c?;s DEPRESSANTS.
Novemher 1966
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A*VI I TABLE 1 ALKYLENEDIAMIXE DERIVATIVES"
R
n
Yield, %
Carbon, yo Calcd Found
BP, " C (mm)
Hydrogen, 70 Calcd Found
Halogen, % Calcd Found
Kitrogen, yo Calcd Found
2 67 90-95 ( 0 .07) b 70.5 70.0 8.9 9.1 20 6 20 i 2 65 85-90 ( 0 , 1 ) " 71.9 i1.4 9.4 9.3 18 i 18 5 2 71 80-83(0.2) 53.0 53.6 5.4 6.7 13 7 13 5 2 74 107-118 ( 0 . 2 ) 44.i 45.1 5.2 37.2 37.9 13 0 4.9 12 3 2 6i 113-122 ( 1 . 2 ) 0-c1 2 72 118-125 ( 0 . 1 ) 56.3 j6.l 6.5 m-C1 6.6 20.8 20.9 16.4 16.4 2 73 144-154 ( 1 . 3 ) 56.3 -56.2 6.5 6.6 20.5 20.5 16.4 16.4 p-c1 2 59 160-170(0.3) 65.0 65.2 8.5 8.7 m-OCH3 16.9 16.7 2 49 125-130 ( 0 . 4 ) 42.3 42.6 6.3 6.4 27.6 27.9 11.0 11.0 m-SCH, 120-130 (0.05)' 42.0 41.9 3 74 5.9 5.5 m-C1 41.3 41.5 10.9 11.3 a These compounds were nsed in the next step without further purification. J. P. Fourneau and Y. de Lestrange [Rul/.Chem. Soc. France, 827 (1947)] report b p 143-145' (15 mm). c L i t b bp 168" (28 mm). Anal. Calcd: F, 27.9. Found: F, 28.3. e Not analyzed. f C . F. Deebel [U. S.Patent 2,953,490 (Sept. 20, 1960)l reports bp 128" (0.1-0.25 mm). Dihydrochloride.
FI
m-CH3 na-CF3 m-Br
Q
TABLE I1 (2-ASILIXOETHYL)UREb DERIVATIVES H,NCONHCH,CH,NH Yield,
R
70
49 H 86 m-CH3 70 m-CF3 83 0-c1 76 m-C1 --13 p-C1 44 m-OCHj 66 m-SCH3 a A, ethyl acetate; B, 13.9.
Mp, OC
Recrystn solvent"
A 102-104 B 126-127 B 89-92 126-130 C A 115-1 17 h 124-126 D 97-98 D 104-105 chloroform-petroleum
Formula
\ GR
Carbon, 70 Calcd Found
Hydrogen, 7" Calcd Found
Halogen, 70 Calcd Found
Nitrogen, yo Calcd Found
CgH,,S,O 60.3 60.0 7.3 7.5 23.5 23.6 CloH15N30 62.2 61.8 '7.8 7.9 21.7 21.8 48.3 5.3 4.9 C10Hi2F3N30 48.4 23.0 23.0 16.9 16.7 C9HizCIS30 50.6 50.5 5.7 16.6 16.i 19.7 19.2 5.8 C5H12CIN30 50.6 5.7 6.0 50.5 16.6 16.6 19.7 19.8 CgHi2ClN30 50.6 50.4 5.7 5,9 16.6 16.8 19.7 19.6 57.3 7.2 7.3 C1oH:jSaOa 57.4 20.1 19.8 53.4 6.i 6.6 C1oHIjN30Sb 53.3 18.7 18.1 ether (bp 30-60"); C, acetone: D, ethanol. *Anal. Calcd: S, 14.2. Foinid: P,
to the side or falling off the rod. Effective doses for reduced rod-walking ability (R\;VDjo)mere calculated or approximated from the data, and the time of peak effect was estimated from the data. B. Reduced Locomotor Activity.-One-half of the RWDjo dose was given intraperitoneally to each mouse in groups of 5. At the time of peak effect, as determined above, each group of mice was put into the actophotometer for a period of 5 min and the motor activity counts were recorded and compared to controls. Those compounds that appeared to reduce
motor activity by 50% were administered to additional groups of five mice a t graded doses and tested similarly. The dose (AIDD50) that caused a 50% reduction in motor activity was estimated. C. Paralysis.-Groups of ten mice for each of three or more graded dose levels mere placed on an inclined screen (60") for a period of 20 min or more, immediately after receiving the agents studied. The proportions of mice falling off the screen a t each dose were recorded, and effective doses (ISDso) were calciilated.
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Ir added The product was filtered off atid recrvstallwed twice from ethanol.- The yield of l-(~n-chloropheiiy1~-3-(2-dimet~iylaminoethyl)-2-imidazolidiiione hydrochloride, mp 215-2118", was 1.4 g (53%). Procedure D. 1-(2-Dimethylaminoethyl)-3-(m-hydroxyphenyl)-2-imidazolidinone Hydrochloride.--A mixture of 1.0 g of 1-(2-dimeth~-lamiiioeth~-l)-3-(m-niethosypheiiyl)-2-imidazolidinone hydrochloride, 20 ml of 487, HRr, aiid 20 ml of acetic acid was heated a t reflux temperature for i 2 hr and then diluted with 75 ml of water. Potassium carbonate was added to p H 8, and the reaction mixture was extracted with chloroform. The chloroform layer was dried (hIgSO1) and concentrated to remove the solvent. The oil that remained was dissolved in ethanol, and 2.2 ml of 1.8 ethanolic HCI and ether were added. The precipitate waq filtered off and recrystallized from ethanol. l-(m-Chlorophenyl)-2-imidazolidinethioneDerivatives (Table V).-A mixture of 25 g of the l-(aminoalkyl)-3-(m-~hlorophenyl)2-imidazolidinone hydrochloride, 100 ml of xylene, and 100 ml of benzene was heated in an oil bath until most of the benzene was distilled off, aiid 25 g of P&wasadded. Thebath temperature a-as held a t 156-160' for 28 hr. The reaction mixture was cooled to about 60", aiid 350 ml of 2 A- KaOH and 200 ml of benzene were added. The mixture was heated until the glassy lower layer dissolved and the organic layer was separated. The aqueous layer was extracted with benzene and then discarded. The combined organic layers were wayhed twice tTith water and then extracted with 260 nil of 1 .Y HC1. The acid layer wa3 extracted once with ether and theii made alkaline by the addition of 60 ml of 5 AT NaOH. The product vaq extracted into ether, and the et,her layer was dried (ALgSOI) and then concentrated. Salts a-ere prepared by addition of the appropriate acid to a aolut,ion of the base iii ether or ethanol. Tetrahydro-2(1H)-pyrimidinone Derivatives (Table VI).The 1-aminoalkyl-3-( m-chlorophenyl)tetrahydro-2( 1H )-pyrimidinones were prepared from 3-bromopropylamine hydrobromide, m-chloroaniline, and t8heappropriate aminoalkyl halide by a threestep process similar to that used in the preparation of the 2imidazolidinones. Yields in the first step were lower than in the 2-imidazolidinone series and products were more difficult to purify. Propertie-J of the intermediates and final products are given in the tables.
Acknowledgment.-We wish to thank N r . L. Brancone and staff for the niicroanalyses and Dr. P. J. Kohlbrenner and associates for t'he preparat'ion of many of the int'erniediates.
