-neck round-bottom flask. The flask was stoppered with a rubber stopper, evacuated, and refilled with nitrogen. MeCN (180 mL) was added, and the mixture was stirred until all starting materials were dissolved. TMS-I (10.0 mL) was added, and the mixture was stirred at room temperature for 2 h. Next, MeOH (5.5 mL) was added, and the mixture was stirred for 1 h. Then, isopropyl acetate / heptane (160 mL, 1:15 v / v) was added, the mixture was cooled (ice bath), and stirred for 60 min. The precipitate was filtered off and washed with isopropyl acetate / heptane (1×50 mL, 1:15 v / v). The solid was dried to give the title compound (7.6 g). LCMS (method 550), retention time = 0.55 min, [M+H] + = 352.5. [Chemical formula]

[0313] A3: (4aR,10aR)-7-(benzyloxy)-6-(methoxymethoxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline To a mixture of (4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol (20 g) in DMF (400 mL) was slowly added NaH (4.17 g, 60% dispersion) at 0 °C. The mixture was stirred at 0 °C for 30 min. Next, MOMCl (3.5 mL) was added dropwise at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water (400 mL) and stirred for 20 min. The aqueous phase was extracted with EtOAc (300 mL×3). The combined organic layers were washed with brine (500 mL), dried over sodium sulfate, filtered, and concentrated to give the title compound (20 g). LCMS (method 10-90AB), retention time = 0.90 min, [M+H] + = 396.3.

[0314] A4: (4aR,10aR)-6-(Methoxymethoxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-ol 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 10% Pd / C (30 g) under N2. The suspension was degassed and purged with H2. The mixture was stirred at 25 °C for 12 h under H2 (50 psi). The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to afford the title compound (15.4 g). LCMS (method 10 - 90AB), retention time = 0.65 min, [M + H] + = 306.1.

[0315] A5: (4aR,10aR)-7-Methoxy-6-(methoxymethoxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline 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 (TMSCH2N2; 2 M in hexane, 246 mL) dropwise over 0.5 h at 20 °C. The mixture was concentrated to afford the title compound (15 g).

[0316] A6: (4aR,10aR)-7-Methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol (4aR,10aR)-7-Methoxy-6-(methoxymethoxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline (15 g) in MeOH and 4 M HCl (150 mL) in MeOH were placed in a reactor (100 mL) at 20 °C. The reaction mixture was stirred at 20 °C for 1 h and then concentrated. The residue was dissolved in water (100 mL), and the aqueous layer was basified to pH 7 - 8 with solid NaHCO3. The aqueous layer was extracted with EtOAc (100 mL×1, 50 mL×1). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated to give the title compound (7 g).

[0317] Preparation of the exemplified compounds of the present invention from compound (I) Compound (1): (4aR,10aR)-1-Propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diylbis(methylcarbamate) [Chemical formula] (4aR,10aR)-1-Propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol hydrochloride (500 mg), ascorbic acid (30 mg) and 4-(dimethylamino)pyridine (11 mg) were weighed into a vial. DMF (5 mL) was added. The vial was evacuated and backfilled with nitrogen. Triethylamine (0.7 mL) and N,N-dimethylcarbamoyl chloride (0.39 mL) were added and the mixture was stirred at room temperature for 2 h. Then, more triethylamine (0.7 mL) and N,N-dimethylcarbamoyl chloride (0.6 mL) were added and the mixture was stirred at room temperature for 1 h. The mixture was purified by chromatography (EtOAc / heptane / triethylamine 20:19:1) to give the crude product. This material was dissolved in THF (20 mL) and cooled to 0 °C. To the thoroughly stirred mixture was added 0.1M HCl in THF dropwise until slightly acidic. A thick white precipitate gradually formed. The mixture was stirred on ice. The solid was collected and dried to give the title compound (233 mg) as the HCl salt. LCMS (Method 550_ESI): Retention time=0.42 min; UV purity 100%; ELS purity 100%; m / z=404.5[M+H] + .

