CA2376023A1 - Therapeutic agents - Google Patents
Therapeutic agents Download PDFInfo
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- CA2376023A1 CA2376023A1 CA002376023A CA2376023A CA2376023A1 CA 2376023 A1 CA2376023 A1 CA 2376023A1 CA 002376023 A CA002376023 A CA 002376023A CA 2376023 A CA2376023 A CA 2376023A CA 2376023 A1 CA2376023 A1 CA 2376023A1
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- tetrahydro
- benzothiazepine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/34—Tobacco-abuse
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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Abstract
The present invention provides a method of treating obesity and related conditions such as bulimia, anorexia, snacking, binge eating, non insolin dependent diabetes meltitus, hyperglycaemia, stress, hyperlipidaemia, and to aid to smoking cessation comprising the administration to a mammal, particularly a human, in need thereof of a therapeutically effective amount of a compound of formula (I) in which: n=0, 1 or 2; R1 and R2 independently represent H or alkyl of 1 to 4 carbon atoms (optionally substituted by one or more halo); R3 and R4 independently represent H or alkyl of 1 to 4 carbon atoms; or together represent a group of formula =NR12 where R12 represents H, hydroxy, alkyl of 1 to 4 carbon atoms, a phenyl or alkoxy of 1 to 4 carbon atoms; each alkyl, phenyl and alkoxy being optionally substituted with one or more halo; R5 represents: (a) H, (b) alkyl of 1 to 4 carbon atoms, (c) a group of formula-COR13 in which R13 represents H, alkyl of 1 to 4 carbon atoms or phenyl, when R3 and R4 represent H or alkyl (optionally substituted with one or more halo, or (d) or a group of formula -S(O)pR14 in which p=1 or 2 and R14 is alkyl of 1 to 4 carbon atoms or phenyl, when R3 and R4 represent H or alkyl (optionally substituted with one or more halo); each alkyl and phenyl being optionally substituted with one or more halo; R6 and R7 are each H; R8 to R11 independently represent H, halo, cyano, nitro, alkyl of 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 or alkanoyloxy optionally substituted with one or more halo; their stereoisomers; and pharmaceutically acceptable salts thereof.
Description
Therapeutic Agents The present invention relates to the use of 2,3,4,5-tetrahydro-1,4-benzothiazepines in the treatment of obesity, eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin . dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, and stress, and as an aid to smoking cessation.
Compounds of formula I
R" ( ~ )n R, s S
Rio s ~ , z Rz Rs s / s a N\ Ra Rs I Rs Rs R~
in which:
n = 0, 1 or 2;
R1, and R2 independently represent H or alkyl of 1 to 4 carbon atoms (optionally substituted by one or more halo);
R3 and R4 independently represent H or alkyl of 1 to 4 carbon atoms; or together represent a group of formula =NR12 where R12 represents H, hydroxy, alkyl of 1 to 4 carbon atoms, phenyl or alkoxy of 1 to 4 carbon atoms; each alkyl, phenyl andalkoxy being optionally substituted with one or more halo;
R5 represents: (a) H, (b) alkyl of 1 to 4 carbon atoms, (c) a group of formula-in which R13 represents H, alkyl of 1 to 4 carbon atoms or phenyl, when R3 and represent H or alkyl (optionally substituted with one or more halo, or (d) or a group of formula -S(O)pRl4 in which p = 1 or 2 and R14 is alkyl of 1 to 4 carbon atoms or phenyl, when R3 and R4 represent H or alkyl (optionally substituted with one or more halo); each alkyl and phenyl being optionally substituted with one or more halo;
Rg and R7 are each H;
Rg to R11 independently represent H, halo, cyano, nitro, alkyl of 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 or alkanoyloxy optionally substituted with one or more halo;
their stereoisomers; and pharmaceutically acceptable salts thereof;
with the proviso that:
(i) when n = 0; at least one of R1 to R11 is other than H;
are disclosed in W094/11360 for the treatment of seizures and neurological disorders.
