3996
SEYXOUR L. SHAPIRO, VINCEST A. PXRRINO AND LOUISFREEDMAN
yield, b.p. 9 5 1 0 3 ' (39 mm.), and converted to cyclohexene oxide in 75y0yield, b.p. 129'.l4 trans-2-Pyrrolidinocyclohexanol (Compound 3, Table III).-Pyrrolidine (20.7 g., 0.29 mole) was heated to reflux with stirring, and 18.6 g. (0.19 mole) of cyclohexene oxide was added dropwise over 30 minutes. After continued heating for 2 hours the excess pyrrolidine was removed and upon distillation the residue gave 19.9 g. of product, b.p. 88-90" ( 5 mm.). In a similar manner other disubstituted aminocyclohexanols were prepared and have been collected in Table 111. trans-2-(4-Methylpiperazino)-cyclohexylBenzoate (Compound 34, Table I).-A solution of 8.0 g. (0.04 mole) of 2-(4methy1piperazino)-cyciohexanol (compound 11, Table 111) in 40 ml. of acetonitrile was added over 30 minutes to 5.6 g. (14) A. E. Osterberg, "Organic Syntheses," Coll. Val. I , John U'iley and Sons, Inc., New York, N. Y., 1951, p. I S 5 For later runs, cyclohexene oxide was purchased from Arapahoe Chemicals, Inc., Boulder, Colo.
[CONTRIBUTION FROM THE ORGANIC
Guanamines.
VOl. S l
(0.04 mole) of benzoyl chloride in 35 ml. of acetonitrile. A vigorous exothermic reaction ensued with precipitation of a white solid. After storage for 20 hours a t 20', the solvent was removed and the residual solid washed with ether and separated. The 12.0 g. so obtained was dissolved in water and made basic with continued cooling with 40% aqueous sodium hydroxide. The liberated free base was extracted with five 100-ml. portions of ether. T h e extracts were combined, dried (anhydrous magnesium sulfate), then filtered and distilled. After removal of the solvent and a small forerun, 9.0 g. of product distilled a t 168-172' (0.1 mm.). The other cyclohexyl esters described in Table I were prepared essentially by the same procedure.
Acknowledgment.-The authors are grateful to Dr. G. Ungar for the pharmacological evaluation of the compounds, and to S. Herbstman and E. Chodos for their technical assistance. YONKERS 1, N. Y.
RESEARCH LABORATORIES OF THE
u. s.\'ITAMIN
AND PHARMACEUTICAL CORP.]
11. Oxyalkylguanamine Anticonvulsants2
BY SEYMOUR L. SHAPIRO, VINCENT-4. PARRINO AND LOUISFREEDMAN RECEIVED FEBRUARY 2 , 1959 A series of oxyalkylguanamines of the type I have been synthesized and examined for anticonvulsant activity. Structureactivity relationships are discussed and peak anticonvulsant responses are noted with selected 2-amino-4-(substituted anilino)-6-oxyalkyltriazines. In the attempted synthesis of 2-amino-4-anilino-6-or-carboxy-ol-chloromethyl-~-triazine, halodecarboxylation by hydrochloric acid was observed to yield 2-amino-4-anilino-6-dichloromethyl-s-triazine.
This paper extends our exploration' of triazine derivatives to oxyalkylguanamines of the type I which have been envisioned as Mephanesin3 analogs (Ia) and examined for anticonvulsant activity. The groups R1 and Rz were varied extensively, CH,OH H,
I
particularly with structures wherein R1was substituted phenyl and Rzwas hydrogen and alkyl (Table 11.4 The synthesis of the guanamines (I) was effected in moderate yield by familiar through reaction of the biguanide with the appropriate (1) Paper I of this series, S. I*. Shapirr,, V. A . Parrino, K . Geiger. S . Kobrin and L . Vreedman, Tms J ~ V R N A79, L , 5084 (1957). ( 2 ) Presented in part a t t h e ?rlertiny-in-AIiniature, N e w York Section, American Chemical Society, Brooklyn, S .Y . , >larch 2 0 , 1939. (3) (a) J. P. Lambooy, THISJ O U R N A L , 73, 349 (3951); (b) Y. 31. Beasley, V. Petrow, 0. Stephenson and A . M . Wild, J . P h a i m . Phaimnod , ,11, 3(j ( l ! l 5 8 ) . (4) Analors of the guanamine I previously prepnred have been derivatives of biguanide and phenylbiguanide: (a) H . J. Sims, H . B. Parseghian and P. L, de Benneville, J . Ovg. C h e m . , 23, 721 (1958),for K I , RZ = hydrogen, R3 = C H I O H ; ( b j J . T. Thurston and M . H. Bradley, U.S Patent 2,309,6381, Feb. 2, 1913, for R i , Rs = H . Ra = CHzCH20 alkkl: (c) F. C. Schaefer, U. S.Patent 2,777,848, Jan. 15, 1957, for RI = phenyl or hydrogen, Rz = H , Ra = CHIO alkyl; (d) S. V. Sokolovskaya, V . N, Sokolova and 0. Yu. Magidson, Zhur. Obshchei Khim , 27, 7(i5 (1957) [C. A , , 51, lCil9Rd (1937)l for RI = phenyl, Rz = hydrogen, Ra = CHIOH; (e) C . G. Overberger and S. L. Shapiro, THISJ O U R N A L , 76, 1061 (1954), for R I = phenyl, Rz = hydrogen, RI = CHsCHzO alkyl.
