JPH02306962A - New n-substituted-1-deoxynojirimycin derivative and metastasis-inhibitor for cancerous cell - Google Patents

Abstract

NEW MATERIAL:An N-substituted-1-deoxynojirimycin derivative expressed by the formula [A is 3-5C hydrocarbon may be substituted with OH, halogenated alkyl or alkoxy (said hydrocarbon may have double or triple bond); Z is phenyl, fluorine-substituted phenyl, biphenyl, cycloalkyl or halogen-substituted alkyl]. EXAMPLE:An N-(3-phenyl-3-trifluoromethyl-2-propenyl)-1-deoxynojirimycin. USE:Used as metastasis-inhibitor for cancerous cell. PREPARATION:For instance, 1-deoxynojirimycin is reacted with various aralkylation agent or aralkenylation agent in the presence of deoxidizer such as alkali hydroxide to afford the compound expressed by the formula.

Description

Detailed Description of the Invention [Field of Industrial Application] The present invention relates to a novel N-substituted-1-deoxynojirimycin derivative that inhibits the formation of metastatic foci of cancer cells, and a method for inhibiting cancer cell metastasis using the substance as an active ingredient. Regarding drugs.

[Conventional technology]

There are various anticancer drugs currently used, but the main ones are
It is a drug that kills cancer cells or kills them via the human immune system, and no drug that is effective for the fundamental treatment of cancer has yet been obtained.

In addition, physical therapy such as surgery and radiation therapy is performed for solid cancers for which chemotherapy drugs are less effective, and the success rate in terms of removing the primary cancer has significantly improved. but,
On the other hand, it is also true that it induces metastasis of cancer cells.

[Problem to be solved by the invention]

As mentioned above, in conventional cancer treatments, the metastasis of cancer cells is the biggest problem that affects the prognosis of cancer treated patients.

Therefore, the development of an anticancer agent that can increase the ability to suppress the metastasis of cancer cells is currently the most desired subject.

The present invention aims to solve this problem by providing a substance that effectively inhibits cancer cell metastasis, and a cancer cell metastasis inhibitor containing the substance as an active ingredient.

[Means to solve the problem]

The present inventors have previously discovered N-substituted-1-deoxynojirimycin derivatives that have the effect of suppressing cancer cell metastasis, and have published JP-A-63-31095, JP-A-63-93673, JP-A-63- Publication No. 97454, JP-A-63-10
It was disclosed in Japanese Patent Application Laid-open No. 4850, Japanese Patent Application Laid-Open No. 147815-1982, and Japanese Patent Application Laid-open No. 147816-1987.

The present inventors further synthesized novel N-substituted derivatives of 1-deoxynojirimycin and conducted extensive evaluation, and found a group of novel compounds that have a strong cancer cell metastasis suppressive effect. completed.

The present invention is based on formula (1) % formula % (1) (wherein A represents a hydrocarbon group having 3 to 5 carbon atoms which may be substituted with a hydroxyl group, a halogenated alkyl group or an alkoxy group, and this hydrocarbon The group may have a double or triple bond, Z represents a phenyl group, a fluoro-substituted phenyl group, a piphenyl group, a cycloalkyl group or a halogen-substituted alkyl group) This is a cancer cell metastasis inhibitor containing a nojirimycin derivative and the same compound or its addition salt with a pharmacologically acceptable acid as active ingredients.

The N-substituted-1-deoxynojirimycin derivative represented by formula (1) of the present invention is a new substance that has not been described in any literature.

Examples of compounds contained in this N-1-substituted-1-deoxynojirimycin derivative include the following substances.

N-(3-methoxymethyl-3-phenyl-2-propenyl)-1-deoxynojirimycin N-(3-7enyl-3-trifluoromethyl-2-propenyl>-i-deoxynojirimycin N-(3- (4-fluorophenyl)-2-propenyl-1-deoxynojirimycin N-C3-(3-fluorophenyl)-2-propenyl)
-1-deoxynojirimycin N-[3-(2-fluorophenyl)-2-propenyl-1-teoxynojirimycin N-(3-(4-biphenylpropyl)]-]1-deoxynojirimycin-C3 -(4-fluorophenyl)-propyl]-1-
Deoxynojirimycin N-(3-7 clohequinluprovir)-1-fox/nojirimycin N-(3-phenyl-2-propynyl)-1-deoxynojirimycin N-(2,3-dihydroxy-3- To phenylpro'-
) -1-f Okinojirimine N -(6,6,6
-)-1-dioxynojirimycin N-(5,5,5-trifluoropentyl)-1-deoxy/silimycin N-(4,4,4-trifluorobutyl)-1-deoxynojirimycin or When the N-substituted-1-deoxynojirimycin derivative of the present invention is used as a cancer cell metastasis inhibitor, pharmacologically acceptable acid addition salts include hydrochloric acid, hydrobromic acid,
Inorganic acids such as sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, conolinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, benzoic acid, salicylic acid, methanesulfonic acid, etc. organic acids, and even aspartic acid.

