JPS6183125A - Inhibitor against cancer metastasis - Google Patents

Abstract

PURPOSE:An inhibitor against cancer metastasis containing a specific N- acetylneuraminic acid derivative as an active ingredient. CONSTITUTION:An inhibitor against cancer metastasis in various forms, containing a compound shown by the formula as an active ingredient. Especially, when it and a stabilizer are processed into a lyophilized agent, and used as an injection, it shows effectively immediate effects. The compound shown by the formula is made into particles with about several mu, pharmaceutically manufactured, and preferably used as an agent for inhalation. A dose is 10-1,000 mg/person/day in the case of intravenous injection, and 12-140 mg/person/day in the case of inhalation. EFFECT:The compound shown by the formula has an action to inhibit action of sialyltransferase existing on the surface of cancerous cell to change properties of the surface of cancerous cell, has low side effects even if it is used for a long period, and it has low toxicity.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention relates to a cancer metastasis inhibitor that significantly inhibits the formation of metastasis of cancer cells, and more specifically, the present invention relates to a cancer metastasis inhibitor that significantly inhibits the formation of metastases of cancer cells. The present invention relates to a cancer metastasis inhibitor containing a specific N-acetylneuraminic acid salt conductor that has the effect of changing the surface properties of cancer cells.

[Conventional technology]

Cancer treatments have made rapid progress in recent years.

In particular, surgery or radiotherapy has greatly improved the success rate for removing primary cancers. However, even if the primary cancer is completely removed, cancer metastasis often leads to death, and there is increasing recognition that prevention of metastasis is an important problem to be overcome in cancer treatment. However, surgery and radiation therapy have limitations in their methods and cannot effectively prevent cancer metastasis.
Chemotherapy using anticancer drugs has a direct effect on cancer cells, but it often has harmful side effects on the host's normal cells, so it cannot necessarily be said to be effective against cancer metastasis. situation.

Furthermore, immunotherapy, which aims to treat cancer by increasing the immune capacity of the host, has not been found to be effective against cancer metastasis.

On the other hand, it has been found that the metastatic ability of cancer cells is closely related to the sugar chain structure on the membrane surface, and in particular, in some cancer cells, the content of sialic acid, which occupies the non-reducing end of the sugar chain, on the membrane surface and the metastatic ability are closely related. Although it has recently been shown that there is a positive correlation between the two, an effective cancer metastasis inhibitor has not yet been found.

[Problem that the invention seeks to solve]

Therefore, the present invention provides a low-toxic cancer metastasis inhibitor that can effectively inhibit cancer metastasis and has few side effects even when used for a long period of time.

[Means for solving problems]

The present invention describes the inhibitory effect of sialic acid derivatives (also referred to as N-acetylneuraminic acid derivatives) that exhibit sialyltransferase inhibitory activity on a metastasis experimental system using a highly metastatic cell line derived from mouse colon cancer cell line 26. This is based on the knowledge that certain sialic acid derivatives have an excellent effect on inhibiting cancer metastasis.

The present invention provides a cancer metastasis inhibitor characterized by containing a compound represented by:

Among the compounds represented by the formula (ri), there are compounds in which the carboxymethyl group at the C-/position and the nucleoside group have different configurations. In other words, those at the α-position and those at the β-position, but usually A mixture of these, the mixing ratio is l:l
It is. Although these depend on the manufacturing method, manufacturing conditions, etc., they have the same physiological activity.

The cancer metastasis inhibitor of the present invention contains the compound of formula (1) as a main component and is used in various forms. In particular, if the drug is made into a lyophilized preparation along with a stabilizer and used as an intravenous injection, the effect will appear quickly and be effective.

It is also preferred to formulate the compound of formula (I) into particles of several microns and use the compound as an inhalation agent. In this case, there are capsule and vial filling methods. In the case of capsules, it is administered using Obi, -, Ra (manufactured by Faisons, UK), and in the case of vials, it is dissolved before use and administered using an inhaler. The appropriate dosage for the compound of formula (1) is 10 to iooomy per day for an adult when administered intravenously, and 12 to 40 m9 per day for an adult when inhaled, but the dose may vary depending on the symptoms. It is possible.

〔Effect of the invention〕

The cancer metastasis inhibitor of the present invention has low toxicity and excellent cancer metastasis inhibiting effect, so that effective cancer treatment can be achieved.

Next, the present invention will be explained with reference to Examples, but the present invention is not limited thereto.

〔Example〕

The method for synthesizing the compound of formula (1) used in the Examples and its anastomological properties are shown below.

