KR20130102814A - Pharmaceutical composition comprising imidazopyridine derivative having pi3-kinase inhibitory activity for inhibiting angiogenesis - Google Patents

Abstract

PURPOSE: A pharmaceutical composition for suppressing angiogenesis is provided to suppress the generation of CD34, vascular endothelial growth factor (VEGF), and vascular endothelial cells using imidazopyridine derivatives which suppress PI3-kinase activity, thereby suppressing angiogenesis. CONSTITUTION: A pharmaceutical composition for suppressing angiogenesis contains N-(5-(3-(5-methyl-1,2,4-oxadiazol-3-yl)imidazo[1,2-a]pyridine-6-yl)pyridine-3-yl)benzenesulfonamide as an active ingredient. The compound suppresses VEGF and CD34. The compound which suppresses PI3-kinase activity is used for treating diseases caused by angiogenesis.

Description

Pharmaceutical composition comprising imidazopyridine derivative having PI3-kinase inhibitory activity for inhibiting angiogenesis}

The present invention provides N- (5- (3- (5-methyl-1,2,4-oxadiazol-3-yl) imidazo [1,2-a] pyridine-6- having PI3-kinase inhibitory activity. The present invention relates to a pharmaceutical composition for inhibiting angiogenesis, comprising: 1) pyridin-3-yl) benzenesulfonamide as an active ingredient.

Angiogenesis is the process by which new capillaries are formed from existing microvessels. Angiogenesis normally occurs during embryonic development, tissue regeneration and wound healing, and the development of the corpus luteum, a change in the genital system of women periodically, and in these cases is strictly controlled (Folkman J et al., Int Rev. Exp. Pathol., 16, pp 207-248, 1976). In adults, vascular endothelial cells grow very slowly and do not divide relatively well compared to other types of cells. Angiogenesis typically involves reconstitution of blood vessels through the formation of lumen through the degradation of vascular basement membranes, transfer of vascular endothelial cells, proliferation, and vascular endothelial differentiation due to proteases secreted by stimulation of angiogenesis promoters. Capillaries are produced.

However, there are diseases caused by angiogenesis that can not be controlled autonomously and grows morbidly. Diseases related to angiogenesis in pathological conditions include cancer, diabetic retinopathy, prematurity retinopathy, corneal graft rejection, neovascular glaucoma, melanoma, proliferative retinopathy, psoriasis, hemophiliac joints, keloids, wound granulation, vascular adhesion , Rheumatoid arthritis, osteoarthritis, autoimmune disease, Crohn's disease, restenosis, atherosclerosis, intestinal adhesion, cat scratch disease, ulcer, liver cirrhosis, glomerulonephritis, diabetic nephropathy, malignant neurosis, thrombotic microangiopathy, organ transplant rejection , Nephropathy, diabetes, inflammatory disease, or neurodegenerative disease, especially cancer growth and metastasis is dependent on angiogenesis (D'Amato RJ et al., Ophthalmology, 102 (9), pp1261 -1262, 1995; Arbiser JL, J. Am. Acad. Dermatol., 34 (3), pp486-497, 1996; O'Brien KD et al. Circulation, 93 (4), pp672-682, 1996; Hanahan D et al., Cell, 86, pp 353-364, 1996).

Arthritis, a representative disease of inflammatory diseases, is caused by autoimmune abnormalities, but as the disease progresses, chronic inflammation in the synovial cavity between joints induces angiogenesis and destroys cartilage. In other words, synovial cells and vascular endothelial cells proliferate in the synovial cavity with the help of inflammation-inducing cytokines, forming joint pannus, a layer of connective tissue that develops in the cartilage as the angiogenesis progresses, destroying cartilage that acts as a cushion. (Koch AE et al., Arthritis. Rheum., 29, pp471-479, 1986; Stupack DG et al., Braz J. Med. Biol. Rcs., 32 (5), pp578-581, 1999; Koch AE , Atrhritis.Rheum., 41 (6), pp951-962, 1998).