acylating agent R3COOC2H6or R3COCl. Of particular interest was the isolation of an equimolar complex4eof the reactant biguanide and product in the synthesis of compounds 3 and 59 of Table I. Similar complexes in polynitrogen systems have been widely described.5-9 An examination of the yields of the guanamines (I), which in the instances of those structures prepared from arylbiguanides and esters are all less than SO%, suggests that in the course of the reaction, one equivalent of biguanide is bound to the formed guanamine and is thus rendered invulnerable to further acylation and cyclization to the desired product. In turn, the stability and ease of isolation of the molecular complex appears to be influenced by steric factors in the reactant biguanide and in the R3gro~p.~e.lOHydrogen-bonded forms, similar to those proposed by BirtwelP between isomers of I1 and the biguanide to yield 11, would account for the molecular complex and the relatively poor yields. As the work progressed, noted activity with selected structures of the type I indicated extension of the structural scope of R3which was further varied as p-pyrrolidinoethyl (coinpoulids 81-83) and as shown for 111. 13) W. J. Close, ibid., 75, 3U19 (1U.38). ( 6 ) S. Birtwell. J . Chem. Soc.. I725 (1963). (7) L. L. Smith, S .4. Muller, hl. > l a x , R. \Vinterbottom and .A. P. Doerschuk, J . Ovg, ( ' h e n . , 23, 721 (1958). ( 8 ) H. Schroeder and C. Grundmann, rZbstracts of Papers of American Chemical Society Meeting, Minneapolis, Minn., September, 1'385, p. 1 4 - 0 . (9) A. C . Cuckler, C . 11. hlalanga, A . J , Basso and R.C. O'h'UIl, S c i e m c , 122, 244 (1955). (10) S. L. Shapiro, V. A. Parrino and I,. Freedman, further papers in this series in preparation.
3997
OXYALICYLGUAN.~~IINE ANTICONVULSAXTS
Aug. 5 , 193'3
TABLE I
OXYALKYLGUANAMINES
7 2
R Mbp.,'4*
No.
Ri
R2
c.
1-~4 N H*
Yield,
%
Formula
Carbon, % Calcd. Found
Analysesc--Hydrogen, % Calcd. Found
Kitrogen, % Calcd. Found
R3 = HOCHr139-141 186-187
40 43
CsH15N50 C10HiiiY50
51.7 55.3
51.7 55.1
7.2 5.1
6.9 5.0
33.5 32.2
33.3 32.0
C2H.jH H H
116-118 185-186 161-163b' 221-223
35 35 42 42
CiaHiiN50 CioHioClN50 CioHioClN50 Ci1HizClN50
60.2 47.9 47.9 49.8
60.2 47.9 47.6 49.9
6.6 4.0 4.0 4.6
6.5 4.0 4.2 4.7
27.0 27.8 27.8 26.4
26.8 28.2 27.6 25.9
CHaH H
141-143 110-112 95-99 100-106 125-127 156-158 91-94 148-150 170-174 155-157 142-146b3 169-171 189-192b4 174-175b2 198-19gb2 145-147 137-139 203-205 139-141 160-162 191-193b2 160-162 163-164b4 195-197 131-132
45 42 61 46 48 41 46 34 47 37 10 27 44 21 30 31 67 46 38 34 21 31 28 30 12
45.9 49.2 53.3 53.3 60.2 57.1 58.8 58.8 60.2 60.2 60.2 60.2 60.2 57.1 60.7
46.0 49.3 53.5 53.3 60.7 57.1 58.6 58.8 60.0 60.3 60.0 59.9 60.0 56.7 60.8
7.2 6.i 8.5 8.5 6.6 5.7 6.2 6.2 6.6 6.6 6.6 6.6 6.6 5.5 5.9
7,9 6.8
6.9 5.7 6.0 6.5 6.3 6.4 6.4 6.7 6.9 6.1 5.9
