M-cholinergic receptor agonist compound and its preparation and use

Abstract

The present invention relates to an M-cholinergic receptor agonist compound represented by formula (A) and its preparation and use. The compound represented by formula (A) of the present invention is effective when used for ophthalmic diseases, particularly for presbyopia, or for ocular miosis, and has a rapid onset of action, a long duration of action, and a high potency. [Formula 1] JPEG2025502536000071.jpg36169

Description

Detailed Description of the Invention

[0001] This application claims priority to two prior applications: Patent Application No. 2022101130948, entitled "M-cholinergic receptor agonist compounds and their preparation and use," filed with the State Intellectual Property Administration of China on January 29, 2022, and Patent Application No. 202210809710.5, entitled "Cholinester phenylacetate derivatives and their preparation and use," filed on July 11, 2022. Both applications are incorporated herein by reference in their entireties.

[0002] [Technical Field] The present invention belongs to the technical field of pharmaceutical compounds, and specifically relates to M-cholinergic receptor agonist compounds and their preparation methods and uses.

[0003] [Background technology] Presbyopia (presbyopia) is a common visual problem in middle-aged and elderly people. As we age, the lens gradually hardens and thickens, and the ability of the eye's muscles to accommodate decreases. This leads to a gradual loss of accommodation, resulting in a decrease in zoom ability. When viewing close-up objects, the image is not fully focused when projected onto the retina, resulting in blurred vision. Presbyopia frequently develops after the age of 40, and without correction, it can significantly impact a person's quality of life and productivity. (Frick et al., 2015, Ophthalmology 122(8):1706-1710; Goertz et al., 2014, Acta Ophthalmologica 92(6):497-500; Patel et al., 2007, Community eye health / International Centre for Eye Health 20(63):40-41).

[0004] The main symptom of presbyopia is the gradual blurring of vision when performing close-up tasks (such as reading, sewing, or working in front of a computer), and it is one of the most prevalent diseases worldwide, significantly affecting the quality of life of middle-aged and elderly people. As the duration of screen use, such as with mobile phones, has increased significantly, the incidence of presbyopia has been increasing year by year.

[0005] The main treatment for presbyopia is the wearing of typical conventional reading glasses, but wearing reading glasses for a long period of time can cause eye fatigue, headaches, dizziness, etc. In addition, reading glasses require frequent putting on and taking off, making them difficult to carry around.

[0006] Currently, several candidate drugs for the improvement or treatment of presbyopia are in the research and development stage. For example, Liquid Vision (PRX-100), which contains low-dose acetonitrile, is an anticholinesterase drug that constricts the pupil, increasing the depth of focus and allowing patients to achieve near vision. On the other hand, CSF-1 drops (Orasis) are a drug that acts on the parasympathetic nervous system. By adding a nonsteroidal anti-inflammatory drug to an oily base, it can cause pupil constriction, increase the depth of focus, and improve presbyopia symptoms. Several topical formulations are also in various stages of development.

[0007] There are also products undergoing clinical research into drug-device combinations for presbyopia. Vision Polar Eye Biosciences announced that ARVN003 has entered Phase 3 clinical trials. This is a pilocarpine hydrochloride eye spray delivered by a micro-dosing device. Developers claim that this device prevents leakage during instillation and reduces the risk of drug or preservative exposure due to overdosing. However, this drug-device combination has drawbacks for commercialization, including price and the relatively high dosage concentration.

[0008] In November 2021, the U.S. Food and Drug Administration (FDA) approved Vuity (pilocarpine HCl, 1.25% eye drops), an ophthalmic drug developed by Allergan, a subsidiary of Abbvie, for the treatment of presbyopia. This is the world's first topical eye drop for presbyopia. As an M-cholinergic receptor agonist, it is instilled into both eyes once daily. It has an onset time of approximately 15 minutes and a retention time of approximately 4 to 6 hours. Patients treated with Vuity showed improved near and intermediate distance vision, without affecting distance vision.

[0009] However, as the first presbyopia medication, Vuity has been reported to cause eye rash, eye discomfort, severe eye irritation, and headaches (incidence >5%) in some patients 5 minutes after instillation. At the same time, improvements in the onset time, duration of action, and usability of Vuity (pilocarpine hydrochloride) are desired.

[0010] Summary of the Invention In order to solve the above technical problems, the present invention provides a compound represented by formula (A) and pharmaceutically acceptable hydrates and solvates thereof: [ka] wherein R1, R2, R3, R4, and R5 are the same or different and independently represent hydrogen, C 1-6 selected from alkyl groups, halogens, cyano groups, and -NR'R''; R' and R'' are the same or different, and each independently represents H, C 1-6 Alkyl group, C 3-10 Cycloalkyl groups, C 6-14 selected from an aryl group, a 5- to 14-membered heteroaryl group, and a 3- to 10-membered heterocyclyl group; R is COOH or [ka] Selected from Wherein, Ra and Rb are the same or different and independently represent hydrogen, C 1-6 Alkyl group, halogen, cyano group, C 3-10 Cycloalkyl groups, C 6-14 selected from an aryl group, a 5- to 14-membered heteroaryl group, and a 3- to 10-membered heterocyclyl group; Above C 1-6 Alkyl group, C 3-10 Cycloalkyl groups, C 6-14 The aryl group, 5- to 14-membered heteroaryl group, and 3- to 10-membered heterocyclyl group may optionally be substituted with oxo, thio, halogen, cyano group, —NR′R″, —COOH, hydroxy group, C 1-6Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 3~10 Cycloalkyl groups, C 6-14 It is substituted with one, two or more groups selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group.

[0011] According to an embodiment of the present invention, the compound represented by formula (A) is selected from the compounds represented by formula I-1 or I-2 below. [ka]

[0012] In some embodiments, in Formula I-1, R1, R2, R3, R4, and R5 are the same or different and each independently represent hydrogen, C 1-6 It is selected from an alkyl group, a halogen, a cyano group, and an amino group.

[0013] In some embodiments, in Formula I-1, R1, R2, R3, R4, and R5 are the same or different and are each independently selected from hydrogen, a methyl group, an ethyl group, an isopropyl group, chlorine, fluorine, and a cyano group.

[0014] In some embodiments, in formula I-1, at least three of R1, R2, R3, R4, and R5 are H.

[0015] In some embodiments, in formula I-1, four of R1, R2, R3, R4, and R5 are H.

[0016] In some embodiments, in Formula I-1, R1, R2, R4, and R5 are all H, and R3 is C 1-6 Alkyl groups, halogens, cyano groups, and -NR'R''.

[0017] In some embodiments, in Formula I-1, R1, R2, R3, and R5 are all H, and R4 is C 1-6 Alkyl groups, halogens, cyano groups, and -NR'R''.

[0018] In some embodiments, in Formula I-2, R1, R2, R3, R4, and R5 are the same or different and each independently represent hydrogen, C 1-6 alkyl group, halogen, or -COOR', where R' is independently selected from H, C 1-6 It is selected from alkyl groups.

[0019] In some embodiments, in Formula I-2, R1, R2, R3, R4, and R5 are the same or different and are each independently selected from hydrogen, a methyl group, an ethyl group, an isopropyl group, chlorine, fluorine, and bromine.

[0020] In some embodiments, in Formula I-2, R a and R b are the same or different and each independently represent hydrogen, C 1-6 is selected from alkyl groups, halogens, and cyano groups, and is preferably hydrogen or C 1-6 It is an alkyl group.

[0021] In some embodiments, in Formula I-2, R1, R2, R3, R4, and R5 are the same or different, and at least two of them are selected from hydrogen, preferably three or four of them are selected from hydrogen.

[0022] In some embodiments, the compound represented by formula I-1 above is selected from the following: [Table 1]

[0023] The compound represented by the above formula (I-2) is selected from the following: [Table 2] JPEG2025502536000007.jpg192169

[0024] Preferably, the compound of formula I-1 above is: [ka]

[0025] Preferably, the compound of formula I-2 above is selected from: [ka]

[0026] The present invention further provides a method for producing the compound represented by the above formula (A), which comprises reacting pilocarpine with a compound represented by formula (A-1) to obtain the compound represented by formula (A), [ka] wherein R, R1, R2, R3, R4, and R5 have the above definitions.

[0027] According to an embodiment of the present invention, the molar ratio of pilocarpine to the compound of formula (A-1) is 1:1.

[0028] According to an embodiment of the present invention, the reaction is carried out at room temperature.

[0029] The present invention further provides a pharmaceutical composition comprising at least one of the compounds represented by the above formula (A) and pharmaceutically acceptable hydrates and solvates thereof.

[0030] According to an embodiment of the present invention, the pharmaceutical composition is used for the prevention or treatment of an ophthalmic disease or condition, and the ophthalmic disease or condition is at least one of presbyopia, cataract, glaucoma, dry eye, diabetic retinopathy, macular degeneration, optic neuritis, and retinitis pigmentosa.

[0031] According to an embodiment of the present invention, in the pharmaceutical composition, the mass concentration of the compound represented by formula (A) is 0.3% to 8%, preferably 0.3% to 4%, or 0.88% to 3.5%.

[0032] According to an embodiment of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable vector or excipient, such as a moisturizing agent, a transdermal absorption enhancer, a preservative, an embedding agent, a film-forming agent, etc.

[0033] According to an embodiment of the present invention, the pharmaceutical composition is formulated for oral, parenteral, ophthalmic, topical, injectable, subcutaneous, transdermal, rectal, buccal or transmucosal administration.

[0034] According to a preferred embodiment of the present invention, the pharmaceutical composition is prepared for ocular administration.

[0035] According to an embodiment of the present invention, the pharmaceutical composition can be prepared in the form of a suspension, gel, ointment, injectable solution, spray or eye drop formulation.

[0036] According to an embodiment of the present invention, the pharmaceutical composition can be combined with other drugs to form a combination formulation, such as an anti-allergic drug, adding a synergistic ingredient, or adding an ingredient to improve comfort.

[0037] According to a preferred embodiment of the present invention, the pharmaceutical composition is in the form of an eye drop preparation.

[0038] The present invention further provides the use of a compound of formula (A) in the manufacture of a medicament for ameliorating or treating an ophthalmic disease or condition.

