Novel catecholamine prodrugs for the treatment of parkinson's disease

Abstract

The present invention provides sulfamate derivative prodrugs of the dopamine agonist (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol, their use in treating conditions for which treatment with a dopamine agonist has therapeutic benefit, and pharmaceutical compositions comprising a compound of the present invention. The compounds according to the present invention have the formula (Id), wherein R1and R2are each independently selected from H and the substituent (iii) below, wherein * indicates the point of attachment to oxygen, wherein R3is selected from H and COR4, and wherein R4is selected from H and C1-C6alkyl, with the proviso that R1and R2cannot both be H, 15or a pharmaceutically acceptable salt thereof.

Description

Technical Field

[0001] This invention provides compounds as prodrugs of an aminosulfonate derivative of the dopamine agonist (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol, and their use in the treatment of Parkinson's disease and / or in the treatment of other conditions for which the use of dopamine agonists has therapeutic benefits, such as restless leg syndrome, Huntington's disease, and Alzheimer's disease, as well as neuropsychiatric disorders and disorders such as schizophrenia, attention deficit hyperactivity disorder, and drug addiction. The invention further provides pharmaceutical compositions comprising the compounds of the invention. Background Technology

[0002] Parkinson's disease (PD) is a common neurodegenerative disorder that becomes increasingly prevalent with age and affects an estimated seven to ten million people worldwide. PD is a multifaceted disease characterized by both motor and nonmotor symptoms. Motor symptoms include resting tremor (shaking), bradykinesia / anekinesis (slow and difficult movement), rigidity, postural instability, and gait dysfunction; while nonmotor symptoms include neuropsychiatric disorders (e.g., depression, psychotic symptoms, anxiety, emotional blunting, mild cognitive impairment, and dementia) as well as autonomic dysfunction and sleep disturbances (Poewe et al., Nature Review, (2017) Vol. 3, entry 17013:1-21).

[0003] A key hallmark of the pathophysiology of Parkinson's disease is the loss of pigment dopaminergic neurons in the substantia nigra pars compacta, which provide dopaminergic innervation to the striatum and other brain regions. This progressive neurodegeneration leads to a decrease in dopamine levels in the striatum, which ultimately results in a series of changes in the basal ganglia circuits, ultimately leading to the four major motor features of Parkinson's disease. The main targets of dopamine in the striatum consist of medium-sized polyspinous γ-aminobutyric acid (MSNs) that selectively express D1 or D2 receptors and await localization projection. γ-aminobutyric acid-MSNs projecting to the lateral pallidus (also known as the striatum-palioidindirect pathway) express D2 receptors (MSN-2); while γ-aminobutyric acid-MSNs projecting to the substantia nigra pars compacta and the lateral pallidus (also known as the striatum-substantia nigra direct pathway) express D1 receptors (MSN-1). Neuronal loss leads to dopamine depletion, resulting in an imbalance of activity in the two pathways, which in turn leads to a significant reduction in the output activity of the thalamus and cortex 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 the review, Poewe et al., Nature Review (2017) Vol. 3, entry 17013:1-21).

[0004] The most effective treatment strategies available for patients with Parkinson's disease, aimed at controlling motor symptoms, primarily consist of indirect and direct dopamine agonists. The classic and gold standard treatment regimen involves chronic oral ingestion of L-3,4-dihydroxyphenylalanine (L-DOPA) (which decarboxylates in the brain to form dopamine). Other methods consist of administration of dopamine receptor agonists, such as apomorphine, which acts on both D1 and D2 receptor subtypes, or pramipexole and ropinirole, which primarily target the D2 receptor subtype. Optimal motor remission is achieved using L-DOPA and apomorphine because they activate both D1 and D2 receptor subtypes and rebalance the overall indirect-direct pathway (i.e., the D2 agonist only reverses the dysfunction of the indirect pathway).

[0005] L-DOPA and apomorphine, which have the structures described below, are currently the most effective PD drugs in clinical use.

[0006]

[0007] L-DOPA is a prodrug of dopamine and remains the most effective drug for the treatment of motor Parkinson's disease. However, after several years of treatment (i.e., the honeymoon period), complications arise due to the inherent progression of the disease (i.e., the continued loss of dopaminergic neurons) and the poor pharmacokinetic (PK) profile of L-DOPA. These complications include: 1) dyskinesia, which is abnormal involuntary movement that occurs during the period of the drug's optimal "on-time effect"; and 2) off-fluctuation, during which the positive effect of L-DOPA disappears and symptoms reappear or worsen (Sprenger and Poewe, CNS Drugs (2013), 27:259-272).

[0008] Direct dopamine receptor agonists activate dopamine autoreceptors and postsynaptic dopamine receptors located on MSN-1 and MSN-2 of medium-sized polyspinous neurons. Apomorphine belongs to a class of dopamine agonists with a 1,2-dihydroxybenzene (catechol) motif. Catecholamines, when combined with phenethylamine motifs, typically have low or no oral bioavailability, as is the case with apomorphine. Apomorphine is used clinically in PD therapy, although in non-oral delivery (typically intermittent subcutaneous administration via a pump or continuous parenteral infusion during the day). Animal studies have shown that percutaneous delivery or implantation can provide possible forms of administration for apomorphine. However, when apomorphine delivery from implantation was studied in monkeys (Campbell 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 implantation. Alternative delivery strategies for apomorphine therapy in PD, such as inhalation and sublingual formulations, have been extensively developed (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).

[0009] Alternatives to non-oral formulations of catecholamines involve using prodrugs that mask the free catechol hydroxyl groups to enable oral administration. However, a known problem associated with the development of prodrugs for clinical use is the difficulty in predicting their conversion to the parent compound in the human body.

[0010] Various ester prodrugs of catecholamines have been reported in the literature, such as enteric-coated N-propyl-noraporphine (NPA) and monopentanoyl esters of apomorphine for duodenal delivery (see, for example, WO 02 / 100377), and the D1-like agonist adrogolide (a diacetyl prodrug of A-86929) (Giardina and Williams; CNS Drug Reviews [CNS Drug Reviews] (2001), Vol. 7(3):305-316). In humans, adrogolide undergoes extensive first-pass metabolism in the liver after oral administration, and as a result, it has low oral bioavailability (approximately 4%). In patients with Parkinson's disease (PD), intravenous (IV) atrolide has anti-Parkinsonian efficacy comparable to L-DOPA (Giardina and Williams; CNS Drug Reviews (2001), Vol. 7 (3): 305-316).

[0011] Besides ester prodrugs of catecholamines, alternative prodrug methods involve masking the two catechol hydroxyl groups with the corresponding methylenedioxy (MDO) derivatives or diacetal derivatives. This prodrug principle has been described, for example, in Campbell et al., Neuropharmacology (1982); 21(10):953-961, and in US 4543256, WO 2009 / 026934, and WO2009 / 026935.

[0012] Another suggested approach for catecholamine prodrugs is to form enone derivatives, as suggested in, for example, WO 2001 / 078713 and Liu et al., Bioorganic Med. Chem. (2008), 16:3438-3444. For further examples of catecholamine prodrugs, see, for example, Sozio et al., Exp. Opin. Drug Disc. (2012); 7(5):385-406.

[0013] The compound (4aR,10aR)-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol, described as compound (I), is disclosed in WO 2009 / 026934. The trans isomer was previously disclosed in Liu et al., J. Med. Chem. (2006), 49:1494-1498 and then in Liu et al., Bioorganic Med. Chem. (2008), 16:3438-3444, which includes pharmacological data indicating low oral bioavailability of the compound in rats. The racemic mixture was first disclosed in Cannon et al., J. Heterocyclic Chem. (1980); 17:1633-1636.

[0014]

[0015] Compound (I) is a dopamine receptor agonist with mixed D1 and D2 activities. Different prodrug derivatives of compound (I) are known in the art.

[0016] Liu et al., J. Med. Chem. (2006), 49:1494-1498 and Liu et al., Bioorganic Med. Chem. (2008), 16:3438-3444 disclosed the following enone derivative having formula (Ia), showing that the enone derivative was converted into the active compound (I) in rats.

[0017]

[0018] WO 2009 / 026934 and WO 2009 / 026935 disclose two types of prodrug derivatives of compound (I), including (6aR,10aR)-7-propyl-6,6a,7,8,9,10,10a,11-octahydro-[1,3]dioxanepenteno[4',5':5,6]benzo[1,2-g]quinoline, having a methylenedioxy (MDO) derivative of formula (Ib):

[0019]

[0020] Compound (Ib) has been demonstrated to be converted to compound (I) in rat and human hepatocytes in WO 2010 / 097092. Furthermore, the in vivo pharmacology of compounds (Ia) and (Ib), as well as the active “parent compound” (I), has been tested in various animal models of Parkinson's disease (WO 2010 / 097092). Compound (I) and both compounds (Ia) and (Ib) were found to be effective, indicating that compounds (Ia) and (Ib) are converted to compound (I) in vivo. All three compounds have been reported to have a longer duration of action compared to those observed against L-dopa and apomorphine.

[0021] Other prodrugs of compound (I) disclosed in WO 2009 / 026934 and WO 2009 / 026935 are conventional ester prodrugs having the following formula (Ic):

[0022]

[0023] Patent application WO 2019101917 discloses additional glucuronide conjugates of compound (I) and sulfate ester conjugates of compound (I) having the following formulas (Id-iia), (Id-iib) and (Id-iiab).

[0024]

[0025] WO 2019101917 discloses the use of glucuronic acid and sulfate derivatives of the disclosed compound (I) as oral active prodrugs of compound (I).

[0026] Other conjugates of compound (I) have been disclosed in WO 2020234274, WO 2020234275, WO2020234276 and WO 2020234277.

[0027] Despite long-standing interest in this field, there remains a clear unmet need for developing highly effective, well-tolerated, and orally active drugs for the treatment of PD. Such unmet needs could be met by prodrug derivatives of mixed D1 / D2 agonists that provide continuous dopaminergic stimulation and favorable PK profiles.

[0028] Previously, for example, aminosulfonate derivatives have been suggested as a prodrug principle for estradiol (Elger et al. JSteroid Biochem Mol Biol [Journal of Steroid Biochemistry and Molecular Biology] 55:395-403, 1995 and Elger et al. Reprod Fertil Dev [Reproduction, Fertility and Development] 13:297-305, 2001). Summary of the Invention

[0029] This invention relates to novel compounds for the treatment of Parkinson's disease. More particularly, this invention relates to a novel aminosulfonate prodrug derivative of compound (4aR,10aR)-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol (compound (I)). The compounds of the present invention have proven particularly useful for oral delivery of compound (I), as demonstrated in the rat PK study of Example 2, where the tested compounds of the present invention were shown to be converted into compound (I) in vivo.

