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Synthesis and Pharmacological Activities of Some N-(2,2,3-Trichloro-1-hydroxypropyl)-amides
Synthesis and Pharmacological Activities of Some N-(2,2,3-TrichloroI-hy droxypropyl) -amides By JOSEPH P. LaROCCA
T h e amides of 2,2,3-trichloropropionaldehydewere synthesized and their physical and chemical constants determined. These compounds showed significant antibeing the most convulsant activity, N - (2,2,3-trichloro-l-hydroxypropyl)-acetamide active. tive (approx. 300 mg./Kg./day), for a period o f thirty days showed no apparent ill effects. Sedative-Hypnotic Activity.--With these compounds, doses of 100 mg./Kg. intraperitoneally in rats do not produce hypnosis. As the dosage levels et al. (3), with slight modification, was em- approach 200 mg./Kg., the animals are very deployed t o prepare a series of N-(2,2,3-trichIoro-l- pressed and most are prostrate. The hypnotic activity shown by doses of 200 mg./Kg. is approxihydroxypropyl) -amides. Nine of these commately that demonstrated by pentobarbital sodium pounds have been prepared (Table I). In addi- in doses of 20 mg./Kg. tion, N-(2,2,3-trichloro-l-hydroxypropyl)-2-pyr- Anticonvulsant Activity.-N-( 2,2,3-Trichloro-l-hyrolidone was prepared b y t h e same method droxypropy1)-acetamide, in oral doses of 300 mg./ (m.p. 129"; yield 85.5 per cent. Analysis for Kg., protects rats and mice for a period of seven hours against hourly doses of 20 mg./Kg. of metrazol nitrogen2-Calcd, : 5.68. Found: 5.69, 5.72). given i. v. It is interesting to note that diphenylThese compounds were screened for pharma- hydantoin will protect mice against metrazol convulsions, but not rats. cological activity. Conditioned Response.-When compared with TABLE I.-N-(2,2,3-TRICHLORO-1-HYDROXYPROPYL)- reserpine for effect on conditioned response, by a standard testing procedure, these compounds were AMIDES (KCONHCH( 0H)CClzCHzCl) found to be inactive. 5 .P., -Nitrogenb-Analgesic Activity.-None of these compounds exAmide Yield C.a Calcd. Found hibited any analgesic activity. 6.30 82.8 168 6.38 Acetaniide
in this laboratory has shown the potentialities of chlorinated amides as sedative-hypnotics and anticonvulsants (1, 2 ) . The method of synthesis described by LaRocca, REVIOUS WORK
6.38
EXPERIMENTAL
Chloroacetamidc
Materials.-2,2,3-Trichloropropionaldehyde, furnished by the Union Carbide Chemicals Co. Synthesis.-Equiniolar portions of 2,2,3-trichloropropionaldehyde and the appropriate amide were mixed and stirred. In most cases the reaction mixture solidified readily without the necessity of heating. If solidification did not occur within thirty minutes, the reaction was then heated on a steam bath for from three t o four hours. Isolation and purification of the product was accomplished in the manner previously described (3). All the compounds are white crystalline solids, insoluble in water, but soluble in alcohol and acetone.
n-But yramide iso-Butyramide
77.0
136
5.63
n-Valerdmide
91.6
124
5.33
iso-Valeramide
81.0
108
5.33
Benzamide
87.9
135
4.96
Phenylacetamide
93.9
124
4.72
Nicotinamide
90.8
155
9.88
5.60 5.61 5.17 5.20 5.67 5.80 4.61 4.64 4.31 4.44 9.62 9.68
a All melting points on calibrated Fisher-Johns apparatus. b Microanlyses by Spang Microanalytical Laboratory, Ann Arbor, Mich.
RESULTS OF PRELIMINARY TESTING Toxicity.-Preliminary tests indicated that all of the compounds are relatively nontoxic. The approximate LDSOi. v. for mice is 100 mg./Kg. Mice fed a diet containing 0.5y0 of the acetamide derivaReceived August 16, 1960 from t h e Pharmaceutical Rksearch Laboratories, t h e University of Georgia, School of Pharmacy, Athens. Accepted for publication October 12, 19fiO. Pharmacological results are made possible through the courtesy of Jack Keith, Research Pharmacologist, S. E. Massengill Co. Presented to T h e Scientific Section, A. PH. A., Washington, D. C., meeting, August, 1960. All melting points on calibrated Fisher-Johns apparatus. 2 Microanalyses by Spang Microanal3 tical Laboratory, Ann Arbor, Mich.
SUMMARY
1. Ten new derivatives of 2,2,3-trichloropropionaldehyde have been synthesized and characterized. 2. Pharmacological d a t a shows these compounds have significant antiepileptic activity. Of this series, N-(2,2,3-trichloro-l-hydroxypropy1)-acetamide is currently undergoing clinical evaluation for possible antiepileptic use REFERENCES (1) Byrum, W. R., and LaRocca, J . P., THISJOURNAL, 41, lOO(1952). (2) LaRocca, J. P., and Byrum, W R.,ibid., 43, 63(1954). (3) LaRocca, J. P.. Leonard, J. M., and Weaver. W. E.. J. Org. C h e m , 16, 47(1951f.