Examples include addition salts with amino acids such as glutamic acid.

All of the compounds of the present invention are new compounds that have not been described in any literature. The synthesis method is nojirimycin (5-amino-
5-deoxy-D-glucobylanose) (Special Publication 1977-
24.2 l-deoxynojirimycin jTetrahedron obtained by reduction of 24.2
125 (1968)] is the most common method. That is, 1-deoxynojirimycin is dissolved in various alcohols, polar solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, and sulfolane, or mixed solvents thereof, with aralkyl halides, alkenyl halides, aralkyl sulfonic acid esters, and aralkenyl halides. The present invention can be prepared by heating at room temperature or in the presence of various aralkyl or aralkenylation reagents represented by sulfonic acid esters and deoxidizing agents such as alkali hydroxides, alkali carbonates, alkali bicarbonates, or appropriate organic amines. An N-substituted AZ group of the compound of formula (1) can be introduced.

Additionally, the hydroxyl group may be protected by a suitable protecting group, such as an acetyl group.

A method may also be adopted in which 1-deoxynojirimycin protected with a benzoyl group, tetrahydropyranyl 2S, t-butyldimethylsilyl group, etc. is used as a raw material, N-fi exchange reaction is performed, and then deprotection is performed.

Further, under reducing conditions using a reagent having a carbonyl group as a reaction reagent, for example, formic acid, sodium cyanoborohydride, sodium borohydride, or a suitable metal catalyst,
For example, platinum oxide, palladium.

A method of performing so-called reductive alkylation in a hydrogen-enriched atmosphere in the presence of Raney nickel, etc., or a method of reducing an amide of 1-deoxynojirimycin and an aralkylcarboxylic acid or an aralkenylcarboxylic acid to obtain the desired product. can be used. These compounds may be subjected to general purification methods such as recrystallization and column chromatography, if necessary, to obtain the compound of formula (1) of the present invention.

Regarding the formation and introduction of substituents into the compounds of the present invention, they can be synthesized by any suitable method. Formula (1
Regarding the production of aralkyl, aralkenyl, and aralkylating agents for constructing the A-Z group of (t), the following five production methods are shown as suitable methods.

Production method 1 Compound (2) and a vinyl metal compound, such as vinylmagnesium chloride or dinymagnesium bromide.

A compound is prepared by reacting vinylmagnesium iodide, vinyllithium, divinylzinc, divinylcopper, divinylcesium, etc. in a nonpolar solvent, preferably ether, tetrahydrofuran, or dioxane at 0°C to room temperature for 10 minutes to 24 hours. (3) can be synthesized. Compound (3) is mixed with hydrochloric acid, hydrobromic acid, oxalyl chloride, thionyl halide, oquine phosphorus halide, trihalogenated phosphorus, pentahalogenated phosphorus, trisubstituted phosphine-tetrahalogenated carbon, allyl or alkylsulfonyl halide. Solvent or benzene, toluene, ether, methylene chloride,
0℃~100℃, 30 minutes~ in a solvent such as acetonitrile
By reacting for 24 hours, compound (4) can be synthesized while the allyl alcohol moiety of compound (3) is transferred.

(In the formula, Y1 is a hydrogen atom, a halogen atom, an aralkyl group,
Represents a hydroxyl group, and Y2 is a hydrogen atom or a halogen atom.

Aralkyl group 1 represents an alkoxy group, a halogen-substituted alkyl group, and X represents a halogen atom, an alkyl, or an allylsulfonyloxy group. Examples of the halogen atom include chlorine, bromine, iodine, etc., and examples of the alkyl or allylsulfonyloxy group include methanesulfonyloxy and trifluoromethanesulfonyloxy groups.

p-) luenesulfonyloxy group, etc. (Mlt represents a monovalent or divalent metal or a salt thereof, and metals include lithium, sodium, potassium, magnesium, zinc, cesium, and copper) Production method 2 Compound (2) is dissolved in a suitable solvent, preferably benzene, toluene, Ether, tetrahydrofuran.

React with carbalkoxymethylene trisubstituted phosphoranes in dioxane, methylene chloride, chloroform, methanol, ethanol at 0°C to 60°C for IO minutes to 24 hours, or with a suitable base such as sodium hydride, potassium hydride, In the presence of alkali hydroxide and alkali carbonate, dialkylphosphonoacetic acid aralkyl ester is heated from 0°C to 6°C.
The unsaturated ester (5
).

Compound (5) is dissolved in a suitable aprotic solvent, preferably ether, tetrahydrofuran, dioxane, with a suitable hydrogenated ri4 complex reducing agent, preferably lithium aluminum hydride, diisobutylaluminum hydride, bis(2-methoxyethoxy) hydride. Compound (6) can be synthesized by reacting with sodium aluminum at 8°C to 100°C for 30 minutes to 18 hours.