[0039] According to an embodiment of the present invention, the ophthalmic disease or condition is at least one of presbyopia, cataract, glaucoma, dry eye, diabetic retinopathy, macular degeneration, optic neuritis, and retinitis pigmentosa.

[0040] According to a preferred embodiment of the present invention, the ophthalmic disease or condition is presbyopia.

[0041] The present invention further provides use of at least one of the compounds represented by formula (A) and pharmaceutically acceptable hydrates and solvates thereof in the manufacture of a miotic medicament.

[0042] According to an embodiment of the present invention, the therapeutically effective amount of the compound is 0.001 to 1000 mg / subject.

[0043] Beneficial effects The compounds of the present invention are obviously effective when used for ophthalmic diseases, particularly for presbyopia, or for ophthalmic miosis, with rapid onset, long duration of action and high potency.

[0044] Specifically, in the case of the pilocarpine benzoate compound shown in formula I-1, In screening various salt forms of pilocarpine, the present researchers unexpectedly discovered that the pupil constriction effect of pilocarpine benzoate compounds was superior overall to that of pilocarpine hydrochloride. In comparative test doses, 1) the pilocarpine benzoate compounds of the present invention had a pupil constriction onset effect after 5 minutes superior to that of pilocarpine hydrochloride, achieving a faster onset of action. 2) Pilocarpine hydrochloride solution had a measured value of -3.13±7.35 when measured at 3 hours, essentially showing no pupil constriction effect. In contrast, the compounds in this series still had a significant pupil constriction effect when measured at 3 hours, and the effect lasted for 4 hours or longer, extending the duration of action by more than 33% compared to pilocarpine hydrochloride. 3) While the maximum percentage change in pupil diameter with pilocarpine hydrochloride is about 35%, the maximum percentage change in pupil diameter with the compounds of the present invention can reach 40% to 45%, with a maximum efficacy of 15 to 30%. It has been found that the pilocarpine benzoate compounds of the present invention have a faster onset of action, a longer duration of action, and greater efficacy, with significant differences in all technical indicators. The efficacy of the pilocarpine benzoate compounds of the present invention can achieve the same or even stronger efficacy than pilocarpine hydrochloride at half the dose.

[0045] Furthermore, as can be seen from the comparison of the irritation of rabbit eyes between pilocarpine hydrochloride solution and pilocarpine benzoate solution, the irritation of rabbit eyes of the pilocarpine benzoate compound of the present invention is comparable to that of pilocarpine hydrochloride. Further reduction in the dose significantly reduces adverse reactions when the same therapeutic effect is achieved.

[0046] Specifically, in the case of the pilocarpine phenylacetate compound shown in formula I-2, The study showed that the duration of miotic action of pilocarpine phenylacetate salts was at least 1 hour longer than that of other pilocarpine salts, and the duration of efficacy was relatively extended by more than 33%, improving the duration of efficacy and reducing the frequency of administration.

[0047] Pilocarpine phenylacetate solution has less irritation to the eyes, faster onset of action, and significant differences in technical indicators. Moreover, even at half the molar concentration of pilocarpine hydrochloride, pilocarpine phenylacetate solution still achieves the same effects as pilocarpine hydrochloride, allowing for reduced dosage.

[0048] The stability of pilocarpine phenylacetate-based raw materials and formulations is generally superior to that of pilocarpine hydrochloride-based raw materials, the growth rate of related impurities is slow, and quality control is easy.In addition, the salt formation ratio in pilocarpine phenylacetate-based solutions can be maintained at about 1:1 under various pH conditions, making them stable over the long term and less prone to precipitation.

[0049] Definitions and explanations of terms "Oxo" refers to "=O".

[0050] "Halogen" refers to fluorine, chlorine, bromine or iodine. Preferably, halogen is fluorine, chlorine or bromine.

[0051] "C 1-6"Alkyl group" should be understood to denote a linear or branched saturated monovalent hydrocarbon group having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl. More particularly, such groups may have 1, 2 or 3 carbon atoms ("C 1-3 alkyl group), such as a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.

[0052] "C 1-6 An "alkoxy group" is a group -OC 1-6 Refers to alkyl groups, and the above C 1-6 The alkyl group has the definition given above.

[0053] "C 1-6 The alkylthio group is -SC 1-6 The above C 1-6 The alkyl group has the definition given above.

[0054] "C 3-10 A "cycloalkyl group" should be understood to denote a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. 3-10 The cycloalkyl group may be, for example, a monocyclic hydrocarbon group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, or a cyclodecyl group, or may be a bicyclic hydrocarbon group such as a decahydronaphthalene ring.

[0055] "C 6-14 An "aryl group" is preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms ("C 6-14aryl groups"), in particular rings having six carbon atoms ("C aryl groups"), such as, for example, phenyl groups, or biphenyl groups, or rings having nine carbon atoms ("C aryl groups"), such as, for example, indanyl or indenyl groups, or rings having ten carbon atoms ("C aryl groups"), such as, for example, tetrahydronaphthyl, dihydronaphthyl or naphthyl groups. 10 aryl group), or a ring with 13 carbon atoms, such as a fluorenyl group ("C 13 aryl group), or a ring having 14 carbon atoms, such as an anthryl group ("C 14 It should be understood that the term "aryl group" refers to an aryl group.

[0056] A "5- to 14-membered heteroaryl group" is to be understood as including a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O and S, and which in each case may be benzo-fused. In particular, heteroaryl groups include thienyl, furan, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl groups and benzo derivatives thereof, such as benzofuran, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, or is selected from a pyridinyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazinyl group, etc., and benzo derivatives thereof, such as a quinolyl group, a quinazolinyl group, an isoquinolyl group, etc., or an azocinyl group, an indolizinyl group, a purinyl group, etc., and benzo derivatives thereof, or a cinnolinyl group, a phthalazinyl group, a quinazolinyl group, a quinoxalinyl group, a naphthyridinyl group, a pteridinyl group, a carbazolyl group, an acridinyl group, a phenazinyl group, a phenothiazinyl group, a phenoxazinyl group, etc.

[0057] A "3- to 10-membered heterocyclyl group" refers to a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1 to 5, preferably 1 to 3, heteroatoms selected from N, O, and S. The heterocyclyl group can be linked to the remainder of the molecule through any one of the carbon atoms or a nitrogen atom (if present). In particular, the heterocyclyl group may include, but is not limited to, a 4-membered ring such as an azetidinyl group or an oxetanyl group; a 5-membered ring such as a tetrahydrofuran group, a dioxolyl group, a pyrrolidinyl group, an imidazolidinyl group, a pyrazolidinyl group, or a pyrrolinyl group; a 6-membered ring such as a tetrahydropyranyl group, a piperidinyl group, a morpholinyl group, a dithianyl group, a thiomorpholinyl group, a piperazinyl group, or a trithianyl group; or a 7-membered ring such as a diazepanyl group. Optionally, the heterocyclyl group may be benzo-fused. The heterocyclyl group may be bicyclic, for example, but not limited to, a 5,5-membered ring such as a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring such as a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The nitrogen atom-containing ring may be partially unsaturated, i.e., contain one or more double bonds, for example, but not limited to, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, or may be benzo-fused, for example, but not limited to, a dihydroisoquinolinyl group.

[0058] A "pharmaceutically acceptable vector" refers to a vector that can be used to prepare a pharmaceutical composition, which vector is generally compatible with the other ingredients of the composition and is not harmful to the subject.

[0059] "Pharmaceutically acceptable vector" includes one or more vectors. Embodiments include vectors for topical, ophthalmic, parenteral, intravenous, intraperitoneal, intramuscular, sublingual, nasal, and oral administration. "Pharmaceutically acceptable vector" also includes reagents for preparing aqueous dispersions and sterile powders for injection or dispersion.

[0060] As used herein, "excipient" includes physiologically compatible additives that can be used to prepare pharmaceutical compositions. Examples of pharmaceutically acceptable vectors and excipients can be found, for example, in Remington Pharmaceutical Sciences (16th Edition).

[0061] "Therapeutically effective amount" refers to the dose of a compound or composition that effectively affects the improvement of presbyopia or is used to treat ocular miosis and other related ocular conditions. As used herein, the term can also refer to an amount effective to produce the desired in vivo effect (improvement of presbyopia or miosis) in an animal (preferably a human).

[0062] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows observation images of changes in rabbit eye irritation caused by 1.25% pilocarpine hydrochloride.

[0063] FIG. 2 shows an observation image of the changes in rabbit eye irritation caused by a 1.82% JQ-1 solution.

[0064] FIG. 3 shows an observation image of the changes in rabbit eye irritation caused by a 1.90% JQ-2 solution.

[0065] FIG. 4 shows an observation image of the changes in rabbit eye irritation caused by a 1.75% JQ-3 solution.

[0066] FIG. 5 shows an observation diagram of the changes in rabbit eye irritation caused by a 0.91% JQ-5 solution.

[0067] FIG. 6 shows observation images of changes in rabbit eye irritation caused by a 1.75% JQ-6 solution.

[0068] FIG. 7 shows an observation diagram of changes in rabbit eye irritation caused by a 1.81% JQ-8 solution.

[0069] FIG. 8 shows an observation diagram of changes in rabbit eye irritation caused by a 1.77% JQ-9 solution.

[0070] Figure 9 shows the observation of the changes in rabbit eye irritation caused by a 1.82% solution of JQ-10.

[0071] FIG. 10 is an observation diagram of eye irritation in rabbits in the physiological saline, hydrochloride, and nitrate groups in Test Example 3.

[0072] FIG. 11 is an observation diagram of the eye irritation caused by salicylate and malic acid in rabbits in Test Example 3.

[0073] FIG. 12 is an observation diagram of eye irritation in rabbits in the maleate and fumarate groups in Test Example 3.

[0074] FIG. 13 is an observation diagram of eye irritation in rabbits in the p-methylbenzoate group of JQ-3 at a concentration of 0.88% in Test Example 4.

[0075] FIG. 14 is an observation diagram of eye irritation in rabbits in the p-methylbenzoate group of JQ-3 at a concentration of 3.50% in Test Example 4.

[0076] FIG. 15 is an observation diagram of the eye irritation of rabbits caused by Compound 1 at a concentration of 1.83% in Test Example 1.

