JPH07118156A - Adenosine deaminase inhibitor - Google Patents

Abstract

PURPOSE:To provide an adenosine deaminase inhibitor containing an adenosine derivative as the active component. CONSTITUTION:A compound of the formula (R1, R2 and R3 are each H or an alkyl; R is H, an alkyl, an alkenyl, an alkynyl, an alkoxy, phenyl, OH, amino, a halogen, etc.; X is H, an alkyl, a cycloalkyl, etc.), e.g. 2'-O-methyladenosine is contained as the active component. This inhibitor is useful for prevention and therapy of ischemic heart disease, diseases caused by cerebrovascular disorder, kidney diseases, inframmatory allergic diseases, etc. In addition, this inhibitor can inactivate active oxygen generated at an ischemic part in recirculation of blood after an operation and is, therefore, useful for prevention and therapy of postoperative complicated diseases. The dosage is 0.1 to 5000mg, preferably 0.2 to 3000mg/day per an adult in the case of oral administration. One third or tenth the dosage in the case of oral administration is administrated in the case of parenteral administration such as injection.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an adenosine deaminase inhibitor containing at least one adenosine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0002]

BACKGROUND OF THE INVENTION Adenosine deaminase is an enzyme that produces inosine by the deamination of adenosine in the living body, and is widely present in the animal and microbial kingdoms. By inhibiting this adenosine deaminase, the concentration of adenosine in the tissue is increased and, conversely, the concentration of inosine is decreased, and inactivation of endogenous adenosine is suppressed. In tissue ischemia, neutrophils produce active oxygen, and adenosine not only inhibits the production of this active oxygen but also has a function of directly eliminating the produced active oxygen. Further, by lowering the concentration of inosine, the supply of hypoxanthine, which is a substrate of the xanthine-xanthine oxidase system, which is one of the active oxygen producing systems, is reduced. Such an adenosine deaminase inhibitor having an action of inhibiting and eliminating active oxygen species is known to exhibit pharmacological actions such as coronary / cerebral vascular circulation improving action, renal disease preventing / treating action, and anti-inflammatory action. . The present inventor
As a result of continuing research on alkylated adenosine derivatives, it was found that the compound of the present invention has an excellent adenosine deaminase inhibitory action, and the present invention was completed.

[0003]

An object of the present invention is to provide a pharmaceutical composition containing an adenosine derivative having an adenosine deaminase inhibitory action as an active ingredient.

[0004]

The present invention is an adenosine deaminase inhibitor containing, as an active ingredient, at least one compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

[Chemical 4] [In the formula, R ₁ , R ₂ and R ₃ represent hydrogen or an alkyl group, and R represents hydrogen, an alkyl group, an alkenyl group, an alkynyl group, a hydroxyalkynyl group, an alkoxy group, a phenyl group, a hydroxyl group, an amino group, an alkylamino group. Represents a hydrogen atom, an alkyl group, an alkynyl group, an allyl group, a methallyl group, a cycloalkyl group, an alkyl group having one or more hydroxyl groups, a phenyl group (one or more halogens, a lower alkyl group). , Optionally substituted with a lower alkoxy group and / or a trifluoromethyl group), one or more phenyl groups (substituted with one or more halogen, lower alkyl group, lower alkoxy group and / or trifluoromethyl group) May have), a bicycloalkyl group, a naphthylalkyl group, an acenaphthylenylalkyl group or Represents a group represented by the following general formula (II) or general formula (III),

[Chemical 5]

[Chemical 6] , - - -CH ₂ hydrogen or hydroxyl, A is Z is hydrogen, hydroxyl or a lower alkoxy group, Q is O -, - S- or a direct bond, Y is - (CH _{2) n} - or a direct bond, n represents 1 The integers from 3 to 3 and the broken line represent a single bond or a double bond. However,
Any one of R ₁ , R ₂ and R ₃ represents a lower alkyl group. ]

In the above general formula (I), R ₁ , R ₂ and R ₃
Each is the same or different and is hydrogen or an alkyl group, preferably R ₁ is hydrogen or methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-
Butyl, pentyl, isopentyl, neopentyl, t-
It represents a linear or branched alkyl group having 1 to 10 carbon atoms such as pentyl, hexyl, dimethylbutyl, heptyl, octyl, nonyl, decyl, and R ₂ and R ₃ are hydrogen or methyl, ethyl, propyl, isopropyl, It represents a linear or branched alkyl group having 1 to 4 carbon atoms such as butyl, isobutyl, sec-butyl, t-butyl, and particularly preferably R ₃ represents hydrogen. However, any one of R ₁ , R ₂ and R ₃ represents an alkyl group.

