Peroxisome proliferator-activated receptor alpha agonist and method of use

Abstract

To provide compounds and compositions for treating ocular diseases and / or conditions such as retinal inflammation, retinal neovascularization, retinal vascular leakage, retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration, and diabetic macular edema as well as kits.SOLUTION: There are provided benzyl derivative compounds having peroxisome proliferator-activated receptor α (PPARα) agonistic activity represented by the following formula, and compositions containing such compounds.SELECTED DRAWING: Figure 2A

Description

[Technical Field]

[0001] Cross-reference of related applications This patent application is in accordance with U.S. Patent Application No. 62 / 643,998, filed on March 16, 2018. Therefore, the entire provisional patent application identified is incorporated by reference, 35 U.S.C. 119 (e They assert their priority based on the following.

[0002] Government support This invention is authorized by the National Institutes of Health (NIH) under certification number R21EY028. This was done with government support under Article 279. The government has certain rights to this invention. [Background technology]

[0003] Retinal inflammation and the resulting neovascularization (NV) are associated with retinopathy of prematurity (ROP) and diabetes. In several eye disorders, such as age-related retinopathy (DR) and age-related macular degeneration (AMD) It is a major cause of blindness. Diabetic macular edema (DME) is caused by retinal vascular leakage. This is a major cause of blindness in diabetic eye diseases. Cumulative evidence indicates that DR is tumor necrosis factor alpha (TNF-α), intercellular adhesion molecule 1 (ICAM-1), and Multiple inflammatory factors, including vascular endothelial growth factor (VEGF), are excessively produced in diabetic retinas. It is suggested that this is a chronic inflammatory disorder. Inflammation affects retinal vascular endothelial function. It plays a role in causing injury, vascular leakage, and subsequent retinal NV. The main treatment options are... Then anti-VEGF drugs emerged, but they required frequent intraocular injections, were expensive, and necessitated specialized facilities. There are issues with the requirements. Furthermore, although it is effective for most patients, it is effective for about 40-50% of patients. The patient is refractory to intravitreal injections of anti-VEGF and corticosteroids. Supporting pathways and factors that have not yet been addressed in interventions are still the causes and progression of the disease. This implies involvement in the row.

[0004] Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone-activated receptors. It is a family and a transcription factor. The PPAR family includes PPAR alpha (PP Three types: ARα, PPAR gamma (PPARγ), and PPAR delta (PPARδ) It includes members, and PPARδ is referred to as PPARbeta (PPARβ) in this art. These three PPAR members share significant sequence homology, but they are different. It has diverse tissue distribution and functions, and can be selectively targeted. PPARγ is mainly produced in adipose tissue. On the other hand, PPARα is found in the liver, vascular endothelial cells (ECs), smooth muscle cells, kidneys, and heart. It is expressed in cells with high mitochondrial activity, including those containing PPARα. PPARα is abundantly expressed in the retina. Previous studies have shown that inflammation, apoptosis and The role of PPARα in regulating angiogenesis (NV) has only recently been clarified. Novel strategies using PPARα agonists as treatments for ocular vascular diseases have been established. When activated by sex or exogenous synthetic agonists, PPARα becomes a retinoid x receptor. It forms a heterodimer with the (RXR) gene, and the PPAR response of the promoter of its target gene It binds to rement (PPRE) and activates the transcription of target genes. Furthermore, PPARα PPARα indirectly regulates other genes by interfering with their transcriptional regulation. This involves activated B cell nuclear factor kappa light chain enhancer (NF-κB), ICAM-1, and Numerous genes involved in lipid metabolism and vascular inflammation, such as interleukin-6 (IL-6). It has been shown to regulate this. Furthermore, PPARα regulates oxidation and angiogenesis. This has been shown. However, the function of PPARα in the retina is not fully understood. Based on findings from the FIELD and ACCORD clinical trials, PPARα agonists are Fenofibrate (a metabolite of fenofibrate) is effective against DR. It has robust and unexpected therapeutic effects, reducing the need for laser treatment in type 2 diabetes patients by 32- The role of PPARα in DR was not recognized until it was demonstrated that it could reduce radiation by 40%. There was no decrease in PPARα levels in the retinas of both type 1 and type 2 diabetic animal models. This has been demonstrated in previous studies. Furthermore, the activation of PPARα by fenofibrate Transformation effectively reduces retinal leukocyte stasis and vascular leakage in diabetic models, and ischemic-induced networks. Improves membrane NV. [Overview of the Initiative]

[0005] Fenofibrate initially lowers cholesterol and triglyceride levels. This capability was recognized, and therefore, for more than 30 years, it has been widely used clinically in the treatment of dyslipidemia. It has been used. Fenofibrate has shown efficacy against NV and DME in DR patients. It is the first clinically proven, low-cost, and safe oral drug for drug use, and therefore, clinicians, This is of great interest to both basic scientists and pharmaceutical companies interested in developing novel drug-resistant treatments. Therefore, the inhibitory effect of fenofibrate on retinal NV and DME is due to its low lipid content. Rather than being correlated with lower activity, the phase between its metabolites, phenofibroic acid and PPARα It has been reported that this is caused by interaction. Therefore, fenofibrate is DR It has significant therapeutic potential for treating AMD, but its binding affinity to PPARα is relatively low. It has relatively low levels of off-target nephrotoxicity and other potential side effects. It is non-invasive. Furthermore, there is a critical need to develop new treatment options that complement existing methods. Furthermore, it further improves the treatment of other inflammatory and angioplasty disorders in the eyes and other parts of the body. To achieve this, it is desirable to develop a high-affinity agonist for PPARα, and this research is heading in that direction. That is the objective.

[0006] The patent or application file must include at least one color drawing. A copy of this patent or patent application publication, including the drawings, will be provided upon request, upon payment of the necessary fees. If available, it will be provided by the United States Patent and Trademark Office. [Brief explanation of the drawing]

[0007] [Figure 1] This figure shows the initial evaluation results for hPPARα agonism of compounds 9-14 and 21-24 in cell-based luciferase assays. Results are presented from one experiment as induction ratio vs. DMSO control ± SE (n=3). Compound GW590735 was evaluated at 5 μM and 10 μM. [Figure 2A] This figure shows the Western blot analysis of 661W mouse cells after treatment with 10 μM, 50 μM, and 100 μM of compound 10 for 24 hours. [Figure 2B] Figure 2A shows the results of quantification of PPARα production by densitometry from Western blot analysis. [Figure 2C] This figure shows the real-time PCR analysis of 661W mouse cells after treatment with compound 10 for 24 hours (n=6). [Figure 2D]This figure shows the results of the HRCEC wound healing assay for compound 10 at both 10-hour and 24-hour incubation times. Unless otherwise noted, the experiments in Figures 2A–D were performed in triplicate three times. All values ​​shown are expressed as mean ± SD. Differences between groups were tested for statistical significance using Student's t-test. *P<0.05, **P<0.01, ***P<0.001. [Figure 3] This figure shows (A) the cocrystal structure of GW590735·hPPARα, (B) the predicted binding mode of 10 hPPARα, and (C) the predicted binding mode of compound 28 to hPPARα. The binding pocket cavity is shown by surface representation. PDB:2P54. [Figure 4] This figure shows the dose-dependent agonism of PPARα induced by A91, demonstrated by luciferase quantification (luminescence) in a cell-based luciferase reporter assay. GW59=GW590735 is used as a positive control (A91=ASD91=10). [Figure 5] This figure shows the dose-dependent agonism of PPARγ induced by A91, demonstrated by luciferase quantification (luminescence) in a cell-based luciferase reporter assay. Rosiglitazone is used as a positive control. (A91=ASD91=10). [Figure 6] This figure shows the dose-dependent agonism of PPARδ induced by A91, demonstrated by luciferase quantification (luminescence) in a cell-based luciferase reporter assay. GW07=GW0742 is used as a positive control (A91=ASD91=10). [Figure 7] This figure shows the dose-dependent agonism of PPARα induced by A190, demonstrated by luciferase quantification (luminescence) in a cell-based luciferase reporter assay. GW59=GW590735 is used as a positive control (A190=190=ASD190). [Figure 8]This figure shows the dose-dependent agonism of PPARγ induced by A190, demonstrated by luciferase quantification (luminescence) in a cell-based luciferase reporter assay. Rosiglitazone is used as a positive control. (A190=190=ASD190). [Figure 9] This figure shows the dose-dependent agonism of PPARδ induced by A190, demonstrated by luciferase quantification (luminescence) in a cell-based luciferase reporter assay. GW07=GW0742 is used as a positive control (A190=190=ASD190). [Figure 10A] This figure shows the in vivo efficacy results of compound ASD91(10) compared to fenofibric acid (FenoFA) on retinal permeability. Male Brown Norway rats aged 7-8 weeks were injected with streptozotocin (STZ, 55 mg / kg). Two weeks after STZ injection, daily treatment with ASD91 or FenoFA (ip injection) was started and continued for 26-28 days. ≠P<0.05 (vs FenoFA), *P<0.05 (vs STZ-DMSO). [Figure 10B] This figure shows the in vivo efficacy results of compound ASD91(10) compared to fenofibric acid (FenoFA) on the hepatic phenotype. Male Brown Norway rats aged 7-8 weeks were injected with streptozotocin (STZ, 55 mg / kg). Two weeks after STZ injection, daily treatment with ASD91 or FenoFA (ip injection) was started and continued for 26-28 days. ≠P<0.05 (vs FenoFA), *P<0.05 (vs STZ-DMSO). [Modes for carrying out the invention]

[0008] As mentioned above, retinal inflammation and neovascularization are associated with retinopathy of prematurity and diabetic retinopathy (DR). It is a major cause of blindness in several eye disorders, including age-related macular degeneration (AMD). Two large prospective clinical trials have shown that the PPARα agonist fenofibre is effective. Brato has been reported to have a robust therapeutic effect on DR. Due to its steric activity, it has effects on retinal endothelial dysfunction, angiogenesis, and inflammation, for example Furthermore, novel claustrophobic agents suggest therapeutic effects on DR and AMD (e.g., exudative AMD). Compounds of DR are disclosed herein. The compositions disclosed herein are not limited to these, but include DR AMD (e.g., exudative AMD), retinal inflammation, retinal neovascularization (NV), retinal vascular leakage, Eye disorders or conditions such as retinopathy of prematurity (ROP) and diabetic macular edema (DME) It may be used in treatment. The compounds of this disclosure may be used to treat inflammation and / or Other diseases and / or conditions related to angiogenesis are listed below.

