JPH11147876A - Tetrahydroisoquinoline derivative and medicine containing the same as active ingredient - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having a strong tumor necrosis factor-α (TNF-α) converting enzyme-inhibiting activity, capable of maintaining a high concentration in blood over a long time, after administered into a living body, ad useful as a TNF-α production inhibitor. SOLUTION: The compound of formula I, for example, N-hydroxy-7- amino-2-(4-methyxybenzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline-3(R)- carboxamide, is obtained by reducing the nitro group of a compound of formula II (Bzl is benzyl; OMe is methoxy) in the presence of a catalyst such as palladium-carbon catalyst in a lower alcohol such as methanol or ethanol and, if necessary, in the presence of water, hydrochloric acid, acetic acid, N,N- dimethylformamide or the like under the flow of hydrogen or under pressurized hydrogen at a temp. from room temperature to 60 deg.C and simultaneously subjecting the product to a hydrogenolysis reaction.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to the following formula (I)

[0002]

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Or a pharmaceutically acceptable salt thereof and a drug containing the compound as an active ingredient.

[0004]

2. Description of the Related Art Tumor necrosis factor-α (hereinafter, TNF-α)
Is a type of cytokine produced by activated macrophages and acts as a mediator of inflammatory activity in inflammatory areas. TNF-α is an important cytokine by nature,
If it is produced in excess, for example, rheumatoid arthritis, osteoarthritis, sepsis, congenital immunodeficiency syndrome (A
IDS), graft-versus-host reaction (GVHD), non-insulin-dependent diabetes, asthma, atopic dermatitis, ulcerative colitis and the like, and are known to cause TNF-
An agent that suppresses α production (TNF-α production inhibitor) may be a prophylactic or therapeutic agent for these diseases.

[0005] TNF-α is secreted on the membrane surface as a membrane-bound precursor consisting of 233 amino acids and having a molecular weight of 26 kDa, is cleaved between amino acids Ala-76 and Val-77, and released outside the cell. The enzyme involved in this cleavage is called TNF-α converting enzyme (hereinafter abbreviated as TACE). Since TACE is an enzyme that produces TNF-α, a compound having TACE inhibitory activity is expected to be used as a TNF-α production inhibitor.

Some MMPs with Hydroxamic Acid
Since an inhibitor inhibits this TACE, it has been reported that TACE is an enzyme similar to extracellular matrix degrading enzyme (hereinafter abbreviated as MMP). (Nature 37
0 (21), 218-220 (1994); Nature 370 (18), 555-557 (199
4); Nature 370 (18), 558-561 (1994)) However, a compound showing a strong MMP inhibitory action has no TACE inhibitory action [J. Med. Chem. 40, 1026-1040 (1997)]. It has been reported that compounds showing MMP inhibitory activity are not necessarily TACE
Does not necessarily impede. European Patent Publication EP606
No. 046 discloses a compound of formula (1) as an MMP inhibitor

[0007]

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Wherein Ar represents a carbocyclic aryl or a heterocyclic aryl, R ₂ represents a hydrogen atom or a lower alkyl group, and R and R ₁ together with the chain to which they are added Form a 1,2,3,4-tetrahydroisoquinoline, piperidine, oxazolidine, thiazolidine or pyrroline ring (each unsubstituted or substituted by a lower alkyl group). The compound represented by the following formula (2) having a tetrahydroisoquinoline skeleton

[0009]

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A compound represented by the formula (I) is disclosed. However, there is no description about the TACE inhibitory action. In PCT International Publication WO97 / 18194, the following formula (3)

[0011]

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Wherein A represents a carboxyl group or a hydroxyaminocarbonyl group, R ′ represents a benzene ring or another substituent, and m and n are integers of 0 to 2 depending on the selection of R ′ and Q. And Q is the following equation (4)
(7)

[0013]

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Wherein D represents an atomic group NR ₄ or a sulfur atom, and R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and R ₈ represent a hydrogen atom, a methoxy group, a methylenedioxo group, an amino group Or a hydroxyl group). The compounds disclosed herein are useful as MMP inhibitors and TNF-α production inhibitors.

However, the compounds of the present invention are not specifically described in any of the publications.

[0016]

As an active ingredient of the TNF-α production inhibitor, a compound having a strong TACE inhibitory activity and maintaining a high blood concentration for a long time after administration to a living body is desired. It is. An object of the present invention is to provide a novel compound which satisfies such a demand and a drug containing the same as an active ingredient, particularly a TNF-α production inhibitor.

