HK1167649A - Heterocyclic compounds as autotaxin inhibitors - Google Patents

Description

Heterocyclic compounds as autotaxin inhibitors

Background

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

The present invention relates to compounds and to the use of compounds for the treatment of diseases accompanied by elevated lysophosphatidic acid levels, furthermore to pharmaceutical compositions comprising these compounds.

In particular, the present invention relates to compounds of formula I, which preferably inhibit one or more enzymes that modulate and/or regulate the level of lysophosphatidic acid (or LPA for short), to compositions comprising these compounds, and to methods of using them for the treatment of diseases and conditions such as angiogenesis, cancer, neoplasia, growth and proliferation, arteriosclerosis, ocular diseases, choroidal neovascularization, and diabetic retinopathy, inflammatory diseases, arthritis, neurodegeneration, restenosis, wound healing, or graft rejection. In particular, the compounds according to the invention are suitable for the treatment or prevention of cancer.

Autotaxin (ATX) is an enzyme responsible for the elevation of lysophosphatidic acid levels in ascites and plasma (Xu et al, 1995, Clinical Cancer Research volume 1, page 1223, and Xu et al, 1995, biochem.j. volume 309, page 933). ATX converts Lysophosphatidylcholine (LPC) to lysophosphatidic acid (Tokumura et al, 2002, j.biol. chem., volume 277, page 39436, and Umezu-Gozo et al, 2002, j.biol. chem., volume 158, page 227). LPA is an intercellular ester medium that affects a variety of biological and biochemical processes, such as, for example, smooth muscle contraction, coagulation factor aggregation, and apoptosis (Tigyi et al, 2003prog.lipid res. vol 42, p 498, and Mills et al, 2003nat.rev.cancer vol 3, p 582, and Lynch et al, 2001 pros.lipid med. vol 64, p 33). In addition, LPA can also be found in increased concentrations in plasma and ascites from patients with early and late stage ovarian cancer. LPA plays a role in tumor cell proliferation and its invasion into adjacent tissues, which can lead to metastasis (Xu et al, 1995, Clinical Cancer Research volume 1, page 1223, and Xu et al, 1995, biochem.j. volume 309, page 933). These biological and pathobiological processes are initiated by LPA activation of G-protein coupled receptors (Contos et al, 2000, mol. pharm. vol 58, p 1188).

For this reason, it is desirable to reduce LPA levels for the treatment of tumor patients. This can be achieved by inhibiting enzymes involved in LPA biosynthesis, such as, for example, autotaxin (ATX, Sano et al, 2002, page 21197 of j.biol.chem. volume 277, and Aoki et al, 2003, page 48737 of j.biol.chem. volume 277). Autotaxin belongs to the nucleotide pyrophosphatase and phosphodiesterase families (Goding et al, 1998, immunol. rev. vol 161, p 11) and is an important initiation site in antitumor therapy (Mills et al, 2003nat. rev. cancer vol 3, p 582, and Goto et al, 2004j. cell. biochem. vol 92, p 1115) because it is expressed to an elevated extent in tumors and causes tumor cells to proliferate and invade adjacent tissues, which can lead to the formation of metastases (Nam et al, 2000, Oncogene, vol 19, p 241). In addition, autotaxin, together with other angiogenic factors, leads to blood vessel formation during angiogenesis (Nam et al, 2001, Cancer Res. Vol.61, page 6938). Angiogenesis is an important process in tumor growth, which ensures the nutrient supply to the tumor. For this reason, inhibition of angiogenesis is an important starting point in cancer and tumor therapy, which can cause some starvation of tumors (Folkman, 2007, Nature Reviews Drug Discovery volume 6, page 273-286).

Surprisingly, it was found that the compounds according to the invention causeSpecific inhibition of the nucleotide pyrophosphatase and phosphodiesterase families, especially autotaxin. The compounds according to the invention preferably exhibit advantageous biological activities which can be readily detected by, for example, the tests described herein. In this type of test, the compounds according to the invention preferably exhibit and cause inhibitory activity, which is generally by IC in a suitable range₅₀Values are reported, preferably in the micromolar range, and more preferably in the nanomolar range.

In general, all solid and non-solid tumors can be treated by the compounds of formula I, such as, for example, monocytic leukemias, brain tumors, genitourinary tumors, tumors of the lymphatic system, stomach cancer, laryngeal cancer, ovarian cancer, and lung cancer, including lung adenocarcinoma and small cell lung cancer. Other examples include prostate, pancreatic and breast cancer.

As discussed herein, the effects of the compounds of the present invention are associated with various diseases. Thus, the compounds according to the invention are useful for the prevention and/or treatment of diseases which are affected by the inhibition of one or more nucleotide pyrophosphatase and/or phosphodiesterase, in particular autotaxin.

The present invention therefore relates to the compounds according to the invention, as medicaments and/or pharmaceutically active ingredients in the treatment and/or prophylaxis of said diseases, and to the use of the compounds according to the invention for the preparation of pharmaceutically active agents for the treatment and/or prophylaxis of said diseases, and also to methods for the treatment of said diseases, which comprise administering one or more compounds according to the invention to a patient in need of such administration.

It can be shown that the compounds according to the invention have a beneficial effect in xenograft tumor models.

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 they provide a model for the treatment of human diseases.

The sensitivity of a cell to treatment with a compound of the invention can be determined by in vitro assays. Typically, cell cultures are combined with varying concentrations of a compound of the invention for a period of time sufficient for the active agent to induce cell death or inhibit migration or block secretion of cells of the pro-angiogenic substance, 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 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 undesirable cells are detected in vivo.

Prior Art

Compounds capable of inhibiting autotaxin are described in Peng et al, Bioorganic & Medicinal Chemistry Letters (17, 2007, pages 1634-1640). The compounds described therein are lipid analogues which do not have any of the same structural features as the compounds according to the invention.

Summary of The Invention

The present invention relates to compounds of formula I and pharmaceutically acceptable salts and stereoisomers thereof, including mixtures thereof in all ratios.

Wherein

R¹Represents H, A, Hal, OR³、N(R³)₂、N＝CR³N(R³)₂、SR³、NO₂、CN、COOR³CON(R³)₂、NR³COA、NR³SO₂A、SO₂N(R³)₂、S(O)_mA、-[C(R³)₂]_nN(R³)₂、O[C(R³)₂]_pN(R³)₂、S[C(R³)₂]_nN(R³)₂、-NR³[C(R³)₂]_nN(R³)₂、NHCON(R³)₂、CON(R³)₂、CONR³[C(R³)₂]_nN(R³)₂Or a combination of the above or other chemical entities,

R³represents a group of a compound represented by the formula H or A,

x represents O, NH or CH₂，

Y represents CH₂、CH₂O or the absence of oxygen or oxygen,

r represents

R⁴Represents a group of H, A or a phenyl group,

het represents

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 groups₂May be replaced with O, NH and/or S,

or

Cycloalkyl having 3 to 7C atoms,

hal represents F, Cl, Br or I,

n represents 0, 1, 2 or 3,

m represents 0, 1 or 2,

p represents 0, 1, 2, 3, 4 or 5.

The compounds of the formula I are also intended to mean the pharmaceutically acceptable salts, optically active forms (stereoisomers), tautomers, polymorphs, enantiomers, racemates, diastereomers and hydrates and solvates thereof. The term solvate of a compound refers to the adduction of inert solvent molecules to the compound, which is formed due to their mutual attraction. Solvates are, for example, mono-or dihydrate or alcoholates.