Compound (6) is mixed with hydrochloric acid, monohydrobromic acid, oxalyl chloride, thionyl halide, phosphorus oxyhalide, and phosphorus trihalide.

Phosphorus pentahalide, 3i? l Phosphine - carbon tetrahalide, allyl or alkyl sulfonyl halide and no solvent or benzene, toluene, ether.

θ℃~100 in solvents such as methylene chloride and acetonitrile
Compound (4) can be synthesized by reacting at ℃ for 30 minutes to 24 hours.

(In the formula, Y, Y2 have the same meanings as above, and R represents a protecting group for a carboxyl group such as an alkyl group) Production method 3 Alkenyl alcohol (6) obtained by production method 2
a suitable organic solvent, such as methanol.

Metal catalysts such as palladium on carbon in ethanol, acetic acid, tetrahydrofuran, ethyl acetate, etc.

30 in a hydrogen atmosphere in the presence of platinum, Raney nickel, etc.
The saturated alcohol (7) can be synthesized by reduction of 1 m5 in minutes to 24 hours. Compound (7) was converted into hydrobromic acid, oxalyl chloride, and thionyl halide.

Oxygen/phosphorus halide, phosphorus trihalide, phosphorus pentahalide, 3Wl-substituted phosphine-carbon tetrahalide.

Compound (8) can be synthesized by reacting in a solvent such as 71fluor or alkylsulfonyl halide at θ°C to 100°C for 30 minutes to 24 hours.

(In the formula, Yl, Y7 and Thereafter, alkynyl alcohol (10) can be synthesized by reacting with formalin. Compound (10) is mixed with oxalyl chloride, thionyl halide, phosphorus oxyhalide, phosphorus trihalide, phosphorus pentahalide, trisubstituted phosphine-carbon tetrahalide, allyl or alkylsulfonyl halide, with no solvent or with benzene or toluene.

0 in solvents such as ether, methylene chloride, acetonitrile, etc.
Compound (11) can be synthesized by reacting at 100°C for 30 minutes to 24 hours.

(In the formula, Y, Y, and X have the same meanings as above.) Manufacturing method 5 As a method for manufacturing the terminal halogen-substituted alkylating agent, for example, the ω-halogen-substituted fatty acid (12) is mixed with a suitable fluorinating agent, For example, sulfur tetrafluoride [＾ngew, Chem.

International, Ed., 1,467 (1962
)) by treatment with trifluoromethyl derivatives (
13) can be synthesized.

X-(CH2)n-C00N -X-(C)12)n-
CL (wherein X has the same meaning as above) aralkyl halide produced by the above production methods 1 to 5,
Various aralkyl or aralkenylation reagents represented by aralkenyl halide, aralkyl sulfonic acid ester, aralkenyl sulfonic acid ester, etc. and various alcohols, dimethylformamide, dimethylacetamide,
This compound can be prepared by heating at room temperature or in a polar solvent such as dimethyl sulfoxide 1-sulfolane or a mixed solvent thereof in the presence of an alkali hydroxide, alkali carbonate, alkali bicarbonate, or a deoxidizing agent such as an appropriate organic amine. Invention formula (1
) can be introduced with an N-substituted A-Z group. In addition, 1-deoxynojirimycin whose hydroxyl group is protected with an appropriate protecting group, such as an acetyl group, benzoyl group, tetrahydropyranyl group, t-butyldimethylsilyl group, etc., is used as a raw material, and after N-substitution reaction is performed. , a method of deprotection is also adopted. Among the compounds included in the present invention, those in which formula (1) is a hydrocarbon substituted with a hydroxyl group can be produced according to Production Method 6 shown below.

Production method 6 Alkenylating agent synthesized according to Production method 11 or 2 and 1-deoxynojirimycin or 1 with protected hydroxyl group
- Reacting the N-substituted-1-deoxynojirimycin derivative (14), which can be synthesized by reacting with deoxynojirimycin, with an appropriate oxidizing agent, such as osmium tetroxide, to obtain the target product (16). I can do it.

(In the formula, Y and Y2 have the same meanings as above, and R' is a hydrogen atom, an acetyl group, a benzyl group, a benzoyl group, a pivaloyl M, and a t-butyldimethylsilyl group.

(represents a tetrahydropyranyl group) Next, a production example of the N-[substituted-]-dedeoxynojirimycin derivative of the present invention will be shown.

