CH655726A5 - 1,2,8,8A-TETRAHYDRO-CYCLOPROPA (C) -BENZO (1,2-B: -4,3-B ') - DIPYRROL-4 (5H) -ON COMPOUNDS AND METHOD FOR PRODUCING THESE COMPOUNDS. - Google Patents

Description

es The present invention relates to 1,2,8,8a-tetra-hydro-cyclopropa [c] -benzo [1,2-b: -4,3-b '] -dipyrrol-4 (5H) -on- Compounds and a new process for the preparation of these compounds.

655 726

The compounds according to the invention have the following formula

(11)

Br

S02CH3

S ° 2CH3

and

OH

S ° 2CH3

(110

wherein

R stands for H, CH3-, -CH2Ph, CH2 = CHCH, - -CH, SCH3, -CH2OCH3- -CH2OCH2CH2OCH3, -CH2CC13 or -CH2CH2Si (R'2) 3,

R2 and R3 are identical or different and denote hydrogen, alkyl having 1 to 5 carbon atoms or the phenyl radical,

R4 represents a radical of the formula -S02R'2, -S02CH2C0-phenyl or -OOCCH2Z, and RSQ-Q-alkyl or phenyl and Z-CH2I, -CC13, -CH2S02R2, the phenyl or fluorenylmethyl radical and

X represents S03R'2, Cl, Br, I or OH.

Preferred compounds of the formula (11) are those of the formulas wherein

R2, R3 and R4 are defined above and X "'stands for S03R'2, Cl, Br or I, and 1 R'2 Ci-C5-alkyl or phenyl, are prepared according to the invention by using a compound of formula

(loo

25th

Reacts compounds of the formula with a corresponding sulfonyl chloride carbon tetrachloride / triphenylphosphine, carbon tetrabromide / triphenylphosphine or N-iodosuccinimide / triphenylphosphine.

The antibiotic CC-1065 is known from US Pat. No. 4,169,888. The structural elucidation of the antibiotic CC-1065 is from D.G. Martin, C.G. Chidester, DJ. Du-35 champ and S.A. Mizsak in «J. Antibiot. », Volume 33, page 902 (1980),« Structure Proof of Antibiotic CC-1065 ». The structure of the antibiotic CC-1065 is shown in Fig. 1. The antibiotic CC-1065 consists of a system of 3 fragments, the most labile part of the molecule of which as 40 l, 2,8,8a-cyclopropa [c] benzo [l, 2-b: -4,3-b '] dipyrol- 4 (5H) -on designated fragment. This is referred to below as compound (12). Attempts to recover this fragment by breaking down the antibiotic CC-1065 have failed. Thus, there is no known method for producing compound (12).

The compound (12) can be prepared by the 11-step process shown in the reaction scheme of FIG. 2. The compound (12) and certain intermediates obtained in its production are active against certain bacteria, for example Bacillus subtilis, Klebsiella pneumonia, Sarcina lutea, Staphylococcus aureus and Mycobacterium avium. Consequently, the compounds in question can be used to disinfect washed and stacked items contaminated with S. aureus that come into contact with food. Furthermore, the antibacterially active compounds can also be used as bacteriostatic rinses for washed clothes, for impregnating paper and tissues, for suppressing the growth of sensitive organisms in plate tests and in mi-60 microbiological media. As a rule, the antibacterially active compounds can be used in the same way as the antibiotic CC-1065 known from US Pat. No. 4,169,888. The relevant fields of application are known to the person skilled in the art dealing with antibiotics 65.

In the process shown schematically in FIG. 2, in which the production of the intermediate according to the invention and also its use for the production of the

655 726 4

Antibiotic of the formula (12) is also described, the reaction is based on the spectroscopic data obtained, the following process steps, which are preferably followed.

are carried out as follows: Step 7: The reduction of the nitro to the amino group

Stage 1: The first stage (aromatic nucleophilic substituent corresponds to that described in connection with stage 4) of the synthetic route is by J. Bourdais and C. Ma-5 Chemismus, but the base is omitted.

hey in «Compt. Redux »[C], 263.84 (1966), (cf. stage 8: indole synthesis. This synthesis is essentially based on J. Bourdais and C. Germain in« Tet. Letters », 195 borrowed from Gassman's indole chemistry (cf. PG (1970)) The various radicals R can be found in Phe-Gassman and co-workers in d.Am. Chem. Soc., 96.5494, nolvorläufer of (1) according to Ver 5508 described in the literature, 5512 (19747) There are, however, certain Gassman driving introductions (cf. here the literatures cited in step 8, neither described nor suggested modifications.) The various malonates used, ß-Keder chemical processes and some toester and ß-diketones are known compounds, intermediates are shown in Fig. 3. The a-thiome-

