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WO1996023790A1 - Acetylimidazobenzodiazepines - Google Patents

Acetylimidazobenzodiazepines Download PDF

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Publication number
WO1996023790A1
WO1996023790A1 PCT/CH1996/000021 CH9600021W WO9623790A1 WO 1996023790 A1 WO1996023790 A1 WO 1996023790A1 CH 9600021 W CH9600021 W CH 9600021W WO 9623790 A1 WO9623790 A1 WO 9623790A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
general formula
compound
imidazo
fluoro
Prior art date
Application number
PCT/CH1996/000021
Other languages
German (de)
English (en)
Inventor
René Borer
Max Gerecke
Ulrich Widmer
Original Assignee
F. Hoffmann-La Roche Ag
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 F. Hoffmann-La Roche Ag filed Critical F. Hoffmann-La Roche Ag
Priority to AU43828/96A priority Critical patent/AU4382896A/en
Publication of WO1996023790A1 publication Critical patent/WO1996023790A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to benzodiazepines.
  • it relates to imidazo [1,2-a] [1,4] benzodiazepines of the general formula
  • R 1 is hydrogen, lower alkyl, hydroxy lower alkyl, lower
  • R 2 phenyl, optionally substituted by 2-halogen
  • R 4 is hydrogen, lower alkyl, hydroxy lower alkyl, carboxy
  • R 5 is hydrogen or lower alkyl
  • the present invention relates to the compounds of formula I and salts thereof as such and as therapeutic active substances, their preparation and their use for therapeutic purposes or for the preparation of corresponding medicaments and medicaments containing a compound of
  • alkyl denotes straight-chain or branched saturated
  • Hydrocarbon radicals such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl and tert-butyl.
  • halogen includes fluorine, chlorine, bromine and iodine.
  • alkanoyl denotes residues such as acetyl, propionyl and the like.
  • propargylamine derivative preferably denotes the radical "lower alkyn-2-ylamine”.
  • Particularly preferred compounds according to the invention are those in which R 1 is methyl, hydrogen, hydroxymethyl or
  • R 2 2-F-phenyl, R 5 methyl and R 4 are hydrogen, methyl or hydroxymethyl.
  • R 2 and R 5 have the meaning given above and Ra is hydrogen
  • R 11 lower alkyl, lower alkanoyloxy lower alkyl, 2-pyridyl or
  • Phenyl optionally substituted by lower alkoxy or di-lower alkylamino and R 41 is lower alkyl, carboxy, lower alkoxycarbonyl or phenyl, optionally substituted by lower alkoxy or di-lower alkylamino,
  • R 2 and R 5 have the meaning given above and R 6 is lower alkyl
  • R 1 and R 4 are hydrogen and R 2 and R 5 have the meaning given above, cyclized, or e) a compound of the general formula
  • R 2 , R 4 and R 5 have the meaning given above, n is 1-4 and X is halogen,
  • R 2 , R 5 and n have the meaning given above, cyclized in the acid medium to give a compound of the general formula I in which R 1 is hydrogen and R 4 is hydroxy-lower alkyl, or h) a compound of the general formula I, wherein R 1 , R 2 and R 3 have the meaning given above and R 4 is lower alkyloxycarbonyl, converted into a compound of the general formula I, in which R 4 represents a carboxy group, or i) from a compound of the general formula
  • R 1 , R 2 and R 4 have the meaning given above and R 7 denotes a protected -COR 5 group
  • the protective group is split off, or j) a compound of the general formula I, in which R 1 , R 2 and R 4 have the abovementioned meaning and R 3 is -C (OH) HR 5 , into a compound of the general formula I, in which R 3 denotes -C (O) R 5 , and k) converts a compound of the general formula I into a pharmaceutically acceptable acid addition salt.
  • a compound of general formula II can be N-alkylated and cyclized to compounds of general formula I.
  • the alkylation takes place according to methods known per se.
  • a compound of the formula II is expediently dissolved in a solvent, for example in dioxane, N, N-dimethylformamide or toluene, with the corresponding
  • the response time can vary between 30 minutes and 24 hours.
