US3867374A - Diazepinoindoles - Google Patents

Diazepinoindoles Download PDF

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US3867374A
US3867374A US828727A US82872769A US3867374A US 3867374 A US3867374 A US 3867374A US 828727 A US828727 A US 828727A US 82872769 A US82872769 A US 82872769A US 3867374 A US3867374 A US 3867374A
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tetrahydro
diazepino
indole
ethyl
carboxylate
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Brian E Reynolds
John R Carson
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Janssen Pharmaceuticals Inc
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McNeilab Inc
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Priority to GB28490/69A priority patent/GB1278787A/en
Priority to FR6918611A priority patent/FR2011901A1/fr
Priority to CH183072A priority patent/CH532599A/de
Priority to GB27573/71A priority patent/GB1278788A/en
Priority to CH860169A priority patent/CH528527A/de
Priority to CH1035071A priority patent/CH537386A/de
Priority to DE19691928726 priority patent/DE1928726A1/de
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    • 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

  • An object of this invention is to provide a novel calss salicylic, Z-phenoxy-benzoic and the like.
  • diazepinoindoles in particular, 2,3,4,5-tetrahydrolthe salt form may be converted in the usual manner.
  • [class a]indoles of this invention may be -oxo-by
  • the compounds of formula (I-a), wherein R, is hythefollo vgg formulas: drogen, may be obtained by the following processes.
  • a lower alkyl l-(3-acetaidopropyl)- indole-2-carboxylate of formula (II) may be cyclized in Wherem R15 a member Selected from the group l the presence of a suitable base such as sodium hydride mg of hydrogen, lower alkoxy chloro and Humor 30 in a suitable high boiling solvent such as xylene, prefera member Selected from the group consisting of y ably under reflux conditions, to yield the corresponding gen, lower alkyl and P y 1 is a member Selected formula (Ia) compounds with R equal to hydrogen.
  • a suitable base such as sodium hydride mg of hydrogen, lower alkoxy chloro and Humor 30
  • a suitable high boiling solvent such as xylene
  • these compounds may be prepared by cyclization of a lower alkyl l-(3-aminopropyl)-indole-2- carboxylate of formula (III) using a base such as so (lower alkyl)-amino-lower alkyl, di-(lower alkyl)- amidomethyl, benzyl and p-tolymethyl, and R" is a member selected from the group consisting of hydro' dium ethoxide in a solvent such as ethanol.
  • lower alkyl, lower alkoxy and 6 lation is readily achieved by first producing the correlower alkanoyl" may be straight or branch chained sponding anion by treatment with a suitable base, c.g., saturated hydrocarbons having from I to about 6 caran ulkflli metal y fit amidc 0r fllkOXidc Such as S hon atoms, such as for example, methyl, ethyl, propyl, dium hydride, sodamide and potassium t-hutoxide, re-
  • a suitable base c.g., saturated hydrocarbons having from I to about 6 caran ulkflli metal y fit amidc 0r fllkOXidc
  • S hon atoms such as for example, methyl, ethyl, propyl, dium hydride, sodamide and potassium t-hutoxide, re-
  • alkoxys such as methalkylatmg agent of formula wherein X oxy, etho y. p p y, isop p y u y. n a chloro or bromo and R' is the same as R except for kan y s such as f rmyl. a tyl, pr pi ny s p pi nyl, hydrogen, such as a lower alkyl halide, a di-( lower albutyryl, etc.
  • the alkylation may be carried out in a variety of polar or nonpolar solvents such as the lower alkanols, e.g., methanol, ethanol and the like; ethers such as diethyl ether, dioxane and the like; dimethylformamide; or aromatic hydrocarbons such as benzene, toluene, xylene and the like.
  • polar or nonpolar solvents such as the lower alkanols, e.g., methanol, ethanol and the like; ethers such as diethyl ether, dioxane and the like; dimethylformamide; or aromatic hydrocarbons such as benzene, toluene, xylene and the like.
