DK141699B - Aminoacetylaminobenzophenone compounds for use as intermediates in the preparation of therapeutically active 5-phenyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-one compounds. - Google Patents

Description

(11) FREMLÆGGELSESSKRIFT 1^1699 DANMARK (51) lnt C|3 c 07 c 103/50 §(21) Ansøgning nr. 5752/72 (22) Indleveret den 17· HOV. 1972 (23) Løbedag 26. HOV. 1968 (44) Ansøgningen fremlagt og « fremlæggelsesskriftet offentliggjort den 27· maj 1 980(11) SUBMISSION WRITTEN 1 ^ 1699 DENMARK (51) lnt C | 3 c 07 c 103/50 § (21) Application No. 5752/72 (22) Filed on 17 · HOV. 1972 (23) Race day 26. HOV. 1968 (44) The application submitted and 'the petition published on 27 · May 1 980

DIREKTORATET FORDIRECTORATE OF

PATENT-OG VAREMÆRKEVÆSENET <3°) Prioritet begæret fra denPATENT AND TRADE MARKET <3 °) Priority requested from it

27- nov. 1967, 42/76005, JPNov 27-Nov. 1967, 42/76005, JP

27- nov. 1967, 42/76007, JPNov 27-Nov. 1967, 42/76007, JP

27. nov. 1967, 42/76008, JPNov 27 1967, 42/76008, JP

1. jul. 1968, 43/45722, JPJuly 1st. 1968, 43/45722, JP

31. aug. 1968, 43/62699, JPAug 31 1968, 43/62699, JP

31. aug. 1968, 43/627ΟΟ, JPAug 31 1968, 43 / 627ΟΟ, JP

18. okt. 1968, 43/76012, JPOct 18 1968, 43/76012, JP

18. okt. 1968, 43/76013, JPOct 18 1968, 43/76013, JP

24. okt. 1968, 43/77498, JPOct 24 1968, 43/77498, JP

24. okt. 1968, 43/77499* JPOct 24 1968, 43/77499 * JP

29. okt. 1968, 43/78768, JPOct 29 1968, 43/78768, JP

(71) SANKYO COMPANY LIMITED, 1 -6, 3-chome, Nihoribashi Hon-cho, Chyou-ku,(71) SANKYO COMPANY LIMITED, 1-6, 3-chome, Nihoribashi Hon-cho, Chyou-ku,

Tokyo, JP.Tokyo, JP.

(72) Opfinder: Ryuji Tachikawa, c/o Shinagawa Factory, Sankyo Company Li= mited, 58-2, 1-cEome, Hlro-tnachi, Shinagawa-ku, Tokyo, JP: Hiromu Ta* kagl, c/o Shinagawa Factory, Sankyo Company Limited, 58-2, 1-chome, Hi= ro-machi, Shinagawa-ku, Tokyo, JP: Tetsuo Miyadera, c/o Shinagawa Fac= tory, Sankyo Company Limited, 58-2, 1-chome, Hiro-raachi, Shinagawa-ku, Tokyo, JP: Toshiharu Kamioka, c/o Shinagawa Factory, Sankyo Company Limited, 58-2, 1-chome, Hiro-machi, Shinagawa-ku, Tokyo, JP: Mitsunobu Fukanaga, c/o Shinagawa Factory, Sankyo Company Limited, 58-2, 1-chome, Hiro-machi, Shinagawa-ku, Tokyo, JP: Yoichi Kawano, c/o Shina™ gawa Factory, Sankyo Company Limited, 58-2, 1-chome, Hiro-machi, Shi* nagawa-ku, Tokyo, JP.(72) Inventor: Ryuji Tachikawa, c / o Shinagawa Factory, Sankyo Company Li = mited, 58-2, 1-cEome, Hlro-tnachi, Shinagawa-ku, Tokyo, JP: Hiromu Ta * kagl, c / o Shinagawa Factory , Sankyo Company Limited, 58-2, 1-chome, Hi = ro-machi, Shinagawa-ku, Tokyo, JP: Tetsuo Miyadera, c / o Shinagawa Fac = tory, Sankyo Company Limited, 58-2, 1-chome, Hiro-raachi, Shinagawa-ku, Tokyo, JP: Toshiharu Kamioka, c / o Shinagawa Factory, Sankyo Company Limited, 58-2, 1-chome, Hiro-machi, Shinagawa-ku, Tokyo, JP: Mitsunobu Fukanaga, c / o o Shinagawa Factory, Sankyo Company Limited, 58-2, 1-chome, Hiro-machi, Shinagawa-ku, Tokyo, JP: Yoichi Kawano, c / o Shina ™ gawa Factory, Sankyo Company Limited, 58-2, 1-chome , Hiro-machi, Shi * nagawa-ku, Tokyo, JP.

(74) Fuldmægtig under sagens behandling:(74) Plenipotentiary in the proceedings:

Ingeniørfirmaet Hofman-Bang & Boutard.Hofman-Bang & Boutard Engineering Company.

(54) Aminoacetylaminobenzophenon-forbindelser til anvendelse som mellem* produkt ved fremstilling af terapeutisk aktive 5-phenyl-2,3,4,5“te= trahydro-1H-1,4-benzodiazepin-2-on-forbindelser.(54) Aminoacetylaminobenzophenone compounds for use as an intermediate product in the preparation of therapeutically active 5-phenyl-2,3,4,5 “-tetrahydro-1H-1,4-benzodiazepin-2-one compounds.

