CH655724A5 - 1,2,8,8A-TETRAHYDRO-CYCLOPROPA (C) -BENZO (1,2-B: -4,3-B ') - DIPYROL-4 (5H) -ON COMPOUNDS AND A METHOD FOR THE PRODUCTION THEREOF. - Google Patents

Description

The present invention relates to 1,2,8,8a-tetra-hydro-cyclopropa [c] -benzo [1,2-b: -4,3-b '] - dipyrol-4 (5H) -one compounds and a process for their manufacture. The compounds according to the invention have the following formula:

R2 and R3, which can be the same or different, are each hydrogen, alkyl having 1 to 5 carbon atoms or the phenyl radical and

R4 is a radical of the formula S02R2 ', S02CH2C0-phenyl or OOCCH2Z, in which R /, Q-Q-Xlkyl or phenyl and Z are CH2I, CCI3, CH2S02R2, the phenyl or fluorenylmethyl radical, characterized in that a compound of the general formula

65

(12)

3,655,724

where mean: Stage 1: The first stage (aromatic nucleophilic substi-

R2 and R3, which can be the same or different, depending) of the synthetic route is described by J. Bourdais and C. Ma-weils hydrogen, alkyl having 1 to 5 carbon atoms or the Phehieu in «Compt. Rendus »[C], 263.84 (1966), described nylrest and (see also J. Bourdais and C. Germain in« Tet. Letters », 195

R4 is a radical of the formula SChRj ', S02CH2C0-Phenyl 5 (1970)). The various Rj radicals can be introduced into the Phe or OOCCH2Z, in which R2'Q-CyAlkyl or phenyl and Z nol precursors of (1) according to Ver-CH2I, CC13, CH2S02R2 described in the literature, the phenyl or fluorenylmethyl processes ( cf. the litera-rest cited at step 8). The different malonates, ß-Ke-

The process for their preparation is new and it is toester and β-diketones are known compounds.

characterized by being a compound of general level 2: reduction. If R3 'for an alkoxy radical and R3

represent hydrogen, diisobutyl aluminum hydride is the reagent of choice. The reaction conditions are very specific with regard to optimal yields. Preparation 1). If R3 '(= R3) represents an alkyl or phenyl radical, 15 one can use standard reduction measures using sodium borohydride.

Level 3: Exchange of a functional group. The chemistry specifically described below applies if (10) X is -0S02CH3. The mesylate or tosylate (for example) is obtained under known standard conditions using 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) are obtained according to known standard measures using R2, R3 and R4, the meaning given above being, for example, Ph3P / CCl4 (CBr4) and N-iodosuccin-zene, with triphenylphosphine / tetrahalocarbon umimide / Triphenylphosphine.

sets and then to form the desired compound stage 4: reduction-cyclization. This level enables a base to be added. a novel production of indolines (dihydroindoles).

The antibiotic CC-1065 30 is known from US Pat. No. 4,169,888. Here a reduction of the nitro to the amino is known. The structural elucidation of the antibiotic grappe with simultaneous intramolecular cyclization un-CC-1065 is reported by D.G. Martin, C.G. Chidester, DJ. Third formation of (5). The champ and S.A. Mizsak in «J. Antibiot. », Volume 33, page 902 reduction stage is reported with H2 and Pt02 in alcohol in counter (1980),« Structure Proof of Antibiotic CC-1065 ». been working a tertiary amine. The structure of the antibiotic CC-1065 is shown in FIG. 1 as standard hydrogenation conditions. It can also be Palladi-poses. The antibiotic CC-1065 consists of a system of um- or nickel catalysts and bases other than a tert-of 3 fragments, the most labile part of the molecule of which is the poor amine, e.g. Pyridine. With other re-

1,2,8,8a-tetrahydro-cyclopropa [c] benzo [l, 2-b: 4,3-b '] dipduction measures can be used to identify Fe or TiCl3 in acid or rol-4 (5H) -one is. This will be used in the following SnCl2. In this case, a separate stage can be referred to as compound (12). Attempts to form a treatment with a base to initiate the recovery of this fragment by breaking down the antibiotic cyclization to (5) may be necessary. An example of the Re-CC-1065 has not led to the goal. Thus there is no reduction with iron, the use of Fe / CH3C02H / known method for the preparation of the compound (12). CH3CH2OH (cf. G.S. Ponticello and J J. Baldwin in «J.