[0030] Example 2 further demonstrates that the tested compounds (II) and (III) of the present invention resulted in lower plasma exposure in rats over the entire 24-hour period than the corresponding exposures observed for prior art compounds (Ia) and (Ib), while being higher than the corresponding exposures for prior art compound (Ic), which was found unsuitable as a prodrug.

[0031] Furthermore, the Cmax value of compound (I) observed after administration of both compounds (II) and (III) in rats was lower than that achievable with prior art compounds (Ia) and (Ib), as well as prior art sulfate conjugates (Id-iia) and (Id-iib). Because the peak concentration of compound (I) is expected to drive side effects at a lower level, higher doses of the compounds of the present invention can be administered, potentially achieving higher overall plasma concentrations of compound (I) compared to those achievable from administered compounds (Ia) and (Ib). Compound (II) showed a Tmax approximately 1 hour later, which was faster than that of prior art sulfate conjugates (Id-iia), (Id-iib), and (Id-iiab), while being comparable to prior art compounds (Ia), (Ib), and (Ic).

[0032] Example 4 shows that compounds (II) and (III) are converted into compound (I) by incubation with human and rat liver S9 fraction. Figure 3 and 4 Furthermore, compared to prior art sulfate conjugates (Id-iia) and (Id-iib), the conversion of compounds (II) and (III) of the present invention to compound (I) is increased by incubation with human liver S9. Figure 3 ).

[0033] Furthermore, Example 3 demonstrates that the compounds of the present invention, particularly compounds (II) and (III), exhibit higher solubility at pH 6 than the corresponding prior art sulfate conjugates (Id-iia) and (Id-iib). This high solubility at pH 6.0 and lower pH levels may facilitate absorption of the compounds after enteral administration.

[0034] In a first aspect, the present invention provides a compound according to the following formula (Id).

[0035]

[0036] R1 and R2 are each independently selected from H and the following substituents (iii).

[0037]

[0038] The asterisk (*) indicates the point of contact with oxygen.

[0039] R3 is selected from H and COR4.

[0040] Furthermore, R4 is selected from H and C1-C6 alkyl groups.

[0041] The premise is that R1 and R2 cannot both be H.

[0042] Or its pharmaceutically acceptable salt.

[0043] In a preferred embodiment of the invention, the compound according to formula (Id) is a compound in which R3 is H.

[0044] In another preferred embodiment of the invention, the compound according to formula (Id) is selected from the group consisting of: (4aR,10aR)-6-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-7-ylaminosulfonate having formula (II) and (4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6-ylaminosulfonate having formula (III).

[0045]

[0046] And its pharmaceutically acceptable salts.

[0047] In other preferred embodiments, the compounds according to the invention are in a separated form substantially free of compounds having formula (I). In other embodiments of the invention, the compounds or pharmaceutically acceptable salts thereof are in solid form.

[0048] Another aspect of the invention provides a pharmaceutically acceptable salt of a compound according to formula (Id).

[0049] Another aspect of the invention provides a compound having formula (Id) or a pharmaceutically acceptable salt thereof for use as a medicine.

[0050] Another aspect of the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (Id) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In a preferred embodiment, the pharmaceutical composition is an oral pharmaceutical composition, such as tablets or capsules for oral administration.

[0051] Another aspect of the invention relates to a compound having formula (Id) or a pharmaceutically acceptable salt thereof for the treatment of neurodegenerative diseases or disorders, such as Parkinson's disease, Huntington's disease, restless limb syndrome, or Alzheimer's disease; or neuropsychiatric diseases or disorders, such as schizophrenia, attention deficit hyperactivity disorder, or substance addiction. In a preferred embodiment, the compound having formula (Id) or a pharmaceutically acceptable salt thereof is used to treat Parkinson's disease.

[0052] Another aspect of the invention provides the use of a compound of formula (Id) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, in the manufacture of a medicament for treating neurodegenerative diseases or disorders such as Parkinson's disease, Huntington's disease, restless limb syndrome, or Alzheimer's disease; or neuropsychiatric diseases or disorders such as schizophrenia, attention deficit hyperactivity disorder, or substance addiction. In a preferred embodiment, the medicament is used to treat Parkinson's disease.

[0053] Another aspect of the invention provides a method for treating neurodegenerative diseases or disorders such as Parkinson's disease, Huntington's disease, restless limb syndrome, or Alzheimer's disease; or neuropsychiatric diseases or disorders such as schizophrenia, attention deficit hyperactivity disorder, or drug addiction; the method comprising administering to a patient in need a therapeutically effective amount of a compound of formula (Id) or a pharmaceutically acceptable salt thereof. Attached Figure Description

[0054] Figure 1

[0055] According to Example 2, PK curves were obtained in Wistar rats after oral administration. The curves are based on the average plasma concentrations from three subjects at each time point for each compound. X-axis: time (hours); Y-axis: plasma concentration (pg / mL) of compound (I) obtained after administration of compound (III).

[0056] Figure 2

[0057] According to Example 2, PK curves were obtained in Wistar rats after oral administration. The curves are based on the average plasma concentrations from 3 subjects at each time point for each compound. X-axis: time (hours); Y-axis: plasma concentration (pg / mL) of compound (I) obtained after administration of compound (II).

[0058] Figure 3

[0059] In human liver S9, compounds (II), (III), (Id-iia), and (Id-iib) are converted into compound (I) in vitro.

[0060] X-axis: Time (min); Y-axis: Increase in concentration of compound (I) compared to the concentration at time = 0 min (pg / mL)

[0061] Solid black circles represent compound (III), hollow circles represent compound (II), crosses (X) represent compound (Id-iia), and triangles represent compound (Id-iib).

[0062] Figure 4

[0063] In rat liver S9, compounds (II), (III), (Id-iia), and (Id-iib) were converted into compound (I) in vitro.

[0064] X-axis: Time (min); Y-axis: Increase in concentration of compound (I) from time = 0 min (pg / mL). Solid black circles represent compound (III), hollow circles represent compound (II), crosses (X) represent compound (Id-iia), and triangles represent compound (Id-iib). Invention Details

[0066] definition

[0067] compound

[0068] References to the compounds covered by this invention include free forms of the compounds of this invention (e.g., free bases or zwitterions), pharmaceutically acceptable salts of the compounds of this invention (e.g., acid addition salts or base addition salts), and polymorphic and amorphous forms of the compounds of this invention and their pharmaceutically acceptable salts. Furthermore, the compounds of this invention and their pharmaceutically acceptable salts may potentially exist as non-solventized forms as well as in solvated forms with pharmaceutically acceptable solvents (e.g., water, ethanol, etc.). This invention covers both solvated and non-solventized forms.

[0069] Combination therapy

[0070] As used herein in the context of the method of the invention (including the combined administration of a therapeutically effective amount of a compound having formula (Id) and another compound that can be used to treat neurodegenerative diseases or disorders), the terms “combined use,” “in combination with,” and “combination of” are intended to mean the simultaneous or sequential (in any order) administration of the compound having formula (Id) together with the other compound.

[0071] Pharmaceutically acceptable salts

[0072] The compounds of the present invention are typically utilized either as free substances or as pharmaceutically acceptable salts. When a compound having formula (Id) contains a free base, such a salt can be prepared in a conventional manner by treating a solution or suspension of the free base having formula (Id) with a molar equivalent of a pharmaceutically acceptable acid. Representative examples of suitable organic and inorganic acids are described below.

[0073] In the context of this invention, pharmaceutically acceptable salts are intended to refer to non-toxic (i.e. physiologically acceptable) salts.

[0074] The term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts, which are salts formed on the nitrogen atom of a parent molecule with an inorganic acid and / or an organic acid. The acid may be selected from, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitrous acid, sulfuric acid, benzoic acid, citric acid, gluconic acid, lactic acid, maleic acid, succinic acid, tartaric acid, acetic acid, propionic acid, oxalic acid, malonic acid, fumaric acid, glutamic acid, pyroglutamic acid, salicylic acid, gentian acid, saccharin, and sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, naphthalene-2-sulfonic acid, 2-hydroxyethanesulfonic acid, and benzenesulfonic acid.

[0075] Further examples of useful acids and bases that form pharmaceutically acceptable salts can be found, for example, in Stahl and Wermuth (eds.), "Handbook of Pharmaceutical Salts: Properties, Selection, and Use," Wiley-VCH, 2008.

[0076] prodrug

[0077] In the context of this invention, the terms "prodrug" or "prodrug derivative" refer to a compound that, upon administration to a living subject (e.g., a mammal, preferably a human), is converted in vivo to its pharmacologically active form. This conversion preferably occurs in mammals, such as mice, rats, dogs, miniature pigs, rabbits, monkeys, and / or humans. In the context of this invention, "prodrug of (4aR,10aR)-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol," or "prodrug of a compound having formula (I)," or "prodrug of compound (I)" is understood to be a compound that, upon administration, is converted in vivo to (4aR,10aR)-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol. The administration can be by any conventional route of administration of pharmaceutical compositions known in the art, preferably by oral administration.

[0078] In the context of this invention, the terms "parent compound" and "parent molecule" refer to the pharmacologically active portion obtained after conversion of the corresponding prodrug. For example, the "parent compound" of one of compounds (Ia), (Ib), (Ic) or any of the compounds of the invention according to formula (Id) (e.g., compounds (II), (III), and (V)) is understood to be a compound having formula (I).

[0079] Substituents

[0080] In the context of this invention, a given range may be indicated by “-” (connector) or “to” interchangeably, for example, the term “C1-C6 alkyl” is equivalent to “C1 to C6 alkyl”.

[0081] The term "alkyl" refers to a straight-chain (i.e., unbranched) or branched saturated hydrocarbon having one to six carbon atoms (including the terminal number). 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, n-pentyl, isopentyl, and n-hexyl.

[0082] Definitions and abbreviations of pharmacokinetics

[0083] As used herein, “PK curve” is an abbreviation for “pharmacokinetics curve”. The pharmacokinetic curves and pharmacokinetic parameters described herein are based on plasma concentration-time data of compounds of formula (I) obtained using a non-compartmental model following oral administration of the compounds of the present invention. The abbreviated PK parameters are: Cmax (maximum concentration); tmax (time to Cmax); t1 / 2 (half-life); AUC0-24 (area under the curve from the time of administration up to 24 hours after administration); and “exposure at 24 hours” is the plasma concentration of the compound of formula (I) as measured 24 hours after administration.