  • the following are particularly suitable as alkylating agents: chloroacetone, phenacyl bromide, 2-bromo-1- (4-methoxy-phenyl) propane, 4-dimethylamino-phenacyl bromide, 1-bromo-1- (methoxy-phenyl) propane-2- on, 2-bromo-1-pyridin-2-ylethanone, 4-hydroxyphenacylbromide, 1-chloro-2-butanone, 3-chloro-2-butanone, 2-chloroacetoacetic acid, ethyl ester and the like.
  • the cyclization takes place
  • a compound of the general formula II is cyclized by advantageously reacting a reactive amine, for example propargylamine hydrochloride and an acetate, for example sodium acetate, in the presence of p-toluenesulfonic acid with a compound of the formula III.
  • a reactive amine for example propargylamine hydrochloride
  • an acetate for example sodium acetate
  • n-butanol is suitable as the solvent.
  • the reaction to the corresponding compounds of formula I takes place over a period of several hours in a temperature range around 120 ° C.
  • Process variant d) produces a compound of the general formula I in which R 1 and R 4 are hydrogen and R 2 and R 5 are as defined above. It is convenient to start from a compound of general formula IV, which is cyclized under acidic conditions. Glacial acetic acid is particularly suitable for the cyclization.
  • one compound of formula IV is dissolved in glacial acetic acid and several
  • Process variant e) comprises the production of
  • a compound of the general formula V is expediently treated with a basic reagent.
  • the procedure is expediently as follows: A compound of the general formula V is optionally treated under an inert gas atmosphere for several hours with an alkali metal hydroxide solution, preferably with sodium hydroxide, or with an alkali metal bicarbonate,
  • Process variant g) comprises the preparation of compounds of the general formula I in which R 1 is hydrogen and R 4 is hydroxy-lower alkyl. Starting from a compound of formula VI, this is expediently treated with a strong acid, for example concentrated sulfuric acid, and several
  • Sodium hydroxide solution is treated under a protective gas atmosphere and saponified to form a compound with an acid group.
  • compounds of the general formula I are formed by splitting off protective groups. Suitable protective groups and methods for their separation are everyone
  • Dioxolane group which can be split off by reaction in an acidic range, for example by reaction in hydrochloric acid.
  • Process variant j) comprises the transfer of a
  • the compounds of formula I can be converted into pharmaceutically acceptable acid addition salts.
  • Both salts with inorganic and salts with organic acids can be considered.
  • Examples of such salts are the hydrochlorides, hydrobromides, sulfates, nitrates, citrates, acetates, maleates, succinates, methanesulfonates, p-toluenesulfonates and the like. These salts can be prepared by methods known per se.
  • R 1 -R 5 have the meaning given above, R 6 means lower alkyl and R 7 means a protected -COR 5 group, Ra means hydrogen, n means 1-4 and X is halogen.
  • Lawesson's reagent treated This is done in one
  • a further reaction of the compound of formula III with a dialkoxyethylamine, e.g. with 2,2-dimethyloxyethylamine at room temperature leads to a corresponding compound of the general formula IV.
  • a compound of the general formula II is advantageously mixed with an aqueous ammonia solution, tetrahydrofuran being very suitable as solvent. Then one
  • Formula V are converted, which can expediently be accomplished with 1,3-dichloroacetone, dissolved in dioxane.
  • Scheme 2 shows the preparation of special intermediates of the formulas VIIa and VIIb, these compounds containing a protective group or a protected carbonyl group on the phenyl ring.
  • a compound of the formula XI can thus be prepared by expediently treating a compound of the formula X (described in DE-OS 2'163'522) with a solution consisting of a sodium hydride dispersion and N, N-dimethylformamide. Phosphoric acid diphenyl ester chloride and then ammonium carbonate are added, and after a number of hours using generally known methods to give a compound of the general
  • a compound of the general formula VIIIb is conveniently obtained by adding a compound of the formula X to propargylamine.
  • Tetrahydrofuran added, cooled and treated with diphenyl ester of phosphoric acid. Then propargylamine is added dropwise and stirred for several hours. The cyclization to the compound of the formula IIIb is then advantageously carried out with an alcohol, for example with n-butanol.
  • Acid addition salts and are therefore particularly suitable for the preparation of aqueous injection solutions.