Level 2: Reduction. If R'3 for an alkoxy radical and R3 thylester are known.

stand for hydrogen, is diisobutylaluminum hydride. The process deviates from the known Gassman way

Reagent of choice. The reaction conditions are based on the fact that the chlorosulfonium complex A is used and is very specific with regard to optimum yields (cf. preparation which is allowed to react with the aniline (6). Gassman 1). If R'3 stands for an alkyl or phenyl radical (R'3 = R3), the chloramine of the aniline is produced and this can be reacted with the thioether to produce standard reduction measures and oxindoles. Second, operate the use of sodium borohydride. are two different in the present method

Level 3: Exchange of a functional group. The one used in the 20 bases, whereas Gassman uses two equivalents of the following specifically described chemistry in the case where aniline and then a base 2 are used. Although triethylamine that X stands for-0S02CH3. The mesylate or tosylate (for example diisopropylethylamine, bis (1,8-dimethylamino) naphthalene, for example) is obtained under known standard conditions and the like, both as a base! and Base2, the preferred method using pyridine (with or without a solvent base! bis (1,8-dimethylamine) naphthalene and the preferred agent such as methylene chloride) or other acid acceptors is 25 Base2 triethylamine. Different solvents such as trialkylamines (with solvent) and the corresponding solvent, such as chloroform, acetonitrile, tetrahydrofuran-containing sulfonyl chloride, can be used. The halogen analogs obtained from (4) and preferably methylene chloride can be used. The known standard measures under usage temperature range from - 50 ° to - 80 ° C. The reaction is carried out, for example, of Ph3P / CCl4 (CBr4) and N-iodosuccin in an inert atmosphere. The cyclisie imide / triphenylphosphine. 30 Oxindole B is best catalyzed by an acid.

Stage 4: reduction-cyclization. This step enables siert (see Gassman: 2N HCl, ether and / or ethyl acetate). a novel production of indolines (dihydroindoles). The final reduction to (9) (reductive elimination)

As described by Gassman, a reduction of the nitro to the amino takes place with a lithium aluminum group with simultaneous intramolecular cyclization of unminium hydride or, better, with diborane reagents to form (5). In the case of the 35 ren described in detail. The reduction stage is preferably carried out for 24 h with H2 and Pt02 in alcohol in counter (CH3) 2S • BH3 in tetrahydrofuran at room temperature.

been working a tertiary amine. This is level 9: This elimination of a protective group (removal

around standard hydrogenation conditions. Palladium of R ^ can also be described in detail for Ri = CH3 in supported or nickel catalysts and other bases as an example 8. Although a number of measures include a tertiary amine, e.g. Pyridine. In other cases where methyl ether cleavage is known, production measures can be carried out using Fe or TiCl3 in acid or only alkyl mercaptides in hexamethylphosphoric acid SnCl2. In this case, a separate step in retriamide (hexamethylphosphor-3-amide) under inert atmospheric form treatment with a base to initiate the sphere (95 ° -1 10 C) can be effective (SC Welch and cyclization to (5) An example of the Re-ASCP Rao in "Tet. Letters", 505 (1977) and TR Kelly, duction with iron is the use of Fe / CH3C02H / 45 HM Dali and WG. Tsang in "Tet. Letters" , 3859 (1977)). CH3CH2OH (see G.S. Ponticello and J.J. Baldwin in «J. It is also suitable for Me2S ■ BBr3 in dichloroethane (see P.G.

Org. Chem. », 44, 4003 (1979)). These conditions are Willard and C.B. Fryhlein «Tet. Letters », 3731 (1980)). required if Ri stands for CH2Ph or -CH2CH = CH2. If R] stands for CH2Ph, standard hydrogenoly-

The concept of a nitroreduction and subsequent in conditions (H2, Pd / C) to eliminate the protective-situ cyclization to indoles is from DE-OS 20 57 840 so group (cf. «Org. Reactions», 7,263 ( 1953)). If R! knows. The teaching in this regard is a clear improvement - CH2SCH3 stands for, removes mercury (II) chloride in ether compared to the older Reissert process of a reducti-acetonitrile / H20 (see RA Holton and RG Da-ven cyclization to indoles ( see RJ Sundberg, "The vis," Tet. Letters ", 533 (1977)). If R] stands for CH2OCH3, Chemistry of Indoles", pages 176-183, publisher Academic provides a moderately strong acid, for example acetic acid, the phenol

Press, New York, 1970). 55 (10) (cf. "J. Med. Chem.", 9.1 (1966) or "Synthesis", 244

