JP2019043872A - Cartilage matrix-degrading enzyme production inhibitor - Google Patents

Abstract

To provide cartilage matrix-degrading enzyme production inhibitors and agents for preventing or mitigating a symptom or disease (e.g., osteoarthritis) caused by decrease of or damage to a cartilage matrix, which contain as an active ingredient a low molecular weight compound that can be relatively simply and inexpensively produced.SOLUTION: One or more compounds selected from the group consisting of compounds represented by the general formulas (I), (II) and (III) in the figure and, when Ris OH, pharmaceutically acceptable salts thereof are used as a cartilage matrix-degrading enzyme production inhibitor or an agent for preventing or mitigating a symptom or disease caused by decrease of or damage to a cartilage matrix.SELECTED DRAWING: None

Description

The present invention comprises compounds represented by the general formula (I ₀ ), the general formula (II), and the general formula (III) described later, and pharmaceutically acceptable salts thereof when R ³ is OH. Of a cartilage matrix-degrading enzyme production inhibitor comprising one or more compounds selected from the group (hereinafter sometimes collectively referred to as “the present compound group”), and such cartilage matrix-degrading enzymes The present invention relates to an agent for preventing or ameliorating a symptom or disease caused by reduction or damage of a cartilage matrix, including a production inhibitor.

  Osteoarthritis is a disease caused by degeneration of articular cartilage, also called cartilage tissue inflammation. Osteoarthritis develops in various joint sites such as knees, hips, hands, and spines with aging, and causes various symptoms such as joint pain, dysfunction, gait disorder, etc., so the daily life of middle-aged and elderly people It is one of the causes that lowers motion (ADL) and quality of life (QOL). According to a report by the Health and Labor Bureau in April 2008, approximately 10 million people complain about subjective symptoms and the number of potential patients is approximately 30 million, the number being the elderly in society It is expected to increase with the progress of

  Articular cartilage is mainly composed of two types of cartilage matrix, collagen type II and aggrecan (proteoglycan). In osteoarthritis, these two types of cartilage matrix respectively represent matrix metalloproteinases (NPL 1) represented by MMP (matrix metalloproteinase) -13 and ADAMTS (metalloprotease-disintegrin) -5. It is produced by being degraded by the cartilage matrix degrading enzyme of Aggrecanase (Non-patent Document 2).

  Compounds such as agar, agarose, agarooligosaccharides (Patent Document 1), ginkgo biloba extract, kumiscutin extract, loquat leaf extract, juvenile shoots (Matteuccia struthiopteris), etc. to inhibit the production of cartilage matrix degrading enzymes Plants (Patent Documents 2 and 3) are used. Moreover, it has also been reported that it has the inhibitory activity of a cartilage matrix degrading enzyme in the fruit of a persimmon fruit (patent document 4) and the extract of the bark of a rose family cherry genus plant (patent document 5).

  On the other hand, the present inventors have reported that the present compound group has an erythropoietin expression enhancing effect (patent document 6) and an organ fibrosis suppressing effect (patent document 7). However, it has not been known until now that the present compound group has a cartilage matrix degrading enzyme production inhibitory effect.

JP, 2011-213707, A JP, 2011-225550, A JP, 2016-193844, A Unexamined-Japanese-Patent No. 2000-159631 JP, 2016-179948, A WO 2014/080640 pamphlet JP, 2015-189670, A

Billinghurst, R. C. et al., J. Clin. Invest. (1997) 99: 1534-1545. Glasson, S. S. et al., Nature. (2005) 434: 644-648.

  The object of the present invention is to use a low-molecular weight compound which can be produced relatively easily and inexpensively as an active ingredient, a production inhibitor of cartilage matrix degrading enzyme, a symptom or disease caused by reduction or damage of cartilage matrix (eg Provide a preventive or ameliorating agent for osteoarthritis).

  The present inventors have been diligently researching to solve the above-mentioned problems. In the process, the present compound group to be described later was found to have an effect of effectively suppressing the production of a cartilage matrix degrading enzyme in chondrocytes, and the present invention has been completed.

That is, the present invention is as follows.
[1] the following general formula (I ₀ );
[Wherein, R ¹ is a benzene ring which is unsubstituted or substituted by an alkyl group having 1 to 7 carbon atoms, an alkoxyl group having 1 to 7 carbon atoms, fluorine and / or chlorine; unsubstituted or substituted by fluorine] A linear or branched alkyl group having 4 to 6 carbon atoms, or methylene or ethylene substituted with a phenyl group or a cyclopentyl group, and the phenyl group is further substituted with one or more phenyl groups And Z ¹ , Z ² , Z ³ and Z ⁴ may be the same or different, and a hydrogen atom, a halogen atom, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C2 to C6 alkynyl group, an organic group represented by OR ^{8, R 8} is an alkyl group of C1 to C7, alkenyl group of C2 -C6, an alkynyl group of C2 -C6, ^{Z 5} is, water Represents an alkyl group of atoms or a C1 ^-C6, R 3 is ^OH, a group selected from any one of the OR 4, NHR ⁴ and ^NR 4 ^{R 5, R 4} and ^{R 5} are the same or different, substituted Or an unsubstituted C1-C4 alkyl group. ]
, General formula (II);
Wherein R ⁶ is hydrogen or methyl, X is an alkylene group having 4 to 6 carbon atoms, or an ether group having 4 carbon atoms, R ³ is OH, OR ⁴ , NHR ⁴ and NR ⁴ R ⁵ And R ⁴ and R ⁵ are the same or different and each is a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms. ]
And General formula (III);
[Wherein, A represents indole or naphthalene, and when A is indole, an acetic acid group and R ⁷ O are substituted at the 3- and 5-positions of indole, respectively, and when A is naphthalene, 1-position of naphthalene An acetic acid group and R ⁷ O are substituted at position 7 and 7, respectively, R ⁷ represents an alkyl group having 1 to 5 carbon atoms or a benzyl group, and the benzene ring of the benzyl group has 1 or 2 or more carbon atoms. R ³ may be substituted with an alkyl group of ̃3 or an alkoxy group having 1 to 3 carbon atoms, and R ³ is a group selected from any one of OH, OR ⁴ , NHR ⁴ and NR ⁴ R ⁵ , R ⁴ and R ⁵ are the same or different and are substituted or unsubstituted alkyl groups having 1 to 4 carbon atoms. ]
An agent for inhibiting the production of a cartilage matrix degrading enzyme, comprising: a compound represented by: and one or more compounds selected from the group consisting of pharmaceutically acceptable salts thereof when R ³ is OH.
[2] The cartilage matrix degrading enzyme is one or more selected from MMP13 (Matrix metalloproteinase 13), ADAMTS4 (A disintegrin and Metalloproteinase with Thrombopondin motifs 4), and ADAMTS 5 (A disintegrin and Metalloproteinase with Thrombosporindin motifs 5) The agent for inhibiting the production of a cartilage matrix degrading enzyme according to [1] above, which is a protein of
[3] The agent for suppressing cartilage substrate degrading enzyme production according to the above [1] or [2], wherein the compound is a compound represented by the following formula (I-2) or a pharmaceutically acceptable salt thereof .
Formula (I-2) (compound # 5 described later in Examples);
[4] An agent for preventing or ameliorating a symptom or disease caused by reduction or damage to a cartilage matrix, comprising the agent for inhibiting cartilage matrix degradation according to any one of the above [1] to [3].

  In another embodiment of the present invention, the method further comprises the step of administering one or more compounds selected from the compound group to a patient in need of increased production of a cartilage matrix degrading enzyme Of one or more compounds selected from the present compound group, for producing a method for increasing cartilage matrix-degrading enzyme production in the present invention, or for use as a cartilage matrix-degrading enzyme production inhibitor, or cartilage matrix-degrading enzyme production 1 type or 2 types selected from the present compound group for producing one or more compounds selected from the present compound group, or a cartilage matrix degrading enzyme production inhibitor for use in suppression Use of the above compounds can be mentioned.

  In another embodiment of the present invention, one or more compounds selected from the present compound group are required to prevent or ameliorate (treat) a symptom or disease caused by reduction or damage to a cartilage matrix. A method for preventing or ameliorating (treating) a condition or disease caused by a decrease or damage to a cartilage matrix, including the step of administering to a subject in question; preventing or ameliorating (treating) a condition or disease caused by a decrease or damage to a cartilage matrix And one or more compounds selected from the compound group for use as an agent) or for use in the prevention or amelioration (treatment) of a condition or disease caused by reduction or damage to a cartilage matrix, The present invention for producing one or more compounds selected from the compound group of the present invention, or an agent for the prophylaxis or amelioration (treatment) of a symptom or disease caused by reduction or damage to a cartilage matrix Use of one or more compounds selected from compounds group can be mentioned.

  According to the present invention, the production of a cartilage matrix degrading enzyme in chondrocytes can be effectively suppressed. In addition, since the present invention uses a low molecular weight compound which can be produced relatively easily and in high yield as an active ingredient for suppressing the production of a cartilage matrix degrading enzyme, it can be produced relatively easily and inexpensively. Excellent prevention or amelioration (treatment) effects are also expected for patients with symptoms or diseases caused by substrate reduction or damage.

It is a figure which shows the result of having analyzed the expression level of mRNA of MMP13 gene in the chondrocytes of each group. The “MMP13 expression level” on the vertical axis is the mRNA expression level of the MMP13 gene in the three groups (chemical conversion # 5 addition group, TNF-α addition group, and TNF-α + activation # 5 addition group) in the control group. It shows as a relative value when the expression level is set to 1 (mean value ± standard deviation, n = 6). “*” In the figure indicates that there is a statistically significant difference (p = 0.05). It is a figure which shows the result of having analyzed the expression level of mRNA of the ADAMTS4 gene in the chondrocytes of each group. The “ADAMTS4 expression level” on the vertical axis is the expression level of the ADAMTS4 gene mRNA in the three groups (chemical conversion # 5 addition group, TNF-α addition group, and TNF-α + activation # 5 addition group) in the control group. It shows as a relative value when the expression level is set to 1 (mean value ± standard deviation, n = 6). “*” In the figure indicates that there is a statistically significant difference (p = 0.03). It is a figure which shows the result of having analyzed the expression level of mRNA of ADAMTS5 gene in the chondrocytes of each group. The “ADAMTS5 expression level” on the vertical axis represents the mRNA expression level of the ADAMTS5 gene in the three groups (chemical conversion # 5 addition group, TNF-α addition group, and TNF-α + activation # 5 addition group) in the control group. It shows as a relative value when the expression level is set to 1 (mean value ± standard deviation, n = 6). “*”, “**” and “***” in the figure are statistically significant (p = 0.04, p = 0.003 and p = 0.001) respectively Indicates

  The agent for suppressing the production of a cartilage matrix degrading enzyme according to the present invention is an active ingredient of one or more compounds selected from the present compound group, which has a limited application of “to suppress the production of a cartilage matrix degrading enzyme”. An agent (hereinafter sometimes referred to as "the present inhibitor"), which prevents or ameliorates a condition or disease caused by reduction or damage to a cartilage matrix according to the present invention An agent containing the inhibitor of the present invention (hereinafter, sometimes referred to as the “prevention / improvement agent of the present invention”) having a limited application of “for preventing or ameliorating the symptoms or disease caused by the agent” or the present prevention For the / improvement agent, the present compounds, which are the respective active ingredients, may be used alone as food or drink or medicine (preparation), and further, additives are mixed to form a composition (food or drink composition or Pharmaceutical composition It may be used as. Such food and drink include, for example, health food (functional food, nutraceuticals, health supplements, fortified food, nutritionally adjusted food, supplements, etc.), health food (food for specified health use, nutrition food, function) Display food etc.) can be mentioned.

  In the present specification, “cartilage matrix degrading enzyme” may be a cartilage matrix, that is, a secreted or non-secreted enzyme that surrounds cartilage cells and degrades the extracellular matrix that constitutes cartilage, for example, MMP1, Examples thereof include MMP2, MMP3, MMP13, ADAMTS1, ADAMTS4, ADAMTS5, ADAMTS8, ADAMTS9 and ADAMTS15, and among these, MMP13, ADAMTS4 and ADAMTS5 are preferable. Examples of the cartilage matrix include type I collagen, type II collagen, type III collagen, type IV collagen, type V collagen, type VII collagen, type IX collagen, type X collagen, type XI collagen, gelatin, laminin, fibronectin, Elastin and proteoglycan can be mentioned. The correspondence between these specific cartilage matrix degrading enzymes and their substrates is shown in Table 1.

  Detailed descriptions of the compounds included in the present compound group are given below.

In one aspect of the present invention, R ¹ in the above general formula (I ₀ ) is a benzene ring which is unsubstituted or substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxyl group having 1 to 4 carbon atoms, fluorine and / or chlorine Benzoylmethyl group. The benzene ring of such benzoylmethyl group may be substituted, and as the substituted one, an alkyl group having 1 to 5 carbon atoms and 1 to 5 carbon atoms, and 1 to 5 carbon atoms having 1 to 5 carbon atoms may be formed on the benzene ring. An alkoxyl group, a fluorine atom of 1 to 5 or a chlorine atom of 1 to 5 or an alkyl group of 1 to 4 carbon atoms, an alkoxyl group of 1 to 4 carbon atoms, a benzoyl group having 1 to 5 of fluorine atoms and chlorine atoms in total A methyl group etc. can be mentioned. Here, examples of the alkyl group having 1 to 7 carbon atoms include methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, 1 -Methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, 1-ethylpropyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, n-hexyl group, 1-methylpentyl group, 2-methyl Pentyl group, 3-methylpentyl group, 4-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,2-dimethylbutyl group, 2, 3 -Dimethylbutyl group, 3,3-dimethylbutyl group, 1,1,2-trimethylpropyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1-ethyl-1-methyl group Ropyl group, 1-ethyl-2-methylpropyl group, n-hexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1,1,2-trimethylpropyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group, n-heptyl group, 1-methylhexyl group, 2-methylhexyl group, 3-methyl Hexyl group, 4-methylhexyl group, 5-methylhexyl group, 1-ethyl pentyl group, 2-ethyl pentyl group, 3-ethyl pentyl group, 4, 4-dimethyl pentyl group And the like 1-propyl butyl group.

  Examples of the alkoxy group having 1 to 7 carbon atoms include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, an n-pentoxy group, 1- Methyl butoxy, 2-methyl butoxy, 3-methyl butoxy, 1-ethyl propoxy, 1,1-dimethyl propoxy, 1, 2- dimethyl propoxy, 2, 2- dimethyl propoxy, n-hexyl Oxy group, 1-methylpentyloxy group, 2-methylpentyloxy group, 3-methylpentyloxy group, 4-methylpentyloxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 1,3 -Dimethylbutoxy group, 2,2-dimethylbutoxy group, 2,3-dimethylbutoxy group, 3,3-dimethyl butto And 1,1,2-trimethylpropoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1-ethyl-1-methylpropoxy, 1-ethyl-2-methylpropoxy and n-heptyloxy groups 1-methylhexyloxy group, 2-methylhexyloxy group, 3-methylhexyloxy group, 4-methylhexyloxy group, 5-methylhexyloxy group, 1-ethylpentyloxy group, 2-ethylpentyloxy group, Examples thereof include 3-ethylpentyloxy group, 4,4-dimethyl pentyloxy group, 1-propylbutoxy group and the like.

In another aspect of the present invention, R ¹ in the general formula (I ₀ ) is a linear or branched alkyl group having 4 to 6 carbon atoms which is unsubstituted or substituted by fluorine. As a linear or branched alkyl group having 4 to 6 carbon atoms which is unsubstituted or substituted by fluorine, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1 -Methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, 1-ethylpropyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, n-hexyl group, 1 -Methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,2 -Dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1,1,2-trimethylpropyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1 And ethyl 1-methylpropyl, 1-ethyl-2-methylpropyl and fluorinated products thereof, preferably 1-ethylbutyl, 2-ethylbutyl, 1-methylpentyl, 2-methyl. Pentyl group, 3-methylpentyl group, 4-methylpentyl group, 5-methylpentyl group, 3,3,4,4,4-pentafluorobutyl group, 4,4,5,5,5-pentafluoropentyl group 5,5,6,6,6-pentafluorohexyl group, more preferably 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, and 4,4,5,5,5-penta It is a fluoropentyl group, and most preferably a 4,4,5,5,5-pentafluoropentyl group.

In another embodiment of the present invention, R ¹ in the general formula (I ₀ ) is methylene or ethylene substituted with a phenyl group or a cyclopentyl group, and the phenyl group is further substituted with one or more phenyl groups. May be The methylene or ethylene substituted by the phenyl group or the cyclopentyl group is a benzyl group, a 2-phenethyl group, a cyclopentylmethyl group or a 2-cyclopentylethyl group. As a benzyl group or 2-phenethyl group substituted by one or more phenyl groups, 3-phenylbenzyl group, 4-phenylbenzyl group, 3,5-diphenylbenzyl group, 2- (1,1'-biphenyl-) Mention may be made of 3-yl) -ethyl, 2- (1,1′-biphenyl-4-yl) -ethyl and 2- (3,5-diphenylphenyl) -ethyl. As R ¹ in the above general formula (I), a 2-pheneethyl group, a cyclopentylmethyl group, a 2-cyclopentylethyl group and a 2- (1,1'-biphenyl-3-yl) -ethyl group are preferably exemplified. Can.

Z ¹ , Z ² , Z ³ and Z ⁴ in the general formula (I ₀ ) may be the same or different, and are a hydrogen atom, a halogen atom, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, alkynyl group C2 -C6, represents an organic group represented by OR ^{8, R 8} is an alkyl group of C1 to C7, alkenyl group of C2 -C6, an alkynyl group of C2 -C6, ^{Z 5} is A hydrogen atom or a C1-C6 alkyl group can be mentioned. As a halogen atom, a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom can be mentioned. As a C1 to C6 alkyl group, a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, a 1-methylbutyl group, 2 -Methylbutyl group, 3-methylbutyl group, 1-ethylpropyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, n-hexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,2-dimethylbutyl group, 2,3-Dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl, 1- Chill-1-methylpropyl group, and a 1-ethyl-2-methylpropyl group or the like. Examples of the C 2 -C 6 alkenyl group include ethenyl group (vinyl group), 1-propenyl group, 2-propenyl group (allyl group), 1-butenyl group, 2-butenyl group, 3-butenyl group, isobutenyl group, 1- A pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group etc. can be mentioned. Examples of the C2 to C6 alkynyl group include ethynyl group, 1-propynyl group, 2-propynyl group (propargyl group), 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 2-methyl-3-butynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 1-methyl-2-butynyl group, 2-methyl-3-pentynyl group, 1-hexynyl group And 1,1-dimethyl-2-butynyl group etc. can be mentioned. (In the organic group represented by OR ^8, when ^{R 8} is an alkyl group of C1 to C7) alkoxyl group of C1 to C7 as the methoxy group, an ethoxy group, a propoxy group, isopropoxy group, n- butoxy Group, isobutoxy group, sec-butoxy group, tert-butoxy group, n-pentoxy group, 1-methylbutoxy group, 2-methylbutoxy group, 3-methylbutoxy group, 1-ethylpropoxy group, 1,1-dimethylpropoxy Group, 1,2-dimethylpropoxy group, 2,2-dimethylpropoxyl group, n-hexyloxy group, 1-methylpentyloxy group, 2-methylpentyloxy group, 3-methylpentyloxy group, 4-methylpentyl group Oxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 1,3-dimethylbutoxy group, , 2-dimethylbutoxy group, 2,3-dimethylbutoxy group, 3,3-dimethylbutoxy group, 1,1,2-trimethylpropoxy group, 1-ethylbutoxy group, 2-ethylbutoxy group, 1-ethyl-1 -Methylpropoxy group, 1-ethyl-2-methylpropoxy group, n-heptyloxy group, 1-methylhexyloxy group, 2-methylhexyloxy group, 3-methylhexyloxy group, 4-methylhexyloxy group, 5 -Methylhexyl oxy group, 1-ethyl pentyloxy group, 2-ethyl pentyloxy group, 3-ethyl pentyloxy group, 4, 4- dimethyl pentyloxy group, 1-propyl butoxy group etc. can be mentioned. Preferably, Z ¹ , Z ² , Z ³ and Z ⁴ may be the same or different and are hydrogen, an ethoxy group, fluorine or chlorine.

R ⁴ and R ⁵ in the above general formula (I ₀ ) are the same or different and are substituted or unsubstituted alkyl groups having 1 to 4 carbon atoms. Examples of the substituted or unsubstituted alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, R ⁴ and R There may be mentioned pyrrolidine in which ⁵ is taken together with nitrogen, and those substituted by these methoxy group, phenyl group, fluorine and chlorine, preferably methyl group, monochloromethyl group, ethyl group, 2-methoxyethyl , 2,2,2-trichloroethyl group, 1-phenylethyl group, 2-phenylethyl group, methoxyethyl group, isopropyl group, hexafluoroisopropyl group, and pyrrolidine, more preferably methyl group and ethyl group It is.

As an embodiment of the above general formula (I ₀ ), a compound represented by the following general formula (I) and, preferably, a compound represented by the general formula (1) are exemplified.

[Wherein, R ¹ and R ³ have the meanings as defined in the above [1]. ]

[Wherein, Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ have the meanings as defined in the above [1]. ]

In the compounds of the above formula (1), Z ¹ , Z ² , Z ³ and Z ⁴ may be the same or different, and are a hydrogen atom, a halogen atom, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, alkynyl group C2 -C6, represents an organic group represented by OR ^{8, R 8} is an alkyl group of C1 to C7, alkenyl group of C2 -C6, an alkynyl group of C2 -C6, ^{Z 5} is Represents a hydrogen atom or a C1-C6 alkyl group.

  As a halogen atom in Formula (1), a fluorine atom, a chlorine atom, a bromine atom, an iodine atom etc. can be mentioned.

  The C1 to C6 alkyl group in the formula (1) means a linear or branched alkyl group having 1 to 6 carbon atoms which may have a substituent, and specifically, a methyl group, Ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group etc. it can.

  Examples of the substituent of the above-mentioned "optionally having a substituent" include a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, and 2 to 6 carbon atoms The alkynyl group and the C6-C10 aryl group can be mentioned. The said C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group is a C1-C6 alkyl group in Formula (1), C2-C6 alkenyl Group, the same as the alkynyl group having 2 to 6 carbon atoms. Moreover, a phenyl group and a naphthyl group can be mentioned as said C6-C10 aryl group.

  The C2 to C6 alkenyl group in the formula (1) means a linear or branched alkenyl group having 2 to 6 carbon atoms which may have a substituent, and specifically, a vinyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1,3-butenyl group, 1-pentenyl group, 1-hexenyl group etc. can be mentioned.

  The C2 to C6 alkynyl group in the formula (1) means a linear or branched alkynyl group having 2 to 6 carbon atoms which may have a substituent, and specifically, an ethynyl group, Examples thereof include 1-propynyl group, 1-butynyl group, 1-pentynyl group and 1-hexynyl group.

Each of Z ¹ , Z ² , Z ³ and Z ⁴ is preferably a hydrogen atom, a halogen atom, a C1 to C6 alkyl group, or an organic oxy group represented by OR ⁸ ; a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group , ethyl group, n- propyl group, an alkyl group of C1~C3 or isopropyl group, an organic group represented by OR ⁸ more preferred.

Said Z ⁵ is preferably a hydrogen atom or an alkyl group C1 to C3, more preferably a hydrogen atom or a methyl group.

The above R ⁸ is preferably a C 1 to C ⁶ alkyl group, and more preferably a C 1 to C 3 alkyl group such as a methyl group, an ethyl group, an n-propyl group or an isopropyl group, and a benzyl group.

  Among the compounds represented by the formula (1), preferably, the compounds represented by the following formulas (2), (3), (4), (5) and (6) or a salt thereof It is.

The formula (2), (3), (4), Equation (5), wherein ^{(6), Z 1, Z} 2, Z 3, Z 4, Z 5 is, ^{Z 1} in Formula (1) , Z ² , Z ³ , Z ⁴ and Z ⁵ have the same definition.

  Specifically, the compounds represented by the formula (1) can be exemplified by the compounds shown below.

  Among the above compounds, preferred are the following compounds.

When R ¹ in the above general formula (I ₀ ) is a 2,4-difluorobenzoylmethyl group, Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ are hydrogen and R ³ is OH, general The compound represented by the formula (I ₀ ) represents a compound # 5 described later in the Examples, and R ¹ in the above general formula (I ₀ ) is a 4-fluorobenzoylmethyl group, and Z ¹ , Z ² , Z ^{When 3} , Z ⁴ and Z ⁵ are hydrogen and R ³ is OH, the compound represented by the general formula (I ₀ ) represents a compound # 4 described later in the Examples, and the compound represented by the above general formula (I ₀₎ In general, when R ^{1 in 4} ) is a 4,4,5,5,5-pentafluoropentyl group, Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ are hydrogen and R ³ is OH, in general compounds that formula (I ₀₎ represents the compound # 21, which will be described later in examples, the general _{(I 0)} in ^{R 1} is 2-cyclopentylethyl ^group, a ^{Z 1, Z 2, Z 3} , Z 4, Z 5 is hydrogen and when ^{R 3} is OH, in the general formula _{(I 0)} The compounds represented represent compound # 24 described later in the Examples. Other than these compounds, specific examples of the compounds represented by the general formula (I ₀ ) include the compounds # 2, 4, 5, and 20 described later in the Examples, and the compounds # described later in the Examples. 17-19, the compound # 22 and 23 mentioned later by an Example, and the compound # 25 mentioned later by an Example can be mentioned.

Linear alkylene groups for X ,, carbon atoms 4-6 in the formula (II), i.e. butylene - _{(CH 2) 4} -, pentylene - _{(CH 2) 5} -, hexylene - _{(CH 2) 6} - Or an ether group having 4 carbon atoms, and examples of the ether group having 4 carbon atoms include methylene-O-propylene group, ethylene-O-ethylene group and propylene-O-methylene group, butylene, hexylene and the like Ethylene-O-ethylene groups are preferred.