Opfindelsen angår hidtil ukendte aminoacetylaminobenzophenon-forbindelser til anvendelse1 som mellemprodukt ved fremstilling af terapeutisk aktive 5-phenyl-2,3»4,5-tetr&hydro-lH-l,4-benzo-diazepin-2-on-forbindelser med den i kravets Indledning angivne formel (I), hvilke aminoacetylaminobenzophenon-forbindelser er ejendommelige ved, at de har den i kravets kendetegnende del angivne formel (II).The invention relates to novel aminoacetylaminobenzophenone compounds for use as an intermediate in the preparation of therapeutically active 5-phenyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-one compounds having the present invention. Formula (I), which aminoacetylaminobenzophenone compounds are characterized in that they have the formula (II) as defined in the characterizing part of the claim.

Forbindelserne med den almene formel I er alle hidtil ukendte forbindelser, som har overraskende høj phychosedativ aktivitet.The compounds of general formula I are all novel compounds which have surprisingly high phychosomatic activity.

2 141699 Nærmere "bestemt udøver de exx "både "beroligende og antidepressiv virkning på centralnervesystemet og frembringer rolighed og afslappelse. Foruden at have sådanne fordelagtige psycholeptiske egenskaber har disse benzodiazepin-forbindelser en yderst lav toxicitet for mennesker og ringe tendens til at frembringe bivirkninger. Således er de nyttige som underordnede beroligelsesmidler til lettelse af forskellige former for psycho-neurotisk depression.Specifically, they exert "exx" both a "calming and antidepressant effect on the central nervous system and produce calm and relaxation. In addition to having such beneficial psycholeptic properties, these benzodiazepine compounds have an extremely low toxicity to humans and little tendency to produce side effects. they are useful as auxiliary tranquilizers for relieving various forms of psycho-neurotic depression.

Mellemproduktet ifølge opfindelsen med formlen (II) kan fremstilles ved, at en forbindelse med den almene formel E4" 0 éXX > m ΈΓ hvori R^·, R? og Έ& har den i kravet angivne betydning, og Q er syreresten af en reaktiv ester, omsattes med en forbindelse med formlen:The intermediate according to the invention of formula (II) can be prepared by a compound of general formula E4 + OXX> m ΈΓ wherein R 2 ·, R 2 and Έ & have the meaning specified in the claim, and Q is the acid residue of a reactive ester , reacted with a compound of the formula:

Η^ϋ - jH - <jH - OH IVΗ ^ ϋ - jH - <jH - OH IV

R Rf hvori R og R' har den i kravet angivne betydning, ved en temperatur under ca. 50°C til dannelse af forbindelsen med formlen (II), eventuelt sammen med en forbindelse med den tidligere angivne formel (I), hvorefter forbindelsen (II) isoleres fra reaktionsblandingen på konventionel måde, f.eks. ved fraktioneret krystallisation eller chromatografi. 1 den angivne formel (III) skal gruppen Q, dvs. "syreresten af en reaktiv ester", omfatte syreresten af sådanne estere som hydro-genhalogenidsyreestere, sulfonsyreestere og phosphorsyreestere. Repræsentative for sådanne syrerester er chlor, brom, iod, en p-toluensulfonyloxygruppe, en methansulfonyloxygruppe og en diphenyl-pho sphorylgrupp e.R Rf wherein R and R 'are as defined in the claim, at a temperature below ca. 50 ° C to form the compound of formula (II), optionally together with a compound of the above-mentioned formula (I), after which the compound (II) is isolated from the reaction mixture in a conventional manner, e.g. by fractional crystallization or chromatography. In the formula (III) indicated, the group Q, i.e. "acid residue of a reactive ester" includes the acid residue of such esters as hydrogen halide acid esters, sulfonic acid esters and phosphoric acid esters. Representative of such acid residues are chlorine, bromine, iodine, a p-toluenesulfonyloxy group, a methanesulfonyloxy group and a diphenylpho sphoryl group e.

3 1416993 141699

Reaktionen kan fortrinsvis udføres i nærvær af et syrebindende middel under anvendelse af et inert organisk opløsningsmiddel som reaktionsopløsningsmiddel.The reaction may preferably be carried out in the presence of an acid-binding agent using an inert organic solvent as the reaction solvent.

Som reaktionsopløsningsmiddel kan tilfredsstillende anvendes ethvert organisk opløsningsmiddel, som ikke vil have en skadelig virkning på reaktionen. Som repræsentative eksempler på disse inerte organiske opløsningsmidler kan nævnes lavere alkanoler, såsom methanol, ethanol, propanol, isopropanol eller butanol, dialkylketoner, såsom acetone, methylethylketon eller diethyl-keton, cycliske ethere, såsom tetrahydrofuran eller dioxan, ha-logenerede carbonhydrider, såsom chloroform eller dichlorethan, alifatiske carboxylsyreestere, såsom ethylacetat, acetonitril, dialkylformamider, såsom dimethylformamid eller diethylformamid.As the reaction solvent can be used satisfactorily any organic solvent which will not have a detrimental effect on the reaction. Representative examples of these inert organic solvents include lower alkanols such as methanol, ethanol, propanol, isopropanol or butanol, dialkyl ketones such as acetone, methyl ethyl ketone or diethyl ketone, cyclic ethers such as tetrahydrofuran or dioxane, halogenated hydrocarbons such as chloroform. or dichloroethane, aliphatic carboxylic acid esters such as ethyl acetate, acetonitrile, dialkylformamides such as dimethylformamide or diethylformamide.

Af disse foretrækkes lavere alkanoler og cycliske ethere.Of these, lower alkanols and cyclic ethers are preferred.

