JP2001122855A - Indole compound and its pharmaceutical use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an indole compound selectively acting on estrogen receptor βand useful as a therapeutic medicine for osteoporosis free from adverse effect. SOLUTION: This indole compound is represented by general formula (1) [wherein R1 is hydrogen atom, a lower alkyl group or the like; R5 and R6 may be the same as or different from each other and each represent hydrogen atom, a halogen atom, hydroxy group, a lower alkyl group, a lower alkoxy group or the like; R7 is hydrogen atom, a halogen atom, a lower alkyl group or the like; A, B, D, E and F are each the same or different and denote each =N-, =CH- or the like and Y is phenyl group or the like] or its pharmaceutically permissible salt.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel indole compound which selectively acts on estrogen receptor β and its pharmaceutical use. More specifically, the present invention relates to a novel compound having an effect of treating osteoporosis and its pharmaceutical use.

[0002]

2. Description of the Related Art Estrogen is a steroid hormone related to reproductive function as a female hormone. However, its action is widely related to bone metabolism, lipid metabolism, arteriosclerosis, blood pressure regulation or the central nervous system or immune system. After menopause, the production of this estrogen in the body is remarkably reduced, which causes various indefinite complaints and mental disorders, and causes so-called menopause. Hormone replacement therapy with estrogen products reduces the symptoms of menopause, treats and prevents osteoporosis, improves the cardiovascular system,
Used for urinary incontinence. However, this hormone replacement therapy has side effects such as uterine bleeding, gastrointestinal disorders, thrombosis, and hepatic disorders, and there is a concern that serious side effects such as uterine cancer and breast cancer may occur particularly when administered for a long time.

[0003] Conventionally, the action of estrogen on bone is
Although it has been considered indirect through calcium-regulating hormone by organs such as the intestinal tract, liver, and kidney, it has been reported that estrogen receptors are present on osteoblasts and osteoclasts (J. BoneMiner. Res. ., 797-802 (19
90)), Studies on the mechanism of action of estrogen receptors on bone metabolism have been advanced.

Estrogen receptors are also found in tissues such as the uterus, vagina, mammary gland, liver, bladder, oviduct, etc., in addition to bone, and may bind to estrogen and induce the synthesis of proteins dependent on specific genes. Elucidated. recent years,
With respect to this estrogen receptor, a new subtype β-receptor has been discovered in addition to the conventional α-receptor, and new research has been developed. Furthermore, it has been clarified that the expression rates of these two types of receptors differ depending on the organ. For example, uterus, mammary gland, hypothalamus, pituitary gland, testis, etc.
In these organs, the expression ratio of β receptor is low. On the other hand, it has been found that β-receptor is highly expressed in prostate and ovary, and is also frequently expressed in bone and the like.

[0005] The fact that the expression ratio of these receptors differs depending on the organ suggests that there is a possibility of developing a more organ-specific drug by causing a selective ligand to act on each receptor. are doing. In the uterus and mammary gland, the expression of α-receptor is high, and when hormone replacement therapy is performed, it is the organ most likely to cause side effects. Therefore, it is considered possible to develop an estrogen agonist which does not have side effects such as uterine bleeding, uterine cancer or breast cancer, and acts only on organs which have high expression of β receptor.
For example, estrogen showed a vasoprotective effect in a vascular disorder model of α-receptor knockout mice (Nature M
Edicine, 545-548 (1997), suggests that β receptors are involved in vascular protection. In addition, indications for cardiovascular disease, Alzheimer's disease, osteoporosis and the like can be considered. In particular, with respect to bone, it is considered possible to develop an estrogen agonist which acts only on the increase in bone mass as a therapeutic agent for osteoporosis and has no side effect such as uterine bleeding or uterine cancer and which selectively acts on β receptor.

[0006] Under such circumstances, research on estrogen agonists or antagonists has been advanced. For example, Japanese Patent Application Laid-Open No. Hei 9-301915 discloses the following general formula as an estrogen agonist:

Embedded image Discloses that the compound has affinity for estrogen receptor and its activity. Japanese Patent Application Laid-Open No. 10-25263 discloses the following general formula:

Embedded image The compound shown in the bone acts as an agonist in the bone, uterus,
It discloses that it acts as an antagonist in the mammary gland. Also,
JP-A-11-71332 discloses the following general formula:

Embedded image Discloses that the triphenylmethane compound selectively inhibits the estrogen receptor α. Further, JP-A-10-231292 discloses that the following general formula:

Embedded image Discloses that the compound represented by is useful as a selective estrogen receptor modulator.
However, there is no disclosure in these prior art documents that the indole compound as in the present invention selectively acts on estrogen receptor β, and no description suggesting them can be found at all.

On the other hand, compounds structurally similar to the compound of the present invention and having an effect as a therapeutic agent for osteoporosis include:
JP-A-8-231394 discloses the following general formula:

Embedded image And a benzofuran compound represented by the following general formula:

Embedded image The benzothiophene compound represented by is disclosed.
However, these compounds have a basic skeleton different from the indole structure which is a feature of the present invention, and do not have a feature that the compound always has a hydroxyl group at the 4-position on the phenyl group substituted at the 3-position of the indole skeleton as in the present application. . In addition, the following compound most structurally similar to the present application is Arch.Pharm.
(Weinheim) 320, 407-417 (1987).

Embedded image This document also discloses that these compounds had affinity for estrogen receptor in vitro, but did not show any activity in vivo. Of course, in this document,
As described in the present application, by acting specifically on the β receptor only, there is no description that it is useful as uterine bleeding and osteoporosis without uterine cancer, which are feared as side effects, and there is no disclosure of data suggesting it. .

[0008] As described above, various compounds have been developed as therapeutic drugs for osteoporosis by acting on estrogen receptors, but none of them has been satisfactory in terms of reducing the activity or side effects. Therefore, development of an excellent therapeutic agent for osteoporosis which is more effective and active and has no side effects has been strongly desired.

[0009]

DISCLOSURE OF THE INVENTION In view of the above problems, the present invention has made intensive studies to find a useful therapeutic agent for osteoporosis without side effects such as uterine bleeding and uterine cancer. As a result, the indole compound represented by the following general formula (1) selectively acts on estrogen receptor β,
They have found that they are useful therapeutic agents for osteoporosis, and have completed the present invention. More specifically, the following (1) to (10)
As shown in FIG.

(1) General formula (1)

Embedded image [Wherein, R ¹ represents a hydrogen atom, a lower alkyl group or-(CH
₂ ) _m- R ² (where R ² is a hydroxyl group, a carboxyl group, a lower alkoxy group, a lower alkoxycarbonyl group or —NR ³ R ⁴ — (where R ³ and R ⁴ are the same or different and are each a hydrogen atom or Together with a lower alkyl group or an adjacent nitrogen atom

Embedded image (Where n is an integer from 1 to 3) and m is an integer from 1 to 5); R ⁵ and R ⁶
Are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group,
R ⁷ is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group; a ring Y is an aryl group, a heteroaryl group or a lower alkyl group, a lower alkoxy group or a lower alkoxyalkyl group;

Embedded image (Where q is an integer from 1 to 2);
N- or = CR ⁸ - (wherein, ^{R 8} is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group)
B is = N-,

Embedded image Or = CR 9 ^- (wherein, R ⁹ is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, lower alkoxycarbonyl group, a carboxyl group, a lower alkylaminocarbonyl group, an acylamino group or a lower alkylsulfonylamino group D is = N-,

Embedded image ＣＲCR ¹⁰ — (where R ¹⁰ is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a carboxyl group, a lower alkylaminocarbonyl group, an acylamino group or a lower alkylsulfonylamino group E) = N-,

Embedded image Or = ^{CR 11} - ^{(wherein, R 11} is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group,
A lower alkoxycarbonyl group, a carboxyl group, a lower alkylaminocarbonyl group, an acylamino group or a lower alkylsulfonylamino group);
−,

Embedded image ＣＲCR ¹² — (where R ¹² is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a carboxyl group, a lower alkylaminocarbonyl group, an acylamino group or a lower alkylsulfonylamino group There is). However, when Y is an aryl group and R ¹ is a hydrogen atom or a lower alkyl group, R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ ,
R ¹¹ and R ¹² are not hydrogen atoms at the same time.] Or a pharmaceutically acceptable salt thereof.

(2) The indole compound according to (1), wherein Y is an aryl group, or a pharmaceutically acceptable salt thereof.

(3) The indole compound or the pharmaceutically acceptable salt thereof according to (2), wherein the aryl group in Y is a phenyl group.

(4) The indole compound according to (3), wherein R ⁸ is a fluorine atom, or a pharmaceutically acceptable salt thereof.

(5) Y is a heteroaryl group or

Embedded image (Wherein q is the same as defined above), or the pharmaceutically acceptable salt thereof according to (1).

(6) Y is pyridyl, pyridyl-N-oxide, pyrimidinyl, thienyl, thiazolyl, isoxazolyl, furyl, imidazolyl,
Pyrazolyl group, 1,3,4-thiadiazol-2-yl group, 2-pyrrolidone-1-yl group or 2-piperidone-
The indole compound according to (5), which is a 1-yl group, or a pharmaceutically acceptable salt thereof.

(7) A pharmaceutical composition comprising the indole compound according to (1) to (6) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

(8) An estrogen receptor agonist comprising the indole compound according to (1) to (6) or a pharmaceutically acceptable salt thereof as an active ingredient.

(9) An estrogen receptor β agonist comprising the indole compound according to (1) to (6) or a pharmaceutically acceptable salt thereof as an active ingredient.

(10) A therapeutic agent for osteoporosis, comprising the indole compound according to (1) to (6) or a pharmaceutically acceptable salt thereof as an active ingredient.

The definition of each substituent used in the present specification is as follows. "Halogen atom" means chlorine atom,
Examples are a bromine atom and a fluorine atom. R ⁵ and R ⁶ are preferably chlorine atoms, R ⁷ and R ⁸ are preferably fluorine atoms, and R ⁹ , R ¹⁰ , R ¹¹ and R
^{In 12} it is preferably a chlorine atom, a bromine atom or a fluorine atom.

