KR20050026535A - Vegfr-2 and vegfr-3 inhibitory anthranylamidopyridines - Google Patents

Abstract

VEGFR-2 and VEGFR-3 inhibitory anthranylamidopyridinamides, the production and use thereof as medicaments for the treatment of diseases caused by persistent angiogenesis and intermediates for production of the compounds are disclosed. Said compounds can be used, for example, in tumour or metastasis growth, psoriasis, Kaposi's sarcoma, restenosis, such as for example, stent-induced restenoses, endometriosis, Crohn's disease, Hodgkin's disease, leukaemia, arthritis, such as rheumatoid arthritis, haemangioma, angiofibroma, eye disease, such as diabetic retinopathy, neovascular glaucoma, renal diseases, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombic microangiopathic syndrome, transplant rejection and glomerulopathy, fibrotic diseases, such as liver cirrhosis, mesangial cell proliferative diseases, artherosclerosis, injuries to nervous tissue and inhibition of the reocclusion of vessels after balloon catheter treatment, in vessel prosthetics, or after the application of mechanical devices to hold open vessels, such as for example, stents, as immune suppressants, as a support for scar-free wound healing, age spots and contact dermatitis. Said compounds may also be used as VEGFR-3 inhibitors in lymphangiogenesis.

Description

VEGFR-2 AND VEGFR-3 INHIBITORY ANTHRANYLAMIDOPYRIDINES}

The present invention relates to VEGFR-2 and VEGFR-3 inhibitory anthranylamide pyridine, their preparation and use as a medicament for the treatment of diseases caused by sustained angiogenesis, as well as intermediate products for the preparation of such compounds.

Sustained angiogenesis may include various diseases, such as tumor or metastatic growth, psoriasis; Arthritis such as rheumatoid arthritis, hemangioma, angiofibroma; Eye diseases such as diabetic retinopathy, neovascular glaucoma; Kidney disease such as glomerulonephritis, diabetic nephropathy, malignant neurosis, thrombotic microangiopathy syndrome, transplant rejection and glomerulopathy; Fibrosis diseases such as cirrhosis, mesangial cell proliferative diseases and atherosclerosis can be caused or presupposed, or worsen these diseases.

Persistent angiogenesis is induced through its receptor by factor VEGF. For VEGF to exert this action, it is necessary for VEGF to bind to its receptor and to induce tyrosine phosphorylation.

Direct or indirect inhibition of VEGF receptors (VEGF = Vascular Endothelial Growth Factor) can be used to treat such diseases and other VEGF-induced pathological angiogenesis and vascular permeation conditions, such as tumor angiogenesis. For example, it is known that tumor growth can be inhibited by soluble receptors and antibodies to VEGF.

psoriasis; Arthritis such as rheumatoid arthritis, hemangioma, angiofibroma; Eye diseases such as diabetic retinopathy, neovascular glaucoma; Kidney disease such as glomerulonephritis, diabetic nephropathy, malignant neurosis, thrombotic microangiopathy syndrome, transplant rejection and glomerulopathy; Mechanical devices for treating fibrotic diseases such as liver cirrhosis, mesangium cell proliferative disease, arteriosclerosis, nerve tissue damage, and after vascular balloon catheter treatment, in vascular prosthetics or for keeping blood vessels open, Anthranylamide pyridones, for example used as agents for inhibiting reocclusion after the use of stents, are known from WO 00/27820 (eg Example 38).

Compounds known from WO 00/27820 are generally valid for the above-mentioned indications, but their effectiveness is not clear.

In addition, anthranilic acid amides that are not only very effective but also have a good inhibitory activity of cytochrome P 450 isoenzyme 3A4 are known from WO 00/27819 (Example 2.54). Cytochrome P 450 isoenzyme 3A4 is one of the metabolic enzymes essential for the breakdown of drugs. Inhibition of this isoenzyme leads to undesirable drug interactions, especially in multi-patient patients (patients with multiple disease states). In addition, in combination therapies with other dosages, there is also a problem of increased toxicity resulting from inhibition of compound degradation and associated excessive serum levels.

There is therefore a need for active ingredients that are effective on the one hand and more compatible on the other or that do not exhibit any undesirable side effects.

There is therefore a need for compounds that are effective on the one hand and more compatible on the other.

The present inventors have now discovered compounds of the formula (I) which exhibit improved properties, ie high efficacy and at the same time lower CYP450 3A4 inhibition, and isomers, diastereomers, tautomers and salts thereof.

In the above formula,

X represents CH or N,

W represents hydrogen or fluorine,

A, B, D, E and Q each independently represent a nitrogen or carbon atom, where at most two nitrogen atoms can be present in the ring,

R ¹ is halogen, hydroxy, C ₁ -C ₁₂ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -alkenyl, C ₂ -C ₆ in the same way or differently at one or more positions -Alkynyl, aralkyloxy, C ₁ -C ₁₂ -alkoxy, halo-C ₁ -C ₆ -alkyl, cyano-C ₁ -C ₆ -alkyl, or a group ═O, —SO ₂ R ⁶ or —OR ⁵ (wherein, C ₁ -C ₆ - alkyl group is also -OR ⁵ or -NR ⁹ R ¹⁰ may be optionally substituted with a) optionally with aryl or heteroaryl which may be substituted,

Y and Z each independently represent a bond or group = CO, = CS or = SO ₂ ,

R ² and R ³ independently of one another are hydrogen or the group -CONR ⁹ R ¹⁰ , -SO ² R ⁶ , -COR ¹¹ , -COC ₁ -C ₆ -alkyl, -CO-C ₁ -C ₆ -alkyl-R ¹¹ , -NR ⁹ R ¹⁰ , or the same way or differently at one or more positions, halogen, cyano, C ₁ -C ₁₂ -alkyl, C ₁ -C ₁₂ -alkoxy, hydroxy-C ₁ -C ₆ -alkyl , Halo-C ₁ -C ₆ -alkyl, or optionally a group -NR ⁷ R ⁸ , -OR ⁵ , -C ₁ -C ₆ -alkyl-OR ⁵ , -SR ⁴ , -SOR ⁴ or -SO ₂ R ⁶ Substituted with C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cycloalkyl, C ₃ -C ₆ -cycloalkenyl, aryl or heteroaryl; or

R ² , R ³ , Y and Z, together with the nitrogen atom, may optionally contain additional heteroatoms in the ring and are halogen, cyano, C ₁ -C ₁₂ -alkyl in the same way or differently at one or more positions , C ₁ -C ₁₂ -alkoxy, halo-C ₁ -C ₆ -alkyl, hydroxy-C ₁ -C ₆ -alkyl, or a group = 0, -OR ⁵ , -SR ⁴ , -SOR ⁴ or -SO ₂ To form a 3- to 8-membered saturated or unsaturated ring which may be optionally substituted with R ⁶ ,

R ⁴ represents C ₁ -C ₁₂ -alkyl, aryl or heteroaryl,

R ⁵ is hydrogen, C ₁ -C ₁₂ -alkyl, C ₃ -C ₁₀ -cycloalkyl, C ₁ -C ₁₂ -alkoxy, halo-C ₁ -C ₁₂ -alkyl or halo-C ₃ -C ₆ -cycloalkyl Indicates,

R ⁶ represents hydrogen, C ₁ -C ₁₂ -alkyl, halo-C ₁ -C ₁₂ -alkyl, aryl or heteroaryl, or a group —NR ⁹ R ¹⁰ , wherein aryl or heteroaryl is itself at least one position In the same way or differently at C ₁ -C ₁₂ -alkyl, C ₁ -C ₆ -alkoxy, halogen or halo-C ₁ -C ₆ -alkoxy,

R ⁷ and R ⁸ independently of one another represent hydrogen or C ₁ -C ₁₂ -alkyl,

R ⁹ and R ¹⁰ independently of one another are hydrogen, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, aryl, C ₃ -C ₈ -cycloalkyl, or a group -CONR ⁷ R ⁸ , or one or more Aryl, morpholino, hydroxy, halogen, C ₁ -C ₁₂ -alkoxy, or a group —NR ⁷ R ⁸ in the same way or differently at the position wherein aryl is by itself the same way at one or more positions or differently C ₁ -C ₆ - alkoxy or halo -C ₁ -C ₆ -, optionally in the optionally may be substituted), an alkyl-substituted C ₁ -C ₁₂ -, or represent alkyl, or

R ⁹ and R ¹⁰ together form a 5 to 8 membered ring which may contain additional heteroatoms,

R ¹¹ is C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxy-C ₁ -C ₆ -alkyl, hydroxy-C ₁ -C ₆ -alkoxy, C ₃ -C ₆ -cycloalkyl, Phenyl, pyridyl, biphenyl, or naphthyl, wherein phenyl may itself be substituted by C ₁ -C ₆ -alkyl or halo-C ₁ -C ₆ -alkyl in the same way or differently at one or more positions. have.

It is noted that the compounds according to the invention inhibit the growth and proliferation of tumors by preventing tyrosine phosphorylation or by stopping persistent angiogenesis, which in particular are less inhibited by the isoforms of Cytochrome P 450 (3A4).

Dosing with the compounds according to the invention can therefore even be carried out without any risk, irrespective of the agents which are co-administered and resolved through these isoforms.

Alkyl is a straight or branched alkyl radical, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl or hectyl, heptyl, octyl, nonyl, decyl, undecyl, or Defined as dodecyl.

