KR20140019113A - Alpha-galactosylceramide analogs, a preparation method thereof, and a pharmaceutical composition for treatment and prevention of diseases by abnormal immune modulation comprising the same - Google Patents

Abstract

The present invention relates to alpha-galactosylceramide analogs, a method for producing the same, and a pharmaceutical composition containing the alpha-galactosylceramide analogs for treating or preventing diseases by abnormal immunomodulation and more specifically, to alpha-galactosylceramide analogs which can induce selective activation of Th1 or Th2 response in NKT cells so effective in treating or preventing diseases by abnormal immunomodulation, a method for producing the same, and a pharmaceutical composition containing the alpha-galactosylceramide analogs for treating or preventing the diseases by abnormal immunomodulation.

Description

[0001] The present invention relates to a pharmaceutical composition for the treatment or prevention of an alpha-galactosylceramide analogue, a preparation method thereof, and a disease caused by immunomodulatory disorders, by abnormal immune modulation comprising the same}

The present invention relates to an alpha-galactosyl ceramide analogue, a method for producing the same, and a pharmaceutical composition for treating or preventing diseases caused by immunomodulatory abnormalities, and more particularly, Alpha-galactosyl ceramide analogues capable of inducing activation, a process for their preparation, and pharmaceutical compositions for the treatment or prevention of diseases caused by immunomodulation disorders.

α-Galactoseride (α-GalCer) is a subset of T cells and is a typical antigen for NKT cells, which play a crucial role in regulating the immune response. After the α-GalCer is loaded onto the CD1d protein in antigen-presenting cells (APCs), the CD1d-α-GalCer 2 molecular complex is recognized by the T cell receptor (TCR) . Thereafter, the activated NKT cells are treated with an inflammation-induced Th1 cytokine (pro-inflammatory T helper 1 (Th1)) such as interferon-γ (IFN-γ), tumor necrosis factor- cytokine); And a number of cytokines including the anti-inflammatory T helper 2 (Th2) cytokine, an anti-inflammatory T 2 (Th2) cytokine such as interleukin-4 (IL-4) and interleukin-10 do. The secreted cytokines are recognized by other cells in the immune system that act on a wide variety of immune responses, including host response to parasites and bacteria, antitumor response and protection against autoimmune disease.

KRN7000 (1) is a well-known molecule of the? -GalCer family (Fig. 1), and its therapeutic effect has been extensively studied in various disease models. However, the in vivo efficacy of 1 has been somewhat limited due to its dual antagonistic effect on both its Th1 and Th2 cytokines, and its dual effects are known to be completely opposite to the immune response (Banchet-Cadeddu A. et al , Org. Biomol. Chem., 2011, 9, 3080-3104). In other words, 1 can stimulate the secretion of both inflammation-inducing and anti-inflammatory cytokines, which can not cause a final change in immunity.

Thus, numerous recent studies have focused on the synthesis of KRN7000 analogs that can selectively activate NKT cells that secrete certain cytokines. For example, structural modifications of sugar moieties in alpha -GalCer have shown that alpha -anomeric galactose is significantly better than other sugars such as glucose, mannose and beta -galactose without selectivity (Kawano T. et al., Science, 1997, 278, 1626-1629). However, the structural modification at the C6 position of the galactosyl moiety in [alpha] -GalCer with 4Cl-3CF3-benzamide substituent (2) showed a potential Thl-polarization effect (Trappeniers M. et al. J. Am. Chem. Soc., 2008, 130, 16468-16469). An α-GalCer analog containing an aromatic group at the end of the N-acyl side chain also induced a Th1 response (Fujio M. et al., J. Am. Chem. Soc., 2006, 128, 9022-9023). This document describes that the enhanced stability of the CD1d-a-GalCer complex by additional non-covalent interactions results in a Th1-biased response. Alternatively, a-GalCer analogs with aliphatic short chains or multiple cis-double bonds on the N-acyl side chain induced a Th2-biased cytokine response (Goff RD et al., J. Am. Chem. Soc., 2004 , 126,13602-13603). A representative α-GalCer analog for a Th2-biased immune response is OCH (3) with a cleavage of the sphingosine skeletal lipid chain of 1 (Miyamoto K. et al., Nature, 2001, 413, 531-534). This example shows that the reduced stability of the CD1d-alpha-GalCer complex causes a Th2 response due to their short retention time at the APCs surface (McCarthy C. et al., J. Exp. Med., 2007, 204, 1131-1144).

However, unlike sugar and N -acyl moieties, extensive modification of the sphingosine skeleton has not yet been actively investigated.

Under these circumstances, the present inventors have prepared α-GalCer analogues having a new sphingosine skeleton containing an aromatic heterocycle such as pyrazole at C5-C7 positions, and have found that they induce selective activation of Th1 or Th2 responses in NKT cells And is effective in the treatment or prevention of diseases due to immunomodulation abnormality, thereby completing the present invention.

It is an object of the present invention to provide alpha-galactosyl ceramide analogs capable of inducing selective activation of Th1 or Th2 responses in NKT cells.

It is another object of the present invention to provide a process for preparing said alpha-galactosyl ceramide analog.

It is still another object of the present invention to provide a pharmaceutical composition for treating or preventing diseases caused by immunomodulation disorders comprising the alpha-galactosyl ceramide analog.

In order to solve the above-mentioned problems, the present invention provides a compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In this formula,

이고, R ₁ is C _{1 -20} alkyl, or

ego,

이며, R ₂ is -NH-CO-R ₄ , or

Lt;

R ₃ is an alkoxy group H, C _{1 -10} alkyl, or C _{1 -10,}

R ₄ is C _{1 -30} alkyl; Or C _{1- 10} alkyl substituted by phenyl,

R ₅ is a C _{1 -30} alkyl,

n is an integer of 1 to 10;

Preferably, R < ₁ > is ethyl or undecanyl.

이고, R₃는 H, 메틸, 에틸, 프로필, 부틸, 펜틸, 헥실, 메톡시, 또는 펜톡시이다.Preferably, R < _{1 >} is

And R ₃ is H, methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, or pentoxy.

Preferably, R ₂ is -NH-CO-R ₄ and R ₄ is hexyl, tricosanyl, pentacosinyl, or 5-phenylpentyl.

이고, R₄는 테트라코사닐이다.
Preferably, R < _{2 >} is

And R < ₄ > is tetracosanyl.

Preferably, the compound represented by the formula (1)

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And

≪ / RTI >

The present invention also provides a process for preparing a compound represented by the following general formula (1), wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and n are as defined above ):

[Reaction Scheme 1]

Reacting a compound represented by the formula (2) with trityl chloride to prepare a compound represented by the formula (3) (step 1);

Reacting a compound represented by the formula (3) with benzyl chloride to prepare a compound represented by the formula (4) (step 2);

Reacting a compound represented by the formula (4) with POCl ₃ to prepare a compound represented by the formula (5) (step 3);

Reacting a compound represented by the formula (5) with a compound represented by the formula (6) to prepare a compound represented by the formula (7) (step 4);

Reacting a compound represented by the formula (7) with mesyl chloride to prepare a compound represented by the formula (8) (step 5);

Reacting a compound represented by the formula (8) with sodium azide to prepare a compound represented by the formula (9) (step 6);

Reacting a compound represented by the formula (9) with p -toluenesulfonic acid to prepare a compound represented by the formula (10) (step 7);

Reacting a compound represented by the formula (10) with 2,3,4,6-tetra-O-benzylgalactosyl iodide to prepare a compound represented by the formula (11) (step 8);

1) wherein, when R ₂ is -NH-CO-R ₄ ,

Reacting a compound represented by the formula (11) with PPh ₃ to prepare a compound represented by the formula (12) (step 9-1);

Reacting a compound represented by the formula (12) with a compound represented by the formula (13) to prepare a compound represented by the formula (14) (step 9-2); And

Reacting a compound represented by the formula (14) with H _{2 in} the presence of Pd (OH) ₂ / C to prepare a compound represented by the formula (1) (step 9-3), or

인 경우,2) when R ₂ is

Quot;

와 반응시켜 화학식 15로 표시되는 화합물을 제조하는 단계(단계 10-1); The compound represented by formula (11)

To obtain a compound represented by the formula (15) (step 10-1);

Reacting the compound of formula (15) with H _{2 in} the presence of Pd (OH) ₂ / C to prepare a compound of formula (1) (step 10-2).

The step 1) is a step of reacting a compound represented by the formula (2) with trityl chloride to prepare a compound represented by the formula (3), wherein the primary alcohol of D-galactan is selectively tritylated to obtain a compound . The reaction of step 1) is preferably carried out in the presence of DMAP (4-dimethylaminopyridine). In addition, the above step 1) can be carried out using pyridine as a solvent, but is not limited thereto. In addition, the above step 1) is preferably carried out at room temperature, more preferably at 20 to 40 ° C. Also, the step 1) is preferably performed for 12 to 24 hours.

Step 2) is a step of reacting a compound represented by the formula (3) with benzyl chloride to prepare a compound represented by the formula (4), wherein the remaining two secondary alcohols of the compound represented by the formula (3) Is a step of preparing a compound represented by the formula The reaction of step 2) is preferably carried out in the presence of NaH and n Bu ₄ NI (tetra- n- butylammonium iodide). In addition, the above step 2) may be carried out using DMF as a solvent, but is not limited thereto. Further, the above step 2) is preferably carried out at room temperature, more preferably at 20 to 40 ° C. In addition, the step 2) is preferably performed for 1 to 5 hours. Further, the reaction of step 2) is preferably carried out under a nitrogen atmosphere.

Step 3) is a step of reacting a compound represented by the formula (4) with POCl ₃ to prepare a compound represented by the formula (5), wherein the compound represented by the formula (4) is formylated via a Vilsmeier- Carbaldehyde, that is, the compound represented by the general formula (5). Step 3) above can be carried out using DMF as a solvent, but is not limited thereto. Further, the above step 3) is preferably carried out at 0 캜 to room temperature, more preferably at 0 to 40 캜. Also, the step 3) is preferably carried out for 6 to 18 hours.

Step 4) is a step of reacting a compound represented by the formula (5) with a compound represented by the formula (6) to prepare a compound represented by the formula (7), wherein D-galactalcarbaldehyde, The dielectrophilic alpha, beta -unsaturated aldehyde moiety is cyclized by reaction with a dinucleophilic alkylhydrazine in MeOH, that is, a compound of formula 6 to give the sphingosine skeleton having an aromatic pyrazole ring of formula 7 Is a step of preparing a compound represented by the formula Step 4) above can be carried out using methanol as a solvent, but is not limited thereto. In addition, the above step 4) is preferably carried out at room temperature, more preferably at 20 to 40 ° C. Also, the step 4) is preferably performed for 1 to 5 hours.

Step 5) is a step of reacting a compound represented by the formula (7) with mesyl chloride to prepare a compound represented by the formula (8), wherein the C2-OH position of the compound represented by the formula (7) ≪ / RTI > compound. The reaction of step 5) is preferably carried out in the presence of DIPEA (N, N-Diisopropylethylamine). In addition, the above step 5) can be carried out using DCM as a solvent, but is not limited thereto. Further, the above step 5) is preferably carried out at room temperature, more preferably at 20 to 40 ° C. Also, the step 5) is preferably performed for 1 to 5 hours.

The step 6) is a step of reacting a compound represented by the formula (8) with sodium azide to prepare a compound represented by the formula (9), wherein the mesylate compound represented by the formula (8) ₃ is used to prepare a compound represented by formula (9), which is an azido compound. Step 6) above may be carried out using DMF as a solvent, but is not limited thereto. In addition, the step 6) is preferably carried out at 100 to 140 캜. Also, the step 6) is preferably performed for 2 to 6 hours. Further, the reaction of step 6) is preferably carried out under microwave irradiation.

Step 7) is a step of reacting a compound represented by the formula (9) with p -toluenesulfonic acid to prepare a compound represented by the formula (10), and reacting the compound represented by the formula (9) with p- Which is a suitably protected sphingosine derivative for galactosidation by dityrilization of the C1-OH position of the compound to be obtained. The above step 7) can be carried out using methanol as a solvent, but is not limited thereto. Further, the step 7) is carried out at room temperature, more preferably at 20 to 40 ° C. Also, the step 7) is preferably performed for 3 to 7 hours.

Step 8) is a step of reacting a compound represented by the formula (10) with 2,3,4,6-tetra-O-benzylgalactosyl iodide to prepare a compound represented by the formula (11) 11 is a step for preparing a compound represented by the formula (11) having an? -Elective glycoside bond through a lactosyl iodide donor and its receptor, which is represented by the formula (10). The reaction of step 8) is preferably carried out using TBAI (tetrabutylammonium iodide) and DIPEA (N, N-diisopropylethylamine). In addition, the above step 8) can be carried out using benzene as a solvent, but is not limited thereto. In addition, the above step 8) is preferably carried out at 50 to 80 캜. Also, the step 8) is preferably performed for 1 to 5 hours. Also, the reaction of step 8) is preferably carried out under an argon atmosphere.

Step 9-1) is a step of reacting a compound represented by the formula (11) with PPh ₃ to prepare a compound represented by the formula (12), wherein the azido group of the compound represented by the formula (11) is subjected to a Staudinger reaction, To an amino group to prepare a compound represented by the formula (12). The above step 9-1) can be carried out using benzene or water as a solvent, but is not limited thereto. In addition, the step 9-1) is preferably carried out at 40 to 80 캜. Also, the step 9-1) is preferably performed for 6 to 14 hours.

Step 9-2) is a step of reacting a compound represented by the formula (12) with a compound represented by the formula (13) to prepare a compound represented by the formula (14), wherein the compound represented by the formula Coupling the compound with the compound represented by the formula (13) in an EDC-mediated amide coupling to prepare a compound represented by the formula (14) which is a galactosyl ceramide derivative. The reaction of step 9-2) is preferably carried out using 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) and 4-dimethylaminopyridine (DMAP). The above step 9-2) can be carried out using THF as a solvent, but is not limited thereto. Further, the step 9-2) is carried out at room temperature, more preferably at 20 to 40 占 폚. Also, the step 9-2) is preferably performed for 18 to 30 hours.