[0017]

As a result of various studies, the present inventors have found that the following formula (I)

[0018]

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It has been found that the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof meets the above-mentioned object, and the present invention has been completed.

The pharmaceutically acceptable salts of the compound (I) of the present invention include, for example, metal salts such as sodium salt, potassium salt and calcium salt, salts with inorganic acids such as hydrochloric acid and nitric acid, and fumaric acid and maleic acid. And salts with organic acids such as acid and methanesulfonic acid.

The compound (I) of the present invention and a pharmaceutically acceptable salt thereof can be produced as follows.

[0022]

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(Wherein Bzl represents a benzyl group and OMe represents a methoxy group.) That is, the compound (I) of the present invention is prepared by converting the compound (II) into a lower alcohol such as methanol or ethanol, if necessary, Hydrochloric acid, acetic acid, N, N-dimethylformamide (hereinafter abbreviated as DMF) and the like are added, and in the presence of a catalyst such as palladium carbon (hereinafter abbreviated as Pd-C).
It can be produced by performing hydrogenolysis simultaneously with reduction of the nitro group at room temperature to 60 ° C. under a stream of hydrogen or under pressure. The compound (I) of the present invention obtained by the above method can be converted into a pharmaceutically acceptable salt thereof by a conventional method.
Next, a method for producing a starting compound will be described. Starting compound (II) can be produced by the following method.

[0024]

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(In the formula, TsOH represents p-toluenesulfonic acid, and Bzl and OMe are the same as described above.) The optically active form (III) is described in the literature [Chem. Pharm. Bull.
(1), 312-314 (1983)]. After the optically active form (III) is neutralized with a base such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, etc.,
(III) Hydrogenolysis is carried out by the above-mentioned method in the presence of 1.0 to 5.0 mol of hydrochloric acid with respect to 1 mol to obtain compound (IV).

Next, the compound (IV) is subjected to methyl esterification. Add methanol to compound (IV), and add
After the thionyl chloride is added dropwise at room temperature to room temperature, the mixture is reacted at room temperature to reflux temperature for 2 to 18 hours to give methyl ester (V).
Is obtained. Next, nitration of the methyl ester (V) is performed by a conventional method. That is, by adding an equivalent amount of concentrated nitric acid to methyl ester (V) using concentrated sulfuric acid as a solvent and reacting at -30 ° C to 0 ° C, a nitro compound (VI) is obtained. Next, DMF, dioxane, tetrahydrofuran (hereinafter, referred to as
Abbreviated as THF. ) Or water or the like as a solvent, and reacting the nitro compound (VI) with 4-methoxybenzenesulfonyl chloride for 1 to 18 hours at room temperature in the presence of a base such as dimethylaminopyridine or triethylamine to give compound (VII). can get. In this case, it is preferable to use 1 to 1.5 mol of 4-methoxybenzenesulfonyl chloride per 1 mol of the nitro compound (VI).

Compound (VII) is dissolved in a solvent usually used for alkaline hydrolysis such as methanol, ethanol, dioxane or water in an amount of 1.0 to 1 mol of (VII).
Hydrolyzing with 0 to 2.0 mol sodium hydroxide or potassium hydroxide at 0 ° C to 60 ° C for 0.5 to 24 hours,
Compound (VIII) is obtained. Then, compound (VIII)
With O-benzylhydroxylamine. This condensation reaction is carried out in an aprotic solvent such as DMF, THF or dichloromethane in a conventional condensing agent used for peptide synthesis, for example, dicyclohexylcarbodiimide (hereinafter abbreviated as DCC), 1-ethyl-3- (3 -Dimethylaminopropyl) carbodiimide hydrochloride (hereinafter abbreviated as WSC) or the like. The reaction is usually performed at 0 ° C. to room temperature for 2 to 24 hours, and the molar ratio of the compound to be subjected to the reaction is generally 1 mol of compound (VIII) and usually 1 mol of 0-benzylhydroxylamine.
0 to 1.5 mol, and 1.0 to 1.5 mol of the condensing agent.

