DE10129028A1 - Soluble Cdk-inhibitory Indirubin Derivatives - Google Patents

Abstract

The invention relates to indirubin derivatives of formula (I) that, by establishing a basic side chain in the 5-position, contain a radically increased solubility with a simultaneous improvement in the biological activity. The invention also relates to intermediate products, to a method for the production thereof, and to their use as Cdk inhibitors for treating cancer such as solid tumors and leukemia, autoimmune diseases such as psoriasis, alopecia and multiple sclerosis, chemotherapeutic agent-induced alopecia and mucositis, cardiovascular diseases such as stenoses, arterioscleroses, restenoses, infectious diseases, e.g. those caused by unicellular parasites, such as Trypanosoma, Toxoplasma or Plasmodium, or caused by fungi, nephrological diseases, e.g. glomerulonephritis, chronic neurodegenerative diseases such as Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease, acute neurodegenerative diseases such as ischemias of the brain and neurotrauma, viral infections such as cytomegalic infections, herpes, hepatitis B and C, and HIV diseases.

Description

The invention relates to Indirubin derivatives, which by establishing a basic Side chain in 5-position a radically increased solubility at the same time Preserve improvement in biological effectiveness as well as intermediates and Process for their preparation and their use as Cdk inhibitors for Treatment of various diseases.

It is known from traditional Chinese medicine that Indirubin and some Indirubin derivatives are effective against certain forms of cancer. So show Indirubin-3'-oxime methyl ether and Indirubin-3'-oxime ethyl ether in addition antineoplastic effects also an in vitro inhibitory effect on various Leukemia cell lines from patients with acute lymphatic, acute myeloid and chronic granulocytic leukemia (Li et al., 1996, Bull. Chem. Soc. Japan, 69, 1621-1627 and Tian et al., 1995, Chemical Research in Chinese Universities, 11, 75-78).

As early as 1913, the Imperial Patent Office patented the Manufacture of alkyl ethers of Indirubinoxime granted (No. 282278).

The synthesis of selected Indirubin derivatives and their properties as active Active substances for the treatment of cancer, for example as a preparation of the Natural cocktails "Dang Gui Lu Hui Wan" is described in Chinese J. Intern. Med. 15, 86-88, (1979).

Basic work on the synthesis of indirubin and indirubin derivatives is given in G.A. Russell, G. Kaupp, J. Am. Chem. Soc. 1969, 91, 3851-3859.

Furthermore, a pharmacological effect of some Indirubin derivatives in the WO 99/62503.

Due to the interesting properties of the connection class, as before, a great need for more selective and more effective Indirubin derivatives for Treatment of various diseases. This includes, for example, cancer, like solid tumors and leukemia, autoimmune diseases like psoriasis, Alopecia and multiple sclerosis, chemotherapy-induced alopecia and Mucositis, cardiovascular diseases such as stenoses, arteriosclerosis and Restenoses, infectious diseases, such as B. by unicellular parasites, such as Trypanosoma, Toxoplasma or Plasmodium, or caused by fungi, nephrological diseases, such as B. Glomerulonephritis, chronic neurodegenerative diseases, such as Huntington's disease, amyotropic lateral sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's Disease, acute neurodegenerative diseases such as ischemia of the brain and neurotrauma, viral infections such as B. cytomegalus infections, herpes, Hepatitis B and C, and HIV diseases.

A major disadvantage of the known Indirubin derivatives, however, is that they are very poorly soluble and therefore less selective and in particular less are effective. They are therefore only used in practice to a limited extent.

It has now been found that compounds of the general formula I


in the
A for the group


Z represents hydrogen or C _1-10 alkyl,
or the group
-N- (CH ₂ ) _n -R ⁷ optionally also a ring of the structure


forms, where the ring may be unsaturated, partially saturated or saturated, Z is 0 and the nitrogen atom of the group -NR ¹⁰ R ¹¹ in the meaning of R ^{7 is} also a further hetero atom in the ring, and the ring optionally with hydroxy C _1-10 alkyl can be substituted,
n stands for 0, 1, 2, 3, 4, 5 or 6,
D for the group


R ¹ for hydrogen or for the group C _1-6 alkyl-CO-NR ¹⁰ R ¹¹ , or for unsubstituted or optionally one or more, the same or different with hydroxy, C _1-6 alkoxy, amino, halogen or the Group -NHC _1-6 alkyl or -N-di-C _1-6 alkyl substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-7 cycloalkyl or C _3-7 -cycloalkyl-C _1-3- alkyl, C _3-7 -cycloalkyl or C _3-7 -cycloalkyl-C _1-3- alkyl interrupted by one or more heteroatoms, or unsubstituted or optionally one or more, the same or differently phenyl substituted with halogen, hydroxy, C _1-6 alkyl or C _1-6 alkoxy, or the group -CF ₃ , -OCF ₃ , -SC _1-6 alkyl or -SCF ₃ ,
R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ and R ⁹ independently of one another for hydrogen, halogen, hydroxy, nitro, amino, C _1-10 alkyl, C _2-10 alkenyl, C _{2- 10} alkynyl, C _3-7 - cycloalkyl, C _3-7 cycloalkyl-C _1-3 alkyl, C _1-6 alkoxy, C _1-6 - alkylthio, benzyloxy, aryl or heteroaryl or the group -SO ₃ H, -PO ₃ H ₂ , -NR ¹⁰ R ¹¹ , -N-di-C _1-6 alkyl, -S (O) R ¹² , -SO ₂ R ¹² , -NR ¹⁰ SO ₂ R ¹¹ , -SO ₂ NR ¹⁰ R ¹¹ , -NR ¹² SO ₂ NR ¹⁰ R ¹¹ , -NR ¹² SO ₂ NH ₂ , -NR ¹⁰ COR ¹¹ , -NR ¹⁰ COOR ¹¹ , -NR ¹⁰ CONHR ¹¹ , -NR ¹² CONH ₂ , -PO (OR ¹⁰ ) (OR ¹¹ ), -POR ¹⁰ (OR ¹¹ ), -CONH ₂ , -CONR ¹⁰ R ¹¹ or -COOR ¹² , or for optionally one or more, the same or different, with hydroxy, halogen, C _{1 -6} -alkoxy, C _1-6 -alkylthio, halo-C _1-6 -alkoxy, amino or the group -SO ₃ H, -PO ₃ H ₂ , -NHC _1-6 -alkyl, -N-di-C _1-6 alkyl, -S (O) R ¹² , -SO ₂ R ¹² , -NR ¹⁰ SO ₂ R ¹¹ , -SO ₂ NR ¹⁰ R ¹¹ , -NR ¹² SO ₂ NR ¹⁰ R ¹¹ , -NR ¹² SO ₂ NH ₂ , -NR ¹⁰ COR ¹¹ , -NR ¹⁰ COOR ¹¹ , -NR ¹⁰ CONHR ¹¹ , -NR ^{1 2} CONH ₂ , -PO (OR ¹⁰ ) (OR ¹¹ ), -POR ¹⁰ (OR ¹¹ ), -CONH ₂ , -CONR ¹⁰ R ¹¹ or -COOR ¹² substituted C _1-10 alkyl, C _2-10 alkenyl C _2-10 alkynyl, C _1-6 alkoxy, C _1-6 thioalkyl, C _3-7 cycloalkyl or C _3-7 cycloalkyl-C _1-3 alkyl, benzyloxy, aryl or heteroaryl,
and C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-7 cycloalkyl or C _3-7 cycloalkyl-C _1-3 alkyl optionally one or more times by a = C = O or = NR ¹⁰ group can be interrupted,
R ^{7 represents} pyridyl or the group -NR ¹⁰ R ¹¹ ,
R ¹⁰ and R ¹¹ independently of one another are hydrogen, amino, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _{1- 3} -alkyl, C _1-6 -alkoxy, C _1-6 -alkylthio, C _1-6 -alkoxy-C _1-6 -alkyl or the group -NR ¹³ R ¹⁴ , -SOR ¹² , -SO ₂ R ¹² , -CONH ₂ , -CONHC _1-6 alkyl, -CON (C _1-6 alkyl) ₂ , -COOH or -COOC _1-6 alkyl, or for optionally one or more, the same or different with hydroxy, halogen , C _1-6 alkoxy, C _1-6 alkylthio, halo-C _1-6 alkoxy or the group -NR ¹⁰ R ¹¹ , -SO ₃ H, -PO ₃ H ₂ , -NHC _1-6 - alkyl , -N-di-C _1-6 alkyl, -S (O) R ¹² , -SO ₂ R ¹² , -NR ¹³ SO ₂ R ¹⁴ , -SO ₂ NR ¹³ R ¹⁴ , -NR ¹² SO ₂ NR ¹³ R ¹⁴ , -NR ¹² SO ₂ NH ₂ , -NR ¹³ COR ¹⁴ , -NR ¹³ COOR ¹⁴ , -NR ¹³ CONHR ¹⁴ , -NR ¹² CONH ₂ , -PO (OR ¹³ ) (OR ¹⁴ ), -POR ¹³ ( OR ¹⁴ ), -CONH ₂ , -CONR ¹³ R ¹⁴ or -COOR ¹² substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-6 alkoxy, C _1-6 -Thioalkyl, C _3-7 cycloalkyl or C _3-7 cycloalkylC _1-3 alkyl, benzylo xy, aryl or heteroaryl, or containing by one to two nitrogen, oxygen or sulfur atoms and / or interrupted by one or more = C = O groups in the ring and / or optionally one or more possible double bonds in the ring C _{3- 7-} cycloalkyl or C _3-7 -cycloalkyl-C _1-3 -alkyl,
or represents unsubstituted or mono- or polysubstituted by halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, halo-C _1-6 alkyl or halo-C _1-6 alkoxy, or
R ¹⁰ and R ¹¹ together form a ring