Level 5: Substitution of an unstable group. This stage (1976)). Indeed, this level 6 protective group may have been lost due to the incompatibility of X with chemism, but it can be done prior to the level 8 implementation. Here, X is reintroduced at standard level 7 under standard conditions (alkali metal carboxylate in acetone, dimethyl formaldehyde. If R stands for -CH2OCH2CH2OCH3, the amide or alcohol can be mixed with an acetate or the conjugated phenol Produce ZnBr2 or ~ TiCl4 in CH2C12 (cf. "Tet. Base of a Q-Cs-alkyl carboxylic acid replaced. Since in the case that Letters", 809 (1976)). If Ri stands for -CH2CH = CH2, X stands for -0S02CH3, a certain hydrolysis can take place, the ether can be of various two-stage dimensions, the reaction mixture is freed from the protective group (Pd / C in Alcohol - treated with acetic anhydride, see "Ang. Chem. Int. Ed.", 15,558 (1976); Se02, CH3C02H

Stage 6: The nitration can be done in a wide variety of 65 in dioxane - cf. «Tet. Letters », 2885 (1970); tert-BuOK, known conditions, e.g. with nitric acid in acetic acid, methyl sulfoxide and then H2S04 in acetone - cf. «J. Acetic anhydride, sulfuric acid, acetic acid / H20, Alko-Chem. Soc. », 1903 (1965); RhCl (PPh3) 3, DABCO in alcohol, hol and nitroalkanes. The location selectivity of this subsequently pH2 - cf. «J. Org. Chem. », 38, 3224 (1973)).

If Rj stands for —CH2CH2Si (R2) 3, the protective group is removed by means of Bu4NF (cf. H. Gerlach and co-workers in “Helv. Chim. Acta”, 60, 3039 (1977)).

Level 10: See Level 3.

Stage 11: This stage (if X = Br) takes place when it comes into contact with silica gel and when it is left to stand (of the reaction mixture) in a protic solvent. This reaction also takes place in the presence of bases such as tertiary amines, pyridine, tert-butoxide and the like, and also weak aqueous bases such as bicarbonates and carbonates.

The following preparations, examples and examples of use are intended to illustrate the invention in more detail. Unless otherwise stated, all percentages mean “percentages by weight”. All quantities in solvent mixtures refer to the volume.

The numbers behind the chemical names refer to the general formulas in Figure 2.

Preparation 1 (level 2)

Preparation of 2-aryl-1,3-propanediol (3) from Aryldi-ethylmalonate (2)

400 ml of tetrahydrofuran, which are cooled in an ice bath under a nitrogen atmosphere, are mixed with 100 g (0.70 mol) of diisobutylaluminum hydride in 400 ml of toluene. 33.0 g (0.105 mol) of the arylmalonate (2) in 100 ml of tetrahydrofuran are added to the resulting solution with stirring. The rate of addition is controlled so that the reaction temperature remains below 5 ° C. When the addition is complete, the ice bath is removed. After a total of 3 hours of reaction, the reaction mixture is quenched by portionwise introduction of the solution into cold 3N HCl with stirring (about 1.5 liters). The mixture is then extracted with 1 liter of ethyl acetate and then 1000 ml of CH2C12. 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 of silica gel using 60% ethyl acetate / hexane -> 100% ethyl acetate (gradient elution) as eluent gives 11.7 g of the diol (3) (U-62.598) in 49% yield light red oil that solidifies when left in the freezer.

Nuclear magnetic resonance spectrum (CDC13): 7.5-7.0 (m, 3H), 3.80 (s, 3H), 4.0-3.3 (m, 7H - including 2 OH). Mass spectrum:

Calculated for C10H13NO5: 227.0794

Found: 227.0780

The elementary analysis of the compound obtained gives the following values:

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plot, with a total of 6.65 g of bis-mesylate (4) (U-62.597) of a (after recrystallization from acetone) mp from 122 ° to 123 ° C in 86% yield.

Nuclear Magnetic Resonance Spectrum (Acet-d6): 7.7-7.2 (m, 3H), 4.62 5 (d, 4H, J = J Hz), 4.11 (t, 1H, J = 7 Hz), 3 , 92 (s, 3H), 3.06 (s, 6H).

The elementary analysis of the connection CI2H17N09S2 gives the following values:

io C H N

calc .: 37.59 4.47 3.65 found: 37.35 4.44 3.59

i5 This compound is tested in a standard dilution series against L1210 mouse leukemia cells in a culture and the following results are obtained: ID50 (Hg / ml) = 6.0 ID90 (ng / ml) = 18

20th

Preparation 3 (level 4).