The condensation of compound (VIII) with O-benzylhydroxylamine can also be carried out by a mixed acid anhydride method. In this case, after dissolving compound (VIII) in the same aprotic solvent as described above and adding an equivalent amount of a tertiary amine such as triethylamine or N-methylmorpholine, preferably at -20 to 5 ° C., ethyl chloroformate or the like is added. An acid chloride such as chlorocarbonate or pivaloyl chloride is added to prepare a mixed acid anhydride. Then, O-benzylhydroxylamine is added and the reaction is carried out preferably at 0 ° C. to room temperature for preferably 2 to 8 hours to obtain the desired compound (II). In the reaction, 1.0 to 1.5 mol of O-benzylhydroxylamine, 1.0 to 1.5 mol of chlorocarbonate or acid chloride per 1 mol of compound (VIII) were used.
Usually moles are used.

The compound (I) of the present invention or a pharmaceutically acceptable salt thereof is orally or parenterally administered to a human. Oral dosage forms include tablets, granules, powders, fine granules,
In addition to solid preparations such as hard capsules, liquid preparations such as syrups and soft capsules are included. Such a preparation can be produced by a conventional method. Tablets, granules, powders or fine granules may be prepared by mixing the compound (I) of the present invention or a pharmaceutically acceptable salt thereof with, for example, lactose, starch, crystalline cellulose, stearin It is produced by mixing with commonly used pharmaceutical additives such as magnesium acid, hydroxypropylcellulose, talc and the like, and hard capsules are produced by appropriately filling the above fine granules or powders into capsules. A syrup is prepared by dissolving or suspending the compound (I) of the present invention or a pharmaceutically acceptable salt thereof in an aqueous solution containing sucrose, carboxycellulose, and the like. The compound (I) of the present invention or a pharmaceutically acceptable salt thereof is dissolved or suspended in a vegetable oil, an oily emulsion, glycol, or the like, and filled in a soft capsule.

Parenteral dosage forms include injections,
Suppositories such as suppositories and vaginal suppositories, and nasal administration agents such as sprays are exemplified. These preparations can be manufactured by conventional methods,
For example, an injection is prepared by adding the compound (I) of the present invention or a pharmaceutically acceptable salt thereof to a physiological saline solution or a lipid excipient, for example,
It is manufactured by dissolving or emulsifying in vegetable oils, oily emulsions, glycols and the like and aseptically encapsulating in ampules or vials.

The dose of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof varies depending on the age, sex, weight or condition of the patient, but is generally 0.1 to 200 mg / kg as the compound (I). Weight / day, preferably 1 to
An appropriate amount is 100 mg / kg body weight / day.
It is administered in two or four divided doses.

[0032]

The compound of the present invention has a stronger TNF-α production inhibitory effect than the comparative compound (see Test Example 1) and maintains a high blood concentration for a long time after administration to a living body (Test Example 2). reference). In addition, the toxicity of the compound of the present invention is low,
It showed a blood sugar lowering effect in diabetic model animals (see Test Example 3). Therefore, the compound of the present invention or a pharmaceutically acceptable salt thereof is suitably used as a TNF-α production inhibitor. Hereinafter, the action and effect of the compound of the present invention will be specifically described with reference to test examples. (Test Example 1) TNF-α production inhibitory action Test compound Compound of the present invention A: N-hydroxy-7-amino-2-
(4-methoxybenzenesulfonyl) -1,2,3,4
-Tetrahydroisoquinoline-3 (R) -carboxamide -Comparative compound X: N-hydroxy-2-benzenesulfonyl-1,2,3,4-tetrahydroisoquinoline-
3 (R) -carboxamide

2. Test method RPM containing 10% fetal bovine serum and 10 ng / ml LPS (lipopolysaccharide; purchased from Difco)
1 × 10 ⁶ THP-1 cells (purchased from Dainippon Pharmaceutical) were suspended in 2 ml of I-1640 medium, and 10% fetal bovine serum was added to a 24-well culture plate (Falcon 3047, manufactured by Becton Dickinson). RPMI-1 including
Final concentration of 10, 5, 2.5, 1.25 with 640 medium
And the test compound prepared at 0.625 μM,
The cells were cultured at 37 ° C. for 24 hours in a 5% CO ₂ atmosphere to obtain a culture supernatant.

The TNF-α concentration in the culture supernatant was quantified using a human TNF-α measurement ELISA kit (manufactured by Amersham). The TNF-α concentration in the culture supernatant without the test compound (A) was used as a control, and the TNF-α concentration in the culture supernatant with the test compound was added (X).
From the following formula

[0035]

[Number 1] TNF-alpha secretion inhibitory rate (%) = a (1-X / A) × 100 was calculated TNF-alpha secretion inhibitory rate (%), IC ₅₀ values were determined by probit method. 3. Test results The results are shown in Table 1.

