JPS5962594A - 3,5-disubstituted-triazolopyrimidine derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:The 3,5-disubstituted-triazolopyrimidine derivative of formula I (R is halogen, OH, lower alkoxy, phenoxy, substituted amino, or benzylthio). EXAMPLE:5-Chloro-3-phenyl-3H-1,2,3-triazolo[4,5-d]pyrimidine. USE:An antitumor agent. PROCESS:The compound of formula I (R is halogen) is prepared e.g. by catalytically reducing the compound of formula II in the presence of a Raney Ni catalyst, etc., and diazotizing and cyclizing the product with sodium nitrite or isoamyl nitrite, etc. The obtained compound can be converted to another compound of formula I (R is R') by reacting with the compound of formula R'H (R is R other than halogen) in a solvent such as methanol.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel 3.5-disubstituted triazolopyrimidine derivatives, more specifically, the following general formula (I) (wherein 1t
represents a rogen atom, a hydroxyl group, a lower alkoxy group, a phenoxy group, a substituted amine group, or a benzylthio group) and a method for producing the same.

Conventionally, as a triazolopyrimidine derivative, 8-azaguanine is known to have an antitumor effect. However, 5-substituted-3-phenyl-3H-1,2,3
-) Riazolo[4,5-d)pyrimidine derivatives, compounds in which R is an amino group in the formula (I) are known (J, Pharm.

and Pharmacol, 9. 4 6
- 67 (1957)': 1, and their anti+HV tumor activity is completely unknown.

Therefore, the present inventor proposed a series of 5-substituted@-3-phenyl-3
As a result of synthesizing 1-(-1,2,3-1-lyazolopyrimidine derivatives and examining their antitumor activity), it was found that the above-mentioned known compounds hardly exhibit antitumor activity; The present invention was completed by discovering that a new compound has excellent antitumor effects.

That is, the first object of the present invention is to provide a novel 3,5-disubstituted triazolopyrimidine derivative (I) having excellent antitumor activity. The object of the present invention is to provide a method for producing novel 3,5-disubstituted triazolopyrimidine derivatives ([).

The 3,5-disubstituted triazolopyrimidine derivatives of the present invention can be roughly classified into the following (Ia) and (Ib) depending on the type of R.

In the formula 1, X represents a halogen atom) (In the formula, It' represents a hydroxyl group, a lower alkoxy group, a phenoxy group, a substituted amine group, or a benzylthio group) In the substituent W of the compound fib) of the present invention, lower alkoxy Examples of the group include methoxy and ethoxy groups, and examples of the substituted amine group include methylamino, benzylamino, dimethylamino, pyrrolidino, and anilino groups.

Compound (la), which is a compound of the present invention and is also a raw material for compound (Ib), has the following general formula ([V) (wherein,
is the same as above) Known compounds represented by (J, Chem, Soc,
.

Perkin [, 1974, 1970) in the presence of a suitable catalyst such as Raney nickel, followed by diazotization with sodium nitrite or isoamyl nitrite, followed by ring closure.

Compound (ib) of the present invention can be produced, for example, by reacting compound (Ia) with a compound represented by general formula (I) in accordance with the following general formula.

(Ia) (lit) (
Ib) This reaction is carried out without a solvent or in a suitable solvent using 1 to several mol of compound (II) per 1 mol of compound [a). In addition, when the compound (IID) is an alcohol, a mercaptan, or an active methylene compound, it is preferable to carry out the reaction using 1 to fi moles of an appropriate base.As a solvent, for example, methanol, ethanol, etc. Alcohols such as Pγ, amides such as l'J and N-dimethylborumamide, or aromatic hydrocarbons such as benzene and toluene are used.

The reaction is allowed to proceed for several minutes to ci hours while cooling with water or heating on a water bath.

After the reaction, the solvent is distilled off or passed through suction P, as it is (Plui 611.11 (extracted with the appropriate solvent and then distilled off) 7: fc, methanol, ethanol, benzene, Chloroform, petroleum benzene, rhohexane. Stone?
+I+J21 The desired compound (lb) can be obtained by re-coating with a solvent such as inpropyl ether.

1.11 This can be purified by ordinary column chromatography according to the requirements.

Next, the results of testing the anti-++I+ tumor activity of representative compounds of the present invention obtained in this manner are shown.

A group of 84 IRC male mice (5 weeks old) was used, and 5 x 10 θ Sarcoma 180 ascites cancer cells were intraperitoneally implanted per animal. The test compound was suspended in physiological saline containing 0.5 CMC at the doses shown in the table below, and was administered 2 days after transplantation.
After 4 hours, the mice were intraperitoneally administered 6 times a day, once a day.

Pharmacological effects were evaluated by calculating the survival rate using the following formula.

The results are shown in Table 1.

Table 1 *Displayed in the examples.

As is clear from Table 1, the compound of the present invention has the above-mentioned cancer δ.
A survival effect was observed in mice transplanted with i11 cells.

Next, examples of the present invention will be given and explained.

Example 1 4-anilino-2-chloro-5-nitrovirimidi 710
Dissolve g in 30rnl of ethanol, add w-2゛Raney nickel 1.0!9- and catalytic reduction at room temperature and normal pressure.
(300-350 ml of hydrogen):
The r liquid was distilled off under reduced pressure. The residue was treated with 2M of 2NIM acid,
Dissolve in 5 ml of water, 5 ml of water, and 5.d of acetic acid and cool on ice. An aqueous solution of 0.16 g of sodium nitrate in water was added dropwise over 15 minutes, and the mixture was stirred for 30 minutes while cooling with water.

