Compounds, compositions and pharmaceutical compositions for treatment of myopia

Abstract

To provide compounds, compositions, pharmaceutical compositions, kits and articles of manufacture for preventing or delaying the onset of myopia.SOLUTION: Provided herein are 8-methyl-8-azabicyclo[3.2.1]octan-3-yl and pyridin-4-ylmethanil ester and amide compounds and compositions.SELECTED DRAWING: None

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims priority to U.S. Provisional Patent Application No. 62 / 800,312, filed on February 1, 2019; U.S. Provisional Patent Application No. 62 / 801,515, filed on February 5, 2019; and U.S. Provisional Application No. 62 / 819,236, filed on March 15, 2019, and incorporates the entire contents of each of them herein by reference.

[0002] (Technical Field) This specification provides ester and amide compounds and compositions of 8 - methyl - 8 - azabicyclo[3.2.1]octan - 3 - yl and pyridin - 4 - ylmethanyl. This specification also provides methods for preventing or delaying the onset of myopia in a subject in need thereof, including administering the compounds or compositions provided herein to the subject. This specification also provides methods for delaying or preventing the progression of myopia in a subject in need thereof, including administering the compounds or compositions provided herein to the subject.

Background Art

[0003] Myopia, also known as nearsightedness or shortsightedness, is a type of refractive error of the eye, characterized by the fact that the visual image focuses in front of the retina, generally resulting in distant objects appearing blurry. Myopia is particularly common among Asians and is reported to affect up to 70 - 90% in Asian countries. Myopia can be corrected by prescription lenses (e.g., glasses or contact lenses), or refractive corrective surgery (e.g., LASIK or phakic intraocular lens implantation). In addition, patients with high myopia are at high risk of developing vision-threatening disorders such as retinal degenerative changes like peripheral lattice degeneration, tears and detachments, neovascularization of the myopic choroid, myopic macular detachment and holes, posterior staphyloma, myopic macular degeneration, early-onset cataract (in the 30s - 40s), open-angle glaucoma, as well as peripapillary atrophy, tilting and pits of the optic nerve head. These disorders, if left untreated, may lead to vision loss later in life. Also, children who develop myopia early are highly likely to eventually have high myopia. A recent Singapore-based paper that pooled data from adult studies in Singapore, China, India, and Malaysia showed that the pathological symptoms of myopia, particularly staphyloma and choroidoretinal atrophy, worsen with age, progression of myopic refraction, and axial length (Non-Patent Document 1). Therefore, the application of a compound or composition that can delay the onset and / or progression of myopia in pediatric patients would have a significant beneficial impact on the patient's life by resulting in a lower outcome (e.g., -5.00D instead of -10.00D) than would occur if myopia progresses, or if these were not applied.

Prior Art Documents

Non-Patent Documents

[0004]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] This application relates to compounds and compositions thereof for preventing or delaying the onset of myopia when administered before the onset of myopia or for preventing or reducing the progression of myopia when myopia is present. Without wishing to be bound by theory, these compounds are thought to act by antagonizing one or more of the muscarinic receptor family. Although much research has been done in the field of muscarinic receptors, there are common side effects such as eye blurring and there is no truly selective antagonist.

Means for Solving the Problems

[0006] In one aspect, the present specification provides a compound of formula I,

Chemical formula

[0007] In another aspect, the present specification provides a compound of formula II

Chemical formula

[0008] In another aspect, the present specification provides a compound of formula III

Chemical formula

[0009] In another aspect, the present specification provides a compound of formula IV

Chemical formula

[0010] In yet another aspect, the present specification discloses compounds of formula (I), compounds of formula (II), compounds of formula (III), compounds of formula (IV), benzeneacetic acid, α-(hydroxymethyl)-(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester, (αR)-benzeneacetic acid, α-(hydroxymethyl)-(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester, (αS)-benzeneacetic acid, α-(hydroxymethyl)-(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester, endo-benzeneacetic acid, α-(hydroxymethyl)-8-(methyl-d3)-8-azabicyclo[3.2.1]oct-3-yl ester,

Chem.

Chem.

Chem.

Chem.

[0011] In another aspect, a compound of formula (I), a compound of formula (II), a compound of formula (III), a compound of formula (IV), benzeneacetic acid, α-(hydroxymethyl)-(3-exo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester, (αR)-benzeneacetic acid, α-(hydroxymethyl)-(3-exo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester, (αS)-benzeneacetic acid, α-(hydroxymethyl)-(3-exo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester, endo-benzeneacetic acid, α-(hydroxymethyl)-8-(methyl-d3)-8-azabicyclo[3.2.1]oct-3-yl ester,

Chem.

Chem.

Chem.

Chem.

[0012] In yet another aspect, the present disclosure provides a method for preventing or delaying the onset of myopia, which includes intravitreal administration to a subject of a composition containing less than 0.1% of a compound of Formula III or Formula IV. In some embodiments, the compound is present in the form of a pharmaceutically acceptable salt. In some embodiments, the composition contains about 0.01% of a compound of Formula III or Formula IV. In some embodiments, the composition contains about 1.0% to 0.0049% of a compound of Formula III or Formula IV. In some embodiments, the subject is a human between 4 and 21 years old. In some embodiments, the subject is a human between 5 and 10 years old. In some embodiments, the subject has pre-myopia. In some embodiments, the composition of the compound of Formula III or Formula IV is administered every other day, or at least once a day, or at least twice a day. In some embodiments, each administration is performed by instilling at least 1 drop, at least 2 drops, or at least 3 drops of the composition into each eye, and each drop contains about 20 to 100 microliters of the composition. In some embodiments, the administration is continued for at least 6 months, or at least 1 year, or at least 2 years, or at least 10 years or more. In some embodiments, the composition further comprises a non-aqueous formulation. In some embodiments, the composition further comprises a non-aqueous formulation containing one or more partially fluorinated hydrocarbons, which are also known as semi-fluorinated alkanes or SFAs. In some embodiments, at least one pharmaceutically acceptable additive is selected from the group consisting of benzalkonium chloride. In some embodiments, benzalkonium chloride is present in the composition at a concentration of about 0.01%. In some embodiments, there is no preservative additive in the composition. In some embodiments, the spherical equivalent (SE) of the eye is in the range of ~1.00 D to -0.49 D before administration of the composition. In some embodiments, the SE is measured by an autorefractor after administration of cycloplegic anesthesia. In some embodiments, the subject does not have astigmatism measured by an autorefractor with or without cycloplegic anesthesia before administration of the composition, or has astigmatism of 1.50 D or less.In some embodiments, the pupil of the eye does not have dilation during the administration period of the composition, or has a dilation of 2 mm or less, for example, a dilation of 1.9 mm or less, 1.8 mm or less, 1.7 mm or less, 1.5 mm or less, 1.49 mm or less. In some embodiments, the eye does not have a clinically significant decrease in accommodation power, or does not experience a loss of accommodation power of 10 D or less, for example, 9 D or less, 8.5 D or less, 8.8 D or less, or 8 D or less. In some embodiments, the eye does not have a clinically significant loss of near vision due to loss of accommodation power. In some embodiments, the onset of myopia is delayed by 6 months, 12 months, 18 months, 2 years, 3 years, 5 years, 6 years, 8 years, or more. In another aspect, the present disclosure provides a method for reducing or preventing the progression of myopia, comprising administering intravitreally to a subject a composition of a compound of formula III or formula IV, the composition being administered at a frequency of once every day, once every two days, or once every three days. In some embodiments, each administration is performed by instilling at least one drop, at least two drops, or at least three drops into the eye, and each drop contains a liquid of about 20 to 100 microliters. In some embodiments, the SE of the eye is less than -1.50 D before administration of the composition. In some embodiments, the SE of the eye is in the range of -0.50 D to -1.50 D before administration of the composition. In some embodiments, the subject is between 4 and 21 years old. In some embodiments, the subject is between 5 and 9 years old. In some embodiments, the composition of the compound of formula III or formula IV is present in perfluorohexyl octane. In some embodiments, the composition of the compound of formula III or formula IV present in perfluorohexyl octane contains about 0.1% to 0.0049% of the compound of formula III or formula IV.

[0013] In some embodiments, the composition further comprises at least one pharmaceutically acceptable additive. In some embodiments, the at least one pharmaceutically acceptable additive is selected from ethyl alcohol.

[0014] In some embodiments, the compositions of Formulas III and IV further comprise an additional therapeutic agent, or a polymorph, zwitterion, solvate, or pharmaceutically acceptable salt of such an additional therapeutic agent. In some embodiments, the compositions of Formulas III and IV further comprise at least one additional therapeutic agent that is a known muscarinic receptor antagonist. In some embodiments, the compositions of Formulas III and IV

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0015] In some embodiments, the average change in SE over two years after the start of administration of the composition is at least 20% less compared to the control. In some embodiments, treating a patient, such as a patient with pre-myopia, reduces the refractive change by at least 10%, at least 20%, at least 30%, or at least 40%, or at least 50%. In some embodiments, treating a patient with pre-myopia using a composition comprising a compound of formula III or formula IV reduces the further increase in axial length by at least 10%, at least 15%, at least 20%, at least 30% over a period of one week, two weeks, one month, two months, six months, one year, two years, or longer from the start of treatment. In some embodiments, treating a patient with pre-myopia with a composition comprising a compound of formula III or formula IV disclosed herein can reduce the refractive change by at least 10%, at least 20%, at least 30%, or at least 40%.

[0016] In some embodiments, administration of a composition comprising a compound of formula III or formula IV disclosed herein reduces the refractive change (i.e., the shift of myopic refractive error) by at least 10%, for example, at least 20%, at least 30%, or at least 40%, at least 50% compared to the control. In some embodiments, during treatment, the pupil of the patient's eye does not dilate or shows a dilation of 1.9 mm or less, 1.8 mm or less, 1.7 mm or less, 1.5 mm or less, 1.49 mm or less during the administration period of the composition comprising a compound of formula III or formula IV. In some embodiments, the eye has no reduction in accommodation power or has a reduction in accommodation power of 10 D or less, for example, 9 D or less, 8.5 D or less, 8.8 D or less, or 8 D or less.

[0017] The present disclosure also provides the use of a compound of formula III or formula IV in the preparation of a composition for preventing or delaying the onset of myopia progression, the composition comprising a partially fluorinated hydrocarbon as a carrier. The compound of formula III can also be used in the treatment of many other eye diseases such as uveitis and amblyopia. BRIEF DESCRIPTION OF THE DRAWINGS

[0018]

Figure 1

Figure 2

Figure 3

DETAILED DESCRIPTION OF THE INVENTION

[0019] In this disclosure, publications and patents are referenced. All U.S. patents or U.S. patent application publications referenced herein are incorporated herein by reference. All percentages, ratios, and proportions used herein are weight percentages unless otherwise specified.

[0020] Esters and amides of 8-methyl-8-azabicyclo[3.2.1]octan-3-yl and pyridin-4-ylmethanyl are provided. Compositions and methods for treating myopia are provided.

