IL33735A - 2-hydroxyamino-5-phenyl-3h-1,4-benzodiazepines - Google Patents

2-hydroxyamino-5-phenyl-3h-1,4-benzodiazepines

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IL33735A
IL33735A IL33735A IL3373570A IL33735A IL 33735 A IL33735 A IL 33735A IL 33735 A IL33735 A IL 33735A IL 3373570 A IL3373570 A IL 3373570A IL 33735 A IL33735 A IL 33735A
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chloro
hydrogen
benzod
phenyl
compound
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IL33735A
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Upjohn Co
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    • 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
    • C07D243/20—Nitrogen atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Fodder In General (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

Description

NOVEL 2-HYDR0XVAMIN9-5-PHENYL 3H-1 , -BENZOOl AZEP I NE8 o»¾rro D»J»BTK» itaa-1,4-3H V»JB-5-I 3»βκ»ο τπ»π-2 ABSTRACT OF THE DISCLOSURE 3H~1, 4' Benzod iazep ines of the formula I I : NH-OR wherein R is selected from the group consisting of hydrogen, lower-alkyl of 1 to carbon atoms, inclusive, lower-al kenyl of 5 to 4 carbon atoms, inclusive, benzyl, -CH2-COOH and -(CH2)2~C00H and the esters thereof derived from an alkanol of 1 to 5 carbon atoms, inclusive, and - (CH2 )η- ^^ !n which n is 2 or 3 and Ra and R4 are lower-alkyl of 1 to 5 carbon atoms, inclusive, or R3 and R4 together are alkylene of to 5 carbon atoms, inclusive; wherein Ri is selected from the group consisting of hydrogen, methyl, halogen, nitro, cyano and -CF3; and wherein R2 is selected from the g roup cons i s t i ng of hydrogen and halogen, are prepared by condensing the corresponding thiolactam compound I : S H N I with a compound of the formula H2N-0R in which R is defined as above. These compounds and their pharmacological ly acceptable acid addition salts have sedative and tranqu i 1 iz ing action and can be used η mammals and birds as tranquil izers.
BACKGROUND OF THE INVENTION FIELD OF THE INVENTION This invention is directed to new organic compounds and is particularly concerned with novel 3H-l, -benzodiazepines and a process for the production thereof.
The novel compounds and the process of production therefor can be illustratively represented as follows: wherein R is selected from the group consisting of hydrogen, lower-alkyl of 1 to 4 carbon atoms, inclusive, 1 ower-al keny 1 of 3 to carbon atoms, inclusive, benzyl, -CH2-C00H and -(CH2)n- C00H and the esters thereof derived from an alkanol with 1 to R 3 carbon atoms, inclusive, and " (CH2 )n-N< ^^^ in which n is 2 or 3 and R3 and R4 are lower-alkyl of 1 to 3 carbon atoms, inclusive, or R3 and R4 together are alkylene of 4 to 5 carbon atoms, inclusive; wherein Ri is selected from the group consisting of hydrogen, methyl, halogen, nitro, cyano and -CF3;. and wherein R2 is selected from the group- cons ist ing of hydrogen and halogen.
The process of this invention comprises heating a thio- lactam of formula ( l) above with an oxyamine H2N-0R in which R is defined as above in an organic solvent or suspending agent to o about 60-80 C for 2 to 18 hours.
Description of the Preferred Embodiment Lower-alkyl groups of 1 to 4 carbon atoms, inclusive, are exempl ified by methyl, ethyl, propyl, isopropyl, butyl, sec-buty.l, isobutyl and tert. -butyl.
Examples of alkenyl of 3 to 4 carbon atoms are ally 1, 2- methylal 1 yl , 2-butenyl (crotyl), 3-butenyl and the l ike.
Examples of the radical -(CH2)n-N<¾ are 2- (dimethyl -amino)ethyl, 2-(diethylaminoethyl ), 2-(d ipropylamino).ethyl , 3- ( d imethyl am i no) propyl , 3-p iper id inopropy 1 , 2- pyrrol id i no-ethyl, 2-piperidinoethyl and the l ike.
The term "halogen" for Ri and R2 means fluoro, chloro arid bromo.
The novel compounds of the formula 1 } including pharmacological ly acceptable acid addition salts thereof have sedative and tranquillizing effects in mammals and birds.
The pharmacologically acceptable acid addition salts of compounds of formula I I contemplated in this invention are the hydrochlo ides, hyd rob rom ides, hydroiodides, sulfates, phosphates, acetates, lactates., tartrates, citrates, sal icylates, succinates, malates, maleates, pamoates, cycl ohexanesul famates, methane-sulfonates and the 1 ike, prepared by reacting a compound of formula I I with the stoichiometrical ly calculated amount of the selected pharmacological ly acceptable acid.
Illustratively, sedative effects of 2- (methoxyam ino) -7-chl oro-5-pheny 1 -3H-1 , -benzod iazepi ne are. shown by the following tes ts in mice: Chimney test[Med. Exp. 4, ll (I96I)] : The effective intraperitoneal dosage for 50$ of mice, ED50,is 28 mg./kg. The test determines the abil ity of mice to back up and out of a vertical glass cyl inder within 50 seconds. At the effective dosage, 50$ of the mice failed doing it.
