WS635 Drug Use

Abstract

The present invention relates to the use of a compound of formula (I) or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharma- ceutically acceptable salt, or prodrug thereof, in the manufacture of a medicament or a pharmaceutical composition for preventing, treating, or alleviating POD. [Formula 1] TIFF2024511111000009.tif67170

Description

[Technical field]

[0001] The present invention belongs to the field of medicine. Specifically, the present invention relates to (3S,6S,9S,12R,15S,18S,21S,24S,27R,30S,33S)-27-((2-(dimethylamino)ethyl)thio)-30-ethyl-33-((1R,2R,E)-1-hydroxy-2-methylhexyl-4-en-1-yl)-24-(2-hydroxy-2-methylpropyl)-6,9,18-triisobutyl-3,21-diisopropyl-1-methyl-2-propenyl ... The present invention relates to the use of 1,4,7,10,12,15,19,25,28-nonamethyl-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecaone (I) (WS635) and pharmaceutical compositions thereof in the manufacture of a medicament for preventing, controlling, treating or alleviating post-operative delirium (POD) in a patient. [Background technology]

[0002] WS635 (compound of formula (I)) is a novel, non-immunosuppressive, cyclosporine-based analogue that exhibits potent inhibition of Hepatitis C Virus (HCV) replication in vitro. WS635 inhibited peptidyl prolyl isomerase activity of cyclophilic protein A at nanomolar concentrations, but showed no detectable inhibition of calcineurin activity at concentrations as high as 2 μM. Metabolic studies indicate that WS635 does not induce the major cytochrome P450 enzymes 1A2, 2B6, and 3A4. WS635 is shown to be a weak inhibitor of P-glycoprotein and a weak matrix metalloproteinase. Functional assays using stimulated Jurkat cells and stimulated human peripheral blood mononuclear cells indicate that WS635 is a weaker inhibitor of interleukin-2 secretion than cyclosporine. A series of two-drug combination studies in vitro are performed. WS635 exhibits synergistic antiviral activity with alpha interferon 2b and synergistic antiviral activity with ribavirin. WS635 has proven to be orally bioavailable in many animal species, and blood and liver concentrations of the produced prototype drug exceed 50% of the effective dose as determined by bis-cisthrombin con1b-derived replicator assays. These results indicate that WS635 warrants further investigation as a novel therapeutic agent for treating chronic HCV-infected individuals.

[0003] Each year, more than 312 million patients undergo surgery under anaesthesia worldwide. Postoperative delirium (POD) is one of the most common postoperative complications in geriatric patients. It has an independent and adverse impact on long-term morbidity, mortality, health care costs and quality of life. Summary of the Invention [Problem to be solved by the invention]

[0004] The present invention will be described in brief, but not limited to, some aspects. These and other aspects will be described more fully. All references herein are incorporated by reference in their entirety into this application. If there is any distinction between the contents of this specification and the cited references, the contents of this specification shall prevail.

[0005] During the course of research and development, the inventors unexpectedly discovered that WS635 can significantly alleviate anesthesia / surgery (1.4% isoflurane and abdominal surgery)-induced cognitive impairment in mice. The inventors will further explore whether WS635 can be used to treat post-operative delirium (POD). [Means for solving the problem]

[0006] Specifically, in one aspect, the present invention provides a compound having formula (I) or a stereoisomer, tautomer, N-oxide, solvate thereof: ,medicine Scientifically acceptable Salt , in the manufacture of a drug or drug composition for preventing, treating or alleviating post-operative delirium (POD). [ka]

[0007] In the course of research and development, the inventors unexpectedly found that WS635 can attenuate anesthesia / surgery-induced changes in buried food test in a dose-dependent manner.The inventors were also surprised to find that WS635 can attenuate anesthesia / surgery-induced changes in open field test and attenuate anesthesia / surgery-induced changes in Y-maze test.According to the examples of the present application, the compound of formula (I) can attenuate anesthesia / surgery-induced delirium-like behavioral changes in mice, and has surprisingly good potential in preventing, treating or alleviating POD.

[0008] In one embodiment, the pharmaceutical composition further comprises a pharma- ceutically acceptable carrier, excipient, adjuvant, or a combination thereof.

[0009] In one embodiment, the pharmaceutical composition further comprises another agent for preventing, treating or alleviating cognitive impairment.

[0010] In one embodiment, the compound is administered in a daily dosage of less than about 900 mg.

[0011] In one embodiment, the compound is administered in a daily dosage of between about 10 mg and about 900 mg.

[0012] In one embodiment, the compound is administered in a daily dosage of about 50 mg to about 600 mg.

[0013] In one embodiment, the compound is administered once daily.

[0014] In one embodiment, the compound is administered once daily as a single dose.

[0015] In one embodiment, the compound is administered by a route selected from the group consisting of oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, liposomal, inhalation, vaginal, intraocular, topical delivery, subcutaneous, intraadipose, intraarticular, intraperitoneal, and intrathecal.

[0016] In one embodiment, the compound is administered orally or intravenously.

[0017] In one embodiment, the compound is administered in the form of a tablet, capsule, or injectable.

[0018] In another aspect, the present application provides a method for preventing, treating or alleviating POD in a patient, comprising administering to the patient a therapeutically effective amount of a compound having formula (I) or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharma- ceutically acceptable salt or prodrug thereof. As described above, the compound of formula (I) can attenuate anesthesia / surgery-induced delirium-like behavioral changes, and has surprisingly good results in preventing, treating or alleviating POD. According to the examples of the present application, the method can effectively prevent, treat or alleviate POD in a patient. [ka]

[0019] In one embodiment, the therapeutically effective amount in mice is 40 mg / kg. The inventors discovered that 40 mg / kg WS635 treatment can effectively attenuate anesthesia / surgery-induced delirium-like behavioral changes in mice.

