EP2352733A1 - Benzonaphtyridine compounds used as inhibitors of autotaxin - Google Patents

Abstract

The invention relates to compounds of formula (I), in which R1, R2, R3, R4, R5,D, Z, X, Y, m and p are defined as cited in claim 1. Said compounds can be used in the treatment of tumours.

Description

 BENZO-NAPHTYRIDINE COMPOUNDS AS INHIBITORS OF AUTOTAXIN

BACKGROUND OF THE INVENTION

The invention had the object of finding new compounds with valuable properties, in particular those that can be used for the production of medicaments.

The present invention relates to compounds and the use of

Compounds for the treatment of diseases associated with an increase in Lysophosphatsäure mirror, also pharmaceutical

Compositions containing these compounds.

In particular, the present invention relates to compounds of the formula I ₁ which preferably inhibit one or more enzymes which contain the

Lysophosphate acid (/ phosphositate / d / c ac / d or LPA for short) regulate and / or modulate levels, compositions containing these

Compounds, as well as methods for their use for the treatment of diseases and conditions such as angiogenesis, cancer, tumorigenesis, growth and spread, arteriosclerosis, eye diseases, choroidal neovascularization and diabetic

Retinopathy, inflammatory diseases, arthritis, neurodegeneration, restenosis, wound healing or graft rejection. In particular, the compounds according to the invention are suitable for the therapy or prophylaxis of cancerous diseases.

Autotaxin (ATX) is an enzyme responsible for increasing lysophosphate levels in ascites and plasma (Xu et al., 1995, Clinical Cancer Research Vol. 1, page 1223, and Xu et al., 1995,

Biochem. J. VoI-309, page 933). ATX adds lysophatidylcholine (LPC) Lysophosphate acid (Tokumura et al., 2002, J. Biol. Chem., Vol. 277, p. 39436, and Umezu-Gozo et al., 2002, J. Biol. Chem., Vol. 158, page 227) LPA is an intercellular lipid mediator a variety of biological and biochemical processes such as smooth

Muscle contraction, platelet aggregation and apoptosis are affected

(Tigyi et al., 2003, Prague Lipid Res., Vol. 42, page 498, and Mills, et al., 2003, Nat. Rev. Cancer Vol. 3, page 582, and Lynch et al., 2001, Prost. Lipid Med., Vol.64, p 33). In addition, LPA is found in increased concentrations in plasma and ascites fluid of ovarian cancer patients of early and late stage, LPA plays a role in tumor cell proliferation and its invasion into adjacent tissues, which can lead to metastasis (Xu et al., 1995, Clinical Cancer Research Vol 1, page 1223 and Xu et al., 1995, Biochem., J. VoI-309, page 933). These biological and phatobiological processes are activated by activation by LPA of G protein-coupled receptors (Contos et al., 2000, Mol. Pharm., Vol. 58, p. 1188).

For this reason, it is desirable for the treatment of tumor patients to lower the LPA level. This can be achieved by the inhibition of enzymes involved in LPA biosynthesis, such as autotaxine (ATX, Sano et al., 2002, J. Biol. Chem. Vol. 277, page 21197, and Aoki et al., 2003, J Biol. Chem. Vol. 277, page 48737). Autotaxin belongs to the enzyme family of nucleotides pyrophosphatases and phosphodiesterases (Goding et al., 1998, Immunol., Rev. Vol. 161, page 11) and is an important starting point for antitumor therapy (Mills et al., 2003, Nat. Rev. Cancer Vol. 3, page 582 and Goto et al., 2004, J. Cell, Biochem., Vol. 92, page 1115) because it is expressed in tumors more intensely and causes tumor cell proliferation and invasion into adjacent tissues, which can lead to metastasis ( Nam et al., 2000, Oncogene, Vol. 19, page 241). In addition causes

Autotaxin together with other angiogenic factors

Blood vessel formation in the context of angiogenesis (Nam et al., 2001, Cancer Res. Vol. 61 page. 6938). Angiogenesis is an important process in tumor growth, which ensures the supply of nutrients to the tumor. For this reason, the inhibition of angiogenesis is an important starting point of cancer and tumor therapy, with which the tumor can be starved to some extent (Folkman, 2007, Nature Reviews Drug Discovery Vol. 6, page 273-286).

It has surprisingly been found that the compounds according to the invention have a specific inhibition of the enzyme family of

Nucleotide pyrophosphatases and phosphodiesterases, in particular autotaxine effect. The compounds of the invention preferably exhibit a beneficial biological activity that is readily detectable in the assay described, for example, herein. In such assays, the compounds of the invention preferably exhibit and effect an inhibiting effect, which is usually documented by IC ₅₀ sites in a suitable range, preferably in the micromolar range, and more preferably in the nanomolar range.

In general, all solid and non-solid tumors can be treated with the compounds of formula I, e.g. monocytic leukemia, brain, urogenital, lymphatic, gastric, laryngeal, ovarian and lung carcinomas, including lung adenocarcinoma and small cell lung carcinoma. Other examples include prostate, pancreatic and breast carcinoma.

As discussed herein, effects of the invention are

Compound relevant for various diseases. Accordingly, the compounds of the invention are useful in the prophylaxis and / or treatment of diseases which are affected by inhibition of one or more nucleotide pyrophosphatases and / or phosphodiesterases, particularly autotaxin. 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 a beneficial effect in a xenograft tumor model.

The host or patient may be of any mammalian species, e.g. B. one

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 sensitivity 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 combined 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 migration or to block the cellular secretion of angiogenesis promoting substances, usually between about an hour and a week. For testing in vitro, cultured cells from a biopsy sample can be used.

The viable cells remaining after treatment become. ... .. then paid. 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 the patient's 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 unwanted cells can be detected in the body.

STATE OF THE ART

Compounds capable of inhibiting auto-taxin are described in Peng et al. Bioorganic & Medicinal Chemistry Letters (17, 2007, pages 1634-1640). The compounds described there are lipid analogues, which structurally have no similarities with the invention

Have connections.

Other naphthyridine derivatives are described in EP 0 997 462.

SUMMARY OF THE INVENTION

The invention relates to compounds of the formula I.

wherein D Ar or Het ¹ ,

Het ^{1 is} a mono- or binuclear, saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms, which is unsubstituted or mono-, di- or trisubstituted by Hal, A, OA, Ar, OH and or = O may be substituted,

R ^{1 are} each independently H, Hal, OA, OH ₁ A, phenyl, Het ² or CN monosubstituted or polysubstituted,

Het ^{2 is} a mononuclear, saturated heterocycle with 1 - 3N- and / or

O atoms, which is unsubstituted or can be substituted once or twice by = O,

R ⁴ each independently of one another H ₁ Hal, OA, OH, A, monosubstituted or polysubstituted,

X, Y are each independently absent, -CH ₂ -, - (CH ₂ ) ₂ -, -CO- or

-CHOH-, where only one of the radicals X or Y may be absent,

R ² , R ^{3 are} each independently R; R ² and R ³ together also form an alkylene chain with 2-6 C atoms, in which also a CH ₂ -

Group is replaced by O, NH or NA ¹ ,

A ¹ alkyl having 1-6 C atoms, or CH ₂ CH ₂ OH, COO (CH ₂ ) _n Ar, (CH ₂ ) _n Ar, (CH ₂ ) _n Het ² , (CH ₂ ) _n NA ₂ or Cyc .

R ^{5 is} H, Hal, NH ₂ , OH ₁ OA or A ₁

RH ₁ A, Cyc, (CH ₂ ) _n Ar or (CH ₂ ) _n Het monosubstituted or polysubstituted, ZO, NH, -CH (CONHA) NH-, CH ₂ NHCONH, -CH = CH- or absent,

Cyc cyclic alkyl with 3-7 C atoms,

A linear or branched alkyl having 1-10 C atoms, in which 1-7 H-

Atoms can be replaced by OR, CN, NR ₂ , F and / or Cl and / or in which one or two non-adjacent CH ₂ groups are represented by O, NH, S, SO, SO ₂ and / or by CH = CH- Groups can be replaced, or cyclic alkyl having 3-7 C atoms,

Ar is unsubstituted or mono-, di-, tri-, tetra- or quintuple

Hal, A, (CR ₂ ) _n OR, O (CR ₂ ) HAr ² , (CR ₂ ) _n NR ₂ , SR, NO ₂ , CN, COOR, CONR ₂ , NRCOA, NRSO ₂ A, SO ₂ NR ₂ , S (O) _m A, CO-Het,

(CR _{2) n} Het, O (CR _{2) n} NR _2, O (CR _{2) n} Het, NHCOOA ₁ NHCONR _2, NHCOO (CR _{2) π} NR _2, NHCOO (CR _{2) n} Het, CR = CRAR ² , SO ₂ Het, NHCONH (CR ₂ ) _n NR ₂ , NHCONH (CR ₂ ) _n Het, OCONH (CR ₂ ) _n NR ₂ ,

CONH (CR ₂ ) _n Het, CONR (CR ₂ ) _n NR ₂ , CONR (CR ₂ ) _n Het and / or

COA substituted phenyl, indanyl, naphthyl or biphenyl,

Het a mono-, di- or trinuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms, the unsubstituted or mono-, di- or trihydric

Hal, A, Ar ² , O (CR ₂ ) _H Ar ² , (CR ₂ ) _n OR, (CR ₂ ) _n NR ₂ , SR, NO ₂ , CN, COOR, CONR ₂ , NRCOA, NRSO ₂ A, SO ₂ NR ₂ , S (O) _q A, CO-Het ² , (CR ₂ ) _n Het ² , O (CR ₂ ) _n NR ₂ , O (CR ₂ ) _π Het ² , NHCOOA ₁ NHCONR ₂ , NHCOO (CR ₂ ) _n NR ₂ , NHCOO (CR ₂ ) _n Het ² , NHCONH (CR ₂ ) _n NR ₂ ,

NHCONH (CR ₂ ) _n Het ² , OCONH (CR ₂ ) _n NR ₂ , OCONH (CR ₂ ) _n Het ² , CO-Het ² , CHO, COA, = S, = NH, = NA and / or = O ( Carbonyl oxygen),

HaI F, Cl, Br or I, n 0, 1 or 2, m 0, 1, 2, 3, 4, or,

P 1, 2, 3, or 4, as well as their pharmaceutically usable salts and stereoisomers, including mixtures thereof in all ratios.

Compounds of the formula I also mean pharmaceutically usable derivatives thereof, optically active forms (stereoisomers), tautomers, polymorphs, enantiomers, racemates, diastereomers and the hydrates and solvates of these compounds. Solvates of the compounds are understood as meaning additions of inert solvent molecules to the compounds, which are due to their mutual attraction

, _; , form. Solvates are, for example, 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.

20

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.

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

O ₀ The term "effective amount" means the amount of a drug or pharmaceutical agent which elicits a biological or medical response in a tissue, system, animal or human, for example, sought or sought by a researcher or physician. 35 In addition, the term "therapeutically effective amount" means an amount that, as compared to a corresponding subject that does not receive that amount, results in: improved healing, healing, prevention or elimination of one

Illness, a disease picture, a disease state, one

Suffering, a disorder or side effects or even the reduction of the progression of a disease, a disease or a disorder. The term "therapeutically effective amount" also includes the amounts effective to increase normal physiological function.

The invention also provides for the use of mixtures of the compounds of the formula I _1, for example mixtures of two diastereomers, for example in a ratio of 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 10, 1: 100 or 1: 1000. Particularly preferred are mixtures of stereoisomeric

Links.

The invention relates to the compounds of formula I and their salts and to a process for the preparation of compounds of formula I according to the claims and their pharmaceutically acceptable salts, and stereoisomers, characterized in that for the preparation of compounds of formula I, is a compound the formula Il

wherein R ² , R ³ , R ⁴ , R ⁵ and p have the meanings given in claim 1,

with a compound of formula IM or IV

wherein

R ¹ , m, D, Z, X and Y have the meanings given in claim 1 and L is a halogen, tosylate, mesylate or triflate,

implements,

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

A is alkyl and is preferably unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C-atoms. Alkyl 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-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2 or 1,2,2-trimethylpropyl, more preferably, for example Trifluoromethyl.

Alkyl 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. Alkyl also means cycloalkyl.

Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl,

Cyclohexyl or cycloheptyl.

Alk preferably denotes unbranched or branched alkylene with 1,

2, 3 or 4 C atoms, more preferably methylene, ethylene, propylene or butylene.

Ar is preferably 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-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p- (N-methylamino) -phenyl, o-, m- or p- (N-methylaminocarbonyl) -phenyl, o-, m- or p-acetamidophenyl, o-, m- or p- Methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, m- or p- (N, N-dimethylamino) -phenyl, o-, m- or p- (N , N-dimethylaminocarbonyl) -phenyl, o-, m- or p- (N-ethylamino) -phenyl, o-, m- or p- (N, N-)

Diethylamino) -phenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p- (methylsulfonamido) -phenyl, o -, m- or p- (methylsulfonyl) -phenyl, 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, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro, 2 -Amino-3-chloro, 2-amino-4-chloro, 2-amino-5-chloro or 2-amino-6-chlorophenyl, 2-nitro-4-N, N-dimethylamino or 3-nitro 4-N, N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl , 2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2 , 5-Difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro

6-methoxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3 Amino-6-methylphenyl, 3-chloro-4-acetamidophenyl, 2,5-dimethyl-4-chlorophenyl, naphthyl or biphenyl.

Ar is preferably 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-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p- (N-methylamino) -phenyl, o-, m- or p- (N-methylaminocarbonyl) -phenyl, o-, m- or p-acetamidophenyl, o-, m- or p- Methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, rn- or p- (N, N-dimethylamino) -phenyl, o-, m- or p- (N , N-dimethylaminocarbonyl) -phenyl, o-, m- or p- (N-ethylamino) -phenyl, o-, m- or p- (N, N-diethylamino) -phenyl, o-, m- or p- Fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p- (methylsulfonamido) -phenyl, o-, m- or p- (methylsulfonyl) -phenyl, 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-dibromophene nyl, 2,4- or 2,5-

Dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3

Amino-4-chloro, 2-amino-3-chloro, 2-amino-4-chloro, 2-amino-5-chloro or 2-amino-6-chlorophenyl, 2-nitro-4-N, N-dimethylamino or 3-nitro-4-N, N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2 Fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3 - Amino-6-methylphenyl, 3-chloro-4-acetamidophenyl, 2,5-dimethyl-4-chlorophenyl, naphthyl or biphenyl.

Ar furthermore preferably denotes unsubstituted or mono-, di-, tri-, tetra- or quintuple phenyl which is substituted by Hal, A and / or (CF 2) _n OR,

Naphthyl or biphenyl substituted phenyl, indanyl, naphthyl or

Biphenyl. Ar ² is preferably phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, , m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, 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-

10 or 3,5-dibromophenyl, 2,5- or 3,4-dimethoxyphenyl, 2,3,4-, 2,3,5-,

2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl !, 2,4,6-triethoxyphenyl !, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 4-fluoro 3-chlorophenyl, 2-fluoro-4- bromophenyl, 2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-x _c 6-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 2, 5-dimethyl-4-chlorophenyl.