In addition, many ocular diseases, which cause millions of blindness worldwide each year, are also caused by angiogenesis (Jeffrey MI et al., J. Clin. Invest., 103, pp1231-1236, 1999). For example, diseases such as macular degeneration, diabetic retinopathy, retinopathy of premature infants, neovascular glaucoma and corneal diseases caused by neovascularization are the diseases caused by neovascularization (Adamis AP). et al., Angiogenesis, 3, pp 9-14, 1999). Among them, diabetic retinopathy is a complication of diabetes, in which capillaries in the retina invade the vitreous body and eventually become blind.

Especially in cancer, angiogenesis plays an important role in the growth and metastasis of cancer cells. Tumors are supplied with nutrients and oxygen for growth and proliferation through neovascularization, and new blood vessels that penetrate the tumor give metastasis to metastatic cancer cells by allowing them to enter the blood circulation (Folkman and Tyler, 1999). Cancer Invasion and metastasis, Biologic mechanisms and Therapy (SB Day ed.) Raven press, New York, pp 94-103, 1977; Polverini PJ, Crit. Rev. Oral. Biol. Med., 6 (3), pp230-247, 1995). It is also reported that the more the neovascularization occurs in the primary tumor, the worse the prognosis and the higher the recurrence rate. Recently, it has been reported that PI3-kinase (PI3K), which is known to play a very important role in tumor formation due to growth, differentiation, survival, migration and metastasis, is involved in angiogenesis in cancer progression. Therefore, studies are underway to target PI3-kinase to inhibit neovascularization and thereby prevent cancer metastasis.

Since the pathological growth of angiogenesis is pointed out as a cause of various diseases, angiogenesis inhibitors can be applied as a therapeutic agent for various angiogenesis-related diseases. Therefore, there is an urgent need for research on new substances that can effectively inhibit angiogenesis and pharmaceutical compositions that can treat angiogenesis-related diseases using the same.

Republic of Korea Patent Application No. 10-2009-0038964

The inventors of the present invention, while studying the substance having an angiogenesis inhibitory effect in the imidazopyridine derivative, N- (5- (3- (5-methyl-1,2,4-oxadiazole) having PI3-kinase inhibitory activity The present invention was completed by confirming that -3-yl) imidazo [1,2-a] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide effectively inhibits angiogenesis.

An object of the present invention is N- (5- (3- (5-methyl-1,2,4-oxadiazol-3-yl) imidazo [1,2-a] pyridine- with PI3-kinase inhibitory activity. It is to provide a pharmaceutical composition for inhibiting angiogenesis comprising 6-yl) pyridin-3-yl) benzenesulfonamide as an active ingredient.

The present invention provides N- (5- (3- (5-methyl-1,2,4-oxadiazol-3-yl) imidazo [1,2-a] pyridine-6- having PI3-kinase inhibitory activity. It provides a pharmaceutical composition for inhibiting angiogenesis comprising 1) pyridin-3-yl) benzenesulfonamide as an active ingredient.

N- (5- (3- (5-methyl-1,2,4-oxadiazol-3-yl) imidazo [1,2-a] pyridine-6 with PI3-kinase inhibitory activity according to the invention -Yl) pyridin-3-yl) benzenesulfonamide is excellent in inhibiting angiogenesis by inhibiting the production of CD34, VEGF and vascular endothelial cells.

1 shows N- (5- (3- (5-methyl-1,2,4-oxadiazol-3-yl) imidazo [1,2-a] pyridine to observe angiogenesis in vitro. -6-yl) pyridin-3-yl) benzenesulfonamide (hereinafter referred to as HS-104) is a diagram showing the results of the formation of the tube through a tube forming assay.
Figure 2 shows the results of observing vascular endothelial cells using an Aortic ring sprouting assay after covering the Matrigel mixed with VEGF and 1μM, 10μM HS-104 in the rat arterial vessels, respectively.
3 is a diagram showing the results of angiogenesis using H & E staining after injection of 10 μM HS-104 and VEGF into the epidermis of rats.
4 is a diagram showing the size of tumors after administration of 10 mg / kg and 30 mg / kg of HS-104 to tumor-induced mice.
5 is a diagram showing the results of confirming the expression levels of VEGF and CD34, angiogenesis markers after administration of HS-104 at 10 mg / kg and 30 mg / kg to tumor-induced mice.
Figure 6 is a diagram showing the results of comparing the effect of VEGF inhibition after induction of hypoxia in liver cancer cells, respectively treated with 1μM, 5μM, 15μM HS-104 and HS-116.
7 is a diagram showing the results of confirming the effect of inhibiting angiogenesis by using a tube forming assay after treating HS-104 or HS-116 of 1μM and 10μM to vascular endothelial cells, respectively.
8 is a diagram showing the results of confirming the effect of inhibiting cell migration after treatment of HS-104 or HS-116 of 1μM and 10μM to vascular endothelial cells, respectively.

