JPS60126285A - 3-aminopyrazolo(3,4-d)pyrimidine derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R1 and R2 are alkyl; R3 and R4 are H, alkyl, etc.; R5 is alkyl, formyl, etc.; the broken line indicates the presence of two double bonds in the pyrazole ring; R5 is linked to either one of the 1- or 2-position). EXAMPLE:3-Amino-5, 7-diethyl-1-methylpyrazolo[ 3, 4-d ]pyrimidine-4, 6( 5H, 7H )- dione. USE:An ameliorant and remedy for chronic rheumarthritis, lumbago, cervical syndrome, etc. having ani-inflammatory, analgesic and antipyretic action with low toxicity. PREPARATION:1mol compound of formula II is reacted with 2-5mol compound of the formula R5NHNH2 in an alcohol to give compounds of formulas I a and I b. The formation ratio between the compounds of formulas I a and I b depends on R5, and the compound of formula I a is mainly formed when R5 is CH3. The compound of formula I b is mainly formed when R5 is tert-C4H9.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel 3-aminopyrazolo (a
, 4-d) open to pyrimidine derivatives.

More specifically, the present invention is based on the general formula (I) [wherein, R and R2 are the same or different cy/L/, and R3
and R4 are hydrogen, aμki IL/ma or ashiμ, respectively.
, R5 is a〃kiρ, aμkoxycarbodiμ or hoμ
a-aminopyrazolo (a, 4-d ) Pyrimidine derivatives and their salts.

In accordance with the above general formula (I), examples of the alkyl group represented by R□ or R2 include apk/L/ groups having an ash number of 1 to 6, and among them, an apkyl group having an ash number of 2 to 5. (e.g. ethyl, propyl, glutinous p, 1-butyl, bench) y,
'1-Bench A/) is preferred tc, a. R31 and R4
The alkyl group represented by is an apkyl group having a prime number of 4 or less
L/ groups (eg methyl, ethyl, glopyl, 1-propyl, butyl, 1-butyl) are preferred, a! //l/ group is Aμkanoi ~ group, especially those with order prime number 7 or less 1
Preferred are acetyl, )lJ7/l/oacetyl, propionyl, gtyryl, valeryl, cyclohexanecarbonyl) or aromatic carbonyl groups (eg, benzyi/I/). The alkyl group as R5 is a lower alkyl group optionally substituted with halogen or hydroxyl group,
Particularly preferred are those having an order prime number of 4 or less, such as methyl, ethyl, globil, butyl, t-butyl), and examples of the alkoxycarbonyl include lower (C1-,) alkoxycarbonyl, and methoxycarbonyl.

Ethoxycarbonyl group is preferred.

The compound of general formula (1) above can be produced, for example, by the a@l method shown below.

(a) (M) (Ia) (Ib) [In the formula, R, R8 and R5 have the same meanings as above] (b) [In the formula, each symbol has the same meaning as above, but R3 and gourd are hydrogen at the same time. ] (c) (II) (Id) (Engineering C) [In the formula, each symbol has the same meaning as above] In the reaction of (a) above, substituted hydrofuzine is added to 1 mole of compound (II). It is best to use 2 to 5 moles and use an alcohol such as methanol/I/, ethano/L/, zolopanol, or 2-methoxyethanol as a solvent.6 Reaction conditions are room temperature to 100°C for about 1 to 5 hours. Open circuit is preferred. (Ia)
The production ratio of and (Ib) depends on R5. When R5 is a methyl group, (Ia) is the main product, and as R5 becomes larger, the production ratio of (Ib) increases, and when R5 is a t-butyl group, (Ib) is the main product. (Ib) is also the main product when R5 is an electron-withdrawing group such as trifluoroethyl or alkoxycarbonyl group. Separation of (Ia) and (more) is carried out by conventional separation means such as silica gel chromatography. Among the raw materials for this reaction (II), those in which R and R2 are methyl groups are known compounds [Chemical and 7 Almaneutical Pretin: Vol. 26, 8208 Sada (1978)]. ].