form, optionally with hydroxy, halogen, amino, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkoxy-C _1-6 alkyl or the group -NHC _1-6 alkyl, N (C _1-6 alkyl) ₂ , -SOC _1-6 alkyl, -SO ₂ C _1-6 alkyl, -CONH ₂ , -CONH-C _1-6 alkyl, -CON (C _1-6 -Alkyl) ₂ , -COOH or -COOC _1-6 -alkyl or can be substituted with phenyl, where appropriate the phenyl one or more times with halogen, hydroxy, C _1-6 -alkyl, C _1-6 -alkoxy, halo -C _1-6 alkyl, halo-C _1-6 alkoxy or C _3-10 cycloalkyl can be substituted, the C _3-10 cycloalkyl being interrupted by one or more nitrogen, oxygen and / or sulfur atoms can be and / or can be interrupted by one or more = C = O groups in the ring and / or optionally one or more possible double bonds can be contained in the ring, optionally one or more times with halogen, hydroxy, amino, C _{1 -6} alkoxy, C _1-6 alkylthio, C _1-6 -alkoxy-C _1-6 - alkyl or the group -NHC _1-6 alkyl, -N (C _1-6 alkyl) ₂ , -SOC _1-6 - alkyl, -SO ₂ C _1-6 alkyl, -CONH ₂ , -CONH-C _1-6 alkyl, -CON (C _1-6 - alkyl) ₂ , -COOH, - COOC _1-6 alkyl can be substituted,
R ^{12 is} hydrogen, amino, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _1-3 alkyl, C _1-6 -alkoxy, C _1-6 -alkylthio, C _1-6 -alkoxy-C _1-6 -alkyl or the group -NR ¹³ R ¹⁴ , -CONH ₂ , -CONH-C _1-6 -alkyl, - CON (C _1-6 alkyl) ₂ , -COOH or -COOC _1-6 alkyl, or for optionally one or more, the same or different with hydroxy, halogen, C _1-6 alkoxy, C _1-6 - Alkylthio, halo-C _1-6 -alkoxy, amino or the group -SO ₃ H, -PO ₃ H ₂ , -NHC _1-6 -alkyl, -N-di-C _1-6 -alkyl, -CONH ₂ , substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-6 alkoxy, C _1-6 thioalkyl, C _3-7 cycloalkyl or C _3-7 - Cycloalkyl-C _1-3 alkyl, benzyloxy, aryl or heteroaryl, or interrupted by one or two nitrogen, oxygen or sulfur atoms and / or by one or more = C = O groups in the ring and / or optionally one or C _3-7 cycloalkyl or C _3-7 cycloalkyl-C _1- containing several possible double bonds in the ring _3- alkyl, or for unsubstituted or mono- or polysubstituted with halogen, hydroxy, C _1-6 -alkyl, C _1-6 -alkoxy, halo-C _1-6 -alkyl or halo-C _1-6 -alkoxy stands,
R ¹³ and R ^{14 are} independently hydrogen, amino, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _{1- 3} -alkyl, C _1-6 -alkoxy, C _1-6 -alkylthio, C _1-6 -alkoxy-C _1-6 -alkyl or the group -CONH ₂ , -CONHC _1-6 -alkyl, -CON (C _1-6 alkyl) ₂ , -COOH or -COOC _1-6 alkyl, or for optionally one or more, identical or different with hydroxy, halogen, C _1-6 alkoxy, C _1-6 alkylthio, halo -C _1-6 alkoxy, amino or the group
-SO ₃ H, -PO ₃ H ₂ , -NHC _1-6 alkyl, -N-di-C _1-6 alkyl, -S (O) R ¹² , -SO ₂ R ¹² , -NR ¹⁰ SO ₂ R ¹¹ , -SO ₂ NR ¹⁰ R ¹¹ , -NR ¹² SO ₂ NR ¹⁰ R ¹¹ , -NR ¹² SO ₂ NH ₂ , -NR ¹⁰ COR ¹¹ , -NR ¹⁰ COOR ¹¹ , -NR ¹⁰ CONHR ¹¹ , -NR ¹² CONH ₂ , -PO (OR ¹⁰ ) (OR ¹¹ ), -POR ¹⁰ (OR ¹¹ ), -CONH ₂ , -CONR ¹⁰ R ¹¹ or -COOR ¹² substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-6 alkoxy, C _1-6 thioalkyl, C _3-7 cycloalkyl or C _3-7 cycloalkyl-C _1-3 alkyl, benzyloxy, aryl or heteroaryl,
or C _3-7 cycloalkyl or C _{3- which is} interrupted by one or two nitrogen, oxygen or sulfur atoms and / or by one or more = C = O groups in the ring and / or optionally one or more possible double bonds in the ring _7- cycloalkyl-C _1-3 alkyl,
or represents unsubstituted or mono- or polysubstituted by halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, halo-C _1-6 alkyl or halo-C _1-6 alkoxy, or
R ¹³ and R ¹⁴ together form a ring


form, optionally with hydroxy, halogen, amino, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkoxy-C _1-6 alkyl or the group -NHC _1-6 alkyl, N (C _1-6 alkyl) ₂ , -SOC _1-6 alkyl, -SO ₂ C _1-6 alkyl, -CONH ₂ , -CONH-C _1-6 alkyl, -CON (C _1-6 -Alkyl) ₂ , -COOH or -COOC _1-6 -alkyl or can be substituted with phenyl, where appropriate the phenyl one or more times with halogen, hydroxy, C _1-6 -alkyl, C _1-6 -alkoxy, halo -C _1-6 alkyl, halo-C _1-6 alkoxy or C _3-10 cycloalkyl can be substituted, the C _3-10 cycloalkyl being interrupted by one or more nitrogen, oxygen and / or sulfur atoms may be and / or may be interrupted by one or more = C = O groups in the ring and / or one or more possible double bonds may optionally be present in the ring, optionally one or more times with halogen, hydroxy, amino, C _{1 -6-} alkoxy, C _1-6 -alkylthio, C _1-6 -alkoxy-C _1-6 -alkyl or the group -NH-C _1-6 -alkyl, -N (C _1-6 -alkyl) ₂ , -SOC _1-6 -alkyl, -SO ₂ C _1-6 -alkyl, -CONH ₂ , -CONH-C _1-6 -alkyl, -CON (C _1-6 -alkyl) ₂ , -COOH, - COOC _1-6 alkyl may be substituted, as well as their isomers and salts, overcome the known disadvantages.

Under alkyl is in each case a straight-chain or branched alkyl radical, such as for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, tert. Butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, To understand tetradecyl, pentadecyl, hexadecyl and octadecyl.

Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and Understand cycloheptyl.

Among the ring systems, where one or more possible Double bonds that may be contained in the ring are, for example, cycloalkenyls such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and To understand cyclooctenyl, the linkage to both the double bond as can also be done on the single bonds.

Halogen is to be understood as fluorine, chlorine, bromine or iodine.

The alkenyl substituents are each straight-chain or branched, where for example the following radicals are meant: vinyl, propen-1-yl, propen-2-yl, But-1-en-1-yl, but-1-en-2-yl, but-2-en-1-yl, but-2-en-2-yl, 2-methyl-prop-2-en- 1-yl, 2-methyl-prop-1-en-1-yl, but-1-en-3-yl, ethinyl, prop-1-in-1-yl, but-1-in-1-yl, But-2-in-1-yl, but-3-en-1-yl, allyl.

The aryl radical has 6-12 carbon atoms such as naphthyl, Biphenyl and especially phenyl.

The heteroaryl radical can in each case be benzo-condensed. For example, as Called 5-ring heteroaromatics: thiophene, furan, oxazole, thiazole, imidazole and Benzo derivatives thereof and as 6-ring heteroaromatics pyridine, pyrimidine, triazine, Quinoline, isoquinoline and benzo derivatives thereof.

If an acidic function is contained, the physiologically acceptable salts are Suitable salts of organic and inorganic bases, such as the good soluble alkali and alkaline earth salts as well as N-methyl-glucamine, dimethyl-glucamine, Ethyl glucamine, lysine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, Serinol, tris-hydroxy-methyl-amino-methane, aminopropanediol, Sovak base, 1-amino-2,3,4-butanetriol.

If a basic function is included, the physiologically acceptable salts are Suitable for organic and inorganic acids such as hydrochloric acid, sulfuric acid, Phosphoric acid, citric acid, tartaric acid u. a.