R is hydrogen, an alkyl group, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl, dimethylbutyl, heptyl, octyl. , Nonyl, decyl, dodecyl, stearyl and other linear or branched alkyl groups having 1 to 20 carbon atoms, alkenyl groups, preferably ethenyl, 1-propenyl, 2-propenyl, 1-butenyl,
A straight-chain or branched C2-C4 alkenyl group such as 2-butenyl and 3-butenyl, an alkynyl group, preferably ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3- Butynyl, sec-butynyl, pentynyl, isopentinyl, 2-pentynyl, 3
-Pentynyl, 4-pentynyl, hexynyl, dimethylbutynyl, heptynyl, octynyl, nonynyl, decynyl, stearinyl and the like straight-chain or branched carbon atoms 2 to 2
0 alkynyl group, hydroxyalkynyl group, preferably hydroxyalkynyl group having a hydroxyl group attached to the alkynyl group, alkoxy group, preferably methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy and the like. A chain or branched alkoxy group having 1 to 4 carbon atoms, a phenyl group, a hydroxyl group, an amino group, an alkylamino group, preferably methylamino, dimethylamino, ethylamino, diethylamino, methylethylamino, propylamino, isopropylamino, Butylamino, isobutylamino, sec-
Linear or branched carbon such as butylamino, t-butylamino, pentylamino, isopentylamino, neopentylamino, t-pentylamino, hexylamino, dimethylbutylamino, heptylamino, octylamino, nonylamino, decylamino It represents a monoalkylamino group, a dialkylamino group, a phenylamino group or a halogen such as fluorine, chlorine, bromine or iodine of the formulas 1 to 10.

X is hydrogen, an alkyl group, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl, dimethylbutyl and the like. Straight-chain or branched alkyl group having 1 to 6 carbon atoms, alkynyl group, preferably propynyl, butynyl, pentynyl, hexynyl, heptynyl, etc., alkynyl group having 1 to 7 carbon atoms, allyl group, methallyl group, cycloalkyl group , Preferably a cycloalkyl group having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, an alkyl group having 1 or more hydroxyl groups, and preferably methyl or ethyl having 1 or 2 hydroxyl groups. , Propyl,
Isopropyl, butyl, isobutyl, sec-butyl,
A linear or branched alkyl group having 1 to 4 carbon atoms such as t-butyl, a phenyl group (which may be substituted with one or more halogen, a lower alkyl group, a lower alkoxy group and / or a trifluoromethyl group). ) One or more phenyl groups (may be substituted with one or more halogen, lower alkyl group, lower alkoxy group and / or trifluoromethyl group)
A phenylalkyl group or diphenylalkyl group having 1 or 2 of the above-mentioned substituted phenyl groups bonded to a linear or branched alkyl group having 1 to 3 carbon atoms such as methyl, ethyl, propyl and isopropyl. , A bicycloalkyl group, preferably an endo- or exo-bicyclo [2,2,1] heptyl group, a naphthylalkyl group, preferably an alkyl group having 1 to 3 carbon atoms such as methyl, ethyl, propyl and isopropyl, and a naphthyl group. A naphthaylenyl group and an acenaphthylenylalkyl group (including 1,2-dihydro form) bound to each other, preferably an acenaphthylenyl group bonded to an alkyl group having 1 to 3 carbon atoms such as methyl, ethyl, propyl and isopropyl. Represented by a phenylenylalkyl group or the above general formula (II) or general formula (III) The stands, particularly preferably X represents an alkyl group having 1 to 3 carbon hydrogen or carbon.

In the general formula (II) and the general formula (III),
Z represents hydrogen, a hydroxyl group or a lower alkoxy group, preferably a linear or branched alkoxy group having 1 to 3 carbon atoms such as methoxy, ethoxy, propoxy and isopropoxy.
Q represents hydrogen or a hydroxyl group, A is -CH ₂ -, - O-,
It represents -S- or a direct bond, Y is - (CH _{2) n} - or a direct bond, n represents an integer of 1 to 3, the broken line represents a single bond or a double bond.

