CN111377993A

CN111377993A - New application of triterpenoid

Info

Publication number: CN111377993A
Application number: CN201811628737.2A
Authority: CN
Inventors: 朱敬杰; 郑钦元; 曲婧; 罗煜; 丁时澄; 孙传民; 秦丽军
Original assignee: Shanghai Selleck Chemicals Co ltd
Current assignee: Shanghai Selleck Chemicals Co ltd
Priority date: 2018-12-28
Filing date: 2018-12-28
Publication date: 2020-07-07

Abstract

The invention relates to a new application of a triterpenoid. Specifically, the invention provides a compound, or an optical isomer or a racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a deuterated compound thereof, wherein the compound has a structure shown in formula I. The compound can prevent and/or treat eye diseases caused by lens pathological changes, such as cataract, is found for the first time, has high safety and small toxic and side effects, and has obvious treatment effect and development and application prospect.

Description

New application of triterpenoid

Technical Field

The invention relates to the field of medicines, in particular to a new application of a triterpenoid.

Background

The lens of the normal human eye is composed of a large number of aligned crystallins, which, if misarranged or stacked, affect the normal transparency and refractive index of the lens. Among them, cataract is a major manifestation and the most blinding disease worldwide. Therefore, the treatment and prevention of lens diseases, especially cataract, is of great importance. Unfortunately, surgery and replacement of intraocular lenses are still the main treatment options for cataract in the clinic.

The focus of ophthalmic research is how to prevent and even treat cataract by simply using drugs. Previous research groups have reported that cataracts in animals can be treated with lanosterol, which has the formula:

however, the sustained-release lanosterol drug has the treatment effect on the cataract of the dog only when being combined with a high-frequency cavity injection administration mode; also, there are different researchers who have also pointed out that the direct administration of lanosterol to the eye or the crystal cannot restore or improve the transparency of cataractous crystals.

Therefore, there is a need in the art to develop a drug that is effective in treating lens disorders or ocular diseases associated with lens disorders.

Disclosure of Invention

The invention aims to provide a medicine capable of effectively treating lens pathology or eye diseases related to the lens pathology and application thereof.

In a first aspect of the present invention, there is provided a compound, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a deuterated compound thereof, the compound having the structure of formula I:

in the formula (I), the compound is shown in the specification,

a is 0, 1 or 2;

z is substituted or unsubstituted C1-C10 hydroxyalkyl, or substituted or unsubstituted C1-C10 mercaptoalkyl;

r1, R2, R3, R4, R5, R6 are each independently hydrogen, substituted or unsubstituted C1-C8 alkyl, or substituted or unsubstituted C3-C10 cycloalkyl;

r7 is hydrogen;

r8 is hydrogen, -OH, -SH, substituted or unsubstituted C1-C6 alkoxy, or substituted or unsubstituted C1-C6 alkylthio;

r9 and R10 are independently hydrogen, substituted or unsubstituted C1-C8 alkyl, or substituted or unsubstituted C3-C10 cycloalkyl;

r11 is hydrogen;

r12 is hydrogen, -OH, -SH, substituted or unsubstituted C1-C6 alkoxy, or substituted or unsubstituted C1-C6 alkylthio;

r13 is hydrogen;

r14 is halogen;

wherein any "substitution" means that one or more (preferably 1, 2,3 or 4) hydrogen atoms on the group are substituted with a substituent selected from the group consisting of: c₁-C₄Alkyl radical, C₁-C₄Alkoxy radical, C₁-C₄Alkylthio, hydroxyl, mercapto, amino, halogen.

In another preferred embodiment, the compound comprises one or more characteristics selected from the group consisting of:

z is substituted or unsubstituted C1-C6 hydroxyalkyl, or substituted or unsubstituted C1-C6 mercaptoalkyl;

r1 is hydrogen;

r2 is substituted or unsubstituted C1-C4 alkyl;

r3 is hydrogen;

r4 is hydrogen;

r5 is hydrogen;

r6 is hydrogen;

r8 is hydroxy, or mercapto;

r9 is substituted or unsubstituted C1-C4 alkyl;

r10 is substituted or unsubstituted C1-C4 alkyl;

r12 is hydroxyl or sulfhydryl.

In another preferred embodiment, a is 1.

In another preferred embodiment, Z is hydroxypropyl, or mercaptopropyl.

In another preferred embodiment, R2 is methyl.

In another preferred embodiment, R9 is methyl.

In another preferred embodiment, R10 is methyl.

