Novel esters of 1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ol compounds and uses thereof

Abstract

Disclosed are compounds of formula (III), methods for making same, and uses thereof.

Description

[Technical field]

[0001] The present disclosure relates to novel esters of 1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ol compounds, methods for preparing such compounds, pharmaceutical compositions containing such compounds, and uses of such compounds. [Background technology]

[0002] Neurodegenerative diseases and neurological disorders are becoming more and more prevalent with the increasing number of aging populations around the world.One of the most common of these diseases and disorders is Parkinson's disease, which is characterized by tremors, movement disorders, and coordination disorders.Parkinson's disease is believed to be caused by the deterioration of dopamine-producing neurons in the brain, especially substantia nigra neurons.

[0003] Currently, there is no known cure for Parkinson's disease. Instead, treatment for Parkinson's disease focuses on providing symptomatic relief.

[0004] The state-of-the-art treatment of Parkinson's disease involves administering L-dopa or apomorphine to the patient. These compounds are known to exert their action by being agonists of D1 and / or D2 dopamine receptors. In the case of L-dopa, its active metabolite dopamine, the species that interacts at D1 and / or D2 dopamine receptors. However, therapy with L-dopa or apomorphine is associated with drawbacks. For example, L-dopa has low and variable biological bioavailability and is dependent on protein intake. Furthermore, the use of L-dopa can result in long-term complications such as dyskinesia. Apomorphine has a very short duration of action, and therefore patients must receive multiple injections per day. Apomorphine is also extensively metabolized and cannot be administered orally or intravenously. In fact, apomorphine can only be administered subcutaneously, such as via injection or infusion.

[0005] The low oral bioavailability of L-dopa and apomorphine is associated with the presence of a catechol moiety in these compounds. To reach the bloodstream and allow transport to the brain, most pharmaceutical drugs must pass through the gastrointestinal tract and liver, and most catecholamines undergo rapid biotransformation. Oral bioavailability can be increased by introducing protective groups to the hydroxyl and / or amino functional groups of the compound, for example, by slowing down the conversion to active metabolites and / or allowing the protected drug to function as a prodrug that can release the drug by removing the protective group by cleavage. One such prodrug of dopamine is, for example, docarpamine, in which the two hydroxyl groups of dopamine are protected as carbonic acid ethyl esters and the amino group is protected with an acetylmethionine moiety.

[0006] J.Med.Chem 2006,49,1494-1498 describes enone prodrugs of dopaminergic catecholamines in the research area of ​​dopamine receptor agonists. It is disclosed that the (-) enantiomer of the trans isomer of compound 1-propyl-2,3,4,4a,5,7,8,9,10,10a-decahydro-1H-benzo[g]quinolin-6-one (also named compound 4) acts as an enone prodrug of dopamine receptor agonists. It is suggested that the enone compound is converted in vivo to the corresponding catechol compound, which is named N-(n-propyl)-6,7-di-OH-benzo[g]quinoline (also named compound 3).

[0007] Bioorganic & Medicinal Chemistry, 16 (2008), 3438-3444, discloses the synthesis and pharmacological evaluation of a compound entitled racemic trans-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol (also named compound 4), which is believed to be the active form of its enone prodrug. It is stated that the catechol moiety of this compound is crucial for the observed low bioavailability. It is further stated that the high efficacy of the compound allows for the possibility of low dose administration, making it a possible candidate for the treatment of Parkinson's disease.

[0008] WO2010 / 097092 describes compounds for treating dyskinesia-related disorders such as Parkinson's disease. The compound (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol (also named compound 10) was found to function as a potent agonist at both D1 and D2 receptors in vitro and to have an active metabolite with a good profile as a dopamine agonist in vivo. It has also been described that a compound designated as (4aR,10aR)-n-1-propyl-2,3,4,4a,5,7,8,9,10,10a-decahydro-1H-benzo[g]quinolin-6-one (also named compound 12) can be used to prepare the aforementioned metabolites as well as in the preparation of a medicament for treating Parkinson's disease while maintaining a low dyskinesia induction profile.

[0009] WO 2001 / 078713 discloses maleate salts of two enantiomers of a compound designated 1-propyl-trans-2,3,4,4a,5,7,8,9,10,10a-decahydrobenzo[g]quinolin-6-one.

[0010] WO2019 / 101917 discloses catecholamine prodrugs for use in the treatment of Parkinson's disease. More specifically, the invention is described as relating to novel prodrug derivatives of the compound (4aR,10aR)-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol, the glucuronide and sulfate conjugates of which are reported to be orally active prodrugs of this compound.

[0011] Both WO2020 / 234270 and WO2020 / 234271 disclose processes for the manufacture of the catecholamine prodrug (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid. The catecholamine prodrug is described as being for use in the treatment of neurodegenerative diseases and disorders, such as Parkinson's disease.

[0012] WO2020 / 234272 discloses new solid forms of the catecholamine prodrug (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid. The catecholamine prodrug is described for use in the treatment of neurodegenerative disorders such as Parkinson's disease.

[0013] WO2020 / 234273 discloses a process for the preparation of two compounds (6aR,10aR)-7-propyl-6,6a,7,8,9,10,10a,11-octahydro-[1,3]dioxolo[4'.5'.5.6]benzo[1,2-g]quinoline and (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol. The compounds are described as being for use in the treatment of neurodegenerative diseases such as Parkinson's disease.

[0014] WO2020 / 234274, WO2020 / 234275, WO2020 / 234276, and WO2020 / 234277 disclose different prodrugs of the catecholamine (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol. The compounds are for use in the treatment of neurodegenerative or neuropsychiatric disorders, such as Parkinson's disease.

[0015] The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is general general knowledge.

[0016] The prior art compound 1-propyl-trans-2,3,4,4a,5,7,8,9,10,10a-decahydro-1H-benzo[g]quinolin-6-one (hereafter named (4aR,10aR)-1-propyl-1,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one), either as the racemate or its (4aR,10aR)-enantiomer, is an orally active prodrug of highly potent dopamine receptor agonists, as mentioned above. However, the administration of these compounds is associated with the risk of rapidly attaining high peak plasma concentrations and / or unexpected side effects such as nausea and vomiting.

[0017] Moreover, in Parkinson's disease, the degeneration of the nigrostriatal dopamine pathway is associated with core motor symptoms. This defect is addressed by available dopamine receptor agonists. However, there is also degeneration of other dopaminergic pathways in the brain. In particular, the degeneration of the mesolimbic dopamine pathway is associated with important non-motor symptoms such as depression and apathy in Parkinson's disease.

[0018] There is a need for new therapeutic agents that allow for the treatment of CNS diseases, disorders, and / or conditions, such as Parkinson's disease. In particular, there is a need for therapeutic agents that are potent, have a long duration of action, and / or have few side effects. Furthermore, there is a need for therapeutic agents that allow for the treatment of non-motor symptoms associated with Parkinson's disease. Summary of the Invention

[0019] It is an object of the present disclosure to provide novel therapeutically active compounds that at least partially overcome or alleviate some of the drawbacks of the aforementioned compounds. A further object is to provide novel therapeutically active compounds that are useful for treating CNS diseases, disorders, and / or conditions, such as Parkinson's disease. A still further object of the present disclosure is to provide novel therapeutically active compounds that are potent, have a long duration of action, and / or have few side effects, such as nausea and vomiting, when used to treat CNS diseases, disorders, and / or conditions, such as Parkinson's disease. It is also an object of the present disclosure to provide novel therapeutic agents that allow for the treatment of non-motor symptoms associated with Parkinson's disease. It is also an object of the present disclosure to provide aspects and / or advantages not provided by previously known techniques.

[0020] The present disclosure relates to a compound of formula III: [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony, Both carbon 4a and carbon 10a have the R configuration; R1 is methyl, ethyl, or n-propyl; R2 is C1-C 10 or a pharma- ceutically acceptable salt thereof.

[0021] The present disclosure also provides pharmaceutical compositions comprising a therapeutically acceptable amount of a compound of Formula III, as described herein, or a pharma- ceutically acceptable salt thereof, in admixture with at least one pharma- ceutically acceptable carrier, excipient, and / or diluent.

[0022] Also provided is a compound of formula III as described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use as a medicament.

[0023] Also provided is a compound of formula III as described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in treating one or more of the following: Parkinson's disease, Huntington's disease, restless legs syndrome, Alzheimer's disease, schizophrenia, attention deficit hyperactivity disorder, and drug addiction.

[0024] The present disclosure also provides the use of a compound of formula III as described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for the manufacture of a medicament for use in treating one or more of the following: Parkinson's disease, Huntington's disease, restless legs syndrome, Alzheimer's disease, schizophrenia, attention deficit hyperactivity disorder, and drug addiction.

[0025] The present disclosure also provides a method for treating one or more of the following: Parkinson's disease, Huntington's disease, restless legs syndrome, Alzheimer's disease, schizophrenia, attention deficit hyperactivity disorder, drug addiction, the method comprising administering to a mammal, such as a human or an animal in need thereof, an effective amount of (i) a compound of formula III as described herein or a pharma- ceutically acceptable salt thereof, or (ii) a pharmaceutical composition as described herein.

[0026] The present disclosure also provides a method for preparing a compound of formula III described herein, or a pharma- ceutically acceptable salt thereof, the method comprising: a) a compound of formula II and a compound of formula IV, [ka] During the ceremony, Both carbon 4a and carbon 10a of the compound of formula II have the R configuration; X is OH, halide, and OC(O)R 2 is selected from the group consisting of R 1 and R 2 is independently as described herein, and a compound of formula II and a compound of formula IV, optionally reacting in the presence of an ester formation promoter, such as a coupling reagent, thereby forming a compound of formula III; b) optionally separating the compound of formula III into a compound of formula IIIa and a compound of formula IIIb as defined herein; c) optionally combining the compound of formula III of step a) or step b) with a pharma- ceutically acceptable acid, thereby providing a pharma- ceutically acceptable salt of the compound of formula III. [Brief description of the drawings]

[0027] [Figure 1] 1 shows a reaction scheme for the preparation of compounds of formula III1. [Diagram 2] Chromatograms of the 6S epimer and 6R epimer of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ol are shown. [Diagram 3] FIG. 1 shows the effect of a prior art compound according to Preparation 4A on locomotor activity when the compound is administered subcutaneously. [Figure 4A] 1 shows the effect of a compound of the present disclosure according to Example 5 on locomotor activity when the compound is administered orally. [Figure 4B] 1 shows the effect of a compound of the present disclosure according to Example 5 on locomotor activity when the compound is administered subcutaneously. [Diagram 5] FIG. 1 shows the effect of a prior art compound according to Preparation 4A and a compound according to Example 5 on gene expression (mRNA) of Arc in different brain regions. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] The present disclosure relates to a compound of formula III: [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony, Both carbon 4a and carbon 10a have the R configuration; R 1 is methyl, ethyl, or n-propyl; R 2 But, C1-C 10 or a pharma- ceutically acceptable salt thereof.

[0029] "C1-C 10 The term "alkyl" refers to a straight or branched chain saturated, acyclic, or cyclic alkyl group of 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like. Alternatively, the alkyl group may be unsaturated, thereby containing 2 to 10 carbons, such as C2-C6. 10 Forms an alkene. C2-C 10 The alkene may be linear, branched, or acyclic and may contain one or more double bonds. 10Examples of alkenes include vinyl, allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl, and 1-nonenyl. Cyclic alkyl groups, i.e., cycloalkyl, can contain 3 to 10 carbon atoms and can include one or more cyclic groups. Examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. Additionally, cyclic alkyl groups can be partially cyclic, such as, for example, cyclopropylmethyl. Additionally, a cyclic alkyl group may contain one or more double bonds.

[0030] As used herein, the term "halide" can be Cl, Br, or I.

[0031] Thus, R of the compounds described herein 1 can be methyl, ethyl, or n-propyl. For example, R 1 can be ethyl or n-propyl. 1 is ethyl. In a further example, R 1 is n-propyl.

[0032] R 2 The substituents are C1-C 10 For example, R 2 can be methyl, ethyl, propyl, or butyl. 2 is methyl.

