Quinoline compound with integrin alpha5beta1 inhibition function and application thereof in fibrosis and fibrosis-related diseases

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a quinoline compound with an integrin alpha5beta1 inhibition function and application of the quinoline compound in fibrosis and fibrosis-related diseases. Specifically, the invention provides a compound, and the compound has a structural general formula as shown in the specification or a pharmaceutically acceptable salt, solvate or hydrate thereof: # imgabs0 #. The compound has obvious inhibitory activity on integrin alpha5beta1, so that the compound can be used for obstacles, diseases or symptoms mediated by the integrin alpha5beta1, and tests prove that the compound has an obvious treatment effect on various fibrosis diseases, so that the compound has a good practical application value.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to a quinoline compound having integrin α5β1 inhibitory function and its application in fibrosis and fibrosis-related diseases. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance understanding of the overall background of the invention and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to those skilled in the art.

[0003] Tissue fibrosis (scarring) is a major cause of morbidity and mortality. Current treatments for fibrotic diseases, such as idiopathic pulmonary fibrosis, liver fibrosis, and systemic sclerosis, primarily target the inflammatory cascade, but are generally ineffective because the mechanisms of fibrosis formation are known to be distinct from those of inflammation.

[0004] Repair of damaged tissue is a fundamental biological process that allows for the orderly replacement of dead or damaged cells in response to inflammation and is a key mechanism for survival. Tissue damage can be caused by a variety of acute or chronic stimuli, including infection, autoimmune reactions, and mechanical injury. The repair process consists of two distinct phases: a regenerative phase (in which damaged cells are replaced by cells of the same type, leaving no permanent signs of damage) and a fibrotic phase (in which connective tissue replaces normal parenchymal tissue). In most cases, both phases need to be initiated to reduce or reverse the damage caused by the injuring agent. However, although the healing process is initially beneficial, if it continues uncontrolled, it can trigger a pathogenic response, leading to significant tissue remodeling and permanent scar tissue formation, which can ultimately lead to organ failure and death. Fibrotic scars are generally defined as an abnormal wound healing response.

[0005] Fibroproliferative diseases are a significant cause of morbidity and mortality worldwide. Fibrotic changes can occur in a variety of vascular diseases (including heart disease, brain disease, and peripheral vascular disease) and in all major tissues and organ systems (including the skin, kidneys, lungs, eyes, bladder, heart, joints, intestinal tissue, connective tissue, reproductive tissue, bone tissue, and liver). Fibrosis is a vexing problem for an increasing number of people and a common pathological sequelae of many persistent inflammatory diseases, such as idiopathic pulmonary fibrosis, progressive kidney disease, and cirrhosis.

[0006] Both wound healing and the dysregulated events leading to fibrosis involve the proliferation and differentiation of certain cell types (tissue-dependent), primarily the differentiation of fibroblasts into myofibroblasts, and the deposition of extracellular matrix. Whether fibroblasts are locally derived or arise from circulating precursor cell populations is unclear. Fibrocytes are a distinct fibroblast-like cell population derived from peripheral blood mononuclear cells that enter sites of tissue injury to promote angiogenesis and wound healing.

[0007] The ocular response to hypoxic and inflammatory stimuli typically results in the formation of neovascularization in the retina or choroid. During development, this process is tightly regulated, resulting in the formation of a well-organized, mature vasculature. However, in the adult eye, this is generally not the case, and associated glial cells (such as astrocytes and Müller cells), microglia, and retinal pigment epithelial (RPE) cells proliferate alongside endothelial cells, leading to fibrosis and scarring. The role of cell adhesion molecules, such as integrins, in regulating the relationship between proliferating vascular cells and their environment has been the focus of much research.

[0008] There is ample evidence that integrin α5β1 interacts with the extracellular matrix during fibroblast differentiation. High levels of integrin α5β1 are detected in activated fibroblasts, and when fibroblasts transition to a fibrotic state, integrin α5β1 accumulates strongly. High levels of integrin α5β1 have been detected in proliferating fetal RPE cells, activated ARPE-19 cells (retinal pigment cells), and the PVR membranes of patients with proliferative vitreoretinopathy (PVR).

