Prodrugs for treating CNS diseases

Abstract

The present invention relates to prodrugs of 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine in the forms of 1a and 1b and 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine in the forms of 2a and 2b, wherein X ‑ is a counter ion; or a pharmaceutically acceptable salt thereof. The present invention also provides a pharmaceutical composition comprising the prodrug of the present invention or a pharmaceutically acceptable salt thereof.

Description

Technical Field

[0001] The present invention relates to 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine in the forms of 1a and 1b, and prodrugs of 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine in the forms of 2a and 2b, wherein X - is a counterion;

[0002]

[0003] or a pharmaceutically acceptable salt thereof.

[0004] The present invention also provides a pharmaceutical composition comprising the prodrug of the present invention or a pharmaceutically acceptable salt thereof. Background Art

[0005] In WO 93 / 22293 and Klaus P. Drug Hunting, the Medicinal Chemistry of 1-Piperazino-3-phenylindans and Related Compounds, 1998, ISBN 87-88085-10-4 (see, for example, Compound 69 in Table 3 on page 47 and Table 9A on page 101), a group of trans isomers of 3-aryl-1-(1-piperazinyl)indans substituted at the 2- and / or 3-positions of the piperazine ring have been described. These compounds are described as having high affinity for dopamine D1 and D2 receptors and 5-HT2 receptors, and are proposed to be useful for treating several diseases of the central nervous system, including schizophrenia.

[0006] Trans-racemic 4-((6-chloro-3-phenyl-inden-1-yl)-1,2,2-trimethyl-piperazine can be synthesized, for example, in a manner similar to the methods outlined in et al., J. Med. Chem., 1995, 38, pp. 4380-4392 and WO 93 / 22293. The preparation of this compound by resolution of trans-racemic 4-((6-chloro-3-phenyl-inden-1-yl)-1,2,2-trimethyl-piperazine has been carried out by et al. described in J. Med. Chem., 1995, 38, pages 4380 - 4392, see Table 5, compound (-)-38. The method described included the use of (+)-dimethylbenzoyl tartaric acid for resolution in ethyl acetate and isolation of the compound as the fumarate.

[0007] Subsequently, 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine has been given the International Nonproprietary Name (INN) zicronapine by the WHO. The salts of 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine have been disclosed in WO 2005 / 016900, while later patent applications have disclosed alternative methods for the manufacture of 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine (WO 2011 / 003423) and the resolution of the same compound (WO 2012 / 093165).

[0008] 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine is 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine enriched in deuterium ([H) at the positions indicated in 2a and 2b. 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine has been disclosed in WO 2012 / 176066, which also discloses the synthetic route for obtaining 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine. 2 H) enriched at the positions indicated in 2a and 2b. 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine has been disclosed in WO 2012 / 176066, which also discloses the synthetic route for obtaining 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine.

[0009] WO 2014 / 096151 discloses another synthetic route for obtaining 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine via the conversion of 3,5-dichloro-1-(phenyl-d5)indanone.

[0010] The present invention provides prodrugs of 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine and 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine. The prodrugs of the present invention can, for example, improve the uptake of 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine and 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine, delay the release of 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine and 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine, or reduce the level of possible adverse events. Summary of the Invention

[0011] The present invention provides compounds which are prodrugs as shown below (1a and 1b; 2a and 2b):

[0012]

[0013] and their pharmaceutically acceptable salts.

[0014] 1a and 2a are of the R-configuration at the chiral nitrogen atom, while 1b and 2b are of the S-configuration at the chiral nitrogen atom.

[0015] In one embodiment, the present invention provides a prodrug as defined above or a pharmaceutically acceptable salt thereof for use in therapy.

[0016] In one embodiment, the present invention provides a pharmaceutical composition comprising a prodrug of the present invention as defined above or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0017] In one embodiment, the present invention provides a prodrug as defined above or a pharmaceutically acceptable salt thereof for use in a method for treating CNS diseases.

[0018] In one embodiment, the present invention provides the use of a prodrug as defined above or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating CNS diseases.

[0019] In one embodiment, the present invention provides a method for treating CNS diseases, the method comprising administering to a patient in need thereof a therapeutically effective amount of a prodrug as defined above or a pharmaceutically acceptable salt thereof. Detailed Description

[0020] The present invention provides compounds that are prodrugs as shown below (1a and 1b; 2a and 2b):

[0021]

[0022] 1a and 2a are of the R-configuration at the chiral nitrogen atom, while 1b and 2b are of the S-configuration at the chiral nitrogen atom.

[0023] R is a straight-chain or branched C1-C 11 alkyl group, such as methyl; or a C3-C 10 cycloalkyl group, such as cyclohexylmethyl or cyclohexylethyl.

[0024] The -CH2OC(O)R attached to 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine or 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine is referred to as a prodrug group.

[0025] X - is selected from the group consisting of: halogen anions, such as chloride, bromide or iodide; C1-C 10 sulfonate, optionally fluorinated, such as mesylate, tosylate, triflate or nonafluorobutanesulfonate; and straight-chain or branched C1-C 11 carboxylate, optionally fluorinated, such as trifluoroacetate.

[0026] Compounds 1a and 1b have a natural hydrogen isotope distribution, while 2a and 2b are enriched in deuterium ( 2 H) at the designated positions.

[0027] Prodrug

[0028] A prodrug is generally a compound that may not have any pharmacological activity per se but is metabolized upon administration to a patient to provide a pharmacologically active compound. More specifically, the prodrugs of the present invention are compounds that are metabolized upon administration to a patient to provide 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine (prodrugs 1a and 1b) or 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine (prodrugs 2a and 2b).

[0029] Salt

[0030] Some of the prodrugs of the present invention can be provided as pharmaceutically acceptable acid addition salts. The term pharmaceutically acceptable salts includes salts formed with inorganic acids and / or organic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitrous acid, sulfuric acid, benzoic acid, citric acid, gluconic acid, lactic acid, maleic acid, succinic acid, tartaric acid, acetic acid, propionic acid, oxalic acid, maleic acid, fumaric acid, glutamic acid, pyroglutamic acid, salicylic acid, saccharin, and sulfonic acids (such as methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, and benzenesulfonic acid). Some of the acids listed above are dibasic or tribasic acids, i.e., acids containing two or three acidic hydrogens (such as phosphoric acid, sulfuric acid, fumaric acid, and maleic acid). Dibasic and tribasic acids can form 1:1, 1:2, or 1:3 (tribasic acid) salts, i.e., salts formed between two or three molecules of the compound of the present invention and one molecule of the acid.

[0031] Additional examples of useful acids and bases for forming pharmaceutically acceptable salts can be found, for example, in Stahl and Wermuth (eds.) "Handbook of Pharmaceutical salts. Properties, selection, and use", Wiley-VCH, 2008.

[0032] Therapeutically effective amount

[0033] In the context of the present invention, the "therapeutically effective amount" of a compound means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications in a therapeutic intervention comprising the administration of said compound. The amount sufficient to achieve this is defined as the "therapeutically effective amount". The effective amount for each purpose will depend on the severity of the disease or injury and the body weight and general condition of the subject. Typically, a prodrug of the present invention is administered to achieve a therapeutic effect comparable to that obtained by administering 1 - 60 mg of 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine or 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine (such as 1 - 30 mg of 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine or 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine, such as 5 mg, 10 mg, 15 mg or 20 mg (calculated as the free base)). This means that, for example, "20 mg of 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine or 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine" means 20 mg of the free base of 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine or 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine, where the actual amount administered must be adjusted for the weight of the prodrug group and further adjusted for the weight of the counterion.

