JPS5931797A - Novel 1-substituted imidazole nucleoside and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R is beta-D-glucopyranosyl, beta-D- galactopyranosyl, 2-acetamido-2-deoxy-beta-D-glucopyranosyl, alpha-L-rhamnopyranosyl, beta-D-ribopyranosyl, beta-D-arabinofuranosyl, etc.). EXAMPLE:4- Carbamoyl-1-( 2,3,4,6- tetra-O- acetyl-beta-D- galactopyranosyl)-imidazolium- 5-olate (I:R=2,3,4,6-tetra-O-acetyl-beta-D-galactopyranosyl). USE:Immunosuppressive agent and antitumor agent. PROCESS:The 4-carbamoylimidazolium-5-olate of formula II or its trimethylsilyl derivative is made to react with the glycose derivative of formula R'-Z (R' is beta-D-glucopyranosyl, beta-D-mannopyranosyl, etc.; Z is halogen, lower alkoxy, etc.) in the presence of stannic chloride and a condensation agent to obtain the compound of formula III, which is if necessary deacylated under basic condition.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new and useful imidazole compound and a method for producing the same.

More specifically, the present invention is based on the general formula (1) (wherein R is a β-D-glucopyranosyl group, a β-D-galactopyranosyl group, a β-D-mannopyranosyl group, -monoacetamide, Z-deoxy -β-D-glucopyranosyl group,
α-L-rhamnopyranosyl group, β-D-fucopi(Hiroshi)-substituted toluoyl, methoxybenzoyl, etc. Furanosyl group, β-D-arabinofuranosyl group, j-deoxy-
β-D-ribofuranosyl groups or 7t have all hydroxyl groups of their respective groups protected with the same acyl group) A
The present invention relates to novel /-substituted imidazole nucleoside derivatives represented by the following formulas and methods for producing them.

In the general formula (I), the acyl group means a lower alkanoyl group, substituted or unsubstituted benzoyl group, and the lower alkano group means a linear or branched carbon number,
Examples of substituted benzoyl groups include lower alkyl of cl-4 or lower alkyl of 1101-4. The imidazole derivative of the general formula (1) of the present invention is an alkoxy-substituted benzoyl group, and more specifically, the imidazole derivative of the general formula (1) of the present invention is a natural imidazole nucleoside having an immunosuppressive effect.
) is a structural isomer of brezinin and its analogs, which are new compounds that have not been described in any literature.They have both immunosuppressive action and excellent antitumor action, and are useful compounds as anticancer agents and immunosuppressants.

The compound represented by the formula (Ill) below, which is the core of the compound of the present invention, was found to have excellent anticancer activity (JP-A-Sho!
;J-,? J/Koda Publication), the solubility in water is not necessarily satisfactory, and compounds with even higher water solubility are desired for practical purposes. In addition, it is known that the compound (IID has multiple reaction sites and gives a complex reaction product [J, 0fHeterocyalic (!h
emistry / 7, /L2j (/RizaO)]
position! □ Development of a selective reaction was desired. We (Ill)
As a result of various studies on the reaction between sugar and sugar, an excellent regioselective reaction was discovered, and the compound (1) of the present invention was found to have an excellent anticancer effect and is an anticancer agent with high solubility in water.The present invention I was able to complete it.

The compound represented by the general formula (I) of the present invention can be synthesized easily and in good yield by the following method.

That is, gucarbamoylimidazolium-3-oleate (m)t or its trimethylsilyl derivative is prepared by the general formula (IV) R'-ZQV) in the presence of stannic chloride and a condensing agent. Substituents, namely β-D-glucopyranosyl group, β-D-mannopyranosyl group, coacetamidocodeoxy-β-D-glucopyranosyl group, α-L-rhamnopyranosyl group, β-D-fucopyranosyl group, β-D-ribopyranosyl group All hydroxyl groups of each of the groups, β-D-xylopyranosyl group, β-D-xylofuranosyl group, β-D-arabinofuranosyl group, and S-deoxy-β-D-ribofuranosyl group are the same acyl group. The protected group is reacted with a sugar derivative represented by the general formula (V) (in which 2 represents a halogen atom, a lower alkoxy group, or a lower alkanoyloxy group).
(R' is the same as above) A compound represented by the following formula is obtained.

In the general formula (transformation), the zvi-constituting halogen atom refers to chlorine, all bromine, and the lower alkoxy group refers to a linear or branched alkoxy group having a carbon number of 1 to 1, and the lower alkanoyloxy group refers to a linear or branched alkoxy group having a carbon number of Shows a branched (7) furukayl group having a carbon number of 0 to 7.

