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CN-121974777-A - Fluoroalkanes, compositions thereof, methods of making and uses thereof

CN121974777ACN 121974777 ACN121974777 ACN 121974777ACN-121974777-A

Abstract

The present disclosure relates to the field of pharmaceuticals, and in particular to fluoroalkanes, compositions thereof, and methods of making and using the same. The present disclosure has the advantage that the present disclosure provides fluoroalkanes, compositions thereof, and methods of preparing and using the same, compounds of formula (I) of the present disclosure or pharmaceutically acceptable salts thereof, stereoisomers, isotopic variants thereof, solvates thereof, or compositions thereof, have the effects of stabilizing tear film, dissolving meibomian, dissolving cerumen, inhibiting evaporation of ocular surface water, increasing tear film lipid layer thickness, improving spreadability to the cornea, wetting ocular surface, ex vivo organ preservation, vitreous filling, intravitreal silicone oil filling cleansing, cornea repair, improving tear film stability, reducing tear evaporation rate, extending tear film break time, treating meibomian abnormalities, treating meibomian gland dysfunction, treating keratoconjunctivitis sicca, treating eye or ear related diseases such as dry eye related diseases, and/or delivering pharmaceutically active ingredients.

Inventors

  • GUO MING
  • YANG QIANG
  • JIN YANG
  • ZHANG WEICHEN
  • WU LULU
  • MENG WEIXU
  • SONG DAN
  • HU JINGQIONG
  • LIU JIDONG

Assignees

  • 沈阳兴齐眼药股份有限公司

Dates

Publication Date
20260505
Application Date
20260409

Claims (18)