Preparation of the 6-methoxyindoline bismesylate (5) from the 2-aryl-1,3-propanediol bismesylate (4)

1.91 g (0.005 mol) of compound (4) in 30 ml of tetrahydrofu-25 ran, 20 ml of ethyl acetate and 150 ml of absolute ethanol are mixed with 1.5 ml of triethylamine and 400 mg of PtO2, followed by 30 minutes under an H2 -Pressure from 48 to 68.7 kPa is shaken. The reaction solution is then filtered through the filter aid Celite and concentrated in vacuo. After repeated azeotropic distillation with CH2C12 in vacuo, the residue is finally taken up in 100 ml of CH2C12 and cooled in an ice bath under an N2 atmosphere. 1.5 ml of triethylamine and then 900 ml of methane-35 sulfonyl chloride are then added dropwise to the stirred solution. After stirring for 30 minutes, the solution is allowed to warm to room temperature within 60 minutes. The solution is then washed with in HCl, dried over Na2SO4 and concentrated. The resulting residue is rapidly chromatographed on 150 g of silica gel 40 using 500 ml of 60% ethyl acetate / hexane and then 1000 ml of 80% ethyl acetate / hexane as the eluent. This gives 1.3 g of a whitish solid (after recrystallization from ethanol) of mp 122 ° to 123 ° C., namely 6-methoxy-45 indoline-bismesylate (5) (U-62,586) in 78% yield. .

Nuclear magnetic resonance spectrum (dimethylformamide-d7): 7.36 (d, IH, J = 8.5 Hz), 7.00 (d, 1H, J = 2 Hz), 6.69 (dd, 1H, 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).

50 Elemental analysis of the compound CI2H17NS206 erber .: found:

C.

52.86 53.40

H

5.76

5.77

N

6.16 5.99

gives the following values:

55

Preparation 2 (level 3)

Preparation of the 2-aryl-1,3-propanediol bismesylate (4) from the 2-aryl-1,3-propanediol (3)

4.7 g (0.2 mol) of the diol (3) in 100 ml of dry pyridine are mixed with 6.8 g (0.06 mol) of methanesulfonyl chloride under an N2 atmosphere at 0 ° to 5 ° C. with stirring. After stirring at 5 ° C. for 30 minutes and stirring at room temperature for 90 minutes, the solution obtained is concentrated in vacuo and then taken up in CH2Cl2 / IN HCl. The organic phase is separated off, dried over Na2SO4 and concentrated to a residue. Trituration with ethyl acetate gives a whitish solid. The mother liquors can be chromatographed on silica gel (eluent: ethyl acetate)

calculated: found:

C.

42.97 42.87

H

5.11 5.27

N

4.18 4.29

This compound is tested as part of a standard dilution series against L1210 mouse leukemia cells in a 60 culture, with the following results being obtained: ID50 (nl / ml) = 4.8 ID90 (ng / ml) = 10

Preparation 4 (level 5).

Preparation of the 6-methoxyindoline acetate (6) from the 6-Me-65 thoxyindoline bismesylate (5)

13.0 g (39 mmol) of 6-methoxyindoline-bismesylate (5) in 30 ml of dimethylformamide are mixed with 800 ml of absolute ethanol and then 32 g of sodium acetate, which

655 726

heated to the heterogeneous solution obtained under an N2 atmosphere for 24 hours at reflux temperature, then cooled and finally concentrated in vacuo. The resulting residue is treated with 100 ml of acetic anhydride for 2 hours (stirring at room temperature) and then concentrated in vacuo. The evaporation residue is then taken up in CH2CI2 / H2O. After the organic phase has been separated off, it is dried over Na2SO4, filtered through charcoal and concentrated to a solidifying oil. 11.6 g of 6-methoxyindoline acetate (6) are obtained (100% yield. If necessary, it can be purified further by chromatography on silica gel using 60% ethyl acetate / hexane as the eluent).

Nuclear Magnetic Resonance Spectrum (CDC13): 7.17 (d, 1H, J = 8.5 Hz), 7.02 (d, 1H, J = 2 Hz), 6.60 (dd, 1H, 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).

The elementary analysis of the compound C13H17N05S gives the following values:

H2 pressure of 68.7 kPa is shaken. Then it is filtered and concentrated in vacuo. When concentrated, 3.0 g of product precipitated. This is filtered off. The mother liquors are quickly poured onto 100 g of silica gel using ethyl

5 acetate as eluent chromatographed, 0.6 g of product being obtained. The overall yield (3.6 g) corresponds to 88% of theory. The 5-amino-6-methoxyindoline acetate (8) obtained has an mp of 134 to 135 C (U-62,697) after recrystallization from acetone / cyclohexane.

10 nuclear magnetic resonance spectrum (CDC13): 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).

The elementary analysis of the connection C13H | 8N205S gives the following values:

15

C H N calc. 49.67 5.77 8.91 found: 49.74 5.72 8.94

20th

calculated: found:

C.