[0318] Compound (2): (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diylbis(ethylcarbamate) [ka] (4aR,10aR)-1-Propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol hydrochloride (500 mg) and ascorbic acid (28 mg) were weighed into a vial and DMF (4.0 mL) was added. The vial was evacuated and backfilled with nitrogen. Triethylamine (1 mL) and ethyl isocyanate (0.35 mL) were added and the mixture was stirred at room temperature for 2 h. The mixture was poured into brine and extracted with EtOAc. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography (EtOAc / heptane / triethylamine 10:9:1) to give the crude product. This material was dissolved in EtOAc (20 mL) and cooled to 0 °C. To the thoroughly stirred mixture was added 0.2 M HCl in EtOAc dropwise until pH 3-4. A white precipitate formed which was collected and dried to give the title compound (239 mg) as the HCl salt. LCMS (Method 550): Retention time = 0.41 min; UV purity 100%; ELS purity 98%; m / z = 404.6 [M+H] + .

[0319] Compound (3): (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diylbis(dimethylcarbamate) [ka] (4aR,10aR)-1-Propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol hydrochloride (500 mg) and ascorbic acid (28 mg) were weighed into a vial and DMF (4.0 mL) was added. The vial was evacuated and backfilled with nitrogen. Triethylamine (1.0 mL) and methyl isocyanate (0.21 mL) were added and the mixture was stirred at room temperature for 2 h. The mixture was poured into brine and extracted with EtOAc. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography (EtOAc / heptane / triethylamine 14:5:1) to give the crude product. This material was dissolved in a hot mixture of THF (10 mL) and EtOAc (15 mL). Heptane (10 mL) was added and the mixture was concentrated to a volume of approximately 15 mL. The solution was cooled to 0° C. causing a solid to precipitate which was collected and dried to give the title compound (310 mg). LCMS (Method 550): Retention time = 0.32 min; UV purity 100%; ELS purity 100%; m / z = 376.53 [M+H] + .

[0320] Compound (4): ((((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]-quinolin-6-yl)oxy)carbonyl)glycine Compound (4) can be prepared, for example, from intermediate (4aR,10aR)-7-(benzyloxy)-1-propyl-2H,3H,4H,4aH,5H,10H,10aH-benzo[g]quinolin-6-ol hydroiodide (compound A2-HI) using the two-step process described below.

[0321] Preparation of benzyl ((((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)carbonyl) glycinate (compound A7) [ka] To a stirred solution of benzyl 2-aminoacetate hydrochloride (1.01 g, 5.0 mmol) and triphosgene (0.59 g, 2.0 mmol) in DCM (50 mL) was added Et3N (1.69 g, 16.7 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. To the above mixture was added ((4aR,10aR)-7-(benzyloxy)-1-propyl-2H,3H,4H,4aH,5H,10H,10aH-benzo[g]quinolin-6-ol hydrogen iodide (2.00 g, 4.2 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water / ice (50 mL). The aqueous layer was extracted with DCM (3 × 50 mL). The combined organic extracts were concentrated. The residue was purified by reverse-phase flash chromatography on a column, C18 silica gel; mobile phase, MeCN in water (0.05% TFA), 0% to 75% gradient in 30 min; detector, UV 220 nm to give the title compound (2.1 g) pure enough for the next step.

[0322] Preparation of (((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)carbonyl)glycine (Compound (4)) from Compound (A7) [Chemical formula] In a 250 mL round-bottom flask, to a solution of benzyl ((((4aR,10aR)-7-(benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)carbonyl)glycinate (2.10 g, 3.9 mmol) in MeOH (100 mL) was added Pd(OH)2 / C (10%, 0.4 g) under a nitrogen atmosphere. The mixture was hydrogenated at room temperature for 2 h under a hydrogen atmosphere using a hydrogen balloon, filtered through a Celite pad, and concentrated under reduced pressure. The residue was purified by triturating with EtOH (100 mL) to give the title compound (693 mg). LC / MS: Retention time: 1.35 minutes, UV purity: 95.5%; (ES, m / z): [M+H] + 363. Instrument: Shimadzu LCMS - 2020 equipped with Shim - Pack XR - ODS C18, column L = 50 mm, D = 3.0 mm, operated at 40 °C. Mobile phase A: 0.05% TFA in water; Mobile phase B: 0.05% TFA in acetonitrile. Flow rate 1.2 mL / min. Gradient: 0 - 3.2 minutes A:B 95:5; 3.2 minutes - 3.7 minutes: A:B 1:1; 3.7 minutes - 4.75 minutes: A:B 0:1; 4.75 minutes - 5.0 minutes: A:B 95:5.