Het ¹ means, notwithstanding further substitutions, for example 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3- , A- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or

20

5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-

Pyrimidinyl, furthermore preferably 1, 2,3-triazoM-, -A- or -5-yl, 1, 2,4-triazol-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-thiadiazol-2 or -5-yl, 1, 2,4-thiadiazol-3-

25 or -5-yl, 1, 2,3-thiadiazol-4 or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, A-, 5-, 6- or 7-indolyl, A- or 5-isoindolyl, indazolyl, 1-, 2-, A- or 5-benzimidazolyl, 1-, 3-, A-, 5-, 6- or 7-benzopyrazolyl, 2-, A- , 5-, 6- or 7-Benzoxazolyl, 3-, A-, 5-, 6- or 7- Benzisoxazolyl, 2-, A-, 5-, 6- or

₃₀ 7-benzothiazolyl, 2-, A-, 5-, 6- or 7-benzisothiazolyl, A-, 5-, 6- or 7-

Benz-2,1,3-oxadiazolyl, 2-, 3-, A-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, A-, 5-, 6-, 7- or 8-isoquinolyl, 3-, A-, 5-, 6-, 7- or 8-cinnolinyl, 2-, A-, 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, A-

35

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

5-yl or dibenzofuranyl. The heterocyclic radicals may also be partially or completely hydrogenated.

Regardless of other substitutions Het can thus z. B. also mean 2,3-

Dihydro-2-, -3-, -A- 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-, -A- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -A- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1, -2- or -4-imidazolyl, 2,3-dihydro-1-, 2-, -3-, -A- or -5-pyrazolyl, tetrahydro-1-, -3- or -A-pyrazolyL 1, 4-dihydro -i-, -2-, -3- or -4-pyridyl, 1, 2,3,4-tetra-hydro-1-, -2-, -3-, -A-, -5- or -6 pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or A-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1, 3 Dioxane-2-, -A- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -A- or -5-pyrimidinyl, 1-, 2 or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, 2-, -3-, -A-, -5-, -6-, -7- or -8-quinolyl, 1, 2,3,4-tetrahydro-1 -, - 2 -, - 3, -A-, -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-

Methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4-

(Difluoromethylenedioxy) phenyl, 2,3-dihydrobenzofuran-5- or 6-yl, 2,3- (2-oxo-methylenedioxy) -phenyl or 3,4-dihydro-2H-1,5-benzodioxepin 6- or -7-yl, further preferably 2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxofuranyl, 3,4-dihydro-2-oxo-1H-quinazolinyl, 2,3-dihydro-benzoxazolyl, 2-oxo -2, 3-dihydro-benzoxazolyl, 2,3-dihydro-benzimidazolyl, 1,3-dihydroindole, 2-oxo-1,3-dihydro-indole or 2-oxo-2,3-dihydrobenzimidazolyl.

Het ¹ further preferably means a mononuclear aromatic

Heterocycle having 1 to 4 N, O and / or S atoms.

Het ¹ particularly preferably denotes unsubstituted or mono-, di- or trisubstituted by A and / or (CH ₂ ) _n Ar-substituted piperazyl, morpholinyl,

Piperidinyl, pyrrolidinyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, Oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl, benzotriazyl, benzofuranyl, 2,3-dihydro-benzoxazolyl, benzoxazolyl, dihydrobenzofuranyl or tetrazolyl.

Het ¹ further means a saturated or aromatic heterocycle which may be substituted with piperazine, morpholine, piperidine and pyrrolidine.

Het, irrespective of further substitutions, for example 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, A- or 5-imidazolyl, 1-, 3-, A- or 5-pyrazolyl _; 2-, A- or 5-oxazo! Y !, 3-, 4- or 5-! Soxazo! Y !, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1, 2,3-triazoM-, -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-thiadiazol-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, indazolyl, 1-, 2-, 4- or 5-benzimidazolyl , 1-, 3-, A-, 5-, 6- or 7-benzopyrazolyl, 2-, A-, 5-, 6- or 7-benzoxazolyl, 3-, A-, 5-, 6- or 7- Benzisoxazolyl, 2-, A-, 5-, 6- or

7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, A-, 5-, 6- or 7- benz-2,1,3-oxadiazolyl, 2-, 3-, A-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 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, 2,1, 3 Benzoxadiazol-5-yl or dibenzofuranyl. The heterocyclic radicals may also be partially or completely hydrogenated.

Regardless of other substitutions Het can thus z. B. also represent 2,3-dihydro-2-, -3-, -A- or -5-furyl, 2,5-dihydro-2-, -3-, -A- or 5-furyl,

Tetrahydro-2- or 3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2-or 3-thienyl,

2,3-dihydro-1-, -2-, -3-, -A- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -A- or

5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or 4-imidazolyl, 2,3-dihydro-1-, 2-, -3-, -A- or -5-pyrazolyl, tetrahydro-1-, -3- or -pyrazolyl, 1,4-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 A-

Morpholinyl, tetrahydro-2-, 3- or 4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2,

-4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -A- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl , 1,2,3,4-Tetrahydro-i, -2-, -3-, -A-, -5-, -6-, -7- or -8-quinolyl, 1, 2,3,4 Tetrahydro-1 -, - 2 -, - 3, -A-, -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-

Methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4- (difluoromethylenedioxy) phenyl, 2,3-dihydrobenzofuran-5- or 6-yl, 2,3- (2-oxo -methylenedioxy) -phenyl or else 3,4-dihydro-2H-1,5-benzodioxepin-6 or -7-yl, furthermore preferably 2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxofuranyl, 3 , 4-dihydro-2-oxo-1 / - / - quinazolinyl, 2,3-dihydrobenzoxazolyl, 2-oxo-2,3-dihydro-benzoxazolyl, 2,3-dihydro-benzimidazolyl, 1,3-dihydroindole, 2-oxo-1,3-dihydro-indole or 2-oxo-2,3-dihydrobenzimidazolyl.

Het furthermore preferably denotes a monocyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms which is unsubstituted or mono-, di- or trisubstituted by A, Ar ² , (CR ₂ ) _n Het ² and / or (CR ₂ ) _n OR may be substituted.

Het very particularly preferably denotes piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl which is unsubstituted or mono- or disubstituted by A, Ar ² , (CR ₂ ) _n Het ² and / or (CR ₂ ) _n OR, Pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl or pyrazinyl. Hal preferably denotes F, Cl or Br, but also I ₁ particularly preferably Br or Cl.

The indices have the following preferred meanings m 1, or 2, n 0, 1, 2, 3, 4, or 5 or, p 1, 2, 3 or 4.

For the entire invention, it is true that all residues that occur several times, such as R _; may be the same or different, ie 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 is particularly those

Compounds of formula I ₁ in which at least one of said

Rests has one of the preferred meanings given above.

Some preferred groups of compounds can be expressed by the following partial formulas Ia to Ie, which correspond to the formula I and in which the unspecified radicals have the meaning given in the formula I, but in which

in Ia R ^{1 is} H, Hal, CN, phenyl, OA or OH;

in Ib R ^{4 is} H, Hal, A or OH;

in Ic R ⁵ H;

in Id R ² , R ³ together are morpholinyl, piperazinyl, 1-methyl-piperazinyl, 1-ethyl-4-methyl-piperazinyl, 2- (4-methylpiperazin-1-yl) -ethyl, 1 Methyl 4-propyl-piperazinyl, 1-cyclopentyl-4-methyl-piperazinyl, 1-benzyl-4-methyl- [1,4] diazepanyl or 1-benzyl-4-methyl-piperazinyl;

1 in Ie Het more preferably means unsubstituted or mono-, di- or trisubstituted by A and / or (CHh) _n Ar piperazyl, morpholinyl, piperidinyl, pyrrolidinyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl , Isothiazolyl, pyridyl, pyrimidinyl, triazolyl,

Benzotriazinyl benzofuranyl, 2,3-dihydro-benzoxazolyl, benzoxazolyl, dihydrobenzofuranyl or tetrazolyl.

In If Het ² particularly preferably denotes unsubstituted or mono- or di-substituted by Hal, OH, OA ₁ A and / or = O substituted pyrrolidinyl, morpholinyl, piperidinyl or piperazinyl.

in Ig R1 is H, Hal, CN, phenyl, OA or OH;

R 4 is H, Hal, A or OH;

R ⁵ H and

R ² , R ³ together are morpholinyl, piperazinyl, 1-methyl-piperazinyl, 1-ethyl-4-methyl-piperazinyl, 2- (4-methylpiperazin-1-yl) -ethyl, 1-methyl-4-propyl piperazinyl, 1-cyclopentyl-4-methylpiperazinyl, 1-benzyl-4-methyl- [1,4] diazepanyl or 1-benzyl-4-methyl-piperazinyl,

Het ¹ particularly preferably denotes unsubstituted or monosubstituted, disubstituted or trisubstituted by A and / or (CH ₂ ) _n Ar

Piperazyl, morpholinyl, perperinyl, pyrrolidinyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl,

Benzotriazylyl, benzofuranyl, 2,3-dihydrobenzoxazolyl,

Benzoxazolyl, dihydrobenzofuranyl or tetrazolyl, Het ² particularly preferably represents pyrrolidinyl, morpholinyl, piperidinyl or piperazinyl which is unsubstituted or mono- or di-substituted by Hal, OH, OA ₁ A and / or OO,

and their pharmaceutically acceptable salts and stereoisomers, including mixtures thereof in all proportions.

Incidentally, the compounds of the formula I and also the starting materials for their preparation are prepared by methods known per se, as described in the literature (eg in the standard works such as Houben-Wey !, Methoden der organischen Chemie, Georg-Thieme-Verlag , Stuttgart), under reaction conditions which are known and suitable for the aforementioned reactions. One can also make use of known per se, not mentioned here variants.

The starting materials can, if desired, also be formed in situ, so that they are not isolated from the reaction mixture, but immediately further reacted to the compounds of formula I.

Compounds of the formula I can preferably be obtained by reacting a compound of the formula II with a compound of the formula III.

Depending on the conditions used, the reaction time is between a few minutes and 14 days, the reaction temperature between about -30 ° and 140 °, normally between -10 ° and 90 °, in particular between about 0 ° and about 70 °. 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), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); Nitriles like

acetonitrile; Sulfoxides such as dimethylsulfoxide (DMSO); Carbon disulphide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of said solvents.

Particularly preferred is pyridine, acetonitrile, dichloromethane and / or DMF.

The starting compounds of formulas II, IM and IV are known in the rule. If they are new, they can be produced by methods known per se. The starting materials are generally also commercially available.

The abovementioned compounds according to the invention can be used in their final non-salt form. On the other hand, the present invention

The invention also relates to 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 methods 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

Reacts 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-methyl-glutamine. The aluminum salts of the compounds of the formula I. count as well. In certain compounds of the formula I, acid addition salts can be formed by reacting these compounds with pharmaceutically acceptable organic and inorganic acids, for example 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 monoarylsulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate, as well as 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 , Cyclopentaneproprionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulphate, ethanesulphonate, 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, methylbenzoate, monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, Persulfate, phenyl acetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but this is not limiting.

Furthermore, the base salts of the invention include

Compounds aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), potassium, sodium and zinc salts, but this should not be a limitation.

Preferred among the above salts are ammonium; the

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

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

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-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine. Piperazine _; Piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine and tris (hydroxymethyl) methylamine (tromethamine), but this is not intended to be limiting.

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

Di (C _r C ₄ ) alkyl sulfates, for example dimethyl, diethyl and diamylsulfate; (C ₁₀ -

C ₁₈₎ alkyl halides, for example 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.

The above-mentioned pharmaceutical salts which are preferred 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 regenerated by contacting the salt form with a base and isolating the free base in a conventional manner. 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 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. Preferred organic amines are N, N'-dibenzylethylenediamine, chloroprocaine,

Choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base addition salts of acidic compounds of this 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, then the

Invention also multiple salts. To 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, one sees that under the expression

"pharmaceutically acceptable salt" as used herein means an active ingredient containing a compound of formula I in the form of one of its salts, particularly when that salt form is the active ingredient compared to the free form of the active ingredient or any other salt form of the active ingredient that has been used earlier confers improved pharmacokinetic properties. The pharmaceutically acceptable salt form of the active substance may also first impart a desired pharmacokinetic property to this active ingredient which it has not previously possessed, and may even positively influence the pharmacodynamics of this active ingredient in terms of its therapeutic activity in the body.

The invention furthermore relates to medicaments comprising at least one compound of the formula I and / or pharmaceutically usable salts 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 can be used in

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, such as above, or a corresponding fraction thereof, 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 bringing the active ingredient together with the carrier (s) or excipient (s).

Pharmaceutical formulations adapted for oral administration may be administered as separate entities, 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 combined with an oral, non-toxic and pharmaceutically acceptable inert carrier, such as, for example, ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate such as starch or mannitol. A flavor, preservative, dispersant and dye may also be present. Capsules are made by preparing a powder mix as described above and filling shaped gelatin casings therewith.

Lubricants such as e.g. fumed silica, talc,

Magnesium stearate, calcium stearate or polyethylene glycol in solid form can be added to the powder mixture before the filling process. A disintegrants or solubilizers, e.g. 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, e.g. Glucose or beta-lactose, corn sweeteners, natural and synthetic gums, e.g. Acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, and the like. The lubricants used in these dosage forms include 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, preparing a powder mix, granulating or dry pressing, adding a lubricant and a disintegrant, and compressing the whole into tablets. A powder mixture is prepared by treating the appropriately comminuted compound with a diluent or a base as described above, and optionally with a

Binders such as carboxymethyl cellulose, an alginate, gelatin or polyvinylpyrrolidone, a Lösungsverlangsamer such as paraffin, a absorption accelerator such as a quaternary salt and / or an absorbent, such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by adding it with a binder such as syrup, starch paste, Acadia slime or Solutions of cellulose or polymer materials wetted and pressed through a sieve. As an alternative to granulation, the powder mixture can be run through a tableting machine to form non-uniformly shaped lumps which are broken up into granules 5. The granules can be added by adding

Stearic acid, a stearate salt, talc or mineral oil are greased to prevent sticking to the tablet molds. The greased mixture is then compressed into tablets. The invention

Compounds may also be combined with a free-flowing inert carrier and then compressed directly into tablets without performing the granulation or dry-pressing steps. A transparent or opaque protective layer, consisting of a

, _c Shellac sealant, 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.

20

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 adding the compound in an aqueous solution

25, while elixirs are prepared using a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers,

_OQ such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavoring additives such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, among others, may also be added.

35

The unit dosage formulations for oral administration may optionally be encapsulated in microcapsules. The formulation can also be prepared so that the release is prolonged or retarded, such as by coating or embedding particulate material in polymers, wax, etc.

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 formula I as well as the salts, solvates and physiologically functional derivatives thereof can also be delivered using monoclonal antibodies 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, polydihydroxypyrans, polycyanoacrylates, and crosslinked 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 used as ointments, creams, suspensions, lotions, powders, solutions,

Be formulated pastes, gels, sprays, aerosols or oils.

For treatments of the eye or other external tissues, e.g. 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.

Among the pharmaceutical formulations adapted for topical application to the eye are 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, lozenges 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.