In another preferred embodiment, the compound is selected from the group consisting of:

in a second aspect of the present invention, there is provided a pharmaceutical composition, wherein the pharmaceutical composition comprises: (i) a compound according to the first aspect, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a deuterated compound thereof; and (ii) a pharmaceutically acceptable carrier.

In another preferred embodiment, in the pharmaceutical composition, the content of the compound of formula I, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its deuterated compound is 0.001-99 wt%, based on the total weight of the pharmaceutical composition.

In another preferred embodiment, the dosage form of the pharmaceutical composition or the preparation is an ophthalmic preparation, and the ophthalmic preparation is an eyedrop, an emulsion, a gel, an ophthalmic ointment, sustained-release microspheres, an intraocular sustained-release implant or a pharmaceutical sustained-release drug film.

In another preferred embodiment, the pharmaceutical composition or formulation further comprises: (c) a second active ingredient, wherein said second active ingredient is selected from the group consisting of: lanosterol, any compound contained in bacteria of the order Fomitopsida or Polyporales (in particular, steroids, terpenoids), azole compounds, glucocorticoids, antibiotics, or combinations thereof.

In another preferred embodiment, the second active ingredient is selected from the group consisting of: lanosterol, any compound contained in bacteria of the order of Hymenochaetales or Polyporales (in particular steroids, terpenoids), azole compounds, amyloid modulators, glucocorticoids, antibiotics, or combinations thereof.

In another preferred embodiment, the second active ingredient is present in an amount of 0.01 to 20 wt%, preferably 5 to 15 wt%, based on the total weight of the composition.

In another preferred embodiment, the lanolin-like compound is selected from the group consisting of: lanosterol, dihydrolanosterol, 25-hydroxycholesterol, or a combination thereof.

In another preferred embodiment, the amyloid-modulating agent is selected from the group consisting of: TPPB (CAS.497259-23-1), rosmarinic acid, and doxycycline.

In another preferred embodiment, the glucocorticoid compound is selected from the group consisting of: dexamethasone, hydrocortisone, or a combination thereof.

In another preferred embodiment, the antibiotic is selected from the group consisting of: tobramycin, gentamicin sulfate, chlortetracycline, chloramphenicol, or combinations thereof.

In another preferred embodiment, the azole compound is selected from econazole, isoconazole, bifonazole, clotrimazole, aripiprazole, ketoconazole, fluconazole, phenylimidazole, miconazole, cyclconazole, triadimenol, tebuconazole, propiconazole, or a combination thereof.

In a second aspect of the present invention, there is provided a use of the compound according to the first aspect, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a deuterated compound thereof, for the preparation of a pharmaceutical composition or formulation for:

(a) preventing and/or treating eye diseases caused by lens pathological changes;

(b) inhibiting and reversing lens protein aggregation; and/or

(c) Preventing and/or treating diseases related to lens protein aggregation.

In another preferred embodiment, the ocular disease caused by lens pathology is selected from the group consisting of: cataract, presbyopia, myopia, cortex opacity, presbyopia nuclear sclerosis, and diabetic ocular complications; and/or

The diseases related to the aggregation of lens proteins are selected from the following group: cataract, presbyopia, myopia, cortical opacity, presbyopia nuclear sclerosis, and diabetic ocular complications.

In another preferred embodiment, the cataract is selected from the group consisting of: traumatic cataract, metabolic cataract, senile cataract, congenital cataract, spontaneous cataract, complicated cataract, or their combination.

In another preferred embodiment, the metabolic cataract includes diabetic metabolic cataract.

In another preferred embodiment, the traumatic cataract includes surgery-related cataract.

In another preferred embodiment, the spontaneous cataract includes senile spontaneous cataract.

In another preferred embodiment, the lens protein comprises α B lens protein.

In a third aspect of the invention, there is provided an in vitro non-therapeutic and non-diagnostic method of improving or maintaining lens transparency, comprising the steps of: contacting the lens with a compound according to the first aspect, or an optical isomer or racemate thereof, or a solvate or prodrug thereof, or a deuterated compound thereof, thereby improving or maintaining lens transparency.

In a third aspect of the present invention, there is provided a method for preventing and/or treating an ocular disease caused by lens pathology, comprising the steps of: administering to a subject in need thereof a compound according to the first aspect, or an optical isomer thereof or a racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a deuterated compound thereof.

In another preferred embodiment, the subject is a human or a non-human mammal. Typically, the non-human mammal includes (but is not limited to): pets (e.g., dogs, cats), livestock (e.g., cattle, sheep, horses, pigs), various zoo animals (pandas, elephants), etc.