[0020] In one embodiment, the therapeutically effective amount in the human body is 4.4 mg / kg.

[0021] In one embodiment, the compound is administered to the subject within one hour prior to surgery.

[0022] In one embodiment, the compound is administered to the subject within 0.5 hours prior to surgery.

[0023] In one embodiment, the compound is administered in a daily dosage of less than about 900 mg.

[0024] In one embodiment, the compound is administered in a daily dosage of between about 10 mg and about 900 mg.

[0025] In one embodiment, the compound is administered in a daily dosage of about 50 mg to about 600 mg.

[0026] In one embodiment, the compound is administered once daily.

[0027] In one embodiment, the compound is administered once daily as a single dose.

[0028] In one embodiment, the compound is administered by a route selected from the group consisting of oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, liposomal, inhalation, vaginal, intraocular, topical delivery, subcutaneous, intraadipose, intraarticular, intraperitoneal, and intrathecal.

[0029] In one embodiment, the compound is administered orally, intravenously, or intraperitoneally.

[0030] In one embodiment, the compound is administered in the form of a tablet, capsule, or injectable.

[0031] In one embodiment, the compound is administered in combination with one or more other agents, other than the compound of Formula I, for preventing, treating or alleviating cognitive impairment.

[0032] In another aspect, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharma- ceutically acceptable salt, or prodrug thereof, for use in treating, preventing, or alleviating post-operative delirium (POD).

[0033] In one embodiment, the composition is prepared in a unit dosage form.

[0034] In one embodiment, the composition is prepared in a single dosage form, the single dosage form containing less than 900 mg of Compound I.

[0035] In one embodiment, such single dosage further comprises one or more other agents other than the compound of Formula I for preventing, treating or alleviating cognitive impairment.

[0036] In another aspect, the present application provides a compound of formula I, or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharma- ceutically acceptable salt, or prodrug thereof, for use in treating, preventing, or alleviating post-operative delirium (POD) in a subject in need thereof. [ka]

[0037] In one embodiment, the compound is administered to the subject within 0.5 hours prior to surgery.

[0038] In one embodiment, the compound is administered in a daily dosage of less than about 900 mg.

[0039] In one embodiment, the compound is administered in a daily dosage of between about 10 mg and about 900 mg.

[0040] In one embodiment, the compound is administered in a daily dosage of about 50 mg to about 600 mg.

[0041] In one embodiment, the compound is administered once daily.

[0042] In one embodiment, the compound is administered once daily as a single dose.

[0043] In one embodiment, the compound is administered by a route selected from the group consisting of oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, liposomal, inhalation, vaginal, intraocular, topical delivery, subcutaneous, intraadipose, intraarticular, intraperitoneal, and intrathecal.

[0044] In one embodiment, the compound is administered orally or intravenously.

[0045] In one embodiment, the compound is administered in the form of a tablet, capsule, or injectable.

[0046] In one embodiment, the compound is administered in combination with one or more other agents, other than the compound of Formula I, for preventing, treating or alleviating cognitive impairment.

[0047] Any embodiment disclosed herein may be combined with other embodiments, even if described in different aspects of the present invention, as long as they are not mutually inconsistent. Any technical feature in one embodiment may be applied to a corresponding technical feature in another embodiment, even if described in different aspects of the present invention, as long as they are not mutually inconsistent.

[0048] The above has outlined only some aspects disclosed herein and is not intended to be limiting in nature. These and other aspects and embodiments are more fully described below. [Brief description of the drawings]

[0049] [Figure 1] FIG. 1 is a schematic diagram of the experimental design. [Diagram 2] We show that anesthesia / surgery can induce delirium-like behavior in mice (buried food test). [Diagram 3] We show that anesthesia / surgery can induce delirium-like behavior in mice (entry in the Y-maze test-novel arm). [Figure 4] We show that anesthesia / surgery can induce delirium-like behavior in mice (Y-maze test-duration in Nobel arm). [Diagram 5] We show that anesthesia / surgery can induce delirium-like behavior in mice (open field test - freezing time). [Figure 6] We show that anesthesia / surgery can induce delirium-like behavior in mice (Open Field Test - Time to Center). [Figure 7] We show that anesthesia / surgery can induce delirium-like behavior in mice (open field test-latency to center). [Figure 8] Figure 1 shows that anesthesia / surgery can induce delirium-like behavior in mice (composite Z-score). [Figure 9] We show that WS635 can attenuate anesthesia / surgery-induced delirium-like behavior (buried food test) in mice. [Figure 10] We show that WS635 can attenuate anesthesia / surgery-induced delirium-like behavior (Y-maze test-entry in the Nobel arm) in mice. [Figure 11] Figure 2 shows that WS635 can attenuate anesthesia / surgery-induced delirium-like behavior in mice (Y-maze test-duration in Nobel arm). [Figure 12] We show that WS635 can attenuate anesthesia / surgery-induced delirium-like behavior (open field test-freezing time) in mice. [Figure 13] We show that WS635 can attenuate anesthesia / surgery-induced delirium-like behavior (open field test-time to center) in mice. [Figure 14]We show that WS635 can attenuate anesthesia / surgery-induced delirium-like behavior (open field test-latency to center) in mice. [Figure 15] Figure 1 shows that WS635 can attenuate anesthesia / surgery-induced delirium-like behavior (composite Z-score) in mice. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0050] Definitions and Common Terms Reference will now be made in detail to some embodiments of the present invention, examples of which are illustrated in the accompanying structures and chemical formulas. The present invention is intended to cover all alternatives, modifications, and equivalents that may fall within the scope of the present invention as defined by the claims. Those skilled in the art should recognize many methods and materials similar or equivalent to those described herein, which can be used to practice the present invention. The present invention is not limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differ from or conflict with the present application (such as defined terms, term usage, and techniques described), the present application shall control.

