Compounds that improve the bioavailability of desipramine, and pharmaceutical compositions thereof, and their use

Abstract

This invention provides compounds that improve the bioavailability of desipramine, as well as pharmaceutical compositions and their uses. [Solution] The structural formula is exemplified below and is a compound that improves the bioavailability of desipramine. JPEG2026115833000052.jpg30164

Description

[Technical Field]

[0001] The present invention relates to the field of pharmaceuticals, and more specifically to compounds that improve the bioavailability of desipramine, as well as pharmaceutical compositions and uses thereof. [Background technology]

[0002] Desipramine is an antidepressant that works by blocking the reuptake of monoamine neurotransmitters such as norepinephrine and serotonin, and is used to treat various types of depression. The most common existing dosage form of desipramine hydrochloride is tablets, available in 25 mg and 50 mg doses. When administered orally, it is readily absorbed from the gastrointestinal tract, and its absorption is not affected by food. It is widely distributed in the body, easily crosses the blood-cerebrospinal fluid barrier, and accumulates in the brain. There is a significant positive correlation between blood concentration and the clinical effect of antidepressant, and in healthy individuals, better results can be obtained with blood concentrations of 115-155 μg / L or higher. Desipramine has a peak time of 4-6 hours and is mainly metabolized in the liver. Initially, 25 mg is administered orally three times a day, gradually increasing to 50 mg three to four times a day, and in patients with severe depression, up to 300 mg per day may be administered. Problems such as low bioavailability, high dosages, and poor patient compliance negatively impact the effectiveness of disease treatment. [Overview of the project]

[0003] According to one aspect of the present invention, the present invention provides compounds that improve the bioavailability of desipramine, as well as pharmaceutical compositions and uses thereof, wherein such compounds can improve the bioavailability of desipramine. [ka] (Here, R1 is selected from H, C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl, R2 is an unsubstituted or substituted C1-C4 alkyl, C5-C20 aryl, or Selected from TIFF2026115833000002.tif2244, R3 is selected from unsubstituted or substituted C1-C4 alkyl or C5-C20 aryl groups. In the definitions of the groups R2 and R3, "substituted" means that 1 to 3 H on the group are hydroxyl, amino, carboxyl, unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted C5-C20 aryl, unsubstituted or substituted 3-20 member heterocyclic groups, condensation groups formed by an unsubstituted or substituted 3-20 member heterocycle and a C5-C20 aromatic ring, and This means that the group is substituted with at least one selected from TIFF2026115833000003.tif2334, where the substituents of the substituted C1-C4 alkyl, C5-C20 aryl, 3-20 membered heterocyclic group, and the substituents of the condensation group formed by the 3-20 membered heterocycle and the C5-C20 aromatic ring are C1-C4 alkyl and hydroxyl, and the heteroatoms of the heterocycle are N, O, or S, with the number of heteroatoms being 1 to 6.

[0004] Unless otherwise specified, the following definitions are intended to explain and define the meaning and scope of various terms used herein in describing the present invention.

[0005] The following definitions of general terms apply whether they are used individually or in combination.

[0006] Any open valence bond appearing on a carbon, oxygen, sulfur, or nitrogen atom in the structures shown herein indicates the presence of a hydrogen atom.

[0007] Unless otherwise specified, the term "substitution" means that a particular group may have one, two, three, four, five, or six substituents. If multiple substituents are possible on a single group and multiple possible substituents are specified, the substituents are independently selected and do not need to be the same.

[0008] The term "unsubstituted" means that a particular group does not have a substituent.

[0009] The term "substituted" means that a particular group is substituted with one or more selected independently from possible substituents.

[0010] When indicating the number of substituents, the term "one or more" means the maximum number of substitutions possible from one substitution, i.e., substitution by substituents of one hydrogen to substitution by substituents of all hydrogens. Unless otherwise specified, 1, 2, 3, 4 or 5 substituents are preferred.

[0011] The term "oxy" refers to the -O- group. "Carboxyl" refers to the -C(=O)OH group. "Amino" refers to the -NH2 group.

[0012] The term "alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon group having, for example, 1 to 4 carbon atoms. "Unsubstituted or substituted C1-C4 alkyl" is divided into unsubstituted alkyl and substituted alkyl. "Unsubstituted alkyl" refers to an alkyl not substituted with a substituent. Examples of "unsubstituted alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc. Substituted alkyl refers to an alkyl substituted with 1 to 3 substituents, and the substituents are, for example, hydroxyl, amino, carboxyl, unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted C5-C20 aryl, unsubstituted or substituted 3- to 20-membered heterocyclic group, a condensed group formed by an unsubstituted or substituted 3- to 20-membered heterocyclic ring and a C5-C20 aromatic ring, and at least one of TIFF2026115833000004.tif2334. Here, the substituents of the substituted C1-C4 alkyl, C5-C20 aryl, 3- to 20-membered heterocyclic group, and the condensed group formed by a 3- to 20-membered heterocyclic ring and a C5-C20 aromatic ring are C1-C4 alkyl or hydroxyl.

[0013] The term "cycloalkyl" refers to a non-aromatic saturated or unsaturated cyclic hydrocarbon group composed of carbon atoms and hydrogen atoms, which may include a fused ring system, a bridged ring system or a spiro ring system. Examples include, but are not limited to, cyclopropyl, cyclobutyl, and cyclopentyl.

[0014] The term "aryl" or "aromatic ring" refers to a conjugated hydrocarbon ring system group having, for example, 5 to 20 carbon atoms, preferably 5 to 10 carbon atoms in the ring portion. Generally, aryl groups include, but are not limited to, groups such as benzene, naphthalene, anthracene, biphenyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl.

[0015] The term "heterocyclic group" or "heterocycle" refers to a stable 3- to 20-membered aromatic or non-aromatic cyclic group composed of 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, which may be a saturated cyclic group or an unsaturated cyclic group. Examples include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, 2(5H) furanonyl, tetrahydropyranyl, morpholino, thiomorpholino, piperazinyl, homopiperazinyl, epoxypropanil, imidazolidinyl, 1,3-dioxolan-2-one, 1,3-dioxolen-2-one, 1,3-dioxane-2-one, N-pyridylurea, pyrimidinonyl and 1,1-dioxo-thiomorpholinyl.

[0016] The term "condensed group formed by a 3- to 20-membered heterocycle and a C5-20 aromatic ring" means a condensed product of an aromatic ring and a heterocycle, for example, a product condensed by 1 to 3 aromatic rings and 1 to 3 single heterocycles. Examples include, but are not limited to, benzopyridine, benzopyrrole or pyridinoisoquinoline.

[0017] * indicates the connecting site.

[0018] The compounds of the present invention may contain chiral or asymmetric centers, and therefore different stereoisomeric forms exist. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, and atropisomers, as well as mixtures thereof such as racemic mixtures, are part of the present invention. In this specification, all stereoisomers are considered when the stereochemistry of a particular chiral atom has not been determined. The present invention also relates to all geometric and positional isomers. The compounds of the present invention may exist in different tautomeric forms, and all such forms are included within the scope of the present invention. All stereoisomers of the compounds of the present invention are intended to include mixtures, or pure or substantially pure forms. Separation can be achieved by physical methods such as fractional crystallization, separation or crystallization of diastereomer derivatives, and separation by chiral column chromatography.

[0019] The term "prodrug" refers to a functional derivative of the compound of formula (I) that is readily converted to the compound of formula (I) in vivo. Suitable derivatives can be selected and prepared by the prior art, which is well known to those skilled in the art.

