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HK1157345B - Dihydropyrazole derivatives as tyrosine kinase modulators for the treatment of tumors - Google Patents

Dihydropyrazole derivatives as tyrosine kinase modulators for the treatment of tumors Download PDF

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Publication number
HK1157345B
HK1157345B HK11111868.3A HK11111868A HK1157345B HK 1157345 B HK1157345 B HK 1157345B HK 11111868 A HK11111868 A HK 11111868A HK 1157345 B HK1157345 B HK 1157345B
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Hong Kong
Prior art keywords
compounds
compound
formula
pharmaceutically acceptable
het
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HK11111868.3A
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Chinese (zh)
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HK1157345A1 (en
Inventor
Dieter Dorsch
Oliver Schadt
Frank Stieber
Andree Blaukat
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Merck Patent Gmbh
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Priority claimed from DE102008025750A external-priority patent/DE102008025750A1/en
Application filed by Merck Patent Gmbh filed Critical Merck Patent Gmbh
Publication of HK1157345A1 publication Critical patent/HK1157345A1/en
Publication of HK1157345B publication Critical patent/HK1157345B/en

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Description

Dihydropyrazole derivatives as tyrosine kinase modulators for the treatment of tumors
Background
The object of the present invention was to find new compounds having valuable properties, in particular those which can be used for the preparation of medicaments.
The present invention relates to compounds and the use of compounds in which the inhibition, regulation and/or modulation of signal transduction by kinases, in particular tyrosine kinases and/or serine/threonine kinases, plays a role, to pharmaceutical compositions comprising these compounds and to the use of these compounds for the treatment of kinase-induced diseases. In particular, the present invention relates to compounds and uses of compounds in which inhibition, regulation and/or modulation of signal transduction by Met kinase plays a role.
One of the major mechanisms by which cellular regulation is achieved is through transmembrane extracellular signal transduction, which in turn regulates biochemical pathways within the cell. Protein phosphorylation represents a process by which intracellular signals propagate from molecule to molecule, ultimately leading to a cellular response. These signal transduction cascades are highly regulated and often overlap, as can be seen by the presence of many protein kinases as well as phosphatases. Protein phosphorylation occurs primarily at serine, threonine or tyrosine residues, and protein kinases have therefore been classified by the specificity of their phosphorylation sites, i.e., serine/threonine kinases and tyrosine kinases. Since phosphorylation is such a ubiquitous process within cells and since cellular phenotypes are largely influenced by the activity of these pathways, it is presently believed that many disease states and/or diseases can be attributed to aberrant activation or functional mutations of the molecular components of the kinase cascade. Therefore, much attention has been devoted to the characterization of these proteins and compounds that modulate their activity (for a review see: Weinstein-Oppenheimer et al, Pharma. &. Therap., 2000, 88, 229-279).
Berthou et al describe the role of receptor tyrosine kinase Met in human neoplasia and the possibility of inhibiting HGF (hepatocyte growth factor) -dependent Met activation in Oncogene, Vol.23, No. 31, p.5387-5393 (2004). The inhibitor SU11274 (a pyrrole-indoline compound) may be suitable for combating cancer. Christensen et al describe another Met-kinase inhibitor for cancer therapy in cancer Res.2003, 63(21), 7345-55. Hov et al reported another tyrosine kinase inhibitor for use against Cancer in Clinical Cancer Research Vol.10, 6686-6694 (2004). The compound PHA-665752 (an indole derivative) is directed against the HGF receptor c-Met. HGF and Met have also been reported to contribute significantly to the malignant process of various forms of cancer, such as multiple myeloma.
Therefore, there is a need to synthesize small compounds that specifically inhibit, regulate and/or modulate signal transduction of tyrosine kinases and/or serine/threonine kinases, particularly Met kinase, which is an object of the present invention.
The compounds of the invention and their salts have been found to have very valuable pharmacological properties, while having good tolerability.
The present invention relates inter alia to compounds of formula I which inhibit, modulate and/or modulate Met kinase signal transduction, compositions comprising these compounds and methods of their use for the treatment of Met kinase-induced diseases and disorders (complains) such as angiogenesis, cancer, neoplasia, growth and spread, arteriosclerosis, eye diseases such as age-induced macular degeneration, choroidal neovascularization and diabetic retinopathy, inflammatory diseases, arthritis, thrombosis, fibrosis, glomerulonephritis, neurodegeneration, psoriasis, restenosis, wound healing, graft rejection, metabolic diseases and immune system diseases, but also autoimmune diseases, cirrhosis, diabetes and vascular diseases, but also instability (instability) and permeability (parameability) and the like in mammals.
Solid tumors, particularly rapidly growing tumors, can be treated with Met kinase inhibitors. These solid tumors include monocytic leukemia, brain cancer, genitourinary cancer, lymphatic cancer, stomach cancer, laryngeal cancer, and lung cancer, including lung adenocarcinoma and small cell lung cancer.
The present invention relates to methods of modulating, modulating or inhibiting Met kinase for the prevention and/or treatment of diseases associated with deregulated or disturbed Met kinase activity. In particular, the compounds of formula I may also be useful in the treatment of certain forms of cancer. The compounds of formula I may also be used to provide additive or synergistic effects in certain existing cancer chemotherapies, and/or may be used to restore the efficacy of certain existing cancer chemotherapies and radiation therapies.
The compounds of formula I may also be used to isolate and study Met kinase activity or expression. Furthermore, they are particularly suitable for use in diagnostic methods for diseases associated with deregulated or disturbed Met kinase activity.
The compounds of the invention can be demonstrated to have an antiproliferative effect in vivo in a xenograft tumor model. The compounds of the present invention are administered to a patient with a hyperproliferative disease, for example, to inhibit tumor growth, reduce inflammation associated with lymphoproliferative diseases, inhibit graft rejection or nerve damage due to tissue repair, and the like. The compounds of the invention are suitable for prophylactic or therapeutic purposes. The term "treatment" as used herein is used to refer to the prevention of disease and the treatment of preexisting disorders. Prevention of proliferation, e.g., prevention of tumor growth, prevention of metastatic growth, reduction of restenosis associated with cardiovascular surgery, etc., is achieved by administering a compound of the invention prior to the onset of overt disease. Alternatively, the compounds are useful for treating an ongoing disease by stabilizing or ameliorating the clinical symptoms of a patient.
The host or patient may belong to any mammalian species, e.g. a primate species, particularly humans; rodents, including mice, rats, and hamsters; a rabbit; a horse; cattle; a dog; cats, and the like. Animal models are of interest for experimental studies and provide a model for the treatment of human diseases.
The sensitivity of a particular cell to treatment with a compound of the invention can be determined by in vitro assays. Typically, cell cultures are combined with different concentrations of a compound of the invention for a period of time sufficient for the active agent to induce cell death or inhibit migration, typically about 1 hour to 1 week. In vitro testing can be performed using cultured cells from a biopsy sample. The remaining viable cells after treatment were then counted.
The dosage will vary with the particular compound employed, the particular disease, the patient's condition, and the like. The therapeutic dose is generally sufficient to significantly reduce the undesirable cell population in the target tissue while maintaining the viability of the patient. Treatment generally continues until a significant reduction occurs, e.g., a reduction in cell burden (cell burden) of at least about 50%, and may continue until substantially no more undesired cells are detected in vivo.
In order to identify signal transduction pathways and to detect interactions between different signal transduction pathways, different scientists have developed suitable models or model systems, such as cell culture models (e.g., Khwaria et al, EMBO, 1997, 16, 2783-93) and transgenic animal models (e.g., White et al, Oncogene, 2001, 20, 7064-. To determine certain stages in the signal transduction cascade, interacting compounds may be used in order to modulate the signal (e.g., Stephens et al, Biochemical j., 2000, 351, 95-105). The compounds of the invention may also be used as reagents for testing kinase-dependent signal transduction pathways in animal and/or cell culture models or in clinical diseases as described herein.
Determination of kinase activity is a well-known technique to those skilled in the art. General test systems for determining kinase activity using substrates such as histones (e.g.Alessi et al, FEBS Lett.1996, 399, 3, page 333-338) or basic myelin proteins are described in the literature (e.g.Campos-Gonz lez, R. and Glenney, Jr., J.R.1992, J.biol.chem.267, page 14535).
To identify kinase inhibitors, various assay systems can be utilized. In the scintillation proximity assay (Sorg et al, j.of.biomolecular Screening, 2002, 7, 11-19) and flash plate assay, gamma ATP is used to measure the radioactive phosphorylation of proteins or peptides as substrates. In the presence of the inhibitory compound, a reduced radioactive signal or no radioactive signal at all can be detected. Furthermore, uniform time-resolved fluorescence resonance energy transfer (HTR-FRET) and Fluorescence Polarization (FP) techniques are also suitable for use as assay methods (Sills et al, J.of Biomolecular Screening, 2002, 191-214).
Other non-radioactive ELISA assays use specific phospho-antibodies (phospho-AB). phospho-AB binds only phosphorylated substrates. This binding can be detected using a peroxidase conjugated anti-sheep secondary antibody based on chemiluminescence (Ross et al, 2002, biochem.j.).
There are many diseases associated with dysregulation of cell proliferation and cell death (apoptosis). Disorders of interest include, but are not limited to, the following. The compounds of the invention are suitable for use in the treatment of a variety of conditions in which there is proliferation and/or migration of smooth muscle cells and/or inflammatory cells into the vascular lining resulting in restricted blood flow through the blood vessel, for example in the case of neointimal occlusive lesions. Occlusive graft vascular diseases of interest include atherosclerosis, post-transplant coronary vascular disease, venous graft stenosis, peri-anastomotic prosthesis restenosis (peri-anatomical prosthetic restenosis), restenosis following angioplasty or stent placement, and the like.
Prior Art
WO 2007/019933 describes other dihydropyrazole derivatives as Met kinase inhibitors.
Other 4, 5-dihydropyrazoles useful against cancer are also disclosed in WO 03/079973A 2.