R ⁴ and R ⁵ in the general formula (II) are the same or different and substituted or unsubstituted alkyl groups having 1 to 4 carbon atoms. Examples of the substituted or unsubstituted alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, R ⁴ and R There may be mentioned pyrrolidine in which ⁵ is taken together with nitrogen, or those substituted with these methoxy, phenyl, fluorine and chlorine, preferably methyl, monochloromethyl, ethyl, 2,2, It is 2-trichloromethyl group, 1-phenylethyl group, 2-phenylethyl group, methoxyethyl group, isopropyl group, hexafluoroisopropyl group, and pyrrolidine, and more preferably methyl group and ethyl group.

When X in the general formula (II) is butylene, R ⁶ is hydrogen, and R ³ is OH, the compound represented by the general formula (II) represents a compound # 15 described later in the Examples. Specific examples of the compound represented by the general formula (I) in addition to the compound # 15 include the compound # 13 described later in the Examples and the compound # 14 described later in the Examples.

R ⁷ in the general formula (III) is an alkyl group having 1 to 5 carbon atoms or a benzyl group. As a linear or branched alkyl group having 1 to 5 carbon atoms, a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, n- And pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl and 2,2-dimethylpropyl groups. be able to. Moreover, between benzene of the said benzyl group may be substituted by the C1-C3 alkyl group of 1 or 2 or more, or the C1-C3 alkoxy group. A methyl group, an ethyl group, n-propyl group, and an isopropyl group can be mentioned as a C1-C3 alkyl group, A methoxy group, an ethoxy group, n- can be mentioned as a C1-C3 alkoxy group A propoxy group and an isopropoxy group can be mentioned. R ⁷ in the above general formula (III) is preferably a methyl group, an ethyl group, a propyl group, an n-butyl group, an n-pentyl group, and a 3,5-dimethoxybenzyl group, more preferably 3,5- It is a dimethoxybenzyl group.

In the above general formula (III), R ⁴ and R ⁵ are the same or different and are substituted or unsubstituted alkyl groups having 1 to 4 carbon atoms. Examples of the substituted or unsubstituted alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, R ⁴ and R There may be mentioned pyrrolidine in which ⁵ is taken together with nitrogen, or those substituted with these methoxy, phenyl, fluorine and chlorine, preferably methyl, monochloromethyl, ethyl, 2,2, It is 2-trichloromethyl group, 1-phenylethyl group, 2-phenylethyl group, methoxyethyl group, isopropyl group, hexafluoroisopropyl group, and pyrrolidine, and more preferably methyl group and ethyl group.

When A in the general formula (III) is indole, R ⁷ is a 3,5-dimethoxybenzyl group, and R ³ is OH, the compound represented by the general formula (III) will be described later in the Examples. Represents compound # 35. Specific examples of the compound represented by the general formula (I ₀ ) other than the compound # 35 include compounds # 36 to 38 described later in the Examples, and compounds # 33 and 34 described later in the Examples. It can be mentioned.

  When a compound selected from the present compound group has an asymmetric carbon atom and an asymmetric point related to axial asymmetry, such a compound includes all possible optical isomers, and these optical isomers are in any ratio. It can be used. For example, an optically active compound can be used as an enantiomer, a racemate or a mixture of enantiomers in any proportion, and when there are a plurality of asymmetric points, it may be used in a mixture of diastereomers in any proportion.

  Pharmaceutically acceptable salts of this compound group include metal salts formed from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine And organic salts produced from ethylenediamine, N-methylglucamine, lysine, procaine and the like.

The synthesis methods of the compounds selected from the present compound group can be exemplified below, but not limited to these methods, generally known synthetic methods can be used. In addition, the compounds shown below can be obtained from Sigma-Aldrich Co., Tokyo Chemical Industry, Wako Pure Chemical Industries, Kanto Chemical and the like. Further, with respect to the reaction solvent and reaction temperature, unless otherwise specified, the reaction is usually carried out using the solvent and temperature used for the reaction. The reaction is usually carried out under an argon or nitrogen atmosphere. Protecting group, Green & Wuts, "PROTECTIVE GROUPS in ORGANIC SYNTHESIS" 3 rd ed.John Wiley & Sons, referring to Inc., can be used.

The compounds represented by the above general formula (I ₀ ) can be synthesized using substituted or unsubstituted benzene and substituted or unsubstituted indole as starting materials. First, 4-aryl-4-oxo-2-butenoic acid is synthesized using Friedel-Crafts reaction of substituted or unsubstituted benzene and maleic anhydride. The Friedel-Crafts reaction is carried out by using Lewis acid, phosphoric acid, polyphosphoric acid or the like as a catalyst, and aluminum chloride is preferably used as the catalyst. As a reaction solvent, a chlorinated solvent is preferable, but substituted or unsubstituted benzene as a starting material can also be used as a solvent. A compound in which a substituted or unsubstituted benzoyloxy group is substituted at the α-position of indole acetic acid by Michael reaction between 4-aryl-4-oxo-2-butenoic acid thus obtained and a substituted or unsubstituted indole is obtained It is possible to construct a basic skeleton of the compound represented by the general formula (I ₀ ). In this Michael reaction, the carboxyl group of 4-aryl-4-oxo-2-butenoic acid may or may not be protected, and usually does not need to be protected, but if it is protected, the protection used Examples of the group include methyl ester, tert-butyl ester, 2,2,2-trichloroethyl ester and tert-butyldimethylsilyl ester. On the other hand, the nitrogen atom of indole may or may not be protected, and in the case of protection, a benzyl-based protecting group is preferable, and an amide-based protecting group is not preferable because it lowers the reactivity. The Michael reaction can also proceed by heating the reaction system, or a catalyst such as Lewis acid can be used. After obtaining the skeleton of the compound represented by the general formula (I ₀ ), the compound represented by the general formula (I ₀ ) can be synthesized by removing the protecting group if necessary. After this, depending on the purpose, the carboxylic acid moiety may be optionally made into an esterification, amidification or a pharmaceutically acceptable salt. Specifically, as shown in the following formula, compound # 5 described later in the Examples can be synthesized from 1,3-difluorobenzene, maleic anhydride and indole.

As another embodiment of the method of synthesizing the compound represented by the above general formula (I ₀ ), there can be mentioned a method of synthesizing a protected product of alcohol and indole acetic acid as a starting material. The hydroxyl group of the alcohol can be converted to iodine or bromine in a direct or two-step reaction. Methods for direct conversion include, but are not limited to, methods in which triphenylphosphine, imidazole and iodine (I ₂ ) are allowed to act on alcohol to substitute iodine (I.), or triphenylphosphine and tetrabromide The method of making carbon act and substituting a bromine can be mentioned. As a method of synthesizing through a plurality of steps, a method in which an alcohol is derived to a sulfonic acid ester such as methanesulfonic acid, trifluoromethanesulfonic acid, toluenesulfonic acid and the like, and then an iodide metal salt of alkali metal or a bromide salt of alkali metal is reacted Can be mentioned. The basic skeleton of the compound represented by the general formula (I ₀ ) can be obtained by nucleophilically reacting the thus obtained halogen with the enolate at the α position generated from the protected indole acetic acid. As a protective group of indole acetic acid, a method of derivatization to methyl ester, tert-butyl ester, 2,2,2-trichloroethyl ester, tert-butyldimethylsilyl ester and the like can be mentioned as protection of carboxyl group. On the other hand, it is preferable to protect the amine site of indole acetic acid as carbonic acid amide, and examples of the protective group include methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl and the like. The basic form of the compound represented by the general formula (I ₀ ) is obtained by causing the protected product of indoleacetic acid thus obtained to act on a base to induce an enolate, and causing the resulting enolate to react nucleophilically with the halogenated product. You can get As a base which can be used in this nucleophilic reaction, carbonates of alkali metals such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate, methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium and the like And alkyl metal lithium, lithium diisopropylamide, lithium hexamethyldisilazane, sodium hexamethyldisilazane, alkali metal amides such as potassium hexamethyldisilazane, and the like. Although the solvent which can be used changes with bases to be used, aprotic polar solvents, such as N, N- dimethylformamide (DMF) and tetrahydrofuran (THF), are preferable. In addition, the addition of hexamethyl phosphate triamide or the like has the effect of promoting the reaction. The desired compound can be obtained by removing the protecting group from the thus obtained protected form. After this, the carboxylic acid moiety may optionally be esterification, amidification or a pharmaceutically acceptable salt thereof. Specifically, as shown in the following formula, compound # 21 described later in the synthesis example using 4,4,5,5,5-pentafluoropentanol and methyl 1-methoxycarbonyl-3-indoleacetic acid as starting materials. Can be synthesized.

  The compound represented by the formula (1) in the present invention can be obtained by an organic synthesis technique using a known organic chemical reaction. For example, as shown below, the Michael reaction of (E) -4- (2,4-difluorophenyl) -4-oxo-2-butenoic acid with the indole derivative represented by the formula (7) gives The compound represented by (1) can be obtained.

^{(Z 1,} Z ^2, Z ³ in the above formula ^(7), Z 4, ^{Z 5} are the same as defined ^{Z 1, Z 2, Z 3} , Z 4, Z 5 in Formula (1).)

  The above (E) -4- (2,4-difluorophenyl) -4-oxo-2-butenoic acid is synthesized by Friedel-Crafts reaction of 1,3-difluorobenzene and maleic anhydride as shown below can do. Such Friedel-Crafts reaction is carried out by using Lewis acid, phosphoric acid, polyphosphoric acid or the like as a catalyst, and aluminum chloride is preferably used as the catalyst.

  A commercial item can be used for the indole derivative represented by said Formula (7). Examples of commercially available indole derivatives include 4-fluoroindole, 4-chloroindole, 4-bromoindole, 6-fluoroindole, 6-chloroindole, 6-bromoindole, 5-methylindole and the like.

The indole derivative represented by the above formula (7) can also be obtained by an organic synthesis technique using a known organic chemical reaction. For example, when R ¹ , R ² , R ³ , R ⁴ and R ⁵ are a halogen atom, commercially available indole is treated with a halogenating agent such as N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide and the like. Thus, the indole derivative represented by the above formula (7) can be obtained. Further, when R ¹ , R ² , R ³ and R ^{4 each} represent a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C2 to C6 alkynyl group, or an organic oxy group represented by OR ⁸ , the above Thus, after halogenating commercially available indole, an indole derivative represented by the above formula (7) can be obtained by a reaction with an organic lithium reagent such as alkyllithium, a Suzuki-Miyaura coupling reaction, or the like. Furthermore, when R ⁵ is a C 1 to C ⁶ alkyl group, an indole derivative represented by the above formula (7) is obtained by reacting a C 1 to C 6 alkyl halide such as bromomethane or bromoethane with a commercially available indole. be able to.

  All the above organic reactions can be carried out in solvents, respectively, but the solvent is appropriately selected depending on the reaction temperature, reactants and the like. Moreover, the reaction temperature of the said organic reaction is suitably selected by conditions, such as a boiling point of the solvent to be used. When a solvent is used in the above organic reaction, the resulting reaction solution may be concentrated if necessary, and then the residue may be used as it is in the next reaction, or after appropriate post-treatment, by the formula (1) You may use as a compound represented. Specific methods of post-treatment include known purification such as extraction treatment and / or crystallization, recrystallization, chromatography and the like.

The synthesis method of the compound represented by the above general formula (I ₀ ) can also be used to synthesize the compound represented by the general formula (II). That is, the compound represented by the general formula (II) has an amino group of tert instead of the protected form of alcohol or indole acetic acid used as the starting material in the method of synthesizing the compound represented by the above general formula (I ₀ ) -Synthesized in the same manner using as protected starting material a straight-chain amino alcohol protected with butoxycarbonyl, or a linear amino alcohol having oxygen in the chain, or a protected form of indole acetic acid in which a methyl group is substituted at the α position. can do. The conversion of a linear amino alcohol and a linear amino alcohol having an oxygen in the chain into tert-butoxycarbonylamide can be carried out by a conventional method, but usually, di-tert-butyl carbonate is used. The protected form of indole acetic acid in which a methyl group is substituted at the α-position is an intermediate obtained when the halide is methyl iodide in the method of synthesizing the compound represented by the above general formula (I ₀ ) Those skilled in the art will readily understand. The compound represented by the general formula (II) can be synthesized by the same method as the method of synthesizing the compound represented by the general formula (I ₀ ) using the starting materials thus prepared. Specifically, Compound # 15 described later in the Examples can be synthesized from 4-aminobutanol and 1-methoxycarbonyl-3-indoleacetic acid methyl ester as starting materials, as shown in the following formula.

The compounds represented by the above general formula (III) are commonly 5-hydroxy-3-indole acetic acid ester or α- (7-hydroxy-1-naphthalenyl) -acetic acid ester when A is indole or naphthalene It can be synthesized as a starting material. 5-hydroxy-3-indole acetic acid ester and α- (7-hydroxy-1-naphthalenyl) -acetic acid ester can be obtained by esterifying the corresponding carboxylic acid, but 5-hydroxy-3-indole acetic acid Has three active protons and α- (7-hydroxy-1-naphthalenyl) -acetic acid has two active protons, and the selectivity of the reaction is a problem. For this reason, after protecting the alcohol part of these compounds and performing esterification, a protecting group can be removed and a starting material can also be obtained. Also, the method described in E. Tsuda et. Al., “Alkoxy-auxins are selective inhibitors of auxin transport mediated by PIN, ABCB, and AUX1 transporters” Journal of Biological Chemistry, 286 (3), 2354-2364; Α- (7-hydroxy-1-naphthalenyl) -acetic acid ethyl ester can also be synthesized according to In addition, as a method for synthesizing 5-hydroxy-3-indole acetic acid ester, an ester with an alcohol used as a solvent can be synthesized with good selectivity by carrying out a reaction under acidic conditions in dried alcohol . As the reaction conditions for the esterification, there may be mentioned commercially available hydrochloric acid / methanol or a method of blowing dry hydrochloric acid into dehydrated alcohol, but acid chloride is dropped to pre-dried alcohol to generate acid in the system The preferred method is After this, the carboxylic acid moiety may optionally be esterification, amidification or a pharmaceutically acceptable salt thereof. The basic skeleton of the compound represented by the general formula (III) can be constructed by reacting the starting material thus prepared with alkyl iodide or alkyl bromide. As a base used for the reaction of these 5-hydroxy-3-indole acetic acid ester or 7-hydroxy-1-naphthalenyl acetic acid ester and alkyl iodide or alkyl bromide, sodium hydride, lithium carbonate, sodium carbonate, Examples include alkali metal carbonates such as potassium carbonate and cesium carbonate. The reaction solvent is preferably an aprotic polar solvent such as DMF or THF. Thus, after obtaining the skeleton of the compound represented by the general formula (III), the compound represented by the general formula (III) can be synthesized by removing the protective group, if necessary. After this, depending on the purpose, the carboxylic acid moiety may be optionally made into an esterification, amidification or a pharmaceutically acceptable salt. Specifically, Compound # 34 described later in the Examples can be synthesized using 1-iodobutane and α- (7-hydroxy-1-naphthalenyl) -acetic acid ethyl ester as starting materials, as shown in the following formula.

  Similarly, compound # 35 described later in the Examples can be synthesized using 3,5-dimethoxybenzyl bromide and 7-hydroxy-3-indole acetic acid as starting materials.

  As the present compound group, Compound # 5 whose effect is specifically shown in the Examples of the present specification is preferable.

  As the additives of the present inhibitor and the present preventive / improving agent, pharmaceutically acceptable common carriers, binders, stabilizers, excipients, diluents, pH buffers, disintegrants, isotonic agents, There can be exemplified compounding ingredients such as additives, coating agents, solubilizers, lubricants, glidants, solubilizers, lubricants, flavors, sweeteners, solvents, gelling agents, nutrients and the like. As such compounding ingredients, specifically, water, physiological saline, animal fats and oils, vegetable oil, lactose, starch, gelatin, crystalline cellulose, gum, talc, magnesium stearate, hydroxypropyl cellulose, polyalkylene glycol, Polyvinyl alcohol and glycerin can be exemplified.

  The dosage form of the present inhibitor and the present preventive / improvement agent may be orally administered in the form of powder, granules, tablets, capsules, syrups, suspensions, etc., solution, emulsion, suspension, etc. There may be mentioned parenteral administration where the dosage form is injected for injection or intranasal administration in the form of spray.

  The doses of the present inhibitor and the present preventive / improving agent are appropriately determined according to age, body weight, sex, symptoms, sensitivity to drugs, etc. Usually, the dose in the range of 1 μg to 200 mg / day, preferably in the range of 2 μg to 2000 μg / day, more preferably in the range of 3 to 200 μg / day, still more preferably 4 to 20 μg / day Although the dose range of day is to be administered once or divided into multiple doses (for example, 2 to 4 times) per day, the dose may be adjusted according to the state of improvement of symptoms.

  The present compound group, as specifically shown in the examples described later, chondrocytes regardless of the presence or absence of inflammatory cytokines (eg, IL [Interleukin] -1β, IL-6, TNF [Tumor necrosis factor] -α) It effectively suppresses the production of cartilage matrix degrading enzymes in Therefore, by ingesting the compound group of the present invention, the cartilage is reduced by suppressing the production of a cartilage matrix-degrading enzyme not caused by inflammatory cytokines or the production of a cartilage matrix-degrading enzyme caused by inflammatory cytokines in cartilage. It is fully expected to increase the substrate.

  In the present specification, examples of the “condition or disease caused by reduction or damage of cartilage matrix” include cartilage damage, joint disk damage, meniscal damage, osteoarthritis, osteoporosis, periarticular shoulder inflammation, chondrogenesis. Abnormalities, Cartilage osteoplasia, Cartilage aplasia, Cartilage aplasia, Cartilage dystrophy, Cartilage chondrosis, articular cartilage herniation, osteomalacia, relapsing polychondritis, Cartilage defect, Dissecting bone Chondritis, damage to articular cartilage due to trauma can be mentioned.

  The present inhibitor and the present preventive / improving agent may contain components other than the present compound group that inhibit the production of a cartilage substrate degrading enzyme, but the present compound group alone is an excellent production inhibitor of the cartilage substrate degrading enzyme. In order to exert the effect, those which do not contain a cartilage matrix degrading enzyme production inhibitory component (eg, protein, DNA, RNA, plant-derived extract) other than the present compound group are preferable.

Below, the synthesis example of the compound represented by general formula (I ₀ ), (II), and (III) is described.

[Synthesis of Compound]
Synthetic raw materials, reaction reagents and the like used in the methods for synthesizing the compounds shown below are general commercially available products. In addition, unless otherwise specified with respect to the reaction solvent and reaction temperature, the reaction is usually carried out using the solvent and temperature used for the reaction. Also, the reaction is carried out under argon or dry nitrogen atmosphere.

[Synthesis of Compound # 1]
4-phenyl-2- (4-chloro-1H-indol-3-yl) -4-oxo-butane (compound # 1) uses 4-chloroindole instead of indole to give compound # 20 described below It synthesize | combined by the synthesis method.

[Synthesis of Compound # 2 and Compound # 3]
4- (4-Chlorophenyl) -2- (1H-indol-3-yl) -4-oxo-butanoic acid (Compound # 2) and 3- (1H-indol-3-yl) -1-oxo-1-l Phenyl-butane (compound # 3) is described in Sayed, GH et al, “Synthesis and reactions of some β-aroyl-α- (indol-3-yl) propionic acids” Journal of the Chemical Society of Pakistan, 7 (4) , 263-72; synthesized according to the method described in 1985.

(Compound # 2)

[Synthesis of Compound # 4]
Trans-4- (4-fluorophenyl) -4-oxo-2-butenoic acid

Dissolve fluorobenzene (0.50 g, 5.21 mmol) with dichloromethane (20 mL) in a 50 mL round bottom flask with nitrogen fill, maleic anhydride (0.51 g, 5.20 mmol) and aluminum chloride (1.40 g, 10) .49 mmol) was added and stirred at room temperature for 4 hours. The reaction mixture was adjusted to pH 1 with 1N hydrochloric acid (10 mL), and extracted three times with ethyl acetate (40 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by recrystallization (benzene) to obtain trans-4- (4-fluorophenyl) -4-oxo-2-butenoic acid. (0.57 g, yield 56%): melting point 114.8-119.6 ° C .; ¹ H NMR (CDCl ₃ ): δ 8.06 (m, 2 H), 7.98 (d, J = 15.4 Hz) , 1H), 7.21 (m, 2H), 6.90 (d, J = 15.4 Hz, 1H); ¹³ C NMR (CDCl ₃ ): δ 187.5, 170.7, 166.3 (d , _JC-F = 255.5 Hz), 138.0, 132.8 (d, _JC-F = 3.2 Hz), 131.7 (d, _JC-F = 9.9 Hz), 131.6 , 116.2 (d, _JC−F = 22.1 Hz); IR (neat): 2972, 1705, 1665 cm ⁻¹ ; FAB−MS m / z 195 [M + H] ⁺ .

4- (4-Fluorophenyl) -2- (1H-indol-3-yl) -4-oxo-butanoic acid (compound # 4)

In a 30 mL round bottom flask, trans-4- (4-fluorophenyl) -4-oxo-2-butenoic acid (0.21 g, 1.08 mmol) is dissolved with benzene (10 mL), indole (0.26 g, 19 mmol) was added, stirred at 80 ° C. for 8 hours, and stirred to room temperature. The reaction solution is distilled off under reduced pressure, and purification is carried out using silica gel column chromatography (chloroform: methanol = 20: 1) to give 4- (4-fluorophenyl) -2- (1H-indol-3-yl) -4- An oxo-butanoic acid (compound # 4) was obtained. (0.15 g, yield 47%): melting point 161.6-166.6 ° C .; ¹ H NMR (DMSO-d ₆ ): δ 8.13 (m, 2 H), 7.68 (d, J = 7) .9 Hz, 1 H), 7. 35 (m, 4 H), 7.09 (t, J = 7.2 Hz, 1 H), 7.00 (t, J = 7.1 Hz, 1 H), 4. 34 (dd , J = 10.7, 3.9 Hz, 1 H), 4.03 (dd, J = 18.1, 10.7 Hz, 1 H), 3.34 (dd, J = 18.1, 3.9 Hz, 1 H) ¹³ C NMR (DMSO-d ₆ ): δ 197.96, 175.61, 166.00 (d, J _{C -F} = 250.0 Hz), 137.16, 134.11, 131.93 (d) _{, J C-F = 10.0Hz)} , 127.15,124.16,122.07,119.97,119.53,116 _{6 (d, J C-F} = 22.0Hz), 112.79,112.42,42.03,38.57; IR (neat): 3419,2925,1679cm -1; HRFAB-MS found m / z 312.1028 [M + H] ⁺ , calcd
for 312.1036 (C ₁₈ H ₁₅ FNO ₃ ).

[Synthesis of Compound # 5]
Trans-4- (2,4-difluorophenyl) -4-oxo-2-butenoic acid

In a 50 mL round bottom flask under nitrogen fill, 1,3-difluorobenzene (0.51 g, 4.47 mmol) is dissolved in dichloromethane (20 mL), maleic anhydride (0.43 g, 4.46 mmol) and aluminum chloride (1 20 g (9.01 mmol) was added, and stirred at room temperature for 4 hours, and stirred until room temperature was reached. The reaction mixture was adjusted to pH 1 with 1N hydrochloric acid (10 mL), and extracted three times with ethyl acetate (40 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by recrystallization from benzene to obtain trans-4- (2,4-difluorophenyl) -4-oxo-2-butenoic acid. (0.57 g, yield 56%): mp 114.8-119.6 ° C .; ¹ H NMR (acetone-d ₆ ): δ 7.98 (m, 1 H), 7.71 (dd, J _{H- F = 15.6,3.4Hz, 1H), 7.23} (m, 2H), 6.75 (dd, J H-F = 15.6,1.2Hz, 1H); 13 C NMR ( acetone - d ₆ ): δ 187.2 (d, J _C-F = 2.6 Hz), 166.9 (dd, J _C-F = 254.5, 12.3 Hz), 166.4, 163.4 (dd , _JC-F = 254.5, 12.9 Hz), 140.0 (d, _JC-F = 6.1 Hz), 134.0 (dd, _JC-F = 10.9, 3.6 Hz) , 133.0 (d, _JC-F = 1.6 Hz), 123.3 (dd, _JC-F = 12.4, 3.6 Hz), 113.4 (dd, J _C-F = 21.5, 3.6 Hz), 105.8 (dd, _JC-F = 27.3, 26.3 Hz); IR (neat): 2917, 1697, 1661 cm- ¹ ; FAB-MS m / Z 213 [M + H] ⁺ .

4- (2,4-Difluorophenyl) -2- (1H-indol-3-yl) -4-oxo-butanoic acid (Compound # 5)

In a 30 mL round bottom flask, trans-4- (2,4-difluorophenyl) -4-oxo-2-butenoic acid (0.39 g, 1.84 mmol) is dissolved with benzene (10 mL), indole (0.43 g, 2.19 mmol) was added, stirred at 80 ° C. for 8 hours, and stirred to room temperature. The reaction solution is distilled off under reduced pressure, and purification is performed using silica gel column chromatography (chloroform: methanol = 20: 1) to give 4- (2,4-difluorophenyl) -2- (1H-indol-3-yl)- 4-Oxo-butanoic acid was obtained. (0.15 g, yield 51%): melting point 180.2-184.6 ° C .; ¹ H NMR (DMSO-d ₆ ): δ 7.98 (m, 1 H), 7.65 (d, J = 7) .9 Hz, 1 H), 7.37 (d, J = 8.1 Hz, 1 H), 7.42 (m, 1 H), 7.28 (d, J = 2.3 Hz, 1 H), 7. 24 (m , 1H), 7.09 (t, J = 7.1 Hz, 1 H), 7.01 (t, J = 7.5 Hz, 1 H), 4. 34 (dd, J = 10.5, 3.5 Hz, _{1H), 3.90 (ddd, J} H-F = 18.5,10.6,2.4Hz, 1H), 3.30 (ddd, J H-F = 18.5,6.1,3. 5 Hz, 1 H); ¹³ C NMR (DMSO-d ₆ ): δ 195.2 (d, J _C-F = 4.1 Hz), 174.8, 165.2 (d, J _C-F = 253.0 , _{3.4Hz), 162.2 (d, J} C-F = 255.5,13.4Hz), 136.4,132.7 (dd, J C-F = 10.8,4.1Hz), 126 .3, 123.3, 122.2 (dd, _JC-F = 12.3, 3.6 Hz), 121.4, 119.1, 118.8, 112.6 (dd, _JC-F = 21.1, 3.6 Hz), 111.9, 111.8, 105.4 (dd, _JC-F = 26.1 Hz), 45.6 (d, _JC-F = 6.3 Hz), 37 ^{.9; IR (neat): 3382,2919,1678cm} -1; HRFA-MS found m / z 330.0910 [M + H] +, calcd for 330.0942 (C 18 H 14 F 2 NO 3).