In general formula (V), the acyl group means a lower alkanoyl group, a substituted or unsubstituted benzoyl group, and a lower alkanoyl group means a linear or branched carbon number, 2
-7 fulcaryl groups, such as acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptazyl, etc. Substituted benzoyl groups include, for example, C1-4 lower alkyl or 1dox-4 lower alkoxy It is a substituted benzoyl group, and more specifically includes Ho, m, and p-substituted toluoyl, methoxybenzoyl, and the like.

Gucarbamoylimidazolium represented by the formula @)!
-Trimethylsilyl derivatives of oleate are already known, for example in JP-A-Sho, ! t O-7,2/core according to the description in the publication, glucarbamoylimidazolium-5-
It can be easily obtained by reacting oleate (V) with a silylating agent (for example, hexamethyldisilazane). By using stannic chloride in the cotton (r) synthesis reaction, the regioselectivity of glycosylation is improved, and the N-7 position is preferentially glycosylated to obtain N-/nucleoside in good yield. At this time, it is presumed that a reactive derivative having a molar ratio of the trimethylsilyl derivative of gucarbamoylimidazolium-5-oleate and stannic chloride of 14/:/ is formed as represented by the formula (Ill). If stannic chloride is not used, the main product of the reaction will be UN-3 nucleoside, and other N-/, N-3 disubstituted products will be produced, and in this case, N-
/ Nucleosides are produced in very small quantities.

Examples of the condensing agent used in the present invention include zinc chloride, titanium tetrachloride, boron trifluoride, aluminum chloride,
Examples include p-toluenesulfonic acid, trichloroacetic acid, trifluoroacetic acid, di(p-nitrophenyl)phosphoric acid, silver trifluoromethanesulfonate, trimethylsilyl triple olomethanesulfonate, trimethylsilyl nonafluorononane sulfonate, trimethylsilyl verchlorate, etc. Preferred is trimethylsilyltrifluoromethanesulfonate. The amount of the condensing agent to be used in trimethylsilyltrifluoromethanesulfonate may range from a catalytic amount to about an equimolar amount to (■).

Trimethylsilyl derivative of gucarbamoylimidazolium-8-oleate represented by formula (■) and general formula QV
), the amount of both to be used is that of sugar'! It is best to use twice the amount of f-o, s~, and the amount of stannic chloride used is approximately equivalent mole (0, i
-8 to 8 times the mole) is preferable, and even if it is more or less, the yield of the N-/isomer decreases. If it is less than 0, tr times the mole, the N-3 and N-7,3 isomers increase. Further, the use of an excessive amount of stannic chloride is undesirable as it significantly impairs the filterability of the target product during post-treatment.

Examples of the solvent used in the above condensation reaction include hydrocarbon solvents such as benzene, toluene, and xylene, polar solvents such as acetonitrile and nitromethane, and haloalkane solvents such as methylene chloride, chloroform, carbon tetrachloride, and dichloroethane. , preferably using dichloroethane. The reaction temperature may range from -7°C to the boiling point of the solvent, but preferably from room temperature to reflux, and under these conditions the reaction is completed within 7 to 3 hours. The acyl derivative (V) thus obtained can be easily purified using conventional techniques. For example, the reaction solution is neutralized, concentrated under reduced pressure, extracted with a solvent in which the desired acyl derivative can be dissolved, and concentrated to obtain a Japanese product. To further purify this, normal-phase or reverse-phase column chromatography can be used, and a highly pure target product can be obtained. Further, this acyl derivative can be easily deacylated to lead to an unoccupied nucleoside in the compound represented by the general formula [I]. Moreover, the above-mentioned extract may be used as it is as the acyl compound used at this time. Conventional methods can be used for deacylation conditions. Namely, amitrilysis using ammonia, -grade amines, hydrazine, hydroxylamine, etc., alcoholysis using alkali metal alcoholades, and aqueous solutions! Examples include hydrolysis using a medium alkali.
arcinoma, Sarcoma /10,
Lewis lung cancer, Colon, 2A and 3g, P3
Examples of the compounds of the present invention that have a strong tumor cell proliferation inhibiting effect on Zato and '[, /, 210, etc.] include the following compounds.