[0020] As used herein, the term “pharmaceutically acceptable salt” refers to a pharmaceutically acceptable organic or inorganic salt of the compound of the present invention. Exemplary salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, acidic sulfates, isonicotinates, lactates, salicylates, acidic citrates, succinates, maleates, fumarates, glucons, formates, mesylates, and pamoates. “pharmaceutically acceptable salt” may also include another molecule, such as a maleate or other counterion. The counterion stabilizes the charge in the parent compound. “pharmaceutically acceptable salt” may have more than one charged atom, and multiple charged atoms may have multiple counterions.

[0021] If the compound of the present invention is a base, the desired "pharmaceutically acceptable salt" can be prepared by treating the free base with an appropriate method, for example, an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid, or an organic acid such as galactopyranoside acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, salicylic acid, glucuronic acid, or galacturonic acid, α-hydroxy acids such as citric acid or tartaric acid, amino acids such as glutamic acid, aromatic acids such as benzoic acid or cinnamic acid, or sulfonic acids such as methanesulfonic acid or p-toluenesulfonic acid.

[0022] If the compound of the present invention is an acid, the desired "pharmaceutically acceptable salt" can be prepared by a suitable method, for example, by treating the free acid with an inorganic or organic base such as an amine, alkali metal hydroxide, or alkaline earth metal hydroxide. Specific examples of suitable salts include, but are not limited to, organic salts obtained from amino acids, salts of primary, secondary, and tertiary amines, salts of cyclic amines such as piperidine, morpholine, and piperazine, and inorganic salts obtained from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0023] The compounds of the present invention can exist in a continuous solid state ranging from completely amorphous to completely crystalline. The term "amorphous" refers to a state in which a material lacks long-range order at the molecular level and may exhibit solid or liquid physical properties depending on the temperature. Typically, such materials do not exhibit a distinct X-ray diffraction pattern and exhibit solid properties, but are formally described as liquids. Upon heating, a change in properties occurs from solid to liquid, characterized by a phase transition, usually a secondary phase transition ("glass transition"). The term "crystalline" refers to a solid phase in which a material has an internal structure with regularly arranged molecules and exhibits a distinctive X-ray diffraction pattern with distinct peaks. Such materials also exhibit liquid properties when sufficiently heated, but the change from solid to liquid is characterized by a phase transition, usually a first-order phase transition ("melting point").

[0024] As used herein, the term “polymorph” refers to different solid crystalline phases resulting from the existence of two or more different molecular configurations in the solid state of a particular compound of the present invention. A particular compound of the present invention may exist in multiple crystalline forms, and the present invention is intended to encompass each crystalline form and mixtures thereof.

[0025] As used herein, the term “solvate” refers to a combination or complex of one or more solvent molecules with a compound of the present invention. Examples of solvents for forming solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine. Since the compounds of the present invention may exist in a non-solvated form or in a solvated form with a pharmaceutically acceptable solvent such as water or ethanol, the present invention includes both solvated and non-solvated forms.

[0026] The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more atoms constituting the compound, and the term “isotope” means having the same number of atoms but having an atomic mass or mass number different from the atomic mass or mass number that is common in nature. For example, the compounds can be labeled with radioactive isotopes such as deuterium (2H), tritium (3H), iodine-125 (125I), or C-14 (14C). All isotopic compositional variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention. Isotope variants can provide specific therapeutic benefits, such as deuterium enrichment that can extend the half-life in vivo or reduce the required dose, or provide standard compounds that can be used for characterizing biological samples. The isotopic-rich compounds of formula (1) may be prepared using suitable isotopic-rich reagents and / or isotopic-rich compounds without requiring many experiments, by ordinary techniques well known to those skilled in the art, or by methods similar to those described herein in the schemes and examples.

[0027] In some preferred embodiments, R2 is an unsubstituted or substituted C1-C4 alkyl, phenyl, or Selected from TIFF2026115833000005.tif2244, where term R3 is as defined above.

[0028] In some preferred embodiments, R2 is selected from unsubstituted or substituted C1-C4 alkyl groups, where substitution means that 1-3 H atoms on the alkyl group are hydroxyl groups. This means that it will be replaced with at least one selected from TIFF2026115833000006.tif36124, preferably R2 is Selected from methylene, which has been replaced in TIFF2026115833000007.tif2334.

[0029] In some preferred embodiments, the compound has the structural formula represented by formula II. [ka] (Here, R1 and R3 are as defined above.)

[0030] In some preferred embodiments, R3 is selected from unsubstituted or substituted C1-C4 alkyl or phenyl, where substitution means that 1-3 H on the alkyl is amino, carboxyl, This means that at least one selected from TIFF2026115833000009.tif3033 is substituted, preferably with amino and carboxyl molecules.

[0031] In some preferred embodiments, R1 is selected from H, C1-C4 alkyl groups, and is preferably methyl.

[0032] The aforementioned compound is one selected from the following compounds. TIFF2026115833000010.tif175151

[0033] The present invention further provides a pharmaceutical composition comprising at least one of the compounds described in any one of the present inventions or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, amorphous form, isotope, polymorph or solvate thereof, and a pharmaceutically acceptable carrier and / or auxiliary agent.

[0034] Accordingly, the compounds used in the present invention may be used together with conventional additives or diluents to prepare pharmaceutical compositions and their unit dosage forms. Such forms include solids (particularly in the form of tablets, filled capsules, powders, and pills), liquids (particularly aqueous or non-aqueous solutions, suspensions, emulsions), or capsules filled with the above, all forms for oral administration, suppositories for rectal administration, ointments for transdermal administration, eye drops for intraocular administration, and sterile injection solutions for parenteral administration. Such pharmaceutical compositions and their unit dosage forms may contain conventional components in the usual proportions, and may or may not contain additional active compounds or components, and such unit dosage forms may contain any appropriate effective amount of the active ingredient corresponding to the desired daily dose range.

[0035] The compounds used in the present invention can be administered in various oral and parenteral dosage forms. It will be apparent to those skilled in the art that the following dosage forms may contain the compounds of the present invention as the active ingredient or pharmaceutically acceptable salts thereof.

[0036] For preparing pharmaceutical compositions using the compounds of the present invention, the pharmaceutically acceptable carrier may be solid or liquid. Solid formulations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier may also function as one or more substances that act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrants, or encapsulating materials.

[0037] In powder form, the carrier is a finely ground solid that is mixed with the finely ground active ingredient.

[0038] In tablets, the active ingredient is mixed with a carrier having the necessary adhesive properties in the appropriate proportions and compressed into the desired shape and size.

[0039] Powders and tablets preferably contain 5%, or 10% to about 70%, of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting-point wax, and cocoa butter. The term "formulation" includes the active compound formulated with an encapsulating material as a carrier, where the encapsulating material provides a shell, and here the active ingredient is surrounded by the carrier, with or without, and thus bound to the carrier. Tablets, powders, capsules, and pills can be used as solid forms suitable for oral administration.

[0040] To prepare the suppositories, first, a low-melting-point wax such as fatty acid glycerides or cocoa butter slurry is melted, and then the active ingredient is uniformly dispersed in it by stirring. After that, this melted homogeneous mixture is poured into a mold of the appropriate size and cooled to harden.

[0041] Compositions suitable for vaginal administration may exist in the form of vaginal suppositories, tampons, creams, gels, pastes, foams, or sprays, and may contain an active ingredient in addition to a suitable carrier known in the art.

[0042] Liquid formulations include solutions, suspensions, and emulsions, such as aqueous solutions or water-propylene glycol solutions. For example, a liquid formulation for parenteral injection may be prepared as a water-polyethylene glycol solution.

