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Publication numberUS3472870 A
Publication typeGrant
Publication dateOct 14, 1969
Filing dateAug 29, 1966
Priority dateAug 29, 1966
Also published asDE1695478A1
Publication numberUS 3472870 A, US 3472870A, US-A-3472870, US3472870 A, US3472870A
InventorsBarbara E Gould, William A Gould, Aubrey A Larsen
Original AssigneeMead Johnson & Co
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
US 3472870 A
Abstract  available in
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Claims  available in
Description  (OCR text may contain errors)

United States Patent U.S. Cl. 260326.12 9 Claims ABSTRACT OF THE DISCLOSURE Tryptamines and N-substituted tryptamines bearing a sulfonamide substituent in the 4, 5, 6 or 7 positions of the indole ring have hypotensive, intestinal relaxant, and central nervous system depressant activity.

Tryptamine has been known for many years as a biological product involved in the intermediary metabolism of proteins, specifically of the amino acid tryptophan. One of the identified functions of tryptamine is an intermediate in formation by the animal organism of biologically active hydroxylated derivatives such as serotonin. The present invention provides a novel group of biologically active compounds having structures resembling tryptamine.

The compounds of this invention are represented by Formula I which appears below. The sulfonamide function illustrated by R SO NR occupies either the 4-, 5-, 6-, or 7-positions R is hydrogen, benzyl, or lower alkyl having up to 4 carbon atoms R is hydrogen, lower alkyl having up to 4 carbon atoms, or carboxyl.

The symbol refers to an N-substituted heterocyclic group having up to 7 carbon atoms, an N-substituted heteropolycyclic group having up to 11 carbon atoms, or an amino group in which R and R may be the same or different. Morpholino, pyrrolidino, piperazino, tetrahydroquinolino, and tetrahydroquinazolino are representative of heterocyclic and heteropolycyclic groups. R is hydrogen, benzyl, or lower alkyl, or lower alkenyl of up to 4 carbon atoms. R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, polycycloalkyl, polycycloalkenyl, polycycloalkylalkyl, polycycloalkenylalkyl, aryl, aralkyl, aralkenyl, aryloxyalkyl, heterocyclic, heterocycloalkyl, heteropolycyclic, or heteropolycycloalkyl, each containing up to 12 carbon atoms, and having up to two substituents selected from hydroxyl, carboxyl, amino, lower alkoxy having up to 4 carbon atoms, lower alkyl having up to 4 carbon atoms, and methylenedioxy.

R is alkyl, alkenyl, cycloalkyl, or cycloalkenyl each having up to 6 carbon atoms, phenyl, phenylalkyl, naphthyl, substituted phenyl, substituted phenylalkyl, or substituted naphthyl, wherein said substituent is alkoxy, alkyl, alkenyl, cycloalkyl, or cycloalkenyl having up to 6 carbon atoms, halogen, or benzyloxy. R is hydrogen or lower alkyl having up to 4 carbon atoms.

Alk is an alkylene group of 2 to 6 carbon atoms with at least 2 carbon atoms separating the indole ring and the aminonitrogen substituent Alk may be straight or branched.

3,472,870 Patented Oct. 14, 1969 The compounds identified by Formula I possess hypotensive, central nervous system depressant, and smooth muscle depressant properties. They are relatively nontoxic, having acute toxicities for mice in the range of 250 to more than 2000 mg./kg. by the intraperitoneal and oral routes. Their pharmacologic effects are, however, elicited in doses below the toxic limit. They are preferably administered by the parenteral routes, although absorption thereof from the alimentary canal following oral or rectal administration is possible.

The process for the preparation of the compounds of Formula I involves the unitary concept of reducing or hydrolyzing a functional side chain in the 3-position of an indole containing a sulfonamido group (R SO N-R in the 4-, 5-, 6-, or 7-positions. The functional chain in the 3-position is so constituted as to provide an aminoalkyl group,

Alk-N of the character shown in Formula I on reduction by chemical or catalytic means, or hydrolysis. Reducible side chains include cyanoalkyl, nitroalkenyl, oxamyl, and acylalkyl. Carboxamido alkyl side chains are contemplated for use in the hydrolytic variation. The process concept is illustrated in the following diagram.

Genealized Reaction Scheme I -alkC)O, and AlkN-COR a a RJSOaN wherein R is lower alkyl and the other symbols have the meaning already assigned.

In those applications of this process employing the cyanoalkyl, nitroalkenyl, or oxamyl intermediates, chemical or catalytic reduction methods known for the transformation of nitriles, nitro compounds, and carboxamides to amines are applicable. Catalytic methods employ either noble metal or Raney nickel catalysts. Platinum oxide catalyst is quite appropriate in low pressure (15-60 p.s.i.) hydrogenations. In the case of the acylalkyl intermediates, catalytic reduction employing preferably a platinum catalyst is employed and the process is carried out in the presence of a primary amine under the conditions ordinarily used for the preparation of secondary amines by reductive alkylation. Chemical reduction methods use any of a variety of reagents known to the art for this purpose, but the hydrides such as lithium aluminum hydride and diborane are the most convenient for small scale Work.

For simplicity of illustration, the description of the synthesis of specific compounds of the present invention is subdivided according to the method used for synthesis of the intermediates of Formula II. Five general methods 3 4 are employed to prepare the intermediates. These (Reactions 11-15), reductive alkylation (Reactions l6- methods are shown below in schematic fashion and illus- 19), and the Fisher indole synthesis (Reactions 20-25). trated by specific working examples which follow. They The first four methods involve reduction variations of the are the gramine synthesis (Reactions 1-6), the Vilsmeier generalized scheme. The Fischer synthesis employs a aldehyde synthesis (Reactions 7-10), the oxamyl method 5 hydrolytic final stage.