The present invention provides N- (5- (3- (5-methyl-1,2,4-oxadiazol-3-yl) imidazo [1,2-a] pyridine-6- having PI3-kinase inhibitory activity. Yl) pyridin-3-yl) benzenesulfonamide (N- (5- (3- (5-methyl-1,2,4-oxadiazol-3-yl) imidazo [1,2-a] pyridin-6-yl It provides a pharmaceutical composition for inhibiting angiogenesis comprising pyridin-3-yl) benzenesulfonamide) as an active ingredient.

Hereinafter, the present invention will be described in detail.

N- (5- (3- (5-methyl-1,2,4-oxadiazol-3-yl) imidazo [1,2-a] pyridine-6- having PI3-kinase inhibitory activity of the present invention I) pyridin-3-yl) benzenesulfonamide inhibits the production of vascular endothelial cells and inhibits vascular endothelial growth factor (VEGF) and CD34.

Thus, N- (5- (3- (5-methyl-1,2,4-oxadiazol-3-yl) imidazo [1,2-a] pyridine with PI3-kinase inhibitory activity according to the present invention -6-yl) pyridin-3-yl) benzenesulfonamide may be usefully used in diseases caused by angiogenesis.

Diseases caused by angiogenesis include cancer, diabetic retinopathy, prematurity retinopathy, corneal graft rejection, neovascular glaucoma, melanoma, proliferative retinopathy, psoriasis, hemophiliac joints, keloids, wound granulation, vascular adhesion, rheumatoid arthritis , Osteoarthritis, autoimmune disease, Crohn's disease, restenosis, atherosclerosis, intestinal adhesion, cat scratch disease, ulcer, cirrhosis, glomerulonephritis, diabetic nephropathy, malignant neurosis, thrombotic microangiopathy, organ transplant rejection, gentleman One or more diseases selected from the group consisting of specific diseases, diabetes mellitus, inflammatory diseases or neurodegenerative diseases.

The cancer may include lung cancer, non-small cell lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, gastric cancer, anal muscle cancer, colon cancer, breast cancer, fallopian tube carcinoma, endometrium Carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine gland cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penis cancer, prostate cancer, chronic or Acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system (CNS) tumor, primary CNS lymphoma, spinal cord tumor, brain stem glioma and pituitary adenoma, liver cancer It may be, but is not limited to, one or more cancers selected from the group.

Pharmaceutical composition for inhibiting angiogenesis of the present invention is N- (5- (3- (5-methyl-1,2,4-oxadiazol-3-yl) imidazo [1,2-a] pyridine-6 It may contain one or more known active ingredients having an angiogenesis inhibitory effect with -yl) pyridin-3-yl) benzenesulfonamide.

The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier, excipient and diluent in addition to the above-mentioned active ingredient for administration.

For example, carriers, excipients and diluents include lactose, textose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline Cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil.

Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient in the active ingredient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, and the like. It is prepared by mixing. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used.

Liquid preparations for oral administration include suspensions, liquid solutions, emulsions, syrups, and the like, and various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to water and liquid paraffin, which are commonly used simple diluents, may be included. have.

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate and the like can be used. Examples of the suppository base include withexol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.

In addition to the oral administration, the pharmaceutical composition of the present invention may be administered by various routes according to the desired method, for example, by oral, rectal, intravenous, intramuscular, subcutaneous, intrauterine dural or cerebrovascular injection. Can be.

