KR20010043288A - Indole derivatives and their use in the treatment of malignant and other diseases caused by pathological cell proliferation - Google Patents

Abstract

The present invention relates to tyrosine kinase inhibitors of bis-indolyl compounds of formula I, medicaments containing them and their use in the treatment of malignant diseases and other diseases due to pathological cell proliferation.

Formula I

Description

Indole derivatives and their use in the treatment of malignant diseases and other diseases due to pathological cell proliferation.

The present invention relates to tyrosine kinase inhibitors of the bis-indolyl compound type, medicaments containing them and their use in the treatment of malignant diseases and other diseases based on pathological cell proliferation.

Activation of tyrosine-specific protein kinases is a major issue in the stimulation of animal cell division. Typically, the stimulation is affected by an exogenous factor, for example, a growth factor, when the proliferation of a particular cell type is required for the overall action of the tissue or organ. In tumors, cell proliferation is also associated with the activity of tyrosine kinases. However, in tumor cells, the overexpression of growth factors, kinase mutants that are constitutively active, or mutation activity of kinases due to dislocation activity often arise. PDGF receptor is one of the growth factors associated with human tumors. PDGF is one of the major mitogens in serum and exists at high concentrations in platelets. The most important function of the person in the adult is wound healing. The undesired activity of the PDGF receptor is associated with the proliferation of various tumors, such as glioma, glioma, sarcoma, carcinoid, ovarian cancer and colon cancer. Mutagenesis of the PDGF / PDGF receptor system also represents a major site in the pathological hyperplasia of mesenchymal cells associated with arteriosclerosis, recurrent stenosis after balloon angioplasty, arthritis and fibrosis.

In addition, some growth factor receptor tyrosine kinases whose tyrosine kinase domain has a high degree of homology to the tyrosine kinase domain of the PGDF receptor are important in tumor progression and pathological hyperplasia. These include receptors for the vascular endothelial growth factor (VEGF) KDR / Flk-1 and Flt-1, which are crucial for tumor vasculogenesis, the Kit / SCF receptor, wherein constitutively active rotations are associated with leukemia It is observed in carcinoma and Flk-2 / Flt-3, which are receptors involved in cell proliferation. It can be expected that additional members of the kinase family involved in pathological proliferation can be identified. Besides inducible stimulation, the ligand action of these receptors also often involves stimulation of cell migration, apoptosis-inhibiting action, and effects on membrane transport systems for ions, water and chemical compounds. To varying degrees, uncontrolled effects of this type also relate to pathological methods in tumors and other diseases.

Of the various possibilities for blocking the signal of receptor tyrosine kinase, the specific direct inhibition of kinase activity is most promising.

Thus, the present invention is directed to the production of compounds suitable as inhibitors of tyrosine kinases, particularly PDGF receptor tyrosine kinases, and further tyrosine kinases such as KDR / Flk-1, Kit / SCF receptor and FLK / Flt-3 . This object is achieved by the compounds of formula (I) according to the invention.

In the above formula (I)

Z is a group of the formula (II)

A may be a nitrogen atom, an oxygen atom or a sulfur atom,

X is a group of formula (III) or (IV)

R ² to R ¹³ are together in the formula II and form a bond of the formula V or the formula VI and, R ² and R ¹³ is the same or different radical or hydrogen in formula VII, R ² and R ¹³ together Lt; RTI ID = 0.0 > formula IX < / RTI >

R ¹ and R ⁷ in the formula II are the same or different and are a hydrogen atom, an alkyl or aminoalkyl radical, a phenylsulfonyl radical, an alkylsilylmethoxymethyl radical, a sugar or a substituted sugar,

R ^3, R ^4, R ⁵ and R ⁶ For the R ^8, R ^9, R ¹⁰ and R ¹¹ in the general formula II are the same or different and are each a hydrogen atom, an alkoxy-, amino-, halogen-, cycloalkyl alkyl-, cycloalkyl, heteroaryl -, alkyl-, aryl-or heteroaryl-O- group in the alkoxy-substituted alkyl, alkoxy or alkoxymethyl group, nitro group, halogen atom or a general formula ^{-O- (C = O) -R 21} ( Wherein R ²¹ is an alkoxy-, amino-, halogen-, cycloalkyl-, cycloheteroalkyl-, aryl- or heteroaryl-substituted alkyl, alkoxy or alkoxymethyl group.

In the above formulas (II) to (VII), (IX) and (X)

B and B 'may be a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom,

The ring system F and the ring system G may be independently a saturated or unsaturated 5-membered or 6-membered ring,

A is as defined above,

l and n are numbers from 0 to 6,

m is 1 and 2,

R ¹⁴ and R ¹⁵ together form an oxygen atom, or R ¹⁴ is a hydroxyl group and R ¹⁵ is a hydrogen atom, or R ¹⁴ and R ¹⁵ are hydrogen atoms,

R ¹⁶ is a hydrogen atom, an alkyl or aryl radical, a halogen-, an amino- or an azido-substituted alkyl or aryl radical, an alkyloxymethyl radical or a substituted alkyloxymethyl radical,

The dotted line is a double bond or a single bond,

R < ¹⁷ > is a halogen atom or a radical of the formula (VIII)

o can be the number 1 or 2,

When W is a carbon atom or a nitrogen atom, q may be a number from 0 to 6,

R ¹⁹ and R ²⁰ may be hydrogen atoms, alkyl radicals or substituted alkyl radicals.

In the above formula (VIII)

p may be 0, 1 or 2, and when p is 0, it is an acyclic primary amine, Y comprises an additional hydrogen atom,

Y may be a carbon atom, an oxygen atom or a nitrogen atom, and when Y is a carbon atom or a nitrogen atom, R ¹⁸ is a hydrogen atom or an alkyl or aryl radical, a substituted alkyl or aryl radical, a saturated or unsaturated heterocycle, an alkoxycarbonyl radical , An aminocarbonylmethyl radical or a substituted aminocarbonylmethyl radical.

Preferred compounds according to the invention is a compound of formula (I) above, wherein, in the case of these compounds corresponding to the following formula (XI) of the compound, Z is a group of formula II, X is a group of formula III, R ^2, and R ¹³ is a hydrogen atom, A is a nitrogen atom, B is a nitrogen, oxygen or sulfur atom and R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹⁴ and R ¹⁵ are as defined above.

Particularly preferred compounds are those of formula (XI) wherein R < ¹⁴ > and R < ¹⁵ > together form an oxygen atom.

Further preferred compounds according to the invention are those compounds of formula (I) wherein Z is a group of formula (II) when these compounds correspond to compounds of formula (XII), X is a group of formula ¹ and R ² is a hydrogen atom, a and B are nitrogen ^{atoms, R 1, R 3, R} 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11 and R ¹⁶ is As defined above.

A further preferred compound according to the invention is a compound of the formula XIII or XIV.

In the above formulas (XIII) and (XIV)

n is 3, 4, 5, 8 or 12,

q is 0, 1, 2, 3, 5 or 6,

R ¹⁹ and R ²⁰ are a hydrogen atom or an alkyl group,

R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹⁶ are the same or different and are as defined above.

A further preferred compound according to the invention is a compound of formula XV:

In the above formula (XV)

n is 1, 2 or 3,

R ¹⁶ is a hydrogen atom or an alkyl group,

R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹⁶ are the same or different and are as defined above.

The compound of formula (XI) may be prepared by one of the following two reaction schemes.

a) LDA / THF, b) HSiPh 3 / THF, c) PDC / DMF, d) 10% NaOH / Et6OH,

e) K ₂ CO ₃ / MeOH, f) N ₂ H ₄ / 2- (2-hydroxyethyloxy) -ethanol

In order to prepare a compound according to the invention in which R ² and R ¹³ are radicals of formula VII or R ² and R ¹³ together form a bond of formula V, formula IX or formula X, The 2,2'-bis-1H-indolylalkane of formula XIa or a derivative thereof is first reacted with dibromomaleimide.

In the above formula (XIa)

X, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are as defined above.

A compound according to the invention wherein R ² and R ¹³ together form a bond of formula VII is then reacted with a primary amine or secondary amine or piperazine of formula XVI or XVII:

In the above formulas XVI and XVII,

p, q, R < ¹⁷ > and W are as defined above.

The following examples illustrate the present invention without limiting it.

Example 1

Bis (N-phenylsulfonylindol-2-yl) -1-methanol

Lithium diisopropylamide is prepared from 30.40 mL (216.3 mmol) of diisopropylamine and 125.3 mL (200.5 mmol) of n-BuLi (1.6 M in hexane) in 200 mL dry THF at -78 & The solution was stirred at -78 占 폚 for 10 minutes and then at 0 占 폚 for 30 minutes before 49.13 g (190.0 mmol) of 1-phenylsulfonylindole in 300 ml of anhydrous THF was added dropwise at 0 占 폚 over 10 minutes . The reaction is stirred at 0 < 0 > C for a further 30 min. After cooling again to -78 [deg.] C, 60.00 g (210.3 mmol) of phenylsulfonyl-2-carbaldehyde in 200 mL of dry THF are added dropwise and the mixture is allowed to warm to room temperature overnight. The mixture is poured into 1% HCl, ether is added and the organic phase is separated off. Washing the organic phase was extracted with ether, the continuous and the combined organic phases with NaHCO _3, and saturated NaCl solution and dried with Na ₂ SO _4. Purified _{by; (CH 2 Cl 2 SiO 2} ) the peeling and the solvents were removed under vacuum and the crude product was purified by column chromatography. Colorless crystals, yield 86.5 g (84%)

Melting point: 185 캜 (MeOH)

The following are similarly prepared.