[0036]

[Table 1]

(Test Example 2) Blood concentration after oral administration Test compound Compound of the present invention A: N-hydroxy-7-amino-2-
(4-methoxybenzenesulfonyl) -1,2,3,4
-Tetrahydroisoquinoline-3 (R) -carboxamide -Comparative compound X: N-hydroxy-2-benzenesulfonyl-1,2,3,4-tetrahydroisoquinoline-
3 (R) -carboxamide Test method 2-1) Determination method of test compound Test compound 0.1 μg, 0.2 μg, 0.5 μg,
1.0 μg and 2.0 μg were respectively added to 0.1 ml of serum, 0.4 ml of acetonitrile was added, and the mixture was stirred for 20 seconds. After centrifugation at 15000 rpm for 5 minutes, 0.4 ml of the supernatant was taken and dried under reduced pressure. To the residue, 0.1 ml of a 0.1% aqueous solution of trifluoroacetic acid / acetonitrile = 3/1 for the compound A of the present invention and 0.1 ml of a 30% aqueous solution of acetonitrile for the comparative compound X are added for more than 5 minutes. After sonication, the supernatant was collected by centrifugation at 15000 rpm for 5 minutes, and 1, 2, 5, 10 and 20 μm
A sample for a calibration curve of g / ml was prepared. Each sample was analyzed by HPLC under the following conditions, and a calibration curve was prepared from the areas of the obtained peaks.

A) HPLC conditions of compound A of the present invention High-performance liquid chromatography: L-6200 (HITAC
HI) Analysis column: L-column ODS 4.6 × 15
0 mm (Chemical Quality Association) Column temperature: 40 ° C. Flow rate: 1.0 ml / min Detector: L-4250 (HITACHI) Detection wavelength: 245 nm Moving layer: 0.1% aqueous trifluoroacetic acid / acetonitrile = 86/14 Elution time : 7.8 minutes b) HPLC condition of comparative compound X Detection wavelength: 214 nm Moving layer: 0.1% aqueous trifluoroacetic acid / acetonitrile = 70/30 Elution time: 7.8 minutes (column temperature, flow rate and detector (Same as (1) above)

2-2) Method for Measuring Blood Concentration The test compound was suspended in 0.5% Tween 80, and administered orally or subcutaneously to mice in groups of 3 animals (in each case, the dose of the test compound was 100 mg / kg). )did. 10 minutes, 3
Blood is drawn at 0 minutes, 1 hour and 3 hours, 15,000 rp
The serum was separated by centrifugation at 5 m for 5 minutes. Serum 0.1m
To 1 was added 0.4 ml of acetonitrile and stirred for 20 seconds. After centrifugation at 15000 rpm for 5 minutes, 0.4 ml of the supernatant was taken and dried under reduced pressure. To the residue, 0.1 ml of a 0.1% aqueous solution of trifluoroacetic acid / acetonitrile (ratio 3/1) in the case of Compound A of the present invention, and 0.1 ml of a 30% aqueous solution of acetonitrile in the case of Comparative Compound X were added.
After sonication for 5 minutes, the mixture was centrifuged at 15000 rpm for 5 minutes, and the supernatant was collected as an analysis sample. HPLC analysis was performed under the above conditions, and the blood concentration (μg / m
l) was calculated and converted to a molar concentration. 3. Test Results Table 2 shows the blood concentration (μM) of each test compound at 10 minutes, 30 minutes, 1 hour and 3 hours after administration.

[0040]

[Table 2]

(Test Example 3) Blood glucose lowering action in a diabetic model mouse Test compound Compound of the present invention A: N-hydroxy-7-amino-2-
(4-methoxybenzenesulfonyl) -1,2,3,4
-Tetrahydroisoquinoline-3 (R) -carboxamide 2. Test method K known as a non-insulin-dependent diabetes model
The following experiment was performed using ^KAy mice. 13-week-old male KK- ^Ay / Ta Jcl mouse (CLEA Japan)
Were divided into 2 groups (control group and test compound administration group) with 7 animals per group. The test compound was treated with 0.5% Tween
n80 solution, and subcutaneously administered once a day for 2 weeks to mice in the test compound administration group at a rate of 200 mg / kg.
Control group mice received 0.5% Tween 8
0 solution was administered subcutaneously once a day for 2 weeks. Before the start of administration and every week during the administration period, a small amount of blood was collected from the fundus venous plexus using a hematocrit blood collection tube, and plasma was separated.
Blood glucose was measured using Glucose B-Test _Wako (Wako Pure Chemical _{Industries, Ltd.} ), and the significance of the test compound administration group relative to the control group was tested by the Dunnett method. 3. Test Results As shown in FIG. 1, the test compound significantly reduced the blood glucose level of KK- ^Ay mice.

