KR102349523B1 - Novel enantioenriched bisindolylmethane sulfamate derivatives and the compositions for treating neuropathy comprising thereof - Google Patents

Abstract

The present invention relates to a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof; a method for preparing the compound; And it relates to a pharmaceutical composition for preventing or treating diabetic neuropathy comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.
The novel optically active bisindorylmethane sulfamate derivative compound of the present invention acts on semi-cells to inhibit the neuroaxon degeneration of Schwann cells and dedifferentiation of Schwann cells, thereby preventing the degeneration of peripheral nerves and effectively preventing or preventing diabetic neuropathy. could be used for treatment. In addition, the method for preparing the compound according to the present invention enables eco-friendly production at a lower cost compared to the case of using a conventional metal catalyst by using an optically active organic catalyst.

Description

Novel enantioenriched bisindolylmethane sulfamate derivatives and the compositions for treating neuropathy comprising thereof

The present invention relates to an optically active bisindolylmethanesulfamate derivative compound or a pharmaceutically acceptable salt thereof; a method for preparing the compound; And it relates to a pharmaceutical composition for preventing or treating a neuropathic disease comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

Peripheral neuropathy (PN) can be defined as damage, inflammation, and degeneration of peripheral nerve fibers. Peripheral neuropathy is caused by a number of causes, such as when the peripheral nerve itself is compressed or injured, when the microvessels that supply nutrients to the nerve are damaged due to vasculitis, metabolic diseases such as diabetes, renal failure, and hypothyroidism There are cases due to nutritional deficiencies such as vitamin deficiency or alcoholism, cases due to abnormalities in the immune system, drugs or toxins such as anticancer drugs, cases due to hereditary neuropathy, etc. Neuropathy caused by trauma or pressure appears locally, whereas metabolic disease or nutritional deficiencies, immune system thalamus, and drugs or toxins appear systemically. Among peripheral neuropathy, neuropathy as a complication of dangnyong is known to be the most common.

Diabetic peripheral neuropathy is one of the complications of neuropathy in diabetic patients. It is a disease that is urgently needed because symptoms appear due to nerve damage and cause great inconvenience to the patient and further severe disability. . However, until now, the root cause treatment and prevention methods for suppressing the onset are not known, and only symptomatic treatment methods exist. There are 420 million people with diabetes worldwide, and most of them have complications such as diabetic neuropathy. Diabetic peripheral neuropathy varies from asymptomatic to severe pain that makes daily life impossible depending on the patient. The main goals of the treatment of diabetic peripheral neuropathy are to prevent nerve degeneration, help regeneration, improve the quality of life, and prevent serious complications, thereby reducing the burden on the patient's own health and family. The current treatment strategies for diabetic peripheral neuropathy are divided into three main categories. ① Treatment to control blood sugar and manage risk factors that are the root cause of diabetic neuropathy. ② Treatment based on etiological studies of the pathogenesis of diabetic neuropathy. ③ Treatment of symptoms related to pain caused by diabetic peripheral neuropathy. Until now, only symptomatic treatment for symptom improvement has been mainly used, and existing etiological treatments caused by peripheral nerve degeneration are ineffective. In addition, prevention of diabetic neuropathy by blood sugar control has its limits, and once degenerated peripheral nerves are damaged, regeneration is impossible due to damage to the nerve cell bodies. Therefore, there is an urgent need to develop a new therapeutic agent to effectively inhibit neurodegeneration during the prevalence of diabetes and to prevent the progression to neuropathy by maintaining nerve function damage.

Korean Patent Registration No. 10-1695207 discloses a composition for preventing or treating anticancer drug-induced peripheral neuropathy containing an extract of Phytolaccae Radix as an active ingredient.

Korean Patent Application No. 10-2018-0012940 (filed on February 01, 2018) discloses a composition for preventing or treating neuropathic pain containing trimethobenzamide.

Korean Publication No. WO2018047175 (published on March 15, 2018) discloses a composition comprising a triterpenoid and its use for treating optic neuropathy.

A sulfamate functional group is an important component found in natural products of various biological activities and therapeutic agents exhibiting pharmacological activity. Molecules containing sulfamate functional groups exhibit a wide range of biological activities such as antibacterial, antifungal, anticonvulsant, anticancer and cardiovascular activities. For example, estriol sulfamate is a steroid-based enzyme inhibitor under development for the treatment of endometriosis, and nucleocidin, a fluorine-containing nucleoside isolated from Streptomyces calcus, inhibits t-RNA synthetase. showing activity. Topiramate is a broad-spectrum anticonvulsant drug for the treatment of epilepsy and migraine prevention, and Pevonedistat is a NEDD8 inhibitor being studied as an anticancer treatment for mantle cell lymphoma.

Accordingly, the present inventors have made intensive research efforts to develop small molecules capable of inhibiting neuropathy. As a result, a high yield of optically active bisindolylmethane sulfamate derivative compounds having novel various substituents by an environmentally friendly method using an organic catalyst and high optical purity, confirmed that they can effectively inhibit the degeneration of peripheral nerves, and completed the present invention.

An object of the present invention is to provide a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

[Formula 1]

Another object of the present invention is to provide a method for preparing the compound.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating neuropathic diseases comprising the compound as an active ingredient.

In order to solve the above problems, the present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

[Formula 1]

wherein R ₁ and R ₂ are hydrogen, C1 to C6 alkyl; R ₃ , R ₄ and R ₅ are each independently hydrogen, halogen or straight or branched C1 to C6 alkyl, aryl or C1 to C6 alkoxy.

Preferably, in the above formula, R ₁ and R ₂ may each independently be methyl, ethyl, isopropyl or benzyl, and R ₃ , R ₄ and R ₅ are each independently hydrogen, bromine, chlorine, methyl, or methoxyyl can In this case, R ₃ , R ₄ and R ₅ may be located at any bondable position on the benzene ring.

Preferably, the compound represented by Formula 1 is

1) 2-((1 H -indol-3yl)(1-methyl- 1H -indol-3-yl)methyl)phenyl sulfamate,

2) 2-((1 H -indol-3yl)(1-methyl- 1H -indol-3-yl)methyl)-4-methylphenyl sulfamate,

3) 2-((1 H -indol-3-yl)(1-methyl-1 H -indol-3-yl)methyl)-5-methylphenyl sulfamate,

4) 2-((1 H -indol-3-yl)(1-methyl- 1H -indol-3-yl)methyl)-5-methoxyphenyl sulfamate,

5) 2-((1 H -indol-3-yl)(1-methyl-1 H -indol-3-yl)-4-fluoromethyl)phenyl sulfamate,

6) 2-((1 H -indol-3-yl)(1-methyl- 1H -indol-3-yl)methyl)4-chlorophenyl sulfamate,

7) 2-((1 H -indol-3-yl)(1-methyl-1 H -indol-3-yl)methyl)4-bromophenyl sulfamate;

8) 2-((1-allyl- 1H -indol-3yl)(1-methyl- 1H -indol-3-yl)methyl)phenyl sulfamate,

9) 2-((1-benzyl-1 H -indol-3yl)(1-methyl-1 H -indol-3-yl)methyl)phenyl sulfamate,

10) (2-((1 H -indol-3yl)(5-methoxy-1-methyl- 1H -indol-3-yl)methyl)phenyl sulfamate;

11) 2-((5-(benzyloxy)-1-methyl-1 H -indol-3yl)(1-methyl-1 H -indol-3-yl)methyl)phenyl sulfamate,

12) 2-((1 H -indol-3yl)(1,7-dimethyl-1-methyl- 1H -indol-3-yl)methyl)phenyl sulfamate,

13) 2-((5-bromo- 1H -indol-3-yl)(1-methyl- 1H -indol-3-yl)methyl)phenyl sulfamate,

14) 2-((6-fluoro-1 H -indol-3-yl)(1-methyl-1 H -indol-3-yl)methyl)phenyl sulfamate;

15) 2-((6-chloro- 1H -indol-3yl)(1-methyl- 1H -indol-3-yl)methyl)phenyl sulfamate,

16) 2-((5-cyano-1 H -indol-3yl)(1-methyl-1 H -indol-3-yl)methyl)phenyl sulfamate;

17) 2-((1 H -indol-3yl)(1-methyl-5-nitro-1 H -indol-3-yl)methyl)phenyl sulfamate,

18) 2-((1 H -indol-3-yl)(1,2-dimethyl- 1H -indol-3-yl)methyl)phenyl sulfamate,

19) 2-(di(1 H -indol-3yl)methyl)phenyl sulfamate, or

20) 2-(bis(1-methyl-1 H -indol-3yl)methyl)phenyl sulfamate.

Compounds 1 to 20 according to the present invention have the following chemical structures, respectively.

[Compound 1]

[Compound 2]

[Compound 3]

[Compound 4]

[Compound 5]

[Compound 6]

[Compound 7]

[Compound 8]

[Compound 9]

[Compound 10]

[Compound 11]

[Compound 12]

[Compound 13]

[Compound 14]

[Compound 15]

[Compound 16]

[Compound 17]

[Compound 18]

[Compound 19]

[Compound 20]

In the above chemical formula, Me is a methyl group, and Bn is a benzyl group.

In another aspect, the present invention provides a method for preparing a compound of Formula 1, comprising reacting a compound represented by Formula 2 with a compound represented by Formula 3 below:

[Formula 1]

[Formula 2]

[Formula 3]

In the above formula, R ₂ to R ₅ are as defined for Formula 1.

