JP2003513008A - Remedies - Google Patents

Abstract

  (57) [Summary] The present invention provides a method of treating obesity and related conditions, wherein the mammal, especially a human in need thereof, is provided with a therapeutically effective amount of a compound of formula (I): wherein n = 0, 1, or 2; R₁And R₂Independently represents H or alkyl of 1 to 4 carbon atoms, optionally substituted by one or more halo;₃And R₄Independently represents H or alkyl having 1 to 4 carbon atoms;₁₂(Where R₁₂Represents H, hydroxy, alkyl having 1 to 4 carbon atoms, phenyl, or alkoxy having 1 to 4 carbon atoms), wherein each alkyl, phenyl and alkoxy may be one or more of Substituted with the above halo; R₅Are (a) H, (b) alkyl having 1 to 4 carbon atoms, (c) R₃And R₄Represents H or alkyl (optionally substituted with one or more halo);₁₃(Where R₁₃Represents H, alkyl having 1 to 4 carbon atoms or phenyl), or (d) R ₃And R₄Represents H or alkyl (optionally substituted with one or more halo);_pR₁₄(Where p = 1 or 2 and R_{1 4}Is alkyl or phenyl having 1 to 4 carbon atoms), wherein each alkyl and phenyl is optionally substituted with one or more halo;₆And R₇Are each H; R₈~ R₁₁Is independently H, halo, cyano, nitro, alkyl having 1 to 4 carbons, alkoxy having 1 to 4 carbons, alkanoyl having 1 to 4 carbons, carboxy, alkanoyloxy having 1 to 4 carbons , Carbamoyl (optionally substituted with alkyl of 1-4 carbon atoms) or sulfamoyl (optionally substituted with alkyl of 1-4 carbon atoms), each alkyl, alkoxy, alkanoyl or alkanoyloxy Is optionally substituted with one or more halo); stereoisomers thereof; and pharmaceutically acceptable salts thereof. Embedded image

Description

Detailed Description of the Invention

The present invention is in the treatment of obesity, such as hyperphagia, anorexia, gluttony, and eating disorders such as binge eating, non-insulin dependent diabetes mellitus, hyperglycemia, hyperlipidemia, and stress. , And a few as an adjunct to smoking cessation
, 4,5-Tetrahydro-1,4-benzothiazepine.

[0002]   Compound of formula I:

[0003]

[Chemical 2] here,   n = 0, 1, or 2; R₁And R_TwoAre independently H or alkyl of 1 to 4 carbon atoms (one or
Optionally substituted by more than one halo);   R_ThreeAnd R_FourAre independently H or alkyl having 1 to 4 carbon atoms;
Or both formula = NR₁₂(Where R₁₂Is H, hydroxy, 1 to 1 carbon atoms
4 alkyl, phenyl, or alkoxy having 1 to 4 carbon atoms)
And each alkyl, phenyl, and alkoxy is optionally one or
Or substituted with more halo;   R₅Is (a) H, (b) alkyl having 1 to 4 carbon atoms, (c) R_ThreeAnd R _Four Represents H or alkyl (optionally substituted with one or more halo)
When forgotten, the formula-COR_Thirteen(Where R_ThirteenIs H, an alkyl group having 1 to 4 carbon atoms
Or a group of (or represents phenyl), or (d) R_ThreeAnd R_FourBut H or
When representing alkyl (optionally substituted with one or more halo), the formula -S
(O)_pR₁₄(Where p = 1 or 2 and R₁₄Is an atom having 1 to 4 carbon atoms
Is alkyl or phenyl), each alkyl and phenyl is
Optionally substituted with one or more halo;   R₆And R₇Are each H;   R₈~ R₁₁Are independently H, halo, cyano, nitro, C1-C4al,
Kill, alkoxy having 1 to 4 carbon atoms, alkanoyl having 1 to 4 carbon atoms, cal
Boxy, alkanoyloxy having 1 to 4 carbon atoms, carbamoyl (1 carbon atom
~ 4 alkyl optionally substituted), or sulfamoyl (C1-C1)
4 optionally substituted with alkyl), each alkyl, alkoxy, alka
Noyl, or alkanoyloxy optionally substituted with one or more halo
);   These stereoisomers; and   A pharmaceutically acceptable salt thereof;   However, when (i) n = 0, R₁~ R₁₁At least one of them is other than H
Those that are subject to the treatment of seizures and neuropathy
It is disclosed in WO94 / 11360.

