Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1982-01-11
1985-12-03
Daus, Donald G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514417, 548465, 548467, A61K 3140, C07D20948, C07D40312
Patent
active
045566739
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to taurine derivatives, their production, and their use in drugs. The compounds are phthalyltaurine sulfonamides with the chemical structure: ##STR3## where
R.sub.1 =H,
R.sub.2 =a lower alkyl group with up to 4 carbonatoms or an acetyl group, ##STR4##
The new compounds synthesized by us are:
In addition, we have synthesized the following compounds previously described in the literature: 2-phthalimidoethane sulfonamide, 2-phthalimidoethanesulfone dimethylamide, 2-phthalimidoethanesulfone tertbutylamide and 2-phthalimidoethane sulfonylacetamide, which were found in pharmacological studies to have the same good drug qualities as the present new compounds.
Taurine, 2-aminoethanesulfonic acid, occurs in rich amounts in human tissues. Particularly high concentrations are found in the spleen, muscles, and brain (Jacobsen J. C. & Smith L. J., Jr Physiol. Rev 48, 424-511, 1968). There is good reason to believe that taurine acts as an inhibitory neurotransmitter in the central nervous system. The role of taurine is not yet definitely clarified. Decreased taurine concentrations have been observed in some cases of epilesy. Taurine has been found to have a direct central anticonvulsive effect in several types of experimental epilepsy. A Barbeau & Donaldson (Arch. Neurol. 30, 50-58, 1974) and R. Takahaski & Y. Nakane (Taurine and Neurological Disorders, 375-385, 1978) have demonstrated an antiepileptic action of taurine in the treatment of epileptic patients.
As taurine is an extremely hydrophilic compound, it seems unlikely that administered external taurine could penetrate into the brain in large enough amounts to produce a direct anticonvulsive effect in epileptic patients with intact bloodbrain barrier. Thus, to reach the brain in sufficient quantities, taurine must be given intracerebrally.
The present taurine derivatives are considerably more lipophilic than taurine, but they still have the same anticonvulsive properties. The synthesized compounds have been shown in pharmacological tests to have a good anticonvulsive effect. Theoretically, thus, it appears that they could be of value in antiepileptic therapy. The compounds have also been found antiarrhythmically active.
The pharmacological actions of taurine derivatives are only sparingly described i the literature. J. F. Mead & J. B. Koepfli (J. Org. Chem. 12, 295-297, 1947) have synthesized pantoyl taurinamide and 2-phthalimido-N-bimethylathane sulfonamide and studied their effect in malaria. R. Winterbottom et al. (J.A.C.S. 69, 1393-1401, 1947) synthesized 2-phthalimidoethane sulfonamide and 2-phthalimidoethanesulfone dimethylamide and studied their antibacterial properties, which did not come up to expectations.
J. W. Griffin & D. H. Hey (J. Chem.Soc. 3334-3340, 1952) describe the synthesis of 2-phthalimidoethanesulfonyl acetamide.
Of more recent publications the following could be mentioned: The European patent application no. 0 002 675 (P. H. Chakrabarti, GAF Corporation, 1979) relates to the production of salt-free N-acyl taurines used as surface-active agents. The French patent publication no. 2412523 (P. Reynard, 1979) relates to injectable forms of N-acetyl taurine, which in pharmacological tests were found to penetrate the bloodbrain barrier.
Gamma-L-glutamyl taurine, whose effect resembles that of vitamin A, has been tested by L. Feuer (Comp. Biochem. Physiol. 62 A, 995-997, 1979) among others. Liisa Ahtee et al. (Proc. B.P.S., Brit. J. Pharmacol. 480P, 1979) have studied the effect of various taurine derivatives on the central nervous system of mice after intraperitoneal administration. They found that N-pivaloyl taurine penetrated the blood-brain barrier.
The present invention is characterized by that the new compounds with the above-described pharmacological properties are synthesized
(A) by conversion of phthalimidoethane sulfonylchloride with a primary amine through the following reaction: ##STR5## where R is a methyl-, ethyl-, n-propyl-, isopropyl- or n-butylgroup
(B) by conversion of phthalimidoethane sulfonylchlori
REFERENCES:
patent: 2184279 (1939-12-01), Christiansen
patent: 4066762 (1978-01-01), Dunn
Chem. Abstracts Subject Index 1967-71, pp. 30082S-30083S.
Greene, Theodora, Protective Groups in Organic Synthesis, John Wiley, New York (1981) pp. 265-267.
Naito, Shunichi; "Aminoethanesulfonyl Derivatives," Chem. Abst. 76: 140209u (1972).
J. F. Mead et al., J. Organic Chemistry 12, (1947) 295.
D. A. Berges et al., J. Heterocyclic Chemistry, 15, (1978), 981.
Andersen Lars H.
Hilden Leif A.
Daus Donald G.
Hendricks G. M.
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