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WO2006090927A1 - Action orexigenique d'un compose de sulfonamide - Google Patents

Action orexigenique d'un compose de sulfonamide Download PDF

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Publication number
WO2006090927A1
WO2006090927A1 PCT/JP2006/304206 JP2006304206W WO2006090927A1 WO 2006090927 A1 WO2006090927 A1 WO 2006090927A1 JP 2006304206 W JP2006304206 W JP 2006304206W WO 2006090927 A1 WO2006090927 A1 WO 2006090927A1
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group
substituent
hydrogen atom
halogen atom
optionally substituted
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Japanese (ja)
Inventor
Takashi Owa
Yoichi Ozawa
Naoto Ono
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Eisai Co Ltd
Eisai R&D Management Co Ltd
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Eisai Co Ltd
Eisai R&D Management Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms

Definitions

  • Sulfonamide compounds enhance food intake
  • 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.
  • 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.
  • 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”
  • E7820 N— [[((4— Black-end phenyl) amino] Carbonyl] —2, 3— Dihydrol 1 H—Indene 5 —Sulfonamide (hereinafter sometimes referred to as LY “186641”)
  • 3 —Dihydrobenzofuran 1-sulfone amide hereinafter sometimes referred to as “LY295501”
  • LY295501 N— (2,4-
  • E7820 has an effect of enhancing feeding and is useful as a therapeutic agent for anorexia ( 6) .
  • 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.
  • 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.
  • 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.
  • the present invention relates to the following.
  • a therapeutic agent for anorexia comprising a sulfonamide compound as an active ingredient.
  • a method for enhancing feeding comprising administering a sulfonamide compound to a patient.
  • a method for treating anorexia characterized by administering a sulfonamide compound to a patient
  • the present invention also relates to the following.
  • a kit for treating anorexia comprising the therapeutic agent according to (2) and an anticancer agent.
  • a method for treating anorexia comprising administering the therapeutic agent according to (2) and an anticancer agent to a patient.
  • 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.
  • 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
  • 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
  • an excellent feeding enhancer Opino or an anorexia remedy is provided.
  • 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.
  • 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.
  • 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.
  • the sulfonamide compound includes a compound represented by the following 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. .
  • 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.
  • 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 can be produced by a known method, for example, by the method described in European Patent Application Publication No. 0222475A1.
  • 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 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.
  • the sulfonamide compound includes a compound represented by the following general formula (II).
  • J represents 10—or 1 NH—
  • R ′′> represents a hydrogen atom ′, a halogen atom, or an optionally substituted d-C 6 alkyl group.
  • 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 7 b is a halogen atom
  • 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
  • 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).
  • the “halogen atom” is preferably a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • 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,
  • 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.
  • 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. .
  • 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.
  • the alkyl group is not particularly limited, but is methyl, ethyl, n-propyl, isopropyl, n-butynole, isobutyl, sec-butynole, tert —Petinole can be mentioned.
  • 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.
  • the substituent to be introduced is not particularly limited.
  • 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
  • silyl group for example, silyl group.
  • the compound represented by the general formula ( ⁇ ) 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.
  • LY-ASAP refers to N— (2,4-dichlorobenzoyl) -4-chlorosulfone amide, whose structural formula is shown in the following formula (XI).
  • LY-ASAP can be produced by a known method.
  • LY-ASAP can be produced by the method described in WO 02/0988848 (WO02 / 098848).
  • examples of the sulfonamide compound include LY573636.
  • LY573636 refers to N- (2,4-dichlorodibenzo) 15-bromothiophene 1-2-sulfonamide, and its structural formula is shown in the following formula (III).
  • LY573636 is preferably a sodium salt.
  • LY573636 can be produced by a known method.
  • 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.
  • LY573636 can be produced by the method described in Example 63 in International Publication No. 2003/035629 (WO2003 / 035629).
  • examples of the sulfonamide compound include CQS.
  • 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.
  • 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.
  • inorganic acid salts such as hydrochloride, hydrobromide, sulfate, and phosphate
  • formic acid acetic acid
  • lactic acid succinic acid
  • fumaric acid maleic acid
  • citrate citrate
  • tartaric acid examples thereof include salts with organic acids such as benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and trifluoroacetic acid.
  • 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)
  • ammonium 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.
  • water alcohol (for example, methanol, ethanol, n-propanol), dimethylformamide or the like can be used.
  • 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.
  • the sulfonamide compound in the present invention is oxidized, reduced, Also included are compounds that produce a sulfonamide compound upon metabolism such as hydrolysis.
  • 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.
  • the sulfonamide compound is as described in “1.
  • Sulfonamide Compound For example, from the general formula (I), the general formula ( ⁇ ), 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. .
  • 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.
  • 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.
  • 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.
