JP2003503344A - Remedies - Google Patents

Abstract

(57) Abstract: In a method of treating obesity and related morbidity in humans, there is provided a compound of formula I comprising its enantiomer and its pharmaceutically acceptable salt. Wherein R ₁ and R ₂ are independently H or methyl, and a therapeutically effective amount of a lipase inhibitor excluding orlistate, to a human in need of such treatment. Wherein the compound of formula I and the lipase inhibitor are administered simultaneously, separately or sequentially.

Description

Detailed Description of the Invention

The present invention relates to methods for treating and preventing obesity and related pathological conditions, as well as formulations and pharmaceutical compositions suitable for use in such methods.
In particular, the present invention includes a method for treating obesity and related pathological conditions by administering sibutramine or a salt or metabolite thereof, and a lipase inhibitor, as well as methods for treating such obesity. Formulations and compositions.

Sibutramine is an inhibitor of 5-hydroxytryptamine and noradrenaline reuptake in vivo (Buckett, WR, Thomas, PC.
& Luscombe, GP (1988). Prog. NeuroPsychopharmacol. Biol. Psychaiat.
12, 575-584 and Luscombe, GP, Hopcroft, RH, Thomas, PC & Buckett, W
.R. (1989). Neuropharmacology, 28, 129-134). Studies have shown that a dual mode of action reduces body weight; reduces satiety by increasing satiety (Fantini, M. & Souquet, A.-M. (1995). Int. . J. Obesity, 1
9, 145; Halford, JCG, Heal, DJ & Blundell, JE (1995). Brit. J ,. P
harmacol. 114, 387P; and Stricker-Krongrad, A., Souquet, A.-M. & Burlet,
C. (1995). Int. J. Obesity, 19, 145) and increases energy consumption by stimulating thermogenicity (Connoley, IP, Heal, DJ & Stock, MJ.
1995). Brit. J. Pharmacol. 114, 388P; and Connoley, IP, Frost, I., Hea
l, D, J, & Stock, MJ (1996). Brit, J. Pharmacol. 117, 170P). Sibutramine is found in the United States and in at least 20 other countries worldwide.
It is approved for use in the treatment of obesity.

The lipase enzyme has the ability to break down ingested fat (Borgstrom, B. (1988).
Biochem. Biophys. Acta. 962 (3), 308-316), which results in the elimination of unabsorbed fat in the feces. One such lipase inhibitor, orlistat, is now approved for use in the treatment of obesity in the United States and Europe and has the chemical name (2S, 3S, 5S) -5-[( S) -2-formamido-4-methylvaleryloxy] -2-hexyl-3-hydroxyhexadecanoic acid lactone. It contains "N-formyl-L-leucine and (3
S, 4S) -3-Hexyl-4-[(2S) -2-hydroxy-tridecyl]-
(-)-Tetrahydrolipstatin, tetrahydrolipstatin and orlystate are known as "esters with 2-oxetanone." Extraction of orlystate and its use in the management and prevention of obesity and hyperlipidemia is described in US Pat. 4598089 (Hoffmann-La Roche Inc.).
. A method of making orlystate is described in US Pat. No. 4,983,746 (Hoffmann-La Roche Inc.). Orlystate and acarbose (ac
Arbose) -containing compositions are described in EP 638317 (Hoffmann-La Roche AGF).

It has been reported that Orlystate should not be combined with an appetite suppressant (The New York Times May 15 1997). Patent PCT / EP98 / 0 pending
8249 discloses the use of a combination of a compound of formula I and orlystate as described below in the treatment of obesity. It was surprisingly found that co-administration of sibutramine hydrochloride monohydrate with a lipase inhibitor results in a beneficial effect on weight loss.

Accordingly, the present invention provides a method for treating obesity and related pathological conditions in mammals, especially humans, in need of such treatment, wherein
This process comprises the formula I, including its enantiomers and its pharmaceutically acceptable salts.

[0006]

[Chemical 3]

A therapeutically effective amount of a compound of the formula where R ¹ and R ² are independently H or methyl and a therapeutically effective amount of a lipase inhibitor are administered to mammals in need of such treatment, in particular Including administration to humans, provided that the lipase inhibitor does not contain orlystate; the compound of formula I and the lipase inhibitor are administered simultaneously, separately or sequentially.

The present invention has the following advantages: First, the maximum weight loss achieved is of formula I
Is greater than that achieved by single administration of the compound or lipase inhibitor. Second, the weight loss obtained by administration of the compound of formula I and lipase inhibitor to the first test group is reduced by the administration of the compound of formula I to the second test group and the third The synergistic effect is greater than the total amount of weight loss achieved by administration of lipase inhibitors to the test group. Third, if weight loss reaches a plateau after administration of a compound of formula I or a lipase inhibitor, further weight loss is achieved by administration of other compounds. Fourth, low doses of compounds of formula I and lipase inhibitors may be used in the present invention, resulting in reduced side effects associated with high doses of the respective compounds. Fifth, in the treatment of pathological conditions associated with obesity, compared to the administration of each compound alone,
Significant improvements may be achieved.