The "lower alkyl group" is a group having 1 to 6 carbon atoms.
Alkyl groups which may be linear or branched, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-
It is a butyl group, a pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a hexyl group, or the like, and is preferably a linear or branched alkyl group having 1 to 4 carbon atoms. Particularly preferred are a methyl group and an ethyl group. R ¹ is preferably a methyl or ethyl group, R ³ and R ⁴ are preferably a methyl or ethyl group, R ⁵ and R ⁶ are preferably a methyl or ethyl group, and R ⁷ and R ⁸ Is preferably a methyl group, and R ⁹ , R ¹⁰ , R ¹¹ and R ¹²
Is preferably a methyl group.

The "lower alkoxy group" refers to a group having 1 to carbon atoms.
Represents six straight or branched chain alkoxy groups, such as
Xy, ethoxy, propoxy, isopropoxy
Group, butoxy group, tert-butoxy group, pentyloxy
Si group, tert-pentyloxy group or hexyloxy
A methoxy group preferably having 1 to 4 carbon atoms,
Ethoxy, isopropoxy, butoxy, tert
-A butoxy group. Particularly preferably, a methoxy group or
It is a toxic group. , R²Is preferably a methoxy group
And R⁵And R⁶Is preferably a methoxy group
Yes, R⁷And R ⁸Is preferably a methoxy group
R⁹, R¹⁰, R¹¹And R¹²Preferred in
Is a methoxy group.

"Lower alkoxyalkyl" means methoxymethyl, methoxyethyl, methoxybutyl,
Ethoxymethyl, ethoxyethyl, ethoxybutyl, butoxymethyl, butoxyethyl, butoxybutyl and the like. Preferred are a methoxymethyl group, a methoxyethyl group, a methoxybutyl group, an ethoxymethyl group, an ethoxyethyl group, and an ethoxybutyl group. R ⁵ and R
⁶ is preferably a methoxymethyl group.

"Lower alkoxycarbonyl group" means a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group or
An alkyl moiety such as a t-butoxycarbonyl group represents an alkoxycarbonyl group having 1 to 5 carbon atoms. Preferably a methoxycarbonyl group, an ethoxycarbonyl group or t
ert-butoxycarbonyl group. R ² is preferably a methoxycarbonyl group, and R ⁹ , R ¹⁰ ,
R ¹¹ and R ¹² are preferably a methoxycarbonyl group.

"Lower alkylsulfonylamino" means methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino, isobutylsulfonylamino, tert-butylsulfonylamino or the like. Represents an alkylsulfonylamino group having 1 to 4 carbon atoms. Preferred is a methylsulfonylamino group and the like. R ⁹ , R ¹⁰ , R ¹¹ and R
^{In 12} it is preferably a methylsulfonylamino group.

The "aryl group" is a phenyl group, a naphthyl group, a biphenyl group or the like, preferably a phenyl group. Y is preferably a phenyl group.

A "heteroaryl group" is a 5- or 6-membered aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms as ring-constituting atoms. , A saturated heterocyclic ring, a saturated heterocyclic ring, or a condensed heterocyclic ring obtained by condensing a heterocyclic ring with a benzene ring, specifically, a thiophen-2-yl group, a thiophen-3-
Yl, furan-2-yl, furan-3-yl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, imidazol-1-yl, imidazol-2-yl Group, imidazol-4-yl group, pyrazol-1-yl group, pyrazol-3-yl group, pyrazol-4-yl group, thiazol-2-yl group, thiazol-
4-yl group, thiazol-5-yl group, oxazole-
2-yl group, oxazol-4-yl group, oxazol-5-yl group, isoxazol-3-yl group, isoxazol-4-yl group, isoxazol-5-yl group, pyrimidin-2-yl group, A pyrimidin-4-yl group, a pyrimidin-5-yl group, a pyridin-2-yl group,
Pyridin-3-yl group, pyridin-4-yl group, benzothiophen-2-yl group, benzothiophen-3-yl group, benzofuran-2-yl group, benzofuran-3-yl group, indol-2-yl group , Indol-3-yl group, benzimidazol-1-yl group, benzimidazol-2-yl group, benzothiazol-2-yl group, benzoxazol-2-yl group, quinolin-2-yl
Yl group, quinolin-3-yl group, quinolin-4-yl group, isoquinolin-1-yl group, isoquinolin-3-yl group, isoquinolin-4-yl group, 1,3,4-thiadiazole-2-group, etc. It is. Y is preferably a thiophen-2-yl group, a thiophen-3-yl group, a furan-2-yl group, a furan-3-yl group, a pyrrol-1-yl group, a pyrrol-2-yl group, a pyrrol-3-yl group. Il group,
Imidazol-1-yl group, imidazol-2-yl group, imidazol-4-yl group, imidazol-5-yl group, pyrazol-1-yl group, pyrazol-3-yl group, pyrazol-4-yl group, pyrazole -5-yl group, thiazol-2-yl group, thiazol-4-yl group, thiazol-5-yl group, oxazol-2-yl group, oxazol-4-yl group, oxazol-5-yl group, isoxazole -3-yl group, isoxazol-4-yl group, isoxazol-5-yl group, pyridin-2-yl group, pyridin-3-yl group, pyrimidin-2-yl group, pyrimidin-3-yl group, Pyrimidine-
A 5-yl group and a 1,3,4-thiadiazol-2-yl group.

The term "lower alkylaminocarbonyl group" refers to an aminocarbonyl group mono- or disubstituted with an alkyl group having 1 to 5 carbon atoms, such as a methylaminocarbonyl group, an ethylaminocarbonyl group, a propylaminocarbonyl group, Butylaminocarbonyl group, dimethylaminocarbonyl group, diethylaminocarbonyl group, dipropylaminocarbonyl group, dibutylaminocarbonyl group and the like, preferably methylaminocarbonyl group, ethylaminocarbonyl group, dimethylaminocarbonyl group or diethylaminocarbonyl group. And particularly preferably a dimethylaminocarbonyl group. R ⁹ , R ¹⁰ , R
^11, preferably in ^{R 12} is a dimethylaminocarbonyl group.

The term "acylamino group" refers to a group having 2 to 5 carbon atoms.
Represents an acylamino group, for example, an acetylamino group,
It is an alkanoylamino group such as a propionylamino group, a butyrylamino group or a pivaloylamino group, and is preferably an acetylamino group. R ⁹ , R ¹⁰ , R ¹¹ , R
Preferred in ¹² is an acetylamino group.

The term "prodrug" refers to a derivative obtained by chemically modifying a drug molecule, which itself does not show any physiological activity, and has a reversible drug effect on the original drug molecule in the body after administration.

"Pharmaceutically acceptable salts" include various inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate and nitrate; acetate, propionate and succinate. , Glycolate, lactate, malate, oxalate, tartrate, citrate, maleate, fumarate, methanesulfonate, benzenesulfonate, p-
Various organic acid addition salts such as toluenesulfonate or ascorbate; salts with various amino acids such as aspartate or glutamate, but are not limited thereto. In some cases, it may be a hydrate, hydrate or solvate.

Next, the various substituents will be described in more detail. R ¹ is preferably a hydrogen atom, a methyl group, an ethyl group or a hydroxyethyl group. The aryl group in ring Y is preferably a phenyl group. In R ⁵ and R ⁶ as the substituent, a hydrogen atom; a lower alkyl group such as a methyl group and an ethyl group; a lower alkoxy group such as a methoxy group; a lower alkoxyalkyl group such as a methoxymethyl group; A halogen atom; or a hydroxyl group. As the heteroaryl group in the ring Y, preferably, a thiophen-2-yl group,
Furan-2-yl group, imidazol-2-yl group, pyrazol-3-yl group, thiazol-2-yl group, oxazol-2-yl group, isoxazol-5-yl group,
Pyridyl-N-oxide group, pyridin-2-yl group,
A pyridin-3-yl group, a pyrimidin-4-yl group, 1,
3,4-thiadiazol-2-yl group. R ⁵ and R ⁶ as the substituent are preferably a hydrogen atom; or a lower alkyl group such as a methyl group. In ring Y

Embedded image (Wherein q is as defined above), is preferably a pyrrolidone-1-yl group. R ⁷ is preferably a hydrogen atom or a fluorine atom, and the substitution position of the fluorine atom of the phenyl group is preferably the 2-position or the 3-position. A
In preferably = CR 8 ^- a and, wherein preferably the R ⁸ is a hydrogen atom or a fluorine atom. B is preferably ＝ CR ⁹ —, wherein R ⁹ is preferably a hydrogen atom; a hydroxyl group; or a lower alkoxy group such as a methoxy group. In D, preferably = CR
^{10 -,} wherein preferably a hydrogen atom in R ^10; a chlorine atom, a fluorine atom, a halogen atom such as a bromine atom, a hydroxyl group, a methoxy group, a lower alkoxy group such as ethoxy group; a lower alkyl group such as a methyl group; carboxyl Group;
A lower alkoxycarbonyl group such as a methoxycarbonyl group; an acylamino group such as an acetylamino group; an alkylaminocarbonyl group such as a dimethylaminocarbonyl group; or a lower alkylsulfonylamino group such as a methylsulfonylamino group. Preferably in E = CR ¹¹
-Wherein R ¹¹ is preferably a hydrogen atom;
A halogen atom such as a chlorine atom; a hydroxyl group; a lower alkoxy group such as a methoxy group. In F, preferably = CR
¹² -, = N- or

Embedded image R ¹² is preferably a hydrogen atom; a hydroxyl group; a lower alkyl group such as a methyl group; or a lower alkoxy group such as a methoxy group.

Here, the compound of the present invention may be a hydrate or a solvate in some cases, and also includes a prodrug compound and a metabolite thereof.