Other substances can be synthesized in the same way.

In reaction (b), compound (Xa) is alkylated or acylated to obtain mono- or polysubstituted product (Ic), where the alkylating agent is an alkyl halide and the acylating agent is an acid anhydride. and acid halides are used.

It is advantageous to use these reagents in an amount of about 1 to 10 mol/L' per 1 mol of compound (Ia) and to carry out the reaction in the presence of a deoxidizing agent. As a deoxidizing agent, potassium acid salt, sodium acid acid, triethylamine, pyridine, etc. are used, and as a solvent, pyridine, dimethylformamide, dimethylacetamide, etc. are used, and the reaction is preferably carried out at room temperature to 100°C for about 1 to 10 hours. . Although the production ratio of chemically substituted and di-substituted products depends on the type and amount of reagent, reaction temperature and time, bulky reagents tend to produce mono-substituted products.

In the reaction (c), the hydrogen of the pizole ring of the compound (111) is replaced with an alkyl, Alskine carbony or formyl group to obtain the target compound (Ia) or (Ie). As the alkylating agent, alkyl halides such as methyl iodide, ethyl iodide, propyl iodide, 1-propyl iodide, miraguchi, and butyl bromide are preferable. For introducing an alkoxycarbonyl group, chloro-reverted methyl, chloro-reverted ethyl, etc. are preferable. These reagents are
Preferably, 1 to 10 mol is used per 1 mol of the raw material ('I#), and the same reaction conditions are used at room temperature to 50'C for 1 to 20 hours in a solvent such as dimethylformamide, dimethylacetamide, dioxane, etc. At this time, as a deoxidizing agent, potassium rehydrate, sodium liquefied acid, tritamine, etc. may be used, or pyridine may be used as a deoxidizing agent and a solvent. As the formylating agent, formic acid-acetic anhydride is used in excess and also serves as a solvent, and reaction conditions of 1 to 5 hours at room temperature to 100°C are preferred. In these reactions, generally
The -substituted product (Step d) is the main product, but the 1-substituted product (I
If e) is produced as a by-product, it can be subjected to US analysis using silica gel chromatography or the like. The raw material (Il[) used in these reactions is produced by a known method [JP-A-58-A16'94] or according to it.

The 3-aminobifuzolo(a,4-d:)pyrimidine derivative (I) and its salts of the present invention have anti-inflammatory, analgesic, and antipyretic effects on mammals, such as chronic onset rheumatism, low back pain, M. It is useful as an agent for improving and treating purity syndrome, etc. In addition, compound (I) has low maternal properties, and when compound (I) is used as such a medicine, it can be used alone or mixed with appropriate pharmacologically acceptable carriers, excipients, and diluents, and it can be used as a powder or granule. 1 tablet, capsule, injection.

It can be safely administered orally or parenterally in dosage forms such as suppositories and ointments. The dosage varies depending on the target disease, symptoms, subject, administration method, etc., but for example, when orally administered to adults with chronic rheumatoid arthritis, a single dose is approximately 0.1 to 20 M9/kV (body weight). , 1 per day
~8 times 4! It is preferable to administer the drug twice.

Reference examples, examples, experimental examples, and formulation examples are shown below.
The present invention will be explained in more detail, but the scope of the present invention is not limited thereto.

Reference example 1 Diethylbarbylic acid 61F was converted to phosphorus oxychloride 224
11/, and 35 ml of dimethylformamide was added dropwise while stirring at room temperature. After dripping.

The reaction solution was refluxed for 8.5 hours. The reaction solution was dried under reduced pressure,
The remaining oil was added portionwise to ice water.

The precipitated crystals were collected to obtain 6-chloro-1,a-diethyl-5-formyluracil s4yt. m point 88~
89°C 50F of ice crystals and 5 oy of hydroxylamine salt were mixed in ethanol/I/ll at room temperature for 80 minutes.

