WO1998042329A1

WO1998042329A1 - Preventives and/or remedies for diseases caused by abnormal neovascularization

Info

Publication number: WO1998042329A1
Application number: PCT/JP1998/001210
Authority: WO
Inventors: Tsukasa Matsubara
Original assignee: Mitsubishi Chemical Corporation
Priority date: 1997-03-21
Filing date: 1998-03-20
Publication date: 1998-10-01

Abstract

Drugs containing as the active ingredient substances selected from the group consisting of phenylacetic acid derivatives represented by general formula (I), their physiologically acceptable salts and hydrates, and solvates thereof. In said formula (I) R1 represents hydrogen or R5CO- (wherein R5 represents C¿1-6? alkyl or C¿6-10 aryl); R?2 and R3¿ independently represent each hydrogen or C¿1-4? alkyl; and R?4¿ represents hydrogen or C¿1-6? alkyl; and being useful in preventing and/or treating diseases caused by abnormal neovascularization such as cancer, rheumatoid arthritis, atherosclerosis, diabetic retinitis, hemangioma, psoriasis, etc.

Description

Description Prevention of diseases caused by abnormal angiogenesis and Z or therapeutic agents

The present invention relates to a prophylactic and / or therapeutic agent for various diseases accompanied by abnormal angiogenesis. Background art

Angiogenesis is an essential biological phenomenon during fetal vascular tree formation and the morphological and functional development of each organ. In healthy adult individuals, angiogenesis is observed only during the female sexual cycle. On the other hand, it is known that the pathological increase in angiogenesis in mature individuals is involved in the onset and progression of various diseases. Specifically, cancer, rheumatoid arthritis, arteriosclerosis atherosclerosis, diabetic retinopathy, hemangiomas, psoriasis, etc. are listed as diseases accompanied by abnormal angiogenesis (Marsha, A., eta 1. , Biotechnology, 9_, 6 30 (1 9 9 1)). In addition, it has been reported that the growth of solid tumors depends on angiogenesis (Folkman J., J. N at. Cancer Inst., 82, 4 (1990)). Angiogenesis inhibitors are expected to be a new treatment for solid tumors. So far, there have been several reports on angiogenesis inhibitors, but no effective substances that can withstand practical use have been found yet (JP-A-3-109324, JP-A-3-23). 6324, JP-A-3-2184, and JP-A-8173176).

Disclosure of the invention

An object of the present invention is to provide a substance having angiogenesis inhibitory activity, and to provide a medicament which contains the substance as an active ingredient and is useful as a preventive and / or therapeutic agent for various diseases associated with angiogenesis abnormality. It is in. In view of the above situation, the present inventors have searched for a substance that has a strong inhibitory activity on angiogenesis and has few side effects. As a result, they have found for the first time that a specific fendronic acid derivative has an angiogenesis inhibitory action, and have completed the present invention. That is, the present invention provides the following formula (I):

[Wherein, R ¹ represents a hydrogen atom or R ⁵ CO— (R ⁵ represents an alkyl group of C s or an aryl group of C ₆ to C,.), And R ² and R ³ each independently represent a hydrogen atom Alternatively, C ₄ represents a C ₄ to C ₄ alkyl group, and R ⁴ represents a hydrogen atom or a C ^ Cs alkyl group. ]

Prevention of diseases caused by abnormal angiogenesis containing as an active ingredient a substance selected from the group consisting of a phenylacetic acid derivative represented by and a physiologically acceptable salt thereof, and a hydrate and a solvate thereof. And / or a therapeutic agent; and the above formula

An angiogenesis inhibitor comprising, as an active ingredient, a phenylacetic acid derivative represented by (I) and a physiologically acceptable salt thereof, and a substance selected from the group consisting of hydrates and solvates thereof. Is provided.

In another aspect, the present invention provides a phenylacetic acid derivative represented by the above formula (I) and a physiologically acceptable product for the manufacture of a prophylactic and / or therapeutic agent for a disease caused by an angiogenic abnormality. Use of a substance selected from the group consisting of a salt thereof, a hydrate thereof, and a solvate thereof; and a method for preventing and / or treating a disease caused by abnormal angiogenesis, A prophylactic and / or therapeutically effective amount of a substance selected from the group consisting of a phenylacetic acid derivative represented by (I) and a physiologically acceptable salt thereof, and a hydrate and a solvate thereof; , Preferred Or a method comprising administering to a human. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graph showing the inhibitory effect of the medicament of the present invention, lactarit, on tube formation (Example 1).

FIG. 2 is a diagram showing the VEGF receptor gene expression-suppressing action of an actaliter of the medicament of the present invention (Example 2). BEST MODE FOR CARRYING OUT THE INVENTION

The medicament of the present invention comprises, as an active ingredient, a substance selected from the group consisting of a fuunylacetic acid derivative represented by the formula (I) and a physiologically acceptable salt thereof, and a hydrate and a solvate thereof. It is characterized by including as.