When the present invention is used as a therapeutic agent for osteoporosis or the like, it is administered systemically or locally, orally or parenterally. The dosage varies depending on the age, body weight, symptoms, therapeutic effects, etc., but is usually in the range of 10 mg to 1 g at a time, and once to several times a day per adult. The compound of the present invention is obtained by mixing a diluent, a dispersant, an adsorbent, a solubilizer, and the like suitable for preparing a solid composition and a liquid composition for oral administration, or a preparation such as an injection for parenteral administration. can do. Further, the compound of the present invention can be used for treatment and prevention of not only humans but also animals other than humans, particularly mammals.

[0035]

Next, an example of a method for producing the indole compound represented by the compound (1) will be described, but the production method of the present invention is not limited thereto. Also,
When performing the reaction described below, the functional group other than the site may be protected in advance as necessary, and may be deprotected at an appropriate stage. Further, in each step, the reaction may be carried out by a usual method, and the isolation and purification may be carried out by appropriately selecting or combining conventional methods such as crystallization, recrystallization, silica gel chromatography, and preparative HPLC. Just do it.

Manufacturing method 1

Embedded image

Where A, B, D, E, F, Y, R ¹ ,
R ⁵ , R ⁶ and R ⁷ are the same as above, R ^1-1 is a lower alkyl group, and R ^1-2 is — (CH ₂ ) _m —R
^2-1 (where m is the same as described above, and R ^2-1 is a carboxyl group or a lower alkoxycarbonyl group)
And R ^{1-3 is-} (CH ₂ ) _m -R ^2-2 (where m is the same as described above, and R ^2-2 is a hydroxyl group)
W is a lower alkyl group or a benzyl group;
Is a halogen atom.)

Step 1 The compound represented by the general formula (2) and the compound represented by the general formula (3) are placed in a solvent such as methanol, ethanol or tetrahydrofuran at room temperature or under heating, preferably under reflux of the solvent under heating. To give a compound represented by the general formula (4).

Step 2 The compound represented by the general formula (4) is dissolved in a solvent such as methanol, ethanol, benzene, toluene or acetic acid using hydrochloric acid,
An acidic catalyst such as a protic acid such as methanesulfonic acid or tosylic acid, or a metal halide (such as a Lewis acid) such as zinc chloride, or a non-catalyst using a high-boiling solvent such as diethylene glycol, at room temperature or under heating, preferably in a solvent. The compound represented by the general formula (5) can be obtained by performing the reaction under heating under reflux.

Step 1 ′ In the production of compound (5), it is not always necessary to isolate compound (4) as described above. That is, the compound represented by the general formula (2) and the compound represented by the general formula (3) are mixed in a solvent such as ethanol or methanol in advance with an acidic catalyst such as sulfuric acid, hydrochloric acid, formic acid, tosylic acid or methanesulfonic acid. In addition, the compound represented by the general formula (5) can be obtained by the treatment.

Step 3 The compound represented by the general formula (5) is subjected to -70 in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, carbon tetrachloride, methanol, tetrahydrofuran, ethyl acetate or acetic acid under an argon atmosphere. At room temperature to room temperature, boron trichloride, boron tribromide, trimethylsilane iodide, silicon tetrachloride, aluminum chloride, bisisopropylthio boron bromide, 48% hydrobromic acid or 25% hydrobromic acid-acetic acid, etc. The deprotection reaction of the substituent W is performed by using a reagent; or by using a hydrogenation reaction using a catalyst such as palladium carbon or palladium hydroxide in a hydrogen atmosphere to obtain the compound represented by the general formula (1). An inventive compound can be obtained.
When W is a benzyl group, the deprotection reaction can be performed simultaneously under the condition of hydrochloric acid / acetic acid used at the time of ring closure in step 2.

Step 4 (when R ¹ is a lower alkyl group) The compound represented by the general formula (5) is dissolved in a solvent such as N, N-dimethylformamide, tetrahydrofuran, toluene or ethanol by using sodium metal, sodium hydride, Formula (6) in the presence of a base such as sodium methoxide, sodium ethoxide, potassium carbonate or sodium carbonate
The compound represented by the general formula (7) can be obtained by reacting the halogen compound represented by the formula under ice-cooling or heating.

Step 3-2 In the same manner as in Step 3, compound (1-2), which is one of the target compounds, can be obtained from compound (7).

Step 5 (when R ¹ is — (CH ₂ ) _m —R ² (where R ² is a carboxyl group or a lower alkoxycarbonyl group)) A compound represented by the general formula (5) is converted to N, A halogen compound represented by the general formula (8) is ice-cooled in a solvent such as N-dimethylformamide, tetrahydrofuran, toluene or ethanol in the presence of a base such as sodium metal, sodium hydride, sodium methoxide or sodium ethoxide. The compound represented by the general formula (9) can be obtained by reacting under heating.

Step 3-3 In the same manner as in Step 3, compound (1-3), which is one of the target compounds, can be obtained from compound (9).

Step 6 (when R ¹ is-(CH ₂ ) _m -R ² (where R ² is a hydroxyl group)) The compound represented by the general formula (9) is converted into a solvent such as ether, tetrahydrofuran, diglyme or the like. In a medium, a metal hydride derivative such as lithium aluminum hydride, lithium borohydride, diborane, diisobutylaluminum hydride or lithium borohydride-aluminum chloride is reacted under ice-cooling or heating to obtain a compound represented by the general formula (10): ) Can be obtained.

Step 3-4 In the same manner as in Step 3, compound (1-4), which is one of the target compounds, can be obtained from compound (10).

Step 7 Compound (1-4), which is one of the target compounds, is obtained by converting compound (1-3) to methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 1,4-dioxane, water or the like, or a mixture thereof. In a mixed solvent, using a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate or ammonnia, ester hydrolysis is carried out at room temperature or under heating, followed by the same method as in step 6. It can also be produced by reacting.

Step 8 The compound represented by the general formula (5) is treated with an oxidizing agent such as m-chloroperbenzoic acid, peracetic acid or aqueous hydrogen peroxide in a halogenated solvent such as methylene chloride or chloroform, or acetic acid. The compound represented by the general formula (11) can be obtained by reacting at a temperature from cold to room temperature.

Step 3-5 Compound (1-5), which is one of the target compounds, can be obtained from compound (11) in the same manner as in step 3.

Step 9 In the case where ring Y is pyridine in the general formula (5), compound (12) can be obtained in the same manner as in step 8.

Step 3-6 A compound (1-6), which is one of the target compounds, can be obtained from the compound (12) in the same manner as in Step 3.

Manufacturing method 2

Embedded image

(Where A, B, D, E, F, R ¹ ,
R ⁵ , R ⁶ , R ⁷ and W are as defined above.

Step 1 Synthetic communication (Synthetic communi
Compounds (13) obtained by cations) 22 (3) and 421 (1992) are dissolved in a solvent such as methanol, ethanol or tetrahydrofuran in a solvent such as N,
N-dimethylformamide dimethyl acetal or N,
Using an acetal compound such as N-dimethylacetamide dimethyl acetal, the reaction is carried out at room temperature or under heating, preferably under reflux without heating with a solvent, to obtain a compound of the general formula (1)
The compound represented by 5) can be obtained.

Step 2 The compound represented by the general formula (16) is reacted with a hydrazine monohydrate in a solvent such as methanol, ethanol, benzene or toluene to give the compound represented by the general formula (15). A compound can be obtained.

Step 3 In the same manner as in Step 3 of Production Method 1, W of compound (16)
By deprotecting, a compound represented by the general formula (1-7), which is one of the target compounds, can be obtained.

Step 4 The compound represented by the general formula (1) is obtained by reacting the compound represented by the general formula (15) with hydroxylamine hydrochloride in a solvent such as methanol, ethanol, benzene or toluene.
The compound represented by 7) can be obtained.

Step 3-2 Compound (1-8), which is one of the target compounds, can be obtained from compound (17) in the same manner as in Step 3.

Step 5 A compound represented by the general formula (13) is prepared in a solvent such as 1,4-dioxane, tetrahydrofuran or toluene in the presence of a base such as pyrrolidine or piperidine.
The compound represented by the general formula (19) can be obtained by reacting the 1,3,5-triazine compound represented by 8) with room temperature or under heating, preferably under heating to reflux.

Step 3-3 Compound (1-9), which is one of the target compounds, can be obtained from compound (19) in the same manner as in step 3.

Manufacturing method 3

Embedded image

(Where A, B, D, E, F, R ¹ , R
^1-1 , R ⁵ , R ⁷ , W, X and q are the same as described above, and W ¹ is a lower alkyl group or a benzyl group.

Step 1 The compound (2) was prepared in the same manner as in Step 1 'of Production Method 1.
The compound represented by the general formula (21) can be synthesized using the compound (0) and the compound (2).

Step 2 The compound represented by the general formula (21) is hydroxylated in methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide or the like or a mixed solvent thereof. Sodium, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, potassium
Using a base such as tert-butoxide or ammonnia, it is allowed to react with an alkyl halide compound represented by the general formula (22) at room temperature or under heating, or to convert a compound represented by the general formula (21) into methanol, ethanol, or the like. Alternatively, the compound represented by the general formula (23) can be obtained by reacting triphenylphosphine with diazocarboxydiethyl or diazocarboxydiisopropyl in a solvent such as tetrahydrofuran.

Step 3 The compound represented by the general formula (23) is treated with methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 1,4-dioxane, water or the like or a mixed solvent thereof with sodium hydroxide or potassium hydroxide. The compound represented by the general formula (24) can be obtained by carrying out ester hydrolysis using a base such as lithium hydroxide, sodium carbonate, potassium carbonate or ammonnia at room temperature or under heating.

Step 4 The compound represented by the general formula (24) is converted into methylene chloride,
2-dichloroethane, chloroform, carbon tetrachloride, benzene, toluene, diethyl ether, tetrahydrofuran,
In a solvent such as N, N-dimethylformamide, dimethylsulfoxide or pyridine, in the presence of N-hydroxybenzotriazole monohydrate and a base such as triethylamine or pyridine, dicyclohexylcarbodiimide (D
CC), using a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide.hydrochloride (WSC.HCl), diisopropylcarbodiimide or carbonyldiimidazole, at room temperature or under heating, with the general formula (25)
By reacting the compound represented by the general formula (2)
The compound represented by 6) can be obtained.