Reaktionen kan som nævnt ovenfor fortrinsvis udføres i nærvær af et syrebindende middel. Da aminderivatet med den angivne formel (IV) også kan virke som et syrebindende middel, er det ikke absolut nødvendigt yderligere at indføre et andet syrebindende middel i reaktionssystemet. Når aminderivatet anvendes med det formål både at virke som reagens og som syrebindende middel, er det ikke kritisk, men praktisk ønskeligt at anvende aminderivatet i et overskud på et ækvivalent eller mere. Når der anvendes et andet syrebindende middel i reaktionen, kan som repræsentative eksempler på sådanne syrebindende midler nævnes organiske og uorganiske baser, hvor den organiske base f.eks. kan være en tertiær amin, såsom trimethylamin, triethylamin, tributylamin, N-methylmorpholin, N-methylpiperidin, N,Ν’-dimethylpiperazin eller dimethylahilin, eller en umættet heterocyclisk base, såsom pyridin, picolin eller quinolin, og den uorganiske base f.eks. kan være en basisk alkalimetalforbindelse, såsom et alkalimetalhydroxid, f.eks. natriumhydroxid, lithiumhydroxid eller kaliumhydroxid, et alkalimetalcar-bonat eller -hydrogencarbonat, f.eks. natriumcarbonat, kalium-carbonat, natriumhydrogencarbonat eller kaliumhydrogencarbonat eller et alkalimetalsalt af en svag carboxylsyre, f.eks. natriumacetat eller kaliumacetat. Alkalimetalsaltene af svage carboxylsyrer foretrækkes ved fremgangsmåden.As mentioned above, the reaction can preferably be carried out in the presence of an acid binding agent. Since the amine derivative of the indicated formula (IV) can also act as an acid binding agent, it is not absolutely necessary to further introduce another acid binding agent into the reaction system. When the amine derivative is used for the purpose of acting both as a reagent and as an acid-binding agent, it is not critical but practically desirable to use the amine derivative in excess of one equivalent or more. When another acid-binding agent is used in the reaction, as representative examples of such acid-binding agents may be mentioned organic and inorganic bases, where the organic base e.g. may be a tertiary amine such as trimethylamine, triethylamine, tributylamine, N-methylmorpholine, N-methylpiperidine, N, Ν'-dimethylpiperazine or dimethylahiline, or an unsaturated heterocyclic base such as pyridine, picoline or quinoline, and the inorganic base e.g. . may be a basic alkali metal compound such as an alkali metal hydroxide, e.g. sodium hydroxide, lithium hydroxide or potassium hydroxide, an alkali metal carbonate or bicarbonate, e.g. sodium carbonate, potassium carbonate, sodium bicarbonate or potassium hydrogen carbonate or an alkali metal salt of a weak carboxylic acid, e.g. sodium acetate or potassium acetate. The alkali metal salts of weak carboxylic acids are preferred by the process.

Reaktionen skal udføres ved en relativt lav temperatur, f.eks. under ca. 50°C, og fortrinsvis i en kort reaktionstid for at op- . 141699 4 nå et bedre udbytte af benzophenon-mellemproduktet (II). Reaktionstiden er ikke kritisk og kan varieres afhængigt af arten og typen af udgangsmaterialet og det anvendte reaktionsopløsningsmiddel og af den anvendte reaktionstemperatur, men det foretrækkes at gennemføre reaktionen i et tidsrum fra ca. 10 minutter til ca.The reaction should be carried out at a relatively low temperature, e.g. below approx. 50 ° C, and preferably for a short reaction time to warm up. Achieve a better yield of the benzophenone intermediate (II). The reaction time is not critical and can be varied depending on the nature and type of the starting material and the reaction solvent used and the reaction temperature used, but it is preferred to carry out the reaction for a period of approx. 10 minutes to approx.

20 timer. Efter fuldførelse af reaktionen kan reaktionsproduktet udvindes fra reaktionsblandingen på konventionel måde. F.eks. kan reaktionsproduktet let udvindes og renses ved fjernelse af opløsningsmidlet ved destillation, ekstraktion af remanensen med et egnet opløsningsmiddel, fjernelse af ekstraktionsopløsningsmidlet ved destillation og omkrystallisation eller chromatografi af remanensen.20 hours. Upon completion of the reaction, the reaction product can be recovered from the reaction mixture in a conventional manner. Eg. For example, the reaction product can be easily recovered and purified by removal of the solvent by distillation, extraction of the residue with a suitable solvent, removal of the extraction solvent by distillation and recrystallization or chromatography of the residue.