Examples of the C ^ Cs alkyl group defined by the formula (I) include a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, an n-butyl group, an iso-butynole group, and a tert-butyl group. , n- pentyl group, hexyl group and the like to the n _, the alkyl group of Ci~ C _4, carbon atoms are those having 1 to 4 be mentioned up among the alkyl groups described above. Also C ₆ -C ₁ . Is an aryl group having 6 to 10 ring carbon atoms, and a monocyclic or bicyclic aryl group can be used. The aryl group may have one or more substituents on the ring, and when it has two or more substituents, they may be the same or different. The substituent on Ariru ring, for example, Omicron, alkyl Omikuronbeta, halogen atom or C, may be mentioned an alkoxy group ~ C _6, as does _c Ariru group be limited to, For example, phenyl, tolyl, xylyl, naphthyl and the like can be used.

Preferred examples of the fendronic acid derivative represented by the formula (I) include compounds represented by the following structural formulas, but the active ingredient of the medicament of the present invention is limited to these compounds. It will not be done. 0 CH ₃

II

CH ₂ COOH H3C-C-HN- CHCOOH

H ₃ CH ₂ C-

H ₂ N- CH ₂ COOC ₂ H ₅ H, N- \ -CH ₂ COOH

H -CH ₂ COOCH ₃

HN -CH ₂ COOCH ₃

Examples of the physiologically acceptable salt that can be formed by the phenylacetic acid derivative represented by the formula (I) include, when R ¹ is R ⁵ CO— and R ⁴ represents a hydrogen atom, for example, sodium Salts with inorganic bases such as alkali metals such as potassium and potassium, and alkaline earth metals such as calcium and magnesium; salts with inorganic bases such as pro-in, N, N'-dibenzylethylenediamine, etc. Pharmaceutically acceptable salts can be mentioned. When R ¹ is a hydrogen atom and R ⁴ represents a C, to C ₄ alkyl group, acid addition salts such as hydrochloride, sulfate, fumarate, maleate, and formate, etc. And pharmaceutically acceptable salts. However, the salts that can be used as the active ingredient of the medicament of the present invention are not limited to the above specific examples.

Further, the phenylacetic acid derivative represented by the above formula (I) and a salt thereof may form a hydrate, or may form a solvate with an appropriate solvent such as methanol or ethanol. These substances may be used as an active ingredient of the medicament of the present invention. Among the above compounds, particularly preferred compounds are

(Generic name: actalit, hereinafter sometimes also referred to as “actalit” in the present specification).

Are tested in various animal tests that are models of rheumatoid arthritis disease, ie, adjuvant arthritis in rats (Fujisawa, H., eta 1., Arzneim. Fors h., 40, 693 (1 990)), collagen arthritis in mice (Fujisawa, H., eta 1., Arznein nm ittelforshung, 44, 64 (1994)), arthritis in MR L / I mice. Nephritis (Fujisawa, H., eta 1., Jpn. J. Inf 1 am., _6, 285 (19986) and Yoshida, H., eta 1., Int. , 3_, 26 1 (1 9 8 7)) and delayed allergic reactions in mice (Nakawa, Y., eta 1., Int. J. Immunotherapy, 6_, 14) 1 (1990) has been shown to have an inhibitory effect. In addition, since actactrit has an effect of activating suppressor T lymphocytes, it is considered that the anti-rheumatic effect of actactrit is through the regulation of the abnormally activated immune response system. J. I mm unother., 6_, 19 (1990). Therefore, actactrit is expected as a prophylactic and therapeutic agent for various diseases accompanied by abnormal immune response (Japanese Patent Application Laid-Open No. 58-198414). However, it has not been suggested or taught at all that actarit has an inhibitory effect on angiogenesis or that it is useful as a prophylactic and / or therapeutic agent for various diseases associated with abnormal angiogenesis.

The compounds represented by the above general formula (I) are all known compounds, and can be easily produced, for example, according to the description in JP-A-58-194814.

The term `` angiogenesis, '' as used herein, should be interpreted in the broadest sense, including primarily the response of vascular endothelial cells in venules to a new vascular network in response to some stimulus. . Various growth factors such as metabolites of cytokines, cytokines and arachidonic acid, and angiogenin have been reported as factors controlling angiogenesis. Growth factors in particular are considered important angiogenic factors, including basic or acidic fibroblast growth factor, transforming growth factors-α and / 3, epidermal growth factor, and vascular endothelial growth factor (VEGF). Are known.

