Prodrug of 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone

Abstract

The present invention relates to a prodrug of 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone, represented by formula (II):

Description

[Technical Field]

[0001] The present invention relates to prodrugs of 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone.

[0002] The present invention also relates to methods for preparing these prodrugs and to pharmaceutical compositions containing such prodrugs. [Background technology]

[0003] International Patent Application No. PCT / EP2020 / 068183, published as WO2021 / 001288, discloses 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone of formula (I): [ka] This compound acts as a D1 Positive Allosteric Modulator and is therefore useful as an agent for the treatment of diseases in which the D1 receptor plays a role.

[0004] International Patent Application No. PCT / EP2020 / 068183, published as WO2021 / 001288, further discloses that the compounds of formula (I) may be useful for the treatment and / or prevention of cognitive and negative symptoms in schizophrenia, cognitive impairment associated with neuroleptic therapy, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinson's disease dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug addiction, sleep disorders, apathy, traumatic spinal cord injury or neuropathic pain.

[0005] It would therefore be desirable to develop a formulation of the compound of formula (I) suitable for administration to patients suffering from any one of the above diseases.

[0006] In particular, Example 2.8 of International Patent Application No. PCT / EP2020 / 068183, published as WO2021 / 001288, discloses, inter alia, a monohydrate crystalline form of 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone. Summary of the Invention [Problem to be solved by the invention]

[0007] This monohydrate crystalline form, 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-hydroxymethyl)-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone, has limited solubility, which can result in formulation difficulties and / or poor bioavailability if oral administration is desired.

[0008] There is therefore a need to improve the solubility of the monohydrate crystalline form of 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone so that it can be incorporated into pharmaceutical compositions, especially for oral administration. [Means for solving the problem]

[0009] The present invention provides a prodrug of 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone, having the formula (II): [ka] (In the formula, R 1 -P(=O)(OH)2, -P(=O)(OM 1 )2, -P(=O)(O - )2M 2 , or -C(=O)R a represents; R a is an amino-substituted C 1-6 represents alkyl; M 1 represents a monovalent cation; M 2 represents a divalent cation.) or a pharmaceutically acceptable salt thereof.

[0010] Thus, in a further aspect, the present invention provides a pharmaceutical composition comprising a prodrug of formula (II) and a pharmaceutically acceptable carrier.

[0011] International Patent Application No. PCT / EP2020 / 068183, published as WO2021 / 001288, discloses that the compounds of formula (I) act as D1 positive allosteric modulators and are therefore useful as agents for the treatment of diseases involving the D1 receptor.

[0012] International Patent Application No. PCT / EP2020 / 068183, published as WO2021 / 001288, further discloses that the compounds of formula (I) may be useful for the treatment and / or prevention of cognitive and negative symptoms in schizophrenia, cognitive impairment associated with neuroleptic therapy, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinson's disease dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug addiction, sleep disorders, apathy, traumatic spinal cord injury or neuropathic pain.

[0013] Thus, in a further aspect, the present invention provides a prodrug of formula (II), or a pharmaceutical composition thereof, for use in the treatment and / or prevention of cognitive and negative symptoms in schizophrenia, cognitive impairment associated with neuroleptic therapy, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinson's disease dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug addiction, sleep disorders, apathy, traumatic spinal cord injury or neuropathic pain. [Brief explanation of the drawings]

[0014] [Figure 1] FIG. 1 depicts a graph of the concentration of Compound (I) in the plasma of three different animals plotted as a function of time after administration of a suspension of prodrug (II-A) prepared according to Example 7, further described herein. [Figure 2]FIG. 2 depicts a graph of the respective concentrations of compounds (I) and (II-B) in the plasma of three different animals plotted as a function of time after administration of a suspension of prodrug (II-B) prepared according to Example 7, further described herein. [Figure 3] FIG. 3 depicts a graph of the concentration of Compound (I) in the plasma of three different animals plotted as a function of time after administration of a suspension of prodrug (II-C) prepared according to Example 7, further described herein. DETAILED DESCRIPTION OF THE INVENTION

[0015] Detailed Description of the Invention As used herein, the term "prodrug," when referring to a prodrug of a compound of formula (I), means a functional derivative of a compound of formula (I) that is readily convertible in vivo into the required compound of formula (I). Prodrugs of compounds of formula (I) according to the present invention are represented by compounds of formula (II), as generally defined above and further described herein.

[0016] As used herein, "C 1-6 The term "alkyl" refers to an aliphatic hydrocarbon group which may be straight or branched and may contain 1 to 6 carbon atoms in the chain. Suitable alkyl groups which may be present on compounds used in the present invention include straight and branched chain C 1-4 Exemplary C alkyl groups include: 1-6 Alkyl groups include methyl, ethyl, propyl and butyl.

[0017] In the first embodiment of the present invention, R 1 represents -P(=O)(OH). In a second embodiment of the present invention, R 1 is -P(=O)(OM 1 In a third embodiment of the present invention, R 1 is -P(=O)(O - )2M 2 In a fourth embodiment of the present invention, R 1 is C(=O)Ra Represents.

[0018] In general, M 1 represents an alkali metal cation. Suitable examples of alkali metal cations include Na + and K. + is.

[0019] In general, M 2 represents an alkaline earth metal cation. Suitable examples of alkaline earth metal cations include Ca 2+ is.

[0020] In general, R a is C substituted by amino 1-6 In a first embodiment, R a represents (amino)butyl. In a second embodiment, R a represents (amino)pentyl.

[0021] Specific examples of compounds of formula (II) according to the present invention are represented by compounds of formulae (II-A), (II-B) and (II-C). [ka]

[0022] In a first embodiment, the present invention relates to prodrugs of formula (II-A).