[0077] FIG. 16 is an observation diagram of the eye irritation of rabbits caused by Compound 2 at a concentration of 1.83% in Test Example 1.

[0078] FIG. 17 is an observation diagram of the eye irritation of rabbits caused by Compound 4 at a concentration of 1.90% in Test Example 1.

[0079] [Mode for Carrying Out the Invention] The technical solutions of the present invention will be described in more detail below with reference to specific examples. It should be understood that the following examples are merely for illustrative purposes and should not be construed as limiting the scope of the claims of the present invention. Any technology realized based on the above content of the present invention is included within the scope of the claims of the present invention.

[0080] Unless otherwise specified, all raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0081] The concentrations of the eye drop solutions in the following examples all refer to mass concentrations.

[0082] The specific production of compounds JQ-1 to JQ-10 will be described below. Example 1 Preparation of Pilocarpine [ka] Pilocarpine nitrate (15.00 g, 55.30 mmol, 1.0 eq) was dissolved in HO (30 mL) at room temperature, and 1 mol / L aqueous NaOH solution (58.00 mL, 58.07 mmol, 1.05 eq) was added dropwise. The mixture was stirred at room temperature for 30 min. When TLC spot plate showed the reaction was complete, the reaction solution was extracted with 50 mL of dichloromethane, and the procedure was repeated three times. The organic phases were combined, washed with 30 mL of HO and 30 mL of saturated aqueous NaCl, dried over anhydrous NaSO, filtered, and the filtrate was collected. The mixture was dried under reduced pressure to give 12.23 g of a colorless liquid, i.e., pilocarpine, in a 79.36% yield.

[0083] Example 2: Preparation of Compound JQ-1 [ka] Pilocarpine (2.00 g, 9.60 mmol, 1.0 eq) was dissolved in EtOH (10 mL) at room temperature, and 4-ethylbenzoic acid (1.44 g, 9.60 mmol, 1.0 eq) was added. The mixture was stirred at room temperature for 1 hour. TLC showed the reaction was complete. The solvent was removed by rotary evaporation, and the residue was stored at -20 °C overnight to give a white solid. The resulting solid was slurried in 20 mL of n-hexane for 1 hour, filtered, and the filter cake was collected and dried under reduced pressure to give 3.31 g of a white solid in 96.21% yield.

[0084] 1 H-NMR characterization: 1 H NMR (400 MHz, DMSO- d6) δ 7.87 (d, J = 8.1 Hz, 2H), 7.56 (s, 1H), 7.33 (d, J = 8.1 Hz, 2H), 6.74 (s, 1H), 4.21 (dd, J = 8.9, 5.8 Hz, 1H), 3.97 (dd, J = 9.0, 3.1 Hz, 1H), 3.55 (s, 3H), 2.90 - 2.80 (m, 1H), 2.77 - 2.62 (m, 4H), 2.36 (dd, J = 15.5, 11.4 Hz, 1H), 1.75 - 1.63 (m, 1H), 1.58 - 1.47 (m, 1H), 1.20 (t, J = 7.6 Hz, 3H), 1.02 (t, J = 7.4 Hz, 3H).

[0085] Example 3 Preparation of Compound JQ-2 [ka] Pilocarpine (2.00 g, 9.60 mmol, 1.0 eq) was dissolved in EtOH (10 mL) at room temperature, and 4-isopropylbenzoic acid (1.58 g, 9.60 mmol, 1.0 eq) was added. The mixture was stirred at room temperature for 1 hour. TLC showed the reaction was complete. The solvent was removed by rotary evaporation, and the residue was stored at -20 °C overnight to give a white solid. The resulting solid was slurried in 20 mL of n-hexane for 1 hour, filtered, and the filter cake was collected and dried under reduced pressure to give 3.42 g of a white solid in 95.59% yield.

[0086] 1 H-NMR characterization: 1H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 8.3 Hz, 2H), 7.55 (s, 1H), 7.36 (d, J = 8.2 Hz, 2H), 6.74 (s, 1H), 4.21 (dd, J = 8.9, 5.8 Hz, 1H), 3.97 (dd, J = 9.0, 3.1 Hz, 1H), 3.55 (s, 3H), 2.01 - 2.91 (m, 1H), 2.90 - 2.80 (m, 1H), 2.76- 2.64 (m, 2H), 2.36 (dd, J = 15.6, 11.4 Hz, 1H), 1.74 - 1.63 (m, 1H), 1.59 - 1.46 (m, 1H), 1.22 (d, J = 6.9 Hz, 3H), 1.02 (t, J = 7.4 Hz, 3H).

[0087] Example 4 Preparation of Compound JQ-3 [ka] Pilocarpine (2.00 g, 9.60 mmol, 1.0 eq) was dissolved in EtOH (10 mL) at room temperature, m-methylbenzoic acid (1.31 g, 9.60 mmol, 1.0 eq) was added, and the mixture was stirred at room temperature for 1 hour. TLC showed the reaction was complete. The solvent was removed by rotary evaporation, and the residue was stored at -20 °C overnight to give a white solid. The resulting solid was slurried in 20 mL of n-hexane for 1 hour, filtered, and the filter cake was collected and dried under reduced pressure to give 3.13 g of a white solid in 94.71% yield.

[0088] 1 H-NMR characterization: 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 8.8 Hz, 2H), 7.54 (s, 1H), 7.00 (d, J = 8.9 Hz, 2H), 6.73 (s, 1H), 4.21 (dd, J = 8.8, 5.8 Hz, 1H), 3.98 (m, 3H), 3.55 (s, 3H), 2.91 - 2.80 (m, 1H), 2.70 (m, 2H), 2.36 (dd, J = 15.6, 11.4 Hz, 1H), 1.80 - 1.62 (m, 3H), 1.53 (m, 1H), 1.00 (m, 6H).

[0089] Example 5 Preparation of Compound JQ-5 [ka] Pilocarpine (2.00 g, 9.60 mmol, 1.0 eq) was dissolved in EtOH (10 mL) at room temperature, and 2,4-dimethylbenzoic acid (1.44 g, 9.60 mmol, 1.0 eq) was added. The mixture was stirred at room temperature for 1 hour. TLC showed the reaction was complete. The solvent was removed by rotary evaporation, and the residue was stored at -20 °C overnight to give a white solid. The resulting solid was slurried in 20 mL of n-hexane for 1 hour, filtered, and the filter cake was collected and dried under reduced pressure to give 3.30 g of a white solid in 95.86% yield.

[0090] 1 H-NMR characterization: 1H NMR (400 MHz, DMSO-d6) δ 7.74 (d, J = 7.8 Hz, 1H), 7.54 (s, 1H), 7.10 (t, J =12Hz 2H), 6.73 (s, 1H), 4.21 (dd, J = 8.9, 5.8 Hz, 1H), 3.97 (dd, J = 9.0, 3.1 Hz, 1H), 3.55 (s, 3H), 2.90 - 2.80 (m, 1H), 2.70 (m,2H), 2.49 (s, 3H), 2.36 (dd, J = 15.6, 11.5 Hz, 1H), 2.31 (s, 3H), 1.75 - 1.62 (m, 1H), 1.59 - 1.46 (m, 1H), 1.02 (t, J = 7.4 Hz, 3H).

[0091] Example 6: Method for producing compound JQ-6 [ka] Pilocarpine (2.00 g, 9.60 mmol, 1.0 eq) was dissolved in EtOH (10 mL) at room temperature, and p-methylbenzoic acid (1.31 g, 9.60 mmol, 1.0 eq) was added. The mixture was stirred at room temperature for 1 hour. TLC showed the reaction was complete. The solvent was removed by rotary evaporation, and the residue was stored at -20 °C overnight to give a white solid. The resulting solid was slurried in 20 mL of n-hexane for 1 hour, filtered, and the filter cake was collected and dried under reduced pressure to give 3.12 g of a white solid in 94.23% yield.

[0092] 1 H-NMR characterization: 1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 8.1 Hz, 2H), 7.55 (s, 1H), 7.30 (d, J = 7.9 Hz, 2H), 6.74 (s, 1H), 4.21 (dd, J = 8.6, 5.8 Hz, 1H), 3.97 (dd, J = 9.0, 3.1 Hz, 1H), 3.55 (s, 3H), 2.85 (m, 1H), 2.70 (m, 2H), 2.41 - 2.31 (m, 4H), 1.75 - 1.62 (m, 1H), 1.53 (m, 1H), 1.02 (t, J = 7.4 Hz, 2H).

[0093] Example 7 Preparation of Compound JQ-8 [ka] Pilocarpine (2.00 g, 9.60 mmol, 1.0 eq) was dissolved in EtOH (10 mL) at room temperature, and p-cyanobenzoic acid (1.41 g, 9.60 mmol, 1.0 eq) was added. The mixture was stirred at room temperature for 1 hour. TLC showed the reaction was complete. The solvent was removed by rotary evaporation, and the residue was stored at -20 °C overnight to give a white solid. The resulting solid was slurried in 20 mL of n-hexane for 1 hour, filtered, and the filter cake was collected and dried under reduced pressure to give 3.23 g of a white solid in 94.69% yield.

[0094] 1 H-NMR characterization: 1H NMR (400 MHz, DMSO-d6) δ 8.12 - 8.06 (m, 2H), 8.00 - 7.94 (m, 2H), 7.67 (s, 1H), 6.80 (s, 1H), 4.22 (dd, J = 8.8, 5.6 Hz, 1H), 3.97 (dd, J = 9.0, 3.2 Hz, 1H), 3.57 (s, 3H), 2.90 - 2.82 (m, 1H), 2.77 - 2.63 (m, 2H), 2.38 (dd, J = 15.6, 11.4 Hz, 1H), 1.72 - 1.65 (m, 1H), 1.57 - 1.49 (m, 1H), 1.02 (t, J = 7.4 Hz, 3H).

[0095] Example 8 Preparation of Compound JQ-9 [ka] Pilocarpine (2.00 g, 9.60 mmol, 1.0 eq) was dissolved in EtOH (10 mL) at room temperature, and p-fluorobenzoic acid (1.35 g, 9.60 mmol, 1.0 eq) was added. The mixture was stirred at room temperature for 1 hour. TLC showed the reaction was complete. The solvent was removed by rotary evaporation, and the residue was stored at -20 °C overnight to give a white solid. The resulting solid was slurried in 20 mL of n-hexane for 1 hour, filtered, and the filter cake was collected and dried under reduced pressure to give 3.17 g of a white solid in 94.67% yield.