[0021] "Alkyl" refers to saturated aliphatic hydrocarbons including straight-chain and branched-chain groups (e.g., C1-C 20 alkyl, C1-C 10 alkyl, or C1-C4 alkyl). Examples of "alkyl" include groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, etc. The alkyl group may or may not be substituted. The substituents may themselves be substituted. When substituted, the substituents are preferably, but not limited to, C1-C4 alkyl, aryl, amino, cyano, hydrogen, alkoxy, or hydroxyl. "C1-C4" alkyl refers to an alkyl group containing from 1 to 4 carbon atoms.

[0022] "Alkenyl" refers to an unsaturated aliphatic hydrocarbon moiety containing straight-chain and branched-chain groups. The alkenyl moiety must contain at least one alkene. "Alkenyl" can be exemplified by groups such as ethenyl, n-propenyl, isopropenyl, n-butenyl, etc. The alkenyl group may be substituted or unsubstituted. Also, the substituent itself may be substituted. When substituted, the substituent is preferably alkyl, halogen, or alkoxy. Also, the substituent itself may be substituted. The substituent is placed on the alkene itself, as well as on the adjacent member atoms or the alkynyl moiety. "C2-C4 alkenyl" refers to an alkenyl group containing 2 to 4 carbon atoms.

[0023] "Alkynyl" refers to an unsaturated aliphatic hydrocarbon moiety containing straight-chain and branched-chain groups. The alkynyl moiety must contain at least one alkyne. "Alkynyl" can be exemplified by groups such as ethynyl, propynyl, n-butynyl, etc. The alkynyl group may be substituted or unsubstituted. When substituted, the substituent is preferably alkyl, amino, cyano, halogen, alkoxyl, or hydroxyl. Also, the substituent itself may be substituted. The substituent is on the adjacent member atoms of the alkynyl moiety, not on the alkyne itself. "C2-C4 alkynyl" refers to an alkynyl group containing 2 to 4 carbon atoms.

[0024] "Acyl" or "carbonyl" refers to a -C(O)R group, where R is alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclic, heterocarbocyclic, alkylaryl, or alkylheteroaryl. Alkylcarbonyl refers to a group having an alkyl chain of 1 to 4 carbon atoms in front of the carbonyl moiety.

[0025] "Alkoxy" refers to an -O-R group, where R is acyl, alkylalkenyl, alkylalkynyl, aryl, carbocyclic, heterocarbocyclic, heteroaryl, C1-C4 alkylaryl, or C1-C4 alkylheteroaryl.

[0026] "Amino" refers to an -NR’R’ group, where each R’ is independently hydrogen, amino, hydroxyl, alkoxyl, alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, C1-C4 alkylaryl or C1-C4 alkylheteroaryl. Two R’ groups may themselves be linked to form a ring. The R’ group may itself be further substituted, in which case the group also known as guanyl is specifically contemplated under the term "amino".

[0027] "Aryl" refers to an aromatic carbocyclic group. "Aryl" can exemplify phenyl. The aryl group may be substituted or unsubstituted. The substituent may itself be substituted. When substituted, the substituent is preferably, but not limited to, heteroaryl, acyl, carboxyl, carbonylamino, nitro, amino, cyano, halogen, or hydroxyl.

[0028] "8-Methyl-8-azabicyclo[3.2.1]octan-3-yl" refers to a bicyclic heteroaliphatic ring structure with the illustrated systematic number

Chem.

[0029] "Pyridin-4-ylmethanyl" refers to a heteroaromatic ring structure with the illustrated systematic number

Chem.

[0030] "Carboxyl" refers to a -C(=O)O-C1-C4 alkyl group.

[0031] "Carbonyl" refers to a -C(O)R group, where each R is independently hydrogen, alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, C1-C4 alkylaryl, or C1-C4 alkylheteroaryl.

[0032] "Carbonylamino" refers to a -C(O)NR’R’, where each R’ is independently hydrogen, alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, C1-C4 alkylaryl, or C1-C4 alkylheteroaryl. The two R’ groups may be linked together by themselves to form a ring.

[0033] "Alkylaryl" refers to an alkyl group having an aryl substituent such that the aryl group is bonded through an alkyl group. "Alkylaryl" can be exemplified by benzyl.

[0034] "Alkylheteroaryl" refers to an alkyl group having a heteroaryl substituent such that the heteroaryl group is bonded through an alkyl group.

[0035] "Carbocyclic group" or "cycloalkyl" means a monovalent saturated or unsaturated hydrocarbon ring. The carbocyclic group is monocyclic or a bicyclic ring system that is fused, spiro, or bridged. The monocyclic carbocyclic group contains 3 to 10 carbon atoms in the ring, preferably 4 to 7 carbon atoms, more preferably 5 to 6 carbon atoms. The bicyclic carbocyclic group contains 8 to 12 carbon atoms in the ring, preferably 9 to 10 carbon atoms. The carbocyclic group may or may not be substituted. Also, the substituent may itself be substituted. Preferred carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, and cycloheptyl. More preferred carbocyclic groups include cyclopropyl and cyclobutyl. The most preferred carbocyclic group is cyclopropyl. The carbocyclic group is not aromatic.

[0036] "Halogen" refers to a fluoro, chloro, bromo or iodo moiety. Preferably, the halogen is fluoro, chloro or bromo.

[0037] "Heteroaryl" or "heteroaromatic" refers to a monocyclic or bicyclic aromatic carbocyclic radical having one or more heteroatoms in the carbocyclic ring. Heteroaryl may be substituted or unsubstituted. When substituted, the substituent itself may also be substituted. Preferred but non-limiting substituents are aryl, C1-C4 alkylaryl, amino, halogen, hydroxy, cyano, nitro, carboxyl, carbonylamino or C1-C4 alkyl. Preferred heteroaromatic groups include isoquinolinyl, benzisothiazolyl, benzisothiadiazolyl, benzothiofuranyl, thienyl, furanyl, tetrazolyl, triazolyl, and pyridyl.

[0038] "Heteroatom" means an atom other than carbon contained in the ring of a heterocyclic group or heteroaromatic group, or in the chain of a heterologous group. Preferably, the heteroatom is selected from the group consisting of nitrogen atoms, sulfur atoms, and oxygen atoms. A group containing two or more heteroatoms may contain different heteroatoms.

[0039] "Heterocyclic carbon group", "heterocycloalkyl", or "heterocyclic" means a monovalent saturated or unsaturated hydrocarbon ring containing at least one heteroatom. The heterocyclic carbon group is monocyclic or a bicyclic ring system that is fused, spiro, or bridged. The monocyclic heterocyclic carbon group contains 3 to 10 carbon atoms in the ring, preferably 4 to 7 carbon atoms, more preferably 5 to 6 carbon atoms. The bicyclic heterocyclic carbon group contains 8 to 12 carbon atoms in the ring, preferably 9 to 10 carbon atoms. The heterocyclic carbon group may be substituted or unsubstituted. Also, the substituent may itself be substituted. Preferred heterocyclic carbon groups include epoxy, tetrahydrofuranyl, azacyclopentyl, azacyclohexyl, piperidyl, and homopiperidyl. More preferred heterocyclic carbon groups include piperidyl and homopiperidyl. The most preferred heterocyclic carbon group is piperidyl. The heterocyclic carbon group is not aromatic.

[0040] "Hydroxy" or "hydroxyl" means a chemical component consisting of -OH. Alcohols contain a hydroxy group. The hydroxy group may be free or protected. Another name for hydroxyl is hydroxy.

[0041] "Linker" means a straight chain consisting of n member atoms, where n is an integer from 1 to 4.

[0042] "Member atom" means a carbon atom, nitrogen atom, oxygen atom, or sulfur atom. The member atom may be substituted up to its normal valence. When the substitution is not specified, the substituent required for the valence is hydrogen.

[0043] "Ring" means a collection of cyclic member atoms. The ring can be carbocyclic, aromatic, heterocyclic, or heteroaromatic, and can be substituted or unsubstituted, saturated or unsaturated. The junction of the ring with the main chain can be fused or a spiro ring. The ring can be monocyclic or bicyclic. The ring contains at least 3 member atoms and at most 10 member atoms. A monocyclic ring contains 3 - 7 member atoms, and a bicyclic ring can contain 8 - 12 member atoms. The bicyclic ring itself can be fused or a spiro ring.

[0044] "Thioalkyl" refers to an -S-alkyl group.

[0045] "Sulfonyl" refers to an -S(O)2R' group, where R' is alkoxy, alkyl, aryl, carbocyclic, heterocarbocyclic, heteroaryl, C1 - C4 alkylaryl, or C1 - C4 alkylheteroaryl.

[0046] "Sulfonylamino" refers to an -S(O)2NR'R' group, where each R' is independently alkyl, aryl, heteroaryl, C1 - C4 alkylaryl, or C1 - C4 alkylheteroaryl.

[0047] "Pharmaceutically acceptable carrier" means a carrier useful for the preparation of a pharmaceutical composition that is generally compatible with the other components of the composition, does not have an adverse effect on the recipient, and is not biologically or otherwise undesirable. "Pharmaceutically acceptable carrier" includes both one carrier and two or more carriers. Embodiments include carriers for topical, ocular, parenteral, intravenous, intraperitoneal, intramuscular, sublingual, intranasal, and oral administration. "Pharmaceutically acceptable carrier" also includes preparations for aqueous dispersions, sterile powders for injection or dispersion.

[0048] As used herein, "additive" includes physiologically compatible additives useful in the preparation of pharmaceutical compositions. Examples of pharmaceutically acceptable carriers and additives can be found, for example, in Remington Pharmaceutical Science, 18th Ed.

[0049] As used herein, "pharmaceutically acceptable salt" refers to an ionizable therapeutic agent that forms a neutral complex upon binding to a counterion. A list of suitable salts is described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is hereby incorporated by reference in its entirety.

[0050] As used herein, the singular forms of "a", "an", and "the" include plural references unless the context clearly dictates otherwise.

[0051] As used herein, the term "comprising" is intended to mean that the compositions and methods include the recited elements but do not exclude other elements.

[0052] "About" and "substantially" are interchangeable and mean a plus or minus percentage (e.g., ±5%) of the numerical value, parameter, or characteristic so modified, as would be appropriate to one of ordinary skill in the scientific context in which the term is used. Further, all numerical values, values, and representations indicating amounts used herein are subject to the various uncertainties of measurements encountered in the art, and thus all indicated values are to be understood as being modified by the term "about" unless otherwise indicated.

[0053] When a numerical range is disclosed in this specification, such a range is continuous and includes both the minimum and maximum values of the range, as well as all values between such minimum and maximum values. Further, when the range refers to integers, all integers between the minimum and maximum values of such range are included. Additionally, when multiple ranges are provided to represent a feature or characteristic, such ranges can be combined. That is, unless otherwise indicated, all ranges disclosed in this specification should be understood to encompass any and all sub-ranges contained therein. For example, the range "1 to 10" should be interpreted to include any and all sub-ranges between the minimum value of "1" and the maximum value of "10".