448
T h e amides of 2,2,3-trichloropropionaldehydewere synthesized and their physical and chemical constants determined. These compounds showed significant antibeing the most convulsant activity, N - (2,2,3-trichloro-l-hydroxypropyl)-acetamide active. tive (approx. 300 mg./Kg./day), for a period o f thirty days showed no apparent ill effects. Sedative-Hypnotic Activity.--With these compounds, doses of 100 mg./Kg. intraperitoneally in rats do not produce hypnosis. As the dosage levels et al. (3), with slight modification, was em- approach 200 mg./Kg., the animals are very deployed t o prepare a series of N-(2,2,3-trichIoro-l- pressed and most are prostrate. The hypnotic activity shown by doses of 200 mg./Kg. is approxihydroxypropyl) -amides. Nine of these commately that demonstrated by pentobarbital sodium pounds have been prepared (Table I). In addi- in doses of 20 mg./Kg. tion, N-(2,2,3-trichloro-l-hydroxypropyl)-2-pyr- Anticonvulsant Activity.-N-( 2,2,3-Trichloro-l-hyrolidone was prepared b y t h e same method droxypropy1)-acetamide, in oral doses of 300 mg./ (m.p. 129"; yield 85.5 per cent. Analysis for Kg., protects rats and mice for a period of seven hours against hourly doses of 20 mg./Kg. of metrazol nitrogen2-Calcd, : 5.68. Found: 5.69, 5.72). given i. v. It is interesting to note that diphenylThese compounds were screened for pharma- hydantoin will protect mice against metrazol convulsions, but not rats. cological activity. Conditioned Response.-When compared with TABLE I.-N-(2,2,3-TRICHLORO-1-HYDROXYPROPYL)- reserpine for effect on conditioned response, by a standard testing procedure, these compounds were AMIDES (KCONHCH( 0H)CClzCHzCl) found to be inactive. 5 .P., -Nitrogenb-Analgesic Activity.-None of these compounds exAmide Yield C.a Calcd. Found hibited any analgesic activity. 6.30 82.8 168 6.38 Acetaniide
in this laboratory has shown the potentialities of chlorinated amides as sedative-hypnotics and anticonvulsants (1, 2 ) . The method of synthesis described by LaRocca, REVIOUS WORK
6.38
EXPERIMENTAL
Chloroacetamidc
Materials.-2,2,3-Trichloropropionaldehyde, furnished by the Union Carbide Chemicals Co. Synthesis.-Equiniolar portions of 2,2,3-trichloropropionaldehyde and the appropriate amide were mixed and stirred. In most cases the reaction mixture solidified readily without the necessity of heating. If solidification did not occur within thirty minutes, the reaction was then heated on a steam bath for from three t o four hours. Isolation and purification of the product was accomplished in the manner previously described (3). All the compounds are white crystalline solids, insoluble in water, but soluble in alcohol and acetone.
n-But yramide iso-Butyramide
77.0
136
5.63
n-Valerdmide
91.6
124
5.33
iso-Valeramide
81.0
108
5.33
Benzamide
87.9
135
4.96
Phenylacetamide
93.9
124
4.72
Nicotinamide
90.8
155
9.88
5.60 5.61 5.17 5.20 5.67 5.80 4.61 4.64 4.31 4.44 9.62 9.68
a All melting points on calibrated Fisher-Johns apparatus. b Microanlyses by Spang Microanalytical Laboratory, Ann Arbor, Mich.
RESULTS OF PRELIMINARY TESTING Toxicity.-Preliminary tests indicated that all of the compounds are relatively nontoxic. The approximate LDSOi. v. for mice is 100 mg./Kg. Mice fed a diet containing 0.5y0 of the acetamide derivaReceived August 16, 1960 from t h e Pharmaceutical Rksearch Laboratories, t h e University of Georgia, School of Pharmacy, Athens. Accepted for publication October 12, 19fiO. Pharmacological results are made possible through the courtesy of Jack Keith, Research Pharmacologist, S. E. Massengill Co. Presented to T h e Scientific Section, A. PH. A., Washington, D. C., meeting, August, 1960. All melting points on calibrated Fisher-Johns apparatus. 2 Microanalyses by Spang Microanal3 tical Laboratory, Ann Arbor, Mich.
SUMMARY
1. Ten new derivatives of 2,2,3-trichloropropionaldehyde have been synthesized and characterized. 2. Pharmacological d a t a shows these compounds have significant antiepileptic activity. Of this series, N-(2,2,3-trichloro-l-hydroxypropy1)-acetamide is currently undergoing clinical evaluation for possible antiepileptic use REFERENCES (1) Byrum, W. R., and LaRocca, J . P., THISJOURNAL, 41, lOO(1952). (2) LaRocca, J. P., and Byrum, W R.,ibid., 43, 63(1954). (3) LaRocca, J. P.. Leonard, J. M., and Weaver. W. E.. J. Org. C h e m , 16, 47(1951f.
448