N- (5- (3- (5-methyl-1,2,4-oxadiazol-3-yl) imidazo [1,2-a] pyridin-6-yl) pyridin-3-yl of the present invention The effective dosage of benzenesulfonamide may vary depending on the age and gender of the patient, but may be characterized in that it is administered at 10 to 50 mg / kg, preferably 20 to 30 mg / kg.

Hereinafter, the present invention will be described in detail by examples and formulation examples. However, the following Examples and Formulation Examples are merely illustrative of the present invention, and the content of the present invention is not limited by the following Examples and Formulation Examples.

Example  1. vascular endothelial cells ( HUVECs ) In N- (5- (3- (5- methyl -1,2,4- Oxadiazole -3 days) Imza [1,2-a] pyridin-6-yl) pyridin-3-yl) Benzenesulfonamide  Angiogenesis inhibitory effect

In vitro tube formation assay (Tube formation assay) was performed to confirm the effects of in vitro angiogenesis. Specifically, Matrigel (BD Biosicence) was slowly dissolved at 4 ° C., coated on a 48 well plate, and vascular endothelial cells were incubated at 37 ° C. for 30 minutes to 1 hour to obtain a gel state. Cultured vascular endothelial cells (HUVECs) were treated with 0.1 μM, 1 μM, and 10 μM N- (5- (3- (5-methyl-1,2,4-oxadiazol-3-yl) imidazo [1,2- a] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide (N- (5- (3- (5-methyl-1,2,4-oxadiazol-3-yl) imidazo [1,2-a ] 5 × 10 ⁴ cells redispersed with medium containing pyridin-6-yl) pyridin-3-yl) benzenesulfonamide (hereinafter referred to as HS-104) and vascular endothelial growth factor (VEGF). After dispensing with water, the cells were incubated for 16 hours. After incubation, the formation of blood vessels in vascular endothelial cells (HUVECs) was observed using an optical microscope.

The results are shown in Fig.

As shown in FIG. 1, as the concentration of HS-104 increased, angiogenesis of vascular endothelial cells (HUVECs) was more effectively inhibited. Therefore, it was confirmed that HS-104 of the present invention is a substance having an antiangiogenic effect in vitro.

Example  2. HS To determine the inhibitory effect of -104 on angiogenesis Aortic ring sprouting assay

Aortic blood vessels were found and separated from rats and washed with Han's Buffered Salt Solution (HBSS) to prevent contamination. After washing, the arterial blood vessels of the rats were placed in a tube containing HBSS and placed in ice to move to a clean bench. Adipose tissue and other unnecessary parts around the arterial vessels were removed with a cotton swab and cut to a size of 1.5 mm. Place 200ul of Matrigel in a 48 well plate, place an artery vessel cut to 1.5mm on Matrigel, cover the Matrigel with 1μM or 10μM HS-104 and VEGF on top again and harden at 37 ° C for 15-30 minutes. . After 7 days in the medium, it was confirmed how vascular endothelial cells (HUVECs) are observed.

The results are shown in Fig.

As shown in FIG. 2, it was confirmed that vascular endothelial cells (HUVECs) were significantly reduced in vascular endothelial cells (HUVECs) compared to the VEGF-treated group in the artery vessels hardened after covering Matrigel in which 1-M or 10-M HS-104 was mixed with VEGF. Therefore, it can be seen that HS-104 effectively inhibits the production of vascular endothelial cells (HUVECs) in arterial vessels.

Example  3. HS To determine the inhibitory effect of -104 Matrigel  Plug Essay

After the matrigel was slowly dissolved at 4 ° C. for 24 hours or more, VEGF (50 ng / ml) was mixed with matrigel as a positive control, and 10 μM of HS-104 and VEGF were mixed with matrigel as an experimental group. Each Matrigel was injected thinly into the dorsal epidermis of 6-7 week-old male mice. After 5-7 days, only Matrigel plugs were taken to make blocks, cut and stained by H & E staining to confirm angiogenesis.

The results are shown in Fig.

