JPH06135837A - Adenosine deaminase inhibitor - Google Patents

Abstract

PURPOSE:To obtain an adenosine deaminase inhibitor showing improving action on coronary vessel and cerebrovascular circulation, preventing and treating action on renal disease, anti-inflammatory action, etc., having excellent inhibitory action on adenosine deaminase, comprising a specific adenosine derivative as an active ingredient. CONSTITUTION:An adenosine deaminase inhibitor comprises a compound of formula I [R1 to R3 are H or alkyl; R is H, lower alkyl, amino or halogen; X is H, alkyl, alkenyl, allyl, methacrylic, cycloalkyl, phenyl, group of formula II (Z is H, OH, etc.; Q is H or OH; A is CH2, direct bond, O, S, etc.), group of formula III, etc., with the proviso that one of R1 to R3 is alkyl] or its pharmaceutically acceptable salt (e.g. 2'-O-methyladenosine) as an active ingredient. This medicine shows inhibitory effect on reduction in action of adenosine analog- based anti-cancer medicine or antiviral agent in chemotherapy of cancer and virus by administration of this medicine before administration of anti-cancer medicine or antiviral agent or by simultaneously administration.

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]

DISCLOSURE OF THE INVENTION 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.

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, R represents hydrogen, a lower alkyl group, an amino group or halogen, and X represents hydrogen, an alkyl group, an alkynyl group, an allyl group or a methallyl group. , A cycloalkyl group, an alkyl group having one or more hydroxyl groups, 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 An alkyl group having (which may be substituted with one or more halogen, a lower alkyl group, a lower alkoxy group and / or a trifluoromethyl group), a bicycloalkyl group,
A naphthylalkyl group, an acenaphthylenylalkyl group or 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, etc., particularly preferably R ₃ represents hydrogen, R represents hydrogen, a lower alkyl group, preferably Is a linear or branched alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, an amino group or fluorine, chlorine, bromine, iodine, etc. Represents halogen. However, any one of R ₁ , R ₂ and R ₃ represents a lower alkyl group.

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-Methyl-2'-O-ethyladenosine [Compound 10] 2-Methyl-2'-O-n-butyladenosine

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

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

[0011] [Compound 31] 2, N ^6, 3'-O- trimethyl adenosine [Compound 32] 2-Chloro -2'-O-methyl adenosine [Compound 33] 2-chloro-3'-O-methyl adenosine [ Compound 34] 2-Fluoro-2'-O-methyladenosine [Compound 35] 2-Amino-2'-O-methyladenosine [Compound 36] 2-Amino-3'-O-methyladenosine [Compound 37] 2 ' , 3'-O-dimethyl adenosine [compound 38] ^{N 6, 2 ', 3'-} O- trimethyl adenosine [compound 39] N ⁶ - methyl -2', 3'-O- diethyl adenosine [compound 40] N ⁶ -N-butyl-2 ', 3'-O-
Dimethyl adenosine

[0012] [Compound 41] 2, 2 ', 3'-O-trimethyl adenosine [Compound 42] ^{2, N 6, 2',} 3'-O- tetramethyl adenosine [Compound 43] N ⁶ - Allyl-2 ' -O- methyl adenosine [compound 44] N ⁶ - methallyl -2'-O-methyl adenosine [compound 45] N ⁶ - (2,3-dihydroxypropyl) -2'-O-methyl adenosine [compound 46] N ⁶ - cyclopropyl -2'-O-methyl adenosine [compound 47] N ⁶ - cyclopentyl -2'-O-methyl adenosine [compound 48] N ⁶ - cyclopentyl -2'-O-ethyl adenosine [compound 49] N ⁶ - Cyclopentyl-2,2'-O
- dimethyl adenosine [Compound 50] N ⁶ - cyclopentyl-2-bromo -
2'-O-methyladenosine