[0023] In a second embodiment, the present invention relates to prodrugs of formula (II-B):

[0024] In a third embodiment, the present invention relates to a prodrug of formula (II-C):

[0025] In a fourth embodiment, the present invention relates to a salt of a compound of formula (II-A). In one aspect of this embodiment, the present invention relates to a salt of a compound of formula (II-B). 1 -P(=O)(OM 1 )2, and M 1 Na +The present invention relates to the disodium salt of the compound of formula (II-A) which corresponds to the compound of formula (II)

[0026] In another aspect of this embodiment, the present invention provides a compound comprising R 1 P(=O)(O - )2M 2 represents M 2 Ca 2+ The present invention relates to the calcium salt of the compound of formula (II-A) which corresponds to the compound of formula (II)

[0027] The prodrugs of formula (II) according to the present invention are generally more soluble than the crystalline form of the monohydrate of the compound of formula (I) (referred to herein as the compound of formula (Ia)). Such improved solubility is particularly advantageous when pharmaceutical compositions need to be prepared for oral administration, since higher bioavailability can be achieved. This can also reduce the dosage and therefore the tablet size to be used when a solid formulation is desired.

[0028] Table 1 of the Examples presents comparative data on the solubility between the compound of formula (II) obtained according to this Example and the compound of formula (Ia), showing a minimum 20-fold increase regardless of the medium used.

[0029] The prodrugs according to the present invention can be further combined with pharmaceutically acceptable excipients such as diluents, binders, disintegrants, lubricants, flow agents or carriers to form suitable pharmaceutical compositions.

[0030] To prepare such pharmaceutical compositions, the prodrugs according to the present invention are intimately admixed with a pharmaceutical diluent or carrier according to conventional pharmaceutical compounding techniques known to those skilled in the art.

[0031] Suitable diluents and carriers can take a wide variety of forms depending on the desired route of administration, for example oral, rectal, parenteral, or intranasal.

[0032] Pharmaceutical compositions suitable for oral administration may be solid or liquid and may, for example, be in the form of tablets, pills, dragees, gelatin capsules, solutions, syrups, chewing gum, or the like.

[0033] For this purpose, the active ingredient may be mixed with an inert diluent or a non-toxic pharmaceutically acceptable carrier such as starch or lactose. Optionally, these pharmaceutical compositions may also contain a binder such as microcrystalline cellulose, gum tragacanth, or gelatin, a disintegrating agent such as croscarmellose sodium or crospovidone alginate, a lubricant such as magnesium stearate, a flow agent such as colloidal silicon dioxide, a sweetener such as sucrose or saccharin, a coloring agent, or a flavoring agent such as peppermint or methyl salicylate, and a coating such as Opadry® (I, II, AMB II, QX, or EZ).

[0034] The present invention also contemplates compositions that can release the active substance in a controlled manner. Pharmaceutical compositions that can be used for parenteral administration are generally in conventional forms such as aqueous or oily solutions or suspensions contained in ampoules, disposable syringes, glass or plastic vials, or infusion containers.

[0035] In addition to the prodrug, these solutions or suspensions may optionally contain a sterile diluent such as water for injection, saline, oil, polyethylene glycol, glycerin, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol, antioxidants such as ascorbic acid or sodium bisulfite, chelating agents such as ethylenediaminetetraacetic acid, buffers such as acetates, citrates or phosphates, tonicity adjusters such as sodium chloride or dextrose, viscosity enhancers such as methylcellulose, hydroxypropylcellulose (HPC-SSL), hypromellose (HPMC), and finally stabilizers such as TWEEN® 80, PPVVA, PVP, PVA.

[0036] These pharmaceutical forms are prepared by methods routinely used by pharmacists.

[0037] The amount of the prodrug of formula (II) according to the present invention in the pharmaceutical composition may be in a wide range of concentrations and depends on various factors such as the patient's sex, age, weight and medical condition, as well as the method of administration. Therefore, the amount of the prodrug for oral administration is generally comprised between about 0.5% and about 80% by weight, suitably between about 20% and about 60% by weight, based on the total weight of the composition.

[0038] International Patent Application No. PCT / EP2020 / 068183, published as WO2021 / 001288, discloses that compounds of formula (I) may be useful for treating diseases and / or disorders in which D1 receptors play a role, in particular cognitive and negative symptoms in schizophrenia, cognitive impairment associated with neuroleptic therapy, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinson's disease dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug addiction, sleep disorders, apathy, traumatic spinal cord injury or neuropathic pain.

[0039] Thus, in a further aspect, the present invention provides a prodrug of formula (II) as described herein, or a pharmaceutical composition thereof, for use in the treatment and / or prevention of cognitive and negative symptoms in schizophrenia, cognitive impairment associated with neuroleptic therapy, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinson's disease dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug addiction, sleep disorders, apathy, traumatic spinal cord injury or neuropathic pain.

[0040] In certain aspects, the present invention provides a prodrug of formula (II) according to the present invention or a pharmaceutical composition thereof for use in the treatment of cognitive and negative symptoms in Parkinson's disease and other movement disorders, Alzheimer's disease, or schizophrenia.

[0041] Compounds of formula (I) may be prepared by a process comprising reacting an intermediate of formula (A) with an intermediate of formula (B). [ka]

[0042] Intermediate (B) can be successfully reacted with an intermediate of formula (A) using an excess of a base, such as N,N-diisopropylethylamine, in the presence of (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) or another coupling agent known to those skilled in the art, in a suitable solvent, such as dimethylformamide.

[0043] The intermediate of formula (B) can be prepared by a process involving reaction of an intermediate of formula (IV). [ka] (wherein Z represents halogen or 1-hydroxy-1-methylethyl; R a represents t-butyldimethylsilyl; R c represents hydrogen or t-butoxycarbonyl.

[0044] In the first step, a compound of formula (IV) (wherein Z represents bromo and R c represents hydrogen.) (hereinafter referred to as intermediate (IVa)) is protected with a suitable protecting group according to a method known to those skilled in the art to give a compound of formula (IV) (wherein Z represents bromo and R c represents t-butoxycarbonyl.) (hereinafter referred to as intermediate (IVb)).