The present invention provides a method of treating obesity and related conditions comprising the administration to a mammal, particularly a human, in need thereof of a therapeutically effective amount of a compound of formula I
R" (1)n Rt S
R,o 8 ~ , z Rz 7 ~ 3 R3 R9 6 ~ s 4 N\ Ra R8 ~ Rs Rs R~
in which:
n = 0, 1 or 2;
R1, and R2 independently represent H or alkyl of 1 to 4 carbon atoms (optionally substituted by one or more halo);
R3 and R4 independently represent H or alkyl of 1 to 4 carbon atoms; or together represent a group of formula =NR12 where R12 represents H, hydroxy, alkyl of 1 to 4 carbon atoms, phenyl or alkoxy of 1 to 4 carbon atoms; each alkyl, phenyl andalkoxy being optionally substituted with one or more halo;
R5 represents: (a) H, (b) alkyl of 1 to 4 carbon atoms, (c) a group of formula-in which R13 represents H, alkyl of 1 to 4 carbon atoms or phenyl, when R3 and represent H or alkyl (optionally substituted with one or more halo, or (d) or a group of formula -S(O)pRl4 in which p = 1 or 2 and R14 is alkyl of 1 to 4 carbon atoms or phenyl, when R3 and R4 represent H or alkyl (optionally substituted with one or more halo); each alkyl and phenyl being optionally substituted with one or more halo;
Compounds of formula I
R" ( ~ )n R, s S
Rio s ~ , z Rz Rs s / s a N\ Ra Rs I Rs Rs R~
in which:
n = 0, 1 or 2;
R1, and R2 independently represent H or alkyl of 1 to 4 carbon atoms (optionally substituted by one or more halo);
R3 and R4 independently represent H or alkyl of 1 to 4 carbon atoms; or together represent a group of formula =NR12 where R12 represents H, hydroxy, alkyl of 1 to 4 carbon atoms, phenyl or alkoxy of 1 to 4 carbon atoms; each alkyl, phenyl andalkoxy being optionally substituted with one or more halo;
R5 represents: (a) H, (b) alkyl of 1 to 4 carbon atoms, (c) a group of formula-in which R13 represents H, alkyl of 1 to 4 carbon atoms or phenyl, when R3 and represent H or alkyl (optionally substituted with one or more halo, or (d) or a group of formula -S(O)pRl4 in which p = 1 or 2 and R14 is alkyl of 1 to 4 carbon atoms or phenyl, when R3 and R4 represent H or alkyl (optionally substituted with one or more halo); each alkyl and phenyl being optionally substituted with one or more halo;
Rg and R7 are each H;
Rg to R11 independently represent H, halo, cyano, nitro, alkyl of 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 or alkanoyloxy optionally substituted with one or more halo;
their stereoisomers; and pharmaceutically acceptable salts thereof;
with the proviso that:
(i) when n = 0; at least one of R1 to R11 is other than H;
are disclosed in W094/11360 for the treatment of seizures and neurological disorders.
The present invention provides a method of treating obesity and related conditions comprising the administration to a mammal, particularly a human, in need thereof of a therapeutically effective amount of a compound of formula I
R" (1)n Rt S
R,o 8 ~ , z Rz 7 ~ 3 R3 R9 6 ~ s 4 N\ Ra R8 ~ Rs Rs R~
in which:
n = 0, 1 or 2;
R1, and R2 independently represent H or alkyl of 1 to 4 carbon atoms (optionally substituted by one or more halo);
R3 and R4 independently represent H or alkyl of 1 to 4 carbon atoms; or together represent a group of formula =NR12 where R12 represents H, hydroxy, alkyl of 1 to 4 carbon atoms, phenyl or alkoxy of 1 to 4 carbon atoms; each alkyl, phenyl andalkoxy being optionally substituted with one or more halo;
R5 represents: (a) H, (b) alkyl of 1 to 4 carbon atoms, (c) a group of formula-in which R13 represents H, alkyl of 1 to 4 carbon atoms or phenyl, when R3 and represent H or alkyl (optionally substituted with one or more halo, or (d) or a group of formula -S(O)pRl4 in which p = 1 or 2 and R14 is alkyl of 1 to 4 carbon atoms or phenyl, when R3 and R4 represent H or alkyl (optionally substituted with one or more halo); each alkyl and phenyl being optionally substituted with one or more halo;
Rg and R7 are each H;
Rg to R11 independently represent H, halo, cyano, nitro, alkyl of 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 or alkanoyloxy optionally substituted with one or more halo;
their stereoisomers; and pharmaceutically acceptable salts thereof.
The term "related conditions" as used herein means eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, and stress, and as an aid to smoking cessation.
In a preferred group of compounds of formula I
R" ( ~ )n R, s S
R'~ s W ~ z Rz 7 ~ 3 R3 Rs s ~~ s 4 N\ Ra R8 I Rs Rs R~
nis0or1;
R1, R2, Rg and R7 are each H;
R3 and R4 are independently H or methyl; or together represent imino, methylimino, phenylimino, hydroxyimino or methoxyimino;
R5 is H or methyl, or when R3 and R4 are independently H or methyl, R5 is H, methyl, formyl, acetyl, propionyl, benzoyl, methylsulphinyl, methylsulphonyl or ethylsulphonyl;
Rg is H, methyl, fluoro or chloro; and Rg, R1 p and R11 are each H;
or a pharmaceutically acceptable salt thereof.
Rg to R11 independently represent H, halo, cyano, nitro, alkyl of 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 or alkanoyloxy optionally substituted with one or more halo;
their stereoisomers; and pharmaceutically acceptable salts thereof.
The term "related conditions" as used herein means eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, and stress, and as an aid to smoking cessation.
In a preferred group of compounds of formula I
R" ( ~ )n R, s S
R'~ s W ~ z Rz 7 ~ 3 R3 Rs s ~~ s 4 N\ Ra R8 I Rs Rs R~
nis0or1;
R1, R2, Rg and R7 are each H;
R3 and R4 are independently H or methyl; or together represent imino, methylimino, phenylimino, hydroxyimino or methoxyimino;
R5 is H or methyl, or when R3 and R4 are independently H or methyl, R5 is H, methyl, formyl, acetyl, propionyl, benzoyl, methylsulphinyl, methylsulphonyl or ethylsulphonyl;
Rg is H, methyl, fluoro or chloro; and Rg, R1 p and R11 are each H;
or a pharmaceutically acceptable salt thereof.