[0033] Compounds of formula III may exist as compounds of formula IIIa and / or compounds of formula IIIb: [ka]

[0034] R of compounds of formula IIIa and formula IIIb 1 and R 2 It will be understood that each of may be as described herein. Additionally, the compounds of formula IIIa and formula IIIb may have a structure in which the carbon atom at carbon 6 (i.e., OC(O)R 2 It is understood that these are epimers with different configurations on the carbon connected to the group. The compound of formula IIIa is the 6R epimer and the compound of formula IIIb is the 6S epimer. The stereochemistry of the tricyclic system of the compounds of formula IIIa and formula IIIb is as shown herein, i.e., the nitrogen-containing ring exhibits a trans configuration, with carbon 4a having the R configuration and carbon 10a having the R configuration. The numbering of the carbon atoms of the compounds of formula III, formula IIIa, and formula IIIb is shown below. [ka]

[0035] In one example, the compound of the present disclosure is a compound of formula IIIa. In a further example, the compound of the present disclosure is a compound of formula IIIb. In yet a further example, the compound of formula III is a mixture of a compound of formula IIIa and a compound of formula IIIb, such as a 1:1 mixture of a compound of formula IIIa and a compound of formula IIIb.

[0036] It will be understood that the nitrogen atoms of the compounds disclosed herein may be provided in an oxidized form, such as the compound of formula III2. One of skill in the art will appreciate that such compounds may be administered to a patient or may be formed in vivo following administration to a patient. [ka]

[0037] The present disclosure also relates to a compound comprising 1 is n-propyl, and R 2is methyl. The compound of formula III1 can be (4aR,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl acetate as shown. [ka]

[0038] It will be understood that the compound of formula III1 is an isomeric mixture of the 6R and 6S epimers, i.e., an isomeric mixture of the compounds of formula IIIa1 and IIIb1 described herein. [ka]

[0039] It will be appreciated that the compound of formula IIIa1 is the 6R epimer of the compound of formula III1 and may be the (4aR, 6R, 10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl acetate shown. It will be further appreciated that the compound of formula IIIb1 is the 6S epimer of the compound of formula III1 and may be the (4aR, 6S, 10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl acetate shown.

[0040] The compounds described herein may be provided as a single diastereomer, such as a diastereomer essentially free of any other diastereomer. A single diastereomer may have an R configuration at carbon 6 and an R configuration at both carbon 4a and carbon 10a. Alternatively, a single diastereomer may have an S configuration at carbon 6 and an R configuration at both carbon 4a and carbon 10a. Furthermore, a single diastereomer may be provided in a diastereomeric excess of 90% or more, such as 95% or more, or 99% or more. As used herein, diastereomeric excess is equal to the percentage of the major diastereomer minus the percentage of the minor diastereomer. For example, a mixture composed of 95% of the major diastereomer and 5% of the minor diastereomer has a diastereomeric excess of 90%.

[0041] The present disclosure provides pharma- ceutically acceptable salts of the compound(s) described herein, such as compounds of formula III, formula IIIa, formula IIIb, formula III2, formula III1, formula IIIa1, and formula IIIb1.

[0042] The pharmaceutically acceptable salt of the compound described herein can be provided as a combination of the compound of formula III described herein and an organic acid.Furthermore, the pharmaceutically acceptable salt of the compound described herein can be provided as a combination of the compound of formula III described herein and an organic acid in a ratio of 1:1 or 2:1.In one example, the ratio is 1:1.In a further example, the ratio is 2:1.The organic acid can be D-tartaric acid.

[0043] For example, a salt of III11, [ka] The salt is a combination of the compound of formula III1 and D-tartaric acid in a ratio of 1:n, [ka] During the ceremony, Salts are provided wherein n is 0.5 or 1. In particular, n may be 1.

[0044] Furthermore, there is provided a salt of IIIa11, [ka] the salt is a combination of the compound of formula IIIa1 and D-tartaric acid in a ratio of 1:n, [ka] During the ceremony, Salts are provided wherein n is 0.5 or 1. In particular, n may be 1.

[0045] Also, a salt of IIIb11, [ka] the salt is a combination of the compound of formula IIIb1 and D-tartaric acid in a ratio of 1:n, [ka] During the ceremony, Salts are provided wherein n is 0.5 or 1. In particular, n may be 1.

[0046] The compounds described herein or their pharma- ceutically acceptable salts may exist in solid form, i.e., may be provided as a solid. For example, the compounds described herein or their pharma- ceutically acceptable salts may be amorphous, crystalline, or a mixture thereof. Furthermore, the compounds described herein or their pharma- ceutically acceptable salts may exist in crystalline form, i.e., may be provided as crystal(s). The degree of crystallinity may be 80%, 85%, 90%, 95%, or 99% or more.

[0047] The compound of formula III as described herein or a pharma- ceutically acceptable salt thereof may be included in a pharmaceutical composition. Thus, a pharmaceutical composition is provided that includes a therapeutically acceptable amount of a compound of formula III as described herein or a pharma- ceutically acceptable salt thereof in admixture with at least one pharma- ceutically acceptable carrier, excipient, and / or diluent. As used herein, the term "therapeutically effective amount" refers to an amount of a compound disclosed herein that is sufficient to induce a desired therapeutic effect in a patient to whom the compound is administered. The pharmaceutical composition may be for oral administration. Additionally or alternatively, the pharmaceutical composition may be for rectal, intracisternal, intravaginal, intraperitoneal, and / or parenteral administration. In one example, parenteral administration may be administered intravenously, intramuscularly, or subcutaneously. Furthermore, the pharmaceutical composition may be provided in a solid form, such as in the form of one or more capsules, tablets, pills, powders, and / or granules. Alternatively, the pharmaceutical composition may be provided in a liquid form, such as in the form of one or more emulsions, solutions, suspensions, and / or syrups.

[0048] Also provided is a compound of formula III as described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use as a medicament.

[0049] Also provided is a compound of formula III as described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in treating one or more of the following: Parkinson's disease, Huntington's disease, Restless Legs Syndrome, Alzheimer's disease, schizophrenia, Attention Deficit Hyperactivity Disorder, and drug addiction. For example, the treatment and may include or consist of the treatment of Parkinson's disease. In a further example, the treatment may include or consist of the treatment of Huntington's disease or Restless Legs Syndrome. In yet a further example, the treatment may include or consist of the treatment of Alzheimer's disease or schizophrenia. In a further example, the treatment may include or consist of the treatment of Attention Deficit Hyperactivity Disorder (ADHD) or drug addiction.

[0050] As used herein, the term treatment may include one or more of therapeutic treatment, palliative treatment, and treatment that reduces the onset or progression of a disorder or disease described herein. For example, treatment may be therapeutic treatment and / or palliative treatment. Additionally or alternatively, treatment may be treatment that reduces the onset or progression of a disorder or disease described herein.

[0051] The present disclosure also provides the use of a compound of formula III as described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for the manufacture of a medicament for use in the treatment of one or more of the following: Parkinson's disease, Huntington's disease, Restless Legs Syndrome, Alzheimer's disease, schizophrenia, Attention Deficit Hyperactivity Disorder, and drug addiction. For example, the treatment may include or consist of the treatment of Parkinson's disease. In a further example, the treatment may include or consist of the treatment of Huntington's disease or Restless Legs Syndrome. In yet a further example, the treatment may include or consist of the treatment of Alzheimer's disease or schizophrenia. In a further example, the treatment may include or consist of the treatment of Attention Deficit Hyperactivity Disorder (ADHD) or drug addiction.

[0052] The present disclosure also provides a method for treating one or more of the following: Parkinson's disease, Huntington's disease, restless legs syndrome, Alzheimer's disease, schizophrenia, attention deficit hyperactivity disorder, drug addiction, the method comprising administering to a mammal, such as a human or animal in need thereof, an effective amount of (i) a compound of formula III as described herein or a pharma- ceutically acceptable salt thereof, or (ii) a pharmaceutical composition as described herein. For example, the disease, condition, and / or disorder may include Parkinson's disease. Thus, a method for treating Parkinson's disease is provided, the method comprising administering to a mammal, such as a human or animal in need thereof, an effective amount of (i) a compound of formula III as described herein or a pharma- ceutically acceptable salt thereof, or (ii) a pharmaceutical composition as described herein. For example, the treatment may include or consist of treatment of Parkinson's disease. In a further example, the treatment may include or consist of treatment of Huntington's disease or restless legs syndrome. In still further examples, treatment may include or consist of treatment of Alzheimer's disease or schizophrenia, hi further examples, treatment may include or consist of treatment of attention deficit hyperactivity disorder (ADHD) or drug addiction.

[0053] As used herein, Parkinson's disease includes motor symptoms with or without non-motor symptoms. Major motor symptoms include tremor, rigidity, slowness of movement, and difficulty walking. Collectively, these major motor symptoms are known as "Parkinsonism" or "Parkinson syndrome." Non-motor symptoms include cognitive decline, depression, anxiety, apathy, and dementia.

[0054] The treatment of Parkinson's disease described herein can be performed without or substantially without inducing side effects such as nausea or vomiting. Thus, the treatment may be associated with no or only mild side effects such as nausea and / or vomiting. Additionally or alternatively, the treatment described herein can include or consist of non-motor symptoms associated with Parkinson's disease. Examples of non-motor symptoms include cognitive decline, depression, anxiety, apathy, and / or Parkinson's dementia. Examples of cognitive decline include problems with memory, language, thinking, learning, and / or judgment.

[0055] The present disclosure also provides a method for preparing a compound of formula III described herein, or a pharma- ceutically acceptable salt thereof, the method comprising: a) a compound of formula II and a compound of formula IV, [ka] During the ceremony, Carbon 4a and carbon 10a of the compound of formula II have the R configuration; X is OH, halide, and OC(O)R 2 is selected from the group consisting of R 1 and R 2 is independently as described herein, and a compound of formula II and a compound of formula IV, optionally reacting in the presence of an ester formation promoter, such as a coupling reagent, thereby forming a compound of formula III; b) optionally separating the compound of formula III into a compound of formula IIIa and a compound of formula IIIb as defined in any one of claims 2 to 10; c) optionally combining the compound of formula III of step a) or step b) with a pharma- ceutically acceptable acid, thereby providing a pharma- ceutically acceptable salt of the compound of formula III.

[0056] The pharma- ceutically acceptable acid in step c) may be a pharma- ceutically acceptable acid as described herein.In particular, the pharma- ceutically acceptable acid may comprise or consist of D-tartaric acid.

[0057] As used herein, the ester formation promoter can be a coupling agent such as dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide (DIC).

[0058] It will be appreciated that the compounds of formula IV described herein may be anhydrides, such as acetic anhydride.

[0059] The compound of formula II used in the method for preparing the compound of formula III or its pharma- ceutically acceptable salt described herein can include a compound of formula IIa and / or formula IIb.In one example, the compound of formula II is provided as a mixture of the compound of formula IIa and the compound of formula IIb, such as a 1:1 mixture.Alternatively, the compound of formula II can be provided as a compound of formula IIa or a compound of formula IIb. [ka]

[0060] R of the compounds of formula IIa and IIb 1 It will be understood that may be as described herein. It will further be understood that the compounds of formula IIa and formula IIb are epimers that differ in the configuration at carbon 6 (i.e., the carbon linked to the OH group). The compound of formula IIa is the 6R epimer and the compound of formula IIb is the 6S epimer.

[0061] R of the compounds of formula II, formula IIa, and formula IIb 1 The group can be n-propyl, thereby providing compounds of Formula II1, Formula IIa1, and / or Formula IIb1. [ka]

[0062] The chemical name of the compound of formula II1 can be (4aR,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ol.

[0063] The chemical name of the compound of formula IIa1 can be (4aR,6R,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ol.

[0064] The chemical name of the compound of formula IIb1 can be (4aR,6S,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ol.

[0065] The compounds of formula II described herein are a) a compound of formula I, [ka] In the formula, R 1 reducing a compound of formula I, wherein R is as described herein, with a reducing agent in the presence of a Lewis acid and a solvent, whereby the carbonyl group is reduced to a hydroxyl group, thereby providing a compound of formula II; b) optionally separating the compound of formula II into a compound of formula IIa and a compound of formula IIb.