Alkoxy is a straight or branched alkoxy radical, for example methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hectyloxy, heptyloxy , Octyloxy, nonyloxy, decyloxy, undecyloxy or dodecyloxy.

Cycloalkyl is a monocyclic alkyl ring, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohetyl, or cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, as well as bicyclic rings or tricyclic rings, for example For example adamantanyl.

Cycloalkyl radicals may contain one or more heteroatoms, such as oxygen, sulfur and / or nitrogen, instead of carbon atoms. Preference is given to heterocycloalkyls having 3 to 8 ring atoms.

Cycloalkenyl is defined as cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl or cyclodecenyl, where the bond can be both a double bond and a single bond, respectively. .

Halogen is defined as fluorine, chlorine, bromine or iodine, respectively.

Halo-alkyl, halo-alkoxy and the like are defined as alkyl, alkoxy and the like substituted at the one or more positions in the same way or differently with halogen.

Alkenyl is defined as straight or branched alkenyl radicals each containing 2-6, preferably 4-6 C atoms. For example, the following radicals: vinyl, propen-1-yl, propen-2-yl, but-1-en-1-yl, but-1-en-2-yl, but-2-ene- 1-yl, but-2-en-2-yl, 2-methyl-prop-2-en-1-yl, 2-methyl-prop-1-en-1-yl, but-1-ene- 3-yl, but-3-en-1-yl and allyl may be mentioned.

The aryl radicals each contain 3-12 carbon atoms and can each be benzo-condensed.

For example, cyclopropenyl, cyclopentadienyl, phenyl, trophyll, cyclooctadienyl, indenyl, naphthyl, azulenyl, biphenyl, fluorenyl, anthracenyl and the like can be mentioned.

Heteroaryl radicals each contain 3-16 ring atoms and, instead of carbon, may contain one or more heteroatoms, identical or different, for example oxygen, nitrogen or sulfur in the ring and are monocyclic, bicyclic , Or tricyclic, and can each be benzo-condensed.

For example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thidiazolyl and the like and benzo derivatives thereof, For example, benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, indazolyl, indolyl, isoindoleyl and the like; Or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like and benzo derivatives thereof such as quinolyl, isoquinolyl and the like; Or azosinyl, indolinyl, furinyl, and the like and benzo derivatives thereof; Or quinolinyl, isoquinolinyl, cinnaolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pterridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenazinyl Noxazinyl, xanthenyl or oxepinyl and the like can be mentioned.

Heteroaryl radicals may each be benzo-condensed. For example, as 5-ring heteroaromatic compounds, thiophene, furan, oxazole, thiazole, imidazole, pyrazole and their benzo derivatives, and as 6-ring heteroaromatic compounds, pyridine, pyrimidine, triazine, Quinolines, isoquinolines and benzo derivatives may be mentioned.

Heteroatoms are defined as oxygen, nitrogen or sulfur atoms.

In the meaning of R ^2, R ^3, Y and Z, source 3 to 8-membered ring formed with the nitrogen atom to hamkkae is C ₃ -C ₈ - is defined as heteroaryl-heteroalkyl and cycloalkyl C ₃ -C _8.

When acidic groups are included, physiologically compatible salts of organic and inorganic salts are salts, for example easily soluble alkaline and alkaline earth salts, as well as N-methyl-glucamine, dimethyl-glucamine, ethyl-glu Carmine, lysine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, cerinol, tris-hydroxy-methyl-amino-methane, aminopropanediol, Sovak base, and 1-amino-2 It is suitable as, 3,4-butanetriol.

Where basic groups are included, physiologically compatible salts of organic and inorganic acids are suitable (eg hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, fumaric acid).

The compounds of the formula (I) according to the invention also contain possible tautomeric forms and include racemates and enantiomers, in the presence of E- or Z-isomers, or chiral centers.

X represents CH,

W represents hydrogen,

A, B, D, E and Q together represent a pyridyl as a ring,

R ¹ is halogen, hydroxy, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₄ -C ₆ -alkenyl, C ₂ -C ₆ -in the same way or differently at one or more positions; Alkynyl, aralkyloxy, C ₁ -C ₆ -alkoxy, halo-C ₁ -C ₆ -alkyl, cyano-C ₁ -C ₆ -alkyl, or a group ═O, —SO ₂ R ⁶ Or -OR ⁵ (wherein, C ₁ -C ₆ - alkyl group is also -OR ⁵ or -NR ⁹ R ¹⁰ may be optionally substituted with a) optionally with aryl or heteroaryl which may be substituted,

Y and Z each independently represent a bond,

R ² and R ³ independently of one another are hydrogen or the group -CONR ⁹ R ¹⁰ , -SO ₂ R ⁶ , -COR ¹¹ , -COC ₁ -C ₆ -alkyl, -CO-C ₁ -C ₆ -alkyl-R ¹¹ , -NR ⁹ R ¹⁰ , or halogen, cyano, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxy-C ₁ -C ₆ -alkyl, in the same manner or differently at one or more positions; Optionally substituted with halo-C ₁ -C ₆ -alkyl or group -NR ⁷ R ⁸ , -OR ⁵ , -C ₁ -C ₆ -alkyl-OR ⁵ , -SR ⁴ , -SOR ⁴ or -SO ₂ R ⁶ a C ₁ -C ₆ - alkyl, C ₃ -C ₆ - cycloalkyl, C ₃ -C ₆ - cycloalkenyl, or represent aryl or heteroaryl, or

R ² , R ³ , Y and Z, together with the nitrogen atom, may optionally contain additional heteroatoms in the ring and are halogen, cyano, C ₁ -C ₁₂ -alkyl in the same way or differently at one or more positions , C ₁ -C ₁₂ -alkoxy, halo-C ₁ -C ₆ -alkyl, hydroxy-C ₁ -C ₆ -alkyl or group = 0, -OR ⁵ , -SR ⁴ , -SOR ⁴ or -SO ₂ R To form a 3- to 8-membered saturated or unsaturated ring which may be optionally substituted by ⁶ ,

R ⁴ represents C ₁ -C ₆ -alkyl, aryl or heteroaryl,

R ⁵ is hydrogen, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, C ₁ -C ₁₂ -alkoxy, C ₃ -C ₁₀ -cycloalkyl or halo-C ₃ -C ₆ -cycloalkyl Indicates,

R ⁶ is hydrogen, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, aryl or heteroaryl, or a group —NR ⁹ R ¹⁰ , wherein aryl or heteroaryl is optionally one as such In the same manner or differently at the above positions or may be substituted with C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen or halo-C ₁ -C ₆ -alkoxy),

R ⁷ and R ⁸ independently of one another represent hydrogen or C ₁ -C ₆ -alkyl,

R ⁹ and R ¹⁰ independently of one another are hydrogen, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, aryl, C ₃ -C ₈ -cycloalkyl, or a group -CONR ⁷ R ⁸ , or one or more Aryl, morpholino, hydroxy, halogen or C ₁ -C ₁₂ -alkoxy, or a group —NR ⁷ R ⁸ , wherein aryl is optionally the same in any one or more positions or differently C ₁ -C ₆ - alkoxy or halo -C ₁ -C ₆ -, optionally substituted with may be substituted), with alkyl C ₁ -C ₆ - represents alkyl,

R ¹¹ is C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxy-C ₁ -C ₆ -alkyl, hydroxy-C ₁ -C ₆ -alkoxy, C ₃ -C ₆ -cycloalkyl, Phenyl, pyridyl, biphenyl or naphthyl, wherein phenyl may itself be substituted by C ₁ -C ₆ -alkyl or halo-C ₁ -C ₆ -alkyl in the same way or differently at one or more positions Compounds of formula (I) and their isomers, diastereomers, tautomers and salts thereof, have proven to be advantageous.

X represents CH,

W represents hydrogen,

A, B, D, E and Q together represent a pyridyl as a ring,

R ¹ is optionally halogen or hydroxy, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkynyl, C ₁ -C ₆ -alkoxy, halo-C ₁ − in the same way or differently at one or more positions; May be substituted with C ₆ -alkyl or cyano-C ₁ -C ₆ -alkyl, wherein C ₁ -C ₆ -alkyl may also be optionally substituted with the group —OR ⁵ or —NR ⁹ R ¹⁰ . Phenyl, quinolinyl, isoquinolinyl or indazolyl,

Y and Z each independently represent a bond or a group = CO,

R ² and R ³ independently of one another are hydrogen or the group -CONR ⁹ R ¹⁰ , -SO ₂ R ⁶ , -COR ¹¹ , -COC ₁ -C ₆ -alkyl, -CO-C ₁ -C ₆ -alkyl-R ¹¹ Or —NR ⁹ R ¹⁰ , or C ₁ -C ₆ -alkyl or phenyl optionally substituted in the same way or differently at one or more positions with the group —NR ⁷ R ⁸ or —OR ⁵ , or

R ² , R ^3, Y and Z, together with the nitrogen atom, may optionally contain further heteroatoms in the ring and in the same way or differently at one or more positions halogen, cyano, C ₁ -C ₁₂ -alkyl , C ₁ -C ₁₂ -alkoxy, halo-C ₁ -C ₆ -alkyl, hydroxy-C ₁ -C ₆ -alkyl or group = 0, -OR ⁵ , -SR ⁴ , -SOR ⁴ or -SO ₂ R To form a 3- to 8-membered saturated or unsaturated ring which may be optionally substituted by ⁶ ,

