JPS58180498A - Novel adenosine derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound (acid addition salt) shown by the formula I (R<1> is lower alkanoyl; R<2> is H or lower alkanoyl; R<3> is lower alkyl). EXAMPLE:2'-O-Acetyladenosine-5'-carboxylic acid methyl ester. USE:Having improved fibrinolysic promoting action, useful as a remedy for thrombosis or embolus diseases such as peripheral arteria thrombosis, pulmonary embolism, coronary occlusion, myocardial infarction, cerebrovascular occlusion, retinal thrombosis, etc. PROCESS:For example, a compound (e.g., a adenosine-5-carboxylic acid methyl ester) shown by the formula II(R<4> and R<5> are lower alkyl) is hydrolyzed with an acid, and, if necessary, the reaction product is made into its acid addition salt, to give a compound shown by the formula I wherein group R<2> is H and group R<1> is COR<5>.

Description

[Detailed description of the invention]

The present invention relates to a novel adenosine derivative and a method for producing the same,
More specifically, the general formula (where R1 is a lower γ-alkanoyl group, R2 is a hydrogen atom or a lower alkanoyl group, and R3 is 5
- Represents a lower alkyl group. ) The present invention relates to an adenosine derivative shown in C and a method for producing the same. Compound CII of the present invention is a new compound and a useful pharmaceutical compound having an excellent fibrinolytic promoting action. Examples of the compounds of the present invention include, in the general formula CII, R1 is a lower alkanoyl group having 2 to 5 carbon atoms, and Ha is a hydrogen atom or a lower alkanoyl group having 2 to 5 carbon atoms. , both are lower γ with carbon number of 2 to 5 fathoms.
Examples include compounds in which the group is a lucanoyl group and Ha is a lower alkyl group having 1 to 4 carbon atoms. Among these, preferred compounds include compounds in which R1 is an acetyl group and R1 is a hydrogen atom, and compounds in which R1 and R8 are both an acetyl group, a propionyl group, a butyryl group, or a valeryl group. According to the present invention, the compound CI'J in which R1 is a lower alkanoyl group and R2 is a hydrogen atom has the general formula (I?3 has the same meaning as above, I and R5
represents a lower alkyl group. ) Acid hydrolyzes the compound represented by the general formula (however, P
and P have the same meanings as above. ) can be produced by preparing the compound [
(2) A compound in which Pl and R2 are both lower alkanoyl groups can be obtained by reacting a compound represented by the general formula -7- (wherein, Y3 represents a lower alkyl group) with a lower alkanoylating agent to obtain the compound represented by the general formula ( However, "furnace" has the same meaning as above, and EA represents a lower alkyl group. One method of the present invention will be specifically explained below. Acid hydrolysis of compound [1] can be easily carried out by reacting compound [11] with an acid. The acid used in this reaction is a formic acid-aqueous solution. Examples include acetic acid-aqueous solution and dilute hydrochloric acid. This reaction is 20
Preferably, the reaction is carried out at a temperature of 70°C to 70°C. Thus, the compound (
1-a] can be easily carried out in a suitable solvent. Examples of the lower alkanoylating agent used in this reaction include acetic anhydride, Preferred examples include propionic anhydride, acetic anhydride, valeric anhydride, etc. Examples of the reaction solvent include pyridine, dimethylformamide, and dimethylacetamide.
Preferably, the reaction is carried out at a temperature of 0 to 50°C. Thus, the compound (
[-b] is obtained. It can be effectively used for the treatment of diabetic embolism. Urokinase is known as a fibrinolytic promoter, but urokinase has no effect when administered orally, and is mostly administered by drop injection. In contrast, the compound [1] of the present invention is effective even when administered orally.
It also has the characteristic of having a fibrinolysis-promoting effect. When the γ-denosine derivative CI'l of the present invention is used as a medicine, it can be used as a free base or with a pharmacologically acceptable acid addition salt thereof. acid addition salts and