Step 5 The compound represented by the general formula (26) is added to a solvent such as 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, toluene or pyridine in a solvent such as Lawesson's reagent, diphosphorus pentasulfide or the like at room temperature. The compound represented by the general formula (27) can be obtained by reacting under heating, preferably under heating.

Step 6 W of compound (27) was prepared in the same manner as in Step 3 of Production Method 1.
By deprotecting, compound (1-10), which is one of the target compounds, can be obtained.

Step 7 The compound represented by the general formula (24) is prepared by using diphenylphosphoric acid azide (DPPA) in a solvent such as toluene, tetrahydrofuran or 1,4-dioxane in the presence of a base such as triethylamine or pyridine. , W ¹ -OH (eg, methanol, ethanol, te)
rt-butyl alcohol or benzyl alcohol) to obtain a compound represented by the general formula (28).

Step 8 The compound represented by the general formula (28) is dissolved in methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 1,4-dioxane, ethyl acetate or water, or a mixed solvent thereof under a hydrogen atmosphere. The compound represented by the general formula (29) can be obtained by performing catalytic reduction using a catalyst such as palladium carbon, palladium hydroxide or Raney nickel.

Step 9 The compound represented by the general formula (29) is dissolved in a solvent such as N, N-dimethylformamide, N, N-dimethylacetamide or tetrahydrofuran in a solvent such as sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate or potassium carbonate. By reacting with a compound represented by the general formula (30) in the presence of a base at room temperature or under heating, a compound represented by the general formula (31) can be obtained.

Step 6-1 A compound (1-11), which is one of the target compounds, can be obtained from the compound (31) in the same manner as in Step 6.

Step 10 A compound represented by the general formula (32) can be prepared in the same manner as in Step 4 of Production Method 1. That is, N, N-
The alkyl halide compound represented by the general formula (6) is ice-cooled in a solvent such as dimethylformamide, tetrahydrofuran, toluene or ethanol in the presence of a base such as sodium metal, sodium hydride, sodium methoxide or sodium ethoxide. The compound represented by the general formula (32) can be obtained by performing the reaction under heating.

Step 11 A compound represented by the general formula (33) can be obtained by ester-hydrolyzing the compound represented by the general formula (32) in the same manner as in Step 3.

Step 12 In the same manner as in Step 4, the compound represented by the general formula (3) is reacted with the compound represented by the general formula (33) by the compound (34).
The compound represented by 5) can be obtained.

Step 13 The compound represented by the general formula (35) is ice-cooled to room temperature in a solvent such as anhydrous diethyl ether or anhydrous tetrahydrofuran under an argon atmosphere in the presence of a methylating agent such as methylmagnesium bromide or methyllithium. By reacting below, a compound represented by the general formula (13-1) can be obtained.

Step 14 By subjecting the compound represented by the general formula (13-1) to a method similar to Steps 1 to 3 of Production Method 2, one of the target compounds represented by the general formula (1-12) ) Can be obtained.

[0079]

EXAMPLES Example 1 2-Fluoro-4- (2-phenyl-1H-indol-3-yl) phenol a) N- [2- (4-benzyloxy-3-fluorophenyl)- 1-phenyl-ethylidene] -N'-phenylhydrazine 2- (4-benzyloxy-3-fluorophenyl)-
1-Phenyl-ethanone (450 mg) was dissolved in ethanol (20 ml), and phenylhydrazine hydrochloride (203 mg) was added. The mixture was heated and refluxed for 12 hours under an argon atmosphere. After returning to room temperature, the reaction solvent was concentrated under reduced pressure, toluene was added to the residue, and the mixture was again concentrated under reduced pressure to obtain the title compound (576 mg).

B) 3- (4-Benzyloxy-3-fluorophenyl) -2-phenyl-1H-indole N- [2- (4-benzyloxy-3) obtained in a) of Example 1. -Fluorophenyl) -1-phenyl-ethylidene] -N'-phenylhydrazine was added with 1N hydrochloric acid / acetic acid (3 ml), stirred at room temperature for 10 minutes, and then heated under reflux for 3 hours. After returning to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. Wash the organic layer with saturated saline,
Further, it was dried with magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was treated with flash column chromatography (hexane: ethyl acetate = 5: 1) to give the title compound (391 mg) as an oil.

C) 2-Fluoro-4- (2-phenyl-
1H-Indole-3-yl) phenol 3- (3-fluoro-4-benzyloxyphenyl) -2-phenyl-1H-indole (391 mg) obtained in b) of Example 1 was added. Tetrahydrofuran (12 ml)
And 10% palladium on carbon (19
0 mg) to carry out a hydrogenation reaction for 15.5 hours. The catalyst was filtered, and the filtrate was sequentially washed with tetrahydrofuran and chloroform, and then concentrated under reduced pressure. The residue was analyzed by thin-layer chromatography (hexane: ethyl acetate = 1: 1).
The title compound (128 mg) was obtained by treating with 3).
Was obtained as a crystalline solid. 1H-NMR (300MHz, δppm, DMSO-d6) 6.90-7.05 (4H, m), 7.15 (1H, dd, J = 7.8,7.2Hz), 7.25-7.50
(7H, m), 9.80 (1H, s), 11.49 (1H, s) FAB (+) MS (low resolution, m / z) 304

Example 1-2 4- [2- (pyridin-3-yl) -1H-indol-3-yl] phenol a) N- [2- (4-methoxyphenyl) -1- (Pyridin-3-yl) -ethylidene] -N'-phenylhydrazine 2- (4-methoxyphenyl) -1- (pyridin-3-
(Il) -ethanone (800 mg) and phenylhydrazine hydrochloride (510 mg) were suspended in ethanol (15 ml) and heated under reflux for 48 hours. After returning to room temperature, the reaction solvent was concentrated under reduced pressure, toluene was added to the residue, and the mixture was again concentrated under reduced pressure to obtain the title compound (1.1 g).

B) 3- (4-methoxyphenyl) -2-
(Pyridin-3-yl) -1H-indole N- [2- (4-methoxyphenyl) -1- (pyridin-3-yl) -ethylidene]-obtained in a) of Example 1-2. N'-phenylhydrazine is converted to 1N hydrochloric acid / acetic acid (8
ml) and heated under reflux for 3.5 hours. After the temperature was returned to room temperature, water was added to the reaction solution, the mixture was made alkaline with potassium carbonate, and extracted with ethyl acetate and saturated saline.
The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was treated with flash column chromatography (chloroform: methanol = 96: 4) to give the title compound (395 mg) as a crystalline solid. Obtained.

C) 4- [2- (pyridin-3-yl)-
1H-Indol-3-yl] phenol 3- (4-methoxyphenyl) -2- (pyridin-3-yl) -1H-indo- obtained in Example 1-2 c).
(150 mg) was dissolved in methylene chloride (15 ml) and cooled to -50 ° C under an argon atmosphere. To this was added a solution of boron tribromide (1.0 mol / l) in methylene chloride (1.5 ml), and the mixture was returned to room temperature and reacted for 2 hours.
Water was further added under ice-cooling, and the mixture was stirred for 1 hour, and then ethyl acetate was added for extraction. The organic layer was washed successively with an aqueous sodium hydrogen carbonate solution and saturated saline, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the residue was treated by flash column chromatography (chloroform: methanol = 98: 2), and recrystallized from chloroform and methanol to obtain the title compound (35 mg). 1H-NMR (300 MHz, δ ppm, DMSO-d6) 6.83 (2H, d, J = 8.8 Hz), 7.00-7.05 (1H, m), 7.14 (1H, d, J = 8.8
Hz), 7.15-7.25 (2H, m), 7.35-7.45 (3H, m), 7.81 (1H, d, J = 8.
1 Hz), 8.46 (1H, d, J = 3.6 Hz), 8.64 (1 H, d, J = 2.1 Hz), 9.43 (1
H, s), 11.58 (1H, s) FAB (+) MS (low resolution, m / z) 287

Example 1-3 4- [1-Ethyl-2- (pyridin-3-yl) -1H
-Indole-3-yl] phenol a) 1-ethyl-3- (4-methoxyphenyl) -2-
(Pyridin-3-yl) -1H-indole 3- (4-methoxyphenyl) -2- (pyridin-3-yl) -1H- obtained in the same manner as in Example 1-2 b).
Indole (150 mg) was dissolved in N, N-dimethylformamide (3.5 ml), and sodium hydride (22 mg) was added with stirring at room temperature. After reacting at room temperature for 1 hour, ethyl bromide (45 μl) was added and reacted for 3 hours. Ethyl acetate and saturated saline were added to the reaction mixture for extraction. The organic layer was washed successively with an aqueous sodium hydrogen carbonate solution and saturated saline, and dried over sodium sulfate. After filtration,
The mixture was concentrated under reduced pressure, and the residue was treated with flash column chromatography (chloroform: methanol = 98: 2) to give the title compound (127 mg) as a crystalline solid.