[0051] It is also to be understood that certain features of the invention which are, for clarity, described in the context of separate implementations, may also be provided in combination in a single implementation. Conversely, various features of the invention which are, for brevity, described in the context of a single implementation, may also be provided alone or in any suitable subcombination.

[0052] Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications mentioned in this application are incorporated herein by reference in their entirety.

[0053] As used herein, the grammatical articles "a," "one," and "the" are intended to include "at least one" or "one or more" unless otherwise indicated herein or clearly contradicted by context. Thus, the articles used herein refer to one or more (i.e., to at least one) of the grammatical object of the article. For example, "in one embodiment" refers to one or more embodiments.

[0054] The term "comprising" is an open term and means to include the subject matter disclosed in this application but not to exclude other subject matter.

[0055] As used herein, the term "pharmaceutical acceptable" refers to those compounds, materials, compositions and / or dosage forms that are suitable, within the scope of reasonable medical judgment, for contact with the tissues of a patient without undue toxicity, irritation, allergic response, or other problem or complication, and which compounds, materials, compositions and / or dosage forms are effective for their intended use, commensurate with a reasonable benefit / risk ratio.

[0056] The term "prodrug" refers to a compound that is converted to a compound of formula (I) in the body. Such conversion can be achieved, for example, by hydrolysis of the prodrug in blood or by enzymes in blood or tissues to convert the prodrug to the original dosage form. The prodrug of the compounds disclosed herein can be, for example, an ester. Common esters that have been used as prodrugs are phenyl esters, aliphatic (C1-24) esters, acyloxymethyl, carbonate esters, carbamates, and amino acid esters. For example, the hydroxy-containing compounds disclosed herein can be acylated at that position in their prodrug form. Other prodrug forms include phosphate esters, such as those phosphate ester compounds that are phosphorylated from a hydroxy on the parent compound. The following references provide detailed discussions of prodrugs: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270; and S. J. Hecker Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345, each of which is incorporated herein by reference.

[0057] A "metabolite" is a product produced by metabolism in the body of a particular compound or its salt. Metabolites of a compound can be identified using routine techniques known in the art, and their activity is determined using those tests described herein. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic degradation, and the like, of an administered compound. Thus, metabolites, including compounds disclosed herein, of the invention include metabolites produced by contacting a compound disclosed herein with a mammal for a sufficient period of time.

[0058] "Pharmaceutically acceptable salt" refers to organic or inorganic salts of the compounds disclosed herein. Pharmaceutically acceptable salts are known in the art. For example, SM Berge et al., J. Pharmaceutical Sciences (1988, 66th issue, pp. 1-19) describes pharma- ceutically acceptable salts and is incorporated herein by reference. Some non-limiting examples of pharma- ceutical acceptable and non-toxic salts include salts of amino groups formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, and malonic acid) or other methods used in the art (e.g., ion exchange). Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogensulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentane propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, gluconate, glyceryl phosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodide, 2-hydroxysulfate, 2-hydroxybutano ... Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, bishydroxynaphthalene, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, paratoluenesulfonate, undecanoate, valerate, etc. ... + (C 1-4The present invention also contemplates the quaternary ammonium addition of any basic nitrogen-containing group of the compounds disclosed herein. Water- or oil-soluble or dispersible products may be obtained by such quaternary ammonium addition. Representative alkali metal or alkaline metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Optionally, other pharma- ceutically acceptable salts include salts containing counterions (e.g., halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Contains non-toxic ammonium, quaternary ammonium, and amine cations formed using cations of 1,2-diphenylmethane, ...

[0059] The term "solvate" refers to an association or complex of one or more solvent molecules with a compound disclosed herein. Examples of solvents that form solvates include, but are not limited to, water, isopropyl alcohol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, ethanolamine, and mixtures thereof. The term "hydrate" refers to a complex where the solvent molecule is water.

[0060] When the solvent is water, the term "hydrate" can be used. In one embodiment, one water molecule can be associated with one molecule of the compounds disclosed herein, such as a hydrate. In another embodiment, one or more water molecules can be associated with one molecule of the compounds disclosed herein, such as a dihydrate. In a further embodiment, less than one water molecule can be associated with one molecule of the compounds disclosed herein, such as a hemihydrate. It is noted that all solvates of the present invention maintain the bioavailability of the non-hydrate forms of the compounds disclosed herein.

[0061] As used herein, the term "therapeutically effective amount" or "therapeutically effective dose" refers to an amount of a compound disclosed herein that elicits a biological or medical response (e.g., reducing or inhibiting the activity of an enzyme or protein, or ameliorating a symptom, alleviating a disease condition, slowing or retarding the progression of a disease, etc.).