A preferred compound of formula I is N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N-dimethylamine or salts thereof, eg of sibutramine hydrochloride Such a hydrochloride salt. The preferred form of this hydrochloride salt is its monohydrate, in which case it is known as sibutramine hydrochloride monohydrate.

Preparation and use of compounds of formula I, for example N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N-dimethylamine and salts thereof, in the treatment of depression. Are described in British Patent Specification No. 2098602. The use of compounds of formula I, for example N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N-dimethylamine and salts thereof, in the treatment of Parkinson's disease is described in PCT application WO88
/ 06444. N- {1- [1 in the treatment of brain dysfunction
The use of-(4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N-dimethylamine and salts thereof is described in U.S. Pat. No. 4,939,175. The use of N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N-dimethylamine hydrochloride in the treatment of obesity is described in EP 397831. ing. A particularly preferred form of this compound is N- {1- [1- (4-chlorophenyl) cyclobutyl]
-3-Methylbutyl} -N, N-dimethylamine hydrochloride monohydrate (sibutramine hydrochloride monohydrate), which is described in EP 230742. N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N-dimethylamine and these for improving glucose tolerance in a human suffering from impaired glucose tolerance or non-insulin dependent diabetes The use of salts according to the invention is described in published PCT application WO 95/20949.

It will be appreciated by those skilled in the art that compounds of formula I contain chiral centers. If the compound of formula I contains a single chiral center, it may exist in the form of two enantiomers. The present invention includes the use of individual enantiomers and mixtures of enantiomers. Enantiomers may be resolved by methods known to those skilled in the art, for example by formation of diastereomeric salts or complexes which may be separated by crystallization, for example crystallization, gas-liquid chromatography or liquid phase. By the formation of diastereomeric derivatives, which may be separated by chromatography, or by selective reaction of one enantiomer with an enantiomer-specific reagent, such as enzymatic oxidation or reduction, subsequent modification of the enantiomer and unmodified. It may be by separation of the qualitative enantiomers, or by gas-liquid phase chromatography in the chiral environment, for example on a chiral support such as silica with a bound chiral ligand, or in a chiral solvent.
It will be appreciated that if the desired enantiomer is converted to another chemical entity by one of the separation steps shown above, then another step is required to liberate the enantiomeric form. Ah Alternatively, specific enantiomers can be converted from one enantiomer to another by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by asymmetric transformation. It may be synthesized by converting. Also, the enantiomers of the secondary and tertiary amines of formula I can be used to prepare the primary amine racemate, resolution of this mixture into its separate enantiomers, and, subsequently, of the reasonably optically pure primary amine enantiomers. It can be prepared by conversion to the preferred secondary amine product or tertiary amine product.

Preferred compounds of formula I include N- {1- [1- (4-chlorophenyl) cyclobutyl] -3, including racemates, individual enantiomers and mixtures thereof.
-Methylbutyl} -N, N-dimethylamine, N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N-methylamine, and N-
1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine,
And pharmaceutically acceptable salts thereof. A particular enantiomer of formula I is (+)-N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N-dimethylamine, (-)-N- {1- [1 -(4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N-dimethylamine, (R
)-(+)-N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N-methylamine, (S)-(-)-N- {1- [1- (4 -Chlorophenyl) cyclobutyl] -3-methylbutyl} -N-methylamine, (R
)-(+)-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine and (S)-(-)-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine. is there.

Suitable lipase inhibitors include pancreatic lipase inhibitors, gastric lipase inhibitors and carboxyl ester inhibitors and include without limitation the following: caulerpenin, JP 1020397 A2, application No. 97JP-0014334; panclicins AE, J. Chem. Soc. , Perkin
Trans. 1 (1998), (8), 1373 to 1382; (-)-panchrysin D, Tetrahedron (1997), 53 (48).
), 16471-16488; procyanidin and its analogs, described in WO9723210; lipase inhibitors isolated from cereals or pulses, JP-A-04321700
No. Gazette A2, application number 91JP-0110814; Formula I

[0014]

[Chemical 4]

[0015] [In the formula, Q is the formula Q1 to Q3.