Pharmaceutically useful derivatives refer, for example, to salts of the compounds of the invention, and also to so-called prodrug compounds.

Prodrug derivatives 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 give 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 a drug or pharmaceutically active ingredient that causes 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 expression "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 a process for the preparation of compounds of formula I and pharmaceutically acceptable salts, stereoisomers thereof according to the claims, characterized in that

a) For the preparation of compounds of the formula I, in which

R represents

Reacting a compound of formula II

Het-NH-CO-CH₂-L II

Wherein

Het has the meaning indicated in claim 1,

and L represents Cl or Br, and,

with compounds of the formula III

Wherein

X、Y、R¹And p has the meaning indicated in claim 1,

or

b) For the preparation of compounds of the formula I, in which

R represents

Reacting a compound of formula IV

Wherein

Het has the meaning indicated in claim 1,

and L represents Cl or Br, and,

with compounds of the formula V

Wherein

X、Y、R¹And p has the meaning indicated in claim 1,

or

c) For the preparation of compounds of the formula I, in which

R represents

Reacting a compound of formula VI

Het-CH₂-CO-L VI

Wherein

Het has the meaning indicated in claim 1,

and L represents Cl, Br, I or a free or reactively functionally modified OH group.

With a compound of the formula V,

or

d) For the preparation of compounds of the formula I, in which

R represents

Reacting a compound of formula VII

Wherein

Het has the meaning indicated in claim 1,

with compounds of the formula VIII

Wherein

R¹And p has the meaning indicated in claim 1,

and the compound is selected from

Carbonyl diimidazole, phosgene, diphosgene and triphosgene,

or

e) For the preparation of compounds of the formula I, in which

R represents

Reacting a compound of formula IX

Wherein

Het has the meaning indicated in claim 1,

with compounds of the formula V

And the compound is selected from

Carbonyl diimidazole, phosgene, diphosgene and triphosgene,

or

f) For the preparation of compounds of the formula I, in which

R represents

Reacting a compound of formula X

Het-NH₂ X

Wherein

Het has the meaning indicated in claim 1,

with compounds of the formula XI

Wherein

X、Y、R¹And p has the meaning indicated in claim 1,

and L represents Cl, Br, I or a free or reactive functionally modified OH group, and/or converting a base or acid of formula I into one of its salts.

A represents an alkyl group, and is preferably unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10C atoms. Alkyl preferably denotes 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, further preferred is, for example, trifluoromethyl.

Alkyl particularly preferably denotes 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. Alkyl also denotes cycloalkyl.

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

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

R¹Preferably represents Hal.

R³Preferably represents H or methyl.

X preferably represents O or CH₂。

Y preferably represents CH₂Or CH₂O。

p preferably represents 1, 2 or 3, furthermore 4 or 5.

n preferably represents 0, 1, 2 or 3.

All groups, such as R, which occur more than once throughout the invention may be the same or different, i.e. independent of each other.

The compounds of formula I may have one or more chiral centers and may therefore occur in different stereoisomeric forms. Formula I includes all of these forms.

Accordingly, the present invention relates in particular to compounds of the formula I in which at least one of the radicals has one of the preferred meanings indicated above.

Some preferred groups of the compounds can be represented by the following sub-formulae Ia to Ie, which correspond to formula I, and wherein the groups not specified in detail have the meanings indicated for formula I, but wherein

In Ia R¹Represents Hal;

in Ib X represents O or CH₂；

In Ic Y represents CH₂Or CH₂O；

In Id p represents 1, 2 or 3;

in Ie R¹The expression Hal is given to the expression,

x represents O or CH₂，

Y represents CH₂Or CH₂O，

R represents

Het represents

A represents an unbranched or straight-chain alkyl group having 1 to 10C atoms,

wherein 1 to 7H atoms can be replaced by F and/or Cl,

hal represents F, Cl, Br or I,

p represents 1, 2 or 3,

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

The compounds of the formula I and the starting materials for their preparation can additionally be prepared by processes known per se, as described in the literature (for example in standard textbooks 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, which are not mentioned here in more detail, can also be used here.

If desired, the starting materials may also be formed in situ, so that they may not be isolated from the reaction mixture but immediately converted further into the compounds of the formula I.

The starting compounds of the formulae II, III, IV, V, VI, VII, VIII, IX, X and XI are generally known. If they are novel, they can be prepared by methods known per se.

The starting materials are also generally commercially available.

In the compounds of the formulae II, IV, VI, XI, L preferably denotes Cl, Br, I or a free or reaction-modified OH group, for example an activated ester, imidazole or an alkylsulfonyloxy group having 1 to 6C atoms, preferably methylsulfonyloxy or trifluoromethylsulfonyloxy group, or an arylsulfonyloxy group having 6 to 10C atoms, preferably phenyl or p-toluenesulfonyloxy.

The compounds of formula I can preferably be obtained by reacting a compound of formula II with a compound of formula III.

The reaction is generally carried out in an inert solvent, preferably in the presence of an acid-binding solvent, preferably in an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of alkali or alkaline earth metal, preferably potassium, sodium, calcium or cesium. The addition of organic bases such as triethylamine, dimethylaniline, pyridine or quinoline may also be advantageous.

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 ℃, generally from-10 ℃ to 90 ℃, particularly preferably from about 0 ℃ to about 70 ℃ and very particularly preferably from 15 ℃ to 35 ℃.

Examples of suitable inert solvents are: 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.

Particular preference is given to pyridine, acetonitrile, dichloromethane and/or DMF.

The compounds of the formula I can furthermore preferably be obtained by reacting compounds of the formula IV with compounds of the formula V under the abovementioned conditions.

The reaction is preferably carried out in acetonitrile at 100 ℃ with addition of NaHCO₃The process is carried out.

The compounds of the formula I can furthermore preferably be obtained by reacting compounds of the formula VI with compounds of the formula V. In the compounds of formula VI, L preferably represents OH. For reaction, the carbonyl group is preferably converted to an active ester.

Activation of the carboxyl group in a typical acylation reaction is 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).

The activated esters are advantageously formed in situ, for example by addition of HOEt or N-hydroxysuccinimide.

The reaction is preferably carried out in the presence of a dehydrating agent, for example, a carbodiimide, such as N, N ' -dicyclohexylcarbodiimide ("DCCl"), 1 ' -Carbonyldiimidazole (CDI) or N-3-dimethylaminopropyl-N ' -ethyl-carbodiimide ("DAPECl"), but also propanephosphonic anhydride (see Angew. chem.92, 129(1980)), diphenylazidophosphoric acid or 2-ethoxy-N-ethoxycarbonyl-1, 2-dihydroquinoline.

The reaction is generally carried out in an inert solvent.

Depending on the conditions used, the reaction time is from a few minutes to 14 days and the reaction temperature is from about-15 ℃ to 150 ℃, usually from-5 ℃ to 90 ℃ and particularly preferably from about 20 ℃ to about 60 ℃.

The reaction is preferably carried out in DMF at room temperature, preferably with the addition of N-methylmorpholine.

The compounds of the formula I can furthermore preferably be obtained by reacting a compound of the formula VII with a compound of the formula VIII and are selected from the group consisting of carbonyldiimidazole, phosgene, diphosphine and triphosgene.