[Synthesis of Compound # 6]
Trans-4- (2,4-dimethylphenyl) -4-oxo-2-butenoic acid

In a 50 mL round bottom flask, m-xylene (1.00 g, 9.42 mmol) is dissolved in dichloromethane (40 mL) under nitrogen fill, and maleic anhydride (0.93 g, 9.42 mmol) and aluminum chloride (2.51 g, 18.84 mmol) was added and stirred at room temperature for 4 hours. The reaction mixture was adjusted to pH 1 with 1N hydrochloric acid (10 mL), and extracted three times with ethyl acetate (40 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by recrystallization (benzene) to obtain trans-4- (2,4-dimethylphenyl) -4-oxo-2-butenoic acid. (1.49 g, yield 77%): mp 85.4-88.8 ° C. ¹ H NMR (CDCl ₃ ): δ 7.75 (d, J = 15.6 Hz, 1 H), 7.56 (d , J = 8.2 Hz, 1 H), 7. 10 (m, 2 H), 6. 70 (d, J = 15.6 Hz, 1 H), 2.50 (s, 3 H), 2. 38 (s, 3 H) ¹³ C NMR (CDCl ₃ ): δ 192.5, 170.9, 143.1, 141.7, 139.5, 133.6, 133.0, 130.9, 130.0, 126.4). , 21.5, 21.2; IR (neat): 2986, 1703, 1667 cm ⁻¹ ; FAB-MS m / z 205 [M + H] ⁺ .

4- (2,4-Dimethylphenyl) -2- (1-propyl-1H-indol-3-yl) -4-oxo-butanoic acid (Compound # 6)

In a 30 mL round bottom flask, trans-4- (2,4-dimethylphenyl) -4-oxo-2-butenoic acid (0.50 g, 2.45 mmol) is dissolved with benzene (10 mL), N-propyl indole (0 .85 g, 4.90 mmol) was added, and the mixture was stirred at 80.degree. C. for 8 hours, and stirred to room temperature. The reaction solution is distilled off under reduced pressure, and purification is performed using silica gel column chromatography (chloroform: acetone = 5: 1) to give 4- (2,4-dimethylphenyl) -2- (1-propyl-1H-indole-3). Y-yl) -4-oxo-butanoic acid is obtained. (0.98 g, yield 67%): mp 139-141 ° C .; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.70 (d, J = 7.8 Hz, 1 H), 7.59 (d, J = 7.8 Hz, 1 H), 7. 28 (d, J = 8.2 Hz, 1 H), 7. 18 (t, J = 15.1 Hz, 1 H), 7.07 (m, 2 H), 6.99 (D, J = 8.7 Hz, 2 H), 4.56 (dd, J = 6.0, 4.1 Hz, 1 H), 3.97 (m, 2 H), 3.92 (m, 1 H), 3 .28 (dd, J = 17.8, 4.1 Hz, 1 H), 2.43 (s, 3 H), 2.30 (s, 3 H), 1.80 (m, 2 H), 0.89 (t) , J = 14.7, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 200.9, 179.7, 142.3, 138.9, 136.3, 134.1, 1 32.8, 129.1, 126.7, 126.2, 126.1, 121.7, 119.4, 119.2, 110.6, 109.5, 48.0, 44.0, 38. 0, 23.4, 21.5, 21.3, 11.5; IR (neat): 3428, 2923, 1707 cm ⁻¹ ; FAB-MS m / z 364 [M + H] ⁺ .

  4-phenyl-2- (1H-5-ethoxyindol-3-yl) -4-oxo-butanoic acid (compound # 7) is the same as compound # 20, using 5-ethoxyindole instead of indole It was synthesized by the method.

  Compounds # 8, 13-15, 17-19, and 21-25 were synthesized using methyl N-methoxycarbonylindole acetate as a key intermediate.

1-Methoxycarbonylindole-3-acetic acid methyl ester

Indole-3-acetic acid methyl ester Indole-3-acetic acid (2.00 g, 11.42 mmol) is dissolved in methanol (40 ml) and acetyl chloride (0.5 ml, 6.688 mmol) is added dropwise thereto at room temperature. Stir for 2 hours. After confirming the completion of the reaction by TLC, a saturated aqueous sodium bicarbonate solution was added to quench the reaction, and extraction was performed three times with ethyl acetate (50 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3) to obtain indole-3-acetic acid methyl ester. (2.14 g, yield 99%): ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.13 (s, 1 H), 6.97 (s, 1 H), 7.59 (d, J = 7. 7 Hz, 1 H), 7.23 (d, J = 7.9 Hz, 1 H), 7.10-7.19 (m, 2 H), 3.67 (s, 3 H), 3.76 (s, 2 H) ¹³ C NMR (100 MHz, CDCl ₃ ): δ 172.3, 136.0, 127.1, 123.2, 122.0, 119.5, 118.6, 111.2, 108.0, 51. 9, 31.0; IR (neat): 3410, 1730, 1458, 1435, 1337, 1164, 1095, 1011 cm ⁻¹ ; EI-MS m / z 189 [M] ⁺ .

1-Methoxycarbonyl-3-indoleacetic acid methyl ester methyl indole-3-acetate (2.00 g, 10.57 mmol) is dissolved in dichloromethane (30 ml) and tetrabutylammonium iodide (TBAI, 30.0 mg, 0. 1) is dissolved therein. 081 mmol), 30% aqueous sodium hydroxide solution (24 ml) was added and cooled to 0 ° C. To the reaction solution was added methyl chloride formate (1.96 g, 20.73 mmol), and the mixture was stirred at 0 ° C. for 2 hours. After confirming the completion of the reaction by TLC, 6N hydrochloric acid was added to quench the reaction. Water (50 ml) was added, extraction was performed three times with chloroform (50 ml), and the organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 2) to obtain methyl N-methoxycarbonylindole-3-acetate. (2.26 g, yield 87%): ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.18 (d, J = 7.0 Hz, 1 H), 7.59 (s, 1 H), 7.53 ( d, J = 7.7 Hz, 1 H), 7. 35 (t, J = 7.5 Hz, 1 H), 7. 27 (t, J = 7.4 Hz, 1 H), 4.00 (s, 3 H), 3.72 (s, 3 H), 3.71 (s, 2 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 171.1, 151.1, 135.2, 129.9, 124.6, 123 .8, 122.8, 118.9, 115.0, 113.8, 53.5, 51.9, 30.6; IR (neat): 1746, 1455, 1382, 1258, 1164, 1089, 1018 cm ^{− 1} ; EI-MS: m / z 247 [M] ⁺ .

  Compounds # 8 and 9 were synthesized according to the method described in WO 2010/045451.

[Synthesis of Compound # 8]
2- (N-tert-butoxycarbonyl-4-piperidinyl) ethanol

2- (4-Piperidinyl) ethanol (1.0 g, 7.7 mmol) was dissolved in methanol (50 ml), di-tert-butyl carbonate (2.0 g, 9.3 mmol) was added thereto and stirred at room temperature for 2 hours . After completion of the reaction was confirmed by TLC, the solvent was evaporated away under reduced pressure and the residue was purified by silica gel column chromatography (hexane: acetone = 9: 1) to obtain N-tert-butoxycarbonyl-2- (4-piperidinyl) ethanol The (1.68 g, 95% yield)

2- (N-tert-butoxycarbonyl-4-piperidinyl) -1-iodoethane

Dissolve triphenylphosphine (2.56 g, 9.760 mmol), imidazole (0.66 g, 9.694 mmol) in dichloromethane (15 ml) and stir for 5 minutes, then add iodine (2.47 g, 9.732 mmol), Stir for 10 minutes. A solution of N-N-tert-butoxycarbonyl-2- (4-piperidinyl) ethanol (1.49 g, 6.497 mmol) in dichloromethane (4 ml) was added dropwise thereto, and the mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction by TLC, the reaction solution was filtered through Celite, and 5% aqueous sodium thiosulfate solution was added to the filtrate to remove iodine. The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain N-tert-butoxycarbonyl-2- (4-piperidinyl) -1-iodoethane. (2.13 g, 96% yield)

α- [2- (N-tert-Butoxycarbonyl-4-piperidinyl) -1-ethyl] -1-methoxycarbonyl-3-indoleacetic acid methyl ester

In a nitrogen atmosphere, 1-methoxycarbonyl-3-indoleacetic acid methyl ester (500 mg, 2.022 mmol) and hexamethylphosphoric acid triamide (HMPA, 1.81 g, 10.11 mmol) were dissolved in tetrahydrofuran (4 ml), Cooled to A 1.5 M cyclohexane solution (2.16 ml, 1.6 eq) of lithium diisopropylamide (LDA) was slowly added dropwise to this, and the mixture was stirred at -78 ° C for 0.5 hours. A solution of 2- (N-tert-butoxycarbonyl-4-piperidinyl) -1-iodoethane (686 mg, 2.022 mmol) in tetrahydrofuran (2 ml) was slowly added dropwise to this reaction solution, and the solution was allowed to drip at -78 ° C for 1 hour. It stirred. After confirming the completion of the reaction by TLC, the temperature was adjusted to 0 ° C., water (15 ml) was added, the reaction was quenched, and extracted three times with ethyl acetate (15 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by silica gel column chromatography (hexane: ethyl acetate = 8: 2), and α-2- (N-tert-butoxycarbonyl-4-piperidinyl) -ethyl-1-methoxycarbonyl- 3-Indolacetic acid methyl ester was obtained. (626 mg, yield 68%): ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.19 (m, 1 H), 7.61 (d, J = 7.8 Hz, 1 H), 7.56 (s, 1H), 7.35 (t, J = 7.7 Hz, 1 H), 7.25-7.30 (m, 1 H), 3.79-4.15 (m, 5 H), 3.77 (t, J = 7.6 Hz, 1 H), 3.68 (s, 3 H), 2. 65 (m, 2 H), 2.05 (m, 2 H), 1. 65 (m, 2 H), 1.25-1 .50 (m, 12 H), 1.05-1. 19 (m, 2 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 173.9, 168.0, 154.8, 135.4, 129. 3, 124.8, 123.1, 122.9, 119.2, 119.2, 115.2, 79.1, 53.7, 53.0, 52.1 , 48.9, 43.7, 42.7, 35.9, 34.3, 32.0, 29.5, 28.4; FAB-MS: m / z 459 [M + H] ⁺ .

α- [2- (1-Acetyl-4-piperidinyl) -ethyl] -1-methoxycarbonyl-3-indole acetic acid methyl ester

α- [2- (N-tert-butoxycarbonyl-4-piperidinyl) -1-ethyl] -1-methoxycarbonyl-3-indoleacetic acid methyl ester (100 mg, 0.218 mmol) is dissolved in 2 ml of dichloromethane, trifluoroacetic acid is dissolved (1.0 ml, 13.07 mmol) was added and stirred at room temperature for 5 minutes. The reaction solution was dropped into 10 mL of 10% aqueous sodium carbonate solution to stop the reaction. The solution was extracted three times with ethyl acetate (10 mL). The organic layer was washed twice with 10 mL of saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give α- [2- (4-piperidinyl) -ethyl] -1-methoxycarbonyl-3-indoleacetic acid methyl ester (74.1 mg). This (74.1 mg, 0.207 mmol) was dissolved in 3 mL of tetrahydrofuran, triethylamine (0.2 mL) and acetyl chloride (10 mg) were added, and the mixture was stirred at room temperature for 1.5 hours. The reaction was quenched by the addition of 10 mL of saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate (10 mL). The organic layer was washed twice with 10 mL of saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by silica gel column chromatography (chloroform: acetone = 9: 1) to obtain α- [2- (1-acetyl-4-piperidinyl) -ethyl] -1-methoxycarbonyl-3- Indole acetic acid methyl ester was obtained. (53.9 mg, yield 65%): ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.18 (d, J = 6.7 Hz, 1 H), 7.61 (d, J = 7.8 Hz, 1 H) , 7.56 (s, 1 H), 7. 35 (t, J = 8.4 Hz, 1 H), 7.25-7. 28 (m, 1 H), 4.57 (d, J = 12.8 Hz, 1H), 4.03 (s, 3H), 3.73-3.79 (m, 2H), 3.68 (s, 3H), 2.99 (t, J = 12.9 Hz, 1H), 2 .50 (t, J = 12.6 Hz, 1 H), 1.91-2. 19 (m, 5 H), 1. 73 (t, J = 10.4 Hz, 2 H), 1.49 (m, 1 H) , 1.26 to 1.32 (m, 2H), 1.05 to 1.12 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 173.8, 168.7, 15 1.2, 135.4, 129.3, 124.8, 122.9, 119.2, 119.1, 115.2, 53.7, 52.1, 46.6, 42.7, 41. 7, 35.9, 34.2, 32.5, 31.6, 29.2, 21.4; FAB-MS: m / z 401 [M + H] ⁺ .

α-2- (1-Acetyl-4-piperidinyl) -ethyl-3-indoleacetic acid (Compound # 8)

α-2- (1-Acetyl-4-piperidinyl) -ethyl-N-methoxycarbonyl-3-indoleacetic acid methyl ester (48.0 mg, 0.120 mmol) is dissolved in methanol (2 ml) and 2N sodium hydroxide is dissolved therein The aqueous solution (0.5 ml) was added and stirred at 70 ° C. for 2 hours. After confirming the completion of the reaction by TLC, 6 N hydrochloric acid was added to acidify (pH = 3 to 4), and the solvent was evaporated under reduced pressure. Water (5 ml) was added and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by silica gel column chromatography (chloroform: acetone = 3: 2), and α-2- (1-acetyl-4-piperidinyl) -ethyl-3-indoleacetic acid (compound # 8) I got (25.5 mg, yield 65%: ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.54 (s, 1 H), 7.67 (d, J = 7.9 Hz, 1 H), 7.31 (d , J = 8.0 Hz, 1 H), 7.16 (t, J = 7.7 Hz, 1 H), 7.07-7.11 (m, 2 H), 4.48 (d, J = 12.7 Hz, 1H), 3.81 (t, J = 7.5 Hz, 1 H), 3.66 (d, J = 13.2 Hz, 1 H), 2.89 (t, J = 12.5 Hz, 1 H), 43 (t, J = 12.6 Hz, 1 H), 1.86-2.17 (m, 5 H), 1.62 (t, J = 16.5 Hz, 2 H), 1.41 (m, 1 H), 1.22-1.28 (m, 2H), 0.93-1.01 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 178.8, 169.3, 1 36.2, 126.5, 122.3, 129.5, 119.5, 119.1, 113.3, 111.4, 46.7, 43.1, 42.0, 35.7, 34. IR (neat): 3410, 1699, 1454, 1271 cm- ¹ ; FAB-MS: m / z 329 [M + H] ⁺ .

  α-2- (1-acetyl-4-piperidinyl) -methyl-3-indoleacetic acid (compound # 9) is N-tert-butoxy instead of 2- (N-tert-butoxycarbonyl-4-piperidinyl) ethanol The compound was synthesized in the same manner as compound # 8 using carbonyl-4-piperidinylmethanol.

[Synthesis of Compound # 10]
α-4-Aminobutyl-N-methoxycarbonyl-3-indoleacetic acid methyl ester

α- (N-tert-Butoxycarbonyl-4-amino-1-butyl) -1-methoxycarbonyl-3-indoleacetic acid methyl ester (150 mg, 0.358 mmol) to trifluoroacetic acid (0.4 ml, 5.227 mmol) Was added and stirred at room temperature. After 5 minutes, the reaction solution was added dropwise to saturated aqueous sodium bicarbonate solution to stop the reaction. Water (5 ml) was added and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain α-4-aminobutyl-N-methoxycarbonyl-3-indoleacetic acid methyl ester.

α- [N- (1-Acetylpyrrolidine-2-carbonyl) -4-aminobutyl] -N-methoxycarbonyl-3-indoleacetic acid methyl ester

α-4-Aminobutyl-N-methoxycarbonyl-3-indoleacetic acid methyl ester (150 mg, 0.493 mmol) is dissolved in tetrahydrofuran (3 ml), in which N-acetyl-L-proline (116 mg, 0.738 mmol), Add N-hydroxysuccinimide (85.0 mg, 0.739 mmol), dicyclohexylcarbodiimide (152 mg, 0.737 mmol), 4-N, N-dimethylaminopyridine (72.0 mg, 0.589 mmol), and add 7 at room temperature. Stir for hours. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by silica gel column chromatography (chloroform: acetone = 7: 3) to obtain α- [N- (1-acetylpyrrolidine-2-carbonyl) -4-aminobutyl] -N-methoxy Carbonyl-3-indoleacetic acid methyl ester was obtained. (107 mg, yield 49%): ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.17 (d, J = 7.1 Hz, 1 H), 7.61 (d, J = 7.7 Hz, 1 H), 7.55 (s, 1 H), 7.33 (t, J = 7.8 Hz, 1 H), 7. 25 (t, J = 7.4 Hz, 1 H), 7.18 (s, 1 H), 4. 50 (d, J = 7.3 Hz, 1 H), 4.02 (s, 3 H), 3. 80 (t, J = 7.6 Hz, 1 H), 3.67 (s, 3 H), 3. 36- 3.58 (m, 2H), 3.10-3.26 (m, 2H), 1.76-2.40 (m, 9H), 1.49-1.56 (m, 2H), 1.. ^{33-1.38 (m, 2H); 13} C NMR (100MHz, CDCl 3): δ 173.8,171.0,170.8,151.1,135.3,129.2,12 .6, 122.9, 122.8, 119.2, 119.1, 115.0, 59.4, 53.6, 51.9, 48.1, 42.3, 38.9, 31.5 , 29.0, 27.2, 24.8, 24.7, 22.3; FAB-MS: m / z 458 [M + H] ⁺ .

α- [N- (1-Acetylpyrrolidine-2-carbonyl) -4-aminobutyl] -3-indoleacetic acid (Compound # 10)

α- [N- (1-Acetylpyrrolidine-2-carbonyl) -4-aminobutyl] -N-methoxycarbonyl-3-indoleacetic acid methyl ester (80.0 mg, 0.175 mmol) is dissolved in 2 ml of methanol, A 2N aqueous solution of sodium hydroxide (0.5 ml) was added and stirred at 70 ° C. for 1.5 hours. After confirming the completion of the reaction by TLC, 6 N hydrochloric acid was added to acidify (pH = 3 to 4), and the solvent was evaporated under reduced pressure. Water (5 ml) was added and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by silica gel column chromatography (chloroform: methanol = 9: 1), and α- [N- (1-acetylpyrrolidine-2-carbonyl) -4-aminobutyl] -3-indole Acetic acid (compound # 10) was obtained. (63.6 mg, yield 94%): ¹ H NMR (400 MHz, acetone-d ₆ ): δ 10.21 (s, 1 H), 8.03 (s, 1 H), 7.70 (d, J = 7.8 Hz, 1 H), 7.38 (d, J = 8.0 Hz, 1 H), 7.27 (s, 1 H), 7.09 (t, J = 7.3 Hz, 1 H), 7.01 ( t, J = 7.6 Hz, 1 H), 4. 35 (d, J = 7.2 Hz, 1 H), 3. 85 (t, J = 7.6 Hz, 1 H), 3.53 (m, 1 H), 3.40-3.46 (m, 1 H), 3.23 (m, 1 H), 3.10-3.17 (m, 1 H), 1.85-2.14 (m, 9 H), ^{36-1.50 (m, 4H); 13} C NMR (100MHz, acetone _-d 6): _δ 175.8,172.1,170.3,137.3,127.5,123.3,1 1.9, 119.7, 119.3, 114.1, 112.0, 60.5, 48.3, 43.3, 39.2, 32.9, 32.5, 25.4, 25. IR (Neat): 3300, 1634, 1456, 1245 cm ^-1 ; FAB-MS: m / z 386 [M + H] ⁺ .

[Synthesis of Compound # 11]
α- [2- (2-Aminoethoxy) -ethyl] -N-methoxycarbonyl-3-indoleacetic acid methyl ester

α- [N-tert-Butoxycarbonyl- (2-aminoethoxyethyl)]-1-methoxycarbonyl-3-indoleacetic acid methyl ester (140 mg, 0.322 mmol) to trifluoroacetic acid (0.3 ml, 3.920 mmol) Was added and stirred at room temperature. After 5 minutes, the reaction solution was added dropwise to saturated aqueous sodium bicarbonate solution to stop the reaction. Water (5 ml) was added and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain α- [2- (2-aminoethoxy) -ethyl] -N-methoxycarbonyl-3-indoleacetic acid methyl ester. (80.0 mg, yield 74%)

α- {N- (1-Acetylpyrrolidine-2-carbonyl)-[2- (2-aminoethoxy) -ethyl]}-N-methoxycarbonyl-3-indoleacetic acid methyl ester

α- [2- (2-Aminoethoxy) -ethyl] -N-methoxycarbonyl-3-indoleacetic acid methyl ester (80.0 mg, 0.239 mmol) is dissolved in tetrahydrofuran (3 ml) and N-acetyl-L is dissolved therein. -Proline (56.4 mg, 0.359 mmol), N-hydroxysuccinimide (41.2 mg, 0.358 mmol), dicyclohexyl carbodiimide (74.0 mg, 0.359 mmol), 4-N, N-dimethylaminopyridine (40.4 mg, 0.359 mmol) 35.0 mg, 0.286 mmol) was added and stirred at room temperature for 7 hours. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by silica gel column chromatography (chloroform: acetone = 7: 3) to obtain α- [N- (1-acetylpyrrolidine-2-carbonyl) -4-aminobutyl] -N-methoxy Carbonyl-3-indoleacetic acid methyl ester was obtained. (76.1 mg, yield 67%): ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.18 (d, J = 7.1 Hz, 1 H), 7.57-7.66 (m, 2 H), 7.35 (t, J = 7.7 Hz, 1 H), 7.25-7.28 (m, 2 H), 4.56 (t, J = 8.3 Hz, 1 H), 4.09 (t, J = 7.6 Hz, 1 H), 4.03 (s, 3 H), 3. 68 (s, 3 H), 3.59 (t, J = 9.0 Hz, 1 H), 3.32-3.52 (m) , 7H), 2.36-2.48 (m, 2H), 1.84-2.18 (m, 7H), 1.49-1.56 (m, 2H), 1.33-1.38. ^{(m, 2H); 13 C} NMR (100MHz, CDCl 3): δ 174.2,171.5,170.8,151.1,135.5,129.3,124.8,123 1, 123.0, 119.4, 118.9, 115.2, 69.4, 68.4, 59.2, 53.8, 52.2, 48.2, 39.5, 39.2, 32.2, 27.8, 25.0, 22.5; FAB-MS: m / z 474 [M + H] ⁺ .

α- [N- (1-Acetylpyrrolidine-2-carbonyl) -4-aminobutyl] -3-indoleacetic acid (Compound # 11)

Dissolve α- [N- (1-acetylpyrrolidine-2-carbonyl) -4-aminobutyl] -N-methoxycarbonyl-3-indoleacetic acid methyl ester (60.0 mg, 0.127 mmol) in methanol (2 ml), Thereto was added 2N aqueous sodium hydroxide solution (0.5 ml), and the mixture was stirred at 70 ° C. for 1.5 hours. After confirming the completion of the reaction by TLC, 6 N hydrochloric acid was added to acidify (pH = 3 to 4), and the solvent was evaporated under reduced pressure. Water (5 ml) was added and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by silica gel column chromatography (chloroform: methanol = 9: 1), and α- [N- (1-acetylpyrrolidine-2-carbonyl) -4-aminobutyl] -3-indole Acetic acid (compound # 11) was obtained. (36.6 mg, yield 72%): ¹ H NMR (400 MHz, acetone-d ₆ ): δ 8.48 (d, J = 13.4 Hz, 1 H), 7.70 (d, J = 7.9 Hz) , 1 H), 7.34 (d, J = 8.1 Hz, 1 H), 7.09-7.21 (m, 3 H), 4.67 (t, J = 8.3 Hz, 1 H), 4.40 -4.11 (m, 1 H), 3.18-3. 76 (m, 8 H), 2.46-2.67 (m, 4 H), 1.86-2.22 (m, 7 H); ¹³ C NMR (100 MHz, acetone-d ₆ ): δ 178.0, 171.6, 171.2, 136.1, 126.5, 122.3, 122.0, 119.4, 118.9, 113. 7, 111.2, 69.3, 68.6, 60.0, 48.5, 4.12, 39.9, 33.7, 29.1, 24.8, 22. ^{; IR (Neat): 3317,1634,1456,1247,1119cm -1} ; FAB-MS: m / z 402 [M + H] +.

[Synthesis of Compound # 12]
α- (N-tert-Butoxycarbonyl-6-amino-1-hexyl) -α- (1-naphthyl) -acetic acid methyl ester

α- (1-Naphthyl) -acetic acid methyl ester (150 mg, 0.75 mmol) was dissolved in tetrahydrofuran, hexamethylphosphoramide (HMPA, 671 mg, 3.75 mmol) was added and cooled to −78 ° C. Lithium diisopropylamide (1.5 M solution in cyclohexane, 0.75 ml, 1 mmol) is added dropwise to this solution, and after stirring for 30 minutes at -78 ° C, N-tert-butoxycarbonyl-6-amino-1-iodohexane (270 mg) , 0.82 mmol) in tetrahydrofuran (2 mL) was added dropwise, and the mixture was stirred at -78 ° C for 1 hour. The temperature of the reaction solution was raised to 0 ° C. over 15 minutes, 50 mL of water was added to the solution, and extraction was performed twice with 50 mL of ethyl acetate. The organic layer was washed with saturated ammonium chloride solution (20 mL) followed by brine (20 mL), dried over sodium sulfate and evaporated to dryness. The reaction product is purified by silica gel column chromatography (hexane: ethyl acetate = 8: 2), and α- (N-tert-butoxycarbonyl-6-amino-1-hexyl) -α- (1-naphthyl) -methyl acetate I got an ester. (271 mg, yield 91%): ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.11 (d, J = 8.5 Hz, 1 H), 7.83 (d, J = 8.0 Hz, 1 H), 7.74 (d, J = 8.1 Hz, 1 H), 7.40-7.54 (m, 4 H), 4.71 (s, 1 H), 4. 36 (t, J = 7.8 Hz, 1 H ), 3.61 (s, 3 H), 3.04 (m, 2 H), 2.07 (m, 2 H), 1.24-1.48 (m, 17 H); ¹³ C NMR (100 MHz, CDCl ₃₎ ): Δ 174.7, 155.9, 135.3, 133.8, 131.3, 128.8, 127.5, 126.1, 125.4, 125.3, 124.6, 122.8 , 78.7, 51.8, 46.5, 40.3, 32.9, 29.7, 28.9, 28.2, 27.6, 26.3; AB-MS: m / z 400 [M + H] +.