Summary of The Invention
The present invention relates to compounds of formula I and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios:
wherein:
R1represents Ar or Het;
R2represents H, A, Hal, OR3、N(R3)2、N＝CR3N(R3)2、SR3、NO2、CN、COOR3、CON(R3)2、NR3COA、NR3SO2A、SO2N(R3)2、S(O)mA、Het、-[C(R3)2]nN(R3)2、-[C(R3)2]nHet、O[C(R3)2]nN(R3)2、O[C(R3)2]nHet、S[C(R3)2]nN(R3)2、S[C(R3)2]nHet、-NR3[C(R3)2]nN(R3)2、-NR3[C(R3)2]nHet、NHCON(R3)2、NHCONH[C(R3)2]nN(R3)2、NHCONH[C(R3)2]nHet、NHCO[C(R3)2]nN(R3)2、NHCO[C(R3)2]nHet、CON(R3)2、CONR3[C(R3)2]nN(R3)2、CONR3[C(R3)2]nHet, COHet or COA;
R3、R3' represents H or A, and is selected from,
together also represent an alkylene group having 2 to 5C atoms;
R4representation H, A or Hal;
d represents a 5-or 6-membered unsaturated or aromatic heterocyclic ring having 1 to 3N, O and/or S atoms, which may be unsubstituted or mono-, di-or trisubstituted by Hal and/or a;
a represents unbranched or branched alkyl having 1 to 10C atoms in which 1 to 7H atoms may be replaced by OH, F, Cl and/or Br, and/or in which one or two CH groups2The radicals being selected from the group consisting of O, NH, S, SO2And/or CH ═ CH group substitution;
or
Cyclic alkyl having 3 to 7C atoms;
ar represents phenyl, naphthyl OR biphenyl, each of which is unsubstituted OR substituted by Hal, A, OR3、N(R3)2、SR3、NO2、CN、COOR3、CON(R3)2、NR3COA、NR3SO2A、SO2N(R3)2And/or S (O)mA is mono-, di-or tri-substituted;
het represents a mono-, bi-or tricyclic saturated, unsaturated or aromatic heterocycle having 1 to 4N, O and/or S atoms, which may be unsubstituted or mono-, di-or trisubstituted by: hal, A, OR3、N(R3)2、SR3、NO2、CN、COOR3、CON(R3)2、NR3COA、NR3SO2A、SO2N(R3)2、S(O)mA、CO-Het1、Het1、[C(R3)2]nN(R3)2、[C(R3)2]nHet1、O[C(R3)2]nN(R3)2、O[C(R3)2]nHet1、NHCOOA、NHCON(R3)2、NHCOO[C(R3)2]nN(R3)2、NHCOO[C(R3)2]nHet1、NHCONH[C(R3)2]nN(R3)2、NHCONH[C(R3)2]nHet1、OCONH[C(R3)2]nN(R3)2、OCONH[C(R3)2]nHet1、CO-Het1CHO, COA, ═ S, ═ NH, ═ NA and/or ═ O (carbonyl oxygen);
Het1represents a monocyclic saturated heterocycle having 1 to 2N and/or O atoms, which may be mono-or disubstituted by a, OA, OH, Hal and/or ═ O (carbonyl oxygen);
hal represents F, Cl, Br or I;
m represents 0, 1 or 2;
n represents 1, 2, 3 or 4.
The compounds of formula I are also useful as hydrates and solvates of these compounds and also as pharmaceutically acceptable derivatives.
The invention also relates to optically active forms (stereoisomers), enantiomers, racemates, diastereomers and hydrates and solvates of these compounds. Solvates of the compounds are used to mean the addition of inert solvent molecules to the compounds, which are formed as a result of their mutual attraction. Solvates are, for example, mono-or di-hydrates or alcoholates.
Pharmaceutically acceptable derivatives are used to refer to, for example, salts of the compounds of the invention, and also to so-called prodrug compounds.
Prodrug derivatives are used to refer to compounds of formula I which are modified with, for example, alkyl or acyl groups, sugars or oligopeptides and are rapidly cleaved in vivo to form the effective compounds of the invention. They also include biodegradable polymer derivatives of the compounds of the invention, such as, for example, int.j.pharm.11561-67 (1995).
The expression "effective amount" means the amount of an agent or pharmaceutically active ingredient that results in a biological or medical response in a tissue, system, animal or human that is, for example, sought or desired by a researcher or physician. Furthermore, the expression "therapeutically effective amount" denotes an amount which has the following result compared to the corresponding individual not receiving this amount: improved treatment, healing, prevention or elimination of a disease, syndrome, condition, disorder or side effect, or also reduction in progression of a disease, disorder or condition. The term "therapeutically effective amount" also includes an amount effective to increase normal physiological function.
The invention also relates to the use of mixtures of compounds of the formula I, for example mixtures of two diastereomers in a ratio of 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 10, 1: 100 or 1: 1000. These are particularly preferably mixtures of stereoisomeric compounds.
The present invention relates to compounds of formula I and salts thereof and to processes for the preparation of compounds of formula I according to claims 1 to 12 and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, characterized in that:
a) for the preparation of wherein R2A compound of formula I representing Het, a compound of formula II:
wherein R is1、R3、R3′、R4And D has the meaning indicated in claim 1;
with a compound of the formula III,
X-R2 III
wherein R is2Represents Het and X represents a boronic acid group (boronic acid radial),
or
b) For the preparation of wherein R2Represents O [ C (R)3)2]nHet of the formula I, or of the formula IV:
wherein R is1、R3、R3′、R4And D has the meaning indicated in claim 1;
with a compound of the formula V,
HO-R2 V，
wherein R is2Represents O [ C (R)3)2]nHet，
Or
c) Reacting a compound of formula VI
R1-CO-CH2-CH2-Cl VI
Wherein R is1Has the meaning indicated in claim 1;
with hydrazine and a compound of the formula VI,
wherein R is2、R3、R3′、R4And D has the meaning indicated in claim 1;
or
d) By acylation or alkylation of the amino group2Conversion to another group R2：
Or
e) Characterised in that they are released from one of their functional derivatives by treatment with a solvolysis or hydrogenolysis reagent;
and/or
Converting the base or acid of formula I into one of its salts.
Unless expressly stated otherwise, groups D, R in the context1、R2、R3、R3' and R4Have the meanings given for formula I.
A represents an alkyl group, unbranched (linear) or branched, having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10C atoms. A preferably represents methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore 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, furthermore preferably, for example, trifluoromethyl.
A very particularly preferably represents alkyl having 1, 2, 3, 4, 5 or 6C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl or 1, 1, 1-trifluoroethyl.
Cyclic alkyl (cycloalkyl) preferably denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
R1Preferably Ar.
R2Preferably H, A, Het, - [ C (R)3)2]nHet or O [ C (R)3)2]nHet。
R4Preferably represents H.
Ar denotes, for example, 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-nitrophenyl, o-, m-or p-aminophenyl, o-, m-or p- (N-methylamino) -phenyl, o-, m-or p- (N-methylaminocarbonyl) -phenyl, o-, m-or p-acetylaminophenyl, o-, m-or p-methoxyphenyl, o-, m-or p-ethoxyphenyl, o-, m-or p-ethoxycarbonyl-phenyl, 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- (methylsulfonylamino) -phenyl, o-, m-or p- (methylsulfonyl) -phenyl, o-, m-or p-methylthiophenyl, o-, m-or p-cyanophenyl, o-, m-or p-carboxyphenyl, o-, m-or p-methoxycarbonylphenyl, o-, m-or p-aminosulfonylphenyl, preferably also 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-4-acetylaminophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, 3-chloro-4-acetylaminophenyl or 2, 5-dimethyl-4-chlorophenyl.
Ar particularly preferably represents phenyl which is unsubstituted or mono-, di-or trisubstituted by Hal and/or CN.
Het represents, regardless of the further substitution, for example 2-or 3-furyl, 2-or 3-thienyl, 1-, 2-or 3-pyrrolyl, 1-, 2-, 4-or 5-imidazolyl, 1-, 3-, 4-or 5-pyrazolyl, 2-, 4-or 5-Azolyl, 3-, 4-or 5-isoOxazolyl, 2-, 4-or 5-thiazolyl, 3-, 4-or 5-isothiazolyl, 2-, 3-or 4-pyridyl, 2-, 4-, 5-or 6-pyrimidinyl, preferably also 1, 2, 3-triazol-1-, -4-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-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-, 4-, 5-, 6-or 7-benzopyrazolyl, 2-, 4-, 5-, 6-or 7-benzo.Azolyl, 3-, 4-, 5-, 6-or 7-benzisoxazoOxazolyl, 2-, 4-, 5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6-or 7-benzisothiazolyl, 4-, 5-, 6-or 7-benzo-2,1，3-oxadiazolyl, 2-, 3-, 4-, 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, preferably also 1, 3-benzodioxol-5-yl, 1, 4-benzodiAlk-6-yl, 2, 1, 3-benzothiadiazol-4-or-5-yl, 2, 1, 3-benzoOxadiazol-5-yl or dibenzofuranyl.
The heterocyclic group may also be partially or fully hydrogenated.
Thus, Het regardless of the further substitution1And Het2It may also represent, for example, 2, 3-dihydro-2-, -3-, -4-or-5-furyl, 2, 5-dihydro-2-, -3-, -4-or-5-furyl, tetrahydro-2-or-3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2-or-3-thienyl, 2, 3-dihydro-1-, -2-, -3-, -4-or-5-pyrrolyl, 2, 5-dihydro-1-, -2-, -3-, -4-or-5-pyrrolyl, 1-, 2-or 3-pyrrolidinyl, tetrahydro-1-, -2-or 4-imidazolyl, 2, 3-dihydro-1-, -2-, -3-, -4-or 5-pyrazolyl, tetrahydro-1-, -3-or 4-pyrazolyl, 1, 4-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-piperidyl, 2-, 3-or 4-morpholinyl, tetrahydro-2-, -3-or 4-pyranyl, 1, 4-diylAlkyl, 1, 3-diAlk-2-, -4-or-5-yl, hexahydro-1-, -3-or-4-pyridazinyl, hexahydro-1-, -2-, -4-or-5-pyrimidinyl, 1-, 2-or 3-piperazinyl, 1, 2, 3, 4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7-or-8-quinolinyl, 1, 2, 3, 4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7-or-8-isoquinolinyl, 2-, 3-, 5-, 6-, 7-or 8-3, 4-dihydro-2H-benzo-1, 4-Oxazinyl, preferably also 2, 3-methylenedioxyphenyl, 3, 4-methylenedioxyphenyl, 2, 3-ethylenedioxyphenyl, 3, 4- (difluoromethylenedioxy) phenyl, 2, 3-dihydro-benzofuran-5-or 6-yl, 2, 3- (2-oxomethylenedioxy) -phenyl or also 3, 4-dihydro-2H-1, 5-benzodioxepin-6-or-7-yl, preferably also 2, 3-dihydrobenzofuranyl, 2, 3-dihydro-2-oxofuranyl, 3, 4-dihydro-2-oxo-1H-quinazolinyl, 2, 3-dihydrobenzo.Azolyl, 2-oxo-2, 3-dihydrobenzoAzolyl, 2, 3-dihydrobenzimidazolyl, 1, 3-indoline, 2-oxo-1, 3-indoline, or 2-oxo-2, 3-dihydrobenzimidazolyl.