[0323] Compound (5): ((((4aR,10aR)-6 - hydroxy - 1 - propyl - 1,2,3,4,4a,5,10,10a - octahydrobenzo[g] - quinolin - 7 - yl)oxy)carbonyl)glycine Compound (5) can be prepared, for example, from the intermediate (4aR,10aR)-7 - (benzyloxy)-1 - propyl - 2H,3H,4H,4aH,5H,10H,10aH - benzo[g]quinolin - 6 - ol hydrogen iodide compound (A2 - HI) using the 4 - step process described below.

[0324] Preparation of (4aR,10aR)-7 - (benzyloxy)-6 - (methoxymethoxy)-1 - propyl - 1,2,3,4,4a,5,10,10a - octahydrobenzo[g]quinoline (Compound (A3))

Chemical Structure

[0325] Preparation of (4aR,10aR)-6-(methoxymethoxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-ol (Compound (A4)) [Chemical formula] To a solution of (4aR,10aR)-7-(benzyloxy)-6-(methoxymethoxy)-1-propyl-2H,3H,4H,4aH,5H,10H,10aH-benzo[g]quinoline (2.40 g, 6.1 mmol) in MeOH (50 mL) was added Pd(OH)2 / C (0.5 g, 10%) under a nitrogen atmosphere. The mixture was hydrogenated at room temperature overnight under a hydrogen atmosphere using a hydrogen balloon. The crude mixture was filtered through a pad of celite and concentrated under reduced pressure to give the title compound (1.9 g) pure enough for the next step.

[0326] Preparation of tert-butyl ((((4aR,10aR)-1-ethyl-6-(methoxymethoxy)-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl)oxy)carbonyl)glycinate (Compound (A8))

Chem.

[0327] Preparation of ((((4aR,10aR)-6-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl)oxy)carbonyl)glycine (Compound (5)) from Compound (A8)

Chem.

[0328] Compound (6): (S)-2-amino-3-(3-(((((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)carbonyl)amino)phenyl)propanoic acid Compound (6) can be prepared, for example, from the intermediate (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3-nitrophenyl)propanoic acid compound (A9) (commercially available from, for example, Nan Jing Peptide Biotechnology Co., Ltd) using a 5-step process as described below.

[0329] Preparation of Benzyl (S)-2-((tert-Butoxycarbonyl)amino)-3-(3-nitrophenyl)propanoate (Compound (A10)) from Compound (A9)

Chemical formula

[0330] Preparation of Benzyl (S)-3-(3-aminophenyl)-2-((tert-Butoxycarbonyl)amino)propanoate (Compound (A11)) from Compound (A10)

Chemical formula

[0331] Preparation of Benzyl (S)-3-(3-(((((4aR,10aR)-7-(Benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]-quinolin-6-yl)oxy)carbonyl)amino)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (Compound (A12))

Chem.

[0332] Preparation of Benzyl (S)-2-amino-3-(3-(((((4aR,10aR)-7-(Benzyloxy)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)carbonyl)amino)phenyl)propanoate Trifluoroacetate (Compound (A13))

Chem.