Water 11 was added to the reaction solution, the precipitate was collected, and 6-chloro-
1,a-diethyl oxime/L/-5-carbaldehyde oxime a2,51 was obtained. Melting point: 115-116° C. Ice crystal 1611 was dissolved in detohydrofuran a20yst, and phosphorus oxychloride aoII was added dropwise while stirring with water, followed by stirring at room temperature for 1 hour. The reaction solution was dried under reduced pressure,
When 200 ml of diisopropyl ether/I was added to the residual solution, pale yellow prismatic crystals 12.4f of 6-chloro-5-cyano-i,a-diethyluracil were precipitated. Melting point 92-94°C Elemental analysis value: C0H engineering. C (%) as H3O2C1 H (96) N (96) Calculated value: 47.48 4.43 18.46 Actual value:
47.29 4. The following compounds were synthesized in the same manner as al 18.85.

I RIR2 melting point ('C) C3H7C3■wa 96-99 C, HoC, H394-9 contains mesomorphs other than Lera (6-chloro-5-formyl, 6-
Chloro-5-cyano form) is difficult to crystallize, so
It was used in the next reaction without making IJ.

Reference example 2 6-chloro-5-cyano-1,8-diethylurasi/1
15f and hydrazine-hydrate 2-2w1 in methanol
/I/220m? I stirred it for 10 minutes at room temperature. The reaction solution was dried under reduced pressure, and the residue was reconstituted from aqueous methanol.
8-Amino-5,7-diethyρbi7zo0(a,4-d
] Pyrimidi: y-5,7 (4H.

4.81 colorless needle crystals of 61)-dione were obtained.

Melting point 246-248°C. The following compound was obtained in the same manner.

I Rz R21M point (°C) C3■7 C3H7227-229 C4H8C4H9192-194 Reference example 8 1.8-Diglopyr parbylic acid 50f was mixed with water 50g/
500xe of phosphorus oxychloride was added dropwise under water-cooling and stirring. The mixture was refluxed for 8 hours and then dried under reduced pressure. When the residue was poured into ice water and stirred, 6-chloro-1,
Yellow crystals 44F of 8-dipropyluracil were precipitated.

Melting point: 59-68° C. This product 449 was suspended in 100 ml of ethanol, 100 gt of hydrazine hydrate was added, and the mixture was stirred for 8 minutes. When the reaction solution was reduced to about half its volume in a thick cotton tube and left to cool, 6-
Yellow crystals of hydrazino-1,3-dipropylwocyl 8
4F was precipitated. Melting point 149-151°C This product 12F and 8.5 wl of methyl isothiocyanate were mixed with 100 sr of dimethylformamide. The mixture was stirred at 100-110°C for 12 hours. When 101IIlt of water was added to the reaction solution and allowed to cool, 8-methylamino-5,7-siglopyrupiozolo (
a, 4. -d) 5.81 light brown crystals of pyrimidine-4,6(5H,7H)-dione were precipitated. Melting point>800
℃ elemental analysis value "clf H19H502 as C (
*) H (%) N (96) Total x*: 54.82 7.22 26.40 Actual value: 54.47 7.26 26.50 Above 6-hydrofusinol 1. 4.521 of a-dipropyl uracil was suspended in 60 ztK of dichloromethane, 3.91 of phosgeneiminium chloride was added little by little while stirring at room temperature, and the mixture was stirred once at room temperature. The reaction solution was dried under reduced pressure, and the residue was recrystallized with hydrous alcohol to give 8-dimethylamino-5,7
-siglovirvituzolo(a,4-a)pyrimidine-4,
4.8f of colorless crystals of 6(5H,7H)-dione were obtained.

