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Anticonvulsants. A study of some alpha, alpha‐disubstituted malondiamides
Anticonwlsants* A Study of Some Alpha, Alpha-Disubstituted Malondiamides By HERBERT. F. SCHWARTZt and ROBERT F. DOERGES The primary purpose of this study was the preparation of a series of a,a-disubstituted malondjamides not previously prepared nor investigated for their pharmacological properties. Because of their structural relationships to well-known compounds having anticonvulsant activity, and furthermore, since two of the lower members of the series have been shown to be without hypnotic activity, a characteristic desirable in a good anticonvulsant,this series was considered worthy for further investigation as anticonvulsants. The prepared compounds were tested for anticonvulsantactivity on the male albino rat against electroshock and against MetrazolB. Some of the compounds exhibited anticonvulsant activity. At the maximum tolerated oral dose the compounds had no action against the stimulating effect of 3 0 mg./Kg. of ephedrine sulfate injected subcutaneously.
A study of the literature shows that many of the drugs in present-day use have an undesirable agement of epilepsy. The first effective medici- sedative action, while there are others which nal agents to be used were the inorganic bro- possess little or no sedative action but do cause mides, which were introduced in England about other undesirable side effects, such as skin 185T. The introduction of phenobarbital in 1912 rashes, photophobia, exaggeration of personality soon led to the replacement of the bromides; in defects, liver damage, and agranulocytosis (Gfact, phenobarbital is still considered to be a 11). This would indicate that there remains a very valuable drug, while the bromides are need for better anticonvulsants and that further rarely, if ever, used in the control of epilepsy. investigation of possible anticonvulsants should Research in the field of anticonvulsants led to be camed on. Many of the synthetic organic compounds prethe testing of certain hydantoins by Putnam and Merritt (1). From their work came DilantinB viously mentioned as anticonvulsants possess in common. However, which still remains as one of the best agents for the group 4 0 - N R grand ma1 epilepsy. Another hydantoin which this structural unit is not essential for anticonhas gained some popularity is Mesantoina (3- vulsant activity. Evidence of this is shown by Putnam and Merritt (l), who found activity in methyl-5,5-phenylethylhydantoin). Drugs which are more specific for the control certain aldehydes and ketones, and also by Berger of petit ma1 epilepsy also have been introduced. (la), working with 2,2-substituted-l,3-propaneTridioneB (3,5,5-trimethyloxazolidine-2,4-dione)diols. With the exception of HibiconB and was introduced in 1945 (2), and Paradionea (3- PhenuroneB, all of the previously mentioned methyl-5,5-methylethyloxazolidine-2,4-dione) in anticonvulsants have a tertiary or quaternary 1947 (3). More recently Milontin@(N-methyl- carbon atom. The structural relationships of a-phenylsuccinimide) has been clinically evalu- the a-,a-dialkylmalondiamides to the effective anticonvulsants, and the fact that the diethyl-, ated (4) and is now commercially available. Other drugs which are now commercially avail- dipropyl- (13’1,and ethyl-( 1-methy1)butylmalonable include: Mebaralm (N-methyl-5,5-phenyl- diamide (14) have no hypnotic activity, indicated ethylbarbituric acid), Gemonil (N-methyL53- that this series was worthy of further investigadiethylbarbituric acid), Mysoline@ (5,5-phenyl- tion as anticonvulsants. Accordingly, a series of ethylhexahydropyrimidine-4,6-dione), Phenur- substituted malondiamides of the following strucone@ (phenylacetylurea), Hibicon@(N-benzyl-P- ture was prepared in order to test their pharmacochloropropionamidex). Clinical investigation of logical activity: Themisonem (a-methylmandelamide) has been 0 reported (5). II R‘ C-NH,
use of anticonvulsant I drugs is the theprimeproper consideration in the manN THE MAIN,
\ /
*
Received August 6,1954. from the College of Pharmacy, University of Texas. Austin. Abstracted from a thesis presented to the Faculty of the Graduate School of the University of Texas by Herbert F. Schwartz in partial fulfillment for the degree of Master of Science in Pharmacy. Special Instructor in Pharmaceutical Chemistry. College of Pharmacy. University of Texas, Austin. t Present Address: Research and Development Division, Smith, Kline and French Laboratories, Philadelphia, Pa.