Examples of the compound contained as an active ingredient of the adenosine deaminase inhibitor of the present invention include the following compounds. [Compound 1] 2'-O-methyladenosine [Compound 2] 3'-O-methyladenosine [Compound 3] 2'-O-ethyladenosine [Compound 4] 2'-O-n-butyladenosine [Compound 5] 2,2'-O-Dimethyladenosine [Compound 6] 2,3'-O-Dimethyladenosine [Compound 7] 2-Isopropyl-2'-O-methyladenosine [Compound 8] 2-Isopropyl-3'-O- Methyladenosine [Compound 9] 2-Methoxy-3'-O-methyladenosine [Compound 10] 2-Methyl-2'-O-ethyladenosine

[Compound 11] 2-methyl-2'-O-
n-Butyladenosine [Compound 12] 5'-O-Methyladenosine [Compound 13] 5'-O-n-Butyladenosine [Compound 14] 2 ', 5'-O-Dimethyladenosine [Compound 15] 3', 5 '-O- dimethyl adenosine [compound 16] 2,5'-O- dimethyl adenosine [compound 17] 2-methyl-5'-O-n-butyl-adenosine [compound 18] N ^6, 2'-O- dimethyl adenosine [compound 19] N ⁶ - ethyl -2'-O-methyl adenosine [compound 20] N ^6-n-butyl -2'-O-methyl adenosine

[Compound 21] N ⁶ -methyl-2′-O
- ethyl adenosine [compound 22] N ⁶ - methyl -2'-O-n-butyl-adenosine [Compound 23] N ⁶ - methyl -2'-O-n-hexyl-adenosine [Compound 24] N ⁶ - methyl-2 ' -O-n-octyl adenosine [compound 25] N ^6, 5'-O- dimethyl adenosine [compound 26] N ^{6-n-butyl-5'-O-methyl} adenosine [compound 27] 2, N ^6, 2 ' -O- trimethyl adenosine [compound 28] 2, N ⁶ - dimethyl -2'-O-ethyl adenosine [compound 29] N ^6-n-butyl -2,2'-O-dimethyl adenosine [compound 30] N ^6, 2'-O-dimethyl-2-hexyladenosine

[0012] [Compound 31] N ^6, 2'-O- dimethyl-2-decyl adenosine [Compound 32] N ^6, 2'-O- dimethyl-2- (1
- hex-1-sulfonyl) adenosine [Compound 33] N ^6, 2'-O- dimethyl-2- (1
- dodecyl-1-sulfonyl) adenosine [Compound 34] 2, N ^6, 5'-O-trimethyl adenosine [Compound 35] N ^6-n-butyl -2,5'-O- dimethyl adenosine [Compound 36] 2, N ^6, 3'-O- trimethyl adenosine [compound 37] 2-phenyl -2'-O-methyl adenosine [compound 38] 2-phenyl-3'-O-methyl adenosine [compound 39] 2-hydroxy-2 ' -O-methyladenosine [Compound 40] 2-hydroxy-3'-O-methyladenosine

[Compound 41] 2-chloro-2'-O-
Methyladenosine [Compound 42] 2-Chloro-3'-O-methyladenosine [Compound 43] 2-Bromo-2'-O-methyladenosine [Compound 44] 2-Bromo-3'-O-methyladenosine [Compound 45] ] 2-bromo -N ^6, 2'-O- dimethyl adenosine [compound 46] 2-bromo -N ^6, 3'-O- dimethyl adenosine [compound 47] 2-iodo -2'-O-methyl adenosine [compound 48] 2-Iodo-3′-O-methyladenosine [Compound 49] 2-Fluoro-2′-O-methyladenosine [Compound 50] 2-Amino-2′-O-methyladenosine

[Compound 51] 2-amino-3'-O-
Methyladenosine [Compound 52] 2-Pentylamino-2'-O-methyladenosine [Compound 53] 2-Phenylamino-2'-O-methyladenosine [Compound 54] 2-Phenylamino-3'-O-methyladenosine [compound 55] 2-phenyl-amino -N ^6, 2'-O
- dimethyl adenosine [Compound 56] 2-phenyl-amino -N ^6, 3'-O
-Dimethyladenosine [Compound 57] 2- (3-hydroxy-1-propyi)
1-nyl) -2'-O-methyladenosine [Compound 58] 2- (3-hydroxy-1-propyi)
1-sulfonyl)-3'-O-methyl adenosine [Compound 59] 2 ', 3'-O- dimethyl adenosine [Compound 60] ^{N 6, 2', 3'-} O- trimethyl adenosine

