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United States Patent Office Patented Feb 3,794,643 United States Patent Office Patented Feb. 26, 1974 1. 2 3,794,643 aZolinedione derivatives are produced by reacting the QUINAZOLINEDONE DERIVATIVES compounds having the following general formula: Takahiro Yabuuchi, Takarazuka, and Hajime Fujimura, Akira Nakagawa, and Ryuichi Kimura, Kyoto, Japan, assignors to Hisamitsu Pharmaceutical Co., Inc., Tosu, Saga Prefecture, Japan No Drawing. Filed Apr. 20, 1971, Ser. No. 135,693 int, C. C07, 51/48 U.S. C. 260-260 8 Claims ABSTRACT OF THE DISCLOSURE O The present invention relates to novel quinazolinedione R3 R2 derivatives possessing excellent anti-inflammatory action and analgesic action, and process for the production (wherein R2 and/or Rs have the same meaning as men thereof by reacting the compounds having the following 5 tioned above) with the general formula, RX or RSO, general formula, (wherein R represents the same substances as mentioned O above), R represents lower alkyl radical, and X repre C Sents halogen atom). Consequently, the reaction of the present invention can be understood as being alkylation. 20 The abovementioned compounds used as starting reac tion materials in the present invention can be obtained in good yield by reacting N-phenylanthranilic acid or N substituted phenylanthranilic acid with urea. The quinazolinedione derivatives used as the afore Rs R 25 said starting reaction materials include 1-phenyl-2,4- (1H,3H)-quinazolinedione or 1-substituted phenyl-2,4- (1H,3H)-quinazolinedione, for example, (wherein R and/or R3 represent hydrogen atom, CFs, 1-(3'-triuuoromethylphenyl-2,4(1H,3H)- one or more of halogen atoms selected from the group quinazolinedione, consisting of Cl, Br and F, methyl-, methoxy- or ethoxy 30 1-(3'-chlorophenyl)-2,4(1H,3H)-quinazolinedione, radical), with the general formula, RX or R2SO4 (where 1-(2',3'-dichlorophenyl)-2,4(1H,3H)-quinazolinedione, in R represents alkyl radical, substituted alkyl radical or 1-(2-chlorophenyl)-2,4(1H,3H)-quinazolinedione, acyl radical, X represents halogen atom, and R represents 1-(4-chlorophenyl)-2,4(1H,3H)-quinazolinedione, lower alkyl radical). 1-(3',4'-dichlorophenyl)-2,4(1H,3H)-quinazolinedione, 35 1-(2,6'-dichlorophenyl)-2,4(1H,3H)-quinazolinedione, The present invention relates to novel quinazolinedione 1-(3'-fluorophenyl)-4-(1H,3H)-quinazolinedione, derivatives and process for the production of same, and, 1-(4-fluorophenyl)-2,4(1H,3H)-quinazolinedione, more particularly, to quinazolinedione derivatives and 1-(3'-bromophenyl)-2,4(1H,3H)-quinazolinedione, process for the production thereof expressed in the follow 40 1-(2',3'-dimethylphenyl)-2,4(1H,3H)-quinazolinedione, ing general formula: 1-(3'-methoxyphenyl)-2,4(1H,3H)-quinazolinedione, 1-(4-ethoxyphenyl)-2,4(1H,3H)-quinazolinedione and O 1-(3'-methylphenyl)-2,4(1H,3H)-quinazolinedione. One group of compounds used as alkylating agent of Yi-R, 45 the abovementioned starting reaction materials in the present invention is expressed by the general formula 9-0 RX, wherein R1 can either be saturated or unsaturated N alkyl or alkyl radical substituted by aryl-, halogen- hy droxy-, amino-, alkoxy-, alkylthio-, phenoxy-, acyloxy-, 50 acyl-, carbamoyloxy- or carbamoylalkoxy-radical, and said R3 R compounds include, for example, ethyl iodide, n-butyl bromide, iso-amyl iodide, benzylbromide, 1-bromo-2- wherein R represents alkyl radical, substituted alkyl rad chloroethane, diethylaminoethylchloride, ethylenebromo ical or acyl radical; Ra and/or R3 represent hydrogen 55 hydrine, chloromethylethylether, 2-bromoethylacetate, 1 atom, CF, one or more of halogen atoms selected from chloro-2-(N,N-dimethylcarbamoyloxy)-ethane, p-chloro the group consisting of Cl, Br and F, methyl-, methoxy benzoylchloride, acetyl chloride benzoylchloride, propi or ethoxy-radical. onyl chloride, 2-bromoethylacetate, dimethylaminopropyl Conventionally, aminopyrine, mefenamic acid, flufe chloride, 2-bromoethylethylether and 2-bromoethylbenzo namic acid and others were known as an anti-inflamma 60 ate. Further, the other group of compounds used as alkyl tory and an analgesic, however, they possessed Such a dis ating agent same as above is expressed by the general advantage to cause gastroenteric trouble. We have found formula R2SO4, wherein R can be lower alkyl radical such that these novel quinazolinedione derivatives have excel as methyl- or ethyl- radical, for example, dimethyl sulfate. lent anti-inflammatory action and analgesic action, as de being most typical. scribed later, without causing gastroenteric trouble. 