Production Example 1 N-(3-phenyl-3-trifluoromethyl-2-propenyl)-1-deoxynojirimycin Step 1 3-phenyl-3-trifluoromethyl-2-propene-
1-ol 2.2.2-)lifluoroacetophenone 1.74 g (1
A solution of 0.0 mmol) in tetrahydrofuran lO- is cooled to -78°C, and a 1M vinylmagnesium bromide tetrahydrofuran solution is added dropwise. After the dropwise addition was completed, the mixture was stirred at the same temperature for 3 hours, then the cold bath was removed and the mixture was stirred for 1 hour. After adding water-cooled water to decompose excess reagent, the solvent is distilled off. Add IQml of 2N sulfuric acid to the residue, and extract with ethyl acetate. The extract is washed with water, dried, and then a-condensed. Residue/silica gel column chromatography [elution solvent: ether]
hexane (1:10)] and purified with 1.66 g (8
2%) of an oil was obtained.

NMR (CD C1,) δ 2.61 (s, IH), 5.5.2 (d, 11
), 5.62 (d, 1B).

6.43 (dd, IH), 7.25-7.70 (m,
5H) Step 2 606 mg (3,00 mmol) of 1-bromo-3-phenyl-3-'l fluoromethyl-2-propene-3-phenyl-3-trifluoromethyl-2-7'ropen-1-ol and Phenylphosphine 943 mg (3.60 mmol)
Dissolve in acetonitrile 4rd and cool on ice. To this was added 1.26 g (3.80 mmol) of carbon tetrabromide in several portions. After stirring for 1 hour under water cooling, the mixture was stirred overnight at room temperature. The reaction solution is diluted with ether 10-1, the precipitated solid is filtered, and the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane) to obtain 440 a+g (55%) of an oil.

NMR (CD ff3) δ 3.80 (dq, 2H), 8.62 (tq, 1t
(), 7.20-7.60 (m, 5H) Step 3 N-(3-phenyl-3-trifluoromethyl-2-propenyl)-1-deoxy/nojirimycin Deoxynojirimycin 163 mg (1,00 318 mg (1,20 mmol) of 1-bromo-3-phenyl-3-) IJ fluoromethyl-2-propene are dissolved in 5 rL of dimethylformamide, and 207 mg of potassium carbonate is dissolved.
mg (1,50 mmol)) and stirred at room temperature for 8 hours. Saturated brine was added to the reaction mixture and extracted with n-butanol. The extract was condensed under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: chloroform-methanol (10:l)] to give 311 mg (
90%) of a colorless solid was obtained.

N! 4R (CD, 00) δ 2.15 (m, 2) 1), 3.10 (dd, LH
), 3.16(t, l1l).

3.31 (m, 01), 3.42 (t, IN),
3.53 (L IH).

3.78 (dd, IH), 3.96 (^OX ty
pe, 2t(), 6°? 2(t, IH), 7
．． 32 (m, 2H), 7.46 (m, 3H
) Production Example 2 N-(3-methoxymethyl-3-phenyl-2-flobenyl)-1-deoxynojirimycin 1-bromo-3-methoxymethyl-3-phenyl-2- synthesized in the same manner as Production Example 1 Synthesized using propene.

! IMR (CD, 00) δ 2.13 (0, 2) 1), 3.06 (dd, 18)
, 3.16 (t, 18).

3.34 (m, 18), 3.44 (t, I
H), 3.3Hm, 1)1).

3, 38 (s, 3H), 3.76 (dd, IH
).

3.97 (^BX type, 2H), 4.1
6 (s, 28).

6.06<t, Ift), 7.15~7.50(
m, 51) Production Example 3 N-(3-(4-fluorophenyl)-2-propenyl]
-1-Deoxynojirimycin Step 1 Methyl-3-(4-fluorophenyl)-2-propenoate 4-fluorobenzaldehyde 1.24 g (l[),
0 mmol) was dissolved in 20 m7' of methylene chloride, and 3.
67 g (11.0 mmol) was added and stirred at room temperature for 3 hours. The solid was filtered off, the filtrate was concentrated, and the residue was purified by silica gel column chromatography [elution solvent: ethyl acetate-hexane (1:4)] to obtain colorless needle crystals.
61 g (90%) was obtained.

! i! JI? (Cllll(?lL)δ 4JO(d, 2N), 6.25(m, 1)1),
6.55 (d, IH).

6.95 (m, 2H), 7.35 (m, 2H) Step 2 3-(4-fluorophenyl)-2-propen-1-olmethyl-3-(4-fluorophenyl)-2-7' Robe/
1.61 g (9,00 mmol) of ethyl ether was dissolved in ether 50-2, and 2 liters of lithium aluminum hydride were dissolved under water cooling.
05 a+g (5.40 mmol) in ether 3rn
Add dropwise to the suspension. After the dropwise addition, the mixture was stirred for 30 minutes, excess reagent was decomposed with water, and solids were filtered off. The filtrate was concentrated to obtain 1.33 g (97%) of 3-(4-fluorophenyl)-2-7'loben-1-ol.