[0084] Therapeutic effective dose

[0085] In the context of this invention, the term "therapeuticly effective amount" for the compounds of this invention means an amount sufficient to alleviate, block, partially block, eliminate, or delay the clinical manifestations of a given disease and its complications in a therapeutic intervention including the administration of said compound. An amount sufficient to achieve the above is defined as a "therapeuticly effective amount." Effective amounts for various purposes will depend, for example, on the severity of the disease or injury and the subject's weight and general condition. It should be understood that determining an appropriate dose can be achieved using conventional experiments by constructing a value matrix and testing the differences in the matrix, all within the scope of ordinary techniques of a trained physician.

[0086] In the context of this invention, the “therapeutic effective amount” of the compound of this invention refers to the amount of the compound of this invention that, when administered to a mammal (preferably a human) via oral route, provides an amount of compound (I) sufficient to alleviate, block, partially block, remove, or delay the clinical manifestations of a given disease and its complications.

[0087] Treatment (and treating)

[0088] In the context of this invention, "treatment" is intended to refer to the management and care of a patient for the purpose of alleviating, blocking, partially blocking, removing clinical manifestations of a disease, or delaying its progression. The patient to be treated is preferably a mammal, particularly a human.

[0089] Pharmaceutical formulations and excipients

[0090] In the following text, the term "excipient" or "pharmaceutically acceptable excipient" refers to a pharmaceutical excipient, including but not limited to carriers, fillers, diluents, anti-adhesion agents, binders, coatings, colorants, disintegrants, flavoring agents, glidants, lubricants, preservatives, adsorbents, sweeteners, solvents, mediators, and excipients.

[0091] The titles and subtitles are used for convenience only and should not be construed as limiting the invention in any way.

[0092] Unless otherwise stated or obviously contradicted by the context, the use of terms such as “comprising,” “having,” “including,” or “containing” in any aspect or multiple aspects of the invention is intended to provide support for similar aspects or multiple aspects of the invention that “comprise that one or more specific elements,” “consistently comprise that one or more specific elements,” or “substantially contain that one or more specific elements” (e.g., unless otherwise stated or obviously contradicted by the context, a composition comprising a specific element described herein should be understood to also describe a composition comprising that element).

[0093] Unless otherwise indicated, any and all instances or exemplary language used in this specification (including “for instance,” “for example,” “eg,” and “as such”) are intended only to better illustrate the invention and do not limit the scope of the invention.

[0094] It should be understood that the various aspects, embodiments, implementations, and features of the invention mentioned herein may be claimed individually or in any combination.

[0095] As permitted by applicable law, this invention includes all modifications and equivalents of the subject matter set forth in the appended claims.

[0096] The compounds of the present invention

[0097] The inventors have identified novel aminosulfonate compounds that can function as prodrugs for 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).

[0098] Oral administration of the representative compounds (II) and (III) of the present invention to Wistar rats provided systemic exposure to compound (I), as measured by plasma concentrations of compound (I), demonstrating the usefulness of said compounds as orally active prodrugs of compound (I).

[0099] For compounds tested in vivo, the dose is corrected by molecular weight to be equal to the dose of compound (Ib) at 300 μg / kg (corresponding to compound (I) at 287 μg / kg).

[0100] Previously, oral administration of compounds (Ia) and (Ib) to Wistar rats has been observed to result in early and high peak plasma concentrations of compound (I). In humans, such high peak concentrations may be associated with dopaminergic side effects such as, for example, nausea, vomiting, and mild headache. In contrast, with compound (II) of the present invention, a slower absorption rate was observed, accompanied by sustained exposure to compound (I), avoiding rapid peak concentrations. Additionally, as shown in Example 2 herein, plasma exposure to compound (I) after oral administration of compounds (II) and (III) to Wistar rats showed moderate exposure, although higher than that observed with compound (Ic). However, because the peak concentration of compound (I) is expected to drive side effects, higher doses of the compounds of the present invention can be administered, potentially achieving higher overall plasma concentrations of compound (I) compared to those achievable from administration of compounds (Ia) and (Ib). When studying the pharmacokinetic properties of compound (Ic), the inventors found that the plasma concentration of compound (I) was extremely low, making compound (Ic) unsuitable as a prodrug for oral administration of compound (I), and confirmed that the oral bioavailability of the compound of the present invention is highly unpredictable.

[0101] Table 2 lists the PK parameters used in PK studies of compounds (II) and (III) in Wistar rats, and... Figure 1 and 2 The PK curve is depicted in the figure.

[0102] Therefore, in summary, the representative compound of the present invention can be used as an orally active prodrug of compound (I), and has been observed in rats to provide a PK curve that avoids the peak C observed for known prodrugs (Ia) and (Ib). max Furthermore, compound (I) provides a higher AUC compared to compound (Ic). Cmax and PK curves can be measured by orally administering the compound of the invention to one or more subjects (e.g., animals, such as rats, miniature pigs, monkeys, or humans, with rats being preferred subjects), and subsequently measuring the plasma concentration of compound (I) as described in Example 2 or Example 3. Therefore, in one embodiment of the invention, the compound having formula (Id) has a PK curve that avoids the peak Cmax observed for known prodrugs (Ia) and (Ib). maxFurthermore, compound (I) exhibits a higher AUC compared to compound (Ic). Therefore, in one embodiment of the invention, the compound having formula (Id) has a Cmax greater than about 90 pg / mL, such as in the range of about 90 pg / mL to about 600 pg / mL, such as in the range of about 90 pg / mL to about 400 pg / mL, such as in the range of about 100 pg / mL to 200 pg / mL, or such as in the range of about 200 pg / mL to about 300 pg / mL, or such as in the range of about 300 pg / mL to about 400 pg / mL. In another embodiment of the invention, the Cmax is less than 3000 pg / mL, more preferably less than 1000 pg / mL, such as in the range of about 50 pg / mL to about 500 pg / mL.

[0103] In another embodiment of the invention, if measured over 24 hours, the AUC of the compound having formula (Id) is greater than 1000 pg*h / mL, such as in the range of about 1500 to about 5000 pg*h / mL, such as in the range of about 1500 pg*h / mL to 4000 pg*h / mL, such as about 1600 pg*h / mL, or such as about 1700 pg*h / mL, or such as about 1800 pg*h / mL, or such as about 19 00 pg*h / mL, or approximately 2000 pg*h / mL, or approximately 2100 pg*h / mL, or approximately 2200 pg*h / mL, or approximately 2300 pg*h / mL, or approximately 2400 pg*h / mL, or approximately 2500 pg*h / mL, or approximately 2600 pg*h / mL, or approximately 2700 pg*h / mL, or approximately 2800 pg*h / mL, or approximately 2900 pg*h / mL L, or approximately 3000 pg*h / mL, or approximately 3100 pg*h / mL, or approximately 3200 pg*h / mL, or approximately 3300 pg*h / mL, or approximately 3400 pg*h / mL, or approximately 3500 pg*h / mL, or approximately 3600 pg*h / mL, or approximately 3700 pg*h / mL, or approximately 3800 pg*h / mL, or approximately 3900 pg*h / mL, or approximately 400 0 pg*h / mL, or approximately 4100 pg*h / mL, or approximately 4200 pg*h / mL, or approximately 4300 pg*h / mL, or approximately 4400 pg*h / mL, or approximately 4500 pg*h / mL, or approximately 4600 pg*h / mL, or approximately 4700 pg*h / mL, or approximately 4800 pg*h / mL, or approximately 4900 pg*h / mL, or approximately 5000 pg*h / mL.

[0104] In even more preferred embodiments of the invention, the Cmax of the compound having formula (Id) is greater than about 90 pg / mL, such as in the range of about 90 pg / mL to about 600 pg / mL, and the AUC measured over 24 hours is in the range of about 1500 to about 5000 pg*h / mL, such as in the range of about 1500 pg*h / mL to 4000 pg*h / mL.

[0105] Example 4 shows that compounds (II) and (III) are converted into compound (I) by incubation with human and rat liver S9 fraction. Figure 3 and 4 Furthermore, it was demonstrated that, compared to prior art sulfate conjugates (Id-iia) and (Id-iib), the conversion of compounds (II) and (III) of the present invention to compound (I) was increased by incubation with human liver S9. Figure 3 ).

[0106] Therefore, in one embodiment of the invention, the conversion of the compound having formula (Id) to compound (I) is increased after incubation with human liver S9, as compared to prior art sulfate conjugates (Id-iia) and (Id-iib). In a more particular embodiment of the invention, when measured using the method described in Example 4 or other equivalent methods known in the prior art, the conversion of the compound having formula (Id) to compound (I) is increased compared to prior art sulfate conjugates (Id-iia) and (Id-iib).

[0107] Furthermore, Example 3 demonstrates that the compounds of the present invention, particularly compounds (II) and (III), exhibit higher solubility at pH 6.0 than the corresponding prior art compounds (Id-iia) and (Id-iib), see Table 3. The solubility of the compounds of the present invention can be measured by dissolving them in a solution (e.g., a buffer solution at a suitable acidic pH, such as phosphate buffer at pH 6.0), as described in Example 3.

[0108] Therefore, in one embodiment of the invention, compared with prior art sulfate conjugates (Id-iia) and (Id-iib), the compound having formula (Id) has increased solubility at acidic pH, such as a measured solubility above about 0.035 mg / mL at pH 6.0, such as in the range of about 0.035 to about 0.01 mg / mL, or above about 0.1 mg / mL, such as in the range of about 0.1 mg / mL to about 1.0 mg / mL, such as about 0.2 mg / mL, or about 0.3 mg / mL, or about 0.4 mg / mL, or about 0.5 mg / mL, or about 0.6 mg / mL, or about 0.7 mg / mL, or about 0.8 mg / mL, or about 0.9 mg / mL, or about 1.0 mg / mL, or above about 1.0 mg / mL, such as in the range of about 1.0 mg / mL to about 5 mg / mL.

[0109] Therefore, one aspect of the present invention provides an aminosulfonate derivative of compound (I) or a pharmaceutically acceptable salt thereof.

[0110] Therefore, in a first aspect, the present invention provides a compound according to the following formula (Id).

[0111]

[0112] R1 and R2 are each independently selected from H and the following substituents (iii).

[0113]

[0114] The asterisk (*) indicates the point of contact with oxygen.

[0115] R3 is selected from H and COR4.

[0116] And R4 is a C1-C6 alkyl group.