In the method for preparing the compound according to the present invention, a Lewis acid is used as a catalyst, preferably Ni(ClO ₄ ) ₂ , Mg(OTf) ₂ , Cu(OTf) ₂ , Zn(OTf) ₂ , Sc( OTf) ₃ , and Yb(OTf) ₃ .

As another aspect, in the method for preparing the compound according to the present invention, it is preferable to include an asymmetric reaction using a chiral binol-phosphate compound represented by the following formula (4) as a catalyst:

[Formula 4]

The catalysts used in the present invention, chiral binol-phosphoric acid compounds, are organic catalysts, which provide superior reproducibility and ease of use compared to metal catalysts used in conventional asymmetric reactions. In addition, the organic catalyst has advantages of being inexpensive, readily available, highly reactive, and nontoxic. Therefore, the asymmetric reaction using the organic catalyst can be an efficient and environmentally friendly method for preparing a single enantiomer having optical activity with high purity (yield) and high optical purity (enantiomeric excess; ee). The chemical structural formulas of the chiral binol-phosphate compounds used in this reaction are summarized in FIG. 2 .

The concentration of the catalyst to be added may be arbitrarily adjusted by those skilled in the art, but preferably, it may be added at a concentration of 1 to 20 mol%, more preferably 10 mol%, based on the amount of the sulfimine derivative compound used as a reactant. . When added at a concentration lower than the concentration range, the yield may decrease, and when added at a concentration exceeding the above range, side reactions may be accompanied.

Preferably, the molar ratio of the sulfamine derivative compound represented by Formula 2 to the indole derivative compound represented by Formula 3 is 1:1. When the molar ratio of the reactants is lower than 1:1, the indole addition reaction does not occur properly and the yield is lowered.

The reaction using the catalyst is preferably carried out at 0 to 40 ℃ for 4 to 120 hours. In addition, it is preferably carried out using methylene chloride, dichloroethane, benzene, ethyl acetate, acetonitrile, toluene, xylene, tetrahydrofuran or a mixture thereof as a solvent. More preferably, a toluene solvent may be used, but is not limited thereto. In the reaction, if the concentration of the reactant is less than 0.05 M, the reaction rate may be slow, and if it is more than 1.0 M, the reactant may not be completely dissolved in the solvent. It is preferred to determine the amount of solvent to remain in the range of to 1.0 M.

When the reaction is carried out at a low temperature of less than 0 ° C, the reaction rate is slowed and the reaction time is prolonged, and when the reaction is carried out at a high temperature of more than 40 ° C. The reaction may be more preferably carried out at 20 to 30 °C, and most preferably at 25 °C.

The reaction time may be appropriately selected by those skilled in the art according to the type of reactant. However, if the reaction time is shorter than 4 hours, the reaction may not be completed, and if it is longer than 120 hours, the reaction may result in continuation of the reaction conditions even after the reaction is already completed.

Furthermore, the reaction may be performed by additionally including 4 Å molecular sieves, thereby further improving the yield or enantioselectivity. The amount of 4 Å molecular sieves to be added can be arbitrarily adjusted by those skilled in the art, but is preferably 0.1 to 0.3 grams per millimol, more preferably 0.1 to 0.3 grams per millimol, relative to the amount of the reactant sulfamine derivative compound used. 0.2 grams may be added.

The preparation method according to the present invention may further include the step of determining the enantioselectivity of the prepared compound. For example, the above step may be performed by performing HPLC analysis using a Chiralcel AD-H column and an AD-H guard column (1.0 mL/min flow rate, λ=220 nm). can be achieved

As another aspect, the present invention provides a pharmaceutical composition for preventing or treating neuropathic diseases, comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. The neuropathy is diabetic neuropathy, post-herpetic neuropathy, trigeminal neuropathy, peripheral neuropathies, mononeuropathy, mononeuritis multiplex, autonomic neuropathy. Neuropathy, inflammatory neuropathy, metabolic or endocrine neuropathy, toxic or drug-induced neuropathy, nutritional neuropathy, vascular inflammation It may be a vasculitic neuropathy, a paraneoplastic neuropathy, a traumatic neuropathy, a hereditary neuropathy and an idiopathic neuropathy.

of the present invention The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof acts on Schwann cells when neurodegeneration begins to inhibit the neuronal axon degeneration of Schwann cells and dedifferentiation of Schwann cells, thereby preventing the degeneration of peripheral nerves and preventing nerve conduction function. keep

The term "prevention" of the present invention means any action that inhibits or delays the occurrence, spread, and recurrence of diabetic disease by administration of the composition of the present invention, and "treatment" refers to any action of the disease by administration of the composition of the present invention. It refers to any action that improves or changes to a favorable condition.

Accordingly, the present invention provides a pharmaceutical composition for inhibiting diabetic neuropathy comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier. The pharmaceutical composition of the present invention may contain the active ingredient, the compound of Formula 1, in an amount of 0.1 to 75% by weight, preferably 1 to 50% by weight, based on the total weight of the composition.

The pharmaceutical composition of the present invention may be formulated in various oral or parenteral dosage forms. Formulations for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, and granules. crose, mannitol, sorbitol, cellulose and/or glycine), lubricants (eg silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol). Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, optionally starch, agar, alginic acid or its It may contain disintegrating or boiling mixtures and/or absorbents, such as sodium salts, coloring, flavoring, and sweetening agents. In addition, a representative formulation for parenteral administration is an injection formulation, preferably an isotonic aqueous solution or suspension.

The composition may be sterilized and/or contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, salts and/or buffers for regulating osmotic pressure and other therapeutically useful substances, and may contain conventional mixing, granulating or coating It can be formulated according to the method.

As an active ingredient, the compound of Formula 1 is administered orally or parenterally in an amount of 2.5 to 100 mg/kg body weight per day, preferably 5 to 60 mg/kg body weight, once a day or divided into human and mammalian subjects. It can be administered via route.

The composition of the present invention is administered in a pharmaceutically effective amount. As used herein, the term "pharmaceutically effective amount" refers to an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and not to cause side effects, and the effective dose level depends on the patient's health condition, disease type, severity, drug activity, sensitivity to drug, administration method, administration time, administration route and excretion rate, duration of treatment, factors including drugs used in combination or concomitantly, and other factors well known in the medical field. can The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art.

Specifically, the effective amount of the compound in the composition of the present invention may vary depending on the age, sex, and weight of the patient, and generally 1 to 100 mg per kg of body weight, preferably 5 to 60 mg, is administered daily or every other day, or 1 It can be administered in divided doses 1 to 3 times a day. However, since it may increase or decrease depending on the route of administration, disease severity, sex, weight, age, etc., the dosage is not intended to limit the scope of the present invention in any way.

The novel optically active bisindorylmethane sulfamate derivative compound of the present invention acts on semi-cells to inhibit the neuroaxon degeneration of Schwann cells and dedifferentiation of Schwann cells, thereby preventing the degeneration of peripheral nerves and effectively preventing or treating neuropathic diseases. could be used In addition, the method for preparing the compound according to the present invention enables eco-friendly production at a lower cost compared to the case of using a conventional metal catalyst by using an optically active organic catalyst.

1 shows a synthesis formula of bisindolylmethane sulfamate according to the present invention.
2 is a diagram showing the chemical structural formulas of chiral binol-phosphate compounds used as catalysts.
3 shows transverse streaks seen in sciatic nerve explants for primary drug screening. Transverse streaks are visible in the sciatic nerve explant for first exploration. Here, 3DIV/5 is tested with compound 20, 3DIV/6a is tested with compound 1, and 3DIV/4 is tested with compound 19. 3DIV/6a-OH was tested with bisindolylmethane phenol.
Figure 4 shows Ovoid-like structures (size bars = 50 μm) seen in stretched sciatic nerve fibers for secondary drug screening.
Figure 5 Quantitative drug effect oocyte number for secondary screening (n = 4 mice, ***P <0.0001).

Hereinafter, an embodiment of the present invention will be described in more detail. However, the following examples only illustrate the present invention, and the content of the present invention is not limited by the following examples.

Example 1: Synthesis of optically active bisindolylmethane sulfamate derivative compound

1.1. 2-((1 H -indole-3yl)(1-methyl-1 H -indol-3-yl)methyl)phenyl sulfamate (2-((1) H -Indol-3-yl)(1-methyl-1 H -indol-3-yl)methyl)phenyl sulfamate; Synthesis of 1a))

4-(1H-Indol-3-yl)-3,4-dihydro-1,2λ6,3-benzoxathiazine-2,2-dione ( 2a ; 0.10 mmol) and 4 Å molecular sives (20 mg) in toluene (0.5 mL), the chiral binol -phosphate compound PA12 (0.010 mmol) as a catalyst was added, and then stirred at room temperature for 10 minutes. Then, N -methylindole (N-methylindole; 3a , 0.10 mmol) was added and stirred for 35 hours. After the reaction was terminated by adding water, the reaction product was extracted with dichloromethane, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and then purified by silica gel column chromatography in ethyl acetate/hexane to obtain the target compound was obtained as a red solid ( 1a ; 77% yield, 80:20% er ).

m.p. 129-131 ° C;

[α] ²⁶ _D = +3.7 ( c = 0.46, EtOAc);

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.00 (s, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.45-7.34 (m, 3H), 7.32-7.14 (m, 6H), 7.02 ( dd, J = 13.9, 7.0 Hz, 2H), 6.76 (s, 1H), 6.62 (s, 1H), 6.27 (s, 1H), 3.89 (s, 2H), 3.69 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 148.7, 137.3, 136.5, 136.3, 130.5, 128.7, 127.9, 126.91, 126.88, 126.5, 124.0, 122.4, 121.9, 121.8, 119.8, 119.7, 119.6, 119.2, 118.2, 116.3 , 111.4, 109.4, 33.8, 32.8;

IR (film) 3403, 3274, 2992, 1480, 1455, 1371, 1329, 1182, 1153, 1108, 919 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₄ H ₂₀ N ₃ O ₃ S: 430.1225 Found: 430.1229;

Chiralpak AD-H column and AD-H guard column (15% i -PrOH:hexanes, 1.0 mL/min flow, λ= 254 nm); minor -isomer t _r = 38.2 min and major -isomer t _r = 61.5 min.