Pharmaceutical formulations adapted for administration by inhalation include fine particulate dusts or mists which may be generated by various types of pressurized dosing dispensers with aerosols, nebulisers or insufflators.

Pharmaceutical adapted to vaginal administration

Formulations can be used as pessaries, tampons, creams, gels ₁ pastes. Foams or spray formulations are presented.

Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions containing the antioxidants, buffers, bacteriostats and solutes, which render the formulation isotonic with the blood of the subject

Recipient is included; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickeners. The formulations may be administered in single or multiple dose containers, e.g. sealed ampoules and vials, and stored in the freeze-dried (lyophilized) state, such that only the addition of the sterile carrier liquid, e.g. Water for

Injections, needed immediately before use. Injection solutions and suspensions prepared by formulation can be prepared from sterile powders, granules and tablets.

It is understood that the formulations, in addition to the above particularly mentioned ingredients, may contain other conventional agents 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, will generally range from 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 Day can be given so that the total daily dose is the same. An effective amount of a salt or solvate or a physiologically functional

Derivatives thereof can be determined as a proportion of the effective amount of the compound according to 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

Packs 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 kit contains suitable containers, such as boxes or boxes, 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 all proportions, and an effective amount of another drug substance is dissolved or in lyophilized form.

Preferably, but not exclusively, the medicaments of Table 1 are combined with the compounds of the formula I. A combination of Formula I and Drugs of Table I can also be combined with compounds of Formula VI.

Table 1.

Alkylating agent Cyclophosphamide Lomustine

Busulfan procarbazine

Ifosfamide altretamine

Melphalan Estram ustin phosphate

Hexamethylmelamine mechlorethamine

Thiotepa streptozocin

Chlorambucil Temozolomide

Dacarbazine Semustin

carmustine

Platinum agent cisplatin carboplatin

Oxaliplatin ZD-0473 (AnorMED)

Spiroplatin Lobaplatin (Aetema)

Carboxyphthalatoplatinum Satraplatin (Johnson

Tetraplatinum Matthey)

Ormiplatin BBR-3464 (Hoffrnann-La

Iproplatin Roche)

SM-11355 (Sumitomo)

AP-5280 (Access)

Antimetabolite azacytidine Tomudex

Gemcitabine trimetrexate

Capecitabine deoxycoformycin 5-fluorouracil fludarabine

Floxuridine pentostatin

2-chlorodeoxyadenosine Raltitrexed

6-mercaptopurine hydroxyurea

6-thioguanine decitabine (SuperGen)

Cytarabine Clofarabine (Bioenvision)

2-Fluorodeoxycytidine Irofulvene (MGI Pharma)

Methotrexate DMDC (Hoffmann-La

Idatrexate Roche)

Ethinylcytidine (Taiho)

Topoisomerase Amsacrine Rubitecane (SuperGen)

Inhibitors Epirubicin Exatecan Mesylate (Daiichi)

Etoposide Quinamed (ChemGenex)

Teniposide or Gimatecan (Sigma-Tau)

Mitoxantrone diflomotecan (Beaufourrinotecan (CPT-11) Ipsen)

7-Ethyl-10-TAS-103 (Taiho) hydroxycamptothecin Elsamitrucine (Spectrum)

Topotecan J-107088 (Merck & Co)

Dexrazoxanet BNP-1350 (BioNumerik)

(TopoTarget) CKD-602 (Chong Kun

Pixantron (Novuspharma) Dang)

Rebeccamycin analog KW-2170 (Kyowa Hakko)

(Exelixis)

BBR-3576 (Novuspharma)

Antitumor Dactinomycin (Actinomycin Amonafide

Antibiotics D) Azonafide

Doxorubicin (adriamycin) anthrapyrazole

Deoxyrubicin Oxantrazole

Valrubicin losoxantrone

Daunorubicin bleomycin sulfate

(Daunomycin) (Blenoxan)

Epirubicin bleomycinic acid

Therarubicin Bleomycin A

Idarubicin bleomycin B

Rubidazone mitomycin C

Plicamycin p MEN-10755 (Menarini)

Porfiromycin GPX-100 (gem

Cyanomorpholinodoxorubi Pharmaceuticals)

Mitoxantrone (Novantrone)

Antimitotic Paclitaxel SB 408075

Agent Docetaxel (GlaxoSmithKline)

Colchicine E7010 (Abbott) Vinblastine PG-TXL (Cell

Vincristin Therapeutics)

Vinorelbine IDN 5109 (Bayer)

Vindesin A 105972 (Abbott)

Dolastatin 10 (NCI) A 204197 (Abbott)

Rhizoxin (Fujisawa) LU 223651 (BASF)

Mivobulin (Warner-D 24851 (ASTA Medica)

Lambert) ER-86526 (Eisai)

Cemadotin (BASF) Combretastatin A4 (BMS)

RPR 109881A (Aventis) isohomohalichondrin-B

TXD 258 (Aventis) (PharmaMar)

Epothilone B (Novartis) ZD 6126 (AstraZeneca)

T 900607 (Tularik) PEG paclitaxel (Enzon)

T 138067 (Tularik) AZ10992 (Asahi)

Cryptophycin 52 (EN Lilly)! DN-5109 (lndena)

Vinflunin (Fabre) AVLB (Prescient

Auristatin PE (Teikoku NeuroPharma)

Hormones) azaepothilone B (BMS)

BMS 247550 (BMS) BNP-7787 (BioNumerik)

BMS 184476 (BMS) CA-4 prodrug (OXiGENE)

BMS 188797 (BMS) Dolastatin-10 (NrH)

Taxoprexin (Protarga) CA-4 (OXiGENE)

Aromatase-aminoglutethimide exemestane

Inhibitors Letrozole Atamestane (BioMedicines)

Anastrazole YM-511 (Yamanouchi)

formestane

Thymidylate Syntha Pemetrexed (EIi Lilly) Nolatrexed (Eximias) se Inhibitors ZD-9331 (BTG) CoFactor ™ (BioKeys)

DNA Trabectedin (PharmaMar) Mafosfamide (Baxter

Antagonists glufosfamide (Baxter International)

International) Apaziquon (Spectrum

Albumin + 32P (Isotope Pharmaceuticals)

Solutions) O6-Benzylguanine

Thymectacin (NewBiotics) (Paligent)

Edotreotide (Novartis)

Famesyltransfera Arglabin (NuOncology Tipifarnib (Johnson & se Inhibitors Labs) Johnson) lonafamib (Schering-Perillyl Alcohol (DOR

Plow) BioPharma)

BAY-43-9006 (Bayer)

Pump CBT-1 (CBA Pharma) Zosuquidar trihydrochloride

Inhibitors Tariquidar (Xenova) (EIi Lilly) MS-209 (Schering AG) Biricodar dicitrate (vertex)

Histone acetyl trans Tacedinalin (Pfizer) pivaloyloxymethyl butyrate erase SAHA (Aton Pharma) (titanium)

Inhibitors MS-275 (Schering AG) Depsipeptide (Fujisawa)

Metalloproteinase neovastate (Aeterna CMT -3 (CollaGenex)

Inhibitors Laboratories) BMS-275291 (Celltech)

Ribonucleosidred Marimastat (British Tezacitabine (Aventis) uktase-Biotech) Didox (Molecules for

Inhibitors gallium maltolate (titanium) Health)

Triapin (Vion)

TNF-alpha-virulizine (Lorus Revimid (Celgene)

Agonists / Antago Therapeutics) nest CDC-394 (Celgene)

Endothelin A Atrasentan (Abbot) YM-598 (Yamanouchi)

Receptor ZD-4054 (AstraZeneca)

antagonists

Retinoic Acid Fenretinide (Johnson & Alitretinoin (Ligand) R-agonist Johnson)

LGD-1550 (ligand)

Immunomodulators Interferon Dexosome Therapy n Oncophage (Antigenics) (Anosys)

GMK (Progenics) Pentrix (Australian Cancer

Adenocarcinoma Vaccine Technology)

(Biomira) JSF-154 (Carrying)

CTP-37 (AVI BioPharma) cancer vaccine (Intercell)

JRX-2 (Immuno-Rx) Norelin (Biostar)

PEP-005 (Peplin Biotech) BLP-25 (Biomira)

Synchrovax vaccines MGV (Progenics)

(CTL Immuno)! 3-Alethine (Dovetail)

Melanoma vaccine (CTL CLL-Thera (Vasogen)

Immuno) p21 RAS vaccine

(GemVax)

Hormonal and estrogenic prednisone antihormonal conjugated estrogens methylprednisolone

Agent ethinyl estradiol prednisolone

Chlorotrienes Aminoglutethimide

Idenestrol Leuprolide

Hydroxyprogesterone caproa Goserelin t Leuporelin Medroxyprogesterone Bicalutamide

Testosterone Flutamide

Testosterone Propionate Octreotide

Fluoxymesterone nilutamide

Methyltestosterone mitotane

Diethylstilbestrol P-04 (Novogen)

Megestrol 2-Methoxyestradiol

Tamoxifen (EntreMed)

Toremofin Arzoxifen (EIi Lilly)

dexamethasone

Photodynamic Talaporfin (Light Sciences) Pd-Bacteriopheophorbide

Central Theralux (Yeda)

(Theratechnologies) Lutetium Texaphyrin

Motexafin gadoiinium (Pharmacyclics)

(Pharmacyclics) Hypericin

Tyrosine kinase imatinib (Novartis) Kahalid F (PharmaMar)

Inhibitors Leflunomide CEP-701 (Cephalon)

(Sugen / Pharmacia) CEP-751 (Cephalon)

ZDI839 (AstraZeneca) MLN518 (Millenium)

Erlotinib (Oncogene PKC412 (Novartis)

Science) phenoxodiol O

Canertjnib (Pfizer) Trastuzumab (Genentech)

Squalamine (Genaera) C225 (ImCIone)

SU5416 (Pharmacia) rhu-Mab (Genentech)

SU6668 (Pharmacia) MDX-H210 (Medarex)

ZD4190 (AstraZeneca) 2C4 (Genentech)

ZD6474 (AstraZeneca) MDX-447 (Medarex)

Vatalanib (Novartis) ABX-EGF (Abgenix)

PK1166 (Novartis) IMC-1 C11 (ImCIone)

GW2016

(GlaxoSmithKline)

EKB-509 (Wyeth)

EKB-569 (Wyeth)

Various SR-27897 (CCK-A-BCX-1777 (PNP inhibitor,

Medium Inhibitor, Sanofi-BioCryst)

Synthelabo) Ranpirnase

Tocladesin (cyclic (ribonuclease stimulant,

AMP agonist, Ribapharm) Alfacell)

Alvocidib (CDK inhibitor, galarubicin (RNA

Aventis) Synthesis Inhibitor, Dong-

CV-247 (COX-2 inhibitor, A)

Ivy Medical) Tirapazamine

P54 (COX-2 inhibitor, (reducing agent, SRI

Phytopharm) International)

CapCell ™ (CYP450-N-acetylcysteine Stimulant, Bavarian (reducing agent,

Nordic) Zambon)

GCS-IOO (gal3-R-flurbiprofen (NF-

Antagonist, kappaB inhibitor, Encore)

GlycoGenesys) 3CPA (NF-kappaB-

G17DT immunogenic inhibitor, Active Biotech)

(Gastrin inhibitor, Aphton) seocalcitol (vitamin D

Efaproxiral (oxygenator, receptor agonist, Leo)

Allos Therapeutics) 131-I-TM-601 (DNA

PI-88 (heparanase antagonist,

Inhibitor, progene) TransMolecular)

Tesmilifen (histamine eflornithine (ODC inhibitor,

10 antagonist, YM ILEX Oncology)

BioSciences) Minodronic acid

Histamine (histamine H2 (osteoclast inhibitor,

Receptor agonist, Maxim) Yamanouchi)

Tiazofurin (IMPDH-indisulam (p53 stimulant,

Inhibitor, Ribapharm) Eisai)

Cilengitide (Integrin Aplidine (PPT inhibitor,

15

Antagonist, Merck KGaA) PharmaMar)

SR-31747 (IL-1 rituximab (CD20-

Antagonist, Sanofi antibody, Genentech)

Synthelabo) gemtuzumab (CD33-

CCI-779 (mTOR kinase antibody, Wyeth Ayerst)

Inhibitor, Wyeth) PG2 (hematopoietic

20 Exisulind (PDE V inhibitor, enhancer,

Cell Pathways) Pharmagenesis)

CP-461 (PDE-V inhibitor, Immunol ™ (triclosan)

Cell Pathways) Oral Irrigation, Endo)

AG-2037 (GART inhibitor, triacetyluridine (uridine)

Pfizer) prodrug, Wellstat)

WX-UK1 SN-4071 (sarcoma agent,

25

(Plasminogen activator Signature BioScience)

Inhibitor, Wilex) TransMID-107 ™

PBI-1402 (PMN stimulant, (immunotoxin, KS

ProMetic LifeSciences) Biomedix)

Bortezomib (proteasome PCK-3145 (apoptosis)

Inhibitor, Millennium) promoter, Procyon)

30 SRL-172 (T-cell doranidazole (apoptosis

Stimulant, SR Pharma) promoter, PoIa)

TLK-286 (glutathione-S-CHS-828 (cytotoxic

Transferase inhibitor, agent, Leo)

Telik) trans-retinoic acid

PT-100 (growth factor (differentiator, NIH)

Agonist, Point MX6 (apoptosis promoter,

35 Therapeutics) MAXIA)

Midostaurin (PKC inhibitor, apomin (apoptosis Novartis) Sponsors, ILEX Oncology)

Bryostatin-1 (PKC-urocidin (apoptosis)

Stimulant, GPC Biotech) promoter, Bioniche)

CDA-II (apoptosis-Ro-31-7453 (apoptosis

Conveyor, Everlife) conveyor, La Roche)

SDX-101 (apoptosis-brostallicin (apoptosis)

Promoter, Salmedix) promoter, Pharmacia)

Ceflatonin (apoptosis

Conveyor, ChemGenex)

Alkylating agent Cyclophosphamide Lomustine

Busulfan procarbazine

Ifosfamide altretamine

Melphalan estramustin phosphate

Hexamethyimeiamin Mechiorethamine

Thiotepa streptozocin

Chlorambucil Temozolomide

Dacarbazine Semustin

carmustine

Platinum agent cisplatin carboplatin

Oxaliplatin ZD-0473 (AnorMED)

Spiroplatin Lobaplatin (Aetema)

Carboxyphthalatoplatinum Satraplatin (Johnson

Tetraplatinum Matthey)

Ormiplatin BBR-3464 (Hoffrnann-La

Iproplatin Roche)

SM-11355 (Sumitomo)

AP-5280 (Access)

Antimetabolite azacytidine Tomudex

Gemcitabine trimetrexate

Capecitabine deoxycoformycin

5-fluorouracil fludarabine

Floxuridine pentostatin

2-chlorodeoxyadenosine Raltitrexed

6-mercaptopurine hydroxyurea

6-thioguanine decitabine (SuperGen)

Cytarabine Clofarabine (Bioenvision)

2-Fluorodeoxycytidine Irofulvene (MGI Pharma)

Methotrexate DMDC (Hoffmann-La

Idatrexate Roche)