[0066] In the method for preparing the compound of formula II, the reducing agent, Lewis acid, and solvent are selected to selectively reduce the carbonyl to a hydroxyl group, i.e., to reduce the carbonyl to a hydroxyl group without reducing the double bond to a single bond or substantially to a single bond. The reducing agent can be a hydride such as sodium borohydride, and / or the Lewis acid can include cerium(III) chloride, such as cerium(III) chloride heptahydrate, and / or the solvent can include a protic solvent, such as an alcohol, such as methanol. This will generally provide a 1:1 mixture of the compound of formula IIa and the compound of formula IIb. If it is desired to produce an excess of the compound of formula IIa or the compound of formula IIb, a chiral reducing agent can be used. For example, a chiral alkylborohydride such as diisopinocampheylborane can be used. Methods generally known in the art can be used to obtain the compound of formula IIa or the compound of formula IIb in chemically and / or stereochemically pure form.

[0067] R of the compound of formula I 1 It will be appreciated that the group can be n-propyl, thereby providing a compound of formula I1 which can have the chemical name (4aR,10aR)-1-propyl-1,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one. [ka]

[0068] Pharmaceutically acceptable salts The compounds of the present disclosure can be provided in the form of pharmaceutically acceptable salts. As used herein, "pharmaceutically acceptable salts" includes salts prepared from pharmaceutically acceptable non-toxic acids, i.e., pharmaceutically acceptable acid addition salts, if such salts are possible. Pharmaceutically acceptable salts can be formed, for example, by combining the compounds described herein with organic or inorganic acids in a desired ratio using methods known in the art. Thus, a pharmaceutically acceptable salt can be a combination of a compound of formula III with an acid, such as a combination of a compound of formula III with an acid in a ratio of 1:1 or 2:1.

[0069] Examples of pharma- ceutically acceptable salts include, but are not limited to, non-toxic inorganic and organic acid addition salts such as hydrochloride, hydrobromide, borate, nitrate, perchlorate, phosphate, sulfate, formate, acetate, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, embonate, enanthate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, propionate, salicylate, sorbate, stearate, succinate, tartrate, toluene-sulfonate, and the like.

[0070] Other acids, such as oxalic acid, may be useful in the preparation of salts as intermediates useful in obtaining the compounds of the present disclosure and their pharma- ceutically acceptable acid addition salts.

[0071] solvate It is understood that the compounds of the present disclosure, their pharma- ceutically acceptable salts, can exist in solvated form. Alternatively, the compounds of the present disclosure or their pharma- ceutically acceptable salts can exist in non-solvated form. The term "solvate" is used herein to describe a molecular complex that comprises the compounds of the present disclosure and one or more pharma- ceutical acceptable solvent molecules (multiple). The term "hydrate" is used when the solvent is water. Thus, the solvated form can include hydrate forms such as monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, etc.

[0072] polymorph The compounds of the present disclosure, or pharma- ceutically acceptable salts thereof, may exist in a continuum of solid states ranging from fully amorphous to fully crystalline, and it is therefore understood that the compounds of the present disclosure may be in polymorphic forms.

[0073] Labeled Compounds The compounds of the present disclosure or their pharma-ceutically acceptable salts can be used in their labeled or unlabeled form.In the context of the present disclosure, a labeled compound has one or more atoms that are replaced by an atom that has different atomic mass or mass number from the atomic mass or mass number that is usually found in nature.Labeling can allow the compound to be easily quantitatively detected.

[0074] For example, tritium ( 3 H), deuterium ( 2 H), or carbon 14 ( 14 Compounds as described herein are provided that are labeled with one or more isotopes, such as C).In one example, the compound is labeled with one or more deuterium atoms.All isotopic variations of the compounds of the present disclosure are intended to be encompassed within the scope of the present disclosure, whether or not they are radioactive.

[0075] Thus, the present disclosure provides compounds as described herein that are labeled with one or more isotopes, such as deuterium. The isotopically labeled compounds as described herein can be combined with an acid as described herein, thereby providing a salt, such as a pharma- ceutically acceptable salt as described herein.

[0076] Dosage It will be understood that the compounds disclosed herein can be administered in a therapeutically acceptable amount. For example, the dosage can be from about 0.0001 mg / kg to about 5 mg / kg of body weight, such as from about 0.001 mg / kg to about 1 mg / kg of body weight. The exact dosage will depend on the frequency and mode of administration, the sex, age, weight, and general condition of the subject being treated, the nature and severity of the condition being treated, any coexisting illness being treated, the desired effect of the treatment, and / or other factors known to those skilled in the art.

[0077] Method of preparation Compounds of the present disclosure can be prepared as described herein. For example, compounds of the present disclosure can be prepared as shown in FIG.

[0078] The end products of the reactions described herein may be isolated by conventional techniques, such as extraction, crystallization, distillation, chromatography, and the like. The compounds of the present disclosure may be prepared in a form that is chemically pure, i.e., they are substantially free of reactants, solvents, impurities, and the like. Furthermore, the compounds of the present disclosure may be prepared in a substantially stereochemically pure form. For example, the compound of formula III may contain a compound of formula IIIa and a compound of formula IIIb in a ratio of 95:5, 96:4, 97:3, 98:2, or 99:1 or more. In a further example, the compound of formula III may contain a compound of formula IIIb and a compound of formula IIIa in a ratio of 95:5, 96:4, 97:3, 98:2, or 99:1 or more.

[0079] Those of skill in the art will appreciate that the individual process steps described above may be performed in a different order and / or the individual reactions may be carried out at different stages in the overall pathway (i.e., chemical transformations may be carried out on different intermediates than those associated with the particular reactions described above) to give the compounds of the present disclosure.

[0080] The present disclosure is illustrated in the following non-limiting examples. EXAMPLES

[0081] The naming of the compounds disclosed herein (preferred IUPAC names) is done using ChemDraw Ultra, version 12.0.2.1076. In this document, in case of a discrepancy between the chemical name and the chemical structure, the chemical structure should be considered as the correct structure.

[0082] General method Chemicals were mainly purchased from Sigma-Aldrich. Preparative HPLC was performed on a Gilson system equipped with a UV detector. For flash chromatography, a Biotage Isolera Vers 1.2 with a Sfar Silica HC D column was used. Analytical HPLC / LCMS was performed using an Agilent 1100 Series Liquid Chromatograph / Mass Selective Detector (MSD) (single quadrupole) equipped with an electrospray interface and a UV diode array detector. Analysis was performed by using either an ACE 3 C8 (3.0×50 mm) column with a gradient of 10-97% acetonitrile in 0.1% aqueous TFA over 3 min and a flow rate of 1 mL / min, or an Xbridge C18 (3.0×50 mm) column with a gradient of 10-97% acetonitrile in 10 mM ammonium bicarbonate over 3 min and a flow rate of 1 mL / min, and UV detection. Alternatively, a gradient of 10-100% acetonitrile in 0.03% acetic acid was used as the eluent. Low-resolution mass spectra were recorded on an HP 5970A instrument operated at an ionization potential of 70 eV. The mass detector was interfaced with an HP5700 gas chromatograph equipped with an HP-5MS UI GC column (15 m, 0.25 mm, 0.25 μm) using a helium gas flow of 40 cm / sec.

[0083] Optical measurements were carried out at 25° C. using a sodium lamp (A=589 nM). 1 H-NMR spectra were recorded on a Varian 400 MHz instrument or a Bruker 600, 700, 800, or 900 MHz instrument at 25 °C where specified. 13 C NMR spectra were obtained using a Bruker instrument operating at 200 MHz.

[0084] Melting points were determined on a Buchi B-545 apparatus and are uncorrected.

[0085] Abbreviation [Table 1]

[0086] Example 1 Synthesis of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one (synthetic intermediate and prior art compound; compound of formula I1) A) trans-1-propyldecahydroquinolin-7-ol (compound 2 in the synthesis of Figure 1).

[0087] To a stirred solution of trans-decahydroquinolin-7-ol (1.32 mL, 12.9 mmol) in DMF (20 mL) was added 1-iodopropane (2.3 g, 13.5 mmol). After 10 min, potassium carbonate (8.9 g, 64 mmol) was added. The reaction mixture was stirred overnight and then diluted with 80 mL of water and extracted with 3×30 ml of DCM. The organic layers were combined, washed with brine (4×40 mL) and concentrated to give trans-1-propyldecahydroquinolin-7-ol as a yellow oil (2.5 g, 12.7 mmol, 98% yield).

[0088] B) trans-1-propyloctahydroquinolin-7(1H)-one (compound 3 in the synthesis of FIG. 1).

[0089] To a stirred solution of oxalyl chloride (2.07 ml, 24 mmol) in DCM (40 mL) at -78°C, DMSO (3.5 mL, 49 mmol) was added dropwise and the reaction mixture was stirred at this temperature for 15 min. Then, a solution of trans-1-propyldecahydroquinolin-7-ol (2.5 g, 12.7 mmol) in 10 mL of DCM was added at -78°C and the reaction mixture was stirred for 1 h. Triethylamine (14 mL, 101 mmol) was added and the reaction mixture was allowed to warm slowly to room temperature and stirred for 2 h. After this, the reaction mixture was washed with saturated NaHCO3, water, and brine. The organic phase was dried over Na2SO4 and concentrated to give trans-1-propyloctahydroquinolin-7(1H)-one as a yellow oil (1.63 g, 8.3 mmol, 66% yield).

[0090] C) (E)-Ethyl 4-(trans-1-propyloctahydroquinolin-7(1H)-ylidene)butanoate (compound 4 in the synthesis of FIG. 1).

[0091] To a stirred suspension of (4-ethoxy-4-oxobutyl)triphenylphosphonium bromide (9.93 g, 22 mmol) in THF (50 mL) at 0° C., sodium tert-butoxide (2 M in THF, 12.5 mL, 25 mmol) was added and the reaction mixture was stirred for 30 min. Then, trans-1-propyloctahydroquinolin-7(1H)-one (2.12 g, 10.9 mmol) in THF (10 mL) was added dropwise at 0° C. for 3 min and the reaction mixture was stirred for 2 days (until the starting material disappeared). The reaction mixture was diluted with cold water (50 mL) with ice bath cooling and extracted with hexane (4×50 mL). The solvent was removed in vacuo and the residue was triturated with 50 mL of hexane, which caused the formation of a precipitate of Ph3PO. The precipitate was removed by filtration and the solution was concentrated to give 3.18 g of crude product (approximately 50% purity). The material was used in the next step without further purification.

[0092] D) (4aR,10aR)-1-propyl-1,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one, a synthetic intermediate in the preparation of compounds of formula III1, which can also be prepared according to the method disclosed in Reference 1.

[0093] A solution of (E)-ethyl 4-(trans-1-propyloctahydroquinolin-7(1H)-ylidene)butanoate (3.18 g, 5.42 mmol) in DCM (3 mL) was added dropwise to PPA (30 g) at 100 °C for 5 min (temperature should not exceed 110 °C), followed by stirring under heating for 2 h. Ice and 50 mL of water were then added and the mixture was extracted with DCM to remove impurities. The aqueous phase was basified with NH3 (28% aq.) and extracted with DCM to give a crude mixture of two isomers. This was purified by column chromatography (silica, gradient of 1-9% MeOH in DCM, with MeOH containing 1% NH3) to give the title compound (860 mg, 30% yield over two steps). MS (ESI+) m / z 248 [M+H]+. This mixture of enantiomers was separated using a preparative HPLC system equipped with a semi-preparative chiral column (CHIRALPAK ID, 5 μm, 10×250 mm) and a mobile phase of heptane / isopropanol / diethylamine 80 / 20 / 0.1 with a flow rate of 4.6 mL / min.

[0094] Peak 1: (4aR,10aR)-1-Propyl-1,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one (360mg, 1.45mmol). Optical: [α] D 25 =-234°(c=0.035,methanol).

[0095] Peak 2: (4aS,10aS)-1-Propyl-1,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one (400mg, 1.62mmol). Optical: [α] D 25=+228°(c=0.032,methanol).

[0096] Example 2 Synthesis of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ol (a mixture of 6R and 6S epimers, i.e., the compound of formula II1 in the synthesis of FIG. 1, which is a synthetic intermediate in the preparation of the compound of formula III1) Cerium(III) chloride heptahydrate (547 mg, 1.47 mmol) was added to a stirred and cooled (0° C.) solution of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one (300 mg, 1.21 mmol) in MeOH (8 mL) and stirred for 15 min. Sodium borohydride (138 mg, 3.6 mmol) was added in three portions over 15 min, and the reaction was complete after 1 h. Water (10 mL) was added to the resulting white slurry and stirred for 20 min. The clear aqueous solution was extracted with EtOAc (4×30 mL) and concentrated to give 190 mg of the product as a mixture of diastereomers.

