United States Patent [19J
`Zinnes et al.
`
`[54] BIS(2·[(DISUBSTITUTED
`AMINO)METHYL]·lH·INDOLE)
`COMPOUNDS
`
`[75]
`
`Inventors: Harold Zinnes, Rockaway; Neil A.
`Lindo, New Providence, both ofN.J.
`
`[73] Assignee: Warner-Lambert, Morris Plains, N.J.
`
`[21] Appl. No.: 861,762
`
`[22] Filed:
`
`Dec. 19, 1977
`
`Int. a.2 ................... A61K 31/495; C07D 403/14
`[51]
`[52] U.S. a ................................. 424/250; 260/325 R;
`544/373;424/274
`[58] Field of Search ..................... 260/268 BC, 325 R;
`544/373; 424/250, 274
`
`[11]
`
`[45]
`
`4,132,792
`Jan.2, 1979
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`3,471,499 10/1969 Archibald et al ............. 260/268 BC
`Primary Examiner-Paul M. Coughlan, Jr.
`Attorney, Agent, or Firm-Stephen Raines; David B.
`Ehrlinger; Frank S. Chow
`[57]
`ABSTRACT
`com(cid:173)
`Bis(2·[( disubstitutedamino )methyl]-lH-indole)
`pounds wherein said 2-[(disubstitutedamino)methyl](cid:173)
`lH-indol-3-ylmethylene moieties are linked together
`through a piperazine or l,3-dihydro-2H-indol-2-one
`fragment and acid addition salts thereof which are use(cid:173)
`ful pharmacological agents, especially antifungals, are
`disclosed. The compounds can be produced by reacting
`a piperazine or l,3-dihydro-2H-indole-2-one compound
`with the appropriate quaternary salt of 2-alkyl-1,2,3,4-
`tetrahydropyrrolo-[3,4-b ]indole.
`
`7 Claims, No Drawings
`
`Argentum EX1030
`
`Page 1
`
`

`

`1
`
`4,132,792
`
`2
`
`BIS(2·[(DISUBSTITUTEDAMINO)METHYL]·1H·
`INDOLE) COMPOUNDS
`
`SUMMARY AND DETAILED DESCRIPTION
`
`The present invention relates to new bis-indoles.
`More particularly, the invention relates to new bis(cid:173)
`indole compounds of the formula
`
`I \
`HN
`NH
`5 ~ R
`wherein RI, R2, R3 and R4 are as previously defined in
`formula I, and X is lower alkylsulfonate, bromine, chlo-
`lO rine or iodine, preferably iodine. Molar ratios of reac(cid:173)
`tants are not critical since the bis, indole product appears
`to be favored. This reaction may be carried out in a
`polar solvent such as an alcohol, water or mixtures
`15 thereof at temperatures of from about so· c. to the
`reflux temperature of the solvent for periods of from
`fifteen minutes up to eight hours. The reaction is
`preferably conducted in water at reflux for a period of
`about two hours. The addition of an acid, such as
`and acid addition salts thereof, and to a method for
`production of the foregoing compounds, where R 1 and 20 hydrochloric acid converts the above formed free base
`to its acid addition salt.
`R 2 are lower alkyl groups, R 3 is hydrogen, a lower alkyl
`group, halogen or a lower alkoxy group and A is a
`Also in accordance with the invention, the foregoing
`molecular fragment of the formula
`compounds of formula I whereiin A is
`
`I \ pert
`
`-N N- or
`
`R4
`
`R
`
`I
`
`N ~O
`I
`H
`
`R4
`
`30
`
`I
`H
`
`0
`
`25 O:t
`'-ti
`The term "lower alkyl" is intended to mean an alkyl D:C
`
`where R4 is hydrogen or lower alkyl. The preferred
`compounds are those wherein R 1 is methyl, R 2 is methyl
`or butyl and R3 and R4 are hydrogen.
`
`35
`
`can be prepared by reacting a compound of the formula
`
`n
`
`~,,,..R 1
`xe
`'R2
`
`R3
`
`N
`I
`8
`
`group of from one to six carbon atoms, such as methyl,
`ethyl, butyl, and isopentyl and the term "lower alkoxy"
`is intended to mean lower alkyl-0-. The term "acid
`addition salt" is intended to mean a salt such as the 40
`hydrochloride, sulfate, acetate, benzoate, citrate, hy-
`drobromide, nitrate, etc. preferably the pharmaceuti-
`cally acceptable salts such as the hydrochloride, sulfate,
`citrate, etc.
