DE10315654A1 - 8-nitro-tryptanthrin and other tryptanthrin derivatives for the treatment of diseases caused by highly proliferating cells - Google Patents

Abstract

The invention relates to medicaments and compounds (8-substituted tryptanthrin compounds, in particular 8-nitro-tryptanthrin, and their multiply substituted derivatives) for the treatment of diseases which are caused by strongly profiling cells such as tumor cells, in particular blasts of children with acute leukemia ,

Description

The The present invention relates to substances and drugs for treatment diseases caused by highly proliferating cells and processes for the production of such substances and drugs.

The Development of leukaemias, malignant solid tumors or other benign hyperproliferative Diseases such as B. psoriasis or the keloid on a disturbed Balance between new tissue formation and regulated death of cells from the tissue association. In clinical practice is achieved through the use of cytotoxic treatment methods such as the Chemotherapy, radiation therapy and hyperthermia, trying this disturbed Bring balance back into balance and the excess tumor cells kill at the same time. It is generally accepted that most are currently in clinical practice Practice used chemotherapy drugs their effect through initiation develop apoptosis (programmed cell death) (Hannun, 1997). However, some of those suffering from malignant tumors develop Patients early chemotherapy and radiation resistance or is primarily refractory to therapy (Hickman, 1996). It is also known that primary tumor and metastases are cytotoxic Often address therapies very differently. Based on recent research is likely to cause resistance in different ways disorders the apoptosis signal cascade (Raisova, 2000).

Especially therapy of relapse of childhood acute lymphoblastic Leukemia (ALL), the most common childhood malignancy is still not satisfactory solved. So die B. Despite aggressive therapy, about 70% of the sick Children in relapse of the ALL. Similar things happen also to other sometimes difficult to treat tumor diseases to how z. B. breast cancer, thyroid cancer, prostate cancer, Melanoma, neuroblastoma, medulloblastoma or glioblastoma.

A benign skin disease that is also treated with such therapies is psoriasis (psoriasis). It represents one of the most common Skin diseases represent two to four percent of people Suffer. The therapy for this disease is also in great need of improvement.

It so there is a strong need Develop substances and medicines with which the healing success and the chances of survival be improved by patients suffering from the diseases listed above Suffer. Especially with tumor diseases and leukaemias it is important to provide new drugs that are highly selective against unnatural proliferating cells act and healthy cells as possible attack little. About that In addition, it is particularly important to use therapeutic substances against such To provide tumors that are already known substances prove to be resistant.

Surprisingly this object is achieved by using the compound of formula (1) according to claim 1 solved. That is natural Existing compound except tryptanthrin. Other embodiments result from the subclaims 2 to 56.

Claimed according to the invention are also new compounds of formula I according to claim 57. The associated sub-claims 58 to 60 relate to preferred embodiments the compound of the invention.

claim 61 relates to a medicament containing the compound according to the invention. This is for triggering suitable for apoptosis.

As Intermediate in the synthesis of the compound of the invention the compound IV is valuable, which is also claimed according to the invention becomes.

The Method according to claim 63 relates to a process for the preparation of the compound according to the invention I using compound (4).

Tryptanthrin is already known chemically (Mitscher, 1981, Muruganandam, 1998) and has previously appeared biologically as an antimicrobial substance against Heliobacter pylori and Mycobacterium tuberculosis (Baker, 1995). Apoptosis and necrosis inducing effects of tryptanthrine have also been reported (T. Kimoto, 1999, T. Kimoto, 2001). Tryptanthrin with residues of R ¹ to R ⁸ as substituents are synthesized in a known manner (Bergmann, 1985). For this purpose, isatins 2, which are either commercially available or were prepared according to the method of Sandmeyer (Sheibley, 1955, Sandmeyer, 1919), are combined with isatoic anhydrides 3 in a basic solvent such as pyridine, quinoline, lutidine or the like. The isatoic anhydrides are prepared by condensing the correspondingly substituted anthranilic acids with phosgene in inert solvents such as carbon tetrachloride, methylene chloride or tetrachloroethane with the addition of bases such as pyridine or triethylamine.

The isatin-antranilic acid amides thus obtained 4 are then condensed to tryptanthrines in a manner known per se at temperatures of the boiling point of the solvent with water-releasing agents such as carbodiimides. The mostly crystalline tryptanthrins 1 are purified using recrystallization or chromatography methods. The substances can be characterized using the methods of instrumental analysis and spectroscopy (method A).

The hitherto known methods for producing tryptanthrins suffer occasionally on a considerable Lack of yield, which can be less than 5%. This contrasts strange with the very good tendency of the compounds to crystallize. Surprisingly leads the Use of a slightly basic solvent, the tetramethyl urea, Formamide or acetamide, dimethylformamide or combinations thereof contains the alternatively possible Cyclization reaction, according to the scheme 1c, d, can be made into a spontaneous reaction (Method B).

2-Chlorisatine (5) are described in the literature and are highly reactive. Individual, through reaction Isatin-2-aniles (7) formed with aromatic amines are known as Intermediate product of Sandmeyer synthesis known as stable. All the more surprising is the spontaneous cyclization under the specified conditions. This eliminates further water-binding additives and due to the omission Side reactions even a chromatographic purification of the compounds in contrast to Bergman's method.

Although tryptanthrin itself has a good apoptosis-inducing effect, this can be increased considerably by varying the substituents R ^1-10 .

The compounds of the invention are represented by the general formulas (1), I, (4) ( 1b ) characterized in which the substituents R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ⁸ , R ⁹ and R ^{10 are} independently selected from:
Hydrogen, hydroxy, halogen, (iso-) cyano, (iso-) thiocyanato, nitro, (amido) sulfonyl, alkanesulfonyl, amino, aminocarbonyl, carboxy, acyl, alkylamino;
saturated, mono- to trisaturated, branched or straight-chain or cyclic hydrocarbon radicals such as alkyl, alkenyl, alkynyl or cycloalkyl, optionally interrupted in each case by heteroatoms such as in particular N, S, O;
or aryl such as phenyl; Heteroaryl such as pyridyl, pyrimidinyl, purinyl;
Alkoxy, cycloalkyloxy, alkenyloxy or alkynyloxy or alkaryloxy radicals such as the benzyloxy group;
Alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkanoyloxy, alkoxycarbonyloxy, alkylthio, cycloalkylthio, aryloxy such as phenoxy, heteroaryloxy such as pyridyloxy or heteroarylthio such as pyridylthio,
where the radicals mentioned can in each case be partially or completely substituted by one or more, identical or different halogen atoms such as trifluoromethyl and or can carry one or more hydroxyl groups such as hydroxyalkyl, trialkylsilyl or trialkyloxysilyl.

In the compounds of the formula (1) (I) or (4), the definitions for the atoms or atomic groups further preferably have the following meanings:
Halogen can mean fluorine, chlorine, bromine or iodine;
Alkyl can be straight-chain or branched-chain or ring-shaped and preferably a C ₁ -C ₆ -alkyl radical, in particular a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, Cyclopropylmethyl, pentyl, isopentyl, tert-pentyl, neopentyl, cyclopropylethyl, cyclobutylmethyl or hexyl group means, where the radicals mentioned can be interrupted by heteroatoms such as O, N, or S.

aryl can preferably phenyl, naphthyl, anthracenyl, biphenylyl, alkylphenyl, and heteroaryl can be pyridyl, quinolinyl, isoquinolinyl, Imidazolyl, oxazolyl, thiophenyl, furanyl.

The radicals to be mentioned below as preferred can likewise be interrupted by heteroatoms such as O, N or S:
Alkylene means, for example, methylene, ethylene, propylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene or decamethylene.

