GB2087884A - Benzopyrrole derivatives and precursors thereof - Google Patents

Abstract

Compounds of the formula <IMAGE> wherein R<1>, R<2> and R<3> are independently selected from hydrogen, C1-5 alkyl and Ph; and R<4> is HSO2, (C1-5 alkyl)sulfonyl, PhSO2, PhCOCH2SO2 or ZCH2COO in which Z is CH2I, CCl3, HSO2CH2, (C1-5 alkyl)sulfonylmethyl, PhSO2CH2, Ph or fluorenylmethyl. The compounds illustrated can be prepared by an 11-step process, starting from 4-chloro-3-nitrophenol and ether derivatives thereof. Many of the intermediates in this process are novel and have, as do the illustrated compounds, antibacterial activity. Novel intermediates have the formulae (I), (II), (III) or (IV> <IMAGE> wherein R<5> is H, CH3, benzyl, allyl, CH3SCH2, CH3OCH2, CH3O- CH2CH2OCH2, CCl3CH2, (C1-5 alkyl)3 SiCH2CH2 or Ph3SiCH2CH2; R<7> is CH3O, C2H5O, C1-5 alkyl or Ph; X is HSO3, (C1-5 alkyl) SO3, PhSO3, Cl, Br, I or OH; X' is as X (except OH, or CH3COO; X'' is as X, or CH3COO; and Y is H, NO2 or NH2.

Description

SPECIFICATION Benzopyrrole derivatives and precursors thereof This invention relates to novel compounds, some of which have antibiotic activity. The active novel compounds bear a partial structural relationship to antibiotic CC-1065 which is disclosed by its chemical and physical parameters in US Patent Specification No. 4,169,888. The structure of antibiotic CC-1065 has been elucidated, as reported by Martin et al, J.Antibiotics, 33(1980)902, and is

A first group of novel compounds of the present invention has the formula

wherein R', R2 and R3 are independently selected from hydrogen, C15 alkyl and phenyl; and R4 is (cm 5 alkyl)sulfonyl, PhSO2, PhCOCH2SO2 or ZCH2COO in which Z is CH2 I, CCl3, (C 5 alkyl)sulfonylmethyl, PhSO2CH2; phenyl or fluorenylmethyl. An example of this group of novel compounds is 1,2,8, 8a-cyclopropaCc]benzo[ 1 ,2-b:4, 3-b']-dipyrrol-4(5 H)-one; this compound is denoted herein as compound (12). Attempts to obtain this compound by degradation of antibiotic CC-1065 have failed.

Compounds of the formula given above, including compound (12), can be prepared by an 1 1step process which is illustrated in the following Chart (wherein R, is H, CH3, PhCH2, CH2 = CHCH2, CH3SCH2, CH3OCH2, CH3OCH2CH2OCH2, Cl3CCH2; R2 is as defined above for R2; R3 is CH30 or C2H50 in compound (2) or CH30, C2H50, C, 5 alkyl or phenyl elsewhere; R4 is HIS02, (Ca s alkyl)sulfonyl, PhSO2, PhCOCH2SO2 or ZCH2COO in which Z is CH2l, CCI3, HS02CH2, (C, 5 alkyl)sulfonylmethyl, PhSO2CH2, phenyl or fluorenylmethyl; X is SO2R2, Cl, Br or I; Y is Li, Na, K or MgX; and Z is CH2l, CCI3, CH2SO2R2, Ph (i.e. phenyl) or fluoroenylmethyl; the P2,s may be the same or different.The Steps in the chart are described subsequently.

Step 1 -The first step (aromatic nucleophilic substitution) in the synthetic approach is described by J. Bourdais and C. Mahieu, Compt. Redux [C], 263, 84 (1966). Also see J. Bourdais and C. Germain, Tet. Letters, 1 95 (1970). The various R, groups can be introduced on the phenol precursor of (1) by procedures described in the literature (appropriate references detailed under step 8). The various malonates, ss- keto esters, and fi-diketones employed are all known compounds.

Step 2 -Reduction: When R2 = alkoxy, diisobutylaluminium hydride is the reagent of choice.

Reaction conditions are quite specific (see Example 1) for optimum yields. When R2 = alkyl or phenyl, standard reduction procedures employing sodium borohydride can be employed.

Step 3 -Functional group interchange: The chemistry described specifically herein is in the case of X = SO2CH3. The mesylate or tosylate (for example) can be prepared under standard conditions known in the art employing pyridine (with or without solvent, such as methylene chloride) or other acid acceptors such as trialkylamines (with solvent) and the corresponding sulfonyl chloride. The halogen analogs of 4 can be prepared under standard procedures known in the art such as Ph3P/CCI4 (CBr4) and N-iodosuccinimide/triphenylphosphine.