B) 4- [1-Ethyl-2- (pyridine-
3-yl) -1H-indol-3-yl] phenol 3- (4-methoxyphenyl) -1-ethyl-2- (2-pyridinyl) obtained in a) of Example 1-3. 3-yl)-
1H-indole (127 mg) was treated with methylene chloride (3 m
1) and cooled to 0 ° C. under an argon atmosphere. To this was added a solution of boron tribromide (1.0 mol / l) in methylene chloride (1.1 ml), and the mixture was returned to room temperature and reacted for 18.5 hours. Water and ethyl acetate were added to the reaction mixture for extraction. The organic layer was washed successively with an aqueous sodium hydrogen carbonate solution and saturated saline, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to flash column chromatography.
(Hexane: ethyl acetate = 1: 1) to give the title compound (98 mg) as a crystalline solid. 1H-NMR (300MHz, δppm, DMSO-d6) 1.14 (3H, t, J = 7.1Hz), 4.12 (2H, q, J = 7.1Hz), 6.69 (2H, d, J =
8.5Hz), 7.01 (2H, d, J = 8.5Hz), 7.12 (1H, t, J = 7.5Hz), 7.25
(1H, t, J = 7.5Hz), 7.50 (1H, dd, J = 4.9,7.8Hz), 7.55-7.60 (2
H, m), 7.84 (1H, d, J = 7.8Hz), 8.51 (1H, s), 8.61 (1H, d, J = 3.3
Hz), 9.32 (1H, s) FAB (+) MS (low resolution, m / z) 315

Example 1-4 4- [5-Chloro-2- (1-methyl-1H-imidazol-2-yl) -1H-indol-3-yl] phenol a) N- [2- (4-methoxyphenyl) -1-pyridin-3-ethylidene] -N′-phenylhydrazine 2- (4-benzyloxyphenyl) -1- (1-methyl-1H-imidazol-2-yl ) -Ethanone (1.
0 g) was dissolved in ethanol (20 ml), and 4-chlorophenylhydrazine hydrochloride (600 mg) was added.
The reaction was performed at 90 ° C. for 24 hours under an argon atmosphere. After returning to room temperature, the title compound (1.
18 g) were obtained.

B) 4- [5-Chloro-2- (1-methyl-1H-imidazol-2-yl) -1H-indol-3-yl] phenol a of Example 1-4 ) -N- [2- (4-methoxyphenyl) -1-pyridine-3-ethylidene] -N '
-1N hydrochloric acid / acetic acid (10 ml) was added to -phenylhydrazine, and the mixture was reacted at 125 ° C for 3 hours. After returning to room temperature,
After adding water (10 ml) and neutralizing with sodium hydrogen carbonate powder,
Extracted with ethyl acetate. Wash the organic layer with saturated saline,
Dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the residue was treated by flash column chromatography (chloroform: methanol = 14: 1), and recrystallized from ethyl acetate and hexane to give the title compound (269).
mg). 1H-NMR (300MHz, δppm, DMSO-d6) 3.07 (3H, s), 6.80 (2H, d, J = 6.4Hz), 7.07 (2H, d, J = 6.4Hz),
7.09 (1H, d, J = 0.7Hz), 7.20 (1H, dd, J = 6.9,2.2Hz), 7.22 (1
H, d, J = 0.7Hz), 7.44 (1H, d, J = 6.5Hz), 7.61 (1H, d, J = 1.4H
z), 9.43 (1H, s), 11.78 (1H, s) FAB (+) MS (low resolution, m / z) 323

Example 1-5 2-Fluoro-4- (2-phenyl-1H-pyrrolo [2,3-b] pyridin-3-yl) phenol a) N- [2- (4-benzyloxy) -3-fluorophenyl) -1-phenyl-ethylidene] -N '-(pyridin-2-yl) hydrazine 2- (4-benzyloxy-3-fluorophenyl)-
1-Phenyl-ethanone (450 mg) and 2-pyridylhydrazine (153 mg) were dissolved in ethanol (20 ml), and acetic acid (3 drops) was added thereto.
The reaction was performed at 00 ° C. for 18 hours. After returning to room temperature, the reaction solvent was concentrated under reduced pressure. Toluene was added to the residue, and the mixture was concentrated under reduced pressure again to obtain the title compound (576 mg).

B) 3- (4-Benzyloxy-3-fluorophenyl) -2-phenyl-1H-pyrrolo [2,3
-B] pyridine N- [2- (4-benzyloxy-3-fluorophenyl) -1-phenyl-ethylidene] -N '-(pyridin-2-yl) obtained in a) of Example 1-5. Diethylene glycol (3 ml) was added to hydrazine and reacted at 225 ° C. for 10.5 hours under an argon atmosphere. After returning to room temperature, water and ethyl acetate were added to the solidified mixture for extraction. The organic layer was washed with a saturated saline solution and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and methano-
Added. The insoluble material was filtered and dried under reduced pressure to obtain the title compound (260 mg).

C) 2-fluoro-4- (2-phenyl-
1H-pyrrolo [2,3-b] pyridin-3-yl) phenol 3- (4-benzyloxy-3-fluorophenyl) -2-phenyl-1H obtained in b) of Example 1-5. -Pyrrolo [2,3-b] pyridine (180 mg) was added to acetic acid (3
ml), and 25% hydrobromic acid / acetic acid (2 ml) was added with stirring at room temperature. Subsequently, the reaction was performed at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate solution (10 ml)
And neutralized with sodium bicarbonate powder.
This was extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate and hexane to give the title compound (100 mg). 1H-NMR (300MHz, δppm, DMSO-d6) 6.95-7.15 (4H, m), 7.30-7.55 (3H, m), 7.86 (2H, d, J = 6.6H
z), 8.26 (1H, d, J = 1.8Hz), 8.28 (1H, d, J = 1.2Hz), 9.85 (1H,
s), 12.09 (1H, s) FAB (+) MS (low resolution, m / z) 305

Example 1-6 4- [1- (2-hydroxyethyl) -2-phenyl-
1H-Indol-3-yl] phenol a) [3- (4-Benzyloxyphenyl) -2-phenyl-1H-indol-1-yl] acetic acid methyl ester In the same manner as in Example 1. The obtained 3- (4-benzyloxyphenyl) -2-phenyl-1H-indole (70
0 mg) in N, N-dimethylformamide (15 ml)
In water and stirred under ice-cooling with sodium hydride (80 mg)
Was added and the mixture was returned to room temperature and stirred for 15 minutes. At room temperature, bromoacetic acid methyl ester (0.2 ml) was added to the reaction mixture. After reacting for 3.5 hours, ethyl acetate and water were added for extraction. The organic layer was washed successively with a saturated aqueous solution of sodium bicarbonate and a saturated saline solution, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was treated with flash column chromatography (hexane: ethyl acetate = 10: 1) to give the title compound (650 mg) as a non-crystalline substance.

B) [3- (4-hydroxyphenyl)-
2-phenyl-1H-indol-1-yl] acetic acid methyl ester [3- (4-benzyloxyphenyl) -2-phenyl-1H-indole- obtained in a) of Example 1-6. 1
-Yl] acetic acid methyl ester (640 mg) was dissolved in tetrahydrofuran (20 ml) and methanol (10 ml), and 7.5% palladium on carbon (65 mg) was added. A hydrogenation reaction was performed under a hydrogen atmosphere for 18 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure, and the residue was treated by flash column chromatography (hexane: ethyl acetate = 10: 1) to obtain the title compound (280 mg).

C) 4- [1- (2-hydroxyethyl)
-2-Phenyl-1H-indol-3-yl] phenol 3- [4- (hydroxyphenyl) -2-phenyl-1H-indole- obtained in b) of Example 1-6. 1-yl] acetic acid methyl ester (180 mg) was dissolved in methanol (2 ml), and a 1N aqueous sodium hydroxide solution (0.92 ml) was added with stirring at room temperature. 50 reaction mixtures
The reaction was carried out at 1.5 ° C. for 1.5 hours. After returning to room temperature, water was added and the mixture was washed with diethyl ether, and the aqueous layer was treated with 1N hydrochloric acid.
Ethyl acetate was added for extraction. The organic layer was washed with a saturated saline solution and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was dissolved in anhydrous tetrahydrofuran (2 ml) under an argon atmosphere, and a solution of diborane (1M) in tetrahydrofuran (2 ml) was added dropwise with stirring at room temperature, followed by reaction at room temperature for 3 hours. Was. Water and ethyl acetate were added for extraction, and the organic layer was washed with saturated saline and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to flash column chromatography (chloroform: methanol = 5).
0: 1). This was crystallized from chloroform to obtain the title compound (42 mg). 1H-NMR (300MHz, δppm, DMSO-d6) 3.50-3.60 (2H, m), 4.05-4.15 (2H, m), 4.10 (1H, t, J = 6.5H
z), 6.66 (2H, d, J = 8.4Hz), 7.00 (2H, d, J = 8.4Hz), 7.09 (1H,
(t, J = 7.5Hz), 7.21 (1H, t, J = 7.5Hz), 7.35-7.45 (5H, m), 7.56
(1H, d, J = 9.0Hz), 9.23 (1H, s) FAB (+) MS (low resolution, m / z) 330

Example 1-7 4- [2- (3-Methyl-1-oxy-pyridine-2-yl)
Yl) -1H-indol-3-yl] phenol a) 2- [3- (4-methoxyphenyl) -1H-indol-2-yl] -3-methylpyridine-N-oxide 3- (4-methoxyphenyl) -2- (3-methylpyridin-2-yl)-obtained in the same manner as in Example 1-2.
1H-indole (306 mg) was treated with methylene chloride (10
ml). Under ice-cooling and stirring, m-chloroperbenzoic acid (70%; 295 mg) was added little by little, and the mixture was allowed to react at 0 ° C for 1 hour. Further, sodium hydrogencarbonate powder was added and stirred. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was treated with flash column chromatography (chloroform: methanol = 100: 7) to give the title compound (150 mg).

B) 4- [2- (3-Methyl-1-oxy-pyridin-2-yl) -1H-indol-3-yl] phenol Obtained in a) of Example 1-7. 3- (4-methoxyphenyl) -2- (3-methylpyridine-N-oxide-
2-yl) -1H-indole (139 mg) was dissolved in anhydrous methylene chloride (5 ml). Under argon atmosphere,
After cooling to −78 ° C., a solution of boron tribromide (1 mol / l) in methylene chloride (1.3 ml) was added, and the mixture was stirred for 10 minutes. Ice was added to the reaction mixture, and the mixture was extracted with ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was washed with a 10% aqueous solution of sodium thiosulfate, and the organic layer was dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the residue was dissolved in methanol, water was added, and the precipitated crystals were filtered to obtain the title compound (80 mg). 1H-NMR (300MHz, δppm, DMSO-d6) 1.74 (3H, s), 6.72 (2H, d, J = 8.7Hz), 7.05-7.10 (3H, m), 7.35
-7.45 (2H, m), 7.68 (1H, d, J = 7.8Hz), 8.30 (1H, d, J = 6.3Hz),
9.33 (1H, s), 11.42 (1H, s) FAB (+) MS (low resolution, m / z) 317

Example 1-8 4- [2- (2-Methyl-2H-pyrazol-3-yl) -1H-indol-3-yl] phenol a) 3- (4-methoxy) Phenyl) -2- (2-methyl-2H-pyrazol-3-yl) -1H-indole 2- (4-methoxyphenyl) -1- (2-methyl-2
H-pyrazol-3-yl) -ethanone (730 mg)
And phenylhydrazine hydrochloride (504 mg) were suspended in ethanol (20 ml), and methanesulfonic acid (0.
67 ml) was added. The reaction was carried out at 80 ° C. for 20 hours, and after returning to room temperature, the reaction solvent was concentrated under reduced pressure. Saturated sodium hydrogen carbonate and ethyl acetate were added to the residue for extraction, and the organic layer was washed with saturated saline and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was treated with flash column chromatography (hexane: ethyl acetate = 3: 2) to give the title compound (593 mg) as a crystalline solid.