[0333] Preparation of (S)-2-amino-3-(3-(((((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)carbonyl)amino)phenyl)propanoic acid (Compound (6)) from Compound (A13)

Chemical formula

[0334] In vitro and in vivo characterization of the compounds of the present invention Example 1: Conversion of the compounds of the present invention in human plasma Frozen human plasma was thawed and then centrifuged at 3200 × g for 5 minutes to remove necrotic tissue fragments. Then, the pH value of the supernatant was measured and 1% phosphoric acid or 1N sodium hydroxide was added to adjust the pH to 7.4 ± 0.1. 2 μL of the dosing solution (50 μM for the test compound, 100 μM for the positive control (propantheline bromide)) was mixed with 98 μL of blank plasma to achieve a final concentration of 1 μM test compound and 2 μM positive control. The mixture was incubated and samples were taken (in duplicate) from the incubation at 37 °C in a water bath at predetermined time points of 0, 0.5, 1, 2, 4 and 6 hours. At each corresponding time point, 10 μL of inhibitor and 20 μL of ascorbic acid and 2 μL of formic acid (20%) were added, and then 400 μL of the "stop solution" (200 ng / mL tolbutamide + 200 ng / mL labetalol in 50% ACN / MeOH) was added to precipitate the protein. The substance was mixed thoroughly and then centrifuged at 4,000 rpm for 20 minutes. Then, an aliquot (50 μL) of the supernatant was transferred from each well to a sample plate and mixed with 100 μL of ultrapure water. The plate was shaken at 800 rpm for about 10 minutes before LC - MS / MS analysis.

[0335] Apparatus used for the analysis of plasma incubation samples: Mass spectrometer (LC-MS / MS) Shimadzu LC 20-AD Shimadzu UHPLC API 4000. Analytical column ACQUITY UPLC (registered trademark) 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 moving from 95 / 5% to 5 / 95% in 2.0 minutes. Flow rate 0.7 mL / min. MRM monitoring (multiple reaction monitoring) of test items and added analytical standards (labetolol or tolbutamide).

[0336] Example 2: 5-HT2B agonist activity and binding assay 5-HT2B agonist activity assay Using the HTRF detection method, Eurofins / Cerep (France) measured the effect of compounds on inositol monophosphate (IP1) production to evaluate the agonist activity of compounds (I), (Ia) and (Ib) at the human 5-HT2B receptor. 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 and then dispensed into microplates 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 measurement of stimulated control, each assay well contained 1 μM 5-HT. After incubation, the cells were lysed and a fluorescent receptor (fluorophen D2-labeled IP1) and a fluorescent donor (anti-IP1 antibody labeled with europium cryptate) were added. After 60 minutes at room temperature, the transfer of fluorescence was measured using a microplate reader (Rubystar, BMG) at λ(Ex) 337 nm and λ(Em) 620 and 665 nm. The IP1 concentration was determined (ratio) by dividing the signal measured at 665 nm by the signal measured at 620 nm. The results were expressed as a percentage of the control response to 1 μM 5-HT. The standard reference agonist was 5-HT, which was tested in each experiment at several concentrations to generate a concentration-response curve from which the EC50 value was calculated as described above for the dopamine functional assay.

[0337] 5-HT2B Binding Assay The affinity of the compounds 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) for 60 minutes at room temperature in the absence or presence of the test compound in a buffer containing 50 mM Tris HCl (pH 7.4), 5 mM MgCl2, 10 μM pargyline and 0.1% ascorbic acid. Nonspecific binding was determined in the presence of 1 μM (±)DOI. After incubation, the samples were rapidly filtered under vacuum through glass fiber filters (GF / B, Packard) presoaked with 0.3% polyethyleneimine (PEI) and rinsed several times with ice-cold 50 mM Tris HCl using a 96-sample cell harvester (Unifilter, Packard). The filters were dried and counted for radioactivity in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard). Results are expressed as percent inhibition of control radioligand specific binding. The standard reference compound was (±)DOI, which was tested at several concentrations in each experiment to obtain a competition curve from which the IC 50 is calculated.

