JPS61207394A - Monomer having nucleotide-like structure and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I [A is substituent group containing polymerization active group; B is adenosine, 1-(DELTA<2>-isopentenyl) adenosine, inosine uridine, etc.; R<1> and R<2> are alkyl, alkenyl, oxyalkyl, etc.]. USE:A raw material for producing a polymer having improved affinity for organism similar to phospholipid constituting biomembrane. PREPARATION:For example, protected nucleoside shown by the formula BH is reacted with 2-chloro-2-oxo-1,3,2-dioxaphosphorane in the presence of a tertiary amine, and reacted with a tertiary amine (e.g., methacrylic acid 2- dimethylaminoethyl ester, etc.) shown by the formula II, to give the aimed monomer.

Description

Detailed Description of the Invention [Field of Industrial Application] The present invention relates to a monomer having a structure similar to that of a nucleic acid, which is a component of living wood, and a method for producing the same. Proposed a method for producing monomers [JP-A-Sho! ! -7? / issue, Tokugan Shojter 3 9t, 2nd issue, Tokugan Shoyu? -62ri/,? issue〕. The compound obtained by this method is similar to phospholipids, which are important constituents in living organisms, and has a polymerization active group, so it can be expected that a single polymerization will yield a polymer with good biocompatibility. Ta.

The present invention further improves physiological activity by introducing into the phospholipid '301-like monomer a structure similar to nucleotides, which are widely distributed in raw ports and play a major role in biological functions such as cell metabolism, growth, and proliferation. This will pave the way for polymer materials that have the same properties.

[Aim of non-invention]

An object of the present invention is to provide a hepatoma having a structure similar to that of a phospholipid constituting biological IN and a nucleic acid that plays an important role in biological a function, and a method for producing the same.

[Structure of the invention]

The present invention relates to a monomer in which a phospholipid-like group having polymerization activity is introduced into the 1-position of a nucleoside represented by the general formula (1), and a method for producing No. 7.

RI Q [Here, A is a group having a polymerization active group, B is an adeno group,
・'nb' (d-isopentenyl) adenosine, N'-(△2-isopentenyl) adenosine, inosine, uridine,! -Hydroxyuridine! -Hydroxymethyluridine, j-hydroxymethyldeoxycytidine, orotidine.

Xanthosine, guanosine, cytidine, dihydrouridine, thymidine, l-thiouridine, deoxyadenosine, deoxyuridine, deoxyguanosine, deoxycytidine, pseudouridine, /-methyladenosine, j
- Represents the residue of a nucleoside selected from the group consisting of methyluridine, 7-methylguanosine, and j-methylcytidine, and this nucleoside is! It is bonded to the phosphoric acid group of the above general formula (1) at the position, and! The hydroxyl group outside the position is protected. R1 and R2 are each an alkyl group, an alkenyl group, a hydroxyalkyl group, or an alkyloxyalkyl group. It has the structure e.

The compound of the general formula (1) of the present invention is of the general formula (II]B
In the presence of H(11) [where B tri is the same as the definition in the above general formula +11], 2-gIf--oxo/, 3,2-dioxaphosphorane is reacted, and then general formula (II) [
Here, A, R', and R'' are the same as defined in General Niyama.

To explain the present invention in detail, the compound of the general formula (11) is adenosine h'(d-isopentenyl)adenosine, N'-(m''-isopentenyl)adenosine, inosine, uridine, !-hydroxyuridine, l
j-hydroxymethyluridine.

! -Hydroxymethyldeoxycytidine, otetratidine,
xanthosine, guanosine, cytidine.

Dihydrouridine, thymidine, l-thiouridine, deoxyadegusine, deoxyuridine.

Deoxyguanosine, deoxycytidine, pseudouridine, l-methyladenosine,! -Methyluridine, Coumethylguanosine,! −Methylcytidine group υ is selected.

Desired! By introducing a phospholipid-like group into the position.

In order to obtain the monomer represented by general formula (I), hydroxyl groups other than the r-position of the compound represented by general formula (0) are protected by known means. Usually, for deoxynucleosides,
Benzyl group, acetyl group, trityl group, etc. are suitable, and in the case of ribonucleosides, acetyl group, isopropylidene group, methoxytetrahydropyranyl group, tetrahydropyranyl group, benzyl group, methoxyethyl derivative ratio, etc. are suitable. .

The reaction is carried out with mono-oxo/3,2-dioxaphosphorane, and the tertiary amine usually includes trialkylamines such as trimethylamine and triethylamine. The amounts of the two components and the tertiary amine used are approximately equimolar to each other. As a solvent used during the reaction.

Preferably, those that can dissolve both components, the tertiary amine, and the reaction product include diethyl ether, tetrahydro-7rane, and the like.