[0009] Various embodiments of the compounds, compositions, and methods disclosed herein are described by illustrative descriptions, examples, and results. Before further detail using the following, the application of the compounds, compositions and methods of this disclosure is as follows: It should be understood that the details of the specific embodiments and examples shown below are not limited to those described below. The statements made herein are for illustrative purposes only and in a limited sense. It is not meant to be interpreted in any way. Therefore, the language used herein is intended to be the broadest possible term. The scope and meaning are intended to be given, and the embodiments and examples are illustrative rather than comprehensive. It is intended to be a certain way. Furthermore, the expressions and terms used in this specification are for illustrative purposes only. It should not be considered limited unless otherwise indicated. Furthermore, the following detailed explanation contains numerous elements to facilitate a more complete understanding of this disclosure. Physical details are provided. However, this disclosure may be carried out without these specific details. This will be obvious to those skilled in the art. In other cases, avoid unnecessarily complicating the explanation. Therefore, features well known to those skilled in the art will not be described in detail. All alternative forms and substitutions that are obvious to those skilled in the art will not be described in detail. Forms, modifications, and equivalents are intended to be included within the scope of this disclosure. All of the compounds, compositions, and methods of production shown, as well as their applications and uses, are hereby referred to in this publication. They can be prepared and carried out in light of the disclosure. Therefore, the compounds and compositions of this disclosure Although the methods and techniques described herein are related to specific embodiments, the general principles described herein are not applicable. Without departing from the scope of the concepts of the present invention, the compounds described herein Modifications may be made to the composition and / or method, as well as to the steps or sequence of steps of the method. It will be obvious to those skilled in the art that it may be used.

[0010] All patents, published patents, and patents referred to herein or referenced anywhere in this application are not included. The patent applications and non-patent publications are incorporated by reference, with each individual patent or publication being incorporated by reference. Just as the specific and individual details are shown, the whole of them is revealed by reference. This is incorporated herein by reference.

[0011] Unless otherwise defined herein, scientific and technical terms used in connection with this disclosure The terms shall have meanings that are generally understood by those skilled in the art. Furthermore, the context shall not require otherwise. Unless otherwise specified, singular terms shall be assumed to include the plural form, and plural terms shall be assumed to include the singular form.

[0012] When used in accordance with the methods and compositions of this disclosure, the following terms shall not apply unless otherwise indicated. It shall be understood that it has the following meaning:

[0013] The term “comprising” as used in the claims and / or herein In some cases, the use of the words "a" or "an" can mean "one," but when it comes to "one" This also corresponds to the meanings of "multiple," "at least one," and "one or more than one." The use of the term "or" in the claims explicitly indicates that it refers only to the substitute. Unless otherwise, or if the substitutes are mutually exclusive, it means "and / or". While used in this disclosure, this disclosure refers only to substitutes and the definition of "and / or". I support this. The use of the term "at least one" is not limited to just one, but is not limited to these. , 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 100 Or it is understood to include any number of integers that fall between them, or any number of more than one. The term "at least one" can mean 100 or 1000 or more, depending on the term it is accompanied by. It may be extended to 100 / 1000. Furthermore, a larger restriction yields better results than the 100 / 1000 limit. It should not be considered limited, as it can also produce [something]. In addition, the term "X The use of "at least one of Y and Z" means not just X only, Y only, and Z only. It is understood that this includes any combination of X, Y, and Z.

[0014] As used herein, all numbers or ranges are defined unless the context otherwise clearly indicates. This includes fractions of values ​​and integers within such ranges and fractions of integers within such ranges. Therefore, to give an example, references to numerical ranges such as 1 to 10 are 1, 2, 3, 4, 5, 6 This includes not only 7, 8, 9, and 10, but also 1.1, 1.2, 1.3, 1.4, 1.5, etc. Therefore, references to the range 1-50 include 1, 2, 3, 4, 5 up to and including 50. , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 2 Not only 0, but also 1.1, 1.2, 1.3, 1.4, 1.5, 2.1, 2.2, 2 This includes .3, 2.4, 2.5, etc. References to a series of ranges refer to different ranges within that series. This includes ranges that combine boundary values. For example, 1 to 10, 10 to 20, 20-30, 30-40, 40-50, 50-60, 60-75, 75-100, 100-150, 150-200, 200-250, 250-300, 300-400, References to a series of ranges such as 400-500, 500-750, and 750-1,000 are, for example, Views 1-20, 10-50, 50-100, 100-500, and 500-1,000 Includes the enclosure.

[0015] As used herein and in the claims, the word "comprising" (and Any form of "comprising," such as "comprise" and "comprises." (Form) "having" (as well as "have" and "has") (any form of having, such as) "including" (and "including (inc) ludes) and any form of "include", such as "include", or "contains" and "contains" The term "containing" (any form of "containing") is comprehensive or non-exclusive. , do not exclude additional unlisted elements or method steps.

[0016] As used herein, the terms "or any combination thereof" refer to the items listed before the term. This refers to all permutations and combinations. For example, "A, B, C or any combination thereof" is A , B, C, AB, AC, BC or ABC, and furthermore, the order is important in a particular context. If so, choose one of the following: BA, CA, CB, CBA, BCA, ACB, BAC, or CAB It is intended to include at least one of these. Following this example, BB, AAA, AAB, BBC , AAABCCCC, CBBAAA, CABABB, etc., one or more items or The combination explicitly includes repetition of terms. Those skilled in the art will understand the context in other ways. Unless otherwise stated, there is typically no limit to the number of items or terms in any combination. They will understand.

[0017] Throughout this application, the terms "about" and "approximately" refer to the value of a composition, the composition administered. This includes variations in errors inherent to the method used, or variations that exist between the test subjects. Used to indicate. When used herein, the modifying phrases "about" or "approximately" are used. It is intended to include precise values, quantities, degrees, directions, or other modified characteristics or values. Furthermore, for example, measurement errors, manufacturing tolerances, stress on various parts or components, observation This is intended to include some degree of slight variation due to user error, wear and tear, and combinations thereof. The term "approximately" or "about" refers to measurable values ​​such as quantity or duration. When used in writing, such variations are appropriate for implementing the disclosed method, As will be understood by those skilled in the art, for example, ±20% or ±15% from a specific value, This includes variations of ±10%, ±5%, ±1%, or ±0.1%. Intended. As used herein, the term “substantially” means the events or events described below. The situation is absolutely certain to occur, or the events or circumstances described thereafter are of a considerable extent. This means that it occurs to a certain degree. For example, the term "substantially" refers to the event described below. Or the situation is such that there is at least a 75% probability, or at least an 80% probability, or less Both have a 90% probability of being born, or at least a 95% probability, or at least a 98% probability. It means to do something.

[0018] When used herein, any reference to “one embodiment” or “embodiment” is an expression of the same meaning. A specific element, feature, structure, or characteristic described in relation to form is at least one implementation form This means that it is included in the form and may be included in other embodiments. The phrase "in one embodiment" does not necessarily mean that all occurrences refer to the same embodiment. It is not limited to a single or specific embodiment.

[0019] The term "pharmaceutically acceptable" means that the substance does not exhibit excessive toxicity, irritation, and / or allergic reactions. A reasonable Benef is suitable for administration to humans and / or animals without adverse side effects. This refers to compounds and compositions that meet the fit / risk ratio. The compounds of this disclosure are compounds or To improve the solubility, deliverability, dispersion, stability, and / or conformational integrity of the complex. Obtaining one or more pharmaceutically acceptable substances comprising a carrier, vehicle, diluent and adjuvant. It may be combined with other excipients.

[0020] As used herein, “pure” or “substantially pure” means the dominant species in which the species of interest exists. It is a dominant species (i.e., more abundant in molar terms than any other species of interest in its composition). In particular, the substantially purified fraction contains a small amount of all polymer species in which the target species exists. This means that it constitutes at least approximately 50 percent (on a molar basis) of the composition. Generally, a substantially pure composition contains more than 80% of all polymer species present in the composition. More specifically, about 85% or more, about 90% or more, about 95% or more. Contains more than 9%. The terms "pure" or "substantially pure" also mean that less of the species of interest is present. Also 60% (w / w) pure, or at least 70% (w / w) pure, or at least 7 5% (w / w) pure, or at least 80% (w / w) pure, or at least 85% (w / w) pure, or at least 90% (w / w) pure, or at least 92% (w (w / w) pure, or at least 95% (w / w) pure, or at least 96% (w / w) ) Pure, or at least 97% (w / w) pure, or at least 98% (w / w) pure A preparation that is pure, or at least 99% (w / w) pure, or 100% (w / w) pure. It refers to an object.

[0021] Non-exclusive examples of animals or mammals within the scope and meaning of this term include dogs, cats, and larvae. Mouth, mouse, rabbit, guinea pig, chinchilla, horse, goat, pig, cow, sheep, animals This includes zoo animals, Old World and New World monkeys, non-human primates, and humans.

[0022] In at least certain embodiments, diseases and / or diseases that can be treated with the compounds of the present disclosure The condition is characterized by inflammation and / or angiogenesis. It can be treated with the compounds of this disclosure. Such diseases and / or conditions having an inflammatory basis include, but are not limited to, these. Inflammatory bowel disease, type 1 or type 2 diabetes, Graves' disease, multiple sclerosis, various types Arthritis, vasculitis, dermatitis, glomerulonephritis, hepatitis, periodontitis, atherosclerosis Arteriosclerosis, heart failure, obesity, Alzheimer's disease and metabolic syndrome, and Other defects and conditions disclosed herein include:

[0023] Examples of ocular diseases with an inflammatory basis that can be treated with the compounds of this disclosure include: While not limited to these, this includes keratitis, endophthalmitis, blepharitis, conjunctivitis, scleritis, herpes inflammation, and bruxism. Dermatitis, vasculitis, arteritis, orbital inflammation, optic neuritis, sympathetic ophthalmitis, retinitis, and other autoimmune diseases. Diseases, age-related macular degeneration, macular edema, diabetic retinopathy, glaucoma, proliferative vitreoretinopathy, cornea These include edema, uveal edema, and retinal edema.

[0024] Diseases and / or conditions having an inflammatory basis that can be treated with the compounds of this disclosure These include, but are not limited to, diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, and retinal dysregulation. Pulse or vein occlusion, corneal transplant rejection, corneal neovascularization, neovascular glaucoma, and sickle cell anemia. Eye diseases and / or conditions such as retinopathy, and, but not limited to, cancer, Non-ocular diseases and skin diseases, including diabetic ulcers, diabetic nephropathy, cardiovascular diseases and seizures. / or states can be listed.

