JPH04283571A - New cyclopropane derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound expectable as an antiviral agent, etc. CONSTITUTION:A compound expressed by formula I (B is nucleic acid base derivative; R1 and R2 are H or protecting group of OH), e.g. 1-1-1,9-[2,2- bishydroxymethyl-1-cyclopropyl]adenine. The above-mentioned compound is obtained by reacting a compound expressed by formula II with a compound expressed by formula III, providing a compound expressed by formula IV, then subjecting the resultant compound expressed by formula IV to cyclizing reaction, further reducing the prepared compound, etc. A purine base expressed by formula V (X1 is H, amino, OH or halogen; X2 is H or amino) and a pyrimidine base expressed by formula VI (Y1 is amino or OH; Y2 is H, halogen, alkyl, etc.) are cited as the B.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to novel nucleic acid derivatives that are expected to be used as medicines such as antiviral agents and anticancer agents, and as reagents.

0002

[Prior Art] Nucleic acids are substances that control the genetic information of living organisms and are closely related to differentiation and proliferation.Therefore, some of their naturally derived or non-natural nucleic acid derivatives control the proliferation of living organisms (including viruses). Many are known. In fact, some of these are in clinical use as effective medicines for cancers that repeatedly proliferate uncontrollably and for viral infections that proliferate only within human cells and cause various diseases. Furthermore, from the standpoint of antiviral agents, most pharmaceuticals are nucleic acid derivatives. For example, known antiviral agents include vidarabine, acyclovir, and azidothymidine. Also, as an anticancer drug, 5-fluorouracil (
5-FU), cytosine arabinoside (Ara-C), and the like are known.

0003

[Problems to be Solved by the Invention] However, the above-mentioned antiviral agents have drawbacks such as a narrow scope of application to viruses and limited administration methods due to factors such as solubility, oral absorption, and metabolism. Furthermore, there are some drugs that impose restrictions on dosage, administration period, etc. due to side effects such as bone marrow toxicity. On the other hand, acquired immunodeficiency disease (AIDS), which has an extremely poor prognosis,
There are many viral diseases for which there are no effective medicines or vaccines, such as human adult T-cell leukemia (ATL) and highly contagious cold syndromes. Therefore, the development of new antiviral agents is strongly desired in the future. Moreover, the above-mentioned anticancer drugs are not necessarily sufficient in terms of their effects, side effects, etc., and the development of new anticancer drugs is desired.

0004

[Means for Solving the Problems] The present invention provides general formula (1)

Novel cyclopropane derivatives represented by [Formula B is a nucleobase derivative, and R1 and R2 each independently represent a hydrogen atom or a hydroxyl group protecting group] and the physiologically acceptable properties of these compounds. Regarding salt.

In general formula (1), the nucleobase of B is represented by formula (2)

[0006]

[Chemical formula 3]

[Here, X1 is a hydrogen atom amino group,
It is a hydroxyl group or a halogen atom, and X2 is a hydrogen atom or an amino group. ], and a purine base represented by the formula (
3)

[0008]

[C4]

[Here, Y1 is an amino group or a hydroxyl group, and Y2 is a vinyl group substituted with a hydrogen atom, a halogen atom, an alkyl group, a halogen atom, or an alkoxycarbonyl group. Examples include pyrimidine bases represented by the following.

Here, examples of halogen atoms include fluorine, chlorine, bromine, and iodine, and examples of alkyl groups include
For example, C1 such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, t-butyl group, isobutyl group, etc.
-C4 alkyl group is mentioned. Examples of the alkoxycarbonyl group include methoxycarbonyl.

The protecting group for the hydroxyl group of R1 in the general formula (1) is not particularly limited as long as it is generally used as a protecting group, and ester-type protecting groups, such as acyl groups such as acetyl group and benzoyl group, or ether type protecting group,
For example, tert-butyldimethylsilyl group, tert-
Substituted silyl groups such as butyldiphenylsilyl groups, (C1-C4 alkoxy)C1-C such as methoxymethyl groups, etc.
4 Alkyl group, cyclic acetal group such as tetrahydrobilanyl group, or benzyl group, 4-methoxybenzyl group,
Examples include methyl groups substituted with one or more substituted or unsubstituted phenyl groups such as trityl groups.

Physiologically acceptable salts include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts, substituted ammonium salts, and mineral acids such as hydrochloric acid, sulfuric acid, and nitric acid. salt,
Examples include organic acid salts such as acetic acid, fumaric acid, maleic acid, tartaric acid, and methanesulfonate.

Next, specific examples of compounds represented by the general formula (1) will be shown. The compounds shown here include all existing isomers, optically active forms, and racemic forms. Also, salt is not shown here.

1-1-1, 9-[2,2-bishydroxymethyl-1-cyclopropyl]adenine 1-1-2,
9-[2,2-bishydroxymethyl-1-cyclopropyl]guanine 1-1-3, 2,6-diamino-9-[2,2-bishydroxymethyl-1-cyclopropyl]purine 1-1-
4,9-[2,2-bishydroxymethyl-1-cyclopropyl]hypoxanthine 1-1-5,2-amino-6-chloro-9-[2,2-
Bishydroxymethyl-1-cyclopropyl purine 1
-1-6,6-chloro-9-[2,2-bishydroxymethyl-1-cyclopropyl]purine

1-
2-1, 1-[2,2-bishydroxymethyl-1-cyclopropyl]cytosine 1-2-2, 1-[2,2-bishydroxymethyl-1-cyclopropyl]thymine 1-2-3, 1-[2,2-bishydroxymethyl-1
-cyclopropyl]uracil 1-2-4, 5-(2-bromovinyl)-1-[2,2
-bishydroxymethyl-1-cyclopropyl]uracil 1-2-5, 5-fluoro-1-[2,2-bishydroxymethyl-1-cyclopropyl]uracil 1-2-6
, 5-iodo-1-[2,2-bishydroxymethyl-
1-cyclopropyl]uracil 1-2-7, 5-(2-
methyloxycarbonylvinyl)-1-[2,2-bishydroxymethyl-1-cyclopropyl]uracil

Among the compounds represented by the general formula (1) of the present invention, purine base type compounds are, for example, those represented by the general formula (4).

001
7]

[C5]

It can be obtained from the compound represented by the formula [wherein R1 and R2 are the same as above] by the reaction route shown in Scheme 1 or Scheme 2, for example.

[0019]

[C6]

[0020]

[C7]

[0021] Further, the pyrimidine base type compound has, for example, the general formula (5)

[0022]

[Chemical formula 8]

From the compound represented by [Here, R1 and R2 are the same as above], for example, Scheme 3 or Scheme 4
It can be obtained by the reaction route shown below.

[0024]

[Chemical formula 9]

[0025]

[Chemical formula 10]

Compounds represented by general formulas (4) and (5), which serve as starting materials in Schemes 1 to 4, can be produced, for example, as shown in Scheme 5 below.

[0027]

[Chemical formula 11]

That is, the compound represented by the general formula (4) is represented by the general formula (7) obtained by the Schmidt rearrangement, Rossen rearrangement, Hofmann rearrangement, or Curtius rearrangement reaction of the compound represented by the general formula (6). It can be produced by direct hydrolysis of isocyanate, which is an unstable intermediate, or by hydrolysis after it is converted into carbamate. Further, the compound represented by the general formula (5) can be produced by adding ammonia to the isocyanate represented by the general formula (7).

Further, an optically active form of the compound represented by the general formula (1) can be produced, for example, as follows. From diastereomeric salts obtained by mixing the racemic compound represented by general formula (2) with various acids such as optically active carboxylic acids, each diastereomer can be separated by chromatography, crystallization, etc. Isolate with These diastereomers can be converted into optically active free bases represented by general formula (2) by conventional methods, such as adding a base to decompose the salt or using an ion exchange resin. Alternatively, in the racemic compounds represented by general formulas (1), (2), and (3), an optically active substituent is introduced at least one of R1 and R2 to form diastereomers, and these are diastereomers. By splitting, optical activity can be introduced into the compound.

[0030]

[Effects] The present invention provides novel cyclopropane derivatives that are expected to be used as antiviral agents, anticancer agents, and reagents.

[0031]

EXAMPLES Next, the production of the compounds of the present invention will be specifically explained with reference to Examples. Note that the compound shown here is a racemate.

Example 1 Preparation of 9-[2,2-bis(hydroxymethyl)-hyclopropyl]adenine

00
33] (1) 6-[2,2-bis(benzyloxymethyl)-cyclopropylamino]-4-chloro-5-
Preparation of formamide-pyrimidine 4,6-dichloro-5-formamidopyrimidine ( 133 mg) and heated under reflux overnight. After the reaction, it was concentrated under reduced pressure, and the resulting residue was subjected to silica gel chromatography (eluent: chloroform-ethanol = 50:1) to obtain the desired product (249 m
g, 90%). 1H-NMR (400MHz, CDCl3, TMS
), δ (Jvalue) 7.94 (1H, d, J1.3
Hz), and 8.29 (1H, s). IR (film); 3250, 1690, 1570,
1500, 1100, 1030, and 740cm-
1.

(2) Production of 9-[2,2-bis(benzyloxymethyl)-cyclopropyl]-6-chloropurine. 6-[2,2-bis(benzyloxymethyl)-cyclopropylamino]-4-chloro-5-formamide-pyrimidine (147 mg) was dissolved in ethyl orthoformate (7 ml).
, N,N-dimethylformamide (3 ml) and 12N hydrochloric acid (0.2 ml), and the reaction solution was stirred at room temperature for 3 days. After the reaction, pour into water (10 ml) and chloroform (10 ml).
x2). The chloroform solution was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (eluent;
The target product (chloroform-methanol = 30:1)
82 mg, 58%). 1H-NMR (400MHz, CDCl3, TMS
), δ(Jvalue)8.25(1H,s), and
8.72 (1H, s). IR (film); 1590, 1560, 1500,
1090 and 740 cm-1.

(3) Production of 9-[2,2-bis(benzyloxymethyl)-cyclopropyl]adenine 9-
A methanol solution (5 ml) of [2,2-bis(benzyloxymethyl)-cyclopropyl]-6-chloropurine (29 mg) and liquefied ammonia (1.5 ml) is heated at 100° C. for 8 hours in a sealed tube. The solvent was distilled off under reduced pressure to obtain the desired product (22 mg, 81%). IR (Nujol); 3300, 3120, 1665,
1590 and 1560 cm-1.

(4) Production of 9-[2,2-bis(hydroxymethyl)-cyclopropyl]adenine 9-[2
, 2-bis(benzyloxymethyl)-cyclopropyl]adenyl (10 mg) in 80% formic acid (0.5 ml) and methanol (0.5 ml) was mixed with Pd-black (4
mg) and reacted for 8 hours at room temperature under a hydrogen atmosphere. After filtering off the catalyst, the solvent was concentrated under reduced pressure, and the resulting residue was purified using a preparative silica gel plate (0.5 mm) and developing solvent: chloroform-methanol = 4:1 to obtain the desired product (4 mg, 75%). ). mp228-231°C 1H-NMR (400MHz, DMSO-d6,),
δ (Jvalue) 1.27 (1H, dd, J5.74
,7.7. Hz), 1.33 (1H, dd, J4.51
, 5.74Hz), 3.08 (1H, d, J11.18
Hz), 3.30 (1H, d, J11.18Hz), 3
．． 47 (1H, d, J11.23Hz), 3.73 (1
H, d, J11.23Hz), 4.65 (1H, br.
), 4.77 (1H, br.), 7.24 (2H, s)
, 8.08 (1H, s.) and 8.13 (1H, s.
). IR (Nujol); 3390, 3200, 1670
, 1610, 1580 and 1020 cm-1.

Example 2 Preparation of 1-[2,2-bis(hydroxymethyl)-cyclopropyl]uracil

00
38] (1) Production of 1-[N'-(3-ethoxyacryloyl)-ureido]-2,2-bis(benzyloxymethyl)cyclopropane 2,2-bis(benzyloxymethyl)cyclopropylureido (107 mg ), dichloromethane (2 ml),
A reaction mixture of pyridine (1 ml) and β-ethoxyacryloyl chloride (178 mg) was stirred and reacted overnight at room temperature. The reaction solution was poured into ice water (20 ml) and extracted with chloroform (10 ml x 3). Chloroform solution in water,
After washing with saturated brine and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (eluent: hexane-ethyl acetate = 1:2) to obtain the desired product (71 mg, 51%). IR (film); 3250, 1710, 1680,
1620 and 1540 cm-1.

(2) Production of 1-[2,2-bis(benzyloxymethyl)-cyclopropyl]uracil 1-
[N′-(ethoxyacryloyl)-ureido]-2,
2-bis(benzyloxymethyl)cyclopropane (1
00 mg) in ethanol (2 ml) and 4% aqueous ammonia (2 ml) and reacted at 80°C for 5 hours. After the reaction, it was concentrated under reduced pressure, and the resulting residue was transferred to a preparative silica gel plate (0.5 mm, developing solvent: hexane-ethyl acetate =
1:1) to obtain the desired product (32 mg, 35%). 1H-NMR (400MHz, CDCl3, TMS
), δ (Jvalue) 1.17 (1H, dd, J4.
8,6.7Hz), 1.34(1H, dd, J6.7,
7.8Hz), 3.09 (1H, dd, J4.8, 7.
8Hz), and 5.54 (1H, d, J8.4Hz
). IR (film); 3190, 1710, 169
0, 1380, 1290, and 1090 cm-1.

(3) Production of 1-[2,2-bis(hydroxymethyl)-cyclopropyl]uracil 1-[2
, 2-bis(benzyloxymethyl)-cyclopropyl]uracil (10 mg) in 80% formic acid (0.5 ml) and methanol (0.5 ml).
mg) and reacted for 4 hours at room temperature under a hydrogen atmosphere. After filtering off the catalyst, the solvent was concentrated under reduced pressure, and the resulting residue was purified using a preparative silica gel plate (0.5 mm, developing solvent: chloroform-methanol = 4:1) to obtain the desired product (
5 mg, 93%). mp165-167℃ 1H-NMR (400MHz, CD3 OD), δ(
Jvalue) 1.11 (1H, dd, J4.6, 6.
6Hz), 1.24 (1H, dd, J6.6, 7.6H
z), 3.09 (1H, dd, J4.6, 7.6Hz)
, 3.50 (2H, s), 3.58 (1H, d, J10
．． 5Hz), 3.73 (1H, d, J10.5Hz),
5.64 (1H, d, J7.8Hz), and 7.5
7 (1H, d, J7.8Hz) IR (Nujol);
3400, 1705, 1670, and 1620
cm-1.

Reference Example 1 Production of 2,2-bis(benzyloxymethyl)cyclopropylisocyanate

00
42] (1) Production of 2,2-bis(benzyloxymethyl)cyclopropylcarboxylic acid 5 of a methanol solution (20ml) of 2,2-bis(benzyloxymethyl)cyclopropylcarboxylic acid ethyl ester (5.4g)
Add 4 equivalents of normal potassium hydroxide/methanol solution,
Stir overnight at room temperature. The solvent was distilled off under reduced pressure, water (60 ml) was added to the residue, and the aqueous solution was diluted with ethyl acetate (50 ml x
2) Extract. The aqueous layer was made acidic with concentrated hydrochloric acid and then extracted with ethyl acetate (50 ml x 3). Ethyl acetate solution in water,
After washing with saturated brine and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (eluent: hexane-ethyl acetate = 1:1) to obtain the desired product (4 g, 80%). 1H-NMR (400MHz, CDCl3, TMS
), δ (Jvalue) 1.19 (1H, dd, J4.
59, 7.81Hz), 1.28 (1H, dd, J4.
59, 5.85Hz), 1.79 (1H, dd, J5.
85, 7.81Hz), 3.34 (1H, d, J9.7
7Hz), 3.59 (1H, d.9.77Hz), 3.
71 (1H, d, J9.76Hz), 3.86 (1H,
d, J9.76Hz), 4.43 (2H, s), 4.5
0 (2H, s) and 7.24 (10H, compl
ex).