[0042]

EXAMPLES The present invention will be described more specifically below with reference to Reference Examples and Examples. Reference Example N-benzyloxy-2- (4-methoxybenzenes)
Ruphonyl) -7-nitro-1,2,3,4-tetrahydride
Production of loisoquinoline-3 (R) -carboxamide (1) 1,2,3,4-tetrahydroisoquinoline-3
(R) -carboxylic acid / hydrochloride: 1,2,3,4-tetrahydroisoquinoline-3 (R) -carboxylic acid benzyl ester / p-toluenesulfonic acid salt 30 g [Chem. Pharm. B
ull., 31 (1), 312-314 (1983). ]
Was neutralized with an aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. After washing the organic layer with saturated saline,
Dried over magnesium sulfate. After removing magnesium sulfate, the solvent was distilled off, and the residue obtained was ethanol 20
0 ml and water 100 ml were added. After adding 12 ml of concentrated hydrochloric acid, the mixture was stirred for 4 hours under a hydrogen atmosphere at a pressure of 3.6 kgf / cm ² using 2.0 g of 10% Pd—C as a catalyst. After removing the catalyst, the solvent was distilled off to obtain 13.1 g of the title compound as a colorless solid.

(2) 1,2,3,4-tetrahydroisoquinoline-3 (R) -carboxylic acid methyl ester hydrochloride: 1,2,3,4-tetrahydroisoquinoline-3
(R) -Carboxylic acid / hydrochloride 13.1 g in methanol 2
After adding 00 ml, 12 ml of thionyl chloride was slowly added dropwise under ice-cooling. After heating under reflux for 3.5 hours, methanol was distilled off to obtain 14.0 g of the title compound.

(3) 7-nitro-1,2,3,4-tetrahydroisoquinoline-3 (R) -carboxylic acid methyl ester: 1,33,4-tetrahydroisoquinoline-3 (R) in 33 ml of concentrated sulfuric acid 5.3 g of carboxylic acid methyl ester / hydrochloride was slowly added and dissolved under ice cooling. 1.5 ml of concentrated nitric acid was added dropwise and stirred for 30 minutes. After pouring the reaction solution into ice water, the solution was neutralized with an aqueous sodium hydroxide solution. The resulting insolubles were extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, and then dried over magnesium sulfate. After removing magnesium sulfate, the residue obtained by distilling off the solvent was recrystallized from diisopropyl ether to obtain 1.8 g of the title compound as a pale red powder.

[0045] _{^{1 H-NMR (CDCl 3)}} δ; 3.13 (1H, dd, J = 9.2
Hz, 17.1Hz), 3.28 (1H, dd, J = 4.8Hz, 17.1Hz), 3.86 (3H, s),
3.8-3.9 (1H, m), 4.21 (1H, d, J = 16.4Hz), 4.31 (1H, d, J = 16.4
Hz), 7.35 (1H, d, J = 8.4Hz), 8.02 (1H, d, J = 2.2Hz), 8.08 (1H,
(dd, J = 2.2Hz, 8.4Hz).

(4) 2- (4-methoxybenzenesulfonyl) -7-nitro-1,2,3,4-tetrahydroisoquinoline-3 (R) -carboxylic acid methyl ester: 7
4.2 g of -nitro-1,2,3,4-tetrahydroisoquinoline-3 (R) -carboxylic acid methyl ester and 2.4 g of dimethylaminopyridine are dissolved in 50 ml of DMF, and 4.1 g of 4-methoxybenzenesulfonyl chloride is dissolved.
Was added and stirred at room temperature overnight. The reaction solution was acidified by adding diluted hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over magnesium sulfate.
The residue obtained by removing magnesium sulfate is subjected to silica gel column chromatography (mobile phase; ethyl acetate / n-
Separation and purification were performed using hexane (1/1) to obtain 6.9 g of the title compound as a colorless powder.