Compounds of the general formula I in which
Compounds of the general formula I in which
A for the group


Z represents hydrogen or C _1-10 alkyl,
or the group
-N- (CH ₂ ) _n -R ⁷ optionally also a ring of the structure


forms, where the ring may be unsaturated, partially saturated or saturated, Z is 0 and the nitrogen atom of the group -NR ¹⁰ R ¹¹ in the meaning of R ^{7 is} also a further hetero atom in the ring, and the ring optionally with hydroxy C _1-10 alkyl can be substituted,
n stands for 0, 1, 2, 3, 4, 5 or 6,
D for the group


R ¹ for hydrogen or for the group C _1-6 alkyl-CO- NR ¹⁰ R ¹¹ , or for unsubstituted or optionally one or more times, the same or different with hydroxy, C _1-6 alkoxy, amino, halogen or the Group -NHC _1-6 alkyl or -N-di-C _1-6 alkyl substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-7 cycloalkyl or C _3-7 -cycloalkyl-C _1-3- alkyl, C _3-7 -cycloalkyl or C _3-7 -cycloalkyl-C _1-3- alkyl interrupted by one or more heteroatoms,
R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ and R ⁹ independently of one another for hydrogen, halogen, hydroxy, nitro, amino, C _1-10 alkyl, C _2-10 alkenyl, C _{2- 10} alkynyl, C _3-7 - cycloalkyl, C _3-7 cycloalkyl-C _1-3 alkyl, C _1-6 alkoxy, C _1-6 - alkylthio, benzyloxy, aryl or heteroaryl or the group -SO ₃ H, -PO ₃ H ₂ , -NR ¹⁰ R ¹¹ , -N-di-C _1-6 alkyl, -S (O) R ¹² , -SO ₂ R ¹² , -NR ¹⁰ SO ₂ R ¹¹ , -SO ₂ NR ¹⁰ R ¹¹ , -NR ¹² SO ₂ NR ¹⁰ R ¹¹ , -NR ¹² SO ₂ NH ₂ , -NR ¹⁰ COR ¹¹ , -NR ¹⁰ COOR ¹¹ , -NR ¹⁰ CONHR ¹¹ , -NR ¹² CONH ₂ , -PO (OR ¹⁰ ) (OR ¹¹ ), -POR ¹⁰ (OR ¹¹ ), -CONH ₂ , -CONR ¹⁰ R ¹¹ or -COOR ¹² , or for optionally one or more, the same or different, with hydroxy, halogen, C _{1 -4} alkoxy, C _1-6 alkylthio, haloC _1-6 alkoxy, amino or the group -SO ₃ H, -PO ₃ H ₂ , -NHC _1-6 alkyl, -N-di-C _1-6 alkyl, -S (O) R ¹² , -SO ₂ R ¹² , -NR ¹⁰ SO ₂ R ¹¹ , -SO ₂ NR ¹⁰ R ¹¹ , -NR ¹² SO ₂ NR ¹⁰ R ¹¹ , -NR ¹² SO ₂ NH ₂ , -NR ¹⁰ COR ¹¹ , -NR ¹⁰ COOR ¹¹ , -NR ¹⁰ CONHR ¹¹ , -NR ^{1 2} CONH ₂ , -PO (OR ¹⁰ ) (OR ¹¹ ), -POR ¹⁰ (OR ¹¹ ), -CONH ₂ , -CONR ¹⁰ R ¹¹ or -COOR ¹² substituted C _1-10 alkyl, C _2-10 alkenyl C _2-10 alkynyl, C _1-6 alkoxy, C _1-6 thioalkyl, C _3-7 cycloalkyl or C _3-7 cycloalkyl-C _1-3 alkyl, benzyloxy, aryl or heteroaryl,
and C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-7 cycloalkyl or C _3-7 cycloalkyl-C _1-3 alkyl optionally one or more times by a = C = O or = NR ¹⁰ group can be interrupted,
R ^{7 represents} pyridyl or the group -NR ¹⁰ R ¹¹ ,
R ¹⁰ and R ¹¹ independently of one another represent hydrogen or C _1-10 -alkyl optionally substituted with hydroxy or the group -NR ¹³ R ¹⁴ , or
R ¹⁰ and R ¹¹ together form a ring


form,
R ^{12 is} hydrogen, amino, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _1-3 alkyl, C _1-6 -alkoxy, C _1-6 -alkylthio, C _1-6 -alkoxy-C _1-6 -alkyl or the group -NR ¹³ R ¹⁴ , -CONH ₂ , -CONH-C _1-6 -alkyl, - CON (C _1-6 alkyl) ₂ , -COOH or -COOC _1-6 alkyl, or for optionally one or more, the same or different with hydroxy, halogen, C _1-6 alkoxy, C _1-6 - Alkylthio, halo-C _1-6 -alkoxy, amino or the group -SO ₃ H, -PO ₃ H ₂ , -NHC _1-6 -alkyl, -N-di-C _1-6 -alkyl, -CONH ₂ , substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-6 alkoxy, C _1-6 thioalkyl, C _3-7 cycloalkyl or C _3-7 - Cycloalkyl-C _1-3 alkyl, benzyloxy, aryl or heteroaryl,
or C _3-7 cycloalkyl or C _{3- which is} interrupted by one or two nitrogen, oxygen or sulfur atoms and / or by one or more = C = O groups in the ring and / or optionally one or more possible double bonds in the ring _7- cycloalkyl-C _1-3 alkyl,
or represents unsubstituted or mono- or polysubstituted by halogen, hydroxy, C _1-6 -alkyl, C _1-6 -alkoxy, halo-C _1-6 -alkyl or halo-C _1-6 -alkoxy,
R ¹³ and R ^{14 are} independently hydrogen, amino, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _{1- 3} -alkyl, C _1-6 -alkoxy, C _1-6 -alkylthio, C _1-6 -alkoxy-C _1-6 -alkyl or the group -CONH ₂ , -CONHC _1-6 -alkyl, -CON (C _1-6 alkyl) ₂ , -COOH or -COOC _1-6 alkyl, or for optionally one or more, identical or different with hydroxy, halogen, C _1-6 alkoxy, C _1-6 alkylthio, halo -C _1-6 alkoxy, amino or the group
-SO ₃ H, -PO ₃ H ₂ , -NHC _1-6 alkyl, -N-di-C _1-6 alkyl, -S (O) R ¹² , -SO ₂ R ¹² , -NR ¹⁰ SO ₂ R ¹¹ , -SO ₂ NR ¹⁰ R ¹¹ , -NR ¹² SO ₂ NR ¹⁰ R ¹¹ , -NR ¹² SO ₂ NH ₂ , -NR ¹⁰ COR ¹¹ , -NR ¹⁰ COOR ¹¹ , -NR ¹⁰ CONHR ¹¹ , -NR ¹² CONH ₂ , -PO (OR ¹⁰ ) (OR ¹¹ ), -POR ¹⁰ (OR ¹¹ ), -CONH ₂ , -CONR ¹⁰ R ¹¹ or -COOR ¹² substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-6 alkoxy, C _1-6 thioalkyl, C _3-7 cycloalkyl or C _3-7 cycloalkyl-C _1-3 alkyl, benzyloxy, aryl or heteroaryl,
or C _3-7 cycloalkyl or C _{3- which is} interrupted by one or two nitrogen, oxygen or sulfur atoms and / or by one or more = C = O groups in the ring and / or optionally one or more possible double bonds in the ring _7- cycloalkyl-C _1-3 alkyl,
or represents unsubstituted or mono- or polysubstituted by halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, halo-C _1-6 alkyl or halo-C _1-6 alkoxy, or
R ¹³ and R ¹⁴ together form a ring


form, optionally with hydroxy, halogen, amino, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkoxy-C _1-6 alkyl or the group -NHC _1-6 alkyl, - N (C _1-6 alkyl) ₂ , -SOC _1-6 alkyl, -SO ₂ C _1-6 alkyl, -CONH ₂ , -CONH-C _1-6 alkyl, -CON (C _1-6 -Alkyl) ₂ , -COOH or -COOC _1-6 -alkyl or can be substituted with phenyl, where appropriate the phenyl one or more times with halogen, hydroxy, C _1-6 -alkyl, C _1-6 -alkoxy, halo -C _1-6 alkyl, halo-C _1-6 alkoxy or C _3-10 cycloalkyl can be substituted, the C _3-10 cycloalkyl being interrupted by one or more nitrogen, oxygen and / or sulfur atoms can be and / or can be interrupted by one or more = C = O groups in the ring and / or optionally one or more possible double bonds can be contained in the ring, optionally one or more times with halogen, hydroxy, amino, C _{1 -6} -alkoxy, C _1-6 -alkylthio, C _1-6 -alkoxy-C _1-6 -alkyl or the group -NH-C _1-6 -alkyl, -N (C _1-6 -alkyl) ₂ , -SOC _1-6 alkyl, -SO ₂ C _1-6 alkyl, -CONH ₂ , -CONH-C _1-6 alkyl, -CON (C _1-6 alkyl) ₂ , -COOH, -COOC _1-6 alkyl may be substituted, and their isomers and salts.

Such compounds of the general formula I, in which
A for the group


Z represents hydrogen or C _1-10 alkyl,
or the group
-N- (CH ₂ ) _n -R ⁷ optionally also a ring of the structure


forms, where the ring may be unsaturated, partially saturated or saturated, Z is 0 and the nitrogen atom of the group -NR ¹⁰ R ¹¹ in the meaning of R ^{7 is} also a further hetero atom in the ring, and the ring optionally with hydroxy C _1-10 alkyl can be substituted,
n stands for 0, 1, 2, 3, 4, 5 or 6,
D for the group


R ¹ for hydrogen or for the group C _1-6 alkyl-CO-NR ¹⁰ R ¹¹ , or for unsubstituted or optionally one or more, the same or different with hydroxy, C _1-6 alkoxy, amino, halogen or the Group -NHC _1-6 alkyl or -N-di-C _1-6 alkyl substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-7 cycloalkyl or C _3-7 -cycloalkyl-C _1-3- alkyl, C _3-7 -cycloalkyl or C _3-7 -cycloalkyl-C _1-3- alkyl interrupted by one or more heteroatoms,
R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ and R ⁹ independently of one another represent hydrogen,
R ^{7 represents} pyridyl or the group -NR ¹⁰ R ¹¹ ,
R ¹⁰ and R ¹¹ independently of one another represent hydrogen or C _1-10 -alkyl optionally substituted with hydroxy or the group -NR ¹³ R ¹⁴ , or
R ¹⁰ and R ¹¹ together form a ring


form,
R ¹³ and R ¹⁴ independently of one another represent hydrogen or C _1-6 alkyl, and their isomers and salts.