[0054] As used herein, "therapeutic agent" refers to a compound or substance in a pharmaceutical composition that is biologically active and provides the effect of the pharmaceutical composition.

[0055] As used herein, the term "pharmaceutical composition" means a composition comprising a therapeutic agent (i.e., the compounds provided herein), additives, carriers, etc. Generally, a pharmaceutical composition is administered to a patient rather than the therapeutic agent alone.

[0056] The term "treatment" refers to the application of one or more specific procedures used for the improvement of a disease. In certain embodiments, the specific procedure is the administration of one or more pharmaceutical agents. "Treatment" of an individual (e.g., a mammal such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. Treatment includes, but is not limited to, the administration of a therapeutic agent or a pharmaceutical composition, which can be performed prophylactically or after contact with a substance that initiates or causes a pathological event. Treatment includes the desired effects on the symptoms or pathology of a disease or condition, e.g., a minimal change or improvement in one or more measurable markers of the disease or condition being treated. Also included is "preventive" treatment, which can slow the progression rate of a disease or condition being treated, delay the onset of a disease or condition, or reduce the severity of the onset.

[0057] As used herein, the term "zwitterion" refers to a molecule or ion having separate positive and negative charged groups.

[0058] As used herein, the term "solvate" refers to a complex of a solute molecule and at least one solvent molecule.

[0059] As used herein, the term "polymorph" or "polymorphism" refers to the ability of a solid material to exist in one or more forms or crystals. The crystal forms may be referred to herein as being characterized by graph data. Such data may include, for example, powder X-ray diffraction and solid NMR spectra. As is well known in the art, graph data potentially provides additional technical information for further defining each solid form (so-called "fingerprint") that cannot necessarily be explained by numerical values or peak positions alone.

[0060] The term "effective amount" or "therapeutically effective amount" refers to the amount of a therapeutic agent, i.e., the dosage, that is administered to a subject (e.g., a mammalian subject, i.e., a human subject) as part of a single administration or a series of administrations and is effective to produce a desired therapeutic effect (e.g., effective to affect, reduce, inhibit, or prevent the activation of kinase activity, or effective to affect, reduce, inhibit, or prevent the activation of kinase activity, or effective to produce a desired in vivo effect in an animal, preferably a human, such as the effect of reducing intraocular pressure).

[0061] As used herein, "administering" refers to administering a compound as necessary to obtain a desired effect.

[0062] As used herein, "ocular disease" includes, but is not limited to, glaucoma, allergy, eye cancer, neurodegenerative eye diseases such as DME and AMD, and dry eye.

[0063] The term "disease or condition related to kinase activity" is used to mean a disease or condition that can be treated, in whole or in part, by inhibition of one or more kinases.

[0064] The term "control a disease or condition" is used to mean altering the activity of one or more kinases in order to affect a disease or condition.

[0065] The term "contact a cell" is used to mean contacting a cell in vitro or in vivo (i.e., within a subject such as a mammal including humans, cats, and dogs).

[0066] The term "non-aqueous solvent" is used to mean a solvent or mixture of solvents containing less than 5% by weight of water. Non-aqueous solvents include mixtures in which the main solvent is a partially fluorinated hydrocarbon. The non-aqueous solvent may or may not have a preservative.

[0067] The term "partially fluorinated hydrocarbon" refers to a hydrocarbon in which some, but not all, of the hydrogen atoms of the hydrocarbon are replaced by fluorine atoms. Non-limiting examples include perfluorohexyl octane, and perfluoropentyl nonane. These are also known in the art as semi-fluorinated alkanes or SFAs.

[0068] The term "myopia" refers to the condition of a patient having at least one eye with an SE value greater than -0.5D, for example -1.0D, -2.0D. Depending on the context, "myopia" can also refer to the condition of an eye with an SE value greater than -0.5D.

[0069] The term "pre-myopia" refers to the condition of a patient having at least one eye with an SE value in the range of -0.49D to 1.00D. Depending on the context, myopia can also refer to the condition of an eye with an SE value in the range of -0.49D to 1.00D.

[0070] The term "low myopia" refers to the condition of a patient having at least one eye with an SE value in the range of -0.501 to -1.501. Depending on the context, "low myopia" can also refer to the condition of an eye with an SE value in the range of -0.50D to -1.50D.

[0071] The term "high myopia" refers to a person having at least one eye with an SE value greater than -5.0D. Depending on the context, "high myopia" can also refer to the condition of an eye with an SE value greater than -5.0D.

[0072] The term "drop" refers to a unit of volume measurement equal to the amount dropped into the eye as one drop from an eye dropper or an eye drop chamber. Usually, a drop, which is aqueous, contains 20 to 100 microliters of liquid. In some cases, a drop contains 30 microliters to 70 microliters, for example, about 50 microliters of liquid. Some drops, especially drops of partially fluorinated hydrocarbons, may be smaller than 30 microliters.

[0073] (Compound) In another aspect, the present specification provides a compound, which is a compound of formula (I) [Chemical formula] or an analog, derivative, solvate, zwitterion, or polymorph thereof, or a pharmaceutically acceptable salt thereof, wherein X 1 is hydrogen, hydroxyl, halogen, C 1-4 alkyl, amino, nitro, cyano, C 1-4 carbonyl, C 1-4 carbonylamino, C 1-4 alkoxy, C 1-4 sulfonyl, C 1-4 sulfonylamino, C 1-4 thioalkyl, or C 1-4 carboxyl, and X 2 is H or lower alkyl, and X3 is H or lower alkyl, J 1 is -CH2-, -N(R 1 ), - or -O-, where R 1 is H or lower alkyl, Z 1 is -CH2-, -N(R 2 ), - or -O-, where R 2 is H or lower alkyl, When the 8-methyl-8-azabicyclo[3.2.1]octan-3-yl moiety is in the endo conformation, J 1 is -O-, X 2 is lower alkyl, or X 3 is lower alkyl.

[0074] In some embodiments, the 8-methyl-8-azabicyclo[3.2.1]octan-3-yl moiety is in the endo conformation.

[0075] In some embodiments, the 8-methyl-8-azabicyclo[3.2.1]octan-3-yl moiety is in the exo conformation.

[0076] In some embodiments, J 1 is -CH 2 -, or -N(R 1 )-.

[0077] In some embodiments, when J 1 is -O-, X 2 is lower alkyl, or X 3 is lower alkyl.

[0078] In some embodiments, Z 1 is CH2, or N(R 2 ).

[0079] In some embodiments, X 2 is lower alkyl, or X 3 is lower alkyl.

[0080] In some embodiments, X 1 is hydroxyl, halogen, C 1-4 alkyl, amino, nitro, cyano, C 1-4 carbonyl, C 1-4 carbonylamino, C 1-4 alkoxy, C 1-4 sulfonyl, C 1-4 sulfonylamino, C 1-4 thioalkyl, or C 1-4 carboxyl.

[0081] In some embodiments, X 1 is hydroxyl, C 1-4 alkyl, amino, nitro, cyano, C 1-4 carbonyl, C 1-4 carbonylamino, C 1-4 alkoxy, C 1-4 sulfonyl, C 1-4 sulfonylamino, C 1-4 thioalkyl, or C 1-4 carboxyl.

[0082] In some embodiments, X 1 is hydroxyl, C 1-4 alkyl, amino, nitro, cyano, C 1-4 carbonyl, C 1-4 carbonylamino, C 1-4 sulfonyl, C 1-4 sulfonylamino, C 1-4 thioalkyl, or C 1-4 carboxyl.

[0083] In some embodiments, Z 1 is -CH2- or -N(R 2 )-, and X 1 is hydrogen, hydroxyl, C 1-4 alkyl, amino, nitro, cyano, C 1-4 carbonyl, C 1-4 carbonylamino, C 1-4 alkoxy, C 1-4 sulfonyl, C 1-4 sulfonylamino, C1-4 thioalkyl, or C 1-4 is carboxyl.

[0084] In some embodiments, the compound is

Chem.

Chem.

Chem.

[0085] In another aspect, the compound is of formula (II)

Chem.

[0086] In some embodiments, formula (II) is formula (IIa)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0087] In some embodiments, formula (II) is formula (IIb-1)

Chemical formula

[0088] In some embodiments, X8 is phenyl or pyridinyl, and X9 is phenyl, pyridinyl, furanyl or thiophenyl.

[0089] In some embodiments, X 4 is hydrogen, a halogen, C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 alkoxy.

[0090] In some embodiments, X 7 is hydrogen, a halogen, or C 1-4 alkyl.

[0091] In some embodiments, -Z 2 -X 6 is -OH or -NH2.

[0092] In some embodiments, X 10 is hydrogen, C 1-4 alkyl, C 3-7 cycloalkyl, or C 1-4 alkyl-phenyl, and X 11 is hydrogen, or C 1-4 alkyl, or X 10 and X 11 together with the atom to which they are attached form C 3-7 cycloalkyl or C 3-7 cycloalkyl-phenyl.

[0093] In some embodiments, the compound is

Chemical formula

Chemical formula

Chemical formula

[0094] (Composition) In another aspect, the present specification provides a composition comprising a compound provided herein.

[0095] In some embodiments, the composition comprises a hydrofluoroalkane.

[0096] In some embodiments, the present specification provides a composition that comprises a hydrofluoroalkane and a compound of formula (I)

Chemical formula

Chemical formula

[0097] In some embodiments, the present specification provides a composition, the composition comprising a semi-fluorinated alkane and a compound, the compound being

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0098] In some embodiments, the semi-fluorinated alkane is perfluorohexyl octane or perfluorohexyl nonane.

[0099] In some embodiments, the composition is a non-aqueous composition.

[0100] In some embodiments, the composition provided herein is a pharmaceutical composition comprising a compound provided herein or a composition provided herein and a pharmaceutically acceptable additive.

[0101] (Kits and Manufactured Articles) Also provided herein is a kit comprising a compound provided herein, a composition provided herein, or a pharmaceutical composition provided herein, and instructions for use thereof.

[0102] Also provided herein is a manufactured article comprising a compound provided herein, a composition provided herein, or a pharmaceutical composition provided herein.

[0103] (Methods) The compounds and compositions provided herein are useful for the treatment of eye diseases or conditions. Accordingly, in one aspect, provided herein is a method of treating myopia in a subject in need thereof, the method comprising administering to the subject a compound provided herein, a composition provided herein, or a pharmaceutical composition provided herein, in a therapeutically effective amount.

[0104] Also provided herein is a method of delaying the progression of myopia in a subject in need thereof, the method comprising administering to the subject a compound provided herein, a composition provided herein, or a pharmaceutical composition provided herein, in a therapeutically effective amount.

[0105] This specification also provides a method for delaying the onset of myopia in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, a composition provided herein, or a pharmaceutical composition provided herein.