M point 186-188℃ Elemental analysis value: C□3 H2□R5
02 as C (shadow) H (%) N (%) Calculation i1! : 55.90 7.56 25.07 Actual value: 56.04 7.67 24.95 The following compound was synthesized in the same manner.

1 Reference example RIR2R3R4 melting point (℃) 4 C3H, C3 horse HC2H5208-2105C,
H2O2 horse HC2H5166-1,686C4H3c
4H9CH3CH314B-1457C5H7C3H7
HCOCH3169-1718C, H8C4H9n C
OCH314a-145 reference example: R1' R2R3R
4 Melting point (°C) 9 1-C3H,,1-C3Hu HCH
3244-24610i-C,B, □ 1-C3Hu
U C2H5122-124111-C3H, □i-C
, HuCH3C1 (3159-16112C6H□□
C3Bll HC13249-2511a C4H3C
2H5HC113289-29214C2E, C4H
9II 0M3 288-290 Example 1 6-chloro-5-one anor x, a-diethylupucyl 2
．． 5F and methylhydrofusine 1.1F in methanol/I/
110g? The mixture was cooled at room temperature for 1 hour.

After drying the reaction solution under reduced pressure, the residue was recrystallized from ethyl acetate-methanol to give 3-amino-5,7-danityl-1-methylpifzolo(a,4-d)pyrimidine-4,6(5H
, 7H)-dione colorless needle crystals 2.2'lf were obtained.

Melting point 193-194℃ Elemental analysis value: C1o1f□5N5
02 as C (%) H (%) N (%) Calculated value: 50.62 6.37 29.52 Actual value:
50.5a 6°11 29.89 Example 2-8 The following compound was obtained in the same manner as in Example 1.

l0H3 Example Rd) 12 m point (℃) 2 C3H9C3I (7126-127a C4U,
C4H0110-112 Example 4 6-chloro-5-cyano-1,3-diethylurasi/L
/1-5F and methoxycarbonylhydrazine 0.9F were refluxed in methanol 40zt for 15 hours. The reaction solution was cooled, and 3-amino-5,7-diethy/L'-2-methoxycarbonylpifzolo[8°4-d]pyrimidine-
Colorless acicular crystals of 4,6(5H,7H)-dione 1. aa
t6 melting point 2209-211℃ Elemental analysis @I: C □, ■ C (%) as 05N504
li (%) N (%) Calculated value: 46.97 5.38 24.90 Measured value:
46.79 5.86 24.81 Example 5-8 In the same manner as in Example 4, the following compound 'f: was obtained.

Example 1 (lI?2R5 Melting point (℃) 5 c2H, C2H3t-C4H, 225-22760
2I (5C2115-CF, 0M2200-2017
C3H7C3nwa CL (3Coo 179-1818
C4H9C4H0C113Coo 151-153 Example 9 6-chloro-5-V ano-1,3-diethyluracil 0
．． 5th floor! : β-Hydroxyethyl hydrogen: 10. a
5f was passed through methanol-120we for 2 hours, and the reaction mixture was dried under reduced pressure. The residue was chromatographed on silica gel 80f, and eluted with chloroform. The first fraction was dried under reduced pressure, and the residual methanol fume was reconstituted from 7-ether to give %8-amino-5,7-dinithyl-1-(β-hydroxyethyl)bioIf(a,
4-d) 190 vv of colorless needle-like crystals of pyrimidi7-4,6(511°7H)-dione were obtained.

Melting point: 150-15a℃ Elemental analysis value 20〇□H□ヮC (m) 1 as N503
1 (%) H (%) Calculated value: 49.48 6.41 26.20 Expected value:
49.21 6.6a 25.94 The second fraction was dried under reduced pressure, and the remaining liquid was recovered from methanol to give 8-amino-5,7
-diethy/L/-2-(β-hydroxyethy/I/)pyrazolo(a,4-d)pyrimidine-4,6(5H,7H
)-Dione colorless needle crystals 240~ were obtained. One point: 20
6-207℃ Elemental analysis value 200, ■□7 C (%) as N503
H (%) N (%) Calculated value: 49.421 6.41 26.20 Actual value: 48.82 6.42 25.76 Example 10-1
2 The following compound was obtained in the same manner as in Example 9.

