JPS60149523A - Anti-inflammatory analgesic agent - Google Patents

Abstract

PURPOSE:To provide an anti-inflammatory analgesic agent containing a specific isoxazole[3,4-d]pyrimidine derivative, and effective to the diseases such as headache, toothache, cervico-brachial syndrome, neuralgia, arthritis, etc. CONSTITUTION:The compound of formula I [R<1>-R<3> are H, lower alkyl, cycloalkyl or (halogen-substituted) aryl], e.g. 3,5,7-trimethyl-5H,7H-isoxazole[3,4-d]pyrimidine-4,6-dione, is used as an active component of the objective agent. It can be administered safely by oral or parenteral means. Dose: preferably 100-600mg daily divided in doses of 30-200mg each. The compound of formula I can be produced e.g. by reacting the compound of formula II with the compound of formula III in a solvent at 100-150 deg.C for 0.5-1hr.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to anti-inflammatory and analgesic agents. More specifically, the present invention relates to inoxazolo(3 , 4-d It relates to an anti-inflammatory and analgesic agent containing a 3-pyrimidine derivative.

Regarding the above general formula, Bl, 1(,2 and I(-
The lower alkyl group shown is preferably a linear or branched lower alkyl group having 6 or less carbon atoms (e.g., methyl, ethyl, ■-propyl, i-propyl, IT-butyl, 1-butyl, 5ec-butyl). , t-butyl, low-pentyl, low-pentyl, 11-hexyl, 1-hexyl, etc.), especially lower alkyl groups having 3 or more carbon atoms (e.g., methyl, ethyl, 11-propyl, 1-hexyl, etc.).
Propyl group is preferred.

Preferably, the cycloalkyl group includes a 5- to 7-membered cycloalkyl group (e.g., cyclopentyl, cyclohegycyl, cyclohebutyl), with a cyclohexyl group being particularly preferred.Aryl groups include phenyl, naphthyl, etc. Preferred are phenyl groups.This aryl group may be substituted with a halogen atom, and the halogen atom is preferably chlorine, bromine, etc., with chlorine being particularly preferred.

Compound (1), for example, has the general formula [wherein II1 and 1-R2 have the same meanings as +jiJ]
The compound represented by the general formula % formula % () [wherein 1 (same meaning as above)] or the general formula R3C (O
R'), (IV) (wherein R3 has the same meaning as above and II4 represents a lower alkyl group).

In the above general formula (1v), the lower argyl group represented by W is preferably the lower alkyl group having 6 or less carbon atoms similar to the above l(', j('' and 1mo8,
Particularly preferred are methyl group and ethyl group.

-1- The raw material compound (IN) used in the production of the compound (1) described above can be synthesized, for example, by the following method.

[Annaren der Hemi, vol. 615, p. 52 (1
958]] [In the above formula, 1 mo! and R'LL+? Same meaning as in Book ii.”

Note that the above compound ('II) may be used in the form of a formal isomer.

In this method, when the starting compound (n is a compound of the general formula (I)), the compound (If) is
N)'l for 1: It is preferable to use about 2 to 10 ml, and usually a solvent that does not interfere with the reaction (e.g., dioxane, toluene, cylene, etc.) is used, and the reaction temperature is about 100 to 150 ml. It is preferable to carry out the reaction at about °C for about 0.5 to 1 hour. Note that compound (M) can also be used as a solvent.

Compound (November: Compound (IV) When compound (IV) 'a' is 1,6, compound (I) is
V) It is preferable to use a solvent in an amount of about 2 to 5000, and usually a solvent that does not interfere with the reaction (eg, dimethylformamide).

The reaction is preferably carried out using dimethylacetamide, formamide, pyridine, picoline, etc. at a temperature of about 100 to 150° C. for about 0.5 to 1 hour.

The target compound CI) thus produced can be separated and purified using conventional separation and purification means, for example, from an appropriate M medium after distilling off the reaction solvent]
By crystallizing 1f, E nitrate I can be easily obtained. In some cases, the target compound (・Ken・1) may be mixed with salt,
For example, it may be isolated in the form of an organic amine salt (eg, choline salt, f:-ethylene diamine salt).