R ⁵ represents hydrogen or C ₁ -C ₆ -alkyl,

R ⁶ is hydrogen, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, phenyl, benzyl, thiophenyl or pyridyl, wherein phenyl, benzyl, thiophenyl and pyridyl are themselves one or more In the same way or differently at the position may be optionally substituted with C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen or halo-C ₁ -C ₆ -alkoxy),

R ⁷ and R ⁸ independently of one another represent hydrogen or C ₁ -C ₆ -alkyl,

R ⁹ and R ¹⁰ independently of one another are hydrogen, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, phenyl, biphenyl, C ₃ -C ₈ -cycloalkyl, naphthyl or group -CONR ⁷ R ⁸ , or in the same way or differently at one or more positions phenyl, morpholino, hydroxy, halogen, C ₁ -C ₁₂ -alkoxy, or a group —NR ⁷ R ⁸ wherein phenyl is itself at least one position in the same manner as or different from C ₁ -C ₆ - alkoxy or halo -C ₁ -C _6- - represents alkyl, - an optionally may be substituted), optionally substituted by C ₁ -C ₆ alkyl

R ¹¹ is C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxy-C ₁ -C ₆ -alkyl, hydroxy-C ₁ -C ₆ -alkoxy, C ₃ -C ₆ -cycloalkyl, Phenyl, pyridyl, biphenyl or naphthyl, wherein phenyl may itself be substituted by C ₁ -C ₆ -alkyl or halo-C ₁ -C ₆ -alkyl in the same way or differently at one or more positions Of particular interest are the compounds of formula (I) and their isomers, diastereomers, tautomers and salts thereof.

The compounds according to the invention, as well as their physiologically compatible salts, inhibit the growth and proliferation of tumors by preventing tyrosine phosphorylation or by stopping sustained angiogenesis, which in particular are compatible with isoforms of cytochrome P 450 (3A4). It is noticeable that less is suppressed. Dosing with the compounds according to the invention can therefore even be carried out without any risk, irrespective of the agents which are co-administered and resolved through these isoforms.

Compounds of formula (I) as well as their physiologically compatible salts can be used as medicaments based on their inhibitory activity on phosphorylation of VEGF receptors. Based on their action profile, the compounds according to the invention are suitable for treating diseases caused by or promoted by sustained angiogenesis.

Since compounds of formula (I) have been found as inhibitors of tyrosine kinase KDR and FLT, they are particularly useful in treating diseases caused or promoted by sustained angiogenesis caused by VEGF receptors or by an increase in vascular permeability. Suitable.

The object of the present invention is also the use of the compounds according to the invention as inhibitors of tyrosine kinase KDR and FLT.

The object of the present invention is therefore also a medicament for their treatment or their use.

The compounds according to the invention can be used for tumor or metastatic growth, psoriasis, Kaposi's sarcoma, restenosis, for example stent-induced restenosis, endometriosis, Crohn's disease, Hodgkin's disease, leukemia; Arthritis such as rheumatoid arthritis, hemangioma, angiofibroma; Eye diseases such as diabetic retinopathy, neovascular glaucoma; Kidney disease such as glomerulonephritis, diabetic nephropathy, malignant neurosis, thrombotic microangiopathy syndrome, transplant rejection and glomerulopathy; Mechanical devices such as stents for the treatment of fibrotic diseases such as cirrhosis, mesangial cell proliferative disease, atherosclerosis, nerve tissue damage, and after vascular balloon catheter treatment, to maintain vascular will or to keep blood vessels open Can be used alone or in preparation for reclosure inhibition, as an immunosuppressive agent, for supporting scar healing, in senile keratosis and as a medicament in contact dermatitis.

In treating nerve tissue damage, rapid scar formation at the site of injury can be prevented with the compounds according to the invention, ie, scar formation is prevented from occurring before axon reconnection. Therefore, the reconstruction of the nerve compound is facilitated.

The compounds according to the invention can also be used to inhibit the formation of ascites in a patient. VEGF-induced edema can also be inhibited.

Lymphangiogenesis plays an important role in lymphoid metastasis (Karpanen, T. et al., Cancere Res. 2001 Mar 1, 61 (5): 1786-90, Veikkola, T., et al., EMBO J. 2001 , Mar 15; 20 (6): 1223-31).

In addition, the compounds according to the present invention are also suitable as effective inhibitors of lymphangiogenesis because of their excellent function as VEGFR kinase 3 inhibitors.

By treatment with the compounds according to the invention, not only the reduction in metastases size but also the number of metastases is achieved.

Such agents, their formulations and uses are also an object of the present invention.

The invention therefore also relates to compounds of formula (I), tumor or metastatic growth, psoriasis, Kaposi's sarcoma, restenosis, eg stent-induced restenosis, endometriosis, Crohn's disease, Hodgkin's disease, leukemia; Arthritis such as rheumatoid arthritis, hemangioma, angiofibroma; Eye diseases such as diabetic retinopathy, neovascular glaucoma; Kidney disease such as glomerulonephritis, diabetic nephropathy, malignant neurosis, thrombotic microangiopathy syndrome, transplant rejection and glomerulopathy; For the treatment of fibrotic diseases such as cirrhosis, mesangial cell proliferative disease, arteriosclerosis, nerve tissue damage, and after vascular balloon catheter treatment, mechanical devices for maintaining vascular will or for keeping blood vessels open, for example It relates to the use of the preparation of a medicament for use in senile keratosis and for contact dermatitis, as an immunosuppressive agent, as an immunosuppressive agent after use of a stent, as a support for scar healing.

The compounds according to the invention can also be used to inhibit the formation of ascites in a patient. VEGF-induced edema can also be inhibited.

For the use of the compounds of formula (I) as medicaments, they are made in the form of pharmaceutical preparations, in which they, in addition to the active ingredient for enteral or parenteral administration, are suitable drugs, organic or inorganic inert carrier substances, for example water, gelatin, Guar gum, lactose, starch, magnesium stearate, talc, vegetable oil, polyalkylene glycol and the like. Pharmaceutical formulations may be present in solid form, such as tablets, coated tablets, suppositories, or capsules, or in liquid form, such as solutions, suspensions or emulsions. They also optionally contain an adjuvant such as preservatives, stabilizers, wetting agents or emulsifiers, salts or buffers for changing the osmotic pressure.

For parenteral administration, especially aqueous solutions of the active compounds in injection solutions or suspensions, in particular polyhydroxyethoxylated castor oil, are suitable.

As the carrier system, surface active adjuvant such as salts of bile acids or animal or plant phospholipids, as well as mixtures thereof, as well as liposomes or their components can also be used.

For oral administration, in particular tablets, coated tablets or talc and / or capsules with hydrocarbon vehicles or binders such as, for example, lactose, corn starch or potato starch are suitable. Administration may also be carried out in liquid form, for example, optionally as a sweetener or juice with one or more flavoring agents added.

Dosages of the active ingredient may vary depending on the method of administration, the age and weight of the patient, the type and depth of the disease to be treated and similar factors. The daily dose is 0.5-1000 mg, preferably 50-200 mg, wherein the dose may consist of a single dose administered once or the daily dose may be divided into two or more times.

Such formulations and dosage forms also correspond to the object of the present invention.

The preparation of the compounds according to the invention is carried out according to methods known in the art. For example, a compound of formula (I) is obtained by first converting a compound of formula (II) to an amine and then acylating or substituting M with an NHCOR group.

In the formula, A, B, D, E, Q, W, X and R ¹ have the meaning described in the formula (I),

M represents halogen.

The compounds of formula (I) can also be prepared by first converting a compound of formula (IIa) to an amide and then replacing the leaving group with an N (YR ² ) -R ³ group, or by first saponifying a compound of formula (III) and then to an amide Obtained.

Wherein R ^y represents C ₁ -C ₆ -alkyl or hydrogen, and FG means a leaving group such as halogen, O-triplate, O-mesylate, O-tosylate or sulfone.

In said formula, R <^2> , R ³ , Y and Z have the meanings described in formula I and R ^y represents C ₁ -C ₆ -alkyl or hydrogen.

Amide formation is carried out according to methods known in the literature.

For amide formation, it is possible to start from the corresponding ester. Such esters are described in J. Chem. Org. Chem. 1995, 8414, and reacts with aluminum trimethyl and the corresponding amine in a solvent such as toluene at a temperature between 0 ° C. and the boiling point of the solvent. If the molecule contains two ester groups, both are converted to the same amide. Instead of aluminum trimethyl, sodium hexamethyldisilazide may be used.

However, for amide formation, all processes known from peptide chemistry are also available. For example, the corresponding acid is obtained using an amine in an aprotic polar solvent, for example dimethylformamide, for example, hydroxybenzotriazole and carbodiimide, for example diisopropylcarbodiimide. Via activated acid derivatives, which can be reacted at a temperature of 0 ° C. to the boiling point of the solvent, preferably 80 ° C. However, the reactants between carboxylic acids and amines can also be used as active reagents, for example HATU (N-dimethylamino-1H-1,2,3-triazolo- [4,5-b] pyridin-1-ylmethylene] -N -Methylmethanealuminum hexafluorophosphate-N-oxide), wherein a polar aprotic solvent, for example dimethylformamide, is suitable for the reaction. It is necessary to add a base, for example N-methylmorpholine. The reaction proceeds at a temperature of 0-100 ° C. and this procedure is preferably carried out at room temperature, but in many cases heating is inevitable. For amide formation, processes with acid halides, mixed acid anhydrides, imidazolides or azides may also be used. For example, prior protection of additional amino groups as amides is not necessary in all cases, but may have a beneficial effect on the reaction.

