United States Patent Office Patented Feb

Home , Chloroethane

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. linedione. yethyl)-2,4(1H, 3H)-quinaz 1-(3'-trifluoromethylphenyl)-3-(2'- oinedione. acetoxyethyl)-2,4 (H3E)-quinazo 460 (430–492) ++ Comparison: Aminopyrine------93(60-143).----- 65(45–94). linedione. 1-(3-trifluoromethylphenyl)-3-(2'-acetoxyethyl)- >400 it 55 Mefenamic acid- - 134(100-180)-----, 140(114-172). 2,4(1H,3H)-quinazolinedione. Flufenamic acid------170(121-238).----- 200-35% peak. 1-(3'-chlorophenyl)-3-ethyl-2,4(H,3H)- 800 +H: quinazolinedione. 1-(3'-chlorophenyl)-3-(2'-hydroxy >400 H ethyl)-2,4(1H.3H)-quinazolinedione. The examples of the present invention are shown be 1-(3'-fluorophenyl)-3-ethyl-24 (1H,3H)- 400 ++++ low which should be considered to be the ones for ill quinazolinedione. 60 Comparison: lustrating the present invention concretely, and not for Mefenamic acid------420 (395-458) +++ limiting the scope of the present invention. Flufenamic acid------200 (180–222) +++ Examples of quinazolinedione derivatives produced ac cording to the present invention Product -R X Molecular formula M.P. or B.P. (C.) Recrystal solvent Appearance BI-CH2-CH-CH3 C18H15F3NO2 M.F. 58------Methanol------Colorless prisms. CE C15H5F3N2O M.F. 1818------do------Do. Br-cí -v YoH, Br-CH-off C C19H17F:NaO M.P., 1118------do------Do. N Cs 3,794,643 TABLE-Continued Product *-R X Molecular formula M.P. or B.P. (C.) Recrystal solvent Appearance Br-C-CH-CH-CH-CH3 C20H1FN2O M.P., 1023------do--- Do. Br-CH-CH-CH-CH-CH-CH Ca2F3N2O2 M.P., 77-8. -- ---do- Do. Br-CH-CH=CH C18H13FsN2O M.P., 123-4------do------Do. C-CH- C C22H14ClFaNaO2 M.P., 196-7------. Ethanol.------Do.

C3H17FNO3 M.P., 203-4------do------, Do. Cl-CH -O C3 Br-C-C-CH-Cl C18H14CIFN302 M.P., 134-5------Methanol------Do. o Ha C19H10ClFN3O M.P., 137-8 (hydrochloride). Ethanol plus n-hexane.... Do. Cl-CH-C-N C3 CH, C20H1 ClFN3O2 M.P., 245 (hydrochloride)--. Ethyl-acetate...... : Do. Cl-CH-CH-CH-N CH3 CH, Ca2H2ClFaNaO2 M.P.,225–6 (hydrochloride).---- do------Do.

C-CH-CH-CH-N Cas / Y C22H23ClFN3O8 M.P., 180-i (hydrochloride).------do------Do. C-C-C-C-N E. ) N-1 -N C28H27 ClF3N4O2 M.P., 272-3 (dihydrochlo- Ethanol.------Colorless prisms. Cl-CH-CH-C-N H N-CH3 ide). N-1 M.P., 252-3 (hydrochloride). Chloroform plus n-hexame Pale yellow prisms

Cl-CH-CH-CH-OH CE15EN2O3 M.P., 106-7------Methanol------Colorless prisms. M.P., 1545.5------Ethanol------D0.

118------Methanol------Do. SigEg;3 SECH 3EN:8: B.P., 205------Pale yellow oil. M.P., 1556.------Methanol------Colorless prisms.

B.P., 285------Paleyellow oil.

C-C-CH-O-CE=CH2 C19H5F3N2O: M.P., 127.5-8.5------Methanol.------Colorless prisms. Cl-C-CH2-O-COCEIs CoEFNOA M.P., 1045------do------Do. CE1F3N2O4 M.P., 150-1------do------Do. Cl-CH-CH-O-CO C-C-COCEIs C133F8N2O3 M.P., 1845------do------Do. g C8220FsN4O4 M.P., 1322.5------Dimethylformamide plus Do. Water. C / N C-CH-CH-N O- N / N

F3C g C3HFN405 M.P., 222-3...... ----. Methanol plus ethylace Colorless prisms. tate. C /

C-CH-O-CH-CH-CH-NOsC N N

FC C-CH-CH-S-CEa-CE3 CEENOS M.P., 90-1. ... Methanol. C-CECE-O-C-CON2 C19H10F8N3O4 M.P., 153-4------do------methylphenyl)-2,NoTE:-The 4(1H,3H)-quinazolinedione.I* shown in the above table represents the general formula of the compounds to be reacted with the above-mentioned 1-(3'-trifluoro 3,794,643

