JP2610889B2 - New crosslinked adenine derivatives - Google Patents

Description

The present invention relates to a novel crosslinked adenine derivative having a cytokinin-like action.

(Conventional technology) Cytokinin is a kind of plant hormone having various physiological activities such as promoting cell division, promoting plant growth, preventing aging, promoting chlorophyll formation, inhibiting chlorophyll degradation, and accumulating amino acids. Various relatives have been synthesized for their usefulness.

(Problems to be Solved by the Invention) The present inventors have studied the synthesis method and pharmacological action of novel cross-linked adenine derivatives, and have found that the cross-linked adenine derivatives of the present invention have cytokinin-like properties. completed.

An object of the present invention is to provide a novel crosslinked adenine derivative having a cytokinin-like action and a pharmaceutically acceptable salt thereof.

(Means for Solving the Problems) The compound of the present invention is a novel crosslinked adenine derivative represented by the following general formula (I).

[Wherein the dashed line represents that-(CH ₂ ) _n -is bonded to any of the 1-, 9- or 6-position amino groups, and n is 3 to 11
Represents an integer. Hereinafter,-(CH ₂ ) _n- bonded to the first position is referred to as 2-1.
A crosslinked product, one linked to the 9-position is called a 2-9 crosslinked product, and one linked to the 6th amino group is called a 2-6N crosslinked product.

The crosslinked adenine derivative of the present invention includes a pharmaceutically acceptable salt of the compound represented by the general formula (I), for example, an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the like, formic acid, acetic acid, citric acid and the like. And acid addition salts with organic acids such as acids and lactic acid.

These salts can be produced from the free crosslinked adenine derivative of the present invention by known methods, or can be mutually converted.

 Next, a method for producing the compound of the present invention will be described.

(1) General formula (II): [In the formula, n represents an integer of 3 to 11. By heating the compound of formula (1) and 5-aminoimidazole-4-carbonitrile in an appropriate solvent such as butanol for several hours to several days under reflux.
A -6N cross-linked compound of the present invention can be obtained.

The production ratio of both products varies with the magnitude of n.
That is, when n is as small as 3 to 5, a 2-1 crosslinked product is mainly produced, but as n increases, a 2-6N crosslinked product is obtained as a main component.
Thus, a 2-6 crosslinked product can be obtained in a high yield of 91%. In this case, when the reaction time is shortened, the yield of the 2-1 crosslinked product tends to increase.

(2) General formula (III): [In the formula, n represents an integer of 3 to 11. The compound represented by the formula (1) is heated and refluxed in an appropriate solvent such as formamide for several minutes to several hours to obtain a 2-6N crosslinked product and a 2-9 crosslinked product.

The compound represented by the above general formula (III) is produced by synthesizing an α-bridged phenylazopyrimidine, converting it into a β-bridged product by Dimroth rearrangement, and then performing reductive formylation in zinc powder / formic acid. it can.

Similarly to the production method (1), the production ratio of both products is adjusted by the size of n. For example, when n is 7, a 2-6N crosslinked product is obtained as a main component, while when n is 11, a 2-9 crosslinked product is mainly obtained.
Is 7, they are synthesized at a close ratio.

The obtained compound of the present invention was purified by usual means such as chromatography, recrystallization and the like.

The produced compound of the present invention has a melting point, elemental analysis, Rf value, NM
It was identified by R, IR, UV, mass spectrum, etc., and the isomers were identified.

(Example) Hereinafter, an example of the manufacturing method of the present invention will be described.

Example 1. 1.80 g of 5-aminoimidazole-4-carbonitrile and 1.24 g of 3,4-dihydro-5-ethoxy-2H-pyrrole were dissolved in 75 ml of butanol and heated under reflux for 2 days.
The reaction solution was evaporated to dryness, and the residue was recrystallized from ethanol to give 8-amino-6,7-dihydro-5H-pyrrolo [1,2-a].
Purine (compound 1: 2-1 crosslinked product, n = 3) was obtained.

Yield: 85% mp:> 330 ° C. (decomposition) Elemental analysis: C ₈ H ₉ N ₅ as C% H% N% Calculated: 54.8 5.2 40.0 Found: 55.0 5.2 39.9 3,4-dihydro-5-ethoxy Instead of -2H-pyrrole, 6-ethoxy-2,3,4,5-tetrahydropyridine, 7-ethoxy-3,4,5,6-tetrahydro-2H-azepine, 2-ethoxyazacyclotridec-1 The following compounds were obtained using -ene.