The compounds of the invention essentially inhibit cyclin-dependent kinases, whereupon their action, for example, against cancer, such as solid tumors and leukemia, autoimmune diseases such as psoriasis, alopecia, and multiple sclerosis, chemotherapy-induced alopecia and mucositis, cardiovascular diseases such as stenoses, arteriosclerosis and restenosis, infectious diseases, such as B. by unicellular parasites, such as Trypanosoma, Toxoplasma or Plasmodium, or caused by fungi, nephrological Diseases such as B. Glomerulonephritis, chronic neurodegenerative Diseases such as Huntington's disease, amyotropic lateral sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease, acute neurodegenerative diseases such as ischemia of the brain and Neurotrauma, viral infections, such as B. cytomegalus infections, herpes, Hepatitis B and C, and HIV diseases based.

The eukaryotic cell division cycle represents the duplication of the genome and its Distribution to the daughter cells safely by having a coordinated and regulated Sequence of events iterates through. The cell cycle is divided into four successive phases divided: The G1 phase represents the time before the DNA replication in which the cell grows and is susceptible to external stimuli is. In the S phase the cell replicates its DNA and in the G2 phase it prepares anticipate entering mitosis. In the mitosis (M phase) the replicated DNA separated and cell division completed.

The Cyclin Dependent Kinases (CDKs), a family of Ser / Thr kinases whose Members bind a cyclin (Cyc) as a regulatory subunit to theirs Need activation, push the cell through the cell cycle. different CDK / Cyc pairs are active in the different phases of the cell cycle. For the fundamental function of the cell cycle are significant CDK / Cyc pairs for example CDK4 (6) / CycD, CDK2 / CycE, CDK2 / CycA, CDK1 / CycA and CDK1 / CycB. Some members of the CDK enzyme family have a regulatory function by affecting the activity of the aforementioned cell cycle CDKs while other members of the CDK enzyme family still have no specific function could be assigned. One of these, CDK5, is characterized by that it is an atypical, different from the cyclin regulatory Has subunit (p35) and its activity is highest in the brain.

The entry into the cell cycle and the passage of the "restriction point", which marks the independence of a cell from further growth signals for the completion of the started cell division, are controlled by the activity of the CDK4 (6) / CycD and CDK2 / CycE complexes. The main substrate of these CDK complexes is the retinoblastoma protein (Rb), the product of the retinoblastoma tumor suppressor gene. Rb is a transcriptional co-repressor protein. Rb binds and inactivates transcription factors of the E2F type, and forms transcriptional repressor complexes with histone deacetylases (HDAC) (Zhang HS et al. (2000) .Exit from G1 and S phase of the cell cycle is regulated by repressor complexes containing HDAC-Rb-hSWI / SNF and Rb-hSWI / SNF. Cell 101, 79-89). The phosphorylation of Rb by CDK5 releases bound E2F transcription factors and leads to transcriptional activation of genes, the products of which are required for DNA synthesis and progression through the S phase. In addition, Rb phosphorylation causes the Rb-HDAC complexes to dissolve, thereby activating additional genes. The phosphorylation of Rb by CDK's is equivalent to the exceeding of the "restriction point". For the progression through the S phase and its completion, the activity of the CDK2 / CycE and CDK2 / GycA complexes is necessary, e.g. B. the activity of the transcription factors of the E2F type is switched off by means of phosphorylation by CDK2 / CycA as soon as the cells have entered the S phase. After complete replication of the DNA, the CDK1 in complex with CycA or CycB controls the entry and the passage of phases G2 and M ( Fig. 1).

This is according to the extraordinary importance of the cell division cycle Going through the cycle strictly regulated and controlled. The enzymes that are for the Progression through the cycle is necessary at the right time be activated and also switched off again as soon as the corresponding Phase has passed. Lock the corresponding checkpoints progression through the cell cycle if DNA damage is detected, or DNA replication or the construction of the spindle apparatus has not yet been completed is.

The activity of the CDKs is controlled by various mechanisms, such as synthesis and Degradation of the cyclin, complexation of the CDKs with the corresponding ones Cyclins, phosphorylation and dephosphorylation of regulatory thr and Tyr residues, and the binding of natural inhibitory proteins, directly controlled. While the protein level of CDKs in a proliferating cell is relative is constant, the amount of the individual cyclines oscillates with the passage of the Cycle. For example, the expression of CycD during early G1 Phase stimulated by growth factors, and the expression of CycE after exceeding the "restriction point" by activating the E2F-type transcription factors induced. The cyclines themselves are made by Ubiquitin-mediated proteolysis degraded. Activating and inactivating Phosphorylation regulates the activity of the CDK's, for example phosphorylate CDK-activating kinases (CAKs) Thr160 / 161 of CDK1, whereas the family of Wee1 / Myt1 kinases CDK1 by phosphorylation inactivate Thr14 and Tyr15. This inactivating phosphorylation can be canceled by cdc25 phosphatases. Very significant is the regulation of the activity of the CDK / Cyc complexes by two families natural CDK inhibitor proteins (CKIs), the protein products of the p21 gene family (p21, p27, p57) and the p16 gene family (p15, p16, p18, p19). Members of the p21 Family bind to cyclin complexes of CDK5 1, 2,4,6, but only inhibit Complexes that contain CDK1 or CDK2. Are members of the p16 family specific inhibitors of the CDK4 and CDK6 complexes.

The lies above this complex direct regulation of the activity of CDK5 Control point regulation level. Control points allow the cell to do this to track the orderly progress of the individual phases during the cell cycle. The main checkpoints are at the transition from G1 to S and from G2 according to M. The G1 checkpoint ensures that the cell does not synthesize DNA starts with other cells or if she is not properly fed Substrate interacts correctly, and their DNA is intact. The G2 / M checkpoint poses the complete replication of the DNA and the structure of the mitotic spindle safe before the cell enters mitosis. The G1 checkpoint is from the Gene product of the p53 tumor suppressor gene activated. After detection of Changes in the metabolism or genomic integrity of the cell activated and can either stop cell cycle progression or apoptosis trigger. The transcriptional activation of CDK expression plays a role here Inhibitor protein p21 through p53 play a crucial role. A second branch of the G1 control point includes activation of ATM and Chk1 kinases after DNA Damage from UV light or ionizing radiation and finally the Phosphorylation and subsequent proteolytic degradation of the cdc25A Phosphatase (Milan N. et al. (2000). Rapid destruction of human cdc25A in response to DNA damage. Science 288, 1425-1429). This results in one Locking of the cell cycle because of the inhibitory phosphorylation of the CDKs is not removed. After activating the G2 / M checkpoint due to damage Both mechanisms are involved in the DNA in a similar way Stop progression through the cell cycle.

Loss of regulation of the cell cycle and loss of function of the Checkpoints are characteristics of tumor cells. The CDK-Rb signaling path is in Over 90% of human tumor cells affected by mutations. These mutations that eventually lead to inactivating phosphorylation of the RB, close the Overexpression of D and E cyclins by gene amplification or chromosomal translocations, inactivating mutations or deletions of P16-type CDK inhibitors, as well as increased (p27) or decreased (CycD) Protein breakdown. The second group of genes caused by mutations in Tumor cells are hit encoding components of the control points. So is p53, which is essential for the G1 and G2 / M control points, is the most common mutated gene in human tumors (approx. 50%). In tumor cells without p53 Express mutation, it is often due to a greatly increased Protein degradation disabled. Similarly, the genes of others are for that Function of the control points of necessary proteins affected by mutations, for Example ATM (inactivating mutations) or cdc25 phosphatases (Overexpression).

Convincing experimental data suggest that CDK2 / Cyc complexes occupy a critical position during cell cycle progression: (1) Both dominant-negative forms of CDK2 and transcriptional repression CDK2 expression by anti-sense oligonucleotides stop the Cell cycle progression. (2) Inactivation of the CycA gene in mice is lethal. (3) The disruption of the function of the CDK2 / CycA complex in cells by means of cell-permeable peptides led to tumor cell-selective apoptosis (Chen Y.N.P. et al. (1999). Selective killing of transformed cells by cyclin / cyclin dependent kinase 2 antagonists. Proc. Natl. Acad. Sci. USA 96, 4325-4329).

Changes in cell cycle control don't just play a role in cancer a role. The cell cycle is characterized by a number of viruses, both by transforming, as through non-transforming, activated to multiply to allow the viruses in the host cell. The wrong entry into the cell cycle of normally post-mitotic cells is made with different related to neurodegenerative diseases.

