JPS60193968A - Imidazoleamidoxime having cyclopentene ring and its preparation - Google Patents

Abstract

NEW MATERIAL:The imidazoleamidoxime having cyclopentene ring and represented by the formula I (R1 and R2 are H or OH-protecting group; R3 is H or OH-protecting group) or its salt. EXAMPLE:5-Amino-1-( 2',3'-dihydroxy-4'-hydroxymethyl-4'-cyclopenten-1'-yl)-imidazole-4-car boxamidoxime. USE:It has the activity to inhibit the proliferation of L-5178Y cell, and is useful as a carcinostatic agent. The compound can be recyclized to neplanocin A by the reaction with ethyl orthoformate, etc., and is useful also as a synthetic raw material of <14>C-labeled compound, or a raw material for inducing to a cyclopentene nucleoside having a 2-substituted purine ring or a base other than purine. PREPARATION:The compound of formula I can be prepared by converting the compound of formula II to an N-oxide, and treating the resultant compound of formula III with an alkali.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel imidazole amidoxime compound having a cyclopentene ring and a method for producing the same.

More specifically, the present invention is a compound represented by the formula (wherein R1 and R2 represent a hydrogen atom or a hydroxyl group-protecting group, and R3 represents a hydrogen atom or a hydroxyl group-protecting group) or a salt thereof. Further, the present invention provides a compound represented by the formula (having the formula) which is N-oxidized to obtain a compound represented by the formula (wherein R1, R2 and R3 have the same meanings as above), and then the compound [ This is a method for producing compound [8] or a salt thereof, which comprises treating compound [2] with an alkali.

As a nucleic acid-related substance having a cyclopentene ring, Ampulliella regularis (Ampull-arie)
lla regularis) A//07 produced by Neplanocin
) A, neplanocin B and neplanocin F are known, and in particular neplanocin A has an inhibitory effect on the growth of plant pathogenic mycelia and L! ;/'7gIt not only has a cell growth inhibitory effect on Y cells, but also has a cell growth inhibitory effect on L/210 cells, and is a useful substance as an anticancer agent [Current Chemotherapy a
ndInfectious Disease, / 53
g ~ / S Otsu / page, /rigo year, The America
n 5ociety for Microbiology
issue], the above formula [1') 17) R1, R2 and R
It is an adenine derivative with a chemical structure in which 3 is a hydrogen atom and has a cyclopentene ring in its sugar moiety, and its chemical structure and physiological activity are of interest.

As a result of continuing various studies on physiologically active neplanocin A derivatives, the present inventor discovered that S-amino-/-(!'
,,? '-dihydroxy-t'-hydroxymethyl-l
'-Cyclopentene-/'-yl)-imidazole-j
-We have completed the present invention by discovering that carboxamite oxime has a proliferation inhibiting effect on L3/7gY cells.

The starting material [1] used in the present invention includes nederanosin A or its 2'-position, 3'-position and/or 57-position.
Examples include derivatives in which the hydroxyl group at position is protected with an appropriate protecting group.

As the above-mentioned hydroxyl group-protecting group, known hydroxyl-protecting groups used in the fields of nucleic acid chemistry or sugar chemistry are used. Examples of protecting groups for the hydroxyl groups at the 27- and 3'-positions include acyl groups such as formi, acetyl, methoxyacetyl, benzy, and p-chlorobenzyloxyacetyl;

Examples include benzyl, α-ethoxyethyl p1α-methoxyisopropyl, tetrahydropiraniμ, methoxytetrahydropyranyl, 0-nitrobenzyl, 9-butyldiphenylsiliμ and the like. Furthermore, the hydroxyl groups at the 2' and 3' positions are protected in such a way that they form a cyclic acetal together with the adjacent oxygen atom.

Such protecting groups include isopropylidene, methoxymethylene, methoxyethylidene, ethoxymethyhine,
Examples include ethoxyethylidene, benzylidene, and cycloalkylidene groups. Examples of the protecting group for the hydroxyl group at position 51 include formyl, ace4-)L/, chloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, piparoyl, benzoyl, β-benzoylpropionylphenoxyacetyl, trityloxyacetyph, etc. Examples include acyl groups, trityl groups such as trityl, monomethoxytrityl, dimethoxytrityl, and trimethoxytrityl, and methoxymethyl groups.

