WO2006090927A1

WO2006090927A1 - Orexigenic action of sulfonamide compound

Info

Publication number: WO2006090927A1
Application number: PCT/JP2006/304206
Authority: WO
Inventors: Takashi Owa; Yoichi Ozawa; Naoto Ono
Original assignee: Eisai R & D Management Co., Ltd.
Priority date: 2005-02-28
Filing date: 2006-02-28
Publication date: 2006-08-31
Also published as: WO2006090932A1; WO2006090921A1

Abstract

The invention relates to an orexigenic agent and a remedy for anorexia comprising a sulfonamide compound as an active ingredient.

Description

Sulfonamide compounds enhance food intake

Technical field

The present invention relates to a food intake enhancer. Further, the present invention relates to an anorexia remedy, and more particularly to an anorexia nervosa, an anorexia nervosa remedy, and an anorexia nervosa associated with cachexia.

Light

Background art

book

Appetite and eating behavior are controlled by a network mechanism in which various regulatory factors are intricately linked. As a result, a constant body environment and weight are maintained. However, in recent years, obesity has increased in children and middle-aged people, while thinness accompanied by loss of appetite has increased, particularly among young women, and the failure of eating control mechanisms has become widely recognized as a disease state. In particular, anorexia nervosa has been increasing year by year, and it can be said that it is one of the diseases that attracts social attention. The disease is characterized by an extreme decline in food intake and thereby a minimum maintenance of normal body weight. Over 90% of patients with this disease are women, and mortality is the highest among adult women. Anorexia nervosa develops because of developmental problems or genetic factors that add psychological trauma (such as an obesity index) or stress, and the main treatment is largely based on inpatient behavioral therapy.

In cancer cachexia, which is observed in about 80% of patients who die of cancer, the accompanying symptoms such as loss of appetite and slimming are problems in considering QOL of cancer patients. More research has been conducted than before.

However, the elucidation of the mechanism of feeding regulation is still in the process of research, and clinical problems related to anorexia and slimming disease have not been fully solved. For this reason, there is a strong demand not only for the currently used therapies, but also for the development of further improvements and new therapies. By the way, a sulfonamide compound has been reported as a useful antitumor agent.

⁽¹ — ⁵⁾ In particular, N- (3_chloro-1H-indole-1-7-no-re) -4 4-sulfamoylbenzenesulfonamide (hereinafter sometimes referred to as "E7070"), N- (3-cyanol 4-methinole) 1 H—Indanol 7— ^) 1 3 _Cyanocene zensulfonamide (hereinafter sometimes referred to as “E7820”), N— [[((4— Black-end phenyl) amino] Carbonyl] —2, 3— Dihydrol 1 H—Indene 5 —Sulfonamide (hereinafter sometimes referred to as LY “186641”), N— [[((3, 4—Dichlorophloene 2-amino) amino] Canolepole]-2, 3 —Dihydrobenzofuran 1-sulfone amide (hereinafter sometimes referred to as “LY295501”), N— (2,4-dichlorobenzoyl) 1—Black mouth phenyl sulphonone amide (hereinafter rLY) -May be referred to as -ASAPj), N— (2,4—Dichloro Oral Benzoyl) — 5—Bromothiophene 2-sulfonamide (hereinafter sometimes referred to as “LY573636”), 2-sulfanilamide 5—Black mouth quinoxaline (hereinafter sometimes referred to as “CQSJ”), etc. It is very useful because it shows activity against various types of tumors.

In recent years, it has been reported that E7820 has an effect of enhancing feeding and is useful as a therapeutic agent for anorexia ( ⁶⁾ .

In recent years, a method for detecting the expression level of a large number of genes at the same time using various DNA microarrays has been established, and DNA microarrays have been applied to a wide range of purposes ( ⁷ and ⁸ ). Moreover, using DNA microarrays (Ma Kuroarei with some membrane filter), it reported that examined gene expression changes that occur when allowed to act anticancer tumor cells have also been made some ⁽⁹ one ^{1 1} > These reports indicate that gene expression variability analysis is a comprehensive study at the molecular level of biological changes caused by cells by comparing the characteristics of multiple cell populations, treating drugs, etc. It is extremely useful.

In addition, by analyzing gene expression profiles of a panel of 60 cancer cell lines from the US National Cancer Institute, these cell lines were reclassified and characterized ( ^{1 2)} . Cell line panel gene expression There have been reports ( ¹³⁾ that considered the relationship between the profile and the sensitivity of each cell line to various anticancer agents.

References

(1) Japanese Patent Application Laid-Open No. 7-16 708

(2) International Publication No. 0 OZ5039 Pamphlet

(3) European Patent Application Publication No. 022247-5 Specification

(4) International Publication No. 02 No. 098848 Pamphlet

(5) International Publication No. 2003/03 56 29th pamphlet

(6) International Publication No. 03/0222 72 Panflate

(7) Schena M, Shalon D, Davis RW, Brown PO. Science, 1995, 270, 467-70.

(8) Lockhart, D.J., Dong, Η, Byrne, M.C., Follettie, M.T., Gallo, M.V., Chee, M.S., Mittmann, M., Wang C, Kobayashi, M., Horton, H.

Brown, E.L., Nature Biotechnology, 1996, 14, 1675-1680.

(9) Rhee CH, Ruan S, Chen S, ChenchikA, Levin VA, Yung AW, Fuller GN, Zhang W, Oncol Rep, 1999, 6, 393-401.

(1 0) Zimmermann J, Erdmann D, Lalande I, Grossenbacher R, Noorani M, F rst P, Oncogene, 2000, 19, 2913-20.

(1 1) Kudoh K, Ramanna M, Ravatn R, Elkahloun AG, Bittner ML, Meltzer PS, Trent JM, Dalton WS, Chin KV, Cancer Res, 2000, 4161-6.

(1 2) Ross DT, ScherfU, Eisen MB, Perou CM, Rees C, Spellman P, Iyer V, Jeffrey SS, Van de Rijn M, \ Valtham M, ergamenschikov A, Lee JC, Lashkari D, Shalon D, Myers TG , Weinstein JN, Botstein D, Brown PO, Nat Genet, 2000, 24, 227-35.

(1 3) ScherfU, Ross DT, Waltham M, Smith LH, Lee JK, Tanabe L, Kohn KW, Reinhold WC, Myers TG, Andrews DT, Scudiero DA, Eisen MB, Sausville EA, Pommier Y, Botstein D, Brown PO , Weinstein JN, Nat Genet, 2000, 24, 236-44. Disclosure of the Invention

An object of the present invention is to find an eating enhancer having an excellent feeding enhancing action and an anorexia remedy based on the feeding enhancing action.

As a result of intensive investigations to solve the above problems, the inventors of the present invention have found that gene changes caused by E7820, E7070, LY186641, LY295501, LY573636 or CQS or combinations thereof in DNA microarray and cancer cell line panel experiments. The pattern and cytostatic activity were found to be highly correlated. In addition, in an assay for measuring cytostatic activity, it was found that the cancer cell lines E7820, LY186641, LY295501, LY-ASAP, LY573636, and CQS that are resistant to E7070 are cross-resistant. From these results, the present inventor has found that E7070, E7820, LY186641, LY295501, LY_ASAP, LY573636 or CQS or a combination thereof has the same or similar mechanism of action, and the same or similar genetic change and The knowledge that it brings about an effect was acquired.

Furthermore, E7820 has been reported to have an effect of enhancing eating and to be useful as a therapeutic agent for anorexia (WO03 / 022272). Therefore, it has been found that sulfonamide compounds, preferably LY186641, LY295501, LY'ASAP, LY573636 or CQS or a combination thereof, have an effect of enhancing feeding and are useful as an anorexia remedy. It came to be completed.

That is, the present invention relates to the following.

(Γ) .A feeding enhancer comprising a sulfonamide compound as an active ingredient.

(2) A therapeutic agent for anorexia comprising a sulfonamide compound as an active ingredient.

(3) A method for enhancing feeding, comprising administering a sulfonamide compound to a patient. (4) A method for treating anorexia characterized by administering a sulfonamide compound to a patient

(5) Use of a sulfonamide compound for the production of an eating enhancer.

(6) Use of a sulfonamide compound for the manufacture of a therapeutic agent for anorexia. The present invention also relates to the following.

(7) A kit for treating anorexia comprising the therapeutic agent according to (2) and an anticancer agent.

(8) A method for treating anorexia, comprising administering the therapeutic agent according to (2) and an anticancer agent to a patient.

(9) Use of a sulfonamide compound for the production of the kit according to (7).