Dish test: Mice in Petri dishes (10 cm. diameter, 5 cm. high, partial ly embedded in wood shav ings ), cl imb out in a very short time, when not treated. If mice remain in the dish for more than 3 minutes, it indicates tranquil i- zation. ED50 equals the effective dosage of test compound at which 5 4> of the mice remain in the dish. ED50 ( intraperitoneal administration) in this test was 2-5 mg./kg.
Pedestal test: The untreated mouse leaves the pedestal in less than one minute to cl imb back to the floor of the standard mouse box. Tranquil ized mice will stay more than one minute. ED50 ( intraper i toneal administration) was 16 mg./kg.
Nicotine antagonism test: Mice in a group of 6 were injected in traper i tonea 11 y with 2-(methoxyam i no) -7- ch 1 oro- 5-phenyl -3H-1, 4-benzod iazepine. Thirty minutes later the mice including control (untreated) mice are injected with 2 mg./kg. nicotine sal icylate. The control mice show overstimulation, i.e., (l) running convulsions followed by (2) tonic extensor fits; followed by (5) death. An intraperitoneal dosage of 2-4 mg./kg. protected 50f of the mice against (2.) and (3) (ED50); oral ED50 was 1.4 mg./kg. The pharmaceutical forms contemplated by this invention include pharmaceutical compositions suited for topical, oral, parenteral and rectal use, e.g., ointments, lotions, tablets, oils, powder packets, cachets, dragees, capsules, solutions, suspensions, s ter ί 1 e i nj ectab 1 e forms, suppositories, bougies, and the 1 ike. Suitable diluents or carriers such as carbohydrates (lactose), proteins, l ipids, calcium phosphate, cornstarch, stearic ac id, methyl eel 1 ul ose and the l ike may be used as carriers or for coating purposes. Oil, e.g., coconut oil, sesame oil, saff lower oil, cottonseed oil, peanut oil may be used for preparing solutions or suspensions of the active drug. Sweetening, coloring and flavoring agents may be added.
For mammals and birds food premixes, with starch, oatmeal, dried fishmeat, fishmeal, flour and the l ike can be prepared.
As tranquil izer the compounds of formula I I can be used in .dosages of 1-50 mg./kg. in oral or injectable preparations as described above, , to a 11 ev iate tens i on and anxiety in mammals or birds, such as, e.g., occurs when animals are in travel.
Other ac id add i t ion: sa 1 ts of the amine compounds of formula I I can be made such as the f 1 uos i 1 i c i c acid add i t ion salts which are useful mothproofing compounds or the tr i chloroacetates useful as herbicides against Johnson grass, Bermuda grass, yellow foxtail and green foxtail, and quack grass.
Starting materials of formula I of this invention, J- < substituted or unsubst i tuted 1,3-d i hydro-5-phenyl -2H-l,4-benzo- d iazepine-2- th iones, and methods for their preparation, are " described by G. Archer and L.H. Sternbach, J. Org. Chem. 20, 251 (196 ); see also U.S. Patent 5,422,091. These compounds . ( I) are prepared by heating 7-substi tuted or unsubst i tuted .1,5- di hydro-5-pheny 1 -2H-l,4-benzod iazepin-2-ones and phosphorus pentasulfide in pyridine for about 45 minutes (Archer et al., ibid; U.S. Patent 5,422,091.) The fol lowing compounds of formula I are representative starting products: l,5-dihydro-5~phenyl -2H-l,4-benzodiazepine-2-thione; -ch loro-1 - d i h dro- 5- hen 1 -2H-1 4- benzod iaze ine-2- th ione ; 7-b romo-1, 3-d ihydro-5- phenyl -2H-l, 4-benzod iazep ine-2-th ione; 7-methyl -1,3-d ihydro-5- phenyl -2H-1, 4-benzod iazep ine-2- th ione; 7-n it ro-1, 3- ihydro-5- phenyl -2H-l,4-benzod iazep ine-2- th ione; 7-f 1 uoro-1, 3-d ihydro-5- phenyl -2H-1, 4-benzod iazepi ne-2- th ione; 7- tr i f 1 uoromethy 1 -1, 3" ihydro-5- phenyl -2H-1, 4-benzod iazep ine-2-th ione; 7- cyano-1, 3-d ihydro-5- phenyl -2H-1, 4-benzod iazep ine-2- th ione ; 7- ch 1 oro-1, 3-d ihydro-5- (o-chlorophenyl )-2H-l, 4-benzod iazepine-: 2-thione; 7-ch1oro-l,3-di hydro-5-(o-fl uorophenyl ) -2H-1, 4-benzod iazepi ne-2-thione; 7-bromo-l , 3~d ihydro-5- (o-f 1 uorophenyl ) -2H-1, 4-benzod iazepi ne-2 -thione; 7-f 1 uo ro-1, 3-d ihydro-5- (o-f 1 uorophenyl ) -2H-1, 4-benzod iazepine-2-thione; ·,· ; 7-n i tro-1, 3-d ihydro-5- (o-chl orophenyl ) -2H-1, 4-benzod iazepi he-2-th i one ; 7-bromo-l, 3-d ihydro-5- (o-bromophenyl ) -2H-1, 4-benzod iazep ine-2-th ione; 7-methyl -1,3-d ihydro-5" (o-chlorophenyl ) -2H-1, 4-benzod iazep ine-2-th ione; 7- cyano-1, 3-d ihydro-5- (o-chlorophenyl ) -2H-1, 4-benzod iazep ine-2-thione; 7-tr i f 1 uoromethyl -1,3-d ihydro-5-(o-chlorophenyl ) -2H-l,,4-benzo-d iazep ine-2-th ione ; 7-f 1 uoro-1, 3-d ihydro-5- ( o-chlorophenyl ) -2H-1, 4-benzod iazep ine- 2-th ione; and the l ike.