In another preferred embodiment, the subject also includes animals other than humans and non-human mammals, such as non-mammals.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Detailed Description

The present inventors have conducted extensive and intensive studies and, for the first time, have unexpectedly found that a compound of formula I can significantly prevent and/or treat ocular diseases caused by lens disorders. The experimental results show that the compound shown in the formula I can quickly achieve the effect of curing and preventing eye diseases caused by lens pathological changes in a simple administration mode. The present invention has been completed based on this finding.

Term(s) for

As herein describedAs used herein, "R1", "R₁"and" R¹The meaning of "is the same. Other similar definitions have the same meaning

As used herein, the term "C1-C8 alkyl" or "C1-C4 alkyl" or "C1-C8 alkyl" refers to a straight or branched chain alkyl group having 1-8 or 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, or the like.

As used herein, the term "C1-C6 alkoxy" or "C1-C4 alkoxy" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, or the like.

As used herein, the term "C1-C6 alkylthio" or "C1-C4 alkylthio" refers to straight or branched chain alkylthio groups having 1-6 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio, or the like.

As used herein, the term "C3-C10 cycloalkyl" refers to a cycloalkyl group having 3-10 carbon atoms, such as cyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl, or the like.

As used herein, the terms "hydroxyalkyl" and "hydroxyalkyl" are used interchangeably and are alkyl substituted with one or more (preferably 1, 2 or 3) hydroxy groups, alkyl (e.g., C1-C8 alkyl) being as defined herein above, provided that the same carbon atom carries no more than one hydroxy group, when the hydroxyalkyl group previously has a carbon atom number limitation, e.g., C₁-C₁₀Hydroxyalkyl means that the alkyl group in said hydroxyalkyl group has 1 to 10 carbon atoms. Representative examples of hydroxyalkyl groups include (but are not limited to): hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2, 3-dihydroxy-propyl, 2-hydroxy-1-hydroxymethylethyl, 2, 3-dihydroxybutyl, 3, 4-dihydroxybutyl, or the like.

As used herein, the terms "mercaptoalkyl" and "hydroxyalkyl" are used interchangeably and are alkyl substituted with one or more, preferably 1, 2 or 3, mercapto groups, alkyl (e.g., C1-C8 alkyl) being as defined herein above, provided that the same carbon atom carries no more than one mercapto group, when the mercaptoalkyl group previously has a carbon atom number limitation, e.g., C₁-C₁₀Mercaptoalkyl means that the alkyl group in said mercaptoalkyl group has 1 to 10 carbon atoms. Representative examples of mercaptoalkyl groups include (but are not limited to): mercaptomethyl, 2-mercaptoethyl, 2-mercaptopropyl, 3-mercaptopropyl, 1- (mercaptomethyl) -2-methylpropyl, 2-mercaptobutyl, 3-mercaptobutyl, 4-mercaptobutyl, 2, 3-dimercapto-propyl, 2-mercapto-1-mercaptomethylethyl, 2, 3-dimercaptobutyl, 3, 4-dimercaptobutyl, or the like.

As used herein, the term "halogen" refers to F, Cl, Br and I.

As used herein, the term "amino" means-NH₂。

As used herein, the term "hydroxy" means-OH.

As used herein, the term "sulfhydryl" denotes SH.

As used herein, the terms "comprises," "comprising," "includes," "including," and "including" are used interchangeably and include not only closed-form definitions, but also semi-closed and open-form definitions. In other words, the term includes "consisting of … …", "consisting essentially of … …".

As used herein, the term "deuterium (D) substituted" refers to a compound or group in which one or more hydrogens are replaced with deuterium. Deuterium can be mono-, di-, poly-, or fully substituted. In another preferred embodiment, the deuterium isotope content of deuterium at the deuterium substitution position is greater than the natural deuterium isotope content (0.015%), more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, more preferably greater than 97%, more preferably greater than 99%, more preferably greater than 99.5%. In another preferred embodiment, the isotopic content of D at the position of the hydrogen atom in the compound is 95% or more, more preferably 99% or more.

As used herein, the term "presbyopia" also known as "presbyopia" refers to the condition of the eye's lens losing its flexibility and thus having difficulty focusing on close objects. Typically, the ocular disease caused by lens disorders does not include conjunctivitis, ocular infections caused by pathogens (e.g., bacteria, viruses, etc.) or ocular inflammation.