[0106] This specification also provides a method for treating a disease or disorder threatening vision in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, a composition provided herein, or a pharmaceutical composition provided herein.

[0107] In some embodiments, the disease or disorder threatening vision includes peripheral lattice degeneration, laceration, detachment, neovascularization of the myopic choroid, myopic macular detachment, myopic macular hole, posterior staphyloma, myopic macular degeneration, early-onset cataract, open-angle glaucoma, peripapillary atrophy, tilt of the optic nerve head, pit of the optic nerve head, or a combination thereof.

[0108] (General synthetic scheme) The 8-methyl-8-azabicyclo[3.2.1]octan-3-yl and pyridin-4-ylmethanyl esters and amide compounds provided herein are synthesized by the general scheme described below.

Chemical formula

[0109] According to Scheme 1, the selected ester (S1) was reacted with an esterase enzyme such as porcine liver esterase to form the desired intermediate (S2). The alcohol (S2) was extracted and purified as needed, and then the process proceeded to Scheme 2.

Chemical formula

[0110] According to Scheme 2, the selected acid (S4) is activated with a suitable reagent such as EDC, and using standard coupling techniques, 8-methyl-8-azabicyclo[3.2.1]octan-3-yl is coupled with pyridin-4-ylmethanol (S5) or amine (S8) to form the desired intermediates (S6, S9, S12 and S15). The protected amine of (S6) or the protected alcohol of (S8, S10, S12 and S15) is reacted with HCl in methylene chloride to directly produce amide (S11).

Chemical formula

[0111] In some embodiments, administering an additional therapeutic agent in combination with the compounds provided herein allows for the administration of other therapeutic agents at lower doses for longer periods of time.

[0112] Compositions comprising alkyl, ester and amide derivatives of 8-methyl-8-azabicyclo[3.2.1]octan-3-yl and pyridin-4-ylmethyl of formula I, II, or III can be obtained in the form of various salts or solvates. As the salt, a physiologically acceptable salt or a salt available as a raw material is used.

[0113] The composition may, if present, contain one or more isoforms of formula I or II or III or IV. If a racemate is present, each enantiomer or diastereomer may be used separately or they may be combined in any ratio. If tautomers are present, all possible tautomers are specifically intended.

[0114] The pharmaceutical compositions used in accordance with the present specification can be formulated by conventional methods using one or more physiologically acceptable carriers or additives. Accordingly, the compounds and their physiologically acceptable salts and solvates can be formulated for administration, for example, by solid administration, eye drops, in oily topical formulations, by injection, by inhalation (either through the mouth or nose), in implants including bioerodible implants placed either anterior or posterior to the eye, or by oral, buccal, parenteral or rectal administration. The techniques and formulations are generally described in "Reminington's Pharmaceutical Sciences" (Meade Publishing Co., Easton, Pa.). The therapeutic compositions should usually be sterile and stable under the conditions of manufacture and storage.

[0115] The compositions provided herein may contain a safe and effective amount of the subject compound and a pharmaceutically acceptable carrier. As used herein, "safe and effective amount" means an amount of the compound sufficient to significantly induce a positive change in the condition to be treated within the scope of sound medical judgment, but low enough to avoid serious side effects (a reasonable benefit / risk ratio). The safe and effective amount of the compound will vary depending on the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of treatment, the nature of combination therapy, the particular pharmaceutically acceptable carrier being used, and similar factors within the knowledge and expertise of the attending physician.

[0116] The type of carrier (component B) to be used is determined by the route of administration and the form of the composition in which the compound (component A) provided herein is administered. The compositions may be in various forms suitable for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implant, or parenteral) or topical administration (e.g., topical application to the skin, eye, liposomal delivery system, or iontophoresis).

[0117] Carriers for systemic administration usually include at least one of a) diluents, b) lubricants, c) binders, d) disintegrants, e) colorants, f) flavoring agents, g) sweeteners, h) antioxidants, j) preservatives, k) lubricants, m) solvents, n) suspending agents, o) wetting agents, p) surfactants, q) biodegradable polymers, r) plasticizers, and combinations thereof. All carriers are optional in the systemic composition.

[0118] Component a) is a diluent. Diluents suitable for solid dosage forms include saccharides such as glucose, lactose, dextrose, and sucrose, diols such as propylene glycol, sugar alcohols such as calcium carbonate, sodium carbonate, and glycerin, and mannitol and sorbitol. The amount of component a) in a systemic or topical composition is usually about 50% to about 90%.

[0119] Component b) is a lubricant. Examples of lubricants suitable for solid dosage forms include solid lubricants such as silica, talc, stearic acid and its magnesium and calcium salts, and calcium sulfate, and liquid lubricants such as vegetable oils like polyethylene glycol, peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and theobroma oil. The amount of component b) in a systemic or topical composition is usually about 5% to about 10%.

[0120] Component c) is a binder. Binders suitable for solid dosage forms include polyvinylpyrrolidone, aluminum magnesium silicate, starches such as corn starch and potato starch, gelatin, tragacanth, and celluloses and their derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, methocelulose, microcrystalline cellulose, and sodium carboxymethyl cellulose. The amount of component c) in a systemic composition is usually about 5 to about 50%, and up to 99% in solid dosage forms for the eye.

[0121] Component d) is a disintegrant. Disintegrants suitable for solid dosage forms include agar, alginic acid and its sodium salts, effervescent mixtures, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clay, and ion exchange resins. The amount of component d) in a systemic or topical composition is usually about 0.1% to about 10%.

[0122] Component e) for solid dosage forms is a colorant such as an FD&C dye. When used, the amount of component e) in a systemic or topical composition is usually about 0.005% to about 0.1%.

[0123] Component f) for solid dosage forms is a flavorant such as menthol, peppermint, or fruit flavors. When used, the amount of component f) in a systemic or topical composition is usually about 0.1% to about 1.0%.

[0124] Component g) in the case of solid dosage forms is a sweetener such as aspartame or saccharin. The amount of component g) in a systemic or topical composition is usually about 0.001% to about 1%.

[0125] Component h) is an antioxidant such as butylated hydroxyanisole (“BHA”), butylated hydroxytoluene (“BHT”), and vitamin E. The amount of component h) in a systemic or topical composition is usually about 0.1% to about 5%.

[0126] Component i) is a preservative such as benzalkonium chloride, methylparaben, or sodium benzoate. The amount of component i) in a systemic or topical composition is usually about 0.01% to about 5%.

[0127] Component k) for solid dosage forms is a lubricant such as silicon dioxide. The amount of component k) in a systemic or topical composition is usually about 1% to about 5%.

[0128] Component m) is a solvent such as a partially fluorinated hydrocarbon, water, isotonic saline, ethyl oleate, glycerin, castor oil hydroxide, alcohols such as ethanol, and a phosphate buffer. The amount of component m) in a systemic or topical composition is usually from about 0 to about 100%.

[0129] Component n) is a suspending agent. Suitable suspending agents include AVICEL® RC-591 (manufactured by FMC Corporation, Philadelphia, Pennsylvania) and sodium alginate. The amount of component n) in a systemic or topical composition is usually from about 1 to about 8%.

[0130] Component o) is a surfactant such as lecithin, polysorbate 80, sodium lauryl sulfate, and TWEENS® from Atlas Powder Company, Wilmington, Delaware. Suitable surfactants include those disclosed in C.T.F.A. Cosmetic ingredient Handbook, 1992, pp.587-592, Remington's Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337, and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp. 238-239. The amount of component o) in a systemic or topical composition is usually from about 0.1 to about 5%.

[0131] Component p) is a surfactant.

[0132] Component q) is a biodegradable polymer. Specifically contemplated are PLA or PLA polymers, and PEA polymers.

[0133] Component r) is a plasticizer. By lowering the TM of the polymer, production under low temperature or other conditions is made possible and the production is made easier. Non-limiting examples.

[0134] The amounts of Component A and Component B in the systemic composition vary depending on the type of the prepared systemic composition, the specific derivative selected for Component A, and the material of Component B. Generally, the systemic composition contains Component A at 0.01% - 50% and Component B at 50 - 99.99%.

[0135] Compositions for parenteral administration generally contain A) 0.1 - 10% of the compounds provided herein, and B) a carrier of 90 - 99.9% including a) diluent and m) solvent. In one embodiment, a) includes propylene glycol and m) includes ethanol or ethyl oleate.

[0136] Compositions for oral administration can have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms contain a safe and effective amount, usually at least about 5%, more particularly about 25% - about 50% of Component A). Oral administration compositions further contain about 50 - about 95% of Component B), more particularly about 50 - about 75% of Component B).

[0137] Tablets can be compressed tablets, powder tablets, enteric coatings, sugar coatings, film coatings, or multi - compressed tablets. Tablets usually consist of Component A and Component B which is a carrier containing components selected from the group consisting of a) diluent, b) lubricant, c) binder, d) disintegrant, e) colorant, f) flavoring agent, g) sweetening agent, k) lubricant, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose, cellulose. Specific binders include starch, gelatin, sucrose. Specific disintegrants include alginic acid, croscarmellose, etc. Lubricants include magnesium stearate, stearic acid, talc. Colorants include FD&C dyes and can be added for appearance. Chewable tablets preferably contain g) sweetening agents such as aspartame, saccharin, f) flavoring agents such as menthol, peppermint, fruit flavors, or combinations thereof.

[0138] Capsules (including implants, sustained-release preparations, and controlled-release preparations) usually contain component A and a carrier containing one or more of the above-mentioned a) diluents in a capsule made of gelatin. Granules usually contain component A and preferably further contain k) lubricants such as silicon dioxide to improve flow properties. Implants can be biodegradable or non-biodegradable. Implants can be prepared using known biocompatible formulations.

[0139] The selection of materials in the carrier for oral compositions depends on secondary considerations including, but not limited to, taste, cost, and storage stability.

[0140] Also, solid compositions can generally be coated by conventional methods using pH-dependent or time-dependent coatings so that component A is released into the digestive tract in the vicinity of the desired application or at various positions and locations to extend the desired action. Coatings usually contain one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, EUDRAGIT coatings (available from Rohm & Haas G.M.B.H., Darmstadt, Germany), waxes, and shellac.

[0141] Compositions for oral administration can also be in liquid form. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-foaming granules, suspensions reconstituted from non-foaming granules, foaming preparations reconstituted from foaming granules, elixirs, tinctures, syrups, etc. Oral liquid compositions generally contain a carrier containing components selected from the group consisting of component A and component B, namely, a) diluents, e) colorants, f) flavoring agents, g) sweetening agents, j) preservatives, m) solvents, n) suspending agents, and o) surfactants. Oral liquid compositions preferably contain one or more components selected from the group consisting of e) colorants, f) flavoring agents, and g) sweetening agents.