[0097] The two diastereomers (epimer 1 and epimer 2) were first separated on an analytical scale, which is shown in the chromatogram in Figure 2, where epimer 1 has a retention time of 1.95 minutes and epimer 2 has a retention time of 2.21 minutes under the following conditions: (Xbridge C18, 50x3.0, 3.5u, 10-97% acetonitrile in 10mM NH4HCO3 (pH10), over 3 minutes, 1ml / min).

[0098] In a separate experiment, the mixture of diastereomers was also separated using preparative HPLC (XBridge™ Prep C18 5 p.m OBD™ 19 x 50 mm column, 15-40% acetonitrile in 50 mM aqueous NH4HCO3 over 6 min). The two epimers eluted in the same order as in the analytical experiment. One of these was the 6S epimer and the other was the 6R epimer, but it was initially unclear which epimer would elute first. X-ray analysis then showed that the first eluting epimer had the 6R configuration and the last eluting epimer had the 6S configuration. The yield of epimer 1 was 110 mg, 36.4% yield, and the yield of epimer 2 was 35 mg, 11.6% yield.

[0099] Final evaporation and drying gave two products as pale yellow oils that solidified over time. The isomers are numbered according to the order of elution from the column.

[0100] Example 3 NMR spectrum of the compound of Example 2. Mixture of epimer 1 and epimer 2: 1H NMR (400 MHz, CDCI3) δ 4.01 (br s, 0.7H), 3.85 (br s, 0.3H), 2.94 (br d, J = 11.2 Hz, 1H), 2.56-2.72 (m, 1H), 2.08-2.42 (multiplet), 0.93-1.09 (m, 1H), 0.85 (t, J = 7.4 Hz, 3H). The overall yield was 48%.

[0101] Epimer 1 (6R epimer): 1H NMR(400MHz,CDCI3):δ4.02(brs,1H),2.95(br d,J=11.4Hz,1H),2.59-2.70(m,1H),2.30-2.41(m,1H),2.12-2.29(m,2H),1.28 -2.09(multiplet),0.96-1.08(m,1H),0.86(t,J=7.3Hz,3H).MS(ESI+)m / z250[M+H]+.

[0102] Epimer 2:1 (6S epimer): 1H NMR(400MHz,CDCI3):δ3.86(brs,1H),2.95(br d,J=10.2Hz,1H),2.60-2.72(m,1H),2.30-2.43(m,2H),2.12-2.27(m,2H),1.39 -2.04(multiplet),0.93-1.08(m,1H),0.86(t,1=7.4Hz,3H).MS(ESI+)m / z250[M+H)+.

[0103] Example 4A Preparation 4A (4aR,10aR)-1-Propyl-1,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one (synthetic intermediate and prior art compound; compound of formula I1) (E)-Ethyl 4-(trans-1-propyloctahydroquinolin-7(1H)-ylidene)butanoate (4.0 g, 13.7 mmol), obtained in a manner similar to Example 1C, was mixed with Eaton's reagent (phosphorus pentoxide, 7.7 wt.% in methanesulfonic acid, 21.1 g) and the mixture was heated at 80° C. for 3 h. The reaction mixture was carefully added dropwise to an ice-cold aqueous solution of NaHCO3 (10%). After three extractions with DCM, the organic solution was dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel chromatography using isooctane / EtOAc / MeOH (gradient, 0-100% EtOAc, then 0-100% MeOH) as eluent. 1.4 g of racemic intermediate was obtained, and then the two enantiomers were separated on a chiral column (Chiralpak IG, 10 mm x 250 mm) using heptane, EtOH, and DEA (90:10:0.1) as eluents. Approximately 25 mg of the racemate was loaded onto the column each time, and the last isomer eluted from the column was collected. After pooling the desired fractions, the product was purified again by silica gel chromatography using isooctane / EtOAc / MeOH as eluents (gradient, 0-100% EtOAc, then 0-100% MeOH). 0.35 g of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one in non-salt form was obtained as an oil. [α] 20 D =-215,6(c, 0.010g / mL, MeOH). 1 H NMR (800MHz, CDCl3): δ0.88(t,3H),1.04(m,1H),1.38(m,1H),1.49(m,2H),1.62(m,1H),1.68(m,2H),1.84(m, 1H),1.98(m,3H),2.16(m,2H),2.26(m,2H),2.35(m,2H),2.42(m,1H),2.52(m,2H),2.67(m,1H),2.97(m,1H).

[0104] The HCl salt of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one was prepared by mixing 518 mg (2.1 mmol) of its non-salt form (synthesized in a similar manner as above) with HCl in ethanol (1.25 M, 4 mL) and then concentrating the formed solution on a rotary evaporator. The residue was co-evaporated with ethanol and then crystallized from ethanol / diethyl ether. 355 mg (60%) of the title compound was obtained as a white powder. Melting point: 220.7 °C. [α] 20 D =-199,6(c, 0.010g / mL, MeOH). 1 H NMR (800MHz, methanol-d4): δ1.07(t,3H),1.40(m,1H),1.77(m,1H),1.86(m,3H),1.9-2.1(m,4H),2.4-2 .5(m,4H),2.56(m,1H),2.68(m,1H),2.92(m,1H),3.10(m,2H),3.23(m,1H),3.32(m,1H),3.62(m,1H).

[0105] Example 4B Epimer 1 of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ol The non-salt form of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one (0.33 g, 1.33 mmol) from Preparation 4A was dissolved in MeOH (8 mL) and cerium(III) chloride heptahydrate (596 mg, 1.6 mmol) was added at 0°C. The mixture was stirred with cooling for 15 min, then NaBH4 was added in three portions over 15 min. The reaction mixture was stirred with cooling for an additional 1 h, then water (10 mL) was added. After stirring for 20 min, the mixture was extracted with EtOAc (4 x 50 mL). The combined organic solutions were evaporated and the two epimers were separated by repeated silica gel chromatography using EtOAc as the eluent. There was obtained 144 mg (43%) of epimer 1 of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ol as an off-white powder. 1 H NMR (800MHz, CDCl3): δ0.86(t,3H),1.02(qd,1H),1.3-1.7(m,7H),1.76(m,2H),1.91(m ,5H),2.02(m,2H),2.21(m,2H),2.35(td,1H),2.65(td,1H),2.95(d,1H),4.01(d,1H). 13 C NMR (201MHz, CDCl3): δ12.1(s), 17.5(s), 19.3(s), 25.6(s), 30.5(s), 32.0(s), 32.7(s) ,35.1(s),36.5(s),37.8(s),52.9(s),55.5(s),61.2(s),70.0(s),129.3(s),130.9(s).

[0106] Example 5 Synthesis of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl acetate (a mixture of 6R and 6S epimers) oxalate [ka] The isomeric mixture of 6R and 6S epimers of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ol (82 mg, 0.33 mmol), obtained in a manner similar to that of Example 2, was dissolved in a mixture of pyridine (1 mL) and acetic anhydride (1 mL). The reaction mixture was stirred at 30-35°C for 4 h and then quenched by the addition of ethanol at room temperature. The volatiles were removed by evaporation and coevaporated several times with ethanol. The residue was dissolved in ethanol (3 mL) together with oxalic acid dihydrate (45 mg, 0.35 mmol). After an effort to obtain the product as a crystalline salt by the addition of ether, the solvent was removed by evaporation. 128 mg of the isomeric mixture of the desired compound was obtained as an oil. MS (ESI+) m / z 292 [M+H] + . 1 H NMR (700 MHz, DMSO-d6) δ 5.0-5.2 (m, 1H), 3.11 (m, 2H), 2.94 (m, 2H), 2.4-2.5 (m, 2H), 2.23 (m, 1H), 2.00 and 2.02 (two doublets, 1H), 1.5-2.0 (m, 14H), 1.22 (m, 1H), 0.92 (t, 3H).

[0107] Example 6 Synthesis of D-tartrate of (4aR,6R,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl acetate [ka] Epimer 1 of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ol (500 mg, 2.0 mmol), obtained in a manner similar to Example 4B, was dissolved in a mixture of pyridine (4 mL) and acetic anhydride (4 mL). The reaction mixture was placed in a fume hood overnight and then quenched by the addition of ethanol at room temperature. After 30 min, the volatiles were removed by evaporation and coevaporation several times with ethanol. The residue was purified by silica gel chromatography using a gradient of EtOAc and MeOH (0-70% MeOH) as eluents. Fractions were analyzed by TLC (silica gel) with visualization of spots with iodine. The Rf value of the ester was 0.35 (MeOH / EtOAc, 1:1) and that of the starting material was 0.23. The desired fractions were evaporated and the residue (330 mg) was dissolved in EtOAc (9 mL) in a round-bottom flask. To the formed solution, D-tartaric acid (170 mg, 1.1 mmol) was added and after stirring at room temperature for 24 h, the mixture became two immiscible liquids. Some of the sticky oil at the bottom of the flask was collected by spatula and transferred with fresh EtOAc into a test tube. After persistently scraping the oil on the inner surface of the tube with a glass rod, crystals eventually formed and these were then transferred to the round-bottom flask containing the main mixture. The flask was stoppered and placed in a fume hood for an additional 24 h and the formed precipitate was isolated by filtration. The filter cake was washed with EtOAc and then dried under vacuum. 270 mg (30%) of the desired D-tartrate salt was obtained as a white powder. Melting point: 83.6 °C. [α] D =-46.5°(c 10mg / mL, MeOH).MS(ESI+)m / z292[M+H] + . 1H NMR (800 MHz, DMSO-d6) δ 5.13 (d, 1H), 4.04 (s, 2H), 3.29 (d, 1H), 2.98 (m, 1H), 2.7-2.8 (m, 3H), 2.40 (m, 1H), 2.16 (m, 1H), 2.00 (s, 3H), 1.8-2.0 (m, 5H), 1.73 (m, 4H), 1.65 (m, 2H), 1.55 (m, 3H), 1.15 (m, 1H), 0.89 (t, 3H). The NMR spectrum showed a 1:1 ratio between the above identified ester and D-tartaric acid. Thus, in this example, the D-tartrate salt of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl acetate is provided as a combination of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl acetate and D-tartaric acid incorporated in a 1:1 ratio.

[0108] Example 7 Synthesis of D-tartrate of (4aR,6R,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl isobutyrate [ka] Epimer 1 of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ol (113 mg, 0.45 mmol), obtained in a similar manner as in Example 4B, was dissolved in DCM (7 mL) and to the solution were added triethylamine (0.20 mL, 1.4 mmol) and isobutyryl chloride (0.10 mL, 0.95 mmol) in the given order. The reaction mixture was stirred overnight at room temperature and then diluted with DCM. After washing the solution with aqueous Na2CO3 (5%), the organic phase was filtered through a phase separator and the volatiles were removed by evaporation. The residue was purified by silica gel chromatography using a gradient of EtOAc and MeOH (0-70% MeOH) as eluents. Fractions were analyzed by TLC (silica gel) with iodine spot visualization. The Rf value of the ester was 0.38 (MeOH / EtOAc, 1:1) and that of the starting material was 0.23. The desired fractions were evaporated and the residue (125 mg) was dissolved in EtOAc (10 mL) in a screw-top bottle (25 mL) whereupon the free amine started to crystallize. D-tartaric acid (59 mg, 0.39 mmol) was added to the slurry and the mixture was heated in a water bath to try to have most of the material in solution. The bottle without the screw cap was placed in a fume hood at room temperature for 3 days whereupon the salt started to precipitate. After an additional 4 days at room temperature with the screw cap closed, the salt was isolated by filtration. The filter cake was washed with EtOAc and then dried under vacuum. 106 mg (49%) of the desired D-tartrate salt was obtained as a white powder. Melting point: 79.1 °C. [α] D =-72.0°(c 1.0mg / mL, MeOH).MS(ESI+)m / z320[M+H] + . 1H NMR (700 MHz, DMSO-d6) δ 5.13 (d, 1H), 4.02 (s, 2H), 3.25 (d, 1H), 2.95 (m, 1H), 2.72 (m, 3H), 2.49 (m, 1H), 2.40 (m, 1H), 2.12 (m, 1H), 1.5-2.0 (m, 14H), 1.13 (m, 1H), 1.08 (m, 6H), 0.89 (t, 3H). The NMR spectrum indicated a 1:1 ratio between the above identified ester and D-tartaric acid. Thus, in this example, the D-tartrate salt of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl 2-methylpropionate is provided as a combination of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl 2-methylpropionate and D-tartaric acid incorporated in a 1:1 ratio.