[0009] Integrin α5β1 plays a key role in inducing the activation, proliferation, and differentiation of pulmonary fibroblasts (PFbs), leading to increased extracellular matrix synthesis during pulmonary fibrosis. Strong expression of integrin α5β1 is observed in proliferating stromal cells with features of fibroblast and myofibroblast differentiation. Changes in fibronectin (FN) mimic those of integrin α5β1. Treatment with transforming growth factor-β1 (TGF-β1) increases the expression of integrin α5β1, fibronectin (FN) mRNA, and related proteins in PFbs. Interactions between bronchial fibroblasts and T cells increase the production of the profibrotic cytokine IL-6. In asthmatic states, this interaction involves CD40L / integrin α5β1. Crosstalk between T cells and structural cells in asthma may maintain local mucosal inflammation.

[0010] Furthermore, integrin α5β1 is expressed and localized in myofibroblast-rich areas of palmar fibromatosis. Hepatic stellate cell (HSC) activation plays an integral role in liver fibrosis. HSC activation increases expression of the fibronectin α5β1 integrin receptor, and interaction of integrin α5β1 with fibronectin increases collagen synthesis. Connective tissue growth factor (CCN2) production, a hallmark of liver fibrosis, regulates integrin expression in primary cultured HSCs and supports HSC adhesion by binding to cell surface integrin α5β1.

[0011] In renal biopsies from patients with mild and severe proteinuria, interstitial integrin α5β1 expression was positively correlated with relative interstitial cortical volume, suggesting that integrin α5β1 may play a role in the pathogenesis of chronic progressive kidney disease. The intensity of interstitial integrin α5β1 immunoexpression was positively correlated with the degree of interstitial fibrosis.

[0012] Retinal fibrosis is seen in age-related macular degeneration (AMD) after anti-vascular endothelial growth factor (VEGF) therapy. Fibrotic lesions in both AMD and proliferative diabetic retinopathy (PDR) are caused by neovascularization. Fibrotic lesions in AMD are not treatable with anti-VEGF drugs, and patients with AMD who do not respond to anti-VEGF therapy are those with fibrotic lesions.

[0013] Currently available treatments for fibrotic diseases include immunosuppressive drugs (such as corticosteroids) and other anti-inflammatory therapies. However, the mechanisms involved in the regulation of fibrosis appear to be distinct from those of inflammation, and thus anti-inflammatory therapies are not always effective in reducing and preventing fibrosis.

[0014] Patients with PDR are resistant to current anti-angiogenic (anti-VEGF) therapies, and patients with AMD who do not respond to anti-VEGF therapy have fibrotic lesions, indicating that there is still a significant unmet medical need, especially in the reduction and prevention of fibrosis and the management of fibrotic diseases. Summary of the Invention

[0015] In response to the problems existing in the prior art, the present invention provides a series of quinoline compounds with novel structures and integrin α5β1 inhibitory function and their applications in fibrosis and fibrosis-related diseases.

[0016] Specifically, the present invention relates to the following technical solutions: The first aspect of the present invention provides a compound having the general structural formula shown in Formula I below or a pharmaceutically acceptable salt, solvate or hydrate thereof:

[0017] in: n = 0, 1, or 2; R 1 、R 2 、R 3 、R 4 are each independently selected from hydrogen, hydroxy, carboxyl, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, amino, acyl, sulfonyl or phosphate, or any combination of these groups; The compound is used to treat fibrosis or fibrosis-related diseases, inflammation or inflammatory diseases, angiogenesis or angiogenesis-related diseases, including acute-stage diseases and chronic diseases.

[0018] One aspect of the present invention is a compound of formula I, wherein R 1 and R 2 Each independently selected from hydrogen; saturated or unsaturated, branched or unbranched C 1-10 Alkyl or C 3-12 Cycloalkyl; substituted or unsubstituted phenyl or benzyl; R 3 is hydrogen; or saturated or unsaturated, branched or unbranched C 1-10 Alkyl or C 3-12 Cycloalkyl; R 4 Is substituted or unsubstituted C6-C 10 Aryl or C5-C9 heteroaryl, wherein heteroatoms are independently selected from N, O and S; or substituted or unsubstituted monocyclic or bicyclic C 3-12 Cycloalkyl or C5-C9 heterocyclyl, wherein the heteroatoms are independently selected from N, O and S; One aspect of the present invention is a compound of formula I, wherein R 1 and R 2 are each independently selected from hydrogen; C 1-4 Alkyl; and C 3-4 Cycloalkyl.