C ₃ -C ₆ alkenyl can be straight-chain or branched and is preferably an allyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 2-pentenyl, 4-pentenyl, 2- Methyl 2-butenyl, 3-methyl-2-butenyl, 2-hexenyl, 5-hexenyl, 4-methyl-3-pentenyl or 2,2-dimethyl-3-butenyl group.

alkenylene means for example ethenylene, propenylene, butenylene, pentenylene, Hexenylene, hexadienylene, heptenylene, octenylene, nonenylene or decenylene.

C ₃ -C ₆ alkynyl can be straight-chain or branched and is preferably a C ₃ -C ₆ alkynyl radical, in particular a propargyl, 2-butynyl, 3-butynyl, 4-pentynyl, 5-hexynyl or 4 methyl-2-pentynyl.

alkynylene means for example propinylene, butinylene, pentinylene, hexinylene, Hexeninylene, heptinylene, octinylene, noninylene or decinylene.

Cycloalkyl is preferably a C ₃ -C ₈ cycloalkyl radical, in particular a cyclopropyl, cyclobu tyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group.

Hydroxyalkyl contains a hydroxyl group in one of the abovementioned alkyl radicals, in particular in a C ₁ -C ₆ -alkyl radical, the hydroxymethyl and the hydroxyethyl radical being preferred among the C ₁ -C ₁₂ -hydroxyalkyl radicals.

alkylamino can mean dialkylamino, alkyl-arylamino, diarylamino.

Alkoxy and alkenyloxy contain, in addition to the oxygen atom, one of the preferred C ₁ -C ₆ -alkyl, C ₃ -C ₁₂ -alkenyl groups mentioned above. Particularly preferred groups are the methoxy, ethoxy, isopropoxy, tert-butoxy, allyloxy, propargyloxy, dodecyloxy group or corresponding branched chain alkoxy group.

Trifluoromethoxy or 2,2,2-trifluoroethoxy is, for example, trifluoromethoxy or completely or partially substituted by fluorine, especially C ₁ -C ₆ alkoxy.

In addition to the sulfur atom, alkylthio or alkenylthio contain one of the above-mentioned C ₁ -C ₆ -alkyl, C ₃ -C ₆ -alkenyl groups. Preferred groups among them are the methylthio, ethylthio, isopropylthio and tert-butylthio group.

Among the C ₃ -C ₈ cycloalkyloxy and C ₃ -C ₈ cycloalkylthio, the cyclopentyloxy and cyclopentylthio or cyclohexyloxy and cyclohexylthio groups are preferred.

alkanoyloxy in addition to the oxygen atom preferably contain an aliphatic acyl group 1 to 11 carbon atoms. Preferred alkanoyloxy groups among them are the acetoxy, propionyloxy and pivaloyloxy and stearoyloxy groups.

Alkoxycarbonyl groups, preferably C ₂ -C ₁₂ alkoxycarbonyl groups, contain one of the abovementioned alkoxy groups in addition to the carbonyl group, in particular the C ₁ -C ₆ alkoxy groups. Preferred alkoxycarbonyl groups are the methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl or dodecyloxycarbonyl group.

Alkoxycarbonyloxy radicals or hydrocarbon-oxycarbonyloxy radicals with an aromatic or aliphatic character preferably contain one of the above-mentioned C ₂ -C ₁₂ alkoxycarbonyl radicals in addition to the oxygen atom. Preferred alkoxycarbonyl groups include the methoxycarbonyloxy, ethoxycarbonyloxy, isopropoxycarbonyloxy, isobutoxycarbonyloxy and tert-butoxycarbonyl groups and the allyloxycarbonyloxy group or contain the corresponding benzyloxy group.

In addition to the carbonyl group, alkylaminocarbonyl, in particular C ₂ -C ₁₂ -alkylaminocarbonyl and dialkylaminocarbonyl radicals, preferably C ₂ -C ₂₄ -dialkylaminocarbonyl radicals, contain an alkylamino or -dialkylamino radical whose alkyl groups, in particular the C ₁ -C ₆ -alkyl groups, correspond to the description above. Preferred groups are the dimethylaminocarbonyl, diethylaminocarbonyl and diisopropylaminocarbonyl group. Correspondingly, phenylethylamine can also be contained therein.

The Dialkylaminocarbonylreste can correspondingly an N-heterocyclic ring such as piperidinylo or morpholino.

In addition to the unsubstituted amino group, an amino group of the formula NR ⁵ R ⁶ means one of the alkylamino groups mentioned below, in particular C ₁ -C ₆ -alkylamino groups or dialkylamino groups, in particular di- (C ₁ -C ₆ -alkyl) amino groups, alkylamino in particular contains one of the above mentioned C ₁ -C ₁₂ alkyl groups. Preferred groups are the methylamino, ethylamino, propylamino, isopropylamino, butylamino, and the tert-butylamino or dodecylamino group.

The preferred di (C ₁ -C ₁₂ alkyl) amino radical carries two identical or different of the above-mentioned alkyl groups on the nitrogen atom. Preferred groups are the dimethylamino, diethylamino, dipropylamino, diisopropylamino, isopropylmethylamino, dibutylamino or tert-butylmethylamino or didodecylamino group.

Acyl, especially C ₁ -C ₁₁ acyl, more preferably C ₁ -C ₆ acyl, means the remainder of an aliphatic saturated or unsaturated, straight-chain, branched or cyclic carboxylic acid. Preferred acyl radicals are the formyl, acetyl, propionyl, acryloyl, butyryl, isobutyryl, methacryloyl, cyclopropylcarbonyl, pentanoyl, pivaloyl, cyclobutylcarbonyl, hexanoyl and dimethylacryloyl or crotonyl or styrylcarbonyl group ,

Alkanesulfonyl, especially C ₁ -C ₁₂ -alkanesulfonyl, is preferably the methanesulfonyl, ethanesulfonyl, propanesulfonyl, butanesulfonyl, pentanesulfonyl and the hexanesulfonyl or dodecyl group.

In addition, two adjacent radicals can be linked together to form a cycle, for example R ₁ = aminoalkyl and R ₂ = carboxy to form an amide function

The radicals R ¹ to R ¹⁰ relate in particular to complex aliphatic and aromatic molecules, such as, for example, the essential purine bases on which the genetic code is based, such as guanine, cytosine, uracil, thymidine, adenine, pyrimidine, natural and synthetic derivatives thereof such as fluorouracil, azidothymidine or oxouridine. It also relates in particular to the compounds of purine bases with phosphate-esterified sugars known under the name nucleotides, for example not only adenine but also adenosine or adenosine triphosphate. Furthermore, these radicals R ¹ to R ^{10 can be} carbohydrates, which can be either O-glycosidic or linked to tryptanthrin via a carbon-carbon bond: these include natural or synthetic carbohydrates such as glucose, fructose, mannose, ribose, ribulose, Deoxyribose, xylose, maltose, cellobiose, trehalose, chitose, tetrahydrofuranyl phosphate etc.

Furthermore, the radicals R ¹ to R ¹⁰ should apply if it is, for. B. carboxyalkyl or carboxyaryl or carboxyaralkyl radicals or alkylamino radicals, the carboxy groups or the nitrogen can be esterified with complex organic molecules that are fluorescent, radioactive or have special magnetic or nonlinear optical properties. For example, tryptanthrin-8-carboxylic acid is said to be esterified with dyes such as fluorescein, rhodamine or bromophenol red. This should include, for example, the amide from safranin T with tryptanthrin-4-acetic acid or the calcium chelator Quin 9 as the salt of tryptanthrin-5-dodecylammonium ion, but also the ester of the fluorescent quin-9-propylcarboxylic acid with 6-hydroxy tryptanthrin or the urea from 3 -Aminotryptanthrin with diamino-2-phenylindolurethane.