[0016]

[Chemical 5]

And R ₁ and R ₂ are alkyl having up to 18 C atoms, substituted by 1 to 3 halogen atoms, or optionally 1,4-arylene Interrupted by a group, optionally substituted at the ω-position by an aryl group,
And optionally substituted by an aryl-C _1-4 -aryl group,
Alkyl, alkenyl, alkynyl or alkadienyl groups having up to 20 C atoms; whereby R ₁ is an O or S atom or by a sulfinyl group or a sulfonyl group to an unsaturated C atom. May be interrupted at a position other than the α-position, or R ₁ is aryl-NH- or aryl-
A C _1-4 -alkyl-OCONH— group, R ₃ and R ₄ are hydrogen or C _1-4 -alkyl, or together with an N atom, optionally with respect to the N atom. forming a saturated 3- to 6-membered ring containing an O or S atom at a position other than the α-position, n is a number of 1 or 0, X is an alkylene group having up to 6 C atoms, In this case, it is optionally interrupted by O or S atoms or by sulfinyl or sulphonyl groups and optionally hydroxy, mercapto, aryl, aryloxy, arylthio, aryl-C _{1- 4} - alkyl, aryl _{-C 1 to 4} - arylthio, aryl _{-C 1 to 4} - _{alkylidyne, C 3 to 7} - cycloalkylidene group or a _{C 1 to 6} - Al Or the alkylidene group, or one or two _{C 1 to 6} - _{alkyl, C 1 to 6} - alkoxy or _{C 1 to 6} -
It is substituted by an alkylthio group, whereby the same C atom on as or two two _C on adjacent C atoms ₆ - _{alkyl, C 1-6} - alkoxy or _{C 1-6} - The alkylthio group may optionally form a mono-unsaturated 3 to 7 membered ring, and optionally the hydroxy or mercapto group present, or optionally the unsaturated C atom present, Must be in a position other than the α-position to an existing O or S atom, or to an optionally present sulfinyl or sulfonyl group, or X is of the formula ═CHN (R, R ⁰ ) or —CHN _{^{(R, R 0) CH 2}} - is a radical, where, R and ^{R 0} is _{hydrogen, C 1 to 4} - _{alkyl, C 1 to 4} - alkyl (CO or OCO) - Aryl, aryl (CO or OCO) -,
Aryl-C _1-4 -alkyl or aryl-C _1-4 -alkyl (CO or OCO)-, and X ₁ is C _1-4 -alkoxy, aryl, aryloxy, arylthio, aryl-C _{1-. 4} - alkyl, aryl _{-C 1 to 4} - alkoxy or aryl -
An alkylene group containing up to 6 C atoms, which may be substituted by C _1-4 -alkylthio groups or by 1 or 2 C _1-6 -alkyl groups, whereby adjacent groups Two C _1-6 -alkyl groups attached to the C atom which can form a 3 to 7 membered ring] 4- (acyloxyethyl) oxetane-2-one; Compounds: (S) -1-[[(2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl (S) -2-isopropylmalonamate, (S) -1- [[(2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl (S or R) -2-carbamoyl-valerate, (all Z, S) -1-[[(2S, 3S ) -3-D Lu-4-oxo-2-oxytanyl] methyl] 9,12-octadecadienyl (S) -2-isopropylmalonamate (S) -1-[[(2S, 3S or 2R, 3R) -4- Oxo-3-pentylthio-2-oxetanyl] methyl] dodecyl (S) -2-isopropylmalonamate (S) -1-[[(2S, 3S or 2R, 3R) -4-oxo-3-pentylthio-2 -Oxetanyl] methyl] dodecyl (S: R (2: 1) -2-isopropylmalonamate (S) -1-[[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] Octadecyl (S or R) -2-t-butyl-malonamate (S) -1-[[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl-1-carbamoyl Chloro-pentanecarboxylate (S) -1-[[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl (RS) -2-benzylmalonamate (S) -1- [[(2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl (3-[(2-carbamoylethyl) thio] -propionate 5-oxo-D-proline (S) -1- [[(2S, 3S) -3-Ethyl-4-
Oxo-2-oxetanyl] methyl] octadecyl ester, 5-oxo-L-proline (S) -1-[[(2S, 3S) -3-ethyl-4-
Oxo-2-oxetanyl] methyl] octadecyl ester, (S) -1-[[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl (S or R) -isopropyl-malonamate ( S) -1-[[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl- (RS) -2-carbamoylvalerate (epimer 1:
1) (all Z, S) -1-[[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] 9,12-octadecadienyl (S or R) -2-isopropyl Malonamate, (S) -1-[[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl (RS) -2-carbamoyl-4-methyl-valerate (
Epimer 1: 1), (S) -1-[[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl 1-carbamoylcyclohexane-carboxylate, (S) -1- [ [(2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl [RS) -2-methylmalonamate, (epimer 1: 1)
, (S) -1-[[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl [RS) -2-ethylmalonamate (epimer 1: 1),
(S) -1-[[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl [RS) -2-butylmalonamate (epimer 1: 1),
(S) -1-[[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl 1-carbamoylcyclohexanecarboxylate,
(S) -1-[[(2S, 3S or 2R, 3R) -4-oxo-3-penylthio-2-oxetanyl] methyl] dodecyl [S: R or R: S (2: 1) -2
-Isopropylmalonamate, (S) -1 [[(2R, 3R) -3-benzyl-4-oxo-2-oxetanyl] methyl] dodecyl [S or R) -2-isopropylmalonamate; formula

[0018]