[7, 9, for example, inorganic acid salts such as hydrochloride, hydrobromide, or oxalate salts such as oxalate, citrate, malate, etc. (preferably 17). Adenosine derivatives of the present invention [ ■] as a medicine (e.g. gum arabic, gelatin, sorbitol, tragatu, polyvinylpyrrolidone, etc.), excipients (e.g. λ is lactose, sugar, cornstarch, phosphoric acid (e.g. potato starch), wetting agent, etc.) (for example,
The dosage forms in which lauryl (quick brewing sodium, etc.) can be used include solid preparations such as tablets, gunpowders, powders, capsules, and granules, or liquid preparations such as solutions and suspensions. When administered parenterally, it can be used as an injection or an infusion. Note that 1 the raw material compound of the present invention ['[I'] is adenosine-5
'-Carboxylic acid [=β-D-1-(6-amino-9H-
Purin-9-yl)-1-deoxy-ribofuranuronic acid] is easily reacted with a compound represented by the general formula % (where P4 and 〆 have the same meanings as above). can be manufactured. Example 1 A mixture of +1+ adenosine-5'-carboxylic acid methyl ester 5,909, methyl orthoacetate 7.20 g,) lychloro-11-orthoacetic acid 7.8411 and dioxane 120 is stirred overnight at room temperature. After the reaction is completed, the reaction solution is poured into 120 mA of a 5% sodium bicarbonate aqueous solution, and the mixed solution is extracted with chloroform. After washing the chloroform layer with water,
Dry over anhydrous sodium sulfate and evaporate the solvent. By recrystallizing the obtained crystals from methanol, prismatic crystals of f,3'0-methoxyethylideneadenosine-5'-
Carboxylic acid methyl ester 633f is obtained. Yield 902
% +2+f, (-o-methoxyethylidene adenosine-
5'-carboxylic acid methyl ester 1. Dissolve Of in 70% aqueous acetic acid @liquid 4me and leave it for 20 minutes at room temperature. After the reaction is complete, add ether to the reaction solution to precipitate.
1 crystal: #i:i. By recrystallizing the obtained crystals (from methanol), a colorless prism product of 2'-〇-acetyladenosine-
5'-carboxylic acid methyl ester 075 is obtained. Yield 78% mp, 205°C/~207°C N MR (IMSO-d6) δ<ppm): 8
．． 15 (s, IH, C2-Fl), 8.38 (
s, IH, CB-J/)6, 30 (d,/”'
5FIz+I Fl, C; El), 4.5
5 (d. J-3,0Hz, I HlCa H), 205
(s r 3H+ Cz 〇-COCI-13),
3.70 (S, 3H, -COOCFI3) Example 2 Adenosine-5'-carboxylic acid methyl ester 2°Of
Dissolve in 30 me of pyridine and add 3 me of acetic anhydride. After stirring at room temperature for 30 minutes, aged chill was added to the reaction solution, and the precipitated crystals were dried in a furnace. The resulting crystals were recrystallized from methanol to obtain 2.39 ml of colorless lism crystals of 2',3'-0-diacetylaquinosyndercarboxylic acid methyl ester. Yield 90% mp, 212°C NrfR(CDCl'3) δ(ppm): 8
．． 2”l(s, IH,C,,-H), 8.37 (
s, IH, C3-H) a, 38 (d, J-5, 5
#z, I HlCs /'/ ), 4.80 (d
+/=2.0Hz, IH, C', -1=), 2.0
3 (s, 3H, CQO-adenosine-5'-carboxylic acid methyl ester 113-47& is dissolved in pyridine 15me, and propionic anhydride 260y is added. After stirring at room temperature for 3 hours, n-hexane is added to the reaction solution. The precipitated crystals are collected. The resulting crystals are recrystallized from methanol to obtain colorless needle-like crystals of f, a'-o-diprobionyladenosyndercarboxylic acid methyl ester 168f. Yield: 82.7 % mp, 183°C to 184°C NMP (CDCe3) δCppm): 8.34
(S+ 1#, C2#), 8.41 (s, IH
,CB H)5''? 6, 35 (d, J ” 粍Lrz, IH, C+ H)
, 4.76 ((/11-1.8/'/z, In2
Bow -t/), 1.07 (t, J=6.5Hz. 3#,"'3), 1.20 (/+/-6,5
11zI3H,-C#a). 3,84 (s, 3H+ -COOCFIa) Example 4 Adenosine-5'-carboxylic acid methyl ester 1°47
9 in pyridine 10me, butyric anhydride 36169
After stirring for 5 hours, the reaction solution was concentrated under ant pressure. The resulting residue was dissolved in ether, washed with a 2% aqueous solution of sodium hydrogencarbonate and then with water, dried, and the solvent was distilled off. The resulting residue is treated with ether and isopropyl ether to obtain r,f-〇-dibutyryladenosine-5'-carboxylic acid methyl ester 15y in the form of an amorphous powder. Yield 528% N IW E (CDCe3) δ (ppm): s
, 35 (5,1#, C2H)+8.43 (s,
tH, ca Fl) 6, 41 (d, J-6, 0H
z, IH, C: H), 4.76 (d. J-” 1.6Hz, l#, C'4-Fl),
0.86 (/, J-"7.0FIz. Example 5 Dissolve IOg of adenosin-dercarboxylic acid methyl ester in 20ml of pyridine, and add 20me of valeric anhydride. After stirring at room temperature for 4 hours, add to the reaction solution. Add n-hexane, stir, and collect the precipitated powder.The obtained powder is washed with n-hexane and dried to obtain 2',3'-o-divaleryladenosine in the form of amorphous powder. Obtain 104 g of 5'-carboxylic acid methyl ester. Yield: 66% -15-NQIR(DMSO-d) δCppm)
: 8.16 (s, IH, C2-H), 840 (S
, IH, C3-H) 6, 38 (d, / "" 5
．． 5H1, IH, Bow-H), 4.86 (br. s, IFI, Bow-H), 07-11 (m16H9-CH
3X2). 3,72 (s, 3H, -COOCH3) Experimental Example 1 [Fibrinolysis promotion effect by intravenous injection in rats] The sample was dissolved in physiological saline, and this solution was added to a group of 4 rats (male SD strain, 6 weeks old). ) was injected into the tail vein at a ratio of 01me/100y body weight. Five minutes after administration, blood was collected from the abdominal aorta under ether anesthesia, and the blood was collected using the method of Ambrus et al. [Current Therapeutic Research: Vol. 12, No. 7]
issue. 451-473 (1970)]. The fibrinolytic promoting effect of the specimen is determined by the dissolution time (E) of the euglobulin clot (guglobulin clot).
LT) was used as an index and Schiff, and the % activity was determined by the following formula, and when the activity was 10% or more, it was judged as effective. Fibrinolytic promoting effect (% activity) - The maximum dose studied was 3 my/Kh, and this administration of FJ
-@ If it was determined that the compound was self-effective, the dose was lowered by a common ratio of 3 and the lowest effective dose was determined for each compound. [Fibrinolysis promoting effect by oral administration to rats] An aqueous solution of the specimen was orally administered to a group of 3 rats (male SD strain, 7 weeks old) using a probe at a ratio of 5πre/l<9. Thirty minutes after oral administration, blood was collected from the abdominal aorta under ether anesthesia. Thereafter, the tau fibrinolytic activity was measured in the same manner as in the case of intravenous administration, and the lowest effective dose was determined. The highest dose to be studied is 1 OOrng / ~, and if this dose is determined to be effective, the dose is lowered by a common ratio of 3 to find the lowest effective dose for each compound [Acute toxicity] A group of 4 mice (male, DD strain, 4 weeks old) was injected intraperitoneally with the specimen, and the maximum tolerated dose (maximum dose at which no deaths were observed) was determined by the presence or absence of death 48 hours later. I asked for [Results] The results are shown in Table 1 below. Table 1 (Test compounds) 1i2'-0-acetyladenosine-5'-carboxylic acid methyl ester 2;2', 0-diacetyladenosine-57-
carboxylic acid methyl ester