NMR (CDα,) δ 4.52 (d, 2H), 6.31 (m, I
H), 7.01(m, 2f().

7.45 (m, 2H) Step 3 1-Bromo-3-(4-fluorophenyl)-2-propene 3-(4-fluorophenyl)-2-nia'loben=1
1.34 g (8.82 mmol) of tri-n-octylphosphine and 4.26 g (11.5 mmol) of tri-n-octylphosphine were dissolved in 20 rnl of ether and 3.52 g (10.6 mmol) of carbon bromide were cooled with water. mol) several times. After stirring at room temperature for 30 minutes, the precipitate was filtered off, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (
Elution solvent: 1.62g (85%) purified with hexane
A colorless oil was obtained.

NMR (CDα,) δ 3.35 (d, 2H), 6.30 (m, 18),
7.00 (m, 2H).

7.40 (m, 2H) Mass m/z 214,216 Step 4 N-(3-(4-fluorophenyl)-2-propenyl)
= 1-deoxynojirimaine 1-bromo-3-(4-
1.61 g (fluorophenyl)-2-broben (7,5
mmol) and 1.22 g of 1-deoquinojirimycin
(7.5 mmol) in 10 m dimethylformamide
1', 3.12 g (22.5 mmol) of potassium carbonate was added thereto, and the mixture was stirred at room temperature for 24 hours. The reaction mixture is poured into water and extracted with n-butanol. After distilling off the solvent, the residue was purified by silica gel column chromatography [elution solvent: chloroform-methanol (10:1)].
1.36 g (61%) of a pale yellow solid was obtained.

! i! JR (CD, 0 units) δ 2.4-4.2 (m, 16B), 6.40 (m,
11(), 6.7(m, LH).

7, 10 (m, 2H), 7.55 (m, 2) 1)
Mass m/z 29g (FD, !J+1) Production Example 4 N-[3-(3-fluorophenyl)-2-propenylcou-1-deoxynojirimycin Synthesized in the same manner as Production Example 3.

N! JR (CD, 00) δ 2.15 (m, 2H), 3.04 (dd, LH)
, 3.14(t, IN>.

3, 2-3.35 (m, IH), 3.39 (t
, LH).

3,49(m, IH), 3.68(dd, IH
).

3.94 (ABX type, 2)1), 6.41
(dt, IH).

6.59 (cl, 1) 1), 6.95 (dt, I
) I), 7.16 (dd, 1) 1).

7.21 (d, IH), 7.31 (ddd, 1B
)Mass m/z 298 (FD, M+
1) Production Example 5 N-C3-(2-fluorophenyl)-2-propenylcou-1-deoxynojirimycin was synthesized in the same manner as in Production Example 3.

N! Jfl(CD, 0[1)δ 2.1~2.25(a+, 2H), 3.06(dd
, IH).

3.14 (t, IH), 3.24-3.35 (m,
IH).

3.39 (t, IH), 3.50 (m, 01),
3.71 (m, 1ll).

3.94 (ABX type, 2H), 6.45 (
dt, 1)1).

6.72(d, 1)l), 7.0-7.16(m,
2)1).

7.2-7.28 (m, IH), 7.53 (dt,
IH) vass m/z (FD, M+1
) Production Example 6 N-[3-(4-biphenyl)propyl]-1-deoxynojirimycin Step 1 1.10 g (6,00 mmol) of methyl-3-(4-biphenyl)acrylate 4-biphenylcarboxaldehyde was added. Dichloroethane20. rd! 3.03 g of carbomethoxymethylenetriphenylphosphorane dissolved in
(9.10 mmol) and stirred at room temperature for 1 hour. After distilling off the solvent, the residue was subjected to silica gel column chromatography [elution solvent: ether-hexane (1:10)]
) to obtain 1.12 g (78%) of colorless crystals.

NH(C['2)δ 3.83 (s, 38), 6.49 (d, IH),
7.30-7.60 (a+, 9H).

7.75(d, IH) Step 2 Methyl-3-(4-biphenyl)propionate Methyl-3-(4-biphenyl)acrylate 1.40
g (4.40 mmol) was dissolved in 50 rnl of dityl acetate, 70 mg of 10% Pd-C was added, and the mixture was exposed to light for 12 hours under normal pressure. After filtering off the catalyst, the solvent was distilled off and 1.01
g (97%) of a colorless oil was obtained.

N! JR (CDcl,) δ 2.68 (t, 2H), 3.00 (t, 2H),
3.68 (s, 3H).

7,20-7.70 (m, 9H) Step 3 3'-(4-biphenyl)-1-proparol Lithium aluminum hydride 110 μm (2,90 mI) under water cooling
J mol) suspended in ether lO-, hemethyl-3-
(4-biphenyl)propionate 1.01g (4,
A solution of 20 mmol) in 35 rnl of ether is added dropwise. After stirring at the same temperature for 1 hour, excess reagent was decomposed with water, inorganic substances were separated by filtration, the filtrate was dried, and concentrated.
mg (96%) of colorless crystals were obtained.