[0034] In the context of the present invention, "treatment" or "treating" is intended to indicate the management and care of a patient for the purpose of alleviating, arresting, partially arresting or delaying the progression of the clinical manifestations of a disease or of curing the disease. The patient to be treated is preferably a mammal, particularly a human.

[0035] disease

[0036] In the context of the present invention, "CNS disease" is intended to indicate a disease of the central nervous system.

[0037] As disclosed, for example, in WO 2005 / 016900 and WO 2012 / 176066, the pharmacological properties of 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine and 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine (i.e., the parent forms of 1a, 1b, 2a, and 2b) are also expected to render the compounds useful for the treatment of CNS disorders, which include but are not limited to psychoses, particularly schizophrenia or other disorders involving psychotic symptoms, such as, for example, schizophrenia, treatment-resistant schizophrenia (TRS), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, and other psychotic disorders or diseases with psychotic symptoms, such as bipolar disorder, such as mania in bipolar disorder. The compounds and / or compositions of the present invention can further be used for the treatment of disorders such as those described, for example, in: U.S. Patent Nos. 5,807,855; 7,648,991; 7,767,683; 7,772,240; 8,076,342; U.S. Patent Publication Nos. 2008 / 0269248; 2010 / 0069676; 2011 / 0178094; 2011 / 0207744; WO2005 / 016900; EP 0 638 073; and J. Med. Chem. [Journal of Medicinal Chemistry] 1995, 38, 4380-4392; each of which is incorporated herein by reference in its entirety. The present invention also relates to the medical use of the compounds of the present invention as combination therapies in combination with other therapeutic agents such as those described, for example, in: U.S. Patent Nos. 5,807,855; 7,648,991; 7,767,683; 7,772,240; 8,076,342; U.S. Patent Publication Nos. 2008 / 0269248; 2010 / 0069676; 2011 / 0178094; 2011 / 0207744; WO 2005 / 016900; EP 0638 073; and J. Med. Chem. [Journal of Medicinal Chemistry] 1995, 38, 4380-4392; each of which is incorporated herein by reference in its entirety.

[0038] In the context of the present invention, treatment-resistant schizophrenia is intended to indicate a lack of satisfactory clinical improvement despite two treatments with antipsychotics at adequate doses and durations.

[0039] Pharmaceutical composition

[0040] The pharmaceutical composition can be specifically formulated for administration by any suitable route, such as oral, rectal, nasal, buccal, sublingual, transdermal, and parenteral (e.g., subcutaneous, intramuscular, and intravenous) routes; the oral route is preferred.

[0041] It should be understood that the route will depend on the general condition and age of the subject to be treated, the nature of the disorder to be treated, and the active ingredient.

[0042] In the context of the present invention, the term "excipient" or "pharmaceutically acceptable excipient" refers to pharmaceutical excipients, including but not limited to fillers, anti-adhesives, binders, coatings, colorants, disintegrants, flavoring agents, glidants, lubricants, preservatives, adsorbents, sweetening agents, solvents, vehicles, and adjuvants.

[0043] The present invention also provides a pharmaceutical composition comprising a 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine prodrug (1a and 1b) or a 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine prodrug (2a and 2b) or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to the present invention can be formulated with pharmaceutically acceptable excipients according to conventional techniques, such as those disclosed in Remington, The Science and Practice of Pharmacy, 22nd Edition (2012), edited by Allen, Loyd V., Jr.

[0044] Pharmaceutical compositions for oral administration include solid oral dosage forms, such as tablets, capsules, powders, and granules; and liquid oral dosage forms, such as solutions, emulsions, suspensions, and syrups, as well as powders and granules to be dissolved or suspended in a suitable liquid.

[0045] Solid oral dosage forms can be presented as discrete units (e.g., tablets or hard capsules or soft capsules), each containing a predetermined amount of the active ingredient and preferably one or more suitable excipients. Where appropriate, according to methods well known in the art, the solid dosage forms can be prepared with coatings, such as enteric coatings, or they can be formulated to provide modified release of the active ingredient, such as delayed release or extended release. Where appropriate, the solid dosage form can be a dosage form that disintegrates in saliva, such as an orally disintegrating tablet.

[0046] Examples of excipients suitable for solid oral preparations include, but are not limited to: microcrystalline cellulose, corn starch, lactose, mannitol, polyvinylpyrrolidone, croscarmellose sodium, sucrose, cyclodextrin, talc, gelatin, pectin, magnesium stearate, stearic acid, and lower alkyl ethers of cellulose. Similarly, solid preparations may contain excipients known in the art for delayed or extended release formulations, such as glyceryl monostearate or hydroxypropyl methylcellulose.

[0047] If a solid material is used for oral administration, the preparation can be made, for example, by mixing the active ingredient with a solid excipient and then compressing the mixture in a conventional tableting machine; or the preparation can be placed, for example, in a hard capsule in the form of a powder, a pill, or a microtablet. The amount of the solid excipient will vary widely, but will typically be in the range from about 25 mg to about 1 g / dose unit.

[0048] Liquid oral dosage forms can be presented, for example, as elixirs, syrups, oral drops, or liquid-filled capsules. Liquid oral dosage forms can also be presented as powders for solution or suspension in aqueous or non-aqueous liquids. Examples of excipients suitable for liquid oral preparations include, but are not limited to, ethanol, propylene glycol, glycerol, polyethylene glycol, poloxamer, sorbitol, polysorbate, glycerol monoesters and diesters, cyclodextrin, coconut oil, palm oil, and water. Liquid oral dosage forms can be prepared, for example, by dissolving or suspending the active ingredient in an aqueous or non-aqueous liquid or by incorporating the active ingredient into an oil-in-water or water-in-oil liquid emulsion.

[0049] Additional excipients (such as coloring agents, flavoring agents, and preservatives, etc.) can be used in solid and liquid oral preparations.

[0050] Pharmaceutical compositions for parenteral administration include: sterile aqueous and non-aqueous solutions, dispersions, suspensions, or emulsions for injection or infusion, concentrates for injection or infusion, and sterile powders to be reconstituted in a sterile solution or dispersion for injection or infusion before use. Examples of excipients suitable for parenteral preparations include, but are not limited to, water, coconut oil, palm oil, and cyclodextrin solutions. Aqueous preparations should be buffered appropriately and made isotonic with sufficient saline or glucose when necessary.

[0051] Other types of pharmaceutical compositions include suppositories, inhalants, creams, gels, transdermal patches, implants, and preparations for buccal or sublingual administration.

[0052] It is essential that the excipients for any pharmaceutical preparation meet the expected route of administration and are compatible with the active ingredient.

[0053] Examples of the present invention

[0054] The present invention is further described in the following examples:

[0055] 1. A prodrug of 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine (in the forms of 1a and 1b) or 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine (in the forms of 1a and 1b)

[0056]

[0057] wherein X - is a counterion selected from the group consisting of: halogen anions such as chloride, bromide or iodide; C1-C 10 sulfonate, optionally fluorinated, such as mesylate, tosylate, triflate or nonafluorobutanesulfonate; and straight-chain or branched C1-C 11 carboxylate, optionally fluorinated, such as trifluoroacetate; or a pharmaceutically acceptable salt thereof.

