JP2009091326A - 1-benzylindole derivative and use thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new HIF-1α activity inhibitor having vascularization inhibiting activity stronger than that of a conventional vascular endothelial growth factor antibody or inhibitor. <P>SOLUTION: The HIF-1α activity inhibitor contains a 1-benzylindole derivative expressed by general formula (1) as an active component. In the formula, X and Y are each independently or dependently a hydrogen atom, a lower alkyl group, a halogen atom, a lower alkoxy group or a benzyloxy group; Z is a hydrogen atom or a lower acyl group; and Ar is an aryl group or a heteroaryl group which may have 1-3 substituents. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to 1-benzylindole derivatives that inhibit HIF-1α activity, and uses thereof.

  In recent years, angiogenesis inhibitors have attracted attention as therapeutic agents for diseases caused by angiogenesis and diseases that require angiogenesis. For example, an example of such a disease is age-related macular degeneration (AMD). AMD is a disease caused by changes in the macular with aging and is one of the causes of blindness in the elderly. In particular, exudative AMD with neovascularization generated from the choroid is often accompanied by a rapid visual loss, and it has been found that it is important to suppress this neovascularization to improve the pathological condition (non-patent) Reference 1). As a main treatment, there is photodynamic therapy (PDT: Photo Dynamic Therapy). That is, after the intravenous injection of the photosensitive substance verteporfin and the drug is accumulated in the choroidal neovascularization, the verteporfin is photoactivated with a laser to retreat the choroidal neovascularization. In recent years, antibodies (Lucentis) and aptamers (Macugen) against vascular endothelial growth factor (VEGF), which is one of angiogenic factors, have been approved as therapeutic agents for AMD, and have been clinically effective. It is coming. However, there are problems such as the limited facilities where PDT can be performed, the high cost, and the fact that both anti-VEGF antibodies and aptamers are polymer preparations and require high medical costs. Therefore, a low molecular weight compound that can effectively suppress angiogenesis is desired. In addition, in the field of cancer diseases, a therapeutic method for suppressing angiogenesis necessary for the growth of cancer has attracted great expectations, and so far anti-VEGF antibody (Avastin) has been approved and applied as a therapeutic agent. Has been.

  However, recently, it has been clarified that transcription factor HIF-1α (Hypoxia-inducing Factor-1α) induces the expression of a plurality of angiogenic factors including VEGF (Non-patent Document 2). -5). This HIF-1α cannot be detected because it is rapidly decomposed after being oxidized by HIF prolyl hydroxylase at a normal oxygen concentration, but this oxidation does not occur in a hypoxic state such as cancer tissue. Strongly activates angiogenic factors (Non-Patent Documents 6 and 7). For this reason, inhibitors of HIF-1α that induce the expression of a plurality of angiogenic factors such as VEGF have come to be expected as drugs having new angiogenesis inhibitory activity.

  As an HIF-1α activity inhibitor, YC-1 described in Non-Patent Document 8 is known. This compound has a 1-benzylindole skeleton as a partial structure, but the substituent at the 3-position of the indole ring is different from the compound of the present invention.

  In addition, the compounds reported in Patent Documents 1 and 2 are known as similar compounds. However, the compound group of Patent Document 1 is different in the substituent at the 3-position of the indole ring, and there is no description about the hydroxymethyl group and the lower acyloxymethyl group, and the use is for the treatment of prostaglandin-related diseases via the EP3 receptor. There is no description about the inhibitory action of HIF-1α.

  The compound group of Patent Document 2 is a compound having a benzoyl group or a phenoxy group at the 1-position, 3-position or 7-position of the indole ring, which is different from the skeleton of the present invention. Moreover, although the effect | action regarding the angiogenesis by tubulin polymerization inhibitor activity is disclosed as a pharmacological action of these compound groups, it does not describe at all about the effect | action with respect to HIF-1 (alpha).

Furthermore, Patent Document 3 discloses a compound group having a carbonyl group and a hydroxymethyl group at the 3-position of the indole ring in the skeleton of this patent (a phenyl group in which Ar ₂ has one methyl group in the following general formula (3)) A Ras inhibitory action of a compound comprising 1- (2,4-dichlorobenzyl) -3- (hydroxymethyl) indole and 1- (3,4-dichlorobenzyl) -3- (hydroxymethyl) indole); Although the cell growth inhibitory effect resulting from it is shown, there is no description about the effect | action with respect to HIF-1 (alpha).

  Patent Document 4 describes an indole derivative having antifungal and antiparasitic activity, but does not describe an action on HIF-1α.

Non-Patent Document 9 includes 5-chloro-1- (4-chlorobenzyl) -3- (hydroxymethyl) indole, 5-fluoro-1- (4-chlorobenzyl) -3- (hydroxymethyl) indole and A compound in which Ar ₂ is a phenyl group having one halogen atom in the general formula (3) and has anti-Leishmania activity is described, but there is no description on the action on HIF-1α . Non-Patent Document 10 includes 1- (3-methoxybenzyl) -3- (hydroxymethyl) indole, and Non-Patent Document 11 includes antibacterial activity 1- (2,4-difluorobenzyl) -3- (hydroxymethyl). Although indole is described, there is no description about the effect | action with respect to HIF-1 (alpha).

Can. J. et al. Ophthamol. , 40, p. 352 (2005). Mol. Cell. Biol. 16, p. 4604 (1996). Genes Dev. , 14, p. 34 (2000). Proc. Natl. Acad. Sci. USA, 99, p. 10423 (2002). Blood, 107, p. 2705 (2006). Nature, 399, p. 271 (1999). Science, 292, p. 468 (2001). J. et al. Natl. Cancer Inst. 95, p. 498 (2003). J. et al. Enzyme Inhibit Med. Chem. , 19, p. 451 (2004). J. et al. Indian Chem. Soc. 76, p. 601 (1999). Eur. J. et al. Med. Chem. , 38, p. 75-87 (2003).

US Patent Application Publication No. 2006/0079520 US Patent Application Publication No. 2005/0267108 International Publication No. 2007/062399 Pamphlet Special Table 2004-509886

  The object of the present invention is to provide a novel inhibitor of HIF-1α activity.

  As a result of various searches for synthetic compounds to solve the above problems, the present inventors have found that 1-benzylindole derivatives have HIF-1α inhibitory activity, and have completed the present invention.

That is, the present invention relates to the general formula (1)