Ethinylcytidine (Taiho) Topoisomerase Amsacrine Rubitecane (SuperGen)

Inhibitors Epirubicin Exatecan Mesylate (Daiichi)

Etoposide Quinamed (ChemGenex)

Teniposide or Gimatecan (Sigma-Tau)

Mitoxantrone diflomotecan (Beaufour

Irinotecan (CPT-11) Ipsen)

7-Ethyl-10-TAS-103 (Taiho) hydroxycamptothecin Elsamitrucine (Spectrum)

Topotecan J-107088 (Merck & Co)

Dexrazoxanet BNP-1350 (BioNumerik)

(TopoTarget) CKD-602 (Chong Kun

Pixantron (Novuspharrna) Dang)

Rebeccamycin analog KW-2170 (Kyowa Hakko)

(Exelixis)

BBR-3576 (Novuspharrna)

Antitumor Dactinomycin (Actinomycin Amonafide

Antibiotics D) Azonafide

Doxorubicin (adriamycin) anthrapyrazole

Deoxyrubicin Oxantrazole

Valrubicin losoxantrone

Daunorubicin bleomycin sulfate

(Daunomycin) (Blenoxan)

Epirubicin bleomycinic acid

Therarubicin Bleomycin A

Idarubicin bleomycin B

Rubidazone mitomycin C

Plicamycin p MEN-10755 (Menarini)

Porfiromycin GPX-100 (gem

Cyanomorpholinodoxorubi Pharmaceuticals)

Mitoxantrone (Novantrone)

Antimitotic Paclitaxel SB 408075

Agent Docetaxel (GlaxoSmithKline)

Colchicine E7010 (Abbott)

Vinblastine PG-TXL (Cell

Vincristin Therapeutics)

Vinorelbine IDN 5109 (Bayer)

Vindesin A 105972 (Abbott)

Dolastatin 10 (NCI) A 204197 (Abbott)

Rhizoxin (Fujisawa) LU 223651 (BASF)

Mivobulin (Warner-D 24851 (ASTA Medica)

Lambert) ER-86526 (Eisai)

Cemadotin (BASF) Combretastatin A4 (BMS)

RPR 109881A (Aventis) isohomohalichondrin-B

TXD 258 (Aventis) (PharmaMar)

Epothion B (Novartis) ZD 6126 (AstraZeneca)

T 900607 (Tularik) PEG paclitaxel (Enzon)

T 138067 (Tularik) AZ10992 (Asahi)

Cryptophycin 52 (Eli Lilly)! DN-5109 (lndena)

Vinflunin (Fabre) AVLB (Prescient

Auristatin PE (Teikoku NeuroPharma)

Hormones) azaepothilone B (BMS)

BMS 247550 (BMS) BNP-7787 (BioNumerik)

BMS 184476 (BMS) CA-4 prodrug (OXiGENE)

BMS 188797 (BMS) Dolastatin-10 (NrH)

Taxoprexin (Protarga) CA-4 (OXiGENE)

Aromatase-aminoglutethimide exemestane

Inhibitors Letrozole Atamestane (BioMedicines)

Anastrazole YM-511 (Yamanouchi)

formestane

Thymidylate Syntha Pemetrexed (EIi Lilly) Nolatrexed (Eximias) se Inhibitors ZD-9331 (BTG) CoFactor ™ (BioKeys)

DNA Trabectedin (PharmaMar) Mafosfamide (Baxter

Antagonists glufosfamide (Baxter International)

International) Apaziquon (Spectrum

Albumin + 32P (Isotope Pharmaceuticals)

Solutions) O6-Benzylguanine

Thymectacin (NewBiotics) (Paligent)

Edotreotide (Novartis)

Farnesyltransfera Arglabin (NuOncology Tipifarnib (Johnson & se-Inhibitors Labs) Johnson) lonafamib (Schering-Perillyl Alcohol (DOR

Plow) BioPharma)

BAY-43-9006 (Bayer) Pump CBT-1 (CBA Pharma) Zosuquidar trihydrochloride

Inhibitors Tariquidar (Xenova) (EIi Lilly)

MS-209 (Schering AG) Biricodar dicitrate (vertex)

Histone acetyl trans Tacedinalin (Pfizer) pivaloyloxymethyl butyrate erase SAHA (Aton Pharma) (titanium)

Inhibitors MS-275 (Schering AG) Depsipeptide (Fujisawa)

Metalloproteinase neovastate (Aeterna CMT -3 (CollaGenex)

Inhibitors Laboratories) BMS-275291 (Celltech)

Ribonucleosidred Marimastat (British Tezacitabine (Aventis) uktase-Biotech) Didox (Molecules for

Inhibitors gallium maltolate (titanium) Health)

Triapin (Vion)

TNF-alpha-virulizine (Lorus Revimid (Celgene)

Agonists / Antago Therapeutics) nest CDC-394 (Celgene)

Endothelin A Atrasentan (Abbot) YM-598 (Yamanouchi)

Receptor ZD-4054 (AstraZeneca)

antagonists

Retinoic Acid Fenretinide (Johnson & Alitretinoin (Ligand) R-agonist Johnson)

LGD-1550 (ligand)

Immunomodulators Interferon Dexosome Therapy n Oncophage (Antigenics) (Anosys)

GMK (Progenics) Pentrix (Australian Cancer

Adenocarcinoma Vaccine Technology)

(Biomira) JSF-154 (Carrying)

CTP-37 (AVI BioPharma) cancer vaccine (Intercell)

JRX-2 (Immuno-Rx) Norelin (Biostar)

PEP-005 (Peplin Biotech) BLP-25 (Biomira)

Synchrovax vaccines MGV (Progenics)

(CTL Immuno)! 3-Alethine (Dovetail)

Melanoma vaccine (CTL CLL-Thera (Vasogen)

Immuno) p21 RAS vaccine

(GemVax) Hormonal and estrogenic prednisone antihormonal conjugated estrogens methylprednisolone

Agent ethinyl estradiol prednisolone

Chlorotrienes Aminoglutethimide

Idenestrol Leuprolide

Hydroxyprogesterone caproa Goserelin t Leuporelin

Medroxyprogesterone Bicalutamide

Testosterone Flutamide

Testosterone Propionate Octreotide

Fluoxymesterone nilutamide

Methyltestosterone mitotane

Diethylstilbestrol P-04 (Novogen)

Megestrol 2-Methoxyestradiol

Tamoxifen (EntreMed)

Toremofin Arzoxifen (EIi Lilly)

dexamethasone

Photodynamic Talaporfin (Light Sciences) Pd-Bacteriopheophorbide

Central Theralux (Yeda)

(Theratechnologies) Lutetium Texaphyrin

Motexafin Gadolinium (Pharmacyclics)

(Pharmacyclics) Hypericin

Tyrosine kinase imatinib (Novartis) Kahalid F (PharmaMar)

Inhibitors Leflunomide CEP-701 (Cephalon)

(Sugen / Pharmacia) CEP-751 (Cephalon)

ZDI839 (AstraZeneca) MLN518 (Millenium)

Erlotinib (Oncogene PKC412 (Novartis)

Science) phenoxodiol O

Canertjnib (Pfizer) Trastuzumab (Genentech)

Squalamine (Genaera) C225 (ImCIone)

SU5416 (Pharmacia) rhu-Mab (Genentech)

SU6668 (Pharmacia) MDX-H210 (Medarex)

ZD4190 (AstraZeneca) 2C4 (Genentech)

ZD6474 (AstraZeneca) MDX-447 (Medarex)

Vatalanib (Novartis) ABX-EGF (Abgenix)

PK1166 (Novartis) IMC-1 C11 (ImCIone)

GW2016

(GlaxoSmithKline)

EKB-509 (Wyeth)

EKB-569 (Wyeth)

Various SR-27897 (CCK-A-BCX-1777 (PNP inhibitor,

Medium Inhibitor, Sanofi-BioCryst)

Synthelabo) Ranpirnase (Ribonuclease

Tocladesin (cyclic stimulant, Alfacell) AMP agonist, ribapharm) galarubicin (RNA

Alvocidib (CDK inhibitor, synthesis inhibitor, Dong-A)

Aventis) Tirapazamine

CV-247 (COX-2 inhibitor, (reducing agent, SRI

Ivy Medical) International)

P54 (COX-2 inhibitor, N-acetylcysteine

Phytopharm) (reducing agent, Zambon)

CapCell ™ (CYP450-R flurbiprofen (NF-

Stimulant, Bavarian kappaB inhibitor, Encore)

Nordic) 3CPA (NF-kappaB-

GCS-IOO (gal3 inhibitor, Active Biotech)

Antagonist, seocalcitol (vitamin D

10 GlycoGenesys) receptor agonist, Leo)

G17DT immunogen 131-I-TM-601 (DNA

(Gastrin inhibitor, Aphton) antagonist,

Efaproxiral (Oxygenator, TransMolecular)

Allos Therapeutics) Eflornithine (ODC inhibitor,

PI-88 (Heparanase ILEX Oncology)

Inhibitor, progens)

15 minodronic acid

Tesmilifen (histamine (osteoclast inhibitor,

Antagonist, YM Yamanouchi)

BioSciences) indisulam (p53 stimulant,

Histamine (histamine H2-eisai)

Receptor agonist, aplidine (PPT inhibitor,

Maxim) PharmaMar)

20 tiazofurin (IMPDH-rituximab (CD20-

Inhibitor, ribapharm) antibody, Genentech)

Cilengitide (integrin-gemtuzumab (CD33-

Antagonist, Merck KGaA) antibodies, Wyeth Ayerst)

SR-31747 (IL-1 PG2 (hematopoietic)

Antagonist, Sanofi amplifier,

Synthelabo) Pharmagenesis)

25 CCI-779 (mTOR kinase Immunol ™ (triclosan)

Inhibitor, Wyeth) Oral Irrigation, Endo)

Exisulind (PDE-V-triacetyluridine (uridine)

Inhibitor, cell pathways) prodrug, Wellstat)

CP-461 (PDE-V inhibitor, SN-4071 (sarcoma agent,

Cell Pathways) Signature BioScience)

30 AG-2037 (GART inhibitor, TransMID-107 ™

Pfizer) (immunotoxin, KS

WX-UK1 Biomedix)

(Plasminogen activator PCK-3145 (apoptosis

Inhibitor, Wilex) promoter, Procyon)

PBI-1402 (PMN-doranidazole (apoptosis)

Stimulant, ProMetic promoter, PoIa)

35 LifeSciences) CHS-828 (cytotoxic

Bortezomib (proteasome agent, Leo) Inhibitor, millennium) trans -retinoic acid

SRL-172 (T-cell (differentiator, NIH)

Stimulant, SR Pharma) MX6 (apoptosis promoter,

TLK-286 (glutathione-S-MAXIA)

Transferase inhibitor, apomin (apoptosis

Telik) Sponsors, ILEX Oncology)

PT-100 urocidin (apoptosis

(Growth factor promoter, Bioniche)

Agonist, Point Ro-31-7453 (apoptosis

Therapeutics) Sponsors, La Roche)

Midostaurin (PKC-brostallicin (apoptosis

Inhibitor, Novartis) promoter, Pharmacia)

Bryostatin-1 (PKC

Stimulant, GPC Biotech)

CDA-Ii (apoptosis

Conveyor, Everlife)

SDX-101 (apoptosis

Conveyor, Salmedix)

Ceflatonin (apoptosis

Conveyor, ChemGenex)

Preferably, the compounds of the formula I are combined with those 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. The synergistic effects of inhibiting VEGF in combination with radiotherapy have been described in the art (see WO 00/61186). "Estrogen receptor modulators" refers to compounds that disrupt or inhibit the binding of estrogen to the receptor, regardless of how this occurs. "" 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 this is not intended to be limiting.

"Androgen receptor modulators" refers to compounds that interfere with or inhibit the binding of androgens to the receptor, regardless of how this occurs, and the androgen receptor modulators include, for example, finasteride and other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide , Liarozole and abiraterone acetate. "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-difluoromethylornithine, ILX23-7553, trans-N- (4'-hydroxyphenyl) -retinamide and N-4-carboxyphenylretinamide.

"Cytotoxic agents" refers to compounds that are primarily derived from direct

Cell death or cell myosis inhibiting or interfering with cell function, including alkylating agents, tumor necrosis factors, intercalators, microtubulin inhibitors and topoisomerase inhibitors.

The cytotoxic agents include, for example, tirapazimine, Sertenef, cachectin, ifosfamide, tasonermine, lonidamine, carboplatin, altretamine, prednimustine, dibromodulcite, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improvisulfan-tosylate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulvene, dexifosfamide, cis -amino-dichloro (2-methylpyridine) -platinum, benzylguanine, glufosfamide, GPX100,

(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, 3'-desamino-3'-morpholino-13-desoxo-10-hydroxycarminomycin, annamycin, galarubicin, elinafide,

MEN10755 and 4-desmethoxy-3-desamino-3-aziridinyl-4-methylsulfonyl-5 daunorubicin (see WO 00/50032), but this is not intended to be limiting.

The microtubulin inhibitors include, for example, paclitaxel, vindesine sulfate, S '' '- dideshydro' '- deoxy-δ'-norvincaleukoblastin, docetaxol,

10 rhizoxin, dolastatin, mivobulin isethionate, 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-valyl-L-prolyl-L-proline-t-butylamide,

, I O - 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

20

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

25 (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 ^L : 6.7) naphtho (2,3-d) -1,3-dioxol-6-one, 2,3- (methylene-

2Q dioxy) -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-

35 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 ocfosfat, fludarabine, capecitabine, galocitabine, Cytarabine, Fosteabin-sodium hydrate, raltitrexed, Paltitrexid, emitefur, Tiazo- furin, decitabine, Nolatrexed, pemetrexed, Nelzarabin, 2'-deoxy-2'-methylidenecytidine, 2 ^I -Fluormethylen -2'-deoxycytidine, N- [5- (2,3-dihydrobenzofuryl) sulfonyl] -N '- (3,4-dichlorophenyl) urea, N6- [4-deoxy-0 4- [N 2 - [2 (E ), 4 (E) -tetradecadienoyl] glycylamino] -L-glycero-BL-manno-heptopyranosyl] 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-8- ₅ (carbamoyloxymethyl) -4-formyl-6-methoxy-14-oxa-1, 11 -diazatetracyclo- (7.4.1.0.0) -tetradeca-2,4,6-trien-9-ylessigsäureester, Swainsonine, lometrexol, dexrazoxane, methioninase, 2'-cyano-2'-deoxy-N4-palmitoyl-1-BD-arabinofuranosylcytosine and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone. The "antiproliferative agents" also include other monoclonal antibodies against growth factors than already among the

"Angiogenesis inhibitors" such as trastuzumab, as well as tumor suppressor genes such as p53, can be delivered via recombinant virus-mediated gene transfer (see, e.g., U.S. Patent No. 5,6,069,134).

Especially preferred is the use of the compound of the invention for the treatment and prophylaxis of tumor diseases.