[0043] Therefore, the compounds used in the present invention may be prepared as formulations for parenteral administration (e.g., injections such as bolus injection or continuous infusion), and may be present in unit dose form in ampoules, pre-filled syringes, small volume infusion bags, or multi-dose containers together with added preservatives. The composition may take the form of a suspension, solution, or emulsion of an oily or aqueous carrier, and may contain formulation components such as suspending agents, stabilizers, and / or dispersants. The active ingredient may also be in powder form, obtained by sterile isolation of a sterile solid or by freeze-drying a solution, and can be reconstituted with a suitable carrier such as sterile non-pyrogenic water immediately before use.

[0044] An aqueous solution suitable for oral administration may be prepared by dissolving the active ingredient in water and adding the desired colorants, flavoring agents, stabilizers, and thickeners.

[0045] An aqueous suspension suitable for oral administration may be prepared by dispersing a micronized active ingredient in water containing a viscous substance such as natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, or other known suspending agents.

[0046] The invention further includes solid formulations designed to be converted into liquid formulations for oral administration immediately before use. Such liquid formulations include solutions, suspensions, and emulsions. Such formulations may contain, in addition to the active ingredient, colorants, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

[0047] For topical administration to the epidermis, the compounds of the present invention may be prepared as ointments, creams, lotions, or transdermal patches. For example, ointments and creams may be prepared by adding a suitable thickener and / or gelling agent to an aqueous or oily base. Lotions may be prepared using an aqueous or oily base and typically further contain one or more of the following: emulsifiers, stabilizers, dispersants, suspending agents, thickeners, or colorants.

[0048] The solution or suspension can be administered directly into the nasal cavity using conventional methods such as droppers, pipettes, or sprayers. The composition may be in single-dose or multi-dose form.

[0049] Administration to the airways may also be achieved by aerosol, in which the active ingredient is packaged in a pressurized package with a suitable propellant, including chlorofluorocarbons (CFCs) such as dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gases. The aerosol may also appropriately further contain surfactants such as lecithin. The drug dose can be controlled by a stock valve.

[0050] In compositions for administration to the airways (including compositions for intranasal administration), the compounds typically have small particle sizes, for example, on the order of 5 microns or less. Such particle sizes can be obtained by methods known in the art, such as micronization.

[0051] If necessary, a composition suitable for sustained release of the active ingredient can be used.

[0052] Tablets or capsules for oral administration, and liquids and continuous infusions for intravenous administration are preferred compositions.

[0053] More detailed information regarding formulation and administration techniques can be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, PA).

[0054] The amount of the active ingredient in a unit dose formulation may vary depending on the specific use and the effect of the active ingredient, and can be adjusted from 0.01 mg to about 0.1 g. For example, in pharmaceutical use, this drug may be administered three times a day in capsules ranging from 0.01 to about 100 mg, and this composition may further contain other suitable therapeutic agents as needed.

[0055] Treatment method In therapeutic use, the compounds used in this invention are administered at a starting dose of 0.001 mg / kg body weight to 10 mg / kg body weight per day. However, these doses may vary depending on the patient's needs, the severity of the condition being treated, and the compound used. Generally, treatment is started with a dose lower than the optimal dose of the compound, and then gradually increased to achieve the best results. For convenience, the total daily dose may also be divided into several doses throughout the day, if necessary.

[0056] Use of a compound, stereoisomer, tautomer, prodrug, pharmaceutically acceptable salt, amorphous form, polymorph, solvate, or pharmaceutical composition described in any one of the present invention in the preparation of a drug for preventing, treating, or alleviating at least one of the following conditions: depression, pain, age-related macular degeneration, and neurological disorders.

[0057] Use of a compound, stereoisomer, tautomer, prodrug, pharmaceutically acceptable salt, amorphous form, polymorph, solvate, or pharmaceutical composition described in any one of the present invention in the preparation of a drug for improving the bioavailability of desipramine or a pharmaceutically acceptable salt thereof. [Effects of the Invention]

[0058] The compound according to the present invention, which improves the bioavailability of desipramine, can be metabolized in vivo to desipramine, and compared to desipramine hydrochloride, it can improve the bioavailability of desipramine, reduce the dose, and improve metabolic stability.

[0059] To facilitate a clear understanding of the present invention, the present invention will be described in further detail below, based on specific embodiments of the invention and with reference to the drawings. [Brief explanation of the drawing]

[0060] [Figure 1] This is the ultraviolet absorption chromatogram of compound DM-A1 at 214 nm. [Figure 2] This is the ultraviolet absorption chromatogram of compound DM-A1 at 254 nm. [Figure 3] This is the mass spectrum of compound DM-A1. [Figure 4] This is the mass spectrum of compound DM-A1 at 214 nm RT 2.509. [Figure 5] This is the mass spectrum of compound DM-A1 at 214 nm RT 2.968. [Figure 6] This is the mass spectrum of compound DM-A1 at 254 nm RT 2.509. [Figure 7] This is the mass spectrum of compound DM-A1 at 254 nm RT 2.968. [Figure 8] This is the NMR spectrum of compound DM-A1. [Figure 9] This is the ultraviolet absorption chromatogram of compound DM-C1 at 214 nm. [Figure 10] This is the ultraviolet absorption chromatogram of compound DM-C1 at 254 nm. [Figure 11] This is the mass spectrum of compound DM-C1. [Figure 12] This is the mass spectrum of compound DM-C1 at 214 nm RT 3.603. [Figure 13] This is the mass spectrum of compound DM-C1 at 214 nm RT 3.676. [Figure 14] This is the mass spectrum of compound DM-C1 at 214 nm RT 4.139. [Figure 15] This is the mass spectrum of compound DM-C1 at 214 nm RT 4.387. [Figure 16] This is the mass spectrum of compound DM-C1 at 254 nm RT 3.603. [Figure 17] This is the mass spectrum of compound DM-C1 at 254 nm RT 3.676. [Figure 18] This is the mass spectrum of compound DM-C1 at 254 nm RT 4.139. [Figure 19] This is the mass spectrum of compound DM-C1 at 254 nm RT 4.387. [Figure 20] This is the NMR spectrum of compound DM-C1. [Figure 21] This is the ultraviolet absorption chromatogram of compound DM-C2 at 214 nm. [Figure 22] This is the ultraviolet absorption chromatogram of compound DM-C2 at 254 nm. [Figure 23] This is the mass spectrum of compound DM-C2. [Figure 24] This is the mass spectrum of compound DM-C2 at 214 nm RT 0.359. [Figure 25] This is the mass spectrum of compound DM-C2 at 214 nm RT 0.688. [Figure 26] This is the mass spectrum of compound DM-C2 at 214 nm RT 3.552. [Figure 27] This is the mass spectrum of compound DM-C2 at 214 nm RT 3.847. [Figure 28] This is the mass spectrum of compound DM-C2 at 254 nm RT 0.359. [Figure 29] This is the mass spectrum of compound DM-C2 at 254 nm RT 0.688. [Figure 30] This is the mass spectrum of compound DM-C2 at 254 nm RT 3.552. [Figure 31] This is the mass spectrum of compound DM-C2 at 254 nm RT 3.851. [Figure 32] This is the mass spectrum of compound DM-C2 at 254 nm RT 5.903. [Figure 33] This is the NMR spectrum of compound DM-C2. [Figure 34] This is the ultraviolet absorption chromatogram of compound DM-C3 at 214 nm. [Figure 35] This is the ultraviolet absorption chromatogram of compound DM-C3 at 254 nm. [Figure 36]This is the mass spectrum of compound DM-C3. [Figure 37] This is the mass spectrum of compound DM-C3 at 214 nm RT 2.361. [Figure 38] This is the mass spectrum of compound DM-C3 at 214 nm RT 2.946. [Figure 39] This is the mass spectrum of compound DM-C3 at 254 nm RT 2.361. [Figure 40] This is the mass spectrum of compound DM-C3 at 254 nm RT 2.964. [Figure 41] This is the NMR spectrum of compound DM-C3. [Figure 42] This is the ultraviolet absorption chromatogram of compound DM-D2 at 214 nm. [Figure 43] This is the ultraviolet absorption chromatogram of compound DM-D2 at 254 nm. [Figure 44] This is the mass spectrum of compound DM-D2. [Figure 45] This is the mass spectrum of compound DM-D2 at 214 nm RT 0.153. [Figure 46] This is the mass spectrum of compound DM-D2 at 214 nm RT 4.554. [Figure 47] This is the 254 nm RT 4.554 mass spectrum of compound DM-D2. [Figure 48] This is the NMR spectrum of compound DM-D2. [Figure 49] This is the ultraviolet absorption chromatogram of compound DM-D3 at 214 nm. [Figure 50] This is the ultraviolet absorption chromatogram of compound DM-D3 at 254 nm. [Figure 51] This is the mass spectrum of compound DM-D3. [Figure 52] This is the mass spectrum of compound DM-D3 at 214 nm RT 0.152. [Figure 53] This is the mass spectrum of compound DM-D2 at 214 nm RT 4.081. [Figure 54] This is the mass spectrum of compound DM-D2 at 254 nm RT 4.081. [Figure 55] This is the NMR spectrum of compound DM-D2. [Figure 56] This is the ultraviolet absorption chromatogram of compound DM-D3 at 214 nm. [Figure 57] This is the ultraviolet absorption chromatogram of compound DM-D3 at 254 nm. [Figure 58] This is the mass spectrum of compound DM-D3. [Figure 59] This is the mass spectrum of compound DM-D3 at 214 nm RT 2.36. [Figure 60] This is the mass spectrum of compound DM-D3 at 214 nm RT 2.65. [Figure 61] This is the mass spectrum of compound DM-D3 at 254 nm RT 2.65. [Figure 62] This is the NMR spectrum of compound DM-D3. [Figure 63] This is the drug blood concentration-time curve for Group 1 in Experimental Example 1 (blood concentration-time curve). [Figure 64] This is the drug blood concentration-time curve for group 2 in experimental example 1. [Figure 65] This is the drug blood concentration-time curve for group 3 in Experimental Example 1. [Figure 66] This is the drug blood concentration-time curve for group 1 in experimental example 2. [Figure 67] This is the drug blood concentration-time curve for group 2 in experimental example 2. [Figure 68] This is the drug blood concentration-time curve for group 3 in experimental example 2. [Figure 69] This is the mean drug blood concentration-time curve for groups 1-3 in Experiment Example 3. [Figure 70] This is the drug blood concentration-time curve for group 1 in experimental example 4. [Figure 71] This is the drug blood concentration-time curve for group 2 in experimental example 4. [Modes for carrying out the invention]