[Compound 61] N ⁶ -methyl-2 ′,
3'-O- diethyl adenosine [Compound 62] N ^6-n-butyl -2 ', 3'-O-
Dimethyl adenosine [Compound 63] 2,2 ', 3'-O- trimethyl adenosine [Compound 64] ^{2, N 6, 2',} 3'-O- tetramethyl adenosine [Compound 65] N ⁶ - Allyl-2' O-methyladenosine [Compound 66] N ⁶ -methallyl-2′-O-methyladenosine [Compound 67] N ^6- (2,3-dihydroxypropyl) -2′-O-methyladenosine [Compound 68] N ⁶ − cyclopropyl -2'-O-methyl adenosine [compound 69] N ⁶ - cyclopentyl -2'-O-methyl adenosine [compound 70] N ⁶ - cyclopentyl -2'-O-ethyl adenosine

[Compound 71] N ⁶ -Cyclopentyl-
2,2'-O-Dimethyl adenosine [Compound 72] N ⁶ - cyclopentyl-2-bromo -
2′-O-methyladenosine [Compound 73] N ⁶ -Cyclohexyl-2′-O-methyladenosine [Compound 74] N ⁶ -Cyclohexyl-2,2′-O
- dimethyl adenosine [Compound 75] N ⁶ - cycloheptyl -2'-O-methyl adenosine [Compound 76] N ^{6-p-methoxyphenyl-2'}
O-methyladenosine [Compound 77] N ⁶ -p-fluorophenyl-2′-
O-methyladenosine [Compound 78] N ⁶ -p-chlorophenyl-2′-O
- methyladenosine [Compound 79] N ⁶ - benzyl -2'-O-methyl adenosine [Compound 80] N ⁶ - (R) - phenyl - isopropyl -2'-O-methyl adenosine

[Compound 81] N ^6- (2,2-diphenylethyl) -2'-O-methyladenosine [Compound 82] N ^6- (exo-dicyclo [2,2,2]
1] heptyl -2'-O-methyl adenosine [Compound 83] N ⁶ - (End - dicyclohexyl [2,2,
1] heptyl -2'-O-methyl adenosine [Compound 84] N ⁶ - (1-naphthyl) methyl-2 '
-O- methyl adenosine [Compound 85] N ⁶ - (1-acenaphthylenyl) methyl -2'-O-methyl adenosine [Compound 86] N ⁶ - (1,2-dihydro-1-acenaphthylenyl) methyl -2'-O - methyladenosine [compound 87] N ⁶ - (2,3-dihydro ─1H- inden-1-yl) -2'-O-methyl adenosine [compound 88] N ⁶ - (2,3-dihydro ─1H- indene 2-yl) -2'-O-methyl adenosine [compound 89] N ⁶ - (2,3-dihydro ─1H- inden-1-yl) methyl -2'-O-methyl adenosine [compound 90] N ⁶ -(3H-inden-1-yl)
Methyl-2'-O-methyladenosine

[Compound 91] N ^6- (5-methoxy-
2,3-dihydro-1H-inden-1-yl) -2 '
-O- methyl adenosine [Compound 92] N ⁶ - (1-tetrahydronaphthyl)
-2'-O-methyl adenosine [Compound 93] N ⁶ - (2-tetrahydronaphthyl)
-2'-O-methyl adenosine [Compound 94] N ⁶ - (3,4-dihydro-1-naphthyl) methyl -2'-O-methyl adenosine [Compound 95] N ⁶ - (5-hydroxy-1-tetrahydro naphthyl) -2'-O-methyl adenosine [compound 96] N ⁶ - (1-hydroxy-1-tetrahydronaphthyl) methyl -2'-O-methyl adenosine [compound 97] N ⁶ - (5-methoxy-1- tetrahydronaphthyl) -2'-O-methyl adenosine [compound 98] N ⁶ - (6- methoxy-1-tetrahydronaphthyl) -2'-O-methyl adenosine [compound 99] N ⁶ - (7- methoxy-1 tetrahydronaphthyl) -2'-O-methyl adenosine [compound 100] N ⁶ - (4-chromanyl) -2'
O-methyladenosine