  • the anorexia is not particularly limited, and examples thereof include anorexia nervosa, anorexic slimming, anorexia associated with cachexia, and leanness associated 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.
  • mammals eg, humans, rats, rabbits, hidges, pigs, rabbits, cats, dogs, monkeys, etc.
  • 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.
  • 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.
  • 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.).
  • “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.
  • 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.
  • 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. .
  • 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.
  • 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.
  • parenteral preparations such as suppositories, suppositories, ointments, and poultices.
  • 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.
  • 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
  • binders include, for example, polyvinylolezoreconole, ethinoresenorelose, methinorescenore.
  • magnesium stearate, talc, silica, etc. are added to pharmaceuticals as colorants, such as loin, gum arabic, hydroxypropyl senololose, hydroxypropenolemethinolecellulose, etc.
  • a flavoring agent for example, cocoa powder, heart muscle, aromatic acid, heart force oil, dragon brain, cinnamon powder and the like are used.
  • these tablets and granules may be appropriately coated with sugar coating, gelatin coating, etc. if necessary.
  • suspending agent examples include methyl cellulose, polysorbate 80, hydroxyl acetylenolose, gum arabic, tragacanth powder, carboxymethyl senolate mouthwater sodium, polyoxyethylene sorbitan monolaurate and the like.
  • solubilizer examples 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
  • 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.
  • 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.
  • a pharmaceutical composition containing a sulfonamide compound for example, a therapeutic agent for anorexia containing the compound as an active ingredient
  • an anticancer agent for example, a therapeutic agent for anorexia containing the compound as an active ingredient
  • the method is preferably a method for treating anorexia associated with cachexia or a method for treating slimming associated with cachexia.
  • 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.
  • the present invention will be described with specific examples, but the present invention is not limited thereto.
  • human colon cancer-derived cell line HCT116 American Type Culture Collection, Manassas, VA, USA
  • human leukemia-derived cell line MOLT-4 American TV e Culture Collection, Manassas, VA, USA
  • 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.
  • E7820 (0.8 ⁇ ), ⁇ 7070 (0.8 ⁇ M), LY295501 (30 z M), CQS (8 ⁇ ), adriamycin (0.2 ⁇ u), daunomycin (0.2.u M), ICRF154 Twelve compounds (80 ⁇ ), ICRF159 (80 ⁇ ), kenpauUone (10 ⁇ ), alsterpullone (10 ⁇ ), trichostatin A (O. l M) and rapamycin (80 / z M) were evaluated. On the other hand, E7070 (0.8 ⁇ M) was evaluated for M0LT-4 cells.
  • 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 ⁇ , alsterpullone Are cyclm-dependent kinases (CDKs) inhibitors
  • trichostatin A is a histone deacetylase inhibitor
  • 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.
  • RNA extraction of total RNA from the collected cells was performed using TRIZOL reagent (manufactured by Invitrogen) according to the attached operation method.
  • RNA was dissolved in sterilized water treated with ⁇ 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.
  • 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 ⁇ M 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.
  • 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.
  • HCT116 cells 10. /. Fetal bovine serum, 100 units / ml penicillin, and 100 g / ml streptomycin in RPMI-1640 medium.
  • 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.
  • MST16 is a catalytic type of DNA topoisomerase II inhibitor, etoposide 3 ⁇ 4 cleavable complex induces the formation of DNA topoisomerase II inhibitory U, ethoxzolamide is carbonic anhydrase P and ⁇ , 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. .
  • CDKs cyclin-dependent kinases
  • Compound treatment concentration is 50% growth inhibitory concentration of each compound on HCT116 cells
  • RNA extraction of total RNA from the collected cells was performed using TRIZOL reagent (manufactured by Invitrogen) according to the attached operation method.
  • 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, ⁇ 7820-1, and ⁇ 7820-2 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.
  • GeneChip Affymetrix
  • the RMA method 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.
  • 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
  • Kenp stands for kenpaullone.
  • 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,
  • HCT15 (1500 / weII, 14.5 h)
  • HGC27 (1500 / weII, 14.6 h)
  • HBC5 2000 / well, 31.8 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)
  • 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.
  • 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
  • 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).
  • 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.
  • the cytostatic activity of E7070 is IC50 against HCT116-C9 (C9).
  • IC50 52.8 ⁇ , 517 ⁇ , 138 ⁇ , 110 ⁇ , and 90.3 ⁇ ⁇ ⁇ ⁇ , respectively.
  • 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).
  • Example 4 the cell growth inhibitory activity of LY573636 was evaluated simultaneously with E7070 using an E7070 resistant strain.
  • 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
  • an excellent feeding enhancer and a Z or anorexia remedy are provided.
  • 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
  • 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.

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Abstract

L'invention concerne un agent orexigénique et un remède contre l'anorexie comprenant un composé de sulfonamide en tant que principe actif.
PCT/JP2006/304206 2005-02-28 2006-02-28 Action orexigenique d'un compose de sulfonamide Ceased WO2006090927A1 (fr)

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JPS6296459A (ja) * 1985-09-23 1987-05-02 イ−ライ・リリ−・アンド・カンパニ− 抗腫瘍化合物
WO2003022272A1 (fr) * 2001-09-05 2003-03-20 Eisai C0. Ltd. Agents stimulant l'appetit et remedes contre l'anorexie

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US6281240B1 (en) * 1997-04-10 2001-08-28 Eli Lilly And Company Diarylsulfonylureas for use in treating secretory diarrhea
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JPS6296459A (ja) * 1985-09-23 1987-05-02 イ−ライ・リリ−・アンド・カンパニ− 抗腫瘍化合物
WO2003022272A1 (fr) * 2001-09-05 2003-03-20 Eisai C0. Ltd. Agents stimulant l'appetit et remedes contre l'anorexie

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