JP2005068141A - Vegf secernent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pharmaceutical for preventing and/or treating a disease accompanied with VEGF (vascular endothelial growth factor) hyposecretion. <P>SOLUTION: A VEGF secernent contains a substance selected from the group consisting of aminoalkoxybibenzyls expressed by formula (1), a pharmaceutical acceptable salt or ester thereof, a solvate thereof, and a hydrate thereof as an active ingredient. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

The present invention relates to a medicament for increasing VEGF concentration.

VEGF is a growth and differentiation factor specific to vascular endothelial cells, and it has been reported that it is involved in the maintenance and repair of vascular endothelium and the maintenance of vascular function. However, VEGF is a cause of aging, hyperlipidemia, diabetes, etc. Necessary VEGF secretion may not be induced, resulting in angiogenesis failure. To date, treatment using VEGF gene has been attempted as an angiogenic therapy (Circulation, 91, 2687-2692, 1995: Non-patent document 1; Circulation, 97, 1114-1123, 1998: Non-patent document 2). Etc.), improvement of the circulation in the ischemic region of lower limb arteriosclerosis patients has been confirmed. However, gene therapy is not easy from the viewpoint of quality control of genes and facilities required for treatment.

で表される塩酸サルポグレラートに代表される特定構造のアミノプロポキシビベンジル類は５HT₂受容体に高い選択性を示し、血圧にほとんど影響を与えないことが報告されており、さらに、重篤な副作用もほとんどなく、高い安全性を示す薬剤である。塩酸サルポグレラートについては、これまで脳循環障害、虚血性心疾患、末梢循環障害等の疾患における、血栓生成及び血管収縮に基づく種々の微小循環障害の改善に有効であることが知られている（特開平２−３０４０２２号公報：特許文献１）。 On the other hand, the following formula (2):

It has been reported that aminopropoxybibenzyls having a specific structure represented by sarpogrelate hydrochloride represented by the above formula show high selectivity for the 5HT ₂ receptor and have little effect on blood pressure. It is a drug that shows high safety. Sarpogrelate hydrochloride has been known to be effective in improving various microcirculatory disorders based on thrombus formation and vasoconstriction in diseases such as cerebral circulation disorder, ischemic heart disease and peripheral circulation disorder. Kaihei 2-304022: Patent Document 1).

In clinical practice, sarpogrelate hydrochloride is used as an antiplatelet agent with an effect of improving peripheral circulation for the improvement of ischemic symptoms associated with chronic arterial occlusion, and its action is caused by the 5HT ₂ receptor present in platelets and vascular smooth muscle. Inhibition of platelet aggregation and vasoconstriction. However, it has not been known that sarpogrelate hydrochloride enhances VEGF secretion. In addition, there is no report that other serotonin antagonists represented by ketanserin enhance VEGF secretion.
Japanese Patent Laid-Open No. 2-304022 Circulation, 91, 2687-2692, 1995 Circulation, 97,1114-1123, 1998

An object of the present invention is to provide a medicament for the prevention and / or treatment of a disease associated with VEGF secretion failure.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that aminopropoxybibenzyls having a specific structure known as 5HT ₂ receptor antagonists have an action of enhancing VEGF secretion. It was. The present invention has been completed based on the above findings.

〔式中、Ｒ₁ は水素原子、ハロゲン原子、Ｃ₁〜Ｃ₅のアルコキシ基、又はＣ₂〜Ｃ₆のジアルキルアミノ基を表わし、Ｒ²は水素原子、ハロゲン原子又はＣ₁〜Ｃ₅のアルコキシ基を表わし、Ｒ³は水素原子、ヒドロキシル基、−Ｏ−（ＣＨ₂）_n−ＣＯＯＨ（式中、ｎは１〜５の整数を表わす。）、又はＯ−ＣＯ−（ＣＨ₂）_l−ＣＯＯＨ（式中、ｌは１〜３の整数を表わす。）を表わし、Ｒ⁴は−Ｎ（Ｒ⁵）（Ｒ⁶）（式中、Ｒ⁵及びＲ⁶はそれぞれ独立して水素原子又はＣ₁〜Ｃ₈のアルキル基を表わす。）又は

（式中、Ａはカルボキシル基で置換されていてもよいＣ₃〜Ｃ₅のアルキレン基を表わす。）を表わし、ｍは０〜５の整数を表わす。〕 That is, the present invention is selected from the group consisting of aminoalkoxybibenzyls represented by the following general formula (1), pharmaceutically acceptable salts or esters thereof, and solvates and hydrates thereof. The present invention provides a VEGF secretion enhancer containing a substance as an active ingredient.