  • the inhibition of the binding of tritiated flumazenil to the specific benzodiazepine receptors in the rat cortex is determined by the respective test substances. It is referred to as the IC 50
  • Test laboratory brought. In the rotating rod test, the animals are placed on a horizontally arranged, smooth metal rod of 3 cm
  • Diameter that rotates at 2 revolutions per minute Diameter that rotates at 2 revolutions per minute. First, the animals are given 30 seconds to familiarize themselves with the test situation. Then those animals are selected that manage to stay on the stick for at least 1 minute. These animals are then the
  • the compounds of the formula I can be used as sedatives /
  • Hypnotics anticonvulsants, muscle relaxants and anxiolytics can be used. They are suitable, for example, as quick but short-acting hypnotics for oral administration, but especially - in the form of aqueous solutions of their acid addition salts - as
  • the compounds of formula I and pharmaceutically acceptable acid addition salts thereof can be used as medicines, for example in the form pharmaceutical preparations, find use.
  • the pharmaceutical preparations can be taken orally, for example in the form of tablets,
  • Coated tablets, coated tablets, hard and soft gelatin capsules, solutions, emulsions or suspensions can be administered.
  • administration can also be rectal, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
  • Acid addition salts thereof are processed with pharmaceutically inert, inorganic or organic carriers.
  • Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used as such a carrier for tablets, coated tablets, coated tablets and hard gelatin capsules.
  • Soft gelatin capsules are suitable as carriers, for example
  • Acid addition salts of compounds of the formula I, auxiliaries such as alcohols, polyols, glycerol, vegetable oils and the like can be used but are generally not necessary.
  • Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
  • the pharmaceutical preparations can also be used as the pharmaceutical preparations.
  • Preservatives solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, aromatizing agents, salts for changing the osmotic pressure, buffers, coating agents or antioxidants. They can also contain other therapeutically valuable substances.
  • a compound of formula I or a pharmaceutically acceptable acid addition salt thereof and a therapeutically inert excipient also the subject of the present invention, also a
  • the compounds of the formula I and pharmaceutically acceptable acid addition salts thereof can be used according to the invention for therapeutic purposes, in particular for anxiolytic and / or anticonvulsive and / or muscle relaxant and / or sedative-hypnotic purposes.
  • Dosage can vary within wide limits and is of course to be adapted to the individual circumstances in each individual case. In general, intravenous administration is likely to result in a
  • the invention also relates, as mentioned at the outset, to the use of compounds of the formula I and of pharmaceutically acceptable acid addition salts thereof for the production of medicaments, in particular of
  • Lawesson's reagent added. The mixture was heated at 100 ° C for 8 hours and then left at room temperature for 16 hours. The
  • Dichloromethane extracts were dried over sodium sulfate and chromatographed on 300 g of silica gel. By-products were eluted with dichloromethane containing 1% to 2% ethanol.
  • Example lb) in 40 ml of dioxane was mixed with 438 mg (2.2 mmol) of phenacyl bromide and 210 mg (2.5 mmol) of sodium hydrogen carbonate and stirred at 100 ° C. for 16 h. Another 87 mg (0.45 mmol)
  • Phenacyl bromide and 210 mg (2.5 mmol) sodium hydrogen carbonate were added and the mixture was stirred at 100 ° C. for 5.5 h. After a further addition of 87 mg (0.45 mmol) phenacyl bromide and 105 mg (1.25 mmol)
  • the reaction mixture was concentrated in vacuo and the residue was taken up in 20 ml of saturated aqueous sodium hydrogen carbonate solution. It was extracted twice with dichloromethane, dried with sodium sulfate, filtered and evaporated in vacuo.
  • the crude product was on 80 g Alox (neutral, act
  • Example 1b) in 5 ml of N, N-dimethylformamide was treated with 684 mg (3.7 mmol) of 2-bromo-1-pyridin-2-ylethanone and 311 mg (3.7 mmol)
  • the reaction mixture was concentrated in vacuo and the residue was taken up in 15 ml of saturated aqueous sodium hydrogen carbonate solution.
  • the precipitated crystals were filtered off with suction, dissolved in dichloromethane, dried with sodium sulfate, filtered and evaporated.
  • the crude product was on 30 g of silica gel with hexane /
  • Example lb) in 5 ml of N, N-dimethylformamide was treated with 504 mg (2.2 mmol) of 4-methoxyphenacyl bromide and 185 mg (2.2 mmol)
  • Example lb) in 10 ml of toluene was added dropwise to 1.95 ml (1.15 mmol) of N-ethyl-diisopropylamine and 1.22 g (1.15 mmol) of 1-chloro-2-butanone added.