`The term "halogen" is intended to mean chlorine,
`fluorine, iodine or bromine.
`In accordance with the invention, the foregoing com(cid:173)
`pounds of formula I wherein A is
`
`/
`
`45 co
`
`with a compound of the formula
`
`R4
`
`~
`0
`
`I
`H
`
`I \
`-N N-
`~ R
`
`can be prepared by reacting a compound of the formula
`
`II
`
`with a compound of the formula
`
`50
`
`in the form of its anion wherein R 1, R2, R3and R4are as
`previously defined in formula I and X is lower alkylsul(cid:173)
`fate, bromine, chlorine or iodine, preferably iodine. The
`anion is formed initially by using a strong base such as
`55 sodium hydride. Molar ratios of reactants are not criti(cid:173)
`cal since the bis indole product appears to be favored.
`This reaction may be carried out in an inert polar sol(cid:173)
`vent such as dimethylformamide, dimethylacetamide or
`mixtures thereof at temperatures of from about so· c. to
`60 about lS0° C. for periods of from fifteen minutes up to
`eight hours. The reaction is preferably conducted in
`dimethylformamide on a steam bath for a period of
`about one hour. The addition of an acid, such as hydro-
`65 chloric acid converts the above formed free base to its
`acid addition salt.
`Compounds of the formula H are prepared by react(cid:173)
`ing a compound of the formula
`
`Page 2
`
`

`

`3
`
`with a compound of the formula
`
`R1X
`
`4,132,792
`
`5
`
`III
`
`IV
`
`4
`EXAMPLE3
`Bis[2-[(n-butylmethylamino )methyl]-1H-indol-3-yl(cid:173)
`methyl]- l,3-dibydro-2H-indol-2-one
`Oxindole, 5.32 g., in dimethylformamide is added to a
`dimethylformamide slurry of fifty percent sodium hy(cid:173)
`dride, 1.92 g., at 10° C. A solution of 2-n-butyl-l,2,3,4-
`tetrahydropyrrolo[3,4-b]indole methiodide in dimethyl-
`10 formamide, 50 ml. is then added, and the resulting mix(cid:173)
`ture heated one hour on a steam bath. After stirring at
`room temperature for sixteen hours, the product is
`poured into ice water. The precipitate, 18.4 g., is col-
`lected, as a slightly wet material containing some min(cid:173)
`eral oil. Two recrystallizations from acetonitrile re(cid:173)
`turned 6.5 g. of pure product, m.p. 127° -9°.
`
`wherein Rl, R2 and R3 are as previously def1Ded. The
`reaction is conducted in a polar solvent. When employ(cid:173)
`ing an alkyl iodide, a rapid reaction takes place at room is
`temperature in an acetone solvent; however, using alkyl
`chlorides and bromides usually requires higher reaction
`temperatures utilizing pressure vessels and reaction
`times of up to twenty-four hours.
`Compounds of the formula III are prepared by reduc- 20
`ing a compound of the formula
`
`R3~NR2
`~!'.'~
`
`I
`H
`
`11
`O
`
`v
`
`25
`
`30
`
`according to procedures reported in the Journal of
`Organic Chemistry 25(1960) 1133 which is incorporated
`by reference.
`The compounds of the invention are new chemical
`compounds of value as antifungal agents. More specifi- 35
`cally, the compounds are active against Candida albi(cid:173)
`cans and Trichophyton mentagrophytes. Activity is
`determined utilizing standard tube dilution tests in the
`absence of serum.
`The invention is further illustrated by the following
`examples.
`
`40
`
`EXAMPLE4
`Bis[2-[(n-dimethylamino )methyl]-1H-indol-3-ylme(cid:173)
`thyl]- l,3-dihydro-2H-indol-2-one
`The above named compound is obtained by utilizing
`the procedure of Example 3 after substituting in the
`place of 2-n-butyl-l,2,3,4-tetrahydropyrrolo[3,4-b]in(cid:173)
`dole methiodide, the following compound 2-methyl(cid:173)
`l,2,3,4-tetrahydropyrrolo[3,4-b ]-indole methiodide.
`The hydrochloride salt of the above named com(cid:173)
`pound is obtained by dissolving said compound in iso(cid:173)
`propanol and adding to it an ether solution of hydrogen
`chloride.