The method according to the invention and also the method Org. Chem. », 44, 4003 (1979)). These conditions are necessary for the preparation of the starting compound of the formula (10) 45, when Rj stands for CH2Ph or -CH2CH = CH2, are shown in the following reaction scheme in FIG. 2. The concept of a nitroreduction and subsequently in FIG. The compound (12) according to the invention as well as the on-site cyclization to indoles is known from DE-OS 20 57 840, certain intermediates obtained in their preparation. The teaching in this regard represents a significant improvement - are active against certain bacteria, for example Bacillus tion compared to the older Reissert method of a reducti-subtilis, Klebsiella pneumonia, Sarcina lutea, Staphylococcus so ven cyclization to indoles (cf. RJ Sundberg, «The aureus and Mycobacterium avium. Accordingly, the Chemistry of Indoles », pages 176-183, publisher Academic, compounds relating to the disinfection of washed press, New York, 1970).

and stacked items contaminated with S. aureus, level 5: substitution of an unstable group. Use this level that comes into contact with food. must because of the incompatibility of X with the chemical Furthermore, the antibacterial compounds 55 of stage 8 can be carried out. In this case, X is, according to the invention, also more sensitive to bacteriostatic rinsing (alkali carboxylate in acetone, dimethyl for washed clothes, for impregnating paper and formamide, or alcohol) by an acetate or the konju fabrics, to suppress growth Base of a Q-Cs alkyl carboxylic acid replaced. Since a certain amount of hydrolysis is used in organisms in plate tests and in microbiological measurement cases that X stands for -OSÓ2CH3. As a rule, the antibacterial can take place, the reaction mixture is treated with acetic anhydride before the insulating compounds according to the invention in the form of (6).

can be used rather like the one from stage 6: the nitration can be carried out in a wide variety of ways

U.S. Patent 4,169,888 known antibiotic CC-1065. The known conditions, e.g. with nitric acid in acetic acid, areas of application are known to acetic anhydride, sulfuric acid, acetic acid / H20, alcohol-related, alcohol experts. 65 hol and nitroalkanes. The location selectivity of this

In the case of the process shown schematically in FIG. 2, the spectroscopic data obtained involve the following process steps; being supported.

Preferred methods are described: Step 7: The reduction of the nitro to the amino group my formula

655 724

corresponds to the chemistry described in connection with stage 4, but the base is omitted.

Stage 8: indole synthesis. This synthesis is essentially based on Gassman's indole chemistry (see P.G. Gassman and co-workers in "J. Am. Chem. Soc.", 96,5494, 5508,5512 (1974)). However, certain modifications, neither described nor suggested by Gassman, are required. The course of the chemical processes and some intermediates are shown in Fig. 3. The a-thiomethyl esters are known.

The method deviates from the known Gassman approach in that the chlorosulfonium complex A is used and this is allowed to react with the aniline (6). Gassman produces the chloramine of the aniline and allows it to react with the thioether to form oxindoles. Second, two different bases are used in the present process, whereas Gassman uses two equivalents of aniline and then one Base2. Although triethylamine, diisopropylethylamine, bis (1,8-dimethylamino) naphthalene and the like both act as Baset and Base2, the preferred basej bis (1,8-dimethylamine) naphthalene and the preferred Base2 is triethylamine. Different solvents such as chloroform, acetonitrile, tetrahydrofuran and preferably methylene chloride can be used. The temperature ranges from - 50 ° to 80 ° C. The reaction is allowed to proceed in an inert atmosphere. The cyclization of oxindole B is best catalyzed by an acid (cf. Gassman: 2N HCl, ether and / or ethyl acetate).

The final reduction to (9) (reductive elimination) can - as described by Gassman - be carried out with lithium aluminum hydride or better with diborane reagents. It is preferable to work with (CH3) 2S-BH3 in tetrahydrofuran at room temperature for 24 h.

Step 9: This elimination of a protective group (removal of R]) is described in detail for Rj = CH3 in preparation 8. Although a number of measures, including methyl ether cleavage, are known, only alkyl mercaptides in hexamethylphosphoric triamide (hexamethylphosphorus -3-amide) have proven to be effective under an inert atmosphere (95 ° -110 ° C) (SC Welch and ASCP Rao in «Tet Letters ”, 505 (1977) and TR Kelly, HM Dali and WG. Tsang in“ Tet. Letters ”, 3859 (1977)). Me2S-BBr3 in dichloroethane is also suitable (cf. P.G. Willard and C.B. Fryhle in "Tet. Letters", 3731 (1980)).

