EP1996586A1 - 4-(pyrrolopyridinyl)pyrimidinyl-2-amine derivatives - Google Patents

Abstract

Compounds of the formula I in which R1 , R2, R3, R4 and R5 are each as defined in claim 1 are inhibitors of cell proliferation/cell vitality and can be used to treat tumors.

Description

 4- (pyrrolopyridinyl> pyrimidinyl-2-amine derivatives

The invention relates to compounds of the formula I.

wherein

R ¹ A, - [C (R ⁶ ) ₂ ] _n Ar, - [C (R ⁶ ) ₂ ] _n Het, - [C (R ⁶ ) ₂ ] n Cycloalkyl, COR ⁷ ,

COOR ⁷ , CON (R ⁷ ) ₂ or SO ₂ R ⁷ , R ² H or A, R ³ , R ^{4 are} each independently H, A, Hal, CN,

- [C (R ⁶ ) ₂ ] _n Ar, - [C (R ⁶ ) ₂ ] _n Het or - [C (R ⁶ ) ₂ ] _n cycloalkyl,

R ^{5 is} H, A, - [C (R ⁶ ) ₂ ] _n Ar, - [C (R ⁶ ) ₂ ] _n Het or

- [C (R ⁶ ) ₂ ] _n cycloalkyl, R

R is H or alkyl having 1-6 C atoms,

R ^{7 is} H, A, - [C (R ⁶ ) ₂ ] n Ar, - [C (R ⁶ ) ₂ l _n Het or

- [C (R ⁶ ) ₂ ] _n cycloalkyl,

A, A ^{1 are} each independently of one another unbranched or branched alkyl having 1-10 C atoms, in which one or two

CH ₂ groups may be replaced by O or S atoms and / or by -CH = CH groups and / or also 1-7 H atoms by F, Hal F, Cl, Br or I, Ar is an unsubstituted one, two, three, four or five times by OH, OA, SH, SA, SOA, SO ₂ A ₁ Hal, NO ₂ , NH ₂ , NHA, NAA ¹ , A, SO ₂ NH ₂ , SO ₂ NHA, SO ₂ NAA ¹ , CONH ₂ , CONHA, CONAA ¹ , NACOA ¹ , NASO ₂ A ¹ , COOH ₁ COOA, COA, CHO or CN substituted saturated, unsaturated or aromatic carbocycle having 5-14 C atoms,

Het a mono-, di- or trinuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms, which is unsubstituted or mono-, di- or trisubstituted by OH, OA, SH, SA, SOA, SO ₂ A, Hal, NO ₂ , NH ₂ , NHA ₁ NAA ¹ , A, SO ₂ NH ₂ , SO ₂ NHA, SO ₂ NAA ¹ , CONH ₂ , CONHA, CONAA ¹ , NACOA ¹ , NASO ₂ A ¹ , COOH, COOA, CHO, COA, CN, = S, = NH, = NA and / or = O (carbonyl oxygen), n is 0, 1 or 2, and their pharmaceutically usable derivatives, solvates, salts,

Tautomers and stereoisomers, including mixtures thereof in all

Conditions.

The object of the invention was to find new compounds with valuable properties, in particular those which can be used for the preparation of medicaments.

It has been found that the compounds of the formula I and their salts and / or solvates possess very valuable pharmacological properties with good compatibility.

In particular, they show an inhibiting effect of cell proliferation /

Cell vitality as antagonists or agonists. The invention

Compounds may therefore be used to combat and / or treat Tumors, tumor growth and / or tumor metastases.

The antiproliferative effect may be demonstrated in a proliferation assay /

Vitality assay to be tested.

Other 4- (pyrrolopyridinyl) -pyrimidinyl-2-amine derivatives are described, for example, by P.M. Fresneda et al. in Tetrahedron 57 (2001) 2355-2363.

10 Other 4- (pyrrolopyridinyl) -pyrimidinyl-2-amine derivatives are also described by A. Karpov in his dissertation, University of Heidelberg, April 2005.

Other amino-pyridine derivatives bearing a 2,2,6,6-tetramethyl-piperidin-4-yl- _* c residue are useful in the treatment of inflammatory and

Autoimmune diseases described in WO 2004/089913.

Accordingly, the compounds of the present invention or a pharmaceutically acceptable salt thereof are used for the treatment of cancer

Including solid carcinomas, such as carcinomas

(eg, the lungs, pancreas, thyroid, urinary bladder, or colon), myeloid diseases (eg, myeloid leukemia), or adenomas (eg, villous colon adenoma). 25 Tumors also include monocytic leukemia, brain,

Genitourinary, lymphatic, gastric, laryngeal and lung carcinomas, including lung adenocarcinoma and small cell lung carcinoma, pancreatic and / or mammary carcinoma.

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The compounds are also useful in the treatment of HIV-1

(Human Immunodeficiency Virus Type 1) induced immunodeficiency.

As cancerous hyperproliferative diseases are brain cancer,

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Lung cancer, squamous cell cancer, bladder cancer, stomach cancer,

Pancreatic cancer, liver cancer, kidney cancer, colorectal cancer, breast cancer, Head and neck cancer, oesophageal cancer, gynecological cancer, thyroid cancer, lymphoma, chronic leukemia and acute leukemia. In particular, cancerous cell growth is a disease that is an object of the present invention. The present invention therefore relates to compounds according to the invention as medicaments and / or active pharmaceutical ingredients in the treatment and / or prophylaxis of said diseases and the use of compounds according to the invention for the preparation of a pharmaceutical for the treatment and / or prophylaxis of said

Diseases, as well as a method of treating said diseases, comprising administering one or more of the compounds of the invention to a patient in need of such administration.

It can be shown that the compounds according to the invention have an antiproliferative action. The invention

Compounds are given to a patient with a hyperproliferative

Administered disease, z. B. for inhibiting tumor growth, for

Reduction of inflammation associated with a lymphoproliferative disorder, inhibition of graft rejection or neurological damage due to tissue repair, etc. The present compounds are useful for prophylactic or therapeutic purposes. As used herein, the term "treating" is used to refer to both the prevention of disease and the treatment of pre-existing conditions Prevention of proliferation / vitality is achieved by administration of the compounds of the invention prior to the development of the apparent disease, e.g. Prevention of Tumor Growth Alternatively, the compounds are used to treat persistent disease

Stabilization or improvement of the clinical symptoms of the patient used. The host or patient may be of any mammalian species, e.g. A primate species, especially humans; Rodents, including mice, rats and hamsters; Rabbits; Horses, cattle, dogs,

Cats, etc. Animal models are for experimental studies of

Interest, being a model for treating a disease of the

To provide people.

The susceptibility of a particular cell to treatment with the compounds of the invention can be determined by testing in vitro. Typically, a culture of the cell is incubated with a compound of the invention at various concentrations for a period of time sufficient to allow the active agents to induce cell death or to inhibit cell proliferation, cell vitality or migration, usually between about one hour and one week. For testing in vitro, cultured cells from a biopsy sample can be used. The amount of cells remaining after treatment are then determined.

The dose will vary depending on the specific compound used, the specific disease, the patient status, etc. Typically, a therapeutic dose will be sufficient to substantially reduce the unwanted cell population in the target tissue while maintaining patient viability. Treatment is generally continued until there is a significant reduction, e.g. B. at least about 50% reduction in cell load and can be continued until essentially no more unwanted cells are detected in the body.

There are many diseases associated with deregulation of cell proliferation and cell death (apoptosis). The ailments of interest include, but are not limited to, the following conditions. The compounds of the invention are useful in the treatment of a

Range of various conditions involving proliferation and / or migration smooth muscle cells and / or inflammatory cells in the intimal layer of a vessel is present, resulting in limited blood flow to this vessel, z. In neointimal occlusive lesions. Too occlusive

Transplant vascular diseases of interest include atherosclerosis, coronary vascular disease after transplantation, vein graft stenosis, peri-anastomotic prosthetic restenosis, restenosis after angioplasty or stent placement, and the like.

The invention also relates to the optically active forms (stereoisomers), salts, the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds. Solvates of the compounds are understood to mean additions of inert solvent molecules to the compounds which form due to their mutual attraction. Solvates are e.g.

Mono or dihydrate or alcoholates.

Pharmaceutically usable derivatives are understood, for example, as the

Salts of the compounds of the invention as well as so-called

Prodrug compounds.

Under prodrug derivatives is understood with z. B. alkyl or acyl groups,

Sugars or oligopeptides modified compounds of formula I, which are rapidly cleaved in the organism to the active compounds of the invention.

These include biodegradable polymer derivatives of the compounds of the invention, as z. In Int. J. Pharm. 115, 61-67 (1995).

The term "effective amount" means the amount of a drug or pharmaceutical agent that elicits a biological or medical response in a tissue, system, animal, or human, such as is sought or sought by a researcher or physician. Moreover, the term "therapeutically effective amount" means an amount which, compared to a corresponding subject who has not received this amount, results in: improved curative treatment, cure, prevention or elimination of a disease, a disease, a disease state, a disease Suffering, a disorder or side effects or even the reduction of the progression of a disease, a disease or a disorder. 10 The term "therapeutically effective amount" also includes the

Amounts effective to increase normal physiological function.