[0058] 2. The prodrug according to embodiment 1, wherein R is selected from the group consisting of: straight-chain or branched C1-C 11 alkyl and C3-C 10 cycloalkyl, or a pharmaceutically acceptable salt thereof.

[0059] 3. The prodrug according to any one of embodiments 1 and 2, wherein R is selected from the group consisting of: methyl, tert-butyl, n-undecane and cyclohexylmethyl, or a pharmaceutically acceptable salt thereof.

[0060] 4. The prodrug according to any one of embodiments 1 to 3, wherein the pharmaceutically acceptable salt is formed from: hydrochloric acid, hydrobromic acid, phosphoric acid, nitrous acid, sulfuric acid, benzoic acid, citric acid, gluconic acid, lactic acid, maleic acid, succinic acid, tartaric acid, acetic acid, propionic acid, oxalic acid, maleic acid, fumaric acid, glutamic acid, pyroglutamic acid, salicylic acid, salicylic acid, saccharin and sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid and benzenesulfonic acid.

[0061] 5. The prodrug according to any one of embodiments 1 to 4, which is selected from the group consisting of: (R)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazin-1-ium, (S)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazin-1-ium, (R)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazin-1-ium, (S)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazin-1-ium, (R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-methyl-1-((pivaloyloxy)methyl)piperazin-1-ium, (S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-methyl-1-((pivaloyloxy)methyl)piperazin-1-ium, (R)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)-1-((pivaloyloxy)methyl)piperazin-1-ium, (S)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)-1-((pivaloyloxy)methyl)piperazin-1-ium, (R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-1,2,2-trimethylpiperazin-1-ium, (S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-1,2,2-trimethylpiperazin-1-ium, (R)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-2,2-dimethyl-1-(methyl-d3)piperazin-1-ium, (S)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-2,2-dimethyl-1-(methyl-d3)piperazin-1-ium, (R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-1,2,2-trimethylpiperazin-1-ium, (S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-1,2,2-trimethylpiperazin-1-ium, (R)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-2,2-dimethyl-1-(methyl-d3)piperazin-1-ium, (S)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-2,2-dimethyl-1-(methyl-d3)piperazin-1-ium, each combined with a counterion selected from the group consisting of: halogen anions such as chloride, bromide or iodide; C1-C, 10 sulfonate, optionally fluorinated, such as mesylate, tosylate, triflate or nonafluorobutanesulfonate; and linear or branched C1-C 11 carboxylate, optionally fluorinated, such as trifluoroacetate; or a pharmaceutically acceptable salt thereof.

[0062] 6. A pharmaceutical composition comprising a prodrug according to any one of Examples 1 to 5 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0063] 7. A compound according to any one of Examples 1 to 5 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to Example 6 for use in therapy.

[0064] 8. Use of a compound according to any one of Examples 1 to 5 or a salt thereof or a pharmaceutical composition according to Example 6 for the manufacture of a medicament for the treatment of central nervous system (CNS) diseases.

[0065] 9. A compound according to any one of Examples 1 to 5 or a pharmaceutical composition according to Example 6 for use in a method for the treatment of CNS diseases.

[0066] 10. A method for the treatment of CNS diseases, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of Examples 1 to 5 or a pharmaceutical composition according to Example 6.

[0067] Examples

[0068] Compounds of the invention

[0069] The compounds of the present invention can be prepared from 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine (1) or 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine (2), both of which are described in the prior art discussed above:

[0070]

[0071] These compounds can be alkylated on the non-benzyl piperazine nitrogen atom either directly by treatment with an alkylating agent 3 or via an in-situ Finkelstein displacement of Y with a more reactive halogen (such as conversion from Y = Cl to Y = I by addition of sodium iodide or from Y = Cl to Y = Br by addition of tetra-n-butylammonium bromide or sodium bromide). Depending on whether 1 or 2 is used as the substrate, the reaction will provide a mixture of N-diastereomers 1a / 1b or 2a / 2b. These N-diastereomers can be separated by recrystallization and / or by chiral chromatography (using high performance liquid chromatography (HPLC), supercritical fluid chromatography (SFC), or simulated moving bed chromatography (SMB)). The anion Y can be exchanged with X using, for example, an ion exchange resin. Y can be selected from the same list as X defined above. The order of the last two operations can be reversed, and both steps can be carried out several times. The alkylating agent 3 is commercially available, such as 3b (catalog number QC-7757) from CombiBlocks, or can be prepared in a similar manner as described for 3a in the specification or as described in the literature (for sulfonates, see, for example, WO 2012 / 137225). - with X - exchange. Y - can be selected from the same list as X - defined above. The order of the last two operations can be reversed, and both steps can be carried out several times. The alkylating agent 3 is commercially available, such as 3b (catalog number QC-7757) from CombiBlocks, or can be prepared in a similar manner as described for 3a in the specification or as described in the literature (for sulfonates, see, for example, WO 2012 / 137225).

[0072] Method for preparing the prodrugs of the present invention.

[0073] For high performance liquid chromatography (HPLC), liquid chromatography / mass spectrometry (LC / MS), supercritical fluid chromatography (SFC), and ion exchange, the following methods are used.

[0074] Method 1: HPLC is performed on an Agela-HP-q-p600 instrument equipped with an Agela Innoval ods 250×80 mm column (10 micron particle size; column temperature 20 °C). Eluent: 0.05% aqueous HCl / acetonitrile 4:1 to 1:1, within 20 min, at a flow rate of 150 mL / min.

[0075] Method 2: LC / MS was performed on an Agilent 1200&1956A instrument equipped with a Phenomenex Luna C18(2) 50×2 mm column (5 μm particle size; column temperature 40 °C). Eluent: 0.037% trifluoroacetic acid in water / 0.018% trifluoroacetic acid in acetonitrile 1:0, for 0.8 min; 1:0 to 2:3, within 6.2 min; 2:3, for 3 min; 2:3 to 1:0, within 0.1 min, at a flow rate of 0.6 mL / min.

[0076] Method 3: HPLC was performed on an Agela-HP-q-p600 instrument equipped with a Phenomenex Luna C18 250×50 mm column (10 μm particle size; column temperature 20 °C). Eluent: 0.05% aqueous HCl / acetonitrile 4:1 to 1:1, within 20 min, at a flow rate of 80 mL / min.

[0077] Method 4: SFC was performed by stacked injection on a Thar SFC80 preparative instrument equipped with a Chiralpak AD-H 250×30 mm column (particle size 5 μm) operating at 40 °C. Eluent: CO2 / 0.1% trifluoroacetic acid in methanol 7:3, for 5 min, at a flow rate of 70 g / min. System back pressure 100 bar.

[0078] Method 5: SFC was performed on a TharAnalytical SFC instrument equipped with a Chiralpak AD-3 100×4.6 mm column (particle size 3 μm; column temperature 40 °C). Eluent: CO2 / 0.05% isopropylamine in methanol 95:5 to 3:2, within 5 min, at a flow rate of 4.0 mL / min. System back pressure 100 bar.

[0079] Method 6: SFC was performed as in Method 4, with a run time of 7 min.

[0080] Method 7: LC / MS was performed on an Agilent 1200&MS1956A instrument equipped with a Phenomenex Luna C18(2) 50×2 mm column (5 μm particle size; column temperature 40 °C). Eluent: 0.037% trifluoroacetic acid in water / 0.018% trifluoroacetic acid in acetonitrile 9:1, for 0.4 min; 9:1 to 0:1, within 3.0 min; 0:1, for 0.45 min; 0:1 to 9:1, within 0.01 min; 9:1, for 0.64 min, at a flow rate of 0.8 mL / min.