Benzophenon-mellemproduktet ifølge opfindelsen med formlen (II) omdannes til den terapeutisk aktive benzodiazepin-forbindelse ved dehydratisering under ringslutning. Denne reaktion kan udføres ved at underkaste · mellemproduktet (II) en thermisk behandling (herunder opvarmning til en forhøjet temperatur, fortrinsvis over ca. 50°C, f.eks. tilbagesvalingstemperaturen for det anvendte opløsningsmiddel, i forholdsvis kort tid, eller holden ved omgivelsernes temperatur, f.eks. stuetemperatur, i forholdsvis lang tid), fortrinsvis i nærvær af en katalytisk mængde af en syre. Reaktionen kan udføres tilfredsstillende i nærvær eller fravær af et inert organisk opløsningsmiddel. Som inert organisk opløsningsmiddel kan nævnes ethvert af de, som er anført ovenfor under fremstillingen af mellemproduktet (II). Repræsentative eksempler på de syrer, der kan anvendes som katalysatorer i dette trin, er mineralsyrer, f.eks. saltsyre, hydrogenbromidsyre, svovlsyre og phosphorsyre, organiske syrer, f.eks. eddikesyre, propionsyre, citronsyre og vinsyre, Lewis-syrer, f.eks. bortrifluorid, idet eddikesyre er den mest foretrukne. Reaktionstiden kan varieres over et bredt område, afhængigt af varmebehandlingen og arten og typen af udgangsmaterialet og det eventuelt anvendte reaktionsopløsningsmiddel. Sædvanligvis, hvor der anvendes opvarmning, er reaktionstiden fra ca. 5 til ca. 30 timer, og hvor der anvendes en relativt lavere temperatur, f.eks. stuetemperatur, er reaktionstiden over ca. 20 timer, fortrinsvis fra ca. 100 til ca. 200 timer. Efter fuldførelse af reaktionen kan reaktionsproduktet, b'enzodiazepin-forbindelsen (i), let udvindes fra reaktionsblandingen. F.eks. kan reaktionsproduktet udvindes og renses ved fjernelse af opløsningsmidlet ved destillation og efterfølgende omkrystallisation af remanensen fra et egnet opløsningsmiddel.The benzophenone intermediate of the invention of formula (II) is converted to the therapeutically active benzodiazepine compound by dehydration during cyclization. This reaction can be carried out by subjecting the intermediate (II) to a thermal treatment (including heating to an elevated temperature, preferably above about 50 ° C, for example the reflux temperature of the solvent used, for a relatively short time, or held at ambient temperature). temperature, e.g., room temperature, for a relatively long time), preferably in the presence of a catalytic amount of an acid. The reaction can be carried out satisfactorily in the presence or absence of an inert organic solvent. As inert organic solvent can be mentioned any of those listed above during the preparation of the intermediate (II). Representative examples of the acids which can be used as catalysts in this step are mineral acids, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, organic acids, e.g. acetic acid, propionic acid, citric acid and tartaric acid; Lewis acids, e.g. boron trifluoride, with acetic acid being the most preferred. The reaction time can be varied over a wide range, depending on the heat treatment and the nature and type of the starting material and optionally used reaction solvent. Usually, when heating is used, the reaction time is from ca. 5 to approx. 30 hours and where a relatively lower temperature is used, e.g. room reaction time, the reaction time is over approx. 20 hours, preferably from approx. 100 to approx. 200 hours. Upon completion of the reaction, the reaction product, the b'enzodiazepine compound (i), can be readily recovered from the reaction mixture. Eg. For example, the reaction product can be recovered and purified by removal of the solvent by distillation and subsequent recrystallization of the residue from a suitable solvent.

141699 5141699 5

Fremstillingen af mellemprodukterne ifølge opfindelsen med den almene formel (II) og omdannelsen af disse til de terapeutisk aktive benzodiazepin-forbindelser med den almene formel (i) 13 4 kan illustreres ved det følgende reaktionsskema, hvori R , R , R , R og R1 har den i kravet angivne betydning, og Q har den ovenstående betydning. Ved reaktionen mellem benzophenon-udgangs-forbindelsen (III) og aminoderivatet (IV) kan mellemproduktet (II) under visse reaktionsbetingelser, issar ved temperaturer på omkring 50° C eller højere og i nærvær af en katalytisk mængde af syre, omdannes til benzodiazepinforbindelsen (I) in situ.The preparation of the intermediates of the invention of general formula (II) and their conversion to the therapeutically active benzodiazepine compounds of general formula (i) 134 can be illustrated by the following reaction scheme wherein R, R, R, R and R the meaning specified in the claim and Q has the above meaning. In the reaction between the benzophenone starting compound (III) and the amino derivative (IV), the intermediate (II) under certain reaction conditions, at temperatures of about 50 ° C or higher and in the presence of a catalytic amount of acid, can be converted to the benzodiazepine compound (I). ) in situ.

,->CC"T-> CC "T

* - CO Q <iu) ' <x R4 * · C0~-CH2 R / C0 NH-CH-CH-OH i11) OC, 1 i R4 ^* - CO Q <iu) '<x R4 * · C0 ~ -CH2 R / C0 NH-CH-CH-OH i11) OC, 1 in R4 ^

~ N - CO~ N - CO

rr ^ch2rr ^ ch2

0/ I ^ CH - R0/1 ^ CH - R

R R* 6 141S9 9R R * 6 141S9 9

De følgende eksempler tjener til at belyse opfindelsen.The following examples serve to illustrate the invention.

Eksempel 1-6 belyser fremstillingen af benzophenon-mellem-produkterne (II) ud fra benzophenon-forbindelserne (III).Examples 1-6 illustrate the preparation of the benzophenone intermediates (II) from the benzophenone compounds (III).

Eksempel 7-10 belyser fremstillingen af benzodiazepin-forbin-delserne (I) ud fra benzophenon-mellemprodukterne (II).Examples 7-10 illustrate the preparation of the benzodiazepine compounds (I) from the benzophenone intermediates (II).

EKSEMPEL 1 5-Chlor-2- (2-hvdroxyethylamino) -ac etvlaminob en2ophenonEXAMPLE 1 5-Chloro-2- (2-hydroxyethylamino) -acetylaminobenophenone

En blanding af 3,5 g 5-chlor-2-chloracetylaminobenzophenon, 0,7 g 2-aminoethanol, 1,4 g triethylamin og 60 ml tetrahydrofuran blev omrørt ved .stuetemperatur i 5 timer. Efter fuldførelse af reaktionen blev opløsningsmidlet af de stilleret under formindsket tryk, og remanensen blev ekstraheret med dichlormethan. Ekstrakten blev vasket med vand, tørret over vandfrit natriumsulfat, og npi gianing.gmn ril at derpå af de stilleret. Remanensen blev omkrystal— liseret fra ethanol, hvorved der blev opnået 3,15 g af det ønskede produkt, som smeltede ved 121-122°C.A mixture of 3.5 g of 5-chloro-2-chloroacetylaminobenzophenone, 0.7 g of 2-aminoethanol, 1.4 g of triethylamine and 60 ml of tetrahydrofuran was stirred at room temperature for 5 hours. Upon completion of the reaction, the solvent of them was quenched under reduced pressure and the residue was extracted with dichloromethane. The extract was washed with water, dried over anhydrous sodium sulfate, and then dried by stirring. The residue was recrystallized from ethanol to give 3.15 g of the desired product, melting at 121-122 ° C.