As shown in FIG. 3, the epidermis of mice injected with Matrigel containing VEGF only occurred actively. In comparison, the epidermis of mice injected with Matrigel containing VEGF and HS-104 were compared Angiogenesis was markedly inhibited. Therefore, it can be seen that HS-104 effectively inhibits angiogenesis even in vivo.

Example  4. In cancer-causing mice HS -104 Cancer proliferation  Inhibitory and Angiogenic Inhibitory Effects

4.1 In Cancer-Induced Mice HS -104 Cancer proliferation  Inhibitory effect

In order to make a xenograft cancer model, hepatic cancer cell line (Huh-7) was inoculated on the back of nude mice, and after 3 weeks, tumor volume was measured. Thereafter, HS-104 was administered once a day to the mouse and the tumor growth inhibition effect of HS-104 was confirmed while measuring the volume of the tumor every two days.

The results are shown in Fig.

As shown in FIG. 4, the tumor volume increase rate was decreased by HS-104 treatment, and the volume increase rate was significantly reduced in mice treated with 30 mg / kg HS-104 than mice treated with 10 mg / kg HS-104. It was confirmed. Therefore, it can be seen that HS-104 has an effect of inhibiting cancer proliferation.

4.2 In cancer-causing mice HS -104 angiogenesis inhibitory effect

In order to confirm the antiangiogenic effect of HS-104 treatment in cancer-induced mice, the expression of anti-angiogenic markers VEGF and CD34 were analyzed. Tissues on prepared slides were fixed in 3.7% paraformaldehyde for about 5 minutes. Tissues of fixed vascular endothelial cells (HUVECs) were washed three times with wash buffer (2% FBS + 0.1% Sodium Azid in PBS) and then washed at a 1: 200 ratio with primary antibodies (anti-VEGF and CD34). The reaction was carried out at ℃ for 24 hours. Afterwards, the tissues were washed three times again with washing buffer to remove the remaining antibodies that did not occur in the reaction, and the antibodies specifically reacted with VEGF and CD34 were identified by DAB (diamino-benzidine) development. The prepared secondary antibody [anti-rabbit (or mouse) antibody] was reacted at room temperature in a 1: 500 ratio for 1 hour. After the reaction was completed, washed again with the wash buffer three times in order to remove the remaining antibody, and then stained brown and analyzed for the degree of expression under a microscope.

The results are shown in Fig.

As shown in FIG. 5, the expression of VEGF and CD34 was markedly decreased by HS-104 treatment at 10 mg / kg or 30 mg / kg, and it was confirmed that HS-104 significantly reduced cancer angiogenesis in cancer-induced mice. It was.

Example  5. HS With -104 HS -116 VEGF  Inhibitory effect comparison

Inhibitory effect of HS-104 on angiogenesis is another PI3-kinase inhibitor N- (5- (3- (3-cyanophenyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) pyridine- 3-yl) benzenesulfonamide [(N- (5- (3- (3-cyanophenyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) pyridin-3-yl) benzenesulfonamide); The following is compared with the angiogenesis inhibitory effect of HS-116].

Induction of hypoxia by treatment of hepatic cancer cells with CoCl ₂ , and 1-μM of HS-104 and HS-116 to compare the effects of HS-104 and HS-116 on the inhibition of VEGF production , 5μM, 10μM were respectively treated and confirmed the effect of VEGF inhibition.

The results are shown in Fig.

As shown in FIG. 6, both HS-104 and HS-116 inhibited the production of VEGF in hypoxia-induced hepatocellular carcinoma cells, but HS-104 significantly reduced the production of VEGF at lower concentrations compared to HS-116. It was confirmed that it could be suppressed.

Example  6. HS With -104 HS -116 vascular endothelial cells ( HUVECs Of angiogenesis inhibitory effects

After inducing blood vessel formation in vascular endothelial cells (HUVECs) with VEGF, HS-104 and HS-116 were treated and the angiogenesis inhibitory effect was compared using the tube formation assay of Example 1 above. HS-104 and HS-116 were treated at low concentration (1 μM) or high concentration (10 μM), respectively, and then the production of blood vessels in vascular endothelial cells (HUVECs) was observed using an optical microscope.

