New solid forms of (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

Abstract

To provide a solid form of a compound useful as a prodrug of a catecholamine for use in treatment of neurodegenerative diseases and disorders such as Parkinson's Disease.SOLUTION: Provided is a solid form of the compound of formula (Id), where the solid form is selected from a) a zwitterion form, b) an alkali metal salt and c) a halogen salt.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to compounds for use in the treatment of neurodegenerative diseases and disorders, such as Parkinson's disease. (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4a R,10aR)-7-Hydroxy-1-propyl-1,2,3,4,4a,5,10,1 0a-Octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-py This paper relates to a new solid form of ran-2-carboxylic acid. [Background technology]

[0002] Parkinson's disease (PD) is a common neurodegenerative disorder that becomes more prevalent with age and is affecting many people worldwide. It affects an estimated 7 to 10 million people worldwide. Parkinson's disease causes loss of movement and It is a multifaceted disease characterized by both motor and non-motor symptoms. Tremor, bradykinesia / akinesia (slowness and lack of movement), rigidity, postural stability and Gait dysfunction and non-motor symptoms include neuropsychiatric disorders (e.g., depression, psychosis, sexual symptoms, anxiety, affective blunting, mild cognitive impairment and dementia) and autonomic nervous system disorders and sleep disorders ( Poewe et al.,Nature Review,(2017)vol3 ar ticle 17013:1-21).

[0003] An important hallmark of the pathophysiology of Parkinson's disease is the increased dopamine transport into the striatum and other brain regions. Loss of pigmented dopaminergic neurons in the substantia nigra pars compacta that provide dopaminergic innervation Such progressive neurodegeneration leads to a decrease in striatal levels of dopamine, which results in As a result, a series of changes in the basal ganglia network eventually occur, resulting in the four main symptoms of Parkinson's disease. The primary target of dopamine in the striatum is the corpus striatum, which has topographical processes projecting from the corpus striatum. In addition, medium spiny GABAergic neurons (MSNs) selectively express D1 or D2 receptors The striatopallidal system is also known as the "indirect pathway" and consists of GABA receptors that project to the lateral pallidum. Neuro-agonistic MSNs express D2 receptors (MSN-2) and are also known as the striatonigral "direct pathway." GABAergic MSNs that project to the substantia nigra pars reticulata and medial pallidum, called The lack of dopamine due to neuronal loss leads to two processes: This leads to an imbalance in the activity of the thalamus and cortical output, resulting in a marked decrease in motor function. Motor dysfunction occurs (Gerfen et al, Science (1990) 250: 1429-32;Delong,(1990)Trends in Neuroscie nce 13:281-5;Alexander et Crutcher,(1990 )Trends in Neuroscience 13:266-71 and overview See Poewe et al., Nature Review (2017) vol. 3. article 17013:1-21).

[0004] Beneficial for patients with Parkinson's disease who want to control motor symptoms The most effective treatment strategies available are primarily indirect and direct dopamine agonists. The classic and gold standard therapy involves administering dopamine, a compound that is decarboxylated in the brain to form dopamine. One example is chronic oral ingestion of L-3,4-dihydroxyphenylalanine (L-DOPA), which Another approach is to develop apomorphine, which acts on both D1 and D2 receptor subtypes. Pynecologic or pramipexole, ropinirole, and D2 receptor subtypes This includes the administration of dopamine receptor agonists, such as other agonists that stimulate D1 and D2 receptors. For activation of both receptor subtypes and for global rebalancing of the indirect-direct pathway Therefore, only D2 agonists reverse the dysfunction of the indirect pathway, resulting in optimal MR. This reduction in symptoms with movement was achieved with both L-DOPA and apomorphine. can be.

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

[0006] L-DOPA is a prodrug of dopamine and has been used to treat motor Parkinson's disease. However, after several years of treatment (i.e., the honeymoon period), period), the specific progression of the disease (i.e., sustained loss of dopaminergic neurons) and Complications arise due to the poor pharmacokinetic (PK) profile of L-DOPA. Complications include 1) abnormal involuntary movements that occur during the optimal "timed effect" of the drug; dyskinesias, and 2) the positive effects of L-DOPA gradually diminished during that period. , periods of non-fluctuation during which symptoms return or worsen (Sprenger and Poew e, CNS Drugs (2013), 27: 259-272).

[0007] Direct dopamine receptor agonists activate dopamine autoreceptors and medium spiny neuron M It can activate postsynaptic dopamine receptors located on SN-1 and MSN-2. Apomorphine is a drug that contains a 1,2-dihydroxybenzene (catechol) moiety. It belongs to the class of paminergic agonists. When combined with a phenethylamine motif, Tetrahydrocannabinol has low oral bioavailability or is associated with low or no oral bioavailability, similar to that of apomorphine. Apomorphine is clinically used parenterally (generally intermittent subcutaneous administration). Although it is administered or pumped (continuous parenteral infusion during the day), it is used to treat PD. Regarding apomorphine, animal studies suggest that it may be possible to administer it via transdermal delivery or implantation. However, it has been shown that delivery of apomorphine from an implant can be achieved in a variety of forms. When they were studied in monkeys (Bibbiani et al., Chase Experiment imental Neurology (2005), 192: 73-78), most In some cases, animals were treated with immunosuppressant drugs to prevent local irritation and other complications after implantation. It turned out that the patient had to be treated with samethasone. Alternative delivery strategies for apomorphine therapy in humans have been extensively explored (e.g., Gros set et al., Acta Neurol Scand. (2013), 128: 166-171 and Hauser et al., Movement Disorder (See 2016), Vol. 32(9): 1367-1372.) However, However, these attempts have not yet been clinically implemented for the treatment of PD.

[0008] An alternative to parenteral formulations of catecholamines is to formulate the free catecholamines so that they can be administered orally. However, for clinical use, A known problem with developing prodrugs of The difficulties associated with this are:

[0009] Enteric-coated N-propyl-noraporphine (N-Propyl-Noraporphine) for Duodenal Delivery PA) and monopivaloyl esters of apomorphine (e.g., WO 02 / 10037 (See Brochure No. 7) and the D1-like agonists adrenocorticoid and A-86929 Diacetyl prodrug of (Giardina and Williams; CNS D Rug Reviews (2001), Vol. 7 (3): 305-316) Various ester prodrugs of cholamines have been reported in the literature. It undergoes extensive hepatic first-pass metabolism in humans after oral administration, resulting in low oral It has a low bioavailability (approximately 4%). In PD patients, Drogolide has anti-Parkinsonian efficacy equivalent to L-DOPA (Giardina and Williams;CNS Drug Reviews(2001), Vol. .7(3):305-316).

[0010] In addition to ester prodrugs of catecholamines, alternative prodrug approaches include The two catecholamines were synthesized as the corresponding methylenedioxy or di-acetaryl derivatives. This prodrug principle involves masking the hydroxyl group. l et al., Neuropharmacology(1982);21(10): 953-961 and U.S. Pat. No. 4,543,256 and WO 2009 / 026 The method described in WO 2009 / 026935 and WO 2009 / 026934 is is.

[0011] Other proposed approaches to catecholamine prodrugs are described, for example, in International Publication No. 2003 / 013363. 001 / 078713 brochure and Liu et al., Bioorganic Enone derivatization proposed in Med. Chem. (2008), 16: 3438-3444 For further examples of catecholamine prodrugs, see, e.g., So zio et al.,Exp.Opin.Drug Disc.(2012);7(5 ):385-406.

[0012] The compound (4aR,10aR)-1-propyl-1, 2,3,4,4a,5,10,10a-Octahydro-benzo[g]quinoline-6,7- Diols are disclosed in WO 2009 / 026934. The cis-isomers indicate that the compound has low oral bioavailability in rats. Liu et al., J. Med. Chem. (2013), including suggestive pharmacological data. 06), 49:1494-1498, then Liu et al., Bioorgani cPreviously disclosed in Med. Chem. (2008), 16:3438-3444. First, Cannon et al., J. Heterocyclic Chem. (1 980);17:1633-1636 discloses the racemic compound. [ka]

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

[0014] Liu et al.,J.Med.Chem.(2006),49:1494-14 98 and Liu et al., Bioorganic Med.Chem. (2008 ), 16:3438-3444, was converted to the active compound (I) in rats. The present invention discloses enone derivatives of formula (Ia) shown below. [ka]

[0015] WO 2009 / 026934 and WO 2009 / 0269 Pamphlet No. 35 discloses methylenedioxy (MDO) derivatives having the following formula (Ib): The present invention discloses two prodrug derivatives of compound (I), including: [ka]

[0016] The conversion of compound (Ib) to compound (I) in rat and human hepatocytes was reported in WO 02 / 04336. In addition, the compound (Ia The in vivo pharmacology of (Ib) and (Ib) and the active "parent compound" (I) has been shown to be relevant to Parkinson's disease. It has been tested in various animal models as a Both compound (I) and compounds (Ia) and (Ib) are effective. It has been shown that compounds (Ia) and (Ib) are converted to compound (I) in vivo. All three compounds were confirmed with respect to L-dopa and apomorphine. It has been reported to have a longer duration of action than

[0017] WO 2009 / 026934 and WO 2009 / 0269 Another prodrug of compound (I) disclosed in the pamphlet of No. 35 is represented by the formula (Ic): It is an ester prodrug. [ka]

[0018] Despite longstanding interest in this field, there are currently no treatments for PD. The need for development of effective, well tolerated and orally active drugs remains clear. The current research has not clearly addressed the need for a PK-stable drug that can provide continuous dopaminergic stimulation. Prodrug derivatives of mixed D1 / D2 agonists that provide a potent agonist profile address these unmet medical needs. This can meet the requirements. Summary of the Invention

[0019] The inventors of the present invention have demonstrated through in vivo and in vitro tests that (2S, 3S, 4S, 5 R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydro Oxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[ g] quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid, Compound (Id) is a prodrug of compounds Ia, Ib, and Ic, it is surprising that the compound is advantageous. Furthermore, the inventors of the present invention have discovered several novel solid forms of the compound of formula (Id). The forms were further specified, among which the heptahydrate, dihydrate and dihydrate of the zwitterion described in Examples 1 to 5 were The dihydrate and potassium salts of the divalent ions are particularly advantageous. More specifically, compound (I d) The potassium salt and dihydrate solid forms of the zwitterion have been shown to have favorable stability. It was found (see Examples 4 and 5). In particular, the dihydrate of the zwitterion of compound (Id) It is very stable in terms of stability tests, water adsorption / desorption, and physical stability after grinding and compression. It was shown to be constant (see Examples 4 and 5).

[0020] The present invention relates to a compound having the formula (Id): -Trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1 ,2,3,4,4a,5,10,10a-Octahydrobenzo[g]quinolin-6-yl This invention relates to a new solid form of tetrahydro-2H-pyran-2-carboxylic acid. [ka]

[0021] Therefore, the present invention a) The zwitterionic form of compound (Id); b) an alkali metal salt of a compound of formula (Id); and c) A halogen salt of a compound of formula (Id) The present invention relates to a solid form of a compound of formula (Id),

[0022] In a specific embodiment, the solid form is crystalline. The solid form is crystalline and is selected from the group consisting of the solid forms listed in Table 2.

[0023] In a specific embodiment, the solid form of the compound of formula (Id) is the amphoteric form of compound (Id). the heptahydrate of the ion, the dihydrate of the zwitterion of compound (Id), or the compound of formula (Id) Alkali metal salts, preferably potassium salts, of the compound of formula (Id). The solid form of compound Id) has one or more of the XRPD peaks listed in group (a) of Table 2. The dihydrate of the zwitterion of compound (Id) characterized by the number of and the like, for example, characterized by one or more of the XRPD peaks listed in group (a) of Table 2. and alkali metal salts of the compound of formula (Id), such as the potassium salt of the compound of formula (Id) do.

[0024] In an even more specific embodiment, the solid form of the compound of formula (Id) is selected from the group consisting of (a) of Table 2. The compound of formula (Id) is characterized by one or more of the XRPD peaks listed in the following group: It is the dihydrate solid form of the ion (DH1).

[0025] In one embodiment, the present invention provides a therapeutically effective amount of a compound of formula (Id) in a solid form according to the present invention. The present invention relates to a pharmaceutical composition comprising the formulation and one or more pharma- ceutically acceptable excipients.

[0026] In one embodiment, the present invention relates to a method for treating Parkinson's disease, Huntington's disease, restless legs syndrome, Neurodegenerative diseases or disorders such as Alzheimer's disease, schizophrenia, attention deficit hyperactivity disorder, For use in the treatment of a neuropsychiatric disease or disorder, such as hyperactivity disorder or drug addiction. The invention relates to solid forms of the compound according to formula (Id).

[0027] In one embodiment, the present invention relates to a method for treating Parkinson's disease, Huntington's disease, restless legs syndrome, Neurodegenerative diseases or disorders such as Alzheimer's disease, schizophrenia, attention deficit hyperactivity disorder, A method for treating a neuropsychiatric disease or disorder, such as hyperactivity disorder or drug addiction, comprising the steps of: The present invention relates to a method comprising administering an effective amount of a solid form of a compound according to formula (Id) of the present invention. do.

[0028] In one embodiment, the present invention relates to a method for treating Parkinson's disease, Huntington's disease, restless legs syndrome, or Alzheimer's disease, or for the treatment of neurodegenerative diseases or disorders, For the treatment of neuropsychiatric diseases or disorders such as ataxia, attention deficit hyperactivity disorder, or drug addiction The use of a solid form of the compound according to formula (Id) of the present invention for the manufacture of a medicament for .

[0029] definition Prodrug In the context of the present invention, the term "prodrug" or "prodrug derivative" refers to a drug that is administered to mammals. After administration to a living subject, such as an animal, preferably a human, the compound is converted to a pharmacologically active site in the body. The conversion is preferably carried out in mice, rats, dogs, minipigs, rabbits, In the context of the present invention, "compound (4aR, 10aR)-1-Propyl-1,2,3,4,4a,5,10,10a-octahydro- "Prodrug of benzo[g]quinoline-6,7-diol" or "Compound of formula (I) "Prodrug" or "Prodrug of Compound (I)" converts Compound (4a) into a prodrug of Compound (I) in the body after administration. R,10aR)-1-Propyl-1,2,3,4,4a,5,10,10a-octahydro It is understood to be a compound that is converted to rho-benzo[g]quinoline-6,7-diol. Said administration is by conventional routes of administration of pharmaceutical compositions known in the art, preferably by oral administration. It can be a given.

[0030] In the context of the present invention, the terms "parent compound" and "parent molecule" refer to the corresponding prodrug For example, the "parent compound" of the compound of formula (Id) means a pharmacologically active site obtained by conversion of the "Product" is understood to be a compound of formula (I).

[0031] Pharmacokinetic Definitions and Abbreviations As used herein, "PK profile" is an abbreviation for "pharmacokinetic profile." The pharmacokinetic profile and pharmacokinetic parameters described herein are represented by the formula (Id ) was administered orally using non-compartmental modelling to determine whether the compound of formula (I) The abbreviated PK parameters are based on plasma concentration-time data obtained at ax (maximum concentration); tmax (time to reach Cmax); t1 / 2 (half-life); AUC 0- 24 (area under the curve from the time of administration to 24 hours after administration), and "24-hour exposure" is The plasma concentrations were measured 24 hours after administration of

[0032] Therapeutically Effective Dose In the context of the present invention, a "therapeutically effective amount" of a compound or solid form of a compound of formula (Id) The term refers to a therapeutic intervention involving the administration of said compound to treat a condition, such as a given disease and its associated Relieve, prevent, partially prevent, eliminate or delay the clinical manifestations of a complication An amount adequate to accomplish this is defined as a "therapeutically effective amount." Effective amounts for each purpose will depend, for example, on the severity of the disease or injury as well as the weight and dosage of the subject. The dosage will vary depending on the patient's overall condition. Determination of appropriate dosage is within the ordinary skill of a skilled physician. Using all the usual experiments, we construct a matrix of values, It will be appreciated that this is accomplished by testing a variety of points.

[0033] In the context of the present invention, a "therapeutically effective amount" of a compound of formula (Id) or a solid form thereof is When the above compounds are administered to a mammal, preferably a human, preferably by oral route, In such cases, the clinical symptoms of a given disease and its complications are reduced, prevented, or partially prevented. The present invention provides an amount of compound (I) sufficient to cause, remove or retard the onset of By "amount" is meant the amount of said compound specified above.

[0034] Treatment and treating In the context of the present invention, "treatment" or "treatment" refers to the treatment of a disease that alleviates or prevents the clinical symptoms of the disease. The management and treatment of patients with the aim of preventing, partially preventing, eliminating or slowing down the progression of The patient to be treated is preferably a mammal, particularly a human. It is.

[0035] Symptoms for treatment The solid forms of formula (Id) prepared by the process of the present invention are useful in treating Parkinson's disease and / or or other conditions for which treatment with a dopamine agonist would be therapeutically beneficial. It is intended for the treatment of neuropsychiatric diseases and disorders.

[0036] The indications for treatment are characterized by motor and / or non-motor disorders and the underlying pathology This includes a variety of central nervous system disorders in which part of the physiology is dysfunction of striatal-mediated circuitry. The functional disorders include, but are not limited to, Parkinson's disease (PD), restless legs syndrome, Huntington's disease, and Neurodegenerative diseases such as, but not limited to, schizophrenia, as well as chronic kidney disease and Alzheimer's disease. It is also seen in neuropsychiatric disorders such as depression, attention deficit hyperactivity disorder and drug addiction.

[0037] In addition to neurodegenerative diseases and disorders, there are other conditions in which increased dopaminergic turnover may be beneficial. In patients with depression, mental functioning, including various aspects of cognition, improves. It may also have a positive effect in the treatment of obesity as an appetite suppressant and in the treatment of drug addiction. It can be used to treat microcephaly dysfunction (MBD), narcolepsy, attention deficit hyperactivity disorder and integrative Potentially negative, positive and cognitive symptoms of schizophrenia may be improved.

[0038] Restless Legs Syndrome (RLS) and Periodic Limb Movement Disorder (PLMD) are disorders that affect dopamine receptors. Another indication that is clinically treated with gonists is impotence, erectile dysfunction, and S. SRI-induced dysfunction, ovarian hyperstimulation syndrome (OHSS) and certain pituitary tumors (prolactin-induced cutinoma) may also be improved by treatment with dopamine agonists. Dopamine is involved in the regulation of the cardiovascular and renal systems, and therefore renal failure and hypertension are These may be considered as alternative indications for the compound of formula (Id) and its solid forms.

[0039] The present invention relates to a method for the treatment of the diseases and disorders listed above, which can be obtained by the process of the present invention. This includes the use of compounds of formula (Id)

[0040] Route of administration Solid forms of the compounds of formula (Id) either as the sole active compound or in combination with other active compounds The pharmaceutical composition comprising the compound can be administered orally, rectally, nasally, buccal, sublingually, pulmonary, transdermal and parenterally ( For administration by any suitable route, such as subcutaneous, intramuscular, and intravenous routes. In the context of the present invention, the oral route is the preferred route of administration.

[0041] The route depends on the general condition and age of the subject being treated, the nature of the condition being treated and the active ingredient. It is understood that this will vary depending on the minute.

[0042] Pharmaceutical Formulations and Excipients In the following, the term "excipient" or "pharmaceutical acceptable excipient" is used without limitation. However, carriers, fillers, diluents, anti-adhesive agents, binders, coatings, colorants, disintegrants, Flavors, glidants, lubricants, preservatives, adsorbents, sweeteners, solvents, excipients "Vehicle" means pharmaceutical excipients such as pharmaceutical agents and adjuvants.

[0043] The present invention relates to compounds of formula Id, such as one of the compounds disclosed in the experimental section herein. The present invention also provides a pharmaceutical composition comprising a solid form of the compound of formula (Id). A process for producing a pharmaceutical composition comprising the R emington,The Science and Practice of Pha rmacy,22th edition(2013),Edited by Allen In accordance with conventional techniques, such as those disclosed in , Loyd V., Jr., ... The composition may be formulated using excipients such as:

[0044] The pharmaceutical compositions comprising the solid forms of the compound (Id) of the present invention are preferably for oral administration. The pharmaceutical composition for oral administration includes tablets, capsules, powders and Solid oral dosage forms, such as granules and tablets, and liquid oral dosage forms, such as solutions, emulsions, suspensions and syrups Forms include powders and granules that are dissolved or suspended in a suitable liquid.

[0045] Solid oral dosage forms are either individual units (e.g., tablets or hard or soft capsules) or each containing a predetermined amount of the active ingredient, preferably one or more Where appropriate, the solid dosage form may contain a coating, such as an enteric coating. The compositions may be prepared using a fluororesin or delayed or delayed release fluororesin according to methods well known in the art. The pharmaceutical composition may be formulated to provide controlled release, such as sustained or sustained release, of the active ingredient. The dosage form may also be one that disintegrates in saliva, such as, for example, an orodispersible tablet.

[0046] Examples of excipients suitable for solid oral dosage forms include, but are not limited to, microcrystalline cellulose, Corn starch, lactose, mannitol, povidone, croscarmellose sodium um, sucrose, cyclodextrin, talcum, gelatin, pectin, magnesium stearate Examples of the alkyl ethers include sodium phosphate, stearic acid and lower alkyl ethers of cellulose. Solid formulations may be prepared using any of the known formulations in the art, such as glyceryl monostearate or hypromellose. It may contain excipients for delayed or sustained release formulations. Solid materials are used for oral administration. In such cases, the formulation may be, for example, prepared by mixing the active ingredient with solid excipients and then inserting the mixture into a conventional tablet. It may be prepared by compressing in a formulation machine, or may be in the form of, for example, a powder, pellet, or The formulation may be in the form of mini tablets and placed inside a hard capsule. The amount of solid excipients may vary widely. However, the dosage unit usually ranges from about 25 mg to about 1 g.

[0047] Liquid oral dosage forms include, for example, elixirs, syrups, oral drops, or liquid filled capsules. Liquid oral dosage forms may be provided as solutions or suspensions in aqueous or non-aqueous liquids. Examples of suitable excipients for liquid oral dosage forms include but are not limited to: However, ethanol, propylene glycol, glycerol, polyethylene glycol, Poloxamer, sorbitol, polysorbates, mono- and diglycerides, cycloglycerides, rhodextrin, coconut oil, palm oil and water. Liquid oral dosage forms include, for example, aqueous or by dissolving or suspending the active ingredient in a non-aqueous liquid, or by using an oil-in-water or oil-based liquid. They may be prepared by incorporating the active ingredient into a water-in-liquid emulsion.