In carrying out the process of the invention, a selected 1,3-d i hydrb-5-phenyl -2H-l,4-benzodiazepine-2-th ione ( I), an oxyamine of formula H2N-0R in which R is defined as above, preferably In the form of a salt such as hydrochloride or hydro-bromide, a base to absorb the acid moiety of the oxyamine and a solvent are refluxed for a period of 2-18 hours. In the preferred embodiment of this i nvent ion/the organic solvent used may be methanol, ethanol, 2-propanol ,or such corsol vents as methanol -dimethy 1 sulfoxide, or the l ike. The oxyamine is usually .used in excess, such as from 1.5 to 5 times the molar equivalent of the thione starting material. The base is used in sufficient quantity to produce the oxyamine in the free base state. After the reaction is terminated, the mixture is filtered, the filtrate concentrated in vacuo and the product obtained by standard procedures such as extraction, crystal - , l ization, recrystal 1 izat ion and chromatography to give the pure ,product, a 2-(oxyamino)-5-phenyi -j5H-l, 4-benzod iazepi ne of formula I I.
The following examples are illustrative of the processes and products of the present invention, but are not to be construed as 1 imiting.
Exampl e 1 2- (Methoxyam i no) -7~chl oro-5- phenyl -;5H-l,4-benzo- diazepine A mixture of 45.6 g. (0.l6o mole) of 7-chloro-l,3-dihydro-5-pheny 1 -2H-1, 4-benzod iazepi ne-2- th ione, 26.7 g. of methoxyam ine hydrochloride, 26.9 g. of sod i urn b i carbonate and 800 ml. of methanol was refluxed under nitrogen for 5.5 hours, cooled and filtered. The filtrate was concentrated in vacuo to give a residue. A solution of the residue in methylene chloride was absorbed on a 5 kg. sil ica gel column which had been prepared with methylene chloride. The column was then eluted with 30# ethyl acetate-70# cyclohexane; 400-ml . fractions were collected. Unreacted starting material was eluted in fractions 15-32. The ethyl acetate to give 29.8 g. (62.3#) of 2- (methoxyam i no) -7-chloro-5-phenyl -3H-l,4-benzod iazepine of melting point 184.5- . o o 186 C. The analytical sample of melting point 185-186 C. was prepared by recrys tal l iz ing this material from methanol . The ultraviolet spectrum (ethanol) had λ max. 212, 253 and 3 3 ιπμ ( e»33, 800, .26,850 and 2,850, respectively) and an inflection Anal . Calcd. for CieHi4ClN30: C, 64.11; H, 4. I; G1, 11.83; N, 14.02.
Found: C, 63.84; H, 4.71; CI, 12.17; N, 13-91.
Example 2 2-(Benzyloxyamino)-7-chloro-5-phenyl -3'H-l ^-benzodiazepine'' A mixture of 1.43 g. (0.005 mole) of 7"chioro-l,3-dihydro-5-phenyl -2H-l,;4-benzod iazepine-2-th ione, I .60 g. (o.01 mole) of benzy loxyamine hydrochloride, 0.84 g. (O.01 mole) sodium bicarbonate and 50 ml. of methanol was refluxed for 10 hours, cooled and filtered. The sol id was recrys ta 11 i zed from methanol to give 1.02 g. (54#) of 2-(benzyloxyamino)-7-chloro~5-phenyl - o 3H-l,4-benzod iazepine of melting point 178-181.5 C. The ana- o lytical samp 1 e, mel t ing point I8O7I81.5· C. , ' was prepared by recrystal 1 iz ing this material from methanol. The ultraviolet spectrum (ethanol ) had · λ max. 209, 254 and 343 πιμ (e≤-33,100, 28,800 and 1,950, respectively) with an inflection at 230 ιτιμ (e-26,450).
. Anal . Calcd. for C22Hi8ClN30: C, 70.30; H, 4.83; CI, 9.43; N, 11.18.
Found: C, 70.12; H, 5.θ6; CI, 9.46; N, .11.32. Ϊ Example 3 2-[:2-(l-Pyrrol idinyl )ethoxyamino]-7-chloro-5_phenyl - 3H-l,4-benzodiazepine and hydrate thereof A mixture of 2.87 g. (O.Ol mole) of 7-chl oro-l,3~d ihydro- - - - - d ze in -2-thi ne 4 06 0 02 mole of 2-(l-pyrrol idinyl )ethoxyamine d (hydrochloride, 3.36 g. (0.04 mole) of sodium bicarbonate and 100 ml . of methanol was re-fluxed under nitrogen for 2 hours, cooled and filtered. The filtrate was concentrated in vacuo and the thus-obtained residue was crystal l ized from ethyl acetate to give 1.69 g. (44.3$) of 2-[2-(l-pyrrol idinyl )ethoxyamino] -7-ch 1 oro-5-phenyl -3H-1,4-benzodiazepine as hydrate, of mel ting point 122.5-130 C. The o analytical sample of melting point 137.5-138.5 C. was prepared by recrystal 1 iz ing some of this material from ethyl acetate.