[0061] The technical solutions of the present invention will be described clearly and completely below, but it is clear that the examples described are not all but a part of the examples of the present invention. All other examples that can be obtained by those skilled in the art without creative effort based on the examples of the present invention are included within the scope of the protection of the present invention. The ratios of solvents used in the purification steps (e.g., preparative thin-layer chromatography, preparative chromatography, etc.) in the following examples are by volume.

[0062] Example 1 In this example, compound DM-C1, named 1-(((3-(10,11-dihydro-5H-dibenzo[b,f]azepine-5-yl)propyl)(methyl)carbamoyl)oxy)ethyl L-tryptophan, was prepared. The synthesis scheme for compound DM-C1 in this embodiment is shown below and specifically includes the following steps. [ka]

[0063] Step 1: Under a nitrogen atmosphere, compound 1 (4.5 g, 16.89 mmol), sodium bicarbonate (3 g, 35.71 mmol), and dichloromethane (60 mL) were added sequentially to the reaction flask. The reaction mixture was cooled to 5°C, and compound 2 (2.58 g, 18.58 mmol) was slowly added dropwise. After the addition was complete, the reaction mixture was stirred at 5-10°C for 5 hours. The reaction was monitored by TLC (thin-layer chromatography) (petroleum ether (PE) / ethyl acetate (EA) = 4 / 1). After monitoring, any undissolved solids were removed by filtration, and the filtrate was collected. The organic phase was washed twice with 1N HCl solution (50 mL), then with saturated brine (50 mL), and the organic phase was dried over anhydrous magnesium sulfate. The filtrate was filtered, concentrated, and 5.85 g of a colorless oily liquid was obtained and used directly in the next step without purification.

[0064] Step 2: Under a nitrogen atmosphere, compound 4 (2.95 g, 8.72 mmol), sodium iodide (3 g, 20.11 mmol), potassium carbonate (2.78 g, 20.11 mmol), and N,N-dimethylformamide (40 mL) were sequentially added to the reaction flask. After homogeneous stirring of the mixture, compound 3 (2.5 g, 6.70 mmol) was added at room temperature, and the mixture was stirred at room temperature for 3 hours. Based on the results of LCMS monitoring (see Table 1 for monitoring conditions), after the reaction was complete, the reaction solution was poured into 400 mL of water. The precipitated oily insoluble material was collected and dissolved in 100 mL of ethyl acetate. The solution was sequentially washed with 100 mL of water and 100 mL of saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by pre-phase preparative chromatography (PE / EA = 1 / 1) to obtain pale yellow solid compound 5 (630 mg, yield: 14%).

[0065] Step 3: Compound 5 (300 mg, 0.44 mmol), Pd(OH)2 / C (150 mg), and ethanol (5 mL) were added sequentially to the reaction flask. After replacing the atmosphere in the reaction flask five times with a hydrogen balloon, the mixture was stirred at room temperature for 3 hours. After the reaction was completed as confirmed by LC-MS monitoring, the filtrate was collected and the filtrate cake was washed twice with ethanol (2 mL x 2). The filtrates were combined and separated by reverse-phase HPLC preparative chromatography (ammonium bicarbonate aqueous solution / acetonitrile system). The separation method is shown in Table 2 below. The prepared solution was directly freeze-dried to obtain a white solid compound DM-C1 (120 mg, yield: 50%). 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.36 - 7.32 (m, 1H), 7.16 - 6.88 (m, 12H), 6.61 - 6.51 (m, 1H), 3.73 - 3.53 (m, 3H), 3.27 - 3.16 (m, 2H), 3.08 (s, 4H), 3.02 - 2.81 (m, 2H), 2.73 - 2.68 (m, 3H), 1.67 - 1.64 (m, 2H), 1.38 - 1.02 (m, 4H). LCMS: m / z[M+H] +=541.27.

[0066] As can be seen from LC-MS (see Table 3 for detection method) and NMR, the obtained product is a pair of diastereomers (molar ratio approximately 1 / 1) having the following structural formula. [ka]

[0067] [Table 1]

[0068] [Table 2]

[0069] [Table 3]

[0070] Example 2 This example prepared compound DM-C2, named 1-(((3-(10,11-dihydro-5H-dibenzo[b,f]azepinepyridine-5-yl)propyl)(methyl)carbamoyl)oxy)ethylbenzoate. The synthesis scheme for compound DM-C2 in this example is shown below and specifically includes the following steps. [ka] Step 1: Under a nitrogen atmosphere, compound 1 (10 g, 37.53 mmol), sodium bicarbonate (6.67 g, 79.28 mmol), and dichloromethane (100 mL) were added sequentially to a reaction flask. The reaction system was cooled to 5°C, and compound 2 (5.90 g, 41.29 mmol) was added dropwise. After the addition was complete, the reaction system was stirred at 5-10°C for 5 hours. After the reaction was complete, the undissolved sodium bicarbonate solid was first removed by filtration, and the filtrate was collected. The organic phase was washed twice with 1N HCl solution, then with saturated brine, and the organic phase was dried over anhydrous magnesium sulfate. The organic phase was concentrated to obtain a colorless oily liquid (13 g, yield: 92.8%), which was used directly in the next step without purification.