[0025] "Treatment" refers to therapeutic treatment. "Prevention" refers to preventive or protective measures or conditions. Alternatively, it refers to reducing the incidence of disease. The term "treatment" means treating a composition for therapeutic purposes and / It refers to administering to a target for the purpose of prevention or treatment. Non-limiting examples of the mode of administration include local administration. This includes both targeted and systemic applications, including oral, topical, retrobulbar, subconjunctival, percutaneous, parenteral, subcutaneous, and nasal administration. These include intramuscular, intraperitoneal, intravitreous, and intravenous pathways. Furthermore, the compositions of this disclosure For example, formulation techniques that incorporate active substances into biodegradable polymers can be used to delay, control, and sustained release. They may also be formulated with a carrier compound that provides sustained release.

[0026] The term "topical" refers to, but is not limited to, administration by external application to the eye. As used herein, this refers to a mode of administration of substances, such as those that are delivered through the epithelial surface. Non-limiting examples of administration include administration by eye drops or administration of particles containing the active substance. It is administered for use.

[0027] The terms "therapeutic composition" and "pharmaceutical composition" are known in the art, or not known. The compounds of this disclosure may be administered to a subject by any method intended herein. This refers to a composition containing (also referred to herein as an active substance), and the administration of the composition is as specified herein. It produces the therapeutic effects described elsewhere. As described, the compositions of this disclosure are appropriate Using advanced formulation technologies, we have designed to provide delayed, controlled, sustained release, and / or prolonged release. It can also be used in calculations.

[0028] The term "effective dose" refers to an excessive amount of harmful side effects (e.g., substantial toxicity, irritation, and allergy). - Sufficient to demonstrate a detectable therapeutic or procedural effect in the subject without accompanied by a response. an amount of the active substance that would result in a reasonable benefit / risk ratio when used in the manner described herein. This refers to the effective dose for a given subject, which depends on the type, size, and health status of the subject, and the condition of the treatment. Nature and severity, method of administration, duration of treatment, nature of concomitant therapy (if any), and specific treatments used. It depends on the specific formulation, etc. Therefore, it is impossible to determine the exact effective dose in advance. However, the effective amount for a given situation is based on the information provided herein and is used on a daily basis. This can be determined by those skilled in the art using experiments. The term "activation enhancement amount" refers to the amount of activity enhancement in cells or subjects. This refers to the amount of active substance sufficient to increase PPARα activity in that context.

[0029] The term "improve" refers to a detectable or measurable improvement in the condition or symptoms of the subject. To taste. Detectable or measurable improvement includes the occurrence, frequency, severity, progression or duration of the condition. A subjective or objective reduction, decrease, inhibition, suppression, limitation or control, or state between This includes improvement of symptoms, underlying causes, or consequences, or reversal of the condition. The results of the treatment will affect the occurrence, frequency, severity, progression or duration of the condition, or the outcome of the condition. To improve, reduce, decrease, inhibit, suppress, or limit the result. The “therapeutic effect” or “benefit” of doing, controlling, or preventing obtain.

[0030] The stabilization of the condition, or any reduction or mitigation of deterioration, is also a result of successful treatment. Therefore, the therapeutic benefit is the treatment of one of the conditions, or any one related to the condition, most of the treatments, or The complete elimination or reversal of all adverse symptoms, complications, consequences, or underlying causes. There is no need to do so. Therefore, a good endpoint is either short-term or long-term (e.g., seconds). Partial reduction or decrease in the occurrence, frequency, severity, progression, or duration of a condition (over a period of minutes, hours, or so). , inhibition, suppression, limitation, control, or prevention, or inhibition or reversal (e.g., stabilization) This can be achieved when there is a gradual increase such as the above.

[0031] As used herein, the terms alkyl, haloalkyl, alkoxyl, and haloalkoxy Unless otherwise specified, syr, alkenil and alkinil generally refer to 1, 2, 3, and 4. This is intended to refer to branched or unbranched structures containing 5, 6, 7, 8, 9, or 10 carbon atoms. Haloalkyls, for example, have 1 to 3 halogen atoms, 1, 2, 3, 4, 5 It may also refer to a haloalkyl group with 6, 7, 8, 9, or 10 carbon atoms. Haloalkoxyls are For example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or having 1 to 3 halogen atoms It may also refer to a 10-carbon haloalkyl group. Halogens include chlorine (Cl) and fluorine (F). , may also refer to bromine (Br) and / or iodine (I). Halogens are used herein as " It is sometimes abbreviated as "Haro".

[0032] In at least certain embodiments, this disclosure relates to eye disorders and conditions, particularly retinal conditions. and disorders, in certain non-limiting embodiments, retinal inflammation, retinal neovascularization, retinal Membrane vascular leakage, retinopathy of prematurity (ROP), diabetic retinopathy (DR), age-related macular degeneration (for example) (e.g., exudative AMD) and diabetic macular edema (DME) (or as otherwise described herein) Eye disorders and conditions, including other disorders or conditions listed, chemical structure I:

[0033] [ka] (In the formula, ring A is benzene or pyridine containing nitrogen (N) at the 2, 4, 5 or 6 positions and in the formula, ring B is benzene or pyridine containing N at the 2, 3, 5 or 6 positions, in the formula, ring C is benzene or pyridine containing N at the 2, 3, 4, 5 or 6 positions , in the formula, X is selected from the group consisting of oxygen (O), NH, sulfur (S) and CH2, in the formula, Y is selected from the group consisting of O, NH, S and CH2, in the formula, k is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, in the formula, in at least certain embodiments, the R of the "A" ring of chemical structure I , , 10 , , 8 , 10 , , 8 , 10 ,

[0035] , , , 11 , , 9 , , , 10 , 9 , , substituents are selected from the following chemical structures i to x shown in Table 1 below). It includes an active substance composition and method for treatment using a compound having

[0034]

Table 1

[0035] In a non-limiting embodiment, R of structure ix in Table 1 8 and R 9 are hydrogen (H), halogen (F, Cl, Br, I), alkyl (e.g., branched or unbranched, C1 - C 10 ), alk oxy (e.g., branched or unbranched, C1 - C 10 ), and cyclo (where R 8 is linked to R 9 ) and can be selected from the group. In structure ix of Table 1, X can be O, NH, S or CH2 . In a non-limiting embodiment, R of structure x in Table 1 10 and R 11 are H, alkyl (e.g., branched or unbranched, C1 - C 10 ​) and cyclo(R 10 R 11 to You can choose from the group of (connected) elements.

[0036] In other non-restrictive examples, R 1 carboxylic acids, and hydroxamic acids, hydroxamic acid Esters, phosphonic acid, phosphinic acid, sulfonic acid, sulfinic acid, sulfonamide, Silsulfonamide, sulfonylurea, acylurea, tetrazole, thiazolidinedione , oxazolidinedione, oxadiazole-5(4H)-one, thiadiazole-5( 4H)-one, oxathiadiazole-2-oxide, oxadiazole-5(4H)- Thione, isoxazole, tetramic acid, cyclopentane 1,3-dione, cyclopentane Tan-1,2-dione, squalate, substituted phenol, heteroarene, amidine, hydr Selected from the group of homologous carboxylic acids including roxiamide and alkylhydroxyamidine. The group may include the exemplary structures shown in Table 2, and may further contain any of the above salts. Born.

[0037] [Table 2] TIFF0007846159000004.tif232118TIFF0007846159000005.tif135118

[0038] In at least certain non-limiting embodiments, the R of chemical structure I 2 The substituents are H, F, Cl, Br, I, nitro(NO2), alkyl (e.g., CH3, CH2CH3, or Any branched or unbranched alkyl chain having 3 to 10 carbon atoms, alkoxy (for example) For example, OCH3, OCH2CH3, or any branch having 3 to 10 carbon atoms or Unbranched alkoxy (alkyoxy) chains, haloalkyl (e.g., CH2Cl, CHBr2, CF3), haloalkoxyls (e.g., OCH2Cl, OCHBr2, OCF3), for example If, then, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each having 1 to 3 halogen atoms. Carbon haloalkyls, for example, 1, 2, 3, 4, 5, having 1 to 3 halogen atoms. Haloalkoxyl, cycloalkyl, halocyclo Lukil, O-para-alkylbenzyl (for example, alkyl is methyl, ethyl or propyl) O-para-alkyloxybenzyl (for example, alkyl is methyl, ethyl) (or propyl) and O-para-halobenzylic (halo = Cl, F, Br or I) Selected from the group.

[0039] In at least certain non-limiting embodiments, the R of the ring "C" in chemical structure I 3 The substituent is H, F, Cl, Br, I, NO2, alkyl (e.g., CH3, CH2CH3, or Any branched or unbranched alkyl chain having 3 to 10 carbon atoms, alkoxy (for example) For example, OCH3, OCH2CH3, or any branch having 3 to 10 carbon atoms or (unbranched alkoxy chains), haloalkyl (e.g., CH2Cl, CHBr2, CF3), Roalkoxyl (e.g., OCH2Cl, OCHBr2, OCF3), e.g., 1 to 3 units A halogen containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms Alkyl, for example, 1, 2, 3, 4, 5, 6, 7, 8, having 1 to 3 halogen atoms. Haloalkoxyls, cycloalkyls and halocycloalkyls with 9 or 10 carbon atoms Selected from the group, the "C" ring is the R 3 Substituting with any combination of substituents, ortho, meta The "C" ring is arranged in any pattern including para, mono, di, tri, tetra and penta substitutions. The R is placed 3 It contains one, two, three, four, or five of the substituents.

[0040] In at least certain non-limiting embodiments, each R of chemical structure I 4 and R 5 substituent These are H, F, Cl, Br, I, NO2, alkyl (e.g., branched or unbranched, C1-C) 10 Select from the group consisting of ) and haloalkyl (e.g., CH2Cl, CHBr2, CF3). It is possible. 4 and R 5 It may also consist of oxygen atoms that are double-bonded together.

[0041] In at least one particular non-limiting embodiment, R 4 and R 5 They come together, 2~ A cycloalkyl group containing 10 carbon atoms, or a group containing 2 to 10 carbon atoms, one or It forms a halocycloalkyl group substituted with multiple halogen (Cl, F, Br, I) atoms. ru.

[0042] In at least one particular embodiment, R 4 and R 5 One of them is (as defined herein) When it is alkyl or cycloalkyl, R 4 and R 5 The other side is H.