The ultraviolet spectrum (ethanol ) had λ max. 212, 254 and 4 ιημ ( e¾32,100, 25,850 and 1,950, respectively) with an inflection at 228 πιμ ( e=24,650. ) Anal . Calcd. for C2iH23C1 Ν 0· H20 : C, 62.91; H, 6.29; CI, 8.85; N, 13.98; Ha0, 4.49.
Found: C, 63.19; H, 6.24; CI, 9.22; N, 13.57; H20, 3.54. o ' . , Heating this hydrate to 110 C. for 72 hours at 15 mm. Hg pressure gave water-free 2-[2-(l-pyrrol idinyl )ethoxyami no] -7-chloro-5-phenyl -3H-I, 4-benzod iazepine.
Examp e 2- ( t-Butoxyam i no) -7_ch 1 oro-5-pheny 1 -3H-1, 4- benzodiazepine A mixture, of 1.43 g. (0.005 mole) of 7-chloro-l,3~d ihydro-5-phenyl -2H-1, 4-benzod iazepine-2-th ione, 1.26 g. (O.Ol mole) of t-butoxyam ine hydrochloride, 0.84 g. (O.Ol mole) of sodium bicarbonate and 50 ml . of methanol was ref 1 uxed under nitrogen for 6 hours. At this time very 1 i tt le react ion could be detected by th in , layer chromatography . D imethyl sulfoxide (5 ml . ) was added, and this mixture was refluxed for 7 hours, cooled and filtered. The result ing sol id was recrystal l ized from ethyl acetat to give 0.24 g. (l4ji) of :2-( t-butox.yam ino) -7-^chl oro-5-pheny 1 -3H-1, 4 o benzodiazepine of mel t ing po int 252 C. (dec). The analytical sample, of melting point 251.5-252 C. (dec), was prepared by recrystal 1 izing this material from ethyl acetate. The ultraviolet spectrum (ethanol) had λ max. 212, 254 and 346 π\μ (e-: **00,. 24,850 and 1,900 respectively).
Anal . Calcd. for Ci9H2oClN30: C, 66.76; H, 5. 0; CI, 10.37; H, 12.29.
Found: C, 66.77; H, 5.9*; CI, 10.66; N, 12.29.
Example 5 2-(Al lyloxyamino)-7-ch1oro-5-phenyl -3H-1,4- benzodiazepine A mixture of 2.87 g. (O.Ol mole) of 7-chloro-l,3-d ihydro-5-phenyl -2H-1, 4-benzodiazepine-2-thionei al lyloxyamine hydrochloride (2.20 g; 0.02 mole), sodium bicarbonate (1.77 g. ; 0.021 mole) and absolute ethanol was refluxed for 4. hours with a slow stream of nitrogen bubbl ing through the reaction mixture. The reaction mixture was cooled and filtered, the filtrate was concentrated in vacuo and the residue was chroma-tog raphed on s i 1 ica gel ( 00 g. ) with 10$ ethyl acetate-90# methyl ene ch lor ide; 100-ml . fractions were col lected. The product was eluted in fractions 30-62 and crystal l ized f rom ether-Skel 1 y-solve B, hexanes to give 1.19 g. of 2-(al 1 y'l oxyam i no) -7- ch 1 oro- o -phehyl -3H-l,4-benzodiazepine of mel ting point 126.5-129 C. The o analytical sample had a mel ting point of 134-135.5 C. The ultraviolet spectrum (ethanol) had λ max. 211 ( e»34,550), 254 (e¾27,350) 343 (erf., 850), inflection 229 "ΐμ ( Anal . Calcd. for Ci8HieClN30: C, 66.36; H, 4.95; CI, 10.88; N, 12.90.
Found: C, 66.20; H, 4.95; CI, 11.12; N, 12.43.
Example 6 2-[2- (D i ethy 1 amino)ethoxyamino] -7-chl oro-5-pheny 1 - 3H-l,4-benzodiazepine and hemihydrate thereof A mixture of 4.3 g. (0.015 mole) of 7-chloro-l,3-dihydro- - - - - - - - - amine (5.96 g.; 0.030 mole) and absolute ethanol ('150 ml.) was refluxed, under nitrogen, for 7 hours and concentrated in vacuo.
The res idue was crystal 1 ized from ethyl acetate-Skel 1 ysol ve B hexanes to give 5*25 g. (91 ) of 2-[2-(diethylamino)ethoxyamino]-7-chloro-5-phenyl -3H-l,4-benzodiazepine as hemihydrate of melting o point 92-100 C. The analytical sample had a melting point of o 99-100 C. The ultraviolet spectrum (ethanol) had λ max. 211 («=53,850)y 25 ( e -25,650), J ( er2,000), inflection 227 ίτιμ Anal . Calcd. for C2iH25ClN40-l/2H20: C, 64.03; H, 6.65; CI, 9.00; N, 14.22.
Found: C, 63.93; H, 6.60; Gl 9.02; , 13.85. o Heating this hydrate to 80 C. for 7 hours at 15 mm. Hg pressure gave water-free 2-[2-(diethylamino)ethoxyamino]-7_chloro 5-pheny 1 -3H-l,4-benzod iazepine.