[0071] Step 2: Under a nitrogen atmosphere, compound 4 (500 mg, 4.02 mmol), N,N-diisopropylethylamine (1.73 g, 13.41 mmol), and N,N-dimethylformamide (15 mL) were sequentially added to the reaction flask and mixed uniformly. Then, compound 3 (1 g, 2.68 mmol) was added at room temperature, and the mixture was stirred for 16 hours at room temperature. After the reaction was complete, the mixture was separated by reverse-phase HPLC preparative chromatography (see Table 4), and the separated solution was freeze-dried to obtain DM-C2, a yellow oily liquid (150 mg, yield: 12.2%). The product was detected by LC-MS (see Table 5 for detection method) and NMR. 1 H NMR (400 MHz, Chloroform-d) δ 8.03 (t, J = 6.4 Hz, 2H), 7.59 - 7.55 (m, 1H), 7.45 - 7.41 (m, 2H), 7.12 - 7.02 (m, 7H), 6.91 (t, J = 7.2 Hz, LCMS: m / z [M+H] + =459.2.

[0072] [Table 4]

[0073] [Table 5]

[0074] Example 3 This example prepared compound DM-C3, whose name is (2R)-2-amino-5-(1-(((3-(10,11-dihydro-5H-dibenzo[b,f]azepine-5-yl)propyl)(methyl)carbamoyl)oxy)ethoxy)-5-oxoglutaric acid. The synthesis scheme for compound DM-C3 in this example is shown below and specifically includes the following steps. [ka] Step 1: Under a nitrogen atmosphere, compound 1 (500 mg, 1.34 mmol), compound 2 (407 mg, 1.34 mmol), potassium carbonate (371 mg, 2.68 mmol), and N,N-dimethylformamide (20 mL) were sequentially added to a reaction flask and mixed uniformly. The mixture was then stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was poured into 80 mL of water and extracted with ethyl acetate (40 mL x 3). The organic phase was washed with saturated brine and water, dried, and concentrated to dryness to obtain the crude product. The crude product was separated in the forward direction (PE:EA = 3:1, Rf = 0.4) to obtain a colorless oily compound 3 (710 mg, yield: 12.2%).

[0075] Step 2: Under a nitrogen atmosphere, compound 3 (610 mg, 0.95 mmol) and dichloromethane (16 mL) were sequentially added to the reaction flask and mixed uniformly. Then, trifluoroacetic acid (8 mL) was added at room temperature, and the reaction was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was concentrated directly to dryness to obtain the crude product. The crude product was separated by reverse-phase HPLC preparative chromatography (aqueous trifluoroacetic acid solution / acetonitrile system), and the separation method is shown in Table 6 below. The acetonitrile was concentrated from the separated solution, and it was freeze-dried to obtain DM-C3 as a white solid (370 mg, yield: 80.3%). 1H NMR (400 MHz, Methanol-d4) δ 7.12 (dq, J = 8.0, 4.5 Hz, 6H), 6.93 (m, 2H), 6.71 (m, 1H), 3.96 (dt, J = 9.2, 6.7 Hz, 1H), 3.82 - 3.71 (m, 2H), 3.39 (dt, J = 14.4, 7.2 Hz, 1H), 3.32 - 3.24 (m, 1H), 3.18 (d, J = 6.8 Hz, 4H), 2.85 - 2.75 (m, 3H), 2.56 (q, J = 7.2 Hz, 2H), 2.29 - 2.07 (m, 2H), 1.81 (p, LCMS: m / z [M+H] + =484.3

[0076] As can be seen from LC-MS (see Table 7 for detection method) and NMR, the obtained product is a pair of diastereomers having the following structural formula, and according to NMR, the molar ratio of the two is approximately 2:3. [ka]

[0077] [Table 6]

[0078] [Table 7]

[0079] Example 4 This example prepared the compound DM-D2, named phenyl(3-(10,11-dihydro-5H-dibenzo[b,f]azepine-5-yl)propyl)(methyl)carbamate. The synthesis scheme for the compound DM-D2 in this example is shown below and specifically includes the following steps. [ka] Under nitrogen protection conditions, compound 1 (1 g, 3.75 mmol), dichloromethane (10 mL), and pyridine (890.80 mg, 11.26 mmol) were sequentially added to a reaction flask and mixed uniformly. Then, compound 2 (881.62 mg, 5.63 mmol) was added under an ice bath, and the reaction was stirred under an ice bath for 2 hours. After the reaction was complete, the mixture was concentrated directly to dryness to obtain the crude product. The crude product was separated by normal-phase HPLC preparative chromatography (PE petroleum ether / EA ethyl acetate), and the separation method is shown in Table 8 below. The separated solution was dry-evaporated, and 10 ml of lyophilized acetonitrile and 10 ml of lyophilized water were added and lyophilized to obtain a colorless oily substance, DM-D2 (870 mg, yield: 59.96%). 1 H NMR (400 MHz, DMSO-d6) δ 7.39 - 7.25 (m, 2H), 7.22 - 7.08 (m, 6H), 7.03 (t, J = 8.8 Hz, 2H), 6.95 - 6.87 (m, 2H), 6.79 (d, J = 8.0 Hz, 1H), 3.75 (q, J = 6.0 Hz, 2H), 3.44 (t, J = 7.0 Hz, 1H), 3.32 (s, 1H), 3.10 (s, 1.7H), 3.07 (s, 2.3H), 2.88 (s,1.2H), 2.86 (s,1.7H), 1.77 (m, 2H).LCMS: m / z [M+H] + =387.2.

[0080] [Table 8]

[0081] [Table 9]

[0082] Example 5 In this example, compound DM-D3, named (5-methyl-2-oxo-1,3-dioxyol-4-yl)methyl(3-(10,11-dihydro-5H-dibenzo[b,f]azepinepyridine-5-yl)propyl)(methyl)carbamate and with the structural formula shown below, was prepared. [ka]

[0083] The synthesis scheme for compound DM-D3 in this embodiment is shown below and specifically includes the following steps. [ka] Step 1: Under a nitrogen atmosphere, compound 1 (200 mg, 1.54 mmol), acetonitrile (4 mL), and pyridine (365 mg, 4.61 mmol) were added sequentially to a reaction flask and mixed uniformly. Then, compound 2 (341 mg, 1.69 mmol) was added at 0°C, and the mixture was slowly allowed to return to room temperature while stirring for 5 hours. After the reaction was complete, the reaction mixture was used directly for the next step to obtain compound 3 (450 mg, yield: 99%, crude product).