`
`Starting Materials
`a. 2-methyl-l,2,3,4-tetrahydropyrrolo[3,4-b ]indole
`methiodide
`Methyl iodide, 37 ml., is added in a single portion to
`a warm, vigorously stirred solution of2-methyl-l,2,3,4-
`tetrahydropyrrolo[3,4-b]indole, 51.6 g., in dry acetone,
`700 ml. A heavy crystalline precipitate of the title com(cid:173)
`pound starts to separate almost immediately, and after
`fifteen minutes of stirring is collected and washed
`thoroughly with additional acetone, giving 80-85 g.
`The product is essentially pure, and can be used
`directly.
`
`EXAMPLE 1
`b. 2-methyl-l,2,3,4-tetrahydropyrrolo[3,4-b ]indole
`3,3' -(l,4-piperazinediyldimethylene)-bis[2-[( dime(cid:173)
`2-Methyl-l,4-dihydropyrrolo[3,4-b ]indol-3(2H)-one,
`thylamino )methyl)]-lH-indole]
`1. 7 g., and LiA114, 2.3 g., are heated in refluxing diox(cid:173)
`2-Methyl-l,2,3,4-tetrahydropyrrolo[3,4-b]indole me-
`ane, 300 ml., for five hours. The mixture is cooled and
`carefully hydrolyzed with excess water. Solids are ftl(cid:173)
`thiodide, 9.42 g., ~d piper~ine, 7.8 g., are refluxed in
`water, 700 ml. Sobds appear ID one-half hour. After one so tered away and washed with dioxane, after which the
`and one-half hours the the mixture is filtered to give 4.9
`filtrate is concentrated to dryness giving 1.4 g. of a
`g. of a white solid, m.p. about 202° C. with decomposi-
`crude. brown product, m.p. 110° -120° C. Since . the
`crude product is sensitive to air oxidation (darkens rap-
`tion. The filtrate is refluxed an additional hour, giving
`another 1.5 g. of product. Recrystallization from a me-
`idly on standing), it is not further purified before methi-
`thanol-methylene chloride mixture gives a near-quan- ss odide preparation.
`1 [3 4-b]" d I 3(2H)
`titative recovery of product, m.p. 202° with decomposi-
`th 1 1 4-dih d
`2
`ID 0 -
`Y ropyrro 0
`tion (darkening at 175°). An analytical specimen was
`c. -me Y - '
`-one
`•
`obtained by recrystallization from tetrahydrofuran,
`l-Methyl-4-carbomethoxy-2,3-dioxopyrrolidine, 8.5
`m.p. 209• -211 • with decomposition.
`g., is heated on the steam bath for about 45 minutes to one
`60 hour in 150 ml. of a twenty percent aqueous hydrochlo-
`ric acid solution. The resulting solution is cooled to
`room temperature and filtered. Sodium acetate is next
`added to neutralize the mixture to a pH of 4 to 5. Water
`is added as necessary to keep most of the solids in solu(cid:173)
`tion. Phenylhydrazine, 5.9 g., is then washed into the
`solution with a little methanol. A solid material precipi-
`tates immediately and is collected and washed with
`water. This crude phenylhydrazone is taken up in 100
`ml. warm acetic acid and treated with 30 ml. concen-
`
`4S
`
`EXAMPLE2
`3,3' -(1,4-piperazinediyldimethylene )-bis[2-[(n-butylme(cid:173)
`thylamino )-methyl]-lH-indole
`The above named compound is obtained by utilizing 6S
`the procedure of Example I after substituting in the
`place of 2-methyl-l,2,3,4-tetrahydropyrrolo[3,4-b]in(cid:173)
`dole methiodide, the following compound; 2-n-butyl(cid:173)
`l,2,3,4-tetrahydropyrrolo[3,4-b ]indole methiodide.
`
`Page 3
`
`

`

`5
`trate hydrochloric acid. A vigorous reaction ensued
`after which the mixture is refluxed for ten minutes. Cool(cid:173)
`ing precipitates crude title compound, 16.7 g., m.p.
`about 300° (dee.). Recrystallization from a large volume
`of methanol raised the m.p. to 303°-6° (dee.).
`
`s
`
`4,132,792
`
`6
`with water gives additional product, 7 g., m.p. after
`recrystallization from methanol: 216°-218°.