1.2. (2-((1 H -indole-3yl)(1-methyl-1 H -indol-3-yl)methyl)-4-methylphenyl sulfamate (2-((1) H -Indol-3-yl)(1-methyl-1 H -indol-3-yl)methyl)-4-methylphenyl sulfamate; Synthesis of 1b))

4-(1H-Indol-3-yl)- in place of 4-(1H-Indol-3-yl)-3,4-dihydro-1,2λ6,3-benzoxathiazine-2,2-dione 2a as a starting material 6-methyl-3,4-dihydro-1,2λ6,3-benzoxathiazine-2,2-dione 2b In the same manner as in Example 1, except for using the target compound 1b (61% yield, 64:36 er ) was obtained.

m.p. 124-127 ° C;

[α] ²⁶ _D = -3.1 ( c = 0.44, EtOAc);

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97 (s, 1H), 7.47-7.29 (m, 5H), 7.20 (dt, J = 14.7, 7.5 Hz, 2H), 7.11 (s, 1H), 7.09- 6.98 (m, 3H), 6.74 (s, 1H), 6.62 (s, 1H), 6.23 (s, 1H), 3.88 (s, 2H), 3.68 (s, 3H), 2.22 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 146.5, 137.3, 136.7, 136.5, 135.8, 130.8, 128.7, 128.5, 126.9, 126.5, 124.0, 122.4, 121.9, 121.6, 119.8, 119.7, 119.6, 119.2, 118.3, 116.4 , 111.4, 109.4, 33.7, 32.8, 21.1; IR (film) 3404, 3284, 2923, 1547, 1485, 1457, 1421, 1372, 1330, 1198, 1169, 1089, 1012, 935 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₅ H ₂₂ N ₃ O ₃ S: 444.1382 Found: 444.1378;

Chiralpak IA column and IA guard column (5% EtOH:hexanes, 1.0 mL/min flow, λ=254 nm); major -isomer t _r = 63.5 min and minor -isomer t _r = 36.5 min.

1.3. (2-((1 H -indole-3yl)(1-methyl-1 H -indol-3-yl)methyl)-5-methylphenyl sulfamate (2-((1) H -Indol-3-yl)(1-methyl-1 H -indol-3-yl)methyl)-5-methylphenyl sulfamate; Synthesis of 1c))

4-(1H-Indol-3-yl)- in place of 4-(1H-Indol-3-yl)-3,4-dihydro-1,2λ6,3-benzoxathiazine-2,2-dione 2a as a starting material 7-methyl-3,4-dihydro-1,2λ6,3-benzoxathiazine-2,2-dione 2c In the same manner as in Example 1, except that the target compound 1c (58% yield, 65:35 er ) was obtained.

m.p. 114-117 ° C;

[α] ²⁶ _D = +3.4 ( c = 0.45, EtOAc);

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.96 (s, 1H), 7.41 (dd, J = 13.5, 8.0 Hz, 2H), 7.32 (t, J = 7.1 Hz, 3H), 7.25-7.15 (m, 3H), 7.02 (dd, J = 12.5, 7.3 Hz, 2H), 6.96 (d, J = 7.7 Hz, 1H), 6.72 (s, 1H), 6.62 (s, 1H), 6.21 (s, 1H), 3.91 (s, 2H), 3.67 (s, 3H), 2.33 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 148.4, 138.1, 137.3, 136.5, 133.1, 130.2, 128.7, 127.7, 126.9, 126.5, 124.0, 122.4, 122.2, 121.9, 119.8, 119.74, 119.69, 119.2, 118.3, 116.5 , 111.4, 109.4, 33.5, 32.8, 21.0; IR (film) 3406, 3274, 2920, 2850, 1712, 1616, 1499, 1457, 1421, 1372, 1329, 1182, 1149, 1083, 1011, 945 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₅ H ₂₂ N ₃ O ₃ S: 444.1382 Found: 444.1373;

Chiralpak IA column and IA guard column (20% i -PrOH:hexanes, 1.0 mL/min flow, λ= 254 nm); minor -isomer t _r = 17.8 min and major -isomer t _r = 27.4 min.

1.4. (2-((1 H -indole-3yl)(1-methyl-1 H -indol-3-yl)methyl)-5-methoxyphenyl sulfamate (2-((1 H -Indol-3-yl)(1-methyl-1 H -indol-3-yl)methyl)-5-methoxyphenyl sulfamate; Synthesis of 1d))

4-(1H-Indol-3-yl)- in place of 4-(1H-Indol-3-yl)-3,4-dihydro-1,2λ6,3-benzoxathiazine-2,2-dione 2a as a starting material 7-methoxy-3,4-dihydro-1,2λ6,3-benzoxathiazine-2,2-dione 2c In the same manner as in Example 1, except that the target compound 1d (54% yield, 56:44 er ) was obtained.

m.p. 129-132 ° C;

[α] ²⁵ _D = -3.4 ( c = 0.41, EtOAc);

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97 (s, 1H), 7.40 (dd, J = 13.2, 7.9 Hz, 2H), 7.35 7.28 (m, 2H), 7.25-7.14 (m, 3H), 7.06 (d, J = 2.5 Hz, 1H), 7.02 (td, J = 7.3, 5.0 Hz, 2H), 6.73 (s, 1H), 6.70 (dd, J = 8.6, 2.5 Hz, 1H), 6.61 (s) , 1H), 6.17 (s, 1H), 3.91 (s, 2H), 3.76 (s, 3H), 3.67 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 158.9, 148.9, 137.3, 136.5, 130.9, 128.6, 128.2, 126.9, 126.4, 123.9, 122.4, 121.9, 119.8, 119.75, 119.72, 119.2, 118.5, 116.6, 112.9, 111.4 , 109.4, 107.4, 55.6, 33.3, 32.8; IR (film) 3044, 3274, 3064, 2927, 1614, 1579, 1498, 1457, 1371, 1329, 1281, 1245, 1182, 1083, 1031, 944 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₅ H ₂₂ N ₃ O ₄ S: 460.1331 Found: 460.1346;

Chiralpak IC column and IC guard column (10% i -PrOH:hexanes, 1.0 mL/min flow, λ= 254 nm); minor -isomer t _r = 42.9 min and major -isomer t _r = 54.1 min.

1.5. (2-((1 H -indole-3yl)(1-methyl-1 H -indol-3-yl)-4-fluoromethyl)phenyl sulfamate (2-((1) H -Indol-3-yl)(1-methyl-1 H -indol-3-yl)methyl)-4-fluorophenyl sulfamate; Synthesis of 1e))

As a starting material, 4-(1H-Indol-3-yl)-3,4-dihydro-1,2λ6,3-benzoxathiazine-2,2-dione 2a was replaced with 6-Fluoro-4-(1H-indol-3 -yl)-3,4-dihydro-1,2λ6,3-benzoxathiazine-2,2-dione 2e In the same manner as in Example 1, except for using the target compound 1e (55% yield, 90:10 er ) was obtained.

m.p. 125-128 ℃;

[α] ²³ _D = +1.1 ( c = 0.43, EtOAc);

¹ H NMR (400 MHz, acetone-d ₆ ) δ 9.91 (s, 1H), 7.42-7.30 (m, 3H), 7.28-7.20 (m, 2H), 7.20 (s, 2H), 7.03-6.86 (m , 3H), 6.86-6.73 (m, 3H), 6.68 (d, J = 1.7 Hz, 1H), 6.58 (s, 1H), 6.29 (s, 1H), 3.59 (s, 3H);

¹³ C NMR (100 MHz, acetone-d ₆ ) δ 160.5 (d, J ¹ = 242.8 Hz), 144.8 (d, J ⁴ = 2.7 Hz), 141.0 (d, J ³ = 7.1 Hz), 137.6, 137.2, 128.5, 127.3, 126.9, 124.2, 123.6 (d, J ³ = 8.9 Hz), 121.4 (d, J ³ = 7.3 Hz), 119.9, 119.6, 118.6, 118.5, 117.1, 116.4, 116.23, 116.21, 113.6 (d, J ² = 23.8 Hz), 111.3, 109.3, 33.8, 31.9;

IR (film) 3048, 3277, 2921, 2851, 1615, 1540, 1479, 1459, 1421, 1370, 1338, 1263, 1183, 1159, 1064, 1010, 938 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₄ H ₁₉ FN ₃ O ₃ S: 464.0836 Found: 464.0839;

Chiralpak IC column and IC guard column (10% i -PrOH:hexanes, 1.0 mL/min flow, λ= 254 nm); minor -isomer t _r = 29.6 min and major -isomer t _r = 34.4 min.

1.6. (2-((1 H -indole-3yl)(1-methyl-1 H -indol-3-yl)methyl)4-chlorophenyl sulfamate (2-((1) H -Indol-3-yl)(1-methyl-1 H -indol-3-yl)methyl)-4-chlorophenyl sulfamate; Synthesis of 1f))

As a starting material, 4-(1H-Indol-3-yl)-3,4-dihydro-1,2λ6,3-benzoxathiazine-2,2-dione 2a was replaced with 6-Chloro-4-(1H-indol-3 -yl)-3,4-dihydro-1,2λ6,3-benzoxathiazine-2,2-dione 2f In the same manner as in Example 1, except that the target compound 1f (60% yield, 94:6 er ) was obtained.

m.p. 130-134 ° C;

[α] ²⁶ _D = +1.9 ( c = 0.42, EtOAc);

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.96 (s, 1H), 7.44-7.35 (m, 3H), 7.31 (dd, J = 11.2, 8.3 Hz, 2H), 7.24-7.15 (m, 4H), 7.02 (dd, J = 12.4, 7.3 Hz, 2H), 6.69 (s, 1H), 6.58 (s, 1H), 6.21 (s, 1H), 4.00 (s, 2H), 3.66 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 147.0, 138.5, 137.3, 136.5, 132.5, 130.1, 128.7, 128.0, 126.7, 126.3, 124.0, 123.2, 122.6, 122.1, 120.0, 119.5, 119.42, 119.39, 117.5, 115.6 , 111.5, 109.6, 33.6, 32.8;

IR (film) 3404, 3277, 2923, 1615, 1544, 1471, 1457, 1372, 1330, 1182, 1156, 1099, 1011, 924 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₄ H ₁₉ ClN ₃ O ₃ S: 448.1131 Found: 448.1121;

Chiralpak IB column and IB guard column (20% i -PrOH:hexanes, 1.0 mL/min flow, λ= 254 nm); major -isomer t _r = 23.8 min and minor -isomer t _r = 29.6 min.

1.7. (2-((1 H -indole-3yl)(1-methyl-1 H -indol-3-yl)methyl)4-bromophenyl sulfamate (2-((1 H -Indol-3-yl) (1-methyl-1 H -indol-3-yl)methyl)-4-bromophenyl sulfamate; Synthesis of 1g))

As a starting material, 4-(1H-Indol-3-yl)-3,4-dihydro-1,2λ6,3-benzoxathiazine-2,2-dione 2a was replaced with 6-Bromo-4-(1H-indol-3 -yl)-3,4-dihydro-1,2λ6,3-benzoxathiazine-2,2-dione 2f In the same manner as in Example 1, 1 g of the target compound (44% yield, 93:7 er ) was obtained.

m.p. 115-118 °C;

[α] ²⁷ _D = +5.9 ( c = 0.50, EtOAc);

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 (s, 1H), 7.46-7.30 (m, 7H), 7.22 (dd, J = 17.8, 7.7 Hz, 2H), 7.05 (dd, J = 13.9, 6.9) Hz, 2H), 6.76 (s, 1H), 6.61 (s, 1H), 6.23 (s, 1H), 3.95 (s, 2H), 3.70 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 147.6, 138.8, 137.3, 136.5, 133.0, 131.0, 128.7, 126.7, 126.3, 124.0, 123.6, 122.6, 122.1, 120.4, 120.0, 119.4 (two peaks overlapping), 119.4, 117.6, 115.6, 111.5, 109.5, 33.6, 32.8;

IR (film) 3045, 3276, 2921, 2852, 1713, 1614, 1545, 1468, 1373, 1330, 1268, 1181, 1155, 1094, 1012, 925 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₄ H ₁₉ BrN ₃ O ₃ S: 508.0330 Found: 508.0315;

Chiralpak IB column and IB guard column (20% i -PrOH:hexanes, 1.0 mL/min flow, λ= 254 nm); major -isomer t _r = 24.1 min and minor -isomer t _r = 30.9 min.

1.8. (2-((1-allyl-1) H -indole-3yl)(1-methyl-1 H -Indol-3-yl)methyl)phenyl sulfamate (2-((1-Allyl-1) H -indol-3-yl) (1 H -indol-3-yl)methyl)phenyl sulfamate; Synthesis of 1h))

The target compound 1h (71% yield, 69:31 er ) was obtained in the same manner as in Example 1, except that N- allylindole 3b was used instead of N- methylindole 3a as a starting material.

m.p. 178-180℃;

[α] ²⁵ _D = +1.9 ( c = 0.44, EtOAc);

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97 (s, 1H), 7.48 (d, J = 8.1 Hz, 1H), 7.43-7.36 (m, 2H), 7.34 (d, J = 8.2 Hz, 1H) , 7.31-7.23 (m, 3H), 7.21-7.10 (m, 3H), 7.01 (dd, J = 13.6, 6.8 Hz, 2H), 6.73 (s, 1H), 6.66 (s, 1H), 6.26 (s) , 1H), 5.91 (ddd, J = 22.3, 10.4, 5.3 Hz, 1H), 5.14 (dd, J = 10.2, 1.1 Hz, 1H), 5.03 (dd, J = 17.1, 1.1 Hz, 1H), 4.62 ( d, J = 5.3 Hz, 2H), 3.87 (s, 2H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 148.6, 136.7, 136.5, 136.2, 133.4, 130.5, 127.9, 127.8, 127.1, 126.9, 126.5, 124.0, 122.4, 122.0, 121.8, 119.8 (two peaks overlapping), 119.6, 119.4, 118.1, 117.2, 116.7, 111.4, 109.9, 48.8, 33.8; IR (film) 3404, 3278, 2922, 1728, 1612, 1544, 1480, 1419, 1366, 1388, 1201, 1178, 1148, 1085, 938 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₆ H ₂₇ N ₃ O ₃ S: 457.1460 Found: 457.1445;

Chiralpak AD-H column and AD-H guard column (20% EtOH:hexanes, 1.0 mL/min flow, λ = 254 nm); minor -isomer t _r = 15.1 min and major -isomer t _r = 22.5 min.

1.9. (2-((1-benzyl-1 H -indole-3yl)(1-methyl-1 H -indol-3-yl)methyl)phenyl sulfamate (2-((1-benzyl-1) H -indol-3-yl) (1 H -indol-3-yl)methyl)phenyl sulfamate; Synthesis of 1i))

The target compound 1i (52% yield, 63:37 er ) was obtained in the same manner as in Example 1, except that N- benzylindole 3c was used instead of N- methylindole 3a as a starting material.

m.p. 173-175 ° C;

[α] ²³ _D = +9.3 ( c = 0.44, EtOAc);

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.90 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.42-7.35 (m, 2H), 7.30-7.18 (m, 7H), 7.13 ( dd, J = 13.4, 5.9 Hz, 3H), 7.06-6.93 (m, 4H), 6.70 (s, 1H), 6.65 (s, 1H), 6.27 (s, 1H), 5.16 (s, 2H), 3.91 (s, 2H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 148.6, 137.6, 136.9, 136.5, 136.2, 130.5, 128.8, 128.3, 127.9, 127.6, 127.2, 127.0, 126.6, 126.5, 124.0, 122.4, 122.2, 121.8, 119.9, 119.8 , 119.7, 119.5, 118.1, 117.0, 111.4, 110.1, 50.0, 33.8; IR (film) 3401, 3275, 2924, 1544, 1479, 1453, 1370, 1334, 1200, 1182, 1152, 1083, 1011, 909 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₃₀ H ₂₅ N ₃ O ₃ S: 507.1617 Found: 507.1606;

Chiralpak IB column and IB guard column (30% i -PrOH:hexanes, 1.0 mL/min flow, λ=254 nm); major -isomer t _r = 13.1 min and minor -isomer t _r = 17.0 min.

1.10. (2-((1 H -indole-3yl)(1-methyl-1 H -indol-3-yl)methyl)phenyl sulfamate (2-((1) H -Indol-3-yl)(5-methoxy-1-methyl-1 H -indol-3-yl)methyl)phenyl sulfamate; Synthesis of 1j))

The target compound 1j (89% yield, 88:12 er ) was obtained in the same manner as in Example 1, except that 5-methoxy-1-methylindole 3d was used instead of N- methylindole 3a as a starting material.

m.p. 187-191 ° C;

[α] ²⁵ _D = +20.8 ( c = 0.43, EtOAc);

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.01 (s, 1H), 7.49 (dd, J = 8.1, 1.1 Hz, 1H), 7.38 (dd, J = 14.5, 8.1 Hz, 2H), 7.28 (dt, J = 13.8, 3.8 Hz, 2H), 7.22-7.13 (m, 3H), 7.06-6.99 (m, 1H), 6.87 (dd, J = 8.8, 2.4 Hz, 1H), 6.85-6.82 (m, 1H) , 6.75 (dt, J = 2.4 Hz, 1H), 6.61 (s, 1H), 6.21 (s, 1H), 3.91 (s, 2H), 3.70 (s, 3H), 3.66 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 153.9, 148.6, 136.5, 136.3, 132.6, 130.5, 129.2, 127.9, 127.1, 126.9, 126.5, 124.0, 122.4, 121.8, 119.8, 119.7, 118.2, 115.9, 112.1, 111.4 , 110.3, 101.3, 55.9, 33.8, 33.0; IR (film) 3413, 3266 2925, 1489, 1475, 1422, 1372, 1271, 1205, 1181, 1144, 1116, 1086, 1038, 909 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₅ H ₂₃ N ₃ O ₄ S: 461.1409 Found: 461.1406;

Chiralpak AD-H column and AD-H guard column (20% EtOH:hexanes, 1.0 mL/min flow, λ = 254 nm); major -isomer t _r = 35.6 min and minor -isomer t _r = 55.6 min.