Claims (1)

[Claims] fl+ An adenosine derivative represented by the general formula (wherein, 〆 represents a lower alkanoyl group, y2 represents a hydrogen atom or a lower alkanoyl group, and /?3 represents a lower alkyl group) or its pharmacological Acceptable acid addition salts. (2) In the general formula], Pl is a lower alkanoyl group having 2 to 5 carbon atoms, and I? The compound according to Claim 1, wherein 2 is a hydrogen atom; 2-(3) General formula date]; Claim 1, wherein R1 and R2 are lower alkanoyl groups having 2 to 5 carbon atoms;
Compounds described in Section. (4) A compound represented by the general formula (where /?3.R' and /?5 represent a lower alkyl group) is subjected to acid hydrolysis, and then, if desired, the product is treated with its pharmacologically acceptable acid. A method for producing an adenosine derivative or a pharmacologically acceptable acid addition salt thereof, characterized in that the adenosine derivative is prepared as an Inn salt. (R5) A compound represented by the general formula (7/?3 represents a lower alkyl group) is reacted with a lower alkanoylating agent, and then, if desired, the product is subjected to a pharmacologically acceptable acidification [III]
It is represented by the general formula (where tj, R3 has the same meaning as above, and ``*'' represents a lower alkyl group), which is characterized in that it is used as a salt. permission to
L″+filtered acid 11 [1 Salt production method.