Example 7 Ethyl [ (7-chloro-5~phenyl -3H-l,4-benzodiazepin-2- y 1 )aminooxy]acetate A mixture of 11.5 g. (0.04 mole) of 7-chloro-l,3-d i hydro-5-phenyl -2H-l,4-benzodiazepine-2-th ione, ethyl am i nooxyacetate (11.9 g.; 0.10 mole), dimethyl sul fox ide (40 ml. ) and absolute ethanol (400 ml.) was refluxed for 7 hours with a stream of nitrogen bubbl ing through the mixture. Additional .ethyl, amino-oxyacetate (6.0 g. ) was added to the mixture which was refluxed for an add i tional 18 hours and concentrated in vacuo. The residue was suspended in water and the mixture was extracted with ether. The ether extract was dried over anhydrous potassium carbonate and concentrated to give a residue. The residue was chroma tog raphed on 'silica gel (750 g.) with 25 ethyl acetate- 75 cyclohexane; 200-ml . fractions were collected. The product of fractions 30-56 was crystal 1 ized from ether-Skel lysolve B o hexanes to ive 2. . of meltin oint II6-II7 C. and 2.07 . of melting point 113-115.5 C. of ethyl [ (7-chloro-5-phenyl-3H-l,4-benzodiazepin-2-yl )amiriooxy]acetate. The analytical sample o had a melting point of 113-114 C. The ultraviolet spectrum (ethanol) had λ max. 210(ej-34, 56o), 252 (e=28,150), 341 (e=2,050), inflection 228 πιμ (er26,300).
Anal . Calcd, for Ci oHi8Cl N303 : , 61.37; H, 4.88; CI, 9.54; N, 11.30.
Found: C, 61.48; H, 5.14; CI, 9.55; N, 11.17.
Exampl e 8 2-(Hydroxyamino)-7-chloro-5-phenyl-3H-l, 4- benzod iazepine A mixture of 14.4 g. (0.05 mole) of 7-chloro-l,3-dihydro- 5- phenyl -2H-1, 4-benzod iazepi ne -2-th i one, hydroxy lam i ne hydro-chloride (4.55 g..)* sod i urn b i carbonate (5.45 g.) and methanol (250 ml.) was refluxed for 1.5 hours with a stream of nitrogen bubbl ing through the mixture. The cooled mixture was filtered and the filtrate was concentrated in vacuo to give a residue.
This residue was chromatographed on silica gel (750 g.); 150-ml . fractions were collected. The product was eluted with 2# triethylamine-13^ methanol -85# ethyl acetate and crystall ized o from ethyl acetate to give 4.92 g. of melting point 122.5-130 C. and 3.38 g. of melting point 128-132 C. of 2-( hydroxyam ino) - 7-chloro-5-phenyl -3H-I, 4-benzod iazepine. The analytical sample o had a melting point of 126-130 C. The ultraviolet spectrum (ethanol) had. λ max. 209 (β=34,05θ), 252 (e=23,750), 34 ( e£ 1,800), inflection 229 Γπ (e-r24,250).
Anal . Calcd. for Ci sH^CI N30 : C, 63.05; H, 4.23; CI, 12.41; N, 14.71.
Found: C, 63.13; H, 4.40; CI, 12.31; N, 14.52.
Example 9 2-(Al lyloxyamino)-7-chloro-5-(o-chlorophenyl )-3H- 1,4- benzodiazepine A mixture of -chloro-l -d ih dro- - o-chloro hen 1 -2H- hydrochloride (1.10 g., 0.01 mole), sodium bicarbonate (Ό.89 g., 0.011 mole) and absolute ethanol (50 ml.) was refluxed for 5 hours with a slow stream of n i trogen bubb 1 ing through the reaction mixture. The mixture was cooled and filtered, and the filtrate was concentrated in vacuo. Crystall ization of the residue from ethyl acetate gave 0.21 g. of recovered starting material, chromato-graphing the mother l iquors on sil ica gel (lOO g.) with 255^ ethyl acetate-75# cyclohexane. Crystall ization from ethyl acetate-Skellysolve B hexanes gave 0.68 g. (37.8#) of 2-(al 1 yloxyamino) -.7-chloro-5-(o-chlorophenyl )-3H-l, -benzodiazepine, melting point o o 130-131 C. The analytical sample, melting point 130-131 C. was prepared by recrys tal 1 iz i ng some of this material from ethyl acetate-Skel 1 ysol ve B hexanes. The ultraviolet spectrum (ethanol ) had λ max. 234 and 5 6 Γπμ (e=26,950 and 2,150, respecti ely) with inflections at 208, 253 and 275 πιμ 21160 and 10,750, respectively).
Anal . Calcd. for C18H15CI2 3O : C, 60.01; H, 4.20; CI, 19.68; N, 11.66.
Found: C, 59.88; H, 4.29; CI, 19.40; N, 11.41.