[0048] Additional excipients such as colorants, flavors and preservatives may be used in both solid and liquid oral formulations.

[0049] Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous solutions for injection or infusion. Solutions, dispersions, suspensions or emulsions, concentrates for injection or infusion, as well as injections ready for use Or sterile powders to be dissolved in sterile solutions or dispersions for injection. Examples of suitable excipients include, but are not limited to, water, coconut oil, palm oil, and cyclodextrin. Aqueous formulations should be suitably buffered, if necessary, and contain sufficient saline. Or it should be made isotonic with glucose.

[0050] Other types of pharmaceutical compositions include suppositories, inhalants, creams, gels, transdermal patches, These include implants and formulations for buccal or sublingual administration.

[0051] Excipients used in pharmaceutical formulations are compatible with the intended route of administration and with the active ingredient. It is essential that:

[0052] dose In one embodiment, the solid form of compound (Id) of the present invention is administered at a dose of about 0.000 per day. It is administered in an amount of 1 to about 5 mg / kg body weight. In particular, the daily dose is 0.001 to about The exact dosage will depend on the subject to be treated and the frequency and mode of administration. the formula, sex, age, weight and general condition of the patient, the nature and severity of the condition to be treated, It will depend on the associated disease, the desired effect of the treatment, as well as other factors known to those skilled in the art.

[0053] The typical oral dosage for adults is 0.1 to 100 ml of the solid form of the compound (Id) of the present invention. g / day, for example, 0.05 to 50 mg / day, 0.1 to 10 mg / day, or 0.1 Conveniently, the compounds of the invention are administered in a range of about 0.01 to 50 mg, e.g. For example, 0.05mg, 0.1mg, 0.2mg, 0.5mg, 1mg, 5mg, 10mg, administered in unit dosage forms containing the compound in amounts up to 15 mg, 20 mg, or 50 mg; .

[0054] non-hygroscopic As used herein, the term "non-hygroscopic" refers to a moisture content of about 0 percent to 80 percent relative moisture. Demonstrates that the mass gain of the drug substance during humidity is less than 0.2 percent.

[0055] Halogen Salts As used herein, the term "halogen salt" refers to a halide salt of compound (Id). The halide salt is, for example, a hydrogen halide salt such as HBr or HCl salt.

[0056] XRPD The term "solid form characterized by XRPD peaks" and the like are defined by the recited peaks. It is used to refer to a solid form identifiable by reference to an X-ray powder diffraction pattern. The peaks listed in Table 2(a) for each solid form identify the solid forms of the invention. It is useful for [Brief description of the drawings]

[0057] [Figure 1] PK profiles in Wistar rats obtained after oral administration according to Example 9. Profiles are based on the average plasma concentrations from 3 subjects for each compound. X-axis: time (hours); Y-axis: plasma concentrations (pg / mL) of compound (I) obtained after administration of the following compounds: ●: compound (Ia); ▲: compound (Ib); ◆: compound (Id). [Diagram 2] Figures 2 and 3: Locomotor activity time course (Figure 2) and total distance traveled (Figure 3) after treatment with vehicle (HO, p.o.) or compound (Id) (10, 30, 100 or 300 μg / kg, p.o.) and compared to standard of care (SoC): apomorphine (APO, 3 mg / kg, s.c.), pramipexole (PPX, 0.3 mg / kg, s.c.). Animals were dosed at t=60 min after a habituation period in the test chamber of 60 min and activity was then monitored for 350 min. Data were evaluated using Kruskal-Wallis tests with Dunn's multiple comparison test, giving an overall P value <0.0001. Figure 2: X-axis: time (min); Y-axis: distance traveled (cm) ± SEM / 5 min-bins. Figure 3: Y-axis: total distance traveled (cm) ± SEM. Significance levels for post-hoc comparisons (vs. vehicle group) are indicated: *<0.05, **<0.01, ***<0.001, ****<0.0001. [Diagram 3] Same as above. [Figure 4] Figures 4 and 5: Relationship between plasma concentrations of compound (Id) and compound (I) and hyperactivity induced by compound (Id) (100 μg / kg, oral) (Figure 4) and the corresponding relationship between plasma apomorphine concentrations and hyperactivity induced by apomorphine (3 mg / kg, subcutaneous) (Figure 5). X-axis time (min); Y-axis left: distance traveled (cm) ± SEM / 5-min-bins; Y-axis right (Figure 4): plasma concentration of compound (I) (pg / mL); Y-axis right (Figure 5): plasma concentration of apomorphine (ng / mL). □: distance traveled (cm) ● plasma concentration. [Diagram 5] Same as above. [Figure 6] Conversion of compound (Id) to compound (I) in rat (Figure 6a) and human (Figure 6b) hepatocytes. X-axis: time (min); Y-axis: concentration of compound (I) (pg / mL). [Figure 7] Conversion of compound (Id) in rat (Figure 7a) and human (Figure 7b) whole blood. X-axis: time (min); Y-axis: concentration of compound (I) (pg / mL). [Figure 8] Characterization of the dihydrate (DH1) of compound (Id) by XRPD (Figure 8a) and TGA (Figure 8b). [Figure 9] Characterization of the anhydrate (AH1) of compound (Id) by XRPD (Figure 9a) and TGA (Figure 9b). [Figure 10] Characterization of the heptahydrate of compound (Id) by XRPD (Figure 10a) and TGA (Figure 10b). [Figure 11] FIG. 1 is an XRPD characterization of Form A of compound (Id). [Figure 12] Figure 2: XRPD characterization of Form B of compound (Id). [Figure 13] FIG. 1 is an XRPD characterization of Form C of compound (Id). [Figure 14] Characterization of the monohydrate (MH1) of compound (Id) by XRPD (Figure 14a) and TGA (Figure 14b). [Figure 15] XRPD (Figure 15a) and TGA (Figure 15b) characterization of the potassium salt of compound (Id). [Figure 16] XRPD (Figure 16a) and TGA (Figure 16b) characterization of the sodium salt Form 1 of compound (Id). [Figure 17] XRPD (Figure 17a) and TGA (Figure 17b) characterization of the sodium salt Form 2 of compound (Id). [Figure 18] XRPD characterization of the hydrochloride salt of compound (Id). [Figure 19] XRPD characterization of the hydrobromide salt of compound (Id). [Figure 20]Characteristic DVS curve of the dihydrate DH1 of the zwitterion of compound (Id). X-axis: time in minutes, Y-axis left: % change in mass-dry, Y-axis right: target relative humidity in %P / Po. The thin wavy lines indicate the relative humidity, which is increased or decreased in steps of 5-10% RH between 5 and 90% RH, and the broad lines indicate the change in mass of the dihydrate DH1 of compound (Id). [Figure 21] Characteristic DVS curve of the potassium salt of compound (Id). X-axis: time in minutes, Y-axis left: % change in mass - dry, Y-axis right: target relative humidity in %P / Po. The thin wavy lines indicate the relative humidity, which is increased or decreased in steps of 5-10% RH, the broad lines indicate the change in mass of the potassium salt of compound (Id). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0058] The X-ray powder diffractograms (XRPD) shown in Figures 8 to 19 show that PANalytic l X'Pert PRO X-ray diffractometer, using CuKα1 radiation (λ=1.5406Å) The samples were measured in reflection mode in the 2θ range of 2–40° or 3–40°, with X'ce The y-axis shows intensity (counts) and the x-axis shows 2 Theta angle (°) is indicated.

[0059] Thermogravimetric analysis (TGA) according to Figures 8, 9, 10, 14, 15, 16, and 17 shows that TA- The measurements were performed using an Instruments Discovery TGA. The mg samples were heated in an open pan at 10° / min under nitrogen flow. The x-axis shows the temperature ( °C) and the y-axis represents weight loss (%).

[0060] Detailed Description of the Invention The present invention relates to a compound (2S,3S,4S,5R,6S)-3, 4,5-Trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propionyl Leu-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6 New solid (-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid and its salts Concerning form. [ka]

[0061] Compounds of formula (Id) have the in vitro data listed in Table 7 of Example 8. (4aR,10aR)-1-propyl-1,2,3,4, 4a,5,10,10a-Octahydro-benzo[g]quinoline-6,7-diol [chemical Compound (I)].

[0062] The inventors have demonstrated that compound (I) is conjugated in rat and human hepatocytes to form sulfate derivatives and The conjugates were observed to be converted to glucuronide derivatives containing the compound (Id). It was shown that deconjugation results in conversion to compound (I).

[0063] Glucuronide and sulfate derivatives are generally known to be unstable in the intestine. The body forms highly polar and soluble metabolic products that facilitate the elimination of compounds from the body. For example, in bile duct-cannulated rats, The glucuronide and sulfate conjugates are often found in the bile, and their deconjugated forms (i.e. The parent compound (i.e. the stool) is found in the feces. Sometimes the parent compound is subsequently reabsorbed. Back-conversion of glucuronides and sulfate conjugates ) is known to be part of the enterohepatic recycling process. As mentioned above, apomorphine Oral administration of phenethylcatecholamines such as catecholamines generally results in low bioavailability. Compound (I) has also proven unsuccessful due to its low oral bioavailability. (Liu et al., Bioorganic Med. Chem. m. (2008), 16:3438-3444). With this in mind, and in the gastrointestinal tract, Considering the instability of the glucuronide and sulfate conjugates in the endothelial cells, oral administration of the compounds of the present invention is It would not be expected that sufficient plasma exposure of the compound could be achieved using

[0064] The principle of application of glucuronide derivatives as prodrugs for oral delivery is Regarding phosphate (Goswami et al., J. Nutritional Biochemistry hem.(2003)14:703-709) and morphine (Stain-T Exier et al., Drug Metab. and Disposition (19 98) 26(5):383-387) are discussed. Exposure levels of the parent compound following oral administration were shown to be very low. Other studies have shown that exposure to the intestinal For the treatment of ulcerative colitis, based on poor absorption of the prodrug from the system itself, Budesonide-β-D-glucose as a prodrug for localized delivery of budesonide to the large intestine The use of clonidine has been suggested (Nolen et al., J. Pharm Sci (1995),84(6):677-681).

[0065] Nevertheless, surprisingly, the compound (I) was metabolized in rats and minipigs. Oral administration of compound (Id), identified as a pharmacopoeia, increased the systemic exposure of compound (I) in plasma. It has been observed that the compounds provide This suggests potential uses.

[0066] According to Example 9, compounds (Ia), (Ib) and (Id) were administered orally to Wistar rats. The plasma profile of compound (I) obtained from oral administration is shown in Figure 1. In this study, a dose of 300 μg / kg of compound (Ib) was administered corresponding to 287 μg / kg of compound (I). The dose was adjusted by molecular weight to be equal to Oral administration of compounds (Ia) and (Ib) to mice resulted in early and high peak concentrations of compound (I). It has been found that such high peak concentrations can result in, for example, nausea, vomiting, and other symptoms in humans. In contrast, compound Id ) resulted in a slower absorption rate and a rapid absorption with sustained exposure of Compound (I) in plasma. In addition, the AUC of compound (I) obtained was 100% after administration of compound (Ib). Although the AUCs obtained in the study were generally lower than those obtained in the study, the plasma exposure of Compound (I) in Wistar rats was The effect is maintained throughout the 24-hour period. However, there are compounds that are expected to induce side effects. Since the peak concentration of compound (I) is low, a higher dose of compound (Id) was administered to of compound (I) compared to the concentrations achievable from administering compounds (Ia) and (Ib) Higher total plasma concentrations could potentially be achieved. When investigating the PK properties of compound (Ic), The present inventors have found that the plasma concentration of compound (I) is very low and that the compound (I) for oral administration is It has been found that compound (Ic) remains unsuitable as a prodrug for compound (I d) The oral bioavailability demonstrated was found to be highly unpredictable. The PK parameters for the PK study in Wistar rats are shown in Table 8 of Example 9. are listed below.

[0067] The in vivo conversion of compound (Id) to compound (I) was observed after oral administration of compound (Id). It was also observed in the nibbuta.

[0068] Bioconversion of compound (Id) in humans was demonstrated in rat and human hepatocytes and This is supported by the experiments in Example 6 which show the conversion of 1,2-dichlorophenyl ... This is shown in Figures 6 and 7.

[0069] Therefore, it can be concluded that the compound of formula (Id) is an orally active prodrug of compound (I). The compound is useful as a prodrug for the known prodrugs (Ia) and (Ib) in rats. The peak Cmax was avoided, and the AUC of compound (I) was significantly higher than that of compound (Ic). It was observed that the PK profile provided

[0070] Compound (Id) was further investigated in the rat locomotor activity assay according to Example 10. The dopaminergic effect obtained after oral administration of compound (Id) was demonstrated by the assay. Compounds of formula (Id) have been shown to inhibit in vitro dopaminergic activity (see Figures 2, 3 and 4). The fact that rat rats do not retain agonistic activity (see Example 7 and Table 3) The effect of compound (Id) in the rat locomotor activity assay was evaluated by comparing the effect of compound (Id) on compound (I). It is further shown that the compound can be obtained by conversion of

[0071] Finally, a significant problem with prior art compound (Ib) is that it inhibits 5-HT2B It is an agonist of the receptor. It is thought to be involved in the pathogenesis of valvular heart disease (VHD) after long-term exposure. As 5-HT2B receptor agonists are relevant, such compounds may be useful in the treatment of chronic diseases. (Rothman et al., Circulation ( 2000), 102:2836-2841 and Cavero and Guillon, J.Pharmacol.Toxicol.Methods(2014),69:150 -161) Thus, a further advantage of the compounds of the present invention is that they are 5-HT2B agonists. (See Example 8 and Table 7).

[0072] The compounds of formula (Id) are useful in treating Parkinson's disease and / or its treatment with dopamine agonists. These compounds are useful in the treatment of neurodegenerative diseases and disorders, as well as other conditions in which they are therapeutically beneficial. Compounds suitable for administration may provide a novel therapeutic paradigm for Parkinson's disease. It has sexuality.

[0073] The International Publication No. 2019101917 brochure describes compound (Id), compound (Id) and uses of compound (Id).

[0074] The present invention provides a new solid form of compound (Id).

[0075] Compounds of formula (Id) can give rise to different major ionic species as shown in Table 1 below It has three pKa values.

[0076] [Table 1]

[0077] At physiological pH, the compounds exist predominantly in zwitterionic form. The present invention includes seven solid forms of the cationized zwitterion.

[0078] At low pH, acid addition salts are formed at the nitrogen atom of compound (Id) with inorganic and / or organic acids. The present invention includes two acid addition salts which have been specified and characterized. These are the hydrochloride and and hydrobromide.

[0079] At high pH, ​​the compound of formula (Id) is basified with inorganic and / or organic bases on the acidic group. Salts may be formed. The present invention includes two types of base addition salts which have been specifically and characterized. These are the sodium and potassium salts.

[0080] The scope of the present invention includes the zwitterionic solid forms of compound (Id); and the halogen salts of the compound of formula (Id). The solid forms of the present invention include hydrated and anhydrous forms as well as various polymorphic forms. Includes.

[0081] Exemplary solid forms encompassed by the present invention and methods for obtaining said forms are set forth below. It is described briefly.

[0082] From a water:EtOH mixture containing 10-30% by volume of water, preferably 15-20% water, The dihydrate (DH1) of the zwitterion of compound (Id) formed by crystallization at room temperature.

[0083] By crystallization at room temperature from water:EtOH mixtures containing 1-5% water by volume or by 10 % water by volume from a water:EtOH mixture at 37°C or higher. The zwitterionic anhydride (AH1) of compound (Id).

[0084] Zwitterionic heptahydrate of compound (Id) formed by crystallization of compound (Id) from water Japanese (HH).

[0085] Zwitterionic forms A, B, and C of compound (Id), which are all non-stoichiometric hydrates. Form A was obtained by storage of HH at room temperature and approximately 5% RH. Form B was obtained by storage of HH at room temperature and approximately 5% RH. Form C was obtained by storage of HH at 10% RH at room temperature and approximately 15% RH. Obtained by preservation of H.

[0086] Monohydrate (MH1) of the zwitterion of compound (Id). MH1 is the product of the reaction of DH1 with 105 °C. MH1 was obtained by heating and subsequent water sorption at ambient conditions. H and subsequent water sorption at ambient conditions.

[0087] The potassium salt of compound (Id), the sodium salt form 1 and the sodium salt of compound (Id) Form 2 was prepared according to the experimental section herein.

[0088] The hydrochloride and hydrobromide salts of compound (Id) were prepared according to the experimental section of this specification. It was done.

[0089] In a specific embodiment, the solid form provided herein is a crystalline form. .

[0090] In one embodiment, the present invention relates to a method for producing a medicament for the detection of cancer, comprising the steps of: or a solid form exhibiting at least one XRPD peak included in Table 2. In one exemplary embodiment, each of the solid forms, when analyzed by XRPD, Regarding the specific form, at least 5 to 10 peaks of 2θ angle ±0.2°2θ included in Table 2 peaks, e.g., 6, 7, 8, or 9 peaks, etc., or for each specific form, At least 10 to 15 peaks at 2θ±0.2° 2θ included in 2, e.g., 11 12, 13, or 14 peaks, etc., for each specific form, the 2θ angle values ​​included in Table 2 At least five peaks at ±0.2° 2θ are shown.

[0091] In additional specific embodiments, each of said solid forms comprises, for each specific form: At least 5 to 10 peaks at 2θ angles ±0.2° 2θ included in Table 2, for example, 6, 7, 8, or 9 peaks, etc., or the 2θ± peaks included in Table 2 for each specific form. At least 10 to 15 peaks at 0.2° 2θ, e.g., 11, 12, 13, or For each specific form, such as 14 peaks, the 2θ angles included in Table 2(a) are ±0. Each is characterized by at least five peaks at 2° 2θ.

[0092] In another more specific embodiment, each of said solid forms is analyzed by XRPD. When doing so, at least 5 of the 2θ angles included in Table 2 for each specific embodiment ±0.1° 2θ shall be used. ~10 peaks, e.g., 6, 7, 8, or 9 peaks, etc., or each specific form At least 10 to 15 peaks at 2θ±0.1° 2θ included in Table 2 for the phase For each specific form, for example, 11, 12, 13, or 14 peaks, see Table 2. At least five peaks at 2θ angles of ±0.1° 2θ are shown.

[0093] In further specific embodiments, each of said solid forms comprises the following: At least 5 to 10 peaks at 2θ angles ±0.1°2θ included in Table 2, for example, 6 , 7, 8, or 9 peaks, etc., or the 2θ peaks included in Table 2 for each specific form. At least 10-15 peaks within ±0.1° 2θ, e.g., 11, 12, 13, For each specific form, such as 14 peaks, the 2θ angle ±0.05% is included in the group in Table 2(a). Each is characterized by at least five peaks at 0.2° 2θ.

[0094] In one embodiment, the present invention relates to a solid of the present invention having an XRPD as shown in Figures 8 to 19. Provide a form.

[0095] In one embodiment, the solid form of the present invention is a purified form. "Solid form" means a solid form that, in some cases, essentially contains other compounds or other forms of the same compound. This indicates that the above does not apply.

[0096] In one particular embodiment, the solid form of the invention comprises compound (Id) in purified form. the heptahydrate of the zwitterion of compound (Id), the dihydrate of the zwitterion of compound (Id), or Preferably, the compound is an alkali metal salt, preferably the potassium salt, of the compound of formula (Id).

[0097] In an even more specific embodiment of the invention, the solid form is a purified form of the compound. (Id) is the dihydrate of the zwitterion

[0098] Exemplary methods for the preparation of solid forms are given in the experimental section.

[0099] EMBODIMENTS OF THE PRESENT DISCLOSURE In the following, embodiments of the present invention are disclosed. The first embodiment is denoted E1, the second This embodiment is denoted E2, and so on:

[0100] E1. A solid form of a compound of formula (Id): [ka] a) The zwitterionic solid form of the compound (Id); b) The alkali metal salts of the compound of formula (Id); and c) The halogen salts of the compound of formula (Id) A solid form selected from.

[0101] E2.a) The solid form according to Embodiment 1, which is the zwitterionic solid form of the compound (Id) .

[0102] E3. The solid form according to any one of Embodiments 1 to 2, which is the dihydrate (DH1) of the zwitterion of the compound (Id) .

[0103] E4. The following 2θ angles: 10.4, 11.6, 12.3, 13.1, 13.6, 14.3 , 15.6, 16.0, 16.8, and 18.5°, having a crystal form characterized by XRPD obtained using CuKα1 radiation (λ = 1.5406 Å), the solid form according to Embodiment 3.

[0104] E5. The following 2θ angles: 12.3, 13.1, 13.6, 16.0, 16.8, 18.5 , 18.9, 19.4, 20.5, 21.4, 23.5, 24.7, 25.4, 26.9 , and 28.7°, having a crystal form characterized by XRPD obtained using CuKα1 radiation (λ = 1.5406 Å), the solid form according to any one of Embodiments 3 to 4 . .

[0105] E6. The solid form according to any one of Embodiments 3 to 5, having a crystal form characterized by XRPD depicted in FIG. 8a and obtained using CuKα1 radiation (λ = 1.5406 Å). .

[0106] E7. The compound (Id) according to any one of embodiments 1-2, which is a zwitterionic anhydride. Solid form.

[0107] E8. The zwitterionic anhydride (AH1) of compound (Id), according to embodiments 1-2 and 7 Solid forms of either

[0108] E9. The following 2θ angles: 8.5, 11.1, 12.4, 12.9, 15.6, 16.7, CuKα1 radiation (λ=1 9. The method of claim 8, wherein the crystalline form is characterized by an XRPD obtained using a method for determining whether the crystalline form is crystalline or not. In solid form.

[0109] E10. The following 2θ angles: 8.5, 12.4, 12.9, 15.6, 16.7, 18.9 , 19.3, 20.0, 21.2, 21.5, 22.2, 23.0, 24.2, 27.3 , and 28.3° peaks were obtained using CuKα1 radiation (λ = 1.5406 Å). A solid form according to any of embodiments 8 to 9, having a crystalline form characterized by XRPD as follows: .

