WO1992001683A1 - Derives de benzodiazepine - Google Patents

Derives de benzodiazepine Download PDF

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Publication number
WO1992001683A1
WO1992001683A1 PCT/JP1991/000952 JP9100952W WO9201683A1 WO 1992001683 A1 WO1992001683 A1 WO 1992001683A1 JP 9100952 W JP9100952 W JP 9100952W WO 9201683 A1 WO9201683 A1 WO 9201683A1
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Prior art keywords
compound
salt
group
formula
substituent
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PCT/JP1991/000952
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English (en)
Inventor
Yoshinari Sato
Hiromichi Itani
Takatomo Ogahara
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Fujisawa Pharmaceutical Co., Ltd.
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Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to AU82171/91A priority Critical patent/AU650034B2/en
Publication of WO1992001683A1 publication Critical patent/WO1992001683A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • 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
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
    • C07D243/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • This invention relates to new benzodiazepin ⁇ derivatives and pharmaceutically acceptable salrs thereof which are useful as a medicament.
  • This invention relates to new benzodiazepine derivatives and pharmaceutically acceptable salts thereof,
  • benzodiazepine derivatives and pharmaceutically acceptable salts thereof which are cholecystokinin (CCK) antagonists and therefore useful as therapeutical and/or preventive agents for emesis, pancreatitis, disorders of appetite requlatory systems, pain, insulinoma, gastroparesis, carcinoma of pancreas, gallbladder disease (e.g. acute cholecystitis, calculus, e ⁇ c), disorders associated with intenstinal smooth muscle hyperactivity (e.g. irritable bowel syndrome, sphincter spasm, etc.), hyperinsulinemia, dyspepsia, nausea, etc.
  • CCK cholecystokinin
  • the benzodiazepine derivatives of this invention can be represented by the following formula (I) :
  • R is heterocyclic group which may have one or more suitable s bstituent(s) , or cyano,
  • 3 R is aryl which may have one or more suitable substituent(s)
  • 4 R is aryl which may have one or more suitable substituent(s) , ar(lower)alkenyl which may have one or more suitable substituent(s) , arylamino which may have one or more suitable substituent(s) , heteromonocyclic group which may have one or more suitable substituent(s) , qninolyl, isoquinolyl, cinnolinyl, indolyl, or guinoxalinyl, and
  • A is lower alkylene
  • R is tetrazolyl which may have one or more suitable substituent(s) and 3 R is halophenyl or ⁇ (ii) R is imidazolyl which may have one or more suitable substituent(s) ,
  • the new benzodiazepine derivatives (I) can be prepared by the processes which are illustrated in the following scheme, Process 1
  • R 1, R2, R3, R4 and A are each as defined above,
  • R 3. is heterocyclic group having a protected i ino group of the formula :
  • R is heterocyclic group having an imino group of the formula :
  • R is ar(lower)alkenyl having a nitro group
  • R is ar(lower)alkenyl having an amino group and X is an acid residue.
  • the starting co ⁇ pounds (II) and (IV) can be prepared by the following processes.
  • R 1, R2, R3, R4 and A are each as defined above, and
  • the starting compound (VII) or a salt thereof can be prepared by the methods disclosed in the Preparations 1-3, 6 and 7 described later or similar manners thereto .
  • Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and include 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.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), an organic acid salt (e.g.
  • 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.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzy
  • heterocyclic group may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like.
  • heterocyclic group may be heterocyclic group such as unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyri idyl, pyrazinyl, pyridazinyl, dihydropyridazinyl, tetrahydropyridazinyl, triazolyl (e.g.
  • tetrazolyl e.g., lH-tetrazolyl, 2H-tetrazolyl, etc.
  • dihydrotriazinyl e.g., 4,5-dihydro-
  • Suitable "substituent" in the terms “heterocyclic group which may have one or more suitable substituent(s)” and “heteromonocyclic group which may have one or more suitable substituent( ⁇ )” may include amino, protected amino as exemplified below, oxo, hydroxy, imino protective group as exemplified below, lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, t-pentyl, hexyl, etc.) and the like.
  • lower alkyl e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, t-pentyl, hexyl, etc.
  • Suitable "protected amino” may include acylamino and the like.
  • Suitable “imino protective group” may include acyl, mono(or di or tri)phenyl(lower)alkyl (e.g. trityl, etc. ) tetrahydropyranyl and the like.
  • acyl and “acyl moiety” in the term “acylamino” may include aliphatic acyl group and acyl group containing an aromatic or heterocyclic ring. And, suitable examples of the said acyl may be lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc. ) ; lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
  • lower alkanoyl e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.
  • lower alkoxycarbonyl e.g. methoxycarbonyl, ethoxycarbonyl
  • ar(lower)alkanoyl e.g. phenylacetyl, phenylpropionyl, etc.
  • ar(lower)alkoxycarbonyl e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.
  • acyl moiety as stated above may have at least one suitable substituent(s) such as halogen (e.g. chlorine, bromine, fluorine and iodine), amino, protected amino
  • suitable substituent(s) such as halogen (e.g. chlorine, bromine, fluorine and iodine), amino, protected amino
  • Suitable "acid residue” may include halogen and the like.
  • Suitable "halogen” may include chlorine, bromine, fluorine and iodine.