Example 10 2-(Methoxyamino)-7-chloro-5~(o-chlorophenyl )-JH- 1,4 -benzodiazepine A solution of 7-chloro-l,3-dihydro-5-(o-chlorophenyl )-2H-l,4-benzodMazepine-2-thione (7.42 g., 0.0244 mole) in a mixture of IN sodium hydroxide solution (28.9 ml.) and methanol (36 ml.) was treated during 20 minutes with a solution of dimethyl sulfate (3.35 g.) in methanol (12 ml.). This mixture was stirred for 10 minutes, diluted with water, made strongly alkal ine with sodium hydroxide and extracted with ether. The extract was washed with water, dried with anhydrous potassium carbonate and concentrated. The residue was chromatographed on sil ica gel (500 g.) with 25$ eth - ether at 0 C. to give 3.71 g. (455*) of 7-chl oro-2-(methy 1 - th io)-5-(o-chlorophenyl )-3H-l,4-benzodiazepine of melting point o o 113-118.5 C. The analytical sample of melting point 118-120 C. was prepared by recrystal 1 iz ing some of this material from methylene chloride-ether. The ultraviolet spectrum (ethanol ) had λ max. 244 and 286 ιτιμ ( es23> 00 and 11,500, respectively) with inflections at 215 and 330 πιμ and 3,650, respectively).
Anal .: Calcd. for CieHi2Cl2 2S : C, 57.32; H, 3.61; CI, 21.15; N, 8.36; S, 9.57.
Found: C, 57.82; H, 3.77; CI, 21.37; N, 8.44; S, 8.97.
A mixture of 7-chloro-2-(methy1 thio)-5~(o-chlorophenyl )- 3H-l,4-benzod iazepine (1.6o g.j 0.00476 mole), methoxyamine hydrochloride (0.794 g.), sodium bicarbonate (0.794 g.) and absolute ethanol (50 ml . ) was refluxed for 4 hours with a slow stream of nitrogen flowing through the reaction mixture. This mixture wasconcentrated in vacuo; the residue was mixed with water and extracted with methylene chloride. The extract was washed with water, dried with anhydrous potassium carbonate and concentrated. Crystall ization of the residue from ethyl acetate gave 1.11 g. (70^) of 2-(methoxyamino)-7-chloro-5-(o-chloro- o phenyl ) -3H-i,4-benzod iazepi ne, melting point 157-159 C. The o ; analytical sample, melting point 158.5-159.5 C. was prepared by recrys tal 1 iz ing this material from ethyl acetate. e ultra-. violet spectrum ( ethanol ) had λ max. 234 and 346 ιτιμ and 2,050, respectively) with inflections as 211, 253 and 275. πιμ 19,650 and 10,200, respectively).
Anal . Calcd. for CieHi3Cl2N30: C, 57.50; H, 3.92; CI, 21.22; N, 12.57.
' Found: C, 57.17; H, 4.00; CI, 21.44; N, 12.35.
Example 11 [7-Chloro-5-pheny 1 -3H-l,4-:benzodiazepin-2-yl )amino — oxy]acetic acid In the manner given in Example 1, 7-ch1oro-l,3-dihydro~5-phenyl -2H-lP4-benzod iazepine-2-thione and am inooxyacet ic acid were refluxed in methanol for 6 hours to gi ve[[ (7-chloro-5-phenyl -3H-l,4-benzodiazepin-2-yl )amjnooxy]acetic acid.
Example 12 2-( E thoxyam ino) -7-b romo-5-pheny 1 -3H-1 , 4- benzodiazepine In the manner given in Example 1, 7-bromo-l,3"d ihydro-5-phenyl -2H-l,4-benzodiazepine-2-thione, ethoxyamine hydrochloride, sod i urn b icarbonate and methanol were refluxed for 6 hours to g i ve 2-( ethoxyami no)-7-bromo-5-pheny 1 -3H-1, 4-benzod iazepi ne.
Example 13 2- ( Butoxyami no) -7- t r i f 1 uoromethy 1 -5-(o-chlorophenyl )- 3H-1, -benzod iazepi ne In the manner given in Example 1, 7- tr if 1 uoromethy 1 -1 ,3-d ihydro-5_(o-chloropheny 1 ) -2H-1, 4-benzod iazepine-2-th ione, butoxyamine hydrochloride, sod i urn ,bi carbonate and methanol were refluxed for 6 hours to give 2-(butoxyamino)-7_trif luoro-methyl -5- (o-chloropheny 1 ) -3H-1, 4-benzod iazepi ne.
Example 14 2-[3~(l-Pyrrol id inyl ) propoxyam i no] -7-cyano-5- (o-f I uorophenyl ) -3H-l,4-benzodiazepine In the manner given in Example 1, 7~cyano-l,3-d ihydro-5-( o-fl uorophenyl ) -2H-1, 4-benzod iazepi ne-2-th ione, 3-(!-pyrrol idinyl) propoxyamine hydrochloride, sodium bicarbonate and methanol were refluxed for 6 hours to give 2-[ 3-(l-py r rol id i ny 1 )propoxyam ino] -7 -cyano-5" (o-fl uorophenyl ) -3H-1, -benzod iazep ine.
Example 15 2-[2-(l-Piperidinyl )ethoxyamino] -7-n i tro-5- (o-bromo- phenyl )-3H-l, -benzod iazep ine In the manner given in Example 1, 7~n i tro-l,3"d ihydro-5-(o-bromopheny 1 ) -2H-1, -benzod iazep ine-2-th ione, 2-(l-p iper idinyl ) -ethox amine h drochloride, sodium bicarbonate and methanol were refluxed for 6 hours to give 2-[2-(l-piper jd inyl )ethoxyam ino] n it ro-5-(o-brpmopheny 1 ) -3H-1, 4-benzod iazep ine.