C
80
Fehruary, 1955
SCIENTIFIC EDITION
81
TABLEPHARMACOLOGICAL DATAON MALONDIAMIDES STUDIES" 0
II
C-NHI
R'
\ / C R/
'C-NHz
II
0 Compound Number
2661 L 2657 L 2653 L 2662 L 2656 L 2664 L
R'
CzHs CZH5
CZH5 CJL CzHb GH5
R*
Maximum Tolerated Oral Dose.. me./Ke. -.
CzHs n-CsH7 n-CrHs
I
> 1000 200
i-C,Hg
200 400
~-C~HII Z'-C5H11
250
> 1000
SEDb
0'
0 0 0 0 0
Test Results SMES C
++ 2+
RSCMd
+
0
2+
0 4+
0 0 0
0
The male albino rat, dosed orally, was used in all the tests. b SED-Sedative: The ability of the compound to control the stimulating action of 30 rng /Kg. ephedrine sulfate injected subcutaneously is recorded on a kymographic record. c SMES-Supramaximal Electroshock Test : The ability of the compound to abolish the hind limb extensor reflex produced by a current of 150 ma delivered for 0.3 second to the 1- rain via the optic pathway is recorded. d RSCM-Rat Subcutaneous MetrazolB Test: The ability
of the compound to block completely the convulsions produced hy Metrazolm injected subcutaneously at a level of 70 mg./Kg. is noted. C Rating System: In all the tests, 0 t o indicates essentially no detectable activity of the compound to produce the desired effect. A rating of 2+ t o 3+ indicates fair to good activity. A 4 f rating indicates complete control or desired effect and from an activity standpoint is the maximum attainable rating.
condensing acetaldehyde, under reducing conditions, with cyanoacetamide. The process used is a modification of one published by Alexander and Cope (15) for the preparation of ethyl-aethylcyanoacetate. The optimum ratio of reactants was found to be one mole of cyanoacetamide to two moles of acetaldehyde. The dialkylcyanoacetamides were prepared from this cnmpound by known procedures. The corresponding dialkylmalondiamides were prepared from the dialkylcyanoacetamides by treatment with cold concentrated sulfuric acid. The malondiamides were screened for anticonvulsant activity by Dr. Raymond W. Cunningham of Lederle Laboratories, to whom the authors are indebted for the pharmacological data reported here (Table I). None of the compounds had a sedative effect when the maximum tolerated oral dose was administered. When both alkyl groups were ethyl the resulting compound was inactive to weakly active. Changing one group to normal propyl abolished any antiMetrazolg activity. The introduction of a normal butyl group in place of an ethyl group gave a compound that possessed fair activity against both Metrazol@ and electroshock; on the other hand, an isobutyl group gave a completely inactive compound. Increasing one alkyl group to normal amyl resulted in a derivative with complete control of electroshock, with no activity against Metrazol@. Again, changing the normal alkyl group to a branched chain led to a completely inactive compound. Goodman, et al., (16) in a study of the anticonvulsant properties of Mysoline@reported that phenylethylmalondiamide was isolated from the urine of the test animals. The possibility that this was the active
antiepileptic substance, to which Mysoline@ is converted, was investigated. They concluded that such was unlikely because they found phenylethylrnalondiamide to be less potent and more toxic than Mysoline@,itself.
+
EXPERIMENTAL' Cyanoacetamide.-This compound was prepared from ethylcyanoacetate (Matheson) and concentrated ammonia water in the manner set forth in "Organic Syntheses" (17). Ethy1cyanoacetamide.-Cyanoacetamide (37.8 Gm.) was dissolved in water (285cc.) and chilled to about 4" in a 500-cc. Pyrex bottle to be used later for the hydrogenation. Ten per cent palladium on charcoal catalyst (0.9 Gm.) (The American Platinum Works) was added and mixed by shaking, followed by previously chilled fresh acetaldehyde (40.5 Gm.) (Eastman). Without delay, the piperidine solution (1.5 cc. of 10% piperidine in glacial acetic acid) was added and hydrogenation begun at once at a pressure of one to two atmospheres, using a Parr low pressure hydrogenation apparatus. When the reaction was complete (eight to twelve hours) the catalyst was removed by filtration. If crystals were present prior to filtration the mixture was warmed slightly. The filtrate was chilled in a n ice bath or refrigerator to yield flake-like crystals. The yield was 36 to 46% with a melting point of 111-112'. Further amounts of impure ethylcyanoacetamide could be obtained by concentrating the mother liquor and chilling. When recrystallized from hot water it melted at 113-114". Literature reports give 112-113" (18) and 113' (19). A mixture of ethylcyanoacetamide prepared by the standard alkylation process and this compound melted at 112.5-113". Table I1 includes the disubstituted cyanoacetamidesall of which were prepared from ethylcyanoacetamide using a method similar, except for the order of the introduction of the alkyl substituents, to that reported by Doerge and Wilson (18). 1
All melting points are uncorrected.