The invention also relates to the use of mixtures of the compounds of the formula I, e.g. Mixtures of two diastereomers, e.g. in the ratio 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1:10, 1: 100 or 1: 1000. These are particularly preferably mixtures of stereoisomeric compounds.

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The invention relates to the compounds of the formula I and their salts and to a process for the preparation of compounds of the formula I according to claims 1-13 and their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, characterized in that

a) a compound of formula II

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R2 wherein R ^{2 represents} an indole protecting group,

R ³ , R ⁴ and R ^{5 have} the meanings given in claim 1, and A is alkyl having 1, 2, 3 or 4 C atoms,

with a compound of formula III

wherein R ^{1 has} the meaning given in claim 1,

and simultaneously or subsequently splits off the indole protective group,

or

b) a compound of formula III with a compound of formula

wherein

R ² , R ³ , R ⁴ and R ^{5 have} the meanings given in claim 1,

implements, or

c) releasing them from one of their functional derivatives by treatment with a solvolyzing or hydrogenolysing agent,

or

d) in a compound of the formula I converts one radical R ¹ and / or R ² into another radical R ¹ and / or R ² by cleaving off i) an amino protective group and / or ii) carrying out an alkylation,

and / or converting a base or acid of the formula I into one of its salts.

Above and below, the radicals R ¹ , R ² , R ³ , R ⁴ and R ^{5 have} the meanings given for the formula I, unless expressly stated otherwise.

A, A ¹ , each independently of one another, is unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms. A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-

Methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-,

2-, 3- or 4-methylpentyl, 1, 1-, 1, 2-, 1, 3-,

2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methyl-propyl, 1-ethyl-2-methylpropyl, 1, 1, 2 or 1, 2,2-trimethylpropyl, more preferably, for example, trifluoromethyl. A very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl , Pentafluoroethyl or

1, 1, 1-trifluoroethyl.

In A, one or two CH ₂ groups may be replaced by O or S atoms and / or by -CH = CH groups. For example, A is also 2-methoxy-ethyl.

Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

A saturated, unsaturated or aromatic carbocycle having 5-14 C-g atoms preferably means cyclopentyl, cyclohexyl, cycloheptyl, phenyl, naphthyl, biphenyl or tetrahydronaphthyl.

Ar means e.g. Phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p- tert.- 0

Butylphenyl, o-, m- or p-trifluoromethylphenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p- Hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-methylsulfonyl- phenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or 5 p-methylaminophenyl, o-, m- or p-dimethylaminophenyl, o-, m- or p-aminosulfonylphenyl, o-, m- or p-methylaminosulfonylphenyl, o-, m- or p-aminocarbonylphenyl, o-, m- or p-carboxyphenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, m- or _Q p -acetylphenyl, o-, m- or p-formylphenyl, o-, m - or p-cyanophenyl, more preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2 , 5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl , 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, p-iodophenyl, 4-fluoro-3-chlorophenyl, 2 Fluoro-4-bromophenyl, 2,5-difluoro-4-5-bromophenyl or 2,5-dimethyl-4-chlorophenyl. Ar is preferably an unsubstituted or mono-, di-, tri- or quinone-substituted by OH, OA, Hal and / or A saturated, unsaturated or aromatic carbocycle having 6-14 C-

Atoms.

Ar is particularly preferably unsubstituted or mono-, di-, tri-, tetra- or quintuple phenyl, substituted by OH, OA, Hal and / or A, phenyl or naphthyl.

Het, irrespective of further substitutions, e.g. 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2 -, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2 -, 4-, 5- or 6-pyrimidinyl, more preferably 1, 2,3-triazole-1, -4- or -5-yl, 1, 2,4-triazole-1, -3 or 5 -yl, 1- or 5-tetrazolyl, 1, 2,3-oxadiazol-4 or -5-yl, 1, 2,4-oxadiazol-3 or -5-yl, 1, 3,4-thiadiazole 2- or -5-yl, 1, 2,4-

Thiadiazol-3 or -5-yl, 1, 2,3-thiadiazol-4 or -5-yl, 3 or 4

Pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-

Isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7- indazolyl, 1-, 3-, 4-, 5-, 6-amino - or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7- benzoxazolyl, 3-, 4-, 5-, 6- or 7- benzisoxazolyl, 2-, 4-, 5-, 6- or 7- benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, Q-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo [1, 4] oxazinyl, more preferably 1, 3-benzodioxol-5-yl, 1, 4-

Benzodioxan-6-yl, 2,1,3-benzothiadiazol-4 or 5-yl or 2,1,3-benzoxadiazol-5-yl.

The heterocyclic radicals may also be partially or completely hydrogenated.

Unsubstituted Het can thus z. B. also mean 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2 - Or 3- furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or 3-thienyl, 2,3-dihydro-1, -2-, -3-, -4- or -5-pyrrolyl, 2, 5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2, 3-dihydro-1-, -

2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1, 4-5

Dihydro-1, -2, -3 or 4-pyridyl, 1, 2,3,4-tetrahydro-1, -2, -3, -4, -5 or -6- pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxane -2-, -4- or -5-yl, hexahydro-1, -3- or -4-pyridazinyl, hexahydro-1, -2-, -4- or -5-

10 pyrimidinyl, 1-, 2- or 3-piperazinyl, 1, 2,3,4-tetrahydro-1-, 2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1, -2, -3, -4, -5, -6, -7- or -8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or 8-3,4-dihydro-2H-benzo [1,4] oxazinyl, more preferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxy-

cis phenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4- (difluoromethylenedioxy) phenyl, 2,3-dihydrobenzofuran-5- or 6-yl, 2,3- (2-oxomethylenedioxy ) -phenyl or else 3,4-dihydro-2H-1,5-benzodioxepin-6 or -7-yl, furthermore preferably 2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl. 20

Het is preferably an unsubstituted mono- or binuclear aromatic heterocycle having 1 to 4 N, O and / or S atoms. Het very particularly preferably denotes pyridyl, pyrimidinyl, thienyl, furyl, quinolyl, isoquinolyl, indolyl, indazolyl, benzimidazolyl, 1,3-benzodioxol-yl, 1,4-benzodioxan-yl, 2,1,3-benzothiadiazole yl or 2,1,3-benzoxadiazol-yl, very particularly preferred is quinolyl.

₃₀ R ¹ is preferably A, - [C (R ⁶⁾ _{2] n} Ar, - [C (R ⁶⁾ _{2] n} Het, COR ^7, CON (R ⁷⁾ ₂ or SO ₂ R ^7, wherein Het ≠ 2 , 2,6 _> 6-tetramethyl-piperidin-4-yl, and wherein R ^{6 is} preferably H, and wherein R ^{7 is} preferably H or alkyl having 1, 2, 3 or 4 C-atoms. R ³ is preferably H or A, more preferably H or alkyl having 1, 2, 3, 4, 5 or 6 C atoms.

R ⁴ is preferably H or A, more preferably H or alkyl having 1, 2, 3, 4, 5 or 6 C atoms.

R ⁵ is preferably H or A, more preferably H or alkyl having 1, 2, 3, 4, 5 or 6 C atoms.

R ⁶ is preferably H or alkyl having 1, 2, 3, 4, 5 or 6 C atoms. R ⁷ is preferably H or A, more preferably H or alkyl having 1, 2, 3, 4, 5 or 6 C atoms.

Hal preferably denotes F, Cl or Br, but also I, particularly preferably F or Cl.

For the entire invention, all residues that occur multiple times may be the same or different, i. are independent of each other.

The compounds of the formula I can possess one or more chiral centers and therefore occur in different stereoisomeric forms.

Formula I encompasses all these forms.

Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the abovementioned

Rests has one of the preferred meanings given above.

Some preferred groups of compounds may be through the following

Partial formulas Ia are expressed to Ik corresponding to the formula I and wherein the unspecified radicals have the meaning given in the formula I, wherein however

in Ia R ¹ A, - [C (R ⁶ ) ₂ ] _n Ar, - [C (R ⁶ ) ₂ ] _n Het, COR ⁷ , CON (R ⁷ ) ₂ or

SO ₂ R ⁷ , wherein Het ≠ 2,2,6,6-tetramethyl-piperidin-4-yl; in Ib R ³ H or A means

in Ic R ^{4 is} H or A;

in Id R ^{5 is} H or A;

in Ie R ^{7 is} H or A;

in If A is unbranched or branched alkyl having 1-6 C atoms, wherein one or two CH ₂ groups may be replaced by O or S atoms and / or also 1-7 H atoms by F, means;

unsubstituted or substituted by one, two, three, four or five times by OH, OA, Hal and / or A in Ig Ar

Phenyl or naphthyl;

in Ih Het an unsubstituted mono- or binuclear aromatic heterocycle having 1 to 4 N-, O- and / or

S atoms, means;

in Ii R ¹ A, - [C (R ⁶ ) ₂ ] _n Ar, - [C (R ⁶ ) ₂ ] _n Het, COR ⁷ , CON (R ⁷ ) ₂ or

SO ₂ R ⁷ , wherein Het ≠ 2,2,6,6-tetramethyl-piperidin-4-yl,

R ^{3 is} H or A,

R ^{4 is} H or A,

R ^{5 is} H or A ₁

R ^{7 is} H or A, A is unbranched or branched alkyl having 1-6 C atoms, in which one or two CH ₂ groups may be replaced by O or S atoms and / or also 1-7 H atoms by F,

Ar is phenyl or naphthyl which is unsubstituted or mono-, di-, tri-, tetra- or quintuple OH, OA, Hal and / or A,

Het an unsubstituted mono- or binuclear aromatic heterocycle having 1 to 4 N-, O- and / or

S atoms, mean;

in Ij R ¹ A, - (CH ₂ ) n Ar, - (CH ₂ ) _n Het, COR ⁷ , CON (R ⁷ ) ₂ or SO ₂ R ⁷ ,

R ^{2 is} H or A,

R ^{3 is} H or alkyl with 1 -6 C atoms,

R ^{4 is} H or alkyl having 1-6 C atoms,

R ^{5 is} H or alkyl having 1-6 C atoms, R ^{7 is} H or alkyl having 1-6 C atoms,

A is unbranched or branched alkyl having 1-6 C atoms, in which one or two CH ₂ groups are substituted by O- or S-

Atoms and / or 1-7 H atoms can be replaced by F,

Ar is unsubstituted or monosubstituted, disubstituted, trisubstituted, trisubstituted or pentane-substituted by OH, OA, Hal and / or A.

