HK1061243B - Bis-heterocyclic compounds with antitumour and chemosensitising activity - Google Patents

Description

Bis-heterocyclic compounds with antitumor and chemosensitive activity

The invention relates to a diheterocyclic compound with anti-tumor and chemical sensitivity activity and general formula (I),

wherein:

a, which may be identical to or different from A', is a mono-or bicyclic ring system having 5 to 7 atoms, containing on one or both rings one or more atoms selected from N, S, O;

a and A' may be bonded to C-X in a symmetrical or asymmetrical manner;

x, which may be the same or different from X', represents:

a) h, OH, X and X' together being ═ O, ═ CH- (CH)₂)_nCH₃N is an integer of 1 to 3;

b) saturated or unsaturated, linear or branched C₁-C₁₈Alkyl chains, possibly substituted with: 1) c₃-C₇A cycloalkyl group; 2) NR (nitrogen to noise ratio)₁R₂Wherein R is₁And R₂May be the same or different and may be H, straight or branched C₁-C₅An alkyl group; 3) an azide; 4) halogen; 5) one OR more ORs₃Group, wherein R₃Represents H, straight or branched C₁-C₅Acyl, or methanesulfonyl, toluenesulfonyl, trifluoromethanesulfonyl (triflyl) or, together with the ortho OH, R₃Represents an isopropylidene group; 6) phenyl, substituted by halogen, nitro, hydroxy, alkoxy or NR₁R₂Amino substitution, wherein R₁And R₂Have the above-mentioned meanings; 7) a free or esterified carboxyl group of a linear or branched alkyl group having 1 to 5 carbon atoms; 8) morpholine or methoxymorpholine;

c)C₃-C₇a cycloalkyl group;

d) phenyl or naphthyl, possibly substituted by halogen, nitro, hydroxy, alkoxy or NR₁R₂Amino substitution, wherein R₁And R₂Have the above-mentioned meanings;

e)C₅-C₇heterocyclic rings, possibly substituted by halogen, nitro, hydroxy, alkoxy or amino groups NR₁R₂Is substituted in which R₁And R₂Have the above-mentioned meanings;

f) saturated heterocyclic rings containing one or more hetero atoms selected from N, O, possibly substituted by OH, CN, O-C₁-C₄Alkyl substitution;

provided that when a ═ a1 ═ indole, X ═ H, X' is not heterocycle or phenyl or alkyl;

wherein R, which may be the same or different from R', represents H, hydroxy, said hydroxy being not esterified or being C₁-C₄Acyl esterification, methylenedioxy, nitro, amino, C which may be mono-or alkylated₁-C₄Mono-or di-C₁-C₄Alkanoyl, carboxyl, alkoxycarbonyl, halogen, C₁-C₄An alkyl group.

If A and A', which may be identical or different, contain a nitrogen atom, may be benzylated or alkylated C₁-C₆。

If A and A', which may be identical or different, contain a sulfur atom, one of the two rings may be oxidized.

The use of antineoplastic drugs in human therapy causes a number of toxic side effects, thus resulting in a reduction in the amount of drug administered and in some cases termination of therapy. A reduction in the amount of drug administered or termination of treatment results in an increase in primary tumor growth and/or the occurrence of tumor metastases. Obviously, the number of patients dying from cancer inevitably increases under these circumstances.

Another very important and strongly recognized aspect in tumor therapy is the onset of resistance to drugs used to treat tumor cells. Cells that are drug resistant are generally resistant to many other antineoplastic drugs, even if the drugs are chemically unrelated or act on different mechanisms of action. Such resistance is known as multidrug resistance (MDR) (Annu. Rev. Med.1991, 42: 277-286; Drugs of the Future 1997, 22: 653-660).

A large number of tumors, such as adrenocortical, colon, renal and jejunal tumors and liver cancers, show resistance from the start of treatment with antineoplastic Drugs (Barrows, L.R Antineoplastic and immunologic Drugs, 1995; 75; 1236-.

In other cases, tumor cells acquire resistance in a similar manner as bacteria resist antibiotics. Such resistance is based on genetic changes in the tumor cells that occur during treatment; these changes allow daughter cells to proliferate in the presence of the anti-tumor agent.

Nevertheless, the therapeutic effect of antitumor therapy is rendered ineffective regardless of the cause of drug resistance.

A number of studies suggest that the conventional form of drug resistance in human tumors arises from the presence of glycoprotein P (Ann. Med. Interna 1997, Mar; 14 (3): 145-53; Acta Scient Venez.2000, 51 (1): 45-52).

This glycoprotein acts as an energy-dependent membrane pump to expel the antitumor drug from the inside of the cell, thereby reducing the concentration of the intracellular drug.

Chemosensitizers are compounds which cause changes in tumor cells or in vivo and which facilitate increased therapeutic efficacy of the anti-tumor agent used.

Chemosensitive agents known to modulate glycoprotein P function include calcium channel blockers (verapamil), calmodulin inhibitors (trifluoperazine), indole alkaloids (reserpine), lysomotropic agents (chloroquine), steroids (progesterone), triphenyl alcohol analogs (tamoxifen), detergents (cremophor EL) and cyclic peptide antibiotics (cyclosporine) (Cancer, Principles & Practice of Oncology, 1993; fourth edition, j.b. lippincott co., philiadepia, Pa., 2661-2664).

Compounds having a diheterocyclic structure are known. For example, WO95/08540 describes bis- (amidinobenzoimidazolyl) alcans having antiviral activity.

WO99/00381 describes bisindole derivatives having antimetastatic activity.

US5,780,461 describes bis-indole derivatives having anti-tumour activity.

The bis-indoles described in the above-cited WO95/08540, WO99/00381 and US5,780,461 are compounds other than the present invention.

There remains a strong need in the medical field for therapeutic means for treating tumors, which can be used alone or in combination with other known anti-tumor drugs.

In this field, there is also a strong need for compounds having antitumor and/or chemosensitive activity, i.e. compounds which are active against drug-resistant tumors and/or which are capable of rendering active against tumors those antitumor drugs which are ineffective due to the onset of the above-mentioned resistance conditions.

It has now been found that the compounds of formula (I) are useful agents as antitumor compounds and chemosensitizers.

The chemosensitivity mechanism of the compounds described herein, i.e., their ability to cause resistance transformation, is not clear to the present invention. It is thought that the mechanism of interaction by tumor cells is involved, regardless of the antineoplastic drug against which the tumor cells have become resistant.

The experimental results obtained (reported below) show that the compounds of formula (I), whether used alone or in combination with other known bacteriostatic agents, are useful agents for the treatment of tumors.

Accordingly, the compounds of the general formula (I) are the subject of the invention described herein.

Another object of the invention described herein are the compounds of general formula (I) and their use in the medical field.

Another object of the invention described herein is a pharmaceutical composition containing a compound of general formula (I) as active ingredient and at least one pharmaceutically acceptable excipient and/or diluent.

Another subject of the invention described herein is the compounds of general formula (I) and the process for their preparation.

Another object of the invention described herein is a pharmaceutical composition comprising as active ingredient a compound of formula (I) for the treatment of neoplastic disorders, wherein the neoplasm is selected from the group consisting of sarcoma, carcinoma, carcinoid tumor, bone tumor, neuroendocrine tumor, lymphoid leukemia, acute promyelocytic leukemia, myelogenous leukemia, monocytic leukemia, megakaryocytic leukemia and Hodgkin's disease.

Another object of the invention described herein is the use of a pharmaceutical composition containing, as active ingredient, a compound of general formula (I) for the treatment of neoplastic pathologies in which the tumour has shown resistance to the antibiotics previously used for its treatment, in which said compound of formula (I) exerts a chemo-sensitizing effect on said resistant tumour.

Another object of the invention described herein is a pharmaceutical composition comprising a compound of general formula (I) as active ingredient, in combination with one or more known anti-tumor agents selected from the group consisting of alkylating agents, topoisomerase inhibitors, anti-tubulin agents, intercalating compounds, anti-metabolites, natural products, such as vinca alkaloids, epipodophyllotoxins, antibiotics, enzymes, tacrine (taxan) and cell differentiating compounds.

Among the cell differentiation antitumor agents, all-trans retinoic acid is preferable.

Another object of the invention described herein is the use of a compound of general formula (I) for the preparation of a medicament for the treatment of neoplastic pathologies.

Another object of the invention described herein is the use of a compound of general formula (I) for the preparation of a medicament for the treatment of neoplastic pathologies in which tumors have shown resistance to previous antitumoral drugs used for their treatment, wherein said compound of formula (I) exerts a chemo-sensitizing effect on said resistant tumors.

Another object of the invention described herein is the use of a compound of general formula (I) in combination with one or more known anti-tumor agents for the preparation of a medicament for the treatment of neoplastic pathologies.

Another object of the invention described herein is the use of a compound of general formula (I) in combination with all-trans retinoic acid for the manufacture of a medicament for the treatment of acute promyelocytic leukemia.

The following examples further illustrate the invention.

Example 1

The compound of example 1 was prepared using the following synthetic scheme 1, wherein steps a and B were performed according to the principles of Casiraghi g, et al, Tetrahedron, 1992, 48(27), 5619; casiraghi g, et al, j.org.chem., 1994, 59(7), 1801; cornia m. et al, j.org.chem., 1991, 56(7), 5466; cornia m. et al, Tetrahedron: the method described in Asymmetry, 1997, 8(17), 2905.

Scheme 1

Step A

Preparation of magnesium alkyl salts

To an anhydrous ether solution containing 2 moles of alkyl-MgBr (prepared from 2 moles of alkyl-Br and 2 moles of Mg in an anhydrous solvent such as diethyl ether or tetrahydrofuran) is added 2 moles of indole, or an indole derivative or one of its analogues, with stirring and at ambient temperature.

The solvent was removed under vacuum and the residue was used directly in the next step.

Step B

Preparation of bisindole derivatives

Dissolving the residue obtained in the previous step in an inert solvent, such as CH₂Cl₂Or CHCl₃Or CHCl₂CHCl₂In (1). Then 2 or more moles of a Lewis acid (e.g., SnCl) is added₄、TiCl₄、CeCl₃、TiCl(OPr)₃) And 1 mole of acetaldehyde. The reaction is carried out at a temperature ranging from-80 ℃ to +80 ℃ for 12-72 hours with stirring. At the end of this period, neutral H, which is slightly alkaline, is used₂O and NaHCO₃、Na₂CO₃The reaction was terminated.

The organic phase is collected with a small amount of H₂O washing, over anhydrous MgSO₄Dried, filtered and concentrated to dryness. The final product is isolated and purified using a conventional chromatography system.

Example 1/1

2, 3-5, 6-di-O-isopropylidene-1, 1-di-7-azaindol-3-yl-1-deoxy-D-mannitol Preparation of (ST1353)

To 890mg (4mmol) of 7-azaindolyl magnesium bromide prepared from 7-azaindole and ethylmagnesium bromide alone in anhydrous ether was added anhydrous CH₂Cl₂To the solution (50ml), SnCl was added₄In the absence of water CH₂Cl₂1M solution 4 in (1)ml and 260.3mg (1mmol) of 2, 3-5, 6-di-O-isopropylidene-di-alpha-D-mannofuranose.

The reaction mixture was heated to reflux under nitrogen for 24 hours and then purified by addition of 50ml of saturated NaHCO₃The aqueous solution is terminated. The resulting mixture was extracted with diethyl ether (3X 100ml) and a small amount of H was added₂Washing the precipitated extract with water and anhydrous MgSO₄Dried, filtered and concentrated to dryness.

The crude residue is in SiO₂Chromatography was performed on the column with a gradient of hexane: ethyl acetate from 9: 1 to 6: 4 as eluent. The pure product was isolated in 8% yield.

C₂₆H₃₀N₄O₅(478) (ii) a Melting point-decomposition at 210 ℃; rf is 0.17 (CH)₂Cl₂/CH₃COCH₃＝1∶1)；

¹H(CD₃OD) δ ═ 8.15-8.08(2H, dd, CH aromatic); 8.10-8.05(1H, d, CH aromatic); 7.95-7.9(1H, d, CH aromatic); 7.60(1H, s, CH aromatic); 7.08(1H, s, CH aromatic); 7.06-6.95(2H, m, CH aromatic); 5.05-5.35(2H, 2m, CH aliphatic); 4.42(1H, d, CH gem); 3.98-3.9(1H, m, CH aliphatic); 3.84-3.76(1H, m, CH aliphatic); 3.45-3.38(1H, m, CH aliphatic); 1.45 of; 1.35; 1.16; 0.78(12H, 4s, CH)₃)；

MS(IS)M^-＝477；

UA calculated C65.26, H6.32, N11.70; found C65.47, H6.35, N12.01.

Example 1/2

Preparation of 4, 4-bis (7-azaindol-3-yl) -1-butanol (ST1866)

The compound was prepared from 7-azaindole and 2-methoxytetrahydrofuran in the same manner as described in example 1/1.

C₁₈H₁₈N₄O (306.37); melting point at 221 ℃Decomposing; rf ═ 0.18 (hexane/AcOEt);

¹H(CD₃OD)δ＝8.10(2H，t，CH)；7.80(7.8d，2H，d，CH)；7.30(2H，s，CH₂)；6.90(2H，m，CH)；4.40(4.4t，1H，t，CH)；3.60(t，2H，t，CH₂)；2.30(2H，m，CH₂)；1.60(2H，m，CH₂)；

MS(IS)M^-＝305；

elemental analysis: calcd for C70.57, H5.92, N18.29; found C70.67, H5.6.00, N18.10.

Example 2

The compound of example 2 was prepared according to the synthesis of scheme 2 below.

Scheme 2

Preparation of bisindole derivatives

In a solution of ethanol and water (e.g., water and ethanol or methanol or isopropanol in varying proportions), 2 moles of indole and 1 to 8 moles of butyraldehyde are dissolved. Then adding inorganic acid (such as HCl), organic acid (such as CH)₃COOH), Lewis acids (particularly effective are triflates of lanthanides, Ln (OTf)₃And, is recoverable and reusable).

The solution is stirred at a temperature in the range of 20-80 ℃ for 12-72 hours. At the end of this period, the alcohol is extracted with an organic solvent. Small amount of H used in organic phase₂O or basic H₂Washing with O, and passing through anhydrous Na₂SO₄Dried, filtered and concentrated to dryness.

The final product is isolated and purified by usual chromatographic methods.

Examples2/1

Preparation of 1, 1-diindol-3-yl-butane (ST1385)

282mg (2.4mmol) of indole in 10ml of CH₃OH and 5ml of H₂O is in; 72mg (1mmol) of butyraldehyde and 240mg of dysprosium triflate- (CF) were added₃SO₃)₃Dy-(0.393mmol)。

The resulting solution was stirred at room temperature for 24 hours. At the end of this period, the methanol was removed under vacuum and the residue was extracted with ethyl acetate (3X 50 ml). The organic extracts were pooled, washed with a small amount of water and dried over anhydrous Na₂SO₄Dried, filtered and concentrated to dryness. Isolating the final product and purifying it in SiO₂Chromatography on column using hexane to ether as eluent, gradient from 9: 1 to 7: 3.

