JPH1160484A - Tnf production inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a TNF production inhibitor efficiently suppressing TNF production, having antitumor activity and useful for treatment of e.g. cancer, rheumatoid arthritis by including a specific morphine derivative (acid-added salt) as an active ingredient. SOLUTION: This inhibitor comprises a morphine derivative or its pharmacologically acceptable acid-added salt thereof expressed by the formula (R is a lower alkanoyl) as an active ingredient, such as 3-acetoxy-6β- acetylthio-10-oxo-N-cyclopropylmethyl-dihydronormorphine. The daily dose of the morphine derivative (acid-added salt) of the formula is preferably 0.02-10 mg/kg body weight per adult.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel TNF production inhibitor. More specifically, the following formula (I)

[0002]

Embedded image (Wherein, R represents a lower alkanoyl group) or a pharmaceutically acceptable acid addition salt thereof represented by the formula:

[0003]

2. Description of the Related Art TNF is a tumor necrosis factor found in 1975 by Old at Sloan Kettering Cancer Institute in the United States.
r). At the beginning of the discovery, its strong antitumor activity attracted attention and was expected to be developed as an anticancer drug. It has been found that the caking substance chachectin and TNF are the same substance, and their side effects hinder clinical trials. It has also been suggested that TNF is an endogenous tumor promoter.

On the other hand, using a receptor, an antibody or an inhibitor for suppressing the production of TNF, a disease accompanied by abnormal production of TNF, for example, inflammatory diseases such as cancer, rheumatoid arthritis, etc.
Crohn's disease, infection, sepsis, diabetes, graft-versus-host disease
Attempts to develop therapeutic agents such as (GVHD) have been actively made.

[0005] By the way, it has recently been found that morphine suppresses the production of TNF and has antitumor activity (Carcinogenesis Vol. 17, no. 11, 2337-234).
1, 1996).

[0006] Among the morphine derivatives represented by the formula (I) or the pharmacologically acceptable acid addition salts thereof, the compounds wherein R is an acetyl group are described in Bioorganic & Medicinal Che.
Mistry Letters, Vol. 5, No. 14, 1505-1508 (1995).

[0007] It has been reported that the morphine derivative represented by the formula (I) or a pharmaceutically acceptable acid addition salt thereof suppresses TNF production and has antitumor activity. Not.

[0008]

The effect of morphine on the inhibition of TNF production is not strong, and there is room for improvement.

It is an object of the present invention to provide a novel TNF production inhibitor.

[0010]

As a result of various studies, the present inventors have found that the morphine derivative represented by the formula (I) or a pharmacologically acceptable acid addition salt thereof suppresses the production of TNF. The inventors have completed the present invention.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, a morphine derivative represented by the above formula (I) or a pharmacologically acceptable acid addition salt thereof is used. The morphine derivative (I) or a pharmacologically acceptable acid addition salt thereof is described, for example, in the aforementioned literature [Bi
oorganic & Medicinal Chemistry Letters, Vol. 5, No. 1
4,1505-1508 (1995)], and can be easily produced (see Production Examples below).

That is, for example, according to Production Example 1 described below, 10-oxo-N-cyclopropylmethyl-dihydronormorphine [compound of Production Example (6)] is obtained from dihydronormorphine. A phenolic hydroxyl group is reacted with an acid anhydride or an acid halide in a conventional manner to introduce a lower alkanoyl group, and then reacted with a thiocarboxylic acid such as thioacetic acid in the presence of triphenylphosphine and diisopropylazocarboxylate. Morphine derivative (I) or a pharmacologically acceptable acid addition salt thereof can be produced.

The morphine derivative or a pharmaceutically acceptable acid addition salt thereof used in the present invention includes, for example, an acetyl group and a propionyl group as the lower alkanoyl group of R in the formula (I). Acetyl groups are preferred.

The pharmacologically acceptable acid addition salts used in the present invention include, for example, salts with organic acids such as citric acid, fumaric acid, maleic acid and tartaric acid, or hydrochloric acid, hydrobromic acid, Examples include salts with inorganic acids such as nitric acid and sulfuric acid.
Hydrochloride is preferred.

Specific examples of the morphine derivative used in the present invention include the following compounds or pharmacologically acceptable acid addition salts thereof.

