JPS58162598A - Adenosine derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:The adenosine derivative of formulaI R<1> is lower alkyl, or (substituted) phenyl-substituted lower alkoxy; R<2> is lower alkoxy-carbonyl, lower alkyl or lower alkoxyalkyl or its salt. EXAMPLE:1-(1-Methyl-6-imino-1,6-dihydro-9H-purin-9-yl)-beta-D-ribofura nuronic acid methyl ester hydroiodide. USE:It has excellent activity to promote fibrolysis, and is useful as a remedy for thrombosis. PROCESS:The compound of formulaIwherein R<1> is lower alkoxy can be prepared by reacting the adenosine derivative of formula II with the halogen compound of formula R<3>X R<3>is (substituted) phenyl-substituted lower alkyl; X is halogen . Another compound of formulaIwherein R<1> is lower alkyl is obtained by reacting the adenosine derivative of formula III with the halogen compound of formula R<4>X (R<4> is lower alkyl).

Description

Detailed Description of the Invention The present invention is based on the general formula (where R1 represents a lower alkyl group or a lower alkoxy group, or a lower alkoxy group substituted with a phenyl group-substituted lower alkoxy group or a phenyl group having a substituent). The present invention relates to an adenosine derivative represented by the following formula (R2 represents a lower alkoxycarbonyl group, a lower alkyl group, or a lower alkoxyalkyl group) or a pharmacologically acceptable acid addition salt thereof, and a method for producing the same.

The compound (1) of the present invention is a novel compound, and is preferred among the compounds of the present invention represented by the above general formula (1), which has an excellent fibrinolytic promoting action and may be a useful pharmaceutical compound as a therapeutic agent for thrombosis. As a compound, R1 is an alkyl group having 1 to 2 carbon atoms,
Alkoxy group having 1 to 2 carbon atoms or formula -o (cHt)n
OY (However, Y is a carboxyl group.

a methoxycarbonyl group, acetylamino group, acetyloxy group, hydroxyl group, methylaminosulfonyl group, or a hydrogen atom, n is an integer of 1 to 2), and R2 is a methoxycarbonyl group, a methyl group, or Examples include compounds that have a methoxymethyl group.

Among the above compounds, particularly preferred compounds include those in which R1 is substituted with an alkyl group having 1 to 2 carbon atoms (methyl group, ethyl group), an alkoxy group having 1 to 2 carbon atoms (methoxy group, ethoxy group), or a phenyl group. carbon number 1~
2 alkoxy group (benzyloxy group, phenethyloxy group) or a phenyl group having at least one type selected from the group consisting of carboxyl group, methoxycarbonyl group, acetylamino group, hydroxyl group, acetyl group, and methylaminosulfonyl group as a substituent 1-2 carbon atoms substituted with
alkoxy groups (e.g. P-hydroxycarbonylbenzyloxy group, P-methoxycarbonylbenzyloxy group, P-acetylaminopenzyloxy group, P-methylaminosulfonylbenzyloxy group, P-hydroxyphenethyloxy group, P-acetoxyphenethyloxy group) ) and R2 is a methoxycarbonyl group, a methyl group, or a methoxymethyl group.

Among the compounds (1) of the present invention, compounds in which R1 is a lower alkoxy group, a lower alkoxy group substituted with a phenyl group, or a lower alkoxy group substituted with a phenyl group having a substituent have the general formula (wherein R2 is a lower alkoxy group). represents an alkoxycarbonyl group, a lower alkyl group, or a lower alkoxyalkyl group) and a compound represented by the general formula % (where R3 represents a lower alkyl group, or a lower alkyl group substituted with a phenyl group or (represents a lower alkyl group substituted with a phenyl group, X represents a halogen atom).In addition, in compound (1), R1 is a lower alkyl group. A compound represented by the general formula (where - represents the same meaning as above) and a compound represented by the general formula %Formula % (1) (However, R4 represents a lower alkyl group and X represents the same meaning as above) It can be produced by carrying out a condensation reaction with the compound represented by the formula.