Example Ra ii Dot ('C) f, Dot (°C) 10
C2H5147-149185-18711C3H7
1a5-1a7 16a-16512C4H8122-
124124-126 dormitory service v] 1B 3-amino-5,7-diethyl-1-methylpyrazolo (
:a, 4-d) Pyrimidine-4,6(5H.

7H)-dione o, 5y and 0.9txl of acetic anhydride to 15g of hyridine? The mixture was stirred at room temperature for 15 hours.

The reaction solution was dried under reduced pressure, and the residue was heated again at α°C from chloroform-isopropylene ether to give 3-acetylamino-5,7-diethyl/L/-i-methylpyrazolo (a, 4
-d) 470q of pale yellow needle crystals of pyrimidine-4,6(5H,7H)-dione were obtained. to 'suitable score 181-182
℃ Elemental analysis value: C, n, ヮC (%) as IJ503
H(*) ff(%) Total sf, Il*“ 2 51.60 6.14 25
．． 08 Actual value: 51.77 5.98 24.84 Example 14 3-amino-5,7-danityl-l-methylpyrazolo(
a, 4-d) Pyrimidine-4,6 (5H.

0.7f of 7H)-dione was heat-fermented to 20% pyridine, 0.88f of cyclohexanecarbonylchloride was added, and the mixture was stirred at 50°C for 2 hours. Dry the reaction solution under reduced pressure 11.
After extracting the residue with chloroform, it was chromatographed on silica gel 35F and eluted with chloroform. Lord! [1] was collected and dried under reduced pressure, and then recrystallized from chloroform isoglobyl ether to give d-cyclohexanecarbonylamino-5,7-danityl-1-methylpiozolo(a,4-d)pyrimidine-4,6( 5H, 7
0.64F colorless prismatic crystals of H)-dione were obtained.

Melting point: 165-167℃ Elemental analysis value: C7 B25
'503 as C (%) H (%) ll (96) Calculated value: 58.77 7.25 20.16 Actual value:
5B-887-8219-56 Example 15-22 The following compound was synthesized in the same manner as in Example 13 or 14.

Example RIR2R3 Melting point (℃) 15 c, E(5c21(5c21(5co 158-
16016' C2H3C2H5C3HwaCo 117
-11917 C2I(6C2H5C61(5C0,2
18-22118C2■l5C2H6CF'3Co I
al-1aa19 C5H7C3H7CH3Co 11
6-11720 C5H7C3H7C3H WaCo 1a
5-13621 C4H3C4H0CH5Co 105
-10822 C4H9C4H9'C3H, Co 10
5 = 107 Example 23 8-Amino-5,7-cyptyl-2-methoxycarponylbiozolo Ca, 4-d) Pyrimidine-4,6 (5H,
71()-dione if, potassium carbonate 6904. Methyl iodide 0. ayzl was stirred in 15 volumes of dimethylformamide at room temperature for 6 hours.

After the reaction solution was dried under reduced pressure, the residue was partitioned between chloroform and water, and the chloroform layer was dried under reduced pressure. The residue was recrystallized from aqueous methanol to give 5.7-s) f--2-methoxycarboniIv-8-methylaminopyrazolo (a, 4-d
) 0.7f of colorless purinum-like crystals of pyrimidine-4,6(5H,7m)-dione were obtained. Melting point: 1a5-136
°C elemental analysis value: CC9 as C16B25 N504
6) H (96) N (%) Calculated value: 54.69 7.17 19.93 Actual value:
54.78 7.16 20.07 Example 24 8-amino-5,7-danityl-1-methylpiozolo(
a, 4-d) Pyrimidine-4,6 (5H.