  • aromatic alkenyl and “arylamino” may include phenyl, naphthyl and the like.
  • Suitable "substituent” in the terms "aryl which may have one or more suitable substituent(s)", ar(lower)alkenyl which may have one or more suitable substituent(s)” and “arylamino which may have one or more suitable substituent(s)” may include hydroxy, protected hydroxy as exemplified below, nitro, lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy, etc.), amino, protected amino as exemplified above, lower alkyl (e.g.
  • Suitable "lower alkenyl moiety" in the term “ar(lower)alkenyl” may include vinyl, allyl, 1-propenyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl and the like.
  • heteromonocyclic group may include saturated or unsaturated heteromonocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like. And, especially preferable heteromonocyclic group may be heteromonocyclic group such as unsaturated 3 to 8-membered heteromonocyclc group containing 1 to 4 nitrogen atom( ⁇ ), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, dihydropyridazinyl, tetrahydropyridazinyl, triazolyl (e.g.
  • 1,2,4-triazolyl 1H-1,2,3-triazolyl, 2H-l,2,3-triazolyl, etc.
  • tetrazolyl e.g., lH-tetrazolyl, 2H-tetrazolyl, etc.
  • dihydrotriazinyl e.g., 4,5-dihydro-l,2,4- triazinyl, 2,5-dihydro-l,2,4-triazinyl, etc.
  • saturated 3 to*-8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) for example, pyrrolidinyl, imidazolidmyl, piperidino, piperazinyl, etc.
  • 1,2,3-thiadiazolyl, etc. saturated 3 to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc.; unsaturated 3 to 8-membered heteromonocyclic group containing an oxygen atom, for example furyl, etc.; unsaturated 3 to 8-membered heteromonocyclic group containing a sulfur atom, for example, thienyl, etc.; and the like.
  • Suitable "lower alkylene” may include straight or branched one having 1 to 6 carbon atom(s), such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene or the like, preferably one having 1 to 4 carbon atom(s).
  • heterocyclic group in the terms
  • H may include unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrroiyl, pyrrolinyl, imidazolyl, pyrazolyl, dihydropyridaziny "1 , tetrahydropyridazinyl, triazolyl (e.g.
  • tetrazolyl e.g., IH-tetrazolyl, 2H-tetrazolyl, etc.
  • dihydrotriazinyl e.g., 4,5-d
  • R is heterocyclic group (more preferably unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom( ⁇ ), most preferably tetrazolyl or imidazolyl) which may have one to three (more preferably one) suitable substituent( ⁇ ) [more preferably tetrazolyl or imidazolyl, each of which may have an imino protective group; most preferably tetrazolyl or imidazolyl, each of which may have monofor di or tri)phenyl(lower)alkyl] , or cyano;
  • 2 R is hydrogen; 3 R is aryl (more preferably phenyl) which may have one to three (more preferably one) suitable substituent( ⁇ )
  • R is aryl (more preferably phenyl or naphthyl) which may have one to three (more preferably one or two) suitable substituent( ⁇ ) [more preferably phenyl or naphthyl, each of which may have one or two substituent(s) selected from the group consisting of halogen and amino; most preferably naphthyl, dihalophenyl or phenyl having halogen and amino] , ar(lower)alkenyl (more preferably phenyl(lower)alkenyl) which may have one to three (more preferably one) suitable substituent( ⁇ ) [more preferably phenyl(lower)alkenyl which may have amino or nitro; most preferably nitrophenyl(lower)alkenyl or aminophenyl(lower)alkenyl] , arylamino (more preferably phenyla ino) which may have one to three (more preferably one) suitable substituent(s) [more preferably phenylamino
  • R is tetrazolyl and 3 R is halophenyl or
  • R is imidazolyl which may have mono(or di or tri)- phenyl(lower)alkyl
  • R is hhaalloopphheennyyl and is ethylene.
  • the compound (I) or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at the amino group or a salt thereof with the compound (III) or its reactive derivative or a salt thereof.
  • Suitable reactive derivative at the amino group of the compound (II) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (II) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (II) with a silyl compound such as N,0-bis(trimethylsilyl)acetamide, N-trimethylsilylacetamide or the like; a derivative formed by the reaction of the compound (II) with phosphorus trichloride or phosgene and the like.
  • Suitable salts of the compound (II) and (III) can be referred to the ones as exemplified for the compound (I).
  • Suitable reactive derivative of the compound (III) may include an acid halide, an acid anhydride, an activated amide, an activated ester, isocyanate and the like.
  • the suitable example may be an acid chloride, an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g.
  • dialkylphosphoric acid phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated pho ⁇ phoric acid, etc.
  • dialkylpho ⁇ phorous acid sulfurous acid, thio ⁇ ulfuric acid,• alkanesulfonic acid (e.g. methanesulfonic acid, ethanesulfonic acid, etc.), ⁇ ulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g. pivalic acid, pentanoic acid, i ⁇ opentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.) or aromatic carboxylic acid (e.g.
  • benzoic acid etc.
  • a ⁇ ymmetrical acid anhydride an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole
  • an activated e ⁇ ter e.g.
  • These reactive derivatives can optionally be selected from them according to the kind of the compound (III) to be used.
  • the reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvents which do not adversely influence the reaction.
  • a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvents which do not adversely influence the reaction.