  • the mixture was heated to 110-120 ° C over 18 h.
  • the water phase was extracted three times with dichloromethane and then made dropwise basic with 5M aqueous sodium hydroxide solution. It was extracted again with dichloromethane, with
  • Example lb) in 30 ml of N, N-dimethylformamide was added dropwise under argon with 1.8 ml (10.5 mmol) of N-ethyl-diisopropylamine and 1.5 ml (11.0 mmol) of ethyl 2-chloro-acetoacetate.
  • the mixture was heated to 100 ° C. for 24 hours.
  • the reaction mixture was concentrated in vacuo, the residue was taken up in water and extracted three times with dichloromethane. It was evaporated and that
  • Acetic acid was stirred at 110 ° C for 60 h. The mixture was evaporated in vacuo, the residue was taken up in saturated aqueous sodium hydrogen carbonate solution and twice with
  • Dichloromethane extracts were dried with sodium sulfate and chromatographed on 100 g of silica gel. With dichloromethane, which contained 2% methanol, 1.4 g (90%) [6- (2-fluoro-phenyl) -2-phenyl-4H-imidazo [1,2-a] [1,4] benzodiazepine] -8 -carboxylic acid methyl ester eluted. This was obtained as a solid foam after evaporation of the solvents, and in this form for the following

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne des imidazo[1,2-a][1,4]benzodiazépines substituées ayant la formule générale (I), dans laquelle R1 désigne hydrogène, alkyle inférieur, hydroxyalkyle inférieur, alcanoyloxy inférieur-alkyle inférieur, 2-pyridyle, phényle, le cas échéant substitué par alcoxy inférieur ou par dialkylamino inférieur; R2 désigne phényle, le cas échéant substitué par 2-halogène; R3 désigne -C(O)R5 ou -C(OH)HR5, R4 désigne hydrogène, alkyle inférieur, hydroxyalkyle inférieur, carboxyle, alcoxycarbonyle inférieur ou phényle, le cas échéant substitué par alcoxy inférieur; R5 désigne hydrogène ou alkyle inférieur. Ces composés, ainsi que leurs sels pharmaceutiquement acceptables, sont utiles comme principes actifs anxiolytiques, anti-convulsifs, relaxants musculaires et/ou sédatifs-hypnotiques.
PCT/CH1996/000021 1995-02-02 1996-01-16 Acetylimidazobenzodiazepines WO1996023790A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU43828/96A AU4382896A (en) 1995-02-02 1996-01-16 Acetylimidazobenzodiazepines

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH28695 1995-02-02
CH286/95-9 1995-02-02

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006044753A3 (fr) * 2004-10-19 2006-08-17 Smithkline Beecham Corp Composes chimiques
US7160880B1 (en) 1999-05-14 2007-01-09 Cenes Limited Short-acting benzodiazepines
WO2013174883A1 (fr) 2012-05-22 2013-11-28 Paion Uk Limited Compositions comprenant des benzodiazépines à action rapide
US8642588B2 (en) 2006-07-10 2014-02-04 Paion Uk Limited Short-acting benzodiazepine salts and their polymorphic forms
US9193730B2 (en) 2006-07-10 2015-11-24 Paion Uk Limited Short-acting benzodiazepine salts and their polymorphic forms
WO2017178663A1 (fr) 2016-04-14 2017-10-19 Paion Uk Limited Benzodiazépines à usage nasal et inhalées par voie orale
US10195210B2 (en) 2010-11-08 2019-02-05 Paion Uk Ltd. Dosing regimen for sedation with CNS 7056 (Remimazolam)
US10414749B2 (en) 2013-03-04 2019-09-17 Paion Uk Limited Process for preparing 3-[(S)-7-bromo-2-((2-oxopropyl)amino)-5-pyridin-2-yl-3H-1,4-benzodiazepin-3-yl]propionic acid methyl ester
US10844070B2 (en) 2014-06-26 2020-11-24 The Johns Hopkins University Peripherally restricted GABA positive allosteric modulators for the treatment of irritable bowel syndrome and other ailments of the peripheral nervous system