[0109] Example 8 Synthesis of D-tartrate of (4aR,6R,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ylcyclopropanecarboxylate [ka] Epimer 1 of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ol (113 mg, 0.45 mmol), obtained in a similar manner as in Example 4B, was dissolved in DCM (7 mL) and to the formed solution, triethylamine (0.30 mL, 2.2 mmol) and cyclopropanecarbonyl chloride (0.20 mL, 2.2 mmol) were added in the given order. The reaction mixture was stirred overnight at room temperature and then diluted with DCM. After washing the solution with aqueous Na2CO3 (5%), the organic phase was filtered through a phase separator and the volatiles were removed by evaporation. The residue was purified by silica gel chromatography using a gradient of EtOAc and MeOH (0-70% MeOH) as eluents and fractions were analyzed by TLC (silica gel) with iodine spot visualization. The Rf value of the ester was 0.38 (MeOH / EtOAc, 1:1) and that of the starting material was 0.23. The desired fraction was evaporated and the residue (110 mg) was dissolved in EtOAc (15 mL) in a screw-top bottle (25 mL). D-tartaric acid (55 mg, 0.37 mmol) was added to the solution and the mixture was heated in a water bath to try to have most of the material in solution. The bottle without the screw cap was placed in a fume hood at room temperature for 1 day and the salt formed was isolated by filtration. The solid material was recrystallized from hot EtOAc and the salt was dried under vacuum. 65 mg (30%) of the desired D-tartrate salt was obtained as a white powder. Melting point: 73.3 °C. [α] D =-42.0°(c 1.0mg / mL, MeOH).MS(ESI+)m / z318[M+H] + . 1H NMR (700 MHz, DMSO-d6) δ 5.15 (d, 1H), 4.02 (s, 2H), 3.25 (d, 1H), 2.95 (m, 1H), 2.6-2.7 (m, 3H), 2.42 (m, 1H), 2.11 (m, 1H), 1.5-2.0 (m, 15H), 1.15 (m, 1H), 0.8-0.9 (m, 7H). The NMR spectrum showed a 1:1 ratio between the above identified ester and D-tartaric acid. Thus, in this example, the D-tartrate salt of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ylcyclopropanecarboxylate is provided as a combination of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ylcyclopropanecarboxylate and D-tartaric acid incorporated in a 1:1 ratio.

[0110] Example 9 Synthesis of (4aR,6R,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl 2,2-dimethylpropionate D-tartrate [ka] Epimer 1 of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ol (170 mg, 0.68 mmol), obtained in a similar manner as in Example 4B, was dissolved in DCM (10 mL) and to the solution were added triethylamine (0.30 mL, 2.1 mmol) and pivaloyl chloride (0.20 mL, 1.63 mmol) in the given order. The reaction mixture was stirred at room temperature for 3 days and then diluted with DCM. After washing the solution with aqueous Na2CO3 (5%), the organic phase was filtered through a phase separator and the volatiles were removed by evaporation. The residue was purified by flash chromatography on silica gel (25 g) using a gradient of EtOAc and MeOH (0-65% MeOH) as eluent. The desired fractions were evaporated and the residue (168 mg) was dissolved in EtOAc (10 mL) together with D-tartaric acid (80 mg, 0.53 mmol). The mixture was stirred at room temperature for 3 days without precipitation of solids. After another 5 weeks at room temperature without stirring using a stoppered flask, the salt precipitated and the solid was isolated by filtration. The filter cake was washed with EtOAc and then dried under vacuum. 168 mg (40%) of the desired D-tartrate salt was obtained as a white powder. Melting point: 82.0 °C. [α] D =-70.0°(c 1.0mg / mL, MeOH).MS(ESI+)m / z334[M+H] + . 1H NMR (700 MHz, DMSO-d6) δ 5.11 (s, 1H), 4.03 (s, 2H), 3.26 (d, 1H), 2.96 (m, 1H), 2.70 (m, 3H), 2.41 (m, 1H), 2.40 (m, 1H), 2.13 (m, 1H), 1.5-2.0 (m, 13H), 1.13 (s, 9H), 1.12 (m, 1H), 0.89 (t, 3H). The NMR spectrum indicated a 1:1 ratio between the above identified ester and D-tartaric acid. Thus, in this example, the D-tartrate salt of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl 2,2-dimethylpropionate is provided as a combination of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl 2,2-dimethylpropionate and D-tartaric acid incorporated in a 1:1 ratio.

[0111] Example 10 Synthesis of D-tartrate of (4aR,6R,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ylcyclobutanecarboxylate [ka] Epimer 1 of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ol (156 mg, 0.63 mmol), obtained in a manner similar to Example 4B, was dissolved in dry DCM (10 mL) and triethylamine (0.30 mL, 2.2 mmol) was added to the solution, followed by dropwise addition of cyclobutanecarbonyl chloride (0.20 mL, 1.7 mmol). The reaction mixture was stirred at room temperature for 4 days and then diluted with DCM. After washing with aqueous Na2CO3 (5%), the aqueous phase was extracted with DCM and the combined organic phase was washed with aqueous Na2CO3 (5%) and then passed through a phase separator. The volatiles were removed by evaporation and the residue (231 mg) was purified by silica gel (25 g) flash chromatography using a gradient of EtOAc and MeOH (0-67% MeOH) as eluent. Fractions were analyzed by TLC (silica gel) with iodine spot visualization. The Rf value of the ester was 0.34 (MeOH / EtOAc, 1:1). After evaporation of the desired fractions, 141 mg of a pink oil was obtained, which was dissolved in EtOAc (15 mL). The solution was filtered through a glass filter funnel. D-tartaric acid (66 mg, 0.44 mmol) was added to the filtrate while stirring. The mixture was stirred at room temperature for 20 h. The stirring was stopped and the round-bottom flask closed with a stopper was left in the hood for 6 days. A small amount of oily precipitate at the bottom of the flask was triturated with a glass rod until crystallization started. The solid formed was collected by filtration and then washed with a small amount of EtOAc. After drying in vacuum at 40° C., 142 mg (47%) of the desired D-tartrate salt was obtained as a pale pink powder. Melting point: 60.2° C. [α] D =-49.7°(c 1.0mg / mL, MeOH).HRMS:C 21 H 34 Calculated m / z for NO2 (M+H) + :332.2589, measured value 332.2589.

[0112] 1H NMR (800 MHz, DMSO-d6) δ 5.15 (s, 1H), 4.02 (s, 2H), 3.25 (d, 1H), 3.13 (m, 1H), 2.95 (m, 1H), 2.70 (m, 3H), 2.39 (m, 1H), 2.14 (m, 5H), 1.6-2.0 (m, 13H), 1.54 (m, 3H), 1.11 (m, 1H), 0.89 (t, 3H). The NMR spectrum indicated a 1:1 ratio between the above identified ester and D-tartaric acid. Thus, in this example, the D-tartrate salt of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ylcyclobutanecarboxylate is provided as a combination of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ylcyclobutanecarboxylate and D-tartaric acid incorporated in a 1:1 ratio.

[0113] Example 11 Synthesis of D-tartrate of (4aR,6R,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl 1-methylcyclopropanecarboxylate [ka] Epimer 1 of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ol (150 mg, 0.60 mmol), obtained in a manner similar to Example 4B, was dissolved in DCM (10 mL). Triethylamine (0.25 mL, 1.8 mmol) and 1-methylcyclopropanecarbonyl chloride (0.18 mL, 1.5 mmol) were added in the given order. The reaction mixture was stirred at room temperature under nitrogen for 3 days, then another portion of triethylamine (0.25 mL, 1.8 mmol) and another portion of 1-methylcyclopropanecarbonyl chloride (0.18 mL, 1.5 mmol) were added. After stirring for an additional 4 days, further portions of triethylamine (0.25 mL, 1.8 mmol) and 1-methylcyclopropanecarbonyl chloride (0.18 mL, 1.5 mmol) were added. The mixture was stirred for an additional 2 days and then diluted with DCM. After washing with aqueous Na2CO3 (5%), the aqueous phase was extracted twice with DCM and the combined organic solutions were washed with brine and dried over Na2SO4. The volatiles were removed by evaporation. The residue was purified by flash chromatography on silica gel (25 g) using a gradient of EtOAc and MeOH (0-80% MeOH). The desired fractions were evaporated to give a light red / brown solid (75 mg). The solid was almost completely dissolved in hot EtOAc (15 mL). D-Tartaric acid (36 mg, 0.24 mmol) was added and the mixture was heated in a water bath until all material was dissolved. The round-bottom flask was equipped with a vacuum adapter to allow for slow evaporation of the solvent while the flask was left in the hood. After 2 weeks, no solids precipitated and the residue was dissolved in water. The water was removed by lyophilization to give 60 mg (55%) of the desired D-tartrate salt as a light brown solid. MS (ESI+) m / z 332 [M+H] + . 1H NMR (700 MHz, DMSO-d6) δ 5.11 (d, 1H), 4.14 (s, 2H), 3.36 (d, 1H), 3.05 (m, 1H), 2.98 (m, 1H), 2.82 (m, 2H), 2.45 (m, 1H), 2.24 (m, 1H), 1.4-2.0 (m, 13H), 1.21 (s, 3H), 1.20 (m, 1H), 1.06 (m, 2H), 0.91 (t, 3H), 0.74 (m, 2H). The NMR spectrum showed a 1:1 ratio between the above identified ester and D-tartaric acid. Thus, in this example, the D-tartrate salt of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl 1-methylcyclopropanecarboxylate is provided as a combination of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl 1-methylcyclopropanecarboxylate and D-tartaric acid incorporated in a 1:1 ratio.

[0114] Example 12 Preparation 1 Epimer 1 of (4aR,10aR)-1-ethyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ol [ka] A) 3-(4-Methoxyphenyl)propanoyl chloride [ka] 3-(4-Methoxyphenyl)propionic acid (50.0 g, 272 mmol) was dissolved in DCM (500 mL) and thionyl chloride (49.3 mL, 680 mmol) was added to the formed solution. The mixture was heated to reflux for 6 h, cooled to room temperature and then evaporated to dryness using a rotary evaporator. The crude acid chloride (52.8 g, 98%) was used in the next step without further purification.

[0115] B) N-Ethyl-3-(4-methoxyphenyl)propanamide [ka] 3-(4-Methoxyphenyl)propanoyl chloride (23.9 g, 120 mmol) was dissolved in dry THF (30 mL) and the formed solution was slowly added to an ice-cold mixture of ethylamine (2 M in THF, 150 mL, 300 mmol) and triethylamine (20 mL, 144 mmol) in THF (80 mL). The reaction mixture was stirred at room temperature for 1 h and then diluted with aqueous sodium carbonate (10%). The mixture was extracted several times with EtOAc and the combined organic solution was washed with brine and dried over sodium sulfate. The solvent was removed by evaporation to give 19.0 g (76%) of the desired amide, which was used in the next step without further purification. GC MS m / z (relative intensity, 70eV)208(10),207(71),135(23),134(79),122(9),121(bp),119(9),108(9),91(19),78(11),77(14).

[0116] C) N-Ethyl-3-(4-methoxyphenyl)propan-1-amine [ka] N-Ethyl-3-(4-methoxyphenyl)propenamide (19.0 g, 91.7 mmol) was dissolved in dry THF (150 mL) and the formed solution was added dropwise to a mixture of LiAlH4 (6.96 g, 183 mmol) in THF (120 mL). The reaction mixture was heated to reflux for 3.5 h, cooled in an ice bath, and then diluted with THF (150 mL). After successive quenching with water (7 mL), aqueous NaOH (15%, 7 mL), and finally water (21 mL), the mixture was stirred for 15 min, and then the solid was removed by filtration. The filter cake was washed with EtOH (3 x 20 mL) and the filtrate was evaporated to dryness using a rotary evaporator. Water (50 mL) was added to the residue and the mixture was extracted several times with EtOAc. The combined organic solutions were washed with brine and then dried over sodium sulfate. The solvent was removed by evaporation to give 16.8 g (95%) of the desired amine, which was used in the next step without further purification: GC MS m / z (relative intensity, 70 eV) 193 (38), 148 (51), 147 (20), 134 (7), 121 (30), 117 (7), 91 (15), 78 (11), 77 (13), 70 (7), 58 (bp).