Among them, VEGF (Leung, DW, eta 1-, Science. 246, 130 (196)) Invitrogen promotes endothelial cell proliferation and enhances histological It has the effect of promoting the production of plasminogen activator and plasminogen activator, and its selective inhibitor PAI-1 and stromal collagenase, Furthermore, since VEGF is a growth factor specific to vascular endothelial cells, its role in various diseases involving angiogenesis, particularly in tumor angiogenesis, has attracted attention (Samoto, K., eta 1. , Cancer Res., 55, 1189 (1959)).

Activation of vascular endothelial cells by VEGF is an intracellular signal via VEGF receptor It is governed by the ring and has two VEGF receptor proteins: Flt-1 fms—liketyrosinekinase—1), LK-1 l, feta 1 liverkinase—1) / KDR (kinase ι nsertdoma in— containing receptor). Are known. These are composed of an extracellular ligand domain, a transmembrane domain, and an intracellular tyrosine kinase domain, and induce receptor autophosphorylation, calcium ion influx, activation of phospholipase C (B rock, TA, eta 1., Am. J. Pathol. 13 8, 3 15 (1991))).

Without wishing to be bound by any particular theory, it is believed that angiogenesis inhibition can be achieved by inhibiting or suppressing the production of angiogenic factors, or by blocking the response of vascular endothelial cells to angiogenic factors. Can be Therefore, the action of the angiogenesis inhibitor of the present invention depends on the degree of inhibition of lumen formation observed when human vascular endothelial cells are cultured (Grant, DS eta 1., In Vitro Ce 1 1. Dev. Biol., 27A (4), 32 7-336 (1991)) or the degree of inhibition of VEGF receptor gene expression by vascular endothelial cells (Boocock, C, A., etal., J. N at. Cancer Inst. 87, 506 (1959) can be confirmed using the index.

As described above, since abnormal angiogenesis is observed in various diseases, the compounds represented by the above general formula (I) including actactrit are used for those diseases, for example, rheumatoid arthritis, solid tumors and the like. It is useful as a prophylactic and / or therapeutic agent for atherosclerosis, diabetic retinitis, hemangiomas, psoriasis, etc. The medicament of the present invention is particularly useful as a prophylactic and / or Z or therapeutic agent for solid cancer, atherosclerosis, diabetic retinopathy, hemangiomas, and psoriasis.

When the prophylactic and / or therapeutic agent of the present invention is administered as a prophylactic / therapeutic agent for various diseases associated with abnormal angiogenesis, tablets, powders, granules, capsules, syrups, and other preparations are orally administered. Or parenterally as a formulation in the form of a spray, a suppository, an injection, an external preparation, a drip and the like. Dosage is ill Depending on conditions such as the type of disease, the severity of the condition, and the age of the patient, the usual adult dosage can range from 50 to 200 Omg per day, divided into one to several doses. The above-mentioned preparations can be produced by a conventional method using a usual preparation carrier. When preparing solid tablets for oral use, excipients and, if necessary, binders, disintegrants, coloring agents, flavoring agents, etc. are added to the substance of the active ingredient, and then tablets and coatings are applied in the usual way. Tablets, granules, powders, capsules and the like can be prepared. These tablets and granules may be sugar-coated, gelatin-coated and, if necessary, coated with an appropriate coating. When preparing injections, add a pH adjuster, buffer, stabilizer, solubilizing agent, etc. to the substance of the active ingredient if necessary, and use the usual methods for subcutaneous, intramuscular, or intravenous injections Can be prepared. Example

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto. Incidentally, the actors used in the following examples are disclosed in

It was prepared according to the method described in JP-A-8-194814. In addition, the inhibitory action on tube formation is as follows: InVitroCelI.Div.Biol., 27A, 327 (1

The expression inhibitory effect of VEGF receptor gene expression was measured as described in J. Nat. 1. Cancer. Inst. 87, 506 (1995). Example 1. Inhibition of lumen formation