[0019] Another aspect of the present invention is a compound of formula I, wherein R 1 and R 2 are each independently selected from hydrogen and C 1-4 alkyl.

[0020] Another aspect of the invention is a compound of formula I, wherein R 1 and R 2 are each independently selected from hydrogen and methyl.

[0021] Another aspect of the invention is a compound of formula I, wherein R 1 It's hydrogen.

[0022] Another aspect of the invention is a compound of formula I, wherein R3 is hydrogen or C 1-4 alkyl.

[0023] Another aspect of the invention is a compound of formula I, wherein R 4 is a substituted or unsubstituted phenyl group.

[0024] Another aspect of the invention is a compound of formula I, wherein n is 0 or 1, for use in the treatment of fibrosis.

[0025] Another aspect of the invention is a compound of formula I, wherein n is 0, for use in the treatment of fibrosis.

[0026] Another aspect of the present invention is that modification of the compound can alter its metabolic pathway, half-life, or interaction with other molecules; increase or decrease its biological activity; or change its target site.

[0027] In one embodiment of the present invention, the specific structural formula of the compound of formula I is as follows:

[0028] Among them, I-4 is the most preferred. In the present invention, it is also named CLT-28643.

[0029] The term "pharmaceutically acceptable salt" as used herein refers to a salt of a compound of the present invention that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include: acid addition salts formed with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; organic acids, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, camphorsulfonic acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, etc.; or salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion or an alkaline earth metal ion; or coordination compounds formed with organic bases, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc.

[0030] The term "solvate" as used herein refers to a compound of the present invention formed by combining with a pharmaceutically acceptable solvent. Pharmaceutically acceptable solvents include, but are not limited to, water, ethanol, acetic acid, and the like. Solvates include both stoichiometric and non-stoichiometric solvates, preferably hydrates. The compounds of the present invention may be crystallized or recrystallized using water or various organic solvents, in which case various solvates may be formed. The solvates of the present invention may be hydrates.

[0031] The subject of the present invention refers to an animal that has been the object of treatment, observation or experiment, preferably a mammal, and most preferably a human.

[0032] Those skilled in the art will appreciate that the compounds of the present invention exist as isomers, such as stereoisomers (including enantiomers and diastereomers) and cis-trans isomers. Therefore, when referring to the compounds of the present invention in this specification, the compounds of the present invention include the compounds of Formula I and pharmaceutically acceptable salts, isomers, solvates, and hydrates thereof. More specifically, the compounds of the present invention include single enantiomers, mixtures of enantiomers, or mixtures of diastereomers.

[0033] Pharmaceutical composition In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt, solvate, or hydrate thereof; a drug that suppresses the immune system or has other beneficial effects on pre-fibrotic processes; and a pharmaceutically acceptable excipient, medium, carrier, diluent, or vehicle.

[0034] Suitable excipients are well known to those skilled in the art, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors known to those skilled in the art, including, but not limited to, the method of administration. For example, oral dosage forms such as tablets may contain excipients that are inappropriate for parenteral dosage forms. The suitability of a particular excipient also depends on the specific active ingredient in the dosage form. For example, the decomposition of some active ingredients may be accelerated by certain excipients, such as lactose, or upon contact with water. Active ingredients containing primary and secondary amines are particularly sensitive to such accelerated decomposition. Therefore, the pharmaceutical compositions or dosage forms provided herein, if any, contain a small amount of lactose or other mono- or di-saccharides. As used herein, the term "lactose-free" means that the amount of lactose present, if any, is substantially insufficient to increase the degradation rate of the active ingredient. In one embodiment, a lactose-free composition comprises an active ingredient provided herein, a binder / filler, and a lubricant. In another embodiment, a lactose-free dosage form comprises an active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0035] The compound provided by the present invention can be used alone or in combination with one or more other compounds provided by the present invention. The pharmaceutical composition comprises a compound of formula I or a pharmaceutically acceptable salt, solvate or hydrate thereof, and the pharmaceutical composition can be formulated into different dosage forms suitable for oral, parenteral and topical administration. The pharmaceutical composition can also be formulated into modified release formulations, including delayed, extended, prolonged, sustained, pulsed, controlled, accelerated, rapid, directed, programmed release, and gastric retention formulations. These formulations can be prepared according to conventional methods and techniques known to those skilled in the art.

[0036] In one embodiment, the pharmaceutical composition is provided in a dosage form for oral administration, comprising a compound of Formula I or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and one or more pharmaceutically acceptable excipients or carriers.