In the above (1) to (9), the sulfonamide compound is

Formula (I)

[Wherein E is 1 O—, 1 N (CH ₃ ) —, _CH ₂ —, 1 CH ₂ CH ₂ — or 1 CH ₂ 0—, D is 1 CH ₂ — or _0_, R ^la represents a hydrogen atom or a halogen atom, and R ^2a represents a halogen atom or a trifluoromethyl group. ]

A compound represented by

Formula (II)

[Wherein, J represents 1 O— or 1 NH—, Rib represents a hydrogen atom, a halogen atom, an optionally substituted d-Cs alkyl group, or an optionally substituted C i—C4 alkoxy group, optionally substituted d—C4 alkylthio group, 1 CF ₃ , 1 OCF ₃ , 1 S CF ₃ , optionally substituted Ci 1 C4 alkoxy

〇2) CH ₃ , 1 N (CH hydroxyl group, phenyl group, substituted phenyl group, pyridinyl group, chenyl group, furyl group, quinolinyl group or triazole group, R ^2b is a hydrogen atom, halogen Atom, cyan group, mono-CF ₃ , optionally substituted d—C ₆ alkyl group, Ci 1 C ₄ alkoxycarbonyl group which may have a substituent, Ci 1 C ₄ alkoxy group which may have a substituent, a phenyl group or a substituent which may have a substituent An optionally substituted quinolinyl group, R ^3b may have a hydrogen atom or a substituent Ci_C ₄ alkoxy group, and R ^4b may have a hydrogen atom or a substituent Ci—C _{A 6} alkyl group (provided that at least one of R ^3b and R ^4b is a hydrogen atom), R ^5b is a hydrogen atom, a halogen atom, or a d-C ₆ alkyl group optionally having a substituent, _CF ₃ or nitro group, R6b may have a hydrogen atom, a halogen atom or a substituent d—C ₆ alkyl group (provided that R ⁶ b may have a substituent d— When a C ₆ alkyl group, R ⁵ b is a hydrogen atom and R ^7b is a halogen atom) ^7b represents a halogen atom, an optionally substituted 1 C ₆ alkyl group or an CF ₃ (wherein either R or R? B may have a substituent Ci — C ₆ alkyl group, or R? B force S, halogen atom or optionally substituted Ci 1 C ₆ alkyl group, either R ^5b or R ^6b Is a hydrogen atom). ]

A compound represented by

Formula (III)

A compound represented by

Formula (IV)

Or at least one compound selected from the group consisting of the compounds represented by: or a pharmacologically acceptable salt thereof or a solvate thereof. According to the present invention, an excellent feeding enhancer Opino or an anorexia remedy is provided.

More specifically, a pharmaceutical composition comprising a sulfonamide compound exhibiting an excellent feeding enhancing effect and an effect of treating Z or anorexia, preferably LY186641, LY295501, LY_ASAP, LY573636 or CQS, or a combination thereof as an effective ingredient. Can be used to treat anorexia nervosa. In addition, a kit containing an anorexia remedy containing an sulfonamido compound as an active ingredient and an anticancer agent is provided, and can be used for the treatment of anorexia. Brief Description of Drawings

FIG. 1 shows the results of hierarchical clustering analysis on the DNA microarray in Example 1.

FIG. 2 shows the correlation coefficient in the DNA microarray in Example 2. FIG. 3 shows the results of hierarchical clustering analysis on the DNA microarray in Example 2.

FIG. 4 shows the correlation coefficient in the DNA microarray in Example 2. FIG. 5 shows the result of hierarchical clustering analysis in the DNA microarray in Example 2.

Fig. 6 shows the growth inhibitory effects of E7070, E7820, CQS, LY186641, LY295501 and LY-ASAP on HCT116-C9, HCT116-C9-C1 and HCT116-C9-C4 in Atsey measuring cell growth inhibitory activity Is.

FIG. 7 shows the growth inhibitory action of E7070 and LY573636 on HCT116-C9, HCT116-C9-C1 and HCT116-C9-C4 in the assay for measuring cytostatic activity. BEST MODE FOR CARRYING OUT THE INVENTION Embodiments of the present invention will be described below. The following embodiment is an example for explaining the present invention, and is not intended to limit the present invention only to this embodiment. The present invention can be implemented in various forms without departing from the gist thereof.

Documents cited in the present specification, as well as patent publications, patent gazettes and other patent documents are incorporated herein by reference.

1. Sulfonamide compounds

In the present invention, the sulfonamide compound includes a compound represented by the following general formula (I).

In the general formula (I), E is 1 O—, 1 N (CH ₃ ) 1, — CH ₂ 1, CH ₂ CH ₂ — or 1 CH ₂ 0 _, D is 1 CH ₂ — or 1 0—, R ^la represents a hydrogen atom or a halogen atom (for example, fluorine atom, chlorine atom, bromine atom, iodine atom), R ^2a represents a halogen atom or a trifluoromethyl group, respectively. .

The compound represented by the general formula (I) of the present invention can be produced by a known method, for example, by the method described in European Patent Application Publication No. 0222475A1.

—In the general formula (I), preferred compounds are LY186641 or LY295501.

LY186641 refers to N — [[((4-Chronophenyl) amino] carbonyl] —2,3-dihydro-1 H-indene-5-sulfonamide, whose structural formula is shown in the following formula (VII) .

LY186641

LY186641 can be produced by a known method, for example, by the method described in European Patent Application Publication No. 0222475A1.

In the present invention, LY295501 refers to N — [[(3,4-dichlorophole) amino] carboninole] 1 2 ′ 3-dihydrobenzofuran 5-s / rehonamide. The structural formula is shown in the following formula (VIII).

LY295501

LY295501 can be produced by a known method, for example, the method described in European Patent Application Publication No. 0222475A1 and / or European Patent Application Publication No. 0555036A2.

In the present invention, the sulfonamide compound includes a compound represented by the following general formula (II).

In the general formula (Π), in the formula, J represents 10—or 1 NH—, R ″> represents a hydrogen atom ′, a halogen atom, or an optionally substituted d-C ₆ alkyl group. Ci 1 C ₄ alkoxy group which may have a substituent, d—C ₄ aralkylthio group which may have a substituent, 1 CF ₃ , 1 OCF ₃ , 1 S CF ₃ , Ci — C4 alkoxycarbonyl group, nitro group, azide group, 1 O (S0 ₂ ) CH ₃ , 1 N (CH ₃ ) 2, hydroxyl group, phenyl group, substituted phenyl group, A pyridinyl group, a chenyl group, a furyl group, a quinolyl group or a triazole group; R is a hydrogen atom, a halogen atom, a cyano group, one CF ₃ , and optionally substituted d—c ₆ Alkyl group, Ci one may have a substituent group C ₄ alkoxycarbonyl group, perforated may have a substituent group Ci_C ₄ alkoxy group, which may have a substituent phenyl group or a substituted group An quinolinyl group that may be substituted, R ^3b is a Ci-C ₄ alkoxy group that may have a hydrogen atom or a substituent, and R ⁴ b is a hydrogen atom or a substituted group. D—C ₆ alkyl group (provided that at least one of R ³ b and R 4b is a hydrogen atom), R ^5b may have a hydrogen atom, a halogen atom, or a substituent Ci — C ₆ alkyl group, 1 CF ₃ or nitro group, R ^6b may have a hydrogen atom, halogen atom or substituent d—C ₆ alkyl group (provided that R ^6b has a substituent) when you have may d-C ₆ alkyl group, R ^5b is a hydrogen atom, R? b is a halogen atom Some), R ⁷ b is halogen atom, a substituted group may have a Ci_C ₆ alkyl group or a CF ₃ (provided that either the R5b or R7b may have a substituent d— C ₆ alkyl group or R

And when R 7 is a halogen atom or an optionally substituted Cl-C ₆ alkyl group, either R ⁵ b or R ⁶ b is a hydrogen atom). '

In the general formula (II), the “halogen atom” is preferably a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

In the general formula (II), “Ci-C ₆ alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, and is not particularly limited, Methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group (amyl group), isopentinole group, neopentyl group, tert —Pentyl group, 1-methyloleptyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, n-hexyl group, isohexyl group,

1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1-ethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,

2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylpropyl group, 1,1,2-trimethylpropyl group, 1, 2, 2-trimethylpropyl group, 1-ethyl 1 means 1-methylpropyl group, 1-ethyl-2-methylpropyl group, etc. Among these, preferred groups are methyl group, ethyl group, n-propyl group, isopropylinole group, n-butyl group, isobutinole group, sec-butynole group, tert-butynole group, n-pentyl group, n- A hexyl group etc. can be mentioned. .

In the general formula (Π), “d—C ₄ alkoxy group” means an alkoxy group having 1 to 4 carbon atoms, and is not particularly limited, but is preferably a methoxy group, an ethoxy group, Examples include n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group and the like.

In the general formula (Π), in the “d—C ₄ alkylthio group”, the alkyl group is not particularly limited, but is methyl, ethyl, n-propyl, isopropyl, n-butynole, isobutyl, sec-butynole, tert —Petinole can be mentioned. In the general formula (Π), examples of the “Ci 1 C ₄ alkoxycarbonyl group” are not particularly limited, but include a methoxycarbonyl group, an ethoxycarbonyl group, an _n -propoxy group, a nonenyl group, an isopropoxy group. Examples thereof include a levonanol group, an n-butoxycanole pononole group, an isobutoxycanolbonyl group, a sec-butoxycanolbonyl group, and a tert-butoxycarbonyl group.

In the general formula (II), the substituent to be introduced is not particularly limited. For example, a d-C ₆ alkyl group (for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group) , n- heptyl group, an isobutyl group, sec- butyl group, tert one butyl group), d-C ₄ alkoxy groups (e.g., main butoxy group, an ethoxy radical, n one propoxy group, isopropoxy group, n- butoxy group , Isobutoxy group, sec-butoxy group, tert-ptoxy group, etc.), amino group, hydroxyl group, halogen atom (for example, fluorine atom, chlorine atom, bromine atom, iodine atom) or silyl group .