The target compound (ShinoR1 or (
and) l(''/l-hydrogen fragment, this hydrogen rg can also be easily converted into other target compound (1ru) by furkylation. As an alkylating agent, for example, an alkyl halide (411IL Methyl iodide, It-'-thyl iodide, propyl iodide.

[isopropyl bromide, butyl iodide, etc.], alkyl sulfates (eg, dimethyl sulfate, diethyl sulfate, etc.). The amount of alkylating agent is about 1 to 1 per 1 part of compound (1).
About 10 equivalents are used, and if necessary, the reaction is carried out in the presence of a deoxidizing agent (eg, sulfur hydroxide, potassium carbonate, etc.), and usually in a solvent such as dimethylformamide or tetrahydrofuran.

Although the reaction temperature varies depending on the type of alkylating agent, it is usually around room temperature, and the reaction time is about 1 to 10 equivalents.

Isoxazolo(8,4-d)pyrimidine derivatives exhibit anti-inflammatory and analgesic effects on various mastal motions Q6, and are effective against diseases such as headache, toothache, tooth extraction pain, condylar-brachial syndrome, neuralgia, and arthritis.

Useful as an analgesic.

Representative isoxazolo(3,4-d)pyrimidine derivatives (IJ anti-inflammatory and analgesic effects are shown in Tables 1 and 2 below).

Table 1: Analgesic effect [mice, phenylquinone Reizinck method]: P<0
．． 05. Future: 1-'<0.01. Future 1f'<0.
001 Table 2: Anti-inflammatory action [Rat, carrageenan edema method] Rice: P<0.05, Future: P<0.01 The acute toxicity of typical isoxazolo [8,4-”d3 pyrimidine derivatives (I)] is as follows. As shown in Table 8.

Table 8: Acute toxicity [mice, observed for 711 days after administration, mortality rate 8 days later] Isoxazolo (at4'') pyrimidine derivative 9 (1)
When used as an anti-inflammatory or analgesic, it can be used by itself or mixed with appropriate pharmacologically acceptable carriers, excipients, and diluents, and in the form of powder, granules, two tablets, capsules, injections, half-open tablets, etc. It can be safely administered orally or parenterally. The animal to be administered differs depending on the target disease, symptoms, subject, administration method, etc., but for example, when administered as an anti-inflammatory or analgesic for headache, toothache, or cervicobrachial syndrome in adults, the dose per oral administration is approximately 80 to The preferred dosage is about 200 μg per day, and about 100 to 600 μ per day.

Regarding inoxazolo[3,4-d]pyrimidine derivatives (1) as anti-inflammatory and analgesic agents, a more preferred embodiment is that in each of the above-mentioned 141, R2, and R'' substitutions, 1 is a lower alkyl group, I(, %-hydrogen atom or lower alkyl group, derivatives in which R8 is a hydrogen atom or a lower alkyl group, especially a hydrogen atom or a methyl group (1
) can be given. The specific explanation of the lower alkyl group is as described above.

Example 1 Manufacture of tablets with the following composition used as anti-inflammatory and analgesic agents [Composition] (118,5,7-I-dimethyl-5H,
30 ml (2J lactose 85mf (3) Cornstarch 84, 5mv (4) Magnesium stearate 0.5m9100 ~ [Preparation] After mixing 22.5mg of cornstarch with (1) and (2), prepare from 7m9 of cornstarch (4) and 5 m2 of corn starch are added to the granules and compressed into tablets with a diameter of 7 stations.

Synthesis examples of intermediates and active ingredients are shown below. In the examples of synthesis of active ingredients, target compounds 1 to 7 and 9 to 26 are new compounds.