If R! stands for CH2Ph, standard hydrogenolysis conditions (H2, Pd / C) are sufficient to eliminate the protective group (cf. «Org. Reactions», 7,263 (1953)). If Ri stands for CH2SCH3, mercury (II) chloride in acetonitrile / H20 removes the ether (cf. R.A. Holton and R.G. Davis, "Tet. Letters", 533 (1977)). When Ri is CH20CH3, it gives a moderately strong acid, e.g. Acetic acid, phenol (10) (cf. "J. Med. Chem.", 9.1 (1966) or "Synthesis", 244 (1976)). In fact, this protective group may have been lost at level 6, but it can be reinstated under standard conditions before performing level 7. If Rj stands for -CH2OCH2CH2OCH3, the phenol can be prepared with ZnBr2 or TiCl4 in CH2C12 (cf. «Tet.-Letters», 809 [1976)). If Rj stands for -CH2CH = CH2, the ether can be freed from the protective group using various two-stage measures (Pd / C in alcohol - see «Ang. Chem. Int. Ed.», 15,558 (1976); Se02, CH3C02H in Dioxane - see "Tet. Letters", 2885 (1970); tert-BuOK, dimethyl sulfoxide and then H2S04 in acetone - see "J. Chem. Soc", 1903 (1965); RhCl (PPh3) 3, DABCO in alcohol, then pH2 - see “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-worker "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. s This reaction also takes place in the presence of bases such as tertiary amines, pyridine, tert-butoxide and the like, as well as weak aqueous bases such as bicarbonates and carbonates.

The following preparations and examples 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.

Preparation 1

15 Preparation of the 2-aryl-1,3-propanediol (3) from the aryl-diethylmalonate (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 time, 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 30 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 35 (3) (U-62.598) in 49% yield. as a 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 Ci0Hi3NO5: 227.0794 "o Found: 227.0780

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

C H N

45 calc .: 52.86 5.76 6.16

found: 53.40 5.77 5.99

Preparation 2

Preparation of the 2-aryl-1,3-propanediol bismesylate (4) from 50 den 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 in a nitrogen atmosphere at 0 ° to 5 ° C. with stirring. After stirring at 5 C for 30 minutes and stirring at 55 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), with a total of 6.65 g of bisme-sylate (4) (U-62.597) (after recrystallization from acetone) mp 122 in 86% yield: up to 123 C can be obtained.

Nuclear Magnetic Resonance Spectrum (Acet-d6): 7.7-7.2 (m, 3H), 4.62 65 (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 compound C12Hi7N09S2 gives the following values:

calculated: found:

C.

37.59 37.35

H

4.47 4.44

N

3.65 3.59

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) = 6.0 ID90 (| xg / ml) = 18

Preparation 3

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

1.91 g (0.005 mol) of compound (4) in 30 ml of tetrahydrofuran, 20 ml of ethyl acetate and 150 ml of absolute ethanol are mixed with 1.5 ml of triethylamine and 400 mg of Pt02, followed by 30 minutes under a pressure of H2 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 CH2CI2 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 (4.1 methanesulphonyl 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 min. The solution is then washed with in HCl, over The residue obtained is then chromatographed rapidly on 150 g of silica gel using 500 ml of 60% ethyl acetate / hexane and then 1000 ml of 80% ethyl acetate / hexane as eluent, giving 1 in a 78% yield 3 g of a whitish solid (after recrystallization from ethanol) mp from 122 ° to 123 ° C, namely the 6-methoxy-indoline-bismesylate (5) (U-62,586).

Nuclear Magnetic Resonance Spectrum (dimethylformamide-d7 :) 7.36 (d, 1H, J = 8.5 Hz), 7.00 (d, 1H, 3 = 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).

