USRE35095EExpiredUtility
Benzothiazepine anti-seizure method
Est. expiryMay 24, 2008(expired)· nominal 20-yr term from priority
A61K 31/55A61P 3/00A61P 25/08A61P 3/14A61K 31/554
22
PatentIndex Score
0
Cited by
9
References
15
Claims
Abstract
Seizures are ameliorated with certain benzothiazepines.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1. A method for ameliorating a generalized tonic clonic type epileptic seizure in a mammal comprising systemically administering to a mammal in need of treatment therefor a Benzothiazepine-compound in an amount effective to ameliorate said seizure, wherein the Benzothiazepine-compound is a benzothiazepine-type compound, or a pharmaceutically acceptable salt thereof, having calcium antagonist activity and which is represented by the following general formula: ##STR3## wherein Q is hydro (H) or halo: R is H, Lower alkoxy, lower haloalkyl, cyano, lower alkyl or halo; Y is OR', wherein R' is H of alkylacyl, provided that then there is full saturation between carbons 2 & 3 of the benzothiazepine nucleus and 2,3-dihydro-functionality thereat as well, or Cl, provided that then there is ethylenic unsaturation between positions 2 & 3 of the ebenzothiazepine nucleus, and R" is 2-[di(lower alkyl)amino ]ethyl, 3-[di(lower alkyl)amino]propyl, 2-(pyrrolidino)ethyl, 3-(pyrrolidino)propyl, 2-(piperidino)ethyl, 3-(piperidino)propyl, 2-(morpholino)ethyl, 3-(morpholino)propyl or (N-pyridinium)alkyl with a suitable counterion being present, provided that, in the cis-configuration, when Q is H or 8-Cl, R is methoxy, R' is acetyl, and R" is 2-(dimethylamino)-ethyl, then the compound is the levorotary isomer.
2. The method of claim 1, wherein the Benzothiazepine-compound is selected from the group consisting of 1-cis-DTZ, 1-cis-TA3090, M11014, ML1016, ML1017, ML1018, ML1020, ML1021, ML1048, ML1063, ML1064, ML1077, ML1078, ML1079, ML1082, ML1096, ML1097, ML1103, ML1104, and pharmaceutically acceptable salt(s) thereof, wherein each particular compound is identified as follows with respect to the formula (I): ______________________________________
Y:R' of
Compound Q R OR' & C R"
______________________________________
1-cis-DTZ H OMe acetyl R"1a
1-cis-TA3090
8-Cl OMe acetyl R"1a
ML1014 H OMe isovaleryl
R"1a
ML1016 H OMe acetyl R"1b
ML1017 H OMe H R"5
ML1018 H OMe acetyl R"5
ML1020 H OMe H R"5
ML1021 H OMe acetyl R"3
ML1048 H OMe H R"6
ML1063 H OMe H R"7
ML1064 H OMe acetyl R"7
ML1077 H Cl H R"1a
ML1078 H CF3 H R"1a
ML1079 H Me H R"1a
ML1082 H CF3 H R"5
ML1096 8-Cl OMe H R"5
ML1097 H OMe *Cl R"1a
ML1103 H OMe H R"5
ML1104 H CN H R"5
______________________________________
wherein also with respect to Q, 8-Cl is 8-chloro; with respect to R, OMe is methoxy; Cl is chloro; CF3 is trifluoromethyl; Me is methyl, and CN is cyano; with respect to Y, *CI indicates vinyl chloride at position 2, 3 of the benzothiazepine nucleus, and with respect to R", R"1a is 2-(dimethylamino)ethyl; R"1b is 2-(diisopropylamino)ethyl; R"3 is 2-(pyrrolidino)ethyl; R"5 is 2-(piperidino)ethyl; R"6 is 3-(piperidino)propyl, and R"7 is 2-(morpholino)ethyl.
3. The method of claim 2, wherein the Benzothiazepine-compound is selected from the group consisting of ML11016, ML1017, ML1018, ML1021, ML1048, ML1077, ML1078, ML1103, and pharmaceutically acceptable salt(s) thereof.
4. The method of claim 2, wherein the Benzothiazephine-compound is selected from the group consisting of ML1021, ML1077, ML11078, ML1082, ML1096, and pharmaceutically acceptable salt(s) thereof.