Phenyl or naphthyl, Het an unsubstituted mono- or binuclear aromatic heterocycle having 1 to 4 N-, O- and / or

S atoms, mean;

in Ik Het pyridyl, pyrimidinyl, thienyl, furyl, quinolyl, isoquinolyl,

Indolyl, indazolyl, benzimidazolyl, 1, 3-benzodioxolyl, 1,4-benzodioxanyl, 2,1,3-benzothiadiazolyl or 2,1,3-benzoxadiazolyl;

and their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios.

The compounds of formula I and also the starting materials for their preparation are otherwise prepared by methods known per se, as described in the literature (eg in the standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart )

. c, under reaction conditions which are known and suitable for the said reactions. One can also make use of known per se, not mentioned here variants.

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Compounds of the formula I can preferably be obtained by reacting compounds of the formula II and with compounds of the formula III.

The compounds of the formula II and of the formula III are generally known. If they are new, they can be produced by methods known per se.

The reaction takes place in an inert solvent and is carried out in the ₃ Q rule in the presence of an acid-binding agent, preferably an organic base such as DIPEA, triethylamine, dimethylaniline, pyridine or quinoline. Also, the addition of an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or other salt of a weak acid of

35

Alkali or alkaline earth metals, preferably potassium, sodium,

Calcium or cesium can be cheap. The reaction time is between a few minutes and 14 days depending on the conditions used, the reaction temperature between about

-15 ° and 150 °, normally between 40 ° and 120 °, particularly preferably between 60 ° and 110 ⁰ C.

Suitable inert solvents are e.g. Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers, such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethyl glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethylsulfoxide (DMSO); Carbon disulphide;

Carboxylic acids such as formic acid or acetic acid; Nitro compounds like

Nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of said solvents.

Particularly preferred are glycol ethers, THF, dichloromethane and / or DMF.

Preferred indole protecting groups are e.g. Sulfonyl protecting groups such as tosyl or mesyl, further protecting groups such as e.g. BOC.

Compounds of the formula I can furthermore be obtained by reacting compounds of the formula III with compounds of the formula IV. The compounds of formula IV are known in the rule. If they are new, they can be produced by methods known per se.

The reaction takes place in an inert solvent and takes place in the

Usually in the presence of an acid-binding agent, preferably one organic base such as DIPEA, triethylamine, dimethylaniline, pyridine or

Quinoline.

Also, the addition of an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or other salt of a weak acid of

Alkali or alkaline earth metals, preferably potassium, sodium,

Calcium or cesium can be cheap.

The reaction time is between a few minutes and 14 days depending on the conditions used, the reaction temperature between about -15 ° and 150 °, usually between 40 ° and 120 °, particularly preferably between 60 ° and 11O ⁰ C. Suitable inert solvents are the mentioned above.

The cleavage of an ether is carried out by methods known to those skilled in the art.

A standard method for ether cleavage, e.g. a methyl ether, is the use of boron tribromide.

Hydrogenolytically removable groups, e.g. the cleavage of a benzyl ether, z. B. by treatment with hydrogen in the presence of a

Catalyst (eg., A noble metal catalyst such as palladium, expediently on a support such as coal) are split off. Suitable solvents are those given above, in particular z. For example, alcohols such as methanol or ethanol or amides such as DMF. The

Hydrogenolysis is usually carried out at temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably at 20-30 ° and 1-10 bar.

Esters can e.g. with acetic acid or with NaOH or KOH in water,

Water THF or water dioxane be saponified at temperatures between 0 and 100 °.

Alkylations on the nitrogen are carried out under standard conditions, as known to those skilled in the art. The compounds of formula I can be further obtained by solubilizing them from their functional derivatives, in particular

Hydrolysis, or set free by hydrogenolysis.

Preferred starting materials for the solvolysis or hydrogenolysis are those which contain, instead of one or more free amino and / or hydroxyl groups, corresponding protected amino and / or hydroxyl groups, preferably those which, instead of an H atom which is substituted by an N- Atom, carry an amino protecting group, z. For example, those corresponding to formula I but containing an NHR ¹ group (where R ^{1 represents} an amino-protecting group, eg, BOC or CBZ) instead of an NH _Σ group.

Furthermore, preference is given to starting materials which, instead of the H atom of a hydroxy group, carry a hydroxyl-protecting group, eg. Those corresponding to formula I, but instead of a hydroxyphenyl group contain an R ¹¹ O-phenyl group (wherein R "means a hydroxy protecting group).

There may also be several - same or different - protected amino and / or hydroxy groups present in the molecule of the starting material. If the protecting groups present are different from each other, they can be selectively cleaved in many cases.

The term "amino protecting group" is well known and refers to groups which are capable of protecting (blocking) an amino group from chemical reactions, but which are readily removable after the desired chemical reaction has been carried out elsewhere in the molecule. In particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups are typical of such groups. Moreover, because the amino protecting groups are removed after the desired reaction (or reaction sequence), their type and size is not critical; however, preference is given to those having 1-20, in particular 1-8 C atoms. The term "acyl group" is to be understood in the broadest sense in the context of the present process. It encloses aliphatic, araliphatic, aromatic or heterogeneous acyl groups derived from cyclic carboxylic acids or sulfonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluyl; Aryloxyalkanoyl such as POA; Alkoxycarbonyl as

Methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC; Arylsulfonyl such as Mtr, Pbf or Pmc. Preferred amino protecting groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl and acetyl.

The term "hydroxy protecting group" is also well known and refers to groups which are suitable for protecting a hydroxy group from chemical reactions, but which are readily removable after the desired chemical reaction has been carried out at other sites on the molecule. Typical of such groups are the abovementioned unsubstituted or substituted aryl, aralkyl or acyl groups, and also alkyl groups. The nature and size of the hydroxy-protecting groups is not critical since they are removed after the desired chemical reaction or reaction sequence; are preferred

Groups with 1-20, in particular 1-10 C-atoms. Examples of hydroxy-protecting groups include i.a. tert-butoxycarbonyl, benzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, with benzyl and tert-butyl being particularly preferred. The COOH groups in aspartic acid and glutamic acid are preferably protected in the form of their tert-butyl esters (eg, Asp (OBut)).

The in-freedom setting of the compounds of formula I from their functional derivatives succeed - depending on the protecting group used - z. B. with strong acids, useful with TFA or perchloric acid, but also with other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary. Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as Tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol, and water. Also suitable are mixtures of the abovementioned solvents. TFA is preferably used in excess without the addition of another solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9: 1. The reaction temperatures for the cleavage are suitably between about 0 and about 50 °, preferably between 15 and 30 ° (room temperature).

The groups BOC, OBut, Pbf, Pmc and Mtr can, for. B. preferably cleaved with TFA in dichloromethane or with about 3 to 5n HCl in dioxane at 15-30 °, the FMOC group with an about 5- to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30 °.

The trityl group is used to protect the amino acids histidine, asparagine, glutamine and cysteine. The cleavage takes place, depending on the desired end product, with TFA / 10% thiophenol, the trityl group is split off from all the above amino acids, when using TFA / anisole or TFA / thioanisole only the trityl group of His, Asn and GIn is cleaved, whereas they remains on the Cys side chain. The Pbf (pentamethylbenzofuranyl) group is used to protect Arg. The cleavage takes place e.g. with TFA in dichloromethane.