[0047] _{^{1 H-NMR (CDCl 3)}} δ; 3.34 (2H, d, J = 4.5H
z), 3.54 (3H, s), 3.92 (3H, s), 4.57 (1H, d, J = 16.1Hz), 4.87
(1H, d, J = 16.1Hz), 5.14 (1H, t, J = 4.5Hz), 7.03 (2H, d, J = 8.9
Hz), 7.33 (1H, d, J = 8.4Hz), 7.84 (2H, d, J = 8.9Hz), 8.02 (1H,
d, J = 8.4Hz), 8.07 (1H, s). (5) 2- (4-methoxybenzenesulfonyl) -7-
Nitro-1,2,3,4-tetrahydroisoquinoline-
3 (R) -carboxylic acid: 2- (4-methoxybenzenesulfonyl) -7-nitro-1,2,3,4-tetrahydroisoquinoline-3 (R) -carboxylic acid methyl ester (6.9 g) in dioxane (30 ml) and water Add 15 ml,
Under ice cooling, 25 ml of 1N aqueous NaOH was added, and the mixture was stirred for 1 hour. The reaction solution was acidified by adding diluted hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over magnesium sulfate. After removing magnesium sulfate,
The solvent was distilled off to obtain 3.8 g of the title compound as a pale red solid.

¹ H-NMR (DMSO-d ₆ ) δ; 3.0-3.3 (2H, m),
3.80 (3H, s), 4.50 (1H, d, J = 16.6Hz), 4.75 (1H, d, J = 16.6H
z), 4.80-4.88 (1H, m), 7.02 (2H, d, J = 8.9Hz), 7.42 (1H, d, J =
8.4Hz), 7.75 (2H, d, J = 8.9Hz), 7.97 (1H, dd, J = 2.0Hz, 8.4H
z), 8.09 (1H, d, J = 2.0 Hz), 13.0 (1H, bs). (6) N-benzyloxy-2- (4-methoxybenzenesulfonyl) -7-nitro-1,2,3,3 4-tetrahydroisoquinoline-3 (R) -carboxamide: 2-
(4-methoxybenzenesulfonyl) -7-nitro-
1,2,3,4-tetrahydroisoquinoline-3 (R)
-Dissolve 3.0 g of carboxylic acid in 50 ml of DMF and add
SC 1.7 g, N-hydroxybenzotriazole 1.
3 g, O-benzylhydroxylamine hydrochloride 1.4
g and triethylamine 0.89 g were sequentially added, and the mixture was stirred at room temperature overnight. The reaction solution was acidified by adding diluted hydrochloric acid, and then extracted with ethyl acetate. The organic layer was treated with aqueous sodium carbonate,
After washing with water and saturated saline, it was dried over magnesium sulfate. After removing magnesium sulfate, the solvent was distilled off to obtain 3.0 g of the title compound as a yellow solid.

[0049] _{^{1 H-NMR (CDCl 3)}} δ; 2.74 (1H, dd, J = 5.3
Hz, 16.0Hz), 3.34 (1H, d, J = 16.0Hz), 3.83 (3H, s), 4.33 (1H,
d, J = 15.8Hz), 4.48 (1H, d, J = 15.8Hz), 4.53-4.65 (1H, m), 4.
85 (2H, s), 6.88 (2H, d, J = 8.8Hz), 7.23 (1H, d, J = 8.3Hz), 7.2
5-7.40 (5H, m), 7.65 (2H, d, J = 8.8Hz), 7.84 (1H, d, J = 2.1H
z), 8.00 (1H, dd, J = 2.1 Hz, 8.3 Hz), 9.10 (1 H, s). Example 1 N-hydroxy-7-amino-2- (4-methoxybenz
Zensulfonyl) -1,2,3,4-tetrahydroiso
Production of quinoline-3 (R) -carboxamide N-benzyloxy-2- (4-methoxybenzenesulfonyl) -7-nitro-1,2,3 obtained in Reference Example.
0.39 g of 4-tetrahydroisoquinoline-3 (R) -carboxamide was dissolved in 20 ml of methanol, and 0.1 g of 10% Pd-C was used as a catalyst under pressure (3.5 k).
gf / cm ² ) for 1 hour. After removing Pd-C, the residue obtained by evaporating the solvent was subjected to HPLC.
(Column: YMC-Pack ODS SH-343-5 S-5 120A, moving bed;
The fraction purified using water / acetonitrile = 3/1) was lyophilized to give 0.2 g of the title compound as a colorless powder. HPLC showed the following retention times:

Column: L-column ODS
6 × 150 mm moving bed; 0.1% aqueous trifluoroacetic acid / acetonitrile = 83/17 flow rate; 1.0 ml / min retention time: 7.4 min ¹ H-NMR (DMSO-d ₆ ) δ; 2.64 (1H, dd, J = 5.9Hz, 15.6H
z), 2.88 (1H, dd, J = 3.7Hz, 15.6Hz), 3.85 (3H, s), 4.3-4.5 (3
H, m), 4.83 (2H, s), 6.31 (1H, d, J = 1.9Hz), 6.35 (1H, dd, J = 1.
9Hz, 8.1Hz), 6.70 (1H, d, J = 8.1Hz), 7.04 (2H, d, J = 8.9Hz),
7.73 (2H, d, J = 8.9Hz), 8.8 (1H, bs), 10.6 (1H, bs). Elementary analysis _{(C 17 H 19 N 3 O} 5 S · 0.5H 2 O ) Calculated value (% ) C, 5.22; H, 52.84; N, 1
0.87 found (%) C, 5.07; H, 52.85; N, 1
0.88

Example 2 Preparation of tablets N-hydroxy-7-amino-2 was contained in one tablet as follows.
-(4-methoxybenzenesulfonyl) -1,2,3,
A tablet is obtained containing 100 mg of 4-tetrahydroisoquinoline-3 (R) -carboxamide (Compound A). [Prescription] [Operation] The main drug, corn starch and microcrystalline cellulose are mixed, and hydroxypropylcellulose dissolved in 50 parts by weight of water is added thereto and kneaded sufficiently. The kneaded product is passed through a sieve, granulated on granules, and dried. Then, the obtained granules are mixed with magnesium stearate and compressed into 250 mg tablets.

Example 3 Preparation of Granules N-hydroxy-7-amino-2- (4-
A granule containing (methoxybenzenesulfonyl) -1,2,3,4-tetrahydroisoquinoline-3 (R) -carboxamide (compound A) is obtained. [Prescription] [Operation] A main drug, lactose and corn starch are mixed, and hydroxypropylcellulose dissolved in 120 parts by weight of water is added and kneaded sufficiently. The kneaded product is passed through a 20-mesh sieve, granulated, dried and sized, and 500 mg
A granule containing 200 mg of the active ingredient is obtained.

Example 4 Preparation of Capsule Preparation of N-hydroxy-7-amino-2- (4-methoxybenzenesulfonyl) -1,1 in one capsule as follows.
A capsule containing 100 mg of 2,3,4-tetrahydroisoquinoline-3 (R) -carboxamide (Compound A) is obtained. [Prescription] [Operation] Thoroughly mix the above components, and mix 2
A capsule is obtained by filling the capsule with the amount of 00 mg.

Example 5 Preparation of injection 0.5 part by weight of N-hydroxy-7-amino-2- (4-methoxybenzenesulfonyl) -1,2,3,4-tetrahydroisoquinoline-3 (R) -carboxamide Distilled water for injection is added to a mixture of 5 parts by weight of sorbitol and dissolved to make 100 parts by weight, and this aqueous solution is filtered through a membrane filter. Put the filtrate in an ampoule with a nitrogen purge.
g, filled, sealed, sterilized at 120 ° C. for 15 minutes, and N-hydroxy-7-amino-2-
(4-methoxybenzenesulfonyl) -1,2,3,4
To obtain an injection containing 25 mg of tetrahydroisoquinoline-3 (R) -carboxamide.

[Brief description of the drawings]

FIG. 1 shows the time course of blood glucose levels when a compound of the present invention was administered to a non-insulin-dependent diabetes model mouse (Test Example 3).

[Explanation of symbols]

The polygonal lines a and b indicate the blood glucose levels of the following groups, respectively. a: Control group b: Group administered with the compound of the present invention Further, the significant difference between the group administered with the compound of the present invention and the control group was tested by the Dunnett method, and indicated by * or **. P <0.05 ** P <0.01

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/47 ACL A61K 31/47 ACL ADA ADA ADP ADP ADP AED AED

Claims (3)

[Claims] (1) The following formula (I): Or a pharmaceutically acceptable salt thereof. 2. A drug comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 3. A TNF-α production inhibitor comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.