[0045] In the second step, for example, a metal-halogen exchange reaction can be carried out in the presence of n-BuLi in a suitable solvent, such as tetrahydrofuran, at low temperature in the presence of dry acetone under continuous flow according to the method described in the subsequent examples to give the corresponding intermediate (IV) (wherein Z represents 1-hydroxy-1-methylethyl, hereinafter referred to as intermediate (IVc)).

[0046] The t-butoxycarbonyl (Boc) group (R c ) was first deprotected, followed by the deprotection of the trimethylsilyl and t-butyldimethylsilyl groups (R a ) can be deprotected to give intermediate (B).

[0047] The intermediate of formula (IVa) can be prepared by a process comprising reaction of an intermediate of formula (V), wherein Y is halogen, for example bromo, and R a is defined above for the intermediate of formula (IV). [ka]

[0048] The reaction is conveniently carried out in the presence of methylmagnesium chloride in a suitable solvent such as tetrahydrofuran at low temperatures.

[0049] Intermediate (V) may be prepared by a two-step process involving reaction of an intermediate of formula (VI). [ka] wherein Y is as defined above for the intermediate of formula (V), and R a represents hydrogen or t-butyl-dimethylsilyl.

[0050] In the first step, intermediate (VI) (wherein R arepresents hydrogen.) is reacted with t-butyldimethylsilyl chloride in the presence of a suitable base, for example 4-dimethylamino-pyridine, at room temperature to give intermediate (VI) (wherein R a represents t-butyl-dimethylsilyl.

[0051] In the second step, intermediate (VI) (wherein R a represents t-butyl-dimethylsilyl.) is reacted with N-chlorosuccinimide (NCS) in a suitable solvent, such as THF, to give intermediate (V).

[0052] Intermediate (VI) (wherein R a represents hydrogen.) can be prepared by a process which involves an intermediate of formula (VII) where Y is as defined above for intermediate (V). [ka]

[0053] The reaction is conveniently carried out in the presence of a strong base, such as sodium hydroxide, in a suitable solvent, such as a mixture of ethanol and water, at elevated temperatures.

[0054] The intermediate of formula (VII) can be prepared by a process comprising reaction of intermediate (VIII). [ka] wherein Y is as defined above for the intermediate of formula (V).

[0055] The reaction is conveniently carried out in the presence of trimethylsilyl triflate and paraformaldehyde in a suitable solvent, such as dichloromethane.

[0056] Intermediate (VIII) can be prepared by a two-step process involving commercially available intermediate (IX). [ka] wherein Y is as defined above for the intermediate of formula (V).

[0057] This reaction is conveniently carried out according to the methods described in the accompanying examples or according to methods known to those skilled in the art.

[0058] The intermediate of formula (A) can be prepared by a multi-step process involving reaction of an intermediate of formula (X). [ka] (In the formula, R 1 represents chloro, amino or nitro; R b represents hydrogen or t-butyl.

[0059] In the first step, a compound of formula (X) (wherein R 1 represents nitro, and R b represents t-butyl.) (hereinafter referred to as intermediate (Xa)) is converted into the corresponding intermediate (X) (R 1 represents amino, and R b represents t-butyl, hereinafter referred to as intermediate (Xb). This reaction is successfully carried out by Pd / C catalyzed hydrogenation under high pressure in a suitable solvent, such as methanol.

[0060] Intermediate (Xb) can be prepared by adding concentrated hydrochloric acid and sodium nitrite, followed by further addition of hydrochloric acid and copper(II) chloride to the corresponding intermediate (X) (wherein R 1 represents chloro, and R b represents hydrogen, hereinafter referred to as intermediate (Xc). This reaction is successfully carried out at low temperatures.

[0061] Intermediate (A) can then be obtained directly from intermediate (Xc) by reaction with N-chlorosuccinimide according to the methods described in the accompanying examples or known to those skilled in the art.

[0062] The intermediate of formula (Xa) may be prepared by a process which involves an intermediate of formula (XI). [ka] (In the formula, R 2 represents hydrogen or methyl.)

[0063] In the first step, a compound of formula (XI) (wherein R 2 A commercially available intermediate of (XIa) (hereinafter referred to as intermediate (XIa)) is reacted with methyl iodide in a suitable solvent, for example, dimethylformamide, in the presence of a strong base, for example, potassium chloride. The resulting intermediate (XI) (R 2 represents methyl; hereinafter referred to as intermediate (XIb).) is reacted with t-butyl 2-chloroacetate in a suitable solvent, such as tetrahydrofuran, in the presence of potassium t-butoxide at low temperature to give intermediate (Xa).

[0064] The prodrug of formula (II) can be obtained by functional group transformation of the compound of formula (I).

[0065] Formula (II)(R 1 represents -P(=O)(OH)2. Compounds of formula (I) are prepared according to the procedure further described in Example 3, or according to any other method known to one skilled in the art.

[0066] Formula (II)(R 1 is -P(=O)(OM 1 )2 or -P(=O)(O - )2M 2 The compound of formula (II) (R 1 represents -P(=O)(OH)2.) by reaction with a base according to methods familiar to those skilled in the art.

[0067] Formula (II)(R 1 is C(=O)R a represents R ais an amino-substituted C 1-6 Compounds of formula (I) are typically prepared in a two-step procedure from compounds of formula (I). (i) reacting a compound of formula (I) with an amino-substituted C 1-6 The alkyl is reacted with the corresponding carboxylic acid, which is generally commercially available. The reaction is conveniently carried out in a suitable solvent such as dichloromethane at room temperature. (ii) The protecting group of the amino group of the compound resulting from step (i) is removed by conventional methods known to those skilled in the art, for example by reaction with an acid.

[0068] Where any of the above processes for preparing compounds according to the invention result in a mixture of products, the desired product may be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC; or by column chromatography, for example utilizing silica and / or alumina in combination with a suitable solvent system.

