JPS6222717A - Anti-inflammatory agent - Google Patents

Abstract

PURPOSE:An anti-inflammatory agent useful for rheumatoid arthritis, etc., be cause of improved anti-inflammatory action is comparison with diuretic and hypotensive action and low toxicity, containing a specific pyrazolo [3, 4-d] pyrimidine derivative or its salt. CONSTITUTION:An anti-inflammatory agent containing a pyrazolo [3, 4-d] pyrimidine derivative shown by the formula (R1 and R2 are different and R1 is 2-4C aliphatic hydrocarbon; R2 is propyl or butyl) or its salt. 7-Butyl-3- methylamino-5-propyl-pyraxolo[3,4-d]pyrimidine-4,6[5H,7H]-dione may be cited as a concrete compound. The compound shown by the formula has especially improved anti-inflammatory action in comparison with diuretic and hypotensive action and low toxicity and is useful as an anti-inflammatory agent. A dose is preferably 30-500mg/day.

Description

[Detailed description of the invention] Industrial applications The present invention relates to anti-inflammatory agents.

Conventional technology A patent application has been filed for 3-aminopyrazolo[3,4-d]pyrimidine derivatives having diuretic, hypotensive, analgesic, and anti-inflammatory effects [Japanese Patent Application Laid-Open No. 53-31694], but 5
Nothing is known about the anti-inflammatory effects of compounds having different substituents at the 7- and 7-positions.

Problems to be Solved by the Invention The present invention provides an anti-inflammatory agent containing a 3-aminopyrazolo[3,4-d]pyrimidine derivative or a salt thereof, which has a particularly superior anti-inflammatory effect compared to its diuretic and antihypertensive effects, and has low toxicity. I will provide a.

Means for Solving the Problems The present invention provides a general formula in which R1 and R5 are different, and R1 has 2 to 2 carbon atoms.
4 is an aliphatic hydrocarbon group, and R2 is a propyl or butyl group.

Regarding the above general formula (T), the aliphatic hydrocarbon group represented by RI includes a linear or branched alkyl group having 2 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, etc. Among them, ethyl and propyl.

Butyl, allyl groups, etc. are preferred.

Examples of the salt of compound (1) include inorganic acid salts such as hydrochloride and hydrobromide, and organic acid salts such as acetate, oxalate, citrate, fumarate, and maleate. Examples include physiologically acceptable salts.

Compound (1) can be produced, for example, by the following method.

[In the formula, RI and R2 have the same meanings as above, and 1X represents a halogen atom (e.g., chlorine, bromine, fluorine)] Compound (II)
The reaction between (III) and (III) proceeds by stirring at around room temperature for 10 to 30 hours in an amide solvent such as trimethylformamide in the presence of a deoxidizing agent such as potassium carbonate. After removing the solvent and inorganic substances from the reaction solution, the product (IV)
It is convenient to subject it to the reaction with hydrazine hydrate without purification.

This reaction proceeds by stirring in an alcoholic solvent such as methanol or ethanol at around room temperature for 1 to 5 hours. After removing the solvent and inorganic substances from the reaction solution, the product (V,) is usually obtained as prismatic or needle-shaped crystals by recrystallization from a mixed solvent of ethanol and ethyl acetate, but it is not necessarily necessary to purify it. The reaction between compound (V) and methylisothiocyanate is carried out in an amide solvent such as dimethylformamide at about 80 to 150°C.
Proceed by stirring for 0 to 20 hours. By adding hydrous alcohol to the reaction solution and cooling it, product (1) is precipitated. Compound (1) is usually obtained as colorless or slightly yellow plate-like or prismatic crystals by recrystallization from a mixed solvent of chloroform and methanol.

The mochi compound (1) has a particularly excellent anti-inflammatory effect compared to its diuretic and antihypertensive effects, and has low toxicity, so it is useful as an anti-inflammatory agent for rheumatoid arthritis and the like. When compound (1) or a salt thereof is used, it can be prepared by itself or mixed with appropriate pharmacologically acceptable carriers, excipients, and diluents, and prepared in the form of powder, granules, one tablet, capsule, suppository, etc. It can be administered orally or parenterally to warm-blooded animals (eg, humans, dogs, rats). The dosage for oral administration is approximately 10 to 200 mg of compound (1) per adult.
The amount of 1'8 is preferably about 30 to 500 mg.

The present invention will be explained in more detail by showing examples (formulation examples) and synthesis examples below, but the present invention should not be limited to these.

A: Example 1, Tablet (1) 7-Butyl-3-methylamino-5-propyl-pyrazolo[3,4'-d]pyrimidine-4,6(5)
(,7H)-dione 10' mg(2) Lactose l(+(l m'g(3) Corn starch 29.5 mg('4)
Hydroxypropylcellulose - ■7 mg (5) Carboxymethylcellulose/calcium
6 mg (6
) Magnesium stearate □Length" Kurofune 150'
Wet granules are made from mg (+), (2), (3), and (4) by a conventional method, and (5)a and (6) are added thereto and tableted.

2. Capsule (■) 7-allyl-5-butyl-3-methylamino-
Pyrazolo[3,4-dlpyrimidine-4,6(5H,7
H)-Dione 10 mg (2) Lactose
140 mg (3) Corn starch 42 mg (4) Hydroxypropylcellulose-L mg (5) Magnesium stearate 2 n+g2
00 mg The above 5 ingredients are mixed and encapsulated in gelatin capsules by a conventional method.