me Product I*--R X Molecular formula M.P. or B.P. (C.) Recrystal solvent Appearance SECC SESQ., M.E.: Si: Methagol: gigs beetles Cl-CH-CH-{ X C3H7F3N2O2 M.P., 122.5-3.5 -...-- do------Colorless needles. obt-(>CH C3H17F3NO2 M.P., 142.5-3.5 -...-- do------ColorleSS prisms. Cs Cao His F.N.O. M.P., 157-8 ..... do------Do. Br-CH-CHO-CON YoH, NOTE. The II shown in the above table represents the general formula of the compounds to be reacted with the above-mentioned 1-(3'-trifluoro methylphenyl)-2,4(E,3H)-quinazolinedione. Product III-R X Molecular formula M.P. or B.P. ( C.) Recrystal solvent Appearance BrCH2CH2OCOCH3 C1sF15FN2O4 M.P., 115.5-6.5 Methanol------Colorless prisms. ICH2CH3 C6H13FN2O2 M.P., 147.5-8.5 -----do---- Do. BrCH2CH2OCH2CH3 C1sH1FN2O3 M.P., 109-10 Do. BrCH2CH2Cl C16H12ClFN2O M.P., 185.5-6.5 Do. NoTE-III" shown in the above table represents the general formula of the compounds to be reacted with the above-mentioned 1-(3'-fluorophenyl)- 2,4(1H, 3H)-quinazolinedione. Product V*-R X Molecular formula M.P. or B.P. ( C.) Recrystal solvent Appearance ICH2CH3 C1313BrN2O2 M.P., 187.5–8.5 Ethanol------Colorless prisms. BrCF2CHOCH2CHs C18H17BrN2O3 M.P., 155-7 Methanol------Do. BrCF2CH2OH. C15H13BrN2O3 M.P., 161.5-2 Methanol plus water. Do. BrCH2CH2Cl C6H12ClBrN2O2 w M.P., 184-6 Dimethyl-formamide------Pale yellow prisms. phenyl)-(2,4(1H,3H)NoTE. They shown quinazolinedione. in the above table represents the general formula of the compounds to be reacted with the above-mentioned 1-(3'-bromo Product V*-R X Molecular formula M.P. or B.P. (° C.) Recrystal solvent Appearance BrCF2CH2O COCHs C20H20N2O M.P., 181-3 M.A.,Es dimethyl- Pale yellow prisms. BrCH2CH2OCH2CHs C20H22N2O3 M.P., 104-6 Methanol ------Colorless needles. NoTE. The V" shown in the above table represents the general formula of the compounds to be reacted with the above-mentioned 1-(2,3'-dimeth ylphenyl)-2,4 (IEI,3H)-quinazolinedione. Product VI- X Molecular formula M.P. or B.P. ( C.) Recrystal solvent Appearance ICEICH3 C16H13FNO2 M.P., 213-5 Methanol plus dimethyl- Colorless prisms. formamide. BrCF2CH2O COCHs C18H15FN2O M.P., 144-6 Methanol------Do. BrCH2CH2C C18H1 ClFN2O2 M.P., 205-8 Dimethylformamide ------Do. NoTE.-The VI shown in the above table represents the general formula of the compounds to be reacted with the above-mentioned 1-(4- fuorophenyl)-2,4(H, 3H) quinazolinedione.

Product VII*-R X Molecular formula M.P. or B.P. ( C.) Recrystal solvent Appearance ICH2CH3 C17H16N2O2 M.P., 139.5-40.5 Methanol------Colorless prisms. BrCH2CH2O COCHs C19H8N2O4 M.P., 150-1 Methanol lformamide- Do. BrCH2CH2O CH2CH3 C1E320N2O3 M.P., 136-7 Methanol------Do. NoTE.-The VII* shown in the above table represents the general formula of the compounds to be reacted with the above-mentioned 1-(3'- methylphenyl)-2,4(1H,3H) quinazolinedione.

Product VII*-R X Molecular formula M.P. or B.P. ( C.) Recrystal solvent Appearance ICH2CH3 C17H16N2O3 M.P., 164-5 Methanol------Colorless prisms. NoTE.-The VIII shown in the above table represents the general formula of the compounds to be reacted with the above-mentioned 1-(3'- methoxyphenyl)-2,4(lH,3H)-quinazolinedione.

Product IX-R X Molecular formula M.P. or B.P. ( C.) Recrystal solvent Appearance ICH2CHs C17H16N2O M.P., 191-3 Ethanol plus dimethyl- Colorless prisms. formamide. BrCH2CH2OCOCH3 C19H8N2O5 M.P., 134.5-5.5 Methanol- Do. BrC2CH2OCH2CH3 C19H2ON2O M.P., 136-8 ----- dc-- D0. BrCH2CH2OH. C17H16N2O M.P., 166.5-8. ----- do------Do. ethoxyphenyl)-2,4(1H,3H)-quinazalinedione.NoTE. The IL" shown in the above table represents the general formula of the compounds to be reacted with the above-mentioned 1-(4'- 3,794,643 9 O Product X-R X Molecular formula, M.P. or B.P. ( C.) Recrystal solvent Appearance ICH2CH3 C15H3CNO M.P., 160-3 Methanol------Colorless prisms. ICH2CH2CHCH C18H17CN2O2 M.P., 144-5 ----- do---- Colorless needles. BrCF2CH2OCOCE C18H15ClN2O4 M.P., 145-7 Ethanol. Pale yellow prisms. BrCF2CH2Cl Cis-3CN2O2 M.P., 169-70 ---- do---- Colorless prisms. BrCH2CH2OCH2CH3 C18H17CN2O3 M.P., 134-6 Methanol. Do, CICICOOCH2CH3 C18H15CN2O4 M.P., 181-3 Ethanol- Colorless needles. BrCH2CH2OH C18H3CINO2 M.P., 145-6 Methanol------Do. chlorophenyl)-2,4(1H,3H)-quinazolinedione.NOTE:-The X shown in the above table represents the general formula of the compounds to be repeated with the above-mentioned 1-(4- Product XI-R, X Molecular formula, M.P. or B.P. ( C.) Recrystal solvent Appearance BrCHCHOCOCE C18H15CN2O4 M.P., 144-5 Methanol--- -- Colorless prisms. BrCF2CH2OCHC C18H17CN2O3 M.P., 129-30 Colorless needles. BrCH2CH2OH. C163CN2O3 M.P., i49–52 - Colorless prisms. NoTE-The XI shown in the above table represents the general formula of the compounds to be reacted with the above-mentioned 1-(2- chlorophenyl)-2, 4(1H,3H)-guinazolinedione. Product XI*. R. X. Molecular formula M.P. or B.P. ( C.) Recrystal solvent Appearance CEICE C16E13CNO2 M.P., 179-80 Ethanol------Colorless prisms. BrCHCHOCH2CH3 C18H17CN2O3 M.P., 15-6 ----- do. DO. BrCECHO.COCE C18H15CNOA M.P., 136-7 Methanol. D0. BrCHCHOE C163CN2O3 M.P., 149-50.5 Do. BrCF2CH2CH2OH CHCN2O3 M.P., 36.5-9.5 Do. CCHCOOCEICE C18H15CN2O4 M.P., 127-9 Do. BrCHCHCl C18H12Cl2N2O2 M.P., 170-1 Do. ICHCHCCl3 C18H17CNO2 M.P., 141-6 DO. oH, C18H17CNO M.P., 121-3 Do. BrCEC CEs. CCECHCH CitiClN2O M.P., 132-4 .---- do------Do. CH, C15CINO; M.P., 140-1.5 ----- do------Colorless needles.