[0117] The premise is that R1 and R2 cannot both be H.

[0118] Or its pharmaceutically acceptable salt.

[0119] Therefore, in one embodiment of the invention, the invention provides a compound according to formula (Id) or a pharmaceutically acceptable salt thereof, wherein at least one of R1 or R2 is a substituent (iii), such as a compound according to formula (Id) wherein R1 is a substituent (iii) and R2 is H; or a compound according to formula (Id) wherein R1 is H and R2 is a substituent (iii); or a compound according to formula (Id) wherein both R1 and R2 are substituents (iii).

[0120] In a preferred embodiment of the invention, the compound of the invention is a compound according to formula (Id) or a pharmaceutically acceptable salt thereof, wherein R1 is a substituent (iii) and R2 is H; or a compound according to formula (Id), wherein R1 is H and R2 is a substituent (iii).

[0121] In a preferred embodiment of the invention, a compound according to formula (Id) or a pharmaceutically acceptable salt thereof is provided, wherein R3 is H.

[0122] In another embodiment of the invention, a compound according to formula (Id) or a pharmaceutically acceptable salt thereof is provided, wherein R3 is COR4, and wherein R4 is selected from H and C1-C6 alkyl groups. Such compounds include compounds according to formula (Id) or pharmaceutically acceptable salts thereof, wherein R3 is COR4, and wherein R4 is selected from the group consisting of hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2-methyl-1-butyl, n-pentyl, isopentyl, and n-hexyl. In even more particular embodiments of the invention, a compound according to formula (Id) or a pharmaceutically acceptable salt thereof is provided, wherein R3 is COR4, and wherein R4 is selected from the group consisting of methyl, ethyl, 1-propyl, and 2-propyl.

[0123] In even more particular embodiments of the invention, a compound according to formula (Id) or a pharmaceutically acceptable salt thereof is provided, wherein R3 is COR4 and wherein R4 is H.

[0124] In even more particular embodiments of the invention, a compound according to formula (Id) or a pharmaceutically acceptable salt thereof is provided, wherein R3 is COR4 and wherein R4 is methyl.

[0125] In even more particular embodiments of the invention, a compound according to formula (Id) or a pharmaceutically acceptable salt thereof is provided, wherein R3 is COR4 and wherein R4 is ethyl.

[0126] In even more particular embodiments of the invention, a compound according to formula (Id) or a pharmaceutically acceptable salt thereof is provided, wherein R3 is COR4 and wherein R4 is 1-propyl.

[0127] In even more particular embodiments of the invention, a compound according to formula (Id) or a pharmaceutically acceptable salt thereof is provided, wherein R3 is COR4 and wherein R4 is 2-propyl.

[0128] In even more particular embodiments of the invention, a compound according to formula (Id) or a pharmaceutically acceptable salt thereof is provided, wherein R3 is COR4 and wherein R4 is 1-butyl.

[0129] In even more particular embodiments of the invention, a compound according to formula (Id) or a pharmaceutically acceptable salt thereof is provided, wherein R3 is COR4 and wherein R4 is 2-butyl.

[0130] In even more particular embodiments of the invention, a compound according to formula (Id) or a pharmaceutically acceptable salt thereof is provided, wherein R3 is COR4 and wherein R4 is 2-methyl-2-propyl.

[0131] In even more particular embodiments of the invention, a compound according to formula (Id) or a pharmaceutically acceptable salt thereof is provided, wherein R3 is COR4 and wherein R4 is 2-methyl-1-butyl.

[0132] In even more particular embodiments of the invention, a compound according to formula (Id) or a pharmaceutically acceptable salt thereof is provided, wherein R3 is COR4 and wherein R4 is n-pentyl.

[0133] In even more particular embodiments of the invention, a compound according to formula (Id) or a pharmaceutically acceptable salt thereof is provided, wherein R3 is COR4 and wherein R4 is isopentyl.

[0134] In even more particular embodiments of the invention, a compound according to formula (Id) or a pharmaceutically acceptable salt thereof is provided, wherein R3 is COR4 and wherein R4 is n-hexyl.

[0135] In a particular embodiment of the invention, the compound of the invention is a compound having formula (Id) or a pharmaceutically acceptable salt thereof, wherein at least one of R1 and R2 is a substituent (iii), and wherein R3 is H. Therefore, in one embodiment of the invention, the compound of the invention is a compound having formula (Id), selected from the group consisting of: (4aR,10aR)-6-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-7-ylaminosulfonate having formula (II).

[0136]

[0137] (4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6-ylaminosulfonate having the following formula (III)

[0138]

[0139] (4aS,10aR)-4a-amino-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-dimethylbis(aminosulfonate) having the following formula (IV)

[0140]

[0141] And pharmaceutically acceptable salts of any of these compounds.

[0142] In a particular embodiment of the invention, the compound of the invention is a compound having formula (Id) or a pharmaceutically acceptable salt thereof, wherein at least one of R1 and R2 is a substituent (iii), and wherein R3 is H. Therefore, in one embodiment of the invention, the compound of the invention is a compound having formula (Id), selected from the group consisting of: (4aR,10aR)-6-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-7-ylaminosulfonate having formula (II).

[0143]

[0144] (4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6-ylaminosulfonate having the following formula (III)

[0145]

[0146] (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-dimethylbis(aminosulfonate) having the following formula (V)

[0147]

[0148] And pharmaceutically acceptable salts of any of these compounds.

[0149] In a preferred embodiment of the invention, the compound of the invention is a compound having formula (Id) or a pharmaceutically acceptable salt thereof, wherein both R1 and R2 are substituents (iii), and wherein R3 is H. Therefore, in a preferred embodiment of the invention, the compound having formula (Id) is (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-dimethylbis(aminosulfonate).

[0150] Example 2 shows that aminosulfonate conjugated compounds (II) and (III) (which are examples of compounds according to formula (Id), wherein one of R1 and R2 is a substituent (iii), and wherein R3 is H) are converted into compound (I) in vivo.

[0151] Therefore, in a preferred embodiment of the invention, the compound of the invention is a compound having formula (Id) or a pharmaceutically acceptable salt thereof, wherein one of R1 and R2 is H and the other is a substituent (iii), wherein R3 is H.

[0152] Therefore, in a preferred embodiment of the invention, the compound according to formula (Id) is selected from the group consisting of (4aR,10aR)-6-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-7-ylaminosulfonate having formula (II).

[0153]

[0154] (4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6-ylaminosulfonate having the following formula (III)

[0155]

[0156] And pharmaceutically acceptable salts of any of these compounds.

[0157] Therefore, in another preferred embodiment of the invention, the compound according to formula (Id) is (4aR,10aR)-6-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-7-ylaminosulfonate having the following formula (II).

[0158]

[0159] Or its pharmaceutically acceptable salt.

[0160] Therefore, in another preferred embodiment of the invention, the compound according to formula (Id) is (4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6-ylaminosulfonate having the following formula (III).

[0161]

[0162] Or its pharmaceutically acceptable salt.

[0163] One embodiment of the present invention provides a pharmaceutically acceptable salt of a compound according to formula (Id). In one embodiment, the pharmaceutically acceptable salt is an acid addition salt as defined herein.

[0164] The purity of the compounds of the present invention can be determined by using different chromatographic methods, optionally in combination with mass spectrometry (e.g., LC / MS methods known in the art, such as those described in the Examples section).

[0165] In one embodiment of the invention, the compound according to formula (Id) or a pharmaceutically acceptable salt thereof is in a separated form that is substantially free of compounds having formula (I).

[0166] In one embodiment of the invention, the compound according to formula (Id) or its pharmaceutically acceptable salt is in a separated form having a purity greater than 90%, such as about 90% to 99.99%, such as 95%, such as 96%, such as 97%, such as 98%, such as 99%, such as 99.5%.

[0167] The compounds of the present invention can exist in different forms, such as amorphous or crystalline forms.

[0168] In one embodiment of the invention, the compound according to formula (Id) or a pharmaceutically acceptable salt thereof is in solid form. In an even more preferred embodiment of the invention, the compound having formula (Id) or a pharmaceutically acceptable salt thereof is in crystalline form.

[0169] The solid form can also be an amorphous solid form. Therefore, in one embodiment of the invention, the compound according to formula (Id) is in an amorphous solid form.

[0170] The present invention also includes isotopically labeled compounds similar to those claimed by formula (Id), wherein one or more atoms are represented by atoms of the same element whose atomic mass or mass number differs from that of atoms commonly found in nature (e.g., 2H, 3H, 11C, 13C, 15N, etc.). Particular mention is made of 2H-substituted compounds, i.e., compounds in which one or more H atoms are represented by deuterium.

[0171] In one embodiment of the invention, one or more hydrogen atoms of the compound having formula (Id) are represented by deuterium. It should be recognized that in most synthetic compounds, the element is present in its natural isotopic abundance, resulting in the inherent incorporation of deuterium. However, the natural isotopic abundance of hydrogen isotopes (such as deuterium) is not significant relative to the degree of stable isotopic substitution of the compounds described herein (approximately 0.015%).

[0172] Pharmaceutical Composition

[0173] Another aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound having formula (Id) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0174] In a preferred embodiment, the pharmaceutical composition comprises a compound having formula (Id) selected from the group consisting of: compound (II), compound (III), and their pharmaceutically acceptable salts.

[0175] Another aspect of the invention provides a method for preparing a pharmaceutical composition comprising a compound having formula (Id) or a pharmaceutically acceptable salt thereof, and more preferably, the method is used for preparing a pharmaceutical composition comprising a compound comprising the group consisting of compounds (II) and (III) herein or a pharmaceutically acceptable salt thereof.

[0176] The pharmaceutical compositions according to the invention can be formulated with pharmaceutically acceptable excipients according to conventional techniques, such as those disclosed in Remington, “The Science and Practice of Pharmacy”, 22nd edition (2013), edited by Allen, Loyd V., Jr.

[0177] Preferably, the pharmaceutical composition comprising the compounds of the present invention is a pharmaceutical composition for oral administration. Pharmaceutical compositions for oral administration include solid oral dosage forms such as tablets, capsules, powders, and granules; and liquid oral dosage forms such as solutions, emulsions, suspensions, and syrups, as well as powders and granules to be dissolved or suspended in a suitable liquid.

[0178] Solid oral dosage forms can be presented as discrete units (e.g., tablets, hard capsules, or soft capsules), each unit containing a predetermined amount of active ingredient and preferably one or more suitable excipients. Where appropriate, these solid dosage forms can be formulated with a coating (e.g., enteric coating) according to methods well known in the art, or they can be formulated to provide modified release of the active ingredient, such as delayed or prolonged release. Where appropriate, solid dosage forms can be saliva-disintegrating dosage forms, such as orally dispersible tablets, for example.