[0037] In another embodiment, the pharmaceutical composition is provided in a dosage form for parenteral administration, comprising a compound of Formula I or a pharmaceutically acceptable salt, solvate or hydrate thereof; and one or more pharmaceutically acceptable excipients or carriers.

[0038] In yet another embodiment, the pharmaceutical composition is provided in a dosage form for topical administration, the dosage form comprising a compound of Formula I or a pharmaceutically acceptable salt, solvate or hydrate thereof; and one or more pharmaceutically acceptable excipients or carriers.

[0039] In yet another embodiment, the pharmaceutical composition can be administered topically to the eye, for example, by intraocular or periocular injection, or in the form of a topical implant, or for topical use in the form of eye drops or ointment.

[0040] Examples of intraocular injections are intravitreal, intracameral, or subretinal. Examples of periocular injections are subconjunctival, juxtabulbar / retrobulbar, juxtascleral, and subocular.

[0041] In the case of topical implants, specialized sustained-release devices can be administered via the intraocular or periocular routes to allow for sustained, slow release of the drug compound into the eye. Other sustained-release systems are microspheres, liposomes, nanoparticles, or other polymer matrices.

[0042] In another aspect of the present invention, the compound of formula I or pharmaceutical composition as described herein can be administered via the intravitreal (IVT) route of administration.

[0043] The pharmaceutical composition provided by the present invention can be provided in single dose form or multiple dose form. As used in the present invention, single dose form refers to a physically discrete unit suitable for application to human and animal subjects, and is packaged separately, as known in the art. Each unit dose contains a predetermined amount of active ingredient sufficient to produce the desired therapeutic effect, as well as the desired pharmaceutical carrier or excipient. Examples of single dose forms include ampoules, syringes, and separately packaged tablets and capsules. For example, a 100 mg unit dose contains approximately 100 mg of active ingredient in a packaged tablet or capsule. Single dose forms can be administered in part or multiple times. Multiple dose forms are multiple identical single dose forms packaged in a single container, administered in separated single dose forms. Examples of multiple dose forms include bottles for glass bottles, tablets, or capsules, or pint or gallon bottles.

[0044] Pharmaceutical composition provided by the invention can be used once, or is used repeatedly at certain intervals. It should be understood that accurate dosage and treatment duration can change with age, body weight and the condition of the patient to be treated, and can be determined empirically using known test protocols or from in vivo or in vitro tests or diagnostic data extrapolation. It should also be understood that for any specific individual, specific dosage regimen should be adjusted over time according to the professional judgment of the people who use or instruct the formulation to use the individual's needs.

[0045] How to use In one embodiment, the present invention provides a method for treating, preventing or ameliorating fibrosis or a fibrosis-related disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate or hydrate thereof, or a pharmaceutical composition thereof.

[0046] In another embodiment, the present invention provides a method for treating, preventing or ameliorating one or more symptoms of fibrosis or fibrosis-related diseases, inflammation or inflammatory diseases, angiogenesis or vascular-related diseases (including acute diseases and chronic diseases) in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate or hydrate thereof, or a pharmaceutical composition.

[0047] In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human.

[0048] In one embodiment, for the treatment of fibrotic diseases, such as those affecting the lungs, liver, kidneys, skin, epidermis, endothelium, muscles, tendons, as well as fibrotic diseases of the cartilage, heart, stomach, large intestine, small intestine, colon, uterus, nervous system, testicles, adrenal glands, arteries, veins, bile ducts, or eyes.

[0049] Specifically include: Liver fibrosis: Liver fibrosis; cirrhosis; reperfusion injury after liver transplantation; necrotizing hepatitis.

[0050] Renal fibrosis: glomerulonephritis; IgA nephropathy; reperfusion injury after renal transplantation; chronic allograft dysfunction; amyloidosis; diabetic nephropathy; mesangial proliferative glomerulonephritis; nephrosclerosis.

[0051] Pulmonary fibrosis: Interstitial lung diseases (ILDs), such as idiopathic pulmonary fibrosis; cystic fibrosis (CF); interstitial pulmonary fibrosis; drug-induced fibrosis; sarcoidosis; diffuse alveolar damage disease; pulmonary hypertension; chronic obstructive pulmonary disease; respiratory distress syndrome; and lymphangioleiomyomatosis.