B) 4- [2- (2-Methyl-2H-pyrazol-3-yl) -1H-indol-3-yl] phenol Obtained in Example 1-8 b). 3- (4-Methoxyphenyl) -2- (2-methyl-2H-pyrazol-3-yl) -1H-indole (300 mg) was treated with 48% hydrobromic acid (1.5 ml) and 25%. % Hydrobromic acid-acetic acid (1.5%
ml) and reacted at 150 ° C. for 1.5 hours. After returning to room temperature, ice water (20 ml) was added to the reaction mixture,
Neutralized with 4N aqueous sodium hydroxide and subsequently made alkaline with saturated aqueous sodium bicarbonate. The precipitated crystals were collected by filtration, washed with methylene chloride and dried to give the title compound (192 mg). 1H-NMR (300MHz, δppm, DMSO-d6) 3.39 (3H, s), 6.43 (1H, d, J = 1.9Hz), 6.78 (2H, d, J = 8.6Hz),
7.08 (2H, d, J = 8.4Hz), 7.08 (1H, t, J = 5.9Hz), 7.20 (1H, t, J = 7.1Hz), 7.43 (1H, d, J = 8.1
Hz), 7.51 (1H, d, J = 1.9 Hz), 7.63 (1H, d, J = 7.9 Hz), 9.40 (1H,
s), 11.49 (1H, s) FAB (+) MS (low resolution, m / z) 290

Examples 1-9 to 1-92 Examples 1-9 to 1-92 were prepared in the same manner as in Examples 1 to 1-8.
1-92 was obtained. The obtained compounds are shown in Tables 1 to 8.

[0100]

[Table 1]

[0101]

[Table 2]

[0102]

[Table 3]

[0103]

[Table 4]

[0104]

[Table 5]

[0105]

[Table 6]

[0106]

[Table 7]

[0107]

[Table 8]

Example 2 4- [5-Chloro-2- (2H-pyrazol-3-yl) -1H-indol-3-yl] phenol a) 3-dimethylamino-1- [ 5-chloro-3- (4
-Methoxyphenyl) -1H-indol-2-yl]
Propent-1-one Synthetic Communication (Synthetic commu
nications) 23 (3), 1- [5-chloro-3- (4-methoxyphenyl) -1H-indol-2-yl] ethanone (1.1) obtained according to (421).
7 g) was suspended in N, N-dimethylformamide dimethyl acetal (10.4 ml) and reacted at 130 ° C. for 40 minutes. After returning to room temperature, toluene and hexane were added to the reaction mixture, and the precipitated crystals were filtered. This was washed with hexane and dried under reduced pressure to give the title compound (894m
g) was obtained.

B) 5-Chloro-3- (4-methoxyphenyl) -2- (2H-pyrazol-3-yl) -1H-
Indole 3-dimethylamino-1- obtained according to Example 2a)
[5-chloro-3- (4-methoxyphenyl) -1H-
Indol-2-yl] propen-1-one (496 m
g) was suspended in ethanol (15 ml), and hydrazine
Monohydrate (0.11 ml) was added with stirring at room temperature. The reaction mixture was reacted at 90 ° C. for 2.5 hours. After returning to room temperature, the reaction solution was concentrated under reduced pressure. 50% hexane / residue
Isopropyl alcohol was added and the crystals were filtered to give the title compound (396 mg).

C) 4- [5-Chloro-2- (2H-pyrazol-3-yl) -1H-indol-3-yl] phenol 5 obtained in b) of Example 2. -Chloro-3- (4-methoxyphenyl) -2- (2H-pyrazol-3-yl)
1H-indole (218 mg) was suspended in 48% hydrobromic acid (2 ml) and 25% hydrobromic acid / acetic acid (2 ml) and reacted at 140 ° C. for 1 hour. After returning to room temperature, the mixture was neutralized with sodium hydrogen carbonate. Subsequently, the mixture was extracted with chloroform, and the organic layer was washed with saturated saline and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was treated with flash column chromatography (ethyl acetate: chloroform = 50: 50) to give the title compound (152 mg) as a crystalline solid. 1H-NMR (300MHz, δppm, DMSO-d6) 6.08 (1H, brs), 6.82 (2H, d, J = 8.7Hz), 7.09 (1H, d, J = 8.7H)
z), 7.20-7.30 (3H, m), 7.42 (1H, d, J = 8.4Hz), 7.69 (1H, br-
s), 9.44 (1H, s), 11.53 (1H, s), 13.02 (1H, br-s) FAB (+) MS (low resolution, m / z) 310

Example 2-2 4- [2- (Isoxazol-5-yl) -1H-indol-3-yl] phenol a) 2- (Isoxazol-5-yl)- 3- (4-
Methoxyphenyl) -1H-indole 3-dimethylamino-1- [3- (4-methoxyphenyl) -1H-indole-2-yl] propene obtained in a similar manner to a) of Example 2. -1-one (350mg)
Was suspended in ethanol (7 ml), hydroxylamine hydrochloride (94 mg) was added, and the mixture was reacted at 90 ° C. for 3 hours. After returning to room temperature, the reaction solvent was concentrated under reduced pressure, and the residue was treated by flash column chromatography (ethyl acetate: chloroform = 10: 90) to obtain the title compound (298 mg).

B) 4- [2- (Isoxazole-5-)
Yl) -1H-Indol-3-yl] phenol 2- (isoxazol-5-yl) -3- (4-methoxyphenyl) -1H obtained in a) of Example 2-2. −
Indole (135 mg) was treated with methylene chloride (10 ml).
And cooled to −42 ° C. under an argon atmosphere, and a solution of boron tribromide (1.0 mol / l) in methylene chloride (1.
4 ml), and the mixture was returned to room temperature and reacted for 3 hours. Water and ethyl acetate were added to the reaction mixture for extraction. The organic layer was washed sequentially with an aqueous sodium hydrogen carbonate solution, a 10% aqueous sodium thiosulfate solution and saturated saline, and the organic layer was dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was treated with flash column chromatography (ethyl acetate: chloroform = 10: 90) to give the title compound (7).
9 mg) as a crystalline solid. 1H-NMR (300MHz, δppm, DMSO-d6) 6.40 (1H, d, J = 2,0Hz), 6.90 (2H, d, J = 8.6Hz), 7.07 (1H, t, J =
8.0Hz), 7.20-7.30 (3H, m), 7.40-7.50 (2H, m), 8.56 (1H, dJ =
2.0Hz), 9.58 (1H, s), 11.94 (1H, s) FAB (+) MS (low resolution, m / z) 276

Example 2-3 4- [2- (pyrimidin-4-yl) -1H-indo-
Ru-3-yl] phenol a) 3- (4-methoxyphenyl) -2- (pyrimidin-4-yl) -1H-indole synthetic communication (Synthetic commu
nications) 23 (3), 1- [3- (4-methoxyphenyl) -1H- obtained according to 421 (1992).
Indole-2-yl] -ethanone (135 mg) and pyrrolidine (0.22 ml) were combined with 1,4-dioxane (10
ml) and reacted at 90 ° C. for 1 hour. 1,3,5-Triazine (41 mg) was added to the reaction mixture,
The reaction was further performed at 90 ° C. for 19 hours. After returning to room temperature, the reaction solvent was concentrated under reduced pressure, and the residue was treated by flash column chromatography (hexane: ethyl acetate = 70: 30) to obtain the title compound (93 mg) as a crystalline solid.

B) 4- [2- (pyrimidin-4-yl)
-1H-Indol-3-yl] phenol 3- (4-methoxyphenyl) -2- (pyrimidin-4-yl) -1H-indole obtained in a) of Example 2-3. (93 mg) in 48% hydrobromic acid (2 ml) and 25
% Hydrobromic acid / acetic acid (2 ml),
The reaction was performed for 0 minutes. After returning to room temperature, water was added to the reaction mixture, the mixture was made alkaline with sodium hydrogen carbonate powder, and extracted with ethyl acetate. Wash the organic layer with saturated saline,
Dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was treated by flash column chromatography (chloroform: ethyl acetate = 70: 30) to give
The title compound (42 mg) was obtained. 1H-NMR (300MHz, δppm, DMSO-d6) 6.92 (2H, d, J = 8.5Hz), 7.03 (1H, t, J = 7.2Hz), 7.15-7.25 (4
H, m), 7.36 (1H, d, J = 8.1Hz), 7.53 (1H, d, J = 8.1Hz), 8.53 (1
H, d, J = 5.5Hz), 9.62 (1H, s), 11.86 (1H, s) FAB (+) MS (low resolution, m / z) 288

Examples 2-4 to 2-6 Examples 2-4 to 2-6 were prepared in the same manner as in Examples 2 to 2-3.
2-6 was obtained. Table 9 shows the obtained compounds.