GRAMINE SYNTHESIS (Reactions 1-6) (I) ommonm (2) CHzCN (3) CHZCN NO NO NO NH N Ra N/ R2 N/ R2 N it (6) OH CH NH (5) 0H20N FORMULAI t- R som I R5SO2N l N/ R2 R2 1 VILSMEIER ALDEHYDE SYNTHESIS (Reactions) (7) CH0 (8) CH=CNO1 (g) crnomvn, msozN R soiN R SOzN R som f f W T R1 R1 1 1 11 lfl FORMULA I OXAMYL SYNTHESIS (Reactions 11-15) R4 Rt 000001 GOCON/ COCON/ NO No, No, NH

y W R1 R1 R1 iv R1 R FORMULAI (15) cOCON\ R5SO2N REDUCTIVE ALKYLATION (Reactions 16-19) f OH=C-NO (16) 011,00 msoiN i L R soiN J: L

R1 R1 N N I i '0 amine, R4

f omoHnHi (18) orncmmm (19) Iusom J: W R5SON FORMULA! a e 60! N R2 ketong, R N R2 FISCHER SYNTHESIS (Reactions -25) (24) R 8 O2N F RMULA I In the foregoing reaction diagrams, Reactions 5, 9, 15, and 17 are representative of reduction methods conforming to the generalized reaction scheme illustrating the unitary process concept. Reaction 24 is illustrative of a hydrolytic method. Reactions 6, 10, 18, 19, and 25 are alternative supplementary steps for the conversion of primary or secondary amines of the present invention (Formula I wherein R and/or R are hydrogen) into secondary or tertiary amines by reductive alkylation (Reaction 18) or reaction with an appropriate R or R halide or other reactive ester suitable for the introduction of other R and R groups as defined for Formula I according to known methods for the alkylation of amines. The following examples are arranged to particularly describe the methods of the foregoing diagrams as follows.

Gramine SynthesisExamp1e 1-25. Vilsmeier Aldehyde SynthesisExample 26. Oxamyl Synthesis-Examples 27-43. Reductive Alkylation-Examples 44-74. Fischer Synthesis-Examples 75-83.

EXAMPLE 1 3- 2'-amino ethyl) -5-methanesulfonamidoindole methanesulfonate (a) 5 methanesulfonamidoindoleacetonitrile. 5-

aminoindole-3acetonitrile is prepared by the reaction sequence S-nitroindole, 5-nitrogramine, S-nitroindole 3- acetonitrile, and thence hydrogenation of a solution of 13.7 g. (0.068 mole) of the latter in 150 ml. of ethanol at room temperature over 0.2 g. of platinum oxide catalyst at 60 p.s.i. 5aminoindole-3acetonitrile is obtained in 88% yield, M.P. 129-135 C. To a cooled solution of 13.2 g. (0.077 mole) of the S-aminoindole-3-acetonitrile in 25 ml. of pyridine there is added dropwise with stirring 8.9 g. (0.077 mole) of methanesulfonyl chloride. The reaction mixture is stirred at room temperature for 3 hrs. and then warmed to 6570 C. for 15 min. The product is recovered by pouring the reaction mixture into 500 ml. of ice water and collecting the precipitate on a filter. It is washed with water, dissolved in 10% aqueous sodium hydroxide, and reprecipitated by acidification with hydrochloric acid, yield, 10.8 g. (57%), M.P. 157-158 C. An analytical sample prepared by recrystallization from isopropanol exhibited melting point 157-159 C.

Analysis.-Calcd. for C H N O S: C, 53.00; H, 4.45; N, 16.86; S, 12.86. Found: C, 52.94; H, 4.68; N, 16.61; S, 12.91.

(b) Hydride reduction.A solution of 5.0 g. (0.02 mole) of 5-methanesulfonamidoindole-3acetonitrile in 50 ml. of dry tetrahydrofuran is added in dropwise fashion to a stirred mixture of 2.3 g. (0.06 mole) of lithium aluminum hydride in 75 ml. of dry tetrahydrofuran. The mixture is refluxed for a period of 2 hrs. and then stirred a NO as N-R4 N--R4 H II overnight at room temperature. A solution of 4.6 ml. of water and 10 ml. of tetrahydrofuran is then added to decompose the excess lithium aluminum hydride and the reaction complex. The mixture is filtered and the filtrate concentrated by distillation at reduced pressure. The residue is dissolved in boiling ethanol, insoluble material filtered, and the filtrate concentrated at reduced pressure. The residue is further purified by trituration with isopropyl ether to yield the product weighing 5 g., M.P. 77-95" C. This material is dissolved in methanol and acidified with methanesulfonic acid to provide 2.4 g. (35%) of the methanesulfonate salt of the desired product, M.P. 229- 235 C. (dec.). This material is recrystallized from hot methanol which is acidified with methanesulfonic acid, M.P. 235-237 C. (dec.).

Analysis.Calcd. for C11H15N3O2S'CH3SO3H: C, 41.25; H, 5.48; N, 12.02; S, 18.35. Found: C, 41.18; H, 5.71; N, 11.79; S, 18.06.

EXAMPLE 2 3 (2'-aminoethyl) -6methanesulfonamidoindole hydrochloride The method of Example 1(a) is applied to 6-nitroindole to provide 6-methanesulfonamidoindoleacetonitrile in 60% yield, M.P. 132-134 C. after recrystallization from isopropyl alcohol.