82
JOURNAL OF THE
AMERICANPHARMACEUTICAL ASSOCIATIOK
vn1.
xT,TV, h'n. 2
TABLE II.---ANALYTICAL DATAON COMPOUNDSSTUDIED^ Compound
Formula
Carbon % Calcd. Found
R(CzHJC(CN)C(O) NHI R = CzHs R = n-C3H7 CSHI~ONZ 62.31 R = i-C:gH, CsHirONz R = n-CdHgh CsHi60Nz 64.26 R = i-C.tH9 CgHlsONz 64.26 R = n-CsHilh CioH~soNz 65.88 R = Z-Cr,Hii CioHi80Nz R = CH3CHzCHzCH(CH3)' CioHisONz 65.88 R(C~H~)C[C(O)NH~]C(O)NHI R = CzHb C~HMOINZ 53.14 R = n-C3H.lb CsH1602Nz 55.80 R = n-CdHgb CgHi802Nz 58.02 R = Z-CqHgb CgHi80zNI 58.02 R = n-C6Hiib CioHzoOzNz 59.95 R = i-CsHiib CioHzoOzNz 59.95
Hydrogen % Calcd. Found
not analyzed 62.67 9.15 not analyzed 64.57 9.59 64.29 9.59 66.07 9.96 not analyzed 66.48 9.96
Yield
yo
63.0 9.19 88.2 62 3 9.57 68.4 9.41 46.3 9.84 44.0 77.9u 9.98 6.6
53.05 8.92 9.03 55.77 9.37 9.23 58.18 9.74 9.65 58.05 9.74 9.48 60.01 10.06 9.84 60.38 10.06 10.01
quant. quant. 77.2 61.5 91.0 84.0
M. p.. "C.
121.5-122' 113.5-114.5" lll-112e 105-105.5 103.5--104 '5 77-77.5 100- 101h 113.5-114.5 218-219'7j 195-196 182-183 211-212 176-177 191-192
a Carbon and hydrogen analyses by Micro-Tech Laboratories, Skokie. 111 b Submitted as new compound c Doerge and Wilson (18) report 120-12lo d Conrad and Zart (20) report 116'. e Doerge and Wilson (18) report 111-112 5 O
I Diierge and Wilson (18) report 127..5-128.5°. Q Initial crude yield. h Pure compound, Doerge and Wilson (18) i Conrad and Zart (20) report 2 2 0 ° . I Fischer report 88-89O and Dilthey (21) report 224' (Corr.)
Ethylisobuty1cyanoacetamide.-This compound melted at 103.5-104.5". Anal.-Calcd. for CeHieNzO: C, 64.26;H,9.59. Found: C, 64.29; H,9.41. Doerge and Wilson (18)reported a melting point of 127.5"and an analysis of C, 67.36;H,10.22. General Method for Conversion of Cyanoacetamides t o Malondiamides.-Sufficient cold, concentrated sulfuric acid was added t o the corresponding cyanoacetamide in a beaker t o form a clear solution. The mixture was then set aside at room temperature for several days, after which time it was poured with stirring over chipped ice. The crystalline material was collected, washed with cold, distilled water, and recrystallized from hot water. Attempted Synthesis of Ethylisopropylmalondiamide.-The starting material was recovered unchanged. A repetition of the experiment gave similar results. No further attempts were made to prepare this compound. Attempted Synthesis of Ethyl-( 1-methylbuty1)malondiamide.-The starting material was recovered when the reaction was run at room temperature, a t 40°,and at 80". No further attempts were made to synthesize this compound. Table I1 presents the analytical data on the compounds reported. Both chemical and pharmacological investigation is being continued on these structures.