General rule for the representation of tryptanthrines

a) Preparation of 2-chloroisatins after James Grimshaw, William J. Bigley, Synthesis 1974, 5.496 (method B)

1.9 g of nitroisatin (MW = 192, 0.001 mol) together with 2.4 g of phosphorus pentachloride (MW = 206, 0.0012) mol) in 10 ml of dry benzene for several hours refluxed. This solves gradually the yellow solid to a red liquid. After 3-4 hours this about a fine frit is filtered to exclude moisture and for crystallization posed. It differs at room temperature after one day Amount of deep red crystals. These are made using a frit sucked off and several hours in a high vacuum without using Heat dried. 1.5 g, 75%

Analogous 2-chloro-5-bromoisatin is prepared.

b) ring closure reaction

The obtained 2-chloro-5-nitroisatin is in a slightly basic or basic solvents such as Tetramethylurea, formamide or acetamide, dimethylformamide, Triethylamine or suspended and with a solution of 4-chloro-2-aminobenzoic acid, 5-chloro-2-aminobenzoic acid, 2-aminoterephthalic acid in one the solvent added. The darkening mixture is then at room temperature touched where thin layer chromatography for completeness checked becomes. Then will the mixture is heated to 100 to 120 ° C for a few minutes and the ring is closed, which is in discoloration and shows crystallization. According to the different solubilities of the compounds can be the addition of another solvent like acetic acid to be required.

8-nitro-3-Chlorotryptanthrin

0.83 g, 25%. Recrystallized from 100–200 ml THF, brownish powder, m.p. 228 ° C. A further amount of 800 mg crystalline can be obtained from the DMF mother liquor again when left to stand in the freezer. Overall yield 50%
IR (KBr, cm ^-1 ): 1729s, 1691vs, 1641w, 1604s, 1586s, 1527s, 1462s, 1415m, 1342s, 1313s, 1285s, 1215w, 1183m, 1128m, 1115m, 1094m, 1067s, 1044m, 951m, 905m, 842m , 780m, 743w, 705w, 682w, 641m, 626w, 554w
¹ H-NMR (CDCl ₃ , ppm): 8.82 (d, J = 8.85, 1H), 8.74 (d, J = 2.25, 1H), 8.67 (dd, J = 8.8 / 2.4, 1H), 8.37 (d, J = 8.4, 1H), 8.02 (d, J = 2.0, 1H), 7.66 (dd, J = 8.4 / 2.0, 1H)
MS (CI, e / m): 329 (1.08), 328 (1.28), 327 (1.9), 326 (2.67), 252 (0.82), 185 (2.89), 146.1 (6.73), 145.1 (100), 144.1 (16.84), 129.1 (7.89)
C ₁₅ H ₆ O ₄ N ₂ Cl: C: calc. 54.7, found. 55.0; H: calc. 1.82, found 1.9; N: calc. 12.76, found. 13.0; Cl: calc. 10.6, found 10.8

8-nitro-2-Chlorotryptanthrin

0.96 G. Recrystallize from 20–25 ml DMF, mp / cens. 282 ° C , From the mother liquor can cooling down 0.5 g of product can still be obtained.

Overall yield 39%
¹ H-NMR (CDCl ₃ , ppm): 8.43 (d, J = 8.9 Hz, 1H), 8.75 (d, J = 2.25 Hz, 1H), 8.68 (dd, J = 2.24 / 8.9 Hz, 1H), 8.41 (d, J = 2.24 Hz, 1H), 7.99 (d, J = 8.23, 1H), 7.83 (dd, J = 2.24 / 8.9 Hz, 1H)
MS (CI, e / m): 329.0 (33.07), 328.1 (19.17), 327.1 (100), 299.2 (2.03), 283.2 (2.03), 282.1 (3.13)
IR (KBr, cm ^-1 ): 3336br, 3093w, 1730s, 1700s, 1615m, 1577w, 1523m, 1459w, 1414w, 1382w, 1344m, 1325w, 1284m, 1245m, 1128m, 1093w, 1064w, 1042w, 952w, 944w, 905w , 863w, 844w, 777w, 742w, 640w, 554w, 526w
C ₁₅ H ₆ O ₂ N ₂ ClBr: C: calc. 49.85, found. 49.9; H: calc. 1.6, gef. 1.9; N: calc. 7.8, found. 8.4; Br: about: 22.0, found 21:16; Cl: calc. 9.7, found. 9.8

8-nitro-tryptanthrine-3-carboxylic acid

Yellow crystal powder, 1.0 g, 43%. Recrystallization from DMF, then washing with acetone by boiling and sucking again, lemon-yellow cubes, mp.> 340 ° C.
¹ H-NMR (DMSO, ppm): 8.73 (dd, J = 8.9 / 2.25 Hz, 1H), 8.68 (d, J = 8.23 Hz, 1H), 8.57 (d, J = 2.25 Hz, 1H), 8.45 ( d, J = 8.22Hz, 1H), 8.38 ("s", 1H), 8.22 (dd, J = 1.5 / 8.23 Hz, 1H)
IR (KBr, cm ^-1 ): 3441br, 3111w, 2924w, 1749m, 1739m, 1689s, 1654w, 1636m, 1600s, 1533m, 1465w, 1437w, 1417w, 1383w, 1346m, 1281s, 1259m, 1233m, 1183w, 1129w, 1111w , 1078w, 1057w, 1040w, 932w, 868w, 765m, 686w, 676w
MS (Cl, e / m): 338.0 (20.94), 337.1 (100), 309.1 (10.28), 307.1 (17.41), 263.0 (18.53)
C ₁₆ H ₇ O ₆ N ₂ : C: calc. 56.9, found. 56.9; H: calc. 2.07, found. 2.0; N: calc. 12.46, found. 12.0;

8-nitro-3-tryptanthrine carbonsäuremethylester

0.34 g of 8-nitro-tryptanthrin-3-carboxylic acid (MW = 338, 1 mmol) is suspended in 20 ml of dry DMF. 0.36 g of oxalyl chloride (MW = 126, 2.85 mmol, 2.85 Eq) is dissolved in 10 ml of dry ether and slowly added dropwise to the DMF solution. Foaming and gas evolution. After stirring for 45 min, the mixture is heated to 70-80 ° C., during which the ether evaporates. After another hour at this temperature, everything has dissolved. It is now 10 ml absolute. Methanol followed by 3 ml of pyridine. Something falls out under heat. Stir overnight. Filtering off the precipitate and recrystallization from acetone. Yellow leaflets. It only dissolves about half, then it is filtered, the rest is hardly soluble. The acetone extract is spun in a little more, 280 mg yellow leaves, 80%.
¹ H-NMR (d ⁶ -acetone, ppm): 8.82 ("dq", 2.3 / 8.8 Hz, 2H), 8.65 (d, J = 2.3 Hz, 1H), 8.52 ("dt", J = 1.5 Hz, 2H), 8.32 ("dt", J = 1.5 Hz, 1H), 3.99 (s, 3H)
MS (CI, e / m): 351.8 (23.72), 350.8 (100), 320.9 (50.91), 319.8 (80.63), 291.9 (19.47), 276.9 (10.1)
IR (KBr, cm ^-1 ): 3100w, 3087w, 3077w, 1735s, 1683vs, 1600s, 1586s, 1464s, 1447m, 1423m, 1347s, 1311m, 1286vs, 1263m, 1236w, 1219w, 1184w, 1119w, 1101w, 1082w, 1067w , 1043w, 955w, 933w, 869w, 762m, 747m, 708w, 685w