[0062] Drug Compositions and Administration of Compounds and Formulations In one aspect, the present application provides a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharma- ceutically acceptable salt, or prodrug thereof, further comprising at least a pharma- ceutically acceptable carrier, adjuvant, or excipient, and optionally other therapeutic and / or prophylactic ingredients.

[0063] Suitable carriers, adjuvants and excipients are well known to those skilled in the art and are described, for example, in Ansel HC et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, Philadelphia; Gennaro AR et al., Remington: The Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe RC, Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.

[0064] As used herein, "pharmaceutical acceptable excipient" refers to a pharmaceutical acceptable material, composition, or vehicle involved in the administration of the form or consistency of a drug composition. Each excipient must be compatible with the other components of the drug composition to avoid significant reduction in the efficacy of the compound of the present invention when administered to a patient and to avoid causing pharmaceutical unacceptable composition interactions when mixed. In addition, each excipient must have sufficient purity to be pharmaceutical acceptable.

[0065] Suitable pharma- ceutically acceptable excipients vary according to the specific dosage form selected. It should be noted that suitable pharma-ceutically acceptable excipients can be selected according to the specific function they can perform in the composition. For example, certain pharma-ceutically acceptable excipients can be selected according to their ability to facilitate the production of homogeneous dosage forms. Certain pharma-ceutically acceptable excipients can be selected according to their ability to facilitate the production of stable dosage forms. Certain pharma-ceutically acceptable excipients can be selected because they can facilitate the transport or transportation of the compounds of the present invention from one organ or part of the body to another organ or part of the body once administered to a patient. Certain pharma-ceutically acceptable excipients can be selected according to their ability to enhance the compliance of the patient.

[0066] Suitable pharma- ceutically acceptable excipients include diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, cosolvents, suspending agents, emulsifiers, sweeteners, flavoring agents, masking agents, colorants, anti-caking agents, wetting agents, chelating agents, plasticizers, thickeners, antioxidants, preservatives, stabilizers, surfactants, and buffers. As one of ordinary skill in the art will appreciate, certain pharma-ceutically acceptable excipients can perform more than one function and can perform alternative functions depending on how much of the excipient is present in the formulation or what other components are present in the formulation.

[0067] One of ordinary skill in the art has the knowledge and skill in the art to be able to select appropriate pharma- ceutical excipients in appropriate amounts for use in the present invention. Numerous resources are available to one of ordinary skill in the art which describe pharma- ceutical acceptable excipients and allow one to select appropriate pharma- ceutical acceptable excipients, including, for example, Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

[0068] Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York (each of which is incorporated herein by reference) disclose various carriers for preparing pharma- ceutically acceptable compositions and known techniques for their manufacture. Use of any conventional carrier medium is contemplated within the scope of the present invention, so long as it is incompatible with the compounds of the present invention, e.g., does not cause undesirable biological effects or interact with any other components of the pharma-ceutically acceptable composition in a deleterious manner.

[0069] In some embodiments, the subject at risk for POD is a child or an elderly person. In various embodiments, the subject is a mammal, such as a human.

[0070] In some implementations, the subject at risk for POD is elderly.

[0071] Generally, the compounds of the present invention are prepared into dosage forms for administration to patients by the required route. For example, dosage forms include: (1) dosage forms suitable for oral administration, such as tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) dosage forms suitable for parenteral administration, such as sterile solutions, suspensions, and powders for reconstitution; (3) dosage forms suitable for transdermal administration, such as transdermal patches; (4) dosage forms suitable for rectal administration, such as suppositories; (5) dosage forms suitable for inhalation, such as aerosols, solutions, and powders; and (6) dosage forms suitable for topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.

[0072] It should further be understood that certain compounds of the present invention may exist in a free form for use in therapy or, where appropriate, as a pharma- ceutically acceptable derivative or prodrug thereof, which, according to the present invention, includes, but is not limited to, a pharma- ceutically acceptable prodrug, salt, ester, salt of such ester, or any other adduct or derivative, which, upon administration to a patient in need thereof, is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.

[0073] In one embodiment, the compounds disclosed herein can be prepared in an oral dosage form. In one embodiment, the compounds disclosed herein can be prepared in an inhaled dosage form. In one embodiment, the compounds disclosed herein can be prepared in a nasal dosage form. In one embodiment, the compounds disclosed herein can be prepared in a transdermal dosage form. In one embodiment, the compounds disclosed herein can be prepared in a topical dosage form.

[0074] The pharmaceutical compositions according to the present application can be provided as compressed tablets, abrasive tablets, chewable tablets, fast dissolving tablets, multiple compressed tablets or enteric coated tablets, sugar-coated or film-coated tablets. Enteric coated tablets are compressed tablets coated with a substance that resists the action of stomach acid but dissolves or disintegrates in the intestine, thus protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylates, waxes, shellac, ammoniated shellac, cellulose phthalates, etc. Sugar-coated tablets are compressed tablets that are surrounded by a sugar coating, which helps to mask unpleasant tastes and odors and protect the tablets from oxidation. Film-coated tablets are compressed tablets that are covered with a thin layer or membrane of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose talate. Film coatings impart similar general properties to sugar coatings. Multiple compressed tablets are compressed tablets that are produced by one or more compression cycles, including layered tablets, compression-coated or dry-coated tablets.

[0075] Tablet dosage forms can be prepared with the active ingredient in powder, crystalline or granular form, alone or in combination with one or more of the carriers or excipients described herein, including binders, disintegrants, sustained release polymers, lubricants, diluents and / or colorants. Flavoring and sweetening agents can be used, particularly to form chewable lozenges and tablets.