CN112142746A (zh) * 2019-06-28 2020-12-29 四川大学华西医院 苯二氮卓类化合物及其制备方法和在医药上的作用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2150732A1 (fr) * 1971-08-04 1973-04-13 Upjohn Co

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2150732A1 (fr) * 1971-08-04 1973-04-13 Upjohn Co

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7160880B1 (en) 1999-05-14 2007-01-09 Cenes Limited Short-acting benzodiazepines
US7435730B2 (en) 1999-05-14 2008-10-14 Cenes Limited Short-acting benzodiazepines
US7473689B2 (en) 1999-05-14 2009-01-06 Cenes Limited Short-acting benzodiazepines
US7485635B2 (en) 1999-05-14 2009-02-03 Cenes Limited Short-acting benzodiazepines
US7528127B2 (en) 1999-05-14 2009-05-05 Cenes Limited Short-acting benzodiazepines
WO2006044753A3 (fr) * 2004-10-19 2006-08-17 Smithkline Beecham Corp Composes chimiques
JP2008516975A (ja) * 2004-10-19 2008-05-22 スミスクライン ビーチャム コーポレーション 化合物
US7888503B2 (en) 2004-10-19 2011-02-15 Glaxosmithkline Llc Benzodiazepine derivatives that inhibit rock
US9193730B2 (en) 2006-07-10 2015-11-24 Paion Uk Limited Short-acting benzodiazepine salts and their polymorphic forms
US8642588B2 (en) 2006-07-10 2014-02-04 Paion Uk Limited Short-acting benzodiazepine salts and their polymorphic forms
US10961250B2 (en) 2006-07-10 2021-03-30 Paion Uk Limited Short-acting benzodiazepine salts and their polymorphic forms
US9777007B2 (en) 2006-07-10 2017-10-03 Paion Uk Limited Short-acting benzodiazepine salts and their polymorphic forms
US12365684B2 (en) 2006-07-10 2025-07-22 Paion Uk Limited Short-acting benzodiazepine salts and their polymorphic forms
US9914738B2 (en) 2006-07-10 2018-03-13 Paion Uk Limited Short-acting benzodiazepine salts and their polymorphic forms
US10472365B2 (en) 2006-07-10 2019-11-12 Paion Uk Limited Short-acting benzodiazepine salts and their polymorphic forms
US10195210B2 (en) 2010-11-08 2019-02-05 Paion Uk Ltd. Dosing regimen for sedation with CNS 7056 (Remimazolam)
US10342800B2 (en) 2010-11-08 2019-07-09 Paion Uk Ltd. Dosing regimen for sedation with CNS 7056 (Remimazolam)
US12201637B2 (en) 2010-11-08 2025-01-21 Paion Uk Ltd. Dosing regimen for sedation with CNS 7056 (Remimazolam)
WO2013174883A1 (fr) 2012-05-22 2013-11-28 Paion Uk Limited Compositions comprenant des benzodiazépines à action rapide
US10414749B2 (en) 2013-03-04 2019-09-17 Paion Uk Limited Process for preparing 3-[(S)-7-bromo-2-((2-oxopropyl)amino)-5-pyridin-2-yl-3H-1,4-benzodiazepin-3-yl]propionic acid methyl ester
US10844070B2 (en) 2014-06-26 2020-11-24 The Johns Hopkins University Peripherally restricted GABA positive allosteric modulators for the treatment of irritable bowel syndrome and other ailments of the peripheral nervous system
US11136322B2 (en) 2014-06-26 2021-10-05 The Johns Hopkins University Peripherally restricted GABA positive allosteric modulators for the treatment of irritable bowel syndrome and other ailments of the peripheral nervous system
EP4556068A2 (fr) 2016-04-14 2025-05-21 Paion UK Limited Benzodiazépines à usage nasal et inhalées par voie orale
WO2017178663A1 (fr) 2016-04-14 2017-10-19 Paion Uk Limited Benzodiazépines à usage nasal et inhalées par voie orale
WO2020259602A1 (fr) * 2019-06-28 2020-12-30 四川大学华西医院 Composé de benzodiazépine, son procédé de préparation et son utilisation en médecine
JP2022539126A (ja) * 2019-06-28 2022-09-07 ウェストチャイナホスピタル、スーチョワンユニバーシティ ベンゾジアゼピン系化合物及びその製造方法並びに医薬における作用
CN112142746A (zh) * 2019-06-28 2020-12-29 四川大学华西医院 苯二氮卓类化合物及其制备方法和在医药上的作用

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Publication number Publication date
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