Analysis.-Calcd. for C H N O S: C, 53.00; H, 4.45; N, 16.86; S, 12.86. Found: C, 52.92; H, 4.68; N, 16.81; S, 13.05. This material is then reduced to 3-(2'-aminoethyl)6methanesulfonamidoindole as described in Example 1(b). In this instance the hydrochloride salt is prepared by-treatmnent of the crude product with an ethanolic solution of hydrogen chloride. The product is obtained in 51% yield, which is purified for analysis by recrystallization from methanol-isopropyl ether mixture, M.P. 218- 220 C.

Analysis.-Calcd. for C H N O S-HCI: C, 45.59; H, 5.57; S, 11.06. Found: C, 45.72; H, 5.68; S, 11.30.

In this preparation the intermediate 6-nitrogramine may alternatively be prepared by nitration of gramine according to the method of Hester, J. Org. Chem. 29, 1158 (1964). 4-Nitrogramine is also obtained by this nitration method.

EXAMPLE 3 3 (2-amin0ethyl 4-methanesulfonamidoindole hydrochloride 4-nitrogramine is prepared according to the method of Hester, loc. cit., and converted to 4-nitroindole-3-acetonitrile, which is then hydrogenated and mesylated as decribed in Example 1(a), yielding 4-methanesulfonamidoindoleacetonitrile in 69% yield, M.P. 210214 C. (dec.). This material is then reduced as described in Example 1(b) to provide the desired product in 16% yield, M.P.

7 8 234-236 C. (dec.) after recrystallization from methaminum hydride according to the method of Example 1(b) nolisopropyl ether. to provide the desired product.

Analysis.-Calcd. for C H N O S-HCl: C, 45.59; H, By substitution of diethyl sulfate, n-propyl chloride, or 5.57; N, 14.49; S, 10.82. Found: C, 45.85; H, 5.73; N, n-butyl bromide for methyl iodide in Example 25, corre- 14.24; S, 10.82. 5 sponding 3-(2'-aminoethyl)-5-[N-(ethyl, n-propyl, or n- EXAMPLES 4-9 butyl)methanesulfonamido]indoles are obtained.

The procedure of Example 1(a) is applied to the fol- EXAMPLE 26 lowing nitroindoles to provide, after reduction of the corresponding methanesulfonamidoindole acetonitrile in- 3 (2 ig g aifiga gz termediates according to Example 1(b), the 3-(2-amino- 10 ethyl)-substituted-indole products listed in the following 50116411afleslllfonamldolndole-3-caIb0Xa1dhydebl The Vilsmeier reagent is prepared by cooling 20 ml. of

TABLE I.3-(2-AMINOETHYL) SUBSTITUTED INDOLES Starting Material Product Substituents Example No:

4 T-nitroindole 7-rnethanesulfonamido.

5... 2-methyl-6-nitroindole G-methauesulfonamido 2-metllyl- 2-methyl-5-nitroindole fi-rnethanesulionamido-2-metl1yl.

7.. 2-methyl-7-nitroindole 7-methanesullonamido-Z-methyl.

8 Z-(n-butyl)--nitroindolo 2-(n-butyl)-5-methanesulionamido.

9 2-(n-propy1)-6-nitroindole.... 6-methanesulfonamido-2-(n-propyl).

EXAMPLES 10-24 dimethylformamide in an ice-salt bath and then adding 5.0 ml. (0.054 mole) of phosphorous oxychloride in drop- The procedure of Example 1(a) is repeated substitutwise fashion with stirring during a min. period. A soluing various R -sulfonyl halides and anhydrides for the tion of 10.0 g. (0.048 mole) of S-methanesulfonamidomethanesulfonyl chloride specified in that example. The indole in 15 ml. of dimethylformamide is then added in resulting 5-R -sulfonamidoindoleacetonitriles are then redropwise fashion during a period of 1 hr. Excess reagent duced by the method of Example 1(b) to the correspondand reaction complex is then hydroyzed by treatment with ing 3-(2'-aminoethyl)-5-R -sulfonamidoindoles ('Formua solution of 22 g. (0.054 mole) of sodium hydroxide in la I) listed in the table. ml. of water after the addition of crushed ice to the TABLE II.3-(2-AMINOETHYL)-5-R 'S ULFONAMID OINDOLE R -substituent of Example No.: Starting Material Product Hexanesultonyl chloride 11.. Beuzenesulfonyl chloride 12.. p-Toluenesulfonyl chloride... p yl. 13.- O-Chlorobenzenesulfonyl chloride o-Chlorophenyl. 14.- m-Bromobenzenesulfonyl bromide... 15- p-Fluorobenzenesultonyl chloride.-. p-Flouorophenyl. l6 p-Methoxybenzenesulfonyl chloride p-Methoxyphenyl. 17.- a-Naphthylenesulfonyl chloride..-

a-Naphthyl. 18.- 2-Methoxynaphthylene-7-sultonyl chloride. 2-methoxy-7-naphthyl. 19 2,5-dimethylbenzenesulfonyl chloride... 2,5-dimethy1phenyl. 20.. 2,5-dich1orobenzenesult'onyl chloride 2,5-dich1orophenyl. 21.. Methanesulfonic anhydride Methyl. 22.- m-Benzyloxybenzenesulfonyl brorm mBenzyloxyphenyI. 23.- p-Ethylbenzenesulionyl chl0ride.- p-Ethylphenyl. 24 Cyclohexauesultonyl chloride Cyclohexyl.