(In the formula, X and Y may be each independently a hydrogen atom, a lower alkyl group, a halogen atom, a lower alkoxy group, or a benzyloxy group, Z represents a hydrogen atom or a lower acyl group, and Ar represents 1-benzyl represented by an aryl group or heteroaryl group which may have 1 to 3 substituents selected from the group consisting of a lower alkyl group, a halogen atom, a lower alkoxy group, and a phenyl group. An inhibitor of HIF-1α activity comprising an indole derivative, a hydrate thereof, a solvate thereof, or a pharmacologically acceptable salt thereof as an active ingredient,
(2) In the general formula (1), one of X and Y is a hydrogen atom, the 1-benzylindole derivative according to (1), a hydrate, a solvate thereof, or a pharmacological thereof An inhibitor of HIF-1α activity comprising a salt acceptable to
(3) The 1-benzylindole derivative, its hydrate, its solvate, or its pharmacologically acceptable salt as described in said (2) whose Z is a hydrogen atom in General formula (1). An HIF-1α activity inhibitor as an active ingredient,
(4) The 1-benzylindole derivative according to (3), wherein either one of X and Y is a hydrogen atom in the general formula (1) and the other is a hydrogen atom, a lower alkyl group or a halogen atom, An inhibitor of HIF-1α activity comprising a hydrate, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient,
(5) The 1-benzylindole derivative according to (4), wherein either one of X and Y is a hydrogen atom in the general formula (1) and the other is a hydrogen atom, a methyl group or a fluorine atom, HIF-1α activity inhibitor comprising a hydrate, a solvate thereof, or a pharmacologically acceptable salt thereof as an active ingredient,
(6) In the general formula (1), Ar is an aryl group which may have 1 to 2 substituents selected from the group consisting of a chlorine atom, a fluorine atom, a methyl group, a methoxy group and a phenyl group. A HIF-1α activity inhibitor comprising as an active ingredient the 1-benzylindole derivative according to (5), a hydrate thereof, a solvate thereof, or a pharmacologically acceptable salt;
(7) In the general formula (1), Ar is 3,4-dichlorophenyl group, 3,4-difluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 3,4-dimethylphenyl group, The 1-benzylindole derivative, its hydrate, its solvate, or its pharmacologically acceptable salt as described in said (6) which is 4-methoxyphenyl group and 4-biphenyl group is used as an active ingredient. HIF-1α activity inhibitor,
(8) The 1-benzylindole derivative, its hydrate, its solvate, or its pharmacologically acceptable as described in said (7) whose both X and Y are hydrogen atoms in General formula (1). A HIF-1α activity inhibitor comprising the salt as an active ingredient,
(9) The 1-benzylindole derivative, its hydrate, its solvate, or its pharmacologically acceptable salt as described in said (2) whose Z is a lower acyl group in General formula (1) An HIF-1α activity inhibitor comprising as an active ingredient,
(10) The 1-benzylindole derivative, its hydrate, its solvate, or its pharmacologically acceptable salt as described in said (9) whose Z is an acetyl group in General formula (1). An HIF-1α activity inhibitor as an active ingredient,
(11) In the general formula (1), one of X and Y is a hydrogen atom, and the other is a hydrogen atom or a methyl group, the 1-benzylindole derivative according to (10), a hydrate thereof, An inhibitor of HIF-1α activity comprising the solvate or a pharmacologically acceptable salt thereof as an active ingredient,
(12) In the general formula (1), X and Y are both hydrogen atoms, and Ar is a phenyl group optionally having 1 to 2 halogen atoms. An inhibitor of HIF-1α activity comprising a benzylindole derivative, a hydrate thereof, a solvate thereof, or a pharmacologically acceptable salt thereof as an active ingredient,
(13) General formula (2)

(In the formula, Y ₁ represents a lower alkyl group, a fluorine atom, a chlorine atom, a lower alkoxy group, or a benzyloxy group, and Ar ₁ represents a heteroaryl group, or a lower alkyl group, a phenyl group, a halogen atom, and a lower alkoxy group. An aryl group optionally having 1 or 2 substituents selected from the group consisting of Ar ₁ is a 4-chlorophenyl group, and Y ₁ is a combination of 5-chlorine atom or 5-fluorine atom; And a 1-benzyl-3- (hydroxymethyl) indole derivative represented by the formula: Ar ₁ is a phenyl group and Y ₁ is a combination of 5-methoxy groups), its hydrate, its solvent Japanese or a pharmacologically acceptable salt thereof,
(14) The 1-benzyl-3- (hydroxymethyl) indole derivative according to (13), wherein Y ₁ is a methyl group, a fluorine atom, a methoxy group, or a benzyloxy group in the general formula (2), and hydration thereof , A solvate thereof, or a pharmaceutically acceptable salt thereof,
(15) The general formula (2), wherein Ar ₁ is an aryl group optionally having 1 to 2 methyl groups, fluorine atoms, chlorine atoms, or methoxy groups, or a pyridyl group. 1-benzyl-3- (hydroxymethyl) indole derivative, hydrate, solvate thereof, or pharmacologically acceptable salt thereof,
(16) In the general formula (2), Y ₁ is a 5-methyl group, 4-methyl group, 7-methyl group, 5-fluorine atom, 6-fluorine atom, 5-methoxy group or 6-methoxy group, The ₁ -benzyl-3 (hydroxymethyl) indole derivative, its hydrate, its solvate, or its pharmacologically acceptable salt as described in said (15) whose Ar < ₁ > is a 3, 4- dichlorophenyl group. ,
(17) General formula (3)

(In the formula, Ar ₂ represents a heteroaryl group or an aryl group having 1 to 2 substituents selected from the group consisting of a lower alkyl group, a halogen atom, a lower alkoxy group, and a phenyl group. ₂ has one halogen atom or methyl group, phenyl group, 3-methoxyphenyl group, 2,4-dichlorophenyl group, 3,4-dichlorophenyl group, 2,4-difluorophenyl group, and 3,5- 1-benzyl-3- (hydroxymethyl) indole derivatives represented by the following formulas, hydrates, solvates, or pharmaceutically acceptable salts thereof:
(18) In general formula (3), Ar ₂ is a pyridyl group, a phenyl group having two substituents selected from the group consisting of a methyl group, a fluorine atom, and a chlorine atom, a 4-methoxy group, or a 4-phenyl group The 1-benzyl-3- (hydroxymethyl) indole derivative according to the above (17), a hydrate, a solvate thereof, or a pharmaceutically acceptable salt thereof,
(19) In the general formula (3), Ar ₂ is 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 3,4-difluorophenyl group, 3,4-dimethylphenyl group, 2,3-dichlorophenyl group. 1-benzyl-3- (hydroxymethyl) indole derivative according to (18), which is a 2,5-dichlorophenyl group, 4-methoxyphenyl group or 4-biphenyl group, a hydrate thereof, a solvate thereof, Or a pharmacologically acceptable salt thereof.
(20) General formula (4)

(In the formula, Y ₃ represents a hydrogen atom, a lower alkyl group, a halogen atom, a lower alkoxy group, or a benzyloxy group, Z ₃ represents a lower acyl group, Ar ₃ represents a lower alkyl group, a halogen atom, or a lower alkoxy group. A 1-benzyl-3- (lower acyloxymethyl) indole derivative represented by the following: an aryl group which may have 1 to 3 substituents in combination consisting of phenyl groups, or a heteroaryl group; Hydrates, solvates thereof, or pharmacologically acceptable salts thereof.
(21) In the general formula (4), 1-benzyl-3- (lower acyloxymethyl) indole derivative according to (20), wherein Z ₃ is an acetyl group, a hydrate, a solvate thereof, or a A pharmacologically acceptable salt,
(22) The 1-benzyl-3- (lower acyloxymethyl) indole derivative according to (21), wherein Y ₃ is a hydrogen atom in the general formula (4), a hydrate, a solvate thereof, or a A pharmacologically acceptable salt,
(23) 1-benzyl-3- (lower acyloxymethyl) according to claim 22, wherein Ar ₃ in formula (4) is a pyridyl group or a phenyl group optionally having 1 or 2 chlorine atoms. Indole derivatives, hydrates thereof, solvates thereof, or pharmacologically acceptable salts thereof,
(24) 3-acetoxymethyl-1- (3,4-dichlorobenzyl) indole, a hydrate, a solvate, or a pharmacologically acceptable salt thereof according to (20),

(25) An angiogenesis inhibitor comprising as an active ingredient the compound according to any one of (1) to (12) or a hydrate, solvate, or pharmacologically acceptable salt thereof. ,
(26) Age-related macular degeneration comprising as an active ingredient the compound according to any one of (1) to (12) above or a hydrate, solvate, or pharmacologically acceptable salt thereof. Disease treatment agent,
About.