The reaction is carried out by mixing both components in a solvent at -SO°C or 0°C.
The reaction may be carried out at .degree. C. for 30 minutes to several hours, and a compound represented by the following general formula (V) [where B is the same as the definition for the general formula (υ)] can be obtained almost quantitatively.

Next, the compound represented by the general formula (VJ) is reacted with a tertiary amine containing a monomerizable active group.

The tertiary amine has the following general formula (Vj represents an organic group), and examples of G include the following.

-C-o-+CH1+h (here h is an integer 0 from 7 to /ko)
0 pancreatic integer) , -(1-00H,0H-0111
, -(co and -t'R' is an alkyl group or OH, (O
H,) represents Co-, pOH! OR' is an integer from θ to j), 0-O-OHO- (where R1+ !-t alkyl group or ○Hs(0"z)
'O-, q is an integer from θ to 20).

OR' ■ Represents a kill group or ○H, (OH,) 00-, r
represents an integer between /θ and /−, and θ represents an integer between θ and −〇).

○H1OR represents the group or OH, (OH, kanCO-, t is /~/
-2 integer, U represents an integer from θ to 2Q), which may be different 1 For example, an alkyl group having up to 30 carbon atoms such as methyl group, ethyl group, hexyl group, ethynyl group, flobenyl group, futhynyl group .

Examples include various unsaturated alkyl groups such as, alkyloxyalkyl groups such as acetoxymethyl group, acetoxyethyl group, glopionyloxymethyl group, and propionyloxyethyl group. Specifically, it is as follows.

Oh.

The reaction between the dioxaphosphorane derivative represented by the above general formula (1) and the tertiary amine derivative containing a polymerizable unsaturated group is as follows:
This is carried out by mixing both components in a solvent such as acetonitrile, N-methyl-2-pyrrolidone or dimethylformamide at a temperature of Q to 200° C. for several hours to several tens of hours. The phospholipid-like compound represented by the general formula (1), which is a reaction product, can be easily purified by a 11C1ftM system by a known purification method such as dissolving it in an appropriate high-performance solvent and then adding a poor solvent thereto to precipitate it. obtain.

The nine compounds of general formula (II) thus obtained are:

It can be easily polymerized by radical polymerization. The hydroxyl groups in the obtained polymer are preserved, for example, by a ketalization reaction, but this protecting group can be removed by treatment with a small amount of trifluoroacetic acid, for example, and a nucleotide-like structure is formed. can be converted into a polymer having this in its side chain.

〔Example〕

The present invention will be explained in more detail with reference to Examples below.

Example r, Of (0,03%k) No2',3'-〇-isopropylidene uridine was dissolved in 100-tetrahydrofuran, and 3.39 (0,033 mol) of triethylamine was added thereto, followed by stirring. while cooling to -2Q°C.

At this temperature, 7 i (0,0 J moles) of 2-chlorochooxo/3,2-dioxaphosphorane were added dropwise. After the completion of the dropwise addition, stirring was continued for 7 hours at Q°C, and the precipitated triethylamine acid salt was separated using a glass filter, and the P solution was condensed using a vacuum pump to obtain a white solid.

The obtained white solid was dissolved in 50-dimethylformamide, 7 fl (0.72 mol) of methacrylic acid λ-dimethylaminoethyl ester was added, and 11
Seal it in an lrt pressure bottle and keep it at %20℃! The mixture was heated and reacted for a period of time. After the reaction, dimethylformamide was distilled off under reduced pressure.
By adding 120 ml of diethyl ether to the slag residue, washing it several times and vacuum drying, the desired monomer IIi was obtained. (Yield Z0% from u', 3″-〇-ingropylidene uridine).

The monomer produced is a sticky white solid that is soluble in methanol, ethanol, acetone, chloroform, and dimethylformamide but insoluble in diethyl ether, and its structure has been confirmed by elemental analysis, engineering, and NMR. Elemental analysis (as -dihydrate) 20 (calculated value, U%, analytical value 4tj, 3/%) 1H (calculated value 6.
56%, analytical value 6.73%), N (calculated value 7.=θ%1
Analysis value 7.16%). The engineering R is shown in Figure 1, and the NMR is shown in Figure 1.9.

Reference PA1/(polymer overproduction) The monomer obtained in Example 1 was dissolved in a small amount of ethanol, azobisisobutyronitrile was added as a polymerization initiator, and the mixture was shaken for 2 hours at 60°C in a sealed tube. , polymerized. After the reaction, the contents were poured into excess diethyl ether, and a white polymer was observed to precipitate. By dissolving this polymer in a small amount of methanol and purifying it by a reprecipitation method by pouring it into excess acetone, a polymer represented by the following formula was obtained. (Polymerization yield 65%) This polymer is a white solid, /! It has a melting point between θ and 77α and carbonizes at 2μθ°C. Soluble in methanol, ethanol, water, soluble in chloroform, dimethylformamide, and acetone.