Preferred compounds of formula I are selected from:
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-formyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
4-acetyl-6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-methylsulphinyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
4-ethylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
3-hydroxyimino-6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
3-methylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine; and 6-chloro-3-phenylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
their stereoisomers; and pharmaceutically acceptable salts thereof.
More preferred compounds of formula I are selected from:
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-formyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-methylsulphinyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine; and 6-chloro-3-phenylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
their stereoisomers; and pharmaceutically acceptable salts thereof.
Most preferred compounds of formula I are selected from 4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide; and 6-fluoro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
their stereoisomers; and pharmaceutically acceptable salts thereof.
A particularly preferred compound of formula I is:
5 4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
its stereoisomers; and pharmaceutically acceptable salts thereof.
The present invention also provides pharmaceutical compositions for the treatment of obesity and related conditions comprising a therapeutically effective amount of compounds of formula I
R" ( ~ )n R~
Rio a y R
s R3 I
Rs s ~ s a N\ Ra R8 ~ R6 Rs R~
in which:
n = 0, 1 or 2;
R1, and R2 independently represent H or alkyl of 1 to 4 carbon atoms (optionally substituted by one or more halo);
R3 and R4 independently represent H or alkyl of 1 to 4 carbon atoms; or together represent a group of formula =NR12 where R12 represents H, hydroxy, alkyl of 1 to 4 carbon atoms, phenyl or alkoxy of 1 to 4 carbon atoms; each alkyl, phenyl andalkoxy being optionally substituted with one or more halo;
R5 represents: (a) H, (b) alkyl of 1 to 4 carbon atoms, (c) a group of formula-in which R13 represents H, alkyl of 1 to 4 carbon atoms or phenyl, when R3 and represent H or alkyl (optionally substituted with one or more halo, or (d) or a group of formula -S(O)pRl4 in which p = 1 or 2 and R14 is alkyl of 1 to 4 carbon atoms or phenyl, when R3 and R4 represent H or alkyl (optionally substituted with one or more halo); each alkyl and phenyl being optionally substituted with one or more halo;
Rg and R7 are each H;
Rg to R11 independently represent H, halo, cyano, nitro, alkyl of 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 or alkanoyloxy optionally substituted with one or more halo;
their stereoisomers; and pharmaceutically acceptable salts thereof;
with the proviso that:
(i) when n = 0; at least one of R1 to R11 is other than H;
together with a pharmaceutically acceptable diluent or carrier.
Preferred pharmaceutical compositions for the treatment of obesity and related conditions comprise a therapeutically effective amount of compounds of formula I in which:
n=Oor1;
R1 and R2 are independently H or methyl;
R3 and R4 are independently H or methyl; or together represent imino, methylimino, phenylimino, hydroxyimino or methoxyimino;
R5 is H or methyl, and when R3 and R4 are H or methyl, R5 is H, methyl, formyl, acetyl, propionyl, benzoyl, methylsulphinyl, methylsulphonyl or ethylsulphonyl;
R6 and R7 are each H; and one of Rg to R11 is H, fluoro, chloro, bromo, iodo, methyl (optionally substituted with one or more halo), methoxy (optionally substituted by one or more halo), nitro, cyano, carboxy, acetyl, dimethylcarbamoyl or dimethylsulphamoyl; the remainder of Rg to R11 being H;
their stereoisomers; and pharmaceutically acceptable salts thereof.
More preferred pharmaceutical compositions for the treatment of obesity and related conditions comprise a therapeutically effective amount of compounds of formula I in which:
n=Oor1;
R1, R2, Rg and R7 are each H;
R3 and R4 are H, or together are methylimino, phenylimino, hydroxyimino or methoxyimino;
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-formyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
4-acetyl-6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-methylsulphinyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
4-ethylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
3-hydroxyimino-6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
3-methylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine; and 6-chloro-3-phenylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
their stereoisomers; and pharmaceutically acceptable salts thereof.
More preferred compounds of formula I are selected from:
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-formyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-methylsulphinyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine; and 6-chloro-3-phenylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
their stereoisomers; and pharmaceutically acceptable salts thereof.
Most preferred compounds of formula I are selected from 4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide; and 6-fluoro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
their stereoisomers; and pharmaceutically acceptable salts thereof.
A particularly preferred compound of formula I is:
5 4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
its stereoisomers; and pharmaceutically acceptable salts thereof.
The present invention also provides pharmaceutical compositions for the treatment of obesity and related conditions comprising a therapeutically effective amount of compounds of formula I
R" ( ~ )n R~
Rio a y R
s R3 I
Rs s ~ s a N\ Ra R8 ~ R6 Rs R~
in which:
n = 0, 1 or 2;
R1, and R2 independently represent H or alkyl of 1 to 4 carbon atoms (optionally substituted by one or more halo);
R3 and R4 independently represent H or alkyl of 1 to 4 carbon atoms; or together represent a group of formula =NR12 where R12 represents H, hydroxy, alkyl of 1 to 4 carbon atoms, phenyl or alkoxy of 1 to 4 carbon atoms; each alkyl, phenyl andalkoxy being optionally substituted with one or more halo;
R5 represents: (a) H, (b) alkyl of 1 to 4 carbon atoms, (c) a group of formula-in which R13 represents H, alkyl of 1 to 4 carbon atoms or phenyl, when R3 and represent H or alkyl (optionally substituted with one or more halo, or (d) or a group of formula -S(O)pRl4 in which p = 1 or 2 and R14 is alkyl of 1 to 4 carbon atoms or phenyl, when R3 and R4 represent H or alkyl (optionally substituted with one or more halo); each alkyl and phenyl being optionally substituted with one or more halo;
Rg and R7 are each H;
Rg to R11 independently represent H, halo, cyano, nitro, alkyl of 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 or alkanoyloxy optionally substituted with one or more halo;
their stereoisomers; and pharmaceutically acceptable salts thereof;
with the proviso that:
(i) when n = 0; at least one of R1 to R11 is other than H;
together with a pharmaceutically acceptable diluent or carrier.