[0117] D) (4aR,8aR)-1-Ethyloctahydroquinolin-7(1H)-one [ka] N-Ethyl-3-(4-methoxyphenyl)propyran-1-amine (16.8 g, 87.0 mmol) was dissolved in dry THF (180 mL) in a three-necked round-bottom flask, the solution was flushed with nitrogen for several minutes, and then t-butanol (16 mL, 192 mmol) was added. The solution was cooled to -60°C, and then anhydrous ammonia was added via a gas inlet with continuous cooling until the volume of the reaction mixture increased by 180 mL. Metallic lithium (2.35 g, 295 mmol) was added slowly in small portions, and the mixture was stirred at -60°C for 4 hours. A mixture of MeOH and saturated aqueous ammonium chloride (1:1, 62 mL) was added to the mixture, which was then warmed to room temperature. After careful heating in a water bath until most of the ammonia had evaporated from the flask, the pH was adjusted to about 1 by the addition of concentrated hydrochloric acid. The mixture was stirred at room temperature for 18 hours, and then the pH was adjusted to above 9 by the addition of 4 M aqueous NaOH at a temperature below 15°C. After the basic mixture was extracted several times with DCM, the combined organic solution was washed with brine and then dried over sodium sulfate. After removing the solvent by evaporation, the product was purified (and the two stereoisomers were separated) by silica gel chromatography using EtOAc / MeOH (gradient, 0-10% MeOH) as eluent. 4.66 g of the first eluted cis isomer was obtained, followed by 0.51 g of the trans isomer, respectively. The cis isomer was then converted to the desired trans isomer by dissolving 4.66 g in ethanolic KOH (1%, 470 mL) and stirring the formed solution at room temperature under nitrogen atmosphere for 4 days, covering the flask with aluminum foil. After performing the same work-up and separation procedures as described above, a total of 3.25 g (20%) of racemic trans isomer was obtained. GC MS m / z (relative intensity, 70eV) 181(14), 166(7), 125(10), 124(bp), 111(6), 110(6), 96(13), 56(4), 55(4). 1H NMR(800MHz,CDCI3)δ2.94(dq,1H),2.81(m,1H),2.78(m,1H),2.53(dq,1H),2.37(m,2H),2.26(t,1H),2.20(td,1H) ,2.09(ddd,1H),1.90(ddt,1H),1.81(dt,1H),1.71(m,2H),1.62(ddd,1H),1.36(tdd,1H),1.05(m,1H),0.99(t,3H).

[0118] E) (E)-Ethyl 4-((4aS,8aR)-1-ethyloctahydroquinolin-7(1H)-ylidene)butanoate [ka] [3-(Ethoxycarbonyl)propyl]triphenylphosphonium bromide (16.7 g, 35.9 mmol) was dissolved in dry DMF (55 mL) and the formed solution was added dropwise to a cooled (0° C.) solution of potassium tert-butoxide (4.1 g, 35.9 mmol) in DMF (6 mL) under nitrogen atmosphere. The mixture was stirred with cooling for 30 min, then a solution of (4aR,8aR)-1-ethyloctahydroquinolin-7(1H)-one (3.25 g, 17.9 mmol) in DMF (7 mL) was added dropwise at 0° C. The reaction mixture was stirred with cooling for 4 h and then at room temperature for 18 h. After cooling in an ice bath, water (120 mL) was added and the product was extracted several times with diethyl ether. The organic solution was washed successively with aqueous LiCl (5%, 75 mL) and brine, dried over sodium sulfate and concentrated to dryness on a rotary evaporator. The residue, consisting of a mixture of the desired ethyl ester and the corresponding tert-butyl ester as a by-product, was dissolved in ethanol (50 mL) with concentrated sulfuric acid (1 mL). The mixture was heated to reflux for 18 h and then cooled to room temperature. The solvent was removed by evaporation and the residue was diluted with water. The pH was adjusted to >10 by addition of saturated aqueous Na2CO3, then the mixture was extracted several times with EtOAc. The combined organic solutions were washed with brine, dried over sodium sulfate, and then evaporated. The product was purified by silica gel chromatography using isooctane / EtOAc / MeOH (gradient, 0-100% EtOAc, then 0-100% MeOH) as eluent. 4.68 g (93%) of the desired ethyl ester was obtained as an oil. GC MS m / z (relative intensity, 70 eV) 279(4), 234(5), 125(10), 124(bp), 111(2), 110(2), 96(5), 91(2), 79(2).

[0119] F) (4aR,10aR)-1-Ethyl-1,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one [ka] (E)-Ethyl 4-((4aS,8aR)-1-ethyloctahydroquinolin-7(1H)-ylidene)butanoate (4.67 g, 16.7 mmol) was mixed with Eaton's reagent (18 mL, phosphorus pentoxide in methanesulfonic acid, 7.7%). The reaction mixture was stirred at 70 °C overnight, allowed to cool to room temperature, and then carefully poured into aqueous Na2CO3 (10%, 300 mL). After extracting the basic mixture several times with DCM, the combined organic solution was washed with brine, dried over sodium sulfate, and then concentrated to dryness using a rotary evaporator. The residue was purified by silica gel chromatography using EtOAc / MeOH (gradient, 0-30% MeOH) as eluent to give 1.86 g (48%) of the racemic product as an oil. The two enantiomers were separated by repeated chiral chromatography (Chiralpak® IG, 250×20 mm) using heptane, IPA, and DEA (60:40:0.1) as eluents to give the (+) enantiomer as the first eluting isomer and the (−) enantiomer as the last eluting isomer, respectively (approximately 45 mg of the racemic mixture was injected onto the column each time). A total of 808 mg of the desired (−) isomer of (4aR,10aR)-1-ethyl-1,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one was obtained as an oil in non-salt form consisting of 99.5% (−) isomer and 0.5% (+) isomer, as determined by analytical chiral chromatography. Also, 795 mg of the (+) isomer of the compound in non-salt form was obtained as an oil.

[0120] Data for the (-) isomer of (4aR,10aR)-1-ethyl-1,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one in non-salt form: MS (ESI+) m / z 234 [M+H] + .[α] D 25 =-199°(c=0.05,methanol). 1H NMR (800 MHz, CDCI3) δ 2.95 (m, 1H), 2.87 (m, 1H), 2.53 (m, 3H), 2.42 (m, 1H), 2.36 (m, 1H), 2.26 (m, 2H), 2.18 (m, 2H), 2.05 (td, 1H), 1.97 (m, 2H), 1.85 (m, 1H), 1.68 (m, 3H), 1.41 (m, 1H), 1.05 (m, 4H). The absolute configurations of the two enantiomers were not determined by X-ray crystallography, but by comparing the sign of optical rotation on a chiral column as well as the elution order with those of the propyl analogue from Example 4a. It was therefore concluded that the (-) isomer has the (4aR, 10aR) configuration and the (+) isomer has the (4aS, 10aS) configuration.

[0121] G) Epimer 1 of (4aR,10aR)-1-ethyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ol [ka] (4aR,10aR)-1-ethyl-1,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one (0.68 g, 2.9 mmol) was dissolved in MeOH (20 mL) and cerium(III) chloride heptahydrate (1.3 g, 3.5 mmol) was added to the formed solution at 0° C. The mixture was stirred for 15 min with cooling. Sodium borohydride (0.33 g, 8.8 mmol) was added in three portions over a period of 15 min and the reaction mixture was stirred for 1 h. Water (30 mL) was added and then stirring was continued for 20 min. The mixture was extracted seven times with EtOAc, after which the combined organic solution was washed with brine, dried over sodium sulfate and then concentrated to dryness using a rotary evaporator. The residue was purified by silica gel chromatography using EtOAc / MeOH (gradient, 0-50% MeOH) as eluent to give 0.14 g (16%) of the first eluting isomer as an oil and 43 mg of epimer 2 as an oil. Data for epimer 1 of (4aR,10aR)-1-ethyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ol: MS (ESI+) m / z 236 [M+H] + . 1 H NMR(800MHz,CDCI3)δ4.02(q,1H),2.92(m,1H),2.84(m,1H),2.55(m,1H),2.22(m,2H),1.5-2.1(m,14H),1.04(m,1H),1.00(m,3H).

[0122] Preparation 2 Epimer 1 of (4aR,10aR)-1-methyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ol [ka] A) (4aR,8aR)-1-Methyloctahydroquinolin-6(2H)-one [ka] (4aR,8aR)-1-methyloctahydroquinolin-6(2H)-one was synthesized in a similar manner to Preparations 1a-1d, but using methylamine instead of ethylamine as the starting material. Starting with 22 g (111 mmol) of 3-(4-methoxyphenyl)propanoyl chloride and 150 mL of methylamine in THF (2 M, 300 mmol), 1 g (6%) of (4aR,8aR)-1-methyloctahydroquinolin-6(2H)-one was obtained as an oil. GC MS m / z (relative intensity, 70eV) 168(2), 167(14), 166(5), 124(3), 111(10), 110(bp), 108(2), 97(1 0),96(11),95(2),94(2),82(5),81(2),70(4),68(3),67(3),55(4),54(3),53(2). 1 H NMR(800MHz,CDCI3)δ2.90(m,1H),2.81(m,1H),2.2-2.4(m,4H),2.06(m,1 H),1.90(m,1H),1.7-1.8(m,4H),1.60(m,1H),1.35(tdd,1H),1.06(m,1H).

[0123] B) (E)-Ethyl 4-((4aS,8aR)-1-methyloctahydroquinolin-7(1H)-ylidene)butanoate [ka] (E)-ethyl 4-((4aS,8aR)-1-methyloctahydroquinolin-7(1H)-ylidene)butanoate was synthesized in a similar manner to 5E, but using (4aR,8aR)-1-methyloctahydroquinolin-6(2H)-one instead of (4aR,8aR)-1-ethyloctahydroquinolin-6(2H)-one as the starting material. Starting with 2.3 g (14 mmol) of (E)-ethyl 4-((4aS,8aR)-1-methyloctahydroquinolin-7(1H)-ylidene)butanoate, 3.6 g (100%) of (E)-ethyl 4-((4aS,8aR)-1-methyloctahydroquinolin-7(1H)-ylidene)butanoate was obtained as an oil.

[0124] C) (4aR,10aR)-1-Methyl-1,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one [ka] The (-) isomer of (4aR,10aR)-1-methyl-1,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one was synthesized in a similar manner to 5F but using (E)-ethyl 4-((4aS,8aR)-1-methyloctahydroquinolin-7(1H)-ylidene)butanoate instead of (E)-ethyl 4-((4aS,8aR)-1-ethyloctahydroquinolin-7(1H)-ylidene)butanoate. Starting with 3.2 g (12 mmol) of (E)-ethyl 4-((4aS,8aR)-1-methyloctahydroquinolin-7(1H)-ylidene)butanoate, 0.53 g (20%) of the (-) isomer of (4aR,10aR)-1-methyl-1,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one was obtained as an oil.

[0125] MS(ESI+)m / z220[M+H] + .[α] D 25 =-244°(c=0.05,methanol). 1 H NMR (800 MHz, CDCI3) δ 2.88 (m, 1H), 2.53 (m, 3H), 2.42 (m, 1H), 2.36 (m, 1H), 2.27 (m, 2H), 2.14 (m, 2H), 1.97 (m, 2H), 1.85 (m, 1H), 1.74 (m, 1H), 1.6-1.7 (m, 3H), 1.40 (m, 1H), 1.06 (m, 1H). The absolute configurations of the two enantiomers were not determined by X-ray crystallography, but by comparing the sign of optical rotation on a chiral column as well as the elution order with those of the propyl analogue from Example 4a. It was therefore concluded that the (-) isomer has the (4aR, 10aR) configuration and the (+) isomer has the (4aS, 10aS) configuration.