[0081] Method 8: Perform HPLC as in Method 3, but with an eluent gradient of 3:2 to 3:7 in 20 min.

[0082] Method 9: Perform SFC by stacked injection on a Thar SFC80 preparative instrument equipped with a Chiralpak AD-H 250×30 mm column (particle size 5 μm; column temperature 40 °C). Eluent: CO2 / 0.1% trifluoroacetic acid in methanol 4:1, for 6 min, at a flow rate of 70 g / min. System back pressure 100 bar.

[0083] Method 10: Perform SFC on a Waters Acquity UPC2 instrument equipped with a Chiralpak AD-3 150×4.6 mm column (particle size 3 μm; column temperature 35 °C). Eluent: CO2 / 0.05% isopropylamine in methanol 3:2, in 6 min or 10 min, at a flow rate of 2.5 mL / min. System back pressure 1500 psi.

[0084] Method 11: Perform ion exchange using an anion exchange resin in the chloride form (717; Domestic 10024160). Dissolve the sample in a 1:1 mixture of acetonitrile and water, and allow the solution to slowly pass through a column with the resin (using approximately six times the amount of resin as the sample). Add acetonitrile / water (1:1) until all the sample is eluted. Concentrate the combined product fractions in vacuo and lyophilize to provide the chloride salts of one or more compounds.

[0085] Method 12: Perform LC / MS on an Agilent 1200&MS1956A instrument equipped with a Phenomenex Luna C18(2) 50×2 mm column (5 μm particle size; column temperature 40 °C). Eluent: 0.037% trifluoroacetic acid in water / 0.018% trifluoroacetic acid in acetonitrile 99:1 to 1:9, in 3.4 min; 1:9 to 0:1, in 0.45 min; 0:1 to 99:1, in 0.01 min; 99:1, for 0.64 min, at a flow rate of 0.8 mL / min.

[0086] Method 13: Perform LC / MS on an Agilent 1200&MS1956A instrument equipped with a Phenomenex Luna C18(2) 50×2 mm column (5 μm particle size; column temperature 40 °C). Eluent: 0.037% trifluoroacetic acid in water / 0.018% trifluoroacetic acid in acetonitrile 3:2 to 0:1, in 3.4 min; 0:1, for 0.45 min; 0:1 to 3:2, in 0.01 min; 3:2, for 0.64 min, at a flow rate of 0.8 mL / min.

[0087] Method 14: LC / MS was performed on an Agilent 1200 & MS 6120 instrument equipped with a Phenomenex Luna C18(2) 50×2 mm column (5 μm particle size; column temperature 40 °C). Eluent: 0.037% trifluoroacetic acid in water / 0.018% trifluoroacetic acid in acetonitrile 3:1 to 0:1, within 3.4 min; 0:1, for 0.45 min; 0:1 to 3:1, within 0.01 min; 3:1, for 0.64 min, at a flow rate of 0.8 mL / min.

[0088] Method 15: LC / MS was performed on an Agilent 1200 & MS 6120B instrument equipped with a Phenomenex Luna C18(2) 50×2 mm column (5 μm particle size; column temperature 40 °C). Eluent: 0.037% trifluoroacetic acid in water / 0.018% trifluoroacetic acid in acetonitrile 9:1 to 1:4, within 4.0 min; 1:4, for 2.0 min; 1:4 to 9:1, within 0.01 min; 9:1, for 2.0 min, at a flow rate of 0.8 mL / min.

[0089] Method 16: SFC was performed as in Method 9, with a running time of 8 min.

[0090] Method 17: LC / MS was performed on an Agilent 1200 & MS1956A instrument equipped with a Phenomenex Luna C18(2) 50×2 mm column (5 μm particle size; column temperature 40 °C). Eluent: 0.037% trifluoroacetic acid in water / 0.018% trifluoroacetic acid in acetonitrile 1:0, for 0.8 min; 1:0 to 2:3, within 6.2 min; 2:3, for 3 min; 2:3 to 1:0, within 0.1 min, at a flow rate of 0.8 mL / min.

[0091] Method 18: Reverse-phase column chromatography was performed on a Biotage One instrument equipped with an Agela 40×10 cm (20 - 40 nM) C18 column at 25 °C. Eluent: water and 0.4% concentrated hydrochloric acid 7:3 to 3:7, within 30 min; 3:7, for 25 min; 0:1, for 10 min, at a flow rate of 120 mL / min.

[0092] Example 1: Preparation of iodomethyl acetate (alkylating agent 3a)

[0093]

[0094] Under darkness, chloroacetyl acetate (3a1; 20.0 g) was added dropwise to a mixture of NaI (29.0 g) and acetonitrile (140 mL) at 20 °C. The reaction was stirred at ambient temperature for 24 h. The resulting mixture was partitioned between methyl tert-butyl ether (MTBE; 160 mL) and water (200 mL), and the aqueous layer was extracted with MTBE (150 mL). The combined organic layers were washed successively with saturated aqueous sodium bicarbonate (200 mL), 10% aqueous sodium sulfite (200 mL), and saturated aqueous sodium chloride (100 mL), then dried over sodium sulfate, filtered, and concentrated to afford iodomethyl acetate (3a; 15.5 g), which was pure enough for the next step.

[0095] Example 2: Preparation of iodomethyl dodecanoate (alkylating agent 3c)

[0096]

[0097] Under an argon atmosphere at -10 °C, dodecanoyl chloride (3c2; 80.0 g) was slowly added to a mixture of paraformaldehyde (22.0 g) and zinc chloride (24.9 g) in acetonitrile (550 mL). The reaction mixture was stirred at this temperature for 1 h and at ambient temperature for 18 h. The crude reaction mixture was purified directly on silica gel by flash column chromatography (gradient eluent: petroleum ether / ethyl acetate 50 / 1 to 2 / 1) to afford chloromethyl dodecanoate (3c1; 45.4 g), which was pure enough for the next step. Under darkness at ambient temperature, compound 3c1 (45.0 g) was added dropwise to a mixture of sodium iodide (32.5 g) in acetonitrile (300 mL). The reaction was stirred at ambient temperature for 24 h. The crude mixture was partitioned between MTBE (300 mL) and water (300 mL), and the aqueous layer was extracted with MTBE (100 mL). The combined organic layers were washed successively with saturated aqueous sodium bicarbonate (200 mL), 10% aqueous sodium sulfite (150 mL), and saturated aqueous sodium chloride (150 mL), then dried over sodium sulfate, filtered, and concentrated to afford iodomethyl dodecanoate (3c; 51.0 g), which was pure enough for the next step.