The reaction is carried out in an inert solvent and under the conditions described above. The reaction is preferably carried out in DMF at room temperature, preferably with the addition of a carbonyl component such as CDI.

The compounds of the formula I can furthermore preferably be obtained by reacting a compound of the formula IX with a compound of the formula V and are selected from carbonyldiimidazole, phosgene, diphosphine and triphosgene.

The reaction is carried out in an inert solvent and under the conditions described above. The reaction is preferably carried out in DMF at room temperature, preferably with the addition of a carbonyl component such as CDI and a base such as triethylamine.

The compounds of the formula I can furthermore preferably be obtained by reacting compounds of the formula VX with compounds of the formula XI.

The reaction is carried out under conditions like the reaction of the compound of formula VI and the compound of formula V.

The compounds according to the invention can be used in their final non-salt form. In another aspect, the invention also includes the use of the compounds in the form of their pharmaceutically acceptable salts, which can be derived from various organic and inorganic acids and bases by methods known in the art. The pharmaceutically acceptable salt forms of the compounds of formula I are prepared in large part by conventional methods. If a compound of formula I contains a carboxyl group, one of its suitable salts may be formed by reacting the 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 (III) salt, iron (II) salt, lithium salt, magnesium salt, manganese (III) salt, manganese (II) salt, potassium salt, sodium salt and zinc salt, but this is not representative 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 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.

Compounds of the invention containing basic nitrogen-containing groups may be quaternized with substances such as (C)₁-C₄) Alkyl halides, e.g. methyl, ethylIsopropyl 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 pharmaceutically acceptable salts as mentioned above 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.

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 certain respects, for example in certain physical properties such as 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 compounds of formula I are formed with metals or amines, such as alkali metals and alkaline earth metals or organic amines. Preferred metals are sodium, potassium, magnesium and calcium. Preferred organic amines are N, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

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 certain respects, for example in certain physical properties such as 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 invention contain more than one group capable of forming such pharmaceutically acceptable salts, the 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" herein refers to an active ingredient of the compound of formula I in a form comprising one of its salts, in particular as long as this salt form confers an improved pharmacokinetic property 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 impact 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 useful salts and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and/or auxiliaries.

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 widely known in the pharmaceutical field.

The pharmaceutical formulations may be adapted for administration by any desired suitable method, for example, 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, for example, 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, for example, 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, for example, glucose or beta-lactose, sweeteners made from corn, natural and synthetic rubbers such as, for example, 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 abovementioned diluents or bases and optionally with binders such as, for example, carboxymethylcellulose, alginates, gelatin or polyvinylpyrrolidone, dissolution retarders such as, for example, paraffin, absorption promoters such as, for example, quaternary salts and/or absorbents such as, for example, bentonite, kaolin or dicalcium phosphate. The powder mixture may be granulated by wetting with a binder such as, for example, 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, for example, solutions, syrups and elixirs can be prepared in dosage unit form so that a given quantity comprises 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. Solubilizers and emulsifiers such as, for example, ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavoring additives such as, for example, 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, for example, by coating the particulate material with or embedding it in a polymer, wax or the like.

The compounds of formula I and salts and physiologically functional derivatives thereof may also be administered in the form of liposome delivery systems such as, for example, unilamellar small vesicles, unilamellar large vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as, for example, cholesterol, stearylamine, or phosphatidylcholines.

The compounds of formula I and salts and physiologically functional derivatives thereof may also be delivered using a monoclonal antibody as a separate carrier, wherein the compound molecule is coupled 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 (polyhydroxypropylmethacrylamidophenol), polyhydroxyethylaspartamidephenol (polyhydroxyethylaspartamidephenol), 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 compound 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 ointments, the active compound may be applied together with a paraffinic or water-miscible cream base. Alternatively, the active compound 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 compound 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 single-or multi-dose containers, for example sealed ampoules and vials, and stored in a freeze-dried (lyophilized) state, 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 on 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 treating tumor growth, e.g., colon or breast cancer, is generally 0.1 to 100mg/kg of recipient (mammalian) body weight per day, and in particular is typically 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 (such as, for example, 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 comprising at least one compound of the formula I and/or pharmaceutically useful derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further pharmaceutically active ingredient.

The invention also relates to a combination (kit) consisting of the following individual packs:

(a) an effective amount of a compound of formula I and/or pharmaceutically useful derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios; and

(b) an effective amount of another pharmaceutically active component.

The combination comprises a suitable container, such as a box, a single bottle, a bag or an ampoule. The combination may comprise, for example, separate ampoules, each containing an effective amount of a compound of formula I and/or pharmaceutically useful derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios; and an effective amount of another pharmaceutically active component in dissolved or lyophilized form.

The medicaments from table 1 below are preferably, but not exclusively, used in combination with compounds of formula I. Combinations of formula I and agents from table 1 may also be combined with compounds of formula VI.

Preferably the compounds of formula I are combined with known anticancer agents.

Such known anti-cancer agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, and other angiogenesis inhibitors. The compounds of the present invention are particularly suitable for administration simultaneously with radiotherapy. Synergistic effects of VEGF inhibition in combination with radiotherapy have been described in the art (see WO 00/61186).

"Estrogen receptor modulators" refers to compounds that can interfere with or inhibit the binding of estrogen to the receptor, regardless of the mechanism. Examples of estrogen receptor modulators include, but are not limited to, tamoxifen, raloxifene, idoxifene, LY353381, LY117081, toremifene, fulvestrant, 4- [7- (2, 2-dimethyl-1-oxopropoxy-4-methyl-2- [4- [2- (1-piperidinyl) ethoxy ] phenyl ] -2H-1-benzopyran-3-yl ] -phenyl 2, 2-dimethylpropionate, 4' -dihydroxybenzophenone-2, 4-dinitrophenyl-hydrazone, and SH 646.

"androgen receptor modulators" refers to compounds that can interfere with or inhibit the binding of androgens to the receptor, regardless of mechanism. Examples of androgen receptor modulators include finasteride and other 5 α -reductase inhibitors, nilutamide, flutamide, bicalutamide, liazole, and abiraterone acetate.

"retinoid receptor modulators" refers to compounds that interfere with or inhibit the binding of retinoids to the receptor, regardless of the mechanism. Examples of such retinoid receptor modulators include bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, α -difluoromethylornithine, ILX23-7553, trans-N- (4' -hydroxyphenyl) retinoamide, and N-4-carboxyphenyl retinoamide.

"cytotoxic agents" refer to compounds that cause cell death primarily by acting directly on cell function or inhibiting or interfering with cell mitosis, including alkylating agents, tumor necrosis factors, intercalating agents, microtubule inhibitors, and topoisomerase inhibitors.

Examples of cytotoxic agents include, but are not limited to, tirapazamine, Sertenef, cachectin, ifosfamide, tasolinamine, lonidamine, carboplatin, hexamethylmelamine, pomalidine, dibromodulcitol, ramustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, Proprsufen tosylate, trofosfamide, nimustine, dibromospiro ammonium chloride, puripine, lobaplatin, satraplatin, mitomycin, cisplatin, ilovin, Right ifosfamide, cis-aminated dichloro (2-methyl-pyridine) platinum, benzylguanine, glufosfamide, GPX100, (trans ) -di-mu- (hexane-1, 6-diamine) mu- [ diamine-platinum (II) ] bis [ diamine (chloro) platinum (II) ] tetrachloride, Tetrahydroxapride, Diazacyclopropenyl spermine, arsenic trioxide, 1- (11-dodecylamino-10-hydroxyundecyl) -3, 7-dimethylxanthine, zorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin, pinafin, valrubicin, amrubicin, antineoplastone (antineoplastone), 3 '-deamino-3' -morpholino-13-deoxo-10-hydroxycarminomycin, Annamycin, calicheacin, eletrinder, MEN10755 and 4-demethoxy-3-deamino-3-cycloethylimino-4-methylsulfonyl-daunorubicin (see WO 00/50032).