Step 4 -Reduction-cyclization: This step is a novel preparation of indolines (dihydroindoles).

This involves the reduction of the nitro to the amino group with concomitant intramolecular cyclization to give (5). The reduction step described in detail herein utilizes H2, PtO2 in alcohol in the presence of a tertiary amine. These are standard hydrogenation conditions in the art. Palladium or nickel catalysts can also be employed and bases other than a tertiary amine, such as pyridine, can be utilized.

Alternative reducing conditions can employ Fe or TiCI3 in acid or SnCl2. This may then require a separate step involving treatment with base to induce the cyclization to (5). An example of a reduction with iron is the use of Fe/CH3CO2H/CH3CH2OH (G. S. Ponticello and J. J. Baldwin, J. Org. Chem., 44, 4003 (1979). These conditions would be required if R, = CH2Ph or -CH2CH = CH2.

The concept of nitro reduction followed by in situ cyclization to indoles is advanced by A. D. Batcho and W. Leimgruber, German Offen. 2057840 (1971), which is a significant improvement over the older Reisset procedure of reductive cyclization to indoles. (See. R. J. Sundberg, The Chemistry of Indoles, pp. 176-183, Academic Press, N.Y. 1970).

Step 5 -Substitution of labile group: This step is required due to the incompatibility of X with the chemistry of step 8. It involves the replacement of X with an acetate or the conjungate base of a C,-C5 alkyl carboxylic acid under standard conditions (alkali carboxylate in acetone, DMF, or alcohol). Since some hydrolysis can occur when X = SO2CH3, the reaction mixture is treated with acetic anhydride prior to isolation of (6).

Step 6 -Nitration can be performed under a variety of conditions described in the literature including nitric acid in acetic acid, acetic anhydride, sulfuric acid, acetic acid/H20, alcohol, and nitroalkanes. The regioselectivity of this reaction is supported by the spectroscopic data obtained.

Step 7 reduction of the nitro to the amino group follows the same chemical description given in step 4 with the omission of base.

Step 8 -Indole synthesis: This procedure is based generally on the indole chemistry of Gassman [P. G. Gassman, etal., J. Am. Chem. Soc., 96, 5494, 5508, 5512 (1 974)]. Several modifications are required which are not disclosed or suggested in Gassman's work. The sequence of the chemical events, and some of the intermedi ates, are shown in the following Chart (the a-thiomethyl esters are known):

This process deviates from the published Gassman route by employing the chlorosul fonium complex, A, and reacting it with the aniline, (6); Gassman prepares the chloroamine of an aniline and reacts it with the thioether in making oxindoles.

Secondly, two different bases are employed in the process, whereas Gassman uses two equivalents of the ailine followed by a base2, Although triethylamine, diisopropy lethylamine, bis(1 8-dimethyl amino)naphthalene, and the like both work for base1 and base2, the preferred for base1 is bis(1 8-dimethylamine)naphthalene, and triethy lamine for base2. Different solvents such as chloroform, acetonitrile, tetrahydrofuran (THF), and methylene chloride can be used, the latter is preferred. The temperature range is from - 50 to - 80' and the reaction is run under an inert atmosphere. The cyclization to the o)tindole B is best promoted by acid catalysis as described by Gassman (2N HCi, ether end/or ethyl acetate,'.

The final reduction to (9), (reductive elimination) can be accomplished with lithium aluminium hydride (as described by Gassman) or diborane type reagents, the latter being far superior. The preferred reagent is (CH3)2S.BH3 in THF at room temperature for 24 hours.

Step 9 -This deprotection step (removal of R) is described in detail for R1 = CHr in Example 8. Although there are a number of procedures described in the art involving methyl ether cleavage, only alkyl mercaptide in hexamethylphosphorictriamide (HMPA) under an inert atmosphere (9 5-1 1 0') have bgeen found to be effective [S. C. Welch and A. S. C. P. Rao, Tet. Letters, 505 (1977) and T. R. Kelly, H. M. Dali, and W-G.

Tsang, Tet. Letters, 3859 (1977), or Me2S.BBr3 in dichloroethane (P. G. Willard and C. B. Fryhle, Tet. Letters, 3731(1980)].

When R, = CH2Ph, standard hydrogenolysis conditions suffice to deprotect (H2, Pd/C) [Org. Reactions, 7,263 (1953)]. When P1 =CH2SCH3, mercuric chloride in acetonitrile/H20 removes the ether (R. A. Holton and R. G. Davis, Tet. Letters, 533 (1977). When R, =CH2OCH3, moderate acid will generate the phenol0, such as acetic acid [J. Med. Chem., 9, 1 (1966) or Synthesis, 244(1976)]. In fact, this protecting group may be lost in step 6, however, it can be reintroduced prior to step 7 under standard conditions. When R, = -CH2OCH2CH2OCH3, the phenol can be generated by ZnBr2 or TiCI4 in CH2CI2 [Tet.Letters, 809 (1 976)]. When R, = -CH2CH = CH2, several two-step procedures will deprotect the ether (Pd/C in alcohol/Ang. Chem. Int. Ed., 15, 558 (1976); SeO2, CH3CO2H in dioxane/Tet.