Hydrogenolytically removable protecting groups (eg CBZ or benzyl) may e.g. By cleavage with hydrogen in the presence of a catalyst (e.g., a noble metal catalyst such as palladium, conveniently on a support such as carbon). Suitable solvents are those given above, in particular z. For example, alcohols such as methanol or ethanol or amides such as DMF. The hydrogenolysis is usually carried out at temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably at 20-30 ° and 1-10 bar. Hydrogenolysis of the CBZ group succeeds z. B. good at 5 to 10% Pd / C in methanol or with ammonium formate (instead of hydrogen) on Pd / C in methanol / DMF at 20-30 °. Pharmaceutical salts and other forms

The abovementioned compounds according to the invention can be used in their final non-salt form. On the other hand, the present invention also encompasses the use of these compounds in the form of their pharmaceutically acceptable salts, which can be derived from various organic and inorganic acids and bases according to procedures known in the art. Pharmaceutically acceptable salt forms of the compounds of formula I are for the most part prepared conventionally. If the compound of the formula I contains a carboxylic acid group, one of its suitable salts can be formed by reacting the compound with a suitable base to give the corresponding base addition salt. Such bases include, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; Alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; Alkali metal alcoholates, e.g. Potassium ethanolate and sodium propanolate; and various organic bases such as piperidine,

Diethanolamine and N-methylglutamine. The aluminum salts of the compounds of formula I are also included. For certain connections the

Formula I acid addition salts can be formed by treating these compounds with pharmaceutically acceptable organic and inorganic acids, e.g. Hydrogen halides such as hydrogen chloride, hydrogen bromide or hydrogen iodide, other mineral acids and their corresponding salts such as sulfate, nitrate or phosphate and the like, and alkyl and monoarylsulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate, and other organic acids and their corresponding salts such as acetate, trifluoroacetate, tartrate , Maleate, succinate, citrate, benzoate, salicylate, ascorbate and the like. Accordingly, pharmaceutically acceptable acid addition salts of the compounds of formula I include the following: acetate, adipate,

Alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate,

Bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride,

Chlorobenzoate, citrate, cyclopentane propionate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galacterate (from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, Isethionate, isobutyrate, lactate, lactobionate, malate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methyl benzoate, monohydrogen phosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, phenylacetate, 3-10 phenylpropionate, phosphate , Phosphonate, phthalate, but this is not limiting.

Furthermore, the base salts of the present invention ^ ₅ compounds include aluminum, ammonium, calcium, copper, iron (III) -, iron (II) -, lithium, magnesium, manganese (lll) -, manganese (II) , Potassium, sodium and zinc salts, but this is not intended to be limiting. Preferred among the above salts are ammonium; the

Alkali metal salts sodium and potassium, as well as the alkaline earth metal salts

20

Calcium and magnesium. Salts of compounds of formula I derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted ones

25 amines, cyclic amines and basic ion exchange resins, e.g.

Arginine, betaine, caffeine, chloroprocaine, choline, N, N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-

_O0 ethylmorphine, N-ethylpiperidine, glucamine, glucosamine, histidine,

Hydrabamine, iso-propylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine and tris- (hydroxymethyl) -methylamine ( Tromethamine), which is not

35

To represent restriction. Compounds of the present invention containing basic nitrogen-containing groups can be reacted with agents such as (C 1 -C ₄ ) alkyl halides, for example methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide;

Di (C 1 -C ₄ ) alkyl sulfates, eg dimethyl, diethyl and diamylsulfate; (C ₁₀ -

Ci ₈ ) alkyl halides, eg decyl, dodecyl, lauryl, myristyl and

Stearyl chloride, bromide and iodide; and aryl- (C 1 -C ₄ ) alkyl halides, eg benzyl chloride and phenethyl bromide, quaternize. With such salts, both water- and oil-soluble compounds of the invention can be prepared.

Preferred pharmaceutical salts include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate,

Meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine, but this is not intended to be limiting.

The acid addition salts of basic compounds of formula I are prepared by contacting the free base form with a sufficient amount of the desired acid to form the salt in a conventional manner. The free base can be prepared by contacting the salt form with a base and isolating the free base to standard

Regenerate way. The free base forms in some sense differ from their corresponding salt forms in terms of certain physical properties such as solubility in polar solvents; however, in the context of the invention, the salts otherwise correspond to their respective free base forms.

As mentioned, the pharmaceutically acceptable base addition salts of the compounds of the formula I are formed with metals or amines such as alkali metals and alkaline earth metals or organic amines.

Preferred metals are sodium, potassium, magnesium and calcium. Before- Suitable organic amines are N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base addition salts of acidic compounds of the invention are prepared by contacting the free acid form with a sufficient amount of the desired base to form the salt in a conventional manner. The free acid can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms in some sense differ from their corresponding salt forms in terms of certain physical properties such as solubility in polar solvents; However, in the context of the invention, the salts otherwise correspond to their respective free acid forms.

If a compound according to the invention contains more than one group which can form such pharmaceutically acceptable salts, the

Invention also multiple salts. Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine,

Diphosphate, disodium and trihydrochloride, but this is not intended to be limiting.

In view of the above, it can be seen that the term "pharmaceutically acceptable salt" in the present context means an active ingredient which contains a compound of the formula I in the form of one of its salts, especially if this salt form is the active ingredient in the Imparts improved pharmacokinetic properties to the free form of the active ingredient or any other salt form of the active ingredient which has previously been used. The pharmaceutically acceptable salt form of the active ingredient may also be this

It is possible to first give the active substance a desired pharmacokinetic property that it did not previously possess, and even pharmacodynamics this drug in terms of its therapeutic efficacy in the body positively influence.

The invention furthermore relates to medicaments comprising at least one compound of the formula I and / or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and / or adjuvants.

Pharmaceutical formulations may be presented in the form of dosage units containing a predetermined amount of active ingredient per unit dose. Such a moiety may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound of the invention, depending on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations may be in the form of dosage units containing a predetermined amount of active ingredient per

Dose unit included, to be presented. Preferred dosage unit formulations are those containing a daily or partial dose as indicated above or a corresponding fraction of an active ingredient. Furthermore, such pharmaceutical formulations can be prepared by any of the methods well known in the pharmaceutical art.

Pharmaceutical formulations may be administered by any suitable route, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) Ways, adapt.

Such formulations can be prepared by any method known in the pharmaceutical art, for example by using Active substance with the carrier (s) or excipient (s) is brought together.

Pharmaceutical formulations adapted for oral administration may be administered as separate units, e.g. Capsules or tablets; Powder or granules; Solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.

Thus, for example, in the case of oral administration in the form of a tablet or capsule, the active ingredient component can be mixed with an oral, non-oral. , toxic and pharmaceutically acceptable inert carrier, e.g. Ethanol, glycerin, water and the like. combine. Powders are prepared by comminuting the compound to a suitable fine size and using a similarly comminuted pharmaceutical grade

Carrier, such as e.g. an edible carbohydrate such as

20

Starch or mannitol is mixed. A flavor, preservative, dispersant and dye may also be present.

Capsules are prepared by preparing a powder mix as described above and filling shaped gelatin shells therewith. Lubricants and lubricants such as finely divided silica, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form can be added to the powder mixture before the filling process. An _OQ disintegrant or solubilizer such as agar-agar, calcium carbonate or sodium carbonate may also be added to improve the availability of the drug after ingestion of the capsule.

In addition, if desired or necessary, suitable binding, lubricating and disintegrants as well as dyes can also be incorporated into the mixture. Suitable binders include starch, Gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol,

Waxes, u.a. Among the lubricants used in these dosage forms are sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. The disintegrating agents include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. The tablets are formulated by

For example, a powder mixture is prepared, granulated or dry pressed, a lubricant and disintegrant are added and the whole is compressed into tablets. A powder mixture is prepared by mixing the appropriately comminuted compound with

a diluent or a base as described above, and optionally with a binder, e.g. Carboxymethylcellulose, an alginate, gelatin or polyvinylpyrrolidone, a dissolution reducer, such as e.g. Paraffin, a resorption accelerator, such as a quaternary salt and / or an absorbent, e.g. bentonite,

20

Kaolin or dicalcium phosphate. The powder mixture can be granulated by mixing it with a binder, e.g. Syrup, starch paste, Acadia slime or solutions of cellulosic or polymer materials is wetted and pressed through a sieve. As an alternative to

25 Granulation can run the powder mixture through a tabletting machine, resulting in irregularly shaped lumps, which are broken up into granules. The granules can be greased by adding stearic acid, a stearate salt, talc or mineral oil

2Q to prevent sticking to the tablet molds. The greased mixture is then compressed into tablets. The compounds according to the invention can also be combined with a free-flowing inert carrier and then pressed directly into tablets without carrying out the granulation or dry-pressing steps.

35

A transparent or opaque protective layer consisting of a shellac seal, a layer of sugar or polymer material and a glossy layer of wax, may be present. Dyes can be added to these coatings in order to differentiate between different dosage units.

Oral fluids, e.g. Solution, syrups and elixirs may be prepared in unit dosage form such that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in an appropriate taste aqueous solution while preparing elixirs using a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers, e.g. ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavoring additives such as e.g. Peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, i.a. can also be added.

The unit dosage formulations for oral administration may optionally be encapsulated in microcapsules. The formulation may also be prepared to prolong or retard release, such as by coating or embedding particulate material in polymers, wax, and the like.

The compounds of formula I as well as salts, solvates and physiologically functional derivatives thereof can also be administered in the form of liposome delivery systems, such as e.g. small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be prepared from various phospholipids, such as e.g. Cholesterol, stearylamine or phosphatidylcholines.

The compounds of the formula I and the salts, solvates and physiologically functional derivatives thereof can also be prepared using mono- clonal antibody as individual carriers to which the compound molecules are coupled. The compounds can also be coupled with soluble polymers as targeted drug carriers.

Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidophenol or polyethyleneoxidepolylysine substituted with palmitoyl radicals. Furthermore, the compounds can be attached to a class of biodegradable polymers suitable for the controlled release of a drug, e.g. Polylactic acid, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxy-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.