9-amino-5,6,7,8-tetrahydropiperidino [1,2
-A] Purine (compound 2: 2-1 crosslinked product, n = 4) Yield: 53% Melting point: 310-312 ° C (decomposition) 10-amino-6,7,8,9-tetrahydro-5H-azepino [ 1,2-a] purine (Compound 3: 2-1 crosslinked product, n = 5) Yield: 54% Melting point: 294-296 ° C (decomposition) 16-aminoazacyclotridecano [1,2-a] purine (Compound 4: 2-1 crosslinked product, n = 11) Yield: 16% Melting point: 283 ° C (decomposition) Example 2. (1) 1.08 g of 5-aminoimidazole-4-carbonitrile and 1.86 g of 9 -Ethoxy-3,4,5,6,7,8-hexahydro-2H-azonin is dissolved in butanol and heated under reflux for 4 days to give crystalline 6,2-iminoheptanopurine (compound 5: 2-6N A crosslinked product, n = 7) was obtained.

Yield: 63% Melting point: 308-309 ° C pKa: 4.96 ± 0.02 Elemental analysis: As C ₁₂ H ₁₇ N ₅ C% H% N% Calculated: 62.3 7.4 30.3 Found: 62.1 7.5 30.3 9-ethoxy-3, Instead of 4,5,6,7,8-hexahydro-2H-azonin, 2-ethoxyazacycloundec-1-ene, 2-ethoxyazacyclotridec-1-ene
Using ene, the following compounds were obtained in the same manner as above. 6,
2-iminononanopurine (compound 6: 2-6N crosslinked product, n =
9) Yield: 80% Melting point: 311-312 ° C pKa: 4.71 ± 0.02 Elemental analysis: C% H% N% as C ₁₄ H ₂₁ N ₅ Calculated: 64.8 8.2 27.0 Found: 64.7 8.1 27.1 6,2- Iminoundecanopurine (Compound 7: 2-6N crosslinked product, n = 11) Yield: 91% Melting point: 288-289 ° C pKa: 3.96 ± 0.03 Elemental analysis: C% H% N% as C ₁₆ H ₂₅ N ₅ Calculated value: 66.9 8.8 24.4 Actual value: 67.1 8.8 24.1 Example 3. (1) 16.9 g of 9-ethoxy-3,4,5,6,7,8-hexahydro-2H-azonin and 5.35 g of ammonium chloride Dissolved in 250 ml of methanol and stirred at room temperature for 2 days. After drying to dryness and washing with ether, the residue was dried using a desiccant under reduced pressure, butanol 150 ml and sodium butoxide 2.76 g
Dissolved in a more conditioned solution. After adding 17 g of phenylazomalononitrile and refluxing the mixture overnight, 50
It was concentrated to 100 ml and diluted with 100 ml of water. After cooling, crude crystals were obtained, washed with water and dried in a desiccator.
30.7 g of the thus obtained yellow crude crystals were dissolved in 250 ml of formic acid, and 30 g of zinc dust was added. The reaction solution was heated under reflux for 15 minutes, the insoluble material was removed by filtration, and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography, and the main fraction was recrystallized from ethanol to give 12-amino-13-formamide-2,11,14-triazabicyclo [8,3,1] tetradeca-1 (14 ), 10,12-Triene (compound A) was obtained.

Yield: 70% Melting point: 226-228 ° C Elemental analysis: C ₁₂ H ₁₉ N ₅ O.2H ₂ O C% H% N% Calculated: 50.1 7.4 24.5 Found: 50.2 7.1 24.5 9-Ethoxy-3, 2-ethoxyazocycloundec-1 instead of 4,5,6,7,8-hexahydro-2H-azonin
The following compounds were obtained in the same manner as described above using -ene and 2-ethoxyazocyclotridec-1-ene.