ICH CEa NoTE.-The XII shown in the above table represents the general formula of the compounds to be reacted with the above-mentioned 1-(3 chlorophenyl)-2,4(H,3H)-quinazolinedione. Product XIII-R, X Molecular formula M.P. or B.P. (C.) Recrystal solvent Appearance ICH2CE C18H1903NO2 M.P., 66-7.5 Methanol------ColorleSS prisms. BrCEICEOCHCH C18H16ClN2O3 M.P., 102.5-4. -- do------DO. BrCECHO C161C3N2O3 M.P.,144.5-6 Methanol plus water Colorless needles. NoTE.-The XIII shownin the above table represents the genreal formula of the compounds to be reacted with the above-mentioned 1-(2',3'- dichlorophenyl-24 (E3E)-quinazolinediane.

Product XIV-R X. Molecular formula M.P. or B.P. ( C.) Recrystal solvent Appearance CHCH C1612Cl2N2O2 M.P., 139-41 Methanol------Colorless prisms. BrCHCHOCOCHs C18H4CNO M.P., 120-1 ----- do--- -- Colorless needles. BrCHCHOCH2CE C18H16ClgNO3 M.P., 14-55 ----- do. D0, BCH2CH2OH. C6H3Cl2N2O3 M.P., 145-7 ----do------Pale yellow prisms. BrCF2CH2Cl C18H11C3N2O2 M.P., 155-6 Ethanol plus dimethylforms Colorless prisms. amide. dichlorophenyl)-2,4CH3)-quinazolinedione.NoTE. The XIV shown in the above.table represents the general formula of the compounds to be reacted with the above-mentioned 1-(3',4'-

Product XW--R X Molecular formula M.P. or B.P. ( C.) Recrystal solvent Appearance ICH2CH3 CH4N2O2 M.P., 196.5-7.5 Ethanol------Colorless prisms. ICH2CH2CECE C18H18N2O2 M.P., 106-7 Methanol plus water- Do. ClCECOOCH2CH3 C18H16N2O4 M.P., 164-5 Methanol.------Do. BrCECHOH C18H1NO3 M.P., 205.5-8 -...-- do--- Do. BrCHCHOCHCE C18H16N2O3 M.P., 93-5 ----- do. Do. BrCF2CH2OCOCH CissNO4 M.P., 159-60.5 - do. D0. BrCH2CH2Cl * , , C6H3CN2O2 M.P., 214-6.5 Dimet Do. BrCHCHCHCl, CH5CNO2 M.P., 153-4 Methanol Pale yellow prisms. (H, CH18N2O4 M.P., 129-30 -----do------Do. ClCHCO OCHCH

BrCHOCH2CON CEN3O M.P., i59.5-60.5 -----do--- Yellow needles. C2H8N2O3 M.P., 188-9 Dimethylformamide.------Colorless needles, CCHCIO