α- (N-tert-butoxycarbonyl-6-amino-1-hexyl) -α- (1-naphthyl) -acetic acid (compound # 12)

Mixed solution of α- (N-tert-butoxycarbonyl-6-amino-1-hexyl) -α- (1-naphthyl) -acetic acid methyl ester (100 mg, 0.25 mmol) in methanol and aqueous sodium hydroxide solution (2 N water It melt | dissolved in sodium oxide aqueous solution: methanol = 1: 4, 5 mL), and heated at 50 degreeC for 1 hour. The reaction solution was adjusted to pH 3.5 with 6 N hydrochloric acid, and methanol was removed by distillation under reduced pressure. To this solution was added water (15 mL) and extracted twice with ethyl acetate (50 mL). The organic layer was washed with saturated ammonium chloride solution (20 mL) followed by brine (20 mL), dried over sodium sulfate and evaporated to dryness. The reaction product is purified by silica gel column chromatography (chloroform: methanol = 95: 5), and α- (N-tert-butoxycarbonyl-6-amino-1-hexyl) -α- (1-naphthyl) -acetic acid (compound) I got # 12). (90 mg, 93% yield): ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.13 (d, J = 8.4 Hz, 1 H), 7.84 (d, J = 7.9 Hz, 1 H), 7.75 (d, J = 8.1 Hz, 1 H), 7.41-7.53 (m, 4 H), 4.56 (s, 1 H), 4. 35 (t, J = 7.4 Hz, 1 H ), 3.03 (m, 2H), 2.05 (m, 2H), 1.22 to 1.46 (m, 17H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 179.0, 156. 0, 135.1, 133.9, 131.6, 128.9, 127.7, 126.2, 125.5, 125.4, 124.9, 123.1, 79.0, 46.6, 40.4, 32.7, 29.8, 29.0, 28.3, 27.7, 26.4; IR (neat): 3417, 170 ^{, 1457,1268,1099cm -1; FAB-MS:} m / z 386 [M + H] +.

[Synthesis of Compound # 13]
N-tert-butoxycarbonyl-6-amino-1-hexanol

6-Amino-1-hexanol (1.0 g, 8.533 mmol) is dissolved in methanol (10 ml), di-tert-butyl carbonate (1.86 g, 8.522 mmol) is added thereto, and stirred at room temperature for 1.5 hours did. After completion of the reaction was confirmed by TLC, the solvent was evaporated away under reduced pressure and the residue was purified by silica gel column chromatography (hexane: acetone = 9: 1) to obtain N-tert-butoxycarbonyl-6-aminohexanol. (1.80 g, 97% yield)

N-tert-butoxycarbonyl-6-amino-1-iodohexane

Dissolve triphenylphosphine (2.35 g, 8.96 mmol), imidazole (0.61 g, 8.96 mmol) in dichloromethane (15 ml) and stir for 5 minutes, then add iodine (2.28 g, 8.98 mmol), Stir for 10 minutes. A solution of N-tert-butoxycarbonyl-6-aminohexanol (1.3 g, 5.98 mmol) in dichloromethane (4 ml) was added dropwise thereto, and the mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction by TLC, the reaction solution was filtered through Celite, and 5% aqueous sodium thiosulfate solution was added to the filtrate to remove iodine. The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain N-tert-butoxycarbonyl-6-amino-1-iodohexane. (1.67 g, 86% yield)

α-Methyl-1-methoxycarbonyl-3-indoleacetic acid methyl ester is Katayama M, Kato Y, Marumo S. “Synthesis, absolute configuration and biological activity of both enantiomers of 2- (5,6-dichloro-3-indolyl) propionic acid: new dichloroindole auxins "Bioscience, Biotechnology, and Biochemistry, 65 (2), 270-276
Synthesized according to the method described in 2001.

α- (N-tert-Butoxycarbonyl-6-amino-1-hexyl) -α-methyl-1-methoxycarbonyl-3-indoleacetic acid methyl ester

Under a nitrogen atmosphere, α-methyl-1-methoxycarbonyl-3-indoleacetic acid methyl ester (83.8 mg, 0.321 mmol) was dissolved in tetrahydrofuran (2 ml) and cooled to -78 ° C. A 1.0 M solution of lithium bistrimethylsilylamide (LHMDS) in tetrahydrofuran (0.69 ml, 1.5 eq) was slowly added dropwise thereto, and the mixture was stirred at -78 ° C for 0.5 hour. A solution of N-tert-butoxycarbonyl-6-amino-1-iodohexane (105 mg, 0.321 mmol) in tetrahydrofuran (1 ml) was slowly added dropwise to this reaction solution, and the mixture was stirred at -78 ° C for 2 hours. After confirming the completion of the reaction by TLC, the temperature was adjusted to 0 ° C., water (5 ml) was added, the reaction was quenched, and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by silica gel column chromatography (hexane: ethyl acetate = 8: 2) to obtain α- (N-tert-butoxycarbonyl-6-amino-1-hexyl) -α-methyl-1 -Methoxycarbonyl-3-indoleacetic acid methyl ester was obtained. (68.6 mg, yield 46%): ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.19 (d, J = 6.3 Hz, 1 H), 7.52 (d, J = 7.9 Hz, 1 H ), 7.48 (s, 1 H), 7.32 (t, J = 7.5 Hz, 1 H), 7.21 (t, J = 7.5 Hz, 1 H), 4.54 (s, 1 H), 4.03 (s, 3 H), 3.62 (s, 3 H), 3.06 (m, 2 H), 2.04-2.12 (m, 2 H), 1.61 (s, 3 H), 1 .17-1.43 (m, 17H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 176.3, 155.9, 151.3, 135.8, 128.6, 124.9, 124.5 , 122.8, 122.0, 120.0, 115.2, 78.9, 53.7, 52.1, 45.5, 40.4, 37.2, 2 9.9, 29.5, 28.3, 26.5, 24.2, 22.5; FAB-MS: m / z 460 [M] ⁺ .

α- (N-tert-butoxycarbonyl-6-amino-1-hexyl) -α-methyl-3-indoleacetic acid (compound # 13)

α- (N-tert-Butoxycarbonyl-6-amino-1-hexyl), α-methyl-1-methoxycarbonyl-3-indoleacetic acid methyl ester (60.0 mg, 0.130 mmol) in methanol (4.6 ml) Melted in Water (0.4 ml) and potassium hydroxide (1.68 g, 30 mmol) were added there, and it stirred at 70 degreeC for 2 hours. After confirming the completion of the reaction by TLC, 6 N hydrochloric acid was added to make it acidic (pH = 3 to 4), and the solvent was evaporated under reduced pressure. Water (5 ml) was added and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by silica gel column chromatography (benzene: acetone = 85: 15) to obtain α- (N-tert-butoxycarbonyl-6-amino-1-hexyl) -α-methyl-3- Indole acetic acid (compound # 13) was obtained. (40.0 mg, yield 79%): ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.26 (s, 1 H), 7.71 (d, J = 8.0 Hz, 1 H), 7.33 ( d, J = 8.0 Hz, 1 H, 7.16 (t, J = 7.4 Hz, 1 H), 7.06 (t, J = 7.3 Hz, 1 H), 7.04 (s, 1 H), 4.52 (s, 1 H), 3.03 (m, 2 H), 2.08-2.17 (m, 2 H), 1.63 (s, 3 H), 1.23-1.48 (m, 2) 17 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 181.7, 156.1, 136.7, 125.5, 121.4, 120.4, 119.2, 118.8, 111.3, 79.1, 45.7, 40.5, 37.5, 29.7, 28.5, 26.5, 24.2, 22.6; IR (neat): 3415, 3339, 1699, 1519, 1460, 1369, 1249, 1170 cm- ¹ ; FAB-MS: m / z 389 [M + H] ⁺ .

[Synthesis of Compound # 14]
2- (N-tert-butoxycarbonyl-2-aminoethoxy) -ethanol

2- (2-Aminoethoxy) -ethanol (1.0 g, 9.511 mmol) is dissolved in methanol (10 ml), di-tert-butyl carbonate (2.07 g, 9.485 mmol) is added thereto, and 2 hours at room temperature It stirred. After confirming the completion of the reaction by TLC, the solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography (hexane: acetone = 3: 2), 2- (N-tert-butoxycarbonyl-2-aminoethoxy) -ethanol I got (1.78 g, 91% yield)

2- (N-tert-butoxycarbonyl-2-aminoethoxy) -1-iodoethane

Dissolve triphenylphosphine (2.87 g, 10.94 mmol), imidazole (0.75 g, 11.02 mmol) in dichloromethane (15 ml) and stir for 5 minutes, then add iodine (2.78 g, 10.95 mmol), Stir for 10 minutes. Thereto was added dropwise a solution of 2- (N-tert-butoxycarbonyl-2-aminoethoxy) -ethanol (1.5 g, 7.308 mmol) in dichloromethane (4 ml) and stirred at room temperature for 1.5 hours. After confirming the completion of the reaction by TLC, the reaction solution was filtered through Celite, and 5% aqueous sodium thiosulfate solution was added to the filtrate to remove iodine. The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 85: 15) to obtain 2- (N-tert-butoxycarbonyl-2-aminoethoxy) -1-iodoethane. (2.19 g, 95% yield)

α- [2- (N-tert-Butoxycarbonyl-2-aminoethoxy) -1-ethyl] -1-methoxycarbonyl-3-indoleacetic acid methyl ester

In a nitrogen atmosphere, 1-methoxycarbonyl-3-indoleacetic acid methyl ester (500 mg, 2.022 mmol) and hexamethylphosphoric acid triamide (HMPA, 1.81 g, 10.11 mmol) were dissolved in tetrahydrofuran (4 ml), Cooled to A 1.5 M solution of lithium diisopropylamide (LDA) in cyclohexane (2.02 ml, 1.5 eq) was slowly added dropwise thereto, and the mixture was stirred at -78 ° C for 0.5 hour. A solution of 2- (N-tert-butoxycarbonyl-2-aminoethoxy) -1-iodoethane (637 mg, 2.022 mmol) in tetrahydrofuran (2 ml) was slowly added dropwise to this reaction solution, and stirred at -78 ° C for 1 hour did. After confirming the completion of the reaction by TLC, the temperature was adjusted to 0 ° C., water (15 ml) was added, the reaction was quenched, and extracted three times with ethyl acetate (15 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by silica gel column chromatography (hexane: ethyl acetate = 8: 2) to obtain α- [2- (N-tert-butoxycarbonyl-2-aminoethoxy) -1-ethyl]- 1-Methoxycarbonyl-3-indoleacetic acid methyl ester was obtained. (645 mg, yield 79%): ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.18 (d, J = 7.0 Hz, 1 H), 7.63 (d, J = 7.7 Hz, 1 H), 7.57 (s, 1 H), 7.34 (t, J = 7.7 Hz, 1 H), 7.26 (t, J = 7.3 Hz, 1 H), 4.98 (s, 1 H), 4. 02-4.06 (m, 4H), 3.69 (s, 3H), 3.43-3.51 (m, 4H), 3.30 (m, 2H), 2.29 (m, 2H) , 1.45 (s, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 173.8, 155.9, 151.2, 135.4, 124.8, 123.1, 122.9, 119 .2, 118.8, 115.2, 79.1, 69.8, 68.3, 52.7, 52.1, 40.3, 39.3, 39.3, 32.2, 2 .3; FAB-MS: m / z 435 [M + H] +.

α- [2- (N-tert-Butoxycarbonyl-2-aminoethoxy) -1-ethyl] -3-indoleacetic acid (Compound # 14)

α- [2- (N-tert-Butoxycarbonyl-2-aminoethoxy) -1-ethyl] -1-methoxycarbonyl-3-indoleacetic acid methyl ester (80.0 mg, 0.184 mmol) in methanol (2 ml) It melt | dissolved, 2 N sodium hydroxide aqueous solution (0.5 ml) was added there, and it stirred at 70 degreeC for 2 hours. After confirming the completion of the reaction by TLC, 6 N hydrochloric acid was added to make it acidic (pH = 3 to 4), and the solvent was evaporated under reduced pressure. Water (5 ml) was added and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by silica gel column chromatography (chloroform: methanol = 9: 1) to obtain α- [2- (N-tert-butoxycarbonyl-2-aminoethoxy) -1-ethyl] -3. -Indoleacetic acid (compound # 14) was obtained. (70.2 mg, yield 87%): ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.40 (s, 1 H), 7.67 (d, J = 7.9 Hz, 1 H), 7.29 ( d, J = 8.0 Hz, 1 H), 7.15 (t, J = 7.8 Hz, 1 H), 7.08 (t, J = 7.3 Hz, 1 H), 7.04 (s, 1 H), 5.03 (s, 1 H), 4.04 (t, J = 7.1 Hz, 1 H), 3.30-3.46 (m, 4 H), 3.23 (m, 2 H), 2.26 (m, 4 H) m, 2H), 1.44 (s, 9H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 179.2, 156.2, 136.2, 126.4, 122.6, 122.1, 119 .5, 119.1, 112.6, 111.3, 79.4, 69.7, 68.5, 40.3, 39.7, 32.3, 28.4; IR (neat): 3406, 3332, 1699, 1520, 1458, 1367, 1252, 1169, 1119 cm- ¹ ; FAB-MS: m / z 385 [M + Na] ⁺ .

[Synthesis of Compound # 15]
N-tert-butoxycarbonyl-4-amino-1-butanol

Dissolve 4-amino-1-butanol (1.0 g, 11.22 mmol) in methanol (10 ml), add di-tert-butyl carbonate (2.53 g, 11.58 mmol) there and stir at room temperature for 1.5 hours did. After completion of the reaction was confirmed by TLC, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane: acetone = 9: 1) to obtain N-tert-butoxycarbonyl-4-amino-1-butanol. . (1.88 g, 89% yield)

N-tert-butoxycarbonyl-4-amino-1-iodobutane

Dissolve triphenylphosphine (3.3 g, 12.58 mmol) and imidazole (0.86 g, 12.63 mmol) in dichloromethane (15 ml) and stir for 5 minutes, then add iodine (3.2 g, 12.61 mmol), Stir for 10 minutes. A solution of N-tert-butoxycarbonyl-4-amino-1-butanol (1.6 g, 8.454 mmol) in dichloromethane (4 ml) was added dropwise thereto, and the mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction by TLC, the reaction solution was filtered through Celite, and 5% aqueous sodium thiosulfate solution was added to the filtrate to remove iodine. The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain N-tert-butoxycarbonyl-4-amino-1-iodobutane. (1.83 g, 72% yield)

α- (N-tert-Butoxycarbonyl-4-amino-1-butyl) -1-methoxycarbonyl-3-indoleacetic acid methyl ester

In a nitrogen atmosphere, 1-methoxycarbonyl-3-indoleacetic acid methyl ester (400 mg, 1.618 mmol) and hexamethylphosphoric acid triamide (HMPA, 1.45 g, 8.086 mmol) are dissolved in tetrahydrofuran (4 ml), Cooled to A 1.5 M solution of lithium diisopropylamide (LDA) in cyclohexane (1.62 ml, 1.5 eq) was slowly added dropwise thereto, and the mixture was stirred at -78 ° C for 0.5 hour. A solution of N-tert-butoxycarbonyl-4-amino-1-iodobutane (484 mg, 1.618 mmol) in tetrahydrofuran (2 ml) was slowly added dropwise to this reaction solution, and the mixture was stirred at -78 ° C for 1 hour. After confirming the completion of the reaction by TLC, the temperature was adjusted to 0 ° C., water (15 ml) was added, the reaction was quenched, and extracted three times with ethyl acetate (15 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by silica gel column chromatography (hexane: ethyl acetate = 8: 2) to obtain α- (N-tert-butoxycarbonyl-4-amino-1-butyl) -1-methoxycarbonyl- 3-Indolacetic acid methyl ester was obtained. (373 mg, yield 55%): ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.18 (d, J = 7.8 Hz, 1 H), 7.60 (d, J = 7.8 Hz, 1 H), 7.55 (s, 1 H), 7.34 (t, J = 7.9 Hz, 1 H), 7. 25 (t, J = 7.7 Hz, 1 H), 4.59 (s, 1 H), 4. 02 (s, 3 H), 3. 80 (t, J = 7.6 Hz, 1 H), 3. 67 (s, 3 H), 3.09 (m, 2 H), 2.03 (m, 2 H), 1 .25-1.53 (m, 13 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 173.9, 155.9, 151.2, 135.5, 129.3, 124.8, 123.0 , 122.9, 119.2, 115.2, 78.9, 53.6, 52.0, 42.5, 40.2, 31.7, 29.8, FAB-MS: m / z 419 [M + H] ⁺ .

α- (N-tert-Butoxycarbonyl-4-amino-1-butyl) -3-indoleacetic acid (Compound # 15)

α- (N-tert-Butoxycarbonyl-4-amino-1-butyl) -1-methoxycarbonyl-3-indoleacetic acid methyl ester (100 mg, 0.239 mmol) is dissolved in methanol (2 ml) and 2N hydroxylated there Aqueous sodium solution (0.5 ml) was added and stirred at 70 ° C. for 2 hours. After confirming the completion of the reaction by TLC, 6 N hydrochloric acid was added to make it acidic (pH = 3 to 4), and the solvent was evaporated under reduced pressure. Water (5 ml) was added and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, and the residue is then purified by silica gel column chromatography (chloroform: methanol = 95: 5) to obtain α- (N-tert-butoxycarbonyl-4-amino-1-butyl) -3-indoleacetic acid (compound I got # 15). (71.8 mg, yield 87%): ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.35 (s, 1 H), 7.67 (d, J = 7.8 Hz, 1 H), 7.28 ( d, J = 7.8 Hz, 1 H), 7. 15 (t, J = 7.7 Hz, 1 H), 7.09 (t, J = 7.3 Hz, 1 H), 7.00 (s, 1 H), 4.57 (s, 1 H), 3.81 (t, J = 7.5 Hz, 1 H), 3.02 (m, 2 H), 1.97 (m, 2 H), 1.23-1.48 ( m, 13 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 179.6, 156.1, 136.1, 126.4, 122.3, 122.0, 119.4, 119.1, 113. 0, 111.3, 79.3, 42.9, 40.3, 31.9, 29.7, 28.4, 24.7; IR (neat): 3 747, 1699, 1520, 1456, 1367, 1250, 1170 cm ⁻¹ ; FAB-MS: m / z 347 [M + H] ⁺ .

[Synthesis of Compound # 17]
2-ethyl-1-iodobutane

Dissolve triphenylphosphine (1.93 g, 7.358 mmol), imidazole (0.5 g, 7.344 mmol) in dichloromethane (5.0 ml) and stir for 5 minutes, then iodine (1.86 g, 7.328 mmol) In addition, it was stirred for 10 minutes. A solution of 2-ethyl-1-butanol (0.5 g, 5.672 mmol) in dichloromethane (2.0 ml) was added dropwise thereto, and the mixture was stirred at room temperature for 1.5 hours. After confirming the completion of the reaction by TLC, the reaction solution was filtered through Celite, and 5% aqueous sodium thiosulfate solution was added to the filtrate to remove iodine. The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane) to obtain 2-ethyl-1-iodobutane. (0.35 g, 34% yield)

α- (2-Ethyl-1-butyl) -1-methoxycarbonyl-3-indoleacetic acid methyl ester

In a nitrogen atmosphere, 1-methoxycarbonyl-3-indoleacetic acid methyl ester (100 mg, 0.404 mmol) and hexamethylphosphoric acid triamide (HMPA, 362 mg, 2.020 mmol) are dissolved in tetrahydrofuran (2 ml) and cooled to -78 ° C. did. A 1.0 M solution of lithium bis (trimethylsilyl) amide (LHMDS) in tetrahydrofuran (0.61 ml, 1.5 eq) was slowly added dropwise thereto, and the mixture was stirred at -78 ° C for 0.5 hours. A solution of 2-ethyl-1-iodobutane (85. 8 mg, 0.405 mmol) in tetrahydrofuran (1 ml) was slowly added dropwise to this reaction solution, and the mixture was stirred at -78 ° C for 1 hour. After confirming the completion of the reaction by TLC, the temperature was adjusted to 0 ° C., water (5 ml) was added, the reaction was quenched, and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain α- (2-ethyl-1-butyl) -1-methoxycarbonyl-3-indoleacetic acid methyl ester Obtained. (104 mg, yield 78%): ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.18 (d, J = 7.0 Hz, 1 H), 7.64 (d, J = 7.8 Hz, 1 H), 7.57 (s, 1 H), 7.34 (t, J = 7.7 Hz, 1 H), 7. 26 (t, J = 7.4 Hz, 1 H), 4.01 (s, 3 H), 3. 93 (t, J = 7.8 Hz, 1 H), 3.67 (s, 3 H), 1.96 (m, 2 H), 1.21-1. 41 (m, 5 H), 0.82-0. 88 (m, 6 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 174.3, 151.3, 135.5, 129.5, 124.7, 122.9, 119.7, 119.3, 115.2, 53.7, 52.0, 40.4, 38.0, 35.6, 25.1, 24.9, 10.4, 10.4; neat): 1738, 1455, 1377, 1256, 1164, 1085 cm ⁻¹ ; EI-MS: m / z 331 [M] ⁺ .

α- (2-Ethyl-1-butyl) -3-indoleacetic acid (Compound # 17)

α- (2-Ethyl-1-butyl) -1-methoxycarbonyl-3-indoleacetic acid (70.0 mg, 0.211 mmol) is dissolved in methanol (2 ml), and 2N aqueous solution of sodium hydroxide (0.5 ml) there Was added and stirred at 70 ° C. for 2.5 hours. After confirming the completion of the reaction by TLC, 6 N hydrochloric acid was added to make it acidic (pH = 3 to 4), and the solvent was evaporated under reduced pressure. Water (5 ml) was added and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 95: 5) to obtain α- (2-ethyl-1-butyl) -3-indoleacetic acid (compound # 17). (52.4 mg, yield 96): ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.02 (s, 1 H), 7.70 (d, J = 7.9 Hz, 1 H), 7.30 (d , J = 8.0 Hz, 1 H), 7.17 (t, J = 7.9 Hz, 1 H), 7.11 (t, J = 7.5 Hz, 1 H), 7.08 (s, 1 H), 3 .97 (t, J = 7.8Hz, 1H), 1.96 (m, 2H), 1.23-1.39 (m, 5H), 0.78-0.84 (m, 6H); 13 C NMR (100 MHz, CDCl ₃ ): δ 181.1, 136.1, 126.6, 122.2, 122.2, 119.7, 119.3, 113.7, 111.2, 40.6, 37.8, 35.9, 25.0, 25.0, 10.4, 10.4; IR (neat): 3414, 1703, 1458, 1293, 1098 cm ⁻¹ ; FAB-MS: m / z 260 [M + H] ⁺ .

[Synthesis of Compound # 18]
3-Methyl-1-iodopentane

Triphenylphosphine (1.93 g, 7.358 mmol), imidazole (0.5)
g, 7.344 mmol) was dissolved in dichloromethane (5.0 ml) and stirred for 5 minutes, then iodine (1.86 g, 7.328 mmol) was added and stirred for 10 minutes. The dichloromethane (2.0 ml) solution of 3-methyl- 1-pentanol (0.5 g, 5.672 mmol) was dripped there, and it stirred at room temperature for 1.5 hours. After confirming the completion of the reaction by TLC, the reaction solution was filtered through Celite, and 5% aqueous sodium thiosulfate solution was added to the filtrate to remove iodine. The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 98: 2) to obtain 3-methyl-1-iodopentane. (0.12 mg, 11% yield)

α- (3-Methyl-1-pentyl) -1-methoxycarbonyl-3-indoleacetic acid methyl ester

In a nitrogen atmosphere, 1-methoxycarbonyl-3-indoleacetic acid methyl ester (50.0 mg, 0.202 mmol) and hexamethylphosphoric acid triamide (HMPA, 181 mg, 1.011 mmol) are dissolved in tetrahydrofuran (1 ml), Cooled to To this, a 1.0 M solution of lithium bis (trimethylsilyl) amide (LHMDS) in tetrahydrofuran (0.30 ml, 1.5 eq) was slowly added dropwise, and the mixture was stirred at -78 ° C for 0.5 hours. A solution of 3-methyl-1-iodopentane (51.5 mg, 0.243 mmol) in tetrahydrofuran (1 ml) was slowly added dropwise to this reaction solution, and the mixture was stirred at -78 ° C for 2 hours. After confirming the completion of the reaction by TLC, the temperature was adjusted to 0 ° C., water (5 ml) was added, the reaction was quenched, and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by silica gel column chromatography (hexane: ethyl acetate = 12: 1) to obtain α- (3-methyl-1-pentyl) -1-methoxycarbonyl-3-indoleacetic acid methyl ester Obtained. (25.8 mg, yield 39%): ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.18 (d, J = 6.7 Hz, 1 H), 7.62 (d, J = 7.7 Hz, 1 H) ), 7.56 (s, 1 H), 7.34 (t, J = 7.8 Hz, 1 H), 7.26 (t, J = 7.2 Hz, 1 H), 4.03 (s, 3 H), 3.77 (t, J = 7.9 Hz, 1 H), 3.68 (s, 3 H), 2.01 (m, 2 H), 1.10-1. 39 (m, 5 H), 0.82- 0.87 (m, 6H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 174.2, 151.3, 135.5, 129.5, 124.8, 122.9, 119.4, 119. 3, 115.2, 53.7, 52.0, 42.9, 34.4, 34.2, 29.8, 29.2, 19.1, 11.3; IR (Neat): 1741, 1145, 1378, 1254, 1084 cm ⁻¹ ; EI-MS: m / z 331 [M] ⁺ .