284mg of product are obtained with a yield of 84%.

C₂₀H₂₀N₂(288) (ii) a Melting point: 150 ℃ and 151 ℃; rf 0.3 (ether/hexane 1: 1);

¹H(CD₃CN) δ ═ 9.10(2H, width-s, NH); 7.60-7.50(4H, d, H4 '-H7'); 7.30(2H, Width-s, NH); 7.00-7.20(4H, t, CH aromatic); 4.60(1H, t, CH); 2.30(2H, m, CH)₂)；1.50(2H，m，CH₂)；1.10(3H，t，CH₃)；

MS(IS)M^-＝287；

Elemental analysis: calculated value (0.77%, H)₂O), C82.65, H7.02, N9.63; found C82.36, H7.17, N9.35.

Example 2/2

Preparation of 1, 1-bis (5-nitroindol-3-yl) butane (ST1429)

ST1429 was prepared from 5-nitroindole and butyraldehyde using the method described in example 2/1.

However, the reaction was heated at reflux for 48 hours.

The final product is in SiO₂Column chromatography using hexane to ether as eluent, and gradient from 6: 4 to 2: 8. The yield thereof was found to be 84%.

C₂₀H₁₈N₄O₄(378)；Rf＝0.4(Et₂O/hexane ═ 8: 2);

¹H(CDCl₃) δ 10.63(2H, width, NH); 8.0(2H, s, CH aromatic); 7.58(2H, d, CH aromatic); 7.18-6.86(4H, m, CH aromatic); 4.17(1H, t, CH); 1.94-1.72(2H, q, CH); 1.02-0.8(2H, m, CH)₂)；0.55(3H，t，CH₃)；

MS(IS)M^-＝377；

Elemental analysis: calcd for C63.48, H4.79, N14.80; found C63.90, H4.75, N14.34.

Example 2/3

Preparation of 1, 1-bis (5-fluoroindol-3-yl) butane (ST1438)

Prepared from 5-fluoroindole and butyraldehyde using the method described in example 2/2. But the reaction was heated at reflux for 24 hours. Isolating the final product and purifying it in SiO₂Column chromatography using hexane to ether as eluent, and gradient from 7: 3 to 4: 6. The yield thereof was found to be 45%.

C₂₀H₁₈F₂N₂(324) (ii) a Melting point: decomposition at > 200 ℃; rf 0.36 (hexane/AcOEt 7: 3);

¹H(CDCl₃) δ ═ 8.95(2H, width, NH); 7.35-7.02(6H, m, CH aromatic); 6.92-6.8(2H, m, CH aromatic); 4.33(1H, t, CH gem); 2.18(2H, q, CH)₂)；1.44-1.32(2H，m，CH₂)；0.96(3H，t，CH₃)；

MS(IS)M^-＝323；

Elemental analysis: calcd for C74.05, H5.59, N8.63, F11.71; found C73.78, H6.01, N8.29, F11.98.

Example 2/4

Preparation of 1, 1-bis (5-hydroxyindol-3-yl) butane (ST1393)

Prepared from 5-hydroxyindole and butyraldehyde using the method described in example 2/2. Isolating the final product and purifying it in SiO₂Column chromatography using hexane to ether as eluent, gradient 7: 3. The yield thereof was found to be 65%.

C₂₀H₂₀N₂O₂(320) (ii) a Melting point: decomposition at > 200 ℃; rf 0.3 (ether: hexane 2: 8);

¹h (dmso) δ 8.40(2H, s, NH); 7.10-7.00(2H, d, CH aromatic); 6.98-6.90(2H, m, CH aromatic); 6.80-6.70(2H, mCH aromatic); 6.60-6.40(2H, m, CH aromatic); 4.20-4.00(1H, t, CH); 2.10-2.0(2H, m, CH)₂)；1.40-1.20(2H，m，CH₂)；1.00-0.80(3H，t，CH₃)；

MS(IS)M^-＝319；

Elemental analysis: calcd for C74.97, H6.29, N8.74; found C74.57, H6.00, N8.41.

Example 2/5

Preparation of 1, 1-bis (5, 6-methylenedioxyindol-3-yl) butane (ST1478)

ST1478 was prepared from 5, 6-methylenedioxyindole and butyraldehyde using the method described in example 2/2. The final product is in SiO₂Column chromatography was performed using a 7: 3 gradient of hexane to ethyl acetate as eluent. The yield thereof was found to be 38%.

C₂₂H₂₀N₂O₄(376) (ii) a Melting point: at > 200 DEG CDecomposing the mixture; rf 0.58 (hexane/AcOEt 6: 4);

¹H(CD₃CN) δ 9.10-8.90(2H, width-s, NH); 7.20(1H, s, CH aromatic); 7.00(2H, d, CH aromatic); 6.80-6.90(2H, d, CH aromatic); 6.30(1H, s, CH); 5.90(4H, s, CH)₂)；4.30(1H，t，CH)；2.30(2H，m，CH₂)；1.50(2H，m，CH₃)；1.10(3H，t，H₄)；

MS(IS)M^-＝375；

Elemental analysis: calcd for C66.65, H6.10, N7.06; found C65.98, H5.90, N6.96.

Example 2/6

Preparation of 1, 1-di (indol-3-yl) cyclohexylmethane (ST1487)

ST1487 was prepared from indole and cyclohexanecarboxaldehyde using the method described in example 2/2.

But the reaction was heated at reflux for 48 hours.

The final product is in SiO₂Chromatographed on a column using 7: 3 hexane/ether as eluent. The yield thereof was found to be 75%.

C₂₃H₂₄N₂(328) (ii) a Melting point: decomposition at > 210 ℃; rf 0.20 (Hexane/Et)₂O＝6∶4)；

¹H(CDCl₃) δ 7.84(2H, width, NH); 7.63(2H, d, CH aromatic); 7.25(2H, d, CH aromatic); 7.18-6.90(4H, m, CH aromatic); 4.25(1H, d, CH); 2.35-2.15(1H, m, CH); 1.90-0.85(10H, mm, CH)₂)；

MS(IS)M^-＝327；

Elemental analysis: calcd for C84.10, H7.36, N8.52; found C83.81, H7.43, N8.30.

Examples2/7

Preparation of 1, 1-bis (7-azaindol-3-yl) butane (ST1436)

ST1436 was prepared from 7-azaindole and butyraldehyde using the method described in example 2/2. But the reaction was heated at reflux for 48 hours. The final product was isolated and purified by chromatography on a silica column using a gradient of CH from 9: 1 to 4: 6₂Cl₂∶CH₃COCH₃And (4) eluting. The yield thereof was found to be 15%.

C₁₈H₁₈N₄(291) (ii) a Melting point: decomposition at > 200 ℃; rf 0.26 (CH)₂Cl₂/CH₃COCH₃＝6∶4)；

¹H(DMSO-D₆) δ ═ 11.32(2H, width, NH); 8.12(2H, d, CH aromatic); 7.85(2H, d, CH aromatic); 7.40(2H, s, CH aromatic); 6.98-6.82(2H, m, CH aromatic); 4.35(1H, t, CH); 2.15(2H, q, CH)₂)；1.35-1，05(2H，m，CH₂)；0.88(3H，t，CH₃Aliphatic);

MS(IS)M^-＝290；

elemental analysis: calcd for C74.95, H6.24, N19.29; found C74.52, H6.38, N18.98.

Example 2/8

Preparation of 1, 3-dihydroxy-2, 2- (diindol-3-yl) propane (ST1368)

Compounds were prepared using the method described in example 2/4, substituting dihydroxyacetone for the aldehyde. The yield thereof was found to be 60%.

C₁₉H₁₈N₂O₂(306.3); melting point: decomposing at 223 ℃; (. alpha.) with a certain degree of freedom_D＝23.8°(0.4％CHCl₃) (ii) a Rf ═ 0.77 (diethyl ether);

¹H(CD₃OD) δ ═ 7.30-7.20(4H, m, CH aromatic); 770-7.60(2H, m, CH aromatic); 7.30-7.05(4H, m, CH aromatic); 7.04-6.96(2H, d, CH aromatic); 6.90-6.80(2H, m, CH); 6.62-6.58(2H, m, CH aromatic); 4.40(4H, s, CH)₂)；

MS(IS)M^-(-H₂O)＝287；

Elemental analysis: calcd for C74.48, H5.92, N9.14, found C74.08, H5.65, N8.97.

Example 2/9

Preparation of 1, 1-diindol-3-yl-tetradecane (ST1369)

The compound was prepared by reacting indole with tetradecaneacetaldehyde using the procedure described in example 2/4. The yield thereof was found to be 80%.

C₃₀H₄₀N₂(428.6); melting point: softening at 50 ℃; rf 0.28 (hexane/AcOEt 85: 15);

¹H(CDCl₃) δ 7.80(2H, s, NH); 7.60-7.44(2H, d, CH aromatic); 7.30-7.20(2H, d, CH aromatic); 7.10-7.00(2H, m, CH aromatic); 7.00-6.90(4H, m, CH aromatic); 4.42-3.938(1H, t, CH); 2.20-2.00(2H, m, CH)₂)；1.40-1.00(22H，m，CH₂)；0.90-0.70(3H，t，CH₃)；

MS(IS)M⁺(+Na)＝451；

Elemental analysis: calcd for C84.05, H9.40, N6.53; found C83.70, H9.77, N6.17.

Example 2/10

Preparation of 1, 1-diindol-3-yl-1-deoxy-D-glucose (ST1350)

The compound was prepared by reacting indole with glucose using the procedure described in example 2/4. The yield thereof was found to be 60%.

C₂₂H₂₄N₂O₅(396.45); melting point: decomposing at 60 deg.C; (. alpha.) with a certain degree of freedom_Dc＝+66.3°(0.5％CH₃OH)；Rf＝0.(CHCl₃/CH₃OH 7∶3)；

¹H(CD₃OD) δ ═ 7.70(1H, d, CH aromatic); 7.60(1H, d, CH aromatic); 7.40(1H, s, CH aromatic); 7.30-7.20(2H, m, CH aromatic); 7.10(1H, s, CH aromatic); 7.10-6.8(4H, m, CH aromatic); 5.0(1H, d, CH); 4.70-4.60(1H, dd, CH); 3.92-3.85(1H, m, CH); 3.803.60(3H, m, CH)₂OH and CH); 3.58-3.40(1H, m, CH);

MS(IS)M^-＝395；

elemental analysis: calculated value (2.2% H)₂O) C65.18, H6.20, N6.87; found C65.10, H6.23, N6.40.

Example 2/11

Preparation of (R, S) -1, 1- (indol-2-yl, indol-3-yl) butane (ST1625)

282mg of indole (2.4mmol) dissolved in 10ml of CH₃OH and 5ml of 1N HCl, then 72mg (1mmol) of butyraldehyde are added.

The resulting solution was heated at 80 ℃ for 16 hours. At the end of this period, the methanol was removed under vacuum and the residue was washed with CH₂Cl₂And (4) extracting. The organic extracts were pooled, washed with water and dried over anhydrous Na₂SO₄Dried, filtered and concentrated to dryness. Isolation of the end product and separation in SiO₂Chromatography on column using hexane to ether as eluent, gradient from 9: 1 to 7: 3. The yield thereof was found to be 62%.

C₂₀H₂₀N₂(288) (ii) a Melting point: decomposition at > 250 ℃; rf 0.25 (ether/hexane 1: 1);

¹H(CDCl₃) δ ═ 8.10(1H, width-s, NH); 7.80(1H, Width-s, NH); 7.60-7.50(4H, d, CH aromatic); 7.30(1H, Width-s, NH);7.20-7.00(4H, t, CH aromatic); 6.50(1H, Width-s, CH); 4.60(1H, t, CH); 2.30(2H, m, CH)₂)；1.50(2H，m，CH₂)；1.10(3H，t，CH₃)；

MS(IS)M^-＝287；

Elemental analysis: calcd for C83.29, H6.99, N9.71; found C82.77, H6.90, N9.41.

Example 2/12

Preparation of (R, S) -5-hydroxy-1, 1- (indol-2-yl, indol-3-yl) pentane (ST1345)

The compound was prepared by reacting indole with 5-hydroxypentanal using the procedure described in example 2/11. The yield thereof was found to be 40%.

C₂₁H₂₂N₂O (31.42); melting point: decomposing at 200 deg.C; rf 0.5 (hexane/i-proh 97.5: 2.5);

¹H(CDCl₃) δ ═ 8.00(1H, s, NH); 7.8(1H, s, NH); 7.54-7.48(1H, m, CH aromatic); 7.40-7.36(1H, d, CH aromatic); 7.30-7.20(1H, d, CH aromatic); 7.1-6.86(6H, m, CH aromatic); 6.40(1H, s, CH aromatic); 4.30(1H, t, CH); 3.5(2H, t, CH)₂)；2.20-2.00(2H，m，CH₂)；1.60-1.40(2H，m，CH₂)；1.40-1.20(3H，m，CH₂eOH)；

MS(IS)M^-＝317；

Elemental analysis: calcd for C79.21, H6.96, N8.79; found C78.64; h7.15, N8.45.

Example 2/13

R, S-5-hydroxy-1, 1- (5, 6-methylenedioxyindol-2-yl, 5, 6-methylenedioxyindole) Preparation of indol-3-yl-pentane (ST1423)

The compound was prepared from the 5, 6-methylenedioxy derivative of indole using the procedure described in example 2/11. The yield thereof was found to be 20%.

C₂₃H₂₂N₂O₅(406) (ii) a Melting point: decomposing at 220 deg.C; rf 0.63 (hexane/i-PrOH 97.5: 2.5);

¹H(CD₃CN) δ 9.1-8.90(2H, width-s, NH); 7.20(1H, s, CH aromatic); 7.00(2H, d, CH aromatic); 6.80-6.90(2H, d, CH aromatic); 6.30(1H, s, CH aromatic); 5.90(4H, s, CH)₂)；4.30(1H，t，H1)；3.50(2H，m，H5)；2.20(2H，m，CH₂)；1.40-1.60(2H，m，CH₂)；

MS(IS)M⁺＝407；

Elemental analysis: calcd for C67.98, H5.42, N6.89; found C67.90; h5.50, N6.82.

Example 2/14

[ bis (2-pyrrolyl) phenyl group]Preparation of methane (ST1430)

Compounds were prepared by reacting pyrrole derivatives with benzaldehyde using the procedure described in example 2/4. The yield thereof was found to be 40%.