(2) Production of 2,2-bis(benzyloxymethyl)cyclopropylisocyanate Acetone solution (3ml) of 2,2-bis(benzyloxymethyl)cyclopropylcarboxylic acid (128.2mg)
) was added with an acetone solution (1 ml) of triethylamine (54 mg) under ice-cooling, and then ethyl chloroformate (0.4 ml) was added to the solution.
1) was added dropwise and stirred for 1 hour. An aqueous solution (2 ml) of sodium azide (39 mg) was added to the reaction solution, and the mixture was stirred for one hour under ice cooling. After the reaction, the product was poured into ice water (40 ml) and dissolved in ether (
Extract with 50ml x 2). After drying the ether solution over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and anhydrous toluene (20 ml) was added to the resulting residue, followed by heating under reflux for 1 hour. When the solvent was distilled off under reduced pressure, the target product (111.6 mg, 88
%). Because it is unstable, it is used in the next reaction without purification. IR (film); 2275 cm-1.

Reference Example 2 1-amino-2,2-bis(
Production of benzyloxymethyl)cyclopropane

004
5] (1) 2,2-bis(benzyloxymethyl)
Preparation of cyclopropylcarbamic acid tert-butyl ester Three drops of triethylamine are added to a solution of 2,2-bis(benzyloxymethyl)cyclopropylisocyanate (121 mg) in tert-butanol (5 ml) and heated under reflux for 40 hours. After the reaction, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel chromatography (eluent: hexane-ethyl acetate = 2:1) to obtain the desired product (101 mg,
68%). 1H-NMR (400MHz, CDCl3, TMS
), δ (Jvalue) 0.71 (1H, t, J5.6
Hz), 1.00 (1H, dd, J5.6, 7.5Hz
), 1.45 (9H, s), and 2.57 (1H,
complex). IR(film) ;3430,3
350, 1700, 1100, 1025, 740, 70
0cm-1.

(2) Production of 1-amino-2,2-bis(benzyloxymethyl)cyclopropane A dichloromethane solution of 2,2-bis(benzyloxymethyl)cyclopropylcarbamic acid tert-butyl ester (51.1 mg) (1 ml) to trifluoroacetic acid (0.5 m
1) and stirred at room temperature for 20 minutes. After the reaction, the mixture was concentrated under reduced pressure, and the residue was made alkaline by adding a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate (30 ml x 2). After drying the ethyl acetate solution over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the desired product (39 mg, 100%). 1H-NMR (400MHz, CDCl3, TMS
), δ (Jvalue) 0.48 (1H, dd, J4.
4,5.3Hz), 0.74(1H, dd, J5.3,
7.0Hz), and 2.37 (1H, dd, J4.
4,7.0Hz). IR (film); 3400, 1600, 1500,
1450, 1090, 1070, 740, 700cm-
1.

Reference Example 3 Production of 2,2-bis(benzyloxymethyl)cyclopropylureido Ammonia gas was added to an ether solution (5 ml) of 2,2-bis(benzyloxymethyl)cyclopropylisocyanate (300 mg) under ice cooling. saturate and leave for 1 hour. The precipitated crystalline substance was filtered off and washed with ether (2 ml) to obtain the desired product (180 mg, 57%). mp; 126-128°C IR (Nujol); 3445, 3180, 168
0, 1620, 1095, 800, 730, and 6
95cm-1.

Claims (1)

[Claims] Claim 1: A novel cyclopropane derivative represented by the general formula (1) [Formula B is a nucleobase derivative, and R1 and R2 each independently represent a hydrogen atom or a hydroxyl group protecting group] and physiologically acceptable salts of these compounds.