Het particularly preferably represents a monocyclic saturated, unsaturated or aromatic heterocycle having 1 to 4N, O and/or S atoms, which may be unsubstituted or substituted by A and/or [ C (R)3)2]nHet1Mono-, di-or tri-substituted.
Het very particularly preferably represents piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl,Oxazolidinyl, pyrazolyl, pyridinyl, pyrimidinyl, furanyl, thienyl,Azolyl group,Oxadiazolyl, imidazolyl, pyrrolyl, isoxazolylAzolyl or imidazolidinyl, where the radicals may also be substituted by A and/or [ C (R)3)2]nHet1Mono-or di-substituted.
Het1Preferably represents piperidyl, pyrrolidinyl, morpholinyl, piperazinyl,Oxazolidinyl or imidazolidinyl, where the radicals may also be mono-or disubstituted by ═ O and/or a.
D represents, regardless of the further substitution, for example, thiazolediyl, thiophenediyl, furandiyl, pyrrolediyl,Azolediyl, isoA diazoldiyl group,Oxadiazolyl, pyrazolediyl, imidazolediyl, thiadiazolediyl, pyridazindiyl, pyrazinediyl, pyridinediyl or pyrimidinediyl, wherein the radicals may also be mono-, di-or trisubstituted by Hal and/or a.
Hal preferably denotes F, Cl or Br, but may also be I, particularly preferably F or Cl.
Throughout the present invention, all groups appearing more than once may be the same or different, i.e. they are independent of each other.
The compounds of formula I may have one or more chiral centers and may therefore occur in a variety of stereoisomeric forms. Formula I includes all of these forms.
The present invention therefore relates in particular to compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred groups of compounds may be represented by the following subformulae Ia to Ij, which conform to formula I and in which the groups not specified in more detail have the meanings indicated for formula I, but wherein:
in Ia, R1Represents Ar;
in Ib, R2Is represented by H, A, Het, - [ C (R)3)2]nHet or O [ C (R)3)2]nHet；
In Ic, Ar represents phenyl which is mono-, di-or trisubstituted by Hal and/or CN;
in Id, A represents an unbranched or branched alkyl group having 1 to 6C atoms;
in Ie, R4Represents H;
in If, D represents a thiazolediyl group, a thiophenediyl group, a furandiyl group, a pyrrolediyl group,Azolediyl, isoA diazoldiyl group,Oxadiazolyl, pyrazoldiyl, imidazoldiyl, thiadiazoldiyl, pyridazindiyl, pyrazindiyl, pyridinediyl or pyrimidinediyl; wherein said radicals may also be mono-, di-or trisubstituted by Hal and/or A;
in Ig Het represents a monocyclic saturated, unsaturated or aromatic heterocycle having 1 to 4N, O and/or S atoms, which may be unsubstituted or substituted by A and/or [ C (R)3)2]nHet1Mono-, di-or tri-substituted;
in Ih Het represents piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl,Oxazolidinyl, pyrazolyl, pyridinyl, pyrimidinyl, furanyl, thienyl,Azolyl group,Oxadiazolyl, imidazolyl, pyrrolyl, isoxazolylAzolyl or imidazolidinyl, where the radicals may also be substituted by A and/or [ C (R)3)2]nHet1Mono-or di-substituted;
in Ii, Het1Represents piperidyl, pyrrolidinyl, morpholinyl, piperazinyl,Oxazolidinyl or imidazolidinyl, where the radicals may also be mono-or disubstituted by ═ O and/or a;
in Ij, R1Represents the group Ar of a compound represented by the formula,
R2is represented by H, A, Het, - [ C (R)3)2]nHet or O [ C (R)3)2]nHet；
R3、R3' represents H or A, and is selected from,
together also represent an alkylene group having 2 to 5C atoms;
R4the expression "H" is used to indicate the formula,
d represents a thiazolediyl group, a thiophenediyl group, a furandiyl group, a pyrrolediyl group,Azolediyl, isoA diazoldiyl group,Oxadiazolyl, pyrazolediyl, imidazolediyl, thiadiazolediyl, pyridazindiyl, pyrazinediyl, pyridinediyl or pyrimidinediyl, wherein the radicals may also be mono-, di-or trisubstituted by Hal and/or A,
a represents an unbranched or branched alkyl group having 1 to 6C atoms,
ar represents phenyl which is mono-, di-or trisubstituted by Hal and/or CN,
het represents a monocyclic saturated, unsaturated or aromatic heterocycle having 1 to 4N, O and/or S atoms, which may be unsubstituted or substituted by A and/or [ C (R)3)2]nHet1Mono-, di-or tri-substituted,
Het1represents piperidyl, pyrrolidinyl, morpholinyl, piperazinyl,Oxazolidinyl or imidazolidinyl, where the radicals may also be mono-or disubstituted by ═ O and/or A,
hal represents F, Cl, Br or I,
n represents 1, 2, 3 or 4,
and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.
Furthermore, the compounds of the formula I and the starting materials for their preparation are prepared by processes known per se, such as those described in the literature (for example in standard works such as Houben-Weyl, Methoden der organischen Chemie [ methods of organic chemistry ], Georg-Thieme-Verlag, Stuttgart), precisely under reaction conditions which are known and suitable for the reaction in question. Variants known per se and not mentioned in more detail here can also be used here.
Preferably the compound of formula I is obtainable by reacting a compound of formula II with a compound of formula III. The reaction is carried out under conditions as known to the person skilled in the art for Suzuki (Suzuki) reactions.
The starting compounds of the formulae II and III are generally known. However, if they are novel, they can be prepared by methods known per se. In the compounds of the formula III, X preferably represents
The reaction was carried out under standard conditions for Suzuki (Suzuki) coupling. Depending on the conditions used, the reaction time is from a few minutes to 14 days and the reaction temperature is from about-30 ° to 140 °, usually from 0 ° to 100 °, in particular from about 60 ° to about 90 °.
Suitable inert solvents are, for example: hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, e.g. diethyl ether, diisopropyl ether, Tetrahydrofuran (THF) or diisopropyl etherAn alkane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether, ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide or Dimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; 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. Dimethoxyethane is particularly preferred.
Furthermore, it is preferred that the compound of formula I is obtainable by reacting a compound of formula IV with a compound of formula V. The starting compounds of the formulae IV and V are generally known. However, if they are novel, they can be prepared by methods known per se. Depending on the conditions used, the reaction time is from a few minutes to 14 days and the reaction temperature is from about-30 ° to 140 °, usually from 0 ° to 100 °, in particular from about 60 ° to about 90 °. Suitable inert solvents are, for example: hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, e.g. diethyl ether, diisopropyl ether, Tetrahydrofuran (THF) or diisopropyl etherAn alkane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether, ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide or Dimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; 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. THF is particularly preferred.
Furthermore, it is preferred that the compound of formula I is obtainable by reacting a compound of formula VI with a compound of formula VII. The starting compounds of the formulae VI and VII are generally known. However, if they are novel, they can be prepared by methods known per se. Depending on the conditions used, the reaction time is from a few minutes to 14 days and the reaction temperature is from about-30 ° to 140 °, usually from 0 ° to 100 °, in particular from about 60 ° to about 90 °. Suitable inert solvents are, for example: hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, e.g. diethyl ether, diisopropyl ether, Tetrahydrofuran (TH)F) Or twoAn alkane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether, ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide or Dimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; 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.
It is also possible to use the radicals R2Conversion to another group R2The compound of formula I is converted to another compound of formula I, for example by reduction of the nitro group to an amino group (for example by hydrogenation over raney nickel or Pd on carbon in an inert solvent such as methanol or ethanol).
Moreover, the free amino group can be acylated in a conventional manner using an acid chloride or anhydride or alkylated using an unsubstituted or substituted alkyl halide, advantageously in an inert solvent such as dichloromethane or THF and/or in the presence of a base such as triethylamine or pyridine at temperatures of-60 ℃ to +30 ℃.
The compounds of the formula I can also be obtained by liberation from their functional derivatives by solvolysis, in particular by hydrolysis or by hydrogenolysis.
Preferred starting materials for solvolysis or hydrogenolysis are those containing the corresponding protected amino and/or hydroxyl group instead of one or more free amino and/or hydroxyl groups, preferably those carrying an amino protecting group instead of a bond of an H atom to an N atom, e.g. corresponding to formula I, but containing a NHR 'group (wherein R' is an amino protecting group such as BOC or CBZ) instead of NH2Those of the group.
Preference is also given to starting materials which carry a hydroxyl-protecting group instead of the H atom of a hydroxyl group, for example those which conform to formula I but contain R 'O-phenyl (where R' is a hydroxyl-protecting group) instead of hydroxy-phenyl.
A plurality of identical or different protected amino and/or hydroxyl groups can also be present in the starting molecule. If the protecting groups present are different from each other, they can in many cases be selectively cleaved off.
The term "amino protecting group" is known in general terms and relates to a group which is suitable for protecting (blocking) an amino group from a chemical reaction, but which is easily removed after the intended chemical reaction has been performed elsewhere in the molecule. Typical of such groups are in particular unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl radicals. Since the amino protecting group is removed after the intended reaction (or reaction sequence), its type and size are not critical; however, those having 1 to 20, in particular 1 to 8, carbon atoms are preferred. The term "acyl" should be understood in the broadest sense of the process of the present invention. It includes acyl groups derived from aliphatic, araliphatic, aromatic and heterocyclic carboxylic or sulfonic acids and especially alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups are: alkanoyl groups such as acetyl, propionyl and butyryl; aralkanoyl, such as phenylacetyl; aroyl groups such as benzoyl and tolyl; aryloxyalkanoyl, such as POA; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2, 2, 2-trichloroethoxycarbonyl, BOC and 2-iodoethoxycarbonyl; aralkoxycarbonyl, such as CBZ ("benzyloxycarbonyl"), 4-methoxybenzyloxycarbonyl, and FMOC; and arylsulfonyl groups such as Mtr, Pbf, and Pmc. Preferred amino protecting groups are BOC and Mtr, as well as CBZ, Fmoc, benzyl and acetyl.
The term "hydroxy-protecting group" is also known in general terms and relates to a group which is suitable for protecting a hydroxy group from chemical reactions, but which is easily removed after the intended chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are the unsubstituted or substituted aryl, aralkyl or acyl groups mentioned above, and in addition alkyl groups. Since the hydroxyl protecting group is removed after the intended reaction or reaction sequence, its nature and size are not critical; preference is given to those having from 1 to 20, in particular from 1 to 10, carbon atoms. Examples of hydroxyl-protecting groups are, in particular, tert-butoxycarbonyl, benzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, with benzyl and tert-butyl being particularly preferred. The COOH groups in aspartic and glutamic acids are preferably protected in the form of their tert-butyl esters (e.g., Asp (OBut)).