As used herein, the term "preventing" refers to administering a therapeutically effective amount of a compound of formula I, or an optical isomer or racemate thereof, or a solvate or solvate thereof, or prodrug thereof, prior to an ocular disease such that the ocular disease is prevented, delayed in onset, or still occurs, but to a lesser extent than if the compound of formula I, or an optical isomer or racemate thereof, or solvate or pharmaceutically acceptable salt thereof, or prodrug thereof, were not administered. The term "treating," as used herein, refers to administering a therapeutically effective amount of a compound of formula I, or an optical isomer or racemate thereof, or a solvate or solvate thereof, or a prodrug thereof, thereby reducing, alleviating or slowing the progression or development of an ocular disease, disorder or condition. In another embodiment, "treating" or "treatment" refers to reducing, slowing the progression of, or ameliorating one or more signs or symptoms of an ocular disease, disorder or condition.

"prevention" and "treatment" as used herein include delaying and stopping the progression of the disease, or eliminating ocular disease caused by lens pathology, without the need for 100% inhibition, elimination, or reversal. In some embodiments, the compounds and compositions or formulations of formula I of the present invention reduce, prevent, inhibit and/or reverse lens pathology-induced ocular disorders (e.g., cataracts) by, for example, at least about 1%, at least about 10%, at least about 30%, at least about 50%, or at least about 80% as compared to levels observed in the absence of the compounds and compositions or formulations of formula I of the present invention (e.g., in a control subject or specimen that is not biologically matched to the compounds and compositions or formulations of formula I of the present invention).

In another preferred embodiment, the term "cataract" refers to diseases or conditions that manifest on the surface and/or interior of the lens causing opacification or causing swelling of the lens, including congenital cataracts as well as acquired cataracts. Typically, the cataract is a cataract that includes (but is not limited to): age-related cataract, diabetic cataract, cataract related to operation, cataract caused by radiation irradiation, cataract caused by hereditary disease, cataract caused by infection, or cataract caused by medicine.

Active ingredient

As used herein, the terms "compound of the present invention", "compound of formula I of the present invention", and the like, are used interchangeably to refer to a compound of formula I, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a deuterated compound thereof. It is to be understood that the term also includes mixtures of the above components, and in the compounds of formula I, if a chiral carbon atom is present, the chiral carbon atom may be in the R configuration, also in the S configuration, or a mixture of both.

The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention with an acid or base that is suitable for use as a pharmaceutical. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is that formed with acids of the compounds of the present invention, and suitable acids for forming salts include (but are not limited to): inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, phenylmethanesulfonic acid, benzenesulfonic acid, etc.; and acidic amino acids such as aspartic acid and glutamic acid. One preferred class of salts are metal salts of the compounds of the present invention formed with bases, suitable bases for forming the salts include (but are not limited to): inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate and sodium phosphate, and organic bases such as ammonia, triethylamine and diethylamine.

The compound of formula I of the present invention can be converted into a pharmaceutically acceptable salt thereof by a conventional method, for example, a solution of the corresponding acid can be added to a solution of the above compound, and the corresponding salt of the compound of the present invention can be obtained by removing the solvent after salt formation is completed.

In the present invention, the term "prodrug" is also referred to as prodrug, etc., and refers to a compound which has a pharmacological action after being converted in vivo. The prodrug has no biological activity or low activity and becomes an active substance after in vivo metabolism, and the process aims at increasing the bioavailability of the medicament, strengthening targeting property and reducing the toxicity and side effect of the medicament. In the present invention, prodrugs of compounds of formula A may be metabolized to compounds of formula I (typically, Inonotus obliquus). In the present invention, a preferred prodrug is an ester of a compound of formula I of the present invention formed by esterification with a compound containing a hydroxyl group or a compound containing a carboxyl group. Typically, the hydroxyl group-containing compounds include C1-C6 lower alcohols (e.g., ethanol, propanol, etc.), lower sugars (e.g., glucose, lactose, etc.). Typically, the carboxyl group containing compounds include C1-C6 lower acids. Typically, the C1-C6 lower acid includes organic or inorganic acids, for example, the C1-C6 lower acid is hydrochloric acid, sulfuric acid, acetic acid, propionic acid, oxalic acid, fumaric acid, maleic acid, malic acid, tartaric acid, and the like.

The compounds of formula I according to the invention can be prepared by methods well known to the person skilled in the art, without particular limitation to the reaction parameters of the individual steps. In addition, the compounds of the present invention are also commercially available. Typically, the compound of formula I according to the present invention is prepared by extraction, isolation and purification from inonotus obliquus.

Use of the compounds of the invention

The compound of the present invention can be used for (a) preventing and/or treating eye diseases caused by lens pathology; (b) inhibiting and reversing lens protein aggregation; and (c) preventing and/or treating a disease associated with lens protein aggregation.