The compound represented by the general formula (Π) of the present invention can be produced by a known method, for example, by the method described in WO 02/0988848 pamphlet (WO02 / 098848). Can be manufactured.

In general formula (II), the preferred compound is LY-ASAP. LY-ASAP refers to N— (2,4-dichlorobenzoyl) -4-chlorosulfone amide, whose structural formula is shown in the following formula (XI).

LY-ASAP

LY-ASAP can be produced by a known method. For example, LY-ASAP can be produced by the method described in WO 02/0988848 (WO02 / 098848).

In the present invention, examples of the sulfonamide compound include LY573636. In the present invention, LY573636 refers to N- (2,4-dichlorodibenzo) 15-bromothiophene 1-2-sulfonamide, and its structural formula is shown in the following formula (III).

LY573636

LY573636 is preferably a sodium salt.

LY573636 can be produced by a known method. For example, LY573636 is commercially available in the same manner as described in WO 02/0 9 8 8 48 8 (WO02 / 098848). It can be produced from sulfosulfuric acid lide and 2,4-dimethyl oral benzoic acid.

Further, LY573636 can be produced by the method described in Example 63 in International Publication No. 2003/035629 (WO2003 / 035629). In the present invention, examples of the sulfonamide compound include CQS. In the present invention, CQS refers to 2_sulfuramide 5-chloroquinoxaline, the structural formula of which is shown in the following formula (IV).

CQS can be produced by a known method, for example, by the method of (J. Am. Chem. Soc, 1947, 71, 6-10). Sulfonamide compounds may form pharmacologically acceptable salts with acids or bases. The sulfonamide compound in the present invention includes these pharmacologically acceptable salts. Examples of salts with acids include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, and phosphate, formic acid, acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, citrate, tartaric acid, Examples thereof include salts with organic acids such as benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and trifluoroacetic acid. In addition, as salts with bases, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, trimethylamine, triethylamine, pyridine, picoline, dihexylhexylamine, N , N, monodibenzylethylenediamine, arginine, lysine and other organic base salts (organic amine salts), and ammonium salts.

The sulfonamide compound may be an anhydride or may form a solvate such as a hydrate. The solvate may be a hydrate or a non-hydrate, but a hydrate is preferred. As the solvent, water, alcohol (for example, methanol, ethanol, n-propanol), dimethylformamide or the like can be used.

In addition, when solvates and / or optical isomers of these compounds exist, the sulfonamide compounds in the present invention include those solvates and / or optical isomers. The sulfonamide compound in the present invention also includes a sulfonamide compound that undergoes metabolism such as oxidation, reduction, hydrolysis, and conjugation in vivo. Furthermore, the sulfonamide compound in the present invention is oxidized, reduced, Also included are compounds that produce a sulfonamide compound upon metabolism such as hydrolysis.

2. Pharmaceutical composition, kit, method for enhancing eating, method for treating anorexia

The present invention relates to a pharmaceutical composition and kit containing a sulfonamide compound as an active ingredient, and a method for enhancing eating and a method for treating anorexia using these.

In the present invention, the sulfonamide compound is as described in “1. Sulfonamide Compound”. For example, from the general formula (I), the general formula (Π), the formula (III), and the formula (IV), At least one compound selected from the group consisting of LY186641, LY295501, LY-ASAP, LY573636 and CQS, more preferably selected from the group consisting of LY295501 and LY573636 At least one compound, particularly preferably the sodium salt of LY573636. .

In the present invention, the sulfonamide compound includes pharmacologically acceptable salts or solvates such as hydrates thereof.

The feeding enhancer and the Z or anorexia remedy of the present invention are pharmaceutical compositions comprising a sulfonamide compound as an active ingredient.

In the present invention, the food intake enhancer is a pharmaceutical composition having an effect of enhancing food intake or an effect of suppressing a decrease in food intake.

In the present invention, the treatment is to reduce the symptoms of the disease, to suppress the progression of the symptoms of the disease, to eliminate the symptoms of the disease, to improve the prognosis of the disease, to prevent the disease. Is also included. The effects of treatment can be confirmed by diet, body weight, biochemical tests, and so on.

In the present invention, the anorexia is not particularly limited, and examples thereof include anorexia nervosa, anorexic slimming, anorexia associated with cachexia, and leanness associated with cachexia.

“Accompanied by cachexia” Diseases (symptoms) such as anorexia and slimming occur in cachexia. Disease, associated symptoms of cachexia, or disease in patients with cachexia.

The feeding enhancer of the present invention and the therapeutic agent for Z or anorexia are administered to mammals (eg, humans, rats, rabbits, hidges, pigs, rabbits, cats, dogs, monkeys, etc.) can do.

The anorexia treatment kit of the present invention is a kit comprising a pharmaceutical composition containing a sulfonamide compound as an active ingredient (for example, a therapeutic agent for anorexia) and an anticancer agent, and a combination thereof. is there.

The kit of the present invention is useful for the treatment of anorexia, and preferably for the treatment of anorexia associated with cachexia or the treatment of leanness associated with cachexia.

Examples of anticancer agents include, but are not limited to, 5-fluorouracil, cisplatin, irinotecan hydrochloride, paclitaxel, and epilubicin. The dosage form of the anticancer agent contained in the kit is not particularly limited.

The said anticancer agent can be manufactured by a well-known method, and can be obtained by purchasing a commercial item.

Substances contained as active ingredients of anticancer agents may form pharmacologically acceptable salts with acids or bases. In addition, the substance may be an anhydride or a solvate. Further, it may be an optical isomer, a substance that undergoes metabolism in vivo, or a substance that is produced by metabolism. Examples of pharmacologically acceptable salts, solvates, isomers, metabolized substances, and metabolized substances are as described in “1. Sulfonamide Compounds”.

The anorexia remedy kit of the present invention can be used for mammals (eg, humans, rats, rabbits, hidges, pigs, mice, cats, dogs, monkeys, etc.). In the present invention, “combined” means a combination for using compounds in combination, and includes both forms in which separate pharmaceutical compositions are used together at the time of administration, and forms as a mixture.

In the anorexia treatment kit of the present invention, the pharmaceutical composition containing the sulfonamide compound as an active ingredient and the anticancer agent may be mixed, or These may be stored separately and packaged together, or may be administered simultaneously, or either one may be administered first.

The anorexia treatment kit of the present invention may contain a packaging container, an instruction manual, a package insert, etc. in addition to a pharmaceutical composition and an anticancer agent containing a sulfonamide compound as an active ingredient. Packaging containers, instruction manuals, package inserts, etc. can describe combinations to be used in combination with compounds. Also, regarding the form in which different pharmaceutical compositions are used together at the time of administration or as a mixture, The dose can be written. Usage and dosage can be described with reference to the following. When using the feeding enhancer, anorexia remedy, or anorexia remedy kit of the present invention, it can be administered orally or parenterally.

When using the food intake enhancer, anorexia remedy, or anorexia remedy kit of the present invention, the dosage of the sulfonamide compound depends on the symptom level, patient age, gender, weight, sensitivity. Difference, administration method, administration time, administration interval, nature of pharmaceutical preparation, preparation, type, type of active ingredient, etc., but not particularly limited, but normal adult (body weight 60 Kg) 10-6000 mg per day, preferably Is 50 to 4000 mg, more preferably 50 to 2000 m, which can be administered usually in 1 to 3 divided doses per day. .

When using the anorexia treatment kit of the present invention, the dosage of the anticancer agent is as follows: symptom severity, patient age, gender, body weight, sensitivity difference, administration method, administration timing, administration interval, properties of the pharmaceutical preparation, It varies depending on the preparation, type, type of active ingredient, etc., and is not particularly limited. Usually, adult (body weight 6 O Kg) 10 to 6000 mg per day, preferably 50 to 4000 m, more preferably 50 to 2000 mg Yes, this can usually be administered in 1 to 3 divided doses per day.

The feeding enhancer Opino or anorexia remedy of the present invention may be prepared in various dosage forms, for example, solid oral preparations, or parenteral preparations such as injections, suppositories, ointments, and poultices. And so on.

In addition, the sulfonamide compound or anticancer agent contained as an active ingredient in the anorexia remedy kit of the present invention is various dosage forms such as oral solid preparations or injections. Preparations such as parenteral preparations such as suppositories, suppositories, ointments, and poultices. When preparing a solid preparation for oral administration, add excipients, and if necessary, binders, disintegrating agents, lubricants, coloring agents, flavoring agents, etc. to the main drug, and then add tablets, Covered tablets, granules, fine granules, powders, capsules, etc. In addition, oral non-solid preparations such as syrups can also be appropriately prepared.