[0098] Example 3: Preparation of iodomethyl 2-cyclohexylacetate (alkylating agent 3d)

[0099]

[0100] Thionyl chloride (69 mL) was added to a solution of 2-cyclohexylacetic acid (3d3; 44.8 g) in toluene (180 mL) under an argon atmosphere, and the mixture was stirred at 110 °C for 12 h. Volatiles were removed in vacuo to afford 2-cyclohexylacetyl chloride (3d2; 42.3 g), which was pure enough for the next step. 2-Cyclohexylacetyl chloride (3d2; 48.6 g - combined material from the previous step and another batch) was added to a solution of zinc chloride (20.6 g) and paraformaldehyde (18.2 g) in acetonitrile (336 mL) at -10 °C under an argon atmosphere. The reaction mixture was stirred at -10 °C for 1 h and then at ambient temperature for 18 h. Volatiles were removed in vacuo. The residue was purified directly on silica gel by flash column chromatography (gradient eluent: petroleum ether / ethyl acetate 1 / 0 to 0 / 1) to afford 2-cyclohexylchloromethyl acetate (3d1; 24.0 g), which was pure enough for the next step. Sodium iodide (18.1 g) in acetonitrile (126 mL) was added dropwise to 2-cyclohexylchloromethyl acetate (3d1; 21.9 g) at ambient temperature in the dark. The reaction was stirred at ambient temperature for 24 h. The crude mixture was partitioned between MTBE (200 mL) and water (200 mL), and the aqueous layer was extracted with MTBE (150 mL). The combined organic layers were washed successively with saturated aqueous sodium bicarbonate (200 mL), 10% aqueous sodium sulfite (200 mL), and saturated aqueous sodium chloride (100 mL), then dried over sodium sulfate, filtered, and concentrated to afford 2-cyclohexyliodomethyl acetate (3d; 27.0 g), which was pure enough for the next step.

[0101] Example 4: Preparation of acetoxymethyl 1a and 1b

[0102]

[0103] A solution of 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine (1; 6.0 g) in acetonitrile (42 mL) was heated to 80 °C, then iodoacetate (3a; 6.76 g) was added. The mixture was stirred at 80 °C for 1 h, then volatiles were removed in vacuo. The residual solid was suspended in MTBE (25 mL) and then filtered off. The filter cake was washed with MTBE (15 mL) and dried to afford approximately 8 g of (R)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazin-1-ium iodide (1a1; X = I -) and (S)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazin-1-ium iodide (1b1; X = I - ) The material was converted from the iodide salt to the corresponding chloride salt by ion exchange (Method 11) to afford the following crude chloride salts: 1a1; X = Cl - and 1b1; X = Cl - . The material was purified by preparative HPLC (Method 1) to give a mixture of (R)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazin-1-ium chloride and (S)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazin-1-ium chloride (1a1; X = Cl - and 1b1; X = Cl - ; 3 g).

[0104] 1 H NMR: 400 MHz methanol-d4 7.56 (broad s, 1H), 7.29 (t, J = 7.2 Hz, 3H), 7.25 - 7.18 (m, 1H), 7.14 - 7.09 (m, 2H), 6.96 (d, J = 7.9 Hz, 1H), 5.50 (broad s, 1H), 5.44 - 5.33 (m, 1H), 4.72 (broad s, 1H), 4.60 - 4.48 (m, 1H), 3.78 (broad d, J = 5.7 Hz, 1H), 3.66 (broad s, 1H), 3.19 - 2.81 (m, 8H), 2.26 (s, 4H), 1.71 - 1.57 (m, 6H).

[0105] LC / MS (Method 17): retention time 6.60 min, 86.5% UV purity (220 nm), m / z mass observed 427.1.

[0106] Example 5: Preparation of acetoxymethyl 2a and 2b

[0107]

[0108] (R)-1-(Acetoxymethyl)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazin-1-ium iodide and (S)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazin-1-ium iodide (2a1; X = I - and 2b1; X = I - ) and a mixture of (R)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazin-1-ium chloride and (S)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazin-1-ium chloride (2a1; X = Cl - and 2b1; X = Cl - ) were prepared in a manner similar to 1a1 and 1b1. The synthesis started from 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine (2; 6.50 g) and iodomethyl acetate (3a; 7.16 g) in acetonitrile (45.0 mL) to afford approximately 8 g of crude iodide and 2.00 g of a mixture of (R)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazin-1-ium chloride and (S)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazin-1-ium chloride (2a1; X = Cl - and 2b1; X = Cl - ) purified by HPLC (Method 1).

[0109] 11H NMR: 400 MHz, methanol-d4, 7.61 - 7.54 (m, 1H), 7.34 - 7.28 (m, 1H), 6.96 (d, J = 8.3 Hz, 1H), 5.51 (broad d, J = 12.7 Hz, 1H), 5.47 - 5.35 (m, 1H), 4.74 (broad s, 1H), 4.56 (broad s, 1H), 3.77 (broad s, 1H), 3.68 (broad s, 1H), 3.27 - 2.78 (m, 5H), 2.26 (d, J = 0.9 Hz, 4H), 1.73 - 1.58 (m, 6H).

[0110] LC / MS (Method 17): retention time 6.56 min, 93.5% UV purity (220 nm), m / z mass observed 435.2.

[0111] Example 6: Preparation of Pivaloyloxymethyl 1a and 1b

[0112]

[0113] (R)-4-((1R,3S)-6-Chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethyl-1-((pivaloyloxy)methyl)piperazin-1-ium iodide and (S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethyl-1-((pivaloyloxy)methyl)piperazin-1-ium iodide (1a2; X = I - and 1b2; X = I - ) and (R)-4-((1R,3S)-6-Chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethyl-1-((pivaloyloxy)methyl)piperazin-1-ium chloride and (S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethyl-1-((pivaloyloxy)methyl)piperazin-1-ium chloride (1a2; X = Cl - and 1b2; X = Cl -) mixture. The synthesis starts from 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine (1; 4.6 g) and iodomethyl pivalate (3b; 6.27 g) in acetonitrile (32 mL) to give approximately 5 g of crude iodide and approximately 4 g of (R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-methyl-1-((pivaloyloxy)methyl)piperazin-1-ium chloride and (S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-methyl-1-((pivaloyloxy)methyl)piperazin-1-ium chloride (1a2; X = Cl - and 1b2; X = Cl - ) mixture purified by HPLC (Method 3). The mixture was separated by chiral SFC (Method 4). The two products were purified as previously using Methods 11 and 3 to give two products:

[0114] First eluted isomer: 1.00 g of (R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethyl-1-((pivaloyloxy)methyl)piperazin-1-ium chloride (1a2; X = Cl - ) or (S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethyl-1-((pivaloyloxy)methyl)piperazin-1-ium chloride (1b2; X = Cl - ).

[0115] 1 1H NMR: 400 MHz, methanol-d4 7.71 (broad s., 1H), 7.39 - 7.27 (m, 3H), 7.26 - 7.19 (m, 1H), 7.18 - 7.10 (m, 2H), 6.97 (d, J = 8.4 Hz, 1H), 5.70 - 5.57 (m, 1H), 5.52 (d, J = 8.8 Hz, 1H), 4.93 (broad s., 1H), 4.69 (t, J = 7.6 Hz, 1H), 3.85 (broad s., 2H), 3.50 - 3.31 (m, 4H), 3.16 (s, 3H), 3.05 - 2.92 (m, 1H), 2.42 - 2.28 (m, 1H), 1.71 (broad s., 6H), 1.31 (s, 9H).

[0116] LC / MS (Method 12): retention time 3.12 min, 98.5% UV purity (220 nm), m / z mass observed 469.2.

[0117] SFC (Method 5): retention time 1.91 min, >99% UV purity (220 nm).

[0118] Second eluted isomer: 0.80 g of (S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethyl-1-((pivaloyloxy)methyl)piperazin-1-ium chloride (1b2; X = Cl - ) or (R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethyl-1-((pivaloyloxy)methyl)piperazin-1-ium chloride (1a2; X = Cl - ).

