Dipole moments and pharmacological activity of cyclic ureas, cyclic

Dipole moments and pharmacological activity of cyclic ureas, cyclic thioureas, and the N,N'-dimethylated compounds. Eric J. C. Lien, and Warren D. Kum...
0 downloads 0 Views 717KB Size
Alarch 196s

DIPOLEJIOMENTS AND ACTIVITY O F CYCLIC

solvent was removed, the residue was dissolved in boiling Hz0, and the mineral oil was removed with decolorizing charcoal. The volume was reduced to 15 ml, and 25 ml of dioxane was added to precipitate XaI. Filtration, removal of dioxane, and distillation gave 1.5 g of crude product, yield 18.876, bp 96-136’ (3 mm). Repeated recrystallization from ether-heptane mixture gave the pure product. N,N’-Dimethyltrimethyleneurea and N,N’-Dimethyltetramethy1eneurea.-The same procedure was used for the NIX’dimethylated cyclic ureas as was used for N,N’-dimethyltetramethylenethiourea except the cyclic ureas were used as starting material and a reflux period of 3 hr was used after addition of MeI. After S a 1 and dioxane were removed the mineral oil from the NaH separated upon cooling. Fractional distillation of the bottom layer gave the desired product. The elementary analyses were done by the Microanalysis Laboratory, Department of Chemistry, University of California. The melting points were corrected. The dipole moments were measured n-ith a WTR dipole meter Model DM01 using a DFL 2 cell. The method of Halverstadt, and Kumler,’Z programmed for an I B l I 1401 computer by Simpson,’3 was used to calculate the moments. The electronic polarizations were calculated from the electron group refractions given by Smyth.“ Solute atomic polarizations were neglected. The standard errors in moments were calciilated as before.’; Ir spectra were measured on a Beckman IR8 spectrophotometer either in KBr or in 0.5-1.576 solution in CC14. The IIV spectra were measured on a Cary recording spectrometer Model 11 in solution in heptane, EtOH, and H20, and the nnir spectra on a Varian A-60A spectrometer sometimes using a time-averaging computer (CAT) C-1024 The positimi of the peaks are with reference to that of TMS. Since not milch pharmacological “history” of these compounds has been reported in the literature, the “blind screening” method of Trirner16 was used. Groups of four Swiss Webster albino mice, two male and two female (23-27 g)) were injected intraperitoneally with a series of logarithmic dosages, starting from 30 mg;kg, and the symptoms were observed continuously for 2 hr, theii at interval. for 3 days. A 0.2% water solution was used for dobage eqrial to or below 100 mg/kg; 2% solritiori was used for dosage of :300 and 1000 nig/kg. For dosage higher than 1000 mg/kg, higher concentration and only two mice were used because of the limited aniouiit of the compound available.

Results and Discussion Table I1 gives the results of the dipole moment measurements in dioxane and in benzene and the difference between the results in dioxane and benzene and the difference between the moments of the S and 0 compounds. The difference between the moments in dioxane and benzene are niuch larger, 1.07-1.60 D, for the nonmethylated compounds than for the dimethylated compounds, 0.01-0.26 D. The difference for the nonmethylated sulfur compounds are all close to 1.1 D (1.091.16), those for the dimethylated sulfur conipounds close to 0.2 D (0.13-0.26 D), those for the dimethylated oxygen compounds close to 0 (-0.01 to 0.06), and those for the two nonmethylated oxygen compounds 1.07 and 1.62 D. The third nonmethylated oxygen compound could not be measured in benzene because of low solubility. In seeking a reason for the large difference between the moments in dioxane and benzene for the nonmethylated compounds compared with the dimethylated com(12) I. F. Halrerstadt and 11.. D . Kumler, J . Am. Chem. Soe., 64, 2988 (1942). (13) T. R. Simpson. Ph.D. Dissertation, University of California Medical Center, San Francisco, Calif., 1964, p 126. (14) C. P. Smyth, “Dielectric Behavior and Structure,” McGraw-Hill Book Co., Inc., New York, N. Y.,1955, Chapter S I V . (15) C. 11.Lee and W.D. Kumler, J . Am. Chem. S O C .83, , 4586 (1961). (16) R. -1.Turner, “screening Methods in Pharmacology,” Academic Press Inc., New York and London, 1965, p 23.

