JPS638960B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the general formula A novel 2-substituted-1,N ⁶ -etheno-adenosine-3',5'-cyclic phosphoric acid (hereinafter referred to as 1,N ⁶ -etheno-adenosine-3′,
5′-cyclic phosphoric acid is abbreviated as εCAMP).

The compound of the formula has excellent pharmacological effects such as antiallergic action, central nervous system stimulant action, platelet aggregation action, diuretic action, action on the circulatory system (e.g. hypotensive action, myocardial depressant action, etc.), and anticancer action. It is useful as a medicine, and is also used as a biochemical reagent, such as a reagent for measuring phosphodiesterase activity.

The compound of the formula (2-cyano-εCAMP) in which R is a cyano group is represented by the following formula It can be produced by reacting 2-halogeno-εCAMP represented by the formula (wherein X means a halogen atom) with an alkali cyanide.

A compound of formula may be, for example, 2-mercapto-
It is obtained by halogenating εCAMP (see JP-A-53-12891), and for example, 2-iodo-εCAMP, 2-chloro-εCAMP or preferably 2-bromo-εCAMP is used. The compounds of these formulas can be used in the form of the free acid in the cyclic phosphoric acid moiety as well as in the form of its salts, such as alkali metal salts, ammonium salts or organic ammonium salts. As the alkali cyanide, for example, potassium cyanide or sodium cyanide is used.

The cyanation reaction can be carried out, for example, as follows. A compound of the formula is preferably dissolved or suspended in a polar organic solvent, such as N,N'-dimethylformamide, and an alkali cyanide is added thereto, followed by reaction at a temperature of room temperature to 60°C for several hours to several days.

A compound of the formula in which R is a carbamoyl group or a carboxyl group (2-carbamoyl-εCAMP or 2-carboxy-εCAMP) is a 2-cyano-
It can be obtained by alkaline hydrolysis of εCAMP depending on the alkaline hydrolysis conditions, such as alkaline strength (PH), reaction time, etc. That is, a cyano group is first hydrolyzed into a carbamoyl group (carbonamide group), and then further hydrolyzed to become a carboxyl group.

Alkaline hydrolysis is generally carried out using a basic substance such as sodium hydroxide, potassium hydroxide, ammonia, or an organic amine in the presence of a hydrophilic solvent such as water or alcohol.

2-Carbamoyl-εCAMP is obtained by alkaline hydrolysis of 2-cyano-εCAMP by addition of a basic substance, for example, at a pH of 10 to 13 and generally at a temperature of 0 to 40°C for several minutes to several hours.

The reaction mixture containing 2-carbamoyl-εCAMP is continued to be hydrolyzed for a longer period of time at a temperature of 0 to 40°C, or an additional amount of a basic substance is added to the reaction mixture to give a pH of 12 to 13.5, generally 0 to 40°C. 40℃
When hydrolysis is carried out for several minutes to several hours at a temperature of
2-carboxy-εCAMP is obtained. Also 2-
Cyano-εCAMP, 2-carbamoyl-εCAMP
Alternatively, dissolve or suspend a mixture of both in a hydrophilic solvent, and add a basic substance to this to adjust the liquid pH to 12.
13.5 and hydrolysis at a temperature of generally 0 to 40° C. for several minutes to several hours, 2-carboxy-εCAMP is obtained.

Isolation and purification of the target substance is carried out by conventional methods, and depending on the operating conditions, a compound of the formula in the form of a free acid or a salt thereof in the cyclic phosphoric acid moiety and/or carboxyl group can be obtained. For example, after concentrating the reaction mixture and adjusting the PH value to 4 or less using an inorganic acid such as hydrochloric acid or an organic acid such as acetic acid, and leaving it for a while, the desired substance in the form of a free acid will precipitate.
When there are by-products such as salts and pigments in the reaction mixture that are difficult to separate, use activated carbon, ion exchange resins such as strongly acidic cation exchange resins or weakly basic anion exchange resins, alumina, silica gel, etc. Column chromatography or organic solvent precipitation using alcohol, acetone, dioxane, etc. can be performed alone or in combination.

When a compound of the formula in the form of a free acid is reacted with a basic substance such as sodium hydroxide, potassium hydroxide, ammonia, an amine, preferably a tertiary amine such as triethylamine, tributylamine, etc. in a conventional manner, it leads to the corresponding salt. Can be done.