Excipients include, for example, lactose, corn starch, sucrose, glucose, sorbite, crystalline cellulose, silicon dioxide, and the like, and binders include, for example, polyvinylolezoreconole, ethinoresenorelose, methinorescenore. For example, magnesium stearate, talc, silica, etc. are added to pharmaceuticals as colorants, such as loin, gum arabic, hydroxypropyl senololose, hydroxypropenolemethinolecellulose, etc. However, as a flavoring agent, for example, cocoa powder, heart muscle, aromatic acid, heart force oil, dragon brain, cinnamon powder and the like are used. Of course, these tablets and granules may be appropriately coated with sugar coating, gelatin coating, etc. if necessary.

When preparing injections, add pH adjusters, buffers, suspending agents, solubilizing agents, solubilizers, tonicity agents, preservatives, etc. to the active ingredient as necessary. Subcutaneous, intramuscular injection, U quotient injection. At that time, if necessary, it can be made into a freeze-dried product by a conventional method.

Examples of the suspending agent include methyl cellulose, polysorbate 80, hydroxyl acetylenolose, gum arabic, tragacanth powder, carboxymethyl senolate mouthwater sodium, polyoxyethylene sorbitan monolaurate and the like.

Examples of the solubilizer include polyoxyethylene hydrogenated castor oil, 'polysorbate 80, nicotinic acid amide, polyoxyethylene sorbitan monolaurate, macrogol, and castor oil fatty acid ethyl ester.

Examples of the stabilizer include sodium sulfite and sodium metasulfite, and examples of the preservative include methyl paraoxybenzoate, ethyl parabenzoate, sorbic acid, phenol, cresol, and chlorocrezonole. be able to.

The present invention also includes the use of a sulfonamide compound for the manufacture of an eating enhancer, an anorexia remedy, or an anorexia remedy kit. The kit is preferably a treatment kit for anorexia associated with cachexia or a treatment kit for slimming associated with cachexia.

Furthermore, the present invention includes a method for enhancing feeding or treating anorexia by administering to a patient a pharmaceutical composition containing a sulfonamide compound as an active ingredient.

The present invention also relates to a method for treating anorexia comprising administering to a patient a pharmaceutical composition containing a sulfonamide compound (for example, a therapeutic agent for anorexia containing the compound as an active ingredient) and an anticancer agent. Is also included. The method is preferably a method for treating anorexia associated with cachexia or a method for treating slimming associated with cachexia. In the method for enhancing eating or the method for treating anorexia of the present invention, the route of administration and the method for administering the pharmaceutical composition or anticancer agent containing the sulfonamide compound are not particularly limited, but the above-mentioned eating enhancer, anorexia remedy or You can refer to the description of the kit. Hereinafter, the present invention will be described with specific examples, but the present invention is not limited thereto. Example 1 DNA microarray analysis

(1) 'Cell culture, compound treatment, and RNA extraction

For the purpose of examining gene expression changes induced by compounds by DNA microarray analysis, human colon cancer-derived cell line HCT116 (American Type Culture Collection, Manassas, VA, USA) and human leukemia-derived cell line MOLT-4 (American TV e Culture Collection, Manassas, VA, USA) was cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum, 100 units / ml penicillin, lOO ^ g / ral streptomycin. In the following, culture and compound treatment are 5% CO ₂ , It was performed in an incubator adjusted to 37 ° C. HCT116 cells and MOLT-4 cells were seeded at a ratio of 2.0 × 10 ⁶ cells and Z dishes in a 10 cm diameter cell culture dish, and the following compound treatment was performed after 24 hours of culture.

For HCT116 cells, E7820 (0.8 μΜ), Ε7070 (0.8 μM), LY295501 (30 z M), CQS (8 Μ), adriamycin (0.2 μu), daunomycin (0.2.u M), ICRF154 Twelve compounds (80 μΜ), ICRF159 (80 μΜ), kenpauUone (10 μΜ), alsterpullone (10 μΜ), trichostatin A (O. l M) and rapamycin (80 / z M) were evaluated. On the other hand, E7070 (0.8 μM) was evaluated for M0LT-4 cells. Here, adriamycin and daunomycin are DNA topoisomerase II inhibitors that interfer with DNA, ICRF154 and ICRF159 are catalytic type DNA topoisomerase II inhibitors [J, kenpauUone and Ό, alsterpullone Are cyclm-dependent kinases (CDKs) inhibitors, trichostatin A is a histone deacetylase inhibitor, and rapamycin is a known compound as an mTOR / FRAP inhibitor. The compound treatment concentration was set as a concentration 3 to 5 times higher than the 50% growth inhibitory concentration of each compound on HCT116 cells (based on the 3-day cell growth inhibitory activity using WST-8). Cells were harvested after treatment for 24 hours at the set concentration indicated in parentheses following the compound name. Similarly, cells cultured for 24 hours without the addition of the compound were also collected.

Extraction of total RNA from the collected cells was performed using TRIZOL reagent (manufactured by Invitrogen) according to the attached operation method.

(2) Gene expression analysis by DNA microarray

The obtained RNA was dissolved in sterilized water treated with ΙΟΟμΙ diethylpyrocarbonate (DEPC) and further purified using RNeasy column (QIAGEN). Superscript Choice System (manufactured by Invitrogen) and T7_d (T) ₂₄ primer Was used to synthesize double-stranded cDNA.

First lO w g RNA with T7-d (T) 24 primer, lx First strand buffer, 10 mM DTT, 500 M dNTP mix, and 20 units / μ 1 Superscript II

Reverse Transcriptase was added and reacted at 42 ° C for 1 hour to synthesize single-stranded DNA did. Then, add lx Second strand buffer, 200 μM dNTP mix, 67 U / ml DNA ligase, 270 U / ml DNA polymerase I, and 13 U / ml RNase H, and react at 16 ° C for 2 hours Double-stranded cDNA was synthesized. Furthermore, 67 U / ml T4 DNA polymerase I was added and reacted at 16 ° C for 5 minutes, and then 0.5 M EDTA of 101 was added to stop the reaction.

The obtained cDNA was purified with phenol / cloform form and labeled with piotinylated UTP and CTP using RNA Transcript Labeling Kit (Enzo Diagnostics) according to the attached procedure. The reaction product was purified with an RNeasy column, and then cRNA was fragmented by heating at 94 ° C for 35 minutes in 200 mM trisacetic acid pH8.1, 150 mM magnesium acetate, 50 mM potassium acetate.

The fragmented cRNA was hybridized to GeneChip (Affymetrix) Human Focus array in 100 mM MES, 1 M sodium salt, 20 mM EDTA, 0.01% Tween 20 at 45 ° C. for 16 hours. After hybridization, GeneChi was washed and stained according to the protocol Midi-euk2 attached to the Affymetrix fluidics station. For staining, streptavidin-phycoerythrin and piotinylated anti-streptavidin antibody were used. The stained GeneChip was scanned using an HP argon ion laser confocal microscope (Hewlett Packard), and the fluorescence intensity was measured. For measurement, excitation is performed at a wavelength of 488 nm, and emission is performed at a wavelength of 570 nm.

All quantitative data analysis was performed using GeneChip software (Affymetrix) and Gene Spring (Silicongenetics) ^. When using GeneChip software to evaluate gene expression changes caused by a compound, the RNA quantitative value is dissociated more than twice between the two conditions of the compound-treated group and the untreated group. In some cases, it was judged that the expression of the gene was significantly “increased” or “decreased”. When evaluating the similarity of gene expression changes induced by each compound using Gene Spring, hierarchical clustering analysis was performed based on the expression changes of all genes in the Human Focus Array.

The results of hierarchical clustering analysis of HCT116 cells are shown in FIG. As a result of the analysis, adriamycin and daunomycin, ICRF154 and ICRF159, Kenpaullone and alsterpullone, which have the same mechanism of action, caused similar genetic changes, respectively (Fig. 1). Therefore, it was confirmed that compounds having the same mechanism of action cause similar genetic changes.

E7070, E7820, LY295501 and CQS caused similar genetic changes (Figure 1). Therefore, this analysis strongly suggests that E7070, E7820, LY295501 and CQS have the same or similar mechanism of action and bring about the same or similar genetic alterations and effects. Example 2 DNA microarray analysis

HCT116 cells, 10. /. Fetal bovine serum, 100 units / ml penicillin, and 100 g / ml streptomycin in RPMI-1640 medium. Hereinafter, the culture opi compound treatment was carried out in an incubator adjusted to 5% CO ₂ and 37 ° C. HCT116 cells were seeded at a rate of 2.0 × 10 ⁶ cells / dish in a 10 cm diameter cell culture dish and cultured for 24 hours, and then treated with the following compounds.

In this example, using HCT116 cells, E7820 (0.16 / ι Μ), E7070 (0.26 M), LY186641 (59 M), LY295501 (24 / z M), LY573636 (9.6 / M), CQS (4.0 μm) Μ) ゝ MST16 (100 μ Μ), etoposide (3 ・ 6 ·), ethoxzolamide (410 μ Μ) ゝ capsaicin (280 // M), trichostatin A (0.16 μ Μ), kenpaullone (7.1 / M) 12 compounds Changes in gene expression when treated with

Here, MST16 is a catalytic type of DNA topoisomerase II inhibitor, etoposide ¾ cleavable complex induces the formation of DNA topoisomerase II inhibitory U, ethoxzolamide is carbonic anhydrase P and 軎, capsaicin is tumor-speciiic plasma membrane NADH oxidase An inhibitor, trichostaun A is a known compound as a histone deacetylase inhibitor, and kenpaullone is a cyclin-dependent kinases (CDKs) inhibitor. .