Step 9-3) is a step of reacting a compound represented by the formula 14 with H _{2 in} the presence of Pd (OH) ₂ / C to prepare a compound represented by the formula 1, wherein Pd (OH) ₂ on carbon And then removing the benzyl protecting group present in the compound represented by the formula (14) through catalytic hydrogenation using the compound of the formula (1). Step 9-3) may be carried out using ethanol or DCM as a solvent, but is not limited thereto. Further, the step 9-3) is carried out at room temperature, more preferably at 20 to 40 占 폚. Further, the step 9-3) is preferably performed for 10 to 20 hours.

와 반응시켜 화학식 15로 표시되는 화합물을 제조하는 단계로서, 트리아졸을 형성하는 단계이다. 상기 단계 10-1)의 반응은 CuSO₄ 및 Sodium ascorbate를 사용하여 수행되는 것이 바람직하다. 상기 단계 10-1)은 용매로서 tBuOH를 사용하여 수행될 수 있으며, 이에 제한되는 것은 아니다. 또한, 상기 단계 10-1)은 18 내지 30 시간 동안 수행되는 것이 바람직하다.
Step 10-1) can be carried out by reacting a compound represented by the formula (11)

To prepare a compound represented by the formula (15), which is a step of forming a triazole. The reaction of step 10-1) is preferably carried out using CuSO ₄ and sodium ascorbate. The above step 10-1) can be carried out using tBuOH as a solvent, but is not limited thereto. Also, the step 10-1) is preferably performed for 18 to 30 hours.

Step 10-2) is a step of reacting a compound represented by Formula 15 with H _{2 in} the presence of Pd (OH) ₂ / C to prepare a compound represented by Formula 1, wherein Pd (OH) ₂ on carbon And then removing the benzyl protecting group present in the compound represented by the formula (15) by catalytic hydrogenation using the compound of the formula (1). Step 10-2) may be carried out using ethanol or DCM as a solvent, but is not limited thereto. Further, the above step 10-2) is carried out at room temperature, more preferably at 20 to 40 占 폚. In addition, the step 9-3) is preferably performed for 18 to 30 hours.

The present invention also provides a pharmaceutical composition for treating or preventing diseases caused by immunomodulation disorders, comprising a compound represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof.

In the present invention, the disease caused by the immunomodulation abnormality may be any one selected from the group consisting of arteriosclerosis, autoimmune disease and arthritis, but is not limited thereto.

In the experimental examples of the present invention, it was confirmed that the compound of Formula 1 can induce selective activation of Th1 or Th2 response in NKT cells.

The pharmaceutical composition of the present invention can be formulated into an oral or injection dosage form. Formulations for oral administration include, for example, tablets, capsules, etc. These formulations may contain, in addition to the active ingredient, a diluent such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, : Silica, talc, stearic acid and its magnesium or calcium salt and / or polyethylene glycol). Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpicoloridine, optionally mixed with starch, agar, A disintegrating or boiling mixture such as a sodium salt and / or an absorbent, a colorant, an anti-agent, and a sweetening agent. As the formulations for injection, isotonic aqueous solutions or suspensions are preferred.

The composition may be sterilized and / or contain adjuvants such as preservatives, stabilizers, wettable or emulsifying accelerators, salts for controlling osmotic pressure and / or buffers, and other therapeutically useful substances.

The formulations may be prepared by conventional mixing, granulating or coating methods and may contain the active ingredient in the range of about 0.1 to 75% by weight, preferably about 1 to 50% by weight. A unit dosage form for a mammal about 50-70 kg contains about 10-200 mg of active ingredient.

The preferred dosage of the compound of the present invention varies depending on the condition and the weight of the patient, the degree of the disease, the form of the drug, the administration route and the period of time, but can be appropriately selected by those skilled in the art. However, for the desired effect, the compound of the present invention is preferably administered at a daily dose of 0.0001 to 100 mg / kg (body weight), preferably 0.001 to 100 mg / kg (body weight). Administration may be by oral or parenteral route, once or divided once a day.

The pharmaceutical composition of the present invention can be administered to mammals including rats, mice, livestock, and humans in various routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine or intracerbroventricular injections.

Hereinafter, the configuration of the present invention will be described in detail.

Although the structure-activity relationship of the [alpha] -GalCer analog is difficult to predict, the present inventors have recognized the importance of the binding affinity in the CD1d-alpha-GalCer complex for selective activation of either the Th1 or Th2 response. Unlike sugar and N -acyl moieties, extensive deformation of the sphingosine skeleton has not yet been actively investigated. Therefore, the inventors have focused on the change of complex stability through the structural diversity of the sphingosine skeleton. It was also confirmed through the crystal structure of CD1d that the N -acyl and phytosphingosine lipid chains of alpha -GalCer tightly fit into each of the two hydrophobic pockets of the CD1d-A 'pocket and the F' pocket (Zajonc DM et al., Nat . Immunol . , 2005, 6, 810-818). Through a structural investigation of the F 'pocket, we found a series of aromatic amino acids, such as Tyr73, Phe77 and Trp133, located in the region of contact with the sphingosine skeleton in the CD1d F' pocket. Thus, we believe that introducing a heteroaromatic moiety into the sphingosine backbone can significantly affect non-covalent interactions between the a-GalCer analog and the CD1d protein, which is an alternative to the Th1 or Th2 response in NKT cells It is assumed that it can induce activation.

The present inventors have made α-GalCer analogs A1 , B1 , C1 , G1 and G5 having a new sphingosine skeleton containing an aromatic heterocycle such as pyrazole at C5-C7 positions (FIG. 1). α-GalCer analogs A1 and B1 were designed to mimic KRN7000 ( 1 ) and OCH ( 3 ), respectively. We also introduced benzene into the sphingosine backbone (α-GalCer analogs C1 , G1 and G5 ) as another aromatic moiety to introduce additional non-covalent interactions in the binding pocket of the CD1d protein.

Also, as shown in 2, α-GalCer analog C1 were well hit the binding pocket of the CD1d, which first and ball crystallized: OK via the docking simulation analysis (docking simulation study) carried out using the (PDB 3HE6) CD1d protein Respectively. Except B1, all α-GalCer analogs have been docked successfully, in silico (in silico ) binding analysis. As a result, these analogs can affect the stability of the CD1d-α-GalCer complex through non-covalent interactions with three aromatic residues in the F 'pocket of CD1d and potentially lead to selective activation of the immune system It can be induced.

The synthesis procedure was initiated using D-galactal, which already had the desired stereochemistry of all chiral centers required for the [alpha] -GalCer analog. As shown in Scheme 2, the primary alcohol of D-galactal was selectively trylated to obtain 9 , and the remaining two secondary alcohols were benzyl-protected. The resulting product 10 was formylated via the Vilsmeier-Haack reaction to give D-galactalcarbaldehyde 11 . At the same time, Cbz-protected alkylhydrazine 12 was prepared via reductive amination of Cbz-hydrazine and the corresponding aldehyde, followed by deprotection of the Cbz group via catalytic hydrogenation to produce alkylhydrazine ( 13 ). Unlike common alkylamines, alkylhydrazines were not easily obtained under typical reductive amination conditions (NaBH ₃ CN, catalytic AcOH). Through systematic screening of various acids (AcOH, p TsOH, HCl and HCO ₂ H), reducing agents (NaBH ₃ CN, BH ₃ , LiAlH ₄ and NaBH ₄ ) and solvents (MeOH, THF and DCM) , It is preferable to use a combination of NaBH ₃ CN, HCO ₂ H and MeOH as optimal conditions for carrying out a reductive amination reaction.

[Reaction Scheme 2]

Subsequent to the 11 dual electrophilic (dielectrophilic) α, β- unsaturated aldehydes sphingosine backbone 14 parts by double nucleophilic (dinucleophilic) Chemistry alkyl hydrazine in MeOH 13 and ring having aromatic pyrazole ring as shown in scheme 3 of Gt; By varying the alkylhydrazine in this step, four different sphingosine-type compounds could easily be obtained. Then, the 14-OH position of the C2 and the mesylation, and the resulting mesylate 15 with NaN ₃ microwave 15 - through the aid of displacement reaction was converted to the azido compound 16. p a C1-16 OH positions of TsOH in methanol solution of di-trityl illustration (detritylation) to prepare a suitably-protected sphingosine derivative 17 for after-galactosidase when retardation (galactosidation). Selective glycoside bonds were obtained in a yield of 61-88% through a highly reactive galactosyl iodide donor and its anhydride bond of its receptor 17. [ 18 was reduced to the amino group via the Staudinger reaction, and the resulting compound was then coupled with EDTA-mediated amide coupling with the sertatic acid to prepare the galactosylceramide derivative 19 . Finally, six benzyl protecting groups in 19 were removed via catalytic hydrogenation over Pd (OH) ₂ on carbon in EtOH-DCM co-solvent under atmospheric hydrogen to give the final compounds A1 , B1 , C1 , G1 and G5 ).

[Reaction Scheme 3]

Then, through an experimental example of the present invention, the biological activity of the? -GalCer analogues of the present invention containing a heteroaromatic group in the sphingosine skeleton can be selectively induced by cytokines such as INF-γ, IL-4 and IL-17 Were monitored using an ELISA. Under the treatment of? -GalCer analogs, the relative amounts of these cytokines released by rat hepatic mononuclear cells (HMNC) containing NKT cells were measured relative to KRN7000 ( 1 ,? Galcer-1). As a result, as shown in FIG. 3 to FIG. 5, it was found that the novel? -GalCer analogue of the present invention can induce selective activation of Th1 or Th2 response in NKT cells.

Consequently, in the present invention, a theoretical design to introduce additional non-covalent interactions with aromatic residues such as Tyr73, Phe77, and Trp133 in the binding pocket of the CD1d protein results in a new series comprising heteroaromatic groups in the sphingosine skeleton Lt; RTI ID = 0.0 > a-GalCer < / RTI > Biological evaluation of the ELISA-based on the produced analogs in rat primary NKT cells revealed that the α-GalCer analogs could induce selective activation of Th1 or Th2 responses in NKT cells.

The present invention provides an alpha-galactosyl ceramide analogue capable of inducing selective activation of a Th1 or Th2 response in NKT cells, a method for producing the same, and a pharmaceutical composition for treating or preventing diseases caused by immunomodulation disorders There is an effect that can be done.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing the structures of KRN7000 (1) and its derivative (2-3), which are typical α-GalCer analogues, and α-GalCer analogs (A1, B1, C1, G1 and G5).
Figure 2 is a schematic representation of a docking simulation of the invention? -GalCer analog C1 in the binding pocket of the mCD1d protein.
Fig. 3 shows the secretion amount of IFN-y in vivo after administering the? -GalCer analog of the present invention.
Figure 4 shows the secretion amount of IL-4 in vivo after administration of the? -GalCer analog of the present invention.
Figure 5 shows the secretion of IL-17 in vivo after administration of the [alpha] -GalCer analog of the present invention.

Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are provided to aid understanding of the present invention, and the scope of the present invention is not limited to the following examples.

Manufacturing example  1: Compound S12 -1 production

Undecanal (5 mL, 24.37 mmol) and benzyl carbazate (4.45 g, 26.8 mmol) were stirred in MeOH (120 mL) at room temperature. After 1 hour, the addition of formic acid (0.5 mL) and _{NaBH 3 CN (7.66 g, 121.85} mmol), and the reaction mixture was stirred at room temperature for 5 hours. The MeOH was then removed by evaporation under reduced pressure, and the resulting mixture was diluted with EtOAc and washed with saturated NaHCO ₃ (aq) and brine. Then, the combined organic layers were dried over anhydrous Na ₂ SO ₄ (s). The filtrate was concentrated under reduced pressure and silica gel flash column chromatography (EtOAc: Hex = 1: 4 , v / v) to yield the title compound as a white solid of amorphous -1 S12 (5.94 g, 76%) as a.

^{1 H NMR (500 MHz, CDCl} 3) δ 7.38-7.26 (m, 5H), 6.31 (br s, 1H), 5.13 (s, 2H), 3.97 (br s, 1H), 2.86 (t, J = 4.5 Hz, 2H), 1.45 (quin, J = 7.1 Hz, 2H), 1.31-1.23 (m, 16H), 0.88 (t, J = 6.8 Hz, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ) 隆 157.5, 136.3, 128.8, 128.5, 128.4, 67.3, 52.3, 32.1, 29.84, 29.83, 29.79, 29.76, 29.57, 28.0, 27.3, 22.9, 14.3; ^{LRMS (ESI +) m / z} calcd for C 25 H 24 O 4 [M + H] +: 321.25; Found: 321.32.

Example  1: Preparation of compound A1

Step 1: Preparation of compound 9

Galactal (3.0 g, 20.53 mmol), trityl chloride (8.58 g, 30.79 mmol) and DMAP (251 mg, 2.053 mmol) were stirred at room temperature for 18 hours in anhydrous pyridine (50 mL). After the reaction was complete by monitoring with TLC, the pyridine was evaporated under reduced pressure and the resulting mixture was diluted with EtOAc and washed with saturated NaHCO ₃ (aq) and brine. The combined organic layers were dried over anhydrous Na ₂ SO ₄ (s). The filtrate was concentrated under reduced pressure and purified by silica gel flash column chromatography (EtOAc: Hex = 1: 1, v / v) to give the title compound 9 as an amorphous white solid (6.2 g, 78%).

[?] _D ²⁵ + 12.3 (c = 1.0, CHCl ₃ ); ^{1 H NMR (500 MHz, CDCl} 3) δ 7.46-7.44 (m, 6H), 7.33-7.23 (m, 12H), 6.42 (dd, J = 6.0, 1.5 Hz, 1H), 4.73 (dt, J = 6.0 , 1.5 Hz, 1H), 4.32 (br s, 1H), 4.01 (d, J = 4.5 Hz, 1H), 3.96 (t, J = 5.3 Hz, 1H), 3.52 (dd, J = 10.0, 5.5 Hz, 1H), 3.38 (dd, J = 10.0, 4.5 Hz, 1H), 2.71 (brs, 1H), 2.56 (brs, 1H); ¹³ C NMR (125 MHz, CDCl ₃ )? 144.7, 143.6, 128.8, 128.2, 127.5, 103.6, 87.6, 75.7, 66.2, 64.5, 63.5; ^{LRMS (ESI +) m / z} calcd for C 25 H 24 O 4 [M + Na] +: 411.16; Found: 411.10.