The above-mentioned protecting group can be introduced using known methods, but it is important to select a protecting group that can be efficiently removed later and that can be removed in one step. is preferred.

The above starting material [1] is N-oxidized to obtain the N-oxide compound [2], and this N-oxidation is carried out by oxidizing with a suitable oxidizing agent. Examples of the oxidizing agent include organic peracids such as metachloroperbenzoic acid and peracetic acid, and hydrogen peroxide. The above oxidation reaction is usually carried out in a suitable reaction solvent. As a reaction solvent,
Examples include inert organic solvents such as acetic acid, acetone, and dioxane, which may contain water. The reaction usually proceeds satisfactorily at room temperature.

To obtain N-oxide [2] from the reaction solution, the reaction solvent can be distilled off, and the product can be purified by column chromatography or the like using a carrier such as silica gel.

Next, the N-oxide form [2] is treated with an alkali to obtain the desired amidoxime form [3]. The alkali mentioned above is usually an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide. Aqueous solutions are used. The above treatment reactions are usually carried out under heating. The progress of the reaction can be confirmed by thin layer chromatography (TLC) using silica gel, high performance liquid chromatography (HPLC), etc., so it can be confirmed that the N-oxide [2] disappears or the amidoxime [8] is produced at maximum. The reaction can be terminated as appropriate by waiting for this to occur. The amidoxime [3] produced from the reaction solution can be collected by passing the reaction solution through a cation exchange resin, concentrating the resulting eluate under reduced pressure, and crystallizing it with a solvent.

The amidoxime compound [3] thus obtained is R
When 1, RQ and/or Ra are hydroxyl-protecting groups, the protecting group can optionally be removed by a known removal method used in nucleic acid chemistry.

The above-mentioned amidoxime compound [8] may form an acid addition salt with a suitable acid as the case requires. Examples include salts with inorganic acids such as sulfuric acid, hydrochloric acid, and phosphoric acid, and salts with organic acids such as acetic acid, propionic acid, malic acid, tartaric acid, citric acid, various amino acids, and various nurphonic acids.

The above-mentioned amidoxime [8] not only has a growth-inhibitory effect on L-S/7ZY cells and is useful as an anticancer agent, but also forms the N-oxide [2] by reaction with ethyl orthoformate. and then reduce the hydrogen sulfide to give 2
When the hydroxyl groups at the ′, 3′, and/or 51st positions are protected with a protecting group, the ring can be reclosed to neplanocin A by removing the protecting group, so a C-labeled compound is synthesized. It is also an important raw material for Furthermore, cyclopentene nucleosides having a purine ring having one substituent at the 2-position or a base other than purine, t. = g It can also be a useful raw material for guiding.

L of the next target compound [8]! ;/7gThe growth inhibiting effect on Y cells will be described.

■Test method Approximately 3 floating culture L3/7gY cells derived from mouse lymphoma
3 ml of test sample Q dissolved in Fisher's medium supplemented with 70% bovine serum is added to 2.7 n+ cell fluid of ×IO'/rd, and cultured at 37°C for 22 hours. The degree of proliferation is observed by the change in color of phenol red added to the medium, and the concentration of the drug that clearly suppresses proliferation compared to the control is calculated as the minimum inhibition of cell proliferation + degree of Ha.

■Test results (minimum inhibitory concentration r/ml) S-amino-/=(2',3'-dihydroxyg'-
Hydroxymethyl-p/-cyclopentene-/'-i/
1/)-imidazole-l-carboxamite oxime 17ml Next, the production examples of the present invention will be specifically explained with reference to Examples.

Examples / Neplanocin A-/- Oxide Neplanocin A2. A3t and m-chloroperbenzoic acid 2.11? was dissolved in a mixture of Qml of water and 200 Tnl of dioxane and stirred at room temperature in the dark for 2 days. The reaction solution was concentrated under reduced pressure, and the residue was purified using Silikage/L7 (Wakogel C-2
00)10? Sprinkle it with the same silikage/L/7
Charge the QV column and add chloroform-methanol
tl, 10: /) 200m1. riau
Elution was carried out in the following order: 20Qml of hot TV moomeknol (3:/), 2001 chloroform-methanol (3:/), 2001 chloroform-methanol (2:/), and 1QQml. Silica gel (manufactured by Merck, Ar is also 37/3) TLC
(Developing solvent; butyl acetate-acetic acid-acetone-water (10:
The fractions around Rf=0.27 were collected and dried under reduced pressure to obtain neplanocin A-/-oxide/, Otsu 32.