Examples of microtubule inhibitors include paclitaxel, vindesine sulfate, 3 ', 4' -didehydro-4 '-deoxy-8' -norvinblastine, docetaxel, rhizomycin, dolastatin, mevalon isethionate, Auristatin, cimadrol, RPR109881, BMS184476, vinflunine, nostoc cyclopeptide, 2, 3, 4, 5, 6-pentafluoro-N- (3-fluoro-4-methoxyphenyl) benzenesulfonamide, anhydrovinblastine (anhydrovinblastine), N-dimethyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-tert-butyramide, TDX258 and BMS 188797.

Some examples of topoisomerase inhibitors are topotecan, Hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3 ', 4' -O-exo-benzylidene churicin, 9-methoxy-N, N-dimethyl-5-nitropyrazolo [3, 4, 5-kl]Acridine-2- (6H) propylamine, 1-amino-9-ethyl-5-fluoro-2, 3-dihydro-9-hydroxy-4-methyl-1H, 12H-benzo [ de]Pyrano [3 ', 4': b, 7]-indolizino [1, 2b]Quinoline-10, 13(9H, 15H) dione, lurtotecan, 7- [2- (N-isopropylamino) ethyl]- (20S) camptothecin, BNP1350, BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzosin, 2 '-dimethylamino-2' -deoxy etoposide, GL331, N- [2- (dimethylamino) ethyl ] etoposide]-9-hydroxy-5, 6-dimethyl-6H-pyrido [4, 3-b]Carbazole-1-carboxamide, Asulacrine, (5a, 5aB, 8aa, 9b) -9- [2- [ N- [2- (dimethylamino) ethyl ] methyl]-N-methylamino radical]Ethyl radical]-5- [ 4-hydroxy-3, 5-dimethoxyphenyl group]-5, 5a, 6, 8, 8a, 9-hexahydrofuro (3 ', 4': 6, 7) naphtho (2, 3-d) -1, 3-dioxol-6-one, 2, 3- (methylenedioxy) -5-methyl-7-hydroxy-8-methoxybenzo [ c ]]-coffee pyridine6, 9-bis [ (2-aminoethyl) amino group]Benzo [ g ]]Isoquinoline-5, 10-dione, 5- (3-aminopropylamino) -7, 10-dihydroxy-2- (2-hydroxyethylaminomethyl) -6H-pyrazolo [4, 5, 1-de]Acridin-6-one, N- [1- [2 (diethylamino) ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]Formamide, N- (2- (dimethylamino) ethyl) acridine-4-carboxamide, 6- [ [2- (dimethylamino) ethyl ] methyl]Amino group]-3-hydroxy-7H-indeno [2, 1-c]Quinolin-7-one and dimesna.

"antiproliferative agents" include antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and INX3001, as well as antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine sodium octadecyl phosphate, Fosteabine sodium hydrate, raltitrexed, Paltixid, emithidine, thiazopurin, decitabine, nolatrexed, pemetrexed, Nezarabine, 2 ' -deoxy-2 ' -methylenecytidine, 2 ' -fluoromethylene-2 ' -deoxycytidine, N- [5- (2, 3-dihydro-benzofuranyl) sulfonyl ] -N ' - (3, 4-dichlorophenyl) urea, N6- [ 4-deoxy-4- [ N2- [2(E), 4(E) -tetradecadienoyl ] glycylamino ] -L-glycero-B-L-manno-heptopyranosyl ] adenine, Aplidine, ecteinascidin, troxacitabine, 4- [ 2-amino-4-oxo-4, 6, 7, 8-tetrahydro-3H-pyrimido [5, 4-B ] [1, 4] thiazin-6-yl- (S) -ethyl ] -2, 5-thiophenoyl-L-glutamic acid, aminopterin, 5-fluorouracil, alanosine, 11-acetyl-8- (carbamoyloxymethyl) -4-formyl-6-methoxy-14-oxa-1, 11-diazepino (7.4.1.0.0) -tetradec-2, 4, 6-trien-9-yl acetate, swainsonine, lometrexol, dexrazoxane, methioninase, 2 '-cyano-2' -deoxy-N4-palmitoyl-1-B-D-arabinofuranosyl cytosine and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone. "antiproliferative agents" also include monoclonal antibodies to growth factors other than those listed under "angiogenesis inhibitors", such as trastuzumab, and tumor suppressor genes, such as p53, which can be delivered by recombinant virus-mediated gene transfer (see, e.g., US patent 6,069,134).

The compounds according to the invention are particularly preferred for the treatment and prophylaxis of tumor diseases.

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

The tumor is also preferably selected from lung adenocarcinoma, small cell lung carcinoma, pancreatic carcinoma, ovarian carcinoma, glioblastoma, colon carcinoma and breast carcinoma.

It is also preferred to use it for the treatment of tumours of the blood and immune system, preferably for the treatment of tumours selected from the group consisting of acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphatic leukaemia and/or chronic lymphatic leukaemia.

In another aspect, the invention includes a method of treating a patient having a tumor, such as a cancer, by administering a compound of formula (I) in combination with an antiproliferative agent. Suitable antiproliferative agents include those provided in table 1.

All temperatures in this context are given in degrees celsius. In the following examples, "conventional treatment" means: if desired, water is added, the pH is adjusted to 2 to 10, if desired, depending on the composition 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 product is purified by chromatography on silica gel and/or by crystallization. The Rt values are determined by HPLC using the eluents mentioned.

Mass Spectrum (MS): EI (Electron impact ionization) M⁺

FAB (fast atom bombardment) (M + H)⁺

ESI (electrospray ionization) (M + H)⁺

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

(A) HPLC method (nonpolar)

Solvent A: water + 0.1% TFA

Solvent B: acetonitrile + 0.1% TFA

Flow rate: 1.5/min

Gradient: 0.0min 4% of B

5.0min 100% B

5.5min 100% B

6.0min 20% of B

6.5min 20% of B

Column: chromolith Performance RP-18e 100-3

(B) HPLC method (polar):

solvent A: water + 0.05% formic acid

Solvent B: acetonitrile + 0.04% formic acid

Flow rate: 2.4ml/min, wavelength: 220nm

Gradient: 0.0min 4% of B

2.8min 100% B

3.3min 100% B

3.4min 4% of B

Column: chromolith Speed ROD RP 18e 50-4.6mm

(C) HPLC method

Column: chromolith Speed ROD 50-4.6mm²(order No.: 1.51450.0001) from Merck

Gradient: 5.0min, t 0min, a: B95: 5, t 4.4 min: b25: 75, t 4.5min to t 5.0 min: a and B are 0: 100

Flow rate: 3.00ml/min

Eluent A: water + 0.01% HCOOH (formic acid)

Eluent B: acetonitrile + 0.01% HCOOH

Wavelength: 220nm

Example 1

Preparation of 3, 5-dichlorobenzyl 4- {2- [ (1H-benzotriazole-5-carbonyl) amino ] ethyl } piperazine-1-carboxylate (5)

1.1 0.14g (0.61mmol) of 1, 0.12g (0.74mmol) of 2 and 0.2ml of 4-methylmorpholine are dissolved in 6ml of DMF. Then 0.14g (0.73mmol) of N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide x HCl (DAPECI) and 0.1g (0.74mmol) of 1-hydroxybenzotriazole (HOBt) are added. The mixture was stirred at RT for 18 h. The solvent was removed in a rotary evaporator, diluted with water (100ml) and extracted 2 times with EA. The organic phase is dried over magnesium sulfate, filtered off and evaporated to dryness to give 0.21g (92.3%) of brown crystals 3.