Human culture of les, strip vein endothelial cells were seeded 2 X 1 0 ⁵ cells in a petri dish of 5 cm coated (passage second generation) in advance with 1% gelatin, final concentration Akutari' bets after bonding 0, 1 0, The cells were added at a concentration of 100, 1000 μg / m 1 and cultured for 48 hours. MATR I GEL Matrl (Beeton Dickinson Labware Chito) 後 r 70 μ after peeling it off with trypsin and EDTA, and incubating for 1 hour at 37 ° C 9 3 X 1 on 6-hole flat bottom plate 0 ³ increments Maki and photographed tube formation after 1 6 hours under a microscope. The length of the vascular / dermal cell tube was measured, and the inhibition rate in the group without the addition of lactolite was determined. As is evident from the results shown in FIG. 1, the actactrite inhibited the luminal formation of vascular endothelial cells in a concentration-dependent manner. Example 2. Inhibition of VEGF receptor gene expression: 1 x 10 ⁶ seeds were plated on human cultured umbilical vein endothelial cells (passage 2nd generation) in a 5 cm petri dish coated with 1% gelatin in advance. Was added to a final concentration of 0, 10, 100 μg Zm 1 and cultured for 16 hours. After detaching the cells with trypsin ♦ EDTA, the cells were resuspended in 1 ml of RPMI · 1640 medium supplemented with 10% fetal bovine serum, and RNA was extracted using ISOGEN (Nippogen). This RNA was subjected to a reverse transcriptase reaction using oligo-dT (GI BCO BRL) and Super ScriptTMRN (GI BCO BRM), and finally J. Natl. Cance r. Inst 87, 506 (1 995), the primers for KDR or f1t (both VEGF receptor gene) and the primer for one actin, which is a partial standard, were added to the tag DNA pol. Amplified with ymerase (BOEHR I NGE R). The amplified product was electrophoresed on a 1.5% agarose gel for 30 minutes and photographed. The photograph was taken with a scanner, and the expression of the VEGF receptor gene was analyzed by NIH Image when the expression of the j3-actin gene was used as an internal standard, and the inhibition rate for the group without the actactite was determined.

As is evident from the results shown in FIG. 2, the actritol inhibited the expression of the VEGF receptor KDR and the f1t gene mRNA in vascular endothelial cells in a concentration-dependent manner. Industrial applicability

The medicament of the present invention has an excellent angiogenesis inhibitory effect, and is useful for treating rheumatoid arthritis, It is useful as a preventive and / or therapeutic agent for diseases such as morphological cancer, atherosclerosis, diabetic retinopathy, hemangiomas, and psoriasis.

Claims

Scope of request Formula (I) below

[Wherein, R ¹ represents a hydrogen atom or R ⁵ CO— (R ⁵ represents an alkyl group of C! Cs or an aryl group of C ₆ to C _1Q ), and R ² and R ³ each independently represent a hydrogen atom Alternatively, C ₄ represents a C ₄ to C ₄ alkyl group, and R ⁴ represents a hydrogen atom or a C i to C ₆ alkyl group. ]

A disease caused by abnormal angiogenesis containing as an active ingredient a substance selected from the group consisting of phenylacetic acid derivatives and physiologically acceptable salts thereof, and hydrates and solvates thereof represented by Prophylactic and Z or therapeutic agents.

2. The claim 1 wherein the substance is a substance selected from the group consisting of 4-acetylaminophenylacetic acid and physiologically acceptable salts thereof, and hydrates and solvates thereof. The prophylactic and Z or therapeutic agents described in 1.

3. The disease according to claim 1, wherein the disease caused by abnormal angiogenesis is a disease selected from cancer, rheumatoid arthritis, atherosclerosis, diabetic retinopathy, hemangioma and psoriasis. Or a therapeutic agent.

4. The preventive and / or therapeutic agent according to claim 1, wherein the disease caused by the angiogenesis abnormality is diabetic retinopathy.

5. The prophylactic, Z or therapeutic agent according to claim 1, which is an inhibitor of angiogenesis.

6. The following formula (I):

[Wherein, represents a hydrogen atom or R ⁵ CO— (R ⁵ represents an alkyl group of ~ ^ or an aryl group of C ₆ -C ₁₀ ), and R ² and R ³ each independently represent a hydrogen atom or R ⁴ is a hydrogen atom or ^ ~. (Represents an alkyl group of;)

An angiogenesis inhibitor comprising, as an active ingredient, a substance selected from the group consisting of a phenylacetic acid derivative represented by and a physiologically acceptable salt thereof, and a hydrate and a solvate thereof.

7. The method according to claim 5, wherein the substance is a substance selected from the group consisting of 4-acetylaminophenylacetic acid and physiologically acceptable salts thereof, and hydrates and solvates thereof. Item 14. The angiogenesis inhibitor according to Item.

8. A phenyldiacid derivative represented by the formula (I) according to claim 1 and a physiologically acceptable compound for the manufacture of a prophylactic and / or therapeutic agent or a therapeutic agent according to claim 1. Or a salt thereof, or a substance selected from the group consisting of hydrates and solvates thereof.

9. A method for preventing and / or treating a disease caused by abnormal angiogenesis, wherein the phenylacetic acid derivative represented by the formula (I) according to claim 1 and a physiologically acceptable salt thereof. And administering to the patient a prophylactically and / or therapeutically effective amount of a substance selected from the group consisting of hydrates and solvates thereof.

10. The disease according to claim 9, wherein the disease caused by abnormal angiogenesis is a disease selected from cancer, rheumatoid arthritis, atherosclerosis, diabetic retinopathy, hemangioma and psoriasis. Method.

11. The method according to claim 9, wherein the disease caused by abnormal angiogenesis is a disease selected from diabetic retinopathy.