52.16 52.13

H

5.76 5.79

N

4.68 5.27

Mass spectrum: 25

Calculated 299.0827 Found: 299.0823

Preparation 5 (level 6)

Preparation of 5-nitro-6-methoxyindoline acetate (7) from 6-methoxyindoline acetate (6)

500 mg (1.67 mmol) of the 6-methoxyindoline acetate (6) in 20 ml of nitromethane are mixed with 90 nl of 90% HN03, whereupon the reaction solution, cooled to 0 ° to 5 ° C., is stirred for 30 minutes and then within 30 is allowed to warm to room temperature for min. Now the solution is diluted with CH2C12 and aqueous sodium bicarbonate solution. After the organic phase has been separated off, it is dried over Na2SO4 and concentrated. The residue obtained is chromatographed on 50 g of silica gel (eluent 60% ethyl acetate / hexane - 100% ethyl acetate), with 440 mg of yellow solid 5-nitro-6-methoxyindoline acetate (after recrystallization from ethanol) in 76% yield. Mp of 175 ° to 177 ° C can be obtained (U-62,696).

Nuclear Magnetic Resonance Spectrum (dimethylformamide-dv): 7.91 (s, 1H), 7.20 (s, 1H), 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).

The elementary analysis of the compound C13H16N207S gives the following values:

This compound is tested in a standard dilution series against LI210 mouse leukemia cells in a culture, with the following results being obtained: IDS0 ((ig / ml) => 50 IDg0 ((ig / ml) => 50

calculated: found:

C.

45.34 44.81

H

4.68 4.77

N

8.14 8.16

This compound is tested in a standard dilution series against L1210 mouse leukemia cells in a culture and the following results are obtained: ID50 (ng / ml) => 50ID90 (ng / ml) => 50

Preparation 6 (level 7)

Preparation of 5-amino-6-methoxyindoline acetate (8) from 5-nitro-6-methoxyindoline acetate (7)

4.5 g (13 mmol) of the 5-nitro-6-methoxyindoline acetate (7) in 50 ml of tetrahydrofuran and 150 absolute ethanol are mixed with 500 mg of Pt02, after which the whole is stopped until the H2 uptake (after about 60 min) under a

Preparation 7 (level 8)

Preparation of 4,5-pyrrolo-7-methoxyindoline (9) from 5-amino-6-methoxyindoline acetate (8)

14 ml of dry CH2C12 are added under a ^ atmosphere at -75 ° C with 6.0 ml of a Cl2 / CH2C12 solution (20 μl. 1 Cl2 / ml CH2C12), followed by 370 nl (2, 5 mmol) CH3 (CH3S) CHC02C2H5 (made from CH3 (Br) CHC02C2H5 and methyl mercaptide according to that of EH Wiek, T. Yamanishi, HC Wertheimer, YE 35 Hoff, BF Praetor and SA Goldblith in "J. Agr. Food Chem." , 9,289 (1961) method) are added. After 5 minutes, a solution of 470 mg (2.2 mmol) of 1,8-bisdimethylaminonaphthalene and 628 mg (2.0 mmol) of the anilinoindoline (8) in 3.0 ml of dry CH 2 Cl 2 is added dropwise within 15 minutes . The red solution formed in this way is stirred for 2 hours at −75 ° C. and then 350 nl of triethylamine in 650 μl of 1 CH2C12 are added dropwise within a few minutes. After removing the cooling bath and reaching room temperature, the reaction solution is briefly concentrated in vacuo. 5 ml of ethyl acetate, 25 ml of ether and 6 ml of 2N HCl are added to the residue, which is then stirred vigorously for 2 hours. After the organic phase has been separated off, the aqueous phase is traced with a 1: 1 mixture of ethyl acetate and Et20 ex-50. The organic phases are combined, dried over Na2SO4 and concentrated. Now the residue is taken up in 10 ml of tetrahydrofuran and treated with 3.0 ml of 2M BH3-SMe2 overnight at room temperature under an N2 atmosphere. On the other hand, the diastereomeric oxindoles (B) obtained in the 55 acid treatment can also be isolated by silica gel chromatography (50 g, 60% ethyl acetate / hexane to 90% ethyl acetate / hexane as eluent).

GS mask spectrum: m / e M + 414 (15%), 227 (100%) - 2 '«0 1% SE-30.

Nuclear Magnetic Resonance Spectrum (CDC13): 8.4 (br. S, 1H), 7.11 (s, 1H), 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 diastereomer (2.5 / 1); the subordinate diastereomer shows the following differences 6S -1.99 (s, 3H), 1.76 (s, 3H) for -SCH3 and -CH3, the NH is 7.7 and the CH2 range is 4.3-3 , 6 ppm.