[0076] The pharmaceutical compositions according to the present application may be provided as soft or hard capsules, which may be made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules (also called dry-filled capsules (DFC)) consist of two sections, one sliding over the other to completely enclose the active ingredient. Soft elastic capsules (SEC) are soft, spherical shells, such as gelatin shells, plasticized by the addition of glycerin, sorbitol, or similar polyhydric alcohols. The soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives include methyl and propyl parahydroxybenzoates, and sorbic acid, as described herein. Liquid, semi-solid, and solid dosage forms according to the present application may be encapsulated. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules of such solutions can be prepared as described in US Patents 4,328,245, 4,409,239 and 4,410,545. As known to those skilled in the art, the capsules can also be coated to alter or maintain dissolution of the active ingredient.

[0077] The pharmaceutical compositions according to the present application can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. An emulsion is a two-phase system in which one liquid is dispersed in the form of small balls into another liquid, which may be oil-in-water or water-in-oil. An emulsion can include a pharma- ceutically acceptable non-aqueous liquid or solvent, an emulsifier, and a preservative. A suspension can include a pharma-ceutically acceptable suspending aid and a preservative. A hydroalcoholic solution can include a pharma-ceutically acceptable acetal, such as a di(lower alkyl)acetal of a lower alkyl aldehyde, such as acetaldehyde diethyl acetal, and a water-miscible solvent having one or more hydroxy groups, such as propylene glycol and ethanol. An elixir is a clear, sweetened hydroalcoholic solution. A syrup is a concentrated solution of a sugar (e.g., sucrose) in water, and may include a preservative. A liquid dosage form (e.g., a solution in polyethylene glycol) can be diluted with a sufficient quantity of a pharma-ceutically acceptable liquid carrier, such as water, to be conveniently measured for administration.

[0078] The present application provides a pharmaceutical composition, which can be prepared into a suitable dosage form for administration to a patient by inhalation, such as a powder, aerosol, suspension or solution composition. In one embodiment, the present invention relates to a dosage form for administration to a patient by inhalation in the form of a powder. In one embodiment, the present invention relates to a dosage form for administration to a patient by inhalation in the form of a powder. A powder composition for delivery to the lungs by inhalation typically comprises a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, as a fine powder, and one or more pharma- ceutically acceptable excipients as a fine powder. Pharmaceutically acceptable excipients that are particularly suitable for powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di-, and polysaccharides. Fine powders can be prepared, for example, by micronization and grinding. Typically, small-sized (e.g., micronized) compounds have a D of about 1-10 microns. 50 The molecular weight can be defined by a specific molecular weight (eg, using laser diffraction measurements).

[0079] Pharmaceutical compositions suitable for transdermal administration can be in the form of discrete patches intended to remain in intimate contact with the patient's epidermis for a prolonged period of time. For example, the active ingredient can be delivered from the patch by iontoelectroosmosis, as generally described in Pharmaceutical Research, 3(6), 318 (1986).

[0080] Drug compositions suitable for topical administration can be prepared as ointments, creams, emulsions, lotions, powders, liquids, pastes, gels, sprays, aerosols or oils. Ointments, creams and gels can be prepared, for example, by adding suitable thickening and / or gelling agents and / or solvents to an aqueous or oily matrix. Such matrices can be, for example, water and / or oils (e.g. liquid paraffin or vegetable oils such as peanut oil or castor oil), or solvents (e.g. polyethylene glycol). Depending on the nature of the matrix, thickening and gelling agents that can be used include soft paraffin, aluminum stearate, spermaceti stearyl alcohol, polyethylene glycol, lanolin, beeswax, carboxypolyethylene and cellulose derivatives, and / or monostearate glycerides and / or nonionic emulsifiers.

[0081] The compounds disclosed herein can be coupled with soluble polymers that are targeted drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylasparaginephenol, or palmitoyl-substituted polyethylene oxide polylysine. The compounds can also be coupled with suitable biodegradable polymers to achieve sustained drug release, such as polylactic acid, poly-ε-caprolactone, polyhydroxybutyric acid, poly(orthoesters), polyacetals, polydihydroxypyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

[0082] The pharmaceutical compositions according to the present application can be administered parenterally by injection, infusion or implantation and are used for local or systemic administration. Parenteral administration as used herein includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.

[0083] The pharmaceutical compositions according to the present application can be prepared in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and solid forms of solution or suspension in liquid prior to injection. Such dosage forms can be prepared by conventional methods known to those skilled in the art of pharmaceutical sciences (see Remington: The Science and Practice of Pharmacy, supra).

[0084] Pharmaceutical compositions for parenteral administration may include one or more pharma- ceutically acceptable carriers and excipients, such as, but not limited to, aqueous carriers, water-miscible carriers, non-aqueous carriers, antimicrobial agents or preservatives to prevent the growth of microorganisms, stabilizers, solubilizing agents, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, blocking or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases.

[0085] The pharmaceutical compositions according to the present application can be formulated in immediate or modified release dosage forms, including delayed, sustained, pulsed, controlled, targeted and programmed release dosage forms.

[0086] The pharmaceutical compositions according to the present application can be used for single or multiple dose administration. Single dose formulations are packaged in ampoules, vials or syringes. Multi-dose parenteral formulations must contain an antibacterial agent to inhibit antibacterial or fungal concentrations. All parenteral formulations must be sterile, as known and practiced in the art.