Letters, 2885 (1970); t-BuOK, DMSO followed by H2SOg in acetone/J. Chem. Soc., 1903 (1965); RhCl(PPh3)3, DABCO (registered Trade Mark) in alcohol followed by PH2 [J. Org. Chem., 38, 3224 (1973)]. When R, = -CH2CH2Si(R2)3 deprotection is effected by Bu4NF [H. Gerlach, et. al., Helv. Chim. Acta, 60, 3039 (1977)].

Step 10-See step 3.

Step ? this step (when X = Br) is promoted by contact with silica gel as well as occurs on standing in protic solvents. This reaction will also proceed in the presence of such bases as tertiary amines, pyridine, t-butoxide, and the like and weak aqueous bases such as bicarbonate and carbonate.

The following examples are illustrative of the products and process of the invention, but are not to be construed as limiting. All percentages are by weight and all solvent mixture proportions are by volume unless otherwise noted.

Example 1 Preparation of the 2-aryl- 1, 3-propandiol (3) from the aryldiethylmalonate (2) To 400 ml of THF under N2 cooled in an ice-water bath is added 100 g of DIBAL (0.70 mole) in 400 ml of toluene. To this stirred solution is added 33.0 9 (0.105 mole) of the arylmalonate (2) in 100 ml of THF. The rate of addition is controlled to keep the reaction temperature below 5 . After the addition is complete the ice bath is removed. The reaction is quenched after 3 hours total reaction time by the portion-wise addition of the solution to cold 3N HCI with stirring (approximately 1.5 1).The mixture is then extracted with 11 of EtOAc followed by 1000 ml CH2Cl2. The combined organic phases are dried over Na2SO4 and concentrated to a red-brown residue (21.2 g). Chromatography of the residue on 500 g silica gel with 60% EtOAc/hexaneo100% EtOAc gradient eluent affords 11.7 g (49% yield) of the diol (3) (U-62,598) as a light red oil (solidifies on standing in the freezer).

NMR (CDCl3): 7.5-7.0 (m, 3H), 3.80 (s, 3H), 4.0-3.3 (m, 7H-includes 2 OH) MS: Calc. for C10H13N05: 227.0794 Found 227.0780 Analysis: Calc: C, 52,86, H, 5.76, N, 6.16 Found: C, 53.40, H, 5.77, N, 5.99 "diisobutyl aluminium hydride Example 2 Preparation of the 2-aryl- 1 ,3-propandiol bismesylate (4) from the 2-aryl- 1,3-propandiol (3) To 4.7 g (0.2 moles) of the diol (3) in 100 ml of dry pyridine under N2 at 0-5" is added with stirring 6.8 g (0.06 mole) of methanesulfonyl chloride.After stirring at 5 for 30 minutes followed by room temperature for 90 minutes, the solution is concentrated in vacuo, then taken up in CH2CL2/1 N HCI. The organic phase is separated, dried over Na2SO4, concentrated to a residue. Trituration with EtOAc affords an off-white solid and the mother liquors can be chromatographed on silica gel (EtOAc eluent) to afford a total yield of 6.65 g (86% yield), m.p.

122-3 (recrystallized from acetone) of compound44), bismesylate (U-62,597).

NMR(Acetd6): 7.7-7.2 (m, 3H), 4.62 (d, 4H, J =J Hz), 4.11 (t, 1H, J =7 Hz), 3.92 (s, 3H), 3.06 (s, 6H).

Analysis: Calc for Cl2H17NOgS2 Calc: C, 37.59, H, 4.47, N, 3.65 Found: C, 37.35, H, 4.44, N, 3.59 This compound was assayed by a standard tube dilution assay against L1210 mouse leukemia cells in culture and gave the following results: ID,,Cug/ml)= 6.0 IDgo(llg/ml) = 1 8 Example 3 Preparation of the 6-methoxyindole bismesylate (5) from the 2-aryl, 1,3-propandiol bismesylate (4) To 1.91 g 9(005 mole) of compound (4) in 30 ml of THF, 20 ml of EtOAc, and 150 ml of absolute ethanol is added 1.5 ml of triethylamine and 400 mg of PtO2. This solution is placed under 7-1 0 psi H2 pressure with shaking for 30 minutes.The reaction solution is then filtrated over 'elite" (registered Trade Mark) and concentrated in vacuo. After several CH2CI2 azeotropes in vacuo, the residue is ultimately taken up in 100 ml of CH2CI2 and cooled under N2 in an ice bath. To the stirred solution is added 1.5 ml of triethylamine followed by the dropwise addition of 900 ILl methane sulfonylchloride. After stirring for 30 minutes, the solution is allowed to come to room temperature for 60 minutes. The solution is then washed with 1N HCI, dried over Na2SO4, and concentrated.The residue is rapidly chromatographed on 150 g silica gel with 500 ml of 60% EtOAc/hexane followed by 1000 ml of 80% elution; recovered 1.3 9 (78% yield) of an off-white solid, m.p. 122-3 (recrystallized from ethanol) of compound (5), the 6-methoxyindoline bismesylate (U-62,596).