The elementary analysis of the connection CI2H17NS206 gives the following values:

C H N

calc .: 42.97 5.11 4.18

found: 42.87 5.27 4.29

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) = 4.8 ID90 (ng / ml) = 10

Preparation 4

Preparation of the 6-methoxyindoline acetate (6) from the 6-methoxyindoline 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, whereupon the heterogeneous solution obtained is heated to the reflux temperature for 24 hours under an N2 atmosphere. then cooled and finally concentrated in vacuo. The resulting residue is treated for 2 hours (stirring at room temperature (with 100 ml of acetic anhydride and then concentrated in vacuo. The evaporation residue is then taken up in CH2Cl2 / H2O. After separating the organic phase, it is dried over Na2SO4, filtered through charcoal and added Concentrated in a solidifying oil to give 11.6 g of 6-methoxyindoline acetate (6) (100% yield. If necessary, further purification by chromatography on silica gel using 60% ethyl acetate / hexane as eluent).

5 655 724

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).

5 The elementary analysis of the compound Q3H17NO5S gives the following values:

C H N

calc .: 52.16 5.76 4.68 found: 52.13 5.79 5.27 10 mass spectrum: calculated: 299.0827

Found: 299.0823

Preparation 5

Preparation of 5-nitro-6-methoxyindoline acetate (7) from 15 of 6-methoxyindoline acetate (6)

500 mg (1.67 mmol) of the 6-methoxyindoline acetate (6) in 20 ml of nitromethane are mixed with 90 (il 90% HN03), whereupon the reaction solution cooled to 0 ° to 5 ° C is stirred for 30 minutes and then within The solution is diluted with CH2C12 and aqueous sodium bicarbonate solution. After the organic phase has been separated off, it is dried over Na2S04 and concentrated. The resulting residue is poured onto 50 g of silica gel (eluent 60% 25% ethyl acetate / Hexane -> 100% ethyl acetate), giving, in 76% yield, 440 mg of yellow solid 5-nitro-6-methoxyindoline acetate (after recrystallization from ethanol) mp from 175 ° to 177 ° C. (U-62,696) .

Nuclear magnetic resonance spectrum (dimethylformamide-d7): 7.91 (s, 30 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 C13Hi6N207S gives the following values:

C H N

35 calc .: 45.34 4.68 8.14

found: 44.81 4.77 8.16

This compound is tested as part of a standard dilution series against L1210 mouse leukemia cells in a culture, with the following results:

ID50 (Hg / ml) => 50 ID90 (ng / ml) => 50

Preparation 6

Preparation of 5-amino-6-methoxyindoline acetate (8) from 45 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) is shaken under a 50 H2 pressure of 68.7 kPa. Then it is filtered and concentrated in vacuo. When concentrated, 3.0 g of product precipitated. This is filtered off. The mother liquors are rapidly chromatographed on 100 g of silica gel using ethyl acetate as the eluent to give 0.6 g of 55 product. The overall yield (3.6 g) corresponds to 88% of theory. The 5-amino-6-methoxyindoline acetate (8) obtained, after recrystallization from acetone / cyclohexane, has an mp of 134 ° to 135 ° C. (U-62,697).

Nuclear Magnetic Resonance Spectrum (CDC13): 7.02 (s, 1H), 6.65 (s, fio 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 Ci3H18N205S gives the following values:

C H N

it calculates: 49.67 5.77 8.91 found: 49.74 5.72 8.94

This connection is established as part of a standard

655 724

Thinning series against L12I0 mouse leukemia cells tested in a culture with the following results:

ID50 (ng / ml) => 50 ID90 (ng / ml) => 50

Preparation 7

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

14 ml of dry CH2C12 are added to 6.0 ml of a Cl2 / CH2C12 solution (20 μl. 1 Cl2 / ml CH2C12) under an N2 atmosphere at −75 ° C., and 370 ml (2.5 ml mmol) CH3 (CH3S) CHC02C2H5 (made from CH3 (Br) CHC02C2H5 and methyl mercaptide according to that of EH Wiek, T. Yamanishi, HC Wertheimer, YE Hoff, BF Proctor and SA Goldblith in "J. Agr. Food Chem.", 9.289 (1961) described methods) are added. After 5 min, 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 CH2C12 is added dropwise within 15 min. The red solution formed in this way is stirred at -75 ° C. for 2 h and then 350 [xl triethylamine in 650 l IL 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. The resulting residue is mixed with 5 ml of ethyl acetate, 25 ml of ether and 6 ml of 2N HCl, whereupon the whole is stirred vigorously for 2 hours. After the organic phase has been separated off, the aqueous phase is extracted with a 1: 1 mixture of ethyl acetate and Et20. 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 acid treatment can also be isolated by silica gel chromatography (50 g, 60% ethyl acetate / hexane to 90% ethyl acetate / hexane as eluent).