Preferred pharmaceutical compositions for the treatment of obesity and related conditions comprise a therapeutically effective amount of compounds of formula I in which:
n=Oor1;
R1 and R2 are independently H or methyl;
R3 and R4 are independently H or methyl; or together represent imino, methylimino, phenylimino, hydroxyimino or methoxyimino;
R5 is H or methyl, and when R3 and R4 are H or methyl, R5 is H, methyl, formyl, acetyl, propionyl, benzoyl, methylsulphinyl, methylsulphonyl or ethylsulphonyl;
R6 and R7 are each H; and one of Rg to R11 is H, fluoro, chloro, bromo, iodo, methyl (optionally substituted with one or more halo), methoxy (optionally substituted by one or more halo), nitro, cyano, carboxy, acetyl, dimethylcarbamoyl or dimethylsulphamoyl; the remainder of Rg to R11 being H;
their stereoisomers; and pharmaceutically acceptable salts thereof.
More preferred pharmaceutical compositions for the treatment of obesity and related conditions comprise a therapeutically effective amount of compounds of formula I in which:
n=Oor1;
R1, R2, Rg and R7 are each H;
R3 and R4 are H, or together are methylimino, phenylimino, hydroxyimino or methoxyimino;
R5 is H or methyl, and when R3 and R4 are H, R5 is H, methyl, formyl, acetyl, propionyl, benzoyl, methylsulphinyl, methylsulphonyl, or ethylsulphonyl;
Rg is H, methyl, fluoro or chloro;
Rg to R11 are all H;
their stereoisomers; and pharmaceutically acceptable salts thereof.
Especially preferred pharmaceutical compositions for the treatment of obesity and related conditions comprise a therapeutically effective amount of compounds of formula I selected from:
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-formyl-2, 3,4, 5-tetrahyd ro-1,4-benzothiazepine;
4-acetyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-2,3,4,5-tetrahydro-1,4-benzothiapine 1-oxide;
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
4-acetyl-6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-propionyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chtoro-4-propionyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-benzoyl-6-chloro-2, 3,4, 5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-methylsulphinyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
6-fluoro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-methyl-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-ethylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
Rg is H, methyl, fluoro or chloro;
Rg to R11 are all H;
their stereoisomers; and pharmaceutically acceptable salts thereof.
Especially preferred pharmaceutical compositions for the treatment of obesity and related conditions comprise a therapeutically effective amount of compounds of formula I selected from:
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-formyl-2, 3,4, 5-tetrahyd ro-1,4-benzothiazepine;
4-acetyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-2,3,4,5-tetrahydro-1,4-benzothiapine 1-oxide;
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
4-acetyl-6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-propionyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chtoro-4-propionyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-benzoyl-6-chloro-2, 3,4, 5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-methylsulphinyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
6-fluoro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-methyl-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-ethylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-ethylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
3-hydroxyimino-6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
3-methoxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-3-methoxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
3-methylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-3-phenylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
their stereoisomers; and pharmaceutically acceptable salts thereof.
The compounds of the present invention may prepared and formulated into pharmaceutical formulations as described in W094/11360.
The compound of formula I may be administered in any of the known pharmaceutical dosage forms. The amount of the compound to be administered will depend on a number of factors including the age of the patient, the severity of the condition and the past medical history of the patient and always lies within the sound discretion of the administering physician but it is generally envisaged that the dosage of the compound to be administered will be in the range 0.1 to 1000 mg preferably 1 to 500 mg per day given in one or more doses.
Oral dosage forms are the preferred compositions for use in the present invention and these are the known pharmaceutical forms for such administration, for example tablets, capsules, granules, syrups and aqueous or oil suspensions.
The excipients used in the preparation of these compositions are theexcipients known in the pharmacist's art. Tablets may be prepared from a mixture of the active compound with fillers, for example calcium phosphate; disintegrating agents, for example maize starch; lubricating agents, for example magnesium stearate;
binders, for example microcrystalline cellulose or polyvinylpyrrolidone and other optional ingredients known in the art to permit tableting the mixture by known methods.
The tablets may, if desired, be coated using known methods and excipients which may include enteric coating using for example hydroxypropylmethylcellulose phthalate.
The tablets may be formulated in a manner known to those skilled in the art so as to give a sustained release of the compounds of the present invention. Such tablets may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate. Similarly, capsules, for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by known methods and, if desired, provided with enteric coatings in a known manner. The contents of the capsule may be formulated using known methods so as to give sustained release of the active compound. The tablets and capsules may conveniently each contain 1 to 500 mg of the active compound.