[0069] If the above-described methods for preparing the compounds of the present invention result in a mixture of stereoisomers, these isomers can be separated by conventional techniques. In particular, if it is desired to obtain a specific enantiomer of a compound of formula (I), it can be prepared from the corresponding enantiomeric mixture using any suitable conventional procedure for resolving enantiomers. Thus, for example, diastereomeric derivatives (such as salts) can be produced by reacting a mixture of enantiomers of formula (I) (e.g., a racemate) with an appropriate chiral compound (e.g., a chiral base). The diastereomers can then be separated by any convenient means, such as crystallization, and the desired enantiomer can be recovered, for example, if the diastereomer is a salt, by treatment with an acid. In another resolution process, chiral HPLC can be used to separate the racemate of formula (I). Furthermore, if desired, a specific enantiomer can be obtained by using an appropriate chiral intermediate in one of the above processes. Alternatively, a specific enantiomer can be obtained by enantiomer-specific enzymatic biotransformation. An example of this biotransformation is the hydrolysis of an ester using an esterase followed by purification of the enantiomerically pure hydrolyzed acid from the unreacted ester antipode. Chromatography, recrystallization, and other conventional separation procedures can also be used on intermediates or final products if it is desired to obtain a specific geometric isomer of the present invention. Alternatively, the undesired enantiomer can be racemized to the desired enantiomer in the presence of acid or base according to methods known to those skilled in the art or as described in the accompanying examples.

[0070] During any of the above synthetic procedures, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups such as those described in Protective Groups in Organic Chemistry, J.F.W. McOmie, Plenum Press, ed., 1973; and T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3rd Edition, 1999. The protecting groups may be removed at any subsequent convenient stage using methods known in the art. [Example]

[0071] Abbreviations / Frequently Used Reagents Ac: Acetyl ACN: acetonitrile Brine: saturated aqueous sodium chloride solution nBu: n-butyl tBu: tert-butyl CV: column volume DCC: dicyclohexylcarbodiimide DCM: dichloromethane DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide ES + : Electrospray positive ionization Et: Ethyl EtOH: ethanol Et2O: Diethyl ether EtOAc: ethyl acetate h:Hour HPLC: High-performance liquid chromatography IPAC: Isopropyl acetate LC: liquid chromatography LCMS: Liquid Chromatography Mass Spectrometry Me: Methyl MeOH: Methanol min:minutes NCS: N-chlorosuccinimide NMR: nuclear magnetic resonance iPr: Isopropyl iPrOH: Isopropanol p-TSA: p-toluenesulfonic acid rt: room temperature RT: retention time SFC: Supercritical Fluid Chromatography SPE: solid phase extraction t-BuOK: Potassium t-butoxide TBS: t-butyldimethylsilyl TEA: Triethylamine TFA: Trifluoroacetic acid THF: tetrahydrofuran TLC: Thin Layer Chromatography TMS: trimethylsilyl UPLC: Ultra-high performance liquid chromatography IUPAC names were generated using Biovia Draw versions 19.1 (2019) and 20.1 (2020).

[0072] 1.Analysis method All reactions involving air- or moisture-sensitive reagents were carried out under a nitrogen or argon atmosphere using dry solvents and glassware. Experiments requiring microwave irradiation were performed in a Biotage Initiator Sixty microwave oven upgraded with operating software version 2.0. Experiments were performed to reach the required temperature as quickly as possible (maximum irradiation power: 400 W, no external cooling). Commercially available solvents and reagents were usually used without further purification; anhydrous solvents were used where necessary (typically Sure-Seal™ products from Aldrich Chemical Company or AcroSeal™ from ACROS Organics). Reactions were generally followed by thin-layer chromatography (HPLC) or mass spectrometry.

[0073] Mass spectrometry measurements in LCMS mode were performed using different methods and instruments, including: - Basic LCMS method 1: A QDA Waters simplified quadrupole mass spectrometer was used for LCMS analysis. The spectrometer was equipped with an ESI source and a UPLC Acquity Classic with a diode array detector (210–400 nm). Data were acquired in a full MS scan from m / z 70–800 in positive / negative mode with basic elution. Reversed-phase separation was performed on a Waters Acquity UPLC BEH C18 1.7 μm (2.1 × 50 mm) column with basic elution at 45 °C. Gradient elution was performed using HO / ACN / ammonium formate (95 / 5 / 63 mg / L) + 100 μL / L NH4OH (solvent A) and ACN / HO / ammonium formate (95 / 5 / 63 mg / L) + 100 μL / L NH4OH (solvent B). Injection volume: 1 μL. Full flow rate on the MS. [Table 1]

[0074] Some reaction mixtures could be processed using Isolute® separator phase cartridges (available from Biotage), acidic columns, or catch-and-release SPE (solid phase extraction) cartridges. Crude materials could be purified by normal phase chromatography, preparative TLC, (acidic or basic) reverse phase chromatography, chiral separation trituration, or recrystallization.

[0075] Normal phase chromatography was performed using a silica gel column (cartridge for a normal phase column chromatography system such as Biotage® Isolera™ Four or Teledyne Isco CombiNormal phase column®, or 100:200 mesh silica gel). The product was typically dried under vacuum before submission for final analysis and biological testing.

[0076] NMR spectra were acquired on a Windows 7 Professional workstation running Topspin 3.2 software and a 5 mm Double Resonance Broadband Probe (PABBI). 1 H / 19 F-BB Z-GRD Z82021 / 0075) or 1mm Triple Resonance Probe (PATXI 1 H / D- 13 C / 15 The data were recorded on a BRUKER AVANCE III 400 MHz-Ultrashield NMR spectrometer equipped with a 1000 MHz NMR spectrometer (N Z-GRD Z868301 / 004).

[0077] Chemical shifts are referenced to signals originating from residual protons of the deuterated solvent (DMSO-d6, MeOH-d4, or CDCl3). Chemical shifts are expressed in parts per million (ppm), and coupling constants (J) are expressed in Hertz (Hz). Spin multiplicities are given as broad (br), singlet (s), doublet (d), triplet (t), quartet (q), and multiplet (m).

[0078] All final products were analyzed by LCMS in both basic and acidic modes as follows: - Basic LCMS method 2: A QDA Waters simplified quadrupole mass spectrometer was used for LCMS analysis. The spectrometer was equipped with an ESI source and a UPLC Acquity Classic with a diode array detector (210–400 nm). Data were acquired in a full MS scan from m / z 70–800 in positive / negative mode with basic elution. Reversed-phase separation was performed on a Waters Acquity UPLC BEH C18 1.7 μm (2.1 × 100 mm) column with basic elution at 45 °C. Gradient elution was performed using HO / ACN / ammonium formate (95 / 5 / 63 mg / L) + 100 μL / L NH4OH (solvent A) and ACN / HO / ammonium formate (95 / 5 / 63 mg / L) + 100 μL / L NH4OH (solvent B). Injection volume: 1 μL. Full flow rate on the MS. [Table 2]

[0079] - Acidic LCMS method: A QDA Waters simplified quadrupole mass spectrometer was used for LCMS analysis. The spectrometer was equipped with an ESI source and a UPLC Acquity Hclass with a diode array detector (210–400 nm). Data were acquired in positive / negative mode with acidic elution, with full MS scans from m / z 70–800. Reversed-phase separation was performed on a Waters Acquity UPLC HSS T3 1.8 μm (2.1 × 100 mm) column with acidic elution at 45 °C. Gradient elution was performed using HO / ACN / TFA (95 / 5 / 0.05%) (solvent A) and ACN (solvent B). [Table 3]

[0080] 2. Preparation of the monohydrate crystalline form of 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone (1a) The compound of formula (Ia) was prepared by applying the same synthetic method as described in Example 2 of co-pending international patent application WO2021 / 001288, which is incorporated herein by reference.

[0081] The following recrystallization protocol was also applied as an alternative to the recrystallization protocol disclosed in section 2.8: Recrystallization is carried out on 5.00 g of crude material solubilized in 240 ml of dimethyl sulfoxide. The solution is heated to 40°C and then filtered on P3 sintered glass. The reactor and filter are rinsed with 35 ml of dimethyl sulfoxide. The filtrate is transferred to a clean reactor and heated to 85°C. 110 ml of water is slowly added over 30 minutes. 250 mg of compound (Ia) (0.5% w / w, monohydrate form) is then added to the reaction mixture. The mixture is stirred at 85°C for 2 hours and 30 minutes and then slowly cooled to 20°C over 12 hours, during which time the crystalline material comes out of solution. The suspension is filtered, and the filter cake is washed successively with water several times and then with 150 ml of ethyl acetate. The filter cake is dried under vacuum at 50-60°C. 46.9 g of compound (Ia) is obtained as an off-white powder. Yield = 94%

[0082]

number

[0083] 3. Preparation of Compound of Formula (II-A)—[(1S,3R)-2-[2-(3,5-dichloro-1-methyl-indazol-4-yl)acetyl]-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-3-yl]methyl dihydrogen phosphate, and its disodium salt (II-A-Na) and calcium salt (II-A-Ca) [ka]

[0084] 3.1. Synthesis of Intermediate (a1) - Synthesis of dibenzyl [(1S,3R)-2-[2-(3,5-dichloro-1-methyl-indazol-4-yl)acetyl]-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-3-yl]methyl phosphate To a suspension of the compound of formula (Ia) (10.0 g, 20.0 mmol) in DCM (210 mL) at room temperature, dibenzyl n,n-diisopropylphosphoramidite (10.8 mL, 31.5 mmol), imidazole (1.43 g, 21.0 mmol), and imidazole hydrochloride (3.29 g, 31.5 mmol) were added successively, and the reaction mixture was stirred at room temperature for 2 hours. Hydrogen peroxide (35% w / w in water, 10.4 mL, 128 mmol) was then added in two portions over 45 minutes, and the reaction mixture was stirred at room temperature for 1 hour and 30 minutes. The reaction mixture was then washed with saturated sodium bisulfite solution (200 mL), and the aqueous phase was extracted twice with DCM. The combined organic phases were washed with brine, dried over MgSO4, and concentrated in vacuo to dryness to give a pale yellow oil. The crude product was purified by flash chromatography on a Biotage Isolera Four (100 g SFAR silica gel column with a gradient of heptane: EtOAc 70:30 to 20:80 over 15 CV (column volume)). The purest fractions were collected and the solvent was evaporated to dryness (30 °C) to give dibenzyl [(1S,3R)-2-[2-(3,5-dichloro-1-methyl-indazol-4-yl)acetyl]-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-3-yl]methyl phosphate (a1) as a white solid (11.9 g, 16.2 mmol, 81% yield).

[0085] Basic LCMS Method 1: 1.71 min (ES + ) 1 peak: 758 / 760 [M+Na] + , 458 / 460[M-(BnO)2P(O)OH+H] + , 87% purity.

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[0086] 3.2. Synthesis of Compound (II-A)—[(1S,3R)-2-[2-(3,5-dichloro-1-methyl-indazol-4-yl)acetyl]-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-3-yl]methyl dihydrogen phosphate Dibenzyl [(1S,3R)-2-[2-(3,5-dichloro-1-methyl-indazol-4-yl)acetyl]-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-3-yl]methyl phosphate (a1) (11.5 g, 15.6 mmol), THF (141 mL), and palladium (5% supported on carbon, Paste JM Type 87L, 764 mg, 0.359 mmol) were introduced into a 300 mL glass Parr reactor, and the reaction mixture was stirred under 4 bar of H for 3 hours. The reaction mixture was then filtered through a pad of Celite, and the filter cake was eluted with THF (200 mL). The filtrate was concentrated in vacuo to dryness to give a white solid. The crude mixture was purified by reverse-phase preparative HPLC GILSON basic mode (YMC Triart-500 g-10 μm-76.5 × 200 mm, gradient elution with ACN (5 mL NH4OH in 1000 mL water) 20 / 80 to 50 / 50). The purest fractions were collected and directly lyophilized to give a white solid. This white solid was purified a second time by reverse-phase flash chromatography Biotage Isolera Four under acidic conditions (1.0 g portions, C18 SNAP 60 g gel column, 12 CV, gradient elution from 20% to 50% ACN in water / formic acid (pH approx. 5)). The purest fractions were collected and directly lyophilized to give [(1S,3R)-2-[2-(3,5-dichloro-1-methyl-indazol-4-yl)acetyl]-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-3-yl]methyl dihydrogen phosphate (II-A) (6.07 g, 10.9 mmol, 70% yield) as a white solid.