In the case of bisacid chloride, cyclic compounds can be prepared. Also, in the case of halogen acid halides, cyclic compounds can be prepared. The ring closure is then completed by optionally adding a base such as sodium alcoholate. This is also valid for sulfonic acid halides, where double sulfonation may also occur.

Ureas are prepared by reaction of amino compounds with isocyanates. Inert solvents such as methylene chloride or dimethylformamide are present at a temperature from room temperature up to 100 ° C., preferably at 60 ° C. Pressure is advantageous for the reaction.

The reaction of halopyridine with an amide is carried out by catalysis, for example palladium or under copper catalysis. In the case of copper catalysis (see Synlett. 2002, 427), a solvent, for example dioxane or dimethylformamide, is used at a temperature below the boiling point of the solvent, preferably at 120 ° C. As the base, potassium phosphate or cesium carbonate is used. Ethylenediamine is advantageous for complexing copper (I) iodide used as a catalyst. The use of pressure is not harmful. For palladium catalysis, palladium (II) salts such as palladium (II) acetate, and palladium (O) complexes such as palladium (O) ₂ dibenzylidene acetone ₃ (JACS 2002, 6043, THL 1999, 2035, Org. Lett 2001, 2539, THL 2001, 4381 or THL 2001, 3681). As the solvent, toluene, dioxane or dimethylformamide are used at room temperature below the boiling point of the solvent, preferably near 100 ° C. As co-ligands, BINAP, DPPF or Xanthphos are used. It also requires a base. For this purpose cesium carbonate, potassium phosphate or sodium t-butylate is used. These components can be combined in various ways.

The preparation of pyridineamine from the corresponding 2-halopyridine is carried out at temperatures up to 200 ° C. in a solvent such as pyridine or a protic polar solvent such as ethylene glycol. Catalysis by the copper (I) salt may be necessary for the reaction. Application of pressure is necessary for the reaction of low boiling amines, but it may also be advantageous to use in conventional amines.

The ether segment is carried out according to known methods, for example by reaction with boron tribromide at a temperature of -78 ° C to room temperature, preferably -78 ° C, in an inert solvent such as methylene chloride.

The following compounds of formulas (II), (IIa) and (III) provide intermediate products which are effective for the preparation of compounds of formula (I) according to the invention and thus also serve the purpose of the invention.

<Formula II>

<Formula IIa>

<Formula III>

Wherein A, B, D, E, Q, W, X, Y, Z, R ² and R ³ have the meanings described in formula (I), M represents halogen, and FG represents a leaving group, e.g. Halogen, O-triplate, O-mesylate, O-tosylate or sulfone, and R ^Y represents C ₁ -C ₆ -alkyl or hydrogen.

Preparation of the compounds according to the invention

The following examples illustrate the preparation of compounds according to the invention and the scope of the claimed compounds is not limited by these examples.

Example 1.0

2-{[2- (2-Dimethylamino-ethylamino) -pyridin-4-ylmethyl] -amino}- N Preparation of-(3-trifluoromethyl-phenyl) -benzamide

90 mg (0.2 mmol) of 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide are dissolved in 3 ml of pyridine and 1 ml of N, N-dimethyl-aminoethylamine was mixed and heated to a bath temperature of 200 ° C. for 5 hours in a pressure vessel. After cooling, concentrated by evaporation, the second 90 mg - {[2- (2- dimethylamino-ethylamino) -pyridin-4-ylmethyl] -amino} - N - (3- trifluoromethyl-phenyl ) -Benzamide was obtained.

Melting point: 100 ℃

In addition, the following compounds were prepared analogously.

Example 2.0

2-[(2-amino-pyridin-4-ylmethyl) -amino]- N Preparation of-(3-trifluoromethyl-phenyl) -benzamide

8.747 g of 2 (19.4 mmol) - [(2- bromo-pyridin-4-ylmethyl) -amino] - N - (3- trifluoromethyl-phenyl) - 175 of the benzamide in 150 ml ethanediol It was heated to 80 ° C. in an autoclave under ammonia pressure of 10 bar for 23 h with mg copper oxide (I). After distilling off the solvent in vacuo, the residue was purified on silica gel using a gradient of ethyl acetate: ethanol = 100: 0 to 0: 100 as eluent. 4.15 g (51% of theory) of 2-[(2-amino-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide having a melting point of 64 ° C. Got it.

The following was prepared analogously.

Example 2.1

2-[(2-amino-pyridin-4-ylmethyl) -amino]- N Isoquinolin-3-yl-benzamide

Melting Point: 202 ℃

Example 2.2

2-[(2-amino-pyridin-4-ylmethyl) -amino]- N -(One H -Indazol-5-yl) -benzamide

MS: m / e 358

Melting point: 200 ℃

Example 2.3

2-[(2-amino-pyridin-4-ylmethyl) -amino]- N -(2-methyl-2 H -Indazol-6-yl) -benzamide

MW: 372.43

Example 3.0

2-{[2- (3-benzyl-ureido) -pyridin-4-ylmethyl] -amino}- N Preparation of-(3-trifluoromethyl-phenyl) -benzamide

37.9 mg of 100 mg (0.26 mmol) of 2-[(2-amino-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide in 2.5 ml of methylene chloride (0.29 mmol) with benzyl isocyanate, which was stirred overnight at room temperature. After concentration by evaporation, the residue was chromatographed. 2, having a melting point of 153 ℃ 66 mg (49% of theory) - {[2- (3-benzyl-ureido) -pyridin-4-ylmethyl] -amino} - N - (3-trifluoromethyl- Phenyl) -benzamide was obtained.

In addition, the following compounds were prepared analogously.

Examples 3.15 and 3.29 were prepared analogously to Example 3.0 using trimethylsilyl isocyanate.

Example 3.30

2-{[2- (3,3-Dimethyl-ureido) -pyridin-4-ylmethyl] -amino}- N Preparation of-(3-isoquinolinyl) -benzamide

2 of 100 mg (0.23 mmol) - [ (2- bromo-pyridin-4-ylmethyl) -amino] - N - (3- isoquinolinyl) - benzamide in 89 ml of dioxane of 2 mg (0.28 mmol) cesium carbonate, 61 mg (0.69 mmol) N, N-dimethylurea, 4.7 mg (0.0046 mmol) dipaladium-tribenzylidene acetone and 7.9 mg (0.014 mmol) xanthphos, under protective gas And a bath temperature of 100 ° C. for 9 hours in a humid environment. Then it was mixed with 20 ml of methylene chloride, incorporated and concentrated by evaporation. The residue was chromatographed on silica gel using ethyl acetate as eluent. 24 mg (24% of theory) 2-{[2- (3,3-dimethyl-ureido) -pyridin-4-yl-methyl] -amino} -N- (3-isoquinolinyl) -benz An amide was obtained.

(MS (CI): 441 (M ⁺ + H))

In addition, the following compounds were prepared analogously.

Example 4.0

2-[(2-methanesulfonylamino-pyridin-4-ylmethyl) -amino]- N Preparation of-(3-trifluoromethyl-phenyl) -benzamide

90 mg (0.2 mmol) of 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide and 23 mg (0.24 mmol) Methanesulfonic acid amide was introduced into 5 ml of dioxane and continuously mixed with 4 mg (0.02 mmol) copper iodide, 85 mg (0.4 mmol) potassium phosphate and 2 mg (0.02 mmol) ethylenediamine. . After 1 h of stirring at a bath temperature of 120 ° C., it was diluted with 20 ml of water and concentrated by evaporation. It was then made alkaline with ammonia and shaken three times with 25 ml of ethyl acetate each. The collected organic phases were washed with water, dried, filtered and concentrated by evaporation. The residue was crystallized using ethyl acetate and some hexane, stirred and aspirated. 2, 24 mg (26% of theory) having a melting point of 214.5 ℃ - [(2- methanesulfonyl-amino-pyridin-4-ylmethyl) -amino] - N - (3-trifluoromethyl-phenyl) Benzamide was obtained.

The following was prepared analogously.

Example 5.0

2-[(2-bismethanesulfonylamino-pyridin-4-ylmethyl) -amino]- N Preparation of-(3-trifluoromethyl-phenyl) -benzamide

193 mg (0.5 mmol) of 2-[(2-amino-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide in 3 ml of dichloromethane (0.6 mmol) methanesulfonic acid chloride and 61 mg (0.6 mmol) triethylamine were mixed and stirred together at room temperature for 1.5 hours. Then washed once with dilute sodium bicarbonate solution, dried, filtered and concentrated by evaporation. The residue was chromatographed via flash chromatography (5 g of Isolute) using a gradient of cyclohexane: ethyl acetate = 100: 0 to 50:50 as eluent. 80 mg (30% of theory) of 2-[(2-bismethanesulfonylamino-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide as resin Got it.