  According to the present invention, it is revealed that 1-benzylindole derivatives have HIF-1α inhibitory activity, and clinical application as antiangiogenic inhibitors and therapeutic agents for neovascular age-related macular degeneration is expected. .

  In the present invention, the lower alkyl group represents a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, ethyl group, n-propyl group, isopropyl group, dimethylpropyl group, isobutyl group, n- A butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an n-hexyl group, and the like can be given. Of these, a preferred group is a methyl group.

  In the present invention, the aryl group represents an aromatic hydrocarbon group having 6 to 14 carbon atoms, and examples thereof include a phenyl group, a naphthyl group, an anthryl group, and a phenanthryl group. Among these, preferred groups include a phenyl group and a naphthyl group. A more preferred group is a phenyl group.

  In the present invention, a heteroaryl group refers to a heteroaromatic group containing 1 to 4 nitrogen atoms, oxygen atoms or sulfur atoms as heteroatoms as the same or different heteroatoms, such as a furyl group, a thienyl group, an imidazolyl group, or a triazolyl group. , Tetrazolyl group, oxazolyl group, thiazolyl group, pyridyl group, indolyl group, thiazolyl group, furazanyl group, pyrimidinyl group, pyridazinyl group, pyrazinyl group, quinoxalyl group and the like. Among these, a preferred group is a pyridyl group.

  In the present invention, the lower alkoxy group means a lower alkyloxy group, and the lower alkyl group represents a linear or branched alkyl group having 1 to 6 carbon atoms as described above, and includes, for example, a methoxy group, an ethoxy group, n- Examples thereof include a propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, and a tert-butoxy group. Among these, a methoxy group can be mentioned as a preferable group.

  In the present invention, the halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Among these, preferred atoms include a fluorine atom and a chlorine atom.

  Examples of the pharmacologically acceptable hydrate of the compound of the present invention include those in a state of being associated with or bound to one or more water molecules. In addition, the hydrate of the compound of the present invention includes the hydrate of the pharmacologically acceptable salt of the compound of the present invention.

  Examples of the pharmacologically acceptable solvate of the compound of the present invention include alcohol solvents such as ethanol or propanol, organic acids such as acetic acid, esters such as ethyl acetate, ethers such as tetrahydrofuran or diethyl ether, And solvates such as dimethyl sulfoxide. The solvate is preferably non-toxic and water-soluble. Moreover, the solvate of the compound of the present invention includes a solvate of a pharmacologically acceptable salt of the compound of the present invention.

  The pharmacologically acceptable salts of the compounds of the present invention include salts with mineral acids such as hydrochloric acid and sulfuric acid, acetic acid, benzoic acid, succinic acid, fumaric acid, maleic acid, citric acid, lactic acid, tartaric acid, methanesulfonic acid And salts with organic acids such as benzenesulfonic acid. These salts can be produced according to a conventional method.

Examples of the compound represented by the general formula (1) include the following compounds.
(1) 1- (3,4-dichlorobenzyl) -3- (hydroxymethyl) indole (2) 1- (2-chlorobenzyl) -3- (hydroxymethyl) indole (3) 1- (3,4- (Dichlorobenzyl) -3-hydroxymethyl-5-methylindole (4) 1- (3,4-difluorobenzyl) -3- (hydroxymethyl) indole (5) 1- (3,4-dichlorobenzyl) -3- Hydroxymethyl-4-methylindole (6) 1- (3,4-dichlorobenzyl) -6-fluoro-3- (hydroxymethyl) indole (7) 1- (2-naphthylmethyl) -3- (hydroxymethyl) Indole (8) 1-benzyl-3- (hydroxymethyl) indole (9) 1- (4-chlorobenzyl) -3- (hydroxymethyl) indole (10 1- (3-chlorobenzyl) -3- (hydroxymethyl) indole

(11) 3- (hydroxymethyl) -1- (2-pyridylmethyl) indole (12) 1- (3,4-dimethylbenzyl) -3- (hydroxymethyl) indole (13) 3-hydroxymethyl-1- (4-Methoxybenzyl) indole (14) 1- (4-biphenylmethyl) -3- (hydroxymethyl) indole (15) 1- (3,4-dichlorobenzyl) -5-fluoro-3- (hydroxymethyl) Indole (16) 1- (3,4-dichlorobenzyl) -3-hydroxymethyl-7-methylindole (17) 1- (3,4-dichlorobenzyl) -3-hydroxymethyl-6-methoxyindole (18) 3-Hydroxymethyl-1- (3-pyridylmethyl) indole (19) 1- (2,3-dichlorobenzyl) -3- (hydro Shimechiru) indole (20) 3-hydroxymethyl-1- (4-pyridylmethyl) indole

(21) 1- (2,5-dichlorobenzyl) -3- (hydroxymethyl) indole (22) 6-benzyloxy-1- (3,4-dichlorobenzyl) -3- (hydroxymethyl) indole (23) 1- (3,4-dichlorobenzyl) -3-hydroxymethyl-5-methoxyindole (24) 5-benzyloxy-1- (3,4-dichlorobenzyl) -3- (hydroxymethyl) indole (25) 4 -Benzyloxy-1- (3,4-dichlorobenzyl) -3- (hydroxymethyl) indole (26) 7-benzyloxy-1- (3,4-dichlorobenzyl) -3- (hydroxymethyl) indole (27 ) 1- (2,6-dichlorobenzyl) -3- (hydroxymethyl) indole (28) 5-benzyloxy-1- (4-ter - butylbenzyl) -3- (hydroxymethyl) indole

(29) 3-acetoxymethyl-1- (3,4-dichlorobenzyl) indole (30) 3-acetoxymethyl-1-benzylindole (31) 3-acetoxymethyl-1- (3,4-dichlorobenzyl)- 5-methylindole (32) 3-acetoxymethyl-1- (3,4-difluorobenzyl) indole

  The 1-benzylindole derivative of the present invention can be synthesized from a compound of the following general formula (5) according to the method of Patent Document 4. In addition, the compound represented by General formula (5) can be easily obtained from a market. That is, the following general formula (5)

（式中、ＸおよびＹは前記に記載の通りである。）で表される化合物に、Ａｒ−ＣＨ₂−Ｑ（ＱはＣｌ、Ｂｒ、ＯＳＯ₂ＣＨ₃、ＯＳＯ₂Ｐｈなどの脱離基を示す）を１〜５当量、好ましくは１〜２当量を加えて、塩基性条件化で反応させることにより、

(Wherein X and Y are as described above), Ar—CH ₂ -Q (Q is a leaving group such as Cl, Br, OSO ₂ CH ₃ , OSO ₂ Ph, etc.) By adding 1 to 5 equivalents, preferably 1 to 2 equivalents, and reacting under basic conditions,

（式中、Ｘ、Ｙ、Ａｒは前記に記載の通りである。）で表される化合物を得ることができる。続いて、この化合物を水素化ホウ素ナトリウム等の還元剤によってアルデヒド基を水酸基へ還元することにより、下記一般式（１）

(Wherein, X, Y, and Ar are as described above) can be obtained. Subsequently, by reducing the aldehyde group to a hydroxyl group with a reducing agent such as sodium borohydride, the following general formula (1)

（式中、Ｘ、Ｙ、Ａｒは前記に記載の通りであり、Ｚは水素原子を示す。）で表される本発明の１−ベンジルインドール誘導体を得ることができる。更には一般式（１）のＺが低級アシル基である化合物群は、Ｚが水酸基である化合物群を塩基性条件下、対応する酸無水物もしくは酸塩化物等の低級アシル化剤で処理することにより、所望の誘導体へ導くことができる。

(Wherein, X, Y, and Ar are as described above, and Z represents a hydrogen atom), the 1-benzylindole derivative of the present invention can be obtained. Further, in the compound group in which Z in the general formula (1) is a lower acyl group, the compound group in which Z is a hydroxyl group is treated with a corresponding lower acylating agent such as acid anhydride or acid chloride under basic conditions. This can lead to the desired derivative.