[0043] In at least certain non-limiting embodiments, each R of chemical structure I 6 and R7 substituent These are H, F, Cl, Br, I, alkyl (e.g., branched or unbranched, C1-C) 10 )oh The group can be selected from the group of haloalkyls (e.g., CH2Cl, CHBr2, CF3). Yes, it's possible. 6 and R 7 It may also consist of oxygen atoms that are double-bonded together.

[0044] In at least one particular non-limiting embodiment, R 6 and R 7 They come together, 2~ A cycloalkyl group containing 10 carbon atoms, or a group containing 2 to 10 carbon atoms, one or It forms a halocycloalkyl group substituted with multiple halogen (Cl, F, Br, I) atoms. ru.

[0045] In at least one particular embodiment, R 6 and R 7 One of them is (as defined herein) When it is alkyl or cycloalkyl, R 6 and R 7 The other side is H.

[0046] As described, in certain embodiments, rings A and / or B of chemical structure I B / or C may be pyridine. In schemes 1-3 below, ring A is pyridine. Examples of structures that can be used to form the structure of the present disclosure, including and / or B. This shows a non-restrictive synthesis route:

[0047] Scheme 1:

[0048] [ka]

[0049] Schemes 2 and 3:

[0050] [ka]

[0051] In at least certain alternative embodiments, the present disclosure relates to eye disorders and conditions, particularly retinal disorders. Conditions and disorders, in certain non-limiting embodiments, include retinal inflammation and retinal neovascularization. , retinal vascular leak, retinopathy of prematurity (ROP), diabetic retinopathy (DR), age-related macular degeneration ( For example, exudative AMD) and diabetic macular edema (DME) (or elsewhere in this specification) Disorders and conditions including other disorders or conditions described in Chemical Structure II:

[0052] [ka] (In the formula, k is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. m is 0, 1, 2, 3, 4, or 5 carbon atoms. n is 0, 1, 2, 3, 4, or 5 carbon atoms. R 2 These are hydrogen (H), chlorine (Cl), fluorine (F), bromine (Br), iodine (I), and nitrate. TORO (NO2), CH3, CH2CH3, branched or unbranched groups containing 3 to 10 carbon atoms. Alkyl chains, OCH3, OCH2CH3, branched or unbranched containing 3 to 10 carbon atoms. Alkoxy chain, haloalkyl, haloalkoxyl, cycloalkyl, halocycloalkyl , O-para-alkylbenzyl, O-para-alkyloxybenzyl and O-para- Selected from the lobenzyl group, R 2 The benzene ring containing the R 2 Any combination of substituents Substituted by, ring in any pattern including ortho, meta, mono, di, tri and tetra substitutions The R is located at 2 Containing one, two, three, or four of the substituents, R 3 It consists of H, Cl, F, Br, I, NO2, CH3, CH2CH3, and 3 to 10 carbon atoms. Branched or unbranched alkyl chains containing atoms, OCH3, OCH2CH3, 3 to 10 carbon atoms Branched or unbranched alkoxy chains containing atoms, haloalkyls, haloalkoxyls, cyclo Lukil, halocycloalkyl, O-para-alkylbenzyl, O-para-alkyloxy Selected from the benzyl and O-para-halobenzyl groups, R 3 The benzene ring containing the preceding Record R 3 Substituting with any combination of substituents, ortho, meta, para, mono, di, tri, tetra and the R arranged in the ring in any pattern including penta substitution 3 1 and 2 of the substituents , including 3, 4 or 5, R 4 is selected from H, alkyl and acyl, R 5 It consists of H, Cl, F, Br, I, NO2, CH3, CH2CH3, and 3 to 10 carbon atoms. Branched or unbranched alkyl chains containing atoms, OCH3, OCH2CH3, 3 to 10 carbon atoms Branched or unbranched alkoxy chains containing atoms, haloalkyls, haloalkoxyls, cyclo Lukil, halocycloalkyl, O-para-alkylbenzyl, O-para-alkyloxy Selected from the benzyl and O-para-halobenzyl groups, R 5 The benzene ring containing the preceding Record R 5 Substituting with any combination of substituents, ortho, meta, para, mono, di, tri and tetra The R arranged in the ring in any pattern including traguing substitution 5Among the substituents 1, 2, and 3 It includes four, R 1 These include carboxylic acids, carboxylic acid isoconformities, hydroxamic acids, and hydroxamic acid esters. phosphonic acid, phosphinic acid, sulfonic acid, sulfinic acid, sulfonamide, acyl sulfonic acid Honamide, sulfonylurea, acylurea, tetrazole, thiazolidinedione, oxa Zolidinedione, oxadiazole-5(4H)-one, thiadiazole-5(4H)- On, oxathiadiazole-2-oxide, oxadiazole-5(4H)-thione, Isooxazole, tetramic acid, cyclopentane 1,3-dione, cyclopentane 1, 2-dione, squalate, substituted phenol, heteroarene, amidine, hydroxya Mido, alkylhydroxyamidine, and

[0053] [ka] Furthermore, selected from the group consisting of these salts, R 8 and R 9 These are H, F, Cl, Br, I, alkyl, alkoxy and R 8 R 9 Independently selected from the group consisting of cycloalkyl groups linked to, R 10 and R 11 H, alkyl and R 10 R 11 Cycloalkyl linked to Independently selected from the group consisting of, X is O, NH, S, or CH2. The present invention includes active substance compositions and methods for treatment using compounds having [specific properties].

[0054] More specifically, in certain non-limiting embodiments of this disclosure, a chemical having chemical structure II Examples of compound compounds (compounds 9-14, 21-24, 26, and 28) are shown below:

[0055] [ka] TIFF0007846159000011.tif23267TIFF0007846159000012.tif21564TIFF0007846159000013.tif20069TIFF0007846159000014.tif23663

[0056] Compounds 9-14, 21-24, 26 and 28 are described herein (for example, in Tables 4 and 5). (And) 117, 91, 120, 122, 118, 119, 116, 114, 12 They are also numbered 3, 121, 92, and 115. Compounds ASD152, ASD160 ASD178, ASD179, ASD181, ASD200, ASD203 and AS D207 is specified in this specification as 152, 160, 178, 179, 181, 200, 2 Also known as 03 and 207.

[0057] In certain embodiments, the compound (except for the methods described herein) has the following structure:

[0058] [ka] Chemical structure II (wherein (1)R 1 =COOH, R 2 ~R 5 =H, and (2)R 1 =COOH, R 3 =CH3, R 2 , R 4 and R 5 Exclude compounds that have (=H). It may happen.

[0059] Certain non-limiting embodiments of this disclosure involve at least one pharmaceutically acceptable carrier. It is a PPARα agonist and has anti-inflammatory and anti-hemorrhagic effects in the eye, especially the retina and macula. This includes one or more compounds described herein that have tube-forming activity. This includes pharmaceutical compositions. Specific, non-limiting, pharmaceutical (therapeutic) compositions formulated in accordance with this disclosure. An example is (a): a PPARα agonist in at least one pharmaceutically acceptable polymer. A pharmaceutical composition comprising a carrier, and (b) at least one other therapeutic activity A substance, and combined with at least one pharmaceutically acceptable carrier such as a polymer. Contains PPARα agonists.

[0060] As described above, the active substances of this disclosure include, for example, DR and AMD (e.g., exudative AM). D), retinal inflammation, retinal neovascularization (NV), retinal vascular leakage, retinopathy of prematurity (ROP), and This includes conditions such as diabetic macular edema (DME), which are associated with retinal endothelial dysfunction, angiogenesis, and inflammation. It can be used to treat diseases and conditions.

[0061] The active substance of this disclosure is used in any concentration that allows the pharmaceutical composition to function in accordance with this disclosure. It may be present in 0.0001%, 0. 0.05%, 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.2% 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0% 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8% , a lower limit level selected from 1.9% and 2.0%; as well as 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18% 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60% The upper limit can be selected from 65%, 70%, 75%, 80%, 85%, 90%, and 95%. It may exist within the range of having a bell. A non-restrictive example of a specific range is approximately 0.0001%~ A range of approximately 95%, a range of approximately 0.001% to 75%, a range of approximately 0.005% to 50%; Ranges of approximately 0.01% to 40%; ranges of approximately 0.05% to 35%; ranges of approximately 0.1% to 30% range; range of approximately 0.1% to approximately 25%; range of approximately 0.1% to approximately 20%; range of approximately 1% to approximately 15% The range includes approximately 2% to 12%, approximately 5% to 10%, etc. The lower limit concentration selected from the lower limit concentrations and the upper limit concentrations listed above. Any other range, including upper limits selected from the above, is also within the scope of this disclosure.

[0062] Suitable carriers, vehicles, excipients, diluents, and other components that may be included in the formulation are, for example, Remington: The Science and Practice of Pharmacy, 21 st Ed. and 22 nd It is written in Ed. The term "pharmaceutically acceptable" means that the carrier does not interfere with the effectiveness of the biological activity of the active substance. This means it is a non-toxic material. The characteristics of the carrier are not limited to this, but the route of administration It depends on various factors, including those mentioned.

[0063] For example, though not limited to, active substances are physiologically acceptable drug carriers, bile ducts, etc. It may be dissolved in a crust, excipient, or diluent, and administered as either a solution or a suspension. This may be done. Non-limiting examples of suitable pharmaceutically acceptable carriers include water and physiological saline. , dextrose solution, fructose solution, ethanol or animal, plant or synthetic ethanol Source oils, or any combination thereof, are examples. Generally, approximating physiological conditions is... It may contain materials that are recognized and / or required by government regulations. The bacterial diluent can be used as a pharmaceutically acceptable carrier. In this regard, sterile diluents The solvent contains sodium chloride, physiological saline, and phosphoric acid to obtain a physiologically acceptable pH. Buffered saline and / or other physiologically acceptable and / or safe to use It may contain buffering agents such as (but not limited to) the following substances.

[0064] The pharmaceutical composition also includes an active substance and a pharmaceutically acceptable carrier (and, if present) In addition to other additional therapeutic active substances, it may contain one or more additional components. Examples of additional components that may be present include, but are not limited to, diluents, fillers, salts, and loosening agents. Examples include saturating agents, preservatives, stabilizers, solvents, and other materials well known in the art. Other specific, non-limiting examples of additional components that may be present in the product are described below in this specification. This is a delivery agent that will be examined in more detail.