Preferably the tablets and capsules each contain 5, 10, 15, 20, 25, 30, 50,100 ,250 or 500mg.
Other dosage forms for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxy-methylcellulose, and oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example arachis oil. The active compound may be formulated into granules with or without additional excipients. The granules may be ingested directly by the patient or they may be added to a suitable liquid carrier (for example, water) before ingestion. The granules may contain disintegrants, eg an effervescent couple formed from an acid and a carbonate or bicarbonate salt to facilitate dispersion in the liquid medium.
The therapeutically active compounds of formula I may be formulated into a composition which the patient retains in his mouth so that the active compound is administered through the mucosa of the mouth.
Dosage forms suitable for rectal administration are the known pharmaceutical forms for such administration, for example, suppositories with cocoa butter or polyethylene glycol bases.
Dosage forms suitable for parenteral administration are the known pharmaceutical forms for such administration, for example sterile suspensions or sterile solutions in a suitable solvent.
Dosage forms for topical administration may comprise a matrix in which the pharmacologically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally. A suitable transdermal composition may be prepared by 5 mixing the pharmaceutically active compound with a topical vehicle, such as a mineral oil, petrolatum and/or a wax, e.g. paraffin wax or beeswax, together with a potential transdermal accelerant such as dimethyl sulphoxide or propylene glycol.
Alternatively the active compounds may be dispersed in a pharmaceutically acceptable cream, gel or ointment base. The amount of active compound contained 10 in a topical formulation should be such that a therapeutically effective amount of the compound is delivered during the period of time for which the topical formulation is intended to be on the skin.
The therapeutically active compound of formula I may be formulated into a composition which is dispersed as an aerosol into the patients oral or nasal cavity.
Such aerosols may be administered from a pump pack or from a pressurised pack containing a volatile propellant.
The therapeutically active compounds of formula I used in the method of the present invention may also be administered by continuous infusion either from an external source, for example by intravenous infusion or from a source of the compound placed within the body. Internal sources include implanted reservoirs containing the compound to be infused which is continuously released for example by osmosis and implants which may be (a) liquid such as an oily suspension of the compound to be infused for example in the form of a very sparingly water-soluble derivative such as a dodecanoate salt or a lipophilic ester or (b) solid in the form of an implanted support, for example of a synthetic resin or waxy material, for the compound to be infused. The support may be a single body containing all of the compound or a series of several bodies each containing part of the compound to be delivered. The amount of active compound present in an internal source should be such that a therapeutically effective amount of the compound is delivered over a long period of time.
3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
3-hydroxyimino-6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
3-methoxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-3-methoxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
3-methylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-3-phenylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
their stereoisomers; and pharmaceutically acceptable salts thereof.
The compounds of the present invention may prepared and formulated into pharmaceutical formulations as described in W094/11360.
The compound of formula I may be administered in any of the known pharmaceutical dosage forms. The amount of the compound to be administered will depend on a number of factors including the age of the patient, the severity of the condition and the past medical history of the patient and always lies within the sound discretion of the administering physician but it is generally envisaged that the dosage of the compound to be administered will be in the range 0.1 to 1000 mg preferably 1 to 500 mg per day given in one or more doses.
Oral dosage forms are the preferred compositions for use in the present invention and these are the known pharmaceutical forms for such administration, for example tablets, capsules, granules, syrups and aqueous or oil suspensions.
The excipients used in the preparation of these compositions are theexcipients known in the pharmacist's art. Tablets may be prepared from a mixture of the active compound with fillers, for example calcium phosphate; disintegrating agents, for example maize starch; lubricating agents, for example magnesium stearate;
binders, for example microcrystalline cellulose or polyvinylpyrrolidone and other optional ingredients known in the art to permit tableting the mixture by known methods.
The tablets may, if desired, be coated using known methods and excipients which may include enteric coating using for example hydroxypropylmethylcellulose phthalate.
The tablets may be formulated in a manner known to those skilled in the art so as to give a sustained release of the compounds of the present invention. Such tablets may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate. Similarly, capsules, for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by known methods and, if desired, provided with enteric coatings in a known manner. The contents of the capsule may be formulated using known methods so as to give sustained release of the active compound. The tablets and capsules may conveniently each contain 1 to 500 mg of the active compound.
Preferably the tablets and capsules each contain 5, 10, 15, 20, 25, 30, 50,100 ,250 or 500mg.
Other dosage forms for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxy-methylcellulose, and oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example arachis oil. The active compound may be formulated into granules with or without additional excipients. The granules may be ingested directly by the patient or they may be added to a suitable liquid carrier (for example, water) before ingestion. The granules may contain disintegrants, eg an effervescent couple formed from an acid and a carbonate or bicarbonate salt to facilitate dispersion in the liquid medium.
The therapeutically active compounds of formula I may be formulated into a composition which the patient retains in his mouth so that the active compound is administered through the mucosa of the mouth.
Dosage forms suitable for rectal administration are the known pharmaceutical forms for such administration, for example, suppositories with cocoa butter or polyethylene glycol bases.
Dosage forms suitable for parenteral administration are the known pharmaceutical forms for such administration, for example sterile suspensions or sterile solutions in a suitable solvent.