  • the compounds of formula (I-b), wherein R is hydrogen, lower alkyl, di-(lower alkyl)-amino-lower alkyl, benzyl or p-tolylmethyl, are readily obtained by reduction of the oxo function of the corresponding compounds of formula (l-a), i.e., where R is other than di- (lower alkyU-amidomethyl.
  • the reduction is carried out according to conventional techniques, for example, by treating the appropriate formula (l-a) compound with a suitable reducing agent such as lithium aluminum hydride, preferably under reflux conditions for about 5-24 hours in a suitable organic-solvent such as 1,2-dimethoxy-ethane (monoglyme).
  • the compounds of formula (I-h possess interesting and useful properties.
  • those compounds in which R and R are as initially described and R" is lower alkanoyl have been found to possess central nervous system depressant activity in laboratory animals, as demonstrated in mice by a decrease in motor activity at doses of 30-300 mg/kg i.p. and ataxia at about 100 mg/kg i.p.
  • Those compounds in which R and R are as initially described and R is lower alkyl, di(lower alkyl)-amino-lower alkyl, benzyl or p-tolylmethyl possess COOalkyl H /Raney Ni blood pressure lowering properties, as demonstrated by a decrease of about 40-l20 mm. Hg when administered IV.
  • the formula (II) compounds may be prepared by the reductive amidation of a corresponding lower alkyl l- (B-cyano-ethyl)-indole-2-carboxylate (IV), for example, by hydrogenating the latter in the presence of acetic anhydride using a catalyst such as Raney nickel.
  • the intermediate compounds of formula (III) may be prepared by reduction of the nitrile function in the formula (IV) compounds, for example, with borane in a suitable organic solvent such as tetrahydrofuran or by hydrogenation using a catalyst such as Raney nickel in a solvent such as ethanol in the presence of a small amount of ammonia.
  • R which also possess novelty when R is phenyl
  • a base such as benzyltrimethylammonium hydroxide.
  • EXAMPLE I Ethyl indole-2-carboxylate (9.84 g., 0.052 mole) is dissolved in ISO ml. dioxane. Acrylonitrile (3.1! g., 0.0588 mole) and benzyltrimethylammonium hydroxide (Triton B) (2 ml.) are added and the mixture is warmed, with stirring, at 50-55 C. for 3/4 hr. The solution is cooled to room temperature and stirred overnight.
  • Triton B benzyltrimethylammonium hydroxide
  • the reaction mixture is added to 500 ml. water containing 3 ml. glacial acetic acid.
  • the mixture is extracted with methylene chloride, the organic layer washed with 2 X 25 ml. water and dried over magnesium sulphate.
  • the solvent is removed under reduced pressure.
  • the remaining oil is dissolved in ether and filtered through alumina with ether as eluant. Evaporation of the ether gives a solid.
  • the product obtained is ethyl N*(,8-cyanoethyl) indole-2-carboxylate; m.p. 84-86 C.
  • EXAMPLE Ill Ethyl l-(3-acetamidopropyl) indole -2-carboxylate (1.44 g., 0.005 mole) is cyclized in the presence of sodium hydride (0.30 g., 0.00625 molar in hydride) in xylene under reflux. A few drops of absolute ethanol are added after 1 hr. reflux. Total reflux time is 2 hrs. The product recovered is crystallized from benzenehexane. The product obtained is 2,3,4,5-tetrahydro-lH-l ,4- diazepine [l,2-a] indol-l-one; m.p., l8l-l83 C.
  • EXAMPLE IV Ethyl N-(B-cyanoethyl) indole-Z-carboxylate (29 g., 0.12 mole) is dissolved in 200 ml. tetrahydrofuran and treated with ml. (0.09 mole) of 1 molar borane solution in tetrahydrofuran. The reaction mixture is stirred for several hours at room temperature and then excess borane is decomposed by careful addition of absolute ethanol.
  • ethyl N-(B-cyanoethyl) indole-2-carboxylate 35.2 g., 0.145 mole
  • the product is recovered as an oil which shows no nitrile absorption in the infrared spectrum.