C₁₅H₁₄N₂(222) (ii) a Rf 0.25 (hexane/AcOEt 8: 2); melting point: decomposing at 200 deg.C;

¹H(CDCl₃) δ ═ 7.90(2H, width-s, NH); 7.30(5H, m, CH aromatic); 6.70(2H, mCH aromatic); 6.20(2H, s CH aromatic); 5.90(2H, s, CH aromatic); 5.50(IH, s, CH);

MS(IS)M^-＝221；

elemental analysis: calcd for C67.56, H6.30, N12.61; found C67.90; h6.50, N12.45.

Example 2/15

Preparation of bis (5-ethoxycarbonylpyrrol-2-yl) phenylmethane (ST1431)

Compounds were prepared by reacting pyrrole derivatives with benzaldehyde using the procedure described in example 2/14. The yield thereof was found to be 30%.

C₂₁H₂₂N₂O₄(366) (ii) a Melting point: decomposing at 200 deg.C; rf 0.25 (hexane/AcOEt 7: 3);

¹H(CDCl₃) δ ═ 9.40(2H, width-s, NH); 7.30(5H, m, CH aromatic); 5.90-6.80(4H, t, CH aromatic); 5.50(1H, s, CH); 4.20(4H, q, CH)₂)；1.30(6H，t，CH₃)；

MS(IS)M^-＝365；

Elemental analysis: calcd for C57.37, H6.01, N7.65; found C57.00, H6.50, N7.52.

Example 2/16

Preparation of 1, 1-bis (2-pyrrolyl) alkane (ST1432)

A compound is prepared by reacting a pyrrole derivative with butyraldehyde using the method described in example 2/4. The yield thereof was found to be 45%.

C₁₂H₁₆N₂(188) (ii) a Melting point: decomposing at 200 deg.C; rf 0.32 (Hexane/AcOEt/NEt)₃＝80∶19∶1)；

¹H(CDCl₃) δ ═ 7.40(2H, width-s, NH); 6.60(2H, s, CH aromatic); 6.20(2H, s, CH aromatic); 6.10(2H, s, CH aromatic); 4.00(1H, t, CH); 2.00(4H, q, CH)₂)；1.30(3H，m，CH₃)；

MS(IS)M^-＝187；

Elemental analysis: calcd for C76.59, H8.51, N14.89; found C76.44, H8.50, N14.38.

Example 2/17

Preparation of 4, 4-bis (1H-indolyl) butanoic acid (ST1961)

282mg of indole (2.4mmol) dissolved in 10ml of CH₃OH and 5ml of H₂To O, 102mg of hemisuccinaldehyde (1mmol) and 240mg of dysprosium trifluoromethanesulfonate- (CF) were then added₃SO₃)₃Dy- (0.393 mmol). The resulting solution was stirred at 35 ℃ for 24 hours. At the end of this period, methanol was removed under vacuum and the residue was extracted with ethyl acetate (3X 50 ml). The organic extracts were pooled, washed with a small amount of water and dried over anhydrous Na₂SO₄Dried, filtered and concentrated to dryness. Isolation of the end product and separation in SiO₂Column chromatography was performed using hexane to isopropanol as eluent and a gradient from 9: 1 to 8: 2.

108mg of product are obtained in 34% yield.

C₂₀H₁₈N₂O₂(318.37); melting point: decomposition at > 200 ℃; rf 0.31 (hexane/isopropanol 8: 2);

¹H(DMSO-D₆) δ ═ 9.18(2H, width-s, NH); 7.55(2H, d, CH aromatic); 7.30(2H, t, CH aromatic); 7.14-6.82(6H, m, CH aromatic); 5.40(1H, Width-s, COOH); 4.45(1H, t, CH); 2.58-2.39(2H, m, CH)₂)；2.39-2.25(2H，m，CH₂)；

MS(IS)M^-＝317；

Elemental analysis: calculated value C75.45; h5.70, N8.80; found C75.12, H5.49, N8.56.

Example 2/18

Preparation of 4-hydroxy-1, 1-bis (5, 6-methylenedioxyindol-3-yl) butane (ST1730)

The compound was prepared from 5, 6-methylenedioxyindole and 2-methoxytetrahydrofuran using the procedure described in example 2/4. The yield thereof was found to be 35%.

C₂₂H₂₀N₂O₅(392.41); melting point: decomposition at > 240 ℃; rf 0.44 (hexane/iPrOH 75/25);

¹H(CD₃CN) δ 9.00(2H, wide, NH); 7.20(2H, s, CH aromatic); 6.90(4H, m, CH aromatic); 6.00(4H, m, CH)₂)；4.30(1H，t，CH)；3.60(2H，q，CH₂)；2.30(2H，m，CH₂)；1.60(2H，m，CH₂)；

MS(IS)M⁺＝393；

Elemental analysis: calcd for C67.34, H5.14, N7.14; found C67.30, H5.20, N7.100.

Example 2/19

(R, S) -4-hydroxy-1, 1-bis (5, 6-methylenedioxyindol-2-yl, 5, 6-methylenedioxy Preparation of the isoindol-3-yl) butane (ST1731)

The compound was prepared from indole 5, 6-methylenedioxyindole using the procedure described in example 2/11. The yield thereof was found to be 15%.

C₂₂H₂₀N₂O₅(392.41); melting point: decomposing at 205 ℃; rf 0.41 (hexane/iPrOH 75/25);

¹H(CD₃CN) δ 9.10(1H, wide, NH); 8.90(1H, Width, NH); 7.20(1H, s, CH aromatic); 7.00(2H, s, CH aromatic); 6.90-6.80(2H, m, CH-aromatic); 6.40(1H, s, CH aromatic); 6.00(4H, m, CH)₂)；4.30(1H，t，CH)；3.70(2H，m，CH₂)；2.20(2H，m，CH₂)；1.60(2H，m，CH₂)；

MS(IS)M^-＝391；

Elemental analysis: calcd for C67.34, H5.14, N7.14; found C67.14, H5.36, N7.10.

Example 2/20

Preparation of 1, 1-bis (indol-3-yl) -4-hydroxybutane (ST1707)

The compound was prepared from indole and 2-methoxytetrahydrofuran using the procedure described in example 2/4.

C₂₀H₂₀N₂O (304.39); melting point: 110-115 ℃; rf 0.26 (hexane/AcOEt 1/1);

¹H(CD₃CN) δ 10.70(2H, width, NH); 7.50(2H, d, CH aromatic); 7.20(4H, m, CH aromatic); 6.90(2H, m, CH aromatic); 6.80(2H, m, CH aromatic); 4.30(1H, t, CH); 3.40(2H, m, CH)₂)；2.20(2H，m，CH₂)；1.40(2H，m，CH₂)；

MS(IS)M^-＝303；

Elemental analysis: calcd for C78.92, H6.62, N9.20; found C78.88, H6.70, N9.10.

Example 2/21

Preparation of 4-hydroxy-1, 1-bis (5, 6-methylenedioxyindol-3-yl) butane (ST1750)

The compound was isolated from the reaction mixture of example 2/20.

C₂₂H₂₀N₂O₅(392.41); melting point: decomposing at 205 ℃; rf 0.60 (hexane/iPrOH 75/25);

¹H(CD₃CN) δ 9.10(2H, width, NH); 7.00-6.90(4H, m, CH aromatic); 6.40(2H, s, CH aromatic); 6.00(4H, s, CH)₂)；4.30(1H，t，CH)；3.60(2H q，CH₂)；2.30(2H，m，CH₂)；1.60(2H，m，CH₂)；

MS(IS)M^-＝391；

Elemental analysis: calcd for C67.34, H5.14, N7.14; found C67.26, H5.35, N7.10.

Example 2/22

Preparation of 1, 1-bis (5-hydroxyindol-3-yl) -5-hydroxypentane

The compound was prepared from 5-hydroxyindole as in example 2/4.

C₂₁H₂₂N₂O₃(350.42); melting point: decomposition at > 200 ℃; rf ═ 0.58 (AcOEt);

¹H(CD₃OD) δ ═ 7.20 to 7.00(2H, d, CH aromatic); 7.00-6.90(2H, m, CH aromatic); 6.90-680(2H, m, CH aromatic); 6.70-6.50(2H, m, CH aromatic); 4.30-4.20(1H, t, CH); 3.60-3.40(2H, t, CH)₂)；2.302.05(2H，m，CH₂)；1.70-1.50(2H，m，CH₂)；1.50-1.40(2H，m，CH₂)；

MS(IS)M^-＝349；

Elemental analysis: calcd for C71.97, H6.32, 7.99; found C71.00, H6.46, N7.50.

Example 3

The compound of example 3 was prepared using the synthesis of scheme 3 below, wherein step a was performed according to dondondononi g. et al, Tetrahedron lett, 1992, 33(29), 4221; dondondoni g, et al, synth, commun, 1994, 24(18), 2537.

Scheme 3

Step A

Preparation of nitrone derivatives

Step B

Preparation of bisindole derivatives

The nitrone derivative of step A is dissolved in an anhydrous solvent (e.g. CH) together with a stoichiometric amount or an excess of indole₂Cl₂AcOEt, THF, dioxane). To the solution thus obtained is added an organic or inorganic acid (for example HCl, acetic acid, trifluoroacetic acid, SnCl) at room temperature₄Trimethylsilyl chloride). The reaction proceeds with disappearance of the indole or indole derivative, and an organic solvent is added and shaken vigorously with an aqueous basic solution to remove the acidity of the solution. After drying with the dehydrating agent, the organic solution was concentrated. The solid residue is chromatographed on a silica gel column to isolate and purify the bisindole derivative.

Example 3/1

Process for preparing (2S) -2, 3-O-isopropylidene-2, 3-dihydroxy-1, 1-diindol-3-yl propane (ST1330) Preparation of

2, 3-O-isopropylideneglyceraldehyde (1.8g, 14mmol), freshly prepared from the diisopropylidene derivative of D-mannitol, and N-benzylhydroxylamine (1.23g, 10mmol) were dissolved in 10ml of CH in a flask₂Cl₂In (1). Suspending 10g of Na in the solution₂SO₄And stirred at room temperature for 16 hours. At the end of the reaction, the solution was filtered and concentrated until a solid was obtained, then crystallized from hexane. The nitrone derivative was obtained as a white solid (2.1g, yield 89%).

A portion of this solid (1.2g, 5.11mmol) was placed in a flask and dissolved in anhydrous CH₂Cl₂(30ml) and indole (1.5g, 12.8mmol) inTo the resulting solution was added dropwise 20ml of CH at room temperature₂Cl₂。

After stirring at room temperature for 16 hours, the reaction mixture was worked up: by CH₂Cl₂(70ml) it was dissolved and reacted with saturated NaHCO₃The solutions were shaken vigorously together. After separation in the funnel, the organic phase was concentrated to dryness. The resulting solid was subjected to silica gel column chromatography (diethyl ether: hexane, 1: 1) to give (2S) -2, 3-O-isopropylidene-2, 3-dihydroxy-1, 1-diindol-3-ylpropane (1.59g, yield 90%).

C₂₂H₂₂N₂O₂(346.4); melting point: decomposing at the temperature of 100-110 ℃; (. alpha.) with a certain degree of freedom_D＝18.3°(0.5％CHCl₃) (ii) a Rf 0.5 (ether/hexane 1: 1);

¹H(CDCl₃) δ ═ 8.00(2H, s, NH); 7.60-7.44(2H, dd, CH aromatic); 7.26-7.24(2H, dd, CH aromatic); 7.20-6.86(6H, m, CH aromatic); 5.00-4.84(1H, mCH); 4.64(1H, d, CH); 4.00-3.80(2H, dd, CH); 1.40(6H, s, CH)₃)；

MS(IS)M^-＝345；

Elemental analysis: calculated value (4% H)₂O, 2.3% AcOEt) C74.34, H6.50, N7.70; found C74.66, H6.84, N7.26.

Example 4

The compound of example 4 was prepared using the synthesis of scheme 4 below.

Scheme 4

Preparation of dibenzoimidazoles and dibenzothiazoles

In a flask equipped with a good stirrer, a dehydrating agent (e.g., polyphosphoric acid or an ester thereof, thionyl chloride, phosphoric anhydride) (1.5 to at most 20mol), a malonic acid ester derivative (1 to 2mol), and 1, 2-phenylenediamine or a derivative thereof (1 to 4mol) are added to give a dibenzoimidazole, or 2-thioaniline or a derivative thereof is added to give a dibenzothiazole. After all additions have been completed, the mixture is heated very slowly to 160-200 ℃ in an anhydrous environment and under deoxygenated atmosphere and held at this temperature for 20-30 hours. At the end of this period, an aqueous basic solution and a water-immiscible organic solvent (e.g., dichloromethane, ethyl acetate, diethyl ether, tetrahydrofuran) are added to the cooled mixture. After dissolution was complete, the organic phase was separated from the aqueous phase and concentrated to give a semi-solid crude reaction product.

All final products were isolated and purified by direct phase chromatography on silica gel column.

Example 4/1

Preparation of phenyldibenzothiazol-2-ylmethane (ST1433)

6g of PPA (polyphosphoric acid), 2.54ml of 2-aminothiophenol (industrial 90%) (23mmol) and 2.60ml (11mmol) of diethyl phenylmalonate were added to the flask under an anhydrous and argon atmosphere. The mixture was slowly heated to 140 ℃ and 145 ℃ and then held at this temperature for about 16 hours or until the amine disappeared.

The reaction was then carried out by adding ethyl acetate (300ml) and saturated sodium bicarbonate solution (200 ml). The organic phase was separated from the aqueous phase and concentrated in vacuo until all solvent was completely removed. The solid obtained is purified on a silica gel column (mobile phase: hexane: dioxane, gradient up to 8: 2) to yield 500mg of the final product (yield 12%).

C₂₁H₁₄N₂S₂(358.5); melting point: 178 ℃; rf 0.41 (hexane/dioxane 8: 2);

¹h (dmso) δ 7.80-7.70(3H, m, CH aromatic); 7.60-7.40(5H, m, CH aromatic); 7.40-7.20(3H, m, CH aromatic); 7.20-7.00(3H, m, CH aromatic, CH).

MS(IS)M^-(-H₂O)＝359；

Elemental analysis: calcd for C70.36, H3.93, N7.81; found C70.10, H3.85, N7.49.

Example 4/2

Preparation of 1, 1-bis (benzimidazol-2-yl) butane (ST1435)

6g of PPA was placed in a flask equipped with a stirrer under an anhydrous argon atmosphere with 1,165g (11mmol) of 1, 2-phenylenediamine and 1,153ml (5.5mmol) of diethyl propylmalonate. After the addition was complete, the reaction mixture was slowly heated to 150 ℃ and 155 ℃ and then held at this temperature for about 16 hours. At the end of this period, after cooling, a saturated sodium bicarbonate solution (100ml) and ethyl acetate (150ml) were added to the reaction mixture. The crude product is purified on a flash column (mobile phase: hexane: THF 8: 2) to give the desired product. The yield thereof was found to be 10%.