  • a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine
  • the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide;
  • the reaction may al ⁇ o be carried out in the presence of an inorganic or organic ba ⁇ e such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorphorine, N,N-di(lower)alkylbenzylarain ⁇ , or the like.
  • an inorganic or organic ba ⁇ e such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorphorine, N,N-di(lower)alkylbenzylarain ⁇ , or the like.
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
  • the compound (lb) or a salt thereof can be prepared by subjecting the compound (Ia) or a salt thereof to elimination reaction of the imino protective group.
  • Suitable method of this reaction may include conventional one such as hydrolysis, reduction and the like.
  • Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g. sodium, potassium, etc.], the hydroxide or carbonate or bicarbonate thereof, trialkylamine [e.g. trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]- non-5-ene, 1,4-diazabicyclo[2.2.2]octane, l,8-diazabicyclo[5.4.0]undec-7-ene, or the like.
  • an alkali metal e.g. sodium, potassium, etc.
  • trialkylamine e.g. trimethylamine, triethylamine, etc.
  • picoline 1,5-diazabicyclo[4.3.0]- non-5-ene
  • 1,4-diazabicyclo[2.2.2]octane 1,4-diazabicyclo[2.2.2]octane
  • Suitable acid may include an organic acid [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an inorganic acid [e.g. hydrochloric acid, hydrobromic acid, sulfuric acic, hydrogen chloride, hydrogen bromide, etc.].
  • organic acid e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.
  • an inorganic acid e.g. hydrochloric acid, hydrobromic acid, sulfuric acic, hydrogen chloride, hydrogen bromide, etc.
  • the elimination using Lewis acid ⁇ uch as trihaloacetic acid [e.g. trichloroacetic acid, trifluoroacetic acid, etc.] or the like is preferably carried out in the presence of cation trapping agent ⁇ [e.g. anisole, phenol, etc.].
  • the reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], N,N-dimethylformamide, methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction.
  • a liquid base or acid can be also used as the solvent.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • Reduction is carried out in a conventional manner, including chemical reduction and catalytic reduction.
  • Suitable reducing agents to be used in chemical reduction are a combination of a metal (e.g. tin, zinc, iron, etc.) or metallic compound (e.g. chromium chloride, chromium acetate, etc.) and an organic or inorganic acid (e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).
  • a metal e.g. tin, zinc, iron, etc.
  • metallic compound e.g. chromium chloride, chromium acetate, etc.
  • organic or inorganic acid e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.
  • Suitable catalysts to be used in catalytic reduction are conventional one ⁇ such as platinum catalysts (e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.), nickel catalysts (e.g. reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalysts (e.g. reduced cobalt, Raney cobalt, etc.), iron catalysts (e.g. reduced iron, Raney iron, etc.), copper catalysts (e.g.
  • platinum catalysts e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.
  • palladium catalysts e.g. spongy palladium, palladium black, palladium oxide, palladium on
  • the reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, N,N-dimethylformamide, tetrahydrofuran, or a mixture thereof.
  • a solvent which does not adversely influence the reaction
  • the above-mentioned acids to be u ⁇ ed in chemical reduction are in liquid, they can also be used as a solvent.
  • reaction temperature of this reduction is not critical and the reaction is u ⁇ ually carried out under cooling to heating.
  • the compound (Id) or a salt thereof can be prepared by subjecting the compound " (Ic) or a salt thereof to reduction reaction.
  • This reduction reaction can be . referred to that of the aforementioned Process 2.
  • the compound (I) or a salt thereof can be prepared by reacting the compound (IV) or a salt thereof with the compound (V) or a salt thereof.
  • Suitable salts of the compounds (IV) and (V) can be referred to the ones as exemplified for the compound (I) .
  • Suitable ba ⁇ e may include an inorganic ba ⁇ e ⁇ uch a ⁇ alkali metal hydride (e.g. sodium hydride, etc.), alkali metal hydroxide (e.g. sodium hydroxide, potas ⁇ ium hydroxide, etc.), alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonate (e.g. sodium bicarbonate, potas ⁇ ium bicarbonate, etc.
  • alkali metal bicarbonate e.g. sodium bicarbonate, potas ⁇ ium bicarbonate, etc.
  • alkali metal acetate e.g. ⁇ odium acetate, pota ⁇ sium acetate, etc.
  • alkaline earth metal phosphate e.g. magnesium phosphate, calcium phosphate, etc.
  • alkali metal hydrogen phosphate e.g. disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.
  • organic base such as trialkylamine (e.g. trimethylamin ⁇ , triethylamine, etc.), picoline, N-methylpyrrolidine, N-methylmorpholine or the like.
  • This reaction is usually carried out in a solvent such as alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, diethyl ether or any other solvent which does not adversely affect the reaction.
  • a solvent such as alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, diethyl ether or any other solvent which does not adversely affect the reaction.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the compound (If) or a ⁇ alt thereof can be prepared by reacting the compound (Ie) or a ⁇ alt thereof with the compound (VI) or a salt thereof.
  • Suitable salt ⁇ of the compounds (Ie) and (If) can be referred to the ones as exemplified for the compound (I).
  • Suitable salt ⁇ of the compound (VI) may include an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and the like.