Dosage forms for topical administration may comprise a matrix in which the pharmacologically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally. A suitable transdermal composition may be prepared by 5 mixing the pharmaceutically active compound with a topical vehicle, such as a mineral oil, petrolatum and/or a wax, e.g. paraffin wax or beeswax, together with a potential transdermal accelerant such as dimethyl sulphoxide or propylene glycol.
Alternatively the active compounds may be dispersed in a pharmaceutically acceptable cream, gel or ointment base. The amount of active compound contained 10 in a topical formulation should be such that a therapeutically effective amount of the compound is delivered during the period of time for which the topical formulation is intended to be on the skin.
The therapeutically active compound of formula I may be formulated into a composition which is dispersed as an aerosol into the patients oral or nasal cavity.
Such aerosols may be administered from a pump pack or from a pressurised pack containing a volatile propellant.
The therapeutically active compounds of formula I used in the method of the present invention may also be administered by continuous infusion either from an external source, for example by intravenous infusion or from a source of the compound placed within the body. Internal sources include implanted reservoirs containing the compound to be infused which is continuously released for example by osmosis and implants which may be (a) liquid such as an oily suspension of the compound to be infused for example in the form of a very sparingly water-soluble derivative such as a dodecanoate salt or a lipophilic ester or (b) solid in the form of an implanted support, for example of a synthetic resin or waxy material, for the compound to be infused. The support may be a single body containing all of the compound or a series of several bodies each containing part of the compound to be delivered. The amount of active compound present in an internal source should be such that a therapeutically effective amount of the compound is delivered over a long period of time.
In some formulations it may be beneficial to use the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling.
The pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula I may be used to treat obesity and related conditions including eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, and stress in mammals particularly humans, and as an aid to smoking cessation in human beings. Whilst the precise amount of active compound administered in such treatment will depend on a number of factors, for example the age of the patient, the severity of the condition and the past medical history, and always lies within the sound discretion of the administering physician, the amount of active compound administered per day is in the range 1 to 1000 mg preferably 5 to 500 mg given in single or divided doses at one or more times during the day.
In yet another aspect, the present invention provides the use of a compound of Formula I in the manufacture of a medicament for use in the treatment of obesity and related conditions including eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, and stress, and as an aid to smoking cessation.
The present invention also provides a method of treating obesity and related conditions including eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia and stress which comprises the administration of a therapeutically effective amount of a compound of Formula I to a patient in need thereof.
The present invention also provides a method of reducing the craving to smoke in human beings which comprises the administration of a therapeutically effective amount of a compound of Formula I to a patient in need thereof. The present invention also provides a method of reducing weight gain after smoking cessation in human beings which comprises the administration of a therapeutically effective amount of a compound of Formula I to a patient in need thereof.
The pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula I may be used to treat obesity and related conditions including eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, and stress in mammals particularly humans, and as an aid to smoking cessation in human beings. Whilst the precise amount of active compound administered in such treatment will depend on a number of factors, for example the age of the patient, the severity of the condition and the past medical history, and always lies within the sound discretion of the administering physician, the amount of active compound administered per day is in the range 1 to 1000 mg preferably 5 to 500 mg given in single or divided doses at one or more times during the day.
In yet another aspect, the present invention provides the use of a compound of Formula I in the manufacture of a medicament for use in the treatment of obesity and related conditions including eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, and stress, and as an aid to smoking cessation.
The present invention also provides a method of treating obesity and related conditions including eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia and stress which comprises the administration of a therapeutically effective amount of a compound of Formula I to a patient in need thereof.
The present invention also provides a method of reducing the craving to smoke in human beings which comprises the administration of a therapeutically effective amount of a compound of Formula I to a patient in need thereof. The present invention also provides a method of reducing weight gain after smoking cessation in human beings which comprises the administration of a therapeutically effective amount of a compound of Formula I to a patient in need thereof.
In addition the compounds of the present invention may be useful in the treatment or prevention of metabolic diseases and conditions arising therefrom, for example non exercise activity thermogenesis and increased metabolic rate.
The compounds of the present invention may be useful in preventing cardio-vascular disease, and in reducing platelet adhesiveness, in aiding weight loss after pregnancy and in aiding weight loss after smoking cessation.
The following in vivo test supports the finding that compounds of formula I
have efficacy in the treatment of obesity.
Marmosets given 4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (50 mg/kg po) daily for 14 days showed reduced bodyweight gain.
The compounds of the present invention may be useful in preventing cardio-vascular disease, and in reducing platelet adhesiveness, in aiding weight loss after pregnancy and in aiding weight loss after smoking cessation.
The following in vivo test supports the finding that compounds of formula I
have efficacy in the treatment of obesity.
Marmosets given 4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (50 mg/kg po) daily for 14 days showed reduced bodyweight gain.