8-Bromo-tryptanthrine-3-carboxylic acid

2.4 g yield (MW = 371, 64%). Recryst. 1.3 g in 30 ml DMF, washing by boiling with acetone.
¹ H-NMR (DMSO, ppm): 8.41 ("t", J = 1.5 Hz, 2H), 8.34 (s, 1H), 8.18 (d, J = 8.23 Hz, 1H), 8.08 (s, 1H), 8.04 (dd, J = 8.18 / 1.5 Hz, 1H)
¹³ C-NMR (DMSO, ppm): 181.6, 166.7, 157.8, 147.0, 146.0, 145.2, 140.5, 137.5, 131.14, 130.4, 128.32, 127.87, 126.7, 124.8, 120.1, 119.66
MS (CI, e / m): 373.1 (34.03), 372 (100), 371.1 (4.65), 370 (90.3), 292.2 (20.79), 170.0 (22.2), 168.0 (53.4)
IR (KBr, cm ^-1 ): 3412br, m, 1737m, 1684vs, 1595m, 1558w, 1458m, 1429w, 1334w, 1300s, 1255w, 1219w, 1186m, 1133w, 1051w, 933w, 854w, 780w, 761w, 683w, 632w

8-bromo-tryptanthrine-3-carbonsäuremethylester

0.37 g of 8-bromo-tryptanthrin-3-carboxylic acid (MW = 372, 1 mmol) suspended in 20 ml of anhydrous DMF and 40 ml of methylene chloride. 0.26 g of oxalyl chloride (MW = 126.2 mmol) was added dropwise with cooling in an ice bath. Gas evolution and foaming. After 30 minutes, when everything is at room temperature, the methylene chloride is removed on a rotary evaporator. After stirring overnight, methanol, 10 ml and pyridine, 2 ml are added and the mixture is stirred again for 24 h. The whole mixture is then stirred into dilute NaOH, 10 ml, some precipitating. This is filtered off and recrystallized from acetone. 100 mg fine yellow powder, 30%.
¹ H-NMR (CDCl ₃ , ppm): 8.65 (d, J = 1.5 Hz, 1H), 8.52 (d, J = 8.23 Hz, 1H), 8.48 ((d, J = 8.23 Hz, 1H), 8.27 ( dd, J = 1.5 / 8.23 Hz, 1H), 8.02 (d, J = 2.5 Hz, 1H), 7.8827 (dd, J = 2.4 / 8.23 Hz, 1H), 3.99 (s, 3H)
MS (CI, e / m): 387.7 (3.56), 386.7 (17.9), 385.7 (100), 384.7 (18.9), 383.7 (94.90), 355.8 (12.88), 354.8 (40.53), 353.8 (7.42), 352.8 (42.82), 326.8 (13.05), 325.8 (5.84), 324.8 (12.9), 305.9 (25.2), 274.9 (13.43)
IR (KBr, cm ^-1 ): 3105w, 3056w, 2953w, 1734s, 1667vs, 1593s, 1558w, 1459s, 1430m, 1338m, 1288s, 1240w, 1217w, 1184m, 1117w, 1097w, 1045w, 983w, 918w, 855w, 838w , 762s, 683w, 632w, 554w, 485ws

8-Nitro-2,3-Dimethoxytryptanthrin

Yield 3.5 g (56%). Recrystallize from DMF, wash the fine needles by boiling with acetone or THF.
Mp 328 ° C (dec.)
¹ H-NMR (CDCl ₃ , ppm): 8.81 (d, J = 8.65, 1H), 8.7 (d, J = 2.1), 8.64 (dd, J = 8.65 / 2.1, 1H), 7.7 (s, 1H) , 7.42 (s, 1H), 4.06 (s, 3H), 4.02 (s, 3H),
IR (KBr, cm ^-1 ): 3459br, 3090w, 1739s, 1686vs, 1636m, 1601m, 1585s, 1534m, 1503vs, 1453m, 1437w, 1421w, 1376m, 1344vs, 1301w, 1293s, 1250w, 1214m, 1186w, 1153w, 1117w , 1078w, 1042w, 990w, 927w, 872w, 851w, 779w, 771w, 745w, 667w
MS (CI, e / m): 354 (30.73), 353 (100), 338 (4.82), 337 (5.49), 191 (3.07)
C ₁₇ H ₁₁ O ₆ N ₂ : C: calc. 57.7, found. 47.9; H: calc. 3.11, found. 3.0; N: calc. 11.9, found. 12.1;

 8-Bromo-2,3-Dimethoxytryptanthrin

Yield: 310 mg (44%). Recrystallization from DMF (relatively poorly soluble, 150 mg in 20 ml) orange needles.
Mp 332 ° C
¹ H-NMR (CDCl ₃ , ppm): 8.49 (d, J = 8.5 Hz, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.8 (dd, J = 8.5 / 2.0 Hz, 1H), 7.73 (s, 1H), 7.4 (s, 1H), 4.04 (s, 3H), 4.0 (s, 3H)
IR (KBr, cm ^-1 ): 3000w, 3100w, 1720s, 1681s, 1627w, 1586m, 1547w, 1502s, 1473w, 1456s, 1437s, 1422s, 1375s, 1338m, 1309s, 1279m, 1249m, 1216s, 1183s, 1119m, 1075w , 1051w, 1041w, 1022w, 994s, 869m, 838m, 786m, 770m, 661w, 600w, 538w, 509m, 418m
MS (CI, e / m): 389 (21.8), 388 (100), 387 (24.9), 386 (86.78), 373 (17.03), 345 (6.96), 308 (5.17)

8-Methyltryptanthrin

• C ₁₆ H ₁₀ O ₂ N ₂ : Ber: C: 73.1, H: 4.0, O: 12.0, N: 11.1; Found: C: 73.15, H: 3.78, N: 10.64
• 2.4 g (70%). Mp 270.5 ° C, from acetone
• MS (CI): 261.9 (100%), 233.8 (24.14), 204.8 (15.5), 130.8 (3.33), 129.8 (3.22), 101.8 (6.15)
• IR (KBr, cm ^-1 ): 3061 (w), 3029 (w), 2933 (w), 1724 (s), 1684 (vs), 1613 (w), 1593 (m), 1558 (w), 1482 (m), 1458 (m), 1340 (m), 1309 (m), 1297 (w), 1261 (w), 1227 (m), 1186 (w), 1154 (w), 1138 (m), 1041 (m), 947 (w), 886 (w), 830 (m), 796 (w), 774 (s), 705 (w), 688 (m), 659 (w)
• ¹ H-NMR (d ⁶ -DMSO, ppm): 8.33 (d, J = 8.23 Hz, 1H), 8.3 (d, J = 7.5 Hz, 1H), 7.93 (s, 1H), 7.92 (s, 1H) , 7.7 ("m", 3H), 2.4 (s, 3H)
• ¹³ C-NMR (d ⁶ -DMSO, ppm): 205.67, 182.6, 157.61, 146.55, 145.31, 144.05, 138.2, 136.75, 135.13, 129.87, 126.95, 124.85, 123.43, 122.4, 116.87, 20.55