Example 2

Bis (5-methoxy-N-phenylsulfonylindol-2-yl) -1-methanol

Melting point: 113-114 캜 (MeOH)

Example 3

(5-methoxy-N-phenylsulfonylindol-2-yl) - (N-phenylsulfonylindol-

Melting point: 104 to 105 캜 (CH ₂ Cl ₂ / hexane)

Example 4

(5-methoxy-N-phenylsulfonylindol-2-yl) - (7-methoxy-N-phenylsulfonylindol-

Melting point: 119 to 121 캜 (CH ₂ Cl ₂ / hexane)

Example 5

(5-methoxy-N-phenylsulfonylindol-2-yl) - (N-phenylsulfonylindol-

Melting point: 99-101 ° C (CH ₂ Cl ₂ / hexane)

Example 6

(5-methoxy-2-phenylmethyloxy) - (1-phenylsulfonylindol-2-yl) methyl-1-phenylsulfonylindole

Melting point: 62 to 64 DEG C

Example 7

Di- (5-methyloxy-1-phenylsulfonylindol-2-yl) phenyl-methyloxymethane

Melting point: 100 to 101 DEG C

Example 8

(3-dimethylaminomethyl-1-phenylsulfonylindol-2-yl) (1-phenylsulfonylindol-2- yl) methan-

Melting point: 116-117 DEG C

Example 9

(7-methoxy-N-phenylsulfonylindol-2-yl) - (N-phenylsulfonylindol-

Melting point: 149-115 DEG C

Example 10

Dibenzothiophen-2-yl-1-methanol

Melting point: 130-131 DEG C

Example 11

1-phenylsulfonyl-1H-2-indolyl (1-phenylsulfonyl-1H-2-indolyl)

Melting point: 180 DEG C

Example 12

Methoxy-1-phenylsulfonyl-1H-2-indolyl (1-phenylsulfonyl-1H-2-indolyl)

Melting point: 148-150 DEG C

Example 13

Benzo [b] thiophen-2-yl (5-methoxy-l-phenylsulfonyl-lH-2-indolyl)

Melting point: 71-73 DEG C

Example 14

Benzo [b] thiophen-2-yl (7-methoxy-l-phenylsulfonyl-lH-2-indolyl)

Melting point: 118-119 DEG C

Example 15

Benzo [b] furan-2-yl (5-methoxy-l-phenylsulfonyl-lH-2-indolyl)

Melting point: 71-73 DEG C

Example 16

Bis (N-phenylsulfonylindol-2-yl) methan-1-one

A solution of 20.00 g (36.9 mmol) of bis (N-phenylsulfonylindol-2-yl) -1-methanol in 200 mL of anhydrous DMF is cooled to 0 占 폚. After 90.4 g of pyridinium dichromate (PDC) was added, the mixture was stirred at room temperature for 20 hours. For the working-up, it is the H ₂ 0 700mL with CH ₂ Cl ₂ 700mL. The aqueous phase is extracted twice with 200 mL of CH ₂ Cl ₂ . Wash the combined organic extracts with H ₂ 0 500mL. The solvent is stripped off under vacuum, CH ₂ Cl ₂ is added and the product is precipitated. Colorless crystals, yield 15.0 g (75%).

Melting point: 244 캜 (MeOH / ether)

The following are similarly prepared.

Example 17

(5-methoxy-N-phenylsulfonylindol-2-yl) - (N-phenylsulfonylindol-2- yl) methan-

Melting point: 205 DEG C (MeOH)

Example 18

Bis (5-methoxy-N-phenylsulfonylindol-2-yl) -1-methanone

Example 19

Bisindol-2-ylmethan-1-one

10.0 g (18.5 mmol) of bis (N-phenylsulfonylindol-2-yl) methan-1-one are dissolved in 380 mL of 99% EtOH. After addition of 210 mL of 10% NaOH, the solution is heated under reflux for 20 hours. For work-up, EtOH is stripped off, 500 mL of saturated NaCl solution and 500 mL of CH ₂ Cl ₂ are added and the phases are separated. The aqueous phase is extracted twice with 200 mL of CH ₂ Cl ₂ , and the combined organic extracts are dried over Na ₂ SO ₄ and concentrated in vacuo. The bisindole can be deposited as a crude product and recrystallized from CH ₂ Cl ₂ . Yellow crystals, yield 4.5 g (93%)

Melting point: 272-273 캜 (CH ₂ Cl ₂ )

The following are similarly prepared.

Example 20

(5-methoxyindol-2-yl) - (indol-2-yl) methan-

Melting point: 233-235 캜 (MeOH)

Example 21

Bis (5-methoxyindol-2-yl) -1-methanone

Melting point: 202 to 204 DEG C

Example 22

Dibenzothiophen-2-yl-1-methanone

Melting point: 161 캜

Example 23

5-methyl-1-phenylsulfonyl-3-indolyl (1-phenylsulfonyl-2-indolyl)

Melting point: 114-116 DEG C

Example 24

(LH-indol-2-yl) - (lH-indol-3-yl)

Melting point: 260-261 DEG C (MeOH)

Example 25

Benzo [b] thiophen-2-yl (7-methoxy-l-phenylsulfonyl-lH-2-indolyl)

Melting point: 190 DEG C

Example 26

Benzo [b] thiophen-2-yl (7-methoxy-lH-2-indolyl)

Melting point: 155 캜

Example 27

Benzo [b] thiophen-2-yl (5-methoxy-l-phenylsulfonyl-lH-2-indolyl)

Melting point: 82-83 DEG C

Example 28

Benzo [b] thiophen-2-yl (5-methoxy-lH-2-indolyl)

Melting point: 200 占 폚

Example 29

Methoxy-l-phenylsulfonyl-lH-2-indolyl (l-phenylsulfonyl-lH-indolyl) methanone

Melting point: 129 - 130 캜

Example 30

Methoxy-1H-2-indolyl (1H-2-indolyl) methanone

Melting point: 151 캜

Example 31

1-phenylsulfonyl-1H-2-indolyl (1-phenylsulfonyl-1H-2-indolyl) methanone

Melting point: 184 - 186 캜

Example 32

6-methoxy-1H-2-indolyl (1H-2-indolyl) methanone

Melting point: 184 - 186 캜

Example 33

1-methyl-1H-2-indolyl (1-ethyl-5-methyloxy-1H-2-indolyl)

Melting point: 148 - 149 캜

Example 34

1H-2-indolyl (1-methyl-5-methyloxy-1H-2-indolyl)

Melting point: 190 DEG C

Example 35

1-methyl-1H-2-indolyl (5-methyloxy-1H-2-indolyl)

Melting point: 176-177 ° C

Example 36

Ethyl-1H-2-indolyl (1-ethyl-5-methyloxy-1H-2-indolyl)

Melting point: 99-100 DEG C

Example 37

1H-2-indolyl (1-ethyl-5-methyloxy-1H-2-indolyl)

Melting point: 142-143 DEG C

Example 38

Ethyl-1H-2-indolyl (5-methyloxy-1H-2-indolyl)

Melting point: 101 to 102 DEG C

Example 39

Benzyl-1H-2-indolyl (1-benzyl-5-methoxy-1H-2-indolyl)

Melting point: 132 占 폚

Example 40

1H-2-indolyl (1-benzyl-5-methoxy-1H-2-indolyl)

Melting point: 180 to 182 DEG C

Example 41

Benzyl-1H-2-indolyl (5-methoxy-1H-2-indolyl)

Melting point: 167 to 168 DEG C

Example 42

5-benzyloxy-1H-2-indolyl (1H-2-indolyl)

Melting point: 199-201 DEG C

Example 43

5-hydroxy-1H-2-indolyl (1H-2-indolyl)

Melting point:> 220 ° C

Example 44

5-ethoxy-1H-2-indolyl (1H-2-indolyl)

Melting point: 168-169 ° C

Example 45

1H-2-indolyl [5- (2-morpholin-1-ylethyloxy) -1H-2-indolyl] methanone

Melting point: 98 to 101 DEG C

Example 46

1H-2-indolyl [5- (3-dimethylaminopropyloxy) -1H-2-indolyl] methanone

Melting point: 163-166 ° C

Example 47

5- (4-Iodobutyloxy) -1H-2-indolyl (1H-2-indolyl)

Melting point: 110 to 113 DEG C

Example 48

1H-2-indolyl [5- (2-dimethylaminoethyloxy) -1H-2-indolyl] methanone

Melting point: 143 - 145 캜

Example 49

5-Cyclohexylmethyloxy-1H-2-indolyl (1H-2-indolyl) methanone

Melting point: 185 占 폚 (decomposition)

Example 50

5- (5-iodopentyloxy) -1H-2-indolyl (1H-2-indolyl)

Melting point: 127-130 DEG C

Example 51

1H-2-indolyl [5- (1-phenylethyloxy) -1H-2-indolyl] methanone

Melting point: 151 - 153 캜

Example 52

1H-2-indolyl [5- (2-piperidin-1-ylethyloxy) -1H-2-indolyl] methanone

Melting point: 104-106 DEG C

Example 53

[2- (1H-2-indolylcarbonyl) -1H-5-indolyl]] ethanoate

Melting point: 223-224 < 0 > C

Example 54

[2- (1H-2-indolylcarbonyl) -1H-5-indolyl]] 4-methoxybenzoate

Melting point:> 230 ° C

Example 55

[2- (1H-2-indolylcarbonyl) -1H-5-indolyl)] butanoate

Melting point: 201 - 204 캜

Example 56

[2- (1H-2-indolylcarbonyl) -1H-5-indolyl]] 2- (N, N) -dimethylaminoethanoate

Melting point: 215 - 217 캜

Example 57

[2- (1H-2-indolylcarbonyl) -1H-5-indolyl)] propanoate

Melting point:> 230 ° C

Example 58

[2- (1H-2-indolylcarbonyl) -1H-5-indolyl]] 2-thiophenylethanoate

Melting point: 224-226 占

Example 59

[2- (1H-2-indolylcarbonyl) -1H-5-indolyl]] O-acetyl salicylate

Melting point: 133-135 DEG C

Example 60

[2- (1H-2-indolylcarbonyl) -1H-5-indolyl]] 4-phenylbenzoate

Melting point:> 220 ° C

Example 61

[2- (1H-2-indolylcarbonyl) -1H-5-indolyl]] 2-phenylpropanoate

Melting point: 211-313 DEG C

Example 62

[2- (1H-2-indolylcarbonyl) -1H-5-indolyl]] a-acetylphenylethanoate

Melting point: 194-196 DEG C

Example 63

[2- (1H-2-indolylcarbonyl) -1H-5-indolyl)] benzoate

Melting point:> 230 ° C

Example 64

[2- (1H-2-indolylcarbonyl) -1H-5-indolyl] 3-methoxyphenylethanoate

Melting point: 212 to 215 캜

Example 65

[2- (1H-2-indolylcarbonyl) -1H-5-indolyl]] 2-chlorobenzoate

Melting point:> 230 ° C

Example 66

[2- (1H-2-indolylcarbonyl) -1H-5-indolyl]] 4-nitrobenzoate

Melting point:> 230 ° C

Example 67

[2- (1H-2-indolylcarbonyl) -1H-5-indolyl) 3,4,5-trimethoxybenzoate

Melting point: 216 - 219 캜

Example 68

[2- (1H-2-indolylcarbonyl) -1H-5-indolyl) cinnamate

Melting point: 226-228 占

Example 69

[2- (1H-2-indolylcarbonyl) -1H-5-indolyl)] 2-furanyl carboxylate

Melting point:> 230 ° C

Example 70

Di (1-phenylsulfonyl-1H-2-indolyl) methane

Trifluoroacetic acid (TFA) for 30 minutes after 22.4mL bis in anhydrous CH ₂ Cl ₂ 400mL (N- phenylsulfonyl-indol-2-yl) -1-methanol 26.67g (49.2mmol) and triphenyl silane 15.00g ( 0.0 > mmol) < / RTI > After stirring at room temperature for 1 hour, H ₂ O is added and the mixture is carefully neutralized with solid Na ₂ CO ₃ while ice-cooling. After separation of the phases, the organic phase is dried over Na ₂ SO ₄ , the solvent is evaporated off and the crude product is purified by column chromatography (SiO ₂ ; CH ₂ Cl ₂ / hexane 6: 4). Colorless crystals, yield: 22.5 g (87%)

Melting point: 144-145 占 폚 (ether)

The following are similarly prepared.