Example 16 2-(Hydroxyamino) -7-f 1 uoro-5-pheny 1 -3H-l,4-benzo- diazepine In the manner given in Example 1, - 1 uoro-1, 3- ihydro-5- phenyl -2H-1, 4-benzod iazepine-2-thione, hydroxyamine hydrochloride, potassium bicarbonate and ethanol were refluxed for 6 hours to give 2-(hydroxyamino)-7_f 1 uoro-5-pheny 1 -3H-1,4- benzodiazepine.
Example 17 2- ( Croty 1 oxyam i no) -5-phenyl -3H-1, 4-benzod i azep i ne In the manner given in Example 1, 1, j5-dihydro-5-phenyl -2H-1, -benzod i azep ine-2-th ione, croty 1 oxyam i ne hydroch lor i de, sod i urn b i carbonate and methanol were refluxed for 6 hours to give 2-( crotyl oxyam ino) -5- pheny I -JH-l, -benzod iazep ine, Example 18 2-( Propoxyami no)-7-methy 1 r5-(-0-f 1 uoropheny 1 ) --35H- 1, 4-benzod iazep ine In the manner given in Example 1, 7-methyl -1,3-d ihydro-5- ( o-f 1 uoropheny 1 ) -2H-1, 4-benzod iazep ine-2- th ione, propoxyami ne hydrochloride, sodium bicarbonate and methanol were refluxed for 6 hours to give 2-( propoxyam i no) -7-methyl -5-(o-fl uoropheny 1 ) -3H-1, 4-benzod iazep ine.
Example 19 2-[3-(D i methyl am ino) propoxyami no] -7- tr i f 1 uoromethy ί -5- (o-chloropheny 1 )-3H-l, 4- benzodiazepine In the manner given in Example 1, 7-tr i fl uoromethy 1 -1,3-d ihydro-5-(o-chlorophenyl )-2H-l,4-benzodiazepine-2-thione, 3-(dimethylamino)propoxyamine hydrochloride, sodium bicarbonate and methanol were refluxed for 6 hours to give 2-[3-(d imethylamino) propoxyam ino]-7 - tr i fl uoromethy 1 -5- (o-chloropheny I ) -3H-l,4-benzo-d iazepine.
Example 20 3-[ (7-Fl uoro-5-phenyl -3H-l,4-benzodiazepin-2-y1 )- aminoox ] ro ionic acid In the manner g iveh In Example 11, 7-f 1 uoro-1, 3~cM hydro-5- phenyl -2H-1, 4-benzod iazep ine-2-thione, 3~ (am i nooxy )prop ion i c ac i d and methanol were refluxed for 6 hours to give 2-[ (7- f 1 uoro- 5 — phenyl -3H-l,4-benzodiazepin-2-yl )aminooxy]propionic acid'.
Exampl e 21 Methy l [ (7-b romo-5-pheny 1 -3H-1, 4-benzod iazepi n^-yl ) - am i nooxy ] ace ta te In the manner given in Example 7,> 7-bromo-l,3-d i hydro-5- phenyl -2H-l,4-benzodiazepine-2-th ipne,. methyl aminooxyacetate, dimethyl sulfoxide and methanol were refluxed for 6 hours to give methyl [ (7- romo- " phenyl -3Η÷1, 4-benzod iazepin-2-yl ) ami nooxy] - acetate.
Exampl e 22 2-( I sobutoxyam ino) -7_.cyano÷5-pheny ί -3H-1, 4- benzodiazepine.
In the manner given in Example 1, 7"Cyano-l,3_dihydro-5- phenyl -2H-1, 4-benzod iazepine-2-^th ione, i sobutoxyami ne hydrochloride, sodium bicarbonate and methanol were refluxed for 6 hours to give 2-( isobutoxyamino)-7-cyano-5-phenyl -3H-1,4- benzod iazep ine. ; . , In. the manner given in the preceding examples, otherr H-1,4- benzodiazepines of formula I I are obtained by treating 2H-1, 4-, benzodiazepine-2-thiones of formula I with an oxyaminp compound H2N-O , wherein R is defined as above. * Representative compounds of formula I I , thus obta ined include: 2-(al lyloxyamino) -7"bromo-5-phenyl - H-l,4-benzodiazepine; - 2-[ (3-buteny 1 oxy )amino] -7- r i f 1 uorbmethy 1 -5-(o-chloropheny 1 ) - 3H-1, 4-benzod iazep ine; 2- ( i sopropoxyamino) - -me thy 1 -5 -phenyl -3H-I, 4 -benzodiazepine ; 2- (benzyloxyami no) -7- fl uoro-5-(p-bromophenyl ) -JH-l, 4-benzod iazep ine 2-( ethoxyami no) -7-chloro-5-(o-f 1 uoropheny 1 ) -3H-I, 4-benzod iazep ine ; 2-( propoxyam ino) -7-cyano-5-pheny 1 -3H-1, 4-benzod iazepine; 2- butox amino - -nitro- - hen l- H-l 4-benzodiaze ine r 2-( isopropoxyamino)-5-(o-bromophenyl )-3H l, -benzodiazep ine; 2-[5-(l-pi per id!nyl )propoxyamino] -5 -phenyl -3H-1, ^-benzodiazepine; 2-[2 - (d i methyl amino)ethoxyami no] -5-(o-f1 uorophenyl ) -.JH-l, 4-benzodiazepine; 2-(al lyloxyamino]-7-ni tro-5-phenyl -3H-l, -benzodiazepine; 2- ( hyd roxyam ino) -7-cyano-5- ( o-b romopheny 1 ) -3H-1 , -benzod i azep i ne ; and the 1 ike.