  1. 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotopic variant, a solvate thereof: (I) Wherein n is selected from integers from 1 to 8; R 1 、R 2 、R 1' 、R 2' is independently selected from hydrogen, C 1 -C 12 alkyl, C 3 -C 8 cycloalkyl, or R 1 and R 2 together with the saturated carbon atom to which they are attached form C 4 -C 8 cycloalkyl, or R 1' and R 2' together with the saturated carbon atom to which they are attached form C 4 -C 8 cycloalkyl, said C 1 -C 12 alkyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl being optionally substituted with one or more halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl or halogenated C 1-6 alkoxy.
  2. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotopic variant, or a solvate thereof, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotopic variant, or a solvate thereof, has a structure of formula (II): (II) In the formula (II), R 1 、R 2 and n are defined as in the formula (I).
  3. 3. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, isotopic variant, solvate thereof, wherein R 1 、R 2 、R 1' 、R 2' is each independently selected from hydrogen, C 1 -C 10 alkyl, C 3 -C 8 cycloalkyl, or wherein R 1 and R 2 together with the saturated carbon atom to which they are attached form C 4 -C 6 cycloalkyl, or wherein R 1' and R 2' together with the saturated carbon atom to which they are attached form C 4 -C 6 cycloalkyl.
  4. 4. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, isotopic variant, solvate thereof, 、 Each independently selected from the following structures: 。
  5. 5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotopic variant, a solvate thereof, wherein n is selected from integers from 4 to 6.
  6. 6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotopic variant, or a solvate thereof, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotopic variant, or a solvate thereof, is selected from the group consisting of: 、 、 、 、 、 、 、 、 、 。
  7. 7. the process for producing a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer, isotopic variant or solvate thereof, wherein the step of producing the compound represented by formula (I) comprises obtaining M-1-0 from fluoroiodoalkane and alkene in step a0, and obtaining the compound represented by formula (I) from M-1-0 in step b 0; Wherein R 1 、R 2 、R 1' 、R 2' , n are each as defined in any one of claims 1 to 6.
  8. 8. The preparation method of the compound shown in the formula (II) according to claim 7, wherein the preparation step of the compound shown in the formula (II) comprises the steps of obtaining M-1 through a step a by fluoroiodoalkane and alkene, and obtaining the compound shown in the formula (II) through a step b by M-1; Wherein R 1 、R 2 , n are each as defined in formula (II).
  9. 9. A composition comprising a compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotopic variant, a solvate thereof, or a compound obtained by the method of preparation of claim 7 or 8, or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotopic variant, a solvate thereof.
  10. 10. The composition according to claim 9, wherein the composition comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an isotopic variant, a solvate thereof as the sole active ingredient.
  11. 11. The composition according to claim 9, wherein the composition further comprises a pharmaceutically active ingredient and/or an oil-soluble ingredient.
  12. 12. The composition of claim 11, wherein the oil-soluble ingredient is selected from one or more of squalene, squalane, omega-3 fatty acids or esters thereof, eicosapentaenoic fatty acid (EPA) or esters thereof, docosahexaenoic fatty acid (DHA) or esters thereof, oleic acid or esters thereof, medium chain triglycerides, hexyl laurate, D-alpha-tocopherol or D-alpha-tocopherol acetate, liquid paraffin, perfluorohexyloctane, perfluorobutylpentane, silicone oil.
  13. 13. The composition of claim 11, wherein the pharmaceutically active ingredient is selected from one or more of immunosuppressants, adrenergic receptor agonists, adrenergic receptor inhibitors, prostanoids, antibiotics, antibacterial compounds, antiparasitics, JAK inhibitors, tyrosine kinase inhibitors, antibacterial compounds, anesthetics, hormonal agents.
  14. 14. The composition of claim 11, wherein the composition comprises, the pharmaceutical active ingredient is selected from cyclosporin, tacrolimus, rapamycin, tafluprost, travoprost, bemeprostin, latanoprost, ivermectin, lotirana, lu Ke tinib, tofacitinib, baritinib, wu Pati ni, phenanthrene Zhuo Tini, pacritinib, abxitinib, digatinib, azithromycin, brimonidine, alcalidine, epinephrine, phenylephrine, timolol, levobunolol, carteolol, pindolol, betaxolol, carvedilol, thymus-amine, nebivolol, unoprostone, ofloxacin, levofloxacin, moxifloxacin, gatifloxacin one or more of besifloxacin, tobramycin, gentamicin, erythromycin, doxycycline, minocycline, vancomycin, teicoplanin, chloramphenicol, polymyxin B, natamycin, albendazole, chlorhexidine, propamidine, hexamidine, sunitinib, pazopanib, axitinib, valapamide, voriconazole, fluconazole, ketoconazole, miconazole, clotrimazole, flucytosine, caspofungin, micafungin, procaine, lidocaine, oxybuprocaine, tetracaine, ropivacaine, propofol, bupivacaine, dexamethasone, prednisolone, loteprednol, and fluorometholone.
  15. 15. The composition according to any one of claims 9 to 14, wherein the composition is formulated as a pharmaceutical preparation selected from one or more of a solution, suspension, drop, lotion, gel, paste, spray, injection, implant.
  16. 16. The composition according to any one of claims 9 to 14, wherein the composition is for topical administration, which is for ophthalmic, otic or topical use.
  17. 17. The composition of claim 16, wherein the ophthalmic is administered into the lacrimal sac, the eyelid site, the surface of the eye, the eye tissue, the eyelashes, the upper eyelid, the lower eyelid, the eyelid margin, the meibomian glands, the meibomian gland ducts, the eyelash follicles, or accessory glands thereof, or any area of eyelid anatomy or eye tissue.
  18. 18. Use of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an isotopic variant, a solvate thereof, a compound obtained by the method of preparation according to claim 7 or 8 or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an isotopic variant thereof, a solvate thereof, or a composition according to any one of claims 9 to 17 for the preparation of a medicament or agent of any one or more of the following (1) - (20): (1) A medicament or agent for treating dry eye and symptoms and conditions associated therewith; (2) A medicament or agent for treating keratoconjunctivitis sicca and symptoms and conditions associated therewith; (3) A medicament or agent for treating meibomian gland dysfunction and symptoms and conditions associated therewith; (4) A drug or agent for stabilizing the tear film; (5) A medicament or agent for dissolving meibum; (6) A medicament or agent for dissolving cerumen; (7) A medicament or agent for inhibiting evaporation of ocular surface moisture; (8) A drug or agent for increasing the thickness of the lipid layer of the tear film; (9) A medicament or agent for treating meibum abnormalities; (10) A medicament or agent for improving the spreadability on the cornea; (11) Drugs or agents as eye surface lubricants; (12) Drugs or agents for ex vivo organ preservation; (13) Drugs or agents for vitreous filling; (14) Drugs or agents for intravitreal silicone oil fill cleansing; (15) Drugs or agents for cornea repair; (16) A drug or agent for improving tear film stability; (17) A drug or agent for reducing tear evaporation rate; (18) A drug or agent for extending tear film break-up time; (19) A medicament or agent for increasing the solubility of a pharmaceutically active ingredient; (20) A medicament or agent for increasing the stability of a pharmaceutically active ingredient.