NMR (DMF-d7): 7.36 (d, 1 H, J = 8.5 Hz), 7.00 (d, 1 H, J = 2 Hz), 6.69 (dd, 1 H, J = 2, 8.5 Hz), 4.47 (2H, d. J = 6 Hz), 4.3-3.6 (m, 3H), 3.80 (s, 3H), 3.20 (s, 3H), 3.07 (s, 3H).

Analysis: Calc for C12H17NS206 Calc: C, 42.97, H, 5.11, N, 4.18 Found: C, 42.87, H, 5.27, N, 4.29 This compound was assyed by a standard tube dilution assay against L1210 mouse leukemia cells in culture and gave the following results: ID50(yg/ml) = 4.8 ID > O(yg/ml) = 10 Example 4 Preparation of the 6-methoxy indoline acetate (6) from the 6-methoxy indoline bismesylate (5) To 13.0 9 (39 mmol) of the 6-methoxy indoline bismesylate (5) in 30 ml of DMF is added 800 ml of abs. ethanol followed by 32 9 of sodium acetate. This heterogeneous solution is refluxed under N2 for 24 hours, cooled, and concentrated in vacuo. The residue is treated with 100 ml of acetic anhydride for 2 hours (stirring at room temperature), then concentrated in vacuo.The residue is taken up in CH2CI2/H20 and the organic phase is separated, dried over Na2SO4, filtered through charcoal, and concentrated to an oil which solidifies; 11.6 g of compound (6), the 6-methoxy indoline acetate (100%; if necessary, further purification is possible with silica gel chromatography employing 60% EtOAc/hexane eluent).

NMR (CDCl3): 7.17 (d, 1 H, J = 8.5 Hz), 7.02 (d, 1 H, J = 2 Hz), 6.60 (dd, 1 H, J = 2, 8.5 Hz), 4 18 (d, 2H, J = 6 Hz), 4.1-3.4 (m, 3H), 3.78 (s, 3H), 2.91 (s, 3H), 2.05 (s, 3H).

Analysis: Calc for C13H,7NOsS Calc: C, 52.16, H, 5,76, N, 4.68 Found: C, 52.13, H, 5.79, N, 5.27 MS: Calc: 299.0827 Found: 229.0823 Example 5 Preparation of the 5-nitro-6-methoxy indoline acetate (7) from the 6-methoxy indoline acetate (6) To 500 mg (1.67 mmole) of the 6-methoxy indoline acetate (6) in 20 ml of nitromethane is added 90 ILl of 90% HNO2. The cooled reaction solution (0.5 ) is stirred for 30 minutes, then warmed to room temperature for 30 minutes. The solution is diluted with CH2CI2 and aqueous sodium bicarbonate. The organic phase is separated, dried over Na2SO4, and concentrated. The residue is chromatographed on 50 g silica gel (60% EtOAc/hexane eluento100% EtOAc) yield; 440 mg (76% yield) of a yellow solid, m.p. 175-7 (recrystallized from ethanol) of compound (7), the 5-nitro-6-methoxy indoline acetate (U-62,696).

NMR (DMF-d7): 7.91 (s, 1 H), 7.20 (s, 1 H), 4.27 (d, 2H J = 6 Hz), 4.3-3.7 (m, 3H), 3.98 (s, 3H), 3.17 (s, 3H), 2.07 (s, 3H).

Analysis: Calc for C13H1N207S Calc: C, 45.34, H, 4.68, N, 8.14 Found: C, 44.81, H, 4.77, N, 8.16 This compound was assayed by a standard tube dilution assay against L1210 mouse leukemia cells in culture and gave the following results: ID50(yg/ml)= > 50 IDgOtug/ml)= > 50 Example 6 Preparation of the 5-amino-6-methoxy indoline acetate (8) from the 5-nitro-6-methoxy indoline acetate (7) To 4.5 g (13 mmole) of the 5-nitro-6-methoxy indoline acetate (7) in 50 ml of THF and 1 50 ml of absolute ethanol is added 500 mg PtO2 and shaken under 10 psi of H2 until uptake ceases (approximately 60 minutes). Filter and concentrate in vacuo. Upon concentration, 3.0 g of product precipitates out.This is filtered off and the mother liquors rapidly chromatographed on 1009 silica gel with EtOAc eluent to afford an additional 0.6 g. The total yield (3.6 g) is 88%; m.p. 134-5 (from acetone/cyclohexane) of compound (8), the 5-amino-6-methoxy indoline acetate (U-62,697).