(MS: m / e 542)

Example 6.0

2-[(2-butyrylamino-pyridin-4-ylmethyl) -amino]- N Preparation of-(3-isoquinolinyl) -benzamide

2 of 100 mg (0.23 mmol) - [ (2- bromo-pyridin-4-ylmethyl) -amino] - N - (3- isoquinolinyl) benzamide in dioxane in 1 ml 89 mg (0.28 mmol) cesium carbonate, 24 mg (0.69 mmol) butyramide, 4.7 mg (0.0046 mmol) dipaladium-tribenzylidene acetone and 7.9 mg (0.014 mmol) xanthphos, under protective gas and in a humid environment Heated to a bath temperature of 90 ° C. for 25 h. Then it was mixed with 20 ml of methylene chloride, incorporated and concentrated by evaporation. The residue was chromatographed on silica gel using hexane first as eluent, then hexanes: ethyl acetate = 8: 2 and then hexanes: ethyl acetate = 1: 1. 45 mg of 2 (42% of theory) - [(2-butyrylamino-4-yl-methyl) -amino] - N - (3- isoquinolinyl) to obtain 173 ℃ having a melting point benzamide .

The following was prepared analogously.

Example 6.32

The following was prepared analogously.

2-{[2- (acetyl-methyl-amino) -pyridin-4-ylmethyl] -amino} -N -isoquinolin-3-yl-benzamide

Melting point 71 ℃

Example 7.0

2-{[2- (2-oxo-pyrrolidin-1-yl) -pyridin-4-ylmethyl] -amino}- N Preparation of-(3-trifluoromethyl-phenyl) -benzamide

156 mg (0.5 mmol) of 2-{[2- (2-oxo-pyrrolidin-1-yl) -pyridin-4-ylmethyl] -amino} -benzoic acid in 0.12 ml (5 ml of dimethylformamide) 1 mmol) 3-aminobenzotrifluoride, 228 mg (0.6 mmol) HATU (N-dimethylamino-1H-1,2,3-triazolo-[4,5-b] pyridin-1-ylmethylene ] -N-methylmethaneammoniumhexafluorophosphate-N-oxide) and 0.14 ml of N-methylmorpholine and stirred overnight at room temperature. It was diluted with ethyl acetate and washed successively with saturated sodium bicarbonate solution, water and saturated common salt solution. The organic phase was dried, filtered and concentrated by evaporation. The residue was chromatographed as mobile solvent on isoroot. 95 mg (42% of theory) of 2 - {[2- (2-oxo-pyrrolidin-1-yl) -pyridin-4-ylmethyl] -amino} - N - (3-trifluoromethyl- Phenyl) -benzamide was obtained.

(MS: m / e 454)

The following was prepared analogously.

R ² , R ³ , Y and Z = G

Example 8.0

The following was prepared similar to Example 6.0.

2-{[2- (2-hydroxymethyl-5-oxo-pyrrolidin-1-yl) -pyridin-4-ylmethyl] -amino}- N Isoquinolin-3-yl-benzamide

The following was prepared analogously.

Example 9.0

2-{[2- (2,5-Dioxo-pyrrolidin-1-yl) -pyridin-4-ylmethyl] -amino}- N Preparation of-(3-trifluoromethyl-phenyl) -benzamide

0.23 ml of 193 mg (0.5 mmol) of 2-[(2-amino-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide in 20 ml of dichloromethane (1.5 mmol) of triethylamine, which was added dropwise to a solution of 93 mg (0.6 mmol) of succinic acid dichloride in 3 ml of methylene chloride and mixed at room temperature. After stirring at room temperature overnight, it was diluted with methylene chloride water and washed successively with saturated sodium bicarbonate solution and saturated common salt solution. The organic phase was then dried, filtered and concentrated by evaporation. The residue was chromatographed on a Separtis Company using a gradient of methylene chloride: ethanol = 100: 0 to 95: 5. 120 mg (51% of theory) of 2 - {[2- (2,5-dioxo-pyrrolidin-1-yl) -pyridin-4-ylmethyl] -amino} - N - (3- trifluoromethyl Romethyl-phenyl) -benzamide was obtained.

(MS: m / e 468)

The following was prepared analogously.

Example 9.1

2-{[2- (3,5-Dioxo-morpholin-4-yl) -pyridin-4-ylmethyl] -amino}- N -(3-trifluoromethyl-phenyl) -benzamide

Melting point 201.9 ℃

Example 10.0

2-[(2- (3-chloropropanesulfonylamino-pyridin-4-ylmethyl) -amino]- N Preparation of-(3-trifluoromethyl-phenyl) -benzamide

135 mg (0.35 mmol) of 2-[(2-amino-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide in 10 ml of dichloromethane 62 mg (0.35 mmol) of 3-chloropropanesulfonic acid chloride and 49 μl (0.35 mmol) of triethylamine were mixed and stirred at room temperature for 2 hours. It was then washed once with saturated sodium bicarbonate solution, filtered and concentrated by evaporation. The residue was chromatographed via flash chromatography (5 g of isoroot) using a gradient of dichloromethane: ethanol = 100: 0 to 90:10 as eluent. 67 mg (36% of theory) of 2-[(2- (3-chloropropanesulfonylamino-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide Got.

(MS (CI): 491 (100%, M ⁺ + H-HCl))

Example 11.0

2-{[2- (1,1-dioxo-1λ ⁶ Isothiazolidin-2-yl) -pyridin-4-ylmethyl] -amino}- N Preparation of-(3-trifluoromethyl-phenyl) -benzamide

58 mg (0.11 mmol) of 2-[(2- (3-chloropropanesulfonylamino-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide Suspended in ml of ethanol and mixed with 5 mg of sodium hydride (55% in mineral oil) The mixture was refluxed for 1 hour, mixed with 10 ml of water and extracted with ethyl acetate. Saturated and extracted repeatedly by stirring overnight with ethyl acetate The combined extracts were concentrated by evaporation and then 50 mg (93% of theory) of 2-{[2- (1,1-dioxo- 1λ ⁶ -Isothiazolidin-2-yl) -pyridin-4-ylmethyl] -amino} -N- (3-trifluoromethyl-phenyl) -benzamide was obtained.

(MS (CI): 491 (100%, M ⁺ + H))

Example 12.0

N- [2- (2-hydroxy-ethyl) -2 H -Indazol-5-yl] -2-{[2- (3-methyl-ureido) -pyridin-4-ylmethyl] -amino} -benzamide

50 mg (0.11 mmol) N- [2- (2-methoxy-ethyl) -2 H -indazol-5-yl] -2-{[2- (3-methyl-ureido) -pyridine-4 -Ylmethyl] -amino} -benzamide was introduced into 5 ml of methylene chloride and mixed dropwise using 0.56 ml of boron tribromide (1 mole in methylene chloride) at -78 ° C under argon and in a humid environment. It was stirred for at least 15 minutes, the cold bath was removed and then stirred for at least 2 hours. It was then mixed with water, methylene chloride was drained, made alkaline with sodium bicarbonate solution, and extracted twice with 15 ml of ethyl acetate each. The collected organic phases were dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel using a gradient of methylene chloride: ethanol = 100: 0 to 90:10 as eluent and is 27 mg of N- [2- (2-hydroxy-ethyl) -2 H-. Sol-5-yl] -2-{[2- (3-methyl-ureido) -pyridin-4-ylmethyl] -amino} -benzamide.

The following was analogously prepared from the corresponding methoxy compound.

Preparation of Intermediate Compounds

Example A

If the preparation of the intermediate compounds is not described, they may be known or prepared analogously to known compounds or processes described herein.

Step 1

a) Preparation of 2-bromopyridine-5-carbaldehyde is described in F. J. Romero-Salguerra et al. THL 40,859 (1999).

b) preparation of 2-bromo-isonicotinic acid

160 g (0.93 mol) of 2-bromo-4-methyl-pyridine was added dropwise to 152 g (0.96 mol) of potassium permanganate in 4 l of water. Then, before adding 152 g (0.96 mol) of potassium permanganate once more, it was stirred under reflux for 1 hour. After stirring for an additional 2 hours under reflux, it was aspirated in Celite at high temperature and washed with water. The aqueous phase was shaken three times with dichloromethane. The aqueous phase was concentrated by evaporation to half its original volume and the pH was fixed at 2 with concentrated hydrochloric acid. Precipitated solids were incorporated and dried at 70 ° C. in vacuo. 56.5 g of white solid product accumulated.

Preparation of 2-bromo-4-hydroxymethyl-pyridine

30.2 ml (295 mmol) of triethylamine were added to 56.5 g (280 mmol) of 2-bromo-isonicotinic acid in 1.2 l of THF. Added. It was then cooled to −10 ° C. and mixed dropwise with 38.2 ml (295 mmol) of isobutyl chloroformate. After continuing stirring at −10 ° C. for 1 hour, it was cooled to −70 ° C. and mixed dropwise with 590 ml (590 mmol) of LiAlH ₄ solution (1 M in THF). Stirring was continued at −70 ° C. for 1 hour and then brought to −40 ° C. 600 ml of 50% acetic acid was added. It was stirred overnight at room temperature. Insoluble components were aspirated and the filtrate was concentrated by evaporation. The residue was purified on silica gel using hexane and hexane / ethyl acetate 1: 1. 28.0 g of white solidified oil accumulated.

Preparation of 2-bromo-4-formyl-pyridine:

149 g (1714 mmol) of manganese dioxide were added in real quantities to 28.0 g (148.9 mmol) 2-bromo-4-hydroxymethyl-pyridine in 500 ml of dichloromethane within 6 hours. Agitation was then continued for 48 hours at room temperature. It was aspirated in celite and concentrated by evaporation. 16.4 g of solidified white oil was accumulated.

