DK143600B - ANALOGY PROCEDURE FOR THE PREPARATION OF 1-SUBSTITUTED 4-PHENYL-2 (1H) QUINAZOLINO DERIVATIVES - Google Patents

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(11) PRESENTATION 143600 (61) Appendix to Patent No. 137647 DENMARK <»'" int ci. " c 07 d 239/82 ± (21) Application No. 4458/71 (22) Filed on 10 Sep. 1971 f (24) Life Day 10 Sep. 1971 (44) The application presented and the petition published on 14.3Θρ. 1981

DIRECTORATE OF

PATENT AND TRADE MARKET <3 °) Priority requested from it

Sep 11 1970, 80173/70, JP

(41) Aim, ref. Mar 12 1972___________ (7i) SUMITOMO CHEMICAL COMPANY LIMITED, Osaka, JP.

(72) Inventor: Shigeho Inaba, JP: Michihiro Yamamoto, JP: Kikuo Ishi = zumi, JP: Kazuo Mori, JP: Masao Koshiba, JP: Hisao Yamamoto, JP.

(74) Plenipotentiary in the proceedings:

The engineering firm Budde, Schou & Co._ (54) Analogous process for the preparation of 1-substituted 4-phenyl-2 (1H) quinazolinone derivatives.

Patent No. 137,647 relates to an analogous process for the preparation of 1-substituted 4-phenyl-2 (1H) -quinazolinone derivatives of the general formula

HpCX ° wherein R is polyhaloalkyl of 2-3 carbon atoms and at least 12 3 2 fluorine atoms, and R, R and R are each hydrogen, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms, nitro, trifluoro methyl, alkylthio of 1-4 carbon atoms, alkylsulfonyl of 1-4 carbon atoms or halogen, and the peculiar feature of the main patent is that a trihaloacetamidobenzophenone derivative of the formula

R yK

N-CO-C-X

wherein R, R, R and R are as defined above and X is halogen, reacted with an ammonium salt in the presence of a solvent.

The present invention relates to another analogous process for preparing the compounds of formula (I).

In the compounds of formula (I), the halogen atom includes chlorine, bromine, iodine and fluorine; methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl, the C ^ ^ - alkoxy group means e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy, the C 1-6 alkylthio group means e.g. methylthio, ethylthio or butylthio, and the polyhaloalkyl group means e.g. difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, chlorodifluoromethyl and pentafluoroethyl.

The 1-substituted 4-phenyl-2 (1H) -quinazolinone derivatives of formula (I) of the invention have excellent anti-inflammatory and analgesic activity with low toxicity to mammals. The anti-inflammatory action of these compounds is more potent than that of 1,2-diphenyl-3,5-dioxo-4-n-butyl-pyrazolidine (phenylbutazone), and the acute, subacute and chronic toxicity is much less than that of phenylbutazone.

From the specification of Danish Patent No. 129,348, it is known that certain 1-substituted 4-phenylquinazoline-2-sub derivatives which are closely related to the subject 1-substituted 4-phenyl-2- (1H) -quinazolinone derivatives of formula (I) ), has anti-inflammatory effect. It has been found that the 1-substituted 4-phenyl-2 (1H) -quinazolinone derivatives of formula (I) have a surprisingly good anti-inflammatory effect over the known compounds mentioned above, which is further illustrated in the above-mentioned compounds. following.

The anti-inflammatory action of the compounds of the invention is further determined by the inhibitory effect on rat hind paw edema caused by the injection of 0.05 µl of 1% carrageenin in sterilized 0.9% sodium chloride solution.

The test compounds are administered orally for 1 hour before the carrageenin injection. For each concentration level, 6 rats are used.

In each rat, the paw volume is measured as an indication of the edema inhibition 3, 4 and 5 hours after the carrageenin injection, and the average value of these measurements is calculated for each rat. The percent feather inhibition is calculated using the formula (1 - T / C) x 100, where T is the average edema volume value for the treated group and C is the average edema volume value for the untreated control group. The test results are given in the table below.

Table

Dose Inhibition of

Compound (rag / kg po) esta (%) - 1- (2 ', 2'-Difluoroethyl) -4-phenyl-6- 41,2-nitro-2 (1H) -quinazolinone 50 61.8 1- ( 2 ', 2', 2'-Trifluoroethyl) -4-phenyl-44,4 -2 (1H) -quinazolinone 100 50,6 1- (2 ', 2', 2'-Trifluoroethyl) -4-phenyl 37.1 -6-chloro-2 (1H) -quinazolinone 100 46.4 1- (2 ', 2', 2'-Trifluoroethyl) -4-phenyl-39.0 -6-methoxy-2 (1H) ) -quinazolinone 100 51.0 1- (2 ', 2', 2'-Trifluoroethyl) -4-phenyl-48,2 -6-nitro-2 (1H) -quinazolinone 100 53.1 1- (2 ') 2 ', 3', 3'-Tetrafluoropropyl-4- 33,3-phenyl-6-methoxy-2 (1H) -quinazolinone 100 53.1 1- (2 ', 2', 2'-Trifluoroethyl) - 4-Phenyl-6- 100 29,7-Chloro-3,4-dihydro-2 (1H) -quinazolinone 200 46.3 (known from the specification for available application no. 3328/71, which has led to patent no. 129.348) 4 143600

The process of the present invention is characterized in that a compound of formula (IIa) or (IIb)

Rf * TT (IIa) R1

R

f R2 1 <: Τ (Ilb) R1

R

Wherein R, R, R and R have the meaning given above are contacted with an oxidizing agent.