Preferably, the ocular disease caused by lens pathology is selected from the group consisting of: cataract, presbyopia, myopia, cortical opacity, presbyopia nuclear sclerosis, and diabetic ocular complications.

Preferably, said disease associated with lens protein aggregation is selected from the group consisting of: cataract, presbyopia, myopia, cortical opacity, presbyopia nuclear sclerosis, and diabetic ocular complications.

Use, pharmaceutical composition or formulation and method of administration of a compound

Since the compound of the present invention has excellent effects of preventing and/or treating eye diseases caused by lens disorders, active ingredients containing the compound of the present invention can be used for: (a) preventing and/or treating eye diseases caused by lens pathological changes; (b) inhibiting and reversing lens protein aggregation; and/or (c) preventing and/or treating a disease associated with lens protein aggregation. The pharmaceutical composition or formulation comprises: a compound of the invention and a pharmaceutically acceptable carrier.

In another preferred embodiment, the pharmaceutical composition or formulation may further comprise: (c) a second active ingredient, wherein said second active ingredient is selected from the group consisting of: lanosterol, any compound contained in bacteria of the order Fomitophthirales or Polyporales, azole, amyloid modulator, glucocorticoid compound, antibiotic, or a combination thereof.

In another preferred embodiment, when the "second active ingredient" is a lanolin compound, the concentration is preferably 10 to 200mM, preferably 15 to 150mM, more preferably 20 to 50 mM; most preferably 20 to 30 mM.

In another preferred embodiment, the lanolin-like compound is selected from the group consisting of: lanosterol.

As used herein, the term "amyloid modulator," also known as amyloid modulators, amyloid inhibitors, specifically refers to a class of molecules or compounds that can modulate or inhibit protein accumulation, adhesion, precipitation, formation of fibrillar protein aggregates.

As used herein, the term "therapeutically effective amount" refers to an amount that produces a function or activity in and is acceptable to humans and/or animals. It will be understood by those skilled in the art that the "effective amount" or "effective dose" may vary with the form of the pharmaceutical composition, the route of administration, the excipients used, the severity of the disease, and the combination with other drugs.

The term "pharmaceutically acceptable carrier" refers to: one or more compatible solid, semi-solid, liquid or gel fillers which are suitable for human or animal use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant that the components of the pharmaceutical composition and the active ingredient of the drug are blended with each other and not significantly detract from the efficacy of the drug.

It is to be understood that, in the present invention, the carrier is not particularly limited and may be selected from materials commonly used in the art, or prepared by a conventional method, or commercially available.

Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., tween), wetting agents (e.g., sodium lauryl sulfate), buffers, chelating agents, thickeners, pH adjusters, transdermal enhancers, colorants, flavors, stabilizers, antioxidants, preservatives, bacteriostats, pyrogen-free water, etc.

In addition to the active pharmaceutical ingredient, the liquid dosage forms may contain inert diluents commonly employed in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide as well as oils, especially cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these materials and the like.

In addition to these inert diluents, the compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents and the like

In the present invention, the dosage form of the pharmaceutical composition includes (but is not limited to) oral preparations, injections, and external preparations. Representative include (but are not limited to): tablet, injection, infusion solution, paste, gel, solution, microsphere, and pellicle.

One preferred dosage form is an ophthalmic formulation. Typically, the ophthalmic preparation is eye drop, emulsion, gel, ophthalmic ointment, sustained-release microspheres, intraocular sustained-release implant and medicinal sustained-release drug film.

The ophthalmic formulation comprises a pharmaceutically acceptable pharmaceutical carrier, typically from the group including but not limited to: solvent or diluent, surfactant, thickening agent, osmotic pressure regulator, pH regulator, bacteriostatic agent and chelating agent.

Solvent(s)

In ophthalmic formulations (e.g., eye drops), solvents or diluents, including aqueous or non-aqueous solvents, are used. The water solvent comprises distilled water, normal saline, water for injection and the like; the non-aqueous solvent includes ethanol, propylene glycol, glycerol, vegetable oil (such as olive oil, castor oil, corn oil, soybean oil for injection), etc.

Surface active agent

In the ophthalmic formulation, the surfactant is selected from an anionic surfactant, a cationic surfactant, a nonionic surfactant, a chaotropic (chaotropic) surfactant, or a combination thereof. Wherein the nonionic surfactant is selected from: tween, span, fatty acid glycerides, polyoxyethylenes, polyoxyethylene-polyoxypropylene copolymers, or combinations thereof. The amount (or content) of the surfactant is generally 0 to 2% by weight, more preferably 0.1 to 1% by weight.