Compound treatment concentration is 50% growth inhibitory concentration of each compound on HCT116 cells

(Based on 3-day cytostatic activity using MTT) Set the degree. Cells were collected after treatment for 24 hours at the set concentration indicated in parentheses following the compound name. Similarly, cells cultured for 24 hours without the addition of the compound were also collected.

Gene expression analysis using a DNA microarray was carried out in the same manner as “(2) Gene expression analysis using DNA microarray” in Example 1.

In addition, this example was performed in duplicate for each sample. (For convenience of experiment, branch numbers are assigned in the manner of control-l, control-2, Ε7820-1, and Ε7820-2 so that each sample can be distinguished. Attached). Then, gene expression change induced by each compound was analyzed using GeneChip (Affymetrix) system (Human Focus array). The RMA method (robust multi-array average method (Biostatistics (2003), 4: 249-264)) was applied to the celj fuinole to the 26 samples obtained in this example (13 samples of control + 12 compounds x2) After normal distribution at the probe level, the log value of the signal intensity at the gene level was calculated. Subsequently, the log value of the signal intensity of the compound-untreated group (control-l) is subtracted from the log value of the signal intensity of the compound-treated group of each gene, and the log value of the signal ratio of the compound-treated group to control-l is obtained. Obtained. The cosine correlation coefficient was calculated and used as the correlation coefficient between experiments (Fig. 2). Based on this correlation coefficient, hierarchical clustering analysis was performed by the UPGMA method (Unweighted Pair Group method with Arithmetic mean method) (Fig. 3). The same calculation was performed for control-2 (Figs. 4 and 5). The software used is R 2.0. L (nttp: 〃 www.r-project.org/) and affy package l.o.8 (http: 〃 www. Bioconductor.org).

2 to 5, “LY1” is LY186641, “: LY2” is LY295501, “: LY5” is LY573636, “CAI” is ethoxzolamide, “Cap” is capsaicin, “MSTJ is MST16, “EtopJ stands for etoposide,“ TSA ”stands for trichostatin A, and“ Kenp ”stands for kenpaullone. In Fig. 3 and Fig. 5, "de hclust

(*, "average")] is a command for statistical analysis. The clustering analysis by R was performed using the average value of the data.

As a result of analysis, the gene changes induced on E7070, E7820, LY186641, LY295501, LY573636 and CQS HCT116 cells showed very high similarity, and any other compound (MST16, etoposide, ethoxzolamide, capsaicin, trichostatin) A and kenpaullone) were also found to be different (Figs. 2 to 5). Therefore, this analysis strongly suggests that E7070, E7820, LY186641, LY295501, LY573636 and CQS have the same or similar mechanism of action, and bring about the same or similar genetic changes and effects. Example 3 Cancer Cell Line Panel Experiment

Using a panel of 36 human cancer cells, the correlation between the cytostatic activity of E7820, E7070, CQS, LY186641, and LY295501 was examined. The cancer cell lines used were DLD-1, HCT15, HCT116, HT29, SW480, SW620, WiDr (above human colon cancer cell lines), A427, A549, LX-1, NCI-H460, NCI-H522, PC -9, PC-10 (above human lung cancer cell line), GT3TKB, HGC27, MKNl, MKN7, MKN28, MKN74 (above human gastric cancer cell line), AsPC-.l, KP-1, KP-4 , MiaPaCall, PANC-1, SUIT-2 (above, human spleen cancer cell lines), BSY-1, HBC5, MCF-7, MDA-MB-231, MDA-MB-435, MDA-MB-468 (above , Human breast cancer cell line), CCRF-CEM, HL60, K562, MOLT-4 (more than human leukemia cell line), all cells are 10% fetal bovine serum, 100 units / ml Bae Nishiri down, and cultured in 5% C0 ₂ under 37 ° C using the RPM 1640 'medium supplemented with scan streptomycin in lOO ^ g / ml (Table 1). table 1

36 human cancer cell lines tested in 3-day MTT assays

Colon Stomach Breast

DLD-l (1250 / well, 16.8 h) GT3TKB (2000 / well, 21.1 h) BSY-l (2000 / well, 46.1 h)

HCT15 (1500 / weII, 14.5 h) HGC27 (1500 / weII, 14.6 h) HBC5 (2000 / well, 31.8 h)

HCT116 (1250 / well, 13.4 h) MKN1 (4000 / weIl, 35.9 h) MCF-7 (3000 / well, 29.5 h)

HT29 (2500 / weIl, 19.8 h) MKN7 (3000 / well, 37.4 h) MDA-MB231 (2000 / well, 21.6 h) SW480 (3000 / well, 19.5 h) MKN28 (2000 / well, 22.7 h) MDA-MB -435 (3000 / well, 24.4 h) SW620 (2500 / well, 17.3 h) MKN74 (4000 / well, 24.8 h) MDA-MB-468 (3000 / well, 34.2 h) WiDr (2000 / weIl, 18.9 h)

Pancreas leukemia

Lung AsPC-l (2500 / well, 28.4 h) CCRF-CEM (1500 / well, 27.2 h) A427 (2500 / well, 32.4 h) KP-1 (2000 / well, 24.8 h) HL60 (1500 / well, 29.5 h)

A549 (1250 / well, 18.9 h) KP-4 (2000 / well, 16.7 h) K562 (1500 / well, 20.6 h)

LX-1 (2000 / well, 17.2 h) MiaPaCall (2500 / well, 19.1 h) MOLT-4 (1500 / well, 22.3 h) NCI-H460 (1000 / well, 13.6 h) PANC-1 (2500 / well, 27.9 h)

NCI-H522 (4000 / weIl, 80.4 h) SUIT-2 (2000 / well, 15.6 h)

PC-9 (2000 / well, 23.7 h)

PC-10 (2000 / well, 24.0 h)

Cell line (initial cell number, doubling time)

Table 1 shows the types of human cancer cell lines, the number of sprinkled cells, and the doubling time in the human cancer cell line panel.

Cells were plated in a 96-well microplate (flat bottom) with the number of cells listed in Table 1 (50 1 / well), and after 3 hours, 3-fold diluted compounds were added (501 / well). After 72 hours, WST-8 (10, α 1 / well) was added and the absorbance at 450 nm was measured. The 50% growth inhibitory inhibitory concentration for all 36 cancer cells was determined by the least square method, and the patterns were compared among the compounds. As a correlation index, Pearson's correlation coefficients were used (Paull, KD et al. Display and analysis oi patterns oi differential activity of drugs against human tumor cell lines: development of mean graph and COMPARE algorithm.J. Natl. Cancer Inst. 1989, 81, 1088-1092; Monks, A. et al. Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. J. Natl. Cancer Inst. 1991, 83, 757-766. ) As a result, E7070, E7820, LY186641, LY295501, and CQS showed a high correlation coefficient in the growth inhibitory activity against each cancer cell line (Table 2). Therefore, this analysis strongly suggests that E7070, E7820, LY186641, LY295501 and CQS have the same or similar mechanism of action, and bring about the same or similar genetic changes and effects. Table 2

E7070 E7820 CQS LY186641 LY295501

E7070 1.00 0.98 0.97 0.93 0.80

E7820 0.98 1.00 0.96 0.95 0.82

CQS 0.97 0.96 1.00 0.92 0.82

LY186641 0.93 0.95 0.92 1.00 0.81

LY295501 0.80 0.82 0.82 0.81 1.00 Table 2 shows the correlation coefficients between compounds (E7070, E7820, CQS, LY186641 and LY295501) in a human cancer cell line panel. Example 4 Cross resistance in E7070 resistant strains

The cell growth inhibitory activity of E7820, LY186641 _S LY295501, LY-ASAP and CQS was evaluated using E7070 resistant strains. HCT116-C9 is a subtype of human colorectal cancer-derived HCT116 (American Type Culture Collection, Manassas, VA, USA) .This HCT116-C9 was cultured in the presence of E7070, and the E7070 concentration was gradually increased. The E7070-resistant substrains obtained by raising the strain to HCT116-C9-C1 and HCT116-C9-C4 (Molecular Cancer Therapeutics, 2002, 1, 275-286).

Three cell lines HCT116-C9, HCT116-C9-C1, and HCT116-C9-C4 were spread on a 96-well microphone mouthplate (flat bottom) at 3000 cells / well (50 l / well) and diluted 3 times after 24 hours. A series of compounds was added (50 ^ 1 / well). Furthermore, after 72 hours, the cell growth inhibitory activity was evaluated by the MTT method (Mossmann T "J. Immunol. Methods, 1983, 65, 55-63). The 50% growth inhibitory concentration against each cancer cell was determined by the least square method. Asked.