The compounds of the formula I are liberated from their functional derivatives, depending on the protective groups used, for example using strong acids, advantageously TFA or perchloric acid, but also using other strong inorganic acids, such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids, such as trichloroacetic acid, or sulfonic acids, such as benzenesulfonic acid or p-toluenesulfonic acid. The presence of additional inert solvents is possible, but not always necessary. Suitable inert solvents are preferably organic solvents, for example: carboxylic acids, such as acetic acid; ethers, e.g. tetrahydrofuran or diAn alkane; amides, such as DMF; halogenated hydrocarbons such as dichloromethane; and also alcohols, such as methanol, ethanol or isopropanol; and water. Mixtures of the above solvents are also suitable. Preferably, an excess of TFA is used and no additional solvent is added, and the perchloric acid is preferably used as a 9: 1 mixture of acetic acid and 70% perchloric acid. The reaction temperature for the cleavage is advantageously from about 0 ° to about 50 °, preferably from 15 ° to 30 ° (room temperature).
The BOC, OBut, Pbf, Pmc and Mtr groups can be, for example, preferably used TFA in dichloromethane or about 3-5N HCl in bisSolutions in alkanes cleave at 15-30 ℃ and FMOC groups can cleave at 15-30 ℃ using about 5-50% solutions of dimethylamine, diethylamine or piperidine in DMF.
The amino acids histidine, asparagine, glutamine and cysteine were protected with trityl. They were cleaved using TFA/10% thiophenol (depending on the desired end product), with the trityl group cleaved from all the amino acids; when TFA/anisole or TFA/thioanisole is used, only the trityl groups of His, Asn and gin are cleaved off, while they are retained on the Cys side chain. Pbf (pentamethylbenzofuranyl) was used to protect Arg. It is cleaved off by using, for example, TFA in dichloromethane.
For example, a protecting group which is removable by hydrogenolysis (e.g. CBZ or benzyl) can be cleaved off, for example, by treatment with hydrogen in the presence of a catalyst (e.g. a noble metal catalyst such as palladium, advantageously on a support such as carbon). Suitable solvents here are those mentioned above, in particular, for example, alcohols, such as methanol or ethanol; or amides, such as DMF. The hydrogenolysis is generally carried out at a temperature of about 0 to 100 ℃ and a pressure of about 1 to 200 bar, preferably 20 to 30 ℃ and 1 to 10 bar. Hydrogenolysis of the CBZ group is very successful, for example on 5-10% Pd/C, in methanol or with ammonium formate (instead of hydrogen) on Pd/C, in methanol/DMF at 20-30 ℃.
Pharmaceutically acceptable salts and other forms
The compounds of the present invention may be used in their final non-salt form. In another aspect, the invention also includes the use of pharmaceutically acceptable salt forms of these compounds, which can be derived from various organic and inorganic acids and bases by procedures known in the art. The pharmaceutically acceptable salt forms of the compounds of formula I are in large part prepared by conventional methods. If a compound of formula I contains a carboxy group, one of its suitable salts may be formed by reacting that compound with a suitable base to yield the corresponding base addition salt. Such bases are, 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 alkoxides such as potassium ethoxide and sodium propoxide; and various organic bases such as piperidine, diethanolamine and N-methyl-glutamine. Also included are aluminum salts of the compounds of formula I. For certain compounds of formula I, acid addition salts may be formed by treating these compounds with pharmaceutically acceptable organic and inorganic acids, for example hydrogen halides, such as hydrogen chloride, hydrogen bromide or hydrogen iodide; other inorganic acids and their corresponding salts, such as sulfates, nitrates or phosphates, etc.; and alkyl-and monoaryl-sulfonates, such as ethanesulfonate, toluenesulfonate and benzenesulfonate; and other organic acids and their corresponding salts, such as acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate, and the like. Thus, pharmaceutically acceptable acid addition salts of the compounds of formula I include the following salts: acetate, adipate, alginate, arginine, aspartate, benzoate, benzenesulfonate (phenylsulfonate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galactarate (from mucic acid), galacturonate, glucoheptonate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, maleate, hydrochloride, hydrobromide, salicylate, and mixtures thereof, Malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate (palmoate), pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but this is not intended to be limiting.
Further, the base salt of the compound of the present invention includes aluminum salt, ammonium salt, calcium salt, copper salt, iron (ll) salt, lithium salt, magnesium salt, manganese (ll) salt, potassium salt, sodium salt and zinc salt, but this is not meant to be limited thereto. Among the above salts, ammonium salts are preferred; alkali metal salt sodium and potassium salts, and alkaline earth metal salt calcium and magnesium salts. Salts of the compounds of formula I derived from pharmaceutically acceptable organic non-toxic bases include salts of: primary, secondary and tertiary amines, substituted amines, and also naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, chloroprocaine, choline, 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 meant to be limiting.
The compounds of the present invention containing basic nitrogen-containing groups may be quaternized with materials such as: (C)1-C4) Alkyl halides such as methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; sulfuric acid di (C)1-C4) Alkyl esters such as dimethyl, diethyl and diamyl sulfate; (C)10-C18) Alkyl halides such as decyl, dodecyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aryl (C)1-C4) Alkyl halides, such as benzyl chloride and phenethyl bromide. Such salts can be used to prepare water-soluble and oil-soluble compounds of the invention.
Preferred such pharmaceutically acceptable salts include, but are not limited to, acetate, trifluoroacetate, benzenesulfonate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine.
Particularly preferred are the hydrochloride, dihydrochloride, hydrobromide, maleate, methanesulfonate, phosphate, sulfate and succinate salts.
The acid addition salts of the 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 form differs from its corresponding salt form in some respects with respect to certain physical properties, for example solubility in polar solvents; however, for the purposes of the present invention, salts are otherwise comparable to their respective free base forms.
As mentioned above, pharmaceutically acceptable base addition salts of the compounds of formula I are formed with metals or amines, such as alkali 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.
Base addition salts of the acidic compounds of the present 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 may be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid form differs from its corresponding salt form in some respects with respect to certain physical properties, for example solubility in polar solvents; however, for the purposes of the present invention, salts are otherwise comparable to their respective free acid forms.
If the compounds of the present invention contain more than one group capable of forming such pharmaceutically acceptable salts, the present invention also includes multiple salts. Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, meglumine, diphosphate, disodium salt, and trihydrochloride, but this is not intended to be limiting.
In the light of the above, it can be seen that the expression "pharmaceutically acceptable salt" in this context refers to an active ingredient comprising a compound of formula I in the form of one of its salts, in particular if this salt form confers improved pharmacokinetic properties on the active ingredient compared to the free form of the active ingredient or any other salt form of the active ingredient used earlier. The pharmaceutically acceptable salt form of the active ingredient may also provide the active ingredient for the first time with desirable pharmacokinetic properties not previously possessed by it, and may even have a positive effect on the pharmacodynamics of the active ingredient in terms of its in vivo therapeutic effect.
The invention also relates to medicaments comprising at least one compound of the formula I and/or pharmaceutically acceptable salts and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and/or adjuvants.
The pharmaceutical preparations may be administered in dosage units containing a predetermined amount of the active ingredient per dosage unit. Such units may comprise, for example, from 0.5mg to 1g, preferably from 1mg to 700mg, particularly preferably from 5mg to 100mg, of a compound of the invention, depending on the condition to be treated, the method of administration and the age, weight and condition of the patient, or pharmaceutical preparations may be administered in dosage units comprising a predetermined amount of active ingredient per dosage unit. Preferred dosage unit formulations are those containing the above-described daily dose or partial dose or a fraction thereof of the active ingredient. In addition, such pharmaceutical preparations may be prepared by methods generally known in the pharmaceutical field.
The pharmaceutical formulations may be adapted for administration by any desired suitable method, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods. Such formulations may be prepared by all methods known in the art of pharmacy, for example by combining the active ingredient with excipients or auxiliaries.
Pharmaceutical formulations adapted for oral administration may be administered in the form of discrete units such as capsules or tablets; a powder or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
Thus, for example, for oral administration in the form of a tablet or capsule, the active ingredient component can be combined with non-toxic pharmaceutically acceptable oral inert excipients such as ethanol, glycerol, water and the like. Powders may be prepared by comminuting the compound to a suitably fine size and mixing it with a pharmaceutical excipient, such as an edible carbohydrate, for example starch or mannitol, comminuted in a similar manner. Flavoring, preservative, dispersing and coloring agents may also be present.
Capsules are prepared by preparing a powder mixture as described above and filling into shaped gelatin capsule shells. Glidants and lubricants, such as highly disperse silicic acid, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form, can be added to the powder mixture before the filling operation. Disintegrating or solubilizing agents such as agar-agar, calcium carbonate or sodium carbonate may also be added to enhance the availability of the drug after the capsule is used.
In addition, if desired or necessary, suitable binders, lubricants and disintegrants and also dyes can be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, sweeteners made from corn, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. Tablets are prepared, for example, by preparing a powder mixture, granulating or dry-compressing the mixture, adding a lubricant and a disintegrant, and compressing the entire mixture into a tablet. Powder mixtures are prepared by mixing the compounds comminuted in a suitable manner with the above-mentioned diluents or bases and optionally with binders such as carboxymethylcellulose, alginates, gelatin or polyvinylpyrrolidone, dissolution retarders such as paraffin, absorption promoters such as quaternary salts and/or absorbents such as bentonite, kaolin or dicalcium phosphate. The powder mixture may be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and sieving. As an alternative to granulation, the powder mixture may be passed through a tablet press to obtain a non-uniformly shaped mass which is broken up to form granules. The granules may be lubricated to prevent sticking to the tablet mould by the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. It is also possible to combine the compounds of the present invention with free flowing inert excipients and then compress directly into tablets without a granulation or dry compression step. There may be a transparent or opaque protective layer consisting of a shellac barrier layer, a layer of sugar or polymer material and a glossy layer of wax. Dyes may be added to these coatings to enable differentiation between different dosage units.
Oral liquids such as solutions, syrups and elixirs may be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in an aqueous solution with a suitable flavoring agent, while elixirs are prepared with a non-toxic alcoholic vehicle. Suspensions may be prepared by dispersing the compound in a non-toxic vehicle. Solubilizing agents and emulsifiers 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, and the like may also be added.
Dosage unit formulations for oral administration may be encapsulated in microcapsules, if desired. The formulations may also be prepared in a form in which the release is extended or delayed, such as by coating the particulate material with or embedding it in a polymer, wax or the like.
The compounds of formula I and salts thereof may also be administered in the form of liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
The compounds of formula I and salts thereof may also be delivered using a monoclonal antibody as a separate carrier, wherein the compound molecule is conjugated to the monoclonal antibody. The compounds may also be coupled to soluble polymers as targeted drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenol, or polyethyleneoxide polylysine, substituted with palmitoyl groups. The compounds may also be coupled to a class of biodegradable polymers suitable for achieving controlled release of a drug, such as polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates, and cross-linked or amphiphilic block copolymer hydrogels.