65 The reaction in the present invention is preferred to be Thus, one of the objects of the present invention is to performed in the presence of metallic compounds such provide the process for producing such novel quinazoline as sodium alcoholate, sodium amide and sodium hydride, excellent anti-inflammatory action and analgesic action. organic base such as pyridine and trimethylamine or inor Further, another object of the present invention is to ganic base such as alkali hydroxide and alkali carbonate. provide the process for producing such novel quinaboline 70 Further, since the reaction of the present invention is dione derivatives in high yield and advantageously. usually made in the organic solvent such as acetone, di According to the present invention, the aforesaid quin methylformamide and others, it is carried out at a wide 3,794,643 3 4. range of temperature. Consequently, the reaction temper In the above table ------ shows that the mean inhibition ature is not critical but can be either normal, warm or rate is 30-39%, and -------- shows that said rate is cool. more than 40%. The compounds obtainable according to the present invention show significant anti-inflammatory action and Testing method of analgesic effect analgesic action as is apparent from the experimental ex 5 Morphinized Haffner method: The test was performed amples as set forth below. by employing healthy male DD mice of 15-17 g., a sin gle group consisted of 10 mice, with regard to inhibition EXAMPLES of withdrawal against simultaneously pressing at the root Tests have been performed on acute toxicity, anti-in IO of the tail using in combination with the threshold dose flammatory effect and analgesic effect of the invented (2.5 mg./kg. s.c.) of morphine hydrochloride. The test compounds. drugs had been given intragastrically 30 minutes before morphine was given, and ED50 and 95% confidence limits Testing method of acute toxicity were calculated by Litchfield-Wilcoxon method from its Tragacanth emulsion was given by intraperitoneally to result. healthy DD mice of 15 to 20 g., and LEDs and its 95% Acetic acid stretching method: This test was performed confidence limits were calculated by Litchfield-Wilcoxon by employing healthy male DD mice of 15-17 g., a sin method from the lethal number after 72 hours. gle group consisted of 6 to 8 mice, with regard to inhibi tion of stretching (or squirm) symptoms by intraperi Testing method of anti-inflammatory effect toneal injection 0.1 ml./10 g. of 0.6% acetic acid. The The drugs subjected to this test were given intragastri 20 test drugs had been given intragastrically 30 minutes cally to healthy female Wistar rats of 100 to 140 g., the before acetic acid was given, and EDs and 95% confi inflammatory substance, carrageenin (1%, 0.1 ml.), was dence limits were calculated by Litchfield-Wilcoxon injected subcutaneously into the soles of the rats' hind method from its result. legs after 60 minutes, and the inhibition rates (percent) 25 In performing the above test, not only the compounds against edema were measured by comparing the edema obtained by the present invention were employed, but the consequently arose to the tested rats with the controls to conventionally known compounds such as mefenamic which the drugs were not given. The amount of drugs acid, flufenamic acid and aminopyrine were also subjected given was 200 mg./kg. and the mean inhibition rates were to the same test. The comparison between the former and shown of 4 to 5 rats in a group. the latter is shown in the following table. In performing the above test, not only the compounds 30 obtained by the present invention were employed, but the TEST EXAMPLES OF THE COMPOUNDS OBTAINED BY THE conventionally known compounds such as mefenamic PRESENT INVENTION acid and flufenamic acid were also subjected to the same Testing method Acetic acid Morphinized test. The comparisons between the former and the latter stretching Haffner method were shown in the following table. method ED50=ng.Ikg. ED50=mg/kg., (C.L. 95%) TEST EXAMPLES OF TEIE COMPOUNDS OBTANED BY Compounds p.0. TE PRESENT INVENTION -(3'-trifluoromethylphenyl)-3- 100-33% peak 148(135-63). ethyl-2,4(1H,3H)-quinazoline Anti-inflam 40 dione. matory effect, 1-(3'-trifluoromethylphenyl)-3-(2'- 35(28–43).-------- 38(26-54). Inhibition hydroxyethyl)-24 (1H,3H)-quinz Acute toxicity Rate against azolinedione. LID50, mg.fkg. Edena in 1-(3'-trifluoromethylphenyl)-3-(2'- 200-60% peak... 100-60% peak, i.p., 95% duced by ethoxyethyl)-2,4(1H,3H) quinaz Compounds C.L. carrageenin olinedione. 5 -(3'-trifluoromethylphenyl)-3-(2- 94(70-126)------ 124(114-135). 1-(3'-trifluoromethylphenyl)-3-methyl 360 (340-381) H acetoxyethyl)-2,4(1H,3H)-quinaz 2,4(1H,3H)-quinazolinedione. olinedione. -(3'-trifluoronethylphenyl)-3-ethyl 373 (341-408) + H+ 1-(3'-chlorophenyl)-3-ethyl-2,4(1E, 177(140-223).---- 100-60% peak. 24(1,3)-quinazolinedione. 3E)-quinazolinedione. 1-(3'-trifluoromethyl)-3-(2'-chloro >800 +++ -(3'-chlorophenyl)-3-(2'-hydrox 56(44-72).-------- 75-55% peak. ethyl)-2,4(H,3H)-quinazolinedione. ' yethyl)-2,4(iH,3R)-quinaz 1-(3'-trifluoromethylphenyl)-3-(2- 158 (137-182) ++++ olinedione. diethylaminoethyl)-2,4(1H,3H)- 50 1-(3'-chlorophenyl)-3-(2-ethox 82(50-34).------- 130-50% peak. ouinazolinedione hydrochloride. yethyl)-2,4(1H,3E)-quinaz -(3'-trifluoromethylphenyl)-3-(2'- 253 (220-291) ++++ olinedione. hydroxyethyl)-2,4(H,3E)-quinazo -(3'-chlorophenyl)-3-(2'-acetox 65(45–94).-------- 75-60% peak.
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