Acid addition salts of compounds of formula II are obtained by reacting the selected compound of formula I I with one or more equivalents of acid to get the desired acid addition salt. The reaction is carried out at room temperature in a solvent, for example, ether, ethyl acetate, anhydrous or aqueous methanol, ethanol, or isopropanol, and the solvent is thereupon evaporated. In this, manner, pharmacologically acceptable acid addition salts, e.g., hydrochlorides, hydrobromides, sulfates, phosphates, acetates, propionates, tartrates, succinates, lactates, citrates, maleates, malates, pheny lacetates, phenyl propionates, benzoates, cinnamates, sal icylates, cyclohexanesul famates, pamoates, methane sulfonates and the l ike of formula I I compounds are obtained.

Claims (2)

ΓΗΑΤ IS CLAIMED IS: A 3H-1, 4-benzod iazepi ne of the formula: where hydrogen, lower r-al kenyl of 3 to d -(CH2)a- C00H . of 1 to 3 carbo h n is 2 or 3 and R3 and R4 are lower-alkyl of 1 to 3 carbon atoms, inclusive, or R'a and R4 together are alkylene of 4 to 5 carbon atoms, inclusive; wherein Ri is selected from the group cons ist ing of hydrogen, methyl, halogen, nitro, cyano and -CF3; and wherein R2 is selected from the group consisting of hydrogen and halogen, and the pharmacolog i ca 11 y acceptabl e acid addition salts thereof. ■.'· ' ' -2r. A compound accord ing to cl a im l . where in Ri is chloro, R2 is hydrogen and R is methyl and the compound is therefore 2-(methoxyaminp) ,-7-chloro-5"Pheny 1 -3H-l,4-benzod iazepine . 4 A compound according to claim 1 wherein i is chloroj 2 is hydrogen and R is benzyl and the compound is therefore 2- (benzyl oxyami no) -7- chloro-5- phenyl -3H-1, 4-benzod iazepi ne. -4- A compound according to claim 1 wherein Ri is chloro, R2 is hydrogen and R is 2-(l-pyrrol id inyl )ethy 1 and the compound is therefore 2-[2-(l-pyrrol id iny 1 )ethoxyamino] -7-chloro-5- phenyl -3H-l,4-benzod iazepine. -5- A compound according to claim 1 wherein Ri is chloro, R2 is hydrogen and R is t-butyl and the compound is therefore 2-( t-butoxyamino)-7"Chloro-5-phenyl -3H-l, -benzodiazepine. ' ■ ■ r -6- A compound according to claim 1 wherein Ri is chloro R2 is hydrogen and R is al lyl and the compound is therefore 2-(allyl- oxyamino) -7- ch loro-5 -phenyl -3H-1, 4-benzod iazepine. -7- A compound according to claim 1 wherein Ri is ch lore*, R2 is .hydrogen and R is 2-(diethylamino)ethyl and the compound is therefore 2-[2-(diethylamino)ethoxyamino]-7-chloro-5-phenyl - 3>H-l,4-benzod iazep ine. -8- A compound according to claim 1 wherein Ri is chloro, R2 is hydrogen and R is -CH2-COOC2HS and the compound is therefore ethyl [ (7-chloro-5-phenyl -3H-1, -benzod iazepi n-2-y 1 )aminooxy]- acetate. -9- A compound according to claim 1 wherein Ri is chloro, R2 is hydrogen and R is hydrogen and the compound is therefore 2- ( hydroxyam ino) -7-chl oro-5- pheny l -3H-1, 4-benzod iazep ine. A compound according to claim 1 wherein Ri and R2 are chloro and R is a 1 lyl and the compound is therefore 2-(allyloxy- amino)-7-chloro-5-(o-chlorophenyl )-3H-l, 4-benzod iazepine. 2520 -11' A compound according to claim 1 wherein Ri and R2 are chloro and R is methyl and the compound is therefore 2-(methoxyamin6) -7-chloro-5-(o-chlorophenyl )-3H-l,4-benzodiazepine.
1 -1
2- A process for the product ion of a 3hhl,4-benzodiazep i ne of the formula I I: wherein R is selected from the group cons i st ing of hydrogen, lower-alkyl of 1 to carbon atoms, inclusive, lower-alkenyl of 3 to 4 carbon atoms, inclusive, benzyl, -CH2-C00H and -(CH2)2-C00H and the esters thereof derived from an alkanol of 1 to 3 carbon > atoms, inclusive, and -(CH?)n-N< :R4 in which n is 2 or 3 3nd R3 and R4 are lower-alkyl of 1 to 3 carbon atoms, inclusive, or R3 and R4 together are alkylene of 4 to 5 carbon atoms, inclusive; wherein Ri is selected from the group consisting of hydrogen, methyl, halogen, nitro, cyano and -CF3; and wherein R2 is selected from the group cons ist ing of hydrogen and halogen, which comprises condens ing a th iolactam of the formula I:
IL33735A 1969-02-28 1970-01-19 2-hydroxyamino-5-phenyl-3h-1,4-benzodiazepines IL33735A (en)

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