In the above, the halogen atom represented by X is preferably a chlorine atom, an iodine atom, or a bromine atom. (1-A) and compound (1-A) or compound (II-B) and compound (1-B) can be carried out in a suitable solvent. As the solvent, dimethylformamide, dimethylacetamide, carbon tetrachloride, chloroform, dichloromethane, acetone, methanol, etc. can be used. The reaction can be carried out, for example, by dissolving the compound (1-A) or [■-B) in an appropriate solvent as mentioned above, adding the compound [A] or (1-BF) to this solution, and heating at 20 to 50°C.
Stir vigorously to make the process go smoothly.

The thus obtained compound (1) of the present invention or a pharmacologically acceptable acid addition salt thereof is effective against thrombosis and embolism, such as peripheral arteriovenous embolism, pulmonary embolism, and coronary artery occlusion, based on its strong fibrinolytic promoting action. It is useful for treating conditions such as myocardial infarction, cerebrovascular occlusion, and retinal arteriovenous thrombosis.

When compound (I) of the present invention is used as a medicine, it can be used either in free form or in the form of a pharmacologically acceptable acid addition salt. salts, sulfates, nitrates.

Inorganic acid salts such as phosphorous salts, hydrobromides, hydroiodides, perchlorates, acetates, chelates, malic salts, maleates, fumarates, citrates These acid addition salts, which include organic salts, can be prepared by ordinary salt-forming reactions or salt exchange equalization. In the case of salt exchange, for example, the acid addition salt of compound (1) is mixed with a suitable solvent (water, methanol, Inorganic acids or P-containing acids dissolved in ethanol, etc.)
It can be obtained as a crystalline or amorphous powder by adding ammonium salt, sodium salt, potassium salt, etc., and cooling the mixture.

Furthermore, the compound [1] of the present invention and its pharmacologically acceptable acid addition salts can be administered orally or parenterally, and can also be used in combination with a suitable pharmaceutical carrier. . Examples of pharmaceutical carriers include binders (syrup, gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, etc.), excipients (lactose, sugar, cornstarch, potassium phosphate, sorbitol, glycine, etc.)
, lubricants (magnesium stearate, talc, polyethylene glycol, silica, etc.), disintegrants (potato starch, etc.), and wetting agents (sodium lauryl sulfate, etc.). The dosage form may be a solid dosage form such as 9 tablets, 9 tablets, powder, capsule, or granule, or a liquid dosage form such as a solution or suspension. Furthermore, when administered parenterally, it can also be used as an injection or a drip injection.

9. All of the raw material compounds (1-B) of the present invention are known compounds, and the raw material compound (1-A) can be obtained by reacting the compound (1-B) with an oxidizing agent as described in Reference Examples. It can be easily manufactured by

Experimental example <Experimental method> (1) Fibrinolysis promotion effect by intravenous injection in rats The specimen was dissolved in physiological saline, and this solution was administered to a group of 4 rats (male 8D).
The mice were injected into the tail vein of a 6-week old) at a rate of 0°1j1j/100P body weight. A certain time after the injection, blood was collected from the abdominal aorta under ether anesthesia.

Ambrus et al.'s method [Current Φ Therapeutic Research; Vol. 12, No. 7.

451-473 (1970)], fibrinolysis was measured.

Furthermore, the fibrinolysis-promoting effect of the specimen is due to the euglobulin clot (euglobulin clot).
lobulin clot) dissolution time (Kn,'r
Fibrinolytic promoting effect (% activity) calculated as % activity using the above formula using the above formula as an index = In the table below, the lowest effective dose is 10% based on the above formula.
This represents the minimum dose required to exhibit the above fibrinolytic promoting effect.

(2) Dissolve the acute toxicity specimen in physiological saline, inject this solution intraperitoneally into a group of 4 mice (male, (1 (IY strain, 4 weeks old) K specimen, and check for mortality after 48 hours. From this, the maximum tolerated dose (maximum dose without death) was determined.