NMR(CDCl3): 7.02 (s, 1H), 6.65 (s, 1H), 4.16 (d, 2H, J = 6 Hz), 4.1-3.5 (m, 3H), 3.83 (s, 3H), 3.6 (br. s, 2H), 2.83 (s, 3H).

Analysis: Calc for C,3H,8N205S Calc: C, 49.67, H, 5.77, N, 8.91 Found: C, 49.74, H, 5.72, H, 8.94 This compound was assayed by a standard tube dilution assay against L1210 mouse leukemia cells in culture and gave the following results: lD50(ltg/ml)= > 50 IDgO(Ilg/ml)= > 50 Example 7 Preparation of the 4, 5-pyrrolo-6-methoxy in do line (9) from the 5-amino-6-methoxy in do line acetate (8) To 14 ml of dry CH2CI2 under N2 at - 75" is added 6.0 ml of a Cl2/CH2CI2 solution (20 yl C12/ml CH2CI2).To this stirred solution is added 370 1ll (2.5 mmole) of CH3(CH3S)CHCO2C2H5 (prepared from CH3(Br)CHCO2C2H5 and methyl mercaptide by the procedure of E. H. Wick, T.

Yamanishi, H. C. Wertheimer, Y. E. Hoff, B. F. Proctor, and S. A. Goldblith, J. Agr. Food Chem., 9,289 (1961)). After 5 minutes a solution of 470 mg (2.2 mmole) of 1,8bisdimethylaminonapthalene and 628 mg (2.0 mmole) of the anilinoindoline (8) in 3.0 ml of dry CH2CI2 is added dropwise over 1 5 minutes. The red solution is stirred for 2 hours at - 75", then 350 ,ul of triethylamine in 650 1ll of CH2CI2 is added dropwise over several minutes. The cooling bath is removed. When the reaction solution reaches room temperature it is briefly concentrated in vacuo. To the residue is added 5 ml EtOAc, 25 ml of ether and 6 ml of 2N HCI and stirred vigorously for 2 hours.The organic phase is separated and the aqueous is extracted with 1:1 EtOAc/Et2O. The organics are combined, dried over Na2SO4 and concentrated. At this point the residue is taken up in 10 ml of THF and treated with 3.0 ml of 2M BH3.SMe2 overnight at room temperature under N2. Alternatively the diastereomeric oxindoles (B) derived from the acid treatment can be isolated at this point by silica gel chromatography (50 9; 60% EtOAc/hexane to 90% EtOAc/hexane).

GS-MS: m/e M+ 414(15%), 227 (100%)-2' 1% SE-30 NMR (CDCl2): 8.4 (br. s, 1 H), 7.11 (s, 1 H), 4.5-3.7 (m, 5H), 3.90 (s, 3H), 2.95 (s, 3H), 2.10 (s, 3H), 1.92 (s, 3H), 1.82 (s, 3H+major diasteromer (2.5/1); minor diastere omer shows the following differences-1 .99 (s, 3H), 1.76 (s, 3H) for -SCH3 and -CH3, the NH is is at 7.7 and the CH2 region is 4.3-3.6 ppm.

The aqueous phase from the acid treatment can be neutralized and extracted with CH2CI2. The CH2CI2 solution can be dried, concentrated, and chromatographed on silica gel with 50% acetone/cyclohexane to give 40% recovery of starting material (anilinoindoline) and 20% deacylated starting material.

The boranedimethylsulfide reductive elimination (on B) reaction is worked up by quenching with 1 N HCI until gas evolution ceases and taking up in CH2CI2/H20. The separated organic phase is dried over Na2SO4 and concentrated. The residue is chromatographed on silica gel (50% acetone/cyclohexane) to afford 155 mg of product (9); 25% isolated yield85% based on recovered starting material), m.p. 182-183 (phase change at 160 , recrystallized from chloroform), the 4,5-pyrrolo-6-methoxy indoline (9) (U-62,233).

NMR: (CDCl3): 8.3 (br. s, 1 H), 6.96 (s, 2H), 4.2-3.5 (m, 5H + OH), 3.92 (s, 3H), 2.87 (s, 3H), 2.41 (s, 3H).