1.11. (2-((5-(benzyloxy)-1-methyl-1 H -indole-3yl)(1-methyl-1 H -Indol-3-yl)methyl)phenyl sulfamate (2-((5-(Benzyloxy)-1-methyl-1 H -indol-3-yl) (1 H -indol-3-yl)methyl)phenyl sulfamate; Synthesis of 1k))

The target compound 1k (75% yield, 85:15 er ) was obtained in the same manner as in Example 1, except that 5-benzyloxy-1-methylindole 3e was used instead of N- methylindole 3a as a starting material.

m.p. 122-124 ℃;

[α] ²⁵ _D = +17.8 ( c = 0.43, EtOAc);

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.96 (s, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.42-7.25 (m, 9H), 7.22-7.11 (m, 3H), 7.03 ( t, J = 7.5 Hz, 1H), 6.96 (dd, J = 8.8, 2.2 Hz, 1H), 6.91 (d, J = 2.1 Hz, 1H), 6.70 (s, 1H), 6.60 (s, 1H), 6.18 (s, 1H), 4.96 (s, 2H), 3.83 (s, 2H), 3.64 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 151.7, 147.6, 136.5, 135.4, 135.2, 131.6, 129.4, 128.3, 127.4, 126.8, 126.7, 126.6, 126.0, 125.9, 125.4, 123.0, 121.3, 120.7, 118.7, 118.6 , 117.0, 114.6, 111.9, 110.3, 109.2, 102.0, 69.7, 32.8, 31.9; IR (film) 3393, 3275, 2919, 1487, 1455, 1424, 1374, 1339, 1259, 1182, 1153, 1084, 1011, 914 cm ^-1 ; HRMS (EI) m/z calcd for [M] ⁺ C ₃₁ H ₂₇ N ₃ O ₄ S: 537.1722 Found: 537.1696; Chiralpak AD-H column and AD-H guard column (20% EtOH:hexanes, 1.0 mL/min flow, λ = 254 nm); major -isomer t _r = 47.0 min and minor -isomer t _r = 79.7 min.

1.12. (2-((1 H -indole-3yl)(1,7-dimethyl-1-methyl-1 H -indol-3-yl)methyl)phenyl sulfamate (2-((1) H -Indol-3-yl) (1,7-dimethyl-1 H -indol-3-yl)methyl)phenyl sulfamate; Synthesis of 1l))

The target compound 11 (81% yield, 86:14 er ) was obtained in the same manner as in Example 1, except that 1,7-dimethylindole 3f was used instead of N- methylindole 3a as a starting material.

m.p. 201-203 °C;

[α] ²⁵ _D = +1.6 ( c = 0.50, EtOAc);

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (s, 1H), 7.48 (dd, J = 8.1, 1.1 Hz, 1H), 7.38 (dd, J = 18.6, 8.1 Hz, 2H), 7.29-7.24 ( m, 2H), 7.17 (dtd, J = 16.1, 7.3, 1.2 Hz, 3H), 7.06-6.99 (m, 1H), 6.92-6.83 (m, 2H), 6.75 (d, J = 1.6 Hz, 1H) , 6.49 (s, 1H), 6.21 (s, 1H), 3.94 (s, 3H), 3.83 (s, 2H), 2.75 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 148.6, 136.4, 136.2, 136.0, 130.5, 130.4, 127.9, 126.9, 126.5, 124.7, 124.0, 122.4, 121.8, 121.5, 119.8 (two peaks overlapping), 119.63, 119.57, 118.2, 117.7, 115.9, 111.3, 36.7, 33.6, 19.7;

IR (film) 3398, 3281, 1558, 1541, 1507, 1475, 1456, 1265, 1208, 1180, 1149, 1087, 1058, 939 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₅ H ₂₃ N ₃ O ₃ S: 445.1460 Found: 445.1489;

Chiralpak AD-H column and AD-H guard column (10% EtOH:hexanes, 1.0 mL/min flow, λ=254 nm); minor -isomer t _r = 49.5 min and major -isomer t _r = 63.3 min.

1.13. (2-((5-bromo-1 H -indole-3yl)(1-methyl-1 H -indol-3-yl)methyl)phenyl sulfamate (2-((5-Bromo-1-methyl-1) H -indol-3-yl) (1 H -indol-3-yl)methyl)phenyl sulfamate; Synthesis of 1m))

The target compound 1m (78% yield, 89:11 er ) was obtained in the same manner as in Example 1, except that 3 g of 5-bromo-1-methylindole was used instead of N- methylindole 3a as a starting material.

m.p. 197-199 ° C;

[α] ²³ _D = -2.6 ( c = 0.44, EtOAc);

¹ H NMR (400 MHz, acetone-d ₆ ) δ 9.91 (s, 1H), 7.49 (d, J = 1.6 Hz, 1H), 7.36 (dd, J = 8.1, 1.2 Hz, 1H), 7.28 (dd, J = 20.7, 8.0 Hz, 2H), 7.21-7.03 (m, 5H), 6.97-6.91 (m, 1H), 6.80-6.71 (m, 1H), 6.61 (d, J = 1.6 Hz, 1H), 6.56 (s, 1H), 6.26 (s, 1H), 3.62 (s, 3H), 2.71 (s, 2H);

¹³ C NMR (100 MHz, acetone-d ₆ ) δ 148.8, 137.5, 137.2, 136.3, 130.0 (two peaks overlapping), 129.1, 127.3, 126.9, 126.2, 124.1, 123.8, 122.3, 121.9, 121.3, 119.7, 118.6, 117.4, 116.7, 111.6, 111.3, 111.2, 33.3, 32.1;

IR (film) 3424, 3367, 3261, 2921, 1731, 1545, 1475, 1454, 1419, 1369, 1293, 1179, 1122, 1085, 1043, 1010, 930 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₄ H ₂₀ BrN ₃ O ₃ S: 509.0409 Found: 509.0392;

Chiralpak AD-H column and AD-H guard column (10% i -PrOH:hexanes, 1.0 mL/min flow, λ= 254 nm); minor -isomer t _r = 22.6 min and major -isomer t _r = 31.9 min.

1.14. (2-((6-fluoro-1 H -indole-3yl)(1-methyl-1 H -Indol-3-yl)methyl)phenyl sulfamate (2-((6-Fluoro-1-methyl-1) H -indol-3-yl) (1 H -indol-3-yl)methyl)phenyl sulfamate; Synthesis of 1n))

The target compound 1n (74% yield, 72:28 er ) was obtained in the same manner as in Example 1, except that 6-fluoro-1-methylindole 3h was used instead of N- methylindole 3a as a starting material.

m.p. 197-198 °C;

[α] ²¹ _D = +0.8 ( c = 0.50, EtOAc);

¹ H NMR (400 MHz, acetone-d ₆ ) δ 7.52-7.36 (m, 4H), 7.33-7.22 (m, 4H), 7.18-7.04 (m, 3H), 6.89 (ddd, J = 8.0, 7.1, 1.0 Hz, 1H), 6.77 (dd, J = 2.4, 0.8 Hz, 1H), 6.71 (ddd, J = 9.8, 8.7, 2.3 Hz, 1H), 6.66 (d, J = 0.9 Hz, 1H), 6.42 ( s, 1H), 3.71 (s, 3H);

¹³ C NMR (100 MHz, acetone-d ₆ ) δ 159.7 (d, J ¹ = 235.1 Hz), 148.8, 137.6 (d, J ⁴ = 12.2 Hz), 137.5 (d, J ² = 58.0 Hz), 130.1, 129.1, 129.0, 127.2, 127.0, 126.2, 124.2, 124.1, 121.8, 121.3, 121.0 (d, J ⁴ = 10.1 Hz), 119.8, 118.56, 117.6, 117.4, 111.3, 106.7 (d, J ³ = 24.5 Hz), 95.5 (d, J ³ = 26.2 Hz), 33.4, 32.0;

IR (film) 3412, 3279, 2924, 1618, 1557, 1477, 1458, 1368, 1335, 1240, 1180, 1150, 1099, 1087, 1049, 944 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₄ H ₂₀ FN ₃ O ₃ S: 449.1209 Found: 449.1216;

Chiralpak IC column and IC guard column (25% i -PrOH:hexanes, 1.0 mL/min flow, λ= 254 nm); minor -isomer t _r = 8.0 min and major -isomer t _r = 16.2 min.