Example 71

Bis (5-methoxy-N-phenylsulfonylindol-2-yl) methane

Melting point: 159-160 캜 (CH ₂ Cl ₂ / hexane)

Example 72

(5-methoxy-N-phenylsulfonylindol-2-yl) - (N-phenylsulfonylindol-

Melting point: 98-100 캜 (CH ₂ Cl ₂ / hexane)

Example 73

(5-methoxy-N-phenylsulfonylindol-2-yl) - (7-methoxy-N-phenylsulfonylindol-

Melting point: 168-170 캜 (CH ₂ Cl ₂ / hexane)

Example 74

Di (1H-2-indolyl) methane

15.0 g (28.5 mmol) of compound (57) are boiled with 800 mL of MeOH and 20 g of K ₂ CO _{3 in} 200 mL of H ₂ O for 14 days. For post-treatment, add 500 mL of saturated NaCl solution and separate the phases. After drying the organic phase, the solvent is stripped off under vacuum. The crude product is purified by column chromatography. Colorless crystals, yield 5.4 g (76%)

Melting point 189-191 C

The following are similarly prepared.

Example 75

(5-methoxyindol-2-yl) - (indol-2-yl) methanone

Melting point: 112 < 0 > C (MeOH)

Example 76

(LH-indol-2-yl) - (lH-indol-3-yl)

Melting point: 161-163 占 폚 (saturated EtOH)

Example 77

1,3-di (1H-2-indolyl) propane

38.0 g (0.21 mol) of trimethylsilyl-o-toluidine are dissolved in 950 mL of anhydrous hexane and 291.0 mL (0.47 mol) of n-BuLi (1.6 M in hexane) is added dropwise at room temperature and the mixture is heated to reflux for 4 hours. It is then cooled to -78 ° C and 20.5 mL (0.11 mol) of diethyl glutarate in 380 mL of dry THF is added dropwise at that temperature. The mixture is stirred at -78 < 0 > C for 1 hour, then slowly warmed to room temperature overnight and then boiled for additional 2 hours. After cooling, it is poured into 1 L of ice water and extracted twice with 500 mL of ethyl acetate, the combined organic phases are dried over Na ₂ SO ₄ and the solvent is stripped off under vacuum. White crystals, yield 6.55 g (23.9 mmol, 22%)

Melting point: 143-145 占 폚 (ethanol)

The following are similarly prepared.

Example 78

1,3-di (1H-2-indolyl) ethane

Melting point: 264 to 267 DEG C

Example 79

1,2-di- (1-phenylsulfonyl-1H-2-indolyl) -1-ethane

TiCl ₄ (17.9 mmol) and Zn powder (2.0 g, 30.5 mmol) are continuously added to the syringe. The mixture is heated under reflux for 30 minutes. Thereafter, 3 g (10.5 mmol) of the compound (22) dissolved in 50 mL of THF is added dropwise again at 0 占 폚. The solution is heated under reflux overnight. Pour 300 mL of 20% K ₂ CO ₃ solution into the cooled solution and stir at room temperature overnight. The sludge residue is then filtered off, washed with THF, the organic phase is separated off from the filtrate and the aqueous phase is extracted with CH ₂ Cl ₂ .

Wash the combined organic phases with water, then dried with Na ₂ SO ₄ and removed from the solvent in vacuo. And purified by; column chromatography (1 CH ₂ Cl ₂ / hexane ₂ SiO 2). Yield: 1.1 g (2.0 mmol, 39%) of yellow crystals

Melting point: 272 DEG C

Example 80

Bis (5-methoxy-N-phenylsulfonylindol-2-yl) phenoxymethane

188 mg of NaH (60% in paraffin) are added to a solution of 2 g (3.7 mmol) of bis (N-phenylsulfonylindol-2-yl) -1-methanol in 20 ml of THF at 0 ° C. 13.5 mg of tetrabutylammonium iodide and 0.45 ml of benzyl bromide are successively added, and the mixture is stirred at 20 占 폚. Then, water and ether are carefully added, the ether phase is separated off and the aqueous phase is washed twice with ether. The organic phase is dried over Na ₂ SO ₄ and the solvent is stripped off. Yield: 0.86 mg (81%)

Melting point: 192 占 폚 (decomposition)

Example 81

[3 ', 4', 3, 4] -cyclohepta [b] indole-3,3,4,8,10-hexahydroindolo [3 ' 1,3-dione

A half of 0.73 mL (9.75 mmol) dry ethyl bromide is added to 236 mg (9.75 mmol) Mg turning in 6 mL dry THF. After initiating the reaction, the remaining ethyl bromide is added dropwise and the solution is continuously boiled. Then, the Mg is boiled until the turning is dissolved (about 30 minutes). After cooling to room temperature, 1.00 g (4.06 mmol) of methylene-2,2'-bisindole in 25 mL of anhydrous toluene and 1 mL of dry THF are added dropwise and the mixture is stirred at 45 ° C. for 45 minutes. After cooling back to room temperature, 1.04 g (4.06 mmol) of dibromomaleimide in 50 mL anhydrous toluene and 2 mL dry THF are added dropwise over 1 hour, and the mixture is heated under reflux overnight. For the post-treatment, 100 g of ice and 50 mL of 20% citric acid are added, and the mixture is extracted by shaking twice with 50 mL of ethyl acetate. The organic extracts were washed with H ₂ 0 and dried with Na ₂ SO ₄ and concentrated. The crude product is purified by column chromatography (SiO ₂ , 1. CH ₂ Cl ₂ / ethyl acetate 8: 2; 2. CH ₂ Cl ₂ / ethyl acetate 7: 1). Red crystals, Yield 290 mg (22%) Melting point: > 350 캜 (ethyl acetate)

The following are similarly prepared.

Example 82

3 ', 4': 3,4] -cyclohepta [b, 3 ', 5,6] pyrrolo [3' ] Indole-1,3-dione

Melting point:> 350 ° C (EtOH)

Example 83

[3 ', 4': 3,4] cyclonona [b] indole [3 ' -1,3-dione

Melting point: 137 캜 (CH ₂ Cl ₂ ) (decomposition)

Example 84

Heptahydro-2-methylindolo [3 ', 2': 5,6] -pyrrolo [3 ', 4': 3,4] -cycloocta [b] indole-1,3-dione

Melting point:> 350 ° C

Example 85

[3 ', 2': 5,6] -Pyrrolo [3 ', 4': 3,4] -cyclohexylcarbodiimide hydrochloride Hepta [b] indole-1,3-dione

Melting point:> 350 ° C (EtOH)

Example 86

2, 3 ', 5,6] pyrrolo [3', 4 ': 3,4] -cyclohepta [b ] Indole-1,3-dione

Melting point:> 350 ° C (CH ₂ Cl ₂ )

Example 87

[3 ', 5', 6] furo [3 ', 4': 1 '] thiophene was obtained in the same manner as in [ 3,4] cyclohepta [b] indole-1,3-dione

Melting point:> 350 ° C (MeOH)

Example 88

Ethyl] indolo [3 ', 2 ': 5,6-dihydroxy- ] Pyrrolo [3 ', 4': 3,4] -cyclohepta [b] indole-1,3-dione

Melting point: 164 to 165 캜 (MeOH)

Example 89

Ethyl] indolo [3 ', 2 ': 5,6] pyrrolo [3,2-d] [3 ', 4': 3,4] -cyclohepta [b] indole-1,3-dione

Melting point: 185 캜 (MeOH)

Example 90

[3 ', 2': 5,6] pyrrolo [3 ', 5 '] thiophene- 4 ': 3,4] cyclohepta [b] indole-1,3-dione

Melting point: 213-214 C (EtOH)

Example 91

L-methyl-2,5-dihydro-lH-pyrrolo [2,3-b] pyrrole- 5-dione

Melting point: 169 DEG C

Example 92

-1H-3-indolyl) -1-methyl-2,5-dihydro-1H-pyrrole-2,5- - Dion

Melting point: 165 占 폚 (decomposition)

Example 93

-1H-3-indolyl) -1-methyl-2,5-dihydro-1H-pyrrole-2,5-dicarboxylic acid - Dion

Melting point: 125 캜 (decomposition)

Example 94

Bis (indol-3-yl) methanone

Prepared analogously to example 31 using triphosgene in place of dibromomaleimide.

