Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-05-03
1996-12-03
Bond, Robert T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540552, A11K 3155, C07D28110
Patent
active
055808662
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP93/03123 filed Nov. 6, 1993. Priority is also claimed of British applications GB 9223441.8 and GB 9223443.4, both filed 9 Nov. 1992.
This invention relates to derivatives of 2,3,4,5-tetrahydro-1,4-benzothiazepines, to pharmaceutical compositions containing them, to processes for their preparation and to their use in the treatment of seizures and/or neurological disorders such as epilepsy and/or as neuroprotective agents to protect against conditions such as stroke.
In particular the present invention provides compounds of formula I ##STR2## in which: n=0, 1 or 2 1 to 4 carbon atoms (optionally substituted with one or more halo); atoms; or together represent a group of formula .dbd.NR.sub.12 where R.sub.12 represents H, hydroxy, alkyl of 1 to 4 carbon atoms, phenyl or alkoxy of 1 to 4 carbon atoms; each alkyl, phenyl and alkoxy being optionally substituted with one or more halo; formula --COR.sub.13 in which R.sub.13 represents H, alkyl of 1 to 4 carbon atoms or phenyl, when R.sub.3 and R.sub.4 represent H or alkyl (optionally substituted with one or more halo), or (d) a group of formula --S(O).sub.p R.sub.14 in which p=1 or 2 and R.sub.14 is alkyl of 1 to 4 carbon atoms or phenyl, when R.sub.3 and R.sub.4 represent H or alkyl (optionally substituted with one or more halo); each alkyl and phenyl being optionally substituted with one or more halo; 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkanoyl of 1 to 4 carbon atoms, carboxy, alkanoyloxy of 1 to 4 carbon atoms, carbamoyl (optionally substituted with alkyl of 1 to 4 carbon atoms) or sulphamoyl (optionally substituted with alkyl of 1 to 4 carbon atoms); each alkyl, alkoxy, alkanoyl and alkanoyloxy being optionally substituted with one or more halo; alkyl; R.sub.4 and R.sub.6 are both H; R.sub.5 is H, alkyl or alkanoyl; and one of R.sub.8 or R.sub.9 and one of R.sub.9 to R.sub.10 are separately H, halo, nitro, alkyl, alkoxy or trifluoromethyl, the remainder of R.sub.8 to R.sub.11 being H; R.sub.7 is other than alkyl; such as epilepsy and/or as neuroprotective agents to protect against conditions such as stroke.
Compounds of formula I where n=0; R.sub.1 to R.sub.4, R.sub.6 to R.sub.8 and R.sub.11 are all H; R.sub.5 is H or acetyl; and R.sub.9 and R.sub.10 are both methoxy; are known from Szabo et al, Chem. Ber., 119, pages 2904-2913, (1986).
Compounds of formula I where n=0 or 2; R.sub.1 to R.sub.6, R.sub.8 and R.sub.11 are all H; R.sub.7 is methyl; and R.sub.9 and R.sub.10 are both methoxy; are known from J. Org. Chem., 30 (8), pages 2812-2818, (1965), (Eng).
Compounds of formula I where n=0; R.sub.1, R.sub.2, R.sub.5, R.sub.6 and R.sub.7 are all H; R.sub.3 is a straight chain alkyl of 1 to 4 carbon atoms; R.sub.4 is a straight chain alkyl of 2 to 4 carbon atoms; and R.sub.8 to R.sub.11 are independently H, halo, nitro, alkyl of 1 to 4 carbon atoms (optionally substituted by one or more halo) or alkoxy of 1 to 4 carbon atoms (optionally substituted by one or more halo); are known as intermediates in the preparation of the compounds claimed in International patent application WO 93/16055 (Wellcome) (see formula XIV, page 18).
Compounds of formula I where n=0, 1 or 2; R.sub.1, R.sub.2 and R.sub.3 are independently H or alkyl of 1 to 4 carbon atoms; R.sub.4 and R.sub.6 are both H; R.sub.5 is H, alkyl of 1 to 4 carbon atoms or alkanoyl of 1 to 5 carbon atoms; R.sub.7 is alkyl of 1 to 4 carbon atoms and one of R.sub.8 or R.sub.9 and one of R.sub.10 or R.sub.11 are independently H, halo, nitro, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or trifluoromethyl, the remainder of R.sub.8 to R.sub.11 being H; are known from French patent application 4916-M (Hoffmann 1a Roche) (corresponding inter alia to AU 409345) and are stated to have pharmaceutical activity as anti-agconvulsants. The application does not contain any pharmaceutical data to support this statement.
Compounds of formula I where n=0; R.sub.1 to R.sub.4, R.sub.6 to R.sub.8, R.sub.10 and R.sub.11 are all H; R.sub.5 is H or bromoacetyl; and R.sub
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Boudet et al, C. R. Acad. Sci. Paris Series .C, 282, 249-251 (26 Jan. 1976).
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Nair et al, Indian J. Chem. 7 (9) 862-865 (1969).
Szabo et al, Chem. Ber. 119 2904-2913 (1986).
Sternbach et al, J. Org. Chem. 30 (8) 2812-2818 (1965).
Szabo et al, Acta Chimica Hungarica 115 (4) 429-437 (1984).
Housley John R.
Jeffery James E.
Nichol Kenneth J.
Sargent Bruce J.
Bond Robert T.
The Boots Company PLC
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