It is a compound of formula (1)! -70 low! , 3'-isopropylidene-, S'-0-(#-N-acetyl-2.
'! -dideoxy-3,l,,7. g-tetra-O-acetyl-l-methoxycal? Nilu O-Glycero-〇-
is lactooctapyranosyl) uridine synthesis method S-fluoro-2',3'-isoglopyridene uridine!
r00my, mercuric cyanide 300mg, mercuric bromide 1h00my, and Molecular Sheep (!A) 7g were added and suspended in 50μ of acetonitrile, and the mixture was stirred at room temperature for 30 minutes. Add methyl-nichlorhoda to this suspension;7. g,
Add 2 g of q-tetra-〇-acetyl-β-D-N-acetylneuraminate (hereinafter referred to as compound A),
The chamber was stirred for /A hour. Furthermore, compound A Ge S /
011 g, mercuric cyanide/3Qx (J and 300 mg of mercuric bromide) were added and stirred for 2 hours. , water 10
0 mt was added to remove insoluble materials, and further ether soluble materials were removed. Next, this water bath solution was saturated with potassium chloride, extracted with ethyl acetate, dried using Glauber's salt, and then the solvent was distilled off to obtain the target compound i, sy. The coarse powder O
, Dahiro fI was dissolved in methanol 1 orst, and silica.
building/. After adding 5I, the solvent was distilled off.

This '2p+g wet column chromatography (silica del:
Ether/methanol C20: /
) The desired compound was obtained with high purity by fractionation. Furthermore, after freeze-drying, vacuum drying is performed to obtain a compound of formula (1) with 0.
2711 was obtained as colorless amorphous crystals.

Physical properties of the compound of formula (1) The physical properties of the compound of formula (1) synthesized by the above method were measured, and the following data were obtained.

Elemental analysis C32H42018N3' Calculated value C-da9. S! ;H bite S, mite Nfall S,
Hiro S actual measurement value C-da 9.31IH-3,65N-5,2
Dual mass spectrometry n1/z 775 (M”) IR SiWF: rxn8, Il=gOS/!r, 3 (km
'H-NMR (CDC4,)δ, (TMS)/, 37
(s, 3H> /, j6(s, 3H) /, g7(
SN J H)/-99<ss AH) 2-02
(sxJH)-2-/j ('% JH) J-
77 (ss JH) Example 1 Using the compound of formula CI), the cancer metastasis inhibiting effect was measured.

Animals: 5PFBALB/c fibrotic mice (g weeks old) Cancer cells: NL-17% Method: NL-/ri cells j The animals are administered intravenously according to the group. 2λ days after cancer cell metastasis, the animals are dissected and the number of metastatic nodules formed in the lungs is calculated.

Experimental group: ■ = saline administration n: NL-/'7 + saline 11: NL-/? (Pretreatment compound I) Ten compounds'vIJI
(0,Say/fish/3 days*)11/:NL-/?
10 compounds 1<0. ! ;'Q/animal/3 mice) v: N Li 7+ Compound I (/, Omp/animal/every 3 days) lA: FIL-/7+ Compound ICO,! rmq/mouse/consecutive days) ￥, 1: NL-/ri+compound m1 (0,,5ri+y/mouse/7 consecutive days only) 0 Results and results are summarized in Table 1, but ll(NL-/?- t
-/f diet) group, inhibition of TG, A~tg using the cancer metastasis inhibitor of the present invention was observed.After 7 hours, continuous administration was performed for 7 days, and then no administration was performed. 'v1 detail was particularly effective. In addition, when comparing the ■group and V-detail, concentration dependence was observed.

Table I Examples Acute toxicity tests on the compound of formula (1) were conducted using female and male mice by oral and intravenous administration.

O Experimental conditions Test animals: Oral DDY mouse, 6 weeks old, male, Intravenous injection, ICR mouse, 6 week old female Drug concentration: 73~/S (ψI/■) Dissolved in distilled water W? 1 level M number of 10 cherry blossom viewing periods/4 days O results As shown in Table 2, it can be seen that the compound of formula (1) has extremely low toxicity.

Table-2

Claims (3)

[Claims] (1) Formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼... A cancer metastasis inhibitor characterized by containing a compound represented by (I). (2) The cancer metastasis inhibitor according to claim (1), wherein the cancer metastasis inhibitor is in the form of intravenous injection. (3) The cancer metastasis inhibitor according to claim (1), wherein the cancer metastasis inhibitor is in an inhaled form.