Melting point: 297 to 299 DEG C

Example 95

Benzyl-β-D-glucopyranosyl) -2-benzyloxymethyl-1,2,3,8,9,10-hexahydroindolo [3 ', 5'- 2 ': 5,6] pyrrolo [3', 4 ': 3,4] cyclohepta [b] indole- 2 ': 5,6] pyrrolo [3 ', 4 ': 3 , 4] cyclohepta [b] indole-1,3-dione

A diastereomeric mixture of disubstituted O-glycosides

2 ': 5,6] pyrrolo [3', 4 ': 3,4] cyclohepta [b] thiophene ] Indole-1,3-dione are added to a suspension of 91.8 mg (3.06 mmol) NaH (80% in paraffin oil) in 16 mL dry THF. After 30 minutes, a solution of 1,2-anhydro-3,4,6-tri-O-benzyl-D-glucopyranose in 16 mL of anhydrous THF is added dropwise. The mixture is stirred at 50 < 0 > C for 5 hours and at 60 < 0 > C for 1 hour. For workup, the reaction mixture is poured into 10 mL of saturated NaHCO ₃ solution and extracted three times with 10 mL of ethyl acetate. Wash the combined organic extracts with saturated NaCl solution, 15mL, dried over Na ₂ SO ₄ and concentrated under vacuum. The product is separated from the by-product and unreacted starting material by column chromatography (column 1: SiO ₂ ; toluene / isopropylamine 8: 2; column ₂ : SiO ₂ ; CH ₂ Cl ₂ / MeOH 12: 1). The diastereomer mixture is separated by HPLC.

Example 96

[3 ', 2': 5,6] pyrrolo [3 ', 4 ': 3,2,3,4,5,6,7,8- hexahydroindolo [ 4 '] cyclohepta [b] indole-1,3-dione and 8- (? - D-mannopyranosyl) -1,2,3,8,9,10-hexahydroindolo [3', 2 ' 5,6] pyrrolo [3 ', 4': 3,4] cyclohepta [b] indole-1,3-dione

(3,4,6-tri-O-benzyl-2-benzyl-oxymethyl-D-glucopyranosyl) -1,2,3,8,9,10-hexahydroindole as a diastereomeric mixture 150 mg (0.17 mmol) of [3 ', 2': 5,6] pyrrolo [3 ', 4': 3,4] cyclohepta [b] indole-1,3-dione was dissolved in 50 mL of dry EtOH and Pd / C (5%) is added and the solution is stirred for 5 hours under a H ₂ atmosphere pressure of 7 bar. It is then filtered off with suction through celite, washed with 50 mL of CH ₂ Cl ₂ and the solution is concentrated in vacuo. Without purification, the product is dissolved in 15 mL of anhydrous THF and the solution is cooled to 0 < 0 > C. Then passes through the NH ₃ for 10 min and the mixture was stirred at room temperature for 1 hour. Purified by the after stirring the THF in vacuo, residual five days was purified by column chromatography _{(2 SiO 2:: CH 2} Cl 2 / MeOH 8). Red oil, yield 10 mg (12%)

Example 97

[3 ', 5'] pyrrolo [3 ', 4': 3,4] cyclohepta [b] indole -1,3-dione

1.20 g (18.4 mmol) of Zn granules are washed twice with 3 mL of 2N HCl, then immediately added to 1.5 mg of H ₂ O and 90 mg (0.33 mmol) of HgCl _{2 in} 1.5 mL of concentrated HCl and the mixture is shaken at room temperature for 10 minutes. The aqueous phase was decanted and the zinc amalgam was further washed twice with 3 mL of diluted HCl, which was then washed with 1.5 mL of 5N HCl, 1.5 mL of EtOH, and 1,2,3,8,9, 10-hexahydroindole Was added to a solution of 60.0 mg (0.18 mmol) of [3 ', 2': 5,6] pyrrolo [3 ', 4': 3,4] cyclohepta [b] indole- . After 1 hour, as soon as the reaction mixture is cooled to room temperature, H ₂ O is added and the mixture is extracted twice with 10 mL of CH ₂ Cl ₂ . The organic extracts are dried over Na ₂ SO ₄ , concentrated in vacuo and purified by column chromatography (SiO ₂ : CH ₂ Cl ₂ / ethyl acetate / MeOH 8: 2: 0.5). Colorless wax, yield 14 mg (23%)

Example 98

Dihydro-3,4-bis (N-trimethylsilylethoxymethylindol-2-yl) -1H-pyrrolo-

1.05 g (1.96 mmol) of 2-tributylstannyl-N-trimethylsilylethoxymethylindole in 5 mL of anhydrous DMF was added to a solution of 22.65 mg (0.02 mmol) of tetrakistriphenylphosphine palladium in 10 mL of anhydrous DMF and 3,4- 2,5-dihydro-1H-pyrrolo-2, 5-dione and the mixture is heated continuously at 110 ° C for 1 hour. After cooling, it is poured into 50 mL of H ₂ O and extracted twice with 50 mL of ether. Extract the ether phase with H ₂ 0 and dried 100mL with Na ₂ SO ₄ and concentrated. The product can be separated by column chromatography (1. column: SiO ₂ ; CH ₂ Cl ₂ / MeOH / hexane 20: 1: 2, column ₂ : SiO ₂ ; CH ₂ Cl ₂ / ethyl acetate 20: 1) .

Yellow wax, yield 200 mg (19%)

The following can be similarly prepared.

Example 99

2,5-dihydro-3,4-bisindol-2-yl-lH-pyrrolo-

Melting point: 197 캜 (decomposition) (CH ₂ Cl ₂ / hexane)

Example 100

2,5-dihydro-3,4- (N-phenylsulfonylindol-2-yl) -lH- pyrrolo-

Melting point: 196-197 占 폚 (decomposition) (acetone)

Example 101

2,5-dihydro-1-methyl-3,4-bis (N-phenylsulfonylindol-2-yl)

Melting point: 147 占 폚 (ether)

Example 102

Dihydro-3,4-bisindol-2-yl-1-methyl-lH-pyrrolo-

Melting point: 247 캜 (CH ₂ Cl ₂ / hexane) (decomposition)

Example 103

Dihydro-3-indol-2-yl-1- [2- (N, N-dimethylamino) Dione

(N-phenylsulfonylindol-2-yl) -lH-pyrrolo [2,3-d] pyrimidin- Dion

4.12 mmol of 2,5-dihydro-3,4-bis (N-phenylsulfonyl-indol-2-yl) -lH-pyrrolo-2,5- dione was dissolved in 30 mL of anhydrous DMF and 200 mg (5.00 mmol ) Is carefully added with stirring. After stirring at room temperature for 1 hour, the halide is added and the mixture is stirred at room temperature for 24 hours. For post-treatment, the mixture is added to ice water. After evaporation of the DMF and H ₂ 0 in vacuo, and the residue was dissolved in CH ₂ Cl ₂ and the solution was washed with H ₂ 0. After drying over Na ₂ SO ₄ , the solvent is stripped off under vacuum and the residue is purified by column chromatography (SiO ₂ ; ethyl acetate). Yield 448 mg. Compound (121) and compound (122) can be separated by column chromatography.

The following are similarly obtained.

Example 104

Dihydro-3,4-bis (indol-2-yl) -1- [2- (N, N- dimethyl- amino) ethyl] -1H- pyrrolo-

Orange wax

Example 105

Dihydro-3,4-bis (N-phenylsulfonyl-indol-2-yl) -lH-pyrrolo [

Tan wax

Example 106

Dihydro-3-indol-2-yl-4- (N-phenylsulfonylindol-2-yl) -lH- pyrrolo-

Melting point: 160 占 폚 (decomposition)

Example 107

Dihydro-3,4-bis (indol-2-yl) -1H-pyrrolo 2, 5-dione

Melting point: 104 to 109 DEG C

Example 108

Dihydro-3,4-bis (N-phenylsulfonylindol-2-yl) -lH-pyrrolo 2, 5-dione

Melting point: 165 占 폚 (decomposition)

Example 109

Dihydro-3-indol-2-yl-4- (N-phenylsulfonylindol-2-yl) -lH- pyrrolo [

Melting point: 190 占 폚 (decomposition)

Example 110

Dihydro-3-indol-2-yl-4- (N-phenylsulfonylindol-2-yl) -lH- pyrrolo 2,

Melting point: 180 占 폚 (decomposition)

Example 111

4- (2- (3- (3- (4-Bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl) Indolyl) propyl) -1H-3-indolyl) -1-methyl-2,5-dihydro-1H-pyrrole-

200 mg (0.7 mmol) of 1,3-di (1H-2-indolyl) propane are dissolved in 4 mL of anhydrous THF and cooled to 0 ° C. Subsequently, 1.09 mL (1.7 mmol) of n-BuLi (1.6M in hexane) was added dropwise over 30 minutes and the mixture was stirred at room temperature for 2 hours. Subsequently, 0.46 g (1.71 mmol) of N-methyldibromomaleimide in 4 mL of dry THF is slowly added dropwise. The mixture is stirred at room temperature overnight and then poured into 10 mL of 2N HCl. Then, the mixture was extracted with ether (2 × 10mL) and ethyl acetate (3 × 10mL), dry the organic phase with Na ₂ SO ₄ and stripped off the solvent in vacuo. The residue was purified by column chromatography _{(SiO 2, CH 2 Cl 2} ). Red powder, yield: 0.20 g (44%).

Melting point: 160 캜 (decomposition).

The following are similarly prepared.

Example 112

4- (2- (5- (3- (4-bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl) Indolyl) pentyl) -1H-3-indolyl) -1-methyl-2,5-dihydro-1H-pyrrole-

Melting point: 137 占 폚 (decomposition)

Example 113 Synthesis of

4- (2- (3- (3- (4-bromo-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl) ) Propyl) -1H-3-indolyl) -2,5-dihydro-lH-pyrrole-2,5-dione

Melting point:> 350 ° C

Example 114

4- (2- (5- (3- (4-bromo-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl) ) Pentyl) -lH-3-indolyl) -2,5-dihydro-lH-pyrrole-2,5-dione

Melting point:> 350 ° C (decomposition)

Example 115

4- (2- (8- (3- (4-Bromo-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl) ) Octyl) -1H-3-indolyl) -2,5-dihydro-1H-pyrrole-2,5-dione

Melting point: 180 占 폚 (decomposition)

Example 116

4- (2- (2- (3- (4-Bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl) Indolyl) ethyl) -1H-3-indolyl) -1-methyl-2,5-dihydro-1H- pyrrole-

Melting point: 179 DEG C

Example 117

4- (2- (4- (3- (4-bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl) Indolyl) butyl) -1H-3-indolyl) -1-methyl-2,5-dihydro-1H-pyrrole-

Melting point: 190 占 폚 (decomposition)

Example 118

4- (2- (8- (3- (4-Bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl) 2-indolyl) octyl) -1H-3-indolyl) -1-methyl-2,5-dihydro-1H- pyrrole-

Melting point: 185 占 폚 (decomposition)

Example 119

4- (2- (10- (3- (4-Bromo-1-methyl-2,5-dioxo-2,5-dioxo-2,5-dihydro- - pyrrolyl) -1H-2-indolyl) decyl) -1H-3-indolyl) -1-methyl-2,5-dihydro-1H- pyrrole-

Melting point: 164 占 폚 (decomposition)

Example 120

4- (2- (10- (3- (4-bromo-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl) ) Decyl) -1H-3-indolyl) -2,5-dihydro-1H-pyrrole-2,5-dione

Melting point: 164 占 폚 (decomposition)

Example 121

4- (2- (12- (3- (4-Bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl) Indolyl) decyl) -1H-3-indolyl) -1-methyl-2,5-dihydro-1H-pyrrole-

Melting point: 126-129 占

The compound of Example 114 is reacted with dimethylamine to give the following.