CECNO2 M.P., 179–80 Methanol------Colorless needles. CCE- -Cl C2H8N2O3 M.P., 178-9 Methanol plus dimethylform- Colorless prisms. CCH- OCH amide. NOTE.-The XV shown in the above table represents the general formula of the compounds to be reacted with the above-mentioned 1-phenyl 2,4-(IH,3H)-quinazolinedione. 3,794,643 1. 2 Examples of process for the production of quinazoline Example 5: 1 g. of 50% sodium hydroxide was added dione derivatives according to the present invention to the mixture of 5.4 g. 1-(3'-trifluoromethylphenyl)-2,4- (1H,3H)-quinazolinedione and 40 cc. dried dimethyl Example 1: The mixture of 5.4 g. 1-(3'-trifluorometh formamide, and the mixture was stirred for one hour. ylphenyl)-2,4(1H,3H)-quinazolinedione, 1.3 g. dimethyl Then, 4 g. of benzylbromide were added and reacted for sulfate, and 30 cc. acetone was heated for 2 hours at 50 3 hours at room temperature. The solvent was then dis 70° C. on a water bath, then the solvent was distilled. tilled under reduced pressure, the residue was added with The residue was then poured into 20% sodium hydroxide water, the crystals produced were filtered and dried, and, solution under cooling for neutralization, the crystals pro upon recrystallization from methyl alcohol, 6 g. of col duced were filtered, washed with water and dried, and, oriess prisms of 1-(3'-trifluoromethylphenyl)-3-benzyl upon recrystallization from ethanol, 4.1 g. Of colorless O prisms of 1-(3'-trifluoromethylphenyl)-3-methyl-2,4(1H, 2,4(1H,3H)-quinazolinedione were obtained. 3H)-quinazolinedione were obtained. Melting point and ultimate analysis value of this sub Melting point and ultimate analysis value of this sub stance were as follows: stance were as follows: Melting point: 183-184 C. Melting point: 189-189.5° C. Ultimate analysis value: C22H15FNO2 Ultimate analysis value: C6H11F3N2O2. Theoretical values: C, 66.66; H, 3.81; N, 7.07. Theoretical values: C, 60.00; H, 3.46; N, 8.75. Found values: C, 66.67; H, 3.90; N, 6.79. Found values: C, 60.01; H, 3.66; N, 8.46. Example 6: 1.3 g, of 50% sodium hydride was added Example 2: 5.4 g. 1-(3'-trifluoromethylphenyl-2,4(1H, to the mixture of 7 g. 1-(3'-trifluoromethylphenyl)-2,4- 3H)-quinazolinedione, and 40 cc. dried dimethylform (1H,3H)-quinazolinedione and 40 cc. dried dimethyl amide were added with 1 g, of 50% sodium hydride and formamide, and the mixture was stirred for one hour. stirred for 7 hours. Then, 3.69 of ethyliodide were fur Then 4.3 g. 1-bromo-2-chloroethane were added and re ther added and reacted for 3 hours at room temperature. acted for 3 hours at room temperature. The solvent was The solvent was then distilled under reduced pressure, then distilled under reduced pressure, the residue was the residue was added with water, the crystals produced added with water, the crystals produced were filtered and were filtered, and, upon recrystallization from ethanol, dried, and, upon recrystallization from methyl alcohol, 5 g. of colorless prisms of 1-(3'-trifluoromethylphenyl)- 6.3.g. of colorless prisms of 1-(3'-trifluoromethylphenyl)- 3-ethyl-2,4(1H,3H)-quinazolinedione were obtained. 30 3-(2' - chloroethyl)-2,4(1H,3H) - quinazolinedione were Melting point and ultimate analysis value of this sub obtained. stance were as follows: Melting point and ultimate analysis value of this sub stance were as follows: Melting point: 156-157° C. Ultimate analysis value: CHFNO2 Melting point: 136-137° C. Theoretical values: C, 61.07; H, 3.92; N,8.38. Ultimate analysis value: C1H12CIFNO2 Found values: C, 61.07; H, 3.98; N, 8.32. Theoretical values: C, 55.37; H, 3.28; N, 7.60. Found values: C, 55.17; H, 3.39; N, 7.50. Example 3: 0.6 g. metallic sodium was added to 10 cc. n-butylalcohol and n-butyl alcoholate was formed. To this 40 Example 7: 1. g. of 50% sodium hydride was added to was added the solution obtained by dissolving 6.5 g. 1 the mixture of 5.4 g. 1-(3'-trifluoromethylphenyl)-2,4- (3' - trifluoromethylphenyl)-2,4(1H,3H)-quinazolinedione (1H,3H)-quinazolinedione and 40 cc. dried dimethyl in 20 cc. dried dimethylformamide, said solution mixture formamide, and the mixture was stirred for one hour. was stirred for 1 hour, then 10.5 g. of n-butylbromide Then, 4.5 g. diethylaminoethylchloride were added and were added and stirred for 3 hours at room temperature. heated for 3 hours at 40-45° C. The solvent was then dis Water was further added, the crystals produced were fil tilled under reduced pressure, the residue was added with tered and dried, and, upon recrystallization from methyl Water, and an oily substance was obtained. Said substance alcohol, 6.1 g, of colorless prisms of 1-(3'-trifluorometh was extracted with ether and, after dehydration, 23% ylphenyl)-3-(n-butyl)-2,4(1H,3H)-quinazolinedione were ethanol hydrochloric acid was added under cooling for obtained. 50 acidification. Then, the solvent was distilled under re Melting point and ultimate analysis value of this sub duced preSSure, the residue was recrystallized from eth stance were as follows: anol and ethyl acetate, and 6.2 g. of colorless prisms of 1-(3 - trifluoromethylphenyl)-3-(2'-diethylaminoethyl)- Melting point: 126-127 C. 2,4(1H,3H) - quinazolinedione hydrochloride were ob Ultimate analysis value: C19H1FN2O2. 