Insoluble in diethyl ether. The structure was confirmed by elemental analysis, engineering R, and NMR. Elemental analysis (as trihydrate): C (calculation (fug3.so3%1 part value 9t3
．． 2.2%], H (calculated value 6.7θ%.

analysis 1 @ 6.26%), lJ (calculated value 6.96% 1 analysis 1 = 6.67%). Iv MR in Figure 3
As shown in the figure, Reference 111-2 (hydrolysis of polymers) Reference; J4; Is the polymer obtained from +/ trifluoroacetic acid? ! A small amount of % aqueous solution was added thereto, and the mixture was left at room temperature for g hours, condensed using a vacuum pump, and then poured into acetone to obtain a white precipitate. (Yield! 5%) This polymer has a melting point of /60-170°C and has a melting point of 26
Carbonizes at 0°C. Soluble in methanol, ethanol, water,
Slightly soluble in chloroform and dimethylformamide, insoluble in acetone and diethyl ether. This thing's engineering Rt-No. Shown in the figure.

〔Effect of the invention〕

According to the present invention, a novel monomer having a macrotide-like structure is provided.

[Brief explanation of the drawing]

Claims (4)

[Claims] (1) General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [Here, A is a substituent having a polymerization active group, B is adenosine, 1-(Δ^2-isopentenyl)adenosine, N^
6-(Δ^2-isopentenyl)adenosine, inosineuridine, 5-hydroxyuridine, 5-hydroxymethyluridine, 5-hydroxymethyldeoxycytidine, orotidine, xanthosine, guanosine, cytidine,
A nucleoside selected from the group consisting of dihydrouridine, thymidine, 4-thiouridine, deoxyadenosine, deoxyuridine, deoxyguanosine, deoxycytidine, pseudouridine, 1-methyladenosine, 5-methyluridine, 7-methylguanosine, and 5-methylcytidine. This nucleoside is bonded to the phosphoric acid group of the above general formula (I) at the 5' position, and the hydroxyl groups other than the 5' position are protected, and R^1 and R^ 2 represents an alkyl group, an alkenyl group, a hydroxyalkyl group, or an alkyloxyalkyl group, respectively] A monomer having a nucleotide-like structure represented by the following. (2) In general formula (I), A is an acryloxyethyl group, a methacryloxyethyl group, an acrylamideethyl group, a methacrylamideethyl group, an acryloxypropyl group, a methacryloxypropyl group, an acrylamidepropyl group, a methacrylamidepropyl group, 2. The monomer having a nucleotide-like structure according to claim 1, which is a polymerization-active substituent selected from the group consisting of an allyl group and a meta-allyl group. (3) In general formula (I), BH is 2',3'-0
-adenosine converted with isopropylidene group, 1-(
Δ^2-isopentenyl) adenosine, N^6-(Δ^
a protected nucleoside selected from the group consisting of (2-isopentenyl) adenosine, uridine, orotidine, xanthosine, guanosine, cytidine, dihydrouridine, 4-thiouridine, pseudouridine, 1-methyladenosine, 5-methyluridine, 5-methylcytidine; A monomer having a nucleotide-like structure according to claim 1 or 2, characterized in that: (4) General formula (II) ▲Mathematical formulas, chemical formulas, tables, etc.▼(II) [Here B is adenosine, 1-(Δ^2-isopentenyl)adenosine, N^6-(Δ^2- isopentenyl) adenosine, inosine, uridine, 5-hydroxyuridine, 5-hydroxymethyluridine, 5-hydroxymethyldeoxycytidine, orotidine, xanthosine, guanosine, cytidine, dihydrouridine, thymidine, 4-thiouridine, deoxyadenosine, deoxyuridine, Deoxyguanosine, deoxycytidine, pseudouridine, 1-methyladenosine, 5-methyluridine, 7-methylguanosine, 5-methylcytidine. In the presence of grade amine, 2
-By reacting with chloro-2-oxo-1,3,2-dioxaphosphorane, the general formula (III) ▲There are numerical formulas, chemical formulas, tables, etc.▼(III) [Here, A is a substitution having a polymerization active group. group, R^1 and R^2 each represent an alkyl group, an alkenyl group, a hydroxyalkyl group, or an alkyloxyalkyl group. A method for producing a monomer having a nucleotide-like structure as shown. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the above formula, A, B, R^1 and R^2 have the same meaning as above]