[0019] [Compound 101] N ⁶ - (4-thiochromanyl) -2'-O-methyl adenosine [Compound 102] N ^{6-9-fluorenyl} -2'-O
- methyladenosine [Compound 103] N ⁶ - (9-fluorenyl) methyl -2'-O-methyl adenosine [Compound 104] N ⁶ - (9-hydroxy-9-fluorenyl) methyl -2'-O-methyl adenosine [ compound 105] N ⁶ - (9-xanthenyl) methyl -2'-O-methyl adenosine

The above-mentioned compounds of the present invention are disclosed, for example, in JP-A-63-
239294, JP-A-2-184696,
It can be produced by the method described in JP-A-2-218689.

The adenosine derivative of the present invention includes a pharmaceutically acceptable salt of the compound represented by the above general formula, for example, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, perchloric acid, thiocyan. Acid, boric acid, formic acid, acetic acid, haloacetic acid, propionic acid, glycolic acid, citric acid, tartaric acid, succinic acid, gluconic acid, lactic acid, malonic acid, fumaric acid, anthranilic acid, benzoic acid, cinnamic acid, p-toluene Acid addition salts with sulfonic acid, naphthalene sulfonic acid, sulfanilic acid, etc., or alkali metals such as sodium, potassium, etc.
Examples thereof include salts with alkaline earth metals such as calcium and magnesium or metals such as aluminum.

The adenosine derivatives of the present invention include their metal complex compounds, and include, for example, zinc, nickel, cobalt,
Complex compounds with copper, iron and the like can be mentioned. These salts or metal complex compounds can be produced from the free furanone derivative of the present invention or converted into each other by a known method. Further, when the compound of the present invention has stereoisomers such as cis-trans isomers, optical isomers and conformational isomers, the present invention includes any of them.

[0023]

【effect】

1. Adenosine deaminase inhibitory effect This enzyme reaction is performed at 25 ° C in 0.05M phosphate buffer (pH
7.5). A reaction solution consisting of 800 μl of a substrate solution (adenosine), 100 μl of a test drug solution and 100 μl of an enzyme solution (adenosine deaminase-type VII, calf intestinal mucosa) was reacted for 5 minutes, and 100 μl
The reaction was stopped by adding acetic acid. Then, the amount of inosine produced was measured by HPLC to determine the inhibitory activity. Performed on various substrate concentrations, Lineweaver-B
The Ki value was obtained from the urk plot. An example of the results is shown in Table 1.
Shown in.

[0024]

[Table 1]

2. Nephritis therapeutic action Puromycin aminonucleoside administration to rats causes pathological conditions similar to hyperproteinuria, hypoproteinemia, hyperlipidemia, nephrotic syndrome, etc. It is used as a model animal. This test method was carried out by modifying Endo et al.'S method [Sogo Clinic, Vol. 38, No. 5, p. 821 (1989)] with some modifications. That is, on day 0, puromycin aminonucleoside (100 mg / kg) was dissolved in physiological saline and administered once to the tail vein to male SD rats weighing about 200 g. The test drug (50 mg / kg) dissolved in physiological saline was orally administered from day 0 for 5 consecutive days. Urine was collected for 24 hours, and urine volume and urinary protein content were measured. Blood was collected on the 10th day, and serum total protein, serum creatinine, urea nitrogen, etc. were measured. Examples of the results are shown in Tables 2 and 3.

[0026]

[Table 2]

[0027]

[Table 3]

3. Inhibitory effect on active oxygen production Human peripheral polynuclear leukocytes (2 x 10
⁶ ), bovine heart-derived cytochrome C-type III (7)
5 nmol), cytochalasin (5 μg) and the test drug (compound 27 of the present invention) were added, and the mixture was incubated at 37 ° C. for 5 minutes (final volume 1 ml, HEPES buffered saline). Then, N-formyl-methionyl-leucyl-phenylalanine (FMLP) was added to a final concentration of 10 ^-7 M, reacted for 5 minutes, and immediately centrifuged at 4 ° C to measure the absorbance (550 nm) of the supernatant. It was measured with a spectrophotometer. A value similarly measured by adding an excess amount of SOD (derived from bovine liver) was used as a blank.