Claims (7)
1) A method of treating obesity and related conditions comprising the administration to a mammal, particularly a human, in need thereof of a therapeutically effective amount of a compound of formula I
in which:
n = 0,1 or 2;
R1, and R2 independently represent H or alkyl of 1 to 4 carbon atoms (optionally substituted by one or more halo);
R3 and R4 independently represent H or alkyl of 1 to 4 carbon atoms; or together represent a group of formula =NR12 where R12 represents H, hydroxy, alkyl of 1 to 4 carbon atoms, phenyl or alkoxy of 1 to 4 carbon atoms; each alkyl, phenyl andalkoxy being optionally substituted with one or more halo;
R5 represents: (a) H, (b) alkyl of 1 to 4 carbon atoms, (c) a group of formula-in which R13 represents H, alkyl of 1 to 4 carbon atoms or phenyl, when R3 and represent H or alkyl (optionally substituted with one or more halo, or (d) or a group of formula -S(O)p R14 in which p = 1 or 2 and R14 is alkyl of 1 to 4 carbon atoms or phenyl, when R3 and R4 represent H or alkyl (optionally substituted with one or more halo); each alkyl and phenyl being optionally substituted with one or more halo;
R6 and R7 are each H;
R8 to R11 independently represent H, halo, cyano, nitro, alkyl of 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 or alkanoyloxy optionally substituted with one or more halo;
their stereoisomers; and pharmaceutically acceptable salts thereof;
with the proviso that:
(i) when n = 0; at least one of R1 to R11 is other than H;
together with a pharmaceutically acceptable diluent or carrier.
in which:
n = 0,1 or 2;
R1, and R2 independently represent H or alkyl of 1 to 4 carbon atoms (optionally substituted by one or more halo);
R3 and R4 independently represent H or alkyl of 1 to 4 carbon atoms; or together represent a group of formula =NR12 where R12 represents H, hydroxy, alkyl of 1 to 4 carbon atoms, phenyl or alkoxy of 1 to 4 carbon atoms; each alkyl, phenyl andalkoxy being optionally substituted with one or more halo;
R5 represents: (a) H, (b) alkyl of 1 to 4 carbon atoms, (c) a group of formula-in which R13 represents H, alkyl of 1 to 4 carbon atoms or phenyl, when R3 and represent H or alkyl (optionally substituted with one or more halo, or (d) or a group of formula -S(O)p R14 in which p = 1 or 2 and R14 is alkyl of 1 to 4 carbon atoms or phenyl, when R3 and R4 represent H or alkyl (optionally substituted with one or more halo); each alkyl and phenyl being optionally substituted with one or more halo;
R6 and R7 are each H;
R8 to R11 independently represent H, halo, cyano, nitro, alkyl of 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 or alkanoyloxy optionally substituted with one or more halo;
their stereoisomers; and pharmaceutically acceptable salts thereof;
with the proviso that:
(i) when n = 0; at least one of R1 to R11 is other than H;
together with a pharmaceutically acceptable diluent or carrier.
2) A method as claimed in claim 1 in which comprises a compound of formula I
in which n is 0 or 1;
R1, R2, R6 and R7 are each H;
R3 and R4 are independently H or methyl; or together represent imino, methylimino, phenylimino, hydroxyimino or methoxyimino;
R5 is H or methyl, or when R3 and R4 are independently H or methyl, R5 is H, methyl, formyl, acetyl, propionyl, benzoyl, methylsulphinyl, methylsulphonyl or ethylsulphonyl;
R8 is H, methyl, fluoro or chloro; and R9, R10 and R11 are each H;
or a pharmaceutically acceptable salt thereof.
3) A method as claimed in claim 1 in which the compound of formula I is selected from:
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-formyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-6-chloro-2, 3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
4-acetyl-6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-methylsulphinyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
4-ethylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
3-hydroxyimino-6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
in which n is 0 or 1;
R1, R2, R6 and R7 are each H;
R3 and R4 are independently H or methyl; or together represent imino, methylimino, phenylimino, hydroxyimino or methoxyimino;
R5 is H or methyl, or when R3 and R4 are independently H or methyl, R5 is H, methyl, formyl, acetyl, propionyl, benzoyl, methylsulphinyl, methylsulphonyl or ethylsulphonyl;
R8 is H, methyl, fluoro or chloro; and R9, R10 and R11 are each H;
or a pharmaceutically acceptable salt thereof.
3) A method as claimed in claim 1 in which the compound of formula I is selected from:
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-formyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-6-chloro-2, 3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
4-acetyl-6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-methylsulphinyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
4-ethylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
3-hydroxyimino-6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
3-methylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine; and 6-chloro-3-phenylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
their stereoisomers; and pharmaceutically acceptable salts thereof.
4) A method as claimed in claim 1 in which the compound of formula I is selected from:
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-formyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
their stereoisomers; and pharmaceutically acceptable salts thereof.
4) A method as claimed in claim 1 in which the compound of formula I is selected from:
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-formyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-6-chloro-2, 3,4, 5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-methylsulphinyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine; and 6-chloro-3-phenylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
their stereoisomers; and pharmaceutically acceptable salts thereof.
6-chloro-4-methylsulphinyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine; and 6-chloro-3-phenylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
their stereoisomers; and pharmaceutically acceptable salts thereof.
5) A method as claimed in claim 1 in which the compound of formula I is selected from:
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide; and 6-fluoro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
their stereoisomers; and pharmaceutically acceptable salts thereof.
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide; and 6-fluoro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
their stereoisomers; and pharmaceutically acceptable salts thereof.
6) A method as claimed in claim 1 in which the compound of formula I is selected from:
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
and pharmaceutically acceptable salts thereof.
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
and pharmaceutically acceptable salts thereof.