[0065] Other embodiments of the pharmaceutical compositions disclosed herein involve the targeted delivery and controlled release of an active substance. and / or various types of drug delivery systems that function to result in an increased half-life This may include incorporating or encapsulating active substances. For example, but is not limited to active substances. The quality is prepared by coacervation technology or by interfacial polymerization. Capsules (for example, hydroxymethylcellulose or gelatin microcapsules, respectively) It can be encapsulated in poly(methyl methacrylate) microcapsules. , the active substance in a macroemulsion or colloidal drug delivery system (for example, these Not limited to liposomes, albumin microspheres, microemulsions, They can be encapsulated in particles, nanocapsules, etc. Such techniques are well known to those skilled in the art. Yes, and therefore no further explanation is considered necessary.

[0066] In one specific, non-limiting example, a pharmaceutical composition is a liposomal composition in which an active substance is incorporated. Liposomes may also be included. In addition to other pharmaceutically acceptable carriers, liposomes may be present in aqueous solutions. Lipids, etc., which exist in aggregated forms as cells, insoluble monolayers, liquid crystals, or lamellar layers, are parenthetical It may contain a medium. Suitable lipids for liposome formulations are not limited to these. However, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponins Examples include bile acids and combinations thereof. The preparation of such liposomal formulations is, for example, For example, the entire contents of each are incorporated herein by reference, U.S. Patent No. 4,235, U.S. Patent No. 871, U.S. Patent No. 4,501,728, U.S. Patent No. 4,837,028 and U.S. As disclosed in Japanese Patent No. 4,737,323, it is well within the scope of the level of skill of those skilled in the art. .

[0067] In other non-limiting examples, the active substance of this disclosure is present in particles of one or more polymer materials. It may be incorporated, as this type of incorporation allows for controlled release from the preparation. This is useful for controlling the duration of action of active substances and therefore increasing their half-life. This is because such cases exist. A non-limiting example of a polymer material that may be used in this way is... Polyester, polyamide, polyamino acid, hydrogel, poly(lactic acid-glycol) Poly(lactic acid), ethylene vinyl acetate copolymer, for example, PEG and poly(l-asphalt), Examples include micelles of palmamide copolymers and combinations thereof.

[0068] In certain non-limiting embodiments, a pharmaceutical composition containing an active substance is applied to the eye of a target. The ophthalmic composition may be in the form used herein. "Product" refers to any composition specifically formulated for direct topical administration to a patient's eye. It is understood that the composition is to be administered topically to the eye or injected into the eye. It may be formulated for intravitreal or intraocular injection. The ophthalmic composition may be administered to the eye. Any formulation that can be administered locally and in which the active substance can function in accordance with this disclosure May be provided. For example, but not limited to, ophthalmic compositions include solutions, intravenous drugs, Mists / sprays, plasters and pressure-sensitive adhesives, ointments, lotions, creams, gels, and freezers. It may be provided in forms such as dry / spray-dried form. In one particular non-limiting embodiment Ophthalmic compositions, however, may be provided in forms for topical application, such as eye drops. The ophthalmic compositions of this disclosure are provided with specific active substances used, and a desired drug release profile. This may vary depending on the file, the condition being treated and / or the patient's medical history. The ophthalmic compositions disclosed herein are formulated using formulation techniques well known in the art, as described elsewhere in this specification. Designed to provide delayed, controlled, sustained release and / or continuous release, as described in [reference]. It's okay.

[0069] Pharmaceutical compositions described herein, or otherwise intended, deliver an active substance to a desired location. It may further include at least one delivery agent to assist in delivery to the target site, for example, While not limited to these, at least one delivery agent is necessary to aid in penetration into the surface of the eye. It may be included in ophthalmic compositions. In certain embodiments, the delivery agent is delivered to the retina of the eye. It can assist in the process. For example, to enable local application, the composition can be a desired combination. Sometimes it is necessary for it to be able to penetrate the surface of the weave so that it can move into the weave. This may include penetration into the conjunctiva and / or cornea.

[0070] When an ophthalmic composition containing an active substance is formulated for administration by injection, The composition may be in the form of an aqueous solution or suspension free of pyrogens. pH, isotonic, stable. The preparation of such a solution, taking into full consideration its properties and other factors, is well within the scope of the skills of those skilled in the art. Suitable carriers are, but are not limited to, isotonic, biocompatible, and pharmaceutically appropriate. Examples of acceptable phosphate-buffered saline solutions include, but are not limited to, The specified ophthalmic composition, in addition to the therapeutic compound, contains sodium chloride injection, Ringer's injection, and Dextrose injection, dextrose and sodium chloride injection, lactated Ringer's injection It may contain an isotonic vehicle such as a liquid or other vehicle known in the art. Generally, materials for intravenous injection into humans are available to those skilled in the art and approved by the U.S. Food and Drug Administration. You should follow the rules established by [the organization / organization].

[0071] In addition to the ophthalmic compositions discussed in detail hereinabove, the therapeutic compositions of the present disclosure are formulated for administration by any other method known in the art or contemplated otherwise, provided that the route of administration enables delivery of the active agent such that the compound can function according to the present disclosure, i.e., as a PPARα agonist. Examples of other routes of administration include, but are not limited to, oral, topical, retrobulbar, subconjunctival, transdermal, parenteral, subcutaneous, intranasal, intramuscular, intraperitoneal, intravitreal, and intravenous routes, including both topical and systemic routes of application.

[0072] Another non-limiting embodiment of the present disclosure relates to a kit containing one or more of any of the pharmaceutical compositions described herein or contemplated otherwise. The kit may further contain the second agent described hereinabove for use in combination with the pharmaceutical composition. If the compositions present in the kit are not provided in a form ready for delivery, the kit may further contain a pharmaceutically (ophthalmically) acceptable carrier, vehicle, diluent, excipient, or other agent to be mixed with the active agent for the preparation of the pharmaceutical composition. Kits containing the composition and / or other reagents may also be packaged together with instructions for packaging for administration and / or dosing of the compositions contained in the kit. The instructions may be prepared as instructions referring to any tangible expression medium such as printed paper, or a computer-readable magnetic or optical medium, or a remote computer data source such as a World Wide Web page accessible via the Internet.

[0073] ​​​​​​​​​​​The kit may contain a single or multiple doses of a pharmaceutical composition. Where multiple doses are present, the doses may be bulk formulated in a single container, or the multiple doses may be individually formulated in the kit. That is, the pharmaceutical composition may be present in the kit in unit dosage form to facilitate accurate dosing. As used herein, the term "unit dosage form" refers to physically discrete units suitable as unit dosages for human subjects and other mammals, each unit containing a predetermined quantity of an active material calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient. Examples of unit dosage forms of typical liquid compositions include pre-filled, pre-measured ampoules or syringes, and for solid compositions, typical unit dosage forms include pills, tablets, capsules, etc. In such compositions, the active substance is a minor component (from about 0.1 to about 50% by weight, such as, but not limited to, from about 1 to about 40% by weight), and the remainder is various vehicles or carriers and processing aids useful for forming the desired dosage form. As is apparent from the above, the active substance of the present disclosure functions as a PPARα agonist for treating, inhibiting, alleviating and / or preventing degenerative retinal disorders. Accordingly, certain non-limiting embodiments of the present disclosure include methods of treating, inhibiting and / or reducing the occurrence of retinal degeneration due to retinal inflammation and angiogenesis. One particular, but non-limiting, embodiment includes methods of treating, inhibiting and / or reducing the occurrence of one or more eye pathologies associated with reduced PPARα activity in a subject. The method involves administering to the subject a therapeutically effective amount of an active substance or pharmaceutical composition as described herein or otherwise contemplated. As is apparent from the above, the active substance of the present disclosure functions as a PPARα agonist for treating, inhibiting, alleviating and / or preventing degenerative retinal disorders As used herein, the term "unit dosage form" refers to physically discrete units suitable as unit dosages for human subjects and other mammals each unit containing a predetermined quantity of an active material calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient Examples of unit dosage forms of typical liquid compositions include pre-filled, pre-measured ampoules or syringes, and for solid compositions, typical unit dosage forms include pills, tablets, capsules, etc. In such compositions, the active substance is a minor component (from about 0.1 to about 50% by weight, such as, but not limited to, from about 1 to about 40% by weight), and the remainder is various vehicles or carriers and processing aids useful for forming the desired dosage form. As is apparent from the above, the active substance of the present disclosure functions as a PPARα agonist for treating, inhibiting, alleviating and / or preventing degenerative retinal disorders As is apparent from the above, the active substance of the present disclosure functions as a PPARα agonist for treating, inhibiting, alleviating and / or preventing degenerative retinal disorders As is apparent from the above, the active substance of the present disclosure functions as a PPARα agonist for treating, inhibiting, alleviating and / or preventing degenerative retinal disorders As is apparent from the above, the active substance of the present disclosure functions as a PPARα agonist for treating, inhibiting, alleviating and / or preventing degenerative retinal disorders As is apparent from the above, the active substance of the present disclosure functions as a PPARα agonist for treating, inhibiting, alleviating and / or preventing degenerative retinal disorders

[0074] As is apparent from the above, the active substance of the present disclosure functions as a PPARα agonist for treating, inhibiting, alleviating and / or preventing degenerative retinal disorders As is apparent from the above, the active substance of the present disclosure functions as a PPARα agonist for treating, inhibiting, alleviating and / or preventing degenerative retinal disorders As is apparent from the above, the active substance of the present disclosure functions as a PPARα agonist for treating, inhibiting, alleviating and / or preventing degenerative retinal disorders As is apparent from the above, the active substance of the present disclosure functions as a PPARα agonist for treating, inhibiting, alleviating and / or preventing degenerative retinal disorders As is apparent from the above, the active substance of the present disclosure functions as a PPARα agonist for treating, inhibiting, alleviating and / or preventing degenerative retinal disorders As is apparent from the above, the active substance of the present disclosure functions as a PPARα agonist for treating, inhibiting, alleviating and / or preventing degenerative retinal disorders As is apparent from the above, the active substance of the present disclosure functions as a PPARα agonist for treating, inhibiting, alleviating and / or preventing degenerative retinal disorders Multiple individuals have experienced retinal or macular degeneration, or have retinal or macular degeneration, Subjects prone to developing other eye conditions or disorders (e.g., but not limited to, suckling animals) The active substance or pharmaceutical composition is administered to the retina of at least one eye of the subject. It is administered to the target in an effective amount that exhibits PPARα agonist activity.

[0075] The eye condition may be any of the conditions described herein, and the eye condition may be the retina and / or macular degeneration may be characterized. In one embodiment, the pharmaceutical composition is localized to the eye of the target. It may be administered in a manner (for example, but not limited to, as eye drops). In an alternative embodiment... The pharmaceutical composition may be administered by injection into the eye or systemically.