  5-Methoxy-1-benzyl-3- (hydroxymethyl) indole and 1- (3,5-difluorobenzyl) -3- (hydroxymethyl) indole are available from a compound library.

  In order to isolate and purify the target product from the reaction mixture obtained by each of the above synthesis methods, solvent extraction, concentration, crystallization, distillation, suspension purification, various chromatographies, etc. are used as necessary. be able to.

  For the 1-benzylindole derivative of the present invention, for example, various conventionally known methods can be applied as a formulation and administration method when used as a pharmaceutical agent such as an angiogenesis inhibitor and a therapeutic agent for age-related macular degeneration. That is, as an administration method, for example, injection (subcutaneous injection, intravenous injection, intraarterial injection, etc.), oral or rectal administration, and the like are possible.

  As long as it does not adversely affect the 1-benzylindole derivative of the present invention, its hydrate, its solvate, or its pharmacologically acceptable salt during formulation, it can be used for various pharmaceuticals. Additives, that is, carriers and other auxiliaries such as stabilizers, preservatives, soothing agents, emulsifiers and the like may be used. In the preparation, the content of the 1-benzylindole derivative, its hydrate, its solvate, or pharmacologically acceptable salt can vary widely depending on the form of the preparation, etc. It contains 100% (weight), preferably 0.1 to 70% (weight). In the case of an oral preparation, it is used in the form of tablets, capsules, powders, granules, liquids, dry syrups and the like together with additives. Capsules, tablets, granules and powders generally contain from 5 to 100% (by weight), preferably from 25 to 98% (by weight) of the active ingredient.

  The dose of the 1-benzylindole derivative of the present invention, its hydrate, its solvate, or its pharmacologically acceptable salt varies depending on the indication, symptoms, administration method, etc. About 0.01 to 800 mg per unit.

  EXAMPLES Next, the present invention will be specifically described with reference to synthesis examples and pharmacological experimental examples of the compounds of the present invention as examples, but the present invention is not limited to these examples. Moreover, below, room temperature shows 10-30 degreeC. LCMS was analyzed by LCMS2010A manufactured by Shimadzu Corporation. LC used Inertsil ODS-3 (φ2.1 × 100 mm) as a column, 0.1% formic acid aqueous solution as eluent A, and acetonitrile as eluent B, respectively. In LCMS (A), the concentration of the eluent B is a flow rate with a gradient of 20 (0 min) -90% (5.5 min) -90% (6.5 min) -20% (6.51 min) -20% (10 min). Elution at 0.3 mL / min. In LCMS (B), the concentration of eluent B is 60 (0 min) -90% (5.5 min) -90% (6.5 min) -60% (6.51 min) -60% Elution with a gradient of (10 min) at a flow rate of 0.3 mL / min. In LCMS (C), the concentration of eluent B is 5 (0 min) -90% (5.5 min) -90% ( Was eluted at a flow rate of 0.3 mL / min with a gradient of .5min) -5% (6.51min) -5% (10min). The retention time (Rt) was the time to the UV detector, and MS was measured in ESI (Positive) mode.

Example 1
Synthesis of 1- (3,4-dichlorobenzyl) -3- (hydroxymethyl) indole Synthesis of 1- (3,4-dichlorobenzyl) indole-3-aldehyde (first step)
Cesium carbonate (32.58 g, 100 mmol) and acetonitrile (100 mL) were added to indole-3-aldehyde (7.26 g, 50.0 mmol), and the mixture was heated to reflux for 2 hours. To this solution was added a solution of 3,4-dichlorobenzyl chloride (10.77 g, 55.0 mmol) in acetonitrile (10 mL), and the mixture was heated to reflux for 1 hour.
After completion of the reaction, the solvent of the reaction solution was distilled off under reduced pressure, water (200 mL) was added, and the mixture was extracted 3 times with dichloromethane (150 mL). The extracted organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain crystals. The crystals were washed with a dichloromethane-n-hexane (1: 3) mixed solution to obtain a light brown target product (13.00 g) in a yield of 85.5%.

Synthesis of 1- (3,4-dichlorobenzyl) -3- (hydroxymethyl) indole (second step)
To a solution of 1- (3,4-dichlorobenzyl) indole-3-aldehyde (6.08 g, 20.0 mmol) obtained in the first step in a tetrahydrofuran (30 mL) -methanol (10 mL) mixed solution at room temperature. Then, sodium borohydride (0.83 g, 21.9 mmol) was added, and the mixture was stirred at the same temperature for 1 hour.
After completion of the reaction, acetone (5 mL) was added and stirred for 10 minutes, and then the solvent was distilled off under reduced pressure to obtain colorless crystals (6.40 g). The crystals were dissolved in dichloromethane (80 mL), and n-hexane (160 mL) was added and recrystallized to obtain the desired product (3.92 g) as colorless crystals in a yield of 64.0%.

1H-NMR (CDCl ₃ , ppm): 7.76 (1H, d, J = 7.5 Hz), 7.35 (1H, d, J = 8.2 Hz), 7.17-7.25 (4H, m), 7.10 (1H, s), 6.90 (1H, dd, J = 8.2, 1.8 Hz), 5.23 (2H, s), 4.88 (2H, d, J = 5.5 Hz), 1.54 (2H, t, J = 5.5 Hz).
LCMS (A): Rt = 6.690min , m / z: 288 (M-H 2 O + H) +.

Example 2
Synthesis of 1- (2-chlorobenzyl) -3- (hydroxymethyl) indole Synthesis of 1- (2-chlorobenzyl) indole-3-aldehyde (first step)
Cesium carbonate (6.52 g, 20.0 mmol) and acetonitrile (20 mL) were added to indole-3-aldehyde (1.45 g, 9.99 mmol), and the mixture was heated to reflux for 2 hours. To this solution was added 2-chlorobenzyl chloride (1.78 g, 11.1 mmol), and the mixture was heated to reflux for 1 hour.
After completion of the reaction, the solvent of the reaction solution was distilled off under reduced pressure, water was added, and the mixture was extracted 3 times with dichloromethane. The extracted organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain crystals. The crystals were washed with acetonitrile and recrystallized from dichloromethane-n-hexane to obtain a light brown target product (1.77 g) in a yield of 66%.

Synthesis of 1- (2-chlorobenzyl) -3- (hydroxymethyl) indole (second step)
To a solution of 1- (2-chlorobenzyl) indole-3-aldehyde (1.50 g, 5.56 mmol) obtained in the first step dissolved in a tetrahydrofuran (8 mL) -methanol (2 mL) mixed solution at room temperature, Sodium borohydride (0.23 g, 6.08 mmol) was added and stirred at the same temperature for 1.5 hours.
After completion of the reaction, acetone (1 mL) was added and stirred for 10 minutes. After the solvent was distilled off under reduced pressure, an oil was obtained. Water was added to this oil and extracted three times with dichloromethane. The extracted organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain crystals (1.55 g). The crystals were washed with diethyl ether-n-hexane (1: 2) to obtain the desired product (1.35 g) as colorless crystals in a yield of 89%.