  • the product is ethyl l-(3-aminopropyl) indole-2- carboxylate.
  • EXAMPLE V Ethyl 1-(3-aminopropyl) indole-2 -carboxylate (25 g.) is dissolved in absolute ethanol and heated under EXAMPLE VI A solution of methyl iodide (3.8 g., 0.040 mole) in dimethylformamide (15 ml.) is added to a stirred mixture of 2,3,4,5-tetrahydro-lH-l,4-diazepino [1,2-a] indol-l-one (7.2 g., 0.036 mole) and potassium tbutoxide (5.3 g.) in dimethylformamide (45 ml.). The mixture is stirred for an additional 2 hrs. and then diluted with water (150 ml.).
  • EXA P E VII Ethyl 5-methoxyindole-2-carboxylate (11 g., 0.05 mole) and acrylonitrile (3.0 g.) are dissolved in 125 ml. dioxane. Triton B (2 ml.) is added and the mixture is stirred at 55 C. for 3/4 hr., cooled to room temperature, and stirred overnight. The solution is poured into 500 ml. water containing 2 ml. glacial acetic acid. The aqueous mixture is extracted with methylene chloride (3 X 150 ml.); the combined organic layers are washed once with water and dried over magnesium sulphate.
  • trate is evaporated to dryness in vacuo.
  • the residue is dissolved in chloroform and washed with sodium hydroxide solution and water.
  • the solution is dried over anhydrous magnesium sulphate and the solvent is removed in vacuo.
  • the residue is crystallized from benzene-hexane and affords ethyl l-(3-acetamidopropyl)- 5-methoxyindole-Z-carboxylate; m.p. 99.5101 C.
  • EXAMPLE lX Ethyl 1-( 3-acetamidopropyl )-5-methoxyindole-2- carboxylate (3.18 g., 0.01 mole) is added to a stirred suspension of approximately 50 percent sodium hydride (0.65 g., 0.0137 molar in hydride) in dry xylene (40 ml.). The stirred mixture is heated under reflux for 6 hrs., and cooled to room temperature overnight. An equal volume of chloroform is added and the solution is washed twice with water, once with 2N hydrochloric acid, and again with water. The dried organic solution is evaporated under reduced pressure.
  • EXAMPLE x Ethyl N-(B-cyanoethyl)-5-methoxyindole-2- carboxylate (5.44 g., 0.02 mole) is dissolved in 35 ml. tetrahydrofuran. A solution of 16 ml. 1 molar borane in tetrahydrofuran solution is added slowly and the resulting mixture is stirred for several hours at room temperature. Excess borane is decomposed by careful addition of absolute ethanol. The solution is evaporated to dryness in vacuo. The oily residue is dissolved in absolute ethanol. The solution is treated with ethereal hydrogen chloride and heated under reflux for 1 hr. The solution is evaporated to dryness.
  • the residue is dissolved in water and the aqueous solution is extracted with ether. The organic extracts are discarded. The aqueous solution is made alkaline with sodium bicarbonate and extracted with chloroform. The chloroform extracts are dried over magnesium sulphate and solvent is removed in vacuo. The infrared spectrum shows no nitrile absorption. The product obtained is ethyl l-(3- aminopropyl)-5-methoxy-indole-2-carboxylate.
  • EXAMPLE XI Ethyl 1-(3-aminopropyl)-5-methoxyindole-2- carboxylate, 2.76 g. (0.01 mole), is dissolved in 25 ml. absolute ethanol and a solution of sodium ethoxide in ethanol added. The mixture is heated under reflux for 3 hrs., solvent is removed under reduced pressure and the residue is suspended in water containing enough hydrochloric acid to give an acid solution. The aqueous mixture is extracted with chloroform and the organics are dried over magnesium sulphate. The solvent is removed.