1.15. (2-((6-chloro-1 H -indole-3yl)(1-methyl-1 H -Indol-3-yl)methyl)phenyl sulfamate (2-((6-Chloro-1-methyl-1) H -indol-3-yl) (1 H -indol-3-yl)methyl)phenyl sulfamate; 1o)) synthesis

The target compound 1o (73% yield, 74:26 er ) was obtained in the same manner as in Example 1, except that 6-chloro-1-methylindole 3i was used instead of N- methylindole 3a as a starting material.

m.p. 207-209°C;

[α] ²⁵ _D = +2.3 ( c = 0.44, EtOAc);

¹ H NMR (400 MHz, acetone-d ₆ ) δ 9.91 (s, 1H), 7.39-7.33 (m, 1H), 7.33-7.23 (m, 4H), 7.22-7.08 (m, 3H), 7.02 (t) , J = 7.0 Hz, 1H), 6.94 (t, J = 7.2 Hz, 1H), 6.80-6.71 (m, 2H), 6.63 (d, J = 1.8 Hz, 1H), 6.57 (s, 1H), 6.28 (s, 1H), 3.61 (s, 3H), 2.73 (s, 1H).;

¹³ C NMR (100 MHz, acetone-d ₆ ) δ 148.7, 138.0, 137.7, 137.2, 130.0, 129.5, 127.3, 127.0, 126.8, 126.20, 126.17, 124.1, 121.8, 121.3, 121.2, 119.7, 118.7, 118.6, 117.5 , 117.4, 111.3, 109.3, 33.4, 32.0; IR (film) 3419, 3276, 2926, 1540, 1479, 1456, 1372, 1329, 1203, 1180, 1149, 1125, 1086, 1047, 1009, 941 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₄ H ₂₀ ClN ₃ O ₃ S: 465.0914 Found: 465.0898;

Chiralpak IC column and IC guard column (25% i -PrOH:hexanes, 1.0 mL/min flow, λ= 254 nm); minor -isomer t _r = 7.7 min and major -isomer t _r = 12.8 min.

1.16. (2-((5-cyano-1 H -indole-3yl)(1-methyl-1 H -Indol-3-yl)methyl)phenyl sulfamate (2-((5-Cyano-1-methyl-1) H -indol-3-yl) (1 H -indol-3-yl)methyl)phenyl sulfamate; Synthesis of 1p))

The target compound 1p (65% yield, 64:36 er ) was obtained in the same manner as in Example 1, except that 5-cyano-1-methylindole 3j was used instead of N- methylindole 3a as a starting material.

m.p. 203-204 °C;

[α] ²⁹ _D = -3.5 ( c = 0.42, EtOAc);

¹ H NMR (400 MHz, acetone-d ₆ ) δ 10.1 (s, 1H), 7.90 (d, J = 0.9 Hz, 1H), 7.58-7.48 (m, 2H), 7.48-7.35 (m, 4H), 7.34-7.22 (m, 2H), 7.18 (dd, J = 10.8, 4.2 Hz, 1H), 7.12-7.04 (m, 1H), 6.91 (dd, J = 11.7, 4.6 Hz, 2H), 6.78 (s, 1H), 6.48 (s, 1H), 3.81 (s, 3H);

¹³ C NMR (100 MHz, acetone-d ₆ ) δ 148.7, 139.0, 137.4, 137.1, 131.1, 129.9, 127.5, 127.2, 126.8, 126.4, 125.3, 124.0, 123.9, 122.0, 121.4, 120.4, 119.6, 118.7, 118.3 , 117.1, 111.3, 110.7, 101.4, 33.3, 32.2; IR (film) 3336, 3242, 2919, 2221, 1558, 1487, 1455, 1382, 1365, 1205, 1182, 1084, 937 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₅ H ₂₀ N ₄ O ₃ S: 456.1256 Found: 456.1239;

Chiralpak IC column and IC guard column (10% EtOH:hexanes, 1.0 mL/min flow, λ=254 nm); minor -isomer t _r = 40.3 min and major -isomer t _r = 55.8 min.

1.17. (2-((1 H -indole-3yl)(1-methyl-5-nitro-1 H -indol-3-yl)methyl)phenyl sulfamate (2-((1) H -Indol-3-yl) (1-methyl-5-nitro-1 H -indol-3-yl)methyl)phenyl sulfamate; Synthesis of 1q))

The target compound 1q (75% yield, 67:33 er ) was obtained in the same manner as in Example 1, except that 1-methyl-5-nitroindole 3k was used instead of N- methylindole 3a as a starting material.

m.p. 198-201 ° C;

[α] ²⁹ _D = -13.4 ( c = 0.41, EtOAc);

¹ H NMR (400 MHz, acetone-d ₆ ) δ 10.07 (s, 1H), 8.47 (d, J = 2.2 Hz, 1H), 8.05 (dd, J = 9.1, 2.2 Hz, 1H), 7.58-7.49 ( m, 2H), 7.42 (dd, J = 19.4, 8.1 Hz, 2H), 7.36 (s, 1H), 7.33-7.24 (m, 2H), 7.22-7.15 (m, 1H), 7.12-7.05 (m, 1H), 6.89 (dd, J = 11.5, 4.5 Hz, 2H), 6.80 (d, J = 1.6 Hz, 1H), 6.53 (s, 1H), 3.86 (s, 3H), 2.86 (s, 1H);

¹³ C NMR (100 MHz, acetone-d ₆ ) δ 148.7, 141.0, 140.3, 137.3, 137.2, 132.0, 129.9, 127.6, 126.9, 126.6, 126.4, 124.3, 122.0, 121.5, 120.1, 119.7, 118.7, 117.1, 117.0 , 116.6, 111.4, 109.8, 33.3, 32.5; IR (film) 3369, 3274, 3106, 2922, 1615, 1556, 1502, 1481, 1452, 1384, 1325, 1310, 1291, 1180, 1160, 1084, 1035, 938 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₄ H ₂₀ N ₄ O ₅ S: 476.1154 Found: 476.1129;

Chiralpak AD-H column and AD-H guard column (20% i -PrOH:hexanes, 1.0 mL/min flow, λ= 254 nm); minor -isomer t _r = 44.5 min and major -isomer t _r = 79.9 min.

1.18. (2-((1 H -indole-3 yl) (1,2-dimethyl-1 H -indol-3-yl)methyl)phenyl sulfamate (2-((1) H -Indol-3-yl) (1,2-dimethyl-1 H -indol-3-yl)methyl)phenyl sulfamate; Synthesis of 1r))

The target compound 1r (79% yield, 58:42 er ) was obtained in the same manner as in Example 1, except that 1,2-dimethylindole 3l was used instead of N- methylindole 3a as a starting material.

m.p. 165-167 °C;

[α] ²⁵ _D = -5.8 ( c = 0.42, EtOAc);

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.95 (s, 1H), 7.51 (dd, J = 8.1, 1.1 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.34 (dd, J = 7.7, 1.6 Hz, 1H), 7.29-7.23 (m, 4H), 7.21-7.07 (m, 3H), 7.05-6.97 (m, 1H), 6.87 (t, J = 7.1 Hz, 1H), 6.72 (d , J = 1.3 Hz, 1H), 6.16 (s, 1H), 3.70 (s, 3H), 3.36 (s, 2H), 2.39 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 149.1, 136.7, 136.1, 135.8, 134.8, 131.1, 127.9, 126.81, 126.77, 126.5, 124.6, 122.3, 120.8, 120.7, 119.8, 119.6, 119.3, 119.1, 117.2, 111.5 , 111.2, 109.2, 34.1, 29.8, 10.6;

IR (film) 3406, 3280, 2821, 2851, 1678, 1552, 1469, 1455, 1366, 1335, 1251, 1182, 1153, 1086, 1017 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₅ H ₂₃ N ₃ O ₃ S: 445.1460 Found: 445.1487;

Chiralpak IC column and IC guard column (10% i -PrOH:hexanes, 1.0 mL/min flow, λ= 254 nm); major -isomer t _r = 58.0 min and minor -isomer t _r = 44.0 min.

1.19. (2-(D(1) H -indol-3yl)methyl)phenyl sulfamate (2-(Di(1) H -indol-3-yl)methyl)phenyl sulfamate; Synthesis of 1s))

After toluene (0.5 mL) was added to 1,2λ6,3-Benzoxathiazine-2,2-dione ( 2g ; 0.10 mmol) and 4 Å molecular sives (20 mg), Yb(OTf) ₃ (0.010 mmol) was added. After that, it is stirred at room temperature for 10 minutes. Then, N -methylindole (N-methylindole; 3a , 0.22 mmol) was added and stirred for 48 hours. After the reaction was terminated by adding water, the reaction product was extracted with dichloromethane, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and then purified by silica gel column chromatography in ethyl acetate/hexane to obtain the target compound was obtained as a red solid ( 1s ; 93% yield).

m.p. 187-189 ° C;

¹ H NMR (400 MHz, acetone-d ₆ ) δ 10.00 (s, 2H), 7.56-7.46 (m, 3H), 7.41 (d, J = 8.2 Hz, 2H), 7.34-7.24 (m, 4H), 7.20-7.13 (m, 1H), 7.13-7.05 (m, 2H), 6.95-6.87 (m, 2H), 6.80 (d, J = 1.6 Hz, 2H), 6.47 (s, 1H);

¹³ C NMR (100 MHz, acetone-d ₆ ) δ 148.9, 137.9, 137.2, 130.2, 127.1 (two peaks overlapping), 126.1, 124.1, 121.7, 121.2, 119.9, 118.47, 117.8, 111.2, 33.6;

IR (film) 3402, 3273, 2919, 2851, 1710, 1548, 1458, 1372, 1337, 1259, 1202, 1181, 1152, 1084, 1041, 1010, 920 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₃ H ₁₉ N ₃ O ₃ S: 417.1147 Found: 417.1128.

1.20. (2-(bis(1-methyl-1) H -indol-3yl)methyl)phenyl sulfamate (2-(Bis(1-methyl-1) H -indol-3-yl)methyl)phenyl sulfamate; Synthesis of 1t))

4-(1-Methyl-1H-indol-3-yl)-3,4-dihydro-1,2λ6,3-benzoxathiazine-2,2-dione ( 2h ; 0.10 mmol) and 4 Å molecular sives (20 mg) Toluene (0.5 mL) was added thereto, and Yb(OTf) ₃ (0.010 mmol) was added as a catalyst, followed by stirring at room temperature for 10 minutes. Then, N -methylindole (N-methylindole; 3a , 0.12 mmol) was added and stirred for 72 hours. After the reaction was terminated by adding water, the reaction product was extracted with dichloromethane, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and then purified by silica gel column chromatography in ethyl acetate/hexane to obtain the target compound was obtained as a red solid ( 1a ; 82% yield).

mp 186-189 ° C; ^One

H NMR (400 MHz, acetone-d ₆ ) δ 7.52-7.44 (m, 3H), 7.34 (d, J = 8.3 Hz, 2H), 7.29-7.22 (m, 4H), 7.17-7.10 (m, 3H) , 6.94-86 (m, 2H), 6.65 (s, 2H), 6.42 (s, 1H), 3.72 (s, 6H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 148.8, 137.9, 137.6, 130.1, 128.4, 127.4, 127.1, 126.1, 121.7, 121.2, 120.0, 118.4, 116.9, 109.2, 33.3, 31.8;

IR (film) 3369, 3279, 2922, 2852, 1547, 1470, 1452, 1371, 1329, 1259, 1183, 1154, 1118, 1084, 1011, 922 cm ^-1 ; HRMS (EI) m/z calcd for [M] ⁺ C ₂₅ H ₂₃ N ₃ O ₃ S: 445.1460 Found: 445.1483.

Example 2: Catalyst and solvent effects on the synthesis of optically active bisindorylmethane sulfamate derivative compounds

In the asymmetric reaction using the chiral binol-phosphoric acid compound as an organic catalyst to prepare an optically active compound, the reaction of Example 1.1 was carried out while changing the catalyst and solvent type to confirm the reaction catalyst and solvent effect, , yield and er values were measured and shown in Table 1. When the yield was somewhat low, it was confirmed by appropriately increasing or decreasing the reaction time. The chemical structural formulas of the chiral binol-phosphate compounds used in this Example are summarized in FIG. 2 .

entry catalyst menstruum Reaction time (hours) transference number(%) er (%) One PA1 toluene 120 59 52:48 2 PA2 toluene 120 57 54:42 3 PA3 toluene 120 30 52:48 4 PA4 toluene 30 76 63:35 5 PA5 toluene 30 74 59:41 6 PA6 toluene 45 64 53:47 7 PA7 toluene 8 85 57:43 8 PA8 toluene 48 74 57:43 9 PA9 toluene 8 45 52:48 10 PA10 toluene 24 81 76:24 11 PA11 toluene 120 67 67:33 12 PA12 toluene 36 77 80:20 13 PA12 o -xylene 36 81 78:22 14 PA12 m -xylene 36 74 79:21 15 PA12 p -xylene 36 78 73:27 16 PA12 CH ₂ Cl ₂ 24 73 76:24 17 PA12 ClCH ₂ CH ₂ Cl 24 70 78:22

Example 3: Analysis of diabetic neuropathy inhibitory activity using sciatic nerve ex vivo culture

Sciatic nerve explant culture

The sciatic nerve is one of the largest peripheral nerves in the nervous system. In peripheral neurodegenerative diseases such as diabetic neuropathy, the most common complication of diabetes, the peripheral nerves degenerate and appear with multiple morphological phenotypes such as annihilation of transverse stripes and ovarian segmentation. A sciatic nerve explant culture system was used to establish an in vitro peripheral neurodegenerative environment. Five-week-old adult male wild-type C57BL/6 mice were purchased from Samtako. After asphyxiating the male mouse with carbon dioxide, the sciatic nerve was removed and cut into three parts with a length of about 3 to 4 mm. Explants were cultured in free-floating condition in Dulbecco's Modified Eagle's Medium (DMEM) at 37 °C under an atmosphere containing 5% CO _{2 .} The medium was supplemented with 10% fetal bovine serum and 100 units/ml of penicillin and streptomycin. The explant cultures were maintained for 3 days. Controls were freshly extracted sciatic nerves, not nerve segments cultured in DMEM medium. The obtained ischial explants were washed with phosphate buffered saline (PBS) and fixed in 4% paraformaldehyde (PFA) for 8 hours.

Teased nerve technique

A portion of the fixed nerve segment was mounted on a gelatin-coated slide, and using fine forceps, it was torn a short distance from the slide to straighten it. Single nerve fibers were placed side by side in close proximity (about 0.2 mm apart). Pulled fibers mounted on slides were stored at -80 °C until use.

Preparation of compound solutions

A dimethyl sulfoxide (DMSO) solution of the compound (1 mM) was prepared and passed through a 0.22 μm sterile polyvinylidene fluoride (PVDF) filter. Mouse sciatic nerve explants (3DIV) were cultured in vitro for 3 days. DMSO solvent itself (maximum concentration: 30 µL/mL culture medium) did not affect the degeneration of the extracted sciatic nerve. Cultures treated with solvent alone were represented by 3DIV.

Quantitative drug effect calculating myelin ovoid number; The number of oocyte structures in the sciatic nerve fibers (oocyte index) is expressed as the number of ovoid structures counted from sciatic nerve fibers teasing 200 μm in length under a Zeiss Axioimager vertical microscope using differential interference contrast medium (DIC). In quantitative data, all data are presented as ± SEM.

result

)(1 mM 용액)을 스크리닝 하였다. 그 결과를 도 3 내지 5에 나타내었다. 도 3에서는 화합물 19가 가장 가로줄무늬의 소멸을 상당히 억제하는 것을 보인다.Based on the notion that the sciatic nerve transverse streaks disappear during peripheral nerve degeneration, bisindorylmethane Sulfamate compounds (1, 19 and 20) (1 mM solution) and bisindorylmethane phenol (

) (1 mM solution) were screened. The results are shown in FIGS. 3 to 5 . 3 shows that compound 19 most significantly inhibits the disappearance of horizontal stripes.

They significantly inhibited the disappearance of transverse streaks within 3 days of in vitro (3DIV) during ex vivo peripheral neurodegeneration ( FIG. 3 ). DMSO is a negative control and N -ethyl-maleimide (NEM) is a positive control. 3 shows statistical significance similar to that of the positive control. Ovoid fragmentation is one of the morphological phenotypes in peripheral neurodegenerative processes. To specify the primary inhibitory effect of these bisindorylmethane sulfamate compounds on neurodegeneration, we conducted a secondary drug screening to count the ovoid structures in the sciatic nerve fibers using a morphological approach under differential interference contrast (DIC). performed. DIC microscopy analysis specifically showed that compound 19 effectively inhibited the appearance of oocyte-like fragments in 3DIV similar to the control (Fig. 4). To quantify the inhibitory effect of the bisindorylmethane sulfamate compound, a morphological analysis of oocyte formation was performed, which showed that it statistically reduced the number of oocytes in 3DIV in the teased nerve fibers (Fig. 5). Therefore, the results of the present invention mean that the bisindorylmethane sulfamate compound according to the present invention has bioactivity to prevent peripheral neurodegeneration.

Claims (26)

A compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof;
[Formula 1]

In the above formula,
R ₁ and R ₂ are hydrogen, C1 to C6 alkyl;
R ₃ , R ₄ and R ₅ are each independently hydrogen, halogen or straight or branched C1 to C6 alkyl, aryl or C1 to C6 alkoxy.
According to claim 1,
R ₁ and R ₂ are the same as each other, or a pharmaceutically acceptable salt thereof.
According to claim 1,
R ₃ and R ₄ are the same as each other, or a pharmaceutically acceptable salt thereof.
According to claim 1,
R ₁ is C1 to C6 alkyl, or a pharmaceutically acceptable salt thereof.
According to claim 1,
R ₂ is C1 to C6 alkyl, or a pharmaceutically acceptable salt thereof.
delete According to claim 1,
R ₃ , R ₄ and R ₅ are each independently hydrogen, halogen, or straight or branched C1 to C6 alkyl, aryl or C1 to C6 alkoxy, or a pharmaceutically acceptable salt thereof.
According to claim 1,
The compound is
1) 2-((1 H -indol-3yl)(1-methyl- 1H -indol-3-yl)methyl)phenyl sulfamate,
2) 2-((1 H -indol-3yl)(1-methyl- 1H -indol-3-yl)methyl)-4-methylphenyl sulfamate,
3) 2-((1 H -indol-3-yl)(1-methyl-1 H -indol-3-yl)methyl)-5-methylphenyl sulfamate,
4) 2-((1 H -indol-3-yl)(1-methyl- 1H -indol-3-yl)methyl)-5-methoxyphenyl sulfamate,
5) 2-((1 H -indol-3-yl)(1-methyl-1 H -indol-3-yl)-4-fluoromethyl)phenyl sulfamate,
6) 2-((1 H -indol-3-yl)(1-methyl- 1H -indol-3-yl)methyl)4-chlorophenyl sulfamate,
7) 2-((1 H -indol-3-yl)(1-methyl-1 H -indol-3-yl)methyl)4-bromophenyl sulfamate;
8) 2-((1-allyl- 1H -indol-3yl)(1-methyl- 1H -indol-3-yl)methyl)phenyl sulfamate,
9) 2-((1-benzyl-1 H -indol-3yl)(1-methyl-1 H -indol-3-yl)methyl)phenyl sulfamate,
10) (2-((1 H -indol-3yl)(5-methoxy-1-methyl- 1H -indol-3-yl)methyl)phenyl sulfamate;
11) 2-((5-(benzyloxy)-1-methyl-1 H -indol-3yl)(1-methyl-1 H -indol-3-yl)methyl)phenyl sulfamate,
12) 2-((1 H -indol-3yl)(1,7-dimethyl-1-methyl- 1H -indol-3-yl)methyl)phenyl sulfamate,
13) 2-((5-bromo- 1H -indol-3-yl)(1-methyl- 1H -indol-3-yl)methyl)phenyl sulfamate,
14) 2-((6-fluoro-1 H -indol-3-yl)(1-methyl-1 H -indol-3-yl)methyl)phenyl sulfamate;
15) 2-((6-chloro- 1H -indol-3yl)(1-methyl- 1H -indol-3-yl)methyl)phenyl sulfamate,
16) 2-((5-cyano-1 H -indol-3yl)(1-methyl-1 H -indol-3-yl)methyl)phenyl sulfamate;
17) 2-((1 H -indol-3yl)(1-methyl-5-nitro-1 H -indol-3-yl)methyl)phenyl sulfamate,
18) 2-((1 H -indol-3-yl)(1,2-dimethyl- 1H -indol-3-yl)methyl)phenyl sulfamate,
19) 2-(di(1 H -indol-3yl)methyl)phenyl sulfamate, and
20) Any one compound selected from the group consisting of 2-(bis(1-methyl- 1H -indol-3yl)methyl)phenyl sulfamate, or a pharmaceutically acceptable salt thereof.
A method for preparing a compound represented by Formula 1, comprising reacting a compound represented by Formula 2 with a compound represented by Formula 3 below;
[Formula 1]

