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WO1996033723A2 - Use of benzamide derivatives for treating and/or preventing meniere's syndrome and motion sickness - Google Patents

Use of benzamide derivatives for treating and/or preventing meniere's syndrome and motion sickness Download PDF

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Publication number
WO1996033723A2
WO1996033723A2 PCT/JP1996/001112 JP9601112W WO9633723A2 WO 1996033723 A2 WO1996033723 A2 WO 1996033723A2 JP 9601112 W JP9601112 W JP 9601112W WO 9633723 A2 WO9633723 A2 WO 9633723A2
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WO
WIPO (PCT)
Prior art keywords
alkyl
hydrogen
meniere
syndrome
acyl
Prior art date
Application number
PCT/JP1996/001112
Other languages
French (fr)
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WO1996033723A3 (en
Inventor
Masayuki Ishie
Original Assignee
Fujisawa Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to JP8524148A priority Critical patent/JPH11503721A/en
Publication of WO1996033723A2 publication Critical patent/WO1996033723A2/en
Publication of WO1996033723A3 publication Critical patent/WO1996033723A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep

Definitions

  • This invention relates to a new use of benzamide
  • benzamide derivatives used in this invention are known as described in European Patent Application Publication No. 0 620 216 that said benzamide derivatives possess activities as vasopressin antagonistic activity, vasodilating activity, hypotensive activity, activity for inhibiting growth of
  • mesangium cells water diuretic activity, platelet agglutination inhibitory activity or oxytocin antagonistic activity and are useful in the treatment and/or prevention of hypertension, heart failure, renal insufficiency, edema, ascites, vasopressin parasecretion syndrome, hepatocirrhosis, hyponatremia,
  • This invention relates to a new use of benzamide
  • liver activity for inhibiting growth of mesangium cells, water diuretic activity, platelet agglutination inhibitory activity or oxytocin antagonistic activity, for treating and/or preventing Meniere's syndrome (e.g. Meniere's disease, etc.) or motion sickness.
  • Meniere's syndrome e.g. Meniere's disease, etc.
  • this invention provides a new use of benzamide derivatives for treating and/or preventing
  • Meniere's syndrome e.g. Meniere's disease, etc.
  • motion sickness e.g. Meniere's syndrome, etc.
  • this invention provides an agent and a
  • Meniere's syndrome e.g. Meniere's disease, etc.
  • motion sickness which comprises said benzamide derivatives.
  • this invention provides a method for treating and/or preventing Meniere's syndrome (e.g. Meniere's disease, etc.) or motion sickness, which comprises
  • the benzamide derivatives used in this invention can be represented by the following general formula (I).
  • R 1 is hydrogen or lower alkyl
  • R 2 is hydrogen, lower alkyl, halo (lower) alkyl, halogen or lower alkoxy,
  • R 3 and R 4 are each hydrogen, lower alkyl or taken
  • R 5 is hydrogen, halogen, nitro, hydroxy, protected
  • R 6 is hydrogen, lowing alkyl or acyl
  • A is K in which
  • R 7 is hydrogen; lower alkyl optionally substituted with halogen, amino, lower alkylamino, protected amino, acyl, a heterocyclic group, hydroxy or
  • R 8 and R 9 are each hydrogen, or taken together to form oxo or thioxo; or
  • R 7 and R 8 are taken together to form a bond
  • R 9 is lower alkylamino, N-lower
  • alkylpiperazinyl or lower alkylthio optionally substituted with lower alkylamino
  • R 10 is hydrogen
  • R 11 is hydrogen, hydroxy, lower alkylamino or lower alkyl optionally substituted with acyl; or
  • R 10 and R 11 are taken together to form oxo or lower alkoxyimino optionally substituted with acyl;
  • R 12 is lower alkyl optionally substituted with acyl
  • R 13 is lower alkyl
  • X 1 is CH or N
  • X 2 is CH or N, in which
  • R 14 is hydrogen, halogen, hydroxy or lower alkoxy
  • R 15 is aryloxy, naphthyl, phenyl substituted with substituent (s) selected from the group consisting of lower alkyl, lower alkoxy, halogen, halo (lower) alkyl, hydroxy, amino (lower) alkyl,
  • R 16 is aryl
  • n 0, 1, 2 or 3
  • Said compound (I) and pharmaceutically acceptable salts thereof are useful in the treatment and/or prevention of Meniere's syndrome (e.g. Meniere's disease, etc.) or motion sickness in mammals.