Results〉 The results are shown in the table below.

Example 1 Adenosine-5'-carboxylic acid methyl ester 0.5J
Dissolve P in dimethylformamide 5d, add 0.511111 methyl iodide, and stir overnight at room temperature. Then, ether is added and the precipitated crystals are collected by filtration. By recrystallizing from methanol, 1-methyladenosine-5'
-carboxylic acid methyl ester [i.e. 1-(1-methyl-6-imino-1,6-cyhydro-9H-purine-9-
yl)-β-D-lipofuranuronic acid methyl ester]・
0.6P of hydroiodide is obtained.

Yield: 81% I! LB198℃ (decomposition) NMR (DMEIO-D,) 8,78 (8,C!-H), 8.78 (8,O
*-H).

6, 14 (d, J=5.0Hz, O't-H),
4.61 (Tun J = 2.0Hs, 0H - H), 3.8
0(8,5'-Co.

C! lI> ) * 3-90 (8s 3 H,
-0Ht) Example 2 Adenosine-5'-carboxylic acid methyl ester o, s
By treating p and 0.5 d of ethyl iodide in the same manner as in Example 1, 1-ethyladenosine-5'-carboxylic acid methyl ester [i.e. -dihydro-9)(-purin-9-yl)
0.58 f of -β-D-ribofuranuronic acid methyl ester] pentahydride is obtained as a white powder.

Yield near 8% NMR (DM80-D@) s, 8 (b, 8, 02-H) e 8-8 (
ζSe Cs -H).

6.14 (d, J=5.0Hz, 0S-H), 3.
80 (8°-0OOOH3), 1.43 (t, J
-8,0Hz, 3H9CHIOH,-) Example 3 Adenosine-5'-carboxylic acid methyl nitrate oxide 0,5P to N, N-i lylamidoamide 51IjIc
Dissolve 9g and add 0.5d of ethyl trichloride. After stirring at room temperature, ether is added. The precipitate is collected by filtration and washed with ether to obtain 1-ethoxyadenosine-5.
'-Carboxylic acid methyl ester [i.e., 1-(1-ethoxy-6-imi2-1,6-sihydro-9H-purine-
9-yl)-/-D-lipofuranuronic acid methyl ester].0.5 P of hydroiodide is obtained as a pale yellow powder.

Yield: 63% NMR (DM80-D4) 8.72 (8,0 Min-III), 9.09 (8,
C@-)i).

e, 06 (tl, J 5.0 Hz, as
'-H) e 4.54 (d-Jy2.OHz,
ci-H), 3.70 (s, s'-0000Hm
), 1.43 (t, J = 7.5 Hz, 3H
, 0HjOHj −).

4.42 (q = J !7-5 Hz * 2 H
-OHs Mountain C-) Example 4 Adenosine-5'-carboxylic acid methyl ester "-oxide 0.27 P to N, N-dimethylacetamide 5-
Dissolve benzyl bromide in 1. Add Od and stir for 30 minutes. Next, ether was added and the precipitated crystals were collected by filtration. The crystals were then dissolved in a small amount of water, 10% ammonium perchlorate aqueous solution #4m was added, and the precipitated crystals were collected by filtration. Oxyadenosine-5'-
Carboxylic acid methyl ester [i.e. 1-(1-benzyloxy-6-imino-1,6-sihydro-9H-purin-9-yl)-β-D-lipofuranuronic acid methyl ester] perchlorate 0.38 p is obtained as colorless prismatic crystals.

Yield: 87% m, p, 194-198°C NMR (DM80-D.) 8.74 (8,0t-H), 8.85 (8,C5-H
), 6.03(d, J-5,0HB, Cf1-H
), 4.55 (d, J = 2.0HzCf<-H)
, 3.78 (8,5'-0000H3), 5.45
(8°No −c=*'@), 7.45(b, S
, 5H, aromatic proton) Example 5 1-(P-hydroxycarbonyl benzyloxy)adenosine-5'-carboxylic acid methyl ester [i.e., 1-(1-P-hydroxycarbonylbenzyloxy-6-imino-1,6-cyhydro 9H]) obtained as powder.