  • the reaction is usually carried out in a conventional ⁇ olvent such as l-methyl-2-pyrrolidinone, N,N-dimethylfor amide, dichloromethane, ethylene chloride or any other solvent which does not adversely influence the reaction.
  • a conventional ⁇ olvent such as l-methyl-2-pyrrolidinone, N,N-dimethylfor amide, dichloromethane, ethylene chloride or any other solvent which does not adversely influence the reaction.
  • the reaction temperature is not critical and the reaction is usually carried out under warming to heating.
  • the compound (II) or a salt thereof can be prepared by subjecting the compound (VII) or a salt thereof to elimination reaction of the amino protective group.
  • Suitable salt ⁇ of the compound (VII) can be referred to the ones as exemplified for the compound (I) .
  • the elimination reaction i ⁇ carried out in accordance with a conventional method ⁇ uch as hydrolysi ⁇ ; reduction; Edman' ⁇ method (phenyl isothiocyanate method); or the like.
  • the hydrolysis may include a method using an acid or base or hydrazine and the like. These methods may be selected depending on the kind of the protective groups to be eliminated. Among these methods, hydrolysis using an acid is one of the most common and preferable method for eliminating the protective groups such as substituted or unsubstituted alkoxycarbonyl, for example, tert-pentyloxycarbonyl, lower alkanoyl (e.g.
  • cycloalkoxycarbonyl substituted or unsubstituted aralkoxycarbonyl
  • aralkyl e.g. trityl
  • substituted phenylthio substituted phenylthio, sub ⁇ tituted aralkylidene, substituted alkylidene, substituted cycloalkylidene or the like.
  • Suitable acid includes an organic or inorganic acid such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid and the like, and the most suitable acid is an acid which can easily be removed from the reaction mixture by a conventional manner such as distillation under reduced pressure, for example, formic acid, trifluoroacetic acid, hydrochloric acid, etc.
  • the acids can be selected according to the kind of the protective group to be eliminated.
  • the elimination reaction reaction using trifluoroacetic acid may be carried out in the presence of anisole.
  • the hydrolysis using hydrazine is commonly applied for eliminating a phthaloyl, succinyl type amino-protective group.
  • Suitable ba ⁇ e may include an inorganic base and an organic base.
  • the reductive elimination is generally applied for eliminating the protective group, for example, haloalkoxycarbonyl (e.g. trichloroethoxycarbonyl, etc.), substituted or unsubstituted aralkoxycarbonyl (e.g. benzyloxycarbonyl, etc.), 2-pyridylmethoxycarbonyl, etc.
  • Suitable reduction may include, for example, reduction with an alkali metal borohydride (e.g. sodium borohydride, etc.), reduction with a combination of a metal (e.g. tin, zinc, iron, etc.) or the said metal together with a metal salt compound (e.g.
  • chromous-chloride chromous acetate, etc.
  • organic or inorganic acid e.g. acetic acid, propionic acid, hydrochloric acid, etc.
  • catalytic reduction e.g. acetic acid, propionic acid, hydrochloric acid, etc.
  • Suitable catalyst includes a conventional one, for example, Raney nickel, platinum oxide, palladium on carbon and the like.
  • the acyl group can generally be eliminated by hydrolysis.
  • halogen sub ⁇ tituted-alkoxycarbonyl and 8-quinolylox ⁇ carbonyl groups are usually eliminated by treating with a heavy metal such as copper, zinc, or the like.
  • the reaction is usually carried out in a conventional solvent such as water, chloroform, methylene chloride, alcohol (e.g., methanol, ethanol, etc.), tetrahydrofuran or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as water, chloroform, methylene chloride, alcohol (e.g., methanol, ethanol, etc.), tetrahydrofuran or any other organic solvent which does not adversely influence the reaction.
  • the reaction temperature is not critical and may suitably be selected in accordance with the kind of the amino protective group and the elimination method as mentioned above, and the reaction is usually carried out under a mild condition such as under cooling or at slightly elevated temperature.
  • the protective groups the acyl group derived from ⁇ -amino acid can be eliminated by Edman's method. Proce ⁇ s B
  • the compound (IV) or a salt thereof can be prepared by reacting the compound (VIII) or its reactive derivative at the amino group or a salt thereof with the compound (III) or its reactive derivative or a salt thereof.
  • the reaction is carried out by substantially the same method as that of Process 1, and therefore the reaction method and conditions are to be referred to said Process 1.
  • the object compound (I) and pharmaceutically acceptable salt ⁇ thereof are. CCK antagonists and therefore useful as therapeutical agents for emesis, pancreatitis, etc.
  • object compound (I) and pharmaceutically acceptable salts thereof have gastric antagonism and are useful as therapeutical and/or preventive agents for ulcers, excess gastric secretion, Zollinger-Ellison Syndrome, etc.
  • Test Compound (3S)-1,3-Dihydro-l-(4-imidazolylmethyl)-3-[ (E)-3-(2- aminophenyl)propenoylamino]-5-(2-fluorophenyl)-2H-l,4- benzodiazepin-2-one dihydrochloride [hereinafter referred to as test compound A]
  • the object compound (I) or pharmaceutically acceptable salt ⁇ thereof can usually be administered to mammals including human being in the form of a conventional pharmaceutical composition such as capsule, micro-capsule, tablet, granule, powder, troche, syrup, aerosol, inhalation, solution, injection, suspension, emulsion, suppository or the like, and the most suitable dosage form is injection.