3 Suppositories (I) 5-butyl-7-ethyl-3-methylamino-
Pyrazolo[3,4-d]pyrimidine-4,6(5H,7
H)-Dione 20 mg (2) Witebuzol
W = 35' 980 mg (trade name, Guinamit Norpel, West Germany) ioofl mg Mix (1) and (2), melt by heating and homogenize, then place in a plastic container for suppositories and cool. .

B: Synthesis Example Synthesis Example I A mixture of 7'g of 6-chloro-3-propyluracil, 0.28g of butyl bromide I, 10.28g of potassium carbonate, 6g of potassium iodide, 80% dimethylene, and 80% diformamide was heated at room temperature for 23 hours. Stirred. After drying the reaction solution under reduced pressure, chloroform and 300% of Sphagnum moss were added to the residue and shaken, and the chloroform layer was washed with water and dried under reduced pressure to give 6-chloro-1-butyl-
3~Propyluracil was obtained as a brown oil. Without refining the main island, dissolve it in ethanol 20% and 100%
20% hydrazine Hitlerd was added and stirred at room temperature for 1 hour.

The reaction solution was dried under reduced pressure, and the residue was washed with water and then recrystallized from ethanol-ethyl acetate-isopropyl ether to obtain 7 g of yellow prismatic crystals of 6-hydrazino-1-butyl-3-propyluracil. Melting point: 146-147°C Elemental analysis value: C (%) as C11H2DN40'2
H (%) N (%) Calculated value ・ 54.98 849 23.31 Actual value: 55.13 8.53 23.41 6.5 g of 6-hydrano-l-butyl-3-propyl uracil and 66 g of methylisothiocyanate and were stirred in dimethylpolamide 707nQ at 120°C for 24 hours. Water-ethanol was added to the reaction solution to cool it, and the precipitated 7-butyl-3-methylamino-5-propylpyrazolo[3,
Pale yellow crystals of 4-dl pyrimidine-4,6(5H,7H)-dione were collected by filtration. Yield 4.6g Melting point 248-
286°C elemental analysis value: C1s H21N s O2
As C (%) l] (%) N (%) Calculated value: 559 [17,5825,07 actual value +
55.95 7.61 25.28 The following compound was obtained in the same manner.

I Synthesis example R,'Rg Melting point (℃) 2
C,)15C,L 28g-2903C2)+5
C3) 17291-2944 C3) IT
c4L 286-2885 CI+2-CH
CHx-, C4N, 280-2826 CHy=C)
l-CI('t C3)1? '2'892
Effects of the 97 Invention The effects of the invention will be explained below by showing experimental examples.

Oh, 7-butyl-3-methylamino-5 was used in the experiment.
-Propylpyrazolo[a:4''' id]pyrimidine-4°6(51(,7)()-dione was used as the analyte.

Experimental example 1 Anti-inflammatory effect (reverse passive Arthus reaction)
C Ernisprague Dowry (J cl:s D
) Using 1 group of 6 rats (7 weeks old, male), their backs were dehaired under ethyl anesthesia, and 1 d of 05% ovalbumin in physiological saline was injected through the tail vein, and then injected into one site on each side of the back. Rabbit anti-ovalbumin serum 0.1- was injected intra-combally, and physiological saline 0.1- was injected into the left side at one site. Three hours later, 1d physiological saline containing 10 mg of Evans blue was administered intravenously, and 30 minutes later, the skin was peeled off and the area (mm') of the blue spots was measured. The sample was intraperitoneally administered at 3 mg/kg immediately before ovalbumin injection. The dye leakage inhibition rate (-edema inhibition rate) was found to be 25% (P < 0.OL) by comparing the areas of the non-treated group and the treated group.

Experimental Example 2 Anti-inflammatory effect (carrageenan edema method) Using the method of Winter et al. Indus of the Society for Experimental Biology and Medicine (Proc.

SOC, EXI), Biol, Med, )111
．． 544 (1962)]. Specimen 50m
One hour after the oral administration of 0.05 g of a 1% carrageenan saline solution, 0.05 g of a 1% carrageenan saline solution was subcutaneously injected into the heel. After 3 hours, the hindlimb volume and the injection site volume were measured, and the edema volume was determined from the difference. When the edema volume of the non-treated group and the treated group was compared to determine the edema suppression rate, it was 308% (p < 0.01).

Experimental Example 3 Acute Toxicity CRJ: Wist
er) Sample 1g/k to 1 group of 5 rats (5 weeks old, male)
g or 2 g/kg was orally administered and observed for 7 days, but there were no deaths in either group.

=11- Procedural amendment (acid) August 21, 1985 2. Name of the invention Anti-inflammatory agent 3. Relationship to the case of the person making the amendment Patent applicant address 2-27 Doshomachi, Higashi-ku, Osaka Name (2)
93) Takeda Pharmaceutical Co., Ltd. Representative: Kanetai Iku 4, Agent address: 2-17-85-5 Jusankamachi, Yodoyo-ku, Osaka City,
"r 248-286°C" in Column 6 of Detailed Description of the Invention of the Specification Subject to Amendment, Page 9, Line 16 of the Specification of Contents of Amendment
Corrected to 284-286°C.

that's all

Claims (2)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1 and R_2 are different, R_1 represents an aliphatic hydrocarbon group having 2 to 4 carbon atoms, and R_2 represents propyl or butyl] Pyrazolo [3,4-d] represented
An anti-inflammatory agent containing a pyrimidine derivative or a salt thereof. (2) Pyrazolo[3,4-d]pyrimidine derivative is 7-
Butyl-3-methylamino-5-propyl-pyrazolo[
The anti-inflammatory agent according to claim 1, which is 3,4-d]pyrimidine-4,6(5H,7H)-dione.