As a result, the cytostatic activity of E7070 is IC50 against HCT116-C9 (C9). Was 0.127 μΜ. In contrast, the activity against HCT116-C9-C1 (C9C1) and HCT116-C9-C4 (C9C4) is IC50 = 31.9 μΜ and 26.9 μΜ, respectively, and the cell growth inhibitory activity of Ε7070 against C9C1 and C9C4 is remarkable. (Fig. 6). The cell growth inhibitory activities of E7820, CQS, LY186641, LY295501, and LY_ASAP were IC50 = 0.080 Μ, 1.73 / Μ, 33.6 ζΜ, 10 · 9μΜ, and 1.63Μ for HCT116-C9, respectively. In contrast, the activities against HCT116-C9-C1 and HCT116-C9-C4 are IC50 = 51.2μΜ, 634μΜ, 134 ^ M, 111μΜ, 113 / Μ for HCT116-C9-C1, respectively. For HCT116-C9.C4, IC50 = 52.8 μΜ, 517 μΜ, 138 Μ, 110 μΜ, and 90.3 それぞれ, respectively. As for the cell growth inhibitory activity of E7820, CQS, LY186641, LY295501, and LY-ASAP, the activity against C9C1 and C9C4 was significantly lower than that against C9 (Fig. 6). Therefore, E7070, E7820, LY186641, LY295501, LY-ASAP and CQS were considered to have the same or similar mechanism of action, strongly suggesting that they would have the same or similar genetic changes and effects. Example 5 Cross resistance in E7070 resistant strains

In exactly the same manner as in Example 4, the cell growth inhibitory activity of LY573636 was evaluated simultaneously with E7070 using an E7070 resistant strain.

As a result, the cytostatic activity of E7070 is higher than that of HCT116-C9 (IC50 = 0.127 / zM), and that of HCT116-C9-C1 and HCT116-C9-C4 (IC50 = 32.7 μΜ and 28.0 それぞれ, respectively). It was confirmed again that it was significantly reduced (Fig. 7). In addition, LY573636 has a cell growth inhibitory activity compared to the activity against HCT116-C9 (IC50 2 5.11 Μ), activity against HCT116-C9-C1 and HCT116-C9-C4 (IC50 = 264 μΜ and 240 μΜ, respectively). It was significantly reduced (Fig. 7). Therefore, LY573636 was considered to have the same or similar mechanism of action as Ε7070, and strongly suggested that LY573636 produces the same or similar genetic changes and effects.

These results (Examples 1 to 5) force, Ε7070, Ε7820, LY186641, It was found that LY295501, LY-ASAP, LY573636 or CQS or combinations thereof produced the same or similar genetic changes and the same or similar actions and effects.

Therefore, as with E7820 (WO03 / 022272), sulfonamide compounds, preferably LY186641, LY295501, LY'ASAP, LY573636 or CQS, or a combination thereof, have an effect of promoting eating and treat anorexia. It became clear that it was useful as an agent. Industrial applicability

According to the present invention, an excellent feeding enhancer and a Z or anorexia remedy are provided.

More specifically, a sulfonamide compound exhibiting an excellent feeding enhancing effect and an effect of treating Z or anorexia, preferably LY186641, LY295501, LY-ASAP, LY573636 or CQS or a combination thereof as an active ingredient Have been provided and can be used to treat anorexia. In addition, a kit containing an anorexia remedy and an anticancer agent containing a sulfonamide compound as an active ingredient is provided, and can be used for the treatment of anorexia.

Claims

The scope of the claims

An eating enhancer comprising a sulfonamide compound as an active ingredient,

The sulfonamide compound is

Formula (I)

[In the formula, E is 1_, _N (CH ₃ )-, 1 CH ₂ —, _CH ₂ CH ₂ — or 1 CH ₂ 0, D is 1 CH ₂ — or 1 O—, R ^la Represents a hydrogen atom or a halogen atom, and R ^2a represents a halogen atom or a trifluoromethyl group, respectively. ]

A compound represented by:

Formula (II)

[Wherein, J represents one O—or —NH—, Rib represents a hydrogen atom, a halogen atom, an optionally substituted d-Ce alkyl group, or an optionally substituted C 1—C4 alkoxy group, optionally substituted Ci—C ₄ alkylthio group, 1 CF ₃ , —OCF ₃ , 1 S CF ₃ , optionally substituted Ci 1 C4 alkoxycarbonyl Group, nitro group, azide group, 1O (S0 2) CH ₃ , _N (CH ₃ ) 2, hydroxyl group, fu: r diyl group, substituted phenyl group, pyridinyl group, chenyl group, furyl group, A quinolinyl group or a triazole group, R 1 is a hydrogen atom, a halogen atom, a cyano group, one CF ₃ , an optionally substituted d-C ₆ alkyl group, or an optionally substituted one; C4 alkoxycarbonyl group, which may have a substituent d-C ₄ alkoxy group which may have a substituent off An enyl group or Is an optionally substituted quinolinyl group, R ^3b is a hydrogen atom or a Ci-C ₄ alkoxy group optionally having a substituent, R ^4b has a hydrogen atom or a substituent Ci—C ₆ alkyl group (provided that at least one of R 3b and R 4b is a hydrogen atom), R ⁵ b may have a hydrogen atom, a halogen atom, or a substituent d --C ₆ alkyl group, one CF ₃ or nitro group, R6b may have a hydrogen atom, a halogen atom or a substituent.One C ₆ alkyl group (provided that Reb has a substituent when even good Ci_C ₆ alkyl group, R ⁵ b is a hydrogen atom, a R ^7b is a halogen atom), R ^7b represents a halogen atom, it may have a location substituent CI- C ₆ alkyl A group or one CF ₃ (wherein either R ⁵ b or R? B may have a substituent Ci 1 C ₆ alkyl group, or R? B force may have halogen atom or substituent d—

In the case of a C ₆ alkyl group, each of R ⁵ b and R <3b is a hydrogen atom). ]

A compound represented by

Formula (III)

A compound represented by

Formula (IV)

The above feeding enhancer, which is at least one compound selected from the group consisting of compounds represented by: or a pharmacologically acceptable salt thereof or a solvate thereof.

2. Sulfonamide compound has a Ν— [[(4--cyclophenyl) amino] force report. Nyl] — 2,3-Dihydr draw 1 H-indene 1-5-sulfonamide, N— [[(3,4-Dichlorophenyl) amino] carbonyl] — 2, 3-dihydrobenzofuran 1-5-sulfonamide, N— (2, 4— Diclonal Benenosinore)-4 Monoclonal Feninores Norehonamide, N— (2,4-Diclonal Benzoinole)-5-—Bromothiophene— 2-Sulphonamide and 2-Snore The feeding enhancer according to claim 1, which is at least one compound selected from the group consisting of faninoreamide 5-chloroquinoxaline, or a pharmacologically acceptable salt thereof, or a solvate thereof. .

3. Sulfonamide compounds are N-[[((3,4-dichlorophenyl) amino] carbonyl] — 2,3-dihydrobenzofuran 1-sulfone amide and N 1 (2,4-dichlorobenzoinole). _ The feeding enhancer according to claim 1, which is at least one compound selected from the group consisting of 5-bromothiophene-1-snorehonamide, or a pharmaceutically acceptable salt thereof, or a solvate thereof. . .

4. The feeding enhancer according to claim 1, wherein the sulfonamide compound is a sodium salt of N— (2,4-dichlorodibenzo) -5-bromothiophene-2-sulfonamide. .

5. A therapeutic agent for anorexia comprising a sulfonamide compound as an active ingredient, wherein the sulfonamide compound comprises:

Formula (I)

[In the formula, E represents 0—, 1 N (CH ₃ ) —, 1 CH ₂ —, 1 CH ₂ CH ₂ — or 1 CH ₂ O1, D represents —CH ₂ — or 1 O— Ria means a hydrogen atom or a halogen atom, and R ^2a means a halogen atom or a trifluoromethyl group. ] Compound represented by

Formula (II)

[Wherein J represents 1 O— or 1 NH—, R ^lb represents a hydrogen atom, a halogen atom, or a Ci 1 C ₆ alkyl group which may have a substituent, or a substituent. Good C 丄 C4 alkoxy group, Ci 1 C ₄ alkylthio group optionally having substituents,-CF ₃ , 1 OC F ₃ , 1 S CF ₃ , Ci 1 C4 optionally having substituents Alkoxycarbonyl group, nitro group, azide group, 1 O (S0 ₂ ) CH ₃ , 1 N (CH ₃ ) 2, hydroxyl group, phenyl group, substituted phenyl group, pyridyl group, chenyl group , A furyl group, a quinolinyl group or a triazole group, R ² b has a hydrogen atom, a halogen atom, a cyano group, one CF ₃ , an optionally substituted Ci 1 C ₆ alkyl group, or a substituted group. has a good Ci one also be C ₄ alkoxycarbonyl group, which may have a substituent group d-C4 alkoxy group, a substituent The good quinolinyl group optionally also have a good phenyl group or substituent have, R ^3b are, have a hydrogen atom or a substituent. Also good Ci-C ₄ alkoxy group, R ^4b is hydrogen Ci—C ₆ alkyl group (provided that at least one of R 3b and R 4b is a hydrogen atom) which may have an atom or a substituent, R ^5b represents a hydrogen atom, a halogen atom or a substituent. Ci_C ₆ alkyl group, _C F ₃ or nitro group which may be present, R6b is hydrogen atom, halogen atom or optionally substituted d-Ce alkyl group (provided that R6b is a substituent) when have may CI- C ₆ alkyl group optionally having a, R ^5b is a hydrogen atom, a R ^7b is a halogen atom), R ^7b represents a halogen atom, which may have a location substituent good one C ₆ alkyl group or a CF ₃ (provided that either one of R or R? b is a substituted group If it is a good Ci one C ₆ alkyl group Der even if Ru force or R? B force S, which may have a halogen atom or a substituent d-C ₆ alkyl group, R ⁵ b Or one of RGb is a hydrogen atom). ] A compound represented by

Formula (III)

A compound represented by

Formula (IV)

The therapeutic agent, which is at least one compound selected from the group consisting of compounds represented by: or a pharmacologically acceptable salt thereof or a solvate thereof.