Example 122

3-N, N-dimethylamino-4- (2- (5- (3- (4-N, N-dimethylamino-2,5-dioxo-2,5-dihydro- ) -1H-2-indolyl) -pentyl) -lH-3-indolyl) -2,5-dihydro-lH-pyrrole-

Example 123

(1-methyl-4- (1-pyrrolidinyl) -2,5-dioxo-2,5 -1H-2-indolyl) pentyl) - lH-3-indolyl) -2,5-dihydro-lH-pyrrole-2,5-dione

4- (2- (5- (3- (4-bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl) -1,5-dihydro-1H-pyrrole-2,5-dione (1.0 g, 1.5 mmol) was dissolved in 5 mL of pyrrolidine (60.6 mmol ) And stirred overnight at room temperature. Then, excess pyrrolidine is distilled off. The residue oil-removed completely from the solvent residues from the vacuum pump, and then column chromatography _{(SiO 2, CH 2 Cl 2} / ethyl acetate 95: 5) to give the. Yield: 480 mg (49%).

Melting point: 289 DEG C

The following are similarly prepared.

Example 124

(1-methyl-3- (1-piperidinyl) -2, 5-dioxo-2,5 -1H-2-indolyl) pentyl) - lH-3-indolyl) -2,5-dihydro-lH-pyrrole-2,5-dione

Melting point: 262 DEG C

Example 125

Methyl-3- (1-morpholinyl) -4- (2- (5- (3- (1-methyl- -1H-2-indolyl) pentyl) - lH-3-indolyl) -2,5-dihydro-lH-pyrrole-2,5-dione

Melting point: 168-170 ° C

Example 126

(1-methyl-3- (1-tetrahydroisoquinolinyl) -4- (2- (5- (3- -1H-2-indolyl) pentyl) -1H-3-indolyl) -2,5-dihydro-1H-pyrrole-2,5 - Dion

Melting point: 141-142 DEG C

Example 127

4- (2- (5- (3- (1-methyl-4- (1- (4- ( 3-pyrrolyl) -1H-2-indolyl) pentyl) -1H-3-indole < EMI ID = Yl) -2,5-dihydro-1H-pyrrole-2,5-dione

Melting point: 140-141 DEG C

Example 128

Methyl-3- (1- (4-isopropylaminocarbonylmethylpiperazinyl)) -4- (2- (5- (3- -1H-3-indolyl) -1H-2-indolyl) pentyl) -1H-3-indolyl) -2,5-dioxo- 2,5-dihydro-lH-pyrrole-2,5-dione

Melting point: 126-128 DEG C

Example 129

Methyl-3- (1- (4-isopropylaminocarbonylmethylpiperazinyl) -4- (2- (5- (3- (4-bromo- -1H-2-indolyl) pentyl) -1H-3-indolyl) -2,5-dihydro-1H-pyrrole-2,5-dione

Melting point: 156 占 폚

Example 130

Methyl-3- (1- (4-pyrrolidinylcarbonylmethylpiperazinyl)) -4- (2- (5- (3- Indolyl) pentyl) -lH-3-indolyl) - 2,5-dioxo-2,5-dihydro-1H- 2,5-dihydro-lH-pyrrole-2,5-dione

Melting point: 158 占 폚 (decomposition)

Example 131

Methyl-3- (1- (4-pyrrolidinylcarbonylmethylpiperazinyl)) -4- (2- (5- (3- (4-bromo- -1H-2-indolyl) pentyl) -1H-3-indolyl) -2,5-dihydro-1H-pyrrole-2,5-dihydro- Dion

Melting point: 158-159 DEG C

Example 132

4- (2- (5- (3- (1-Methyl-4- (1- (4-piperidinopiperidyl) 2-indolyl) pentyl) -1H-3-indolyl) -2,5-dihydro-1H- -1H-pyrrole-2,5-dione

Melting point: 230 to 232 占 폚 (decomposition)

Example 133

Methyl-3- (1- (4-piperidinopiperidinyl)) - 4- (2- (5- (3- (4-bromo- -1H-2-indolyl) pentyl) -1H-3-indolyl) -2,5-dihydro-1H-pyrrole-2,5-dione

Melting point: 162 to 164 캜

Example 134

4- (2- (5- (3- (1-Methyl- (4-ethoxycarbonylpiperazin-1-yl) -1H-2-indolyl) pentyl) -1H-3-indolyl) -2,5-dihydro- Dihydro-lH-pyrrole-2,5-dione

Melting point: 149-150 DEG C

Example 135

4- (2- (5- (3- (1-Methyl- (4-bromo-2-methyl- -1H-2-indolyl) pentyl) - lH-3-indolyl) -2,5-dihydro-lH-pyrrole- 2,5-dione

Melting point: 120 to 122 占 폚 (decomposition)

Example 136

4- (2- (4- (3- (1-Methyl- (4-bromo-2,5-dihydro- -1H-2-indolyl) pentyl) -1H-3-indolyl) -2,5-dihydro-1H-pyrrole-2,5 - Dion

Melting point: 180 占 폚 (decomposition)

Example 137

4- (2- (4- (3- (1-Methyl- (4- (N-1,2-dihydro- -1H-2-indolyl) butyl) -1H-3-indolyl) -2,5-di Hydro-lH-pyrrole-2,5-dione

Melting point:> 240 ° C (decomposition)

Example 138

4,39-Dimethyl-1,4,14,29,39,42-hexaazaoctacyclo- [40.2.2.0 (2,6) .0 (7,15) .0 (8,13) (36) .0 (30,35) .0 (37,41)] hexatetracona-2 (6), 7 (15), 8 (13), 9,11,28 (36) , 31,33,37 (41) -decane-3,5,38,40-tetraene

4- (2- (12- (3- (4-Bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl) 2-indolyl) dodecyl) -1H-3- indolyl) -1-methyl-2,5-dihydro -1H- pyrrole-2,5-dione the 0.75mmol dissolved in 200mL anhydrous DMF and anhydrous NEt ₃ 0.5 lt; RTI ID = 0.0 > 80 C. < / RTI > Subsequently, a solution of 0.75 mmol of piperazine in 100 mL of anhydrous DMF and 0.5 mL of NEt ₃ is slowly added dropwise to the lukewarm solution, and the mixture is stirred at 80 캜 for 48 hours. The solvent is then removed as much as possible in vacuo and the residue is treated with 100 mL of 1N HCl. The solution is then extracted with ethyl acetate (about 600 mL total), the combined extracts are dried over Na ₂ SO ₄ and the solvent is stripped off in vacuo. And purified _{by: (0.5 SiO 2, CH 2} Cl 2 / EA 9.5) column chromatography.

Orange crystals, Yield: 0.267 g (52%)

Melting point: 194 to 195 캜

The following are similarly prepared.

Example 139

8,43-dimethyl-5,8,18,33,43,46-hexaazanocyclo- [44.2.2.2 (2,5) .0 (6,10) (17,15) .0 (32,40) .0 (34,39) .0 (41,45)] pentaaconta-6 (10), 11 (19), 12 (17), 13,15,32 40), 34 (39), 35,37,41 (45) -decaren-7,9,42,44-tetra

Melting point:> 250 ° C

Example 140

9,44-dimethyl-6,9,19,34,44,47-hexaazanocyclo- [45.2.2.2 (3,6) .0 (7,11) .0 (12,20) (11), 12 (20), 13 (18), 14, 16, 33 (41) , 35 (40), 36, 38, 44 (46) -decayene-8,10,43,45-tetra

Melting point: 286 DEG C (decomposition)

Example 141

10,45-dimethyl-7,10,20,35,45,48-hexaazanocyclo- [46.2.2.2 (4,7) .0 (8,12) .0 (13,21) , 19) .0 (34,42) .0 (36,41) .0 (43,47)] tetrapentaconta-8 (12), 13 (21), 14 (19), 15,17,34 42), 36 (41), 37, 39, 43 (47) -decayene-9,11,44,46-tetraene

Melting point:> 250 ° C

Example 142 [

11,46-dimethyl-8,11,21,36,46,49-hexaazanocyclo- [47.2.2.2 (5,8) .0 (9,13) .0 (14,22) , 13 (20), 15 (20), 16, 18, 35 (13, 14) 43), 37 (42), 38, 40, 44 (48) -decaren-10,12,45,47-tetra

Melting point: 276 占 폚 (decomposition)

Example 143

13,48-dimethyl-10,13,23,38,48,51-hexaazanocyclo- [49.2.2.2 (7,10) .0 (11,15) .0 (16,24) Heptapentaconta-11 (15), 16 (24), 17 (22), 18, 20, 37 (22) 45), 39 (44), 40, 42, 46 (50) -12,14, 47,

Melting point: 245 캜 (decomposition)

Example 144

14,24-dimethyl-11,14,24,39, 49,52-hexaazanocyclo- [50.2.2.2 (8,11) .0 (12,16) Octapentaconta-12 (16), 17 (25), 18 (23), 19, 21, 38 (23) 46), 40 (45), 41, 43, 47 (51) -decaren-13,15,48,50-

Melting point: 325 캜 (decomposition)