[Chemical 6]

[0019] [In the formula, R₁And R_TwoAre independently saturated or, in some cases, 8
Interrupted by up to double or triple bonds and / or optionally
Is an O or S atom present at a position other than the α-position with respect to the unsaturated C atom.
Thus interrupted C_1-17Alkyl or up to 3 C_1-6−
Alkyl- (O or S)_{1 or 0}Phenyl, benzyl, substituted by groups
Le or -C₆H_Four-X-C₆H₅A ring and X is oxygen, sulfur or (CH_Two) _0-3 And R_ThreeIs hydrogen, C_1-3-Alkyl or C_1-3-Alkanoyl
, R_FourIs hydrogen or C_1-3-Alkyl and R₅Is hydrogen and the group A
r or Ar-C_1-3-Alkyl, or optionally interrupted by Y
, And C optionally interrupted by Z_1-7-Alkyl or
R is R_FourIs R₅Form a 4- to 6-membered saturated ring together with Y, oxygen and sulfur
Or the group N (R₆), C (O) N (R₆) Or N (R₆) C (O), Z is a group-
(O or S) -R₇, -N (R₇, R₈), -C (O) N (R₇, R₈)Also
Is -N (R₇) C (O) R₈And n is a number of 1 or 0, provided that n is
R if 1₅Is hydrogen and Ar is unsubstituted or up to 3
Group R in₉Or OR₉Is phenyl substituted by and R₆, R₇ , R₈And R₉Are independently hydrogen or C_1-3-Alkyl, provided that R _Three Formyl, R₅Is isobutyl, or R_ThreeIs acetyl, R₅Is
Lubamoylmethyl and at the same time R_TwoIs undecyl or 2,5-un
Decadienyl, R₁Is n-hexyl, R_FourIs other than hydrogen
Ru] N-formylleucine 1- (oxetanonylmethyl) alkyl ester
And its analogs, its enantiomers or diastereomers, or
Are these pharmaceutically acceptable acid addition salts, in which case they are described in US Pat.
31463, US Pat. No. 5,175,186 and US Pat. No. 52.
No. 46960, in particular a compound selected from one of the following:
object: N-formyl- (S) -leucine (S) -1 [[(2S, 3S) -3-ethyl-
4-oxo-2-oxetanyl] methyl] octadecyl ester or their
Pharmaceutically acceptable acid addition salts, especially: N-formyl-L-leucine 1-[(trans-3-ethyl-4-oxo-2-
Oxetanyl) methyl] dodecyl ester N-formyl-L-leucine 1-[(trans-3-allyl-4-oxo-2-
Oxetanyl) methyl] dodecyl ester N-formyl-S-leucine (S, 9Z, 12Z) -1 [[(2S, 3S) -3
-Ethyl-4-oxo-2-oxetanyl] methyl] -9,12-octadecadi
Enyl ester N-formyl-S-leucine (S, Z) -1 [[(2S, 3S) -3-ethyl-
4-Oxo-2-oxetanyl] methyl] -9-octadecenyl ester N-formyl-S-leucine (R) -α-[[(2S, 3S) -3-ethyl-4
-Oxo-2-oxetanyl] methyl] -p-phenoxy-benzyl ester;
Or a pharmaceutically acceptable acid addition salt thereof; The formula in which R is ethyl

[0020]

[Chemical 7]

A tetrahydrolipstatin analog of Helv. Chim. Acta (1987
), 70 (5), 1412-18, formula

[0022]

[Chemical 8]

[Wherein X ¹ is undecyl or 2Z, 5Z-undecadienesil, and C ₆ is n
Hexyl, Y is isobutyl and Z is formyl or Y is carbamoylmethyl and Z is acetyl] oxetanone, European Patent No. 189
577; 1-Substituted 2-alkanone derivatives, Chem. Pharm. Bull. (1986
), 34 (3), 1118-27; soy protein, J. Am. Lipid Res. (1984), 25 (11), 12
14-21; Formula

[0024]

[Chemical 9]

Taurine and glycine derivatives, wherein R is H, alkanoyloxy, BzO; R ₁ is CO ₂ H, alkoxycarbonyl, CH ₂ SO ₃ H; m, n is 0, 1; US Pat. No. 4,104,285. 1,2-Dioleoyl-3-([alpha] -1-adamantoyl) -sn-glycerol and 1-adamantanecarboxylic acid, which are described in J. Phem. Sci
(1976), 65 (8), 1243-5; a peptide derivative from wheat, which in this case is described in JP07330794A; contains a C-terminal fragment of pancreatic lipase containing a site for recognizing co-lipase. Peptides, in this case described in WO9830588; flavonoids (flavanoid (s)) and their glycosides (glycoside (s)), J
P09143070A; triterpene, described in JP08268882A; hinokitiol, described in JP08268882A; flavonoid compound, described in JP07061927A; (metal-substituted (substd.)) Chlorophyllin (s), JP0525.
2898A; Formula I