EKSEMPEL 2 5-Chlor-2-(2-hvdroxy- n-oronvlamino)-acetvlam.inobenzo'PhenonEXAMPLE 2 5-Chloro-2- (2-hydroxy-n-oronylamino) -acetylaminobenzo'Phenone

En blanding.af 6,0 g 5-chlor-2-chloracetylaminobenzophenon, 1,6 g isopropanolamin, 2,5 g natriumacetat og 120 ml ethanol blev omrørt ved stuetemperatur i 14 timer. Efter fuldførelse af reaktionen blev reaktionsblandingen behandlet på samme måde soin i eksempel 1 med undtagelse af, at der blev omkrystalliseret fra ether, hvorved der blev opnået 6,2 g af det ønskede produkt, som smeltede ved 92-94°C.A mixture of 6.0 g of 5-chloro-2-chloroacetylaminobenzophenone, 1.6 g of isopropanolamine, 2.5 g of sodium acetate and 120 ml of ethanol was stirred at room temperature for 14 hours. After completion of the reaction, the reaction mixture was treated in the same manner as in Example 1 except that it was recrystallized from ether to give 6.2 g of the desired product, which melted at 92-94 ° C.

7 U18S9 EKSEMPEL 3 5-Eitro-2-( 2-hvdro^-'J>LProT3vlgmino)-acetvlnminobenzophenpn ·EXAMPLE 3 5-Eitro-2- (2-hydroxy-1H-LProT3-ylmino) -acetylminobenzophenyl

En blanding af 7,3 g 5-nitro-2-bromacetylaminobenzophenon, 1,6 g isopropanolamin, 2,4 g triethylamin og 80 ml dioxan blev omrørt ved stuetemperatur i 5 timer. Efter fuldførelse af reaktionen blev reaktionsblandingen behandlet på samme måde som i eksempel 1 med undtagelse af, at der blev omkrystalliseret fra ether, hvorved der blev opnået 6,2 g af det ønskede produkt,'som smeltede ved 106 -108,5° C.A mixture of 7.3 g of 5-nitro-2-bromoacetylaminobenzophenone, 1.6 g of isopropanolamine, 2.4 g of triethylamine and 80 ml of dioxane was stirred at room temperature for 5 hours. Upon completion of the reaction, the reaction mixture was treated in the same manner as in Example 1 except that it was recrystallized from ether to give 6.2 g of the desired product, which melted at 106 -108.5 ° C.

EKSEMPEL· 4 5-Brom-2-(2-hydroxy-n-propylamino)-acetylaminobenzophenonEXAMPLE 4 5-Bromo-2- (2-hydroxy-n-propylamino) -acetylaminobenzophenone

En blanding af 7,9 g 5-brom-2-bromacetylaminobenzophenon, 3,3 g isopropanolamin og 100 ml dichlormethan blev omrørt ved stue- -temperatur i 2 timer. Efter fuldførelse af reaktionen blev reaktionsblandingen vasket med vand,, tørret over vandfrit natriumsulfat, og opløsningsmidlet derpå afdestilleret. Remanensen blev omkrystalliseret fra ethanel, hvorved der blev opnået 6,5 g af det ønskede produkt, som smeltede ved 93 - 96° C.A mixture of 7.9 g of 5-bromo-2-bromoacetylaminobenzophenone, 3.3 g of isopropanolamine and 100 ml of dichloromethane was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was washed with water, dried over anhydrous sodium sulfate and the solvent was then distilled off. The residue was recrystallized from ethanel to give 6.5 g of the desired product, which melted at 93 - 96 ° C.

På i det vesentlige samme måde som anført ovenfor blev der opnået følgende benzophenon-derivater: 5-chlor-2-( 2-hydroxy-n-propylamino) -acetylamino-o-chlorbenzophenon (smp. 108 - 110° C, dekomp.)j 5-chlor-2-(2-hydroxyethylamino)-acetylamino-o-chlorbenzophenon (smp. 107 - 109° C, dekomp.)* 5-nitro-2-(2-hydroxy-n-propylamino)-acetylamino-o-chlorbenzophenon (smp. 125 - 127° C)j 5-nitro-2-( 2-hydroxye thylamino) -acetylamino-o-chlorbenzophenon (smp. 129 - 132° C); 141699 8 5-brom-2-( 2-hydroxyethylamino)-acetylamino-o-chlorbenzophenon (smp. 125 - 127° C); 5-brom-2-( 2-hydroxy—n-propylamino) -acetylamino-o-chlorbenzophenon (smp. 93 - 96° 0); 5-chlor-2- (2-hydroxy-1-methylethylamino) -acetylamino-o-chlor-benzophenon (smp. 116 - 119° C under dekomponering); og 5-chlor-2-(2-hydroxy-l-methyl-n-propylamino)-acetylaminobenzo-phenon (smp, 92 - 94° C).In substantially the same manner as stated above, the following benzophenone derivatives were obtained: 5-chloro-2- (2-hydroxy-n-propylamino) -acetylamino-o-chlorobenzophenone (mp 108 - 110 ° C, decomp.) 5-Chloro-2- (2-hydroxyethylamino) -acetylamino-o-chlorobenzophenone (m.p. 107 - 109 ° C, decomp.) * 5-nitro-2- (2-hydroxy-n-propylamino) -acetylamino-o -chlorobenzophenone (m.p. 125 - 127 ° C); 5-nitro-2- (2-hydroxy-thylamino) -acetylamino-o-chlorobenzophenone (m.p. 129-132 ° C); 5-bromo-2- (2-hydroxyethylamino) -acetylamino-o-chlorobenzophenone (mp 125 - 127 ° C); 5-bromo-2- (2-hydroxy-n-propylamino) -acetylamino-o-chlorobenzophenone (mp 93-96 °); 5-chloro-2- (2-hydroxy-1-methylethylamino) -acetylamino-o-chloro-benzophenone (mp 116 - 119 ° C during decomposition); and 5-chloro-2- (2-hydroxy-1-methyl-n-propylamino) -acetylaminobenzo-phenone (m.p. 92 - 94 ° C).

