Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1999-01-21
2000-02-22
Ford, John M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514212, 544 8, 540598, C07D28516, A61K 3154
Patent
active
060280689
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to novel 6H-1,3,4-thiadiazin-2-amine derivatives, to the use of them in medicine and veterinary as anaesthetics, cardiovascular and hypometabolic agents and to the pharmaceutical compositions containing them.
BACKGROUND OF THE INVENTION
Anaesthesia may generally be described as a state in which noxious events such as surgical procedures are rendered imperceptible by the body, the state being accompanied either by loss of consciousness (general anaesthesia) or no loss of consciousness (local anaesthesia). A complete or general anaesthetic given by inhalation or intravenous route produces a state of profound sleep and loss of motor activity (hypnosis), analgesia, muscle relaxation and protection against the increase in blood pressure and heart rate resulting from surgical stress. Anaesthetics generally display hypometabolic activity and frequently act as respiratory or cardiovascular depressants. Certain anaesthetics can be used to produce deliberate hypotensive effects which are very valuable in intracranial and other surgical procedures. Although a large number of agents having anaesthetic and cardiovascular activity have been identified and/or commercialised, there is a continuing need for new materials having hypometabolic activity, which are valuable for inducing sleep, reduction in motor activity, hypotension, bradycardiac, hypocoagulative, anti-aggregant and other hypobiosis effects such as reduced oxygen consumption and reduced body temperature, which would be valuable for use in complex surgical procedures or in the treatment of life threatening and/or traumatic situations such as brain stroke and myocardial infarction, and which have excellent potency, duration and CNS and cardiovascular toxicity profiles with absence of side effects such as tremor, convulsions and irregular breathing and heart beat.
There is considerable body of data concerning 6-R-1,3,4-thiadiazin-2-amines (for reviews see [1-3]). Also patent literature provides data on myo-relaxant [4-7], sedative [8,9], spasmolytic [10-12] and other types of biological activity [3]. A number of 5-aryl derivatives of 1,3,4-thiadiazines have been specifically described in the art [14-20] as well as 6-alkyl and 6-phenyl analogs thereof [13 and 21]. The value of 6-R-1,3,4-thiadiazin-2-amines as hypometabolic anaesthetic and cardiovascular agents has not hitherto been recognised however. Moreover, many of these compounds are apparently novel and have not been previously described in the literature.
The prior art on 6-R-1,3,4-thiadiazin-2-amines includes: Geterotsikl. Soedin., No 4, 435, (1991). Soedin., No 11, 1443, (1991) 30(2), 162-5 (1990).
SUMMARY OF THE INVENTION
According to one aspect of the invention, there is provided the use of substituted 6H-1,3,4-thiadiazin-2-amines of the following general formula as anaesthetic, cardiovascular and hypometabolic agents: ##STR3## wherein ##STR4## represents a morpholino, thiomorpholino, piperdino, pyrrolidino, or hexamethylenimino moiety; or pharmaceutically acceptable salts of said compounds.
According to a further aspect of the invention, there is provided novel substituted 6H-1,3,4-thiadiazin-2-amines of the general formula set out above.
According to a still further aspect of the invention, there is provided a pharmaceutical composition comprusing one or more of substituted 6H-1,3,4-thiadiazin-2-amines described above or pharmaceutically acceptable salts thereof.
DISCLOSURE OF THE INVENTION
1,3,4-Thiadiazines suitable for use herein are substituted at the 5 position of the thiadiazine ring with an ethoxalyl oxime moiety, they are presented by compounds in free form or by pharmaceutically-acceptable salts thereof. In addition, compounds are substituted at the 2 position of the thiadiazine ring with a cycloalkylimine moiety preferably selected from morpholino, thiomorpholino, piperidino and hexamethylenimino moieties.
The invention also relates to a process for the preparation of the 1,3,4-thiadiazines described above in which an ester (preferably ethyl
REFERENCES:
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Committee of the Russian Federation on Patents and Trade Marks Translation of RU 94007001 dated Dec. 20, 1995.
Osipova, N. A. "Evaluation of the Effect of Narcotic, Analgetic and Psychotropic Agents in Clinical Anesthesiology." The Meditsina Publishers, Leningrad (1988) Chapter 2, pp. 14-16 (English Translation of "Otsenka Effekta Narkoticheskikh, Analgeticheskikh I psikhotropnykh sredsto v klinicheskoi Anesteziologii." 1988, Meditsina, Leningrad, pp. 18-19).
Textbook of Anesthesiology, The Meditsina Publishers (1994) pp. 10-13 (English Translation of "Rukovodstvo po anesteziologii" pod redaktsiei Bunyatina A.A. (1994) Meditsina (Moscow) pp. 80-81).
"Side Effects of Drugs" Meditsina Publishers, Moscow (1983) pp. 1-6 (English Translation of "Pobochnye Deistvya Lekarstvennykh Sredstv" pod redaktsiei Djuska M.N.G. (1983) Meditsina, Moscow pp. 89-93).
The State Patent Office of the USSR (Gospatent of the USSR) English Translation of the Specification of SU 1827257 dated Jul. 15, 1993.
Usoltseva S.V., et al. "1,3,4-Thiadiazines: Method of Synthesis and Reactivity." Khim. Geterotsikl. Soedin No. 4 (1991) pp. 435-448 And English comments thereon.
Novikova A.P., et al. "Synthesis and Properties of Functional Derivatives of 1,3,4. Thiadiazines . . . " Khim. Geterotsikl. Soedin No.: 11 (1991) pp. 1443-1457 And English comments thereon.
Rasina L.N., et al. "On Some Mechanisms of Action of Radioprotectors of Various Chemical Classes In Intestinal Syndrome" Radiobiologiya, 30(2) (1990) pp. 162-165 And English comments thereon.
Belik A.V. et al., "Prediction of A Class of Strong Toxicity of 1,3,4-Thiadiazine Derivatives" Khim-Farm. Zh., 26(3), (1992) pp. 62-64 And English comments thereon.
Perova N.M. et al., "Transformation of 2-Cycloalkylimino-6H-1-3-4-Thiadiazines under UV Irradiation" Khim. Geterotsikl. Soedin., No. 4, (1993) pp. 565-600 And English comments thereon.
Frasier et al. CA accession No. 1994:270462, 1994.
Chupakhin Oleg Nikolaevich
Novikova Antonina Petrovna
Perova Natalya Mikhailovna
Sidorova Larisa Petrovna
Tarakhty Emma Afanasievna
Ford John M.
Nauchno-Tekhnologicheskoe Predpriyatie "Ligand"(Tovarischestvo S
The Procter & Gamble & Company
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