  • lower is intended to mean a group having 1 to 6 carbon atom (s), preferably one having 1 to 4 carbon
  • lower alkyl and lower alkyl moiety in the terms "halo (lower) alkyl", “amino (lower) alkyl”, “N-lower alkylpiperazinyl”, “lower alkylthio”, “N-lower alkyl- piperazinylcarbonyl", “lower alkylsulfonyl”,
  • acylamino (lower) alkyl may be straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl or the like, in which preferable one is C 1 -C 4 alkyl such as methyl, ethyl, propyl, isobutyl or tert-butyl.
  • Suitable "aryl” and aryl moiety in the terms “aryloxy” and “arylsulfonyl” may be phenyl, naphthyl, phenyl
  • lower alkyl e.g. tolyl, xylyl, mesityl, cumenyl, di (tert-butyl) pentyl, etc.
  • preferable one is phenyl or tolyl.
  • Suitable "halogen” may be fluorine, chlorine, bromine and iodine, in which preferable one is fluorine or chlorine.
  • Suitable "lower alkoxy” and lower alkoxy moiety in the term “lower alkoxyimino” may be methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like, in which preferable one is methoxy or propoxy.
  • Suitable "lower alkylamino” may be mono or di (lower alkyl) amino such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, isobutylamino, pentylamino, hexylamino, dimethylamino, diethylamino,
  • preferable one is dimethylamino.
  • Suitable “lower alkylamino (lower) alkyl” may be mono or di (lower alkyl) amino substituted lower alkyl such as
  • methylaminomethyl methylaminoethyl, methylaminopropyl, methylaminobutyl, methylaminohexyl, ethylaminomethyl,
  • ethylaminohexyl dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, dimethylaminobutyl, dimethylaminohexyl, diethylaminomethyl, diethylaminoethyl, diethylaminopropyl, diethylaminobutyl, diethylaminohexyl or the like, in which preferable one is dimethylaminoethyl, dimethylaminopropyl or dimethylaminobutyl.
  • Suitable "halo (lower) alkyl” may be chloromethyl, fluoromethyl, bromomethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2-fluoroethyl and the like, in which preferable one is trifluoromethyl.
  • heterocyclic group and a heterocyclic moiety in the terms "a heterocyclic (lower) alkyl” and "a
  • heterocycliccarbonyl may be one containing at least one hetero atom selected from nitrogen, sulfur and oxygen atom, and may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group, and preferable heterocyclic group may be N-containing heterocyclic group such as
  • unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [e.g. 4H-1,2,4-triazolyl, 1H-1,2,3- triazolyl, 2H-1,2,3-triazolyl, etc.], tetrazolyl [e.g. 1H- tetrazolyl, 2H-tetrazolyl, etc.], etc.;
  • unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms for example, indolyl, isoindolyl,
  • unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom for example, pyranyl, furyl, etc.;
  • oxazolyl isoxazolyl
  • oxadiazolyl e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.
  • unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms e.g. benzofurazanyl, benzoxazolyl, benzoxadiazolyl, etc.];
  • unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4- thiadiazolyl, 1,2,5-thiadiazolyl, etc.], etc.;
  • unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms e.g., benzothiazolyl, benzothiadiazolyl, etc.
  • unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms e.g. benzofuranyl, benzodioxolyl, etc.
  • unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms e.g. benzofuranyl, benzodioxolyl, etc.
  • heterocyclic group may be substituted with lower alkyl optionally substituted with hydroxy, acyloxy, amino, protected amino, acyl, aryl or methylenedioxyphenyl; acyl or a heterocyclic group, in which preferable one is piperazinyl, N-methylpiperazinyl, N,N-dimethylpiperazinyl,
  • N-tert-butoxycarbonylpiperazinyl N-pyridylpiperazinyl, dimethylaminopiperidyl, pyrrolyl, pyridyl, piperidyl, morpholinyl or quinuclidinyl.
  • acylamino (lower) alkyl and “acyl (lower) alkyl” may be
  • alkylsulfonyl alkylsulfonyl, arylsulfonyl and the like.
  • the esterified carboxy may be substituted or
  • unsubstituted lower alkoxycarbonyl e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,
  • aryloxycarbonyl e.g. phenoxycarbonyl
  • substituted or unsubstituted ar (lower) alkoxycarbonyl e.g. benzyloxycarbonyl, phenethyloxycarbonyl,
  • the lower alkylcarbamoyl may be mono or
  • di (lower) alkylcarbamoyl such as methylcarbamoyl