[Wherein, R ₁ represents a hydrogen atom, a halogen atom, a C ₁ -C ₅ alkoxy group, or a C ₂ -C ₆ dialkylamino group, and R ² represents a hydrogen atom, a halogen atom, or a C ₁ -C ₅ Represents an alkoxy group, R ³ represents a hydrogen atom, a hydroxyl group, —O— (CH ₂ ) _n —COOH (wherein n represents an integer of 1 to 5), or O—CO— (CH ₂ ) _l. -COOH (wherein 1 represents an integer of 1 to 3), R ⁴ is -N (R ⁵ ) (R ⁶ ) (wherein R ⁵ and R ⁶ are each independently a hydrogen atom or represents an alkyl group of C ₁ ~C _8.) or

(Wherein, A represents a C _{3 to} C ₅ alkylene group which may be substituted with a carboxyl group), and m represents an integer of 0 to 5. ]

アミノアルコキシビベンジル類が下記（３）で表わされる化合物である上記のＶＥＧＦ分泌亢進剤；

及び塩酸塩の形態の上記のＶＥＧＦ分泌亢進剤が提供される。 According to a preferred embodiment of the above invention, the VEGF secretion enhancer described above, wherein the aminoalkoxybibenzyl is a compound represented by the following (2):

The above-mentioned VEGF secretion enhancer, wherein the aminoalkoxybibenzyl is a compound represented by the following (3):

And the above-mentioned VEGF secretion enhancer in the form of hydrochloride.

From another aspect, the present invention provides the above-mentioned VEGF secretion enhancer for use in the prevention and / or treatment of diseases associated with VEGF secretion failure. In addition, aminoalkoxybibenzyls represented by the above general formula (1) for producing the VEGF secretion enhancer, pharmaceutically acceptable salts or esters thereof, solvates thereof and water thereof The use of a substance selected from the group consisting of Japanese is also provided by the present invention.

Further, an aminoalkoxybibenzyl represented by the general formula (1), a pharmaceutically acceptable salt or ester thereof, and a substance selected from the group consisting of solvates and hydrates thereof as an active ingredient A medicament for preventing and / or treating a disease associated with VEGF secretion failure is also provided by the present invention. According to a preferred aspect of the present invention, there is provided the above medicament, wherein the aminoalkoxybibenzyls are in the form of a compound represented by the above formula (2) or (3), preferably a hydrochloride.

Further, from another viewpoint, a method for enhancing VEGF secretion, which is a method for enhancing secretion of VEGF in mammals including humans, aminoalkoxybibenzyls represented by the above general formula (1), pharmaceutically acceptable salts or esters thereof, And a method comprising the steps of administering an effective amount of a substance selected from the group consisting of solvates and hydrates thereof; and a method for preventing and / or treating a disease associated with VEGF secretion deficiency, comprising: A substance selected from the group consisting of the aminoalkoxybibenzyls represented by the above general formula (1), pharmaceutically acceptable salts or esters thereof, and solvates and hydrates thereof There is provided a method comprising the step of administering a prophylactic and / or therapeutically effective amount.

Since the VEGF secretion enhancer of the present invention can increase the VEGF concentration, it is useful as an active ingredient of a medicament for the prevention and / or treatment of a disease associated with VEGF secretion failure.

The VEGF secretion enhancer of the present invention comprises aminoalkoxybibenzyls represented by the above general formula (1), pharmaceutically acceptable salts or esters thereof, and solvates and hydrates thereof. Contains a substance selected from the group as an active ingredient.

R ¹ represents a hydrogen atom; a halogen atom such as a chlorine atom or a fluorine atom; a C _{1 to} C ₅ alkoxy group such as a methoxy group, an ethoxy group or a butoxy group; a C ₂ such as a dimethylamino group, a diethylamino group or a methylethylamino group. shows a dialkylamino group -C _6. R ² represents a hydrogen atom; a halogen atom such as a chlorine atom or a fluorine atom; a C ₁ -C ₅ alkoxy group such as a methoxy group, an ethoxy group, or a butoxy group. R ³ is a hydrogen atom; a hydroxyl _{group; -O- (CH 2) 2 -COOH} , -O- (CH 2) 3 -COOH, etc. -O- (CH ₂₎ in _n -COOH (wherein, n is 1 to 5 represents an integer of); - O-CO- (CH 2) 2 -COOH, -O-CO- (CH 2) 3 -O-CO- (CH 2 -COOH, etc.) in _l -COOH (wherein, l represents an integer of 1 to 3). R ⁴ represents an amino group or an alkyl group having 1 to 8 carbon atoms such as a methylamino group, an ethylamino group, a butylamino group, a hexylamino group, a heptylamino group, a dimethylamino group, a diethylamino group, or a methylethylamino group. A 4- to 6-membered polymethyleneamino group which represents an amino group having ˜2 or a ring such as a trimethyleneamino group, a pentamethyleneamino group or a 3-carboxypentamethyleneamino group may be substituted with a carboxyl group Represents.