EXAMPLE 25 reaction mixture. The resulting solution is heated to boiling, cooled to room temperature, acidified with concen- 'ammoethyl)'5'(Nlmgtglylmethanesulfonamldo) trated hydrochloric acid, and the resulting precipitate colm 06 lected on a filter and washed with water; yield, 8.4 g. 5-methanesulfonamidoindole 3 acetonitrile, 7.8 g. 0 (66%), MP. 215-217 C. (dec.). A portion recrystal- (0.031 mole), is dissolved in ethanolic sodium hydroxide lized from ethanol for analysis melted at 219-221 C. solution prepared by diluting 3.5 ml. of 9.15 N sodium (dec.). hydroxide with 250 ml. of ethanol. A solution of 4.0 ml. Analysis.calcd. for C H N o S: C, 50.41; H, 4.23; (0.062 mole) of methyl iodide in 25 ml. of ethanol is then N, 11.76; S, 13.46. Found: C, 50.69; H, 4.50; N, 11.60; S, added in dropwise fashion with stirring at room tem- 5 13.31.

perature. The mixture is stirred at room temperature for (b) 5 methanesulfonamido 3-(2'-nitro-l'-propenyl)- 4 hrs. and then the solvent removed by distillation at reindole. 5 methanesulfonamidoindole 3-carboxaldeduced pressure. The residue is triturated with water and hyde, 6.4 g. (0.027 mole), is mixed with m1. of nitrothe solid product, 5-(N-methylmethanesulfonamido)inethane containing 0.5 g. of ammonium acetate and heatdole-3-acetonitrile, is collected, yield, 6.5 g. This 70 ed at for 16 hrs. The relatively insoluble carboxaldematerial is twice recrystallized from isopropanol to yield hyde gradually dissolves, affording a homogeneous reacthe purified intermediate, M.P. 144-146 C. tion mixture. Subsequently the desired product com- Analysis.--Calcd. for C H N O S: C, 54.73; H, 4.98; mences to precipitate. At the end of the reflux period the N, 15.96; S, 12.18. Found: C, 54.54; H, 5.28; N, 16.02; reaction mixture is cooled and the precipitated product S, 12.39. This material is then reduced with lithium alu- 75 collected by filtration; yield, 6.2 g. (78%), MP. 268- 270 C. (dec.), after washing with isopropanol and drying. A portion recrystallized from methanol for analysis exhibited melting point 273-275 C. (dec.).

Analysis.Calcd. fOl' C12H13N304S: C, H, N, 14.23; S, 10.86. Found: C, 48.91; H, 4.66; N, 14.05; S, 10.92.

(c) Hydride reduction-A mixture of 10.0 g. (0.034 mole) of S-methanesulfonamidoindole-3-(2'-nitro-1'- propenyl)-indole and 200 ml. of dry tetrahydrofuran is added in portionwise fashion to a stirred suspension of 5.4 g. (0.14 mole) of lithium aluminum hydride in 100 ml. of dry tetrahydrofuran. The mixture is refluxed for 24 hrs., cooled, and a solution of 11 ml. of water in 25 ml. of tetrahydrofuran is added thereto in dropwise fashion. The mixture is then stirred for an additional 30 min., and insoluble material collected by filtration. The product is recovered from the filter cake by extraction with three 400 ml. portions of boiling ethanol. The combined ethanolic extracts are acidified with ethanolic hydrogen chloride and then concentrated at reduced pressure. The residue remaining after evaporation of the solvent is triturated with isopropanol, collected, and dried; yield, 3.5 g. (34%), M.P. 250-255 C. (dec.). This material is recrystallized from a methanol-isopropyl ether mixture affording 3 (2'-aminopropyl)-S-methanesulfonamidoindole hydrochloride, M.P. 261-263 C. (dec.).

Analysis.Calcd. for C H N O S'HCI: C, 47.44; H, 5.97; N, 13.83; S, 10.55. Found: C, 47.46; H, 6.21; N, 14.13; S, 10.52.

The method of Example 26 (a) is equally applicable to other methanesulfonamidoindoles to provide the corresponding aldehydes. For example, 6-methanesulfonamidoindole 3 carboxaldehyde and 7-methanesulfonamidoindole-3-carboxaldehyde and 5 (N-methylmethanesulfonamido)indole-3-carboxaldehyde may be prepared in similar fashion. These aldehydes may be condensed with nitroethane as exemplified in Example 26 (b) to provide the corresponding 3 (2-aminopropyl)methanesulfonarnidoindoles. In some instances the reduction can be better accomplished by catalytic means, such as with platinum oxide catalyst, than it can by lithium aluminum hydride reduction as is illustrated in Example 26 (c). If a trial run according to the lithium aluminum hydride method yields the starting material unreacted, that method is probably inapplicable. The recovered nitropropenyl starting material is then reduced catalytically to afford the desired product. A variety of methanesulfonamidoindoles which may be employed according to this method are described in copending application of W. A. Gould and A. A. Larsen, Ser. No. 492,836, filed October 4, 1965. Nitromethane, l-nitropropane, and l-nitrobutane may be substituted in the process of Example 26 (b) to afford 3- indolylnitrovinyl, -nitrobuteny1, and -nitropentenyl intermediates convertible into the corresponding 3 indolylaminoalkyl compounds by reduction.

EXAMPLE 27 N-benzyl-N-methyl-S-methanesulfonamidoindole-3- oxalylamide (a) N-benzyl-N-methyl-5-nitroindole-3-oxalylamide. 5-nitroindole, 15.0 g. (0.0925 mole), is dissolved in 450 ml. of anhydrous ether and treated at C. with 25.0 g. (0.20 mole) of oxalyl chloride dissolved in 50 ml. of ether. Treatment is in dropwise fashion during a period of 1 hr. and is followed by an 18 hr. period at room temperature to allow completion of the reaction. The yellow precipitate, which is nitroindole 3 oxalyl chloride, is then collected by filtration, mixed with 250 ml. of tetrahydrofuran, and treated in dropwise fashion with 45.0 g. (0.37 mole) of benzylmethylamine dissolved in 50 ml. of tetrahydrofuran. The mixture is stirred overnight; by-product benzylmethylamine hydrochloride is separated by filtration. The filtrate is concentrated to dryness, and the residue washed first with ether and then with water before 10 recrystallizing from ethanol; yield, 10.5 g. (34%), M.P. 215216 C.