Example 145

4,30-dimethyl-1,4,14,20,30,33-hexaazaoctacyclo- [31.2.2.0 (2,6) .0 (7,15) Heptatriaconta-2 (6), 7 (15), 8 (13), 9, 11-19 (27), 21 (26) ), 22,24,28 (32) -decane-3,5,29,31-tetraene

Melting point: 314 to 318 DEG C

Example 146

8,34-dimethyl-5,8,18,24,34,37-hexaazanocyclo- [35.2.2.2 (2,5) .0 (6,10) .0 , 17) .0 (23,31) .0 (25,30) .0 (32,36)] Tetetramontane-6 (10), 11 (19), 12 (17), 13,15,23 31), 25 (30), 26,28,32 (36) -decaren-7,9,33,35-tetra

Melting point: 197-200 ° C

Example 147

9,35-dimethyl-6,9,19,25,35,38-hexaazanocyclo- [36.2.2.2 (3,6) .0 (7,11) .0 (12,20) , 18) .0 (24,32) .0 (26,31) .0 (33,37)] tetra tetramontane-7 (11), 12 (20), 13 (18), 14,16,24 32), 26 (31), 27,29,33 (37) -decayene-8,10,34,36-tetraene

Melting point: 337 DEG C (decomposition)

Example 148

10,36-dimethyl-7,10,20,26,36,39-hexaazanocyclo- [37.2.2.2 (4,7) .0 (8,12) .0 , 19) .0 (25,33) .0 (27,32) .0 (34,38)] Pentatetracona-8 (12), 13 (21), 14 (19), 15,17,25 33), 27 (32), 28,30,34 (38) -decaren-9,11,35,37-tetraene

Melting point: 245 캜 (decomposition)

Example 149

11,37-dimethyl-8,11,21,27,37,40-hexaazanocyclo- [38.2.2.2 (5,8) .0 (9,13) .0 (14,22) (20,20) .0 (26,34) .0 (28,33) .0 (35,39)] hexatetracona-9 (13), 14 (22), 15 (20), 16,18,26 34), 28 (33), 29,31,35 (39) -decayene-10,12,36,38-tetraene

Melting point: 325 캜 (decomposition)

Example 150

13,39-dimethyl-10,13,23,29,39,42-hexaazanocyclo- [40.2.2.2 (7,10) .0 (11,15) .0 (16,24) (22, 0) (0, 28, 36) .0 (30,35) .0 (37,41)] octatetracona-11 (15), 16 (24), 17 (22), 18,20,28 36), 30 (35), 31,33,37 (41) -decaren-12,14,38,40-tetraene

Melting point: 245 캜 (decomposition)

Example 151

14,40-dimethyl-11,14,24,30,40,43-hexaazanocyclo- [41.2.2.2 (8,11) .0 (12,16) .0 (17,25) , 23 (25), 18 (23), 19, 21, 29 (16), 17 37), 31 (36), 32,34,38 (42) -decayene-13,15,39,41-tetraene

Melting point: 325 캜 (decomposition)

Example 152

(2,6) .0 (7,15) .0 (8,13) .0 (21,29) .0 23, 28) .0 (30,34)] nonatriaconta-2 (6), 7 (15), 8 (13), 9,11,21 (29), 23 (28) 30 (34) -decane-3,5,31,33-tetraene

Melting point: 314 to 318 DEG C

Example 153

5,8,18,26,36,39-hexaazanocyclo- [37.2.2.2 (2,5) .0 (6,10) .0 (11,19) .0 (12,17) 25,33) .0 (27,32) .0 (34,38)] Pentatetracona-6 (10), 11 (19), 12 (17), 13,15,25 ), 28,30,34 (38) -decaren-7,9,35,37-tetraene

Melting point: 197-200 ° C

Example 154

9,37-dimethyl-6,9,19,27,37,40-hexaazanocyclo- [38.2.2.2 (3,6) .0 (7,11) .0 (12,20) , 18) .0 (26,34) .0 (28,33) .0 (35,39)] hexatetracona-7 (11), 12 (20), 13 (18), 14,16,26 34), 28 (33), 29, 31, 35 (39) -decayene-8,10,36,38-tetraene

Melting point:> 350 ° C

Example 155

7,10,20,28,38,41-hexazanonacyclo- [39.2.2.2 (4,7) .0 (8,12) .0 (13,21) .0 (29,34) .0 (36,40)] -heptatetracona-8 (12), 13 (21), 14 (19), 15,17,27 34), 30,32,36 (40) -decaren-9,11,37,39-tetraene

Melting point: 290-292 占

Example 156

11,39-dimethyl-9,11,21,29,39,42-hexaazanocyclo- [40.2.2.2 (5,8) .0 (9,13) , 20 (20), 0 (28,36) .0 (30,35) .0 (37,41)] octatetracona-9 (13), 14 (22), 15 (20), 16,18,28 36), 30 (35), 31,33,37 (41) -decaren-10,12,38,40-tetraene

Melting point: 310 占 폚 (decomposition)

Example 157

13,41-dimethyl-10,13,23,31,41,44-hexaazanocyclo- [42.2.2.2 (7,10) .0 (11,15) .0 (16,24) (22,30) .0 (32,37) .0 (39,43)] Pentaconta-11 (15), 16 (24), 17 (22), 18,20,30 ), 32 (37), 33,35,39 (43) -decaren-12,14,40,42-tetraene

Melting point: 310 占 폚 (decomposition)

Example 158

14,42-dimethyl-11,14,24,32,42,45-hexaazanocyclo- [43.2.2.2 (8,11) .0 (12,16) .0 (17,25) (23,38) .0 (33,38) .0 (40,44)] Unpentaconta-12 (16), 17 (25), 18 (23), 19,21,31 39), 33 (38), 34,36,40 (44) -decaren-13,15,41,43-tetra

Melting point: 321 to 324 DEG C

Example 159

6,13-dimethyl-5,6,7,8,9,10,11,12,13,14,19,20,21,22,23,24-hexadecahydrodipyrrolo [3 ', 4 ': B,] indole-5, 6 '] indole-2', 3 ': 13,14] [1,4] diazacyclohexadecino [ 7,12,14-tetra

Melting point:> 240 ° C

Example 160

(2, 6) .0 (7, 15) .0 (8, 13) .0 (28, 36) .0 30,35) .0 (37,41)] hexatetracona-2 (6), 7 (15), 8 (13), 9,11,28 (36), 30 (35), 31,33,37 (41) -decane-3,5,38,40-tetraene

Melting point: 194 to 195 캜

Example 161

5,8,18,33,43,46-hexazanonacyclo- [44.2.2.2 (2,5) .0 (6,10) .0 (11,19) .0 (12,17) .0 32,40) .0 (34,39) .0 (41,45)] pentaaconta-6 (10), 11 (19), 12 (17), 13,15,32 ), 35,37,41 (45) -decaren-7,9,42,44-tetra

Melting point: 236-238 占

Example 162

6,9,19,34,44,47-hexaazanocyclo- [45.2.2.2 (3,6) .0 (17,11) .0 (12,20) .0 (15,18) .0 (11), 12 (20), 13 (18), 14, 16, 33 (41), 35 (40) 36,38,42 (46) -decayene-8,10,43,45-tetraene

Melting point: 231 to 233 DEG C

Example 163

(14,19) .0 (34,34) .0 (8,12) .0 (14,19) .0 (42,41) .0 (43,47)] - tetrapentaconta-8 (12), 13 (21), 14 (19), 15,17,34 ), 37,39,43 (47) -decaren-9,11,44,46-tetraene

Melting point: 209 to 211 DEG C

Example 164

(9,13) .0 (14,22) .0 (15,20) .0 (35, , 43) .0 (37, 42) .0 (44, 48)] -pentapentaconta-9 (13), 14 (22), 15 (20), 16, 18, 35 ), 38,40,44 (48) -decaren-10,12,45,47-tetra

Melting point: 282-284 占

Example 165

(11,15) .0 (16,24) .0 (17,22) .0 (37,10) Heptapentaconta-11 (15), 16 (24), 17 (22), 18,20,37 (45), 39 (44) , 40,42,46 (50) -decaren-12,14,47,49-tetraene

Melting point: 176-179 ° C

Example 166

(11,14,24,39,49,52-hexazanonacyclo [50.2.2.2 (8,11) .0 (12,16) .0 (17,25) .0 , 46 (0) (40,45) .0 (47,51)] - Octapentaconta-12 (16), 17 (25), 18 (23), 19,21,38 ), 41,43,47 (51) -decaren-13,15,48,50-tetraene

Melting point: 147-150 DEG C

Example 167

(21,15) .0 (8,13) .0 (19,27) .0 (21, 21,30,33,20,30,33-hexaazaoctacyclo [ , 26) .0 (28,32)] -heptatriaconta-2 (6), 7 (15), 8 (13), 9,11,19 (27), 21 (26) 28 (32) -decane-3,5,29,31-tetraene

Melting point: 350 占 폚 (decomposition)

Example 168

5,8,18,24,34,37-hexaazanocyclo [35.2.2.2 (2,5) .0 (6,10) .0 (11,19) .0 (12,17) .0 , 31) .0 (25,30) .0 (32,36)] - tristetracona-6 (10), 11 (19), 12 (17), 13,15,23 ), 26,28,32 (36) -decayene-7,9,33,35-tetraene

Melting point: 285 DEG C (decomposition)

Example 169

6,9,19,25,35,38-hexazanonacyclo [36.2.2.2 (3,6) .0 (7,11) .0 (12,20) .0 , 32) .0 (26,31) .0 (33,37)] -tetra tetracona-7 (11), 12 (20), 13 (18), 14,16,24 ), 27,29,33 (37) -decaren-8,10,34,36-tetra

Melting point: 215 DEG C

Example 170

7,10,20,26,36,39-hexazanonacyclo [37.2.2.2 (4,7) .0 (8,12) .0 (13,21) .0 , 33) .0 (27,32) .0 (34,38)] - Pentatetracona-8 (12), 13 (21), 14 (19), 15,17,25 ), 28,30,34 (38) -decaren-9,11,35,37-tetra

Melting point: 330 占 폚 (decomposition)

Example 171

8,11,21,27,37,40-hexazanonacyclo [38.2.2.2 (5,8) .0 (9,13) .0 (14,22) .0 (15,20) , 34) .0 (28,33) .0 (35,39)] -hexatetracona-9 (13), 14 (22), 15 (20), 16,18,26 ), 29,31,35 (39) -decayene-10,12,36,38-tetraene