Gucarbamoyl-1-(,z,3,4t,a-tetra-0-acetyl-β-D-galactopyranosyl)imidazolium-j-oite l-carbamoyl-/-β-
D-glucopyranosylimidazolium-3-oleto-rubamoyl/-(,2,,?,s-tree0
-acetyl-β-D-ribopyranosyl)imidazolium-5-oleate -carbamoyl-/-(,2,,?,j-1'ly〇-benzoyl-β-D-xylofuranosyl)imidazolium-5-oleate Carbamoyl-/-(2,y,4t-tree〇-7
cetyl-α-L-rhamnopyranosyl)imidazolium-
J-oleito-rubamoyl-/-β-D-ribopyranosylimidazolium-J-oite-l-carbamoyl-/-β-D-xylofuranosylimidazolium-3-oleito-rubamoyl-/-β-D- Galactopyranosylimidazolium-5-ositoyl-rubamoyl/-α
-L-rhamnopyranosylimidazolium-5-oleto-rubamoyl/-(, z, 3.4t, g-tetra-0-7cetyl-β-D-mannopyranosyl)imidazolium-5-oleate q-carbamoyl- /-(,2-acetamido-deoxy-3,4t,t-tree〇-7cetyl-β-D-
glucopyranosyl) imidazolium-j-oletocucarbamoyl-/-(, z, y, g-tri〇-acetyl-β-D-fucopyranosyl) imidazolium-8
-Oletogluvamoyl-/-(x,3.y,-tri〇-acetyl-β-D-xylopyranosyl)imidazolium-
8-Oleitogucarbamoyl-t-(,2,3,s-tri〇-acetyl-β-D-arabinofuranosyl)imidazolium-5-oleitogucarbamoyl-/-(2,,?-G〇 -7 cetyl-β-D-ribofuranosyl)imidazolium-j-oleitol-rubamoyl/-β-D-mannopyranosylimidazolium-J-oleitol-rubamoyl/-(,2-7cetamide λ-deoxy-β- D-glucopyranosyl)imidazolium-
δ-oleito-rubamoyl-/-β-D-furopyranosylimidazolium-5-oleito-rubamoyl-/-β-D-xylopyranosylimidazolium-8-oleito-rubamoyl/-β-D -Arabinofuranosyl imidazolium-5-oleto-rubamoyl/-β
-D-Ribofuranosylimidazolium-5-oleate The compound of the present invention has the following tautomers, and the present invention includes both isomers.

The compounds of the invention can be mixed with suitable auxiliaries and compressed into solid dosage unit forms, such as rounds, tablets or coated tablets, or they can be filled into capsules. Injectables may also be prepared in the form of suspensions, solutions, emulsions in oily or aqueous vehicles, with added preservatives and suitable solubility aids. A typical tablet, capsule or injection contains the entire active ingredient in a mixture with a suitable carrier or diluent. ; Contains 0-sooq.

Next, the present invention will be explained in more detail with reference to Examples, but these are only a part of the present invention and the present invention is not limited to these in any way.・Example/Gucarbamoyl-/-(J,,?.

da2g-tetra0-7 cetyl-β-D-galactopyranosyl) imidazolium-5-convex oleate (English: R-approved, 8. Da2g-tetra0-7cetyl-β-D-galactopyranosyl) Gucarbamoylimidazolium-yo-oite 2J4
After refluxing the mixture consisting of 12" dry anhydrous ammonium sulfate for 2 hours, the solvent and excess hexamethyldisilazane were distilled off under reduced pressure, and l-carbamoylimidazo A trimethylsilyl compound of lium-yo-oleate was obtained.The silyl compound was then made into a dry dichloromethane 9',t(!;Od!.) solution.Next, the trimethylsilyl compound was dissolved in cetyl-D-galactopyranose 7 at room temperature.
l07g.

stannic chloride a. //d, trimethylsilyltrifluoromethanesulfonate 0. , 3tt di was added, and the mixture was stirred under reflux for 2 hours.

After cooling the reaction mixture to room temperature, methanol 200% to 117%
The mixture was poured into a mixture of heavy soybean aog and stirred for 7 hours.

After filtration through Celite, concentrate under reduced pressure over liquid F to obtain a slag-like substance.
J. 2g was obtained. This residue was purified by reverse phase silica gel column chromatography to obtain A. 10.2 g of glucarbamoyl-/-(co,3.

g,t-tetler 〇-7 cetyl-β-D-galactopyranosyl) imidazolium-yo-oleate was obtained.

Melting point /. ? □ C- 19'C (Recrystallization solvent) (Ethanol-containing acid-isobrobyl ether) Elemental analysis result 0 (@H part) N (A) Calculated value Q4. , </j. J. 2 L3/.