[0179] In a preferred embodiment of the invention, the pharmaceutical composition is for oral administration and is selected from the group consisting of tablets and capsules.

[0180] 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, talc, gelatin, pectin, magnesium stearate, stearic acid, and lower alkyl ethers of cellulose. Similarly, solid dosage forms may include excipients known in the art for delayed or prolonged release formulations, such as glyceryl monostearate or hydroxypropyl methylcellulose. If the solid material is intended for oral administration, the formulation may be prepared, for example, by mixing the active ingredient with the solid excipient and subsequently compressing the mixture in a conventional tableting machine; or the formulation may be, for example, placed in hard capsules in the form of powder, pills, or microtablets. The amount of solid excipient will vary widely, but will typically range from about 25 mg to about 1 g per dose unit.

[0181] Liquid oral dosage forms can take the form of, for example, elixirs, syrups, oral drops, or liquid-filled capsules. Liquid oral dosage forms can also take the form of powders for use as solutions or suspensions in aqueous or non-aqueous liquids. Examples of excipients suitable for liquid oral formulations include, but are not limited to, ethanol, propylene glycol, glycerin, polyethylene glycol, poloxamer, sorbitol, polysorbate, monoglycerides and diglycerides, cyclodextrin, coconut oil, palm oil, and water. Liquid oral dosage forms can be prepared, for example, by dissolving or suspending the active ingredient in an aqueous or non-aqueous liquid, or by incorporating the active ingredient into an oil-in-water or water-in-oil liquid emulsion.

[0182] Other excipients (such as colorants, flavoring agents, and preservatives) can be used in solid and liquid oral formulations.

[0183] Pharmaceutical compositions intended 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 will be reconstituted in a sterile solution or dispersion for injection or infusion prior to use. Examples of excipients suitable for parenteral formulations include, but are not limited to, water, coconut oil, palm oil, and cyclodextrin solutions. Aqueous formulations should be appropriately buffered where necessary, and made isotonic with sufficient saline or glucose.

[0184] Other types of pharmaceutical compositions include suppositories, inhalers, creams, gels, skin patches, implants, and formulations for buccal or sublingual administration.

[0185] Excipients used in any pharmaceutical formulation must conform to the intended route of administration and be compatible with the active ingredient.

[0186] Uses and methods for treatment

[0187] Other aspects of the invention provide a compound of formula (Id) for use as a medicament, and a treatment method wherein the compound of formula (Id) is administered to a subject in need.

[0188] Medical indications and conditions for treatment

[0189] The compounds of the present invention are conjugated versions of dopamine agonists, and therefore the compounds of the present invention are intended for use in the treatment of neurodegenerative diseases and disorders, such as Parkinson's disease, and / or other conditions for which there is therapeutic benefit when treated with dopamine agonists.

[0190] Therapeutic indications for the use of dopamine agonists with therapeutic benefit include a variety of central nervous system disorders characterized by motor and / or nonmotor disturbances, and for which, an underlying pathophysiological part is dysfunction of striatal-mediated circuits. Such functional disturbances can be seen in neurodegenerative diseases, such as, but not limited to, Parkinson's disease (PD), restless lower extremities syndrome, Huntington's disease, and Alzheimer's disease, and / or neuropsychiatric disorders, such as, but not limited to, schizophrenia, attention deficit hyperactivity disorder, and substance addiction.

[0191] Therefore, in one embodiment of the invention, a compound of formula (Id) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the invention, is used to treat neurodegenerative diseases or disorders or neuropsychiatric diseases or disorders.

[0192] More specifically, in one embodiment of the invention, a compound of formula (Id) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the invention, is used to treat neurodegenerative diseases or disorders such as Parkinson's disease, Huntington's disease, restless limb syndrome or Alzheimer's disease, or neuropsychiatric diseases or disorders such as schizophrenia, attention deficit hyperactivity disorder or drug addiction.

[0193] The present invention also provides a method for treating the following diseases or disorders: neurodegenerative diseases or disorders, such as Parkinson's disease, Huntington's disease, restless limb syndrome, or Alzheimer's disease; or neuropsychiatric diseases or disorders, such as schizophrenia, attention deficit hyperactivity disorder, or drug addiction; the method comprising administering to a patient in need a therapeutically effective amount of a compound of formula (Id) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present invention.

[0194] Compounds suitable for oral administration have the potential to provide a new treatment paradigm for Parkinson's disease. Therefore, in a preferred embodiment of the invention, a compound of the invention according to formula (Id) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the invention, is used in a method for treating Parkinson's disease.

[0195] Besides neurodegenerative diseases and disorders, increased dopaminergic turnover may be beneficial in other conditions involving improvements in mental function, including different cognitive aspects. It also has a positive effect in patients with depression, and it can be used as an appetite suppressant to treat obesity, as well as in the treatment of drug addiction. It can improve mild brain dysfunction (MBD), narcolepsy, attention deficit hyperactivity disorder, and potentially, negative, positive, and cognitive symptoms of schizophrenia.

[0196] Restless lower limb syndrome (RLS) and periodic limb movement disorder (PLMD) are alternative indications, which are clinically treated with dopamine agonists. Additionally, impotence, erectile dysfunction, SSRI-induced sexual dysfunction, ovarian hyperstimulation syndrome (OHSS), and certain pituitary tumors (prolactinomas) may also be improved by treatment with dopamine agonists. Dopamine is involved in the regulation of the cardiovascular and renal systems, and therefore renal failure and hypertension can be considered alternative indications for the compounds of this invention.

[0197] dose

[0198] The compounds of the present invention according to formula (Id) can be used for treatment at various doses required for therapy. Thus, in one embodiment, the compounds of the present invention are administered at doses ranging from about 0.0001 mg / kg body weight to about 5 mg / kg body weight per day. Specifically, the daily dose can range from about 0.001 mg / kg body weight to about 2 mg / kg body weight per day. The precise dosage will depend on the frequency and pattern of administration, the sex, age, weight and general condition of the subject to be treated, the nature and severity of the condition to be treated, any comorbidities to be treated, the desired therapeutic effect, and other factors known to those skilled in the art.

[0199] Typical oral doses for adults will be in the range of 0.01-100 mg / day of the compounds of the present invention, such as 0.05-50 mg / day, such as 0.1-10 mg / day, or 0.1-5 mg / day, or 1 mg / day-10 mg / day, or 10 mg / day-15 mg / day, 15 mg / day-25 mg / day, 25 mg / day-35 mg / day, 35 mg / day-45 mg / day, or such as 55 mg / day-65 mg / day, or 70 mg / day-85 mg / day, or 80 mg / day-95 mg / day.

[0200] Conveniently, the compounds of the present invention are administered in unit dosage forms containing amounts of the compounds as follows: about 0.01 to 100 mg, such as about 0.01 to 50 mg, such as 0.05 mg, 0.1 mg, 0.2 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or up to 50 mg of the compounds of the present invention.

[0201] Application route

[0202] Pharmaceutical compositions comprising a compound having formula (Id) (either as the sole active compound or in combination with another active compound) can be specifically formulated for administration via any suitable route, such as oral, rectal, nasal, buccal, sublingual, pulmonary, transdermal, and parenteral (e.g., subcutaneous, intramuscular, and intravenous) routes. In the context of this invention, oral administration is the preferred route of administration.

[0203] It will be understood that the pathway will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated, and the active ingredient.

[0204] Another aspect of the invention relates to a method for treating neurodegenerative diseases or disorders such as Parkinson's disease, Huntington's disease, restless limb syndrome, or Alzheimer's disease; or neuropsychiatric diseases or disorders such as schizophrenia, attention deficit hyperactivity disorder, or drug addiction; the method comprising administering to a patient in need a therapeutically effective amount of a compound having formula (Id) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the invention.

[0205] In a preferred embodiment of the invention, the treatment method is used to treat neurodegenerative diseases or disorders, and even more preferably to treat Parkinson's disease.

[0206] Another aspect of the invention relates to the use of a compound according to formula (Id) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the invention, in the manufacture of a medicament for the treatment of neurodegenerative diseases or disorders such as Parkinson's disease, Huntington's disease, restless limb syndrome, or Alzheimer's disease; or for the treatment of neuropsychiatric diseases or disorders such as schizophrenia, attention deficit hyperactivity disorder, or drug addiction.

[0207] In a preferred embodiment of the invention, a compound having formula (Id) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the invention, is used to manufacture a medicament for treating neurodegenerative diseases or disorders; and even more preferably, for manufacturing a medicament for treating Parkinson's disease.

[0208] In one embodiment of the invention, a compound having formula (Id) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the invention, is used as the sole active compound for treatment alone.

[0209] In one embodiment of the invention, a compound having formula (Id) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the invention, is used as a standalone treatment for neurodegenerative diseases or disorders such as Parkinson's disease.

[0210] combination

[0211] In another embodiment of the invention, a compound having formula (Id) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the invention, may be used in combination with other agents that can be used to treat neurodegenerative diseases or disorders such as Parkinson's disease.

[0212] In one embodiment of the invention, a compound selected from the group consisting of compounds (II), (III), and (IV), or a pharmaceutically acceptable salt of any of these compounds, is used in combination with other agents that can be used to treat neurodegenerative diseases or disorders (such as Parkinson's disease). In one embodiment of the invention, a compound selected from the group consisting of compounds (II), (III), and (V), or a pharmaceutically acceptable salt of any of these compounds, is used in combination with other agents that can be used to treat neurodegenerative diseases or disorders (such as Parkinson's disease). In even more particular embodiments, a compound selected from the group consisting of compounds (II) and (III), or a pharmaceutically acceptable salt of any of these compounds, is used in combination with other agents that can be used to treat neurodegenerative diseases or disorders (such as Parkinson's disease).

[0213] These two compounds can be administered simultaneously or at intervals between their administration. They can be administered as part of the same pharmaceutical preparation or composition, or in separate pharmaceutical preparations or compositions. They can be administered on the same day or on different days. They can be administered via the same route, such as, for example, oral administration, subcutaneous injection, transdermal administration, via a reservoir, via intramuscular injection, or intravenous injection; or via different routes, where one compound is administered, for example, or placed in a reservoir, and the other compound is administered, for example, by injection. These two compounds can be administered via the same dosing regimen or at the same time interval, such as once or twice daily, weekly, or monthly; or via different dosing regimens, for example, one administered once daily, and the other twice daily, weekly, or monthly.