Melting point: 335.5 DEG C (decomposition)

Example 172

(11,15) .0 (16,24) .0 (17,22) .0 (28,30) (36), 30 (35), 0 (37, 41)] Octatetracona-11 (15), 16 (24), 17 (22) , 31,33,37 (41) -decaren-12,14,38,40-tetraene

Melting point: 243 to 245 DEG C

Example 173

(11,14,24,30,40,43-hexaazanocyclo [41.2.2. 2 (8,11) .0 (12,16) .0 (17,25) .0 , 17 (25), 18 (23), 19, 21, 29 (37), 31 (36) , 32,34,38 (42) -decaren-13,15,39,41-tetraene

Melting point: 258 to 260 캜

Example 174

4,32-dimethyl-1,4,14,22,32,35-hexaazanocyclo- [33.2.2.2 (2,6) .0 (7,15) .0 (8,13) (29), 0 (23,28) .0 (30,34)] Nonatriaconta-2 (6), 7 (15), 8 (13), 19,11,21 ), 24,26,30 (34) -decane-3,5,31,33-tetraene

Melting point:> 350 ° C

Example 175

8,36-dimethyl-5,8,18,26,36,39-hexazanonacyclo [37.2.2.2 (2,5) .0 (6,10) (25,33) .0 (27,32) .0 (34,38)] pentatetracona-6 (10), 11 (19), 12 (17), 13,15,25 ), 27 (32), 28,30,34 (38) -decaren-7,9,35,37-tetraene

Melting point: 310 占 폚 (decomposition)

Example 176

10,38-dimethyl-7,10,20,28,38,41-hexaazanocyclo [39.2.2.2 (4,7) .0 (8,12) 0 (27,35) .0 (29,34) .0 (36,40)] heptatetraconat-8 (12), 13 (21), 14 (19), 15,17,27 ), 29 (34), 30,32,36 (40) -decayene-9,11,37,39-tetraene

Melting point: 280 占 폚 (decomposition)

Example 177

13,46-dimethyl-1,7,10,13,23,36,46,49-octaazanocyclo [47.2.2.2 (7,10) .0 (11,15) .0 (16,24). 0 (17,22) .0 (35, 43) .0 (37, 42) .0 (44, 48)] Pentapentaconta-11 (15), 16 (24), 17 , 35 (43), 37 (42), 38,40, 44 (48) -decayene-12,14,45,47-tetra

Melting point:> 220 ° C

Example 178

4,31-dimethyl-1,4,14,21,31,34-hexaazanocyclo- [32.2.2.2 (2,6) .0 (7,15) , 28 (0) (22,27) .0 (29,33)] octatriaconta-2 (6), 7 (15), 8 (13), 9,11,20 ), 23,25,29 (33) -decane-3,5,309,32-tetraene

Melting point:> 240 ° C (decomposition)

Example 179

8,35-dimethyl-5,8,18,25,35,38-hexazanonacyclo [36.2.2.2 (2,5) .0 (6,10) 17) .0 (24,32) .0 (26,31) .0 (33,37)] tetra tetramontane-6 (10), 11 (19), 12 (17), 13,15,24 ), 26 (31), 27,29, 33 (37) -decane-7,9,34,36-tetra

Melting point:> 240 ° C (decomposition)

Example 180

(1- (2-dimethylaminoethyl) -1H-3-indolyl) (1H-3-indolyl)

0.5 g of bis (indol-3-yl) methanone is dissolved in 30 ml of acetone. 0.92 g of K ₂ CO ₃ and 0.27 g of 2-dimethylamino-1-chloroethanehydrochloride are added, and the mixture is heated to reflux for 70 hours. The acetone is stripped off and the residue is treated with 30 mL of water and 30 mL of ethyl acetate. After stirring for 15 minutes, the organic phase is separated off and the aqueous phase is extracted twice with 15 mL of ethyl acetate each time with shaking. Dry the combined organic phase with Na ₂ SO ₄ and the solvent stripped off. Column chromatography _{(SiO 2, EA / MeOH 10} : 1) to give. Yield: 0.14 g (20%)

Melting point: 180 to 182 DEG C

The following are similarly prepared.

Example 181

(1- (2-morpholinoethyl) -1H-3-indolyl) (1H-3-indolyl)

Melting point: 192 to 194 DEG C

Example 182

Bis (1- (2-morpholinoethyl) -1H-3-indolyl) -1-methanone

Melting point: 91 to 93 占 폚

Example 183

(1- (2-piperidinoethyl) -1H-3-indolyl) (1H-3-indolyl)

Melting point: 223 to 225 캜

Example 184

Bis (1- (2-piperidinoethyl) -1H-3-indolyl) -1-methanone

Melting point: 152 to 155 캜

Example 185

(1- (3-dimethylaminopropyl) -1H-3-indolyl) (1H-3-indolyl)

Melting point: 144-146 占 폚

Example 186

(1- (3-pyrrolidinopropyl) -1H-3-indolyl) (1H-3-indolyl)

Melting point: 148 to 152 캜

Example 187

(1- (2-dimethylaminoethyl) -1H-2-indolyl) (1H-2-indolyl)

Melting point: 147-150 DEG C

Example 188

(1- (2-morpholinoethyl) -1H-2-indolyl) (1H-2-indolyl)

Wax

Example 189

(1- (2-piperidinoethyl) -1H-2-indolyl) (1H-2-indolyl)

Wax

Example 190

(1- (2-pyrrolidinoethyl) -1H-2-indolyl) (1H-2-indolyl)

Wax

Example 191

11,46-Dimethyl-21,36-bis (2- (1-piperidinyl) ethyl-8,11,21,36,46,49-hexaazanocyclo- [47.2.2.2 (5,8). 0 (9,13) .0 (14,22) .0 (15,20) .0 (35,43) .0 (37,42) .0 (44,48)] Pentapentaconta-9 (13) , 14 (22), 15 (20), 16,18,35, (43), 37 (42), 38,40,44 (48) -decaren-10,12,45,47-

Melting point: 125-130 DEG C

Example 192

3,3'-dimethoxydiglyoxyl-1,8- (2,2'-bisindolyl) octane

Oxalyl dichloride is added dropwise to a solution of 1.15 g (4.00 mmol) of 1,8- (2,2'-bisindolyl) octane in 20 mL of dry THF at 0 ° C under N ₂ atmosphere and the mixture is stirred at room temperature for 2 hours do. Then, 20 mL of MeOH is added dropwise. The mixture is stirred at room temperature overnight. For work-up, the mixture is treated with 100 mL of 1N HCl and neutralized with 2N NaOH and the mixture is extracted with EA (3 x 25 mL). After drying over Na ₂ SO ₄ , the solvent is stripped off.

Melting point:> 250 ° C (decomposition)

Example 193

3- (2- (4- (1H-2-indolyl) butyl) -1H-3-indolyl) -1-methyl-2,5-pyrrolidinedione

LH-3-indolyl) - l-methyl-2,5-dihydro-lH-pyrrole-lH- A solution of 240 mg (0.50 mmol) of 2,5-dione and 140 mg (0.25 mmol) of Pd (OH) ₂ / C (20%) is stirred under H ₂ atmosphere at room temperature for 24 hours. Purified by For the working-up, the mixture was filtered and the filtrate was concentrated and the residue was purified by column chromatography _{(5 SiO 2:: CH 2} Cl 2 / EA 95). When the pure fraction is concentrated, PE is added to crystallize the product. Yield: 48.0 mg (24%), beige powder

Melting point: 180 to 182 DEG C

Example 194

Tests for determining inhibition of PDGF-dependent tyrosine phosphorylation on compounds according to the invention

Swiss 3T3 cells were cultured for one week under standard conditions [glutamine, glucose 4 g / L, 10% FCS antibiotics, DMEM with 5-7.5% CO ₂ ], fused at the end of the culture period and further propagated Do not. The medium is replaced with serum-free DMEM and the cells are incubated for 2 hours at 37 [deg.] C using DMSO (final concentration 0.1-1%) in a control experiment using compounds according to the invention. Cells are then stimulated with a final concentration of 100 ng / mL for 5 minutes at room temperature with the addition of PDGF-BB, and the corresponding solvent is added in the control. Cells were then washed twice with ice-cold PBS and resuspended in lysis buffer containing Triton X-100 (see: Selective platelet-derived growth factor receptor blockers reverse sis-transformation M. Kovalenko, A. Gazit, A. Bohmer , Compositions and methods as described in C. Rorsman, L. Ronnstrand, CH Heldin, J. Waltenberger, FD Bohmer, A. Levitzki (1994) Cancer Res. 54, 6106-6114). Centrifuge the lysate and measure the protein concentration. 10 [mu] g of the lysate protein is directly applied to a nitrocellulose membrane (corresponding multi-well plate with dot-blot apparatus or nitrocellulose base).

Tyrosine phosphorylation is detected by standard methods using anti-phosphotyrosine antibodies. Typically, detection of POD activity by chemiluminescent detection and monoclonal anti-phosphotyrosine antibody conjugated to horseradish peroxidase (POD) is used. Quantification is carried out by the gray value analysis of the luminescence detection film or by using the luminescence measurement system directly. Typically, PDGF stimulation of cells results in a 3- to 10-fold increase in signal.

The compound is initially used twice at a final concentration of 10 mu g / mL. For the active compound, the titration is carried out at the steps of 30 μM, 10 μM, 3 μM, 1 μM, 0.3 μM and 0.1 μM as double measurements. The results are shown in Table 1.