Step 2: Preparation of compound 10

Sodium hydride (1.48 g in 60% mineral oil, 37.06 mmol) was added over 15 minutes to a solution of compound 9 (3.0 g, 7.72 mmol) in DMF (50 mL) with stirring at 0 ° C. The reaction mixture was stirred for 30 minutes and allowed to warm to room temperature. Then, benzyl chloride (2.13 mL, 18.53 mmol) and tetra- n -butylammonium iodide (683 mg, 1.853 mmol) were carefully added dropwise. The mixture was stirred under nitrogen atmosphere for 3 hours at ambient temperature. After the reaction was complete by monitoring with TLC, the product was diluted with EtOAc and washed twice with brine. The combined organic layers were dried over anhydrous Na ₂ SO ₄ (s). The filtrate was concentrated under reduced pressure and purified by silica gel flash column chromatography (EtOAc: Hex = 1: 3, v / v) to give the title compound 10 as an amorphous white solid (3.6 g, 82%).

[?] _D ²⁵ - 6.8 (c = 1.1, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ )? 7.42-7.39 (m, 7H), 7.34-7.17 (m, 18H), 6.32 (d, J = 10.3 Hz, J = 16.5, 9.5 (m, 2H), 3.97-3.96 (m, 1H), 3.60 (dd, J = Hz, 1H); ^{13 C NMR (75 MHz, CDCl} 3) δ 144.3, 144.0, 138.7, 138.5, 128.8, 128.5, 128.3, 128.1, 128.0, 127.6, 127.6, 127.1, 100.2, 87.0, 77.4, 76.2, 73.5, 71.4, 70.9, 62.4 ; LRMS (ESI ⁺ ) m / z calcd for C ₃₉ H ₃₇ O ₄ [M + H] ⁺ : 569.27; Found: 569.33.

Step 3: Preparation of compound 11

The _{POCl 3 (1.45 mL, 15.83 mmol} ) with stirring at 0 over ℃ to 10 (3.0 g, 5.28 mmol) solution of the compound in DMF (30 mL) for 30 minutes was added. The reaction mixture was stirred for 1 hour and allowed to warm to room temperature. After 12 h, the product was diluted with EtOAc and washed with saturated NaHCO ₃ (aq) and brine. Then, the combined organic layers were dried over anhydrous Na ₂ SO ₄ (s). The filtrate was concentrated under reduced pressure and purified by silica gel flash column chromatography (EtOAc: Hex = 1: 4, v / v) to afford the title compound 11 as white syrup (1.69 g, 54%).

[?] _D ²⁵ - 12.2 (c = 1.1, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ )? 9.25 (s, 1H), 7.39-7.05 (m, 26H), 4.71-4.44 (m, 6H), 3.77-3.60 (m, 3H); ^{13 C NMR (75 MHz, CDCl} 3) δ 189.5, 164.6, 144.0, 138.8, 137.7, 128.9, 128.6, 128.3, 128.0, 127.9, 127.8, 127.6, 127.4, 127.1, 119.3, 87.1, 79.2, 77.4, 73.7, 73.3 , 71.5, 65.0, 62.6; LRMS (ESI ⁺ ) m / z calcd for C ₄₀ H ₃₇ O ₅ [M + H] ⁺ : 597.26; Found: 597.19.

Step 4: Preparation of compound S14 -1

MeOH (20 mL) was stirred in the compound S12 -1 (1.61 g, 5.03 mmol ) 3 time, Pd / C out for carefully added, and the atmosphere of the reaction mixture under H ₂ gas solution. The mixture was purged with argon gas for 5 minutes and Compound 11 was added thereto. The reaction mixture was further stirred at room temperature for 3 hours. The resulting mixture was then filtered through a Celite ^® -filled glass filter and washed several times with ethyl acetate. The filtrate was concentrated under reduced pressure and silica gel flash column chromatography (EtOAc: Hex = 1: 3 , v / v) to give the to give the title compound S14 -1 as a colorless oil (1.1 g, 86%).

[?] _D ²⁵ - 18.8 (c = 1.2, CHCl ₃ ); ^{1 H NMR (500 MHz, CDCl} 3) δ 7.42-7.36 (m, 7H), 7.29-7.21 (m, 18H), 7.02-7.00 (m, 2H), 4.52 (d, J = 12.0 Hz, 1H), 4.47 (d, J = 6.0 Hz , 1H), 4.36 (d, J = 11.0 Hz, 1H), 4.32-4.29 (m, 2H), 4.05 (t, J = 7.2 Hz, 2H), 4.01 (br s, 1H), 3.86-3.84 (m, 1H), 3.18-3.16 (m, 2H), 2.59 (d, J = 4.0 Hz, , 0.87 (t, J = 7.0 Hz, 3H); ^{13 C NMR (125 MHz, CDCl} 3) δ 144.1, 139.0, 138.3, 138.1, 128.9, 128.8, 128.6, 128.4, 128.3, 128.0, 127.91, 127.85, 127,8, 127.2, 119.3, 86.8, 81.8, 74.7, 73.4 , 70.4, 64.6, 52.5, 32.1, 30.6, 29.8, 29.7, 29.5, 29.3, 26.8, 22.9, 14.3; LRMS (ESI ⁺ ) m / z calcd for C ₅₁ H ₆₁ N ₂ O ₄ [M + H] ⁺ : 765.46; Found: 765.77.

Step 5: Preparation of compound S15 -1

The dry DCM (4 mL) of compound S14 -1 (345 mg, 0.451 mmol ) and DIPEA (242 μL, 1.363 mmol) to the solution, MsCl (70 μL, 0.902 mmol ) was added dropwise. After stirring the reaction mixture for 3 hours, diluted with EtOAc and the product was washed with saturated NaHCO ₃ (aq) and brine. Then, the combined organic layers were dried over anhydrous Na ₂ SO ₄ (s). Filtered and concentrated under reduced pressure and silica gel flash column chromatography (EtOAc: Hex = 1: 2 , v / v) to give the to give the title compound S15 -1 as a colorless oil (343 mg, 92%).

^{_{[α] D 25 - 17.2 (}} c = 0.7, CHCl 3); ^{1 H NMR (500 MHz, CDCl} 3) δ 7.37-7.34 (m, 7H), 7.30-7.12 (m, 18H), 7.16 (s, 1H), 7.12 (s, 1H), 4.79 (d, J = 11.0 Hz, 1H), 4.58-4.55 (m , 1H), 4.49 (d, J = 11.5 Hz, 1H), 4.42 (d, J = 11.0 Hz, 1H), 4.34 (d, J = 4.5 Hz, 1H), 4.28 (d, J = 11.5 Hz , 1H), 4.23 (dd, J = 6.0, 5.0 Hz, 1H), 4.01 (t, J = 7.2 Hz, 2H), 3.43 (dd, J = 11.3, 2.2 Hz, 1H J = 7.0 Hz, 1H), 2.90 (dd, J = 11.0, 4.5 Hz, 1H), 2.85 (s, 3H), 1.80 3H); ^{13 C NMR (125 MHz, CDCl} 3) δ 143.4, 139.6, 138.3, 138.2, 129.5, 128.9, 128.8, 128.6, 128.55, 128.4, 128.2, 128.0, 127.9, 127.8, 127.4, 117.4, 87.2, 82.8, 80.8, 75.8 , 72.3, 69.7, 63.5, 52.5, 38.6, 32.1, 30.4, 29.8, 29.8, 29.7, 29.5, 29.3, 26.8, 22.9, 14.3; LRMS (ESI ⁺ ) m / z calcd for C ₅₂ H ₆₃ N ₂ O ₆ S [M + H] ⁺ : 843.44; Found: 843.31.

Step 6: Preparation of compound S16 -1

The compound S15 -1 (333 mg, 0.395 mmol ) and _{NaN 3 (257 mg, 3.95 mmol} ) was dissolved in DMF (4 mL) was irradiated with microwaves (30 watt) at 120 ℃ for 4 hours. After completion of the reaction as indicated by TLC, the resulting mixture was diluted with EtOAc and washed with brine. The combined organic layers were dried over anhydrous Na ₂ SO ₄ (s). Filtered and concentrated under reduced pressure and silica gel flash column chromatography (EtOAc: Hex = 1: 4 , v / v) to give the to give the title compound S16 -1 as a colorless oil (250 mg, 80%).

[?] _D ²⁰ - 13.7 (c = 3.3, CHCl ₃ ); ^{1 H NMR (500 MHz, CDCl} 3) δ 7.50 (d, J = 0.5 Hz, 1H), 7.48-7.43 (m, 6H), 7.34-7.21 (m, 18H), 7.03-7.01 (m, 2H), 4.61 (d, J = 11.0 Hz , 1H), 4.57 (d, J = 4.5 Hz, 1H), 4.46 (d, J = 11.0 Hz, 2H), 4.23 (d, J = 11.5 Hz, 1H), 4.08 ( td, J = 7.2, 2.0 Hz , 2H), 3.78 (dd, J = 7.0, 5.0 Hz, 1H), 3.54 (td, J = 7.3, 2.3 Hz, 1H), 3.47 (dd, J = 10.0, 3.0 Hz 1H), 3.38 (dd, J = 9.7, 7.8 Hz, 1H), 1.86-1.83 (m, 2H), 1.30-1.25 (m, 16H), 0.90 (t, J = 7.0 Hz, 3H); ^{13 C NMR (125 MHz, CDCl} 3) δ 143.9, 139.5, 138.4, 138.2, 129.2, 128.9, 128.5, 128.4, 128.1, 128.0, 127.99, 127.8, 127.7, 127.69, 127.2, 117.7, 87.3, 80.8, 74.8, 74.7 , 70.6, 63.9, 63.4, 60.6, 52.5, 32.1, 30.5, 29.8, 29.7, 29.5, 29.3, 26.9, 22.9, 21.3, 14.4, 14.3; LRMS (ESI ⁺ ) m / z calcd for C ₅₁ H ₆₀ N ₅ O ₃ [M + H] ⁺ : 790.47; Found: 790.33.

Step 7: Preparation of compound S17 -1

Compound was dissolved in the S16 -1 (170 mg, 0.215 mmol) and p TsOH (61 mg, 0.323 mmol ) to MeOH (2 mL) and the mixture was stirred at room temperature for 5 hours. After the reaction was complete, as indicated by TLC, the resulting mixture was diluted with EtOAc and washed with saturated NaHCO ₃ (aq) and brine. The combined organic layers were dried over anhydrous Na ₂ SO ₄ (s). The filtrate was concentrated under reduced pressure and silica gel flash column chromatography (EtOAc: Hex = 1: 3 , v / v) to give the to give the title compound S17 -1 as a colorless oil (98 mg, 83%).

[?] _D ²⁵ - 47.0 (c = 0.5, CHCl ₃ ); ^{1 H NMR (500 MHz, CDCl} 3) δ 7.54 (s, 1H), 7.39 (s, 1H), 7.35-7.26 (m, 8H), 7.22-7.21 (m, 2H), 4.64-4.57 (m, 3H ), 4.54 (d, J = 11.5 Hz, 1H), 4.32 (d, J = 11.5 Hz, 1H), 4.09 (t, J = 7.3 Hz, 2H), 3.86 (t, J = 5.5 Hz, 1H), 3.79 (br s, 2H), 3.86 (q, J = 5.2 Hz, 1H), 2.34 (br s, 1H), 1.87-1.83 (m, 2H), 1.29-1.24 (m, 16H), 0.87 (t, J = 7.0 Hz, 3H); ^{13 C NMR (125 MHz, CDCl} 3) δ 139.3, 138.0, 137.8, 129.2, 128.64, 128.63, 128.4, 128.1, 128.0, 127.98, 117.9, 81.9, 74.9, 74.1, 70.6, 63.6, 62.3, 52.6, 32.1, 30.5 , 29.77, 29.75, 29.7, 29.5, 29.3, 26.8, 22.9, 14.3; ^{LRMS (ESI +) m / z} calcd for C 32 H 46 N 5 O 3 [M + H] +: 548.36; Found: 548.25.

Step 8: Preparation of compound S18 -1

To a solution of 1-O-acetyl-2,3,4,6-tetra-O-benzyl-D-galactopyranoside (287 mg, 0.493 mmol) in CH ₂ Cl ₂ (3 mL) at 0 ° C was added TMSI 70 [mu] L, 0.493 mmol) and stirred at 0 < 0 > C for 30 min. 3 mL of anhydrous toluene was added to quench the reaction and the remaining TMSI was removed by azeotropic evaporation with anhydrous toluene three times. The pale yellow residue obtained above was dissolved in anhydrous benzene (1 mL) and placed under an argon atmosphere. Remove the round bottom flask in the (RBF), molecular sieve (MS, 4 Å, 100 mg ), TBAI (546 mg, 1.48 mmol), compound S17 -1 (90 mg, 0.164 mmol ), and DIPEA (86 μL, 0.493 mmol) was added to anhydrous benzene (1 mL). The reaction mixture was stirred at 65 < 0 > C for 10 minutes under argon. After TBAI was completely dissolved, glycosyl iodide in the anhydrous benzene was added to the flask, and the reaction mixture was stirred at 65 DEG C for 3 hours. The reaction was quenched by the addition of EtOAc (10 mL) and cooled to 0 < 0 > C. The white precipitate and MS were filtered off by washing with EtOAc through a Celite®-packed glass filter. The filtrate was washed with saturated Na ₂ S ₂ O ₃ (aq) (2 × 10 mL) and brine, and dried over anhydrous Na ₂ SO ₄ (s). Filtered and concentrated under reduced pressure and silica gel flash column chromatography (EtOAc: Hex = 1: 3 , v / v) to give the to give the title compound S18 -1 as a colorless oil (154 mg, 88%).