The mechanisms of cell cycle regulation, their changes in diseases and a variety of approaches to developing inhibitors of the Cell cycle progression and specifically the CDKs have been seen in several Publications described in detail (Sielecki T. M. et al. (2000). Cyclin-dependent kinase inhibitors: useful targets in cell cycle regulation. J. Med. Chem. 43, 1-18; Fry D.W. & Garrett M.D. (2000). Inhibitors of cyclin dependent kinases as therapeutic agents for the treatment of cancer. Curr. Opin. Oncol. Endo. Metab. Invest. Drugs 2, 40-59; Rosiania G.R. & Chang Y.T. (2000). Targeting hyperproliferative disorders with cyclin dependent kinase inhibitors. Exp. Opin. Ther. Patents 10, 215-230; Meijer L. et al. (1999). Properties and potential applications of chemical inhibitors of cyclin dependent kinases. Pharmacol. Ther. 82, 279-284; Senderowicz A.M. & Sausville E.A. (2000). Preclinical and clinical development of cyclin dependent kinase modulators. J. Natl. Cancer Inst. 92, 376-387).

The use of the compounds according to the invention as pharmaceuticals brought this into the form of a pharmaceutical preparation, which in addition to the Active pharmaceutical ingredient suitable for enteral or parenteral administration, organic or inorganic inert carrier materials, such as water, Gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, contains vegetable oils, polyalkylene glycols, etc. The pharmaceutical preparations can be in solid form, for example as tablets, coated tablets, suppositories, Capsules or in liquid form, for example as solutions, suspensions or Emulsions are present. If necessary, they also contain auxiliary substances, such as preservatives, stabilizers, wetting agents or emulsifiers; Salts for Change in osmotic pressure or buffer.

These pharmaceutical preparations are also the subject of the present Invention.

In particular, injection solutions or are for parenteral use Suspensions, especially aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, suitable.

Surfactant auxiliaries such as salts of the Bile acids or animal or vegetable phospholipids, but also Mixtures thereof as well as liposomes or their components are used.

For oral use in particular tablets, coated tablets or capsules are included Talc and / or hydrocarbon carriers or binders, such as lactose, Corn or potato starch, suitable. The application can also be in liquid form take place, such as as juice, which may have a sweetener added.

The enteral, parenteral and oral applications are also a subject of the present invention.

The dosage of the active ingredients can vary depending on the route of administration, age and weight of the patient, type and severity of the disease to be treated and the like Factors vary. The daily dose is 0.5-1000 mg, preferably 50-200 mg, taking the dose as a single dose or divided can be given in 2 or more daily doses.

The present invention also relates to the use of Compounds of general formula I, for the manufacture of a medicament for Treatment of cancer, autoimmune diseases, cardiovascular Diseases, chemotherapy-induced alopecia and mucositis, infectious Diseases, nephrological diseases, chronic and acute neurodegenerative diseases and viral infections, with cancer solid tumors and leukemia, among autoimmune psoriasis, alopecia and multiple sclerosis, stenoses among cardiovascular diseases, Atherosclerosis and restenosis, among infectious diseases unicellular parasite-induced diseases, among nephrological Diseases glomerulonephritis, among chronic neurodegenerative Huntington's Disease, amyotropic lateral sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease, under acute neurodegenerative diseases ischemia of the brain and Neurotrauma, and among viral infections, cytomegalus infections, herpes, Hepatitis B or C, and HIV diseases are to be understood.

The present invention also relates to medicaments for Treatment of the diseases listed above, at least one Contain compound according to general formula I, as well as drugs with suitable formulation and carrier substances.

The compounds of general formula I according to the invention are under other excellent inhibitors of cyclin-dependent kinases, such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9, as well as the Glycogen synthase kinase (GSK-3β).

Preparation of the compounds according to the invention

The following examples illustrate the preparation of the invention Connections without the scope of the claimed connections to them Restrict examples.

The compounds according to the invention are prepared in accordance with the following process variants:

Example 1.0

Production of


599 mg (1.66 mmol) of compound (ii) from scheme 1, 30 mg of DMAP and 0.42 ml of N, N, N-trimethylethylenediamine are stirred at 60 ° C. for 8 hours. After cooling, the crystals are suctioned off, washed with ethanol and water, dried and dried at 60 ° C. in vacuo. 601 mg of compound 1.0 (85% of theory) are obtained. Production of the starting product (ii)

2 g (5.48 mmol) of the literature compound (i) from Scheme 1 are carefully mixed with 32 ml (440 mmol) of thionyl chloride while stirring.

The mixture is then stirred at 80 ° C for 3 hours. After cooling, be careful added to ice / water with stirring. Stir for 20 minutes suction filtered, washed with water and in vacuo at room temperature dried. Yield: 1.49 g of the intermediate of compound (ii) (75% of theory).

The following are prepared in an analogous manner to Example 1.0:

Example 2.0

Production of


100 mg of the compound from Example 1.0, 73 mg (0.234 mmol) of hydroxylammonium chloride and 293 mg of powdered potassium hydroxide are refluxed in 3 ml of ethanol for 2 hours. It is then poured onto about 25 ml of water and extracted 3 times with 25 ml of methylene chloride / isopropanol 4: 1. The combined organic phases are dried over magnesium sulfate and concentrated. Yield: 33 mg of compound 2.0 (32% of theory).

The following are produced in an analogous procedure:

Example 3.0

Production of

Become a solution of 38 mg of the compound from Example 2.0 Tetramethylguanidine (0.04 ml) in ethanol (2 ml) and 70 mg of the literature Intermediate compound (v) given in Scheme 1 and refluxed for 6 hours held. It was then concentrated. After column chromatography Purification gave 16 mg of compound 3.0.

Example 4.0

Production of

Please insert manufacturing process!

The following connections are also produced in an analogous manner:

Example 5.0

Production of


55 mg [0.1 mmol] of the intermediate (iv) and 51 mg [0.5 mmol] of N, N, N'-trimethylethylenediamine are stirred after adding a spatula tip of sodium iodide in 2 ml of DMF at 60 ° C. for 12 h. After cooling, it is poured onto 50 ml of water and the product is filtered off with suction. It is washed twice with 15 ml of water and then dried in vacuo at 50 ° C. Yield: 28 mg of compound 5.0 (58% of theory). Production of intermediate products Production of intermediate product (iii)

600 mg [1,662 mmol] of the (Indirubin-5-yl) sulfonic acid chloride (ii) (see Scheme 1) are mixed with 225 mg [3 mmol] N-methanolamine and a spatula tip of dimethylaminopyridine (DMAP) at 60 ° C under protective gas and Reflux stirred overnight. The reaction mixture is cooled and the product is suctioned off. It is washed twice with about 10 ml of ethanol and once with 2-3 ml of water and then dried at 50 ° C in a vacuum. Yield: 550 mg of intermediate (iii) (83% of theory). Production of the intermediate (iv)

200 mg [0.5 mmol] of the intermediate (iii) and 142 mg [0.75 mmol] tosylsulfonic acid chloride are dissolved in 3 ml of pyridine and stirred under protective gas at room temperature for 24 hours. It is poured onto a little ice and stirred for 15 minutes. It is then filtered off, washed three times with 25 ml of water and dried at 50 ° C in a vacuum. Yield: 245.5 mg of compound (iv) (89% of theory).

In an analogous procedure to Example 5.0, the following is produced:


Example 6.0 Scheme 2

Establishing connection 6.0

131 mg of compound 1.10 are dissolved in 4 M HCl in dioxane (2 ml), methanol (2 ml) and dichloromethane (2 ml) and stirred for 12 hours at room temperature. The crystals which have precipitated out are filtered off with suction and dried in vacuo. Yield: 82 mg of compound 6.0. Example 7.0 Scheme 3

Establishing connection 7.0

A solution of imidazole (82 mg, 1.2 eq) in DMF (3 ml) is added NaH suspension (55%, 44 mg, 1 eq) added at room temperature. After 15 minutes 200 mg (0.55 eq) of the intermediate (ii) and DMAP (20 mg) added. The reaction mixture is stirred at 80 ° C. for 5 hours. After that cooled, poured onto water (100 ml) and suction filtered. The blue-violet Solid is washed with water and, after drying in vacuo 140 mg of compound 7.0 (64% of theory).

The intermediates according to the invention, which can preferably be used for the preparation of the end products of the general formula I according to the invention, are likewise the subject of the present invention. Indirubin intermediates of the general formula Ia are very particularly preferred


in the
R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ⁹ , A, D, Z and n have the meanings given in the general formula I and
R ^{7 represents} the group -NR ¹⁰ R ¹¹ , and
R ¹⁰ and R ¹¹ independently of one another are C ₁ -C ₁₀ alkyl or the group -COO-C ₁ -C ₁₀ alkyl.

As far as the preparation of the starting compounds is not described these are known or analogous to known compounds or described here Process can be produced. It is also possible to do all of those described here Reactions in parallel reactors or using combinatorial Perform work techniques.

The isomer mixtures can by conventional methods such as Crystallization, chromatography or salt formation in the enantiomers or E / Z isomers are separated.

The salts are prepared in a conventional manner by adding a solution to the Compound of formula I with the equivalent amount or an excess of one Base or acid, which is optionally in solution, and the precipitate separates or works up the solution in the usual way.

Description of the picture

Fig. 1 shows the simplified scheme of cell cycle regulation in vertebrates.

The following examples describe the biological effects of Compounds according to the invention and the increase in the solubility of Compounds according to the invention compared to the known compounds, without restricting the invention to these examples.

example 1 CDK2 / CycE kinase assay

Recombinant CDK2 and CycE-GST fusion proteins purified from baculovirus infected insect cells (Sf9) were developed by Dr. Dieter Marmé, Clinic for Tumor biology Freiburg. Histone IIIS used as a kinase substrate was bought from Sigma.