[0096] 1 H-NMR characterization: 1H NMR (400 MHz, DMSO-d6) δ 8.05 - 7.97 (m, 2H), 7.56 (s, 1H), 7.32 (m, 2H), 6.74 (s, 1H), 4.22 (dd, J = 8.9, 5.8 Hz, 1H), 3.97 (dd, J = 9.0, 3.1 Hz, 1H), 3.55 (s, 3H), 2.91 - 2.80 (m, 1H), 2.74 - 2.64 (m, 2H), 2.36 (dd, J = 15.6, 11.4 Hz, 1H), 1.74 - 1.63 (m, 1H), 1.58 - 1.47 (m, 1H), 1.02 (t, J = 7.4 Hz, 3H).

[0097] Example 9 Preparation of Compound JQ-10 [ka] Pilocarpine (2.00 g, 9.60 mmol, 1.0 eq) was dissolved in EtOH (10 mL) at room temperature, and 3-ethylbenzoic acid (1.44 g, 9.60 mmol, 1.0 eq) was added. The mixture was stirred at room temperature for 1 hour. TLC showed the reaction was complete. The solvent was removed by rotary evaporation, and the residue was stored at -20 °C overnight to give a white solid. The resulting solid was slurried in 20 mL of n-hexane for 1 hour, filtered, and the filter cake was collected and dried under reduced pressure to give 3.25 g of a white solid in 94.48% yield.

[0098] 1 H-NMR characterization: 1H NMR (400 MHz, DMSO-d6) δ 7.77(t, J = 12.0, 2H), 7.55 (s, 1H), 7.48 - 7.39 (m, 2H), 6.73 (s, 1H), 4.21 (dd, J = 8.8, 5.8 Hz, 1H), 3.96 (dd, J = 9.0, 3.0 Hz, 1H), 3.54 (s, 3H), 2.89 - 2.81 (m, 1H), 2.76- 2.64 (m, 4H), 2.36 (dd, J = 15.5, 11.5 Hz, 1H), 1.74 - 1.63 (m, 1H), 1.58 - 1.47 (m, 1H), 1.20 (t, J = 7.6 Hz, 3H), 1.01 (t, J = 7.4 Hz, 3H).

[0099] The synthesis flow chart below shows a specific synthesis route for the compound of formula (I-2) of the present invention. [ka]

[0100] Example 10 Preparation of Compound 1 [ka] Pilocarpine (5.00 g, 24 mmol, 1.0 eq) was dissolved in EtOH (15 mL) at room temperature, and 3-methylphenylacetic acid (3.61 g, 24 mmol, 1.0 eq) was added. The mixture was stirred at room temperature for 1 hour. HPLC showed the reaction was complete, and the solvent was removed by rotary evaporation. The residue was then stored at -20 °C overnight. A white solid was obtained. The resulting solid was slurried in 16 mL of n-hexane for 1 hour, filtered, and the filter cake was collected and dried under reduced pressure to give compound 1 (8.42 g, 97.8% yield).

[0101] 1H NMR (400 MHz, DMSO-d6) δ 7.53 (s, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.09 - 7.01 (m, 3H), 6.73 (s, 1H), 4.21 (dd, J = 8.9, 5.8 Hz, 1H), 3.96 (dd, J = 9.0, 3.1 Hz, 1H), 3.54 (s, 3H), 3.51 (s, 2H), 2.90 - 2.80 (m, 1H), 2.73 (dd, J = 15.4, 7.3 Hz, 1H), 2.66 (dd, J = 15.6, 4.3 Hz, 1H), 2.35 (dd, J = 15.6, 11.4 Hz, 1H), 2.29 (s, 3H), 172 - 1.65 (m, 1H), 1.59 - 1.46 (m, 1H), 1.02 (t, J = 7.4 Hz, 3H).

[0102] Example 11 Preparation of Compound 2 [ka] Pilocarpine (5.00 g, 24 mmol, 1.0 eq) was dissolved in EtOH (15 mL) at room temperature, and 4-methylphenylacetic acid (3.61 g, 24 mmol, 1.0 eq) was added. The mixture was stirred at room temperature for 1 hour. HPLC showed the reaction was complete, and the solvent was removed by rotary evaporation. The residue was then stored at -20 °C overnight. A white solid was obtained. The resulting solid was slurried in 16 mL of n-hexane for 1 hour, filtered, and the filter cake was collected and dried under reduced pressure to give compound 2 (8.40 g, 97.6% yield).

[0103] 1H NMR (400 MHz, DMSO-d6) δ 7.54 (s, 1H), 7.17-7.09 (m, 4H), 6.73 (s, 1H), 4.21 (dd, J = 8.9, 5.8 Hz, 1H), 3.96 (dd, J = 9.0, 3.1 Hz, 1H), 3.54 (s, 3H), 3.50 (s, 2H), 2.90 - 2.80 (m, 1H), 2.73 (dd, J = 15.2, 7.5 Hz, 1H), 2.66 (dd, J = 15.6, 4.3 Hz, 1H), 2.36 (dd, J = 15.6, 11.4 Hz, 1H), 2.28 (s, 3H), 1.75 - 1.62 (m, 1H), 1.59 - 1.46 (m, 1H), 1.02 (t, J = 7.4 Hz, 3H).

[0104] Example 12 Preparation of Compound 3 [ka] Pilocarpine (3.80 g, 18 mmol, 1.0 eq) was dissolved in EtOH (15 mL) at room temperature, and 2-(4-ethylphenyl)-2-methylpropionic acid (3.50 g, 18 mmol, 1.0 eq) was added. The mixture was stirred at room temperature for 1 hour. HPLC showed the reaction was complete, and the solvent was removed by rotary evaporation. The residue was then stored at -20 °C overnight. A white solid was obtained. The resulting solid was slurried in 12 mL of n-hexane for 1 hour, filtered, and the filter cake was collected and dried under reduced pressure to give compound 3 (6.95 g, 95.2% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.53 (s, 1H), 7.25 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.3 Hz, 2H), 6.72 (s, 1H), 4.21 (dd, J = 8.9, 5.7 Hz, 1H), 3.96 (dd, J = 9.0, 3.1 Hz, 1H), 3.54 (s, 3H), 2.90 - 2.80 (m, 1H), 2.76 - 2.64 (m, 2H), 2.57 (q, J = 7.6 Hz, 2H), 2.35 (dd, J = 15.6, 11.4Hz, 1H), 1.75 - 1.47 (m, 2H), 1.45 (s, 6H), 1.17 (t, J = 7.6 Hz, 3H), 1.02 (t, J = 7.4 Hz, 3H).

[0105] Example 13 Preparation of compound 4 [ka] Pilocarpine (3.84 g, 18 mmol, 1.0 eq) was dissolved in EtOH (15 mL) at room temperature, and 2-phenylisobutyric acid (3.03 g, 18 mmol, 1.0 eq) was added. The mixture was stirred at room temperature for 1 hour. HPLC showed the reaction was complete, and the solvent was removed by rotary evaporation. The residue was then stored at -20 °C overnight. A white solid was obtained. The resulting solid was slurried in 12 mL of n-hexane for 1 hour, filtered, and the filter cake was collected and dried under reduced pressure to give compound 4 (6.60 g, 96.1% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.54 (s, 1H), 7.40 - 7.29 (m, 4H), 7.28 - 7.19 (m, 1H), 6.73 (s, 1H), 4.21 (dd, J = 8.8, 5.8 Hz, 1H), 3.97 (dd, J = 9.0, 3.0 Hz, 1H), 3.54 (s, 3H), 2.89 - 2.81 (m, 1H), 2.76 - 2.64 (m, 2H), 2.36 (dd, J = 15.5, 11.4 Hz, 1H), 1.76 - 1.50 (m, 2H), 1.47 (s, 6H), 1.02 (t, J = 7.4 Hz, 3H).

[0106] Example 14 Preparation of Compound 5 [ka] Pilocarpine (3.35 g, 16.1 mmol, 1.0 eq) was dissolved in EtOH (15 mL) at room temperature, and 4-fluorophenylacetic acid (2.48 g, 16.1 mmol, 1.0 eq) was added. The mixture was stirred at room temperature for 1 hour. HPLC showed the reaction was complete, and the solvent was removed by rotary evaporation. The residue was then stored at -20 °C overnight. A white solid was obtained. The resulting solid was slurried in 10 mL of n-hexane for 1 hour, filtered, and the filter cake was collected and dried under reduced pressure to give compound 5 (5.48 g, 94.0% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.58 (s, 1H), 7.30 (dd, J = 8.4, 5.7 Hz, 2H), 7.13 (t, J = 8.9 Hz, 2H), 6.76 (s, 1H), 4.21 (dd, J = 8.9, 5.8 Hz, 1H), 3.97 (dd, J = 9.0, 3.0 Hz, 1H), 3.57 (s, 2H), 3.55 (s, 3H), 2.89 - 2.81 (m, 1H), 2.76 - 2.64 (m, 2H), 2.36 (dd, J = 15.5, 11.5 Hz, 1H), 1.76 - 1.45 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H).

[0107] Example 15 Preparation of compound 6 [ka] Pilocarpine (3.27 g, 15.7 mmol, 1.0 eq) was dissolved in EtOH (15 mL) at room temperature, and 3-fluorophenylacetic acid (2.42 g, 15.7 mmol, 1.0 eq) was added. The mixture was stirred at room temperature for 1 h. HPLC showed the reaction was complete. The solvent was evaporated, and the residue was placed at -20 °C overnight. A white solid was obtained. The resulting solid was slurried in 10 mL of n-hexane for 1 h, filtered, and the filter cake was collected and dried under reduced pressure to give a white solid, compound 6 (5.60 g, 98.4% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.56 (s, 1H), 7.35 (dd, J = 15.0, 7.3 Hz, 1H), 7.09 (dd, J = 16.6, 8.0 Hz, 3H), 6.74 (s, 1H), 4.21 (dd, J = 8.8, 5.9 Hz, 1H), 3.97 (dd, J = 9.0, 2.9 Hz, 1H), 3.62 (s, 2H), 3.55 (s, 3H), 2.87 - 2.83 (m, 1H), 2.76 - 2.64 (m, 2H), 2.36 (dd, J = 15.5, 11.4 Hz, 1H), 1.75 - 1.46 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H).