Description

Fluoroalkanes, compositions thereof, methods of making and uses thereof Technical Field The present disclosure relates to the field of medicine, and in particular to topical ophthalmic compounds and/or compositions thereof useful for the treatment of keratoconjunctivitis sicca and/or meibomian gland dysfunction and symptoms associated therewith. The present disclosure relates specifically to fluoroalkanes, compositions thereof, and methods of making and using the same. Background Keratoconjunctivitis sicca, also known as dry eye or tear dysfunction syndrome, is a disorder of the tear film or ocular surface microenvironment caused by abnormalities in tear quality, volume and dynamics, and can be accompanied by chronic ocular surface diseases caused by factors such as ocular surface inflammatory responses, tissue damage, nerve abnormalities and the like, and is mainly characterized in that the tear film imbalance is combined with various symptoms of the eye, and can cause various uncomfortable symptoms or visual dysfunction of the eye. With the wide applicability of climate change, environmental pollution, air conditioning and electronic screens and the change of people's living habits, the onset of dry eye is gradually younger and the incidence of dry eye is rising year by year. The tear film is a dynamic structure composed of an innermost mucus layer, an aqueous layer positioned above the mucus layer and a lipid layer covered by the aqueous layer, and is covered on the ocular surface to lubricate, wash inflammatory factors and protect cornea conjunctiva. The meibum of the lipid layer constituting the tear film is synthesized and secreted by the largest sebaceous gland of human body, namely the meibomian gland, is a mixture composed of various lipids, has unique physicochemical properties and important physiological functions, and has an important role in maintaining the stability of the tear film in the normal physiological state. Meibomian gland dysfunction (meibomian gland dysfunction, MGD) is a group of chronic, diffuse meibomian gland abnormalities, mainly manifested by terminal vessel obstruction, lipid quality or quantity changes, etc., ultimately leading to altered tear film stability, leading to ocular inflammation, ocular surface cell damage and irritation discomfort. The development of dry eye is chronic and multifactorial, while abnormalities in the stability, composition or secretion of the tear film are the central mechanisms of dry eye development. Dry eye can be classified into aqueous-deficient dry eye, lipid-abnormal dry eye, mucin-abnormal dry eye, tear-dynamics-abnormal dry eye, mixed dry eye, and the like, according to tear components or functional abnormalities. The prior art ophthalmic compounds or compositions are limited in variety, and the presently disclosed ophthalmic compounds or compositions often contain irritating solvents such as ethanol or the like, or have poor solubility (e.g., cyclosporine, etc.) in poorly soluble pharmaceutically active ingredients (Active Pharmaceutical Ingredient, abbreviated "API"). CN102652022B discloses that perfluorohexyl octane and perfluorobutyl pentane together with small amounts of ethanol increase their solubility to cyclosporine, although it is believed that the ethanol content does not adversely affect the tolerance of the composition in this patent, in theory ethanol is somewhat irritating to the human eye. CN109906085A discloses an ophthalmic composition comprising a cyclosporin dissolved in 1-perfluorobutyl-pentane, which still has poor solubility for cyclosporin. Thus, there is a need to develop novel ophthalmic compounds or compositions thereof for stabilizing the tear film, dissolving meibum, treating meibum abnormalities, and/or delivering pharmaceutically active ingredients. Disclosure of Invention The present disclosure is directed to fluoroalkanes, compositions thereof, and methods of making and using the same. The fluoroalkanes or compositions thereof of the present disclosure have the effect of stabilizing tear film, dissolving meibum, dissolving cerumen, ocular surface lubricants, ex vivo organ preservation, vitreous filling, intravitreal silicone oil filling cleansing, cornea repair, treating meibum abnormalities, treating meibomian gland dysfunction, treating keratoconjunctivitis sicca, treating dry eye related diseases, and/or delivering pharmaceutically active ingredients (particularly poorly soluble pharmaceutically active ingredients). In order to achieve the technical purpose, the technical scheme adopted by the present disclosure is as follows: in one aspect, the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotopic variant thereof, a solvate thereof: (I) Wherein n is selected from integers from 1 to 8; R 1、R2、R1'、R2' is independently selected from hydrogen, C 1-C12 alkyl, C 3-C8 cycloalkyl, or R 1 and R 2 together with the saturated c