Yield: 94% NMR (DM80-D6): 8.83 (8,0l-H), 9.11 (8,Us
-H), 6.07 (d.

Jm5.0Hz, σt-”)s 4.57(b8.C
'4-1'l)e 3゜76 (8,5' -cooa
Small) * s, 53 (8-No-c) Il -adenosine-5'-carboxylic acid methyl ester W-oxide 0.
5P and P-monomethylbenzoic acid methyl ester 0.6
By performing the same treatment as in Example 4 using P, 1-(P
-methoxycarbonylbenzyloxy)adenosine-5
'-Carboxylic acid methyl ester [i.e. 1-(1-P-
methoxycarbonylbenzyloxy-6-imino-i,
e-dihydro-9H-purin-9-yl)-1-D-lipofuranuronic acid methyl ester] Hydrogen bromide 0,'
121 is obtained as a white powder.

Yield: 83% NMR (DM80-D,) 8.80 (8, (jt-H), 9.14 (8, U@-
H), 6.08(d-J” 5.0 Hz e
O; -H), 3.78 (S-5'-Co.

(8,:1. (:)-aooaH*), 7.90(
aromaitcproton) Example 7 Adenosine-5'-carboxylic acid methyl ester W-oxide 0.55 P and P-acetylaminobenzyl bromide o, e p Treated in the same manner as in Example 4 k
1-(P-acetylaminobenzyloxy)adenosine-51-carboxylic acid methyl ester (ill, 1-
(1-p-acetylaminobenzyloxy-6-imino-1,6-sihydro〇H-1 phosphorus-9-yl)-β-
D-lipofuranuronic acid methyl ester]/perchlorate 0
．． Get 95 P.

Yield: 96% m, p, 165°C (decomposed) (recrystallized from water) NMR (D
M80-DI) 8.82 (8-Cs-H) e a, 82 (8-Cs
-H) -6,05 (d, J proverb 5.0 turtle -0't-H),
4.57 (d, J Tomi 2.〇Upper bow-H), 3.76 (
8,5'-aooca, ), 5.37 (S.

No-0dantQNaooca3), 2.02(s,
3H,CtNH-(300Hn), 5.59 (4H
, aromatic protan) Practical Example 8 Adenosine-5'-carboxylic acid methyl ethyl N'-oxide 0.33 P and P-hydroxy 7enethyl bromide 1. 1-(P-hydroxyphenethyloxy)adenosine-5'-carboxylic acid methyl ester [i.e., 1-(1-
P-hydroxyphenethyloxy-6-imino-1,6
-Sihydro9H-purin-9-yl)-/-D-lipofuranuronic acid methyl ester] Hydrobromide 0.46
9 is obtained as a white powder.

Yield: 82% NMR (DM80-D4) 8.33 (8,C5-H), 9.16 (8,0s-H
), 6.15(d -J-5-OHl -c's
-H)e 3.81 (S -0OOOI(3) Example 9 Treated in the same manner as in Example 4 using adenosine-51-carboxylic acid methyl ester N'-oxide 0.339, P-acetoxif, netyl bromide 1.OP By doing 1
-(P-acetoxyphenethyloxy)adenosine-5
'-Carboxylic acid methyl ester [i.e. 1-(1-P-
Acetoxyphenethyloxy-6-imino-1,6-cyhydro-9H-purin-9-yl)-β-D-lipofuranuronic acid methyl ester] hydrobromide 0.397 as a white powder. Yield: 67 % NMR (DM80-D,) 8.85 (8,0s-H), 9.20 (s, 0s
-H), 6.15(a, J-5,0Hz dt-
a), 3.78(s,-cooca,), 2.28
(8,3L Q-ococas), 7. OO'(d
- Example 10 0.25 t of 5'-deoxyadenosine N'-oxide is dissolved in 5 dK of N,N-dimethylacetamide, 0.4 SP of P-acetylaminobenzyl bromide is added, and the mixture is stirred at room temperature for 3 hours. Then, ether is added, and the precipitate is collected by filtration and washed with ether. Then, after redissolving the mixture in methanol, ether was added and the precipitate was collected by filtration. 1-(P-acetylaminobenzyloxy)
-5'-deoxyadenosine [i.e., 1-(1-p-cetylaminobenzyloxy-6-imino-1,6-cyhydro-9H-purin-9-yl)-D-5-deoxylipofuranose]・Hydrobromide 0.29 S P
is obtained as a white powder.