[0110] E11. The image depicted in Figure 9a was obtained using CuKα1 radiation (λ = 1.5406 Å). A solid form according to any of embodiments 8 to 10, having a crystalline form characterized by an XRPD of .

[0111] E12. The compound according to any one of embodiments 1 to 2, which is the heptahydrate (HH) of the zwitterion of compound (Id). A solid form of either

[0112] E13. The following 2θ angles: 7.0, 8.6, 10.2, 11.1, 11.9, 13.4, CuKα1 radiation (λ=1 3. The method of claim 1, wherein the crystalline form is characterized by an XRPD obtained using a method for determining whether the crystalline form is crystalline or not. 2 in solid form.

[0113] E14. The following 2θ angles: 7.0, 8.6, 10.2, 11.1, 11.9, 14.0, 17.0, 22.2, 25.9, 27.3, 28.3, 30.8, 34.0, 34.8, and 35.2°, obtained using CuKα1 radiation (λ=1.5406 Å). 14. A solid form according to any of embodiments 12-13, having a crystalline form characterized by an XRPD of Status.

[0114] E15. The image depicted in Figure 10a is obtained using CuKα1 radiation (λ = 1.5406 Å). 15. A solid according to any of embodiments 12 to 14, having a crystalline form characterized by XRPD as follows: form.

[0115] E16. The compound according to any one of embodiments 1 to 2, which is the zwitterionic form A of compound (Id). A solid form.

[0116] E17. The following 2θ angles: 7.6, 9.5, 10.0, 11.2, 12.0, 14.3, CuKα1 radiation (λ=1 3. The method of claim 1, wherein the crystalline form is characterized by an XRPD obtained using a method for determining whether the crystalline form is crystalline or not. Solid form by 6.

[0117] E18. The following 2θ angles: 7.6, 9.5, 10.0, 11.2, 12.0, 14.3, 14.6, 15.3, 15.5, 18.7, 19.3, 23.9, 28.8, 33.7, and 38.7°, obtained using CuKα1 radiation (λ=1.5406 Å). 18. A solid form according to any of embodiments 16-17, having a crystalline form characterized by an XRPD of Status.

[0118] E19. The image depicted in FIG. 11 was obtained using CuKα1 radiation (λ=1.5406 Å). 19. A solid form according to any of embodiments 16 to 18, having a crystalline form characterized by an XRPD of Status.

[0119] E20. The compound according to any one of embodiments 1 to 2, which is the zwitterionic form B of compound (Id). A solid form.

[0120] E21. The following 2θ angles: 7.6, 9.0, 10.9, 12.3, 14.3, 15.0, CuKα1 radiation (λ=1 2. The crystalline form of the compound is characterized by an XRPD obtained using a method for determining whether the compound is a crystalline form or not, using a method for determining whether the compound is a crystalline form or not. Solid form by 0.

[0121] E22. Obtained using CuKα1 radiation (λ=1.5406 Å), depicted in FIG. 22. A solid form according to any one of embodiments 20 to 21, having a crystalline form characterized by an XRPD of Status.

[0122] E23. The compound (Id) according to any one of embodiments 1 to 2, which is the zwitterionic form C. A solid form.

[0123] E24. The following 2θ angles: 7.5, 8.1, 10.3, 12.6, 13.5, 13.8, CuKα1 radiation (λ=1 2. The crystalline form of the compound is characterized by an XRPD obtained using a method for determining whether the compound is a crystalline form or not, using a method for determining whether the compound is a crystalline form or not. 3 in solid form.

[0124] E25. The following 2θ angles: 7.5, 8.1, 10.3, 12.6, 13.5, 13.8, 14.9, 17.5, 18.5, 20.6, 21.6, 22.9, 23.1, 24.0, and a peak at 25.4°, obtained using CuKα1 radiation (λ = 1.5406 Å), characterized by XRPD, having a crystalline form, solid form according to any of Embodiments 23 - 24 .

[0125] E26. Characterized by XRPD obtained using CuKα1 radiation (λ = 1.5406 Å) as depicted in Figure 13, having a crystalline form, solid form according to any of Embodiments 23 - 25 .

[0126] E27. A solid form according to any of Embodiments 1 - 2, which is the monohydrate (MH1) of the zwitterion of compound (Id).

[0127] E29. The following 2θ angles: 9.2, 10.2, 11.8, 12.6, 13.6, 15.7 , 16.0, 16.5, 17.5, and a peak at 18.1°, characterized by XRPD obtained using CuKα1 radiation (λ = 1.5406 Å), having a crystalline form, solid form according to Embodiment 27.

[0128] E30. The following 2θ angles: 9.2, 10.2, 11.8, 12.6, 13.6, 16.0 , 16.5, 17.5, 18.1, 18.7, 19.6, 22.9, 24.7, 25.4 , and a peak at 26.0°, characterized by XRPD obtained using CuKα1 radiation (λ = 1.5406 Å), having a crystalline form, solid form according to any of Embodiments 27 - 28 .

[0129] E31. Characterized by XRPD obtained using CuKα1 radiation (λ = 1.5406 Å) as depicted in Figure 14, 30. A solid form according to any of embodiments 27 to 29, having a crystalline form characterized by an XRPD of Status.

[0130] E32.b) A solid form according to embodiment 1, which is an alkali metal salt of the compound of formula (Id). .

[0131] E33. Any of embodiments 1 and 32, wherein the salt is a potassium salt of the compound of formula (Id). A solid form of either.

[0132] E34. The potassium salt has the following 2θ angles: 3.0, 9.0, 12.6, 13.6, 1 C shows peaks at 5.0, 17.1, 18.0, 18.4, 18.8, and 19.4°. The crystalline form was characterized by XRPD obtained using uKα1 radiation (λ=1.5406 Å). 34. A solid form according to embodiment 33, comprising:

[0133] E35. The potassium salt has the following 2θ angles: 3.0, 9.0, 12.6, 13.6, 1 5.0, 18.0, 19.4, 21.8, 24.7, 27.1, 29.8, 33.3, 3 CuKα1 radiation (λ=1.5406Å) showing peaks at 5.6, 38.6, and 39.6° Any of embodiments 33-34, wherein the crystalline form is characterized by XRPD obtained using A solid form of either

[0134] E36. The potassium salt is obtained using CuKα1 radiation (λ=1.5406 Å). Any of embodiments 33 to 35, having a crystalline form characterized by the XRPD depicted in FIG. A solid form of either

[0135] E37. Any of embodiments 1 and 36, wherein the salt is a sodium salt of the compound of formula (Id). A solid form of either

[0136] E38. The solid form according to embodiment 37, wherein the sodium salt is the sodium salt form 1 of the compound of formula (Id).

[0137] E39. The solid form according to any one of embodiments 37-38, wherein the sodium salt exhibits peaks at the following 2θ angles: 5.9, 8.9, 11.9, 12.8, 13.8, 14.9, 17.7, 18.6, 19.0, and 19.5°, and is characterized by XRPD obtained using CuKα1 radiation (λ = 1.5406 Å).

[0138] E40. The solid form according to any one of embodiments 38-39, wherein the sodium salt exhibits peaks at the following 2θ angles: 8.9, 12.8, 13.8, 14.9 , 17.7, 18.6, 19.0, 19.5, 21.5, 21.8, 22.2, 22.6 , 22.9, 23.4, and 25.1°, and is characterized by a crystal form having XRPD obtained using CuKα1 radiation (λ = 1.540 6 Å).

[0139] E41. The solid form according to any one of embodiments 38-40, wherein the sodium salt has a crystal form characterized by XRPD depicted in FIG. 16 and obtained using CuKα1 radiation (λ = 1.5406 Å).

[0140] E42. The solid form according to embodiment 37, wherein the sodium salt is the sodium salt form 2 of the compound of formula (Id).

[0141] E43. The sodium salt exhibits peaks at the following 2θ angles: 5.6, 8.5, 12.6, 13.6, 14.1, 15.0, 16.7, 17.0, 18.8, and 19.8°. Crystalline morphology characterized by XRPD obtained using CuKα1 radiation (λ=1.5406 Å) 43. A solid form according to any of embodiments 37 and 42, having the formula:

[0142] E44. The sodium salt has the following 2θ angles: 5.6, 8.5, 12.6, 13.6, 14.1, 15.0, 17.0, 18.8, 19.8, 21.0, 23.4, 28.5, CuKα1 radiation (λ=1.5406) ​​showing peaks at 34.3, 37.3, and 38.5° 2. The crystalline form of the embodiment 37 or 42 is characterized by XRPD obtained using ~43 solid forms.

[0143] E45. The sodium salt is obtained using CuKα1 radiation (λ=1.5406 Å). 17. The compound according to claim 37, wherein the compound has a crystalline form characterized by an XRPD depicted in FIG. ~44 solid forms.

[0144] E46. A solid form according to embodiment 1, which is a halogen salt of the compound of formula (Id).

[0145] E47. Any of embodiments 1 and 46, wherein the salt is the hydrochloride salt of the compound of formula (Id). In solid form.

[0146] E48. The hydrochloride salt has the following 2θ angles: 5.7, 7.3, 10.6, 13.3, 15. 3, 15.4, 16.2, 20.1, 22.5, and 23.0° peaks, CuK It has a crystalline form characterized by XRPD obtained using α1 radiation (λ=1.5406 Å). 48. A solid form according to embodiment 47.

[0147] E49. The hydrochloride has the following 2θ angles: 5.1, 5.7, 7.3, 10.6, 13.3 , 15.3, 15.4, 16.2, 16.7, 18.1, 20.1, 22.5, 23.0 The CuKα1 radiation (λ = 1.5406 Å) was used, which shows peaks at 23.6, 23.8°, and 24.7°. 49. Any of embodiments 47 to 48, wherein the crystalline form is characterized by XRPD obtained using In solid form.

[0148] E50. The hydrochloride salt is obtained using CuKα1 radiation (λ=1.5406 Å), FIG. 50. Any of embodiments 47 to 49, having a crystalline form characterized by an XRPD depicted in FIG. 18. or in solid form.

[0149] E51. Any of embodiments 1 and 46, wherein the salt is the hydrobromide salt of the compound of formula (Id). A solid form of either

[0150] E52. The hydrobromide salt has the following 2θ angles: 12.5, 13.9, 14.5, 15. The peaks were 6, 18.6, 18.9, 19.8, 21.3, 22.0, and 22.4°. The crystals were characterized by XRPD obtained using CuKα1 radiation (λ=1.5406 Å). A solid form according to embodiment 51, having the form:

[0151] E53. The hydrobromide salt has the following 2θ angles: 12.5, 13.9, 14.5, 15. 6, 18.6, 18.9, 19.8, 21.3, 22.0, 22.4, 23.3, 24. CuKα1 radiation (λ=1.54 51 to 5, wherein the crystalline form is characterized by XRPD obtained using a method such as X-ray diffraction (XRPD) using 0.06 Å. In solid form according to either 2.

[0152] E54. The hydrobromide salt was obtained using CuKα1 radiation (λ=1.5406 Å). 54. The method of claim 51, wherein the compound has a crystalline form characterized by an XRPD depicted in FIG. Solid form by either.

[0153] E55. A compound of formula (Id) according to any of embodiments 1 to 54 for use in therapy. The solid form of something.

[0154] E56. A compound of formula (Id) according to any of embodiments 1 to 54 for use as a medicament. A solid form of the compound.

[0155] E57. The pharmaceutical is an oral pharmaceutical, such as a tablet or capsule for oral administration. A solid form of the compound of formula (Id) according to embodiment 56.

[0156] E58. A therapeutically effective amount of a compound of formula (Id) according to any of embodiments 1 to 54. A pharmaceutical composition comprising the formulation and one or more pharma- ceutically acceptable excipients.

[0157] E59. The pharmaceutical composition according to embodiment 58, which is for oral administration.

[0158] E60. A pharmaceutical composition according to any of embodiments 58-59, which is an oral pharmaceutical composition.

[0159] E61. The pharmaceutical composition according to any of embodiments 58-60, which is a solid oral dosage form.

[0160] E62. Any of embodiments 58-61, which is a tablet or capsule for oral administration. A pharmaceutical composition according to the present invention.

[0161] E63. Other drugs useful in treating neurodegenerative diseases or disorders, such as Parkinson's disease 63. The pharmaceutical composition according to any of embodiments 58-62, further comprising an agent.

[0162] E64. L-DOPA, droxidopa, folliculax, selegiline or rasagi MAO-B inhibitors such as cyclosporine, COMT inhibitors such as entacapone or tolcapone, Adenosine 2a antagonists such as istradefylline, amantadine or memantine antiglutamic acid agents such as ribastigmine, donepezil or galantamine Acetylcholinesterase inhibitors and quetiapine, clozapine, risperidone, pimapine Vanserin, olanzapine, haloperidol, aripiprazole or brexpiprazole Antipsychotics such as benzodiazepines or antibodies targeting α-synuclein, Tau or A-β proteins The method according to any one of embodiments 58 to 63, further comprising a compound selected from the group consisting of: A pharmaceutical composition.

[0163] E65. Parkinson's disease, Huntington's disease, restless legs syndrome or Alzheimer's disease Treatment of neurodegenerative diseases or disorders such as schizophrenia, attention deficit hyperactivity disorder, or The method according to any one of embodiments 1 to 54 for use in treating a neuropsychiatric disease or disorder, such as drug addiction. A solid form of a compound of formula (Id) according to any of the following:

[0164] E66. For use in the treatment of a neurodegenerative disease or The compound of formula (Id) according to any of embodiments 1 to 54, wherein the disorder is Parkinson's disease. A solid form of.

[0165] E67. For use in the treatment of any of embodiments 65-66, The compounds may be useful in treating neurodegenerative diseases or disorders, such as Parkinson's disease, as well as other drugs. A solid form of the compound of formula (Id) according to any one of the embodiments 1 to 54, used in conjunction with Status.

[0166] E68. For use in the treatment of any of embodiments 66-67, The compound is L-DOPA, droxidopa, follicullux, selegiline or rasagi. MAO-B inhibitors such as cyclosporine, COMT inhibitors such as entacapone or tolcapone, Adenosine 2a antagonists such as istradefylline, amantadine or memantine antiglutamic acid agents such as ribastigmine, donepezil or galantamine Acetylcholinesterase inhibitors and quetiapine, clozapine, risperidone, pimapine Vanserin, olanzapine, haloperidol, aripiprazole or brexpiprazole in combination with a compound selected from the group consisting of antipsychotics such as benzodiazepines, or antibody targeted α- In combination with synuclein, Tau or A-β proteins, embodiments 1 to 54 A solid form of the compound of formula (Id) according to any one of the following:

[0167] E69. For use in the treatment of any of embodiments 66-68, The treatment is carried out by oral administration of said compound, A solid form of compound (Id).

[0168] E70. For use in the treatment of any of embodiments 66-69, The compound is included in a pharmaceutical composition, such as a tablet or capsule for oral administration. A solid form of a compound of formula (Id) according to any of forms 1-54.

[0169] E71. Parkinson's disease, Huntington's disease, restless legs syndrome or Alzheimer's disease Neurodegenerative diseases or disorders such as idiopathic encephalopathy, schizophrenia, attention deficit hyperactivity disorder or drug addiction A method for treating a psychiatric or neurological disease or disorder, such as an addiction, comprising administering a therapeutically effective amount of Administering a solid form of the compound of formula (Id) according to any of claims 1 to 4 to a patient in need thereof. The method includes:

[0170] E72. The method according to embodiment 71, wherein the neurodegenerative disease or disorder is Parkinson's disease. Law.

[0171] E73. The compound according to any one of embodiments 1 to 54 or a pharma- ceutically acceptable salt thereof. in combination with another agent useful in the treatment of a neurodegenerative disease or disorder, such as Parkinson's disease. 73. The method according to any of embodiments 71 to 72, wherein

[0172] E74. The compound according to any one of embodiments 1 to 23 or a pharma- ceutically acceptable salt thereof. However, L-DOPA, droxidopa, foliglurax, and selenium MAO-B inhibitors such as gyramine or rasagiline, entacapone or tolcapone COMT inhibitors, adenosine 2a antagonists such as istradefylline, Antiglutamic acid drugs such as tadine or memantine, rivastigmine, donepezil, or Acetylcholinesterase inhibitors such as galantamine, quetiapine, and clozapine , risperidone, pimavanserin, olanzapine, haloperidol, aripiprazole, or in combination with a compound selected from the group consisting of antipsychotics such as brexpiprazole. or in conjunction with antibodies targeting alpha-synuclein, Tau, or A-beta proteins. The method according to any one of embodiments 72 to 73,

[0173] E75. The method according to any one of embodiments 71 to 74, wherein the administration is by oral route. How to do it.

[0174] E76. The compound according to any one of embodiments 1 to 23 or a pharma- ceutically acceptable salt thereof. is contained in an oral pharmaceutical composition, such as a tablet or capsule for oral administration, Any of the methods from 71 to 75.

[0175] E77. Parkinson's disease, Huntington's disease, restless legs syndrome or Alzheimer's disease for the treatment of neurodegenerative diseases or disorders such as encephalopathy, schizophrenia, attention deficit hyperactivity disorder, In the manufacture of medicines for the treatment of psychiatric and neurological disorders or disorders, such as mental health problems or drug addiction , the use of a solid form of the compound of formula (Id) according to any of embodiments 1 to 54.

[0176] E78. The method according to embodiment 77, wherein the neurodegenerative disease or disorder is Parkinson's disease. Law.

[0177] E79. The medicament is useful in the treatment of neurodegenerative diseases or disorders such as Parkinson's disease. The use according to any of embodiments 77-78, wherein the agent is used in combination with another agent which is

[0178] E80. The medicine is L-DOPA, droxidopa, folligralax, selegiline or MAO-B inhibitors such as rasagiline, C OMT inhibitors, adenosine 2a antagonists such as istradefylline, amantadine or antiglutamic acid agents such as memantine, rivastigmine, donepezil, or galectin. Acetylcholinesterase inhibitors such as lanthamine, quetiapine, clozapine, and risperidone peridol, pimavanserin, olanzapine, haloperidol, aripiprazole, or in combination with a compound selected from the group consisting of antipsychotics such as brexpiprazole; is used in conjunction with antibodies targeting alpha-synuclein, Tau, or A-beta proteins , Use according to any of embodiments 78 to 79.

[0179] E81. The pharmaceutical is an oral pharmaceutical, such as a tablet or capsule for oral administration. Use according to any of the embodiments 77 to 80.

[0180] item The following items serve to further define the invention.

[0181] Item 1. A solid form of a compound of formula (Id): [ka] a) The zwitterionic form of compound (Id); b) an alkali metal salt of a compound of formula (Id); and c) A halogen salt of a compound of formula (Id) A solid form selected from:

[0182] Item 2. A solid form according to item 1, which is a crystalline form.

[0183] Item 3. A compound according to any one of Items 1 to 2, which is a zwitterionic solid form of compound (Id). Solid form according to.

[0184] Item 4. A hydrate of the zwitterion of compound (Id), which is prepared by any one of items 1 to 3. A solid form.

[0185] Item 5. A compound selected from the group consisting of a monohydrate form, a dihydrate form, and a heptahydrate form. The solid form of the zwitterion of compound (Id) according to any one of items 1 to 4. Body form.

[0186] Item 6. A compound (Id) selected from the group consisting of a dihydrate form and a heptahydrate form. 6. The solid form according to any one of items 1 to 5, which is a hydrate of the sexual ion.

[0187] Item 7. Any of Items 1 to 6, which is a dihydrate (DH1) of the zwitterion of compound (Id). A solid form of one of these.

[0188] Item 8. The following 2θ angles ±0.2° 2θ: 10.4, 11.6, 12.3, and 13.1 The results were obtained using CuKα1 radiation (λ=1.5406 Å), including peaks at 13.6° and 14.7°. 8. The solid form according to item 7, which is a crystalline form characterized by an X-ray powder diffraction pattern according to item 7.

[0189] Item 9. The following 2θ angles ±0.1°2θ: 10.4, 11.6, 12.3, 13.1, and Obtained using CuKα1 radiation (λ=1.5406Å), including peaks at 13.6° and 14.2°. A solid according to any one of items 7 to 8, which is in a crystalline form characterized by an X-ray powder diffraction pattern. Body form.

[0190] Item 10. The X-ray powder diffraction pattern has the following 2θ angles ±0.2° 2θ: 14.3, 1 One or more peaks selected from the group consisting of peaks at 5.6, 16.0, 16.8, and 18.5° 10. The solid form according to any one of items 8 to 9, further comprising a plurality of peaks.

[0191] Item 11. The following 2θ angles ±0.2°2θ: 10.4, 11.6, 12.3, 13.1, Including peaks at 13.6, 14.3, 15.6, 16.0, 16.8, and 18.5°; The X-ray powder diffraction patterns were obtained using CuKα1 radiation (λ = 1.5406 Å). 11. The solid form according to any one of items 8 and 10, which is a crystalline form having

[0192] Item 12. The following 2θ angles ±0.1°2θ: 10.4, 11.6, 12.3, 13.1, Including peaks at 13.6, 14.3, 15.6, 16.0, 16.8, and 18.5°; The X-ray powder diffraction patterns were obtained using CuKα1 radiation (λ = 1.5406 Å). 11. The solid form according to any one of items 9 to 10, wherein the solid form is a crystalline form.

[0193] Item 13. The following 2θ angles ±0.2°2θ: 10.4, 11.6, 12.3, 13.1, Including peaks at 13.6, 14.3, 15.6, 16.0, 16.8, and 18.5°; The X-ray powder diffraction patterns were obtained using CuKα1 radiation (λ = 1.5406 Å). 12. The solid form according to any one of items 7, 8, 10, and 11, wherein the solid form is a crystalline form having a crystal structure.

[0194] Item 14. The following 2θ angles ±0.1°2θ: 10.4, 11.6, 12.3, 13.1, Including peaks at 13.6, 14.3, 15.6, 16.0, 16.8, and 18.5°; The X-ray powder diffraction patterns were obtained using CuKα1 radiation (λ = 1.5406 Å). 13. The solid form according to any one of items 7, 9, and 12, which is a crystalline form having

[0195] Item 15. The following 2θ angles ±0.2°2θ: 12.3, 13.1, 13.6, 16.0, 16.8, 18.5, 18.9, 19.4, 20.5, 21.4, 23.5, 24.7, CuKα1 radiation (λ=1.5406) ​​including peaks at 25.4, 26.9, and 28.7° 8. The crystalline form is characterized by an X-ray powder diffraction pattern obtained using a method according to claim 7, 8. , 10, 11, and 13.