CDK2 / CycE (50 ng / measuring point) was in assay buffer [50 mM Tris / HCl pH 8.0 for 15 min at 22 ° C. in the presence of various concentrations of test substances (0 μM, as well as within the range 0.01-100 μM) , 10 mM MgCl ₂ , 0.1 mM Na ortho-vanadate, 1.0 mM dithiothreitol, 0.5 µM adenosine trisphosphate (ATP), 10 µg / measuring point histone IIIS, 0.2 µCi / measuring point ³³ P-gamma ATP, 0 , 05% NP40, 12.5% dimethyl sulfoxide]. The reaction was stopped by adding EDTA solution (250 mM, pH 8.0, 14 μl / measuring point).

10 μl of each reaction mixture were applied to P30 filter strips (Wallac), and ³³ P-ATP which had not been incorporated was removed by washing the filter strips three times for 10 min each in 0.5% strength phosphoric acid. After the filter strips had dried for 1 hour at 70 ° C., the filter strips were covered with scintillator strips (MeltiLex ™ A, Wallac) and baked at 90 ° C. for 1 hour. The amount of ³³ P incorporated (substrate phosphorylation) was determined by scintillation measurement in a gamma radiation measuring device (Wallac).

Example 2

proliferation assay

Cultivated human MCF7 tumor cells were at a density of 5000 Cells / measuring point in a 96-well multi-titer plate in 200 µl of the corresponding Growth medium plated. After 24 hours the cells became a plate (Zero point plate) colored with crystal violet (see below), while the medium of other plates with fresh culture medium (200 µl) containing the test substances in various concentrations (0 µM, as well as in the range 0.01-30 µM; the final Concentration of the solvent dimethyl sulfoxide was 0.5%) were added, replaced. The cells were kept for 4 days in the presence of the test substances incubated. Cell proliferation was determined by staining the cells with crystal violet determined: The cells were 11% by adding 20 ul / measurement point Glutaraldehyde solution fixed at room temperature for 15 min. After three times Washing the fixed cells with water, the plates were at room temperature dried. The cells were made 0.1% by adding 100 μl / measuring point Crystal violet solution (pH adjusted to 3 by adding acetic acid) colored. After washing the stained cells three times with water, the Plates dried at room temperature. The dye was obtained by adding 100 µl / measuring point of a 10% acetic acid solution dissolved. The absorbance was determined photometrically at a wavelength of 595 nm. The percentage Change in cell growth was normalized to the measured values Absorbance values of the zero point plate (= 0%) and the extinction of the untreated (0 µM) cells (= 100%) calculated.

The results are shown in the table below.

Comparison of the effectiveness of non-basic indirubin derivatives with the basic indirubin derivatives according to the invention.

The comparison shows that the non-basic indirubin derivatives are less effective are than the Indirubinderivate invention.

Claims (14)

1. Compounds of the general formula I


in the
A for the group


Z represents hydrogen or C _1-10 alkyl,
or the group
-N- (CH ₂ ) _n -R ⁷ optionally also a ring of the structure


forms, where the ring may be unsaturated, partially saturated or saturated, Z is 0 and the nitrogen atom of the group -NR ¹⁰ R ¹¹ in the meaning of R ^{7 is} also a further hetero atom in the ring, and the ring optionally with hydroxy C _1-10 alkyl can be substituted,
n stands for 0, 1, 2, 3, 4, 5 or 6,
D for the group


R ¹ for hydrogen or for the group C _1-6 alkyl-CO- NR ¹⁰ R ¹¹ , or for unsubstituted or optionally one or more times, the same or different with hydroxy, C _1-6 alkoxy, amino, halogen or the Group -NHC _1-6 alkyl or -N-di-C _1-6 alkyl substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-7 cycloalkyl or C _3-7 -cycloalkyl-C _1-3- alkyl, C _3-7 -cycloalkyl or C _3-7 -cycloalkyl-C _1-3- alkyl interrupted by one or more heteroatoms, or unsubstituted or optionally one or more, the same or differently phenyl substituted with halogen, hydroxy, C _1-6 alkyl or C _1-6 alkoxy, or the group -CF ₃ , -OCF ₃ , -SC _1-6 alkyl or -SCF ₃ ,
R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ and R ⁹ independently of one another for hydrogen, halogen, hydroxy, nitro, amino, C _1-10 alkyl, C _2-10 alkenyl, C _{2- 10} -alkynyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _1-3 -alkyl, C _1-6 -alkoxy, C _1-6 -alkylthio, benzyloxy, aryf or heteroaryl or the group -SO ₃ H , -PO ₃ H ₂ , -NR ¹⁰ R ¹¹ , -N-di-C _1-6 -alkyl, -S (O) R ¹² , -SO ₂ R ¹² , -NR ¹⁰ SO ₂ R ¹¹ , -SO ₂ NR ¹⁰ R ¹¹ , -NR ¹² SO ₂ NR ¹⁰ R ¹¹ , -NR ¹² SO ₂ NH ₂ , -NR ¹⁰ COR ¹¹ , -NR ¹⁰ COOR ¹¹ , -NR ¹⁰ CONHR ¹¹ , -NR ¹² CONH ₂ , -PO ( OR ¹⁰ ) (OR ¹¹ ), -POR ¹⁰ (OR ¹¹ ), -CONH ₂ , -CONR ¹⁰ R ¹¹ or -COOR ¹² , or optionally one or more times, identically or differently, with hydroxyl, halogen, C _{1- 6} -alkoxy, C _1-6 -alkylthio, halo-C _1-6 -alkoxy, amino or the group -SO ₃ H, -PO ₃ H ₂ , -NHC _1-6 -alkyl, -N-di-C _{1 -6} -alkyl, -S (O) R ¹² , -SO ₂ R ¹² , -NR ¹⁰ SO ₂ R ¹¹ , -SO ₂ NR ¹⁰ R ¹¹ , -NR ¹² SO ₂ NR ¹⁰ R ¹¹ , -NR ¹² SO ₂ NH ₂ , -NR ¹⁰ COR ¹¹ , -NR ¹⁰ COOR ¹¹ , -NR ¹⁰ CONHR ¹¹ , -NR ¹² C ONH ₂ , -PO (OR ¹⁰ ) (OR ¹¹ ), -POR ¹⁰ (OR ¹¹ ), -CONH ₂ , -CONR ¹⁰ R ¹¹ or -COOR ¹² substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-6 alkoxy, C _1-6 thioalkyl, C _3-7 cycloalkyl or C _3-7 cycloalkylC _1-3 alkyl, benzyloxy, aryl or heteroaryl , and C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-7 cycloalkyl or C _3-7 cycloalkyl-C _1-3 alkyl optionally one or more times by one = C = O or = NR ¹⁰ group can be interrupted,
R ^{7 represents} pyridyl or the group -NR ¹⁰ R ¹¹ ,
R ¹⁰ and R ¹¹ independently of one another are hydrogen, amino, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _{1- 3} -alkyl, C _1-6 -alkoxy, C _1-6 -alkylthio, C _1-6 -alkoxy-C _1-6 -alkyl or the group -NR ¹³ R ¹⁴ , -SOR ¹² , -SO ₂ R ¹² , -CONH ₂ , -CONHC _1-6 alkyl, -CON (C _1-6 alkyl) ₂ , -COOH or -COOC _1-6 alkyl, or for optionally one or more, the same or different with hydroxy, halogen , C _1-6 alkoxy, C _1-6 alkylthio, halo-C _1-6 alkoxy or the group -NR ¹³ R ¹⁴ , -SO ₃ H, -PO ₃ H ₂ , -NHC _1-6 alkyl , -N-di-C _1-6 alkyl, -S (O) R ¹² , -SO ₂ R ¹² , -NR ¹³ SO ₂ R ¹⁴ , -SO ₂ NR ¹³ R ¹⁴ , -NR ¹² SO ₂ NR ¹³ R ¹⁴ , -NR ¹² SO ₂ NH ₂ , -NR ¹³ COR ¹⁴ , -NR ¹³ COOR ¹⁴ , -NR ¹³ CONHR ¹⁴ , -NR ¹² CONH ₂ , -PO (OR ¹³ ) (OR ¹⁴ ), -POR ¹³ ( OR ¹⁴ ), -CONH ₂ , -CONR ¹³ R ¹⁴ or -COOR ¹² substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-6 alkoxy, C _1-6 -Thioalkyl, C _3-7 -cyclo-alkyl or C _3-7 -cycloalkyl-C _1-3 -alkyl, benzylox y, aryl or heteroaryl, or interrupted by one or two nitrogen, oxygen or sulfur atoms and / or by one or more = C = O groups in the ring and / or optionally one or more possible double bonds in the ring containing C _{3- 7-} cycloalkyl or C _3-7 -cycloalkyl-C _1-3- alkyl, or for unsubstituted or one or more times with halogen, hydroxy, C _1-6 -alkyl, C _1-6 -alkoxy, halo-C _{1- 6-} alkyl or halo-C _1-6 alkoxy substituted phenyl, or
R ¹⁰ and R ¹¹ together form a ring