¹ H-NMR (CDCl ₃ , ppm): 7.76 (1H, d, J = 7.7 Hz), 7.41 (1H, dd, J = 7.9, 1.0 Hz), 7.17-7 .25 (6H, m), 6.66 (1H, dd, J = 7.7, 0.6 Hz), 5.38 (2H, s), 4.89 (2H, d, J = 5.3 Hz) 1.52 (2H, t, J = 5.3 Hz).
LCMS (A): Rt = 6.384min , m / z: 254 (M-H 2 O + H) +.

  The compounds of Examples 3 to 28 shown below are synthesized according to the method of synthesizing the compound of Example 1, and the compound having a corresponding substituent instead of indole-3-aldehyde in the first step is further added to 3 This was carried out using the corresponding benzyl chloride instead of 1,4-dichlorobenzyl chloride. The physicochemical properties of each compound obtained for Examples 3 to 28 are shown below.

Example 3
1- (3,4-Dichlorobenzyl) -3-hydroxymethyl-5-methylindole LCMS (A): Rt = 7.229 min, m / z: 302 (M−H ₂ O + H) ⁺ .

Example 4
1- (3,4-Difluorobenzyl) -3- (hydroxymethyl) indole LCMS (B): Rt = 2.491 min, m / z: 256 (M−H ₂ O + H) ⁺ .

Example 5
1- (3,4-Dichlorobenzyl) -3-hydroxymethyl-4-methylindole LCMS (A): Rt = 7.135 min, m / z: 302 (M−H ₂ O + H) ⁺ .

Example 6
1- (3,4-Dichlorobenzyl) -6-fluoro-3- (hydroxymethyl) indole LCMS (A): Rt = 6.954 min, m / z: 306 (M−H ₂ O + H) ⁺ .

Example 7
1- (2-Naphtylmethyl) -3- (hydroxymethyl) indole LCMS (A): Rt = 6.622 min, m / z: 270 (M−H ₂ O + H) ⁺ .

Example 8
1-benzyl-3- (hydroxymethyl) indole LCMS (A): Rt = 5.990 min, m / z: 220 (M−H ₂ O + H) ⁺ .

Example 9
1- (4-Chlorobenzyl) -3- (hydroxymethyl) indole LCMS (A): Rt = 6.368 min, m / z: 254 (M−H ₂ O + H) ⁺ .

Example 10
1- (3-Chlorobenzyl) -3- (hydroxymethyl) indole LCMS (A): Rt = 6.311 min, m / z: 254 (M−H ₂ O + H) ⁺ .

Example 11
3- (hydroxymethyl) -1- (2-pyridylmethyl) indole LCMS (C): Rt = 4.815 min, m / z: 239 (M + H) ⁺ .

Example 12
1- (3,4-Dimethylbenzyl) -3- (hydroxymethyl) indole LCMS (B): Rt = 3.275 min, m / z: 248 (M−H ₂ O + H) ⁺ .

Example 13
3-hydroxymethyl-1- (4-methoxybenzyl) indole LCMS (B): Rt = 2.240 min, m / z: 250 (M−H ₂ O + H) ⁺ .

Example 14
1- (4-biphenylmethyl) -3- (hydroxymethyl) indole LCMS (A): Rt = 3.864 min, m / z: 296 (M−H ₂ O + H) ⁺ .

Example 15
1- (3,4-Dichlorobenzyl) -5-fluoro-3- (hydroxymethyl) indole LCMS (A): Rt = 6.917 min, m / z: 306 (M−H ₂ O + H) ⁺ .

Example 16
1- (3,4-Dichlorobenzyl) -3-hydroxymethyl-7-methylindole LCMS (A): Rt = 7.148 min, m / z: 302 (M−H ₂ O + H) ⁺ .

Example 17
1- (3,4-Dichlorobenzyl) -3-hydroxymethyl-6-methoxyindole LCMS (A): Rt = 6.738 min, m / z: 318 (M−H ₂ O + H) ⁺ .

Example 18
3-hydroxymethyl-1- (3-pyridylmethyl) indole LCMS (C): Rt = 3.933 min, m / z: 239 (M + H) ⁺ .

Example 19
1- (2,3-dichlorobenzyl) -3- (hydroxymethyl) indole LCMS (A): Rt = 6.854 min, m / z: 288 (M−H ₂ O + H) ⁺ .

Example 20
3-hydroxymethyl-1- (4-pyridylmethyl) indole LCMS (C): Rt = 3.724 min, m / z: 239 (M + H) ⁺ .

Example 21
1- (2,5-dichlorobenzyl) -3- (hydroxymethyl) indole LCMS (A): Rt = 6.757 min, m / z: 288 (M−H ₂ O + H) ⁺ .

Example 22
6-Benzyloxy-1- (3,4-dichlorobenzyl) -3- (hydroxymethyl) indole LCMS (A): Rt = 7.581 min, m / z: 394 (M−H ₂ O + H) ⁺ .

Example 23
1- (3,4-dichlorobenzyl) -3-hydroxymethyl-5-methoxyindole LCMS (A): Rt = 6.732 min, m / z: 318 (M−H ₂ O + H) ⁺ .

Example 24
5-Benzyloxy-1- (3,4-dichlorobenzyl) -3- (hydroxymethyl) indole LCMS (A): Rt = 7.671 min, m / z: 394 (M−H ₂ O + H) ⁺ .

Example 25
4-Benzyloxy-1- (3,4-dichlorobenzyl) -3- (hydroxymethyl) indole LCMS (A): Rt = 7.841 min, m / z: 394 (M−H ₂ O + H) ⁺ .

Example 26
7-Benzyloxy-1- (3,4-dichlorobenzyl) -3- (hydroxymethyl) indole LCMS (A): Rt = 7.815 min, m / z: 394 (M−H ₂ O + H) ⁺ .

Example 27
1- (2,6-dichlorobenzyl) -3- (hydroxymethyl) indole LCMS (A): Rt = 6.647 min, m / z: 288 (M−H ₂ O + H) ⁺ .

Example 28
5-Benzyloxy-1- (4-tert-butylbenzyl) -3- (hydroxymethyl) indole LCMS (B): Rt = 4.371 min, m / z: 276 (M−H ₂ O + H) ⁺ .

Example 29
Synthesis of 3-acetoxymethyl-1- (3,4-dichlorobenzyl) indole 1- (3,4-dichlorobenzyl) -3- (hydroxymethyl) indole obtained in Example 1 (153 mg, 0.500 mmol) Was dissolved in pyridine (0.5 mL), acetic anhydride (1.0 mL, 10.6 mmol) was added, and the mixture was stirred at room temperature overnight.
After completion of the reaction, toluene was added to the reaction solution, and the solvent and acetic anhydride were distilled off under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate. The extracted organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain an oil. The oil was purified by silica gel column chromatography to obtain a colorless target product (71.3 mg) in a yield of 41%.
LCMS (A): Rt = 5.337min , m / z: 288 (M-CH 3 COOH + H) +.

Test example 1
HIF-1α-dependent transcriptional activity inhibitory action (1-1) Preparation of a reporter vector for measuring HIF-1α-dependent transcription VEGF known as HIF-1α-responsive element for measuring HIF-1α-dependent transcription The 47 bp HRE (Hypoxia Responsible Element) sequence existing upstream of the -A (basal endothelial growth factor-A) gene was used.

  The HRE oligonucleotide (Molecular and Cellular Biology, 16 (9), p. 4604-4613 (1996)) shown in SEQ ID Nos. 1 and 2 in the sequence listing was synthesized (requested from Operon Biotechnologies) to be 100 μM. Diluted with distilled water.