[0196] Item 16. The following 2θ angles ±0.1°2θ: 12.3, 13.1, 13.6, 16.0, 16.8, 18.5, 18.9, 19.4, 20.5, 21.4, 23.5, 24.7, CuKα1 radiation (λ=1.5406) ​​including peaks at 25.4, 26.9, and 28.7° Item 7, Item 9 are crystalline forms characterized by an X-ray powder diffraction pattern obtained using a method according to claim 1, , and a solid form according to any one of 14.

[0197] Item 17. Essentially Fig. 8a obtained using CuKα1 radiation (λ = 1.5406 Å) Any of items 7 to 16, which is a crystalline form characterized by an X-ray powder diffraction pattern depicted in or one in solid form.

[0198] Item 18. When heated to about 30°C to about 150°C, as measured using thermogravimetric analysis, When the heating rate was 10°C / min, the weight loss was about 7.6% (weight ratio) compared to the initial weight. 17. A solid form according to any one of items 7 to 17.

[0199] Item 19. Thermogravimetric analysis (using a heating rate of 10 °C / min) essentially as depicted in Figure 8b was performed. 19. The solid form according to any one of items 7 to 18, wherein the solid form is a crystalline form characterized by the above-mentioned.

[0200] Item 20. A compound according to any one of Items 1 to 3, which is a zwitterionic anhydride of compound (Id). Solid form according to.

[0201] Item 21. The compound (Id) of Items 1 to 3 and 2, which is a zwitterionic anhydride (AH1) of the compound (Id). Solid form by any one of 0.

[0202] Item 22. The following 2θ angles ±0.2°2θ: 8.5, 11.1, 12.4, 12.9, and The peaks at 15.6° and 16.7° are obtained using CuKα1 radiation (λ=1.5406 Å). The compound according to any one of items 20 to 22, which is a crystalline form characterized by an X-ray powder diffraction pattern. A solid form.

[0203] Item 23. The following 2θ angles ±0.1°2θ: 8.5, 11.1, 12.4, 12.9, and The peaks at 15.6° and 16.7° are obtained using CuKα1 radiation (λ=1.5406 Å). The compound according to any one of items 20 to 22, which is a crystalline form characterized by an X-ray powder diffraction pattern. A solid form.

[0204] Item 24. The X-ray powder diffraction pattern has the following 2θ angles ±0.2° 2θ: 16.7, 1 One or more peaks selected from the group consisting of 8.9, 19.3, 20.0, and 21.2° peaks 24. The solid form according to any one of items 22 to 23, further comprising a plurality of peaks.

[0205] Item 25. The following 2θ angles ±0.2°2θ: 8.5, 11.1, 12.4, 12.9, 1 C, including peaks at 5.6, 16.7, 18.9, 19.3, 20.0, and 21.2° The X-ray powder diffraction pattern was characterized by the use of uKα1 radiation (λ=1.5406 Å). 25. The solid form according to any one of items 20 to 22 and 24, which is a crystalline form.

[0206] Item 26. The following 2θ angles ±0.1°2θ: 8.5, 11.1, 12.4, 12.9, 1 C, including peaks at 5.6, 16.7, 18.9, 19.3, 20.0, and 21.2° The X-ray powder diffraction pattern was characterized by the use of uKα1 radiation (λ=1.5406 Å). 26. The solid form according to any one of items 20 to 25, which is a crystalline form.

[0207] Item 27. The following 2θ angles ±0.2°2θ: 8.5, 12.4, 12.9, 15.6, 1 6.7, 18.9, 19.3, 20.0, 21.2, 21.5, 22.2, 23.0, 2 CuKα1 radiation (λ=1.5406Å) with peaks at 4.2, 27.3, and 28.3° 20 to 2 are crystalline forms characterized by an X-ray powder diffraction pattern obtained using 5 in solid form.

[0208] Item 28. The following 2θ angles ±0.1°2θ: 8.5, 12.4, 12.9, 15.6, 1 6.7, 18.9, 19.3, 20.0, 21.2, 21.5, 22.2, 23.0, 2 CuKα1 radiation (λ=1.5406Å) with peaks at 4.2, 27.3, and 28.3° 20 to 2 are crystalline forms characterized by an X-ray powder diffraction pattern obtained using 7 in solid form.

[0209] Item 29. Essentially Figure 9a, obtained using CuKα1 radiation (λ=1.5406 Å). 20 to 23, which is a crystalline form characterized by an X-ray powder diffraction pattern as depicted in 28 solid forms.

[0210] Item 30. When heated to about 30°C to about 150°C, as measured using thermogravimetric analysis, (heating rate 10°C / min), the weight loss is less than 1% (by weight) of the initial weight. , a solid form according to any one of items 20 to 29.

[0211] Item 31. Thermogravimetric analysis essentially as depicted in FIG. 9b (heating rate 10° C. / min). The solid form according to any one of items 20 to 30, which is a crystalline form characterized by the above-mentioned (use).

[0212] Item 32. Any of Items 1 to 6, which is the heptahydrate (HH) of the zwitterion of compound (Id). A solid form of one of these.

[0213] Item 33. The following 2θ angles ±0.2° 2θ: 7.0, 8.6, 10.2, 11.1, and X obtained using CuKα1 radiation (λ=1.5406Å), including a peak at 11.9° 33. The solid form according to item 32, which is a crystalline form characterized by a linear powder diffraction pattern.

[0214] Item 34. The following 2θ angles ±0.1°2θ: 7.0, 8.6, 10.2, 11.1, and X obtained using CuKα1 radiation (λ=1.5406Å), including a peak at 11.9° 34. The method according to claim 32, wherein the crystalline form is characterized by a 1-line powder diffraction pattern. Solid form.

[0215] Item 35. The X-ray powder diffraction pattern has the following 2θ angles ±0.2° 2θ: 13.4, 1 One or more peaks selected from the group consisting of peaks at 4.0, 14.5, 17.0, and 17.4° 35. The solid form according to any one of items 33 to 34, further comprising a plurality of peaks.

[0216] Item 36. The following 2θ angles ±0.2°2θ: 7.0, 8.6, 10.2, 11.1, 11 Cu, including peaks at .9, 13.4, 14.0, 14.5, 17.0, and 17.4° Characterized by an X-ray powder diffraction pattern obtained using Kα1 radiation (λ=1.5406 Å) 36. The solid form according to any one of items 32 to 33 and 35, which is a crystalline form.

[0217] Item 37. The following 2θ angles ±0.1°2θ: 7.0, 8.6, 10.2, 11.1, 11 Cu, including peaks at .9, 13.4, 14.0, 14.5, 17.0, and 17.4° Characterized by an X-ray powder diffraction pattern obtained using Kα1 radiation (λ=1.5406 Å) 37. The solid form according to any one of items 32 to 36, which is a crystalline form.

[0218] Item 38. The following 2θ angles ±0.2°2θ: 7.0, 8.6, 10.2, 11.1, 11 .9, 14.0, 17.0, 22.2, 25.9, 27.3, 28.3, 30.8, 34 CuKα1 radiation (λ=1.5406Å) with peaks at .0, 34.8, and 35.2° 32 to 33, which is a crystalline form characterized by an X-ray powder diffraction pattern obtained using and a solid form according to any one of 35 to 36.

[0219] Item 39. The following 2θ angles ±0.1°2θ: 7.0, 8.6, 10.2, 11.1, 11 .9, 14.0, 17.0, 22.2, 25.9, 27.3, 28.3, 30.8, 34 CuKα1 radiation (λ=1.5406Å) with peaks at .0, 34.8, and 35.2° 32 to 38. A crystalline form characterized by an X-ray powder diffraction pattern obtained using A solid form of either one of the following:

[0220] Item 40. Essentially Fig. 10 obtained using CuKα1 radiation (λ = 1.5406 Å) Item 32. The crystalline form characterized by an X-ray powder diffraction pattern as depicted in FIG. ~39 solid forms.

[0221] Item 41. When heated to about 20°C to about 150°C, as measured using thermogravimetric analysis, When heated at a rate of 10°C / min, the weight loss was approximately 21% (by weight) compared to the initial weight. , a solid form according to any one of items 32 to 40.

[0222] Item 42. Thermogravimetric analysis essentially as depicted in FIG. 10b (heating rate 10° C. / min 42. The solid form according to any one of items 32 to 41, which is a crystalline form characterized by the use of

[0223] Item 43. Any one of items 1 to 4, which is a zwitterionic form A of compound (Id). Solid form according to.

[0224] Item 44. The following 2θ angles ±0.2°2θ: 7.6, 9.5, 10.0, 11.2, and X obtained using CuKα1 radiation (λ=1.5406Å), including a peak at 12.0° 44. The solid form according to item 43, which is a crystalline form characterized by a 1-ray powder diffraction pattern.

[0225] Item 45. The following 2θ angles ±0.1°2θ: 7.6, 9.5, 10.0, 11.2, and X obtained using CuKα1 radiation (λ=1.5406Å), including a peak at 12.0° 45. The method according to claim 43, wherein the crystalline form is characterized by a 1-line powder diffraction pattern. Solid form.

[0226] Item 46. The X-ray powder diffraction pattern has the following 2θ angles ±0.2° 2θ: 14.3, 1 One or more peaks selected from the group consisting of peaks at 4.6, 15.3, 15.5, and 19.3° 46. ​​The solid form according to any one of items 44 to 45, further comprising a plurality of peaks.

[0227] Item 47. The following 2θ angles ±0.2°2θ: 7.6, 9.5, 10.0, 11.2, 12 Cu, including peaks at 0.0, 14.3, 14.6, 15.3, 15.5, and 19.3° Characterized by an X-ray powder diffraction pattern obtained using Kα1 radiation (λ=1.5406 Å) 47. The solid form according to any one of items 43 to 44 and 46, which is a crystalline form.

[0228] Item 48. The following 2θ angles ±0.1°2θ: 7.6, 9.5, 10.0, 11.2, 12 Cu, including peaks at 0.0, 14.3, 14.6, 15.3, 15.5, and 19.3° Characterized by an X-ray powder diffraction pattern obtained using Kα1 radiation (λ=1.5406 Å) 48. The solid form according to any one of items 43 to 47, which is a crystalline form.

[0229] Item 49. The following 2θ angles ±0.2°2θ: 7.6, 9.5, 10.0, 11.2, 12 .0, 14.3, 14.6, 15.3, 15.5, 18.7, 19.3, 23.9, 28 CuKα1 radiation (λ=1.5406Å) with peaks at .8, 33.7, and 38.7° Items 43 to 44 are crystalline forms characterized by an X-ray powder diffraction pattern obtained using and a solid form according to any one of 46 to 47.

[0230] Item 50. The following 2θ angles ±0.1°2θ: 7.6, 9.5, 10.0, 11.2, 12 .0, 14.3, 14.6, 15.3, 15.5, 18.7, 19.3, 23.9, 28 CuKα1 radiation (λ=1.5406Å) with peaks at .8, 33.7, and 38.7° Items 43 to 49 are crystalline forms characterized by an X-ray powder diffraction pattern obtained using A solid form of either one of the following:

[0231] Item 51. Essentially Figure 11 obtained using CuKα1 radiation (λ = 1.5406 Å). 43 to 45 are crystalline forms characterized by an X-ray powder diffraction pattern as depicted in Solid form by any one of 50.

[0232] Item 52. Any one of Items 1 to 4, which is the zwitterionic form B of compound (Id). Solid form according to.

[0233] Item 53. The following 2θ angles ±0.2°2θ: 7.6, 9.0, 10.9, 12.3, and X obtained using CuKα1 radiation (λ=1.5406Å), including a peak at 14.3° 53. The solid form according to item 52, which is a crystalline form characterized by a linear powder diffraction pattern.

[0234] Item 54. The following 2θ angles ±0.1°2θ: 7.6, 9.0, 10.9, 12.3, and X obtained using CuKα1 radiation (λ=1.5406Å), including a peak at 14.3° 54. The method according to any one of items 52 to 53, which is a crystalline form characterized by a 1-line powder diffraction pattern. Solid form.

[0235] Item 55. The X-ray powder diffraction pattern has the following 2θ angles ±0.2° 2θ: 15.0, 2 One or more peaks selected from the group consisting of peaks at 1.5, 22.1, 22.6, and 23.7° 55. The solid form according to any one of items 53 to 54, further comprising a plurality of peaks.

[0236] Item 56. The following 2θ angles ±0.2°2θ: 7.6, 9.0, 10.9, 12.3, 14 Cu, including peaks at .3, 15.0, 21.5, 22.1, 22.6, and 23.7° Characterized by an X-ray powder diffraction pattern obtained using Kα1 radiation (λ=1.5406 Å) 56. The solid form according to any one of items 52 to 53 and 55, which is a crystalline form.

[0237] Item 57. Essentially Fig. 12 obtained using CuKα1 radiation (λ = 1.5406 Å) 52 to 54 are crystalline forms characterized by an X-ray powder diffraction pattern as depicted in 57 in solid form.

[0238] Item 58. Any one of items 1 to 4, which is the zwitterionic form C of compound (Id). Solid form according to.

[0239] Item 59. The following 2θ angles ±0.2°2θ: 7.5, 8.1, 10.3, 12.6, and X obtained using CuKα1 radiation (λ=1.5406Å), including a peak at 13.5° 59. The solid form according to item 58, which is a crystalline form characterized by a linear powder diffraction pattern.

[0240] Item 60. The following 2θ angles ±0.1°2θ: 7.5, 8.1, 10.3, 12.6, and X obtained using CuKα1 radiation (λ=1.5406Å), including a peak at 13.5° 59. The compound according to claim 58, which is a crystalline form characterized by a 1-line powder diffraction pattern. Solid form.

[0241] Item 61. The X-ray powder diffraction pattern has the following 2θ angles ±0.2° 2θ: 13.8, 1 One or more peaks selected from the group consisting of peaks at 4.9, 17.5, 18.5, and 20.6° 61. The solid form according to any one of items 59 to 60, further comprising a plurality of peaks.

[0242] Item 62. The following 2θ angles ±0.2°2θ: 7.5, 8.1, 10.3, 12.6, 13 Cu, including peaks at 0.5, 13.8, 14.9, 17.5, 18.5, and 20.6° Characterized by an X-ray powder diffraction pattern obtained using Kα1 radiation (λ=1.5406 Å) 62. The solid form according to any one of items 58 to 59 and 61, which is a crystalline form.

[0243] Item 63. The following 2θ angles ±0.2°2θ: 7.5, 8.1, 10.3, 12.6, 13 Cu, including peaks at 0.5, 13.8, 14.9, 17.5, 18.5, and 20.6° Characterized by an X-ray powder diffraction pattern obtained using Kα1 radiation (λ=1.5406 Å) 63. The solid form according to any one of items 58-59 and 61-62, which is a crystalline form.

[0244] Item 64. The following 2θ angles ±0.1°2θ: 7.5, 8.1, 10.3, 12.6, 13 Cu, including peaks at 0.5, 13.8, 14.9, 17.5, 18.5, and 20.6° Characterized by an X-ray powder diffraction pattern obtained using Kα1 radiation (λ=1.5406 Å) 64. The solid form according to any one of items 58 to 63, which is a crystalline form.

[0245] Item 65. The following 2θ angles ±0.2°2θ: 7.5, 8.1, 10.3, 12.6, 13 .5, 13.8, 14.9, 17.5, 18.5, 20.6, 21.6, 22.9, 23 CuKα1 radiation (λ=1.5406 Å) with peaks at .1, 24.0, and 25.4° Items 58 to 59 are crystalline forms characterized by an X-ray powder diffraction pattern obtained using and a solid form according to any one of 61 to 63.

[0246] Item 66. The following 2θ angles ±0.1°2θ: 7.5, 8.1, 10.3, 12.6, 13 .5, 13.8, 14.9, 17.5, 18.5, 20.6, 21.6, 22.9, 23 CuKα1 radiation (λ=1.5406 Å) with peaks at .1, 24.0, and 25.4° Items 58 to 65 are crystalline forms characterized by an X-ray powder diffraction pattern obtained using A solid form of either one of the following:

[0247] Item 67. Essentially Fig. 13 obtained using CuKα1 radiation (λ = 1.5406 Å) 58 to 59 are crystalline forms characterized by an X-ray powder diffraction pattern as depicted in 66 solid forms.

[0248] Item 68. A compound according to any one of Items 1 to 6, which is a monohydrate (MH1) of the zwitterion of compound (Id). A solid form of either one.

[0249] Item 69. The following 2θ angles ±0.2°2θ: 9.2, 10.2, 11.8, 12.6, 1 X-rays obtained using CuKα1 radiation (λ=1.5406Å) containing a peak at 3.6° A solid form according to item 68, which is a crystalline form characterized by a powder diffraction pattern.

[0250] Item 70. The following 2θ angles ±0.1°2θ: 9.2, 10.2, 11.8, 12.6, 1 X-rays obtained using CuKα1 radiation (λ=1.5406Å) containing a peak at 3.6° A solid according to any one of items 68 to 69, which is a crystalline form characterized by a powder diffraction pattern. Body form.

[0251] Item 71. The X-ray powder diffraction pattern has the following 2θ angles ±0.2° 2θ: 15.7, 1 One or more peaks selected from the group consisting of peaks at 6.0, 16.5, 17.5, and 18.1 degrees 71. The solid form according to any one of items 69 to 70, further comprising a plurality of peaks.

[0252] Item 72. The following 2θ angles ±0.2°2θ: 9.2, 10.2, 11.8, 12.6, 1 C, including peaks at 3.6, 15.7, 16.0, 16.5, 17.5, and 18.1° The X-ray powder diffraction pattern was characterized by the use of uKα1 radiation (λ=1.5406 Å). 72. The solid form according to any one of items 68 to 69 and 71, which is a crystalline form.

[0253] Item 73. The following 2θ angles ±0.1°2θ: 9.2, 10.2, 11.8, 12.6, 1 C, including peaks at 3.6, 15.7, 16.0, 16.5, 17.5, and 18.1° The X-ray powder diffraction pattern was characterized by the use of uKα1 radiation (λ=1.5406 Å). 73. The solid form according to any one of items 68 to 72, which is a crystalline form.

[0254] Item 74. The following 2θ angles ±0.2°2θ: 9.2, 10.2, 11.8, 12.6, 1 3.6, 16.0, 16.5, 17.5, 18.1, 18.7, 19.6, 22.9, 2 CuKα1 radiation (λ=1.5406Å) with peaks at 4.7, 25.4, and 26.0° 68 to 6 are crystalline forms characterized by an X-ray powder diffraction pattern obtained using 9 and any one of 71 to 72 in a solid form.

[0255] Item 75. The following 2θ angles ±0.1°2θ: 9.2, 10.2, 11.8, 12.6, 1 3.6, 16.0, 16.5, 17.5, 18.1, 18.7, 19.6, 22.9, 2 CuKα1 radiation (λ=1.5406Å) with peaks at 4.7, 25.4, and 26.0° 68 to 7, which are crystalline forms characterized by an X-ray powder diffraction pattern obtained using 4 in solid form.

[0256] Item 76. Essentially Fig. 14 obtained using CuKα1 radiation (λ = 1.5406 Å) Item 68. The crystalline form characterized by an X-ray powder diffraction pattern as depicted in FIG. ~75 solid forms.

[0257] Item 77. When heated to about 20°C to about 150°C, as measured using thermogravimetric analysis, When heated at a rate of 10°C / min, the weight loss was about 4% (weight ratio) compared to the initial weight. A solid form according to any one of items 68 to 76.

[0258] Item 78. Thermogravimetric analysis essentially as depicted in FIG. 14b (heating rate 10° C. / min 78. The solid form according to any one of items 68 to 77, wherein the solid form is a crystalline form characterized by the use of

[0259] Item 79. Any one of items 1 and 2, which is an alkali metal salt of a compound of formula (Id). In solid form.

[0260] Item 80. A compound of formula (Id) selected from the group consisting of potassium salts and sodium salts. 79. A solid form according to claim 79, which is an alkali metal salt of

[0261] Item 81. Any of Items 79 to 80, wherein the salt is a potassium salt of the compound of formula (Id). or in solid form.

[0262] Item 82. The potassium salt has the following 2θ angles ±0.2°2θ: 3.0, 9.0, 12. CuKα1 radiation (λ=1.5406Å) including peaks at 6, 13.6, and 15.0° 82. The solid form according to claim 81, having a crystalline form characterized by XRPD obtained using

[0263] Item 83. The potassium salt has the following 2θ angles ±0.1°2θ: 3.0, 9.0, 12. CuKα1 radiation (λ=1.5406Å) including peaks at 6, 13.6, and 15.0° 83. Any one of items 81 to 82, having a crystalline form characterized by XRPD obtained using Solid form by.

[0264] Item 84. The X-ray powder diffraction pattern has the following 2θ angles ±0.2° 2θ: 17.1, 1 One or more peaks selected from the group consisting of peaks at 8.0, 18.4, 18.8, and 19.4° 84. The solid form according to any one of items 81 to 83, further comprising a plurality of peaks.

[0265] Item 85. The potassium salt has the following 2θ angles ±0.2°2θ: 3.0, 9.0, 12. 6, 13.6, 15.0, 17.1, 18.0, 18.4, 18.8, and 19.4° The XRPD obtained using CuKα1 radiation (λ = 1.5406 Å) was characterized, including the peak 85. The solid form according to any one of items 81 to 82 and 84, having a crystalline form as defined above.

[0266] Item 86. The potassium salt has the following 2θ angles ±0.1°2θ: 3.0, 9.0, 12. 6, 13.6, 15.0, 17.1, 18.0, 18.4, 18.8, and 19.4° The XRPD obtained using CuKα1 radiation (λ = 1.5406 Å) was characterized, including the peak 86. The solid form according to any one of items 81 to 85, having a crystalline form as defined above.

[0267] Item 87. The potassium salt has the following 2θ angles ±0.2°2θ: 3.0, 9.0, 12. 6, 13.6, 15.0, 18.0, 19.4, 21.8, 24.7, 27.1, 29. CuKα1 radiation (λ 8, 33.3, 35.6, 38.6, and 39.6°) Item 8, having a crystalline form characterized by XRPD obtained using a method for determining the molecular weight of the compound (I) having a molecular weight of 1.0 or less, and a molecular weight of 1.0 or less. 1 to 82 and 84 to 85 in a solid form.