Analysis.Calcd. for C H N O C, 64.09; H, 4.48; N, 12.46. Found: C, 64.32; H, 4.73; N, 12.34.

(b) N benzyl N methyl 5-aminoindole-3-oxalylamide-The oxalylamide derivative described in (a) preceding, 3.6 g. (0.0106 mole), is dissolved in ml. of ethanol nad hydrogenated over 0.2 g. of platinum oxide catalyst until 0.0318 mole of hydrogen has been absorbed by the reaction. The catalyst is removed by filtration, and the filtrate concentrated to a yellow oil which is employed in the next step without purification.

(c) N-benzyl-N-methyl-S-methanesulfonamidoindole-3- 0xalylamide.The aminoindole prepared in (b) preceding as a yellow oil, 0.0106 mole, is treated in 25 ml. of pyridine with 1.2 g. (0.0106 mole) of methanesulfonyl chloride with stirring. The mixture is stirred at room temperature for 2 hrs. and then warmed to 6070 C. It is then poured into ice water. This product separates as an oil. The aqueous layer is decanted, and the oil is dissolved in 10% aqueous sodium hydroxide. The solution is filtered and acidified with concentrated hydrochloric acid. The product is again obtained as an oil, which is converted to a powder by boiling with benzene. The powder is crystallized from hot ethanol; yield, 0.9 g., M.P. -172 C.

Analysis.Calcd. for C H N O S: C, 59.21; H, 4.97; N, 10.90; S, 8.32. Found: C, 59.14; H, 5.24; N, 10.79; S, 8.47.

The product of Example 27(0) is then reduced to provide '3 [2-(N-benzyl-N-methylamino)ethyl]-5-methanesulfonamidoindole by means of a reducing agent such as sodium, propanol, a metal hydride, or catalytically at from 1 to 4 atmospheres pressure employing 5% palladium-onbarium sulfate catalyst under acid conditions. Under the latter conditions the N-benzyl group is lost by hydrogenolysis to provide 3-(Z-methylarninoethyl)-5-methanesulfonamidoindole.

This method is convenient for the preparation of the compounds of Formula I having a variety of R and R substituents, simply by substituting various amines for 'benzylmethylamine in the procedure of Example 27 (a).

TABLE III.3(2-R LRfi-AMINOETHYL)5-METH ANE- iSiULFONAMIDOINDOLES [Examples 28-43] /R4 N Substituent of Product Amine 3 28 Diethylamine 'N(C2H5)2 29 Indoline Example No.

30 N -methylpiperazine 31 N-benzylpiperazine 32 Pyrrolidine 33 Piperidine 34 Hexamethyleneimino TABLE III.-Cutinued R4 N Substltuent of Example Amine Product N0. R3

35 'lllialuorplrollne N-S 36 Morpholine N -O 37 Styrylamlue -NHCH=CHC H 38 Nortropano N Z 39 Perhydroisoqulnollne N 40 Cyclohex-3-enylamine Ill 41 Benzylamlne --NHOH 42 N-acetylcthylencdiamiue. NHCH CHzNHC H H 43 fi-Naphthylarnine N 12 is collected on a filter and the filtrate concentrated to afford a second crop of material affording a total yield of 63% of the desired product, which on recrystallization from ethanol-isopropanol mixture exhibits melting point 140141 C.

Analysis.Calcd. for C H N O S: C, 54.12; H, 5.29; N, 10.52. Found: C, 53.81; H, 5.68; N, 10.36.

(b) Reductive alkylation.A mixture of 3.5 g. (0.013 mole) of 5-methanesulfonamidoindole-3acetone, 3.1 g. (0.026 mole) of phenethylamine, 0.8 g. (0.013 mole) of acetic acid, and 0.2 g. of platinum oxide in 150 ml. of ethanol is hydrogenated at p.s.i. until 0.013 mole of hydrogen have been absorbed. The catalyst is filtered, the filtrate acidified with concentrated hydrochloric acid, and concentrated at reduced pressure. The residue, after removal of the solvent, is triturated with isopropanol, affording 3.6 g. (68%) of 5 -methanesulfonamido-3-[2- (phenethylamino)propyl]-indole hydrochloride, which is recrystallized from isopropanol (charcoal treatment), M.P. 188190 C.

Analysis.Calcd. for C H N O S-HCl: C, 58.88; H, 6.41; N, 10.30; S, 7.86. Found: C, 58.98; H, 6.43; N, 10.02; S, 7.88.

EXAMPLES 45-73 The following amines are substituted for phenethylamine on a chemically equivalent basis in the procedure of Example 44(b). The products named in the table are obtained in analogous fashion by reductive alkylation according to that method.


66 2-aminopyr1diuc 67.- Cyclohexyhnethylamine- (652.- l-amlnoadamantane 2-aminobicyclo-[2,2,11-0ctane Z-aminomethylbicyclo-[2,2,1]octane..

2-amino-2-methyl-1-propanol 3-aminoazabicyclo-[2,2,2]octane 1-(2-aminoethyl) pyrrole 1-(4-methoxyphenyl)-2-propyl. 1-(3,4-dimethoxyphenyl)-2-propyl. Isopropyl. l-methyl-3-phenylpropyl. 1-(3,4 methylenedl0xyphenyD-2-propyl. 2-(4-tolyl) ethyl. 1-phenoxy-2-propyl.