215

U R E A DERIVaTIVES

TABLE I1 ----Dipole Dioxane

Compd

moment (H), D-Benzene

7

Diff

1.07 N,N ’-Et,hyleneurea 4.01 f 0 . 0 2 2.94 z t 0 . 0 2 N,N’-Trimethyleneurea 4.67 f 0.04 1.60 N,N’-Tet,ramethpleneurea 4.43 i 0 , 0 1 2.83 =t0.02 1.09 N,N’-Ethylenethiourea 5.60 f 0.02 4.51 f 0.06 N ,S ’-Trimethylene1.10 thiourea 5.79 10.0.5 4.69 i 0.06 N,N’-Tetramethylenethiourea 5 . 3 6 1 0 . 0 2 4.20 3 ~ 0 . 0 2 1.16 NIX’-Dimethylethylene0.04 urea 4.09 f 0.01 4.03 10.01 N,N’-Dimethyltrimeth0.06 yleneurea 4.23 1 0 . 0 1 4 . 1 7 1 0 . 0 1 N,S’-Dimethyltetramethyleneurea 3 , 7 5 1 0 . 0 2 3.76 f O . O 1 -0.01 K,N’-Dimethylethylene0.13 thiourea 5.32 f 0.02 3.19 i 0.01 SIN’-Dimethyltrinieth0.15 ylenethiourea 5.63 1 0 . 0 2 5.48 zk0.01 N,N’-Dimethyltetra0.26 methylenethiourea 5.29 10 . 0 2 5.03 f 0 . 0 1 Ring memberq

Vnsubstitiited Five Six Seven Dimethyl Five Six Seven

,------Dipoie ---Dioxane---

moment ( P ) , D---------Benzene--Diff S 0

s

0

.i.60 3.79 5,36

4 01 4 6T 4 43

1 39 1 12 0 93

4 51 4 69 4 30

2 94

1 ,57

2 83

1 37

5.32 5.63 3.29

4 09 4 23 3 75

1 23 1 40 1 -54

3 19 .i 45 5 03

4 0; 4 li 3 76

1 14

Diff

1 31 1 27

poundb, the fact that the former can hydrogen bond and the latter cannot is pertinent. A possible explanation is that in benzene one is actually measuring a mixture of a monomer and a hydrogen-bonded dimer which has a lower moment, while in dioxane the dimers are broken up by the solvent. This explanation does not seem valid, however, because if it were so the dielectric constant-weight fraction plots would not be straight lines and pains were taken to have the solutions dilute enough so these plots were straight lines. A more reasonable way of accounting for the observation is that the local dipoles of the dioxane can get closer to the dipoles in the nonmethylated compounds and increase the contributions of the forms with a separation of charge, thus giving rise to a higher observed moment. The local dipoles of dioxane are more effective in polarizing the nonmethylated compounds than for the dimethylated ones. The fact that the differences between the moments in dioxane and benzene are greater for the dimethyl sulfur compounds than for the dimethyl oxygen compounds lends support to this view because sulfur is inherently more polarizable than oxygen. The cyclic sulfur compounds all have higher moments than the corresponding oxygen compounds, and the differences here are considerably greater, 0.93-1.59 D, than was the difference between the moments of urea and thiourea, Ap = 0.33 D.17 The reason sulfur compounds of this type have higher moments than the corresponding oxygen compounds have been discussed previo~sly,’~ and ~’~ is due in the sulfur compounds to the (17) W.D . Kumler and G. hl. Fohlen, J . Am. Chem. Soc., 64, 19-14 (1942) (18) H. G. Mantner and IT. D . Kumler, t M . , 78, 97 (1956). (19) C. 11. Lee and 1V. K. Kumler. J . O r y . Chem., 27, 2052 (1962).

~ I O L E C U !L !-EIG IHR T,

217

DIPOLENOMENTS ASD ACTIVITYOF CYCLIC UREADERIVATIVES

Narch 1965

TABLE I11 DIPOLE1 I O M E X T ( p ) , ?\IEDI.U EFFECTIVE DOSE(EDm), AND 1IEDl.LK LETHAL DOSE (LI)jo) UREis, A N D THE N,N'-DIMETHYLATED COMPOCSDS

O F THE CYCLIC

-LDjo. Compd

11

=

!-%

(mmoles, kg)

lmmoles kg)

mg kg

(>46.3) (>40.0)

( 2 4 . 2 i 1.645)

>4000 >4000 2840

( 1 4 . 2 i 0.78) ( i . 7 . 5 I 0.28) ( 4 . 1 i 0.37)

>2000 ,560 21-5

(>19.6) ( 4 . 8 i 0.2.5) ( 1 . 7 i 0.11)

(11.4 i 1.4%) ( 7 . 0 i 1.38) (21.1 =tll..?)

2840 1300 700

( 2 4 . 9 i 1.OY) t l O . l i 0.47) 14.9 i 0.36)

(0 23 i 0 01) (0 07 i 0 002) (0 20 i 0 003)

17.5 118 82

11 3 i 0 06) 10 8 i 0 03) (0 3 i 0 01)

H, -4= 0

n = 2 n = 3 n = 4 It = H, A = S n = 2 n = 3 n = 4 11 = CHB, A = 0 n = 2 n = 3 n = 4

R

XI01I'\

= CH,, A = S n = 2 n = 3 n = 4 a Standard error.