38.2 35.9 31.1 31.1 27.0 30.3 28.6 28.6 27.0 27.0 27.0 27.0 27.0 25.6 27.2 25.6
38.0 36.2 31.0 31.0 27.0 30.3 29.0 29.2 26.8 27.0 27.4 26.8 27.1 25.4 27.3 26.0
61.5 62.1 49.8 42.5 51.7 51.7 44.5 44.0 53.6
61.4 62.6 50.1 42.5 51.6 52.3 44.2 44.6 53.8
i.0 7.4 4.6 3.9 5.0 5.0 4.4 3.i 5.9
6.9 7.0 4.6 4.0 5.0 5.1 4.1 4.0 5.6
24.4 26.4 22.6 25.0 25.0
24.0 26.0 23.2 25.0 25.2
23.3 24.0
23.3 24.2
58.8 60.2 61.5 61.5 53.2 44.4 38.8 45.9 45.9 45.9 56.7 62.7 56.0
58.1 59.8 61.5 61.5 52.9 44.1 39.0 46.2 45.3 45.5 56.8 62.2 56.0
6.2 6.6 7.0 i.0 5.5 4.4 3.8 1.2 4.2 4.2 6.2 7.4 6.3
5.9 6.5 7.1 7.0 5.5 4 6 4.1 4.0 4.1 4.6 6.3 7.5 G.0
28.6 27.0 25.6 25.6 23.8 21.6 18.9 32.3 22.3
28.5 26.9 25.2 25.9 23.8 21.8 19.5 22.6 22.3
25.4 24.4 21.8
25.2 24.2 22.2
57.3 61.7
56.7 61.7
8.4 7.0
8.4 6.9
27.9 25.6
27.9 25.4
60.2
60.1
6.6
6.8
27.0
27 2
1 2d
H
3e 4 5 6
H
"
R3 = CH30CHr-
8 9 10 11 12 13 14 15 16 17 18 19 20 21
H CHIH H H H H H
H H H CZHQCZH5H H H H H H H H
€I H H H H H €I H H €I H CzHs-
H H H €I CI 11-
CJ
rb-
168- 169 198-199 168-181 165-167 173-174 84-87 153-155 186-188 100-101 195-200 143-144 230-232 86-87
8.7 8.7
Vol. SI TABLE I (continued) _
.
~
64.1 ti*5.1
67.8 60 ti ti2.9 GO. 3
-Analyses'----
~
Hydrogen, YP Calcd. Found
-, . -,
~
. .
__
Sitrogen. 70 Calcd. Found
8.0 6 3 6 6 7 4 n ii
60 2 ( 2 0.
(j
.51.7
.i (J
li
70
35. 1 -3i) 8 44.2 Xi. 8 .53. 0
4.4 4 1 5 . .4
01 7
3. x
62. i ti1.8
7.4 8.0
61.0 60.9 64 0 55.6 38 3
7.1)
63 7 67.4
- .
3 9
- -
.I
i
-7 .0 I
,
fi 3 li 0 ..i 2
0.3
Cj7. 0
8.8 04.4 7.4 60 11 ii 1 T h e recrystallizing solvent is acetonitrile unless otherwise shown; b 1 ethanol; a Melting points are t t o t corrected. h Z I-propaniil; b 3 benzene; b 4 isopropyl alcohol; h j methanol. .inalJ ' by b'eiler and Strauss, Oxford, England. Reported in ref. 4d, imp. 191J-191°. e The conipiiund was isolated as a n equimolar complex with the reactant biguanitie, 111.1). 131-133" (65%). Anal. Calcd. for C.?H3~Slr10: C, 58.6; H , 6.7; S,31.2. Found: C, 59.7; H, 6.6; K, 31.2. This complex was further characterized hy the preparation of the constituent picrates following the procedure outlined in ref. l e . 'The dipicrate of ( o - e t h ~ l p h e n y l ) - h i g u a i i i ~5o e formed melted :it 175-176"(water) and did not depress the inelting point of the authentic dipicrate, mixed r n . p 1 3 17.5". :Inn/. C;ilccl. for C ~ 2 H ~ 1 S l 1 0S, 1 d23.2. : F I I I I I IS, ~ : 23.0. The picrate o f thc desired product, 2-arninri-~-(o-ctli!~la11iliii1i i-Ci-li!-tir~isvi7ictli!.l-.s-tri~~itie,melted a t 185,". z l n n l . Calcd fnr C I R H I R Sa08:C, 45,6; H, 3.8; N , 2 3 ii Fiiuntl: C,Xi.0; €1, 4.0;S ,2:j.S. CIH,-- = a l I > - l CIII,CH:CH?- with t h e a t ~ d char;tctcrizerl ; i 5 t h e Iiicrate, 111.11. 160-~l!i2°(wateri. tached nitrogei~represents t h e ii~diili~iiigroup * 'l'lic c o i n p ~ i ~ i iwas .Innl. Calcd. for CYIIIII.2NnOli: C, i 7 . 9 ; IT, 4.4; S , 22 :