2-blcyclo-[2,2,l]octylmethyl. Cyclohexyl. 1-(l-carboxy-Zmethyl)propyl. 2-phenylcyclopropyl. Cyclopentylmethyl. Cyclopropyl. 1,3-dimethylbutyl. 1,4-di1nethy1penty1.




. l-naphthyl.


Cyclohexylmethyl. l-adamantanyl. 1-hydroxy-2-methyl-2-propyl. Azabicyclo[2,2,2]oct-3-y1. 1-(2-aminoethyl) pyrrolidine.

72.- l-naphthylmethylamlne l-naphthylmethyl. 73 Z-dimethylaminoethylamine 2-dimethylaminoethyl.

EXAMPLE 44 EXAMPLE 74 S-methanesulfonarnido-Ii-[Z-(phenethylaminojpropyl]indole hydrochloride 5-methanesulfonamido-3- (Z-isopropylaminoethyl) indole 3-(Z-aminoethyl)-5-methanesulfonamidoindole, 5.0 g. (0.0198 mole), is dissolved in 100 ml. of absolute ethanol and 3.5 g. (0.06 mole) of acetone is added thereto. The solution is then subjected to catalytic hydrogenation at room temperature and a pressure of 2 atmospheres employing platinum oxide catalyst. The calculated quantity of hydrogen (0.0198 mole) is absorbed in the course of 75 1 to 2 hrs., and the product is isolated by separation of the 13 catalyst and concentration of the ethanolic solution in vacuo.

EXAMPLE 75 3-(Z-aminoethyl)-5-methanesulfonamidoindole-2- carboxylic acid hydrochloride (a) 2,3-dioxopiperidine 3p-nitrophenylhydrazone.-- 3-carbethoxy-Z-piperidone, 25.0 g. (0.147 mole), is kept overnight with an aqueous solution of 8.8 g. of potassium hydroxide in 450 ml. of water. A solution of pnitrobenzenediazonium chloride is then prepared by dissolving 22.4 g. of 4-nitroaniline in 450 ml. of hot Water containing 37.5 g. of hydrogen chloride, with 12.5 g. of sodium nitrite dissolved in 75 ml. of water. This solution is then clarified by filtration and added to the piperidone solution, while maintaining the temperature at 510 C. The mixture is stirred for 4 hr. at this temperature, at which time evolution of carbon dioxide has ceased. The precipitated product is collected by filtration, washed with water, and dried; yield, 28.1 g. (77%), M.P. 230-235 C.

(b) 6 nitro 1,2,3,4 tetrahydro 9H pyrido[3,4b]- indol-1-one.--A mixture of 60 g. of polyphosphoric acid and 10.0 g, (0.04 mole) of 2,3-dioxopiperidine 3-p-nitrophenyl hydrozone is heated at 110 C. until gas evolution ceases. The mixture is then mixed with 500 ml. of ice water and the solid precipitate collected on a filter. It is recrystallized from 9:1 acetic acid-water, and then washed with isopropanol; yield, 6.4 g., fails to melt at 300 C.

(c) 6 amino 1,2,3,4 tetrahydro 9H pyrido[3,4b]- indol-1-one.--The product of (b) preceding, 6.0 g. (0.026 mole), is hydrogenated over 0.5 g. of platinum oxide catalyst employing 200 ml. of absolute ethanol as reaction medium. Hydrogenation is carried out at 60 psi. for a period sufiicient to permit the consumption of 0.078 mole of hydrogen. The reaction mixture is then heated to boiling and diluted with sufiicient ethanol to dissolve the precipitated organic material. The catalyst is then removed by filtration and the filtrate allowed to cool, resulting in crystallization of the product; weight, 2.5 g., M.P. 279- 281 C. (dec.). The filtrate is concentrated to provide additional crops of material for a total yield of 6.3 g. (84%).

(d) 6 methanesulfonamido 1,2,3,4 tetrahydro 9H- pyrido[3,4b]indol 1 one.6 amino 1,2,3,4 tetrahydro 9H pyrido[3,4b]indol 1 one, 6.5 g. (0.0325 mole), is dissolved in 50 ml. of pyridine and treated in dropwise fashion with 3.8 g. (0.0325 mole) of methanesulfonyl chloride. The mixture is stirred at room temperature for 4 hrs., heated to 6570 C. for 15 min, and then poured into 500 ml. of ice water. The product is collected on a filter and purified by dissolving in aqueous 2 N sodium hydroxide and reprecipitating by acidifying with concentrated hydrochloric acid. The product is collected, washed with water, and dried, yield, 7.7 g. (85% M.P. 279-281 C, (dec.). This material is recrystallized from acetic acid-water, M.P. 282-283 C. (dec.).

Analysis.--Calcd. for C H N O S: C, 51.60; H, 4.69; N, 15.04; S, 11.48. Found: C, 51.68; H, 4.85; N, 15.01; S, 11.29.

(e) Hydrolysis-The product of (d) preceding, 2.8 g. (0.01 mole), is refluxed overnight with a solution of 10 g. of potassium hydroxide in 40 ml. of water and 60 ml. of ethanol. The mixture is cooled, filtered, and the filtrate diluted with 300 ml. of water. Acidification with concentrated hydrochloric acid results in precipitation of 3 (2 aminoethyl) methanesulfonamidoindole 2- carboxylic acid hydrochloride; yield, 2.7 g. (78%), M.P. 282283 C. (dec.). This material is recrystallized from methanol-isopropyl ether, M.P. 271.5272 C. (dec.).