  • EXAMPLE Xlll A 2.76 g. (0.01 mole) quantity of ethyl 5- chloroindole N(B-cyanoethyl)-2-carboxylate is suspended in acetic anhydride (20 ml.). The suspension is hydrogenated on a Parr shaker in the presence of Raney nickel catalyst. The uptake of hydrogen is complete after 2 /2 hrs. The material recovered is crystallized from benzene-hexane. The product obtained is ethyl 1-( 3-acetamidopropyl )-5-chloroindole-2- carboxylate; m.p. 130.5l3l.5 C.
  • EXAMPLE XIV Ethyl l-(3-acetamidopropyl)-5-chloroindole-2- carobxylate (1.63 g., 0.005 mole) is cyclized in the presence of sodium hydride (0.30 g., 0.00625 molar in hydride) in xylene under reflux. A few drops of ethanol are added after 1 hr. reflux. The total reflux time is 2 hrs. The material recovered is crystallized from chloroform-hexane. The product obtained is 9-chloro- 2,3,4,5-tetrahydro-1Hl,4-diazepino-[1,2-a]-indol- 1-one;m.p. 222223 C.
  • EXAMPLE XV Ethyl N-(B-cyanoethyl)--chloroindole-2- carboxylate (2.76 g., 0.01 mole) is dissolved in 20 ml. tetrahydrofuran and treated with ml. 1 molar borane in tetrahydrofuran solution. The mixture is stirred for a further 2 hrs. and excess borane decomposed with ab' solute ethanol. The solution is evaporated to dryness in vacuo, dissolved in water and extracted with ether. The organic extracts are discarded. The aqueous solution is made alkaline with sodium bicarbonate and extracted with chloroform.
  • the chloroform extracts are dried over magnesium sulphate and solvent is removed in vacuo.
  • the infrared spectrum shows no nitrile absorption.
  • the product obtained is ethyl l-(3-aminopropyl)- 5-chloroindole-2-carboxylate.
  • EXAMPLE XVl Ethyl l-(3-aminopropyl)-5-chloroindole-2- carboxylate (50 g, 0.18 mole) is dissolved in absolute ethanol and heated under reflux for several hours in the presence of a trace of sodium ethoxide. The solution is evaporated to dryness in vacuo and the residue suspended in water containing enough hydrochloric acid to give an acid reaction to pH paper. The mixture is extracted with chloroform (3 X 50 ml.), the combined extracts are washed once with water, dried over magnesium sulphate and solvent removed in vacuo.
  • EXAMPLE XXl A mixture of 9chloro-2,3,4,5-tetrahydro-.lH-l,4- diazepino [1,2-a] ind0l-l-one (5.3 g., 0.023 mole), potassium t-butoxide (3.4 g., 0.03 mole) and 30 ml. of dimethylformamide is stirred at room temperature. To the stirring solution, N.N-dimethyl chloroacetamide (3.6 g., 0.03 mole) in 25 m1. of dimethylformamide is added dropwise. The mixture is stirred an additional 1% hrs. and then is treated with water. The solid is filtered and recrystallized from chloroform-hexane.
  • the product obtained is 9-ehloro-2,3,4,5-tetrahydro-N, -tetrahydro-N,N-dimethyl-l-oxo- 1 l-l-l ,4-diazepino [1,2- a] indole-2acetamide; m.p. 183185 C.
  • EXAMPLE XXll A suspension of 9-ch1oro'2,3,4,5 tetrahydro1H-l,4- diazepino [1,2-a] indol-l-one (4.69 g., 0.02 mole) and 1.2 g. 50% sodium hydride in toluene ml.) is stirred under reflux for 2 hrs. Freshly distilled dimethylaminoethylchloride (3.22 g., 0.03 mole) in 10 ml. toluene is added. The mixture is heated under reflux for an additional 3 hrs. The mixture is cooled to room temperature, filtered, and the solvent is removed in vacuo. Ethereal hydrogen chloride is added to an ethanol solution of this solid.