  • a conventional pharmaceutical composition such as capsule, micro-capsule, tablet, granule, powder, troche, syrup, aerosol, inhalation, solution, injection, suspension, emulsion, suppository or the like, and the most suitable dosage form is injection.
  • the pharmaceutical composition of this invention can contain various organic or inorganic carrier materials, which are conventionally used for pharmaceutical purpose, such as excipient (e.g. sucrose, starch, annit, sorbit, lactose, glucose, cellulose, talc, calcium phosphate calcium carbonate, etc.), binding agent (cellulose, methyl cellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose, starch, etc.), disintegrator (e.g.
  • excipient e.g. sucrose, starch, annit, sorbit, lactose, glucose, cellulose, talc, calcium phosphate calcium carbonate, etc.
  • binding agent cellulose, methyl cellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose, starch, etc.
  • disintegrator e.g.
  • starch carboxymethyl cellulo ⁇ e, calcium salt of carboxymethyl cellulose, hydroxypropylstarch, sodium glycole-starch, ⁇ odium bicarbonate, calcium pho ⁇ phate, calcium citrate, etc.
  • lubricant e.g. magnesium stearate, talc, sodium laurylsulf te, etc.
  • flavoring agent e.g. citric acid, mentol, glycine, orange powders, etc.
  • preservative e.g. sodium benzoate, sodium bisulfite, methylparaben, propylparaben, etc.
  • stabilizer e.g. citric acid, sodium citrate, acetic acid, etc.
  • su ⁇ pending agent e.g.
  • methyl cellulose methyl cellulose, polyvinylpyrrolidone, aluminum ⁇ tearate, etc.
  • dispersing agent e.g. water
  • aqueous diluting agent e.g. water
  • base wax e.g. cacao butter, polyethyleneglycol, white petrolatum, etc.
  • the effective ingredient may u ⁇ ually be admini ⁇ tered with a unit dose of 0.01 mg/kg to 50 mg/kg, 1 to 4 times a day.
  • the above dosage may be increased or decreased according to age, weight, conditions of the patient or the administering method.
  • the fractions containing the other object compound were combin ⁇ d and ⁇ vaporat ⁇ d to giv ⁇ an amorphous mass, which was susp ⁇ nd ⁇ d in dii ⁇ opropyl ether and collect ⁇ d by filtration to giv ⁇ (3R)-3-[ ( (2S)-2-amino-3-ph ⁇ nyl- propanoyl)amino]-1,3-dihydro-5-(2-fluorophenyl)-!-[(1H- tetrazol-5-yl)methyl]-2H-l,4-benzodiaz ⁇ pin-2-on ⁇ (4.76 g) .
  • Th ⁇ resultant powder was collected by filtration and washed with diisopropyl eth ⁇ r to giv ⁇ (3 ⁇ )-3-[[(2S)-2- ⁇ N'-(ph ⁇ nyl)thioureido ⁇ -3-phenyl- propanoyl]amino]-l,3-dihydro-5-(2-fluoroph ⁇ yl)-l-[ (1H- t ⁇ trazol-5-yl)m ⁇ thyl]-2H- ⁇ ,4-b ⁇ nzodiaz ⁇ pin-2-on ⁇ (5.63 g) .
  • Th ⁇ product obtain ⁇ d abov ⁇ was ⁇ u ⁇ p ⁇ nd ⁇ d in tetrahydrofuran (35 ml) and * 4N-hydrogen chloride in ethyl acetate (33.5 ml) wa ⁇ added dropwise thereto under ice-cooling. The mixture was stirred, for 5 hours and then evaporated in vacuo to give a viscous oil, which wa ⁇ washed with ethyl acetat ⁇ by stirring for 3 hours.
  • the mixture was stirred for 3 hours and allowed to stand overnight.
  • the reaction mixture was poured into a mix-ture of ⁇ thyl acetate and water under stirring.
  • the ⁇ eparat ⁇ d organic lay ⁇ r was wa ⁇ hed with water twice and dried.
  • the solvent was removed under reduced pressur ⁇ to giv ⁇ an amorphous residue, which was purified by column chromatography on silica gel with an eluen-t of chloroform.
  • the fractions containing the desired product were combined and evaporated to afford an amorphous mass, which was pulverized and stirred for several hours in diisopropyl ether.
  • Example 3 To a solution of (3RS)-l,3-dihydro-l-[ (1- tritylimidazol-4-yl)methyl]-3-amino-5-(2-fluorophenyl)-2H- l,4-benzodiazepin-2-one (1.0 g) in methylene chloride (10 ml) were added successive ⁇ ively triethylamine (340 mg) and 2-naphthoyl chloride (320 mg) . The mixture wa ⁇ stirred for 1.5 hours. The reaction mixture was washed with water and dried. The solvent was removed under reduced pre ⁇ ur ⁇ to give an amorphous residue, which was purified by column chromatography on silica gel with an eluent of chloroform.
  • reaction mixture was filtered through celite and the filtered mass was washed with hot ethanol several times. From the filtrate and the washings, ethanol was removed under reduced pressure. To the residual mixture wa ⁇ added a ⁇ aturated aqueous ⁇ olution of ⁇ odium bicarbonate (100 ml) and the mixture was extracted with ethyl acetate (100 ml).