[0126] D) Epimer 1 of (4aR,10aR)-1-methyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ol [ka] Epimer 1 of (4aR,10aR)-1-methyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ol was synthesized in a similar manner to 5G, but using (4aR,10aR)-1-methyl-1,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one instead of (4aR,10aR)-1-ethyl-1,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one. Starting with 460 mg (2 mmol) of (4aR,10aR)-1-methyl-1,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one, 0.136 mg (29%) of epimer 1 of (4aR,10aR)-1-methyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ol was obtained as an oil. MS (ESI+) m / z 222 [M+H] + . 1 H NMR(800MHz,CDCI3)δ4.01(t,1H),2.25(s,3H),2.23(m,1H),2.09(td,1H),2.00(m,1H),1.95(m,1H),1.90(m,4H),1.4-1.8(m,10H),1.04(m,1H).

[0127] Example 13 Synthesis of D-tartrate of (4aR,10aR)-1-ethyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl acetate [ka] The epimer 1 of (4aR,10aR)-1-ethyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ol (77 mg, 0.33 mmol) obtained in preparation 1 was dissolved in pyridine (1 mL) and acetic anhydride (1 mL, 10.6 mmol) was added to the solution. The reaction mixture was stirred at room temperature overnight and then diluted with EtOH (10 mL). After stirring at room temperature for 30 min, the mixture was concentrated and then coevaporated from EtOH several times to constant weight (91 mg). The light red oily residue was dissolved in EtOAc (8 mL). D-(-)-tartaric acid (50 mg, 0.33 mmol) was added and the mixture was stirred and heated at 50 °C for about 30 min to obtain a solution. Some insoluble dark material was removed with a spatula and the resulting clear mixture was stirred at room temperature for 2 days without the use of a stopper. A white precipitate then formed, which was isolated by filtration. The solid was washed with EtOAc and dried under vacuum to give 74 mg (53%) of the desired D-tartrate salt as a beige powder.

[0128] Melting point: 136.4℃.MS(ESI+)m / z278[M+H] + . 1 H NMR (800 MHz, DMSO-d6) δ 5.14 (m, 1H), 3.99 (s, 2H), 3.23 (d, 1H), 3.11 (m, 1H), 2.89 (m, 1H), 2.7-2.8 (m, 1H), 2.72-2.64 (m, 1H), 2.37 (dd, 1H), 2.13 (t, 1H), 2.00 (s, 3H), 1.9-2.0 (m, 3H), 1.8-1.9 (m, 2H), 1.6-1.8 (m, 5H), 1.5-1.6 (m, 2H), 1.1-1.2 (m, 4H). The NMR spectrum showed a 1:1 ratio between the above identified ester and D-tartaric acid. Thus, in this example, the D-tartrate salt of (4aR,10aR)-1-ethyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl acetate is provided as a combination of (4aR,10aR)-1-ethyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl acetate and D-tartaric acid incorporated in a 1:1 ratio.

[0129] Example 14 Synthesis of (4aR,6R,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ylhexanoate [ka] Epimer 1 of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ol (150 mg, 0.60 mmol), obtained in a similar manner to Example 4B, was dissolved in DCM (10 mL). Triethylamine (0.26 mL, 1.8 mmol) and hexanoic acid chloride (0.18 mL, 1.3 mmol) were added in the given order. The reaction mixture was stirred at room temperature for 3 days with the flask exposed to air, and then the residue was dissolved in DCM. The formed solution was washed with saturated aqueous NaHCO3 (5 mL) and the volatiles were removed by evaporation. The product was purified by flash chromatography on silica gel using a gradient of 0-50% MeOH in EtOAc as eluent to give 66 mg (31%) of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ylhexanoate in unsalted form as an oil that gradually darkened. MS (ESI+) m / z 348 [M+H] + . 1 H NMR(600MHz,CDCl3)δ5.23(m,1H),3.08(m,1H),2.73(m,1H),2.47(m,1H),2.1-2.4(m,5H),1.5-2.0(m,14),1.30(m,4H),0.99(m,1H),0.88(m,6H).

[0130] Example 15 Synthesis of D-tartrate of (4aR,10aR)-1-methyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl isobutyrate [ka] Epimer 1 of (4aR,10aR)-1-methyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ol obtained in preparation 2 (100 mg, 0.45 mmol) was dissolved in DCM (4 mL) together with triethylamine (0.20 mL, 1.4 mmol). Isobutyryl chloride (0.1 mL, 0.95 mmol) was added to the formed solution and the mixture was stirred at room temperature overnight. Additional triethylamine (0.1 mL) and isobutyryl chloride (0.05 mL) were added and the mixture was stirred at room temperature for another 4 h. The mixture was washed with saturated aqueous NaHCO3 solution (5 mL) and the aqueous phase was extracted with DCM. The combined organic layers were filtered through a phase separator and then concentrated. The product was purified by flash chromatography on silica gel using a gradient of 0-50% MeOH in EtOAc as eluent to give 82 mg of the ester as a brown oil. The residue was dissolved in EtOAc (7 mL). D-(-) tartaric acid (41 mg, 0.27 mmol) was added and the mixture was stirred and heated at 50°C for approximately 30 min to give a clear solution. The mixture was stirred at room temperature with the flask exposed to air, resulting in a slow evaporation of the solvent.

[0131] After 2 days, a few mL of solvent still remained and a precipitate had formed. The solid material was isolated by filtration, washed with EtOAc, and dried under vacuum to give 66 mg (55%) of the desired D-tartrate salt as a beige powder.

[0132] Melting point: 97.3℃.MS(ESI+)m / z292[M+H] + . 1H NMR (700 MHz, DMSO) δ 5.1-5.2 (m, 1H), 4.02 (s, 2H), 3.19 (d, 1H), 2.6 (m, 2H), 2.54 (s, 3H), 2.4-2.5 (m, 2H), 2.39 (dd, 1H), 2.0-2.2 (m, 1H), 1.9-2.0 (m, 3H), 1.6-1.8 (m, 7H), 1.4-1.6 (m, 2H), 1.0-1.1 (m, 7H). The NMR spectrum showed a 1:1 ratio between the above identified ester and D-tartaric acid. Thus, in this example, the D-tartrate salt of (4aR,10aR)-1-methyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl 2-isobutyrate is provided as a combination of (4aR,10aR)-1-methyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl 2-isobutyrate and D-tartaric acid incorporated in a 1:1 ratio.

[0133] Example 16 Crystallization experiments on (4aS,6S,10aS)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl acetate and (4aR,6R,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl acetate, respectively. The following experiment was aimed at preparing a crystalline salt of (4aS,6S,10aS)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl acetate (i.e., the non-salt form of the compound of formula IIIa1 described herein and the compound according to Example 6), which is the opposite enantiomer of (4aR,6R,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl acetate. The reason for using the opposite undesired enantiomer rather than the desired enantiomer (i.e., the compound of formula IIIa1) is that the undesired isomer has no or little effect on dopamine receptors and therefore the resulting material has no or little value in research aimed at dopamine receptor agonists. However, any chemical or physicochemical properties found in a non-chiral environment, such as solubility and crystallinity, will be the same for the two enantiomers, and therefore any conclusions about the undesired enantiomer can be extrapolated to the desired enantiomer. Thus, in a manner similar to Example 4B, but using the (+) enantiomer of 1-propyl-1,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one instead of the (-) enantiomer of 1-propyl-1,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one, epimer 1 of (4aS,10aS)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ol (1.1 g, 4.4 mmol) was dissolved in a mixture of pyridine (8 mL) and acetic anhydride (8 mL). The reaction mixture was placed in a fume hood overnight and then quenched by the addition of room temperature ethanol. After 30 min, the volatiles were removed by evaporation and co-evaporation several times with ethanol, and the residue was purified by silica gel chromatography using a gradient of EtOAc and MeOH (0-70% MeOH) as eluent.0.78 g (61%) of (4aS,6S,10aS)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl acetate in non-salt form was obtained as an oil. The material was transferred to nine different vials (78 mg of oil in each vial). Ethyl acetate (2 mL) was added to each of the vials along with one equivalent of one acid selected from nine different acids (i.e., maleic acid, oxalic acid, fumaric acid, succinic acid, L-tartaric acid (natural tartaric acid), benzoic acid, salicylic acid, benzenesulfonic acid, and citric acid). Each vial was then equipped with a magnetic stirrer and each mixture was stirred at room temperature for a week, with no precipitate observed in any of the vials except for the vial containing L-tartaric acid, which provided a white precipitate after 24 hours. The tartrate salt was isolated by filtration and the solid was dried in a hood to give 86 mg (73%) of the desired L-tartrate salt as a white powder. Melting point: 83.4° C. [α]. D =+50.9°(c 10mg / mL, MeOH).MS(ESI+)m / z292[M+H] + NMR spectra showed a 1:1 ratio between the above identified esters and L-tartaric acid. Thus, in this example, the L-tartrate salt of (4aS,6S,10aS)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl acetate is provided as a combination of (4aS,6S,10aS)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl acetate and L-tartaric acid incorporated in a 1:1 ratio.

[0134] It is noteworthy to note that attempts to carry out the above experiment using (4aR,6R,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl acetate and L-tartaric acid did not provide a solid salt but only a sticky oil. Instead, the only counterion that provided a crystalline salt with this compound was D-tartrate, which is a non-natural form of tartrate.

[0135] It has therefore been unexpectedly found that the unnatural form of tartaric acid, i.e. D-tartaric acid, allows for the formation of a crystalline salt with (4aR,6R,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl acetate. The D-tartrate salt of (4aR,6R,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl acetate was a combination of D-tartaric acid and (4aR,6R,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl acetate incorporated in a 1:1 ratio.

[0136] Example 17 Locomotor activity: Behavioral activity was measured using eight Digiscan activity monitors (RXYZM(16)TAO, Omnitech Electronics, Columbus, OH, USA) connected to an Omnitech Digiscan analyzer and an Apple Macintosh computer equipped with a digital interface board (NB DIO-24, National Instruments, USA). Each activity monitor consisted of a secondary metal frame (W×L=40 cm×40 cm) equipped with a light beam sensor. During behavioral activity measurements, rats were placed in a clear acrylic cage (W×L×H, 40×40×30 cm), which in turn was placed in the activity monitor. Each activity monitor contained three rows of infrared light beam sensors, each row consisting of 16 sensors. Two rows were placed at a 90° angle along the front and sides of the cage floor, and a third row was placed 10 cm above the floor to measure vertical activity. The light beam sensors were spaced 2.5 cm apart. Each activity monitor was mounted in an identical sound- and light-attenuating box containing weak room lighting and a fan. Computer software was written using object-oriented programming (LabVIEW™, National instruments, Austin, TX, USA). Behavioral data from each activity monitor, representing the animal's position (horizontal center of mass and vertical activity) at each time point, were recorded at a sample collection frequency of 25 Hz and collected using the custom written LABView™ application. Data from each recording session were stored and analyzed for distance traveled. Each behavioral recording session began approximately 5 minutes after injection of the test compound and lasted 180 minutes.

[0137] Compounds disclosed herein were tested for their effect on spontaneous locomotor activity in non-pretreated Sprague-Dawley rats and Sprague-Dawley rats given a single dose of 0.3 μmol / kg (n=5, SC) (based on cumulative distance traveled 0-180 min post-dose) compared to a control group of animals given saline (SC) (n=5). Prior art compounds from Preparation 4A were administered subcutaneously (SC). Compounds from Example 5 were administered orally (PO) and subcutaneously (SC), respectively. Distance traveled units are arbitrary units.

[0138] FIG. 3 shows the average distance traveled after subcutaneous administration of either 0.3 μmol / kg of a prior art compound ((4aR,10aR)-1-propyl-1,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one) with Preparation 4A or saline (control experiment) to drug-naive rats. Immediately after administration, animals were placed in the locomotor meter and locomotor activity was recorded for 180 min. Results are presented as distance traveled for control (open bars) and drug-fed animals (filled bars).

[0139] FIG. 4A shows the average distance traveled after oral administration of either 0.3 μmol / kg of the compound according to Example 5 (a mixture of the 6R and 6S epimers of the oxalate salt of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl acetate) or saline (control experiment) to drug-naive rats. Immediately after administration, animals were placed in the locomotor meter and locomotor activity was recorded for 180 min. Results are presented as distance traveled for control (empty bars) and drug-fed animals (filled bars).