C₁₈H₁₈N₄(290.3); melting point: decomposing at 260 ℃; rf 0.38(AcOEt/MeOH 95: 0.5);

¹H(DMSO+D₂o) δ ═ 7.50 to 7.40(4H, m, CH aromatic); 7.207.00(4H, m, CH aromatic); 4.60-4.50(1H, t, CH); 2-40-2.20(2H, m, CH)₂)；1.40-1.20(2H，m，CH₂)；1.00-0.90(3H，t，CH₃)；

MS(IS)M^-＝289；

Elemental analysis: calcd for C74.45, H6.24, N19.29; found C74.21, H5.98, N18.90.

Example 5

The compound of example 5 was prepared using the synthesis in scheme 5 below:

scheme 5

Preparation of N-oxo-dibenzoimidazole and S-oxo-dibenzothiazole derivatives

In a flask equipped with a good stirrer are added a dehydrating agent (e.g., polyphosphoric acid or its ester, thionyl chloride, phosphoric anhydride) (1.5 to at most 20mol), a malonic acid ester derivative (1 to 2mol) and 1, 2-phenylenediamine or its derivative (1 to 4mol) to give a dibenzoimidazole, or 2-thioaniline or its derivative to give a dibenzothiazole. After these additions were completed, the mixture was heated very slowly to 160-200 ℃ and held at this temperature for 20-30 hours.

At the end of this period, an aqueous basic solution and a water-immiscible organic solvent (e.g., dichloromethane, ethyl acetate, diethyl ether, tetrahydrofuran) are added to the cooled mixture. After dissolution was complete, the organic phase was separated from the aqueous phase and concentrated to give a semi-solid crude reaction product.

All final products were isolated and purified by direct phase chromatography on silica gel column.

Example 5/1

Preparation of (benzothiazol-2-yl, benzothiazol-3-oxido-2-yl) phenylmethane (ST1424) Prepare for

6g of PPA (polyphosphoric acid), 2.54ml of 2-aminothiophenol (industrial 90%) (23mmol) and 2.60ml (11mmol) of diethyl phenylmalonate were charged into a flask equipped with a good stirrer. The mixture was slowly heated to 140 ℃ and 160 ℃ and then held at this temperature for about 16 hours.

At the end of this period, the reaction was carried out by adding ethyl acetate (300ml) and adding saturated sodium bicarbonate solution (200ml) with vigorous shaking. The organic phase was separated from the aqueous phase and concentrated in vacuo. The solid obtained is purified for the first time on a silica gel column (hexane: dioxane 8: 2) and then for the second time on a reverse phase preparative HPLC column (Hibar column, 250X 25mm, RP-18, flow: 10ml/min, RT, 28min, UV detector: 360 nm). (benzothiazol-2-yl, benzothiazol-3-oxide-2-yl) phenylmethane is obtained in a yield of 15%.

C₂₁H₁₄N₂OS₂(374.5); melting point: 152 ℃ C; rf 0.33 (hexane/dioxane 8: 2);

¹h (dmso) δ ═ 8.5(1H, s, NH); 8.14-8.08(2H, d, CH aromatic); 8.04-7.98(2H, d, CH aromatic); 7.80-7.68(2H, d, CH aromatic); 7.60-7.40(7H, m, CH aromatic);

MS(IS)M⁺(-H₂O)＝357；

elemental analysis: calcd for C67.38, H3.70, N7.47; found C67.39, H3.80, N7.39.

Example 6

The compound of example 6 was prepared using the synthesis in scheme 6 below, wherein step a was performed according to the method described in Diez-Barra e, et al, synth. And step B was performed according to the method described in h.latta d.j., Tetrahedron lett, 1990, 31(41), 5833.

Scheme 6

Step A

Preparation of N-alkyl derivatives of imidazole

Step B

Preparation of N-alkyl-2-alkanoyl or N-alkyl-2-aroyl derivatives of N-alkylimidazoles Prepare for

Step C

Preparation of bisimidazole derivatives

1 mole of N-alkylimidazole (prepared according to the procedure described in Diez-Barra E. et al, Synth. Commun, 1993, 23(13), 1783) was dissolved in an anhydrous organic solvent (e.g. hexane, diethyl ether, dioxane or tetrahydrofuran) in a flask equipped with a stirrer under an anhydrous environment and an inert atmosphere. To this solution (from-10 to-70 ℃) is added a solution or suspension of a molar or slight excess of a basic agent (for example butyllithium, sodium hydride, lithium dialkylamine, sodium amide, tert-butyllithium) at low temperature. After the end of the addition, after allowing the mixture to react further for a certain time (from 10 minutes to 1 hour), a solution of the ketone derivative of N-alkylimidazole is added dropwise in stoichiometric or excess (1 to 2mmol) with respect to the N-alkylimidazole (prepared according to the method described in h.latta d.j., Tetrahedron lett, 1990, 31(41), 5833).

After an additional 30 minutes at the initial temperature, the reaction mixture was warmed to room temperature (25-30 ℃) and stirred until the N-alkylimidazole completely disappeared. To the reaction mixture were added an organic solvent and a saturated aqueous solution of sodium chloride. After separation of the organic solvent from the aqueous phase, the latter is dried over sodium sulfate and concentrated. The solid obtained is chromatographed on silica gel or crystallized to give the desired product.

Example 6/1

Preparation of phenyl, hydroxy, bis (N, N-dibenzylimidazol-2-yl) methane (ST1440)

10ml of anhydrous TH0.8g (5mmol) of N-benzylimidazole in F (prepared as described in Diez-Barra E. et al, Synth. Commun., 1993, 23(13), 1783) was cooled to-70 ℃. When the temperature was reached, 3.5ml (5.6mmol) of a 1.6M solution of n-butyllithium in hexane (5.6mmol) were added. 1.47g (5.6mmol) of N-benzyl-2-benzoylimidazole (prepared as described in H.Lasta D.J., Tetrahedron Lett., 1990, 31(41), 5833) dissolved beforehand in THF (1.5ml) are subsequently added dropwise. After the addition was complete, the reaction mixture was warmed to 25 ℃ and held under stirring for 16 hours. At the end of this period, the solution was treated with 200ml of CH₂Cl₂Diluted and shaken vigorously with a saturated solution of NaCl (100 ml). Separating organic phase from aqueous phase with Na₂SO₄Drying and concentration gave a crude product which was purified by crystallization from ethyl acetate to give phenyl, hydroxy, bis (N, N-dibenzylimidazol-2-yl) methane in 71.4% yield.

C₂₇H₂₄N₄O (420.51); melting point: decomposing at 160 ℃; rf & lt 0.72 (AcOEt/NH)₃98∶0.2)；

¹H(CDCl₃) δ -7.30-7.10 (12H, m, CH aromatic, OH); 7.00(2H, s, CH imide); 6.98-6.82(4H, m, CH aromatic); 6.80(2H, s, CH imide); 5.408(4H, d, CH)₂)；

MS(IS)M⁺＝421；

Elemental analysis: calcd for C77.11, H5.75, N13.32; found C77.07, H5.44, N13.45.

Example 7

The compound of example 7 was prepared using the synthesis in scheme 7 below, wherein step a was as follows, Cornia m. et al, Tetrahedron: asymmetry 1997, 8(17), 2905; the method described in Casiraghi G, et al, Tetrahedron1992, 48(27), 5619, and the method described in example 1, step A.

Scheme 7

Step A

Preparation of indole salts and derivatives thereof

Step B

Condensation reaction for preparing bis-indole and bis-indole derivatives

The salt (1 mole) in step a is dissolved in an anhydrous inert organic solvent (e.g., hydrochloride solvent, dioxane, THF, diethyl ether) and poured into phosgene (with an organic solvent, such as CH)₂Cl₂Toluene, THF, diethyl ether) in cold (from-15 to-50 ℃ C.). After 1 hour, the temperature is raised (0-50 ℃) and the solution is held at this temperature for 10-24 hours. At the end of this period, the reaction mixture was filtered and the liquid was concentrated. The solid thus obtained was purified on a silica gel column to obtain a condensation product.

Example 7/1

Preparation of 1, 1-diindol-3-yl-oxomethane (ST1463)

Magnesium salt of indole (2.43g, 11mmol) (obtained as described in Casiraghi G. et al Tetrahedron1992, 48(27), 5619) was dissolved in 12ml CH₂Cl₂Then phosgene in toluene (6.2ml) and CH were poured in₂Cl₂(10ml) in a 20% solution. The reaction mixture was left at +5 ℃ for 16 hours. The organic phase was separated from the solid by filtration and concentrated to dryness. The resulting solid was purified over a silica gel column using ethyl acetate: hexane 6: 4 as the mobile phase to give diindolyloxomethane as a yellow solid. The yield thereof was found to be 90%.

C₁₇H₁₂N₂O (260.29); melting point: decomposing at 300 ℃; rf 0.54 (hexane/ethyl acetate 4: 6);

¹h (DMSO-D6) δ 8.36-8.24(2H, D, CH aromatic); 8.20(2H, s, CH indole); 7.90(2H, Width, NH); 7.60-7.50(2H, d, CH aromatic); 7.30-7.10(4H, m, CH aromatic);

MS(IS)M^-＝259；

elemental analysis: calcd for C77.84, H5.38, N10.68; found C77.79, H5.02, N10.62.

Example 8

The compound of example 8 was prepared according to the procedure described in Diez-Barra e, et al, synth. commu., 1993, 23(13), 1783, using the synthesis in scheme 8 below.

Scheme 8

Example 8/1

Preparation of bis (N-benzylindol-3-yl) oxomethane (ST1473)

The compounds were prepared according to the methods described in Diez-Barra e, et al, synth. commu., 1993, 23(13), 1783, starting from the product prepared as described in example 7/1.

A yellow solid was obtained. The yield thereof was found to be 90%.

C₃₁H₂₄N₂O (440.54); melting point: decomposing at 305 deg.C; rf 0.52 (hexane/ethyl acetate 7: 3);

¹H(DMSO-D₆) δ -8.50-8.48 (2H, m, CH aromatic); 8.40-8.30(2H, m, CH aromatic);7.60-7.50(2H, m, CH aromatic); 7.42-7.20(14H, m, CH aromatic, indole); 5.62-5.58(4H, m, CH)₂)；

MS(IS)M⁺＝441；

Elemental analysis: calcd for C84.51, H5.49, N6.35; found C84.19, H5.98, N6.29.

Example 9

The compound of example 9 was prepared according to the synthesis in scheme 9 below.

Scheme 9

Alkylation and alkylation/dehydration of oxomethane derivatives

1 mol of an oxomethane derivative (prepared by the method described in example 8/1) was dissolved in an anhydrous solvent (e.g., THF, dioxane, diethyl ether), and an excess (2 to 10mol) of an alkyl salt (e.g., lithium salt, magnesium salt, copper salt, phosphonium salt) of the desired derivative to be prepared was added to the substrate at a low temperature (-50 to +10 ℃). After the addition was complete, the temperature of the reaction mixture was raised to room temperature (22 to 30 ℃). At the completion of the reaction, the solution is concentrated by evaporation of the solvent in vacuo and the semi-solid thus obtained is used with CH₂Cl₂And (6) diluting.

The solution was washed with water and then with a saturated solution of NaCl. The organic phase was again concentrated and the resulting solid was purified to give the desired product.

Example 9/1

1, 1-bis (N-benzylindol-3-yl) -1-butene and (N-benzylindol-3-yl, N-benzyl-2-propane Preparation of isoindol-3-yl) oxomethane (ST1492 and ST1494)

The compound described in example 8/1 (1g, 2.3mmol) was dissolved in anhydrous THF (13ml), and the resulting solution was cooled to +5 ℃. A2M solution of propylmagnesium chloride in 7ml of diethyl ether was added. After 1 hour, 100ml of CH are added₂Cl₂And 50ml of water. The organic phase is washed with 100ml of saturated NaCl solution before concentration to dryness. The crude reaction product thus obtained was chromatographed on silica gel, eluting with an 8: 2 mixture of hexane: ethyl acetate. In this way, the final product was isolated from the crude reaction product and purified (yield of both compounds 10%).

(ST1492)C₃₄H₃₀N₂(466.63); melting point: decomposition at 240 ℃; rf 0.31 (hexane/ethyl acetate 9: 1);

¹H(DMSO-D₆) δ -7.60-6.80 (20H, m, CH aromatic, indole); 6.20-6.00(1H, t, CH); 5.42(2H, s, CH)₂)；5.30(2H，s，CH₂)；2.24-2.18(2H，q，CH₂)；1.10-1.00(3H，t，CH₃)；

MS(IS)M^-＝465；

Elemental analysis: calcd for C87.51, H6.48, N6.00; found C87.74, H6.48, N5.79;

(ST1494)C₃₄H₃₀N₂o (482.63); melting point: decomposing at 325 ℃; rf 0.68 (hexane/ethyl acetate 7: 3);

¹H(DMSO-D₆) δ -8.20-8.10 (1H, m, CH aromatic, indole); 8.00(1H, s, CH); 7.70-6.60(1H, m, CH); 7.40-7.00(16H, m, aromatic, indole); 5.60(2H, s, CH)₂)；5.50(2H，s，CH₂)；3.00-2.90(2H，q，CH₂)；1.60-1.40(2H，m，CH₂)；0.90-0.80(3H，t，CH₃)；

MS(IS)M^-＝465；

Elemental analysis: calcd for C84.61, H6.26, N5.80; found C84.54, H6.38, N5.69.

Example 10

The compound of example 10 was prepared using the synthesis in scheme 10 below.

Scheme 10

Example 10/1

Preparation of phenylbis (1-N-benzylimidazol-2-yl) methane (ST1447)

0.84g (2mmol) of the compound prepared as described in example 6/1 are dissolved together with 2g of graphite in 12ml of HCOOH and the resulting mixture is heated at reflux for 24 hours. At the end of this period, the solution was cooled and diluted with 50ml of MeOH, filtered over celite, and concentrated to dryness. The final product was isolated from the crude reaction product by silica gel chromatography (elution solvent hexane: ethyl acetate 7: 3). The yield thereof was found to be 40%.

C₂₇H₂₄N₄(404.51); melting point: decomposition at > 200 ℃; rf 0.66 (hexane/ethyl acetate 7: 3);

¹H(DMSO-D₆) δ -8.30-8.20 (4H, m, CH aromatic); 7.80-7.70(2H, m, CH aromatic); 7.68-7.50(4H, m, CH aromatic and imide); 7.40-7.20(10H, m, CH aromatic, imide, and CH); 5.70-5.60(4H, m, CH)₂)；

MS(IS)M^-＝403；

Elemental analysis: calcd for C80.16, H5.98, N13.85; found C80.10, H5.89, N13.54.

Example 11

According to Diez-Barra E, et al, Synth. 1993, 23(13), 1783 to prepare the compound of example 11.