[0084] Step 2: Under a nitrogen atmosphere, compound 4 (325 mg, 1.22 mmol) and acetonitrile (3 mL) were added sequentially to the reaction flask and mixed uniformly. Then, compound 3 (450 mg, 1.52 mmol) was added at 0°C, and the mixture was slowly returned to room temperature and mixed for 12 hours. After the reaction was complete, the mixture was concentrated directly to dryness to obtain the crude product. The crude product was separated by reverse-phase HPLC preparative chromatography (aqueous formic acid solution / acetonitrile system), and the separation method is shown in Table 10 below. The acetonitrile was concentrated from the separated solution and freeze-dried to obtain DM-D3, a yellow oily liquid (200 mg, yield: 31%). 1H NMR (400 MHz, Chloroform-d) δ 7.18 - 7.01 (m, 6H), 6.92 (td, J = 7.4, 1.3 Hz, 2H), 4.79 (s, 0.9H), 4.58 (s, 1.2H), 3.74 (t, J = 6.4 Hz, 2H), 3.29 (dt, J = 10.4, 7.2 Hz, 2H), 3.17 (d, J = 5.6 Hz, 4H), 2.79 (s, 1.7H), 2.74 (s, 1.3H), 2.14 (d, J = 3.4 Hz, 3H), 1.79 (dp, J = 13.2, 7.0 Hz, 2H).LCMS: m / z [M+1]+=423.1.

[0085] [Table 10]

[0086] [Table 11]

[0087] Example 6 This example prepared the compound DM-D4, named (phosphonoxy)methyl(3-(10,11-dihydro-5H-dibenzo[b,f]azepine-5-yl)propyl)(methyl)carbamate. The synthesis scheme for the compound DM-D4 in this example is shown below and specifically includes the following steps. [ka] Step 1: Under a nitrogen atmosphere, compound 1b (500 mg, 1.88 mmol), sodium bicarbonate (371 mg, 2.68 mmol), and dichloromethane (5 mL) were added sequentially to a reaction flask. The reaction system was cooled to 5°C, and compound 1a (266 mg, 2.06 mmol) was added dropwise. After the addition was complete, the reaction system was stirred at 5-10°C for 5 hours. After the reaction was complete, the undissolved sodium bicarbonate solid was first removed by filtration, the filtrate was collected, the organic phase was dried over anhydrous magnesium sulfate, and the organic phase was concentrated to obtain a colorless oily liquid (660 mg, yield: 97.1%), which was used directly in the next step without purification.

[0088] Step 2: At room temperature, compound 2b (600 mg, 1.67 mmol), compound 2a (558 mg, 2.01 mmol), cesium carbonate (1.63 g, 5.02 mmol), and acetonitrile (10 mL) were sequentially added to the reaction flask and mixed uniformly. The temperature was then raised to 50°C and the mixture was stirred for 16 hours. After the reaction was complete, the mixture was filtered and concentrated to obtain the crude product. The crude product was separated in the forward direction (PE:EA = 2:1, Rf = 0.5) to obtain a colorless oily compound 3a (540 mg, yield: 53.8%).

[0089] Step 3: In a hydrogen atmosphere, compound 3a (540 mg, 0.89 mmol), ethanol (20 mL), and Pd / C (105 mg, 0.99 mmol) were sequentially added to the reaction flask, and after homogeneous stirring, the reaction was allowed to proceed at room temperature for 5 hours. After the reaction was complete, the mixture was concentrated directly to dryness to obtain the crude product. The crude product was then separated by reverse-phase HPLC preparative chromatography (aqueous formic acid solution / acetonitrile system), and the separation method is shown in Table 12 below. The separated solution was concentrated with acetonitrile and then freeze-dried to obtain the white solid compound DM-D4 (220 mg, yield: 58.2%). 1H NMR (400 MHz, Chloroform-d) δ 7.37 (s, 3H), 7.07 (h, J = 8.0 Hz, 6H), 6.90 (q, J = 7.2 Hz, 2H), 5.50 (d, J = 12.8 Hz, 1H), 5.34 (d, J = 12.8 Hz, 1H), 3.69 (dt, J = 12.8, 6.5 Hz, 2H), 3.24 (q, J = 6.4 Hz, 2H), 3.14 (s, 4H), 2.71 (d, J = 6.4 Hz, 3H), 1.75 (p, J = 6.8 Hz, 2H). LCMS: m / z [M+H]+=421.1.

[0090] [Table 12]

[0091] [Table 13]

[0092] Comparative Example 1 In this comparative example, compound DM-A1, whose name is (S)-4-amino-5-((3-(10,11-dihydro-5H-dibenzo[b,f]azepine-5-yl)propyl)(methyl)amino)-5-oxopenthenoic acid, was prepared. The synthesis scheme for compound DM-A1 in this comparative example is shown below and specifically includes the following steps. [ka] Step 1: In a nitrogen atmosphere, add dichloromethane (15 mL) to a reaction flask, and then add compound 1 (500 mg, 1.65 mmol), N,N,N’,N’-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (1.06 g, 3.30 mmol), and N,N-diisopropylethylamine (639 mg, 4.94 mmol). Replace nitrogen three times. Stir the reaction solution at room temperature for 10 minutes. Add compound 2 (483 mg, 1.81 mmol) to the reaction solution and stir at this temperature for 3 hours. After completion of the reaction, add 50 mL of water, and then extract twice with dichloromethane (30 mL each time). Wash the organic phase with saturated brine, dry it, and concentrate to obtain a crude product. Purify the crude product by silica gel column chromatography to obtain compound 3 as a colorless transparent oily product (700 mg, yield: 77%).

[0093] Step 2: In a nitrogen atmosphere, add dichloromethane (10 mL) and trifluoroacetic acid (10 mL) to a reaction flask, and then add compound 3 (700 mg, 1.27 mmol). Stir the reaction at room temperature for 3 hours. After completion of the reaction, directly concentrate the reaction solution to obtain a crude product. Separate the crude product by reverse-phase high-performance liquid chromatography (water (0.225% formic acid) / acetonitrile system) to obtain compound DM-A1 as a white solid product (260 mg, yield: 52%). 1 H NMR (400 MHz, DMSO-d6) δ 7.19 - 7.03 (m, 6H), 6.96 - 6.84 (m, 2H), 3.98 - 3.59 (m, 3H), 3.33 (m, 2H), 2.89 (s, 2H), 2.69 (s, 1H), 2.37 - 2.14 (m, 2H), 1.69 (m, 3H), 1.51 (m, 1H). LCMS: m / z [M+H] + =396.2.

[0094] Experimental Example 1 Pharmacokinetic experiment in SD rats after single administration of DM-A1 and desipramine Pharmacokinetic Experiment: Eighteen SD rats were randomly divided into three groups of six. Each rat weighed between 180 and 200 g, and the test drugs were DM-A1 and desipramine hydrochloride, respectively. The test drug solution was prepared using a carboxymethylcellulose sodium solution (prepared by mixing 5 ml of dimethyl sulfoxide with 95 ml of a 0.5 wt% aqueous solution of carboxymethylcellulose sodium) as the solvent. The dosage and administration method are as shown in the table below. Rats were fasted for at least 12 hours and up to 18 hours before intragastric administration, and fed 4 hours after administration. Fluid intake was not restricted before or after administration. Fasting and fluid intake were not restricted before or after tail vein injection. All administrations were single doses, and the administration volume was 5 mL / kg.