[0119] 1 1H NMR: 400 MHz, methanol-d4 7.69 (broad s., 1H), 7.37 - 7.26 (m, 3H), 7.26 - 7.18 (m, 1H), 7.14 (d, J = 7.2 Hz, 2H), 6.96 (d, J = 8.4 Hz, 1H), 5.58 - 5.40 (m, 2H), 4.90 (broad s., 1H), 4.65 (broad s., 1H), 3.94 (broad s., 1H), 3.70 (d, J = 14.0 Hz, 1H), 3.36 (broad s., 3H), 3.22 (broad s., 3H), 3.16 - 2.90 (m, 2H), 2.39 - 2.25 (m, 1H), 1.79 - 1.56 (m, 6H), 1.31 (s, 9H).

[0120] LC / MS (Method 7): retention time 2.72 min, 97% UV purity (220 nm), m / z mass observed 469.2.

[0121] SFC (Method 5): retention time 2.36 min, >96% UV purity (220 nm).

[0122] Example 7: Preparation of pivaloyloxymethyl 2a and 2b

[0123]

[0124] (R)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)-1-((pivaloyloxy)methyl)piperazin-1-ium iodide and (S)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)-1-((pivaloyloxy)methyl)piperazin-1-ium iodide (2a2; X = I - and 2b2; X = I - ) and a mixture of (R)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)-1-((pivaloyloxy)methyl)piperazin-1-ium chloride and (S)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)-1-((pivaloyloxy)methyl)piperazin-1-ium chloride (2a2; X = Cl - and 2b2; X = Cl - ). The synthesis starts from 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine (2; 6.00 g) and iodomethyl pivalate (3b; 8.00 g) in acetonitrile (42 mL) to give approximately 5 g of the crude iodide and approximately 4 g of a mixture of (R)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)-1-((pivaloyloxy)methyl)piperazin-1-ium chloride and (S)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)-1-((pivaloyloxy)methyl)piperazin-1-ium chloride (2a2; X = Cl - and 2b2; X = Cl - ). The mixture was separated by chiral SFC (method 6). The two products were purified as previously using methods 11 and 3 to give two products:

[0125] First eluted isomer: 1.00 g of (R)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)-1-((pivaloyloxy)methyl)piperazin-1-ium chloride (2a2; X = Cl -) or (S)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)-1-((pivaloyloxy)methyl)piperazin-1-ium chloride (2b2; X = Cl - ).

[0126] 1 H NMR: 400 MHz, methanol-d4: 7.71 (broad s, 1H), 7.36 (dd, J = 2.0, 8.1 Hz, 1H), 6.97 (d, J = 7.9 Hz, 1H), 5.61 (broad s, 1H), 5.52 (d, J = 8.8 Hz, 1H), 5.00 - 4.89 (m, 1H), 4.68 (s, 1H), 3.85 (broad s, 2H), 3.54 - 3.31 (m, 3H), 3.28 - 3.16 (m, 1H), 2.99 (broad dd, J = 10.3, 13.8 Hz, 1H), 2.43 - 2.28 (m, 1H), 1.71 (broad s, 6H), 1.32 (s, 9H).

[0127] LC / MS (method 7): retention time 2.72 min, 98.9% UV purity (220 nm), m / z mass observed 477.3

[0128] SFC (method 5): retention time 1.79 min, >99% UV purity (220 nm).

[0129] Second eluting isomer: 0.72 g of (S)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)-1-((pivaloyloxy)methyl)piperazin-1-ium chloride (2b2; X = Cl - ) or (R)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)-1-((pivaloyloxy)methyl)piperazin-1-ium chloride (2a2; X = Cl - ).

[0130] 11H NMR: 400 MHz in methanol-d4: 7.44 (d, J = 2.2 Hz, 1H), 7.25 (dd, J = 2.0, 8.1 Hz, 1H), 6.94 (d, J = 8.3 Hz, 1H), 5.52 - 5.45 (m, 1H), 5.45 - 5.39 (m, 1H), 4.58 (dd, J = 3.9, 7.9 Hz, 1H), 4.46 (t, J = 7.7 Hz, 1H), 3.74 (broad s, 1H), 3.53 (broad d, J = 12.7 Hz, 1H), 3.09 - 2.74 (m, 4H), 2.63 (broad s, 1H), 2.21 - 2.04 (m, 1H), 1.69 - 1.48 (m, 6H), 1.38 - 1.24 (m, 9H).

[0131] LC / MS (Method 7): retention time 2.72 min, 97.6% UV purity (220 nm), m / z mass observed 477.3.

[0132] SFC (Method 5): retention time 2.1 min, >97% UV purity (220 nm).

[0133] Example 8: Preparation of Dodecanoyloxymethyl 1a and 1b

[0134]

[0135] (R)-4-((1R,3S)-6-Chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-1,2,2-trimethylpiperazin-1-ium iodide and (S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-1,2,2-trimethylpiperazin-1-ium iodide (1a3; X = I - and 1b3; X = I - ) and (R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-1,2,2-trimethylpiperazin-1-ium chloride and (S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-1,2,2-trimethylpiperazin-1-ium chloride (1a3; X = Cl - and 1b3; X = Cl -) mixture. The synthesis started from 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine (1; 7.00 g) and iodomethyl laurate (3c; 16.8 g) in acetonitrile (49 mL) to afford approximately 5.5 g of the crude iodide. The material was purified by reverse-phase column chromatography (Method 18), followed by ion exchange (Method 11) to afford 3.2 g of (R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-1,2,2-trimethylpiperazin-1-ium chloride and (S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-1,2,2-trimethylpiperazin-1-ium chloride (1a3; X = Cl - and 1b3; X = Cl - ) mixture.

[0136] 1 H NMR: 400 MHz methanol-d4 7.45 (s, 1H), 7.31 - 7.23 (m, 3H), 7.23 - 7.17 (m, 1H), 7.13 - 7.07 (m, 2H), 6.94 (d, J = 8.3 Hz, 1H), 5.52 (broad s, 1H), 5.40 (dd, J = 3.9, 8.8 Hz, 1H), 4.64 - 4.55 (m, 1H), 4.47 (broad t, J = 7.2 Hz, 1H), 3.81 - 3.64 (m, 1H), 3.56 (broad d, J = 14.5 Hz, 1H), 3.11 (d, J = 7.5 Hz, 3H), 3.04 - 2.91 (m, 2H), 2.86 - 2.75 (m, 2H), 2.57 (dt, J = 1.8, 7.5 Hz, 2H), 2.19 - 2.06 (m, 1H), 1.71 - 1.56 (m, 8H), 1.29 (broad s, 17H), 0.93 - 0.84 (m, 3H).

[0137] LC / MS (Method 13): retention time 2.66 min, 99.3% UV purity (220 nm), m / z mass observed 567.3.

[0138] Example 9: Preparation of dodecanoyloxymethyl 2a and 2b

[0139]

[0140] (R)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-2,2-dimethyl-1-(methyl-d3)piperazin-1-ium iodide and (S)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-2,2-dimethyl-1-(methyl-d3)piperazin-1-ium iodide (2a3; X = I - and 2b3; X = I - ) and a mixture of (R)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-2,2-dimethyl-1-(methyl-d3)piperazin-1-ium chloride and (S)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-2,2-dimethyl-1-(methyl-d3)piperazin-1-ium chloride (2a3; X = Cl - and 2b3; X = Cl - ) were prepared in a manner similar to 1a3 and 1b3. The synthesis began with 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine (2; 5.60 g) and iodomethyl laurate (3c; 10.5 g) in acetonitrile (39 mL) to afford approximately 5 g of the crude iodide and 3.1 g of a mixture of (R)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-2,2-dimethyl-1-(methyl-d3)piperazin-1-ium chloride and (S)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-2,2-dimethyl-1-(methyl-d3)piperazin-1-ium chloride (2a3; X = Cl - and 2b3; X = Cl - ).