Melting point: 2! ;gN2/°C (decomposition) Elemental analysis [as C, ■03N, 04・1j/2H, O] 0% N% N% Calculated value, evening g2 lAg9 21A2, measured value l1
Sentence g3 44 Ota 21A3ri Mass (El,)
; 2 Otsu 3CM-01, /3 Otsu, /33 20 UViλ 233.2 Otsu 2.2ri 5HmNMR (FX-
200-F T , DMS, 0-d6) δppm
i 4', / 2 (ya, br,,, IH, H-6/
Enter≠3 / (Ill,, / H, H-2', D20
By adding d, d, ), l1l12 (d, d, , /
With the addition of H, H-3', and D20, d, )≠73(also,,/
H, OH-Otsu', disappeared with the addition of D20), Kutata, left/
7C each d,, /HX2,0H-2', 3', D20
disappears upon addition), YoJ5 (d, d, , /H.

I(-/'), 573 (d,, /I(,H-I')
,ff, /Otsu(br, ,j H,NH2-Otsu,D
20i! #disappeared with addition), and Otsu/ (a,, / H,H
-2) Example coS-amino-/-C2',3'-dihydroxy-14'
-Hydroxymethyl-p/-cyclopenten-/'-yl)-imidazole-carpoxamide oxime nepfunomin A-/-oxide 3.33ft jN-N
a Heated to reflux in 3 wtl of aqueous OH for 1 S min, then cooled as quickly as possible and diluted with water. Do this
ex50WX, 2 (100-200 mesh, ammonium type) was charged to 200 rnl and bathed with water.

Each fraction was tracked with TLC (carrier silica gel, Merck Art37/31 developing solvent; butyl acetate-acetic acid-acetone-water (10:32 t), Rf = 0.2
Fractions around 0 were collected and concentrated under reduced pressure. The residue was crystallized from water and recrystallized from methanol-water to give the title compound.

NMR (F, X-100-FX, in DMSO-d 6)
δppm i 3. L! r to (m, , / H, H
=2', d, d, ), lA//(and s
br,,2H,H-6'),≠3'I ('d, d
, , /H,i(-3'),d with addition of D20),
11. gg (d, d,, /H,H-/'), ≠g~yo0 (m,, -2H,0Hx2.Disappears by addition of D20)
, left/7 (disappeared with the addition of s br,, 2H, NH2, D20), soil 23 (disappeared with the addition of /H, OHX/, D20), ri 33 (disappeared with the addition of s br, 2, NH2), D
(disappeared by adding 20) r72 (d,, /H,H-3'
Enter 7.0/ (s,, /H,H-2), II 3 (s
,,/H.

N-OR, D20 disappeared by addition) Patent Applicant Toyo Jozo Co., Ltd. Representative Atsushi Tetsuo Takada Procedural Amendment/Representation of the Case 1982 Patent Application No. g75g No. λ1 Invention Name Cyclohentene JJJ Imidazole amidoxime Manufacturing method 3. Relationship with the case of the person making the amendment Patent applicant address: 32, Miwata, Ohito-cho, Tagata-gun, Shizuoka Prefecture / Voluntary Corrects ``simethihin'' to ``dimethylene.''

Specification No. 1/Page 1st line "Final concentration" Correct it to "final concentration."

Claims (1)

Claims: A compound represented by the formula (wherein R1 and R2 represent a hydrogen atom or a hydroxyl group-protecting group, and R3 represents a hydrogen atom or a hydroxyl group-protecting group) or a salt thereof. 2) A compound represented by the formula 0 (in the formula, R1 and R2 represent a hydrogen atom or a hydroxyl group-protecting group, and R3 represents a hydrogen atom or a hydroxyl group-protecting group) is N-oxidized to form a compound represented by the formula (in the formula, R1 , R, and R,ll have the same meanings as above), and then treat the compound with an alkali (in the formula, R1, R
2 and R3 have the same meanings as above) or a salt thereof. 8) The production method according to claim 2, wherein the N-oxidation is carried out by oxidizing with an organic peracid or hydrogen peroxide. 4) The production method according to claim 2, wherein the alkali is an aqueous alkali metal hydroxide solution.