[0026]

[Chemical 10]

[Wherein R ₁ and R ₂ are O at positions other than the α- or β-positions, as the case may be.
Alkyl having up to 17 C atoms interrupted by atoms; or benzyl, optionally ring substituted by _{1 to} 3 C _1-6 -alkyl or C _1-6 -alkoxy groups, X is hydrogen or a group of formula (R ₃ , R ₄ ) NCH (R ₅ ) (CH ₂ ) _n- CO-, R ₃ is hydrogen, C _1-3 -alkyl or C _1-3 -alkanoyl. R ₄ is hydrogen or C _1-3 -alkyl, and R ₅ is hydrogen, Ar or an Ar—C _1-3 -alkyl group, or optionally Y
A C _1-7 -alkyl group interrupted by and optionally substituted by Z, or R ₄ and R ₅ together with the N atom form a 4-6 membered ring, Y is oxygen, sulfur or a group N (R ₆ ), C (O) N (R ₆ ), or N (R ₆ ) C (
O), Z is a group — (O or S) —R ₇ , NR ₇ , R ₈ ), or N (R ₇ ) C (O) R ₈ and n is 1 or 0, where When n is 1, R ₅ is hydrogen, Ar is phenyl substituted by 1 to 3 groups R ₉ or OR ₉ , and R _{6 to} R ₉ are hydrogen or C _{1 to 3} -Alkyl] and a salt of a weak acid with an oxetanone of formula I wherein X is not hydrogen, in which case it is described in EP 443449A; lipstatin (excluding orlystate) lipstatin) and tetrahydrolipstatin derivatives, described in EP129748A; non-absorbing cation derivatives of olefin-maleic acid copolymers, US Pat. No. 42.
No. 11765A; Bile acids and triglycerides absorbent resins, described in British Patent No. 1286949; and compounds described in the patent application which protect this compound and its analogs, such as ATL-962 and the like. It is an analog.

In the method of the invention, the compound of formula I and the lipase inhibitor are combined or in parallel, eg in the form of separate dosage units to be used simultaneously, separately or sequentially. It may be administered.

In another aspect, the invention provides an enantiomer and pharmaceutically acceptable thereof for simultaneous, separate or sequential use for the treatment of obesity and related pathological conditions. A compound of formula I wherein R ₁ and R ₂ are independently H or methyl, and a lipase inhibitor except for orlistate.

In another embodiment, the present invention relates to enantiomers and their enantiomers as a combination for simultaneous, separate or sequential use for the treatment of obesity and related pathological conditions. Provided are compounds of formula I, wherein R ₁ and R ₂ are independently H or methyl, including pharmaceutically acceptable salts thereof, and lipase inhibitors other than orlystate.

In another aspect, the present invention provides enantiomers and pharmaceutically acceptable pharmaceuticals as a combination for the simultaneous, separate or sequential use in the treatment of obesity and related pathological conditions. There is provided a formulation comprising a compound of formula I, wherein R ₁ and R ₂ are independently H or methyl, including a salt, and a lipase inhibitor except orlystate.

In another embodiment, the present invention provides a compound of formula I wherein R ₁ and R ₂ are independently H or methyl, including its enantiomers and pharmaceutically acceptable salts, with a lipase other than orlystate. Provided for use in the manufacture of a medicament for the treatment of obesity and related pathological conditions in a patient being treated with an inhibitor.

In another embodiment, the invention comprises applying an adjunctive therapy containing a compound of formula I and a therapeutically effective amount of a lipase inhibitor other than orlystate to a patient in need thereof. Methods of treating obesity and related pathological conditions are provided.

Furthermore, the present invention provides the use of a combination of the aforementioned agents in the manufacture of a medicament for the treatment of obesity and related pathological conditions. Additionally, this is
Provided are combinations for use in the treatment of obesity.

As used herein, the term “associated pathological condition” means a medical condition known from the prior art that is associated with obesity. The terms include, without limitation, the following: diabetes including non-insulin dependent diabetes mellitus, glucose intolerance, depression, anxiety psychosis (eg, schizophrenia), tardive dyskinesia, drug addiction, substance abuse, cognitive impairment, Alzheimer's. Disease, cerebral ischemia, obsessive-compulsive behavior, panic attacks, social phobia, eating disorders such as bulimia, anorexia, snacking and modest eating, hyperglycemia, hyperlipidemia, and mammals, especially humans Stress in.

Furthermore, the present invention relates to metabolic disorders and the symptoms resulting therefrom, such as non exercise activity thermogenesis and increased metabolic rate, sexual dysfunction, sleep apnea, premenstrual syndrome, Urinary incontinence, including stress incontinence, hyperactivity disorder, hiatal hernia and reflux esophagitis, pain, especially neuropathic pain, weight gain associated with drug treatment, chronic fatigue syndrome, osteoarthritis and gout, associated with weight gain It may be used to treat or prevent cancer, menstrual dysfunction, gallstones, orthostatic hypotension and pulmonary hypertension.