3. Five new dialkylmalondiamides were prepared. 4. The attempted synthesis of ethylisopropylmalondiamide and ethyl-( 1-methylbutv1)malondiamide from the corresponding cyanoacetamides are reported. 5. Some of t h e malondiamides showed anticonvulsant activity when tested on male albino rats.
SUMMARY 1. A procedure for the synthesis of monoethylcyanoacetamide, by t h e condensation of acetaldehyde with cyanoacetamide under reducing conditions, has been presented. 2. Three new dialkylcyanoacetamides were prepared.
REFERENCES (1) Putnam, T. J., and Merritt, H. El., Arch. Nefkrol. Psychiaf.,39, 1003(1938). (2) Richards, R. K.. and Perlstein, M. A,, ibid., 55. 164 (1946). (3) Davis, J. P., and Lennox, W. G., Research Publ. Assoc. Research Nervous Menfal Disease, 26, 423( 1947). , l n l(4) ? \ Zimmerman, F. T., Arch. NeuroL. Psychiaf., 66, 156 ,la*l,.
(5) Stamps, F. W.>el al., J . Pharmacol. E x p f l . Therap.,
In6 4 1 x ~ l a__,. .53~ __", ___\_"
(6) Kaufman, I. C., and Iseuberg, S., M e d . Clin. A'. Amer. 36 1381(1952). (7)' Pekstein, M. A., and Mizell. I., Quarf. Bull. Norfhwrsfern Uniu. M c d . School, 27, 59(1952). (8) Lennox, W. G., J. A m . , M c d . Assoc., 129, 1068(1915). (9) Lennox. W. G., J . Pedrot., 29, 356(1946). (10) Tyler, M. W., and King, E. Q.. J. Am. Med. Asroc.,
- -.(11) , - .,- - ,. Fetterman lA'7
17/1051> -1
J. L. ibid., 114, 396(1940). (12) Berner. - . F.'M., Proc. Soc. Exall. B i d . M e d . , 71, 270 (1949). 113) Frankel. S . "Arzneimittel Svnthese." 6th ed... Tulius _ Spkinger, Berlin. 1927, p. 522. (14) Maynert, E.. and Van Dyke, H. B.,J. Pharmacol. E x p f l . Therap., 98, 174(1950). (15) Alexander, E. R., and Cope, A. C., J. A m . Chem. Soc., 66 887(1944). il6) Goodman, L. S . , ef al., J . Pharmacol ExgLl Therap , 108 433(1953). (i7) Gilman. H., and Blatt, A. H (Editors), "Organic Syntheses Coll. Vol. 1 2nd ed., John Wiley and Sons, Inc , New Y o r i , 1941, p. 1731 (18) Doerge, R. F., and Wilson, C. 0 ,THISJOURNAL, 40. 4- -n. m ,.-9.51) - .,. (19) Hessler J. C., A m . Chem J . 22 169(1899). (20) Conrad' M. and Zart A. A h i40 3 W i 9 0 5 ) (21) Fischer: E ,'and Dilth'ey. k , H;r , 35, 844(1!102).