55 tained. Theoretical values: C, 62.98; H, 4.73; N, 7.73. Melting point and ultimate analysis value of this sub Found values: C, 63.39; H, 5.04; N, 7.95. Stance were as follows: Example 4: 0.5 g. sodium amide was added to the mix ture of 3.6 g. 1-(3'-trifluoromethylphenyl)-2,4(1H,3H)- Melting point: 229-230° C. quinazolinedione and 30 cc. dried dimethylformamide, 60 Ultimate analysis value: C2H23CIFNO2 and the mixture was stirred for one hour. Then, 5.9 g, Theoretical values: C, 57.08; H, 5.25: N, 9.51. of iso-amyliodide were added and reacted for 3 hours at Found values: C, 57.05; H, 5.47; N, 9.43. room temperature. The solvent was then distilled under reduced pressure, the residue was added with water, the Example 8: 2.4 g. of 50% sodium hydride were added crystals produced were filtered and dried, and, upon re 65 to the mixture of 9.2 g. 1-(3'-trifluoromethylphenyl)-2,4- crystallization from methyl alcohol, 3.9 g, of colorless (1H,3H)-quinazolinedione and 80 cc. dried dimethylform prisms of 1-(3'-trifluoromethylphenyl)-3-(iso-amyl)-2,4- amide, and the mixture was stirred for one hour. Then, (1H,3H)-quinazolinedione were obtained. ethylene bromohydrin was added and reacted for 3 hours Melting point and ultimate analysis value of this sub at room temperature. The solvent was then distilled under stance were as follows: 70 reduced pressure, the residue was added with water, the crystals produced were filtered and dried, and, upon re Melting point: 115-115.5 C. crystallization from methyl alcohol, 10 g. of colorless Ultimate analysis value: C20H19FN2O2 prisms of 1 - (3 - trifluoromethylpheny) - 3 - (2'-hy Theoretical values: C, 63.82; H, 5.09; N, 7.44. droxyethyl) - 2, 4(1H, 3H) - quinazolinedione were ob Found values: C, 63.95; H, 5.18; N, 7.38. 75 tained. 3,794,643 13 14 Melting point and ultimate analysis value of this sub trifluoromethylphenyl) - 3 - (2' - N,N - dimethylcar stance were as follows: bamoyloxyethyl) - 2,4(1H,3H) - quinazolinedione were Melting point: 138-139° C. obtained. Ultimate analysis value: CHFNO Melting point and ultimate analysis value of this sub Theoretical values: C, 58.29; H, 3.74; N, 8.00. stance were as follows: Found values: C, 58.40; H, 3.71; N, 8.11. Melting point: 157-158 C. Example 9: 1 g. of 50% sodium hydride was added to Ultimate analysis value: CHFNO the mixture of 5.4g. 1 - (3 - trifluoromethylphenyl) - 2,4- Theoretical values: C, 57.01; H, 4.31; N, 9.97. (1H,3H)-quinazolinedione and 40 cc. dried dimethylform Found values: C, 57.23; H, 4.20; N, 10.0. amide, and the mixture was stirred for one hour. Then O Example 13: 1 g of sodium hydride was added to the 3.4 g. of chloromethyl ethyl ether were added and re mixture of 5.4 g. 1 - (3' - trifluoromethylphenyl) - 2,4 acted for 3 hours. The solvent was then distilled under (1H,3H) - quinazolinedione and 40 cc. dried dimethyl reduced pressure, the residue was added with water, the formamide, and the mixture was stirred for one hour. crystals produced were filtered and dried, and, upon re Then, 4 g. of P-chlorobenzoylchloride were added and crystallization from methyl alcohol, 5 g. of colorless 5 reacted for 3 hours at room temperature. The solvent was prisms of 1-(3'-trifluoromethylphenyl) - 3 - ethoxymethyl then distilled under reduced pressure, the residue was 2,4(1H,3H)-quinazolinedione were obtained. added with water, the crystals produced were filtered and Melting point and ultimate analysis value of this sub dried, and, upon recrystallization from ethanol, 5.7 g. stance were as follows: 20 of colorless prisms of 1-(3'-trifluoromethlyphenyl) - 3 - Melting point: 157.5-159 C. (4' - chlorobenzoyl) - 2, 4(1H,3H) - quinazolinedione Ultimate analysis value: CHFNO2 were obtained. Theoretical values: C, 59.34; H, 4.15; N, 7.69. Melting point and ultimate analysis value of this sub Found values: C, 59.61; H, 4.42; N, 7.58. stance were as follows: Example 10: l g. of 50% sodium hydride was added to 25 Melting point: 196-197° C. the mixture of 5.4 g. 1 - (3 - trifluoromethylphenyl)-2,4 Ultimate analysis value: CHCIFNO (1H,3H)-quinazolinedione and 40 cc. dried dimethylform Theoretical values: C, 61.33; H, 3.28; N, 6.50. amide, and the mixture was stirred for one hour. Then, Found values: C, 61.45; H, 3.32; N, 6.33. 6.7 g. of 2-bromoethyl acetate were added and reacted 30 Example 14: 0.7 g. of sodium hydride was added to for 3 hours at room temperature. The solvent was then the mixture of 3.1 g. 1-(3'-trifluoromethylphenyl) - 2,4 distilled under reduced pressure, the residue was added (1H,3H) - quinazolinedione and 40 cc. dried dimethyl with water, the crystals produced were filtered and dried, formamide, and the mixture was stirred for one hour. and, upon recrystallization from methyl alcohol, 5.7 g. of Then, 2 g. of acetyl chloride were added dropwise and colorless prisms of 1 - (3'-trifluoromethylphenyl)-3-(2'- 35 reacted for 3 hours at room temperature. The solvent acetoxyethyl) - 24 (1H,3H) - quinazolinedione were ob was then distilled under reduced pressure, the residue tained. was added with water, the crystals produced were filtered Melting point and ultimate analysis value of this sub and dried, and, upon recrystallization from methyl alco stance were as follows: hol, 2.5 g. of colorless prisms of 1-(3'-trifluoromethyl Melting point: 111.5-112 C. 40 phenyl) - 3 - acetyl - 2,4(1H,3H) - quinazolinedione Ultimate analysis value: C19H1sFN2O4 were obtained. Theoretical values: C, 58.16; H, 3.85; N, 7.14. Melting point and ultimate analysis value of this sub Found values: C, 58.28; H, 3.64; N, 7.15. stance were as follows: Example 11: 0.5 g. of 50% sodium hydride was added Melting point: 165-166 C. to the mixture of 2.7 g. 1-(3'-trifluoromethylphenyl)-2,4- Ultimate analysis value: CHFNO (1H,3H)-quinazolinedione and 20 cc.dried dimethylform Theoretical values: C, 58.62; H, 3, 18; N, 8.05. amide, and the mixture was stirred for one hour. Then, Found values: C, 58.87; H, 3.26; N, 7.91. a solution obtained by dissolving 3.4 g. 1-(3'-trifluoro methylphenyl) - 3 - monochloromethoxymethyl-2,4(1H, Example 15: The mixed solution consisting of 2 g. 1 50 (3' - trifluoromethylphenyl) - 2,4(1H,3H) - quinazoline 3H)-quinazolinedione in 20 cc. dried dimethylformamide dione, 30 cc. dried dimethylformamide and 1.6 g. dried was added and reacted for 4 hours at room temperature. pyridine was heated to 80° C. Then, 4.2 g. of benzoyl The solvent was then distilled under reduced pressure, the chloride were added dropwise and reacted for 3 hours at residue was added with water, the crystals produced were 80-90° C. It was then filtered, the filtrate was distilled filtered and dried, and, upon recrystallization from methyl 55 under reduced pressure, the residue was added with water, alcohol and ethylacetate, 58 g. of colorless prisms of bis the crystals produced were filtered, and, upon recrystalli 3-(1,3'-trifluoromethylphenyl) - 2,4 (1H, 3H) - quinaz zation from methyl alcohol, 1.8 g. of colorless prisms of olinedione-methylether were obtained. 