[0108] Example 16 Preparation of compound 7 [ka] Pilocarpine (3.23 g, 15.5 mmol, 1.0 eq) was dissolved in EtOH (15 mL) at room temperature, and 4-chlorophenylacetic acid (2.65 g, 15.5 mmol, 1.0 eq) was added. The mixture was stirred at room temperature for 1 hour. HPLC showed the reaction was complete. The solvent was removed by rotary evaporation, and the residue was placed at -20 °C overnight. A white solid was obtained. The resulting solid was slurried in 10 mL of n-hexane for 1 hour, filtered, and the filter cake was collected and dried under reduced pressure to give compound 7 (5.75 g, 97.8% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.55 (s, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 6.73 (s, 1H), 4.21 (dd, J = 9.0, 5.8 Hz, 1H), 3.97 (dd, J = 9.0, 3.1 Hz, 1H), 3.59 (s, 2H), 3.55 (s, 3H), 2.90 - 2.80 (m, 1H), 2.76 - 2.64 (m, 2H), 2.36 (dd, J = 15.6, 11.4 Hz, 1H), 1.75 - 1.46 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H).

[0109] Example 17 Preparation of compound 8 [ka] Pilocarpine (3.18 g, 15.3 mmol, 1.0 eq) was dissolved in EtOH (15 mL) at room temperature, and 4-bromophenylacetic acid (3.28 g, 15.3 mmol, 1.0 eq) was added. The mixture was stirred at room temperature for 1 hour. HPLC showed the reaction was complete, and the solvent was removed by rotary evaporation. The residue was then stored at -20 °C overnight. A white solid was obtained. The resulting solid was slurried in 10 mL of n-hexane for 1 hour, filtered, and the filter cake was collected and dried under reduced pressure to give a white solid, namely, compound 8 (6.18 g, 95.7% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.57 (s, 1H), 7.53 - 7.46 (m, 2H), 7.23 (d, J = 8.4 Hz, 2H), 6.75 (s, 1H), 4.21 (dd, J = 8.9, 5.7 Hz, 1H), 3.97 (dd, J = 9.0, 3.1 Hz, 1H), 3.57 (s, 2H), 3.55 (s, 3H), 2.91 - 2.80 (m, 1H), 2.76 - 2.64 (m, 2H), 2.36 (dd, J = 15.6, 11.4 Hz, 1H), 1.75 - 1.46 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H).

[0110] Example 18 Preparation of compound 9 [ka] Pilocarpine (3.58 g, 17.2 mmol, 1.0 eq) was dissolved in EtOH (15 mL) at room temperature, and 2,3-difluorophenylacetic acid (2.95 g, 17.2 mmol, 1.0 eq) was added. The mixture was stirred at room temperature for 1 hour. HPLC showed the reaction was complete, and the solvent was removed by rotary evaporation. The residue was then stored at -20 °C overnight. A white solid was obtained. The resulting solid was slurried in 10 mL of n-hexane for 1 hour, filtered, and the filter cake was collected and dried under reduced pressure to give compound 9 (6.34 g, 97.1% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.55 (s, 1H), 7.39 - 7.28 (m, 1H), 7.21 - 7.10 (m, 2H), 6.74 (s, 1H), 2.90 - 2.80 (m, 1H), 2.76 - 2.64 (m, 2H), 2.36 (dd, J = 15.6, 11.4 Hz, 1H), 1.75 - 1.46 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H).

[0111] Example 19 Preparation of Compound 10 [ka] Pilocarpine (3.37 g, 16.2 mmol, 1.0 eq) was dissolved in EtOH (15 mL) at room temperature, and 2,4-dichlorophenylacetic acid (3.32 g, 16.2 mmol, 1.0 eq) was added. The mixture was stirred at room temperature for 1 hour. HPLC showed the reaction was complete. The solvent was evaporated, and the residue was placed at -20 °C overnight. A white solid was obtained. The resulting solid was slurried in 10 mL of n-hexane for 1 hour, filtered, and the filter cake was collected and dried under reduced pressure to give compound 10 (6.45 g, 96.4% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.61 (d, J = 2.0 Hz, 1H), 7.56 (s, 1H), 7.45 - 7.38 (m, 2H), 6.74 (s, 1H), 4.21 (dd, J = 8.9, 5.7 Hz, 1H), 3.97 (dd, J = 9.0, 3.1 Hz, 1H), 3.72 (s, 2H), 3.55 (s, 3H), 2.91 - 2.79 (m, 1H), 2.76 - 2.64 (m, 2H), 2.36 (dd, J = 15.6, 11.4 Hz, 1H), 1.75 - 1.46 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H).

[0112] Example 20 Preparation of compound 11 [ka] Pilocarpine (3.00 g, 14.4 mmol, 1.0 eq) was dissolved in EtOH (15 mL) at room temperature, and 3,4-dichlorophenylacetic acid (2.95 g, 14.4 mmol, 1.0 eq) was added. The mixture was stirred at room temperature for 1 hour. HPLC showed the reaction was complete, and the solvent was removed by rotary evaporation. The residue was then stored at -20 °C overnight. A white solid was obtained. The resulting solid was slurried in 10 mL of n-hexane for 1 hour, filtered, and the filter cake was collected and dried under reduced pressure to give a white solid, namely, compound 11 (5.65 g, 95.0% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.59 - 7.55 (m, 3H), 7.27 (dd, J = 8.2, 2.0 Hz, 1H), 6.73 (s, 1H), 4.21 (dd, J = 9.0, 5.8 Hz, 1H), 3.96 (dd, J = 9.0, 3.1 Hz, 1H), 3.64 (s, 2H), 3.55 (s, 3H), 2.90 - 2.80 (m, 1H), 2.76 - 2.64 (m, 2H), 2.36 (dd, J = 15.6, 11.4 Hz, 1H), 1.76 - 1.46 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H).

[0113] Example 21 Preparation of compound 12 [ka] Pilocarpine (3.41 g, 16.4 mmol, 1.0 eq) was dissolved in EtOH (15 mL) at room temperature, and 2,4,5-trifluorophenylacetic acid (3.11 g, 16.4 mmol, 1.0 eq) was added. The mixture was stirred at room temperature for 1 h. HPLC showed the reaction was complete. The solvent was evaporated, and the residue was placed at -20 °C overnight. A white solid was obtained. The resulting solid was slurried in 10 mL of n-hexane for 1 h, filtered, and the filter cake was collected and dried under reduced pressure to give a white solid, compound 12 (6.21 g, 95.2% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.56 (s, 1H), 7.54-7.44 (m, 2H), 6.74 (s, 1H), 4.21 (dd, J = 8.9, 5.8 Hz, 1H), 3.96 (dd, J = 9.0, 3.1 Hz, 1H), 3.63 (s, 2H), 3.55 (s, 3H), 2.92 - 2.79 (m, 1H), 2.76 - 2.64(m, 2H), 2.36 (dd, J = 15.6, 11.4 Hz, 1H), 1.75 - 1.45 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H).

[0114] Example 22 Synthesis of Compound 13 [ka] Pilocarpine (3.04 g, 15 mmol, 1.0 eq) was dissolved in EtOH (15 mL) at room temperature, and 3,4-difluorophenylacetic acid (2.50 g, 15 mmol, 1.0 eq) was added. The mixture was stirred at room temperature for 1 hour. HPLC showed the reaction was complete, and the solvent was removed by rotary evaporation. The residue was then stored at -20 °C overnight. A white solid was obtained. The resulting solid was slurried in 12 mL of n-hexane for 1 hour, filtered, and the filter cake was collected and dried under reduced pressure to give a white solid, namely, compound 13 (5.34 g, 96.4% yield).

[0115] 1H NMR (400 MHz, DMSO-d6) δ 7.59 (s, 1H), 7.35 (dd, J = 19.5, 8.5 Hz, 2H), 7.14 - 7.07 (m, 1H), 6.76 (s, 1H), 4.21 (dd, J = 8.9, 5.8 Hz, 1H), 3.97 (dd, J = 9.0, 3.0 Hz, 1H), 3.60 (s, 2H), 3.56 (s, 3H), 2.90 - 2.82 (m, 1H), 2.79 - 2.61 (m, 2H), 2.37 (dd, J = 15.6, 11.5 Hz, 1H), 1.76 - 1.46 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H).

[0116] Example 23 Synthesis of Compound 14 [ka] Pilocarpine (3.80 g, 18 mmol, 1.0 eq) was dissolved in EtOH (15 mL) at room temperature, and 2-p-methylbenzoic acid (3.00 g, 18 mmol, 1.0 eq) was added. The mixture was stirred at room temperature for 1 hour. HPLC showed the reaction was complete, and the solvent was removed by rotary evaporation. The residue was then stored at -20 °C overnight. A white solid was obtained. The resulting solid was slurried in 12 mL of n-hexane for 1 hour, filtered, and the filter cake was collected and dried under reduced pressure to give a white solid, namely, compound 14 (6.55 g, 96.3% yield).

[0117] 1H NMR (400 MHz, DMSO-d6) δ 7.58 (d, J = 6.0 Hz, 1H), 7.35 - 7.27 (m, 4H), 7.26 - 7.20 (m, 1H), 6.75 (d, J = 3.6 Hz, 1H), 4.20 (dd, J = 8.9, 5.8 Hz, 1H), 3.96 (dd, J = 9.0, 2.9 Hz, 1H), 3.67 (q, J = 7.1 Hz, 1H), 3.54 (s, 3H), 2.90 - 2.80 (m, 1H), 2.77 - 2.62 (m, 2H), 2.36 (dd, J = 15.4, 11.6 Hz, 1H), 1.76 - 1.45 (m, 2H), 1.36 (d, J = 7.1 Hz, 3H), 1.01 (t, J = 7.4 Hz, 3H).