5. The method of claim 2, wherein the Benzothiazephine-compound is selected from the group consisting of d-cis-ML1014, d-cis-ML1016, cis-ML1017, cis-ML1018, cis-ML1020, cis-MLI1021, cis-ML1048, cis-ML1063, cis-ML1064, cis-ML1077, .[.cis.]. .Iadd.trans.Iaddend.-ML1078, cis-ML1079, .[.cis.]. .Iadd.trans.Iaddend.-ML1082, trans-ML1096, trans-ML1103, cis-ML1104, and pharmaceutically acceptable salt(s) thereof.
6. The method of claim 2, wherein the Benzothiazephine-compound is selected from the group consisting of cis-ML1016, cis-ML1017, cis-ML1018, cis-ML1021, cis-ML1048, cis-ML1077, .[.cis.]. .Iadd.trans.Iaddend.-ML1078, trans-ML1103, and pharmaceutically acceptable salt(s) thereof.
7. The method of claim 2, wherein the Benzothiazephine-compound is selected from the group consisting of cis-ML1077, .[.cis.]. .Iadd.trans.Iaddend.-ML1078, .[.cis.]. .Iadd.trans.Iaddend.-ML1082, trans-ML1096, and pharmaceutically acceptable salt(s) thereof.
8. The method of claim 7, wherein the pharmaceutically acceptable salt is a hydrochloride salt.
9. The method of claim 2, wherein the Benzothiazephine-compound is 1-cis-TA3090, or a pharmaceutically acceptable salt thereof.
10. The method of claim 9, wherein the pharmaceutically acceptable salt is a maleate salt.
11. The method of claim 2, wherein the Benzothiazephine-compound is 1-cis-DTZ, or a pharmaceutically acceptable salt thereof.
12. The method of claim 11, wherein the pharmaceutically acceptable salt is a hydrochloride salt.
13. The method of claim 2, wherein the Benzothiazepine-compound is ML1097, or a pharmaceutically acceptable salt thereof.
14. The method of claim 13, wherein the pharmaceutically acceptable salt is a hydrochloride salt.
15. The method of claim 1, wherein the Benzothiazepine-compound is selected from the group consisting of the following salts, identified as follows with respect to the formula (I): ______________________________________
Y:R' of
Compound Q R OR' & C R" Salt
______________________________________
1-cis-DTZ H OMe acetyl R"1a HCl
1-cis-TA3090
8-Cl OMe acetyl R"1a maleate
d-cis-ML1013
H OMe valeryl R"1a fumerate
d-cis-ML1014
H OMe isovaleryl
R"1a fumerate
d-cis-ML1015
H OMe pivalyl R"1a fumerate
d-cis-ML1016
H OMe acetyl R"1b HCl
dl-cis-ML1017
H OMe H R"5 HCl
dl-cis-ML1018
H OMe acetyl R"5 HCl
dl-cis-ML1020
H OMe H R"3 HCl
dl-cis-ML1021
H OMe acetyl R"3 HCl
d-cis-ML1047
8-Cl OMe pivalyl R"1a fumerate
dl-cis-ML1048
H OMe H R"6 HCl
dl-cis-ML1063
H OMe H R"7 HCl
dl-cis-ML1064
H OMe acetyl R"7 HCl
dl-cis-ML1065
H OMe H +R" Br/Cl
9a-X
dl-cis-ML1066
H OMe acetyl +R" Br/Cl
9a-X
dl-cis-ML1077
H Cl H R"1a HCl
dl-trans-ML1078
H CF3 H R"1a HCl
dl-cis-ML1079
H Me H R"1a HCl
d-cis-ML1080
H OMe adaman- R"1a fumerate
tylcarboxy
dl-cis-ML1082
H CF3 H R"5 HCl
dl-trans-ML1096
8-Cl OMe H R"5 HCl
ML1097 H OMe *Cl R"1a HCL
dl-cis-ML1098
H H H R"5 HCl
dl-trans-ML1103
H OMe H R"5 HCl
dl-cis-ML1104
H CN H R"5 HCl
______________________________________
wherein also with respect to Q, 8-Cl is 8-chloro; with respect to R, OMe is methoxy; Cl is chloro; CF3 is trifluoromethyl; Me is methyl, and CN is cyano; with respect to Y, *Cl indicates vinyl chloride at position 2,3 of the benzothiazepine nucleus, and with respect to R", R"1a is 2-(dimethylamino)ethyl; R"1b is 2-(diisopropylamino)ethyl: R"3 is 2-(pyrrolidino)ethyl; R"5 is 2-(piperidino)ethyl; R"6 is 3-(piperidino)propyl; R"7 is 2-(morpholino)ethyl, and +R"9a-X is 2-(N-pyridinium)ethyl with a bromide and/or chloride counterion being present.Cited by (0)
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