The aqueous phase from the acid treatment can be neutralized and extracted with GHUCU. The CH2C12 solution

The solution can then be dried, concentrated and chromatographed on silica gel using 50% acetone / cyclohexane, recovering 40% starting material (anilinoindoline) and 20% deacylated starting material.

The reaction mixture from the reductive elimination (at B) with borane dimethyl sulfide is worked up by quenching with In HCl until the gas escape has ceased and then being taken up in CH2C12 / H20. The separated organic phase is dried over Na2S04 and concentrated. The resulting residue is chromatographed on silica gel (eluent: 50% acetone / cyclohexane), 155 mg of 4,5-pyrrolo-7-methoxyindoline (9) having an mp of 182 ° to 183 ° C. (phase change at 160 ° C., recrystallized) Chloroform) are obtained (25% isolated yield - 85%, based on the recovered starting material) (U-62,233).

Nuclear Magnetic Resonance Spectrum (CDC13): 8.3 (br. S, 1H), 6.96 (s, 2H), 4.2-3.5 (m, 5H + OH), 3.92 (s, 3H), 2 , 87 (s, 3H), 2.41 (s, 3H).

The elementary analysis of the compound C] 4H18N204S gives the following values:

calculated: found:

C.

54.17 53.49

H

5.84 5.96

N

9.03 9.42

GC mass spectrum: of the O-acetate - m / e M + 352 (13%), 213 (100%) - 2'-1% SE-30, temperature: 150-1260 ° C (10 ° / min); single peak.

This compound is tested in a standard dilution series against L1210 mouse leukemia cells in a culture and the following results are obtained:

ID5o (| ig / ml) => 4 IDgo (| ig / ml => 4.

Preparation 8 (level 9 J

Preparation of 4,5-pyrrolo-7-hydroxyindoline (10) from 4,5-pyrrolo-7-methoxyindoline (9)

10 ml of dry, degassed hexamethylphosphoric acid triamide are mixed with 350 ml of butyl mercaptan under an N 2 atmosphere at room temperature. The solution is cooled in an ice water bath and 2.0 ml of 1.5M n-butyllithium in hexane are added dropwise. After the reaction mixture has reached room temperature, 100 mg (0.3 mmol) of indole (9) are added with stirring, and the solution is then heated to 100 ° C. for 2.5 hours. After the reaction, the reaction mixture was subjected to thin layer chromatography using 50% acetone / cyclohexane as the eluent. When the conversion is considered to be 75% complete (spray: vanillin / phosphoric acid), the heating is stopped. The cooled solution is poured into HCl (100 ml) and extracted with 20 ml of ethyl acetate. The separated organic phase is washed with a further 50 ml of water. The aqueous phases are combined and back extracted with 20 ml of ethyl acetate. After combining, the organic phases are dried over Na2S04, concentrated in vacuo and poured onto a 100 g silica gel column. It is eluted with 50% acetone / cyclohexane. 25 mg of starting material and 45 mg of the product 4,5-pyrrolo-7-hydroxyindoline (10) are obtained (44% isolated yield, 69% based on the recovered starting material) (U-62.370).

Nuclear Magnetic Resonance Spectrum (Acet-d6): 7.8 (br. S, 1H), 7.03 (s, 1H), 6.83 (s, 1H), 4.25-3.25 (m, 5H), 2 , 86 (s, 3H), 2.36 (s,

3H).

The product obtained is treated with 1.0 ml of acetic anhydride and 20 mg of sodium acetate overnight and then

7 655 726

recorded in CH2C12 / H20. The organic phase is then separated off, dried over Na2SO4 and concentrated.

Nuclear Magnetic Resonance Spectrum (CDC13): 7.8 (br. S, 1H), 7.16 (s, 1H), 6.97 (s, 1H), 4.42.4.20 (dd, 2H), 4.2 -3.7 (m, 3H), 2.86 (s, s 3H), 2.40 (s, 3H), 2.35 (s, 3H), 2.06 (s, 3H).

GC mass spectrum: m / e M + 380 (25%), 199 (100%) - 2'-1% SE-30.

This compound is tested as part of a standard dilution series against L1210 mouse leukemia cells in an io culture, the following results being obtained: ID50 ((xg / ml) => 5 ID90 (| ig / ml) => 5.

Example 1 (level 10)

Preparation of 4,5-pyrrolo-7-hydroxyindoline bromide (11 15 from 4,5-pyrrolo-7-hydroxyindoline alcohol (10)

25 mg (65 jiMol) of the substrate alcohol in 1.0 ml of dry acetonitrile are mixed with 33 mg (100 uMole) of CBr4 and 26 mg (100 jiMole) of triphenylphosphine (Ph3P) under N2 atmosphere at room temperature. After stirring for 30 minutes, a further 11 mg of CBr4 and 8 mg of Ph3P are added. After a total of 60 min, the reaction mixture is taken up in CH2C12 / H20. The organic phase is separated off, dried over Na2SO4 and concentrated. The residue obtained is applied to three 20 cm × 20 cm silica gel 25 plates (250 μm) and eluted with 50% acetone / cyclohexane. 8 mg of the product having the higher Rr value (0.64; alcohol Rr value: 0.45) are obtained. This is 4,5-pyrrolo-7-hydroxyindoline bromide (11) (U-62,694).