[0142] Other compositions useful for achieving systemic delivery of the compound of interest include implant, sublingual, buccal, and nasal dosage forms. Such compositions typically include a) diluents (including sucrose, sorbitol, and mannitol), and c) one or more soluble or biodegradable filler substances such as binders (e.g., acacia, crystalline cellulose, carboxymethyl cellulose, and hydroxypropylmethyl cellulose). Such compositions may further include b) lubricants, e) colorants, f) flavorants, g) sweeteners, h) antioxidants, and k) glidants. Implant formulations include q) biodegradable polymers, and optionally r) plasticizers.

[0143] In one embodiment, the compounds provided herein are administered topically. Topical compositions that can be applied topically to the eye can be in any form known in the art, non-limiting examples of which include solids, gellable drops, sprays, ointments, or sustained or non-sustained release units placed in the conjunctival fornices of the eye, the eye cavity, the aqueous humor, the vitreous humor, or another suitable location.

[0144] Topical compositions that can be applied topically to the skin can be in any form, including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, etc. The topical composition includes component A, which is the compound described above, and component B, which is a carrier. The carrier of the topical composition preferably aids in the penetration of the compound into the eye. Component B may further include one or more optional components.

[0145] The dosage range of the compound for systemic administration is from about 0.0001 to about 1000 μg / kg per day per body weight, preferably from about 0.1 to about 100 μg / kg per body weight, and most preferably in the form of about 1 to about 50 μg / kg. These dosages are based on the daily dosage, but the clinically required amount can also be calculated using the cumulative dosage per week or per month.

[0146] The dosage may vary depending on the patient being treated, the condition being treated, the severity of the condition being treated, the route of administration, etc., in order to obtain the desired effect.

[0147] The compounds provided herein are useful in reducing intraocular pressure. Thus, these compounds are useful in treating glaucoma. The preferred route of administration for treating glaucoma is topical.

[0148] The exact amount of each component in a topical composition depends on a variety of factors. The amount of component A added to a topical composition is determined by the IC 50 For example, the IC of a drug 50 When the IC of the drug is 1 nM, the amount of component A is about 0.0001 to about 0.3%. 50 When the IC of the drug is 10 nM, the amount of component A) is about 0.001 to about 1%. 50 When the IC of the drug is 100 nM, the amount of component A is about 0.01 to about 10%. 50 is 1000 nM, the amount of component A is 1-100%, preferably 5%-50%. If the amount of component A is outside the range specified above (i.e., if it is low), the efficacy of the treatment may decrease. The remainder of the composition up to 100% is component B.

[0149] The amount of carrier employed in combination with component A is sufficient to provide a practical amount of the composition for administration per unit dose of pharmaceutical. Techniques and compositions for making dosage forms useful in the methods provided herein are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2001, eds. (1982); nd Ed., (1976).

[0150] Component B may include a single component or a combination of two or more components. In a topical composition, Component B includes a topical carrier. Suitable topical carriers include one or more components selected from the group consisting of partially fluorinated hydrocarbons, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetrical alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, combinations thereof, and the like. More specifically, the carrier for skin application includes a partially fluorinated hydrocarbon, propylene glycol, dimethyl isosorbide, and water. Even more specifically, it includes a partially fluorinated hydrocarbon, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetrical alcohols.

[0151] The carrier of the topical composition may further include one or more components selected from the group consisting of q) emollients, r) propellants, s) solvents, t) wetting agents, u) thickeners, v) powders, w) fragrances, x) pigments, and y) preservatives.

[0152] Ingredient q) is an emollient. The amount of ingredient q) in the topical composition based on skin is usually about 5 to about 95%. Suitable emollients include stearyl alcohol, glyceryl monolinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl thioglycolate, decyl oleate, octadecane-2-ol, isocetyl alcohol, cetyl palmitate, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohol, etc. It includes petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Specific emollients for skin include stearyl alcohol and polydimethylsiloxane.

[0153] Ingredient r) is a propellant. The amount of ingredient r) in the topical composition is usually about 0 to about 95%. Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof.

[0154] Ingredient s) is a solvent. The amount of ingredient s) in the topical composition is usually about 0 to about 95%. Suitable solvents include partially fluorinated hydrocarbons, water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, and combinations thereof. Specific solvents include ethyl alcohol and homotopic alcohols.

[0155] Component t) is a wetting agent. The amount of component t) in the topical composition is usually from 0 to 95%. Suitable wetting agents include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. A specific wetting agent includes glycerin.

[0156] Component u) is a thickening agent. The amount of component u) in the topical composition is usually from about 0 to about 95%.

[0157] Component v) is a powder. The amount of component v) in the topical composition is usually from 0 to 95%. Suitable powders include beta-cyclodextrin, hydroxypropyl cyclodextrin, chalk, talc, fuller's earth, kaolin, starch, gum, colloidal silicon dioxide, sodium polyacrylate, tetraalkylammonium smectite, trialkylarylammonium smectite, chemically modified aluminum magnesium silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate, and combinations thereof. Specific powders for ophthalmic applications include beta-cyclodextrin, hydroxypropyl cyclodextrin, and sodium polyacrylate. For gel-administered ophthalmic formulations, sodium polyacrylate may be used.

[0158] Component w) is a fragrance. The amount of component x) in the topical composition is generally from about 0 to about 0.5%, particularly from about 0.001 to about 0.1%. In ophthalmic applications, fragrances are generally not used.

[0159] Component (x) is a pigment. Pigments suitable for skin use include inorganic pigments, organic lake pigments, true pearl luster pigments, and mixtures thereof. Useful inorganic pigments provided herein include rutile or anatase titanium dioxide coded with reference number CI 77,891 in the Color Index, black, yellow, red, and brown iron oxides coded with reference numbers CI 77,499, 77,492, and 77,491, manganese violet (CI 77,742), ultramarine blue (CI 77,007), chromium oxide (CI 77,288), chromium hydrate (CI 77,289), and ferric blue (CI 77,510), selected from the group consisting of.

[0160] Useful organic pigments and lakes provided herein include those selected from the group consisting of dyes or lakes based on D&C Red No. 19 (CI 45,170), D&C Red No. 9 (CI 15,585), D&C Red No. 21 (CI 45,380), D&C Orange No. 4 (CI 15,510), D&C Orange No. 5 (CI 45,370), D&C Red No. 27 (CI 45,410), D&C Red No. 13 (CI 15,630), D&C Red No. 7 (CI 15,850), D&C Red No. 6 (CI 15,850), D&C Yellow No. 5 (CI 19,140), D&C Red No. 36 (CI 12,085), D&C Orange No. 10 (CI 45,425), D&C Yellow No. 6 (CI 15,985), D&C Red No. 30 (CI 73,360), D&C Red No. 3 (CI 45,430), Cochineal Carmine (CI 75,570), or mixtures thereof.

[0161] The useful pearlescent pigments provided in this specification include those selected from the group consisting of titanium oxide, white pearlescent pigments such as mica coated with bismuth oxychloride, titanium mica added with iron oxide, colored pearlescent pigments such as ferric blue, titanium mica added with chromium oxide, titanium mica added with organic pigments of the types described above, those based on bismuth oxychloride as well, and mixtures thereof. The amount of pigment in the topical composition is generally about 0% to about 10%. For ophthalmic use, pigments are generally not used.

[0162] In another embodiment, there is generally provided a topical pharmaceutical composition for ophthalmic administration, comprising component A and component B (a carrier), wherein component B is selected from the group consisting of, for example, purified water and one or more components selected from the group consisting of y) dextran, especially saccharides or sugar alcohols such as mannitol and dextran 70, z) cellulose or its derivatives, aa) salts, bb) sodium EDTA (disodium edetate), and cc) pH adjusters.

[0163] Examples of suitable z) cellulose derivatives for use in topical pharmaceutical compositions for ophthalmic administration include sodium carboxymethylcellulose, ethyl cellulose, methyl cellulose, hydroxypropyl-methylcellulose, especially including hydroxypropyl-methylcellulose.

[0164] Examples of suitable aa) salts for use in topical pharmaceutical compositions for ophthalmic administration include monosodium phosphate, disodium phosphate, and trisodium phosphate, sodium chloride, potassium chloride, and combinations thereof.

[0165] Examples of cc) pH adjusters include HCl or NaOH in an amount sufficient to adjust the pH of the topical pharmaceutical composition for ophthalmic administration to 4.5 to 7.5.

[0166] Component A may be included in a kit that includes Component A, the above-described systemic or topical composition or both, and information, instructions, or both indicating that the treatment of cosmetic and medical conditions in mammals (especially humans) can be obtained by using the kit. The information and instructions can be in the form of words, pictures, or both, etc. In addition to or instead of this, the kit may include a drug, a composition, or both, and preferably information, instructions, or both regarding the method of application of a drug or composition having the advantage of treating or preventing cosmetic and medical conditions in mammals (e.g., humans).

[0167] The following illustrative examples should be construed as non-limiting.

[0168] Specific procedures for preparing 8-methyl-8-azabicyclo[3.2.1]octan-3-yl and pyridin-4-ylmethanyl esters and amides are described in the following examples.

[0169] All temperatures are in degrees Celsius. Reagents and starting materials were purchased commercially or prepared according to procedures in the published literature.

[0170] Unless otherwise indicated, purification by HPLC was performed, where appropriate, by redissolving the compound in a small amount of DMSO and filtering through a 0.45 micron (nylon disk) syringe filter. Subsequently, this solution was purified using, for example, a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 C8 column, and a general initial elution mixture of 40 - 80% MeOH:H2O was selected as appropriate for the target compound. This initial gradient was maintained for 0.5 minutes and then increased to 100% MeOH:0% H2O over 5 minutes. 100% MeOH was maintained for an additional 2 minutes and then re-equilibrated back to the initial gradient. The general total run time was 8 minutes. The obtained fractions were analyzed, combined if necessary, and evaporated to obtain the purified product.

[0171] Proton magnetic resonance ( 11H NMR spectra were recorded on a Varian INOVA 800 MHz ( 1 1H) NMR spectrometer, a Varian INOVA 500 MHz ( 1 1H) NMR spectrometer, a Varian Mercury 300 MHz ( 1 1H) NMR spectrometer, or a Varian Mercury 200 MHz ( 1 1H) NMR spectrometer. All spectra were measured in the solvents described. Chemical shifts are reported in downfield (ppm) from tetramethylsilane, but 1 in 1H NMR the residual proton peaks of the solvents' peaks were used as references. Proton coupling constants are reported in hertz (Hz).

[0172] Analytical LCMS spectra were obtained using a Waters ZQ MS ESI instrument equipped with an Alliance 2695 HPLC and a 2487 dual wavelength UV detector. Spectra were analyzed at 254 nm and 230 nm. Samples were passed through a Waters Symmetry C18 4.6 x 75 mm 3.5 µm column, with the option of using a guard column (3.9 x 20 mm 5 µm). The gradient was carried out using mobile phase A: 0.1% formic acid (in H2O), mobile phase B: ACN, at a flow rate of 0.8 mL / min. Two gradients are shown in Table 1.

Table 1

[0173] The MS probe settings were a cone voltage of 38 V and a desolvation temperature of 250 °C. Variations in these methods are described below.