A study of the literature shows that many of the drugs in present-day use have an undesirable agement of epilepsy. The first effective medici- sedative action, while there are others which nal agents to be used were the inorganic bro- possess little or no sedative action but do cause mides, which were introduced in England about other undesirable side effects, such as skin 185T. The introduction of phenobarbital in 1912 rashes, photophobia, exaggeration of personality soon led to the replacement of the bromides; in defects, liver damage, and agranulocytosis (Gfact, phenobarbital is still considered to be a 11). This would indicate that there remains a very valuable drug, while the bromides are need for better anticonvulsants and that further rarely, if ever, used in the control of epilepsy. investigation of possible anticonvulsants should Research in the field of anticonvulsants led to be camed on. Many of the synthetic organic compounds prethe testing of certain hydantoins by Putnam and Merritt (1). From their work came DilantinB viously mentioned as anticonvulsants possess in common. However, which still remains as one of the best agents for the group 4 0 - N R grand ma1 epilepsy. Another hydantoin which this structural unit is not essential for anticonhas gained some popularity is Mesantoina (3- vulsant activity. Evidence of this is shown by Putnam and Merritt (l), who found activity in methyl-5,5-phenylethylhydantoin). Drugs which are more specific for the control certain aldehydes and ketones, and also by Berger of petit ma1 epilepsy also have been introduced. (la), working with 2,2-substituted-l,3-propaneTridioneB (3,5,5-trimethyloxazolidine-2,4-dione)diols. With the exception of HibiconB and was introduced in 1945 (2), and Paradionea (3- PhenuroneB, all of the previously mentioned methyl-5,5-methylethyloxazolidine-2,4-dione) in anticonvulsants have a tertiary or quaternary 1947 (3). More recently Milontin@(N-methyl- carbon atom. The structural relationships of a-phenylsuccinimide) has been clinically evalu- the a-,a-dialkylmalondiamides to the effective anticonvulsants, and the fact that the diethyl-, ated (4) and is now commercially available. Other drugs which are now commercially avail- dipropyl- (13’1,and ethyl-( 1-methy1)butylmalonable include: Mebaralm (N-methyl-5,5-phenyl- diamide (14) have no hypnotic activity, indicated ethylbarbituric acid), Gemonil (N-methyL53- that this series was worthy of further investigadiethylbarbituric acid), Mysoline@ (5,5-phenyl- tion as anticonvulsants. Accordingly, a series of ethylhexahydropyrimidine-4,6-dione), Phenur- substituted malondiamides of the following strucone@ (phenylacetylurea), Hibicon@(N-benzyl-P- ture was prepared in order to test their pharmacochloropropionamidex). Clinical investigation of logical activity: Themisonem (a-methylmandelamide) has been 0 reported (5). II R‘ C-NH,
use of anticonvulsant I drugs is the theprimeproper consideration in the manN THE MAIN,
\ /
*
Received August 6,1954. from the College of Pharmacy, University of Texas. Austin. Abstracted from a thesis presented to the Faculty of the Graduate School of the University of Texas by Herbert F. Schwartz in partial fulfillment for the degree of Master of Science in Pharmacy. Special Instructor in Pharmaceutical Chemistry. College of Pharmacy. University of Texas, Austin. t Present Address: Research and Development Division, Smith, Kline and French Laboratories, Philadelphia, Pa.
C
80
Fehruary, 1955
SCIENTIFIC EDITION
81
TABLEPHARMACOLOGICAL DATAON MALONDIAMIDES STUDIES" 0
II
C-NHI
R'
\ / C R/
'C-NHz
II
0 Compound Number
2661 L 2657 L 2653 L 2662 L 2656 L 2664 L
R'
CzHs CZH5
CZH5 CJL CzHb GH5
R*
Maximum Tolerated Oral Dose.. me./Ke. -.
CzHs n-CsH7 n-CrHs
I
> 1000 200
i-C,Hg
200 400
~-C~HII Z'-C5H11
250
> 1000
SEDb
0'
0 0 0 0 0
Test Results SMES C
++ 2+
RSCMd
+
0
2+
0 4+
0 0 0
0
The male albino rat, dosed orally, was used in all the tests. b SED-Sedative: The ability of the compound to control the stimulating action of 30 rng /Kg. ephedrine sulfate injected subcutaneously is recorded on a kymographic record. c SMES-Supramaximal Electroshock Test : The ability of the compound to abolish the hind limb extensor reflex produced by a current of 150 ma delivered for 0.3 second to the 1- rain via the optic pathway is recorded. d RSCM-Rat Subcutaneous MetrazolB Test: The ability
of the compound to block completely the convulsions produced hy Metrazolm injected subcutaneously at a level of 70 mg./Kg. is noted. C Rating System: In all the tests, 0 t o indicates essentially no detectable activity of the compound to produce the desired effect. A rating of 2+ t o 3+ indicates fair to good activity. A 4 f rating indicates complete control or desired effect and from an activity standpoint is the maximum attainable rating.