30 nuclear magnetic resonance spectrum (CDC13): 8.5 (br. S, 1H), 7.1 (s, 1H), 6.9 (s, 1H), 4.23 (d, 2H, J = Hz), 4, 0-3.5 (m, 3H), 2.89 (s, 3H), 2.38 (s, 3H).

Beilstein test: positive.

Mass spectrum: calculated for C16H23N-> 0379BrSSi: 35 430.0382, found 430.0375 (mono-TMS); m / e M + 430/432 (14%), 271 (90%), 147 (100%).

This compound is tested as part of a standard dilution series against L1210 mouse leukemia cells in a culture, with the following results being obtained: ID50 (ng / ml) = 0.12 ID90 (ng / ml) = 0.37.

Example 2 (Level 10.2. Procedure).

45 Preparation of 4,5-pyrrolo-7-hydroxyindoline mesylate (11) from 4,5-pyrrolo-7-hydroxyindoline alcohol (10)

20 mg (65 µmoles) of the alcohol substrate (10) in 1.0 ml pyridine are mixed in an ice bath with stirring and N2 atmosphere with 8 | il (70 µmoles) methanesulfonyl chloride, so after 30 min a further 2 ml CH3S02C1 are added . After a total reaction time of 60 minutes, the whole is worked up with 2N HC1 / CH2CI2. The organic phase is separated off, dried over Na2SO4 and concentrated. In thin layer chromatography, there is primarily a 55 product with a low Rp value (0.28 in 50% acetone / cyclohexane, alcohol Rr value: 0.46) and some product with a higher Rr value (0.66). Preparative thin layer chromatography 3-20 x 20 cm silica gel plates, 250 (im) provides 2 mg of a material with a higher Rr value (the nuclear magnetic resonance 60 spectrum shows only one CH3S02 group, this is probably the chloride) and 9 mg of a material with a lower Rr value. It is the connection (11) (U-62,695).

Nuclear Magnetic Resonance Spectrum (Acet-d6): 8.6 (br. S, 1H), 6.97 (s, es 1H), 6.74 (s, 1H), 4.3 (m, 2H), 4.1- 3.6 (m, 3H), 2.96 (s, 3H), 2.79 (s, 3H), 2.26 (s, 3H).

This compound is used in a standard dilution series against L1210 mouse leukemia cells in one

655 726

Culture tested, the following results being obtained: ID50 (ng / ml) = 1.0 ID90 (| ig / ml) = 3.3.

Application example 1 (level 11).

Preparation of 1,2,8,8-tetrahydro-cyclopropa [C] benzo- [1,2-b: 4,3-b '] dipyrol-4 (5H) -one (12), N- (methylsulfonyl)

If, as part of the measures for the preparation of 4,5-pyrrolo-7-hydroxyindoline bromide (stage 10), instead of isolating the bromide formed with the higher Rf value (0.64), the reaction mixture is concentrated in vacuo and directly applied to thick silica gel layer plates, a new band appears with a lower Rr value (0.32). This is connection (12).

Nuclear Magnetic Resonance Spectrum (CDC13): 9.5 (broad s, 1H), 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 Jc'd = 9.7 Jd, e = 4.7 Je, f = 7.7 Je, g = 4.4 Jf, g = 4.4 Jnh, 3 1 2.0

Yes, ch3 = <1.0

8th

Mass spectrum: Silylation with BSTFA (dimethylform amide containing 1% TMS-Cl) gives m / e M + 386/388 (22, 12% corresponding to the product -1- Me3SiCl).

UV spectrum in methanol: X 224,272,338.

5 This compound is tested in a standard dilution series against L1210 mouse leukemia cells in a culture and the following results are obtained: ID50 (ng / ml) = 0.13 ID90 (| ig / ml) = 0.42

Application example 2 (level 11).

Another method of making compound (12).

The 4,5-pyrrolo-7-hydroxyindoline bromide (or mesylate) (0.1 mmol) in 1 ml methylene chloride is mixed with 0.1 mmol di-isopropylethylamine, and the whole is stirred under an atmosphere for 24 hours at room temperature . Now the reaction solution is taken up in 10 ml of methylene chloride, washed with 0.1 HCl, dried over Na2SO4 and concentrated to the desired product. Another 20 purification can be accomplished by silica gel chromatography.