3-acetoxy-6β-acetylthio-1
0-oxo-N-cyclopropylmethyl-dihydronormorphine The TNF production inhibitor of the present invention is usually administered orally or parenterally to a human.

The dosage form for oral administration includes tablets, granules, fine granules, powders and the like. These preparations are prepared by using morphine derivative (I) or a pharmaceutically acceptable acid addition salt thereof. , Lactose, corn starch, microcrystalline cellulose,
Magnesium stearate, carboxymethyl cellulose
It is manufactured by a conventional method by appropriately mixing with ordinary pharmaceutical additives such as scalcium, hydroxypropylcellulose and talc.

Examples of dosage forms for parenteral administration include injections. Injectables can be manufactured by a conventional method, and if necessary, mannitol, sodium chloride, glucose
Sorbitol, glycerol, xylitol, fructose, maltose, mannose, and the like; sodium sulfite, a stabilizer such as albumin; benzyl alcohol; methyl parahydroxybenzoate And the like can be added to the preparation. The injection can also be a lyophilized preparation for dissolution before use. The freeze-dried preparation can be produced by a conventional method, and the above-mentioned isotonic agent, stabilizer, preservative and the like can be appropriately added to the preparation.

The TNF production inhibitor of the present invention is useful for diseases associated with abnormal production of TNF, such as cancer, inflammatory diseases such as rheumatoid arthritis, Crohn's disease, infection, sepsis, diabetes,
It can be used for graft-versus-host disease (GVHD) and the like.

The TNF production inhibitor of the present invention has the property of being an agonist for κ-opioid receptor.
[Arch.international Pharmacodynam.Therap., 331 (2), 1
36-152 (1996)], showing strong analgesic activity and having less physical and mental dependence than morphine, especially for cancer,
It can be suitably used for these diseases accompanied by pain, such as rheumatoid arthritis.

The dose of the TNF production inhibitor of the present invention varies depending on the disease, condition, administration route, age, body weight, etc. of the patient, but is usually 0.02 to 10 mg / kg per day for the adult morphine derivative (I). Range, which is at once or 2
Administer in 3 divided doses.

[0022]

The morphine derivative which is the active ingredient of the TNF production inhibitor of the present invention has a superior TNF as compared with morphine.
Shows a production inhibitory effect (see Test Example 1).

The morphine derivative, which is an active ingredient of the TNF production inhibitor of the present invention, exhibits excellent antitumor activity as compared with morphine (see Test Example 2).

The TNF production inhibitor of the present invention does not show any serious side effects when administered in an effective amount, and is highly safe.

Therefore, the TNF production inhibitor of the present invention
It is useful as a therapeutic agent for diseases associated with abnormal production of NF.

Hereinafter, the effects of the present invention will be described in detail with reference to test examples.

Test Example 1 (TNF production inhibitory action) (1) Test compound • 3-acetoxy-6β-acetylthio-10-oxo-N-cyclopropylmethyl-dihydronormorphine hydrochloride (Compound A) • Morphine hydrochloride (positive) Control)

(2) Test method The above literature (Carcinogenesis Vol. 17, no. 11, 2337-2341, 1
996).

That is, BALB / 3T3 cells (2 × 10 ⁵ cells)
s) and a physiological saline solution of the test compound were cultured in 0.45 ml of a minimum essential medium containing 10% fetal calf serum at 37 ° C. for 1 hour, and then treated with 0.2 μM okadaic acid (cancer promoter). Next, the medium (total volume: 0.5 ml) was cultured at 37 ° C. for 24 hours. After the culture, 0.1 ml of the culture supernatant was collected by centrifugation, and the amount of TNF-α produced by the enzyme immunoassay kit for TNF-α measurement was measured. As a negative control, the amount of TNF-α in the group not treated with the drug was measured in the same manner.

The TNF production inhibition rate (%) was calculated by the following equation.

[0031]

Formula 1: TNF production inhibition rate (%) = [1- (TNF-α amount of test compound treated group / TNF-α amount of negative control group)] ×
Next, the test compound concentration (IC ₅₀ ) at which the above-mentioned TNF production inhibition rate (%) becomes 50% was determined by a regression equation.

(3) Test Results The results are shown in Table 1.