Pharmaceutical formulations adapted for transdermal administration may be administered as a separate plaster in intimate contact with the epidermis of the recipient for an extended period of time. Thus, for example, iontophoresis may be used to deliver the active ingredient from a plaster, as described in general terms in Pharmaceutical Research, 3(6), 318 (1986).
Pharmaceutical compounds suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
For the treatment of the eye or other external tissues, such as the mouth and skin, the formulations are preferably applied in the form of a topical ointment or cream. In the case of formulating an ointment, the active ingredient may be applied together with a paraffinic or water-miscible cream base. Alternatively, the active ingredient may be formulated as a cream in an oil-in-water cream base or a water-in-oil base.
Pharmaceutical formulations suitable for topical application to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, particularly an aqueous solvent.
Pharmaceutical formulations adapted for topical application in the mouth include lozenges, pastilles and mouthwashes.
Pharmaceutical preparations suitable for rectal administration may be administered in the form of suppositories or enemas.
Pharmaceutical preparations suitable for nasal administration, in which the carrier substance is a solid, comprise a coarse powder having a particle size of, for example, 20 to 500 μm, which can be administered in an olfactory manner, i.e. by rapid inhalation from a powder-containing container near the nose via the nasal passage. Suitable formulations for administration as liquid carrier materials, as nasal sprays or nasal drops, comprise solutions of the active ingredient in water or oil.
Pharmaceutical formulations adapted for administration by inhalation comprise a fine particulate powder or mist which may be produced by various types of aerosol-containing pressurised dispensers, nebulisers or insufflators.
Pharmaceutical formulations adapted for vaginal administration may be administered in the form of pessaries, tampons, creams, gels, pastes, foams or spray formulations.
Pharmaceutical formulations suitable for parenteral administration include: aqueous and non-aqueous sterile injection solutions containing antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the recipient being treated; and aqueous and non-aqueous sterile suspensions which may contain a suspending medium and a thickening agent. The formulations may be administered in unit-dose or multi-dose containers, for example sealed ampoules and vials, and stored in a freeze-dried (lyophilized) condition so that the addition of a sterile carrier liquid, for example water for injections, is required only immediately prior to use. Injection solutions and suspensions prepared according to the prescription can be prepared from sterile powders, granules, and tablets.
It is understood that the formulations may contain, in addition to the ingredients particularly mentioned above, other materials conventionally used in the art for the particular type of formulation; thus, for example, formulations suitable for oral administration may contain flavouring agents.
The therapeutically effective amount of a compound of formula I will depend upon a number of factors including, for example, the age and weight of the animal, the precise condition to be treated and its severity, the nature of the formulation and the method of administration, and will ultimately be at the discretion of the attendant physician or veterinarian. However, an effective amount of a compound of the invention for use in the treatment of tumor growth, e.g., colon or breast cancer, is generally from 0.1 to 100mg/kg of recipient (mammal) weight per day, and in particular is typically from 1 to 10mg/kg of body weight per day. Thus, for an adult mammal weighing 70kg, the actual amount per day is typically 70 to 700mg, wherein the amount may be administered as a single dose per day or typically in a series of partial doses per day (e.g., two, three, four, five or six partial doses) such that the total daily dose is the same. An effective amount of a salt or solvate or physiologically functional derivative thereof may be determined as an effective amount fraction of the compound of the present invention per se. Similar dosages may be considered suitable for the treatment of the other conditions mentioned above.
The invention also relates to medicaments which comprise at least one compound of the formula I and/or pharmaceutically acceptable salts and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further pharmaceutically active ingredient.
The invention also relates to a kit (kit) consisting of the following individual pharmaceutical packs:
(a) an effective amount of a compound of formula I and/or pharmaceutically acceptable salts and stereoisomers thereof, including mixtures thereof in all ratios;
(b) an effective amount of other pharmaceutically active ingredients.
The kit comprises a suitable container, such as a box, individual bottle, pouch or ampoule. The kit may comprise, for example, separate ampoules each containing an effective amount of a compound of formula I and/or pharmaceutically acceptable salts and stereoisomers thereof, including mixtures thereof in all ratios; and an effective amount of other pharmaceutically active ingredients, in dissolved or lyophilized form.
Applications of
The compounds of the invention are suitable as pharmaceutical active ingredients for mammals, especially for humans, for the treatment of tyrosine kinase-induced diseases. These diseases include tumor cell proliferation, pathological neovascularization (or angiogenesis) that promotes the growth of solid tumors, ocular neovascularization (diabetic retinopathy, age-induced macular degeneration, etc.), and inflammation (psoriasis, rheumatoid arthritis, etc.).
The invention encompasses the use of a compound of formula I and/or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of cancer. Preferred cancers to be treated are cancers derived from brain, genitourinary tract, lymphatic system, stomach, larynx and lung cancers. Another group of preferred forms of cancer are monocytic leukemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic carcinoma, glioblastoma and breast carcinoma.
Also included is the use of a compound of claim 1 of the present invention and/or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of diseases in which angiogenesis is involved.
Such diseases in which angiogenesis is involved are ocular diseases such as retinal vascularization, diabetic retinopathy, age-induced macular degeneration and the like.
The use of compounds of formula I and/or physiologically acceptable salts and solvates thereof for the preparation of a medicament for the treatment or prevention of inflammatory diseases also falls within the scope of the present invention. Examples of such inflammatory diseases include rheumatoid arthritis, psoriasis, contact dermatitis, delayed type hypersensitivity reactions, and the like.
Also included is the use of a compound of formula I and/or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a tyrosine kinase-induced disease or a tyrosine kinase-induced disorder in a mammal, wherein for the method a therapeutically effective amount of a compound of the invention is administered to a mammal in need of such treatment. The amount of treatment will vary depending on the particular disease and can be determined by one skilled in the art without undue experimentation.
The invention also encompasses the use of a compound of formula I and/or physiologically acceptable salts and solvates thereof for the preparation of a medicament for the treatment or prevention of retinal vascularization.
Methods for treating or preventing ocular diseases such as diabetic retinopathy and age-induced macular degeneration are also part of the invention. The use for the treatment or prevention of inflammatory diseases such as rheumatoid arthritis, psoriasis, contact dermatitis and delayed hypersensitivity and the use for the treatment or prevention of bone diseases from osteosarcoma, osteoarthritis and rickets also fall within the scope of the present invention.
The expression "tyrosine kinase-induced disease or condition" refers to a pathological condition that depends on the activity of one or more tyrosine kinases. Tyrosine kinases are involved directly or indirectly in signal transduction pathways for a variety of cellular activities, including proliferation, adhesion and migration, and differentiation. Diseases associated with tyrosine kinase activity include tumor cell proliferation, pathological neovascularization that promotes the growth of solid tumors, ocular neovascularization (diabetic retinopathy, age-induced macular degeneration, etc.), and inflammation (psoriasis, rheumatoid arthritis, etc.).
The compounds of formula I may be administered to a patient in order to treat cancer, particularly rapidly growing tumors.
The invention thus relates to the use of compounds of formula I and their pharmaceutically acceptable salts and stereoisomers, including mixtures thereof in all ratios, for the preparation of medicaments for the treatment of diseases in which inhibition, modulation and/or modulation of kinase signal transduction plays a role.
Preferably, Met kinase is involved herein.
The use of preferred compounds of the formula I and their pharmaceutically acceptable salts and stereoisomers, including mixtures thereof in all ratios, for the preparation of medicaments for the treatment of diseases which are influenced by the inhibition of tyrosine kinases by compounds according to claim 1.
Particularly preferred is the use for the preparation of a medicament for the treatment of diseases which are influenced by the inhibition of Met kinase by the compounds of claim 1. Particularly preferred is the use for the treatment of a disease, wherein the disease is a solid tumor.
The solid tumor is preferably selected from tumors of the lung, squamous epithelium, bladder, stomach, kidney, head and neck, esophagus, cervix, thyroid, intestine, liver, brain, prostate, genito-urinary tract, lymphatic system, stomach and/or larynx.
The solid tumor is also preferably selected from lung adenocarcinoma, small cell lung carcinoma, pancreatic carcinoma, glioblastoma, colon carcinoma and breast carcinoma.
Also preferred is the use for the treatment of tumors of the blood and immune system, preferably tumors selected from the group consisting of acute myeloid leukemia, chronic myeloid leukemia, acute lymphoid leukemia and/or chronic lymphoid leukemia.
The disclosed compounds of formula I may be used in combination with other known therapeutic agents, including anticancer agents. The term "anti-cancer agent" as used herein relates to any substance administered to a cancer patient intended to treat cancer.
The anti-cancer therapies defined herein may be administered as monotherapy or may include, in addition to a compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following classes of antineoplastic agents:
(i) antiproliferative/antineoplastic/DNA-damaging agents and combinations thereof, such as for medical oncology, such as alkylating agents (e.g., cisplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, and nitrosoureas); antimetabolites (e.g., antifolates such as fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytarabine, hydroxyurea, and gemcitabine); antitumor antibiotics (e.g., anthracyclines such as adriamycin, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, actinomycin D, and mithramycin); antimitotic agents (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine and taxanes such as taxol and taxotere); topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, irinotecan, and camptothecin) and cellular differentiation agents (e.g., all-trans retinoic acid, 13-cis-retinoic acid, and fenretinide);
(ii) cytostatics, such as antiestrogens (e.g., tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene (idoxifene), estrogen receptor down-regulators (e.g., fulvestrant), antiandrogens (e.g., bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprolide and buserelin), pregnones (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorazole (vorozolozole) and exemestane), and 5 α -reductase inhibitors such as finasteride;
(iii) substances that inhibit cancer cell invasion (e.g., metalloproteinase inhibitors such as marimastat and urokinase-plasminogen activator receptor function inhibitors);
(iv) inhibitors of growth factor function, e.g., such inhibitors include growth factor antibodies, growth factor receptor antibodies (e.g., anti-erbb 2-antibody trastuzumab [ Herceptin ]TM]And the anti-erbb 1-antibody cetuximab [ C225]) Farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, e.g. inhibitors of the epidermal growth factor family (e.g. inhibitors of the EGFR family of tyrosine kinases, such asN- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine (gefitinib, AZD1839),N- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy) quinazolin-4-amine (erlotinib, OS1-774) and 6-acrylamido-N- (3-chloro-4-fluorophenyl) -7- (3-morpholinopropoxy) quinazolin-4-amine (Cl 1033)); such as platelet derived growth factor family inhibitors and such as hepatocyte growth factor family inhibitors;
(v) anti-angiogenic agents, such as those that inhibit vascular endothelial growth factor (e.g., anti-vascular endothelial growth factor antibody bevacizumab [ Avastin ]TM]Those compounds as disclosed in published international patent applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that act through other mechanisms (e.g., linoamine, integrin- α v β 3 function inhibitors and angiostatin);
(vi) vascular damaging agents such as combretastatin a4 and the compounds disclosed in international patent applications WO99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
(vii) antisense therapies, such as those involving the above targets, such as the anti-Ras antisense lSlS 2503;
(viii) gene therapy approaches including, for example, approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA 2; GDEPT (gene-directed enzyme prodrug therapy) approaches such as those using cytosine deaminase, thymidine kinase, or bacterial nitroreductase; and means for increasing the patient's tolerance to chemotherapy or radiation therapy, such as multi-drug resistance gene therapy; and
(ix) immunotherapy approaches, including for example ex vivo and in vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor; means for reducing T-cell anergy; means of using transfected immune cells such as cytokine-transfected dendritic cells; means for using cytokine-transfected tumor cell lines; and means for using anti-idiotype antibodies.