The present invention is a method of treating obesity and related conditions, wherein a mammal, especially a human, in need thereof is treated with a therapeutically effective amount of a compound of formula I:

[0005]

[Chemical 3] here,   n = 0, 1, or 2;   R₁And R_TwoAre independently H or alkyl of 1 to 4 carbon atoms (one or
Optionally further substituted by halo).   R_ThreeAnd R_FourAre independently H or alkyl having 1 to 4 carbon atoms; Or both formula = NR₁₂(Where R₁₂Is H, hydroxy, 1 to 1 carbon atoms
4 alkyl, phenyl, or alkoxy having 1 to 4 carbon atoms)
And each alkyl, phenyl, and alkoxy represents one or more
Optionally substituted with halo;   R₅Is (a) H, (b) alkyl having 1 to 4 carbon atoms, (c) R_ThreeAnd R _Four Represents H or alkyl (optionally substituted with one or more halo)
When forgotten, the formula-COR_Thirteen(Where R_ThirteenIs H, alkyl having 1 to 4 carbon atoms,
Or phenyl) or (d) R_ThreeAnd R_FourBut H or Al
When representing kill (optionally substituted with one or more halo), the formula -S (O
)_pR₁₄(Where p = 1 or 2 and R₁₄Is an alky having 1 to 4 carbon atoms
And each phenyl and phenyl is
Thus substituted with one or more halo;   R₆And R₇Are each H;   R₈~ R₁₁Are independently H, halo, cyano, nitro, C1-C4al,
Kill, alkoxy having 1 to 4 carbon atoms, alkanoyl having 1 to 4 carbon atoms, cal
Boxy, alkanoyloxy having 1 to 4 carbon atoms, carbamoyl (1 carbon atom
~ 4 alkyl optionally substituted), or sulfamoyl (C1-C1)
4 optionally substituted with alkyl), each alkyl, alkoxy, alka
Noyl, or alkanoyloxy may optionally be one or more ha.
Replaced by b;   These stereoisomers; and   Pharmaceutically acceptable salts thereof, Is provided.

As used herein, the term “the associated condition” refers to, for example, anorexia,
Anorexia nervosa, eating disorders such as eating and eating, non-insulin-dependent diabetes mellitus, hyperglycemia, hyperlipidemia, and stress are also indicated, and as an adjunct to smoking cessation. means.

[0007]   In a preferred group of compounds of formula 1:

[0008]

[Chemical 4] n = 0 or 1; R ₁ , R ₂ , R ₆ , and R ₇ are each H; R ₃ and R ₄ are independently H or methyl; or both are imino, methylimino, phenylimino R ₅ is H or methyl, or when R ₃ and R ₄ are independently H or methyl, then R ₅ is H, methyl, formyl, acetyl, Is propionyl, benzoyl, methylsulfinyl, methylsulfonyl, or ethylsulfonyl; R ₈ is H, methyl, fluoro, or chloro; and R ₉ , R ₁₀ , and R ₁₁ are each H; It is an acceptable salt of this.

Preferred compounds of formula I are 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-methylsulfinyl-2,3,4,5-tetrahydro-1,
4-Benzothiazepine; 4-Methylsulfonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide; 4-Ethylsulfonyl-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. −
Benzothiazepines, their stereoisomers; and pharmaceutically acceptable salts thereof.

Further preferred compounds of formula 1 are: 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-methylsulfinyl-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-
Benzothiazepines; their stereoisomers; and pharmaceutically acceptable salts thereof.

The most preferred compounds of formula 1 are 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-methylsulfonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine; 6-chloro-4-methylsulfonyl-2, 3,4,5-tetrahydro-1,4
-Benzothiazepine; 6-chloro-4-methylsulfonyl-2,3,4,5-tetrahydro-1,4
-Benzothiazepine 1-oxide; and 6-fluoro-4-methylsulfonyl-2,3,4,5-tetrahydro-1,
4-benzothiazepine; these stereoisomers; and pharmaceutically acceptable salts thereof.