Analysis: Calc for C14H18N2O4S Calc: C, 54.17, H, 5.84, N, 9.03 Found: C, 53.49, H, 5.96, N, 9.42 GC-MS: of O-acetate--m/e M+ 352 (13%), 213 (100%)-2'-1% SE-30, temperature 150-260" (10'/minute); single peak This compound was assayed by a standard tube dilution assay against L1210 mouse leukemia cells in culture and gave the following results: ID,,(yg/ml)= > 4 lD90(g/ml) = > 4 Example 8 Preparation of the 4, 5-pyrrolo-6-hydroxy indoline (10) from the 4, 5-pyrrolo-6-methoxy indoline (9) To 10 ml of dry, degassed HMPA (hexamethylphosphorictriamide) under N2 at room temperature is added 350 pl of butyl mercaptan.The solution is cooled in an ice-water bath and 2.0 ml of 1.5M n-BuLi in hexane is added dropwise. After allowing the reaction to come to room temperature 100 mg (0.3 mmole) of the indole (9) is added with stirring. The solution is heated to 100" for 2.5 hours. The reaction is followed by tic (50% acetone/cyclohexane) and when conversion appears approximately 75% complete (by vanillin/phosphoric acid spray), heating is terminated. The cooled solution is poured into 1 N HCI (100 ml) and extracted with 20 ml EtOAc. The separated organic phase is washed with additional 50 ml of water. The aqueous phases are combined and back-extracted with 20 ml of EtOAc. The organic phases are then combined, dried over Na2SO4, concentrated in vacuo, and applied to a 100 g silica gel column and eluted with 50% acetone/cyclohexane.Afforded are 25 mg of starting material and 45 mg of product (10) (44% isolated yield, 69% based on recovered S.M.), the 4,5-pyrrolo-6hydroxy indoline (U-62,370).

NMR (Acet-d6): 7.8 (br. s. 1 H), 7.03 (s, 1 H), 6.83 (s, 1 H), 4.25-3.25 (m, 5H), 2.86 (s, 3H), 2.36 (s, 3H) This product was treated with acetic anhydride (1.0 ml) and 20 mg of NaOAc overnight, then taken up in CH2CI2/H20. The organic phase was separated, dried over Na2SO4, and concentrated.

NMR(CDCl3): 7.8 (br. s, 1 H), 7.16 (s, 1 H), 6.97 (s, 1 H), 4.42, 4.20 (dd, 2H), 4.2-3.7 (m, 3H), 2.86 (s, 3H), 2.40 (s, 3H), 2.35 (s, 3H), 2.06 (s, 3H) GC-MS: m/e M + 380(25%), 199 (100%)-2'-1% SE-30 This compound was assayed by a standard tube dilution assay against L1210 mouse leukemia cells in culture and gave the following results:: [D50(yg/ml)= > 5 IDgo(yg/ml)= > 5 Example 9 Preparation of the 4, 5-pyrrolo-6-hydroxy indoline bromide (I 1) from the 4,5-pyrrolo-6hydroxyindoline alcohol (10) To 25 mg (65 mole) of the substrate alcohol in 1.0 ml of dry acetonitrile under N2 at room temperature is added 33 mg (100,umole) of CBr4 and 26 mg (100,umole} of triphenyl phosphine (Ph2P). After stirring for 30 minutes an additional 11 mg CBr4 and 8 mg of Ph3P are added. The reaction is taken up in CH2CI2/H20 after 60 minutes (total). The organic phase is separated, dried over Na2SO4, and concentrated. The residue is placed on three 20 X 20 cm 250 y silica gel plates and eluded with 50% acetone/cyclohexane. Approximately 8 mg of the higher Rf product (0.64; alcohol Rf = 0.45) is recovered, compound (11), the 4,5-pyrrolo-6hydroxy indoline bromide (U-62,694).

NMR(CDCl3): 8.5 (br. s, 1H), 7.1 (s, 1H), 6.9 (s, 1H), 4.23 (d, 2H, J = 6 Hz), 4.0-3.5 (m, 3H), 2.89 (s, 3H), 2.38 (s, 3H).

Beilstein test: positive MS: Calc. for Ct6H23N20379BrSSi = 430.0382, Found 430.0375 (mono-TMS); m/e M + 430/432 (14%), 271(90%), 147 (100%).