Suitable oxidizing agents are e.g. alkali metal permanganate such as sodium permanganate and potassium permanganate, manganese dioxide, magnesium dioxide, alkali metal ferricyanide such as potassium ferricyanide and mercuric acetate.

The reaction may preferably be carried out in the presence of a solvent or solvent mixture. The choice of solvent depends on the oxidizing agent used, and the solvent is selected from benzene, toluene, ether, tetrahydrofuran, dioxane, acetone, water, ethanol, isopropanol and dimethyl sulfoxide.

The reaction is usually carried out at a temperature in the range of approx. room temperature up to the boiling point of the solvent used.

The method according to the invention is further explained in the following examples which illustrate preferred embodiments.

5 143600

Example 1.

To a solution of 7.77 g of 1- (2,2,2-trifluoroethyl) -4-phenyl-6-chloro-3,4-dihydro-2 (1H) -quinazolinone in 100 ml of dioxane is added dropwise a suspension of 3.6 g of potassium permanganate in 30 ml of water at 20-30 ° C. The mixture is then stirred at room temperature for 3 hours.

To the resulting mixture is added 1 g of formic acid and stirring is continued. The brown precipitate formed is filtered off and washed with 30 ml of dioxane. The filtrate and washings are combined and concentrated under reduced pressure. The residue is dissolved in 50 ml of chloroform and the chloroform solution is washed with water and dried over anhydrous sodium sulfate.

The solvent is removed under reduced pressure and the residue is recrystallized from isopropyl alcohol to give 6.95 g of 1- (2,2,2-trifluoroethyl) -4-phenyl-6-chloro-2 (1H) -quinazolinone, m.p. 185-186 ° C.

Example 2.

Analogous to the procedure described in Example 1, the following compounds are prepared: 1- (2,2,2-trifluoroethyl) -4-phenyl-2 (1H) -quinazolinone, m.p. 181-182 ° C, 1- (2,2,2-trifluoroethyl) -4-phenyl-6-nitro-2 (1H) -quinazolinone, m.p. 207-208 ° C, 1- (2,2,2-trifluoroethyl) -4-phenyl-6-methoxy-2 (1H) -quinazolinone, m.p. 157-158 ° C, 1- (2,2,2-trifluoroethyl) -4-phenyl-6-trifluoromethyl-2 (1H) -quinazolinone, m.p. 173-174 ° C, 1- (2,2,2-trifluoroethyl) -4- (o-fluorophenyl) -6-chloro-2 (1H) -quinazolinone, m.p. 194.5-195.5 ° C, 1- (2,2,2-trifluoroethyl) -4- (m-nitrophenyl) -6-nitro-2 (1H) -quinazolinone, m.p. 205-206 ° C, 1- (2,2-difluoroethyl) -4-phenyl-6-nitro-2 (1H) -quinazolinone, m.p.

197-197.5 ° C, 1- (2,2,3,3-tetrafluoropropyl) -4-phenyl-6-methoxy-2 (1H) -quinazolinone m.p. 151-152 ° C, 1- (2,2,3,3,3-pentafluoropropyl) -4-phenyl-6-methyl-2 (1H) -quinazolinone, m.p. 175-176 ° C and 1- (2,2,3,3,3-pentafluoropropyl) -4-phenyl-6-methoxy-2 (1H) -quinazolinone, m.p. 135-136 ° C.

6 143600

Example 3

By analogy to the procedure described in Example 1, however, instead of 1- (2,2,2-trifluoroethyl) -4-phenyl-6-chloro-3,4-dihydro-2 (1H) -quinazolinone, 1 - (2,2,2-Trifluoroethyl) -4-phenyl-6-chloro-1,2-dihydroquinazoline, 1- (2,2,2-trifluoroethyl) -4-phenyl-6-chloro-2 ( IH) -quinazolinone, m.p. 185-186 ° C,

Claims (1)

143600 7 Patent Claims. Analogous process for preparing the 1-substituted 4-phenyl-2 (1H) -quinazolinone derivatives of the formula disclosed in Patent No. 137,647. Wherein R, R and R are each hydrogen, halogen, C 1-4 alkyl, alkoxy, nitro, trifluoromethyl, alkylthio or alkylsulfonyl, R is a polyhaloalkyl group having 2- 3 carbon atoms and at least 2 fluorine atoms, characterized in that a compound of formula (IIa) or (IIb) 4 - R3 R2 I (Ha) R1 R • in '*' "''! Γ i-R r 2 γ dib) R1 I R 12 3 where R, R, R and R have the meaning given above are contacted with an oxidizing agent.