[0087] Basic LCMS Method 2: 4.00 min (ES +) 1 peak: 554 / 556 [MH] - , 97% purity. Acidic LCMS method 1: 2.30 min (ES + ) 1 peak: 554 / 556 [MH] - , 97% purity.

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[0088] Crystallization of compound II-A was optimized using 100 mg of compound in 10 mL of ethanol / pentane (10 / 1). After 3 weeks, white crystals were obtained (20 mg, 20% yield). Crystallization was scaled up using 10 mL of ethanol / pentane (10 / 1), dividing 700 mg into five 140 mg batches. After 3 weeks, white crystals of [(1S,3R)-2-[2-(3,5-dichloro-1-methyl-indazol-4-yl)acetyl]-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-3-yl]methyl dihydrogen phosphate (II-Ax) were obtained (203 mg, 29% yield, combined from five experiments).

[0089] 3.3. Synthesis of Compound (II-A-Na) - Synthesis of Disodium [(1S,3R)-2-[2-(3,5-dichloro-1-methyl-indazol-4-yl)acetyl]-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-3-yl]methyl phosphate To a solution of [(1S,3R)-2-[2-(3,5-dichloro-1-methyl-indazol-4-yl)acetyl]-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-3-yl]methyl dihydrogen phosphate (II-A) (1.0 equiv., 275 mg, 0.490 mmol) in water (0.1 M, 5 mL) at 0° C. was added sodium hydroxide solution (2.0 equiv., 1 mL, 1 mmol, 1 M solution) and the reaction was stirred at room temperature for 1 hour. The reaction mixture was lyophilized overnight to give disodium [(1S,3R)-2-[2-(3,5-dichloro-1-methyl-indazol-4-yl)acetyl]-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-3-yl]methyl phosphate (II-A-Na) (250 mg, 0.402 mmol, 82% yield) as a pale yellow solid.

[0090]

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[0091] 3.4. Synthesis of Compound (II-A-Ca) - Synthesis of calcium [(1S,3R)-2-[2-(3,5-dichloro-1-methyl-indazol-4-yl)acetyl]-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-3-yl]methyl phosphate To a solution of [(1S,3R)-2-[2-(3,5-dichloro-1-methyl-indazol-4-yl)acetyl]-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-3-yl]methyl dihydrogen phosphate (II-A) (1.0 equiv., 100 mg, 0.178 mmol) in water (0.1 M, 2 mL) at 0° C. was added calcium hydroxide solution (1.0 equiv., 14 mg, 0.183 mmol), and the reaction was stirred at room temperature for 1 hour. The reaction mixture was lyophilized overnight to give calcium [(1S,3R)-2-[2-(3,5-dichloro-1-methyl-indazol-4-yl)acetyl]-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-3-yl]methyl phosphate (II-A-Ca) (110 mg, 0.179 mmol, 100% yield) as a white solid.

[0092]

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[0093] 4. Preparation of Compound (II-B) - Preparation of [(1S,3R)-2-[2-(3,5-dichloro-1-methyl-indazol-4-yl)acetyl]-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-3-yl]methyl (2S)-2-amino-3-methyl-butanoate [ka]

[0094] 4.1. Synthesis of Intermediate (a2) - [(1S,3R)-2-[2-(3,5-dichloro-1-methyl-indazol-4-yl)acetyl]-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-3-yl]methyl (2S)-2-(t-butoxycarbonylamino)-3-methyl-butanoate To a solution of the compound of formula (Ia) (8.00 g, 16.2 mmol) in DCM (170 mL) was added (2S)-2-(t-butoxycarbonylamino)-3-methyl-butanoic acid (Boc-L-Valine, 7.30 g, 33.2 mmol), DMAP (1.00 g, 8.40 mmol), and DCC (6.93 g, 33.6 mmol) at room temperature, and the mixture was stirred at room temperature for 18 hours. A saturated solution of NaHCO was then added, and the aqueous layer was extracted with DCM (3 times). The combined organic layers were washed with brine, dried over MgSO, filtered, and evaporated to dryness to give a white solid. The crude mixture was purified by reverse-phase preparative HPLC (Gilson Basic mode, YMC Triart 500 g, 10 μm, 76.5 × 200 mm, gradient elution with ACN (5 mL NH4OH in 1000 mL water) 60 / 40 to 90 / 10). The purest fractions were collected and concentrated to dryness to give [(1S,3R)-2-[2-(3,5-dichloro-1-methyl-indazol-4-yl)acetyl]-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-3-yl]methyl (2S)-2-(t-butoxycarbonylamino)-3-methyl-butanoate (A2) (10.0 g, 14.8 mmol, 91% yield) as a white solid.

[0095] Basic LCMS Method 1: 1.78 min (ES + ) 1 peak: 675 / 677 [M+H] + , 575 / 577[M-Boc+H] + , 98% purity.