[0076] The amount of active substance effective for the treatment described herein is determined using prior art in similar circumstances. The results obtained may be determined by a physician skilled in the art. For example, in one non-limiting embodiment of the procedure, these are used to determine the therapeutically effective dose. However, this does not limit the species, size, age and general health status of the subject, the specific disease involved and The condition, the degree of the disease and / or condition, the lesion and / or severity, individual Elephant response, specific active substances or other therapeutic compounds administered, mode of administration, preparation of administration. The bioavailability characteristics of the substance, the selected dosage regimen, the use of concomitant medications, and other factors. Numerous factors, including related circumstances, may be considered by the diagnosing physician. Pharmaceutical composition of the present disclosure The therapeutically effective dose also controls and / or reduces or improves the disease and / or condition. This refers to the amount of active substance that is effective in achieving a certain goal.

[0077] For example, without limitation, the active substances used in the present disclosure at a therapeutically effective amount are generally contain an active ingredient sufficient to be delivered in the range of about 0.01 μg / kg to about 10 mg / kg (weight of the active ingredient / weight of the patient). For example, without limitation, the composition contains an active ingredient sufficient to be delivered in the range of about 0.1 μg / kg to about 5 mg / kg, more particularly about 1 μg / kg to about 1 mg / kg is delivered.

[0078] The implementation of the method of the present disclosure involves administering to a subject, in any suitable systemic and / or topical formulation, an amount effective to deliver the dosages listed above of a pharmaceutical composition (containing an active substance). The dosage may be administered, for example, without limitation, once or multiple times (e.g., without limitation, once to five times a day or once or twice a week). The pharmaceutical composition may be administered alone or in combination with other therapeutic agents in accordance with the concepts of the invention disclosed herein.

[0079] Certain specific novel embodiments of the present disclosure generally described so far are included for the purpose of merely exemplifying certain aspects and embodiments of the present disclosure and are not intended to be limiting. They will be more readily understood by referring to the following examples. The following detailed examples should be construed as merely illustrative as described above and should not be construed as limiting the present disclosure in any way. Those skilled in the art will immediately recognize appropriate modifications from various compositions, structures, components, procedures, and methods.

Examples

[0081] [ka]

[0082] A series of derivatives with some structural similarities to Y-0452 were subjected to PPARα agonism. We evaluated the following: Compounds 9-14 and 21-24 were placed in the hydrophobic binding pocket of PPARα. It was designed to satisfy the requirements more efficiently.

[0083] Derivatives 9-14 were synthesized as shown in Scheme 4. Commercially available 4-hydroxybenz Aldehydes are coupled with various benzyl bromides 3-8 to produce benzaldehyde 3a-8. a was obtained. 3a to 8a were treated with 3-aminobenzoic acid to obtain their respective imines in sit. It is produced with u, and then reduced by the addition of sodium triacetoxyborohydride. 9-14 were obtained with unoptimized yields of 40-82%.

[0084] [ka]

[0085] With the aim of improving efficacy and establishing selectivity for PPARα compared to other isoforms. In addition to benzoic acid derivatives 9-14, it is necessary to incorporate the classic "head" of fenofibrate. There was a need for this. The preparation of these analogs is shown in Scheme 5. Commercially available 3-nitrophenol It was coupled with ethyl α-bromoisobutyrate to obtain 15, which was then subjected to catalytic hydrogenation conditions (H2 It was reduced to the corresponding aniline (16) under Pd / C in ethanol. 16 was reduced to 3a, 4 Treat with a, 6a, or 8a, followed by reduction with sodium triacetoxyborohydride. By doing so, values ​​of 17-20 were obtained. The pendant ester was hydrolyzed and optimized. Desired products 21-24 were obtained in yields of 46-88%.

[0086] [ka]

[0087] Once we have a concentrated subset of analogs, we can use these derivatives in PPARα-agon We then moved on to an attempt to evaluate the 'nism'. In the preliminary evaluation, commercially available PPARα luciferase... A cell reporter assay (Indigo Biosciences) was used. Cell lines were manipulated to constitutively express high levels of hPPARα. In interaction, hPPARα translocates to the nucleus, binds to PPRE, and intercepts the inserted lucifera. It upregulates the transcription of genes including the luciferase gene. It is detected indirectly by quantifying the production of . First, 9-14 and 21-24 The agonism level was evaluated at 5 μM and 50 μM concentrations, and the agonism level was determined at two 10-fold increments. As shown in Figure 1, at one or both of the evaluated concentrations, numerous compounds were positive. Levels equivalent to or exceeding those of the sex control GW590735 (5 μM and 10 μM) It showed hPPARα agonism. 9 / 21, 10 / 22, 12 / 23, 14 / 24 A direct comparison, when incorporating the "head" of fenofibrate, shows that PPARα at 50 μM This indicates that the level of gonism is amplified. However, this data also shows that 21-24 is 5 While none of the benzoic acid analogs 9-14 induce activity recognizable at μM concentrations, all of them do not induce activity at low concentrations. Since it shows a significant PPARα agonism at a certain degree, the "head" of fenofibrate is incorporated. This indicates that the potency decreases when mixed. Compounds 10 and 22 were selected for further detailed evaluation. Select and perform a more comprehensive 10-point dose-response evaluation for EC 50 Value obtained (Table 3): 10 (5.6 (μM) and 22 (25.3 μM).

[0088] This 4-benzyloxy-benzylamino chemical species acts as a PPARα agonist. To further confirm this, compound 10 was evaluated using various biochemical assays. PPA As expected for Rα agonists, it is derived from the C57BL / 6N mouse photoreceptor (661W). As demonstrated by Western blot analysis using the cell line, 10 is dose-dependent. PPARα expression was conservatively induced (Figures 2A and 2B). Similarly, in the same cell line RT-PCR testing revealed that treatment at 10 resulted in the removal of medium-chain acyl-CoA dehydrogenase (Ac adm), carnitine palmitoyltransferase 1A (Cpt1a), fatty acid binding Protein 3 (Fabp3) and solute transporter family 25 member 20 (Slc25) Since the expression of various PPARα target genes, including a20), is induced, PPARα Agonism is confirmed (Figure 2C). Furthermore, compound 10 is used in human retinal capillary endothelial cells ( Evaluation was performed using an in vitro wound healing assay utilizing HRCEC. PPARα jaw Nism reduces cell migration, 12 ,10 actually inhibits wound closure in a dose-dependent manner. (Figure 2D).

[0089] 4-benzyloxy-benzylamino derivatives exhibit characteristic PPARα in multiple biochemical settings. Based on evidence that it showed agonist activity, 10 PPARδ and PPARγ were used. The selectivity for PPARα agonism was evaluated. Essential luciferase reporter Luciferase assays in which gene expression depends on the exogenous activation of each isoform, P For syngeneic cell lines that have been engineered to overexpress either PARδ or PPARγ The experiment was conducted. As shown in Table 3, compound 10 was compared to hPPARδ and hPPARγ. While 22 shows selectivity of ≥20 times for hPPARα, 22 exhibits panagonism. The "head" of the fibrate was explained as an important feature of PPARα's selectivity. However, this 4-benzyloxy-benzylamino chemical species appears to be harmful. That's interesting.

[0090] [Table 3]

[0091] Better 4-benzyloxy-benzylamino derivatives in the hPPARα binding pocket To visualize this, the GW590735·hPPARα cocrystal structure PDB2P54 Docking was evaluated using [this method]. GW590735 uses PPARγ and PPARδ and In comparison, it is a selective PPARα agonist that exhibits ≥500 times selectivity for PPARα. Without wishing to be bound by it, compound 10 is G as shown in Figures 3A and 3B. It is predicted that it will bond with an orientation similar to that of W590735. However, interestingly, 1 0 is a key enhancer of selectivity and potency in GW590735. The gem-dimethyl "head" and amide linker domain, which were assumed to be determinants, are missing. However, the 10 acids are Ser280, Tyr314, His440 and Tyr46 It is predicted that 4 hydrogen bonds will form, which will lead to the decomposition of the quinoline core of Y-0452. (Deconstruction) and carboxylic acid rearrangement result in a significant improvement in PPARα agonism. This aligns with the concept of 4-benzyloxy-benzylamination. The species are located below GW590735 (Figure 3A), Met330, Tyr334, Gl u282, Thr279, Met320, Val324, Leu321, Ile317 It can be extended to utilize an apparent amphiphilic pocket consisting of Met220. This piqued my interest. These researchers functionalized the meta position of the ether bond in the B ring of 10 rings. By doing so (Schemes 5 and 6), the optimal path to approach this amphiphilic pocket is obtained. We assumed that this was possible. To the best of our knowledge, PPARα agonists utilize this pocket. The number of domains is small, and this domain is small in terms of agonism and / or isoform selectivity. The SAR (Service Area Rating) that exists for the effect of occupying space is minimal.

[0092] To investigate the potential effects of occupying the amphiphilic pocket, two further invitations Conductors 26 and 28 were synthesized (Scheme 6). Briefly, commercially available 2,4-dihydroxy Benzaldehyde is converted to 4-methoxybenzaldehyde in acetone in the presence of potassium carbonate. The material was processed to produce di-p-methoxybenzyl (PMB) functionalized resorcinol 25. The intermediate is coupled to either 3-aminobenzoic acid or 16 to produce the imine. By reducing these, analog 26 and methyl ester 27 were obtained, The desired derivative 28 was obtained in 75% yield. The 4-methoxybenzyl motif was replaced with a "third Incorporating it as an "arm" is somewhat arbitrary at this point, and 4-methoxybenzylmo The chief stated that 1) it is compatible with the predicted binding environment, and 2) the chemicals already used by these researchers Based on the idea that it can be easily synthesized by dialkylation of aldehydes found in Bentley I selected it.

[0093] [ka] Derivatives 26 and 28 were used to test the hPPARα agonist activity in luciferase cell lines. The selectivity was also evaluated. Data analysis revealed that the benzoic acid derivatives (comparing 10 and 26) Regarding the comparison, the additional 4-methoxybenzyl substituent was at least within the range of the evaluated doses. It is suggested that it does not affect efficacy and maintains selectivity. However, the fibrate's In derivatives containing the "head" (comparing 22 and 28), adding a third substituent to the B ring has an effect. While the force increased tenfold, the panagonist profile was maintained. 26 and 28 are These were all docked using models pre-generated by the researchers, as shown in Figure 3C. To enable this, the additional 4-methoxybenzyl group actually enters the amphiphilic pocket. This is predicted.