2-bromo-4-formyl-pyridine can also be prepared in two steps from 2-bromo-4-picolin according to THL 42,6815 (2001).

Step 2

Preparation of 2-[(6-bromo-pyridin-3-ylmethyl) -amino] -N -isoquinolin-3-yl-benzamide

3.46 g (13.17 mmol) of 2-amino- N -isoquinolin-3-yl-benzamide are introduced into 50 ml of methanol, 1.5 ml of glacial acetic acid, as well as 2.45 g (13.17 mmol) of 2-bromopyridine Mix with -5-carbaldehyde and stir for 24 hours under argon and in a humid environment at room temperature. It was then mixed with 828 mg (13.17 mmol) sodium cyanoborohydride and stirred for a further 24 hours at room temperature. After concentration by evaporation in vacuo, the residue was taken up in dilute sodium bicarbonate solution and aspirated. The residue obtained was precipitated by absorption in some ethyl acetate and aspirated repeatedly. The residue obtained in this case was chromatographed on silica gel using hexanes: ethyl acetate = 1: 1 as eluent. 3.27 g (57% of theory) of 2-[(6-bromo-pyridin-3-ylmethyl) -amino] -N -isoquinolin-3-yl-benzamide were obtained.

The following was prepared analogously.

2-[(2-bromo-pyridin-4-ylmethyl) -amino]- N Isoquinolin-3-yl-benzamide

2-[(2-bromo-pyridin-4-ylmethyl) -amino]- N -(3-trifluoromethyl-phenyl) -benzamide

Example B

First step

Preparation of 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -benzoic acid methyl ester

6.04 g (40 mmol) of anthranilic acid methyl ester in 600 ml of methanol was mixed with 3.2 ml of acetic acid and 7.4 g (40 mmol) of 2-bromopyridine-4-carbaldehyde and stirred at 40 ° C. overnight. . 3.8 g (60 mmol) of sodium cyanoborohydride were added thereto and stirred at 40 ° C overnight. 3.8 g (60 mmol) of sodium cyanoborohydride were added again and stirred at 40 ° C. over the weekend. It was mixed with water and concentrated mostly by evaporation. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried, filtered and concentrated by evaporation. The crude product was chromatographed on silica gel using a gradient consisting of hexane and hexane / ethyl acetate 1: 3 and hexane / ethyl acetate 1: 1 as eluent. 10.0 g (78% of theory) of 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -benzoic acid methyl ester were obtained as a colorless oil.

Example C

First step

Preparation of 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -benzoic acid

Dissolve 10.0 g (31.2 mmol) of 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -benzoic acid methyl ester in 290 ml of ethanol and mix with 31.2 ml of 2 M sodium hydroxide solution. I was. After stirring overnight at room temperature, the ethanol was drained off and the aqueous phase was shaken using ethyl acetate. Concentrated hydrochloric acid was used to acidify the aqueous phase. The precipitate formed was incorporated and dried. 5.93 g (62%) of 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -benzoic acid accumulated in the form of a white solid.

2nd step

2-[(2-bromo-pyridin-4-ylmethyl) -amino]- N -(2-methyl-2 H Preparation of -indazol-6-yl) -benzamide

0.500 g (1.6 mmol) of 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -benzoic acid in 25 ml of dimethylformamide, 0.471 g (3.2 mmol) of 2-methyl-2 H- Indazole-6-ylamine, 0.4 ml (3.68 mmol) N-methylmorpholine and 0.729 g (1.92 mmol) O- (7-azabenzotriazol-1-yl) -1,1,3,3 Tetramethyluronium hexafluorophosphate (HATU) was stirred for 16 hours at room temperature. Dimethylformamide was discharged in an oil pump vacuum. The remaining residue was drained in saturated sodium bicarbonate solution. It was extracted three times with ethyl acetate and the combined organic phases were dried, filtered and concentrated by evaporation. The residue was chromatographed on silica gel using a gradient consisting of hexane: acetone = 100: 0 to 50:50 as eluent. Benzamide - 0.669 g of 2 (96% of theory) of [(2-bromo-pyridin-4-ylmethyl) -amino] - N - (2-methyl -2 H-indazol-6-yl) Obtained in the form of a beige foam.

In addition, the following compounds were prepared analogously.

2-[(2-bromo-pyridin-4-ylmethyl) -amino]- N -(1-methyl-1 H -Indazol-6-yl) -benzamide

2-[(2-bromo-pyridin-4-ylmethyl) -amino]- N -(One H -Indazol-6-yl) -benzamide

2-[(2-bromo-pyridin-4-ylmethyl) -amino]- N -(One H -Indazol-5-yl) -benzamide

Example D

Step 1

Preparation of 2-{[2- (2-oxo-pyrrolidin-1-yl) -pyridin-4-ylmethyl] -amino} -benzoic acid methyl ester

870 mg (2.78 mmol) 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -benzoic acid methyl ester, 53 mg (0.28 mmol) copper iodide (I), 1.126 g (5.5 mmol) Potassium phosphate and 0.26 ml (3.6 mmol) of pyrrolidin-2-one were refluxed in 15 ml of dioxane for 8 hours. After addition of water, the dioxane was distilled in vacuo, made alkaline with about 12% ammonia solution and shaken several times with ethyl acetate. The collected ethyl acetate was washed, dried, filtered and concentrated by evaporation. As residue, 700 mg (77% of theory) of 2-{[2- (2-oxo-pyrrolidin-1-yl) -pyridin-4-ylmethyl] -amino} -benzoic acid methyl ester Which was used without further purification in the next step.

The following was prepared analogously.

Step 3

Preparation of 2-{[2- (2-oxo-pyrrolidin-1-yl) -pyridin-4-ylmethyl] -amino} -benzoic acid

700 mg (2.15 mmol) of 2-{[2- (2-oxo-pyrrolidin-1-yl) -pyridin-4-ylmethyl] -amino} -benzoic acid methyl ester in 2.7 ml of 15 ml methanol It was mixed with 1N sodium hydroxide solution and refluxed for 1 hour. After methanol was distilled off in vacuo, it was diluted with water and shaken once with ethyl acetate. The aqueous phase was mixed with 5 ml of 1 mol citric acid solution and stirred overnight. Solid precipitate was incorporated and dried very quickly. 600 mg of 2-{[2- (2-oxo-pyrrolidin-1-yl) -pyridin-4-ylmethyl] -amino} -benzoic acid was obtained which is used as a crude product in the next step.

The following was prepared analogously.

Example E

2-[(2-bromo-pyridin-4-ylmethyl) -amino]- N -(1-methyl-1 H -Indazol-5-yl) -benzamide And 2-[(2-bromo-pyridin-4-ylmethyl) -amino]- N -(2-methyl-2 H Preparation of -indazol-5-yl) -benzamide

4.22 g (10 mmol) of 2-[(2-bromo-pyridin-4-ylmethyl) with cooling with ice with 3.6 g (11 mmol) cesium carbonate and 0.68 ml (11 mmol) methyl iodide ) - amino] - N - (1 H-indazol-5-yl) are mixed in dimethylformamide in the benzamide 30 ml, and the mixture was stirred at room temperature overnight. It was then stirred in 250 ml of ice cold water and stirring continued for 15 minutes and aspirated. The filter cake was dried very quickly and chromatographed using a gradient of ethyl acetate: hexane = 1: 1 to 100: 0 on silica gel as eluent. 2 of 1.79 g (41% of theory) having a melting point of 173.8 ℃ - [(2- bromo-pyridin-4-ylmethyl) -amino] - N - (1- methyl -1 H-indazol-5-yl ) -benzamide, 2 19%) of 830 mg (theoretical value having a melting point of 183.8 ℃ as well as - [(2-bromo-pyridin-4-ylmethyl) -amino] - N - (2-methyl -2 H -Indazol-5-yl) -benzamide was obtained.

The following was prepared analogously.

2 - [(2-bromo-pyridin-4-ylmethyl) -amino] - N - (1- isopropyl -1 H-indazol-5-yl) -benzamide,

2-[(2-bromo-pyridin-4-ylmethyl) -amino]- N -(2-isopropyl-2 H -Indazol-5-yl) -benzamide,

2 - [(2-bromo-pyridin-4-ylmethyl) -amino] - N - (1- ethyl -1 H-indazol-5-yl) -benzamide,

2-[(2-bromo-pyridin-4-ylmethyl) -amino]- N -(2-ethyl-2 H -Indazol-5-yl) -benzamide,

2-[(2-bromo-pyridin-4-ylmethyl) -amino]- N -(1- [2-methoxyethyl] -1 H -Indazol-5-yl) -benzamide,

2-[(2-bromo-pyridin-4-ylmethyl) -amino]- N -(2- [2-methoxyethyl] -2 H -Indazol-5-yl) -benzamide,

2-[(2-bromo-pyridin-4-ylmethyl) -amino]- N -(1- [cyanomethyl] -1 H -Indazol-5-yl) -benzamide,

2-[(2-bromo-pyridin-4-ylmethyl) -amino]- N -(2- [cyanomethyl] -2 H -Indazol-5-yl) -benzamide,

2-[(2-bromo-pyridin-4-ylmethyl) -amino]- N -(1- [2-dimethylaminoethyl] -1 H -Indazol-5-yl) -benzamide,

2-[(2-bromo-pyridin-4-ylmethyl) -amino]- N -(2- [2-dimethylaminoethyl] -2 H -Indazol-5-yl) -benzamide,