  • the lower alkanoyl may be substituted or unsubstituted one such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl or the like, in which preferable one is formyl or acetyl.
  • the aroyl may be substituted or unsubstituted one such as benzoyl, naphthoyl, toluoyl, di (tert-butyl) benzoyl,
  • the lower alkylsulfonyl may be methylsulfonyl
  • the arylsulfonyl may be substituted or unsubstituted one such as phenylsulfonyl, tolylsulfonyl,
  • N-Protective group in “protected amino” may be common N-protective group such as substituted or unsubstituted lower alkanoyl [e.g. formyl, acetyl, propionyl, trifluoroacetyl, etc.], phthaloyl, lower alkoxycarbonyl [e.g.
  • nitrophenylsulfenyl aralkyl [e.g. trityl, benzyl, etc.] or the like, in which preferable one is phthaloyl or tert- butoxycarbonyl.
  • Protected hydroxy may be commonly protected hydroxy such as substituted lower alkoxy such as lower
  • alkoxy (lower) alkoxy [e.g. methoxymethoxy, etc.]
  • propionyloxy, pivaloyloxy, etc.] aroyloxy [e.g. benzoyloxy, fluorenecarbonyloxy, etc.], lower alkoxycarbonyloxy [e.g.
  • the phenyl group for R 15 may be substituted with 1 to 5 substituent (s) as mentioned above, wherein the preferable number of the substituent (s) is 1 to 2.
  • Preferable compound (I) is one which has hydrogen for R 1 , hydrogen, lower alkyl or halogen for R 2 , hydrogen for R 3 , hydrogen for R 4 , hydrogen or lower alkoxy for R 5 , hydrogen for R 6 , (wherein R 7 is lower alkyl
  • R 11 is hydrogen, lower alkylamino or acyl (lower) alkyl) for
  • More preferable compound (I) is one which has hydrogen for R 1 , hydrogen, lower alkyl or halogen for R 2 , hydrogen for R 3 , hydrogen for R 4 , hydrogen or lower alkoxy for R 5 , hydrogen for R 6 , - (wherein R 7 is lower alkyl
  • alkylpiperazinylcarbonyl for A, CH for X 1 , CH for X 2 , (wherein R 15 is phenyl substituted with lower alkyl or di (lower alkyl)) for Y, and 0, 1 or 2 for n.
  • compound (I) is 5- ⁇ 4-[2-(4- methylphenyl)benzoylamino]benzoyl ⁇ -1-[(4-methyl-1- piperazinyl)carbonylmethyl]-1,3,4,5-tetrahydro-1,5- benzodiazepin-2(2H)-one.
  • Suitable pharmaceutically acceptable salts of the compound (I) are conventional non-toxic salts and include an acid addition salt such as an inorganic acid addition salt [e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.], an organic acid addition salt [e.g. formate, acetate,
  • a metal salt such as an alkali metal salt [e.g. sodium salt, potassium salt, etc.] and an alkaline earth metal salt [e.g. calcium salt, magnesium salt, etc.] and the like.
  • the compound (I) may include one or more stereoisomer (s) such as optical isomer(s) and
  • Guinea-pigs were anesthetized with sodium pentobarbital (30mg/kg, i.p.). After tracheotomy, animals were maintained under artificial respiration. The cochlea was exposed using a ventrolateral approach. Endocochlear potential (EP) was recorded by means of a glass microelectrode inserted into the scala media. The Ag/AgCl reference electrode was placed on the exposed neck muscle.
  • EP Endocochlear potential
  • Arginine vasopressin (AVP) and the test compound were dissolved in saline. AVP (10 -5 M), the test compound
  • the compound (I) of this invention has an inhibitory activity against a negative deflection of endocochlear potential induced by arginine vasopressin and is useful for treating and/or preventing Meniere's syndrome (e.g. Meniere's disease, etc.) or motion sickness.
  • pharmaceutically acceptable salts thereof of the present invention can be used in a form of pharmaceutical preparation containing one of said compounds, as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external (topical) administration.
  • a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external (topical) administration.
  • the pharmaceutical preparations may be capsules, tablets, dragees, granules, solution, suspension, emulsion, ointment, or the like. If desired, there may be included in these preparations, auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives.
  • an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound (I) may be effective for treating and/or preventing Meniere's syndrome (e.g. Meniere's disease, etc.) or motion sickness.
  • Meniere's syndrome e.g. Meniere's disease, etc.
  • motion sickness e.g. motion sickness, etc.
  • amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.