Synthesis Example 1 of Intermediate Nimethyl-3-cyclohexyl-6-hydroUxyaminouracil a) 57 g of methyl isocyanate was dissolved in 500 g of ethyl ether.
When dissolved in 100 mg of cyclohexylamine and added 997 yen drops of cyclohexylamine, crystals precipitate immediately. δI = crystal ether
105p of N-methyl-N'-cyclohexylurea is obtained. Melting point 160-161℃ Elemental analysis value (C8H1
6ON2) Calculated value C61,50H10,32
N 17.98 Experimental value C61,67H10,78N
17.54b) N-Methyl-N'-cycloheginolurea 55'1 malonic acid is dissolved in 15++/acetic acid by heating,
Acetic anhydride was added dropwise over 15 minutes at 70°C. Further 8 (after heating at 1-90℃ for 2 hours, add 5 tnlk of water and 7
After heating at 0° C. for 30 minutes and concentrating to dryness, a pale yellow oil is obtained. If this is dissolved in methanol and left in an ice chamber, needle-shaped crystals will precipitate. Take 1 yen of crystals and wash with ethanol to obtain 6.95+ colorless needle-shaped 1-methyl-3-cyclohexylbarbic acid. Melting point 81-82℃ Elemental analysis value (as C11H1608N2) Calculated value
C58,911-17,19N 12.49 Experimental value C
58,77N7J4 N12.08li 1-methyl-3
- Mix 35 g of cyclohexylbarbic acid with 15 g of water, add 150 ml of phosphorus oxychloride and react.

After boiling for an additional hour, the reaction mixture was added to 2 parts of ice water to obtain yellow crystals 352 (when dry). The crystals were dissolved in a small amount of chloroform, and chromatography was performed using a silica gel column (400S+). The first fraction was collected and concentrated to dryness, resulting in colorless crystals of 1-methyl-3-cyclohexyl- 14 grams of 6-chlorouracil are obtained. Melting point 181-188℃ Elemental analysis value (C,,H,50℃N2C1) Calculated directly CI 14.64 Experimental value CI 15.01 d) 1-Methyl-8-cyclohexyl-6-chlorouracil 7g , Sodium acetate (trihydrate) 18g, Hydroxylamine hydrochloride 77, Methyl cellosolve loOmA
After boiling the mixture consisting of
Methyl-3-cyclohexyl-6-hydroxyaminouracil 41 is obtained. Melting point 158-155℃ Elemental analysis value (as C1, H1703NB) Calculated value C
55,211-17,16N17.56 Experimental value C55
, 48N7.58 N17.24 Intermediate Synthesis Example 2 1-Methyl-6-hydroxyaminouracil l-methyl-6-aminouracil 2y-, hydroxylamine hydrochloride 27 and methyl cellosolve 80ml! After boiling for 2 hours, insoluble materials are removed, and liquid F is concentrated to dryness. Water is added to the resulting crystalline residue, which is ground to obtain crystals. When this is recrystallized from ethanol, pale yellow crystals of the title compound 1.
57 is obtained. Melting point 247-250℃ (decomposition) Elemental analysis value (C6H708N8 calculated value C38,2
2H4,49N26.74★Experimental value C88,57H4,
21N 26.88 Synthesis Examples 3 to 9 of Intermediates The fourth
The compounds shown in the table are obtained.

[In the formula, Iυ and RN have the same meanings as above] Synthesis example 1 of self-effective ingredient 8.5.7-1limethyl-51-1,7H-isoxazolo(8,4,-d)pyrimidine-4,6- Dione 1,8-dimethyl-6-hydroxyaminouracil 1 is boiled with 1 liter of acetic anhydride at 140'C for 1 hour, the insoluble matter is once removed by P, and the P solution is concentrated to dryness to give a colorless needle-like compound. Compound 0.72? iI will be beaten.

When recrystallized at /-/I/ for 1 night, the melting point is 200-202℃0
Calculation of fluorine analysis value (as C8H908N8) 4i C4
9,2a tI4.65 N 21.58 Experimental value C4
8,77H4,42N22.08 Ultraviolet absorption spectrum (aqueous solution): λrtiax 289 mμ Synthesis example 2 of active ingredient 8-phenyl-5,7-dimethyl-5H,7H-isoxazolo[8,4-dnopyrimidine-4.6- Dione 1.8-dimethyl-6-hydroxyaminouracil 0.
51 was dissolved in 10 ml of dioxane, and benzoic anhydride 4
7 and boiled at 120° C. for 4 hours, dioxane was distilled off, and 20 tnl of ether was added to the residue to remove 1 insoluble material. Washing with ether gives 0.85p of the title compound. Melting point: 195-19 when recrystallized from ethanol
6℃.