  • Example XXIV The procedure of Example XIX is repeated except that an equivalent amount of benzyl bromide is used as the alkylating agent instead of a-bromo-p-xylene, and an equivalent amount of an appropriate diazepinoindole is used as the material to be alkylated, to yield the following products: 2,3,4,S-tetrahydro-Z-benzyl-1H-l,4-diazepino[ 1,2- alindol-l-one; 9-methoxy-2,3,4,5-tetrahydro-2 benzyl-1H-l,4- diazepino[1,2-a]indol-l-one; and 9-chloro-2,3,4,5-tetrahydro-2-benztll H-1 ,4- diazepino-[1,2-b I-one.
  • EXAMPLE XXV A. Aniline (27.9 g., 0.3 moles) is dissolved in 300 ml. percent hydrochloric acid and 300 g. ice and diazotised with a solution of sodium nitrite (22.5 g.) in 60 ml. ice water. The diazonium salt solution is added rapidly to a stirred mixture of ethyl a-ethylacetoacetate (50.6 g., 0.32 mole), 300 g. ice, 300 ml. absolute ethanol and 246 g. anhydrous sodium acetate. The mixture is stirred for 2 hrs. and extracted with benzene.
  • the benzene extract is washed with water, dried over magnesium sulphate and the solvent removed in vacuo.
  • the residual oil is dissolved in 60 ml. absolute ethanol and treated with 150 ml. ethanolic hydrogen chloride.
  • the mixture is heated under reflux for 2 hrs. and then cooled to room temperature.
  • the mixture is diluted with water and the solid separated by filtration and triturated with chloroform.
  • the chloroform mixture is dried and evaporated to give ethyl 3-methylindole-2-carboxylate as an off-white solid, mp. 134.5-l36C.
  • Example XXV-A The procedure of Example XXV-A is repeated except that an equivalent quantity of ethyl a-benzylacetoacetate and ethyl a-propylacetoacetate is substituted for the ethyl a-ethylacetoacetate used therein to yield, as respective products, ethyl 3-phenylindole-2- carboxylate and ethyl 3-ethylindole-2-carboxylate.
  • EXAMPLE XXVI A Ethyl 3-methylindole-2-carboxylate (39.1 g., 0.192 mole) is dissolved in dioxane (250 ml.) followed by the addition of acrylonitrile (12 g., 0.22 mole) and Triton B (5 ml.)v The mixture is stirred at 50-60C for 7 hrs. and then at room temperature overnight. The reaction mixture is poured into water made acidic with acetic acid. This mixture is extracted with chloroform and the chloroform extracts are washed with sodium bicarbonate and water, dried over sodium sulfate and evaporated in vacuo.
  • EXAMPLE xxvu A. Ethyl 3-methy1-N-(B-cyanoethyl)indole-2- carboxylate (58.0 g., 0.22 mole) is suspended in acetic anhydride (400 ml.) and hydrogenated on a Parr shaker over Raney nickel. After the uptake of hydrogen ceases, the catalyst is separated by filtration and washed with absolute ethanol. The combined filtrates are evaporated to dryness in vacuo. The residue is dissolved in chloroform and washed with sodium hydroxide to remove any residual acetic anhydride and then washed with water. The chloroform layer is dried over magnesium sulfate and the solvent removed in vacuo.
  • Example XXVII-A The reductive amidation procedure of Example XXVII-A is repeated using an equivalent quantity of each of the products obtained from Example XXVI-B to yield, as respective products, the 3'phenyl and 3- ethyl derivatives of ethyl l-(3-acetamidopropyl)- indole-2-carboxylate.
  • EXAMPLE XXVIII A Ethyl 1-(3-acetylaminopropyl)-3-methylindole-2- carboxylate (20 g., 0.066 mole) is added to a suspension of sodium hydride (3.9 g., 0.16 mole) in dry xylene -(280 ml.) and the mixture heated under reflux for 5 hrs. The reaction mixture is poured onto water and the resulting yellow precipitate is separated and dissolved in chloroform. The chloroform solution is washed with water, dried over magnesium sulfate and evaporated in vacuo.