This compound was assayed by a standard tube dilution assay against L1210 mouse leukemia cells in culture and gave the following results: ID50(yg/ml) = 0.12 ID90( g/ml) = 0.37 Example 10 Preparation of the 4,5-pyrrolo-6-hydroxy indoline mesylate (11) from the 4,5-pyrrolo-6hydroxy indoline alcohol (10) To 20 mg (65 pmole) of the alcohol substrate (10) in 1.0 ml pyridine in an ice bath with stirring under N2 is added 8,ul of methanesulfonyl chloride (70 ymole). After 30 minutes an additional 2/11 of CH3SO2CI is added and worked up with 2N HCI/CH2CI2 after 60 minutes total reaction time. The organic phase is separated, dried over Na2SO4, and concentrated.Tlc indicates mostly lower R, product (0.28 in 50% acetone/cyclohexane, alcohol Rf = 0.46) and some higher R, product (0.66). Preparative tic (3-20 x 20 cm 250 silica gel plates) affords 2 mg of higher R, material (NMR indicated only one CH3SO2 group; it is probably the chloride) and 9 mg of the lower R, material, compound (ii) (U-62,695).

NMR(Acet-d6): 8.6 (br. s, 1 H), 6.97 (s, 1 H), 6.74 (s, 1 H), 4.3 (m. 2H), 4.1-3.6 (m, 3H), 2.96 (s, 3H), 2.79 (s, 3H), 2.26 (s, 3H).

This compound was assayed by a standard tube dilution assay against L1210 mouse leukemia cells in culture and gave the following results: ID50(/lg/ml) = 1.0 IDgO(Mg/ml) = 3.3 Example 11 Preparation of 1,2,8,8a-cyclopropa[c]benzo[1,2-b:4,3-B']dipyrol-4(5H)-one (12), N-(methylsulfonyl) In the following the procedure to prepare the 4,5-pyrollo-6-hydroxy indoline bromide (step 10), if the reaction mixture prior to work-up is concentrated in vacuo and applied to thick-layer silica gel plates directly, instead of isolating the higher Rf (0.64) product bromide, a new lower R, band (0.32) is noted and recovered as compound (12).

NMR(CDCl3): 9.5 (br. s, 1 H), 6.83 (dd, Ha), 6.34 (s, Hb), 4.10 (d, Hc), 3.93 (dd, Hd), 3.04 (s, 3H), 2.93 (m, He), 2.00 (d, 3H), 1.97 (dd, Hf), 1.37 (dd, Hg).

Jce = 0.0 Hz Jeg = 4.4 Jc.d = 9.7 Jf.g = 4.4 Jd.o = 4.7 JNH.a = 2.0 Je.f = 7.7 Ja.CH3 = < 1.0 MS: silylation with BSTFA (DMF containing 1% TMS-CI) gave m/e M+ 386/388 (22, 12% corresponding to product + Me3SiCi) UV: (methanol) A224, 272, 338.

This compound was assayed by a standard tube dilution assay against L1210 mouse leukemia cells in culture and gave the following results: ID50(g,'ml) = 0.1 3 IDgO(yg/ml) = 0.42 Example 12 Alternative preparation of compound (12) To the 4,5-pyrrolo-6-hydroxy indoline bromide (or mesylate) (0.1 mmole) in 1 ml of methylene chloride is added 0.1 mmole of diisopropylethyl amine and stirred under N2 for 24 hours at room temperature. The reaction solution is taken up in 10 ml of methylene chloride, washed with 0.1 N HCI, dried over Na2SO4, and concentrated to give the desired product.

Further purification can be accomplished by silica gel chromotography.

Compounds (11) and (1 2) exhibit antibacterial activity against B. subtilis, K. pneumonia, S.

lutea, S. aureus and M. avium.

U-62.598 is 2-( 1, 3-dihydroxy-2-propyl)-5-methoxynitrobenzene. U-62,597 is U-62,598 in which two OH have been replaced by OSO2CH3. U-62,586 is the compound of claim 3 when R2 and R3 are each hydrogen; R4 is SO2CH3; R5 is CH3; and JC is CH3SO3. The product of Example 4 is the same as U-62,586, except that X is CH3COO. U-62,696 and U-62,697 are the same as the product of Example 4 except that, respectively, Y is NO2 and NH2, rather than hydrogen, U-62,233 is the compound of claim 2 when R1 and R5 are each CH3; R2 and R3 are each hydrogen, R4 is CH3SO2; and X is OH. U-92,370 is the same as U-62,233 except that R5 is hydrogen.U-62,694 and U-62,695 are the same as U-92,370 except that, respectively, X is Br and CH3SOs. U-62,736 is the compound of claim 1 when Rl is CH3; R2 and R3 are each hydrogen; and R4 is CH3SO2.

As will be apparent from the data given above, compounds of the invention are active against certain bacteria, including Bacillus subtilis, Klebsiella pneumonia, Sarcina lutea, Staphylococcus aureus and Mycobacterium avium. Accordingly, these compounds can be used to disinfect washed and stacked food utensils contaminated with S. aureus. Further, the antibacteriallyactive compounds of this invention can be used as bacteriostatic rinses for laundered clothes, and for impregnating papers and fabrics. They can also be used for suppressing the growth of sensitive organisms in plate assays and microbiological media. In general, the anti-bacteriallyactive compounds of this invention can be used in the same manner as disclosed for antibiotic CC-1065 in U.S. Patent Specfication No. 4,169,888. These uses are well known.