7H)-dione 500gIIf/, potassium carbonate 8'1
0111゜Methiiodide ILI940Q was stirred in dimethylacetamide 15Mt at 70°C for 15 hours. After drying the reaction solution under M pressure, it was partitioned between chloroform and water, and the chloroform layer was chromatographed on 7Lica gel 85F and eluted with chloroform. The main fractions were collected, dried under reduced pressure, and then reconstituted from chloroform-isopropyl ether to give 3-dimethylamino-5,7-danityl-1-
Methylpifzolo[a,4-d)pyrimidine-4,6(5
Colorless prismatic crystals 260q of n,7n)-dione were obtained. Melting point: 1a4-135℃ Elemental analysis value: C□gH19
C (%) H (96) R (%) Total: J9: Value: 54. B2 7.22 26.40
Actual value: 54.04 7.84 26.29 Example 2
5 3-Amino-5,7-diethy/I/-1-methylpyrazolo(a,4-d)pyrimidine-4,6(5H.

7H)-dione it, potassium carbonate L, '16f.

Ethyl iodide 2f in dimethylacetamide aOgi,
The mixture was reacted at 0°C for 5 hours. The reaction solution was treated according to Example 24 to obtain a-ethylamino-5,7-diethy A/-1
-Methyl biozoro CB, 4-d) pyrimidine-4,6 (
Colorless prismatic crystals of 5H,7H)-dione 580'I
I got v. Melting point: 188-185℃ Elemental analysis value: 0□2H□, C (th) H as N5o2
(96) N(51;) Calculated value: 54.82 7.22 26.40 Actual measurement fi
t: 54.01 7.05 26. a66 implementation 2
6 8-ethylamino-5,7-dinithylbirazolo (a, 4
'-d) Pyrimidine-4,6(5H,7H)-dione 1
．． 1f, potassium carbonate xy, methyl atomide/l/1 m
1 was stirred in 80 wl of dimethylacetamide at 40°C for 4 hours. The reaction solution was partitioned between chloroform and water, and the chloroform layer was subjected to chromatography using Nrikag/I/aoy.
Elution was done with chloroform. Main/I/-2-methylpyrazolo(:a,4-d:)pyrimidine-4,6(5m1,7
0.7 f of colorless needle crystals of H)-dione were obtained. Melting point: 1
50-152℃ elemental analysis value: C12B191'502
As C (%) H (%) N (%) Calculated value: 54.82 7.22 26.40 Actual measurement it
! :54.48 6.90 26.50 Example 27-4
1 The following compound was synthesized in the same manner as in Example 26.

1 Example RI R2R3R4R5 Melting point (°C) 27 C2
H5C2f15 HC113CH, 180-18828
C2H5' CaH5HCH, 172-17a2 to C2
9 C2H5C,+! [5H1-C4H,C,, Els
135-13780 C3Hq C3H7HCH3C
H31a5-1a8al C3H7C3By HC2H
, CHs 117-119a 2 Cs HpI Cs
';Jr CH3CH3CH384-86aa C41
19C4H9HC113CH3145-146a4 C
4H9C4H9HCll3C2H, 75-78 Examples
RI R2R3R4R5 Melting point ('C) 35 C,H,C
,H2N C2H,CH38l-8a216 C,H9
C4H8CH,CH,CH349-51a7 C4E,
C,H,HC0CB3CH3180-182a8 C,
H2O, [1, HHCH31a2-18489 1-C
, H□□i-C, H□, HCH30M3105-110
40 C, H□0. t%c5H□, HCH3CH312
0-12141C4H7C2H5HCH, CH3180
-132 Example 42 8-Methylamino-5,7-dideropyrpifuzolo (a,
4-a) Pyrimidine-4,6 (5H.