^{_{[α] D 25 + 9.9 (}} c = 1.1, CHCl 3); ^{1 H NMR (500 MHz, CDCl} 3) δ 7.50 (s, 1H), 7.38-7.15 (m, 31H), 4.93 (d, J = 11.5 Hz, 1H), 4.87 (d, J = 3.5 Hz, 1H) 2H), 4.48-4.46 (m, 2H), 4.36 (d, J = 12.0 Hz, 1H), 4.30 (s, 2H) , J = 3.5 Hz, 1H) , 4.06-4.03 (m, 3H), 3.98 (dd, J = 10.0, 2.5 Hz, 1H), 3.95-3.90 (m, 4H), 3.70 (dd, J = 11.0, 7.0 Hz, 1H), 3.51-3.45 (m, 3H), 1.83-1.80 (m, 2H), 1.30-1.26 (m, 16H), 0.87 (t, J = 7.0 Hz, 3H); ^{13 C NMR (125 MHz, CDCl} 3) δ 139.5, 139.0, 138.91, 138.89, 138.5, 138.4, 138.2, 129.3, 128.64, 128.57, 128.54, 128.53, 128.48, 128.46, 128.44, 128.42, 128.41, 128.37, 128.34, 128.2 , 128.9, 127.98, 127.93, 127.89, 127.86, 127.80, 127.77, 127.75, 127.72, 127.6, 127.5, 117.8, 98.8, 80.7, 79.1, 76.5, 75.3, 75.0, 74.9, 74.6, 73.7, 73.4, 73.3, , 69.9, 69.2, 67.9, 62.3, 52.5, 32.1, 30.5, 29.79, 29.78, 29.68, 29.5, 29.3, 26.9, 22.9, 14.3; LRMS (ESI ⁺ ) m / z calcd for C ₆₆ H ₈₀ N ₅ O ₈ [M + H] ⁺ : 1070.60; Found: 1070.66.

Preparation of compound S19 -1: Step 9 and Step 10

Compound S18 was dissolved in -1 (56 mg, 0.0523 mmol) and _{PPh 3 (27 mg, 0.1046 mmol} ) , benzene (600 μL) and H ₂ O (6 μL). The mixture was then stirred at 60 < 0 > C for 12 hours (step 9). After the reaction was complete by monitoring with TLC, the reaction mixture was concentrated under reduced pressure and redispersed in anhydrous THF (300 [mu] L). (48 mg, 0.1203 mmol), EDCI (23 mg, 0.1203 mmol) and DMAP (catalytic amount) were added to the mixture and stirred at room temperature for 24 hours (step 10). After completion of the reaction, the resulting mixture was diluted with EtOAc and washed with brine. The combined organic layers were dried over anhydrous Na ₂ SO ₄ (s). Filtered and concentrated under reduced pressure and silica gel flash column chromatography (EtOAc: Hex = 1: 3 , v / v) to give the to give the title compound S19 -1 as a colorless oil (63 mg, 85%).

[?] _D ²⁰ - 2.7 (c = 0.9, CHCl ₃ ); ¹ H NMR (500 MHz, CDCl ₃ )? 7.53 (s, IH), 7.41 (s, IH), 7.37-7. 21 (m, 30H), 6.16 (d, J = 9.5 Hz, J = 11.5 Hz, 1H), 4.80-4.71 (m, 5H), 4.63 (d, J = 11.5 Hz, 1H), 4.57-4.54 (m, 2H), 4.49-4.45 (m, 3H), 4.36 (d , J = 12.0 Hz, 1H) , 4.22 (d, J = 12.0 Hz, 1H), 4.10-4.01 (m, 4H), 3.95-3.86 (m, 5H), 3.55 (dd, J = 10.5, 3.5 Hz, 1H), 3.48 (dd, J = 9.3, 6.8 Hz, 1H), 3.36 (dd, J = 9.3, 6.2 Hz, 1H), 1.96-1.87 (m, 2H), 1.83-1.80 -1.47 (m, 2H), 1.31-1.23 (m, 60H), 0.91-0.86 (m, 6H); ^{13 C NMR (75 MHz, CDCl} 3) δ 172.9, 139.7, 138.8, 138.7, 138.6, 137.8, 129.6, 128.61, 128.59, 128.56, 128.54, 128.48, 128.45, 128.2, 128.1, 128.06, 128.0, 127.9, 127.8 127.6, 29.97, 29.7, 29.7, 29.7, 29.7, 29.7, 29.7, 29.7, 29.7, 29.5, 29.61, 29.58, 29.54, 29.4, 26.9, 25.9, 24.7, 22.9, 14.3; LRMS (ESI ⁺ ) m / z calcd for C ₉₂ H ₁₃₂ N ₃ O ₉ [M + H] ⁺ : 1423.00; Found: 1423.07.

Step 11: Preparation of compound A1

Compound is dissolved in S19 -1 (18 mg, 12.65 μmol ) and _{Pd (OH) 2 / C (} 18 mg, 20 wt% loading (dry weight basis)) to EtOH (1.2 mL) and DCM (0.4 mL). The mixture was then stirred under H ₂ atmosphere (1 atm) for 15 hours. After completion of the reaction as indicated by TLC, the catalyst was filtered off through a 0.45 μm PTFE syringe filter and washed with MeOH / DCM (1: 1, v / v) solution. The filtrate was concentrated under reduced pressure to give the title compound A1 as an amorphous white solid (9.7 mg, 87%).

[?] _D ²⁰ + 41.9 (c = 0.56, CHCl ₃ / MeOH = 1: 1); ^{1 H NMR (500 MHz, CDCl} 3 / CD 3 OD = 1: 1; reference peak: CD 3 OD at 3.31 ppm) δ 7.59 (s, 2H), 4.93 (d, J = 4.0 Hz, 1H), 4.70 ( d, J = 5.5 Hz, 1H ), 4.11 (t, J = 7.2 Hz, 2H), 4.05 (dt, J = 7.7, 3.5 Hz, 1H), 3.94 (d, J = 2.5 Hz, 1H), 3.88- 3.72 (m, 7H), 2.22 (t, J = 7.7 Hz, 2H), 1.85 (quin, J = 7.0 Hz, 2H), 1.62 (quin, J = 7.0 Hz, 2H), 1.35-1.25 (m, 60H ), 0.90-0.86 (m, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) 隆 175.4, 155.1, 108.2, 32.7, 30.4, 30.2, 30.2, 30.1, 23.4, 14.5; HRMS (FAB ⁺ ) m / z calcd for C ₅₀ H ₉₆ N ₃ O ₉ [M + H] ⁺ : 882.7147; Found: 882.7143.

Example  2 to 4: Preparation of compounds A2 to A4

Compounds A2 to A4 were obtained in the same manner as in Example 1, as described below.

1) Example 2 (Compound A2)

^{1 H NMR (500 MHz, CDCl} 3 / CD 3 OD = 1: 1; reference peak: CD 3 OD at 3.31 ppm) δ 7.50 (s, 1H), 7.49 (s, 1H), 4.89 (d, J = 3.7 Hz, 1H), 4.67 (d , J = 5.6 Hz, 1H), 4.06 (t, J = 7.2 Hz, 2H), 3.91-3.90 (m, 1H), 3.88-3.68 (m, 7H), 2.18 (t , J = 7.3 Hz, 2H) , 1.81 (quin, J = 7.0 Hz, 2H), 1.59 (quin, J = 7.0 Hz, 2H), 1.30-1.25 (m, 56H), 0.88-0.85 (m, 6H)

2) Example 3 (Compound A3)

^{1 H NMR (500 MHz, CDCl} 3 / CD 3 OD = 1: 1; reference peak: CD 3 OD at 3.31 ppm) δ 7.50 (s, 1H), 7.49 (s, 1H), 4.89 (d, J = 3.7 Hz, 1H), 4.67 (d , J = 5.6 Hz, 1H), 4.06 (t, J = 7.2 Hz, 2H), 3.91-3.90 (m, 1H), 3.88-3.68 (m, 7H), 2.18 (t , J = 7.3 Hz, 2H) , 1.81 (quin, J = 7.0 Hz, 2H), 1.59 (quin, J = 7.0 Hz, 2H), 1.30-1.25 (m, 56H), 0.88-0.85 (m, 6H)

3) Example 4 (Compound A4)

^{1 H NMR (500 MHz, CDCl} 3 / CD 3 OD = 1: 1; reference peak: CD 3 OD at 3.31 ppm) δ 7.48 (s, 2H), 7.23-7.20 (m, 2H), 7.15-7.10 (m , 3H), 4.89 (d, J = 3.7 Hz, 1H), 4.65 (d, J = 5.5 Hz, 1H), 4.05 (t, J = 7.3 Hz, 2H), 3.89 (d, J = 3.3 Hz, 1H ), 3.83-3.68 (m, 67) , 2.59 (t, J = 7.7 Hz, 2H), 2.18 (dd, J = 8.4, 6.2 Hz, 2H), 1.80 (quin, J = 7.2 Hz, 2H), 1.66 2H), 1.27-1.24 (m, 16H), 0.85 (t, J = 7.0 Hz, 3H)

Example  5: Preparation of compound A5

Following the same procedure as in steps 1 to 8 of Example 1, Compound A5 was obtained by the following method.

Add the compound S18 -1 (0.3 mmol) and hexacosyne (0.35 mmol) of tBuOH (1.5 mL) and, CuSO ₄ (0.03 mmol) and sodium ascorbate (0.06 mmol) was placed in H ₂ O (1.5 mL). The reaction mixture was heated at 80 < 0 > C for 24 hours. After dissolving 30 mg of the product and 150 mg of Pd (OH) ₂ / C in EtOH (1.5 mL) and DCM (0.5 mL), the reaction mixture was reacted under hydrogen gas conditions under 1 atmosphere for 24 hours to give the title compound Respectively.

^{1 H NMR (500 MHz, CDCl} 3 / CD 3 OD = 1: 1; reference peak: CD 3 OD at 3.31 ppm) δ 8.12 (s, 1H), 7.64 (s, 1H), 7.58 (s, 1H), 4.86 (d, J = 3.7 Hz , 1H), 4.52 (d, J = 6.9 Hz, 1H), 4.28 (dd, J = 11.3, 3.4Hz, 2H), 4.16-4.08 (m, 4H), 3.87 (d , J = 2.9 Hz, 1H) , 3.77 (dd, J = 10.0, 3.9 Hz, 1Hz), 3.72-3.63 (m, 4H), 2.75 (t, J = 7.8 Hz, 2H), 1.82 (quin, J = 6.9 Hz, 2H), 1.68 (quin, J = 7.1 Hz, 2H), 1.29-1.23 (m, 58H), 0.87-0.84

Manufacturing example  2: Compound S12 -2 production

Wherein the preparation of Example 1, the title compound as a white solid of amorphous S12 -2 from acetaldehyde by the same procedure was synthesized (yield: 62%).

^{1 H NMR (500 MHz, CDCl} 3) δ 7.38-7.26 (m, 5H), 6.38 (br s, 1H), 5.13 (s, 2H), 3.97 (br s, 1H), 2.91 (q, J = 6.5 Hz, 2H), 1.07 (t, J = 7.0 Hz, 3H); ^{13 C NMR (125 MHz, CDCl} 3) δ 157.4, 136.3, 128.8, 128.5, 128.4, 67.3, 46.4, 13.0; LRMS (ESI ⁺⁾ m / z calcd for C ₁₀ H ₁₅ O ₂ N ₂ [M + H] ^+: 195.11; Found: 195.32.

Example  6: Preparation of compound B1

Compound 11 was obtained in the same manner as in Steps 1 to 3 of Example 1.

Preparation of compound S14 -2: Step 4

Example 1 Step 4 by the same procedure as compound 11 (500 mg, 0.838 mmol) and the compound was synthesized from the title compound S14 S12 -2 -2 as a colorless oil from (488 mg, 2.514 mmol) (yield: 496 mg, 93%).

[?] _D ²⁵ - 20.8 (c = 1.8, CHCl ₃ ); ^{1 H NMR (500 MHz, CDCl} 3) δ 7.42-7.38 (m, 7H), 7.31-7.21 (m, 18H), 7.02-7.00 (m, 2H), 4.53 (d, J = 12.0 Hz, 1H), 4.47 (d, J = 6.0 Hz , 1H), 4.38-4.29 (m, 3H), 4.13 (q, J = 7.3 Hz, 2H), 4.01-3.98 (m, 1H), 3.85 (dd, J = 6.2, 3.3 Hz, 1H), 3.17 (d, J = 5.5 Hz, 2H), 2.58 (d, J = 6.5 Hz, 1H), 1.45 (t, J = 7.2 Hz, 3H); ^{13 C NMR (125 MHz, CDCl} 3) δ 144.1, 139.0, 138.3, 138.2, 128.9, 128.6, 128.4, 128.4, 128.2, 128.0, 127.9, 127.9, 127.8, 127.2, 119.4, 86.8, 81.8, 74.8, 73.5, 70.5 , 70.5, 64.6, 47.2, 15.7; LRMS (ESI ⁺ ) m / z calcd for C ₄₂ H ₄₃ N ₂ O ₄ [M + H] ⁺ : 639.32; Found: 639.15.

Preparation of compound S16 -2: Step 5 and Step 6

The embodiment of step 15 and as a colorless oil by the same procedure from the sixth compound 14-2 (458 mg, 0.717 mmol) was synthesized from the title compound S16 -2 (2 step yield: 359 mg, 75%).

^{_{[α] D 25 - 15.5 (}} c = 1.2, CHCl 3); ^{1 H NMR (500 MHz, CDCl} 3) δ 7.49 (s, 1H), 7.43-7.41 (m, 6H), 7.31-7.19 (m, 18H), 7.00-6.98 (m, 2H), 4.60 (d, J = 11.0 Hz, 1H), 4.56 (d, J = 5.0 Hz, 1H), 4.44 (dd, J = 11.3, 2.8 Hz, 2H), 4.21 (d, J = 11.5 Hz, 1H), 4.13 (qd, J = 7.5, 1.5 Hz, 2H) , 3.50 (td, J = 7.4, 2.7 Hz, 1H), 3.45 (dd, J = 9.7, 2.7 Hz, 1H), 2.58 (dd, J = 9.7, 7.7 Hz, 1H) , 1.44 (t, J = 7.2 Hz, 3 H); ^{13 C NMR (125 MHz, CDCl} 3) δ 143.8, 139.5, 138.4, 138.1, 128.9, 128.5, 128.5, 128.3, 128.1, 128.0, 127.7, 127.7, 127.7, 127.2, 117.8, 87.3, 80.7, 74.8, 74.7, 70.6 , 63.9, 63.3, 47.2, 15.6; LRMS (ESI ⁺ ) m / z calcd for C ₄₂ H ₄₂ N ₅ O ₃ [M + H] ⁺ : 664.33; Found: 664.23.