[0033]

[Table 1]

Test Example 2 (Anti-Tumor Activity) (1) Test Compound Same as Test Example 1.

(2) Test Method The antitumor activity of the active ingredient of the TNF production inhibitor of the present invention was determined according to the aforementioned literature (Carcinogenesis Vol. 17, no. 11, 23).
37-2341, 1996). That is, the human leukemia cell line HL-60 (2 × 10 ⁵ cells / ml) and a physiological saline solution of the test compound were cultured in 1 ml of RPMI1640 medium containing 10% fetal bovine serum for 4 days. Four days later, the number of viable cells was measured by the trypan blue method. In addition, as a negative control, the number of viable cells in the group not treated with the drug was similarly measured.

The cell growth inhibition rate (%) was calculated by the following equation.

[0037]

Formula 2: Cell growth inhibition rate (%) = [1- (number of living cells in test compound treated group / number of living cells in negative control group)] × 100 Next, the above cell growth inhibition rate (%) is 50%. The test compound concentration (IC ₅₀ ) was determined by a regression equation. (3) Test results The results are shown in Table 2.

[0038]

[Table 2]

[0039]

The present invention will be described more specifically below with reference to examples and production examples.

Example 1 (tablets) : 3-acetoxy-6β
-Acetylthio-10-oxo-N-cyclopropylmethyl-dihydronormorphine hydrochloride (100 g), lactose (890
g), crystalline cellulose (900 g), carboxymethyl cellulose
Squalium (70 g), talc (25 g) and magnesium stearate (15 g) are uniformly mixed and compressed into tablets of 200 mg / tablet.

Example 2 (injection) : 3-acetoxy-6
β-acetylthio-10-oxo-N-cyclopropylmethyl-dihydronormorphine hydrochloride (1 g) was dissolved in distilled water for injection, made up to 1000 ml, sterile filtered, and added to an ampoule.
Dispense 1ml each. After freeze-drying, the mixture is sealed to obtain an injection for dissolution at the time of use.

Production Example 1 3-acetoxy-6β-acetylthio-10-oxo-
N-cyclopropylmethyl-dihydronormorphine hydrochloride
Salt Production: Bioorganic & Medicinal as shown below
Production was performed according to Chemistry Letters, Vol. 5, No. 14, 1505-1508 (1995). (1) N-benzyloxycarbonyl-dihydronormo
Lucine: dihydronormorphine (560 g, 2.05 m
mol) in an aqueous methanol solution (MeOH: H ₂ O = 4:
1) and dissolved at 0 ° C. in sodium carbonate (65 mg,
0.62 mmol) and benzyloxycarbonyl chloride (88 μg, 0.62 mmol) every 3 minutes for 3-4.
After repeated addition, the mixture was extracted with chloroform. After the solvent was distilled off, the obtained residue was subjected to silica gel column chromatography (developing solvent; chloroform: methanol = 30:
Purification in 1) gave N-benzyloxycarbonyl-dihydronormorphine (67 mg, 81%) as a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 4.03 (bs, 1H), 4.56 (d, J = 5.28 Hz, 1H),
4.65 (bs, 1H), 5.10-5.22 (m, 2H), 6.51-6.55 (m, 1H), 6.68
(d, J = 8.25 Hz, 1 H), 7.34-7.37 (m, 5 H); ¹³ C-NMR (CDCl ₃ ) δ: 155.31 (s), 145.31 (s), 137.60 (s), 13
6.66 (s), 128.93 (s), 128.50 (d), 128.03 (d), 127.85 (d), 12
5.08 (s), 177.80 (d), 90.27 (d), 67.28 (t), 67.19 (d), 51.51
(d), 51.27 (d), 42.62 (s), 39.65 (d), 39.33 (d), 37.98 (t), 3
6.76 (t), 28.90 (t), 26.79 (t), 18.88 (t) .IR (CHCl ₃ ; cm ^-1 ) 3000, 2875, 1675 FABMS m / z 407 [H ⁺ ] HRMS (FAB) calculated value [ ^{_{M +] C 24 H 25 NO}} 5 407.1726; Found 407.1
733 [α] ²⁷ _D = -101.6 ° (c = 0.1, CHCl ₃ )