Example 11/1

Preparation of 1, 1-bis (N-benzylindol-3-yl) butane (ST1442)

ST13851, 1-diindol-3-ylbutane, 290mg (1mmol) was thoroughly mixed with potassium tetrabutylate (280mg) and tetrabutylammonium bromide (20mg) and doped. The mixture thus obtained was stirred ultrasonically at room temperature. 640mg of benzyl chloride (5mmol) were then added at 0 ℃ and stirring with ultrasound continued at room temperature for 2 hours. At the end of this period, with H₂O/CHCl₃Treating the reaction mixture; the chloroform phase was separated, washed with a small amount of water and passed over Na₂SO₄Dried, filtered and concentrated to dryness. The final product was isolated and purified by chromatography on silica gel eluting with hexane: ethyl acetate 95: 5. The product was obtained in 351mg, yield 78%.

C₃₄H₃₂N₂(468) (ii) a Melting point: decomposition at > 210 ℃; rf 0.53 (hexane/ether 8/2);

¹H(CDCl₃) δ ═ 7.55(2H, d, CH aromatic); 7.16-7.05(10H, mm, CH aromatic); 7.04-6.88(12H, mm, CH aromatic); 5.22(4H, s, CH)₂Aromatic); 4.42(1H, t, CH); 2.13(2H, q, CH)₂)；1.40-1.23(2H，m，CH₂)；0.98(3H，t，CH₃)；

MS(IS)M^-＝467；

Elemental analysis: calcd for C87.13, H6.88, N5.17; found C86.83, H7.04, N4.99.

Example 11/2

Preparation of 1, 1-di (N-methylindol-3-yl) butane (ST1534)

The title compound was prepared in exactly the same manner as described in example 11/1, starting from ST1385 and methyl iodide. The yield thereof was found to be 84%.

C₂₂H₂₄N₂(316) (ii) a Melting point: decomposition at > 200 ℃; rf 0.45 (hexane/AcOEt 9/1);

¹H(CDCl₃) δ ═ 7.29(2H, d, CH aromatic); 7.24(2H, d, CH aromatic); 7.21(2H, t, CH aromatic); 7.08(2H, t, CH aromatic); 6.88(2H, s, CH aromatic); 4.52(1H, s, CH); 3.72(6H, s, CH)₃)；2.22(2H，q，CH₂)；1.56-1.39(2H，m，CH₂)；0.99(3H，t，CH₃)；

MS(IS)M^-＝315；

Elemental analysis: calcd for C83.50, H7.64, N8.85; found C82.98, H7.49, N8.72.

Example 11/3

Preparation of 5, 5-bis (1-methyl-1H-indol-3-yl) -1-pentanol (ST1974)

The title compound was prepared in exactly the same manner as described in example 11/1, starting from ST1346 and methyl iodide. The yield thereof was found to be 75%.

C₂₃H₂₆N₂O (346.47); rf 0.25 (hexane/AcOEt 7: 3);

¹H(CDCl₃) δ ═ 7.62(2H, d, CH aromatic); 7.35-7.15(4H, m, CH + CH aromatic); 7.12-6.98(2H, m, CH aromatic); 6.85(2H, s, CH aromatic); 4.60(1H, t, CH); 3.75(6H, s, N-CH)₃)；3.65(2H，t，CH₂O)；2.35-2.16(2H，m，CH₂)；1.76-1.58(2H，m，CH₂)；1.58-1.39(2H，m，CH₂)；

MS(IS)M^-＝345；

Elemental analysis: calcd for C79.73, H7.56, N8.08; found C79.61, H7.49, N8.01.

Example 12

The compound of example 12 was prepared using the method described in Angyal s.j., Beveridge r.j., carbohydrar.res., 1978, 65, 229.

Example 12/1

Preparation of (2S) -2, 3-dihydroxy-1, 1-diindol-3-ylpropane (ST1331)

The title compound was obtained in 95% yield starting from the compound prepared as described in example 3/1 using the method described in Angyal s.j., Beveridge r.j., carbohydr.res., 1978, 65, 229.

C₁₉H₁₈N₂O₂(346.47); melting point: decomposing at 200 deg.C; (. alpha.) with a certain degree of freedom_D＝+38.5°(0.5％CH₃OH); rf ═ 0.5 (ethyl acetate);

¹H(CDCl₃) δ ═ 8.00(2H, width, NH); 7.62-7.48(2H, dd, CH aromatic); 7.26-7.20(2H, m, CH aromatic); 7.20-6.86(6H, m, CH aromatic); 4.64(1H, d, CH); 4.60-4.20(1H, d, CH); 3.80-3.26(2H, dd, CH); 1.80(2H, Wide, OH).

MS(IS)M^-＝305；

Elemental analysis: calculated value (4% H)₂O, 2.7% diethyl ether) C72.03, H6.60, N8.81; found C72.51, H6.47, N7.75.

Example 12/2

Preparation of 1, 1-diindol-3-yl-1-deoxy-D-mannitol (ST1349)

The title compound was obtained starting from the compound of example 1, step a using the procedure described in Angyal s.j., Beveridge r.j., carbohydr.res., 1978, 65, 229. The yield thereof was found to be 84%.

C₂₂H₂₄N₂O₅(396) (ii) a Melting point: decomposing at 60 deg.C; (. alpha.) with a certain degree of freedom_D＝-38.6°(0.07％CH₃OH)；Rf＝0.5(CHCl₃/CH₃OH＝7/3)；

¹H(DMSO-D₆) δ -10.60-10.70 (2H, width-s, NH); 7.50(2H, t, CH aromatic); 7.25(2H, d, CH aromatic); 7.13(2H, s, CH aromatic); 6.90(2H, m, CH aromatic); 6.80(2H, m, CH aromatic); 5.00(1H, Width-s, CH); 4.00-4.40(5H, m, OH); 3.30-3.60(6H, m, CH)₂)；

MS(IS)M^-＝395；

Elemental analysis: calculated value (3% H)₂O) C65.18, H6.20, N6.87; found C65.00, H6.40, N6.35.

Example 13

The compound of example 13 was prepared using the method described in Sainbury m, Hogan i.t., Synthesis, 1984, 4, 872.

Example 13/1

Preparation of 1, 3-diacetoxy-2, 2- (diindol-3-yl) propane (ST1370)

Ac was treated using the method described in Sainbury M., Hogan I.T., Synthesis, 1984, 4, 872₂The moles of O and AcONa were doubled to obtain the title compound starting from the compound of example 2/8. The yield thereof was found to be 70%.

C₂₃H₂₂N₂O₄(390.4); melting point: 183-185 ℃ C; rf ═ 0.78 (diethyl ether);

¹H(CDCl₃) δ ═ 8.10(2H, s, NH); 7.32-7.24(2H, d, CH aromatic); 7.22-7.16(2H, m, CH aromatic); 7.14-7.08(2H, d, CH aromatic); 7.04-6.98(2H, t, CH aromatic); 6.80-6.64(2H, t, CH aromatic; 4.84(4H, s, CH)₂)；1.90(6H，s，CH₃)；

MS(IS)M^-＝390；

Elemental analysis: calcd for C70.75, H5.68, N7.17; found C70.50, H5.35, N6.83.

Example 13/2

Preparation of 5-acetoxy-1, 1-diindol-3-ylpentane (ST1371)

The title compound was obtained starting from the compound of example 2/4 using the procedure described in Sainbury m, Hogan i.t., Synthesis, 1984, 4, 872. The yield thereof was found to be 80%.

C₂₃H₂₄N₂O₂(360.4); melting point: decomposition at > 200 ℃; rf 0.42 (ether/hexane 7: 3);

¹H(CDCl₃) δ 7.80(2H, width, NH); 7.62-7.48(2H, dd, CH aromatic); 7.24-7.20(2H, d, CH aromatic); 7.16-7.10(2H, m, CH aromatic); 7.00-6.86(4H, m, CH aromatic); 4.42-4.40(1H, t, CH); 4.00-3.84(2H, t, CH)₂)；2.22-1.86(2H，m，CH₂)；1.90(3H，s，CH₃)；1.80-1.60(2H，m，CH₂)；1.50-1.40(2H，m，CH₂)；

MS(IS)M⁺＝361；

Elemental analysis: calcd for C76.57, H6.65, N7.77; found C76.27, H6.78, N7.25.

Example 13/3

Preparation of 1, 1-diindol-3-yl-1-deoxypentaacetyl-D-glucose (ST1363)

A10-fold excess of Ac was used using the method described in Sainbury M., Hogan I.T., Synthesis, 1984, 4, 872₂O and AcONa from example 2/10 to give the title compound. The yield thereof was found to be 70%.

C₃₂H₃₄N₂O₁₀(606.1); melting point: 190 ℃; (. alpha.) with a certain degree of freedom_D＝-23.8°(0.4％CHCl₃)；Rf＝0.8(CHCl₃/CH₃OH 9∶1)；

¹H(CDCl₃) δ ═ 8.00(2H, s, NH); 7.70-7.60(2H, m, CH aromatic); 7.30-7.05(4H, m, CH aromatic); 7.04-6.90(4H, m, CH aromatic); 5.80-5.70(1H, t, CH); 5.40-5.20(2H, m, CH); 5.0(2H, m, CH); 4.00-3.80(2H, m, CH); 2.10(3H, s, CH)₃)；2.00(3H，s，CH₃)；1.82(3H，s，CH₃)；1.68(3H，s，Ac)；1.64(3H，s，Ac)；

MS(IS)M^-＝605；

Elemental analysis: calculated value (3.4% H)₂O) C65.18, H6.20, N6.87; found C65.10, H6.23, N6.40.

Example 14

Preparation of 1, 1-bis (indol-3-yl) -5-methanesulfonyloxypentane (ST1488)

Using Kim, j.h.; yang, m, et al, j.chem.soc.perkin.trans, 1; 1998, (17), 2877-2880 starting from the compound of example 2/4, the title compound was obtained. The yield thereof was found to be 60%.

C₂₂H₂₄N₂O₃S (396); melting point: decomposition at > 200 ℃; rf 0.18 (Et)₂O/hexane 6: 4);

¹H(CDCl₃) δ 7.90(2H, s, NH); 7.3-7.5(2H, d, CH aromatic); 6.95-7.10(2H, t, CH aromatic); 6.90(1H, s, CH aromatic); 4.20(1H, t, CH); 2.80(3H, s, CHsS); 1.60-2.40(8H, m, CH)₂)；

MS(IS)M^-＝395；

Elemental analysis: calcd for C66.66, H6.06, N7.07; found C66.54, H6.24, N6.98.

Example 15

The compound of example 15 was prepared using the procedure described in Tao, m, et al, bioorg.med.chem.lett., 1996, 6(24), 3009.

Example 15/1

Preparation of phenyl, hydroxy, di (imidazolyl-2-yl) methane (ST1441)

4.20g (10mmol) of the compound from example 6/1 and 1g of Pd (OH) in 200ml of methanol₂H of a mixture of compositions at 60p.s.i.₂The hydrogenation is carried out under pressure. The hydrogenation reaction was carried out at room temperature for 16 hours.

At the end of this period, the Pd was removed by filtration and the solution was concentrated; the resulting solid was purified. The final product was isolated and purified by chromatography on silica gel (mobile phase AcOEt: MeOH 1: 1). The yield thereof was found to be 98%.

C₁₃H₁₂N₄(240.26); melting point: decomposing at 200 deg.C; rf 0.65 (AcOEt/MeOH/NH)₃ 90∶10∶0.2)；

¹H(DMSO-D₆) δ -10-11.80 (2H, width, NH); 7.40-7.34(3H, m, CH aromatic); 7.30-7.14(4H, m, CH imide); 7.20-6.8(4H, m, CH aromatic, OH);

MS(IS)M⁺＝241；

elemental analysis: calcd for C64.98, H5.03, N23.32; found C64.36, H5.23, N23.00.

Example 15/2

Preparation of 1, 1-bis (5-aminoindol-3-yl) butane.2 HCl (ST1437)

250mg (0.66mmol) of ST1429, 1, 1-bis (5-nitroindol-3-yl) butane were hydrogenated with 100mg of Pd/c in 5% ethanol in the presence of 2ml of 15% (in absolute ethanol) HCl at 15 p.s.i.. Finishing the reduction after 4 hours; the solution was filtered, concentrated to a smaller volume, and then acetone was added with stirring. The product precipitated and was filtered off in vacuo and dried. 216mg of pure product are obtained in 84% yield.

C₂₀H₂₂N₄2HCl (391); melting point: decomposition at 248-243 deg.C; rf 0.62 (CH)₃CN/EtOH＝6∶4)；

¹H(DMSO-D₆) δ 11.95(2H, width, NH); 10.50(4H, Width, NH)₂) (ii) a 7.55(2H, s, CH aromatic); 7.50-7.25(3H, m, CH aromatic); 7.10-6.90(2H, m, CH aromatic); 4.35(1H, t, CH); 2.15(2H, q, CH)₂)；1.40-1.15(2H，m，CH₂)；0.90(3H，t，CH₃Aliphatic);

MS(IS)M⁺＝319；

elemental analysis: calcd for C61.38, H6.18, N14.31, Cl 18.11; found C61.08, H6.25, N14.02, Cl 18.48.

Example 16

The compound of example 16 was prepared using the procedure described in Smith, s.o. et al, j.org.chem., 1997, 62(11), 3638.

Example 16/1

Preparation of 1, 1- (diindol-3-yl) -5-fluoropentane (ST1381)

The compound (318 mg; 1mmol) from example 2/4 was dissolved in CH₂Cl₂(20 ml). DAST (200. mu.l; 1.5mmol) was added to the solution maintained at 25 ℃ and the mixture was reacted for 30 minutes.

At the end of this period, 10% NaHCO was added to the reaction mixture₃(10ml) and CH₂Cl₂(10 ml). The organic phase is separated and passed over Na₂SO₄Dried and concentrated until a solid is obtained. Make itThe product was separated and purified by HPLC using a reverse phase preparative column (RP-18 column, mobile phase CH)₃CN∶H₂O60: 40). The yield thereof was found to be 15%.

C₂₁H₂₀N₂(300) (ii) a Melting point: decomposing at 206-208 ℃; rf 0.78 (hexane/iPrOH 9/1);

¹H(DMSO-D₆) δ -10.40-10.80 (2H, width-s, NH); 7.52(1H, d, CH aromatic); 7.45(1H, m, CH aromatic); 7.37(1H, d, CH aromatic); 7.20(1H, m, CH aromatic); 7.07(1H, t, CH); 6.95(2H, m, CH); 6.68(1H, s, CH); 4.65(1H, Width-s, CH); 2.75-3.00(2H, m, CH)₂)；1.95-2.40(2H，m，CH₂)；1.90-1.60(2H，m，CH₂)；1.70(2H，m，CH₂)；

MS(IS)M^-＝299；

Elemental analysis: calcd for C84.00, H6.66, N9.33; found C84.19, H6.50, N9.03.