7) The use of a compound of Formula I as described in any one of claims 1-6 in the manufacture of a medicament for use in the treatment of obesity and related conditions including eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, and stress, and as an aid to smoking cessation.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9914745.6 | 1999-06-24 | ||
| GBGB9914745.6A GB9914745D0 (en) | 1999-06-24 | 1999-06-24 | Therapeutic agents |
| PCT/EP2000/005541 WO2001000185A2 (en) | 1999-06-24 | 2000-06-16 | 1,4-denzothiazepines to treat obesity related disorders |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2376023A1 true CA2376023A1 (en) | 2001-01-04 |
Family
ID=10855956
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002376023A Abandoned CA2376023A1 (en) | 1999-06-24 | 2000-06-16 | Therapeutic agents |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP1218010A2 (en) |
| JP (1) | JP2003513008A (en) |
| AU (1) | AU5973600A (en) |
| CA (1) | CA2376023A1 (en) |
| GB (1) | GB9914745D0 (en) |
| MX (1) | MXPA01013420A (en) |
| WO (1) | WO2001000185A2 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8710045B2 (en) | 2004-01-22 | 2014-04-29 | The Trustees Of Columbia University In The City Of New York | Agents for preventing and treating disorders involving modulation of the ryanodine receptors |
| US7704990B2 (en) * | 2005-08-25 | 2010-04-27 | The Trustees Of Columbia University In The City Of New York | Agents for preventing and treating disorders involving modulation of the RyR receptors |
| EP2123644B1 (en) * | 2007-03-07 | 2014-12-17 | Takeda Pharmaceutical Company Limited | Benzoxazepine derivatives and use thereof |
| JP2012508692A (en) | 2008-11-12 | 2012-04-12 | シェーリング コーポレイション | Inhibitors of fatty acid binding protein (FABP) |
| WO2013064231A1 (en) | 2011-10-31 | 2013-05-10 | Phenex Pharmaceuticals Ag | SEVEN-MEMBERED SULFONAMIDES AS MODULATORS OF RAR-RELATED ORPHAN RECEPTOR-GAMMA (RORγ, NR1F3) |
| EP2708535A1 (en) | 2012-05-11 | 2014-03-19 | Les Laboratoires Servier | Agents for treating disorders involving modulation of ryanodine receptors |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3361760A (en) * | 1963-03-21 | 1968-01-02 | Squibb & Sons Inc | Benzothiazepines |
| US3794639A (en) * | 1966-03-10 | 1974-02-26 | Squibb & Sons Inc | Benzoxazepines and benzothiazepines |
| JP2871811B2 (en) * | 1990-02-28 | 1999-03-17 | サントリー株式会社 | 7-membered condensed ring compound |
| GB9203347D0 (en) * | 1992-02-17 | 1992-04-01 | Wellcome Found | Hypolipidaemic compounds |
| JP3093419B2 (en) * | 1992-03-30 | 2000-10-03 | 麒麟麦酒株式会社 | 1,4-benzothiazepine derivatives |
| WO1994011360A1 (en) * | 1992-11-09 | 1994-05-26 | The Boots Company Plc | 1,4-benzothiazepines useful as neurological agents |
| EP0673371A1 (en) * | 1992-12-11 | 1995-09-27 | Novartis AG | Benzazepinone derivatives |
| IL108634A0 (en) * | 1993-02-15 | 1994-05-30 | Wellcome Found | Hypolipidaemic heterocyclic compounds, their prepatation and pharmaceutical compositions containing them |
| ZA941003B (en) * | 1993-02-15 | 1995-08-14 | Wellcome Found | Hypolipidaemic compounds |
| ZA956647B (en) * | 1994-08-10 | 1997-02-10 | Wellcome Found | Hypolipidaemic compounds. |
| DK0864582T3 (en) * | 1997-03-14 | 2003-09-29 | Aventis Pharma Gmbh | Hypolidemic 1,4-benzothiazepine-1,1-dioxides |
| EP1021190B1 (en) * | 1997-08-22 | 2006-11-08 | Kaken Pharmaceutical Co., Ltd. | Amid derivatives as growth hormone release promotors |
-
1999
- 1999-06-24 GB GBGB9914745.6A patent/GB9914745D0/en not_active Ceased
-
2000
- 2000-06-16 EP EP00945759A patent/EP1218010A2/en not_active Withdrawn
- 2000-06-16 AU AU59736/00A patent/AU5973600A/en not_active Abandoned
- 2000-06-16 JP JP2001505895A patent/JP2003513008A/en not_active Withdrawn
- 2000-06-16 CA CA002376023A patent/CA2376023A1/en not_active Abandoned
- 2000-06-16 WO PCT/EP2000/005541 patent/WO2001000185A2/en not_active Application Discontinuation
- 2000-06-16 MX MXPA01013420A patent/MXPA01013420A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| WO2001000185A2 (en) | 2001-01-04 |
| AU5973600A (en) | 2001-01-31 |
| WO2001000185A3 (en) | 2002-04-11 |
| EP1218010A2 (en) | 2002-07-03 |
| JP2003513008A (en) | 2003-04-08 |
| GB9914745D0 (en) | 1999-08-25 |
| MXPA01013420A (en) | 2002-07-22 |
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