The present invention may be used in the prevention of cardiovascular disorders and reduction of platelet adhesion, promotion of weight loss after pregnancy, reduction of the desire to smoke and promotion of weight loss after smoking cessation. The invention also serves to reduce uric acid and lipid levels in mammals, especially humans.

The amount of each compound to be administered depends on many factors, including the age of the patient, the severity of the symptoms and the patient's past medical history, and is usually within the discretion of the administering physician. However, in general, however, the dose of the compound of formula I to be administered is 0.1 to 50 mg, preferably 1 to 30 mg, and more preferably 1 or more times per day. , 10mg per day, 15m
g, 20 mg, 25 mg or 30 mg, and most preferably 20 mg
Is. The dose of lipase inhibitor to be administered is 5-2000 mg in one or more doses, preferably 50-1500 in three doses per day.
mg, more preferably 100 to 1000 mg. The compound of formula I, preferably sibutramine hydrochloride monohydrate, may be administered in any known pharmaceutical dosage form. The lipase inhibitor is preferably administered orally.

In a preferred embodiment of the invention, sibutramine hydrochloride monohydrate is
Preferably the initial dose is given in the morning and the lipase inhibitor is given three times daily with or before meals. Preferably, the dose of sibutramine hydrochloride monohydrate, once daily, is 20 mg to 30 mg, and the dose of lipase inhibitor is 50 mg, 100 mg, 120 mg or 150 mg, with a meal. Or three times daily before meals. Most preferably, the administration of sibutramine hydrochloride monohydrate is prior to the first administration of the lipase inhibitor, preferably in the range of 30 minutes to 3 hours, eg 30 before the first administration of the lipase inhibitor.
Minutes ago, 1 hour ago, 1.5 hours ago, 2 hours ago, 2.5 hours ago or 3 hours ago.

In another aspect of the invention, the invention provides a compound of formula I containing its enantiomer and its pharmaceutically acceptable salt.

[0041]

[Chemical 11]

A pharmaceutical composition comprising a compound of the formula where R ₁ and R ₂ are independently H or methyl and a lipase inhibitor except for orlystate, and a pharmaceutically acceptable diluent or carrier. provide.

Oral dosage forms are the preferred compositions for use in the invention, and these are administrations such as tablets, capsules, granules, syrups and aqueous or oily suspensions. Is a known pharmaceutical form for. The excipients used in the manufacture of these compositions are those known to the physician. Tablets contain the active compound and a bulking agent, such as calcium phosphate; a disintegrant, such as corn starch; a lubricant, such as magnesium stearate; a binder, such as microcrystalline cellulose or polyvinylpyrrolidone, and in other cases in known ways. Manufactured from a mixture with the ingredients according to, and the mixture can be tabletted by known methods. In preferred cases, tablets may be coated using known methods and known excipients, including, for example, enteric coating with hydroxypropylmethylcellulose phthalate. A tablet may be prepared by known methods to the extent that a sustained release of the compound of the invention is obtained. If preferred, such tablets may be provided with enteric coating by known methods, for example by the use of cellulose acetate phthalate. Similarly, capsules containing the active compound with or without excipients, such as hard gelatin capsules or soft gelatin capsules, may be prepared by known methods, preferably with known enteric coatings. Provided. The content of capsules may be formulated using known methods so that a sustained release of the active compound is obtained. Tablets and capsules usually contain 1-50 mg of the compound of formula I and 1-100 lipase inhibitor, respectively.
It may contain 0 mg.

Other dosage forms for oral administration are, for example, non-toxic suspensions, for example aqueous suspensions containing the active compound in an aqueous suspension in the presence of sodium carboxy-methylcellulose, and suitable Vegetable oils, for example oily suspensions containing the active compound in peanut oil. The active compound may be formulated into granules with or without additional excipients. The granules may be taken directly by the patient or they may be taken in a suitable liquid carrier (eg
Water). Granules may contain a disintegrating agent, for example an effervescent couple formed from an acid and a carbonate or bicarbonate, in which case it facilitates dispersion in the liquid medium. Let

The compounds of formula I may be prepared in a composition that the patient will hold in the mouth and thus the active compound will be administered by the oral mucosa.

Dosage forms of the compounds of formula I suitable for rectal administration are the known pharmaceutical forms for administration, for example suppositories containing cocoa butter or a polyethylene glycol base.

Dosage forms of the compounds of formula I suitable for parenteral administration are the known pharmaceutical forms for administration, eg sterile suspensions or solutions in suitable solvents.