[0118] Example 24 Synthesis of Compound 15 [ka] Pilocarpine (3.85 g, 18 mmol, 1.0 eq) was dissolved in EtOH (15 mL) at room temperature, and 2-phenylpropionic acid (2.78 g, 18 mmol, 1.0 eq) was added. The mixture was stirred at room temperature for 1 h. HPLC showed the reaction was complete. The solvent was evaporated, and the residue was placed at -20 °C overnight. A white solid was obtained. The resulting solid was slurried in 12 mL of n-hexane for 1 h, filtered, and the filter cake was collected and dried under reduced pressure to give compound 15 (6.32 g, 95.3% yield).

[0119] 1H NMR (400 MHz, DMSO-d6) δ 7.58 (d, J = 6.0 Hz, 1H), 7.35 - 7.27 (m, 4H), 7.26 - 7.20 (m, 1H), 6.75 (d, J = 3.6 Hz, 1H), 4.20 (dd, J = 8.9, 5.8 Hz, 1H), 3.96 (dd, J = 9.0, 2.9 Hz, 1H), 3.67 (q, J = 7.1 Hz, 1H), 3.54 (s, 3H), 2.90 - 2.80 (m, 1H), 2.77 - 2.62 (m, 2H), 2.36 (dd, J = 15.4, 11.6 Hz, 1H), 1.76 - 1.45 (m, 2H), 1.36 (d, J = 7.1 Hz, 3H), 1.01 (t, J = 7.4 Hz, 3H).

[0120] Test Example 1 Preparation of eye drop solution: The reagents were pilocarpine hydrochloride (obtained from Nanjing Jiqun Pharmaceutical Technology Co., Ltd.), compounds JQ-1, JQ-2, JQ-3, JQ-5, JQ-6, JQ-8, JQ-9, JQ-10, compound 1, compound 2, and compound 4 (prepared in the above examples), and the saline solution was 500 mL and 4.5 g in volume.

[0121] The following eye drop solutions for groups 1) to 12) were prepared using physiological saline. 1) Prepare a 1.25% pilocarpine hydrochloride solution using physiological saline. 2) Prepare a 1.82% solution of JQ-1 using physiological saline. 3) Prepare a 1.90% solution of JQ-2 using physiological saline. 4) Prepare a 1.75% solution of JQ-3 using physiological saline. 5) Prepare a 0.91% solution of JQ-5 using physiological saline. 6) Prepare a 1.75% solution of JQ-6 using physiological saline. 7) Prepare a 1.81% solution of JQ-8 using physiological saline. 8) Prepare a 1.77% solution of JQ-9 using saline. 9) Prepare a 1.82% solution of JQ-10 using physiological saline. 10) Prepare a solution of Compound 1 at a concentration of 1.83% using saline; 11) Prepare a solution of Compound 2 at a concentration of 1.83% using saline; 12) A 1.90% solution of Compound 4 was prepared using physiological saline.

[0122] Groups 1 to 12 above had equimolar concentrations of pilocarpine in the eye drop solutions, except for group 5. The molar concentration of pilocarpine in the eye drop solutions of group 5 was half the molar concentration of pilocarpine in the solutions of the other 11 groups.

[0123] The effects of the eye drops prepared above in groups 1) to 12) on pupil constriction and irritation in rabbits were tested.

[0124] 1. Materials and Methods 1.1 Experimental animals Species and lineage: New Zealand rabbit Grade: Normal grade Source: Qinglongshan Animal Breeding Farm, Jiangning District, Nanjing City Manufacturing license number: SCXK (Su) 2016-0008 Animal age: Approximately 110 days old at the time of administration Animal weight: Approximately 2.5-3.5 kg at the time of administration Animal Gender: All male Feed: Rabbit pellet feed Breeding conditions: Air-conditioned room, temperature 18-26°C, relative humidity 40-80%

[0125] 1.2 Equipment Digital caliper: standard 0~150mm, measurement accuracy 0.01mm, manufacturer: Guilin Guanglu.

[0126] 1.3 Testing (1) Administration route The drug was administered to the left eye of each rabbit by dropwise administration (pipette), and the administration volume was 100 μL in each case.

[0127] (2) Examination Schedule Number of animals: 6 rabbits / compound for JQ series compounds, 5 rabbits / compound for compounds 1, 2 and 4; Dosage cycle: single dose, Metrics and time points: For JQ compounds, the pupil diameter of the left eye of each rabbit was measured at -0.5 h (i.e., the first half of the administration period), 5 min, 10 min, 15 min, 0.5 h, 3 h, and 4 h after administration, and each time point was repeated three times for each rabbit (the measurement time point was extended if necessary). For Compounds 1, 2 and 4, the pupil diameter of the left eye of the rabbits was measured 3 hours and 4 hours after administration, and each time point was measured three times for each rabbit (the measurement time point was extended if necessary). Irritation: The rabbits' eyes were examined for irritation changes at each time point. Percentage change in pupil diameter after administration % = (after administration - before administration) / before administration × 100% Measurements for each rabbit at each time point were expressed as the mean of triplicate measurements.

[0128] 2.1. Test results The results of the effects of different eye drops containing benzoic acid and hydrochloride on the ocular irritation of rabbits at various times are shown in Figures 1 to 9. The results of the rabbit pupil change test are shown in Tables 1-1 to 1-9. The average values ​​and standard deviations of the pupil diameter change percentages at each time point are shown in Tables 1-1 to 1-9.

number

[0129] [Table 3]

[0130] [Table 4]

[0131]

Table 5

[0132]

Table 6

[0133]

Table 7

[0134]

Table 8

[0135]

Table 9

[0136]

Table 10

[0137]

Table 11

[0138]

Table 12

[0139] As can be seen from Tables 1-10, the pupil constriction effects of the pilocarpine benzoate compounds of the present invention are generally superior to those of pilocarpine hydrochloride. Specifically, the following points are noted: 1) The pilocarpine benzoate compounds of the present invention all have a superior pupil constriction onset effect after 5 minutes compared to pilocarpine hydrochloride, achieving a faster onset of action. 2) Pilocarpine hydrochloride solution has a measured value of -3.13±7.35 when measured at 3 hours, essentially showing no pupil constriction effect. In contrast, the compounds of the present invention still have a significant pupil constriction effect when measured at 3 hours, and the effect lasts for 4 hours or even longer. Statistical results show that the duration of action is extended by more than 33% compared to pilocarpine hydrochloride. 3) While the percentage change in pupil diameter with pilocarpine hydrochloride is at most about 35%, the percentage change in pupil diameter with the compounds of the present invention can reach a maximum of 40% to 45%, with a maximum efficacy of 15 to 30%. As can be seen from the above, the pilocarpine benzoate compounds of the present invention have a faster onset of action, a longer duration of action, and a greater efficacy, which are statistically significantly different.

[0140] As can be seen from the comparison results of rabbit eye irritation between the pilocarpine hydrochloride solution in Figure 1 and the series of solutions in which benzoic acid is substituted with pilocarpine in Figures 2-9, the irritation of the series of compounds in which benzoic acid is substituted with pilocarpine of the present invention was equivalent to that of the hydrochloride salt.

[0141] 2.2. Test results The results of the effects of different eye drop solutions of phenylacetic acid compounds on the eye irritation of rabbits at various times are shown in Figures 15 to 17, and the test results of rabbit pupil change values ​​for different eye drop solutions are shown in Tables 1-11, 1-12, and 1-13.

[0142] [Table 13]

[0143] [Table 14]

[0144] [Table 15]

[0145] Test Example 2 Reagents: Normal saline solution, 500 mL, 4.5 g, was purchased from Jiangxi Kelun Pharmaceutical Co., Ltd.

[0146] Preparation of solutions: Pilocarpine hydrochloride: molecular weight 244.72, purity >95%, obtained from Nanjing Jequn Pharmaceutical Technology Co., Ltd., prepared into a 1.25% solution in saline.

[0147] Pilocarpine nitrate: molecular weight 271.27, purity 98%, obtained from Nanjing Jequn Pharmaceutical Technology Co., Ltd., prepared into a 1.38% solution in saline.

[0148] Pilocarpine salicylate: molecular weight 346.24, purity 99.73%, obtained from Nanjing Jequn Pharmaceutical Technology Co., Ltd., prepared into a 1.76% solution in saline.

[0149] Pilocarpine malate: molecular weight 342.21, purity 99.72%, obtained from Nanjing Jequn Pharmaceutical Technology Co., Ltd., prepared into a 1.74% solution in saline.

[0150] Pilocarpine maleate: molecular weight 324.19, purity 99.76%, obtained from Nanjing Jequn Pharmaceutical Technology Co., Ltd., prepared into a 1.65% solution in saline.

[0151] Pilocarpine fumarate: molecular weight 324.19, purity 99.74%, obtained from Nanjing Jequn Pharmaceutical Technology Co., Ltd., prepared into a 1.65% solution in saline.

[0152] Pilocarpine lipoate: molecular weight 414.58, 99.56%, obtained from Nanjing Jequn Pharmaceutical Technology Co., Ltd., prepared into a 2.11% solution with saline.

[0153] Note: Each compound was at a different concentration, but all had an equimolar amount of pilocarpine.

[0154] Each group received a single dose of 100 μL instilled into the left eye of each rabbit. The pupil and iris diameters of the rabbits' left eyes were measured at -0.5 h (i.e., the first half of the administration period), 0.5 h, 3 h, and 4 h after administration (the observation period could be extended if necessary). Each rabbit was measured five times at each time point. The entire measurement process was performed by the same person. The measurement data are shown in Tables 2-1 and 2-2. At each measurement point, photographs were taken and recorded, along with a discussion of the ocular irritation status of each group. Observed symptoms were noted in the original records. Specific conditions are shown in Figures 10 to 12. (Note: Upon administration of lipoic acid salt, irritation was evident, and hyperemia was evident, which lasted for a long time and was difficult to resolve. Furthermore, the rabbits made stressful noises upon administration of lipoic acid salt.)

[0155] [Table 16]

[0156] Comprehensive comparison of the data in Table 2-1 above and Table 1-10 in Test Example 1 reveals that the overall effects of the pilocarpine benzoate compounds of the present invention are stronger than those of pilocarpine hydrochloride, nitrate, salicylate, etc. Correspondingly, the duration of action of the pilocarpine benzoate compounds was longer, and the efficacy was relatively longer-lasting.