The compounds (11) and (12) show antibacterial activity against B. subtilis, K. pneumonia, S. lutea, S. aureus and M. avium.

Figure 1

9

Figure 2

655 726

Level 5

ococh ^

Level 6

0C0CH-.

4th

Level 7

° 2NN ^

R10

0C0CH-,

N ^ R,

(8th)

(7)

655726

10th

(8th)

(11)

Level 11

Level 8

Level 10

Definitions:

Ri = CH3 -, - CH2Ph, CH2 = CHCH-r -, - CH2SCH3, CH2OCH3, -CH, OCH2CH2OCH3, -CH2CC13, -CH, CH2Si (R'2) 3

R2 = alkyl (C, -C5), phenyl, hydrogen R'3 = O-alkyl (C, -C2), alkyl (Q-Q), phenyl R3 = hydrogen, Q-Cy-alkyl, phenyl

Figure 3

R4 = SOiR2, S02CH-> C0Ph, OOCCH2Z X = SOR'j, Cl, Br, I

Z = CH2I, CC13, CH2S02R2, Ph, fluorenylmethyl Among "alkyl residues with 1 or 2 carbon atoms (s)" "alkyl residues with 1 to 5 carbon atoms (s)" include methyl, ethyl, propyl, butyl and To understand pentyl radicals and their branched chain isomers.

Ra— / v

, co2c2h5

Cl:

SCH,

CH2C12 -75 "

> R, - {

co2c2hs

-Cl

U)

Base,

+ S "™ 1

^ CH3, Cl solvent

-75 ° __

sh-

(9) 4

4th

acid

11

655 726

Figure 4

Preparation 1 co2C2H3

c02c2H3

Level 2

- »I

CT:

U-62.598

Preparation 2

ch30

level 3

pr

CII3 °

oso2ch3

so2ch3

no;

jeff u-62,597

Preparation 3

ch3O

yof "

.OSO ^ CH 2

OSO2CH2

Level 4

IODINE

> 0SO2CH3

C4T

Preparation 4

CH30 ^ K

.1

so ch

^ j u-62.586

ai3o

'oso2ch3

Level 5

ch3o coch-

N

For s02ch3

Ufr s02ch3

Preparation 5

cooks

S02Me

Level 6

° 2n ^

c? ch3

SC ^ CH ^

u-62.696

Preparation 6

o2u ch30

ococh m

N

I.

s02ch3

Level 7

h2n

I.

ococh-

ch3o "^" k '

so2ch3 j ^ 8f u-62,697

655 726

12

Preparation 7

, CH3

so2CH3

Example2

s ° 2CH3

por

Application example 1 CR

Br

(pr so2CH3

Level 8

ch3o

S&T S02 ^ 2

U-62.233

Level 9

->

SCHCK-j pO) 'U-92,370

Level OK

Br.

SO2CH3

U-62,694

StufelO

->

OS02CH3

S02CH3

! M) U-62.695

CHq

Level 11

by

^ CH3

U-62.736

C.

Claims (7)

655726 PATENT CLAIMS 1. Compounds of the general formula (11) Br S02CH3 according to claim 1. 3. Compound of the formula S02CH3 according to claim 1. 4. Compound of the formula (11 ') wherein R stands for H, CH3-, -CH2Ph, CH2 = CHŒU-, -CH, SCH3, -CH2OCH3, -CH2OCH2CH2OCH3, -CH2CC1, or -CH2CH2Si (R'2) 3, R2 and R3 are identical or different and denote hydrogen, alkyl having 1 to 5 carbon atoms or the phenyl radical, R4 represents a radical of the formula -S02R'2, -S02CH2C0-phenyl or -OOCCH2Z, as well as R'2 Ci-C5-alkyl or phenyl and Z represent -CH2I, -CC13, -CH2S02R2, the phenyl or fluorenylmethyl radical and X represents S03R'2, Cl, Br, I or OH. 2. Compound of the formula wherein R2, R3 and R4 have the meaning given in claim 1 and X '"represents S03R'2, Cl, Br or I, and R'2 is C] -C5-alkyl or phenyl, characterized in that a compound of the general formula (10 ') 30 with a corresponding sulfonyl chloride, carbon tetrachloride / triphenylphosphine, carbon tetrabromide / triphenylphosphine or N-iodosuccinimide / triphenylphosphine. 6. The method according to claim 5 for the preparation of a compound of the formula 35 CH. 40 45 S ° 2CH3 characterized in that a compound of the formula 50 55 HN S02CH3 OH S ° 2CH3 according to claim 1. 5. Process for the preparation of compounds of the general formula 60 with triphenylphosphine / carbon tetrabromide.