[0095] [Table 14]

[0096] Blood samples were collected before administration (0h) and at 5 min, 10 min, 20 min, 30 min, 1 h, 2 h, 4 h, 6 h, 12 h, and 24 h after administration. Plasma was obtained from the samples, and DM-A1 and desipramine were quantified by LC-MS / MS. The chromatography conditions were as follows: ACE 5 C18 column, 50 × 2.1 mm; mobile phase A: aqueous solution of 0.1% FA, B: ACN containing 0.1% FA, gradient elution, elution procedure: 0 → 0.3 min → 0.7 min → 1.5 min → 1.6 min → 2.1 min, volume percentage of mobile phase A: 70% → 70% → 5% → 5% → 70% ~ 70%, volume percentage of mobile phase B: 30% → 30% → 95% → 95% → 30% → 30%, column temperature: 45°C, flow rate: 0.4 mL / min. The MS conditions were as follows: Ionization mode of DM-A1: Positive / MRM, Q1 / Q3: 396.3 / 378.2, DP: 70V, CE: 15V. Ionization mode of desipramine hydrochloride: Positive / MRM, Q1 / Q3: 266.9 / 236.2, DP: 70V, CE: 21V. The following pharmacokinetic parameters for DM-A1 and desipramine are defined as the area under the blood concentration-time curve (AUC). 0-t ), maximum blood concentration (C max), peak hours (T max ), half-life (t 1 / 2 ), clearance (CL), and bioavailability (F) were calculated. The experimental results are shown in the table below.

[0097] [Table 15]

[0098] Experimental results: When DM-A1 was administered intragastricly to SD rats, desipramine was not detected in the plasma. Therefore, desipramine-related parameters were not evaluated or calculated in the DM-A1 group (group 1). The DM-A1-related parameters are shown in the table. On the other hand, desipramine was detected in both the intragastric administration group and the intravenous injection group (groups 2 and 3).

[0099] Experimental Example 2: Pharmacokinetic experiments on single-dose administration of DM-C2, DM-C3, and desipramine to SD rats. Pharmacokinetic Experiment: Fourteen SD rats were randomly divided into three groups. One group consisted of six rats, and the other two groups consisted of four rats each. Each rat weighed between 180 and 200 g, and the test drugs were DM-C2, DM-C3, and desipramine hydrochloride, respectively. The test drug solutions were prepared using a carboxymethylcellulose sodium solution (prepared by mixing 5 ml of dimethyl sulfoxide with 95 ml of a 0.5 wt% carboxymethylcellulose sodium solution) as the solvent. The dosage and administration method are shown in the table below. The rats were fasted for at least 12 hours and up to 18 hours before intragastric administration, and fed 4 hours after administration. Water intake was not restricted before or after administration. All administrations were single doses, and the administration volume was 10 mL / kg.

[0100] [Table 16]

[0101] In this experiment, the dose conversion used desipramine hydrochloride as a baseline, and the doses of the other two test substances were converted using the same molar amount of desipramine. Factors such as the type and purity of the salt were taken into consideration in the calculation process.

[0102] Blood samples were collected before administration (0h) and at 5 min, 10 min, 20 min, 30 min, 1 h, 2 h, 4 h, 6 h, 12 h, and 24 h after administration. Plasma was obtained from the samples, and DM-C2, DM-C3, and desipramine were quantified by LC-MS / MS. The chromatography conditions were as follows. XB-C8 (2.1 mm × 50 mm, 5 μm), Welch; Mobile phase A: 0.1% FA aqueous solution, B: 0.1% FA-containing ACN, gradient elution, elution procedure: 0.01 min → 1 min → 3 min → 4.5 min → 4.51 min → 5.5 min, Volume percentage of mobile phase A: 80% → 80% → 2% → 2% → 80% → 80%, Volume percentage of mobile phase B: 20% → 20% → 98% → 98% → 20% → 20%, Column temperature: 45°C, Flow rate: 0.5 mL / min. MS conditions are as follows: DM-C2 ionization mode: Positive / MRM, Q1 / Q3: 459.43 / 234.3, DP: 58 V, CE: 30 V. Ionization mode of DM-C3: Positive / MRM, Q1 / Q3: 484.4 / 311.4, DP: 90V, CE: 22V. Ionization mode of desipramine hydrochloride: Positive / MRM, Q1 / Q3: 267.4 / 71.9, DP: 80V, CE: 20V.

[0103] The pharmacokinetic parameter of desipramine is the area under the blood concentration-time curve (AUC). 0-t ), maximum blood concentration (C max ), peak hours (T max ), half-life (t 1 / 2 ), and the clearance (CL) was calculated.

[0104] The experimental results are shown in the table below.

[0105] [Table 17]

[0106] Experimental results: DM-C2 and DM-C3 were not detected in the plasma samples of the DM-C2 and DM-C3 groups, therefore their related parameters were not evaluated or calculated. On the other hand, desipramine was detected in both the DM-C2 and DM-C3 groups. The table shows the parameters for desipramine. In particular, the AUC in the DM-C3 group was high. 0-t (9882.5 h*ng / mL) and C max All of the values ​​(681.75 ng / mL) are the AUC of the desipramine hydrochloride group. 0-t (4653.33 h*ng / mL) and C max The levels were higher than (400 ng / mL). This suggests that DM-C3 may increase systemic exposure to desipramine in vivo in SD rats.

[0107] Experimental Example 3: Pharmacokinetic experiments on single-dose administration of DM-C3 and desipramine to SD rats. Pharmacokinetic Experiment: Eighteen SD rats were randomly divided into three groups of six. Each rat weighed 180-200g, and the test drugs were DM-C3 and desipramine hydrochloride, respectively. The test drug solutions were prepared using a carboxymethylcellulose sodium solution (prepared by mixing 5ml of dimethyl sulfoxide with 95ml of a 0.5wt% carboxymethylcellulose sodium solution) as the solvent. The dosage and administration method are as shown in the table below. The rats were fasted for at least 12 hours before intragastric administration, and feed was resumed 4 hours after administration. Water intake was not restricted before or after administration. All administrations were single doses, and the administration volume was 10mL / kg, 6mL / kg, and 2mL / kg for each group, in that order.

[0108] [Table 18]

[0109] In this experiment, dose conversion was performed using the dose of desipramine hydrochloride administered intragastricly as a baseline, and the dose of DM-C3 was converted using the same molar amount of desipramine. Factors such as the type and purity of the salt were taken into consideration in the calculation process.

[0110] For intravenous injection, blood samples were collected before administration (0h) and at 5 min, 10 min, 20 min, 1 h, 2 h, 4 h, 6 h, 12 h, and 24 h after administration. For intragastric administration, blood samples were collected before administration (0h) and at 10 min, 20 min, 30 min, 1 h, 2 h, 4 h, 6 h, 12 h, 24 h, and 48 h after administration. Plasma was obtained from the samples, and DM-C3 and desipramine were quantified by LC-MS / MS. The chromatography conditions were as follows. YMC Triart C18 column, 5 μm 50 × 2.0 mm; mobile phase A: aqueous solution of 0.1% FA (formic acid), B: ACN containing 0.1% FA (formic acid), gradient elution, elution procedure: 0 → 1.0 min → 1.8 min → 1.9 min → 2.6 min, volume percentage of mobile phase B: 30% → 95% → 95% → 30% → stop, column temperature: 35°C, flow rate: 0.8 mL / min. MS conditions are as follows: DM-C3 ionization mode: Positive / MRM, Q1 / Q3: 484.5 / 311, DP: 98 V, CE: 23 V. Desipramine hydrochloride ionization mode: Positive / MRM, Q1 / Q3: 267.2 / 236.3, DP: 40 V, CE: 22 V.

[0111] The pharmacokinetic parameter of desipramine is the area under the blood concentration-time curve (AUC). 0-t ), maximum blood concentration (C max ), peak hours (T max ), average stay time (MRT last ), and the bioavailability (F%) was calculated.

[0112] The experimental results are shown in the table below.