EKSEMPEL_5 5-0hlor-2-( 2-hydroxyethylamino) - ac etylaminobehzophenonEXAMPLE 5 5-Chloro-2- (2-hydroxyethylamino) - ac ethylaminobehzophenone

En blanding af 8,9 g 5-chlor-2-tosyloxyacetylaminobenzophenon, 2,7 g 2-aminoethanol og 100 ml tetrahydrofuran blev omrørt ved ca, 40° C i 12 timer. Efter fuldførelse af reaktionen blev opløsningsmidlet afdestilleret, og remanensen derpå ekstraheret med dichlormethan. Ekstrakten blev vasket med vand, tørret over vandfrit natriumsulfat, og opløsningsmidlet derpå afdestilleret. Remanensen blev .omkrystalliseret fra ethanol, hvorved man opnåede det ønskede produkt, som smeltede ved 121 - 122,5°.C.A mixture of 8.9 g of 5-chloro-2-tosyloxyacetylaminobenzophenone, 2.7 g of 2-aminoethanol and 100 ml of tetrahydrofuran was stirred at about 40 ° C for 12 hours. After completion of the reaction, the solvent was distilled off and the residue then extracted with dichloromethane. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was then distilled off. The residue was recrystallized from ethanol to give the desired product, which melted at 121 - 122.5 ° C.

EKSEMPEL 5 5-Chlor-2-(2-hydroxy-n-Oropylamino)-acetylaminobenzophenonEXAMPLE 5 5-Chloro-2- (2-hydroxy-n-Oropylamino) -acetylaminobenzophenone

En blanding af 6,6 g 5-chlor-2-tosyloxyacetylaminobenzophenon, 2,5 g isopropanolamin og 100 ml tetrahydrofuran blev omrørt ved 40° C i 16 timer. Efter fuldførelse af reaktionen blev reaktionsblandingen behandlet på samme måde som i eksempel 29, hvorved der blev opnået 4,6 g af det ønskede produkt, som smeltede ved 92,5 - 94° G.A mixture of 6.6 g of 5-chloro-2-tosyloxyacetylaminobenzophenone, 2.5 g of isopropanolamine and 100 ml of tetrahydrofuran was stirred at 40 ° C for 16 hours. After completion of the reaction, the reaction mixture was treated in the same manner as in Example 29 to give 4.6 g of the desired product, which melted at 92.5 - 94 ° G.

Ted i det væsentlige samme procedure som beskrevet ovenfor blev der fremstillet følgende benzophenon—derivaters 5-nitro-2-(2-hydroxy-n-propylamino)-acetylaminobenzophenon (smp, 106 - 108° C); 5-brom-2-(2-hydroxy-n-propylamino)-acetylaminobenzophenon (smp, 93 - 95,5° C); 9 141699 5-brom-2-(2-hydroxyethylamino) -acetylaminobenzophenon (smp. 140 -- 142° C); 5-n±tro-2-(2-hydroxyethylamino)-acetylaminobenzophenon (Bmp.^135,5 -137° C) | 5-chlor-2-( 2 -hy d r oxy-n-pr opyl amino) - ac e tyIne thy 1 aminob e nz o phenon (bleggul olie, analyse beregnet for C 63»50> H 5,87, N 7,77, Cl 10,17 fundets - C 63,17, H 5,71, N 7,83, Cl 10,06); 5-chlor-2-( 2-hydr oxy-n-pr opyl amino) -ace tylamino-o-chlorbenzophenon (smp. 107,5 - 110° C, dekomp.); 5-chlor-2-( 2-hydroxyethylamino) -acetylamino-o-chlorbenzophenon (smp. 107 - 109° C, dekomp.); 5-brom-2-( 2-hydroxyethylamino) -aeetylamino-o-chlorbenzophenon (emp. 125 -127,5° C)5 og 5-brom—2-( 2-hydrory-n-propylamino)-acetylamino-o—chlorbenzophenon (smp. 92 - 96° C).In substantially the same procedure as described above, the following benzophenone derivatives of 5-nitro-2- (2-hydroxy-n-propylamino) -acetylaminobenzophenone (mp, 106 - 108 ° C) were prepared; 5-bromo-2- (2-hydroxy-n-propylamino) -acetylaminobenzophenone (m.p. 93 - 95.5 ° C); 5-bromo-2- (2-hydroxyethylamino) -acetylaminobenzophenone (mp 140-142 ° C); 5-n ± tro-2- (2-hydroxyethylamino) -acetylaminobenzophenone (mp 135.5 -137 ° C) | 5-Chloro-2- (2-hydroxy-n-pr opyl amino) - ac e thylene thi 1 aminob e nz o phenone (pale yellow oil, analysis calculated for C 63 50> H 5.87, N 7). 77, Cl 10.17 found - C 63.17, H 5.71, N 7.83, Cl 10.06); 5-chloro-2- (2-hydroxy-n-pr opyl amino) -acetylamino-o-chlorobenzophenone (mp 107.5 - 110 ° C, decomp); 5-chloro-2- (2-hydroxyethylamino) -acetylamino-o-chlorobenzophenone (m.p. 107 - 109 ° C, decomp.); 5-bromo-2- (2-hydroxyethylamino) -ethylamino-o-chlorobenzophenone (emp. 125 -127.5 ° C) 5 and 5-bromo-2- (2-hydrory-n-propylamino) -acetylamino-o- chlorobenzophenone (mp 92-96 ° C).