The tumor is preferably selected from the group of squamous cell tumors, bladder, stomach, kidney, head and neck,

Esophagus, cervix, thyroid, intestine, liver, 5 of the brain, prostate, genitourinary tract, lymphoid

System, the stomach, the larynx and / or the lungs. The tumor is furthermore preferably selected from the group of lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, ovarian carcinoma, 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 myelotic leukemia, acute lymphoblastic leukemia and / or chronic lymphocytic leukemia.

In another aspect, the invention includes a treatment of a patient having a neoplasm such as a cancer by administering a compound of the formula (I) in combination with an antiproliferative agent. Suitable antiproliferative agents include those described in U.S. Pat

Table 1 provided.

Above and below all temperatures are given in ⁰ C. In the following examples, "usual work-up" means adding water if necessary, if necessary, adjusting to pH values between 2 and 10, depending on the constitution of the final product, extracted with

Ethyl acetate or dichloromethane, separates, the organic phase is dried over sodium sulfate, evaporated and purified by chromatography on silica gel and / or by crystallization. Rt values are determined by HPLC with mentioned eluents.

Mass spectrometry (MS): El (electron impact ionization) M ⁺

FAB (Fast Atom Bombardment) (M + H) ⁺ ESI (electrospray ionisation) (M + H) ⁺ APCI-MS (atmospheric pressure chemical ionization - mass spectrometry) (M + H) ⁺ Method LC / MS:

Solvent A: water + 0.1% HCOOH

Solvent B: acetonitrile + 0.1% HCOOH flow: 2.4 ml / min

Gradient: 0.0 min 4% B

2.6 min, 100% B Column: Chromolith ^® Speed ROD RP-18e 50-4, 6 mm

Method HPLC:

Solvent A: water + 0.1% HCOOH solvent B: acetonitrile + 0.08% HCOOH

Flow: 1, 5 ml / min

Gradient: 0.0 - 0.5 min 100% A

0.5 - 3.5 min to 100% B 3.5 - 4.5 min 100% B 4.5 - 4.6 min to 100% A 4.6 - 5.0 min 1000% A

Column: Si-ROD ^® UM9423 / 100 3 mm

example 1

Synthesis of N- (5-chloro-2-methoxy-phenyl) -2- [10- (4-methylpiperazine-1-carbonyl) -3,4-dihydro-1H-benzo [b] [1, 6 ] naphthyridin-2-yl] -acetamide ("A1", rtfmin] 2.45) is carried out analogously to the scheme below

"A1"

a. 0.48 g (1.5 mmol) of 1 and 0.70 g (1.5 mmol) of PyBroP are dissolved in 20 ml of DMF and stirred for 5 min. Thereafter, 1.67 ml (1.5 mmol) of methylpiperazine are added and the mixture is stirred at room temperature (RT) for 2 hours. The solvent is removed on a rotary evaporator, diluted with water (100 ml) and extracted twice with EA. The organic phase is dried over magnesium sulfate, filtered off and evaporated to dryness. Purification by preparative HPLC gives 0.29 g (48.3%) of 2 as a colorless amorphous product.

b. 0.26 g (0.65 mmol) of 2 are dissolved in 5 ml of THF, 2 ml of methanol and 0.3 ml of acetic acid (100%), mixed with 0.3 g of Pd / C 5% and hydrogenated at RT for 32 h. Thereafter, the catalyst is filtered off and the solvent i. Vak evaporated. The residue is purified by preparative HPLC. 76 mg (37.7%) of educt 3 are obtained as amorphous product. c. 0.79 g (5 mmol) of 5-chloro-2-methoxy-phenylamine are dissolved in 50 ml of DCM. 0.7 ml (5 mmol) of triethylamine are added. While cooling with ice, 0.42 ml (5 mmol) of bromoacetic acid chloride are then added dropwise.

Thereafter, the mixture is stirred for 2 h at RT. The mixture is washed with water.

Then the organic phase is dried over sodium sulfate, filtered off and the solvent i. Vak. evaporated. The educt (4, 1, 2 g, 86%) is reacted further without purification.

d. 72 mg (0.23 mmol) of 3, 65 mg (0.23 mmol) of 4 and 76 mg (0.23 mmol) of cesium carbonate are stirred in 5 ml of DMF for 18 hours. Then the batch is mixed with water and extracted with glacial acetic acid. The organic phase is dried over magnesium sulfate, filtered off and evaporated to dryness. The residue is purified by preparative HPLC. This gives 54 mg (46%) of the substance "A1" as an amorphous product.

1 H-NMR (DMSO-d6): d [ppm] for "A1"

2.86 (s, 3H), 3.14-5.57 (m, 9H), 3.68 (m, 1H), 3.90 (m, 5H), 4.46-4.85 (m .

4H), 7.15 (d, 1H), 7.23 (dd, 1H), 7.77 (m, 1H), 7.83-8.03 (m, 2H), 8.10 ( m,

1H), 8.15 (d, 1H), 10.20 (s, 1H) ^*

The following compounds are prepared using the ensprechenden precursors (3 and 4) analogous to Example 1:

(2-Benzyl-1,2,3,4-tetrahydro-benzo [b] [1,6-naphthyridin-10-yl) - (4-methylpiperazin-1-yl) -methanone ("A2", rt [min] 1, 63)

"A2" N- (5-chloro-2-methoxy-phenyl) -2- [10- (4-ethylpiperazine-1-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridine -2-yl] -acetamide ("A23", rt [min] 2.37)

1 H-NMR (DMSO-d6): d [ppm] for "A23"

1, 25 (m, 3H), 2.97-4.05 (3m, 17H), 4.43-4.88 (m, 4H), 7.12 (d, 1H), 7.21 (dd , 1H), 7.74 (m, 1H), 7.80-8.10 (3m, 3H), 8.13 (d, 1H), 10.20 (s, 1H) ^* Compound N - (5-Chloro-2-methoxy-phenyl) -2- [10- (4-ethylpiperazine-1-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridine 2-yl] acetamide ("A24", rt [min] 2.37)

1 H-NMR (DMSO-d6): d [ppm] for "A24"

2.11-3.92 (9m, 22H), 4.36 (t, 2H), 7.04 (d, 1H), 7.10 (dd, 1H), 7.63 (m,

2H), 7.77 (dt, 1H), 8.00 (d, 1H), 8.29 (d, 1H), 9.73 (s, 1H)

4- {2 - [(5-Chloro-2-methoxyphenylcarbamoyl) -methyl] -1, 2,3,4-tetrahydrobenzo [b] [1.δ-naphthyridine-1-carbonyl-1-piperazine-i-carboxylic acid benzyl ester ("25", rt [min] 4.08)

1 H-NMR (DMSO-d6): d [ppm] for "A25"

3.11 (m, 3H), 3.37 (m, 2H), 3.53 (m, 1H), 3.75 (m, 2H), 3.80-3.99 (m, 7H) ₁ 4.55 dd, 2H), 4.70 (dd, 2H), 5.07 (m, 2H), 7.05 (d, 1H), 7.15 dd, 1H), 7.30 (m, 5H), 7.78 ( m, 1H), 7.90 (d, 1H), 7.98 (m, 1H), 8.09 (d, 1H), 8.18 (d, 1H), 8.33 ( m, 1H), 10.12 (s, 1H) ^*

2- [10- (4-Benzyl- [1,4] diazepan-1-carbonyl) -3,4-dihydro-1H-benzot-1-naphthyridine-1-yl-N, δ-chloro-1-methoxy-phenyl acetamide ("A26", rt [min] 2.83)

Compound N- (5-chloro-2-methoxy-phenyl) -2- [10- (piperazine-1-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridine-2-one yl] acetamide ("A27", rt [min] 2.37)

"A27 ¹¹ N- (5-chloro-2-methoxy-phenyl) -2- [10- (4-cyclopentyl-piperazine-1-carbonyl) -3,4-dihydro-i H-benzo [b] [1,6] naphthyridine -2-yl] acetamide ("A28", rt [min] 2.64)

1 H-NMR (DMSO-d6): d [ppm] for "A28" 1.43-2.11 (4m, 12H), 2.72-3.96 (6m, 12H), 4.43-4, 85 (m, 4H), 7.08 (d, 1H), 7.17 (m, 1H), 7.74 (m, 1H), 7.83 (m, 1H), 7.92 (m, 1H), 8.00 (m, 1H), 8.10 (d, 1H) ₁ 9.75 (S, 1H) ^*

N- (5-Chloro-2-methoxy-phenyl) -2- [10- (4-propyl-piperazine-1-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] -naphthyridine 2-yl] -acetamide ("A29", rtfmin] 2.48)

1 H-NMR (DMSO-d6): d [ppm] for "A29"

0.87 (m, 3H), 1.65 (m, 2H), 2.93-3.97 (5m, 17H), 4.47-4.82 (m, 4H), 7.08 (d, 1H ), 7.17 (m, 1H), 7.75 (m, 1H), 7.86 (m, 1H), 7.93 (m, 1H), 8.04 (m, 1H) , 8.13 (d, 1H), 9.78 (s, 1H) ^* 2- [10- (4-Benzyl-piperazine-1-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6-naphthyridin-2-yl] -N- (5-chloro-2 -methoxy-phenyl) -acetamide ("A30", rt [min] 3.01)

{2 - [(5-Chloro-benzofuran-7-ylamino) -methyl] -1,3,3,4-tetrahydrobenzo [b] [1,6] naphthyridin-10-yl} - [4- (2 -hydroxy-ethyl) -piperazin-1-yl] -methanone ("A57", rt [min] 2.40)

4-Chloro-2 - ({10- [4- (2-hydroxy-ethyl) -piperazine-1-carbonyl] -3,4-dihydro-1H-benzo [b] [1, 6] naphthyridine-2 ylmethyl} amino) benzonitrile ("A58", rt [min] 2.27)

4-Chloro-2 - ({10- [4- (2-hydroxy-ethyl) -piperazine-1-carbonyl] -3,4-dihydro-1H-benzo [b] [1, 6] naphthyridine-2 ylmethyl} -amino) -benzoic acid methyl ester ("A59", rt [min] 2.75)

N- (5-chloro-2-isopropoxyphenyl) -2- {10- [4- (2-hydroxy-ethyl) -piperazine-1-carbonyl] -3,4-dihydro-1H-benzo [b] [1, 6] naphthyridin-2-yl} -acetamide ("A60", rt [min] 2.88)

N- [5-Chloro-2- (2-hydroxy-ethoxy) -phenyl] -2- {10- [4- (2-hydroxy-ethyl) -piperazine-1-carbonyl] -3,4-dihydro-1 H-benzo [b] [1,6] naphthyridin-2-yl} -acetamide ("A61", rt [min] 2,16)

N- (5-fluoro-2-methoxy-phenyl) -2- {10- [4- (2-hydroxy-ethyl) -piperazine-1-carbonyl] -3,4-dihydro-1H-benzo [b] [1, 6] naphthyridin-2-yl} -acetamide ("A62", rt [min] 2.24)

4-chloro-2- (2- {10- [4- (2-hydroxyethyl) piperazine-1-carbonyl] -3,4-dihydro-1H-benzo [b] [1,6] naphthyridine 2-yl} -acetylamino) -benzoic acid ("A63", rtfmin] 2.27)

N- [3-chloro-4- (2-oxopyrrolidin-1-yl) -phenyl] -2- {10- [4- (2-hydroxy-ethyl) -piperazine-1-carbonyl] -3,4 -dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl} -acetamide ("A64", rt [min] 1, 95)

N- [3-chloro-4- (3-oxomorpholin-4-yl) -phenyl] -2- {10- [4- (2-hydroxy-ethyl) -piperazine-1-carbonyl] -3,4 -dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl} -acetamide ("A65", rtfmin] 1, 87)

N- (5-chloro-2-methoxy-phenyl) -2- {10- [4- (2-piperidin-1-yl-ethyl) -piperazine-1 ^■ carbonyl] -3,4-dihydro-1 H- benzo [b] [1, 6] naphthyridin-2-yl} -acetamide ("A66", rt [min] 2.61)

N- (5-chloro-2-methoxy-phenyl) -2- {10- [4- (2-dimethylamino-ethyl) -piperazine-1-carbonyl] -3,4-dihydro-1H-benzo [b] [1, 6] naphthyridin-2-yl} -acetamide (A "67",

N- (5-chloro-2-methoxy-phenyl) -2- {10- [4- (2-morpholin-4-yl-ethyl) -piperazine-1-carbonyl] -3,4-dihydro-1 H- benzo [b] [1, 6] naphthyridin-2-yl} -acetamide ("A68", rt [min] 2.48)

N- (5-bromo-2-methoxy-phenyl) -2- {10- [4- (2-hydroxy-ethyl) -piperazine-1-carbonyl] -3,4-dihydro-1H-benzo [b] [1, 6] naphthyridin-2-yl} -acetamide ("A69", rt [min] 2.53)

1 - (6-Chloro-2,3-dihydro-benzo [1,4] oxazin-4-yl) -2- {10- [4- (2-hydroxy-ethyl) -piperazine-1-carbonyl] -3 , 4-dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl} -ethanone ("A70", rt [min] 2.21)

N- (5-Chloro-2,4-dimethoxy-phenyl) -2- {10- [4- (2-hydroxy-ethyl) -piperazine-1-carbonyl] -3,4-dihydro-1H-benzo [ b] [1, 6] naphthyridin-2-yl} -acetamide ("A71", rt [min] 2.38)

N- (3-chloro-4-methoxy-phenyl) -2- {10- [4- (2-hydroxy-ethyl) -piperazine-1-carbonyl] -3,4-dihydro-1H-benzo [b] [1, 6] naphthyridin-2-yl} -acetamide ("A72", rt [min] 2.31) •

N- (3-chloro-4-methylphenyl) -2- {10- [4- (2-hydroxyethyl) piperazine-1-carbonyl] -3,4-dihydro-1H-benzo [b] [1, 6] naphthyridin-2-yl} -acetamide ("A73", rt [min] 2.44)

N- (3-chloro-4-fluoro-phenyl) -2- {10- [4- (2-hydroxy-ethyl) -piperazine-1-carbonyl] -3,4-dihydro-1H-benzo [b] [1, 6] naphthyridin-2-yl} -acetamide ("A74", rtfmin] 2.43)

N- (2,5-dichlorophenyl) -2- {10- [4- (2-hydroxyethyl) piperazine-1-carbonyl] -3,4-dihydro-1H-benzo [b] [1 , 6] naphthyridin-2-yl} -acetamide ("A75", rt [min] 2.42)

N- (3,4-dichloro-phenyl) -2- {10- [4- (2-hydroxy-ethyl) -piperazine-1-carbonyl] -3,4-dihydro-1H-benzo [b] [1 , 6} πaphthyrϊdin-2-yl} -acetamide ("A76", rtfminj 2.52)

N- (3-chloro-2-fluoro-phenyl) -2- {10- [4- (2-hydroxy-ethyl) -piperazine-1-carbonyl] -3,4-dihydro-1H-benzo [b] [1, 6] naphthyridin-2-yl} -acetamide ("A77", rtfmin] 2.38)

N- (5-chloro-2-fluoro-phenyl) -2- {10- [4- (2-hydroxy-ethyl) -piperazine-1-carbonyl] -3,4-dihydro-1H-benzo [b] [1, 6] naphthyridin-2-yl} -acetamide ("A78", rt [min] 2,35)