[0116]

[Table 9]

Example 3 1- [3- (4-Hydroxyphenyl) -1H-indol-2-yl] -pyrrolidin-2-one a) 3- (4-hydroxyphenyl) -1H-indo-
2-Carboxylic acid ethyl ester 3- (4-hydroxyphenyl) pyruvic acid (6.05
g) was dissolved in ethanol (100 ml), concentrated sulfuric acid (1.0 ml) was added, and the mixture was heated under reflux for 4 hours. After returning to room temperature, phenylhydrazine hydrochloride (5.20 g) was added, and the mixture was reacted at 90 ° C. for 18 hours. By concentrating the reaction solvent under reduced pressure, adding toluene to the residue and filtering the precipitated crystals,
The title compound (3.65 g) was obtained.

B) 3- (4-methoxyphenyl) -1H
-Indole-2-carboxylic acid ethyl ester 3- (4) obtained in a) of Example 3 under an argon atmosphere.
-Hydroxyphenyl) -1H-indole-2-carboxylic acid ethyl ester (3.60 g), methanol (0.9 ml) and triphenylphosphine (2.3
6 g) was dissolved in tetrahydrofuran (30 ml).
At 50 ° C., diisopropyl azodicarboxylate (1.67 m
l) An anhydrous tetrahydrofuran solution (10 ml) was added, and the mixture was returned to room temperature and reacted for 3.5 hours. The reaction solvent was concentrated under reduced pressure, and the residue was subjected to flash column chromatography.
(Hexane: ethyl acetate = 9: 1) to give the title compound (2.6 g).

C) 3- (4-methoxyphenyl) -1H
-Indole-2-carboxylic acid Ethanol (2.58 g) of 3- (4-methoxyphenyl) -1H-indole-2-carboxylic acid ethyl ester (2.58 g) obtained in b) of Example 3 was obtained. 20 ml) 2 in solution
N sodium hydroxide aqueous solution (2.0 ml)
Stirred at C for 4 hours. The reaction solution was concentrated under reduced pressure, and water was added to the residue. After acidification with concentrated hydrochloric acid, the precipitated crystals were extracted with ethyl acetate, and the organic layer was dried over sodium sulfate. After filtration,
Concentration under reduced pressure gave the title compound (2.02 g) as a crystalline solid.

D) 3- (4-methoxyphenyl) -1H
-Indole-2-carbamic acid benzyl ester 3- (4-methoxyphenyl) -1H-indole-2-carboxylic acid (2.02) obtained in c) of Example 3
g) in a toluene solution (30 ml) under an argon atmosphere,
Diphenylphosphate azide (3.22 ml) and triethylamine (2.32 ml) were added. After stirring at 60 ° C. for 40 minutes, benzyl alcohol (20 ml) was added. After stirring for another 3 hours, the reaction mixture was concentrated in vacuo,
The residue was treated with flash column chromatography (hexane: ethyl acetate = 9: 1) to give the title compound (1.3 g) as a crystalline solid.

E) 3- (4-methoxyphenyl) -1H
-Indole-2-amine 3- (4-methoxyphenyl) -1H-indole-2-carbamic acid benzyl ester (1.25 g) obtained in d) of Example 3 was added to ethyl acetate (20 ml). And 7.5% palladium-carbon (450 mg) was added. A hydrogenation reaction was performed for 6 hours under a hydrogen atmosphere. The catalyst was filtered off and concentrated under reduced pressure to give the title compound (83
0 mg) was obtained as an oil.

F) 1- [3- (4-methoxyphenyl)
-1H-Indol-2-yl] -pyrrolidin-2-one 3- (4-methoxyphenyl) -1H-indole-2-amine (830 mg) obtained in e) of Example 3 was added to N , N-dimethylformamide (30 ml),
4-bromobutyryl chloride (0.44
ml) was added. After stirring for 3 hours, potassium carbonate (1.5 g) was added and reacted at room temperature for 18 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted. The obtained organic layer was washed with a saturated saline solution and dried with sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to flash column chromatography (chloroform: ethyl acetate = 9).
7: 3) to give the title compound (560 m
g) was obtained as a crystalline solid.

G) 1- [3- (4-Hydroxyphenyl) -1H-indol-2-yl] -pyrrolidine-2
1- [3- (4-Methoxyphenyl) -1H-indol-2-yl] -pyrrolidine- obtained in Example 3, f).
2-One (560 mg) was dissolved in anhydrous methylene chloride (20 ml) under an argon atmosphere and cooled to -60 ° C.
Next, a methylene chloride solution (5 ml) of boron tribromide (1.0 mol / l) was added, and the mixture was stirred for 10 minutes, then returned to room temperature and reacted for 1 hour. Ice was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate and hexane to give the title compound (100 m
g) was obtained. 1H-NMR (300MHz, δppm, DMSO-d6) 2.04 (2H, dq, J = 15.3,7.5Hz), 2.43 (2H, t, J = 7.8Hz), 3.51 (2
H, t, J = 6.9Hz), 6.84 (2H, d, J = 8.4Hz), 7.02 (1H, t, J = 7.8H
z), 7.12 (1H, t, J = 8.1Hz), 7.25 (2H, d, J = 8.7Hz), 7.37 (1H,
d, J = 7.8Hz), 7.52 (1H, d, J = 8.1Hz), 9.38 (1H, s), 11.31 (1
H, s) FAB (+) MS (low resolution, m / z) 293

Example 3-2 4- [2-([1,3,4] thiadiazol-2-yl) -1H-indol-3-yl] phenol a) N'-formyl-N- [3- (4-Methoxyphenyl) -1H-indol-2-yl] carbohydrazide 3- (4-methoxyphenyl) -1H-indole- obtained in the same manner as in Example 3C). 2-Carboxylic acid (0.35 g) was added to N, N-dimethylformamide (5 m
l) and dissolved in N-hydroxybenzotriazole monohydrate (0.30 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.3
7g) were added sequentially. After reacting at room temperature for 1 hour, a solution of formohydrazide (0.11 g) in N, N-dimethylformamide (5 ml) was added, and the mixture was reacted for 1.5 hours.
Ethyl acetate and saturated saline were added to the reaction solution. The extracted organic layer was washed successively with 1N hydrochloric acid and a saturated aqueous solution of sodium hydrogen carbonate, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (373m).

B) 3- (4-methoxyphenyl) -2-
[1,3,4] thiadiazol-2-yl) -1H-indole N′-formyl-N- obtained in a) of Example 3-2.
[3- (4-methoxyphenyl) -1H-indole-
2-yl] carbohydrazide (370 mg) was dissolved in pyridine (6 ml), a Lawesson's reagent (600 mg) was added, and the mixture was reacted at 100 ° C. for 24 hours. After returning to room temperature, the reaction solvent was concentrated under reduced pressure, and the residue was extracted with a saturated aqueous solution of sodium hydrogen carbonate and ethyl acetate. The organic layer was dried with sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to flash column chromatography (chloroform:
The title compound (260 mg) was obtained by treatment with methanol = 96: 4).

C) 4- [2-([1,3,4] thiadiazol-2-yl) -1H-indol-3-yl] phenol Obtained in b) of Example 3-2. 3- (4-methoxyphenyl) -2-([1,3,4] -thiadiazol-5
Il) -1H-indole (127 mg) was dissolved in anhydrous methylene chloride (10 ml) under an argon atmosphere. −
After cooling to 45 ° C., a methylene chloride solution (1.24 ml) of boron tribromide (1.0 mol / l) was added, and the mixture was stirred for 5 minutes, then returned to room temperature and reacted for 4 hours. Water was added under ice cooling, and the mixture was stirred for 1 hour, and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was treated by flash column chromatography (chloroform: methanol = 96: 4) to give the title compound (52 mg) as a crystalline solid. 1H-NMR (300 MHz, δ ppm, DMSO-d6) 6.94 (2H, d, J = 8.8 Hz), 7.00-7.10 (1H, m), 7.20-7.25 (3H,
m), 7.30-7.40 (1H, m), 7.50 (1H, d, J = 8.1Hz), 9,39 (1H, s),
9,67 (1H, s), 12.14 (1H, s) FAB (+) MS (low resolution, m / z) 294

Example 3-3 4- [1-Methyl-2- (2H-pyrazol-3-yl) -1H-indol-3-yl] phenol a) 3- (4-methoxy) Phenyl) -1-methyl-1H
-Indole-2-carboxylic acid ethyl ester 3- (4-methoxyphenyl) -1H-indole-2-carboxylic acid ethyl ester (0.84 g) obtained in the same manner as in Example 3 was added to N, It was dissolved in N-dimethylformamide (4 ml), and sodium hydride (60% inoil suspension: 0.2
7g) was added. After reacting on ice for 25 minutes, methyl iodide (0.8 ml) was added and reacted for 1.5 hours. The reaction mixture was poured into a saturated saline solution and extracted with ethyl acetate.
The organic layer was washed with a saturated saline solution and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to flash column chromatography (0.3% ethyl acetate / chloroform).
To give the title compound (0.57 g) as an oil.

B) 3- (4-methoxyphenyl) -1-
Methyl-1H-indole-2-carboxylic acid ethyl 3- (4-methoxyphenyl) -1-methyl-1H-indole-2-carboxylic acid ethyl ester obtained in a) of Example 3-3 ( 0.57 g) in ethanol (10
ml) and a 2N aqueous sodium hydroxide solution (2 m
1) was added, and the reaction mixture was reacted at 60 ° C. for 8 hours, and then the reaction solvent was concentrated under reduced pressure. Water was added to the residue, and the mixture was acidified with 2N hydrochloric acid under ice-cooling and stirring. The precipitated crystals are filtered,
Wash with water and dry under reduced pressure to give the title compound (0.4
8g) was obtained as a crystalline solid.

C) 3- (4-methoxyphenyl) -1-
Methyl-1H-indole-2-carboxylic acid methoxymethylamide 3- (4-methoxyphenyl) -1-methyl-1H-indole-2-carboxylic acid obtained in b) of Example 3-3 (0.47 g) in N, N-dimethylformamide (5
n-hydroxybenzotriazole hydrate (0.40 g), N, O-dimethylhydroxylamine hydrochloride (0.25 g), triethylamine (1.2 ml) under stirring at room temperature. And 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.
5 g) were added in sequence and reacted at room temperature for 3.5 hours. A saturated saline solution and ethyl acetate were added to the reaction mixture, and the organic layer was extracted. The obtained organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water, 1N hydrochloric acid and saturated saline, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 3
-(4-methoxyphenyl) -1-methyl-1H-indole-2-carboxylic acid methoxymethylamide (0.
49 g) was obtained as an oil.