EKSEMPEL 7 7-Chlor-5-phenyl-tetrahydrooxazol[5,4-b]-2,3,4,5-tetrahydro-1H-1,4- benzodiazepin-2-on fil en opløsning af 10 g 5-chlor-2-( 2-hydroxyethylamino) -acetyl-aainobenzophenon i Θ0 ml xylen sattes 2 dråber eddikesyre, fien resulterende blanding blev opvarmet under tilbagesvaling i 12 timer. Efter fuldførelse af reaktionen blev opløsningsmidlet afdestilleret fra reaktionsblandingen, og remanensen derpå omkrystal-liseret fra methanol, hvorved der blev opnået 5,6 g af det ønskede produkt, som smeltede ved 175 - 176° C.Example 7 7-Chloro-5-phenyl-tetrahydrooxazole [5,4-b] -2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-one Fil A solution of 10 g of 5-chloro 2- (2-hydroxyethylamino) -acetyl-aainobenzophenone in ml0 ml of xylene was added 2 drops of acetic acid, the resulting mixture was heated under reflux for 12 hours. After completion of the reaction, the solvent was distilled off from the reaction mixture and the residue was then recrystallized from methanol to give 5.6 g of the desired product, which melted at 175 - 176 ° C.

EKSEMPEL 8 7-Chlor-5-phenyl-5’-methyltetrahydrooxazol[5,4-b]-2,3,4,5-tetra-hydro-1H-1,4-benzodiazepin-2-onExample 8 7-Chloro-5-phenyl-5'-methyltetrahydrooxazole [5,4-b] -2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-one

Til en opløsning af 10 g 5-chlor-2-(2-hydroxy-n-propylamino)-acetylaminobenzophenon i 100 ml ethanol sattes nogle dråber eddi- 10 141699 kesyre. Ben resulterende blanding blev opvarmet under tilbagesva-•ling i 16 timer. Efter fuldførelse af reaktionen blev reaktionsblandingen koncentreret til et lille rumfang, hvorved der udskiltes et krystallinsk stof, som derpå blev udvundet ved filtrering, hvorved der blev opnået 7,5 g af det ønskede produkt, som smelteue ved 186 - 188,5° C.To a solution of 10 g of 5-chloro-2- (2-hydroxy-n-propylamino) -acetylaminobenzophenone in 100 ml of ethanol was added a few drops of acetic acid. Bone resulting mixture was heated at reflux for 16 hours. Upon completion of the reaction, the reaction mixture was concentrated to a small volume to separate a crystalline substance which was then recovered by filtration to give 7.5 g of the desired product as a melting pot at 186 - 188.5 ° C.

Ted i det væsentlige samme procedure som beskrevet ovenfor blev der fremstillet følgende benzodiazepin-derivater; 7-nitro-5-phenyl-5'-methyltetrahydrooxazolf 5,4-b]-2,3,4,5-tetra-hydro-1H-1,4-benzodiazepin-2-on (smp. 209° G); 7-brom-5-phenyl-5 *-methyltetrahydrooxazol[5,4-b]-2,3,4,5-tetra-hydro-1H-1,4-benzodiazepin-2-on (smp. 180° C)j 7-brom-5-phenyi-tetrahydrooxazol[5»4-b-2,3,4j5-tetrahydro-lH-1,4-benzodiazepin-2-on (smp. 190 - 191° C)j 7-rdtro-5-phenyl-tetrahydrooxazol[5,4-b]-2,5,4,5-tetrahydro-1H- 1,4-benzodiazepin-2-on (smp. 218 - 220° C); 7-chlor-5-(2-chiorphenyl)-5L-methyltetrahydrooxazol[5,4-&J-z»i»4»5-tetrahydro-1H-1,4-benzodiazepin-2-on (smp. 192° C, dekomp.); 7-chlor-5-(2-chlorphenyl)-tetrahydrooxazol[5,4-b ]-2,3»4,5-tetra-hyclro-lH-1,4-benzodiazepin-2-on (smp. 204° C, dekomp.); 7-nitro-5-(2-chlorphenyl)-tetrahydrooxazol[5,4-b]-2,3,4,5-tetra-hydro-1H-1,4-benzodiazepin-2-on (smp. 230 - 235° C» dekomp.); og 7-nitro-5-(2-chlorphenyl)-5 *-methyltetrahydrooxazol[5»4-b]-2,3,4,5-tetrahydro-1H-l,4-benzodiazepin-2-on (smp. 223 - 226° C, dekomp.).In substantially the same procedure as described above, the following benzodiazepine derivatives were prepared; 7-nitro-5-phenyl-5'-methyltetrahydrooxazole 5,4-b] -2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-one (mp 209 ° G); 7-Bromo-5-phenyl-5 * -methyltetrahydrooxazole [5,4-b] -2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-one (mp 180 ° C) 7-Bromo-5-phenyl-tetrahydrooxazole [5,4-b-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-one (m.p. 190 - 191 ° C) 5-phenyl-tetrahydrooxazole [5,4-b] -2,5,4,5-tetrahydro-1H-1,4-benzodiazepin-2-one (mp 218 - 220 ° C); 7-Chloro-5- (2-chlorophenyl) -5L-methyltetrahydrooxazole [5,4- &lt; 2 &gt; 4 &gt; 5-tetrahydro-1H-1,4-benzodiazepin-2-one (mp 192 ° C, dec.); 7-Chloro-5- (2-chlorophenyl) -tetrahydrooxazole [5,4-b] -2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-one (mp 204 ° C , decomp.); 7-Nitro-5- (2-chlorophenyl) -tetrahydrooxazole [5,4-b] -2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-one (mp 230-2335 ° C decomp.); and 7-nitro-5- (2-chlorophenyl) -5 * -methyltetrahydrooxazole [5,4-b] -2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-one (mp 223) - 226 ° C, decomp.).