N- (5-chloro-benzooxazol-7-yl) -2- {10- [4- (2-hydroxy-ethyl) -piperazine-1-carbonyl] -3,4-dihydro-1H-benzo [b] [1, 6] naphthyridin-2-yl} -acetamide ("A79", rt [min] 2.21)

N- (3,5-dichloro-2-methoxy-phenyl) -2- {10- [4- (2-hydroxy-ethyl) -piperazine-1-carbonyl] -3,4-dihydro-1H-benzo [ b] [1,6] naphthyridin-2-yl} -acetamide ("A80", rt [min] 2.46)

N- (5-chloro-2-oxo-2,3-dihydro-benzooxazol-7-yl) -2- {10- [4- (2-hydroxy-ethyl) -piperazine-1-carbonyl] -3,4 -dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl} -acetamide ("A81", rt [min] 2,11)

N- (6-chloro-3H-benzotriazol-4-yl) -2- {10- [4- (2-hydroxyethyl) piperazine-1-carbonyl] -3,4-dihydro-1H-benzo [ b] [1, 6] naphthyridin-2-yl} -acetamide ("A82", rt [min] 2.14)

Example 2

Synthesis of N- (5-chloro-2-methoxyphenyl) -2- [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridine-2 -yl] -acetamide ("A7") is carried out analogously to the scheme below

"A7"

1 H-NMR (DMSO-d6): d [ppm] for "A7"

3.07 (m, 4H), 3.43-3.59 (m, 4H), 3.77 (dt, 2H), 3.82-3.95 (m, 5H), 4.50-4.64 (m, 3H), 4.78 (m , 1 H), 7.15 (d, 1 H), 7.23 (dd, 1 H) ₁ 7.81 (m, 1 H), 7.91 (d, 1 H), 7.99 (m , 1H), 8.16 (m, 2H), 10.08 (s, 1H) *

The following compounds are prepared using the corresponding precursor (8) analogously to Example 2:

(2-Benzyl-1,2,3,4-tetrahydrobenzo [b] [1,6] naphthyridin-10-yl) -morpholin-4-yl-methanone ("A8", rt [min] 1, 80 )

1 H-NMR (DMSO-d6): d [ppm] for "A8") 2.89-3.05 (m, 3H), 3.38-3.53 (m, 3H), 3.60 (m, 1H), 3.73-3.93 (m, 5H), 4.28 (m, 1H), 4.58 (dd, 2H), 4.72 (d, 1H), 7.52 (m, 3H), 7.62 (m, 2H), 7.73 (t, 1H), 7.80 (d, 1H), 7.91 (dt, 1H), 8.10 (d, 1H) * N-CS-chlorophenyl ^ -flO ^ morpholine ^ -carbonyO- S ^ -dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl] -acetamide ("A9", rt [min] 2,96)

N- (2-Methoxy-phenyl) -2- [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6-naphthyridin-2-yl] -acetamide ( "A10", rt [min] 2.85)

N- (5-chloro-2-methylphenyl) -2- [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl ] -acetamide ("A11", rt [min] 3.07)

1 H-NMR (DMSO-d6): d [ppm] for "A11")

2.24 (s, 3H), 3.08 (m, 2H), 3.51 (m, 2H), 3.70-3.97 (m, 8H), 4.55 (dd, 2H), 4.72 (dd, 2H), 7.20 (d, 1H), 7.28 (d, 1H), 7.65 (s, 1H), 7.76 (t, 1H), 7.87 (d,

1H), 7.94 (t, 1H), 8.13 (d, 2H), 9.05 (s, 1H) *

N- (2-Methoxy-5-methylphenyl) -2- [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl ] -acetamide ("A12", rt [min] 3.07)

N- (5-bromo-2-methoxy-phenyl) -2- [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl ] -acetamide ("A13", rt [min] 3.39)

1 H-NMR (DMSO-d6): d [ppm] for "A13")

3.07 (m, 4H), 3.43-3.58 (m, 4H), 3.76 (m, 2H), 3.81-3.99 (m, 5H), 4.47-4.79 (m, 4H), 7.06 (d, 1H), 7.32 (dd, 1H), 7.76 (m, 1H), 7.86 (d, 1H), 7.94 (m, 1H), 8.14 ( d, 1H), 8.23 (m, 1H), 10.08 (s, 1H) * N- (4-methoxybiphenyl-3-yl) -2- [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl ] -acetamide ("A14", rtfmin] 3.71)

1 H-NMR (DMSO-d6): d [ppm] for "A14")

3.09 (m, 4H), 3.46-3.62 (m, 2H), 3.74 (m, 2H), 3.79 - 4.00 (m, 7H), 4.58 dd,

2H), 4.73 (dd, 2H), 7.20 (d, 1H), 7.32 (m, 1H), 7.44 (m, 3H), 7.58 (m, 2H),

7.76 (m, 1H), 7.86 (d, 1H) ₁ 7.94 (m, 1H), 8.14 (d, 1H), 8.33 (m, 1H), 10.11

(s, 1H) ^*

N- (5-chloro-2-ethoxy-phenyl) -2- [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl ] -acetamide ("A41")

N- (5-Bromo-benzofuran-7-yl) -2- [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl ] -acetamide ("A43", rt [min] 3.36)

2- [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6-naphthyridin-2-yl] -N- (2-trifluoromethoxy-5-trifluoromethyl) phenyl ) -acetamide ("A44", rt [min] 3.92)

N-Benzofuran-7-yl-2- [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl] -acetamide ("A45 ", rt [min] 2.80)

N- (2,3-dihydro-benzofuran-7-yl) -2- [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridine-2 -yl] -acetamide ("A46", rtfmin] 2.61)

N- (4-chloropyridin-2-yl) -2- [10- (morpholine-4-carbonyl) -3,4-clihydro-1H-benzo [b] [1,6] naphthyridin-2-yl ] -acetamide ("A47", rt [min] 2.75)

N- (5-chloro-benzofuran-7-yl) -2- [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl ] -acetamide ("A48", rt [min] 3.33)

N-Cδ-chloro -isopropoxy-phenyl-O-tiO ^ morpholine -carbonyO-S-dihydro-1H-benzo [b] [1,6-naphthyridin-2-yl] -acetamide ("A49", rtfmin ] 3.81)

N- (4-chloro-2-hydroxy-phenyl) -2- [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl ] -acetamide ("A53", rt [min] 2.99)

N- [5-chloro-2- (2-hydroxy-ethoxy) -phenyl] -2- [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1, 6 ] naphthyridin-2-yl] -acetamide ("A54", rt [min] 2.83)

The following compounds are prepared using the corresponding precursors (7 and 8) analogously to Example 2: N- (5-chloro-2-methoxy-phenyl) -2- [7-chloro-10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl] -acetamide ("A15", rt [min] 3.95)

1 H-NMR (DMSO-d6): d [ppm] for "A15"

3.09 (m, 2H), 3.53 (m, 2H), 3.77 (m, 2H), 3.84-3.97 (m, 9H), 4.51-4.85 (m, 4H), 7,14 (d, 1H) ₁ 7,22 (dd, 1H), 7,71 (dd, 1H), 7,85 (d, 1H), 8,13 (m, 2H), 10, 08 (s, 1H) ^*

N- (5-Chloro-2-methoxy-phenyl) -2- [6-chloro-10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] -naphthyridine 2-yl] -acetamide ("A16", rt [min] 3.87)

1 H-NMR (DMSO-d6): d [ppm] for "A16"

3.05 (m, 2H), 3.41-5.57 (m, 4H), 3.74 (m, 2H), 3.81 (m, 1H), 3.84- 3.97 (m, 6H), 4.48-4.82 (m, 4H), 7.10 (d, 1H), 7.18 (dd, 1H), 7.61 (t, 1H), 7.73 (d, 1H ), 7.99 (dd, 1H), 8.11 (d, 1H), 10.11 (s, 1H) *

N- (5-chloro-2-methoxy-phenyl) -2- [7-ethyl-10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] -naphthyridine 2-yl] -acetamide ("A17", rtfmin] 3.60)

1 H-NMR (DMSO-d6): d [ppm] for "A17"

1.30 (t, 3H), 2.91 (dd, 2H), 3.08 (m, 2H), 3.46-3.96 (5m, 13H), 4.49-4.79 (m, 4H), 7,10 (d, 1H), 7,19 (dd, 1H), 7,72 (d, 1H), 7,86 (d, 1H), 8.01 (s, 1H), 8,10 ( d, 1H), 10.05 (s, 1H) *

3- {2- [10- (Morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl] -2-oxo-ethylamino} -benzonitrile ( "A21", rtfmin] 3.33)

1 H-NMR (DMSO-d6): d [ppm] for "A21"

3.04 (m, 4H), 3.19 (m, 2H), 3.36-5.5 (m, 4H), 3.68-3.93 (m, 12H), 6.86 (d, 1H), 7.06 (d, 1H), 7.12 (dd, 1H), 7.42 (d, 1H) ₁ 7.92 (d, 1H), 8.28 (d, 1H), 9, 70 (s, 1H)

2- [6-Bromo-10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl] - N- (5-chloro 2-methoxy-phenyl) -acetamide

( "A40")

2- [7-Bromo-10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6-naphthyridin-2-yl] -N- (5-chloro-2 -methoxy-phenyl) -acetamide ("A42 ¹¹ , rt [min] 3.84)

1 - (6-chloro-2,3-dihydroindol-1-yl) -2- [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1, 6 ] naphthyridin-2-yl] -ethanone ("A83", rtfmin] 2.67)

"A83" 1 - (3,4-Dihydro-2H-quinolin-1-yl) -2- [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridine -2-yl] -ethanone ("A84", rt [min] 2.52)

1 - (2,3-Dihydro-benzo [1,4] oxazin-4-yl) -2- [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1 , 6] naphthyridin-2-yl] -ethanone ("A85", rt [min] 2.37)

N- (5-chloro-2-methoxy-phenyl) -N-methyl-2- [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridine -2-yl] -acetamide ("A86", rt [min] 2.51)

N- (5-chloro-2-methoxy-phenyl) -N-methyl-2- [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridine -2-yl] -acetamicl ("A87", rt [min] 2.46)

Example 3

Synthesis of 3- (2,4-dichlorophenyl) -1 - [10- (4-methylpiperazine-1-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridine -2-yl] -propane-1-one ("A31", rt [min] 2.75)

"A31"

0.17 g (0.5 mmol) of 3 (synthesis is described in Example 1), 0.11 g (0.5 mmol) of 2,4-dichlorophenyl-propionic acid, 96 mg (0.5 mmol) of N- (dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, 68 mg (0.5 mmol) of HOBt and 0.07 ml (0.5 mmol) of triethylamine are dissolved in 5 ml of DMF and stirred at RT for 20 h. Then the solvent is evaporated on a rotary evaporator. The residue is taken up in aqueous Na ₂ CO ₃ solution and EA and extracted by shaking. The organic phase is separated and dried over magnesium sulfate, filtered off and evaporated to dryness. The residue is dissolved in 1N HCl and freeze-dried. 0.18 g (66%) of 6 is obtained as a colorless amorphous product.

The following compounds are prepared using the corresponding precursor (9) analogously to Example 3: 1 - [10- (4-Methyl-piperazine-1-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl] -2-phenylamino-ethanone ("A3 ", rt [min] 2,11)

2- (2-chloro-5-methoxy-phenylamino) -1 - [10- (4-methylpiperazine-1-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridine -2-yl] -ethanone ("A4", rt [min] 2.53)

4- {2- [10- (4-Methylpiperazin-1-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl] -2-oxo-ethylamino } benzonitrile ("A5", rtfmin]

2,11)

3- {2- [10- (4-Methylpiperazin-1-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl] -2-oxo-ethylamino } benzonitrile ("A6", rt [min]

2.21)

3- (2,5-Dimethoxy-phenyl) -1 - [10- (4-methylpiperazine-1-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridine-2 -yl] -propan-1-one ("A32", rt [min] 2.27)

3- (4-chloro-2-fluoro-phenyl) -1 - [10- (4-methylpiperazine-1-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridine -2-yl] -propan-1-one ("A33", rt [min] 2.59)

1 H-NMR (DMSO-d6): d [ppm] for "A33"

2.74 - 2.95 (m, 8H), 3.05 (m, 1H), 3.15 - 3.52 (m, 6H), 3.66 (m, 1H), 3.90 (m, 1H), 4.06 (m, 1H), 4.67 - 5.02 (m, 3H), 7.16 (m, 1H), 7.25 (m, 1H), 7.35 (m, 1H) H) 7.90 (t, 1H), 7.99-8.15 (m, 2H), 8.24 (d, 1H) *

Example 4 Synthesis of 3- (2,4-dichlorophenyl) -1 - [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridine-2 yl] -propan-1-one ("A35", rt [min] 3.81)

"A35"

1 H-NMR (DMSO-d6): d [ppm] for "A35"

2.85 (m, 2H), 3.00 (m, 2H), 3.16 (m, 3H), 3.41-3.60 (m, 3H) 3.69-4.09 (m, 6H ), 4.69 - 4.95 (m, 2H), 7.34 (m, 1H), 7.44 (m, 1H), 7.53 (m, 1H) 7.97 (t, 1H), 8.07 (d, 1H), 8.15 (t, 1H), 8.28 (d, 1H) ^*

The following compounds are prepared using the corresponding precursor (10) analogously to Example 4:

3- (4-chloro-2-fluoro-phenyl) -1 - [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl ] -propan-1-one ("A34", rt [min] 3.63)

1 - [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl] -2-phenylamino-ethanone ("AI 8 ", rt [min] 3.04)

4- {2- [10- (Morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl] -2-oxo-ethylamino} -benzonitrile ( "A19", rt [min] 3,04)

3- {2- [10- (Morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl] -2-oxo-ethylamino} -benzonitrile ( "A20", rt [min] 3,15)

3- (2,5-Dimethoxyphenyl) -1 - [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyrdin-2-y!] -propan-1-one ("A22", rt [m! n] 3.65)

3- (2,5-Dimethoxyphenyl) -1 - [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl] - propane-1-one ("A36", rt [min] 3.20)

1 H-NMR (DMSO-d6): d [ppm] for "A36"

2.69-2.85 (m, 5H), 3.12 (m, 2H), 3.30-3.58 (m, 5H), 3.59-3.77 (m, 6H), 3, 77-4.04 (m, 4H), 4.64-4.88 (m, 2H), 6.63-6.90 (m, 3H), 7.93 (t, 1H), 8.02 (d, 1H), 8.12 (t, 1H), 8.23 (d, 1H) * 3- (3-chlorophenyl) -1 - [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl] -propane 1-on ("A37", rt [min] 3.55)

1 H-NMR (DMSO-d6): d [ppm] for "A37"

2.83-2.98 (m, 5H), 3.11-3.24 (m, 3H), 3.41-3.60 (m, 2H), 3.72-4.10 (m, 6H 4.71-4.98 (m, 2H), 7.20-7.38 (m, 4H), 7.96 (t, 1H), 8.08 (d, 1H), 8, 16 (t, 1H), 8.31 (d, 1H) ^*

3- (3,4-dichlorophenyl) -1 - [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl] - propan-1-one ("A38", rt [min] 3.71)