Thickening agent

In the eye preparation, the thickening agent can be used for improving the viscosity of a system, so that the system is kept in a uniform and stable suspension state or an emulsion state, and the retention time of the medicine in the eye is prolonged by adding a proper amount of the thickening agent, so that the absorption of effective small components by the eye is increased.

In the ophthalmic preparation, the thickener is preferably chitosan, Hydroxypropylmethylcellulose (HPMC), Methylcellulose (MC), and povidone (PVP), gelatin, sodium carboxymethylcellulose (CMC-Na), and the like. Generally, the thickener is used in an amount (or content) of 0 to 6 wt%, preferably 0.1 to 5 wt%.

Osmotic pressure regulator

The eye preparation is added with proper osmotic pressure regulator to make the osmotic pressure of the eye preparation similar to that of human eye environment, so as to reduce the irritation to eyes. Typically, commonly used osmolytes include, but are not limited to, acetic acid, sodium acetate, sodium bicarbonate. Generally, the amount (or amount) of the tonicity modifier is such that the ophthalmic formulation is maintained in an isotonic or isotonic environment.

pH regulator

The eye preparation is added with a proper pH regulator to keep the pH value of the eye preparation in a proper range, which is similar to the pH value of the eye environment of a human body, so that the eye irritation is reduced. Typically, commonly used pH adjusting agents include, but are not limited to, sodium chloride, potassium chloride, glucose. Typically, the amount (or amount) of the pH adjusting agent is such that the pH of the ophthalmic formulation is maintained between 5 and 9.

Bacteriostatic agent

In the eye preparation, the bacteriostatic agent can kill or inhibit the growth of bacteria in cream, prevent the bacteria from breeding too much and harm the health of human bodies. In the present invention, the bacteriostatic agent is not particularly limited, and may be one or a combination of more of paraben alcohol and paraben ester. Typically, the bacteriostatic agent in the present invention is selected from the group consisting of: methyl paraben, ethyl paraben, propyl paraben, or combinations thereof.

Chelating agents

In ophthalmic formulations, the stability of the formulation can be increased by the appropriate addition of an amount of a chelating agent, such as EDTA. Typically, the concentration of the chelating agent is in the range of 0 to 0.05 wt%. The mode of administration of the composition or formulation of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): topical administration, oral administration, injection, etc.

One preferred mode of administration is topical ocular administration of the composition or formulation, including but not limited to conjunctival, retrobulbar, periocular, retinal, suprachoroidal, or intraocular administration, and the like, typically by instillation of eye drops, intraocular injection, ocular mucosal coating, and the like.

The pharmaceutical preparation should be compatible with the mode of administration. The agents of the invention may also be used with (including before, during or after) other co-therapeutic agents. In using the pharmaceutical composition or formulation, a safe and effective amount of the drug, typically at least about 10 micrograms/kg body weight, and in most cases no more than about 8 mg/kg body weight, preferably from about 10 micrograms/kg body weight to about 1 mg/kg body weight, is administered to a subject in need thereof (e.g., a human or non-human mammal). Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.

The main advantages of the invention include:

(a) the invention discovers that the compound can prevent and/or treat eye diseases, such as cataract, and has obvious treatment effect for the first time.

(b) The compound of the invention has excellent safety and little or no toxic and side effect.

(c) The compound has good development and application prospects for treatment of eye diseases.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.

Example 1

Compound 1

Compound 1 is a known compound, available commercially, or synthesized according to the literature.

Compound 2

The preparation method of the compound 1 and the compound 2 comprises the following steps:

synthesis of a to c

Inonotus obliquus alcohol (200mg, derived from Inonotus obliquus extract 2) was dissolved in dichloromethane (4mL), acetic anhydride (180mg) and pyridine (1mL) were added, the reaction was stirred at room temperature for 6h, TLC showed disappearance of the starting material, and the solvent was removed by concentration to give compound b (240 mg).

Compound b (200mg) was dissolved in dichloromethane (4mL), m-CPBA (m-chloroperoxybenzoic acid) (85%, 85mg) and sodium bicarbonate (42mg) were added to the above solution in three portions with 2h intervals under ice bath, washed once with aqueous sodium bicarbonate solution, concentrated and subjected to column chromatography to give product c (154 mg).

c to d Synthesis

Red aluminum solution (70% in toluene, 0.1mL) was added to tetrahydrofuran (10mL), and Compound c (200mg) was added and the reaction was controlled at-10 ℃ for 5 h. Pouring into diluted hydrochloric acid, extracting with ethyl acetate, drying with sodium sulfate, concentrating, and performing column chromatography to obtain compound d (120 mg).