condensing acetaldehyde, under reducing conditions, with cyanoacetamide. The process used is a modification of one published by Alexander and Cope (15) for the preparation of ethyl-aethylcyanoacetate. The optimum ratio of reactants was found to be one mole of cyanoacetamide to two moles of acetaldehyde. The dialkylcyanoacetamides were prepared from this cnmpound by known procedures. The corresponding dialkylmalondiamides were prepared from the dialkylcyanoacetamides by treatment with cold concentrated sulfuric acid. The malondiamides were screened for anticonvulsant activity by Dr. Raymond W. Cunningham of Lederle Laboratories, to whom the authors are indebted for the pharmacological data reported here (Table I). None of the compounds had a sedative effect when the maximum tolerated oral dose was administered. When both alkyl groups were ethyl the resulting compound was inactive to weakly active. Changing one group to normal propyl abolished any antiMetrazolg activity. The introduction of a normal butyl group in place of an ethyl group gave a compound that possessed fair activity against both Metrazol@ and electroshock; on the other hand, an isobutyl group gave a completely inactive compound. Increasing one alkyl group to normal amyl resulted in a derivative with complete control of electroshock, with no activity against Metrazol@. Again, changing the normal alkyl group to a branched chain led to a completely inactive compound. Goodman, et al., (16) in a study of the anticonvulsant properties of Mysoline@reported that phenylethylmalondiamide was isolated from the urine of the test animals. The possibility that this was the active
antiepileptic substance, to which Mysoline@ is converted, was investigated. They concluded that such was unlikely because they found phenylethylrnalondiamide to be less potent and more toxic than Mysoline@,itself.
+
EXPERIMENTAL' Cyanoacetamide.-This compound was prepared from ethylcyanoacetate (Matheson) and concentrated ammonia water in the manner set forth in "Organic Syntheses" (17). Ethy1cyanoacetamide.-Cyanoacetamide (37.8 Gm.) was dissolved in water (285cc.) and chilled to about 4" in a 500-cc. Pyrex bottle to be used later for the hydrogenation. Ten per cent palladium on charcoal catalyst (0.9 Gm.) (The American Platinum Works) was added and mixed by shaking, followed by previously chilled fresh acetaldehyde (40.5 Gm.) (Eastman). Without delay, the piperidine solution (1.5 cc. of 10% piperidine in glacial acetic acid) was added and hydrogenation begun at once at a pressure of one to two atmospheres, using a Parr low pressure hydrogenation apparatus. When the reaction was complete (eight to twelve hours) the catalyst was removed by filtration. If crystals were present prior to filtration the mixture was warmed slightly. The filtrate was chilled in a n ice bath or refrigerator to yield flake-like crystals. The yield was 36 to 46% with a melting point of 111-112'. Further amounts of impure ethylcyanoacetamide could be obtained by concentrating the mother liquor and chilling. When recrystallized from hot water it melted at 113-114". Literature reports give 112-113" (18) and 113' (19). A mixture of ethylcyanoacetamide prepared by the standard alkylation process and this compound melted at 112.5-113". Table I1 includes the disubstituted cyanoacetamidesall of which were prepared from ethylcyanoacetamide using a method similar, except for the order of the introduction of the alkyl substituents, to that reported by Doerge and Wilson (18). 1
All melting points are uncorrected.
82
JOURNAL OF THE
AMERICANPHARMACEUTICAL ASSOCIATIOK
vn1.
xT,TV, h'n. 2
TABLE II.---ANALYTICAL DATAON COMPOUNDSSTUDIED^ Compound
Formula
Carbon % Calcd. Found
R(CzHJC(CN)C(O) NHI R = CzHs R = n-C3H7 CSHI~ONZ 62.31 R = i-C:gH, CsHirONz R = n-CdHgh CsHi60Nz 64.26 R = i-C.tH9 CgHlsONz 64.26 R = n-CsHilh CioH~soNz 65.88 R = Z-Cr,Hii CioHi80Nz R = CH3CHzCHzCH(CH3)' CioHisONz 65.88 R(C~H~)C[C(O)NH~]C(O)NHI R = CzHb C~HMOINZ 53.14 R = n-C3H.lb CsH1602Nz 55.80 R = n-CdHgb CgHi802Nz 58.02 R = Z-CqHgb CgHi80zNI 58.02 R = n-C6Hiib CioHzoOzNz 59.95 R = i-CsHiib CioHzoOzNz 59.95
Hydrogen % Calcd. Found
not analyzed 62.67 9.15 not analyzed 64.57 9.59 64.29 9.59 66.07 9.96 not analyzed 66.48 9.96
Yield
yo
63.0 9.19 88.2 62 3 9.57 68.4 9.41 46.3 9.84 44.0 77.9u 9.98 6.6
53.05 8.92 9.03 55.77 9.37 9.23 58.18 9.74 9.65 58.05 9.74 9.48 60.01 10.06 9.84 60.38 10.06 10.01