Example compound IC50 ([mu] M) 19 Bisindol-2-ylmethan-1-one One 20 (5-methoxyindol-2-yl) - (indol-2-yl) methan- 0.1 - 0.3 21 Bis (5-methoxyindol-2-yl) -1-methanone 10 - 30 28 Benzo [b] thiophen-2-yl (5-methoxy-lH-2-indolyl) One 43 5-hydroxy-1H-2-indolyl (1H-2-indolyl) 0.1 - 0.3 45 1H-2-indolyl [5- (2-morpholin-1-ylethyloxy) -1H-2-indolyl] methanone 1 - 3 48 1H-2-indolyl [5- (2-dimethylaminoethyloxy) -1H-2-indolyl] methanone 0.3 - 1 53 [2- (1H-2-indolylcarbonyl) -1H-5-indolyl] ethanoate 0.1 - 0.3 55 [2- (1H-2-indolylcarbonyl) -1H-5-indolyl] butanoate 1 - 3 56 [2- (1H-2-indolylcarbonyl) -1H-5-indolyl] -2- (N, N) -dimethylaminoethanoate 0.1 57 [2- (1H-2-indolylcarbonyl) -1H-5-indolyl] propanoate 0.3 - 1 58 [2- (1H-2-indolylcarbonyl) -1H-5-indolyl] 2-thiophenylethanoate 0.3 - 1

Cell lysates are analyzed by polyacrylamide gel electrophoresis and immunoblotting using an anti-phosphotyrosine antibody according to standard methods to perform qualitative detection of effects on tyrosine phosphorylation of PDGF receptors and cellular substrates.

Compounds according to the invention are tested in A431 cells (in some cases also Swiss 3T3 plasma membranes) using purified plasma membranes from Swiss 3T3 cells and purified from overexpressing cells and for possible inhibition of EGF receptor tyrosine kinase, Additional studies are performed in vitro using the PDGF receptor tested for inhibition of Src kinase. The results are selected in Table 2.

DNA synthesis studies in Swiss 3T3 cells stimulated with different growth factors are suitable for the selective antiproliferative action of receptor tyrosine kinase inhibitors. PDGF-BB, bFGF, FCS, and insulin in combination with insulin to study the compounds in relation to their effect on stimulated DNA synthesis in these cells. These stimuli increase DNA synthesis in Swiss 3T3 cells, which are nearly equipotential and pre-growth inhibited, by 5-fold to 20-fold. The dose dependence of the corresponding experiments and the IC50 values obtained are also given in Table 2.

In addition, sib-modified NIH3T3 cells are used to study the compounds for possible self-modification. In these cells, a modified phenotype characterized by amorphous multilayer growth and colony formation, particularly in soft agar, is maintained by the expression of PDGF-BB and the permanent activation of the exogenous PDGF receptor. The IC50 values obtained are also shown in Table 2.

Thus, the action on PDGF receptor kinase by the compound is found in the following test.

- PDGF receptor autophosphorylation in untouched Swiss 3T3 cells

- PDGF receptor autophosphorylation in isolated membranes of Swiss 3T3 fibroblasts

- PDGF receptor autophosphorylation in purified receptor formulations

No effect was observed in a similar test using receptor tyrosine kinase for endothelial growth factor and cytosol tyrosine kinase Src at a concentration of 30 μM or less. Thus, the compounds have specificity for the inhibition of the PDGF receptor tyrosine kinase in relation to other tyrosine kinases.

exam IC 50 ([mu] M) Example 19 Example 20 Example 21 In vivo PDGFR phosphorylation (Swiss 3T3 cells) One 0.1 - 0.3 10 - 30 In vitro PDGFR phosphorylation (Swiss 3T3 membrane) 0.3 - 1 <0.03 n.d. In vitro PDGFR phosphorylation (purified PDGF receptor) 0.1 - 0.3 n.d. n.d. In vivo EGFR phosphorylation (A 431 cells) > 10 > 10 n.d. In vivo src kinase phosphorylation (src NIH cells) > 30 > 30 n.d. Conversion of modified forms of sis-3T3 cells +++ n.d. n.d. DNA synthesis (Swiss 3T3 cells) PDGF-stimulated FGF-stimulated EGF / insulin-stimulated 10% FCS 3 - 103 - 10> 30> 30 n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. Colony formation (sis-3T3 cells) 3 - 10 n.d. n.d.

Claims (24)

&Lt; / RTI &gt; Formula I In the above formula (I) Z is a group of the formula (II) A may be a nitrogen atom, an oxygen atom or a sulfur atom, X is a group of formula (III) or (IV) R ² to R ¹³ are together in the formula II and form a bond of the formula V or the formula VI and, R ² and R ¹³ is the same or different radical or hydrogen in formula VII, R ² and R ¹³ together Lt; RTI ID = 0.0 &gt; formula IX &lt; / RTI &gt; R ¹ and R ⁷ in the formula II are the same or different and are a hydrogen atom, an alkyl or aminoalkyl radical, a phenylsulfonyl radical, an alkylsilylmethoxymethyl radical, a sugar or a substituted sugar, R ^3, R ^4, R ⁵ and R ⁶ For the R ^8, R ^9, R ¹⁰ and R ¹¹ in the general formula II are the same or different and are each a hydrogen atom, an alkoxy-, amino-, halogen-, cycloalkyl alkyl-, cycloalkyl-heteroalkyl-aryl-or heteroaryl-O- group in the alkoxy-substituted alkyl, alkoxy or alkoxymethyl group, nitro group, halogen atom or a general formula ^{-O- (C = O) -R 21} ( where R ²¹ is an alkoxy-, amino-, halogen-, cycloalkyl-, cycloheteroalkyl-, aryl- or heteroaryl-substituted alkyl, alkoxy or alkoxymethyl group. (II) (III) Formula IV Formula V VI Formula VII IX X In the above formulas (II) to (VII), (IX) and (X) B and B 'may be a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom, The ring system F and the ring system G may be independently a saturated or unsaturated 5-membered or 6-membered ring, A is as defined above, l and n are numbers from 0 to 6, m is 1 and 2, R ¹⁴ and R ¹⁵ together form an oxygen atom, or R ¹⁴ is a hydroxyl group and R ¹⁵ is a hydrogen atom, or R ¹⁴ and R ¹⁵ are hydrogen atoms, R ¹⁶ is a hydrogen atom, an alkyl or aryl radical, a halogen-, an amino- or an azido-substituted alkyl or aryl radical, an alkyloxymethyl radical or a substituted alkyloxymethyl radical, The dotted line is a double bond or a single bond, R &lt; ¹⁷ &gt; is a halogen atom or a radical of the formula (VIII) o can be the number 1 or 2, When W is a carbon atom or a nitrogen atom, q may be a number from 0 to 6, R ¹⁹ and R ²⁰ may be hydrogen atoms, alkyl radicals or substituted alkyl radicals. VIII In the above formula (VIII) p may be 0, 1 or 2, and when p is 0, it is an acyclic primary amine, Y comprises an additional hydrogen atom, Y may be a carbon atom, an oxygen atom or a nitrogen atom, and when Y is a carbon atom or a nitrogen atom, R ¹⁸ is a hydrogen atom or an alkyl or aryl radical, a substituted alkyl or aryl radical, a saturated or unsaturated heterocycle, an alkoxycarbonyl radical , An aminocarbonylmethyl radical or a substituted aminocarbonylmethyl radical. 10. A compound of formula (XI) according to claim 1. XI In the above formula (XI) A is a nitrogen atom, B is a nitrogen atom, an oxygen atom or a sulfur atom, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹⁴ and R ¹⁵ are as defined in claim 1. A compound according to claim 1, wherein X is a group of formula III or formula IV according to claim 1, R ¹ and R ² are hydrogen atoms and A and B are nitrogen atoms and R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹⁶ are as defined in claim 1. The compound according to claim 1, which is one of the formulas (XIII) and (XIV). XIII XIV In the above formulas (XIII) and (XIV) n is 3, 4, 5, 8 or 12, q is 0, 1, 2, 3, 5 or 6, R ¹⁹ and R ²⁰ are a hydrogen atom or an alkyl group, Wherein R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹⁶ are the same or different and are as defined in claim 1. 10. A compound of formula (XV) according to claim 1. XV In the above formula (XV) n is 1, 2 or 3, R ¹⁶ is a hydrogen atom or an alkyl group, Wherein R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹⁶ are the same or different and are as defined in claim 1. 17. A bisindol-2-ylmethan-1-one according to claim 1. (5-Methoxyindol-2-yl) - (indol-2-yl) methan-1-one according to claim 1. Bis (5-methoxyindol-2-yl) -1-methanone according to claim 1. Benzo [b] thiophen-2-yl (5-methoxy-lH-2-indolyl) -1-methanone according to claim 1. The 5-hydroxy-1H-2-indolyl (1H-2-indolyl) methanone according to claim 1. 1H-2-indolyl [5- (2-morpholin-1-ylethyloxy) -1H-2-indolyl] methanone according to claim 1. 1H-2-indolyl [5- (2-dimethylaminoethyloxy) -1H-2-indolyl] methanone according to claim 1. [2- (1H-2-Indolylcarbonyl) -1H-5-indolyl] ethanoate according to claim 1. [2- (1H-2-Indolylcarbonyl) -1H-5-indolyl] butanoate according to claim 1. [2- (1H-2-Indolylcarbonyl) -1H-5-indolyl] 2- (N, N) -dimethylaminoethanoate according to claim 1. [2- (1H-2-Indolylcarbonyl) -1H-5-indolyl] propanoate according to claim 1. [2- (1H-2-Indolylcarbonyl) -1H-5-indolyl] 2-thio phenylethanoate according to claim 1. 18. A medicament comprising a compound according to any one of claims 1 to 17. Use of a compound according to any one of claims 1 to 17 as a tyrosine kinase inhibitor. 18. Use of a compound according to any one of claims 1 to 17 as a PDGF receptor tyrosine kinase or a structurally related receptor tyrosine kinase inhibitor. 18. Use of a compound according to any one of claims 1 to 17 for the treatment of tumors. 17. The use of a compound according to any one of claims 1 to 17 for the treatment of arteriosclerosis, restenosis, arthritis and fibrosis after balloon angioplasty. R ² and R ¹³ are radicals of formula V according to claim 1, or R ² is a radical of formula V according to claim 1, characterized in that 2,2'-bis-1H-indolylalkane of formula XIa or a derivative thereof is reacted with dibromomaleimide. ² and R &lt; ¹³ &gt; together form a bond of formula VII according to claim 1. XIa In the above formula (XIa) X, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are as defined in claim 1. The 2,2'-bis-1H-indolylalkane of formula XIa or a derivative thereof is first reacted with dibromomaleimide and then with a primary amine of formula XVI or formula XVII or a secondary amine or piperazine Characterized in that R ² and R ¹³ together form a bond of formula (IX) or (X) according to claim 1. XIa XVI XVII In the above formulas XIa, XVI and XVII, X, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , p, q, R ¹⁷ and W are as defined in claim 1.