  • Acetic acid (2 ml) was added to the reaction mixture.
  • Th ⁇ r ⁇ sultant mixtur ⁇ was pour ⁇ d into a mixtur ⁇ of ⁇ thyl ac ⁇ tat ⁇ (200 ml) and wat ⁇ r (200 ml) und ⁇ r stirring.
  • Th ⁇ mixture was adjusted to pH 8 with an aqueous solution of sodium bicarbonate.
  • the s ⁇ parated organic layer was washed with water.
  • the solvent was r ⁇ mov ⁇ d und ⁇ r r ⁇ duced pressure to give an amorphous residue, which was purified by column chromatography on silica gel with an eluent of chloroform.
  • Example 9 To a solution of (3RS)-l,3-dihydro-3-(2-naphthoyl- amino)-5-(2-fluorophenyl)-2H-l,4-benzodiazepin-2-on ⁇ (1.25 g) in N,N-dimethylformamid ⁇ (31 ml) was add ⁇ d sodium hydrid ⁇ (60% susp ⁇ nsion in mineral oil, 130 mg) under stirring and cooling at 0 Q C in an ice-salt bath in a stream of nitrogen. After the mixture was stirred at room temperature for 45 minutes, a solution of chloroace onitril ⁇ (270 mg) in N,N-dim ⁇ thylformamide (5 ml) was added to the mixture at 0°C under stirring.
  • the resultant mixture was stirred overnight at room temperature. Acetic acid (0.5 g) was added to the reaction mixture. The resultant mixture was poured into a mixture of ethyl acetate (200 ml) and water (300 ml) under stirring. The mixture was adjusted to pH 8 with an aqueous solution of sodium bicarbonate. The separated organic layer was washed with water. The solvent was remov ⁇ d under reduced pressure to give amorphous residue, which was purified by column chromatography on silica gel with an ⁇ lu ⁇ nt of chloroform.
  • Example 11 To a solution of (3RS)-l,3-dihydro-l-[2-(1-trityl- imidazol-4-yl) ⁇ thyl]-3-(3-quinolylcarbonylamino)-5-(2- fluoroph ⁇ nyl)-2H-l,4-b ⁇ nzodiaz ⁇ pin-2-on ⁇ (740 mg) in N,N-dim ⁇ thylformamid ⁇ (7.4 ml) wa ⁇ added 6N-hydrochloric acid (5.18 ml) under ⁇ tirring and cooling in an ice-bath. The mixture was warmed to 60-70°C and stirred for one hour.
  • the r ⁇ sultant precipitates were collect ⁇ d by filtration, wash ⁇ d with wat ⁇ r and purified by column chromatography on ⁇ ilica gel with an eluent of chloroform. The fraction ⁇ containing the de ⁇ ired product were combined and ⁇ vaporated to afford an amorphous mass, which was pulverized and stirred for ⁇ everal hour ⁇ in diisopropyl ether. Collection by filtration, washing with dii ⁇ opropyl eth ⁇ r and drying und ⁇ r r ⁇ duced pressur ⁇ gave
  • Example 18 To a su ⁇ pension of 2-indolecarboxylic acid (161.2 g) in methylene chloride (3.25 ml) was added thionyl chloride (119.0 mg) and one drop of N,N-dimethylformamid ⁇ und ⁇ r stirring at ambient temperature. The mixture was reflux ⁇ d for 1 hour with stirring.
  • Example 19 the following compound was obtained according to a similar manner to that of Example 18.

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Abstract

L'invention se rapporte à des dérivés de benzodiazépine, représentés par la formule (I), où R1 représente un groupe hétérocyclique pouvant comporter un ou plusieurs substituants appropriés, ou un cyano, R2 représente un hydrogène ou un halogène, R3 représente un aryle pouvant comporter un ou plusieurs substituants appropriés, R4 représente un aryle pouvant comporter un ou plusieurs substituants appropriés, etc., et A représente un alkylène inférieur, ainsi qu'à des sels pharmaceutiquement acceptables de ces dérivés, qui peuvent être utilisés comme médicament.