Preparation of compound S17 -2: Step 7

Example 1 Step S17 -2 title compound as a colorless oil from the same procedure as compound 16-2 (277 mg, 0.4173 mmol) and 7 was synthesized (yield: 152 mg, 86%).

[?] _D ²⁵ - 41.5 (c = 1.6, CHCl ₃ ); ^{1 H NMR (500 MHz, CDCl} 3) δ 7.55 (s, 1H), 7.40 (s, 1H), 7.36-7.27 (m, 8H), 7.23-7.21 (m, 2H), 4.65 (d, J = 11.0 Hz, 1H), 4.56 (d , J = 5.0 Hz, 1H), 4.61-4.58 (m, 2H), 4.55 (d, J = 11.5 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.86 (t, J = 7.2 Hz, 1H), 3.81-3.76 (m, 2H), 3.50 (dd, J = 10.0, 5.5 Hz, 1H), 1.48 (t, J = 7.2 Hz, 3H); ^{13 C NMR (75 MHz, CDCl} 3) δ 139.3, 138.0, 137.8, 128.6, 128.5, 128.4, 128.1, 128.0, 118.0, 81.8, 77.4, 74.9, 74.2, 70.6, 63.5, 62.3, 47.3, 15.7; LRMS (ESI ⁺ ) m / z calcd for C ₂₃ H ₂₉ N ₅ O ₃ [M + H] ⁺ : 422.22; Found: 422.08.

Preparation of compound S18 -2: Step 8

Example By the same procedure as in Step 8, compounds of 117-2 was synthesized as a colorless oil from the title compound S18 -2 (123 mg, 0.2918 mmol) (yield: 168 mg, 61%).

^{_{[α] D 25 + 10.7 (}} c = 0.25, CHCl 3); ^{1 H NMR (500 MHz, CDCl} 3) δ 7.51 (s, 1H), 7.38-7.15 (m, 31H), 4.93 (d, J = 11.5 Hz, 1H), 4.87 (d, J = 3.0 Hz, 1H) , 4.82 (d, J = 12.0 Hz, 1H), 4.79 (d, J = 12.0 Hz, 1H), 4.73 (d, J = 12.0 Hz, 1H), 4.68 (d, J = 12.0 Hz, 1H), 4.62 -4.59 (m, 2H), 4.56 (d, J = 11.0 Hz, 1H), 4.48 (d, J = 11.5 Hz, 1H), 4.44 (d, J = 12.0 Hz, 1H), 4.35 (d, J = 11.5 Hz, 1H), 4.31 ( d, J = 12.0 Hz, 1H), 4.11 (q, J = 7.3Hz, 2H), 4.05 (dd, J = 11.0, 4.0 Hz, 1H), 3.98 (dd, J = (M, 2H), 1.45 (t, J = 7.5 Hz, 3H), 3.9 (d, J = 10.8, 6.8 Hz, 1H) ); ^{13 C NMR (125 MHz, CDCl} 3) δ 139.5, 139.0, 138.9, 138.89, 138.9, 138.4, 138.2, 128.6, 128.6, 128.5, 128.5, 128.4, 128.4, 128.4, 128.4, 128.1, 128.0, 127.9, 127.8, 127.8 , 127.7, 127.7, 127.6, 117.9, 98.8, 80.6, 79.1, 77.4, 76.5, 75.2, 74.9, 74.9, 74.8, 74.6, 73.6, 73.4, 73.2, 70.5, 69.9, 69.2, 68.0, 62.2, 47.2, 15.7; LRMS (ESI ⁺ ) m / z calcd for C ₅₇ H ₆₂ N ₅ O ₈ [M + H] ⁺ : 944.46; Found: 944.20.

Preparation of compound S19 -2: Step 9 and Step 10

The embodiment of step 19 and 10 in the same procedure as a colorless oil from the compound 18-2 (60 mg, 63.55 μmol) ethylamine The title compound S19 -2 (2-step yield: 82 mg, 63%).

[?] _D ²⁰ - 4.2 (c = 0.38, CHCl ₃ ); ^{1 H NMR (500 MHz, CDCl} 3) δ 7.54 (s, 1H), 7.44 (s, 1H), 7.37-7.21 (m, 30H), 6.15 (d, J = 9.0 Hz, 1H), 4.91 (d, J = 11.5 Hz, 1H), 4.81-4.71 (m, 5H), 4.63 (d, J = 11.5 Hz, 1H), 4.60-4.55 (m, 2H), 4.50-4.45 , J = 12.0 Hz, 1H) , 4.23 (d, J = 12.0 Hz, 1H), 4.11 (q, J = 7.3 Hz, 2H), 4.07-4.01 (m, 2H), 3.97 (dd, J = 11.0, 4.0 Hz, 1H), 3.93 ( dd, J = 8.0, 3.5 Hz, 1H), 3.90-3.86 (m, 3H), 3.53 (dd, J = 11.0, 3.5 Hz, 1H), 3.48 (dd, J = 9.2 2H), 1.44 (t, J = 7.3 Hz, 1 H), 6.8 Hz, 1H), 3.34 (dd, J = 9.2, 5.7 Hz, 1H), 1.97-1.88 (m, , 1.30-1.23 (m, 44H), 0.88 (t, J = 6.8 Hz, 3H); ^{13 C NMR (75 MHz, CDCl} 3) δ 172.9, 139.7, 138.7, 138.6, 138.6, 137.8, 129.1, 128.6, 128.6, 128.5, 128.4, 128.3, 128.1, 128.1, 128.0, 127.9, 127.8, 127.6, 127.6, 117.6 , 99.8, 80.3, 79.0, 77.4, 75.3, 74.9, 74.9, 74.5, 73.7, 73.7, 73.1, 70.3, 70.2, 69.4, 50.2, 47.1, 36.9, 32.1, 29.9, 29.9, 29.8, 29.7, 29.6, 29.6, 25.9 , 22.9, 15.7, 14.3; LRMS (ESI ⁺ ) m / z calcd for C ₈₃ H ₁₁₄ N ₃ O ₉ [M + H] ⁺ : 1296.86; Found: 1297.00.

Step 11: Preparation of compound B1

The title compound B1 was synthesized as an amorphous white solid (yield: 11.6 mg, 77%) from compound 19-2 (20 mg, 15.42 μmol) by the same procedure as in step 11 of Example 1 above.

[?] _D ²⁰ + 37.6 (c = 1.0, CHCl ₃ / MeOH = 1: 1); ^{1 H NMR (500 MHz, CDCl} 3 / CD 3 OD = 1: 1; reference peak: CD 3 OD at 3.31 ppm) δ 7.69 (d, J = 9.0 Hz, 1H), 7.51 (s, 1H), 7.48 ( J = 1.5 Hz, 1H), 4.89 (d, J = 3.5 Hz, 1H), 4.11 (q, J = 7.3 Hz, 2H), 4.07-4.02 3.85-3.70 (m, 8H), 2.18 (t, J = 7.5 Hz, 2H), 1.60-1.57 (m, 2H), 1.43 (t, J = 7.3 Hz, 3H), 1.31-1.24 (m, 44H) , 0.85 (t, J = 7.0 Hz, 3 H); ^{13 C NMR (75 MHz, CDCl} 3) δ 175.4, 138.7, 128.8, 122.3, 100.6, 78.5, 74.8, 71.7, 71.0, 70.5, 69.7, 67.9, 62.4, 51.3, 47.4, 37.1, 32.6, 30.4, 30.3, 30.1 , 30.1, 26.6, 23.3, 20.7, 15.9, 14.5; ^{HRMS (FAB +) m / z} calcd for C 41 H 78 N 3 O 9 [M + H] +: 756.5738; Found: 756.5742.

Example  7 to 9: Preparation of compounds B2 to B4

Compounds B2 to B4 were obtained as described below in a similar manner to Example 6 above.

1) Example 7 (Compound B2)

¹ H NMR (500 MHz, CDCl ₃ / CD ₃ OD = 1: 1; reference peak: CD ₃ OD at 3.31 ppm)? 7.60 (s, 1H), 7.51 4.89 (d, J = 3.9 Hz , 1H), 4.66 (d, J = 5.6 Hz, 1H), 4.12 (q, J = 7.3 Hz, 2H), 4.04 (dt, J = 6.5, 4.2 Hz, 1H), 2H), 1.43 (t, J = 7.2 Hz, 3H), 3.91 (d, J = 2.7 Hz, 1H), 3.84-3.68 (m, 7H), 2.19-2.16 , 1.31-1.24 (m, 40H), 0.86 (t, J = 7.0 Hz, 3H)

2) Example 8 (Compound B3)

^{1 H NMR (500 MHz, CDCl} 3 / CD 3 OD = 1: 1; reference peak: CD 3 OD at 3.31 ppm) δ 7.52 (s, 1H), 7.49 (s, 1H), 4.89 (d, J = 3.7 Hz, 1H), 4.66 (d , J = 5.4 Hz, 1H), 4.12 (q, J = 7.3 Hz, 2H), 4.06-4.03 (m, 1H), 3.90 (d, J = 3.2 Hz, 1H), (M, 2H), 1.61-1.58 (m, 1H), 1.43 (t, J = 7.3 Hz, 3H), 1.31-1.25 (m, 8H), 0.87 t, J = 7.2 Hz, 3H)

3) Example 9 (Compound B4)

Example  10: Preparation of compound B5

Compound B5 was obtained in a similar manner to Example 5,

^{1 H NMR (500 MHz, CDCl} 3 / CD 3 OD = 1: 1; reference peak: CD 3 OD at 3.31 ppm) δ 8.28 (s, 1H), 7.75 (s, 1H), 7.67 (s, 1H), 5.18 (dt, J = 7.6, 4.0 Hz, 1H), 4.87 (d, J = 3.91 Hz, 1H), 4.58 (d, J = 7.3 Hz, 1H), 4.34 (dd, J = 11.6, 3.6 Hz, 1H ), 4.23 (q, J = 7.3 Hz, 2H), 4.19-4.12 (m, 2H), 3.87 (d, J = 3.2 Hz, 1H), 3.78 (dd, J = 10.0, 3.9 Hz, 1H), 3.74 2H), 1.48 (t, J = 7.3 Hz, 3H), 1.31-1.25 (m, 42H), 0.87 (m, 2H) , ≪ / RTI > J = 7.0 Hz, 3H)

Manufacturing example  3: Compound S12 -3 production

By the same procedure as Preparation Example 1 4- n - hexyl-benzaldehyde was prepared the title compound as a white solid of amorphous -3 S12 from (3.1 g, 16.29 mmol) (yield: 1.432 g, 29%).

^{1 H NMR (500 MHz, CDCl} 3) δ 7.36-7.31 (m, 5H), 7.23-7.22 (m, 5H), 7.13 (d, J = 8.0 Hz, 2H), 6.33 (br s, 1H), 5.14 (s, 2H), 3.97 (s, 2H), 2.58 (t, J = 7.8 Hz, 2H), 1.59 (quin, J = 7.5 Hz, 2H), 1.35-1.25 (m, 6H) J = 6.8 Hz, 2H); ¹³ C NMR (125 MHz, CDCl ₃ ) 隆 157.3, 142.6, 136.2, 134.6, 129.1, 128.8, 128.5, 128.4, 67.3, 55.7, 35.8, 31.9, 31.7, 29.2, 22.8, 14.3; ^{LRMS (ESI +) m / z} calcd for C 21 H 29 N 2 O 2 [M + H] +: 341.22; Found: 341.03.

Example  11: Compound C1 Manufacturing

Compound 11 was obtained in the same manner as in Steps 1 to 3 of Example 1.

Preparation of compound S14 -3: Step 4

The example compounds by the same procedure as Step 4 in 1 11 (400 mg, 0.67 mmol ) and compound S12 S14 -3 -3 title compound as a colorless oil from (684 mg, 2.009 mmol) was synthesized (yield: 436 mg, 83%).

[?] _D ²⁵ - 18.5 (c = 1.2, CHCl ₃ ); ¹ H NMR (500 MHz, CDCl ₃ )? 7.45 (s, 1H), 7.41-7.39 (m, 6H), 7.29-7.17 (m, 18H), 7.11-7.08 (m, 4H), 6.94-6.92 2H), 5.22 (s, 2H), 4.50 (d, J = 12.0 Hz, 1H), 4.46 (d, J = 6.5 Hz, 1H), 4.30-4.24 1H), 3.81 (dd, J = 6.5, 3.0 Hz, 1H), 3.18 (dd, J = 9.2, 5.8 Hz, 1H), 3.13 (dd, J = 9.5, 6.0 Hz, 1H), 2.56 (t, J = 7.8 Hz, 2H), 1.55 (quin, J = 7.6 Hz, 2H), 1.32-1.26 (m, 6H), 0.87 (t, J = 7.0 Hz, 3H); ^{13 C NMR (125 MHz, CDCl} 3) δ 144.1, 143.1, 139.4, 138.2, 138.0, 133.8, 129.1, 129.0, 128.9, 128.6, 128.4, 128.3, 128.0, 128.8, 127.9, 127.8, 127.8, 127.2, 120.1, 86.8 , 81.7, 74.7, 73.3, 70.5, 70.4, 64.6, 56.1, 35.8, 31.9, 31.6, 29.2, 22.8, 14.3; LRMS (ESI ⁺ ) m / z calcd for C ₅₃ H ₅₇ N ₂ O ₄ [M + H] ⁺ : 785.43; Found: 785.20.

Preparation of compound S16 -3: Step 5 and Step 6

Example 1 step 5, and 6 and S 14 in the same procedure the compounds of the title compound S16 -3 -3 was synthesized as a colorless oil from (436 mg, 0.555 mmol) ( 2 step yield: 363 mg, 81%).