The medicaments from table 1 below are preferably, but not exclusively, used in combination with compounds of formula I.
Such combination therapy may be achieved by means of simultaneous, sequential or separate dispensing of the components of the therapy. This type of combination uses the compounds of the present invention.
Assay method
The compounds of formula I described in the examples were tested by the assays described below and found to have kinase inhibitory activity. Other assays are known in the literature and can be readily performed by those skilled in the art (see, e.g., Dhanabal et al, Cancer Res.59: 189-197; Xin et al, J.biol.chem.274: 9116-9121; Sheu et al, Anticancer Res.18: 4435-4441; Ausprunk et al, Dev.biol.38: 237-248; Gimbron et al, J.Natl.cancer lnst.52: 413-427; Nicosia et al, ln Vitro 18: 538-549).
Determination of Met kinase Activity
Met kinase was expressed according to the manufacturer's data (Met, activity, Upstate, cat # 14-526) with the aim of producing the protein in insect cells (Sf 21; Spodoptera frugiperda), followed by affinity chromatography purification as "N-terminal 6 His-tagged" recombinant human protein in a baculovirus expression vector.
Can be used forKinase activity is measured using a variety of available assay systems. Radiolabeled ATP is used in scintillation proximity assays (Sorg et al, J.of. biomolecular Screening, 2002, 7, 11-19), flash plate methods, or filter binding assays (II)32P-ATP，33P-ATP) to measure the radioactive phosphorylation of proteins or peptides as substrates. In the presence of the inhibitory compound, a reduced radioactive signal or no signal at all can be detected. Furthermore, uniform time-resolved fluorescence resonance energy transfer (HTR-FRET) and Fluorescence Polarization (FP) techniques can be used as assay methods (Sills et al, J.of biomolecular Screening, 2002, 191-214).
Other non-radioactive ELISA assays use specific Phospho-antibodies (Phospho-AB). The phospho-antibody binds only to phosphorylated substrates. This binding can be detected by chemiluminescence using a peroxidase-conjugated secondary antibody (Ross et al, 2002, biochem.j.).
Flash plate method (Met kinase)
The test plate used was a 96-well Flashplate from Perkin elmer (Perkin Eimer)RMicroplate (catalog number SMP 200). The following kinase reaction components were pipetted into the assay plate. Met kinase and substrate poly Ala-Glu-Lys-Tyr (pAGLT, 6: 2: 5: 1) are reacted with radiolabeled33P-ATP was incubated together in a total volume of 100. mu.l for 3 hours at room temperature in the presence and absence of the test substance. The reaction was stopped using 150. mu.l of 60mM EDTA solution. After a further incubation for 30 minutes at room temperature, the supernatant was filtered off with suction and the wells were washed three times with 200. mu.l of 0.9% NaCl solution each time. Bound radioactivity was measured with a scintillation counter (Topcount NXT, perkin elmer).
The full value used is the kinase response without inhibitor. It should be in the range of approximately 6000 and 9000 cpm. The pharmacological zero value used was staurosporine at a final concentration of 0.1 mM. Inhibition values (lC50) were determined using the RS1_ MTS program.
Kinase reaction conditions in each well:
30 μ l assay buffer
10 μ l of a solution of the test substrate containing 10% DMSO in assay buffer
10 μ l ATP (final concentration 1 μ M non-radioactive, 0.35 μ Ci)33P-ATP)
A solution of 50 μ l Met kinase/substrate mixture in assay buffer;
(10ng enzyme/well, 50ng pAGLT/well)
The solutions used were:
-assay buffer:
50mM HEPES
3mM magnesium chloride
3 μ M sodium orthovanadate
3mM manganese chloride (ll)
1mM Dithiothreitol (DTT)
pH 7.5 (set using sodium hydroxide)
-a stop solution:
60mM Titriplex lll(EDTA)
-33p-ATP: perkin elmer company;
-Met kinase: upstate, catalog number 14-526, stock 1 μ g/10 μ l; specific activity 954U/mg;
-poly-Ala-Glu-Lys-Tyr, 6: 2: 5: 1: sigma company catalog number P1152
In vivo testing
Experimental procedures: female Balb/C mice (breeder: Charles River Wiga) were 5 weeks old at arrival. They were acclimatized to our breeding environment for 7 days. Each mouse was then injected subcutaneously in the renal area with 4 million TPR-Met/NIH3T3 cells (without Ca + + and Mg + +) in 100. mu.l PBS. 5After day, animals were randomized into 3 groups of 9 mice each, resulting in an average tumor volume of 110 μ l (range 66-165) per group. The control group was administered 100. mu.l of vehicle per day (0.25% methylcellulose/100 mM acetate buffer (pH5.5)), and the treatment group was administered 200mg/kg of "A56" or "A91" (volume likewise 100. mu.l/animal) per day, in each case via gastric tube. After 9 days, the control group had an average volume of 1530. mu.l, and the experiment was terminated.
Determination of tumor volume: the length (L) and width (B) were measured with a vernier caliper and the tumor volume was calculated from the formula L.times.BxB/2.
Feeding conditions: 4 or 5 animals per cage were fed with commercial mouse food (Sniff).
In this context, all temperatures are expressed in degrees Celsius. In the following examples, "conventional work-up" refers to: if necessary, adding water; if necessary, the pH is adjusted to 2-10, depending on the constitution of the end product, the mixture is extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate and evaporated, and the residue is purified by chromatography on silica gel and/or by crystallization. Rf on silica gel; eluent: ethyl acetate/methanol 9: 1.
Mass Spectrum (MS): el (Electron impact ionization) M+
FAB (Rapid atom bombardment) (M + H)+
ESI (electrospray ionization) (M + H)+
APCI-MS (atmospheric pressure chemical ionization-mass spectrometry) (M + H)+。
HPLC method:
the method A comprises the following steps: gradient: 4.5 min/flow: 3 ml/min 99: 0.1-0: 100
Water + 0.1% by volume of TFA: acetonitrile + 0.1% by volume of TFA
0.0 to 0.5 minutes: 99: 01
0.5 to 3.5 minutes: 99: 01 → 0: 100
3.5 to 4.5 minutes: 0: 100
Column: chromolith SpeedROD RP18e 50-4.6
Wavelength: 220nm
The method B comprises the following steps: gradient: 4.2 min/flow: 2 ml/min 99: 0.1-0: 100
Water + 0.1% by volume of TFA: acetonitrile + 0.1% by volume of TFA
0.0 to 0.2 minutes: 99: 01
0.2 to 3.8 minutes: 99: 01 → 0: 100
3.8 to 4.2 minutes: 0: 100
Column: chromolith Performance RP18e 100mm length with 3mm internal diameter
Wavelength: 220nm
Retention time RtIn minutes [ min ]]To represent
Example 1
The preparation of 1- [3- (2, 5-dichlorophenyl) -4, 5-dihydropyrazol-1-yl ] -2- (3- {5- [1- (2-pyrrolidin-1-ylethyl) -1H-pyrazol-4-yl ] pyrimidin-2-yl } phenyl) ethanone ("A1") was carried out in analogy to the following scheme.
1.1 to a mixture of 14.7g (100mmol) of 1, 4-dichlorobenzene and 9.62ml (100mmol) of 3-chloropropionyl chloride maintained at 110 ℃ 16.0g (120mmol) of aluminum chloride are added in portions. The reaction mixture was cooled to room temperature, diluted with dichloromethane and ice was added. The organic phase is separated off and the aqueous phase is extracted several times with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated. The residue was chromatographed over a silica gel column using petroleum ether/dichloromethane as eluent: 3-chloro-1- (2, 5-dichlorophenyl) -propan-1-one as a brownish liquid;
1H-NMR(d6-DMSO)：δ[ppm]＝3.50(t，J＝6.1Hz，2H)，3.89(t，J＝6.1Hz，2H)，7.61(m，2H)，7.80(dd，J1＝2.3Hz，J2＝0.5Hz，1H).
1.2 addition of 4.60g (19.4mmol) of 3-chloro- (2, 5-dichlorophenyl) -propan-1-one to 1.90ml (39.1mmol) of hydrogen hydroxideIn a solution of 40ml of DMF kept under nitrogen, the mixture was stirred at room temperature for 1 hour. Then 4.25g (19.4mmol) of 3-bromo-phenylacetic acid and 4.76g (24.8mmol) of N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (DAPECI) were added successively and the resulting solution was stirred at room temperature for 18 hours. Water was added to the reaction mixture. The precipitate obtained is filtered off with suction and washed with water. The residue was dissolved in dichloromethane and filtered. The filtrate was chromatographed on a column of silica gel using petroleum ether/tert-butyl methyl ether as eluent: 2- (3-bromophenyl) -1- [3- (2, 5-dichlorophenyl) -4, 5-dihydropyrazol-1-yl]Ethanone, as a yellowish crystal; ESI 413.
1.3 to a solution of 1.01g (2.45mmol) of 2- (3-bromophenyl) -1- [3- (2, 5-dichlorophenyl) -4, 5-dihydropyrazol-1-yl ] ethanone and 796mg (3.06mmol) of bis (pinacolato) diboron in 6ml of DMF, 722mg (7.35mmol) of potassium acetate are added and the mixture is heated to 80 ℃ under nitrogen. 52mg (0.074mmol) of bis (triphenylphosphine) palladium (ll) chloride are then added and the mixture is heated at 80 ℃ for 18 hours. The reaction mixture was partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on a silica gel column using petroleum ether/tert-butyl methyl ether as eluent: 1- [3- (2, 5-dichlorophenyl) -4, 5-dihydropyrazol-1-yl ] -2- [3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] ethanone as a brown viscous oil; ESI 459.