1.2 0.21g (0.56mmol) of 3 are dissolved in 20ml of 5N HCl/isopropanol and stirred at RT for 2 h. To precipitate the product completely, 20ml of ether were added to the reaction batch. The product is filtered off with suction. And dried in a vacuum oven at 45 deg.C to yield 157mg (80%) of brown crystals.

1.3 50mg (0.28mmol) of 3, 5-dichlorobenzyl alcohol and 60mg (0.37mmol) of 1, 1' -Carbonyldiimidazole (CDI) are dissolved in 2ml of DMF and stirred at RT for 3 h. Then 0.1g (0.32mmol) of 4 are added and stirred at RT for 18 h. The mixture was washed with water. The organic phase is then dried over sodium sulfate, filtered off and the solvent is evaporated off in vacuo. The residue was purified by preparative HPLC to give 62mg (46%) of light brown crystals 5.

Example 2

Preparation of 3, 5-dichlorobenzyl 4- { [ (2-oxo-2, 3-dihydrobenzoxazol-6-ylcarbamoyl) methyl ] amino } piperidine-1-carboxylate (11)

2.1 169.0g (1.13mol) of 9 and 470ml of triethylamine (3.39mol) are initially introduced into 2L of dichloromethane (CH)₂Cl₂) In (1). 128g (1.13mol) of chloroacetyl chloride are added to 1l of CH₂Cl₂The solution of (1) was added under ice-cooling at a rate at which the internal temperature did not exceed 8 ℃. The mixture is refluxed and boiled for 20h. After the reaction mixture was cooled, 3L of water was added and stirred, during which time a precipitate was formed. The precipitate is filtered off with suction and washed with water and a little methanol to yield 183g (71.7%) of amorphous solid substance 10.

2.2.5 g (2.8mmol) of 3, 5-dichlorobenzyl alcohol and 0.55g (3.4mmol) of 1, 1' -Carbonyldiimidazole (CDI) are dissolved in 10ml of CH₂Cl₂Neutralized and stirred at RT for 3 h. Then 0.56g (2.8mmol) of 6 are added and stirred at RT for 18 h. The mixture was washed with water. The organic phase is dried over sodium sulfate, filtered off and the solvent is evaporated off in vacuo. The residue was purified by preparative HPLC to give 1.0g (88%) of white crystals 7.

2.3 1.0g (2.48mmol) of 7 are dissolved in 100ml of 5N HCl/isopropanol and stirred at RT for 2 h. To precipitate the product completely, 200ml of ether were added to the batch. The product was filtered off with suction and dried in a vacuum oven at 45 ℃ to give 0.81g (96%) of white crystals 8.

2.4 0.92g (2.44mmol) of 8 and 0.54ml (3.9mmol) of NEt3 were initially introduced into 10ml of DMF, followed by the addition of 0.56g (2.44mmol) of 10. The mixture was stirred at RT for 48 h. 30ml of water were added to the reaction mixture, and the precipitated crystals were filtered off with suction. CH (CH)₂Cl₂MeOH column chromatography gave 0.26g (21%) of brown crystals 11;

RT [ min ]3.68 (method A).

Example 3

Preparation of 3, 5-dichlorobenzyl 4- [ 3-hydroxy-3- (2-oxo-2, 3-dihydrobenzoxazol-6-yl) propyl ] piperazine-1-carboxylate (13)

0.1g of 12(0.21mmol) is dissolved in 5ml of ethanol, and 30.0mg (0.79mmol) of sodium borohydride are then added. The mixture was stirred at RT for 14 h. The solvent was then evaporated in vacuo and the residue was purified by preparative HPLC to give 66mg (65%) of a slightly yellowish solid material 13; RT [ min ]3.57 (method A).

Example 4

Preparation of 4-chlorobenzyl 4- [ (Z) -3-chloro-3- (2-oxo-2, 3-dihydrobenzoxazol-6-yl) allyl ] piperazine-1-carboxylate (15)

0.1g of 14(0.23mmol) was mixed with 0.3g (1.2mmol) of 1, 2-phenylenedioxytrichlorophosphorane and heated at 100 ℃ for 2 h. 5ml of methanol were added to the dark brown melt and the mixture was treated in an ultrasonic bath for 20min, during which time pale yellow solid matter precipitated out. The precipitate was filtered off with suction, dried at 45 ℃ in a vacuum oven and purified by preparative HPLC to give 5.8mg (6%) of a slightly yellowish solid substance 15; RT [ min ]3.57 (method A).

Example 5

Preparation of 4-chlorobenzyl 4- [3, 3-difluoro-3- (2-oxo-2, 3-dihydrobenzoxazol-6-yl) propyl ] piperazine-1-carboxylate (17)

5.1 3.1g (7.0mmol) of 14 are dissolved in 2ml of glacial acetic acid and 30ml of DCM. Air was removed and 1.3ml (15mmol) of dimercaptoethane was added, followed by dropwise addition of 0.98ml (7mmol) of boron trifluoride/acetic acid complex and air was removed. The mixture is stirred for 72h at RT, then 50ml of NaHCO are added₃And (3) solution. The crystals precipitated were filtered off with suction. This is the starting material. The organic phase is separated off and MgSO₄Dried and evaporated in vacuo. Purification by column chromatography on silica gel eluting with ethyl acetate gave 0.1g (3%) of amorphous solid material 16.

5.2 57mg (0.2mmol) of 1, 3-dibromo-5, 5-dimethylhydantoin were initially introduced into 3ml of dichloromethane. 0.23ml (4mmol) of pyridine/hydrogen fluoride are added at-78 ℃ with removal of air. Then 100mg (0.19mmol) of 16 suspended in 5ml of dichloromethane were added. Stirring was continued for 20 min. Then the cooling was removed and 15ml of NaHCO were added₃The solution was added to the reaction mixture. The organic phase was separated, dried using MgSO4 and evaporated in vacuo. Purification by preparative HPLC gave 15mg (17%) of solid material 17; RT [ min ]]2.96 (method C).

Example 6

Preparation of 3, 5-dichlorobenzyl 4- {2- [3- (2-oxo-2, 3-dihydrobenzoxazol-6-yl) -4, 5-dihydropyrazol-1-yl ] -ethyl } piperazine-1-carboxylate (21)

6.1 10.0g (44mmol) of 18 are dissolved in 100ml of ethanol. 4.0g (52mmol) of hydroxyethylhydrazine are then added, followed by 7.0ml (53mmol) of triethylamine. The mixture was stirred at RT for 2 h. The resulting yellow precipitate was suction-filtered off and dried in a drying cabinet under vacuum at 45 ℃ to give 4.1g (37.4%) of yellow crystals 19.