(2) 3-benzyloxy-N-benzyl
Oxycarbonyl-dihydronormorphine: N-benzyloxycarbonyl-dihydronormorphine (1.49
g, 3.66 mmol) in anhydrous dimethylformamide (10 ml) and benzyl bromide (480 μl,
4.03 mmol) and anhydrous potassium carbonate (557 mg,
403 mmol) and stirred at 60 ° C. for 5 hours. After cooling, the solution was filtered through celite, the residue was washed with chloroform, and the solvent was distilled off under reduced pressure. Dissolve the residue in water,
After extraction with chloroform, the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol = 50: 1) to give 3-benzyloxy-N-benzyloxycarbonyl-dihydronormorphine (1.64 g, 90%) in yellow. Obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 2.70 (dd, J = 18.14, 5.94 Hz, 1H), 4.40
(bs, 1H), 4.52 (d, J = 5.61Hz, 1H), 5.09-5.28 (m, 4H), 6.56-
6.60 (m, 1H), 6.79 (d, J = 8.25Hz, 1H), 7.25-7.44 (m, 10H); 13 C-NMR (CDCl 3) δ: 155.72 (s), 146.72 (s), 140.82 ( s), 13
6.77 (s), 129.51 (s), 128.74 (d), 128.60 (d), 128.47 (d), 12
8.19 (d), 128.06 (d), 127.91 (d), 127.81 (d), 127.49 (s), 12
7.44 (d), 127.37 (d), 126.87 (d), 119.69 (d), 116.71 (d), 9
0.04 (d), 71.63 (t), 67.14 (t), 66.80 (d), 51.36 (d), 42.11
(s), 40.25 (d), 38.04 (t), 36.57 (t), 28.86 (t), 27.31 (t), 1
8.54 (t) .IR (CHCl ₃ , cm ^-1 ) 2890, 2870, 1670 FABMS m / z 497 [H ⁺ ] HRMS (FAB) calculated [M ⁺ ] C ₃₁ H ₃₁ NO ₅ 497.2199; found 497.22
02 [α] ²⁷ _D = -180.6 ° (c = 0.12, CHCl ₃ )

(3) 6-acetoxy-3-benzyloxy
C-N-benzyloxycarbonyl-dihydronormol
Hine: 3-benzyloxy-N-benzyloxycarbonyl-dihydronormorphine (1.64 g, 3.30 m)
mol) was dissolved in acetic anhydride (64 ml) in the presence of pyridine (0.82 ml) and stirred at 90 ° C. for 6 hours. After the reaction solution was cooled and the solvent was distilled off, a saturated sodium hydrogen carbonate solution was added, and this was extracted with chloroform. This was recrystallized from ethyl acetate to give 6-acetoxy-3-benzyloxy-N-benzyloxycarbonyl-dihydronormorphine (1.74 g, 98%) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.77 (s, 3H), 4.62 (d, J = 5.94 Hz, 1H),
5.08-5.38 (m, 4H), 6.56-6.61 (m, 1H), 6.78 (d, J = 8.24Hz, 1
H), 7.27-7.46 (m, 10H); ¹³ C-NMR (CDCl ₃ ) δ: 170.06 (s), 155.28 (s), 147.31 (s), 14
0.45 (s), 137.38 (s), 128.85 (s), 128.63 (d), 128.60 (d), 12
8.49 (d), 128.41 (d), 127.99 (s), 127.84 (d), 127.63 (d), 12
5.81 (s), 119.44 (d), 117.21 (d), 87.13 (d), 71.99 (t), 67.5
6 (d), 67.16 (t), 51.45 (d), 42.51 (s), 40.74 (d), 38.45 (t),
36.05 (t), 28.90 (t), 26.10 (t), 20.61 (q), 18.85 (t) .IR (CHCl ₃ , cm ^-1 ) 3010,2980,1740,1690,1630 FABMS m / z 539 [M ⁺ ] HRMS (FAB) calculated [M ⁺ ] C ₃₃ H ₃₃ NO ₆ 539.2305; found 539.23
08 [α] ²⁷ _D = -99.8 ° (c = 0.61, CHCl ₃ )