1 - [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl] -3-phenyl-propan-1-one ("A39 ", rt [min] 3,20)

1 H-NMR (DMSO-d6): d [ppm] for "A39"

2.76-2.93 (m, 5H), 3.04-3.20 (m, 2H), 3.35-5.58 (m, 3H), 3.63-4.04 (rn, 6H ), 4.64-4.90 (m, 2H), 7.12-7.30 (m, 5H), 7.93 (t, 1H), 8.03 (d, 1H), 8, 12 (t, 1H), 8.30 (d, 1H) ^*

N- (5-chloro-2-methoxy-phenyl) -2- [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl ] -2-oxo-acetamide ("A55", rt [min] 3.73)

The following compounds can be prepared by the skilled artisan analogously to the previously described methods:

HPLC method:

Solvent A: water + 0.05% HCOOH Solvent B: acetonitrile + 0.04% HCOOH Flow: 2.0 ml / min Gradient: 0.0 - 0.5 min 99% A 0.2-3.8 minutes at 100% B 3.8-4.4 minutes 100% B 4.4-5.0 minutes at 100% A

Column: Si-ROD ^® UM9423 / 100 3 mm

2- {10- [4- (2-Hydroxyethyl) piperazine-1-carbonyl] -3,4-dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl} -N- (1-methyl-1H-pyrazol-4-yl) -acetamide ("B1"_> rt [min] 2.08)

2- (4-chloro-phenyl) -2- (2- {10- [4- (2-hydroxy-ethyl) -piperazine-1-carbonyl] -3,4-dihydro-1H-benzo [b] [1 , 6] naphthyridin-2-yl} -acetylamino) -N-methyl-acetamide ("B2", rt [min] 2.03)

2- (2- {10- [4- (2-Hydroxyethyl) piperazine-1-carbonyl] -3,4-dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl} -acetylamino) -N-methyl-2-phenyl-acetamide ("B3", rt [min] 1.66)

N- (5-chloro-2-trifluoromethoxy-phenyl) -2- {10- [4- (2-hydroxy-ethyl) -piperazine-1-carbonyl] -3,4-dihydro-1H-benzo [b] [1, 6] naphthyridin-2-yl} -acetamide ("B4", rt [min] 2.75)

N- (5-chloro-2-trifluoromethoxy-phenyl) -2- [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl ] -acetamide ("B5", rt [min] 3.73)

2 - [(5-chloro-2-methoxy-phenylcarbamoyl) -methyl] -1, 2,3,4-tetrahydrobenzo [b] [1,6] naphthyridine-10-carboxylic acid (1H-benzotriazole-5- yl) amide ("B22", rt [min] 4,19)

{2- [2- (3-chloro-phenyl) -2H-pyrazino-3-ylmethyl] -1, 2,3,4-tetrahydrobenzo [b] [1,6] naphthyridin-10-yl} -morpholine -4-yl-methanone ("B23", rt [min] 3.28)

N- (5-Bromo-3-fluoro-2-methoxyphenyl) -2- [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridine -2-yl] -acetamide ("B24", rtfmin] 3.71)

N- (4'-amino-5-fluoro-4-methoxybiphenyl-3-yl) -2- [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [ 1, 6] naphthyridin-2-yl] -acetamide ("B35", rt [min] 3.07)

The following HPLC method applies to the following compounds:

Solvent A: water + 0.05% HCOOH

Solvent B: acetonitrile + 0.04% HCOOH

Flow: 2.0 ml / min

Gradient: 0.0 - 0.5 min 99% A

0.2-3.8 min at 100% B 3.8-4.4 min 100% B 4.4-5.0 min at 100% A

Column: Si-ROD ^® UM9423 / 100 3 mm

{2- [2- (1H-Benzoimidazol-2-yl) ethyl] -1,3,3,4-tetrahydrobenzo [b] [1,6] naphthyridin-10-yl} - [4- ( 2-hydroxy-ethyl) -piperazine-1-yl] -methanone ("B6", rt [min] 3.39)

[2- (1H-Benzoimidazol-2-ylmethyl) -1, 2,3,4-tetrahydrobenzo [b] [1,6] naphthyridin-10-yl] - [4- (2-hydroxy-ethyl) -piperazine-1-yl] -methanone ("B7", rt [min] 2.08)

N- (5-chlorobenzothiazol-7-yl) -2- {10- [4- (2-hydroxy-ethyl) -piperazine-1-carbonyl] -3,4-dihydro-1H-benzo [b] [1, 6] naphthyridin-2-yl} -acetamide ("B8", rt [min] 2,20)

Acetic acid 4-chloro-2- (2- {10- [4- (2-hydroxy-ethyl) -piperazine-1-carbonyl] -3,4-dihydro-1H-benzo [b] [1, 6] naphthyridin-2-yl} -acetylamino) benzyl ester ("B9", rt [min] 2.33)

N- (5-chloro-2-hydroxymethylphenyl) -2- {10- [4- (2-hydroxyethyl) piperazine-1-carbonyl] -3,4-dihydro-1H-benzo [b] [1, 6] naphthyridin-2-yl} -acetamide ("B10", rt [min] 2,20)

{2- [5- (5-Chloro-2-methoxy-phenyl) - [1, 2,4] oxadiazol-3-ylmethyl] -1, 2,3,4-tetrahydro-benzo [b] [1, 6 ] naphthyridin-10-yl} - [4- (2-hydroxy-ethyl) -piperazin-1-yl] -methanone ("B11", rt [min] 2.30)

2- {10- [4- (2-Hydroxyethyl) piperazine-1-carbonyl] -3,4-dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl} -N- phenyl-acetamide ("B12", rt [min] 2.04)

2- {10- [4- (2-Hydroxyethyl) piperazine-1-carbonyl] -3,4-dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl} -N- (2-trifluoromethylsulfanyl-phenyl) -acetamide ("BI 3", rt [min] 2.36)

{2- [2- (5-Chloro-2-methoxy-phenylamino) ethyl] -1,3,3,4-tetrahydrobenzo [b] [1,6] naphthyridin-10-yl} - [4- (2-hydroxy-ethyl) -piperazine-1-yl] -methanone ("B14", rt [min] 2.21)

[2- (6-chloro-1H-benzoimidazol-2-ylmethyl) -1, 2,3,4-tetrahydrobenzo [b] [1,6] naphthyridin-10-yl] - [4- (2- hydroxy-ethyl) -piperazine-1-yl] -methanone ("B15", rt [min] 2,12)

1 - (4-chloro-benzyl) -3- {2- [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl] -ethyl} -urea ("B16", rt [min] 2,37)

N- (5-chloro-2-methylsulfanylphenyl) -2- {10- [4- (2-hydroxyethyl) piperazine-1-carbonyl] -3,4-dihydro-1H-benzo [b] [1, 6] naphthyridin-2-yl} -acetamide ("B17", rt [min] 2.42)

[4- (2-Hydroxy-ethyl) -piperazin-1-yl] - [2- (5-methylamino- [1,4-oxadiazol-2-ylmethyl] -1, 2,3,4-tetrahydro- benzo [b] [1, 6] naphthyridin-10-yl] -methanoπ ("B18", rt [min] 2.03)

2- (4-chloro-3H-imidazo [4,5-c] pyridin-2-ylmethyl) -1,2,3,4-tetrahydrobenzo [b] [1,6] naphthyridine-10-carboxylic acid (1 -methylpiperidin-4-yl) amide ("B19", rt [min] 2 _: 02)

2- [5- (5-Chloro-2-methoxy-phenyl) - [1, 2,4] oxadiazol-3-ylmethyl] -1, 2,3,4-tetrahydro-benzo [b] [1, 6] naphthyridine-10-carboxylic acid (1-methylpiperidin-4-yl) -amide ("B20", rt [min] 2.35)

N-biphenyl-3-yl-2- {10- [4- (2-hydroxyethyl) piperazine-1-carbonyl] -3,4-dihydro-1H-benzo [b] [1,6] naphthyridine -2-yl} -acetamide ("B21", rt [min] 2.37)

2- [2- (5-Fluoro-2-methoxyphenyl) -1H-imidazol-4-ylmethyl] -1,2,3,4-tetrahydrobenzo [b] [1,6] naphthyridine-10 carboxylic acid (1-methylpiperidin-4-yl) -amide ("B25", rtfmin] 2.05)

2- (5-chlorobenzothiazol-2-ylmethyl) -1, 2,3,4-tetrahydrobenzo [b] [1,6] naphthyridine-10-carboxylic acid (1-methylpiperidin-4-yl) - amide

("B26", rtfmin] 2.35)

"B26" 2- [3- (5-Chloro-2-methoxy-phenyl) - [1, 2,4] oxadiazol-5-ylmethyl] -1, 2,3,4-tetrahydro-benzo [b] [1, 6] naphthyridine-10-carboxylic acid (1-methylpiperidin-4-yl) -amide ("B27", rt [min] 2.35)

2- (7-chloro-1H-benzoimidazol-2-ylmethyl) -1, 2,3,4-tetrahydrobenzo [b] [1,6] naphthyridine-10-carboxylic acid (1-methyl-4-piperidine) yl) amide ("B28", rt [min] 2,11)

2- [5- (5-Chloro-2-methoxy-phenyl) - [1,4-oxadiazol-2-ylmethyl] -1,2,3,4-tetrahydro-benzo [b] [1, 6] naphthyridine-10-carboxylic acid (2-dimethylaminoethyl) -amide ("B29", rt [min] 2.33)

"B29" [5- (5-Chloro-2-methoxy-phenyl) - [1,4-oxadiazol-2-ylmethyl] - [2- ({2- [5- (5-chloro-1-methoxy-phenoxy-fi .a. ^ oxadiazol ^ -ylmethylJ-1 ^ .S ^ -tetrahydrobenzo [b] [1,6] naphthyridine-10-carbonyl} -amino) -ethyl] -dimethylammonium ("B30", rt [min ] 2.57)

2- [5- (5-Chloro-2-methoxy-phenyl) - [1,4-oxadiazol-2-ylmethyl] -1,2,3,4-tetrahydro-benzo [b] [1, 6] Naphthyridine-10-carboxylic acid (2-methoxy-ethyl) amide ("B31", rt [min] 2.68)

2- [5- (5-Chloro-2-methoxy-phenyl) - [1,4-oxadiazol-2-ylmethyl] -1,2,3,4-tetrahydro-benzo [b] [1, 6] naphthyridine-10-carboxylic acid ethylamide ("B32", rt [min] 2.71)

2- [5- (5-Chloro-2-methoxy-phenyl) - [1,4-oxadiazol-2-ylmethyl] -1,2,3,4-tetrahydro-benzo [b] [1, 6] naphthyridine-10-carboxylic acid (1-methylpiperidin-4-yl) -amide ("B33", rt [min] 2.31)

2- {2- [N '- (5-chloro-2-methoxybenzoyl) hydrazino] -2-oxo-ethyl} -1, 2,3,4-tetrahydrobenzo [b] [1, 6] Naphthyridine-10-carboxylic acid (1-methylpiperidin-4-yl) -amide ("B34", rt [min] 2,10)

(2- {2- [5- (5-Chloro-2-methoxy-phenyl) - [1,4-oxadiazol-2-yl] -ethyl} -1, 2,3,4-tetrahydro-benzo [ b] [1,6-naphthyridin-10-yl) -morpholin-4-yl-methanone ("B36", rt [min] 2.51)

"B36" 2- [2- (2-Amino-5-chloro-phenylcarbamoyl) -ethyl] -1,3,3,4-tetrahydrobenzo [b] [1,6] naphthyridine-10-carboxylic acid (1-methyl-piperidine -4-yl) -amide ("B37", rt [min] 2.03)

2- [3- (5-chloro-2-methoxy-phenyl) -propionyl] -1,3,3,4-tetrahydrobenzo [b] [1,6] naphthyridine-10-carboxylic acid (1-methyl-piperidine -4-yl) -amide ("B38", rt [min] 2.42)

2- [5- (5-Chloro-2-methoxy-phenyl) - [1,4-oxadiazol-2-ylmethyl] -1,2,3,4-tetrahydro-benzo [b] [1, 6] naphthyridine-10-carboxylic acid amide ("B39", rt [min] 2.55)

2 - [(E) -3- (5-chloro-2-methoxy-phenyl) -acryloyl] -1,3,3,4-tetrahydrobenzo [b] [1,6] naphthyridine-10-carboxylic acid (1 -methyl-piperidin-4-yl) -amide ("B40", rt [min] 2.51)

10- (1-Methyl-piperidin-4-ylcarbamoyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridine-2-carboxylic acid 5-chloro-2-methoxy-benzyl ester ("B41 ", rt [min] 2.44)

"B41" 2 - [(5-chloro-2-methoxy-phenylcarbamoyl) -methyl] -1,3,3,4-tetrahydrobenzo [b] [1,6] naphthyridine-10-carboxylic acid (2-fluoro-ethyl) - amid ("B42", rt [min] 2.74)

2 - [(5-chloro-2-methoxy-phenylcarbamoyl) -methyl] -1, 2,3,4-tetrahydrobenzo [b] [1,6] naphthyridine-10-carboxylic acid (tetrahydro-pyran-4-yl ) amide ("B43, rt [min] 2.68)

2- [1- (5-chloro-2-methoxyphenyl) -2-oxopyrrolidin-3-ylmethyl] -1, 2,3,4-tetrahydrobenzo [b] [1,6] naphthyridine-10 -carboxylic acid (1-methylpiperidin-4-yl) -amide ("B44", rt [min] 2,14)

N- (5-Chloro-2-methoxy-phenyl) -2- [10- (4-dimethylamino-piperidine-1-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] -naphthyridine -2-yl] -acetamide ("B45", rt [min] 2.42)

2 - ((S) -7-chloro-2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl) -1,2,3,4-tetrahydrobenzo [b] [1,6] naphthyridine -10-carboxylic acid (1-methylpiperidin-4-yl) -amide ("B46", rt [min] 2.23)

2 - [(5-Chloro-2-methoxy-phenylcarbamoyl) -methyl] -1,3,3,4-tetrahydrobenzo [b] [1,6] naphthyridine-10-carboxylic acid (2-oxo-piperidine-3 -yl) -amide ("B47", rtfmin] 2.58)

2- (6-Chlorochroman-3-ylmethyl) -1, 2,3,4-tetrahydrobenzo [b] [1,6] naphthyridine-10-carboxylic acid (1-methylpiperidin-4-yl) - amid ("B48" rt [min] 2.23)

2- (6-chloro-2H-chromen-3-ylmethyl) -1, 2,3,4-tetrahydrobenzo [b] [1,6] naphthyridine-10-carboxylic acid (1-methylpiperidin-4-yl ) -amide ("B49", rt [min] 2.23)

2- (6,8-dichloro-2-oxo-2H-chromen-3-carbonyl) -1 _! 2 _! 3 _! 4-tetrahydrobenzo [b] [1, 6] naphthyridine-10-carboxylic acid (1-methylpiperidin-4-yl) -annide ("B50", rtfmin] 2.49)