[0094] Various non-limiting embodiments of the compounds disclosed herein and their cellular luciferase activity These are shown in Tables 4-7. Chemical structure IIa (Tables 4 and 5) is a version of chemical structure II. k=0. Chemical structure IIb (Tables 6 and 7) is the version of chemical structure IIa. R 1 The element is located at the para position of ring A.

[0095] [ka]

[0096] [Table 4] TIFF0007846159000023.tif99169

[0097] [Table 5] TIFF0007846159000025.tif118170

[0098] [ka]

[0099] [Table 6]

[0100] [Table 7]

[0101] The data in Tables 4-7 shows that this chemical species is active in a whole-cell setting and is the desired target PPA. This demonstrates association with Rα. Furthermore, the results show a clear structure-activity relationship and adjustable level. The agonism of this species, and its selectivity for PPARα compared to other isoforms of this chemical species. The profile is demonstrated. The results shown in Figures 4-6 show that compound 91(10) is based on cells. It exhibits dose-dependent activity and shows >20 times higher selectivity compared to other isoforms. This demonstrates that compound 190, based on cell-based activity, is effective when administered by dose. The results shown in Figures 7-9 are as follows: It demonstrated dependent activity and showed >2000 times higher selectivity compared to other isoforms. This improves the potency of this chemical species while simultaneously enhancing or maintaining its selectivity. This will be proven.

[0102] The data in Figures 10A and 10B are as reported in the FIELD and ACCORD trials. Furthermore, pharmacological activation of PPARα in humans contributes to a reduction in the prevalence of diabetic retinopathy. This demonstrates that it has clinical benefits. In Figures 10A and 10B, the researchers showed that compound 91 This was observed in vivo in the well-established STZ-rat model of diabetic retinopathy (DR). This demonstrates the effectiveness of compound 91. As shown in Figures 10A and 10B, compound 91 In diabetic rats, diabetic macular edema and the resulting blindness are the main causes. It reduces certain retinal vascular leakage. Interestingly, compound 91 gives dose-limiting toxicity. It appears that there are no signs of hepatomegaly, a common side effect of fenofibrate in some cases. These initial results indicate that compound 91 is (1) related to the DR model after systemic administration. (2) demonstrate efficacy in vivo, (3) cross the blood-eye barrier and reach the retina, (4) Bioavailable and sufficient to maintain efficacy, first pass and (5) It tolerates the clearance mechanism and has a relatively safe profile after daily injections for one month. This provides a proof of concept demonstrating that there is no observable toxicity.

[0103] These tests include, but are not limited to, retinal inflammation, retinal neovascularization, and retinal vascular leakage. Retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration, and diabetic macular edema, as well as this specification Other eye and non-eye diseases and / or conditions described in the book, including eye disorders and conditions. This demonstrates the therapeutic use of ophthalmic compositions containing this novel class of compounds for placement.

[0104] This disclosure has been described herein with certain embodiments so that its aspects may be understood and recognized in more detail, but this disclosure is not limited to these specific embodiments. Rather, all alternative forms, modifications and equivalents are intended to be included within the scope of this disclosure as defined herein. Accordingly, the above examples, including specific embodiments, serve to illustrate the implementation of the concepts of the invention as described herein, and the details shown are illustrative and intended solely for illustrative purposes of specific embodiments, and furthermore, are presented to provide what is deemed to be the most useful and easily understandable description of the procedures and the principles and conceptual aspects of this disclosure. Without departing from the spirit and scope of this disclosure, changes may be made to the formulation of the various compositions described herein, the methods described herein, or the steps or order of steps of the methods described herein. Furthermore, various embodiments of this disclosure are described in the following claims, but this disclosure is not limited to these specific claims. Furthermore, the present invention shall encompass the following embodiments. [1] Chemical structure II: [ka] (In the formula, k is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. m is 1, 2, 3, 4, 5 or 0 carbon atoms. n is 1, 2, 3, 4, 5 or 0 carbon atoms. R 2 is hydrogen (H), CH 3 O-para-alkoxybenzyl, chlorine (Cl), fluorine (F), bromine (Br), iodine (I), nitro (NO)2 ), CH 2 CH 3 , branched or unbranched alkyl chains containing 3 to 10 carbon atoms, OCH 3 OCH 2 CH 3 Selected from the group consisting of branched or unbranched alkoxy chains containing 3 to 10 carbon atoms, haloalkyl, haloalkoxyl, cycloalkyl, halocycloalkyl, O-para-alkylbenzyl and O-para-halobenzyl, R 2 The benzene ring containing the R 2 The R is substituted with any combination of substituents and arranged in the ring in any pattern including ortho, meta, mono, di, tri, and tetra substitutions. 2 Containing one, two, three, or four of the substituents, R 3 OCH 3 F, Cl, Br, I, NO 2 , H, CH 3 CH 2 CH 3 , branched or unbranched alkyl chains containing 3 to 10 carbon atoms, OCH 2 CH 3 Selected from the group consisting of branched or unbranched alkoxy chains containing 3 to 10 carbon atoms, haloalkyl, haloalkoxyl, cycloalkyl, halocycloalkyl, O-para-alkylbenzyl, O-para-alkyloxybenzyl, and O-para-halobenzyl, R 3 The benzene ring containing the R 3 The R is substituted with any combination of substituents and arranged in the ring in any pattern including ortho, meta, para, mono, di, tri, tetra, and penta substitutions. 3 Containing 1, 2, 3, 4, or 5 of the substituents, R 4 It is selected from the group consisting of H, alkyl, and acyl. R 5 These are H, Cl, F, Br, I, NO 2 CH 3 CH 2 CH 3 , branched or unbranched alkyl chains containing 3 to 10 carbon atoms, OCH 3 OCH 2 CH 3 Selected from the group consisting of branched or unbranched alkoxy chains containing 3 to 10 carbon atoms, haloalkyl, haloalkoxyl, cycloalkyl, halocycloalkyl, O-para-alkylbenzyl, O-para-alkyloxybenzyl, and O-para-halobenzyl, R 5 The benzene ring containing the R 5 The R is substituted with any combination of substituents and arranged in the ring in any pattern including ortho, meta, para, mono, di, tri, and tetra substitutions. 5 Containing one, two, three, or four of the substituents, R 1 COOH, carboxylic acids, carboxylic acid isoconjugates, hydroxamic acid, hydroxamic acid esters, phosphonic acid, phosphinic acid, sulfonic acid, sulfinic acid, sulfonamide, acylsulfonamide, sulfonylurea, acylurea, tetrazole, thiazolidinedione, oxazolidinedione, oxadiazole-5(4H)-one, thiadiazole-5(4H)-one, oxathiadiazole-2-oxide, oxadiazole-5(4H)-thione, isoxazole, tetramic acid, cyclopentane 1,3-dione, cyclopentane 1,2-dione, squalate, substituted phenol, heteroarene, amidine, hydroxyamide, alkylhydroxyamidine, and

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[10] The method according to [7], wherein the disorder is selected from inflammatory bowel disease, type 1 diabetes, type 2 diabetes, Graves' disease, multiple sclerosis, osteoarthritis, rheumatoid arthritis, vasculitis, dermatitis, glomerulonephritis, hepatitis, periodontitis, atherosclerosis, heart failure, obesity, Alzheimer's disease, and metabolic syndrome.

[11] The method according to [7], wherein the disorder or condition is an ocular disorder or condition selected from keratitis, endophthalmitis, blepharitis, conjunctivitis, scleritis, herpetic inflammation, uveitis, vasculitis, arteritis, orbital inflammation, optic neuritis, sympathetic ophthalmitis, retinitis, macular edema, glaucoma, proliferative vitreoretinopathy, corneal edema, uveal edema, and retinal edema.

[12] The method according to [7], wherein the disorder or condition is selected from retinal artery or vein occlusion, corneal transplant rejection, corneal neovascularization, neovascular glaucoma, sickle cell retinopathy, cancer, skin disease, diabetic ulcer, diabetic nephropathy, cardiovascular disease and seizure.

[13] The method according to [7], wherein the compound is provided in a composition formulated to result in delayed release, controlled release, sustained release and / or prolonged release of the compound.