8-Bromotryptanthrin

• C ₁₅ H ₇ O ₂ N ₂ Br: calc. C: 55.0 H: 2.1, O: 10, N: 8.8, Br: 24; Found C: 54.73, N: 2.2, N: 8.52, Br: 23.44
• 51%, from chloroform. Mp 276 ° C MS (Cl): 328.8 (15%), 327.8 (96.8), 326.8 (14.5), 325.8 (100), 299.8 (24.35), 297.8 (23.75), 247.8 (10.7), 218.8 (18.9), 190.9 (44.1), 163.8 (15.6)
• IR (KBr, cm ^-1 ): 3067.9 (w), 1731 (m), 1674 (vs), 1592 (m), 1458 (m), 1429 (w), 1338 (m), 1300 (m), 1262 (w), 1181 (m), 1127 (w), 1041 (w), 872 (w), 772 (m), 687 (w),
• ¹ H-NMR (CDCl ₃ , ppm): 8.28 (d, J = 8.23 Hz, 1H), 8.18 (dd, J = 8.23 Hz, 1.5 Hz, 1H), 7.7 ("m", 2H), 7.6 (" q ", 2H), 7.4 (" t ", 1H)
• ¹³ C-NMR (d ⁶ -DMSO, ppm): 181.56, 157.98, 146.45, 145.15, 140.04, 135.7, 130.33, 130.3, 127.45, 127.43, 124.6, 123.47, 119.47, 119.28

8-Chlorotryptanthrin

• C ₁₅ H ₇ O ₂ N ₂ Cl: calc. C: 63.8, H: 2.5, O: 11.3, N: 9.9, Cl: 12.4; Found C: 63.8, H: 2.5, N: 9.9, Cl: 12.5
• 38% from acetone. Mp. 287 ° C
• MS (Cl): 282 (100), 283 (35.85), 284 (34.12), 285 (11.84), 254 (11.24), 226 (4.95), 191 (24.52), 164 (2.81)
• IR (KBr, cm ^-1 ): 3069w, 1730s, 1674vs, 1594s, 1558m, 1459s, 1450w, 1341s, 1300s, 1263w, 1218w, 1182m, 1125m, 1042w, 915w, 877w, 843w, 772m, 742w, 787w
• ¹ H-NMR (CDCl ₃ , ppm): 8.55 (d, J = 8.98 Hz, 1H), 8.41 (dd, J = 8.23 / 1.5 Hz, 1H), 8.01 (d, J = 8.23 Hz, 1H), 7.84 (dt, J = 6.73 / 1.5 Hz, 2H), 7.72 (dd, 8.98 / 2.25 Hz, 1H), 7.67 (t, 6.5 Hz, 1H)
• ¹³ C-NMR (CDCl ₃ , ppm): 181.43, 157.9, 144.5, 143.94, 137.73, 135.31, 133.3, 130.89, 130. 55, 127.6, 125.23, 124.24, 123.6, 123.1, 119.2

8-Fluorotryptanthrin

• C ₁₅ H ₇ O ₂ N ₂ F: calc. C: 67.66, H: 2.63, O: 12.03, N: 10.52, F: 7.14, found C: 67.86, H: 2.77, N: 10.71, F: 6.44
• 54% from THF. Mp. 271.5 ° C
• MS (CI): 267 (37.18), 266 (100), 238 (14.11), 210 (7.53), 148 (3.75), 130 (10), 120 (4.82), 108 (21.93)
• IR (KBr, cm ^-1 ): 1722s, 1687s, 1592w, 1558w, 1484s, 1456w, 1351m, 1305w, 1269w, 1232w, 1185w, 1135w, 1116w, 1040w, 890w, 836m, 770s, 703w, 684w,
• ¹ H-NMR (CDCl ₃ , ppm): 8.6 (dd, J = 8.98 / 3.74 Hz, 1H), 8.4 (dd, J = 8.22 / 1.5 Hz, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.82 (dt, J = 8.23 / 1.5 Hz, 1H), 7.65 (t, 7.48 Hz, 1H), 7.54 (dd, 6.73 / 2.99 Hz, 1H), 7.44 (dt, 8.97 / 2.99 Hz, 1H)
• ¹³ C-NMR (CDCl ₃ , ppm): 181.7, 162.35, 159.86, 157.87, 146.5, 144.28, 142.5, 135.22,
• 130.67 (d, ² J _CF = 34.9 Hz), 127.54, 124.81 (d, ² J _CF = 24.3 Hz), 124.15, 123.68, 123.33 (d, ² J _CF = 7.7 Hz), 119.67 (d, ² J _CF = 6.8 Hz), 112.05 (d, ² J _CF = 25.26 Hz)

8-Nitrotryptanthrin

• C ₁₅ H ₇ O ₄ N ₃ : Ber: C: 61.1, H: 2.0, O: 22.0, N: 14.1; Found: C: 61.52, H: 2.58, N: 14.13
• 23% from THF. Mp 298 ° C
• MS (CI): 293.8 (21.55%), 292.7 (100), 264.8 (21.6), 262.9 (24.31), 218.8 (32.82), 190.8 (16.22), 164.8 (7.34)
• IR (KBr, cm ^-1 ): 3089 (w), 3029 (w), 2939 (w), 1734 (s), 1682 (vs), 1607 (s), 1590 (s), 1522 (s), 4660 (m), 1444 (m), 1341 (vs), 1324 (s), 1309 (m), 1300 (s), 1278 (vs), 1218 (w), 1194 (w), 1156 (w), 1125 (m), 1090 (w), 1062 (w), 1039 (w), 951 (w), 923 (w), 889 (w), 853 (m), 839 (w), 803 (w), 784 (m), 747 (f), 726 (f), 690 (f), 660 (f), 626 (f)
• ¹ H NMR (CDCl ₃ , ppm): 8.85 (d, J = 8.98 Hz, 1H), 8.75 (d, J = 2.24 Hz, 1H), 8.69 (dd, J = 8.98, 2.24 Hz, 1H), 8.47 (dd, J = 7.48, 1.49 Hz, 1H), 8.06 (d, J = 7.48 Hz, 1H), 7.9 (t, J = 1.49, 1H), 7.73 (t, J = 7.6 Hz, 1H)

8-Bromo-2-chloro-tryptanthrine

• Mp 304 ° C
• ¹ H-NMR (CDCl ₃ , ppm): 8.5 (d, J = 8.6Hz, 1H), 8.37 (d, J = 2.2, 1H), 8.0 (d, J = 2.2, 1H), 7.95 (d, 8.6 , 1H), 7.88 (dd, 8.5 / 2.2Hz, 1H), 7.78 (dd, J = 8.5 / 2.28, 1H)
• IR (KBr, cm ^-1 ): 3349br, 3069w, 1731vs, 1674vs, 1648m, 1587m, 1456s, 1431w, 1332m, 1298m, 1262m, 1211m, 1181m, 1131w, 1084w, 1036w, 943w, 905w, 845s, 782w, 748m , 707w, 645w, 616w, 560w
• MS (CI, e / m): 364 (20.9), 363 (24.65), 362 (100), 361 (18.82), 360 (69.31), 334 (10.07), 332 (7.75), 225 (4.24)
• C ₁₅ H ₆ O ₂ N ₂ ClBr: C: calc. 49.85, found. 49.6; H: calc. 1.6, found 1.8; N: calc. 7.8, found. 7.4; Br: about: 22.0, found 21.8; Cl: calc. 9.7, found. 9.7