The novel compounds of the formula
It is also important as an intermediate for the synthesis of CAMP. For example, deethenoization of 2-carbamoyl-εCAMP or 2-carboxy-εCAMP yields 2-carbamoyl-CAMP or 2-carboxy-CAMP. 2-carboxy-
CAMP is 2-carbamoyl-εCAMP or 2-carbamoyl-εCAMP
It can also be obtained by deethenoizing cyano-εCAMP and then subjecting it to alkaline hydrolysis.

Example 1 2.0 g of 2-bromo-εCAMP was suspended in 500 ml of dimethylformamide, and 1.0 g of potassium cyanide was added to it.
After stirring thoroughly, the mixture was reacted at room temperature for 16 hours with stirring.

After the reaction is complete, add Dowex 50-
After neutralizing by adding X8 (H ⁺ type),
Evaporate the liquid to dryness. The residue was dissolved in a small amount of water, passed through a column (1.4φ x 30cm) packed with Dowex 50-X8 (H ⁺ type, 100-200 mesh), eluted with water, and then the target compound was extracted. When the eluted fraction containing the fraction is concentrated and left at 5°C, 2-cyano-εCAMP crystallizes, and when this is separated and dried, 1.11 g of crystals of 2-cyano-εCAMP are obtained.

Melting point: 191-193℃ (decomposition) Elemental analysis: C ₁₃ H ₁₁ N ₆ O ₆ P・0.5H ₂ O C H N Theoretical value (%) 40.37 3.03 21.66 Actual value (%) 40.31 3.10 21.71 Ultraviolet absorption spectrum : λ ^0.1N-HCl _nax 242.5, 249.0 (shoulder), 273.0 (shoulder), 281.
0,
294.0, 333.5nm Example 2 1.0g of 2-cyano-εCAMP was dissolved in 10ml of 0.7N aqueous sodium hydroxide solution (PH12.9), and the
Allow to react under stirring for a minute. Adjust the pH of the reaction mixture to 1.0 using concentrated hydrochloric acid, collect the precipitated crystals,
After washing with a small amount of water and drying, 793 mg of 2-carbamoyl-εCAMP crystals are obtained.

Melting point: 196-199℃ (decomposition) Elemental analysis: C ₁₃ H ₁₃ N ₆ O ₇ P・H ₂ O C H N Theoretical value (%) 37.65 3.34 20.12 Actual value (%) 37.68 3.62 20.29 Ultraviolet absorption spectrum: λ ^0.1N-HCl _nax 239.5, 278.0, 308.5nm Example 3 1.0g of 2-carbamoyl-εCAMP was dissolved in 10ml of 1.3N-sodium hydroxide aqueous solution (PH13.2),
After reacting at room temperature for 20 minutes with stirring, the pH of the reaction mixture is adjusted to 1.0 using concentrated hydrochloric acid. The precipitated crystals were separated and dried to obtain 843 mg of 2-carboxy-εCAMP crystals.

Melting point: 220-202℃ (decomposed) Elemental analysis: C ₁₃ H ₁₂ N ₅ O ₈ P・1.5H ₂ O C H N Theoretical value (%) 36.57 3.47 16.61 Actual value (%) 36.79 3.54 16.51 Ultraviolet absorption spectrum : λ ^0.1N-HCl _nax 237.5, 276.5, 284.0 (shoulder), 306.0 (shoulder) n
m λ ^0.1N-NaOH _nax 237.5, 270.0 (shoulder), 322.0 nm By operating in the same manner as above but using 2-cyano-εCAMP instead of 2-carbamoyl-εCAMP, 2-carboxy-εCAMP is obtained.

Claims (1)

[Claims] 1. General formula (wherein R means a cyano group, carbamoyl group or carboxyl group) 2-substituted-
1,N ⁶ -etheno-adenosine-3',5'-cyclic phosphoric acid. 2 General formula (In the formula, X means a halogen atom) 2-halogeno-1,N ⁶ -etheno-adenosine-3',5'-cyclic phosphoric acid is reacted with an alkali cyanide. formula (wherein R means a cyano group, carbamoyl group or carboxyl group) 2-substituted-
1. Method for producing N ⁶ -etheno-adenosine-3',5'-cyclic phosphoric acid. 3. The method according to claim 2, wherein X is exchanged with a carbamoyl group or a carboxyl group by reacting with an alkali cyanide and then performing alkali hydrolysis.