[0214] In some cases, when treatment is initiated with a compound having formula (Id) or a pharmaceutically acceptable salt thereof, the patient may already be being treated with one or more other compounds that can be used to treat neurodegenerative diseases or disorders. In other cases, when treatment is initiated with one or more other compounds that can be used to treat neurodegenerative diseases or disorders, the patient may already be being treated with a compound having formula (Id). In still other cases, treatment with a compound having formula (Id) and treatment with one or more other compounds that can be used to treat neurodegenerative diseases or disorders are initiated simultaneously.

[0215] The compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions according to the present invention, may be used in combination with one or more compounds typically used to treat neurodegenerative diseases or disorders (such as Parkinson's disease). Therefore, in one embodiment of the present invention, compounds having formula (Id) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions according to the present invention, are used in combination with compounds selected from the group consisting of: L-DOPA, droxidopa, foliglurax, MAO-B inhibitors (such as selegiline or rasagiline), COMT inhibitors (such as entacapone or tolcapone), adenosine 2a antagonists (such as isradefylline), and antiglutaminase agents (such as amantadine). Acetylcholinesterase inhibitors (such as rivastigmine, donepezil, or galantamine) and antipsychotics (such as quetiapine, clozapine, risperidone, pimavanserin, olanzapine, haloperidol, aripiprazole, and brexpiprazole).

[0216] In one embodiment of the invention, a compound selected from the group consisting of compounds (II), (III), and (IV), or a pharmaceutically acceptable salt of any of these compounds, is used in combination with a compound selected from the group consisting of: L-DOPA, droxidopa, foliglurax, MAO-B inhibitors (such as selegiline or rasagiline), COMT inhibitors (such as entacapone or tocapone), adenosine 2a antagonists (such as itratheline), antiglutaminase agents (such as amantadine or memantine), acetylcholinesterase inhibitors (such as rivastigmine, donepezil, or galantamine), and antipsychotic agents (such as quetiapine, clozapine, risperidone, pimovancrine, olanzapine, haloperidol, aripiprazole, and epipiprazole).

[0217] In one embodiment of the invention, a compound selected from the group consisting of compounds (II), (III), and (V), or a pharmaceutically acceptable salt of any of these compounds, is used in combination with a compound selected from the group consisting of: L-DOPA, droxidopa, foliglurax, MAO-B inhibitors (such as selegiline or rasagiline), COMT inhibitors (such as entacapone or tocapone), adenosine 2a antagonists (such as itratheline), antiglutaminase agents (such as amantadine or memantine), acetylcholinesterase inhibitors (such as rivastigmine, donepezil, or galantamine), and antipsychotic agents (such as quetiapine, clozapine, risperidone, pimovancrine, olanzapine, haloperidol, aripiprazole, and epipiprazole).

[0218] In even more specific embodiments, a pharmaceutically acceptable salt of a compound selected from the group consisting of compounds (II) and (III) or any of these compounds is used in combination with a compound selected from the group consisting of: L-DOPA, droxidopa, foliglurax, MAO-B inhibitors (such as selegiline or rasagiline), COMT inhibitors (such as entacapone or tocapone), adenosine 2a antagonists (such as itratheline), antiglutaminogen agents (such as amantadine or memantine), acetylcholinesterase inhibitors (such as rivastigmine, donepezil, or galantamine), and antipsychotic agents (such as quetiapine, clozapine, risperidone, pimovasselin, olanzapine, haloperidol, aripiprazole, and epipiprazole).

[0219] In addition to small molecules, compounds used in combination with the compounds of the present invention may also include emerging biologic approaches for the treatment of neurodegenerative diseases or disorders, such as antibodies targeting α-synuclein, τ protein, or A-β protein.

[0220] Therefore, in one embodiment of the invention, a compound having formula (Id) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the invention, is used in combination with other agents for the treatment of Parkinson's disease, such as compounds selected from the group consisting of: L-DOPA, droxidopa, foliglurax, MAO-B inhibitors (such as selegiline or rasagiline), COMT inhibitors (such as entacapone or tocapone), adenosine 2a antagonists (such as itratheline), antiglutaminogen agents (such as amantadine or memantine), acetylcholinesterase inhibitors (such as rivastigmine, donepezil, or galantamine), antipsychotic agents (such as quetiapine, clozapine, risperidone, pimovancrine, olanzapine, haloperidol, aripiprazole, or epipiprazole); or in combination with antibodies targeting α-synuclein, τ protein, or A-β protein.

[0221] In one embodiment of the invention, a compound selected from the group consisting of compounds (II), (III), and (IV), or a pharmaceutically acceptable salt of any of these compounds, is used in combination with a compound selected from the group consisting of: L-DOPA, droxidopa, foliglurax, MAO-B inhibitors (such as selegiline or rasagiline), COMT inhibitors (such as entacapone or tocapone), adenosine 2a antagonists (such as itratheline), antiglutaminogen agents (such as amantadine or memantine), acetylcholinesterase inhibitors (such as rivastigmine, donepezil, or galantamine), antipsychotic agents (such as quetiapine, clozapine, risperidone, pimovasselin, olanzapine, haloperidol, aripiprazole, or epipiprazole); or in combination with an antibody targeting α-synuclein, τ protein, or A-β protein.

[0222] In one embodiment of the invention, a compound selected from the group consisting of compounds (II), (III), and (V), or a pharmaceutically acceptable salt of any of these compounds, is used in combination with a compound selected from the group consisting of: L-DOPA, droxidopa, foliglurax, MAO-B inhibitors (such as selegiline or rasagiline), COMT inhibitors (such as entacapone or tocapone), adenosine 2a antagonists (such as itratheline), antiglutaminogen agents (such as amantadine or memantine), acetylcholinesterase inhibitors (such as rivastigmine, donepezil, or galantamine), antipsychotic agents (such as quetiapine, clozapine, risperidone, pimovancrine, olanzapine, haloperidol, aripiprazole, or epipiprazole); or in combination with an antibody targeting α-synuclein, τ protein, or A-β protein.

[0223] In even more specific embodiments, a pharmaceutically acceptable salt of a compound selected from the group consisting of compounds (II) and (III) or any of these compounds may be used in combination with a compound selected from the group consisting of: L-DOPA, drosidopa, foliglurax, MAO-B inhibitors (such as selegiline or rasagiline), COMT inhibitors (such as entacapone or tocapone), adenosine 2a antagonists (such as itratheline), antiglutaminogen agents (such as amantadine or memantine), acetylcholinesterase inhibitors (such as rivastigmine, donepezil, or galantamine), antipsychotic agents (such as quetiapine, clozapine, risperidone, pimovasselin, olanzapine, haloperidol, aripiprazole, or epipiprazole); or in combination with an antibody targeting α-synuclein, τ protein, or A-β protein.

[0224] In one embodiment, the compound according to formula (Id) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention, is used as the sole medicament for treating the patient. In another embodiment, the compound according to formula (Id) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention, is used to treat a patient who has not yet been treated with another medicament selected from the above list.

[0225] One aspect of the invention provides the use of a compound according to formula (Id) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the invention, in the manufacture of a medicament for treating neurodegenerative diseases or disorders such as Parkinson's disease, Huntington's disease, restless limb syndrome, or Alzheimer's disease; or neuropsychiatric diseases or disorders such as schizophrenia, attention deficit hyperactivity disorder, or substance addiction. In a preferred embodiment, the medicament is used to treat Parkinson's disease.

[0226] Exemplary compounds of the present invention

[0227] Table 1: Overview of exemplary compounds of the present invention

[0228] Example

[0229] Example 1 - Preparation of the compound of the present invention

[0230] The compounds of the present invention having the general formula Id (wherein R1 and R2 are as defined above) can be prepared by the methods outlined in the following examples. In the described methods, variations or modifications known to a skilled chemist in the art or readily apparent to those skilled in the art are possible. Furthermore, other methods for preparing the compounds of the present invention, according to the following examples, will be readily apparent to those skilled in the art.

[0231] The starting materials used in this paper are commercially available or can be prepared by conventional methods known in the art, such as those described in standard reference books (e.g., "Compendium of Organic Synthetic Methods," Volumes I-XII, published by Wiley-Interscience). Preferred methods include, but are not limited to, those described below.

[0232] More specifically, the compound (4aR,10aR)-1-n-propyl-2H,3H,4H,4aH,5H,10H,10aH-benzo[g]quinoline-6,7-diol can be prepared according to, for example, the description in WO 2009 / 026934.

[0233] These schemes are representative of methods that can be used to synthesize the compounds of this invention. They are not intended to limit the scope of this invention in any way.

[0234] Compound (II)

[0235] (4aR,10aR)-6-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-7-ylaminosulfonate

[0236]

[0237] Formic acid (1.32 g, 28.7 mmol) was added dropwise to a stirred solution of chlorosulfonyl isocyanate (4.07 g, 28.6 mmol) in acetonitrile (20 mL) at room temperature. The resulting mixture was stirred overnight at room temperature. (4aR,10aR)-1-n-propyl-2H,3H,4H,4aH,5H,10H,10aH-benzo[g]quinoline-6,7-diol (1.50 g, 5.7 mmol) and N,N-dimethylacetamide (10 mL) were added to the mixture. The resulting mixture was stirred for another 6 hours at room temperature. The reaction was quenched by adding 10 mL of ammonium hydroxide solution at room temperature. The resulting mixture was concentrated under reduced pressure.

[0238] The residue was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 19*250 mm, 10 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 17% B to 32% B over 10 min; 220 nm; retention time: 9-10 min) to give (4aR,10aR)-6-hydroxy-1-propyl-2H,3H,4H,4aH,5H,10H,10aH-benzo[g]quinoline-7-ylaminosulfonate (406 mg).

[0239] LC-MS instrument and protocol: Shimadzu LCMS-2020, equipped with a Shim-Pack XR-ODS C18 column (L=50mm, D=3.0mm) operating at 40°C. Mobile phase A: 0.05% TFA aqueous solution; Mobile phase B: 0.05% TFA acetonitrile solution. Flow rate: 1.2 mL / min.

[0240] gradient:

[0241] 0-3.2min A:B 95:5;

[0242] 3.2min–3.7min: A:B 1:1;

[0243] 3.7min–4.75min: A:B 0:1;

[0244] 4.75min–5.0min: A:B 95:5.