86.1 100.1 114.1

4 . 0 1 i 0.02= 4.67 i 0.04 4.43 i 0.01

102.2 116.2 130.2

.5.60 i 0.02 5.79 i 0.05 5.36 i 0.02

603 900 (extrapolated) 530 (extrapolated)

114.2 128.2 142,2

4.09 i 0.01 4.23 i 0.01 3.73 i 0 . 0 2

1300 900 3000 (extrapolated)

130.2 . i . 3 2 i 0.02 144.2 .i..i6 i 0 . 0 2 5.29 i 0 . 0 2 138.3 One standard deviation.

2760

30. d 10 32

(1 g/kg), and all of the thiourea derivatives except ethylenethiourea. The dosage for the thioureas causing convulsion was 1 g/kg for trimethylenethiourea, 300 mg/kg for tetramethylenethiourea and K,X'-dimethylethylenethiourea, 100 mg/kg for S,r\"-dimethyltrimethylenethiourea, arid 75 mg/kg for S.S'-dimethyltetramethylenethiourea, respectively. Ataxia was observed for ethylenethiourea ( 2 g 'kg) and N,S'-diniethylethyleneurea ( 2 g/kg). Initial stimulation of respiration followed by progressive depression of respiration, diaphragmatic respiration, and finally asphyxia were observed for S,S'-dimethyltrimethyleneurea ( 2 g/kg). The median effective dose (ED5o), which was arbitrarily defined as the dose required to increase the respiration rate by 30%, the median lethal dose (IAD;o),the dipole moment, and the molecular weight are summarized in Table 111. The E& and LDSO were obtained by the graphic calculation of lliller and Tainter .3o =2mong these compounds, X,N'-dimethyltrimethyleiiethiourea is the most potent respiratory stimulant; it increased the respiration rate by 50% a t 10 mg/kg (0.07 mmole/kg); its LDSo/EDjo is 11.5. X,K'-Dimethyltetramethylenethiourea is the most potent convulsant with an LD,, of 79 mg/kg (0.5 mmole'kg). This compound is more toxic than peritylenetetrazole which has an LDjo of 92 m g k g (0.67 mmole/kg) in mice by intraperitoneal injection. 3 1 Analeptic Action.-Since X,',S'-dimethyltrimethylenethiourea was the most potent respiratory stimulant in the series studied, it was chosen for further study against the C S S depression of barbiturate. Two

124,9 i 1 . 0 Y , b )

groups of 12 Swiss Webster mice (both sexes, weighing 25-27 g) mere inject~edwith sodium pentobarbital (60 mg/kg) intraperit~o~ieally.~~ To one group. 30 mg/kg of S,S'-dimethyltrimethyleriethiourea was given by the same route 10 min after the injection of sodium pent'obarbital. The respiration rate counted at, 20 miri after the injection of pentobarbital and the sleeping time, which was defined as the interval between the loss arid the spontaneous return of the righting r e f l e ~ , ~ are 3 summarized in Table IV. TABLE I\' ANALEPTIC EFFECT O F ?;,N'-DIhlETHrLTRI.\iETHVLE?iE1.HIOI.REA IX ITICE PRETRE.ITED M'ITH SODIL-11 PESTOII.IRHIT.iL

Group

Drug(s) injected (mg/kg)

Resp rate. times min

Sleeping time, min

A

Sodium pentobarbital 89 i 10'' .54 i 14a (60) B Sodium pentobarbital (60) N,X'-dimethyltri135 i :32, :%Ii 10, 28'; methylenethiourea (30) t 32'; 9%55;confidence limit,s using Student'. t distrihutiuii.

+

a

The data show that in mice pretreated with pentobarbital (60 mg/kg) the respiration rate wti* increased about 52% (P < 0.01), and the ileepiiig time was shortened about 28% (P < 0.10) by S,S'-dimethyltrimethylenethiourea (30 mg 'kg) . This compound failed t o antagonize the pentobarbital-caused C S S depression in Sprague-Dawley rats or in guinea pigs and the respiratory depression in these animals caused by morphine.

(30) L. C. 3Iiller a n d M. L. Tainter, Proc. SOC.Ezptl. Biol. .Wed., 6 1 , 261 (1944).

(31) C. D. Barnes and L. G . Eltherington. "Drug Dosage in Lahoratory Animals," Uniyersits of California Press, Berkeley and Los Anpeles, Calif., 1964.

(32) F. H. S h a a , S. E. Simon, N . Cam, and Shulman. S u t u r e , 114, 403 (1954).

( 3 3 ) E. T. Kimura and R . I