Synthesis of d to e

Compound d (200mg) was dissolved in methanol (4mL), and potassium carbonate (100mg) was added to the solution, which was heated to 50 ℃ for reaction for 6 hours. After filtration, the residue was concentrated and subjected to column chromatography to give compound e (i.e., Compound 1) (145 mg).

¹H NMR(CD₃Cl，400MHz):δ(ppm)3.7(1H，m)，3.25(1H，m)0.69(3H，s)；¹³C NMR(CDCl₃，100MHz):δ(ppm)134.5，134.2，79.0，73.4，70.3，50.4，49.4，47.2，44.8，41.6，40.0，38.9，37.0，35.6，30.9，29.5，29.1，28.0，27.8，26.8，26.5，26.0，24.3，21.0，19.2，18.2，18.0，15.7，15.4，12.6。

Synthesis of e to f

Dissolving the compound e (200mg) in dichloromethane (6mL), adding pyridine (1mL) and TBDMSCl (65mg), reacting at room temperature until the substrate disappears, washing with water, adding dess-Martin oxidant (170mg), reacting at room temperature for 6h, washing with aqueous sodium bicarbonate solution, concentrating to remove the solvent, adding tetrahydrofuran (6mL), tetrabutylammonium fluoride (170mg), reacting at room temperature for 5h, concentrating, adding dichloromethane, washing with water, concentrating, and performing column chromatography to obtain the compound f (93 mg).

Synthesis of f to g

Compound f (200mg) was dissolved in methylene chloride (6mL), triethylamine (1mL) and TBSOTf (340mg) were added to the solution and the mixture was reacted at room temperature for 2 hours, washed with water and concentrated to remove the solvent and column chromatography to obtain g (302 mg).

Synthesis of ghi

Dissolving the compound g (200mg) in DMF (6mL), adding 1-chloromethyl-4-fluoro-1, 4-diazotized bicyclo 2.2.2 octane bis (tetrafluoroborate) salt (selectifluor, 88mg), reacting at room temperature for 1h, adding dichloromethane, washing with an aqueous solution of sodium bicarbonate, concentrating under reduced pressure to remove the solvent, adding ethanol (6mL), sodium borohydride (10mg), reacting at room temperature for 1h, adding dilute hydrochloric acid to the above system, concentrating to remove the solvent, extracting with ethyl acetate, concentrating, performing column chromatography to obtain a white solid, adding tetrahydrofuran (6mL), tetrabutylammonium fluoride (130mg), reacting at room temperature for 5h, concentrating, adding dichloromethane, washing with water, concentrating, and separating the compounds h (43mg) and i (8mg) by preparing a liquid phase. h (i.e., compound 2):¹H NMR(CD₃Cl，400MHz):δ(ppm)5.01-4.86(1H，m)，3.68(1H，d)，0.67(3H，s)；¹³C NMR(CDCl₃，100MHz):δ(ppm)134.7，133.9，91.4，76.7，73.0，71.1，50.5，49.9，47.2，46.3，42.5，41.6，35.8，35.6，31.0，30.9，29.7，29.5，29.4，28.4，28.2，26.2，25.4，24.3，21.3，21.2，20.3，18.8，15.4，12.6。i：¹H NMR(CD₃Cl，400MHz):δ(ppm)4.64-4.50(1H，m)，3.28(1H，dd)，0.68(3H，s)；¹³C NMR(CDCl₃，100MHz):δ(ppm)134.9，133.5，93.4，81.1，73.0，71.1，50.4，49.8，47.2，46.3，42.5，41.6，36.7，36.5，30.8，30.7，29.7，29.3，29.2，28.4，28.2，26.2，25.4，24.3，21.3，21.1，18.7，18.0，15.4，12.6。

example 2

In example 2, we selected a part of compound 1 and compound 2 prepared in example 1, performed intracellular mutant crystallin (α B-crystallin R120G) aggregation inhibition assay (experimental method as described in chinese patent CN 201580057679), evaluated the aggregation inhibitory activity of compound 1 and compound 2 of the present invention on crystallin mutants, and screened compounds effective for the treatment of cataract.