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Abstract

This invention relates to use of a compound of formula (I) wherein each symbol is as defined in the description, or its pharmaceutically accpetable salt, for treating and/or preventing Meniere's syndrome or motion sickness.

Description

USE OF BENZAMIDE DERIVATIVES FOR TREATING AND/OR PREVENTING
MENIERE'S SYNDROME AND MOTION SICKNESS
TECHNICAL FIELD
This invention relates to a new use of benzamide
derivatives which possess activities as vasopressin
antagonistic activity, vasodilating activity, hypotensive activity, activity for inhibiting saccharide release in
liver, activity for inhibiting growth of mesangium cells, water diuretic activity, platelet agglutination inhibitory activity or oxytocin antagonistic activity, for treating and/or preventing Meniere's syndrome (e.g. Meniere's disease, etc.) or motion sickness. BACKGROUND ART
The benzamide derivatives used in this invention are known as described in European Patent Application Publication No. 0 620 216 that said benzamide derivatives possess activities as vasopressin antagonistic activity, vasodilating activity, hypotensive activity, activity for inhibiting growth of
mesangium cells, water diuretic activity, platelet agglutination inhibitory activity or oxytocin antagonistic activity and are useful in the treatment and/or prevention of hypertension, heart failure, renal insufficiency, edema, ascites, vasopressin parasecretion syndrome, hepatocirrhosis, hyponatremia,
hypokalemia, diabetic, circulation disorder, oxytocin relating diseases [e.g. premature delivery, dysmenorrhea, endometritis, etc.] and the like in human beings and animals. DISCLOSURE OF INVENTION
This invention relates to a new use of benzamide
derivatives, which possess activities as vasopressin
antagonistic activity, vasodilating activity, hypotensive activity, activity for inhibiting saccharide release in
liver, activity for inhibiting growth of mesangium cells, water diuretic activity, platelet agglutination inhibitory activity or oxytocin antagonistic activity, for treating and/or preventing Meniere's syndrome (e.g. Meniere's disease, etc.) or motion sickness.
Accordingly, this invention provides a new use of benzamide derivatives for treating and/or preventing
Meniere's syndrome (e.g. Meniere's disease, etc.) or motion sickness.
Further, this invention provides an agent and a
pharmaceutical composition for treating and/or preventing
Meniere's syndrome (e.g. Meniere's disease, etc.) or motion sickness, which comprises said benzamide derivatives.
Still further, this invention provides a method for treating and/or preventing Meniere's syndrome (e.g. Meniere's disease, etc.) or motion sickness, which comprises
administering said benzamide derivatives to mammals.
The benzamide derivatives used in this invention can be represented by the following general formula (I).
Figure imgf000004_0001
wherein R1 is hydrogen or lower alkyl,
R2 is hydrogen, lower alkyl, halo (lower) alkyl, halogen or lower alkoxy,
R3 and R4 are each hydrogen, lower alkyl or taken
together to form oxo,
R5 is hydrogen, halogen, nitro, hydroxy, protected
hydroxy, lower alkyl or lower alkoxy optionally substituted with lower alkylamino,
R6 is hydrogen, lowing alkyl or acyl,
A is K
Figure imgf000005_0001
in which
R7 is hydrogen; lower alkyl optionally substituted with halogen, amino, lower alkylamino, protected amino, acyl, a heterocyclic group, hydroxy or
protected hydroxy; or acyl; and
R8 and R9 are each hydrogen, or taken together to form oxo or thioxo; or
R7 and R8 are taken together to form a bond;
and
R9 is lower alkylamino, N-lower
alkylpiperazinyl or lower alkylthio optionally substituted with lower alkylamino;
R10 is hydrogen;
R11 is hydrogen, hydroxy, lower alkylamino or lower alkyl optionally substituted with acyl; or
R10 and R11 are taken together to form oxo or lower alkoxyimino optionally substituted with acyl;
R12 is lower alkyl optionally substituted with acyl; and
R13 is lower alkyl;
X1 is CH or N,
X2 is CH or N,
Figure imgf000006_0001
in which
R14 is hydrogen, halogen, hydroxy or lower alkoxy,
R15 is aryloxy, naphthyl, phenyl substituted with substituent (s) selected from the group consisting of lower alkyl, lower alkoxy, halogen, halo (lower) alkyl, hydroxy, amino (lower) alkyl,
azido (lower) alkyl,
lower alkylamino (lower) alkyl,
acylamino (lower) alkyl,
hydroxy (lower) alkyl, cyano and acyl, or a heterocyclic group, and
R16 is aryl,
and
n is 0, 1, 2 or 3,
and pharmaceutically acceptable salts thereof.