Example 16/2

Preparation of (R, S) -5-fluoro-1, 1- (indol-2-yl, indol-3-yl) pentane (ST1421)

The compound (318 mg; 1mmol) from example 2/12 was dissolved in CH₂Cl₂(20 ml). DAST (200. mu.l; 1.5mmol) was added to the solution maintained at 25 ℃ and the mixture was reacted for 30 minutes.

At the end of this period, 10% NaHCO was added to the reaction mixture₃(10ml) and CH₂Cl₂(10 ml). The organic phase is separated and passed over Na₂SO₄Dried and concentrated until a solid is obtained. The product was separated and purified by HPLC using a reverse phase preparative column (RP-18 column, mobile phase CH)₃CN∶H₂O60: 40). The yield thereof was found to be 15%.

C₂₁H₂₁FN₂(320) (ii) a Melting point: 77-81 ℃; rf 0.44 (hexane/iPrOH 85/15);

¹H(CH₃CN) δ 9.00-8.80(2H, width-s, NH); 7.40(4H, m, CH aromatic); 7.30(1H, Width-s, CH); 6.95(4H, m, CH aromatic); 6.60(1H, s, H3' b); 4.65(1H, t, CH); 4.50-4.75(2H, t, CH)₂)；2.20(2H，m，CH₂)；1.70-1.80(2H，m，CH₂)；1.40(2H，m，CH₂)；

MS(IS)M^-＝319；

Elemental analysis: calcd for C78.75, H6.56, F5.93, N8.75; found C78.85, H6.70, F5.90, N8.94.

Example 17

Bis [1, 1-di (N-carbonylindol-3-yl) butane](ST1533) preparation of

580mg (2mmol) of ST1385 and 500mg of carbonyldiimidazole (3mmol) are dissolved in 10ml of anhydrous dimethyl sulfoxide. The reaction was held at 125 ℃ for 2 hours with stirring. At the end of this period, the reaction mixture was cooled and 200ml of ice water was slowly added. The product precipitated and was filtered off, washed on the filter with ice water and then crystallized from methanol. 520mg of the title compound are obtained. The yield thereof was found to be 82.7%.

The product comprises a mixture of two stereoisomers, one with two butyl chains (butyric chains) in cis position (65%) and the remaining in trans position (35%).

C₂₁H₁₄N₂S₂(358.5); melting point: 178 ℃; rf 0.41 (hexane/dioxane 8: 2);

¹H(DMSO-D₆) δ -7.80-7.70 (3H, m, CH aromatic); 7.60-7.40(5H, m, CH aromatic); 7.40-7.20(3H, m, CH aromatic); 7.20-7.00(3H, m, CH aromatic, CH);

MS(IS)M⁺(-H₂O)＝359；

elemental analysis: calcd for C70.36, H3.93, N7.81; found C70.10, H3.85, N7.49.

Example 18

Preparation of 3- (5-bromo-1- (1H-indol-3-yl) pentyl) -1H-indole (ST1880)

The title compound was prepared from ST1346 using the procedure described in Campbell, J.A., et al, J.org.chem., 1996, 61(18), 6313-6325.

ST1346, 318mg (1mmol) are dissolved in 20ml of anhydrous CH₂Cl₂(ii) a The solution was cooled to-5 ℃ and 904mg of triphenylphosphine (4mmol) and 1.324g of tetrabromomethane (4mmol) were added continuously and slowly. The reaction mixture was left at-5 ℃ for 42 hours and then, when the reaction was completed, concentrated to complete dryness. The residue is in SiO₂The column was chromatographed using hexane: ethyl acetate 8: 2 as eluent. 297mg of pure product are obtained in 78% yield.

C₂₁H₂₁BrN₂(381.32); rf 0.68 (hexane/AcOEt 6: 4);

¹H(CDCl₃) δ ═ 7.86(2H, width-s, -NH); 7.66(2H, d, CH aromatic); 7.34(2H, d, CH aromatic); 7.27-7.16(2H, m, CH aromatic); 7.16-7.03(2H, m, CH aromatic); 6.37(2H, s, CH aromatic); 4.53(1H, t, CH); 3.40(2H, t, CH)₂Br)；2.37-2.19(2H，m，CH₂)；2.05-1.97(2H，m，CH₂)；1.71-1.49(2H，m，CH₂)；

MS(IS)M^-＝380；

Elemental analysis: calcd for C66.15, H5.55, br20.95, N7.35; found C66.28, H5.51, Br20.64, N7.29.

Example 19

Preparation of 4- (5, 5-bis (1H-indol-3-yl) pentyl) -2-morpholinomethyl ether (ST1860)

According to Dutta, A.K., et al; the title compound is prepared from ST1880 and 2-methylmorpholine starting from the procedure described in J.Med.Chem., 1996, 39(3), 749-756, wherein the 2-methylmorpholine is prepared as described in Caviraghi, G.et al, J.heterocyclic.Chem., 18, 825 (1981).

381mg (1mmol) ST1880, 2-methoxymorpholine 234mg (2mmol) and finely ground K₂CO₃690mg (5mmol) were thoroughly mixed with 5ml of anhydrous DMA and heated to 80 ℃ for 5 hours with stirring. At the end of this period, 30ml of H were added₂O and extracted with ethyl acetate (3X 50 ml). The organic phases were pooled, washed with a small amount of water and dried over anhydrous Na₂SO₄Dried and concentrated to dryness. The residue is passed through SiO₂The column was purified using a gradient from 7: 3 to 4: 6 hexanes to ethyl acetate to give 160mg of product (38% yield).

C₂₆H₃₁N₃O₂(417.55); rf 0.19 (hexane/AcOEt 6: 4);

¹H(CDCl₃) δ ═ 7.93(2H, width-s, -NH); 7.55(2H, d, CH aromatic); 7.32(2H, d, CH aromatic); 7.19-7.07(2H, m, CH aromatic); 7.06-6.93(4H, m, 2CH aromatic); 4.60(1H, t, CH morpholine); 4.45(1H, t, CH gem); 4.02-3.89(1H, m, CH morpholine); 3.72-3.58(1H, m, CH morpholine); 3.42(3H, s, CH)₃)；2.52-2.43(2H，m，CH₂)；2.42-2.28(2H，m，CH₂Morpholine); 2.28-2.15(2H, m, CH)₂)；1.82-1.47(4H，m，CH₂e CH₂Morpholine); 1.47-1.35(2H, m, CH)₂)；

MS(IS)M^-＝416；

Elemental analysis: calcd for C74.79, H7.48, N10.06; found C74.98, H7.36, N9.93.

Example 20

Cytotoxicity assays on sensitive tumor cell lines (lines)

This test was used to assess the viability of the human cell lines MCF-7 (human breast carcinoma), LoVo (human colon adenocarcinoma) and MES-SA (human uterine sarcoma). Tumor cells were incubated with compound at scalar concentrations (500. mu.M/0.97. mu.M) for 24 hours; compounds were then removed and cell survival was assessed after 48 hours using the sulforodamine B test (j. natl. cancer inst., 82, 1107-. With IC processed into a curve-fit table (am.J. Physiol., 1978, 235, E97-E102)₅₀(concentration of molecules that inhibit 50% of cell survival) compounds were assessed for antiproliferative activity and expressed in μ M ± SD.

The compounds tested and the results obtained are shown in tables 1, 2 and 3 below.

TABLE 1

(antiproliferative Activity on MCF-7 cell line)

ST(a)	Test compounds(b)	MCF-7(c)
			1363	1, 1-diindol-3-yl-1-deoxypentaacetyl-D-glucose	25±2.8
1371	5-acetoxy-1, 1-diindol-3-ylpentane	27.7±4.2
			1382	1, 1- (diindol-3-yl) -5-fluoropentane	28.5±6
1385	1, 1-di (indol-3-yl) butane	27±3.2
			1393	1, 1-bis (5-hydroxyindol-3-yl) butane	5.9±0.8
1421	(R, S) -5-fluoro-1, 1- (indol-2-yl, indol-3-yl) pentane	20.4±2.8
			1422	5-hydroxy-1, 1-bis (5, 6-methylenedioxyindol-3-yl) pentane	43.1±1.2
1429	1, 1-bis (5-nitroindol-3-yl) butane	10.4±0.3
			1431	Bis (5-ethoxycarbonylpyrrol-2-yl) phenylmethane	20.3±1.4
1437	1, 1-bis (5-aminoindol-3-yl) butane dihydrochloride	8.3±1.2
			1438	1, 1-bis (5-fluoroindol-3-yl) butane	28.1±0.9
1440	Phenyl, hydroxy, bis (N, N-dibenzylimidazol-2-yl) methane	17±2.9
			1477	1, 1-bis (5-acetamidoindol-3-yl) butane	33.1±2.9
1478	1, 1-bis (5, 6-methylenedioxyindol-3-yl) butane	11.8±0.4
			1487	1, 1-di (indol-3-yl) cyclohexylmethane	29.9±0.006
1488	1, 1-bis (indol-3-yl) -5-methanesulfonyloxypentane	13.4±2.2
			1625	(R, S) -1, 1- (indol-2-yl, indol-3-yl) butane	13.4±1
1730	4-hydroxy-1, 1-bis (5, 6-methylenedioxyindol-3-yl) butane	24.5±3.7
			1731	(R, S) -4-hydroxy-1, 1-bis (5, 6-methylenedioxyindol-2-yl, 5, 6-methylenedioxyindol-3-yl) butane	30.1±4

(a) The compounds were tested for confirmation codes.

(b) Chemical name of the test compound.

(c) Expressed as IC₅₀Anti-proliferative activity value (μ M ± s.d.).

TABLE 2

(antiproliferative Activity on Mes-Sa cell line)

ST(a)	Test compounds(b)	Mes-Sa(c)
			1363	1, 1-diindol-3-yl-1-deoxypentaacetyl-D-glucose	33.6±5.9
1371	5-acetoxy-1, 1-diindol-3-ylpentane	nd
			1382	1, 1- (diindol-3-yl) -5-fluoropentane	40.2±4.1
1385	1, 1-di (indol-3-yl) butane	19.5±4.0
			1393	1, 1-bis (5-hydroxyindol-3-yl) butane	5.7±0.1
1421	(R, S) -5-fluoro-1, 1- (indol-2-yl, indol-3-yl) pentane	nd
			1422	5-hydroxy-1, 1-bis (5, 6-methylenedioxyindol-3-yl) pentane	79.3±7.8
1429	1, 1-bis (5-nitroindol-3-yl) butane	15±2.5
			1431	Bis (5-ethoxycarbonylpyrrol-2-yl) phenylmethane	nd
1437	1, 1-bis (5-aminoindol-3-yl) butane dihydrochloride	4.4±0.06
			1438	1, 1-bis (5-fluoroindol-3-yl) butane	21.8±4.4
1440	Phenyl, hydroxy, bis (N, N-dibenzylimidazol-2-yl) methane	4.7±0.4
			1477	1, 1-bis (5-acetamidoindol-3-yl) butane	28.7±0.2
1478	1, 1-bis (5, 6-methylenedioxyindol-3-yl) butane	17±2
			1487	1, 1-di (indol-3-yl) cyclohexylmethane	38.7±0.03
1488	1, 1-bis (indol-3-yl) -5-methanesulfonyloxypentane	15.8±1.8
			1625	(R, S) -1, 1- (indol-2-yl, indol-3-yl) butane	14.1±3.8
1730	4-hydroxy-1, 1-bis (5, 6-methylenedioxyindol-3-yl) butane	nd
			1731	(R, S) -4-hydroxy-1, 1-bis (5, 6-methylenedioxyindol-2-yl-5, 6-methylenedioxyindol-3-yl) butane	nd

(a) The compounds were tested for confirmation codes.

(b) Chemical name of the test compound.

(c) Expressed as IC₅₀Anti-proliferative activity value (μ M ± s.d.).

nd is undetermined.

TABLE 3

(antiproliferative Activity on LoVo cell line)

ST(a)	Test compounds(b)	Lovo(c)
			1363	1, 1-diindol-3-yl-1-deoxypentaacetyl-D-glucose	31.3±1.6
1371	5-acetoxy-1, 1-diindol-3-ylpentane	33±3
			1382	1, 1- (diindol-3-yl) -5-fluoropentane	33.5±3.7
1385	1, 1-di (indol-3-yl) butane	26.4±0.4
			1393	1, 1-bis (5-hydroxyindol-3-yl) butane	3.0±0.5
1421	(R, S) -5-fluoro-1, 1- (indol-2-yl, indol-3-yl) pentane	20.7±0.7
			1422	5-hydroxy-1, 1-bis (5, 6-methylenedioxyindol-3-yl) pentane	23±4.4
1429	1, 1-bis (5-nitroindol-3-yl) butane	23.6±0.5
			1431	Bis (5-ethoxycarbonylpyrrol-2-yl) phenylmethane	35.6±0.5
1437	1, 1-bis (5-aminoindol-3-yl) butane dihydrochloride	16.7±3.4
			1438	1, 1-bis (5-fluoroindol-3-yl) butane	20±0.8
1440	Phenyl, hydroxy, bis (N, N-dibenzylimidazol-2-yl) methane	11.7±0.2
			1477	1, 1-bis (5-acetamidoindol-3-yl) butane	59.4±6.9
1478	1, 1-bis (5, 6-methylenedioxyindol-3-yl) butane	15.4±1.8
			1487	1, 1-di (indol-3-yl) cyclohexylmethane	24.9±0.1
1488	1, 1-bis (indol-3-yl) -5-methanesulfonyloxypentane	11±1.6
			1625	(R, S) -1, 1- (indol-2-yl, indol-3-yl) butane	17.1±3.8
1730	4-hydroxy-1, 1-bis (5, 6-methylenedioxyindol-3-yl) butane	9.3±0.9
			1731	(R, S) -4-hydroxy-1, 1-bis (5, 6-methylenedioxyindol-2-yl-5, 6-methylenedioxyindol-3-yl) butane	23.9±0.7

(a) The compounds were tested for confirmation codes.

(b) Chemical name of the test compound.

(c) Expressed as IC₅₀Anti-proliferative activity value (μ M ± s.d.).

Example 21

Cytotoxicity assays against drug-resistant tumor cell lines

This test was used to assess the survival of human cell lines resistant to doxorubicin (about 100-fold) and cross-resistant to orthomycin, actinomycin D, mitoxantrone hydrochloride, vincristine, vinblastine, taxol, colchicine and etoposide.

The following cell lines were used: MCF-7-Dx (human breast carcinoma), LoVo-Dx (human colon adenocarcinoma), and MES-SA Dx (human uterine sarcoma).

The compounds tested are given in tables 4, 5 and 6. Before using the compounds tested in combination with doxorubicin, the cytotoxicity of the cells was assessed (alone) using the test compounds as follows: cells were incubated with compound at scalar concentrations (500. mu.M/0.97. mu.M) for 24 hours; the compounds were then removed and cell survival was assessed after 48 hours using the sulforodamine B test described above. Using IC processed into the curve-fit table₅₀(concentration of molecules that inhibit 50% of cell survival) compounds were evaluated for their antiproliferative activity.