2-[(2-bromo-pyridin-4-ylmethyl) -amino]- N -(1-methyl-1 H -Indazol-6-yl) -benzamide,

2-[(2-bromo-pyridin-4-ylmethyl) -amino]- N -(2-methyl-2 H -Indazol-6-yl) -benzamide,

2-[(2-bromo-pyridin-4-ylmethyl) -amino]- N -(1-isopropyl-1 H -Indazol-6-yl) -benzamide,

2-[(2-bromo-pyridin-4-ylmethyl) -amino]- N -(2-isopropyl-2 H -Indazol-6-yl) -benzamide,

2-[(2-bromo-pyridin-4-ylmethyl) -amino]- N -(1-ethyl-1 H -Indazol-6-yl) -benzamide,

2-[(2-bromo-pyridin-4-ylmethyl) -amino]- N -(2-ethyl-2 H -Indazol-6-yl) -benzamide,

2-[(2-bromo-pyridin-4-ylmethyl) -amino]- N -(1- [2-methoxyethyl] -1 H -Indazol-6-yl) -benzamide,

2-[(2-bromo-pyridin-4-ylmethyl) -amino]- N -(2- [2-methoxyethyl] -2 H -Indazol-6-yl) -benzamide,

2-[(2-bromo-pyridin-4-ylmethyl) -amino]- N -(1- [cyanomethyl] -1 H -Indazol-6-yl) -benzamide and

2-[(2-bromo-pyridin-4-ylmethyl) -amino]- N -(2- [cyanomethyl] -2 H -Indazol-6-yl) -benzamide.

2-[(2-bromo-pyridin-4-ylmethyl) -amino]- N -(1- [2-dimethylaminoethyl] -1 H -Indazol-6-yl) -benzamide and

2-[(2-bromo-pyridin-4-ylmethyl) -amino]- N -(2- [2-dimethylaminoethyl] -2 H -Indazol-6-yl) -benzamide.

The following sample applications illustrate the biological action and use of the compounds according to the invention, which are not limited by the examples.

Required solution for the test

Storage solution

Stock solution A: 3 mmol of ATP in water, pH 7.0 (-70 ° C.)

Stock solution B: g-33P-ATP 1 mCi / 100 μl

Stock solution C: 10 mg / ml poly- (Glu4Tyr) in water

Diluent Solution

Substrate solvent: 10 mmol of DTT, 10 mmol of manganese chloride, 100 mmol of magnesium chloride

Enzyme solution: 120 mmol Tris / HCl, pH 7.5, 10 μΜ sodium vanadium oxide

Sample Application Example 1

Inhibition of KDR- and FLT-1 kinase activity in the presence of a compound according to the invention

In a microtiter plate tapering to one point (no protein binding), 10 μl of substrate mixture (10 μl volume of ATP stock solution A + 25 μCi g-33P-ATP (about 2.5 μl stock solution B) + 30 μl poly- (Glu4Tyr) stock solution C + 1.21 ml substrate solvent), 10 μl inhibitor solution (substance corresponding to dilution, 3% DMSO in substrate solvent as control) and 10 μl enzyme solution (11.25 μg Enzyme storage solution (KDR or FLT-1 kinase) was added in 1.25 ml of enzyme solution (dilution) at 4 ° C. It was thoroughly mixed and incubated for 10 minutes at room temperature, then 10 μl of stop solution ( 250 mmol EDTA, pH 7.0) was added, mixed and 10 μl of this solution was transferred to a P 81 phosphocellulose filter, which was then washed several times in 0.1 M phosphoric acid The filter paper was dried and Meltirex Coated with (Meltilex) and microphone It was measured in a beta counter (microbeta counter).

IC50 values were determined from inhibitor concentrations necessary to inhibit phosphate incorporation for 50% uninhibited incorporation after removal of the blank read (EDTA-stop reaction).

The results of the kinase inhibition IC50 at μM are shown in the table below.

Sample Application Example 2

Cytochrome P450 Inhibition

Crespi et al. Cytochrome P450 inhibition was performed using baculovirus / insect cell-expressed human cytochrome P 450 isoenzyme (3A4) according to (Anal. Biochem., 248, 188-190 (1997)). It was.

The results are shown in the table below.

From the above results, it can be clearly seen that the compound according to the present invention has an excellent function compared to the known compound.

Claims (11)