Said compound (I) and pharmaceutically acceptable salts thereof are useful in the treatment and/or prevention of Meniere's syndrome (e.g. Meniere's disease, etc.) or motion sickness in mammals.
Particulars of the various definitions mentioned in this specification and preferred examples thereof are explained in the following.
The term "lower" is intended to mean a group having 1 to 6 carbon atom (s), preferably one having 1 to 4 carbon
atom(s), unless otherwise provided.
Suitable "lower alkyl" and lower alkyl moiety in the terms "halo (lower) alkyl", "amino (lower) alkyl", "N-lower alkylpiperazinyl", "lower alkylthio", "N-lower alkyl- piperazinylcarbonyl", "lower alkylsulfonyl",
"azido (lower) alkyl", "lower alkylamino (lower) alkyl",
"acylamino (lower) alkyl", "hydroxy (lower) alkyl", "lower alkylcarbamoyl", "acyl (lower) alkyl" and "lower alkylamino" may be straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl or the like, in which preferable one is C1-C4 alkyl such as methyl, ethyl, propyl, isobutyl or tert-butyl.
Suitable "aryl" and aryl moiety in the terms "aryloxy" and "arylsulfonyl" may be phenyl, naphthyl, phenyl
substituted with lower alkyl [e.g. tolyl, xylyl, mesityl, cumenyl, di (tert-butyl) pentyl, etc.] and the like, in which preferable one is phenyl or tolyl.
Suitable "halogen" may be fluorine, chlorine, bromine and iodine, in which preferable one is fluorine or chlorine.
Suitable "lower alkoxy" and lower alkoxy moiety in the term "lower alkoxyimino" may be methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like, in which preferable one is methoxy or propoxy.
Suitable "lower alkylamino" may be mono or di (lower alkyl) amino such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, isobutylamino, pentylamino, hexylamino, dimethylamino, diethylamino,
dipropylamino, dibutylamino, diisopropylamino, dipentylamino, dihexylamino, N-methylethylamino or the like, in which
preferable one is dimethylamino.
Suitable "lower alkylamino (lower) alkyl" may be mono or di (lower alkyl) amino substituted lower alkyl such as
methylaminomethyl, methylaminoethyl, methylaminopropyl, methylaminobutyl, methylaminohexyl, ethylaminomethyl,
ethylaminoethyl, ethylaminopropyl, ethylaminobutyl,
ethylaminohexyl, dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, dimethylaminobutyl, dimethylaminohexyl, diethylaminomethyl, diethylaminoethyl, diethylaminopropyl, diethylaminobutyl, diethylaminohexyl or the like, in which preferable one is dimethylaminoethyl, dimethylaminopropyl or dimethylaminobutyl.
Suitable "halo (lower) alkyl" may be chloromethyl, fluoromethyl, bromomethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2-fluoroethyl and the like, in which preferable one is trifluoromethyl.
Suitable "heterocyclic group" and a heterocyclic moiety in the terms "a heterocyclic (lower) alkyl" and "a
heterocycliccarbonyl" may be one containing at least one hetero atom selected from nitrogen, sulfur and oxygen atom, and may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group, and preferable heterocyclic group may be N-containing heterocyclic group such as
unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [e.g. 4H-1,2,4-triazolyl, 1H-1,2,3- triazolyl, 2H-1,2,3-triazolyl, etc.], tetrazolyl [e.g. 1H- tetrazolyl, 2H-tetrazolyl, etc.], etc.;
saturated 3 to 7-membered heteromonocyclic group containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, homopiperazinyl, etc];
saturated heteropolycyclic group containing 1 to 4 nitrogen atoms, for example, quinuclidinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl,
indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,
indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g.
tetrazolofl, 5-b]pyridazinyl, etc.], etc.;
unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, furyl, etc.;
unsaturated, 3 to 6-membered heteromonocyclic group
containing 1 to 2 sulfur atoms, for example, thienyl, etc.; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.], etc.;
saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.
morpholinyl, etc.];
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzofurazanyl, benzoxazolyl, benzoxadiazolyl, etc.];
unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4- thiadiazolyl, 1,2,5-thiadiazolyl, etc.], etc.;
saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,
thiazolidinyl, etc.];
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl, etc.];
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms [e.g. benzofuranyl, benzodioxolyl, etc.] and the like.