Particularly preferred compounds of formula 1 are: 4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine; stereoisomers thereof; and pharmaceutically acceptable These salts are.

The present invention also provides a method of treating obesity and related conditions, wherein a therapeutically effective amount of a compound of formula I:

[0014]

[Chemical 5] here,   n = 0, 1, or 2;   R₁And R_TwoAre independently H or alkyl of 1 to 4 carbon atoms (one or
Optionally further substituted by halo).   R_ThreeAnd R_FourAre independently H or alkyl having 1 to 4 carbon atoms; Or both formula = NR₁₂(Where R₁₂Is H, hydroxy, 1 to 1 carbon atoms
4 alkyl, phenyl, or alkoxy having 1 to 4 carbon atoms)
And each alkyl, phenyl, and alkoxy is optionally one or
Or substituted with more halo;   R₅Is (a) H, (b) alkyl having 1 to 4 carbon atoms, (c) R_ThreeAnd R _Four Represents H or alkyl (optionally substituted with one or more halo)
When forgotten, the formula-COR_Thirteen(Where R_ThirteenIs H, alkyl having 1 to 4 carbon atoms,
Or phenyl) or (d) R_ThreeAnd R_FourBut H or Al
When representing kill (optionally substituted with one or more halo), the formula -S (O
)_pR₁₄(Where p = 1 or 2 and R₁₄Is an alky having 1 to 4 carbon atoms
And each phenyl and phenyl is
Thus substituted with one or more halo;   R₆And R₇Are each H;   R₈~ R₁₁Are independently H, halo, cyano, nitro, C1-C4al,
Kill, alkoxy having 1 to 4 carbon atoms, alkanoyl having 1 to 4 carbon atoms, cal
Boxy, alkanoyloxy having 1 to 4 carbon atoms, carbamoyl (1 carbon atom
~ 4 alkyl optionally substituted), or sulfamoyl (C1-C1)
4 optionally substituted with alkyl), each alkyl, alkoxy, alka
Noyl, or alkanoyloxy optionally substituted with one or more halo
Was done;   These stereoisomers; and   A pharmaceutically acceptable salt thereof;   However, when (i) n = 0, R₁~ R₁₁At least one of them is other than H
If there is a condition that it is   Also provided are pharmaceutical compositions that include a pharmaceutically acceptable diluent or carrier.
.

A preferred pharmaceutical composition for the treatment of obesity and related conditions is a therapeutically effective amount of Formula I
A compound of: wherein n = 0 or 1; R ₁ and R ₂ are independently H or methyl; R ₃ and R ₄ are independently H or methyl; or both are imino, methylimino Represents phenylimino, hydroxyimino, or methoxyimino; R ₅ is H or methyl, and when R ₃ and R ₄ are H or methyl, R ₅ is H, methyl, formyl, acetyl, propionyl. , Benzoyl, methylsulfinyl, methylsulfonyl, or ethylsulfonyl; R ₆ and R ₇ are each H; and one of R _{8 to} R ₁₁ is H, fluoro, chloro, bromo, iodo, methyl. (Optionally substituted with one or more halo), methoxy (optionally substituted with one or more halo), nitro, Ano, carboxy, acetyl,
Dimethylcarbamoyl, or dimethylsulfamoyl, the rest of R _{8 to} R ₁₁ is H; these stereoisomers; and pharmaceutically acceptable salts thereof.

A more preferred pharmaceutical composition for the treatment of obesity and related conditions is a therapeutically effective amount of a compound of formula I: wherein n = 0 or 1; R ₁ , R ₂ , R ₆ and R ₇ Are each H; R ₃ and R ₄ are H or both are methylimino, phenylimino,
Hydroxyimino, or methoxyimino; R ₅ is H or methyl, and when R ₃ and R ₄ are H, R ₅ is H,
Methyl, formyl, acetyl, propionyl, benzoyl, methylsulfinyl, methylsulfonyl, or ethylsulfonyl; R ₈ is H, methyl, fluoro, or chloro; R _{9 to} R ₁₁ are all H, these Stereoisomers; and pharmaceutically acceptable salts thereof.