Then, profiles of doxorubicin alone and doxorubicin in the presence of a non-toxic concentration (IC ≦ 20) of the test compound are plotted.

IC shown in tables 4, 5 and 6₅₀The values show the degree of enhancement of doxorubicin activity induced by the compound (MDR ratio).

TABLE 4

(chemosensitive Activity on MCF-7Dx cell line)

ST(d)	Test compounds(e)	MCF-7Dx(f)
				IC50(μM)	MDR ratio
		1339	2, 3-5, 6-di-O-isopropylidene-1, 1-diindol-3-yl-1-deoxy-D-mannitol			98.2±12	3.2/1.0＝3.2***(IC0＝20)；3.6/1.6＝2.2***(IC0＝10)
1350	1, 1-diindol-3-yl-1-deoxy-D-glucose			70.8±3.7	6.6/1.6＝4.1***(IC2＝50)；7.2/3.6＝2.0**(IC0＝25)

1353	2, 3-5, 6-di-O-isopropylidene-1, 1-di-7-azaindol-3-yl-1-deoxy-D-mannitol	＞500	6.5/1.0＝6.5***(IC17＝500)
				1363	1, 1-diindol-3-yl-1-deoxypentaacetyl-D-glucose	65.4±0.7	5.8/1.9＝3**(IC6＝20)
1371	5-acetoxyl-1, 1-Diindol-3-ylpentane	74.1±2.5	11.1/2.6＝4.3***(IC0＝30)5.5/2.5＝2.2****(IC5＝40)
				1382	1, 1- (diindol-3-yl) -5-fluoropentane	40.2±3	6.1/3.6＝1.7*(IC4＝10)；7.4/1.9＝3.8***(IC9＝20)
1385	1, 1-di (indol-3-yl) butane	34.6±2.0	3.9/1.9＝2.0**(IC2＝20)4.4/4.3＝1.0(IC0＝10)
				1393	1, 1-bis (5-hydroxyindol-3-yl) butane	9.2±0.4	5.3/4.5＝1.1(IC0＝4)6.1/4.6＝1.3(IC0＝2)
1422	5-hydroxy-1, 1-bis (5, 6-methylenedioxyindol-3-yl) pentane	40.1±1.2	7.8/4.6＝1.7(IC3＝20)3.3/3.2＝1(IC7＝10)
				1429	1, 1-bis (5-nitroindol-3-yl) butane	12.9±0.7	nd
1437	1, 1-bis (5-aminoindol-3-yl) butane dihydrochloride	28.6±5.518.4±1.4	nd
				1438	1, 1-bis (5-fluoroindol-3-yl) butane	41.8±5.3	10.7/3.5＝3*(IC1＝20)

1440	Phenyl, hydroxy, bis (N, N-dibenzylimidazol-2-yl) methane	29.7±2.6	14.2/5.6＝2.5(IC8＝10)1.8/1.3＝1.4(IC8＝5)
				1473	Bis (N-benzylindol-3-yl) oxomethane	＞500	3.4/1.1＝3.2*(IC19＝50)
1478	1，1-bis (5, 6-methylenedioxyindol-3-yl) butane	15.2±1.9	9.4/4.5＝2.1*(IC0＝2)
				1487	1, 1-di (indol-3-yl) cyclohexylmethane	15.3±1	nd
1488	1, 1-bis (indol-3-yl) -5-methanesulfonyloxypentane	9.7±1.3	7.1/1.2＝5.7**(IC0＝4)2.6/4＝0.65(IC0＝4)
				1492	1, 1-bis (N-benzylindol-3-yl) -1-butene	＞500117±7	8/0.8＝9.6****(IC5＝50)1.5/0.51＝3***(IC0＝10)2.4/0.3＝7.1***(IC0＝5)
1494	(N-benzylindol-3-yl, N-benzyl-2-propylindol-3-yl) oxomethane	＞200	2.1/0.17＝12.2***(IC10＝50)0.9/0.28＝3.1*(IC8＝5)1.2/0.37＝3.3**(IC3＝10)

(d) The compounds were tested for confirmation codes.

(e) Chemical name of the test compound.

(f) The chemical sensitivity activity value, expressed as the MDR ratio, was calculated as follows: IC (integrated circuit)₅₀Adriamycin/IC₅₀Doxorubicin was conjugated to a sub-toxic concentration of the test compound.

^*P＜0.05，^**P＜0.01，^****P＜0.001，^****P < 0.0001 is the P value calculated using the curve-fit table above, for comparison of the doxorubicin curves in the presence and absence of the test compound.

Indicated in brackets are the subtoxic μ M concentrations of the products used to calculate the MDR ratio.

IC for test Compounds alone is given in the left column₅₀Values, expressed in μ M ± s.d.; in processing ICs₅₀In the process, the value of the sub-toxic concentration IC ≦ 20 of the test compound was also evaluated.

TABLE 5

(chemosensitive Activity on Mes-Sa Dx cell line)

ST(d)	Test compounds(e)	Mes-Sa Dx(f)
						IC50(μM)	MDR ratio
1339	2, 3-5, 6-di-O-isopropylidene-1, 1-diindol-3-yl-1-deoxy-D-mannitol	56.1±11	nd
				1350	1, 1-diindol-3-yl-1-deoxy-D-glucose	81.4±8.0	2.4/1.4＝1.7*(IC0＝50)
1353	2, 3-5, 6-di-O-isopropylidene-1, 1-di-7-azaindol-3-yl-1-deoxy-D-mannitol	nd	nd
				1363	1, 1-diindol-3-yl-1-deoxypentaacetyl-D-glucose	nd	nd
1371	5-acetoxy-1, 1-diindol-3-ylpentane	53±0.4	nd
				1382	1, 1- (diindol-3-yl) -5-fluoropentane	12.45±0.3	0.7/0.9＝0.82(IC20＝5)
1385	1, 1-di (indol-3-yl) butane	33.6±2.9	nd
				1393	1, 1-bis (5-hydroxyindol-3-yl) butane	7.5±0.3	3.03/2.2＝1.4*(IC7＝3)
1422	5-hydroxy-1, 1-bis (5, 6-methylenedioxyindol-3-yl) pentane	73.3±2.7	1.8/1.8＝1(IC3＝15)
				1429	1, 1-bis (5-nitroindol-3-yl) butane	15.3±0.4	3.4/0.8＝4.3***(IC0＝10)
1437	1, 1-bis (5-aminoindol-3-yl) butane dihydrochloride	12.2±0.8	2.8/2.4＝1.2(IC5＝5)3.2/2.4＝1.3(IC5＝2.5)
				1438	1, 1-bis (5-fluoroindol-3-yl) butane	35.6±1.7	2.6/2.2＝1.2(IC20＝20)2.1/3.2＝0.7(IC0＝10)

1440	Phenyl, hydroxy, bis (N, N-dibenzylimidazol-2-yl) methane	14.9±2.5	6/2.2＝2.8**(IC8＝5)
				1473	Bis (N-benzylindol-3-yl) oxomethane	＞500	nd
1478	1, 1-bis (5, 6-methylenedioxyindol-3-yl) butane	7.8±1.5	1.2/1.5＝0.8(IC3＝2)
				1487	1, 1-di (indol-3-yl) cyclohexylmethane	16±3.5	1.3/1.6＝0.8(IC11＝4)
1488	1, 1-bis (indol-3-yl) -5-methanesulfonyloxypentane	10.3±1.9	0.95/0.72＝1.3(IC15＝5)
				1492	1, 1-bis (N-benzylindol-3-yl) -1-butene	178.3±41	nd
1494	(N-benzylindol-3-yl, N-benzyl-2-propylindol-3-yl) oxomethane	＞200	nd

(d) The compounds were tested for confirmation codes.

(e) Chemical name of the test compound.

(f) The chemical sensitivity activity value, expressed as the MDR ratio, was calculated as follows: IC (integrated circuit)₅₀Adriamycin/IC₅₀Doxorubicin was conjugated to a sub-toxic concentration of the test compound.

^*P＜0.05，^**P＜0.01，^***P＜0.001，^****P < 0.0001 is the P value calculated using the curve-fit table above, for comparison of the doxorubicin curves in the presence and absence of the test compound.

Indicated in brackets are the subtoxic μ M concentrations of the products used to calculate the MDR ratio.

IC for test Compounds alone is given in the left column₅₀Values, expressed in μ M ± s.d.; in processing ICs₅₀In the processThe value of the sub-toxic concentration IC ≦ 20 of the test compound was also evaluated.

TABLE 6

(chemosensitive Activity on LoVo Dx cell line)

ST(d)	Test compounds(e)	Lovo Dx(f)
						IC50(μM)	MDR ratio
1339	2, 3-5, 6-di-O-isopropylidene-1, 1-diindol-3-yl-1-deoxy-D-mannitol	11±0.6	3.8/1.4＝2.8***(IC9＝4)3.5/1.8＝2**(IC15＝8)
				1350	1, 1-diindol-3-yl-1-deoxy-D-glucose	＞500	nd

1353	2, 3-5, 6-di-O-isopropylidene-1, 1-di-7-azaindol-3-yl-1-deoxy-D-mannitol	367±82	nd
				1363	1, 1-diindol-3-yl-1-deoxypentaacetyl-D-glucose	121±12	nd
1371	5-acetoxy-1, 1-diindol-3-ylpentane	47.9±4.7	1.93/1.95＝0.98(IC0＝15)
				1382	1, 1- (diindol-3-yl) -5-fluoropentane	34.3±6.9	2.2/2.6＝0.9(IC 16＝20)3.4/5.4＝0.6(IC0＝10)
1385	1, 1-di (indol-3-yl) butane	17.6±0.9	2.7/1.4＝1.9(IC14＝10)1.4/2.8＝0.5(IC31＝5)
				1393	1, 1-bis (5-hydroxyindol-3-yl) butane	2.7±0.4	3.4/1.75＝1.95(IC7＝0.5)
1422	5-hydroxy-1, 1-bis (5, 6-methylenedioxyindol-3-yl) pentane	22.3±2.9	1.8/2.1＝0.9(IC11＝15)4.2/1.7＝2.4(IC0＝7.5)
				1429	1, 1-bis (5-nitroindol-3-yl) butane	10.2±0.5	2.6/1.2＝2.1*(IC0＝5)2.4/2.2＝1.1(IC14＝2.5)
1437	1, 1-bis (5-aminoindol-3-yl) butane dihydrochloride	8±0.6	4.7/4.1＝1.2(IC14＝2)
				1438	1, 1-bis (5-fluoroindol-3-yl) butane	25.9±3.1	5/9.2＝0.5(IC0＝10)
1440	Phenyl, hydroxy, bis (N, N-dibenzylimidazol-2-yl) methane	4.6±0.6	5.6/14.9＝0.4(IC0＝2)
				1473	Bis (N-benzylindol-3-yl) oxomethane	8.6±2.9	3.7/1.2＝3.1(IC0＝0.5)
1478	1, 1-bis (5, 6-methylenedioxyindol-3-yl) butane	10.7±0.6	2.3/2.8＝0.8(IC19＝4)
				1487	1, 1-di (indol-3-yl) cyclohexylmethane	27.8±2.1	2.2/1.3＝1.7*(IC0＝2)

1488	1, 1-bis (indol-3-yl) -5-methanesulfonyloxypentane	18.1±0.6	3.8/3.2＝1.2(IC15＝3.5)
				1492	1, 1-bis (N)-benzylindol-3-yl) -1-butene	＞350	1.8/0.4＝4.4***(IC9＝50)1.82/0.49＝3.7**(IC2＝25)
1494	(N-benzylindol-3-yl, N-benzyl-2-propylindol-3-yl) oxomethane	＞200	2.2/0.12＝18***(IC5＝50)

(d) The compounds were tested for confirmation codes.

(e) Chemical name of test Compound

(f) The chemical sensitivity activity value, expressed as the MDR ratio, was calculated as follows: IC (integrated circuit)₅₀Adriamycin/IC₅₀Doxorubicin was conjugated to a sub-toxic concentration of the test compound.

^*P＜0.05，^**P＜0.01，^***P＜0.001，^****P < 0.0001 is the P value calculated using the curve-fit table above, for comparison of the doxorubicin curves in the presence and absence of the test compound.

Indicated in brackets are the subtoxic μ M concentrations of the products used to calculate the MDR ratio.

IC for test Compounds alone is given in the left column₅₀Values, expressed in μ M ± s.d.; in processing ICs₅₀In the process, the value of the sub-toxic concentration IC ≦ 20 of the test compound was also evaluated.

Example 22

Chemosensitivity of all-cis retinoic acid (ATRA) to acute promyelocytic leukemia cells Effect

ATRA is a potent inducer of terminal differentiation in Acute Promyelocytic Leukemia (APL).

Clinical studies have demonstrated that treatment of APL patients with ATRA results in increased survival and event-free survival (EFS). (Blood 72 (2): 567-72, 1988; Blood 76: 1704-09, 1990; N.Engl.J.Med.324 (20): 1385-93, 1991; Blood 78 (6): 1413-19, 1991).

Therapeutic doses of ATRA are administered (10)^-6M) causes a skin or liver toxicity-like response (ATRA syndrome) in the treated patient (Blood 76: 260a (abstr. suppl), 1990; ann.lntern.med.117 (4): 292-96, 1992).

Experiments were conducted to verify the possibility of using lower doses of ATRA and as a result, it was found that a reduction in side effects was caused by the compound while maintaining the same therapeutic effect.

To achieve this, a number of compounds described herein were used and their ability to enhance ATRA sensitivity and their antiproliferative, cytocidal and apoptotic effects on a number of leukemia cell lines were simultaneously studied.

In the experiments performed as follows, two APL cell lines were used.

The first cell line used was the NB4 cell line, which underwent a t (15; 17) chromosomal translocation that produced the fusion protein PML/RAR α. The dose of the strain on ATRA (10)^-7-10^-6M) is very sensitive to differentiation.

The second line used was the HL60 cell line that responded to ATRA (but was less sensitive than the NB4 cell line). This cell line does not show the chromosomal translocations described above.

HL60 and NB4 cells were seeded at a density of 150,000 cells/ml in RPMI1640 culture medium containing 10% fetal bovine serum and treated with the test compound in the dark in the presence or absence of the optimum dose of ATRA (NB 4: 5-10nM and HL 60: 0.5. mu.M, respectively) and returned to the incubator for 3 days without changing the culture medium.

The greatest ATRA-induced differentiation effect was generally observed on the third or fourth day of treatment, with a marked growth arrest.

Control medium treated with the same concentration of DMSO was used to dilute the test compound and ATRA, which vectors were self-differentiating under the specific assay conditions.