The compounds of formula (I) and their isomers, diastereomers, tautomers and salts thereof. <Formula I> In the above formula, X represents CH or N, W represents hydrogen or fluorine, A, B, D, E and Q each independently represent a nitrogen or carbon atom, where at most two nitrogen atoms can be present in the ring, R ¹ is halogen, hydroxy, C ₁ -C ₁₂ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -alkenyl, C ₂ -C ₆ in the same way or differently at one or more positions -Alkynyl, aralkyloxy, C ₁ -C ₁₂ -alkoxy, halo-C ₁ -C ₆ -alkyl, cyano-C ₁ -C ₆ -alkyl, or a group ═O, —SO ₂ R ⁶ or —OR ⁵ (wherein, C ₁ -C ₆ - alkyl group is also -OR ⁵ or -NR ⁹ R ¹⁰ may be optionally substituted with a) optionally with aryl or heteroaryl which may be substituted, Y and Z each independently represent a bond or group = CO, = CS or = SO ₂ , R ² and R ³ independently of one another are hydrogen or the group -CONR ⁹ R ¹⁰ , -SO ² R ⁶ , -COR ¹¹ , -COC ₁ -C ₆ -alkyl, -CO-C ₁ -C ₆ -alkyl-R ¹¹ , -NR ⁹ R ¹⁰ , or the same way or differently at one or more positions, halogen, cyano, C ₁ -C ₁₂ -alkyl, C ₁ -C ₁₂ -alkoxy, hydroxy-C ₁ -C ₆ -alkyl , Halo-C ₁ -C ₆ -alkyl, or optionally a group -NR ⁷ R ⁸ , -OR ⁵ , -C ₁ -C ₆ -alkyl-OR ⁵ , -SR ⁴ , -SOR ⁴ or -SO ₂ R ⁶ Substituted with C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cycloalkyl, C ₃ -C ₆ -cycloalkenyl, aryl or heteroaryl; or R ² , R ³ , Y and Z, together with the nitrogen atom, may optionally contain additional heteroatoms in the ring and are halogen, cyano, C ₁ -C ₁₂ -alkyl in the same way or differently at one or more positions , C ₁ -C ₁₂ -alkoxy, halo-C ₁ -C ₆ -alkyl, hydroxy-C ₁ -C ₆ -alkyl, or a group = 0, -OR ⁵ , -SR ⁴ , -SOR ⁴ or -SO ₂ To form a 3- to 8-membered saturated or unsaturated ring which may be optionally substituted with R ⁶ , R ⁴ represents C ₁ -C ₁₂ -alkyl, aryl or heteroaryl, R ⁵ is hydrogen, C ₁ -C ₁₂ -alkyl, C ₃ -C ₁₀ -cycloalkyl, C ₁ -C ₁₂ -alkoxy, halo-C ₁ -C ₁₂ -alkyl or halo-C ₃ -C ₆ -cycloalkyl Indicates, R ⁶ represents hydrogen, C ₁ -C ₁₂ -alkyl, halo-C ₁ -C ₁₂ -alkyl, aryl or heteroaryl, or a group —NR ⁹ R ¹⁰ , wherein aryl or heteroaryl is itself at least one position In the same way or differently at C ₁ -C ₁₂ -alkyl, C ₁ -C ₆ -alkoxy, halogen or halo-C ₁ -C ₆ -alkoxy, R ⁷ and R ⁸ independently of one another represent hydrogen or C ₁ -C ₁₂ -alkyl, R ⁹ and R ¹⁰ independently of one another are hydrogen, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, aryl, C ₃ -C ₈ -cycloalkyl, or a group -CONR ⁷ R ⁸ , or one or more Aryl, morpholino, hydroxy, halogen, C ₁ -C ₁₂ -alkoxy, or a group —NR ⁷ R ⁸ in the same way or differently at the position wherein aryl is by itself the same way at one or more positions or differently C ₁ -C ₆ - alkoxy or halo -C ₁ -C ₆ -, optionally in the optionally may be substituted), an alkyl-substituted C ₁ -C ₁₂ -, or represent alkyl, or R ⁹ and R ¹⁰ together form a 5 to 8 membered ring which may contain additional heteroatoms, R ¹¹ is C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxy-C ₁ -C ₆ -alkyl, hydroxy-C ₁ -C ₆ -alkoxy, C ₃ -C ₆ -cycloalkyl, Phenyl, pyridyl, biphenyl, or naphthyl, wherein phenyl may itself be substituted by C ₁ -C ₆ -alkyl or halo-C ₁ -C ₆ -alkyl in the same way or differently at one or more positions. have. The method of claim 1, X represents CH, W represents hydrogen, A, B, D, E and Q together represent a pyridyl as a ring, R ¹ is halogen, hydroxy, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₄ -C ₆ -alkenyl, C ₂ -C ₆ -in the same way or differently at one or more positions; Alkynyl, aralkyloxy, C ₁ -C ₆ -alkoxy, halo-C ₁ -C ₆ -alkyl, cyano-C ₁ -C ₆ -alkyl, or a group ═O, —SO ₂ R ⁶ Or -OR ⁵ (wherein, C ₁ -C ₆ - alkyl group is also -OR ⁵ or -NR ⁹ R ¹⁰ may be optionally substituted with a) optionally with aryl or heteroaryl which may be substituted, Y and Z each independently represent a bond, R ² and R ³ independently of one another are hydrogen or the group -CONR ⁹ R ¹⁰ , -SO ₂ R ⁶ , -COR ¹¹ , -COC ₁ -C ₆ -alkyl, -CO-C ₁ -C ₆ -alkyl-R ¹¹ , -NR ⁹ R ¹⁰ , or halogen, cyano, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxy-C ₁ -C ₆ -alkyl, in the same manner or differently at one or more positions; Optionally substituted with halo-C ₁ -C ₆ -alkyl or group -NR ⁷ R ⁸ , -OR ⁵ , -C ₁ -C ₆ -alkyl-OR ⁵ , -SR ⁴ , -SOR ⁴ or -SO ₂ R ⁶ a C ₁ -C ₆ - alkyl, C ₃ -C ₆ - cycloalkyl, C ₃ -C ₆ - cycloalkenyl, or represent aryl or heteroaryl, or R ² , R ³ , Y and Z, together with the nitrogen atom, may optionally contain additional heteroatoms in the ring and are halogen, cyano, C ₁ -C ₁₂ -alkyl in the same way or differently at one or more positions , C ₁ -C ₁₂ -alkoxy, halo-C ₁ -C ₆ -alkyl, hydroxy-C ₁ -C ₆ -alkyl or group = 0, -OR ⁵ , -SR ⁴ , -SOR ⁴ or -SO ₂ R To form a 3- to 8-membered saturated or unsaturated ring which may be optionally substituted by ⁶ , R ⁴ represents C ₁ -C ₆ -alkyl, aryl or heteroaryl, R ⁵ is hydrogen, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, C ₁ -C ₁₂ -alkoxy, C ₃ -C ₁₀ -cycloalkyl or halo-C ₃ -C ₆ -cycloalkyl Indicates, R ⁶ is hydrogen, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, aryl or heteroaryl, or a group —NR ⁹ R ¹⁰ , wherein aryl or heteroaryl is optionally one as such In the same manner or differently at the above positions or may be substituted with C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen or halo-C ₁ -C ₆ -alkoxy), R ⁷ and R ⁸ independently of one another represent hydrogen or C ₁ -C ₆ -alkyl, R ⁹ and R ¹⁰ independently of one another are hydrogen, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, aryl, C ₃ -C ₈ -cycloalkyl, or a group -CONR ⁷ R ⁸ , or one or more Aryl, morpholino, hydroxy, halogen or C ₁ -C ₁₂ -alkoxy, or a group —NR ⁷ R ⁸ , wherein aryl is optionally the same in any one or more positions or differently C ₁ -C ₆ - alkoxy or halo -C ₁ -C ₆ -, optionally substituted with may be substituted), with alkyl C ₁ -C ₆ - represents alkyl, R ¹¹ is C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxy-C ₁ -C ₆ -alkyl, hydroxy-C ₁ -C ₆ -alkoxy, C ₃ -C ₆ -cycloalkyl, Phenyl, pyridyl, biphenyl or naphthyl, wherein phenyl may itself be substituted by C ₁ -C ₆ -alkyl or halo-C ₁ -C ₆ -alkyl in the same way or differently at one or more positions Isomers and diastereomers, tautomers and salts thereof. The method according to claim 1 or 2, X represents CH, W represents hydrogen, A, B, D, E and Q together represent a pyridyl as a ring, R ¹ is optionally halogen or hydroxy, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkynyl, C ₁ -C ₆ -alkoxy, halo-C ₁ − in the same way or differently at one or more positions; May be substituted with C ₆ -alkyl or cyano-C ₁ -C ₆ -alkyl, wherein C ₁ -C ₆ -alkyl may also be optionally substituted with the group —OR ⁵ or —NR ⁹ R ¹⁰ . Phenyl, quinolinyl, isoquinolinyl or indazolyl, Y and Z each independently represent a bond or a group = CO, R ² and R ³ independently of one another are hydrogen or the group -CONR ⁹ R ¹⁰ , -SO ₂ R ⁶ , -COR ¹¹ , -COC ₁ -C ₆ -alkyl, -CO-C ₁ -C ₆ -alkyl-R ¹¹ Or —NR ⁹ R ¹⁰ , or C ₁ -C ₆ -alkyl or phenyl optionally substituted in the same way or differently at one or more positions with the group —NR ⁷ R ⁸ or —OR ⁵ , or R ² , R ^3, Y and Z, together with the nitrogen atom, may optionally contain further heteroatoms in the ring and in the same way or differently at one or more positions halogen, cyano, C ₁ -C ₁₂ -alkyl , C ₁ -C ₁₂ -alkoxy, halo-C ₁ -C ₆ -alkyl, hydroxy-C ₁ -C ₆ -alkyl or group = 0, -OR ⁵ , -SR ⁴ , -SOR ⁴ or -SO ₂ R To form a 3- to 8-membered saturated or unsaturated ring which may be optionally substituted by ⁶ , R ⁵ represents hydrogen or C ₁ -C ₆ -alkyl, R ⁶ is hydrogen, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, phenyl, benzyl, thiophenyl or pyridyl, wherein phenyl, benzyl, thiophenyl and pyridyl are themselves one or more In the same way or differently at the position may be optionally substituted with C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen or halo-C ₁ -C ₆ -alkoxy), R ⁷ and R ⁸ independently of one another represent hydrogen or C ₁ -C ₆ -alkyl, R ⁹ and R ¹⁰ independently of one another are hydrogen, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, phenyl, biphenyl, C ₃ -C ₈ -cycloalkyl, naphthyl or group -CONR ⁷ R ⁸ , or in the same way or differently at one or more positions phenyl, morpholino, hydroxy, halogen, C ₁ -C ₁₂ -alkoxy, or a group —NR ⁷ R ⁸ wherein phenyl is itself at least one position in the same manner as or different from C ₁ -C ₆ - alkoxy or halo -C ₁ -C _6- - represents alkyl, - an optionally may be substituted), optionally substituted by C ₁ -C ₆ alkyl R ¹¹ is C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxy-C ₁ -C ₆ -alkyl, hydroxy-C ₁ -C ₆ -alkoxy, C ₃ -C ₆ -cycloalkyl, Phenyl, pyridyl, biphenyl or naphthyl, wherein phenyl may itself be substituted by C ₁ -C ₆ -alkyl or halo-C ₁ -C ₆ -alkyl in the same way or differently at one or more positions Compounds of formula I, and isomers, diastereomers, tautomers and salts thereof. A medicament comprising at least one compound of formula (I). The method of claim 4, further comprising: tumor or metastasis growth, psoriasis, Kaposi's sarcoma, restenosis, eg stent-induced restenosis, endometriosis, Crohn's disease, Hodgkin's disease, leukemia; Arthritis such as rheumatoid arthritis, hemangioma, angiofibroma; Eye diseases such as diabetic retinopathy, neovascular glaucoma; Kidney disease such as glomerulonephritis, diabetic nephropathy, malignant neurosis, thrombotic microangiopathy syndrome, transplant rejection and glomerulopathy; Fibrotic diseases, such as cirrhosis, mesangial cell proliferative disorders, arteriosclerosis, nerve tissue damage, vascular balloon catheter treatment, vascular prosthetics or mechanical devices that keep blood vessels open, such as stents Inhibition of obstruction and as an immunosuppressive agent and for use in supporting scar healing, in senile keratosis and for use in contact dermatitis. 6. The medicament according to claim 5, for use as a VEGFR kinase 3-inhibitor of lymphangiogenesis. A compound according to any one of claims 1 to 3, and a medicament according to any one of claims 4 to 6, having a suitable agent and vehicle. Use of a compound of formula (I) according to any one of claims 1 to 3 as a tyrosine kinase KDR and FLT inhibitor. Intestinal, parenteral and oral administration of a compound of formula (I) according to any one of claims 1 to 3 in the form of a pharmaceutical formulation. Tumor or metastatic growth, psoriasis, Kaposi's sarcoma, restenosis such as stent-induced restenosis, endometriosis, Crohn's disease, Hodgkin's disease, leukemia of the compound according to any one of claims 1 to 3; Arthritis such as rheumatoid arthritis, hemangioma, angiofibroma; Eye diseases such as diabetic retinopathy, neovascular glaucoma; Kidney disease such as glomerulonephritis, diabetic nephropathy, malignant neurosis, thrombotic microangiopathy syndrome, transplant rejection and glomerulopathy; Fibrous diseases, such as cirrhosis, mesangium cell proliferative disease, arteriosclerosis, nerve tissue damage, and vascular balloon catheter treatment, after use of mechanical devices, such as stents, in vascular support or to keep blood vessels open For inhibiting reclosure, and as an immunosuppressive agent, and for supporting scar-free healing, and for use in senile keratosis and in contact dermatitis. Compounds of the following formulas II, IIa and III as intermediates for the preparation of compounds of formula I according to the invention. <Formula II> <Formula IIa> <Formula III> Wherein A, B, D, E, Q, W, X, Y, Z, R ² and R ³ have the meanings described in formula (I), M represents halogen, and FG represents a leaving group, e.g. Halogen, O-triplate, O-mesylate, O-tosylate or sulfone, and R ^Y represents C ₁ -C ₆ -alkyl or hydrogen.