NIJR (COcl*) δ 1.56 (br, IH), 1.94 (+t+, 2
H), 2°77 (m, 2H).

3,71(m, 2H), 7.15-7.76(+n
, 9H) Step 4 3-(4-biphenyl)-1-bromopropane 3-(
4-biphenyl)-1-prop/-ol 419 mg <
2.00 mmol) and triphenylphosphine 629
mg (2,40 mmol) dissolved in 10 d of ether and cooled with water to give 930 mg (2,80 mmol) of convex carbon bromide).
Add several times. After stirring for 1 hour at room temperature, the precipitate was filtered off, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (elution solvent: hexane).
mg" (92%) of a colorless oil was obtained.

NMR(C(]C1,)δ 2.20(quin, 2)1), 2.83(t,
2B), 3.44(t, 2H).

7.23-7.65 (m, 9H) Step 5 N-C3-(4-biphenyl)propyl-1-deoxynojirimycin 3-(44'phenyl)-1-bromopropane 140
mg < (1,50 mmol) and 82 mg (0,5 mmol) of 1-deoxynojirimycin were dissolved in 1 bottle of dimethylformamide, and 136 mg of potassium carbonate (
1,00 mmol) was added thereto and heated at 80°C for 4 hours.

The reaction mixture was poured into water, acidified with hydrochloric acid, washed with ether, the aqueous layer was made ammonia alkali, and extracted with n-butanol. After removing the solvent, the residue was purified by silica gel column chromatography [elution solvent: chloroform-methanol (to:1), 117 IIg (66
%) of solids was obtained.

N! JR (CD, 0 shares) δ 1.86 (m, 28), 2.20 (br, 28)
, 2.65 (m, 3N).

2.89(m, it(n), 3.00(width,
1N), 3.14(t, 1)1).

3.47(m, 1)I), 3.84Cd, 2H)
, 7.15-7.65 (m, 9H) Production Example 7 N-(3-(4-fluorophenylpropyl)]-]t-
Deoxynojirimycin was synthesized in the same manner as in Example 6.

NMR (CD, OD) δ 1.38 (m, 2H), 2.05-2.22 (m,
2) 1), 2.64 (m, 2) 1) 2.98 (d
d, 1)1), 3.13<t, IH), 3.3
0(m, 1tD.

3, 38 (t, IH), 3.45 (m, IH).

3.64 (m, IH), 3.85 (m, 2H),
? , 18-7.35 (m, 4H) Production Example 8 N-(3-cyclohexylpropyl)-1-f''oxidinojirimycin Synthesized in the same manner as in Production Example 6.

N! JR (CLO exit) δ 0.75-1.08 (m, 2H), 1.08-1.
45 (m, 7H).

1, 45~2.00 (m, 6H), 2.70~
3.83 (m, 8H).

4,00 (80X type, 2f() Production example 9 N-(phenyl-2-propynyl)-1-deoxynojirimycin Step 1 1-phenyl-3-bromopropyne 1-phenyl-2-propyn-1-ol 660q (
5,00 mmol) and carbon tetrabromide 4.98 g (15
, 0 mmol) was dissolved in 30 d of tetrahydrofuran,
Triphenylphosphine 2.62g (10,
0 mmol) in several portions. After stirring at room temperature for 10 hours, the solids were filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: hexane) to obtain 181 mg (65%) of a colorless oil.

NMR (CDC1,) δ 1.20 (br, 1)I), 2.2
7(S,'IH), 7.15 ~ 7.40(
L 5H) Step 2 N-(phenyl-2-7'rovinyl)-1-deoxynojirimycin 1-deoxynojirimycin 163 ll1g (1,
00 mmol) and 1-phenyl-3-bromopropyne 2
15■ (1.10 mmol) in dimethylformamide 3
Potassium carbonate 166 mg dissolved in 0.20 ml
mmol) and stirred at room temperature for 8 hours. The reaction mixture was poured into water, acidified with hydrochloric acid, washed with ether, the aqueous layer was made ammonia alkali, and extracted with n-butyl. After distilling off the solvent, the residue was subjected to silica gel column chromatography [elution solvent: chloroform-methanol (10:
1)) to obtain 181 mg (65%) of a solid.

NMR (CD20) δ 2.31 (d, IH), 2.57 (t, IH),
2.98 (dd, IH), 3.19 (t,
IH), 3.50 (t, IH), 3.6
1(m, 1)1).