The results are shown in Fig.

As shown in Figure 7, the control group treated with VEGF only confirmed that the angiogenesis occurs actively, it was confirmed that both the treatment of HS-104 and HS-116 effectively inhibit the angiogenesis. In particular, HS-104 effectively inhibited angiogenesis at both low and high concentrations (1 μM) and high concentrations (10 μM), and this resulted in more potent antiangiogenic effects than HS-116, which showed minimal angiogenesis at low concentrations. .

Example  7. HS With -104 HS -116 vascular endothelial cells ( HUVECs ) Comparison of Movement Inhibitory Effects

When angiogenesis occurs, cell migration occurs, and therefore, HS-104 and HS-116 were treated at low concentration (1 μM) or high concentration (10 μM), respectively, and the effects of inhibiting vascular endothelial cells (HUVECs) migration were compared.

The results are shown in Fig.

As shown in FIG. 8, VEGF-treated vascular endothelial cells (HUVECs) (control) confirmed cell migration, but HS-104 and HS-116 treated vascular endothelial cells (HUVECs) inhibited cell migration. It became. In particular, HS-104 effectively inhibited vascular endothelial cell migration at both low and high concentrations (1 μM) and high concentrations (10 μM), thereby making HS-104 more potent angiogenesis than HS-116, which had minimal angiogenesis inhibition at low concentrations. It was confirmed to exhibit an inhibitory effect.

Formulation example . Pharmaceutical preparations

1. Manufacturing of powder

HS-104 2g

1g lactose

The above components were mixed and packed in airtight bags to prepare powders.

2. Preparation of tablets

HS-104 100mg

Corn Starch 100mg

Lactose 100mg

2 mg magnesium stearate

After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

3. Preparation of Capsule

HS-104 100mg

Corn Starch 100mg

Lactose 100mg

2 mg magnesium stearate

After mixing the above components, the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.

Claims (4)

N- (5- (3- (5-methyl-1,2,4-oxadiazol-3-yl) imidazo [1,2-a] pyridin-6-yl) pyridine with PI3-kinase inhibitory activity -3-yl) pharmaceutical composition for inhibiting angiogenesis comprising benzenesulfonamide as an active ingredient.
The compound of claim 1, wherein the N- (5- (3- (5-methyl-1,2,4-oxadiazol-3-yl) imidazo [1,2-a] pyridin-6-yl) pyridine -3-yl) benzenesulfonamide is a pharmaceutical composition for inhibiting angiogenesis, characterized in that it inhibits vascular endothelial growth factor (VEGF) and CD34.
According to claim 1 or 2, wherein the pharmaceutical composition is a disease caused by angiogenesis, cancer, diabetic retinopathy, prematurity retinopathy, corneal graft rejection, neovascular glaucoma, erythematosis, proliferative retinopathy, psoriasis, hemophilia Sexual joints, keloids, wound granulation, vascular adhesions, rheumatoid arthritis, osteoarthritis, autoimmune diseases, Crohn's disease, restenosis, atherosclerosis, intestinal adhesion, cat scratch disease, ulcers, cirrhosis, glomerulonephritis, diabetic nephropathy, Pharmaceutical for angiogenesis, characterized in that the composition for the treatment or prevention of one or more diseases selected from the group consisting of malignant neurosis, thrombotic microangiopathy, organ transplant rejection, renal glomerulopathy, diabetes, inflammatory disease or neurodegenerative disease Composition.
According to claim 3, wherein the cancer is lung cancer, non-small cell lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, gastric cancer, anal muscle cancer, colon cancer, breast cancer , Fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine gland cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer , Prostate cancer, chronic leukemia, acute leukemia, lymphocyte lymphoma, bladder cancer, kidney cancer, ureter cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system tumor, primary CNS lymphoma, spinal cord tumor, brain stem glioma, pituitary adenoma, liver cancer Pharmaceutical composition for inhibiting angiogenesis, characterized in that at least one selected from the group consisting of.

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