GS mass spectrum: m / e M + 414 (15%), 227 (100%) - 2 '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 -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 CH2C12. The CH2C12 solution can then be dried, concentrated and chromatographed on silica gel using 50% acetone / cyclohexane, recovering 40% starting material (anilinoindoline) and 20% deatylated 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 C14H18N204S gives the following values:

C H N

calc .: 54.17 5.84 9.03 5 found: 53.49 5.96 9.42

GC mass spectrum: of the O-acetate - m / e M + 352 (13%), 213 (100%) - 2'-1% SE-30, temperature: 150-1260: C (107min); single peak.

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

IDjo (ng / ml) => 4 ID90 (ng / ml => 4.

15 preparation 8

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 nl of butyl mercaptan under an N2 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, 25 and the solution is 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 with 3o tel: vanillin / phosphoric acid), the heating is stopped. The cooled solution is poured into In 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 product 40 4,5-pyrrolo-7-hydroxyindoline (10) are obtained (44% isolated yield, 69% based on 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, 45 3H).

The product obtained is treated overnight with 1.0 ml of acetic anhydride and 20 mg of sodium acetate and then taken up in CH2C12 / H20. The organic phase is then separated off, dried over Na2SO4 and concentrated, so nuclear magnetic resonance spectrum (CDC13): 7.8 (br. S, 1H), 7.16 (s, 1H), 6.97 (s, 1H), 4. 42.3.20 (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 mass spectrum: m / e M + 380 (25%), 199 (100%) - 2'-1% SE-30.

55 This compound is tested in a standard dilution series against LI210 mouse leukemia cells in a culture and the results are as follows:

ID50 (ng / ml) => 5 ID90 (ng / ml) => 5.

60 preparation 9

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

20 mg (65 (xMoles) of the alcohol substrate (10) in 1.0 ml pyridine are mixed with 8 p.1 (70 (iMoles) methanesulfonyl chloride in an ice bath with stirring and N2-Atmo-65 sphere. After 30 min another 2 nl of CH3S02C1 is added and after a total reaction time of 60 minutes, the whole is worked up with 2N HC1 / CH2C12 and the organic phase is removed

separated, dried over Na2S04 and concentrated. In thin layer chromatography, there is primarily a product with a low Rr 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 µm) provides 2 mg of a material with a higher Rr value (the nuclear magnetic resonance 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, 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 tested in a standard dilution series against L1210 mouse leukemia cells in a culture and the following results are obtained:

ID50 (ng / ml) = 1.0 ID90 (ng / ml) = 3.3.

example 1

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

If the reaction mixture is isolated as part of the measures for the preparation of 4,5-pyrrolo-7-hydroxyindoline bromide (preparation 9, stage 10) instead of isolating the bromide formed with the higher Rr value (0.64), and applied directly 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 Jcid = 9.7 Jd.e = 4.7 Je, f = 7.7 Je, g = 4.4 Jf, g = 4.4 JNH.a = 2.0 Yes, CH3 = <1.0

Mass spectrum: Silylation with BSTFA (dimethylformamide containing 1% TMS-Cl) gives m / e M + 386/388 (22.12% corresponding to the product + Me3SiCl).

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

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

7 655 724

Culture tested with the following results: ID50 (ng / ml) = 0.13 ID90 (ng / ml) = 0.42

Example 2a

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

25 mg (65 nmoles) of the substrate alcohol in 1.0 ml of dry acetonitrile are mixed with 33 mg (100 nmoles) of CBr4 and 26 mg (100 nmoles) of triphenylphosphine (Ph3P) under an 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 in this process is applied to three 20 cm × 20 cm silica gel plates (250 nm) 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-20 bromide (11) (U-62,694).

Nuclear Magnetic Resonance Spectrum (CDC13): 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.

25 Mass spectrum: calculated for Ci6H23N203 79BrSSi: 430.0382, found 430.0375

(Mono-TMS); m / e M + 430/432 (14%), 271 (90%), 147 (100%).

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) = 0.12 ID90 (ng / ml) = 0.37.