Experimental methods

The tumor cell line HeLa was selected as host cells transfected with the expression plasmid for the mutant lens protein (α B-crystallin R120G), the culture medium was DMEM containing 10% FBS, the culture conditions were 37 ℃ and saturation humidity, 5% carbon dioxide cell incubator, mycoplasma detection was negative, the transfection procedure was to inoculate a suitable number of HeLa cells on a pre-coated slide, when the fully adherent cells had grown to a cell density of about 75%, the expression vector was transfected with liposomes, the normal medium was changed after 4 hours of transfection, incubation was continued for 13 hours in the cell incubator to express the foreign mutant lens protein, after which the medium was changed, containing each of the compounds of formula I of the invention to be tested (all stock solutions used DMSO as solvent), wherein each compound had a final concentration of 10 μ M, the negative control was 1.5% DMSO solvent, the positive control was lanosterol (10 μ M), the culture medium containing each of the compound to be tested, 1.5% DMSO solvent and lanosterol was treated for 3.5 hours, the fresh medium containing no test compound, no DMSO solvent and the final spot of the mutant lens protein was cultured for each day, the normal cell culture medium containing the pi protein was continued for 3 hours, the test compounds, the final spot of the normal cell aggregation was determined by using the pi protein, the normal antibody for each day, the normal cell culture medium containing each day 2 g of the test protein.

Table 1 compounds 1 and 2 of the invention

Effect on intracellular aggregation of Lectin mutant (α B-crystallin R120G)

Compound numbering	Inhibiting effect
		Compound 1	+
Compound 2	+
		Lanosterol	++
Negative control	+++

Note: the symbols used for the inhibition effect in the table correspond to the percentage of cells containing agrin:

"+" indicates that 45% or less of the cells in the field of view contain protein aggregates;

"+ +" indicates that > 45% and ≦ 60% of the cells in the field of view contained protein aggregates;

"+ + + +" indicates that > 60% of the cells in the field of view contain protein aggregates.

It can be seen from table 1 that compound 1 and compound 2 have excellent effects of reducing intracellular lens protein aggregation and treating diseases caused by lens disorders.

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims

1. A compound, or an optical isomer or racemate thereof, or a solvate or prodrug thereof, or a deuterated compound thereof,

the compound has the structure of formula I:

in the formula (I), the compound is shown in the specification,

a is 0, 1 or 2;

r7 is hydrogen;

r11 is hydrogen;

r13 is hydrogen;

r14 is halogen;

wherein any "substitution" means that one or more (preferably 1, 2,3 or 4) hydrogen atoms on the group are selected fromSubstituted with a substituent of group (d): c₁-C₄Alkyl radical, C₁-C₄Alkoxy radical, C₁-C₄Alkylthio, hydroxyl, mercapto, amino, halogen.

2. The compound of claim 1, wherein the compound comprises one or more characteristics selected from the group consisting of:

r1 is hydrogen;

r2 is substituted or unsubstituted C1-C4 alkyl;

r3 is hydrogen;

r4 is hydrogen;

r5 is hydrogen;

r6 is hydrogen;

r8 is hydroxy, or mercapto;

r9 is substituted or unsubstituted C1-C4 alkyl;

r10 is substituted or unsubstituted C1-C4 alkyl;

r12 is hydroxyl or sulfhydryl.

3. The compound of claim 1, wherein said compound is selected from the group consisting of:

4. the compound of claim 1, wherein said compound is selected from the group consisting of:

5. a pharmaceutical composition, comprising: (i) the compound of claim 1, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a deuterated compound thereof; and (ii) a pharmaceutically acceptable carrier.

6. Use of a compound according to claim 1, or an optical isomer or racemate thereof, or a solvate or prodrug thereof, or a deuterated compound thereof, for the preparation of a pharmaceutical composition or formulation for:

(b) inhibiting and reversing lens protein aggregation; and/or

(c) Preventing and/or treating diseases related to lens protein aggregation.

7. The use of claim 6, wherein the ocular disease caused by lens pathology is selected from the group consisting of: cataract, presbyopia, myopia, cortex opacity, presbyopia nuclear sclerosis, and diabetic ocular complications; and/or

8. The use of claim 7, wherein said cataract is selected from the group consisting of: traumatic cataract, metabolic cataract, senile cataract, congenital cataract, spontaneous cataract, complicated cataract, or their combination.

9. The use of claim 7, wherein said lens protein comprises α B lens protein.

10. A method for in vitro non-therapeutic and non-diagnostic improvement or maintenance of lens transparency by contacting the lens with the compound of claim 1, or an optical isomer or racemate thereof, or a solvate or pharmaceutically acceptable salt thereof, or prodrug thereof, or deuterated compound thereof, thereby improving or maintaining lens transparency.