α- (3-Methyl-1-pentyl) -3-indoleacetic acid (Compound # 18)

α- (3-Methyl-1-pentyl) -1-methoxycarbonyl-3-indoleacetic acid methyl ester (20.0 mg, 0.060 mmol) is dissolved in methanol (1 ml), and 2N aqueous sodium hydroxide solution (0. 25 ml) was added and stirred at 70 ° C. for 2.5 hours. After confirming the completion of the reaction by TLC, 6 N hydrochloric acid was added to make it acidic (pH = 3 to 4), and the solvent was evaporated under reduced pressure. Water (5 ml) was added and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 95: 5) to obtain α- (3-methyl-1-pentyl) -3-indoleacetic acid (compound # 18). (16.8 mg, yield 89%): ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.07 (s, 1 H), 7.70 (d, J = 7.8 Hz, 1 H), 7.33 ( d, J = 8.1 Hz, 1 H), 7.19 (t, J = 8.0 Hz, 1 H), 7.10-7.13 (m, 2 H), 3.82 (t, J = 6.7 Hz , 1 H), 1.97 (m, 2 H), 1.10 to 1.36 (m, 5 H), 0.79 to 0.85 (m, 6 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 180.4, 136.1, 126.6, 122.2, 122.2, 119.7, 119.3, 113.7, 111.2, 3.42, 34.5, 34.3, 30. 1,29.2,19.1,11.3; IR (neat): 3418,1704,1456,1294,1098cm - ; EI-MS: m / z 259 [M] +.

[Synthesis of Compound # 19]
2-Methyl-1-iodopentane

Dissolve triphenylphosphine (1.93 g, 7.358 mmol), imidazole (0.5 g, 7.344 mmol) in dichloromethane (5.0 ml) and stir for 5 minutes, then iodine (1.86 g, 7.328 mmol) In addition, it was stirred for 10 minutes. Thereto was added dropwise a solution of 2-methyl-1-pentanol (0.5 g, 5.672 mmol) in dichloromethane (2.0 ml) and stirred at room temperature for 1.5 hours. After confirming the completion of the reaction by TLC, the reaction solution was filtered through Celite, and 5% aqueous sodium thiosulfate solution was added to the filtrate to remove iodine. The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane) to obtain 2-methyl-1-iodopentane. (0.56 g, 54% yield)

α- (2-Methyl-1-pentyl) -1-methoxycarbonyl-3-indoleacetic acid methyl ester

In a nitrogen atmosphere, 1-methoxycarbonyl-3-indoleacetic acid methyl ester (100 mg, 0.404 mmol) and hexamethylphosphoric acid triamide (HMPA, 362 mg, 2.020 mmol) are dissolved in tetrahydrofuran (2 ml) and cooled to -78 ° C. did. A 1.0 M solution of lithium bis (trimethylsilyl) amide (LHMDS) in tetrahydrofuran (0.61 ml, 1.5 eq) was slowly added dropwise thereto, and the mixture was stirred at -78 ° C for 0.5 hours. A solution of 2-methyl-1-iodopentane (85. 8 mg, 0.405 mmol) in tetrahydrofuran (1 ml) was slowly added dropwise to this reaction solution, and the mixture was stirred at -78 ° C for 1 hour. After confirming the completion of the reaction by TLC, the temperature was adjusted to 0 ° C., water (5 ml) was added, the reaction was quenched, and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to give α- (2-methyl-1-pentyl) -1-methoxycarbonyl-3-indoleacetic acid methyl ester Obtained. (101 mg, yield 75%): ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.18 (d, J = 5.7 Hz, 1 H), 7.63 (d, J = 7.8 Hz, 1 H), 7.55 (s, 1 H), 7.34 (t, J = 7.6 Hz, 1 H), 7. 27 (t, J = 7.5 Hz, 1 H), 4.03 (s, 3 H), 3. 91-3.97 (m, 1 H), 3.68 (s, 3 H), 1.58-2.24 (m, 2 H), 1.10-1. 50 (m, 5 H), 0.83- 0.97 (m, 6H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 174.4, 151.2, 135.4, 129.4, 124.7, 122.9, 122.8, 119. 9, 119.4, 115.2, 53.7, 52.0, 40.4, 39.6, 39.3, 30.7, 19.8, 19.4, 14.2; IR (neat): 1739, 1456, 1373, 1217, 1087 cm ⁻¹ ; EI-MS: m / z 331 [M] ⁺ .

α- (2-Methyl-1-pentyl) -3-indoleacetic acid (compound # 19)

α- (2-Methyl-1-pentyl) -1-methoxycarbonyl-3-indoleacetic acid methyl ester (70.0 mg, 0.211 mmol) is dissolved in methanol (2 ml), and 2N aqueous sodium hydroxide solution (0. 5 ml) was added and stirred at 70 ° C. for 2.5 hours. After confirming the completion of the reaction by TLC, 6 N hydrochloric acid was added to make it acidic (pH = 3 to 4), and the solvent was evaporated under reduced pressure. Water (5 ml) was added and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 95: 5) to obtain α- (2-methyl-1-pentyl) -3-indoleacetic acid (compound # 19). (51.9 mg, yield 95%): ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.12 (s, 1 H), 7.70 (d, J = 7.8 Hz, 1 H), 7.30 ( d, J = 8.0 Hz, 1 H, 7.17 (t, J = 7.4 Hz, 1 H), 7.1 1 (t, J = 7.2 Hz, 1 H), 7.06 (s, 1 H), 3.96-4.02 (m, 1 H), 1.60-2.22 (m, 2 H), 1.12-1.51 (m, 5 H), 0.79-0.94 (m, 6 H) ¹³ C NMR (100 MHz, CDCl ₃ ): δ 180.9, 136.1, 126.5, 122.3, 122.2, 119.7, 119.3, 113.3, 111.2, 40 .7, 39.9, 39.2, 30.3, 19.8, 19.4, 14.3; IR (neat): 3417, 1699, 14 57, 1292, 1099 cm ⁻¹ ; EI-MS: m / z 259 [M] ⁺ .

[Synthesis of Compound # 20]
4-phenyl-2- (1H-indol-3-yl) -4-oxo-butanoic acid (compound # 20)

Dissolve trans-4-phenyl-4-oxo-2-butenoic acid (1.0 g, 5.65 mmol) in benzene (25 mL) in a 30 mL round bottom flask and add indole (0.79 g, 6.77 mmol) The mixture was stirred at 80 ° C. for 5 hours and stirred to room temperature. The reaction solution was evaporated under reduced pressure, and recrystallization from benzene was performed to obtain 4-phenyl-2- (1H-indol-3-yl) -4-oxo-butanoic acid (compound # 20). (1.24 g, yield 75%): mp 149-150 ° C .; ¹ H NMR (400 MHz, acetone-d ₆ ): δ 10.17 (1 H, brs, 1 H), 8.05 (2 H, d, J = 8.2 Hz), 7.80 (1 H, d, J = 8.3 Hz), 7.57 (1 H, t, J = 7.8 Hz), 7.51 (2 H, dd, J = 8.2, 7.8 Hz), 7.41 (1 H, d, J = 8.2 Hz), 7.37 (1 H, s), 7.13 (1 H, t, J = 8.2 Hz), 7.06 (1 H, 1 H, t) t, J = 8.2 Hz), 4.57 (1 H, dd, J = 11.0, 4.1 Hz), 4. 13 (1 H, dd, J = 17.8, 11.0 Hz), 3.41 (1H, dd, J = 17.8, 4.1 Hz);
^{IR: (neat): 3400,3055,1711,1677,1453cm -1} ; HRFAB-MS found m / z 294.1143 [M + H] +, calcd for 294.1130 (C 18 H 16 NO 3).

[Synthesis of Compound # 21]
4,4,5,5,5-pentafluoro-1-iodopentane

Dissolve triphenylphosphine (1.1 g, 4.211 mmol), imidazole (0.29 g, 4.211 mmol) in dichloromethane (5.0 ml) and stir for 5 minutes, then iodine (1.07 g, 4.211 mmol) In addition, it was stirred for 10 minutes. A solution of 4,4,5,5,5-pentafluoro-1-pentanol (0.5 g, 2.807 mmol) in dichloromethane (2.0 ml) was added dropwise thereto, and the mixture was stirred at room temperature for 1.5 hours. After confirming the completion of the reaction by TLC, the reaction solution was filtered through Celite, and 5% aqueous sodium thiosulfate solution was added to the filtrate to remove iodine. The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane) to obtain 4,4,5,5,5-pentafluoro-1-iodopentane. (0.36 g, 45% yield)

α- (4,4,5,5,5-Pentafluoro-1-pentyl) -1-methoxycarbonyl-3-indoleacetic acid methyl ester

In a nitrogen atmosphere, 1-methoxycarbonyl-3-indoleacetic acid methyl ester (50.0 mg, 0.202 mmol) and hexamethylphosphoric acid triamide (HMPA, 181 mg, 1.011 mmol) are dissolved in tetrahydrofuran (1 ml), Cooled to To this, a 1.0 M solution of lithium bis (trimethylsilyl) amide (LHMDS) in tetrahydrofuran (0.30 ml, 1.5 eq) was slowly added dropwise, and the mixture was stirred at -78 ° C for 0.5 hours. A solution of 4,4,5,5,5-pentafluoro-1-iodopentane (81.4 mg, 0.283 mmol) in tetrahydrofuran (1 ml) was slowly added dropwise to this reaction solution, and the mixture was stirred at -78 ° C for 1 hour. did. After confirming the completion of the reaction by TLC, the temperature was adjusted to 0 ° C., water (5 ml) was added, the reaction was quenched, and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by silica gel column chromatography (hexane: ethyl acetate = 85: 15) to obtain α- (4,4,5,5,5-pentafluoro-1-pentyl) -1-methoxy. Carbonyl-3-indoleacetic acid methyl ester was obtained. (59.8 mg, yield 73%): ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.19 (d, J = 7.6 Hz, 1 H), 7.60 (d, J = 7.8 Hz, 1 H) ), 7.57 (s, 1 H), 7.36 (t, J = 7.5 Hz, 1 H), 7. 27 (t, J = 6.9 Hz, 1 H), 4.03 (s, 3 H), 3.83 (t, J = 7.6 Hz, 1 H), 3.69 (s, 3 H), 1.98-2.23 (m, 4 H), 1.62-1.68 (m, 2 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 173.5, 151.3, 135.5, 129.1, 125.0, 123.1, 123.1, 119.2, 118.6, 115.3 , 53.8, 52.2, 42.3, 31.4, 30.6, 30.3, 30.1, 18.6; IR (neat): 17 ^{9,1456,1378,1257,1198cm -1; EI-MS: m} / z 407 [M] +.

α- (4,4,5,5,5-Pentafluoro-1-pentyl) -3-indoleacetic acid (Compound # 21)

Dissolve α- (4,4,5,5,5-pentafluoro-1-pentyl) -1-methoxycarbonyl-3-indoleacetic acid methyl ester (55.5 mg, 0.183 mmol) in methanol (1 ml) To the mixture was added 2N aqueous solution of sodium hydroxide (0.25 ml), and stirred at 70.degree. C. for 1 hour. After confirming the completion of the reaction by TLC, 6 N hydrochloric acid was added to make it acidic (pH = 3 to 4), and the solvent was evaporated under reduced pressure. Water (5 ml) was added and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by silica gel column chromatography (chloroform: methanol = 95: 5) to obtain α- (4,4,5,5,5-pentafluoro-1-pentyl) -3-indoleacetic acid. (Compound # 21) was obtained. (43.9 mg, yield 97%): ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.06 (s, 1 H), 7.67 (d, J = 7.9 Hz, 1 H), 7.33 ( d, J = 8.1 Hz, 1 H), 7.20 (t, J = 8.0 Hz, 1 H), 7.12 (t, J = 7.9 Hz, 1 H), 7.09 (s, 1 H), 3.87 (t, J = 7.5 Hz, 1 H), 1.95-2.22 (m, 4 H), 1.60-1.67 (m, 2 H); ¹³ C NMR (100 MHz, CDCl ₃ ) : Δ 179.9, 136.2, 126.2, 122.4, 129.9, 119.9, 119.1, 112.5, 111.4, 42.7, 31.5, 30.6, 30.3,30.1,18.6; IR (neat): 3418,1704,1459,1198cm -1; EI-MS ^{m / z 335 [M] +} .

[Synthesis of Compound # 22]
3- (2-hydroxy-1-ethyl) -1,1′-biphenyl

Dissolve 2- (3-bromophenyl) -1-ethanol (200 mg, 0.995 mmol) in a mixed solvent (3.0 ml) of dimethoxyethane: ethanol (= 5: 1), phenylboronic acid (242 mg, 1.985 mmol) A 2M aqueous solution of sodium carbonate (1.5 ml) and tetrakis (triphenylphosphine) palladium (0) (Pd (PPh ₃ ) ₄ , 56.0 mg, 0.048 mmol) were added, and the mixture was stirred for 4 hours while heating under reflux. After confirming the completion of the reaction by TLC, the reaction solution was filtered through celite, hydrochloric acid was added to the filtrate for neutralization, and extraction was performed three times with ethyl acetate (10 ml). The organic layer is washed twice with saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated away under reduced pressure, and then purified by silica gel column chromatography (hexane: ethyl acetate = 8: 2) to obtain 3- (2- (2-) Hydroxy-1-ethyl) -1,1′-biphenyl was obtained. (172 mg, yield 87%)

3- (2-iodo-1-ethyl) -1,1'-biphenyl

Dissolve triphenylphosphine (327 mg, 1.248 mmol) and imidazole (85.0 mg, 1.249 mmol) in dichloromethane (3.0 ml) and stir for 5 minutes, then add iodine (317 mg, 1.248 mmol), and then add 10 minutes. It stirred. Thereto was added dropwise a solution of 3- (2-hydroxy-1-ethyl) -1,1′-biphenyl (165 mg, 0.832 mmol) in dichloromethane (0.5 ml) and stirred at room temperature for 1 hour. After confirming the completion of the reaction by TLC, the reaction solution was filtered through Celite, and 5% aqueous sodium thiosulfate solution was added to the filtrate to remove iodine. The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 98: 2) to obtain 3- (2-iodo-1-ethyl) -1,1′-biphenyl. (185 mg, 72% yield)

α- [2- (1,1'-Biphenyl-3-yl) -1-ethyl] -1-methoxycarbonyl-3-indoleacetic acid methyl ester

In a nitrogen atmosphere, 1-methoxycarbonyl-3-indoleacetic acid methyl ester (80 mg, 0.324 mmol) and hexamethylphosphoric acid triamide (HMPA, 290 mg, 1.618 mmol) are dissolved in tetrahydrofuran (2 ml) and cooled to -78 ° C. did. A 1.5 M solution of lithium diisopropylamide (LDA) in cyclohexane (0.32 ml, 1.5 eq) was slowly added dropwise thereto, and the mixture was stirred at -78 ° C for 0.5 hour. A solution of 3- (2-iodo-1-ethyl) -1,1'-biphenyl (99.7 mg, 0.324 mmol) in tetrahydrofuran (1 ml) was slowly added dropwise to this reaction solution, and the reaction was allowed to proceed at -78 ° C for 1 hour. It stirred. After confirming the completion of the reaction by TLC, the temperature was adjusted to 0 ° C., water (5 ml) was added, the reaction was quenched, and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by silica gel column chromatography (hexane: ethyl acetate = 85: 15) to obtain α- [2- (1,1′-biphenyl-3-yl) -1-ethyl] -1 -Methoxycarbonyl-3-indoleacetic acid methyl ester was obtained. (132 mg, yield 96%): ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.19 (d, J = 6.8 Hz, 1 H), 7.55 to 7.58 (m, 4 H), 7. 31-7.44 (m, 7H), 7.24 (t, J = 8.1 Hz, 1 H), 7.15 (d, J = 7.5 Hz, 1 H), 4.02 (s, 3 H), 3.86 (t, J = 7.5 Hz, 1 H), 3.65 (S, 3 H), 2.73 (t, J = 7.7 Hz, 2 H), 2.25-2.58 (m, 2 H) ¹³ C NMR (100 MHz, CDCl ₃ ): δ 173.8, 151.2, 141.4, 141.3, 141.1, 135.5, 129.3, 128.8, 128.6, 127 , 127.2, 127.1, 124.9, 124.8, 123.1, 122.9, 119.3, 118.9, 115.1, 53.7, 52.1, 41.8, 33.7, 33.5; EI-MS: m / z 427 [M] ⁺ .

α- [2- (1,1′-biphenyl-3-yl) -1-ethyl] -3-indoleacetic acid (compound # 22)

Dissolve α- [2- (1,1'-biphenyl-3-yl) -1-ethyl] -1-methoxycarbonyl-3-indoleacetic acid methyl ester (80.0 mg, 0.187 mmol) in methanol (2 ml) Thereto was added 2N aqueous solution of sodium hydroxide (0.5 ml), and the mixture was stirred at 70 ° C. for 1.5 hours. After confirming the completion of the reaction by TLC, 6 N hydrochloric acid was added to make it acidic (pH = 3 to 4), and the solvent was evaporated under reduced pressure. Water (5 ml) was added and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by silica gel column chromatography (chloroform: methanol = 95: 5) to obtain α- [2- (1,1′-biphenyl-3-yl) -1-ethyl] -3-3. Indole acetic acid (compound # 22) was obtained. (60.3 mg, yield 91%): ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.01 (s, 1 H), 7.65 (d, J = 7.9 Hz, 1 H), 7.53- 7.55 (m, 2H), 7.29-7.41 (m, 7H), 7.17 (t, J = 7.2 Hz, 1 H), 7.07-7.13 (m, 3 H), 3.91 (t, J = 7.5 Hz, 1 H), 2.71 (t, J = 7.7 Hz, 2 H), 2. 39 (m, 2 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 180.3, 141.8, 141.3, 141.2, 136.1, 128.8, 128.7, 127.4, 127.4, 127.2, 126.4, 124.9, 122. 4, 122.3, 119.8, 119.3, 112.9, 111.3, 42.2, 33.8, 33.7; neat): 3420, 1699, 1456, 1216, 1097 cm- ¹ ; EI-MS: m / z
355 [M] ⁺ .

[Synthesis of Compound # 23]
α- (2-Phenyl-1-ethyl) -1-methoxycarbonyl-3-indoleacetic acid methyl ester

In a nitrogen atmosphere, 1-methoxycarbonyl-3-indoleacetic acid methyl ester (300 mg, 1.213 mmol) and hexamethylphosphoric acid triamide (HMPA, 1.09 g, 6.067 mmol) were dissolved in tetrahydrofuran (2 ml), Cooled to A 1.5 M cyclohexane solution (1.21 ml, 1.5 eq) of lithium diisopropylamide (LDA) was slowly added dropwise to this, and the mixture was stirred at -78 ° C for 0.5 hour. A solution of 1-bromo-2-phenylethane (292 mg, 1.577 mmol) in tetrahydrofuran (2 ml) was slowly added dropwise to this reaction solution, and the mixture was stirred at -78 ° C for 1 hour. After confirming the completion of the reaction by TLC, the temperature was adjusted to 0 ° C., water (10 ml) was added, the reaction was quenched, and extracted three times with ethyl acetate (10 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (benzene) to obtain α- (2-phenyl-1-ethyl) -1-methoxycarbonyl-3-indoleacetic acid methyl ester. (228 mg, 54% yield): ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.18 (d, J = 6.0 Hz, 1 H), 7.57 (s, 1 H), 7.55 (d, J = 8.0 Hz, 1 H), 7.31 (t, J = 7.8 Hz, 1 H), 7.13-7.26 (m, 6 H), 3.94 (s, 3 H), 3.83 ( t, J = 7.5 Hz, 1 H), 3.64 (s, 3 H), 2. 66 (t, J = 7.8 Hz, 2 H), 2. 35 (m, 2 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 173.8, 151.2, 140.9, 135.4, 129.3, 128.4, 128.3, 126.0, 124.8, 123.1, 122.9, 119 .3, 119.0, 115. 2, 53.7, 52.0, 41.8, 33.5; EI-MS: m / z 351 [ ] ^+.

α- (2-phenyl-1-ethyl) -3-indole acetic acid (compound # 23)

α- (2-phenyl-1-ethyl) -1-methoxycarbonyl-3-indoleacetic acid methyl ester (150 mg, 0.427 mmol) is dissolved in methanol (2 ml), and 2N aqueous sodium hydroxide solution (0.5 ml) there Was added and stirred at 70 ° C. for 1.5 hours. After completion of the reaction was confirmed by TLC, 6 N hydrochloric acid was added to acidify (pH = 3 to 4), and the solvent was evaporated under reduced pressure. Water (5 ml) was added and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 95: 5) to obtain α- (2-phenyl-1-ethyl) -3-indoleacetic acid (compound # 23). (85.3 mg, yield 72%): ¹ H NMR (400 MHz, acetone-d ₆ ): δ 10.16 (s, 1 H), 7.67 (d, J = 8.0 Hz, 1 H), 7. 40 (d, J = 8.1 Hz, 1 H), 7.09-7.32 (m, 7 H), 7.03 (t, J = 7.6 Hz, 1 H), 3.93 (t, J = 7) .4 Hz, 1 H), 2.67 (t, J = 5.4 Hz, 2 H), 2. 35 (m, 2 H); ¹³ C NMR (100 MHz, acetone-d ₆ ): δ 175.4, 142.4 , 137.2, 128.8, 128.7, 127.2, 126.2, 123.2, 121.8, 119.4, 119.2, 113.6, 111.8, 42.5, 34 .9, 34.1; IR (neat): 3416, 1700, 1457, 1246, 1098 cm- ¹ ; FA B-MS: m / z 280 [M + H] ⁺ .

[Synthesis of Compound # 24]
2-Cyclopentyl-1-iodoethane

Dissolve triphenylphosphine (1.03 g, 3.942 mmol) and imidazole (0.27 g, 3.937 mmol) in dichloromethane (5 ml) and stir for 5 minutes, then add iodine (1.0 g, 3.940 mmol), Stir for 10 minutes. Thereto was added dropwise a solution of 2-cyclopentyl-1-ethanol (0.3 g, 2.627 mmol) in dichloromethane (1 ml) and stirred at room temperature for 2 hours. After confirming the completion of the reaction by TLC, the reaction solution was filtered through Celite, and 5% aqueous sodium thiosulfate solution was added to the filtrate to remove iodine. The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane) to obtain 2-cyclopentyl-1-iodoethane. (0.46 g, 84% yield)

1-Methoxycarbonyl-3-indoleacetic acid methyl ester

Indole 3-acetic acid methyl ester (2.00 g, 10.57 mmol) is dissolved in 30 ml of dichloromethane and tetrabutyl ammonium iodide (30.0 mg, 0.1%) is dissolved therein.
081 mmol), 24 ml of a 30% aqueous solution of sodium hydroxide were added, and the mixture was cooled to 0 ° C. Methyl chloroformate (1.96 g, 20.73 mmol) was added to the reaction solution, and the mixture was stirred at 0 ° C. for 2 hours. After confirming the completion of the reaction by TLC, 6N hydrochloric acid was added to quench the reaction. 50 ml of water was added, extraction was performed three times with 50 ml of chloroform, and the organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 2) to obtain 1-methoxycarbonyl-3-indoleacetic acid methyl ester. (2.26 g, yield 87%): ¹ H NMR (400 M
Hz, CDCl ₃ ): d 8.18 (d, J = 7.0 Hz, 1 H), 7.59 (s, 1 H), 7.53 (d, J = 7.7 Hz, 1 H), 7.53 (d t, J = 7.5 Hz, 1 H), 7.27 (t, J = 7.4 Hz, 1 H), 4.00 (s, 3 H), 3.72 (s, 3 H), 3.71 (s, 2 H); ¹³ C-NMR (100 MHz, CDCl ₃ ): d 171.1, 151.1, 135.2, 129.9, 124.6, 123.8, 122.8, 118.9, 115. 0, 113.8, 53.5, 51.9, 30.6; EI-MS: m / z 247 [M] ⁺

α- (2-Cyclopentyl-1-ethyl) -1-methoxycarbonyl-3-indoleacetic acid methyl ester

Under a nitrogen atmosphere, 1-methoxycarbonyl-3-indoleacetic acid methyl ester (150 mg, 0.607 mmol) and hexamethylphosphoric acid triamide (544 mg, 3.036 mmol) were dissolved in 2 ml of anhydrous tetrahydrofuran and cooled to -78 ° C. Lithium diisopropylamide (1.5 M cyclohexane solution, 0.61 ml, 1.5 eq) was slowly added dropwise thereto, and the mixture was stirred at -78 ° C for 0.5 hour. A 1 ml solution of 2-cyclopentyl-1-iodoethane (204 mg, 0.910 mmol) in anhydrous tetrahydrofuran was slowly added dropwise to this reaction solution, and the mixture was stirred at -78 ° C for 1 hour. After confirming the completion of the reaction by TLC, the temperature was adjusted to 0 ° C., 5 ml of water was added to quench the reaction, and extraction was performed 3 times with 5 ml of ethyl acetate. The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5) to give α- (2-cyclopentyl-1-ethyl) -1-methoxycarbonyl-3-indoleacetic acid methyl ester Obtained. (151 mg, yield 72%): ¹ H NMR
(400 MHz, CDCl3): d 8.18 (d, J = 6.8 Hz, 1 H), 7.62 (d, J = 7.7 Hz, 1 H), 7.56 (s, 1 H), 7.34 (T, J = 7.4 Hz, 1 H), 7. 26 (t, J = 7.3 Hz, 1 H), 4.02 (s, 3 H), 3. 79 (t, J = 7.6 Hz, 1 H) ,
3.68 (s, 3H), 2.03 (m, 2H), 1.73-1.77
(M, 3H), 1.48-1.58 (m, 4H), 1.34 (q, J = 7.2 Hz, 2H), 1.04-1.07 (m, 2H); 13C-NMR (100 MHz, CDCl3): d 174.2, 151.3, 135.5, 129.5, 124.7, 122.9, 119.5, 119.3, 115.2, 53.7, 52. 0, 42.8, 39.9, 34.1, 32.6, 32.5, 31.4, 25.1; EI-MS: m / z 343 [M] ⁺

α- (2-Cyclopentyl-1-ethyl) -1-methoxycarbonyl-3-indoleacetic acid methyl ester (compound # 24)

α- (2-Cyclopentyl-1-ethyl) -1-methoxycarbonyl-3-indoleacetic acid methyl ester (100 mg, 0.291 mmol) is dissolved in methanol (2 ml) and 2N aqueous solution of sodium hydroxide (0.5 ml) Was added and stirred at 70 ° C. for 2.5 hours. After confirming the completion of the reaction by TLC, 6 N hydrochloric acid was added to make it acidic (pH = 3 to 4), and the solvent was evaporated under reduced pressure. Water (5 ml) was added and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by silica gel column chromatography (chloroform: methanol = 95: 5) to obtain α- (2-cyclopentyl-1-ethyl) -1-methoxycarbonyl-3-indoleacetic acid methyl ester (compound # 24) got. (78.5 mg, yield 99%): ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.19 (s, 1 H), 7.69 (d, J = 7.9 Hz, 1 H), 7.29 ( d, J = 8.0 Hz, 1 H), 7.16 (t, J = 8.0 Hz, 1 H), 7. 10 (t, J = 7.5 Hz, 1 H), 7.06 (s, 1 H), 3.83 (t, J = 7.6 Hz, 1 H), 2.01 (m, 2 H), 1. 70 -1. 75 (m, 3 H), 1. 45-1.5 5 (m, 4 H), 1.34-1.37 (m, 2H), 0.98-1.03 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 180.7, 136.1, 126.5, 122 .2, 122.0, 119.5, 119.2, 113.4, 111.2, 43.1, 39.9, 34.1, 32.5, 31.6, 2 5.1; IR (neat): 3415, 1703, 1457, 1339, 1098 cm ⁻¹ ; FAB-MS: m / z 294 [M + Na] ⁺ .