1- (5-chloro-2-hydroxy-phenyl) -2- [10- (morpholine-4-carbonyl) -3,4-dihydro-1H-benzo [b] [1,6] naphthyridin-2-yl ] -ethanone ("B51", rt [min] 2.50)

"B51" [2- (2-chloropyridin-4-ylmethyl) -1, 2,3,4-tetrahydrobenzo [b] [1,6] naphthyridin-10-yl] morpholin-4-yl-methanone (" B52 ", rt [min]

1, 87)

2 - [(5-chloro-2-methoxy-phenylcarbamoyl) -methyl] -1,3,3,4-tetrahydrobenzo [b] [1,6] naphthyridine-10-carboxylic acid piperidin-3-ylamide ("B53 ", rt [min] 2.35)

2- [2- (5-Bromo-2-methoxyphenyl) -thiazol-4-ylmethyl] -1, 2 ₎ 3,4-tetrahydrobenzo [b] [1,6] naphthyridine-10-carboxylic acid (1 -methylpiperidin-4-yl) amide ("B54", rt [min] 2.31)

"B54" 2- [2- (5-Bromo-2-methoxy-phenyl) -thiazol-4-ylmethyl] -1,3,3,4-tetrahydrobenzo [b] [1,6] naphthyridine-10-carboxylic acid (1 -methyl-piperidin-4-yl) -amide ("B55", rtfmin] 2.56)

{2- [2- (5-chloro-2-methoxyphenyl) -pyridin-4-ylmethyl] -1, 2,3,4-tetrahydrobenzo [b] [1,6] naphthyridin-10-yl} -morpholin-4-yl-methanone ("B56", rt [min] 2.60)

2- (5,7-dichloro-8-hydroxy-quinolin-2-ylmethyl) -1, 2,3,4-tetrahydrobenzo [b] [1,6] naphthyridine-10-carboxylic acid (1-methyl-piperidine -4-yl) -amide ("B57", rt [min] 2.45)

Pharmacological data

Autotaxin Inhibition (Enzyme Test) Table 1

Table 2

IC50: <100 nM = A 100 nM-1 μM = B> 1 μM = C Example A: Autotaxi n Test (Enzyme Test)

test Description

The autotaxin activity is measured indirectly with the Amplex Red reagent. Here, Amplex Red is measured as a fluorogenic indicator for the resulting H2O2. In detail, autotaxine converts the substrate lysophosphatidylcholine (LPC) into phosphocholine and lysophosphatidic acid (LPS). After this reaction, the phosphocholine is activated with alkaline phosphatase to inorganic phosphate and choline. In the next step, choline is oxidized to betaine by choline oxidase to form H ₂ O ₂ . H ₂ O ₂ reacts in the presence of peroxidase (horseradish peroxidase) with the Amplex Red reagent in a 1: 1 stoichiometry and forms the highly fluorescent resorufin. The fluorescence is measured in a reaction-dependent kinetic mode so that fluorescent signals of possible other fluorescent substances that are not involved in the reaction can be corrected out.

Test execution 5 1, 5 μl of a standard solution or the test substances (substances with the name A (n)) dissolved in individual concentrations in 2OmM Hepes pH 7.2 with a maximum of 7.7% DMSO together with 10 ul (16 ng) highly purified recombinant autotaxin in a black 384Q wells are preincubated at 22 ° C for 30 min. Thereafter, the reaction is started by adding 5 μl of L-α-lysophosphatidylcholine (LPC), the final concentration of LPC being 75 μM. The mixture is 90 min. incubated at 37 ° C. After

Incubation is added to Amplex Red Reagent, Peroxidase (Horseradish5 peroxidase) and Choline Oxidase and fluorescence is immediately added 612 nm at 485 nm excitation in a "Tecan Ultra multimode" reader The activity of autotaxin is calculated indirectly by detecting the accumulating H ₂ O ₂ .

Material:

Microtiter plate: PS microplate, 384 wells, small volume, black Corning, Cat # 3677

Protein: Recombinant Autotaxin (Bacuioviral Hi5 Expression)

Substrate: L-α-lysophosphatidylcholine (chicken egg)); Avanti Polar Lipids # 830071 P

Standard: C14 LPA, Avanti Polar Lipids, Cat # 85712OP

Detection Reagent: Amplex Red Reagent; Invitrogen # A12222; dissolved in 1,923 ml of DMSO peroxidase type VI-A

(horseradish) from Sigma # P6782; dissolved in 7.45 ml assay buffer, choline oxidase; Sigma # C5896; dissolved in 2.47 ml of test buffer

Detection Reagent Mix: 1: 100 Dilution of Amplex Red Regeneration in

Test buffer

Test buffer: 200 mM Tris-HCl, Merck, Cat # 1.08219, pH 7.9,

0.1% BSA, lipid-free, Roche Cat # 775835

The following examples relate to drugs: Example B: Injection jars

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 2 l of bidistilled water with 2N hydrochloric acid, filtered sterile, filled into injection jars, lyophilized under sterile conditions and closed under sterile conditions. Each injection jar contains 5 mg of active ingredient.

Example e: 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 D: Solution

A solution is prepared from 1 g of an active compound of the formula I, 9.38 g

NaH ₂ PO ₄ ^• 2H ₂ O, 28.48 g Na ₂ HPO ₄ ^• 12H ₂ O and 0.1 g benzalkonium chloride in 940 ml double distilled water. Adjust to pH 6.8, make up to 1 liter and sterilize by irradiation. This solution can be in

Form of eye drops can be used.

Example E: ointment

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

A mixture of 1 kg of active ingredient of the formula I, 4 kg lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in the usual way to tablets, such that each tablet contains 10 mg of active ingredient.

Example G: 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 H: Capsules

2 kg of active ingredient 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 I: 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

Λ c in which

D Ar or Het ¹ ,

Het ^{1 is} a mono- or binuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S

20

Atoms that are unsubstituted or one, two or three times through

Hal, A, OA, Ar, OH and or = O may be substituted,

R ^{1 are} each independently H ₁ Hal, OA, OH, A, phenyl or

25 CN may be monosubstituted or polysubstituted,

Het ^{2 is} a mononuclear, saturated heterocycle with 1 - 3N- and / or

O atoms, which is unsubstituted or can be substituted once or twice by O _Q = 0,

R ⁴ each independently of one another H, Hal, OA, OH, A, may be monosubstituted or polysubstituted,

35 X, Y are each independently absent, -CH ₂ -, - (CH ₂ ) ₂ -, -CO- or

-CHOH-, where only one of the radicals X or Y may be absent,

R ² , R ^{3 are} each independently R; R ² and R ³ together also represent an alkyl chain having 2-6 C atoms, in which also a CH ₂ group may be replaced by O, NH or NA ¹ ,

A ¹ alkyl of 1 -6 C atoms, or CH ₂ CH ₂ OH, COO (CH ₂ ) _n Ar, (CH ₂ ) _n Ar, (CH ₂ ) _n Het ² , (CH ₂ ) _n NA ₂ or Cyc .

R i5 ° H, Hal, NH ₂ , OH, OA or A,

RH ₁ A, Cyc, (CH ₂ ) _n Ar or (CH ₂ ) _n Het may be monosubstituted or polysubstituted,

ZO, NH, -CH (CONHA) NH-, CH ₂ NHCONH, -CH = CH- or absent,

Cyc cyclic alkyl with 3-7 C atoms,

A linear or branched alkyl having 1-10 C atoms, in which 1-7 H-

Atoms can be replaced by OR, CN, NR ₂ , F and / or Cl and / or in which one or two non-adjacent CH ₂ groups are represented by O, NH, S, SO, SO ₂ and / or by CH = CH- Groups can be replaced, or cyclic alkyl having 3-7 C atoms,

Ar is unsubstituted or mono-, di-, tri-, tetra- or quintuple

Hal, A, (CR ₂ ) _n OR, O (CR ₂ ) _n Ar ² , (CR ₂ ) _n NR ₂ , SR, NO ₂ , CN, COOR, CONR ₂ , NRCOA, NRSO ₂ A, SO ₂ NR ₂ , S (O) _n A CO-Het, (CR ₂ ) _n Het, O (CR ₂ ) _n NR ₂ , O (CR ₂ ) _n Het, NHCOOA, NHCONR ₂ ,

NHCOO (CR ₂ ) _n NR ₂ , NHCOO (CR ₂ ) _n Het, CR = CRAr ² , SO ₂ Het, NHCONH (CR ₂ ) n NR ₂ , NHCONH (CR ₂ ) _n Het, OCONH (CR ₂ ) _n NR ₂ , CONH (CR ₂ ) _n Het, CONR (CR ₂ ) _n NR _2l CONR (CR ₂ ) _n Het and / or COA substituted phenyl, indanyl, naphthyl or biphenyl,

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 Hal, A, Ar ² , 0 (CR ₂ J _n Ar ² , (CR ₂ ) _n OR, (CR ₂ ) _n NR ₂₎ SR, NO ₂ , CN, COOR, CONR ₂ , NRCOA, NRSO ₂ A, SO ₂ NR ₂ , S (OJqA ₁ CO-Het ² ,

(CR ₂ ) _n Het ² , 0 (CR ₂ J _n NR ₂ , O (CR ₂ ) _n Het ² , NHCOOA, NHCONR ₂ , NHCOO (CR ₂ J _n NR ₂ , NHCOO (CR ₂ ) _n Het ² , NHCONH (CR ₂ J _n NR ₂ , NHCONH (CR ₂ ) _n Het ² , OCONH (CR ₂ J _n NR ₂ , OCONH (CR ₂ ) _n Het ² , CO-Het ² , CHO ₁ COA ₁ = S, = NH, = NA and / or = 0 can be substituted,

HaI F, Cl, Br or I,

n is 0, 1 or 2, m is O, 1, 2, 3, 4, or 5 p is 1, 2, 3, or 4

and their pharmaceutically acceptable salts and stereoisomers, including mixtures thereof in all proportions.

2. Compounds according to claim 1, wherein R ^{1 is} H ₁ Hal ₁ CN, phenyl, OA or OH, and their pharmaceutically acceptable salts and stereoisomers, including mixtures thereof in all proportions.

3. Compounds according to claim 1 or 2, wherein R ^{4 is} H ₁ Hal, A, OA or OH, and their pharmaceutically usable derivatives, solvates, 5

Tautomers, salts and stereoisomers, including theirs

Mixtures in all proportions.

4. Compounds according to one or more of claims 1-3, wherein 10 R ⁵ H and their pharmaceutically acceptable salts and stereoisomers, including mixtures thereof in all proportions.

_{1 5} 5. Compounds according to one or more of claims 1-4, wherein R ² , R ³ together morpholinyl, piperazinyl, 1-methyl-piperazinyl, 1-ethyl-4-methyl-piperazinyl, 2- (4-methyl-piperazine 1 -yl) -ethyl, 1-methyl-4-propyl-piperazinyl, 1-cyclopentyl-4-methyl-piperazinyl, 1-benzyl-4-methyl- [1,4] diazepanyl or 1-benzyl-4-methyl -piperazinyl, as well as their pharmaceutically acceptable salts and stereoisomers, including mixtures thereof in all proportions.

25 6. Compounds according to one or more of claims 1-5, wherein Het ¹ particularly preferably unsubstituted or mono-, di- or trisubstituted by A and / or (CH ₂ ) _n Ar substituted piperazyl, morpholinyl, piperidinyl, pyrrolidinyl, furanyl, Thienyl, pyrrolyl,

_O0 imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,

Pyridyl, pyrimidinyl, triazolyl, benzotriazinyl, benzofuranyl, 2,3-dihydro-benzoxazolyl, benzoxazolyl, dihydrobenzofuranyl or tetrazolyl.

35

7. Compounds according to one or more of claims 1-6, wherein Het ² particularly preferably unsubstituted or mono- or two by HaI, OH, OA ₁ A and / or = O substituted pyrrolidinyl, morpholinyl,

Piperidinyl or piperazinyl means. 5

8. Compounds according to one or more of claims 1-7, wherein

R ^{1 is} H, Hal, CN, phenyl, OA or OH; R ^{4 is} H, Hal, A, OA or OH; 10 R ⁵ H and

R ² , R ³ together are morpholinyl, piperazinyl, 1-methylpiperazinyl, 1-ethyl-4-methyl-piperazinyl, 2- (4-methylpiperazin-1-yl) -ethyl, 1-methyl-4 propyl-piperazinyl, 1-cyclopentyl-4-methyl- _{* 5-} piperazinyl, 1-benzyl-4-methyl- [1,4] diazepanyl or 1-benzyl-

4-methyl-piperazinyl,

Het ¹ particularly preferably unsubstituted or mono-, di- or trisubstituted by A and / or (CH ₂ ) _n Ar substituted piperazyl,

Morpholinyl, piperidinyl, pyrrolidinyl, furanyl, thienyl, pyrrolyl,

20

Imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl,

Isothiazolyl, pyridyl, pyrimidinyl, triazolyl, Benzotriazylyl, benzofuranyl, 2,3-dihydro-benzoxazolyl, Benzoxazolyl, dihydrobenzofuranyl or tetrazolyl, 25 Het ² particularly preferably unsubstituted or mono- or di- by Hal, OH, OA ₁ A and / or = O is substituted pyrrolidinyl, morpholinyl, piperidinyl or piperazinyl,

_OQ and their pharmaceutically acceptable salts and stereoisomers, including mixtures thereof in all ratios.

35

9. Compounds according to claim 1 selected from the group

and their pharmaceutically acceptable salts and stereoisomers, including mixtures thereof in all proportions.

10. A process for the preparation of compounds of formula I and their pharmaceutically acceptable salts, and stereoisomers, characterized in that a compound of the formula II

wherein R ² , R ³ , R ⁴ , R and p have the meanings given in claim 1, with a compound of formula III or formula IV

wherein

R ¹ , m, D, Z, X and Y have the meanings given in claim 1 and L is a halogen, tosylate, mesylate or triflate.

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

11. A pharmaceutical composition containing at least one compound of the formula I according to claim 1 to 9 and / or their pharmaceutically acceptable

Salts and stereoisomers, including mixtures thereof in all ratios, and optionally excipients and / or auxiliaries.

12. Use of compounds according to claim 1 to 9 and their pharmaceutically acceptable salts, solvates, tautomers and stereoisomers, including mixtures thereof in all proportions, for the manufacture of a medicament for the treatment of diseases in which the inhibition, regulation and / or

Modulation of phosphodiesterase or lysophospholipase autotaxin plays a role.

13. Use of compounds according to claim 1 to 9, to

Preparation of a medicament for the treatment and prophylaxis of

Cancer diseases.

14. Use according to claim 13, wherein the cancerous diseases with a tumor from the group of tumors of the squamous epithelium, the

Blisters, stomach, kidneys, head and neck, esophagus, cervix, thyroid, intestine, liver,

Brain, prostate, genitourinary tract, lymphatic system, stomach, larynx and / or lungs.

The use of claim 14, wherein the tumor is from the group of monocytic leukemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, ovarian carcinoma, glioblastoma and breast carcinoma and colon carcinoma.

Use according to claim 15, wherein the disease to be treated is a tumor of the blood and immune system.

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.

18. Use of compounds of the formula I according to claim 1 to 9 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 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

Inhibitor and 10) other angiogenesis inhibitors is administered.