01 6H23N3 01 1 ・3/40H3 00
Actual measured value as 2H. 3 Jo.
21 B. ? 7 UV spectrum example = p-carbamoyl-/-β-D-glucopyranosylimidazolium-5-oleate (R-β-D-glucopyranosyl) glucarbamoyl-/-(co,, 3.II, , A-tetra-0-7 cetyl-β-D-glucopyranosyl) imidazolium-yo-oleate (37.2 g) was dissolved in 0 ml of dry methanol, and a methanol solution of 2zatisodium methoxide was prepared at room temperature. , 4<7 g was added thereto, and the mixture was stirred at the same temperature for an hour.

Dovrex j OX 'I after vacuum concentration below room temperature
(manufactured by Dow Chemical Company) (H10 type, /goal)
After the flaxicon containing the target product was concentrated under reduced pressure, methanol was added to crystallize it to obtain 7.3 ♂ of dark carbamoyl/-β-D-glucopyranosylimidazolium-5-oleate gold. O Melting point Details, r'c (foam decomposition) Example 3 The following compound was obtained in the same manner as in Example/and.

Gucarbamoyl-/-(,2,39,Tardley0-
7cetyl-β-D-ribopyranosyl)imidazolium-
5-oleite melting point, 2o7cc foam decomposition) Gucarbamoyl-/-(J, ,?, ,s-
Tri〇-benzoyl-β-D-xylofuranosyl) imidazolium-5-oleate Melting point /O~/70'c Gucarbamoyl-/-(,2,3,'Coutrie0-
Fusety-L-rhamnopyranosyl) imidazolium-8-oleate melting point /3♂C (foam decomposition) Gucarbamoyl-/-β-D-ribopyranosylimidazolium-5-oleate melting point, 2sgC (foam decomposition) Gucarbamoyl/-β-D-xylofuranosylimidazolium-3-oleate Melting point x, v, sc (foam decomposition) Dacarbamoyl/-β-D-galactopyranosylimidazolium-5-oleate □ Melting C to point /♂ (
Foam decomposition) Gucarbamoyl-/-α-L-rhamnopyranosylimidazolium-5-oleate Melting point 2.2oCC Foam decomposition) 1 Indication of the incident 1982 Patent Application No. /41371,2 2, Invention Name victory/-Substituted imidazole nucleoside and its manufacturing method 3, relationship with the amended person's case Patent applicant address 5-15 Kitahama, Higashi-ku, Osaka Name (20
9) Hijikata, Representative of Sumitomo Chemical Industries, Ltd.
Take 4, agent address: 5-15 Kitahama, Higashi-ku, Osaka City, Column 2 of the [detailed description of the invention between stations] section of the statement. Contents of amendment (1) The specification will be amended as follows.

(-2 complete) 1231-

Claims (2)

[Claims] (1) General formula (wherein R is β-D-glucopyranosyl group, β-D-galactopyranosyl group, β-D-mannopyranosyl group, coacetamidocodeoxy-β-D-glucopyranosyl group, α-L -rhamnopyranosyl group, β-D-fucopyranosyl group, β-D-ribopyranosyl group, β-D-xylopyranosyl group, β-D-xylofuranosyl group, β-D
- represents an arabinofuranosyl group, an S-deoxy-β-D-ribofuranosyl group, or a group protected with each of them. ) /-substituted imidazole nucleoside (2) Gucarbamoylimidazolium-5-oleate or its trimethylsilyl derivative represented by the formula (wherein R' is the following substituent, namely β-D-glucopyranosyl group, β-D-mannopyranosyl group, Acetamido-2-deoxy-β-D-glucopyranosyl group, α-L-rhamnopyranosyl group, β-D-7cobyranosyl group, β-D-ribopyranosyl group, β-D-xylopyranosyl group, β-D-xylofuranosyl group, β -D-arabinofuranosyl group or sugar derivative represented by (1! All alkanoyloxy groups of each group of r-deoxy-β-D-ribofuranosyl group), all stannic chloride, and a condensing agent to obtain a compound represented by the general formula (wherein R' is the same as above) and, if necessary, deacylated under basic conditions. -D-
glucopyranosyl group, β-D-galactopyranosyl group,
β-D-mannopyranosyl group, coacetamido-deoxy-β-D-gullopyranosyl group, α-L-rhamnopyranosyl group, β-D(3) ranosyl group, -β-D-ribopyranosyl group, β-7copyranosyl group, β -D-ribopyranosyl group, β-D-xylopyranosyl group, β-D-xylofuranosyl group, β-D
-75 pinofuranosyl group, 5-deoxy-β-D to ribofuranosyl group, fc represents a group in which all hydroxyl groups of each of these groups are protected with the same acyl group) law