[Synthesis of Compound # 25]
Cyclopentyl iodomethane

Dissolve triphenylphosphine (1.18 g, 4.491 mmol), imidazole (0.31 g, 4.495 mmol) in dichloromethane (5 ml) and stir for 5 minutes, then add iodine (1.14 g, 4.492 mmol), Stir for 10 minutes. A solution of cyclopentylmethanol (0.3 g, 2.995 mmol) in dichloromethane (1 ml) was added dropwise thereto, and the mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction by TLC, the reaction solution was filtered through Celite, and 5% aqueous sodium thiosulfate solution was added to the filtrate to remove iodine. The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane) to obtain cyclopentyliodomethane. (0.53 g, 84% yield)

α-Cyclopentylmethyl-1-methoxycarbonyl-3-indoleacetic acid methyl ester

In a nitrogen atmosphere, 1-methoxycarbonyl-3-indoleacetic acid methyl ester (150 mg, 0.607 mmol) and hexamethylphosphoric acid triamide (HMPA, 544 mg, 3.036 mmol) are dissolved in tetrahydrofuran (2 ml) and cooled to -78 ° C. did. A 1.5 M solution of lithium diisopropylamide (LDA) in cyclohexane (0.61 ml, 1.5 eq) was slowly added dropwise thereto, and the mixture was stirred at -78 ° C for 0.5 hours. A solution of cyclopentyliodomethane (153 mg, 0.728 mmol) in tetrahydrofuran (1 ml) was slowly added dropwise to this reaction solution, and the mixture was stirred at -78 ° C for 1 hour. After confirming the completion of the reaction by TLC, the temperature was adjusted to 0 ° C., water (5 ml) was added, the reaction was quenched, and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 13: 1) to obtain α-cyclopentylmethyl-1-methoxycarbonyl-3-indoleacetic acid methyl ester. (153 mg, yield 76%): ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.18 (d, J = 6.0 Hz, 1 H), 7.63 (d, J = 7.8 Hz, 1 H), 7.57 (s, 1 H), 7.32 (t, J = 7.4 Hz, 1 H), 7. 25 (t, J = 7.4 Hz, 1 H), 3.99 (s, 3 H), 3. 88 (t, J = 7.7 Hz, 1 H), 3.67 (s, 3 H), 2.05 (m, 2 H), 1.76 to 1.79 (m, 3 H), 1.59-1. 62 (m, 2H), 1.47-1.50 (m, 2H), 1.12-1.17 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 174.1, 151. 1, 135.4, 129.4, 124.6, 122.8, 119.4, 119.2, 115.1, 53.6, 51.9, 41.7, 3 8.5, 37.9, 32.5, 32.3, 24.9; EI-MS: m / z 329 [M] ⁺ .

α-Cyclopentylmethyl-3-indoleacetic acid (compound # 25)

α-Cyclopentylmethyl-1-methoxycarbonyl-3-indoleacetic acid methyl ester (100 mg, 0.304 mmol) is dissolved in methanol (2 ml), 2N aqueous sodium hydroxide solution (0.5 ml) is added thereto, and Stir for .5 hours. After confirming the completion of the reaction by TLC, 6 N hydrochloric acid was added to make it acidic (pH = 3 to 4), and the solvent was evaporated under reduced pressure. Water (5 ml) was added and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 95: 5) to obtain α-cyclopentylmethyl-3-indoleacetic acid (compound # 25). (58.3 mg, yield 75%); ¹ H NMR (400 MHz, acetone-d ₆ ): δ 10.13 (s, 1 H), 7.70 (d, J = 7.8 Hz, 1 H), 7. 38 (d, J = 8.1 Hz, 1 H), 7. 28 (s, 1 H), 7. 10 (t, J = 8.0 Hz, 1 H), 7.02 (t, J = 7.1 Hz, 1 H ), 3.73 (t, J = 7.7 Hz, 1 H), 2.06 (m, 2 H), 1.78 to 1.83 (m, 3 H), 1.47 to 1.61 (m, 4 H) ), 1.17-1.20 (m, 2H); ¹³ C NMR (100 MHz, acetone-d ₆ ): δ 175.8, 137.3, 127.4, 123.1, 121.8, 119. 5, 119.2, 114.1, 111.9, 42.4, 39.6, 38.7, 32.9, 32.9, 25.3, 25.3; IR (Neat): 3418, 1699, 1456, 1339, 1097 cm-1; FAB-MS: m / z 258 [M + H] ⁺ .

Compound # 26-31 is a compound of Muro Fumihito et. Al. “Discovery of trans-4- [1-[[2,5-Dichloro-4- (1-methyl-3-indolylcarboxamido) phenyl] acetyl]-(4S) -methoxy- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic Acid: An Orally Active, Selective Very Late Antigen-4 Antagonist ”Journal of Medicinal Chemistry, 52 (24), 7974-7992; 2009.
It synthesize | combined according to the method as described in.

[Synthesis of Compound # 26]
N-Methyl-3-indoleacetic acid methyl ester

3-Indolacetic acid methyl ester (200 mg, 1.1 mmol) was dissolved in N, N-dimethylformamide (3 mL) and sodium hydride (60 mg) was added. To this solution, methyl iodide (223 mg, 1.58 mmol) was added and stirred at room temperature for 6 hours. After completion of the reaction was confirmed by TLC, 6 N hydrochloric acid was added to acidify (pH = 3 to 4), water (5 ml) was added, and the mixture was extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain N-methyl-3-indole acetic acid methyl ester. (140 mg, yield 65%); ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.60 (d, J = 7.9 Hz, 1 H), 7.29 (d, J = 8.2 Hz, 1 H), 7.23 (dd, J = 8.2, 7.9 Hz, 1 H), 7.12 (dd, J = 8.2, 7.9 Hz, 1 H), 7.03 (s, 1 H), 3.75 (S, 3 H), 3.77 (s, 2 H), 3.69 (s, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 172.6, 136.9, 127.7, 121.7 (2C), 119.26, 118.9, 109.3, 106.8, 51.9, 32.7, 31.0.

N-methyl-3-indoleacetic acid (compound # 26)

N-Methyl-3-indoleacetic acid methyl ester (120 mg, 0.59 mmol)
Was dissolved in tetrahydrofuran (0.5 ml), methanol (0.5 ml) and 2N aqueous sodium hydroxide solution (0.25 ml) were added thereto, and the mixture was stirred at 50 ° C. for 3 hours. After confirming the completion of the reaction by TLC, 6 N hydrochloric acid was added to make it acidic (pH = 3 to 4), and the solvent was evaporated under reduced pressure. Water (5 ml) was added and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain N-methyl-3-indoleacetic acid (compound # 26). (108 mg, yield 96%); ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.59 (d, J = 8.0 Hz, 1 H), 7.35
(D, J = 8.1 Hz, 1 H), 7.18 (s, 1 H), 7.16 (dd, J = 7.0, 6.1 Hz, 1 H), 7.04 (dd, J = 8. 1, 6.7 Hz, 1 H), 3.79 (s, 3 H), 3.73 (s, 2 H). ¹³ C NMR (100 MHz, CDCl ₃ ): δ 177.6, 136.8, 127.9, 127.5, 121.8, 119.2, 118.9, 109.5, 106.1, 53.7 , 31.7.

[Synthesis of Compound # 27]
N-Ethyl-3-indoleacetic acid methyl ester

3-indole acetic acid methyl ester (200 mg, 1.1 mmol) was dissolved in N, N-dimethylformamide (3 mL) and sodium hydride (60 mg) was added. To this solution was added ethyl iodide (246 mg, 1.58 mmol) and stirred at room temperature for 6 hours. After completion of the reaction was confirmed by TLC, 6 N hydrochloric acid was added to acidify (pH = 3 to 4), water (5 ml) was added, and the mixture was extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain N-ethyl-3-indole acetic acid methyl ester. (133 mg, yield 58%); ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.60 (d, J = 7.8 Hz, 1 H), 7.31 (d, J = 8.3 Hz, 1 H), 7.21 (dd, J = 8.3, 7.8 Hz, 1 H), 7.11 (dd, J = 8.3, 7.8 Hz, 1 H), 7.09 (s, 1 H), 4.11 (Q, J = 7.3 Hz, 2 H), 3.76 (s, 2 H), 3.68 (s, 3 H), 1.43 (t, J = 7.3, 3 H); ¹³ C NMR (100 MHz) , CDCl ₃ ): δ 172.6, 160.8, 135.9, 127.8, 125.9, 121.6, 119.0, 109.3, 51.9, 40.8, 31.1, 15.4.

N-ethyl-3-indole acetic acid (compound # 27)

N-methyl-3-indoleacetic acid methyl ester (120 mg, 0.59 mmol) is dissolved in tetrahydrofuran (0.5 ml), to which methanol (0.5 ml) and 2N aqueous sodium hydroxide solution (0.25 ml) are added, Stir at 50 ° C. for 3 hours. After confirming the completion of the reaction by TLC, 6 N hydrochloric acid was added to make it acidic (pH = 3 to 4), and the solvent was evaporated under reduced pressure. Water (5 ml) was added and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain N-methyl-3-indoleacetic acid (compound # 27). (108 mg, yield 97%); ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.60 (d, J = 7.9 Hz, 1 H), 7.40
(D, J = 8.2 Hz, 1 H), 7. 25 (s, 1 H), 7. 15 (ddd, J = 7.5, 7.6 Hz, 1 H), 7.04 (ddd, J = 7. 3, 7.5 Hz, 1 H), 4. 20 (q, J = 7.3 Hz, 2 H), 3. 74 (s, 2 H), 1. 39 (t, J = 7.3 Hz, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 173.3, 136.8, 129.0, 127.1, 122.0, 119.8, 119.4, 110.1, 108. 1, 41.1, 31 .9, 15.8.

[Synthesis of Compound # 28]
N-Propyl-3-indoleacetic acid methyl ester

3-Indolacetic acid methyl ester (200 mg, 1.1 mmol) was dissolved in N, N-dimethylformamide (3 mL) and sodium hydride (60 mg) was added. To this solution, propyl iodide (268 mg, 1.58 mmol) was added and stirred at room temperature for 6 hours. After completion of the reaction was confirmed by TLC, 6 N hydrochloric acid was added to acidify (pH = 3 to 4), water (5 ml) was added, and the mixture was extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to obtain N-propyl-3-indoleacetic acid methyl ester. (136 mg, yield 56%); ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.60 (d, J = 7.8 Hz, 1 H) 7.31 (d, J = 8.3 Hz, 1 H) 7. 21 (dd, J = 8.0, 7.1 Hz, 1 H) 7.11 (dd, J = 7.7, 6.9 Hz, 1 H) 7.08 (s, 1 H) 4.04 (t, J = 7.1 Hz, 2H) 3.77 (s, 2 H) 3.69 (s, 3 H) 1.86 (m, 2 H) 0.93 (t, J = 7.3 Hz, 3 H); ¹³ C NMR (100 MHz) , CDCl ₃ ): δ 172.6, 136.2, 127.70, 126.7, 121.5, 119.0, 119.0, 109.4, 106.6, 51.9, 47.9, 31.1, 23.5, 11.5.

N-Propyl-3-indoleacetic acid (compound # 28)

N-Propyl-3-indoleacetic acid methyl ester (120 mg, 0.52 mmol
) Was dissolved in tetrahydrofuran (0.5 ml), methanol (0.5 ml) and 2N aqueous sodium hydroxide solution (0.25 ml) were added thereto, and stirred at 50 ° C. for 3 hours. After confirming the completion of the reaction by TLC, 6 N hydrochloric acid was added to make it acidic (pH = 3 to 4), and the solvent was evaporated under reduced pressure. Water (5 ml) was added and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain N-propyl-3-indoleacetic acid (compound # 28). (103 mg, yield 98%); ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.60 (d, J = 8.0 Hz, 1 H), 7.
32 (d, J = 8.2 Hz, 1 H), 7.21 (dd, J = 7.2, 8.0 Hz, 1 H), 7.11 (dd, J = 7.3, 9.8 Hz, 1 H) , 7.09 (s, 1 H), 4.04 (
t, J = 7.1, 2H), 3.79 (s, 2H), 1.85 (m, 2H), 0.92 (t
, J = 7.4 Hz, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 177
. 5, 136.2, 127.6, 127.0, 121.6, 119.1, 119.0, 109.5, 106.0, 53.7, 31.7, 23.5, 11.5.

[Synthesis of Compound # 29]
N-Butyl-3-indoleacetic acid methyl ester

3-Indolacetic acid methyl ester (200 mg, 1.1 mmol) was dissolved in N, N-dimethylformamide (3 mL) and sodium hydride (60 mg) was added. To this solution was added butyl iodide (290 mg, 1.58 mmol) and stirred at room temperature for 6 hours. After completion of the reaction was confirmed by TLC, 6 N hydrochloric acid was added to acidify (pH = 3 to 4), water (5 ml) was added, and the mixture was extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to obtain N-butyl-3-indole acetic acid methyl ester. (137 mg, yield 53%); ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.60 (d, J = 7.8 Hz, 1 H), 7.32 (d, J = 8.2 Hz, 1 H), 7.21 (dd, J = 8.5, 9.8 Hz, 1 H), 7.11 (dd, J = 9.7, 7.4 Hz, 1 H), 7.08 (s, 1 H), 4.08 (T, J = 7.1 Hz, 2H), 3.77 (s, 2H), 3.69 (s, 3H), 1.80 (m, 2H), 1.34 (m, 2H), 0. 93 (t, J = 7.4 Hz, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 172.6, 136.2, 127.7, 126.7, 121.5, 119.0, 119. 0, 109.4, 106.7, 51.9, 46.0, 32.3, 31.1, 20.2, 13.7.

N-butyl-3-indoleacetic acid (compound # 29)

N-Butyl-3-indoleacetic acid methyl ester (120 mg, 0.52 mmol)
Was dissolved in tetrahydrofuran (0.5 ml), methanol (0.5 ml) and 2N aqueous sodium hydroxide solution (0.25 ml) were added thereto, and the mixture was stirred at 50 ° C. for 3 hours. After confirming the completion of the reaction by TLC, 6 N hydrochloric acid was added to make it acidic (pH = 3 to 4), and the solvent was evaporated under reduced pressure. Water (5 ml) was added and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain N-butyl-3-indoleacetic acid (compound # 29). (104 mg, yield 98%); ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.59 (d, J = 7.9 Hz, 1 H), 7.31
(D, J = 8.2 Hz, 1 H), 7. 20 (dd, J = 7.1, 7.9 Hz, 1 H), 7.1 1 (dd, J = 7.3, 7.5 Hz, 1 H), 7.07 (s, 1 H), 4.06 (t, J = 7.2 Hz, 2 H), 3.78 (s, 2 H), 1.79 (m, 2 H), 1.33 (m, 2 H) , 0.92 (t, J = 7.4, ₃ H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 178.0, 136.1, 127.6, 126.9, 121.6119. 10, 119 ., 109.5, 106.0, 53.6, 31.7, 29.1, 20.2, 13.7.

[Synthesis of Compound # 30]
N-Hexyl-3-indoleacetic acid methyl ester

3-Indolacetic acid methyl ester (200 mg, 1.1 mmol) was dissolved in N, N-dimethylformamide (3 mL) and sodium hydride (60 mg) was added. To this solution, hexyl iodide (334 mg, 1.58 mmol) was added and stirred at room temperature for 6 hours. After completion of the reaction was confirmed by TLC, 6 N hydrochloric acid was added to acidify (pH = 3 to 4), water (5 ml) was added, and the mixture was extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to obtain N-hexyl-3-indoleacetic acid methyl ester. (147 mg, yield 51%); ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.60 (d, J = 7.8 Hz, 1 H) 7.31, (d, J = 8.2 Hz, 1 H), 7.20 (ddd, J = 8.6, 5.6 Hz, 1 H), 7.11 (ddd, J = 8.0, 7.3 Hz, 1 H), 7.08 (s, 2 H), 4.06 (T, J = 7.2 Hz, 2 H), 3.77 (s, 2 H), 3.69 (s, 3 H), 1.81 (m, 2 H), 1. 30 (m, 6 H), 0. 87 (t, J = 6.9 Hz, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 172.6, 136.1, 127.7, 126.7, 121.5, 119.0, 119. 0, 109.4, 106.6, 51.9, 46.3, 31.4, 31.1, 30.2, 22.6, 22.5, 14.0.

N-Hexyl-3-indoleacetic acid (compound # 30)

N-Hexyl-3-indoleacetic acid methyl ester (120 mg, 0.52 mmol
) Was dissolved in tetrahydrofuran (0.5 ml), methanol (0.5 ml) and 2N aqueous sodium hydroxide solution (0.25 ml) were added thereto, and stirred at 50 ° C. for 3 hours. After confirming the completion of the reaction by TLC, 6 N hydrochloric acid was added to make it acidic (pH = 3 to 4), and the solvent was evaporated under reduced pressure. Water (5 ml) was added and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain N-hexyl-3-indoleacetic acid (compound # 30). (103 mg, yield 96%); ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.59 (d, J = 7.9 Hz, 1 H), 7.
31 (d, J = 8.2 Hz, 1 H), 7. 20 (ddd, J = 7.9, 7.3 Hz, 1 H), 7. 20 (ddd, J = 7.4, 7.7 Hz, 1 H) , 7.07 (1 H, s, 1 H), 4.05 (t, J = 7.2 Hz, 2 H), 3.78 (s, 2 H), 1.81 (m, 2 H), 1.31 (m , 6H), 0.88 (t, J = 6.3 Hz, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 178.0, 136.1, 127.6, 127.6, 121.6, 119.1, 119.0, 109.5, 106.0, 53.7, 31.7, 29.2, 28.9, 27.0, 23.0, 14.02.

[Synthesis of Compound # 31]
N-Heptyl-3-indoleacetic acid methyl ester

3-Indolacetic acid methyl ester (200 mg, 1.1 mmol) was dissolved in N, N-dimethylformamide (3 mL) and sodium hydride (60 mg) was added. To this solution, heptyl iodide (358 mg, 1.58 mmol) was added and stirred at room temperature for 6 hours. After completion of the reaction was confirmed by TLC, 6 N hydrochloric acid was added to acidify (pH = 3 to 4), water (5 ml) was added, and the mixture was extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to obtain N-heptyl-3-indoleacetic acid methyl ester. (148 mg, yield 49%); ¹ H NMR (400 MHz, CDCl ₃ ): δ 3.69 (3 H, s), 7. 60 (1 H, d, J = 7.8), 7.31 (1 H, 1 H, d, J = 8.2) 7.11 (1 H, dd, J = 8.2, 6.7), 7.08 (1 H, s), 4.06 (2 H, t, J = 7.1) , 3.77 (2H, s) 3.59 (1 H, dd, J = 8.2, 6.7), 1.82 (2 H, m), 1.29 (8 H, m), 0.87 ( 3H, t, J = 7.1). ¹³ C NMR (100 MHz, CDCl ₃ ): δ 172.57, 136.16, 127.70, 126.66, 121.54, 118.98, 118.98, 109.43, 106.64, 51. 89, 46.31, 31.67, 31.11, 30.24, 28.89, 26.96, 22.55, 14.02.

N-Heptyl-3-indoleacetic acid (compound # 31)

N-Heptyl-3-indoleacetic acid methyl ester (120 mg, 0.52 mmol
) Was dissolved in tetrahydrofuran (0.5 ml), methanol (0.5 ml) and 2N aqueous sodium hydroxide solution (0.25 ml) were added thereto, and stirred at 50 ° C. for 3 hours. After confirming the completion of the reaction by TLC, 6 N hydrochloric acid was added to make it acidic (pH = 3 to 4), and the solvent was evaporated under reduced pressure. Water (5 ml) was added and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain N-heptyl-3-indoleacetic acid (compound # 31). (180 mg, yield 95%); ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.59 (1 H, d, J = 7.96), 7.31 (1 H, d, J = 8.17), 7.21 (1H, ddd, J = 8.49, 6.73), 7.11 (1 H, ddd, J = 7.21, 7.29), 7.08 (1 H, S), 4.06 (2H, t, J = 7. 25), 3. 79 (2 H, s) 1.81 (2 H, m) 1. 29 (8 H, m) 0.87 (3 H, t, J = 6.83) ¹³ C NMR (100 MHz, CDCl ₃ ): δ 177.81, 136.10, 127.55, 126.85, 121.62, 119.11, 118.94, 109.49, 105.91, 53. 63, 46, 32, 30.99, 29. 68, 29. 16, 26. 64, 22. 49, 13.99.

  Compounds # 33 and # 34 were synthesized using α- (7-hydroxy-1-naphthalenyl) -acetic acid ethyl ester as a key intermediate. α- (7-hydroxy-1-naphthalenyl) -acetic acid ethyl ester is disclosed in E. Tsuda et. al., “Alkoxy-auxins are selective inhibitors of auxin transport mediated by PIN, ABCB, and AUX1 transporters” Journal of Biological Chemistry, 286 (3), 2354-2364; synthesized according to the method described in 2011.

[Synthesis of Compound # 33]
α- (7-Butoxy-1-naphthalenyl) -acetic acid ethyl ester

α- (7-hydroxy-1-naphthalenyl) -acetic acid ethyl ester (90 mg, 0.39 mmol) is dissolved in N, N-dimethylformamide (5 ml) and 1-iodobutane (107 mg, 0.58 mmol) is added to this solution. Was added dropwise, cesium carbonate (127 mg, 0.39 mmol) was added, and the mixture was stirred at room temperature for 6 hours. After confirming the completion of the reaction by TLC, water (5 ml) was added to the reaction solution, and extracted three times with ethyl acetate (10 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3) to obtain α- (7-butoxy-1-naphthalenyl) -acetic acid ethyl ester as a colorless oil. (92 mg, yield 83%); ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.71 (d, J = 8.9 Hz, 1 H), 7. 35 (d, J = 6.9 Hz, 1 H), 7.67 (d, J = 8.1 Hz, 1 H), 7. 27 (d, J = 2.3 Hz, 1 H), 7. 25 (dd, J = 8.1, 6.9 Hz, 1 H), 7 .14 (q, J = 8.9, 2.3 Hz, 1 H), 4.12 (q, J = 7.1 Hz, 2 H), 4.07 (t, J = 6.6 Hz, 2 H), 3. 97 (s, 2H), 1.82 (m, 2H), 1.53 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H), 0.96 (t, J = 7. ^{5Hz, 3H); 13 C NMR} (100MHz, CDCl 3): δ 171.5,157.4,133.2,130.0,129.3,129.1,128.3 127.6, 123.0, 118.5, 103.2, 67.6, 60.8, 39.5, 31.2, 19.2, 14.1, 13.8; IR (neat): 2958 , 1733, 1510, 1459, 1210, 1156 cm ⁻¹ ; HREI-MS found m / z 286.1556 [M] ⁺ , calcd for 286. 1569 (C ₁₈ H ₂₂ O ₃ ).

α- (7-Butoxy-1-naphthalenyl) -acetic acid (compound # 33)

Dissolve α- (7-butoxy-1-naphthalenyl) -acetic acid ethyl ester (75 mg, 0.26 mmol) in a mixed solution of tetrahydrofuran: methanol: 2 M aqueous solution of sodium hydroxide = 2: 2: 1 (1.5 ml), room temperature Stir for 1 hour. After confirming the completion of the reaction by TLC, 6 N hydrochloric acid was added to make it acidic (pH = 3 to 4), and the solvent was evaporated under reduced pressure. Water (5 ml) was added and extracted three times with ethyl acetate (10 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 9: 1) to obtain α- (7-butoxy-1-naphthalenyl) -acetic acid (compound # 33). (67 mg, yield 98%): mp 102-104 ° C .; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.75 (d, J = 8.9 Hz, 1 H), 7.71 (d, J = 8 .1 Hz, 1 H), 7.34 (d, J = 6.9 Hz, 1 H), 7.26 (dd, J = 8.1, 6.9 Hz, 1 H), 7.23 (d, J = 2. 0 Hz, 1 H), 7.16 (q, J = 8.9, 2.0 Hz, 1 H), 4.05 (t, J = 6.5 Hz, 2 H), 4.00 (s, 2 H), 1. 51 (m, 2 H), 1. 80 (m, 2 H), 0.98 (t, J = 7.4 Hz, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 177.6, 157.6, 133.2, 130.2, 129.1, 128.6, 127.9 (2C), 123.0, 118.7, 103.1, 67.7, IR (neat): 3021, 2931, 1699, 1457, 1138 cm ⁻¹ ; HREI-MS found m / z 258.1268 [M] ⁺ , calcd for _{258.1256 (C 16 H 18 O 3} ).

