Condensed pyrroles bearing an N-phenyl substituent
United States Patent 1 Allen et al.  
 [451 Apr. 15, 1975 [54] CONDENSED PYRROLES BEARING AN N-PHENYL SUBSTITUENT [75] Inventors: Richard C. Allen, Somerville; V.  
 Brian Anderson, High Bridge, both of NJ.  
 [73] Assignee: American Hoechst Corporation,  
 Bridgewater, NJ.  
 [22] Filed: Mar. 1, 1973 [2!] Appl. No.: 336,919  
 [52] US. Cl. 260/326.12 R; 260/326.13 R;  
  260/586 R; 260/592; 424/274 [51] Int. Cl C07d 27/56 [58] Field of Search 260/326.l3 R, 326.27  
 [56] References Cited UNITED STATES PATENTS 8/1972 Shen et al. 260/302 X Primary E.\&#39;aminerJoseph A. Narcavage Attorney, Agent, or FirmCurtis, Morris &amp; Safford [57] ABSTRACT Novel N-phenylpyrroles are disclosed that are effective in the treatment of inflammation and pain in mammals and have the formula wherein R is a hydrogen, alkyl of l to 6 carbon atoms, thienyl, phenyl or phenyl substituted by halogen, trifluoromethyl, alkyl of l to 6 carbon atoms, alkoxy of l to 6 carbon atoms, alkanoyloxy of l to 6 carbon atoms, alkanoylamino of l to 6 carbon atoms, nitro, cyano, hydroxyl, amino or phenyl;  
 R is carboxyl, alkoxycarbonyl of 2 to 7 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2 to 7 carbon atoms, N,N-dialkylcarbamoyl of 3 to 7 carbon atoms, hydroxycarbamoyl or dialkylphosphinylalkoxycarbonyl of 4 to 10 carbon atoms;  
 R2 is hydrogen, hydroxyl, mercapto, halogen, trifluoromethyl, alkyl of l to 6 carbon atoms, alkoxy of l to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms, alkylthio of l to 6 carbon atoms, amino, alkylamino or I to 6 carbon atoms, dialkylamino of 2 to 6 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, alkanoylthio of 1 to 6 carbon atoms, thiocarbamoyloxy, alkylthiocarbamoyloxy of 2 to 6 carbon atoms, dialkylthiocarbamoyloxy of 3 to 7 carbon atoms, carbamoylthio, alkylcarbamoylthio of l to 6 carbon atoms, dialkylcarbamoylthio of 2 to 7 carbon atoms, carbamoylamino, alkylcarbamoylamino of 2 to 6 carbon atoms or dialkylcarbamoylamino of 3 to 7 carbon atoms;  
 R is hydrogen, alkanoyl of l to 6 carbon atoms, or phenyl;  
 X is alkylene of 3 to 5 carbon atoms, alkylene of 3 to 5 carbon atoms substituted by alkyl or alkoxy of l to 6 carbon atoms, divinylene, divinylene substituted by alkyl of l to 6 carbon atoms,  
 wherein D is hydrogen, alkyl of l to 6 carbon atoms, alkoxy of l to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, halogen, amino, nitro or trifluoromethyl; and n is l or 2.  
 12 Claims, N0 Drawings CONDENSED PYRROLES BEARING AN N-PHENYL SUBSTITUENT This invention relates to novel N-phenylpyrroles having anti-inflammatory and analgesic activity. to methods of preparing the same and to a method of treatment therewith for reducing inflammation and pain in mammals.  
  German Offenlegungsschriftl,938,9()4 relates to N- arylpyrroles of the formula Err e. 1  
 in which R and R are methyl-, phenyl-, methylphenylor halogenated phenyl and the N-phenyl group may carry one or two substituents. These compounds are described to be useful as anti-inflammatory and analgesic agents.  
  We have found a genus ofN-phenylpyrroles having superior anti-inflammatory and analgesic activity, and minimal side effects. These are compounds of the formula  3 X ll ll R wherein R is hydrogen, alkyl of l to 6 carbon atoms, thienyl,  
 phenyl or phenyl substituted by halogen, trifluoro-.  
 methyl, alkyl of l to 6 carbon atoms, alkoxy of l to 6 carbon atoms, alkanoyloxy of l to 6 carbon atoms, alkanoylamino of l to 6 carbon atoms, nitro, cyano, hydroxyl, amino or phenyl;  
  R, is carboxyl, alkoxycarbonyl of 2 to 7 carbon atoms, carbamoyl, .N-alkylcarbamoyl of 2 to 7 carbon atoms, N,N-dialkylcarbamoyl of 3 to 7 carbon atoms, hydroxycarbamoyl or dialkylphosphinylalkoxycarbonyl of 4 to 10 carbon atoms;  
 R is hydrogen, hydroxyl, mercapto, halogen, trifluoromethyl, alkyl of l to 6 carbon atoms, alkoxy of l to 6 carbon atoms, alkanoyloxy of l to 6 carbon atoms, alkylthio of l to 6 carbon atoms, amino, alkylamino of l to 6 carbon atoms, dialkylamino of 2 to 6 carbon atoms, alkanoylamino of l to 6 carbon atoms, alkan- U oylthio of l to 6 carbon atoms, thiocarbamoyloxy, alkylthiocarbamoyloxy of 2 to 6 carbon atoms, dialkyl thiocarbamoyloxy of 3 to 7 carbon atoms, carbamoylthio, alkylcarbamoylthio of l to 6 carbon atoms, dialkylcarbamoylthio of 2 to 7 carbon atoms, carbamoylamino, alkylcarbamoylamino of 2 to 6 carbon atoms or dialkylcarbamoylamino of 3 to 7 carbon atoms;  
  R;, is hydrogen, alkanoyl of l to 6 carbon atoms, or phenyl:  
  X is alkylene of 3 to carbon atoms, alkylene of 3 to 5 carbon atoms substituted by alkyl or alkoxy of l to 6 carbon atoms, divinylene, divinylene substituted by alkyl of l to 6 carbon atoms,  
 wherein D is hydrogen. alkyl of l to 6 carbon atoms. alkoxy&#39;of l to 6 carbon atoms, alkanoyloxy of l to 6 carbon atoms, alkanoylamino of l to 6 carbon atoms. halogen, amino, nitro or trifluoromethyl; and n is l or 7 The compounds that are preferred are those in which R is alkyl of l to 6 carbon atoms, thienyl, phenyl, diphenyl or phenyl substituted by halogen, trifluoromethyl, alkyl of l to 6 carbon atoms, alkoxy of l to 6 carbon atoms, nitro, cyano or hydroxy;  
  R is hydrogen, hydroxyl, mercapto, halogen, trifluoromethyl, alkoxy of l to 6 carbon atoms. alkanoyloxy of l to 6 carbon atoms, amino, alkanoylamino of l to 6 carbon atoms, dialkylthiocarbamoyloxy of 3 to 7 carbon atoms or dialkylcarbamoylthio of 3 to 7 carbon atoms; and  
  Dis hydrogen, alkoxy of l to 6 carbon atoms or halogen are particularly desirable as are compounds in which R is a tertiary butyl, thienyl, phenyl, diphenyl or phenyl substituted by chlorine,&#39;bromine, fluorine, hydroxyl, trifluoromethyl, methyl, methoxy, nitro or cyano;  
  R is carboxyl, methoxycarbonyl, ethoxycarbonyl, carbamoyl, N-ethylcarbamoyl. N,N-diethylcarbamoyl, hydroxycarbamoyl or dimethylphosphinylmethoxycarbonyl;  
  R- is hydrogen, hydroxyl, mercapto, chlorine, bromine, trifluoromethyl, methoxy, acetyl, acetylamino, dimethylthiocarbamoyloxy or dimethylcarbamoylthio;  
 R is hydrogen, acetyl or phenyl; and  
  X is X alkylene of 3 to 5 carbon atoms, butylene substituted by methyl, tertiary butyl or methoxy, d-ivinylene, divinylene substituted by tertiary butyl,  
 wherein D is hydrogen, methoxy or chlorine.  
 Optimum results have been obtained with 3-( 3-carboxy-4-hydroxyphenyl )-4,5-dihydro-2- phenylbenz[e]indole,  
 3-( 4-acetoxy-3-carboxyphenyl )-4,5-dihydro-2- phenylbenzlelindole, i  
 3-( 3-carboxy-4-h&#39;ydroxyphenyl )-2- phenylbenzl e]indole, v i  
 l-( 3-carboxy-4-hydroxyphenyl )-2-phenylindole, and  
  3 l-( 3-carboxy-4-hydroxyphenyl )-2-phenyl-4,5.6.7- tetrahydroindole.  
  The compounds of the present invention are obtainable by any of several syntheses described immediately below. These generally involve. as a first step. the formation of a y-diketone, &#39;y-ketoaldehyde, or B-acetylenic ketone. and second, condensation of this intermediate with an appropriately substituted aniline in the presence of an acid catalyst. In the case of fully aromatic compounds. the second step is followed by an aromatization reaction. Methods A and B:  
  An oz-haloketone. ketal. aldehyde, or acetal is condensed with an enamine of an appropriate ketone in a solvent such as dimethylformamide or toluene at a temperature of to 120C. for a time of 1 hour to 72 hours, followed by hydrolysis at a temperature of 25 to l00C. for a period of l to 24 hours. to provide a &#39;y-diketone or y-ketoaldehyde.  
  hal A x t IHR H x I R3 0 ha] CHR3 P. X i o R5\N l R6 Methods C and D An a-haloketone. ketal. aldehyde or acetal is reacted with an appropriate ketone in the presence of a base such as sodium hydride in a solvent such as toluene at a temperature of 70-l C. for a time of l to 72 hours to provide a y-diketone or y-ketoaldehyde.  
 Method E A sterically hindered B-ketoalkanoate is treated with an a-haloketone, ketal, aldehyde or acetal in the presence of a base such as sodium hydride in a solvent such as dimethylformamide or toluene at a temperature of 0 to l 10C. for a period of l to 24 hours followed by acid hydrolysis to provide a y-diketone or &#39;y-ketoaldehyde.  
  A B-ketosulfoxide is treated with an a-haloketone. ketal, aldehyde. or acetal in the presence of a base such as sodium hydride in a solvent such as dimethylsulfoxide at a temperature of 0 to 100C. for a period of l to 24 hours followed by reduction with a reagent such as aluminum amalgam in a solvent such as aqueous tetrahydrofuran, to provide a &#39;y-diketone or &#39;y-ketoaldehyde.  
  soca W H X (IZHRB x R3 MethodG Method H An enol lactone of a y-ketocarboxylic acid is treated with an N,N-dialkylnamine in a solvent such as acetonitrile at a temperature of 25 to 100C. for a period of 1 minute to 5 hours followed by acid hydrolysis to provide a &#39;y-diketone or &#39;y-ketoaldehyde.  
 Method 1 An appropriately substituted furan is treated with bromine in the presence of a base such as sodium carbonate at a temperature of to 10C. in a solvent such as methanol followed by hydrogenation at a pressure of l to 2 atmospheres with a catalyst such as 5 percent on CaCO for a period of l to 24 hours with subsequent acid hydrolysis. to provide a &#39;y-diketone or &#39;y-ketoaldehyde.  
 Method J An enamine of an appropriate ketone is condensed with a substituted a-haloacetylene in a solvent&#39;such as 7 dimethylformamide at a temperature of 0 to 100C. for a period of l to 72 hours, followed by hydrolysis at a temperature of to 100C. for a period of l to 6 hours and treated with a reagent such as mercurated Amberlite IR 120 resin in a solvent such as methanol at a temperature of 25 to 75C. for a period of l to 10 hours, to provide a y-diketone.  
 hal  
 c n i R CH R Method L An enamine of an appropriate ketone is condensed with a substituted oz-haloacetylene in a solvent such as dimethylformamide at a temperature of 0 to 100C for a period of l to 72 hours followed by hydrolysis at a temperature of 25 to 100C for a period of l to 6 hours, to provide a B-acetylenic ketone.  
 Method M An appropriate ketone is treated with a substituted a-haloacetylene in the presence of a base such as potassium t-butoxide in a solvent such as t-butanol for a period of l to 10 hours at a temperature of 25 to 100C. to provide a B-acetylenic ketone.  
  CH R I X 2 C -i=- x 3 so u MethodN An a,,B-unsaturated ketone is reacted with a substituted diethynylcopperlithium-tributyl phosphine in a solvent such as tetrahydrofuran at a temperature of 25 100 to -50C. for a period of l to 24 hours, to provide a B-acetylenic ketone.  
  CHR R g -4. (RC-:- C) CuLi x 3 t 1% C I R In the foregoing schematically illustrated reactions, R. R R R and X are as hereinbefore defined; hal is chlorine, bromine or iodine; R,-, and R are the same or different alkyl groups of 1 to 6 carbon atoms each so fused to form, with the nitrogen atom to which they are attached, a cyclic secondary amine having a 5&#39; to 6 membered ring such as pyrrolidine, morpholine or piperidine; R is alkyl of 1 to 6 carbon atoms or both R s of a group are fused to form a chain of 2 or 3 carbon atoms; R, is a branched or cyclic alkyl of4 to 8 carbon atoms. For the second step in the reaction sequence, a y-diketone of y-ketoaldehyde is reacted with an appropriately substituted aniline under acidic conditions in a solvent such as acetic acid for a period of 5 minutes to 8 hours at a temperature of 50 to C to provide a pyrrole of the present invention (Method 0). Alternatively, a B-acetylenic ketone is reacted with an appropriately substituted aniline in a solvent such as ethanol fora period of 1 hour to 24 hours at a temperature of 50 to 200C. in the presence ofa catalyst such as cuprous ion to provide a pyrrole of the present invention (Method P).  
  An optional third step in the reaction sequence is the aromatization of a partially saturated pyrrole of the invention by treatment with a catalyst such as percent Pd/C in a solvent such as xylene at a temperature of l00 to 200C. for 6 to 72 hours to form a fully aromatic pyrrole.  
  An aryl carboxylic group of a compoundprepared according to Methods 0 or P (R being carboxyl) can be reacted in known manner (a) to yield the corresponding ester (Method Q; R being alkoxycarbonyl with l to 6 carbon atoms), or (b) to prepare the corresponding acyl chloride (Method R; R being carbonyl chloride), or (c) to prepare the corresponding amide (Method T; R being carboxamide).  
  Further, an aryl carboxylic acid ester group of a compound prepared according to Method 0, P (R, being alkoxycarbonyl with l to 6 carbon atoms) can be reacted in known manner (a) with hydroxylamine to provide the corresponding hydroxamic acid (Method S; R being hydroxycarbamoyl) or (b) with alkylamine to yield the corresponding N-alkyl amide (Method T; R being alkylcarbamoyl with l to 6 carbon atoms).  
  Comparative tests of representative compounds of the invention with aspirin and phenylbutazone indicate that the compounds of the invention have antiinflammatory-analgesic-antipyretic activity in mammals that makes them useful in the treatment of arthritis and other inflammatory diseases with exceptionally minimal side effects, notably gastrointestinal irritation. These conclusions follow from the data in Table I below.  
  The first column of data demonstrates the ability of the compounds of the present invention to suppress edema induced by carrageenin in rat paws, a standard laboratory procedure to assess useful antiinflammatory activity [Proc. Soc. Exp. Biol. Med, 111, 544 (1962); J. Pharmacol. Exp. Ther., I41, 369 (1963)]. Their activity is expressed as ED.-,n, the dose (mg/kg) needed to produce a 50 percent reduction in edema as compared to non-treated controls.  
  The second column of data compares analgesic activity as demonstrated by ability to suppress the characteristic writhing induced in mice by 2-phenyl-l,4- benzoquinone [Proc. Soc. Exp. Biol. Med., 95, 729  
 (1957)]. The activity of several representative compounds of the present invention and of aspirin and phenylbutazone is expressed as ED the dose (mg/kg) of compund producing a 50 percent reduction in the number of writhes as compared to non-treated Z-phenyll ,4-benzoquinone dosed controls.  
  A common property of useful anti-inflammatory agents is their ability to lower elevated body temperatures. The third column of the data demonstrates the ability of the compounds of the present invention to reverse yeast-induced pyrexia in rats. Groups of ten female Charles River or Wistar rats l 50 gm) are injected with a 20 percent water suspension of Brewers Yeast&#34; subcutaneously into the nape of the neck (10 ml/kg.). The animals are starved (water ad lib.) and 18 hours later rectal temperatures are monitored (Tele- Thermometer, Yellow Springs Instrument Co., lnc., Yellow Springs, Ohio). Animals with a temperature 2 372C. are considered fevered. Drugs are administered orally 10 ml/kg) using distilled water and, if insoluble, one drop ofa dispersing agent, e.g. Tween 80, per 10 ml. Temperatures are recorded 2 hours post drug. Significant activity is a reduction in rectal temperature 3 1 from the mean control temperature. The activity of the compounds tested is expressed as ED the dose (mg/kg) of a compound producing a reduction of 2- 1 in rectal temperature of fevered rats from the mean fevered control temperature in 50 percent of the animals.  
  A common but undesirable side effect of antiinflammatory agents is the production of gastric irritation in mammals. The fourth column of data demonstrates that the compounds of the present invention show a low incidence of gastric irritation when tested in fasted rats. Groups of male or female rats (Wistar, Long Evans or Charles River), -180 gm, are utilized for this assay using 10 animals per dose group. The animals are starved for 48 hours (H O ad lib) prior to administration of drug orally at 10 ml/kg. Drugs are prepared using distilled water solutions or, if insoluble, 1 drop of a dispersing agent, e.g. Tween 80&#34;/l0 ml, is used with homogenization. The control group receives the vehicle only (10 ml/kg). For a time response, animals are treated with a highly active anti-inflammatory dose of the test compound, then sacrificed at 2, 3 and 5 hours or 3, 5 and 7 hours post drug. Stomachs are removed and examined for gastric irritation, which is defined as ulceration and/or hemmorhage of gastricmu- The compounds of the present invention also possess the ability to suppress adjuvant-induced arthritis in rats. another standard laboratory procedure to assess useful anti-inflammatory activity [D. T. Walz, M. M.  
 COS, The resence of a Sin le ulcer or hemmorha 5 Dolan. M. .l. DiMartino. S. L. Yankell, Proc. Soc. Exp.  
  P g f Biol. &amp; Med. :37. I466 (197] The efficacy of Sev- 5pot posmve stomachs must be clefm eral representative compounds ofthe present invention to be negatwe&#39; A dose response run at the peak and comparable data for aspirin and phenylbutazone. at least foul&#34; dose [He&#39;s of test gthe two commonly used antiinflammatory agents in mamgasmc lrrlmblhty expressed as an the dose (mg/kg) mals is illustrated in Table ll, where activity is indicated of compound producing iritation in 50 percent of the as percent decrease (at various doses) in lnt&#39;lammatiion animals after 7 hours. compared to adjuvant treated controls.  
 Table l CARRA- PHENYLQUI- ANTIPYRETIC GASTRIC GEENIN NONE PAW wn r rgigio- ASSAY-RATS IRRITATION EDEMA-RATS ASSAY-RATS Treatment ED (mg/kg) EDF, (mg/kg) ED (mg/kg) ID (mg/kg) Aspirin l-l40 53 42 Phenylbutazone 83 89 50 75 l-(3-carboxy-4- 87 17 4] I30 hydroxyphenyl)- 2-phenyl-4,5,6, 7-tetrahydr0indole l-(3-carboxy-4 l l0 l0 50 I25 hydroxyphenyl)- Z-phenyl-l 4,5. 6-tetrahydrocyclopentalblpyrrole 3-(3-carboxy-4- 63 I0 69 300-350 hydroxyphenyl 4.5-dihydrd-2- phenylbenz[ e] indole l-( 3-carboxy-4- 125 I0 I00 200 hydroxyphenyl l,4,5 ,6,7,8-hexahydr0-2&#39;phenylcyclohepta[b]pyrrole 3-(3-carb0xy-4- 90 16.5 l00 200 hyd roxyphenyl 2-phenylbenzle] ind e l-( 3-carboxy-4- 8 8 hydroxyphenyl 2-(4-fluorophenyl) 4,5,6.7- tetrahy,droindole 3-( 4-acetoxy-3- 70 16.5 300 carboxyphenyl 4.5-dihydro-2- phenylbenzle] indol l-( 3-carboxy-4- I40 mercaptophenyl)- 2-phenyl-4,5 6,7- tetrahydroindole Table ll Dose Inhibition of Edema on Day 2] (mg/kg/day) Adjuvant Injected Non-Injected Treatment Paw Paw Aspirin 200 37 47 Phenylbutazone 50 7| l-(3-carboxy-4- 7 I00 8O hydroxyphenyl)-2- 50 38 72 phenyl-4.5.6,7- tetrahydroindole l-( 3-carboxy-4- I00 57 75 hydroxyphenyl)-2- phenyl- 1 ,4,5,6- tctrahydrocyclopenta [blpyrrole 3-( 3-carboxy-4- IO 27 29 hydroxyphenyl)-4,5- 25 49 72 dihydro henylbenz 50 69 81 [e llndo e l-(3-carboXy-4- 75 9O hydroxyphenyl)- l,4,5,6,7.8-  
 hexahydro-Z-phenylcyclohepta[ b lpyrrole Table Il-Continued Dose Inhibition of Edema on Day 21 (mg/kg/day) Adjuvant Injected Non-Injected Treatment Paw Paw 3-(3-carhoxy-4- 25 45 50 hydroxyphenyU-L 50 70 70 p enylbenz[e]indo1e l-(3-carhoxy-4- 100 56 64 hydroxyphenyl )-2- (4-fluoropheny1)- 4.5.6.7-tetrahydroindole 3-(4-acetoxy-3- 50 56 68 carboxyphenyl)-4.5- 100 82 93 dihydro-Z-phenylbenz [elindole l-(3-carboxy-4- 23 23 mercaptophenyU-Z- 25 43 57 phenyl-4.5.6.7- 50 67 80 tetrahydroindole In summary. the data in Tables 1 and 11 show that the EXAMPLE 1 compounds of the present invention are effective antiinflammatory agents in mammals at doses of from about 1 to about 200 mg/kg per day while displaying an unusual minimum of undesirable side effects.  
  The compounds of the present invention may be administered by any convenient route such as orally. intramuscularly. intravenously, subcutaneously. or interperitoneally. The preferred route of administration is oral. for example, with an inert diluent or with an edible carrier or in gelatin capsules or tablets. For the purpose of oral therapeutic administration. the active compounds of this invention may be incorporated with excipients and used in the form of tablets. troches. capsules. elixirs. suspensions, syrups. wafers, chewing gum. and the like. These preparations should contain at least 0.5 percent of active compound. but may be varied depending upon the particular form and may conveniently be between 7 percent to about 70 percent of the weight of the unit. The amount of active compound in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that an oral dosage unit form contains between 10 and 200 milligrams of active compound.  
  The tablets. pills. capsules. troches. and the like may also contain the following ingredients: a binder such as gum tragacanth or gelatin; an cxcipient such as starch or lactose. or disintegrating agent such as alginic acid. potato starch and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose or saccharin may be added or a flavoring agent such as peppermint. methyl salicylate. or orange flavoring. When the dosage un&#39;it form is a capsule. it may contain. in addition to materials of the above type. a liquid carrier such as a fatty oil. Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit. for example. as coatings. Thus. tablets or pills may be coated with sugar. shellac. or both. A syrup may contain. in addition to the active compounds. sucrose as a sweetening agent. and certain perservatives. dyes and colorings. and flavors. Materials used in preparing these various compositions must be pharmaceutically pure and non-toxic in the amounts utilized.  
  The following examples are representative of the compounds of the invention and their preparation. Temperatures are expressed in C.  
 a. Z-Phenacyl-l-tetralone To a stirred refluxing solution of 20.2 g. (0.1 mole of 1-( l-pyrrolidino)-3.4-dihydronaphthalene and 50 ml. of toluene was added dropwiise during 30 minutes under nitrogen a solution of 20.1 g. (0.1 mole) of phenacyl bromide in 65 ml. of dry toluene. The mixture was heated under reflux for 6 hours. diluted with 50 ml. of water. refluxed for 4 hours. and cooled. The layers were separated and the aqueous phase was extracted with benzene. The organic solution was dried over sodium sulfate and concentrated to a semi-solid. Trituration with cold 30-60 petroleum ether gave 23.6 g. (78%) of solid. m.p. 7376. Recrystallization from 60-90 petroleum ether raised the melting point to 8788.  
 Calc. for C H O 81.79% C; 6.10% H;  
  A solution of 10.5 g. (0.04 &#39;mole) of 2-phenacyl-ltetralone (m.p. 73-76). 5.5 g. (0.04 mole) of maminobenzoic acid, and 35 m1. of glacial acetic acid was heated under reflux for 3 H2 hours. cooled and filtered. The filter cake was washed with water and dried to provide 8.6 g. of solid. m.p. 225-228. Recrystallization from ethanol and from ethanol-water gave offwhite crystals. m.p. 253.5255.  
 Calc. for C ,,H NO 82.17% C; 5.24% H; 3.83% N; Found 81.51% C; 5.32% H: 3.80% N.  
 EXAMPLE 2 a. Z-Phenacylcyclohexanone A solution of 60.9 g (0.31 mole) of phenacyl bromide in 150 ml. of toluene was added dropwise with stirring .to a refluxing solution of 46.6 g. of l-pyrrolidino-lcyclohexene in 150 ml. of toluene. The mixture was heated under reflux for 2 hours. diluted with 150 ml. of water, refluxed for 3 hours and cooled. The layers were separated, and the aqueous phase was extracted with ether. The organic solution was dried and concentrated to an oil. Distillation gave 42.1 g. (64%) of orange liquid, b.p. l3514l (0.05 mm.), which solidified. Recrystallization from ether-petroleum ether gave tan crystals, m.p. 4445.  
 Calc. for C H O 77.78% C; 7.41% H;  
 Found 77.73% C; 7.58% H.  
  b. l-(3-Carboxyphenyl)-2-phenyl-4.5,6.7- tetrahydroindole A solution of 10.8 g. (0.05 mole) of 2-phenacylcyclohexanone, 6.85 g. (0.05 mole) of m-aminobenzoic acid and 30 ml. of glacial acetic acid was heated under reflux for 6 hours, cooled and filtered. The filter cake was washed with water and recrystallized from ethanol to provide 5.7 g. (36%) of crystals, m.p. l9ll93.  
 Calc. for C H NO z 79.50% C; 5.99% H; 4.42% N;  
 Found: 79.16% C; 6.09% H: 4.40% N.  
 EXAMPLE 3 1-( 2-Methoxycarbonylphenyl )-2-phenyl-4,5,6,7- tetrahydroindole A solution of 10.8 g. (0.05 mole) of Z-phenacylcyclohexanone, 7.55 g. (0.05 mole) of methyl anthranilate; and 30 ml. of glacial acetic acid was heated under reflux for 7 hours, cooled, and diluted with water. The layers were separated, and the aqueous phase was extracted with ether. The combined organic phase was washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to an oil. Chromatography on silica gel with toluene as the elutent gave 2.91 g. (18%) of a yellow oil.  
 Calc. for C- H NO 79.76% C; 6.34% H; 4.23% N;  
 Found: 79.29% C; 6.54% H; 3.91% N.  
 EXAMPLE 4 1-( 4-Carboxyphenyl )-2-phenyl-4,5 ,6,7- tetrahydroindole A solution of 10.8 g. (0.05 mole) of Z-phenacylcyclohexanone, 6.85 g. (0.05 mole) of p-aminobenzoic acid and 30 ml. of glacial acetic acid was heated under reflux for 5 hours and cooled. The solid which separated was collected and recrystallized from ethanol to provide 5.85 g. (37%) of pale yellow crystals, m.p. 244246.  
 Calc. for C- H,,,NO. 79.50% C; 5.99% H; 4.42% N;  
 Found: 79.30% C; 6.09% H; 4.53% N.  
 EXAMPLE 5 1-( 3-Carboxy-4-hydroxyphenyl )-4.5-dihydro-2- phenylbenzl glindole l l N EXAMPLE 6 l-( 4-Carboxy-3-hydroxyphenyl )-2-phenyl-4,5 ,6,7- tetrahydroindole CO H  A solution of 32.4 g. (0.15 mole) of Z-phenacylcyclohexanone, 23.0 g. (0.15 mole) of 4-aminosalicyclic acid and ml. of glacial acetic acid was heated under reflux for 7 hours, cooled, diluted with 90 m1. of water and extracted with ether. The ether solution was dried over sodium sulfate and concentrated. The residue was recrystallized from benzene-ethanol to provide 3.36 g. (7%) of yellow crystals, m.p. 193195.  
 Calc. for C ,H, NO;,: 75.66% C; 5.74% H; 4.20% N; Found: 75.50% C; 5.81% H; 4.00% N.  
 EXAMPLE 7 1-( Z-Carboxyphenyl )-4,5-dihydro&#39;2- phenylbenzlglindole A mixture of 20.0 g. (0.076 mole) of Z-phenacyl-ltetralone, 9.86 g. (0.072 mole) of anthranilic acid. and 70 ml. of glacial acetic acid was heated under reflux for 50/2 hours and concentrated to an oil, which crystallized from isopropyl alcohol to provide 10.7 g. (41%) of solid, m.p. 170185. Recrystallization from ethanol-water, isopropyl alcohol, and cyclohexanemethanol gave 4.0 g. of yellow crystals, m.p. 223.5224.5.  
 Calc. for C ,-,H,,,NO 82.17% C; 5.24% H; 3.83% N;  
 Found: 81.76% C; 5.30% H; 3.82% N.  
 EXAMPLE 8 l-( 4-Dimethylphosphinylmethoxycarbonylphenyl 4,5-dihydro-2-phenylbenzl g]indole CO CH PO CH 2 A mixture of 2.6 g. (0.01 mole) of Z-phenacyl-ltetralone, 2.3 g. (0.01 mole) of dimethylphosphinylmethyl p-aminobenzoate, 0.4 g. of p-toluenesulfonic acid. and 250 ml. of dry toluene was heated under reflux for 73 hours, concentrated to about 100 ml., diluted with ml. of cyclohexane. and cooled. The solid which separated was collected to provide 2.6 g. (57%) of solid, m.p. l7l-l73.Recrystallization from cyclohexane-henzene gave pale yellow crystals, m.p. 180-181.  
  Calc. for C ,,H- NO P: 73.83% C; 5.75% H; 3.08% N; Found 73.75% C; 5.56% H; 2.94% N.  
 EXAMPLE 9 1-( 3-Carboxy-4-hydroxphenyl )-2-phenyl-4,5,6. tetrahydroindole A solution of 49.7 G. (0.23 mole) of Z-phenacylcyclohexanone, 35.2 g. (0.23 mole) of S-aminosalicylic acid. and ml. of glacial acetic acid was heated under reflux under nitrogen for 3% hours. A solid separated and was collected, washed with water, and recrystallized from acetic acid to provide 46.9 g. (60%) of pale yellow crystals, m.p. 209-211.  
 Calc. for C- H NO 75.66% C; 5.74% H; 4.20% N;  
 Found: 75.61% C; 5.75% H; 4.30% N.  
 EXAMPLE l0 1-( 3-Carboxy-4-methoxyphenyl )-2-phenyl-4,5,6,7- tetrahydroindole To a stirred mixture of 5.86 g. (0.018 mole) of 1-(3- carboxy-4-hydroxphenyl)-2-phenyl-4,5,6,7- tetrahydroindole, 2.49 G. (0.044 mole) of powdered potassium hydroxide, and 50 ml. of acetone was added dropwide during 10 minutes at room temperature a solution of 5.31 g. (0.042 mole) of dimethyl sulfate in 15 ml. of acetone. After 3 hours, the solvent was removed under reduced pressure, the residue was suspended in water, and the mixture was extracted with ethyl acetate. The organic phase was washed with sodium bicarbonate solution, dried over magnesium sulfate, and concentrated to 63 g. of 1-( l-methoxy-3- methoxycarbonylphenyl)-2-phenyl-4,5,6,7- tetrahydroindole as an amber oil.  
  A mixture of this oil, 50 ml. of methanol, 20 ml. of water, and 2.13 g. (0.038 mole) of potassium hydroxide was heated under reflux for 2 hours, concentrated to about 50 ml.. diluted with water, and acidified with hydrochloric acid. The solid which separated was collected and recrystallized from acetonitrile to provide 3.6 g. (51%) of crystals, m.p. l79l89.  
 Calc. for C H NO z 76.06% C; 6.09% H; 4.03% N;  
 Found: 75.34% C; 6.08% H; 4.03% N.  
 EXAMPLE ll 1-( 4-Acet0xy-3-carboxyphenyl )-2-phenyl-4,5 ,6,7- tetrahydroindole OCOCH A mixture of 25.0 g. (0.075 mole) of l-(3-carboxy-4- hydroxyphenyl )-2-phenyl-4,5,6,7-tetrahydroindole and 225 g. (2.25 mole) of acetic anhydride was heated under reflux for 3 hours, diluted with 200 ml. of&#39;tetrahydrofuran, and poured into 3 l. of water. An oil separated and slowly solidified. Recrystallization from acetic acid gave a tan solid, m.p. 162.  
 Calc. for c H..No.= 73.58% c&#39;;&#34;5.64% H-.&#39; 3.73% N; Found: 73.37% Ci 5.58% H; 3.78%N.  
 EXAMPLE 12 l-( 4-Hydroxy-3-methoxycarbonylphenyl )-2-p henyl- 4.5 .6.7-tetrahydroindole CO CH Hydrogen chloride gas was bubbled through a boiling mixture of 25.0 g. (0.075 mole) of l-( 3-carboxy-4- hydroxyphenyl)-2-pheny&#39;l-4.5.6,7 tetrahydroindole and 750 ml. of methanol for 2 hours. The mixture was heated under reflux for 18.5 hours, cooled and filtered to provide 19.6 g (75%) of white solid. Recrystalliz&#39;ation jfrom methanol gave colorless crystals. m.p.  
 Calc. for C H NO;,: 76.06% C; 9.06% H; 4.03% N. Found 1 76.00% C; 6.03% H; 3.91% N.  
 EXAMPLE l3 1-(4-N,N-Dimethylthiocarbamoyloxy-3- methoxycarbonylphenyl )-2-phenyl-4.5,6.7- tetrahydroindole O CH  A mixture of 3.47 g. (0.0] mole) of l-(4-hydroxy-3- methoxycarbonylphenyl)-2-phenyl-4.5,6,7- tetrahydroindole. 3.36 g. (0.03 mole) of L4- diazabicyclo[2.2.21octane, 3.70 g. (0.03 mole) of N,N-dimethylthiocarbamoyl chloride. and ml. of dry dimethyl formamide was heated at 60 for 2 hours, diluted with water. and extracted with benzene. The organic phase was washed with water, dried over sodium sulfate. and concentrated to an oil. Recrystallization from methanol gat&#39;e 2.8 g. (65% or colorless solid. m.p.  
 EXAM PLE l4 l-(4-N,N-Dimethylcarbamoylthio-3- methoxycarbonylphenyl)-2-phenyl-4.5,6.7- tetrahydroindole dimethylthiocarbamoyloxy-3- methoxycarbonylphenyl)-2-phenyl-4.5.6.7- tetrahydroindole was heated for 2 hours at 220-230. cooled. and treated with isopropyl alcohol to provide 6.9 g. (77%) of yellow solid. Recrystallization from ether gave colorless crystals. m.p. -l4l.  
 Calc. for C ,-,H .;N O;,S 69.l0% C; 6.03% H; 6.45%  
 Found 68.95% C; 6.23% H; 6.37% N.  
 EXAMPLE l5 l-( 3-Carboxy-4-mercaptophenyl )-2-phenyl-4.5 .6,7- tetrahydroindole CO H  A mixture of 3.7 g. (0.009 mole) of l-(4-N.N- dimethylcarbamoylthio-3-methoxycarbonylphenyl )-2- phenyl-4,5.6,7-tetrahydroindole. 2.4 g. (0.04 &#39;mole) of potassium hydroxide, 35 ml. of methanol and 10 ml. of water was heated under reflux for 3 hours. diluted with water, and acidified. The solid which separated was collected and recrystallized fromacetic acid to provide l.6 g. (54%) of colorless crystals. m.p. l86-l88.  
  Calc.for C ,H ,,NO S 72.l8% C; 5.48% H; 4.01% N;  
 Found 72.02% C; 5.56% H; 3.96% N. I  
 EXAMPLE 16 l 3-Carboxy-4-hydroxyphenyl )-2-phenylindole CO H  A mixture of 3.33 g. (0.0] mole) of l-(3-carboxy-4- hydroxyphenyl )-2-phenyl-4,5 ,6.7 -tetrahydroindole 4.0 g. of 10 percent palladium on carbon. and 250 ml. of xylene was heated under reflux with stirring under nitrogen for&#39;3 days. filtered. and concentrated to a solid. Trituration with cyclo&#39;hexane afforded 2.4 g. (73%) of solid, m.p. 2 1 0-&#34;2 1 2; Recrystallization from acetic acid gave colorless crystals, m.p. 2l3.5-214.5.  
 Calc. for C- H NO 76.58% C; 4.59% H: 4.25% N; Found 77.09% C: 4.62% H; 4.22% N.  
 EXAMPLE 17 l-( 4-Acetoxy-3-carboxyphenyl )-2-phenylindole I CO H C0CH EXAMPLE 18 a. 2-(p-Bromophenacyl)cyclohexanone A suspension of 50 g. (0.18 mole) of pbromophenacyl bromide in 2l5 ml; of-toluene was added in small portions to a stirred boiling solution of 27.2 g. (0.18 mole) of l-pyrr0lidino-l-cyclohexene in 90 ml. of toluene. The mixture was heated under reflux for 2 hours. diluted with 90 ml. of water. and refluxed for 3 hours. The layers were separated and the aqueous phase was extracted with ether. The organic solution was dried over sodium sulfate and concentrated to an oil which solidified. Recrystallization from cyclohexane-ethanol gave l9.8 g. (37%) of colorless crystals. m.p. 78-80.  
  Calc. for C H BrO; 56.95% C; 5.08% H; 27.l2% Br;  
 Found 56.88% C; 4.99% H; 27.37% Br.  
  b. 2-( 4-Bromophenyl l 3-carboxyphenyl )-4.5.6.7- tetrahydroindole CO H  A mixture of 44.3 g. (0.l5 mole) of 2-(pbromophenacyl) cyclohexanone. 20.6 g. (0.15 mole) of m-aminobenzoic acid. and 90 ml. of glacial acetic acid was heated under reflux for 5 hours. cooled and rcfilted to provide 13.8 g. (23%) of solid. m.p. 242-244. Recrystallization from ethanol-water gave crystals, m.p. 242-243.  
  Calc. for C H BrNO 63.64% C; 4.55% H; 20.20% Br; 3.54% N.  
 Found 63.5l% C; 4.66% H; 20.l5% Br; 3.47% N.  
 EXAMPLE 19 a 2-( m-Trifluoromethylphenacyl )cyclohexanone A stirred mixture of 15.9 g. (0.ll mole) of l-pyrrolidino-l-cyclohexene. 28.0 g. (0.ll mole) of m-trifluoromethylphenacyl bromide. and l00 ml. of toluene was heated under reflux for 2 hours. diluted with water and refluxed for 2 hours. The layers were separated. and the organic phase was dried and concentrated to 25 g. of liquid. Distillation provided 12.0 g- (42% of liquid. b.p. l37-l38 (0.075 mm.).  
  b. l-( 3 -Carboxy-4-hydroxyphenyl )-2-( 3- trifluoromethylphenyl )-4,5 .6.7-tetrahydroindoIe CO H  A mixture of 12.0 g. (0.042 mole) of 2-(mtrifluoromethylphenacyl)cyclohexanone. 6.45 g. (0.042 mole) of S-aminosalicylic acid, and 30 ml. of glacial acetic acid was heated under reflux for 4 hours and filtered. The filtrate was diluted with water and the supernatant was decanted from the oil which separated. Trituration with cyclohexane gave 7.7 g. of solid. m.p. 2l5-225. Recrystallization from isopropyl alcohol-water afforded 4.1 g. (47%) of crystals, m.p. 223--225.  
 Found 65.64% C: 4.71% H; 3.61% N.  
  I EXAMPLE 20 a.&#34;2-(p-Methoxyphenacyl)cyclohexanone Reaction of 33.0 g. (0.22 mole) of l-pyrrolidino-lcyclohexene with 50.0 g. (0.22 mole) of pmethoxyphenacyl bromide by the method described in Example 2a gave 45 g. (84%) of crystal. m.p. 98-99.  
  b. l-( 3-Carboxy-4-hydroxyphenyl )-2-( 4- methoxyphenyl )-4.5.6.7-tetrahydroindole Calc. for C H F NO 65.83% C; 4.52% H; 3.49%-  
 OCH  
 EXAMPLE 21 a. 2-Phenacyl-cyclopentanone A solution of 72.4 g. (0.36 mole) of phenacyl bromide in 175 ml. of toluene was added dropwise during 30 minutes to a stirred, boiling solution of 50.0 g. (0.36 mole) of 1-pyrrolidino-1-cyc1opentene and 200 ml. of toluene. The mixture was heated under reflux for 3 hours. diluted cautiously with 200 ml. of water. re fluxed for 4 hours and cooled. The layers were separated. the aqueous phase extracted with benzene. and the combined organic phase was dried over sodium sulfate and concentrated to an oil. Distillation gave 24.8 g. (34%) of liquid. b.p. 138-140 (0.05 mm.).  
  b. l-( 3-Carboxy-4-hydroxyphenyl )-2-phenyl-l ,4.5,6- tetrahydrocyclopenta[b]pyrrole A mixture of 20.5 g. (0.1 mole) of Z-phenacylcyclopentanone. 15.3 g. (0.1 mole) of S-aminosalicylic acid. and 60 ml. of glacial acetic acid was heated under reflux for 3 hours, cooled and filtered. The filter cake was washed with water. dried and recrystallized from acetic acid to provide 9.5 g. (30%) of crystals, m.p.  
 Calc. for C H NQ, 75.22% C; 5.37% H; 4.39% N;  
 Found 75.19% C; 5.40% H; 4.45% N.  
 EXAMPLE 22 2-(4-Bromopheny1)- 1-( 3-carboxy-4- hydroxyphenyl )-4,5 .6,7-tetrahydroindole CO H  A &#39;mixture of 44.3 g. (0.15 mole) of 2 -(pbromophenacyl)cyclohexanone, 23.0 g. (0.15 mole) of S-aminosalicylic acid. and 1 15 ml. of glacial acetic acid was heated under reflux for 2 hours. cooled and filtered. The filter cake was washed with water. dried and recrystallized from acetic acid to provide 1 1.9 g 19% of tan crystals, m.p. 231232.  
  Calc. for C H BrNO 61.17% C; 4.37% H; 19.42% Br; 3.40% N;  
 Found 61.17% C; 4.27% H; 19.23% Br; 3.44% N.  
 EXAMPLE 23 1-( 3-Carboxy-4-hydroxyphenyl )-2-( 4-cyanophenyl 4.5,6.7-tetrahydroindole A mixture of 6.18 g. (0.015 mole) of 2-(4- bromophenyl 1 3-carboxy-4-hydroxyphenyl 4.5,6,7-tetrahydroindo1e. 1.6 g. (0.018 mole) of cuprous cyanide, and 10 m1. of dimethyl formamide was heated under reflux for 6 hours. poured into a solution of 3 g. of sodium cyanate and 10 ml. of water. and after 5 minutes diluted with 46 m1. of water. The solution was acidified to pH 1-2 with hydrochloric acid and the solid which separated was collected. Recrystallization from acetic acid gave 1.21 g. (23%) of crystals, m.p. 242-244.  
 Calc. for C H N Q, 73.73% C; 5.06% H; 7.82% N;  
 Found 72.89% C; 5.09% H; 7.73% N.  
 EXAMPLE 24 a. 1-Phenacy1-2-tetra1one A solution of g. (0.1 mole) of phenacyl bromide and 65 ml. of toluene was added during 30 minutes to a boiling, stirred solution of 20 g. (0.1 mole) of H34 dihydro-Z-naphthyl)pyrrolidine and 50 m1. of toluene. The the mixture was heated under reflux for 3 hours. diluted with 50 ml. of water, refluxed for 4 hours and cooled. The layers were separated. the aqueous phase was extracted with benzene. and the organic solution was dried and concentrated to an oil. Crystallization from 3060 petroleum ether-ether gave 16.7 g. (63% of tan crystals. m.p. 48-52.  
  b. 3-(3-Carboxy-4-hydroxyphenyl)-4 5-dihydro-2- pheny1benz[e]indole A mixture of 16.6 g. (0.063 mole) of 1-phenacy1-2- tetralone. 9.65 g. (0.063 mole) of S-aminosalicylic acid. and 60 ml. of glacial acetic acid was heated under reflux under nitrogen for 2 hours, cooled and filtered.  
 The collected solid was washed with acetic acid and water. dried and recrystallized from acetic acid to provide 16.3 g. (68%) of crystals, m.p. 223-225.  
 Calc. for C. ,,-,H ,NO;, 78.72% C; 5.02%. H; 3.67% N; Found 78.58% C; 4.97% H; 3.73% N.  
 EXAMPLE 4.5-Dihydro-3-(4-hydroxy-3- methoxycarbo&#39;nylphenyl )-2-phenylbenz[ e]indo1e CO CH Hydrogen chloride gas was bubbled through a stirred, boiling mixture of 30.0 g. (0.08 mole) of 3-(3-carboxy- 4-hydroxypheny1)-4.5-dihydro-2-pheny1benz[e]indole and 790 ml. of methanol for 1 hour. The mixture was stirred under reflux for 6 hours. cooled and filtered to provide 28.4 g. (91%) of solid. Recrystallization from acetontrile gave colorless crystals, m.p. 164.5165.5.  
 Calc. for C H NO 78.97% C; 5.35% H; 3.57% N;  
 Found 79.16% C; 5.47% H; 3.56% N.  
 EXAMPLE 26 4.5-Dihydro-3-( 4-N,N-dimethylthiocarbamoyloxy-3- methoxycarbonylphenyl )-2-phenylbenz[e]indole A mixture of 21.4 g&#39;. (0.054 mole) of 4,5-dihydro-3- (4-hydroxy-3-methoxycarbony1pheny1)-2- phenylbenz[e]indole, 18.3 g. (0.16 mole) of 1.4- diazabicyclo[2.2.2]octane, ml. of dimethyl formamide, and 20.7 g. (0.16 mole) or N,N-dimethy1thiocarbamoyl chloride was stirred at 60 for 45 minutes, cooled, diluted with water and extracted with benzene. The organic phase was washed with dilute hydrochloric acid and water, dried over sodium sulfate, and concentrated to a solid. Recrystallization from acetonitrile gave 1 1.7 g. (45%) of off-white crystals, m.p. 2 22-224.  
  Calc. for C ,,H N O S 72.17% C; 5.43% H; 5.81%  
 Found 72.45% C; 5.35% H; 5.97% N.  
 EXAMPLE 27 4,5-Dihydro-3-(4-N,N-dimethy1carbamoy1thio-3- methoxycarbonyl-phenyl )-2-phenylbenz[ e lindole sqmcH A 10.1 g. (0.021 mole) sample of 4,5-dihydro-3-( 4- N.N-dimethylthiocarbamoyloxy-3- methoxycarbonylphenyl)-2-pheny1benz[elindole was heated at 220225 under nitrogen for 50 minutes. Trituration of the resulting solid with methanol gave 9.5 g. (94% of yellow solid. Recrystallization from acetonitrile gave off-white crystals, m.p. 203204.5.  
  Calc. for C H N O S 72.17% C; 5.43% H; 5.81% N;  
 Found 72.55% C; 5.33% H; 5.97% N.  
 EXAMPLE 28 4.5-Dihydro-3-( 3-ethoxycarbonyl-4- hydroxyphenyl )-2-pheny1benzl e]indo1e z z s A boiling solution of 7.5 g. (0.02 mole) of 3-(3- carboxy-4-hydroxyphenyl)-4,5-dihydro-2- phenylbenzlelindole and 200 ml. of ethanol was satu&#39; rated with hydrogen chloride. then heated under reflux for 26 hours and cooled. The solid which separated was collected and recrystallized from ethanol to provide 4.1 g. (51%) of off-white crystals, m.p. l34135.  
 Calc. for C- H- ;,NO 79.20% C; 5.66% H; 3.42% N.  
 Found 79.11% C; 5.70% H; 3.58% N.  
 EXAMPLE 29 l-Acetyl-3-( 3-carboxy-4-hydroxyphenyl )-4,5- dihydro-Z-phenylbenzl elindole A mixture of 1.25 g. (0.0033 mole) of 3-(3-carboxy- 4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[elindole, 1 ml. of acetic anhydride, ml. of glacial acetic acid, and 0.1 g. of p-toluenesulfonic acid was stirred at room temperature under nitrogen for 6 days. The solid which separated was collected, washed with acetic acid and petroleum ether. dried and recrystallized from methanol to provide 0.23 g. (16%) of 3-(4-acetoxy-3- carboxyphenyl)-l-acetyl-4.S-dihydro-2- phenylbenzlelindole. Concentration of the mother liquor, followed by recrystallization of the residue from ethanol-water. gave 0.25 g. (18%) of crystals. m.p. 223-226.  
 Calc. for C- H ,NO 76.58% C; 5.00% H; 3.31% N;  
 Found: 76.29% C; 5.17% H; 3.26% N.  
 EXAMPLE 3-(4-Acetoxy-3-carboxyphenyl)-4,5-dihydro-2- phenylbenzle1indole EXAMPLE 31 3-( 3-Carboxy-4-hydroxyphenyl )-2- phenylbenzl elindole A mixture of 7.6 g. (0.02 mole) of 3-(3-carboxy-4- hydroxyphenyl)-4.5-dihydro-Z-phenylbenzle]indole. 9.1 g. of 10 percent palladium on carbon. and 350 m1. of xylene was heated under reflux with stirring under nitrogen for 24 hours and then filtered. The filtrate was concentrated to ml. and cooled. The solid which separated was collected and recrystallized from xylene to provide 3.6 g. (48%) of yellow crystals, m.p. 241.5242.5.  
 Calc. for C. -,H NO 79.14% C; 4.52% H; 3.69% N;  
 Found 79.76% C; 4.58% H; 3.76% N.  
 EXAMPLE 32 a. Z-(p-Phenylphenacyl)cyclohexanone Reaction of 27.4 g. (0.18 mole) of l-pyrrolidino-lcyclohexene and 50 g. (0.18 mole) of pphenylphenacyl bromide by the method described in Example 2a gave 23.6 g. (45%) of crystals. m.p. 108ll2.  
  b. 2-( 4-Biphenyl l 3-carboxy-4-hydroxyphenyl 4,5,6,7-tetrahydroindole A mixture of 23.4 g. (0.08 mole) of 2-(pphenylphenacyl)cyclohexanone, 12.2 g. (0.08 mole) of S-aminosalicylic acid, and 80 ml. of glacial acetic acid was heated under reflux under nitrogen for 3 hours, cooled and filtered. The filter cake was washed with acetic acid and water. dried and recrystallized from acetic acid to provide 8.2 g. (22% of crystals. m.p. 192-199.  
 Calc. for C H NO 79.20% C; 5.66% H; 3.42% N. Found: 79.63% C; 5.68% H; 3.15% N.  
 EXAMPLE 33 a. Z-(m-Methoxyphenacyl)cyclohexanone OCH  Reaction of 33 g. (0.22 mole) of l-pyrrolidino-lcyclohexene and 50 g. (0.22 mole) of mmethoxyphenacyl bromide by the described in Example 2a gave 31.2 g. (58%) of an amber oil. b.p. 178-182 (0.15 mm.)  
  b. 1-( 3-Carboxy-4-hydroxyphenyl )-2-( 3- methoxyphenyl)-4,5,6,7-tetrahydroindole OCH  A mixture of 24.6 g. (0.1 mole) of 2-(mmethoxyphenacyl)cyclohexanone, 15.3 g. (0.1 mole) of -aminosalicylic acid. and 65 ml. of glacial acetic acid was heated for 2 hours under reflux under nitrogen and cooled. The solid which separated was collected, washed with acetic acid and water. dried and recrystallized from acetic acid to provide 23.4 g. (65%) of crystals, m.p. 175-177.  
 Calc. for C.,.,H.,,NO 72.71% C; 5.82% H; 3.85% N;  
 Found 72.79% C; 5.80% H; 3.91% N. 9  
 EXAMPLE 34 a. 2-Phenacylcycloheptanone Reaction of 64.1 g. (0.4 mole) of lpyrrolidino-lcycloheptene and 79.2 g. (0.4 mole) of phenacyl bromide by the method described in Example 2a gave 22.8 g. (25%) of tan crystals, m.p. 42-44.  
  b. 1-(3-Carboxy-4-hydroxyphenyl)-1,4,5,6,7,8- hexahydro-2-phenylcycloheptalb]pyrrole A mixture of 18.4 g. (0.08 mole) of Z-phenacylcycloheptanone, 12.1 g. (0.08 mole) of 5-aminosalicyclic acid, and 140 ml. of glacial acetic acid was heated under reflux under nitrogen for 2 hours and cooled. The solid which separated was collected and recrystallized from ethanol to provide 16.5 g. (59%) of yellow crystals, m.p. 238239.  
 Calc. for C H NO 76.08% C; 6.05% H; 4.03% N;  
 Found 75.72% C; 6.10% H; 4.18% N.  
 EXAMPLE 35 a. 2-(p-Chlorophenacyl)cyclohexanone Reaction of 69.5 g. (0.46 mole) of l-pyrrolidino-l -cyclohexene and g. (0.46 mole) of pchlorophenacyl bromide by the method described in Example 2a gave 82.4 g. (72%) of tan crystals. m.p. 5658 from ether-petroleum ether.  
  b. 1-(3-Carboxy-4-hydroxyphenyl)-2-(4- chlorophenyl)-4,5 6,7-tetrahydroindole EXAMPLE 36 a. 2-(o-Methoxyphenacyl)cyclohexanone O OCH Reaction of 19.6 g. (0.13 mole) of 1-pyrrolidino-lcyclohexene and 30.0 g. (0.13 mole) of omethoxyphenacyl bromide by the method described in Example 2a gave 17.7 g. (55%) of a semi-solid.  
  b. 1-( 3-Carboxy-4-hydroxyphenyl)&#39;2-( 2- methoxyphenyl )-4,5 ,6,7-tetrahydroindole mole) of S-aminosalicylic acid, and 90 m1. of glacial acetic acid was heated under reflux for 4 hours and cooled. The solid which separated was collected, washed with water and recrystallized from ethanol to provide 0.2 g. (1%) of tan solid, m.p. 212-2l4.  
 Calc. for C--H- NO 72.73% C; 5.79% H; 3.86% N.  
 Found 272.08% C; 5.69% H; 4.09% N.  
 EXAMPLE 37 Z-Phenyll S-carboxy-4-hydroxy-2- trifluoromethylphenyl-4,5 ,6,7-tetrahydroindole A mixture of 6.5 g. (0.029 mole) of 5-amino-4- trifluoromethylsalicylic acid, 6.35 g. (0.029 mole) of Z-phenacylcyclohexanone, and 30 ml. of glacial acetic acid was heated under reflux for 3 hours, cooled and filtered. The filter cake was recrystallized from acetic acid to provide 4.6 g. (39%) of gold crystals. m.p. l88-l90.  
  Calc. for C H,,,F;,NO 65.83% C; 4.52% H; 3.49% N;  
 Found 65.90% C; 4.51% H; 3.54% N.  
 EXAMPLE 38 a. 2-(p-Fluorophenacyl)cyclohexanone Reaction of 18.1 g. (0.12 mole) of l-pyrrolidino-lcyclohexane and 25.0 g. (0.12 mole) of pfluorophenacyl bromide by the method described in Example 2a gave 17.9 g. (64%) of solid.  
  b. l-(3-Carboxy-4-hydroxyphenyl)-2-(4- fluorophenyl)-4,5,6.7-tetrahydroindole CO H A solution of 17.9 g. (0.077 mole) of 2-(pfluorophenacyl)cyclohexanone, 11.8 g. (0.077 mole) of 5-aminosalicylic acid, and ml. of glacial acetic acid was heated under reflux under nitrogen for 4 A; hours, cooled and filtered. The collected solid was washed with water and recrystallized from acetic acid to provide 10.0 g. (37%) of yellow crystals, m.p. 239240.  
  Calc. for C- H FNO 71.79% C; 5.13% H; 5.47% F; 3.99% N;  
 Found 70.83% C; 5.09% H; 4.92% F; 3.92% N.  
 EXAMPLE 39 a. 2=(p-Methylphenacyl)cyclohexanone A solution of 50 g. (0.23 mole) of p-methylphenacyl bromide in 120 ml. of dry dimethyl formamide was added dropwise during one-half hour into a stirred. cooled solution of 35.4 g. (0.23 mole) of l-pyrrolidinol-cyclohexene in 200 ml. of dimethyl formamide at a rate to maintain a temperature of 25. After 5 V2 hours. the solution was diluted with water and extracted with chloroform. The chloroform solution was washed with water, dried over sodium sulfate and concentrated to an oil. Distillation gave 28.5 g. (53%) of liquid, b.p. l6l165 (0.2 mm.), which solidifed (m.p. 65-70).  
  b. 1-( 3-Carboxy-4-hydroxyphenyl )-2-( 4- methylphenyl)-4,5,6,7-tetrahydroindole CO H A mixture of 23 g. (0.1 mole) of 2-(pmethylphenacyl) cyclohexanone, 15.3 g. (0.1 mole) of S-aminosalicylic acid and m1. of glacial acetic acid was heated under reflux for 45 minutes. cooled and filtered. The collected solid was recrystallized from acetonitrile to provide 23.0 g. (66%) of yellow crystals. m.p. 212.5-214.5. V  
 Calc. for (7 11 .810. 76.06% C; 6.09% H; 4.03% N: Found: 76.30% C; 6.13% H; 3.98% N.  
 EXAMPLE 40 a. 4-(t-Butyl&#39;)-2-phenacylcyclohexanone (c11 r-Q Reaction of 61.0 g. (0.30 mole) of 4-(t-butyl)-1- cyclohexene and 59.7 g. (0.30 mole) of phenacyl bromide by the method described in Example 39a provided 31.7 g. (39%) ofsolid. m.p. 1271 29 from ethan01.  
  b. 5-(t-Butyl)-1-( 3-carboxy-4-hydroxyphenyl)-2- phenyl-4.5.6.7-tetrahydroindole COH  A solution of 20.0 g. (0.074 mole) of 4-(t-butyl)-2- phenacylcyclohexanone. 11.3 g. (0.074 mole) of 5- aminosalicylic acid, and 132 ml. of glacial acetic acid was heated under reflux under nitrogen for 2 hours. cooled and filtered. The collected solid was recrystallized from acetonitrile to provide 19.9 g. (69% of crystals. m.p. 260262.  
  Calc. for C ,-,H. NO:, 77.12% C; 6.94% H; 3.60% N; Found 76.90% C; 6.99% H; 3.64% N.  
 EXAMPLE 41 5-(t-Buty1)-1-(3-carboxy-4-hydroxyphenyl)-2- phenylindole EXAMPLE 42 a. 1-(3,3-Dimethyl-2-oxobutyl)-2-tetralone LII  C(CH 0 3 3 Reaction of 17.9 g. (0.1 mole) of l-bromo-3,3- dimethyl-Z-butanone and 19.9 g. (0.1 mole) of l-(3,4- dihydro-Z-naphthyl)pyrrolidine by the method described in Example 39a gave 15.6 g. (64%) of liquid, b.p. 149-151(0.()7 mm.).  
  b. 2-(t-Buty1)-3-(3-carboxy-4-hydroxyphenyl)-4.5- dihydrobenzle] indole i il l l s s CO H  A mixture of 15.2 g. (0.062 mole) of H33- dimethyl-Z-oxobutyl)-2-tetralone, 9.5 g. (0.062 mole) of 5-aminosalicylic acid, and 50 m1. of glacial acetic acid was heated under reflux under nitrogen for 1.5 hours, cooled and filtered. The collected solid was washed with acetic acid and petroleum ether and then recrystallized from acetonitrile to provide 10.4 g. (46%) of off-white crystals. m.p. 258-260.  
 Calc. for C H NO 76.43% C; 6.41% H; 3.88% N;  
 Found 76.38% C; 6.39% H; 4.02% N.  
 EXAMPLE 43 1-( 3-Carboxy-5-ch1oro-4-hydroxyphenyl )-2-phenyl- 4,5,6.7-tetrahydroindo1e C] CO A mixture of 10.3 g. (0.047 mole) of Z-phenacylcyv clohexanone, 8.8 g. (0.047 mole) of 5-amino-3- chlorosalicylic acid, and 45 ml. of glacial acetic acid was heated under reflux for 1 hour, cooled and filtered. The collected solid was recrystallized from acetonitrile to provide 13.3 g. (77%) of crystals, m.p. 223225.  
  Calc. for C H CINO 68.57% C; 4.93% H; 3.81%  
 Found 568.62% C; 4.90% H; 3.83% N.  
 EXAMPLE 44 a. Z-(p-Hydroxyphenacyl)cyclohexanone OH G Reaction of 43 g. (0.2 mole) of p-hydroxyphenacyl bromide and 30 g. (0.2 mole) of l-pyrrolidino-lcyclohexene by the method described in Example 39a gave 28 g. (61%) of solid. m.p. l20-125.  
  1-( 3-Carboxy-4-hydroxyphenyl )-2-( 4- hydroxyphenyl )-4.5 .6.7-tetrahydroindole CO H  A mixture of 11.5 g. (0.05 mole) of 2-(phydroxyphenacyl)cyclohexanone. 7.6 g. (0.05 mole) of S-aminosalicylic acid. and 40 ml. of glacial acetic acid was heated under reflux under nitrogen for 1.5 hours. cooled and filtered to provide 10.6 g. (61%) of solid. m.p. 2142l7. Recrystallization from acetonitrile gave crystals. m.p. 217-219.  
 Calc. for C ,H,,,NO 72.19% C; 5.48% H; 4.01% N;  
 Found 72.15% C; 5.50% H; 4.37% N.  
 EXAMPLE 45 a. 4-Methyl-2-phenacylcyclohexanone 1 Reaction of 72.5 g. (0.44 mole) of 4-methyl-l-pyrrolidino-l-cyclohexene and 87.6 g. (0.44 mole) of phenacyl bromide by the method described in Example 39a gave 75.3 g. (74%) of a viscous oil.  
  b. l-(3-Carboxy-4-hydroxyphenyl )-5-methyl-2- phenyl-4.5.6.7-tetrahydroindole N Q c0 11 A solution of 50 g. (0.22 mole) of 4-mcthyl-2- phenacylcyclohexanone. 33.7 g. (0.22 mole) of 5- aminosalicylic acid. and 257 ml. of glacial acetic acid was heated under reflux for 3 hours. cooled and filtered. The collected solid was washed with water and recrystallized from acetonitrile to provide 43.3 g. (57%) of yellow crystals. m.p. 213215.  
 Calc. for C- H- NQ, 76.08% C; 6.05% H; 4.03% N;  
 Found 75.73% C; 6.16% H; 4.05% N.  
 EXAMPLE 46 1-( 4-Acetamido-3-carboxyphenyl )-2-phenyl-4.5 .6.7- tetrahydroindole NHCOCH COH  A mixture of 1 1.7 g. (0.054 mole) of Z-phenacylcyclohexanone. 10.5 g. (0.054 mole) of Z-acetamido-S- aminobenzoic acid. and 50 ml. of glacial acetic acid was heated under reflux for 4 hours. cooled. diluted with 15 ml. of methanol and filtered. The collected solid was recrystallized from acetonitrile to provide 9.45 g. (47%) of crystals, m.p. 192194.  
 Calc. for C H N O 73.78% C; 5.92% H; 7.48% N;  
 Found 73.56% C; 5.96% H; 7.56% N.  
  A mixture of 4.0 g. (0.01 1 mole) of 1-(4-acetamido- 3-carboxyphenyl)-2-phenyl-4.5,6.7-tetrahydroindole. 50 ml. of ethanol. 10 ml. of water. and 2 ml. of conc. hydrochloric acid was heated under reflux under nitrogen for 4 hours. concentrated to 10 ml.. diluted with 100 ml. of water. adjustedto pH 4 and filtered. Recrystallization of the collected solid from ethanol gave 0.83 g. (23%) of crystals, m.p. 205.5206.5.  
 Calc. for c H mo, 75.88% C; 6.06% H; 8.43% N;  
 Found 75.85% C; 6.01% H; 8.45% N.  
 EXAMPLE 48 l-( 5-Acetamido-3-carboxy-4-hydroxyphenyl )-2- phenyl-4.5.6.7-tetrahydr0indole A mixture of 10.3 g. (0.048 mole) of 2-phenacylcyclohexanone. 10 g. (0.048 mole) of 3-acetamido-5- aminosalicylic acid, and 70 ml. of glacial acetic acid was heated under reflux under nitrogen for 1 hour. cooled and filtered. Recrystallization of the collected solid from acetic acid gave 10.5 g. (57%) of crystals. m.p. 232234.  
 Calc. for C H N O 70.75% C; 5.68% H; 7.17% N;  
 Found 1 70.54% C; 5.74% H: 7.32% N.  
 EXAMPLE 49 1-( 5-Brom0-3-carboxy-4-hydroxyphenyl )-2-pheny1- 4.5.6.7-tetrahydroindole Br CO H A mixture of 8.1 g. (0.038 mole) of Z-phenacylcyclohexanone. 8.7 g. (0.038 mole) of 5-amino-3- bromosalicylic acid. and 50 ml. of glacial acetic acid was heated under reflux for 1 hour, cooled and filtered. Recrystallization of the collected solid from acetonitrile gave 7.0 g. (46%) of yellow crystals. m.p. 2092l0.  
  Calc. for C H BrNO 61.17% C; 4.40% H; 3.40% N;  
 Found 61.03% C; 4.48% H; 3.46% N.  
 EXAMPLE 50 a. 4-Methoxy-2-phenacylcyclohexanone Reaction of61.4 g. (0.31 mole) of phenacyl bromide and 55.7 g. (0.31 mole) of 4-methoxy-l-pyrrolidino-lcyclohexene by the method described in Example 39a gave 68.0 g. (90%) of anamber oil.  
  b. 1-( 3-Carboxy-4-hydroxyphenyl)-5-methoxy-2- phenyl-4.5,6,7-tetrahydroindole CO H  A mixture of 24.6 g; (0.1 mole) of 4-methoxy-2- phenacylcyclohexanone, 15.3 g. (0.1 mole) of 5- aminosalicylic acid, and 80 ml. of glacial acetic acid was heated under reflux&#39; for lj hours, filtered, cooled and again filtered. Thecollec&#39;ted solid was washed with acetic acid and petroleum ether and recrystallized from LII acetonitrile to provide 22.5 g. (62%) of crystals, m.p. 207210.  
 Calc. for C H NO 72.71% C; 5.82% H; 3.85% N; Found 72.60% C; 5.89% H; 4.09% N.  
 EXAMPLE 51 a. 2-( 3,4-Dichlorophenacyl)cyclohexanone Reaction of 28.7 g. (0.19 mole) of l-pyrrolidino-lcyclohexene and 51.2 g. (0.19 mole) of 3.4-  
 dichlorophenacyl bromide by the method described in Example 39a gave 32.6 g. (60%) of crystals. m.p. 78-79 (from ethanol).  
 1-( 3-Carboxy-4-hydroxyphenyl )-2-( 3.4- )-4,5,6,7-tetrahydroindole b. dichlorophenyl EXAMPLE 52 a. Z-(p-Bromophenacyl )cyclopentanone Reaction of 24.7 g. (0.18 mole) of l-pyrrolidino-lcyclopentene and 50 g. (0.18 mole) of pbromophenacyl bromide by the method described in Example 39a gave 20.8 g. (41%) of crystals, m.p. 59-61 (from ethanol).  
  b. 2-(4-Bromophenyl)-l-(3-carboxy-4- hydroxyphenyl) 1,4,5,6-tetrahydrocyclopenta[b]pyrrole N Br CO H  
 A solution of 20.8 g. (0.07 mole) of 2-(pbromophenacyl)cyclopentanone. 10.71 g. (0.07 mole) of S-aminosalicylic acid. and 88 ml. of glacial acetic acid was heated under reflux under nitrogen for 3 hours, cooled and filtered. The collected solid was chromatographed on silica gel. The solid eluted with benzene was recrystallized from ethanol-water to provide tan crystals. m.p. 215-2l6.  
  Calc. for C H BrNo 60.30% C; 4.02% H; 20.10% Br; 3.52% N;  
 Found 59.70% C; 4.02% H; 20.24% Br; 3.43% N.  
 EXAMPLE 53 1-( 3-Carboxy-4-chlorophenyl)-2-pheny1-4,5.6,7- tetrahydroindole A mixture of 21.6 g. (0.1 mole) of Z-phenacylcyclohexanone, 17.2 g. (0.1 mole) of 5-amino-2- chlorobenzoic acid. and 60 ml. of glacial acetic acid was heated under reflux for 2 hours. cooled and filtered to provide 15.3 g. (44% oflight pink solid. Recrystal1i zation from acetonitrile gave pale pink crystals, m.p. 2l02l2.  
  Calc. for C H ClNo- 71.69% C; 5.16% H; 3.98% N;  
 Found 71.13% C; 5.31% H; 4.26% N.  
 EXAMPLE 54 a. Z-(a-Phenylphenacyl)cyclohexanone Reaction of 75.0 g. (0.5 mole) of l-pyrrolidino-lcyclohexane and 68.7 g. (0.25 mole) of a-phenylphenacyl bromide by the method described in Example 39a gave 73 g. of colorless semi-solid.  
  b. 1-(3-Carboxy-4-hydroxyphenyl&#39;)-2;3 diphehyl- 4.5.6 .7-tetrahydroindo1e A solution of 10.5 g. (0.036 mole) of 2-(aphenylphenacyl)cyclohexanone. 5.5 g. (0.036 mole) of 5-aminosalicylic acid. and 40 ml. of glacial acetic acid was heated under reflux for 1 /3 hours. cooled and liltered. The collected solid was washed with petroleum ether and recrystallized from acetonitrile to provide 7.3 g. (50%) of pale yellow crystals. m.p. 246247.  
 Calc. for Cg&#39;fHggNOg 79.20% C; 5.66% H; 3.42% N;  
 Found 79.10% C; 5.92% H; 3.52% N.  
 EXAMPLE 55 a. Z-(p-Nitrophenacyllcyclohexanone Reaction of 52.9 g. (0.35 mole) of l-pyrrolidino-lcyclohexene and 85.0 g. (0.35 mole) of pnitrophenacyl bromide by the method described in Ex- .ample 39:! gave 81.3 g. (89%) ofcrystals, m.p.6163  
 (from ethanol).  
  b. l-( 3-Carboxy-4-hydroxyphenyl )-2-(4- nitrophenyl)-4.5.6.7-tetrahydroindole CO H  A mixture of 40 g. (0.15 mole) of 2-(pnitrophenacyl)cyclohexanone, 23 g. (0.15 mole) of 5 aminosalicylic acid and 187 ml. of glacial acetic acid was heated under reflux under nitrogen for 3 hours, diluted with water and extracted with ethyl acetate. The ethyl acetate solution was dried over sodium sulfate and concentrated to a red solid which was chromatographed on silica gel. The material eluted with 3 percent methanol in chloroform was recrystallized from acetonitrile to provide 3.8 g. (7% of orange crystals, m.p. 241242.  
 CalC. for C l-1 N 0 Found 66.60% C; 4.88% H; 7.69% N.