  1 μL of each was mixed, heated at 95 ° C. for 5 minutes, and then returned to room temperature and annealed. As a vector to be introduced, a pBluescriptKS (+) vector (manufactured by Toyobo Co., Ltd.) was used. The pBluescriptKS (+) vector was cleaved with a restriction enzyme EcoRV (manufactured by Toyobo Co., Ltd.), and ethanol precipitated. Next, this DNA was washed with 70% ethanol and dissolved in TE solution (10 mM Tris-hydrochloric acid (pH 8), 1 mM EDTA). The DNA and the annealed HRE oligonucleotide were mixed at a molar ratio of 1: 100 and connected using a DNA ligation kit (Takara Shuzo). Hereinafter, this plasmid is referred to as pBSKS (+) / HRE vector.

  Subsequently, the pBSKS (+) / HRE vector was cleaved with restriction enzymes SacI (Toyobo) and XhoI (Toyobo) and fractionated by 0.8% agarose electrophoresis. A fragment containing the HRE sequence was extracted and purified (hereinafter referred to as HRE / SacI, XhoI). For purification, EASYTRAP (Takara Shuzo) was used. As a vector to be introduced, a pGL3-neo-promoter vector in which a neomycin resistance gene as a selection marker was introduced into a BamHI site of a pGL3-promoter vector (manufactured by Promega), which is a luciferase reporter vector, was used. The pGL3-neo-promoter vector was cleaved with SacI and XhoI, 1 μL of shrimp alkaline phosphatase (Takara Shuzo) was added, and the terminal was dephosphorylated by incubation at 37 ° C. for 30 minutes. Subsequently, after incubating at 65 ° C. for 15 minutes to inactivate the enzyme, 20 μg of glycogen was added, and the DNA was recovered by ethanol precipitation. Next, this DNA was washed with 70% ethanol and then dissolved in TE solution. This DNA solution was fractionated by 0.8% agarose electrophoresis, extracted and purified (hereinafter referred to as pGL3-neo-promoter / SacI, XhoI (SAP)). EASYTRAP was used for purification. Subsequently, HRE / SacI, XhoI and pGL3-neo-promoter / SacI, XhoI (SAP) were connected using a DNA ligation kit. Hereinafter, this vector is referred to as pGL3-neo-promoter / HRE.

(1-2) Acquisition of Cell Line Holding Reporter Vector Next, acquisition of cells holding the reporter vector and functional evaluation were performed according to the following methods.
One million HCT-116 cells were spread on a culture dish having a diameter of 60 mm. The medium used was RPMI 1640 medium (Iwaki) (hereinafter referred to as RPMI / 10% FBS) supplemented with 10% fetal bovine serum (manufactured by Moregate). These were cultured for 24 hours at 37 ° C. in the presence of 5% carbon dioxide, and then the medium was replaced with OPTI-MEM (Gibco). Subsequently, 2 μg of pGL3-neo-promoter / HRE vector was introduced. The plasmid was introduced using Lipofectamine reagent (Invitrogen). Specifically, 125 μL of OPTI-MEM (manufactured by Gibco) and 12 μL of lipofectamine reagent were added to the plasmid solution, stirred well, and then incubated at room temperature for 15 minutes. This was administered to the HCT-116 cell line cultured according to the above procedure, mixed gently, and cultured at 37 ° C. for 3 hours in the presence of 5% carbon dioxide to incorporate the plasmid. Subsequently, the medium was replaced with RPMI 1640/10% FBS, and the cells were cultured at 37 ° C. for 21 hours in the presence of 5% carbon dioxide. Subsequently, the cells were detached from the dish by trypsin treatment and spread on a culture dish having a diameter of 100 mm. After culturing at 37 ° C. for 2 days, 1.2 mg / mL Geneticin (manufactured by Invitrogen) was added as a selective drug. By exchanging the medium every 3 days and further culturing for 2 weeks under the above conditions, cells in which the gene in the plasmid was introduced into the intracellular gene and became geneticin resistant were selected. It is considered that pGL3-neo-promoter / HRE has been introduced into this cell line.

  A plurality of cell groups that formed colonies on the dish were isolated, spread on a 24-well culture dish, and the culture was continued. These clones can be expected to show increased luciferase activity in response to hypoxic stimulation and hypoxic mimic stimulation (The EMBO Journal 17 (22) pp. 6573-6586, 1998). Next, the reactivity of these clones to 2,2'-dipyridyl was examined by the following procedure. Ten thousand cloned cells per well were spread on a 96-well plate. As the medium, RPMI 1640/10% FBS was used. These were cultured in the presence of 5% carbon dioxide at 37 ° C. for 2 days, then treated with 100 μM 2,2′-dipyryl and cultured at 37 ° C. for 8 hours. Subsequently, by measuring the luciferase activity of these cells, it was examined whether luciferase activation by hypoxic mimic stimulation was observed. That is, after removing the medium in each well, 50 μL of a lysis solution (25 mM Tris-HCl (pH 7.8), 2 mM dithiothreitol, 2 mM CDTA, 10% glycerol, 0.2% Triton X-100) was added, Incubated for 15 minutes at room temperature. 20 μL of this cell lysate was collected, and a substrate solution (20 mM tricine-sodium hydroxide (pH 7.8), 1.07 mM basic magnesium carbonate, 2.67 mM magnesium sulfate, 0.1 mM EDTA, 33.3 mM dithiothreitol). After adding 50 μL of 270 μM coenzyme A, 470 μM luciferin, 530 μM adenosine triphosphate), the chemiluminescence intensity was measured with a luminometer (manufactured by PerkinElmer). A clone showing a significant increase in luciferase activity by 2,2'-dipyridyl stimulation was selected and used for the following evaluation. Hereinafter, HCT-116 / HRE cl. Indicated as 9.

(1-3) Examination of HIF-1α-dependent transcription activity inhibitory action 10,000 HCT116 / HRE cl. Nine cells were spread on a 96-well plate with 50 μL of medium. As the medium, RPMI 1640/10% FBS was used. After culturing these at 37 ° C. for 4 days in the presence of 5% carbon dioxide, 150 μL of medium was added to each well, and further 10 μL of the compound was treated. Subsequently, these cells were put into an incubator with an oxygen concentration control function (Ikemoto Rika Kogyo Co., Ltd.), the oxygen concentration was reduced to 1%, and the cells were cultured at 37 ° C. for 8 hours in the presence of 5% carbon dioxide. After removing the medium in each well, the inhibitory effect on the transcriptional activity dependent on HIF-1α was observed by measuring the luciferase activity in the cells by the same method as described above. Table 1 shows the inhibitory effect on the transcriptional activity dependent on HIF-1α by the compounds of the present invention.

Table 1 HIF-1α-dependent transcriptional activity inhibitory action of benzylindole derivatives
Compound IC50 (μM)
Example 1 0.015
Example 2 0.097
Example 3 0.035
Example 4 0.009
Example 5 0.010
Example 5 0.010
Example 7 0.014
Example 8 0.017
Example 9 0.013
Example 10 0.013
Example 11 0.024
Example 12 0.025
Example 13 0.033
Example 14 0.037
Example 15 0.067
Example 16 0.077
Example 17 0.11
Example 18 0.11
Example 19 0.14
Example 20 0.14
Example 21 0.33
Example 22 0.31
Example 23 1.2
Example 29 0.017

  As described above, it was revealed that the 1-benzylindole derivative of the present invention strongly inhibits HIF-1α-dependent transcription activity.