Dosage forms of a compound of formula I for topical application may contain a matrix in which the pharmaceutically active compound of this invention is dispersed, thus administering the compound transdermally. For the purpose of, the compound is held in close proximity to the skin. Suitable transdermal compositions include pharmaceutically active compounds and topical excipients such as mineral oils,
It may be prepared by mixing with petrolatum and / or waxes, such as paraffin wax or beeswax, and potential transdermal absorption agents, such as dimethylsulfoxide or propylene glycol. Alternatively, the active compound may be dispersed in a pharmaceutically acceptable cream, gel or ointment base. The amount of each active compound included in the topical formulation should be such that a therapeutically effective amount of each compound is delivered during the time that the topical formulation will be on the skin.

The compounds of formula I may be formulated into compositions that are dispersed as an aerosol in the oral cavity or nasal cavity of the patient. Such an aerosol may be administered from a pump pack or a pressurized pack containing a volatile propellant.

Furthermore, the compounds of formula I may be administered exogenously, for example by intravenous infusion or by continuous infusion, from compounds placed in vivo. The body source comprises an inserted reservoir containing the compound to be infused, in which case it is continuously released, for example by osmosis and insertion, in which case it is (a) a liquid, For example, it may be an oily suspension of the compound to be injected in a form of a rather slightly water-soluble derivative, eg dodecanoate salt or lipophilic ester, or (b) a solid, eg It may be in the form of an inserted support, synthetic resin or wax-like material for the compound to be injected. The support may be a single shape containing all the compounds or a series of several shapes containing the respective moieties to be delivered. The amount of active compound present in the body's source should be such that a therapeutically effective amount of each compound is delivered over an extended period of time.

In some formulations it is advantageous to use the compounds of the invention in the form of particles of very small size, such as are obtained by fluid energy mills.

In the compositions of the present invention, the active compound may, if desired, be associated with other compatible pharmaceutically active ingredients. Optionally, vitamin supplements may be administered with the compounds of this invention.

Pharmaceutical compositions containing both a compound of formula I and a lipase inhibitor are an important embodiment of the invention. Such pharmaceutical compositions contain therapeutically effective amounts of the respective compounds. Each dosage unit may contain daily doses of both compounds or may contain divided doses of the daily dose, eg 1/3
May be a dose of Alternatively, each dosage unit may contain a total amount of one compound and a divided dose of another compound. In such cases, the patient may take one of the combination dosage units daily and one or more units containing only the other compound.

The use of the compounds of the invention in the manufacture of pharmaceutical compositions is illustrated by the description below. As used herein, the term "active compound" refers to one compound or both compounds of the invention, unless otherwise indicated.

A) Capsules In the preparation of capsules, 10 parts by weight of active compound and 240 parts by weight of lactose were deagglomerated and mixed. The mixture is loaded into hard gelatin capsules, in which case each capsule contains a unit dose or part of a unit dose of the active compound.

[0056] b) tablets   A tablet is made from the following ingredients:

Parts by weight active compound 10 lactose 190 corn starch 22 polyvinylpyrrolidone 10 magnesium stearate 3 active compound, lactose and some starch, deagglomerated and mixed,
And the resulting mixture is granulated with a solution of polyvinylpyrrolidone in ethanol. The dry granules are mixed with magnesium stearate and the rest of the starch. Thereafter, the mixture is compressed in a tablet machine to give tablets each containing a unit dose or part of a unit dose of the active compound.

Enteric Coated Tablets Tablets are manufactured by the method described in (b) above. Tablets are conventionally enteric coated with a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol: dichloromethane (1: 1).

D) Suppositories (compounds of formula I only) In the manufacture of suppositories, 100 parts by weight of the active compound are admixed with 1300 parts by weight of triglyceride suppository base and the mixture is treated therapeutically with active ingredients. It was formed into suppositories each containing an effective amount.

[0060] Dispensing I   Hard gelatin capsules are made using the following ingredients:

[0061]

[Table 1]

[0062] Dispensing II   A tablet is made using the following ingredients:

[0063]

[Table 2]

[0064]   The ingredients are mixed and compressed into tablets.

The advantages of the present invention can be demonstrated by one or more of the following tests.

Test 1 A group of normal Sptague-Dawley CD adult male rats (n = 8 to 12) was subjected to the following treatments.

A) Group 1; sibutramine hydrochloride monohydrate (1, 3 or 10 mg / kg orally) and lipase inhibitor vehicle given orally daily.

B) Group 2; lipase inhibitors (eg 10, 20, 30, 40, 50
, 100 or 150 mg / kg orally, preferably 10 or 20 mg / k
g) and sibutramine vehicle were given orally twice daily.

C) Group 3; Orally given combination with doses of sibutramine hydrochloride monohydrate and lipase inhibitor.

D) Group 4; control group, sibutramine vehicle and lipase inhibitor vehicle given orally.

Rats were fed a high fat diet ad libitum. Food intake, water intake and body weight were measured daily and the treatment period was 15 days, 21 days or 28 days.

Test 2 Hyperfertilized female Zucker rats (n = 8-12) maintained on a high fat diet were subjected to the following treatments.