Said "heterocyclic group" may be substituted with lower alkyl optionally substituted with hydroxy, acyloxy, amino, protected amino, acyl, aryl or methylenedioxyphenyl; acyl or a heterocyclic group, in which preferable one is piperazinyl, N-methylpiperazinyl, N,N-dimethylpiperazinyl,
N-methylhomopiperazinyl, N- droxyethyl) piperazinyl,
N-(2-acetoxyethyl) piperazinyl, N-(3-phthalimidopropyl)- piperazinyl, N-(3-aminoproρyl) piperazinyl,
N-(pyrrolidinylcarbonylmethyl) piperazinyl,
N-(methylenedioxyphenylmethyl) piperazinyl,
N-ethoxycarbonylpiperazinyl, N-carboxypiperazinyl,
N-tert-butoxycarbonylpiperazinyl, N-pyridylpiperazinyl, dimethylaminopiperidyl, pyrrolyl, pyridyl, piperidyl, morpholinyl or quinuclidinyl.
Suitable "acyl" and acyl moiety in the terms
"acylamino (lower) alkyl" and "acyl (lower) alkyl" may be
carboxy, esterified carboxy, carbamoyl, lower alkylcarbamoyl, lower alkanoyl, aroyl, a heterocycliccarbonyl, lower
alkylsulfonyl, arylsulfonyl and the like.
The esterified carboxy may be substituted or
unsubstituted lower alkoxycarbonyl [e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,
tert-butoxycarbonyl, hexyloxycarbonyl,
2-(dimethylamino) ethoxycarbonyl, 2-iodoethoxycarbonyl,
2,2,2-trichloroethoxycarbonyl, etc.], substituted or
unsubstituted aryloxycarbonyl [e.g. phenoxycarbonyl,
4-nitrophenoxycarbonyl, 2-naphthyloxycarbonyl, etc.],
substituted or unsubstituted ar (lower) alkoxycarbonyl [e.g. benzyloxycarbonyl, phenethyloxycarbonyl,
benzhydryloxycarbonyl, 4-nitrobenzyloxycarbonyl, etc.] and the like, in which preferable one is lower alkoxycarbonyl or 2-(dimethylamino) ethoxycarbonyl.
The lower alkylcarbamoyl may be mono or
di (lower) alkylcarbamoyl such as methylcarbamoyl,
ethylcarbamoyl, propylcarbamoyl, dimethylcarbamoyl,
diethylcarbamoyl, N-methyl-N-ethylcarbamoyl or the like.
The lower alkanoyl may be substituted or unsubstituted one such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl or the like, in which preferable one is formyl or acetyl.
The aroyl may be substituted or unsubstituted one such as benzoyl, naphthoyl, toluoyl, di (tert-butyl) benzoyl,
tolylbenzoyl, aminobenzoyl, tolylbenzoylaminobenzoyl and the like.
The lower alkylsulfonyl may be methylsulfonyl,
ethylsulfonyl, propylsulfonyl, butylsulfonyl and the like.
The arylsulfonyl may be substituted or unsubstituted one such as phenylsulfonyl, tolylsulfonyl,
dimethoxyphenylsulfonyl or the like, in which preferable one is dimethoxyphenylsulfonyl.
"N-Protective group" in "protected amino" may be common N-protective group such as substituted or unsubstituted lower alkanoyl [e.g. formyl, acetyl, propionyl, trifluoroacetyl, etc.], phthaloyl, lower alkoxycarbonyl [e.g.
tert-butoxycarbonyl, tert-amyloxycarbonyl, etc.], substituted or unsubstituted aralkoxycarbonyl [e.g. benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.], substituted or unsubstituted arenesulfonyl [e.g. benzenesulfonyl, tosyl, etc.],
nitrophenylsulfenyl, aralkyl [e.g. trityl, benzyl, etc.] or the like, in which preferable one is phthaloyl or tert- butoxycarbonyl.
"Protected hydroxy" may be commonly protected hydroxy such as substituted lower alkoxy such as lower
alkoxy (lower) alkoxy [e.g. methoxymethoxy, etc.],
lower alkoxy (lower) alkoxy (lower) alkoxy [e.g.
methoxyethoxymethoxy, etc.], substituted or unsubstituted ar (lower) alkoxy [e.g. benzyloxy, nitrobenzyloxy, etc.], etc., acyloxy such as lower alkanoyloxy [e.g. acetoxy,
propionyloxy, pivaloyloxy, etc.], aroyloxy [e.g. benzoyloxy, fluorenecarbonyloxy, etc.], lower alkoxycarbonyloxy [e.g.
methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, isopropoxycarbonyloxy, butoxycarbonyloxy,
isobutoxycarbonyloxy, tert-butoxycarbonyloxy,
pentyloxycarbonyloxy, hexyloxycarbonyloxy, etc.], substituted or unsubstituted ar (lower) alkoxycarbonyloxy [e.g.
benzyloxycarbonyloxy, bromobenzyloxycarbonyloxy, etc.] etc., tri (lower) alkylsilyloxy [e.g. trimethylsilyloxy, etc.] and the like.
The phenyl group for R15 may be substituted with 1 to 5 substituent (s) as mentioned above, wherein the preferable number of the substituent (s) is 1 to 2. Preferable compound (I) is one which has hydrogen for R1, hydrogen, lower alkyl or halogen for R2, hydrogen for R3, hydrogen for R4, hydrogen or lower alkoxy for R5, hydrogen for R6, (wherein R7 is lower alkyl
Figure imgf000012_0001
optionally substituted with amino, lower alkylamino,
protected amino, acyl or piperidino) or - (wherein
Figure imgf000012_0003
R11 is hydrogen, lower alkylamino or acyl (lower) alkyl) for
A, CH for X1, CH for X2, (wherein R15 is phenyl
Figure imgf000012_0002
substituted with substituent (s) selected from the group consisting of lower alkyl, lower alkoxy, halogen,