Test example 2
Examination of HIF-1α Stabilization Inhibitory Action (2-1) Preparation of HIF-1α Protein Fraction 500,000 Hep3B cells were spread on a culture dish having a diameter of 60 mm. As the medium, RPMI / 10% FBS was used. After culturing overnight at 37 ° C. in the presence of 5% carbon dioxide, the compounds of Example 1 and Example 2 were each treated to 0.32 μM to 10 μM and further cultured for 16 hours. Then, it moved to the incubator with an oxygen concentration adjustment function, the oxygen concentration was reduced to 1%, and HIF-1 (alpha) was stabilized by culturing for 2 hours. Thereafter, the cells were taken out, the medium was removed by suction, and 1 mL of ice-cooled phosphate buffered saline (PBS (−)) was added to wash the cells. Subsequently, 1 mL of ice-cold PBS (−) was added, and the cells were collected in an Eppendorf tube with a scraper. The cells were precipitated by centrifuging at 7000 rpm for 1 minute at 4 ° C. using a small centrifuge. After removing the supernatant by aspiration, 100 μL of cell lysate (0.5 M sucrose, 15 mM Tris-HCl (pH 7.5), 60 mM potassium chloride, 0.25 mM EDTA, 0.125 mM EGTA, 1 mM dithiothreitol, 1 mM phenyl Methylsulfonyl fluoride, 0.4% Nonidet P-40) was added, and the cells were lysed by allowing them to stand on ice for 5 minutes. Then, using a small centrifuge, the crude nuclear fraction was precipitated by centrifuging at 3000 rpm for 10 minutes at 4 ° C., and the supernatant was removed. Add 30 μL of nucleoprotein extraction solution (50 mM Tris-hydrochloric acid (pH 6.5), 2% sodium dodecyl sulfate (SDS)) to the precipitated crude nuclear fraction, and perform ultrasonic disruption using a probe-type sonicator. It was. Subsequently, the nuclear extract was recovered in the supernatant by centrifuging at 15000 rpm for 30 minutes at 4 ° C. using a small centrifuge. The protein concentration was measured using a BCA protein assay kit (Pierce).

(2-2) Quantification of HIF-1α protein amount using Western blotting 15 μg of each protein was fractionated by SDS-polyacrylamide gel electrophoresis. The concentration of acrylamide was 10%. The electrophoresed gel was transferred to a PVDF membrane using a mini-trans blot cell blotting device (Bio-Rad). Subsequently, the PVDF membrane to which the protein was transferred was gently placed in a TBS-T solution (10 mM Tris-HCl (pH 7.5), 150 mM sodium chloride, 0.05% Tween 20) containing 5% skim milk for 30 minutes at room temperature. Blocking was performed by shaking.

  Subsequently, reaction with the primary antibody was performed. Anti-HIF-1α antibody (NB100-123: manufactured by Novus) diluted 1000-fold with a TBS-T solution containing 5% skim milk was reacted with a PVDF membrane at 4 ° C. overnight with gentle shaking. After removing the antibody solution, washing was performed 3 times with a TBS-T solution containing 5% skim milk (at room temperature for 10 minutes, 10 minutes, 5 minutes) to remove non-specific antibodies. Subsequently, a reaction with a secondary antibody was performed. A Horseradish Peroxidase (HRP) -conjugated anti-mouse IgG antibody (NA931V GE Healthcare) diluted 2000-fold with a TBS-T solution containing 5% skim milk was added, and the reaction was performed with gentle shaking at room temperature for 2 hours. After removing the antibody solution, washing was performed 3 times with a TBS solution containing 5% skim milk (at room temperature for 10 minutes, 10 minutes, 5 minutes) to remove non-specific antibodies. Subsequently, a protein band reacted with the anti-HIF-1α antibody was detected using an ECL western blotting detection reagent (manufactured by GE Healthcare). The hypoxia-dependent HIF-1α stabilization inhibitory action was evaluated by estimating the change in intracellular HIF-1α protein amount due to drug treatment.

  As shown in FIG. 1, the amount of HIF-1α protein not detected under normal oxygen concentration (NORMOXIA) was increased by 1% oxygen concentration for 2 hours (HYPOXIA). This is presumably because the decomposition of HIF-1α was suppressed in low oxygen. On the other hand, both of the compounds of Example 1 and Example 2 decreased the amount of HIF-1α protein in HYPOXIA in a concentration-dependent manner. Therefore, it was shown that the compounds of Example 1 and Example 2 suppressed the degradation of HIF-1α due to hypoxia and inhibited the stabilization of HIF-1α.

  Since the HIF-1α activity inhibitor of the present invention has a HIF-1α-dependent transcription activity inhibitory action and inhibits the stabilization of HIF-1α under hypoxia, such as VEGF that regulates the expression of HIF-1α. It is possible to suppress the expression of angiogenic factors. Therefore, the HIF-1α activity inhibitor of the present invention is suitable for the treatment of diseases caused by angiogenesis.

It is a figure which shows the stabilization inhibitory effect of HIF-1 alpha by the HIF-1 alpha activity inhibitor of the present invention.

Explanation of symbols

Lane 1: shows expression of HIF-1α in Hep3B cells under normal oxygen concentration (NORMOXIA).
2 lanes: HIF-1α expression of Hep3B cells in 2% culture (HYPOXIA) with an oxygen concentration of 1%.
Lane 3 shows the expression of HIF-1α in Hep3B cells treated with 0.32 μM of the compound of Example 1 after treatment with HYPOXIA.
Lane 4 shows the expression of HIF-1α in Hep3B cells treated with 1 μM of the compound of Example 1 after treatment with HYPOXIA.
Lane 5 shows the expression of HIF-1α in Hep3B cells treated with 3.16 μM of the compound of Example 1 after HYPOXIA treatment.
Lane 6: shows HIF-1α expression in Hep3B cells treated with 10 μM of the compound of Example 1 after HYPOXIA treatment.
Lane 7: shows HIF-1α expression in Hep3B cells treated with 0.32 μM of the compound of Example 2 after treatment with HYPOXIA.
8 lane: shows HIF-1α expression in Hep3B cells treated with 1 μM of the compound of Example 2 after HYPOXIA treatment.
9 lane: shows HIF-1α expression in Hep3B cells treated with 3.16 μM of the compound of Example 2 after HYPOXIA treatment.
Lane 10: shows HIF-1α expression in Hep3B cells treated with 10 μM of the compound of Example 2 after HYPOXIA treatment

SEQ ID NO: 1 in the sequence listing represents an oligonucleotide containing an HRE (Hypoxia Responsible Element) sequence. SEQ ID NO: 2 in the sequence listing represents an oligonucleotide complementary to SEQ ID NO: 1.