A) Group 1; a dose (1, 3 or 10 mg) of sibutramine hydrochloride monohydrate that significantly reduces body weight compared to the vehicle-treated control group for 14 days. / Kg oral administration). Oral administration of the same dose of sibutramine hydrochloride monohydrate and the dose of lipase inhibitor (eg 10, 20, 30, 40, 50, 100 or 150 mg over the following 14 days).
/ Kg oral dose, preferably 10 or 20 mg / kg) was given daily.

B) Group 2; daily oral administration of sibutramine hydrochloride monohydrate for 14 days. During the following 14 days, oral administration of sibutramine and oral administration of a lipase inhibitor vehicle were performed.

C) Group 3; Oral administration of sibutramine hydrochloride monohydrate excipient for 14 days followed by oral administration of sibutramine hydrochloride monohydrate excipient for 14 days. Administration and oral administration of the lipase inhibitor vehicle were performed.

Test 3 A group of Sprague-Dawley CD adult male rats (n = 8 to 12) was subjected to the following treatments.

A) Group 1; oral administration of sibutramine hydrochloride monohydrate (1, 3 or 10 mg / kg orally) and lipase inhibitor vehicle b) Group 2; of lipase inhibitor and sibutramine vehicle Oral administration c) Group 3; Oral administration of lipase inhibitor and sibutramine vehicle d) Group 4; Oral administration of lipase inhibitor vehicle and sibutramine vehicle Sibutramine was administered once daily and lipase inhibitor was administered once. Give up to 3 times daily (with appropriate dose). Groups 1, 3 and 4 are fed a high fat diet at all times. The second group was pair-fed with the sibutramine treated group (the first group), that is, the animals consumed the amount of food consumed by the sibutramine treated group over the previous 24 hours (
High fat diet). Food intake and body weight are measured daily and the treatment duration is 4
~ 5 days.

Statistical comparison of animal weights in each group in one or more of the above tests provides results demonstrating the benefits of the present invention.

[Procedure amendment]

[Submission date] January 15, 2002 (2002.15)

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] Claim 8

[Correction method] Change

[Contents of correction]

[Chemical 2] A pharmaceutical composition comprising a compound of [R ₁ and R ₂ are independently H or methyl], and a lipase inhibitor except for orlystate.

─────────────────────────────────────────────────── ─── Continued front page    (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE), OA (BF, BJ , CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, K E, 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, CA, C H, CN, CR, CU, CZ, DE, DK, DM, DZ , EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, K G, KP, KR, KZ, LC, LK, LR, LS, LT , LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, S D, SE, SG, SI, SK, SL, TJ, TM, TR , TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor David John Heal             United Kingdom Nottingham Pennyfoot             To Street Earl 3 F term (reference) 4C084 AA19 MA02 NA05 NA14 ZA701                 4C206 AA01 AA02 FA08 MA02 MA04                       NA05 NA14 ZA70

Claims (8)

[Claims] 1. A method of treating obesity and related pathological conditions in humans, comprising the enantiomers and pharmaceutically acceptable salts thereof, Formula I: Comprising administering to a human a therapeutically effective amount of a compound of the formula where R ₁ and R ₂ are independently H or methyl, and a lipase inhibitor other than orlystate, wherein A method of treating obesity and related pathological conditions in humans in need of such treatment, which comprises administering the compound of formula I and a lipase inhibitor simultaneously, separately or sequentially. 2. The compound of formula I is N- {1- [1- (4-chlorophenyl)
The method according to claim 1, which is cyclobutyl] -3-methylbutyl} -N, N-dimethylamine or a salt thereof. 3. The compound of formula I is administered from 30 minutes to 3 minutes before administration of the lipase inhibitor.
The method of claim 1, wherein the method is administered over time. 4. R ₁ comprising its enantiomers and its pharmaceutically acceptable salts for simultaneous, separate or sequential use for the treatment of obesity and related pathological conditions. And a compound of formula I, wherein R ₂ is independently H or methyl, and a lipase inhibitor except orlystate. 5. An enantiomer and a pharmaceutically acceptable salt thereof, which are used simultaneously, separately or sequentially for the treatment of obesity and related pathological conditions as a combination. A compound of formula I, wherein R ₁ and R ₂ are independently H or methyl, and a lipase inhibitor except orlystate. 6. A combination preparation comprising the enantiomers and pharmaceutically acceptable salts thereof, for simultaneous, separate or sequential use in the treatment of obesity and related pathological conditions, A product containing a compound of formula I wherein R ₁ and R ₂ are independently H or methyl, and a lipase inhibitor except for orlystate. 7. An enantiomer and a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating obesity and related pathological conditions in patients treated with lipase inhibitors other than orlystate. Use of a compound of formula I, wherein R ₁ and R ₂ are independently H or methyl. 8. A compound of formula I, including its enantiomer and its pharmaceutically acceptable salt. A compound of [R ₁ and R ₂ are independently H or methyl], and a lipase inhibitor except for orlystate.