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[0096] 4.2. Synthesis of Compound (II-B)—[(1S,3R)-2-[2-(3,5-dichloro-1-methyl-indazol-4-yl)acetyl]-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-3-yl]methyl (2S)-2-amino-3-methyl-butanoate To a solution of [(1S,3R)-2-[2-(3,5-dichloro-1-methyl-indazol-4-yl)acetyl]-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-3-yl]methyl (2S)-2-(t-butoxycarbonylamino)-3-methyl-butanoate (a2) (10.0 g, 14.8 mmol) in 2-propanol (100 mL) was added hydrochloric acid (37% in water, 36.2 mL, 434 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 30 minutes. DCM and a saturated solution of NaHCO3 were then added to the resulting mixture until the pH reached 7-8, and the layers were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were then dried over MgSO4, filtered, and concentrated to dryness to give a white solid. The crude mixture was purified by reverse-phase preparative HPLC GILSON basic mode (YMC Triart-500 g-10 μm-76.5 × 200 mm, gradient elution with ACN (5 mL NH4OH in 1000 mL water) 50 / 50 to 100 / 0). The purest fractions were collected and concentrated to dryness to give the title product as a white solid. This product was recrystallized in a mixture of 5:2 EtOAc / pentane (35 mL / g) to give [(1S,3R)-2-[2-(3,5-dichloro-1-methyl-indazol-4-yl)acetyl]-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-3-yl]methyl (2S)-2-amino-3-methyl-butanoate (II-B) (3.30 g, 5.75 mmol, 39% yield) as white crystals.

[0097] Basic LCMS Method 2: 4.59 min (ES + ) 1 peak: 575 / 577 [M+H] + , 98% purity. Acidic LCMS method 1: 4.45 min (ES + ) 1 peak: 575 / 577 [M+H] + , 99% purity.

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[0098] 5. Synthesis of Compound (II-C) - [(1S,3R)-2-[2-(3,5-dichloro-1-methyl-indazol-4-yl)acetyl]-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-3-yl]methyl (2S)-2-amino-4-methyl-pentanoate [ka]

[0099] 5.1. Synthesis of Intermediate (a3) ​​- [(1S,3R)-2-[2-(3,5-dichloro-1-methyl-indazol-4-yl)acetyl]-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-3-yl]methyl (2S)-2-(t-butoxycarbonylamino)-4-methyl-pentanoate To a suspension of (2S)-2-(t-butoxycarbonylamino)-4-methyl-pentanoic acid (Boc-L-leucine, 9.50 g, 40.3 mmol) and the compound of formula (Ia) (10.0 g, 20.2 mmol) in DCM (200 ml) was added DMAP (1.24 g, 10.1 mmol) and DCC (8.35 g, 40.5 mmol) at room temperature, and the resulting reaction mixture was stirred at room temperature for 18 hours. After LCMS monitoring showed incomplete conversion, additional DCC (2.09 g, 10.1 mmol) and (2S)-2,4-dimethylpentanoic acid (2.39 g, 10.1 mmol) were added to the reaction mixture, and the resulting reaction mixture was stirred at room temperature for 20 hours. After LCMS monitoring showed complete conversion, the reaction mixture was diluted with water and DCM, and the layers were separated. The organic layer was washed with saturated aqueous NH4Cl, saturated aqueous NaHCO3, water, brine, dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography Biotage Isolera Four (solid loaded on Celite, 220 g of SFAR silica gel in a gradient of heptane / EtOAc 100 / 0 to 40 / 60). The fractions containing the desired compound were collected and concentrated to give a residue, which was then purified by flash chromatography Biotage Isolera Four (liquid loaded in DCM, 220 g of SFAR silica gel in a gradient of DCM / EtOAc 100 / 0 to 80 / 20). Fractions containing the desired product were combined and partially evaporated under reduced pressure until all DCM was removed to give a suspension which was filtered to give a solution and concentrated to give [(1S,3R)-2-[2-(3,5-dichloro-1-methyl-indazol-4-yl)acetyl]-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-3-yl]methyl (2S)-2-(t-butoxycarbonylamino)-4-methyl-pentanoate (a3) ​​(11.3 g, 16.4 mmol, 81% yield) as a white solid.

[0100] Basic LCMS Method 2: 1.82 min (ES + ) 1 peak: 589 [M+H-Boc] + , 98% purity. Acidic LCMS method 1: 1.82 min (ES + ) 1 peak: 589 [M+H-Boc] + , 98% purity.

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[0101] 5.2. Synthesis of Compound (II-C) - [(1S,3R)-2-[2-(3,5-dichloro-1-methyl-indazol-4-yl)acetyl]-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-3-yl]methyl (2S)-2-amino-4-methylpentanoate To a solution of [(1S,3R)-2-[2-(3,5-dichloro-1-methyl-indazol-4-yl)acetyl]-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-3-yl]methyl (2S)-2-(t-butoxycarbonylamino)-4-methyl-pentanoate (a3) ​​(10.0 g, 14.5 mmol) in 2-propanol (150 mL) was added hydrochloric acid (37% w / w in water, 36.2 mL, 434 mmol) at 0 °C, and the reaction mixture was stirred at 4 °C to room temperature for 8 days. The reaction mixture was diluted with DCM (600 mL), and saturated aqueous NaHCO was slowly added until pH = 8. The layers were separated, and the aqueous layer was extracted with DCM (2 × 400 mL). The combined organic layers were washed with half-saturated aqueous NaCl (800 mL), brine, dried over NaSO, filtered, and concentrated to give the crude product. The crude product was purified twice by flash chromatography on Biotage Isolera Four (220 g of SFAR silica gel, liquid loading in DCM, gradient of heptane / EtOAc / MeOH 50 / 50 / 0 to 0 / 100 / 0, then 0 / 100 / 0 to 0 / 90 / 10) to give a white solid. The solid was dissolved in EtOAc (100 mL) and diluted with pentane (250 mL). The entire mixture was stirred at 35° C. for 30 minutes until a clear solution was obtained. The solution was allowed to cool to room temperature and stirred at 150 rpm at room temperature for 6 days to give a white suspension, which was filtered. The solid was dried under high vacuum at room temperature for 24 hours to give [(1S,3R)-2-[2-(3,5-dichloro-1-methyl-indazol-4-yl)acetyl]-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-3-yl]methyl (2S)-2-amino-4-methylpentanoate (II-C) (2.56 g, 4.35 mmol, 30% yield) as white crystals.