`We claim:
`1. A compound of the formula
`
`d. 2-n-butyl-1,2,3,4-tetrahydropyrrolo[3,4-b ]indole
`methiodide
`A slurry of 4.3 g. of 2-n-butyl-1,2,3,4-tetrahydropyr(cid:173)
`rolo[3,4-b]indole in dimethylformamide, 30 ml., is 10
`treated with methyl iodide, 4.3 g. After thirty minutes
`excess methyl iodide is removed using reduced pres-
`sure.
`
`and pharmaceutically acceptable acid addition salts
`thereof wherein R 1 and R 2 are lower alkyl, R3 is hydro(cid:173)
`lS gen, lower alkyl, halogen or lower alkoxy and A is a
`molecular fragment of the formulae
`
`e. 2-n-butyl-l,2,3,4-tetrahydropyrrolo[3,4-b ]indole
`2-n-Butyl-1,4-dihydropyrrolo[3,4-b ]indole-
`3(2H)-one, 20 g., in dry tetrahydrofuran, 400 ml., is
`added slowly to a slurry ofLiAIH.i, 14 g., in tetrahydro-
`furan, 250 ml. After refluxing twenty hours, the reaction
`mixture is hydrolyzed with 30 ml. of water, and filtered. 20
`After the solvent is removed, one obtains 20.1 g. of a
`reddish-brown solid. Recrystallization from methanol,
`200 ml., gives 11 g. of the title compound, m.p. 151°-2°.
`f. 2-n-butyl-1,4-dihydropyrrolo[3,4-b]indol-3(2H)-one. 2s wherein R4 is hydrogen or .lower ~yl.
`,
`2. The compound of claun 1 havmg the name 3,3 -
`.
`. .
`(1,4-piperazinediyldimethylene)~bis[2-[(dime-
`1-n-Butyl-4:carbomethoxy-2,3-dioxopyrrolidme, 107
`J. Org. Chem.
`g.,
`[Southwick and Owellen,
`thylamino)methyl)]-IH-indole], and acid addition salts
`25(1960)1133] is heated to boiling in a mixture of600 ml.
`thereof.
`3. The compound of claim 1 having the name 3,3'-
`of a twenty percent aq~eous hydrochloric acid soluti~n 30
`and about 100 ml. of nme~y-five per~nt ethanol. Sohds
`(l,4-piperazinediylmethylene)-bi:s[2-[(n-butylme-
`dissolved in about ten mmu~es to give a ~ellow solu-
`thylamino)methyl]-lH-indole], and acid addition salts
`tion. After one hour of heating, the flask 1s cooled to
`thereof.
`4. The compound of claim 1 having the name bis[2-
`about room temperature. Sodium acetate is then added
`to neutralize the reaction mixture. to a pH of ~5. In 3s [(n-butylmethylamino)methyl]-lH-indol-3-yl-methyl]-
`addition about 500 ml. of water is ad~ed d~g ~e
`1,3-dihydro-2H-indol-2-one, and acid addition salts
`neutralization to insure that most materials will remam
`thereof.
`5. The compound of claim 1 having the name bis[2-
`in solution. Phenylhydrazine, S4 g., is then washed into
`the stirred mixture with methanol, 2.0 ml. The ~henyl
`[(dimethylamino)methyl]-lH-indol-3-ylmethyl]-1,3-
`hydrazone starts to separate immediately, and is col- 40 dihydro-2H-indol-2-one, and acid addition salts thereof.
`6. An antifungal pharmaceutical composition com-
`lected after ten minutes of cooling and stirring. The
`material is dissolved in 200 ml. of acetic acid at ~5° ~d prising an antifugal effective amount of a compound of
`claim 1 and a pharmaceutical carrier.
`treated with 100 ml. of concentrated hydrochlonc acid.
`7. A method for treating a fungal infection which
`A strong exotherm takes the temperature up to about
`110° which causes vigorous refluxing. Filtration of 4s comprises administering a pharmaceutical composition
`of claim 6.
`the cooled slurry yields 78 g. of the title compound,
`• • • • •
`m.p. 215"-218° sinters at 210°. Dilution of the filtrate
`
`I \ Pr±
`
`-N N- or
`
`'-+!
`
`R4
`
`R
`
`I
`N ~O
`I
`H
`
`so
`
`SS
`
`60
`
`6S
`
`Page 4
`
`