[0141] 11H NMR: 400 MHz, methanol-d4, 7.49 (broad s, 1H), 7.27 (d, J = 8.3 Hz, 1H), 6.94 (d, J = 8.3 Hz, 1H), 5.52 (broad s, 1H), 5.46 - 5.36 (m, 1H), 4.69 - 4.58 (m, 1H), 4.50 (broad t, J = 7.5 Hz, 1H), 3.86 - 3.66 (m, 1H), 3.61 (broad s, 1H), 3.16 - 2.79 (m, 4H), 2.57 (dt, J = 1.3, 7.5 Hz, 2H), 2.23 - 2.07 (m, 1H), 1.76 - 1.51 (m, 8H), 1.47 - 1.19 (m, 17H), 0.95 - 0.83 (m, 3H).

[0142] LC / MS (Method 13): retention time 2.68 min, 98.9% UV purity (220 nm), m / z mass observed 575.4.

[0143] Example 10: Preparation of cyclohexylacetoxymethyl 1a and 1b

[0144]

[0145] (R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-1,2,2-trimethylpiperazin-1-ium iodide and (S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-1,2,2-trimethylpiperazin-1-ium iodide (1a4; X = I - and 1b4; X = I - ) and (R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-1,2,2-trimethylpiperazin-1-ium chloride and (S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-1,2,2-trimethylpiperazin-1-ium chloride (1a4; X = Cl - and 1b4; X = Cl -) mixture. The synthesis started from 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine (1, 6.00 g) and iodomethyl 2-cyclohexylacetate (3d; 11.9 g) in acetonitrile (42 mL) to give approximately 8 g of crude iodide and 3.2 g of a mixture of (R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-1,2,2-trimethylpiperazin-1-ium chloride and (S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-1,2,2-trimethylpiperazin-1-ium chloride (1a4; X = Cl - and 1b4; X = Cl - ) HPLC-purified mixture (Method 8). The mixture was separated by chiral SFC (Method 9). The two products were purified as before using Methods 11 and 8 to give two products:

[0146] First eluting isomer: 1.00 g of (R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-1,2,2-trimethylpiperazin-1-ium chloride (1a4; X = Cl - ) or (S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-1,2,2-trimethylpiperazin-1-ium chloride (1b4; X = Cl - ).

[0147] 1 1H NMR: 400 MHz, methanol-d4 7.57 (broad s, 1H), 7.32 - 7.26 (m, 3H), 7.25 - 7.19 (m, 1H), 7.15 - 7.09 (m, 2H), 6.95 (d, J = 8.3 Hz, 1H), 5.56 (broad s, 1H), 5.45 (d, J = 8.8 Hz, 1H), 4.74 (broad s, 1H), 4.57 (broad t, J = 7.5 Hz, 1H), 3.84 - 3.60 (m, 2H), 3.27 - 2.77 (m, 8H), 2.46 (d, J = 7.0 Hz, 2H), 2.23 (td, J = 7.2, 14.5 Hz, 1H), 1.99 - 1.47 (m, 12H), 1.39 - 1.13 (m, 3H), 1.12 - 0.96 (m, 2H)

[0148] LC / MS (Method 14): retention time 2.85 min, 97.4% UV purity (220 nm), m / z mass observed 509.3.

[0149] SFC (Method 10): retention time 2.45 min, >99% UV purity (220 nm).

[0150] Second eluting isomer: 0.33 g of (S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-1,2,2-trimethylpiperazin-1-ium chloride (1b4; X = Cl - ) or (R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-1,2,2-trimethylpiperazin-1-ium chloride (1a4; X = Cl - ).

[0151] 1 H NMR: 400 MHz in methanol-d4 7.51 (s, 1H), 7.33 - 7.26 (m, 3H), 7.25 - 7.19 (m, 1H), 7.14 - 7.09 (m, 2H), 6.96 (d, J = 8.8 Hz, 1H), 5.56 - 5.47 (m, 1H), 5.46 - 5.39 (m, 1H), 4.72 - 4.64 (m, 1H), 4.52 (broad t, J = 7.7 Hz, 1H), 3.79 (broad s, 1H), 3.62 (broad s, 1H), 3.21 - 2.77 (m, 8H), 2.46 (d, J = 6.8 Hz, 2H), 2.26 - 2.12 (m, 1H), 1.85 - 1.55 (m, 12H), 1.43 - 1.16 (m, 3H), 1.12 - 0.97 (m, 2H).

[0152] LC / MS (Method 15): retention time 3.66 min, 97.7% UV purity (220 nm), m / z mass observed 509.2.

[0153] SFC (Method 10): retention time 6.41 min, >97% UV purity (220 nm).

[0154] Example 11: Preparation of cyclohexylacetoxymethyl 2a and 2b

[0155]

[0156] (R)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-2,2-dimethyl-1-(methyl-d3)piperazin-1-ium iodide and (S)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-2,2-dimethyl-1-(methyl-d3)piperazin-1-ium iodide (2a4; X = I - and 2b4; X = I - ) and a mixture of (R)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-2,2-dimethyl-1-(methyl-d3)piperazin-1-ium chloride and (S)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-2,2-dimethyl-1-(methyl-d3)piperazin-1-ium chloride (2a4; X = Cl - and 2b4; X = Cl - ). The synthesis started from 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine (2; 6.00 g) and iodomethyl 2-cyclohexylacetate (3d; 11.7 g) in acetonitrile (42 mL) to afford approximately 7.8 g of the crude iodide and 6 g of a mixture of (R)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-2,2-dimethyl-1-(methyl-d3)piperazin-1-ium chloride and (S)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-2,2-dimethyl-1-(methyl-d3)piperazin-1-ium chloride (2a4; X = Cl - and 2b4; X = Cl - ) purified by HPLC (Method 8). The mixture was separated by chiral SFC (Method 16). The two products were purified as before using Methods 11 and 8 to afford the two products:

[0157] First eluted isomer: 1.10 g of (R)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-2,2-dimethyl-1-(methyl-d3)piperazin-1-ium chloride (2a4; X = Cl - ) or (S)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-2,2-dimethyl-1-(methyl-d3)piperazin-1-ium chloride (2b4; X = Cl - ).

[0158] 1 H NMR: 400 MHz methanol-d4 7.50 (broad s, 1H), 7.30 (broad d, J = 8.2 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 5.54 (broad s, 1H), 5.49 - 5.41 (m, 1H), 4.66 (broad s, 1H), 4.58 - 4.48 (m, 1H), 3.73 (broad s, 1H), 3.62 (broad s, 1H), 3.21 - 2.74 (m, 5H), 2.47 (d, J = 6.8 Hz, 2H), 2.26 - 2.12 (m, 1H), 1.92 - 1.57 (m, 12H), 1.38 - 1.17 (m, 3H), 1.14 - 0.98 (m, 2H).

[0159] LC / MS (method 14): retention time 2.68 min, 96.6% UV purity (220 nm), m / z mass observed 517.2.

[0160] SFC (method 10): retention time 2.33 min, >97% UV purity (220 nm).

[0161] Second eluted isomer: 1.10 g of (S)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-2,2-dimethyl-1-(methyl-d3)piperazin-1-ium chloride (2b4; X = Cl - ) or (R)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-2,2-dimethyl-1-(methyl-d3)piperazin-1-ium chloride (2a4; X = Cl - ).