halo (lower) alkyl, hydroxy, amino (lower) alkyl,
azido (lower) alkyl, lower alkylamino (lower) alkyl,
acylamino (lower) alkyl, hydroxy (lower) alkyl, cyano and acyl) for Y, and 0, 1 or 2 for n.
More preferable compound (I) is one which has hydrogen for R1, hydrogen, lower alkyl or halogen for R2, hydrogen for R3, hydrogen for R4, hydrogen or lower alkoxy for R5, hydrogen for R6, - (wherein R7 is lower alkyl
Figure imgf000012_0004
substituted with N-lower alkylpiperazinylcarbonyl or lower alkyl substituted with di (lower) alkylamino) or
Figure imgf000012_0005
(wherein R11 is lower alkyl substituted with N-lower
alkylpiperazinylcarbonyl) for A, CH for X1, CH for X2, (wherein R15 is phenyl substituted with lower
Figure imgf000012_0006
alkyl or di (lower alkyl)) for Y, and 0, 1 or 2 for n.
Most preferable compound (I) is 5-{4-[2-(4- methylphenyl)benzoylamino]benzoyl}-1-[(4-methyl-1- piperazinyl)carbonylmethyl]-1,3,4,5-tetrahydro-1,5- benzodiazepin-2(2H)-one.
Suitable pharmaceutically acceptable salts of the compound (I) are conventional non-toxic salts and include an acid addition salt such as an inorganic acid addition salt [e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.], an organic acid addition salt [e.g. formate, acetate,
trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], a metal salt such as an alkali metal salt [e.g. sodium salt, potassium salt, etc.] and an alkaline earth metal salt [e.g. calcium salt, magnesium salt, etc.] and the like.
It is to be noted that the compound (I) may include one or more stereoisomer (s) such as optical isomer(s) and
geometrical isomer(s) due to asymmetric carbon atoms and double bond(s), and all of such isomers and mixture thereof are included within the scope of this invention.
Now in order to show the utility of the compound (I) and pharmaceutically acceptable salts thereof in this invention, the test data of the representative compound of this
invention is shown in the following.
Effect on Endocochlear Potential
1. Test Method:
Guinea-pigs were anesthetized with sodium pentobarbital (30mg/kg, i.p.). After tracheotomy, animals were maintained under artificial respiration. The cochlea was exposed using a ventrolateral approach. Endocochlear potential (EP) was recorded by means of a glass microelectrode inserted into the scala media. The Ag/AgCl reference electrode was placed on the exposed neck muscle.
Arginine vasopressin (AVP) and the test compound were dissolved in saline. AVP (10-5M), the test compound
(0.1mg/ml), or both of them were administered through the vertebral artery. 2 ml of each drug solution was injected over a period of 2 minutes.
2. Test Compound:
5-{4-[2-(4-Methylphenyl)benzoylamino]benzoyl)- 1-[(4-methyl-1-piperazinyl)carbonylmethyl]- 1,3,4,5-tetrahydro-l,5-benzodiazepine-2(2H)-one
(hereinafter referred to as Compound A)
3. Test Result:
Data was expressed as Change in EP (ΔEP, mV). AVP produced a large negative deflection of EP from +80 to +35mV, whereas simultaneous administration of AVP and FR161282 made no change in EP.
Figure imgf000014_0001
The result show that the compound (I) of this invention has an inhibitory activity against a negative deflection of endocochlear potential induced by arginine vasopressin and is useful for treating and/or preventing Meniere's syndrome (e.g. Meniere's disease, etc.) or motion sickness.
For therapeutic purpose, the compounds (I) and
pharmaceutically acceptable salts thereof of the present invention can be used in a form of pharmaceutical preparation containing one of said compounds, as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external (topical) administration. The pharmaceutical preparations may be capsules, tablets, dragees, granules, solution, suspension, emulsion, ointment, or the like. If desired, there may be included in these preparations, auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives.
While the dosage of the compounds (I) will vary
depending upon the age and condition of the patiθO to ent, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound (I) may be effective for treating and/or preventing Meniere's syndrome (e.g. Meniere's disease, etc.) or motion sickness. In general, amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.
The following example is given for the purpose of illustrating the present invention.
Example 1
(Capsule)
5-{4-[2-(4-Methylphenyl)benzoylamino]benzoyl}-
1-[(4-methyl-1-piperazinyl)carbonylmethyl]-
1,3,4,5-tetrahydro-l,5-benzodiazepine-2(2H)-one 5 mg Lactose 80 mg
The above-mentioned ingredients, were mixed and the mixture was encapsulated to provide the capsule.