14-Amino-15-formamido-2,13,16-triazabicyclo [10,3,1] hexadec-1 (16), 12,14-triene (compound B) Yield: 84% Melting point: 195-198 ℃ elemental _{analysis: C 14 H 23 N 5 O} · 2 / 3H 2 O as C% H% N% calculated: 58.1 8.5 24.2 Found: 58.2 8.7 23.9 16 amino-17-formamide -2,15,18- Triazabicyclo [12,3,1] octadeca-1 (18), 14,16-triene (Compound C) Yield: 31% Melting point: 220-221 ° C Elemental analysis: C ₁₆ C ₂₇ N ₅ O · 1 / 4% EtOH C% H% N% Calculated: 62.5 9.1 22.2 Found: 62.3 9.0 22.2 (2) 11.8 g of compound A was heated at 165 ° C. for 1 hour in 150 ml of formamide. The residue obtained by evaporation to dryness was dissolved in chloroform-ethanol, and then separated and purified by silica gel column chromatography to obtain Compound 5 (63% yield).
And 6-amino-2,9-heptanopurine (compound 8: 2-9
A crosslinked product, n = 7) was obtained.

Yield: 3% Melting point: 237-238 ° C pKa: 5.32 ± 0.02 Elemental analysis: C% H% N% as C ₁₂ H ₁₇ N ₅ Calculated: 62.3 7.4 30.3 Observed: 62.1 7.5 30.3 Same as for compound B And the compound 6 (yield
28%) and 6-amino-2,9-nonanopurine (compound 9: 2
-9 crosslinked product, n = 9).

Yield: 47% Melting point: 222-223 ° C pKa: 4.60 ± 0.03 Elemental analysis: C% H% N% as C ₁₄ H ₂₁ N ₅ Calculated: 64.8 8.2 27.0 Found: 64.8 8.5 26.8 Same as for compound C Was carried out to obtain compound 7 (yield 5%) and 6-amino-2,9-undecanopurine (compound 10: 2-9 crosslinked product, n = 11).

Yield: 70% Melting point: 216-218 ° C pKa: 4.42 ± 0.02 Elemental analysis: C ₁₆ H ₂₅ N ₅ C% H% N% Calculated: 66.9 8.8 24.4 Actual: 68.0 8.9 24.2 2-6N crosslinked Table 1 shows some of the NMR data used to identify and identify the 2-9 crosslinked product.

(Action) The cytokinin-like action of the crosslinked adenine derivative of the present invention will be described below.

(1) Chlorophyll (chlorophyll) degradation inhibitory action 10 ml of an aqueous solution of the test drug was added to a schulle lined with three filter papers, and a diameter 11 cut out from radish leaves was added thereto.
Ten leaf sections were placed. After standing in the dark at 25 ° C. for 3 days, the sections were ground with 50 ml of 80% ethanol. 30
After standing for a minute, the absorbance at 665 nm of the supernatant was measured to quantify the amount of chlorophyll.

Three tests were performed for each sample, and the average value was determined. The amount of chlorophyll before immersion in the test drug was defined as 100%, and the amount of residual chlorophyll was expressed as a percentage.

 One example of the results is shown in FIG.

(Effect) As is clear from FIG. 1, the crosslinked adenine derivative of the present invention has an excellent chlorophyll decomposition inhibitory action. The effect was equal to or higher than that of benzyladenine used as a comparative drug.

In addition, as a result of examining the effect of the compound of the present invention on the initial growth of rice, benzyladenine, which is known to have a root growth inhibitory effect, has a seed root growth inhibitory effect of about 45% at a concentration of 10 ^{-8 to} 10 ^-6 M. Was observed, whereas the compound of the present invention hardly exhibited such an inhibitory effect. As described above, since the compound of the present invention does not have an effect of inhibiting root growth, it can be used more advantageously than benzyladenine when used as an agricultural drug.

As described above, since the crosslinked adenine derivative of the present invention has an excellent cytokinin-like action, it is useful as an agricultural drug such as a cell division promoter, a plant growth regulator, an antiaging agent, a chlorophyll degradation inhibitor, and an amino acid accumulating agent. is there.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing the results of examining the chlorophyll degradation inhibitory effect of the compound of the present invention.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Wolfgang Friedler Germany Day 7750 Konstanz Lindauer Strasse 47

Claims (1)

(57) [Claims] 1. A compound of the general formula (I): [Wherein the dashed line represents that-(CH ₂ ) _n -is bonded to any of the 1-, 9- or 6-position amino groups, and n is 3 to 11
Represents an integer. ] The bridge | crosslinking adenine derivative represented by these, and its pharmacologically acceptable salt.