Yield: 63.7% NMR (DM80-D6) 8.80 (8, Ct-H), 8.93 (8, O*-H
), 5.75 (de J = 5.0 Hs *
O'1-H), 1.33 (d, J-6,0H
z*4'-〇Hs ) m s, 40 (8-No -0
H2u NHCOCH3), 2.02 (8, Q-C
OOHs), 7.63 (m, 4H, aromat
ic proton) Example 11 1-(P-hydroxyphenethyloxy) -5'-deoxyadenosine [i.e., 1-(1-P-hydroxyphenethyloxy-
0°357 of 6-imino-1,6-cyhydro-9H-purin-9-yl)-β-D-5-deoxylipofuranose hydroiodide is obtained as a white powder.

Yield near λ6% NMR (DM80 Ds) 8.76 (8,02-H), 9.07 (S, 0s
-H), 5.93(a, J=5.0Hz+ai
-H)s 1.36(d, J-5,0Hz.

7.15((1,J-8,5Hz, 2H,)CI:
) Example 12 5'-methyladenosine N'-oxide 0.2P is N,
Dissolve 5jljK of N-dimethylacetamide, add 0.4t of P-acetaminobenzylbromide, and stir at room temperature for 3 hours. Ether is added to this, and the precipitate that precipitates is collected by filtration and washed with ether. Then, dissolve it again in methanol and add ether. By filtering the precipitate, 1-(P-acetaminobenzyloxy)5'-methyladenosine [i.e., 1-(1-P-acetaminobenzyloxy-6-imino-1,6-cyhydro9) Yield: Quantitative NMR (DM80-D6) 8.67 (s , c yi-H), &88(S, C@-H)
, 5.93(6*J=lI5.OHz*(
fl-H) e a, 30 (8* 0H2-OCR))
, 5.35 (8, No-0Hj-C>NT(OCH3
), 2.06(s, C>-NHCOCH3), 7
．． 80 (+!1.4H, arcmatic procedure
n) Example 13 5'-methyladenosine N'-oxide 0.2P and P-
N-methylsulfonylbenzyl bromide 0.5? 1-(P-N-
1-(1-P-N-methylaminosulfonylbenzyloxy-6-imino-1,6-cyhydro-9H-purin-9-yl)-D -5-0-
0.38 p of methyllipo-7lanose] odoriferous arsenate was obtained as a white powder.

Yield: Quantitative NMR (DM80-D,) 8.78 (S, 0x-H), 9.20 (S, O
・-)1), 6.00 (a, J=5.0Hz+ -H), 3.53 (s, -CH2-0 smooth), 5.36
(s, NOC Qso, -Nu・OH,).

2.53 (C>5ot)Ili(j), 7.9
(5(m, 4H, 21r□-matic proto
n) Reference Example 1 1) Adenosine-5'-carboxylic acid methyl ester 3,
Dissolve Of in dimethylformamide 1Qaj.

Add 2.7 JP of metachloroperbenzoic acid (80%) and stir at room temperature for 30 minutes. Then, liquefied reaction ether was added and the resulting precipitate was collected by filtration to obtain adenosine-5'-carboxylic acid methyl ester N'-oxide 2.9P.