Among the compounds included in the general formula (1), some of the compounds preferably used in the present invention are shown in Table-1.

Among these, a compound in which the aminoalkoxy group —OCH ₂ C (R ³ ) H— (CH ₂ ) _m —R ⁴ is bonded to the 2-position of the phenyl group is preferable. R ¹ is preferably a hydrogen atom, a C ₁ -C ₅ alkoxy group, or a C ₂ -C ₆ dialkylamino group, R ² is preferably a hydrogen atom, and R ⁴ is at least one C ₁ -C _8. It is preferably a 4-6 membered polymethyleneamino group having an alkyl group or a trimethylene group or a pentamethylene group, and m is preferably an integer of 0-2. Particularly preferred is ^{No. 1 wherein} R ¹ is a methoxy group, R ² is a hydrogen atom, R ³ is a hydroxyl group, and R ⁴ is a dimethylamino group. 15 and its succinic acid ester No. 15 14 compounds.

Examples of the acid forming a pharmaceutically acceptable salt of the compound represented by the general formula (1) include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, succinic acid, adipic acid, and propion. Acid, tartaric acid, maleic acid, succinic acid, citric acid, benzoic acid, toluenesulfonic acid, methanesulfonic acid and the like are used. Further, a solvate or hydrate of the compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof can also be used. Among these, (±) -1- [O- [2- (m-methoxyphenyl) ethyl] phenoxy] -3- (dimethylamino) -2-propyl represented by the following formula (4) is particularly preferable. Hydrogen succinate hydrochloride (hereinafter, this substance is sometimes referred to as “sarpogrelate hydrochloride” in this specification).

The aminoalkoxybibenzyls represented by the general formula (1), and pharmaceutically acceptable salts and esters thereof are known and can be obtained by the method described in JP-A-58-32847 or a method analogous thereto. Easy to synthesize. The sarpogrelate hydrochloride represented by the above formula (4) is commercially available as “Amprag (registered trademark)” from Mitsubishi Pharma Corporation. In the present invention, the commercially available “Amplag” can be used as it is. is there.

In the present specification, a disease accompanied by VEGF secretion failure is used in a sense including a disease caused by VEGF secretion failure.
The VEGF secretion enhancer of the present invention has an action of increasing the VEGF concentration as compared with the pre-administration value. In addition, the VEGF secretion enhancer of the present invention has an action of increasing the concentration of VEGF and / or suppressing the decrease in the concentration of VEGF in blood, organ, tissue, cell, etc. It can inhibit the development of vascular disorders and the like. Here, VEGF concentration reduction is synonymous with a state in which vascular injury or the like is advanced. Therefore, the VEGF secretion enhancer of the present invention is useful as a medicament for the prevention and / or treatment of diseases associated with VEGF secretion failure. Moreover, it is useful as a pharmaceutical for the prevention and / or treatment of the disease which generally accompanies and / or is caused by a decrease in VEGF concentration. VEGF secretion failure means, for example, that a sufficient concentration of VEGF is secreted in a case where VEGF is secreted and a mechanism for forming a new blood vessel (angiogenesis) needs to be triggered in an affected part of an ischemic disease or the like. It means no state. Thus, it includes not only a state where it is hardly secreted but also a state where an insufficient amount is secreted. Examples of diseases associated with VEGF secretion failure include vascular disorders. Specifically, for example, cerebral infarction, ischemic heart disease, and peripheral circulation disorder, preferably cerebral infarction, myocardial infarction, intermittent claudication, lower limb arterial occlusive sclerosis, and chronic arterial occlusive disease, more preferably intermittent Include, but are not limited to, sexual claudication, lower limb arterial occlusive sclerosis, and chronic arterial occlusive disease.

The administration method when the VEGF secretion enhancer of the present invention is used as a medicine can be appropriately selected by those skilled in the art. For example, it is possible to select any administration route of parenteral administration such as subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, or oral administration. The dosage can be appropriately determined depending on conditions such as the age, health condition, and weight of the patient, the conditions such as the type and frequency of administration, or the nature of the desired effect, if there are drugs to be administered simultaneously. In general, the daily dose of the active ingredient is 0.5 to 50 mg / kg body weight, usually 1 to 30 mg / kg body weight, and can be administered once or more per day.

When the VEGF secretion enhancer of the present invention is used as a medicine, it is preferable to prepare and administer a pharmaceutical composition containing the above active ingredient and one or more additives for pharmaceutical preparation. Examples of the pharmaceutical composition suitable for oral administration include tablets, capsules, powders, solutions, elixirs, and the like, and examples of the pharmaceutical composition suitable for parenteral administration include solutions or suspensions. An example is a sterilized liquid pharmaceutical composition such as an agent.