Then, it is stirred at room temperature for 1 hour, and the precipitated crystals are suctioned at P'3M, washed with water, and air-dried. When ()1 crystals are formed from a mixture of benzene and petroleum benzene, colorless needle-like crystals of 5-chloro-3- phenyl-3H-1,2,3-)riazolo(4
,5-(1':l pyrimidine (compound number 1) is 0,4
81-(yield: 52 cm) was obtained.

Example 2 5-chloro-3-phenyl-3H-1,2,3-triazolo(4,5-d)pyrimidine (compound number 1) 0,3
09- is dissolved in 30 rnl of methanol, 0.30 g of potassium carbonate is added, and the mixture is stirred at room temperature for 4 hours, then the methanol is distilled off, and the residue is washed with water and air-dried.

When recrystallized from inpropyl ether, colorless needle-like crystals of 5-methoxy-3-phenyl-3H-1,2°3-triazolo[4,5-d]pyrimidine (Compound No. 2)
．． 1.7 y- (yield: 58 y) was obtained.

Example 3 5-chloro-3-phenyl-3J(-1,2,3-triazolo(4,5-d)pyrimidine (compound number 1) 0.
Dissolve 10 yen in 20 grams of ethanol, add phenol 0.1
．． 2' Add 0.10P of potassium carbonate and stir at room temperature for 8 hours. Distill the solvent, wash with water, air dry, and recrystallize from a mixture of benzene-n-hexane. 5-phenoxy as colorless needles. -3-phenyl-31-1-1,2,
3-1-riazolo[4,5-d]pyrimidine (compound number 3) is obtained (0.06y-C yield: 48%).

Example 4 5-Chloro:3-phenyl:N-12,3-triazo[I4.5-d]pyrimidine (Compound No. 1)
0, ] Ozo dimethylformamide 3m/! Add 05M of 40-thimethylamine aqueous solution and 50°C
Warm for 30 minutes. Dilute with ice water 1. The precipitated crystals are filtered under suction, washed with water, and then air-dried. Recrystallization from benzene gives colorless needle-shaped crystals of 5-methylamino-3-phenyl-
3H-1,,2,3-triazolo I! , 5-d] pyrimidine (Compound No. 14 No. 4) was 0.08 V- (yield 82%
)can get.

Example 5 5-chloro-3-phenyl-38-1,2,3-)riazolo[4,5-d)pyrimidine (compound number 1) 0,0
5 Ll− was dissolved in 3 ml of dimethylformamide,
Adding 70.5 ml of aniline, treating in the same manner as in Example 4, and recrystallizing from chloroform yields colorless fine needle-like crystals of 5-anilino-3-phenyl-311-1,2,3-)riazolo(
4,5-d) pyrimidine (compound number 5) is 0.055
1 yield of 80 g) was obtained.

Example 5 - Chlor-3-phenyl-31-1-1,2,3-triazolo[4,5-d]pyrimidine (Compound No. 1) 0
．． 255'& ethanol 30 rnl K (volume 'P), benzyl mercaptan 0.207 potassium carbonate 0.
309-Add and stir at room temperature for 8 hours. 1. Precipitate crystals? Extract with chloroform, wash with saturated aqueous solution of hydrogen carbonate, then with water, and dry over anhydrous sodium sulfate. Chloroform was distilled off and the residue was recrystallized from benzene to give colorless needle-like crystals of 5-benzylthio-3-phenyl-31-1-1.
,,2,3-triazolo[4,5-d'lpyrimidine (
0.40 g of compound number 6) (yield: 97) is obtained.

Example 7 The compounds shown in Table 2 V were obtained in the same manner as in Examples 1-6. In addition, the compounds obtained in Examples 1 to 6 are also listed in detail in the table. Wakamatsu O ('Udono 1, 'Iil'l's front small Showa 5711' Special agreement 1qj No. 171172-'
i2 Name of ``Departure'' 3.5-Digane exchange-triasoropyrimidine fatty conductor and its manufacturing method 37 Yama II Name' Width I' Relationship with I'I Applicant fi: +'Ji Nihonbashihama-cho, Chuo-ku, Tokyo No. 2-12-4 Name: J = Sues Pharmaceutical Co., Ltd. Representative Nookata Yasumichi 4th generation Misaki 6th Column 7 of “Detailed explanation of the invention” of the specification subject to amendment 1, Contents of the amendment (11 Akira #llI m In the middle, page 3, line 14, ``their'' is corrected to ``that''.

(2) Same, page 4, line 2 It says "that" "Those" and stop.

(3) Chapter 6, line 2 [Perkin I + J is corrected to read [Perkin Trans, I + J].

(4) Times, page 6, 3 lines from the bottom or 2 lines from the bottom “
``Alcohols, mercaptan D or active methylene compounds'' should be corrected to ``1-alcohols or mercaptans''.

(5) Times, page 10, line 14 1-0.1 Of addition" Add rO, 1Or.'' Correct.

(6) times, 11th negative, 5th line and same, 16th line F-
The text "Add 0.5m" should be corrected to "Add 0.5-."

(Force times, 12th negative, line 5 [add 0.20 f of mercaptan and 0.302 of potassium carbonate] is corrected to [add 0.20 f of mercaptan and 0.307 of potassium carbonate].

Claims (1)

[Scope of Claims] 1 3, 5 represented by the following formula (1) (wherein l represents a halogen atom, a hydroxyl group, a lower alkoxy group, a phenoxy group, a substituted amine group, or a benzylthio group) -Disubstituted-triazolopyrimidine derivative. 2. A triazolopyrimidine compound represented by the following general formula (la) (in the formula, X represents a halogen atom) is converted to the following general formula (1) % formula % () The following general formula (Ib) (wherein R' represents a hydroxyl group, a lower alkoxy group, a phenoxy group, a substituted amine group, or a benzylthio group) is the same as above) A method for producing a 3,5-disubstituted triazolopyrimidine derivative represented by: