US3939177_TOT

US3939177_TOT - United States Patent[191 Alexander et al[11...

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Unformatted text preview: United States Patent [191 Alexander et al. [11] 3,939,177 [45] Feb. 17, 1976 [54] 4-AMINOMETHYL-9-BENZYL-l,2,3,4- TETRAHYDROCARBAZOLES [75] Inventors: Ernest John Alexander, East Greenbush; Aram Mooradian, Schodack, both of NY. [73] Assignee: Sterling Drug Inc., New York, NY. [22] Filed: Nov. 22, 1972 [21] Appl. No.: 308,674 '[52] US. Cl...... 260/315; 260/268 TR; 260/293.61; 424/250; 424/267; 424/274 ' [51] Int. Cl.2 ...................................... .. C07D 209/86 [58] Field of Search ................................... .. 260/315 [56] References Cited 7. . UNITED STATES PATENTS 3,752,823; ~8/1973 McMa‘nu's‘ ...... .... ........ .3260/3‘15 OTHER PUBLICATIONS JACS 79: 356143564, (1957), Shaw et al. Primary Examiner—Sherman D. Winters Attorney, Agent, or Firm—Frederik W. Stonner; B. Woodrow Wyatt [57] I ' , ABSTRACT Novel 4-R,R2NCH2-9ubenzyl-6-R3-7-R4-1,2,3 ,4- tetrahydrocarbazoles having antibacterial activity are disclosed. The compounds are prepared by the chemi- cal reduction of the corresponding 4-R lR2NCO~9—benzyl-6-R3-7-R4- 1 ,2,3,4- tetrahydrocarbazoles. ,8 Claims, No Drawings 3,939,177 1" 4-AMINOMETHYL-9-BENZYLHZZ,3,2t-TETRAHY- DROCARBAZOLES ' This invention relates to compositions of matter clas- sifiedin the art of chemistry as l,2,3,4-tetrahydrocar- bazoles. _ , _ V In one aspect» the invention Sought to be patented resides in the chemical compounds designated as 4- R1RzNCHz-Q-benzyl-6-R3-7-R4-1,2,3,4-tetrahydrocar- bazoles having the formula: , (.‘.I'I,‘:_,NR]_I‘I2 “3 “1: I CHa I wherein g ‘ R1 and R2 are each'hydrogen, lower-alkyl, or benzyl, or ’ " ’ NRIR2 is l-pyrrolidyl, l-piperidyl, or 4—phenyl-1- piperazinyl; and R3 and R4 are each hydrogen, lower-alkyl, or lower-‘ alkoxy. In a second aspect the invention sought to be pa- tented resides in the novel chemical compounds desig- nated as 4-R1R2NCO-9—ben2yl-6-R3-7—R4:1,2,3,4-tet- rahydrocai'bazoles having the formula: C ONRIRQ V,II wherein , . . R1 and R2 are each hydrogen, lower-alkyl, or benzyl, "or ~ ‘ u NRlRQ is l—pyrrolidyl, piperazinyl; and R3 and R4 are each hydrogen, 'lower-alkyl, or lower- ‘ alkoxy. ' The compounds of. the invention having formula I exhibit antibacterial activity as more fullydescribed herei'nbelow. I-piperidyl, or 4-‘phenyl— I- 10 15 20 25 3o 35 40 45 50 55 ,0 65 2 The compounds of the invention having formula II are useful as intermediates in the preparation of com- pounds of this invention having formula I. The compounds having formula I are prepared by chemical reduction of the corresponding 4-R1R2NCO- 9—benzyl-6-R3»7-R4-1 ,2,3 ,4-tetrahydrocarbazoles (II ). The reduction is carried out by treating the amide II with a suitable chemical reducing agent in a suitable solvent, e.g., lithium aluminum hydride in ether, tetra- hydrofuran, di-n-butyl ether, or dioxane; or diborane in tetrahydrofuran or diglyme. The reduction is carried out preferably at a temperature of about 20°C. to 100°C. for about 1 to 24 hours. The reaction is conve- niently carried out by treating the amide II in tetrahy- drofuran under reflux with a slight molar excess of lithium aluminum hydride for about 4 to‘about 6 hours. Alternatively, the compounds of formula I where R1 and R2 are hydrogen are prepared by chemical reduc- , tiOn of the corresponding 4—cyano-9-benzyl-6—R3-7—R4- 1,2,3,4—tetrahydrocarbazoles (Ill) using the procedures deseribed hereinbefore for the reduction of the amide II. ‘ , The intermediate 4-R1R2NCO-9-benzyI-6-R3—7~R4— 1,2,3,4-tetrahydrocarbazole (II) is prepared from the corresponding 9-benzyl-6-R3—7-R4- I ,2,3,4-tetrahy- drocarbazole-4-carboxylic acid halide (IV), where hal- ide is chloride or bromide, by reaction with an amine of the formula RleNI-I (V). The reaction is carried out by treating the acid halide in a suitable solvent, e.g., benzene, methylene dichloride or pyridine, with at least one equivalent of amine V, at temperatures from about 0°C. to ambient temperatures. Preferably, the reaction is carried out in the presence of at least one equivalent of a suitable acid-acceptor,te.g., triethylamine, pyridine or potassium bicarbonate; if desired, excess amine V may be used as the acid—acceptor. The reaction is con- ‘ veniently carried out by reacting the acid halide IV with at least two equivalents of amine V, in aqueous solution‘if desired, in benzene with ice-bath cooling. The intermediate cyano compound III is prepared by dehydration of the corresponding 4-carbamyl—9—ben- zyl-6-R3-7-R4-1,2,3,4-tetrahydrocarbazole (II, R, = R2 = H). The reaction is carried out in a suitable solvent, e. g., benzene or pyridine, in the presence of a suitable dehydrating agent, e.g., phosphorus oxychloride, thio- nyl chloride, or benzenesulphonyl chloride, preferably at temperatures of about 20°C. to 100C. The reaction can be conveniently carried out by treating the ‘4-car- bamyl compound in pyridine with benzenesulphonyl‘ chloride on a steam bath for about one to two hours. The intermediate acid halide IV is preparedfrom the correspon ding 9-benzyl-6-R3—7-R4— l ,2 ,3 ,4-tetrahy— droca'rbazole—4-‘carboxylic acid, (VI) using standard procedures, e.g., by reaction‘in a suitable solvent, e.g., ethylene dichloride, chloroform, or benzene, with an appropriate'halogenating agent, such as thionyl chlo- ride or oxalyl chloride. The reaction is conveniently carried out by reacting an alkali metal salt, e.g., sodium salt, of the carboxylic. acid VI' in, benzene witha slight excess of thionyl chloride, ‘ ‘ i The 9-benzyl—6-R3-7-R4— I ,2,3,4—tetrahydrocarbazolc— 4-carb0xylic acid ,(VI) and intermediates therefor be— long to classes of compounds which tOgether with de- tailed methods for the preparation thereof are dis- closed in US; Pat. No. 3,687,969. Thus, they are pre— pared for example ' by reaction of N—(4-R3-3-R4- phenyI)-N-benzylamine (VII) with 6-bromocyclohexa- none-2-carbo‘xylic acid ester (VIII), e.g., methyl or 3,939,177 3 ethyl ester, and subsequent hydrolysis; the intermediate N-phenyl-N-benzylamines (VII) are known compounds that are readily prepared by standard procedures, e.g., from the corresponding known anilines and benzalde- hydes. As used throughout this specification, the terms low- eralkyl and lower-alkoxy mean such groups containing from one to six carbon atoms which can be arranged as straight or branched chains, and, without limiting the generality of the foregoing, are illustrated by methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, amyl, hexyl, and the like for Iower-alkyl; and methoxy, ethoxy, propoxy, isobutoxy, tert—butoxy, hexyloxy,,and the like for lower—alkoxy. The compounds of the invention having formula I are useful both in the free base form and in the form of acid-addition salts, and both forms are within the pur- view of the invention. The acid-addition salts are sim- ply a more convenient form for use, and in practice, use of the salt form inherently amounts to use of the base form. When the compounds of the invention having formula I are to be utilized for pharmaceutical pur- poses, the acids which can be used to prepare the acid— addition salts include preferably those which produce, when combined with the free base, medicinally accept— able salts, that is, salts whose anions are relatively in- nocuous to the animal organism in medicinal doses of the salts, so that the beneficial properties inherent in the free base are not vitiated by side effects ascribable to the anions. Appropriate medicinally acceptable salts within the scope of the invention are those derived from mineral acids such as hydrochloric acid, hydro- bromic acid, hydriodic acid, nitric acid, phosphoric acid, sulfamic acid, and sulfuric acid; and organic acids such as acetic acid, citric acid, tartaric acid, lactic acid, cyclohexanesulfamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluene- sulfonic acid, quinic acid, and the like, giving the hy- drochloride, hydrobromide, hydriodide, nitrate, phos- phate, sulfamate, acetate, citrate, tartrate, lactate, cy- clohexanesulfamate, methanesulfonate, ethanesulfon- 10 15 20 25 30 4 1414—1416 (1968) in which a 1,000 mcg./ml. solution of the test compound is prepared. To the first cup of the Autotray is 'add'ed'Ogl :rnlf ‘of thexteSt solution. 'Acti- vation of the Autotitcr initiates a sequence of opera- tions by which 0.05 ml. of thevtest compound solution is withdrawn from this cup by a Microtit'er transfer lo‘op and diluted in‘0.'05 ml. of sterile semi-synthetic m’edium‘ (glucose). After this operation, 0.05 ml. of inoculated semi-synthetic medium is added autOmatic'ally' to each cup. The overall ope'ration'results in final drug concen- trations ranging from 500‘ to 0.06 mcg./ml. in twofold decrements. The Autotray is incubated for -1 8—20 hours at 37°C., at which time the trays are examined visually for growth as evidenced by turbidity, and the concen- tration of the last sample in the series showing no growth (or "no turbidity) is recorded as the minimal inhibitory concentration (MIC). By way of illustration, the compounds of Examples 18 to 8B inclusive and 9C were found to be antibacteri- ally effective against Staphylococcus aureus at concen- trations from 7.8 meg/ml. to 500'mcg./ml.; and the‘ compound of Example 10C was found to be antibac- terially effective against PSeudomonas aeruginosa at a concentration of 125 mcg.’/ml.; additionally, certain of these compounds were found also to be antibacterially effective, as disclosed specifically in the examples here- inbelow, against one or more Of the following microor- ganisms: Pseudomonas aeruginosa, Escherichia coli, and Proteus vulgaris. The actual determination of the numerical biological data definitiverfor a particular compound is readily . determined by standard test procedures by technicians- 35 4O ate, benzenesulfonate, p-toluenesulfonate and quinate , respectively. The acid-addition salts of said basic compounds are prepared either by dissolving the free base in aqueous or aqueous-alcohol solution containing the appropriate acid and isolating the salt by evaporating the solution, 45 or by reacting the free base and acid ,in an organic ‘ solvent, in which case the salt separates directly or can be obtained by concentration of the solution or dilution of the solution with a solvent in which the salt is insolu- ble or only slightly soluble. _ Although medicinally acceptable salts of said basic compounds are preferred for pharmaceutical purposes, all acid—addition salts are within the scope of the inven- tion. All acid-addition salts are useful as sources of the free base form even if the particular salt per se is de- sired only as an intermediate product as for example when the salt is formed only for purposes of purifica- tion or identification, or when it is used as an interme— diate in preparing a medicinally acceptable salt by ion exchange procedures. The compounds of formula I possess useful antibac- terial activity, thus indicating the utility of the com- pounds of formula I as antibacterial agents. The antibacterial activities were determined using a modification of the Autotitcr method described by Goss et 211., Applied Microbiology 16 (No. 9), 50 55 60 65 fl ‘ A. To 088 g. of ‘having ordinary skill in pharmacological test proce- dures, without the need for any extensive experimenta: tion. 3 . The compounds of the invention having formula I can be formulated for use by preparing a dilute solution in an? aqueous medium'or in a solution containing a surfactant, or alternatively in an organic .medium in , which the compounds are soluble, for-example ethyl alcohol, and are applied to a surface to be disinfected by conventional means such as spraying, ,swabbing, immersion, and the like. Alternatively, the compounds can be formulated as ointments or creams by incorpo- rating them in conventional ointment or cream bases, for example alkylpolyether alcohols, cetyl alcohol,- stearyl alcohol, and the like, or as jellies by incorporat- ing 'them in conventional jelly bases as glycerol and tragacanth. They can also be formulated for use as " aerosol sprays or foams. The molecular structures of the compounds of the invention were assigned on the basis of the method of their synthesis and study of their infrared spectra, and confirmed by the correspondence between calculated and found values for the elementary analysis for repre- sentative examples. The invention is illustrated by the following examples without, however, being limited thereto. _ EXAMPLE 1_ sodium hydride in 200 ml. dry 'ben- zene was added portionwise 312.3 g. of 9-ben2yl-6- m'ethoxy-l ,2,3,4-tetrahydrocarbazole-44carboxylic acid and the mixture was stirred for one hour. To this mixture was added dropwise 2.7 ml. of thionyl chloride, stirring was continuedfor one-half hour and the mix- ture containing the resulting 9-benzyl-6-methoxy- 1,2,3,4-tetrahydrocarbazole-4-carboxylic acid chloride ' 3,939,177 5 was poured into 32 m1. of 25% aqueous dimethylamine with ice-bath cooling. The mixture was stirred for 1 hour, washed with water, sodium bicarbonate and satu- rated salt solution, dried, diluted with n—pentane, cooled and filtered to give 7.9 g. of 4~dime- thy]aminocarbonyl-9-benzyl-6-methoxy-1,2,3,4-tet- rahydrocarbazole, m.p. 153°—155°C. - B. To 1.2 g. of lithium aluminum hydride in 200 ml. of dry tetrahydrofuran was added portionwise 11.4 g. of 4«dimethylaminocarbonyl-9-benzyl-6—methoxy- 1,2,3,4-tetrahydrocarbazole and the mixture was 10 heated under reflux for 5 hours and allowed to stand at ‘ room temperature for 15 hours. Water (2.4 ml.) was added to the mixture which was then heated under reflux for 1 hour, filtered hot, and the filtrate was treated with darco, filtered and evaporated under re- ‘duced pressure to give 12 g. of crude residue consisting largely of 4-dimethylaminomethyl-9—benzyl-6- methoxy—l,2,3,4-tetrahydrocarbazole, 4 g. of which .was dissolved in ether and treated with ethereal hydro- r '- gen ‘chloride. The resulting solid was filtered to give 2.6 i ' g. ' of 4-dimethylaminomethyl-9-benzyl-6-methoxy- ' 1,2,3,4—tetrahydrocarbazole hydrochloride, m.p. 238°—'24Q°C. (absolute alcohol/ether). ‘ 4—Dimethylaminomethyl-9-benzyl-6-methoxy- 1,2,3,4-tetrahydrocarbazole hydrochloride was found. to be antibacterially effective against Staphylococcus aureus at 62.5 meg/ml. EXAMPLE 2 A. Following a procedure similar to that described in Example 1A but using 2.13 g. of sodium hydride in 510 ml. of benzene, 2.74 g. of 9-benzyl41,2,3,4-tetrahy- drocarbazole—4—carboxylic acid, 6.6 m1. of thionyl chlo- ' ride, and 7.8 ml.‘of 25% aqueous dimethylamine, there. was obtained 2.6 g. of 4udimethylaminocarbonyl-9- .benzyl-l ,2,3,4—tetrahydrocarbazole, m‘.p. 180°—‘l 83°C. (tetrahydrofuran/n-pentane). ' B. Following a procedure similar to that described in 15 . tetrahydrocarbazole, 20 25 ' ‘ 1,2,3,4—tetrahydr0carbazole 3O 35. Example 13 but using 2.1 g. oflithium aluminumghy- 40 .‘dride in 200 ml. of ‘tetrahydro’fuyran, and 17.3,: g. of , 4-dimethylaminocarbonyl-9-benzyl-1,2,3 ,4-tetr‘ahy— drocarbazole, there was obtained 18.4 g. of crude resi- due consisting largely of 4-dimethylaminomethyl-9- , 'u,g.benzyl-l,2,3,4-tetrahydrocarbazole, ‘3. g. of which , yielded 2.3 g. of 4-dimethylaminomethyl-9-benzyl- ‘1,2,3,4—tetrahydrocarbazole hydrochldrideh .m.p. 208°~21'0°C. ‘ . “ K : y ‘ 4-Dimethylaminomethyl-Q-beniyl-1 ,2,3,4-tetrahy- drocarbazole hydrochloride was found to be antibac- terially effective against Staphylococcus aurcus and Escherichia coli at 125 meg/ml; ' EXAMPLE 3 A. Following a procedure similar to that described in _ [Example 1A but using 1.97 g. of sodium hydride in 470 ml. of benzene, 25 g. of 9-benzyl-l ,2,3,4-tetrahy- 45. 50 6 benzyl—l,2,3,4-tetrahydrocarbazole, 10 g. of which yielded 5.4 g. of 4—[(lg-piperidyl)methyl]-9-benzyl- 1,2,3,4-tetrahydr0carbazole hydrochloride, 'm.p. 249°—252°C. 4-[( 1—Piperidyl)methyl]-9-benzyl-1 ,2,3,4-tetrahy- drocarbazole hydrochloride was found to be antibac- terially effective against Staphylococcus aureus at 31.2 mcg.[ml. EXAMPLE 4 A. Following a procedure similar to that described in Example 1A but using 2.66 g. of sodium hydride in 240 m1. of benzene, 34 g. of 9-benzyl-1,2,3,4—te'trahy— drocarbazoIe—4-carboxylic acid, 8.3 ml. of thionyl chlo- ride, and' 19 g. Of pyrrolidine (neat), there was obtained 8 g. of 4-[(1‘-pyrrolidyl)ucarbonyl]-9-bEnzyl-l,2,3,4- m.p. 161°—163°C. (tetrahy- drofuran/n-pent'ane). B. Following a procedure similar to that described in Example 1B but 'using 2.6 g. of lithium aluminum hy- dride in 250. ml. of tetrahydrofuran, and 23.1 g. of 4-[ ( l-pyrrolidyl)carbonyl]-9—benzy]-‘1,2,3,4—tetrahy— ' drocarbazole, there was obtained 20.1 g. of crude resi- ‘ due consisting largely of 4—[(l-pyrrolidyl)methyl]-9- benzyl-1,2,3,4-tetrahydrocarbazole, 8 g. of which yielded 2.6 g. of 4-[(1-pyrrolidyl)methyI]-9—benzyl— hydrochloride, m.p. 232°—234°C. 4-[( 1—Pyrrolidy1)methyl]—9-benzyl- 1 ,2,3 ,4—tetrahy- drocarbazole hydrochloride was found to be antibac—- terially effective against Staphylococcus aureus, Pseudo— 'monas aeruginosa, Escherichia coli and Proteus vulgaris at 62.5 mcg./ml., 500 mcg./ml., 125 meg/ml. and 500 meg/ml. respectively. . ' I 7 EXAMPLE 5 A. Following a procedure similar to that described, in Example 1A but using 0.72 g. of sodium hydride in 175 ml. of benzene, 10 g. of 9-benzyl—6-methoxy-l,2,3,4-_ tetrahydrocarbazole-4-carboxylic acid, 2.2 ml. of thioJ' nyl chloride, and‘ 1.9 g. of methylamine in‘ a small‘ ' amount of benzene, there was obtained 7.6 g. of 4- methylamino‘carbonyl-9-benzyl—6-methoxy— l ,2,3 ,4-tet-., rahydrocarbazole,’ m.p. 163°~166°C. (ether). B. Following a procedure similar to that described in Example 1B but using 0.9 g. of lithium aluminum hy- dride in 150 ml. of‘tetrahydrofuran, and 7.6 oh 4- methylaminocarbonyl-9—benzyl-6-methoxy-1,2,3,4—tet— rahydrocarbazole,»there was obtained 82 g. Of crude residue consisting largely of ,4-methyla‘minomethyl-9- . benzylL6-methoxy-l,2,3,4—tetrahydrocarbazole, which 1 55 drocarbazole—4-carboxylic acid, 6:1 ml. of thionyl chlo— ‘ ' . ride, and 14 g. of piperidine in a small amount of water, there was obtained 3.6 g. of 4—[( l—piperidyl)carbonyl]- 9-benzyl-l ,2,3,44tetrahydrocarbazole, ’ ' m.p. I40°—l43°C. (tetrahydrofuran/n—pentane). . B. Following a procedure similar to that described in Example 1B but using 2.6 g. of lithium aluminum hy- 60 i . dride in 250 ml. of tetrahydrofuran, and 23.7 g. of 55 4—[( l-piperidyl)carbonyll—9-benzyl-1,2,3,4-tetrahy- drocarbazole, there was obtained 22.3 g. of crude resi— due consisting largely of 4-[(1-piperidyl)methyl]—9- yielded 4.8yg.’ of 4—methylamin‘omethy179-benzyl-6¥ methoxy-1,2,3,4—tetrahydrocarbazole hydrochloride, ’ m.p. 259°—261°C. . 4—Methylaminomethyl-9-benzyl-6-methoxy- 1 ,2,3,4- tetrahydrocarbazole hydrochloride was found to be, antibacterially effective against Staphylococcus aureus at 62.5 meg/ml. » . ‘ EXAMPLE 6 A. Following a procedure similar to that described in Example 1A but using 1.3 g. of sodium hydride in 310 ml. of benzene, 17.2 g. of 79-benzyl-1,2,3,4—tetrahy- drocarbazole-4-carboxylic acid, 4.1 ml. of thionyl chlo- ride, 9.1 g. of N—phenylpiperazine, and 30 ml. of trieth- ylamine (as acid-acceptor), there was obtained 8.6 g. of 4-[(.4—phenyl-l~piperazinyl)carbonyl1-9-benzyl- l,2,3,4-tetrahydrocarbazole, m.p. 135°~137°C. (ethyl 3,939,177 7 acetate/n~pentane). B. Following a procedure similar to that described in Example 18 but using 1.1 g. of lithium aluminum hy— dride in 75 ml. oftetrahydrofuran, and 12.6 g. of 4-[(4- phenyl-1-piperazinyl)-carbonyl]»9-benzyl-l ,2,3,4-tet- rahydrocarbazole, there was obtained 12.3 g. of crude residue consisting largely ofr 4-[(4-phenyl—1- piperazinyl )methyl ]-9-benzyl-1 ,2,3,4tetrahydrocar— bazole, which yielded 5 g. of 4-[(4—pheny1—1— piperazinyl)methyl]-9-ben2yl-1,2,3 ,4-tetrahydrocar- bazole hydrochloride, m.p. 273—274°C. (dimethylfor- mamide/ether). 4—[(4-Phenyl’1-piperazinyl)methyl]—9-benzyl- 1,2,3,4-tetrahydrocarbazole hydrochloride was found to be antibacterially effective against Staphylococcus aureus at 250 meg/ml. EXAMPLE 7 A. Following a procedure similar to that described in Example 1A but using 0.24 g. of sodium hydride in 100 ml. of benzene, 5.8 g. of 9-benzyl-6-methoxy-1,2,3,4- tetrahydrocarbazole-4-carboxylic acid, 1.28 ml. of thi- onyl chloride, 3 g. of N—phenylpiperazine, and 10 ml. of triethylamine (as acid-acceptor) in a small amount of water, there was obtained 3.1 g. of 4-[(4—phenyl-l- piperazinyl)carbonyl]-9-benzyl-6-methoxy-1,2 ,3 ,4-tet- rahydrocarbazole, m.p. l70°—172°C. (benzene/n—hex- ane). B. Following a procedure similar to that described in Example 13 but uisng 0.38 g. of lithium aluminum hydride in 100 ml. of tetrahydrofuran, and 5 g. of 4- [(4-phenyl- 1 —piperazinyl )carbonyl]-9-benzyl—6- methoxy-l,2,3,4—tetrahydrocarbazole, there was ob- tained crude residue consisting largely of product in free base form which on recrystallization from tetrahy- drofuran/n-hexane/ether yielded 3.5 g. of 4-[(4-phe- nyl-1-piperazinyl)methyl]-9-benzyl-6-methoxy- l,2,3,4-tetrahydrocarbazole, m.p. l42°—143°C. 4-[(4-Phenyl- l -piperazinyl)methyl]—9-benzyl-6- methoxy-l,2,3,4-tetrahydrocarbazole was found to be antibacterially effective against Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli at 500 meg/m1. EXAMPLE 8 A. Following a procedure similar to that described in Example 1A but using 0.72 g. of sodium hydride in 170 ml. of benzene, 10 g. of 9-benzyl-6-methoxy—l,2,3,4— tetrahydrocarbazole~4-carboxylic acid, 2.2 g. of thionyl chloride, and 6.4 g. of benzylamine, there was obtained 2.9 g. of 4-benzylaminocarbonyl-9-benzyl-6-methoxy— 1,2,3,4-tetrahydrocarbazole, m.p. 176°—l79°C. (tetra— hydrofuran). B. A mixture of 24.8 g. of 4-benzylaminbcarbonyl-9— benzyl—6—methoxy—l,2,3,4—tetrahydrocarbazole in 460 ml. of tetrahydrofuran was added dropwise to 240 ml. of a one molar solution of diborane in tetrahydrofuran at 0°C. in a nitrogen atmosphere, and the solution was allowed to stand at room temperature for 64 hours. Chilled 6-N-hydrochloric acid (37 ml.) was added, and the solution was concentrated on a steam bath. The resulting solid was filtered and recrystallized from me- thanol~ether to give 7.3 g. of 4-benzylaminomethyl-9- benzyl—6-methoxy— l ,2,3,4-tetrahydrocarbazole hydro— chloride, m.p. 274°~278°C. 4-Benzylaminomethyl-9-benzyl—6-methoxy-l ,2,3,4- tetrahydrocarbazole hydrochloride was found to be 10 15 2O 25 3O 35 40 45 50 55 60 65 8 antibacterially effective against Staphylococcus aureus at 7.8 meg/ml. EXAMPLE 9 A. Following a procedure similar to that described in Example 1A but using 2.4 g. of sodium hydride in 580 ml. of benzene, 33.6 g. of 9-benzyl-6-methoxy-l,2,3,4- tetrahydrocarbazole-4-carboxylic acid, 7.4 ml. of thio- nyl chloride, and 47 ml. of concentrated ammonium hydroxide, there was obtained 12.5 g. of 4-carbamyl—9— benzyl-6-methoxy-l ,2,3,4-tetrahydrocarbazole, m.p. 156°—-158°C. (ethyl alcohol/tetrahydrofuran/water). B. To 47.9 g. of 4—carbamyl-9-benzyl-6~methoxy- l,2,3,4—tetrahydrocarbazole in 140 ml. of pyridine was added 17.9 ml. of benzenesulphonyl chloride, and the mixture was warmed on a steam bath until solution was complete, allowed to stand for 15 hours at room tem- perature and poured into water. The mixture was chilled, and the resulting precipitate was filtered, washed with dilute hydrochloric acid and water, and dried to give 24.5 g. of 4-cyan0—9—benzyl-6-methoxy- 1,2,3,4—tetrahydrocarbazole, m.p. 130°—137°C. C._To 1.3 g. of lithium aluminum hydride in 200 ml. of tetrahydrofuran was added portionwise 10 g. of 4- cyano-9-benzyl—6-methoxy-l ,2 ,3 ,4»tetrahydrocar- bazole, and the mixture was heated under reflux for 5 hours. Water (2.6 ml.) was added and heating under reflux was continued 1 hour and the mixture was then filtered. The filtrate was evaporated to dryness under reduced pressure and an ethyl acetate solution of the resulting crude residue, consisting largely of 4- aminomethyl-9-benzyl-6—methoxy—1 ,2,3,4-tetrahy- drocarbazole, was treated with 1.8 ml. of glacial acetic acid and chilled. The resulting solid was filtered, washed with ethyl acetate and ether, and dried to give 3.7 g. of 4-aminomethyl-9-benzyl—6-methoxy-1,2,3,4- tetrahydrocarbazole acetate, m.p. 171°——l75°C. 4-Aminomethyl-9-benzyl—6-methoxy-1 ,2,3,4-tetrahy- drocarbazole acetate was found to be antibacterially effective against Staphylococcus aureus and Escherichia coli at 62.5 mcg./ml. and 125 meg/ml. respectively. EXAMPLE 10 A. A mixture of 36 g. of N-(3,4-dimethoxyphenyl)- N-benzylamine and 15.3 g. of ethyl 6—bromocyclohexa- none-2-carboxylate was maintained at about 35°C. for several days. Powdered zinc chloride (25 g.) was added and the mixture was heated at 125°C. for 1%. hours. The cooled mixture was slurried in water and extracted with ether. The ether extract was washed with 5% hy- drochloric acid and water, dried and evaporated to dryness. The residual crude ethyl ester was treated with a solution of 24 g. of potassium hydroxide in 100 ml. of water and 100 ml. of ethyl alcohol at reflux tempera~ ture for 3 hours. The solution was evaporated to dry— ness under reduced pressure, the resulting residue was dissolved in water and the aqueous solution was ex- tracted with 58% ether/n-hexane and acidified with 10% hydrochloric acid. The resulting solids were col— lected and recrystallized from tetrahydrofuran/n-pen- tane to give 7.1 g. of 9-benzyl-6,7-dimethoxy-l,2,3,4- tetrahydrocarbazole-4-carboxylic acid, m.p. 177°—l79°C. B. Following a procedure similar to that described in Example 1A but using 0.47 g. of sodium hydride in 1 10 ml. of benzene, 7.1 g. of 9—benzyl-6,7-dimethoxy~ l,2,3,4-tetrahydrocarbazole-4-carboxylic acid, 1.46 ml. of thionyl chloride, 3.14 g. of N-phenylpiperazine, r 3,939,177 9 and ll'rnlii'bf triethylamine (as acid-acceptor) in a small amount of benzene, there was obtained 2.8 g. of 4-[(4-phenyl- 1-piperaziny1)carbonyl]-9-benzyl-6,7- dimethoxy- 1 ,2,3 ,4-tetrahydrocarbazole, . m.p. l33°—136°C. (ethyl acetate/ether/n-pentane). C. Following a procedure similar to. that described in Example 18 but using 2 g..of lithium aluminum hydride in 250 ml. of tetrahydrofuran and 26 g. of 4-[(4-phe- nyl- l -piperazinyl )-carbony1I-9-benzyl-6,7-dimethoxy- 1,2,3,4-tetrahydrocarbazole, there was obtained 10 g. of crude residue consisting largely of 4-[(4-pheny-l- piperazinyl )methyl]—9-benzyl—6,7-dimethoxy-l ,2,3,4- tetrahydrocarbazole,-pheny1-yielded 4.9 g. of 4—[(4- phenyl- 1-piperaziny1)methyl]-9-benzyl-6,7-dimethoxy- 1,2,3,4—tetrahydrocarbazole dihydrochloride, m.p. 245°—247°C. ‘ 4-[ ( 4«Phenyl— l -piperazinyl )methy1]-9~benzyl-6,7— dimethoxy— l ,2 ,3 ,4—tetrahydrocarbazole dihydrochlor— ide was found to be antibacterially effective against Pseudomonas aeruginosa at 125 meg/ml. EXAMPLE 1 1 ' A. Following a procedure similar to that described in Example 1A but using 0.72 g. of sodium hydride in 170 ml. of benzene, 10 g. of 9—benzyl-6-methoxyi1,2,3,4- tetrahydrocarbazole-44carboxylic acid, 2.2 ml. of thio— nyl chloride, and 2.7 g. of ethylamine, there was ob- tained 6.5 g. of 4-ethy1aminocarbonyl—9-benzyl—6— methoxy-l ,2,3 ,4-tetrahydrocarbazole, m.p. 168°—l69°C. (tetrahydrofuran/n-hexane). B. Following a procedure similar to that described in Example 13 but using 1 g. of lithium aluminum hydride in one liter of tetrahydrofuran, and 3.6 g. of 4- ethylaminocarbonyl-9-benzyl-6-methoxy-1 ,2,3 ,4—tet— rahydrocarbazole, and increasing the reflux time to 10 hours, there was obtained 4 g. of crude residue consist- ing largely of 4-ethylaminomethyl—9—benzyl-6-methoxy- 5 10 15 20 25 3O 35 1,2,3,4-tetrahydrocarbazole, which yielded 1 g. of 4- . ethylaminomethyl-9-benzyl-6-methoxy-1 ,2,3,4-tet— rahydrocarbazole hydrochloride, m.p. 233°—235°C. EX'AMPLE 12 A. Following a procedure similar to that described in Example 1A but using 0.72 g. of sodium hydride in 170 ml. of benzene, 10 g. of 9—benzyl—6-methoxy-l,2,3,4- tetrahydrocarbazole-4-carboxylic acid, 2.2 ml. of thio— nyl chloride, and 3.6 g. of propylamine, there was ob- tained 7 g. of 4—propylaminocarbony1-9—benzyl—6- methoxy-l ,2 ,3 ,4-tetrahydrocarbazole, m .p. l80°—181°C. (ethyl acetate). B. Following a procedure similar to that described in Example 1 1A but substituting for the amide used 40 45 50 therein an equivalent amount of 4-propylaminocarbo- . nyl-9—benzy1—6«methoxy- l ,2,3 ,4—tetrahyd rocarbazole there is obtained 4-pr0pylaminomethyI—9—benzyl—6— methoxy—l,2,3,4-tetrahydrocarbazole and the hydro- chloride salt thereof. 55 By following a procedure similar to that described in 1 Example 10A but substituting for N-(3,4-dimethoxy- phenyl)-N—benzy1amine an equivalent amount of the 1 following amines: N—( 4-methy1phenyl)—N-benzylamine; N-(4-n-hexylphenyl)-N-benzylamine; N-(4-tert-butylphenyl)—N-benzylamine; N-(4—isopentyloxphenyl)-N-benzylamine; and N—(4—methy1~3—methoxypheny1)—N-benzy1amine; there are obtained respectively: 60 65 1 0 l3. 9—benzy1-6-methyl-l ,2,3,4-tetrahydrocarbazole— 4-carboxylic acid; 14. 9-benzyl-6-n—hex'y141,2,3,4-tetrahydrocarbazole- 4-carboxy1ic acid; ' 15. 9-benzyl-6-tert-butyl- 1 ,2,3,4-tetrahydrocar- bazole-4-carboxylic acid; 16. 9-benzyl-6-isopentyloxy—1,2,3 ,4-tetrahydrocar- bazole-4-carboxylic acid; and 17. 9-benzyI-6-methyl-7—methoxy-l ,2,3,4-tetrahy- drocarbazole-4-carboxylic acid. The phenylbenzylamines used in the preparation of the carboxylic acids 13-17 above are obtained by react- ing benzaldehyde with 4-methy1aniline, 4-n—hexylani- line, 4-tert-butylaniline, 4-isopentyloxyaniline, and 4- methyl-3-methoxyaniline respectively, using the proce- dures described in.U.S. Pat. No. 3,687,969. By following a procedure similar to that described in Example 1A but substituting for 9-benzyl-6—methoxy- 1,2,3,4-tetrahydrocarbazole-4-carboxylic acid an equivalent amount of the carboxylic acids 13-17 above, and for dimethylamine an equivalent amount of the following amines: N-(n-hexyl)-N—methylamine; dibenzylamine; N—(benzyl)—N-methylamine; di-n-hexylamine; and diethylamine; there are obtained respectively: 138. 4-(N-n-hexyl—N-methy1aminocarbonyl)-9-ben2yl- 6-methyl- l ,2,3,4-tetrahydrocarbazole; 19. ‘ 4-dibenzylaminocarbon‘yl—9—benzyl-6-n-hexy1— I 1 ,2,3 ,4-tetrahydrocarbazole; 20. 4-(N-benzyl-N—methylaminocarbonyl)-9nbenzyl- 6-tert-butyl-1 ,2,3,4-tetrahydrocarbazole; 2 1. 4-di—n-hexy1aminocarbony1—9-benzyl-6‘isopen- tyloxy-l ,2,3,4-tetrahydrocarbazole; and 22. 4-diethylaminocarbonyl-Q-benzyl-6—methyl-7- methoxy- l ,2,3,4~tetrahydrocarbazole. .By following a procedure similar to that described in Example 1B but substituting for 4-dimethylaminocar- bonyl-9-benzyl—6-methoxy- 1 ,2,3,4-tetrahydrocar- bazole an equivalent amount of the amides 18-22 above there are obtained respectively: ‘ 23. 4-(N—n-hexyl-N—methy1aminomethyl)-9-benzyl- 6-methyl-l ,2,3 ,4-tetrahydrocarbazole; 24. 4-dibenzylaminomethyl-9-benzyl-6-n—hexyl- l ,2 ,3 ,4—tetrahydrocarbazole; ' 25. 4—(N-benzyer-methylaminomethyl)-9-benzyl-6- tert-butyl— l ,2,3 ,4—tetrahydrocarbazole; 26. 4-di-n-hexylaminomethyl-9-benzyl-6—isopen- tyloxy-l ,2,3 ,4-tetrahydrocarbazole; and 27. 4—diethylaminomethyl-9-benzyl-6—methyl-7- methoxy-1,2,3_,4-tetrahydrocarbazole. We Claim: 1. 4-R lR2NCl-12-9-benzyl—6-R3'7—R4- l ,2,3,4—tetrahy- drocarbazole having the formula: 3,939,177: 1 l 12 CHZNRIR2 V CONRIR2 R 3 R v 5 ' R3 l 4 N R 'l 4 N CH 2 ‘ Lag 10 wherein _ " 15 RI and R2 are each hydrogen, lower-alkyl or benzyl, wherein and ~ R1 and R2 are each hydrogen, lower-alkyl, or benzyl, » R3 and R4 are each hydrogen, lower—alkyl, or lower- and alkoxy. R3 and R4 are each hydrogen, lower-alkyl, or lower- 2. A compound according to claim 1 wherein R4 is 20 alkoxy. . 7 hydrogen. 6. A compound according to claim 5 wherein R4 is 3. 4-Dimethylaminomethyl-9-benzyl-6-methoxy- hydrogen. _ l,2,3,4-tetrahydrocarbazole according to claim 2. 7. 4-Dimethylaminocarbonyl-9-benzyl-6-methoxy- ‘ 4. 4-Benzylaminomethyl-9-benzyl-6-methoxy- 1,2,3,4-tetrahydrocarbazole according to claim‘6. l,2,3,4-tetrahydrocarbazole according to claim 2. 25 8. 4-Benzylaminoearbonyl-9—benzyl-6-methoxy- 5. 4-R,R2NC0-9-benzyl-6-R3-7-R4-l,2,3,4—tetrahy— 1,2,3,4,-tetrahydrocarbazole according to claim 6. drocarbazole having the formula: * * * * * . 30 35 4O 45 50 55 60 65 ...
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US3939177_TOT - United States Patent[191 Alexander et al[11...

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