[?] _D ²⁵ - 10.2 (c = 1.7, CHCl ₃ ); ¹ H NMR (500 MHz, CDCl ₃ )? 7.52 (s, 1H), 7.42-7.40 (m, 6H), 7.30-7.08 ), 4.52-4.50 (m, 2H) , 4.41 (d, J = 3.0 Hz, 1H), 4.39 (d, J = 2.5 Hz, 1H), 4.17 (d, J = 11.5 Hz, 1H), 3.72 (dd , J = 6.8, 5.2 Hz, 1H), 3.54 (td, J = 7.1, 2.5 Hz, 1H), 3.42 (dd, J = 10.0, 3.0 Hz, 1H), 3.35 (dd, J = 9.7, 7.8 Hz, 1H), 2.56 (t, J = 8.0 Hz, 2H), 1.56 (quin, J = 7.5 Hz, 2H), 1.32-1.26 (m, 6H), 0.87 (t, J = 6.8 Hz, 3H); ^{13 C NMR (75 MHz, CDCl} 3) δ 143.8, 143.1, 139.8, 138.3, 138.1, 133.7, 129.5, 129.0, 128.9, 128.5, 128.3, 128.1, 128.0, 127.9, 127.8, 127.7, 127.2, 118.6, 87.3, 80.8 , 74.7, 74.6, 70.6, 63.8, 63.5, 56.1, 35.8, 31.9, 31.6, 29.2, 22.8, 14.3; LRMS (ESI ⁺ ) m / z calcd for C ₅₃ H ₅₆ N ₅ O ₃ [M + H] ⁺ : 810.44; Found: 810.38.

Preparation of compound S17 -3: Step 7

The title compound was carried -3 S17 as a colorless oil from Example 1 step 7, and the compound S 16 The same procedure -3 (333 mg, 0.411 mmol) in was synthesized (yield: 214 mg, 92%).

[?] _D ²⁵ - 37.5 (c = 1.5, CHCl ₃ ); ^{1 H NMR (500 MHz, CDCl} 3) δ 7.59 (s, 1H), 7.38 (s, 1H), 7.34-7.24 (m, 8H), 7.16-7.13 (m, 6H), 5.26 (s, 2H), 4.59-4.49 (m, 4H), 4.29 (d, J = 12.0 Hz, 1H), 3.83 (t, J = 5.7 Hz, 1H), 3.78-3.77 (m, 2H), 3.53 (dd, J = 10.2, 5.3 Hz, 1H), 2.58 ( t, J = 8.0 Hz, 2H), 2.24 (br s, 1H), 1.58 (quin, J = 7.6 Hz, 2H), 1.33-1.26 (m, 6H), 0.87 (t , ≪ / RTI > J = 7.0 Hz, 3H); ^{13 C NMR (125 MHz, CDCl} 3) δ 143.2, 139.6, 137.9, 137.7, 133.6, 129.4, 129.1, 128.7, 128.6, 128.4, 128.1, 128.0, 127.9, 118.7, 82.0, 77.4, 74.9, 73.9, 70.6, 63.5 , 62.3, 56.2, 35.8, 31.9, 31.6, 29.2, 22.8, 14.3; ^{LRMS (ESI +) m / z} calcd for C 34 H 42 N 5 O 3 [M + H] +: 568.33; Found: 568.23.

Preparation of compound S18 -3: Step 8

The title compound was carried -3 S18 as a colorless oil from Example 1, Step 8, and S 17 in the same process, compounds -3 (167 mg, 0.2942 mmol) of was synthesized (yield: 215 mg, 67%).

^{_{[α] D 25 + 9.3 (}} c = 0.75, CHCl 3); ^{1 H NMR (500 MHz, CDCl} 3) δ 7.54 (s, 1H), 7.38-7.15 (m, 31H), 7.13-7.09 (m, 4H), 5.21 (s, 2H), 4.93 (d, J = 11.5 Hz, 1H), 4.86 (d , J = 3.5 Hz, 1H), 4.82 (d, J = 12.0 Hz, 1H), 4.78 (d, J = 12.0 Hz, 1H), 4.73 (d, J = 11.5 Hz, 1H), 4.67 (d, J = 12.0 Hz, 1H), 4.58-4.52 (m, 4H), 4.45-4.42 (m, 2H), 4.34 (d, J = 12.0 Hz, 1H), 4.27 (d, J J = 6.5, 3.5 Hz, 1H), 3.97 (dd, J = 10.0, 3.0 Hz, 1H), 3.93-3.87 (m, 4H), 3.69 (dd, J = 10.5, 7.0 Hz, 1H), 3.53 (td, J = 6.5, 2.5 Hz, 1H), 3.47-3.46 (m, 2H), 2.57 (t, J = 7.8 Hz, 2H), 1.57 (quin, J = 7.5 Hz, 2H), 1.34-1.26 (m, 6H), 0.87 (t, J = 6.5 Hz, 3H); ^{13 C NMR (7 MHz, CDCl} 3) δ 143.1, 139.8, 139.0, 138.9, 138.9, 138.4, 138.3, 138.2, 129.6, 129.1, 128.6, 128.5, 128.4, 128.0, 128.0, 127.9, 127.9, 127.7, 127.6, 118.7 , 98.8, 80.8, 79.1, 76.5, 75.2, 74.9, 74.8, 74.4, 73.6, 73.4, 73.3, 70.5, 69.9, 69.2, 67.9, 62.3, 56.1, 35.8, 31.9, 29.9, 29.2, 22.8, 14.3; LRMS (ESI ⁺ ) m / z calcd for C ₆₈ H ₇₆ N ₅ O ₈ [M + H] ⁺ : 1090.57; Found: 1090.51.

Preparation of compound S19 -3: Step 9 and Step 10

The embodiment of step 19 and 10 in the same procedure as a colorless oil from the compound S 18 -3 (30 mg, 27.5 μmol) of the title compound was synthesized S19 -3 (2 step yield: 31 mg, 78%).

[?] _D ²⁰ - 2.9 (c = 0.31, CHCl ₃ ); ^{1 H NMR (500 MHz, CDCl} 3) δ 7.58 (s, 1H), 7.43 (s, 1H), 7.36-7.18 (m, 30H), 7.12-7.08 (m, 4H), 6.07 (d, J = 9.0 Hz, 1H), 5.23 (d , J = 15.0 Hz, 1H), 5.19 (d, J = 15.0 Hz, 1H), 4.91 (d, J = 11.5 Hz, 1H), 4.80-4.76 (m, 3H), 4.71 (d, J = 12.0 Hz , 1H), 4.66 (d, J = 11.0 Hz, 1H), 4.62 (d, J = 12.0 Hz, 1H), 4.55 (d, J = 12.0 Hz, 1H), 4.51 ( d, J = 11.5 Hz, 1H ), 4.46-4.44 (m, 3H), 4.35 (d, J = 12.0 Hz, 1H), 4.20 (d, J = 12.0 Hz, 1H), 4.13-4.08 (m, 1H ), 4.02 (dd, J = 10.0, 3.5 Hz, 1H), 3.94-3.85 (m, 5H), 3.55 (dd, J = 10.8, 3.8 Hz, 1H), 3.48 (dd, J = 9.2, 6.8 Hz, 1H), 3.35 (dd, J = 9.5, 6.0 Hz, 1H), 2.55 (t, J = 7.8 Hz, 2H), 1.95-1.83 (m, 2H), 1.56 (quin, J = 7.4 Hz, 2H), 1.46 (quin, J = 7.1 Hz, 2H), 1.31-1.25 (m, 50H), 0.92-0.85 (m, 6H); ^{13 C NMR (75 MHz, CDCl} 3) δ 172.9, 140.2, 138.8, 138.7, 138.6, 137.9, 129.0, 128.6, 128.6, 128.5, 128.5, 128.5, 128.2, 128.1, 128.0, 128.0, 127.9, 127.8, 127.6, 118.4 , 99.7, 81.0, 79.0, 75.0, 75.0, 74.9, 74.5, 73.7, 73.6, 73.1, 70.3, 69.4, 56.0, 50.3, 36.9, 35.8, 32.1, 31.9, 31.6, 29.9, 29.9, 29.8, 29.7, 29.6, 29.6 , 29.2, 25.9, 22.9, 22.8, 14.3, 14.3; ^{LRMS (ESI +) m / z} calcd for C 94 H 128 N 3 O 9 [M + H] +: 1442.97; Found: 1443.87.

Step 11: Preparation of compound C1

The title compound C1 as a white amorphous solid from the same procedure as in Step 11 of the Example 1 compound S 19 -3 (27 mg, 18.7 μmol) was synthesized (yield: 13.2 mg, 78%).

[?] _D ²⁰ + 34.1 (c = 1.13, CHCl ₃ / MeOH = 1: 1); ^{1 H NMR (500 MHz, CDCl} 3 / CD 3 OD = 1: 1; reference peak: CD 3 OD at 3.31 ppm) δ 7.58 (d, J = 9.0 Hz, 1H), 7.52 (s, 1H), 7.50 ( s, 1H), 7.11 (s , 4H), 5.20 (s, 2H), 4.89 (d, J = 3.5 Hz, 1H), 4.64 (d, J = 6.0 Hz, 1H), 4.09-4.05 (m, 1H ), 3.90 (d, J = 2.5 Hz, 1H), 3.83-3.67 (m, 8H), 2.54 (t, J = 7.8 Hz, 2H), 2.15 (t, J = 7.3 Hz, 2H), 1.56-1.52 (m, 4H), 1.26-1.24 (m, 50H), 0.87-0.84 (m, 6H); ^{13 C NMR (75 MHz, CDCl} 3) δ 175.3, 143.6, 139.0, 134.3, 129.6, 129.4, 128.4, 123.0, 100.5, 74.9, 71.6, 70.9, 70.5, 69.6, 67.8, 62.4, 56.2, 51.2, 50.0, 49.7 , 49.4, 49.1, 48.9, 48.6, 48.3, 37.0, 36.2, 32.6, 32.4, 32.1, 30.3, 30.1, 30.0, 29.6, 26.6, 23.3, 23.2, 14.5; HRMS (FAB ⁺ ) m / z calcd for C ₅₂ H ₉₂ N ₃ O ₉ [M + H] ⁺ : 902.6834; Found: 902.6840.

Example  12 to 14: Compound C2  To C4 Manufacturing

The following compounds C2 to C4 were obtained in a similar manner to Example 11.

1) Example 12 (Compound C2)

^{1 H NMR (500 MHz, CDCl} 3 / CD 3 OD = 1: 1; reference peak: CD 3 OD at 3.31 ppm) δ 7.55 (s, 1H), 7.52 (s, 1H), 7.50 (s, 1H), 7.11 (s, 4H), 5.20 (s, 2H), 4.89 (d, J = 3.4 Hz, 1H), 4.65 (d, J = 5.9 Hz, 1H), 4.06 (d, J = 5.1 Hz, 1H), 3.90 (d, J = 2.5 Hz , 1H), 3.84-3.64 (m, 8H), 2.55 (t, J = 7.7 Hz, 2H), 2.15 (dd, J = 8.3, 6.4 Hz, 2H), 1.57-1.52 (m, 4H), 1.31-1.18 (m, 46H), 0.86-0.84 (m, 6H)

2) Example 13 (Compound C3)

^{1 H NMR (500 MHz, CDCl} 3 / CD 3 OD = 1: 1; reference peak: CD 3 OD at 3.31 ppm) δ 7.57 (s, 1H), 7.52 (s, 1H), 7.51 (s, 1H), 7.11 (s, 4H), 7.03 (d, J = 2.2 Hz, 1H), 5.20 (s, 2H), 4.89 (d, J = 3.7 Hz, 1H), 4.64 (d, J = 5.9 Hz, 1H), (D, J = 6.4, 4.3 Hz, 1H), 3.90 (dd, J = 3.3,1.0 Hz, 1H), 3.84-3.64 (m, 8H), 2.56-2.53 (m, 2H), 2.17-2.13 m, 2H), 1.58-1.53 (m, 4H), 1.31-1.24 (m, 14H), 0.87-0.83

3) Example 14 (Compound C4)

^{1 H NMR (500 MHz, CDCl} 3 / CD 3 OD = 1: 1; reference peak: CD 3 OD at 3.31 ppm) δ 7.53 (s, 2H), 7.23-7.20 (m, 2H), 7.14-7.09 (m , 7H), 5.21 (s, 2H), 4.88 (d, J = 3.9 Hz, 1H), 4.65 (d, J = 5.9 Hz, 1H), 4.08-4.04 (m, 1H), 3.89 (dd, J = J = 7.7 Hz, 2H), 2.54 (t, J = 7.7 Hz, 2H), 2.16 (td, J = 7.6,2.6 Hz, 1H), 3.84-3.68 (m, 8H) 2H), 1.65-1.59 (m, 4H ), 1.56-1.52 (m, 2H), 1.37-1.25 (m, 8H), 0.85 (t, J = 7.5 Hz, 3H)

Example  15: Compound C5 Manufacturing

Compound C5 was obtained in a similar manner to Example 5,

^{1 H NMR (500 MHz, CDCl} 3 / CD 3 OD = 1: 1; reference peak: CD 3 OD at 3.31 ppm) δ 8.07 (s, 1H), 7.58 (s, 1H), 7.55 (s, 1H), 2H), 4.89 (d, J = 3.9 Hz, 1H), 4.85 (d, J = 3.7 Hz, 1H), 4.52 (s, 2H) (d, J = 6.8 Hz, 1H), 4.29-4.26 (m, 1H), 4.14-4.08 (m, 3H), 3.88-3.86 (m, 1H), 3.81-3.62 m, 8H), 2.55 (t , J = 7.5 Hz, 2H), 2.16 (td, J = 7.6, 2.6 Hz, 2H), 1.70-1.63 (m, 2H), 1.57-1.51 (m, 2H), 1.37 -1.21 (m, 48H), 0.86-0.83 (m, 6H)

Example  16 to 19: Compound D1  To D4 Manufacturing

The following compounds D1 to D4 were obtained in a similar manner to Example 1,

1) Example 16 (Compound D1)

^{1 H NMR (500 MHz, CDCl} 3) δ 7.50 (s, 1H), 7.49 (s, 1H), 7.06 (d, J = 7.5 Hz, 2H), 7.04 (d, J = 8.0 Hz, 2H), 4.89 (d, J = 4.0 Hz, 1H), 4.66 (d, J = 6.0 Hz, 1H), 4.07-4.01 (m, 3H), 3.90 (d, J = 3.0 Hz, 1H), 3.84-3.67 (m, 8H), 2.60-2.52 (m, 4H ), 2.18 (t, J = 7.7 Hz, 2H), 1.84 (quin, J = 7.5 Hz, 2H), 1.64-1.58 (m, 4H), 1.33-1.24 (m , 46H), 1.19 (t, J = 7.7 Hz, 3H), 0.86 (t, J = 7.0 Hz, 3H); HRMS (FAB +) m / z calcd for C ₅₂ H ₉₂ N ₃ O ₉ [M + H] ⁺ : 902.6834; Found: 902.6845.