Pharmaceutical adapted to transdermal administration

Formulations may be presented as discrete plasters for prolonged, intimate contact with the epidermis of the recipient. For example, the drug may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3 (6), 318 (1986).

Pharmaceutical compounds adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

For treatments of the eye or other external tissues, eg mouth and skin, the formulations are preferably applied as a topical ointment or cream. When formulated into an ointment, the active ingredient can be used with either a paraffinic or water miscible cream base. Alternatively, the active ingredient can be formulated into a cream with an oil-in-water cream base or a water-in-oil base. The pharmaceutical formulations adapted for topical application to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouth include lozenges, troches and mouthwashes.

Pharmaceutical formulations adapted for rectal administration may be presented in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in which the vehicle is a solid contain a coarse powder having a particle size, for example, in the range of 20-500 microns, which is administered in the manner in which snuff is received, i. by rapid inhalation via the nasal passages from a container held close to the nose with the powder.

Suitable formulations for administration as a nasal spray or

Nasal drops containing a liquid carrier include drug solutions in water or oil.

For administration by inhalation adapted pharmaceutical

Formulations include fine particulate dusts or mists that can be generated by various types of pressurized dosing dispensers with aerosols, nebulizers or insufflators.

Pharmaceutical adapted to vaginal administration

Formulations may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

Among the adapted for parenteral administration pharmaceutical

Formulations include aqueous and non-aqueous sterile injection solutions containing antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickeners. The formulations may be presented in single or multi-dose containers, such as sealed vials and vials, and stored in the freeze-dried (lyophilized) state so that only the addition of the sterile carrier liquid, eg water for injections, is required immediately before use.

Injection solutions and suspensions prepared by formulation can be prepared from sterile powders, granules and tablets.

It will be understood that in addition to the above particularly mentioned ingredients, the formulations may include other means conventional in the art with respect to the particular type of formulation; for example, formulations suitable for oral administration

Flavors contain.

A therapeutically effective amount of a compound of formula I depends on a number of factors including, but not limited to, the age and weight of the animal, the exact condition requiring treatment, as well as its severity, nature of the formulation and route of administration determined by the attending physician or veterinarian. However, an effective amount of a compound of the invention for the treatment of neoplastic growth, eg, colon or breast carcinoma, is generally in the range of 0.1 to 100 mg / kg body weight of the recipient (mammal) per day, and more typically in the range of 1 to 10 mg / kg body weight per day. Thus, for a 70 kg adult mammal, the actual amount per day would usually be between 70 and 700 mg, this amount as a single dose per day or more commonly in a number of divided doses (such as two, three, four, five or six) per Given day can be so that the total daily dose is the same. An effective amount of a salt or solvate or a physiologically functional derivative thereof can be determined as a proportion of the effective amount of the compound of the invention per se. It can be assumed that similar dosages are suitable for the treatment of the other, above-mentioned disease states.

The invention furthermore relates to medicaments comprising at least one compound of the formula I and / or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further active pharmaceutical ingredient.

The invention is also a set (kit), consisting of separate packages of

(A) an effective amount of a compound of formula I and / or its pharmaceutically acceptable derivatives, solvates and stereoisomers, including mixtures thereof in all proportions, and

(b) an effective amount of another drug.

The set contains suitable containers, such as boxes or boxes, 5 individual bottles, bags or ampoules. The set may e.g. containing separate ampoules, in each of which an effective amount of a compound of formula I and / or its pharmaceutically acceptable derivatives, solvates and stereoisomers, including mixtures thereof in Q of all ratios, and an effective amount of another drug substance is dissolved or in lyophilized form.

5 USE

The instant compounds are useful as pharmaceutical agents for mammals, particularly for humans, in the treatment and control of cancers.

The present invention comprises the use of the compounds of the formula I and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment or prevention of cancer. Preferred carcinomas for the treatment are from the group of brain carcinoma, genitourinary tract carcinoma, carcinoma of the lymphatic system, gastric carcinoma, laryngeal carcinoma and lung carcinoma

Colorectal cancer. Another group of preferred forms of cancer are monocyte leukemia, lung adenocarcinoma, small cell lung carcinoma,

Pancreatic cancer, glioblastomas and breast carcinoma.

Also included is the use of the compounds of the formula I and / or their physiologically acceptable salts and solvates

A pharmaceutical composition for the treatment and / or control of a tumorigenic disease in a mammal, which process comprises administering to a diseased mammal in need of such treatment a therapeutically effective amount of a compound of the invention. The therapeutic amount depends on the particular disease and can be determined by the skilled person without great effort.

Particularly preferred is the use for treating a

Illness, where the disease is a solid tumor.

The solid tumor is preferably selected from the group of squamous cell tumors, bladder, stomach, kidney, head and neck, esophagus, cervix, thyroid, intestine, liver, brain, prostate, genitourinary tract, lymphatic system, stomach, larynx and / or lungs.

The solid tumor is furthermore preferably selected from the group of lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma, colon carcinoma and breast carcinoma.

Further preferred is the use for the treatment of a tumor of the blood and immune system, preferably for the treatment of a tumor selected from the group of acute myeloid leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia and / or chronic lymphocytic leukemia.

The invention further relates to the use of the compounds according to the invention for the treatment of bone pathologies, wherein the bone pathology from the group osteosarcoma, osteoarthritis and

Rickets originate.

The compounds of formula I may also be coadministered with other well-known therapeutics selected for their particular suitability for the condition being treated. The present compounds are also useful for combination with known anticancer agents. These known anticancer agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors and other angiogenesis inhibitors. The present compounds are particularly suitable for co-administration with radiotherapy.

"Estrogen receptor modulators" refers to compounds that have the

Interfere with or inhibit the binding of estrogen to the receptor, regardless of how this happens. To the estrogen receptor modulators include, for example, tamoxifen, raloxifene, idoxifen, LY353381, LY 117081, toremifene, fulvestrant, 4- [7- (2,2-dimethyl-1-oxopropoxy-4-methyl-2- [4- [2- (1 - piperidinyl) ethoxy] phenyl] -2H-1-benzopyran-3-yl] phenyl 2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone and SH646, but no

To represent restriction.

"Androgen receptor modulators" refers to compounds that have the

Interfere with or inhibit binding of androgens to the receptor,

10 regardless of how this happens. To the

Androgen receptor modulators include, for example, finasteride and other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate.

M Π "retinoid receptor modulators" refers to compounds that interfere with or inhibit the binding of retinoids to the receptor, regardless of how this occurs: such retinoid receptor modulators include, for example, bexarotene, tretinoin, 13-cis-retinoic acid,

9-cis-retinoic acid, α-difluoromethyl-omithine, ILX23-7553, trans-N- (4'-hydroxy)

20-phenyl) -retinamide and N-4-carboxyphenylretinamide.

"Cytotoxic agents" refers to compounds which cause cell death primarily by direct action on cell function or which inhibit or interfere with cell myosis, including alkylating agents, tumor necrosis

25 factors, intercalators, microtubulin inhibitors and topoisomerase inhibitors.

The cytotoxic agents include, for example, tirapazimine, sertenef, cachectin, ifosfamide, tasonermine, lonidamine, carboplatin, altretamine, prednimustine,

_O0 Dibromodulcite, Ranimustin, Fotemustin, Nedaplatin, Oxaliplatin,

Temozolomide, Heptaplatin, Estramustine, Improsulfan-tosylate, Trofosfamide, Nimustin, Dibrospidium chloride, Pumitepa, Lobaplatin, Satraplatin, Profiromycin, Cisplatin, Irofulvene, Dexifosfamide, cis-Amine dichloro (2-methylpyridine) platinum, Benzylguanine, Glufosfamide, GPX100,

35

(trans, trans, trans) -bis-mu (hexane-1,6-diamine) -mu- [diamine-platinum (II)] bis-

[diamine (chloro) platinum (II)] tetrachloride, diarizidinylspermine, arsenic trioxide, 1- (11- Dodecylamino-10-hydroxyundecyl) -3,7-dimethylxanthine, zorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin, pinafid, valrubicin, amrubicin, antineoplaston, S'-desamino-S'-morpholino-IS-deoxo-10-hydroxycarminomycin , Annamycin, Galarubicin, Elinafid,

MEN 10755 and 4-desmethoxy-3-desamino-3-aziridinyl-4-methylsulfonyl-daunorubicin (see WO 00/50032), but this is not intended to be limiting.

The microtubulin inhibitors include, for example, paclitaxel, vindesine sulfate, S '''-dideshyrmM'-deoxy-δ'-norvincaleukoblastin, docetaxol, rhizoxin, dolastatin, mivobulinisethionate, auristatin, cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin , 2,3,4, 5,6-pentafluoro-N- (3-fluoro-4-methoxyphenyl) benzenesulfonamide, anhydrovinblastine, N ₁ N-dimethyl-L-valyl-L-valyl-N-methyl-L-valy lL -prolyl-L-proline t-butylamide, TDX258 and BMS188797.