Example 2b

35 Other process for the preparation of 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 N2 atmosphere for 24 hours at room temperature. The reaction solution is then taken up in 10 ml of methylene chloride, washed with 0.1 HCl, dried over Na2SO4 and concentrated to the desired product. Further purification can be accomplished using silica gel chromatography.

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

Figure 1

655 724

Figure 2

8th

0r

(D

Cl

Ri Cr ^ / ^ NO

(4)

Level 4

ny

step 1

<r

level 3

R ^ O

4th

(5)

Level 5

RiO

Level 2

OCOCH-

Penalty 6

0C0CH-

4-

Level 7

OCOCH-

R10> S-AN ^ R3

(8th)

(7)

(8th)

Level s

■>

655 724

(9)

Level 9

StufelO

(IO)

N '

I.

R4 (12)

(12)

Definitions:

Ri = CH3 -, - CH2Ph, CH2 = CHCH2 -, - CH2SCH3, -CH2OCH3, -CH2OCH2CH2OCH3, -CH2CC13, -CH2CH2Si (R2) 3

R2 = alkyl (Ct-C5), phenyl, hydrogen R3 = O-alkyl (C, -C2), alkyl (Q-Q), phenyl, hydrogen (note: R3 '= O-alkyl only for compound (2))

r3 = hydrogen, alkyl (Ci-C5), phenyl R4 = S02R2, S02CH2C0Ph, OOCCH2Z,

X = 0S02R2, Cl, Br, I

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

655 724

10th

Figure 3

(Level 8)

CO2C2H5

R2-V _JÇ]

crs3

* SCH;

CH2C12 -75

V.

co2c2h5 l *]

+ s *

-cl

base

CH3) Cl solvent

1

nc e! -750

Cl CO2C2H5

to room temperature

Base-

0 SCH3

(9) ^ reduction Y /

OAc

R3 ^ acid

Figure 4

Preparation 1

ch3 °

co2c2h3

002 ^ 2 ^ 3 NOo

(2)

Level 2

-> Il I

CH3o '^^ v-Nq2 (3)

U-62.598

Preparation 2

ch3o

(3)

level 3

oso2ch3

SC ^ CHß

U-62.597

11

655

Preparation 3

0s02ch 3

ch3O

xxr oso2CH3

Level 4

->

CH3O

(4)

S02CK3

so.ch

(5) '^ J U-62.586

Preparation 4

C1I30

0s02ch3 level 5

(5)

n '

I.

so2ch3

ch-jo coch-

(6)

s02CH3

Preparation 5

CH3O

coch:

(6)

N

S02Me

Level 6

o2n

■> »

. CH3 °

COCH-

n so2ch3

(7) U-62,696

Preparation 6

ococh

(7)

SO2CH3

Level 7

->

OCOCH.

U-62,697

Preparation 7

H K 2

0

II

'occh ch o ^ a,

(8th)

3 level 8

- N

I.

so2ch3

ch3O #

(9) so2ch3

U-62.233

655724

12

Preparation 8

(io)

so2ch3

Level 9

15

Level 10

>

(10)

S02CH3

u-62, 370

(11)

s02ch3

U-62,694

Preparation 9

s02ch3

(10)

cb

-CC_y-

StufelO ^ /

OSO2CH2

ho ^ v r i so2ch3

(11) U-62.695

Example 2b

(11)

SO2CHß

Level 11

(12)

s ^ ch3

U-62.736

c

Claims (4)

655 724 2nd PATENT CLAIMS 1. Compounds of the formula (12) in which mean: R2 and R3, which may be the same or different, each represent hydrogen, alkyl having 1 to 5 carbon atoms or the phenyl radical and R4 is a radical of the formula S02R2 ', S02CH2C0-phenyl or OOCCH2Z, where R2' is Q-C5-alkyl or phenyl and Z is CH2I, CCI3, CH2S02R2, the phenyl or fluorenylmethyl radical. 2. Compound of the formula S02CH3 (10) wherein R2, R3 and R4 have the meaning given above, reacting with triphenylphosphine / tetrahalocarbon and then adding a base to form the desired compound. 4. The method according to claim 3 for the preparation of a compound of the formula (12a) (12a) S ° 2CH3 characterized in that a starting compound of the formula (10) is a compound of the formula 35 according to claim 1. 3. Process for the preparation of compounds of the general formula 40 45 so2ch3 starts. 50 (12)