1.4 to a solution of 780mg (1.70mmol) of 1- [3- (2, 5-dichlorophenyl) -4, 5-dihydropyrazol-1-yl ] -2- [3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] ethanone and 508mg (1.78mmol) of 2-bromo-5-iodopyrimidine in 3ml of ethylene glycol dimethyl ether, 1.08g (5.10mmol) of tripotassium phosphate trihydrate are added and the mixture is heated to 80 ℃ under nitrogen. Then 24mg (0.02mmol) bis (triphenylphosphine) palladium (ll) chloride and one drop of triethylamine were added and the reaction mixture was stirred under nitrogen at 80 ℃ for 18 h. The reaction mixture was partitioned between water and dichloromethane. The organic phase is evaporated and the residue is chromatographed on a silica gel column using petroleum ether/tert-butyl methyl ether as eluent: 2- [3- (5-bromopyrimidin-2-yl) phenyl ] -1- [3- (2, 5-dichlorophenyl) -4, 5-dihydropyrazol-1-yl ] ethanone as yellowish crystals; ESI 491.
1.5A solution of 10.0g (50.5mmol) of pinacol pyrazole-4-borate is dissolved in 100ml of acetonitrile, and 17.5g (101mmol) of N- (2-chloroethyl) pyrrolidine hydrochloride and 49.4g (152mmol) of cesium carbonate are added. The resulting suspension was stirred at room temperature for 18 hours. The reaction mixture was filtered off with suction and washed with acetonitrile. The filtrate was evaporated and partitioned between ethyl acetate and saturated sodium chloride solution. The organic phase was dried over sodium sulfate and evaporated: 1- (2-pyrrolidin-1-ylethyl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole as light orange oil;
1H-NMR(d6-DMSO)：δ[ppm]＝1.25(s，12H)，1.65(m，4H)，2.44(m，4H)，2.79(t，J＝6.8Hz，2H)，4.21(t，J＝6.8Hz，2H)，7.56(s，1H)，7.93(s，1H).
1.6A suspension of 269mg (0.53mmol)2- [3- (5-bromopyrimidin-2-yl) phenyl ] -1- [3- (2, 5-dichlorophenyl) -4, 5-dihydropyrazol-1-yl ] ethanone, 171.2mg (0.59mmol)1- (2-pyrrolidin-1-ylethyl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole and 227mg (1.07mmol) tripotassium phosphate trihydrate in 2ml 1, 2-dimethoxyethane is heated to 80 ℃ under nitrogen. Then 31.9mg (45. mu. mol) of bis (triphenylphosphine) palladium chloride (ll) and 10. mu.l of triethylamine were added, and the mixture was stirred at 80 ℃ for 18 hours. The reaction mixture was cooled and partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed over a silica gel column using dichloromethane/methanol as eluent: 1- [3- (2, 5-dichlorophenyl) -4, 5-dihydropyrazol-1-yl ] -2- (3- {5- [1- (2-pyrrolidin-1-ylethyl) -1H-pyrazol-4-yl ] pyrimidin-2-yl } phenyl) ethanone ("a 1") as an amorphous solid; ESI 574;
1H-NMR(d6-DMSO)：δ[ppm]＝1.68(m，4H)，2.89(m，2H)，3.34(m，4H)，3.42(t，J＝10Hz，2H)，3.95(t，J＝10Hz，2H)，4.12(s，2H)，4.28(t，J＝6.3Hz，2H)，7.47(m，2H)，7.56(dd，J1＝9Hz，J2＝2.5Hz，1H)，7.63，(d，J＝9Hz，1H)，7.80(d，J＝2.5Hz，1H)，8.11(s，1H)，8.27(d，J＝7Hz，1H)，8.38(s，1H)，8.45(s，1H)，9.13(s，2H).
compound "a 2" was obtained similarly:
example 2
The preparation of 1- [3- (2, 5-dichlorophenyl) -4, 5-dihydropyrazol-1-yl ] -2- {3- [5- (1-methylpiperidin-4-ylmethoxy) pyrimidin-2-yl ] phenyl } ethanone ("A3") was carried out in analogy to the following scheme.
Compound "a 4" was obtained similarly:
example 3
The preparation of 3- {1- [2- (3- {5- [1- (2-pyrrolidin-1-ylethyl) -1H-pyrazol-4-yl ] pyrimidin-2-yl } phenyl) acetyl ] -4, 5-dihydro-1H-pyrazol-3-yl } -benzonitrile ("a 5") was carried out in analogy to the following scheme:
3.1 mu.l of 37% aqueous hydrochloric acid are added to a suspension of 725mg (5.00mmol) of 3-acetylbenzonitrile, 195mg of paraformaldehyde and 530mg (6.50mmol) of dimethylammonium chloride in 1ml of ethanol. The reaction mixture was stirred at 80 ℃ for 18 hours. The reaction mixture, a solid mass, was cooled to room temperature, dissolved in acetone, filtered and washed with a small amount of acetone. The residue was dissolved in water and extracted with dichloromethane. The aqueous phase was adjusted to pH9 with 10ml 1N NaOH and extracted with dichloromethane. The organic phase was dried over sodium sulfate and evaporated: 3- (3-dimethylamino-propionyl) -benzonitrile as a brown oil; the ESI 203.
3.2 to a solution of 677mg (3.35mmol) of 3- (3-dimethylamino-propionyl) -benzonitrile in 5ml of THF 1.0ml (17mmol) of iodomethane are added and the mixture is left at room temperature for 48 hours. The resulting precipitate was filtered off with suction, washed with tert-butyl methyl ether and dried in vacuo: [3- (3-cyanophenyl) -3-oxo-propyl ] -trimethyl-ammonium iodide as a camel-colored crystal; ESI 217.
3.3 mg (1.37mmol) of [3- (3-cyanophenyl) -3-oxo-propyl]A solution of trimethyl-ammonium iodide in 2ml of DMF kept under nitrogen was warmed to 50 ℃ and 139. mu.l (2.87mmol) of hydroxide was added. Will be provided withThe reaction mixture was stirred at 50 ℃ for 1 hour and then cooled to room temperature. 294mg (1.37mmol) of 3-bromophenyl-acetic acid and 340mg (1.78mmol) of N- (3-dimethylaminopropyl) -N' -ethyl-carbodiimide hydrochloride are added. The reaction mixture was stirred at room temperature for 18 hours and then partitioned between water and dichloromethane. The organic phase is separated off, dried over sodium sulfate and evaporated. The residue was chromatographed on a silica gel column using petroleum ether/tert-butyl methyl ether as eluent: 3- {1- [2- (3-bromophenyl) acetyl group]-4, 5-dihydro-1H-pyrazol-3-yl } -benzonitrile as a yellowish solid; ESI 368, 370.
Example 4
1- [3- (2, 5-dichlorophenyl) -4, 5-dihydropyrazol-1-yl ] is carried out in analogy to the following scheme]-2- [3- (5-methyl-1, 2, 4-)Oxadiazol-3-yl) phenyl]Preparation of ethanone ("A6").
Example 5
Preparation of 3- (1- {2- [3- (5-bromopyrimidin-2-yl) phenyl ] acetyl } -4, 5-dihydro-1H-pyrazol-3-yl) -benzonitrile ("A7") and 3- {1- [2- (3- {5- [1- (2-pyrrolidin-1-ylethyl) -1H-pyrazol-4-yl ] pyrimidin-2-yl } phenyl) acetyl ] -4, 5-dihydro-1H-pyrazol-3-yl } -benzonitrile ("A5"):
5.1 to a suspension of 29.6g (200mmol) of 3-acetylbenzonitrile, 7.81m of paraformaldehyde and 21.2g (260mmol) of dimethylammonium chloride in 32ml of ethanol, 1ml of 37% aqueous hydrochloric acid solution are added. The reaction mixture was stirred at 80 ℃ for 18 hours. The reaction mixture, a solid mass, was cooled to room temperature, dissolved in acetone, filtered and washed with a small amount of acetone. The residue was dissolved in water and extracted with dichloromethane. The aqueous phase was adjusted to pH9 with 1N NaOH and extracted with dichloromethane. The organic phase was dried over sodium sulfate and evaporated: 3- (3-dimethylamino-propionyl) -benzonitrile as a yellow-orange oil; the ESI 203.
5.2 2g (10.0mmol) of 3- (3-dimethylamino-propionyl) -benzonitrile and 1.31ml (26.9mmol) of hydrox-ydroxideThe solution in 3.5ml ethanol was boiled under nitrogen and heated for 2 hours. The reaction mixture was evaporated and the residue partitioned between water and tert-butyl methyl ether. The organic phase was dried over sodium sulfate and evaporated: crude 3- (4, 5-dihydro-1H-pyrazol-3-yl) -benzonitrile as viscous yellow oil; ESI 172. It was stored under nitrogen and used for the next reaction without further purification.
5.3A solution of 1.60g (ca. 6.6mmol) of crude 3- (4, 5-dihydro-1H-pyrazol-3-yl) -benzonitrile and 1.86g (7.97mmol) of (3-bromophenyl) -acetyl chloride in 13ml of dichloromethane kept under nitrogen is cooled to 0 ℃ and 1.38ml (9.96mmol) of triethylamine are added. After the mixture had been stirred at room temperature for 5 hours, 25ml of saturated sodium carbonate solution were added. The reaction mixture was partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on a silica gel column using petroleum ether/tert-butyl methyl ether as eluent: 3- {1- [2- (3-bromophenyl) acetyl ] -4, 5-dihydro-1H-pyrazol-3-yl } -benzonitrile as a yellow solid; ESI 368, 370.
5.4 to a solution of 748mg (2.03mmol) of 3- {1- [2- (3-bromophenyl) acetyl ] -4, 5-dihydro-1H-pyrazol-3-yl } -benzonitrile and 659mg (2.54mmol) of bis (pinacolato) diboron in 4ml of DMF, 598mg (6.09mmol) of potassium acetate are added and the mixture is heated to 80 ℃ under nitrogen. 45mg (0.061mmol) of 1, 1-bis (diphenylphosphino) ferrocene-palladium dichloride (ll) are then added and the mixture is stirred at 80 ℃ for 18 hours. The reaction mixture was partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on a column of silica gel with dichloromethane/methanol as eluent: 3- (1- {2- [3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetyl } -4, 5-dihydro-1H-pyrazol-3-yl) -benzonitrile as a brown solid; ESI 416.