[0087] The pharmaceutical compositions according to the present application can be prepared with other active ingredients which do not impair the necessary therapeutic action, or with substances which supplement the necessary action.

[0088] In one embodiment, the methods of treatment disclosed herein include administering to a patient in need of treatment a safe and effective amount of a compound of the invention or a pharmaceutical composition comprising a compound of the invention. Each of the embodiments disclosed herein treats the disease or disorder by administering to a patient in need of treatment a safe and effective amount of a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

[0089] In one embodiment, the compound of the present invention or a pharmaceutical composition thereof may be administered by any suitable route of administration, including systemic administration and local administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, and rectal administration. Parenteral administration is an administration route other than enteral or transdermal, and is usually performed by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion. Local administration includes dermal and intraocular, otic, intravaginal, inhalation, and intranasal administration. In one embodiment, the compound of the present invention or a pharmaceutical composition thereof may be administered orally. In one embodiment, the compound of the present invention or a pharmaceutical composition thereof may be administered by inhalation. In another embodiment, the compound of the present invention or a pharmaceutical composition thereof may be administered intranasally.

[0090] In one embodiment, the compound of the present invention or its pharmaceutical composition may be administered once or in multiple doses at different time intervals within a given time period, depending on the administration means. For example, the dose may be administered once, twice, three times or four times a day. In one embodiment, the dose is administered once a day. In another embodiment, the dose is administered once every two days. The dose may be administered until the desired therapeutic effect is achieved, or the desired therapeutic effect may be maintained indefinitely. The appropriate administration means for the compound of the present invention or its pharmaceutical composition depends on the pharmacokinetic properties of the compound, such as absorption, distribution and half-life, and can be determined by one of ordinary skill in the art. It should be noted that for the compound of the present invention or its pharmaceutical composition, the appropriate administration means (including the duration of such administration means) depends on the disease to be treated, the severity of the disease to be treated, the age and physical condition of the patient to be treated, the medical history of the patient to be treated, the nature of any concurrent therapy, the desired therapeutic effect, and similar factors within the knowledge and expertise of the artisan. One of ordinary skill in the art will appreciate that the appropriate administration means may be adjusted depending on the response of an individual patient to the administration means or the time changes required by the individual patient.

[0091] The compounds of the present invention can be administered simultaneously with, before or after one or more other therapeutic agents. The compounds of the present invention can be administered alone, by the same or different route of administration, or in the same pharmaceutical composition as the other agents.

[0092] The compounds of the present application may be used in combination with sedatives, hypnotics, anxiolytics, antipsychotics, anxiolytics, cyclopyrrolidones, imidazole pyridines, pyrazolopyrimidines, minor sedatives, melatonin agonists and antagonists, melatonin agonists, benzodiazepines, barbiturates, 5HT-2 antagonists, etc., such as adinazolan, allobarbital, aromidone, alprazolam, amitriptyline, isopentobarbital, amoxapine, bentaxepam, taixidine, brotezolam, bupropion, buspirone, parabutylbarbital, isobutybarbital, caprea, carbochloral, chloral betaine, chloral chloral hydrate, chlorodyne, clomipramine, clonazepam, domperidone, methaminodiazepoxide, chloroethylene diester, clozapine, ciprazepam, dicipamide, dexclamo, diazepam, chloralsaamide, divalproic acid, diphenhydramine, doxepin, estazolam, eschlorvynol, etomidate, fenoban, flunitrazepam, flurazepam, trifluoropentoximamide, fluoxetine, fosazepam, phenethylpiperidone, halazepam , hydroxyzine, imipramine, lithium, chloroxynordiazepam, lorazepam, maprotiline, mecloqualone, melatonin, methylphenobarbital, meprobamate, methaqualone, midaflu, midazolam, nefazodone, nixomate, nitrazepam, nortriptyline, oxazepam, paraformaldehyde, paroxetine, pentobarbital, pyrapine, phenothiazine, phenelzine, phenobarbital, prazepam, promethazine, isopropyl These include ruphenol, protriptyline, quazepam, licazepam, rolipram, secobarbital, sertraline, sulpar, temazepam, thioridazine, tracazole esters, transypromine, trazodone, triazole benzodiazepines, tripiperim, triethylamine, trichloroethyl phosphate, trifluoperazine, trimethozine, trimethoprim, lorazepam, venlafaxine, zaleplon, zolazepam, zolpidem, and salts and compositions thereof.Alternatively, physical methods such as light therapy or electrical stimulation can be used during administration of the compounds disclosed herein.

[0093] The compounds of formula (I) can also be administered as prodrugs. As used herein, a "prodrug" of a compound of the invention is a functional derivative of the compound that will eventually release the compound of the invention in the body after administration to a patient. By administering a compound of the invention as a prodrug, one skilled in the art can do one or more of the following: (a) change the effectiveness of the compound in the body; (b) change the duration of action of the compound in the body; (c) change the transport or distribution of the compound in the body; (d) change the solubility of the compound in the body; and (e) overcome side effects or other difficulties encountered by the compound. Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in the body. Such modifications include the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, which are well known to those skilled in the art.

[0094] Uses of the Compounds and Pharmaceutical Compositions

[0095] The compound WS635 or pharmaceutical composition disclosed in the present application is effective for treating or preventing POD.