form, optionally with hydroxy, halogen, amino, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkoxy-C _1-6 alkyl or the group -NHC _1-6 alkyl, - N (C _1-6 alkyl) ₂ , -SOC _1-6 alkyl, -SO ₂ C _1-6 alkyl, -CONH ₂ , -CONH-C _1-6 alkyl, -CON (C _1-6 -Alkyl) ₂ , -COOH or -COOC _1-6 -alkyl or can be substituted with phenyl, where appropriate the phenyl one or more times with halogen, hydroxy, C _1-6 -alkyl, C _1-6 -alkoxy, halo -C _1-6 alkyl, halo-C _1-6 alkoxy or C _3-10 cycloalkyl can be substituted, the C _3-10 cycloalkyl being interrupted by one or more nitrogen, oxygen and / or sulfur atoms can be and / or can be interrupted by one or more = C = O groups in the ring and / or optionally one or more possible double bonds can be contained in the ring, optionally one or more times with halogen, hydroxy, amino, C _{1 -6-} alkoxy, C _1-6 -alkylthio, C _1-6 -alkoxy-C _1-6 -alkyl or the group -NHC _1-6 -alkyl, -N (C _1-6 -alkyl) ₂ , -SOC _1-6 alkyl, -SO ₂ C _1-6 alkyl, -CONH ₂ , -CONH-C _1-6 alkyl, -CON (C _1-6 alkyl) ₂ , -COOH, -COOC _1-6 alkyl may be substituted,
R ^{12 is} hydrogen, amino, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _1-3 alkyl, C _1-6 -alkoxy, C _1-6 -alkylthio, C _1-6 -alkoxy-C _1-6 -alkyl or the group -NR ¹³ R ¹⁴ , -CONH ₂ , -CONH-C _1-6 -alkyl, - CON (C _1-6 alkyl) ₂ , -COOH or -COOC _1-6 alkyl, or for optionally one or more, the same or different with hydroxy, halogen, C _1-6 alkoxy, C _1-6 - Alkylthio, halo-C _1-6 alkoxy, amino or the group -SO ₃ H, -PO ₃ H ₂ -NHC _1-6 -alkyl, -N-di-C _1-6 -alkyl, -CONH ₂ , substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-6 alkoxy, C _1-6 thioalkyl, C _3-7 cycloalkyl or C _3-7 cycloalkyl -C _1-3 alkyl, benzyloxy, aryl or heteroaryl, or interrupted by one or two nitrogen, oxygen or sulfur atoms and / or by one or more = C = O groups in the ring and / or optionally one or more Possible double bonds in the ring containing C _3-7 cycloalkyl or C _3-7 cycloalkyl-C _1-3 - Is alkyl, or is phenyl which is unsubstituted or substituted one or more times by halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkyl or haloC _1-6 alkoxy,
R ¹³ and R ^{14 are} independently hydrogen, amino, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _{1- 3} -alkyl, C _1-6 -alkoxy, C _1-6 -alkylthio, C _1-6 -alkoxy-C _1-6 -alkyl or the group -CONH ₂ , -CONHC _1-6 -alkyl, -CON (C _1-6 alkyl) ₂ , -COOH or -COOC _1-6 alkyl, or for optionally one or more, identical or different with hydroxy, halogen, C _1-6 alkoxy, C _1-6 alkylthio, halo -C _1-6 alkoxy, amino or the group -SO ₃ H, -PO ₃ H ₂ , -NHC _1-6 alkyl, -N-di-C _1-6 alkyl, -S (O) R ¹² , -SO ₂ R ¹² , -NR ¹⁰ SO ₂ R ¹¹ , -SO ₂ NR ¹⁰ R ¹¹ , -NR ¹² SO ₂ NR ¹⁰ R ¹¹ , -NR ¹² SO ₂ NH ₂ , -NR ¹⁰ COR ¹¹ , -NR ¹⁰ COOR ¹¹ , -NR ¹⁰ CONHR ¹¹ , -NR ¹² CONH ₂ , -PO (OR ¹⁰ ) (OR ¹¹ ), -POR ¹⁰ (OR ¹¹ ), -CONH ₂ , -CONR ¹⁰ R ¹¹ or -COOR ¹² substituted C _{1 -10} alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-6 alkoxy, C _1-6 thioalkyl, C _3-7 cycloalkyl or C _3-7 cycloalkyl-C _1-3 alkyl, benzyloxy, aryl or heteroaryl, or by egg n to two nitrogen, oxygen or sulfur atoms and / or C _3-7 cycloalkyl or C _{3-7 which is} interrupted by one or more = C = O groups in the ring and / or optionally contains one or more possible double bonds in the ring - Cycloalkyl-C _1-3 - alkyl, or for unsubstituted or one or more times with halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, halo-C _1-6 - alkyl or halo-C _{1- 6-} alkoxy substituted phenyl, or
R ¹³ and R ¹⁴ together form a ring


form, optionally with hydroxy, halogen, amino, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkoxy-C _1-6 alkyl or the group -NHC _1-6 alkyl, - N (C _1-6 alkyl) ₂ , -SOC _1-6 alkyl, -SO ₂ C _1-6 alkyl, -CONH ₂ , -CONH-C _1-6 alkyl, -CON (C _1-6 -Alkyl) ₂ , -COOH or -COOC _1-6 -alkyl or can be substituted with phenyl, where appropriate the phenyl one or more times with halogen, hydroxy, C _1-6 -alkyl, C _1-6 -alkoxy, halo -C _1-6 alkyl, halo-C _1-6 alkoxy or C _3-10 cycloalkyl can be substituted, the C _3-10 cycloalkyl being interrupted by one or more nitrogen, oxygen and / or sulfur atoms can be and / or can be interrupted by one or more = C = O groups in the ring and / or optionally one or more possible double bonds can be contained in the ring, optionally one or more times with halogen, hydroxy, amino, C _{1 -6-} alkoxy, C _1-6 -alkylthio, C _1-6 -alkoxy-C _1-6 -alkyl or the group -NH-C _1-6 -alkyl, -N (C _1-6 -alkyl) ₂ , -SOC _1-6 -alkyl, -SO ₂ C _1-6 -alkyl, -CONH ₂ , -CONH- C _1-6 -alkyl, -CON (C _1-6 -alkyl) ₂ , -COOH, - COOC _1-6 alkyl may be substituted, and their isomers and salts. 2. Compounds of general formula I, according to claim 1, in which
A for the group


Z represents hydrogen or C _1-10 alkyl,
or the group
-N- (CH ₂ ) _n -R ⁷ optionally also a ring of the structure


forms, where the ring may be unsaturated, partially saturated or saturated, Z is 0 and the nitrogen atom of the group -NR ¹⁰ R ¹¹ in the meaning of R ^{7 is} also a further hetero atom in the ring, and the ring optionally with hydroxy C _1-10 alkyl can be substituted,
n stands for 0, 1, 2, 3, 4, 5 or 6,
D for the group


for hydrogen or for the group C _1-6 -alkyl-CO- NR ¹⁰ R ¹¹ , or for unsubstituted or optionally one or more times, identical or different with hydroxy, C _1-6 -alkoxy, amino, halogen or the group - NHC _1-6 alkyl or -N-di-C _1-6 alkyl substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-7 cycloalkyl or C _{3- 7-} cycloalkyl-C _1-3- alkyl, C _3-7 -cycloalkyl or C _3-7 -cycloalkyl-C _1-3- alkyl interrupted by one or more heteroatoms,
R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ and R ⁹ independently of one another for hydrogen, halogen, hydroxy, nitro, amino, C _1-10 alkyl, C _2-10 alkenyl, C _{2- 10} -alkynyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _1-3 -alkyl, C _1-6 -alkoxy, C _1-6 -alkylthio, benzyloxy, aryl or heteroaryl or the group -SO ₃ H, -PO ₃ H ₂ , -NR ¹⁰ R ¹¹ , -N-di-C _1-6 alkyl, -S (O) R ¹² , -SO ₂ R ¹² , -NR ¹⁰ SO ₂ R ¹¹ , -SO ₂ NR ¹⁰ R ¹¹ , -NR ¹² SO ₂ NR ¹⁰ R ¹¹ , -NR ¹² SO ₂ NH ₂ , -NR ¹⁰ COR ¹¹ , -NR ¹⁰ COOR ¹¹ , -NR ¹⁰ CONHR ¹¹ , -NR ¹² CONH ₂ , -PO (OR ¹⁰ ) (OR ¹¹ ), -POR ¹⁰ (OR ¹¹ ), -CONH ₂ , -CONR ¹⁰ R ¹¹ or -COOR ¹² , or for optionally one or more, the same or different, with hydroxy, halogen, C _{1 -6} -alkoxy, C _1-6 -alkylthio, halo-C _1-6 -alkoxy, amino or the group -SO ₃ H, -PO ₃ H ₂ , -NHC _1-6 -alkyl, -N-di-C _1-6 alkyl, -S (O) R ¹² , -SO ₂ R ¹² , -NR ¹⁰ SO ₂ R ¹¹ , -SO ₂ NR ¹⁰ R ¹¹ , -NR ¹² SO ₂ NR ¹⁰ R ¹¹ , -NR ¹² SO ₂ NH ₂ , -NR ¹⁰ COR ¹¹ , -NR ¹⁰ COOR ¹¹ , -NR ¹⁰ CONHR ¹¹ , -NR ¹² CONH ₂ , -PO (OR ¹⁰ ) (OR ¹¹ ), -POR ¹⁰ (OR ¹¹ ), -CONH ₂ , -CONR ¹⁰ R ¹¹ or -COOR ¹² substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-6 alkoxy, C _1-6 thioalkyl, C _3-7 cycloalkyl or C _3-7 cycloalkylC _1-3 alkyl, benzyloxy, aryl or heteroaryl , and C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-7 cycloalkyl or C _3-7 cycloalkyl-C _1-3 alkyl optionally one or more times by one = C = O or = NR ¹⁰ group can be interrupted,
R ^{7 represents} pyridyl or the group -NR ¹⁰ R ¹¹ ,
R ¹⁰ and R ¹¹ independently of one another represent hydrogen or C _1-10 -alkyl optionally substituted with hydroxy or the group -NR ¹³ R ¹⁴ , or
R ¹⁰ and R ¹¹ together form a ring