Claims

1. Use of a compound of the formula :
Figure imgf000016_0001
wherein R1 is hydrogen or lower alkyl,
R2 is hydrogen, lower alkyl, halo (lower) alkyl, halogen or lower alkoxy,
R3 and R4 are each hydrogen, lower alkyl or taken together to form oxo,
R5 is hydrogen, halogen, nitro, hydroxy,
protected hydroxy, lower alkyl or lower alkoxy optionally substituted with lower alkylamino,
R6 is hydrogen, lower alkyl or acyl,
A is
Figure imgf000016_0002
in which
R7 is hydrogen; lower alkyl optionally substituted with halogen, amino, lower alkylamino, protected amino, acyl, a heterocyclic group, hydroxy or protected hydroxy; or acyl; and R8 and R9 are each hydrogen, or taken
together to form oxo or thioxo; or R7 and R8 are taken together to form a bond; and
R9 is lower alkylamino, N-lower
alkylpiperazinyl or lower alkylthio optionally substituted with lower alkylamino;
R10 is hydrogen;
R11 is hydrogen, hydroxy, lower alkylamino or lower alkyl optionally
substituted with acyl; or
R10 and R11 are taken together to form oxo or lower alkoxyimino optionally substituted with acyl;
R12 is lower alkyl optionally substituted with acyl; and
R13 is lower alkyl;
X1 is CH or N,
X2 is CH or N,
Figure imgf000017_0001
in which
R14 is hydrogen, halogen, hydroxy or lower alkoxy,
R15 is aryloxy, naphthyl, phenyl
substituted with substituent (s) selected from the group consisting of lower alkyl, lower alkoxy,
halogen, halo (lower) alkyl, hydroxy, amino (lower) alkyl,
azido (lower) alkyl,
lower alkylamino (lower) alkyl, acylamino (lower) alkyl,
hydroxy (lower) alkyl, cyano and acyl, or a heterocyclic group, and
R16 is aryl,
and
n is 0, 1, 2 or 3,
or its pharmaceutically acceptable salt for treating and/or preventing Meniere's syndrome or motion sickness.
2. A use of the compound defined in Claim 1 as an agent for treating and/or preventing Meniere's syndrome or motion sickness.
3. An agent for treating and/or preventing Meniere's
syndrome or motion sickness, which comprises the
compound defined in Claim 1.
4. A method for treating and/or preventing Meniere's
syndrome or motion sickness, which comprises
administering the compound defined in Claim 1 to
mammals.
5. A use of the compound defined in Claim 1 for
manufacturing a medicament for treating and/or
preventing Meniere's syndrome or motion sickness.
6. A pharmaceutical composition for treating and/or
preventing Meniere's syndrome or motion sickness, which comprises the compound defined in Claim 1 in admixture with a carrier or excipient.
7. A Process for preparing the pharmaceutical composition of Claim 6, which is characterized by admixing the compound with a carrier or excipient.
PCT/JP1996/001112 1995-04-28 1996-04-24 Use of benzamide derivatives for treating and/or preventing meniere's syndrome and motion sickness WO1996033723A2 (en)

Priority Applications (1)

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GBGB9508637.7A GB9508637D0 (en) 1995-04-28 1995-04-28 New use
GB9508637.7 1995-04-28

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WO1996033723A3 WO1996033723A3 (en) 1997-01-30

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US9096546B2 (en) 2007-05-10 2015-08-04 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydrobenzo-1,4-diazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US9241942B2 (en) 2007-06-08 2016-01-26 Mannkind Corporation IRE-1α inhibitors
US9422281B2 (en) 2013-11-18 2016-08-23 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
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GB9307527D0 (en) * 1993-04-13 1993-06-02 Fujisawa Pharmaceutical Co New venzamide derivatives,processes for the preparation thereof and pharmaceutical composition comprising the same

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US7351709B2 (en) 2004-06-09 2008-04-01 Wyeth Estrogen receptor ligands
US9096546B2 (en) 2007-05-10 2015-08-04 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydrobenzo-1,4-diazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US9241942B2 (en) 2007-06-08 2016-01-26 Mannkind Corporation IRE-1α inhibitors
US9546149B2 (en) 2007-06-08 2017-01-17 Mannkind Corporation IRE-1α inhibitors
US9981901B2 (en) 2007-06-08 2018-05-29 Fosun Orinove Pharmatech, Inc. IRE-1α inhibitors
US9422281B2 (en) 2013-11-18 2016-08-23 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US10336722B2 (en) 2013-11-18 2019-07-02 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US10377769B2 (en) 2013-11-18 2019-08-13 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US10611750B2 (en) 2013-11-18 2020-04-07 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as bet bromodomain inhibitors
US10703764B2 (en) 2013-11-18 2020-07-07 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US11084831B1 (en) 2013-11-18 2021-08-10 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US11111229B2 (en) 2013-11-18 2021-09-07 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors

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JPH11503721A (en) 1999-03-30
GB9508637D0 (en) 1995-06-14

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