PCT/JP1991/000952 1990-07-19 1991-07-17 Derives de benzodiazepine WO1992001683A1 (fr)

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AU82171/91A AU650034B2 (en) 1990-07-19 1991-07-17 Benzodiazepine derivatives

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GB909015879A GB9015879D0 (en) 1990-07-19 1990-07-19 Benzodiazepine derivatives

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GB (1) GB9015879D0 (fr)
HU (1) HUT63627A (fr)
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IL (1) IL98873A0 (fr)
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Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0508799A1 (fr) * 1991-04-10 1992-10-14 Merck & Co. Inc. Antagonistes de cholécystokinine
EP0508797A1 (fr) * 1991-04-10 1992-10-14 Merck & Co. Inc. Antagonistes de cholecystokinine
US5220018A (en) * 1991-04-10 1993-06-15 Merck & Co., Inc. Cholecystokinin antagonists
US5220017A (en) * 1991-04-10 1993-06-15 Merck & Co., Inc. Cholecystokinin antagonists
WO1993019052A1 (fr) * 1992-03-24 1993-09-30 Merck Sharp & Dohme Limited 3-ureido substitue benzodiazepin-2-ones presentant une activite antagoniste de la cholecystokinine et/ou de la gastrine et leur utilisation therapeutique
US5360802A (en) * 1992-05-11 1994-11-01 Merck Sharpe & Dohme Ltd. Benzodiazepine derivatives, compositions containing them and their use in therapy
WO1994026723A2 (fr) * 1993-05-14 1994-11-24 Genentech, Inc. INHIBITEURS DE LA ras FARNESYL-TRANSFERASE
US5378838A (en) * 1993-01-13 1995-01-03 Merck & Co., Inc. Benzodiazepine cholecystokinin antagonists
WO1995003299A1 (fr) * 1993-07-20 1995-02-02 Glaxo S.P.A. Derives de 1,5-benzodiazepine utiles comme antagonistes de ckk ou de gastrine
WO1996004254A2 (fr) * 1994-07-29 1996-02-15 Fujisawa Pharmaceutical Co., Ltd. Derives de benzodiazepine
US5698691A (en) * 1993-09-24 1997-12-16 Takeda Chemical Industries, Ltd. Condensed cyclic compounds and their use
WO1998000406A1 (fr) * 1996-07-02 1998-01-08 Merck & Co., Inc. Procede de traitement du travail preterme
US5929071A (en) * 1996-07-02 1999-07-27 Merck & Co., Inc. Method for the treatment of preterm labor
US6509331B1 (en) 1998-06-22 2003-01-21 Elan Pharmaceuticals, Inc. Deoxyamino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6528505B1 (en) 1998-06-22 2003-03-04 Elan Pharmaceuticals, Inc. Cyclic amino acid compounds pharmaceutical compositions comprising same and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6541466B2 (en) 1996-12-23 2003-04-01 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6569851B1 (en) 1998-06-22 2003-05-27 Elan Pharmaceutials, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6683075B1 (en) 1996-12-23 2004-01-27 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use
EP1398033A3 (fr) * 1999-04-30 2004-06-30 The Regents Of The University Of Michigan Utilisation de benzodiazépine pour traiter des maladies autoimmunes, inflammations, néoplasies, infections virales et athérosclerose
US6774125B2 (en) 1998-06-22 2004-08-10 Elan Pharmaceuticals, Inc. Deoxyamino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6838455B2 (en) 1998-06-22 2005-01-04 Athena Neurosciences, Inc. Deoxyamino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting beta-amyloid peptide release and/or its synthesis by use of such compounds
US6958330B1 (en) 1998-06-22 2005-10-25 Elan Pharmaceuticals, Inc. Polycyclic α-amino-ε-caprolactams and related compounds
US7572788B2 (en) 1999-04-30 2009-08-11 The Regents Of The University Of Michigan Compositions and methods relating to novel compounds and targets thereof
US7638624B2 (en) 2005-01-03 2009-12-29 The Regents Of The University Of Michigan Compositions and methods relating to novel benzodiazepine compounds and derivatives
US7683046B2 (en) 1999-04-30 2010-03-23 The Regents Of The University Of Michigan Benzodiazepine compositions for treating epidermal hyperplasia and related disorders
US9126978B2 (en) 2009-11-17 2015-09-08 The Regents Of The University Of Michigan 1,4-benzodiazepine-2,5-diones and related compounds with therapeutic properties

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JPH07119217B1 (fr) * 1990-12-25 1995-12-20
GB0221923D0 (en) * 2002-09-20 2002-10-30 Arrow Therapeutics Ltd Chemical compounds

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US4820834A (en) * 1984-06-26 1989-04-11 Merck & Co., Inc. Benzodiazepine analogs
EP0349949A2 (fr) * 1988-07-07 1990-01-10 Fujisawa Pharmaceutical Co., Ltd. Derivés de benzodiazépine

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EP0349949A2 (fr) * 1988-07-07 1990-01-10 Fujisawa Pharmaceutical Co., Ltd. Derivés de benzodiazépine

Cited By (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0508799A1 (fr) * 1991-04-10 1992-10-14 Merck & Co. Inc. Antagonistes de cholécystokinine
EP0508797A1 (fr) * 1991-04-10 1992-10-14 Merck & Co. Inc. Antagonistes de cholecystokinine
US5218114A (en) * 1991-04-10 1993-06-08 Merck & Co., Inc. Cholecystokinin antagonists
US5218115A (en) * 1991-04-10 1993-06-08 Merck & Co., Inc. Cholecystokinin antagonists
US5220018A (en) * 1991-04-10 1993-06-15 Merck & Co., Inc. Cholecystokinin antagonists
US5220017A (en) * 1991-04-10 1993-06-15 Merck & Co., Inc. Cholecystokinin antagonists