1 - (3'-trifluoromethylphenyl) - 3 - benzoyl - 24 (1H, Melting point and ultimate analysis value of this Sub 3H)-quinazolinedione were obtained. stance were as follows: 60 Melting point and ultimate analysis value of this sub Melting point: 114-114.5' C. stance were as follows: Ultimate analysis values: Cs2H2FeNOs Melting point: 166-167 C. Theoretical values: C, 58.72; H, 3.08; N, 8.56. Ultimate analysis value: C22HFNO3 Found values: C, 58.90; H, 2.86; N, 8.57. 65 Theoretical values: C, 64.39;H, 3.19; N, 6.83. Example 12: 1 g, of 50% sodium hydride was added to Found values: C, 64.24; H, 3.30; N, 6.87. the mixture of 5.4 g. 1-(3'-trifluoromethylphenyl)-2,4(1H, Example 16: A mixed solution consisting of 3 g. 1-(3'- 3H)-quinazolinedione and 40 cc. dried dimethylforma trifluoromethylphenyl)-2,4 (1H,3H)-quinazolinedione, 30 mide, and the mixture was stirred for one hour. Then, 4.3 cc. dimethylformamide and 4 g. triethylamine was heated g. of 1-chloro-2-(N, N-dimethylcarbamoyloxy)-ethane 70 to 80° C. Then, 2.8 g. of propionyl chloride were added were added and reacted for 4 hours at room temperature. dropwise and reacted for 3 hours at 80-90° C. It was then The solvent was then distilled under reduced pressure, the filtered, the filtrate was dried by evaporation under reduced residue was added with water and was held under cool pressure, the residue was added with water, the crystals ing. The crystals produced were recrystallized from produced were filtered, and, upon recrystallization from methyl alcohol, and 5.2 g of colorless prisms of 1-(3'- 75 methyl alcohol, 2.8 g. of colorless needles of 1-(3'-tri 3,794,643 15 16 fluoromethylphenyl) - 3 - propionyl - 2,4(1H,3H)-quinaz Melting point and ultimate analysis value of this sub olinedione were obtained. stance were as follows: Melting point and ultimate analysis value of this sub melting point: 145-146 C. stance were as follows: ultimate analysis value: C6H3ClNO2. melting point: 177.5-178.5 C. theoretical values: C, 63.90; H, 4.36; N, 9.31. ultimate analysis value: C19H16FN3O4. found values: C, 63.96; H, 4.27; N, 9.42. theoretical values: C, 56.02; H, 3.96; N, 10.32. Example 21: 0.7 g of 50% sodium hydride was added found values: C, 56.21; H, 3.83; N, 10.24. to the mixture of 2.7 g. 1-(4-chlorophenyl)-2,4(1H,3H)- Example 17: The mixture of 5 g. 1-(3'-chlorophenyl)- IO quinazolinedione and 30 cc.dried dimethylformamide, and 2,4(1H,3H)-quinazolinedione, 1.3 g. dimethyl sulfate and the mixture was stirred for one hour. Then, 3.6 g. of 50 cc. acetone was heated for 2 hours at 50-70' C. on a dimethylamino-propylchloride were added and reacted for water bath, then the solvent was distilled, the residue was 3 hours at room temperature. The solvent was distilled poured into 20% sodium hydroxide solution under cooling under reduced pressure, the residue was added with water for neutralization, the crystals produced were filtered, 15 the crystals produced were filtered, and, upon recrystalli washed with water and dried, and, upon recrystallization zation from methyl alcohol, 2.9 g, of colorless needles from dimethylformamide, 4.2 g of colorless prisms of of 1-(4-chlorophenyl)-3-(3' - dimethylaminopropyl)-2,4 1-(3'-chlorophenyl)-3-methyl-2,4(1H,3H) - quinazolinedi (1H,3H)-quinazolinedione were obtained. one were obtained. Melting point and ultimate analysis value of this sub Melting point and ultimate analysis value of this sub 20 stance were as follows: stance were as follows: melting point: 164.5-165.5 C. melting point: 223-226 C. ultimate analysis values: C19H2ClNO2. ultimate analysis value: C5H11ClN2O2. theoretical values: C, 63.77; H, 5.63; N, 11.74. theoretical values: C, 62.84; H, 3.87; N, 9.77. 25 found values: C, 63.62; H, 5.65; N, 11.50. found values: C, 62.75; H, 3.84; N, 9.79. Example 22: 1.1 g of sodium amide were added to the Example 18: 1 g, of 50% sodium hydride was added to mixture of 4.5 g. 1-(3',4'-dichlorophenyl) - 2,401H,3H)- the mixture of 4.1 g. 1-(3'-chlorophenyl)-2,4(1H,3H)- quinazolinedione and 40 cc. dimethylformamide, and the quinazolinedione and 40 cc. dried dimethylformamide, and mixture was stirred for one hour. Then, 7.3 g of ethyl the mixture was stirred for one hour. Then, 3.3 g. of 30 bromoacetate were added and reacted for one hour. The glycerol-o-monochlorohydrin were added and reacted for solvent was then distilled under reduced pressure, the 1.5 hours at room temperature. The solvent was distilled residue was added with water, the crystals produced were under reduced pressure, the residue was added with water, filtered, and, upon recrystallization from the mixed solvent the crystals produced were filtered, and, upon recrystalliza consisting of dimethylformamide and ethanol, 4.6 g. of tion from methyl alcohol, 4.2 g of colorless needles of 35 colorless prisms of 1-(3',4'-dichlorophenyl)-2,4(1H,3H)- 1-(3'-chlorophenyl) - 3-(2',3' - dihydroxypropyl) - 2,4 quinazolinedione-3-acetic acid ethyl ester were obtained. (1H,3H)-quinazolinedione were obtained. Melting point and ultimate analysis value of this sub Melting point and ultimate analysis value of this sub stance were as follows: stance were as follows: 40 melting point: 157.5-158.5 C. melting point: 163-164 C. ultimate analysis value: CHCl2N2O4. ultimate analysis value: C17H15ClN2O4. theoretical values: C, 54.98; H, 3.59; N, 7.12. theoretical values: C, 58.88; H, 4.36; N, 8.08. found values: C, 54.93; H, 3.53; N, 7.06. found values: C, 59.08; H, 4.37; N, 8.07. 