Assessment of cell differentiation by analysis of reduction of Nitrobluetetrazolium (NBT)

To analyze the differentiation effect of test compounds on ATRA, 500,000 viable cells were collected from each sample on the third day of treatment, centrifuged at 1,000rpm for 10 minutes and suspended in 1ml RPMI1640 medium containing 10% fetal bovine serum, 1mg/ml Nitro Blue Tetrazolium (NBT) and 100ngPMA (phorbol 12-myristate 13-acetate).

The cells thus resuspended were incubated for 60 minutes at 37 ℃ in the dark.

At the end of the incubation, the cell suspension was centrifuged at 10,000rpm for 10 minutes; the resulting particles were resuspended in 1ml PBS containing 10% Triton X-100 and sonicated for solubilization.

The spectrophotometric value of the sample was read at a wavelength of 540 nm: the control sample and/or the sample containing undifferentiated cells are colorless or at least nearly colorless by moving the sample containing differentiated cells to the ultraviolet light.

Flow cytofluorimetric analysis of cell circulation

To assess the effect of test compounds on different cycles of the cell cycle, 500,000 cells were collected on the third day of treatment, centrifuged at 1,000rpm for 10 minutes, washed twice with PBS w/o (calcium and magnesium free PBS) and fixed in 50% PBS w/o + 50% methanol/acetone (1: 4v/v) for at least one hour; the cells were then centrifuged as described above, washed twice with PBS w/o and centrifuged again.

Then, 200. mu.l of clofibrate (propidium iodide) at 100. mu.g/ml and 200. mu.l of ribonuclease at 150KU/mg were added to the cell particles.

After incubation in the dark at room temperature for 30 minutes, the samples were analyzed with a flow cytofluorimeter.

Example 22/1

Use of 5-hydroxy-1, 1-di (indol-3-yl) pentane (ST1346) in combination with optimal dosage Differentiation of ATRA-treated NB4 cells

Treatment of NB4 cells with ST1346 and ATRA (0.5-0.01 μ M) alone or in combination at doses of 1, 5, 10 and 50 μ M in vitro experiments showed that the test compound (ST1346) was able to sensitize ATRA (most modest dose administration) substantially at the time of induction of terminal differentiation, with maximal effect already at the 10 μ M dose.

The results obtained are given in Table 1 and show that the bonding treatment gives AC₅₀The value was 1.5. + -. 0.5. mu.M; (overlap Induction: 3.0)

AC₅₀(activation concentration) is the concentration at which the test compound induces 50% differentiation.

The overlap induction is an increase in the differentiation value of the cell sample treated with test compound + ATRA over the differentiation value of the cell sample treated with ATRA alone. This value provides an indication that the test compound enhances the ability of ATRA to induce cell differentiation.

Example 22/2

Evaluation of ST1346 Effect on cell cycle of NB4 cell line in the Presence and absence of ATRA Estimation of

The effect of treating NB4 cell cycles with ST1346 alone at doses of 1, 5, 10, and 50 μ M or in combination with the most appropriate dose of ATRA was evaluated.

The results obtained show that high doses of the test compound alone caused growth arrest (at G0/G1 phase of the cell cycle) and apoptosis, whereas the combination of the compounds of the invention with ATRA caused dramatic growth arrest (depending on the dose) at G0/G1 phase of the cycle, while inducing cell differentiation (table 1).

The results obtained are given in table 7.

It should be noted that when the compounds of the present invention are administered in combination with ATRA, their apoptotic effect is lost even at the highest doses.

TABLE 7

(ST1346 chemical sensitive Effect on ATRA cell cycle at NB 4)

Treatment of	G0/G1	G2/M	S	Apoptosis
					Control	46.2	12.3	41.5	18.5
ST1346 1μM	46.9	15.7	37.4	23
					ST1346 5μM	47.4	13.8	38.8	24
ST1346 10μM	50.0	14.7	35.3	23
					ST1346 50μM	59.4	7.3	33.3	46
ATRA 0.01μM	54.6	14.4	31.0	10
					ATRA 0.01μM+ST1346 1μM	61.5	12.9	25.6	14
ATRA 0.01μM+ST1346 5μM	58.0	13.5	28.5	13.5
					ATRA 0.01μM+ST1346 10μM	60.0	12.6	27.4	13
ATRA 0.01μM+ST1346 50μM	84.2	6.3	9.5	17

Example 22/3

Effect of ST1346 on inducing differentiation of HL60 cells in Beam phase in the Presence or absence of ATRA Fruit

In this assay, the effect of the compounds of the invention to induce terminal differentiation of HL60 cells was evaluated.

ST1346 was plotted against HL60 cell dose at 1, 5, 10, and 50 μ M in the presence or absence of the optimal dose of ATRA.

The results obtained are shown in Table 2 and show that the compounds of the invention are capable of activating, in a dose-dependent manner, essentially ATRA-induced terminal cell differentiation of tumor cells, the AC thereof₅₀The value was 14.8. + -. 1.6. mu.M; and (3) overlapping induction: 2.7.

example 22/4

Evaluation of 1, 1-bis (indol-3-yl) -4-hydroxybutane in the Presence or absence of ATRA (ST1707) Effect on differentiation and NB4 cell cycle

To evaluate the enhanced differentiation capacity of test compounds, NB4 cells were treated with scalar doses of 1, 5, 10, and 50 μ M ST1707 in the presence or absence of the most appropriate dose of ATRA.

The results obtained are shown in Table 3 and show that the test compounds have a significant ability to enhance the terminal differentiation of ATRA-induced leukemia cells in a dose-dependent manner (AC)₅₀: 8.3 +/-0.05 mu M; and (3) overlapping induction: 2.5).

The results obtained from the cell cycle analysis are shown in table 8, which shows that when the compound of the present invention is administered alone, the percentage of cells present in each phase of the cell cycle is not changed and apoptosis is not induced, compared to the control group. When ST1707 was administered in combination with ATRA, it clearly induced a dose-dependent cessation of G0/G1 phase cells of the cell cycle as a marker of cell differentiation.

TABLE 8

(ST1707 chemosensitive Effect on the cell cycle of ATRA at NB 4)

Treatment of	G0/G1	G2/M	S	Apoptosis
					Control	52.9	9.6	37.5	20.5
ST1707 1μM	51.7	10.1	38.2	17.0
					ST1707 5μM	52.5	11.1	36.4	19.5
ST1707 10μM	52.2	10.8	37.0	17.5
					ST1707 50μM	52.0	12.0	36.0	17.0
ATRA 0.01μM	65.0	11.0	24.0	17.5
					ATRA 0.01μM+ST1707 1μM	65.4	11.8	22.8	17.0
ATRA 0.01μM+ST1707 5μM	69.8	11.3	18.9	14.0
					ATRA 0.01μM+ST1707 10μM	70.4	11.5	18.1	13.0
ATRA 0.01μM+ST1707 50μM	80.6	9.0	10.4	11.5

Example 22/5

Evaluation of 5-hydroxy-1.1-bis (5, 6-methylene-dioxyindole in the Presence or absence of ATRA -3-yl)Effect of pentane (ST1422) on inducing terminal differentiation of NB4 cells

In this assay, ST1422 at doses of 1, 5, 10, and 50 μ M was evaluated for activity on NB4 cells in the presence or absence of the optimal dose of ATRA. The results obtained are shown in Table 4, which shows that the NBT test described above shows that the test compounds have a significant induction effect on increasing the terminal differentiation induced by ATRA, AC₅₀The value was 9.8. + -. 0.1. mu.M; and (3) overlapping induction: 1.85.

example 22/6

Evaluation of 5-hydroxy-1, 1-bis (5, 6-methylenedioxyindole) in the Presence or absence of ATRA Effect of 3-yl) pentane (ST1422) on inducing terminal differentiation and HL60 cell cycle

In this experiment, the effect of ST1422 at doses of 1, 5, 10, and 50 μ M on induction of terminal differentiation and HL60 cell cycle was evaluated in the presence or absence of the optimal dose of ATRA. The results obtained are shown in Table 5 and show that the compounds of the invention are capable of eliciting substantially equivalent induction of ATRA-induced terminal differentiation in the tested tumor cell lines, AC₅₀The value was 13.6. + -. 2.6. mu.M; and (3) overlapping induction: 2.2.

however, the results obtained from the cell cycle analysis reported in table 9 show that even in this case, the compounds of the invention are able to induce the cessation of cell growth in the G0/G1 phase of ATRA intervention. The compounds of the invention, when tested alone, showed no effect on inducing apoptosis.

TABLE 9

(ST1707 chemosensitive Effect on ATRA in HL60 cell cycle)

Treatment of	G0/G1	G2/M	S
				Control	59.1	9.2	31.7
ST1707 1μM	56.2	10.0	33.8
				ST1707 5μM	57.6	10.4	32.0
ST1707 10μM	57.8	10.5	31.7
				ST1707 50μM	65.8	16.4	17.8
ATRA 0.5μM	63.3	11.0	25.7
				ATRA 0.5μM+ST1707 1μM	66.8	11.0	22.2
ATRA 0.5μM+ST1707 5μM	65.1	11.4	23.5
				ATRA 0.5μM+ST1707 10μM	62.5	12.5	25.0
ATRA 0.5μM+ST1707 50μM	75.7	13.8	10.5

Example 22/7

5, 5-bis (1-methyl-1H-indol-3-yl) -1-pentanol in the presence or absence of ATRA (ST1974) Effect on NB4 cells

In this assay, the effect of the compounds of the invention on NB4 cells at doses of 1, 5, 10, and 50 μ M was evaluated in the presence or absence of the optimal dose of ATRA.

The results obtained are reported in Table 6 and show that the compounds of the invention are useful as agentsThe amount-dependent manner substantially increases the differentiating effect of ATRA, AC₅₀The value was 7.8. + -. 2.6. mu.M; and (3) overlapping induction: 1.8.

example 22/8

5, 5-bis (1-methyl-1H-indol-3-yl) -1-pentanol in the presence or absence of ATRA (ST1974) Effect on terminal differentiation Induction and HL60 cell cycle

In this assay, the effect of compounds of the invention at doses of 1, 5, 10, and 50 μ M on induction of terminal differentiation and HL60 cell cycle was evaluated in the presence or absence of the optimal dose of ATRA.

The results obtained are reported in table 7 and show that the NBT test described above shows that the compounds of the invention have a dose-dependent inductive effect on the ability of ATRA to induce terminal differentiation of HL60 cells, AC₅₀The value was 9.5. + -. 2.6. mu.M; and (3) overlapping induction: 1.6.

when a compound of the invention is administered in combination with ATRA, it induces a significant arrest in cells in the G0/G1 phase of the cell cycle.

The results obtained are given in table 10.

Watch 10

(ST1974 chemical sensitive Effect on ATRA in HL60 cell cycle)

Treatment of	G0/G1	G2/M	S
				Control	59.1	9.2	31.7
ST1974 1μM	58.9	11.1	30
				ST1974 5μM	59.3	11.4	29.3
ST1974 10μM	57.8	12.2	30
				ST1974 50μM	67.7	12.3	20
ATRA 0.5μM	63.4	11.0	25.6
				ATRA 0.5μM+ST 1974μM	62.0	11.7	26.3
ATRA 0.5μM+ST1974 5μM	63.8	10.5	25.7
				ATRA 0.5μM+ST1974 10μM	65.4	10.5	24.1
ATRA 0.5μM+ST1974 50μM	81.8	10.6	7.6

Example 22/9

Induction of 4, 4-bis (1H-indol-3-yl) -butyric acid (ST1961) in the Presence or absence of ATRA Effects of end-lead differentiation and NB4 cell cycling

In this assay, the effect of the compounds of the invention on induction of terminal differentiation and NB4 cell cycling at doses of 1, 5, 10, and 50 μ M was evaluated in the presence or absence of the optimal dose of ATRA.

The results obtained are shown in table 8: NBT test shows that the compound has induction effect on the capability of promoting terminal differentiation induction by ATRA, and AC₅₀The value was 6.6. + -. 2.0. mu.M; and (3) overlapping induction: 1.4.

in addition, the results obtained from cell cycle analysis are shown in Table 11, which shows that high doses of test compounds have substantially comparable potentiating effects on ATRA activity in inducing cell arrest at G0/G1.

TABLE 11

(Effect of combination of ST1961 and ATRA on NB4 cell cycle)

Treatment of	G0/G1	G2/M	S	Apoptosis
					Control	45.5	14.5	40.0	22.0
ST1961 1μM	47.5	15.6	36.9	18.5
					ST1961 5μM	49.7	13.0	37.3	24.0
ST1961 10μM	48.4	14.1	37.5	24.0
					ST1961 50μM	56.3	14.0	29.7	24.0
ATRA 0.01μM	55.8	17.3	26.9	12.5
					ATRA 0.01μM+ST 1346 1μM	57.1	13.9	29.0	17.5
ATRA 0.01μM+ST1346 5μM	58.4	13.9	27.7	17.0
					ATRA 0.01μM+ST1346 10μM	58.4	13.0	28.6	15.0
ATRA 0.01μM+ST1346 50μM	82.2	8.0	9.8	10.0

Claims (11)

1. A compound selected from (N-benzylindol-3-yl, N-benzyl-2-propylindol-3-yl) oxomethane and bis (N-benzylindol-3-yl) -oxomethane.

2. A pharmaceutical composition for the treatment of tumors comprising, as active ingredient, a compound according to claim 1, and at least one pharmaceutically acceptable excipient and/or diluent.

3. The composition of claim 2, wherein the compound is administered in combination with one or more known anti-tumor agents.

4. The composition of claim 3, wherein the anti-tumor agent is selected from the group consisting of alkylating agents, topoisomerase inhibitors, anti-tubulin agents, intercalating compounds, anti-metabolites, vinca alkaloids, epipodophyllotoxins, antibiotics, enzymes, tacrine, and cell differentiating compounds.

5. The composition of claim 4, wherein the cell differentiation anti-tumor compound is all-trans retinoic acid.

6. Use of a compound of claim 1 for the preparation of a medicament with anti-tumor activity.

7. Use of a compound according to claim 1 for the preparation of a medicament for the treatment of neoplastic disorders wherein a tumor has shown resistance to a prior antibiotic used for its treatment, wherein said compound has a chemo-sensitizing effect on said resistant tumor.

8. The use of claim 6 or 7, wherein the tumor is selected from the group consisting of sarcoma, carcinoma, carcinoid tumor, bone tumor, neuroendocrine tumor, lymphatic system leukemia, acute promyelocytic leukemia, spinal cord leukemia, monocytic leukemia, megakaryocytic leukemia, and Hodgkin's disease.

9. The use of claim 8, wherein the tumor is acute promyelocytic leukemia.

10. The use of claim 6 or 7, wherein the compound is used in combination with one or more known anti-tumor agents.

11. The use of claim 10, wherein the anti-neoplastic agent is all-trans retinoic acid.