A pharmaceutical composition according to the invention comprises a compound of the invention, in association with a physiologically acceptable excipent.

Claims (23)

1. A compound of the formula

wherein R1, R2 and R3 are independently selected from hydrogen, C, 5 alkyl and phenyl; and R4 is HSO2, (C1 5 alkyl)sulfonyl, PhSO2, PhCOCH2SO2 or ZCH2COO in which Z is CH21, CCl3, HSO2CH2, (C1-6 alkyl)sulfonylmethyl, PhSO2CH2, phenyl or fluorenylmethyl.

2. A compound of the formula

wherein R1, R2, R3 and R4 are as defined in claim 1; R5 is H, CH3, PhCH2, CH2 = CHCH2, CH3SCH2, CH3OCH2, CH3OCH2CH2OCH2, Cl3CC H2 or (R6}3SiCH2CH2 in which each R8 is C15 alkyl or phenyl; and X is HSO3, (C15 alkyl)sulfonyloxy, PhSO2, Cl, Br, I or OH.

3. A compound of the formula

wherein R2, R3 and R4 are as defined in claim 1; R5 is as defined in claim 2; X' is HIS02, (C1 5 alkyl)sulfonyloxy, PhSO3, CI, Br, I or CH3COO; and Y is H, NO2 or NH2.

4. A compound of the formula

wherein R2 and R3 are as defined in claim 1; R5 is as defined in claim 2; and X" is HSO3, (C, 5 alkyl)sulfonyloxy, PhSO3, Cl, Br, I, OH or CH3COO.

5. A compound of the formula

wherein R3 is as defined in claim 1; R5 is as defined in claim 2; and R7 is CH30, C2H50, Cur 5 alkyl or phenyl.

6. The compound claimed in claim 1, when R' is methyl; R2 and R3 are each hydrogen; and R4 is CH2SO2.

7. The compound claimed in claim 2, when R1, R2, R3 and R4 are as defined in claim 6; R5 is hydrogen; and X is Br.

8. The compound claimed in claim 2, when R', R2, R3, R4 and R5 are as defined in claim 7; and X is OH.

9. The compound claimed in claim 2, when Ra, R2, R3 and R4 are as defined in claim 6; R5 is CH3; and X is OH.

10. The compound as claimed in claim 3, when R2, R3, R4 and R5 are as defined in claim 9; X' is CH3COO; and Y is NH2.

11. The compound claimed in claim 3, when R2, R3, R4, R5 and X' are as defined in claim 10; and Y is NO2.

1 2. The compound claimed in claim 3, when R2, R3, R4, R5 and X' are as defined in claim 10; and Y is H.

1 3. The compound claimed in claim 3, when R2, R3, R4, R5 and Y are as defined in claim 12; and X' is CH3SO3.

14. The compound claimed in claim 4, when R2, R3 and R5 are as defined in claim 9; and X" is CH2SO3.

1 5. The compounds claimed in claim 4, when R2, R3 and R5 are as defined in claim 9; and X" is OH.

16. A process for preparing a compound as claimed in claim 1, which comprises reacting a compound as claimed in claim 2, when X is OH, with triphenylphosphine and a carbon tetrahalide, and subsequently adding a base.

1 7. A process for preparing the compound claimed in claim 6, which comprises reacting the compound claimed in claim 8 with triphenylphosphine and a carbon tetrahalide, and subsequently adding a base.

1 8. A process for preparing a compound as claimed in claim 2, when X is other than OH, which comprises reacting a compound as claimed in claim 2, when X is OH, with a reagent selected from sulfonyl chlorides, carbon tetrachloride/triphenylphosphine, carbon tetrabromide/triphenylphosphine and N-iodosuccinimide/triphenylphosphine.

1 9. A process for preparing the compound claimed in claim 7, which comprises reacting the compound claimed in claim 8 with carbon tetrabromide/triphenylphosphine.

20. A process for preparing a compound as claimed in claim 3, when Y is H, which comprises reducing a compound as claimed in claim 4, and acylating the resultant secondary amine.

21. A process for preparing the compound claimed in claim 13, which comprises reacting the compound claimed in claim 14 with hydrogen in the presence of platinum dioxide and acylating the resultant secondary amine with methanesulfonyl chloride.

22. A process substantially as herein described with reference to any of the Examples.

23. A pharmaceutical composition comprising a compound as claimed in any of claims 1 to 15, in association with a physiologically acceptable excipient.