  • Example XXVIII-A In accordance with the cyclization procedure outlined in Example XXVIII-A, except that an equivalent quantity of each of the esters obtained from Example XXVII-B is substituted for the ethyl 1( 3- acetylaminopropyl)-3-methylindole-2-carboxylate used therein, the following respective products are obtained: 2,3,4,5-tetrahydro-1l-phenyl-1H-l,4-diazepino[1,2- a]indoll-one; and 2,3,4,5-tetrahydro-1l-ethyl-lI-I-l,4-dia2epino[1,2- a]indol-1-one.
  • EXAMPLE XXX Ethyl 5-chloro3methylindole-Z-carboxylate (38 g., 0.16 mole) is dissolved in dioxane (300 ml.), followed by the addition of acrylonitrile (10.8 g., 0.19 mole) and Triton B (5 ml.). The mixture is stirred at 5060C for 4% hrs.. then at room temperature overnight. The reaction mixture is poured into water made acidic with acetic acid. The resulting solid is filtered off and dissolved in chloroform and the chloroform solution is washed with sodium bicarbonate and water, dried over sodium sulfate, and evaporated in vacuo.
  • Example XXXI The method of Example XXVII-A is repeated except that ethyl 5-chlor0-N(,B-cyanoethyl)-3-methylindole-2- carboxylate (24 g., 0.083 mole) is suspended in acetic anhydride (250 ml.). The uptake of hydrogen is complete after 5 hrs. Work-up of the reaction mixture gives an oil that is crystallized from aqueous ethanol to yield ethyl l-(acetamidopropyl)-5-chloro-3- methylindole-Z-carboxylate as a white solid in about 80 percent yield, m.p. 1l2114C.
  • EXAMPLE XXXII Ethyl l-(acetamidopropyl)-5-chloro-3-methylindole- Z-carboxylate (13.7 g., 0.041 mole) is added to a suspension of sodium hydride (2.l g., 0.045 mole) in dry xylene I50 ml.) and the mixture is heated under reflux for 6 hrs. The reaction mixture is filtered and the filtrate evaporated. The residue obtained is stirred with water and extracted with chloroform. The chloroform extracts are washed with 2N hydrochloric acid, then water, dried over magnesium sulfate and evaporated in vacuo.
  • Example XXXIII The indole synthesis procedure described in Example XXV-A may be used to prepare the compounds of formula (V). Accordingly, by using equivalent quantities of an appropriately substituted aniline and an appropriately substituted acetoacetate, the following indoles are obtained: methyl 5-fluoroindole-2-carboxylate; ethyl 5-fluoro-3methylindole-Z-carboxylate; ethyl 5-chloro3phenylindole-Z-carboxylate; methyl 5-ethoxy-3'ethylindole-Z-carboxylate; ethyl 5methoxy-3-phenylindole-2-carboxylate; and methyl 5-fluoro-3-ethylindole-Z-carboxylate.
  • Example XXXV The reductive amidation procedure of Example XXVII-A may he followed to prepare the acetamidopropyl indoles of formula (II).
  • the following respective products are obtained: methyl l-( 3-acetamidopropyl )-5-fluoroindole-2- 14 carboxylate; ethyl l-(3-acetamidopropyl)-5-fluoro-3-methylindole- Z-carboxylate; ethyl l-(3-acetamidopropyl)-5-chloro-3-phenylindole- 2-carboxy1ate; methyl l-(3-acetamidopropyl)-5-eth0xy-3-ethylindolecarboxylate; ethyl l-(3-acetamidopropy
  • Example XXXVI The cyclization procedure of Example XXVIII-A is repeated with an equivalent quantity of each of the idole esters obtained from Example XXXV to yield as respective products: 2,3,4,5-tetrahydro-9-fluorol H-1 ,4- diazepinol1,2alindol-l-one; 2,3,4,5-tetrahydro -9-fluoro-l l-methyl-l H-1 ,4- diazepino[l,2a]indol-l-one; Y 2,3,4,5-tetrahydro-9-chloro-l l-phenyl-lH-l ,4- diazepinol l ,2a]indol- I one; 2,3,4,5-tetrahydro-9-ethoxy-1 1-ethyl-lH-1,4- diazepinoI l ,2a]indol- 1 -one; 2,3,4,5-tetrahydro-9-methoxy
  • a]-indole (6.6 g., 0.03 mole) is heated on a steam-bath for 3 hrs. with 50 ml. acetic anhydride. The reaction mixture is concentrated under reduced pressure, dissolved in chloroform and washed with sodium hydroxide solution. The organic layer is washed with water and dried over anhydrous magnesium sulphate. Removal of the solvent in vacuo and crystallization of the resulting oil from aqueous ethanol affords 2-acetyl-9- chloro-2,3,4,5-tetrahydro-1H-l,4diazepino[1,2- alindole, m.p. l36.5C.
  • Woelm neutral alumina activity grade 1 the elution being carried out with benzene.
  • the solid obtained is recrystallized from aqueous ethanol to yield 2-acetyl-9-chloro-2,3,4,5-tetrahydroll-methyl-lH-l,4-diazepino[1,2-a]indole as a white powder, m.p. 120l22C.
  • EXAMPLE XLVIl The procedures of Examples XLlIl through XLVI demonstrate the general method of acylating the 9-R-l l-R-Z-unsubstituted compounds of formula (l-b) to yield the corresponding 2'lower alkanoyl derivatives. Accordingly, by following such procedures, except that equivalent quantities are used of an appropriate acylating agent and an appropriate Z-unsubstituted formula (l'b) compound to be acylated, the following 1.
  • R is a member selected from the group consisting of hydrogen. lower alkoxy, chloro and fluoro
  • R IS a member selected from the group consisting of hydrogen, lower alkyl and phenyl
  • R is a member selected from the group consisting of hydrogen lower alkyl, di-(lower alkyl)-amino-lower alkyl, di-(lower alkyl)-amidomethyl, benzyl and ptolylmethyl
  • R" is a member selected from the group consisting of hydrogen, lower alkyl, di-(lower alkyl)-amino-lower alkyl, benzyl, p-tolylmethyl and lower alkanoyl; and the therapeutically active acid addition salts of the foregoing basic nitrogen containing compounds.
  • Y is selected from the group consisting of methylene and carbonyl
  • R is selected from the group consisting of hydrogen, halogen and lower alkoxy and R is selected from the group consisting of hydrogen and lower alkyl.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Indole Compounds (AREA)
US828727A 1968-06-05 1969-05-28 Diazepinoindoles Expired - Lifetime US3867374A (en)

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Application Number Priority Date Filing Date Title
US828727A US3867374A (en) 1968-06-05 1969-05-28 Diazepinoindoles
FR6918611A FR2011901A1 (de) 1968-06-05 1969-06-05
CH183072A CH532599A (de) 1968-06-05 1969-06-05 Verfahren zur Herstellung neuer Indolderivate und deren Verwendung
GB27573/71A GB1278788A (en) 1968-06-05 1969-06-05 Lower alkyl indole-2-carboxylate derivatives
GB28490/69A GB1278787A (en) 1968-06-05 1969-06-05 Diazepinoindoles
CH860169A CH528527A (de) 1968-06-05 1969-06-05 Verfahren zur Herstellung neuer Indolderivate und deren Verwendung
CH1035071A CH537386A (de) 1968-06-05 1969-06-05 Verfahren zur Herstellung neuer Indolderivate
DE19691928726 DE1928726A1 (de) 1968-06-05 1969-06-06 Diazepinoindole

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3980797A (en) * 1974-06-14 1976-09-14 Merck Patent Gesellschaft Mit Beschrankter Haftung Hexahydro-diazepino-indole derivatives
US4287196A (en) * 1980-02-26 1981-09-01 Sandoz, Inc. Method of inhibiting prolactin secretion
US4352753A (en) * 1980-08-11 1982-10-05 American Home Products Corporation 3-[[(2,3-Dihydro-1H-indol-2-yl)carbonyl]thio]propanoic (and acetic) acids as intermediates
US4545935A (en) * 1983-09-12 1985-10-08 Iowa State University Research Foundation, Inc. Amidoalkylation reactions of anilines
WO1985004554A1 (en) * 1984-04-11 1985-10-24 Mcneilab, Inc. Amidine benzodiazepines, methods for their use and intermediates
US4587349A (en) * 1983-10-11 1986-05-06 Mcneilab, Inc. 1-amino-or nitro-benzyl)indoles useful as intermediates
US6734301B2 (en) 2000-03-14 2004-05-11 Pharmacia & Upjohn Company 2,3,4,5-Tetrahydro-1H-[1,4]diazepino[1,7-a]indole compounds
CN105246895A (zh) * 2013-04-02 2016-01-13 豪夫迈·罗氏有限公司 哌嗪并[1，2-a]吲哚-1-酮和[1，4]二氮杂*并[1，2-a]吲哚-1-酮

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3404806A1 (de) 1984-02-10 1985-08-22 Georg 8386 Thannenmais Aigner Vorrichtung zum fuehren von werkstuecken an werkzeugmaschinen, insbesondere holzbearbeitungsmaschinen
FR2559772B1 (fr) * 1984-02-22 1988-07-15 Sandoz Sa Nouveaux diazepinoindoles, leur preparation et leur utilisation comme medicaments
GB2215422A (en) * 1988-02-25 1989-09-20 Ford Motor Co Clutch release bearing assembly with sleeve for protecting shaft

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3980797A (en) * 1974-06-14 1976-09-14 Merck Patent Gesellschaft Mit Beschrankter Haftung Hexahydro-diazepino-indole derivatives
US4287196A (en) * 1980-02-26 1981-09-01 Sandoz, Inc. Method of inhibiting prolactin secretion
US4352753A (en) * 1980-08-11 1982-10-05 American Home Products Corporation 3-[[(2,3-Dihydro-1H-indol-2-yl)carbonyl]thio]propanoic (and acetic) acids as intermediates
US4545935A (en) * 1983-09-12 1985-10-08 Iowa State University Research Foundation, Inc. Amidoalkylation reactions of anilines
US4587349A (en) * 1983-10-11 1986-05-06 Mcneilab, Inc. 1-amino-or nitro-benzyl)indoles useful as intermediates
WO1985004554A1 (en) * 1984-04-11 1985-10-24 Mcneilab, Inc. Amidine benzodiazepines, methods for their use and intermediates
AU575162B2 (en) * 1984-04-11 1988-07-21 Mcneilab, Inc. Amidine benzodiazepines
US6734301B2 (en) 2000-03-14 2004-05-11 Pharmacia & Upjohn Company 2,3,4,5-Tetrahydro-1H-[1,4]diazepino[1,7-a]indole compounds
US20040209870A1 (en) * 2000-03-14 2004-10-21 Ennis Michael Dalton Novel 2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole compounds
CN105246895A (zh) * 2013-04-02 2016-01-13 豪夫迈·罗氏有限公司 哌嗪并[1，2-a]吲哚-1-酮和[1，4]二氮杂*并[1，2-a]吲哚-1-酮
CN105246895B (zh) * 2013-04-02 2017-09-22 豪夫迈·罗氏有限公司 哌嗪并[1，2‑a]吲哚‑1‑酮和[1，4]二氮杂环庚烷并[1，2‑a]吲哚‑1‑酮

Also Published As

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GB1278787A (en) 1972-06-21
FR2011901A1 (de) 1970-03-13
DE1928726A1 (de) 1969-12-11
GB1278788A (en) 1972-06-21
CH532599A (de) 1973-01-15
CH528527A (de) 1972-09-30

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