EKSEMPEL. 9.EXAMPLE. 9th

7-Chlor-5-phenyl-tetrahydrooxazol[5,4-b]-2,3,4,5-tetrahydro-lH- 1,4-benzodiazepin-2-on7-Chloro-5-phenyl-tetrahydrooxazole [5,4-b] -2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-one

Til en opløsning af 10 g 5-chlor-2-(2-hydrcxyethylamino)-acetyl-aminobenzophenon i 80 ml xylen sattes 2 dråber eddikesyre. Een resulterende blanding blev omrørt ved stuetemperatur i 100 timer. Efter fuldførelse af reaktionen blev opløsningsmidlet afdestille- n 141699 ret under formindsket tryk, og remanensen blev omkrystalliseret fra methanol, hvorved man opnåede det ønskede produkt, som smeltede ved 175 - 176° C.To a solution of 10 g of 5-chloro-2- (2-hydroxyethylamino) -acetyl-aminobenzophenone in 80 ml of xylene was added 2 drops of acetic acid. One resulting mixture was stirred at room temperature for 100 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was recrystallized from methanol to give the desired product, which melted at 175 - 176 ° C.

EKSEMPEL 10 7-Chlor-5-phenyl-5 ’ -methyltetrahydrooxazol[5,4-b]-2,3,4,5-tetra-hydro-1H-1,4-benzodiazeOin-2-on lil en opløsning af 10 g 5-chlor-2-(2-hydroxy-n-propylamino)-aoetylaminobenzophenon i 1CO mi ethanol sattes nogle dråber eddikesyre* Den resulterende blanding blev omrørt ved stuetemperatur i 160 timer. Efter fuldførelse af reaktionen blev reaktionsblandingen koncentreret til et lille rumfang, og koncentratet fik lov at henstå ved omgivelsernes temperatur, hvorved der udskiltes et krystallinsk stof, som derpå blev udvundet, ved filtrering, hvorved an opnåede det ønskede produkt, som smeltede ved 186 - 188,5° C.Example 10 7-Chloro-5-phenyl-5'-methyltetrahydrooxazole [5,4-b] -2,3,4,5-tetrahydro-1H-1,4-benzodiazole-2-one solution g of 5-chloro-2- (2-hydroxy-n-propylamino) -aoethylaminobenzophenone in 1CO in ethanol was added a few drops of acetic acid * The resulting mixture was stirred at room temperature for 160 hours. After completion of the reaction, the reaction mixture was concentrated to a small volume and the concentrate was allowed to stand at ambient temperature, which separated a crystalline substance which was then recovered by filtration to give the desired product, which melted at 186 - 188 , 5 ° C.

Ted i det væsentlige samme procedure sene beskrevet ovenfor blev der opnået følgende benzodiazepin-derivatert 7-nitro-5-phenyl-51-methyltetrahydrooxazol[5,4-b]-2,3,4,5-tetra-hydro-lH-1,4-benzodiazepin-2-on (smp. 209° C); 5-brom-5~phenyl-5 *-methyltetrahydrooxazol[5,4--b]-2,3,4,5-tetra-hydro-lH-1,4-benzodiazepin-2-on (sep. 180 - 183,5° C) i 7-brom-5-phenyl-te trahydrooxazol[ 5,4~b ]-2,3,4,5-te trahydro-1H-1,4-benzodiazepin-2-on (smp. 190 - 191,5° C)f 7-ni tr o-5 -phenyl-te tr ahydr ooxazol[ 5,4-b ]-2,3,4,5-tetrahydro-TH- 1,4-benzodiazepin-2-on (smp. 218 - 220° 0)j ·_ 7 -chlor-5-( 2-chlorphenyl) -5 * -me thyltetrahydrooxazol [ 5,4-b j-2,4,5-tetrahydro-lH-1,4-benzodiazepin-2-on (sap. .192° 0» dekomp.)f 7-chlor-5-(2-chlorphenyl)-tetr ahydrooxazol[5,4-b]-2,3,4,5-tetra-hydro-1H-1,4-benzodiazepin-2-on (amp. 204° C, dekomp.).In essentially the same procedure as described above, the following benzodiazepine derivative 7-nitro-5-phenyl-51-methyltetrahydrooxazole [5,4-b] -2,3,4,5-tetrahydro-1H-1 was obtained. 4-benzodiazepin-2-one (mp 209 ° C); 5-Bromo-5-phenyl-5 * -methyltetrahydrooxazole [5,4-b] -2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-one (Sep. 180-18 (5 ° C) in 7-bromo-5-phenyl-te trahydrooxazole [5,4-b] -2,3,4,5-te trahydro-1H-1,4-benzodiazepin-2-one (m.p. 190 - 191.5 ° C) 7-N-Trio-5-phenyl-tetrahydrooxazole [5,4-b] -2,3,4,5-tetrahydro-TH-1,4-benzodiazepine-2 7 (Chloro-5- (2-chlorophenyl) -5 * -methyltetrahydrooxazole [5,4-b] -2,4,5-tetrahydro-1H-1 (mp 218-220 °) 4-Benzodiazepin-2-one (sap. 192 ° C) decomp. 7-Chloro-5- (2-chlorophenyl) -tetr ahydrooxazole [5,4-b] -2,3,4,5-tetra -hydro-1H-1,4-benzodiazepin-2-one (amp. 204 ° C, decomp.).