45 Example 23: 0.6 g. of 50% sodium hydrate was added Example 19: 0.5 g. of 50% sodium hydride was added to the mixture of 1.7 g. 1-(2,6'-dichlorophenyl)-2,4(1H, to the mixture of 1.5 g. 1-(2',3'-dichlorophenyl)-2,4(1H, 3H)-quinazolinedione and 30 cc. dried dimethylformam 3H-)-quinazolinedione and 30 cc. dried dimethylformam ide, and the mixture was reacted for one hour at room ide, and the mixture was stirred for one hour. Then, 5 g. temperature. Then, 5 g. of ethyliodide were added, and the of 2-bromoethylacetate were added and reacted for 3 hours 50 mixture was further reacted for two hours at room tem at room temperature. The solvent was then distilled under perature. Then, the solvent was distilled under reduced reduced pressure, the residue was added with water, the pressure, the residue was added with water, the crystals crystals produced were then recrystallized from ethanol, produced were filtered, and, upon recrystallization from and 1.7 g of colorless needles of 1-(2',3'-dichlorophenyl)- methyl alcohol, 1.5 g. of colorless prisms of 1-(2,6'-di 3-(2'-acetoxyethyl)-2,4(1H,3H) - quinazolinedione were 55 chlorophenyl)-3-ethyl-2,4(1H,3H)-quinazolinedione were obtained. obtained. Melting point and ultimate analysis value of this sub Melting point and ultimate analysis value of this sub stance were as follows: stance were as follows: melting point: 183.5-184.5 C. 60 melting point: 174.5-175.5 C. ultimate analysis value: C18H14Cl2N2O4. ultimate analysis value: CH2Cl2.N.O. theoretical values: C, 54.98; H, 3.59; N, 7.13. theoretical values: C, 57.33; H, 3.61; N, 8.36. found values: C, 55.00; H, 3.53; N, 7.14. found values: C, 57.43; H, 3.49; N, 8.34. Example 24: 0.8 g. of 50% sodium hydride was added Example 20: 0.6 g. metallic sodium was added to 10 cc. 65 to the mixture of 3 g. 1-(3'-fluorophenyl)-2,4(1H,3H)- ethyl alcohol, and sodium ethyl alcoholate was formed. quinazolinedione and 30 cc. dried dimethyl formamide, Then, a solution obtained by dissolving 5.8 g. of 1-(2- and the mixture was stirred for one hour. Then, 3.7 g. chlorophenyl) - 2,4(1H,3H) - quinazolinedione in 20 cc. of ethylene-bromohydrin were added and reacted for 3 dried dimethylformamide was added. Further, 6.6 g. of hours at room temperature. The solvent was then distilled ethyliodide were added and reaction was performed for 3 70 under reduced pressure, the residue was added with water, hours at room temperature. Then, water was added, the the crystals produced were then recrystallized from the crystals produced were filtered and dried, and, upon re mixed solvent consisting of methyl alcohol and water, crystallization from methyl alcohol, 5.4 g. of colorless and 2.9 g, of colorless prisms of 1-(3'-fluorophenyl)-3- prisms of 1-(2-chlorophenyl)-3-ethyl-2,4(1H,3H)-quinaz (2'-hydroxyethyl)-2,4(1H,3H) - quinazolinedione were olinedione were obtained. 75 obtained. 3,794,643 17 18 Melting point and ultimate analysis value of this sub dimethylphenyl) - 3 - ethyl-2,4(1H,3H)-quinazolinedione stance were as follows: were obtained. Melting point and ultimate analysis value of this sub Melting point: 136.5-137.5° C. were as follows: Ultimate analysis value: CHFNO Theoretical values: C, 63.99; H, 4.36; N, 9.33. Melting point: 202-205 C. Found values: C, 64.15; H, 4.07; N, 9.37. Ultimate analysis value: CahiaNO Example 25: The mixture of 1.8 g. 1-(4-fluorophenyl)- Theoretical values: C, 73.45; H, 6.16; N, 9.52. 2,4(1H,3H)-quinazolinedione, 3 g. diethyl sulfate and 50 Found values: C, 72.80; H, 5.93;N, 9.64. cc. acetone was heated for 2 hours at 50–70 C. on a O water bath. The solvent was then distilled, the residue was Example 29: 0.5 g. of 50% sodium hydride was added poured into 20% sodium hydroxide solution under cooling to the mixture of 1.5 g. 1 - (3 - methoxyphenyl) - 2,4- for neutralization, the crystals produced were filtered and (1H,3H)-quinazolinedione and 30 cc, dried dimethylform washed with water, and, upon recrystallization from the amide, and the mixture was stirred for one hour. Then, 5g. mixed solvent consisting of methyl alcohol and dimethyl 5 of 2-bromoethylacetate were added and reacted for 3 formamide, 1.6 g. of colorless prisms of 1 - (4 - fluoro hours at room temperature. The solvent was distilled phenyl) - 3 - ethyl - 24(1H,3H)-quinazolinedione were under reduced pressure, the residue was added with water, obtained. the crystals produced were filtered, and, upon recrystalli Melting point and ultimate analysis value of this sub zation from methyl alcohol, 1.8 g. of colorless prisms of stance were as follows: 20 1 - (3' - methoxyphenyl) - 3 - (2' - acetoxyethyl)-2,4- (1H,3H)-quinazolinedione were obtained. Melting point: 213-215 C. Melting point and ultimate analysis value of this sub Ultimate analysis value: CHFNO stance were as follows: Theoretical values: C, 67.60; H, 4.61; N, 9.85. 