quant. quant. 77.2 61.5 91.0 84.0
M. p.. "C.
121.5-122' 113.5-114.5" lll-112e 105-105.5 103.5--104 '5 77-77.5 100- 101h 113.5-114.5 218-219'7j 195-196 182-183 211-212 176-177 191-192
a Carbon and hydrogen analyses by Micro-Tech Laboratories, Skokie. 111 b Submitted as new compound c Doerge and Wilson (18) report 120-12lo d Conrad and Zart (20) report 116'. e Doerge and Wilson (18) report 111-112 5 O
I Diierge and Wilson (18) report 127..5-128.5°. Q Initial crude yield. h Pure compound, Doerge and Wilson (18) i Conrad and Zart (20) report 2 2 0 ° . I Fischer report 88-89O and Dilthey (21) report 224' (Corr.)
Ethylisobuty1cyanoacetamide.-This compound melted at 103.5-104.5". Anal.-Calcd. for CeHieNzO: C, 64.26;H,9.59. Found: C, 64.29; H,9.41. Doerge and Wilson (18)reported a melting point of 127.5"and an analysis of C, 67.36;H,10.22. General Method for Conversion of Cyanoacetamides t o Malondiamides.-Sufficient cold, concentrated sulfuric acid was added t o the corresponding cyanoacetamide in a beaker t o form a clear solution. The mixture was then set aside at room temperature for several days, after which time it was poured with stirring over chipped ice. The crystalline material was collected, washed with cold, distilled water, and recrystallized from hot water. Attempted Synthesis of Ethylisopropylmalondiamide.-The starting material was recovered unchanged. A repetition of the experiment gave similar results. No further attempts were made to prepare this compound. Attempted Synthesis of Ethyl-( 1-methylbuty1)malondiamide.-The starting material was recovered when the reaction was run at room temperature, a t 40°,and at 80". No further attempts were made to synthesize this compound. Table I1 presents the analytical data on the compounds reported. Both chemical and pharmacological investigation is being continued on these structures.
3. Five new dialkylmalondiamides were prepared. 4. The attempted synthesis of ethylisopropylmalondiamide and ethyl-( 1-methylbutv1)malondiamide from the corresponding cyanoacetamides are reported. 5. Some of t h e malondiamides showed anticonvulsant activity when tested on male albino rats.
SUMMARY 1. A procedure for the synthesis of monoethylcyanoacetamide, by t h e condensation of acetaldehyde with cyanoacetamide under reducing conditions, has been presented. 2. Three new dialkylcyanoacetamides were prepared.
REFERENCES (1) Putnam, T. J., and Merritt, H. El., Arch. Nefkrol. Psychiaf.,39, 1003(1938). (2) Richards, R. K.. and Perlstein, M. A,, ibid., 55. 164 (1946). (3) Davis, J. P., and Lennox, W. G., Research Publ. Assoc. Research Nervous Menfal Disease, 26, 423( 1947). , l n l(4) ? \ Zimmerman, F. T., Arch. NeuroL. Psychiaf., 66, 156 ,la*l,.
(5) Stamps, F. W.>el al., J . Pharmacol. E x p f l . Therap.,
In6 4 1 x ~ l a__,. .53~ __", ___\_"
(6) Kaufman, I. C., and Iseuberg, S., M e d . Clin. A'. Amer. 36 1381(1952). (7)' Pekstein, M. A., and Mizell. I., Quarf. Bull. Norfhwrsfern Uniu. M c d . School, 27, 59(1952). (8) Lennox, W. G., J. A m . , M c d . Assoc., 129, 1068(1915). (9) Lennox. W. G., J . Pedrot., 29, 356(1946). (10) Tyler, M. W., and King, E. Q.. J. Am. Med. Asroc.,
- -.(11) , - .,- - ,. Fetterman lA'7
17/1051> -1
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