Particularly preferred pharmaceutical compositions for the treatment of obesity and related conditions are therapeutically effective amounts of a compound 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-tetrahydro-1,4-benzothiazepine; 4-acetyl-2, 3,4,5-tetrahydro-1,4-benzothiazepine; 4-acetyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 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 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-chloro-4-propionyl-2,3,4,5-tetrahydro- 1,4-benzothiazepine; 4-benzoyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1; 6-chloro-4-methylsulfinyl-2,3,4 5-Tetrahi (B) -1,
4-Benzothiazepine; 4-Methylsulfonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine; 4-Methylsulfonyl-2,3,4,5-tetrahydro-1,4-benzothi Azepine 1-oxide; 6-chloro-4-methylsulfonyl-2,3,4,5-tetrahydro-1,4
-Benzothiazepine; 6-chloro-4-methylsulfonyl-2,3,4,5-tetrahydro-1,4
-Benzothiazepine-oxide; 6-fluoro-4-methylsulfonyl-2,3,4,5-tetrahydro-1,
4-benzothiazepine; 6-methyl-4-methylsulfonyl-2,3,4,5-tetrahydro-1,4
4-benzothiazepine; 4-ethylsulfonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine; 6-chloro-4-ethylsulfonyl-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; these stereoisomers; and pharmaceutically acceptable salts thereof.

The compounds of the present invention may be prepared and formulated as pharmaceutical formulations described in WO 94/11360.

The compound of formula I may be administered in any of the known dosage forms. The amount of compound administered depends on the age of the patient, the severity of this condition, and the patient's past medical history (m
It depends on a number of factors including the medical history), and always depends on the normal judgment of the doctor who administers the compound. Generally, the dose of the compound to be administered is 0.1 or more times a day. Within the range of ~ 1000 mg, preferably 1-500 mg.

Oral dosage forms are the preferred compositions for use in the present invention, these being the known pharmaceutical forms for such administration, such as tablets, capsules, granules, syrups and aqueous or oily suspensions. It is a liquid. The excipients used in the preparation of these compositions are those known in the art of pharmaceutical manufacturers. Tablet
The active compound and fillers, such as calcium phosphate; disintegrants, such as corn starch; lubricants, such as magnesium stearate; binders, such as microcrystalline cellulose or polyvinylpyrrolidone, and the mixture can be tabletted by known techniques, It may be prepared from a mixture with other optional ingredients known in the art. These tablets may, if desired, be coated using known methods and excipients which may include enteric coatings, for example with hydroxypropylmethylcellulose phthalate. These tablets may be formulated in a manner known to those skilled in the art to give sustained release of the compounds of the invention. Such tablets may, if desired, be provided with an enteric coating by known methods, for example with cellulose acetate phthalate. Similarly, capsules, such as hard or soft gelatin capsules, containing the active compound with or without added excipients, can be prepared by known methods and, if desired, enteric-coated by known methods. It may be coated. The contents of the capsule may be formulated using known methods to give sustained release of the active compound. These tablets and capsules may conveniently each contain from 1 to 500 mg of active compound. Preferably these tablets and capsules are 5, 10, 15, 20, 25, 30, 50,
Contains 100, 250, or 500 mg.

Other dosage forms for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of non-toxic suspending agents such as sodium carboxy-methylcellulose, and suitable vegetable oils such as An oily suspension containing the compound of the invention in peanut oil is included. The active compound may be formulated as granules with or without additional excipients. These granules may be ingested directly by the patient or they may be added to a suitable liquid carrier (eg water) prior to ingestion. These granules may contain effervescent couples, such as effervescent couples, formed from acids and carbonates or bicarbonates to facilitate dispersion in the liquid medium.

The therapeutically active compound of formula I may be formulated as a composition that the patient holds in the oral cavity such that the active compound is administered through the mucous membranes of the oral cavity.

Suitable dosage forms for rectal administration are the known pharmaceutical forms for such administration, for example cocoa butter or polyethylene glycol-based suppositories.

Suitable dosage forms for parenteral administration are the known pharmaceutical forms for such administration, eg sterile suspensions or solutions in suitable solvents.