[0268] Item 88. The potassium salt has the following 2θ angles ±0.1°2θ: 3.0, 9.0, 12. 6, 13.6, 15.0, 18.0, 19.4, 21.8, 24.7, 27.1, 29. CuKα1 radiation (λ 8, 33.3, 35.6, 38.6, and 39.6°) Item 8, having a crystalline form characterized by XRPD obtained using a method for determining the molecular weight of the compound (I) having a molecular weight of 1.0 or less, and a molecular weight of 1.0 or less. 1 to 87 in a solid form.

[0269] Item 89. The potassium salt is obtained using CuKα1 radiation (λ=1.5406 Å). having a crystalline morphology characterized by an XRPD pattern essentially as depicted in Figure 15a; A solid form according to any one of items 81 to 88.

[0270] Item 90. When heated to about 20°C to about 150°C, as measured using thermogravimetric analysis, When heated at a rate of 10°C / min, the weight loss was less than 1% (by weight) of the initial weight. 89. A solid form according to any one of items 81 to 89.

[0271] Item 91. Thermogravimetric analysis essentially as depicted in FIG. 15b (heating rate 10° C. / min The solid form according to any one of items 81 to 90, wherein the solid form is a crystalline form characterized by the use of

[0272] Item 92. Items 1, 2, and 79, wherein the salt is a sodium salt of the compound of formula (Id). ~80 solid forms.

[0273] Item 93. The sodium salt is sodium salt form 1 of the compound of formula (Id). Solid form by eye 92.

[0274] Item 94. The sodium salt has the following 2θ angles ±0.2°2θ: 5.9, 8.9, 11 The CuKα1 radiation (λ=1.5406Å) was used, which includes peaks at .9, 12.8, and 13.8°. 94. The solid form according to claim 93, having a crystalline form characterized by XRPD obtained using

[0275] Item 95. The sodium salt has the following 2θ angles ±0.1°2θ: 5.9, 8.9, 11 The CuKα1 radiation (λ=1.5406Å) was used, which includes peaks at .9, 12.8, and 13.8°. 95. Any one of items 93 to 94, having a crystalline form characterized by XRPD obtained using In solid form.

[0276] Item 96. The X-ray powder diffraction pattern has the following 2θ angles ±0.2° 2θ: 14.9, 1 One or more peaks selected from the group consisting of peaks at 7.7, 18.6, 19.0, and 19.5° 96. The solid form according to any one of items 94 to 95, further comprising a plurality of peaks.

[0277] Item 97. The sodium salt has the following 2θ angles ±0.2°2θ: 5.9, 8.9, 11 .9, 12.8, 13.8, 14.9, 17.7, 18.6, 19.0, and 19.5° The XRPD obtained using CuKα1 radiation (λ=1.5406 Å) was characterized. A solid form according to any one of items 93-94 and 95-96, having a crystal morphology characteristic of Status.

[0278] Item 98. The sodium salt has the following 2θ angles ±0.1°2θ: 5.9, 8.9, 11 .9, 12.8, 13.8, 14.9, 17.7, 18.6, 19.0, and 19.5° The XRPD obtained using CuKα1 radiation (λ=1.5406 Å) was characterized. 98. A solid form according to any one of items 93 to 97, having a crystalline morphology characteristic of said solid form.

[0279] Item 99. The sodium salt has the following 2θ angles ±0.2°2θ: 8.9, 12.8, 1 3.8, 14.9, 17.7, 18.6, 19.0, 19.5, 21.5, 21.8, 2 CuKα1 radiation, including peaks at 2.2, 22.6, 22.9, 23.4, and 25.1° (λ=1.5406 Å) A solid form according to any one of orders 93-94 and 96-97.

[0280] Item 100. The sodium salt has the following 2θ angles ±0.1°2θ: 8.9, 12.8, 13.8, 14.9, 17.7, 18.6, 19.0, 19.5, 21.5, 21.8, CuKα1, including peaks at 22.2, 22.6, 22.9, 23.4, and 25.1° having a crystalline form as characterized by XRPD obtained using the λ=1.5406 Å line, A solid form according to any one of items 93 to 99.

[0281] Item 101. The sodium salt is obtained using CuKα1 radiation (λ=1.5406 Å). and having a crystalline form characterized by an XRPD pattern essentially as depicted in FIG. 93. A solid form according to any one of items 93 to 100.

[0282] Item 102. When measured using thermogravimetric analysis, for example, at temperatures between about 20°C and about 175°C When heated (heating rate 10°C / min), the weight loss was about 2% (weight ratio) of the initial weight. 102. A solid form according to any one of items 93 to 101.

[0283] Item 103. Thermogravimetric analysis essentially as depicted in FIG. 16b (heating rate 10° C. / A solid form according to any one of items 93 to 102, which is a crystalline form characterized by the use of a crystalline form (using a crystalline form) Status.

[0284] Item 104. The sodium salt is the sodium salt form 2 of the compound of formula (Id). Solid form by eye 92.

[0285] Item 105. The sodium salt has the following 2θ angles ±0.2°2θ: 5.6, 8.5, 1 CuKα1 radiation (λ=1.5406Å) including peaks at 2.6, 13.6, and 14.1° 105. The solid form according to item 104, having a crystalline form characterized by XRPD obtained using

[0286] Item 106. The sodium salt has the following 2θ angles ±0.1°2θ: 5.6, 8.5, 1 CuKα1 radiation (λ=1.5406Å) including peaks at 2.6, 13.6, and 14.1° Any of items 104 to 105, having a crystalline form characterized by XRPD obtained using or one in solid form.

[0287] Item 107. The X-ray powder diffraction pattern has the following 2θ angles ±0.2° 2θ: 15.0; One selected from the group consisting of peaks at 16.7, 17.0, 18.8, and 19.8° 107. The solid form according to any one of items 105 to 106, further comprising a plurality of peaks.

[0288] Item 108. The sodium salt has the following 2θ angles ±0.2°2θ: 5.6, 8.5, 1 2.6, 13.6, 14.1, 15.0, 16.7, 17.0, 18.8, and 19.8 The XRPD obtained using CuKα1 radiation (λ = 1.5406 Å) containing a peak at A solid according to any one of items 104 to 105 and 107, having a characteristic crystalline form. form.

[0289] Item 109. The sodium salt has the following 2θ angles ±0.1°2θ: 5.6, 8.5, 1 2.6, 13.6, 14.1, 15.0, 16.7, 17.0, 18.8, and 19.8 The XRPD obtained using CuKα1 radiation (λ = 1.5406 Å) containing a peak at 109. A solid form according to any one of items 104 to 108, having a characterized crystalline morphology.

[0290] Item 110. The sodium salt has the following 2θ angles ±0.2°2θ: 5.6, 8.5, 1 2.6, 13.6, 14.1, 15.0, 17.0, 18.8, 19.8, 21.0, 2 CuKα1 radiation, including peaks at 3.4, 28.5, 34.3, 37.3, and 38.5° (λ=1.5406 Å) A solid form according to any one of orders 104-105 and 107-108.

[0291] Item 111. The sodium salt has the following 2θ angles ±0.1°2θ: 5.6, 8.5, 1 2.6, 13.6, 14.1, 15.0, 17.0, 18.8, 19.8, 21.0, 2 CuKα1 radiation, including peaks at 3.4, 28.5, 34.3, 37.3, and 38.5° (λ=1.5406 Å) A solid form according to any one of orders 104 to 110.

[0292] Item 112. The sodium salt is obtained using CuKα1 radiation (λ=1.5406 Å). and having a crystalline form characterized by an XRPD pattern essentially as depicted in FIG. 112. A solid form according to any one of items 104 to 111.

[0293] Item 113. When heated to about 20°C to about 175°C, such as when measured using thermogravimetric analysis When heated (heating rate 10℃ / min), the weight loss is about 5% (weight ratio) of the initial weight. 113. A solid form according to any one of items 104 to 112.

[0294] Item 114. Thermogravimetric analysis essentially as depicted in FIG. 17b (heating rate 10° C. / A solid according to any one of items 104 to 113, which is a crystalline form characterized by a crystallization step (using a crystallization step). form.

[0295] Item 115. Any one of items 1 to 2, which is a halide salt of a compound of formula (Id). In solid form.

[0296] Item 116. A compound of formula (Id) selected from the group consisting of hydrochloride and hydrobromide salts A solid form according to items 1 and 115, which is a halide salt of the compound of formula (Id).

[0297] Item 117. Items 1 and 115 to 116, wherein the salt is a hydrochloride salt of the compound of formula (Id). Solid forms of either

[0298] Item 118. The hydrochloride has the following 2θ angles ±0.2° 2θ: 5.7, 7.3, 10.6 CuKα1 radiation (λ=1.5406Å) was used, including peaks at 13.3, 15.3°. 118. Any one of items 115 to 117, having a crystalline form characterized by XRPD obtained by In solid form.

[0299] Item 119. The hydrochloride salt has the following 2θ angles ±0.1°2θ: 5.7, 7.3, 10.6 CuKα1 radiation (λ=1.5406Å) was used, including peaks at 13.3, 15.3°. 119. Any one of items 115 to 118, having a crystalline form characterized by XRPD obtained by In solid form.

[0300] Item 120. The X-ray powder diffraction pattern has the following 2θ angles ±0.2° 2θ: 15.4; One selected from the group consisting of peaks at 16.2, 20.1, 22.5, and 23.0° 119. The solid form according to any one of items 118 to 119, further comprising a plurality of peaks.

[0301] Item 121. The hydrochloride has the following 2θ angles ±0.2° 2θ: 5.7, 7.3, 10.6 , 13.3, 15.3, 15.4, 16.2, 20.1, 22.5, and 23.0° The XRPD was characterized using CuKα1 radiation (λ=1.5406Å), including the 121. The solid form according to any one of items 115 to 118 and 120, having a crystalline form in which

[0302] Item 122. The hydrochloride has the following 2θ angles ±0.1°2θ: 5.7, 7.3, 10.6 , 13.3, 15.3, 15.4, 16.2, 20.1, 22.5, and 23.0° The XRPD was characterized using CuKα1 radiation (λ=1.5406Å), including the 122. The solid form according to any one of items 115 to 121, having a crystalline form according to claim 115.

[0303] Item 123. The hydrochloride has the following 2θ angles ±0.2° 2θ: 5.1, 5.7, 7.3, 10.6, 13.3, 15.3, 15.4, 16.2, 16.7, 18.1, 20.1, CuKα1 radiation (λ=1 Item 115 having a crystalline form characterized by XRPD obtained using a method for obtaining the compound of the present invention ... ~118 and 121 in a solid form.

[0304] Item 124. The hydrochloride has the following 2θ angles ±0.1° 2θ: 5.1, 5.7, 7.3, 10.6, 13.3, 15.3, 15.4, 16.2, 16.7, 18.1, 20.1, CuKα1 radiation (λ=1 Item 115 having a crystalline form characterized by XRPD obtained using a method for obtaining the compound of the present invention ... ~123 in solid form.

[0305] Item 125. The hydrochloride salt is obtained using CuKα1 radiation (λ=1.5406 Å). 18, having a crystalline form characterized by an XRPD that is essentially as depicted in FIG. 115-124 in solid form.

[0306] Item 126. The salt of items 1 and 115 to 125, wherein the salt is the hydrobromide salt of the compound of formula (Id). 116 in solid form.

[0307] Item 127. The hydrobromide salt has the following 2θ angles ±0.2° 2θ: 12.5, 13.9 CuKα1 radiation (λ=1.5406Å) including peaks at 14.5, 15.6, and 18.6° 126. The solid form according to claim 126, having a crystalline form characterized by XRPD obtained using Status.

[0308] Item 128. The hydrobromide salt has the following 2θ angles ±0.1°2θ: 12.5, 13.9 CuKα1 radiation (λ=1.5406Å) including peaks at 14.5, 15.6, and 18.6° Any of items 126 to 127, having a crystalline form characterized by XRPD obtained using A solid form of either one.

[0309] Item 129. The X-ray powder diffraction pattern has the following 2θ angles ±0.2° 2θ: 18.9; One selected from the group consisting of peaks at 19.8, 21.3, 22.0, and 22.4° 129. The solid form according to any one of items 127 to 128, further comprising a plurality of peaks.

[0310] Item 130. The hydrobromide salt has the following 2θ angles ±0.2° 2θ: 12.5, 13.9 , 14.5, 15.6, 18.6, 18.9, 19.8, 21.3, 22.0, and 22 XRP obtained using CuKα1 radiation (λ=1.5406Å) containing a peak at .4° 127, 128 or 129, having a crystalline form characterized by: Solid form.

[0311] Item 131. The hydrobromide salt has the following 2θ angles ±0.1°2θ: 12.5, 13.9 , 14.5, 15.6, 18.6, 18.9, 19.8, 21.3, 22.0, and 22 XRP obtained using CuKα1 radiation (λ=1.5406Å) containing a peak at .4° 131. The solid form according to any one of items 126 to 130, having a crystalline form characterized by D.

[0312] Item 132. The hydrobromide salt has the following 2θ angles ±0.2° 2θ: 12.5, 13.9 , 14.5, 15.6, 18.6, 18.9, 19.8, 21.3, 22.0, 22.4 , CuKα including peaks at 23.3, 24.4, 25.5, 28.2, and 28.9° The crystal form is characterized by XRPD obtained using the .1 line (.lamda.=1.5406 .ANG.). , a solid form according to any one of items 126 to 127 and 129 to 131.

[0313] Item 133. The hydrobromide salt has the following 2θ angles ±0.1°2θ: 12.5, 13.9 , 14.5, 15.6, 18.6, 18.9, 19.8, 21.3, 22.0, 22.4 , CuKα including peaks at 23.3, 24.4, 25.5, 28.2, and 28.9° The crystal form is characterized by XRPD obtained using the .1 line (.lamda.=1.5406 .ANG.). , a solid form according to any one of items 126 to 132.

[0314] Item 134. The hydrobromide salt was obtained using CuKα1 radiation (λ=1.5406 Å). and having a crystalline form characterized by an XRPD that is essentially as depicted in FIG. , a solid form according to any one of items 126 to 133.

[0315] Item 135. DH1 as defined in items 7 to 19, HH as defined in items 32 to 42, and and the potassium salts as defined in items 80 to 91. The solid form of something.

[0316] Item 136. DH1 defined in items 7 to 19 and potassium defined in items 80 to 91 A solid form of the compound of formula (Id) selected from the group consisting of:

[0317] Item 137. When heated to about 30°C to about 150°C, as measured using thermogravimetric analysis, When the heating rate was 10°C / min, the weight loss was about 7.6% (by weight) compared to the initial weight. Shown is the zwitterionic solid form of compound (Id).

[0318] Item 138. Thermogravimetric analysis essentially as depicted in FIG. 8b (heating rate 10° C. / min A zwitterionic solid form of compound (Id), which is a crystalline form characterized by the use of

[0319] Item 139. When heated to about 30°C to about 150°C, as measured using thermogravimetric analysis, When heated at a rate of 10°C / min, the weight loss was less than 1% (by weight) of the initial weight. , a zwitterionic solid form of compound (Id).

[0320] Item 140. Thermogravimetric analysis essentially as depicted in FIG. 9b (heating rate 10° C. / min A zwitterionic solid form of compound (Id), characterized by

[0321] Item 141. When heated to about 20°C to about 150°C, as measured using thermogravimetric analysis, When heated at a rate of 10°C / min, the weight loss was approximately 21% (weight ratio) compared to the initial weight. , a zwitterionic solid form of compound (Id).

[0322] Item 142. Thermogravimetric analysis essentially as depicted in Figure 10b (heating rate 10°C / A zwitterionic solid form of compound (Id), characterized by a solubility of 1000 mol / L (using solubility-1000 mol / L).

[0323] Item 143. When heated to about 20°C to about 150°C, as measured using thermogravimetric analysis, When heated at a rate of 10°C / min, the weight loss was approximately 4% (by weight) compared to the initial weight. , a zwitterionic solid form of compound (Id).

[0324] Item 144. Thermogravimetric analysis essentially as depicted in FIG. 14b (heating rate 10° C. / A zwitterionic solid form of compound (Id), characterized by a solubility of 1000 mol / L (using solubility-1000 mol / L).

[0325] Item 145. When heated to about 20°C to about 150°C, as measured using thermogravimetric analysis, When heated at a rate of 10°C / min, the weight loss was less than 1% (by weight) of the initial weight. A solid form of compound (Id), which is the potassium salt shown below.

[0326] Item 146. Thermogravimetric analysis essentially as depicted in FIG. 15b (heating rate 10° C. / A solid form of compound (Id), which is a potassium salt, characterized by:

[0327] Item 147. When measured using thermogravimetric analysis, for example, at temperatures between about 20°C and about 175°C When heated (heating rate 10°C / min), the weight loss was about 2% (weight ratio) of the initial weight. The solid form of compound (Id) shown is the sodium salt form.

[0328] Item 148. Thermogravimetric analysis essentially as depicted in FIG. 16b (heating rate 10° C. / The solid form of the zwitterion of compound (Id) is the sodium salt form, characterized by the use of Status.

[0329] Item 149. When measured using thermogravimetric analysis, for example, at temperatures between about 20°C and about 175°C When heated (heating rate 10℃ / min), the weight loss is about 5% (weight ratio) of the initial weight. The solid form of compound (Id) shown is the sodium salt form.

[0330] Item 150. Thermogravimetric analysis essentially as depicted in FIG. 17b (heating rate 10° C. / A solid form of compound (Id), which is a sodium salt, characterized by:

[0331] Item 151. A compound of formula (Id) according to any one of items 1 to 150 for use in therapy. A solid form of the compound.

[0332] Item 152. A DH1 form according to any one of items 7 to 19 for use in therapy.

[0333] Item 153. Potassium salts according to any one of items 80 to 91 for use in therapy. form.

[0334] Item 154. A compound of formula (Id) according to any one of items 1 to 150 for use as a medicament. A solid form of the compound.

[0335] Item 155. A solid DH according to any one of items 7 to 19 for use as a medicine. 1 form.

[0336] Item 156. A solid capsule according to any one of Items 80 to 91 for use as a medicine. In the form of sodium salt.

[0337] Item 157. The medicine is an oral medicine such as a tablet or capsule for oral administration. 157. A solid form of a compound of formula (Id) according to any one of items 151 to 156.

[0338] Item 158. A therapeutically effective amount of a compound of formula (Id) according to any one of items 1 to 150. A pharmaceutical composition comprising the compound of formula (I) and one or more pharma- ceutically acceptable excipients.

[0339] Item 159. The solid form is a compound of formula (Id) according to any one of items 7 to 19. 159. The pharmaceutical composition according to item 158, wherein the zwitterion dihydrate DH1 is

[0340] Item 160. The solid form is a compound of formula (Id) according to any one of items 80 to 91. 159. The pharmaceutical composition according to claim 158, wherein the compound is a potassium salt of the compound.

[0341] Item 161. For oral administration, according to any one of items 158 to 160 Pharmaceutical compositions.

[0342] Item 162. A pharmaceutical composition according to any one of Items 158 to 161, which is an oral pharmaceutical composition. Composition.

[0343] Item 163. A pharmaceutical composition according to any one of items 158 to 162, which is a solid oral dosage form. thing.

[0344] Item 164. Any of Items 158 to 163 that is a tablet or capsule for oral administration. A pharmaceutical composition comprising any one of the above.

[0345] Item 165. Other drugs useful for treating neurodegenerative diseases or disorders such as Parkinson's disease 165. The pharmaceutical composition according to any one of items 158 to 164, further comprising:

[0346] Item 166. L-DOPA, droxidopa, foligralax, selegiline or MAO-B inhibitors such as rasagiline, COMT inhibitors such as entacapone or tolcapone antidepressants, adenosine 2a antagonists such as istradefylline, amantadine or Antiglutamic acid agents such as memantine, rivastigmine, donepezil, or galantamine Acetylcholinesterase inhibitors such as acetaminophen, quetiapine, clozapine, and risperidone , pimavanserin, olanzapine, haloperidol, aripiprazole, or brexit a compound selected from the group consisting of antipsychotics such as spiprazole; or an antibody targeted α- 165. The method according to claim 158, further comprising administering to said patient a synuclein, Tau, or A-β protein. A pharmaceutical composition according to any one of the above.

[0347] Item 167. Parkinson's disease, Huntington's disease, restless legs syndrome, or Alzheimer's disease Neurodegenerative diseases or disorders, such as rheumatoid arthritis, schizophrenia, attention deficit hyperactivity disorder, or Items 1 to 150 for use in the treatment of psychiatric or neurological disorders, such as drug addiction A solid form of the compound of formula (Id) according to any one of the following:

[0348] Item 168. A zwitterionic dimer of a compound of formula (Id) according to any one of items 7 to 19. A solid form for use according to item 167, which is a hydrate DH1.

[0349] Item 169. A compound of formula (Id) defined by any one of items 80 to 91. 167. A solid form for use according to item 167, in the form of a sodium salt.

[0350] Item 170. The neurodegenerative disease or disorder is Parkinson's disease. A solid form of the compound of formula (Id) for use according to any of the preceding claims.

[0351] Item 171. The solid form is a compound of formula (Id) according to any one of items 7 to 19. and the neurodegenerative disease or disorder is Parkinson's disease. 170. A solid form for use according to item 170.

[0352] Item 172. The solid form is a compound represented by the formula (I) defined by any one of items 80 to 91. d) the potassium salt form of the compound of formula (I) above, wherein the neurodegenerative disease or disorder is Parkinson's disease. 170. A solid form for use according to item 170.

[0353] Item 173. Other compounds useful in the treatment of neurodegenerative diseases or disorders such as Parkinson's disease The use of any one of items 167 to 172 is to be performed in conjunction with In solid form for use.

[0354] Item 174. L-DOPA, droxidopa, foligralax, selegiline or MAO-B inhibitors such as rasagiline, COMT inhibitors such as entacapone or tolcapone antidepressants, adenosine 2a antagonists such as istradefylline, amantadine or Antiglutamic acid agents such as memantine, rivastigmine, donepezil, or galantamine Acetylcholinesterase inhibitors such as acetaminophen, quetiapine, clozapine, and risperidone , pimavanserin, olanzapine, haloperidol, aripiprazole, or brexit in combination with a compound selected from the group consisting of antipsychotics such as spiprazole; or an antibody target should be used in conjunction with targeted α-synuclein, Tau, or A-β proteins. 173. A solid form for use according to any of items 167 to 173.