[0157] As can be seen from the measurement results in Table 2-1 above and Tables 1-11, 1-12, and 1-13 of Test Example 1, pilocarpine hydrochloride, pilocarpine nitrate, pilocarpine salicylate, pilocarpine malate, pilocarpine maleate, and pilocarpine fumarate basically had no miotic effect on rabbit pupils 3 hours after administration, whereas Compound 1 solution in Table 1-11, Compound 2 solution in Table 1-12, and Compound 4 solution in Table 1-13 still had miotic effect 3 hours after administration. This indicates that the pilocarpine phenylacetate system has a prolonged duration of action of at least 1 hour compared to the pilocarpine salt system in Table 2-1, and the duration of efficacy is relatively extended by more than 33%, improving the duration of efficacy and reducing the administration frequency.

[0158] Test Example 3 The differences in onset time, strength, duration of action, and irritation of 1.25% pilocarpine hydrochloride and different concentrations of pilocarpine p-methylbenzoate (0.88%, 1.75%, 3.50%) formulated in saline were investigated.

[0159] (1) Study Grouping [Table 17]

[0160] (2) Experiment (1) Administration route The drug was administered to the left eye of each rabbit by dropwise administration (pipette), and the administration volume was 100 μL in each case.

[0161] (2) Examination Schedule Number of animals: 6 rabbits / compound Dosage cycle: single dose, Metrics and time points: The pupil diameter of the left eye of each rabbit was measured at -0.5 h (i.e., the first half of the administration period), 5 min, 10 min, 15 min, 0.5 h, 3 h, and 4 h after administration, with each rabbit measuring three times at each time point. Irritation: Discussion ensued.

[0162] The numerical values ​​of the pupil change results are shown in Tables 3-1 to 3-4, and the changes in the eye irritation phenomenon are shown in FIGS.

[0163] [Table 18]

[0164] [Table 19]

[0165] [Table 20]

[0166] [Table 21]

[0167] As can be seen from the data in the table above, compared with the 1.25% pilocarpine hydrochloride group, the potency at each time point of 0.88% pilocarpine p-methylbenzoate (of which the pilocarpine molar concentration is only half that of 1.25% pilocarpine hydrochloride) was increased. Because the drug concentration was reduced by half, a more favorable effect was observed, allowing for a significant reduction in dosage, which in turn significantly reduced drug side effects and associated impurities. In the case of 1.75% pilocarpine p-methylbenzoate (of which the pilocarpine molar concentration was the same as that of 1.25% pilocarpine hydrochloride), the potency at each time point was more significantly increased compared with 1.25% pilocarpine hydrochloride. 3.50% pilocarpine p-methylbenzoate (in which the molar concentration of pilocarpine was twice that of 1.25% hydrochloride) also showed significantly increased potency at all time points compared to 1.25% pilocarpine hydrochloride.

[0168] Figures 13 and 14 show the observation of eye irritation in rabbits caused by pilocarpine p-methylbenzoate at concentrations of 0.88% and 3.50%, respectively. As can be seen from the figures, the eye irritation caused by 0.88% pilocarpine p-methylbenzoate was clearly less than that caused by 3.50% pilocarpine p-methylbenzoate.

[0169] Test Example 4 Reagents: Normal saline solution, 500 mL, 4.5 g, was purchased from Jiangxi Kelun Pharmaceutical Co., Ltd.

[0170] Compound 1, compound 2 (obtained from Nanjing Jigun Pharmaceutical Science and Technology Co., Ltd.).

[0171] 1) Prepare a solution of Compound 1 at a concentration of 0.915% using saline; 2) A solution of Compound 2 at a concentration of 0.915% was prepared using physiological saline.

[0172] Using the method of Test Example 2, the miotic effects of a 0.915% solution of Compound 1 and a 0.915% solution of Compound 2 were measured, and the measurement results are shown in Tables 4-1 and 4-2 below.

[0173] [Table 22]

[0174] [Table 23]

[0175] Comparing the data results of Test Example 2 with those of this Test Example, it was found that the miotic effect of Compounds 1 and 2 at half the concentration was equivalent to the effect of pilocarpine hydrochloride, and that the administration concentration of pilocarpine phenylacetic acid derivative salts could be reduced.

[0176] Test Example 5 Detection of pharmaceutical ingredients and efficacy Formulation 1: A fixed amount of Compound 1, boric acid, sodium citrate, sodium chloride, and appropriate amounts of sodium hydroxide / hydrochloric acid (for pH adjustment) were used to prepare a formulation solution with a concentration of 18.3 mg / mL (10.6 mg / mL with pilocarpine), 10 mg / mL boric acid, 0.15 mg / mL sodium citrate, and 1 mg / mL sodium chloride, with a pH of 4.5.

[0177] Formulation 2: A fixed amount of Compound 1, boric acid, sodium citrate, sodium chloride, and appropriate amounts of sodium hydroxide / hydrochloric acid (to adjust the pH) were used to prepare a formulation solution with a concentration of 9.15 mg / mL (5.3 mg / mL with pilocarpine) of Compound 1, 10 mg / mL of boric acid, 0.15 mg / mL of sodium citrate, and 1 mg / mL of sodium chloride, with a pH of 4.5.

[0178] Formulation 3: A fixed amount of Compound 2, boric acid, sodium citrate, sodium chloride, and appropriate amounts of sodium hydroxide / hydrochloric acid (pH adjusted) were taken to prepare a formulation solution with a concentration of 18.3 mg / mL (10.6 mg / mL with pilocarpine) of Compound 2, 10 mg / mL of boric acid, 0.15 mg / mL of sodium citrate, and 1 mg / mL of sodium chloride, and a pH of 4.5.

[0179] Formulation 4: A fixed amount of Compound 2, boric acid, sodium citrate, sodium chloride, and appropriate amounts of sodium hydroxide / hydrochloric acid (pH adjusted) were taken to prepare a formulation solution containing Compound 2 at a concentration of 9.15 mg / mL (5.3 mg / mL with pilocarpine), 10 mg / mL boric acid, 0.15 mg / mL sodium citrate, and 1 mg / mL sodium chloride, with a pH of 4.5.

[0180] Formulation 5: A fixed amount of the compound pilocarpine hydrochloride, boric acid, sodium citrate, sodium chloride, and sodium hydroxide / hydrochloric acid were mixed together in appropriate amounts (pH adjusted) to prepare a formulation solution with a concentration of 12.5 mg / mL (10.6 mg / mL for pilocarpine) pilocarpine hydrochloride, 10 mg / mL boric acid, 0.15 mg / mL sodium citrate, and 1 mg / mL sodium chloride, and a pH of 4.5.

[0181] The reagents of formulations 1, 3 and 5 had equimolar concentrations of pilocarpine, while formulations 2 and 4 contained half the molar concentration of pilocarpine as formulations 1, 3 and 5. The miotic effect of each of the solutions of Preparations 1 to 5 was measured using the measurement method of Test Example 2, and the measurement results are shown in Table 5-1 below.

[0182] [Table 24]

[0183] Comparing the data in Table 5-1, it can be seen that Preparations 1, 3, and 5 have the same effect at the same pilocarpine concentration, and the duration of action of Preparations 1 and 3 is longer than that of Preparation 5 by more than 1 hour, and the effects of Preparations 2 and 4, which have half the molar concentration, are comparable to, and in some cases even superior to, that of Preparation 5. From the above, it can be seen that the duration of miotic action of the pilocarpine phenylacetic acid-based preparation of the present invention is significantly longer than that of the commercially available product pilocarpine hydrochloride.

[0184] Test Example 6 Stability testing (1) Compound raw material stability test Samples: Compound 1, Compound 2, solid particles of pilocarpine hydrochloride raw material High-temperature testing: Compound 1, Compound 2, and pilocarpine hydrochloride raw materials (1 g each) were placed in a 40°C thermostatic chamber with the opening open, and samples were taken at 0 and 5 days to determine stability as the main consideration. The stability of the raw materials themselves and the trends of the influencing factors on stability under the test conditions were observed.

[0185] Strong light irradiation test: 1 g of compound 1, compound 2, and pilocarpine hydrochloride raw material was taken and placed in a lighting box with an opening, and the illuminance was set to 4500 lx ± 500 lx. Sampling was performed at 0 days and 5 days, and stability was detected as a key consideration.

[0186] High humidity test: 1 g of compound 1, compound 2, and pilocarpine hydrochloride raw material was taken and placed in a humidity-controlled sealed container with an opening. Sampling was performed on days 0 and 5 at 25°C and a relative humidity of 75%±5%, and stability was the main consideration.

[0187] According to the European Pharmacopoeia, the substances of interest for pilocarpine include impurity A isopilocarpine (ZA), impurity B pilocarpic acid (ZB), and impurity C isopilocarpic acid (ZC). Samples taken at different times during the high temperature test, strong light exposure test, and high humidity test were each analyzed using high performance liquid chromatography to observe the change in stability of the influencing factors under the test conditions.

[0188] Related substances were determined by high-performance liquid chromatography (Chinese Pharmacopoeia 2020, Four Parts General Rule 0512).

[0189] Test solution: An appropriate amount of test product was accurately weighed, dissolved in water, and diluted to a solution containing 1 mg per mL.

[0190] Chromatographic conditions: Octadecyl-bonded silica gel was used as the packing material [Kromasil 100-5-C18 column (4.0 mm × 125 m) or a column equivalent in performance], 0.679 g / L tetrabutylammonium dihydrogen phosphate-methanol-acetonitrile 885:55:60 (adjusted to pH 7.7 with dilute aqueous ammonia) was used as mobile phase A, and acetonitrile-water 80:20 was used as mobile phase B. Gradient elution was performed according to Table 6-1, with the column temperature set at 30°C, the flow rate set at 1.0 mL / min, the detection wavelength set at 220 nm, and the injection volume set at 20 μL. [Table 25]

[0191] The detection was carried out by the above method, and the detection results are shown in Table 6-2. [Table 26]

[0192] As can be seen from the comparison in the above table, when the raw materials of Compounds 1 and 2 and the raw material of pilocarpine hydrochloride were used under conditions of 40°C and high light irradiation, the growth rate of the raw material impurities of Compounds 1 and 2 was equivalent to that of pilocarpine hydrochloride impurities, but when left for 5 days under high humidity conditions of RH 75%, the growth rate of the raw material impurities of Compounds 1 and 2 was significantly slower than that of pilocarpine hydrochloride. Overall, the stability of the pilocarpine phenylacetic acid-based raw material of the present invention was superior to that of pilocarpine hydrochloride.