(4) 6-acetoxy-3-benzyloxy
C-N-benzyloxycarbonyl-10-oxo-di
Hydronormorphine: 6-acetoxy-3-benzyloxy-N-benzyloxycarbonyl-dihydronormorphine (500 mg, 0.93 mmol) is dissolved in 1,4-dioxane (50 ml), and selenium dioxide is added to the substrate. 0 equivalent (500 mg, 0.93 mmol) was added, and the mixture was heated in a sealed tube at 180 ° C. for 24 hours. The reaction solution was allowed to cool, selenite was removed by filtration with Celite, a saturated sodium hydrogen carbonate solution was added, the mixture was extracted with chloroform, and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography (developing solvent; chloroform: methanol = 5).
0: 1), 6-acetoxy-3-benzyloxy-N-benzyloxycarbonyl-10-oxo-
Dihydronormorphine (503 mg, 98%) was obtained as a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.76 (s, 3H), 4.0
5-4.18 (m, 1H), 4.70 (d, J = 5.61Hz, 1H), 6.94 (d, J = 9.57Hz, 1
H), 7.30-7.46 (m, 12H); ¹³ C-NMR (CDCl ₃ ) δ: 191.92 (s), 169.74 (s), 159.73 (s), 15
5.18 (s), 147.86 (s), 146.76 (s), 137.35 (s), 136.21 (s), 12
8.44 (s), 128.65 (d), 128.51 (d), 128.35 (d), 128.21 (d), 12
8.06 (d), 128.87 (d), 137.68 (d), 127.58 (d), 124.23 (s), 12
4.14 (d), 119.57 (d), 86.98 (d), 86.70 (d), 71.89 (t), 67.72
(t), 67.51 (d), 60.32 (d), 59.94 (d), 43.73 (d), 43.46 (s), 3
8.72 (t), 35.98 (t), 25.56 (t), 20.58 (q), 18.72 (t) .IR (CHCl ₃ ; cm ^-1 ) 3000,2900,1720,1680,1600 FABMS m / z 554 [M ⁺ + H], 543 [M ⁺ ] HRMS (FAB) Calculated [M ⁺ + H] C ₃₃ H ₃₂ NO ₇ 554.2180; found 55
4.2179 [α] ²⁶ _D = -197.7 ° (c = 0.10, CHCl ₃ )

(5) 6-acetoxy-10-oxo-3
-Cyclopropylmethoxy-N-cyclopropylmethyl
-Dihydronormorphine : 6-acetoxy-3-benzyloxy-N-benzyloxycarbonyl-10-oxo-dihydronormorphine (1.01 g, 1.81 mm
ol) in ethanol (20 ml) and 10% Pd (O
H) ₂ / C (1.0 g) was added, and the mixture was stirred under a pressure of 6 kgf / cm ² for 2 hours. Filtered through celite and washed several times with ethanol. After the solvent was distilled off, the residue was dissolved in chloroform, a saturated sodium hydrogen carbonate solution was added, and the mixture was extracted. The solvent was distilled off to obtain 6-acetoxy-10-oxo-dihydronormorphine as a white solid. This compound was dissolved in anhydrous dimethylformamide (20 ml) under a stream of argon, and anhydrous potassium carbonate (1.06 g, 7.67 mm) was dissolved.
o1) and bromomethylcyclopropane (745 μm)
1, 7.67 mmol) was added dropwise and heated at 100 ° C. for 5 hours. This solution was filtered through Celite, the residue was washed with chloroform, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol = 2: 1) to give 6-acetoxy-10-oxo-3-cyclopropylmethoxy-.
N-Cyclopropylmethyl-dihydronormorphine (1.23 g, 92%) was obtained as a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 0.05-0.52 (m, 8H), 0.61-0.68 (m, 2H),
0.87-0.92 (m, 1H), 1.78 (s, 3H), 3.95-4.09 (m, 1H), 4.97 (d,
J = 5.94Hz, 1H, H-5), 6.83 (d, J = 8.58Hz, 1H), 7.35 (d, J = 8.64
Hz, 1H); ¹³ C-NMR (CDCl ₃ ) δ: 193.33 (s), 169.75 (s), 147.75 (s, aro
matic), 146.28 (s, aromatic), 137.82 (s, aromatic), 125.1
4 (s, aromatic), 118.82 (s, aromatic), 116.01 (d), 87.88
(d), 74.61 (t), 67.93 (d), 67.72 (d), 60.09 (t), 45.57 (t), 4
4.57 (d), 43.62 (s), 36.39 (t), 25.97 (t), 20.51 (q), 19.03
(t), 10.42 (d), 10.42 (d), 4.40 (t), 4.38 (t), 3.26 (t), 3.22
(t) .IR (CHCl ₃ ; cm ^-1 ) 3400, 2975, 2910, 1720, 1650, 1600 FABMS m / z 438 [M ⁺ + H], 437 [M ⁺ ] HRMS (FAB) calculated value [M ⁺ + H] C ₂₆ H ₃₂ NO ₅ 438.2282; found 438.
2280 [α] ²⁴ _D = -85.6 ° (c = 0.05, CHCl ₃ )