6. Sulfonamide compound is N — [[(4 monophenyl) amino] carbonyl] 1,2,3-dihydr 1 H-indene 1 5-sulfonamide, N—

[[(3,4-dichlorophenyl) amino] carbonyl] —2,3, dihydrobenzofuran 1—5-snorehon amide, N— (2,4—diclonal benzoinole) 1—4-south phenylenolesnorephone At least one compound selected from the group consisting of amide, N— (2,4-dichlorobenzoinole) 1-promothiophene 2-sunorehon amide and 2-sulfaninoreamido 5-clocloquinoxaline, The therapeutic agent according to claim 5, which is a pharmacologically acceptable salt or a solvate thereof.

7. Sulfonamide compound is N — [[((3,4-Dichlorophenyl) amino] canoleboninole] —2,2,3-dihydrobenzofuran 1-sulfone amide N- (2,4-dichlorobenzene 6. The treatment according to claim 5, which is at least one compound selected from the group consisting of 1-bromothiophene 1 2-snorephoneamide, or a pharmaceutically acceptable salt thereof, or a solvate thereof. Agent.

8. Sulfonamide compound is N— (2,4-dichlorobenzene) The therapeutic agent according to claim 5, which is a sodium salt of mothiophene 2-sulfonamide.

9. Anorexia is at least one disease selected from the group consisting of anorexia nervosa, anorexic slimming disease, and anorexia and leanness associated with cachexia. 9. The therapeutic agent according to any one of 8.

10. A kit for treating anorexia comprising the therapeutic agent according to any one of claims 5 to 8 and an anticancer agent.

1 1. A feeding promotion method characterized by administering a sulfonamide compound to a patient.

The sulfonamide compound is

Formula (I)

Wherein, E _{is, _0- - N (CH 3)} -, one CH ₂ -, one CH ₂ CH ₂ - or one CH ₂ 0-, D is, -. CH ₂ - or a O- and R ^la means a hydrogen atom or a halogen atom, and R ^2a means a halogen atom or a trifluoromethyl group. ]

A compound represented by

Formula (II)

[Wherein, J represents 1 O— or 1 NH—, Rib represents a hydrogen atom, a halogen atom, an optionally substituted Ci 1 C ₆ alkyl group, or an optionally substituted group. C 1 C 4 alkoxy group, which may have a substituent d—C ₄ alkylthio group, 1 CF ₃ , —OCF ₃ , 1 S CF ₃ , Ci 1 C4 alkoxy which may have a substituent Sicarbonyl group, nitro group, azide group, 100 (S02) CH ₃ , 1 N (CH ₃ ) 2, hydroxyl group, phenyl group, substituted funil group, pyridinyl group, chenyl group, furyl group, A quinolinyl group or a triazole group, R ^2b may have a hydrogen atom, a halogen atom, a cyano group, one CF ₃ , an optionally substituted Ci—C ₆ alkyl group, or an optionally substituted group Ci_C ₄ alkoxycarbonyl group, optionally substituted Ci 1 C ₄ alkoxy group, optionally substituted phenyl group or optionally substituted quinolinyl group, R ^3b Is a hydrogen atom or a substituent d—C ₄ alkoxy group, R ^4b is a hydrogen atom or a substituent Ci 1 C ₆ alkyl group (provided that R 3b and R ^4b At least

— Is a hydrogen atom), R ^5b is a hydrogen atom, a halogen atom, an optionally substituted Ci—C ₆ alkyl group, _CF ₃ or a nitro group, and R6b is a hydrogen atom. D—Ce alkyl group which may have an atom, a halogen atom or a substituent (provided that R ⁶ b is a Ci—C ₆ alkyl group which may have a substituent, R is a hydrogen atom) the R ^7b is a halogen atom), R? b is a halogen atom, CI_ may have a location substituent C ₆ alkyl group or a _ CF ₃ (proviso that R ⁵ b or the R? b Either one is an optionally substituted d-C ₆ alkyl group, or R? B force S, a halogen atom or an optionally substituted d-C ₆ alkyl group , Each of R ⁵ b and RSb is a hydrogen atom) '. ]

A compound represented by

Formula (III)

A compound represented by

Formula (IV)

Or at least one compound selected from the group consisting of compounds represented by: or a pharmacologically acceptable salt thereof or a solvate thereof.

1 2. The sulfonamide compound is N — [[((4 chlorophenyl) amino) carbonyl] 1,2,3-dihydrol 1 H—indene 5—sulfonamide, N— [[(3,4— Diclonal phenyl) Amino] Carboninole] 1, 2, 3-Dihydro benzofuran 1-Snorehon amide, N— (2, 4-Dichlorobenzoinole) One 4-—Chloropheno-renoreno amide, N— ( 2, 4-diclomental benzoinole) at least one compound selected from the group consisting of 15-promothiophene 2-sulphonamide and 2-sunorefanamide 5-sucral quinoxaline, or a pharmacological thereof The method according to claim 11, wherein the salt is an acceptable salt or a solvate thereof.

1 3. The sulfonamide compound is N-[[((3,4-diphenyl) phenyl) amino] canolebonile] —2,3-dihydrobenzofuran 5-snorephone amide and N— (2,4-dichloro Orally, it is at least one compound selected from the group consisting of 2-bromothiophene-2-sunolehonamide, or a pharmaceutically acceptable salt thereof, or a solvate thereof. The method of description.

14. The method according to claim 11, wherein the sulfonamide compound is a sodium salt of N— (2,4-dichloro-benzozyl) 15-powder mothiophene 2-sulfonamide.

15. A method for treating anorexia characterized by administering a sulfonamide compound to a patient, comprising:

The sulfonamide compound is

Formula (I)

[Where E is _0—, _N (CH ₃ ) —, one CH ₂ —, one CH ₂ CH ₂ — or one CH ₂ 0_, D is one CH ₂ — or one O—, R ^la represents a hydrogen atom or a halogen atom, and R ^2a represents a halogen atom or a trifluoromethyl group. ]

A compound represented by

Formula (II)

[Wherein J is _0— or 1 NH—, Rib is a hydrogen atom, a halogen atom, an optionally substituted Ci—Cs alkyl group, or an optionally substituted C i —C ₄ alkoxy group, optionally substituted Cl_C4 alkylthio group, —CF ₃ , —OCF ₃ ^ — S CF ₃ , optionally substituted C — C ₄ alkoxycarbonyl group , Nitro group, Azide group, 1 O (S0 ₂ ) CH ₃ , 1 N (CH ₃ ) 2, Minamata group, Fuer group, Phenyl group with substituent, Pyridinyl group, Chenyl group, Furyl group, Quinolinyl R ^2b is a hydrogen atom, a halogen atom, a cyano group, one CF ₃ , an optionally substituted d-Ce alkyl group, or an optionally substituted C 1_ C ₄ alkoxycarbonyl group, which may have a substituent Cl— C4 alkoxy group, which may have a substituent A phenol group or a quinolinyl group optionally having a substituent, R ^3b is a hydrogen atom or a d-C4 alkoxy group optionally having a substituent, R ^4b is a hydrogen atom or a substituent Ci—C ₆ alkyl group (provided that at least one of R 3b and R 4b is a hydrogen atom) which may have a group, R ^5b has a hydrogen atom, a halogen atom or a substituent. which may Ci_C ₆ alkyl group, an CF ₃ or nitro, R ^6b is water Elemental, halogen, or optionally substituted C ₆ alkyl group (provided that R ⁶ b is optionally substituted d—C ₆ alkyl group, R ^5b is a hydrogen atom R ^7b is a halogen atom), R ^7b is a halogen atom, an optionally substituted Ci—C ₆ alkyl group or a single CF ₃ (where R ⁵ b or R? any one of b may have a substituent d—C ₆ alkyl group, or R ⁷ b may have a halogen atom or a substituent Ci 1 C ₆ alkyl In the case of a group, each of R ⁵ b and Reb is a hydrogen atom). ]

A compound represented by

Formula (III)

A compound represented by

Formula (IV)

Or at least one compound selected from the group consisting of compounds represented by: or a pharmacologically acceptable salt thereof or a solvate thereof. 6 · 'Sulfonamide compound is N — [[((4-Cyclophenyl) amino) carbono]] 2,3-Dihydr Draw 1 H—Indene 5—Snorephone Amid, N— [[((3, 4 —Dichlorophenol) Amino] Carbon] 1, 2, 3-Dihydrobenzofuran 1—Sulfoamide, N— (2,4-Dichlorobenzoenol) 1—4-Chlorophenylsulfonamide, N— ( 1,4-dichlorophenobenzene) at least one compound selected from the group consisting of 1-promothiophene 2-snorephone amide and 2-sunophaninoleamide 5-crocin quinoxaline, Or a pharmacologically acceptable salt thereof or a solvate thereof.