Further, since there is a possibility that adenosine deaminase has been partially removed during the preparation of the above human peripheral polymorphonuclear leukocytes, the same measurement is performed in a system to which 0.02 units of adenosine deaminase (derived from bovine liver) is added. It was The superoxide production inhibition rate was calculated by the following formula, and an example of the results is shown in Table 4. Production suppression rate (%) = (1-A ₅₅₀ [addition of test drug] -A
₅₅₀ [SOD addition] / A ₅₅₀ [Control] -A ₅₅₀
[SOD addition]) x 100

[0030]

[Table 4]

4. Inhibitory effect on ischemic edema After a rubber band was wrapped around the right hind leg of an 11-week-old ICR male mouse to stop blood circulation for 20 minutes, the rubber was removed and blood flow was restarted. The test drug was intravenously administered immediately before the ischemia treatment, the weight of both hind limbs of the mouse was measured, and the suppression rate of edema was determined by the weight difference between the treated limb and the untreated limb. An example of the results is shown in Table 5.

[0032]

[Table 5]

5. Effects on extracellular adenosine and inosine concentrations Human peripheral polynuclear leukocytes (2 × 10 ⁶ cells), cytochalasin (5 μg) and the compound 27 of the present invention as a test drug were added (final volume 0.5 ml, HEPES buffered saline). 5,
Incubated for minutes. Then use FMLP at a final concentration of
^-7 M and added and incubated for 10 minutes.
As a result of analyzing this reaction liquid using HPLC, FMLP
The peak of inosine increased in the treated group compared with the control group. As a result of adding the compound of the present invention to this FMLP-treated group, the peak of inosine was decreased and the peak of adenosine was significantly increased as compared with the group not added.

As shown in Table 1, the compounds of the present invention have excellent adenosine deaminase inhibitory activity. By inhibiting adenosine deaminase, which is an adenosine metabolizing enzyme, the concentration of adenosine in tissues is increased. In tissue ischemia, neutrophils produce reactive oxygen species,
Adenosine not only inhibits the production of this active oxygen, but also has the action of directly eliminating the produced active oxygen. Conversely, by lowering the concentration of inosine, the supply of hypoxanthine, which is a substrate of the xanthine-xanthine oxidase system, which is one of the active oxygen producing systems, is reduced. Such an adenosine deaminase inhibitor having the action of inhibiting and eliminating the production of reactive oxygen species exhibits pharmacological actions such as coronary / cerebral vascular circulation improving action, renal disease preventing / treating action, and anti-inflammatory action.

Further, as shown in Tables 2 and 3, in a pharmacological test using a puromycin aminonucleoside-induced nephritis pathological model animal, the compound of the present invention having an adenosine deaminase inhibitory activity showed a urinary protein content and a serum content. As a result of evaluation using total protein, serum creatinine, urea nitrogen and the like as indicators, a clear therapeutic effect was observed. Therefore,
The compound of the present invention having an adenosine deaminase inhibitory activity is angina, myocardial infarction, ischemic heart disease such as arrhythmia, cerebral hemorrhage, cerebral infarction, stroke and its sequelae, diseases caused by cerebrovascular disorders such as cerebral arteriosclerosis, Renal diseases such as nephritis, renal failure,
It is useful as a drug for preventing and treating various diseases such as asthma, allergic rhinitis, allergic conjunctivitis, urticaria, and inflammatory allergic diseases such as rheumatism. By inactivating the generated active oxygen, it is very useful as a drug for preventing / treating the onset of postoperative comorbidities.

Adenosine analogs such as 3'-deoxyadenosine and xylosyladenine, which are anticancer agents, and arabinosyladenine, which has an anti-herpes effect, are easily deaminated and inactivated by adenosine deaminase in vivo. Therefore, by administering the compound of the present invention having an adenosine deaminase inhibitory activity before or simultaneously with the administration of the above-mentioned anti-cancer agent or anti-viral agent, in the chemotherapy of cancer or virus, the action of the above-mentioned adenosine analog anti-cancer / anti-viral agent The effect of stopping the decrease can also be expected. Adenosine has a pharmacological action such as a coronary vasodilatory action and a platelet aggregation inhibitory action, and is used as a circulatory function improving agent for treating diseases such as heart failure and myocardial infarction. Since adenosine is metabolized and inactivated by adenosine deaminase, a decrease in the pharmacological action of adenosine can be suppressed by administering the compound of the present invention before or simultaneously with the administration of adenosine, similarly to the above-mentioned adenosine analog.