[0052] Skin fibrosis: scleroderma; keloids; hypertrophic scars; dermatofibromas; chronic wounds; psoriasis; Dupuytren's contracture; pemphigoid; burns.

[0053] Gastric and intestinal fibrosis: dysmotility; hypertrophic pyloric stenosis; megacolon; piebald megacolon; idiopathic obstructive pulmonary disease; collagenous colitis; villous atrophy and crypt hyperplasia; polyp formation; fibrosis in Crohn's disease; gastric ulcer.

[0054] Ocular fibrosis: acute and fibrosing sympathetic ophthalmia; Graves' disease; fibrosis after glaucoma surgery; fibrosis after cataract surgery; anterior capsule cataract; corneal scarring; pemphigoid; diabetic microaneurysms; capsule opacification; elastosis of the conjunctiva leading to pingueculae and pterygium (fibrovascular growths on the corneal surface); vision loss secondary to pingueculae; filtering bleb survival disease; macular degeneration; or retinal and vitreoretinal disorders, such as proliferative diabetic retinopathy and proliferative vitreoretinopathy (PVR).

[0055] Other fibrosis: endometriosis; uterine fibroids; fibromyalgia; systemic sclerosis; atherosclerosis; restenosis; chronic myeloproliferative disorders; fibrodysplasia ossificans progressiva; myelodysplasia; osteoporosis; myelofibrosis; osteosclerosis; rheumatoid pannus formation in rheumatoid arthritis and osteoarthritis; peritoneal fibrosis; myocardial fibrosis; pancreatic fibrosis; chronic pancreatitis; glial scar tissue formation in HIV-related cognitive motor disorders and spongiform encephalopathies; or gingival hypertrophy secondary to drugs and fibrocystic disease.

[0056] Ocular disorders associated with choroidal neovascularization and possible subsequent fibrosis: ocular histoplasmosis syndrome; high myopia; vascular streaks; choroidal rupture; optic disc drusen; optic pits; acute posterior multifocal lamellar pigment epitheliopathy; filiform choroiditis; Harada's disease; Stargardt's disease; toxoplasmosis; sarcoidosis; central serous retinopathy; congenital rubella; coloboma; morning glory syndrome; choroidal hemangioma; choroidal melanoma; choroidal nevus; choroidal osteoma; toxocariasis; branch retinal vein occlusion; central retinal vein occlusion; juxtafoveal telangiectasia; retinitis pigmentosa; Best's disease; adult foveal macular dystrophy; problems after photocoagulation or retinal vascular disease, Examples include hypertensive retinopathy; diabetic retinopathy; sickle cell retinopathy; retinopathy of prematurity; background retinopathy; other ocular diseases associated with neovascularization and / or integrin-mediated interactions, such as proliferative vitreoretinopathy; proliferative diabetic retinopathy; Behçet's disease, retinal cavernous hemangioma; choroidal rupture; retinal telangiectasia; cystoid maculopathy; Eale's disease; idiopathic central serous choroidopathy; iris neovascularization; malignant choroidal melanoma; preretinal macular fibrosis; ocular histoplasmosis; retinal capillary hemangioma; iris and ciliary body tumors; diseases with pathological corneal neovascularization; and pterygium.

[0057] Another aspect of the present invention is a compound according to formula I or a pharmaceutical composition disclosed herein for use in the treatment of lymphangioleiomyomatosis (LAM).

[0058] As is well known, fibrosis and inflammation may be the reasons for the failure of surgical treatment. Therefore, another aspect of the present invention is the compound or pharmaceutical composition according to Formula I disclosed herein, which is used to treat fibrosis or inflammatory conditions associated with surgery. The example of surgical intervention that can benefit from the concomitant treatment of the compounds of this invention (before or after or before and after surgical intervention) is: the surgical procedure is selected from laser trabeculoplasty, laser cyclophotocoagulation, laser cyclophotocoagulation (cycloablation) for late glaucoma, acute angle-closure glaucoma surgery, drainage implant (tube shunt), deep sclerectomy, rapid micro-shunt, trabeculectomy, iridotomy, iridectomy, canaloplasty, viscostomy and goniotomy.

[0059] One aspect of the present invention is the use of a compound of formula I or a pharmaceutical composition disclosed herein in the preparation of a medicament for the treatment of fibrosis.