[Compound 51] N ⁶ -Cyclohexyl-
2'-O- methyl adenosine [Compound 52] N ⁶ - cyclohexyl -2,2'-O
- dimethyl adenosine [Compound 53] N ⁶ - cycloheptyl -2'-O-methyl adenosine [Compound 54] N ^{6-p-methoxyphenyl-2'}
O-methyladenosine [Compound 55] N ⁶ -p-fluorophenyl-2′-
O-methyladenosine [Compound 56] N ⁶ -p-chlorophenyl-2′-O
- methyladenosine [Compound 57] N ⁶ - benzyl -2'-O-methyl adenosine [Compound 58] N ⁶ - (R) - phenyl - isopropyl -2'-O-methyl adenosine [Compound 59] N ⁶ - (2 , 2-diphenylethyl)
-2'-O-methyl adenosine [Compound 60] N ⁶ - (exo - dicyclohexyl [2,2,
1] heptyl-2'-O-methyladenosine

[Compound 61] N ^6- (endo-dicyclo [2,2,1] heptyl-2′-O-methyladenosine [Compound 62] N ^6- (1-naphthyl) methyl-2 ′
-O- methyl adenosine [Compound 63] N ⁶ - (1-acenaphthylenyl) methyl -2'-O-methyl adenosine [Compound 64] N ⁶ - (1,2-dihydro-1-acenaphthylenyl) methyl -2'-O - methyladenosine [compound 65] N ⁶ - (2,3-dihydro ─1H- inden-1-yl) -2'-O-methyl adenosine [compound 66] N ⁶ - (2,3-dihydro ─1H- indene 2-yl) -2'-O-methyl adenosine [compound 67] N ⁶ - (2,3-dihydro ─1H- inden-1-yl) methyl -2'-O-methyl adenosine [compound 68] N ⁶ -(3H-inden-1-yl)
Methyl -2'-O-methyl adenosine [Compound 69] N ⁶ - (5-methoxy-2,3-dihydro -1H- inden-1-yl) -2'-O-methyl adenosine [Compound 70] N ⁶ - (1-tetrahydronaphthyl)
-2'-O-methyladenosine

[Compound 71] N ^6- (2-Tetrahydronaphthyl) -2'-O-methyladenosine [Compound 72] N ^6- (3,4-Dihydro-1-naphthyl) methyl-2'-O-methyl Adenosine [Compound 73] N ^6- (5-Hydroxy-1-tetrahydronaphthyl) -2′-O-methyladenosine [Compound 74] N ^6- (1-Hydroxy-1-tetrahydronaphthyl) methyl-2′-O- methyladenosine [compound 75] N ⁶ - (5-methoxy-1-tetrahydronaphthyl) -2'-O-methyl adenosine [compound 76] N ⁶ - (6- methoxy-1-tetrahydronaphthyl) -2'-O- Methyladenosine [Compound 77] N ^6- (7-methoxy-1-tetrahydronaphthyl) -2′-O-methyladenosine [Compound 78] N ^6- (4-Chloro) Manil) -2'-O
- methyladenosine [Compound 79] N ⁶ - (4-thiochromanyl) -2 '
-O- methyl adenosine [Compound 80] N ^{6-9-fluorenyl} -2'-O-
Methyl adenosine

[Compound 81] N ^6- (9-fluorenyl) methyl-2′-O-methyladenosine [Compound 82] N ^6- (9-hydroxy-9-fluorenyl) methyl-2′-O-methyladenosine [Compound 81] Compound 83] N ^6- (9-xanthenyl) methyl-
2'-O-methyladenosine

The compounds of the present invention described above 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 derivative of the present invention includes a metal complex compound thereof, such as 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.

[0020]

【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.

[0021]

[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.

[0023]

[Table 2]

[0024]

[Table 3]

As shown in Table 1, the compound of the present invention has an excellent adenosine deaminase inhibitory action. 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 the prevention and treatment of 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.

[0028]

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, potato starch and the like.
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 an adult 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.

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Claims (4)

[Reference number] PC-214 [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, R represents hydrogen, a lower alkyl group, an amino group or halogen, and X represents hydrogen, an alkyl group, an alkynyl group, an allyl group or a methallyl group. , A cycloalkyl group, an alkyl group having one or more hydroxyl groups, 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 An alkyl group having (which may be substituted with one or more halogen, a lower alkyl group, a lower alkoxy group and / or a trifluoromethyl group), a bicycloalkyl group,
A naphthylalkyl group, an acenaphthylenylalkyl group or 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.