[0096] An "effective amount," "therapeutically effective amount," or "effective dosage" of the compounds disclosed herein or their stereoisomers, tautomers, N-oxides, solvates, metabolites, pharma- ceutically acceptable salts, or prodrugs, or pharma- ceutical acceptable compositions is an amount that effectively treats or reduces the severity of postoperative cognitive dysfunction. The compounds and pharma- ceutical acceptable compositions are effectively administered in a fairly wide dosage range. For example, the daily dosage is about 0.1 mg to 1000 mg per person, and the compounds or pharma- ceutical acceptable compositions can be administered in a single dose or in several divided doses per day. The methods, compounds, and compositions disclosed herein can be administered in any amount and by any route of administration that effectively treats or reduces the severity of postoperative cognitive dysfunction. The exact amount required varies from subject to subject and depends on the species, age, and general condition of the subject, the severity of the infection, the specific agent, its administration pattern, etc. The compounds or pharmaceutical compositions disclosed herein can be administered with one or more of the above-mentioned other therapeutic agents.

[0097] In some embodiments, the compounds of the present application can be administered to a subject within 1 hour prior to surgery or within 0.5 hours prior to surgery. The compounds of the present application can be administered in a daily dose of less than about 900 mg, for example, in a daily dose of about 10 mg to about 900 mg, or in a daily dose of about 50 mg to about 600 mg. The compounds can be administered once daily, or as a single dose once daily.

[0098] In addition to being used for human therapy, WS635 and compositions thereof can be used for veterinary treatment of animals, such as mammals, including companion animals, exotic animals, and farm animals. In other embodiments, animals disclosed herein include horses, dogs, and cats. As used herein, the compounds disclosed herein include pharma- ceutically acceptable derivatives thereof.

[0099] Working Example Materials and Methods For mouse anesthesia and surgery, 18-month-old C57BL / J6 female mice were adapted for 3 days in the laboratory. Mice were randomly allocated to anesthesia / surgery or control groups according to body weight. Mice in the anesthesia / surgery group were subjected to a simple laparotomy under isoflurane anesthesia using the method described in a previous study. Specifically, in a clear acrylic chamber, each mouse was anesthetized with 1.4% isoflurane in 100% oxygen. After induction for 15 minutes, the mouse was removed from the chamber. Isoflurane anesthesia was maintained with a pyramidal apparatus, and one 16-gauge needle was inserted into the pyramidal apparatus near the mouse's nose to monitor the concentration of isoflurane. A longitudinal midline incision was made in the skin, abdominal muscle, and peritoneum 0.5 cm proximal to the pubic symphysis from the xiphoid process. The incision was then sutured layer by layer with 5-0 coated Vicryl Plus antibacterial sutures.

[0100] Isoflurane anesthesia-induced cognitive impairment in mice. 8-month-old C57BL / 6J mice. Anesthesia: 1.4% isoflurane, 2 hours.

[0101] Treatment of cognitive impairment induced by isoflurane anesthesia in mice with WS635. WS635 was dissolved in 10% DMSO and corn oil. 30 min before anesthesia, each mouse received 26.4 mg / kg WS635 or the same volume of vehicle (10% DMSO and corn oil). Then, the mice were tested in the Fear Conditioning System 48 h and 7 days after anesthesia.

[0102] WS635 treatment. WS635 was dissolved in corn oil containing 10% DMSO, and each mouse was injected with WS635 solution via IP with a 27G x 1 / 2 needle 30 min prior to control condition or anesthesia / surgery, with a dosage of 40 mg / kg, 0.2 ml. Mice in the control group received 0.2 ml of corn oil containing 10% DMSO.

[0103] Behavioral testing. As shown in the schematic (Figure 1), all mice were subjected to multiple behavioral tests, starting 24 hours before anesthesia / surgery or control conditions (baseline), and then 6, 9, and 24 hours after anesthesia / surgery, followed by a buried food test, followed by an open field test, and finally a Y-maze test. Behavioral testing was performed in groups of 3 mice, which completed the test within 50 minutes, simulating certain features of the clinical assessment of delirium in patients.

[0104] Buried food test. Specifically, two days before the test, each mouse is given two tablets of sweetened corn. On all test days, the mouse is habituated for one hour by placing the cage with the mouse in the test room before the test. The test cage is provided with a clean mat (3 cm high). One sweetened corn granule is buried 0.5 cm below the surface of the mat so that it is not visible. The position of the food granule is changed in a random manner each time. The mouse is placed in the center of the test cage, and the latency of eating the mouse food is measured. The latency is defined as the time from when the mouse is placed in the test cage until the mouse finds the food granule and grasps it with its front claws and / or teeth. The mouse is allowed to eat the found granule and then returned to their home cage. The observation time is 5 minutes. If the mouse cannot find the granule within 5 minutes, the test stage ends and the latency of the mouse is defined as 300 seconds. After each test, the mat is emptied from the test cage and the cage is cleaned with a 70% ethanol solution to prevent the spread of olfactory cues. Gloves are changed after each test.

[0105] Open field test. Specifically, mice are gently placed in the center of an open room (40 × 40 × 40 cm) in dim light and allowed to move freely for 5 min. The mouse's movement parameters are monitored and analyzed by a camera connected to an arbitrary maze animal tracking system software (Stoelting Co., Wood Dale, IL). The total distance traveled (meters), the time taken to reach the center of the open field (seconds), the freezing time (seconds), and the latency to the center of the open field (the time it takes the mouse to reach the position in the first attempt (seconds)) are recorded and analyzed. Between each test, the floor of the open field is cleaned with 70% ethanol solution.