[0355] Item 175. The treatment of any one of items 167 to 174, wherein the treatment is carried out by oral administration of the compound. A solid form for use by any one of

[0356] Item 176. The compound is an oral pharmaceutical composition, such as a tablet or capsule for oral administration. 175. A solid form for use according to any one of items 167 to 175, comprising

[0357] Item 177. Parkinson's disease, Huntington's disease, restless legs syndrome, or Alzheimer's disease Neurodegenerative diseases or disorders, such as rheumatoid arthritis, schizophrenia, attention deficit hyperactivity disorder, or A method for treating a psychiatric or neurological disease or disorder, such as drug addiction, comprising administering to a subject a therapeutically effective amount of A solid form of a compound of formula (Id) according to any one of items 1 to 150, in a patient in need thereof. The method comprises administering to a subject.

[0358] Item 178. A therapeutically effective amount of a compound of formula (Id) according to any one of items 7 to 19. A method according to item 177, comprising administering a dihydrate of the zwitterion to a patient in need thereof. .

[0359] Item 179. A therapeutically effective amount of a compound of the formula (Id) defined by any one of items 80 to 91. ) in a solid form in the form of a potassium salt of the compound of formula (I) to a patient in need thereof. Method according to 177.

[0360] Item 180. The neurodegenerative disease or disorder is Parkinson's disease. Either one of the methods.

[0361] Item 181. A therapeutically effective amount of a compound of formula (Id) according to any one of items 7 to 19. The method comprises administering to a patient in need thereof a dihydrate of the zwitterion, 181. The method according to any one of items 177 and 180, wherein the disorder is Parkinson's disease.

[0362] Item 182. A therapeutically effective amount of a compound of the formula (Id) defined by any one of items 80 to 91. The method includes administering to a patient in need thereof a solid form of the potassium salt form of the compound of formula (I), According to items 177, 179 and 180, the neurodegenerative disease or disorder is Parkinson's disease. method.

[0363] Item 183. The solid form of the compound (Id) is useful for treating neurodegenerative diseases such as Parkinson's disease or Any of items 177 to 182 is used in conjunction with another drug that is useful in the treatment of a disorder. Either one of the methods.

[0364] Item 184. The solid form of the compound (Id) is L-DOPA, droxidopa, folidopa, or the like. MAO-B inhibitors such as glabraxol, selegiline or rasagiline, entacapone or or COMT inhibitors such as tolcapone, or adenosine 2a antagonists such as istradefylline. agonists, antiglutamate agents such as amantadine or memantine, rivastigmine acetylcholinesterase inhibitors such as acetaminophen, donepezil, or galantamine; Aspirin, clozapine, risperidone, pimavanserin, olanzapine, haloperidol, Selected from the group consisting of antipsychotics such as aripiprazole or brexpiprazole or in combination with an antibody targeting α-synuclein, Tau, or A-β tandem 2. The method according to any one of items 177 to 183, used in conjunction with a protein.

[0365] Item 185. Any one of Items 177 to 184, wherein the administration is carried out by oral route. Method by one.

[0366] Item 186. The solid form is an oral pharmaceutical composition such as a tablet or capsule for oral administration. The method according to any one of items 177 to 185, which is contained in a composition.

[0367] Item 187. Parkinson's disease, Huntington's disease, restless legs syndrome, or Alzheimer's disease Treatment of neurodegenerative diseases or disorders, such as Hymer's disease; or schizophrenia, attention deficit hyperactivity disorder, or in the manufacture of a medicine for the treatment of a psychiatric or neurological disease or disorder, such as drug addiction. 150. Use of a solid form of a compound of formula (Id) according to any one of items 1 to 150.

[0368] Item 188. The solid form is a compound of formula (Id) according to any one of items 7 to 19. Use according to item 187, which is the zwitterion DH1.

[0369] Item 189. The solid form is a compound represented by the formula (I) defined by any one of items 80 to 91. d) in the potassium salt form of the compound according to item 187.

[0370] Item 190. The neurodegenerative disease or disorder is Parkinson's disease, Items 172 to 174. Use by any one of the following:

[0371] Item 191. The medicament is for treating a neurodegenerative disease or disorder such as Parkinson's disease. Use according to any one of items 187 to 190, when used in conjunction with another drug that is useful. .

[0372] Item 192. The medicine is L-DOPA, droxidopa, folliculorax, selegiline. MAO-B inhibitors such as rasagiline or entacapone or tolcapone COMT inhibitors, adenosine 2a antagonists such as istradefylline, and amanta antiglutamic acid drugs such as rifabutin or memantine, rivastigmine, donepezil, or acetylcholinesterase inhibitors such as galantamine, quetiapine, clozapine, Risperidone, pimavanserin, olanzapine, haloperidol, aripiprazole, or in combination with a compound selected from the group consisting of antipsychotics such as brexpiprazole. or in conjunction with antibodies targeting alpha-synuclein, Tau, or A-beta proteins. Use of any one of items 187 to 191.

[0373] Item 193. The medicine is an oral medicine such as a tablet or capsule for oral administration. , use of any one of items 187 to 192.

[0374] All references cited herein, including publications, patent applications, and patents, are incorporated herein by reference in their entirety. and each reference is individually and specifically indicated to be incorporated by reference. to the same extent as if set forth in its entirety (to the fullest extent permitted by law). No. 6,399,433, filed on Oct. 23, 2003, and is incorporated herein by reference in its entirety.

[0375] Headings and sub-headings are used herein for convenience only and are not intended to limit the invention. It should never be interpreted.

[0376] When referring to one or more elements, the terms "comprise," "have," "include," or "contain" In the present specification, any aspect of the invention or aspects of the invention may be used with the term "adjusted" or "adjusted" or the like. Unless otherwise indicated or clearly contradicted by context, any description given may refer to one or more of the The terms "consisting of," "consisting essentially of," or "substantially comprising" a particular element are used interchangeably with the term "consisting of" or "substantially comprising" a particular element. It is intended to provide support for embodiments or aspects of the invention (e.g., identifying particular elements). Compositions described herein as comprising include, unless otherwise indicated or clearly contradicted by context. (To the extent not otherwise specified, the term should be understood to also describe a composition comprising that element.)

[0377] Any and all examples or exemplary terms ("for example") in this specification "for example," "for example," and " The use of "as such," "as is," etc. is intended merely to make the invention more clear and is not intended to be limiting unless otherwise specified. Unless otherwise stated, it is not intended to limit the scope of the invention.

[0378] The various aspects, embodiments, items, implementations and features of the invention described herein may be taken separately or in combination. It is to be understood that any combination may be claimed.

[0379] The present invention is limited to the scope of the invention as permitted by applicable law and as set forth in the claims appended hereto. The scope encompasses all modifications and equivalents of the subject matter described. EXAMPLES

[0380] Experimental Section Example 1: Preparation of compound (Id) Compounds of formula (Id) can be prepared by synthetic methods known in the art of organic chemistry or by modifications familiar to those skilled in the art. The starting materials used herein are: They are commercially available or can be prepared by conventional methods known in the art, for example, from the "Compendium m of Organic Synthetic Methods,Vol.I-XII " (Wiley-Interscience Publishing) and other standard reference books. Preferred methods include, but are not limited to, the following: can be done.

[0381] The schemes represent methods useful for synthesizing compounds of the invention. It is not intended to be limiting in any way.

[0382] For example, it can be prepared as disclosed in WO 2009 / 026934. Compound (I) was used as an intermediate in the synthesis of compounds of the present invention.

[0383] WO 2019101917 describes a method for producing compound (Id): Further disclosure.

[0384] LC-MS method LC-MS analytical data was obtained using the methods identified below.

[0385] Method 550: Column Manager, Binary Solvent Manager, Sample Organizer, PDA detector (operated at 254 nM), an ELS detector and an APPI source operated in positive ion mode. Waters Aquity, which includes a TQ-MS equipped with LC-MS was performed using a ty UPLC-MS. LC conditions: The column was eluted with water + 0.05% trifluoroacetic acid (A) and acetonitrile / water ( A binary gradient of 1.2 ml / min consisting of 95:5) + 0.05% trifluoroacetic acid was used. Acquity UPLC BEH C18 1.7 μm; 2.1× operated at 60 °C It was 50mm. Gradient (Linear): 0.00 minutes 10%B 1.00 minutes 100%B 1.01 minutes 10%B 1.15 minutes 10%B Total execution time: 1.15 minutes

[0386] Method 551: Column Manager, Binary Solvent Manager, Sample Organizer, PDA detector (operating at 254 nM), an ELS detector and an APPI source operating in positive ion mode. Waters Aquity, which includes a TQ-MS equipped with LC-MS was performed using a ty UPLC-MS. LC conditions: The column was eluted with water + 0.05% trifluoroacetic acid (A) and acetonitrile / water ( A binary gradient of 1.2 ml / min consisting of 95:5) + 0.05% trifluoroacetic acid was used. Acquity UPLC HSS T3 1.8μm; 2.1×5 operated at 60℃ It was 0mm. Gradient (Linear): 0.00 min 2%B 1.00 minutes 100%B 1.15 minutes 2%B Total execution time: 1.15 minutes

[0387] Method 555: Column Manager, Binary Solvent Manager, Sample Organizer, PDA detector (operating at 254 nM), an ELS detector and an APPI source operating in positive ion mode. Waters Aquity, which includes a TQ-MS equipped with LC-MS was performed using a ty UPLC-MS. LC conditions: The column was eluted with water + 0.05% trifluoroacetic acid (A) and acetonitrile / water ( A binary gradient of 0.6 ml / min consisting of 95:5) + 0.05% trifluoroacetic acid was used. Acquity UPLC BEH C18 1.7 μm; 2.1× operated at 60 °C It was 150mm. Gradient (Linear): 0.00 minutes 10%B 3.00 minutes 100%B 3.60 minutes 10%B Total execution time: 3.6 minutes

[0388] Preparative LCMS was performed using the methods identified below. Waters AutoPurification with Combined Mass / UV Detection system. Column: Sunfire 30×100mm, particle size 5um. Water + 0.05% trifluoroacetate A dilution consisting of acetic acid (A) and acetonitrile / water (3:5) + 0.05% trifluoroacetic acid The component gradient is run at 40° C. at 90 ml / min. Gradient (Linear): 0.00min 98%A 5.00 min 50%A 5.50 min 98%A 6.00 min 98%A

[0389] Bruker equipped with electrospray operated in positive or negative mode High-resolution (HighRes) MS was performed on a Compact qTOF. Calibration was performed with sodium formate.

[0390] Compound (Id) was prepared along with compound (Id') depicted below, and the two compounds were , and were isolated from each other in the final step. [ka]

[0391] Example 2: Preparation of intermediates for the preparation of compounds (Id) and (Id') Intermediates: (4aR,10aR)-1-Propyl-7-((triisopropylsilyl)oxy)- 1,2,3,4,4a,5,10,10a-Octahydrobenzo[g]quinolin-6-o (4aR,10aR)-1-propyl-6-((triisopropylsilyl)oxy) 1,2,3,4,4a,5,10,10a-Octahydrobenzo[g]quinoline 7-all. [ka] (4aR,10aR)-1-Propyl-1,2,3,4,4a,5,10,10a-o Cutahydrobenzo[g]quinoline-6,7-diol hydrochloride (2.21 g, 7.43 mm ol) was suspended in dichloromethane (80 ml) at room temperature under a nitrogen atmosphere to obtain N,N-dichloromethane. Isopropylethylamine (4.44 g, 6.0 ml, 34.4 mmol) was added and the mixture was stirred for 1 hour. Triisopropylsilyl chloride (2.73 g, 3.0 ml, 14.16 mmol) 10 mL of MeOH was added and the crude mixture was stirred at room temperature for 92 h. It was evaporated, coevaporated twice with dichloromethane / heptane, and redissolved in dichloromethane. Evaporation directly onto the filter aid and column chromatography (eluent: n-heptane / ethyl acetate) were performed. The oil was purified by ethyl acetate / triethylamine (100:0:0 to 35:60:5). (4aR,10aR)-1-propyl-7-((triisopropylsilyl)oxy) )-1,2,3,4,4a,5,10,10a-Octahydrobenzo[g]quinoline-6 -ol (3.14 g) and (4aR,10aR)-1-propyl-6-((triisopropyl) (propylsilyl)oxy)-1,2,3,4,4a,5,10,10a-octahydrobenzoate 3.14 g was obtained as a mixture with zo[g]quinolin-7-ol. NMR (CDCl3 ) was found to be a >30:1 mixture of silylated isomers.

[0392] Intermediate: t-Butyl((4aR,10aR)-1-propyl-7-((triisopropyl Silyl)oxy)-1,2,3,4,4a,5,10,10a-octahydrobenzo[g ]quinolin-6-yl) carbonate [A] and t-butyl ((4aR,10aR)-1 -propyl-6-((triisopropylsilyl)oxy)-1,2,3,4,4a,5, 10,10a-Octahydrobenzo[g]quinolin-7-yl)carbonate [B]. [ka] The mixture from the previous step (4aR,10aR)-1-propyl-7-((triisopropyl) (silyl)oxy)-1,2,3,4,4a,5,10,10a-octahydrobenzo[ g]quinolin-6-ol and (4aR,10aR)-1-propyl-6-((triisopropyl) Propylsilyl)oxy)-1,2,3,4,4a,5,10,10a-octahydrobe Benzo[g]quinolin-7-ol (2.94 g, 7.04 mmol) was added under a nitrogen atmosphere. The mixture was dissolved in dichloromethane (30 ml) and cooled to 0°C. ) followed by the addition of di-t-butyl dicarbonate (6.30 g) and the reaction mixture was stirred for 3-4 h. The reaction mixture was allowed to warm to room temperature for 1 hour and then stirred at room temperature overnight. 10 mL of MeOH was added and the reaction mixture was Evaporate, coevaporate twice with dichloromethane / n-heptane, and dissolve in dichloromethane. The mixture was filtered and evaporated onto a filter aid. Column chromatography (eluent: n-heptane / acetic acid) Purification with ethyl / triethylamine (100:0:0 to 75:20:5) As the alkyl group, t-butyl ((4aR,10aR)-1-propyl-7-((triisopropyl (silyl)oxy)-1,2,3,4,4a,5,10,10a-octahydrobenzo[ g]quinolin-6-yl) carbonate [A] and t-butyl ((4aR,10aR)- 1-Propyl-6-((triisopropylsilyl)oxy)-1,2,3,4,4a,5 ,10,10a-Octahydrobenzo[g]quinolin-7-yl) carbonate [B] and After drying, NMR (CDCl3) showed that the mixture was a mixture of positional isomers (3.6 g). Things were shown.

[0393] Intermediate: (4aR,10aR)-6-((t-butoxycarbonyl)oxy)-1-pro Pil-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline- 7-yl acetate and (4aR,10aR)-7-((t-butoxycarbonyl)oxy) 1-Propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[ g]quinolin-6-yl acetate. [ka] t-Butyl((4aR,10aR)-1-propyl-7-((triisopropylsilyl )Oxy)-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quino Phosphorus-6-yl)carbonate (3.600 g, 6.95 mmol) (from the previous step [A]:[B] mixture) was dissolved in THF (150 ml) at 0°C under a nitrogen atmosphere, Triethylamine trihydrofluoride (2.97 g, 3.00 ml, 18.42 mmol) 1l) was added and the mixture was stirred at 0° C. After 3 h at 0° C., pyridine (10.0 ml, 1 24 mmol) and acetic anhydride (4.33 g, 4.00 ml, 42.4 mmol) at 0°C. The reaction mixture was added directly to the reaction mixture and the reaction mixture was allowed to warm to room temperature. After 16 h, 20 mL of MeOH was added The reaction mixture was evaporated, redissolved in dichloromethane / n-heptane and filtered onto a filter aid. This was then evaporated to dryness and purified by vacuum column chromatography to give (4aR, 10aR )-6-((t-butoxycarbonyl)oxy)-1-propyl-1,2,3,4,4a ,5,10,10a-Octahydrobenzo[g]quinolin-7-yl acetate and (4 aR,10aR)-7-((t-butoxycarbonyl)oxy)-1-propyl-1,2 ,3,4,4a,5,10,10a-Octahydrobenzo[g]quinolin-6-ylacetate The tate was obtained as an oil / foam. LCMS (Method 550) rt=0.56 min, [M+H]+=404 m / z.

[0394] Intermediate: (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-acetic acid Toxic-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo [g] Quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H -pyran-3,4,5-triyl triacetate and (2S,3R,4S,5S,6S) -2-(((4aR,10aR)-6-acetoxy-1-propyl-1,2,3,4,4 a,5,10,10a-octahydrobenzo[g]quinolin-7-yl)oxy)-6- (Methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate Quote. [ka] (4aR,10aR)-6-((t-butoxycarbonyl)oxy)-1-propyl- 1,2,3,4,4a,5,10,10a-Octahydrobenzo[g]quinoline-7-yl Acetate (2.489 g, 6.17 mmol) (assumed, (4aR, 10aR) -6-((t-butoxycarbonyl)oxy)-1-propyl-1,2,3,4,4a, 5,10,10a-Octahydrobenzo[g]quinolin-7-yl acetate and (4a R,10aR)-7-((t-butoxycarbonyl)oxy)-1-propyl-1,2, 3,4,4a,5,10,10a-Octahydrobenzo[g]quinolin-6-ylacetate The mixture (with ethyl acetate) was dissolved in dichloromethane (60 ml) at room temperature under a nitrogen atmosphere, (2S,3R,4S,5S,6S)-6-(Methoxycarbonyl)tetrahydro-2H- Pyran-2,3,4,5-tetrayltetraacetate (7.529 g, 20.01 mm ol) was added, followed by boron trifluoride diethyl etherate (6.72 g, 6.0 ml , 47.3 mmol) was added and the mixture was stirred at room temperature for 5 days. The mixture was diluted with methanol and MeOH and evaporated onto a filter aid. and purified by (2S,3R,4S,5S,6S)-2-(((4aR,10aR)- 7-Acetoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydro (benzo[g]quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydrofuran 2H-pyran-3,4,5-triyl triacetate and (2S,3R,4S,5S ,6S)-2-(((4aR,10aR)-6-acetoxy-1-propyl-1,2,3 ,4,4a,5,10,10a-Octahydrobenzo[g]quinolin-7-yl)oxy )-6-(Methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl A mixture with the reacetate (4.37g) was obtained as a foam / solid. LC-MS (Method 555) rt=1.94 min, [M+H]+=620 m / z.

[0395] (Id) (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR ,10aR)-7-Hydroxy-1-propyl-1,2,3,4,4a,5,10,10 a-Octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyra 2-carboxylic acid, and

[0396] (Id'): (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR ,10aR)-6-Hydroxy-1-propyl-1,2,3,4,4a,5,10,10 a-Octahydrobenzo[g]quinolin-7-yl)oxy)tetrahydro-2H-pyra 2-carboxylic acid, and [ka] (2S,3R,4S,5S,6S)-2-(((4aR,10aR)-7-acetoxy -1-Propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g] Quinolin-6-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyra 2S,3R,4S,5S,6S)-2- (((4aR,10aR)-6-Acetoxy-1-propyl-1,2,3,4,4a,5 ,10,10a-Octahydrobenzo[g]quinolin-7-yl)oxy)-6-(meth oxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate ( A mixture of 3.82 g, 6.17 mmol) was dissolved in MeOH (100 ml) and water (20 ml ), cooled to 0°C, and potassium cyanide (7.295g, 112mmol) was added. The suspension was allowed to warm slowly to room temperature for 17.5 hours. The crude mixture was evaporated onto filter aid to dryness. The mixture was dried and then purified by silica gel column chromatography (eluent: ethyl acetate / MeOH / water 1 The crude mixture was purified by HPLC using a HPLC-HPLC system (HPLC: 00:0:0 to 0:50:50) to obtain (Id') and (Id). A ratio of 5-6:1 was obtained. The mixture was separated by preparative LCMS.

[0397] The collected peak containing (Id') was pooled, evaporated and prepared in the same manner. This was combined with another batch of 186 mg of (Id')-TFA and evaporated to dryness with MeOH. The solid was obtained by drying. (Id') was resuspended in 10 mL of EtOH and 100 mL of MTBE. The resulting suspension was stirred at room temperature for 8 hours, the suspension was filtered, and the precipitate was collected by filtration using 2 × 10 ml The mixture was washed with 1L MTBE and dried overnight in a vacuum oven to give (2S,3S,4S,5R, 6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-6-hydroxy -1-Propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g] quinolin-7-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid 1.601 g of (Id') was obtained as a solid.

[0398] The two collected peaks containing (Id) were pooled, evaporated, and then diluted with MeOH in a small Transfer to a flask, evaporate, redissolve in approximately 12 mL of MeOH, and re-purify by preparative LCMS. The appropriate fractions were pooled and evaporated to give a small foam / solid. Transfer to LASCO with MeOH, evaporate, and use the same procedure to prepare 40.7 mg (Id). The combined batches were dissolved in 2.5 mL of EtOH and mixed with 25 mL of MTBE. mL was added and the suspension was stirred at room temperature. After 8 h, the suspension was filtered and the precipitate was separated by 2 × 2. Wash with 5 mL MTBE and dry in a vacuum oven overnight to obtain (Id)3 as a solid. 62.2 mg was obtained. (Id) was suspended in about 10 mL of EtOH and 50 mL of MTBE was added. The suspension was stirred at room temperature and filtered after 19 hours, and the precipitate was washed with 2 × 10 mL MTBE. The solids were washed and dried at 40°C in a vacuum oven to obtain (2S, 3S, 4S, 5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy Roxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo [g] Quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid (I d) 0.279 g was obtained.

[0399] (Id') LCMS (Method 551) rt=0.37 min, [M+H]+=438.1 m / z. 1H NMR (600 MHz, methanol-d4) δ 7.02 (d, J = 8.4 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 4.73 (d, J = 7.7 Hz, 1H ), 3.89 (d, J = 9.7 Hz, 1H), 3.68 - 3.58 (m, 2H), 3.5 4 (dd, J = 9.3, 7.7 Hz, 1H), 3.49 (t, J = 9.1 Hz, 1H), 3.47 - 3.36 (m, 2H), 3.30 (dt, J = 11.2, 5.6 Hz, 1H) , 3.21 - 3.11 (m, 3H), 2.85 (dd, J = 15.4, 11.3 Hz, 1 H), 2.35 (dd, J = 17.6, 11.5 Hz, 1H), 2.12 - 2.02 (m , 2H), 2.02 - 1.84 (m, 3H), 1.81 - 1.71 (m, 1H), 1.4 9 (qd, J = 13.0, 3.7 Hz, 1H), 1.09 (t, J = 7.3 Hz, 3H) .