Dosage forms for topical administration include a dispersion of the pharmacologically active compounds of this invention such that these compounds remain in contact with the skin for transdermal administration. The matrix may be included. Suitable transdermal compositions include a pharmaceutically active compound and a topical vehicle such as mineral oil, petrolatum, and / or a wax such as paraffin wax or beeswax, a potential transdermal enhancer such as dimethyl sulfoxide or propylene. It can be prepared by mixing with glycol. Alternatively, the active compound may be dispersed in a pharmaceutically acceptable cream, gel, or ointment base. The amount of active compound included in the topical formulation should be such that a therapeutically effective amount of the compound is delivered during the time that the topical formulation should be on the skin.

The therapeutically active compound of formula I may be formulated as a composition that is dispersed as a propellant in the oral cavity or nasal cavity of the patient. Such propellants may be dispensed from pump containers or pressurized containers containing volatile propellants.

The therapeutically active compound of formula I used in the method of the invention may also be administered by external infusion, eg by intravenous infusion, or by continuous infusion from a compound source placed inside the body. Internal sources include, for example, an embedded reservoir containing the compound to be injected, which is continuously released by osmosis, and (a) a liquid, for example a very poorly water soluble derivative form, for example a dodecanoate salt or a lipophilic ester. Oily suspensions of the compounds injected in the form of, or (b) implants for the injected compounds, which may be solid, for example in the form of embedded supports of synthetic resins or wax-containing materials. The support may be a simple substance containing all of the compound or a series of multiple components each containing a portion of the compound to be delivered. The amount of active compound present in the internal source should be such that a therapeutically effective amount of this compound is delivered over an extended period of time.

In some formulations, for example obtained by fluid energy milling,
It may be advantageous to use the compounds of the invention in the form of particles of very small size.

A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I can be used to treat obesity in mammals, especially humans, and eating disorders such as hyperphagia, anorexia, gluttony, and binge eating, non-insulin dependent. It can be used for the treatment of diabetes mellitus, hyperglycemia, hyperlipidemia, and related conditions including stress, and as an adjunct to smoking cessation in humans. The precise amount of the active compound administered in such treatment will depend on several factors, including, for example, the age of the patient, the severity of the condition, and past medical history, and always Depending on the normal judgment of the administering physician, the amount of compound administered per day will be in the range of 1 to 1000 mg, preferably 5 to 500 mg, once or more times a day.

In yet another aspect, the invention provides for obesity and eating disorders such as hyperphagia, anorexia, gluttony, and binge eating, non-insulin dependent diabetes mellitus, hyperglycemia, high fat. Provided is the use of a compound of formula I in the treatment of blood pressure and its related conditions including stress, and in the manufacture of a medicament for use as an adjunct to quit smoking.

The present invention also addresses obesity and eating disorders such as hyperphagia, anorexia, gluttony and binge eating, non-insulin dependent diabetes mellitus, hyperglycemia, hyperlipidemia, and stress. Also provided is a method of treating a related condition comprising, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I.

The present invention also provides a method of reducing the desire to smoke in humans, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I. The present invention also provides a method of reducing weight gain in a human being after smoking cessation, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I.

Furthermore, the compounds of the present invention are useful for metabolic diseases and conditions resulting therefrom, such as non-exercise activity thermogenesis.
genesis) and increased metabolic rate.

The compounds of the present invention may also be useful in preventing cardiovascular disease and in reducing platelet adhesion, helping to reduce weight after pregnancy, and helping to lose weight after quitting smoking.

The following in vivo test confirms the finding that compounds of formula I have efficacy in the treatment of obesity.

Marmosets fed 4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (50 mg / kg po) daily for 14 days show reduced weight gain. It was

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 25/18 A61P 25/18 25/34 25/34 C07D 281/10 C07D 281/10 C (81) designation Country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG) , CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW) ), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, A, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP , KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW [Continued Summary]

Claims (7)