[0060] The term "fibrosis" is defined herein as a fibroproliferative disease. In general, fibrotic disorders are characterized by the hyperproliferation or transdifferentiation of non-cancerous primary fibroblasts.

[0061] The term "fibrosis-related disease" is defined herein as a disease or condition that may occur due to, be associated with, or be exacerbated by fibrosis. Examples of such fibrosis-related diseases are, without limitation, solid cancers, chronic inflammation, infections, and psoriasis. Fibrosis-related diseases may also be conditions that occur due to fibrosis following surgical intervention.

[0062] The term "interstitial lung disease (ILD)" encompasses a wide range of different conditions in which lung inflammation and fibrosis are the final common pathways of pathology. There are over 150 causes of ILD, including sarcoidosis, silicosis, drug reactions, infections, and collagen vascular diseases such as rheumatoid arthritis and systemic sclerosis (also known as scleroderma).

[0063] Idiopathic pulmonary fibrosis is the most common type of interstitial lung disease (ILD) and has no known cause.

[0064] The term "liver cirrhosis" has similar causes to interstitial lung disease (ILD), with viral hepatitis, schistosomiasis, and chronic alcoholism being the leading causes worldwide.

[0065] The term "fibrotic nephropathy" may be caused by diabetes, which can damage the kidneys and cause scarring, leading to a progressive loss of function.

[0066] Corneal diseases may be secondary to infection (e.g., herpetic keratitis) or inflammation (e.g., pterygium). Degeneration of the conjunctival elastomer leads to lingual bodies and pterygium (fibrovascular growths on the corneal surface). The final common event in all these diseases is usually inflammatory changes associated with neovascularization, tissue edema, and ultimately fibrosis of the corneal stroma, which leads to opacity and decreased vision.

[0067] The term "trauma-related scarring" includes, but is not limited to, surgical complications where scar tissue may form between internal organs, leading to contractures, pain, and, in some cases, infertility, which can be severe if persistent. Another example is fibrosis caused by burns.

[0068] The term “chemotherapeutic-induced fibrosis” includes, but is not limited to, fibrosis induced by certain drugs, such as drug-induced lung disease, or ocular fibrosis that may be induced by treatment with anti-VEGF monoclonal antibodies such as bevacizumab or ranibizumab.

[0069] The term "radiation-induced fibrosis (RIF)" includes, but is not limited to, fibrosis, a serious and common complication of radiation therapy that can cause chronic pain, neuropathy, limited joint motion, and lymph node swelling. It most commonly occurs in the breast, head, neck, and connective tissue. RIF may develop 4-6 months to 1-2 years after radiation therapy and becomes more severe over time. Risk factors for developing RIF include high radiation doses, exposure of large amounts of tissue to radiation, and the combination of radiation with surgery, chemotherapy, or both.

[0070] The term "lymphangioleiomyomatosis (LAM)" refers to a rare lung disease that causes disordered smooth muscle growths (leiomyomas) to proliferate throughout the lungs, in the bronchioles, alveolar septa, perivascular spaces, and lymphatic vessels. This can lead to obstruction of the small airways (causing lung cyst formation and pneumothorax) and lymphatic vessels (causing chylous pleural effusions). LAM occurs sporadically, affecting only women, typically of childbearing age. LAM also occurs in patients with tuberous sclerosis complex.

[0071] The term "subretinal fibrosis" is defined herein as age-related macular degeneration (ARMD).

[0072] Beneficial technical effects of one or more of the above technical solutions: The compounds designed by the above technical scheme have obvious inhibitory activity on integrin α5β1, and can therefore be used for integrin α5β1-mediated disorders, diseases or symptoms. Experiments have shown that they have significant therapeutic effects on various fibrotic diseases, and therefore have good practical application value. DETAILED DESCRIPTION

[0073] It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the present application. Unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present application belongs.

[0074] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit the exemplary embodiments according to the present application. As used herein, unless the context clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprise" and / or "include" are used in this specification, they indicate the presence of features, steps, operations, devices, components and / or combinations thereof.

[0075] The present invention will be further described with reference to specific examples. The following examples are intended only to illustrate the present invention and are not intended to limit its contents. Experimental conditions not specified in the examples are generally based on conventional conditions or those recommended by the sales company. Materials and reagents used in the examples are commercially available unless otherwise specified.