(6) 10-oxo-N-cyclopropyl
Methyl-dihydronormorphine: 6-acetoxy-10
-Oxo-3-cyclopropylmethoxy-N-cyclopropylmethyl-dihydronormorphine (1.23 g,
(2.82 mmol) was dissolved in 25% diluted sulfuric acid (20 ml) and heated under reflux for 10 hours. After cooling the solution,
After adjusting the pH to 9 by adding 8% aqueous ammonia, the mixture was extracted with chloroform, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol = 10: 1), and 10-oxo-N-cyclopropylmethyl-dihydronormorphine (952 mg, 99%) was converted into a yellow oily substance. As obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.11-0.28 (m, 4H), 3.98-4.01 (m, 1H, H
-6), 4.65 (d, J = 4.94Hz, 1H), 6.75 (d, J = 8.24Hz, 1H), 7.28
(d, J = 8.60 Hz, 1H); ¹³ C-NMR (CDCl ₃ ) δ: 193.27 (s), 146.21 (s, aromatic), 145.
27 (s, aromatic), 138.00 (s, aromatic), 124.49 (s, aromati
c), 119.12 (s, aromatic), 118.53 (s, aromatic), 89.98 (d),
67.83 (d), 67.36 (d), 60.24 (t), 45.41 (t), 44.23 (s), 41.95
(d), 36.41 (t), 25.93 (t), 19.76 (t), 8.76 (d), 4.55 (t), 3.3
. 9 (t) IR (CHCl 3; cm -1) 2950,1670,1620,1600 FABMS m / z 342 [M + + H], 341 [M +] HRMS (FAB) calcd [M ^{+ +} H] C ₂₀ H ₂₄ NO ₃ 342.1707; found 34
_{^{2.1705 [α] 20 D = -125.7}} ° (c = 0.105, CHC1 3)

(7) 3-acetoxy-10-oxo-N
-Cyclopropylmethyl-dihydronormorphine: 10
-Oxo-N-cyclopropylmethyl-dihydronormorphine (200 mg, 0.587 mmol) was dissolved in acetic anhydride (0.6 ml), and water (6.6 ml) and sodium hydrogen carbonate (660 mg, 7.86 mmol) were added. And stirred at room temperature for 1 hour. Thereafter, the pH was adjusted to 8 with sodium hydrogen carbonate, and chloroform: ethanol = 3: 1.
And the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 30: 1), and 3-acetoxy-10-oxo-N-cyclopropylmethyl-dihydronormorphine (225 mg, 100%) was obtained as a yellow oily substance. As obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.05-0.30 (m, 4H), 0.51-0.52 (m, 2H),
0.86-0.91 (m, 1H), 2.35 (s, 3H), 4.13-4.10 (m, 1H), 4.64 (d,
J = 5.24Hz, 1H), 6.93 (d, J = 8.54Hz, 1H), 7.33 (d, J = 8.58Hz, 1
H); ¹³ C-NMR (CDCl ₃ ) δ: 193.65 (s), 168.20 (s), 149.17 (s, aro
matic), 140.23 (s, aromatic), 137.18 (s, aromatic), 129.5
1 (s, aromatic), 12.47 (s, aromatic), 117.18 (s, aromati
c), 92.218 (d), 67.75 (d), 66.47 (d), 60.04 (t), 45.48 (d), 4
5.39 (t), 43.15 (s), 36.29 (t), 28.04 (t), 20.66 (q), 18.13
. (t), 9.12 (t ), 4.32 (t), 3.35 (t) IR (CHC1 3; cm -1) 3500,2950,1675,1610 FABMS m / z 384 [M + + H], 383 [M ^+] HRMS (FAB) calcd _{^{[M + + H] C 22}} H 26 NO 5 384.1805; Found 384.
1811 [α] ²⁴ _D = -146.5 ° (c = 0.05, CHCl ₃ )

