Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-12-08
2001-11-06
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S217050, C514S236200, C544S008000
Reexamination Certificate
active
06313111
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel 6H-1,3,4-thiadiazine-2-amines, to their use in medicine or veterniary as anaesthetic, cardiovascular and hypometablic agents and to pharmaceutical compositions containing them.
BACKGROUND OF THE INVENTION
Anaesthesia can 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 anesthetics 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 hypomethabolic 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 used 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, consulvions and irregular breathing and heart beat.
There is considerable body of data concering 6-R-1,3,4-thiadiazin-2-amines (for reviews see [1-3]). Also a 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 6H-1,3,4-thiadiazin-2-amines as hypometabolic anaesthetic and cardiovascular agents has not hitherto been recognised however. Moreever, 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:
1. H. Beyer, Z. Chem., Bd. 9, S. 361, (1969).
2. S.V. Usoltseva, G.P. Andronnikova, and V.S. Mokreushin, Khim. Geterotsikl. Soedin., No 4, 435, (1991).
3. A.P. Novikova, N. M. Perova, and O. N. Chupakhin, Khim. Geterotsikl. Soedin., No 11, 1443, (1991)
4. W. D. Jones and F. P. Miller. US-A-4,309,426 (1982).
5. W. D. Jones and F. P. Miller. BE-A-884,991 (1980).
6. W. D. Jones and F. P. Miller. DE-A-3,042,295 (1982).
7. FR-A-2,493,844 (1982).
8. US-A-4,272,532 (1981).
9. F. P. Miller and W. D. Jones. BE-A-884,990 (1980).
10. W. D. Jones and F. P. Miller. DE-A-3,031,703 (1981).
11. Fisons PLC, Japan Kokai, Tokyo Koho JP-A-6253976.
12. W. P. Pfeiffer and E. Bulka, DD-A-220311 (1985).
13. N. Yoshida, K. Tanaka, and Y. Iizuka. Japan Kokai 7488889 (1974).
14. L. N. Rasina, O. N. Chupakhin and M. V. Chibiryak. Radiobiologiya, 30(2), 162-5 (1990).
15. A. V. Belik et al, Khim.-Farm. Zh., 26(3), 62-64 (1992).
16. N. M. Perova et al, Khim. Geterotsikl. Soedin., No 4, 565-6 (1993).
17. E Bulka and W. D. Pfeiffer. DD-A-288824.
18. W. D. Pfeiffer and E Bulka, Synthesis, No 7, 485-486 (1977).
19. T. Werner et al, US-A-4,940,790 (1990).
20. A. P. Novikova et al, SU-A-1726478.
21. E. Bulka et al, DD-A-228248.
SUMMARY OF THE INVENTION
According to one aspect of the invention, there is provided the use of substitued 6H-1,3,4-thiadiazin-2-amines of the following general formula as anaesthetic, cardiovascular and hypometabolic agents:
wherein Ar is phenyl optionally substituted with one or more chloro, bromo atoms, C
1
-C
4
alkoxy or C
1
-C
4
alkyl groups; and wherein
represents a morpholino, thiomorpholino, piperidino, pyrrolidino, or hexamethylenimino moiety.
According to the further aspect of the invention, there are provided pharmaceutical composition which includes one ore more of substituted 6H-1,3,4-thiadiazin-2-amines as defined above or pharmaceutically acceptable salts thereof.
According to the still further aspect of the invention, there are provided certain novel substituted 6H-1,3,4-thiadiazin-2-amines of the general formula set out above. Novel compounds of this class include compounds in which
represents thiomorpholino moiety; compounds in which Ar is phenyl substituted with one or more bromo atoms, C
1
-C
4
alkoxy or C
1
-C
4
alkyl groups, and
represents piperidino, pyrrolidino moiety; and compounds in which Ar is phenyl substituted at the 2 or 3 positions with one or more bromo atoms, C
1
-C
4
alkoxy or C
1
-C
4
alkyl groups, and
represents morpholino.
DISCLOSURE OF THE INVENTION
1,3,4-Thiadiazines suitable for the use according to the present invention contain at the 5 position of the thiadiazine ring unsubstituted phenyl or phenyl substituted with one or more straight or branched chain C
1
-C
4
alkyl, alkenyl, alkoxy or acyloxy groups, or one or more hydroxy groups or halogen atoms. In preferred compounds, Ar represents unsubstituted phenyl or phenyl substituted with one or more alkyl, alkoxy groups, or chloro or bromo atoms. Moreover said compounds are substituted at the 2 position of the thiadiazine ring with a cycloalkylimine moiety, preferably selected from morpholino, thiomorpholino, piperidino, pyrrolidino and hexamethylenimino.
The invention further relates to a process for the preparation of the 1,3,4-thiadiazines described herein in with an &agr;-haloarylalkanone having the formula Ar—CO—CH(R
1
)X is reacted with a thiosemicarbazide of formula
wherein X is halo, preferably chloro or bromo, and Ar, R
1
and
are as defined above.
According to the present invention the 1,3,4-thiadiazines may be isolated and/or used in free from or converted into additive salts with pharmacologically acceptable mineral or organic acids. Suitable for the preparation of acid addition salts are, for example, mineral acids, such as hydrobromic acid, hydrochloric acid, sulfuric acid or phosphoric acid; organic carboxylic acids, such as acetic acid, lactic acid, maleic acid, fumaric acid, oxalic acid, tartaric acid, citric acid or gluoconic acid; or organic sulfonic acids, such as benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid and cyclohexylamidosulfonic acid.
The &agr;-haloarylalkanone used as starting materials in the manufacture of the thiadiazines described above are known from the literature or may be prepared starting from arylalkanones by the reaction with a suitable halogenating agent according to the methods described in Houben-Weyl, Vol. E4 (1960), pp. 171-189. Suitable compounds are, for example, &agr;-bromarylethanones in which aryl may be selected from phenyl and substituted phenyl and prepared by halogenating the correspondent substituted 1-arylalkanoes with bromine or copper (II) bromide according to the method of King and Ostrum, J. Org. Chem. 29 (1964), pp. 3459-3461.
The substituted thiosemicarbazides which are used as starting materials are generally known in the art or they may be prepared by the methods described in Houben-Weyl, Vol. E4, pp. 506-515, and by K. Jensen et al., Acta Chem. Scand. 22 (1968), pp. 1-50. Thus, the thiosemicarbazides may be obtained by adding hydrazine to isothiocyanates or by the reaction of suitable N,N-di-substituted thiocarbamoyl chlorides with hydrazine or by the reaction of ethyl dithiocarbarates of formula
with hydrazine. In order to avoid interfering side reactions, said preparations are advantageously carried out in aprotic solvents, such as, for example, chloroform, tetrachloro
Chupakhin Oleg Nikolaevich
Novikova Antonina Petrovna
Perova Natalya Mikhailovna
Sidorova Larisa Petrovna
Tarakhty Emma Afanasievna
Ford John M.
Ladas & Parry
The Procter & Gamble & Company
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