[0106] Y-maze test. Specifically, a Y-maze made of gray polyphenylenevinylene is placed in a quiet and illuminated room. Each maze consists of three arms (8 × 30 × 15 cm, width × length × height), with an angle of 120 degrees between each arm. The three arms include a start arm where the mouse starts exploring (always open), a Nobel arm that is blocked during the first test but opens during the second test, and other arms (always open). In the experiment, the start arm and other arms are randomly designed to avoid spatial memory errors. The Y-maze test consists of two tests, and the two tests are separated by a fixed inter-trial interval (ITI). The first test (training) lasts for 10 minutes, which allows the mouse to explore two arms of the maze (the start arm and the other arm) and the Nobel arm is blocked. After a 2-hour (6 and 24-hour study after anesthesia / surgery) or 4-hour (9-hour study after anesthesia / surgery) ITI, a second test (withheld) is performed. For the second test, the mouse is placed back into the maze in the same start arm and allowed to freely access all three arms for 5 min. A camera connected to any maze animal tracking system software is installed 60 cm above the room to monitor and analyze the number of entries and time taken into each arm. The time taken to enter the Nobel arm and the time taken to enter the Nobel arm indicate spatial recognition memory (learning behavior). Clean each arm of the Y-maze with 70% ethanol solution between tests.

[0107] result

[0108] The experimental design is shown in Figure 1.

[0109] Mice are anesthetized with isoflurane (anesthesia / surgery) and subjected to behavioral testing 24 hours (baseline) prior to lower abdominal surgery, and then 9 hours after anesthesia / surgery.

[0110] WS635 can attenuate anesthesia / surgery-induced changes in mice in the buried food test.

[0111] Compared with the control condition, anesthesia / surgery significantly increased the latency of mice to eat food in the buried food test. Treatment with 40 mg / kg WS635 could attenuate these anesthesia / surgery-induced delirium-like behavioral changes in mice.

[0112] WS635 can attenuate anesthesia / surgery-induced changes in mice in a Y-maze experiment.

[0113] Compared with the control condition, anesthesia / surgery can reduce the number of entries into the Nobel arm in the Y-maze test. Compared with the control condition, anesthesia / surgery can significantly shorten the duration in the Nobel arm in the Y-maze test. WS635 treatment at 40mg / kg can attenuate these anesthesia / surgery-induced delirium-like behavioral changes in mice.

[0114] WS635 can attenuate anesthesia / surgery-induced changes in mice in the open field test.

[0115] Compared with the control condition, anesthesia / surgery can significantly shorten the freezing time in the open field test. Compared with the control condition, anesthesia / surgery can significantly shorten the time to the center of the open field. Compared with the control condition, anesthesia / surgery can significantly increase the latency to the center of the open field test. WS635 treatment at 40mg / kg can attenuate these anesthesia / surgery-induced delirium-like behavioral changes in mice.

[0116] In the present specification, the terms "in some embodiments," "in one embodiment," "in another embodiment," "in one example," "particular example," or "some examples" refer to a particular feature, structure, material, or characteristic described in combination with the embodiment or example that is included in at least one embodiment or example of the present application. Thus, the appearance of "in some embodiments," "in one embodiment," "in one embodiment," "in other examples," "in an example," "in a particular example," or "in some examples" in different locations in the present specification does not necessarily refer to the same implementation or example of the present application. It should be noted that the particular feature, structure, material, or characteristic may be combined in any suitable manner in one or more embodiments or examples.

Claims

1. 1. Use of a compound of formula (I) or a stereoisomer, tautomer, N-oxide, solvate, or pharma- ceutically acceptable salt thereof in the manufacture of a medicament or pharmaceutical composition for preventing, treating, or alleviating post-operative delirium (POD). 【Chemistry 1】

2. The use of claim 1, wherein the pharmaceutical composition further comprises a pharma- ceutical acceptable carrier, excipient, adjuvant, or a combination thereof.

3. The use according to claim 1, wherein the pharmaceutical composition further comprises another agent for preventing, treating or alleviating cognitive impairment.

4. 2. The use of claim 1, wherein the compound is administered in a daily dosage of less than about 900 mg.

5. The use of claim 1, wherein the compound is administered in a daily dosage of between about 10 mg and about 900 mg.

6. 2. The use of claim 1, wherein the compound is administered in a daily dosage of about 50 mg to about 600 mg.

7. The use of claim 1, wherein the compound is administered once daily.

8. 2. The use according to claim 1, wherein the compound is administered once daily as a single dose.

9. 2. The use of claim 1, wherein the compound is administered by a route selected from the group consisting of oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, liposomal, inhalation, vaginal, intraocular, topical delivery, subcutaneous, intraadipose, intraarticular, intraperitoneal and intrathecal.

10. The use according to claim 1, wherein the compound is administered orally or intravenously.

11. The use according to claim 1, wherein the compound is administered in the form of a tablet, capsule or injection.

12. A pharmaceutical composition for use in treating, preventing or alleviating post-operative delirium (POD), comprising a therapeutically effective amount of a compound of formula I or a stereoisomer, tautomer, N-oxide, solvate or pharma- ceutically acceptable salt thereof. 【Chemistry 3】

13. The pharmaceutical composition of claim 12, wherein the composition is prepared in a unit dosage form.

14. 13. The pharmaceutical composition of claim 12, wherein the composition is prepared in a single dosage form, the single dosage form containing less than 900 mg of Compound I.

15. 15. The pharmaceutical composition of claim 14, wherein the single dosage further comprises an agent other than the compound of formula I for preventing, treating or alleviating cognitive impairment.

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