3.82 (ABX type, 2N), 3.
98 (dcl, 2N) Production Example] 0 N-C(2,3-dihydroxy)-3-phenylpropylcyt-deoxynojirimycin Step 1 N-(3-phenyl-2-propenyl)-1-deoxynojirimycin tetra Acetate cinnamyl bromide 1
．． 42 g (7,20 mmol) and 978 mg (6,0 mmol) of 1-deoxynojirimycin were suspended in 10 ml of dimethylformamide,
Add 96 ll1 g (7.20 mmol) and heat to 60-65° C. for 4 hours. Cold soak, methylene chloride 3-
diluted with 3.06 g (30.0 mmol) of acetic anhydride.
and 2.37 g (30.0 mmol) of pyridine were added and stirred at room temperature for 16 hours. Dilute the reaction solution with 15 dimethyl acetate
0rd! After washing with saturated sodium hydrogen carbonate and water sequentially and drying, the solvent was distilled off. The residue was purified by silica gel column chromatography [elution solvent: hexane-ethyl acetate (3:1)], and 2.12 g (
81%) of crystals were obtained.

! jt4R (CDCl2) δ 2.01 (8,611), 2.03 (s, 3H),
2.09 (s, 3H).

2.38 (dd, IH), 2.70 (dt, IH
), 3.25 (dd, IH).

3.38(dd, 1)1), 3.59(ddd,
1N), 4.19 (dd, LH).

4.32 (dd, LH), 4.90-5.20 (m
, 3H), 6.22 (dt, IN) 6.56 (d
, 18), 7.15-7.50 (m, 5H) Step 2 N-((2,3-dihydroxy)-3-phenylpropyl-1-deoxynojirimycin tetraacetate N-(3-phenyl-2-propenyl )-1 = Deoxynojirimycin tetraacetate 305 mg (0,70
98 mg (0.84 mmol) of N-methylmorpholine-N-oxide and 98 mg (0.84 mmol) of 50% acetone.
-, add 2 mtz of osmium tetroxide, and stir for 2 hours. After adding 250 mg of sodium sulfite and 3 mj of water and stirring for 1 hour, the mixture was diluted with 30 rnl of water, extracted with ethyl acetate, washed with water, dried, and then the solvent was distilled off. The residue was subjected to silica gel column chromatography [elution solvent: hexane-ethyl acetate <1:l)'J FF L, 222
mg (68%) of caramel was obtained. This compound is 2
The mixture of stereoisomers of the species is m (2: l).

NMR (CDCL) δ 2.32 (dd), 2.57 (dd), 2.70 (
ABX type), 2.85 (dd).

2.97 (m), 3.11 (s), 3.12 (dd
), 3.16(s), 3.22(dd).

3, 82 (br), 4.13 (8 BKtype)
, 4.20 (ABX type).

4.48(t), 4.53(mu), 4.86-5.
12(n+).

7.2-7゜4 (+n, 5) 1) Step 3 N-((2,3-dihydroxy)-3-phenylpropyl-1-deoquinnojirimycin N-((2,3-dihydroxy)-3- phenylpropyl]-1-deoxy/silimycin tetraacetate 196 ■(0,42
mmol) is dissolved in methanol 5-, 1 g of potassium carbonate 3II is added, and the mixture is stirred at room temperature for 3 hours. After distilling off the solvent, the residue was subjected to silica gel column chromatography [
Elution solvent: chloroform-methanol (3; 1))
Purification was performed to obtain 128 mg (98%) of colorless caramel. This compound is a mixture of two stereoisomers (2:
1).

N! JR (CD30D) δ 2.05 (dd), 2.17 (dd), 2.23~
2.35 (m), 2.54 (dd).

2.87 (dd), 2.98 (dd), 3.10 (
t), 3.14(t).

3.2-4.0 (m), 4.50 (d), 4.68
(d).

7, 15-7.50 (m, 5) 1).

Next, the evaluation results of the cancer cell metastasis suppressing effect of the N-1i-deoxynojirimycin conductor of the present invention will be shown.

Efficacy Test Test Method Fidler's method (Method in
CancerResearch, 15.339-4
The B16 highly metastatic strain was selected and used based on 39.1978). The metastasis inhibitory effect was evaluated using Kijimasuda (nii j
+ma-5uda) et al. (Proc,.

Natl,, ^cad,, Sci,, U, S, ^,
, 83.1752-1756゜1985; Cance
rRe5earch, 46.858-862.19
86. ). First, a B16 highly metastatic strain was planted in Dulbecco's ME medium (DME medium) supplemented with fetal bovine serum, and N-substituted monoadeoxynojirimycin represented by general formula (1) was added, and 5% CL was added for 2 to 4 days. in the presence of 3
The cells were cultured at 7°C, and the proliferated cells were detached from the culture vessel using a trypsin-EDTA solution. This cell is called Ca-”!J
Live cells were suspended in Dulbecot's balanced salt solution without g- to a density of 1 x 10'' cells per rn1.