The type of pharmaceutical additive used for preparing the pharmaceutical composition is not particularly limited, and it is possible to select an appropriate pharmaceutical additive depending on the form of various pharmaceutical compositions. The pharmaceutical additive may be either solid or liquid, and for example, a solid carrier or a liquid carrier can be used. As an example of the solid carrier, a normal gelatin type capsule can be used. In addition, for example, the active ingredient can be tableted together with one or more pharmaceutical additives, or without using pharmaceutical additives, or can be prepared and packaged as a powder. These capsules, tablets, and powders can generally contain 5 to 95% by weight, preferably 5 to 90% by weight, of the active ingredient relative to the total weight of the preparation, and the dosage unit form is 5 to 500 mg. Preferably it contains 25 to 250 mg of active ingredient. As the liquid carrier, water, oils of animal or vegetable origin such as petroleum, peanut oil, soybean oil, mineral oil, sesame oil or synthetic oils are used. In general, physiological saline, dextrol or similar sucrose solution, glycols such as ethylene glycol, propylene glycol, polyethylene glycol and the like are preferable as the liquid carrier, and in the case of an injection solution using physiological saline, it is usually 0.00. It can be prepared to contain 5 to 20%, preferably 1 to 10% by weight of the active ingredient.

Hereinafter, the present invention will be described more specifically with reference to examples. However, the scope of the present invention is not limited to the following examples. In addition, as the sarpogrelate hydrochloride used below, “Amprag (registered trademark)” commercially available from Mitsubishi Pharma Corporation was used.

Sarpogrelate hydrochloride 100 mg tablets were administered 3 times a day for 17 years to 17 diabetic patients with obstructive arteriosclerosis (male: female = 10: 7). Before and after administration, the concentrations of VEGF, thrombomodulin and serotonin (5HT) in the blood of all subjects were measured. The VEGF concentration and thrombomodulin concentration were measured by enzyme immunoassay, and the serotonin concentration was measured by HPLC.

As can be seen from the results in Table 3, after administration of sarpogrelate hydrochloride, the VEGF concentration in the blood was significantly increased as compared with that before administration. In addition, serotonin levels decreased in all subjects, and thrombomodulin levels, which tend to increase due to vascular injury, decreased in all subjects.

Claims (12)

A substance selected from the group consisting of aminoalkoxybibenzyls represented by the following general formula (1), pharmaceutically acceptable salts or esters thereof, and solvates and hydrates thereof as active ingredients VEGF secretion enhancer.

[Wherein, R ₁ represents a hydrogen atom, a halogen atom, a C ₁ -C ₅ alkoxy group, or a C ₂ -C ₆ dialkylamino group, and R ² represents a hydrogen atom, a halogen atom, or a C ₁ -C ₅ Represents an alkoxy group, R ³ represents a hydrogen atom, a hydroxyl group, —O— (CH ₂ ) _n —COOH (wherein n represents an integer of 1 to 5), or O—CO— (CH ₂ ) _l. -COOH (wherein 1 represents an integer of 1 to 3), R ⁴ is -N (R ⁵ ) (R ⁶ ) (wherein R ⁵ and R ⁶ are each independently a hydrogen atom or represents an alkyl group of C ₁ ~C _8.) or

(Wherein, A represents a C _{3 to} C ₅ alkylene group which may be substituted with a carboxyl group), and m represents an integer of 0 to 5. ] The VEGF secretion enhancer according to claim 1, wherein the aminoalkoxybibenzyl is a compound represented by the following (2).

The VEGF secretion enhancer according to claim 1, wherein the aminoalkoxybibenzyl is a compound represented by the following (3).

The VEGF secretion enhancer according to claim 2 or 3 in the form of hydrochloride. A substance selected from the group consisting of aminoalkoxybibenzyls represented by the general formula (1) according to claim 1, pharmaceutically acceptable salts or esters thereof, and solvates and hydrates thereof. A medicament for the prevention and / or treatment of diseases associated with VEGF secretion failure, comprising as an active ingredient. The pharmaceutical according to claim 5, wherein the aminoalkoxybibenzyl is a compound represented by the formula (2) according to claim 2. The pharmaceutical according to claim 5, wherein the aminoalkoxybibenzyl is a compound represented by the formula (3) according to claim 3. 8. A medicament according to claim 6 or 7 in the form of a hydrochloride. The medicament according to any one of claims 5 to 8, wherein the disease is a vascular disorder. The medicament according to claim 9, wherein the disease is selected from the group consisting of cerebral infarction, ischemic heart disease, and peripheral circulation disorder. The medicament according to claim 9, wherein the disease is selected from the group consisting of cerebral infarction, myocardial infarction, intermittent claudication, lower limb arterial occlusive sclerosis, and chronic arterial occlusive disease. The medicament according to claim 9, wherein the disease is selected from the group consisting of intermittent claudication, lower limb arterial occlusive sclerosis, and chronic arterial occlusive disease.