71)-dione 1. A5f was dissolved in 35 g of pyridine, ethyl chlorocarbonate/I/IMt was added, and the mixture was stirred overnight at room temperature. The reaction solution was dried under reduced pressure, and the residue was dissolved in chloroform-
After partitioning with water, the chloroform layer was chromatographed on silica gel 50f and eluted with chloroform. The main fractions were collected and dried under reduced pressure, and then reconsolidated from water-containing ethanol to give 2-ethoxycarbonyl-8-methylamino-5,7-siglovir pizowa [8°4-d]. 0.9F of colorless needle-like crystals of pyrimidine-4,6(5H,7H)-dione were obtained. Melting point = 119-121℃ Elemental analysis value: C15B23 C (96
) H (96) N (%) Calculated value: 53.40 6.87 20.76 Actual value:
5a-59(i, 88 20-90 Example 48 5.7-Diamyl-3-methylaminopizzolo(3,4
-d,l pyrimidine-4,45(5H,7U)-dione 1.5F was suspended in dioxane 60xt.

Triethylamine 2.71 and methyl chlorocarbonate 2-24
zt and stirred at 40°C for 6 hours.

The reaction solution was dried under reduced pressure, the residue was partitioned between chloroform and water, and the chloroform layer was dried under reduced pressure, then subjected to chromatography on 45 d of silica gel, and extracted with chloroform.
8-Methylaminobiozolo[8゜4-d]pyrimidine-
Colorless acicular crystals of 4,6(5H,7H)-dione 850
Melting point = 187-189℃ Elemental analysis i + li: C16k32g H60, C (%) H (96) N (%) Calculated value: 56.98 7.70 18.46 Actual value:
57.07 7.79 18.17 Examples 44-49 The following compounds were synthesized in the same manner as in Example 42.4a.

1 Example RIR2R3R4R5 Melting point ("C) 44 C,
H9C4H9HCH3CO2C2H5119-1214
5C,H,C3HnHC■3Co2C2H597-10
046C4H9C4H0HHCo2C2h5122-1
2447 C4H9C4H9CH5CH3Co2C2H
566-6848C4H3C, H8CH3CH3Co2
C1l(3102-1044904H9C2H5HCH
3GO2C2H515a-156 Example 50 3-ethylamino-5,7-ziprobilvirazolo (a
, 0.7 g of 4-dl pyrimidine-4,6(5H,7H)-dione was dissolved in formic acid-acetic anhydride for 10 days at 80-85°C.
I stirred at 2 o'clock. The reaction solution was dried under pressure, and the residue was chromatographed on #20'l of silicage gel to give ethylamino-2-formyl-5,7-siglobilvirazolo(a,4-d)pyrimidine-4,6(5H ,7H)-dione as colorless needle crystals of 0.58f were obtained. Melting point: 114-116°C Elemental analysis value: C grade. C(96) as H21J4503
H (%) N (%) Calculated value: 54.71 6.89 22.79 Expected value:
54.71 6.97 22.91 Examples 51-53 The following compounds were synthesized in the same manner as in Example 50.

B1 Example RIR2R3R4 Melting point ('C)51 C3H,
C3H7HH1a9-14152 C4H9C4H9H
CH31aO-1825a 04H8C41(, CH3
CH369-71 Example 54 3-amino-5,7-ethyl-1-methylpyrazolo (
aj4-d) Pyrimidine-4,6(5H.

711)-Xion 4y! i/-11; Dissolved in dOyl, added 15 mt of ethanol fed with hydrogen chloride, and allowed to cool.
2.71 colorless needle-like crystals of H, 7)-dione hydrochloride were precipitated.

Melting point: 196-196.5℃ Elemental analysis 111: C1oH□5N, 02-HCI
-H20 c (<4.) H (%) N (95
) Calculated value: 41. ts 6.22 24.01 Actual value: 41.68 6.32 24.41 Actual Extraction Example 1 Anti-inflammatory effect (carrageenan floating method) Jcl: SD flat 6 overage, male) using 6 animals per group, Winter and others B (1?roc, 8oc, exp
-Biol-Med, , ±11.544 (1962)
I searched according to , :l. 1 hour after oral administration of sample 50Q! 0.05 lb of lagenin saline solution was injected into the skin of the leg kick. Hindlimb volume and injection 1+ after 8 hours
'l valley 4. ．． 1 was measured and the edema volume was calculated from the difference.