US5681833A (en) * 1992-03-24 1997-10-28 Merck, Sharp & Dohme Ltd. Benzodiazepine derivatives
WO1993019052A1 (fr) * 1992-03-24 1993-09-30 Merck Sharp & Dohme Limited 3-ureido substitue benzodiazepin-2-ones presentant une activite antagoniste de la cholecystokinine et/ou de la gastrine et leur utilisation therapeutique
US5360802A (en) * 1992-05-11 1994-11-01 Merck Sharpe & Dohme Ltd. Benzodiazepine derivatives, compositions containing them and their use in therapy
US5378838A (en) * 1993-01-13 1995-01-03 Merck & Co., Inc. Benzodiazepine cholecystokinin antagonists
WO1994026723A2 (fr) * 1993-05-14 1994-11-24 Genentech, Inc. INHIBITEURS DE LA ras FARNESYL-TRANSFERASE
WO1994026723A3 (fr) * 1993-05-14 1995-02-02 Genentech Inc INHIBITEURS DE LA ras FARNESYL-TRANSFERASE
US5843941A (en) * 1993-05-14 1998-12-01 Genentech, Inc. Ras farnesyl transferase inhibitors
US5532359A (en) * 1993-05-14 1996-07-02 Genentech, Inc. Ras farnesyl transferase inhibitors
WO1995003299A1 (fr) * 1993-07-20 1995-02-02 Glaxo S.P.A. Derives de 1,5-benzodiazepine utiles comme antagonistes de ckk ou de gastrine
US5698691A (en) * 1993-09-24 1997-12-16 Takeda Chemical Industries, Ltd. Condensed cyclic compounds and their use
WO1996004254A3 (fr) * 1994-07-29 1996-06-20 Fujisawa Pharmaceutical Co Derives de benzodiazepine
WO1996004254A2 (fr) * 1994-07-29 1996-02-15 Fujisawa Pharmaceutical Co., Ltd. Derives de benzodiazepine
WO1998000406A1 (fr) * 1996-07-02 1998-01-08 Merck & Co., Inc. Procede de traitement du travail preterme
US5929071A (en) * 1996-07-02 1999-07-27 Merck & Co., Inc. Method for the treatment of preterm labor
US6541466B2 (en) 1996-12-23 2003-04-01 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6683075B1 (en) 1996-12-23 2004-01-27 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use
US7153847B2 (en) 1996-12-23 2006-12-26 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6544978B2 (en) 1996-12-23 2003-04-08 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6559141B2 (en) 1996-12-23 2003-05-06 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6951854B1 (en) 1996-12-23 2005-10-04 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6579867B2 (en) 1996-12-23 2003-06-17 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6632811B2 (en) 1996-12-23 2003-10-14 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6653303B1 (en) 1996-12-23 2003-11-25 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6667305B1 (en) 1996-12-23 2003-12-23 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6774125B2 (en) 1998-06-22 2004-08-10 Elan Pharmaceuticals, Inc. Deoxyamino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6958330B1 (en) 1998-06-22 2005-10-25 Elan Pharmaceuticals, Inc. Polycyclic α-amino-ε-caprolactams and related compounds
US6509331B1 (en) 1998-06-22 2003-01-21 Elan Pharmaceuticals, Inc. Deoxyamino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6528505B1 (en) 1998-06-22 2003-03-04 Elan Pharmaceuticals, Inc. Cyclic amino acid compounds pharmaceutical compositions comprising same and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6838455B2 (en) 1998-06-22 2005-01-04 Athena Neurosciences, Inc. Deoxyamino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting beta-amyloid peptide release and/or its synthesis by use of such compounds
US6906056B2 (en) 1998-06-22 2005-06-14 Elan Pharmaceuticals, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6569851B1 (en) 1998-06-22 2003-05-27 Elan Pharmaceutials, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6696438B2 (en) 1998-06-22 2004-02-24 Elan Pharmaceuticals, Inc. Cyclic amino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
EP1398033A3 (fr) * 1999-04-30 2004-06-30 The Regents Of The University Of Michigan Utilisation de benzodiazépine pour traiter des maladies autoimmunes, inflammations, néoplasies, infections virales et athérosclerose
US7572788B2 (en) 1999-04-30 2009-08-11 The Regents Of The University Of Michigan Compositions and methods relating to novel compounds and targets thereof
US7683046B2 (en) 1999-04-30 2010-03-23 The Regents Of The University Of Michigan Benzodiazepine compositions for treating epidermal hyperplasia and related disorders
US8168626B2 (en) 1999-04-30 2012-05-01 The Regents Of The University Of Michigan Benzodiazepine compositions for treating epidermal hyperplasia and related disorders
US7638624B2 (en) 2005-01-03 2009-12-29 The Regents Of The University Of Michigan Compositions and methods relating to novel benzodiazepine compounds and derivatives
US9126978B2 (en) 2009-11-17 2015-09-08 The Regents Of The University Of Michigan 1,4-benzodiazepine-2,5-diones and related compounds with therapeutic properties
US9849138B2 (en) 2009-11-17 2017-12-26 The Regents Of The University Of Michigan 1,4-benzodiazepone-2,5-diones and related compounds with therapeutic properties

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HUT63627A (en) 1993-09-28
HU9300403D0 (en) 1993-05-28
PT98370A (pt) 1992-05-29
ZA915423B (en) 1992-04-29
JPH06502620A (ja) 1994-03-24
EP0539591A1 (fr) 1993-05-05
GB9015879D0 (en) 1990-09-05
AU650034B2 (en) 1994-06-09
CN1059141A (zh) 1992-03-04
AU8217191A (en) 1992-02-18
IE912428A1 (en) 1992-01-29
CA2090023A1 (fr) 1992-01-20
IL98873A0 (en) 1992-07-15

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