Claims (26)

General formula (1)

(In the formula, X and Y may be each independently a hydrogen atom, a lower alkyl group, a halogen atom, a lower alkoxy group, or a benzyloxy group, Z represents a hydrogen atom or a lower acyl group, and Ar represents 1-benzyl represented by an aryl group or heteroaryl group which may have 1 to 3 substituents selected from the group consisting of a lower alkyl group, a halogen atom, a lower alkoxy group, and a phenyl group. An HIF-1α activity inhibitor comprising an indole derivative, a hydrate thereof, a solvate thereof, or a pharmacologically acceptable salt thereof as an active ingredient. The 1-benzylindole derivative, its hydrate, its solvate, or its pharmacologically acceptable one according to claim 1, wherein in the general formula (1), either X or Y is a hydrogen atom. A HIF-1α activity inhibitor comprising a salt as an active ingredient. In formula (1), Z is a hydrogen atom, The 1-benzylindole derivative according to claim 2, its hydrate, its solvate, or its pharmacologically acceptable salt is used as an active ingredient. HIF-1α activity inhibitor. In the general formula (1), either one of X and Y is a hydrogen atom, and the other is a hydrogen atom, a lower alkyl group or a halogen atom, 1-benzylindole derivative according to claim 3, its hydrate, A HIF-1α activity inhibitor comprising the solvate or a pharmacologically acceptable salt thereof as an active ingredient. In the general formula (1), one of X and Y is a hydrogen atom, and the other is a hydrogen atom, a methyl group, or a fluorine atom, The 1-benzylindole derivative, its hydrate, A HIF-1α activity inhibitor comprising a solvate or a pharmacologically acceptable salt thereof as an active ingredient. 6. In the general formula (1), Ar is an aryl group which may have one or two substituents selected from the group consisting of a chlorine atom, a fluorine atom, a methyl group, a methoxy group and a phenyl group. A HIF-1α activity inhibitor comprising the described 1-benzylindole derivative, hydrate, solvate, or pharmacologically acceptable salt thereof as an active ingredient. In the general formula (1), Ar is 3,4-dichlorophenyl group, 3,4-difluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 3,4-dimethylphenyl group, 4-methoxy. HIF-1α activity comprising as an active ingredient a 1-benzylindole derivative, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof according to claim 6, which is a phenyl group or a 4-biphenyl group. Inhibitor. The 1-benzylindole derivative, its hydrate, its solvate, or its pharmacologically acceptable salt of Claim 7 whose X and Y are both hydrogen atoms in General formula (1). A HIF-1α activity inhibitor as an active ingredient. The general formula (1), wherein Z is a lower acyl group, the 1-benzylindole derivative according to claim 2, its hydrate, its solvate, or its pharmacologically acceptable salt as an active ingredient HIF-1α activity inhibitor. In the general formula (1), Z is an acetyl group. The 1-benzylindole derivative, hydrate, solvate, or pharmacologically acceptable salt thereof according to claim 9 is used as an active ingredient. HIF-1α activity inhibitor. The 1-benzylindole derivative, its hydrate, and its solvate according to claim 10, wherein in general formula (1), one of X and Y is a hydrogen atom and the other is a hydrogen atom or a methyl group. Or a HIF-1α activity inhibitor comprising a pharmacologically acceptable salt thereof as an active ingredient. The 1-benzylindole derivative according to claim 11, wherein in the general formula (1), X and Y are both hydrogen atoms, and Ar is a phenyl group which may have 1 to 2 halogen atoms. , A hydrate, a solvate thereof, or a pharmacologically acceptable salt thereof, as an active ingredient. General formula (2)

(In the formula, Y ₁ represents a lower alkyl group, a fluorine atom, a chlorine atom, a lower alkoxy group, or a benzyloxy group, and Ar ₁ represents a heteroaryl group, or a lower alkyl group, a phenyl group, a halogen atom, and a lower alkoxy group. An aryl group optionally having 1 or 2 substituents selected from the group consisting of Ar ₁ is a 4-chlorophenyl group, and Y ₁ is a combination of 5-chlorine atom or 5-fluorine atom; And a 1-benzyl-3- (hydroxymethyl) indole derivative represented by the formula: Ar ₁ is a phenyl group and Y ₁ is a combination of 5-methoxy groups), its hydrate, its solvent Japanese or a pharmacologically acceptable salt thereof. The 1-benzyl-3- (hydroxymethyl) indole derivative according to claim 13, a hydrate thereof, a solvent thereof, wherein Y ₁ in the general formula (2) is a methyl group, a fluorine atom, a methoxy group or a benzyloxy group Japanese or a pharmacologically acceptable salt thereof. In the general formula (2), Ar ₁ is a methyl group, a fluorine atom, a chlorine atom or an aryl group optionally having 1 or 2 methoxy groups, or a pyridyl group. 3- (hydroxymethyl) indole derivatives, hydrates, solvates thereof, or pharmacologically acceptable salts thereof. In the general formula (2), Y ₁ is a 5-methyl group, 4-methyl group, 7-methyl group, 5-fluorine atom, 6-fluorine atom, 5-methoxy group or 6-methoxy group, and Ar ₁ is The 1-benzyl-3 (hydroxymethyl) indole derivative according to claim 15, which is a 3,4-dichlorophenyl group, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. General formula (3)

(In the formula, Ar ₂ represents a heteroaryl group or an aryl group having 1 to 2 substituents selected from the group consisting of a lower alkyl group, a halogen atom, a lower alkoxy group, and a phenyl group. ₂ has one halogen atom or methyl group, phenyl group, 3-methoxyphenyl group, 2,4-dichlorophenyl group, 3,4-dichlorophenyl group, 2,4-difluorophenyl group, and 3,5- 1-benzyl-3- (hydroxymethyl) indole derivatives, hydrates, solvates, or pharmacologically acceptable salts thereof represented by the following formula: In the general formula (3), Ar ₂ is a pyridyl group, or a phenyl group having two substituents selected from the group consisting of a methyl group, a fluorine atom, and a chlorine atom, a phenyl group having a 4-methoxy group or a 4-phenyl group. The 1-benzyl-3- (hydroxymethyl) indole derivative, hydrate, solvate, or pharmacologically acceptable salt thereof according to claim 17, which is a group. In the general formula (3), Ar ₂ is 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 3,4-difluorophenyl group, 3,4-dimethylphenyl group, 2,3-dichlorophenyl group, 2, The 1-benzyl-3- (hydroxymethyl) indole derivative according to claim 18, which is a 5-dichlorophenyl group, a 4-methoxyphenyl group or a 4-biphenyl group, a hydrate, a solvate thereof, or a pharmacology thereof Acceptable salt. General formula (4)

(In the formula, Y ₃ represents a hydrogen atom, a lower alkyl group, a halogen atom, a lower alkoxy group, or a benzyloxy group, Z ₃ represents a lower acyl group, Ar ₃ represents a lower alkyl group, a halogen atom, or a lower alkoxy group. A 1-benzyl-3- (lower acyloxymethyl) indole derivative represented by the following: an aryl group which may have 1 to 3 substituents in combination consisting of phenyl groups, or a heteroaryl group; Hydrates, solvates thereof, or pharmacologically acceptable salts thereof. In the general formula (4), Z ₃ is an acetyl group, The 1-benzyl-3- (lower acyloxymethyl) indole derivative, hydrate, solvate thereof, or pharmacologically thereof according to claim 20 Acceptable salt. The 1-benzyl-3- (lower acyloxymethyl) indole derivative according to claim 21, a hydrate, a solvate thereof, or a pharmacologically thereof according to general formula (4), wherein Y ₃ is a hydrogen atom. Acceptable salt. The 1-benzyl-3- (lower acyloxymethyl) indole derivative according to claim 22, wherein Ar ₃ in formula (4) is a pyridyl group or a phenyl group optionally having 1 or 2 chlorine atoms. Its hydrate, its solvate, or its pharmacologically acceptable salt. The 3-acetoxymethyl-1- (3,4-dichlorobenzyl) indole, hydrate, solvate, or pharmacologically acceptable salt thereof according to claim 20. The angiogenesis inhibitor which uses the compound as described in any one of Claims 1-12, its hydrate, its solvate, or its pharmacologically acceptable salt as an active ingredient. The therapeutic agent for age-related macular degeneration which uses the compound as described in any one of Claims 1-12, its hydrate, its solvate, or its pharmacologically acceptable salt as an active ingredient.

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