[0174] The following preparations show the procedures for preparing intermediates and the methods for preparing alkyl, ester, and amide derivatives of 8-methyl-8-azabicyclo[3.2.1]octan-3-yl and pyridin-4-ylmethanyl.

[0175] (Example) (Example 1: Preparation of (1R,3S,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-((tert-butoxycarbonyl)amino)-2-phenylpropanoate) [Chemical formula] To 3-((tert-butoxycarbonyl)amino)-2-phenylpropanoic acid in CH2Cl2, EDC, DMAP, and 3-((tert-butoxycarbonyl)amino)-2-phenylpropanoic acid were added, and the solution was stirred overnight. The mixture was poured into NaHCO3 (saturated), extracted with CH2Cl2, dried (Na2SO4), filtered, and evaporated to obtain crude 2. Pure (1R,3S,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-((tert-butoxycarbonyl)amino)-2-phenylpropanoate was obtained by column chromatography on EtOAc-hexane.

[0176] (Example 2: Preparation of (1R,3S,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-amino-2-phenylpropanoate dihydrochloride) [Chemical formula] To (1R,3S,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-((tert-butoxycarbonyl)amino)-2-phenylpropanoate in CH2Cl2, 4N HCl-dioxane was added, and the solution was stirred overnight. The solvent was evaporated and dried to obtain (1R,3S,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-amino-2-phenylpropanoate dihydrochloride (E3).

[0177] According to the above-described procedure, specific compounds provided in this specification including those in Table 2 could be produced by substituting appropriate starting materials. Table 2 [Table 2-1]

Table 2-2

Table 2-3

Table 2-4

[0178] Using techniques known in the art, the following compounds

Chemical formula

Chemical formula

Chemical formula

[0179] (Example 3: Induction of Form Deprivation Myopia in Mice) The eyes of mice have a very similar structure and biochemistry to human eyes, and the usefulness of myopia model mice has been confirmed in previous studies. Therefore, mice are a good preclinical model for evaluating pharmacological treatment methods for myopia. In addition, the eyes of mice have the same pharmacological targets as human eyes. The results show that when an analog of 8-methyl-8-azabicyclo[3.2.1]octan-3-yl is locally administered before the eye experiences a treatment that induces myopia, some or all of the changes in myopia can be avoided. The relevance of all muscarinic receptor types present in the fibroblasts of the sclera, a tough outer connective tissue that covers the eyeball, has been shown to be similar in the eyes of mice and humans.

[0180] In general, form-deprivation myopia ("FDNT") in mice can be reliably induced by wearing an -IOD lens over the eyes of the mice for 6 weeks. This causes an increase in axial length and refractive abnormalities in the eyes of the mice. In this procedure, prior to fitting the -IOD lens over the eye, an analog of 8-methyl-8-azabicyclo[3.2.1]octan-3-yl is administered to the eye once daily for 1 - 14 days. The initial experimental groups (n = 8 / group) were: a) not fitted with a lens and treated with an analog of 8-methyl-8-azabicyclo[3.2.1]octan-3-yl starting on day 21 and continuing for 4 weeks; b) fitted with an -IOD lens on day 35 after 2 weeks of treatment with an analog of 8-methyl-8-azabicyclo[3.2.1]octan-3-yl and continuing the lens treatment for 4 weeks; c) fitted with an -IOD lens on day 35 after 1 week of treatment with an analog of 8-methyl-8-azabicyclo[3.2.1]octan-3-yl and continuing the lens treatment for 4 weeks; d) fitted with a lens on day 35 without prior treatment with an analog of 8-methyl-8-azabicyclo[3.2.1]octan-3-yl and continuing for 4 weeks; e) a control group not using either a lens or an analog of 8-methyl-8-azabicyclo[3.2.1]octan-3-yl.

[0181] After initiating the experimental treatment, the mice are monitored for changes in axial length and refractive abnormalities every week using procedures that have already been published. Refractive index and biometric measurements are taken every week. Axial length is measured using in vivo low coherence light interferometry (OLCT AcMaster). Refraction is measured using an automated eccentric photorefractor. Details of the methods have been described previously (Barathi VA & Beuerman RW, 2011; Barathi et al 2013).

[0182] (Example 4: Effect of eye drops of an analog of 8-methyl-8-azabicyclo[3.2.1]octan-3-yl before inducing form-deprivation myopia in a mouse model) (Method) Animals: Breeding pairs of B6J (Mus musculus) mice were obtained from Jackson Lab and allowed to produce offspring. Non-dosed control animals were housed in groups of six, and experimental animals were individually placed in standard mouse cages on postnatal day 21 and maintained at 25 °C on a 12:12 h light / dark schedule, with free access to mouse pellets and water.

[0183] Mouse myopia model: -IOD contact lenses (light gray PMMA contact lenses, 8.5 mm in diameter, 8 mm base curve, refractive index 1.43 (axial), 0.5 mm thick) were applied to the right eye on day 21 by adhering them to the Velcro annular portion and then attaching to the matching Velcro portion pre-sewn to the skin around the eye. The spectacle lenses were cleaned daily in a dimly lit place, and the left eye was left uncovered as a control. All optical devices were removed on postnatal day 63.

[0184] (Treatment protocol) Delayed-onset FDM was induced in four groups of mice (Groups 1 - 4). Group 1 (n = 6, 3 batches) received daily topical administration of 1% of an analog of 8-methyl-8-azabicyclo[3.2.1]octan-3-yl at 10 μL per day for 4 weeks on day 35. Group 2 (n = 6, 3 batches) received daily topical administration of 1% of an analog of 8-methyl-8-azabicyclo[3.2.1]octan-3-yl at 10 μL per day for 2 weeks on day 21, then had -IOD lenses fitted and myopia induced for 4 weeks (pATG+LIM). Group 3 (n = 6, 3 batches) was treated with -IOD lenses only to induce myopia (lenses were fitted on day 21 and continued for 6 weeks). Group 4 (n = 3 [both eyes non-dosed controls], 3 batches) was used as a non-dosed control. In all groups, the right eye was used for the experiment and the left eye served as a contralateral control. Note that experimentally induced myopia in mice has consistently been found to affect the contralateral side, whether induced or with drug intervention.

[0185] Ocular Biometric Evaluation: Refractive and biometric measurements were recorded weekly until the end of the study. Axial length was measured by in vivo low coherence interferometry (OLCI - AcMaster). Refraction was measured by an auto - eccentric photorefractor. Details of the methods have been described previously (Barathi VA et al, 2013; Barathi VA & Beuerman RW, 2011).

[0186] Statistical Analysis: Statistical analysis was performed using SPSS software (Version 11.0, Chicago, USA). All results were expressed as mean ± standard error of the mean (SEM). All values of the lens - induced eyes were statistically compared with the fellow - eye values within the same group using paired - sample t - tests. Between the experimental and normal groups, independent - sample t - tests were performed using the mean inter - ocular difference. Inter - group statistical analysis was performed by one - way analysis of variance (ANOVA), and statistical significance was considered at p < 0.05.

[0187] (Results) Treatment with an analog of 8 - methyl - 8 - azabicyclo[3.2.1]octan - 3 - yl delayed the induction of myopia. The treatment was effective in reducing the expected effects on axial length and refraction. Eyes that received an analog of 8 - methyl - 8 - azabicyclo[3.2.1]octan - 3 - yl before induction of myopia (- 10D lens for 4 weeks) maintained hyperopia.

[0188] The topical pharmaceutical composition for the treatment of myopia is prepared by conventional methods and formulated as shown in Table 3. [Table 3]

[0189] The compounds provided herein are used as derivatives of 8 - methyl - 8 - azabicyclo[3.2.1]octan - 3 - yl and pyridin - 4 - ylmethanyl esters. When the compound is topically administered to the eye once a day, the above composition reduces the progression rate of myopia.

[0190] (Example 5)

Chem.

[0191] (Example 6) Repeat Example 1 using 8-methyl-8-azabicyclo[3.2.1]octan-3-yl and pyridin-4-ylmethanilamide provided herein. When administered as one drop twice a day, the above composition prevents the onset of myopia in pre-myopic patients.

[0192] (Example 7) Repeat Example 1 using 8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(4-fluorophenyl)-3-hydroxypropanoate toluenesulfonate provided herein. When administered as one drop three times a day, the above composition substantially reduces allergic symptoms and alleviates dry eye syndrome.

[0193] (Example 8)

Chem.

[0194] (Example 9) Repeat Example 1 using substantially 8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxypropanoate hydrochloride (E44S) provided herein. When administered as a single drop four times a day, the above composition substantially slows down the progression rate of myopia.

[0195] (Example 10) [Chemical formula] Repeat Example 1 using the S-isomer (E21) of 8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(3-chlorophenyl)-3-hydroxy-2-methyl-2-phenylpropanoate hydrochloride provided herein. When administered as a single drop twice a day, the above composition substantially reduces intraocular pressure.

[0196] (Example 11) [Chemical formula] Repeat Example 1 using substantially (S)-3-amino-2-(4-(hydroxymethyl)phenyl)-N-((1R,3-endo,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)propanamide ditosylate (E20S) provided herein. When administered as a single drop twice a day, the above composition substantially reduces intraocular pressure and allergic symptoms and alleviates dry eye syndrome.

[0197] The topical pharmaceutical composition for preventing and treating myopia is prepared by a conventional method and formulated as shown in Table 4. [Table 4]

[0198] The topical pharmaceutical composition for preventing and treating myopia is prepared by a conventional method and formulated as shown in Table 5. [Table 5]

[0199] The topical pharmaceutical composition for preventing and treating myopia is prepared by a conventional method and formulated as shown in Table 6. [Table 6]

[0200] The topical pharmaceutical composition for preventing and treating myopia is prepared by a conventional method and formulated as shown in Table 7. [Table 7]

[0201] The topical pharmaceutical composition for preventing and treating myopia is prepared by a conventional method and formulated as shown in Table 8. [Table 8]

[0202] Figures 1, 2, and 3 show the excellent stability of the above SFA formulation (Table 8) for the compounds provided in this specification compared to the aqueous formulation.

[0203] The topical ointment pharmaceutical composition for preventing and treating myopia is prepared by a conventional method and formulated as shown in Table 9. [Table 9]

[0204] (Example 12: Preparation of Salt Form) Methanesulfonic acid (2.5 eq. or 1.2 eq.) is added dropwise to a stirred solution of the compound provided herein (5.0 g, 1 eq.) in DCM (dichloromethane) (10 vol). The reaction mixture is stirred at room temperature for 4 hours, and the completion of the reaction is confirmed by HPLC. Thereafter, a stepwise solvent switch from dichloromethane to 2-BuOH is performed. The solution of the DCM solvent is removed by distillation under vacuum. Next, 2-BuOH is added to the residue twice, followed by vacuum distillation. 2-BuOH (10 vol) is added to the residue, and the reaction mixture is stirred at room temperature for 15 hours.