Elemental analysis value (as 018H1108Ni1) Calculated value
C60, 69H4, 81N16.84 Experimental value C60,
881 (4,16N16.46 ultraviolet absorption spectrum (
(in methanol): λInaX282mμ Synthesis Example 8 of Active Ingredients 3-isopropyl-5,7-dimethyl-5H.

Example of synthesis of active ingredients: 71-1-ynoxazolo (8,4-(1,1pyrimidine-4,6-dione 1,8-dimethyl-6-hydroxyaminouracil 5g, some xylene, isobutyric anhydride i o rue) When reacted in the same manner as in 1, the title compound 8.
2fI is obtained as colorless needles. Melting point: 106°C.

Elemental analysis value (as C1oH, 308N8) d1 calculated value
C58,80N5.87 N18.88 Experimental value C58
, 21N5.66 N18.98 Synthesis example 4 of active ingredients
7 According to the method of Active Ingredient Synthesis Example 1 or 3, the compounds shown in Table 5 are obtained by the reaction described below.

Table 5 Synthesis Example 8 for 1 Substance 5.7-dimethyl-511.71-1 to isookylyzolo[3,4-dJpyrimidine-4,6-dione 1.3
- 2 g of dimethyl-6-hydroxyaminouracil, 20 ml of dimethylformamide and 20 ml of ethyl orthoformate
After boiling trtl at 160° C. for 1 hour, the solvent is distilled off, and ethanol is added to the residue to collect crystals. When this is recrystallized with hot water, a colorless columnar title compound 1.07 is obtained. Melting point 170-171°C.

Elemental analysis value (as 07H708N8) Calculated value C46
, 41H8, 90N28.20 Experimental value C46, 48I
-18,79N 23.80 Ultraviolet absorption spectrum: λ
M4 14234,260 (shoulder) mμ Active ingredient synthesis example 9 8.5.7-1-limethyl-51-1,71-1-isoxazoloC3t4-dJpyrimidine-4,6-+2one 1.8-dimethyl- 6-hydroxyaminouracil 57
．． 100ml of dimethylacetamide and ortho^'I
When ethyl acid 20m(!) is reacted in the same manner as in Synthesis Example 8 of Self-Effective Component, the title compound 2 is obtained.

Even when the crystal was mixed with the compound obtained by the method of Synthesis Example 1 of the active ingredient, it did not show any decrease in melting point.

Synthesis Example 10 of Active Ingredients 5-Methyl-7-phenyl-5I-1, 71-1-isoxazolo[+4-dJ pyrimidine=4, 6-dione 1-phenyl-3-methyl-6-hydroxyaminouracil 2), Dimethylformamide 100g, ethyl orthoformate 10ml 17; 7 By reacting in the same manner as in Synthesis Example 8, the title compound 0.989 is obtained.

Melting point 219-221°C.

Elemental analysis value (as C1□H3O8N3) Calculated value C
59,26118,73N17.28 experimental value C58,
85H3,51N17.06 Active ingredient synthesis examples 11-1
9 Following the method of Synthesis Example 8 of Active Ingredients, the compounds shown in Table 6 are obtained by the reaction in G. 3. Synthesis Example 2 of Self-Effective Ingredients
0 5-Methyl-7-cyclohexyl-51-1,7H-isoxazolo[8,4-d]pyrimidine-4,6-dione 7-nocrohegysyl-5H,71-1- obtained according to Synthesis Example 15 of active ingredient Inoxazolo [3,4-(1
] One portion of pyrimidine-4,6-dione was dissolved in 50 g of dimethylformamide, 800 g of potassium carbonate and 1 ml of methyl iodide were added, and the mixture was stirred at room temperature for 20 hours. After removing the residue with gloloborum and removing the insoluble matter, chloroform is distilled off and the residue is recrystallized from water-ethanol to obtain the title compound o, sy in the form of a light colored plate.Melting point 194-19
7°C6 elemental analysis value (CC12H1508N, 11 people - 1 value C57,82116,07N16.8
6 Experimental value C57,61) 15.87 N16.71 Synthesis example of active ingredient 21 7-Methyl-5-ethyl-5H,711-4soA'xazolo8.4-d,Jpyrimidine-4,6- 7-Methyl-5 obtained by Synthesis Example 16 of Dione Active Ingredients
11,71-1-Isoxazolo[8,4-d3pyrimidine-4,6-i;/one 27 was dissolved in 50 rul of dimethylformamide, 1.62 ml of potassium carbonate and 2 ml of ethyl iodide were added, and Synthesis Example 20 of Self-Effective Ingredient After the reaction, 0.92% of the title compound is obtained as colorless crystals. Melting point 87-88°C.