25 Found values: C, 67.51; H, 4.38; N, 9.91. Melting point: 130-131 C. Ultimate analysis value: C19H8N2O5 Example 26: 0.7 g. of 50% sodium hydride was added Theoretical values: C, 64.40; H, 5.12; N, 7.91. to the mixture of 1.8 g. 1 - (4'-fluorophenyl)-2,4(1H,3H)- Found values: C, 64.52; H, 4.96; N, 7.85. quinazolinedione and 30 cc, dried dimethylformamide, 30 and the mixture was stirred for one hour. Then, 3.2 g. Example 30: 0.2 g. of sodium amide was added to the of 2-bromoethylethyl ether were added and reacted for 3 mixture of 1. g. 1 - (4 - ethoxyphenyl)-2,4(1H,3H)-quin hours at room temperature. The solvent was then distilled azolinedione and 20 cc. dried dimethylformamide, and the under reduced pressure, the residue was added with water, mixture was stirred for one hour. Then, 1.9 g, of bromo the crystals produced were filtered, and, upon recrystalliza 35 chloroethane were added and the mixture was reacted for tion from the mixed solvent consisting of methyl alcohol 3 hours at room temperature. The solvent was then dis and water, 1.8 g. of colorless needles of 1 - (4 - fluoro tilled under reduced pressure, the residue was added with phenyl) - 3 - (2' - ethoxyethyl)-2,4(1H,31H)-quinazoline water, the crystals produced were filtered, and, upon re dione were obtained. crystallization from methyl alcohol, 1.0 g. of colorless Melting point and ultimate analysis value of this sub 40 needles of 1 - (4 - ethoxyphenyl) - 3 - (2'-chloroethyl)- stance were as follows: 2,4(1H,3H)-quinazolinedione was obtained. Melting point and ultimate analysis value of this sub Melting point: 112-113 C. stance were as follows: Ultimate analysis value: CHFNO Theoretical values: C, 65.85; H, 5.22; N, 8.53. 45 Melting point: 144-146 C. Found values: C, 65.79; H, 5.34; N, 8.64. Ultimate analysis value: CHCINO Example 27: 0.4 g of 50% sodium hydride was added Theoretical values: C, 62.70; H, 4.97; N, 8.12. to the mixture of 2 g. 1 - (3 - bromophenyl)-2,4(1H,3H)- Found values: C, 62.66; H, 4.96; N, 8.25. quinazolinedione and 30 cc. dried dimethylformamide, and 50 the mixture was stirred for one hour. Then, 5 g. of 2-bro Example 31: 0.6 g. of 50% sodium hydride was added moethylacetate were added and reacted for 3 hours at to the mixture of 2.4 g. 1-phenyl-2,4(1H,3H)-quinazoline room temperature. The solvent was then distilled under dione and 30 cc. dried dimethylformamide, and the mix reduced pressure, the residue was added with water, the ture was stirred for one hour. Then, 6.8 g. of 2-bromo crystals produced were filtered, and, upon recrystalliza 55 ethylbenzoate were added and reacted for 3 hours at room tion from methyl alcohol, 1.8 g. of colorless prisms of temperature. The solvent was then distilled under reduced 1-(3' - bromophenyl) - 3-(2'-acetoxyethyl)-2,4(1H,3H)- pressure, the residue was added with water, the crystals quinazolinedione were obtained. produced were then recrystallized from the mixed solvent Melting point and ultimate analysis value of this sub consisting of dimethylformamide and methyl alcohol, and stance were as follows: 3.9 g of 1 - phenyl - 3 - benzoyloxyethyl)-2,4(1H,3H)- 60 quinazolinedione were obtained. Melting point: 145-146 C. Melting point and ultimate analysis value of this sub Ultimate analysis value: C18H15BrNOA stance were as follows: Theoretical values: C, 53.61; H, 3.75; N, 6.95. Found values: C, 53.46; H, 3.71; N, 6.80. 65 Melting point: 150.5-151 C. Ultimate analysis values: Example 28: 0.6 g. metallic sodium was added to 10 cc. Theoretical values: C, 71.49;H, 4.70; N, 7.25. ethyl alcohol and sodium ethylate was formed. Then, a Found values: C, 71.41; H, 4.79; N, 7.35. solution obtained by dissolving 5.3g. 1 - (2',3'-dimethyl phenyl)-2,4(1H,3H)-quinazolinedione in 20 cc. dried di 70 Example 32: 2.8 g. of propionyl chloride were added methylformamide was added. Further, 4.6 g. of ethyl dropwise to the mixed solution consisting of 5.6 g. 1 iodide were added, and the mixture was reacted for 3 phenyl-2,4(1H,3H)-quinazolinedione, 30 cc. dried di hours at room temperature. Then, water was added, the methylformamide and 4 g. triethylamine, and the mixture crystals produced were filtered, and, upon recrystallization was reacted for 3 hours at 80-90° C. The solvent was from methyl alcohol, 4.7 g of colorless needles of 1-(2,3'- 75 then distilled under reduced pressure, the residue was 3,794,643 19 20 added with water, the crystals produced were filtered, What we claim is: and, upon recrystallization from methyl alcohol, 2.3 g. 1. Quinazolinedione derivative of the formula: of colorless needles of 1-phenyl-3-propionyl-2,4(1H,3H)- quinazolinedione were obtained. Melting point and ultimate analysis value of this sub stance were as follows: melting point: 154-155 C. ultimate analysis value: CHNO3 O CF's theoretical values: C,69.37; H4.79; N,9.52. found values: C,69.21; H4.87; N,9.31. wherein R represents methyl, ethyl, chloroethyl, diethyla minoethyl, hydroxyethyl, ethoxyethyl or acetoxyethyl. Example 33: 0.7 g of 50% sodium hydride was added 5 2. The compound of claim 1 wherein R1 is methyl. to the mixture of 1.9 g. 1-(3methylphenyl)-2,4(1H,3H)- 3. The compound of claim 1 wherein R is ethyl. 4. The compound of claim 1 wherein R1 is chloroethyl. quinazolinedione and 30 cc. dried dimethylformamide, 5. The compound of claim 1 wherein R is diethyla and the mixture was stirred for one hour. Then, 3 g. of minoethyl. ethylenebromohydrin were added and reacted for 3 hours 6. The compound of claim 1 wherein R is hydrox at room temperature. The solvent was then distilled under yethyl. 7. The compound of claim 1 wherein R is ethoxyethyl. reduced pressure, the residue was added with water, the 8. The compound of claim 1 wherein R is acetox crystals produced were filtered, and, upon recrystalliza yethyl. tion from the mixed solvent consisting of methyl alcohol 25 References Cited and water, 1.9 g, of colorless prisms of 1-(3methylphen UNITED STATES PATENTS yl)-3-(2'-hydroxyethyl) - 2,4(1H,3H) - quinazolinedione 3,235,363 2/66 Luckenbough ------260-260 were obtained. 3,503,978 3/70 Zeidler ------260-260 Melting point and ultimate analysis value of this 30 3,544,575 12/70 Scheuerer ------260-260 substance were as follows: 3,551,429 12/70 Zeidler ------260-260 melting point: 152-154 C. DONALD G. DAUS, Primary Examiner ultimate analysis value: CH16N2O3 A. M. T. TIGHE, Assistant Examiner theoretical values: C,68.91; H,5.44; N,9.45. U.S. C. X.R. found values: C,68.74; H,5.24; N,9.45. 424-251