[0205] The dimesylate salt or monomesylate salt is filtered under nitrogen and separated as a solid. It is washed with 2-BuOH (2×1 vol) and heptane (2×1 vol), and the solid is dried in a vacuum oven at 50 °C for 15 hours. Various salt forms of the compound provided herein can be prepared according to this procedure.

[0206] (Example 13) Synthesis of endo 8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-amino-2-phenylpropanoate dihydrochloride (3) [Chemical formula] To 3-((tert-butoxycarbonyl)amino)-2-phenylpropanoic acid in CH2Cl2, DCC, DMAP and tropine were added, and the solution was stirred at room temperature overnight. Thereafter, the mixture was filtered, extracted with NaHCO3 (saturated) and NaCl (saturated), dried (Na2SO4), filtered and evaporated. Pure endo 8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-(tert-butoxycarbonyl)amino-2-phenylpropanoate (2) was obtained by column chromatography 0-5% MeOH-CH2Cl2.

[0207] To endo 8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-amino-2-phenylpropanoate (2, 30%) in CH2Cl2 was added HCl (4N in dioxane), and the solution was stirred overnight. The solvent was evaporated to give endo 8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-(tert-butoxycarbonyl)amino-2-phenylpropanoate dihydrochloride (3, >90%).

[0208] (Example 14) Synthesis of endo 8-methyl-8-azabicyclo[3.2.1]octan-3-yl 4,4,4-trifluoro-2-phenylbutanoate (5) [Chemical formula] To 4,4,4-trifluoro-2-phenylbutanoic acid (4) in CH2Cl2 were added DCC, DMAP and tropine, and the solution was stirred at room temperature overnight. Then the mixture was filtered, extracted with NaHCO3 (saturated) and NaCl (saturated), dried (Na2SO4), filtered and evaporated. Pure endo 8-methyl-8-azabicyclo[3.2.1]octan-3-yl 4,4,4-trifluoro-2-phenylbutanoate (5, 36%) was obtained by column chromatography on 0-10% MeOH-CH2Cl2.

[0209] (Example 15) Synthesis of exo-3-hydroxy-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2-phenylpropanamide (7) [Chemical formula] To tropic acid (6) in MeOH, exo-8-methyl-3-amino-azabicyclo[3.2.1]octane and DMTMM were added, and the solution was stirred at room temperature overnight. The mixture was evaporated and taken up in EtOAC and saturated NaHCO3. The pH of the aqueous solution was adjusted to pH 10 with K2CO3 solution and further extracted with 2-methyl THF. The solvent was dried (Na2SO4), filtered, and evaporated. Column chromatography with 0% - 90% (EtOH / 2N NH3-MeOH (85 / 15)-CH2Cl2 gave pure exo-3-hydroxy-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2-phenylpropanamide (7, 30%).

[0210] (Example 16) Synthesis of 3-hydroxy-N-((6-methoxypyridin-3-yl)methyl)-2-phenylpropanamide (8) [Chemical formula] To tropic acid (6) in MeOH, (6-methoxypyridin-3-yl)methanamine and DMTMM were added, and the solution was stirred at room temperature overnight. The mixture was poured into water and extracted with ethyl acetate. The organic matter was washed with saturated NaCl, dried (MgSO4), filtered, and evaporated. Column chromatography with 0 - 8% MeOH-CH2Cl2 gave 3-hydroxy-N-((6-methoxypyridin-3-yl)methyl)-2-phenylpropanamide (8, 51%).

[0211] Using most of the procedures shown in Examples 13 - 16, the compounds in Table 10 were prepared by substituting appropriate starting materials. [Table 10-1] [Table 10-2] [Table 10-3]

[0212] (Example 17: Storage Stability of Compounds and Compositions) The compounds provided herein are prepared and placed in a container for storage at ambient temperature or elevated temperature. When the compounds are stored in a polyolefin plastic container as compared to a polyvinyl chloride plastic container, the discoloration of the compounds is reduced whether they are dissolved or suspended in a liquid composition (e.g., an aqueous or organic liquid solution) or are in solid form. Without being bound by theory, the container reduces the exposure of the compounds to electromagnetic radiation, whether it is visible light (e.g., having a wavelength of about 380 - 780 nm) or ultraviolet (UV) light (e.g., having a wavelength of about 190 - 320 nm (UV - B light) or about 320 nm - 380 nm (UV - A light)). Also, some containers include the ability to reduce the exposure of the contents of the container to infrared radiation or a second component having such capacity. The containers used include those made from polyolefins such as polyethylene, polypropylene, polyethylene terephthalate, polycarbonate, polymethylpentene, polybutene, or combinations thereof, particularly those made from polyethylene, polypropylene, or combinations thereof. The container can be further placed within a second container, for example, within a container of paper, cardboard, or foil, which can further reduce the exposure of the contents of the container to UV, visible light, or infrared radiation. Compounds and compositions that benefit from reduced discoloration, decomposition, or both during storage include ophthalmic solutions containing the compounds provided herein or compositions thereof. The ophthalmic solutions may require storage for up to 3 months or longer. The containers described herein may be ophthalmic containers. The container can be in any form suitable for containing the contents, for example, it can be a bag or a bottle.

[0213] Other suitable containers and packaging are described, for example, in International Publication Nos. WO 2018 / 159700, WO 2018 / 159701, and WO 2018 / 159702, and Japanese Patent No. 6236167, the contents of which are incorporated herein by reference.

[0214] The composition disposed within the described container can include boric acid, D-mannitol, benzalkonium chloride, polyoxyl 40 stearate, polyethylene glycol 400, ethylenediaminetetraacetic acid, or combinations thereof, and water or other suitable solvent vehicle.

[0215] [Appendix] [Appendix 1] A compound, wherein the compound is of formula (I) [Chemical formula] or an analog, derivative, solvate, zwitterion or polymorph thereof, or a pharmaceutically acceptable salt thereof, X 1 is hydrogen, hydroxyl, halogen, C 1-4 alkyl, amino, nitro, cyano, C 1-4 carbonyl, C 1-4 carbonylamino, C 1-4 alkoxy, C 1-4 sulfonyl, C 1-4 sulfonylamino, C 1-4 thioalkyl, or C 1-4 carboxyl, X 2 is H or lower alkyl, X 3 is H or lower alkyl, J 1 is -CH2-, -N(R 1 )-, or -O-, where R 1 is H or lower alkyl, Z 1 is -CH2-, -N(R 2 )-, or -O-, where R 2 is H or lower alkyl, when the 8-methyl-8-azabicyclo[3.2.1]octan-3-yl moiety is in the endo conformation, J 1 is -O-, X 2 is lower alkyl, or X3 is a lower alkyl, a compound characterized thereby.

[0216] [Appendix 2] wherein the 8-methyl-8-azabicyclo[3.2.1]octan-3-yl moiety is in the endo conformation, a compound according to Appendix 1, characterized thereby.

[0217] [Appendix 3] wherein the 8-methyl-8-azabicyclo[3.2.1]octan-3-yl moiety is in the exo conformation, a compound according to Appendix 1, characterized thereby.

[0218] [Appendix 4] J 1 is -CH 2 -, or -N(R 1 ), a compound according to any one of Appendices 1 to 3, characterized thereby.

[0219] [Appendix 5] J 1 is -O-, when X 2 is a lower alkyl, or X 3 is a lower alkyl, a compound according to any one of Appendices 1 to 4, characterized thereby.

[0220] [Appendix 6] Z 1 is CH2, or N(R 2 ), a compound according to any one of Appendices 1 to 5, characterized thereby.

[0221] [Appendix 7] X 2 is a lower alkyl, or X 3 is a lower alkyl, a compound according to any one of Appendices 1 to 6, characterized thereby.

[0222] [Appendix 8] X1 is hydroxyl, halogen, C 1-4 alkyl, amino, nitro, cyano, C 1-4 carbonyl, C 1-4 carbonylamino, C 1-4 alkoxy, C 1-4 sulfonyl, C 1-4 sulfonylamino, C 1-4 thioalkyl, or C 1-4 carboxyl, A compound according to any one of Appendices 1 to 7, characterized in that

[0223] [Appendix 9] X 1 is hydroxyl, C 1-4 alkyl, amino, nitro, cyano, C 1-4 carbonyl, C 1-4 carbonylamino, C 1-4 alkoxy, C 1-4 sulfonyl, C 1-4 sulfonylamino, C 1-4 thioalkyl, or C 1-4 carboxyl, A compound according to any one of Appendices 1 to 7, characterized in that

[0224] [Appendix 10] X 1 is hydroxyl, C 1-4 alkyl, amino, nitro, cyano, C 1-4 carbonyl, C 1-4 carbonylamino, C 1-4 sulfonyl, C 1-4 sulfonylamino, C 1-4 thioalkyl, or C 1-4 carboxyl, A compound according to any one of Appendices 1 to 7, characterized in that

[0225] [Appendix 11] Z 1 is -CH2- or -N(R 2 )-, X 1 is hydrogen, hydroxyl, C 1-4Alkyl, amino, nitro, cyano, C 1-4 Carbonyl, C 1-4 Carbonylamino, C 1-4 Alkoxy, C 1-4 Sulfonyl, C 1-4 Sulfonylamino, C 1-4 Thioalkyl, or C 1-4 Carboxyl, The compound according to Appendix 1, characterized in that.

[0226] [Appendix 12] The compound is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0227] [Appendix 13] The compound is of formula (II)

Chemical formula

[0228] [Appendix 14] Formula (II) is Formula (IIa) [Chemical formula] Formula (IIb) [Chemical formula] Formula (IIc) [Chemical formula] Formula (IId) [Chemical formula] Formula (IIe) [Chemical formula] Formula (IIf) [Chemical formula] Or, formula (IIg) [Chemical formula] is the compound according to appended note 13, characterized in that

[0229] [Appended note 15] Formula (II) is formula (IIb-1) [Chemical formula] is the compound according to appended note 13, characterized in that

[0230] [Appended note 16] X 8 is phenyl or pyridinyl, X 9 is phenyl, pyridinyl, furanyl, or thiophenyl, the compound according to appended note 13, characterized in that

[0231] [Appended note 17] X 4 is hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 alkoxy, the compound according to any one of appended notes 13 to 16, characterized in that

[0232] [Appended note 18] X 7 is hydrogen, halogen, or C 1-4 alkyl, the compound according to any one of appended notes 13 to 17, characterized in that

[0233] [Appended note 19] -Z 2 -X 6 is -OH or -NH2, the compound according to any one of appended notes 13 to 18, characterized in that

[0234] [Appended note 20] X 10 is hydrogen, C 1-4 alkyl, C3-7 Cycloalkyl, or C 1-4 is alkyl-phenyl, and X 11 is hydrogen, or C 1-4 is alkyl, or, X 10 and X 11 together with the atoms to which they are attached form a C 3-7 cycloalkyl or C 3-7 cycloalkyl-phenyl, A compound according to any one of appendices 13 to 19, characterized in that.