2) Example 17 (Compound D2)

^{1 H NMR (500 MHz, CDCl} 3 / CD 3 OD = 1: 1; reference peak: CD 3 OD at 3.31 ppm) δ 7.51 (s, 1H), 7.50 (s, 1H), 7.08-7.04 (m, 4H ), 4.90 (d, J = 3.9 Hz, 1H), 4.67 (d, J = 5.4 Hz, 1H), 4.08-4.02 (m, 3H), 3.91 (d, J = 2.9 Hz, 1H), 3.85-3.69 (m, 8H), 2.61-2.53 (m, 4H), 2.19 (t, J = 7.7 Hz, 2H), 1.87-1.82 (m, 2H), 1.65-1.59 , 42H), 1.19 (t, J = 7.6 Hz, 3H), 0.87 (t, J = 7.0 Hz,

3) Example 18 (Compound D3)

^{1 H NMR (500 MHz, CDCl} 3 / CD 3 OD = 1: 1; reference peak: CD 3 OD at 3.31 ppm) δ 7.50 (s, 2H), 7.07-7.03 (m, 4H), 4.89 (d, J = 3.9 Hz, 1H), 4.66 (d, J = 5.6 Hz, 1H), 4.07-4.02 (m, 3H), 3.90 (d, J = 3.2 Hz, 1H), 3.84-3.68 2H), 1.64-1.56 (m, 4H), 1.33-1.25 (m, 10H), 1.19 (t, J = 7.5 Hz, 3H), 0.86 (t, J = 7.1 Hz, 3H)

4) Example 19 (Compound D4)

¹ H NMR (500 MHz, CDCl ₃ / CD ₃ OD = 1: 1; reference peak: CD ₃ OD at 3.31 ppm) 隆 7.48 (s, 1H), 7.47 (s, 1H), 7.23-7.20 ), 7.14-7.10 (m, 3H), 7.07-7.02 (m, 4H), 4.89 (d, J = 3.9 Hz, 1H), 4.65 (d, J = 5.8 Hz, 1H) 3H), 3.90 (d, J = 2.5 Hz, 1H), 3.84-3.68 (m, 8H), 2.60-2.52 (m, 6H), 2.19-2.16 (m, 2H), 1.86-1.80 (m, 2H) , 1.65-1.57 (m, 6H), 1.38-1.28 (m, 4H), 1.18 (t, J = 7.7 Hz,

Example  20: Compound D5 Manufacturing

Compound D5 was obtained in a similar manner to Example 5,

¹ H NMR (500 MHz, CDCl ₃ / CD ₃ OD = 1: 1; reference peak: CD ₃ OD at 3.31 ppm)? 7.83 (s, 1H), 7.49 7.07-7.02 (m, 4H), 4.93-4.90 (m, 1H), 4.85 (d, J = 3.9 Hz, 1H), 4.43 (d, J = 6.1 Hz, 1H), 4.22-4.17 (m, 2H) , 4.08-4.04 (m, 3H), 3.87 (d, J = 2.9 Hz, 1H), 3.77 (dd, J = 10.0, 3.9 Hz, 1H), 3.70-3.58 (m, 4H), 2.70-2.67 , 2H), 2.59-2.52 (m, 4H), 1.87-1.81 (m, 2H), 1.68-1.57 (m, 4H), 1.38-1.24 (m, 44H), 1.18 (t, J = 7.5 Hz, 3H ), 0.86 (t, J = 7.2 Hz, 3 H)

Example  21 to 24: Compound E1  To E4 Manufacturing

Compounds E1 to E4 were obtained in a similar manner to Example 1,

1) Example 21 (Compound E1)

^{1 H NMR (500 MHz, CDCl} 3 / CD 3 OD = 1: 1; reference peak: CD 3 OD at 3.31 ppm) δ 7.61 (s, 1H), 7.57 (s, 1H), 7.03 (d, J = 8.0 2H), 4.00 (d, J = 8.0 Hz, 2H), 4.89 (d, J = 3.5 Hz, 1H), 4.13-4.09 , J = 3.5 Hz, 1H) , 3.83-3.61 (m, 8H), 2.52 (t, J = 7.5 Hz, 2H), 2.28 (s, 3H), 2.24-2.17 (m, 2H), 1.82 (quin, J = 7.1 Hz, 2H), 1.60-1.54 (m, 4H), 1.32-1.24 (m, 48H), 0.85 (t, J = 7.0 Hz, 3H); ^{13 C NMR (75 MHz, CDCl} 3) δ 175.4, 138.7, 128.8, 122.3, 100.6, 78.5, 74.8, 71.7, 71.0, 70.5, 69.7, 67.9, 62.4, 51.3, 47.4, 37.1, 32.6, 30.4, 30.3, 30.1 , 30.1, 26.6, 23.3, 20.7, 15.9, 14.5; HRMS (FAB +) m / z calcd for C ₅₂ H ₉₂ N ₃ O ₉ [M + H] ⁺ : 902.6834; Found: 902.6827.

2) Example 22 (Compound E2)

^{1 H NMR (500 MHz, CDCl} 3 / CD 3 OD = 1: 1; reference peak: CD 3 OD at 3.31 ppm) δ 7.60 (s, 1H), 7.56 (s, 1H), 7.04-7.00 (m, 4H ), 4.89 (d, J = 3.9 Hz, 1H), 4.09-4.07 (m, 2H), 4.03-4.00 (m, 1H), 3.90 (d, J = 3.6 Hz, 1H), 3.84-3.69 (m, 8H), 2.52 (t, J = 7.6 Hz, 2H), 2.27 (s, 3H), 2.22-2.17 (m, 2H), 1.81 (quin, J = 7.1 Hz, 2H), 1.60-1.54 (m, 4H ), 1.32-1.24 (m, 44H), 0.86 (t, J = 7.1 Hz, 3H)

3) Example 23 (Compound E3)

¹ H NMR (500 MHz, CDCl ₃ / CD ₃ OD = 1: 1; reference peak: CD ₃ OD at 3.31 ppm)? 7.59 (s, 1H), 7.47 (s, 1H), 7.04-6.99 ), 4.88 (d, J = 4.0 Hz, 1H), 4.65 (d, J = 5.5 Hz, 1H), 4.05-4.02 (m, 3H), 3.90 (d, J = 3.3 Hz, 1H), 3.82-3.67 (m, 8H), 2.51 (t, J = 7.5 Hz, 2H), 2.26 (s, 3H), 2.18-2.15 (m, 2H), 1.79 (quin, J = 7.2 Hz, 2H), 1.59-1.52 m, 4H), 1.29-1.23 (m, 12H), 0.88 (t, J = 7.0 Hz,

4) Example 24 (Compound E4)

^{1 H NMR (500 MHz, CDCl} 3 / CD 3 OD = 1: 1; reference peak: CD 3 OD at 3.31 ppm) δ 7.49 (s, 1H), 7.48 (s, 1H), 7.23-7.20 (m, 2H J = 3.7 Hz, 1H), 4.65 (d, J = 5.5 Hz, 1H), 4.06-4.01 (m, 3H), 3.89 (d, J = 3.3 Hz, 1H), 3.84-3.66 (m, 8H), 2.60-2.57 (m, 2H), 2.53-2.50 (m, 2H), 2.26 (s, 3H), 2.20 2H), 1.81-1.78 (m, 2H), 1.66-1.53 (m, 6H), 1.38-1.25 (m, 6H)

Example  25: Compound E5 Manufacturing

Compound E5 was obtained in a similar manner to Example 5,

^{1 H NMR (500 MHz, CDCl} 3 / CD 3 OD = 1: 1; reference peak: CD 3 OD at 3.31 ppm) δ 7.71 (s, 1H), 7.45 (s, 1H), 7.44 (s, 1H), 7.04-6.99 (m, 4H), 4.84 (d, J = 3.7 Hz, 1H), 4.39 (d, J = 5.6 Hz, 1H), 4.21-4.16 (m, 2H), 4.05-4.02 (m, 3H) , 3.86 (d, J = 3.2 Hz, 1H), 3.77 (dd, J = 10.2,3.8 Hz, 1H), 3.70-3.62 (m, 3H), 3.58 J = 7.2 Hz, 2H), 1.67-1.53 (m, 4H), 1.32-1.24 (m, 46H), 2.52 (t, J = 7.7 Hz, 2H) , 0.86 (t, J = 7.0 Hz, 3 H)

Example  26 to 33: Preparation of compounds F1 to F8

In the same manner as in Example 1, the compounds F1 to F8 were obtained as follows.

1) Example 26 (Compound F1)

2) Example 27 (Compound F2)

3) Example 28 (Compound F3)

4) Example 29 (Compound F4)

5) Example 30 (Compound F5)

6) Example 31 (Compound F6)

7) Example 32 (Compound F7)

8) Example 33 (Compound F8)

Manufacturing example  4: Compound S12 -4 production

The title compound S12-4 was synthesized from 4-n-methylbenzaldehyde as an amorphous white solid in the same manner as in Preparation Example 1,

Example  34: Compound G1 Manufacturing

Compound 11 was obtained in the same manner as in Steps 1 to 3 of Example 1.

Step 4: Preparation of compound S14-4

Example 1 compound by the same procedure as step 411 of (500 mg, 0.838 mmol), and as a colorless oil from the compound S12 -4 (453 mg, 1.676 mmol ) was synthesized from the title compound S14 -4 (yield: 514 mg, 86%).

[?] _D ²⁵ - 19.0 (c = 1.0, CHCl ₃ ); ¹ H NMR (500 MHz, CDCl ₃ )? 7.45 (s, 1H), 7.41-7.38 (m, 6H), 7.28-7.17 (m, 18H), 7.11-7.07 (m, 4H), 6.93-6.92 , 2H), 5.21 (s, 2H), 4.50 (d, J = 12.0 Hz, 1H), 4.46 (d, J = 6.5 Hz, 1H), 4.29-4.23 (m, 3H), 4.02-4.00 (m, 1H), 3.80 (dd, J = 6.8,3.2 Hz, 1H), 3.19-3.12 (m, 2H), 2.55 (d, J = 6.5 Hz, 1H), 2.31 (s, 3H); ^{13 C NMR (125 MHz, CDCl} 3) δ 144.0, 139.3, 139.3, 138.2, 138.0, 138.0, 133.5, 129.7, 129.0, 129.0, 128.9, 128.6, 128.4, 128.3, 128.0, 127.9, 127.8, 127.8, 127.8, 127.2 , 120.1, 86.8, 81.8, 74.7, 73.3, 73.3, 70.5, 70.4, 70.4, 70.3, 64.6, 56.1, 21.4, 21.3; LRMS (ESI ⁺ ) m / z calcd for C ₄₈ H ₄₇ N ₂ O ₄ [M + H] ⁺ : 715.35; Found: 715.48.

Preparation of compound S18 -4: Step 5 to Step 8

Example 1 the title compound S18 -4 was synthesized by the same procedure as steps 5 to 8 as a colorless oil from the compound S14 of -4.

^{_{[α] D 25 + 9.1 (}} c = 1.7, CHCl 3); ^{1 H NMR (500 MHz, CDCl} 3) δ 7.54 (s, 1H), 7.38-7.08 (m, 29H), 7.13-7.08 (m, 6H), 5.20 (s, 2H), 4.93 (d, J = 11.5 Hz, 1H), 4.86 (d , J = 3.0 Hz, 1H), 4.82 (d, J = 12.0 Hz, 1H), 4.78 (d, J = 12.0 Hz, 1H), 4.72 (d, J = 12.0 Hz, 1H), 4.67 (d, J = 12.0 Hz, 1H), 4.58-4.52 (m, 4H), 4.43 (dd, J = 11.8, 3.2 Hz, 2H), 4.35 (d, J = 12.0 Hz, 1H), 4.27 (d, J = 11.5 Hz , 1H), 4.04 (dd, J = 10.0, 3.0 Hz, 1H), 3.97 (dd, J = 10.0, 2.5 Hz, 1H), 3.92-3.87 (m, 4H), 3.68 (dd, J = 10.7,7.3 Hz, 1H), 3.51 (td, J = 6.6, 2.3 Hz, 1H), 3.47-3.46 (m, 2H), 2.32 (s, 3H); ^{13 C NMR (75 MHz, CDCl} 3) δ 139.8, 139.0, 138.9, 138.8, 138.4, 138.3, 138.2, 138.0, 133.5, 129.7, 129.5, 128.6, 128.5, 128.4, 128.0, 127.9, 127.8, 127.7, 127.6, 118.7 , 98.8, 80.8, 79.1, 77.4, 76.5, 75.2, 74.9, 74.8, 74.4, 73.6, 73.4, 73.3, 70.5, 69.9, 69.2, 67.9, 62.2, 56.1, 21.3; LRMS (ESI ⁺ ) m / z calcd for C ₆₃ H ₆₆ N ₅ O ₈ [M + H] ⁺ : 1020.49; Found: 1020.53.

Preparation of compound S19 -4: Step 9 and Step 10

The embodiment of step 19 and 10 in the same procedure the compound 18-4 was synthesized as a colorless oil from the title compound S19 -4 (20 mg, 0.0196 mmol) (2-step yield: 17 mg, 63%).

[?] _D ²⁰ - 0.5 (c = 1.60, CHCl ₃ ); ^{1 H NMR (500 MHz, CDCl} 3) δ 7.58 (s, 1H), 7.42 (s, 1H), 7.37-7.18 (m, 30H), 7.11-7.07 (m, 4H), 6.08 (d, J = 9.0 Hz, 1H), 5.20 (d , J = 3.0 Hz, 1H), 4.79-4.76 (m, 3H), 4.71 (d, J = 11.5 Hz, 1H), 4.66 (d, J = 11.0 Hz, 1H), 4.62 (d, J = 12.0 Hz , 1H), 4.55 (d, J = 11.5 Hz, 1H), 4.51 (d, J = 11.0 Hz, 1H), 4.46-4.43 (m, 3H), 4.34 (d, J = 12.0 Hz, 1H), 4.20 (d, J = 12.0 Hz, 1H), 4.12-4.06 (m, 1H), 4.01 (dd, J = 10.3, 3.7 Hz, 1H), 3.93-3.85 (m, 5H) , 3.55 (dd, J = 11.0 , 3.5 Hz, 1H), 3.48 (dd, J = 9.5, 6.5 Hz, 1H), 3.35 (dd, J = 9.5, 6.0 Hz, 1H), 2.31 (s, 3H), 1.95-1.83 (m, 2H), 1.46 (quin, J = 7.4 Hz, 2H), 1.31-1.23 (m, 44H), 0.88 (t, J = 6.8 Hz, 3H; LRMS (ESI +) m / z calcd for C ₈₉ H ₁₁₈ N ₃ O ₉ [M + H] < ⁺ >:1372.89; Found: 1372.83.