Topoisomerase inhibitors are, for example, topotecan, hycaptamine, irinotecan, rubitecane, 6-ethoxypropionyl-3 ', 4'-O-exo-benzylidene-chartreusine, 9-methoxy-N, N-dimethyl-5-nitropyrazolo [3,4; 5-kl] acridine-2

(6H) propanamine, 1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl

1 H, 12H-benzo [de] pyrano [3 ^I, 4 ': b, 7] indolizino [1, 2b] quinoline-10, 13 (9H, 15H) - dione, lurtotecan, 7- [2- (N- isopropylamino) ethyl] - (20S) camptothecin, BNP1350, BNPH 100, BN80915, BN80942, etoposide-phosphate, teniposide, sobuzoxan, 2'-dimethylamino-2'-deoxy-etoposide, GL331, N- [2-

(Dimethylamino) ethyl] -9-hydroxy-5,6-dimethyl-6H-pyrido [4,3-b] carbazole-1-carboxamide, asulacrine, (5a, 5aB, 8aa, 9b) -9- [2- [ N- [2- (dimethylamino) ethyl] -N-methylamino] ethyl] -5- [4-hydroxy-3,5-dimethoxyphenyl] -5,5a, 6,8,8a, 9-hexohydrofuro (3 ', 4 ¹ : 6,7) naphtho (2,3-d) -1,3-dioxol-6-one, 2,3- (methylenedioxy) -5-methyl-7-hydroxy-8-methoxybenzo [c] -phenanthridinium , 6,9-bis [(2-aminoethyl) amino] benzo [g] isoquinoline-5,10-dione, 5- (3-aminopropylamino) -7,10-dihydroxy-2- (2-hydroxyethylaminomethyl) -6H- pyrazolo [4,5,1-de] - acridin-6-one, N- [1- [2 (diethylamino) ethylamino] -7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl] formamide, N- (2- (dimethylamino) ethyl) acridine-4- carboxamide, 6 - [[2- (dimethylamino) ethyl] amino] -3-hydroxy-7H-indeno [2, 1-c] quinolin-7-one and dimesna.

Antiproliferative agents include antisense RNA and DNA

Oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and

INX3001, as well as antimetabolites such as enocitabine, carmofur, tegafur,

Pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabic sodium hydrate, raltitrexed, paltitrexide, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, x-deoxy-2'-methylidenecytidine, 2 ^l -fluoromethylene 2'-deoxycytidine, N- [5- (2,3-dihydrobenzofuryl) sulfonyl] -N '- (3,4-dichlorophenyl) urea, N6- [4-deoxy-4- [N 2 - [2 (E), 4 (E) -tetradecadienoyl] glycylamino] -L-glycero-BL-mannoheptopyranosyl] adenine, aplidine, ecteinascidin, troxacitabine, 4- [2-amino-4-oxo-4,6,7 ₎ 8-tetrahydro-3H -pyrimidino [5,4-b] [1,4] thiazin-6-yl- (S) -ethyl] -2,5-thienoyl-L-glutamic acid, aminopterin, 5-fluorouracil, alanosine, 11-acetyl-δ -Carbamoyloxymethy O -formyl-δ-methoxy- ^ -oxa-i, i -diazetetracyclo (7.4.1.0.0) -tetradeca-2,4,6-trien-9-ylacetic acid ester, swainsonine,

Lometrexol, dexrazoxane, methioninase, 2'-cyano-2'-deoxy-N4-palmitoyl-1

B-D-arabinofuranosylcytosine and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone. The "antiproliferative agents" also include other monoclonal antibodies against growth factors than those already listed under the "angiogenesis inhibitors", such as trastuzumab, as well as tumor suppressor genes, such as p53, which can be delivered via recombinant virus-mediated gene transfer (see, eg, US Patent No. 6,069,134 ).

Proof of action of pharmacological inhibitors on the

Proliferation / vitality of tumor cells in vitro

1.0 Background

In the present experimental description, the inhibition of

Tumor cell proliferation / tumor cell vitality described by drugs. The cells are seeded in suitable cell density in microtiter plates (96-well format). On the following day, the test substances are added in the form of a concentration series. After two more days of culture in serum-containing medium, the cell density is determined photometrically by staining the cells with crystal violet.

2.0 experimental procedure

10

2.1 cell culture

For example, commercially available colon carcinoma cell lines. The cells are cultured in medium. At intervals of 3-4 days <\ 5, the cells are detached from the culture dishes using trypsin solution and seeded in fresh medium at a suitable dilution. The cells are cultured at 37 ° C and 10% CO ₂ .

2.2. Sowing of the cells 0

• A cell culture flask is washed with 1-fold PBS

• Addition of 3mL 1-fold trypsin solution. Incubation for 5 min at 37 ⁰ C in the incubator.

• Stop by adding 7 ml of medium

Centrifugation of the cells (for example for 5 minutes at 150 x g (1200 rpm))

• Tilt the medium and resuspend cells in fresh medium

30 • Cell counting, for example, with trypan blue solution (1: 2 dilution) in number chamber

• Dilute cell suspension to 25000 cells / ml and plate 100 μl / well (2500 cells / well)

35 • Incubate the microtiter plate at 37 ^° C. in 10% CO ₂ overnight 2.3. Addition of the test substances

• The test substances are dissolved, for example, in DMSO and then in appropriate concentration (if necessary

5

Dilution series) in the cell culture medium. The dilution steps can be adjusted depending on the efficiency of the active ingredients and the desired spread of the concentrations. The test substances are mixed in appropriate concentrations with cell culture medium. Within

10 of the dilution series may be the final concentration of DMSO in the

Cell culture medium be constant (for example, at 0.5%). The addition of the test substances to the cells can take place one day after the cells have been boiled out. For this, the medium is removed from the cells and the

Test compound dilutions are added to the cells (at the desired concentrations in the cell culture medium). The cells are incubated for a further 48 hours at 37 ° C and 10% CO ₂ .

2.4. Crystal Violet Färbunq

20

The medium is removed from the cells and the cells are washed with PBS. After removing the PBS wash solution, 100 μl / well of Crystal Violet is added and allowed to stand for 15 minutes, for example

25 incubate a shaker at room temperature. The crystal violet is discarded and the cells are washed with water until no more large quantities of dye can be washed out. The plates are dried (oven at 37 ⁰ C for about an hour or at

30 room temperature overnight). After calcination, the crystal violet is dissolved by adding 200μl_ of methanol (per well). An absorption measurement is carried out at a suitable wavelength, for example 550 nm, in the microtiter plate reader (for example TECAN

Genios No F129004). If the absorbance values are outside the linear 35 Measuring range of the spectrophotometer, these can be diluted accordingly.

3. Evaluation

The absorbance value of the medium control (no use of cells and test substances) is subtracted from all other extinction values. The controls (cells without test substance) with the solvent DMSO are set equal to 100 percent and all other extinction values related thereto (expressed as% of control, for example):

Invoice: 100 * (mean of the individual values - mean background) (mean of the 100% individual values - mean background)

The determination of IC ₅₀ values (50% inhibition) is carried out with the aid of statistical programs such as RS1

IC 50 data of some compounds according to the invention are given in Table 1.

4. Materials and solutions

Crystal Violet Solution (500 ml): 0.5% Crystal Violet 2.5g

20% methanol 10OmL

First dissolve crystal violet in pure methanol, then make up with water and then filter.

APCI-MS (atmospheric pressure chemical ionization - mass spectrometry) (M + H) ⁺ .

HPLC Gradientensvstem

Pillar:

Chromolith Performance RP-18e (Merck KGaA, Cat 1.02129.0001)

eluent:

Eluent A: 0.1 M aq. NaH 2 PO 4 eluent B: acetonitrile + 10% water flow rate: 4 ml / min

Gradient:

0 min 1% B

1 min 1% B 7 min 99% B 8 min 99% B

example 1

The preparation of 3- (2-phenylamino-pyrimidin-4-yl) -1 / - / - pyrrolo [2,3-b] pyridine ("A1") and 1- (2-methoxy-ethyl) -3- ( 2-phenylamino-pyrimidin-4-yl) - 1H-pyrrolo [2,3-ιb] pyridine ("A2") is carried out analogously to the following scheme

1.1 To a solution of 15.5 g (131 mmol) of 7-azaindole in 100 ml of chlorobenzene, a solution of 52.8 ml (229 mmol) of tin tetrachloride in 100 ml of chlorobenzene is added dropwise with ice cooling and then stirred for 15 minutes under ice cooling. Then a solution of 16.2 ml (227 mmol) of acetyl chloride in 100 ml of chlorobenzene is added dropwise and the reaction mixture is stirred for 24 hours at room temperature. The resulting precipitate is filtered off, washed with dichloromethane and the residue dried in vacuo. This solid is then stirred with 100 ml of water and filtered with suction. The residue is stirred with 2N aqueous sodium hydroxide solution, filtered off with suction, washed with water and washed in Vacuum dried. This solid is extracted several times with hot ethyl acetate. The ethyl acetate solution is evaporated: 1- (1H-pyrrolo [2,3-o] pyridin-3-yl) -ethanone as colorless crystals; ESI 161, F. 208 -

210 °.