6.2 0.5g (2.0mmol) of 19 are dissolved in 10ml of DMF. Then 0.5ml (6.9mmol) of thionyl chloride was added and the mixture was stirred at RT for 30 min. The reaction mixture was evaporated in vacuo. The residue is triturated with 10ml of acetonitrile, filtered off with suction and dried in air to give 0.32g (60%) of slightly greenish crystals 20.

6.3 0.12g (0.4mmol) of 20, 0.13g (0.4mmol) of 3, 5-dichlorobenzylpiperazine-1-carboxylate and 0.1g (1.2mmol) of NaHCO₃Stirred in 3ml acetonitrile at 100 ℃ for 16 h. After cooling, 20ml of water are added to the reaction mixture, followed by CH₂Cl₂The extraction was performed twice. The organic phase is Na₂SO₄Drying and vacuum steamingAnd (4) sending. Purification by column chromatography on silica gel eluting with ethyl acetate/methanol gave 21mg (10%) of yellow-brown crystals 21; RT [ min ]]2.80 (method A).

Example 7

Preparation of 4-chlorobenzyl 4- (2-1H-benzotriazol-5-ylacetyl) piperazine-1-carboxylate (24)

7.1 5.0g (26mmol) of ethyl 3, 4-diaminophenylacetate are dissolved in 40ml of 50% acetic acid and cooled in an ice bath. 2.7g (39mmol) of sodium nitrite in 20ml of water are added dropwise at a rate such that the temperature is kept below 10 ℃. The mixture was stirred at 10-20 ℃ for 3 h. The batch was then diluted with 200ml ethyl acetate and washed with water. Using Na₂SO₄The organic phase was dried and evaporated in vacuo to yield 5.7g (108%) of a brown oil 22 (also containing a small amount of solvent).

7.2 5.7g (28mmol) of 22 are dissolved in 25ml of water and 10ml of EtOH and added to 75ml of 5% aqueous NaOH solution. The mixture was heated at reflux for 3 h. After cooling, the mixture was evaporated in vacuo. The residue was dissolved in 100ml of water and adjusted to pH 4 using 5-6N HCl in propanol. The precipitated crystals were filtered off with suction to give 3.3g (56%) of brown crystals 23.

7.3 220mg (1.24mmol) of 23, 362mg (1.24mmol) of 4-chlorobenzylpiperazine-1-carboxylate hydrochloride, 168mg (1.24mmol) of 1-hydroxybenzotriazole (HOBt), 143mg (1.24mmol) of N-methylmorpholine and 238mg (1.24mmol) of 3-dimethylaminopropylcarbodiimide hydrochloride (DAPECI) are stirred in 10ml of DMF at RT for 48 h.

The reaction mixture was then evaporated in vacuo. Purification by preparative HPLC gave 16mg (3%) of a colourless solid substance 24; RT [ min ]3.73 (method A);

¹H-NMR(DMSO-d₆)δ[ppm]7.86(d，J＝8.5，1H)，7.75(d，J＝1.4，1H)，7.46-7.36(m，4H)，7.34(dd，J＝8.5，1.4，1H)，5.10(s，2H)，3.95(s，2H)，3.65-3.30(m，7H)。

example 8

Preparation of 6- (2- {4- [3- (4-chlorophenoxy) propionyl ] piperazin-1-yl } acetyl) -3H-benzoxazol-2-one (27)

8.1 500mg (2.5mmol) of 3- (4-chlorophenoxy) propionic acid, 464mg (2.5mmol) of Boc-piperazine and 253mg (2.5mmol) of 4-methylmorpholine were initially introduced into 3ml of DMF. 478mg (2.5mmol) of DAPECI and 337mg (2.5mmol) of HOBt are then added and the mixture is stirred at RT for 16 h. The reaction mixture was poured onto water and the resulting precipitate was filtered off with suction and dried to yield 894mg (97%) of 25.

8.2 894mg (2.4mmol) of 25 are introduced into 10ml of a 5-6N HCl in propanol and stirred at RT for 0.5 h. The resulting precipitate was suction-filtered off and then dried to yield 661mg (89%) of 26.

8.3 104mg (0.49mmol) of 6- (2-chloroacetyl) -3H-benzoxazolone (synthesis described in the reference file, 102007047737.8 from the German patent office) are initially introduced into 3ml of acetonitrile. 150mg (1.5mmol) of triethylamine and 150mg (0.49mmol) of 26 are then added and the mixture is stirred at RT for 16h and at 80 ℃ for a further 16 h. The resulting precipitate was filtered off and the filtrate was dried in vacuo. Purification by column chromatography on silica gel eluting with EA afforded 6mg (3%) of 27; RT [ min ]3.04 (method A);

¹H-NMR(DMSO-d₆)δ[ppm]11.66(s，1H)，7.90-7.84(m，2H)，7.31(d，J＝9.0，2H)，7.19(d，J＝7.6，1H)，6.95(d，J＝9.0，2H)，4.18(t，J＝6.2，2H)，3.86(s，2H)，3.62-3.30(m，8H)，2.80(t，J＝6.2，2H)。

example 9

Preparation of 4-chlorobenzyl 4- [2- (1H-benzotriazol-5-ylcarbamoyl) ethylcarbamoyl ] piperidine-1-carboxylate (32)

9.1 2.7g (20mmol) of 5-aminobenzotriazole, 3.8g (20mmol) of 3-tert-butoxycarbonylaminopropionic acid, 3.5g of HOBt (26mmol) and 4.2g (22mmol) of DAPECI were dissolved in 30ml of DMF and stirred at RT for 16 h. The reaction mixture was then evaporated in vacuo. The residue is taken up in 200ml of ethyl acetate and washed twice with water with shaking. The organic phase is MgSO₄And (5) drying. Purification by column chromatography on silica gel eluting with ethyl acetate gave 5.7g (93%) of 28.

9.2 5.7g (19mmol) of 28 are dissolved in 60ml of 6N HCl in isopropanol and stirred at RT for 1 h. The reaction mixture was then evaporated under vacuum. The residue was triturated with dichloromethane and filtered with suction to give 4.1g (91%) of a light brown amorphous solid material 29.

9.3 0.97g (4.0mmol) of 29, 0.92g (4.0mmol) of 1-butoxycarbonylpiperidine-4-carboxylic acid, 0.54g of HOBt (4.0mmol) and 0.77g (4.0mmol) of DAPECI and 0.55ml of triethylamine (4.0mmol) are dissolved in 10ml of DMF and stirred at RT for 16 h. The reaction mixture was then evaporated in vacuo. The residue is taken up in 100ml of ethyl acetate and washed twice with water with shaking. The organic phase is MgSO₄Dried and evaporated in vacuo. Purification by column chromatography on silica gel eluting with ethyl acetate gave 1.4g (84%) of 30.

9.4 1.4g (3.4mmol) of 30 are dissolved in 20ml of 6N HCl in isopropanol and stirred at RT for 1 h. The reaction mixture was then evaporated in vacuo to yield 1.1g (93%) of brown amorphous solid material 31.

9.5 81mg (0.5mmol) of CDI and 78mg (0.5mmol) of 4-chlorobenzyl alcohol are dissolved in 3ml of DMF and stirred at RT for 2 h. 176mg (0.5 m) are then addedmol) of 31, the mixture is stirred at RT for 16 h. The reaction mixture is then evaporated in vacuo and the residue is taken up in 20ml of ethyl acetate and washed with water with shaking. The organic phase is MgSO₄Dried and evaporated in vacuo. The residue was crystallized from ethanol to yield 77mg (32%) of light brown crystals 32; RT [ min ]]3.36 (method C).