Yield: 91% tu203-204°C (recrystallized from methanol-water) Reference Example 2 5'-Deoxyadenosine N'-oxide 1.49P is obtained by processing.

Yield: 82.7% m, P, 206-208°C (recrystallized from methanol) Reference Example 3 0.67 P of 5'-methyladenosine N'-oxide is obtained by processing.

Yield: 81.3% m, p, 204-205°C (recrystallized from methanol, colorless needle crystals) Voluntary procedure amendment 1967 6JJ // Mouth 1, case description Showa Lev 1996 patent application No. 4- yto'yg No. 2, Name of the invention Attenon no Sakezeni No Leopard Otsudo' Firefly water production 3, Relationship to the case of the person making Supplement I Patent applicant 3-21 Doshomachi, Higashi-ku, Osaka-shi, Osaka Prefecture Street address (〒541) (
295) Tanabe Pharmaceutical Co., Ltd. Representative Matsubara Part 4, Agent 3-16-89 Kashima, Yodogawa-ku, Osaka-shi, Osaka (532
5. The number of inventions will increase due to the amendment. 1. "T cetyl group" on page 8, line 1 of the specification is corrected to "acetyloxy group."

λ　At the end of the 5th line from the bottom of page 20 "No-C car" “No-C C<3　Corrected to J.

3, page 27, line O "P-shoulder methyl" Corrected to "P-N-methylamyl."

Claims (1)

[Claims] 1) General formula (where R1 represents a lower alkyl group or a lower alkoxy group, or a phenyl group-substituted lower alkoxy group or a lower alkoxy group substituted with a phenyl group having a substituent, and R2 represents a lower alkoxycarbonyl group, a lower alkyl group, or a lower alkoxyalkyl group) or a pharmacologically acceptable acid addition salt thereof. 2) If the general formula (1) K is ignored, R1 is an alkyl group having 1 to 2 carbon atoms, an alkoxy group having 1 to 2 carbon atoms, or a
H,)n -Q-y (However, Y is a carboxyl group. It represents a methoxycarbonyl group, an acetylamino group, an acetyloxy group, a hydroxyl group, a methylaminosulfonyl group, or a hydrogen atom, and n represents an integer of 1 to 2) The compound according to claim 1, wherein R2 is a group represented by the following formula: and R2 is a methoxycarbonyl group, a methyl group, or a methoxymethyl group. 3) -4 Formula (1) Km and R1 is a methyl group, ethyl group, ethoxy group, benzyloxy group, P-hydroxycarbonylbenzyloxy group, P-methoxycarbonylbenzyloxy group, P-acetylaminobenzyloxy group, P -hydroxyphenethyloxy group, P-acetoxyphenethyloxy group, or P-methylaminosulfonylbenzyloxy group, and R1 is a methoxycarbonyl group, methyl group, or methoxymethyl group, according to claim 1 or 2. compound. 4) Adenosine derivatives represented by the general formula (wherein R2 represents a lower alkoxycarbonyl group, lower alkyl group, or lower alkoxyalkyl group) and the general formula % (wherein R3 represents a lower alkyl group or 7enyl) Represents a lower alkyl group substituted with a group-substituted lower alkyl group or a lower alkyl group substituted with a peryanyl group (having a substituent), and X represents a halogen atom) is reacted with a halogen compound represented by allowable steep addition (however, IN
and R3 have the same meanings as above) or a pharmaceutically acceptable acid addition salt thereof. 5) Adenosine derivatives represented by the general formula (wherein R2 represents a lower alkoxycarbonyl group, lower alkyl group, or lower alkoxyalkyl group) and the general formula % (wherein R4 represents a lower alkyl group and X is a halogen atom) (representing R11 and R4 as above) and optionally converting the reaction product into a pharmacologically acceptable acid addition salt (wherein R11 and R4 are A method for producing an adenosine derivative or a pharmacologically acceptable acid addition salt thereof, which has the same meaning as