5.5 to a suspension of 333mg (0.77mmol) of 3- (1- {2- [3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetyl } -4, 5-dihydro-1H-pyrazol-3-yl) -benzonitrile and 348mg (1.19mmol) of 2-bromo-5-iodopyrimidine in 1.5ml of ethylene glycol dimethyl ether, 490mg (2.31mmol) of tripotassium phosphate trihydrate are added, and the mixture is heated to 80 ℃ under nitrogen. 22mg (0.03mmol) of bis (triphenylphosphine) -palladium (ll) chloride and a drop of triethylamine are then added and the reaction mixture is stirred under nitrogen at 80 ℃ for 18 hours. The reaction mixture was partitioned between water and dichloromethane. The organic phase is evaporated and the residue is chromatographed on a column of silica gel using petroleum ether/tert-butyl methyl ether as eluent: 3- (1- {2- [3- (5-bromopyrimidin-2-yl) phenyl ] acetyl } -4, 5-dihydro-1H-pyrazol-3-yl) -benzonitrile ("a 7") as colorless crystals; ESl 446, 448;
1H-NMR(d6-DMSO)δ[ppm]3.32(t，J＝10.0Hz，2H)，3.96(t，J＝10Hz，2H)，4.15(s，2H)，7.48(t，J＝7.5Hz，1H)，7.53(d，J＝7Hz，1H)，7.72(t，J＝7.8Hz，1H)，7.95(d，J＝7.6Hz，1H)，8.15(d，J＝7.8Hz，1H)，8.23(m，2H)，8.41(s，1H)，9.07(s，2H).
5.6A suspension of 153mg (0.32mm0l) of 3- (1- {2- [3- (5-bromopyrimidin-2-yl) phenyl ] acetyl } -4, 5-dihydro-1H-pyrazol-3-yl) -benzonitrile, 159mg (0.48mmol) of 1- (2-pyrrolidin-1-ylethyl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole and 136mg (1.07mmol) of tripotassium phosphate trihydrate in 1ml of 1, 2-dimethoxyethane and 1ml of dimethylformamide is heated to 80 ℃ under nitrogen. 22.5mg (32. mu. mol) of bis (triphenylphosphine) -palladium (ll) chloride and one drop of triethylamine were added, and the mixture was stirred at 80 ℃ for 42 hours. The reaction mixture was cooled and partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on a column of silica gel with dichloromethane/methanol as eluent: 3- {1- [2- (3- {5- [1- (2-pyrrolidin-1-ylethyl) -1H-pyrazol-4-yl ] pyrimidin-2-yl } phenyl) acetyl ] -4, 5-dihydro-1H-pyrazol-3-yl } -benzonitrile ("a 5") as a brown solid; ESI 532;
1H-NMR(d6-DMSO)：δ[ppm]1.68(m，4H)，2.90(t，J＝6.5Hz，2H)，3.33(m，6H)，3.97(t，J＝10Hz，2H)，4.15(s，2H)，4.29(t，J＝6.3Hz，2H)，7.48(m，2H)，7.72(t，J＝7.9Hz，1H)，7.95(d，J＝7.6Hz，1H)，8.10(s，1H)，8.17(d，J＝7.8Hz，1H)，8.23(s 1H)8.26(d，J＝6.7Hz，1H)，8.44(s，1H)，8.45(s，1H)9.13(s，2H).
example 6
Preparation of 1- [3- (2, 5-dichlorophenyl) -4, 5-dihydropyrazol-1-yl ] -2- {3- [5- (2-morpholin-4-yl-ethoxy) pyrimidin-2-yl ] phenyl } ethanone ("A8"):
starting material) preparation of 2- [3- (5-bromopyrimidin-2-yl) phenyl ] -1- [3- (2, 5-dichlorophenyl) -4, 5-dihydropyrazol-1-yl ] ethanone) is described in example 1.
The preparation of pyrimidinol (1- [3- (2, 5-dichlorophenyl) -4, 5-dihydropyrazol-1-yl ] -2- [3- (5-hydroxypyrimidin-2-yl) phenyl ] ethanone) is described in example 2.
6.1A suspension of 646mg (1.31mmol) of 2- [3- (5-bromopyrimidin-2-yl) phenyl ] -1- [3- (2, 5-dichlorophenyl) -4, 5-dihydropyrazol-1-yl ] ethanone, 417mg (1.63mmol) of bis (pinacolato) diboron, 383mg (3.90mmol) of potassium acetate and 18.3mg (0.026mmol) of bis (triphenylphosphine) -palladium (ll) chloride in 5ml of THF, which suspension is maintained under nitrogen, is heated at 80 ℃ for 18 hours. The reaction mixture was diluted with THF, activated carbon was added, and the mixture was filtered while hot and washed with THF. The filtrate was evaporated in vacuo to a volume of about 4 ml. 4ml of water and 195mg of sodium perborate are added and the resulting suspension is stirred at room temperature for 4 hours. The reaction mixture was cooled to 4 ℃ and filtered with suction. The residue was washed with THF and water, dried in vacuo: 1- [3- (2, 5-dichlorophenyl) -4, 5-dihydropyrazol-1-yl ] -2- [3- (5-hydroxypyrimidin-2-yl) phenyl ] ethanone as colorless crystals; ESI 457.
6.2A suspension of 108mg (0.253mmol) of 1- [3- (2, 5-dichlorophenyl) -4, 5-dihydropyrazol-1-yl ] -2- [3- (5-hydroxypyrimidin-2-yl) phenyl ] ethanone, 100mg (0.38mmol) of triphenylphosphine and 64.4. mu.l of 2-morpholinoethanol in 0.5ml of THF is cooled in an ice bath and 74. mu.l (0.38mmol) of diisopropyl azodicarboxylate is slowly added dropwise. The reaction mixture was stirred at room temperature for 16 hours. The mixture was evaporated and the residue was chromatographed on a column of silica gel with dichloromethane/methanol as eluent: 1- [3- (2, 5-dichlorophenyl) -4, 5-dihydropyrazol-1-yl ] -2- {3- [5- (2-morpholin-4-yl-ethoxy) pyrimidin-2-yl ] phenyl } ethanone ("A8") as colorless crystals; ESI 540;
1H-NMR(d6-DMSO)δ[ppm]2.56(m，4H)，2.81(m，2H)，3.48(t，J＝10Hz，2H)，3.65(t，J＝4.2Hz，4H)，4.00(t，J＝10Hz，2H)，4.16(s，2H)，4.38(t，J＝5.3Hz，2H)，7.48(m，2H)，7.62(dd，J1＝9Hz，J2＝2.5Hz，1H)，7.69(d，J＝9Hz，1H)，7.86(d，J＝2.5Hz，1H)，8.24(d，J＝7Hz，1H)，8.37(s，1H)，8.71(s，2H).
pharmacological data
Met kinase inhibition
Table 1:
IC50：1nM-0,1μM＝A
0,1μM-10μM＝B
＞10μM＝C
example A: injection vial
A solution of 100g of the active ingredient of the formula I and 5g of disodium hydrogen phosphate in 3 l of distilled water is adjusted to pH 6.5 using 2N hydrochloric acid, sterile-filtered, transferred into injection vials, freeze-dried under sterile conditions and sealed under sterile conditions. Each injection vial contained 5mg of active ingredient.
Example B: suppository
A mixture of 20g of the active ingredient of formula I with 100g of soya lecithin and 1400g of cocoa butter is melted, poured into a mould and allowed to cool. Each suppository contains 20mg of active ingredient.
Example C: solution preparation
Comprises 1g of active ingredient of formula I, 9.38g of NaH2PO4·2H2O、28.48g Na2HPO4·12H2O and 0.1g benzalkonium chloride in 940ml double distilled water. The pH was adjusted to 6.8, the solution was made up to 1 liter and sterilized by irradiation. The solution can be used in the form of eye drops.
Example D: ointment formulation
500mg of the active ingredient of the formula I are mixed with 99.5g of vaseline under sterile conditions.
Example E: tablet formulation
A mixture of 1kg of active ingredient of the formula I, 4kg of lactose, 1.2kg of potato starch, 0.2kg of talc and 0.1kg of magnesium stearate is compressed in the conventional manner to tablets, so that each tablet contains 10mg of active ingredient.
Example F: candy tablet
Tablets were compressed in a similar manner to example E and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and dye.
Example G: capsule preparation
2kg of active ingredient of formula I are introduced into hard gelatin capsules in a conventional manner so that each capsule contains 20mg of active ingredient.
Example H: ampoule agent
A solution of 1kg of the active ingredient of the formula I in 60 l of redistilled water is sterilized by filtration, transferred into ampoules, freeze-dried under sterile conditions and sealed under sterile conditions. Each ampoule contains 10mg of active ingredient.

Claims (11)

1. A compound or a pharmaceutically acceptable salt, tautomer, including mixtures thereof in all ratios, wherein the compound is selected from the group consisting of:
2. a medicament comprising at least one compound according to claim 1 or a pharmaceutically acceptable salt, tautomer, mixture including all ratios thereof and optionally excipients and/or adjuvants.
3. The use of compounds according to claim 1 and pharmaceutically acceptable salts, tautomers, including mixtures thereof in all ratios, for the preparation of medicaments for the treatment of diseases in which inhibition of Met kinase signal transduction plays a role.
4. The use according to claim 3, wherein the disease to be treated is a solid tumor.
5. Use according to claim 4, wherein the solid tumor originates from a tumor of the squamous epithelium, bladder, stomach, kidney, head and neck, esophagus, cervix, thyroid, intestine, liver, brain, prostate, genitourinary tract, lymphatic system, larynx and/or lung.
6. The use of claim 4, wherein the solid tumor is derived from monocytic leukemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic carcinoma, glioblastoma, and breast cancer.
7. The use of claim 4, wherein the solid tumor is derived from lung adenocarcinoma, small cell lung carcinoma, pancreatic carcinoma, glioblastoma, colon carcinoma and breast carcinoma.
8. Use according to claim 3, wherein the diseases to be treated are hematological and immune system tumors.
9. Use according to claim 8, wherein the tumour is derived from acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphatic leukaemia and/or chronic lymphatic leukaemia.
10. A medicament comprising at least one compound according to claim 1 or a pharmaceutically acceptable salt, tautomer, mixture including all ratios thereof and at least one further pharmaceutically active ingredient.
11. A kit consisting of individual cartridges as follows:
(a) an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, tautomer, mixture including all ratios thereof; and
(b) an effective amount of other pharmaceutically active ingredients.
HK11111868.3A 2008-05-29 2009-04-24 Dihydropyrazole derivatives as tyrosine kinase modulators for the treatment of tumors HK1157345B (en)

Applications Claiming Priority (3)

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DE102008025750.8 2008-05-29
DE102008025750A DE102008025750A1 (en) 2008-05-29 2008-05-29 Dihydropyrazolderivate
PCT/EP2009/003030 WO2009143945A1 (en) 2008-05-29 2009-04-24 Dihydropyrazole derivatives as tyrosine kinase modulators for the treatment of tumors

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