[0400] (Id) LCMS (method 551) rt = 0.39 min, [M + H]+ = 438.1 m / z. 1H NMR (600 MHz, methanol-d4) δ 6.87 (d, J = 8.3 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 4.62 (d, J = 7.9 Hz, 1H ), 3.75 (dd, J = 17.7, 4.9 Hz, 1H), 3.66 - 3.62 (m, 2 H), 3.61 - 3.51 (m, 2H), 3.50 - 3.35 (m, 3H), 3.31 - 3.22 (m, 1H), 3.14 (qd, J = 12.7, 4.0 Hz, 2H), 2.83 (dd, J = 15.2, 11.3 Hz, 1H), 2.37 (dd, J = 17.7, 11. 7 Hz, 1H), 2.12 (d, J = 13.4 Hz, 1H), 2.08 - 2.00 (m, 1H), 1.98 - 1.83 (m, 3H), 1.81 - 1.71 (m, 1H), 1.44 (qd,J=13.2,3.9Hz,1H),1.09(t,J=7.3Hz,3H).

[0401] Example 3: Preparation of exemplified solid forms of the present invention This example describes the preparation of the solid forms of the invention and the X-ray powder diffractogram (XRP) The characterization of the solid form with respect to D) and thermogravimetric analysis (TGA) is described below. This was carried out using the methods described.

[0402] XRPD: X-ray powder diffractograms were obtained using CuKα1 radiation (λ=1.5406 Å) The measurements were performed on a Nalytical X'Pert PRO X-ray diffractometer. The measurements were performed using an X'celerator detector in the 2θ range of 2-40° or 3-40°. It was determined.

[0403] Selected peaks: Peak, panalytical's program "HighScore Plus" The peaks were found by peak search of the diffractogram using the The ten selected peaks are listed in Table 2(a) below, along with the 15 peaks with the highest intensity for each compound. The diffraction data are given to ±0.1°. Characterization of batches of the same solid form It is well known that the relative strength between polymerizations can vary significantly due to preferred orientation effects.

[0404] [Table 2]

[0405] TGA: Thermogravimetric analysis (TGA) was performed using the TA-instruments Discovery TG A 1-10 mg sample was measured in an open pan at 10° / min under nitrogen gas. Heat under flow. Sample size approximately 2-6.4 mg.

[0406] Preparation of dihydrate (DH1) of compound (Id): Example a): In a 250 mL single-neck round-bottom flask, 4.0 g of compound (Id) (containing some water of hydration) was added. ), water (12 mL), and ethanol (12 mL). The white suspension was heated to 75° C. A clear solution was obtained. The solution was cooled to 55°C. Ethanol (5 6 mL) was added over 10 min. The suspension was stirred at 50° C. overnight. The suspension was stirred for 6 h. It was cooled to 23°C and filtered. The filter cake was washed twice with ethanol (2 x 10 mL). The white filter cake was transferred to a drying tray and left at constant weight for one day in a fume hood. Air-dried until .05 ml. Yield 3.8 grams DH1.

[0407] Example B): In a 5 L three-neck round bottom flask was added compound (Id) (197 g, including some water of hydration), Water (0.60 L) and ethanol (0.60 L) were added. The white suspension was heated to reflux. A clear solution was obtained. The solution was kept at reflux for 30 minutes and then heated to 54°C for 35 minutes. The dihydrate (DH1) of compound (Id) in ethanol (0.10 L) was dissolved at 54° C. A slurry of 100% ethanol (0.10 L) was added in one portion, followed by additional ethanol (0.10 L). The temperature of the resulting suspension was raised from 52-54°C in 5 minutes, followed by ethanol. Add ethanol (1.60 L) over 17 min while maintaining the temperature of the suspension at 53-55°C during the addition. The suspension was stirred for 1 hour at 53°C and then cooled slowly to 23°C overnight. The suspension was filtered and the resulting filter cake was washed twice with ethanol (2 x 0.40 L). The white filter cake was transferred to a drying tray and kept in a fume hood for 2 days. Air-dried to weight. Yield 188g DH1.

[0408] The prepared DH1 was characterized by XRPD (see Table 2 and FIG. 8) and TGA (see FIG. 8). It has become.

[0409] Preparation of the anhydride (AH1) of compound (Id): Example a) In a 500 mL round bottom flask equipped with a stir bar, 8.8 g of compound (Id) (other batches) were added. The mother liquor of 1,2-dichlorophenyl ether (evaporated from 1,2-dichlorophenyl ether) was suspended in 9:1 EtOH / HO (90 mL) and heated at 95° C. The suspension was stirred (320 rpm) at 95° C. for 1 h 20 min. The bath was switched off and the mixture was stirred (320 rpm) for 2 h until the bath reached room temperature. The material was collected by vacuum filtration and the flask / filter cake was washed with EtOH (2 x 50 mL). The resulting solid was dried on the filter pad (with vacuum) for 1 hour and then Scrape into a crystallization dish and air dry for 48 hours. Yield: 7.4 g AH1.

[0410] Example b) In a 250 mL single-neck round-bottom flask, compound (Id) (3.0 g), water (9 mL), and ethanol were added. Alcohol (9 mL) was added. The suspension was heated to 75° C. to give a clear solution. The mixture was cooled to 55° C. Ethanol (162 mL) was added at 50-55° C. over 15 minutes. Precipitation was observed during the addition of ethanol. The suspension was stirred overnight at 50°C. The mixture was cooled to 23° C. over a period of time and filtered. The filter cake was diluted with ethanol (2×10 mL). The filter cake was transferred to a drying tray and left in a fume hood for a day. Air dried to weight. Yield 2.7g AH1.

[0411] The prepared AH1 was analyzed by XRPD (see Table 2 and FIG. 9A) and TGA (see FIG. 9B). Characterized.

[0412] Preparation of heptahydrate (HH) of compound (Id) The heptahydrate (HH) of compound (Id) was prepared by precipitation from water. 45.5 mg of the compound (Id) DH1 prepared was added to 0.5 mL of water and stirred for approximately 2 minutes. The wet crystals were removed from the solution and analyzed by XRPD, which showed that HH had formed. (See Table 2 and Figure 10A.) HH was further analyzed by TGA (Figure 1). See 0b).

[0413] Preparation of Form A of compound (Id): Form A was obtained by storage of the heptahydrate (HH) of compound (Id) at room temperature and approximately 5% RH. obtain.

[0414] The prepared compound (Id) Form A was characterized by XRPD (see Table 2 and Figure 11). .

[0415] Preparation of Form B of compound (Id): Form B was obtained by storage of the heptahydrate (HH) of compound (Id) at room temperature and approximately 10% RH. It was possible.

[0416] The prepared form B of compound (Id) was characterized by XRPD (see Table 2 and Figure 12). .

[0417] Preparation of Form C of compound (Id): Form C was obtained by storage of the heptahydrate (HH) of compound (Id) at room temperature and approximately 15% RH. It was possible.

[0418] The prepared compound (Id) form C was characterized by XRPD (see Table 2 and Figure 13). .

[0419] Preparation of monohydrate (MH1) of compound (Id): (MH1) was synthesized by heating (DH1) to 105 °C and subsequent water sorption at ambient conditions. The monohydrate was formed by drying (DH1) at room temperature and 0% RH. and subsequent water sorption at ambient conditions.

[0420] The prepared MH1 was analyzed by XRPD (see Table 2 and FIG. 14a) and TGA (see FIG. 14b). More characterized.

[0421] Preparation of the potassium salt of compound (Id): In a 25 mL round-bottom flask equipped with a magnetic stir bar, compound (Id) heptahydrate (0.50 g) Then, water (0.5 mL) and an aqueous solution of potassium hydroxide (0.11 g, 0.07 5 mL, 0.90 mmol, 46% (wt.) was added, and the mixture became a slurry. The mixture was heated to 80°C and then cooled to 50-60°C. Additional water (0.2 mL) was added. Upon addition, an almost clear solution resulted. i-PrOH (1.5 mL) was added dropwise until A clear solution was obtained initially, then a white solid precipitated. The temperature was raised to 80°C, and a clear A solution was obtained. i-PrOH (2.5 mL) was added dropwise and the mixture was then warmed to reflux. Then, 1-2 mL was distilled off, i-PrOH (1-2 mL) was added, and the distillation / addition was repeated once. The mixture was slowly cooled to 5°C and filtered to give 0.41 g of potassium compound (Id). I gave him Umami salt.

[0422] The potassium salts prepared were analyzed by XRPD (see Table 2 and Figure 15a) and TGA (see Figure 15b). ) was characterized.

[0423] Preparation of the sodium salt form 1 of compound (Id): In a 25 mL round bottom flask equipped with a magnetic stir bar was placed (Id) heptahydrate (0.5 g). Then water (0.500 ml) and NaOH (0.083 ml, 10.8 mol) were added. The mixture became a slurry. The mixture was heated to 50° C. and then additional water (0.5 00ml) was added, resulting in a clear solution. The temperature was raised to 80°C and i-PrOH (3. 50 ml) was added dropwise, causing a gelatinous solid to precipitate. The mixture was stirred for 30 minutes and then slowly cooled. The precipitate was then filtered off very slowly (at least 100 ml) and cooled to room temperature and then to 5°C. The precipitate was isolated by filtration over a period of 6 h and washed with 2 × 0.5 mL of iPrOH. The solid was dried overnight in a vacuum oven at 40° C. This resulted in the formation of the nanoparticles of compound (Id). The thorium salt (0.35 g) was produced as a solid.

[0424] The sodium salt Form 1 prepared was analyzed by XRPD (see Table 2 and FIG. 16a) and TGA (FIG. 1 6b).

[0425] Preparation of the sodium salt form 2 of compound (Id): 51.73 mg was added to 70 μl of water, and the mixture was heated to 60°C to dissolve, after which 150 μl of iPrOH was added. The mixture was then heated to 60° C. and 250 μl of iPrOH was added. ROH was added and the mixture was heated to 60° C. After standing at room temperature, precipitation occurred. The solid part was then aspirated and brought to 90°C where it partially dissolved, and it was then removed from the heat again. , sodium salt form 2 was obtained.

[0426] The sodium salt Form 2 prepared was analyzed by XRPD (see Table 2 and FIG. 17a) and TGA (FIG. 1 7b).

[0427] Preparation of the hydrochloride salt of compound (Id): Approximately 500 mg of compound (Id) heptahydrate was weighed out and then dissolved in 3.75 mL of IPA. Slurry and add 1.05 equivalents of HCl to 2.5 mL of IPA. Drug Substance / Counterion / The solvent mixture was temperature cycled between ambient and 40°C for 4 hours. After about one day, the preparation dissolved at 40° C. It was observed that the mixture contained a rubbery material at ambient temperature. The material was evaporated in 500 μL of IPA. It appeared rubbery after polymerization.

[0428] Scale-up was re-brewed using less IPA, approximately 50% Weigh out 0.0 mg of compound (Id) heptahydrate and then slurried in 0.9 mL of IPA, 1.05 equivalents of HCl was added to 2.5 mL of IPA. The drug substance / counterion / solvent mixture was The mixture was then temperature cycled between ambient and 40°C for 4 hour periods. After approximately 1 day, the solids present were Due to limited space available, the concoction was allowed to evaporate in the surrounding area. After incomplete evaporation, the material was removed using a spatula. The mixture was collected by scraping with a filter, isolated by centrifugal filtration, and dried under vacuum at ambient temperature for approximately 20 hours. I did.

[0429] The hydrochloride salt prepared was characterized by XRPD (see Table 2 and Figure 18).

[0430] Preparation of the hydrobromide salt of compound (Id): Approximately 500 mg of compound (Id) heptahydrate was weighed out and slurried in 3.75 mL of IPA. The drug substance / counterion / solvent ratio was 1.05 equivalents of HBr was added to 2.5 mL of IPA. The mixture was temperature cycled between ambient and 40° C. on 4 hour cycles for approximately 3 days.

[0431] The hydrobromide salt prepared was characterized by XRPD (see Table 2 and Figure 19).

[0432] Example 4: Stability testing of selected solid forms Stability studies were performed on the heptahydrate (HH), dihydrate (DH1), and potassium hydroxide (KOH) of compound (Id). The materials were packed in a sealed cardboard box as a secondary packaging material. During stability, different batches were examined for appearance, assay, and (calculated as anhydrous, i.e., water-free compound), impurities, and water content. In addition, XRPD was performed at selected time points as described in Example 3.

[0433] In addition, stress stability tests were performed on the heptahydrate (HH), dihydrate (DH) and hydrate (DHA) of compound (Id). 1) and potassium salt (K+ salt). For stress stability tests, in open dishes in the dark at 40°C / 75% RH, 60°C, and 60°C / 80% RH. Saved.

[0434] The following methods were used for characterization:

[0435] LC-UV Method (Assay and Impurities) LC-UV was performed using an Agi system including an autosampler and a DAD detector (operating at 278 nm). The analysis was performed on an Agilent HPLC system consisting of an Agilent 1200 HPLC or equivalent. .

[0436] LC conditions: The column was run at 40°C with water / acetonitrile + 2ml TFA / ml (90: 10) (A) and water / acetonitrile + 2ml TFA / ml (35:65) (B) Synergi Polar-RP 4 μm operated at 1.0 ml / min of a binary gradient of It was 4.6 x 150 mm. gradient: 0.0 minutes 0%B 2.0 minutes 10%B 12.0 minutes 100%B 14.0 minutes 100%B 14.1 minutes 0%B 19.0 minutes 0%B Total execution time: 19 minutes

[0437] The amount of impurity was determined as the area percentage of the impurity peak relative to the area of ​​the main peak.

[0438] Karl Fischer test (water test) The moisture content was measured according to the European Pharmacopoeia, Chapter 2.5.32 (Metrohm 874 Oven Sample Processor and Metrohm 851 KF Cou The water content was measured by Karl Fischer coulometric titration according to the Karl Fischer titration method (KF-1000). The water vapor was evaporated by heating to 150 °C and transported by nitrogen to the titration chamber, where it Hydranal Coulomat AG Oven (product number 34739) titration reagent was used to titrate to the endpoint.

[0439] result stability Less than 0.1% decomposition, as measured by LC-UV, was observed for the heptahydrate (HH ), potassium salt (K+ salt), and dihydrate (DH1). A change in the amount and physical form (XRPD) was observed in the heptahydrate (HH). 40℃ / 75% After 3 months at RH, the heptahydrate turned slightly gray in appearance and converted to the dihydrate. 2 At 5℃ / 60%RH, in addition to obvious changes in physical form, slight color changes occur over time. The results are shown in Table 3 below.

[0440] [Table 3]

[0441] For the potassium salt, the results showed that the samples remained in the same physical form as measured by XRPD. However, some change in moisture content was observed and the formation of brown lumps was also observed. The results observed during the stability study for the potassium salt of compound (Id) are summarized in Table 4 below. show.

[0442] [Table 4]

[0443] For the dihydrate, there is no change in appearance, water content, or physical form (XRPD) at 40°C / 75% No changes were observed in the 6-month stability tests at 25°C / 60%RH and 25°C / 60%RH. Even after 10 months at 25% RH, no changes in physical appearance or moisture content were observed. A summary of the results for the dihydrate of compound (Id) is shown in Table 5 below.

[0444] [Table 5]

[0445] The stability test results showed that the zwitterionic dihydrate (DH1) of compound (Id) was stable at 40°C / Physical appearance, moisture content and composition measured at 75% RH and for 6 months at 25°C / 60% RH It was shown that it had the best stability in terms of physical morphology.

[0446] Stress Stability The stress stability test was carried out as described above, and the amount of decomposition products was measured using the LC-UV method described above. The measurements were based on the above.

[0447] The total impurities after 6 months storage are shown in Table 6 below.

[0448] [Table 6]

[0449] The results of the stress stability tests in Table 6 show that the solid forms tested, especially the dihydrate and potassium The salts are found to be relatively stable with respect to chemical decomposition.

[0450] Example 5: Further stability testing of selected solid forms The following examples are the heptahydrate (HH), dihydrate (DH1), and compound (Id). Further characterization of the potassium salt of compound (Id) is described.

[0451] DVS Dynamic Vapor Sorption (DVS) was further used to evaluate selected solid forms. The dehydration behavior can be investigated by DVS analysis. The study was carried out using a DVS Advantage 01 instrument from Curement Systems. Samples of 4-10 mg in solid form were used for the analysis. Water absorption / desorption of the target solid was Monitor the relative humidity by changing it between about 0% and about 90% in increments of about 5-10% RH. did.

[0452] Figures 20 and 21 show the resulting curves for DH1 and K+ salt.

[0453] For DH1, DVS analysis showed that the moisture content of DH1 is very stable in the humidity range of 5-90% RH. Less than 0.1% water is absorbed or desorbed.

[0454] In the potassium salt form (K+ salt) of compound (Id), the DVS is reduced to 0.6% at 80% RH. At 95% RH only, a uniform weight change of 1% was observed. A weight gain was observed, but the curves showed that water desorbed as soon as the humidity decreased again. The curve for the second cycle shows the same behavior as the first cycle, and therefore the crystal lattice No changes occur and the salt is stable to changes in humidity.

[0455] DVS analysis of the heptahydrate (HH) showed that the heptahydrate could be hydrated at 20% RH and 9% RH without changing its crystal morphology. It was shown to absorb and desorb water at humidities between 5% RH and 7% RH. Hydrates (HH) can change to other less hydrated forms, and the material cannot be exposed to high humidity. I won't go back to the heptahydrate for now.

[0456] Therefore, the DVS analysis concluded that DH1 is non-hygroscopic in the humidity range of 5-80% RH. It can be argued.

[0457] Crushing and Pressing Compound (Id) HH A sample of the heptahydrate was hand ground using a mortar and pestle for 2 minutes and then analyzed by XRPD. The analysis was carried out by:

[0458] The XRPD was compared to the XRPD before and after grinding. Upon grinding, the reflections became a bit broader, The amorphous halo became visible. The crushed sample was stored at 95% RH for one week, and then XRPD analysis showed that the reflections corresponded to the original sample before grinding. The hydrate regained crystallinity after storage.

[0459] Compound (Id) DH1 A sample of DH1 of compound (Id) was manually ground using a mortar and pestle for 2 minutes and then The samples were pressurized at 0.00 PSI for 5 minutes.

[0460] The samples were then analyzed by XRPD. XRPD after processing was consistent with the results of the crush and pressure tests. The XRPD of the first sample prior to 2000 showed no signs of reduced crystallinity.

[0461] Additionally, another sample of compound (Id) DH1 was milled. The XRPD of the mechanically crushed sample compared to the uncrushed material showed a change in the XRPD pattern. Therefore, the XRPD comparison did not reveal any obvious change in the crystallinity of the DH1 sample. showed that there was no

[0462] Therefore, DH1 of compound (Id) is highly stable against physical stress. It can be concluded that:

[0463] Potassium salt of compound (Id) A sample of the K+ salt form described in Table 2 of Example 3 was ground in a mortar and pestle or subjected to IR- The samples were then compressed for 5 minutes using a press. After processing, the samples were analyzed by XRPD. The samples were then placed at 95% RH for 1 week and reanalyzed by XRPD.

[0464] Results: Grinding leads to severe broadening of the XRPD reflections, but subsequent exposure to high humidity Exposure to high pressure also results in sharper reflections, although to a lesser extent than crushing. This results in some broadening of the D reflex. The sharp reflex is restored by exposure to humidity. Therefore, the K+ salt form regained crystallinity after storage at high humidity.

[0465] In conclusion, the DVS and grinding tests of this example demonstrate that the zwitterionic dihydrate of compound (Id) The solvate is the most stable solid form because it is non-hygroscopic and stable when tested after grinding and pressing. It was shown that the results were consistent.

[0466] Examples 6-10: In vitro and in vivo characterization of compound (Id) Example 6a: Conversion of the compound of formula (Id) in rat and human hepatocytes Contains HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) Human or rat IgG was suspended in DMEM (Dulbecco's modified Eagle's medium) (pH 7.4). Compound (Id) was incubated with hepatocytes derived from the mice at 1 μg / mL. The cell concentration in the incubation was 1 × 106 viable cells / mL. was carried out in glass tubes at 37°C with a total incubation volume of 3.5 mL. Duplicate incubations were performed for each test item. Hepatocyte suspension Equilibrate 3.5 mL in a water bath set at 37 °C for 10 min, then add DMSO (dimethyl ether) Add 3.5 μL of the stock solution of the test item in toluene (dimethyl sulfoxide) and gently incubate the tube. Incubation was started by inverting the plate. The final solvent concentration in the culture was 0.1% DMSO. This ensured homogeneity of the hepatocyte suspension. After incubation, 600 μL of the sample was added at the designated time points of 0.25, 5, 15, 30, and 60 min. The samples were collected from the lysis bath. Ice-cold ascorbic acid (100 mg / mL) in 0.5 M citric acid was 1 on wet ice containing 60 µL of 100 mM glycerol and 30 µL of ice-cold 100 mM glycerol 1,4-lactone. The collected volume was added to a 10 mL Nunc cryotube. The tube was mixed and placed on ice. Add 35 μL of cold 20% formic acid solution. Mix the tube thoroughly and store at -80°C. Analytical methods and devices used for the analysis of (I) from the administration of (Id) is used for the analysis of compound (I) from the administration of compounds (Ic) and (Id) The methods and apparatus described in Examples 9 and 10 in the "Apparatus" section were as follows.

[0467] From FIG. 7, the time-dependent increase in the activity of (Id) to compound (I) in both rat and human hepatocytes was observed. Existential transformation is indicated.

[0468] Example 6b: Conversion of the compound of formula (Id) in fresh rat and human blood (Id) in human blood (average of 3 donors) and rat blood (average of 45 donors) Conversion to (I) was shown in fresh blood spiked with (Id) 1 μg / mL at 37° C. (I) was measured in isolated plasma at 0, 5, 15, 30 and 60 minutes. In the section "Apparatus used for the analysis of compound (I) from the administration of (Id)" and the analytical methods and apparatus described in Examples 9 and 10 below.