[0245] LC-MS (MH+): m / z = 341.2, retention time (min) = 1.523

[0246] 1H NMR (400MHz, DMSO) δ7.01-6.99(d,1H),6.62-6.60(d,1H),2.94-2..911(m,1H),2.85-2.79(m,1H),2.72-2.66(m,1H),2.51-2 .49(m,1H),2.45-2.28(m,1H),2.16-2.06(m,3H),1.85-1.82(m,1H),1.64-1.40(m,5H),1.09-1.06(m,1H),0.86-0.83(t,3H).

[0247] Compound (III)

[0248] (4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6-ylaminosulfonate

[0249]

[0250] Formic acid (1.32 g, 28.7 mmol) was added dropwise to a stirred solution of chlorosulfonyl isocyanate (4.07 g, 28.6 mmol) in acetonitrile (20 mL) at room temperature. The resulting mixture was stirred overnight at room temperature. (4aR,10aR)-1-n-propyl-2H,3H,4H,4aH,5H,10H,10aH-benzo[g]quinoline-6,7-diol (1.50 g, 5.7 mmol) and N,N-dimethylacetamide (10 mL) were added to the mixture. The resulting mixture was stirred for another 6 hours at room temperature. The reaction was quenched by adding 10 mL of ammonium hydroxide solution at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 19*250 mm, 10 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 17% B to 32% B over 10 min; 254 nm; retention time: 8.18 min) to give (4aR,10aR)-7-hydroxy-1-propyl-2H,3H,4H,4aH,5H,10H,10aH-benzo[g]quinoline-6-ylaminosulfonate (297 mg).

[0251] LC-MS instrument and protocol: Shimadzu LCMS-2020, equipped with a Shim-Pack XR-ODS C18 column (L=50mm, D=3.0mm) operating at 40°C. Mobile phase A: 0.05% aqueous solution of TFA; Mobile phase B: 0.05% acetonitrile solution of TFA. Flow rate: 1.2 mL / min.

[0252] gradient:

[0253] 0-3.2min A:B 95:5;

[0254] 3.2min–3.7min: A:B 1:1;

[0255] 3.7min–4.75min: A:B 0:1;

[0256] 4.75min–5.0min: A:B 95:5.

[0257] LC-MS (MH+): m / z = 341.2, retention time (min) = 1.42

[0258] 1H NMR (400MHz, DMSO) δ6.82-6.84(d,1H),6.73-6.70(d,1H),3.12-3.07(m,1H),2.95-2.90(m,1H),2.72-2.63(m,1H),2.53-2. 51(m,1H),2.50-2.43(m,1H),2.41-2.32(m,3H),1.82-1.79(m,1H),1.64-1.39(m,5H),1.07-1.02(m,1H),0.86-0.82(t,3H).

[0259] Compound (V)

[0260] (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-dimethylbis(aminosulfonate)

[0261] Formic acid (1.32 g, 28.7 mmol) was added dropwise to a stirred solution of chlorosulfonyl isocyanate (4.07 g, 28.6 mmol) in acetonitrile (20 mL) at room temperature. The resulting mixture was stirred overnight at room temperature. (4aR,10aR)-1-propyl-2H,3H,4H,4aH,5H,10H,10aH-benzo[g]quinoline-6,7-diol (1.50 g, 5.7 mmol) and N,N-dimethylacetamide (10 mL) were added to the mixture. The resulting mixture was stirred for another 6 hours at room temperature. The reaction was quenched by adding ammonium hydroxide solution (10 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 19*250 mm, 10 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 17% B to 32% B over 10 min; 254 nm) to give (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-dimethylbis(aminosulfonate).

[0262] Example 2 – In vivo conversion to dopamine agonist (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol

[0263] This example demonstrates that the selected compound of the present invention is converted into compound (I) in rats.

[0264] PK experiment in rats

[0265] For experiments involving compounds (Ia), (Ib), (Ic), (Id-iia), (Id-iib), and (Id-iiab), these compounds were synthesized as described in the following literature: WO 2019101917; Liu et al., J. Med. Chem. (2006), 49:1494-1498; Liu et al., Bioorganic Med. Chem. (2008) and WO 2009 / 026934. Approximately 0.68 mL of blood was drawn from the tail vein or sublingual vein and placed in a pre-cooled K3EDTA tube prepared with a stable aqueous solution consisting of 80 μL of 100 mg / mL ascorbic acid and 40 μL of an inhibitor solution containing 0.5 M citric acid and 100 mM D-gluconic acid 1,4-lactone in water. Gently invert these tubes 6–8 times to ensure thorough mixing, and then place them on wet ice. Keep the collection tubes on wet ice for up to 30 minutes until centrifugation (3000G for 10 minutes at 4°C). Once removed from the wet ice, begin centrifugation immediately. Immediately after centrifugation, return the sample to the wet ice. Transfer two subsamples of 130 μL of plasma to each of two appropriately labeled cryovials containing 6.5 μL of pre-chilled formic acid (20% aqueous solution v / v). Immediately cap the tubes and thoroughly mix the plasma solution by gently inverting 6–8 times. Place the plasma samples on water-ice as close to the surface as possible and freeze-store at nominal -70°C for up to 60 minutes after sampling.

[0266] For experiments involving compounds (II) and (III), the above protocol was used, except that the K3EDTA tubes were prepared with a stable aqueous solution consisting of 80 μL of 100 mg / mL ascorbic acid and 40 μL of an inhibitor solution containing 100 mg / mL citric acid, 21 mg / mL D-gluconic acid 1,4-lactone and 29 mg / mL tris-(2-carboxyethyl)phosphine (TCEP).

[0267] Plasma samples were analyzed by solid-phase extraction or direct protein precipitation followed by UPLC-MS / MS. MS detection was performed in positive ion mode using electrospray ionization, where specific mass-charge transitions of compound (I) were monitored, and the response was corrected using an internal standard. Concentration-time data were analyzed using standard software and appropriate non-compartmental techniques to obtain estimates of derived PK parameters.

[0268] Instruments for analyzing compound (I) derived from drug-administered compound (Ia):

[0269] Mass spectrometer (LC-MS / MS): Waters Acquity-Sciex API 5000. Analytical column: Waters BEH UPLC Phenyl 100x2.1 mm column, 1.7 μm particle size. Mobile phase A: 20 mM ammonium formate (aqueous solution) + 0.5% formic acid. Mobile phase B: acetonitrile. Gradient run from 95% / 5% to 2 / 98 in 6.1 min. Flow rate: 0.5 mL / min. MRM (multiple reaction monitoring) of test items and added analytical standards.

[0270] Administration of compound (Ia) and blood sampling:

[0271] Han Wistar rats were supplied by Charles River Laboratories, Sulzfeld, Germany. A 12-hour artificial, automated light and dark cycle was maintained. The rats received a standard laboratory diet from Brogaarden (Altromin 1324 granules). No dietary restrictions were imposed on the rats. During the study (4-week toxicity study), the rats received the (Ia) dose orally once daily via gavage. Blood samples were collected from three male satellite animals from rats administered 300 μg / kg (Ia) at the following time points on day 29: 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-administration.

[0272] Instruments for analyzing compound (I) derived from drug-administered compound (Ib):

[0273] Mass spectrometer (LC-MS / MS): Waters Acquity-Sciex API 5000. Analytical column: Waters BEH UPLC Phenyl 100x2.1 mm column, 1.7 μm particle size. Mobile phase A: 20 mM ammonium formate (aqueous solution) + 0.5% formic acid. Mobile phase B: acetonitrile. Gradient run from 95% / 5% to 2 / 98 in 6.1 min. Flow rate: 0.5 mL / min. MRM monitoring of test items and added analytical standards.

[0274] Administration of compound (Ib) and blood sampling:

[0275] Han Wistar rats were supplied by Charles River Laboratories, UK. A 12-hour artificial, automated light and dark cycle was maintained. Rats received a standard laboratory diet (Teklad 2014C diet). No dietary restrictions were imposed on the rats. During the study (26-week toxicity study), rats received the dose (Ib) orally once daily via gavage. Blood samples were collected from three male satellite animals from rats administered 300 μg / kg (Ib) at the following time points on day 182: 0.5, 1, 2, 4, 8, and 24 hours post-administration.

[0276] Instruments for analyzing compounds (I) derived from prior art compound (Ic) and (4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6-yl hydrogen sulfate (compound Id-iia), and (4aR,10aR)-6-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-7-yl hydrogen sulfate (compound Id-iib), and (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-dimethylbis(hydrogen sulfate) (compound (Id-iiab)):

[0277] Mass spectrometer (LC-MS / MS): Waters Acquity-Waters Xevo TQ-S. Analytical column: Acquity BEH C18 100x2.1 mm, 1.7 μm. Mobile phase A: 20 mM NH4-formate + 0.2% formic acid. Mobile phase B: acetonitrile + 0.2% formic acid. Gradient run from 95% / 5% to 5% / 95% over 11.0 min. Flow rate: 0.3 mL / min. MRM monitoring of test items and added analytical standards.

[0278] Dosing and blood sampling for compounds (Id-iia) and (Id-iib):

[0279] Han Wistar rats were supplied by Charles River Laboratories, Wiga GmbH, Germany. A 12-hour artificial, automated light and dark cycle was maintained. The rats received a standard laboratory diet from Brogaarden (Altromin 1324 pellets). No dietary restrictions were imposed. Male Han Wistar rats were administered (Id-iia) and (Id-iib) via single oral gavage. Blood samples were collected from three male rats at 392 μg / kg (Id-iia) and (Id-iib) on day 1 at the following time points: 1, 2, 4, 6, 8, and 24 hours post-administration.

[0280] Dosing and blood sampling for compounds (Ic) and (Id-iiab):

[0281] Han Wistar rats were supplied by Envigo, UK. A 12-hour artificial, automated light and dark cycle was maintained. The rats received a standard laboratory diet of Teklad 2014C. No dietary restrictions were imposed. Male Han Wistar rats were administered (Ic) and (Id-iiab) via single oral gavage. The dosages were 703 μg / kg (Id-iiab) and 494 μg / kg (Ic). Blood samples were collected from three male animals at the following time points on day 1: 1, 2, 4, 6, 8, and 24 hours post-administration.

[0282] Dosing and blood sampling for compounds (II) and (III):

[0283] Han Wistar rats were supplied by Envig Ltd., UK. An artificial, automated light and dark cycle was maintained for 12 hours. Rats were fed a standard laboratory diet of Teklad 2014C. No dietary restrictions were imposed on the rats. Male Han Wistar rats were administered compound (II) or (III) via a single oral gavage. Rats were given either 390 μg / kg of compound (II) or 390 μg / kg of compound (III). Blood samples were collected from three male animals at the following time points on day 1 post-administration: 5 min, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h.