[0037]

EXAMPLES The compound of the present invention can be made into a medicine by combining it with a suitable pharmaceutical carrier or diluent, and can be formulated by any ordinary method. It can be solid or semisolid for oral or parenteral administration. , Liquid or gas dosage forms. In the formulation, the compound of the present invention may be used in the form of a pharmaceutically acceptable salt thereof, the compound of the present invention can be used alone or in an appropriate combination, and a compounding agent with another pharmaceutically active ingredient can be used. May be

The preparation for oral administration may be used as it is or together with suitable additives, for example, conventional excipients such as lactose, mannitol, corn starch and potato starch.
Crystalline cellulose, cellulose derivatives, gum arabic, corn starch, gelatin and other binders, corn starch, potato starch, carboxymethyl cellulose potassium and other disintegrants, talc, magnesium stearate and other lubricants, other extenders, wetting agents Tablets, powders, granules or capsules can be prepared by appropriately combining buffers, preservatives, perfumes and the like. Further, it may be mixed with an oily base such as cocoa butter, an emulsion base or a water-soluble base such as macrogol, a hydrophilic base or the like to give a suppository.

The injection may be an aqueous or non-aqueous solvent such as distilled water for injection, physiological saline, Ringer's solution, vegetable oil, synthetic fatty acid glyceride, higher fatty acid ester, propylene glycol solution or suspension. it can. Further, depending on the condition of the patient and the type of disease, it is possible to appropriately formulate into a dosage form other than the above-mentioned one which is most suitable for the treatment, for example, an inhalant, an aerosol, an ointment, a poultice, an eye drop and the like.

Although the desirable dose of the compound of the present invention varies depending on the administration subject, dosage form, administration method, administration period and the like, in order to obtain a desired effect, the compound of the present invention is generally administered to adults in a daily dose of 0. It can be orally administered in an amount of 1 to 5000 mg, preferably 0.2 to 3000 mg. In the case of parenteral administration of injections and the like, a dose level of 3 to 1/10 of the above oral dose and a small dose are often preferable due to the effects of absorption and the like.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 31/70 ACV // C07H 19/167

Claims (6)

[Reference number] PC-226 [Claims] 1. An adenosine deaminase inhibitor containing, as an active ingredient, at least one compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof. [Chemical 1] [In the formula, R ₁ , R ₂ and R ₃ represent hydrogen or an alkyl group, and R represents hydrogen, an alkyl group, an alkenyl group, an alkynyl group, a hydroxyalkynyl group, an alkoxy group, a phenyl group, a hydroxyl group, an amino group, an alkylamino group. Represents a hydrogen atom, an alkyl group, an alkynyl group, an allyl group, a methallyl group, a cycloalkyl group, an alkyl group having one or more hydroxyl groups, a phenyl group (one or more halogens, a lower alkyl group). , Optionally substituted with a lower alkoxy group and / or a trifluoromethyl group), one or more phenyl groups (substituted with one or more halogen, lower alkyl group, lower alkoxy group and / or trifluoromethyl group) May have), a bicycloalkyl group, a naphthylalkyl group, an acenaphthylenylalkyl group or Represents a group represented by the following general formula (II) or general formula (III): [Chemical 3] , - - -CH ₂ hydrogen or hydroxyl, A is Z is hydrogen, hydroxyl or a lower alkoxy group, Q is O -, - S- or a direct bond, Y is - (CH _{2) n} - or a direct bond, n represents 1 The integers from 3 to 3 and the broken line represent a single bond or a double bond. However,
Any one of R ₁ , R ₂ and R ₃ represents an alkyl group. ] 2. The adenosine deaminase inhibitor according to claim 1, wherein R ₃ is hydrogen. 3. The adenosine deaminase inhibitor according to claim 2, wherein X is hydrogen. 4. The adenosine deaminase inhibitor according to claim 2, wherein X is an alkyl group having 1 to 3 carbon atoms. 5. A pharmaceutical composition comprising an adenosine deaminase inhibitor represented by the general formula (I) and adenosine or an adenosine analog as active ingredients. 6. A suppressant for reducing the pharmacological action of adenosine or an adenosine analog, which contains an adenosine deaminase inhibitor represented by the general formula (I) as an active ingredient.