[0076] The present invention is further explained by the following examples, but is not intended to limit the present invention. It should be understood that these examples are only intended to illustrate the present invention and are not intended to limit the scope of the present invention.

[0077] Example 1 Preparation of 4-[(4-methoxyphenyl)amino]-6-(methylcarbamoyl)quinoline-3-carboxylic acid (the above compound I-4) hydrochloride The hydrochloride salt of compound 4-[(4-methoxyphenyl)amino]-6-(methylcarbamoyl)quinoline-3-carboxylic acid (compound 1-4 above, prepared as disclosed in Example 4 of WO 2009 / 063070) was obtained from ethyl 6-(methylcarbamoyl)-4-[(4-methoxyphenyl)amino]quinoline-3-carboxylate hydrochloride obtained as described in Example 3 of WO 2009 / 063070.

[0078] To a solution of ethyl 6-(methylcarbamoyl)-4-[(4-methoxyphenyl)amino]quinoline-3-carboxylate hydrochloride (100.0 g, 0.2636 mol, 1.0 equiv) in THF (4.0 L) at room temperature was added 1N aqueous NaOH (1.320 L, 52.8 g, 1.3 mol, 5.0 equiv). The clear red solution was heated to 50°C and stirred continuously for 3 hours. The reaction was monitored by TLC (10% MeOH in CHCl₃, Rf: 0.1). The reaction mixture was allowed to reach room temperature and diluted with H₂O (5.0 L), resulting in the formation of two layers. The suspension was evaporated under reduced pressure to remove most of the THF. The remaining red aqueous layer was washed with MTBE (2 x 2.5 L). The pale yellow aqueous layer was cooled to 0°C (ice bath) and acidified with 1N aqueous HCl (2.0 L) under vigorous stirring until the pH of the reaction mixture reached 1. During this time, a yellow solid precipitated. After the addition was complete, the mixture was stirred vigorously at room temperature for 16 hours. The yellow solid was filtered through a Buchner funnel and washed with H2O (2 x 500 mL) and then with MTBE (500 mL). The yellow solid was freeze-dried for 45 hours to provide the final compound I-4 (86.0 g, 93%) as a mobile yellow powder.

[0079] MW 351.37 (free base), MW 387.83 hydrochloride. 1 H NMR (300 MHz, D6-DMSO) 9.05 (s, 1H, aromatic), 8.70 (bm, 2H, aromatic and NH), 8.20 (d, 1H, aromatic), 8.00 (d, 1H, aromatic), 7.4 (d, 2H, aromatic), 7.00 (d, 2H, aromatic), 3.88 (s, 1H, —OCH3), 2.7 (s, 3H, —NCH3); LC-MS (m / z) 352.0 (M+1). Biological evaluation Cell adhesion assay The cell adhesion assay is used to study the inhibition of cell attachment (adhesion) of fibroblasts or RPE cells (retinal epithelial cells) or HUVEC (human umbilical vein endothelial cells) to fibronectin as an in vitro method to predict anti-fibrotic effects in the eye and other organs.

[0080] 48-well plates were coated with 10 µg / mL human fibronectin overnight at 4°C and then blocked with 2% BSA (bovine serum albumin) in PBS (phosphate-buffered saline) at 37°C for 1 hour.

[0081] Cells (mouse fibroblasts (3T3), human fibroblasts, human retinal epithelial cells (RPE), or cell line ARPE19, vascular endothelial cells, etc.) were washed twice with buffer 3 (0.14 M NaCl, 4.7 mM KCl, 0.65 mM MgSO4, 1.2 mM CaCl2, 10 mM Hepes pH 7.4), counted, and diluted to the appropriate concentration in buffer 3. Cells were preincubated on ice with control substances (antibodies or RGD peptides) or CLT-28643 (twice the desired final concentration) for 30 minutes.

[0082] Wash the plate three times with Buffer 3, then add 0.1 mL of Buffer 3 to each well. Place the plate on ice and add 0.1 mL of the cell solution to each well. Transfer the plate to 37°C and incubate for 15, 30, or 60 minutes (one plate per time point). After the designated incubation time, remove the plate from 37°C and discard the cell solution. Carefully wash the wells twice with Buffer 3, and add 0.1 mL of substrate solution (3.75 mM p-nitrophenyl-N-acetyl-β-D-glucamide, 0.25% Triton X-100, 0.05 M sodium citrate, pH 5.0) to each well. Store the plate at -20°C.