[0162] 11H NMR: 400 MHz, methanol-d4, 7.48 (broad s, 1H), 7.28 (d, J = 8.2 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 5.49 (broad s, 1H), 5.44 - 5.38 (m, 1H), 4.64 (broad d, J = 4.0 Hz, 1H), 4.49 (broad s, 1H), 3.83 - 3.70 (m, 1H), 3.58 (broad d, J = 13.2 Hz, 1H), 3.16 - 2.63 (m, 5H), 2.45 (d, J = 6.8 Hz, 2H), 2.16 (broad dd, J = 6.9, 10.7 Hz, 1H), 1.91 - 1.51 (m, 12H), 1.43 - 1.16 (m, 3H), 1.13 - 0.95 (m, 2H).

[0163] LC / MS (Method 7): retention time 2.99 min, 99.4% UV purity (220 nm), m / z mass observed 517.3.

[0164] SFC (Method 10): retention time 4.87 min, >97% UV purity (220 nm).

[0165] Example 12: Plasma Stability Determination

[0166] Thawed frozen human plasma (stored at -80 °C) in a water bath and then centrifuged at 3200 × g for 5 min to remove debris. The pH of the supernatant was then measured and adjusted to 7.4 ± 0.1 by adding 1% phosphoric acid or 1 N sodium hydroxide.

[0167] For each test compound, 2 μL of the dosing solution (50 μM for the test compound and 100 μM for the positive control; propantheline bromide) was spiked into 98 μL of blank plasma to achieve a final concentration of 1 μM test compound and 2 μM positive control.

[0168] The test compound and positive control were incubated in duplicate with human plasma in a water bath at 37 °C at 6 different time points (0 h, 0.5 h, 1 h, 2 h, 4 h, and 6 h) (final DMSO concentration < 1%). At each corresponding time point, the incubation was terminated by adding an appropriate volume of quenching solution to stop the reaction.

[0169] Then, the plasma sample was vortexed briefly and then centrifuged at 3200×g for 20 min. The supernatant was transferred to a 96-well plate and diluted at a ratio of 1:2 with 200 μL of ultrapure water before LC-MS / MS analysis. The peak area ratio (PAR) of the analyte / internal standard was used to semi-quantitatively determine the concentrations of the test compound and the control compound. The percentage of the remaining test compound relative to the 0-minute sample was reported at each time point.

[0170] When determining the in vitro elimination constant (ke) of the parent drug and the control, the analyte / internal standard peak area ratio was converted to the remaining percentage using the following formula:

[0171]

[0172] The percentage of metabolite formation was calculated from the analyte / internal standard peak area ratio of the metabolite drug relative to T0 (absolute) and converted to a percentage.

[0173] The half-lives (T1 / 2) (T1 / 2 = 0.693 / ke) of the parent drug and the control compound were calculated from the log-linear plot of the analyte / internal standard peak area ratio against time.

[0174] Compounds 1a2, 1b2, 2a2, and 2b2 were incubated in human plasma as described above, and the half-lives were determined to be 0.5 - 1.5 h by the formation of 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine and 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine, which were formed at 15% - 35% respectively.

Claims

1. A prodrug of 4 - ((1R,3S) - 6 - chloro - 3 - phenyl - 2,3 - dihydro - 1H - inden - 1 - yl) - 1,2,2 - trimethylpiperazine in the form of 1a or 1b or 4 - ((1R,3S) - 6 - chloro - 3 - (phenyl - d5) - 2,3 - dihydro - 1H - inden - 1 - yl) - 2,2 - dimethyl - 1 - (methyl - d3)piperazine in the form of 2a and 2b wherein X - is a counterion selected from the group consisting of: chloride anion, bromide anion or iodide anion; and wherein R is a straight - chain or branched C1 - C 11 alkyl; or a pharmaceutically acceptable salt thereof.

2. The prodrug according to claim 1, wherein, R is selected from methyl or tert-butyl, or a pharmaceutically acceptable salt thereof.

3. The prodrug according to claim 1 or 2, wherein, The pharmaceutically acceptable salts are selected from the group consisting of salts formed by the following: hydrochloric acid, hydrobromic acid, phosphoric acid, nitrous acid, sulfuric acid, benzoic acid, citric acid, gluconic acid, lactic acid, succinic acid, tartaric acid, acetic acid, propionic acid, oxalic acid, maleic acid, fumaric acid, glutamic acid, pyroglutamic acid, salicylic acid, saccharin, and sulfonic acid.

4. The prodrug according to claim 3, wherein, The sulfonic acid is selected from methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, and benzenesulfonic acid.

5. The prodrug according to claim 1, selected from the group consisting of: (R) - 4 - ((1R,3S) - 6 - chloro - 3 - phenyl - 2,3 - dihydro - 1H - inden - 1 - yl) - 2,2 - dimethyl - 1 - methyl - 1 - ((pivaloyloxy)methyl)piperazin - 1 - ium, (S) - 4 - ((1R,3S) - 6 - chloro - 3 - phenyl - 2,3 - dihydro - 1H - inden - 1 - yl) - 2,2 - dimethyl - 1 - methyl - 1 - ((pivaloyloxy)methyl)piperazin - 1 - ium, (R) - 4 - ((1R,3S) - 6 - chloro - 3 - (phenyl - d5) - 2,3 - dihydro - 1H - inden - 1 - yl) - 2,2 - dimethyl - 1 - (methyl - d3) - 1 - ((pivaloyloxy)methyl)piperazin - 1 - ium, (S) - 4 - ((1R,3S) - 6 - chloro - 3 - (phenyl - d5) - 2,3 - dihydro - 1H - inden - 1 - yl) - 2,2 - dimethyl - 1 - (methyl - d3) - 1 - ((pivaloyloxy)methyl)piperazin - 1 - ium, each of which is combined with a counterion selected from the group consisting of: chloride anion, bromide anion or iodide anion; or a pharmaceutically acceptable salt thereof.

6. The prodrug according to claim 1, selected from: (R) - 4 - ((1R,3S) - 6 - chloro - 3 - phenyl - 2,3 - dihydro - 1H - inden - 1 - yl) - 2,2 - dimethyl - 1 - methyl - 1 - ((pivaloyloxy)methyl)piperazin - 1 - ium chloride, (S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-methyl-1-((pivaloyloxy)methyl)piperazin-1-ium chloride, (R)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)-1-((pivaloyloxy)methyl)piperazin-1-ium chloride, (S)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)-1-((pivaloyloxy)methyl)piperazin-1-ium chloride; or a pharmaceutically acceptable salt thereof.

7. The prodrug according to claim 1, wherein The prodrug is (R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-methyl-1-((pivaloyloxy)methyl)piperazin-1-ium chloride.

8. The prodrug according to claim 1, wherein The prodrug is (S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-methyl-1-((pivaloyloxy)methyl)piperazin-1-ium chloride.

9. The prodrug according to claim 1, wherein The prodrug is (R)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)-1-((pivaloyloxy)methyl)piperazin-1-ium chloride.

10. The prodrug according to claim 1, wherein The prodrug is (S)-4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)-1-((pivaloyloxy)methyl)piperazin-1-ium chloride.

11. A pharmaceutical composition comprising the prodrug according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

12. Use of the prodrug according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 11 for the manufacture of a medicament for the treatment of central nervous system (CNS) diseases.

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