[0338] [Table 3]

[0339] Example 3: PK Experiment in Rats For all experiments, approximately 0.68 mL of blood sample was collected from the tail or sublingual vein and placed into K3EDTA tubes that were pre-cooled and prepared with a stabilization solution consisting of 80 μL of ascorbic acid in water and 40 μL of 100 mM D - gluconic acid 1,4 - lactone. The tubes were gently inverted 6 - 8 times to mix well and then placed on wet ice. The collection tubes were placed on wet ice for up to 30 minutes until centrifugation. After removal from wet ice, centrifugation was started immediately. The samples were returned to wet ice immediately after centrifugation was completed. Three sub - samples of 130 μL of plasma were transferred to each of three appropriately labeled cryotubes containing pre - cooled formic acid (20%) (the tubes were pre - spiked and stored refrigerated before use). The lids of the tubes were replaced immediately and the plasma solution was mixed thoroughly by gently inverting 6 - 8 times. The samples were cryopreserved at nominally - 70 °C within 60 minutes after sampling. The centrifugation conditions were 3000 G at 4 °C for 10 minutes. After collection, the plasma was placed on ice water. Final storage at approximately - 70 °C.

[0340] Following solid - phase extraction or direct protein precipitation, plasma samples were analyzed by UPLC - MS / MS. MS detection was performed in positive ion mode by electrospray using monitoring of specific mass / charge transitions of compound (I) using an internal standard to correct the response. Concentration - time data were analyzed using standard software with appropriate non - compartmental techniques to obtain estimates of the derived PK parameters.

[0341] Apparatus used for the analysis of compound (I) from the administration of compound (Ia): Mass spectrometer (LC - MS / MS) Waters Acquity - Sciex API 5000. Analytical column Waters BEH UPLC Phenyl 100×2.1 mm column, particle size 1.7 μm. Mobile phase A: 20 mM ammonium formate (aqueous)+0.5% formic acid. Mobile phase B: acetonitrile. Gradient moving from 95 / 5% to 2 / 98% at 6.1 minutes. Flow rate 0.5 mL / min. MRM (multiple reaction monitoring) of the test item and added analytical standards. Administration and blood sampling: Han Wistar rats were supplied by Charles River Laboratories, Sulzfeld, Germany. An automated controlled artificial 12-hour light and dark cycle was maintained. A standard laboratory diet (Altromin 1324 pellets) obtained from Brogaarden was given to the rats. The rats had free access to the diet. During the study (4-week toxicity study), the dose of (Ia) was orally administered to the rats once a day by enteral nutrition. Blood samples were taken from 3 male satellite animals at the following time points on day 29 after (Ia) 300 μg / kg was administered: 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after administration.

[0342] Apparatus used for the analysis of compound (I) from the administration of compound (Ib): Mass spectrometer (LC-MS / MS) Waters Acquity-Sciex API5000. Analytical column Waters BEH UPLC Phenyl 100×2.1 mm column, particle size 1.7 μm. Mobile phase A: 20 mM ammonium formate (aqueous) + 0.5% formic acid. Mobile phase B: acetonitrile. Gradient moving from 95 / 5% to 2 / 98 in 6.1 minutes. Flow rate 0.5 mL / min. MRM monitoring of test items and added analytical standards. Administration and blood sampling: Han Wistar rats were supplied by Charles River Laboratories (UK). An automated controlled artificial 12-hour light and dark cycle was maintained. A standard laboratory diet (Teklad 2014C Diet) was given to the rats. The rats had free access to the diet. During the study (26-week toxicity study), the dose of (Ib) was orally administered to the rats once a day by enteral nutrition. Blood samples were taken from 3 male satellite animals at the following time points on day 182 after (Ib) 300 μg / kg was administered: 0.5, 1, 2, 4, 8, and 24 hours after administration.

[0343] Apparatus used for the analysis of compound (I) from the administration of compound (Ic), compound (1), compound (2), and compound (3): Mass spectrometer (LC-MS / MS): Waters Acquity - Waters Xevo TQ-S. Analytical column: Acquity BEH C18 100×2.1 mm, 1.7 μm. Mobile phase A: 20 mM ammonium formate + 0.2% formic acid. Mobile phase B: acetonitrile + 0.2% formic acid. Gradient moving from 95 / 5% to 5 / 95% at 11.0 minutes. Flow rate 0.3 mL / min. MRM monitoring of test items and added analytical standards.