1 The method according to 5.

1 7. The sulfonamide compound is N — [[((3,4-dichlorophenyl) amino] carbonyl] -1,2,3-dihydrobenzofuran-1,5-sulfonamide and N— (2,4 (1) dichlorobenzoinole) 1) 5-promothiophene 1) 2-snolehonamide, or at least one compound selected from the group consisting of pharmaceutically acceptable salts or solvates thereof. 1 The method described in 5.

1 8. The method according to claim 15, wherein the sulfonamide compound is a sodium salt of N- (2,4-dichlorobenzoyl) 15-bucc mothiophene-2-sulfonamide.

1 9. Anorexia is at least one disease selected from the group consisting of anorexia nervosa, anorexic slimming disease, and anorexia and leanness associated with cachexia. The method according to any one of 1 to 8.

20. A method for treating anorexia characterized by administering the therapeutic agent according to any one of claims 5 to 8 and an anticancer agent to a patient.

2 1. Use of a sulfonamide compound for the production of a food intake enhancer, wherein the sulfonamide compound is

Formula (I)

[In the formula, E represents −1, 1 N (CH ₃ ), 1 CH ₂ —, 1 CH ₂ CH ₂ — or 1 CH ₂ 0—, D represents 1 CH ₂ — or 1 O—. And R ^la means a hydrogen atom or a halogen atom, and R ² a means a halogen atom or a trifluoromethyl group, respectively. ]

A compound represented by General formula (ID

[Wherein, J represents 10—or 1 NH—, R ^lb represents a hydrogen atom, a halogen atom, an optionally substituted C ₆ alkyl group, or an optionally substituted group. C 1-C4 alkoxy group, d_ C4 alkylthio group optionally having substituent,

CF _3, -〇_CF _3, One S CF _3, substituents include optionally may Ci one even C4 an alkoxy carbonyl group, nitro group, azido group, one O (S_〇 ₂₎ CH _3, one N (CH ₃ ) 2, hydroxyl group, phenol group, substituted phenyl group, pyridinyl group, chenyl group, furyl group, quinolinyl group or triazole group, R ^2b is hydrogen atom, halogen atom, cyano group, single CF _3, which may have a substituent d-C ₆ alkyl group, which may have a substituent CI- C ₄ alkoxycarbonyl group, which may have a substituent Ci-C ₄ alkoxy group A substituted or unsubstituted phenyl group or an optionally substituted quinolinyl group, R ^3b represents a hydrogen atom or an optionally substituted d-C ₄ alkoxy group. , R ⁴ b is not a hydrogen atom or a substituent. or Cl @ - C ₆ alkyl group (however , At least one of R ^3b and R ^4b, the a is) hydrogen atom, R ^5b is a hydrogen atom, a halogen atom, an optionally have a substituent Ci_C ₆ alkyl group, an CF ₃ or nitro group , R6b is water atom, and a halogen atom or an optionally substituted Ci-Ce alkyl group (伹, when R ^6b is optionally substituted d-C ₆ alkyl group, R ^5b is a hydrogen atom, a R ^7b is a halogen atom), R ^7b represents a halogen atom, which may have a location substituent Ci one C ₆ alkyl group or a CF ₃ (proviso, R ⁵ Either b or R? b may have a substituent d-Ce alkyl group, or R? b force a halogen atom or a substituent d- In the case of a C ₆ alkyl group, each of R ^{5b and} R ^6b is a hydrogen atom). ]

A compound represented by Formula (III)

A compound represented by

Formula (IV)

(IV)

2 2. The sulfonamide compound is N — [[(4-chlorophenyl) amino] carbonyl] 1,2,3-dihydro 1 H—indene 1—5-sulfonamide, N—

[[(3,4-dichlorophenyl) amino] force ruponyl] 2,3-dihydrobenzofuran-5-sunorehoamide, N— (2,4-dichlorobenzoinole) -4 chlorosulphone sulfoneamide, At least one compound selected from the group consisting of N— (2,4-dichlorodichloro) 1-bromothiophene 2-snorephone amide and 2-sunophaninoleamide 5-chloroquinoxaline, or a pharmacological thereof The use according to claim 21, which is an acceptable salt or a solvate thereof.

2 3: The sulfonamide compound is N — [[((3,4-dichlorophenyl) amino] -powered LLP--2,3-dihydrobenzofuran 1—Snorephone amide and N— (2,4 (5) -bromothiophene (2) -at least one compound selected from the group consisting of sulphonone amide, or a pharmaceutically acceptable salt thereof, or a solvate thereof. Use as described in 1.

2 4. The sulfonamide compound is N— (2,4—Dichlorobenzene) The use according to claim 21, which is a sodium salt of oral mothiophene 2-sulfonamide.

25. Use of a sulfonamide compound for the manufacture of a therapeutic agent for anorexia, wherein the sulfonamide compound comprises:

Formula (I)

Wherein, E represents one _{O-, _N (CH 3) -} , one CH ₂ - one CH2CH2- or an CH ₂ 〇 one, D is one CH ₂ - or - O-a, R ^la is , A hydrogen atom or a halogen atom, and R ^2a means a halogen atom or a trifluoromethyl group, respectively. ]

A compound represented by

Formula (II)

[Wherein J represents 101 or 1 NH—, Rib represents a hydrogen atom, a halogen atom, an optionally substituted Ci—C ₆ alkyl group, or an optionally substituted group. Ci—C4 alkoxy group, optionally substituted Ci 1 C ₄ alkylthio group, 1 CF ₃ , 1 OCF ₃ , 1 S CF ₃ , optionally substituted Ci_C4 alkoxycarbonyl Group, nitro group, azide group, mono-Oz S0 ₂ ) CH ₃ , -N (CH ₃ ) 2, hydroxyl group, phenyl group, substituted phenyl group, pyridinyl group, chael group, furyl group, A quinolinyl group or a triazole group, R ² b is a hydrogen atom, a halogen atom, a cyano group, one CF ₃ , an optionally substituted d-C ₆ alkyl group, or an optionally substituted group; good CI- C ₄ alkoxycarbonyl group, which may have a substituent Ci one C4 alkoxy groups, substituted Good phenyl groups can also be Is an optionally substituted quinolinyl group, R ^3b is a hydrogen atom or a d-C ₄ alkoxy group optionally having a substituent, and R ⁴ b is a hydrogen atom or substituent. Ci—C ₆ alkyl group (in which at least one of R 3b and R 4b is a hydrogen atom), and R ^5b may have a hydrogen atom, a halogen atom, or a substituent. d—C ₆ alkyl group, one CF ₃ or nitro group, R ^6b is a hydrogen atom, halogen atom or optionally substituted Ci—Ce alkyl group (provided that R ⁶ b represents a substituent) when good Ci one C ₆ alkyl group which may have, R ⁵ b is a hydrogen atom, a R ^7b is a halogen atom), R ^7b represents a halogen atom, which may have a location substituent Good Ci—Cs alkyl group or one CF ₃ (wherein either R or R? B may have a substituent Ci— A C ₆ alkyl group, or R ⁷ b force S, optionally having a halogen atom or a substituent d—

In the case of a C ₆ alkyl group, each of R ^{5b and} R ^6b is a hydrogen atom). ]

A compound represented by:

Formula (III)

A compound represented by

Formula (IV)

Or at least one compound selected from the group consisting of compounds represented by: or a pharmacologically acceptable salt thereof or a solvate thereof. 6. Sulfonamide compound is N — [[((4—Black mouth) amino] carbonyl] — 2,3-Dihydr Draw 1 H—Indene _ 5—Snorethone Amid, N— [[(3,4-Dichlorophenyl) amino] Carbonyl] 1,2,3-Dihydrobenzofuran, 5-Snolehonamide, N— (2,4-Dichlorophenobenzene) At least one compound selected from the group consisting of: 5-N- (2,4-dicyclophenobenzene) 1-bromothiophene 2-sulfonamide and 2-sunorefinolide amide 5-quinoquinoline, or The use according to claim 25, which is a pharmacologically acceptable salt or a solvate thereof.

2 7. The sulfonamide compound is N — [[((3,4-dichlorophenyl) amino] carbonyl] — 2,3-dihydrobenzofuran 1-sulfonamide and N— (2,4 1) -promothiophene 1-sulphonamide, at least one compound selected from the group consisting of 1-promothiophene 1-sulphonamide, a pharmaceutically acceptable salt thereof, or a solvate thereof. 2 Use as described in 5.

28. The use according to claim 25, wherein the sulfonamide compound is a sodium salt of N- (2,4-dichlorobenzoyl) 15-butyl mothiophene 2-sulfonamide.

2 9. The anorexia is at least one disease selected from the group consisting of anorexia nervosa, anorexia nervosa, and anorexia and slimming associated with cachexia. The use according to any one of 5 to 28.

30. Use of a sulfonamide compound for the manufacture of a kit according to claim 10.