[0113] [Table 19]

[0114] Experimental results: DM-C3 was not detected in the plasma samples of the DM-C3 group, therefore its related parameters were not evaluated or calculated. AUC of the DM-C3 group. last(9984 h*ng / mL) and C max (682 ng / mL) is the AUC for the oral desipramine hydrochloride administration group. last (8964 h*ng / mL) and C max The level was higher than (712.8 ng / mL). The absolute bioavailability of the DM-C3 group (116.84%) was higher than that of the oral desipramine hydrochloride group (104.9%).

[0115] Since DM-C3 was not detected in the DM-C3 group samples, its related parameters were not evaluated or calculated.

[0116] The number of animals No. 2 and No. 8 in the DM-C3 oral administration group and the desipramine hydrochloride oral administration group was abnormal, and individual differences in the animals were thought to lead to detection bias, so they were not included in the parameter calculations.

[0117] In summary, after oral administration of DM-C3 to SD rats, the amount of desipramine produced by metabolism and entering the systemic circulation was greater than the amount produced by oral administration of desipramine hydrochloride. This indicates that DM-C3 can increase the systemic exposure of desipramine in SD rats and improve its oral bioavailability.

[0118] Experimental Example 4: Pharmacokinetic experiments on single-dose administration of DM-D4 and desipramine to SD rats. Pharmacokinetic experiment: Twelve SD rats were randomly divided into two groups of six. Each rat weighed 180-200g, and the test drugs were DM-D4 and desipramine hydrochloride, respectively. The test drug solutions were prepared using a carboxymethylcellulose sodium solution (prepared by mixing 5ml of dimethyl sulfoxide with 95ml of a 0.5wt% carboxymethylcellulose sodium solution) as the solvent. The dosage and administration method are as shown in the table below. The rats were fasted for at least 12 hours, and up to 18 hours, before intragastric administration, and fed 4 hours after administration. Water intake was not restricted before or after administration. All administrations were single doses, and the administration volume was 10mL / kg.

[0119] [Table 20]

[0120] In this experiment, the dose conversion used desipramine hydrochloride as a baseline, and the dose of DM-D4 was converted using the same molar amount of desipramine. Factors such as the type and purity of the salt were taken into consideration in the calculation process.

[0121] Blood samples were collected before administration (0h) and at 10 min, 20 min, 30 min, 1 h, 2 h, 4 h, 6 h, 12 h, and 24 h after administration. Plasma was obtained from the samples, and DM-D4 and desipramine were quantified by LC-MS / MS. The chromatography conditions were as follows. ACE Excel5 C18, 2.1x50mm, 5μm; Mobile phase A: Aqueous solution of 0.1% FA and 5mM NH4FA (ammonium formate), B: ACN containing 0.1% FA, gradient elution, elution procedure: 0.01min→0.5min→1.2min→2.0min→2.1min→3.0min, Volume percentage of mobile phase A: 65%→65%→5%→5%→65%→65%, Volume percentage of mobile phase B: 35%→35%→95%→95%→35%→35%, Column temperature: 40℃, Flow rate: 0.5mL / min. MS conditions are as follows: Ionization mode of DM-D4: Positive / MRM, Q1 / Q3: 421.3 / 234.2, DP: 80V, CE: 35V. Ionization mode of desipramine hydrochloride: Positive / MRM, Q1 / Q3: 267.2 / 72.2, DP: 80V, CE: 30V.

[0122] The pharmacokinetic parameter of desipramine is the area under the blood concentration-time curve (AUC). 0-t and AUC 0-∞ ), maximum blood concentration (C max ), peak hours (T max ), half-life (t 1 / 2 ), and the clearance (CL) was calculated.

[0123] The experimental results are shown in the table below.

[0124] [Table 21]

[0125] [Table 22]

[0126] Experimental results: Since DM-D4 was not detected in any of the samples in the DM-D4 group, its related parameters were not evaluated or calculated. AUC of the DM-D4 group 0-t (2805 hng / mL) and C max (222.5 ng / mL) is the AUC of the desipramine hydrochloride group. 0-t (1895 hN / mL) and C max The level was higher than (173 ng / mL). When DM-D4 was orally administered to SD rats, the amount of desipramine produced by metabolism and entering the systemic circulation was higher than the amount produced by oral administration of desipramine hydrochloride, indicating that DM-D4 can increase the systemic exposure of desipramine in vivo in SD rats and improve its oral bioavailability.

[0127] Clearly, the embodiments described above are merely illustrative examples and are not intended to limit the embodiments. Those skilled in the art can make other different forms of modifications or alterations based on the above description. A complete list of all embodiments is neither necessary nor possible here. Any obvious changes or alterations derived therefrom still fall within the scope of the invention.

Claims

1. A compound that improves the bioavailability of desipramine, whose structural formula is shown below. 【Chemistry 1】 (Here, R 1 is selected from H, C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl, R 2 This includes unsubstituted or substituted C1-C4 alkyl, C5-C20 aryl, or 【change】 Selected from, R 3 These are selected from unsubstituted or substituted C1-C4 alkyl or C5-C20 aryl compounds. R 2 and R 3 In the definition of the group, "substituted" means that 1 to 3 H on the group are hydroxyl, amino, carboxyl, unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted C5-C20 aryl, unsubstituted or substituted 3-20 membered heterocyclic groups, condensation groups formed by an unsubstituted or substituted 3-20 membered heterocycle and a C5-C20 aromatic ring, and 【change】 This means that the group is substituted with at least one selected from the following, where the substituents of the substituted C1-C4 alkyl, C5-C20 aryl, 3-20 membered heterocyclic group, and the substituent of the condensation group formed by the 3-20 membered heterocycle and the C5-C20 aromatic ring are C1-C4 alkyl or hydroxyl, the heteroatoms of the heterocycle are N, O, or S, and the number of heteroatoms is 1 to 6.

2. R 2 This includes unsubstituted or substituted C1-C4 alkyl, phenyl, or Selected from, where term R 3 A compound that improves the bioavailability of desipramine according to claim 1, characterized in that it is as defined in claim 1.

3. R 2 It is selected from unsubstituted or substituted C1-C4 alkyl groups, where substitution means that 1-3 H atoms on the alkyl group are hydroxyl groups. is replaced by at least one selected from, preferably, R 2 is A compound that improves the bioavailability of desipramine according to claim 2, characterized by being selected from methylene substituted with .

4. A compound that improves the bioavailability of desipramine according to claim 1, characterized by having the structural formula shown in formula II. 【Chemistry 2】 (Here, R 1 and R 3 (This is as defined in claim 1.)

5. R 3 C is either non-substituted or substituted. 1 ~C 4 Selected from alkyl or phenyl, substitution means that 1 to 3 H atoms on the alkyl group are replaced with amino, carboxyl, A compound that improves the bioavailability of desipramine according to claim 4, characterized in that it is substituted with at least one selected from, preferably, an amino and a carboxyl.

6. R 1 A compound that improves the bioavailability of desipramine according to any one of claims 1 to 5, characterized in that it is selected from H, C1 to C4 alkyl, and preferably methyl.

7. A compound that improves the bioavailability of desipramine according to claim 1, characterized by being one selected from the following compounds.

8. A pharmaceutical composition comprising a compound that improves the bioavailability of desipramine according to any one of claims 1 to 7, and a pharmaceutically acceptable carrier and / or auxiliary agent.

9. Use of a compound that improves the bioavailability of desipramine according to any one of claims 1 to 7 in the preparation of a drug for preventing, treating or alleviating at least one of the following conditions: depression, pain, macular degeneration in dry skin, and neuropathy.

10. The use of a compound that improves the bioavailability of desipramine according to any one of claims 1 to 7 in the preparation of a drug that improves the bioavailability of desipramine or a pharmaceutically acceptable salt thereof.

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