form,
R ^{12 is} hydrogen, amino, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _1-3 alkyl, C _1-6 -alkoxy, C _1-6 -alkylthio, C _1-6 -alkoxy-C _1-6 -alkyl or the group -NR ¹³ R ¹⁴ , -CONH ₂ , -CONH-C _1-6 -alkyl, - CON (C _1-6 alkyl) ₂ , -COOH or -COOC _1-6 alkyl, or for optionally one or more, the same or different with hydroxy, halogen, C _1-6 alkoxy, C _1-6 - Alkylthio, halo-C _1-6 -alkoxy, amino or the group -SO ₃ H, -PO ₃ H ₂ , -NHC _1-6 -alkyl, -N-di-C _1-6 -alkyl, -CONH ₂ , substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-6 alkoxy, C _1-6 thioalkyl, C _3-7 cycloalkyl or C _3-7 - Cycloalkyl-C _1-3 alkyl, benzyloxy, aryl or heteroaryl, or interrupted by one or two nitrogen, oxygen or sulfur atoms and / or by one or more = C = O groups in the ring and / or optionally one or several possible double bonds in the ring containing C _3-7 cycloalkyl or C _3-7 cycloalkyl-C _1-3 -Alkyl, or phenyl which is unsubstituted or substituted one or more times by halogen, hydroxy, C _1-6 -alkyl, C _1-6 -alkoxy, halo-C _1-6 -alkyl or halo-C _1-6 -alkoxy .
R ¹³ and R ^{14 are} independently hydrogen, amino, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _{1- 3} -alkyl, C _1-6 -alkoxy, C _1-6 -alkylthio, C _1-6 -alkoxy-C _1-6 -alkyl or the group -CONH ₂ , -CONHC _1-6 -alkyl, -CON (C _1-6 alkyl) ₂ , -COOH or -COOC _1-6 alkyl, or for optionally one or more, identical or different with hydroxy, halogen, C _1-6 alkoxy, C _1-6 alkylthio, halo -C _1-6 alkoxy, amino or the group -SO ₃ H, -PO ₃ H ₂ , -NHC _1-6 alkyl, -N-di-C _1-6 alkyl, -S (O) R ¹² , -SO ₂ R ¹² , -NR ¹⁰ SO ₂ R ¹¹ , -SO ₂ NR ¹⁰ R ¹¹ , -NR ¹² SO ₂ NR ¹⁰ R ¹¹ , -NR ¹² SO ₂ NH ₂ , -NR ¹⁰ COR ¹¹ , -NR ¹⁰ COOR ¹¹ , -NR ¹⁰ CONHR ¹¹ , -NR ¹² CONH ₂ , -PO (OR ¹⁰ ) (OR ¹¹ ), -POR ¹⁰ (OR ¹¹ ), -CONH ₂ , -CONR ¹⁰ R ¹¹ or -COOR ¹² substituted C _{1 -10} alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-6 alkoxy, C _1-6 thioalkyl, C _3-7 cycloalkyl or C _3-7 cycloalkyl-C _1-3 alkyl, benzyloxy, aryl or heteroaryl, or by egg n to two nitrogen, oxygen or sulfur atoms and / or C _3-7 cycloalkyl or C _{3-7 which is} interrupted by one or more = C = O groups in the ring and / or optionally contains one or more possible double bonds in the ring - Cycloalkyl-C _1-3- alkyl, or for unsubstituted or one or more times with halogen, hydroxy, C _1-6 -alkyl, C _1-6 -alkoxy, halo-C _1-6 -alkyl or halo-C _{1- 6-} alkoxy substituted phenyl, or
R ¹³ and R ¹⁴ together form a ring


form, optionally with hydroxy, halogen, amino, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkoxy-C _1-6 alkyl or the group -NHC _1-6 alkyl, - N (C _1-6 alkyl) ₂ , -SOC _1-6 alkyl, -SO ₂ C _1-6 alkyl, -CONH ₂ , -CONH-C _1-6 alkyl, -CON (C _1-6 -Alkyl) ₂ , -COOH or -COOC _1-6 -alkyl or can be substituted with phenyl, where appropriate the phenyl one or more times with halogen, hydroxy, C _1-6 -alkyl, C _1-6 -alkoxy, halo -C _1-6 alkyl, halo-C _1-6 alkoxy or C _3-10 cycloalkyl can be substituted, the C _3-10 cycloalkyl being interrupted by one or more nitrogen, oxygen and / or sulfur atoms can be and / or can be interrupted by one or more = C = O groups in the ring and / or optionally one or more possible double bonds can be contained in the ring, optionally one or more times with halogen, hydroxy, amino, C _{1 -6-} alkoxy, C _1-6 -alkylthio, C _1-6 -alkoxy-C _1-6 -alkyl or the group -NH-C _1-6 -alkyl, -N (C _1-6 -alkyl) ₂ , -SOC _1-6 -alkyl, -SO ₂ C _1-6 -alkyl, -CONH ₂ , -CONH- C _1-6 -alkyl, -CON (C _1-6 -alkyl) ₂ , -COOH, - COOC _1-6 alkyl may be substituted, and their isomers and salts. 3. Compounds of general formula I, according to claims 1 and 2, in the
A for the group


Z represents hydrogen or C _1-10 alkyl,
or the group
-N- (CH ₂ ) _n -R ⁷ optionally also a ring of the structure


forms, where the ring may be unsaturated, partially saturated or saturated, Z is 0 and the nitrogen atom of the group -NR ¹⁰ R ¹¹ in the meaning of R ^{7 is} also a further hetero atom in the ring, and the ring optionally with hydroxy C _1-10 alkyl can be substituted,
n stands for 0, 1, 2, 3, 4, 5 or 6,
D for the group


R ¹ for hydrogen or for the group C _1-6 alkyl-CO- NR ¹⁰ R ¹¹ , or for unsubstituted or optionally one or more times, the same or different with hydroxy, C _1-6 alkoxy, amino, halogen or the Group -NHC _1-6 alkyl or -N-di-C _1-6 alkyl substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-7 cycloalkyl or C _3-7 -cycloalkyl-C _1-3- alkyl, C _3-7 -cycloalkyl or C _3-7 -cycloalkyl-C _1-3- alkyl interrupted by one or more heteroatoms,
R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ and R ⁹ independently of one another represent hydrogen,
R ^{7 represents} pyridyl or the group -NR ¹⁰ R ¹¹ ,
R ¹⁰ and R ¹¹ independently of one another represent hydrogen or C _1-10 -alkyl optionally substituted with hydroxy or the group -NR ¹³ R ¹⁴ , or
R ¹⁰ and R ¹¹ together form a ring


form,
R ¹³ and R ¹⁴ independently of one another represent hydrogen or C _1-6 alkyl, and their isomers and salts. 4. Use of the compounds of general formula I, according to Claims 1 to 3 for the manufacture of a medicament for treatment of cancer, autoimmune diseases, chemotherapy-induced Alopecia and mucositis, cardiovascular diseases, infectious Diseases, nephrological diseases, chronic and acute neurodegenerative diseases and viral infections. 5. Use according to claim 4, characterized in that under cancer solid tumors and leukemia, among autoimmune psoriasis, Alopecia and multiple sclerosis, among cardiovascular diseases Stenoses, atherosclerosis and restenosis, among infectious Diseases caused by unicellular parasites, under nephrological diseases glomerulonephritis, under chronic neurodegenerative diseases Huntington's disease, amyotropic lateral sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease, among acute neurodegenerative diseases Brain ischemia and neurotrauma, and among viral infections Cytomegalus infections, herpes, hepatitis B and C and HIV diseases are to be understood. 6. Medicament containing at least one compound according to Claims 1 to 3. 7. Medicament according to claim 6, for the treatment of cancer, Autoimmune diseases, cardiovascular diseases, infectious Diseases, nephrological diseases, neurodegenerative Diseases and viral infections. 8. Compounds according to claims 1 to 3 and pharmaceuticals according to the Claims 6 and 7 with suitable formulation and carrier substances. 9. Use of the compounds of general formula I, according to Claims 1 to 3, as inhibitors of the cyclin-dependent kinases. 10. Use according to claim 9, characterized in that the kinase CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 or CDK9. 11. Use of the compounds of general formula I, according to Claims 1 to 3, as inhibitors of glycogen synthase kinase (GSK-3β). 12. Use of the compounds of general formula I, according to Claims 1 to 3, in the form of a pharmaceutical preparation for the enteral, parenteral and oral application. 13. Indirubin intermediates of the general formula Ia


in the
R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ⁹ , A, D, Z and n have the meanings given in the general formula I and
R ^{7 represents} the group -NR ¹⁰ R ¹¹ , and
R ¹⁰ and R ¹¹ independently of one another are C ₁ -C ₁₀ alkyl or the group -COO-C ₁ -C ₁₀ alkyl. 14. Use of the Indirubin intermediates according to claim 13 for Production of indirubin derivatives with a basic side chain in the 5-position of the general formula I.