[Claims] 1. A method of treating obesity and its related conditions, which method requires it.
To a mammal, especially a human being, a therapeutically effective amount of a compound of formula I:     [Chemical 1] here,   n = 0, 1, or 2;   R₁And R_TwoAre independently H or alkyl of 1 to 4 carbon atoms (one or
Optionally further substituted by halo).   R_ThreeAnd R_FourAre independently H or alkyl having 1 to 4 carbon atoms; Or both formula = NR₁₂(Where R₁₂Is H, hydroxy, 1 to 1 carbon atoms
4 alkyl, phenyl, or alkoxy having 1 to 4 carbon atoms)
And each alkyl, phenyl, and alkoxy is optionally one or
Or substituted with more halo;   R₅Is (a) H, (b) alkyl having 1 to 4 carbon atoms, (c) R_ThreeAnd R _Four Represents H or alkyl (optionally substituted with one or more halo)
When forgotten, the formula-COR_Thirteen(Where R_ThirteenIs H, alkyl having 1 to 4 carbon atoms,
Or phenyl) or (d) R_ThreeAnd R_FourBut H or Al
When representing kill (optionally substituted with one or more halo), the formula -S (O
)_pR₁₄(Where p = 1 or 2 and R₁₄Is an alky having 1 to 4 carbon atoms
And each phenyl and phenyl is
Thus substituted with one or more halo;   R₆And R₇Are each H;   R₈~ R₁₁Are independently H, halo, cyano, nitro, C1-C4al,
Kill, alkoxy having 1 to 4 carbon atoms, alkanoyl having 1 to 4 carbon atoms, cal
Boxy, alkanoyloxy having 1 to 4 carbon atoms, carbamoyl (1 carbon atom
~ 4 alkyl optionally substituted), or sulfamoyl (C1-C1)
4 optionally substituted with alkyl), each alkyl, alkoxy, alka
Noyl, or alkanoyloxy may optionally be one or more ha.
Replaced by b;   These stereoisomers; and   A pharmaceutically acceptable salt thereof;   However, when (i) n = 0, R₁~ R₁₁At least one of them is other than H
If there is a condition that it is   A method comprising administering with a pharmaceutically acceptable diluent or carrier. 2. A compound of formula I: wherein n is 0 or 1; R ₁ , R ₂ , R ₆ and R ₇ are each H; R ₃ and R ₄ are independently H Or methyl or both together represent imino, methylimino, phenylimino, hydroxyimino, or methoxyimino; R ₅ is H or methyl, or R ₃ and R ₄ are independently H or methyl Wherein R ₅ is H, methyl, formyl, acetyl, propionyl,
Benzoyl, methylsulfinyl, methylsulfonyl, or ethylsulfonyl; R ₈ is H, methyl, fluoro, or chloro; and R ₉ , R ₁₀ , and R ₁₁ are each H, or pharmaceutically The method of claim 1 comprising acceptable salts thereof. 3. A compound of formula I is 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-methylsulfinyl-2,3,4,5-tetrahydro-1,
4-Benzothiazepine; 4-Methylsulfonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide; 4-Ethylsulfonyl-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. −
The method of claim 1, selected from benzothiazepine; these stereoisomers; and pharmaceutically acceptable salts thereof. 4. A compound of formula I is 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-methylsulfinyl-2,3,4,5-tetrahydro-1,
4-benzothiazepine; 6-chloro-3-hydroxyimino-2,3,4,5-tetrahydro-1,4
-Benzothiazepine; 6-chloro-3-phenylimino-2,3,4,5-tetrahydro-1,4-
The method of claim 1, selected from benzothiazepine; these stereoisomers; and pharmaceutically acceptable salts thereof. 5. The compound of formula I is 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-methylsulfonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine; 6-chloro-4-methylsulfonyl-2, 3,4,5-tetrahydro-1,4
-Benzothiazepine; 6-chloro-4-methylsulfonyl-2,3,4,5-tetrahydro-1,4
-Benzothiazepine 1-oxide; and 6-fluoro-4-methylsulfonyl-2,3,4,5-tetrahydro-1,
The method of claim 1, selected from 4-benzothiazepines; stereoisomers thereof; and pharmaceutically acceptable salts thereof. 6. A compound of formula I is selected from 4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine; and pharmaceutically acceptable salts thereof. The method of claim 1, wherein the method comprises: 7. Obesity and, for example, increased appetite, loss of appetite, and eating (
in the treatment of eating disorders such as snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycemia, hyperlipidemia, and its related conditions including stress, and for quitting smoking. Use of a compound of formula I according to any one of claims 1 to 6 in the manufacture of a medicament for use as an adjuvant.