AnalysiS.-Calcd, for CI2H15N3O4S'HCII C, H, 4.83; N, 12.59; S, 9.60. Found: C, 43.27; H, 4.92; N, 12.60; S, 9.52,

. EXAMPLE 76 3- (2-aminoethy1)-5-methanesulfonamido-l-methylindole- 2-carboxylic acid hydrochloride (a) 6 nitro 9 methyl 1,2,3,4 tetrahydro 9H- pyrido[3,4d]indole 1 one.--6 nitro 1,2,3,4 tetrahydro 9H pyrido[3,4b] indol 1 one, 2.0 g. (0.0087 mole, Example 75 (b), is dissolved in 40 ml. of acetone containing 6 ml. of 20% aqueous potassium hydroxide, heated to reflux, and 3.2 ml. of dimethylsulfate added, The product appears as a yellow precipitate which is collected after diluting the reaction mixture with water. It is washed with water and then with cold alcohol; yield, 2.3 g., M.P. 287-288 C. (dec.).

(b) 6 amino 9 methyl l,2,3,4 tetrahydro 9H- pyrido[3,4b]indol-1one.--The product of (a) preceding, 13.3 g. (0.054 mole), is hydrogenated over 0.5 g. of platinum oxide at 60 psi. employing 250 ml. of absolute ethanol as reaction medium. After absorption of 0.162 mole of hydrogen, the catalyst is filtered and the residue concentrated by distillation of the solvent. The residue is triturated with isopropanol and filtered; yield, 9.6 g. (82%), M.P. 158-161 C.

(c) 6 methanesulfonylamido-9-rnethyl-l,2,3,4-tetrahydro-9H-pyrido[3,4b]indol-1-one.The product of (b) preceding, 3.8 g. (0.0175 mole), is dissolved in 35 ml. of pyridine and treated in dropwise fashion with 2.1 g. (0.0175 mole) of methanesulfonyl chloride. The mixture is stirred for 4 hrs. at room temperature and then warmed for 10 min. at 60-70 C. The product is recovered by pouring the mixture into 500 ml. of ice water and filtering. It is a light purple-colored solid which is dissolved in dilute aqueous sodium hydroxide solution, filtered, and acidified with dilute hydrochloric acid. The precipitate is collected and Washed with water; yield, 4.0 g. (79%), M.P. 265-268 C. (dec.), as obtained and after recrystallization from acetic acid-water.

Analysis.--Calcd. for C H N O S: C, 53.23; H, 5.15; N, 14.33; S, 10.93. Found: C, 53.47; H, 5.32; N, 14.19; S, 11.00.

((1) Hydrolysis-The product of (c) preceding, 2.9 g. (0.01 mole), is refluxed overnight with a solution of 10 g. of potassium hydroxide in 40 ml. of water and 60 ml. of ethanol. The mixture is then cooled, filtered, and diluted to 300 ml. of water. The filtrate is acidified with concentrated hydrochloric acid, the 3-(2-aminoethyl)-5-methanesulfonamido-1-methylindole-2-carboxylic acid hydrochloride, which precipitates, is collected on a filter, washed with hydrochloric acid, and dried; yield, 3.1 g. (89%), M.P. 253-255 C. (dec.). This material is recrystallized from methanol-isopropyl ether, M.P. 243.5 C. (dec.) :3.

Analysis.Calcd. for C H N O S: C, 44.89; H, 5.21; N, 12.0; S, 9.22. Found: C, 45.03; H, 5.38; N, 11.96; S, 9.34.

EXAMPLE 77 3-(2-aminoethyl)-5-(N-methylmethanesulfonamido) indole-2-carboxylic acid (a) 6-(N-methylmethanesulfonamido) 1,2,3,4-tetrahydro 9H pyrido[3,4b]indol-l-one.6 methanesulfonamido 1,2,3,4 tetrahydro-9H-pyridol[3,4b]indol-1-one, 8.4 g. (0.03 mole, Example 75 (d)) is dissolved in 200 ml. of ethanol containing 0.031 mole of sodium hydroxide. A solution of 4.0 ml. of methyl iodide in 25 ml. of ethanol is then carefully added thereto. The mixture is stirred at room temperature for 20 hrs., filtered, the filter cake Washed with ethanol, and dried; yield, 7.4 g., M.P. 265- 273 C. This material is triturated with a small volume of aqueous 2 N sodium hydroxide, filtered, and dried; weight, 3.2 g., M.P. 217220 C. Approximately 3.7 g. of unreacted starting material is recovered by acidification of the sodium hydroxide filtrate. The product is recrystallized from acetonitrile to provide the purified material, M.P. 226.5-228 C.

Analysis.-Calcd. for C H N O S: C, 53.23; H, 5.15; SN, 14.33; S, 10.93. Found: C, 53,49; H, 5.38; N, 14.55;

(b) Hydrolysis.-Tl1e product of (a) preceding is hydrolyzed with alcoholic potassium hydroxide as described 3,472,870 15 16 in Example 75 (e) to provide the desired product in the wherein the group fashion described there.