1.2 Under nitrogen, to a suspension of 1.25 g (52.0 mmol) of sodium hydride in 100 ml of DMF, a solution of 6.89 g (43.0 mmol) 1- (1H-pyrrolo [2,3-b] pyridin-3-yl) -ethanone in 50 ml of DMF added dropwise. The mixture is stirred for one hour at room temperature and then cooled to 0 °. A solution of 9.92 g (52.0 mmol) of toluene-4-sulfonyl chloride in 50 ml of DMF is added dropwise and the reaction mixture is stirred for 2 hours at 0 °. The reaction mixture is partitioned between ethyl acetate and water. The organic phase is dried over sodium sulfate, evaporated and the residue is stirred with water. It is filtered off with suction and the residue is dried in vacuo: 1- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-ib] pyridin-3-yl] -ethanone as colorless crystals; ESI 315, F. 187 - 189 °.

1.3 A solution of 4.29 g (13.6 mmol) of 1- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-o] pyridin-3-yl] -ethanone and 3.56 ml (26.8 mmol) of N ₁ N-dimethylformamide dimethyl acetal in 100 ml of DMF is heated at 110 ° for 8 hours. The reaction solution is cooled and partitioned between water and ethyl acetate. The organic phase is dried over sodium sulfate, evaporated and the residue recrystallized from methanol: (E) -3-dimethylamino-1- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-ib] pyridine-3 -yl] - propenone as slightly yellowish crystals; ESI 370, F. 220-223 °.

1.4 A solution of 369 mg (1.00 mmol) of (E) -3-dimethylamino-1- [1-

(toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -propenone and 296 mg (1.50 mmol) of phenylguanidine carbonate in 2 ml of ethylene glycol monomethyl ether are mixed with 290 mg (2.10 mmol) Potassium carbonate is added and the

Mixture heated to boiling for 24 hours. After cooling, that will Spread mixture between water and ethyl acetate. The organic phase is dried over sodium sulfate, evaporated and the residue is chromatographed by preparative HPLC. This gives "A1" as a colorless solid, ESI 288 and "A2" as a colorless solid; ESI 346.

"AT: ¹ H NMR (250 MHz, DMSO-d ₆ ) δ 6.98 (t, J = 7 Hz, 1 H), 7.22 (dd, Ji = 7.5 Hz, J ₂ = 5 Hz, 1H) ₁ 7.33 (m , 3H), 7.82 (d, J = 8Hz, 2H), 8.32 (d, J = 3.5Hz, 1H), 8.37 (d, J = 5Hz, 1H), 8.47 (s, 1H), 8.96 (i.e. , J = 7.5 Hz, 1H), 9.45 (s, 1H), 12.33 (bs, 1H).

"A2": ¹ H NMR (250 MHz, DMSO-d ₆ ) δ 3.32 (s, 3H), 3.85 (t, J = 5.3 Hz, 2H), 4.58 (t, J = 5.3 Hz, 2H), 7.04 ( t, J = 7 Hz, 1H), 7.32 (m, 2H), 7.38 (t, J = 7.5 Hz, 2H), 7.87 (d, J = 7.5 Hz, 2H), 8.42 (dd, J ₁ = 4.5 Hz , J ₂ = 1 Hz, 1H), 8.45 (d, J = 5 Hz, 1H), 8.58 (s, 1H), 9.00 (d, J = 7.5 Hz, 1H), 9.52 (s, 1H), 12.33 ( bs, 1 H).

Analogously, the following compounds are obtained

= 5 5 H)

Example 2

The preparation of 3- (2-phenylamino-6-propyl-pyrimidin-4-yl) -1H-pyrrolo [2,3-o] pyridine ("B1") is carried out analogously to the following scheme

2.1 A solution of 5.16 g (15.0 mmol) of tert -butyl 3-iodo-pyrrolo [2,3-t>] pyridine-1-carboxylate in 100 ml of tetrahydrofuran is treated with 526 mg (0.75 mmol) of bis (triphenylphosphine). Palladium (II) chloride and 57.2 mg (0.30 mmol) of copper (I) iodide added. Carbon monoxide is introduced into this solution in an autoclave apparatus. Then, 2.22 ml (22.5 mmol) of 1-pentyne and 1.52 g (15 mmol) of triethylamine are added. The reaction mixture is stirred in the autoclave apparatus for 48 hours under a pressure of 1 atm of carbon monoxide. The reaction mixture is washed with saturated sodium chloride solution and the aqueous phase extracted with dichloromethane. The combined organic phases are dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with petroleum ether / ethyl acetate as eluent: tert-butyl 3-hex-2-ynylpyrrolo [2,3-b] pyridine-1-carboxylate as colorless oil; ESI 313.

A solution of 300 mg (0.96 mmol) of tert-butyl 3-hex-2-ynyl-pyrrolo [2,3-b] pyridine-1-carboxylate and 284 mg (1.44 mmol) of phenylguanidine carbonate in 2 ml of ethylene glycol monomethyl ether with 278 mg (2.0 mmol) of sodium carbonate and the mixture is heated to boiling for 24 hours. After cooling, the mixture is partitioned between water and ethyl acetate. The organic phase is dried over sodium sulfate, evaporated and the residue is chromatographed by preparative HPLC. "B1" is obtained as a colorless solid; ESI 330.

¹¹ BI ": ¹ H NMR (250 MHz, DMSO-d ₆ ) δ 0.98 (t, J = 7.5 Hz, 3H), 1.79 (sextet, J = 7.5 Hz, 2H), 2.62 (t, J = 7.5 Hz, 2H), 6.95 (t, J = 7 Hz, 1 H),

10 7.20 (dd, J ₁ = 8 Hz, J ₂ = 4.5 Hz, 1H), 7.23 (s, 1 H), 7.31 (t, J = 7.5 Hz, 2H), 7.85 (d, J = 7 Hz, 2H ), 8.30 (m, 1H), 8.43 (m, 1H), 8.93 (m, 1H), 9.36 (s, 1H), 12.24 (s, 1H).

- _j 5 Analogously, the following compounds are obtained

20

25

30

35

Table 1

Inhibition on the proliferation / vitality of tumor cells

IC ₅₀ [mol / l]

The following examples relate to drugs:

Example A: Injection glasses

A solution of 100 g of an active compound of the formula I and 5 g of disodium hydrogen phosphate is adjusted to pH 6.5 in 3 l of bidistilled water with 2N hydrochloric acid, filtered sterile, filled into injection jars, lyophilized under sterile conditions and sealed under sterile conditions , Each injection jar contains 5 mg of active ingredient.

Example B: Suppositories

A mixture of 20 g of an active compound of the formula I is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.

Example C: Solution

A solution of 1 g of an active ingredient of the formula I ₁ 938 g of NaH ₂ PO ₄ .2H ₂ O, 28.48 g of Na ₂ HPO ₄ ^.12H ₂ O and 0.1 g of benzalkonium chloride in 940 is prepared ml of double distilled water. Adjust to pH 6.8, make up to 1 liter and sterilize by irradiation. This solution can be used in the form of eye drops.

Example D: Ointment

500 mg of an active compound of the formula I are mixed with 99.5 g of Vaseline under aseptic conditions. Example E: Tablets

A mixture of 1 kg of active ingredient of the formula I ₁ 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is in the usual

Way pressed into tablets, such that each tablet contains 10 mg of active ingredient.

Example F: dragees

Tablets are pressed analogously to Example E, which are then coated in the usual way with a coating of sucrose, potato starch, talc, tragacanth and dye.

Example G: Capsules

2 kg of active compound of the formula I are filled in the usual way in hard gelatin capsules, so that each capsule contains 20 mg of the active ingredient.

Example H: Ampoules

A solution of 1 kg of active compound of the formula I in 60 l of bidistilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each vial contains 10 mg of active ingredient.

Claims

 claims

1. Compounds of the formula I

wherein 5 R ¹ A, - [C (R ⁶ ) ₂ ] n Ar, - [C (R ⁶ ) ₂ ] _n Het, - [C (R ⁶ ) ₂ ] _n cycloalkyl,

COR ⁷ , COOR ⁷ , CON (R ⁷ ) ₂ or SO ₂ R ⁷ , wherein Het ≠ 2,2,6,6-tetramethyl-piperidin-4-yl, R ² H or A, O R ³ , R ⁴ each independently of one another H, A, Hal, CN,

- [C (R ⁶ ) ₂ ] _n Ar, - [C (R ⁶ ) ₂ ] _n Het or - [C (R ⁶ ) ₂ ] _n cycloalkyl,

R ^{5 is} H, A, - [C (R ⁶ ) ₂ ] _n Ar, - [C (R ⁶ ) ₂ ] _n Het or

- [C (R ⁶ ) ₂ ] _n cycloalkyl,

25 R ^{6 is} H or alkyl having 1-6 C atoms,

R ^{7 is} H, A, - [C (R ⁶ ) ₂ ] _n Ar, - [C (R ⁶ ) ₂ ] _n Het or

- [C (R ⁶ ) ₂ ] _n cycloalkyl,

A, A ^{1 are} each independently unbranched or

O ₀ branched alkyl having 1-10 C atoms, wherein one or two CH ₂ groups replaced by O or S atoms and / or by -CH = CH groups and / or 1-7 H atoms by F. could be,

HaI F, Cl, Br or I,

35

Ar is an unsubstituted or one, two, three, four or five times OH, OA, SH, SA, SOA, SO ₂ A, Hal, NO ₂ , NH ₂ , NHA, NAA ¹ , A, SO ₂ NH ₂ , SO ₂ NHA, SO ₂ NAA ¹ , CONH ₂ , CONHA, CONAA ¹ , NACOA ¹ , NASO ₂ A ¹ , COOH, COOA, COA, CHO or CN saturated, unsaturated or aromatic carbocycle with 5-14

C-atoms,

Het a mono-, di- or trinuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms, which is unsubstituted or 0 one, two or three times by OH, OA, SH, SA , SOA,

SO ₂ A, Hal, NO ₂ , NH ₂ , NHA, NAA ¹ , A, SO ₂ NH ₂ , SO ₂ NHA, SO ₂ NAA ¹ , CONH ₂ , CONHA, CONAA ¹ , NACOA ¹ , NASO ₂ A ¹ , COOH , COOA, CHO, COA, CN, = S, = NH, _c = NA and / or = O (carbonyl oxygen) may be substituted, n is O, 1 or 2, and their pharmaceutically usable derivatives, solvates, salts, 0

Tautomers and stereoisomers, including mixtures thereof in all ratios.