[0235] [Appendix 21] The compound is

Chemical formula

Chemical formula

[0236] [Appendix 22] A composition comprising a compound according to any one of appendices 1 to 21.

[0237] [Appendix 23] A semi-fluorinated alkane, and, A compound of formula (I)

Chemical formula

Chemical formula

[0238] [Appendix 24] comprising a semi-fluorinated alkane and a compound, wherein the compound is [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] benzenecarboxylic acid, α-(hydroxymethyl)-(3-exo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester, (αR)-benzenecarboxylic acid, α-(hydroxymethyl)-(3-exo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester, (αS)-benzenecarboxylic acid, α-(hydroxymethyl)-(3-exo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester, exo-benzenecarboxylic acid, α-(hydroxymethyl)-8-(methyl-d3)-8-azabicyclo[3.2.1]oct-3-yl ester, [Chemical formula] , the (3R,2’R)-enantiomer of EA-3167, [Chemical formula] wherein X is Cl, Br or I, [Chemical formula] wherein X is Cl, Br or I, [Chemical formula] [Chemical formula] [Chemical formula] or an analog, derivative, solvate, zwitterion, or polymorph thereof, or a pharmaceutically acceptable salt thereof, A composition characterized by the above.

[0239] [Appendix 25] The semi-fluorinated alkane is perfluorohexyl octane or perfluorohexyl nonane, The composition according to Appendix 23 or 24, characterized by the above.

[0240] [Appendix 26] The composition is a non-aqueous composition, The composition according to any one of Appendices 22 to 25, characterized by the above.

[0241] [Appendix 27] A pharmaceutical composition comprising a compound according to any one of Appendices 1 to 21 or a composition according to any one of Appendices 22 to 26 and a pharmaceutically acceptable additive.

[0242] [Appendix 28] A method for treating myopia in a subject in need of treating myopia, comprising administering to the subject a therapeutically effective amount of the compound according to any one of Appendices 1 to 21, the composition according to any one of Appendices 22 to 26, or the pharmaceutical composition according to Appendix 27.

[0243] [Appendix 29] A method for suppressing the progression of myopia in a subject in need of suppressing the progression of myopia, comprising administering to the subject a therapeutically effective amount of the compound according to any one of Appendices 1 to 21, the composition according to any one of Appendices 22 to 26, or the pharmaceutical composition according to Appendix 27.

[0244] [Appendix 30] A method for delaying the onset of myopia in a subject in need of delaying the onset of myopia, comprising administering to the subject a therapeutically effective amount of the compound according to any one of Appendices 1 to 21, the composition according to any one of Appendices 22 to 26, or the pharmaceutical composition according to Appendix 27.

[0245] [Appendix 31] A method for treating a disease or disorder threatening vision in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of the compound according to any one of Appendices 1 to 21, the composition according to any one of Appendices 22 to 26, or the pharmaceutical composition according to Appendix 27.

[0246] [Appendix 32] wherein the disease or disorder threatening vision includes peripheral lattice degeneration, laceration, detachment, neovascularization of myopic choroid, myopic macular detachment, myopic macular hole, posterior uveal effusion, myopic macular degeneration, early-onset cataract, open-angle glaucoma, peripapillary atrophy, tilt of the optic nerve head, pit of the optic nerve head, or a combination thereof. The method according to Appendix 31, characterized in that.

[0247] [Appendix 33] A kit comprising the compound according to any one of Appendices 1 to 21, the composition according to any one of Appendices 22 to 26, or the pharmaceutical composition according to Appendix 27, and their instructions for use.

[0248] [Appendix 34] A product comprising the compound according to any one of Appendices 1 to 21, the composition according to any one of Appendices 22 to 26, or the pharmaceutical composition according to Appendix 27.

Claims

1. The compound of formula (II) 【Chemistry 1】 or a solvate, zwitterion, or polymorph thereof, or a pharmaceutically acceptable salt thereof; X ４ is hydrogen, hydroxyl, halogen, C １－４ Alkyl, C １－４ haloalkyl, amino, nitro, cyano, —C(O)(C 1-4 alkyl), —C(O)N(C 1-4 alkyl)(C 1-4 alkyl), C １－４ alkoxy, —S(O) 2 (C 1-4 alkyl), —S(O) 2 N(C 1-4 alkyl)(C 1-4 alkyl), —S(C 1-4 alkyl), or —C(═O)O(C 1-4 alkyl); X ５ is H or C 1-4 alkyl; X ６ is H or C 1-4 alkyl; X ７ is hydrogen, hydroxyl, halogen, C １－４ Alkyl, amino, nitro, cyano, —C(O)(C 1-4 alkyl), —C(O)N(C 1-4 alkyl)(C 1-4 alkyl), C １－４ alkoxy, —S(O) 2 (C 1-4 alkyl), —S(O) 2 N(C 1-4 alkyl)(C 1-4 alkyl), —S(C 1-4 alkyl), or —C(═O)O(C 1-4 alkyl); X ８ is phenyl, pyridinyl, pyrimidinyl or thienopyridinyl, X ９ is phenyl, pyridinyl, pyrimidinyl, furanyl or thiophenyl; X １０ is hydrogen, halogen, C １－４ Alkyl, C ３－７ Cycloalkyl, C １－４ alkoxy, —S(C 1-4 alkyl), or C １－４ alkyl-phenyl; X １１ is hydrogen, halogen, C １－４ Alkyl, C ３－７ Cycloalkyl, C １－４ alkoxy, —S(C 1-4 alkyl), or C １－４ alkyl-phenyl; Or X １０ and X １１ are C together with the atoms to which they are attached. ３－７ Cycloalkyl or C ３－７ Cycloalkyl-(X １２ ) ｐ Forming X １２ are each independently a halogen, a hydroxyl, or C １－４ Alkyl, C １－４ Alkoxy, C １－４ haloalkyl, or phenyl, and p is 0, 1, 2, or 3; J ２ Ga-CH ２ -, -N(R ３ )- or -O-, where R ３ is H or C 1-4 alkyl; Z ２ Ga-CH ２ -, -N(R ４ )- or -O-, where R ４ is H or C 1-4 alkyl; n is 0 or 1; A compound characterized by:

2. Formula (II) is Formula (IIa) 【Chemistry 2】 Formula (IIb) 【Transformation 3】 Formula (IIc) 【Chemistry 4】 Formula (IId) 【Transformation 5】 Formula (IIe) 【Transformation 6】 Formula (IIf) 【Transformation 7】 Or, formula (IIg) 【Transformation 8】 That is, The compound according to claim 1 .

3. Formula (II) is represented by formula (IIb-1) 【Chemistry 9】 That is, The compound according to claim 1 .

4. X ８ is phenyl or pyridinyl, X ９ is phenyl, pyridinyl, furanyl, or thiophenyl; The compound according to claim 1 .

5. X ４ is hydrogen, halogen, C １－４ Alkyl, C １－４ haloalkyl, or C １－４ is an alkoxy, 5. A compound according to any one of claims 1 to 4.

6. X ７ is hydrogen, halogen, or C １－４ is alkyl, 6. A compound according to any one of claims 1 to 5.

7. -Z ２ -X ６ is -OH or -NH ２ That is, 7. A compound according to any one of claims 1 to 6.

8. X １０ is hydrogen, C １－４ Alkyl, C ３－７ cycloalkyl, or C １－４ alkyl-phenyl, and X １１ is hydrogen, or C １－４ is alkyl, or X １０ and X １１ are C together with the atoms to which they are attached. ３－７ Cycloalkyl or C ３－７ forming a cycloalkyl-phenyl, A compound according to any one of claims 1 to 7.

9. The compound is 【Chemistry 10】 【Chemistry 11】 or a solvate, zwitterion, or polymorph thereof, or a pharmaceutically acceptable salt thereof.

10. A composition comprising a compound according to any one of claims 1 to 9.

11. A composition comprising a semifluorinated alkane and a compound according to any one of claims 1 to 9.

12. a semifluorinated alkane and a compound, The compound is 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 Benzeneacetic acid, α-(hydroxymethyl)-(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester, (αR)-benzeneacetic acid, α-(hydroxymethyl)-(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester, (αS)-benzeneacetic acid, α-(hydroxymethyl)-(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester, endo-benzeneacetic acid, α-(hydroxymethyl)-8-(methyl-d3)-8-azabicyclo[3.2.1]oct-3-yl ester, 【Chemistry 16】 , the (3R,2'R)-enantiomer of EA-3167, 【Chemistry 17】 wherein X is Cl, Br or I; [Chemistry 18] wherein X is Cl, Br or I; 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 or a solvate, zwitterion, or polymorph thereof, or a pharmaceutically acceptable salt thereof; A composition characterized by:

13. The semifluorinated alkane is perfluorohexyl octane or perfluorohexyl nonane; 13. The composition according to claim 11 or 12.

14. The composition is a non-aqueous composition.

14. The composition according to any one of claims 10 to 13.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or a composition according to any one of claims 10 to 14, and a pharmaceutically acceptable excipient.

16. A pharmaceutical composition for treating myopia in a subject in need thereof, comprising a compound according to any one of claims 1 to 9, a composition according to any one of claims 10 to 14, or a pharmaceutical composition according to claim 15, wherein the compound, the composition, or the pharmaceutical composition is administered to the subject in a therapeutically effective amount.

17. A pharmaceutical composition for inhibiting the progression of myopia in a subject in need thereof, comprising a compound described in any one of claims 1 to 9, a composition described in any one of claims 10 to 14, or a pharmaceutical composition described in claim 15, wherein the compound, the composition, or the pharmaceutical composition is administered to the subject in a therapeutically effective amount.

18. A pharmaceutical composition for delaying the onset of myopia in a subject in need thereof, comprising a compound described in any one of claims 1 to 9, a composition described in any one of claims 10 to 14, or a pharmaceutical composition described in claim 15, wherein the compound, composition, or pharmaceutical composition is administered to the subject in a therapeutically effective amount.

19. A pharmaceutical composition for treating a vision-threatening disease or disorder in a subject in need thereof, comprising a compound according to any one of claims 1 to 9, a composition according to any one of claims 10 to 14, or a pharmaceutical composition according to claim 15, wherein the compound, the composition, or the pharmaceutical composition is administered to the subject in a therapeutically effective amount.

20. The vision-threatening disease or disorder comprises peripheral lattice degeneration, fissures, detachments, myopic choroidal neovascularization, myopic macular schisis, myopic macular hole, posterior staphyloma, myopic macular degeneration, early-onset cataract, open-angle glaucoma, peripapillary atrophy, optic disc tilt, optic disc pit, or a combination thereof; 20. The pharmaceutical composition of claim 19.

21. A kit comprising a compound according to any one of claims 1 to 9, a composition according to any one of claims 10 to 14, or a pharmaceutical composition according to claim 15, and instructions therefor.

22. 16. An article of manufacture comprising a compound according to any one of claims 1 to 9, a composition according to any one of claims 10 to 14, or a pharmaceutical composition according to claim 15.

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