[0193] (2) Formulation stability test The stability of the above-mentioned formulations 1, 3 and 5 was tested.

[0194] (1) Preparations 1, 3, and 5 were taken and placed in a constant temperature condition of 40°C so that they were opened. Samples were taken at 0 and 5 days, and the growth of impurities in the solution was monitored for 10 days, with stability as the main consideration. The stability of the drug substance itself and the trend of changes in stability under the test conditions of the influencing factors were observed.

[0195] (2) Formulations 1 and 3 were taken and placed in an open-type container at a constant temperature of 40°C and a constant humidity of 25% RH. Stability was the main consideration, and the impurity growth in the solution was monitored for 5 days and 10 days. The stability of the drug substance itself and the trends of changes in stability under the test conditions of the influencing factors were observed. The results are shown in Table 6-3 below. [Table 27]

[0196] As can be seen from the results in Table 6-3, the stability of Formulations 1 and 3 was superior to that of Formulation 5 at 40°C, indicating that the stability of the pilocarpine phenylacetic acid compound formulation of the present invention was superior to that of the pilocarpine hydrochloride formulation.

[0197] Test Example 7 Determination of the salt formation ratio of pilocarpine salt preparations. The salt formation ratio of the pilocarpine salt formulation was measured using high-performance liquid chromatography under the following test conditions: column C18, injection volume 10 μL, mobile phase KHPO (pH adjusted to 6.50±0.1 with phosphoric acid)-methanol-acetonitrile 63:2:35, flow rate 0.7 mL / min, column temperature 30°C, detection wavelength 215 nm. Gradient elution measurements were performed, and the salt formation ratio was calculated from the peak areas of the free acid and pilocarpine.

[0198] A fixed amount of Compound 1, boric acid, sodium citrate, and sodium chloride was taken to prepare a solution of Compound 1 at a concentration of 18.3 mg / mL (10.6 mg / mL with pilocarpine), 10 mg / mL boric acid, 0.15 mg / mL sodium citrate, and 1 mg / mL sodium chloride. An appropriate amount of sodium hydroxide / hydrochloric acid (to adjust the pH) was then added to prepare Compound 1 formulation solutions at different pH levels. The salt formation ratios of the different formulations of Compound 1 were measured by injection. At the same time, the stability and salt formation ratios of Compound 1 formulation solutions at different pH levels were measured using the stability analysis method described above. The results are shown in Table 7-1 below. [Table 28]

[0199] A fixed amount of Compound 2, boric acid, sodium citrate, and sodium chloride was taken to prepare a solution of Compound 2 at a concentration of 18.3 mg / mL (10.6 mg / mL with pilocarpine), 10 mg / mL boric acid, 0.15 mg / mL sodium citrate, and 1 mg / mL sodium chloride. An appropriate amount of sodium hydroxide / hydrochloric acid was then added (to adjust the pH) to prepare Compound 2 formulation solutions at different pH levels. The salt formation ratios of different formulations of Compound 2 were measured by injection, and the stability salt formation ratios of Compound 2 formulation solutions at different pH levels were measured using the above-mentioned stability analysis method. The results are shown in Table 7-2 below. [Table 29]

[0200] As can be seen from the above table, the salt formation ratio of the preparations of Compound 1 and Compound 2 was basically stable under different concentrations and different conditions, and the efficacy was stable.

[0201] Although the embodiments of the present invention have been described above, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention are intended to be included within the scope of the claims of the present invention. [Brief explanation of the drawings]

[0202] [Figure 1] FIG. 1 is an observation diagram of changes in rabbit eye irritation caused by 1.25% pilocarpine hydrochloride. [Figure 2] FIG. 1 shows an observation image of changes in rabbit eye irritation caused by a 1.82% JQ-1 solution. [Figure 3] FIG. 1 shows an observation image of changes in rabbit eye irritation caused by a 1.90% JQ-2 solution. [Figure 4] FIG. 1 shows an observation image of changes in rabbit eye irritation caused by a 1.75% JQ-3 solution. [Figure 5] FIG. 1 shows an observation image of changes in rabbit eye irritation caused by a 0.91% JQ-5 solution. [Figure 6] FIG. 1 shows an observation image of changes in rabbit eye irritation caused by a 1.75% JQ-6 solution. [Figure 7] FIG. 1 shows an observation image of changes in rabbit eye irritation caused by a 1.81% JQ-8 solution. [Figure 8] FIG. 1 shows an observation image of changes in rabbit eye irritation caused by a 1.77% JQ-9 solution. [Figure 9] This is an observation diagram of the irritation changes in the rabbit eye caused by a 1.82% solution of JQ-10. [Figure 10] FIG. 1 is an observation diagram of eye irritation in rabbits in the physiological saline, hydrochloride, and nitrate groups in Test Example 3. [Figure 11] FIG. 1 is an observation diagram of rabbit eye irritation caused by salicylate and malic acid in Test Example 3. [Figure 12]FIG. 1 is an observation diagram of eye irritation in rabbits in the maleate and fumarate groups in Test Example 3. [Figure 13] FIG. 1 is an observation diagram of eye irritation in rabbits in the p-methylbenzoate group of JQ-3 at a concentration of 0.88% in Test Example 4. [Figure 14] FIG. 1 is an observation diagram of eye irritation in rabbits in the p-methylbenzoate group of JQ-3 at a concentration of 3.50% in Test Example 4. [Figure 15] 1 is an observation diagram of rabbit eye irritation caused by Compound 1 at a concentration of 1.83% in Test Example 1. FIG. [Figure 16] 1 is an observation diagram of eye irritation in rabbits caused by Compound 2 at a concentration of 1.83% in Test Example 1. FIG. [Figure 17] FIG. 1 is an observation diagram of eye irritation in rabbits caused by Compound 4 at a concentration of 1.90% in Test Example 1.

Claims

1. Compounds of formula (A) and pharma- ceutically acceptable hydrates or solvates thereof, 【Chemistry 1】 Among them, R 1 , R 2 , R 3 , R 4 , R 5 are identical or different, and each independently represents hydrogen, C 1-6 An alkyl group, a halogen atom, a cyano group, or -NR'R'', where R' and R'' are the same or different, and each independently represent H, C 1-6 Alkyl group, C 3-10 Cycloalkyl groups, C 6-14 selected from an aryl group, a 5- to 14-membered heteroaryl group, and a 3- to 10-membered heterocyclyl group; Said C 1-6 Alkyl group, C 3-10 Cycloalkyl groups, C 6-14 The aryl group, the 5- to 14-membered heteroaryl group, and the 3- to 10-membered heterocyclyl group may optionally be oxo, thio, halogen, cyano group, -NR'R'', -COOH, hydroxy group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 3-10 Cycloalkyl groups, C 6-14 substituted with one, two or more groups selected from the group consisting of aryl and 5- to 14-membered heteroaryl groups; R is COOH or 【Chemistry 2】 Selected from Wherein, Ra and Rb are the same or different, and each independently represents hydrogen, C 1-6 Alkyl group, halogen, cyano group, C 3-10 Cycloalkyl groups, C 6-14 selected from an aryl group, a 5- to 14-membered heteroaryl group, and a 3- to 10-membered heterocyclyl group; The compound and its pharma- ceutically acceptable hydrates or solvates.

2. The compound represented by formula (A) is selected from the compounds represented by the following formula I-1 or I-2: 【Chemistry 3】 The compound according to claim 1 .

3. In formula I-1, the R 1 , R 2 , R 3 , R 4 , R 5 are identical or different, and each independently represents hydrogen, C 1-6 selected from an alkyl group, a halogen, a cyano group, and an amino group; Alternatively, in formula I-2, R 1 , R 2 , R 3 , R 4 , R 5 are identical or different, and each independently represents hydrogen, C 1-6 R' is independently selected from H, C 1-6 selected from alkyl groups, 3. The compound according to claim 1 or 2.

4. In formula I-1, the R 1 , R 2 , R 3 , R 4 , R 5 at least three are H; Alternatively, in formula I-2, R 1 , R 2 , R 3 , R 4 , R 5 are the same or different and are each independently selected from hydrogen, a methyl group, an ethyl group, an isopropyl group, chlorine, fluorine and bromine; Alternatively, in formula I-2, the Ra and Rb are the same or different and each independently represents hydrogen, C 1-6 Selected from an alkyl group, a halogen, and a cyano group; The compound according to claim 3.

5. The compound of formula I-1 is 【Table 1】 Selected from The compound of formula I-2 is 【Table 2】 Selected from The compound according to claim 1 .

6. A method for producing a compound represented by formula (A) according to any one of claims 1 to 5, comprising the steps of: reacting pilocarpine with a compound of formula (A-1) to obtain a compound of formula (A), 【Chemistry 4】 Among them, R, R 1 , R 2 , R 3 , R 4 , R 5 has the definition according to any one of claims 1 to 5, A manufacturing method comprising the steps of:

7. The present invention relates to a compound represented by formula (A) according to any one of claims 1 to 5, and at least one of its pharma- ceutically acceptable hydrates and solvates. Pharmaceutical compositions.

8. In the pharmaceutical composition, the mass concentration of the compound represented by formula (A) is 0.3% to 8%. The pharmaceutical composition according to claim 7.

9. Use of a compound of formula (A) according to any one of claims 1 to 5 or a pharmaceutical composition according to claim 7 or 8 in the manufacture of a drug for improving or treating an ophthalmic disease or condition, or in the manufacture of a miosis drug, use.

10. The ophthalmic disease or condition is at least one of presbyopia, cataract, glaucoma, dry eye, diabetic retinopathy, macular degeneration, optic neuritis, and retinitis pigmentosa; Preferably, the ophthalmic disease or condition is presbyopia.

10. The use according to claim 9.

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