The edema suppression rate was determined by comparing the edema volume between the non-treated group and the treated group.

The results are shown in Table 1.

Anti-inflammatory effect (reverse reception Arthus reaction) Jcl: SD flat 7 weeks old, male) using 106 mice,
Hair was removed from the back under ether anesthesia, and 0.5 ovalbumin
% physiological saline solution was injected into the tail vein, and a circular anti-egg argmin blood rl'10-IMt was injected into one place each on the left and right of the back.
Injected saline at 111111 points on the left.
I parted ways with 1ttt. After 8 hours, the thickness of the skin in each section at ℃ was measured with a caliper to calculate the size of edema. The sample was administered intraaxillally at a dose of 20 to 100 mg immediately before ovalbumin injection. The size of edema between the non-treated group and the treated group was compared to determine the edema suppression rate.The results are shown in Table 1.

The relationship between the edema suppression rate and the strength of anti-inflammatory effect in these two methods is shown below.

Edema suppression rate (%) Strength of anti-inflammatory effect 0- 9 - 10-19 ± 20-89 + 40-59 ++ >60 +++ + Experimental example 2 Analgesic effect (phenylquinone rising method) 81c: Engineering CR mouse (4 Using the method of Sigmund et al. (Proc, Sac・exp・B1o17) using 10 animals per group
Med-, 95, 729 (1957)). Specimen 50q was orally administered, and 30 minutes later, 0.02% phenylquinone water scar solution was intraperitoneally injected into the body mtof at a rate of pQ, l*t. The number of rises was counted for each animal over a period of 20 minutes. The writhing suppression rate was determined by comparing the number of reactions between the non-treated group and the treated group. The results are shown in Table 1. The relationship between this inhibition rate and the symbol of the strength of the 116 action is shown below.

Rising suppression rate? Strength of IA abstraction 0-29 - aO-49± 50-69 -1- 70-89 ++ >90 +++ (Left below blank) Formulation Example The compound (I) of the present invention can be used to treat, for example, rheumatoid arthritis and M purity syndrome. When used as a therapeutic drug, it can be used in the following formulations:

1. Tablet (1) 3-butyrylamino-5,7-danityl-l-methylpyrazolo(a,4-d)pyrimidine-4,6(5H
,7)1)-Dione 10-(2) Lactose a5
#4/ (3) Corn starch 150q (4) Microcrystalline cellulose aOq (5) Magnesium stearate 5-cho 309 (1), (2), (3) and (4)t/)2/a
After mixing (5) and (172), the mixture is granulated. The remaining portions (4) and (5) are added to the granules and pressure molded into tablets.

2. Capsules (υ 5,7-cyptyl-2-ethoxycarbonyl-3
-methylaminopyrazolo(a,4-d]pyrimidine-4
, 6(5H,7H)-dione 101ny (2) Lactose 100 Ml/ (3) Microcrystalline cellulose 70q (4) Magnesium stearate IOF/190 g
/ () Mix 1/2 of (2), (3) and (4), add 111 sheets, and granulate.Add the remaining amount of () to the granules.
Add 4) and encapsulate the whole in a gelatin capsule.

Claims (1)

[Scope of Claims] Formula [wherein R and R2 represent the same or different sia μp, R3 and R1 each represent hydrogen, alkyl or alkyl μ, R5 represents 7μ/I/, alkoxycarbonyl μ
or Homiμ, the broken line indicates the presence of two double bonds in the pyrazole ring, and R5 is bonded to either the 1st or 2nd position] or a salt thereof.