Step 11: Preparation of compound G1

The title compound G1 was synthesized as an amorphous white solid (yield: 8.5 mg, 94%) from compound 19-4 (15 mg, 10.9 μmol) by the same procedure as in step 11 of Example 1 above.

[?] _D ²⁰ + 49.0 (c = 0.83, CHCl ₃ / MeOH = 1: 1); ¹ H NMR (500 MHz, CDCl ₃ / CD ₃ OD = 1: 1; reference peak: CD ₃ OD at 3.31 ppm) 隆 7.59-7.57 (m, 2H), 7.14-7.10 (m, 4H), 5.23 2H), 4.88 (d, J = 3.5 Hz, 1H), 4.66 (d, J = 5.5 Hz, 1H), 4.10-4.00 (m, 1H), 3.91-3.66 J = 7.9, 2.0 Hz, 2H), 1.62-1.56 (m, 2H), 1.30-1.24 (m, 44H), 0.86 (t, J = 7.0 Hz, 3H); ^{13 C NMR (75 MHz, CDCl} 3) δ 175.3, 138.8, 138.6, 133.9, 130.1, 130.0, 128.4, 123.2, 100.6, 100.6, 78.5, 74.9, 71.7, 71.0, 70.5, 69.7, 67.8, 62.4, 56.2, 37.0 , 32.6, 30.4, 30.3, 30.1, 30.1, 26.6, 23.3, 21.4, 14.5; HRMS (FAB ⁺ ) m / z calcd for C ₄₇ H ₈₂ N ₃ O ₉ [M + H] ⁺ : 832.6051; Found: 832.6063.

Example  35 to 37: Compound G2  To G4 Manufacturing

Compound G2 to G4 were obtained as described below in a similar manner to Example 1,

1) Example 35 (Compound G2)

2) Example 36 (Compound G3)

3) Example 37 (Compound G4)

Manufacturing example  5: Compound S12 Production of -5

By the same procedure as Preparation Example 1 4- n - ethylamine The title compound S12 -5 as a white amorphous solid from pentoxy benzaldehyde.

Example  38: Compound G5 Manufacturing

Compound 11 was obtained in the same manner as in Steps 1 to 3 of Example 1.

Preparation of compound S14 -5: Step 4

Example 1 compound by the same procedure as step 411 of (500 mg, 0.838 mmol), and as a colorless oil from the compound S12 -5 (861 mg, 2.514 mmol ) was synthesized from the title compound S14 -5 (yield: 387 mg, 59%).

^{_{[α] D 25 - 19.4 (}} c = 1.1, CHCl 3); ^{1 H NMR (500 MHz, CDCl} 3) δ 7.44 (s, 1H), 7.41-7.38 (m, 6H), 7.28-7.18 (m, 18H), 7.13-7.10 (m, 2H), 6.93-6.91 (m , 2H), 6.81-6.79 (m, 2H), 5.18 (s, 2H), 4.50 (d, J = 12.0 Hz, 1H), 4.46 (d, J = 6.5 Hz, 1H), 4.32-4.27 (m, 3H), 4.05-4.02 (m, 1H ), 3.88 (t, J = 6.5 Hz, 2H), 3.80 (dd, J = 6.2, 3.3 Hz, 1H), 3.22-3.15 (m, 2H), 2.56 (d J = 6.5 Hz, 1H), 1.75 (quin, J = 7.0 Hz, 2H), 1.45-1.34 (m, 4H), 0.92 (t, J = 7.3 Hz, 3H); ^{13 C NMR (125 MHz, CDCl} 3) δ 159.2, 144.041, 139.3, 138.2, 138.0, 129.4, 128.9, 128.5, 128.4, 128.3, 128.0, 127.9, 127.8, 127.8, 127.2, 120.0, 114.9, 86.8, 81.7, 74.7 , 73.4, 70.5, 70.3, 68.2, 64.6, 55.9, 29.1, 28.4, 22.6, 14.4; LRMS (ESI ⁺ ) m / z calcd for C ₅₂ H ₅₅ N ₂ O ₅ [M + H] ⁺ : 787.41; Found: 787.50.

Preparation of compound S18 -5: Step 5 to Step 8

Example 1 the title compound S18 -5 was synthesized by the same procedure as steps 5 to 8 as a colorless oil from the compound S14 of -5.

^{_{[α] D 25 + 8.7 (}} c = 1.3, CHCl 3); ^{1 H NMR (500 MHz, CDCl} 3) δ 7.54 (s, 1H), 7.38-7.08 (m, 33H), 6.83 (d, J = 8.5 Hz, 2H), 5.17 (s, 2H), 4.93 (d, J = 11.5 Hz, 1H), 4.86 (d, J = 3.5 Hz, 1H), 4.82 (d, J = 11.5 Hz, 1H), 4.79 (d, J = 12.0 Hz, 1H), 4.73 (d, J = 12.0 Hz, 1H), 4.67 ( d, J = 12.0 Hz, 1H), 4.58-4.51 (m, 4H), 4.42-4.42 (m, 2H), 4.34 (d, J = 11.5 Hz, 1H), 4.26 ( d, J = 11.5 Hz, 1H ), 4.04 (dd, J = 10.0, 3.5 Hz, 1H), 3.97 (dd, J = 10.0, 3.0 Hz, 1H), 3.93-3.87 (m, 6H), 3.68 (dd , J = 11.0, 7.0 Hz, 1H), 3.51 (td, J = 6.6, 2.2 Hz, 1H), 3.46 (d, J = 6.0 Hz, 2H), 1.76 (quin, J = 7.0 Hz, 2H), 1.45 -1.35 (m, 4H), 0.92 (t, J = 7.3 Hz, 3H); ^{13 C NMR (75 MHz, CDCl} 3) δ 159.2, 139.7, 139.0, 138.9, 138.8, 138.4, 138.3, 138.2, 129.5, 129.3, 128.6, 128.5, 128.4, 128.2, 128.2, 128.0, 127.9, 127.9, 127.8, 127.749 , 127.697, 127.6, 118.6, 114.9, 98.8, 80.8, 79.1, 77.4, 76.5, 75.2, 74.9, 74.8, 74.4, 73.6, 73.4, 73.2, 70.5, 69.9, 69.2, 68.2, 67.9, 62.2, 55.9, 29.3, 28.4 , 22.7, 14.2; LRMS (ESI ⁺ ) m / z calcd for C ₆₇ H ₇₄ N ₅ O ₉ [M + H] ⁺ : 1092.55; Found: 1092.71.

Preparation of compound S19 -5: Step 9 and Step 10

The embodiment of step 19 and 10 the title compound was synthesized from S19 -5 as a colorless oil from the same procedure as compound 18-5 (33 mg, 30.2 μmol) (2 step yield: 33 mg, 75%).

[?] _D ²⁰ - 2.3 (c = 0.94, CHCl ₃ ); ^{1 H NMR (500 MHz, CDCl} 3) δ 7.57 (s, 1H), 7.40 (s, 1H), 7.36-7.17 (m, 30H), 7.12 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.5 Hz, 2H), 6.09 (d, J = 9.0 Hz, 1H), 5.20-5.14 (m, 2H), 4.91 (d, J = 11.5 Hz, 1H), 4.79-4.76 4.71 (d, J = 12.0 Hz , 1H), 4.66 (d, J = 11.5 Hz, 1H), 4.62 (d, J = 11.5 Hz, 1H), 4.55 (d, J = 11.5 Hz, 1H), 4.50 ( d, J = 11.5 Hz, 1H ), 4.46-4.43 (m, 3H), 4.34 (d, J = 12.0 Hz, 1H), 4.19 (d, J = 11.5 Hz, 1H), 4.11-4.06 (m, 1H ), 4.01 (dd, J = 10.5, 3.5 Hz, 1H), 3.94-3.85 (m, 7H), 3.54 (dd, J = 11.0, 4.0 Hz, 1H), 3.48 (dd, J = 9.5, 6.5 Hz, 1H), 3.34 (dd, J = 9.5, 6.0 Hz, 1H), 1.96-1.83 (m, 2H), 1.76 (quin, J = 7.0 Hz, 2H), 1.49-1.33 (m, 6H), 1.28-1.23 (m, 44H), 0.92 (t, J = 7.0 Hz, 3H), 0.88 (t, J = 6.8 Hz, 3H); LRMS (ESI ⁺ ) m / z calcd for C ₉₃ H ₁₂₆ N ₃ O ₁₀ [M + H] ⁺ : 1444.94; Found: 1445.12.

Step 11: Preparation of compound G5

The title compound G5 was synthesized as an amorphous white solid (yield: 5.4 mg, 96%) from compound 19-5 (9 mg, 6.23 μmol) by the same procedure as in step 1 of Example 1 above.

[?] _D ²⁰ + 42.2 (c = 0.53, CHCl ₃ / MeOH = 1: 1); ^{1 H NMR (500 MHz, CDCl} 3 / CD 3 OD = 1: 1; reference peak: CD 3 OD at 3.31 ppm) δ 7.60 (s, 1H), 7.58 (s, 1H), 7.17 (d, J = 9.0 Hz, 2H), 6.84 (d , J = 8.5 Hz, 2H), 5.21 (s, 2H), 4.88 (d, J = 4.0 Hz, 1H), 4.65 (d, J = 5.5 Hz, 1H), 4.01- 3.98 (m, 1H), 3.92 (t, J = 6.5 Hz, 2H), 3.90-3.66 (m, 9H), 2.16 (td, J = 7.6, 2.5 Hz, 2H), 1.75 (quin, J = 7.0 Hz , 2H), 1.58-1.56 (m, 2H), 1.43-1.33 (m, 4H), 1.28-1.23 (m, 44H), 0.91 (t, J = 7.3 Hz, 3H), 0.86 (t, J = 7.0 Hz, 3H); ¹³ C NMR (75 MHz, CDCl ₃ )? 160.1, 130.1, 115.6, 101.0, 78.9, 71.2, 70.7, 68.9, 68.0, 32.8, 30.5, 30.4, 30.2, 29.1, 23.5, 23.3, 14.5; HRMS (FAB ⁺ ) m / z calcd for C ₅₁ H ₉₀ N ₃ O ₁₀ [M + H] ⁺ : 904.6626; Found: 904.6619.

Example  39: Compound G6 Manufacturing

Compound G6 was obtained as described below in a similar manner to Example 1,

Experimental Example  1: Evaluation of biological activity of the compound of the present invention

In order to stimulate NKT cells in vivo, mice were intravenously administered with 2 [mu] g of the [alpha] -GalCer analogs of Examples 1 to 39 above. Sixteen hours after the administration, serum was collected and cytokines such as IFN-y, IL-4 and IL-17 secreted by ELISA were quantitated. The ELISA was performed as follows.

First, ELISA plates (Costar, Cambridge, Mass.) Were coated overnight with anti-IFN-, anti-IL-4 or anti-IL-17 monoclonal antibodies (BD Pharmingen, San Diego, CA) at 4 ° C. Wells were blocked with PBS containing 1% bovine serum albumin (Sigma Aldrich, USA) for 1 hour at room temperature and incubated with the sera at 4 ° C. After washing, the plate was incubated with biotinylated anti-IFN-y, anti-IL-4 or anti-IL-17 antibody for 1 hour at room temperature and incubated with strepavidin-conjugated horseradish peroxidase for 1 hour at room temperature Respectively. TMB solution (eBioscience, San Diego, Calif.) And absorbance was measured at 450 nm using Multiskan Ascent (Labsystems, USA).

The measurement results of each analogue of the present invention are shown in Table 1 as KRN7000 ( 1 , αGalcer-1), 4Cl-3CF ₃ BzNH-α-GalCer ( 2 , αGalcer-2), OCH ( 3 , αGalcer- K6-102) were compared.

The results of the above experiment are shown in Figs. 3 to 5. FIG. 3 shows the secretion amount of IFN-.gamma. In vivo after administering the .alpha.-GalCer analog of the present invention, FIG. 4 shows the secretion amount of IL-4 and FIG. 5 shows the secretion amount of IL-17.

Claims (8)

1. A compound represented by the following formula (1): < EMI ID =
[Chemical Formula 1]

In this formula,
R ₁ is C _{1 -20} alkyl, or

ego,
R ₂ is -NH-CO-R ₄ , or

Lt;
R ₃ is an alkoxy group H, C _{1 -10} alkyl, or C _{1 -10,}
R ₄ is C _{1 -30} alkyl; Or C _{1- 10} alkyl substituted by phenyl,
R ₅ is a C _{1 -30} alkyl,
n is an integer of 1 to 10;
2. The compound of claim 1, wherein R < ₁ > is ethyl or undecanyl, or a pharmaceutically acceptable salt thereof.
2. The compound of claim ₁ wherein R < ₁ > And R ₃ is H, methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, or pentoxy, or a pharmaceutically acceptable salt thereof.
The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ₂ is -NH-CO-R ₄ , and R ₄ is hexyl, tricosanyl, pentacosanyl, or 5-phenylpentyl.
2. The compound of claim 1, wherein R < ₂ &_gt;

And R < ₄ > is tetracosanyl, or a pharmaceutically acceptable salt thereof.
The compound according to claim 1, wherein the compound represented by the formula (1)

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

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,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

And

≪ / RTI > or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition for the treatment or prevention of diseases caused by immunomodulatory disorders, comprising a compound represented by the general formula (1) of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.
10. The composition according to claim 9, wherein the disease caused by the immunomodulation abnormality is any one selected from the group consisting of arteriosclerosis, autoimmune disease and arthritis.

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