[Formula 2]

[Formula 3]

In the above formula,
R ₁ and R ₂ are hydrogen, C1 to C6 alkyl;
R ₃ , R ₄ and R ₅ are each independently hydrogen, halogen or straight or branched C1 to C6 alkyl, aryl or C1 to C6 alkoxy. 10. The method of claim 9,
The reaction is a Lewis acid Ni(ClO ₄ ) ₂ , Mg(OTf) ₂ , Cu(OTf) ₂ , Zn(OTf) ₂ , Sc(OTf) ₃ , and Yb(OTf) ₃ Any one selected from the group consisting of A method for producing a compound represented by Formula 1, characterized in that using a catalyst. 10. The method of claim 9,
The reaction is a method for preparing a compound represented by Formula 1, characterized in that it is an asymmetric reaction using a binol-phosphate compound of Formula 4 as a catalyst;
[Formula 4]

In Formula 4, R is hydrogen; iodine; SIPH ₃ ; phenyl; 1-naphthyl; 2-naphthyl; 4-MeO-C ₆ H ₄ ; 4-Ph-C ₆ H ₄ ; 4-NO _2- C ₆ H ₄ ; 3,5-Me ₂ -C ₆ H ₃ ; 3,5-(CF ₃ ) ₂ -C ₆ H ₃ ; or 2,4,6-Me ₃ -C ₆ H ₂ . 10. The method of claim 9,
A method for producing a compound represented by Formula 1, characterized in that the molar ratio of the compound represented by Formula 2 to the compound represented by Formula 3 is 1:1.
10. The method of claim 9,
A method for producing a compound represented by Formula 1, characterized in that the amount of the compound represented by Formula 2 and the catalyst is 1 to 20 mol%.
10. The method of claim 9,
The method for producing a compound represented by Formula 1, characterized in that the reaction is carried out at 0 to 40 ℃ for 4 to 120 hours.
11. The method according to any one of claims 9 or 10,
The reaction of the compound represented by Formula 1, characterized in that it is carried out in a solvent selected from the group consisting of methylene chloride, dichloroethane, benzene, ethyl acetate, acetonitrile, toluene, xylene, tetrahydrofuran, and mixtures thereof manufacturing method.
11. The method according to any one of claims 9 or 10,
The method for producing a compound represented by Formula 1, wherein the reaction is carried out by additionally including molecular sieves.
A composition for preventing or treating neuropathy comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof;
[Formula 1]

In the above formula,
R ₁ and R ₂ are hydrogen, C1 to C6 alkyl;
R ₃ , R ₄ and R ₅ are each independently hydrogen, halogen or straight or branched C1 to C6 alkyl, aryl or C1 to C6 alkoxy. 18. The method of claim 17,
R ₁ and R ₂ are a compound or a pharmaceutically acceptable salt thereof, characterized in that they are identical to each other, a composition for preventing or treating neuropathy.
18. The method of claim 17,
R ₃ and R ₄ are a compound or a pharmaceutically acceptable salt thereof, characterized in that the same as each other, the composition for preventing or treating neuropathy.
18. The method of claim 17,
R ₁ is a C1 to C6 alkyl compound or a pharmaceutically acceptable salt thereof. A composition for preventing or treating neuropathy.
18. The method of claim 17,
R ₂ is a C1 to C6 alkyl compound or a pharmaceutically acceptable salt thereof. A composition for preventing or treating neuropathy.
delete 18. The method of claim 17,
R ₃ , R ₄ and R ₅ are each independently hydrogen, halogen or a straight or branched C1 to C6 alkyl, aryl or C1 to C6 alkoxy compound or a pharmaceutically acceptable salt thereof. for composition.
18. The method of claim 17,
The compound is
1) 2-((1 H -indol-3yl)(1-methyl- 1H -indol-3-yl)methyl)phenyl sulfamate,
2) 2-((1 H -indol-3yl)(1-methyl- 1H -indol-3-yl)methyl)-4-methylphenyl sulfamate,
3) 2-((1 H -indol-3-yl)(1-methyl-1 H -indol-3-yl)methyl)-5-methylphenyl sulfamate,
4) 2-((1 H -indol-3-yl)(1-methyl- 1H -indol-3-yl)methyl)-5-methoxyphenyl sulfamate,
5) 2-((1 H -indol-3-yl)(1-methyl-1 H -indol-3-yl)-4-fluoromethyl)phenyl sulfamate,
6) 2-((1 H -indol-3-yl)(1-methyl- 1H -indol-3-yl)methyl)4-chlorophenyl sulfamate,
7) 2-((1 H -indol-3-yl)(1-methyl-1 H -indol-3-yl)methyl)4-bromophenyl sulfamate;
8) 2-((1-allyl- 1H -indol-3yl)(1-methyl- 1H -indol-3-yl)methyl)phenyl sulfamate,
9) 2-((1-benzyl-1 H -indol-3yl)(1-methyl-1 H -indol-3-yl)methyl)phenyl sulfamate,
10) (2-((1 H -indol-3yl)(5-methoxy-1-methyl- 1H -indol-3-yl)methyl)phenyl sulfamate;
11) 2-((5-(benzyloxy)-1-methyl-1 H -indol-3yl)(1-methyl-1 H -indol-3-yl)methyl)phenyl sulfamate,
12) 2-((1 H -indol-3yl)(1,7-dimethyl-1-methyl- 1H -indol-3-yl)methyl)phenyl sulfamate,
13) 2-((5-bromo- 1H -indol-3-yl)(1-methyl- 1H -indol-3-yl)methyl)phenyl sulfamate,
14) 2-((6-fluoro-1 H -indol-3-yl)(1-methyl-1 H -indol-3-yl)methyl)phenyl sulfamate;
15) 2-((6-chloro- 1H -indol-3yl)(1-methyl- 1H -indol-3-yl)methyl)phenyl sulfamate,
16) 2-((5-cyano-1 H -indol-3yl)(1-methyl-1 H -indol-3-yl)methyl)phenyl sulfamate;
17) 2-((1 H -indol-3yl)(1-methyl-5-nitro-1 H -indol-3-yl)methyl)phenyl sulfamate,
18) 2-((1 H -indol-3-yl)(1,2-dimethyl- 1H -indol-3-yl)methyl)phenyl sulfamate,
19) 2-(di(1 H -indol-3yl)methyl)phenyl sulfamate, and
20) 2-(bis(1-methyl- 1H -indol-3yl)methyl)phenyl sulfamate for preventing neuropathy, characterized in that it is any one compound selected from the group consisting of or a pharmaceutically acceptable salt thereof therapeutic composition. 25. The method according to any one of claims 17 to 21, 23 and 24, wherein the neuropathy is diabetic neuropathy, postherpetic neuropathy, trigeminal neuropathy, multiple. Peripheral Neuropathies, mononeuropathy, mononeuritis multiplex, autonomic neuropathy, inflammatory neuropathy, metabolic or endocrine neuropathy, poisoning or Toxic or drug-induced neuropathy, nutritional neuropathy, vasculitic neuropathy, paraneoplastic neuropathy, traumatic neuropathy, genetic neuropathy ( A composition for preventing or treating neuropathy, characterized in that hereditary neuropathy or idiopathic neuropathy.
25. The method according to any one of claims 17 to 21, 23 and 24
A composition for preventing or treating neuropathy, characterized in that the composition acts on Schwann cells to inhibit the neuroaxon degeneration of Schwann cells and dedifferentiation of Schwann cells.

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