[Synthesis of Compound # 34]
α- (7-Pentoxy-1-naphthalenyl) -acetic acid ethyl ester

α- (7-hydroxy-1-naphthalenyl) -acetic acid ethyl ester (90 mg, 0.39 mmol) is dissolved in N, N-dimethylformamide (5 ml), and 1-iodopentane (116 mg, 0.58 mmol) is added to this solution. ) Was added dropwise, cesium carbonate (127 mg, 0.39 mmol) was added, and the mixture was stirred at room temperature for 6 hours. After confirming the completion of the reaction by TLC, water (5 ml) was added to the reaction solution, and extracted three times with ethyl acetate (10 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3) to obtain α- (7-pentoxy-1-naphthalenyl) -acetic acid ethyl ester as a colorless oil. (103 mg, yield 88%): ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.00 (t, J = 7.2 Hz, 3 H), 1.26 (t, J = 7.1 Hz, 3 H), 1.48 (m, 2H), 1.55 (m, 2H), 1.91 (m, 2H), 4.03 (s, 2H), 4.13 (t, J = 6.5 Hz, 2H) , 4.19 (q, J = 7.1 Hz, 2 H), 7. 20 (dd, J = 8.9, 2.5 Hz, 1 H), 7.31 (dd, J = 8.1, 7.0 Hz) , 1 H), 7.33 (d, J = 2.5 Hz, 1 H), 7.41 (d, J = 7.0 Hz, 1 H), 7.74 (d, J = 8.1 Hz, 1 H), 7 ^{.78 (d, J = 8.9Hz,} 1H); 13 C NMR (100MHz, CDCl 3): δ 171.5,157.4,133.2,130.0,129.3,12 1, 128.4, 127.6, 123.0, 118.5, 103.2, 67.8, 60.8, 39.6, 28.9, 28.2, 22.4, 14.1 , 14.0; IR (neat): 2969, 1734, 1509, 1459, 1160 cm ⁻¹ ; HREI-MS found m / z 300.1727 [M] ⁺ , calcd for 300.1725 (C ₁₉ H ₂₄ O ₃ ) .

α- (7-Pentoxy-1-naphthalenyl) -acetic acid (compound # 34)

Dissolve α- (7-pentoxy-1-naphthalenyl) -acetic acid ethyl ester (90 mg, 0.30 mmol) in a mixed solution of tetrahydrofuran: methanol: 2 M aqueous solution of sodium hydroxide = 2: 2: 1 (1.5 ml), room temperature Stir for 1 hour. After confirming the completion of the reaction by TLC, 6 N hydrochloric acid was added to make it acidic (pH = 3 to 4), and the solvent was evaporated under reduced pressure. Water (5 ml) was added and extracted three times with ethyl acetate (10 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 6: 1) to obtain α- (7-pentoxy-1-naphthalenyl) -acetic acid (compound # 34). (75 mg, yield 92%): mp 104-106 ° C .; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.71 (d, J = 8.1 Hz, 1 H), 7.39 (d, J = 6) .9 Hz, 1 H), 7.26 (t, J = 8.1, 6.9 Hz, 1 H), 7.21 (d, J = 2.1 Hz, 1 H), 7.15 (dd, J = 8). 9, 2.1 Hz, 1 H), 4.03 (t, J = 6.5 Hz, 2 H), 4.00 (s, 2 H), 3.87 (d, J = 8.9 Hz, 1 H), 1. 82 (m, 2 H), 1. 45 (m, 2 H), 1. 39 (m, 2 H), 0.93 (t, J = 7.1 Hz, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 177.6, 157.6, 133.2, 130.2, 129.1, 128.6, 128.4, 128.0, 123.0, 118. 7, 103.1, 68.0, 39.1, 28.9, 28.2, 22.5, 14.0; IR (neat): 3014, 2945, 1689, 1463, 1169 cm- ¹ ; HREI-MS found m / z 272.1378 [M] ⁺ , calcd for 272.1412 (C ₁₇ H ₂₀ O ₃ ).

  Compounds # 35-37 were synthesized using 5-hydroxy-3-indoleacetic acid methyl ester as a key intermediate.

5-hydroxy-3-indole acetic acid methyl ester

1.00 g of 5-hydroxy-3-indole acetic acid was dissolved in methanol (25 ml), 1.0 ml of acetyl chloride was slowly added dropwise, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction was confirmed by TLC, the reaction was quenched by adding a saturated aqueous sodium bicarbonate solution, the solvent was evaporated under reduced pressure, water (20 ml) was added, and the mixture was extracted three times with ethyl acetate (50 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to obtain 5-hydroxy-3-indoleacetic acid methyl ester. (1.05 g, yield 98%); ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.20 (s, J = 8.7 Hz, 1 H), 7. 13 (d, J = 2.4 Hz, 1 H ) 7.00 (d, J = 2.4 Hz, 1 H), 6.78 (dd, J = 8.8, 2.4 Hz, 1 H), 3.72 (s, 2 H), 3. 70 (s) , 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 172.6, 149.6, 131.4, 127.9, 124.2, 112.1, 111.9, 103.4, 107.8 , 52.0, 31.2; IR (neat): 3411, 3000, 295, 1728, 1459, 1459, 1154 cm- ¹ ; EI-MS m / z [M] ⁺ 205, 146; HREI-MS found m / ^{z 205.0761 [M] +, calcd} f _{r 205.0739 (C 11 H 11 NO} 3).

[Synthesis of Compound # 35]
5- (3,5-Dimethoxybenzyloxy) -3-indoleacetic acid methyl ester

5-hydroxy-3-indoleacetic acid methyl ester (42.9 mg, 0.21 mmol) is dissolved in N, N-dimethylformamide (DMF), in which 3,5-dimethoxybenzyl bromide (82.2 mg, 0.36 mmol) The reaction mixture was added dropwise, tetra-N-butylammonium iodide (83.0 mg, 2.00 mmol) and cesium carbonate (136.37 mg, 0.42 mmol), which were separately stored in separate containers, were added and stirred at room temperature for 1 hour. After completion of the reaction was confirmed by TLC, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted three times with ethyl acetate (50 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to obtain methyl 5- (3,5-dimethoxybenzyloxy) -3-indoleacetic acid. (81.5 mg, yield 94%); ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.17 (d, J = 2.2 Hz, 1 H), 7.12 (d, J = 8.7 Hz, 1 H ), 7.04 (s, 2 H), 6. 92 (dd, J = 8.7, 2.2 Hz, 1 H), 6.64 (d, J = 2. 2, 2 H), 6.41 (t , J = 2.2Hz, 1H), 5.13 (s, 2H), 3.78 (s, 6H), 3.72 (s, 2H), 3.67 (s, 3H); 13 C NMR ( 100 MHz, CDCl ₃ ): δ 172.5, 160.9 (2 C), 153.2, 140.0, 131.4, 124.0, 127.5, 113.0, 111.9, 107.9, 105.2 (2C), 102.2, 99.8, 70.8, 55.3 (2C), 51.9, 31.2; IR (neat): 3 396, 2948, 1734, 1449, 1159 cm ^-1 .

5- (3,5-Dimethoxybenzyloxy) -3-indoleacetic acid (compound # 35)

5- (3,5-Dimethoxybenzyloxy) -3-indoleacetic acid methyl ester (81.5 mg, 0.23 mmol) is dissolved in tetrahydrofuran (0.5 ml) and methanol (0.5 ml) and 2N hydroxylated there Aqueous sodium solution (0.25 ml) was added and stirred at room temperature for 0.5 hours. After confirming the completion of the reaction by TLC, 6 N hydrochloric acid was added to make it acidic (pH = 3 to 4), and the solvent was evaporated under reduced pressure. Water (5 ml) was added and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain 5- (3,5-dimethoxybenzyloxy) -3-indoleacetic acid (Compound # 35). (55.2 mg, yield 100%); melting point 146.1-148.6 ° C .; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.19 (d, J = 8.8 Hz, 1 H), 7.12 (D, J = 2.2 Hz, 1 H), 7.06 (s, 1 H), 6. 92 (dd, J = 8.8, 2.2 Hz, 1 H), 6.68 (d, J = 2. 2 Hz, 2 H), 6.40 (t, J = 2.2 Hz, 1 H), 5.01 (S, 2 H), 3.77 (S, 6 H), 3.73 (s, 2 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 177.5, 160.8 (2 C), 153.3, 140.0, 131.4, 127.5, 124.1, 113.1, 112.0, 107.4 , 105.3 (2C), 102.2, 99.9, 70.9, 55.3 (2C), 31.1; IR (neat) : 3406, 2957, 2926, 1702, 1458, 1155 cm- ¹

[Synthesis of Compound # 36]
5-methoxy-3-indoleacetic acid methyl ester

5-hydroxy-3-indoleacetic acid methyl ester (99.3 mg, 0.48 mmol) is dissolved in N, N-dimethylformamide (2 ml), to which iodomethane (206.2 mg, 1.45 mmol) is added dropwise, and the mixture is separated. To the mixture was added potassium carbonate (200.8 mg, 1.45 mmol), and the mixture was stirred at room temperature overnight, and then stirred at 80 ° C. for 4 hours. After completion of the reaction was confirmed by TLC, 20 ml of 10% aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (50 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3) to obtain 5-methoxy-3-indoleacetic acid methyl ester (58.6 mg, yield 55.2%) ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.22 (1 H, d. J = 8.8), 7.1 1 (d, J = 2.3 Hz, 1 H), 7.05 (d, J) = 1.3 Hz, 1 H), 6.93 (dd, J = 8.8, 2.3 Hz, 1 H), 3.70 (s, 3 H), 3.85 (s, 3 H), 3.74 (s) , 2H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 172.5, 154.2, 131.2, 127.6, 123.8, 112.5, 111.9, 108.1, 100.6 , 55.9, 51.9, 31.2; IR (neat): 3403, ^{951,1729,1486,1213,1154cm -1; EI-MS m /} z [M] + 219,160; HREI-MS found m / z 219.0886 [M] +, calcd for 219.0895 (C 12 H ₁₃ NO ₃ ).

5-methoxy-3-indole acetic acid (compound # 36)

[Synthesis of Compound # 36]
5-Methoxy-3-indole acetic acid methyl ester (60.0 mg, 0.27 mmol) was dissolved in methanol (2 ml), lithium hydroxide (19.7 mg, 0.82 mmol) was added and stirred at room temperature for 3 hours. After confirming the completion of the reaction by TLC, 6 N hydrochloric acid was added to make it acidic (pH = 3 to 4), and the solvent was evaporated under reduced pressure. Water (5 ml) was added and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 9: 1) to obtain 5-methoxy-3-indoleacetic acid (compound # 36). (15.3 mg, yield 27.2%); melting point 147.0-149.8 ° C .; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.28 (d, J = 8.8 Hz, 1 H), 7 .26 (s, 1 H), 7.11 (d, J = 2.3 Hz, 1 H), 6.77 (dd, J = 8.8, 2.3 Hz, 1 H), 3.80 (s, 3 H) , 3.71 (s, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 173.3, 154.8, 132.6, 128.9, 125.2, 112.7, 112.4, 108 IR (neat): 3359, 2996, 2851, 1705, 1456, 1137 cm ⁻¹ ; EI-MS m / z [M] ⁺ 205 (75%), 160; HREI-MS found m / z 205.0737 [M _{^{+, Calcd for 205.0739 (C 11}} H 11 NO 3).

[Synthesis of Compound # 37]
5-ethoxy-3-indole acetic acid methyl ester

5-hydroxy-3-indoleacetic acid methyl ester (109.0 mg, 0.53 mmol) is dissolved in N, N-dimethylformamide (2 ml), to which iodoethane (248.74 mg, 1.60 mmol) is added dropwise, and another container is added. To the mixture were added potassium carbonate (220.5 mg, 1.60 mmol), stirred at room temperature for 2 hours, and stirred at 80 ° C. for 4 hours. After completion of the reaction was confirmed by TLC, 20 ml of 10% aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (50 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3) to obtain 5-ethoxy-3-indoleacetic acid methyl ester. (100.7 mg, yield 81.2%); ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.86 (q, J = 7.0 Hz, 2 H), 7.23 (d, J = 8.8 Hz) , 1 H), 7.05 (d, J = 2.3 Hz, 1 H), 7.12 (d, J = 2.0 Hz, 1 H), 6.87 (dd, J = 8.8, 2.3 Hz, 1 H), 3.75 (s, 2 H), 3. 70 (s, 3 H), 1. 45 (t, J = 7.0 Hz, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 172.5 , 153.4, 131.2, 127.6, 123.7, 113.0, 111.8, 108.1, 101.8, 64.2, 52.0, 31.2, 15.0; IR (Neat): 3404, 2978, 1729, 1474, 1211, 1154 cm- ¹ ; HREI-MS fou ^{nd m / z 233.1034 [M]} +, calcd for 233.1052 (C 13 H 15 NO 3).

5-ethoxy-3-indole acetic acid (compound # 37)

5-Ethoxy-3-indoleacetic acid methyl ester (90.2 mg, 0.27 mmol) was dissolved in methanol (4 ml), lithium hydroxide (13.9 mg, 0.58 mmol) was added, and the mixture was stirred overnight at room temperature. After confirming the completion of the reaction by TLC, 6 N hydrochloric acid was added to make it acidic (pH = 3 to 4), and the solvent was evaporated under reduced pressure. Water (5 ml) was added and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 9: 1) to obtain 5-ethoxy-3-indole acetic acid (compound # 37). (83.8 mg, yield 98.9%); mp 86.0-92.7 ° C .; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.23 (d, J = 8.8 Hz, 1 H), 7 12 (d, J = 1.9 Hz, 1 H), 7.04 (d, J = 2.3 Hz, 1 H), 6.86 (dd. J = 8.8, 2.3 Hz, 1 H); 09 (q, J = 7.0 Hz, 2 H), 3.80 (s, 2 H), 1.42 (t, J = 7.0 Hz, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 177. 4, 153.5, 131.2, 127.5, 124.0, 113.2, 111.9, 107.7, 101.7, 642, 31.1, 15.0; IR (neat) : 3354, 3066, 2930, 1695, 1457, 1112 cm- ¹ ; EI-MS
m / z [M] ⁺ 219, 205 (40%), 190, 174, 162 (70%), 160 (50%); HREI-MS found m / z 219.0886 [M] ⁺ , calcd for 219. _{0895 (C 12 H 13 NO 3} ).

[Synthesis of Compound # 38]
5- (1-propoxy) -3-indole acetic acid methyl ester

5-hydroxy-3-indoleacetic acid methyl ester (108.4 mg, 0.53 mmol) is dissolved in N, N-dimethylformamide (2 ml), to which iodopropane is added dropwise, and potassium carbonate (in a separate container) 219.3 mg, 1.59 mmol) was added and the mixture was stirred at room temperature for 2 hours, and stirred at 80 ° C. for 4 hours. After confirming the completion of the reaction by TLC, 20 ml of 10% aqueous sodium bicarbonate solution was added and extracted with ethyl acetate (50 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3) to obtain methyl 5- (1-propoxy) -3-indoleacetic acid. (78.6 mg, yield 60.1%); melting point 38.6-41.0 ° C .; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.21 (d, J = 8.8 Hz, 1 H), 7 .10 (d, J = 2.3 Hz, 1 H), 7.05 (d, J = 2.3 Hz, 1 H), 6.86 (dd, J = 8.8, 2.3 Hz, 1 H), 4. 01 (t, J = 6.7 Hz, 2 H), 3.74 (s, 2 H), 3.70 (s, 3 H), 1.82 (m, 2 H), 1.07 (t, J = 6. 7 Hz, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 172.5, 153.6, 131.2, 127.6, 123.7, 113.0, 111.8, 108.0, 101. 7, 70.4, 52.0, 31.2, 22.8, 10.6; IR (neat): 3355, 3061, 2961, 16 ^{95,1457,1126cm -1; EI-MS m /} z [M] + 247 (70%), 188 (30%), 149,131 (75%); HREI-MS found m / z 247.1225 [M ⁺ , Calcd for 247.1208 (C ₁₄ H ₁₇ NO ₃ ).

5- (1-propoxy) -3-indoleacetic acid (compound # 38)

Dissolve 5- (1-propoxy) -3-indoleacetic acid methyl ester (64.3 mg, 0.26 mmol) in methanol (2 ml), add lithium hydroxide (9.35 mg, 0.39 mmol) and stir for 4 hours at room temperature It stirred. After confirming the completion of the reaction by TLC, 6 N hydrochloric acid was added to make it acidic (pH = 3 to 4), and the solvent was evaporated under reduced pressure. Water (5 ml) was added and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 9: 1) to obtain 5- (1-propoxy) -3-indoleacetic acid (Compound # 38). (59.3 mg, yield 97.7%); melting point 133.6-136.8 ° C .; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.23 (d, J = 8.8 Hz, 1 H), 7 .13 (s, 1 H), 7.04 (d, J = 2.2 Hz, 1 H), 6.87 (dd, J = 8.1, 2.2 Hz, 1 H), 3.96 (t, J = 6.6 Hz, 2 H), 3.76 (s, 3 H), 1.82 (m, 2 H), 1.05 (t. J = 7.4 Hz, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 177.4, 153.7, 131.2, 127.5, 123.9, 113.2, 111.9, 107.5, 101.7, 70.4, 31.0, 22.8, 10 IR (neat): 3407, 2954, 1728, 1456, 1213, 1160 cm- ^{1 ; EI-MS m / z [} M] + 233,191 (50%); HREI-MS found m / z 233.1043 [M] +, calcd for 233.1052 (C 12 H 15 NO 3).

[Synthesis of Compound # 39]
5- (1-Butoxy) -3-indole acetic acid methyl ester

5-hydroxy-3-indoleacetic acid methyl ester (108.4 mg, 0.53 mmol) is dissolved in N, N-dimethylformamide (2 ml), into which iodobutane is added dropwise, and potassium carbonate (184 .2 mg, 1.33 mmol) was added and stirred at 80.degree. C. for 4 hours. After confirming the completion of the reaction by TLC, 10% aqueous sodium bicarbonate solution (20 ml) was added, and the mixture was extracted with ethyl acetate (50 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3) to obtain methyl 5- (1-butoxy) -3-indoleacetic acid. (140.2 mg, yield 80.5%); ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.21 (d, J = 7.2 Hz, 1 H), 7.10 (d, J = 2.3 Hz) , 1 H), 7.05 (d, J = 2.3 Hz, 1 H), 6.86 (dd, J = 8.8, 2.3 Hz, 1 H), 4.01 (t, J = 6.5 Hz, 2H), 3.74 (s, 2H), 3.70 (s, 3H), 1.82 (m, 2H), 1.52 (m, 2H), 0.98 (t, J = 7.4 Hz , 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 172.5, 153.6, 131.2, 127.6, 123.7, 113.0, 111.8, 108.0, 101.7 , 68.5, 51.9, 31.9, 31.2, 19.3, 13.9; IR (neat): 3355, 2957, 16 ^{4,1459,1127cm -1; HREI-MS found m} / z 261.137 [M] +, calcd for 261.1365 (C 15 H 19 NO 3).

5- (1-Butoxy) -3-indoleacetic acid (compound # 39)

Dissolve 5- (1-butoxy) -3-indoleacetic acid methyl ester (91.0 mg, 0.35 mmol) in methanol (2 ml), add lithium hydroxide (12.5 mg, 0.52 mmol) and stir at room temperature for 6 hours It stirred. After confirming the completion of the reaction by TLC, 6 N hydrochloric acid was added to make it acidic (pH = 3 to 4), and the solvent was evaporated under reduced pressure. Water (5 ml) was added and extracted three times with ethyl acetate (5 ml). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 9: 1) to obtain 5- (1-butoxy) -3-indoleacetic acid (Compound # 39). (43.8 mg, yield 51.0%); melting point 137.8-141.1 ° C .; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.24 (d, J = 8.8 Hz, 1 H), 7 .14 (s, 1 H), 7.04 (d, J = 2.0 Hz, 1 H), 6.87 (dd, J = 8.8, 2.0 Hz, 1 H), 4.01 (t, J = 6.6 Hz, 2 H), 3.76 (s, 2 H), 1.78 (m, 2 H), 1.05 (t. J = 7.4 Hz, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 173.3, 153.8, 131.2, 123.9, 113.2, 111.6, 107.5, 101.6, 31.6, 29.7, 19.3, 13.9; IR ^{(neat): 3407,2954,1728,1456,1213,1160cm -1; EI} -MS m / z [ ^{] + 247,191 (60%);} HREI-MS found m / z 247.1189 [M] +, calcd for 247.1208 (C 14 H 17 NO 3).

[Synthesis of Compound of Formula (1)]

Synthesis of 4- (2,4-difluorophenyl) -2- (6-fluoro-1H-indol-3-yl) -4-oxobutanoic acid (compound (4-1))

  After 6-fluoroindole (485 mg, 3.59 mmol) was put in a 50 mL round bottom flask, (E) -4- (2,4-difluorophenyl) -4-oxo-2-butenoic acid (508 mg, 2.39 mmol) ) Was dissolved in benzene (20 mL) and heated to reflux at 80 ° C. for 7 hours. Distilled water (50 mL) was added to the reaction solution and then extracted with ethyl acetate (50 mL). The organic layer was washed with brine (30 mL) then dried over anhydrous sodium sulfate and concentrated in vacuo. The product obtained by concentration was purified by silica gel chromatography (hexane: acetone = 2: 1), 4- (2,4-difluorophenyl) -2- (6-fluoro-1H-indol-3-yl ) -4-oxobutanoic acid (433 mg, yield 52%) was obtained as colorless crystals.

Mp 210-214 ° C;
¹ H-NMR (400 MHz, CDCl ₃ ) δ 10.31 (s, 1 H), 8.01 (m, 1 H), 7.47 (dd, J = 8.8, 5.2, 1 H), 7.34 (d, J = 2.0, 2 H), 7.12 -7.20 (m, 3H), 6.92 (td, J = 9.6, 2.4, 1H), 4.54 (dd, J = 10.4, 4.0, 1H), 4.01 (ddd, J = 18.8, 10.8, 3.2, 1H), 3.38 (td, J = 18.8, 3.2, 1H);
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 195.18, 174.85, 166.28 J _CF (dd, 254, 13 Hz), 163.42 J _CF (dd, 254, 13 Hz), 161.74, 159.4, 137.54 J _CF (d, 13 Hz), 133.47 J _CF (dd, 11,
3 Hz), 123.35 J _CF (d, 4 Hz), 123.02 J _CF (dd, 13, 4 Hz), 120.97 J _CF (d, 11 Hz),
113.51, 112.94 J _CF (dd, 10, 2 Hz), 108.27 J _CF (d, 24 Hz), 105.59 J _CF (t, 27
Hz), 98.27 J _CF (d, 26 Hz), 46.68 J _CF (d, 7 Hz), 38. 47;
FAB-MS m / z = 348 [M + H] ⁺

Synthesis of 4- (2,4-difluorophenyl) -2- (5-fluoro-1H-indol-3-yl) -4-oxobutanoic acid (compound (3-1))

  After placing 5-fluoroindole (925 mg, 6.85 mmol) in a 50 mL round bottom flask, (E) -4- (2,4-difluorophenyl) -4-oxo-2-butenoic acid (969 mg, 4.57 mmol) ) Was dissolved in benzene (20 mL) and heated to reflux at 80 ° C. for 11 hours. Distilled water (50 mL) was added to the reaction solution and then extracted twice with ethyl acetate (50 mL). The organic layer was washed with brine (30 mL) then dried over anhydrous sodium sulfate and concentrated in vacuo. The product obtained by concentration is filtered through a Kiriyama funnel, recrystallized from chloroform and ethyl acetate, and 4- (2,4-difluorophenyl) -2- (5-fluoro-1H-indol-3-yl ) -4-oxobutanoic acid (1122 mg, yield 71%) was obtained as colorless crystals.

Melting point 207-208 [deg.] C;
¹ H-NMR (400 MHz, acetone-d ₆ ) δ 10.34 (s, 1 H), 8.02 (m, 1 H), 7.47 (dd, J = 10.4, 2.8,
1H), 7.39-7.43 (m, 2H), 7.13-7.21 (m, 2H), 6.93 (td, J = 9.2, 2.8, 1H), 4.52 (dd, J = 10.4, 3.6, 1H), 4.03 (ddd , 18.4, 10.8, 3.6, 1H), 3.40 (td, 18.4, 3.6, 1H); ¹³ C-NMR (100 MHz, acetone-d ₆ ) δ 195.17, 174.86, 166.52 J _CF (dd, 254, 13 Hz), _{163.58 J CF (dd, 254,} 13 Hz), 159.52, 157.21, 134.25, 133.46 J CF (dd, 11, 4 Hz), 127.66 J CF (d, 11 Hz), 123.01 J CF (dd, 10, 4 Hz ), 113.42 J _CF (d, 5 Hz), 113.28
J _CF (d, 10 Hz), 113.51 J _CF (dd, 21, 4 Hz), 110.56 J _CF (d, 27 Hz), 105.61 J _CF
(t, 27 Hz), 104.65 J _CF (d, 24 Hz), 46.68 J _CF (d, 8 Hz), 38. 48;
FAB-MS m / z = 348 [M + H] ⁺

Synthesis of 2- (7-chloro-1H-indol-3-yl) -4- (2,4-difluorophenyl) -4-oxobutanoic acid (compound (5-1))

  After 7-chloroindole (1094 mg, 5.16 mmol) was placed in a 50 mL round bottom flask, (E) -4- (2,4-difluorophenyl) -4-oxo-2-butenoic acid (935 mg, 4.41 mmol) ) Was dissolved in benzene (20 mL) and heated to reflux at 80 ° C. for 10 hours. Distilled water (50 mL) was added to the reaction solution and then extracted twice with ethyl acetate (50 mL). The organic layer was washed twice with brine (30 mL), then dried over anhydrous sodium sulfate and concentrated in vacuo. The product obtained by concentration is filtered through a Kiriyama funnel, recrystallized from benzene and acetone, and 2- (7-chloro-1H-indol-3-yl) -4- (2,4-difluorophenyl) -4-oxobutanoic acid (1017 mg, 54% yield) was obtained as colorless crystals.

