Journal of Medicinal Chemistry, 1977, Vol. 20, No. 3 379
2-Methyl-3-(o-tolyl)-4(3H)-quinazolone Unpurified guinea pig SRS-A was prepared as previously described' and a dose was selected which produced similar repetitive submaximal contractions of the ileum. Each contraction was recorded for 90 s; then the tissue was washed several times to allow complete relaxation. Five minutes was allowed between successive doses of SRS-A. The compound under test was added to the organ bath 30 s before a dose of SRS-A and was present during the induced contraction. Three concentrations of the test compound were chosen which gave inhibitory effects ranging between 10 and 90%. The concentration of compound which would inhibit the ileum contraction due to SRS-A by 50% (IC,) was calculated from the log doseresponse graphs. One operator was responsible for all the experimental results reported in this paper. The reproducibility of IC, values in this test system can be assessed by reference to a standard compound FPL 557127 which gave an IC, of 0.005 f 0.001 (mean standard error) Fg/ml in six experiments.
Acknowledgment. We wish to express our thanks to Mr. D. Carter who was involved in the work which led to the discovery of compound 38, to Mr. J. Fuher and Mr. B. Springthorpe for technical assistance, and to Mr. K. Vendy for the biological screening of the compounds in this paper. References and Notes (1) W. E. Brocklehurst, J . Physiol. (London),151,416 (1960). (2) P. A. Armitage, H. Herxheimer, and L. Rosa, Br. J . Pharmacol., 7, 625 (1952).
(3) P. Sheard, P. G. Killingback, and A. M. J. N. Blair, Nature (London),216, 283 (1967). (4) L. S. Goodman and A. Gilman, "The Pharmacological Basis of Therapeutics", 4th ed,Macmillan, New York, N.Y., 1970, p 635. (5) P. Sheard and A. M. J. N. Blair, Int. Arch. Allergy, 38,217 (1970). (6) H. J. Sanders, Chem. Eng. News, 134 (May 11, 1970). (7) J. Augstein, J. B. Farmer, T. B. Lee, P. Sheard, and M. L. Tattersall, Nature (London),New Biol., 245, 215 (1973). (8) M. E. Grieg and R. L. Griffin, J. Med. Chem., 18,112 (1975). (9) H. Cairns, C. Fitzmaurice, D. Hunter, P. B. Johnson, J. King, T. B. Lee, G. H. Lord, R. Minshull, and J. S. G. Cox, J . Med. Chem., 15, 583 (1972). (10) S. Ruhemann and H. E. Stapleton, J. Chem. SOC.,77,1179 (1900). (11) G. Barker and G. P. Ellis, J . Chem. SOC.C , 2230 (1970). (12) A. 0. Fitton and B. T. Hatton, J . Chem. SOC.C, 2518 (1970). (13) W. Baker and 0. M. Lothian, J . Chem. SOC.,628 (1925). (14) C. S. Gibson and B. Levin, J . Chem. SOC.,2388 (1931). (15) H. Meerwein, G. Dittmar, R. Gollner, K. Hafner, F. Mensch, and 0. Steinfort, Chem. Ber., 90, 841 (1957). (16) V. A. Zasosov, E. I. Metel'kova, and S. N. Mibvanova, Zh. Obshch. Khim., 26,2499 (1956); Chem. Abstr., 51,4994d (1957). (17) H. Wojahn, Arch. Pharm. (Weinheim, Ger.),271,417 (1933). (18) M. Hamada, Botyu-Kayaki, 21, 22 (1956); Chem. Abstr., 51, 3519d (1957). (19) D. Butler and R. Milburn, Can. J . Chem., 50, 1249 (1972).
Synthesis and Central Nervous System Activity of Quinazolones Related to 2-Methyl-3-( o.tolyl)-4(3 H)-quinazolone (Methaqualone) I. R. Ager, D. R. Harrison, P. D. Kennewell, and J. B. Taylor* Roussel Laboratories, Kingfisher Drive, Covingham, Swindon, Wiltshire, England. Received April 12, 1976 A number of derivatives of 2-methyl-3-(o-tolyl)-4(3H)-quinazolonebearing new substituents on the 2-methyl group have been synthesized. It was established that most substitutions at this position reduce or remove the CNS depressant activity of methaqualone. From the series prepared only the 2-fluoromethyl derivative or certain isothiouronium salts, which-could be hydrolyzed in vivo to the 2-mercaptomethyl derivative, showed activity of the same magnitude as methaqualone.