[0102] Basic LCMS Method 2: 4.80 min (ES + ) 1 peak: 589 [M+H] + , 100% purity. Acidic LCMS method 1: 3.93 min (ES + ) 1 peak: 589 [M+H] +, 100% purity.

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[0103] 6. Solubility of Compounds of Formulae (II-A), (II-Ax), (II-B) and (I) The solubilities of the compound of formula (Ia) obtained according to Example 2.12, and the compounds of formulae (II-A), (II-Ax), and (II-B) obtained according to Examples 3.2 and 4.2, respectively, were measured in different media using the shake-flask method. Excess solids corresponding to a concentration of 5 mg / mL of the compound of formula (I) for (II-Ax) and (II-B), and to a concentration of 1 mg / mL of the compound of formula (I) for (II-A), were suspended in 5 mL of the buffer / biorelevant medium specified in Table 1 and incubated in sealed glass vials (10 mL) at room temperature or 37°C (as indicated below) in a climatic chamber equipped with a rotary mixer for 24 hours. The solubility was assumed to have been reached at 24 hours, at which point the suspensions were filtered through a 0.45 μm ultrafree filter (Merck Millipore) and the drug content was measured by HPLC. The solubilities of compounds (Ia), (II-A), (II-Ax), and (II-B) were measured three times (n=3), and the average values ​​were calculated.

[0104] The media tested were water, phosphate buffer, FasSGF, FASSIF-V2, and FeSSIF-V2. FasSG represents fasting gastric juice. FasSGF was prepared at pH 1.6 and contained 0.08 mM taurocholate, 0.02 mM phospholipids, 34 mM sodium, and 59 mM chloride. FaSSIF-V2 and FeSSIF-V2 represent biologically relevant media for fasted and fed states, respectively. FaSSIF-V2 was prepared at pH 6.5 and contained 3 mM taurocholate, 0.2 mM phospholipids, 106 mM sodium, 69 mM chloride, and 19 mM maleic acid. FeSSIF-V2 was prepared at pH 5.8 and contained 10 mM taurocholate, 2 mM phospholipids, 0.8 mM oleate, 5 mM glycerol monooleate, 218 mM sodium, 125 mM chloride, and 55 mM maleic acid.

[0105] [Table 1]

[0106] The results obtained above show that, regardless of the vehicle used, at least a 20-fold increase in the solubility of prodrugs (II-A), (II-Ax) and (II-B) is obtained compared to the compound of formula (Ia).

[0107] 7. In vivo bioavailability of suspensions of (II-A), (II-B), and (II-C) 7.1. Suspensions of (II-A), (II-B), and (II-C) The formulation vehicle used in the following suspensions is a mixture of 1% (w / v) methylcellulose (400 cps), 0.1% (w / v) TWEEN® 80, 0.1% (w / v) Antifoam 1510US in 25 mM phosphate buffer, pH 3.0 in water.

[0108] The compound of formula (II) was weighed into the container of an ultrasonication system (Covaris S220X) and the above formulation vehicle was added to give a concentration of the compound of formula (II) of 0.72 g / ml. Homogenize the solution by sonicating for 1 min three times.

[0109] 7.2. Dosing and Bioavailability Measurements Three male Sprague-Dawley rats were administered a single oral dose of each of the suspensions of (II-A), (II-B) and (II-C) described in paragraph 7.1 above, equivalent to 3 mg / kg of the compound of formula (I).

[0110] Plasma samples were collected at 0.12, 0.25, 0.5, 1, 2, 4 and 8 hours post-dose. Plasma concentrations of compound (I) and each of compounds (II-A), (II-B) and (II-C) were quantified by LC / MS (liquid chromatography / mass spectrometry).

[0111] Figures 1 and 3 show that all prodrugs (II-A) and (II-C) are completely cleaved to the compound of formula (I) and circulate in the bloodstream. FIG. 2 shows that the prodrug (II-B) is partially cleaved to give the compound of formula (I).

Claims

1. A prodrug of 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone, having the formula (II): 【Chemical 1】 (In the formula, R １ is -P(=O)(OH) ２ , -P(=O)(OM １ ) ２ , -P(=O)(O － ) ２ M ２ or -C(=O)R ａ represents; R ａ is an amino-substituted C １－６ represents alkyl; M １ represents a monovalent cation; M ２ represents a divalent cation.) A prodrug represented by the formula:

2. R １ -P(=O)(OH) ２ The prodrug of claim 1 represented by formula (II)

3. R ａ is substituted with amino １－６ The prodrug of claim 1, wherein the formula (II) represents alkyl.

4. R ａ The prodrug of claim 3 , wherein represents (amino)butyl.

5. R ａ The prodrug of claim 3 , wherein represents (amino)pentyl.

6. The prodrug of formula (II) according to claim 1, which is selected from the compounds of formula (II-A), (II-B) and (II-C): 【Chemistry 2】

7. The prodrug of claim 6, which is a compound of formula (II-A).

8. The prodrug of claim 6, which is a compound of formula (II-B):

9. The prodrug of formula (II) according to claim 6, which is a compound of formula (II-C).

10. A prodrug represented by formula (II) according to claim 1, During the ceremony, R １ is P(=O)(OM １ ) ２ or -P(=O)(O － ) ２ M ２ represents M １ is Na ＋ represents M ２ is Ca ２＋ A prodrug.

11. A pharmaceutical composition comprising a prodrug of formula (II) according to claim 1 together with a pharmaceutically acceptable diluent or carrier.

12. A prodrug of formula (II) according to any one of claims 1 to 10, or a pharmaceutical composition according to claim 11, for use in the treatment and / or prevention of cognitive and negative symptoms in schizophrenia, cognitive impairment associated with neuroleptic therapy, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinson's disease dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug addiction, sleep disorders, apathy, traumatic spinal cord injury, or neuropathic pain.

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