8-Bromo-3-chloro-tryptanthrine

• Mp 303 ° C
• ¹ H-NMR (CDCl ₃ , ppm): 8.49 (d, J = 8.3 Hz, 1H), 8.34 (d, J = 8.5 Hz, 1H), 8.0 (d, J = 2.0 Hz, 1H), 7.98 (d , J = 2.0, 1H), 7.88 (dd, J = 8.3 / 2.0 Hz, 1H), 7.62 (dd, J = 8.6 / 2.0 Hz, 1H)
• IR (KBr, cm ^-1 ): 3000w, 3100w, 1734s, 1675vs, 1584s, 1455m, 1431w, 1419w, 1338m, 1300m, 1274w, 1212w, 1181s, 1133w, 1117w, 1072w, 1038w, 943w, 900w, 888w, 842w , 778w, 741w, 702w, 688w, 634w
• MS (CI, e / m): 363.6 (20.92, 363.6 (21.15), 362.6 (100), 360.6 (16.74), 359.6 (69.05), 333.6 (16.56), 331.7 (12.74), 252.9 (5.15), 224.7 (13.49),
• C ₁₅ H ₆ O ₂ N ₂ ClBr: C: calc. 49.85, found. 49.9; H: calc. 1.6, found 1.9; N: calc. 7.8, found. 8.4; Br: about: 22.0, found 21:16; Cl: calc. 9.7, found. 9.8

The to be used according to the invention from Tryptanthrin-derived substances or the compounds according to the invention, are used according to the invention for the manufacture of a medicament for the treatment of malignant diseases of the Bone marrow or other hematopoietic organs, solid tumors, epithelial tumors, benign or semimalignant rapidly proliferating Tumors or skin diseases, especially psoriasis vulgaris, keloids and basaliomas, lymphomas, in particular Hodgkin and non-Hodgkin lymphomas, inflammatory, chronically inflammatory, bacterial and autoimmune diseases, as well as antibacterial, antifungal, anti-protozoa, anti-plasmodia, antiviral, anti-helminthic or immunosuppressive therapy.

The Medicaments according to the invention and compounds are unexpectedly useful for the therapy of pathologically rapidly proliferating tissue, especially bone marrow, but also of solid tumors, such as epithelial tumors or in particular Brain tumors. Furthermore, the applicability of the described extends Substances also used to treat benign, hyperproliferative Skin disorders such as B. the psoriasis or the keloid. The pharmaceuticals and substances of the invention are characterized by this from that they are particularly are capable of selectively growing highly proliferating cells to inhibit. As a result, they direct apoptosis from highly proliferating ones Cells and thus cause their destruction, taking healthy cells very little affected become.

The Substances are particularly membrane-permeable, which leads to a high intracellular active ingredient concentration leads. The high effectiveness is therefore likely due to the pronounced lipophilicity the substances achieved. The substances differ fundamentally of known cytostatics used for therapy. she are able to break existing cytostatic resistances.

The Medicaments and compounds of the invention are particularly suitable for the treatment of tumor diseases and leukemia. You lead the apoptotic Cell death not only in permanent cell lines created from tumor cells (BJAB cells), but also in primary cells from patients with one acute lymphoblastic leukemia (Alone. This allows the substances according to the invention against malignant diseases of the bone marrow, but also against tumors another provenance, such as B. epithelial tumors, sarcomas or malignant diseases of the skin, etc. are used. Especially it should be noted that with the developed substances due to their lipophilicity, an overshoot the blood-brain barrier is possible is, and therefore also for malignant brain tumors, such as B. the medulloblastoma or gliomas used can be. Overall, can the substances according to the invention for the treatment of malignant diseases of the bone marrow or other hematopoietic Organs, solid tumors, epithelial tumors, benign or semimalignant rapidly proliferating skin diseases, especially psoriasis vulgaris, keloids and basaliomas, as well as inflammatory and chronically inflammatory Diseases are used. They are also suitable for antiviral, antibacterial, antifungal, anti-protozoa, anti-helminthic or immunosuppressive therapy.

In the 2 It is shown that tryptanthrin from a concentration of 12.5 μmol / l in cell culture medium triggers apoptosis in 20–30% of BJAB cells (human Burkitt lymphoma cell line). The measurement of apoptosis is based on a method that demonstrates the fragmentation of DNA typical of apoptosis at the individual cell level, which distinguishes this cell death form from necrosis. For this purpose, BJAB cells were treated with different concentrations of tryptanthrin for 72 h. Controls included corresponding amounts of the solubilizer dimethyl sulfoxide (DMSO). After the treatment, the fragmentation of the DNA was stained with propidium iodide and then quantified by flow cytometry as described by Eßmann et al. (2000). The values are given as% apoptotic cells of the total population ± SD (n = 3).

However, the substances have a proapoptotic effect not only on permanent cell lines, but also on lymphoblasts that were obtained directly from children with an ALL ( 3 ). In contrast to the already known and widely used chemotherapeutic agents etoposide, daunorubicin and doxorubicin (abbreviated to Eto, Dau and Dox) tryptanthrin and its derivatives T1, T2, T3 and T4 (T1 = 8-methyl-tryptanthrin, T2 = 8- Bromine tryptanthrin, T3 = 7-methyl-tryptanthrin and T4 = 8-nitro-tryptanthrin) also apoptosis in therapy-resistant patient cells in vitro ( 3 ). In this experiment, lymphoblasts from children with acute lymphoblastic leukemia (ALL) were isolated and after dilution with cell culture medium for 72 h with 12.5 μM and 25 μM tryptanthrin and as a positive control with 10 μM etoposide and 9 μM daunorubicin (Dau) or doxorubin (Dox ) treated. Controls contained appropriate amounts of the solubilizer DMSO. After the treatment, the fragmentation of the DNA was measured by staining with propidium iodide and subsequent quantification using flow cytometry. The values are given as% apoptotic cells of the total population.

The usability of substances according to the invention for the therapy of various malignant diseases of the hematopoietic system was tested on cells from patients with different diseases. For this purpose, cells from patients with various leukaemias were isolated and, after dilution in cell culture medium, treated with tryptanthrin and the derivatives T1, T2, T3 and T4 in the concentrations given below for 36 h. Controls contained appropriate amounts of the solubilizer ethanol. After the treatment, the fragmentation of the DNA was again measured by staining with propidium iodide and subsequent quantification by means of flow cytometry. The result is 4 refer to. The measured values are given as% apoptotic cells of the total population and represent the mean of two independent experiments. 4 shows that both tryptanthrin and its derivatives (T1, T2, T3, T4) also trigger apoptotic cell death in primary lymphoblasts of patients with a recurrence of acute lymphoblastic leukemia (ALL-Rez).

With tryptanthrin and its derivatives T1, T2, T3 and T4, substances of the general structural formula (1) are thus provided as effective agents against certain tumor cells, in particular those of childhood ALL, but also against other malignant diseases of different origins. In summary, in 4 showed that even in recurrence of a child's ALL, the substance T4 in vitro in particular has a significantly better pro-apoptotic effect compared to primary lymphoblasts than the established cytostatics etoposide and anthracyclines (here: epirubicin). Tryptanthrin and its derivatives are obviously able to break through existing anthracycline resistance. In contrast to tryptanthrin, 8-nitro-tryptanthrin (T4) and its derivatives, particularly 8-nitro-3-chloro-tryptanthrin, show a potent cytostatic effect and selectivity against tumor cells compared to primary lymphocytes (data not shown).

The sequence of apoptosis leads to the activation of a family of cysteine proteases, the so-called caspases, which dissolve the cell from the inside during the ongoing death program (Cohen, 1997). To investigate the specificity of the substances according to the invention in more detail, the processing and activation of caspase-3 was demonstrated in a Western blot ( 5 ). For this purpose, BJAB cells were treated for 48 h or 72 h with a concentration of 50 μmol / l tryptanthrin (Trp). Controls contained appropriate amounts of the solubilizer DMSO. A medium containing taxol (tax) for inducing apoptosis served as a positive control. After the treatment, the processing of Procaspase-3 was carried out by means of specific immunodetection in a Western blot, as described by Prokop et al. (2000). The positions of the Procaspase-3 and the processed subunit in the SDS polyacrylamide gel are indicated by dashes on the left edge of 5 characterized. The addition of 50 μmol / l tryptanthrin to the medium of BJAB cells triggers a processing of Procaspase-3 in these cells. You can see the specific, immunochemical detection of the active subunit of caspase-3 in treated cells in contrast to the corresponding control cells. The result makes it clear that the substances according to the invention specifically induce an apoptotic cascade.