[0083] For adherent cell assays: Transfer 50 µL from each well of a 48-well plate to a 96-well plate and incubate at 37°C for the appropriate time (30 minutes to 4 hours, depending on the cell type). Simultaneously prepare a standard curve using cell samples of known cell mass. Develop the plate by adding 75 µL / well of developing buffer (45 mM glycine, 4.5 mM EDTA, pH 10.4) and read the absorbance at 405 nm.

[0084] The above embodiments are intended only to illustrate the technical concepts and features of the present invention. Their purpose is to enable those skilled in the art to understand the contents of the present invention and implement them accordingly. They are not intended to limit the scope of protection of the present invention. Any equivalent changes or modifications made in accordance with the spirit of the present invention are intended to be covered by the scope of protection of the present invention.

Claims

1. A compound, characterized in that The compound has the general structural formula shown in the following formula I or a pharmaceutically acceptable salt, solvate or hydrate thereof: in: n = 0, 1, or 2; R 1 、R 2 、R 3 、R 4 are each independently selected from hydrogen, hydroxy, carboxyl, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, amino, acyl, sulfonyl or phosphate, or any combination of these groups; The compound is used to treat fibrosis or fibrosis-related diseases, inflammation or inflammatory diseases, angiogenesis or angiogenesis-related diseases, including acute-stage diseases and chronic diseases.

2. The compound according to claim 1, wherein R 1 and R 2 Each independently selected from hydrogen; saturated or unsaturated, branched or unbranched C 1-10 Alkyl or C 3-12 Cycloalkyl; substituted or unsubstituted phenyl or benzyl; R 3 is hydrogen; or saturated or unsaturated, branched or unbranched C 1-10 Alkyl or C 3-12 Cycloalkyl; R 4 Is substituted or unsubstituted C6-C 10 Aryl or C5-C9 heteroaryl, wherein heteroatoms are independently selected from N, O and S; or substituted or unsubstituted monocyclic or bicyclic C 3-12 Cycloalkyl or C5-C9 heterocyclyl, wherein the heteroatoms are independently selected from N, O and S.

3. The compound according to claim 1, wherein R 1 and R 2 are each independently selected from hydrogen; C 1-4 Alkyl; and C 3-4 Cycloalkyl; R 3 is hydrogen or C 1-4 Alkyl; R 4 is a substituted or unsubstituted phenyl group.

4. The compound according to claim 1, wherein Modification of the compound can change its metabolic pathway, half-life, or interaction with other molecules; increase or decrease its biological activity; and change its target site.

5. The compound according to claim 1, wherein The specific structural formula of the compound of formula I is as follows: Among them, the compound I-4 is preferred.

6. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: (i) the compound according to any one of claims 1 to 5; (ii) drugs that suppress the immune system or have other beneficial effects on pro-fibrotic processes; for simultaneous, separate or sequential administration.

7. The pharmaceutical composition according to claim 6, wherein The pharmaceutical composition further comprises pharmaceutically acceptable adjuvants, media, carriers, diluents or excipients.

8. Use of the compound according to any one of claims 1 to 5 or the pharmaceutical composition according to any one of claims 6 to 7 in the preparation of a medicament for treating fibrosis or fibrosis-related diseases, inflammation or inflammatory diseases, angiogenesis or vascular-related diseases; the diseases include acute diseases and chronic diseases.

9. The use according to claim 8, characterized in that The fibrosis or fibrosis-related disease, inflammation or inflammatory disease, angiogenesis or vascular-related disease is a fibrosis or fibrotic disease, inflammation or inflammatory disease, angiogenesis or vascular-related disease that affects the pancreas, lungs, liver, kidneys, skin, epidermis, endothelium, muscles, tendons, cartilage, heart, stomach, large intestine, small intestine, colon, uterus, nervous system, testicles, adrenal glands, arteries, veins, bile duct or eyes.

10. The use according to claim 8, characterized in that The fibrotic disease, inflammation or inflammatory disease, angiogenesis or blood vessel related disease is associated with a surgical procedure selected from laser trabeculoplasty, laser cyclophotocoagulation, laser cyclophotocoagulation for advanced glaucoma (cycloablation), acute angle closure glaucoma surgery, drainage implant (tube shunt), deep sclerectomy, rapid micro-shunt, trabeculectomy, iridotomy, iridectomy, canaloplasty, capsulotomy and goniotomy.

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