[0344] Administration and blood sampling: Han Wistar rats were supplied by Envigo, UK. An automated controlled artificial 12-hour light and dark cycle was maintained. Standard laboratory diet Teklad 2014C was given to the rats. The rats had free access to the diet. The test compound was orally administered to male Han Wistar rats by gavage in a single dose via oral gavage. The rats were administered (Ic) 494 μg / kg, compound (1) 0.505 mg / kg, compound (2) 0.505 mg / kg, compound (3) 0.430 mg / kg, and compound (2) 551 μg / kg. Blood samples from 3 male animals were collected at the following time points on day 1: 1, 2, 4, 6, 8, and 24 hours after administration.

[0345]

Table 4

[0346] Example 4: Competitive binding study The following assay described in WO 06014429 pamphlet is used to determine the binding affinity of the amino acid or peptide carbamate derivatives of the present invention for hPEPT1.

[0347] The Ki values of the amino acid or peptide-carbamate derivative compounds (1) to (6) can be determined using 3H glycine-sarcosine (Gly-Sar) in an hPEPT1 overexpressing cell line (DC5). Plate DC5 cells in a 96-well tissue culture plate (Falcon) (12,000 cells / well) and allow them to grow for 4 days. Wash the cells once with 200 μL of uptake buffer and aspirate. Cool the plate to 4°C and add 25 μL of uptake buffer containing 50 μM Gly-Sar (0.5 μCi / ml). The uptake buffer also contains test compounds at various concentrations. Start the uptake by placing the plate in a shaking water bath (37°C) and terminate it in 10 minutes by rapidly washing with PBS (Sigma) at 4°C multiple times. The radioactive peptide is extracted from the cell layer with 200 μL of methanol:water (1:1) and counted with 4 mL of CytoScint ESTM scintillation cocktail (ICN). Nonlinear regression analysis of the data is used to determine the IC50 using the solver function of Microsoft Excel. It should be noted that the present invention includes the following aspects. [Aspect 1] Formula (Ie)

Chemical formula

Chemical formula

Chemical formula

Chem.

Claims

**Claim 1** (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diylbismethylcarbamate; (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diylethylbiscarbamate; and (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diyldimethylcarbamate A compound selected from the group consisting of or a pharmaceutically acceptable salt of any of the foregoing compounds. **Claim 2** The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diylbismethylcarbamate. **Claim 3** The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diylethylbiscarbamate. **Claim 4** The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diyldimethylcarbamate. **Claim 5** A pharmaceutical composition comprising the compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. **Claim 6** The pharmaceutical composition according to claim 5, wherein the pharmaceutical composition is for oral administration. **Claim 7** The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof for use as a medicament.

8. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof for use in the treatment of a neurodegenerative disease or disorder including Parkinson's disease, Huntington's disease, restless legs syndrome or Alzheimer's disease; or a neuropsychiatric disease or disorder including schizophrenia, attention deficit hyperactivity disorder or drug addiction.

9. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof for use in the treatment according to claim 8, wherein the neurodegenerative disease or disorder is Parkinson's disease.

10. A pharmaceutical composition for the treatment of a neurodegenerative disease or disorder including Parkinson's disease, Huntington's disease, restless legs syndrome or Alzheimer's disease; or a neuropsychiatric disease or disorder including schizophrenia, attention deficit hyperactivity disorder or drug addiction, the pharmaceutical composition comprising the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

11. The pharmaceutical composition according to claim 10, wherein the neurodegenerative disease or disorder is Parkinson's disease.

12. Use of the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a neurodegenerative disease or disorder including Parkinson's disease, Huntington's disease, restless legs syndrome or Alzheimer's disease; or for the treatment of a neuropsychiatric disease or disorder including schizophrenia, attention deficit hyperactivity disorder or drug addiction.

13. The use according to claim 12, wherein the neurodegenerative disease or disorder is Parkinson's disease.

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