0.1rnl of this suspension was injected into the tail vein of the mouse, the cells were transplanted, and the cells were raised for 14 days, after which the lungs were removed through laparotomy.
The number of metastatic nodules of the B16 highly metastatic strain formed on and inside the lungs was counted and compared with a control that was not treated with the drug.

Test Example 1 A cytotoxic BIS highly metastatic strain was cultured at 37°C in the presence of 5% CD in DME medium supplemented with 10% tallow serum, and trypsin-E
Peel it from the culture container with DTA solution and
' Suspended to form cells. 150 of this suspension
μl was added to 50 μm of each test drug or control drug solution and mixed. Thereafter, the cells were cultured for 4 days, and the viability was observed under an inverted microscope to determine cytotoxicity. The results were as shown in Table 1.

Table 1 In the table, + indicates growth and - indicates death.

From the above test results, the compound of the present invention did not exhibit cytotoxicity against the 816 highly metastatic strain.

Test Example 2 Anti-metastatic effect B16 highly metastatic strain was planted in a DME medium supplemented with 1% tallow serum, 30 μg of each test drug was added per rnl, and cultured at 37° C. for 3 days in the presence of 5% CO2.

Cells were detached from the culture container in the same manner as in Test Example 1.

These cells were suspended as living cells in Dulbecot's balanced salt solution that does not contain Ca'' and IJg'' so that 1 IXIQ@cell was obtained, and 0.1 of the cells were suspended in BDF.

The cells were injected into the tail vein of a mouse (8 weeks old, male) and transplanted. After 14 days of rearing and observation, the lungs were removed through laparotomy, and the number of metastatic nodules of the B16 highly metastatic strain formed on and inside the lungs was counted. The results are shown in Table 2.

Table 2 From the above results, the number of metastatic nodules formed in the lungs was significantly reduced by treatment with the compound of the present invention.

The cancer cell metastasis inhibitor of the present invention is an oral or parenteral preparation containing the above-mentioned N-substituted-1-deoxynojirimycin derivative, and is clinically administered intravenously, arterially, cutaneously, subcutaneously, intradermally, rectally, and intramuscularly. Administered via or orally. Also! till
A stronger effect can be expected by direct administration to IN. The dosage varies depending on the dosage form, dosage form, patient's age, weight, and disease symptoms, but is generally 100 to 3000 m/day.
g in one or several doses.

Parenteral preparations include sterile aqueous or non-aqueous solutions or emulsions. Bases for non-aqueous solutions or emulsions include propylene glycol, polyethylene glycol, glycerin, olive oil, corn oil,
Examples include ethyl oleate.

Oral preparations include capsules, tablets, granules, powders, and the like.

Starch, lactose, mannitol, ethylcellulose, sodium carboxydimethylcellulose, etc. are blended into these preparations as excipients, and magnesium stearate or calcium stearate is added as a lubricant. As the binder, gelatin, gum arabic, cellulose ester, polyvinylpyrrolidone, etc. are used.

Next, formulation examples of the present invention will be explained.

〔Example〕

N-(3-(4-fluorophenyl)-2-propenyl]-1-deoxynojirimycin 200 mg Lactose 130 ■Potato starch 70 mg Polyvinylpyrrolidone 10 mg Magnenium stearate 2.5 mg Lactose and potato 11
The mixture was mixed with a 20% ethanol solution of polyvinylpyrrolidone, wetted uniformly, passed through a 1 mm mesh sieve, dried at 45°C, and passed through a 1 mm mesh sieve again. The neck grains thus obtained were mixed with magnesium stearate and formed into tablets.

〔Effect of the invention〕

The present invention is an extremely useful substance that suppresses cancer cell metastasis. The cancer cell metastasis inhibitor containing this substance as an active ingredient is an extremely useful invention that solves cancer cell metastasis, which is the biggest problem that affects the prognosis of cancer treatment patients, as there are currently almost no means to prevent this. .

Claims (1)

[Claims] 1. Formula ▲ Numerical formula, chemical formula, table, etc. ▼ In the formula, A represents a hydrocarbon group having 3 to 5 carbon atoms that may be substituted with a hydroxyl group, a halogenated alkyl group, or an alkoxy group. , this hydrocarbon group may have a double or triple bond, Z represents a phenyl group, a fluoro-substituted phenyl group, a biphenyl group, a cycloalkyl group, or a halogen-substituted alkyl group -1-deoxynojirimycin derivative. 2. Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the formula, A represents a hydrocarbon group having 3 to 5 carbon atoms that may be substituted with a hydroxyl group, a halogenated alkyl group, or an alkoxy group, and this hydrocarbon group is N-substituted-1-deoxynojirimycin derivatives, which may have a double or triple bond, and Z represents a phenyl group, a fluoro-substituted phenyl group, a biphenyl group, a cycloalkyl group, or a halogen-substituted alkyl group or an addition salt thereof with a pharmacologically acceptable acid as an active ingredient.