[0469] From FIG. 8, the time-dependent conversion of (Id) to compound (I) in both rat and human blood is shown. The conversion is shown.

[0470] Example 7: Dopamine agonist activity Dopamine D1 receptor agonism Using a protocol developed by HD Biosciences (China) Dopamine D1 receptor agonism using HTRF cAMP from CisBio Briefly, the assay measures natural cAMP produced by cells and XL-66 cAMP production by cells in a competitive immunoassay with 5-labeled cAMP This is a homogeneous time-resolved fluorescence resonance energy transfer (HTRF) assay that measures A cryptate-labeled anti-cAMP antibody visualizes the tracer. The assay was performed accordingly.

[0471] Test compounds were added to the wells of a microplate (384 format). Human D1 Receptor-expressing HEK-293 cells were plated at 1000 cells / well and incubated at room temperature. The wells were incubated at 4°C for 30 min. cAMP-d2 tracer was added to the wells, followed by Add the cAMP antibody-cryptate preparation and incubate for 1 hour at room temperature in the dark. The donor was excited with a 337 nm laser ("TRF light unit"), followed by 20 Cryptate and d2 emissions at 615nm and 665nm over a 0 microsecond time window. (H by measuring a time window of 2000 μs / 100 flashes between repetitions) TRF cAMP was measured (delay time 100 μs). Envision Micro HRTF measurements were performed using a plate reader (PerkinElmer). The HTRF signal was calculated as the ratio of emission at 665 nm to 615 nm. Control wells containing DMSO vehicle or 30 μM dopamine were used to measure the HTRF ratio readings for compounds were normalized to 0% and 100% stimulation. Using t4 (IDBS, Guildford, Surrey, UK, model 205) , test compound potency (E) was calculated by nonlinear regression using a sigmoidal dose-response (variable slope). C50) was estimated. y=(A+((BA) / (1+((C / x)^D)))) where y is the normalized HTRF ratio measurement for a given concentration of the test compound, and x is the concentration of the test compound, A is the estimated potency at infinite compound dilution, and B is the maximum potency C is the EC50 value and D is the Hill slope coefficient. EC50 Estimates were obtained from independent experiments and logarithmic means were calculated.

[0472] Dopamine D2 receptor agonism Calcium mobilization assay developed by HD Biosciences (China) Dopamine D2 receptor agonism was measured using the Say protocol. HEK293 / G15 cells expressing D2 receptors were cultured at a density of 15,000 cells / well. Plate them into clear-bottom Matrigel-coated 384-well plates. The cells were incubated at 37°C in the presence of 5% CO2 for 24 hours. The cells were incubated with the fluorescent dye Fluo8 for 60-90 min at 37°C in the dark. Test compounds were prepared in 3-fold concentrated solutions in 1× HBSS buffer with Ca2+ and Mg2+. The compound plate was then transferred to the FLIPR (Molecular Devices) After compound addition to the cell plate, calcium influx signals were recorded immediately. The data was normalized to unstimulated (buffer) and fully stimulated (F1) for 0% and 100% stimulation, respectively. Responses to stimulation (1 μM dopamine) were obtained using Xlfit4 (IDBS, Guildf ord, Surrey, UK, model 205) was used to determine the sigmoidal dose-response (variable The slope of the curve was used to estimate test compound potency (EC50) by non-linear regression. y=(A+((BA) / (1+((C / x)^D)))) where y is the normalized ratio measurement for a given concentration of the test compound and x is the is the concentration of the compound, A is the estimated potency at infinite compound dilution, and B is the maximum potency C is the EC50 value and D is the Hill slope coefficient. The EC50 estimates are based on independent experiments. The logarithmic mean was calculated.

[0473] Example 8: 5-HT2B agonist activity and binding assays 5-HT2B agonist activity assay Using HTRF detection, Eurofins / Cerep (France) The effect of compounds on inositol monophosphate (IP1) production was measured to determine the effect of human 5-HT2B The agonist activity of compounds (I), (Ia) and (Ib) at the receptor was evaluated. In one study, human 5-HT2B receptors were expressed in transfected CHO cells. mM Hepes / NaOH (pH7.4), 4.2mM KCl, 146mM NaC l, 1 mM CaCl2, 0.5 mM MgCl2, 5.5 mM glucose and 50 mM Cells were then suspended in a buffer containing LiCl at a density of 4,100 cells / well. The mixture was then dispensed into a microplate containing buffer (basal control), test compound or reference The stimulated control was incubated in the presence of the agonist for 30 min at 37°C. For roll measurements, each assay well contained 1 μM 5-HT. After incubation, the cells were lysed and the fluorescent receptor (fluorophen D2-labeled IP1) and a fluorescent donor (anti-IP1 labeled with europium cryptate After 60 minutes at room temperature, λ(Ex) 337 nm and λ(Em) 62 A microplate reader (Rubystar, BMG) was used at 0 and 665 nm. The fluorescence transfer was measured using the same method as in Example 1. The signal measured at 665 nm was compared with the signal measured at 620 nm. The IP1 concentration was determined by dividing the signal by the total signal (ratio). The responses were expressed as a percentage of the control response to -HT. 5-HT, which was tested in several concentrations in each experiment to generate a concentration-response curve. From the curve, the EC50 value was calculated as described above for the dopamine functional assay. It is calculated.

[0474] 5-HT2B binding assay The affinity of compound (Id) for the human 5-HT2B receptor was evaluated by Eurofins / Determined in a radioligand binding assay at Cerep (France). 50 mM Tris-HCl (pH 7.4), 5 mM MgCl2, 10 μM pargyline and in the absence or presence of test compound in buffer containing 0.1% ascorbic acid In this study, membrane homogenates prepared from CHO cells expressing human 5HT2B receptors were 0.2nM [125I](±)DOI(1-(4-iodo-2,5-dimethoxyphenyl ) propan-2-amine) for 60 minutes at room temperature. Nonspecific binding was , determined in the presence of 1 μM (±) DOI. After incubation, Glass fiber filters (GF / B, Packa) presoaked with triethyleneimine (PEI) were The samples were rapidly filtered under vacuum through a 96-sample cell harvester (Un ifilter (Packard), and rinse several times with ice-cold 50 mM Tris-HCl. The filters were dried and stained with a scintillation cocktail (Microscint 0, P A scintillation counter (Topcount, Packard) was used to measure the The radioactivity was counted at 100 μl / well. The results are expressed as a percentage of the control. The standard reference compound was (±) DOI, which was A competition curve was obtained from which the IC50 was calculated. It is calculated.

[0475] [Table 7]

[0476] Example 9: PK studies in rats For all experiments, approximately 0.68 mL of blood samples were collected from the tail or sublingual vein and 80 μL of ascorbic acid and 100 mM D-glucose 1,4-lactate in water were cooled. The blood sample was placed in a tube prepared with 40 μL of stabilizing solution consisting of K3EDTA. Gently invert the tube 6-8 times to mix thoroughly, then place on wet ice. The collection tubes were placed on wet ice for up to 30 minutes prior to centrifugation. After centrifugation, centrifugation was started immediately. Immediately after centrifugation was completed, the samples were placed back on wet ice. Three appropriately labeled cryotubes containing pre-chilled formic acid (20%) Three subsamples of 130 μL of plasma were transferred to each of the tubes (the tubes were pre-spiked (The tube was immediately replaced with a new cap and gently inverted 6-8 times.) The plasma solution was thoroughly mixed by inverting the tube. Samples were then aliquoted within 60 min after sampling. The cells were frozen and stored at -70°C. The centrifugation conditions were 4°C, 3000G, 10 minutes. After collection, the plasma was placed on ice for final storage at approximately -70°C.

[0477] Plasma samples were analyzed by solid-phase extraction or direct protein precipitation followed by UPLC-MS / MS. The specific mass / charge transcriptome of compound (I) was analyzed using an internal standard to correct the response. MS detection using electrospray in positive ion mode with dilution monitoring Concentration-time data are generated using standard software with suitable noncompartmental techniques. The data were analyzed to obtain estimates of derived PK parameters.

[0478] Equipment used for the analysis of compound (I) from administering compound (Ia): Mass spectrometer (LC-MS / MS)Waters Acquity-Sciex API 5000. Analytical column: Waters BEH UPLC Phenyl 100×2. 1 mm column, particle size 1.7 μm. Mobile phase A: 20 mM ammonium formate (aqueous) + 0.5 % formic acid. Mobile phase B: acetonitrile. Gradient moving from 95 / 5% to 2 / 98% in 6.1 min. Flow rate 0.5 mL / min. MRM monitoring of test items and added analytical standards ( Multiple reaction monitoring). Dosing and blood sampling: Charles River Laboratories, Han Wistar rats were provided by Sulzfeld, Germany. A controlled artificial 12-h light and dark cycle was maintained. Obtained from Brogaarden The rats were fed a standard laboratory diet (Altromin 1324 pellets) containing 100% ethanol. The animals had free access to food. During the study (a 4-week toxicity study), they were fed by gavage. Rats were orally administered a dose of (Ia) once a day. (Ia) was administered at 300 μg / kg. Blood samples from three male satellite animals were collected from the rats at the following time points on day 29: Samples were taken at 0.5, 1, 2, 4, 6, 8, 12 and 24 hours after injection.

[0479] Equipment used for the analysis of compound (I) from the administration of compound (Ib): Mass spectrometer (LC-MS / MS)Waters Acquity -Sciex AP I5000. Analytical column: Waters BEH UPLC Phenyl 100×2. 1 mm column, particle size 1.7 μm. Mobile phase A: 20 mM ammonium formate (aqueous) + 0.5 % formic acid. Mobile phase B: acetonitrile. Gradient moving from 95 / 5% to 2 / 98 in 6.1 min. Flow rate 0.5mL / min. MRM monitoring of test items and added analytical standards. Administration and blood sampling: Charles River Laboratories ( Han Wistar rats were supplied by the University of Cambridge (UK). A standard laboratory diet (Teklad 2014C Diet) was used to maintain a dark cycle. The rats had free access to food. During the study, rats were orally administered a dose of (Ib) once daily by gavage. From the rats dosed with 300 μg / kg, blood samples from three male satellite animals were collected. The following time points were collected on day 82: 0.5, 1, 2, 4, 8 and 24 hours post-dose.

[0480] Equipment used for the analysis of compound (I) from the administration of compounds (Ic) and (Id): Mass spectrometer (LC-MS / MS)Waters Acquity-Waters Xe vo TQ-S. Analytical column: Acquity BEH C18 100 x 2.1 mm, 1 .7μm. Mobile phase A: 20mM ammonium formate + 0.2% formic acid. Mobile phase B: acetonite lysine + 0.2% formic acid. Gradient moving from 95 / 5% to 5 / 95% in 11.0 min. Flow rate 0. 3mL / min. MRM monitoring of test items and added analytical standards. Compound (Id) administration and blood sampling: Charles River Laboratories Han Wistar rats are produced by Wiga GmbH, German An automatically controlled artificial 12-hour light and dark cycle was maintained. Rats were fed a standard laboratory diet (Altromin 1324 pellets) obtained from rden. Rats had free access to food. Compound (Id) was administered by single oral gavage. Compound (I) was orally administered to male Han-Wistar rats by gavage. d) From rats dosed with 633 μg / kg, blood samples from three male animals were collected on day 1. The following time points were collected: 1, 2, 4, 6, 8 and 24 hours post-dose. Compound (Ic) administration and blood sampling: Hanwhi The rats were fed star rats and maintained on an automatically controlled artificial 12-h light and dark cycle. The rats were fed a standard laboratory diet, Teklad 2014C. (Ic) was administered to male Han Wistar rats by single oral gavage ( Ic) 494 μg / kg. Blood samples from 3 male animals were collected at the following time points on day 1: : Samples were collected 1, 2, 4, 6, 8 and 24 hours after administration.

[0481] Equipment used for apomorphine analysis: Mass spectrometer (UPCLC-MS / MS)Waters Acquity I-Clas s-Waters Xevo TQ-S. Analytical column Acquity HSS T3 C 18 50×2.1 mm, 1.8 μm. Mobile phase A: 10 mM formic acid NH4 0.2% formic acid: Acetonitrile (95:5). Mobile phase B: 10 mM formic acid NH4 0.2% formic acid:acetonitrile Trill (5:95). Gradient moving from 95 / 5% to 5 / 95% in 2.40 minutes. Flow rate 0 .3mL / min. MRM detection of test items and added analytical standards.

[0482] Apomorphine administration and blood sampling: The animals used for the study were as described in Example 10. In addition, rats were administered a single dose of apoE. Morphine was administered subcutaneously. From rats administered 3000 μg / kg (apomorphine), Blood samples from three male animals were collected at the following time points on day 1: 0.25, 0.5, and 10 days after SC dosing. , 1, 1 and a half, 2, 3, 5, and 7 hours.

[0483] [Table 8]

[0484] Example 10: PK / P of Compound (Id) / Compound (I) in the Rat Hyperactivity Assay D animal A total of 206 fish weighing between 200 and 250 grams (165 to 190 grams on arrival) Male CD rats (Charles River, Germany) were used in the study. The animals were kept at standard temperature (22±1°C) and in a light-controlled environment (7:00 a.m. to 8:00 p.m.). The mice were housed in a 24-well room (with lights on) with free access to food and water. , Charles River Discovery Research Service According to the standard operating procedures of nat es Finland Ltd regarding animal testing ional Animal Experiment Board of Finland (Elaeinkoelautakunta, ELLA) authority provided.

[0485] Locomotor activity test, open field The test apparatus was a square Plexiglas arena (dimensions 40 × 40 × 40 cm) The movement path of the rats was monitored by an activity monitor (Med.Associates Inc.). Rats are allowed to habituate to their testing cages for 60 min before the testing session begins. Once habituation was complete, animals were treated with either compound or vehicle and given an open field. The primary test parameter measured was walking distance (5 min intervals). The total measurement time after the first treatment was 360 minutes. The total follow-up period was 420 min, including a 60-min run-in period.

[0486] result Oral administration of compound (Id) was evaluated in a rat locomotor activity assay, and this function was then evaluated. The objective readings correlated with the plasma concentrations of Compound (I). The drug also exhibited no significant effects in this assay against a control drug (i.e., a known standard treatment in the Parkinson's field). Plasma concentrations were analyzed with respect to apomorphine, with each dose tested simultaneously as a single dose of chemotherapy (SOC).

[0487] As shown in FIG. 2, compound (Id) (10-300 μg / kg, oral) inhibited locomotor activity. The effect began approximately 2 hours after administration (at approximately 180 minutes) and continued until the end of the recording. In contrast, apomorphine (3 mg / kg, subcutaneously) The induced increase in locomotor activity (hyperactivity) was immediate, but the effect disappeared 1.5 hours after administration. Pramipexole (0.3 mg / kg , subcutaneous) also induces increased activity, but the effect appears about 1 hour after administration and is not seen for 2.5 hours. The total migration distance seen in Figure 3 was approximately 100% for the tested compound (Id). Both of the two control drugs demonstrated significantly increased activity, and this effect was consistent with the dopamine agonist This is to be expected.

[0488] In parallel with the locomotor activity assessment, plasma samples were collected 6 days after administration in animals treated with compound (Id). Satellite animals were harvested at three different time points (1.5, 2, 3, 4, 5, and 7 hours). Pharmacokinetic analysis showed that the behavioral effects of compound (Id) (100 μg / kg, oral) were The behavioral effects of compound (Id) were correlated with the plasma concentrations of compound (I) (see FIG. 4). This demonstrates that the effect is driven by compound (I) and not by compound (Id) itself. of apomorphine administered subcutaneously (at 1.25, 1.5, 2, 3, 5, and 7 hours after administration) The corresponding exposure analysis yielded a correlation between apomorphine plasma concentrations and hyperactivity behavior ( See Figure 5).

[0489] Reference List US4543256 WO2001 / 078713 WO 02 / 100377 WO2009 / 026934 WO2009 / 026935 WO2010 / 097092 WO2019101917 Alexander et Crutcher,(1990)Trends in Ne uroscience 13:266-71; Bibbiani et al.,Chase Experimental Neuro logy(2005),192:73-78; Campbell et al.,Neuropharmacology(1982); 21(10):953-961; Cannon et al.,J.Heterocyclic Chem.(1980) ;17:1633-1636; Cavero and Guillon,J.Pharmacol.Toxicol.M ethods(2014),69:150-161; Delong,(1990)Trends in Neuroscience 13:2 81-5; Gerfen et al,Science(1990)250:1429-32; Giardina and Williams;CNS Drug Reviews(2 001),Vol.7(3):305-316; Goswami et al.,J.Nutritional Biochem.(20 03)14:703-709; Grosset et al.,Acta Neurol Scand.(2013), 128:166-171; Hauser et al., Movement Disorders(2016), Vol.32(9):1367-1372; Liu et al.,J.Med.Chem.(2006),49:1494-149 8; Liu et al.,Bioorganic Med.Chem.(2008), 1 6:3438-3444; Nolen et al.,J.Pharm Sci.(1995),84(6): 6 77-681; Poewe et al.,Nature Review,(2017)vol 3 a rticle 17013:1-21; Remington,“The Science and Practice of P harmacy”,22th revised edition(2013),Edit ed by Allen,Loyd V.,Jr. Rothman et al.,Circulation(2000),102: 28 36-2841; Sprenger and Poewe,CNS Drugs(2013), 27:2 59-272; Sozio et al.,Exp.Opin.Drug Disc.(2012);7 (5):385-406; Stain-Texier et al.,Drug Metab.and Dispo sition(1998)26 5):383-387; Wiley-Interscience(publisher):Compendium of Organic Synthetic Methods, Vol.I-XII

Claims

1. Formula (Id) 【Chemistry 1】 A solid form of the compound of a) the zwitterionic form of compound (Id); b) an alkali metal salt of the compound of formula (Id); and c) a halogen salt of the compound of formula (Id) A solid form selected from:

2. 2. The solid form of claim 1, wherein the solid form is a crystalline form.

3. The solid form is a dihydrate of the zwitterion of compound (Id), and the potassium salt of compound (Id).

3. A solid form according to claim 1 or 2.

4. The solid form is the dihydrate of the zwitterion of compound (Id) or the zwitterion of compound (I 4. The solid form of any one of claims 1 to 3, wherein said potassium salt of formula (d) is

5. The solid form is one or more of the solid forms listed for the dihydrate in Table 2, group (a). X-ray powder obtained using CuKα1 radiation (λ=1.5406 Å) including XRPD peaks The dihydrate according to any one of claims 1 to 4, characterized by a diffraction pattern Solid form.

6. The solid form has the following 2θ angles ±0.2° 2θ: 10.4, 11.6, 12.3 and 1 Using CuKα1 radiation (λ=1.5406 Å), including peaks at 3.1 and 13.6° The dihydrate according to any one of claims 1 to 5, characterized by an X-ray powder diffraction pattern obtained.

3. The solid form according to claim 1 .

7. The X-ray powder diffraction pattern has the following 2θ angles ±0.2° 2θ: 14.3, 15.6, 1 One or more peaks selected from the group consisting of peaks at 6.0, 16.8 and 18.5 degrees 7. The solid form of claim 6, further comprising .

8. The solid form is essentially the same as that obtained using CuKα1 radiation (λ=1.5406 Å). The crystalline form of any one of claims 2 to 7, characterized by an X-ray powder diffraction pattern depicted in FIG. 8a.

2. The solid form of any one of claims 1 to 11.

9. The solid form is heated to about 30° C. to about 150° C., as measured using thermogravimetric analysis. When heated (heating rate 10°C / min), the weight loss was about 7.6% (weight ratio) of the initial weight.

9. The solid form of any one of claims 1 to 8, which exhibits low

10. The solid form is one or more of the compounds listed for potassium salts in Table 2, group (a). X-rays obtained using CuKα1 radiation (λ=1.5406 Å) containing the XRPD peaks The potassium salt according to any one of claims 1 to 2, characterized by a powder diffraction pattern. The solid form of the compound.

11. The potassium salt has the following 2θ angles ±0.2° 2θ: 3.0, 9.0, 12.6, 13. The spectrum was obtained using CuKα1 radiation (λ=1.5406 Å), including peaks at 6.0° and 15.0°.

11. The solid form of claim 10, having a crystalline morphology characterized by XRPD as follows:

12. The X-ray powder diffraction pattern has the following 2θ angles ±0.2° 2θ: 17.1, 18.0, 1 One or more peaks selected from the group consisting of peaks at 8.4, 18.8 and 19.4 degrees The solid form of claim 11, further comprising:

13. When heated to about 20°C to about 150°C (as measured using thermogravimetric analysis), 10° C. / min), exhibiting a weight loss of less than about 1% (by weight) relative to the initial weight.

13. The solid form according to any one of claims 1-3 and 11-12.

14. A compound of formula (Id) according to any one of claims 1 to 13 for use as a medicament. The solid form of something.

15. A therapeutically effective amount of a solid form of a compound of formula (Id) according to any one of claims 1 to 13. and one or more pharma- ceutically acceptable excipients.

16. Parkinson's disease, Huntington's disease, restless legs syndrome, Alzheimer's disease, etc. or a neurodegenerative disease or disorder, such as schizophrenia, attention deficit hyperactivity disorder, or drug addiction. A compound according to any one of claims 1 to 13 for use in the treatment of a psychiatric or neurological disease or disorder of A solid form of the compound of formula (Id) as described above.

17. Parkinson's disease, Huntington's disease, restless legs syndrome, Alzheimer's disease, etc. or a neurodegenerative disease or disorder, such as schizophrenia, attention deficit hyperactivity disorder, or drug addiction. A method for treating a psychiatric or neurological disease or disorder comprising administering a therapeutically effective amount of any one of claims 1 to 13. Administering a solid form of a compound of formula (Id) according to any one of claims 1 to a patient in need thereof. Methods including:

18. Parkinson's disease, Huntington's disease, restless legs syndrome, Alzheimer's disease, etc. or for the treatment of a neurodegenerative disease or disorder of schizophrenia, attention deficit hyperactivity disorder or drug addiction. Claims 1 to 13 in the manufacture of a medicament for the treatment of a psychiatric or neurological disease or disorder such as addiction.

2. Use of a solid form of a compound of formula (Id) according to any one of claims 1 to 11.

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