Claims

1. Chemical structure II: 【Chemistry 1】 A compound represented by, (a) k is 0, m is 1, n is 1, R １ COOH is R ２ ga 2-CH ３ And R ３ 4-F, R ４ H is R ５ Compounds in which H is present; (b) k is 0, m is 1, n is 1, R １ is COOH, R ２ is H, R ３ is 4 - OCH ３ and R ４ is H, R ５ is H; (c) k is 0, m is 1, n is 1, R １ COOH is R ２ ga 3-CH ３ And R ３ 4-F, R ４ H is R ５ Compounds in which H is present; (g) k is 0, m is 1, n is 1, R １ That is tetrazole, R ２ H is R ３ 4-F, R ４ H is R ５ Compounds in which H is present; (h) k is 0, m is 1, n is 1, R １ B(OH) ２ And R ２ H is R ３ ga 4-OCH ３ And R ４ H is R ５ Compounds in which H is present; (i) k is 0, m is 1, n is 1, R １ COOH is R ２ H is R ３ 4-F, R ４ ga CH ３ And R ５ Compounds in which H is present; (k) k is 0, m is 1, n is 1, R １ COOH is R ２ H is R ３ 4-I, R ４ H is R ５ Compounds in which H is present; (l) k is 0, m is 1, n is 1, R １ COOH is R ２ H is R ３ 4-Br, R ４ H is R ５ Compounds in which H is present; (m) k is 0, m is 1, n is 1, R １ COOH is R ２ ga 2-CH ３ And R ３ is 2,4-difluoro, and R ４ H is R ５ Compounds in which H is present; (n) k is 0, m is 1, n is 1, R １ COOH is R ２ ga 2-CH ３ And R ３ It is 3,4-difluoro, and R ４ H is R ５ Compounds in which H is present; (q) k is 0, m is 1, n is 1, R １ COOH is R ２ 2-F, R ３ 4-F, R ４ H is R ５ Compounds in which H is present; (s) k is 0, m is 1, n is 1, R １ COOH is R ２ H is R ３ 4-F, R ４ H is R ５ Compounds in which H is present; (t) k is 0, m is 1, n is 1, R １ OC(CH ３ ) ２ COOH, R ２ H is R ３ ga 4-OCH ３ And R ４ H is R ５ Compounds in which H is present; (u) k is 0, m is 1, n is 1, R １ OC(CH ３ ) ２ COOH, R ２ is 3-O-para-methoxybenzyl, and R ３ ga 4-OCH ３ And R ４ H is R ５ Compounds in which H is present; (v) k is 0, m is 1, n is 1, R １ is OC(CH ３ ) ２ COOH, R ２ is H, R ３ is H, R ４ is H, R ５ is H; a compound (w) k is 0, m is 1, n is 1, R １ COOH is R ２ H is R ３ It is 2,4-dichloro, and R ４ H is R ５ Compounds in which H is present; where (x) k is 0, m is 1, n is 1, R １ is COOH, R ２ is H, R ３ is 3,5-difluoro, R ４ is H, and R ５ is H; (y) k is 0, m is 1, n is 1, R １ COOH is R ２ H is R ３ 4-NO ２ And R ４ H is R ５ Compounds in which H is present; (z) k is 0, m is 1, n is 1, R １ OC(CH ３ ) ２ COOH, R ２ H is R ３ It is 3,5-difluoro, and R ４ H is R ５ Compounds in which H is present; (aa) k is 0, m is 1, n is 1, R １ COOH is R ２ H is R ３ is 4-Cl, and R ４ H is R ５ Compounds in which H is present; (bb) k is 0, m is 1, n is 1, R １ OC(CH ３ ) ２ COOH, R ２ H is R ３ is 4-Cl, and R ４ H is R ５ Compounds in which H is present; (cc) k is 0, m is 1, n is 1, R １ COOH is R ２ H is R ３ ga 4-CF ３ And R ４ H is R ５ Compounds in which H is present; (ee) k is 0, m is 1, n is 1, R １ COOH is R ２ H is R ３ 4-F, R ４ H is R ５ Compounds in which 4-F; (ff) k is 0, m is 1, n is 1, R １ COOH is R ２ H is R ３ ga 4-OCH ３ And R ４ H is R ５ Compounds in which 4-F; (gg) k is 0, m is 1, n is 1, R １ COOH is R ２ H is R ３ 4-F, R ４ H is R ５ Compounds in which 5-F is present; (hh) k is 0, m is 1, n is 1, R １ COOH is R ２ is 3-O-para-methoxybenzyl, and R ３ ga 4-OCH ３ And R ４ H is R ５ Compounds in which H is present; (ii) k is 0, m is 1, n is 1, R １ COOH is R ２ H is R ３ is 2,4-difluoro, and R ４ H is R ５ Compounds in which H is present; (jj) k is 0, m is 1, n is 1, R １ COOH is R ２ is 2-O-para-fluorobenzyl, and R ３ 4-F, R ４ H is R ５ Compounds in which H is present; and A compound selected from the group consisting of any of the above salts.

2. Chemical structure II: 【Chemistry 2】 A compound represented by, (a) k is 0, m is 1, n is 1, R １ COOH is R ２ ga 2-CH ３ And R ３ 4-F, R ４ H is R ５ A compound or salt thereof in which H is present.

3. (b) k is 0, m is 1, n is 1, R １ COOH is R ２ H is R ３ ga 4-OCH ３ And R ４ H is R ５ Compounds in which H is present; (t) k is 0, m is 1, n is 1, R １ OC(CH ３ ) ２ COOH, R ２ H is R ３ ga 4-OCH ３ And R ４ H is R ５ Compounds in which H is present; (u) k is 0, m is 1, n is 1, R １ OC(CH ３ ) ２ COOH, R ２ is 3-O-para-methoxybenzyl, and R ３ ga 4-OCH ３ And R ４ H is R ５ Compounds in which H is present; (v) k is 0, m is 1, n is 1, R １ OC(CH ３ ) ２ COOH, R ２ H is R ３ H is R ４ H is R ５ Compounds in which H is present; (w) k is 0, m is 1, n is 1, R １ COOH is R ２ H is R ３ It is 2,4-dichloro, and R ４ H is R ５ Compounds in which H is present; (x) k is 0, m is 1, n is 1, R １ COOH is R ２ H is R ３ It is 3,5-difluoro, and R ４ H is R ５ Compounds in which H is present; (y) k is 0, m is 1, n is 1, R １ COOH is R ２ H is R ３ 4-NO ２ And R ４ H is R ５ Compounds in which H is present; (z) k is 0, m is 1, n is 1, R １ OC(CH ３ ) ２ COOH, R ２ H is R ３ It is 3,5-difluoro, and R ４ H is R ５ Compounds in which H is present; (aa) k is 0, m is 1, n is 1, R １ COOH is R ２ H is R ３ is 4-Cl, and R ４ H is R ５ Compounds in which H is present; (bb) k is 0, m is 1, n is 1, R １ OC(CH ３ ) ２ COOH, R ２ H is R ３ is 4-Cl, and R ４ H is R ５ Compounds in which H is present; (hh) k is 0, m is 1, n is 1, R １ COOH is R ２ is 3-O-para-methoxybenzyl, and R ３ ga 4-OCH ３ And R ４ H is R ５ Compounds in which H is present; and The compound according to claim 1, selected from the group consisting of any of the salts described above.

4. (c) k is 0, m is 1, n is 1, R １ COOH is R ２ ga 3-CH ３ And R ３ 4-F, R ４ H is R ５ Compounds in which H is present; (g) k is 0, m is 1, n is 1, R １ That is tetrazole, R ２ H is R ３ 4-F, R ４ H is R ５ Compounds in which H is present; (h) k is 0, m is 1, n is 1, R １ B(OH) ２ And R ２ H is R ３ ga 4-OCH ３ And R ４ H is R ５ Compounds in which H is present; (i) k is 0, m is 1, n is 1, R １ COOH is R ２ H is R ３ 4-F, R ４ ga CH ３ And R ５ Compounds in which H is present; (k) k is 0, m is 1, n is 1, R １ COOH is R ２ H is R ３ 4-I, R ４ H is R ５ Compounds in which H is present; (l) k is 0, m is 1, n is 1, R １ COOH is R ２ H is R ３ 4-Br, R ４ H is R ５ Compounds in which H is present; (m) k is 0, m is 1, n is 1, R １ COOH is R ２ ga 2-CH ３ And R ３ is 2,4-difluoro, and R ４ H is R ５ Compounds in which H is present; (n) k is 0, m is 1, n is 1, R １ COOH is R ２ ga 2-CH ３ And R ３ It is 3,4-difluoro, and R ４ H is R ５ Compounds in which H is present; (q) k is 0, m is 1, n is 1, R １ COOH is R ２ 2-F, R ３ 4-F, R ４ H is R ５ Compounds in which H is present; (s) k is 0, m is 1, n is 1, R １ COOH is R ２ H is R ３ 4-F, R ４ H is R ５ Compounds in which H is present; (cc) k is 0, m is 1, n is 1, R １ COOH is R ２ H is R ３ ga 4-CF ３ And R ４ H is R ５ Compounds in which H is present; (ee) k is 0, m is 1, n is 1, R １ COOH is R ２ H is R ３ 4-F, R ４ H is R ５ Compounds in which 4-F; (ff) k is 0, m is 1, n is 1, R １ COOH is R ２ H is R ３ ga 4-OCH ３ And R ４ H is R ５ Compounds in which 4-F; (gg) k is 0, m is 1, n is 1, R １ COOH is R ２ H is R ３ 4-F, R ４ H is R ５ Compounds in which 5-F is present; (ii) k is 0, m is 1, n is 1, R １ COOH is R ２ H is R ３ is 2,4-difluoro, and R ４ H is R ５ Compounds in which H is present; (jj) k is 0, m is 1, n is 1, R １ COOH is R ２ is 2-O-para-fluorobenzyl, and R ３ 4-F, R ４ H is R ５ Compounds in which H is present; and The compound according to claim 1, which is a compound selected from the group consisting of any of the salts described above.

5. A composition comprising one or more compounds according to any one of claims 1 to 4, wherein the composition is incorporated into a pharmaceutically acceptable carrier, vehicle or diluent, or is formulated to result in delayed release, controlled release, sustained release and / or sustained release of the one or more compounds.

6. The composition according to claim 5, which is for increasing the peroxisome proliferator-activated receptor α (PPARα) activity of retinal cells.

7. The composition according to claim 5, for treating a disorder or condition by increasing peroxisome proliferator-activated receptor alpha (PPARα) activity.

8. The composition according to claim 7, wherein the disorder or condition is selected from the group consisting of retinal inflammation, retinal neovascularization, retinal vascular leakage, retinopathy of prematurity (ROP), diabetic retinopathy (DR), age-related macular degeneration (AMD), and diabetic macular edema (DME).

9. The composition according to claim 7, wherein the disorder or condition is characterized by inflammation and / or angiogenesis.

10. The composition according to claim 7, wherein the disorder is selected from inflammatory bowel disease, type 1 diabetes, type 2 diabetes, Graves' disease, multiple sclerosis, osteoarthritis, rheumatoid arthritis, vasculitis, dermatitis, glomerulonephritis, hepatitis, periodontitis, atherosclerosis, heart failure, obesity, Alzheimer's disease, and metabolic syndrome.

11. The composition according to claim 7, wherein the disorder or condition is an ocular disorder or condition selected from keratitis, endophthalmitis, blepharitis, conjunctivitis, scleritis, herpetic inflammation, uveitis, vasculitis, arteritis, orbital inflammation, optic neuritis, sympathetic ophthalmitis, retinitis, macular edema, glaucoma, proliferative vitreoretinopathy, corneal edema, uveal edema, and retinal edema.

12. The composition according to claim 7, wherein the disorder or condition is selected from retinal artery or vein occlusion, corneal transplant rejection, corneal neovascularization, neovascular glaucoma, sickle cell retinopathy, cancer, skin disease, diabetic ulcer, diabetic nephropathy, cardiovascular disease, and seizure.

13. A kit comprising the compound according to any one of claims 1 to 4 and instructions for its use in treating a target disorder or condition.

14. The kit according to claim 13, wherein the disorder or condition is an ocular disorder or condition selected from the group consisting of retinal inflammation, retinal neovascularization, retinal vascular leakage, retinopathy of prematurity (ROP), diabetic retinopathy (DR), age-related macular degeneration (AMD), macular edema, diabetic macular edema (DME), keratitis, endophthalmitis, blepharitis, conjunctivitis, scleritis, herpetic inflammation, uveitis, vasculitis, arteritis, orbital inflammation, optic neuritis, sympathetic ophthalmitis, retinitis, glaucoma, proliferative vitreoretinopathy, corneal edema, uveal edema, and retinal edema.

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