Example 10

Preparation of 4-chlorobenzyl 4- [2- (1H-benzotriazol-5-ylcarbamoyl) ethylcarbamoyl ] piperazine-1-carboxylate (33)

121mg (0.5mmol) of 29 are initially introduced into 3ml of DMF and 0.035ml of triethylamine and 81mg (0.5mmol) of CDI are added. The mixture is stirred at RT for 1h, then 146mg (0.5mmol) of 4-chlorobenzylpiperazine-1-carboxylate hydrochloride are added and 0.035ml of triethylamine are added. The mixture was then stirred at RT for 2 h. The reaction mixture was evaporated in vacuo. The residue is taken up in 20ml of ethyl acetate and washed twice with water with shaking. The organic phase is MgSO₄Dried and evaporated in vacuo. The residue was recrystallized from ethanol to yield 81mg (33%) of light brown crystals 33; RT [ min ]]3.25 (method C).

Example 11

Preparation of 4-chlorobenzyl 4- [2- (1H-benzotriazol-5-ylcarbamoyl) acetylamino ] piperidine-1-carboxylate (39)

11.1 5.23g (27.5mmol) of 34 and 3.8ml (27.5mmol) of triethylamine are initially introduced into 50ml of dichloromethane. 4.14g (27.5mmol) of malonic acid ethyl ester chloride was added dropwise under ice cooling, followed by stirringThe mixture was stirred at RT for a further 1 h. The reaction mixture is extracted with water, the organic phase is then separated, Na is used₂SO₄Dried and evaporated in vacuo. Purification by column chromatography on silica gel eluting with ethyl acetate gave 2.85 (34%) of colorless crystals 35.

11.2 2.0g (6.6mmol) of 35 are dissolved in 20ml of THF and 20ml of glacial acetic acid, 2g of 5% Pd/C are added and the mixture is hydrogenated. The catalyst was filtered off. 6N HCl was added and the solvent was evaporated in vacuo to yield 1.6g (97%) of solid 36.

11.3 1.5g (10.5mmol) of 4-chlorobenzyl alcohol, 1.7g (10.5mmol) of CDI are stirred at RT in 10ml of DMF for 2h, then 1.04ml (7.5mmol) of triethylamine and 1.6g (7.5mmol) of 36 are added and the mixture is stirred at RT for 16 h. The reaction mixture was then added to water. The precipitate obtained is filtered off with suction and purified by chromatography on a silica gel column eluted with petroleum ether/ethyl acetate (1: 1) to give 1.46g (51%) of pale yellow crystals 37.

11.4 1.46g (3.8mmol) of 37 are dissolved in 10ml of ethanol, 3.0ml of 2N aqueous NaOH solution are added and the mixture is stirred at RT for 16 h. The solution was acidified with 1N HCl and evaporated in a rotary evaporator. The residue was taken up in ethyl acetate and washed with water. With Na₂SO₄The organic phase was dried and evaporated in a rotary evaporator to yield 0.47g (35%) of amorphous solid material 38.

11.5 0.47g (1.32mmol) of 38, 0.178g (1.32mmol) of 5-aminobenzotriazole, 0.28g (1.46mmol) of DAPECI and 0.20g (1.46mmol) of HOBt are dissolved in 5ml of DMF and stirred at RT for 16 h. The reaction mixture was then evaporated in vacuo. The residue is taken up in 20ml of ethyl acetate and washed twice with water with shaking. The organic phase is MgSO₄Dried and evaporated in vacuo. During this time a white precipitate precipitated out and was filtered off with suction and dried to give 0.14g (22%) of a colourless solid substance 39; RT [ min ]]3.33 (method C).

The following compounds were obtained in analogy to the above examples.

The following compounds

Pharmacological data

Autotaxin inhibition (enzyme assay)

TABLE 1

Compound numbering	IC5O
		″11″	B
″13″	B
		″15″
″17″	B
		″21″	C
″24″	C
		″27″	C
″32″
		″33″	C
″39″	B
		″A1″	B
″A2″	C
		″A3″	C
″A4″
		″A5″
″A6″
		″A7″
″A8″	C
		″A9″
″A10″	C
		″A11″
″A12″
		″A13″	C
″A14″	C
		″A15″
″A16″	C
		″A17″	C
″A18″	C

IC50：＜100nM＝A

100nM-1μM＝B

＞1μM＝C

Example A: autotaxin test (enzyme test)

Description of the test

Autotaxin activity was measured indirectly using Amplex Red reagent. Herein as H formed in pair₂O₂The fluorescent indicator of (a) measures Amplex Red. Specifically, autotaxin converts the substrate Lysophosphatidylcholine (LPC) to phosphorylcholine and lysophosphatidic acid (LPA). This reaction is followed by the reaction of phosphorylcholine with alkaline phosphatase to produce inorganic phosphate and choline. In the next step, choline is oxidized by choline oxidase to produce betaine and form H₂O₂. H in the presence of peroxidase (horseradish peroxidase) at 1: 1 stoichiometry₂O₂Reacts with Amplex Red reagent and forms highly fluorescent resorufin. The fluorescence is measured in a reaction-dependent kinetic model to correct out the fluorescence signal from possible other fluorescent substances not related to the reaction. Testing methodMethod of

1.5. mu.l of standard solution or test substance (substance with the name A (n)) dissolved in 20mM Hepes (pH 7.2 with up to 7.7% DMSO) at each concentration was incubated with 10. mu.l (16ng) of highly purified recombinant autotaxin in 384-well black microtiter plates at 22 ℃ for 30 minutes. The reaction was then initiated by the addition of 5 μ l L- α -Lysophosphatidylcholine (LPC), with a final concentration of 75 μ M LPC. The mixture was incubated at 37 ℃ for 90 minutes. After incubation, amplex red reagent, peroxidase (horseradish peroxidase) and choline oxidase were added and fluorescence was measured immediately under 485nm excitation at 612nm with a "Tecan Ultra multimode" reader. By detecting H formed₂O₂Autotaxin activity was calculated indirectly.

Material

Microtiter plates: PS microplates, 384-well, small volume, black Corning, Cat #3677

Protein: recombinant autotaxin (Baculovirale Hi5 expression)

Substrate: l- α -lysophosphatidylcholine (egg); avanti Polar Lipids #830071P

Standard substance: c14LPA, Avanti Polar Lipids, Cat #857120P

Detection reagent: amplex Red reagent, Invitrogen # a12222, dissolved in 1.923ml DMSO; peroxidase type VI-A (horseradish peroxidase), from Sigma # P6782, dissolved in 7.45ml of test buffer; choline oxidase, Sigma # C5896, was dissolved in 2.47ml of test buffer.

Detection reagent mixture: 1: 100 dilution of Amplex Red reagent in test buffer

Test buffer: 200mM Tris HCl, Merck, Cat #1.08219, pH 7.9, 0.1% BSA, no fat, Roche Cat #775835

The following examples relate to pharmaceuticals:

example B: injection vial

A solution of 100g of the active ingredient of the formula I and 5g of disodium hydrogenphosphate in 3l of bidistilled water is adjusted to pH 6.5 using 2N hydrochloric acid, sterile-filtered, transferred into injection vials, lyophilised under sterile conditions and sealed under sterile conditions. Each injection vial contained 5mg of active ingredient.