[0140] FIG. 4B shows the average distance traveled after subcutaneous administration of either 0.3 μmol / kg of the compound according to Example 5 (a mixture of the 6R and 6S epimers of the oxalate salt of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl acetate) or saline (control experiment) to drug-naive rats. Immediately after administration, animals were placed in the locomotor meter and locomotor activity was recorded for 180 min. Results are presented as distance traveled for control (empty bars) and drug-fed animals (filled bars).

[0141] As shown in Figures 3, 4A, and 4B, both of the two compounds tested affect the locomotor activity pattern in normal non-pretreated rats. Thus, the prior art compound from preparation 4A as well as the compound from Example 5 induce hyperactivity. The desired effect lasts for at least 180 minutes for both of the two compounds, indicating that the two compounds have a long duration of action. This trend suggests that the compound from Example 5 appears to have a longer duration of action compared to the prior art compound, since for the compound from Example 5, an increase in the desired effect is observed very late in the experiment. Furthermore, an even more obvious difference between the two compounds is the onset of action, i.e., the increase in the distance traveled is faster for the prior art compound (20-25 minutes) compared to the compound from Example 5 (35-40 minutes), with an initial decrease in the distance traveled occurring immediately after administration followed by an increase in the distance traveled. A further difference is that the immediate effect of the prior art compound on locomotor activity is very steep, with a long distance traveled already within 20-45 minutes. Taken together, these data indicate that animals given the prior art compound have a more rapid peak plasma concentration of the active species resulting from the administered drug compared to that of the compound according to Example 5. As a result, the data indicate that the compound according to Example 5 is associated with no or a mild side effect profile due to its slower onset of action.

[0142] Example 18 m-RNA analysis: The animals were killed by decapitation 60 min after injection of the drugs.

[0143] The brain was sectioned into left and right sections. The left section was analyzed for gene expression and was sectioned into four different regions: the limbic system (containing the nucleus accumbens, most of the olfactory tubercle, ventral pallidum, and amygdala), the striatum, the frontal cortex, and the hippocampus.

[0144] Total RNA was prepared using the RNeasy Plus Universal Tissue Mini Kit (Qiagen).

[0145] The RNA pellet was dissolved in RNAse-free water and stored at −80° C. Spectrophotometric sample concentrations were determined by NanoDrop ND-1000.

[0146] Two-step reverse transcription was performed by using the SuperScript III kit (Invitrogen). 1 μg of total RNA was reverse transcribed with 5 μl of 2×RT reaction mixture, 1 μl of RT enzyme, and the mixture volume was adjusted to 10 μl with RNAse-free water. The samples were incubated at 25°C for 10 min, 50°C for 30 min, and finally at 85°C for 5 min. After incubation at 37°C for 20 min and 85°C for 5 min, 1 U of E. coli RNase H was added. The cDNA solution was diluted 40-fold in Tris EDTA buffer pH 8 (Merck) and stored at -20°C.

[0147] The three sequences (arc and two reference genes) were amplified together in a triplex PCR reaction. For real-time PCR measurements: 5 μl of cDNA reaction was amplified in a 20 μl reaction mixture containing 10 μl of PerfeCTa MultiPlex qPCR SuperMix (Quantabio), 3.5 μl of RNAse-free water, 0.15 μM of each primer, and 0.1 μM of each probe. Real-time PCR was measured on a CFX96 (Bio-Rad) using the following settings for all genes: pre-incubation at 95° C. for 3 min, followed by 40 cycles of denaturation at 95° C. for 15 s, annealing, and extension at 60° C. for 1 min. The reference genes are HPRT and cyclophilin.

[0148] TaqMan simplex and duplex PCR for analysis of EGR-1 and Npas4 Real-time PCR reactions consisted of 10 μl of Sso Advanced Universal Probes Supermix, 1 μl of primers / probes, 1 μl of reference gene or 1 μl of MQ water, and 8 μl of cDNA (40-fold diluted from RT-PCR). Real-time PCR reactions were performed in a CFX96 real-time PCR detector (Bio-Rad) with the following cycling conditions: initial denaturation at 95°C for 2 min, followed by 40 cycles of 95°C for 5 s and 60°C for 30 s. All genes of interest were labeled at the 5' end with the fluorescent dye FAM, and the reference genes (HPRT and ppia (also named cyclophilin)) were labeled with HEX. TaqMan primers and probes were synthesized by Bio-rad (Coralville, Iowa, USA) and used according to the manufacture's protocol.

[0149] EGR-1 (Early Growth Response qRnoCEP0022872) was analyzed in duplicate with the reference gene HPRT (Hypoxanthine phosphoribosyltransferase qRnoCEP0050840).

[0150] Npas4 (neuronal PAS domain protein 4 qRnoCEP0029461) was analyzed in singleplex.

[0151] To quantify gene expression of genes of interest, the reference gene Ppia (cyclophilin A peptidyl-propyl cis-trans isomerase qRnoCIP0050815) was also analyzed.

[0152] Figure 5 shows the effect on tissue levels of Arc mRNA in four different brain regions (limbic region, striatum, frontal cortex, and hippocampus) after subcutaneous administration of two different compounds at two different doses compared to that of the corresponding control experiment. The bars on the left half of the figure represent the effect on ARC of a prior art compound ((4aR,10aR)-1-propyl-1,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one) from Preparation 4A, and the bars on the right half of the figure represent the effect on ARC of a compound of the present disclosure ((4aR,10aR)-1-propyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl acetate) (mixture of 6R and 6S epimers) from Example 5, oxalate. The effects of both of the aforementioned compounds on tissue levels of Arc were measured at two different doses (0.3 μmol / kg and 1 μmol / kg) and the effects are presented as percentage of control mean ± SEM. Statistical significance was assessed using Student's t-test (two-tailed) versus control.

[0153] As shown in the diagram of FIG. 5, both of the two compounds dose-dependently increase tissue levels of Arc in the frontal cortex, which is sometimes observed with dopamine receptor agonists. Also shown in the diagram is that the compound according to Example 5 dose-dependently increases tissue levels of Arc in the limbic region, a property that the prior art compound according to Preparation 4A does not have. Since Arc is a biomarker of synaptic activity, this attribute of the compound according to Example 5 allows it to provide a unique therapeutic profile, such as improvements related to emotions, behavior, and / or long-term memory. Furthermore, the compound according to Example 5 increases tissue levels of other genes in the limbic region, such as, for example, Npas4. The compound does so to a greater extent than that of the prior art compound according to Preparation 4A, and this observed effect allows for improved treatment for patients with neurodegenerative diseases and / or neurological disorders.

[0154] Sequence Listing The primer and probe sequences for the measurement of arc are as follows:

[0155] Arc (Activity Regulatory Gene) (Accession No. U19866) Sense: 5'-GGA GTT CAA GAA GGA GTT TC-3' (SEQ ID NO: 1) Antisense: 5'-CCA CAT ACA GTG TCT GGT A-3' (SEQ ID NO: 2) Probe: CCG CTT ACG CCA GAG GAA CT (SEQ ID NO: 3) Dye: 5'FAM Quencher: 3'BHQ1 Product size: 149

[0156] Hypoxanthine phosphoribosyltransferase (HPRT) (Accession number AF001282) Sense: 5'-AGG GAT TTG AAT CAT GTT TG-3' (SEQ ID NO: 4) Antisense: 5'-CTG CTA GTT CTT TAC TGG C-3' (SEQ ID NO: 5) Probe: TGT AGA TTC AAC TTG CCG CTG TC (SEQ ID NO: 6) Pigment: 5'HEX Quencher: 3'BHQ1 Product size: 121

[0157] Cyclophilin A (cyclo) (Accession No. M19533) Sense: 5'-CTG GAC CAA ACA CAA ATG-3' (SEQ ID NO: 7) Antisense: 5'-ATG CCT TCT TTC ACC TTC-3' (SEQ ID NO: 8) Probe: TTG CCA TCC AGC CAC TCA GT (SEQ ID NO: 9) Pigment: 5'Texas red Quencher: 3'BHQ2 Product size: 100

[0158] References 1. Liu et al., “Extremely Potent Orally Active Benzo[g]quinoline Analogue of the Dopaminergic Prodrug: 6-(N,N-Di-n-propyl)amino-3,4,5,6,7,8-hexahydro-2H-naphtalen-1-one”, J.Med.Chem., 2006, 49, 1494-1498 (the title of this article was soon revised to “Extremely Potent Orally Active Benzo[g]quinoline Analogue of the Dopaminergic Prodrug: 1-Propyl-trans-2,3,4,4a,5,7,8,9,10,10a-decahydro-1H-benzo[g]quinoline-6-one”, J.Med.Chem., 2006, 49, 6930) 2.Liu et al.,“A novel synthesis and pharmacological evaluation of a potential dopamine D1 / D2 agonist:1-Propyl 1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol”Bioorganic&Medicinal Chemistry,16(2008),3438-3444 3.WO2010 / 097092 4.WO2001 / 078713 5.WO2019 / 101917 6.WO2020 / 234270 7.WO2020 / 234271 8.WO2020 / 234272 9.WO2020 / 234273 10.WO2020 / 234274 11.WO2020 / 234275 12.WO2020 / 234276 13.WO2020 / 234277

Claims

1. Formula III1: 【Chemistry 1】 Formula III1 A compound of or a pharmaceutically acceptable salt thereof During the ceremony, A compound or a pharmaceutically acceptable salt thereof, wherein both carbon 4a and carbon 10a have an R configuration.

2. Carbon 6 has an R configuration, thereby forming formula IIIa1: 【Chemistry 2】 Formula IIIa1 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which provides the compound.

3. Carbon 6 has an S configuration, thereby forming formula IIIb1: 【Transformation 3】 Formula IIIb1 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which provides the compound.

4. A pharmaceutically acceptable salt of a compound according to any one of claims 1 to 3, wherein the salt is a combination of the compound of formula III1 and an organic acid.

5. The pharmaceutically acceptable salt according to claim 4, wherein the salt is a combination of the compound of formula IIIa1 and an organic acid.

6. The pharmaceutically acceptable salt according to claim 4, wherein the salt is a combination of the compound of formula III1 and an organic acid in a 2:1 ratio.

7. The pharmaceutically acceptable salt according to claim 4, wherein the salt is a 1:1 combination of the compound of formula III1 and an organic acid.

8. The pharmaceutically acceptable salt according to claim 4, wherein the organic acid is D-tartaric acid.

9. A compound or salt according to any one of claims 1 to 3, which is in a crystalline form.

10. A pharmaceutical composition comprising a therapeutically acceptable amount of the compound or salt according to any one of claims 1 to 3, in a state of miscibility with at least one pharmaceutically acceptable carrier, excipient and / or diluent.

11. A pharmaceutical composition according to claim 10 for use as a pharmaceutical.

12. The use of any one of the compounds or salts described in claims 1 to 3 for the manufacture of a pharmaceutical product for use in the treatment of one or more of the following: Parkinson's disease, Huntington's disease, restless legs syndrome, Alzheimer's disease, schizophrenia, attention deficit hyperactivity disorder, and drug addiction.

13. The use according to claim 12, wherein the treatment includes or consists of treatment for Parkinson's disease.

14. The use according to claim 12, wherein the treatment is not associated with any side effects, or is associated with mild side effects including and / or vomiting.

15. The use according to claim 12, wherein the treatment further comprises the treatment of non-motor symptoms associated with Parkinson's disease, which include or consist of one or more of the following: cognitive decline, depression, anxiety, apathy, and Parkinson's disease dementia.

16. A method for preparing a compound of formula III1 or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 3, The method described above is a) Compound of formula II1 to compound of formula IV 【Chemistry 4】 Formula II1 Formula IV (In the formula, In the compound of formula II1, both carbon 4a and carbon 10a have an R configuration. X is OH, halide, and OC(O)R ２ Selected from the group consisting of, R ２ (But it is methyl) The step involves optionally reacting in the presence of an ester formation promoter such as a coupling reagent. The step of reacting to form the compound of formula III1, b) The step of optionally separating the compound of formula III1 into the compound of formula IIIa1 and the compound of formula IIIb1 as defined in any one of claims 2 to 3, c) A step of optionally combining the compound of formula III1 obtained in step a) or step b) with a pharmaceutically acceptable acid, thereby providing a pharmaceutically acceptable salt of the compound of formula III1. Methods that include...

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