(8) 3-acetoxy-6β-acetylthio
O-10-oxo-N-cyclopropylmethyl-dihydrido
Lonormorphine (hydrochloride) : diisopropylazocarboxylate (713 μl, 3.0 ml) in a tetrahydrofuran solution (50 ml) of triphenylphosphine (984 mg, 3.62 mmol) under an argon stream at 0 ° C.
62 mmol) was added dropwise and stirred for 30 minutes. To the resulting white salt, 3-acetoxy-10-oxo-N-cyclopropylmethyl-dihydronormorphine (256.6 mg,
0.723 mmol) in tetrahydrofuran (10
ml), and thioacetic acid (260 μl, 3.62 mm
ol) and stirred overnight. Add ether to this,
Decantation was performed to remove triphenylphosphine. After distilling off the ether, the residue was subjected to silica gel column chromatography (developing solvent; hexane: ethyl acetate =
2: 1 and chloroform: methanol = 50: 1) to give 3-acetoxy-6β-acetylthio-10
-Oxo-N-cyclopropylmethyl-dihydronormorphine (81.5 mg, 45%) was obtained as a yellow oil. The obtained compound was converted into a hydrochloride according to a conventional method. ¹ H-NMR (CDCl ₃ ) δ: 0.08-0.93 (m, 5H), 2.31 (s, 3H), 2.33
(s, 3H), 3.37 (d, J = 8.23Hz, 1H), 4.62 (d, J = 8.6Hz, 1H), 7.03
(d, J = 8.6 Hz, 1 H), 7.39 (d, J = 8.2 Hz, 1 H); ¹³ C-NMR (CDCl ₃ ) δ: 194.50 (s), 193.52 (s), 167.38 (s), 14
9.68 (s, aromatic), 139.88 (s, aromatic), 138.35 (s, aroma
tic), 129.72 (s, aromatic), 123.40 (d, aromatic), 117.66
(d, aromatic), 92.227 (d), 77.47 (s), 77.20 (s), 77.00 (s),
67.49 (s), 59.96 (d), 45.54 (d), 45.38 (s), 45.15 (s), 35.01
(d), 30.75 (d), 29.31 (d), 24.96 (d), 20.67 (q), 9.11 (q), 4.
36 (d), 3.32 (d) .IR (CHCl ₃ ; cm ^-1 ) 3000, 2920, 1760, 1675, 1610 HRMS (FAB) calculated [M ⁺ + H] C ₂₄ H ₂₇ O ₅ NS 442.1688; measured Value44
2.1695 mp 154 ° C [α] ²⁴ _D = -90.99 ゜ (c = 1.2, CHCl ₃ ) 1HClsalt: IR (CHCl ₃ ; cm ^-1 ) 3400,2900,1760,1675,1595 HRFAB calculated value C ₂₄ H ₂₇ NO _{5 S · HC1 · 0.5H 2 0:} C59.18, H5.91, N2.9
3: Actual value: C59.19, H6.00, N2.88 [α] ²⁴ _D = -67 ° (c = 1.2, MeOH)

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/485 ADZ A61K 31/485 ADZ AED AED C07D 489/00 C07D 489/00

Claims (5)

[Claims] (1) The following formula (I): (In the formula, R represents a lower alkanoyl group.) A TNF production inhibitor comprising, as an active ingredient, a morphine derivative represented by the following formula or a pharmacologically acceptable acid addition salt thereof. 2. The TNF production inhibitor according to claim 1, wherein in the formula (I), R is an acetyl group. 3. A therapeutic agent for a disease associated with abnormal production of TNF, comprising the TNF production inhibitor according to any one of claims 1 and 2. 4. The therapeutic agent according to claim 3, wherein the disease associated with abnormal production of TNF is cancer. 5. The therapeutic agent according to claim 3, wherein the disease associated with abnormal production of TNF is rheumatoid arthritis.