Considerable interest in the pharmacological activity of quinazolones was generated by the observation that febrifugine, the antimalarial principal in an ancient Chinese herbal remedy, was a derivative of 4-quinazolone.' Subsequently, the quinazolones have been shown to possess, inter alia, CNS depressant,2 d i ~ r e t i c antihy,~ perten~ive,~ antiinflammat~ry,~ and bronchodilator act i ~ i t y . " While ~ investigating simple derivatives of febrifugine, Gujral and his co-workers2discovered the potent CNS depressant properties of 2-methyl-3-(o-tolyl)-4(3H)-quinazolone(methaqualone, Ia), a product which has achieved significant clinical use as a hypnotic agent.*-" Our interest in methaqualone (Ia) led us to synthesize some novel derivatives in an attempt to prepare improved hypnotics and the results are reported here. At the commencement of this work such derivatives were unknown, although Japanese" and Russian'* workers have subsequently prepared some of the compounds described. Chemistry. The 2-alkyl-3-arylquinazolonesI were prepared as shown in Scheme I via the POC13 catalyzed condensation of acetyl anthranilates IIa with the appropriate ar~1amine.l~ Bromination of Ia gives a variety of products, the precise nature of which depends on the experimental conditions (Scheme 11). The reaction with bromine in glacial acetic acid gives a mixture of products from which the major
Scheme I
Bx
aco2H Ax- dir, "COR
IIa, R = CH, b, R = CH,Cl
+
R
Ia, R = CH,; X = o-CH, e , R = CH,Cl; X = o-CH,
product, 2-bromomethyl-3-(o-tolyl)-4(3H)-quinazolone (Ib), can be isolated by crystallization. Alternatively, reaction of Ia with bromine in dimethyl sulfoxide solution results in an exothermic reaction and the 2-dibromomethyl-3(o-tolyl)-4(3H)-quinazolone (IC)can be readily isolated. It has recently been reported14that bromination of Ia using N-bromosuccinimide in C C 4 results in reaction at the methyl group of the o-tolyl ring to give 3-(o-bromomethylphenyl)-2-methyl-3(4H)-quinazolone(Id). The product Ib was the key compound for further synthetic work and formed the basis of our preferred approach in contrast to that of the Russian workers12 who used the chloro analogue Ie, synthesized from chloroacetyl anthranilate IIb. The bromine atom of Ib could be readily displaced by nitrogen, oxygen, and sulfur nucleophiles (Scheme ID). The compounds prepared by these reactions are listed in Tables I-VI. Amines, alkoxides, and thiols
380 Journal of Medicinal Chemistry, 1977, Vol. 20, No. 3 Table I.
Ager, Harrison, Kennewell, Taylor
2-Halomethyl-3-aryl-4(3H)-quinazolones
R X 1 CH,Br 2-CH3 2 CH,Br 2-F CH,Br 2-c1 3 4 CH,Br H CH,Br 4-CI 5 6 CH,Br 2-C02CH, 7 CH,F 2-CH3 8 CH,I 2-CH3 CH,F 2-c1 9 10 CH,F 2-CH3-3-C1 CHF, 11 2-CH3 12 CHBr, 2-CH3 13 2-CH, CF, See Experimental Section.
Compdno.
Yield, %
Mp, " C
Solvent
Methoda
49 85 52 41 61 73 53 87 42 66 12 63 51
125-126 146-148 156-158 183-185 162-163 202-205 105.5-106.5 148-149 115-116 164-166 145-146 143-144 146-147
MeOH MeOH MeOH CHC1,-petr ether Acetone-petr ether Acetone MeOH MeOH MeOH EtOH MeOH EtOH EtOH
A A A A A
Analyses c , H, N c, H, N c , H, N C, H, N c , H, N C, H, N, c, H, N c, H, N C, H, N , C. H. N. C; H[ N' C, H, N, C. H. N
A
B C B B D E D
Br C1 Cl Br
Table 11. 2-Aminomethvl-3-( o-tolvl)-4( 3H)-auinazolones
19
'" 20 21
H H
Yield, %
Mp, "C
Solvent
90
135-136b
CHC1,-petr ether
83
138-140
Et,O-petr ether
54
189-191
EtOH
53 80
105-106.5 176-178'
Petr ether EtOH
;r'
80
265-266
Acetone-HzO
n-C,H, Me
59 16
94.5-96 112-1 1 4
Petr ether MeOH-H,O
70
255-256
MeOH
/=\
22 a