EXAMPLES 78-83 The following R -sulfonyl halides are substituted for methanesulfonyl chloride in the procedure of Example 5 s located 1n the r 7-P0S1tl0HS 0f the lhdOle 75(d). The resulting product is then hydrolyzed according rlng and to procedure 75 (e) to give various 3-(2-aminoethyl)-5- Alk is an alkylene group of 2 to 6 carbon atoms with R -sulfonamidoindole-2-carboxylic acids. Table V cona least two carbon atoms separating the ring and tains a listing of various sulfonyl halides that may be 10 the nitrogen a employed, and identifies the product resulting from this R is hydrogen, benzyl, or lower alkyl having up to procedure. 4 carbon atoms,

TAB LE V.3-(2-AMINOETHYL)-5-R -S ULFONAMID OIND OLE- Z-CARB OXYLIC ACID S R -Substituent Sulfonyl halide of Product Example N o:

78 Vinylsulfonyl chloride CH =CH- 79. Prop-2-enylsulfonyl chloride CHZZCHCHP 80 Styrylsulfonyl chloride CtH CH=OH 83 Benzylsulfonyl chloride C5H5CHz- The compounds of Formula I are amphoteric sub- R is hydrogen, carboxyl, or lower alkyl having up to stances, forming salts with both acids and bases. These 4 carbon atoms,

salts are also considered part of the present invention and R is hydrogen, benzyl, lower alkyl, or lower alkenyl it is intended to include not only the pharmaceutically having up to 4 carbon atoms,

acceptable salts which have the physiological uses re- R is selected from the g p consisting of hydrogen, ferred to above, but also other salts, since they have utility alkyl, alkenyl, alkynyl, cycloalkyl and phenylalkyl, as intermediates in preparation of pharmaceutically preeach containing up to 12 carbon atoms,

ferred forms of the present products, including the free R is alkyl or alkenyl, each having up to 10 carbon base. For example, acid addition salts with optically atoms, and

active acids such as D-camphorsulfonic acid, L- or R is hydrogen or lower alkyl having up to 4 carbon D-tartaric acid are useful for resolution of enantiomort and (b) the pharmaceutically acceptable phic pairs of the present compounds and are considered acid addition and metal Salts of part of this invention. 2. The compound of claim 1 in which Alk is ethylene,

Examples of pharmaceutically acceptable acid addition R4 nd R are hydrogen atoms, and R is the salts include the hydrochloride, hydrobromide, acetate, methyl group. propionate, phosphate, nitrate, succinate, gluconate, mu- 3-(Z-amiHOethYI)-4-methflneslllfonamidonindolecate, sulfate, methanesulfonatc, ethanesulfonate, p-tolu- 3-( y n n enesulfonate etc. salts. Pharmaceutically acceptable metal 5. 3-(2-aminoethyl)-6-methanesulfonamidoindole.

salts include the sodium, potassium, lithium, magnesium, 6. The compound of claim 1 wherein Alk is propylcalcium, barium, zinc, and aluminum salts. The sulfoaniene, R R R R and R are hydrogen, and R is lide free bases of Formula I are also pharmaceutically methyl.

acceptable forms. 7. 3- (Z-aminopropyl)-5-methanesulfonamidoindole.

The present salts may be prepared in conventional fash- 8. The compound of claim 1 wherein R R R and ion by treatment of one of the present compounds with an R are hydrogen, R is methyl, R is phenethyl, and Alk acid or base. For the preparation of salts with monobasic is propylene.

acids and monoacidic bases, use of equimolar quantities 9. S-methanesulfonamido 3 [2 (phenethylamino)- of the two reactants is convenient. In the formation of propyl]indole.

salts of polyacidic bases and polybasic acids, it is con- References Cited venient to reduce the molecular proportion of the acid or UNITED STATES PATENTS base so that but one chemical equivalent thereof 1s employmi 0 3,205,236 9/1965 Alla1s et a1. 260326.15

What is claimed is: 1. A compound of the group (a) having the formula ALEX MAZEL Pnmary Exammer J. A. NARCAVAGE, Assistant Examiner R 5 & A1kN\ U.S. Cl. X.R.

UNITED S"A ES PATENT OFFIQE CERTIFICATE OF CORRECTION :ent No. 3, l 72,870 Dated October 1, 1969 Jent0r(s) AUBREY A. IARSEN and WILLIAM A. GOULD (deceased) BARBARA E. GOULD widow 8: legal rep. of the-estate of WM. A. GOUI It is certified that error appears in the above-identified patent :1 that said Letters Patent are hereby corrected as shown below:

,1. 2, line 2-9, "Genealized" should be Generalized line +8, after "COR" insert a comma ale. 2 bottom 1' page, REDUCTIVE ALKYLATION "R should a R ""o 15. 3 bottom of page, REDUCEIVE ALKYLATION, "CH CHNHR 'should be ca sium 1. 5, line 37, "Example" should be Examples 1. 7, Table II, Example 13, "0-chlorobenzenesulfonyl" should be o-chlorobenzenesulfonyl 1. 8, line 33, "hydroyzed" should be hydrolyzed :1. 10, line 8, nad" should be and line 75 Example n, should be 91. 11 Example 53, "cotane" should be octane 01. 13, line 23, "hydrozone" should be hydrazone ol. 1%, line 19, "methanesulfonylamido" should be 5-- methanesulfonamido line 72, "53, 49" should be 01. 15, Table V, Example 82, "enysulfonyl" should be enylsulfonyl Continued J GM. 15, 11:1: 65 (claim 1), 1n the tornu1a "R SO N" should be 001. 16, 1m 15 (china 3), "nethanuulfomnidonindole" should km nethnnoaultonnmidoindole SIGNED AND SEALED MAY 2 6 1970 M Attest:

Edward M.Fletche1',1r WIMIAII 2. 50mm, J1

Attestine Officnr 810her of Patent.

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U.S. Classification548/504, 546/86, 546/112, 546/201, 548/505, 546/278.1, 548/507, 546/146, 548/492, 546/148, 546/277.4, 544/143, 548/494, 548/493, 546/126, 544/373, 548/509
International ClassificationC07D209/10, C07D209/12, C07D209/18, C07D209/16
Cooperative ClassificationC07D209/12, C07D209/10, C07D209/16, C07D209/18
European ClassificationC07D209/12, C07D209/16, C07D209/10, C07D209/18