Melting point 225-227 [deg.] C;
¹ H-NMR (400 MHz, acetone-d ₆ ) δ 10.55 (s, 1 H), 8.01 (m, 1 H), 7. 75 (d, J = 8.4, 1 H), 7. 45 (d, J = 2.8, 1 H), 7.06-7.14 (m, 4H), 7.08 (t. J = 7.6, 1H), 4.57 (dd, J = 10.4, 3.6, 1H), 4.03 (ddd, 18.4, 10.8, 3.6, 1H), 3.41 (td, 18.4, 3.6, 1H);
¹³ C-NMR (100 MHz, acetone-d ₆ ) δ 195.06, 74.67, 166.53, J _CF (dd, 252, 12 Hz), 163.63 J _CF (dd, 252, 12 Hz), 134.45, 133.46 J _CF (dd , 11, 5 Hz), 129.25, 124.97, 122.98 J _CF (dd, 13, 4 Hz), 121.91, 120.84, 119.03, 117.22, 114.73, 112.99 J _CF (dd, 21, 3 Hz), 105.61 J _CF (t , 27 Hz), 46.71 J _CF (d, 8 Hz), 38.50;
FAB-MS m / z = 364 [M + H] ⁺

Synthesis of 2- (5-chloro-1H-indol-3-yl) -4- (2,4-difluorophenyl) -4-oxobutanoic acid (compound (3-2))

  After placing 5-chloroindole (1000 mg, 6.61 mmol) in a 50 mL round bottom flask, (E) -4- (2,4-difluorophenyl) -4-oxo-2-butenoic acid (935 mg, 4.41 mmol) ) Was dissolved in benzene (20 mL) and heated to reflux at 80 ° C. for 7 hours. Distilled water (50 mL) was added to the reaction solution and then extracted twice with ethyl acetate (50 mL). The organic layer was washed twice with brine (30 mL), then dried over anhydrous sodium sulfate and concentrated in vacuo. The product obtained by concentration is filtered through a Kiriyama funnel, recrystallized from benzene and acetone, and 2- (5-chloro-1H-indol-3-yl) -4- (2,4-difluorophenyl) -4-oxobutanoic acid (1084 mg, yield 63%) was obtained as pale yellow crystals.

Melting point 236-239 ° C;
¹ H-NMR (400 MHz, acetone-d ₆ ) δ 10.45 (s, 1 H), 8.02 (q, J = 8.3, 1 H), 7.80 (d, J = 1.6,
1H), 7.44 (m, 2H), 7.11-7.22 (m, 3H), 4.54 (dd, J = 10.4, 3.8, 1H), 4.01 (ddd, J = 18.7, 10.7, 3.2, 1H), 3.41 (td , J = 18.7, 3.2, 1 H);
¹³ C-NMR (100 MHz, acetone-d ₆ ) δ 195.10, 174.76, 166.52 J _CF (dd, 253, 12 Hz), 163.62 J _CF (dd, 253, 12 Hz), 136.06, 133.44 J _CF (dd, 12 , 42.5 Hz, 128.47, 125.62, 122.96 J _CF (dd, 13, 4 Hz), 122.48, 119.33, 113.77, 113.12, 112.96 J _CF (dd, 22, 3 Hz), 105.61 J _CF (t, 27 Hz) , 46.72 J _CF (d, 8 Hz), 38.35;
FAB-MS m / z = 364 [M + H] ⁺

Synthesis of 2- (4-chloro-1H-indol-3-yl) -4- (2,4-difluorophenyl) -4-oxobutanoic acid (compound (2-1))

  After 4-chloroindole (903 mg, 5.98 mmol) was placed in a 50 mL round bottom flask, (E) -4- (2,4-difluorophenyl) -4-oxo-2-butenoic acid (842 mg, 3.97 mmol) ) Was dissolved in benzene (20 mL) and heated to reflux at 80 ° C. for 7 hours. Distilled water (50 mL) was added to the reaction solution and then extracted with ethyl acetate (50 mL). The organic layer was washed with brine (30 mL) then dried over anhydrous sodium sulfate and concentrated in vacuo. The product is purified by silica gel chromatography (chloroform: methanol = 9: 1) and then recrystallized from benzene and acetone to give 2- (4-chloro-1H-indol-3-yl) -4- (2, 4-difluorophenyl) -4-oxobutanoic acid (602 mg, yield 51%) was obtained as colorless crystals.

Melting point 203-204 [deg.] C;
¹ H-NMR (400 MHz, acetone-d ₆ ) δ 10.24 (s, 1 H), 8.01 (m, 1 H), 7. 77 (d, J = 8.4, 1 H), 7.42 (d, J = 8.0, 1 H), 7.21 to 7.03 (m, 4H), 4.57 (dd, J = 10.8, 3.6, 1H), 4.03 (ddd 18.8, 10.8, 3.2, 1H), 3.38 (td, 18.8, 3.2, 1H);
¹³ C-NMR (100 MHz, acetone-d ₆ ) δ 195.28, 174.97, 166.55 J _CF (dd, 254, 12 Hz), 163.62 J _CF (dd, 254, 12 Hz), 137.646, 137.49, 133.46 J _CF ( dd, 11, 4 Hz), 127.37, 123.70, 123.54, 123.05 J _CF (dd, 13, 4 Hz), 122.39, 119.88, 119.79, 112.95 J _CF (dd, 22, 4 Hz), 105.58 J _CF (t, 26 Hz), 46.95 J _CF (d, 8 Hz), 38.47;
FAB-MS m / z = 364 [M + H] ⁺

Synthesis of 4- (2,4-difluorophenyl) -2- (5-methyl-1H-indol-3-yl) -4-oxobutanoic acid (compound (3-3))

  After placing 5-methylindole (171 mg, 1.31 mmol) in a 50 mL round bottom flask, (E) -4- (2,4-difluorophenyl) -4-oxo-2-butenoic acid (185 mg, 0.87 mmol) ) Was dissolved in benzene (20 mL) and heated to reflux at 80 ° C. for 7 hours. Distilled water (50 mL) was added to the reaction solution and then extracted with ethyl acetate (50 mL). The organic layer was washed with brine (30 mL) then dried over anhydrous sodium sulfate and concentrated in vacuo. The product obtained by concentration is filtered through a Kiriyama funnel, recrystallized from benzene and acetone, and 4- (2,4-difluorophenyl) -2- (5-methyl-1H-indol-3-yl) 4-oxobutanoic acid (200 mg, yield 67%) was obtained as colorless crystals.

Mp 200-202 ° C;
¹ H-NMR (400 MHz, acetone-d ₆ ) δ 10.10 (s, 1 H), 8.01 (m, 1 H), 7.54 (s, 1 H), 7.20-7.31 (m, 2 H), 7.13-7.20 (m, 7 1H), 7.96 (d, J = 6.8, 1H), 4.53 (dd, J = 10.6, 3.6, 1H), 4.01 (ddd 18.8, 10.6, 3.2, 1H), 3.36 (td, 18.8, 3.2, 1H), 2.40 (s, 3H);
¹³ C-NMR (100 MHz, acetone-d ₆ ) δ 195.33, 175.08, 166.54 J _CF (dd, 254, 12 Hz), 163.49 J _CF (dd, 254, 12 Hz), 136.01, 133.45 J _CF (dd, 11, 4 Hz), 128.59, 127.63, 124.02, 123.52, J _CF (dd, 13, 4 Hz), 119.43, 112.94 J _CF (dd, 22, 4 Hz), 112.74, 112.03, 105.59 J _CF (t, 26 Hz), 47.01 J _CF (d, 7 Hz), 38.45, 21.64;
FAB-MS m / z = 344 [M + H] ⁺

Synthesis of 4- (2,4-difluorophenyl) -2- (1-methyl-1H-indol-3-yl) -4-oxobutanoic acid (compound (6-1))

  After placing 1-methylindole (2512 mg, 19.17 mmol) in a 50 mL round bottom flask, (E) -4- (2,4-difluorophenyl) -4-oxo-2-butenoic acid (2710 mg, 12.78 mmol) ) Was dissolved in benzene (20 mL) and heated to reflux at 80 ° C. for 1 hour. Distilled water (50 mL) was added to the reaction solution and then extracted twice with ethyl acetate (50 mL). The organic layer was washed twice with brine (30 mL), then dried over anhydrous sodium sulfate and concentrated in vacuo. The product obtained by concentration is filtered through a Kiriyama funnel, recrystallized from benzene and acetone, and 4- (2,4-difluorophenyl) -2- (1-methyl-1H-indol-3-yl) 4-oxobutanoic acid (3898 mg, 89% yield) was obtained as colorless crystals.

Melting point 192-193 ° C
¹ H-NMR (400 MHz, acetone-d ₆ ) δ 8.00 (m, 1 H), 7.75 (d, J = 7.6, 1 H), 7.37 (d, J = 8.4, 1 H), 7.12-7.22 (m, 4 H) , 7.07 (t, J = 7.6, 1H), 4.54 (dd, J = 10.8, 3.6, 1H), 4.00 (ddd, 18.8, 10.4, 3.6, 1H), 3.79 (s, 3H), 3.36 (td, 18.8) , 3.6, 1 H);
¹³ C-NMR (100 MHz, acetone-d ₆ ) δ 195.22, 174.94, 166.52 J _CF (dd, 253, 13 Hz), 163.57 J _CF (dd, 253, 13 Hz), 138.08, 133.46 J _CF (dd, 11, 14 Hz), 128.00, 127.79, 123.03 J _CF (dd, 13, 4 Hz), 122.36, 120.07, 119.72, 112.94 J _CF (d, 22, 4 Hz), 112.33, 110.32, 105.60 J _CF (t, 27 Hz), 47.01 J _CF (d, 8 Hz), 38.36, 32.72;
FAB-MS m / z = 344 [M + H] ⁺

Synthesis of (Compound (5-2)) of 4- (2,4-difluorophenyl) -2- (7-methoxy-1H-indol-3-yl) -4-oxobutanoic acid

  After placing 7-methoxyindole (1083 mg, 7.36 mmol) in a 50 mL round bottom flask, (E) -4- (2,4-difluorophenyl) -4-oxo-2-butenoic acid (1041 mg, 4.90 mmol) ) Was dissolved in benzene (20 mL) and heated to reflux at 80 ° C. for 14 h. Distilled water (50 mL) was added to the reaction solution and then extracted with ethyl acetate (50 mL). The organic layer was washed with brine (30 mL) then dried over anhydrous sodium sulfate and concentrated in vacuo. The product obtained by concentration is filtered through a Kiriyama funnel, recrystallized from benzene and acetone, then recrystallized from chloroform to give 4- (2,4-difluorophenyl) -2- (7). -Methoxy-1H-indol-3-yl) -4-oxobutanoic acid (1179 mg, yield 67%) was obtained as colorless crystals.

Melting point 181-183 ° C;
¹ H-NMR (400 MHz, acetone-d ₆ ) δ 10.26 (s, 1 H), 8.01 (m, 1 H), 7. 35 (d, J = 8.0, 1 H), 7. 28 (d, J = 2.8, 1 H), 7.12-7.20 (m, 2H), 6.98 (t, J = 7.8, 1H), 6.67 (d, J = 7.8, 1H),
4.54 (dd, J = 10.8, 3.6, 1H), 4.03 (ddd 18.8, 10.6, 3.3, 1H), 3.92 (s, 3H), 3.36
(td, 18.6, 3.2, 1H);
¹³ C-NMR (100 MHz, acetone-d ₆ ) δ 1195.28, 174.98, 166.54 J _CF (dd, 252, 12 Hz), 163.48 J _CF (dd, 252, 12 Hz), 147.35, 133.44 J _CF (dd, 11, 4 Hz), 128.81, 127.83, 123.22, 123.05 J _CF (dd, 13, 4 Hz), 120.43, 113.76, 112.94 J _CF (dd, 22, 4 Hz), 112.7, 105.59 J _CF (t, 27 Hz) ), 102.52, 55.52, 46.97 J _CF (d, 8 Hz), 38.59;
FAB-MS m / z = 360 [M + H] ⁺

Synthesis of 4- (2,4-difluorophenyl) -2- (5-methoxy-1H-indol-3-yl) -4-oxobutanoic acid (compound (3-4))

  After placing 5-methoxyindole (1166 mg, 7.93 mmol) in a 50 mL round bottom flask, add (E) -4- (2,4-difluorophenyl) -4-oxo-2-butenoic acid and add benzene (20 mL) The solution was dissolved and heated to reflux at 80.degree. C. for 10 hours. Distilled water (50 mL) was added to the reaction solution and then extracted twice with ethyl acetate (50 mL). The organic layer was washed twice with brine (30 mL), then dried over anhydrous sodium sulfate and concentrated in vacuo. The product obtained by concentration is filtered through a Kiriyama funnel, recrystallized from benzene and acetone, then recrystallized from chloroform to give 4- (2,4-difluorophenyl) -2- (5). -Methoxy-1H-indol-3-yl) -4-oxobutanoic acid (1478 mg, yield 75%) was obtained as colorless crystals.

Mp 205-206 ° C;
¹ H-NMR (400 MHz, acetone-d ₆ ) δ 10.09 (s, 1 H), 8.02 (m, 1 H), 7.27-7.31 (m, 3 H), 7.13-7.20 (m, 2 H), 6.79 (dd, J = 8.8, 2.4, 1H), 4.52 (dd, J = 10.8, 3.6, 1H), 4.00 (ddd, 18.8, 10.4, 3.4, 1H), 3.80 (s, 3H), 3.38 (td, 18.6, 3.4, 1H;
¹³ C-NMR (100 MHz, acetone-d ₆ ) δ 195.35, 175.03, 166.53, J _CF (dd, 253, 12 Hz), 163.61 J _CF (dd, 253, 12 Hz), 154.84, 133. 45 J _CF (dd , 11, 4 Hz), 132.72, 127.78, 124.22, 123.04 J _CF (dd, 12, 4 Hz), 112.95 J _CF (dd, 22, 4 Hz), 112.96, 112.68, 105.61 J _CF (t, 26 Hz) , 101.58, 55.79, 46.9 J _CF (d, 8 Hz), 38.67;
FAB-MS m / z = 360 [M + H] ⁺

Synthesis of 2- (6-benzyloxy-1H-indol-3-yl) -4- (2,4-difluorophenyl) -4-oxobutanoic acid (compound (4-2))

  After 6-benzyloxindole (1255 mg, 5.62 mmol) was placed in a 50 mL round bottom flask, (E) -4- (2,4-difluorophenyl) -4-oxo-2-butenoic acid (795 mg, 3.F. 74 mmol) was added, dissolved in benzene (20 mL) and heated to reflux at 80 ° C. for 9 hours. Distilled water (50 mL) was added to the reaction solution and then extracted with ethyl acetate (50 mL). The organic layer was washed with brine (30 mL) then dried over anhydrous sodium sulfate and concentrated in vacuo. The product obtained by concentration is filtered through a Kiriyama funnel and recrystallized from chloroform to give 2- (6-benzyloxy-1H-indol-3-yl) -4- (2,4-difluorophenyl) -4-oxobutanoic acid (531 mg, 33% yield) was obtained as pale yellow crystals.

Melting point 177-178 [deg.] C;
¹ H-NMR (400 MHz, acetone-d ₆ ) δ 10.0 4 (s, 1 H), 8.01 (m, 1 H), 7.65 (d, J = 8.8, 1 H), 7.48 (d, J-7.6, 2 H), 7.38 (t, J = 7.2, 2H), 7.31 (m, 1H), 7.13-7.20 (m, 3H), 7.03 (d, J = 2.0, 1H), 6.83 (dd, J = 8.4, 2.0, 1H) , 4.51 (dd, J = 10.4, 3.6, 1H), 4.01 (ddd, 18.1, 10.4, 3.3, 1H), 3.36 (td, 18.1, 3.3, 1H);
¹³ C-NMR (100 MHz, acetone-d ₆ ) δ 195.29, 175.00, 166.54 J _CF (dd, 254, 12 Hz), 163.52 J _CF (dd, 254, 12 Hz), 156.33, 138.85, 138.45, 133.45, _{J CF (dd, 11, 4} Hz), 129.17, 128.37, 128.23, 123.01 J CF (dd, 13, 4 Hz), 122.49, 121.97, 120.54, 113.24,
_{113.06 J CF (dd, 21,} 4 Hz), 110.73, 105.59 J CF (t, 27 Hz), 96.89, 70.70, 46.94 J CF (d, 8 Hz), 38.57;
FAB-MS m / z = 436 [M + H] ⁺

[Reference Example 1]
(E) -4- (2,4-difluorophenyl) -4-oxo-2-butenoic acid

  The (E) -4- (2,4-difluorophenyl) -4-oxo-2-butenoic acid used in the synthesis of the present compound # 1-10 was synthesized as follows. That is, after placing 1,3-difluorobenzene (1300 mg, 11.39 mmol) in a 100 mL round bottom flask, maleic anhydride (894 mg, 9.12 mmol) was added, dissolved with dichloromethane (40 mL) and stirred with a stirrer . With stirring, anhydrous aluminum chloride (2279 mg, 17.09 mmol) was gradually added and stirred at room temperature for 6 hours. The reaction solution is poured into ice water (100 mL) in a round bottom flask, the reaction is quenched, the aqueous layer is extracted with ethyl acetate (150 mL), and the organic layer is extracted twice with brine (100 mL). After operation, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a solid. The solid is purified by recrystallization from benzene and a small amount of acetone in a hot water bath to obtain (E) -4- (2,4-difluorophenyl) -4-oxo-2-butenoic acid as pale yellow crystals. Obtained at a rate of 48%.

Melting point 136.0-139.0 ° C;
¹ H-NMR (400 MHz, acetone-d ₆ ) δ 7.98 (m, 1 H), 7.72 (dd, J = 15.6, 3.6, 1 H), 7.20-7.28 (m, 2 H), 6.75 (d, J = 15.6, 2H);
¹³ C-NMR (100 MHz, acetone-d ₆ ) δ 187.13, 166.86 J _CF (dd, 254, 12 Hz), 166.35, 163.33 J _CF (dd, 254, 12 Hz), 139.95 J _CF (d, 7 Hz) ), 133.98 J _CF (dd, 66, 59 Hz), 132.91, 123.22 J _CF (d, 9 Hz), 113.33 J _CF (dd, 22, 3 Hz), 105.76, J _CF (t, 22 Hz)

Hereinafter, the present invention will be more specifically described by way of examples, but the technical scope of the present invention is not limited to these examples. In the following examples, culture of chondrocytes was carried out under conditions of 5% CO ₂ /20% O ₂ at 37 ° C. using a 25 cm ² flask. In addition, as a culture solution for chondrocytes, 10% fetal calf serum (FCS) in 5 mL of α-MEN (α-Modified Eagle Medium) (1 ×) (manufactured by life technologies, REF: 12571-063) (Manufactured by life technologies, REF: 26140-079), 1% Insulin Transfellin Seline (manufactured by life technologies, REF: 41400-045), 100 U / mL penicillin-100 μg / mL streptomycin combination drug (manufactured by LONZA, REF: 17 What added -602E) was used.

Confirmation that the present compound group has a cartilage matrix degrading enzyme production inhibitory effect [Method]
Pieces of cartilage in macroscopically healthy areas from 6 femoral heads (3 males, 3 females, average age 76 years) removed when performing femoral head replacement surgery for femoral neck fractures It was collected. Pieces of cartilage were sequentially treated with 10% trypsin / EDTA for 0.5 hours, 1 mg / mL hyaluronidase for 0.25 hours, and 10 mg / mL collagenase for 12 to 15 hours to isolate chondrocytes. After that, four T25 flasks are prepared, and four kinds of culture solution (a culture solution containing 10 μM TNF-α [TNF so that the concentration of chondrocytes is 0.5 to 1.0 × 10 ⁵ cells / mL can be obtained. -Α-added group], a culture solution containing 10 μM of TNF-α and 3 μM of compound # 5 ["TNF-α + -modified # 5 added group"], a culture liquid containing 3 μM of compound # 5 [chemical- # 5 added group] And culture medium without TNF-α and compound # 5 (control group)), added to each flask, and cultured until it became confluent (about 21 to 28 days). Chondrocytes after culture are collected, total RNA is extracted and purified with AllPrep DNA / RNA Mini (manufactured by QIAGEN), and Oligo (dT) primer is used, according to High Capacity cDNA Transcription Kit (manufactured by Applied Biosystems). cDNA was prepared. The expression levels of mRNA of three types of cartilage matrix degrading enzymes (MMP13, ADAMTS4, and ADAMTS5) were shown in the following 1) -2) quantitative PCR using TaqMan Universal PCR Master Mix II (manufactured by Applied Biosystems). Conducted under conditions and detected. The GAPDH gene was used as an internal standard.

1) 1 cycle of 50 ° C for 2 minutes and 95 ° C for 10 minutes (activation of polymerase)
2) 40 cycles of 1 cycle of 95 ° C., 15 seconds and 60 ° C., 1 minute (amplification of cDNA by primer set [forward primer and reverse primer])

  Gene Expression Assay Mix (manufactured by Applied Biosystems) was used as a primer and probe set for amplifying and detecting cDNAs of the above three types of cartilage matrix degrading enzyme genes and GAPDH gene (see Table 2).

  Measure the number of PCR cycles (threshold cycle; Ct value) at which PCR products become constant using Baseline software (Applied Biosystems), and compare Ct method (delta-delta Ct method) of cDNA amplification product of GAPDH gene The relative value of the Ct value of the cDNA amplification product of the above three types of cartilage substrate degrading enzyme genes based on the Ct value is determined, and the cDNA of the above three types of cartilage substrate degrading enzyme genes (mRNA The relative amount of) was calculated (see the vertical axis in FIGS. 1 to 3).

[result]
The amount of mRNA expression of three types of cartilage matrix degrading enzymes (MMP13, ADAMTS4, and ADAMTS5) in the chondrocytes of "chemical group # 5 addition group" was decreased compared to "control group" (see FIGS. 1 to 3A) In particular, the expression level of the ADAMTS5 gene mRNA was significantly reduced (see FIG. 3A). In addition, the expression level of mRNA of the above-mentioned cartilage matrix degrading enzyme 3 type gene in the chondrocytes of the “TNF-α + -modified # 5 addition group” was significantly reduced as compared with the “TNF-α addition group” (FIG. 1) 3B).
These results indicate that the present compound group (compound # 5) produces cartilage matrix degrading enzymes, specifically, normal cartilage matrix degrading enzymes (in the absence of inflammatory cytokine [TNF-α]) And the production of cartilage matrix degrading enzymes in the presence of inflammatory cytokines (TNF-α) and the production of cartilage matrix degrading enzymes caused by inflammatory cytokines (TNF-α) have been shown to be suppressed. .

  The present invention contributes to the prevention or amelioration (treatment) of a condition or disease caused by reduction or damage of cartilage matrix such as osteoarthritis.

Claims (4)

The following general formula (I ₀ );
[Wherein, R ¹ is a benzene ring which is unsubstituted or substituted by an alkyl group having 1 to 7 carbon atoms, an alkoxyl group having 1 to 7 carbon atoms, fluorine and / or chlorine; unsubstituted or substituted by fluorine] A linear or branched alkyl group having 4 to 6 carbon atoms, or methylene or ethylene substituted with a phenyl group or a cyclopentyl group, and the phenyl group is further substituted with one or more phenyl groups And Z ¹ , Z ² , Z ³ and Z ⁴ may be the same or different, and a hydrogen atom, a halogen atom, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C2 to C6 alkynyl group, an organic group represented by OR ^{8, R 8} is an alkyl group of C1 to C7, alkenyl group of C2 -C6, an alkynyl group of C2 -C6, ^{Z 5} is, water Represents an alkyl group of atoms or a C1 ^-C6, R 3 is ^OH, a group selected from any one of the OR 4, NHR ⁴ and ^NR 4 ^{R 5, R 4} and ^{R 5} are the same or different, substituted Or an unsubstituted C1-C4 alkyl group. ]
, General formula (II);
Wherein R ⁶ is hydrogen or methyl, X is an alkylene group having 4 to 6 carbon atoms, or an ether group having 4 carbon atoms, R ³ is OH, OR ⁴ , NHR ⁴ and NR ⁴ R ⁵ And R ⁴ and R ⁵ are the same or different and each is a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms. ]
And General formula (III);
[Wherein, A represents indole or naphthalene, and when A is indole, an acetic acid group and R ⁷ O are substituted at the 3- and 5-positions of indole, respectively, and when A is naphthalene, 1-position of naphthalene An acetic acid group and R ⁷ O are substituted at position 7 and 7, respectively, R ⁷ represents an alkyl group having 1 to 5 carbon atoms or a benzyl group, and the benzene ring of the benzyl group has 1 or 2 or more carbon atoms. R ³ may be substituted with an alkyl group of ̃3 or an alkoxy group having 1 to 3 carbon atoms, and R ³ is a group selected from any one of OH, OR ⁴ , NHR ⁴ and NR ⁴ R ⁵ , R ⁴ and R ⁵ are the same or different and are substituted or unsubstituted alkyl groups having 1 to 4 carbon atoms. ]
An agent for inhibiting the production of a cartilage matrix degrading enzyme, comprising: a compound represented by: and one or more compounds selected from the group consisting of pharmaceutically acceptable salts thereof when R ³ is OH.   The cartilage matrix degrading enzyme is one or more proteins selected from MMP13 (Matrix metalloproteinase 13), ADAMTS4 (A disintegrin and Metalloproteinase with Thrombopondin motifs 4), and ADAMTS 5 (A disintegrin and Metalloproteinase with Thrombosporindin motifs 5) The agent for suppressing the production of a cartilage matrix degrading enzyme according to claim 1. The cartilage matrix degrading enzyme production inhibitor according to claim 1 or 2, wherein the compound is a compound represented by the following formula (I-2) or a pharmaceutically acceptable salt thereof.
Formula (I-2);
  An agent for preventing or ameliorating a symptom or disease caused by reduction or damage of a cartilage matrix, comprising the agent for inhibiting the production of a cartilage matrix degrading enzyme according to any one of claims 1 to 3.