Elemental analysis value (C81-L, 0BNs Toshi C) total p value
C49,28H4,65N21.53 Experimental value C49,
2584,62N 21.36 "Synthesis example 2 of 1 effect and 1 part
2 3.5-dimethyl-5H,7H-inoxazolo(j,
4-(IJ pyrimidino 4,6 dione 8-methyl-
6-Hydroxylaminourasol 0,. 5! , 5 ml of pyridine, and 5 ml of m-acid anhydride are subjected to anti-LQ reaction in the same manner as in Synthesis Example 1 of the self-active ingredient to obtain the title compound 0°357 as colorless needle crystals. Melting point: 260°C.

Elemental analysis value (as C7H708N8) = 1 calculated value U
46.41 ft 8.90 N 28.20 Experimental value C46,56H8,82N22.86 Synthesis example 23 of active ingredient 3.7-dimethyl-5H,71-1-yne oxazolo(
-8,4-'dJ pyrimidine-4,6-dione l-methyl-6-hydroxylaminouracil o, 5p, anhydrous sodium acetate 0.5! When 10 ml of acid-resistant anhydride is inverted 1,6 in the same manner as in Synthesis Example 1 of the active ingredient, the title compound is 0.
39 is a colorless crystal bound C obtained 1') Jl. Melting point: 259°C.

Elemental analysis value (C711708N8 Toshi-C) calculated value
C46, 41148, 90N23.20 Experimental value C46
, 72H8, 74N22.95 Active ingredient synthesis example 24 3-butyl-7-ethyl-5H, phH-isoxazolo(8,4-d)pyrimidine-4,6-dione l-ethyl-6-hydroxolaminouracil 3g, potassium carbonate 37. When anhydride -rI't' + acid 15me is reacted in the same manner as in Synthesis Example 1 of the active ingredient, the title compound 2. l
It is obtained as colorless crystals. Melting point 129'-18o
'c.

Elemental analysis value (C11lI160+lN, and (2te) tl
Calculated value C55,68H6J7 N17.71 Experimental value C
p5. '18 116.42 N17.48 Synthesis example of therapeutic ingredient 25 5-ethyl-3,7-dimethyl-5H,7H-isoxazolo[8,4-dJpyrimidine-4゛.

8,7-dimethyl-5 obtained in Synthesis Example 28 of 6-dione active ingredient
H,? 1-1-1 Sooxazolo (8,4-dJ pyrimidine-4,6-dione) The same procedure as in Synthesis Example 21 of pyrimidine-4,6-dione yields square crystals of the title compound. Melting point 1
08-104℃.

Elemental analysis value (as C, H, 10, N) Calculated value C5
1,67H5,80N20.09 Experimental value C3L50
H5,08N20.00 Active ingredient synthesis example 26 Two-ethyl-8,5-dimethyl ~50. Tl-1 isoxazolo[8,4-d3pyrimidine-4゜6-dione 7-ethyl-3-methyl-5H, phenyleneoxazolo[3,4-dJpyrimidine-4] obtained in Synthesis Example 6 of active ingredient , 6-dione active ingredient Synthesis Example 20 yields the title compound as a colorless product. Melting point 88-
It's 9℃.

Claims (1)

[Claims] (1) General formula [wherein R', R% and I (% is a hydrogen atom,
An anti-inflammatory and analgesic agent containing an isoxazolo(8,4-d,]pyrimidine derivative represented by a lower alkyl group, a cycloalkyl group, or an aryl group optionally substituted with a halogen atom). (2) IL ice The isoxazolo [8゜4-
d] Anti-inflammatory and analgesic agents containing pyrimidine derivatives. (a) An anti-inflammatory and analgesic agent containing the isoxazoloCat4-dj pyrimidine derivative according to claim No. +1) or (2), wherein (i2) is a hydrogen atom or a lower alkyl group. (4) Claim No. 1 (1) which is a sensitive lower alkyl group
), (2), or (3).