Example C: 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 D: solutions of

From 1g of active ingredient of the formula I, 9.38g of NaH₂PO₄·2H₂O, 28.48g of 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 1l and sterilized by radiation. The solution may be used in the form of eye drops.

Example E: ointment formulation

500mg of active ingredient of the formula I are mixed with 99.5g of vaseline under sterile conditions.

Example F: tablet formulation

A mixture of 1kg of active ingredient of formula I, 4kg of lactose, 1.2kg of potato starch, 0.2kg of talc and 0.1kg of magnesium stearate is compressed in a conventional manner into tablets, so that each tablet contains 10mg of active ingredient.

Example G: sugar-coated pill

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 H: capsule

2kg of active ingredient of the formula I are introduced into hard gelatin capsules in a conventional manner so that each capsule contains 20mg of active ingredient.

Example I: ampoule (CN)

A solution of 1kg of the active ingredient of the formula I in 60l of bidistilled water is sterile-filtered, transferred into ampoules, lyophilised under sterile conditions and sealed under sterile conditions. Each ampoule contains 10mg of active ingredient.

Claims (16)

1. A compound of formula I

Wherein

R¹Represents 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、-[C(R³)₂]_nN(R³)₂、O[C(R³)₂]_pN(R³)₂、S[C(R³)₂]_nN(R³)₂、-NR³[C(R³)₂]_nN(R³)₂、NHCON(R³)₂、CON(R³)₂、CONR³[C(R³)₂]_nN(R³)₂Or a combination of the above or other chemical entities,

R³represents a group of a compound represented by the formula H or A,

x represents O, NH or CH₂，

Y represents CH₂、CH₂O or the absence of oxygen or oxygen,

r represents

R⁴Represents a group of H, A or a phenyl group,

het represents

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 groups may be replaced with O, NH and/or S,

or

Cycloalkyl having 3 to 7C atoms,

hal represents F, Cl, Br or I,

n represents 0, 1, 2 or 3,

m represents 0, 1 or 2,

p represents 0, 1, 2, 3, 4 or 5,

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

2. A compound according to claim 1, wherein R is R, and pharmaceutically acceptable salts and stereoisomers thereof, including mixtures thereof in all ratios¹Represents Hal.

3. A compound according to claim 1 or 2, wherein X represents O or CH, and the pharmaceutically acceptable salts and stereoisomers thereof, including mixtures thereof in all ratios₂。

4. A compound according to one or more of claims 1 to 3, in which Y represents CH, and the pharmaceutically acceptable salts and stereoisomers thereof, including mixtures thereof in all ratios₂Or CH₂O。

5. Compounds according to one or more of claims 1 to 4, in which a denotes unbranched or branched alkyl having 1 to 10C atoms in which 1 to 7H atoms may be replaced by F and/or Cl, as well as the pharmaceutically acceptable salts and stereoisomers thereof, including mixtures thereof in all ratios.

6. Compounds according to one or more of claims 1 to 5, in which p denotes 1, 2 or 3, as well as the pharmaceutically acceptable salts and stereoisomers thereof, including mixtures thereof in all ratios.

7. The compound according to one or more of claims 1 to 6, wherein

R¹The expression Hal is given to the expression,

x represents O or CH₂，

Y represents CH₂Or CH₂O，

R represents

Het represents

A represents an unbranched or branched alkyl radical having 1 to 10C atoms in which 1 to 7H atoms may be replaced by F and/or Cl,

hal represents F, Cl, Br or I,

p represents 1, 2 or 3,

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

8. A compound according to claim 1, selected from:

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

9. Process for the preparation of compounds of formula I and pharmaceutically acceptable salts and stereoisomers thereof, characterized in that

a) For the preparation of compounds of the formula I, in which

R represents

Reacting a compound of formula II

Het-NH-CO-CH₂-L II

Wherein

Het has the meaning indicated in claim 1,

and L represents Cl or Br, and,

with compounds of the formula III

Wherein

X、Y、R¹And p has the meaning indicated in claim 1,

or

b) For the preparation of compounds of the formula I, in which

R represents

Reacting a compound of formula IV

Wherein

Het has the meaning indicated in claim 1,

and L represents Cl or Br, and,

with compounds of the formula V

Wherein

X、Y、R¹And p has the meaning indicated in claim 1,

or

c) For the preparation of compounds of the formula I, in which

R represents

Reacting a compound of formula VI

Het-CH₂-CO-L VI

Wherein

Het has the meaning indicated in claim 1,

and L represents Cl, Br, I or a free or reactive functionally modified OH group,

with a compound of the formula V,

or

d) For the preparation of compounds of the formula I, in which

R represents

Reacting a compound of formula VII

Wherein

Het has the meaning indicated in claim 1,

with compounds of the formula VIII

Wherein

R¹And p has the meaning indicated in claim 1,

and the compound is selected from

Carbonyl diimidazole, phosgene, diphosgene and triphosgene,

or

e) For the preparation of compounds of the formula I, in which

R represents

Reacting a compound of formula IX

Wherein

Het has the meaning indicated in claim 1,

with compounds of the formula V

And the compound is selected from

Carbonyl diimidazole, phosgene, diphosgene and triphosgene,

or

f) For the preparation of compounds of the formula I, in which

R represents

Reacting a compound of formula X

Het-NH₂ X

Wherein

Het has the meaning indicated in claim 1,

with compounds of the formula XI

Wherein

X、Y、R¹And p has the meaning indicated in claim 1,

and L represents Cl, Br, I or a free or reactive functionally modified OH group, and/or converting a base or acid of formula I into one of its salts.

10. Pharmaceutical comprising at least one compound of the formula I according to claims 1 to 8 and/or its pharmaceutically acceptable salts and stereoisomers, including mixtures thereof in all ratios, and optionally excipients and/or auxiliaries.

11. Use of compounds according to claims 1 to 8 for the preparation of medicaments for the treatment and prophylaxis of cancer diseases.

12. Use according to claim 11, wherein the cancer disease involves tumors of the squamous epithelium, bladder, stomach, kidney, head and neck, esophagus, cervix, thyroid, small intestine, liver, brain, prostate, urogenital tract, lymphatic system, stomach, pharynx and/or lung.

13. Use according to claim 12, wherein the tumour is derived from monocytic leukaemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic carcinoma, ovarian carcinoma, glioblastoma and breast and colon carcinoma.

14. Use according to claim 13, wherein the diseases to be treated are hematological and immune system tumors.

15. Use according to claim 14, wherein the tumour is derived from acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphatic leukaemia and/or chronic lymphatic leukaemia.

16. Use of compounds of formula I and/or physiologically acceptable salts and solvates according to claims 1 to 8 for the preparation of a medicament for the treatment of tumors, wherein a therapeutically effective amount of a compound of formula I is administered in combination with radiation therapy and a compound of the following class: 1) an estrogen receptor modulator, 2) an androgen receptor modulator, 3) retinoid receptor modulator, 4) a cytotoxic agent, 5) an antiproliferative agent, 6) a prenyl-protein transferase inhibitor, 7) an HMG-CoA reductase inhibitor, 8) an HIV protease inhibitor, 9) a reverse transcriptase inhibitor and 10) other angiogenesis inhibitors.