2. Compounds according to claim 1, wherein 5 R ¹ A, - [C (R ⁶ ) ₂ ] _n Ar, - [C (R ⁶ ) ₂ ] _n Het, COR ⁷ , CON (R ⁷ ) ₂ or

SO ₂ R ⁷ , wherein Het ≠ 2,2,6,6-tetramethyl-piperidin-4-yl, _0, and their pharmaceutically usable derivatives, solvates, salts,

Tautomers and stereoisomers, including mixtures thereof in all ratios.

3. Compounds according to claim 1 or 2, wherein ⁵ R ^{3 is} H or A, and their pharmaceutically usable derivatives, solvates, salts, tautomers and stereoisomers, including mixtures thereof in all ratios.

4. Compounds according to claim 1, 2 or 3, wherein R ^{4 is} H or A, and their pharmaceutically acceptable derivatives, solvates, salts, tautomers and stereoisomers, including mixtures thereof in all proportions.

5. Compounds according to one or more of claims 1-4, wherein R ^{5 is} H or A,

Λ C and its pharmaceutically usable derivatives, solvates, salts,

Tautomers and stereoisomers, including mixtures thereof in all ratios.

6. Compounds according to one or more of claims 1-5, wherein ²⁰ R ⁷ is H or A, and pharmaceutically usable derivatives, solvates, salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios. 25

7. Compounds according to one or more of claims 1-6, wherein A is unbranched or branched alkyl having 1-6 C atoms, wherein one or two CH ₂ groups by O- or S- _O0 atoms and / or also 1-7 H atoms can be replaced by F, and their pharmaceutically usable derivatives, solvates, salts,

Tautomers and stereoisomers, including mixtures thereof

35 all proportions.

8. Compounds according to one or more of claims 1-7, wherein Ar is unsubstituted or mono-, di-, tri-, tetra- or quintuple OH, OA, Hal and / or A substituted phenyl or naphthyl, and their pharmaceutically usable derivatives, solvates, salts, tautomers and stereoisomers, including mixtures thereof in all ratios. 10

9. Compounds according to one or more of claims 1-8, wherein Het is an unsubstituted mononuclear or dinuclear aromatic heterocycle having 1 to 4 N, O and / or ^ ₅ S atoms, and their pharmaceutically usable derivatives, solvates , Salts, tautomers and stereoisomers, including mixtures thereof in all proportions. 20

10. Compounds according to one or more of claims 1-9, wherein R ^{1 is} A, - [C (R ⁶ ) ₂ ] _n Ar, - [C (R ⁶ ) ₂ ] _n Het, COR ⁷ , CON (R ⁷ ) ₂ or

SO ₂ R ⁷ ,

25 wherein Het ≠ 2,2,6,6-tetramethyl-piperidin-4-yl,

R ^{3 is} H or A,

R ^{4 is} H or A,

R ^{5 is} H or A,

₃₀ R ⁷ H or A,

A is unbranched or branched alkyl having 1-6 C atoms, in which one or two CH ₂ groups may be replaced by O or S atoms and / or also 1-7 H atoms by F, 35 Ar unsubstituted or mono-, di-, tri-, tetra- or quintuple OH, OA, Hal and / or A substituted

Phenyl or naphthyl, Het an unsubstituted mono- or binuclear aromatic heterocycle having 1 to 4 N-, O- and / or

S atoms, and their pharmaceutically usable derivatives, solvates, salts, tautomers and stereoisomers, including mixtures thereof in all ratios.

1. Compounds according to one or more of claims 1-10, wherein R ^{1 is} A, - (CHz) _n Ar, - (CH ₂ ) _n Het, COR ⁷ , CON (R ⁷ ) ₂ or SO ₂ R ⁷ ,

R ^{2 is} H or A,

R ^{3 is} H or alkyl having 1-6 C atoms,

R ^{4 is} H or alkyl having 1-6 C atoms,

R ^{5 is} H or alkyl having 1 -6 C atoms, R ^{7 is} H or alkyl having 1-6 C atoms,

A is unbranched or branched alkyl having 1-6 C atoms, in which one or two CH ₂ groups may be replaced by O or S atoms and / or also 1-7 H atoms by F,

Ar unsubstituted or mono-, di-, tri-, tetra- or quintuple OH, OA, Hal and / or A-substituted phenyl or naphthyl, Het an unsubstituted mononuclear or bicyclic aromatic heterocycle having 1 to 4 N-, O- and or S-atoms, and their pharmaceutically usable derivatives, solvates, salts,

Tautomers and stereoisomers, including mixtures thereof in all ratios.

12. Compounds according to one or more of claims 1-1 wherein

Het pyridyl, pyrimidinyl, thienyl, furyl, quinolyl, isoquinolyl,

Indolyl, indazolyl, benzimidazolyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, 2,1,3-benzothiadiazolyl or 2,1,3-benzoxadiazolyl,

10 and their pharmaceutically usable derivatives, solvates, salts,

Tautomers and stereoisomers, including mixtures thereof in all ratios.

^ ₅ 13. A compound according to claim 1, selected from the group

20

25

30

35

and their pharmaceutically usable derivatives, solvates, salts, tautomers and stereoisomers, including mixtures thereof in all ratios.

14. A process for the preparation of compounds of the formula I according to claims 1-13 and their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, characterized in that

a) a compound of formula II

R ²

wherein R ^{2 represents} an indole protecting group,

R ³ , R ⁴ and R ^{5 have} the meanings given in claim 1, and A is alkyl having 1, 2, 3 or 4 C atoms,

with a compound of formula III

wherein R ^{1 has} the meaning given in claim 1,

and simultaneously or subsequently splits off the indole protective group,

or

b) a compound of formula III with a compound of formula

wherein 10 R ² , R ³ , R ⁴ and R ^{5 have} the meanings given in claim 1,

implements,

or

15

c) that one of their functional derivatives by treatment with a solvolysierenden or hydrogenolyzing

Set means at liberty, 0 or

converts d) in a compound of formula I a radical R ¹ and / or R ² in 25 another radical R ¹ and / or R ² by cleaving i) an amino and / or ii) alkylation is carried out, o U

and / or converting a base or acid of the formula I into one of its salts.

15. A pharmaceutical composition containing at least one compound of the formula I according to claim 1-13 and / or pharmaceutically acceptable Derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios, and optionally excipients and / or adjuvants.

16. Use of compounds according to claim 1-13 and their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios, for the manufacture of a medicament for the treatment of tumors, tumor growth, tumor metastases and / or AIDS.

17. Use according to claim 16, wherein the tumor is selected from the group

^ 5 of the squamous cell tumors, bladder, stomach, kidney, head and neck, esophagus, cervix, thyroid, intestine, liver, brain, prostate, genitourinary tract, lymphatic system, Stomach, of

Larynx and / or the lung is derived. 20

18. Use according to claim 16, wherein the tumor is selected from the group of monocytic leukemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, colon carcinoma,

25 glioblastomas and / or breast carcinoma originates.

19. Use according to claim 16, wherein it is a tumor of the blood and immune system.

30

The use of claim 16, wherein the tumor is from the group of acute myeloid leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia and / or chronic lymphocytic leukemia. 35

21. Use of compounds of the formula I according to claim 1-13 and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment of tumors, wherein a therapeutically effective amount of a compound of formula I in combination with a compound from group 1 ) estrogen receptor modulator, 2) androgen receptor modulator, 3) retinoid receptor modulator, 4) cytotoxic agent, 5) antiproliferative agent, 6) prenyl protein transferase inhibitor, 7) HMG-CoA reductase inhibitor, 8) HIV protease inhibitor, 9) Reverse transcriptase

Inhibitor and 10) other angiogenesis inhibitors is administered.

22. Use of compounds of the formula I according to claim 1-13 and / or their physiologically acceptable salts and solvates

Preparation of a medicament for the treatment of tumors wherein a therapeutically effective amount of a compound of formula I in combination with radiotherapy and a compound from the group

1) estrogen receptor modulator, 2) androgen receptor modulator, 3)

Retinoid receptor modulator, 4) cytotoxic agent, 5) antiproliferative agent,

6) prenyl-protein transferase inhibitors, 7) HMG-CoA reductase inhibitors, 8) HIV protease inhibitors, 9) reverse transcriptase inhibitors, and 10) other angiogenesis inhibitors.