D) 1- [3- (4-methoxyphenyl)
-1-Methyl-1H-indole-2-yl] -ethanone 3- (4-methoxyphenyl) -1-methyl-1H-indole-2- obtained in c) of Example 3-3. Carboxylic acid methoxymethylamide (0.49 g) was dissolved in anhydrous tetrahydrofuran (15 ml) under an argon atmosphere,
Methyl magnesium bromide (0.92
mol / l) in tetrahydrofuran (6.6 ml)
It was dropped. After reacting for 4 hours, a 10% aqueous citric acid solution (15 ml) was added, the reaction solvent was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of sodium bicarbonate and a saturated saline solution, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was treated with flash column chromatography (0.5% ethyl acetate / chloroform) to give the title compound (0.42 g).
Was obtained as an oil.

E) 3- (4-methoxyphenyl) -1-
Methyl-2- (2H-pyrazol-3-yl) -1H-
Indole 1- [3- (4-Methoxyphenyl) -1-methyl-1H-indole-2-yl] -ethanone (0.42 g) obtained in d) of Example 3-3 was added to N , N-dimethylformamide dimethyl acetal (65 ml).
The reaction was carried out at 30 ° C. for 96 hours. After returning to room temperature, the reaction solvent was concentrated under reduced pressure. The residue was dissolved in ethanol (4 ml) and hydrazine monohydrate (0.2 ml) was added. After reacting the reaction mixture at 100 ° C. for 2 hours, the reaction solvent was concentrated under reduced pressure, and the residue was subjected to flash column chromatography.
(Chloroform: ethyl acetate = 85: 15) to give the title compound (0.28 g) as a crystalline solid.

F) 4- [1-Methyl-2- (2H-pyrazol-3-yl) -1H-indol-3-yl] phenol Obtained in Example 3-3 e). 3- (4-methoxyphenyl) -1-methyl-2- (2H-pyrazol-3-yl) -1H-indole (0.14 g) was treated with 48% hydrobromic acid (1.1 m). And 25% hydrobromic acid / acetic acid (1.1
m) and reacted at 140 ° C. for 2 hours. After returning to room temperature, the mixture was neutralized with sodium hydrogen carbonate and extracted with chloroform. The obtained organic layer was washed with a saturated saline solution,
Dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to flash column chromatography (chloroform: ethyl acetate = 40: 60), whereby
The title compound (74 mg) was obtained as a crystalline solid. 1H-NMR (300MHz, δppm, DMSO-d6) 3.62 and 3.80 (3H, s), 6.10 and 6.42 (1H, s), 6.74 (1H, d,
J = 8.4Hz), 7.00-7.30 (4H, m), 7.45-7.60 (2H, m), 7.77 (1H,
s), 9,30 (1H, s), 13.08 (1H, brs) FAB (+) MS (low resolution, m / z) 290 The compounds obtained in Examples 3 to 3-3 are shown in Table 10. Was.

[0133]

[Table 10]

Pharmacological test Estrogen receptor agonist activity (reporter gene assay) CHO (Chinese Hamster Ovary) cells were cultured in a medium (Eagl
e-MEM (Minimum Essential Medium), 10% horse serum (HS), 0.1 mM MEM non-essential amino acid solution,
CHO cells were suspended in 100 μg / ml penicillin, 100 μg / ml streptomycin) and 6 × 10 ⁶ c
The cells were cultured in cells / flash at 75 cm ² flash and cultured for 24 hours. Serum-free Eagle-MEM 5m
After washing twice with l, serum-free Eagle-MEM 5m
1 was added. On the other hand, 600 μl of serum-free Eagle-ME
M to 24 μl of lipofection reagent (Trans-I
TLT-1) was added and the mixture was gently stirred. After standing for 5 minutes,
This solution contains human estrogen receptor
orα (hERα) expression vector (hERα / pcDN
A3) or hERβ expression vector (hERβ / pcD
NA3) and estrogen response ele
luciferase with ment (ERE) inserted
The receptor gene (ERE / Luc) was added and stirred (hERα / pcDNA3 for CHO cells).
2 μg, ERE / Luc 10 μg or hERβ /
pcDNA3 2 μg, ERE / Luc 10 μg). 5
After standing for 1 minute, this solution was added to the cells washed with Eagle-MEM described above, and allowed to stand in a CO ₂ incubator for 4 hours. The solution was removed by suction, and 12 ml of a medium was added and cultured. After 12 hours, trypsin / EDTA (Ethylene
Diamine Tetra Acetic Acid) was added, the cells were detached, suspended in a medium, and added to a 96-well-white plate.
te was seeded at 3 × 10 ⁴ cells / well. 8
After a period of time, the compound diluted in the medium was added to the cells (a medium containing DMSO (Dimethyl Sulfoxide) for the control group, and a medium containing 17β-estradiol for the positive control group). After culturing for 24 hours, the medium was removed, a luciferase substrate (Piccagene LT7.5) was added, and the luciferase activity was measured by a top count, and used as an indicator of the agonist activity. For the compound-free group,
When the maximum luciferase activity of the 17β-estradiol-added group is defined as 100% agonist activity, 50%
The concentration of compound that exhibits agonist activity and EC _50,
It was used as an indicator of the activity of the compound. The results are shown in Tables 11 to 13.

[0135]

[Table 11]

[0136]

[Table 12]

[0137]

[Table 13]

[0138]

As is clear from the above tests, the novel compounds of the present invention and pharmaceutically acceptable salts thereof selectively act on estrogen receptors, particularly β. Therefore, the compound of the present invention is useful as a therapeutic drug for osteoporosis, which does not have side effects such as uterine bleeding and uterine cancer, which are feared as side effects by administering estrogen.

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (Reference) A61K 31/437 A61K 31/437 31/4439 31/4439 A61P 5/30 A61P 5/30 5/32 5/32 19 / 10 19/10 43/00 111 43/00 111 C07D 401/04 C07D 401/04 403/04 403/04 405/04 405/04 409/04 409/04 417/04 417/04 471/04 104 471 / 04 104Z (72) Inventor Akihiko Fujii 1-1, Muramachi, Takatsuki-shi, Osaka F-term in Japan Tobacco Inc. Pharmaceutical Research Institute 4C063 AA01 BB01 CC12 CC22 CC25 CC62 CC75 CC92 DD06 EE01 4C065 AA04 BB04 CC01 DD02 EE02 HH01 JJ01 JJ03 KK02 KK04 PP03 4C086 AA01 AA02 AA03 BC13 BC17 BC36 BC38 BC82 CB05 GA02 GA04 GA07 GA08 GA10 MA01 MA04 NA06 NA14 ZA97 ZC11 ZC41 4C204 BB01 CB02 DB07 DB15 EB03 FB01 GB22 GB03 GB25 GB25

Claims (10)

[Claims] 1. A compound of the general formula (1) [Wherein, R ¹ represents a hydrogen atom, a lower alkyl group or-(CH
₂ ) _m- R ² (where R ² is a hydroxyl group, a carboxyl group, a lower alkoxy group, a lower alkoxycarbonyl group or —NR ³ R ⁴ — (where R ³ and R ⁴ are the same or different and are each a hydrogen atom or Together with a lower alkyl group or an adjacent nitrogen atom (Where n is an integer from 1 to 3) and m is an integer from 1 to 5); R ⁵ and R ⁶
Are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group,
R ⁷ is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group; a ring Y is an aryl group, a heteroaryl group, or a lower alkyl group, a lower alkoxy group or a lower alkoxyalkyl group; (Where q is an integer from 1 to 2);
N- or = CR ⁸ - (wherein, ^{R 8} is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group)
B is = N-, Or = CR 9 ^- (wherein, R ⁹ is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, lower alkoxycarbonyl group, a carboxyl group, a lower alkylaminocarbonyl group, an acylamino group or a lower alkylsulfonylamino group D is = N-, embedded image ＣＲCR ¹⁰ — (where R ¹⁰ is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a carboxyl group, a lower alkylaminocarbonyl group, an acylamino group or a lower alkylsulfonylamino group E is = N-, Or = ^{CR 11} - ^{(wherein, R 11} is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group,
A lower alkoxycarbonyl group, a carboxyl group, a lower alkylaminocarbonyl group, an acylamino group or a lower alkylsulfonylamino group);
-, ＣＲCR ¹² — (where R ¹² is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a carboxyl group, a lower alkylaminocarbonyl group, an acylamino group or a lower alkylsulfonylamino group There is). However, when Y is an aryl group and R ¹ is a hydrogen atom or a lower alkyl group, R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ ,
R ¹¹ and R ¹² are not hydrogen atoms at the same time.] Or a pharmaceutically acceptable salt thereof. 2. The indole compound according to claim 1, wherein Y is an aryl group, or a pharmaceutically acceptable salt thereof. 3. The indole compound according to claim 2, wherein the aryl group in Y is a phenyl group, or a pharmaceutically acceptable salt thereof. 4. The indole compound according to claim 3, wherein R ⁸ is a fluorine atom, or a pharmaceutically acceptable salt thereof. (5) Y is a heteroaryl group or (Wherein q is as defined above), or the pharmaceutically acceptable salt thereof. 6. Y is a pyridyl, pyridyl-N-oxide, pyrimidinyl, thienyl, thiazolyl, isoxazolyl, furyl, imidazolyl, pyrazolyl, 1,3,4-thiadiazol-2-yl group. , 2
The indole compound or the pharmaceutically acceptable salt thereof according to claim 5, which is a pyrrolidone-1-yl group or a 2-piperidone-1-yl group. 7. A pharmaceutical composition comprising the indole compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 8. An estrogen receptor agonist comprising the indole compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 9. An estrogen receptor β agonist comprising the indole compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 10. An agent for treating osteoporosis, comprising the indole compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.