Further investigations showed that the BJAB cells are driven into the mitochondrial apoptosis signaling pathway by tryptanthrin. This was done by staining the cells with the mitochondrial-specific dye JC-1, as described by Wieder et al. (2001). Incubation of the cells with tryptanthrin led to a concentration-dependent increase in the proportion of cells with a reduced mitochondrial membrane potential (ΔΨ _m ), which indicates a strong activation which indicates mitochondria during the apoptotic process ( 6 ).

The Medicaments according to the invention can oral, topically or intravenously be applied. With intravenous Application are the substances in the concentration range between 0.1 to 100 μg / ml on the patient's blood volume. The substances will in a concentration of 0.1 to 5 wt .-%, based on the finished Preparation, rubbed into the diseased skin.

7 shows the selectivity of the compound 8-nitro-3 chlorotryptanthrin according to the invention. Good induction of apoptosis can be seen in leukemia cells (BJAB cells, black bars), but only slight induction of apoptosis after 72 h treatment with NT1 in "normal" primary leukocytes (white bars).

references

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Claims (63)

Use of the compound of formula (1) for the manufacture of a medicament for inducing apoptosis other than tryptanthrin

where the substituents R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ⁸ , R ⁹ and R ^{10 are} independently selected from: hydrogen, hydroxy, halogen, (iso-) cyano, (iso-) thiocyanato, Nitro, (amido) sulfonyl, alkanesulfonyl, amino, aminocarbonyl, carboxy, acyl, alkylamino; saturated, mono- to trisaturated, branched or straight-chain or cyclic hydrocarbon radicals such as alkyl, alkenyl, alkynyl or cycloalkyl, optionally interrupted in each case by heteroatoms such as in particular N, S, O; or aryl such as phenyl; Heteroaryl such as pyridyl, pyrimidinyl, purinyl; Alkoxy, cycloalkyloxy, alkenyloxy or alkynyloxy or alkaryloxy radicals such as the benzyloxy group; Alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkanoyloxy, alkoxycarbonyloxy, alkylthio, cycloalkylthio, aryloxy such as phenoxy, heteroaryloxy such as pyridyloxy or heteroarylthio such as pyridylthio, where the radicals mentioned are in each case partially or completely substituted by one or more, the same or different, halogen atoms carry one or more hydroxy groups, such as hydroxyalkyl, trialkylsilyl or trialkyloxysilyl. Use according to claim 1, wherein the res te have the following meanings: halogen is fluorine, chlorine, bromine or iodine; Alkyl is a straight-chain or branched-chain or ring-shaped radical, in particular a C ₁ -C ₆ -alkyl radical, such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, , Cyclopropylmethyl, pentyl, isopentyl, tert-pentyl, neopentyl, cyclopropylethyl, cyclobutylmethyl or hexyl group, Use according to claim 2, wherein said residues are interrupted by heteroatoms such as O, N, or S. Use according to claims 1 to 3, wherein aryl is a Phenyl, naphthyl, anthracenyl, biphenylyl, alkylphenyl or Heteroaryl is like pyridyl, quinolinyl, isoquinolinyl, Imidazolyl, oxazolyl, thiophenyl, furanyl is. Use according to at least one of claims 1 to 4, where alkenyl is methylene, ethylene, propylene, tetramethylene, Pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene or decamethylene residue. Use according to claim 5, wherein C ₃ -C ₆ alkenyl is straight-chain or branched. Use according to claim 6, wherein C ₃ -C ₆ alkenyl is an allyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 2-pentenyl, 4-pentenyl, 2-methyl 2-butenyl, 3-methyl-2-butenyl, 2-hexenyl, 5-hexenyl, 4-methyl-3-pentenyl or 2,2-dimethyl-3-butenyl group. Use according to at least one of claims 1 to 7, where alkenylene is an ethenylene, propenylene, butenylene, pentenylene, Hexenylene, hexadienylene, heptenylene, octenylene, nonenylene or Is decenylene group. Use according to at least one of claims 1 to 8, wherein C ₃ -C ₆ alkynyl is straight-chain or branched. Use according to claim 9, wherein C ₃ -C ₆ alkynyl is propargyl, 2-butynyl, 3-butynyl, 4-pentynyl, 5-hexynyl or 4-methyl-2-pentynyl. Use according to at least one of claims 1 to 10, where alkynylene is a propinylene, butinylene, pentinylene, hexinylene, Hexeninylene, heptinylene, octinylene, noninylene or decinylene group is. Use according to at least one of claims 1 to 11, wherein cycloalkyl is a C ₃ -C ₈ cycloalkyl radical; is in particular a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group. Use according to at least one of claims 1 to 12, wherein hydroxyalkyl is a hydroxyl group in one of the above contains alkyl radicals mentioned. Use according to claim 13, wherein the hydroxyalkyl radical is a C ₁ -C ₁₂ hydroxyalkyl radical. Use according to claim 14, wherein the hydroxyalkyl radical is a C ₁ -C ₆ alkyl radical. Use according to claim 15, wherein the hydroxyalkyl radical is the hydroxymethyl and / or the hydroxyethyl radical. Use according to at least one of claims 1 to 16, wherein alkylamino is a dialkylamino, alkyl, arylamino, diarylamino group is. Use according to at least one of claims 1 to 16, wherein alkoxy and alkenyloxy groups contain, in addition to the oxygen atom, one of the above-mentioned C ₁ -C ₆ alkyl, C ₃ -C ₁₂ alkenyl groups. Use according to claim 18, wherein the alkoxy group a methoxy, ethoxy, isopropoxy, tert-butoxy, allyloxy, propargyloxy, Is dodecyloxy group or a branched chain alkoxy group. Use according to at least one of claims 1 to 19, where alkoxy wholly or partly by fluorine and / or chlorine is substituted. Use according to claim 20, wherein the whole or partially substituted by fluorine alkoxy group trifluoromethoxy Difluorochloromethoxy, fluorodichloromethoxy, trichloromethoxy, or 2,2,2-trifluoroethoxy group. Use according to at least one of claims 1 to 21, wherein alkylthio or alkenylthio groups contain one of the C ₁ -C ₆ alkyl or C ₃ -C ₆ alkenyl groups mentioned above in addition to the sulfur atom. Use according to claim 22, wherein alkylthio or Alkenylthio groups the methylthio, ethylthio, isopropylthio and are tert-butylthio group. Use according to at least one of claims 1 to 23, wherein the C ₃ -C ₈ cycloalkyloxy and C ₃ -C ₈ cycloalkylthio group is the cyclopentyloxy, cyclopentylthio or cyclohexyloxy or cyclohexylthio group. Use according to at least one of the An Proverbs 1 to 24, wherein alkanoyloxy radicals contain an aliphatic acyl group with 1 to 11 carbon atoms in addition to the oxygen atom. Use according to claim 25, wherein the alkanoyloxy radicals Are alkanoyloxy groups which are the acetoxy, propionyloxy and pivaloyloxy and stearoyloxy group. Use according to at least one of claims 1 to 26, wherein the alkoxycarbonyl groups are C ₂ -C ₁₂ alkoxycarbonyl groups which, in addition to the carbonyl group, have one of the abovementioned alkoxy groups, in particular the C ₁ -C ₆ alkoxy groups. Use according to claim 27, wherein the alkoxycarbonyl groups the methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, are tert-butoxycarbonyl or dodecyloxycarbonyl group. Use