[0284] Instruments for analyzing compound (I) derived from compounds (II) and (III):

[0285] Mass spectrometer (LC-MS / MS): Waters Acquity-Waters Xevo TQ-S. Analytical column: Acquity BEH C18 100x2.1 mm, 1.7 μm. Mobile phase A: 20 mM NH4-formate + 0.2% formic acid. Mobile phase B: acetonitrile + 0.2% formic acid. Gradient ran from 95% / 5% to 5% / 95% in 9.1 min. Flow rate: 0.3 mL / min. MRM monitoring of test items and added analytical standards.

[0286] The mean plasma concentrations of (4aR, 10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol (compound (I)) measured in plasma from three subjects at different time points after administration of compounds (II) and (III) were as follows: Figure 2 and 1 It is displayed in the middle.

[0287] Table 2 below further summarizes the PK parameters based on the measured average plasma concentration.

[0288] The results in Table 2 indicate that the plasma exposure of tested compounds (II) and (III) over the entire 24-hour period was lower than the corresponding exposures observed with prior art compounds (Ia) and (Ib), but higher than the corresponding exposures with prior art compound (Ic), which was found unsuitable for use as a prodrug. Furthermore, the Cmax of compound (I) observed after administration of both compounds (II) and (III) was lower than the Cmax achievable with prior art compounds (Ia) and (Ib), as well as prior art sulfate conjugates (Id-iia) and (Id-iib).

[0289] For compounds (II) and (III), since the peak concentration (Cmax) of compound (I) which is expected to drive side effects is lower, higher doses of the compounds of the present invention can be administered, thereby potentially achieving higher overall plasma concentrations of compound (I) compared to the results achievable from administering compounds (Ia), (Ib), (Id-iia), and (Id-iib).

[0290] For compound (II), Tmax was observed after 1 hour, similar to prior art compounds (Ia), (Ib) and (Ic), while prior art compounds (Id-iia), (Id-iib) and (Id-iiab) had Tmax after several hours.

[0291] Table 2. According to Example 2, when 0.300 mg / kg (Ia), 0.300 mg / kg (Ib), 0.494 mg / kg (Ic), 0.392mg / kg (Id-iia), 0.392mg / kg (Id-iib), 0.703mg / kg (Id-iiab), 0.39mg / kg compound (II) Following oral administration of compound (III) at 0.39 mg / kg to Wistar rats, (4aR,10aR)-1-propyl-1,2,3,4,4a,5, PK parameters of 10,10a-octahydro-benzo[g]quinoline-6,7-diol (compound (I))

[0292]

[0293] Example 3 - Solubility of the compound of the present invention

[0294] The following examples demonstrate that the compounds of the present invention have higher solubility at pH 6.0 compared to prior art sulfate derivative compounds.

[0295] Experimental procedure:

[0296] For compound (III), a sample was prepared using an excess of compound (III) to establish a saturated solution. 4.2 mg of compound (III) was transferred to a vial and 0.5 mL of buffer (25 mM phosphate buffer, NaH₂PO₄ / Na₂HPO₄, pH 6) was added. The sample was mixed by rotation for 24 hours. The pH of the sample was measured at t = 0 (before rotation) and t = 24 h (after 24 h rotation). Subsequently, some of the sample was filtered through a 0.22 μm polyvinylidene fluoride filter, discarding the first few drops, and the sample was then subjected to reversed-phase HPLC (C0). 18 The concentration of dissolved compound (III) was quantified using a 3.5 μm, 4.6 x 150 mm column with 20 mM ammonium buffer (pH 2.4) and methanol (80:20) as eluent.

[0297] The remaining undissolved material was extracted and air-dried on a metal plate for approximately 20 minutes, then analyzed by X-ray powder diffraction (XRPD). CuKa1 radiation was applied using a PANalytical X'Pert PRO X-ray diffractometer. Obtain XRPD diffraction patterns. Measure the sample using an X'celerator detector in reflection mode within the 2θ range of 3–39.9°.

[0298] For compound (Id-iib), a similar analysis was performed using 0.799 mg of compound (Id-iib) in 0.5 mL buffer.

[0299] Additionally, use ADMET Predictor TM Version 10.3.0.7 (Simulations Plus) predicts physical and chemical property values.

[0300] Table 3 shows the predicted Log P and Log D values ​​and the measured solubility for the following compounds:

[0301]

[0302] result:

[0303] The measured solubility of compound III was determined to be 0.89 mg / mL. The crystalline form remained the same before and after mixing with the buffer, indicating no change in solid form.

[0304] For the prior art sulfate derivative compound (Id-iib), a solubility of 0.037 mg / mL was determined. The crystalline form was the same before and after mixing with buffer, indicating no change in solid form.

[0305] The sulfate derivative compounds (Id-iia) and (Id-iib) are structurally very similar, resulting in highly similar predicted pKa values, as well as Log P and D. Therefore, the expected solubility of compound (Id-iia) is very similar to the measured solubility of compound (Id-iib).

[0306] Furthermore, the aminosulfonate derivative compounds (II) and (III) are structurally very similar, resulting in very similar predicted pKa values, as well as Log P and D. Therefore, the solubility of compound II is expected to be very similar to the measured solubility of compound III.

[0307] In summary, the data from this embodiment demonstrate that the compounds of the present invention have higher solubility than prior art sulfate derivatives.

[0308] Example 4: Transformation of the compounds of the present invention in rat and human liver S9

[0309] Compounds (II), (III), (Id-iia), and (Id-iib) were incubated at 1 μM with rat and human liver S9 fractions suspended in 50 mM phosphate-buffered saline (containing 5 mM MgCl2, 200 U / mL superoxide dismutase, and 1 mM ascorbic acid) at pH 7.4. Human liver S9 fractions (from a pool of 50 donors) and rat liver S9 fractions (from a pool of 240 Wistar Han rats) were purchased from Sekisui XenoTech, USA. The protein concentration during incubation was 4 mg / mL. Incubation was performed at 37 °C in 96-well plates using an automated Hamilton liquid handling system, with a total incubation volume of 150 μL / well. Each compound was incubated in triplicate in three wells at each time point. The liver S9 suspension was pre-incubated at 37 °C, and the reaction was initiated by adding the stock solution of the test compound to the incubation well. The test compound was dissolved in dimethyl sulfoxide (DMSO) and further diluted in water. The stock solution was then added to the incubation wells. The final DMSO concentration during incubation was 0.1%. The test compound was incubated with liver S9 fraction for 0, 5, 10, 15, 30, 45, and 60 minutes. Incubation was terminated by transferring 100 μL of the incubated sample to a 96-well plate containing 100 μL of a cold (approximately +4 °C) termination reagent containing 2% formic acid, 20 mg / mL ascorbic acid, 10 mg / mL citric acid, and 3 mg / mL TCEP (tris(2-carboxyethyl)phosphine). After mixing, the sample was transferred to a Nunc 1.0 mL cryovial and immediately frozen at -80 °C until analysis. The concentration of compound (I) was determined after solid-phase extraction of the sample and subsequent LC-MS / MS analysis. The increase in the concentration of compound (I) at different time points was calculated by subtracting the concentration of compound (I) in the sample obtained at time 0 from the concentration of compound (I) in the sample obtained at different time points.

[0310] Instruments for analyzing compound (I) derived from incubated compounds (II), (III), (Id-iia), and (Id-iib):

[0311] Mass spectrometer (LC-MS / MS): Waters Acquity-Waters Xevo TQ-S. Analytical column: Acquity BEH C18, 50 x 2.1 mm, 1.7 μm. Mobile phase A: 0.2% formic acid in 20 mM NH4-formate. Mobile phase B: 0.2% formic acid in acetonitrile. Gradient was run from 5% B to 95% B over 3.5 min. Flow rate: 0.6 mL / min. Multiple reaction monitoring (MRM) with positive polarization was used to monitor the precursor-product ion pair transition of compound (I) and its deuterated internal standard.

[0312] result:

[0313] Figure 3 and 4 This shows the effect on human liver S9 ( Figure 3 ) and rat liver S9 ( Figure 4 The increase in the concentration of compound (I) was measured at different time points after incubation of the S9 fraction with compounds (II), (III), (Id-iia), and (Id-iib). This was based on data from the human S9 liver fraction. Figure 3 The results showed that, compared with prior art sulfate conjugates (compounds (Id-iia) and (Id-iib)), the conversion of compounds (II) and (III) of the present invention to compound (I) was increased in the human liver S9 fraction. Incubation in rat liver S9 fractions showed that compounds (II), (III), and (Id-iib) were converted to compound (I).

[0314] References

[0315] US4543256

[0316] WO2001 / 078713

[0317] WO 02 / 100377

[0318] WO2009 / 026934

[0319] WO2009 / 026935

[0320] WO2010 / 097092

[0321] WO2019101917

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[0329] Elger,W;Barth,A;Hedden,A;Reddersen,G;Ritter,P;Schneider,B;Züchner,J;Krahl,E;Müller,K;Oettel,M;Schwarz,S;“Estrogen sulfamates:a new approach tooralestrogen therapy”;Reproduction,fertility and development(2001)13(4)p.297-305

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Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: (4aR,10aR)-6-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-7-ylaminosulfonate having the following formula (II) and (4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6-ylaminosulfonate having the following formula (III). And its pharmaceutically acceptable salts.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is (4aR,10aR)-6-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-7-ylaminosulfonate having the following formula (II). Or its pharmaceutically acceptable salt.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is (4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6-ylaminosulfonate having the following formula (III). Or its pharmaceutically acceptable salt.

4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein the compound is substantially free of the isolated form of a compound having the following formula (I):

5. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein the compound or a pharmaceutically acceptable salt thereof is in solid form.

6. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is in solid form.

7. A pharmaceutically acceptable salt of the compound according to any one of claims 1-6.

8. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1-6 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

9. The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is an oral pharmaceutical composition.

10. The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is a tablet or capsule for oral administration.

11. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, or the pharmaceutical composition according to any one of claims 8-10, in the manufacture of a medicament for the treatment of neurodegenerative diseases or disorders or neuropsychiatric diseases or disorders.

12. The use according to claim 11, wherein the drug is used to treat Parkinson's disease, Huntington's disease, restless limb syndrome, or Alzheimer's disease.

13. The use according to claim 11, wherein the drug is used to treat schizophrenia, attention deficit hyperactivity disorder, or drug addiction.

14. The use according to claim 11, wherein the drug is used to treat Parkinson's disease.

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