according to at least one of claims 1 to 28, wherein alkoxycarbonyloxy radicals or hydrocarbon oxycarbonyloxy radicals having an aromatic or aliphatic character contain one of the above-mentioned C ₂ -C ₁₂ alkoxycarbonyl radicals in addition to the oxygen atom. Use according to claim 29, wherein the alkoxycarbonyl groups the methoxycarbonyloxy, ethoxycarbonyloxy, isopropoxycarbonyloxy, Isobutoxycarbonyloxy and tert-butoxycarbonyl group and the allyloxycarbonyloxy group or contain the corresponding benzyloxy group. Use according to claim 29, wherein the alkylaminocarbonyl group contains C ₂ -C ₁₂ alkylaminocarbonyl and dialkylaminocarbonyl radicals, in particular C ₂ -C ₂₄ dialkylaminocarbonyl radicals, in addition to the carbonyl group, an alkylamino or dialkylamino radical, their alkyl groups, in particular the C ₁ -C ₆ alkyl groups have the above meaning. Use according to claim 31, wherein the dialkylaminocarbonyl radicals the dimethylaminocarbonyl, diethylaminocarbonyl and diisopropylaminocarbonyl group, optionally with phenylethylamine. In a similar way can also be included. Use according to claim 31, wherein the dialkylaminocarbonyl radicals an N-heterocyclic ring such as a piperidinyl or morpholino ring form. Use according to at least one of claims 1 to 33, wherein an amino group of the formula NR ¹¹ R ^{12 is} provided in which R ¹¹ and R ¹² each independently of one another are hydrogen and / or one of the alkylamino groups mentioned below, in particular C ₁ -C ₆ -alkylamino groups or Dialkylamino groups, in particular di- (C ₁ -C ₆ -alkyl) amino groups. Use according to claim 34, wherein alkylamino radical is one of the aforementioned C ₁ -C ₁₂ alkyl groups. Use according to claim 35, wherein alkylamino residue the methylamino, ethylamino, propylamino, isopropylamino, butylamino, and the tert-butylamino or dodecylamino group. Use according to one of claims 34 to 36, wherein the di- (C ₁ -C ₁₂ alkyl) amino radical on the nitrogen atom carries two identical or different of the above-mentioned alkyl groups. Use according to claim 37 wherein the alkylamino group the dimethylamino, diethylamino, dipropylamino, diisopropylamino, Isopropyl-methylamino, dibutylamino or tert-butylmethylamino or didodecylamino group is. Use according to at least one of claims 1 to 39, wherein the acyl group is C ₁ -C ₁₁ acyl, in particular C ₁ -C ₆ acyl. Use according to claim 39, wherein the acyl residues the rest of an aliphatic saturated or unsaturated, carry straight-chain, branched or cyclic carboxylic acid. Use according to claim 40, wherein the acyl residues the formyl, acetyl, propionyl, acryloyl, butyryl, isobutyryl, Methacryloyl, cyclopropylcarbonyl, pentanoyl, pivaloyl, cyclobutylcarbonyl, hexanoyl and dimethylacryloyl or crotonyl, styrylcarbonyl or stearoyl group are. Use according to at least one of claims 1 to 41, wherein the alkanesulfonyl group is a C ₁ -C ₁₂ alkanesulfonyl group. Use according to claim 42, wherein the alkanesulfonyl group a methanesulfonyl, ethanesulfonyl, propanesulfonyl, butanesulfonyl, Is pentanesulfonyl and the hexanesulfonyl or dodecyl group. Use according to at least one of claims 1 to 43, wherein two adjacent residues are linked together to form a cycle Use according to at least one of claims 1 to 44, wherein the radicals R ¹ to R ^{10 are} interrupted by heteroatoms such as O, N, or S. Use according to at least one of the An claims 1 to 44 wherein the radicals R ¹ to R ^{10 are} aliphatic and aromatic groups which are selected from the group consisting of guanine, cytosine, uracil, thymidine, adenine, pyrimidine and natural and synthetic derivatives thereof. Use according to claim 46, wherein the derivatives Are fluorouracil, azidothymidine or oxouridine. Use according to claim 46 and / or 47, wherein the radicals R ¹ to R ^{10 are} nucleotides. Use according to claim 48, wherein the nucleotides There are compounds of purine bases with phosphate-esterified sugars such as that of adenine, adenosine or adenosine triphosphate. Use according to at least one of claims 1 to 49, wherein the radicals R ¹ to R ^{10 are} carbohydrates, these being either Oglycosidisch or attached to the tryptanthrin via a carbon-carbon bond. Use according to claim 50, wherein the carbohydrates natural or are synthetic carbohydrates. Use according to claim 51, wherein the carbohydrates Glucose, fructose, mannose, ribose, ribulose, deoxyribose, xylose, Maltose, cellobiose, trehalose, chitose, tetrahydrofuranyl phosphate. Use according to at least one of claims 1 to 49, wherein the radicals R ¹ to R ¹⁰ , if they are carboxyalkyl or carboxyaryl or carboxyaralkyl radicals or alkylamino radicals, the carboxy groups are esterified or the nitrogen is amidated with signaling organic structural units. Use according to claim 53, wherein the signaling Structural units fluoresce, are radiolabelled or special have magnetic or nonlinear optical properties. Use according to at least claim 53 and / or 54, with tryptanthrin-8-carboxylic acid, 8-nitrotryptanthrin-3-carboxylic acid and 8-bromo-tryptanthrin-3-carboxylic acid Dyes is esterified. Use according to claim 55, wherein the dyes selected are from the group consisting of fluorescein, rhodamine or bromophenol red, the amide from safranin T with tryptanthrin-4-acetic acid, the Calcium chelator Quin 9 as salt of tryptanthrin-5-dodecylammonium ion, the ester of fluorescent quin-9-propylcarboxylic acid with 6-hydroxy-tryptanthrin or the urea from 3-aminotryptanthrine with diamino-2-phenylindolurethane. Compound of the general formula I

where R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ each independently of one another is a hydrogen atom or a radical with the abovementioned meanings, A ^{3 is} a chemical group or atom with an -I effect and B ^{8 is} a chemical group or atom with -M effect. Compound according to Claim 57, characterized in that B ^{8 is} -NO ₂ or an organic radical which has a double bond system conjugated to a -NO ₂ group. Compound according to claim 57 and / or 58, characterized in that A ^{3 is} a halogen atom, -SO ₂ -R, -NR ¹¹ R ¹² , where R ¹¹ or R ¹² independently of one another is a hydrogen atom, a saturated or unsaturated hydrocarbon group with 1-6 Carbon atoms is, at least partially halogenated, in particular fluorinated and / or chlorinated alkyl compounds, heteroaromatic with an -I effect or a COOR or a radical which can be converted into a COOH group and R is a hydrogen atom or any organic radical. Compound according to Claim 59, characterized in that the group which can be converted into a COOH is a -CH ₂ OH, -CHO group. Medicament containing at least one compound according to at least one of the claims 1 to 4 and their physiologically acceptable salts. Compound with Formula IV

the rest having the meaning given above. Process for making connection with the Formula (1) from the compound of formula 4 being based on the connection 7 the connection (1) by forming a ring under Dehydration in the presence of a slightly basic solvent, the tetramethylurea, formamide or acetamide, dimethylformamide or combinations thereof.